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6c9de1e8817a9f3b40b09d6b486799356c76b16d | wikidoc | Radiogenic | Radiogenic
A radiogenic nuclide is one that is produced by a process of radioactive decay.
Radiogenic nuclides (more commonly referred to as 'radiogenic isotopes') form some of the most important tools in Geology. They are used in two principal ways:
1) In comparison with the quantity of the radioactive 'parent isotope' in a system, the quantity of the radiogenic 'daughter product' is used as a radiometric dating tool (e.g. uranium-lead geochronology).
2) In comparison with the quantity of a non-radiogenic isotope of the same element, the quantity of the radiogenic isotope is used as an isotopic tracer (e.g. 206Pb/204Pb). This technique is discussed in more detail under the heading isotope geochemistry.
# Examples
Lead is perhaps the best example of a radiogenic substance, as it is produced from the radioactive decay of uranium and thorium. Specifically, Pb-206 is formed from U-238, Pb-207 from U-235, and Pb-208 from Th-232. Other substances considered radiogenic are argon-40, formed from radioactive potassium, and nitrogen-14, which is formed by the decay of carbon-14. U-238, U-235, and Th-232 themselves are likely to be radiogenic as well, being formed from the decay of those nuclei of the elements heavier than uranium which do not undergo spontaneous fission, just after they were formed in stellar supernovae.
Other important examples of radiogenic elements are radon and helium, both of which form during the decay of heavier elements in bedrock. The global supply of helium is radiogenic.
# Radiogenic isotopes used in Geology
The following table lists some of the most important radiogenic isotope systems used in Geology, in order of decreasing half-life of the radioactive parent isotope. The values given for half-life and decay constant are the current consensus values in the Isotope Geology community. Extinct nuclides are not presently included. indicates ultimate decay product of a series. | Radiogenic
A radiogenic nuclide is one that is produced by a process of radioactive decay.
Radiogenic nuclides (more commonly referred to as 'radiogenic isotopes') form some of the most important tools in Geology. They are used in two principal ways:
1) In comparison with the quantity of the radioactive 'parent isotope' in a system, the quantity of the radiogenic 'daughter product' is used as a radiometric dating tool (e.g. uranium-lead geochronology).
2) In comparison with the quantity of a non-radiogenic isotope of the same element, the quantity of the radiogenic isotope is used as an isotopic tracer (e.g. 206Pb/204Pb). This technique is discussed in more detail under the heading isotope geochemistry.
# Examples
Lead is perhaps the best example of a radiogenic substance, as it is produced from the radioactive decay of uranium and thorium. Specifically, Pb-206 is formed from U-238, Pb-207 from U-235, and Pb-208 from Th-232. Other substances considered radiogenic are argon-40, formed from radioactive potassium, and nitrogen-14, which is formed by the decay of carbon-14. U-238, U-235, and Th-232 themselves are likely to be radiogenic as well, being formed from the decay of those nuclei of the elements heavier than uranium which do not undergo spontaneous fission, just after they were formed in stellar supernovae.
Other important examples of radiogenic elements are radon and helium, both of which form during the decay of heavier elements in bedrock. The global supply of helium is radiogenic.
# Radiogenic isotopes used in Geology
The following table lists some of the most important radiogenic isotope systems used in Geology, in order of decreasing half-life of the radioactive parent isotope. The values given for half-life and decay constant are the current consensus values in the Isotope Geology community.[1] Extinct nuclides are not presently included. **indicates ultimate decay product of a series. | https://www.wikidoc.org/index.php/Radiogenic | |
bf687c8936ed268a35d6faffd88c235152ff3fb6 | wikidoc | Ran (gene) | Ran (gene)
Ran (RAs-related Nuclear protein) also known as GTP-binding nuclear protein Ran is a protein that in humans is encoded by the RAN gene. Ran is a small 25 kDa protein that is involved in transport into and out of the cell nucleus during interphase and also involved in mitosis. It is a member of the Ras superfamily.
Ran is a small G protein that is essential for the translocation of RNA and proteins through the nuclear pore complex. The Ran protein has also been implicated in the control of DNA synthesis and cell cycle progression, as mutations in Ran have been found to disrupt DNA synthesis.
# Function
## Ran cycle
Ran exists in the cell in two nucleotide-bound forms: GDP-bound and GTP-bound. RanGDP is converted into RanGTP through the action of RCC1, the nucleotide exchange factor for Ran. RCC1 is also known as RanGEF (Ran Guanine nucleotide Exchange Factor). Ran's intrinsic GTPase-activity is activated through interaction with Ran GTPase activating protein (RanGAP), facilitated by complex formation with Ran-binding protein (RanBP). GTPase-activation leads to the conversion of RanGTP to RanGDP, thus closing the Ran cycle.
Ran can diffuse freely within the cell, but because RCC1 and RanGAP are located in different places in the cell, the concentration of RanGTP and RanGDP differs locally as well, creating concentration gradients that act as signals for other cellular processes. RCC1 is bound to chromatin and therefore located inside the nucleus. RanGAP is cytoplasmic in yeast and bound to the nuclear envelope in plants and animals. In mammalian cells, it is SUMO modified and attached to the cytoplasmic side of the nuclear pore complex via interaction with the nucleoporin RanBP2 (Nup358). This difference in location of the accessory proteins in the Ran cycle leads to a high RanGTP to RanGDP ratio inside the nucleus and an inversely low RanGTP to RanGDP ratio outside the nucleus. In addition to a gradient of the nucleotide bound state of Ran, there is a gradient of the protein itself, with a higher concentration of Ran in the nucleus than in the cytoplasm. Cytoplasmic RanGDP is imported into the nucleus by the small protein NTF2 (Nuclear Transport Factor 2), where RCC1 can then catalyze exchange of GDP for GTP on Ran.
## Role in nuclear transport during interphase
Ran is involved in the transport of proteins across the nuclear envelope by interacting with karyopherins and changing their ability to bind or release cargo molecules. Cargo proteins containing a nuclear localization signal (NLS) are bound by importins and transported into the nucleus. Inside the nucleus, RanGTP binds to importin and releases the import cargo. Cargo that needs to get out of the nucleus into the cytoplasm binds to exportin in a ternary complex with RanGTP. Upon hydrolysis of RanGTP to RanGDP outside the nucleus, the complex dissociates and export cargo is released.
## Role in mitosis
During mitosis, the Ran cycle is involved in mitotic spindle assembly and nuclear envelope reassembly after the chromosomes have been separated. During prophase, the steep gradient in RanGTP-RanGDP ratio at the nuclear pores breaks down as the nuclear envelope becomes leaky and disassembles. RanGTP concentration stays high around the chromosomes as RCC1, a nucleotide exchange factor, stays attached to chromatin. RanBP2 (Nup358) and RanGAP move to the kinetochores where they facilitate the attachment of spindle fibers to chromosomes. Moreover, RanGTP promotes spindle assembly by mechanisms similar to mechanisms of nuclear transport: the activity of spindle assembly factors such as NuMA and TPX2 is inhibited by the binding to importins. By releasing importins, RanGTP activates these factors and therefore promotes the assembly of the mitotic spindle . In telophase, RanGTP hydrolysis and nucleotide exchange are required for vesicle fusion at the reforming nuclear envelopes of the daughter nuclei.
## Ran and the androgen receptor
RAN is an androgen receptor (AR) coactivator (ARA24) that binds differentially with different lengths of polyglutamine within the androgen receptor. Polyglutamine repeat expansion in the AR is linked to spinal and bulbar muscular atrophy (Kennedy's disease). RAN coactivation of the AR diminishes with polyglutamine expansion within the AR, and this weak coactivation may lead to partial androgen insensitivity during the development of spinal and bulbar muscular atrophy.
# Interactions
Ran has been shown to interact with:
- KPNB1,
- NEK9,
- NUTF2,
- RANBP1,
- RANGAP1,
- RCC1,
- TNPO1,
- TNPO2,
- XPO1, and
- XPO5.
# Regulation
The expression of Ran is repressed by the microRNA miR-10a. | Ran (gene)
Ran (RAs-related Nuclear protein) also known as GTP-binding nuclear protein Ran is a protein that in humans is encoded by the RAN gene. Ran is a small 25 kDa protein that is involved in transport into and out of the cell nucleus during interphase and also involved in mitosis. It is a member of the Ras superfamily.[1][2][3]
Ran is a small G protein that is essential for the translocation of RNA and proteins through the nuclear pore complex. The Ran protein has also been implicated in the control of DNA synthesis and cell cycle progression, as mutations in Ran have been found to disrupt DNA synthesis.[4]
# Function
## Ran cycle
Ran exists in the cell in two nucleotide-bound forms: GDP-bound and GTP-bound. RanGDP is converted into RanGTP through the action of RCC1, the nucleotide exchange factor for Ran. RCC1 is also known as RanGEF (Ran Guanine nucleotide Exchange Factor). Ran's intrinsic GTPase-activity is activated through interaction with Ran GTPase activating protein (RanGAP), facilitated by complex formation with Ran-binding protein (RanBP). GTPase-activation leads to the conversion of RanGTP to RanGDP, thus closing the Ran cycle.
Ran can diffuse freely within the cell, but because RCC1 and RanGAP are located in different places in the cell, the concentration of RanGTP and RanGDP differs locally as well, creating concentration gradients that act as signals for other cellular processes. RCC1 is bound to chromatin and therefore located inside the nucleus. RanGAP is cytoplasmic in yeast and bound to the nuclear envelope in plants and animals. In mammalian cells, it is SUMO modified and attached to the cytoplasmic side of the nuclear pore complex via interaction with the nucleoporin RanBP2 (Nup358). This difference in location of the accessory proteins in the Ran cycle leads to a high RanGTP to RanGDP ratio inside the nucleus and an inversely low RanGTP to RanGDP ratio outside the nucleus. In addition to a gradient of the nucleotide bound state of Ran, there is a gradient of the protein itself, with a higher concentration of Ran in the nucleus than in the cytoplasm. Cytoplasmic RanGDP is imported into the nucleus by the small protein NTF2 (Nuclear Transport Factor 2), where RCC1 can then catalyze exchange of GDP for GTP on Ran.
## Role in nuclear transport during interphase
Ran is involved in the transport of proteins across the nuclear envelope by interacting with karyopherins and changing their ability to bind or release cargo molecules. Cargo proteins containing a nuclear localization signal (NLS) are bound by importins and transported into the nucleus. Inside the nucleus, RanGTP binds to importin and releases the import cargo. Cargo that needs to get out of the nucleus into the cytoplasm binds to exportin in a ternary complex with RanGTP. Upon hydrolysis of RanGTP to RanGDP outside the nucleus, the complex dissociates and export cargo is released.
## Role in mitosis
During mitosis, the Ran cycle is involved in mitotic spindle assembly and nuclear envelope reassembly after the chromosomes have been separated.[5][6] During prophase, the steep gradient in RanGTP-RanGDP ratio at the nuclear pores breaks down as the nuclear envelope becomes leaky and disassembles. RanGTP concentration stays high around the chromosomes as RCC1, a nucleotide exchange factor, stays attached to chromatin.[7] RanBP2 (Nup358) and RanGAP move to the kinetochores where they facilitate the attachment of spindle fibers to chromosomes. Moreover, RanGTP promotes spindle assembly by mechanisms similar to mechanisms of nuclear transport: the activity of spindle assembly factors such as NuMA and TPX2 is inhibited by the binding to importins. By releasing importins, RanGTP activates these factors and therefore promotes the assembly of the mitotic spindle . In telophase, RanGTP hydrolysis and nucleotide exchange are required for vesicle fusion at the reforming nuclear envelopes of the daughter nuclei.
## Ran and the androgen receptor
RAN is an androgen receptor (AR) coactivator (ARA24) that binds differentially with different lengths of polyglutamine within the androgen receptor. Polyglutamine repeat expansion in the AR is linked to spinal and bulbar muscular atrophy (Kennedy's disease). RAN coactivation of the AR diminishes with polyglutamine expansion within the AR, and this weak coactivation may lead to partial androgen insensitivity during the development of spinal and bulbar muscular atrophy.[8][9]
# Interactions
Ran has been shown to interact with:
- KPNB1,[10][11][12]
- NEK9,[13]
- NUTF2,[14][15]
- RANBP1,[10][16][17]
- RANGAP1,[18][19][20]
- RCC1,[16][17][21][22]
- TNPO1,[23][24]
- TNPO2,[24]
- XPO1,[10][25][26] and
- XPO5.[27]
# Regulation
The expression of Ran is repressed by the microRNA miR-10a.[28] | https://www.wikidoc.org/index.php/Ran_(gene) | |
3ed505d908f1b5cd671c5823aad4f2ea38fd6cf3 | wikidoc | Randomness | Randomness
The word random is used to express lack of order, purpose, cause, or predictability in non-scientific parlance. A random process is a repeating process whose outcomes follow no describable deterministic pattern, but follow a probability distribution.
The term randomness is often used in statistics to signify well defined statistical properties, such as lack of bias or correlation. Monte Carlo Methods, which rely on random input, are important techniques of computational science. Random selection is an official method to resolve tied elections in some jurisdictions, and is even an ancient method of divination, as in tarot, the I Ching, and bibliomancy.
# History
Humankind has been concerned with random physical processes since pre-historic times. Examples are divination (cleromancy, reading messages in casting lots), the use of allotment in the Athenian democracy, and the frequent references to the casting of lots found in the Old Testament.
Despite the prevalence of gambling in all times and cultures, for a long time there was little inquiry into the subject. Though Gerolamo Cardano and Galileo wrote about games of chance, the first mathematical treatments were given by Blaise Pascal, Pierre de Fermat and Christiaan Huygens. The classical version of probability theory that they developed proceeds from the assumption that outcomes of random processes are equally likely; thus they were among the first to give a definition of randomness in statistical terms. The concept of statistical randomness was later developed into the concept of information entropy in information theory.
In the early 1960s Gregory Chaitin, Andrey Kolmogorov and Ray Solomonoff introduced the notion of algorithmic randomness, in which the randomness of a sequence depends on whether it is possible to compress it.
# Randomness in science
Many scientific fields are concerned with randomness:
- Algorithmic probability
- Chaos theory
- Cryptography
- Game theory
- Information theory
- Pattern recognition
- Probability theory
- Quantum mechanics
- Statistics
- Statistical mechanics
## In the physical sciences
In the 19th century scientists used the idea of random motions of molecules in the development of statistical mechanics in order to explain phenomena in thermodynamics and the properties of gases.
According to several standard interpretations of quantum mechanics, microscopic phenomena are objectively random. That is, in an experiment where all causally relevant parameters are controlled, there will still be some aspects of the outcome which vary randomly. An example of such an experiment is placing a single unstable atom in a controlled environment; it cannot be predicted how long it will take for the atom to decay; only the probability of decay within a given time can be calculated. Thus quantum mechanics does not specify the outcome of individual experiments but only the probabilities. Hidden variable theories attempt to escape the view that nature contains irreducible randomness: such theories posit that in the processes that appear random, unobservable (hidden) properties with a certain statistical distribution are somehow at work, behind the scenes, determining the outcome in each case.
## In biology
The theory of evolution ascribes the observed diversity of life to random genetic mutations some of which are retained in the gene pool due to the improved chance for survival and reproduction that those mutated genes confer on individuals who possess them.
The characteristics of an organism arise to some extent deterministically (e.g., under the influence of genes and the environment) and to some extent randomly. For example, the density of freckles that appear on a person's skin is controlled by genes and exposure to light; whereas the exact location of individual freckles seems to be random.
Randomness is important if an animal is to behave in a way that is unpredictable to others. For instance, insects in flight tend to move about with random changes in direction, making it difficult for pursuing predators to predict their trajectories.
## In mathematics
The mathematical theory of probability arose from attempts to formulate mathematical descriptions of chance events, originally in the context of gambling but soon in connection with situations of interest in physics. Statistics is used to infer the underlying probability distribution of a collection of empirical observations. For the purposes of simulation it is necessary to have a large supply of random numbers, or means to generate them on demand.
Algorithmic information theory studies, among other topics, what constitutes a random sequence. The central idea is that a string of bits is random if and only if it is shorter than any computer program that can produce that string (Kolmogorov randomness) — this basically means that random strings are those that cannot be compressed. Pioneers of this field include Andrey Kolmogorov and his student Per Martin-Löf, Ray Solomonoff, Gregory Chaitin, and others.
## In information science
In information science irrelevant or meaningless data is considered to be noise. Noise consists of a large number of transient disturbances with a statistically randomized time distribution.
In communication theory, randomness in a signal is called noise and is opposed to that component of its variation that is causally attributable to the source, the signal.
## In finance
The random walk hypothesis considers that asset prices in an organized market evolve at random.
Other so called random factors intervene in trends and patterns to do with Supply and Demand distributions. As well as this, the random factor of the environment itself results in fluctuations in stock and broker markets.
## Randomness versus unpredictability
Randomness is an objective property. Nevertheless, what appears random to one observer may not appear random to another observer. Consider two observers of a sequence of bits, only one of whom has the cryptographic key needed to turn the sequence of bits into a readable message. The message is not random, but is unpredictable for one of the observers.
One of the intriguing aspects of random processes is that it is hard to know whether the process is truly random. The observer can always suspect that there is some "key" that unlocks the message. This is one of the foundations of superstition and is also what is a driving motive, curiosity, for discovery in science and mathematics.
Under the cosmological hypothesis of determinism there is no randomness in the universe, only unpredictability.
Some mathematically defined sequences exhibit some of the same characteristics as random sequences, but because they are generated by a describable mechanism they are called pseudorandom. To an observer who does not know the mechanism, a pseudorandom sequence is unpredictable.
Chaotic systems are unpredictable in practice due to their extreme dependence on initial conditions. Whether or not they are unpredictable in terms of computability theory is a subject of current research. At least in some disciplines of computability theory the notion of randomness turns out to be identified with computational unpredictability.
Randomness of a phenomenon is not itself 'random'. It can often be precisely characterized, usually in terms of probability or expected value. For instance quantum mechanics allows a very precise calculation of the half-lives of atoms even though the process of atomic decay is a random one. More simply, though we cannot predict the outcome of a single toss of a fair coin, we can characterize its general behavior by saying that if a large number of tosses are made, roughly half of them will show up "Heads". Ohm's law and the kinetic theory of gases are precise characterizations of macroscopic phenomena which are random on the microscopic level.
# Randomness and religion
Randomness has been associated closely with the notion of free will in a number of ways. If a person has free will (as defined by incompatibilists), then his actions will be unpredictable by other people and will contain an element of irreducible indeterminacy. By religious or supernatural
conceptions of incompatibilist free will, such human actions may be the only source of randomness in the universe. (According to the naturalistic conception, by contrast, incompatibilist free will arises from pre-existing indeterminacy in physical laws and is not necessarily a unique feature of humans. According to the compatibilist conception, there is no randomness and humans are merely too complex to be easily predicted).
Some theologians have attempted to resolve the apparent contradiction between an omniscient deity, or a first cause, and free will using randomness. Discordians have a strong belief in randomness and unpredictability. Buddhist philosophy states that any event is the result of previous events (karma) and as such there is no such thing as a random event nor a 'first' event.
Martin Luther, the forefather of Protestantism, believed that there was nothing random based on his understanding of the Bible. As an outcome of his understanding of randomness he strongly felt that free will was limited to low level decision making by humans. Therefore, when someone sins against another, decision making is only limited to how one responds preferably through forgiveness and loving actions. He believed based on Biblical scripture that humans cannot will themselves, faith, salvation, sanctification, or other gifts from God. Additionally, the best people could do according to his understanding was not sin but they fall short and free will cannot achieve this objective. Thus, in his view absolute free will and unbounded randomness are severely limited to the point that behaviors may even be patterned or ordered and not random. This is a point emphasized by the field of behavioral psychology.
These notions and more in Christianity often lend to a highly deterministic worldview and that the concept of random events is not possible. Especially, if purpose is part of this universe then randomness, by definition, is not possible. This is also one of the rationales for religious opposition to Evolution, where, according to theory, (non-random) selection is applied to the results of random genetic variation.
Donald Knuth, a Stanford computer scientist and Christian commentator, remarks that he finds pseudo-random numbers useful and applies them with purpose. He then extends this thought to God who may use randomness with purpose to allow free will to certain degrees. Knuth believes that God is interested in peoples decisions and limited free will allows a certain degree of decision making. Knuth, based on his understanding of quantum computing and entanglement, comments that God exerts dynamic control over the world without violating any laws of physics suggesting that what appears to be random to humans may not, in fact, be so random.
C.S. Lewis, a 20th century Christian philosopher, discussed free will at length. On the matter of human will, Lewis wrote: "God willed the free will of men and angels in spite of His knowledge that it could lead in some cases to sin and thence to suffering: i.e., He thought freedom worth creating even at that price." In his radio broadcast Lewis indicated that God "gave free will. He gave them free will because a world of mere automata could never love…" Lewis, believing in free will, had an indirect belief in randomness by setting up a dependency of love on free will.
# Applications and use of randomness
In most of its mathematical, political, social and religious use, randomness is used for its innate "fairness" and lack of bias.
Political: Greek Democracy was based on the concept of isonomia (equality of political rights) and used complex allotment machines to ensure that the positions on the ruling committees that ran Athens were fairly allocated. Allotment is now restricted to selecting jurors in Anglo-Saxon legal systems and in situations where "fairness" is approximated by randomization, such as selecting jurors and military draft lotteries.
Social: Random numbers were first investigated in the context of gambling, and many randomizing devices such as dice, shuffling playing cards, and roulette wheels, were first developed for use in gambling. The ability to fairly produce random numbers is vital to electronic gambling and, as such, the methods used to create them are usually regulated by government Gaming Control Boards. Throughout history randomness has been used for games of chance and to select out individuals for an unwanted task in a fair way (see drawing straws).
Mathematical: Random numbers are also used where their use is mathematically important, such as sampling for opinion polls and for statistical sampling in quality control systems. Computational solutions for some types of problems use random numbers extensively, such as in the Monte Carlo method and in genetic algorithms.
Medicine: Random allocation of a clinical intervention is used to reduce bias in controlled trials (e.g. Randomized controlled trials).
Religious: Although not intended to be random, various forms of Divination such as Cleromancy see what appears to be random events as a means for a divine being to communicate their will. (See also Free will and Determinism).
## Generating randomness
It is generally accepted that there exist three mechanisms responsible for (apparently) random behavior in systems :
- Randomness coming from the environment (for example, Brownian motion, but also hardware random number generators)
- Randomness coming from the initial conditions. This aspect is studied by chaos theory, and is observed in systems whose behavior is very sensitive to small variations in initial conditions (such as pachinko machines, dice ...).
- Randomness intrinsically generated by the system. This is also called pseudorandomness, and is the kind used in pseudo-random number generators. There are many algorithms (based on arithmetics or cellular automaton) to generate pseudorandom numbers. The behavior of the system can be determined by knowing the seed state and the algorithm used. These methods are quicker than getting "true" randomness from the environment.
The many applications of randomness have led to many different methods for generating random data. These methods may vary as to how unpredictable or statistically random they are, and how quickly they can generate random numbers.
Before the advent of computational random number generators, generating large amounts of sufficiently random numbers (important in statistics) required a lot of work. Results would sometimes be collected and distributed as random number tables.
## Randomness measures and tests
There are many practical measures of randomness for a binary sequence. These include measures based on frequency, discrete transforms, and complexity or a mixture of these. These include tests by Kak, Phillips, Yuen, Hopkins, Beth and Dai, Mund, and Marsaglia and Zaman.
## Links related to generating randomness
- Hardware random number generator
- Entropy (computing)
- Information entropy
- Probability theory
- Pseudorandomness
- Pseudorandom number generator
- Random number
- Random sequence
- Random variable
- Randomization
- Stochastic process
- White noise
# Misconceptions/logical fallacies
Popular perceptions of randomness are frequently wrong, based on logical fallacies. The following is an attempt to identify the source of such fallacies and correct the logical errors. For a more detailed discussion, see Gambler's fallacy.
## A number is "due"
This argument says that "since all numbers will eventually appear in a random selection, those that have not come up yet are 'due' and thus more likely to come up soon". This logic is only correct if applied to a system where numbers that come up are removed from the system, such as when playing cards are drawn and not returned to the deck. It's true, for example, that once a jack is removed from the deck, the next draw is less likely to be a jack and more likely to be some other card. However, if the jack is returned to the deck, and the deck is thoroughly reshuffled, there is an equal chance of drawing a jack or any other card the next time. The same truth applies to any other case where objects are selected independently and nothing is removed from the system after each event, such as a die roll, coin toss or most lottery number selection schemes. A way to look at it is to note that random processes such as throwing coins don't have memory, making it impossible for past outcomes to affect the present and future.
## A number is "cursed"
This argument is almost the reverse of the above, and says that numbers which have come up less often in the past will continue to come up less often in the future. A similar "number is 'blessed'" argument might be made saying that numbers which have come up more often in the past are likely to do so in the future. This logic is only valid if the roll is somehow biased and results don't have equal probabilities — for example, with weighted dice. If we know for certain that the roll is fair, then previous events have no influence over future events.
Note that in nature, unexpected or uncertain events rarely occur with perfectly equal frequencies, so learning which events are likely to have higher probability by observing outcomes makes sense. What is fallacious is to apply this logic to systems which are specially designed so that all outcomes are equally likely — such as dice, roulette wheels, and so on. | Randomness
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
The word random is used to express lack of order, purpose, cause, or predictability in non-scientific parlance. A random process is a repeating process whose outcomes follow no describable deterministic pattern, but follow a probability distribution.
The term randomness is often used in statistics to signify well defined statistical properties, such as lack of bias or correlation. Monte Carlo Methods, which rely on random input, are important techniques of computational science.[1] Random selection is an official method to resolve tied elections in some jurisdictions[2], and is even an ancient method of divination, as in tarot, the I Ching, and bibliomancy.
# History
Humankind has been concerned with random physical processes since pre-historic times. Examples are divination (cleromancy, reading messages in casting lots), the use of allotment in the Athenian democracy, and the frequent references to the casting of lots found in the Old Testament.
Despite the prevalence of gambling in all times and cultures, for a long time there was little inquiry into the subject. Though Gerolamo Cardano and Galileo wrote about games of chance, the first mathematical treatments were given by Blaise Pascal, Pierre de Fermat and Christiaan Huygens. The classical version of probability theory that they developed proceeds from the assumption that outcomes of random processes are equally likely; thus they were among the first to give a definition of randomness in statistical terms. The concept of statistical randomness was later developed into the concept of information entropy in information theory.
In the early 1960s Gregory Chaitin, Andrey Kolmogorov and Ray Solomonoff introduced the notion of algorithmic randomness, in which the randomness of a sequence depends on whether it is possible to compress it.
# Randomness in science
Many scientific fields are concerned with randomness:
- Algorithmic probability
- Chaos theory
- Cryptography
- Game theory
- Information theory
- Pattern recognition
- Probability theory
- Quantum mechanics
- Statistics
- Statistical mechanics
## In the physical sciences
In the 19th century scientists used the idea of random motions of molecules in the development of statistical mechanics in order to explain phenomena in thermodynamics and the properties of gases.
According to several standard interpretations of quantum mechanics, microscopic phenomena are objectively random. That is, in an experiment where all causally relevant parameters are controlled, there will still be some aspects of the outcome which vary randomly. An example of such an experiment is placing a single unstable atom in a controlled environment; it cannot be predicted how long it will take for the atom to decay; only the probability of decay within a given time can be calculated. [3]Thus quantum mechanics does not specify the outcome of individual experiments but only the probabilities. Hidden variable theories attempt to escape the view that nature contains irreducible randomness: such theories posit that in the processes that appear random, unobservable (hidden) properties with a certain statistical distribution are somehow at work, behind the scenes, determining the outcome in each case.
## In biology
The theory of evolution ascribes the observed diversity of life to random genetic mutations some of which are retained in the gene pool due to the improved chance for survival and reproduction that those mutated genes confer on individuals who possess them.
The characteristics of an organism arise to some extent deterministically (e.g., under the influence of genes and the environment) and to some extent randomly. For example, the density of freckles that appear on a person's skin is controlled by genes and exposure to light; whereas the exact location of individual freckles seems to be random.[4]
Randomness is important if an animal is to behave in a way that is unpredictable to others. For instance, insects in flight tend to move about with random changes in direction, making it difficult for pursuing predators to predict their trajectories.
## In mathematics
The mathematical theory of probability arose from attempts to formulate mathematical descriptions of chance events, originally in the context of gambling but soon in connection with situations of interest in physics. Statistics is used to infer the underlying probability distribution of a collection of empirical observations. For the purposes of simulation it is necessary to have a large supply of random numbers, or means to generate them on demand.
Algorithmic information theory studies, among other topics, what constitutes a random sequence. The central idea is that a string of bits is random if and only if it is shorter than any computer program that can produce that string (Kolmogorov randomness) — this basically means that random strings are those that cannot be compressed. Pioneers of this field include Andrey Kolmogorov and his student Per Martin-Löf, Ray Solomonoff, Gregory Chaitin, and others.
## In information science
In information science irrelevant or meaningless data is considered to be noise. Noise consists of a large number of transient disturbances with a statistically randomized time distribution.
In communication theory, randomness in a signal is called noise and is opposed to that component of its variation that is causally attributable to the source, the signal.
## In finance
The random walk hypothesis considers that asset prices in an organized market evolve at random.
Other so called random factors intervene in trends and patterns to do with Supply and Demand distributions. As well as this, the random factor of the environment itself results in fluctuations in stock and broker markets.
## Randomness versus unpredictability
Randomness is an objective property. Nevertheless, what appears random to one observer may not appear random to another observer. Consider two observers of a sequence of bits, only one of whom has the cryptographic key needed to turn the sequence of bits into a readable message. The message is not random, but is unpredictable for one of the observers.
One of the intriguing aspects of random processes is that it is hard to know whether the process is truly random. The observer can always suspect that there is some "key" that unlocks the message. This is one of the foundations of superstition and is also what is a driving motive, curiosity, for discovery in science and mathematics.
Under the cosmological hypothesis of determinism there is no randomness in the universe, only unpredictability.
Some mathematically defined sequences exhibit some of the same characteristics as random sequences, but because they are generated by a describable mechanism they are called pseudorandom. To an observer who does not know the mechanism, a pseudorandom sequence is unpredictable.
Chaotic systems are unpredictable in practice due to their extreme dependence on initial conditions. Whether or not they are unpredictable in terms of computability theory is a subject of current research. At least in some disciplines of computability theory the notion of randomness turns out to be identified with computational unpredictability.
Randomness of a phenomenon is not itself 'random'. It can often be precisely characterized, usually in terms of probability or expected value. For instance quantum mechanics allows a very precise calculation of the half-lives of atoms even though the process of atomic decay is a random one. More simply, though we cannot predict the outcome of a single toss of a fair coin, we can characterize its general behavior by saying that if a large number of tosses are made, roughly half of them will show up "Heads". Ohm's law and the kinetic theory of gases are precise characterizations of macroscopic phenomena which are random on the microscopic level.
# Randomness and religion
Randomness has been associated closely with the notion of free will in a number of ways. If a person has free will (as defined by incompatibilists), then his actions will be unpredictable by other people and will contain an element of irreducible indeterminacy. By religious or supernatural
conceptions of incompatibilist free will, such human actions may be the only source of randomness in the universe. (According to the naturalistic conception, by contrast, incompatibilist free will arises from pre-existing indeterminacy in physical laws and is not necessarily a unique feature of humans. According to the compatibilist conception, there is no randomness and humans are merely too complex to be easily predicted).
Some theologians have attempted to resolve the apparent contradiction between an omniscient deity, or a first cause, and free will using randomness. Discordians have a strong belief in randomness and unpredictability. Buddhist philosophy states that any event is the result of previous events (karma) and as such there is no such thing as a random event nor a 'first' event.
Martin Luther, the forefather of Protestantism, believed that there was nothing random based on his understanding of the Bible. As an outcome of his understanding of randomness he strongly felt that free will was limited to low level decision making by humans. Therefore, when someone sins against another, decision making is only limited to how one responds preferably through forgiveness and loving actions. He believed based on Biblical scripture that humans cannot will themselves, faith, salvation, sanctification, or other gifts from God. Additionally, the best people could do according to his understanding was not sin but they fall short and free will cannot achieve this objective. Thus, in his view absolute free will and unbounded randomness are severely limited to the point that behaviors may even be patterned or ordered and not random. This is a point emphasized by the field of behavioral psychology.
These notions and more in Christianity often lend to a highly deterministic worldview and that the concept of random events is not possible. Especially, if purpose is part of this universe then randomness, by definition, is not possible. This is also one of the rationales for religious opposition to Evolution, where, according to theory, (non-random) selection is applied to the results of random genetic variation.
Donald Knuth, a Stanford computer scientist and Christian commentator, remarks that he finds pseudo-random numbers useful and applies them with purpose. He then extends this thought to God who may use randomness with purpose to allow free will to certain degrees. Knuth believes that God is interested in peoples decisions and limited free will allows a certain degree of decision making. Knuth, based on his understanding of quantum computing and entanglement, comments that God exerts dynamic control over the world without violating any laws of physics suggesting that what appears to be random to humans may not, in fact, be so random.[5]
C.S. Lewis, a 20th century Christian philosopher, discussed free will at length. On the matter of human will, Lewis wrote: "God willed the free will of men and angels in spite of His knowledge that it could lead in some cases to sin and thence to suffering: i.e., He thought freedom worth creating even at that price." In his radio broadcast Lewis indicated that God "gave [humans] free will. He gave them free will because a world of mere automata could never love…" Lewis, believing in free will, had an indirect belief in randomness by setting up a dependency of love on free will.[citation needed]
# Applications and use of randomness
In most of its mathematical, political, social and religious use, randomness is used for its innate "fairness" and lack of bias.
Political: Greek Democracy was based on the concept of isonomia (equality of political rights) and used complex allotment machines to ensure that the positions on the ruling committees that ran Athens were fairly allocated. Allotment is now restricted to selecting jurors in Anglo-Saxon legal systems and in situations where "fairness" is approximated by randomization, such as selecting jurors and military draft lotteries.
Social: Random numbers were first investigated in the context of gambling, and many randomizing devices such as dice, shuffling playing cards, and roulette wheels, were first developed for use in gambling. The ability to fairly produce random numbers is vital to electronic gambling and, as such, the methods used to create them are usually regulated by government Gaming Control Boards. Throughout history randomness has been used for games of chance and to select out individuals for an unwanted task in a fair way (see drawing straws).
Mathematical: Random numbers are also used where their use is mathematically important, such as sampling for opinion polls and for statistical sampling in quality control systems. Computational solutions for some types of problems use random numbers extensively, such as in the Monte Carlo method and in genetic algorithms.
Medicine: Random allocation of a clinical intervention is used to reduce bias in controlled trials (e.g. Randomized controlled trials).
Religious: Although not intended to be random, various forms of Divination such as Cleromancy see what appears to be random events as a means for a divine being to communicate their will. (See also Free will and Determinism).
## Generating randomness
It is generally accepted that there exist three mechanisms responsible for (apparently) random behavior in systems :
- Randomness coming from the environment (for example, Brownian motion, but also hardware random number generators)
- Randomness coming from the initial conditions. This aspect is studied by chaos theory, and is observed in systems whose behavior is very sensitive to small variations in initial conditions (such as pachinko machines, dice ...).
- Randomness intrinsically generated by the system. This is also called pseudorandomness, and is the kind used in pseudo-random number generators. There are many algorithms (based on arithmetics or cellular automaton) to generate pseudorandom numbers. The behavior of the system can be determined by knowing the seed state and the algorithm used. These methods are quicker than getting "true" randomness from the environment.
The many applications of randomness have led to many different methods for generating random data. These methods may vary as to how unpredictable or statistically random they are, and how quickly they can generate random numbers.
Before the advent of computational random number generators, generating large amounts of sufficiently random numbers (important in statistics) required a lot of work. Results would sometimes be collected and distributed as random number tables.
## Randomness measures and tests
There are many practical measures of randomness for a binary sequence. These include measures based on frequency, discrete transforms, and complexity or a mixture of these. These include tests by Kak, Phillips, Yuen, Hopkins, Beth and Dai, Mund, and Marsaglia and Zaman.[6]
## Links related to generating randomness
- Hardware random number generator
- Entropy (computing)
- Information entropy
- Probability theory
- Pseudorandomness
- Pseudorandom number generator
- Random number
- Random sequence
- Random variable
- Randomization
- Stochastic process
- White noise
# Misconceptions/logical fallacies
Popular perceptions of randomness are frequently wrong, based on logical fallacies. The following is an attempt to identify the source of such fallacies and correct the logical errors. For a more detailed discussion, see Gambler's fallacy.
## A number is "due"
This argument says that "since all numbers will eventually appear in a random selection, those that have not come up yet are 'due' and thus more likely to come up soon". This logic is only correct if applied to a system where numbers that come up are removed from the system, such as when playing cards are drawn and not returned to the deck. It's true, for example, that once a jack is removed from the deck, the next draw is less likely to be a jack and more likely to be some other card. However, if the jack is returned to the deck, and the deck is thoroughly reshuffled, there is an equal chance of drawing a jack or any other card the next time. The same truth applies to any other case where objects are selected independently and nothing is removed from the system after each event, such as a die roll, coin toss or most lottery number selection schemes. A way to look at it is to note that random processes such as throwing coins don't have memory, making it impossible for past outcomes to affect the present and future.
## A number is "cursed"
This argument is almost the reverse of the above, and says that numbers which have come up less often in the past will continue to come up less often in the future. A similar "number is 'blessed'" argument might be made saying that numbers which have come up more often in the past are likely to do so in the future. This logic is only valid if the roll is somehow biased and results don't have equal probabilities — for example, with weighted dice. If we know for certain that the roll is fair, then previous events have no influence over future events.
Note that in nature, unexpected or uncertain events rarely occur with perfectly equal frequencies, so learning which events are likely to have higher probability by observing outcomes makes sense. What is fallacious is to apply this logic to systems which are specially designed so that all outcomes are equally likely — such as dice, roulette wheels, and so on. | https://www.wikidoc.org/index.php/Random | |
7f64a6baa611df9c248ef4fe52c439fe1b66309c | wikidoc | Ranolazine | Ranolazine
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# Overview
Ranolazine is an Anti-anginal that is FDA approved for the treatment of treatment of chronic angina.. Common adverse reactions include constipation, nausea , dizziness, headache.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- initial dosage: 500 mg PO bid
- maximum dosage: 1000 mg PO bid (based on clinical symptoms)s
### Dose modification
- Dosing information
- Maximum dosage: 500 mg PO bid in patients on moderate CYP3A inhibitors such as diltiazem, verapamil, and erythromycin.
- Use of Ranexa with strong CYP3A inhibitors is contraindicated.
- Use of P-gp inhibitors, such as cyclosporine, may increase exposure to Ranexa. Titrate Ranexa based on clinical response.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information about Off-Label Guideline-Supported Use of Ranolazine in adult patients.
### Non–Guideline-Supported Use
There is limited information about the non–guideline-supported off-label use.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
FDA Package Insert for Ranolazine contains no information regarding FDA-labeled indications and dosage information.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information about Off-Label Guideline-Supported Use of Ranolazine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information about Off-Label Non–Guideline-Supported Use of Ranolazine in pediatric patients.
# Contraindications
Ranexa is contraindicated in patients:
- Taking strong inhibitors of CYP3A.
- Taking inducers of CYP3A.
- With liver cirrhosis.
# Warnings
Ranolazine blocks IKr and prolongs the QTc interval in a dose-related manner.
Clinical experience in an acute coronary syndrome population did not show an increased risk of proarrhythmia or sudden death. However, there is little experience with high doses (> 1000 mg twice daily) or exposure, other QT-prolonging drugs, potassium channel variants resulting in a long QT interval, in patients with a family history of (or congenital) long QT syndrome, or in patients with known acquired QT interval prolongation.
Acute renal failure has been observed in some patients with severe renal impairment (creatinine clearance < 30 mL/min) while taking Ranexa. If acute renal failure develops (e.g., marked increase in serum creatinine associated with an increase in blood urea nitrogen ), discontinue Ranexa and treat appropriately.
Monitor renal function after initiation and periodically in patients with moderate to severe renal impairment (CrCL < 60 mL/min) for increases in serum creatinine accompanied by an increase in BUN.
# Adverse Reactions
## Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
A total of 2,018 patients with chronic angina were treated with ranolazine in controlled clinical trials. Of the patients treated with Ranexa, 1,026 were enrolled in three double-blind, placebo-controlled, randomized studies (CARISA, ERICA, MARISA) of up to 12 weeks' duration. In addition, upon study completion, 1,251 patients received treatment with Ranexa in open-label, long-term studies; 1,227 patients were exposed to Ranexa for more than 1 year, 613 patients for more than 2 years, 531 patients for more than 3 years, and 326 patients for more than 4 years.
At recommended doses, about 6% of patients discontinued treatment with Ranexa because of an adverse event in controlled studies in angina patients compared to about 3% on placebo. The most common adverse events that led to discontinuation more frequently on Ranexa than placebo were dizziness (1.3% versus 0.1%), nausea (1% versus 0%), asthenia, constipation, and headache (each about 0.5% versus 0%). Doses above 1000 mg twice daily are poorly tolerated.
In controlled clinical trials of angina patients, the most frequently reported treatment-emergent adverse reactions (> 4% and more common on Ranexa than on placebo) were dizziness(6.2%), headache (5.5%), constipation(4.5%), and nausea (4.4%). Dizziness may be dose-related. In open-label, long-term treatment studies, a similar adverse reaction profile was observed.
The following additional adverse reactions occurred at an incidence of 0.5 to 4.0% in patients treated with Ranexa and were more frequent than the incidence observed in placebo-treated patients:
- Cardiac Disorders – bradycardia, palpitations
- Ear and Labyrinth Disorders – tinnitus, vertigo
- Eye Disorders – blurred vision
- Gastrointestinal Disorders – abdominal pain, dry mouth, vomiting, dyspepsia
- General Disorders and Administrative Site Adverse Events – asthenia, peripheral edema
- Metabolism and Nutrition Disorders – anorexia
- Nervous System Disorders – syncope (vasovagal)
- Psychiatric Disorders – confusional state
- Renal and Urinary Disorders – hematuria
- Respiratory, Thoracic, and Mediastinal Disorders – dyspnea
- Skin and Subcutaneous Tissue Disorders – hyperhidrosis
- Vascular Disorders – hypotension, orthostatic hypotension
- Other (< 0.5%) but potentially medically important adverse reactions observed more frequently with Ranexa than placebo treatment in all controlled studies included: angioedema, renal failure, eosinophilia, chromaturia, blood urea increased, hypoesthesia, paresthesia, tremor, pulmonary fibrosis, thrombocytopenia, leukopenia, and pancytopenia.
A large clinical trial in acute coronary syndrome patients was unsuccessful in demonstrating a benefit for Ranexa, but there was no apparent proarrhythmic effect in these high-risk patients.
Ranexa produces small reductions in hemoglobin A1c. Ranexa is not a treatment for diabetes.
Ranexa produces elevations of serum creatinine by 0.1 mg/dL, regardless of previous renal function, likely because of inhibition of creatinine's tubular secretion. In general, the elevation has a rapid onset, shows no signs of progression during long-term therapy, is reversible after discontinuation of Ranexa, and is not accompanied by changes in BUN. In healthy volunteers, Ranexa 1000 mg twice daily had no effect upon the glomerular filtration rate. More marked and progressive increases in serum creatinine, associated with increases in BUN or potassium, indicating acute renal failure, have been reported after initiation of Ranexa in patients with severe renal impairment.
## Postmarketing Experience
The following adverse reactions have been identified during postapproval use of Ranexa. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure:
- Nervous System Disorders : Tremor, paresthesia, abnormal coordination, and other serious neurologic adverse events have been reported to occur, sometimes concurrently, in patients taking ranolazine. The onset of events was often associated with an increase in ranolazine dose or exposure. Many patients reported symptom resolution following drug discontinuation or dose decrease.
- Psychiatric Disorders – hallucination
- Renal and Urinary Disorders – dysuria, urinary retention
- Skin and Subcutaneous Tissue Disorders – angioedema, pruritus, rash
# Drug Interactions
- Strong CYP3A Inhibitors
- Do not use Ranexa with strong CYP3A inhibitors, including ketoconazole, itraconazole, clarithromycin, nefazodone, nelfinavir, ritonavir, indinavir, and saquinavir.
- Moderate CYP3A Inhibitors
- Limit the dose of Ranexa to 500 mg twice daily in patients on moderate CYP3A inhibitors, including diltiazem, verapamil, erythromycin, fluconazole, and grapefruit juice or grapefruit-containing products.
- P-gp Inhibitors
- Concomitant use of Ranexa and P-gp inhibitors, such as cyclosporine, may result in increases in ranolazine concentrations. Titrate Ranexa based on clinical response in patients concomitantly treated with predominant P-gp inhibitors such as cyclosporine.
- CYP3A Inducers
- Do not use Ranexa with CYP3A inducers such as rifampin, rifabutin, rifapentine, phenobarbital, phenytoin, carbamazepine, and St. John's wort.
- Drugs Metabolized by CYP3A
- Limit the dose of simvastatin in patients on any dose of Ranexa to 20 mg once daily, when ranolazine is co-administered. Dose adjustment of other sensitive CYP3A substrates (e.g., lovastatin) and CYP3A substrates with a narrow therapeutic range (e.g., cyclosporine, tacrolimus, sirolimus ) may be required as Ranexa may increase plasma concentrations of these drugs.
- Drugs Transported by P-gp
- Concomitant use of ranolazine and digoxin results in increased exposure to digoxin. The dose of digoxin may have to be adjusted.
- Drugs Metabolized by CYP2D6
- The exposure to CYP2D6 substrates, such as tricyclic antidepressants and antipsychotics, may be increased during co-administration with Ranexa, and lower doses of these drugs may be required.
- Drugs Transported by OCT2
- In subjects with type 2 diabetes mellitus, concomitant use of Ranexa 1000 mg twice daily and metformin results in increased plasma levels of metformin. When Ranexa 1000 mg twice daily is co-administered with metformin, metformin dose should not exceed 1700 mg/day. Monitor blood glucose levels and risks associated with high exposures of metformin. Metformin exposure was not significantly increased when given with Ranexa 500 mg twice daily.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
In animal studies, ranolazine at exposures 1.5 (rabbit) to 2 (rat) times the usual human exposure caused maternal toxicity and misshapen sternebrae and reduced ossification in offspring. These doses in rats and rabbits were associated with an increased maternal mortality rate. There are no adequate well-controlled studies in pregnant women. Ranexa should be used during pregnancy only when the potential benefit to the patient justifies the potential risk to the fetus.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ranolazine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Ranolazine during labor and delivery.
### Nursing Mothers
It is not known whether ranolazine is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from ranolazine in nursing infants, decide whether to discontinue nursing or to discontinue Ranexa, taking into account the importance of the drug to the mother.
### Pediatric Use
Safety and effectiveness have not been established in pediatric patients.
### Geriatic Use
Of the chronic angina patients treated with Ranexa in controlled studies, 496 (48%) were ≥ 65 years of age, and 114 (11%) were ≥ 75 years of age. No overall differences in efficacy were observed between older and younger patients. There were no differences in safety for patients ≥ 65 years compared to younger patients, but patients ≥ 75 years of age on Ranexa, compared to placebo, had a higher incidence of adverse events, serious adverse events, and drug discontinuations due to adverse events. In general, dose selection for an elderly patient should usually start at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease, or other drug therapy.
### Gender
There is no FDA guidance on the use of Ranolazine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Ranolazine with respect to specific racial populations.
### Renal Impairment
A pharmacokinetic study of Ranexa in subjects with severe renal impairment (CrCL < 30 mL/min) was stopped when 2 of 4 subjects developed acute renal failure after receiving Ranexa 500 mg twice daily for 5 days (lead-in phase) followed by 1000 mg twice a day (1 dose in one subject and 11 doses in the other). Increases in creatinine, BUN, and potassium were observed in 3 subjects during the 500 mg lead-in phase. One subject required hemodialysis, while the other 2 subjects improved upon drug discontinuation. Monitor renal function periodically in patients with moderate to severe renal impairment. Discontinue Ranexa if acute renal failure develops.
In a separate study, Cmax was increased between 40% and 50% in patients with mild, moderate or severe renal impairment compared to patients with no renal impairment, suggesting a similar increase in exposure in patients with renal failure independent of the degree of impairment. The pharmacokinetics of ranolazine has not been assessed in patients on dialysis.
### Hepatic Impairment
Ranexa is contraindicated in patients with liver cirrhosis. In a study of cirrhotic patients, the Cmax of ranolazine was increased 30% in cirrhotic patients with mild (Child-Pugh Class A) hepatic impairment, but increased 80% in cirrhotic patients with moderate (Child-Pugh Class B) hepatic impairment compared to patients without hepatic impairment. This increase was not enough to account for the 3-fold increase in QT prolongation seen in cirrhotic patients with mild to moderate hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Ranolazine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Ranolazine in patients who are immunocompromised.
### Use in Patients with Heart Failure
Heart failure (NYHA Class I to IV) had no significant effect on ranolazine pharmacokinetics. Ranexa had minimal effects on heart rate and blood pressure in patients with angina and heart failure NYHA Class I to IV. No dose adjustment of Ranexa is required in patients with heart failure.
A population pharmacokinetic evaluation of data from angina patients and healthy subjects showed no effect of diabetes on ranolazine pharmacokinetics. No dose adjustment is required in patients with diabetes.
Ranexa produces small reductions in HbA1c in patients with diabetes, the clinical significance of which is unknown. Ranexa should not be considered a treatment for diabetes.
# Administration and Monitoring
### Administration
Initiate Ranexa dosing at 500 mg twice daily and increase to 1000 mg twice daily, as needed, based on clinical symptoms. Take Ranexa with or without meals. Swallow Ranexa tablets whole; do not crush, break, or chew.
The maximum recommended daily dose of Ranexa is 1000 mg twice daily.
If a dose of Ranexa is missed, take the prescribed dose at the next scheduled time; do not double the next dose.
Dose adjustments may be needed when Ranexa is taken in combination with certain other drugs. Limit the maximum dose of Ranexa to 500 mg twice daily in patients on moderate CYP3A inhibitors such as diltiazem, verapamil, and erythromycin. Use of Ranexa with strong CYP3A inhibitors is contraindicated. Use of P-gp inhibitors, such as cyclosporine, may increase exposure to Ranexa. Titrate Ranexa based on clinical response.
### Monitoring
- Monitor renal function after initiation and periodically in patients with moderate to severe renal impairment (CrCL < 60 mL/min) for increases in serum creatinine accompanied by an increase in BUN.
- Monitor blood glucose levels and risks associated with high exposures of metformin.
- Monitor renal function periodically in patients with moderate to severe renal impairment.
- In addition to general supportive measures, continuous ECG monitoring may be warranted in the event of overdose.
# IV Compatibility
FDA Package Insert for Ranolazine contains no information regarding IV Compatibility.
# Overdosage
High oral doses of ranolazine produce dose-related increases in dizziness, nausea, and vomiting. High intravenous exposure also produces diplopia, paresthesia, confusion, and syncope. In addition to general supportive measures, continuous ECG monitoring may be warranted in the event of overdose. Severe tremor, unsteady gait/incoordination, dysphasia, and hallucinations have been reported in cases of overdose with Ranexa.
Since ranolazine is about 62% bound to plasma proteins, hemodialysis is unlikely to be effective in clearing ranolazine.
# Pharmacology
## Mechanism of Action
The mechanism of action of ranolazine's antianginal effects has not been determined. Ranolazine has anti-ischemic and antianginal effects that do not depend upon reductions in heart rate or blood pressure. It does not affect the rate-pressure product, a measure of myocardial work, at maximal exercise. Ranolazine at therapeutic levels can inhibit the cardiac late sodium current (INa). However, the relationship of this inhibition to angina symptoms is uncertain.
The QT prolongation effect of ranolazine on the surface electrocardiogram is the result of inhibition of IKr, which prolongs the ventricular action potential.
## Structure
Ranexa (ranolazine) is available as a film-coated, non-scored, extended-release tablet for oral administration.
Ranolazine is a racemic mixture, chemically described as 1-piperazineacetamide, N-(2,6-dimethylphenyl)-4--, (±)-. It has an empirical formula of C24H33N3O4, a molecular weight of 427.54 g/mole, and the following structural formula:
Ranolazine is a white to off-white solid. Ranolazine is soluble in dichloromethane and methanol; sparingly soluble in tetrahydrofuran, ethanol, acetonitrile, and acetone; slightly soluble in ethyl acetate, isopropanol, toluene, and ethyl ether; and very slightly soluble in water.
Ranexa tablets contain 500 mg or 1000 mg of ranolazine and the following inactive ingredients: carnauba wax, hypromellose, magnesium stearate, methacrylic acid copolymer (Type C), microcrystalline cellulose, polyethylene glycol, sodium hydroxide, and titanium dioxide. Additional inactive ingredients for the 500 mg tablet include polyvinyl alcohol, talc, Iron Oxide Yellow, and Iron Oxide Red; additional inactive ingredients for the 1000 mg tablet include lactose monohydrate, triacetin, and Iron Oxide Yellow.
## Pharmacodynamics
Patients with chronic angina treated with Ranexa in controlled clinical studies had minimal changes in mean heart rate (< 2 bpm) and systolic blood pressure (< 3 mm Hg). Similar results were observed in subgroups of patients with CHF NYHA Class I or II, diabetes, or reactive airway disease, and in elderly patients.
Dose and plasma concentration-related increases in the QTc interval, reductions in T wave amplitude, and, in some cases, notched T waves, have been observed in patients treated with Ranexa. These effects are believed to be caused by ranolazine and not by its metabolites. The relationship between the change in QTc and ranolazine plasma concentrations is linear, with a slope of about 2.6 msec/1000 ng/mL, through exposures corresponding to doses several-fold higher than the maximum recommended dose of 1000 mg twice daily. The variable blood levels attained after a given dose of ranolazine give a wide range of effects on QTc. At Tmax following repeat dosing at 1000 mg twice daily, the mean change in QTc is about 6 msec, but in the 5% of the population with the highest plasma concentrations, the prolongation of QTc is at least 15 msec. In cirrhotic subjects with mild or moderate hepatic impairment, the relationship between plasma level of ranolazine and QTc is much steeper.
Age, weight, gender, race, heart rate, congestive heart failure, diabetes, and renal impairment did not alter the slope of the QTc-concentration relationship of ranolazine.
No proarrhythmic effects were observed on 7-day Holter recordings in 3,162 acute coronary syndrome patients treated with Ranexa. There was a significantly lower incidence of arrhythmias (ventricular tachycardia, bradycardia, supraventricular tachycardia, and new atrial fibrillation) in patients treated with Ranexa (80%) versus placebo (87%), including ventricular tachycardia ≥ 3 beats (52% versus 61%). However, this difference in arrhythmias did not lead to a reduction in mortality, a reduction in arrhythmia hospitalization, or a reduction in arrhythmia symptoms.
## Pharmacokinetics
Ranolazine is extensively metabolized in the gut and liver and its absorption is highly variable. For example, at a dose of 1000 mg twice daily, the mean steady-state Cmax was 2600 ng/mL with 95% confidence limits of 400 and 6100 ng/mL. The pharmacokinetics of the (+) R- and (-) S-enantiomers of ranolazine are similar in healthy volunteers. The apparent terminal half-life of ranolazine is 7 hours. Steady state is generally achieved within 3 days of twice-daily dosing with Ranexa. At steady state over the dose range of 500 to 1000 mg twice daily, Cmax and AUC0–τ increase slightly more than proportionally to dose, 2.2- and 2.4-fold, respectively. With twice-daily dosing, the trough:peak ratio of the ranolazine plasma concentration is 0.3 to 0.6. The pharmacokinetics of ranolazine is unaffected by age, gender, or food.
After oral administration of Ranexa, peak plasma concentrations of ranolazine are reached between 2 and 5 hours. After oral administration of 14C-ranolazine as a solution, 73% of the dose is systemically available as ranolazine or metabolites. The bioavailability of ranolazine from Ranexa tablets relative to that from a solution of ranolazine is 76%. Because ranolazine is a substrate of P-gp, inhibitors of P-gp may increase the absorption of ranolazine.
Food (high-fat breakfast) has no important effect on the Cmax and AUC of ranolazine. Therefore, Ranexa may be taken without regard to meals. Over the concentration range of 0.25 to 10 µg/mL, ranolazine is approximately 62% bound to human plasma proteins.
Ranolazine is metabolized mainly by CYP3A and, to a lesser extent, by CYP2D6. Following a single oral dose of ranolazine solution, approximately 75% of the dose is excreted in urine and 25% in feces. Ranolazine is metabolized rapidly and extensively in the liver and intestine; less than 5% is excreted unchanged in urine and feces. The pharmacologic activity of the metabolites has not been well characterized. After dosing to steady state with 500 mg to 1500 mg twice daily, the four most abundant metabolites in plasma have AUC values ranging from about 5 to 33% that of ranolazine, and display apparent half-lives ranging from 6 to 22 hours.
## Nonclinical Toxicology
Ranolazine tested negative for genotoxic potential in the following assays: Ames bacterial mutation assay, Saccharomyces assay for mitotic gene conversion, chromosomal aberrations assay in Chinese hamster ovary (CHO) cells, mammalian CHO/HGPRT gene mutation assay, and mouse and rat bone marrow micronucleus assays.
There was no evidence of carcinogenic potential in mice or rats. The highest oral doses used in the carcinogenicity studies were 150 mg/kg/day for 21 months in rats (900 mg/m2/day) and 50 mg/kg/day for 24 months in mice (150 mg/m2/day). These maximally tolerated doses are 0.8 and 0.1 times, respectively, the maximum recommended human dose (MRHD) of 2 grams on a surface area basis. A published study reported that ranolazine promoted tumor formation and progression to malignancy when given to transgenic APC (min/+) mice at a dose of 30 mg/kg twice daily. The clinical significance of this finding is unclear.
Animal reproduction studies with ranolazine were conducted in rats and rabbits.
There was an increased incidence of misshapen sternebrae and reduced ossification of pelvic and cranial bones in fetuses of pregnant rats dosed at 400 mg/kg/day (2 times the MRHD on a surface area basis). Reduced ossification of sternebrae was observed in fetuses of pregnant rabbits dosed at 150 mg/kg/day (1.5 times the MRHD on a surface area basis). These doses in rats and rabbits were associated with an increased maternal mortality rate.
# Clinical Studies
CARISA (Combination Assessment of Ranolazine In Stable Angina) was a study in 823 chronic angina patients randomized to receive 12 weeks of treatment with twice-daily Ranexa 750 mg, 1000 mg, or placebo, who also continued on daily doses of atenolol 50 mg, amlodipine 5 mg, or diltiazem CD 180 mg. Sublingual nitrates were used in this study as needed.
In this trial, statistically significant (p < 0.05) increases in modified Bruce treadmill exercise duration and time to angina were observed for each Ranexa dose versus placebo, at both trough (12 hours after dosing) and peak (4 hours after dosing) plasma levels, with minimal effects on blood pressure and heart rate. The changes versus placebo in exercise parameters are presented in Table 1. Exercise treadmill results showed no increase in effect on exercise at the 1000 mg dose compared to the 750 mg dose.
The effects of Ranexa on angina frequency and nitroglycerin use are shown in Table 2.
Tolerance to Ranexa did not develop after 12 weeks of therapy. Rebound increases in angina, as measured by exercise duration, have not been observed following abrupt discontinuation of Ranexa.
Ranexa has been evaluated in patients with chronic angina who remained symptomatic despite treatment with the maximum dose of an antianginal agent. In the ERICA (Efficacy of Ranolazine In Chronic Angina) trial, 565 patients were randomized to receive an initial dose of Ranexa 500 mg twice daily or placebo for 1 week, followed by 6 weeks of treatment with Ranexa 1000 mg twice daily or placebo, in addition to concomitant treatment with amlodipine 10 mg once daily. In addition, 45% of the study population also received long-acting nitrates. Sublingual nitrates were used as needed to treat angina episodes. Results are shown in Table 3. Statistically significant decreases in angina attack frequency (p = 0.028) and nitroglycerin use (p = 0.014) were observed with Ranexa compared to placebo. These treatment effects appeared consistent across age and use of long-acting nitrates.
Effects on angina frequency and exercise tolerance were considerably smaller in women than in men. In CARISA, the improvement in Exercise Tolerance Test (ETT) in females was about 33% of that in males at the 1000 mg twice-daily dose level. In ERICA, where the primary endpoint was angina attack frequency, the mean reduction in weekly angina attacks was 0.3 for females and 1.3 for males.
There were insufficient numbers of non-Caucasian patients to allow for analyses of efficacy or safety by racial subgroup.
14.2 Lack of Benefit in Acute Coronary Syndrome
In a large (n = 6,560) placebo-controlled trial (MERLIN-TIMI 36) in patients with acute coronary syndrome, there was no benefit shown on outcome measures. However, the study is somewhat reassuring regarding proarrhythmic risks, as ventricular arrhythmias were less common on ranolazine and there was no difference between Ranexa and placebo in the risk of all-cause mortality (relative risk ranolazine:placebo 0.99 with an upper 95% confidence limit of 1.22).
# How Supplied
Ranexa is supplied as film-coated, oblong-shaped, extended-release tablets in the following strengths:
- 500 mg tablets are light orange, with GSI500 on one side
- 1000 mg tablets are pale yellow, with GSI1000 on one side
Ranexa (ranolazine) extended-release tablets are available in:
## Storage
Store Ranexa tablets at 25°C (77°F) with excursions permitted to 15° to 30°C (59° to 86°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
To ensure safe and effective use of Ranexa, the following information and instructions should be communicated to the patient when appropriate.
Patients should be advised:
- that Ranexa will not abate an acute angina episode
- to inform their physician of any other medications when taken concurrently with Ranexa, including over-the-counter medications
- that Ranexa may produce changes in the electrocardiogram (QTc interval prolongation)
- to inform their physician of any personal or family history of QTc prolongation, congenital long QT syndrome, or if they are receiving drugs that prolong the QTc interval such as Class Ia (e.g., quinidine) or Class III (e.g., dofetilide, sotalol, amiodarone) antiarrhythmic agents, erythromycin, and certain antipsychotics (e.g., thioridazine, ziprasidone)
- to inform their physician if they have impaired renal function before or while taking Ranexa
- that patients with severe renal impairment may be at risk of renal failure while on Ranexa
- that Ranexa should not be used in patients who are receiving drugs that are strong CYP3A inhibitors (e.g., ketoconazole, clarithromycin, nefazodone, ritonavir)
- that initiation of treatment with Ranexa should be avoided during administration of inducers of CYP3A (e.g., rifampin, rifabutin, rifapentine, barbiturates, carbamazepine, phenytoin, St. John's wort)
- to inform their physician if they are receiving drugs that are moderate CYP3A inhibitors (e.g., diltiazem, verapamil, erythromycin)
- to inform their physician if they are receiving P-gp inhibitors (e.g., cyclosporine)
- that grapefruit juice or grapefruit products should be limited when taking Ranexa
- that Ranexa should not be used in patients with liver cirrhosis
- that doses of Ranexa higher than 1000 mg twice daily should not be used
- that if a dose is missed, the usual dose should be taken at the next scheduled time. The next dose should not be doubled
- that Ranexa may be taken with or without meals
- that Ranexa tablets should be swallowed whole and not crushed, broken, or chewed
- to contact their physician if they experience fainting spells while taking Ranexa
- that Ranexa may cause dizziness and lightheadedness; therefore, patients should know how they react to this drug before they operate an automobile, or machinery, or engage in activities requiring mental alertness or coordination
# Precautions with Alcohol
Alcohol-Ranolazine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
Ranexa
# Look-Alike Drug Names
There is limited information about the Look-Alike Drug Names.
# Drug Shortage Status
# Price
# Price | Ranolazine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, M.D. [2]; Anusha Vege, M.B.B.S. [3]
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# Overview
Ranolazine is an Anti-anginal that is FDA approved for the treatment of treatment of chronic angina.. Common adverse reactions include constipation, nausea , dizziness, headache.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- initial dosage: 500 mg PO bid
- maximum dosage: 1000 mg PO bid (based on clinical symptoms)s
### Dose modification
- Dosing information
- Maximum dosage: 500 mg PO bid in patients on moderate CYP3A inhibitors such as diltiazem, verapamil, and erythromycin.
- Use of Ranexa with strong CYP3A inhibitors is contraindicated.
- Use of P-gp inhibitors, such as cyclosporine, may increase exposure to Ranexa. Titrate Ranexa based on clinical response.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information about Off-Label Guideline-Supported Use of Ranolazine in adult patients.
### Non–Guideline-Supported Use
There is limited information about the non–guideline-supported off-label use.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
FDA Package Insert for Ranolazine contains no information regarding FDA-labeled indications and dosage information.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information about Off-Label Guideline-Supported Use of Ranolazine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information about Off-Label Non–Guideline-Supported Use of Ranolazine in pediatric patients.
# Contraindications
Ranexa is contraindicated in patients:
- Taking strong inhibitors of CYP3A.
- Taking inducers of CYP3A.
- With liver cirrhosis.
# Warnings
Ranolazine blocks IKr and prolongs the QTc interval in a dose-related manner.
Clinical experience in an acute coronary syndrome population did not show an increased risk of proarrhythmia or sudden death. However, there is little experience with high doses (> 1000 mg twice daily) or exposure, other QT-prolonging drugs, potassium channel variants resulting in a long QT interval, in patients with a family history of (or congenital) long QT syndrome, or in patients with known acquired QT interval prolongation.
Acute renal failure has been observed in some patients with severe renal impairment (creatinine clearance [CrCL] < 30 mL/min) while taking Ranexa. If acute renal failure develops (e.g., marked increase in serum creatinine associated with an increase in blood urea nitrogen [BUN]), discontinue Ranexa and treat appropriately.
Monitor renal function after initiation and periodically in patients with moderate to severe renal impairment (CrCL < 60 mL/min) for increases in serum creatinine accompanied by an increase in BUN.
# Adverse Reactions
## Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
A total of 2,018 patients with chronic angina were treated with ranolazine in controlled clinical trials. Of the patients treated with Ranexa, 1,026 were enrolled in three double-blind, placebo-controlled, randomized studies (CARISA, ERICA, MARISA) of up to 12 weeks' duration. In addition, upon study completion, 1,251 patients received treatment with Ranexa in open-label, long-term studies; 1,227 patients were exposed to Ranexa for more than 1 year, 613 patients for more than 2 years, 531 patients for more than 3 years, and 326 patients for more than 4 years.
At recommended doses, about 6% of patients discontinued treatment with Ranexa because of an adverse event in controlled studies in angina patients compared to about 3% on placebo. The most common adverse events that led to discontinuation more frequently on Ranexa than placebo were dizziness (1.3% versus 0.1%), nausea (1% versus 0%), asthenia, constipation, and headache (each about 0.5% versus 0%). Doses above 1000 mg twice daily are poorly tolerated.
In controlled clinical trials of angina patients, the most frequently reported treatment-emergent adverse reactions (> 4% and more common on Ranexa than on placebo) were dizziness(6.2%), headache (5.5%), constipation(4.5%), and nausea (4.4%). Dizziness may be dose-related. In open-label, long-term treatment studies, a similar adverse reaction profile was observed.
The following additional adverse reactions occurred at an incidence of 0.5 to 4.0% in patients treated with Ranexa and were more frequent than the incidence observed in placebo-treated patients:
- Cardiac Disorders – bradycardia, palpitations
- Ear and Labyrinth Disorders – tinnitus, vertigo
- Eye Disorders – blurred vision
- Gastrointestinal Disorders – abdominal pain, dry mouth, vomiting, dyspepsia
- General Disorders and Administrative Site Adverse Events – asthenia, peripheral edema
- Metabolism and Nutrition Disorders – anorexia
- Nervous System Disorders – syncope (vasovagal)
- Psychiatric Disorders – confusional state
- Renal and Urinary Disorders – hematuria
- Respiratory, Thoracic, and Mediastinal Disorders – dyspnea
- Skin and Subcutaneous Tissue Disorders – hyperhidrosis
- Vascular Disorders – hypotension, orthostatic hypotension
- Other (< 0.5%) but potentially medically important adverse reactions observed more frequently with Ranexa than placebo treatment in all controlled studies included: angioedema, renal failure, eosinophilia, chromaturia, blood urea increased, hypoesthesia, paresthesia, tremor, pulmonary fibrosis, thrombocytopenia, leukopenia, and pancytopenia.
A large clinical trial in acute coronary syndrome patients was unsuccessful in demonstrating a benefit for Ranexa, but there was no apparent proarrhythmic effect in these high-risk patients.
Ranexa produces small reductions in hemoglobin A1c. Ranexa is not a treatment for diabetes.
Ranexa produces elevations of serum creatinine by 0.1 mg/dL, regardless of previous renal function, likely because of inhibition of creatinine's tubular secretion. In general, the elevation has a rapid onset, shows no signs of progression during long-term therapy, is reversible after discontinuation of Ranexa, and is not accompanied by changes in BUN. In healthy volunteers, Ranexa 1000 mg twice daily had no effect upon the glomerular filtration rate. More marked and progressive increases in serum creatinine, associated with increases in BUN or potassium, indicating acute renal failure, have been reported after initiation of Ranexa in patients with severe renal impairment.
## Postmarketing Experience
The following adverse reactions have been identified during postapproval use of Ranexa. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure:
- Nervous System Disorders : Tremor, paresthesia, abnormal coordination, and other serious neurologic adverse events have been reported to occur, sometimes concurrently, in patients taking ranolazine. The onset of events was often associated with an increase in ranolazine dose or exposure. Many patients reported symptom resolution following drug discontinuation or dose decrease.
- Psychiatric Disorders – hallucination
- Renal and Urinary Disorders – dysuria, urinary retention
- Skin and Subcutaneous Tissue Disorders – angioedema, pruritus, rash
# Drug Interactions
- Strong CYP3A Inhibitors
- Do not use Ranexa with strong CYP3A inhibitors, including ketoconazole, itraconazole, clarithromycin, nefazodone, nelfinavir, ritonavir, indinavir, and saquinavir.
- Moderate CYP3A Inhibitors
- Limit the dose of Ranexa to 500 mg twice daily in patients on moderate CYP3A inhibitors, including diltiazem, verapamil, erythromycin, fluconazole, and grapefruit juice or grapefruit-containing products.
- P-gp Inhibitors
- Concomitant use of Ranexa and P-gp inhibitors, such as cyclosporine, may result in increases in ranolazine concentrations. Titrate Ranexa based on clinical response in patients concomitantly treated with predominant P-gp inhibitors such as cyclosporine.
- CYP3A Inducers
- Do not use Ranexa with CYP3A inducers such as rifampin, rifabutin, rifapentine, phenobarbital, phenytoin, carbamazepine, and St. John's wort.
- Drugs Metabolized by CYP3A
- Limit the dose of simvastatin in patients on any dose of Ranexa to 20 mg once daily, when ranolazine is co-administered. Dose adjustment of other sensitive CYP3A substrates (e.g., lovastatin) and CYP3A substrates with a narrow therapeutic range (e.g., cyclosporine, tacrolimus, sirolimus ) may be required as Ranexa may increase plasma concentrations of these drugs.
- Drugs Transported by P-gp
- Concomitant use of ranolazine and digoxin results in increased exposure to digoxin. The dose of digoxin may have to be adjusted.
- Drugs Metabolized by CYP2D6
- The exposure to CYP2D6 substrates, such as tricyclic antidepressants and antipsychotics, may be increased during co-administration with Ranexa, and lower doses of these drugs may be required.
- Drugs Transported by OCT2
- In subjects with type 2 diabetes mellitus, concomitant use of Ranexa 1000 mg twice daily and metformin results in increased plasma levels of metformin. When Ranexa 1000 mg twice daily is co-administered with metformin, metformin dose should not exceed 1700 mg/day. Monitor blood glucose levels and risks associated with high exposures of metformin. Metformin exposure was not significantly increased when given with Ranexa 500 mg twice daily.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
In animal studies, ranolazine at exposures 1.5 (rabbit) to 2 (rat) times the usual human exposure caused maternal toxicity and misshapen sternebrae and reduced ossification in offspring. These doses in rats and rabbits were associated with an increased maternal mortality rate. There are no adequate well-controlled studies in pregnant women. Ranexa should be used during pregnancy only when the potential benefit to the patient justifies the potential risk to the fetus.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ranolazine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Ranolazine during labor and delivery.
### Nursing Mothers
It is not known whether ranolazine is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from ranolazine in nursing infants, decide whether to discontinue nursing or to discontinue Ranexa, taking into account the importance of the drug to the mother.
### Pediatric Use
Safety and effectiveness have not been established in pediatric patients.
### Geriatic Use
Of the chronic angina patients treated with Ranexa in controlled studies, 496 (48%) were ≥ 65 years of age, and 114 (11%) were ≥ 75 years of age. No overall differences in efficacy were observed between older and younger patients. There were no differences in safety for patients ≥ 65 years compared to younger patients, but patients ≥ 75 years of age on Ranexa, compared to placebo, had a higher incidence of adverse events, serious adverse events, and drug discontinuations due to adverse events. In general, dose selection for an elderly patient should usually start at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease, or other drug therapy.
### Gender
There is no FDA guidance on the use of Ranolazine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Ranolazine with respect to specific racial populations.
### Renal Impairment
A pharmacokinetic study of Ranexa in subjects with severe renal impairment (CrCL < 30 mL/min) was stopped when 2 of 4 subjects developed acute renal failure after receiving Ranexa 500 mg twice daily for 5 days (lead-in phase) followed by 1000 mg twice a day (1 dose in one subject and 11 doses in the other). Increases in creatinine, BUN, and potassium were observed in 3 subjects during the 500 mg lead-in phase. One subject required hemodialysis, while the other 2 subjects improved upon drug discontinuation. Monitor renal function periodically in patients with moderate to severe renal impairment. Discontinue Ranexa if acute renal failure develops.
In a separate study, Cmax was increased between 40% and 50% in patients with mild, moderate or severe renal impairment compared to patients with no renal impairment, suggesting a similar increase in exposure in patients with renal failure independent of the degree of impairment. The pharmacokinetics of ranolazine has not been assessed in patients on dialysis.
### Hepatic Impairment
Ranexa is contraindicated in patients with liver cirrhosis. In a study of cirrhotic patients, the Cmax of ranolazine was increased 30% in cirrhotic patients with mild (Child-Pugh Class A) hepatic impairment, but increased 80% in cirrhotic patients with moderate (Child-Pugh Class B) hepatic impairment compared to patients without hepatic impairment. This increase was not enough to account for the 3-fold increase in QT prolongation seen in cirrhotic patients with mild to moderate hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Ranolazine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Ranolazine in patients who are immunocompromised.
### Use in Patients with Heart Failure
Heart failure (NYHA Class I to IV) had no significant effect on ranolazine pharmacokinetics. Ranexa had minimal effects on heart rate and blood pressure in patients with angina and heart failure NYHA Class I to IV. No dose adjustment of Ranexa is required in patients with heart failure.
A population pharmacokinetic evaluation of data from angina patients and healthy subjects showed no effect of diabetes on ranolazine pharmacokinetics. No dose adjustment is required in patients with diabetes.
Ranexa produces small reductions in HbA1c in patients with diabetes, the clinical significance of which is unknown. Ranexa should not be considered a treatment for diabetes.
# Administration and Monitoring
### Administration
Initiate Ranexa dosing at 500 mg twice daily and increase to 1000 mg twice daily, as needed, based on clinical symptoms. Take Ranexa with or without meals. Swallow Ranexa tablets whole; do not crush, break, or chew.
The maximum recommended daily dose of Ranexa is 1000 mg twice daily.
If a dose of Ranexa is missed, take the prescribed dose at the next scheduled time; do not double the next dose.
Dose adjustments may be needed when Ranexa is taken in combination with certain other drugs. Limit the maximum dose of Ranexa to 500 mg twice daily in patients on moderate CYP3A inhibitors such as diltiazem, verapamil, and erythromycin. Use of Ranexa with strong CYP3A inhibitors is contraindicated. Use of P-gp inhibitors, such as cyclosporine, may increase exposure to Ranexa. Titrate Ranexa based on clinical response.
### Monitoring
- Monitor renal function after initiation and periodically in patients with moderate to severe renal impairment (CrCL < 60 mL/min) for increases in serum creatinine accompanied by an increase in BUN.
- Monitor blood glucose levels and risks associated with high exposures of metformin.
- Monitor renal function periodically in patients with moderate to severe renal impairment.
- In addition to general supportive measures, continuous ECG monitoring may be warranted in the event of overdose.
# IV Compatibility
FDA Package Insert for Ranolazine contains no information regarding IV Compatibility.
# Overdosage
High oral doses of ranolazine produce dose-related increases in dizziness, nausea, and vomiting. High intravenous exposure also produces diplopia, paresthesia, confusion, and syncope. In addition to general supportive measures, continuous ECG monitoring may be warranted in the event of overdose. Severe tremor, unsteady gait/incoordination, dysphasia, and hallucinations have been reported in cases of overdose with Ranexa.
Since ranolazine is about 62% bound to plasma proteins, hemodialysis is unlikely to be effective in clearing ranolazine.
# Pharmacology
## Mechanism of Action
The mechanism of action of ranolazine's antianginal effects has not been determined. Ranolazine has anti-ischemic and antianginal effects that do not depend upon reductions in heart rate or blood pressure. It does not affect the rate-pressure product, a measure of myocardial work, at maximal exercise. Ranolazine at therapeutic levels can inhibit the cardiac late sodium current (INa). However, the relationship of this inhibition to angina symptoms is uncertain.
The QT prolongation effect of ranolazine on the surface electrocardiogram is the result of inhibition of IKr, which prolongs the ventricular action potential.
## Structure
Ranexa (ranolazine) is available as a film-coated, non-scored, extended-release tablet for oral administration.
Ranolazine is a racemic mixture, chemically described as 1-piperazineacetamide, N-(2,6-dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-, (±)-. It has an empirical formula of C24H33N3O4, a molecular weight of 427.54 g/mole, and the following structural formula:
Ranolazine is a white to off-white solid. Ranolazine is soluble in dichloromethane and methanol; sparingly soluble in tetrahydrofuran, ethanol, acetonitrile, and acetone; slightly soluble in ethyl acetate, isopropanol, toluene, and ethyl ether; and very slightly soluble in water.
Ranexa tablets contain 500 mg or 1000 mg of ranolazine and the following inactive ingredients: carnauba wax, hypromellose, magnesium stearate, methacrylic acid copolymer (Type C), microcrystalline cellulose, polyethylene glycol, sodium hydroxide, and titanium dioxide. Additional inactive ingredients for the 500 mg tablet include polyvinyl alcohol, talc, Iron Oxide Yellow, and Iron Oxide Red; additional inactive ingredients for the 1000 mg tablet include lactose monohydrate, triacetin, and Iron Oxide Yellow.
## Pharmacodynamics
Patients with chronic angina treated with Ranexa in controlled clinical studies had minimal changes in mean heart rate (< 2 bpm) and systolic blood pressure (< 3 mm Hg). Similar results were observed in subgroups of patients with CHF NYHA Class I or II, diabetes, or reactive airway disease, and in elderly patients.
Dose and plasma concentration-related increases in the QTc interval, reductions in T wave amplitude, and, in some cases, notched T waves, have been observed in patients treated with Ranexa. These effects are believed to be caused by ranolazine and not by its metabolites. The relationship between the change in QTc and ranolazine plasma concentrations is linear, with a slope of about 2.6 msec/1000 ng/mL, through exposures corresponding to doses several-fold higher than the maximum recommended dose of 1000 mg twice daily. The variable blood levels attained after a given dose of ranolazine give a wide range of effects on QTc. At Tmax following repeat dosing at 1000 mg twice daily, the mean change in QTc is about 6 msec, but in the 5% of the population with the highest plasma concentrations, the prolongation of QTc is at least 15 msec. In cirrhotic subjects with mild or moderate hepatic impairment, the relationship between plasma level of ranolazine and QTc is much steeper.
Age, weight, gender, race, heart rate, congestive heart failure, diabetes, and renal impairment did not alter the slope of the QTc-concentration relationship of ranolazine.
No proarrhythmic effects were observed on 7-day Holter recordings in 3,162 acute coronary syndrome patients treated with Ranexa. There was a significantly lower incidence of arrhythmias (ventricular tachycardia, bradycardia, supraventricular tachycardia, and new atrial fibrillation) in patients treated with Ranexa (80%) versus placebo (87%), including ventricular tachycardia ≥ 3 beats (52% versus 61%). However, this difference in arrhythmias did not lead to a reduction in mortality, a reduction in arrhythmia hospitalization, or a reduction in arrhythmia symptoms.
## Pharmacokinetics
Ranolazine is extensively metabolized in the gut and liver and its absorption is highly variable. For example, at a dose of 1000 mg twice daily, the mean steady-state Cmax was 2600 ng/mL with 95% confidence limits of 400 and 6100 ng/mL. The pharmacokinetics of the (+) R- and (-) S-enantiomers of ranolazine are similar in healthy volunteers. The apparent terminal half-life of ranolazine is 7 hours. Steady state is generally achieved within 3 days of twice-daily dosing with Ranexa. At steady state over the dose range of 500 to 1000 mg twice daily, Cmax and AUC0–τ increase slightly more than proportionally to dose, 2.2- and 2.4-fold, respectively. With twice-daily dosing, the trough:peak ratio of the ranolazine plasma concentration is 0.3 to 0.6. The pharmacokinetics of ranolazine is unaffected by age, gender, or food.
After oral administration of Ranexa, peak plasma concentrations of ranolazine are reached between 2 and 5 hours. After oral administration of 14C-ranolazine as a solution, 73% of the dose is systemically available as ranolazine or metabolites. The bioavailability of ranolazine from Ranexa tablets relative to that from a solution of ranolazine is 76%. Because ranolazine is a substrate of P-gp, inhibitors of P-gp may increase the absorption of ranolazine.
Food (high-fat breakfast) has no important effect on the Cmax and AUC of ranolazine. Therefore, Ranexa may be taken without regard to meals. Over the concentration range of 0.25 to 10 µg/mL, ranolazine is approximately 62% bound to human plasma proteins.
Ranolazine is metabolized mainly by CYP3A and, to a lesser extent, by CYP2D6. Following a single oral dose of ranolazine solution, approximately 75% of the dose is excreted in urine and 25% in feces. Ranolazine is metabolized rapidly and extensively in the liver and intestine; less than 5% is excreted unchanged in urine and feces. The pharmacologic activity of the metabolites has not been well characterized. After dosing to steady state with 500 mg to 1500 mg twice daily, the four most abundant metabolites in plasma have AUC values ranging from about 5 to 33% that of ranolazine, and display apparent half-lives ranging from 6 to 22 hours.
## Nonclinical Toxicology
Ranolazine tested negative for genotoxic potential in the following assays: Ames bacterial mutation assay, Saccharomyces assay for mitotic gene conversion, chromosomal aberrations assay in Chinese hamster ovary (CHO) cells, mammalian CHO/HGPRT gene mutation assay, and mouse and rat bone marrow micronucleus assays.
There was no evidence of carcinogenic potential in mice or rats. The highest oral doses used in the carcinogenicity studies were 150 mg/kg/day for 21 months in rats (900 mg/m2/day) and 50 mg/kg/day for 24 months in mice (150 mg/m2/day). These maximally tolerated doses are 0.8 and 0.1 times, respectively, the maximum recommended human dose (MRHD) of 2 grams on a surface area basis. A published study reported that ranolazine promoted tumor formation and progression to malignancy when given to transgenic APC (min/+) mice at a dose of 30 mg/kg twice daily. The clinical significance of this finding is unclear.
Animal reproduction studies with ranolazine were conducted in rats and rabbits.
There was an increased incidence of misshapen sternebrae and reduced ossification of pelvic and cranial bones in fetuses of pregnant rats dosed at 400 mg/kg/day (2 times the MRHD on a surface area basis). Reduced ossification of sternebrae was observed in fetuses of pregnant rabbits dosed at 150 mg/kg/day (1.5 times the MRHD on a surface area basis). These doses in rats and rabbits were associated with an increased maternal mortality rate.
# Clinical Studies
CARISA (Combination Assessment of Ranolazine In Stable Angina) was a study in 823 chronic angina patients randomized to receive 12 weeks of treatment with twice-daily Ranexa 750 mg, 1000 mg, or placebo, who also continued on daily doses of atenolol 50 mg, amlodipine 5 mg, or diltiazem CD 180 mg. Sublingual nitrates were used in this study as needed.
In this trial, statistically significant (p < 0.05) increases in modified Bruce treadmill exercise duration and time to angina were observed for each Ranexa dose versus placebo, at both trough (12 hours after dosing) and peak (4 hours after dosing) plasma levels, with minimal effects on blood pressure and heart rate. The changes versus placebo in exercise parameters are presented in Table 1. Exercise treadmill results showed no increase in effect on exercise at the 1000 mg dose compared to the 750 mg dose.
The effects of Ranexa on angina frequency and nitroglycerin use are shown in Table 2.
Tolerance to Ranexa did not develop after 12 weeks of therapy. Rebound increases in angina, as measured by exercise duration, have not been observed following abrupt discontinuation of Ranexa.
Ranexa has been evaluated in patients with chronic angina who remained symptomatic despite treatment with the maximum dose of an antianginal agent. In the ERICA (Efficacy of Ranolazine In Chronic Angina) trial, 565 patients were randomized to receive an initial dose of Ranexa 500 mg twice daily or placebo for 1 week, followed by 6 weeks of treatment with Ranexa 1000 mg twice daily or placebo, in addition to concomitant treatment with amlodipine 10 mg once daily. In addition, 45% of the study population also received long-acting nitrates. Sublingual nitrates were used as needed to treat angina episodes. Results are shown in Table 3. Statistically significant decreases in angina attack frequency (p = 0.028) and nitroglycerin use (p = 0.014) were observed with Ranexa compared to placebo. These treatment effects appeared consistent across age and use of long-acting nitrates.
Effects on angina frequency and exercise tolerance were considerably smaller in women than in men. In CARISA, the improvement in Exercise Tolerance Test (ETT) in females was about 33% of that in males at the 1000 mg twice-daily dose level. In ERICA, where the primary endpoint was angina attack frequency, the mean reduction in weekly angina attacks was 0.3 for females and 1.3 for males.
There were insufficient numbers of non-Caucasian patients to allow for analyses of efficacy or safety by racial subgroup.
14.2 Lack of Benefit in Acute Coronary Syndrome
In a large (n = 6,560) placebo-controlled trial (MERLIN-TIMI 36) in patients with acute coronary syndrome, there was no benefit shown on outcome measures. However, the study is somewhat reassuring regarding proarrhythmic risks, as ventricular arrhythmias were less common on ranolazine and there was no difference between Ranexa and placebo in the risk of all-cause mortality (relative risk ranolazine:placebo 0.99 with an upper 95% confidence limit of 1.22).
# How Supplied
Ranexa is supplied as film-coated, oblong-shaped, extended-release tablets in the following strengths:
- 500 mg tablets are light orange, with GSI500 on one side
- 1000 mg tablets are pale yellow, with GSI1000 on one side
Ranexa (ranolazine) extended-release tablets are available in:
## Storage
Store Ranexa tablets at 25°C (77°F) with excursions permitted to 15° to 30°C (59° to 86°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
To ensure safe and effective use of Ranexa, the following information and instructions should be communicated to the patient when appropriate.
Patients should be advised:
- that Ranexa will not abate an acute angina episode
- to inform their physician of any other medications when taken concurrently with Ranexa, including over-the-counter medications
- that Ranexa may produce changes in the electrocardiogram (QTc interval prolongation)
- to inform their physician of any personal or family history of QTc prolongation, congenital long QT syndrome, or if they are receiving drugs that prolong the QTc interval such as Class Ia (e.g., quinidine) or Class III (e.g., dofetilide, sotalol, amiodarone) antiarrhythmic agents, erythromycin, and certain antipsychotics (e.g., thioridazine, ziprasidone)
- to inform their physician if they have impaired renal function before or while taking Ranexa
- that patients with severe renal impairment may be at risk of renal failure while on Ranexa
- that Ranexa should not be used in patients who are receiving drugs that are strong CYP3A inhibitors (e.g., ketoconazole, clarithromycin, nefazodone, ritonavir)
- that initiation of treatment with Ranexa should be avoided during administration of inducers of CYP3A (e.g., rifampin, rifabutin, rifapentine, barbiturates, carbamazepine, phenytoin, St. John's wort)
- to inform their physician if they are receiving drugs that are moderate CYP3A inhibitors (e.g., diltiazem, verapamil, erythromycin)
- to inform their physician if they are receiving P-gp inhibitors (e.g., cyclosporine)
- that grapefruit juice or grapefruit products should be limited when taking Ranexa
- that Ranexa should not be used in patients with liver cirrhosis
- that doses of Ranexa higher than 1000 mg twice daily should not be used
- that if a dose is missed, the usual dose should be taken at the next scheduled time. The next dose should not be doubled
- that Ranexa may be taken with or without meals
- that Ranexa tablets should be swallowed whole and not crushed, broken, or chewed
- to contact their physician if they experience fainting spells while taking Ranexa
- that Ranexa may cause dizziness and lightheadedness; therefore, patients should know how they react to this drug before they operate an automobile, or machinery, or engage in activities requiring mental alertness or coordination
# Precautions with Alcohol
Alcohol-Ranolazine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
Ranexa
# Look-Alike Drug Names
There is limited information about the Look-Alike Drug Names.
# Drug Shortage Status
# Price
# Price | https://www.wikidoc.org/index.php/Ranexa | |
889f12ec8d9caf701610c793b920660728e12ef7 | wikidoc | Ropinirole | Ropinirole
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# Overview
Ropinirole is a dopamine agonist that is FDA approved for the {{{indicationType}}} of parkinson’s disease (PD) and primary restless legs syndrome (RLS). Common adverse reactions include nausea, somnolence, dizziness, syncope, asthenic condition, viral infection, leg edema, vomiting, and dyspepsia.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- The recommended starting dose for Parkinson’s disease is 0.25 mg three times daily. Based on individual patient therapeutic response and tolerability, if necessary, the dose should then be titrated with weekly increments as described in Table 1. After Week 4, if necessary, the daily dose may be increased by 1.5 mg/day on a weekly basis up to a dose of 9 mg/day, and then by up to 3 mg/day weekly up to a maximum recommended total daily dose of 24 mg/day (8 mg three times daily). Doses greater than 24 mg/day have not been tested in clinical trials.
- REQUIP should be discontinued gradually over a 7-day period in patients with Parkinson’s disease. The frequency of administration should be reduced from three times daily to twice daily for 4 days. For the remaining 3 days, the frequency should be reduced to once daily prior to complete withdrawal of REQUIP.
- Renal Impairment
- No dose adjustment is necessary in patients with moderate renal impairment (creatinine clearance of 30 to 50 mL/min). The recommended initial dose of ropinirole for patients with end-stage renal disease on hemodialysis is 0.25 mg three times a day. Further dose escalations should be based on tolerability and need for efficacy. The recommended maximum total daily dose is 18 mg/day in patients receiving regular dialysis. Supplemental doses after dialysis are not required. The use of REQUIP in patients with severe renal impairment without regular dialysis has not been studied.
- Dosing Information
- The recommended adult starting dose for RLS is 0.25 mg once daily 1 to 3 hours before bedtime. After 2 days, if necessary, the dose can be increased to 0.5 mg once daily, and to 1 mg once daily at the end of the first week of dosing, then as shown in Table 2 as needed to achieve efficacy. Titration should be based on individual patient therapeutic response and tolerability, up to a maximum recommended dose of 4 mg daily. For RLS, the safety and effectiveness of doses greater than 4 mg once daily have not been established.
- In clinical trials of patients treated for RLS with doses up to 4 mg once daily, REQUIP was discontinued without a taper.
- Renal Impairment
- No dose adjustment is necessary in patients with moderate renal impairment (creatinine clearance of 30 to 50 mL/min). The recommended initial dose of ropinirole for patients with end-stage renal disease on hemodialysis is 0.25 mg once daily. Further dose escalations should be based on tolerability and need for efficacy. The recommended maximum total daily dose is 3 mg/day in patients receiving regular dialysis. Supplemental doses after dialysis are not required. The use of REQUIP in patients with severe renal impairment without regular dialysis has not been studied.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ropinirole in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ropinirole in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Ropinirole in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ropinirole in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ropinirole in pediatric patients.
# Contraindications
- REQUIP is contraindicated in patients known to have a hypersensitivity/allergic reaction (including urticaria, angioedema, rash, pruritus) to ropinirole or to any of the excipients.
# Warnings
### Precautions
- Falling Asleep during Activities of Daily Living and Somnolence
- Patients treated with REQUIP have reported falling asleep while engaged in activities of daily living, including driving or operating machinery, which sometimes resulted in accidents. Although many of these patients reported somnolence while on REQUIP, some perceived that they had no warning signs, such as excessive drowsiness, and believed that they were alert immediately prior to the event. Some have reported these events more than 1 year after initiation of treatment.
- In controlled clinical trials, somnolence was commonly reported in patients receiving REQUIP and was more frequent in Parkinson's disease (up to 40% REQUIP, 6% placebo) than in Restless Legs Syndrome (12% REQUIP, 6% placebo).
- It has been reported that falling asleep while engaged in activities of daily living usually occurs in a setting of preexisting somnolence, although patients may not give such a history. For this reason, prescribers should reassess patients for drowsiness or sleepiness, especially since some of the events occur well after the start of treatment. Prescribers should also be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities.
- Before initiating treatment with REQUIP, patients should be advised of the potential to develop drowsiness and specifically asked about factors that may increase the risk with REQUIP such as concomitant sedating medications, the presence of sleep disorders (other than RLS), and concomitant medications that increase ropinirole plasma levels (e.g., ciprofloxacin). If a patient develops significant daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., driving a motor vehicle, conversations, eating), REQUIP should ordinarily be discontinued. If a decision is made to continue REQUIP, patients should be advised to not drive and to avoid other potentially dangerous activities. There is insufficient information to establish that dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living.
- Syncope
- Syncope, sometimes associated with bradycardia, was observed in association with ropinirole in both patients with Parkinson’s disease and patients with RLS. In controlled clinical trials in patients with Parkinson’s disease, syncope was observed more frequently in patients receiving REQUIP than in patients receiving placebo (early Parkinson’s disease without L-dopa: REQUIP 12%, placebo 1%; advanced Parkinson’s disease: REQUIP 3%, placebo 2%). Syncope was reported in 1% of patients treated with REQUIP for RLS in 12-week, placebo-controlled clinical trials compared with 0.2% of patients treated with placebo. Most cases occurred more than 4 weeks after initiation of therapy with REQUIP, and were usually associated with a recent increase in dose.
- Because the trials of REQUIP excluded patients with significant cardiovascular disease, patients with significant cardiovascular disease should be treated with caution.
- Approximately 4% of patients with Parkinson’s disease enrolled in Phase 1 trials had syncope following a 1-mg dose of REQUIP. In two trials in patients with RLS that used a forced-titration regimen and orthostatic challenge with intensive blood pressure monitoring, 2% of RLS patients treated with REQUIP compared with 0% of patients receiving placebo reported syncope.
- In Phase 1 trials including healthy volunteers, the incidence of syncope was 2%. Of note, 1 subject with syncope developed hypotension, bradycardia, and sinus arrest; the subject recovered spontaneously without intervention.
- Hypotension/Orthostatic Hypotension
- Dopamine agonists in clinical trials and clinical experience appear to impair the systemic regulation of blood pressure, with resulting orthostatic hypotension, especially during dose escalation. In addition, patients with Parkinson’s disease appear to have an impaired capacity to respond to a postural challenge. For these reasons, patients should be monitored for signs and symptoms of orthostatic hypotension, especially during dose escalation, and patients should be informed of the risk for syncope and hypotension.
- Although the clinical trials were not designed to systematically monitor blood pressure, there were individual reported cases of orthostatic hypotension in early Parkinson’s disease (without L-dopa) in patients treated with REQUIP. Most of these cases occurred more than 4 weeks after initiation of therapy with REQUIP and were usually associated with a recent increase in dose.
- In 12-week, placebo-controlled trials of patients with RLS, the adverse event orthostatic hypotension was reported by 4 of 496 patients (0.8%) treated with REQUIP compared with 2 of 500 patients (0.4%) receiving placebo.
- In two Phase 2 studies in patients with RLS, 14 of 55 patients (25%) receiving REQUIP experienced an adverse event of hypotension or orthostatic hypotension compared with none of the 27 patients receiving placebo. In these studies, 11 of the 55 patients (20%) receiving REQUIP and 3 of the 26 patients (12%) who had post-dose blood pressure assessments following placebo, experienced an orthostatic blood pressure decrease of at least 40 mm Hg systolic and/or at least 20 mm Hg diastolic.
- In Phase 1 trials of REQUIP with healthy volunteers who received single doses on morethan one occasion without titration, 7% had documented symptomatic orthostatic hypotension. These episodes appeared mainly at doses above 0.8 mg and these doses are higher than the starting doses recommended for patients with either Parkinson’s disease or with RLS. In most of these individuals, the hypotension was accompanied by bradycardia but did not develop into syncope.
- Although dizziness is not a specific manifestation of hypotension or orthostatic hypotension, patients with hypotension or orthostatic hypotension frequently reported dizziness. In controlled clinical trials, dizziness was a common adverse reaction in patients receiving REQUIP and was more frequent in patients with Parkinson’s disease or with RLS receiving REQUIP than in patients receiving placebo (early Parkinson’s disease without L-dopa: REQUIP 40%, placebo 22%; advanced Parkinson’s disease: REQUIP 26%, placebo 16%; RLS: REQUIP 11%, placebo 5%). Dizziness of sufficient severity to cause trial discontinuation of REQUIP was 4% in patients with early Parkinson’s disease without L-dopa, 3% in patients with advanced Parkinson’s disease, and 1% in patients with RLS.
- Hallucinations/Psychotic-like Behavior
- In double-blind, placebo-controlled, early-therapy trials in patients with Parkinson’s disease who were not treated with L-dopa, 5.2% (8 of 157) of patients treated with REQUIP reported hallucinations, compared with 1.4% of patients on placebo (2 of 147). Among those patients receiving both REQUIP and L-dopa in advanced Parkinson’s disease studies, 10.1% (21 of 208) were reported to experience hallucinations, compared with 4.2% (5 of 120) of patients treated with placebo and L-dopa.
- The incidence of hallucination was increased in elderly patients (i.e., older than 65 years) treated with extended-release REQUIP.
- Postmarketing reports indicate that patients may experience new or worsening mental status and behavioral changes, which may be severe, including psychotic-like behavior during treatment with REQUIP or after starting or increasing the dose of REQUIP. Other drugs prescribed to improve the symptoms of Parkinson’s disease can have similar effects on thinking and behavior. This abnormal thinking and behavior can consist of one or more of a variety of manifestations including paranoid ideation, delusions, hallucinations, confusion, psychotic-like behavior, disorientation, aggressive behavior, agitation, and delirium.
- Patients with a major psychotic disorder should ordinarily not be treated with REQUIP because of the risk of exacerbating the psychosis. In addition, certain medications used to treat psychosis may exacerbate the symptoms of Parkinson’s disease and may decrease the effectiveness of REQUIP.
- Dyskinesia
- REQUIP may potentiate the dopaminergic side effects of L-dopa and may cause and/or exacerbate pre-existing dyskinesia in patients treated with L-dopa for Parkinson’s disease. In double-blind, placebo-controlled trials in advanced Parkinson’s disease, dyskinesia was much more common in patients treated with REQUIP than in those treated with placebo. Among those patients receiving both REQUIP and L-dopa in advanced Parkinson’s disease trials, 34% were reported to experience dyskinesia, compared with 13% of patients treated with placebo. Decreasing the dose of the dopaminergic drug may ameliorate this adverse reaction.
- Impulse Control/Compulsive Behaviors
- Case reports suggest that patients can experience intense urges to gamble, increased sexual urges, intense urges to spendmoney, binge or compulsive eating, and/or other intense urges, and the inability to control these urges while taking one or more of the medications, including REQUIP, that increase central dopaminergic tone and that are generally used for the treatment of Parkinson’s disease and RLS. In some cases, although not all, these urges were reported to have stopped when the dose was reduced or the medication was discontinued. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending, binge or compulsive eating, or other urges while being treated with REQUIP. Physiciansshould consider dose reduction or stopping the medication if a patient develops such urges while taking REQUIP.
- Withdrawal-emergent Hyperpyrexia and Confusion
- A symptom complex resembling the neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in dopaminergic therapy. Therefore, it is recommended that the dose be tapered at the end of treatment with REQUIP for Parkinson’s disease as a prophylactic measure.
- Melanoma
- Epidemiological studies have shown that patients with Parkinson’s disease have a higher risk (2- to approximately 6-fold higher) of developing melanoma than the general population. Whether the increased risk observed was due to Parkinson’s disease or other factors, such as drugs used to treat Parkinson’s disease, is unclear.
- For the reasons stated above, patients and providers are advised to monitor for melanomas frequently and on a regular basis when using REQUIP for any indication. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists).
- Augmentation and Early-morning Rebound in Restless Legs Syndrome
- Reports in the literature indicate treatment of RLS with dopaminergic medications can result in recurrence of symptoms in the early morning hours, referred to as rebound. Augmentation has also been described during therapy for RLS. Augmentation refers to the earlier onset of symptoms in the evening (or even the afternoon), increase in symptoms, and spread of symptoms to involve other extremities. Rebound refers to new onset of symptoms in the early morning hours. Augmentation and/or early-morning rebound have been observed in a postmarketing trial. If augmentation or early-morning rebound occurs, the use of REQUIP should be reviewed and dosage adjustment or discontinuation of treatment should be considered.
- Fibrotic Complications
- Cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, pleural thickening, pericarditis, and cardiac valvulopathy have been reported in some patients treated with ergot-derived dopaminergic agents. While these complications may resolve when the drug is discontinued, complete resolution does not always occur.
- Although these adverse reactions are believed to be related to the ergoline structure of these compounds, whether other, non-ergot‑derived dopamine agonists such as ropinirole can cause them is unknown.
- Cases of possible fibrotic complications, including pleural effusion, pleural fibrosis, interstitial lung disease, and cardiac valvulopathy have been reported in the development program and postmarketing experience for ropinirole. While the evidence is not sufficient to establish a causal relationship between ropinirole and these fibrotic complications, a contribution of ropinirole cannot be excluded.
- Retinal Pathology
- Retinal degeneration was observed in albino rats in the 2-year carcinogenicity study at all doses tested (equivalent to 0.6 to 20 times the maximum recommended human dose for Parkinson’s disease on a mg/m2 basis), but was statistically significant at the highest dose (50 mg/kg/day). Retinal degeneration was not observed in a 3-month study in pigmented rats, in a 2-year carcinogenicity study in albino mice, or in 1‑year studies in monkeys or albino rats. The significance of this effect for humans has not been established but involves disruption of a mechanism that is universally present in vertebrates (e.g., disk shedding).
- Ocular electroretinogram (ERG) assessments were conducted during a 2-year, double-blind, multicenter, flexible dose, L-dopa-controlled clinical trial of ropinirole in patients with Parkinson’s disease; 156 patients (78 on ropinirole, mean dose: 11.9 mg/day, and 78 on L-dopa, mean dose: 555.2 mg/day) were evaluated for evidence of retinal dysfunction through electroretinograms. There was no clinically meaningful difference between the treatment groups in retinal function over the duration of the trial.
- Binding to Melanin
- Ropinirole binds to melanin-containing tissues (i.e., eyes, skin) in pigmented rats. After a single dose, long-term retention of drug was demonstrated, with a half-life in the eye of 20 days
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug (or of another development program of a different formulation of the same drug) and may not reflect the rates observed in practice.
- Parkinson’s Disease
- During the premarketing development of REQUIP, patients received REQUIP either without L-dopa (early Parkinson’s disease trials) or as concomitant therapy with L-dopa (advanced Parkinson’s disease trials). Because these two populations may have differential risks for various adverse reactions, this section will in general present adverse reaction data for these two populations separately.
- Early Parkinson’s Disease (without L-dopa)
- In the double-blind, placebo-controlled trials in patients with early-stage Parkinson’s disease, the most commonly observed adverse reactions in patients treated with REQUIP (incidence at least 5% greater than placebo) were nausea, somnolence, dizziness, syncope, asthenic condition (i.e., asthenia, fatigue, and/or malaise), viral infection, leg edema, vomiting, and dyspepsia.
- Approximately 24% of patients treated with REQUIP who participated in the double-blind, placebo-controlled early Parkinson’s disease (without L-dopa) trials discontinued treatment due to adverse reactions compared with 13% of patients who received placebo. The most common adverse reactions in patients treated with REQUIP (incidence at least 2% greater than placebo) of sufficient severity to cause discontinuation were nausea and dizziness.
- Table 3 lists treatment-emergent adverse reactions that occurred in at least 2% of patients with early Parkinson’s disease (without L-dopa) treated with REQUIP participating in the double-blind, placebo-controlled trials and were numerically more common than the incidence for placebo-treated patients. In these trials, either REQUIP or placebo was used as early therapy (i.e., without L-dopa).
- aPatients may have reported multiple adverse reactions during the trial or at discontinuation; thus, patients may be included in more than one category.
- b Asthenic condition (i.e., asthenia, fatigue, and/or malaise).
- Advanced Parkinson’s Disease (with L-dopa)
- In the double-blind, placebo-controlled trials in patients with advanced-stage Parkinson’s disease, the most commonly observed adverse reactions in patients treated with REQUIP (incidence at least 5 % greater than placebo) were dyskinesia, somnolence, nausea, dizziness, confusion, hallucinations, increased sweating, and headache.
- Approximately 24% of patients who received REQUIP in the double-blind, placebo-controlled advanced Parkinson’s disease (with L-dopa) trials discontinued treatment due to adverse reactions compared with 18% of patients who received placebo. The most common adverse reaction in patients treated with REQUIP (incidence at least 2% greater than placebo) of sufficient severity to cause discontinuation was dizziness.
- Table 4 lists treatment-emergent adverse reactions that occurred in at least 2% of patients with advanced Parkinson’s disease (with L-dopa) treated with REQUIP who participated in the double-blind, placebo-controlled trials and were numerically more common than the incidence for placebo-treated patients. In these trials, either REQUIP or placebo was used as an adjunct to L-dopa.
- aPatients may have reported multiple adverse reactions during the trial or at discontinuation; thus, patients may be included in more than one category.
- Restless Legs Syndrome
- In the double-blind, placebo-controlledtrials in patients with RLS, the most commonly observed adverse reactions in patients treated with REQUIP (incidence at least 5% greater than placebo) were nausea, vomiting, somnolence, dizziness, and asthenic condition (i.e., asthenia, fatigue, and/or malaise).
- Approximately 5% of patients treated with REQUIP who participated in the double-blind, placebo-controlled trials in the treatment of RLS discontinued treatment due to adverse reactions compared with 4% of patients who received placebo. The most common adverse reaction in patients treated with REQUIP (incidence at least 2% greater than placebo) of sufficient severity to cause discontinuation was nausea.
- Table 5 lists treatment-emergent adverse reactions that occurred in at least 2% of patients with RLS treated with REQUIP participating in the 12-week, double-blind, placebo-controlled trials and were numerically more common than the incidence for placebo-treated patients.
- aPatients may have reported multiple adverse reactions during the trial or at discontinuation; thus, patients may be included in more than one category.
- b Asthenic condition (i.e., asthenia, fatigue, and/or malaise).
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Ropinirole in the drug label.
# Drug Interactions
- CYP1A2 Inhibitors and Inducers
- In vitro metabolism studies showed that CYP1A2 is the major enzyme responsible for the metabolism of ropinirole. There is thus the potential for inducers or inhibitors of this enzyme to alter the clearance of ropinirole. Therefore, if therapy with a drug known to be a potent inducer or inhibitor of CYP1A2 is stopped or started during treatment with REQUIP, adjustment of the dose of REQUIP may be required. Coadministration of ciprofloxacin, an inhibitor of CYP1A2, increases the AUC and Cmax of ropinirole. Cigarette smoking is expected to increase the clearance of ropinirole since CYP1A2 is known to be induced by smoking.
- Estrogens
- Population pharmacokinetic analysis revealed that higher doses of estrogens (usually associated with hormone replacement therapy ) reduced the clearance of ropinirole. Starting or stopping HRT may require adjustment of dosage of REQUIP.
- Dopamine Antagonists
- Because ropinirole is a dopamine agonist, it is possible that dopamine antagonists such as neuroleptics (e.g., phenothiazines, butyrophenones, thioxanthenes) or metoclopramide may reduce the efficacy of REQUIP.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- There are no adequate and well-controlled studies in pregnant women. In animal reproduction studies, ropinirole has been shown to have adverse effects on embryo-fetal development, including teratogenic effects. REQUIP should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus.
- Oral treatment of pregnant rats with ropinirole during organogenesis resulted in decreased fetal body weight, increased fetal death, and digital malformations at 24, 36, and 60 times, respectively, the maximum recommended human dose (MRHD) for Parkinson’s disease (24 mg/day) on a mg/m2 basis. The combined oral administration of ropinirole at 8 times the MRHD and a clinically relevant dose of L‑dopa to pregnant rabbits during organogenesis produced a greater incidence and severity of fetal malformations (primarily digit defects) than were seen in the offspring of rabbits treated with L-dopa alone. No effect on fetal development was observed in rabbits when ropinirole was administered alone at an oral dose 16 times the MRHD on a mg/m2 basis. In a perinatal-postnatal study in rats, impaired growth and development of nursing offspring and altered neurological development of female offspring were observed when dams were treated with 4 times the MRHD on a mg/m2 basis.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ropinirole in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Ropinirole during labor and delivery.
### Nursing Mothers
- Ropinirole inhibits prolactin secretion in humans and could potentially inhibit lactation. Ropinirole has been detected in rat milk. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when REQUIP is administered to a nursing woman.
### Pediatric Use
- Safety and effectiveness in pediatric patients have not been established.
### Geriatic Use
- Dose adjustment is not necessary in elderly (65 years and older) patients, as the dose of REQUIP is individually titrated to clinical therapeutic response and tolerability. Pharmacokinetic trials conducted in patients demonstrated that oral clearance of ropinirole is reduced by 15% in patients older than 65 years compared with younger patients.
- In clinical trials of extended-release ropinirole for Parkinson’s disease, 387 patients were 65 years and older and 107 patients were 75 years and older. Among patients receiving extended-release ropinirole, hallucination was more common in elderly patients (10%) compared with non-elderly patients (2%). The incidence of overall adverse reactions increased with increasing age for both patients receiving extended-release ropinirole and placebo.
### Gender
There is no FDA guidance on the use of Ropinirole with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Ropinirole with respect to specific racial populations.
### Renal Impairment
- No dose adjustment is necessary in patients with moderate renal impairment (creatinine clearance of 30 to 50 mL/min). For patients with end-stage renal disease on hemodialysis, a reduced maximum dose is recommended.
- The use of REQUIP in patients with severe renal impairment (creatinine clearance less than 30 mL/min) without regular dialysis has not been studied.
### Hepatic Impairment
- The pharmacokinetics of ropinirole have not been studied in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Ropinirole in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Ropinirole in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Ropinirole in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Ropinirole in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- The symptoms of overdose with REQUIP are generally related to its dopaminergic activity.
- In the Parkinson’s disease program, there have been patients who accidentally or intentionally took more than their prescribed dose of ropinirole. The largest overdose reported with ropinirole in clinical trials was 435 mg taken over a 7-day period (62.1 mg/day). Of patients who received a dose greater than 24 mg/day, reported symptoms included adverse events commonly reported during dopaminergic therapy (nausea, dizziness), as well as visual hallucinations, hyperhidrosis, claustrophobia, chorea, palpitations, asthenia, and nightmares. Additional symptoms reported for doses of 24 mg or less or for overdoses of unknown amount included vomiting, increased coughing, fatigue, syncope, vasovagal syncope, dyskinesia, agitation, chest pain, orthostatic hypotension, somnolence, and confusional state.
### Management
- General supportive measures are recommended. Vital signs should be maintained, if necessary.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Ropinirole in the drug label.
# Pharmacology
## Mechanism of Action
- Ropinirole is a non-ergoline dopamine agonist. The precise mechanism of action of ropinirole as a treatment for Parkinson’s disease is unknown, although it is thought to be related to its ability to stimulate dopamine D2 receptors within the caudate-putamen in the brain. The precise mechanism of action of ropinirole as a treatment for Restless Legs Syndrome is unknown, although it is thought to be related to its ability to stimulate dopamine receptors.
## Structure
- REQUIP contains ropinirole, a non-ergoline dopamine agonist, as the hydrochloride salt. The chemical name of ropinirole hydrochloride is 4--1,3-dihydro-2H-indol-2-one and the empirical formula is C16H24N2OHCl. The molecular weight is 296.84 (260.38 as the free base).
- Ropinirole hydrochloride is a white to yellow solid with a melting range of 243° to 250°C and a solubility of 133 mg/mL in water.
- Each pentagonal film-coated TILTAB® tablet with beveled edges contains 0.29 mg, 0.57 mg, 1.14 mg, 2.28 mg, 3.42 mg, 4.56 mg , or 5.70 mg ropinirole hydrochloride equivalent to ropinirole, 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, or 5 mg. Inactive ingredients consist of croscarmellose sodium, hydrous lactose, magnesium stearate, microcrystalline cellulose, and one or more of the following: carmine, FD&C Blue No. 2 aluminum lake, FD&C Yellow No. 6 aluminum lake, hypromellose, iron oxides, polyethylene glycol, polysorbate 80, titanium dioxide.
## Pharmacodynamics
- Clinical experience with dopamine agonists, including ropinirole, suggests an association with impaired ability to regulate blood pressure with resulting orthostatic hypotension, especially during dose escalation. In some patients in clinical trials, blood pressure changes were associated with the emergence of orthostatic symptoms, bradycardia, and, in one case in a healthy volunteer, transient sinus arrest with syncope.
- The mechanism of orthostatic hypotension induced by ropinirole is presumed to be due to a D2-mediated blunting of the noradrenergic response to standing and subsequent decrease in peripheral vascular resistance. Nausea is a common concomitant symptom of orthostatic signs and symptoms.
- At oral doses as low as 0.2 mg, ropinirole suppressed serum prolactin concentrations in healthy male volunteers.
- Ropinirole had no dose-related effect on ECG wave form and rhythm in young, healthy, male volunteers in the range of 0.01 to 2.5 mg.
- Ropinirole had no dose- or exposure-related effect on mean QT intervals in healthy male and female volunteers titrated to doses up to 4 mg/day. The effect of ropinirole on QTc intervals at higher exposures achieved either due to drug interactions, hepatic impairment, or at higher doses has not been systematically evaluated.
## Pharmacokinetics
- Ropinirole displayed linear kinetics over the dosing range of 1 to 8 mg three times daily. Steady-state concentrations are expected to be achieved within 2 days of dosing. Accumulation upon multiple dosing is predictive from single dosing.
- Absorption
- Ropinirole is rapidly absorbed after oral administration, reaching peak concentration in approximately 1 to 2 hours. In clinical trials, more than 88% of a radiolabeled dose was recovered in urine and the absolute bioavailability was 45% to 55%, indicating approximately 50% first-pass effect.
- Relative bioavailability from a tablet compared with an oral solution is 85%. Food does not affect the extent of absorption of ropinirole, although its Tmax is increased by 2.5 hours and its Cmax is decreased by approximately 25% when the drug is taken with a high-fat meal.
- Distribution
- Ropinirole is widely distributed throughout the body, with an apparent volume of distribution of 7.5 L/kg. It is up to 40% bound to plasma proteins and has a blood-to-plasma ratio of 1:1.
- Metabolism
- Ropinirole is extensively metabolized by the liver. The major metabolic pathways are N-despropylation and hydroxylation to form the inactive N-despropyl metabolite and hydroxy metabolites. The N-despropyl metabolite is converted to carbamyl glucuronide, carboxylic acid, and N-despropyl hydroxy metabolites. The hydroxy metabolite of ropinirole is rapidly glucuronidated.
- In vitro studies indicate that the major cytochrome P450 enzyme involved in the metabolism of ropinirole is CYP1A2, an enzyme known to be induced by smoking and omeprazole and inhibited by, for example, fluvoxamine, mexiletine, and the older fluoroquinolones such as ciprofloxacin and norfloxacin.
- Elimination
- The clearance of ropinirole after oral administration is 47 L/h and its elimination half-life is approximately 6 hours. Less than 10% of the administered dose is excreted as unchanged drug in urine. N-despropyl ropinirole is the predominant metabolite found in urine (40%), followed by the carboxylic acid metabolite (10%), and the glucuronide of the hydroxy metabolite (10%).
- Drug Interactions
- Digoxin: Coadministration of REQUIP (2 mg three times daily) with digoxin (0.125 to 0.25 mg once daily) did not alter the steady-state pharmacokinetics of digoxin in 10 patients.
- Theophylline: Administration of theophylline (300 mg twice daily, a substrate of CYP1A2) did not alter the steady-state pharmacokinetics of ropinirole (2 mg three times daily) in 12 patients with Parkinson’s disease. REQUIP (2 mg three times daily) did not alter the pharmacokinetics of theophylline (5 mg/kg IV) in 12 patients with Parkinson’s disease.
- Ciprofloxacin: Coadministration of ciprofloxacin (500 mg twice daily), an inhibitor of CYP1A2, with REQUIP (2 mg three times daily) increased ropinirole AUC by 84% on average and Cmax by 60% (n = 12 patients).
- Estrogens: Population pharmacokinetic analysis revealed that estrogens (mainly ethinylestradiol: intake 0.6 to 3 mg over 4-month to 23-year period) reduced the oral clearance of ropinirole by 36% in 16 patients.
- L-dopa: Coadministration of carbidopa + L-dopa (10/100 mg twice daily) with REQUIP (2 mg three times daily) had no effect on the steady-state pharmacokinetics of ropinirole (n = 28 patients). Oral administration of REQUIP 2 mg three times daily increased mean steady-state Cmax of L-dopa by 20%, but its AUC was unaffected (n = 23 patients).
- Commonly Administered Drugs: Population analysis showed that commonly administered drugs, e.g., selegiline, amantadine, tricyclic antidepressants, benzodiazepines, ibuprofen, thiazides, antihistamines, and anticholinergics, did not affect the clearance of ropinirole. An in vitro study indicates that ropinirole is not a substrate for P-gp. Ropinirole and its circulating metabolites do not inhibit or induce P450 enzymes; therefore, ropinirole is unlikely to affect the pharmacokinetics of other drugs by a P450 mechanism.
- Specific Populations
- Because therapy with REQUIP is initiated at a low dose and gradually titrated upward according to clinical tolerability to obtain the optimum therapeutic effect, adjustment of the initial dose based on gender, weight, or age is not necessary.
- Age
- Oral clearance of ropinirole is reduced by 15% in patients older than 65 years compared with younger patients. Dosage adjustment is not necessary in the elderly (older than 65 years), as the dose of ropinirole is to be individually titrated to clinical response.
- Gender
- Female and male patients showed similar clearance.
- Race
- The influence of race on the pharmacokinetics of ropinirole has not been evaluated.
- Cigarette Smoking
- Smoking is expected to increase the clearance of ropinirole since CYP1A2 is known to be induced by smoking. In a trial in patients with RLS, smokers (n = 7) had an approximately 30% lower Cmax and a 38% lower AUC than did nonsmokers (n = 11) when those parameters were normalized for dose.
- Renal Impairment
- Based on population pharmacokinetic analysis, no difference was observed in the pharmacokinetics of ropinirole in subjects with moderate renal impairment (creatinine clearance between 30 to 50 mL/min) compared with an age-matched population with creatinine clearance above 50 mL/min. Therefore, no dosage adjustment is necessary in patients with moderate renal impairment.
- A trial of ropinirole in subjects with end-stage renal disease on hemodialysis has shown that clearance of ropinirole was reduced by approximately 30%. The recommended maximum dose should be lower in these patients.
- The use of ropinirole in subjects with severe renal impairment (creatinine clearance less than 30 mL/min) without regular dialysis has not been studied.
- Hepatic Impairment
- The pharmacokinetics of ropinirole have not been studied in patients with hepatic impairment. Because ropinirole is extensively metabolized by the liver, these patients may have higher plasma levels and lower clearance of ropinirole than patients with normal hepatic function.
- Other Diseases
- Population pharmacokinetic analysis revealed no change in the clearance of ropinirole in patients with concomitant diseases such as hypertension, depression, osteoporosis/arthritis, and insomnia compared with patients with Parkinson’s disease only.
## Nonclinical Toxicology
- Carcinogenesis
- Two-year carcinogenicity studies of ropinirole were conducted in mice at oral doses of 5, 15, and 50 mg/kg/day and in rats at oral doses of 1.5, 15, and 50 mg/kg/day.
- In rats, there was an increase in testicular Leydig cell adenomas at all doses tested. The lowest dose tested (1.5 mg/kg/day) is less than the MRHD for Parkinson’s disease (24 mg/day) on a mg/m2 basis. The endocrine mechanisms believed to be involved in the production of these tumors in rats are not considered relevant to humans.
- In mice, there was an increase in benign uterine endometrial polyps at a dose of 50 mg/kg/day. The highest dose not associated with this finding (15 mg/kg/day) is three times the MRHD on a mg/m2 basis.
- Mutagenesis
- Ropinirole was not mutagenic or clastogenic in in vitro (Ames, chromosomal aberration in human lymphocytes, mouse lymphoma tk) assays or in the in vivo mouse micronucleus test.
- Impairment of Fertility
- When administered to female rats prior to and during mating and throughout pregnancy, ropinirole caused disruption of implantation at oral doses of 20 mg/kg/day (8 times the MRHD on a mg/m2 basis) or greater. This effect in rats is thought to be due to the prolactin-lowering effect of ropinirole. In rat studies using a low oral dose (5 mg/kg) during the prolactin-dependent phase of early pregnancy (gestation days 0 to 8), ropinirole did not affect female fertility at oral doses up to 100 mg/kg/day (40 times the MRHD on a mg/m2 basis). No effect on male fertility was observed in rats at oral doses up to 125 mg/kg/day (50 times the MRHD on a mg/m2 basis).
# Clinical Studies
- Parkinson’s Disease
- The effectiveness of REQUIP in the treatment of Parkinson’s disease was evaluated in a multinational drug development program consisting of 11 randomized, controlled trials. Four trials were conducted in patients with early Parkinson’s disease and no concomitant levodopa (L-dopa) and seven trials were conducted in patients with advanced Parkinson’s disease with concomitant L-dopa.
- Three placebo‑controlled trials provide evidence of effectiveness of REQUIP in the management of patients with Parkinson’s disease who were and were not receiving concomitant L-dopa. Two of these three trials enrolled patients with early Parkinson’s disease (without L-dopa) and one enrolled patients receiving L-dopa.
- In these trials a variety of measures were used to assess the effects of treatment (e.g., the Unified Parkinson’s Disease Rating Scale , Clinical Global Impression scores, patient diaries recording time “on” and “off,” tolerability of L-dopa dose reductions).
- In both trials of patients with early Parkinson’s disease (without L-dopa), the motor component (Part III) of the UPDRS was the primary outcome assessment. The UPDRS is a multi-item rating scale intended to evaluate mentation (Part I), activities of daily living (Part II), motor performance (Part III), and complications of therapy (Part IV). Part III of the UPDRS contains 14 items designed to assess the severity of the cardinal motor findings in patients with Parkinson’s disease (e.g., tremor, rigidity, bradykinesia, postural instability) scored for different body regions and has a maximum (worst) score of 108. In the trial of patients with advanced Parkinson’s disease (with L-dopa), both reduction in percent awake time spent “off” and the ability to reduce the daily use of L-dopa were assessed as a combined endpoint and individually.
- Trials in Patients with Early Parkinson’s Disease (without L-dopa)
- Trial 1 was a 12-week multicenter trial in which 63 patients with idiopathic Parkinson’s disease receiving concomitant anti-Parkinson medication (but not L-dopa) were enrolled and 41 were randomized to REQUIP and 22 to placebo. Patients had a mean disease duration of approximately 2 years. Patients were eligible for enrollment if they presented with bradykinesia and at least tremor, rigidity, or postural instability. In addition, they must have been classified as Hoehn & Yahr Stage I-IV. This scale, ranging from I = unilateral involvement with minimal impairment to V = confined to wheelchair or bed, is a standard instrument used for staging patients with Parkinson’s disease. The primary outcome measure in this trial was the proportion of patients experiencing a decrease (compared with baseline) of at least 30% in the UPDRS motor score.
- Patients were titrated for up to 10 weeks, starting at 0.5 mg twice daily, with weekly increments of 0.5 mg twice daily to a maximum of 5 mg twice daily. Once patients reached their maximally tolerated dose (or 5 mg twice daily), they were maintained on that dose through 12 weeks. The mean dose achieved by patients at trial endpoint was 7.4 mg/day. Mean baseline UPDRS motor score was 18.6 for patients treated with REQUIP and 19.9 for patients treated with placebo. At the end of 12 weeks, the percentage of responders was greater on REQUIP than on placebo and the difference was statistically significant (Table 6).
- Trial 2 in patients with early Parkinson’s disease (without L-dopa) was a double‑blind, randomized, placebo-controlled, 6-month trial. In this trial, 241 patients were enrolled and 116 were randomized to REQUIP and 125 to placebo. Patients were essentially similar to those in the trial described above; concomitant use of selegiline was allowed, but patients were not permitted to use anticholinergics or amantadine during the trial. Patients had a mean disease duration of 2 years and limited (not more than a 6-week period) or no prior exposure to L-dopa. The starting dosage of REQUIP in this trial was 0.25 mg three times daily. The dosage was titrated at weekly intervals by increments of 0.25 mg three times daily to a dosage of 1 mg three times daily. Further titrations at weekly intervals were at increments of 0.5 mg three times daily up to a dosage of 3 mg three times daily, and then weekly at increments of 1 mg three times daily. Patients were to be titrated to a dosage of at least 1.5 mg three times daily and then to their maximally tolerated dosage, up to a maximum of 8 mg three times daily. The mean dose attained in patients at trial endpoint was 15.7 mg/day.
- The primary measure of effectiveness was the mean percent reduction (improvement) from baseline in the UPDRS motor score. At the end of the 6-month trial, patients treated with REQUIP showed improvement in motor score compared with placebo and the difference was statistically significant (Table 7).
- Trial in Patients with Advanced Parkinson’s Disease (with L-dopa)
- Trial 3 was a double-blind, randomized, placebo-controlled, 6-month trial that randomized 149 patients (Hoehn & Yahr II‑IV) who were not adequately controlled on L-dopa. Ninety-five patients were randomized to REQUIP and 54 were randomized to placebo. Patients in this trial had a mean disease duration of approximately 9 years, had been exposed to L-dopa for approximately 7 years, and had experienced “on-off” periods with L-dopa therapy. Patients previously receiving stable doses of selegiline, amantadine, and/or anticholinergic agents could continue on these agents during the trial. Patients were started at a dosage of 0.25 mg three times daily of REQUIP and titrated upward by weekly intervals until an optimal therapeutic response was achieved. The maximum dosage of trial medication was 8 mg three times daily. All patients had to be titrated to at least a dosage of 2.5 mg three times daily. Patients could then be maintained on this dosage level or higher for the remainder of the trial. Once a dosage of 2.5 mg three times daily was achieved, patients underwent a mandatory reduction in their L-dopa dosage, to be followed by additional mandatory reductions with continued escalation of the dosage of REQUIP. Reductions in the dosage of l-dopa were also allowed if patients experienced adverse reactions that the investigator considered related to dopaminergic therapy. The mean dose attained at trial endpoint was 16.3 mg/day. The primary outcome was the proportion of responders, defined as patients who were able both to achieve a decrease (compared with baseline) of at least 20% in their L-dopa dosage and a decrease of at least 20% in the proportion of the time awake in the “off” condition (a period of time during the day when patients are particularly immobile), as determined by subject diary. In addition, the mean change in “off” time from baseline and the percent change from baseline in daily L-dopa dosage were examined.
- At the end of 6 months, the percentage of responders was greater on REQUIP than on placebo and the difference was statistically significant (Table 8).
- Based on the protocol-mandated reductions in L-dopa dosage with escalating doses of REQUIP, patients treated with REQUIP had a 19.4% mean reduction in L-dopa dosage while patients treated with placebo had a 3% reduction. Mean daily L-dopa dosage at baseline was 759 mg for patients treated with REQUIP and 843 mg for patients treated with placebo.
- The mean number of daily “off” hours at baseline was 6.4 hours for patients treated with REQUIP and 7.3 hours for patients treated with placebo. At the end of the 6-month trial, there was a mean reduction of 1.5 hours of “off” time in patients treated with REQUIP and a mean reduction of 0.9 hours of “off” time in patients treated with placebo, resulting in a treatment difference of 0.6 hours of “off” time.
- Restless Legs Syndrome
- The effectiveness of REQUIP in the treatment of RLS was demonstrated in randomized, double-blind, placebo-controlled trials in adults diagnosed with RLS using the International Restless Legs Syndrome Study Group diagnostic criteria. Patients were required to have a history of a minimum of 15 RLS episodes/month during the previous month and a total score of ≥15 on the International RLS Rating Scale (IRLS scale) at baseline. Patients with RLS secondary to other conditions (e.g., pregnancy, renal failure, anemia) were excluded. All trials employed flexible dosing, with patients initiating therapy at 0.25 mg REQUIP once daily. Patients were titrated based on clinical response and tolerability over 7 weeks to a maximum of 4 mg once daily. All doses were taken between 1 and 3 hours before bedtime.
- A variety of measures were used to assess the effects of treatment, including the IRLS scale and Clinical Global Impression-Global Improvement (CGI-I) scores. The IRLS scale contains 10 items designed to assess the severity of sensory and motor symptoms, sleep disturbance, daytime somnolence, and impact on activities of daily living and mood associated with RLS. The range of scores is 0 to 40, with 0 being absence of RLS symptoms and 40 the most severe symptoms. Three of the controlled trials utilized the change from baseline in the IRLS scale at the Week 12 endpoint as the primary efficacy outcome.
- Three hundred eighty patients were randomized to receive REQUIP (n = 187) or placebo (n = 193) in a US trial (RLS-1); 284 were randomized to receive either REQUIP (n = 146) or placebo (n = 138) in a multinational trial (excluding US) (RLS-2); and 267 patients were randomized to REQUIP (n = 131) or placebo (n = 136) in a multinational trial (including US) (RLS-3). Across the three trials, the mean duration of RLS was 16 to 22 years (range: 0 to 65 years), mean age was approximately 54 years (range: 18 to 79 years), and approximately 61% were women. The mean dose at Week 12 was approximately 2 mg/day for the three trials.
- At baseline, mean total IRLS score was 22.0 for REQUIP and 21.6 for placebo in RLS-1, was 24.4 for REQUIP and 25.2 for placebo in RLS-2, and was 23.6 for REQUIP and 24.8 for placebo in RLS-3. In all three trials, a statistically significant difference between the treatment group receiving REQUIP and the treatment group receiving placebo was observed at Week 12 for both the mean change from baseline in the IRLS scale total score and the percentage of patients rated as responders (much improved or very much improved) on the CGI-I (see Table 9).
- Long-term maintenance of efficacy in the treatment of RLS was demonstrated in a 36‑week trial. Following a 24-week, single-blind treatment phase (flexible dosages of REQUIP of 0.25 to 4 mg once daily), patients who were responders (defined as a decrease of >6 points on the IRLS scale total score relative to baseline) were randomized in double-blind fashion to placebo or continuation of REQUIP for an additional 12 weeks. Relapse was defined as an increase of at least 6 points on the IRLS scale total score to a total score of at least 15, or withdrawal due to lack of efficacy. For patients who were responders at Week 24, the mean dose of REQUIP was 2 mg (range: 0.25 to 4 mg).Patientscontinued on REQUIP demonstrated a significantly lower relapse rate compared with patients randomized to placebo (32.6% versus 57.8%, P = 0.0156).
# How Supplied
- Each pentagonal film-coated TILTAB® tablet with beveled edges contains ropinirole hydrochloride equivalent to the labeled amount of ropinirole as follows:
- 0.25 mg: white tablets imprinted with “SB” and “4890” in bottles of 100 (NDC 0007-4890-20)
- 0.5 mg: yellow tablets imprinted with “SB” and “4891” in bottles of 100 (NDC 0007-4891-20)
- 1 mg: green tablets imprinted with “SB” and “4892” in bottles of 100 (NDC 0007-4892-20)
- 2 mg: pale yellowish-pink tablets imprinted with “SB” and “4893” in bottles of 100 (NDC 0007-4893-20)
- 3 mg: pale to moderate reddish-purple tablets, imprinted with “SB” and “4895” in bottles of 100 (NDC 0007-4895-20)
- 4 mg: pale brown tablets imprinted with “SB” and “4896” in bottles of 100 (NDC 0007-4896-20)
- 5 mg: blue tablets imprinted with “SB” and “4894” in bottles of 100 (NDC 0007-4894-20)
- Storage
- Store at controlled room temperature 20° - 25°C (68° - 77°F) . Protect from light and moisture. Close container tightly after each use.
## Storage
There is limited information regarding Ropinirole Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise the patient to read the FDA-approved patient labeling (Patient Information).
- Dosing Instructions
- Instruct patients to take REQUIP only as prescribed. If a dose is missed, advise patients not to double their next dose. REQUIP can be taken with or without food.
- Ropinirole is the active ingredient in both REQUIP XL and REQUIP tablets (the immediate‑release formulation). Ask your patients if they are taking another medication containing ropinirole.
- Hypersensitivity/Allergic Reactions
- Advise patients about the potential for developing a hypersensitivity/allergic reaction including manifestations such as urticaria, angioedema, rash, and pruritus when taking any ropinirole product. Inform patients who experience these or similar reactions to immediately contact their healthcare professional.
- Falling Asleep during Activities of Daily Living and Somnolence
- Alert patients to the potential sedating effects caused by REQUIP, including somnolence and the possibility of falling asleep while engaged in activities of daily living. Because somnolence is a frequent adverse reaction with potentially serious consequences, patients should not drive a car, operate machinery, or engage in other potentially dangerous activities until they have gained sufficient experience with REQUIP to gauge whether or not it affects their mental and/or motor performance adversely. Advise patients that if increased somnolence or episodes of falling asleep during activities of daily living (e.g., conversations, eating, driving a motor vehicle, etc.) are experienced at any time during treatment, they should not drive or participate in potentially dangerous activities until they have contacted their physician.
- Advise patients of possible additive effects when patients are taking other sedating medications, alcohol, or other central nervous system depressants (e.g., benzodiazepines, antipsychotics, antidepressants, etc.) in combination with REQUIP or when taking a concomitant medication (e.g., ciprofloxacin) that increases plasma levels of ropinirole.
- Syncope and Hypotension/Orthostatic Hypotension
- Advise patients that they may experience syncope and may develop hypotension with or without symptoms such as dizziness, nausea, syncope, and sometimes sweating while taking REQUIP, especially if they are elderly. Hypotension and/or orthostatic symptoms may occur more frequently during initial therapy or with an increase in dose at any time (cases have been seen after weeks of treatment).Postural/orthostatic symptoms may be related to sitting up or standing. Accordingly, caution patients against standing rapidly after sitting or lying down, especially if they have been doing so for prolonged periods and especially at the initiation of treatment with REQUIP.
- Hallucinations/Psychotic-like Behavior
- Inform patients that they may experience hallucinations (unreal visions, sounds, or sensations), and that other psychotic-like behavior can occur while taking REQUIP. The elderly are at greater risk than younger patients with Parkinson’s disease. This risk is greater in patients who are taking REQUIP with L-dopa or taking higher doses of REQUIP and may also be further increased in patients taking any other drugs that increase dopaminergic tone. Tell patients to report hallucinations or psychotic-like behavior to their healthcare provider promptly should they develop.
- Dyskinesia
- Inform patients that REQUIP may cause and/or exacerbate pre-existing dyskinesias.
- Impulse Control/Compulsive Behaviors
- Advise patients that they may experience impulse control and/or compulsive behaviors while taking one or more of the medications (including REQUIP) that increase central dopaminergic tone, that are generally used for the treatment of Parkinson’s disease. Advise patients to inform their physician or healthcare provider if they develop new or increased gambling urges, sexual urges, uncontrolled spending, binge or compulsive eating, or other urges while being treated with REQUIP. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking REQUIP.
- Withdrawal-emergent Hyperpyrexia and Confusion
- Advise patients to contact their healthcare provider if they wish to discontinue REQUIP or decrease the dose of REQUIP.
- Melanoma
- Advise patients with Parkinson’s disease that they have a higher risk of developing melanoma. Advise patients to have their skin examined on a regular basis by a qualified healthcare provider (e.g., dermatologist) when using REQUIP for any indication.
- Augmentation and Rebound
- Inform patients with RLS that augmentation and/or rebound may occur after starting treatment with REQUIP.
- Nursing Mothers
- Because of the possibility that ropinirole may be excreted in breast milk, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Advise patients that REQUIP could inhibit lactation because ropinirole inhibits prolactin secretion.
- Pregnancy
- Because ropinirole has been shown to have adverse effects on embryo-fetal development, including teratogenic effects, in animals, and because experience in humans is limited, advise patients to notify their physician if they become pregnant or intend to become pregnant during therapy.
# Precautions with Alcohol
- Alcohol-Ropinirole interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- REQUIP®
# Look-Alike Drug Names
- rOPINIRole hydrochloride® — risperiDONE®
# Drug Shortage Status
# Price | Ropinirole
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2]
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# Overview
Ropinirole is a dopamine agonist that is FDA approved for the {{{indicationType}}} of parkinson’s disease (PD) and primary restless legs syndrome (RLS). Common adverse reactions include nausea, somnolence, dizziness, syncope, asthenic condition, viral infection, leg edema, vomiting, and dyspepsia.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- The recommended starting dose for Parkinson’s disease is 0.25 mg three times daily. Based on individual patient therapeutic response and tolerability, if necessary, the dose should then be titrated with weekly increments as described in Table 1. After Week 4, if necessary, the daily dose may be increased by 1.5 mg/day on a weekly basis up to a dose of 9 mg/day, and then by up to 3 mg/day weekly up to a maximum recommended total daily dose of 24 mg/day (8 mg three times daily). Doses greater than 24 mg/day have not been tested in clinical trials.
- REQUIP should be discontinued gradually over a 7-day period in patients with Parkinson’s disease. The frequency of administration should be reduced from three times daily to twice daily for 4 days. For the remaining 3 days, the frequency should be reduced to once daily prior to complete withdrawal of REQUIP.
- Renal Impairment
- No dose adjustment is necessary in patients with moderate renal impairment (creatinine clearance of 30 to 50 mL/min). The recommended initial dose of ropinirole for patients with end-stage renal disease on hemodialysis is 0.25 mg three times a day. Further dose escalations should be based on tolerability and need for efficacy. The recommended maximum total daily dose is 18 mg/day in patients receiving regular dialysis. Supplemental doses after dialysis are not required. The use of REQUIP in patients with severe renal impairment without regular dialysis has not been studied.
- Dosing Information
- The recommended adult starting dose for RLS is 0.25 mg once daily 1 to 3 hours before bedtime. After 2 days, if necessary, the dose can be increased to 0.5 mg once daily, and to 1 mg once daily at the end of the first week of dosing, then as shown in Table 2 as needed to achieve efficacy. Titration should be based on individual patient therapeutic response and tolerability, up to a maximum recommended dose of 4 mg daily. For RLS, the safety and effectiveness of doses greater than 4 mg once daily have not been established.
- In clinical trials of patients treated for RLS with doses up to 4 mg once daily, REQUIP was discontinued without a taper.
- Renal Impairment
- No dose adjustment is necessary in patients with moderate renal impairment (creatinine clearance of 30 to 50 mL/min). The recommended initial dose of ropinirole for patients with end-stage renal disease on hemodialysis is 0.25 mg once daily. Further dose escalations should be based on tolerability and need for efficacy. The recommended maximum total daily dose is 3 mg/day in patients receiving regular dialysis. Supplemental doses after dialysis are not required. The use of REQUIP in patients with severe renal impairment without regular dialysis has not been studied.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ropinirole in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ropinirole in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Ropinirole in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ropinirole in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ropinirole in pediatric patients.
# Contraindications
- REQUIP is contraindicated in patients known to have a hypersensitivity/allergic reaction (including urticaria, angioedema, rash, pruritus) to ropinirole or to any of the excipients.
# Warnings
### Precautions
- Falling Asleep during Activities of Daily Living and Somnolence
- Patients treated with REQUIP have reported falling asleep while engaged in activities of daily living, including driving or operating machinery, which sometimes resulted in accidents. Although many of these patients reported somnolence while on REQUIP, some perceived that they had no warning signs, such as excessive drowsiness, and believed that they were alert immediately prior to the event. Some have reported these events more than 1 year after initiation of treatment.
- In controlled clinical trials, somnolence was commonly reported in patients receiving REQUIP and was more frequent in Parkinson's disease (up to 40% REQUIP, 6% placebo) than in Restless Legs Syndrome (12% REQUIP, 6% placebo).
- It has been reported that falling asleep while engaged in activities of daily living usually occurs in a setting of preexisting somnolence, although patients may not give such a history. For this reason, prescribers should reassess patients for drowsiness or sleepiness, especially since some of the events occur well after the start of treatment. Prescribers should also be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities.
- Before initiating treatment with REQUIP, patients should be advised of the potential to develop drowsiness and specifically asked about factors that may increase the risk with REQUIP such as concomitant sedating medications, the presence of sleep disorders (other than RLS), and concomitant medications that increase ropinirole plasma levels (e.g., ciprofloxacin). If a patient develops significant daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., driving a motor vehicle, conversations, eating), REQUIP should ordinarily be discontinued. If a decision is made to continue REQUIP, patients should be advised to not drive and to avoid other potentially dangerous activities. There is insufficient information to establish that dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living.
- Syncope
- Syncope, sometimes associated with bradycardia, was observed in association with ropinirole in both patients with Parkinson’s disease and patients with RLS. In controlled clinical trials in patients with Parkinson’s disease, syncope was observed more frequently in patients receiving REQUIP than in patients receiving placebo (early Parkinson’s disease without L-dopa: REQUIP 12%, placebo 1%; advanced Parkinson’s disease: REQUIP 3%, placebo 2%). Syncope was reported in 1% of patients treated with REQUIP for RLS in 12-week, placebo-controlled clinical trials compared with 0.2% of patients treated with placebo. Most cases occurred more than 4 weeks after initiation of therapy with REQUIP, and were usually associated with a recent increase in dose.
- Because the trials of REQUIP excluded patients with significant cardiovascular disease, patients with significant cardiovascular disease should be treated with caution.
- Approximately 4% of patients with Parkinson’s disease enrolled in Phase 1 trials had syncope following a 1-mg dose of REQUIP. In two trials in patients with RLS that used a forced-titration regimen and orthostatic challenge with intensive blood pressure monitoring, 2% of RLS patients treated with REQUIP compared with 0% of patients receiving placebo reported syncope.
- In Phase 1 trials including healthy volunteers, the incidence of syncope was 2%. Of note, 1 subject with syncope developed hypotension, bradycardia, and sinus arrest; the subject recovered spontaneously without intervention.
- Hypotension/Orthostatic Hypotension
- Dopamine agonists in clinical trials and clinical experience appear to impair the systemic regulation of blood pressure, with resulting orthostatic hypotension, especially during dose escalation. In addition, patients with Parkinson’s disease appear to have an impaired capacity to respond to a postural challenge. For these reasons, patients should be monitored for signs and symptoms of orthostatic hypotension, especially during dose escalation, and patients should be informed of the risk for syncope and hypotension.
- Although the clinical trials were not designed to systematically monitor blood pressure, there were individual reported cases of orthostatic hypotension in early Parkinson’s disease (without L-dopa) in patients treated with REQUIP. Most of these cases occurred more than 4 weeks after initiation of therapy with REQUIP and were usually associated with a recent increase in dose.
- In 12-week, placebo-controlled trials of patients with RLS, the adverse event orthostatic hypotension was reported by 4 of 496 patients (0.8%) treated with REQUIP compared with 2 of 500 patients (0.4%) receiving placebo.
- In two Phase 2 studies in patients with RLS, 14 of 55 patients (25%) receiving REQUIP experienced an adverse event of hypotension or orthostatic hypotension compared with none of the 27 patients receiving placebo. In these studies, 11 of the 55 patients (20%) receiving REQUIP and 3 of the 26 patients (12%) who had post-dose blood pressure assessments following placebo, experienced an orthostatic blood pressure decrease of at least 40 mm Hg systolic and/or at least 20 mm Hg diastolic.
- In Phase 1 trials of REQUIP with healthy volunteers who received single doses on morethan one occasion without titration, 7% had documented symptomatic orthostatic hypotension. These episodes appeared mainly at doses above 0.8 mg and these doses are higher than the starting doses recommended for patients with either Parkinson’s disease or with RLS. In most of these individuals, the hypotension was accompanied by bradycardia but did not develop into syncope.
- Although dizziness is not a specific manifestation of hypotension or orthostatic hypotension, patients with hypotension or orthostatic hypotension frequently reported dizziness. In controlled clinical trials, dizziness was a common adverse reaction in patients receiving REQUIP and was more frequent in patients with Parkinson’s disease or with RLS receiving REQUIP than in patients receiving placebo (early Parkinson’s disease without L-dopa: REQUIP 40%, placebo 22%; advanced Parkinson’s disease: REQUIP 26%, placebo 16%; RLS: REQUIP 11%, placebo 5%). Dizziness of sufficient severity to cause trial discontinuation of REQUIP was 4% in patients with early Parkinson’s disease without L-dopa, 3% in patients with advanced Parkinson’s disease, and 1% in patients with RLS.
- Hallucinations/Psychotic-like Behavior
- In double-blind, placebo-controlled, early-therapy trials in patients with Parkinson’s disease who were not treated with L-dopa, 5.2% (8 of 157) of patients treated with REQUIP reported hallucinations, compared with 1.4% of patients on placebo (2 of 147). Among those patients receiving both REQUIP and L-dopa in advanced Parkinson’s disease studies, 10.1% (21 of 208) were reported to experience hallucinations, compared with 4.2% (5 of 120) of patients treated with placebo and L-dopa.
- The incidence of hallucination was increased in elderly patients (i.e., older than 65 years) treated with extended-release REQUIP.
- Postmarketing reports indicate that patients may experience new or worsening mental status and behavioral changes, which may be severe, including psychotic-like behavior during treatment with REQUIP or after starting or increasing the dose of REQUIP. Other drugs prescribed to improve the symptoms of Parkinson’s disease can have similar effects on thinking and behavior. This abnormal thinking and behavior can consist of one or more of a variety of manifestations including paranoid ideation, delusions, hallucinations, confusion, psychotic-like behavior, disorientation, aggressive behavior, agitation, and delirium.
- Patients with a major psychotic disorder should ordinarily not be treated with REQUIP because of the risk of exacerbating the psychosis. In addition, certain medications used to treat psychosis may exacerbate the symptoms of Parkinson’s disease and may decrease the effectiveness of REQUIP.
- Dyskinesia
- REQUIP may potentiate the dopaminergic side effects of L-dopa and may cause and/or exacerbate pre-existing dyskinesia in patients treated with L-dopa for Parkinson’s disease. In double-blind, placebo-controlled trials in advanced Parkinson’s disease, dyskinesia was much more common in patients treated with REQUIP than in those treated with placebo. Among those patients receiving both REQUIP and L-dopa in advanced Parkinson’s disease trials, 34% were reported to experience dyskinesia, compared with 13% of patients treated with placebo. Decreasing the dose of the dopaminergic drug may ameliorate this adverse reaction.
- Impulse Control/Compulsive Behaviors
- Case reports suggest that patients can experience intense urges to gamble, increased sexual urges, intense urges to spendmoney, binge or compulsive eating, and/or other intense urges, and the inability to control these urges while taking one or more of the medications, including REQUIP, that increase central dopaminergic tone and that are generally used for the treatment of Parkinson’s disease and RLS. In some cases, although not all, these urges were reported to have stopped when the dose was reduced or the medication was discontinued. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending, binge or compulsive eating, or other urges while being treated with REQUIP. Physiciansshould consider dose reduction or stopping the medication if a patient develops such urges while taking REQUIP.
- Withdrawal-emergent Hyperpyrexia and Confusion
- A symptom complex resembling the neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in dopaminergic therapy. Therefore, it is recommended that the dose be tapered at the end of treatment with REQUIP for Parkinson’s disease as a prophylactic measure.
- Melanoma
- Epidemiological studies have shown that patients with Parkinson’s disease have a higher risk (2- to approximately 6-fold higher) of developing melanoma than the general population. Whether the increased risk observed was due to Parkinson’s disease or other factors, such as drugs used to treat Parkinson’s disease, is unclear.
- For the reasons stated above, patients and providers are advised to monitor for melanomas frequently and on a regular basis when using REQUIP for any indication. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists).
- Augmentation and Early-morning Rebound in Restless Legs Syndrome
- Reports in the literature indicate treatment of RLS with dopaminergic medications can result in recurrence of symptoms in the early morning hours, referred to as rebound. Augmentation has also been described during therapy for RLS. Augmentation refers to the earlier onset of symptoms in the evening (or even the afternoon), increase in symptoms, and spread of symptoms to involve other extremities. Rebound refers to new onset of symptoms in the early morning hours. Augmentation and/or early-morning rebound have been observed in a postmarketing trial. If augmentation or early-morning rebound occurs, the use of REQUIP should be reviewed and dosage adjustment or discontinuation of treatment should be considered.
- Fibrotic Complications
- Cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, pleural thickening, pericarditis, and cardiac valvulopathy have been reported in some patients treated with ergot-derived dopaminergic agents. While these complications may resolve when the drug is discontinued, complete resolution does not always occur.
- Although these adverse reactions are believed to be related to the ergoline structure of these compounds, whether other, non-ergot‑derived dopamine agonists such as ropinirole can cause them is unknown.
- Cases of possible fibrotic complications, including pleural effusion, pleural fibrosis, interstitial lung disease, and cardiac valvulopathy have been reported in the development program and postmarketing experience for ropinirole. While the evidence is not sufficient to establish a causal relationship between ropinirole and these fibrotic complications, a contribution of ropinirole cannot be excluded.
- Retinal Pathology
- Retinal degeneration was observed in albino rats in the 2-year carcinogenicity study at all doses tested (equivalent to 0.6 to 20 times the maximum recommended human dose [MRHD] for Parkinson’s disease [24 mg/day] on a mg/m2 basis), but was statistically significant at the highest dose (50 mg/kg/day). Retinal degeneration was not observed in a 3-month study in pigmented rats, in a 2-year carcinogenicity study in albino mice, or in 1‑year studies in monkeys or albino rats. The significance of this effect for humans has not been established but involves disruption of a mechanism that is universally present in vertebrates (e.g., disk shedding).
- Ocular electroretinogram (ERG) assessments were conducted during a 2-year, double-blind, multicenter, flexible dose, L-dopa-controlled clinical trial of ropinirole in patients with Parkinson’s disease; 156 patients (78 on ropinirole, mean dose: 11.9 mg/day, and 78 on L-dopa, mean dose: 555.2 mg/day) were evaluated for evidence of retinal dysfunction through electroretinograms. There was no clinically meaningful difference between the treatment groups in retinal function over the duration of the trial.
- Binding to Melanin
- Ropinirole binds to melanin-containing tissues (i.e., eyes, skin) in pigmented rats. After a single dose, long-term retention of drug was demonstrated, with a half-life in the eye of 20 days
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug (or of another development program of a different formulation of the same drug) and may not reflect the rates observed in practice.
- Parkinson’s Disease
- During the premarketing development of REQUIP, patients received REQUIP either without L-dopa (early Parkinson’s disease trials) or as concomitant therapy with L-dopa (advanced Parkinson’s disease trials). Because these two populations may have differential risks for various adverse reactions, this section will in general present adverse reaction data for these two populations separately.
- Early Parkinson’s Disease (without L-dopa)
- In the double-blind, placebo-controlled trials in patients with early-stage Parkinson’s disease, the most commonly observed adverse reactions in patients treated with REQUIP (incidence at least 5% greater than placebo) were nausea, somnolence, dizziness, syncope, asthenic condition (i.e., asthenia, fatigue, and/or malaise), viral infection, leg edema, vomiting, and dyspepsia.
- Approximately 24% of patients treated with REQUIP who participated in the double-blind, placebo-controlled early Parkinson’s disease (without L-dopa) trials discontinued treatment due to adverse reactions compared with 13% of patients who received placebo. The most common adverse reactions in patients treated with REQUIP (incidence at least 2% greater than placebo) of sufficient severity to cause discontinuation were nausea and dizziness.
- Table 3 lists treatment-emergent adverse reactions that occurred in at least 2% of patients with early Parkinson’s disease (without L-dopa) treated with REQUIP participating in the double-blind, placebo-controlled trials and were numerically more common than the incidence for placebo-treated patients. In these trials, either REQUIP or placebo was used as early therapy (i.e., without L-dopa).
- aPatients may have reported multiple adverse reactions during the trial or at discontinuation; thus, patients may be included in more than one category.
- b Asthenic condition (i.e., asthenia, fatigue, and/or malaise).
- Advanced Parkinson’s Disease (with L-dopa)
- In the double-blind, placebo-controlled trials in patients with advanced-stage Parkinson’s disease, the most commonly observed adverse reactions in patients treated with REQUIP (incidence at least 5 % greater than placebo) were dyskinesia, somnolence, nausea, dizziness, confusion, hallucinations, increased sweating, and headache.
- Approximately 24% of patients who received REQUIP in the double-blind, placebo-controlled advanced Parkinson’s disease (with L-dopa) trials discontinued treatment due to adverse reactions compared with 18% of patients who received placebo. The most common adverse reaction in patients treated with REQUIP (incidence at least 2% greater than placebo) of sufficient severity to cause discontinuation was dizziness.
- Table 4 lists treatment-emergent adverse reactions that occurred in at least 2% of patients with advanced Parkinson’s disease (with L-dopa) treated with REQUIP who participated in the double-blind, placebo-controlled trials and were numerically more common than the incidence for placebo-treated patients. In these trials, either REQUIP or placebo was used as an adjunct to L-dopa.
- aPatients may have reported multiple adverse reactions during the trial or at discontinuation; thus, patients may be included in more than one category.
- Restless Legs Syndrome
- In the double-blind, placebo-controlledtrials in patients with RLS, the most commonly observed adverse reactions in patients treated with REQUIP (incidence at least 5% greater than placebo) were nausea, vomiting, somnolence, dizziness, and asthenic condition (i.e., asthenia, fatigue, and/or malaise).
- Approximately 5% of patients treated with REQUIP who participated in the double-blind, placebo-controlled trials in the treatment of RLS discontinued treatment due to adverse reactions compared with 4% of patients who received placebo. The most common adverse reaction in patients treated with REQUIP (incidence at least 2% greater than placebo) of sufficient severity to cause discontinuation was nausea.
- Table 5 lists treatment-emergent adverse reactions that occurred in at least 2% of patients with RLS treated with REQUIP participating in the 12-week, double-blind, placebo-controlled trials and were numerically more common than the incidence for placebo-treated patients.
- aPatients may have reported multiple adverse reactions during the trial or at discontinuation; thus, patients may be included in more than one category.
- b Asthenic condition (i.e., asthenia, fatigue, and/or malaise).
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Ropinirole in the drug label.
# Drug Interactions
- CYP1A2 Inhibitors and Inducers
- In vitro metabolism studies showed that CYP1A2 is the major enzyme responsible for the metabolism of ropinirole. There is thus the potential for inducers or inhibitors of this enzyme to alter the clearance of ropinirole. Therefore, if therapy with a drug known to be a potent inducer or inhibitor of CYP1A2 is stopped or started during treatment with REQUIP, adjustment of the dose of REQUIP may be required. Coadministration of ciprofloxacin, an inhibitor of CYP1A2, increases the AUC and Cmax of ropinirole. Cigarette smoking is expected to increase the clearance of ropinirole since CYP1A2 is known to be induced by smoking.
- Estrogens
- Population pharmacokinetic analysis revealed that higher doses of estrogens (usually associated with hormone replacement therapy [HRT]) reduced the clearance of ropinirole. Starting or stopping HRT may require adjustment of dosage of REQUIP.
- Dopamine Antagonists
- Because ropinirole is a dopamine agonist, it is possible that dopamine antagonists such as neuroleptics (e.g., phenothiazines, butyrophenones, thioxanthenes) or metoclopramide may reduce the efficacy of REQUIP.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- There are no adequate and well-controlled studies in pregnant women. In animal reproduction studies, ropinirole has been shown to have adverse effects on embryo-fetal development, including teratogenic effects. REQUIP should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus.
- Oral treatment of pregnant rats with ropinirole during organogenesis resulted in decreased fetal body weight, increased fetal death, and digital malformations at 24, 36, and 60 times, respectively, the maximum recommended human dose (MRHD) for Parkinson’s disease (24 mg/day) on a mg/m2 basis. The combined oral administration of ropinirole at 8 times the MRHD and a clinically relevant dose of L‑dopa to pregnant rabbits during organogenesis produced a greater incidence and severity of fetal malformations (primarily digit defects) than were seen in the offspring of rabbits treated with L-dopa alone. No effect on fetal development was observed in rabbits when ropinirole was administered alone at an oral dose 16 times the MRHD on a mg/m2 basis. In a perinatal-postnatal study in rats, impaired growth and development of nursing offspring and altered neurological development of female offspring were observed when dams were treated with 4 times the MRHD on a mg/m2 basis.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ropinirole in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Ropinirole during labor and delivery.
### Nursing Mothers
- Ropinirole inhibits prolactin secretion in humans and could potentially inhibit lactation. Ropinirole has been detected in rat milk. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when REQUIP is administered to a nursing woman.
### Pediatric Use
- Safety and effectiveness in pediatric patients have not been established.
### Geriatic Use
- Dose adjustment is not necessary in elderly (65 years and older) patients, as the dose of REQUIP is individually titrated to clinical therapeutic response and tolerability. Pharmacokinetic trials conducted in patients demonstrated that oral clearance of ropinirole is reduced by 15% in patients older than 65 years compared with younger patients.
- In clinical trials of extended-release ropinirole for Parkinson’s disease, 387 patients were 65 years and older and 107 patients were 75 years and older. Among patients receiving extended-release ropinirole, hallucination was more common in elderly patients (10%) compared with non-elderly patients (2%). The incidence of overall adverse reactions increased with increasing age for both patients receiving extended-release ropinirole and placebo.
### Gender
There is no FDA guidance on the use of Ropinirole with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Ropinirole with respect to specific racial populations.
### Renal Impairment
- No dose adjustment is necessary in patients with moderate renal impairment (creatinine clearance of 30 to 50 mL/min). For patients with end-stage renal disease on hemodialysis, a reduced maximum dose is recommended.
- The use of REQUIP in patients with severe renal impairment (creatinine clearance less than 30 mL/min) without regular dialysis has not been studied.
### Hepatic Impairment
- The pharmacokinetics of ropinirole have not been studied in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Ropinirole in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Ropinirole in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Ropinirole in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Ropinirole in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- The symptoms of overdose with REQUIP are generally related to its dopaminergic activity.
- In the Parkinson’s disease program, there have been patients who accidentally or intentionally took more than their prescribed dose of ropinirole. The largest overdose reported with ropinirole in clinical trials was 435 mg taken over a 7-day period (62.1 mg/day). Of patients who received a dose greater than 24 mg/day, reported symptoms included adverse events commonly reported during dopaminergic therapy (nausea, dizziness), as well as visual hallucinations, hyperhidrosis, claustrophobia, chorea, palpitations, asthenia, and nightmares. Additional symptoms reported for doses of 24 mg or less or for overdoses of unknown amount included vomiting, increased coughing, fatigue, syncope, vasovagal syncope, dyskinesia, agitation, chest pain, orthostatic hypotension, somnolence, and confusional state.
### Management
- General supportive measures are recommended. Vital signs should be maintained, if necessary.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Ropinirole in the drug label.
# Pharmacology
## Mechanism of Action
- Ropinirole is a non-ergoline dopamine agonist. The precise mechanism of action of ropinirole as a treatment for Parkinson’s disease is unknown, although it is thought to be related to its ability to stimulate dopamine D2 receptors within the caudate-putamen in the brain. The precise mechanism of action of ropinirole as a treatment for Restless Legs Syndrome is unknown, although it is thought to be related to its ability to stimulate dopamine receptors.
## Structure
- REQUIP contains ropinirole, a non-ergoline dopamine agonist, as the hydrochloride salt. The chemical name of ropinirole hydrochloride is 4-[2-(dipropylamino)ethyl]-1,3-dihydro-2H-indol-2-one and the empirical formula is C16H24N2O•HCl. The molecular weight is 296.84 (260.38 as the free base).
- Ropinirole hydrochloride is a white to yellow solid with a melting range of 243° to 250°C and a solubility of 133 mg/mL in water.
- Each pentagonal film-coated TILTAB® tablet with beveled edges contains 0.29 mg, 0.57 mg, 1.14 mg, 2.28 mg, 3.42 mg, 4.56 mg , or 5.70 mg ropinirole hydrochloride equivalent to ropinirole, 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, or 5 mg. Inactive ingredients consist of croscarmellose sodium, hydrous lactose, magnesium stearate, microcrystalline cellulose, and one or more of the following: carmine, FD&C Blue No. 2 aluminum lake, FD&C Yellow No. 6 aluminum lake, hypromellose, iron oxides, polyethylene glycol, polysorbate 80, titanium dioxide.
## Pharmacodynamics
- Clinical experience with dopamine agonists, including ropinirole, suggests an association with impaired ability to regulate blood pressure with resulting orthostatic hypotension, especially during dose escalation. In some patients in clinical trials, blood pressure changes were associated with the emergence of orthostatic symptoms, bradycardia, and, in one case in a healthy volunteer, transient sinus arrest with syncope.
- The mechanism of orthostatic hypotension induced by ropinirole is presumed to be due to a D2-mediated blunting of the noradrenergic response to standing and subsequent decrease in peripheral vascular resistance. Nausea is a common concomitant symptom of orthostatic signs and symptoms.
- At oral doses as low as 0.2 mg, ropinirole suppressed serum prolactin concentrations in healthy male volunteers.
- Ropinirole had no dose-related effect on ECG wave form and rhythm in young, healthy, male volunteers in the range of 0.01 to 2.5 mg.
- Ropinirole had no dose- or exposure-related effect on mean QT intervals in healthy male and female volunteers titrated to doses up to 4 mg/day. The effect of ropinirole on QTc intervals at higher exposures achieved either due to drug interactions, hepatic impairment, or at higher doses has not been systematically evaluated.
## Pharmacokinetics
- Ropinirole displayed linear kinetics over the dosing range of 1 to 8 mg three times daily. Steady-state concentrations are expected to be achieved within 2 days of dosing. Accumulation upon multiple dosing is predictive from single dosing.
- Absorption
- Ropinirole is rapidly absorbed after oral administration, reaching peak concentration in approximately 1 to 2 hours. In clinical trials, more than 88% of a radiolabeled dose was recovered in urine and the absolute bioavailability was 45% to 55%, indicating approximately 50% first-pass effect.
- Relative bioavailability from a tablet compared with an oral solution is 85%. Food does not affect the extent of absorption of ropinirole, although its Tmax is increased by 2.5 hours and its Cmax is decreased by approximately 25% when the drug is taken with a high-fat meal.
- Distribution
- Ropinirole is widely distributed throughout the body, with an apparent volume of distribution of 7.5 L/kg. It is up to 40% bound to plasma proteins and has a blood-to-plasma ratio of 1:1.
- Metabolism
- Ropinirole is extensively metabolized by the liver. The major metabolic pathways are N-despropylation and hydroxylation to form the inactive N-despropyl metabolite and hydroxy metabolites. The N-despropyl metabolite is converted to carbamyl glucuronide, carboxylic acid, and N-despropyl hydroxy metabolites. The hydroxy metabolite of ropinirole is rapidly glucuronidated.
- In vitro studies indicate that the major cytochrome P450 enzyme involved in the metabolism of ropinirole is CYP1A2, an enzyme known to be induced by smoking and omeprazole and inhibited by, for example, fluvoxamine, mexiletine, and the older fluoroquinolones such as ciprofloxacin and norfloxacin.
- Elimination
- The clearance of ropinirole after oral administration is 47 L/h and its elimination half-life is approximately 6 hours. Less than 10% of the administered dose is excreted as unchanged drug in urine. N-despropyl ropinirole is the predominant metabolite found in urine (40%), followed by the carboxylic acid metabolite (10%), and the glucuronide of the hydroxy metabolite (10%).
- Drug Interactions
- Digoxin: Coadministration of REQUIP (2 mg three times daily) with digoxin (0.125 to 0.25 mg once daily) did not alter the steady-state pharmacokinetics of digoxin in 10 patients.
- Theophylline: Administration of theophylline (300 mg twice daily, a substrate of CYP1A2) did not alter the steady-state pharmacokinetics of ropinirole (2 mg three times daily) in 12 patients with Parkinson’s disease. REQUIP (2 mg three times daily) did not alter the pharmacokinetics of theophylline (5 mg/kg IV) in 12 patients with Parkinson’s disease.
- Ciprofloxacin: Coadministration of ciprofloxacin (500 mg twice daily), an inhibitor of CYP1A2, with REQUIP (2 mg three times daily) increased ropinirole AUC by 84% on average and Cmax by 60% (n = 12 patients).
- Estrogens: Population pharmacokinetic analysis revealed that estrogens (mainly ethinylestradiol: intake 0.6 to 3 mg over 4-month to 23-year period) reduced the oral clearance of ropinirole by 36% in 16 patients.
- L-dopa: Coadministration of carbidopa + L-dopa (10/100 mg twice daily) with REQUIP (2 mg three times daily) had no effect on the steady-state pharmacokinetics of ropinirole (n = 28 patients). Oral administration of REQUIP 2 mg three times daily increased mean steady-state Cmax of L-dopa by 20%, but its AUC was unaffected (n = 23 patients).
- Commonly Administered Drugs: Population analysis showed that commonly administered drugs, e.g., selegiline, amantadine, tricyclic antidepressants, benzodiazepines, ibuprofen, thiazides, antihistamines, and anticholinergics, did not affect the clearance of ropinirole. An in vitro study indicates that ropinirole is not a substrate for P-gp. Ropinirole and its circulating metabolites do not inhibit or induce P450 enzymes; therefore, ropinirole is unlikely to affect the pharmacokinetics of other drugs by a P450 mechanism.
- Specific Populations
- Because therapy with REQUIP is initiated at a low dose and gradually titrated upward according to clinical tolerability to obtain the optimum therapeutic effect, adjustment of the initial dose based on gender, weight, or age is not necessary.
- Age
- Oral clearance of ropinirole is reduced by 15% in patients older than 65 years compared with younger patients. Dosage adjustment is not necessary in the elderly (older than 65 years), as the dose of ropinirole is to be individually titrated to clinical response.
- Gender
- Female and male patients showed similar clearance.
- Race
- The influence of race on the pharmacokinetics of ropinirole has not been evaluated.
- Cigarette Smoking
- Smoking is expected to increase the clearance of ropinirole since CYP1A2 is known to be induced by smoking. In a trial in patients with RLS, smokers (n = 7) had an approximately 30% lower Cmax and a 38% lower AUC than did nonsmokers (n = 11) when those parameters were normalized for dose.
- Renal Impairment
- Based on population pharmacokinetic analysis, no difference was observed in the pharmacokinetics of ropinirole in subjects with moderate renal impairment (creatinine clearance between 30 to 50 mL/min) compared with an age-matched population with creatinine clearance above 50 mL/min. Therefore, no dosage adjustment is necessary in patients with moderate renal impairment.
- A trial of ropinirole in subjects with end-stage renal disease on hemodialysis has shown that clearance of ropinirole was reduced by approximately 30%. The recommended maximum dose should be lower in these patients.
- The use of ropinirole in subjects with severe renal impairment (creatinine clearance less than 30 mL/min) without regular dialysis has not been studied.
- Hepatic Impairment
- The pharmacokinetics of ropinirole have not been studied in patients with hepatic impairment. Because ropinirole is extensively metabolized by the liver, these patients may have higher plasma levels and lower clearance of ropinirole than patients with normal hepatic function.
- Other Diseases
- Population pharmacokinetic analysis revealed no change in the clearance of ropinirole in patients with concomitant diseases such as hypertension, depression, osteoporosis/arthritis, and insomnia compared with patients with Parkinson’s disease only.
## Nonclinical Toxicology
- Carcinogenesis
- Two-year carcinogenicity studies of ropinirole were conducted in mice at oral doses of 5, 15, and 50 mg/kg/day and in rats at oral doses of 1.5, 15, and 50 mg/kg/day.
- In rats, there was an increase in testicular Leydig cell adenomas at all doses tested. The lowest dose tested (1.5 mg/kg/day) is less than the MRHD for Parkinson’s disease (24 mg/day) on a mg/m2 basis. The endocrine mechanisms believed to be involved in the production of these tumors in rats are not considered relevant to humans.
- In mice, there was an increase in benign uterine endometrial polyps at a dose of 50 mg/kg/day. The highest dose not associated with this finding (15 mg/kg/day) is three times the MRHD on a mg/m2 basis.
- Mutagenesis
- Ropinirole was not mutagenic or clastogenic in in vitro (Ames, chromosomal aberration in human lymphocytes, mouse lymphoma tk) assays or in the in vivo mouse micronucleus test.
- Impairment of Fertility
- When administered to female rats prior to and during mating and throughout pregnancy, ropinirole caused disruption of implantation at oral doses of 20 mg/kg/day (8 times the MRHD on a mg/m2 basis) or greater. This effect in rats is thought to be due to the prolactin-lowering effect of ropinirole. In rat studies using a low oral dose (5 mg/kg) during the prolactin-dependent phase of early pregnancy (gestation days 0 to 8), ropinirole did not affect female fertility at oral doses up to 100 mg/kg/day (40 times the MRHD on a mg/m2 basis). No effect on male fertility was observed in rats at oral doses up to 125 mg/kg/day (50 times the MRHD on a mg/m2 basis).
# Clinical Studies
- Parkinson’s Disease
- The effectiveness of REQUIP in the treatment of Parkinson’s disease was evaluated in a multinational drug development program consisting of 11 randomized, controlled trials. Four trials were conducted in patients with early Parkinson’s disease and no concomitant levodopa (L-dopa) and seven trials were conducted in patients with advanced Parkinson’s disease with concomitant L-dopa.
- Three placebo‑controlled trials provide evidence of effectiveness of REQUIP in the management of patients with Parkinson’s disease who were and were not receiving concomitant L-dopa. Two of these three trials enrolled patients with early Parkinson’s disease (without L-dopa) and one enrolled patients receiving L-dopa.
- In these trials a variety of measures were used to assess the effects of treatment (e.g., the Unified Parkinson’s Disease Rating Scale [UPDRS], Clinical Global Impression [CGI] scores, patient diaries recording time “on” and “off,” tolerability of L-dopa dose reductions).
- In both trials of patients with early Parkinson’s disease (without L-dopa), the motor component (Part III) of the UPDRS was the primary outcome assessment. The UPDRS is a multi-item rating scale intended to evaluate mentation (Part I), activities of daily living (Part II), motor performance (Part III), and complications of therapy (Part IV). Part III of the UPDRS contains 14 items designed to assess the severity of the cardinal motor findings in patients with Parkinson’s disease (e.g., tremor, rigidity, bradykinesia, postural instability) scored for different body regions and has a maximum (worst) score of 108. In the trial of patients with advanced Parkinson’s disease (with L-dopa), both reduction in percent awake time spent “off” and the ability to reduce the daily use of L-dopa were assessed as a combined endpoint and individually.
- Trials in Patients with Early Parkinson’s Disease (without L-dopa)
- Trial 1 was a 12-week multicenter trial in which 63 patients with idiopathic Parkinson’s disease receiving concomitant anti-Parkinson medication (but not L-dopa) were enrolled and 41 were randomized to REQUIP and 22 to placebo. Patients had a mean disease duration of approximately 2 years. Patients were eligible for enrollment if they presented with bradykinesia and at least tremor, rigidity, or postural instability. In addition, they must have been classified as Hoehn & Yahr Stage I-IV. This scale, ranging from I = unilateral involvement with minimal impairment to V = confined to wheelchair or bed, is a standard instrument used for staging patients with Parkinson’s disease. The primary outcome measure in this trial was the proportion of patients experiencing a decrease (compared with baseline) of at least 30% in the UPDRS motor score.
- Patients were titrated for up to 10 weeks, starting at 0.5 mg twice daily, with weekly increments of 0.5 mg twice daily to a maximum of 5 mg twice daily. Once patients reached their maximally tolerated dose (or 5 mg twice daily), they were maintained on that dose through 12 weeks. The mean dose achieved by patients at trial endpoint was 7.4 mg/day. Mean baseline UPDRS motor score was 18.6 for patients treated with REQUIP and 19.9 for patients treated with placebo. At the end of 12 weeks, the percentage of responders was greater on REQUIP than on placebo and the difference was statistically significant (Table 6).
- Trial 2 in patients with early Parkinson’s disease (without L-dopa) was a double‑blind, randomized, placebo-controlled, 6-month trial. In this trial, 241 patients were enrolled and 116 were randomized to REQUIP and 125 to placebo. Patients were essentially similar to those in the trial described above; concomitant use of selegiline was allowed, but patients were not permitted to use anticholinergics or amantadine during the trial. Patients had a mean disease duration of 2 years and limited (not more than a 6-week period) or no prior exposure to L-dopa. The starting dosage of REQUIP in this trial was 0.25 mg three times daily. The dosage was titrated at weekly intervals by increments of 0.25 mg three times daily to a dosage of 1 mg three times daily. Further titrations at weekly intervals were at increments of 0.5 mg three times daily up to a dosage of 3 mg three times daily, and then weekly at increments of 1 mg three times daily. Patients were to be titrated to a dosage of at least 1.5 mg three times daily and then to their maximally tolerated dosage, up to a maximum of 8 mg three times daily. The mean dose attained in patients at trial endpoint was 15.7 mg/day.
- The primary measure of effectiveness was the mean percent reduction (improvement) from baseline in the UPDRS motor score. At the end of the 6-month trial, patients treated with REQUIP showed improvement in motor score compared with placebo and the difference was statistically significant (Table 7).
- Trial in Patients with Advanced Parkinson’s Disease (with L-dopa)
- Trial 3 was a double-blind, randomized, placebo-controlled, 6-month trial that randomized 149 patients (Hoehn & Yahr II‑IV) who were not adequately controlled on L-dopa. Ninety-five patients were randomized to REQUIP and 54 were randomized to placebo. Patients in this trial had a mean disease duration of approximately 9 years, had been exposed to L-dopa for approximately 7 years, and had experienced “on-off” periods with L-dopa therapy. Patients previously receiving stable doses of selegiline, amantadine, and/or anticholinergic agents could continue on these agents during the trial. Patients were started at a dosage of 0.25 mg three times daily of REQUIP and titrated upward by weekly intervals until an optimal therapeutic response was achieved. The maximum dosage of trial medication was 8 mg three times daily. All patients had to be titrated to at least a dosage of 2.5 mg three times daily. Patients could then be maintained on this dosage level or higher for the remainder of the trial. Once a dosage of 2.5 mg three times daily was achieved, patients underwent a mandatory reduction in their L-dopa dosage, to be followed by additional mandatory reductions with continued escalation of the dosage of REQUIP. Reductions in the dosage of l-dopa were also allowed if patients experienced adverse reactions that the investigator considered related to dopaminergic therapy. The mean dose attained at trial endpoint was 16.3 mg/day. The primary outcome was the proportion of responders, defined as patients who were able both to achieve a decrease (compared with baseline) of at least 20% in their L-dopa dosage and a decrease of at least 20% in the proportion of the time awake in the “off” condition (a period of time during the day when patients are particularly immobile), as determined by subject diary. In addition, the mean change in “off” time from baseline and the percent change from baseline in daily L-dopa dosage were examined.
- At the end of 6 months, the percentage of responders was greater on REQUIP than on placebo and the difference was statistically significant (Table 8).
- Based on the protocol-mandated reductions in L-dopa dosage with escalating doses of REQUIP, patients treated with REQUIP had a 19.4% mean reduction in L-dopa dosage while patients treated with placebo had a 3% reduction. Mean daily L-dopa dosage at baseline was 759 mg for patients treated with REQUIP and 843 mg for patients treated with placebo.
- The mean number of daily “off” hours at baseline was 6.4 hours for patients treated with REQUIP and 7.3 hours for patients treated with placebo. At the end of the 6-month trial, there was a mean reduction of 1.5 hours of “off” time in patients treated with REQUIP and a mean reduction of 0.9 hours of “off” time in patients treated with placebo, resulting in a treatment difference of 0.6 hours of “off” time.
- Restless Legs Syndrome
- The effectiveness of REQUIP in the treatment of RLS was demonstrated in randomized, double-blind, placebo-controlled trials in adults diagnosed with RLS using the International Restless Legs Syndrome Study Group diagnostic criteria. Patients were required to have a history of a minimum of 15 RLS episodes/month during the previous month and a total score of ≥15 on the International RLS Rating Scale (IRLS scale) at baseline. Patients with RLS secondary to other conditions (e.g., pregnancy, renal failure, anemia) were excluded. All trials employed flexible dosing, with patients initiating therapy at 0.25 mg REQUIP once daily. Patients were titrated based on clinical response and tolerability over 7 weeks to a maximum of 4 mg once daily. All doses were taken between 1 and 3 hours before bedtime.
- A variety of measures were used to assess the effects of treatment, including the IRLS scale and Clinical Global Impression-Global Improvement (CGI-I) scores. The IRLS scale contains 10 items designed to assess the severity of sensory and motor symptoms, sleep disturbance, daytime somnolence, and impact on activities of daily living and mood associated with RLS. The range of scores is 0 to 40, with 0 being absence of RLS symptoms and 40 the most severe symptoms. Three of the controlled trials utilized the change from baseline in the IRLS scale at the Week 12 endpoint as the primary efficacy outcome.
- Three hundred eighty patients were randomized to receive REQUIP (n = 187) or placebo (n = 193) in a US trial (RLS-1); 284 were randomized to receive either REQUIP (n = 146) or placebo (n = 138) in a multinational trial (excluding US) (RLS-2); and 267 patients were randomized to REQUIP (n = 131) or placebo (n = 136) in a multinational trial (including US) (RLS-3). Across the three trials, the mean duration of RLS was 16 to 22 years (range: 0 to 65 years), mean age was approximately 54 years (range: 18 to 79 years), and approximately 61% were women. The mean dose at Week 12 was approximately 2 mg/day for the three trials.
- At baseline, mean total IRLS score was 22.0 for REQUIP and 21.6 for placebo in RLS-1, was 24.4 for REQUIP and 25.2 for placebo in RLS-2, and was 23.6 for REQUIP and 24.8 for placebo in RLS-3. In all three trials, a statistically significant difference between the treatment group receiving REQUIP and the treatment group receiving placebo was observed at Week 12 for both the mean change from baseline in the IRLS scale total score and the percentage of patients rated as responders (much improved or very much improved) on the CGI-I (see Table 9).
- Long-term maintenance of efficacy in the treatment of RLS was demonstrated in a 36‑week trial. Following a 24-week, single-blind treatment phase (flexible dosages of REQUIP of 0.25 to 4 mg once daily), patients who were responders (defined as a decrease of >6 points on the IRLS scale total score relative to baseline) were randomized in double-blind fashion to placebo or continuation of REQUIP for an additional 12 weeks. Relapse was defined as an increase of at least 6 points on the IRLS scale total score to a total score of at least 15, or withdrawal due to lack of efficacy. For patients who were responders at Week 24, the mean dose of REQUIP was 2 mg (range: 0.25 to 4 mg).Patientscontinued on REQUIP demonstrated a significantly lower relapse rate compared with patients randomized to placebo (32.6% versus 57.8%, P = 0.0156).
# How Supplied
- Each pentagonal film-coated TILTAB® tablet with beveled edges contains ropinirole hydrochloride equivalent to the labeled amount of ropinirole as follows:
- 0.25 mg: white tablets imprinted with “SB” and “4890” in bottles of 100 (NDC 0007-4890-20)
- 0.5 mg: yellow tablets imprinted with “SB” and “4891” in bottles of 100 (NDC 0007-4891-20)
- 1 mg: green tablets imprinted with “SB” and “4892” in bottles of 100 (NDC 0007-4892-20)
- 2 mg: pale yellowish-pink tablets imprinted with “SB” and “4893” in bottles of 100 (NDC 0007-4893-20)
- 3 mg: pale to moderate reddish-purple tablets, imprinted with “SB” and “4895” in bottles of 100 (NDC 0007-4895-20)
- 4 mg: pale brown tablets imprinted with “SB” and “4896” in bottles of 100 (NDC 0007-4896-20)
- 5 mg: blue tablets imprinted with “SB” and “4894” in bottles of 100 (NDC 0007-4894-20)
- Storage
- Store at controlled room temperature 20° - 25°C (68° - 77°F) [see USP]. Protect from light and moisture. Close container tightly after each use.
## Storage
There is limited information regarding Ropinirole Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise the patient to read the FDA-approved patient labeling (Patient Information).
- Dosing Instructions
- Instruct patients to take REQUIP only as prescribed. If a dose is missed, advise patients not to double their next dose. REQUIP can be taken with or without food.
- Ropinirole is the active ingredient in both REQUIP XL and REQUIP tablets (the immediate‑release formulation). Ask your patients if they are taking another medication containing ropinirole.
- Hypersensitivity/Allergic Reactions
- Advise patients about the potential for developing a hypersensitivity/allergic reaction including manifestations such as urticaria, angioedema, rash, and pruritus when taking any ropinirole product. Inform patients who experience these or similar reactions to immediately contact their healthcare professional.
- Falling Asleep during Activities of Daily Living and Somnolence
- Alert patients to the potential sedating effects caused by REQUIP, including somnolence and the possibility of falling asleep while engaged in activities of daily living. Because somnolence is a frequent adverse reaction with potentially serious consequences, patients should not drive a car, operate machinery, or engage in other potentially dangerous activities until they have gained sufficient experience with REQUIP to gauge whether or not it affects their mental and/or motor performance adversely. Advise patients that if increased somnolence or episodes of falling asleep during activities of daily living (e.g., conversations, eating, driving a motor vehicle, etc.) are experienced at any time during treatment, they should not drive or participate in potentially dangerous activities until they have contacted their physician.
- Advise patients of possible additive effects when patients are taking other sedating medications, alcohol, or other central nervous system depressants (e.g., benzodiazepines, antipsychotics, antidepressants, etc.) in combination with REQUIP or when taking a concomitant medication (e.g., ciprofloxacin) that increases plasma levels of ropinirole.
- Syncope and Hypotension/Orthostatic Hypotension
- Advise patients that they may experience syncope and may develop hypotension with or without symptoms such as dizziness, nausea, syncope, and sometimes sweating while taking REQUIP, especially if they are elderly. Hypotension and/or orthostatic symptoms may occur more frequently during initial therapy or with an increase in dose at any time (cases have been seen after weeks of treatment).Postural/orthostatic symptoms may be related to sitting up or standing. Accordingly, caution patients against standing rapidly after sitting or lying down, especially if they have been doing so for prolonged periods and especially at the initiation of treatment with REQUIP.
- Hallucinations/Psychotic-like Behavior
- Inform patients that they may experience hallucinations (unreal visions, sounds, or sensations), and that other psychotic-like behavior can occur while taking REQUIP. The elderly are at greater risk than younger patients with Parkinson’s disease. This risk is greater in patients who are taking REQUIP with L-dopa or taking higher doses of REQUIP and may also be further increased in patients taking any other drugs that increase dopaminergic tone. Tell patients to report hallucinations or psychotic-like behavior to their healthcare provider promptly should they develop.
- Dyskinesia
- Inform patients that REQUIP may cause and/or exacerbate pre-existing dyskinesias.
- Impulse Control/Compulsive Behaviors
- Advise patients that they may experience impulse control and/or compulsive behaviors while taking one or more of the medications (including REQUIP) that increase central dopaminergic tone, that are generally used for the treatment of Parkinson’s disease. Advise patients to inform their physician or healthcare provider if they develop new or increased gambling urges, sexual urges, uncontrolled spending, binge or compulsive eating, or other urges while being treated with REQUIP. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking REQUIP.
- Withdrawal-emergent Hyperpyrexia and Confusion
- Advise patients to contact their healthcare provider if they wish to discontinue REQUIP or decrease the dose of REQUIP.
- Melanoma
- Advise patients with Parkinson’s disease that they have a higher risk of developing melanoma. Advise patients to have their skin examined on a regular basis by a qualified healthcare provider (e.g., dermatologist) when using REQUIP for any indication.
- Augmentation and Rebound
- Inform patients with RLS that augmentation and/or rebound may occur after starting treatment with REQUIP.
- Nursing Mothers
- Because of the possibility that ropinirole may be excreted in breast milk, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Advise patients that REQUIP could inhibit lactation because ropinirole inhibits prolactin secretion.
- Pregnancy
- Because ropinirole has been shown to have adverse effects on embryo-fetal development, including teratogenic effects, in animals, and because experience in humans is limited, advise patients to notify their physician if they become pregnant or intend to become pregnant during therapy.
# Precautions with Alcohol
- Alcohol-Ropinirole interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- REQUIP®[2]
# Look-Alike Drug Names
- rOPINIRole hydrochloride® — risperiDONE®[3]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/ReQuip_Follow_on_Pack | |
84c8d3ab74f712ed426ebd0186091f816e4c201a | wikidoc | Reboxetine | Reboxetine
Reboxetine (brand names: Edronax (AU, IE, IL, NZ, ZA, UK), Prolift (AR,† BR, CL, VE†)) is a drug of the norepinephrine reuptake inhibitor class, marketed as an antidepressant by Pfizer for use in the treatment of unipolar depression, although it has also been used off-label for panic disorder and ADHD. It is approved for use in many countries worldwide, but has not been approved for use in the United States. Although its efficacy as an antidepressant has been challenged in multiple published reports, its popularity has continued to increase.
# Medical uses
## Major depressive disorder
There has been much debate as to whether reboxetine is more efficacious than placebo into the treatment of depression. According to a 2009 meta-analysis of 12 second-generation antidepressants, reboxetine was no more effective than placebo, and was "significantly less" effective, and less acceptable, than the other drugs in treating the acute-phase of adults with unipolar major depression.
The British MHRA said in September 2011 that the study had several limitations, and that "Overall the balance of benefits and risks for reboxetine remains positive in its authorised indication." A UK and Europe-wide review of available efficacy and safety data has confirmed that reboxetine has benefit over placebo in its authorised indication. Efficacy was clearly shown in patients with severe or very severe depression.
According to a systematic review and meta-analysis by IQWiG, including unpublished data, published data on reboxetine overestimated the benefit of reboxetine versus placebo by up to 115% and reboxetine versus SSRIs by up to 23%, and also underestimated harm, concluding that reboxetine was an ineffective and potentially harmful antidepressant. The study also showed that nearly three quarters of the data on patients who took part in trials of reboxetine were not published by Pfizer until now.
## Panic disorder
In a randomised double-blind placebo-controlled trial reboxetine significantly improved the symptoms of panic disorder. Another randomised controlled trial that compared paroxetine to reboxetine found that paroxetine significantly outperformed reboxetine as a treatment for panic disorder. Despite this discouraging finding an open-label trial examining the efficacy of reboxetine in SSRI-resistant panic disorder demonstrated significant benefit from reboxetine treatment.
## Attention deficit hyperactivity disorder
Numerous clinical trials have provided support for the efficacy of reboxetine in the treatment of attention deficit hyperactivity disorder (ADHD) in both the short and long-term and in both children/adolescents and adults.
## Other uses
A case series and open-label pilot study have demonstrated the efficacy of reboxetine in treating bulimia nervosa. Reboxetine's efficacy in treating therapy-resistant paediatric nocturnal enuresis. A pilot study demonstrated the efficacy of reboxetine in the treatment of narcolepsy. Reboxetine may also attenuate olanzapine-induced weight gain.
# Adverse effects
Incidence of adverse effects
Very common (>10% incidence) adverse effects include:
- Insomnia
- Nausea
- Excessive sweating
- Dry mouth
- Constipation
Common (1-10%) adverse effects include:
- Appetite loss
- Agitation
- Anxiety
- Headache
- Dizziness
- Paraesthesia
- Akathisia
- Dysgeusia
- Accommodation disorder
- Tachycardia
- Palpitations
- Vasodilatation
- Hypotension (low blood pressure)
- Hypertension (high blood pressure)
- Vomiting
- Rash
- Sensation of incomplete bladder emptying
- Urinary tract infection
- Dysuria (painful or very difficult urination)
- Urinary retention
- Chills
- Erectile dysfunction
- Ejaculatory pain
- Ejaculatory delay
Uncommon (0.1-1%) adverse effects include:
- Mydriasis
- Vertigo
Rare (<0.1%) adverse effects include:
- Glaucoma
Unknown frequency adverse effects include:
- Hyponatraemia (low blood sodium)
- Aggressive behaviour
- Hallucination
- Suicidal Ideation/behaviour
- Increased intraocular pressure
- Peripheral coldness
- Raynaud`s phenomenon
- Allergic dermatitis
- Testicular pain
- Irritability
Overall in the aforementioned 2009 meta-analysis reboxetine was significantly less well-tolerated than the other 11 second-generation antidepressants compared in the analysis.
## Contraindications
Reboxetine is contraindicated in narrow-angle glaucoma, cardiovascular disease, epilepsy, bipolar disorder, urinary retention, prostatic hypertrophy, patients concomitantly on MAOIs and those hypersensitive to reboxetine or any of its excipients.
## Interactions
Because of its reliance on CYP3A4, reboxetine O-desethylation is markedly inhibited by papaverine and ketoconazole. It weakly inhibits CYP2D6 and CYP3A4. Reboxetine is an intermediate-level inhibitor of P-glycoprotein, which gives it the potential to interact with ciclosporin, tacrolimus, paroxetine, sertraline, quinidine, fluoxetine, fluvoxamine.
## Overdose
Reboxetine is considered a relatively low-risk antidepressant in overdose. The symptoms are as follows:
- Sweating
- Tachycardia
- Changes in blood pressure
# Pharmacology
Pharmacodynamics
Reboxetine is a fairly selective norepinephrine reuptake inhibitor (NRI) with approximately 20.4x selectivity for the norepinephrine transporter over the serotonin transporter. Despite this selectivity reboxetine does slightly inhibit the reuptake of serotonin at therapeutic doses.
Reboxetine has been found to inhibit both brain and cardiac GIRKs, a characteristic it shares with the norepinephrine reuptake inhibitor atomoxetine.
Binding profile
Pharmacokinetics
Both the (R,R)-(–) and (S,S)-(+)-enantiomers of reboxetine are predominantly metabolized by the CYP3A4 isoenzyme.
The primary metabolite of reboxetine is O-desethylreboxetine, and there are also three minor metabolites—Phenol A, Phenol B, and UK1, Phenol B being the most minor.
# Chemistry
Reboxetine has two chiral centers. Thus, four stereoisomers may exist, the (R,R)-, (S,S)-, (R,S)-, and (S,R)-isomers. The active ingredient of reboxetine is a racemic mixture of two enantiomers, the (R,R)-(–)- and (S,S)-(+)-isomer.
# Society and culture
## Brand names
Edronax is the brand name of reboxetine in every English-speaking country that has approved it for clinical use. Brand names include (where † denotes a product that is no longer marketed):
- Davedax (IT)
- Edronax (AU, AT, BE, CZ, DK, FI, DE, IE, IL, IT, MX, NZ, NO, PH, PL, PT, RU, ZA, SE, CH, TH, TR, UK)
- Irenor (ES)
- Norebox (ES)
- Prolift (AR,† BR, CL, VE†)
- Solvex (DE)
- Yeluoshu (CN)
- Zuolexin (CN) | Reboxetine
Reboxetine (brand names: Edronax (AU, IE, IL, NZ, ZA, UK), Prolift (AR,† BR, CL, VE†))[3] is a drug of the norepinephrine reuptake inhibitor class, marketed as an antidepressant by Pfizer for use in the treatment of unipolar depression, although it has also been used off-label for panic disorder and ADHD. It is approved for use in many countries worldwide, but has not been approved for use in the United States. Although its efficacy as an antidepressant has been challenged in multiple published reports, its popularity has continued to increase.[4]
# Medical uses
## Major depressive disorder
There has been much debate as to whether reboxetine is more efficacious than placebo into the treatment of depression. According to a 2009 meta-analysis of 12 second-generation antidepressants, reboxetine was no more effective than placebo, and was "significantly less" effective, and less acceptable, than the other drugs in treating the acute-phase of adults with unipolar major depression.[5]
The British MHRA said in September 2011 that the study had several limitations, and that "Overall the balance of benefits and risks for reboxetine remains positive in its authorised indication."[6] A UK and Europe-wide review of available efficacy and safety data has confirmed that reboxetine has benefit over placebo in its authorised indication. Efficacy was clearly shown in patients with severe or very severe depression.[6]
According to a systematic review and meta-analysis by IQWiG, including unpublished data, published data on reboxetine overestimated the benefit of reboxetine versus placebo by up to 115% and reboxetine versus SSRIs by up to 23%, and also underestimated harm, concluding that reboxetine was an ineffective and potentially harmful antidepressant. The study also showed that nearly three quarters of the data on patients who took part in trials of reboxetine were not published by Pfizer until now.[4]
## Panic disorder
In a randomised double-blind placebo-controlled trial reboxetine significantly improved the symptoms of panic disorder.[7] Another randomised controlled trial that compared paroxetine to reboxetine found that paroxetine significantly outperformed reboxetine as a treatment for panic disorder.[8] Despite this discouraging finding an open-label trial examining the efficacy of reboxetine in SSRI-resistant panic disorder demonstrated significant benefit from reboxetine treatment.[9]
## Attention deficit hyperactivity disorder
Numerous clinical trials have provided support for the efficacy of reboxetine in the treatment of attention deficit hyperactivity disorder (ADHD) in both the short[10][11][12][13] and long-term[14][15] and in both children/adolescents[11][12][14][15] and adults.[10][13]
## Other uses
A case series and open-label pilot study have demonstrated the efficacy of reboxetine in treating bulimia nervosa.[16][17] Reboxetine's efficacy in treating therapy-resistant paediatric nocturnal enuresis.[18] A pilot study demonstrated the efficacy of reboxetine in the treatment of narcolepsy.[19] Reboxetine may also attenuate olanzapine-induced weight gain.[20]
# Adverse effects
Incidence of adverse effects[21][22]
Very common (>10% incidence) adverse effects include:
- Insomnia
- Nausea
- Excessive sweating
- Dry mouth
- Constipation
Common (1-10%) adverse effects include:
- Appetite loss
- Agitation
- Anxiety
- Headache
- Dizziness
- Paraesthesia
- Akathisia
- Dysgeusia
- Accommodation disorder
- Tachycardia
- Palpitations
- Vasodilatation
- Hypotension (low blood pressure)
- Hypertension (high blood pressure)
- Vomiting
- Rash
- Sensation of incomplete bladder emptying
- Urinary tract infection
- Dysuria (painful or very difficult urination)
- Urinary retention
- Chills
- Erectile dysfunction
- Ejaculatory pain
- Ejaculatory delay
Uncommon (0.1-1%) adverse effects include:
- Mydriasis
- Vertigo
Rare (<0.1%) adverse effects include:
- Glaucoma
Unknown frequency adverse effects include:
- Hyponatraemia (low blood sodium)
- Aggressive behaviour
- Hallucination
- Suicidal Ideation/behaviour
- Increased intraocular pressure
- Peripheral coldness
- Raynaud`s phenomenon
- Allergic dermatitis
- Testicular pain
- Irritability
Overall in the aforementioned 2009 meta-analysis reboxetine was significantly less well-tolerated than the other 11 second-generation antidepressants compared in the analysis.[5]
## Contraindications
Reboxetine is contraindicated in narrow-angle glaucoma, cardiovascular disease, epilepsy, bipolar disorder, urinary retention, prostatic hypertrophy, patients concomitantly on MAOIs and those hypersensitive to reboxetine or any of its excipients.[1][23]
## Interactions
Because of its reliance on CYP3A4, reboxetine O-desethylation is markedly inhibited by papaverine and ketoconazole.[24] It weakly inhibits CYP2D6 and CYP3A4.[21] Reboxetine is an intermediate-level inhibitor of P-glycoprotein, which gives it the potential to interact with ciclosporin, tacrolimus, paroxetine, sertraline, quinidine, fluoxetine, fluvoxamine.[25]
## Overdose
Reboxetine is considered a relatively low-risk antidepressant in overdose.[26] The symptoms are as follows:[26]
- Sweating
- Tachycardia
- Changes in blood pressure
# Pharmacology
Pharmacodynamics
Reboxetine is a fairly selective norepinephrine reuptake inhibitor (NRI) with approximately 20.4x selectivity for the norepinephrine transporter over the serotonin transporter.[27] Despite this selectivity reboxetine does slightly inhibit the reuptake of serotonin at therapeutic doses.[22]
Reboxetine has been found to inhibit both brain and cardiac GIRKs, a characteristic it shares with the norepinephrine reuptake inhibitor atomoxetine.[28]
Binding profile[29][30]
Pharmacokinetics
Both the (R,R)-(–) and (S,S)-(+)-enantiomers of reboxetine are predominantly metabolized by the CYP3A4 isoenzyme.[24]
The primary metabolite of reboxetine is O-desethylreboxetine, and there are also three minor metabolites—Phenol A, Phenol B, and UK1, Phenol B being the most minor.[24]
# Chemistry
Reboxetine has two chiral centers. Thus, four stereoisomers may exist, the (R,R)-, (S,S)-, (R,S)-, and (S,R)-isomers. The active ingredient of reboxetine is a racemic mixture of two enantiomers, the (R,R)-(–)- and (S,S)-(+)-isomer.[31]
# Society and culture
## Brand names
Edronax is the brand name of reboxetine in every English-speaking country that has approved it for clinical use. Brand names include (where † denotes a product that is no longer marketed):[3]
- Davedax (IT)
- Edronax (AU, AT, BE, CZ, DK, FI, DE, IE, IL, IT, MX, NZ, NO, PH, PL, PT, RU, ZA, SE, CH, TH, TR, UK)
- Irenor (ES)
- Norebox (ES)
- Prolift (AR,† BR, CL, VE†)
- Solvex (DE)
- Yeluoshu (CN)
- Zuolexin (CN) | https://www.wikidoc.org/index.php/Reboxetine | |
31cb2ce39c3b33c819d7b80e28693d19656a9ac8 | wikidoc | Rebreather | Rebreather
A rebreather is a type of breathing set that provides a breathing gas containing oxygen and recycles exhaled gas. This recycling reduces the volume of breathing gas used, making a rebreather lighter and more compact than an open-circuit breathing set for the same duration in environments where humans cannot safely breathe from the atmosphere. In the armed forces it is sometimes called "CCUBA" (Closed Circuit Underwater Breathing Apparatus).
# Basics
Rebreather technology is used in many environments:
- Underwater - where it is sometimes known as "closed circuit scuba" or "semi closed scuba", or CCUBA = "closed circuit underwater breathing apparatus", as opposed to Aqua-Lung-type equipment, which is known as "open circuit scuba".
- Mine rescue and in industry - where poisonous gases may be present or oxygen may be absent.
- Space suits - outer space is, for all intents and purposes, a vacuum where there is no oxygen to support life.
- Hospital anaesthesia breathing systems - to supply controlled proportions of gases to patients without letting anaesthetic gas get into the atmosphere that the staff breathe.
- Submarines and hyperbaric oxygen therapy chambers - where the gas in the habitat must remain safe. Here the rebreather is big and is connected to the air in the habitat.
This article is mainly about diving rebreathers.
As a person breathes, the body consumes oxygen and makes carbon dioxide. A person with an open-circuit breathing set typically only uses about a quarter of the oxygen in the air that is breathed in. The rest is breathed out along with nitrogen and carbon dioxide.
With a rebreather, the exhaled gas is not discharged to waste. The rebreather recovers the exhaled gas for re-use. It absorbs the carbon dioxide, which otherwise would accumulate and cause carbon dioxide poisoning. It adds oxygen to replace what was consumed. Thus, the gas in the rebreather's circuit remains breathable and supports life processes. Nearly always, the oxygen comes from a gas cylinder, and the carbon dioxide is absorbed in a canister full of some absorbent chemical designed for diving applications such as Sofnolime, Dragersorb or Sodasorb. Some systems also use a prepackaged Reactive Plastic Curtain (RPC) based cartridge, a common brand name for these RPC cartridges is ExtendAir. These absorbents may contain small amounts of soda lime, but are generally less toxic. Pure oxygen is not considered to be safe for recreational diving below 6 meters, so recreational rebreathers also have a diluent cylinder to reduce the percentage of oxygen breathed and enable them to be used to greater depths.
# History of rebreathers
Around 1620 in England, Cornelius Drebbel made an early oar-powered submarine. Records show that, to re-oxygenate the air inside it, he likely generated oxygen by heating saltpetre (sodium or potassium nitrate) in a metal pan to make it emit oxygen. That would turn the saltpetre into sodium or potassium oxide or hydroxide, which would tend to absorb carbon dioxide from the air around. That may explain how Drebbel's men were not affected by carbon dioxide build-up as much as would be expected. If so, he accidentally made a crude rebreather nearly three centuries before Fluess and Davis: see this link.
This page describes and shows a rebreather designed in 1853 in Belgium by Professor T. Schwann; he exhibited it in Paris in 1878.
The first certainly known closed circuit breathing device using stored oxygen and absorption of carbon dioxide by an absorbent (here caustic soda), was invented by Henry Fluess in 1879 to rescue mineworkers who were trapped by water.
The Davis Escape Set was the first rebreather which was practical for use and produced in quantity. It was designed about 1900 in Britain for escape from sunken submarines. Various industrial oxygen rebreathers (e.g. the Siebe Gorman Salvus and the Siebe Gorman Proto) were descended from it; this link shows a Draeger rebreather used for mines rescue in 1907.
The first known systematic use of rebreathers for diving was by Italian sport spearfishers in the 1930s. This practice came to the attention of the Italian Navy, which developed its frogman unit, which had a big effect in World War II. Image of wartime Italian frogman.
In World War II captured Italian frogmen's rebreathers influenced design of British frogman's rebreathers. Ref British commando frogmen#1942 at "April" for more information: Many British frogmen's breathing sets' oxygen cylinders were German pilot's oxygen cylinders recovered from shot-down German Luftwaffe planes. Those first breathing sets may have been modified Davis Submarine Escape Sets; their fullface masks were the type intended for the Siebe Gorman Salvus. But in later operations different designs were used, leading to a fullface mask with one big face window. One version had a flip-up single window for both eyes to let the user get binoculars to his eyes when on the surface. They used bulky thick diving suits called Sladen suits. Early British frogman's rebreathers had rectangular breathing bags on the chest like Italian frogman's rebreathers; later British frogman's rebreathers had a square recess in the top so they could extend further up onto his shoulders; in front they had a rubber collar that was clamped around the absorbent canister, as in the CGI image below.
US Navy rebreathers were developed by Dr. Christian J. Lambertsen in the early 1940s for underwater warfare. Dr. Lambertsen, who currently works at the University of Pennsylvania, is considered by the US Navy as "the father of the Frogmen". Information about early history of USA frogman's rebreathers is scarce because the many available photographs of UDT men and training and operations rarely show a rebreather, as if there was a secrecy law against it.
## Innovations in recreational diving rebreather technology
Over the past ten or fifteen years rebreather technology has advanced considerably often driven by the growing market in recreational diving equipment. Innovations include:
- The electronic, fully closed circuit rebreather itself - use of electronics and electro-galvanic fuel cells to monitor oxygen concentration within the loop and maintain a certain partial pressure of oxygen
- Automatic diluent valves - these inject diluent gas into the loop when the loop pressure falls below the limit at which the diver can comfortably breathe.
- Dive/surface valves or bailout valves - a device in the mouthpiece on the loop which connects to a bailout demand valve and can be switched to provide gas from either the loop or the demand valve without the diver taking the mouthpiece from his or her mouth. An important safety device when carbon dioxide poisoning occurs.
- Integrated decompression computers - these allow divers to take advantage of the decompression benefits provided by the ideal mix in the loop of a fully closed circuit rebreather. By monitoring the oxygen content of the mix they can work out the inert gas content and generate a schedule of decompression stops.
- Carbon dioxide scrubber life monitoring systems - temperature sensors monitor the progress of the reaction of the soda lime and provide an indication of when the scrubber will be exhausted.
# Advantages of rebreather diving
## Efficiency advantages
The main advantage of the rebreather over other breathing equipment is the rebreather's economical use of gas. With "open circuit" scuba, the entire breath is expelled into the surrounding water when the diver exhales. A breath inhaled from an open circuit scuba system whose cylinder(s) are filled with ordinary air is about 21% oxygen. When that breath is exhaled back into the surrounding environment, it has an oxygen level in the range of 15 to 16% when the diver is at atmospheric pressure. This leaves the available oxygen utilization at about 25%; the remaining 75% is lost.
At depth, the advantage of a rebreather is even more marked. The amount of CO2 in exhaled gas is not a constant percentage, but a constant partial pressure of about 0.04bar. The amount of oxygen used from each breath is about the same - so as the ambient pressure increases (as a result of going deeper), the percentage of oxygen used from each breath drops. At 30m (100ft), a diver's exhaled breath contains about 20% oxygen and about 1% CO2.
## Feasibility advantages
Long or deep dives using open circuit equipment may not be feasible as there are limits to the number and weight of diving cylinders the diver can carry. The economy of gas consumption is also useful when the gas mix being breathed contains expensive gases, such as helium. In normal use only oxygen is consumed: small volumes of expensive inert gases can be reused for many dives.
## Other advantages
Rebreathers produce far fewer bubbles and make less noise than open-circuit scuba; this can conceal military divers and allow divers engaged in marine biology and underwater photography to avoid alarming marine animals and thereby get closer to them. The electronic fully closed circuit rebreather, is able to minimise the proportion of inert gases in the breathing mix, and therefore minimise the decompression requirements of the diver, by maintaining a specific and relatively high oxygen partial pressure at all depths. The breathing gas in a rebreather is warmer and more moist than the dry and cold gas from open circuit equipment making it more comfortable to breathe on long dives and causing less dehydration in the diver.
# Parts of a rebreather
## The loop
Although there are several design variations of diving rebreather, all types have a gas-tight loop that the diver inhales from and exhales into. The loop consists of components sealed together. The diver breathes through a mouthpiece or a fullface mask (or with industrial breathing sets, sometimes a mouth-and-nose mask). This is connected to one or more tubes bringing inhaled gas and exhaled gas between the diver and a counterlung or breathing bag. This holds gas when it is not in the diver's lungs. The loop also includes a scrubber containing carbon dioxide absorbent to remove from the loop the carbon dioxide exhaled by the diver. Attached to the loop there will be at least one valve allowing injection of gases, such as oxygen and perhaps a diluting gas, into the loop. There may be valves allowing venting of gas from the loop.
Most modern rebreathers have a twin hose mouthpiece or breathing mask where the direction of flow of gas through the loop is controlled by one-way valves. Some have a single pendulum hose, where the inhaled and exhaled gas passes through the same tube in opposite directions. The mouthpiece often has a valve letting the diver take the mouthpiece from the mouth while underwater or floating on the surface without water getting into the loop. Many rebreathers have "water traps" in the counterlungs, to stop large volumes of water from entering the loop if the diver removes the mouthpiece underwater without closing the valve, or if the diver's lips get slack letting water leak in.
## Carbon dioxide scrubber
The exhaled gases are forced through the chemical scrubber which removes the carbon dioxide from the gas mixture and leaves the oxygen and other gases available for re-breathing. The active ingredient of the scrubber is often soda lime. The carbon dioxide passing through the scrubber absorbent is removed when it reacts with the absorbent in the canister; this chemical reaction is exothermic. This reaction occurs along a "front" which is a cross section of the canister, of the unreacted soda lime that is exposed to carbon dioxide-laden gas. This front moves through the scrubber canister, from the gas input end to the gas output end, as the reaction consumes the active ingredients. However, this front would be a wide zone, because the carbon dioxide in the gas going through the canister needs time to reach the surface of a grain of absorbent, and then time to penetrate to the middle of each grain of absorbent as the outside of the grain becomes exhausted.
In larger environments, such as recompression chambers, a fan is used to pass gas through the canister.
### Scrubber failure
The term "break through" means the failure of the "scrubber" to continue removing carbon dioxide from the exhaled gas mix.
There are several ways that the scrubber may fail or become less efficient:
- Complete consumption of the active ingredient ("break through").
- The scrubber canister has been incorrectly packed or configured. This allows the exhaled gas to bypass the absorbent. In a rebreather, the soda lime must be packed tightly so that all exhaled gas comes into close contact with the granules of soda lime and the loop is designed to avoid any spaces or gaps between the soda lime and the loop walls that would let gas avoid contact with the adsorbent. If any of the seals, such as o rings, or spacers that prevent bypassing of the scrubber, are not cleaned or lubricated or fitted properly, the scrubber will be less efficient, or outside water or gas may get in circuit.
- When the gas mix is under pressure caused by depth, the inside of the canister is more crowded by other gas molecules (oxygen or diluent) and the carbon dioxide molecules are not so free to move around to reach the absorbent. In deep diving with a nitrox or other gas-mixture rebreather, the scrubber needs to be bigger than is needed for a shallow-water or industrial oxygen rebreather, because of this effect. Among British naval rebreather divers, this type of carbon dioxide poisoning was called shallow water blackout.
- A Caustic Cocktail - Soda lime is caustic and can cause burns to the eyes and skin. A "caustic cocktail" is a mixture of water and soda lime that occurs when the "scrubber" floods. It gives rise to a chalky taste, which should prompt the diver to switch to an alternative source of breathing gas and rinse his or her mouth out with water. Many modern diving rebreather absorbents are designed not to produce "cocktail" if they get wet.
### Failure prevention
- An indicating dye in the soda lime. It changes the colour of the soda lime after the active ingredient is consumed. For example, a rebreather absorbent called "Protosorb" supplied by Siebe Gorman had a red dye, which was said to go white when the absorbent was exhausted. With a transparent canister, this may be able to show the position of the reaction "front". This is useful in dry open environments, but is not useful on diving equipment, where:
A transparent canister would likely be brittle and easily cracked by knocks.
Opening the canister to look inside would flood it with water or get unbreathable outside gas in circuit.
The canister is usually out of sight of the user, e.g. inside the breathing bag or inside a backpack box.
- A transparent canister would likely be brittle and easily cracked by knocks.
- Opening the canister to look inside would flood it with water or get unbreathable outside gas in circuit.
- The canister is usually out of sight of the user, e.g. inside the breathing bag or inside a backpack box.
- Temperature monitoring. As the reaction between carbon dioxide and soda lime is exothermic, temperature sensors, most likely digital, along the length of the scrubber can be used to measure the position of the front and therefore the life of the scrubber.
- Diver training. Divers are trained to monitor and plan the exposure time of the soda lime in the scrubber and replace it within the recommended time limit. At present, there is no effective technology for detecting the end of the life of the scrubber or a dangerous increase in the concentration of carbon dioxide causing carbon dioxide poisoning. The diver must monitor the exposure of the scrubber and replace it when necessary.
- Carbon dioxide gas sensors exist, but they are not sensitive enough to be used in a rebreather - the scrubber "break through" occurs quite suddenly and the diver shows symptoms before the sensor indicates a dangerous build-up of carbon dioxide. Even if a sensitive carbon dioxide sensor is developed, it may not be useful as the primary tool for monitoring scrubber life when underwater, because mixed gas rebreathers allow very long dives where long decompression stops may be needed: knowing that the rebreather will begin to deliver a poisonous breathing gas in five minutes may not be useful to a diver needing to carry out an hour or more of decompression stops.
## Effectiveness
In rebreather diving, the typical effective duration of the scrubber will be half an hour to several hours of breathing, depending on the granularity and composition of the soda lime, the ambient temperature, the design of the rebreather, and the size of the canister. In some dry open environments, such as a recompression chamber or a hospital, it may be possible to put fresh absorbent in the canister when break through occurs.
## Controlling the mix
A basic need with a rebreather is to keep the amount of oxygen in the mix, or more technically known as the partial pressure of oxygen or ppO2, from getting too low (causing anoxia or hypoxia) or too high (causing oxygen toxicity).
With humans, the urge to breathe is caused by a build-up of carbon dioxide rather than lack of oxygen. When using a rebreather, as the oxygen in circuit is used, the resulting carbon dioxide is removed from the breathing gas by the scrubber, suppressing this natural warning. If not enough new oxygen is being added, and the oxygen in circuit is a long way from 100% pure, the proportion of oxygen may get too little to support life while plenty of gas seems to be in circuit. The resulting serious hypoxia causes sudden blackout with little or no warning. This makes hypoxia a deadly problem for rebreather divers: it was sometimes called "shallow water blackout".
In many rebreathers the diver can control the gas mix and volume in the loop manually by injecting each of the different available gases to the loop and by venting the loop. The loop often has a pressure relief valve preventing the "hamster cheek" effect on the diver caused by over-pressure of the loop.
In some early rebreathers the diver had to manually open and close the valve to the oxygen cylinder to refill the counter-lung each time. In others the oxygen flow is kept constant by a pressure-reducing flow valve like the valves on blowtorch cylinders; the set also has a manual on/off valve called a bypass. In some modern rebreathers, the pressure in the breathing bag controls the oxygen flow like the demand valve in open-circuit scuba; for example, trying to breathe in from an empty bag makes the cylinder release more gas. Most modern closed-circuit rebreathers have electro-galvanic fuel cell sensors and onboard electronics, which monitor the ppO2, injecting more oxygen if necessary or issuing an audible warning to the diver if the ppO2 reaches dangerously high or low levels.
## Counterlung
Underwater, the position of the breathing bag, on the chest, over the shoulders, or on the back, has an effect on the ease of breathing. The design of the rebreather also affects the swimming diver's streamlining and thus ease of swimming.
For use out of water, this does not matter so much: for example, in an industrial version of the Siebe Gorman Salvus the breathing bag hangs down by the left hip.
A rebreather whose counterlung is rubber and not in an enclosed casing, should be sheltered from sunlight when not in use, to prevent the rubber from perishing.
## Bailout
Some diving rebreather sets include a bailout regulator allowing the user to bail onto open-circuit using his diluent tank. This lets the diver ascend on a separate gas supply. The majority of rebreather trainers teach students to also carry an open-circuit scuba cylinder and regulator as a separate bailout source. Bailout is a key area of discussion for rebreather diving, as when the depth starts to increase the bailout strategy becomes a crucial part of planning particularly for technical diving.
## Casing
Many rebreathers have their main parts in a hard backpack casing. This casing needs venting to let surrounding water or air in and out to allow for volume changes as the breathing bag inflates and deflates. In a diving rebreather this needs fairly large holes, including a hole at the bottom to drain the water out when the diver comes out of water. The SEFA, which is used for mine rescue, to keep grit and stones out of its working, is completely sealed, except for a large vent panel covered with metal mesh, and holes for the oxygen cylinder's on/off valve and the cylinder pressure gauge. Underwater the casing also serves for streamlining, e.g. in the IDA71 and Cis-Lunar.
# Main rebreather design variants
## Oxygen rebreather
This is the oldest type of rebreather and was commonly used by navies from the early twentieth century. The only gas that it supplies is oxygen. As pure oxygen is toxic when inhaled at pressure, oxygen rebreathers are limited to a depth of 6 meters (20 feet); some say 9 meters (30 feet). Oxygen rebreathers are also sometimes used when decompressing from a deep open-circuit dive, as breathing pure oxygen makes the nitrogen diffuse out of the blood more rapidly.
In some rebreathers, e.g. the Siebe Gorman Salvus, the oxygen cylinder has two first stages in parallel. One is constant flow; the other is a plain on-off valve called a bypass; both feed into the same exit pipe which feeds the breathing bag. In the Salvus there is no second stage and the gas is turned on and off at the cylinder. Some simple oxygen rebreathers had no constant-flow valve, but only the bypass, and the diver had to operate the valve at intervals to refill the breathing bag as he used the oxygen.
## Semi-closed circuit rebreather
Military and recreational divers use these because they provide good underwater duration with fairly simple and cheap equipment. Semi-closed circuit equipment generally supplies one breathing gas such as air or nitrox or trimix. The gas is injected at a constant rate. Excess gas is constantly vented from the loop in small volumes.
The diver must fill the cylinders with gas mix that has a maximum operating depth that is safe for the depth of the dive being planned. As the amount of oxygen required by the diver increases with work rate, the oxygen injection rate must be carefully chosen and controlled to prevent either oxygen toxicity or unconsciousness in the diver due to hypoxia.
## Fully closed circuit rebreather
Military, photographic and recreational divers use these because they allow long dives and produce no bubbles. Closed circuit rebreathers generally supply two breathing gases to the loop: one is pure oxygen and the other is a diluent or diluting gas such as air, nitrox or trimix.
The major task of the fully closed circuit rebreather is to control the oxygen concentration, known as the oxygen partial pressure, in the loop and to warn the diver if it is becoming dangerously low or high. The concentration of oxygen in the loop depends on two factors: depth and the proportion of oxygen in the mix. Too low a concentration of oxygen results in hypoxia leading to sudden unconsciousness and ultimately death when the oxygen is exhausted. Too high a concentration of oxygen results in oxygen toxicity, a condition causing convulsions, which make the diver spit his regulator out when they occur underwater and can lead to drowning.
In fully automatic closed-circuit systems, a mechanism injects oxygen into the loop when it detects that the partial pressure of oxygen in the loop has fallen below the required level. Often this mechanism is electrical and relies on oxygen sensitive electro-galvanic fuel cells called ppO2 meters to measure the concentration of oxygen in the loop.
The diver may be able to manually control the mixture by adding diluent gas or oxygen. Adding diluent can prevent the loop's gas mixture becoming too oxygen rich. Manually adding oxygen is risky as additional small volumes of oxygen in the loop can easily raise the partial pressure of oxygen to dangerous levels.
## Rebreathers whose absorbent releases oxygen
There have been a few rebreather designs (e.g. the Oxylite) which had an absorbent canister filled with potassium superoxide, which gives off oxygen as it absorbs carbon dioxide: 4KO2 + 2CO2 = 2K2CO3 + 3O2; it had a very small oxygen cylinder to fill the loop at the start of the dive. This system is dangerous because of the explosively hot reaction that happens if water gets on the potassium superoxide. The Russian IDA71 military and naval rebreather was designed to be run in this mode or as an ordinary rebreather.
## Rebreathers which store their oxygen as liquid oxygen
If used underwater, the liquid-oxygen tank must be well insulated against heat coming in from the water. As a result, industrial sets of this type may not be suitable for diving, and diving sets of this type may not be suitable for use out of water. They include these types:
- Aerophor.
- Aerorlox. See .
- Cryogenic rebreather: see below.
### Cryogenic rebreather
There have been plans for a "cryogenic rebreather". It has a tank of liquid oxygen and no absorbent canister. The carbon dioxide is frozen out in a "snow box" by the cold produced as the liquid oxygen expands to gas as the oxygen is used and is replaced from the oxygen tank.
Such a rebreather called the S-1000 was built around or soon after 1960 by Sub-Marine Systems Corporation. It had a duration of 6 hours and a maximum dive depth of 200 meters of salt water. Its ppO2 could be set to anything from 0.2 bar to 2 bar without electronics, by controlling the temperature of the liquid oxygen, thus controlling the equilibrium pressure of oxygen gas above the liquid. The diluent could be either liquid nitrogen or helium depending on the depth of the dive. The set could freeze out 230 grams of carbon dioxide per hour from the loop, corresponding to an oxygen consumption of 2 liters per minute. If oxygen was consumed faster (high workload), a regular scrubber was needed. See:
- Fischel H., Closed circuit cryogenic SCUBA, "Equipment for the working diver" 1970 symposium, Washington, DC, USA. Marine Technology Society 1970:229-244.
- Cushman, L., Cryogenic Rebreather, Skin Diver magazine, June 1969, and reprinted in Aqua Corps magazine, N7, 28, 79.
There are articles on the web about a cryogenic rebreather called Titanic II. These articles are a hoax; some of them include unrealistic technology.
## Other designs
- In the Siebe Gorman Proto the absorbent was in a flexible-walled compartment in the bottom of the breathing bag and not in a canister.
- This link describes an experimental drysuit (with built-in hood and fullface mask) and rebreather combination where the drysuit acts as the breathing bag, like in an old Draeger standard diving suit variant which had a rebreather pack attached.
- Some British naval rebreathers (e.g. the Siebe Gorman CDBA) had a backpack weight pouch instead of the diver having a separate weight belt.
# Risks and precautions with rebreather diving
Many diver training organizations teach the "diluent flush" technique as a safe way to restore the mix in the loop to a level of oxygen that is neither too high nor too low. It only works when partial pressure of oxygen in the diluent alone would not cause hypoxia or hyperoxia, such as when using a normoxic diluent and observing the diluent's maximum operating depth. The technique involves simultaneously venting the loop and injecting diluent. This flushes out the old mix and replaces it with a known proportion of oxygen from the diluent.
Divers using oxygen rebreathers are advised to flush the system when they start the dive, to get surplus nitrogen out of the system.
In addition to the other diving disorders suffered by divers, rebreather divers are also more susceptible to:
- Sudden blackout due to hypoxia caused by too low a partial pressure of oxygen in the loop. A particular problem when using a closed circuit rebreather is the drop in ambient pressure caused by the ascent phase of the dive, which reduces the partial pressure of oxygen to hypoxic levels leading to what is sometimes called deep water blackout.
- Seizures due to oxygen toxicity caused by too high a partial pressure of oxygen in the loop. This can be caused by the rise in ambient pressure caused by the descent phase of the dive, which raises the partial pressure of oxygen to hyperoxic levels. In fully closed circuit equipment, aging oxygen sensors may become "current limited" and fail to measure high partial pressures of oxygen resulting in dangerously high oxygen levels.
- Disorientation, panic, headache, and hyperventilation due to excess of carbon dioxide caused by incorrect configuration, failure or inefficiency of the scrubber. The scrubber must be configured so that no exhaled gas can bypass it; it must be packed and sealed correctly. Another problem is the diver producing carbon dioxide faster than the absorbent can handle, for example, during hard work or fast swimming. The solution to this is to slow down and let the absorbent catch up. The scrubber efficiency may be reduced at depth where the increased concentration of other gas molecules, due to pressure, stops all the carbon dioxide molecules reaching the active ingredient of the scrubber.
- The rebreather diver must keep breathing in and out all the time, to keep the exhaled gas flowing over the carbon dioxide absorbent, so the absorbent can work all the time. Divers need to lose any air conservation habits that may have been developed while diving with open-circuit scuba. In closed circuit rebreathers, this also has the advantage of mixing the gases preventing oxygen-rich and oxygen-lean spaces developing within the loop, which may give inaccurate readings to the oxygen control system.
- "Caustic cocktail" in the loop if water comes into contact with the soda lime used in the carbon dioxide scrubber. The diver is normally alerted to this by a chalky taste in the mouth. A safe response is to bail out to "open circuit" and rinse the mouth out.
When compared with Aqua-Lungs, rebreathers have some disadvantages including expense, complexity of operation and maintenance and fewer failsafes. A malfunctioning rebreather can supply a gas mixture which cannot sustain life. Various rebreathers try to solve these problems by monitoring the system with electronics, sensors and alarm systems. Many very competent divers have died using rebreathers in accidents, which are often put down to operator error. Rebreathers are generally considered safer in extreme conditions such as deep dives (75m = 246 feet or more) or overhead environments, as they reduce the risk of running out of breathable gas.
The bailout requirement of rebreather diving can sometimes also require a rebreather diver to carry almost as much bulk of cylinders as an open-circuit diver so the diver can complete the necessary decompression stops if the rebreather fails completely. Some rebreather divers prefer not to carry enough bailout for a safe ascent breathing open circuit, but instead rely on the rebreather, believing that an irrecoverable rebreather failure is very unlikely. This practice is known as alpinism or alpinist diving and is generally maligned due to the perceived extremely high risk of death if the rebreather fails.
# Some makes of rebreather
- The Davis Submerged Escape Apparatus was the first or nearly the first rebreather to be made in quantity.
- The "Universal" rebreather was a long-dive derivative of the Davis Submerged Escape Apparatus, intended to be used with the Sladen Suit, which see for more information about it.
- Military rebreathers (VIPER and SIVA) made by Carleton Life Support and the Viper E made by Carleton and Juergensen Defense Corporation
- Russian IDA71 military and naval rebreather
- CDBA = "Clearance Diver's Breathing Apparatus":
Siebe Gorman CDBA: see there also for CDMBA, SCBA, SCMBA, UBA
A type introduced in 1999 in the British Navy, being an update of the BioMarine/Carleton MK16: description; images:
- Siebe Gorman CDBA: see there also for CDMBA, SCBA, SCMBA, UBA
- A type introduced in 1999 in the British Navy, being an update of the BioMarine/Carleton MK16: description; images:
- In the British Navy the Carleton CDBA is (as at June 2007) planned to be superseded by the CDLSE = "Clearance Divers' Life Support Equipment" made by Divex in Aberdeen in Scotland. It is an electronic closed circuit rebreather allowing diving to 60 meters = 197 feet.; Google search for information
- Siebe Gorman Salvus
- The Savox was made by Siebe Gorman. See this link and the image at this link. It was an oxygen rebreather with a use duration of 45 minutes. It was worn in front of the body. It had no hard casing.
- The Blackett's Aerophor is a nitrox semi-closed-circuit rebreather with liquid gas storage made in England from 1910 onwards for use in mine rescue and other industrial uses.
- SEFA is a make of industrial oxygen rebreather with 2 hours duration on a filling.
- SDBA is a type of frogman's oxygen rebreather. It has a nitrox variant called ONBA.
- FROGS (= Full Range Oxygen Gas System) is the make of frogman's oxygen rebreather which has been used in France since 15 October 2002: see this link (in French): image at this link: it is made by the diving gear makers Aqualung: see this link for more information.
- Some military rebreathers (for example the US Navy MK-25 and the MK-16 mixed-gas rebreather), and the Phibian CCS50 and CCS100 rebreathers, were developed by Oceanic. (Stuart Clough of Undersea Technologies developed the Phibian's electronics package .)
- The current US Navy Mark 16 Mod 2 (Explosive Ordinance Disposal) and Mark 16 Mod 3 (Naval Special Warfare) units utilize the Juergensen Defense Corporation Mark V Control System.
- The KISS line of manually operated closed circuit rebreathers designed by Gordon Smith of Jetsam Technologies | Rebreather
A rebreather is a type of breathing set that provides a breathing gas containing oxygen and recycles exhaled gas. This recycling reduces the volume of breathing gas used, making a rebreather lighter and more compact than an open-circuit breathing set for the same duration in environments where humans cannot safely breathe from the atmosphere. In the armed forces it is sometimes called "CCUBA" (Closed Circuit Underwater Breathing Apparatus).
# Basics
Rebreather technology is used in many environments:
- Underwater - where it is sometimes known as "closed circuit scuba" or "semi closed scuba", or CCUBA = "closed circuit underwater breathing apparatus", as opposed to Aqua-Lung-type equipment, which is known as "open circuit scuba".
- Mine rescue and in industry - where poisonous gases may be present or oxygen may be absent.
- Space suits - outer space is, for all intents and purposes, a vacuum where there is no oxygen to support life.
- Hospital anaesthesia breathing systems - to supply controlled proportions of gases to patients without letting anaesthetic gas get into the atmosphere that the staff breathe.
- Submarines and hyperbaric oxygen therapy chambers - where the gas in the habitat must remain safe. Here the rebreather is big and is connected to the air in the habitat.
This article is mainly about diving rebreathers.
As a person breathes, the body consumes oxygen and makes carbon dioxide. A person with an open-circuit breathing set typically only uses about a quarter of the oxygen in the air that is breathed in. The rest is breathed out along with nitrogen and carbon dioxide.
With a rebreather, the exhaled gas is not discharged to waste. The rebreather recovers the exhaled gas for re-use. It absorbs the carbon dioxide, which otherwise would accumulate and cause carbon dioxide poisoning. It adds oxygen to replace what was consumed. Thus, the gas in the rebreather's circuit remains breathable and supports life processes. Nearly always, the oxygen comes from a gas cylinder, and the carbon dioxide is absorbed in a canister full of some absorbent chemical designed for diving applications such as Sofnolime, Dragersorb or Sodasorb. Some systems also use a prepackaged Reactive Plastic Curtain (RPC) based cartridge, a common brand name for these RPC cartridges is ExtendAir. These absorbents may contain small amounts of soda lime, but are generally less toxic. Pure oxygen is not considered to be safe for recreational diving below 6 meters, so recreational rebreathers also have a diluent cylinder to reduce the percentage of oxygen breathed and enable them to be used to greater depths.
# History of rebreathers
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Around 1620 in England, Cornelius Drebbel made an early oar-powered submarine. Records show that, to re-oxygenate the air inside it, he likely generated oxygen by heating saltpetre (sodium or potassium nitrate) in a metal pan to make it emit oxygen. That would turn the saltpetre into sodium or potassium oxide or hydroxide, which would tend to absorb carbon dioxide from the air around. That may explain how Drebbel's men were not affected by carbon dioxide build-up as much as would be expected. If so, he accidentally made a crude rebreather nearly three centuries before Fluess and Davis: see this link.
This page describes and shows a rebreather designed in 1853 in Belgium by Professor T. Schwann; he exhibited it in Paris in 1878.
The first certainly known closed circuit breathing device using stored oxygen and absorption of carbon dioxide by an absorbent (here caustic soda), was invented by Henry Fluess in 1879 to rescue mineworkers who were trapped by water.
The Davis Escape Set was the first rebreather which was practical for use and produced in quantity. It was designed about 1900 in Britain for escape from sunken submarines. Various industrial oxygen rebreathers (e.g. the Siebe Gorman Salvus and the Siebe Gorman Proto) were descended from it; this link shows a Draeger rebreather used for mines rescue in 1907.
The first known systematic use of rebreathers for diving was by Italian sport spearfishers in the 1930s. This practice came to the attention of the Italian Navy, which developed its frogman unit, which had a big effect in World War II. Image of wartime Italian frogman.
In World War II captured Italian frogmen's rebreathers influenced design of British frogman's rebreathers. Ref British commando frogmen#1942 at "April" for more information: Many British frogmen's breathing sets' oxygen cylinders were German pilot's oxygen cylinders recovered from shot-down German Luftwaffe planes. Those first breathing sets may have been modified Davis Submarine Escape Sets; their fullface masks were the type intended for the Siebe Gorman Salvus. But in later operations different designs were used, leading to a fullface mask with one big face window. One version had a flip-up single window for both eyes to let the user get binoculars to his eyes when on the surface. They used bulky thick diving suits called Sladen suits. Early British frogman's rebreathers had rectangular breathing bags on the chest like Italian frogman's rebreathers; later British frogman's rebreathers had a square recess in the top so they could extend further up onto his shoulders; in front they had a rubber collar that was clamped around the absorbent canister, as in the CGI image below.
US Navy rebreathers were developed by Dr. Christian J. Lambertsen in the early 1940s for underwater warfare. Dr. Lambertsen, who currently works at the University of Pennsylvania, is considered by the US Navy as "the father of the Frogmen". Information about early history of USA frogman's rebreathers is scarce because the many available photographs of UDT men and training and operations rarely show a rebreather, as if there was a secrecy law against it.
## Innovations in recreational diving rebreather technology
Over the past ten or fifteen years rebreather technology has advanced considerably often driven by the growing market in recreational diving equipment. Innovations include:
- The electronic, fully closed circuit rebreather itself - use of electronics and electro-galvanic fuel cells to monitor oxygen concentration within the loop and maintain a certain partial pressure of oxygen
- Automatic diluent valves - these inject diluent gas into the loop when the loop pressure falls below the limit at which the diver can comfortably breathe.
- Dive/surface valves or bailout valves - a device in the mouthpiece on the loop which connects to a bailout demand valve and can be switched to provide gas from either the loop or the demand valve without the diver taking the mouthpiece from his or her mouth. An important safety device when carbon dioxide poisoning occurs.
- Integrated decompression computers - these allow divers to take advantage of the decompression benefits provided by the ideal mix in the loop of a fully closed circuit rebreather. By monitoring the oxygen content of the mix they can work out the inert gas content and generate a schedule of decompression stops.
- Carbon dioxide scrubber life monitoring systems - temperature sensors monitor the progress of the reaction of the soda lime and provide an indication of when the scrubber will be exhausted.
# Advantages of rebreather diving
## Efficiency advantages
The main advantage of the rebreather over other breathing equipment is the rebreather's economical use of gas. With "open circuit" scuba, the entire breath is expelled into the surrounding water when the diver exhales. A breath inhaled from an open circuit scuba system whose cylinder(s) are filled with ordinary air is about 21%[1] oxygen. When that breath is exhaled back into the surrounding environment, it has an oxygen level in the range of 15 to 16% when the diver is at atmospheric pressure. [1] This leaves the available oxygen utilization at about 25%; the remaining 75% is lost.
At depth, the advantage of a rebreather is even more marked. The amount of CO2 in exhaled gas is not a constant percentage, but a constant partial pressure of about 0.04bar. The amount of oxygen used from each breath is about the same - so as the ambient pressure increases (as a result of going deeper), the percentage of oxygen used from each breath drops. At 30m (100ft), a diver's exhaled breath contains about 20% oxygen and about 1% CO2.
## Feasibility advantages
Long or deep dives using open circuit equipment may not be feasible as there are limits to the number and weight of diving cylinders the diver can carry. The economy of gas consumption is also useful when the gas mix being breathed contains expensive gases, such as helium. In normal use only oxygen is consumed: small volumes of expensive inert gases can be reused for many dives.
## Other advantages
Rebreathers produce far fewer bubbles[1] and make less noise than open-circuit scuba; this can conceal military divers and allow divers engaged in marine biology and underwater photography to avoid alarming marine animals and thereby get closer to them. The electronic fully closed circuit rebreather, is able to minimise the proportion of inert gases in the breathing mix, and therefore minimise the decompression requirements of the diver, by maintaining a specific and relatively high oxygen partial pressure at all depths. The breathing gas in a rebreather is warmer and more moist than the dry and cold gas from open circuit equipment making it more comfortable to breathe on long dives and causing less dehydration in the diver.
# Parts of a rebreather
## The loop
Although there are several design variations of diving rebreather, all types have a gas-tight loop that the diver inhales from and exhales into. The loop consists of components sealed together. The diver breathes through a mouthpiece or a fullface mask (or with industrial breathing sets, sometimes a mouth-and-nose mask). This is connected to one or more tubes bringing inhaled gas and exhaled gas between the diver and a counterlung or breathing bag. This holds gas when it is not in the diver's lungs. The loop also includes a scrubber containing carbon dioxide absorbent to remove from the loop the carbon dioxide exhaled by the diver. Attached to the loop there will be at least one valve allowing injection of gases, such as oxygen and perhaps a diluting gas, into the loop. There may be valves allowing venting of gas from the loop.
Most modern rebreathers have a twin hose mouthpiece or breathing mask where the direction of flow of gas through the loop is controlled by one-way valves. Some have a single pendulum hose, where the inhaled and exhaled gas passes through the same tube in opposite directions. The mouthpiece often has a valve letting the diver take the mouthpiece from the mouth while underwater or floating on the surface without water getting into the loop. Many rebreathers have "water traps" in the counterlungs, to stop large volumes of water from entering the loop if the diver removes the mouthpiece underwater without closing the valve, or if the diver's lips get slack letting water leak in.
## Carbon dioxide scrubber
The exhaled gases are forced through the chemical scrubber which removes the carbon dioxide from the gas mixture and leaves the oxygen and other gases available for re-breathing[1]. The active ingredient of the scrubber is often soda lime. The carbon dioxide passing through the scrubber absorbent is removed when it reacts with the absorbent in the canister; this chemical reaction is exothermic. This reaction occurs along a "front" which is a cross section of the canister, of the unreacted soda lime that is exposed to carbon dioxide-laden gas. This front moves through the scrubber canister, from the gas input end to the gas output end, as the reaction consumes the active ingredients. However, this front would be a wide zone, because the carbon dioxide in the gas going through the canister needs time to reach the surface of a grain of absorbent, and then time to penetrate to the middle of each grain of absorbent as the outside of the grain becomes exhausted.
In larger environments, such as recompression chambers, a fan is used to pass gas through the canister.
### Scrubber failure
The term "break through" means the failure of the "scrubber" to continue removing carbon dioxide from the exhaled gas mix.
There are several ways that the scrubber may fail or become less efficient:
- Complete consumption of the active ingredient ("break through").
- The scrubber canister has been incorrectly packed or configured. This allows the exhaled gas to bypass the absorbent. In a rebreather, the soda lime must be packed tightly so that all exhaled gas comes into close contact with the granules of soda lime and the loop is designed to avoid any spaces or gaps between the soda lime and the loop walls that would let gas avoid contact with the adsorbent. If any of the seals, such as o rings, or spacers that prevent bypassing of the scrubber, are not cleaned or lubricated or fitted properly, the scrubber will be less efficient, or outside water or gas may get in circuit.
- When the gas mix is under pressure caused by depth, the inside of the canister is more crowded by other gas molecules (oxygen or diluent) and the carbon dioxide molecules are not so free to move around to reach the absorbent. In deep diving with a nitrox or other gas-mixture rebreather, the scrubber needs to be bigger than is needed for a shallow-water or industrial oxygen rebreather, because of this effect. Among British naval rebreather divers, this type of carbon dioxide poisoning was called shallow water blackout.
- A Caustic Cocktail - Soda lime is caustic and can cause burns to the eyes and skin. A "caustic cocktail" is a mixture of water and soda lime that occurs when the "scrubber" floods. It gives rise to a chalky taste, which should prompt the diver to switch to an alternative source of breathing gas and rinse his or her mouth out with water. Many modern diving rebreather absorbents are designed not to produce "cocktail" if they get wet.
### Failure prevention
- An indicating dye in the soda lime. It changes the colour of the soda lime after the active ingredient is consumed. For example, a rebreather absorbent called "Protosorb" supplied by Siebe Gorman had a red dye, which was said to go white when the absorbent was exhausted. With a transparent canister, this may be able to show the position of the reaction "front". This is useful in dry open environments, but is not useful on diving equipment, where:
A transparent canister would likely be brittle and easily cracked by knocks.
Opening the canister to look inside would flood it with water or get unbreathable outside gas in circuit.
The canister is usually out of sight of the user, e.g. inside the breathing bag or inside a backpack box.
- A transparent canister would likely be brittle and easily cracked by knocks.
- Opening the canister to look inside would flood it with water or get unbreathable outside gas in circuit.
- The canister is usually out of sight of the user, e.g. inside the breathing bag or inside a backpack box.
- Temperature monitoring. As the reaction between carbon dioxide and soda lime is exothermic, temperature sensors, most likely digital, along the length of the scrubber can be used to measure the position of the front and therefore the life of the scrubber. [1]
- Diver training. Divers are trained to monitor and plan the exposure time of the soda lime in the scrubber and replace it within the recommended time limit. At present, there is no effective technology for detecting the end of the life of the scrubber or a dangerous increase in the concentration of carbon dioxide causing carbon dioxide poisoning. The diver must monitor the exposure of the scrubber and replace it when necessary.
- Carbon dioxide gas sensors exist, but they are not sensitive enough to be used in a rebreather - the scrubber "break through" occurs quite suddenly and the diver shows symptoms before the sensor indicates a dangerous build-up of carbon dioxide. Even if a sensitive carbon dioxide sensor is developed, it may not be useful as the primary tool for monitoring scrubber life when underwater, because mixed gas rebreathers allow very long dives where long decompression stops may be needed: knowing that the rebreather will begin to deliver a poisonous breathing gas in five minutes may not be useful to a diver needing to carry out an hour or more of decompression stops.
## Effectiveness
In rebreather diving, the typical effective duration of the scrubber will be half an hour to several hours of breathing, depending on the granularity and composition of the soda lime, the ambient temperature, the design of the rebreather, and the size of the canister. In some dry open environments, such as a recompression chamber or a hospital, it may be possible to put fresh absorbent in the canister when break through occurs.
## Controlling the mix
A basic need with a rebreather is to keep the amount of oxygen in the mix, or more technically known as the partial pressure of oxygen or ppO2, from getting too low (causing anoxia or hypoxia) or too high (causing oxygen toxicity).
With humans, the urge to breathe is caused by a build-up of carbon dioxide rather than lack of oxygen. When using a rebreather, as the oxygen in circuit is used, the resulting carbon dioxide is removed from the breathing gas by the scrubber, suppressing this natural warning. If not enough new oxygen is being added, and the oxygen in circuit is a long way from 100% pure, the proportion of oxygen may get too little to support life while plenty of gas seems to be in circuit. The resulting serious hypoxia causes sudden blackout with little or no warning. This makes hypoxia a deadly problem for rebreather divers: it was sometimes called "shallow water blackout".
In many rebreathers the diver can control the gas mix and volume in the loop manually by injecting each of the different available gases to the loop and by venting the loop. The loop often has a pressure relief valve preventing the "hamster cheek" effect on the diver caused by over-pressure of the loop.
In some early rebreathers the diver had to manually open and close the valve to the oxygen cylinder to refill the counter-lung each time. In others the oxygen flow is kept constant by a pressure-reducing flow valve like the valves on blowtorch cylinders; the set also has a manual on/off valve called a bypass. In some modern rebreathers, the pressure in the breathing bag controls the oxygen flow like the demand valve in open-circuit scuba; for example, trying to breathe in from an empty bag makes the cylinder release more gas. Most modern closed-circuit rebreathers have electro-galvanic fuel cell sensors and onboard electronics, which monitor the ppO2, injecting more oxygen if necessary or issuing an audible warning to the diver if the ppO2 reaches dangerously high or low levels.
## Counterlung
Underwater, the position of the breathing bag, on the chest, over the shoulders, or on the back, has an effect on the ease of breathing. The design of the rebreather also affects the swimming diver's streamlining and thus ease of swimming.
For use out of water, this does not matter so much: for example, in an industrial version of the Siebe Gorman Salvus the breathing bag hangs down by the left hip.
A rebreather whose counterlung is rubber and not in an enclosed casing, should be sheltered from sunlight when not in use, to prevent the rubber from perishing.
## Bailout
Some diving rebreather sets include a bailout regulator allowing the user to bail onto open-circuit using his diluent tank. This lets the diver ascend on a separate gas supply. The majority of rebreather trainers teach students to also carry an open-circuit scuba cylinder and regulator as a separate bailout source. Bailout is a key area of discussion for rebreather diving, as when the depth starts to increase the bailout strategy becomes a crucial part of planning particularly for technical diving.
## Casing
Many rebreathers have their main parts in a hard backpack casing. This casing needs venting to let surrounding water or air in and out to allow for volume changes as the breathing bag inflates and deflates. In a diving rebreather this needs fairly large holes, including a hole at the bottom to drain the water out when the diver comes out of water. The SEFA, which is used for mine rescue, to keep grit and stones out of its working, is completely sealed, except for a large vent panel covered with metal mesh, and holes for the oxygen cylinder's on/off valve and the cylinder pressure gauge. Underwater the casing also serves for streamlining, e.g. in the IDA71 and Cis-Lunar.
# Main rebreather design variants
## Oxygen rebreather
This is the oldest type of rebreather and was commonly used by navies from the early twentieth century. The only gas that it supplies is oxygen. As pure oxygen is toxic when inhaled at pressure, oxygen rebreathers are limited to a depth of 6 meters (20 feet); some say 9 meters (30 feet). Oxygen rebreathers are also sometimes used when decompressing from a deep open-circuit dive, as breathing pure oxygen makes the nitrogen diffuse out of the blood more rapidly.
In some rebreathers, e.g. the Siebe Gorman Salvus, the oxygen cylinder has two first stages in parallel. One is constant flow; the other is a plain on-off valve called a bypass; both feed into the same exit pipe which feeds the breathing bag. In the Salvus there is no second stage and the gas is turned on and off at the cylinder. Some simple oxygen rebreathers had no constant-flow valve, but only the bypass, and the diver had to operate the valve at intervals to refill the breathing bag as he used the oxygen.
## Semi-closed circuit rebreather
Military and recreational divers use these because they provide good underwater duration with fairly simple and cheap equipment. Semi-closed circuit equipment generally supplies one breathing gas such as air or nitrox or trimix. The gas is injected at a constant rate. Excess gas is constantly vented from the loop in small volumes.
The diver must fill the cylinders with gas mix that has a maximum operating depth that is safe for the depth of the dive being planned. As the amount of oxygen required by the diver increases with work rate, the oxygen injection rate must be carefully chosen and controlled to prevent either oxygen toxicity or unconsciousness in the diver due to hypoxia.
## Fully closed circuit rebreather
Military, photographic and recreational divers use these because they allow long dives and produce no bubbles. Closed circuit rebreathers generally supply two breathing gases to the loop: one is pure oxygen and the other is a diluent or diluting gas such as air, nitrox or trimix.
The major task of the fully closed circuit rebreather is to control the oxygen concentration, known as the oxygen partial pressure, in the loop and to warn the diver if it is becoming dangerously low or high. The concentration of oxygen in the loop depends on two factors: depth and the proportion of oxygen in the mix. Too low a concentration of oxygen results in hypoxia leading to sudden unconsciousness and ultimately death when the oxygen is exhausted. Too high a concentration of oxygen results in oxygen toxicity, a condition causing convulsions, which make the diver spit his regulator out when they occur underwater and can lead to drowning.
In fully automatic closed-circuit systems, a mechanism injects oxygen into the loop when it detects that the partial pressure of oxygen in the loop has fallen below the required level. Often this mechanism is electrical and relies on oxygen sensitive electro-galvanic fuel cells called ppO2 meters to measure the concentration of oxygen in the loop.
The diver may be able to manually control the mixture by adding diluent gas or oxygen. Adding diluent can prevent the loop's gas mixture becoming too oxygen rich. Manually adding oxygen is risky as additional small volumes of oxygen in the loop can easily raise the partial pressure of oxygen to dangerous levels.
## Rebreathers whose absorbent releases oxygen
There have been a few rebreather designs (e.g. the Oxylite) which had an absorbent canister filled with potassium superoxide, which gives off oxygen as it absorbs carbon dioxide: 4KO2 + 2CO2 = 2K2CO3 + 3O2; it had a very small oxygen cylinder to fill the loop at the start of the dive. This system is dangerous because of the explosively hot reaction that happens if water gets on the potassium superoxide. The Russian IDA71 military and naval rebreather was designed to be run in this mode or as an ordinary rebreather.
## Rebreathers which store their oxygen as liquid oxygen
If used underwater, the liquid-oxygen tank must be well insulated against heat coming in from the water. As a result, industrial sets of this type may not be suitable for diving, and diving sets of this type may not be suitable for use out of water. They include these types:
- Aerophor.
- Aerorlox. See http://www.healeyhero.co.uk/rescue/glossary/aerorlox.htm .
- Cryogenic rebreather: see below.
### Cryogenic rebreather
There have been plans for a "cryogenic rebreather". It has a tank of liquid oxygen and no absorbent canister. The carbon dioxide is frozen out in a "snow box" by the cold produced as the liquid oxygen expands to gas as the oxygen is used and is replaced from the oxygen tank.
Such a rebreather called the S-1000 was built around or soon after 1960 by Sub-Marine Systems Corporation. It had a duration of 6 hours and a maximum dive depth of 200 meters of salt water. Its ppO2 could be set to anything from 0.2 bar to 2 bar without electronics, by controlling the temperature of the liquid oxygen, thus controlling the equilibrium pressure of oxygen gas above the liquid. The diluent could be either liquid nitrogen or helium depending on the depth of the dive. The set could freeze out 230 grams of carbon dioxide per hour from the loop, corresponding to an oxygen consumption of 2 liters per minute. If oxygen was consumed faster (high workload), a regular scrubber was needed. See:
- Fischel H., Closed circuit cryogenic SCUBA, "Equipment for the working diver" 1970 symposium, Washington, DC, USA. Marine Technology Society 1970:229-244.
- Cushman, L., Cryogenic Rebreather, Skin Diver magazine, June 1969, and reprinted in Aqua Corps magazine, N7, 28, 79.
There are articles on the web about a cryogenic rebreather called Titanic II. These articles are a hoax; some of them include unrealistic technology.
## Other designs
- In the Siebe Gorman Proto the absorbent was in a flexible-walled compartment in the bottom of the breathing bag and not in a canister.
- This link describes an experimental drysuit (with built-in hood and fullface mask) and rebreather combination where the drysuit acts as the breathing bag, like in an old Draeger standard diving suit variant which had a rebreather pack attached.
- Some British naval rebreathers (e.g. the Siebe Gorman CDBA) had a backpack weight pouch instead of the diver having a separate weight belt.
# Risks and precautions with rebreather diving
Many diver training organizations teach the "diluent flush" technique as a safe way to restore the mix in the loop to a level of oxygen that is neither too high nor too low. It only works when partial pressure of oxygen in the diluent alone would not cause hypoxia or hyperoxia, such as when using a normoxic diluent and observing the diluent's maximum operating depth. The technique involves simultaneously venting the loop and injecting diluent. This flushes out the old mix and replaces it with a known proportion of oxygen from the diluent.
Divers using oxygen rebreathers are advised to flush the system when they start the dive, to get surplus nitrogen out of the system.
In addition to the other diving disorders suffered by divers, rebreather divers are also more susceptible to:
- Sudden blackout due to hypoxia caused by too low a partial pressure of oxygen in the loop. A particular problem when using a closed circuit rebreather is the drop in ambient pressure caused by the ascent phase of the dive, which reduces the partial pressure of oxygen to hypoxic levels leading to what is sometimes called deep water blackout.
- Seizures due to oxygen toxicity caused by too high a partial pressure of oxygen in the loop. This can be caused by the rise in ambient pressure caused by the descent phase of the dive, which raises the partial pressure of oxygen to hyperoxic levels. In fully closed circuit equipment, aging oxygen sensors may become "current limited" and fail to measure high partial pressures of oxygen resulting in dangerously high oxygen levels.
- Disorientation, panic, headache, and hyperventilation due to excess of carbon dioxide caused by incorrect configuration, failure or inefficiency of the scrubber. The scrubber must be configured so that no exhaled gas can bypass it; it must be packed and sealed correctly. Another problem is the diver producing carbon dioxide faster than the absorbent can handle, for example, during hard work or fast swimming. The solution to this is to slow down and let the absorbent catch up. The scrubber efficiency may be reduced at depth where the increased concentration of other gas molecules, due to pressure, stops all the carbon dioxide molecules reaching the active ingredient of the scrubber.
- The rebreather diver must keep breathing in and out all the time, to keep the exhaled gas flowing over the carbon dioxide absorbent, so the absorbent can work all the time. Divers need to lose any air conservation habits that may have been developed while diving with open-circuit scuba. In closed circuit rebreathers, this also has the advantage of mixing the gases preventing oxygen-rich and oxygen-lean spaces developing within the loop, which may give inaccurate readings to the oxygen control system.
- "Caustic cocktail" in the loop if water comes into contact with the soda lime used in the carbon dioxide scrubber. The diver is normally alerted to this by a chalky taste in the mouth. A safe response is to bail out to "open circuit" and rinse the mouth out.
When compared with Aqua-Lungs, rebreathers have some disadvantages including expense, complexity of operation and maintenance and fewer failsafes. A malfunctioning rebreather can supply a gas mixture which cannot sustain life. Various rebreathers try to solve these problems by monitoring the system with electronics, sensors and alarm systems. Many very competent divers have died using rebreathers in accidents, which are often put down to operator error. Rebreathers are generally considered safer in extreme conditions such as deep dives (75m = 246 feet or more) or overhead environments, as they reduce the risk of running out of breathable gas.
The bailout requirement of rebreather diving can sometimes also require a rebreather diver to carry almost as much bulk of cylinders as an open-circuit diver so the diver can complete the necessary decompression stops if the rebreather fails completely. Some rebreather divers prefer not to carry enough bailout for a safe ascent breathing open circuit, but instead rely on the rebreather, believing that an irrecoverable rebreather failure is very unlikely. This practice is known as alpinism or alpinist diving and is generally maligned due to the perceived extremely high risk of death if the rebreather fails.
# Some makes of rebreather
- The Davis Submerged Escape Apparatus was the first or nearly the first rebreather to be made in quantity.
- The "Universal" rebreather was a long-dive derivative of the Davis Submerged Escape Apparatus, intended to be used with the Sladen Suit, which see for more information about it.
- Military rebreathers (VIPER and SIVA) made by Carleton Life Support and the Viper E made by Carleton and Juergensen Defense Corporation
- Russian IDA71 military and naval rebreather
- CDBA = "Clearance Diver's Breathing Apparatus":
Siebe Gorman CDBA: see there also for CDMBA, SCBA, SCMBA, UBA
A type introduced in 1999 in the British Navy, being an update of the BioMarine/Carleton[2] MK16: description; images: [3] [4] [5]
- Siebe Gorman CDBA: see there also for CDMBA, SCBA, SCMBA, UBA
- A type introduced in 1999 in the British Navy, being an update of the BioMarine/Carleton[2] MK16: description; images: [3] [4] [5]
- In the British Navy the Carleton CDBA is (as at June 2007) planned to be superseded by the CDLSE = "Clearance Divers' Life Support Equipment" made by Divex in Aberdeen in Scotland. It is an electronic closed circuit rebreather allowing diving to 60 meters = 197 feet.[2]; Google search for information
- Siebe Gorman Salvus
- The Savox was made by Siebe Gorman. See this link and the image at this link. It was an oxygen rebreather with a use duration of 45 minutes. It was worn in front of the body. It had no hard casing.
- The Blackett's Aerophor is a nitrox semi-closed-circuit rebreather with liquid gas storage made in England from 1910 onwards for use in mine rescue and other industrial uses.
- SEFA is a make of industrial oxygen rebreather with 2 hours duration on a filling.
- SDBA is a type of frogman's oxygen rebreather. It has a nitrox variant called ONBA.
- FROGS (= Full Range Oxygen Gas System) is the make of frogman's oxygen rebreather which has been used in France since 15 October 2002: see this link (in French): image at this link: it is made by the diving gear makers Aqualung: see this link for more information.
- Some military rebreathers (for example the US Navy MK-25 and the MK-16 mixed-gas rebreather), and the Phibian CCS50 and CCS100 rebreathers, were developed by Oceanic. (Stuart Clough of Undersea Technologies developed the Phibian's electronics package [6].)
- The current US Navy Mark 16 Mod 2 (Explosive Ordinance Disposal) and Mark 16 Mod 3 (Naval Special Warfare) units utilize the Juergensen Defense Corporation Mark V Control System.
- The KISS line of manually operated closed circuit rebreathers designed by Gordon Smith of Jetsam Technologies
# External links
Template:Cleanup-spam
## Other information sources
- Rebreatherworld, The largest online rebreather forum and community.
- Page in Russian describing the images at the next link. (Click each thumbnail to get a fullsized image).
- Links to images of old and modern Russian rebreathers
- 100 Dollar Rebreather - Rebreather built from a hot water bottle
- Richard Pyle's rebreather page
- British Sub-Aqua Club - BSAC Technical Diving Resource Centre
- Some photos of various Soviet-Russian rebreathers (text in Russian)
- Diver Dave's site. It has many detailed photographs of rebreathers and their components.
- www.rebreathers.it: English and Italian language versions
- Rebreather Articles: English and French articles about rebreathers (Cedric Verdier)
- Rebreather Scuba Diving Information on rebreathers, includes a rebreather library and rebreather forums, and info on rebreather trips and vacations and holidays.
which includes: Rebreather Forums a big set of rebreather forums
- which includes: Rebreather Forums a big set of rebreather forums
- Shallow Water Blackout
- Images of LAR-6 and LAR-7 and FGT II and LAR V rebreathers, and other combat frogman's kit
- Teknosofen homepage - General rebreather theory and rebreather tear-downs
- The Rebreather Site, including long lists of types of rebreathers
which includes: huge database with 400 rebreathers data and pictures of units from all over the world
- which includes: huge database with 400 rebreathers data and pictures of units from all over the world
- DIRrebreather a website dedicated to rebreather in the DIR philosophy
- TMIShop.com a website dedicated to rebreather information dissemination
## Surface-only (industrial) rebreather manufacturers
(see SCBA)
- BioPak 240R Revolution - claim to make a 4-hour-duration rebreather
## Diving rebreather manufacturers
- Narked at 90 - Rebreather controllers, safety devices, upgrades, bespoke parts and components. Winners of the DEMA Innovation award 2007.
- Ambient Pressure Diving - maker of the Inspiration and Evolution rebreathers.
- Analytical Industries - manufacturer of oxygen sensors for rebreathers.
- Carleton Life Support Technologies - manufacturer of the VIPER and SIVA military rebreathers.
- CCR2000 for CCR2000 rebreathers.
- Cis-Lunar - made closed-circuit automatic rebreathers, now operated by Juergensen Marine.
- Closed Circuit Research Ltd - manufacturer of the Ouroboros rebreather.
- Divematics - maker of the Shadow Pac II rebreather.
- Dive Rite - technical SCUBA gear pioneer established in 1984. Manufacturer of the O2ptima FX closed circuit rebreather.
- Divex Ltd - manufacturer of several military semi-closed and closed circuit rebreathers.
- Draeger Safety - maker of various semi-closed circuit rebreathers.
- Halcyon - maker of a semi-closed circuit rebreather.
- Jetsam - maker of the KISS rebreather.
- Laguna Research Inc. manufacturer of rebreather controller and monitoring systems.
- Megalodon & Mini Meg - The Megalodon Expedition class rebreather.
- O.M.G. Italy - manufacturer of the AZIMUTH and many military rebreathers.
- Rebreatherlab - Manufacturers of the Pelagian rebreather.
- Rebreather US - The Juergensen Marine Hammerhead Electronic System.
- Rebreathers Australia - maker of the Abyss and Stingray closed circuit rebreathers.
- Siebe Gorman, see also Siebe Gorman. Important in diving history, but now closed down.
- Shearwater Research - Rebreather monitors, controllers, and computers.
- Steam Machines - Prism rebreathers.
- Submatix Rebreather - manufacturer of the Submatix SCR 100 ST.
- Subsea Systems - manufacturer of rebreather electronics.
- Teledyne Analytical Instruments - manufacturer of oxygen sensors for rebreathers. | https://www.wikidoc.org/index.php/Rebreather | |
8da9a4e13197b70c1e41eff7ba2698ec6f30dd16 | wikidoc | Refraction | Refraction
Refraction is the change in direction of a wave due to a change in its speed. This is most commonly seen when a wave passes from one medium to another. Refraction of light is the most commonly seen example, but any type of wave can refract when it interacts with a medium, for example when sound waves pass from one medium into another or when water waves move into water of a different depth. Refraction is described by Snell's law, which states that the angle of incidence is related to the angle of refraction by
-r
where v_1 and v_2 are the wave velocities through the respective media.
# Explanation
In optics, refraction occurs when light waves travel from a medium with a given refractive index to a medium with another. At the boundary between the media, the wave's phase velocity is altered, it changes direction, and its wavelength increases or decreases but its frequency remains constant. For example, a light ray will refract as it enters and leaves glass; understanding of this concept led to the invention of lenses and the refracting telescope.
Refraction can be seen when looking into a bowl of water. Air has a refractive index of about 1.0003, and water has a refractive index of about 1.33. If a person looks at a straight object, such as a pencil or straw, which is placed at a slant, partially in the water, the object appears to bend at the water's surface. This is due to the bending of light rays as they move from the water to the air. Once the rays reach the eye, the eye traces them back as straight lines (lines of sight). The lines of sight (shown as dashed lines) intersect at a higher position than where the actual rays originated. This causes the pencil to appear higher and the water to appear shallower than it really is. The depth that the water appears to be when viewed from above is known as the apparent depth. This is an important consideration for spearfishing from the surface because it will make the target fish appear to be in a different place, and the fisher must aim lower to catch the fish.
The diagram on the right shows an example of refraction in water waves. Ripples travel from the left and pass over a shallower region inclined at an angle to the wavefront. The waves travel more slowly in the shallower water, so the wavelength decreases and the wave bends at the boundary. The dotted line represents the normal to the boundary. The dashed line represents the original direction of the waves. The phenomenon explains why waves on a shoreline never hit the shoreline at an angle. Whichever direction the waves travel in deep water, they always refract towards the normal as they enter the shallower water near the beach.
Refraction is also responsible for rainbows and for the splitting of white light into a rainbow-spectrum as it passes through a glass prism. Glass has a higher refractive index than air and the different frequencies of light travel at different speeds (dispersion), causing them to be refracted at different angles, so that you can see them. The different frequencies correspond to different colors observed.
While refraction allows for beautiful phenomena such as rainbows it may also produce peculiar optical phenomena, such as mirages and Fata Morgana. These are caused by the change of the refractive index of air with temperature.
Snell's law is used to calculate the degree to which light is refracted when traveling from one medium to another.
Recently some metamaterials have been created which have a negative refractive index.
With metamaterials, we can also obtain the total refraction phenomena when the wave impedances of the two media are matched. There is no reflected wave.
Also, since refraction can make objects appear closer than they are, it is responsible for allowing water to magnify objects. First, as light is entering a drop of water, it slows down. If the water's surface is not flat, then the light will be bent into a new path. This round shape will bend the light outwards and as it spreads out, the image you see gets larger.
A useful analogy in explaining the refraction of light would be to imagine a marching band as they march from pavement (a fast medium) into mud (a slower medium) The marchers on the side that runs into the mud first will slow down first. This causes the whole band to pivot slightly toward the normal (make a smaller angle from the normal).
# Ophthalmology
In medicine, particularly ophthalmology and optometry, refraction (also known as refractometry) is a clinical test in which a phoropter is used to determine the eye's refractive error and the best corrective lenses to be prescribed. A series of test lenses in graded optical powers or focal lengths are presented to determine which provide the sharpest, clearest vision.
# Acoustics
In underwater acoustics, refraction is the bending or curving of a sound ray that results when the ray passes through a sound speed gradient from a region of one sound speed to a region of a different speed. The amount of ray bending is dependent upon the amount of difference between sound speeds, that is, the variation in temperature, salinity, and pressure of the water.
Similar acoustics effects are also found in the Earth's atmosphere. The phenomenon of refraction of sound in the atmosphere has been known for centuries; however, beginning in the early 1970s, widespread analysis of this effect came into vogue through the designing of urban highways and noise barriers to address the meteorological effects of bending of sound rays in the lower atmosphere. | Refraction
Refraction is the change in direction of a wave due to a change in its speed. This is most commonly seen when a wave passes from one medium to another. Refraction of light is the most commonly seen example, but any type of wave can refract when it interacts with a medium, for example when sound waves pass from one medium into another or when water waves move into water of a different depth. Refraction is described by Snell's law, which states that the angle of incidence is related to the angle of refraction by
or
where <math>v_1</math> and <math>v_2</math> are the wave velocities through the respective media.
# Explanation
In optics, refraction occurs when light waves travel from a medium with a given refractive index to a medium with another. At the boundary between the media, the wave's phase velocity is altered, it changes direction, and its wavelength increases or decreases but its frequency remains constant. For example, a light ray will refract as it enters and leaves glass; understanding of this concept led to the invention of lenses and the refracting telescope.
Refraction can be seen when looking into a bowl of water. Air has a refractive index of about 1.0003, and water has a refractive index of about 1.33. If a person looks at a straight object, such as a pencil or straw, which is placed at a slant, partially in the water, the object appears to bend at the water's surface. This is due to the bending of light rays as they move from the water to the air. Once the rays reach the eye, the eye traces them back as straight lines (lines of sight). The lines of sight (shown as dashed lines) intersect at a higher position than where the actual rays originated. This causes the pencil to appear higher and the water to appear shallower than it really is. The depth that the water appears to be when viewed from above is known as the apparent depth. This is an important consideration for spearfishing from the surface because it will make the target fish appear to be in a different place, and the fisher must aim lower to catch the fish.
The diagram on the right shows an example of refraction in water waves. Ripples travel from the left and pass over a shallower region inclined at an angle to the wavefront. The waves travel more slowly in the shallower water, so the wavelength decreases and the wave bends at the boundary. The dotted line represents the normal to the boundary. The dashed line represents the original direction of the waves. The phenomenon explains why waves on a shoreline never hit the shoreline at an angle. Whichever direction the waves travel in deep water, they always refract towards the normal as they enter the shallower water near the beach.
Refraction is also responsible for rainbows and for the splitting of white light into a rainbow-spectrum as it passes through a glass prism. Glass has a higher refractive index than air and the different frequencies of light travel at different speeds (dispersion), causing them to be refracted at different angles, so that you can see them. The different frequencies correspond to different colors observed.
While refraction allows for beautiful phenomena such as rainbows it may also produce peculiar optical phenomena, such as mirages and Fata Morgana. These are caused by the change of the refractive index of air with temperature.
Snell's law is used to calculate the degree to which light is refracted when traveling from one medium to another.
Recently some metamaterials have been created which have a negative refractive index.
With metamaterials, we can also obtain the total refraction phenomena when the wave impedances of the two media are matched. There is no reflected wave.
Also, since refraction can make objects appear closer than they are, it is responsible for allowing water to magnify objects. First, as light is entering a drop of water, it slows down. If the water's surface is not flat, then the light will be bent into a new path. This round shape will bend the light outwards and as it spreads out, the image you see gets larger.
A useful analogy in explaining the refraction of light would be to imagine a marching band as they march from pavement (a fast medium) into mud (a slower medium) The marchers on the side that runs into the mud first will slow down first. This causes the whole band to pivot slightly toward the normal (make a smaller angle from the normal).
# Ophthalmology
In medicine, particularly ophthalmology and optometry, refraction (also known as refractometry) is a clinical test in which a phoropter is used to determine the eye's refractive error and the best corrective lenses to be prescribed. A series of test lenses in graded optical powers or focal lengths are presented to determine which provide the sharpest, clearest vision.[1]
# Acoustics
In underwater acoustics, refraction is the bending or curving of a sound ray that results when the ray passes through a sound speed gradient from a region of one sound speed to a region of a different speed. The amount of ray bending is dependent upon the amount of difference between sound speeds, that is, the variation in temperature, salinity, and pressure of the water.[2]
Similar acoustics effects are also found in the Earth's atmosphere. The phenomenon of refraction of sound in the atmosphere has been known for centuries;[3] however, beginning in the early 1970s, widespread analysis of this effect came into vogue through the designing of urban highways and noise barriers to address the meteorological effects of bending of sound rays in the lower atmosphere.[4] | https://www.wikidoc.org/index.php/Refract | |
497fd802e502edaab4736d0b0bb00fab12ffdd15 | wikidoc | Regucalcin | Regucalcin
Regucalcin is a protein that in humans is encoded by the RGN gene
The protein encoded by this gene is a highly conserved, calcium-binding protein, that is preferentially expressed in the liver, kidney and other tissues. It may have an important role in calcium homeostasis. Studies in rats indicate that this protein may also play a role in aging, as it shows age-associated down-regulation. This gene is part of a gene cluster on chromosome Xp11.3-Xp11.23. Alternative splicing results in two transcript variants having different 5' UTRs, but encoding the same protein.
Regucalcin is a proposed name for a calcium-binding protein that was discovered in 1978 This protein is also known as Senescence Marker Protein-30 (SMP30). Regucalcin differs from calmodulin and other Ca2+-related proteins as it does not contain an EF-hand motif of Ca2+-binding domain. It may regulate the effect of Ca2+ on liver cell functions. From many investigations, regucalcin has been shown to play a multifunctional role in many cell types as a regulatory protein in the intracellular signaling system.
# Gene
Regucalcin and its gene (rgn) are identified in 16 species consisting of regucalcin family. Regucalcin is greatly expressed in the liver of rats, although the protein is found in small amounts in other tissues and cells. The rat regucalcin gene consists of seven exons and six introns, and several consensus regulatory elements exist upstream of the 5’-flanking region. The gene is localized on the proximal end of rat chromosome Xq11.1-12 and human Xp11.3-Xp11.23. AP-1, NFI-A1, RGPR-p117, and Wnt/β-catenin/TCF4 can bind to the promoter region of the rat regucalcin gene to mediate the Ca2+ and other siganaling responses with various hormones and cytokines for transcriptional activation.
# Function
Regucalcin plays a pivotal role in the keep of intracellular Ca2+ homeostasis due to activating Ca2+ pump enzymes in the plasma membrane (basolateral membrane), microsomes (endoplasmic reticulum) and mitochondria of many cells. Regucalcin is localized in the cytoplasm, mitochondria, microsomes and nucleus. Regucalcin is translocated from cytoplasm to nucleus with hormone stimulation. Regucalcin has a suppressive effect on calcium signaling from the cytoplasm to the nucleus in the proliferative cells. Also, regucalcin has been demonstrated to transport into the nucleus of cells, and it can inhibit nuclear protein kinase, protein phosphatase, and deoxyribonucleic acid and ribonucleic acid synthesis. Regucalcin can control enhancement of cell proliferation due to hormonal stimulation. Moreover, regucalcin has been shown to have an inhibitory effect on aminoacyl t-RNA synthetase, a rate limiting enzyme at translational process of protein synthesis and an activatory effect on cystein protease and superoxide dismutase in liver and kidney cells.
Regucalcin is expressed in the neuron of brain tissues, and the decrease of brain regucalcin causes accumulation of calcium in the brain microsomes. Regucalcin has an inhibitory effect on protein kinase and protein phospatase activity dependent on Ca signaling. Regucalcin has been shown to have an activatory effect on Ca pumping enzyme (Ca-ATPase) in heart sarcoplasmic reticulum. Regucalcin plays a role in the promotion of urinary calcium transport in the epithelial cells of kidney cortex. Overexpression of regucalcin suppresses cell death and apoptosis in the cloned rat hepatoma cells and normal rat kidney epithelial cells (NRK52E) induced by various signaling factors.
Thus, regucalcin plays a multifunctional role in the regulation of cell functions in liver, kidney cortex, heart and brain. Thus, regucalcin plays a pivotal role in keep of cell homeostasis and function. Regucalcin plays a pivotal role as a suppressor protein for cell signaling systems in many cell types.
# Pathophysiologic role
Overexpressing of regucalcin in rats (transgenic rats) has been shown to induce bone loss and hyperlipidemia with increasing age, indicating a pathophysiologic role. Regucalcin transgenic rat may be a useful tool as animal model in osteoporosis and hyperlipidemia. Also, regucalcin/SMP30-knockout mice are known to induce a suppression in ascorbic acid biosynthesis. The disorder of regucalcin expression has been proposed to be induced cancer, brain function, heart injury, kidney failure, osteoporosis, and hyperlipidemia. Regucalcin plays a novel role as a suppressor in carcinogenesis of human patients with various types of cancer including pancreatic cancer, breast cancer, hepatoma, and lung cancer. Of note, it has been conducted a systematic search to identify biomarker candidates for a frailty biomarker panel. Gene expression databases were searched ( including GenAge, An Age, LongevityMap, CellAge, DrugAge, Digital Aging Atlas) to identify genes regulated in aging, longevity, and age-related diseases with a focus on secreted factors or molecules detectable in body fluids as potential frailty biomarkers. A total of 44 markers were evaluated in the seven categories listed above, and 19 were awarded a high priority score, 22 identified as medium priority and three were low priority. In each category high and medium priority markers were identified. Regucalcin (RGN) was proposed to be a core gene (protein) with high priority of frailty biomarkers in order to ascertain their diagnostic, prognostic and therapeutic potential. | Regucalcin
Regucalcin is a protein that in humans is encoded by the RGN gene[1][2][3]
The protein encoded by this gene is a highly conserved, calcium-binding protein, that is preferentially expressed in the liver, kidney and other tissues.[4][5][6][7] It may have an important role in calcium homeostasis. Studies in rats indicate that this protein may also play a role in aging, as it shows age-associated down-regulation. This gene is part of a gene cluster on chromosome Xp11.3-Xp11.23. Alternative splicing results in two transcript variants having different 5' UTRs, but encoding the same protein.[3]
Regucalcin is a proposed name for a calcium-binding protein that was discovered in 1978 [8][9][10][11] This protein is also known as Senescence Marker Protein-30 (SMP30).[12][13] Regucalcin differs from calmodulin and other Ca2+-related proteins as it does not contain an EF-hand motif of Ca2+-binding domain.[9][14] It may regulate the effect of Ca2+ on liver cell functions.[11] From many investigations, regucalcin has been shown to play a multifunctional role in many cell types as a regulatory protein in the intracellular signaling system.
# Gene
Regucalcin and its gene (rgn) are identified in 16 species consisting of regucalcin family.[7][14] Regucalcin is greatly expressed in the liver of rats, although the protein is found in small amounts in other tissues and cells. The rat regucalcin gene consists of seven exons and six introns, and several consensus regulatory elements exist upstream of the 5’-flanking region.[15] The gene is localized on the proximal end of rat chromosome Xq11.1-12 and human Xp11.3-Xp11.23. AP-1, NFI-A1, RGPR-p117, and Wnt/β-catenin/TCF4 can bind to the promoter region of the rat regucalcin gene to mediate the Ca2+ and other siganaling responses with various hormones and cytokines for transcriptional activation.[16]
# Function
Regucalcin plays a pivotal role in the keep of intracellular Ca2+ homeostasis due to activating Ca2+ pump enzymes in the plasma membrane (basolateral membrane), microsomes (endoplasmic reticulum) and mitochondria of many cells. Regucalcin is localized in the cytoplasm, mitochondria, microsomes and nucleus. Regucalcin is translocated from cytoplasm to nucleus with hormone stimulation. Regucalcin has a suppressive effect on calcium signaling from the cytoplasm to the nucleus in the proliferative cells. Also, regucalcin has been demonstrated to transport into the nucleus of cells, and it can inhibit nuclear protein kinase, protein phosphatase, and deoxyribonucleic acid and ribonucleic acid synthesis. Regucalcin can control enhancement of cell proliferation due to hormonal stimulation. Moreover, regucalcin has been shown to have an inhibitory effect on aminoacyl t-RNA synthetase, a rate limiting enzyme at translational process of protein synthesis and an activatory effect on cystein protease and superoxide dismutase in liver and kidney cells.
Regucalcin is expressed in the neuron of brain tissues, and the decrease of brain regucalcin causes accumulation of calcium in the brain microsomes. Regucalcin has an inhibitory effect on protein kinase and protein phospatase activity dependent on Ca signaling. Regucalcin has been shown to have an activatory effect on Ca pumping enzyme (Ca-ATPase) in heart sarcoplasmic reticulum. Regucalcin plays a role in the promotion of urinary calcium transport in the epithelial cells of kidney cortex. Overexpression of regucalcin suppresses cell death and apoptosis in the cloned rat hepatoma cells and normal rat kidney epithelial cells (NRK52E) induced by various signaling factors.
Thus, regucalcin plays a multifunctional role in the regulation of cell functions in liver, kidney cortex, heart and brain. Thus, regucalcin plays a pivotal role in keep of cell homeostasis and function.[17] Regucalcin plays a pivotal role as a suppressor protein for cell signaling systems in many cell types.
# Pathophysiologic role
Overexpressing of regucalcin in rats (transgenic rats) has been shown to induce bone loss and hyperlipidemia with increasing age, indicating a pathophysiologic role. Regucalcin transgenic rat may be a useful tool as animal model in osteoporosis and hyperlipidemia.[18] Also, regucalcin/SMP30-knockout mice are known to induce a suppression in ascorbic acid biosynthesis. The disorder of regucalcin expression has been proposed to be induced cancer, brain function, heart injury, kidney failure, osteoporosis, and hyperlipidemia.[19] Regucalcin plays a novel role as a suppressor in carcinogenesis of human patients with various types of cancer including pancreatic cancer, breast cancer, hepatoma, and lung cancer.[20][21][19] Of note, it has been conducted a systematic search to identify biomarker candidates for a frailty biomarker panel. Gene expression databases were searched (http://genomics.senescence.info/genes including GenAge, An Age, LongevityMap, CellAge, DrugAge, Digital Aging Atlas) to identify genes regulated in aging, longevity, and age-related diseases with a focus on secreted factors or molecules detectable in body fluids as potential frailty biomarkers. A total of 44 markers were evaluated in the seven categories listed above, and 19 were awarded a high priority score, 22 identified as medium priority and three were low priority. In each category high and medium priority markers were identified. Regucalcin (RGN) was proposed to be a core gene (protein) with high priority of frailty biomarkers in order to ascertain their diagnostic, prognostic and therapeutic potential.[22] | https://www.wikidoc.org/index.php/Regucalcin | |
2fb72f080fe168d205e97d7d59345caf7d4a988e | wikidoc | Renal cyst | Renal cyst
# Overview
A renal cyst is a fluid collection in the kidney. There are several types based on the Bosniak classification. The majority are benign, simple cysts that can be monitored and not intervened upon. However, some are cancerous or are suspicious for cancer and are commonly removed in a surgical procedure called nephrectomy.
Numerous renal cysts are seen in the cystic kidney diseases, which include polycystic kidney disease and medullary sponge kidney.
# Epidemiology and Demographics
Up to 27% of individuals greater than 50 years of age may have simple renal cysts that cause no symptoms.
# Classification
## Bosniak classification
Renal cysts are classified as either malignant or benign using the Bosniak Classification System. The system was created by Dr. Morton Bosniak, a faculty member at the NYU Langone Medical Center in New York City.
The Bosniak classification categorizes renal cysts into five groups.
# Causes
## Drug Side Effect
- Crizotinib
# Differentiating renal cyst from other disease
Simple renal cyst must be differentiated from other diseases presenting as renal cysts such as:
- Autosomal dominant polycystic kidney disease
- Autosomal recessive polycystic kidney disease
- Medullary sponge kidney
- Tuberous sclerosis complex
- Von Hippel-Lindau disease
For more information on differentiating simple renal cyst, click here.
# Complications
- An infected cyst may cause fever and pain.
- A burst cyst causes severe pain in back or side.
- A kidney cyst that obstructs the normal flow of urine may lead to swelling of the kidney (hydronephrosis). | Renal cyst
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: M. Khurram Afzal, MD [2]
# Overview
A renal cyst is a fluid collection in the kidney. There are several types based on the Bosniak classification. The majority are benign, simple cysts that can be monitored and not intervened upon. However, some are cancerous or are suspicious for cancer and are commonly removed in a surgical procedure called nephrectomy.
Numerous renal cysts are seen in the cystic kidney diseases, which include polycystic kidney disease and medullary sponge kidney.
# Epidemiology and Demographics
Up to 27% of individuals greater than 50 years of age may have simple renal cysts that cause no symptoms.[1]
# Classification
## Bosniak classification
Renal cysts are classified as either malignant or benign using the Bosniak Classification System. The system was created by Dr. Morton Bosniak, a faculty member at the NYU Langone Medical Center in New York City. [2]
The Bosniak classification categorizes renal cysts into five groups.[3]
# Causes
## Drug Side Effect
- Crizotinib
# Differentiating renal cyst from other disease
Simple renal cyst must be differentiated from other diseases presenting as renal cysts such as:
- Autosomal dominant polycystic kidney disease
- Autosomal recessive polycystic kidney disease
- Medullary sponge kidney
- Tuberous sclerosis complex
- Von Hippel-Lindau disease
For more information on differentiating simple renal cyst, click here.
# Complications
- An infected cyst may cause fever and pain.
- A burst cyst causes severe pain in back or side.
- A kidney cyst that obstructs the normal flow of urine may lead to swelling of the kidney (hydronephrosis). | https://www.wikidoc.org/index.php/Renal_cyst | |
25c770575036c21a7bafbd2cdf0d8f4fe9b7748d | wikidoc | Renal lobe | Renal lobe
# Overview
The renal lobe is a portion of a kidney consisting of a renal pyramid and the renal cortex above it.
It is visible without a microscope, though it is easier to see in humans than in animals.
It is comprised of many renal lobules, which are not visible without a microscope. | Renal lobe
Template:Infobox Anatomy
# Overview
The renal lobe is a portion of a kidney consisting of a renal pyramid and the renal cortex above it. [1]
It is visible without a microscope, though it is easier to see in humans than in animals.
It is comprised of many renal lobules, which are not visible without a microscope. | https://www.wikidoc.org/index.php/Renal_lobe | |
b9a25846220eb5d4b20171cab58c75f43d8430cd | wikidoc | René Spitz | René Spitz
# Overview
René Árpád Spitz (1887, Vienna - November 11, 1974, Denver) was an American psychoanalyst of Hungarian origin. Fleeing Nazi Germany, he settled in the United States and worked at the University of Denver.
His interest was in the relationship between mother and child. He developed the concepts of hospitalism and anaclitic depression, starting from the emotional deficiencies which he observed in the child and their consequences on its psycho-emotional development.
In 1957 he filmed the seminal film Psychogenic Disease in Infancy showing examples of children with insecure attachment resulting from hospitalism.
# Ego development
Spitz noted three organising principles in the psychological development of the child:
- the smiling response, which appears at around three months old in the presence of an unspecified person;
- anxiety in the presence of a stranger, around the eighth month;
- semantic communication, in which the child learns how to be obstinate, which the psychoanalysts connect to the obsessional neurosis.
de:René A. Spitz
he:רנה שפיץ | René Spitz
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
René Árpád Spitz (1887, Vienna - November 11, 1974, Denver) was an American psychoanalyst of Hungarian origin. Fleeing Nazi Germany, he settled in the United States and worked at the University of Denver.
His interest was in the relationship between mother and child. He developed the concepts of hospitalism and anaclitic depression, starting from the emotional deficiencies which he observed in the child and their consequences on its psycho-emotional development.
In 1957 he filmed the seminal film Psychogenic Disease in Infancy showing examples of children with insecure attachment resulting from hospitalism.
# Ego development
Spitz noted three organising principles in the psychological development of the child:
- the smiling response, which appears at around three months old in the presence of an unspecified person;
- anxiety in the presence of a stranger, around the eighth month;
- semantic communication, in which the child learns how to be obstinate, which the psychoanalysts connect to the obsessional neurosis.
Template:Hungary-bio-stub
Template:US-med-bio-stub
de:René A. Spitz
he:רנה שפיץ | https://www.wikidoc.org/index.php/Ren%C3%A9_Spitz | |
e8fd2815d39a69e120ae32b8187edb0a8c652ff9 | wikidoc | Reoviridae | Reoviridae
# Overview
Reoviridae is a family of viruses that can affect the gastrointestinal system (such as Rotavirus) and respiratory tract. Viruses in the family Reoviridae have genomes consisting of segmented, double-stranded RNA (dsRNA). The name "Reoviridae" is derived from respiratory enteric orphan viruses. The term "orphan virus" means that a virus that is not associated with any known disease. Even though viruses in the Reoviridae family have more recently been identified with various diseases, the original name is still used.
Reovirus infection occurs often in humans, but most cases are mild or subclinical. The virus can be readily detected in feces, and may also be recovered from pharyngeal or nasal secretions, urine, cerebrospinal fluid, and blood. Despite the ease of finding Reovirus in clinical specimens, their role in human disease or treatment is still uncertain.
Reoviruses are non-enveloped and have an iscohedral capsid (T-13) composed of an outer and inner protein shell.
The genomes of viruses in Reoviridae contain 10-12 segments which are grouped into three categories corresponding to their size: L (large), M (medium) and S (small). Segments range from ~ 3.9 kbp – 1kbp and each segment encodes 1-3 proteins. Reoviridae proteins are denoted by the Greek character corresponding to the segment it was translated from (the L segment encodes for λ proteins, the M segment encodes for μ proteins and the S segment encodes for σ proteins).
Since these viruses have dsRNA genomes, replication occurs exclusively in the cytoplasm and the virus encodes several proteins which are needed for replication and conversion of the dsRNA genome into (+)-RNAs. The virus can enter the host cell via a receptor on the cell surface. The receptor is not known but is thought to inlcude sialic acid and junctional adhesion molecules (JAMs). The virus is partially uncoated by proteases in the endolysosome, where the capsid is partially digested to allow further cell entry. The core particle then enters the cytoplasm by a yet unknown process where the genome is transcribed conservatively causing an excess of (+) sense strands, which are used as mRNA templates to synthesize (-) sense strands. Viral particles begin to assemble in the cytoplasm 6-7 hours after infection.
Work is also being done using the reovirus in approaches for combative cancer research. Oncolytics Biotech Inc in Canada has various Type I & II trials going forward using their compounded REOLYSIN® designed to focused on the development of oncolytic viruses as potential cancer therapeutics. Oncolytics’ clinical program includes a variety of Phase I and Phase I/II human trials.
# Genera and type species
- Genus Orthoreovirus: type species Mammalian orthoreovirus
- Genus Orbivirus: type species Bluetongue virus
- Genus Rotavirus: type species Rotavirus A - a common cause of diarrhea
- Genus Coltivirus: type species Colorado tick fever virus (CTFV)
- Genus Aquareovirus: type species Aquareovirus A
- Genus Cypovirus: type species Cypovirus 1 (CPV 1)
- Genus Fijivirus: type species Fiji disease virus
- Genus Phytoreovirus: type species Rice dwarf virus
- Genus Oryzavirus: type species Rice ragged stunt virus
- Genus Idnoreovirus: type species Idnoreovirus 1
- Genus Mycoreovirus: type species Mycoreovirus 1 | Reoviridae
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Reoviridae is a family of viruses that can affect the gastrointestinal system (such as Rotavirus) and respiratory tract. Viruses in the family Reoviridae have genomes consisting of segmented, double-stranded RNA (dsRNA). The name "Reoviridae" is derived from respiratory enteric orphan viruses. The term "orphan virus" means that a virus that is not associated with any known disease. Even though viruses in the Reoviridae family have more recently been identified with various diseases, the original name is still used.
Reovirus infection occurs often in humans, but most cases are mild or subclinical. The virus can be readily detected in feces, and may also be recovered from pharyngeal or nasal secretions, urine, cerebrospinal fluid, and blood. Despite the ease of finding Reovirus in clinical specimens, their role in human disease or treatment is still uncertain.
Reoviruses are non-enveloped and have an iscohedral capsid (T-13) composed of an outer and inner protein shell.
The genomes of viruses in Reoviridae contain 10-12 segments which are grouped into three categories corresponding to their size: L (large), M (medium) and S (small). Segments range from ~ 3.9 kbp – 1kbp [2] and each segment encodes 1-3 proteins. Reoviridae proteins are denoted by the Greek character corresponding to the segment it was translated from (the L segment encodes for λ proteins, the M segment encodes for μ proteins and the S segment encodes for σ proteins).
Since these viruses have dsRNA genomes, replication occurs exclusively in the cytoplasm and the virus encodes several proteins which are needed for replication and conversion of the dsRNA genome into (+)-RNAs. The virus can enter the host cell via a receptor on the cell surface. The receptor is not known but is thought to inlcude sialic acid and junctional adhesion molecules (JAMs). The virus is partially uncoated by proteases in the endolysosome, where the capsid is partially digested to allow further cell entry. The core particle then enters the cytoplasm by a yet unknown process where the genome is transcribed conservatively causing an excess of (+) sense strands, which are used as mRNA templates to synthesize (-) sense strands. Viral particles begin to assemble in the cytoplasm 6-7 hours after infection.
Work is also being done using the reovirus in approaches for combative cancer research. Oncolytics Biotech Inc in Canada has various Type I & II trials going forward using their compounded REOLYSIN® designed to focused on the development of oncolytic viruses as potential cancer therapeutics. Oncolytics’ clinical program includes a variety of Phase I and Phase I/II human trials.
# Genera and type species
- Genus Orthoreovirus: type species Mammalian orthoreovirus
- Genus Orbivirus: type species Bluetongue virus
- Genus Rotavirus: type species Rotavirus A - a common cause of diarrhea
- Genus Coltivirus: type species Colorado tick fever virus (CTFV)
- Genus Aquareovirus: type species Aquareovirus A
- Genus Cypovirus: type species Cypovirus 1 (CPV 1)
- Genus Fijivirus: type species Fiji disease virus
- Genus Phytoreovirus: type species Rice dwarf virus
- Genus Oryzavirus: type species Rice ragged stunt virus
- Genus Idnoreovirus: type species Idnoreovirus 1
- Genus Mycoreovirus: type species Mycoreovirus 1 | https://www.wikidoc.org/index.php/Reoviridae | |
7d6e7b6c507a93ee9c7b25e073edc40b7419f7ec | wikidoc | Reslizumab | Reslizumab
# Disclaimer
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# Black Box Warning
# Overview
Reslizumab is an interleukin-5 antagonist monoclonal antibody (IgG4 kappa) that is FDA approved for the treatment of patients with severe asthma aged 18 years and older, and with an eosinophilic phenotype (add-on maintenance treatment). There is a Black Box Warning for this drug as shown here. Common adverse reactions include oropharyngeal pain (2%).
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Reslizumab is indicated for the add-on maintenance treatment of patients with severe asthma aged 18 years and older with an eosinophilic phenotype.
Limitation of Use:
- Reslizumab is not indicated for treatment of other eosinophilic conditions.
- Reslizumab is not indicated for the relief of acute bronchospasm or status asthmaticus.
Reslizumab is for intravenous infusion only. Do not administer as an intravenous push or bolus.
The recommended dosage regimen is 3 mg/kg once every 4 weeks administered by intravenous infusion over 20-50 minutes.
Discontinue the infusion immediately if the patient experiences a severe systemic reaction, including anaphylaxis.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Reslizumab in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Reslizumab in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Reslizumab is not indicated for use in pediatric patients less than 18 years of age. The safety and effectiveness in pediatric patients (aged 17 years and younger) have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Reslizumab in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Reslizumab in pediatric patients.
# Contraindications
Reslizumab is contraindicated in patients who have known hypersensitivity to reslizumab or any of its excipients.
# Warnings
Anaphylaxis to Reslizumab was reported in 0.3% of asthma patients in placebo-controlled clinical studies. These events were observed during or within 20 minutes after completion of the Reslizumab infusion and reported as early as the second dose of Reslizumab. Manifestations included dyspnea, decreased oxygen saturation, wheezing, vomiting, and skin and mucosal involvement, including urticaria. In all 3 cases, Reslizumab was discontinued.
Anaphylaxis can be life-threatening. Reslizumab should be administered in a healthcare setting by a healthcare professional prepared to manage anaphylaxis. Patients should be observed for an appropriate period of time after Reslizumab administration. If severe systemic reactions, including anaphylaxis, occur, stop administration of Reslizumab immediately and provide appropriate medical treatment. Prior to discharge, inform patients of the signs and symptoms of anaphylaxis and instruct them to seek immediate medical care if symptoms occur. Discontinue Reslizumab use permanently if the patient experiences signs or symptoms of anaphylaxis.
Reslizumab should not be used to treat acute asthma symptoms or acute exacerbations. Do not use Reslizumab to treat acute bronchospasm or status asthmaticus. Patients should seek medical advice if their asthma remains uncontrolled or worsens after initiation of treatment with Reslizumab.
In placebo-controlled clinical studies, 6/1028 (0.6%) patients receiving 3 mg/kg Reslizumab had at least 1 malignant neoplasm reported compared to 2/730 (0.3%) patients in the placebo group. The observed malignancies in Reslizumab-treated patients were diverse in nature and without clustering of any particular tissue type. The majority of malignancies were diagnosed within less than six months of exposure to Reslizumab.
No clinical studies have been conducted to assess reduction of maintenance corticosteroid dosages following administration of Reslizumab. Do not discontinue systemic or inhaled corticosteroids abruptly upon initiation of therapy with Reslizumab. Reductions in corticosteroid dose, if appropriate, should be gradual and performed under the supervision of a physician. Reduction in corticosteroid dose may be associated with systemic withdrawal symptoms and/or unmask conditions previously suppressed by systemic corticosteroid therapy.
Eosinophils may be involved in the immunological response to some helminth infections. Patients with known parasitic infections were excluded from participation in clinical studies. It is unknown if Reslizumab will influence the immune response against parasitic infections. Treat patients with pre-existing helminth infections before initiating Reslizumab. If patients become infected while receiving treatment with Reslizumab and do not respond to anti-helminth treatment, discontinue treatment with Reslizumab until infection resolves.
# Adverse Reactions
## Clinical Trials Experience
The following adverse reactions are discussed in other sections of the labeling:
- Anaphylaxis
- Malignancy
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
Overall, 2195 subjects received at least 1 dose of Reslizumab. The data described below reflect exposure to Reslizumab in 1611 patients with asthma, including 1120 exposed for up to 16 weeks, 1006 exposed for 6 months, 759 exposed for 1 year, and 249 exposed for longer than 2 years. The above referenced safety exposure for Reslizumab is derived from placebo-controlled studies ranging from 15 to 52 weeks in duration (Reslizumab 0.3 mg/kg and 3 mg/kg and placebo ) and 480 new Reslizumab 3 mg/kg exposures (previously on placebo) from a single open-label extension study (n=1051). While a lower dose of Reslizumab 0.3 mg/kg (n=103) was included in a clinical trial, 3 mg/kg is the only recommended dose. Of the 1611 patients, 1596 received the 3 mg/kg dose, 1028 of which were in the placebo-controlled studies. In the placebo-controlled asthma studies, the population studied was 12 to 76 years of age, 62% female, and 73% white. While subjects aged 12 to 17 years were included in these trials, Reslizumab is not approved for use in this age group.
Serious adverse reactions that occurred in placebo-controlled studies in more than 1 subject and in a greater percentage of subjects treated with Reslizumab (n=1131) than placebo (n=730) included anaphylaxis (3 subjects vs. 0 subjects, respectively). The 3 subjects who experienced anaphylaxis were discontinued from the clinical studies. Malignancy also occurred more commonly in patients treated with Reslizumab than placebo (0.6% and 0.3%, respectively).
Adverse reactions that occurred at greater than or equal to 2% incidence and more commonly than in the placebo group included 1 event: oropharyngeal pain (2.6% vs. 2.2%).
- CPK elevations and muscle-related adverse reactions
Elevated baseline creatine phosphokinase (CPK) was more frequent in patients randomized to Reslizumab (14%) versus placebo (9%). Transient CPK elevations in patients with normal baseline CPK values were observed more frequently with Reslizumab (20%) versus placebo (18%) during routine laboratory assessments. CPK elevations >10 x ULN, regardless of baseline CPK value, were 0.8% in the Reslizumab group compared to 0.4% in the placebo group. CPK elevations >10 x ULN were asymptomatic and did not lead to treatment discontinuation.
Myalgia was reported in 1% (10/1028) of patients in the Reslizumab 3 mg/kg group compared to 0.5% (4/730) of patients in the placebo group. On the day of infusion, musculoskeletal adverse reactions were reported in 2.2% and 1.5% of patients treated with Reslizumab 3 mg/kg and placebo, respectively. These reactions included (but were not limited to) musculoskeletal chest pain, neck pain, muscle spasms, extremity pain, muscle fatigue, and musculoskeletal pain.
As with all therapeutic proteins, there is a potential for immunogenicity. In placebo-controlled studies, a treatment-emergent anti-reslizumab antibody response developed in 53/983 (5.4%) of Reslizumab-treated patients (3 mg/kg). In the long-term, open-label study, treatment-emergent anti-reslizumab antibodies were detected in 49/1014 (4.8%) of Reslizumab-treated (3 mg/kg) asthma patients over 36 months. The antibody responses were of low titer and often transient. Neutralizing antibodies and product-specific IgE antibodies were not evaluated. There was no detectable impact of the antibodies on the clinical pharmacokinetics, pharmacodynamics, clinical efficacy, and safety of Reslizumab.
The data reflect the percentage of patients whose test results were positive for antibodies to reslizumab in specific assays. The observed incidence of antibody response is highly dependent on several factors, including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medication, and underlying disease. For these reasons, comparison of the incidence of antibodies to reslizumab with the incidence of antibodies to other products may be misleading.
## Postmarketing Experience
There is limited information regarding Reslizumab Postmarketing Experience in the drug label.
# Drug Interactions
No formal clinical drug interaction studies have been performed with Reslizumab.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
N
- Risk Summary
The data on pregnancy exposure from the clinical trials are insufficient to inform on drug-associated risk. Monoclonal antibodies, such as reslizumab, are transported across the placenta in a linear fashion as pregnancy progresses; therefore, potential effects on a fetus are likely to be greater during the second and third trimester of pregnancy. Reslizumab has a long half-life. This should be taken into consideration.
In animal reproduction studies, there was no evidence of embryo-fetal adverse developmental effects with intravenous administration of reslizumab during organogenesis to pregnant mice and rabbits at doses that produced exposures up to approximately 6 times the exposure at the maximum recommended human dose (MRHD) in mice and approximately 17 times the exposure at the MRHD in rabbits.
The estimated background risk of major birth defects and miscarriage for the indicated population(s) are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
- Clinical Considerations
- Disease-Associated Maternal and/or Embryo-Fetal Risk
In women with poorly or moderately controlled asthma, evidence demonstrates that there is an increased risk of preeclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate. The level of asthma control should be closely monitored in pregnant women and treatment adjusted as necessary to maintain optimal control.
- Data
- Animal Data
In 2 separate embryo-fetal development studies, pregnant mice and rabbits received a single reslizumab dose during the period of organogenesis at 2, 10, and 50 mg/kg (0.4, 1.5, and 6 times the exposures achieved at the MRHD in mice on an AUC basis and 0.67, 3.3, and 17 times the exposures achieved at the MRHD in rabbits on a mg/kg basis). Reslizumab was not teratogenic in mice or rabbits. Embryo-fetal development of interleukin-5 (IL-5) deficient mice has been reported to be generally unaffected relative to wild-type mice.
In a prenatal and postnatal development study, pregnant CD-1 mice received reslizumab during organogenesis on gestation days 6 and 18 and on postnatal day 14 at 10 or 50 mg/kg (1.5 and 6 times the exposures achieved at the MRHD on an AUC basis). Reslizumab did not have any effects on fetal development up to approximately 4 months after birth. Reslizumab crossed the placenta of pregnant mice. Serum concentrations in pups were approximately 6-8% of those in the dams (parental female mice) on postnatal day 14.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Reslizumab in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Reslizumab during labor and delivery.
### Nursing Mothers
- Risk Summary
It is not known whether reslizumab is present in human milk, and the effects of reslizumab on the breast fed infant and on milk production are not known. However, human IgG is known to be present in human milk. Reslizumab was present in the milk of lactating mice following dosing during pregnancy. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Reslizumab and any potential adverse effects on the breast-fed child from Reslizumab or the underlying maternal condition.
- Data
Reslizumab was excreted in milk of lactating CD-1 mice that received reslizumab at 10 or 50 mg/kg (1.5 and 6 times the exposures achieved at the MRHD on an AUC basis) during pregnancy on gestation days 6 and 18 and on postnatal day 14. Levels of reslizumab in milk were approximately 5-7% of maternal serum concentrations.
### Pediatric Use
Reslizumab is not indicated for use in pediatric patients less than 18 years of age. The safety and effectiveness in pediatric patients (aged 17 years and younger) have not been established.
Reslizumab was evaluated in 39 patients aged 12 to less than 18 years with asthma in two 52-week exacerbation studies and one 16-week lung function study. In the exacerbation studies, patients were required to have at least 1 asthma exacerbation requiring systemic corticosteroid use in the year prior to study entry. In these studies, the asthma exacerbation rate was higher in adolescent patients treated with Reslizumab than placebo (Reslizumab n=14, rate 2.86, 95% CI and placebo n=11, rate 1.37, 95% CI : rate ratio 2.09, 95% CI ).
### Geriatic Use
Reslizumab was evaluated in 122 patients aged 65 years and older with asthma in two 52-week exacerbation studies and two 16-week lung function studies. No overall differences in safety or effectiveness were observed between these patients and younger patients. Based on available data, no adjustment of the dosage of Reslizumab in geriatric patients is necessary.
### Gender
There is no FDA guidance on the use of Reslizumab with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Reslizumab with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Reslizumab in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Reslizumab in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Reslizumab in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Reslizumab in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Reslizumab is provided as a solution in a single-use vial for intravenous infusion only and should be prepared by a healthcare professional using aseptic technique as follows:
- Remove Reslizumab from the refrigerator. To minimize foaming, do not shake Reslizumab.
- Inspect visually for particulate matter and discoloration prior to administration. Reslizumab solution is clear to slightly hazy/opalescent, colorless to slightly yellow liquid. Since Reslizumab is a protein, proteinaceous particles may be present in the solution that appear as translucent to white, amorphous particulates. Do not administer if discolored or if other foreign particulate matter is present.
- Withdraw the proper volume of Reslizumab from the vial(s), based on the recommended weight-based dosage. Discard any unused portion.
- Dispense syringe contents slowly into an infusion bag containing 50 mL of 0.9% Sodium Chloride Injection, USP to minimize foaming of Reslizumab (Reslizumab is compatible with polyvinylchloride (PVC) or polyolefin infusion bags). Gently invert the bag to mix the solution. Do not shake. Do not mix or dilute with other drugs.
- Administer immediately after preparation. If not used immediately, store diluted solutions of Reslizumab in the refrigerator at 2°C to 8°C (36°F to 46°F) or at room temperature up to 25ºC (77ºF), protected from light, for up to 16 hours. The time between preparation of Reslizumab and administration should not exceed 16 hours.
- Reslizumab should be administered in a healthcare setting by a healthcare professional prepared to manage anaphylaxis.
- If refrigerated prior to administration, allow the diluted Reslizumab solution to reach room temperature.
- Use an infusion set with an in-line, low protein-binding filter (pore size of 0.2 micron). Reslizumab is compatible with polyethersulfone (PES), polyvinylidene fluoride (PVDF), nylon, and cellulose acetate in-line infusion filters.
- Infuse the diluted solution of Reslizumab intravenously, over a 20–50 minute period. Infusion time may vary depending on the total volume to be infused as based upon patient weight.
- Do not infuse Reslizumab concomitantly in the same intravenous line with other agents. No physical or biochemical compatibility studies have been conducted to evaluate the co-administration of Reslizumab with other agents.
- Observe the patient over the infusion and for an appropriate period of time following infusion.
- Upon completion of the infusion, flush the intravenous administration set with 0.9% Sodium Chloride Injection, USP to ensure that all Reslizumab has been administered.
### Monitoring
There is limited information regarding Reslizumab Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Reslizumab and IV administrations.
# Overdosage
Single doses of up to 732 mg have been administered intravenously to subjects in clinical trials without evidence of dose-related toxicities.
There is no specific treatment for an overdose with Reslizumab. If overdose occurs, the patient should be treated supportively with appropriate monitoring as necessary.
# Pharmacology
## Mechanism of Action
Reslizumab is an interleukin-5 antagonist (IgG4, kappa). IL-5 is the major cytokine responsible for the growth and differentiation, recruitment, activation, and survival of eosinophils. Reslizumab binds to IL-5 with a dissociation constant of 81 pM, inhibiting the bioactivity of IL-5 by blocking its binding to the alpha chain of the IL-5 receptor complex expressed on the eosinophil surface. Inflammation is an important component in the pathogenesis of asthma. Multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, cytokines) are involved in inflammation. Reslizumab, by inhibiting IL-5 signaling, reduces the production and survival of eosinophils; however, the mechanism of reslizumab action in asthma has not been definitively established.
## Structure
Reslizumab is a humanized interleukin-5 antagonist monoclonal antibody (IgG4κ). Reslizumab is produced by recombinant DNA technology in murine myeloma non-secreting 0 (NS0) cells. Reslizumab has a molecular weight of approximately 147 kDa.
Reslizumab is a sterile, preservative-free, clear to slightly hazy/opalescent, colorless to slightly yellow solution (injection) for intravenous infusion. Since Reslizumab is a protein, proteinaceous particles may be present in the solution that appear as translucent to white, amorphous particulates. Each single-use vial contains 100 mg reslizumab in 10 mL. Each mL contains 10 mg of reslizumab, glacial acetic acid (0.12 mg), sodium acetate trihydrate (2.45 mg), and sucrose (70 mg), with a pH of 5.5.
## Pharmacodynamics
In clinical studies with Reslizumab 3 mg/kg, reductions in blood eosinophil counts were observed following the first dose and maintained through 52 weeks of treatment with no signs of tachyphylaxis. Mean eosinophil counts were 696 cells/mcL (n=245) and 624 cells/mcL (n=244) at baseline, and were 55 cells/mcL (92% reduction, n=212) and 496 cells /mcL (21% reduction, n=212) at the Week 52 visit for the Reslizumab and placebo treatment groups, respectively. Early eosinophil reduction was apparent in a subset of patients who had blood eosinophil counts assessed at days 2-3: 220 cells/mcL and 610/mcL for Reslizumab (n=35) and placebo (n=32), respectively. Eosinophils returned towards baseline in those Reslizumab-treated patients who completed a 90-day follow-up assessment (n=35, 480 cells/mcL), approximately 120 days after the last dose of Reslizumab.
Reductions of blood eosinophils were related to reslizumab serum levels, i.e., greater reductions of blood eosinophils were observed in subjects with higher reslizumab serum concentrations.
Treatment-emergent anti-reslizumab antibodies did not interfere with the blood eosinophil reduction effect by reslizumab.
## Pharmacokinetics
The pharmacokinetics (PK) of reslizumab were characterized in healthy adults (n=130), in patients with asthma (n=438), and in other patient populations (n=236). The PK characteristics of reslizumab were similar across these populations. Inter-individual variability in peak and overall exposure was approximately 20-30%.
Peak serum concentrations were typically observed at the end of the infusion. Serum reslizumab concentrations generally declined from peak in a biphasic manner. Following multiple doses, serum concentrations of reslizumab accumulated approximately 1.5 to 1.9-fold.
Systemic exposure to reslizumab appeared to be unaffected by the presence of treatment-emergent anti-reslizumab antibodies.
- Distribution
Reslizumab has a volume of distribution of approximately 5 liters, suggesting minimal distribution to the extravascular tissues.
- Metabolism
Similar to other monoclonal antibodies, reslizumab is degraded by enzymatic proteolysis into small peptides and amino acids. As reslizumab binds to a soluble target, it is not expected to go through a target-mediated clearance.
- Elimination
Reslizumab clearance was approximately 7 mL/hour. Reslizumab has a half-life of about 24 days.
- Specific Populations
- Age, Race, and Gender
Population PK analyses demonstrated that there was no significant effect of age, race, or gender on the PK of reslizumab.
- Hepatic Impairment
No clinical studies were conducted to assess the effect of hepatic impairment on the PK of reslizumab. The results of population PK analyses indicated that there was no significant difference in the PK of reslizumab between patients with normal liver function tests (total bilirubin less than or equal to the ULN and aspartate aminotransferase less than or equal to the ULN) and mildly increased liver function tests (total bilirubin above the ULN and less than or equal to 1.5-times the ULN or AST greater than ULN and total bilirubin less than or equal to the ULN).
- Renal Impairment
No clinical studies have been conducted to assess the effect of renal impairment on the PK of reslizumab. The results of population PK analyses indicated that there was no significant difference in the PK of reslizumab between patients with normal renal function (estimated glomerular filtration rate greater than or equal to 90 mL/min/1.73 m2), mild renal impairment (eGFR 60-89 mL/min/1.73 m2), and moderate renal impairment (eGFR 30-59 mL/min/1.73 m2).
- Drug Interactions
In vitro data indicate that IL-5 and reslizumab are unlikely to affect CYP1A2, 2B6, or 3A4 enzyme activity.
No formal clinical drug interaction studies have been conducted with reslizumab. Population PK analyses indicate that concomitant use of either leukotriene antagonists or corticosteroids does not affect the PK of reslizumab.
## Nonclinical Toxicology
In a 6-month bioassay, reslizumab was administered intravenously once every 2 weeks for 26 consecutive weeks (14 total doses) to Tg.rasH2 mice at doses up to 516 mg/kg/dose. There was no evidence of carcinogenicity.
Published literature using animal models suggests that IL-5 and eosinophils are part of an early inflammatory reaction at the site of tumorigenesis and can promote tumor rejection. However, other reports indicate that eosinophil infiltration into tumors can promote tumor growth. Therefore, the malignancy risk in humans from an antibody to IL-5 such as reslizumab is unknown.
In a fertility study, administration of reslizumab to parental mice at doses up to 50 mg/kg (approximately 6 times the MRHD on an AUC basis) had no effects on male or female mating or fertility.
# Clinical Studies
The asthma development program for Reslizumab 3 mg/kg (administered once every 4 weeks) included 4 randomized, double-blind, placebo-controlled studies (Studies I-IV) 16 to 52 weeks in duration involving 981 patients 12 years of age and older. While patients aged 12 to 17 years were included in these trials, Reslizumab is not approved for use in this age group. All subjects continued their background asthma therapy throughout the duration of the studies.
- Studies I and II
Studies I and II were 52-week studies in 953 patients with asthma who were required to have a blood eosinophil count of at least 400/mcL (within 3 to 4 weeks of dosing), and at least 1 asthma exacerbation requiring systemic corticosteroid use over the past 12 months. The majority of patients (82%) were on medium-high dose inhaled corticosteroids plus a long-acting beta agonist (ICS/LABA) at baseline. Maintenance oral corticosteroids (OCS) (up to 10 mg of prednisone per day or equivalent) were allowed; 106 (11%) patients were on OCS at baseline. Reslizumab 3 mg/kg administered once every 4 weeks for a total of 13 doses was evaluated compared with placebo.
- Study III
Study III was a 16-week study in 315 patients who were required to have a blood eosinophil count of at least 400/mcL at screening (within 3 to 4 weeks of dosing). Maintenance OCS were not allowed. Reslizumab 3 mg/kg or 0.3 mg/kg administered once every 4 weeks for a total of 4 doses was evaluated compared with placebo. While 2 doses of Reslizumab were studied, Reslizumab 3 mg/kg is the only recommended dose.
- Study IV
Study IV was a 16-week study in 496 patients unselected for baseline blood eosinophil levels (approximately 80% of patients had a screening blood eosinophil count of less than 400/mcL). Maintenance OCS were not allowed. Reslizumab 3 mg/kg administered once every 4 weeks for a total of 4 doses was evaluated compared with placebo.
The demographics and baseline characteristics of these 4 studies is provided in Table 1.
- Table 1: Demographics and Baseline Characteristics of Patients in Asthma Studies
Exacerbations
The primary endpoint for Studies I and II was the frequency of asthma exacerbations for each patient during the 52-week treatment period. An asthma exacerbation was defined as a worsening of asthma that required at least 1 of the following medical interventions:
1)Either the use of a systemic corticosteroid, or ≥ 2-fold an increase in the use of ICS for 3 or more days, and/or
2)Asthma-related emergency treatment including at least 1 of the following: an unscheduled visit to their healthcare professional for nebulizer treatment or other urgent treatment to prevent worsening of asthma symptoms; a visit to the emergency room for asthma-related treatment; or an asthma-related hospitalization.
The medical intervention had to be corroborated with at least 1 of the following: 1) a decrease in forced expiratory volume in 1 second (FEV 1) by 20% or more from baseline, 2) a decrease in peak expiratory flow rate (PEFR) by 30% or more from baseline on 2 consecutive days, or 3) worsening of symptoms or other clinical signs per physician evaluation of the event.
In Studies I and II, patients receiving Reslizumab 3 mg/kg administered once every 4 weeks had significant reductions in the rate of all asthma exacerbations compared to placebo (Table 2). Exacerbations requiring the use of a systemic corticosteroid (e.g., OCS) as well as exacerbations resulting in hospitalization or an emergency room visit were each reduced with Reslizumab 3 mg/kg.
- Table 2: Frequency of Asthma Exacerbations during the 52-Week Treatment Period in Patients with Severe Asthma with an Eosinophilic Phenotype (Studies I and II)*
CINQAIR: Reslizumab's Brand name
The proportion of patients who did not experience an asthma exacerbation during the 52-week treatment period was higher in the Reslizumab 3 mg/kg group (62% and 75%) compared with the placebo group (46% and 55%), in Studies I and II, respectively. The time to first asthma exacerbation was significantly longer for the groups receiving Reslizumab 3 mg/kg compared with placebo in both Studies I and II. A representative figure from Study I is shown below (Figure 1). Study II showed similar results.
- Figure 1: Time to First Asthma Exacerbation by Treatment Group in Patients with Severe Asthma with an Eosinophilic Phenotype (Study I)
CINQAIR: Reslizumab's Brand name
Lung Function
The effect of Reslizumab 3 mg/kg administered once every 4 weeks on FEV1 over time relative to placebo was assessed in all 4 studies (Table 3). FEV1 was the primary endpoint in the 16-week lung function studies: Study III (Figure 2) and Study IV.
Study III also studied a lower dose, Reslizumab 0.3 mg/kg, that produced significant but numerically smaller changes in FEV1 and blood eosinophil reduction compared with the 3 mg/kg dose. While 2 doses of Reslizumab were studied, Reslizumab 3 mg/kg is the only recommended dose.
Study IV was the only study to test Reslizumab 3 mg/kg in asthma patients unselected for blood eosinophils (measured 3 to 4 weeks prior to dosing); association of treatment effect (i.e., difference between Reslizumab and placebo in the change in FEV1 at Week 16) and baseline blood eosinophils was not observed.
- Table 3: Mean Change (95% CI) from Baseline in FEV1 in mL Over 16 Weeks (Difference from Reslizumab and Placebo) in Patients with Severe Asthma with an Eosinophilic Phenotype
Improvements in FEV1 were observed at 4 weeks following the first dose of Reslizumab for Studies I and II and maintained through Week 52.
- Figure 2: Mean Change from Baseline in FEV1 in Patients with Severe Asthma with an Eosinophilic Phenotype (Study III)
CINQAIR: Reslizumab's Brand name
The Asthma Control Questionnaire-7 (ACQ-7) and Asthma Quality of Life Questionnaire (AQLQ) were both assessed in Studies I, II, and III. The responder rate for both measures was defined as an improvement in score of 0.5 or more as threshold over 16 weeks.
- For ACQ-7, the responder rate for those randomized to Reslizumab vs. placebo was 69% vs. 65% for Study I, 70% vs. 58% for Study II, and 64% vs. 58% for Study III.
- For AQLQ, the responder rate for those randomized to Reslizumab vs. placebo was 66% vs. 58% for Study I, 67% vs. 55% for Study II, and 64% vs. 48% for Study III.
# How Supplied
Reslizumab injection, 100 mg/10 mL (10 mg/mL), is supplied as a preservative-free, sterile, clear to slightly hazy/opalescent, colorless to slightly yellow solution in single-use vials. The following packaging configuration is available:
- NDC 59310-610-31: 100 mg/10 mL (10 mg/mL) single-use vial.
## Storage
Refrigerate at 2 ºC to 8ºC (36°F to 46°F). Do not freeze. Do not shake. Protect the vials from light by storing in the original package until time of use.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
See FDA approved patient labeling (Patient Information).
- Hypersensitivity/Anaphylaxis
Inform patients that hypersensitivity reactions, including anaphylaxis, have occurred with administration of Reslizumab. Educate patients on the signs and symptoms of hypersensitivity reactions and anaphylaxis (e.g., skin or mucosal involvement, airway compromise, reduced blood pressure). Instruct patients to contact their healthcare professional immediately if they experience symptoms of an allergic reaction after they have received their infusion of Reslizumab.
- Not for Acute Symptoms or Deteriorating Disease
Inform patients that Reslizumab does not treat acute asthma symptoms or acute exacerbations. Inform patients to seek medical advice if their asthma remains uncontrolled or worsens after initiation of treatment with Reslizumab.
- Malignancy
Counsel Reslizumab-treated patients about the risk of malignancies.
- Reduction of Corticosteroid Dosage
Inform patients not to discontinue systemic or inhaled corticosteroids except under the direct supervision of a physician. Inform patients that reduction in corticosteroid dose may be associated with systemic withdrawal symptoms and/or unmask conditions previously suppressed by systemic corticosteroid therapy.
# Precautions with Alcohol
Alcohol-Reslizumab interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
CINQAIR®
# Look-Alike Drug Names
There is limited information regarding Reslizumab Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Reslizumab
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Martin Nino [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Black Box Warning
# Overview
Reslizumab is an interleukin-5 antagonist monoclonal antibody (IgG4 kappa) that is FDA approved for the treatment of patients with severe asthma aged 18 years and older, and with an eosinophilic phenotype (add-on maintenance treatment). There is a Black Box Warning for this drug as shown here. Common adverse reactions include oropharyngeal pain (2%).
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Reslizumab is indicated for the add-on maintenance treatment of patients with severe asthma aged 18 years and older with an eosinophilic phenotype.
Limitation of Use:
- Reslizumab is not indicated for treatment of other eosinophilic conditions.
- Reslizumab is not indicated for the relief of acute bronchospasm or status asthmaticus.
Reslizumab is for intravenous infusion only. Do not administer as an intravenous push or bolus.
The recommended dosage regimen is 3 mg/kg once every 4 weeks administered by intravenous infusion over 20-50 minutes.
Discontinue the infusion immediately if the patient experiences a severe systemic reaction, including anaphylaxis.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Reslizumab in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Reslizumab in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Reslizumab is not indicated for use in pediatric patients less than 18 years of age. The safety and effectiveness in pediatric patients (aged 17 years and younger) have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Reslizumab in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Reslizumab in pediatric patients.
# Contraindications
Reslizumab is contraindicated in patients who have known hypersensitivity to reslizumab or any of its excipients.
# Warnings
Anaphylaxis to Reslizumab was reported in 0.3% of asthma patients in placebo-controlled clinical studies. These events were observed during or within 20 minutes after completion of the Reslizumab infusion and reported as early as the second dose of Reslizumab. Manifestations included dyspnea, decreased oxygen saturation, wheezing, vomiting, and skin and mucosal involvement, including urticaria. In all 3 cases, Reslizumab was discontinued.
Anaphylaxis can be life-threatening. Reslizumab should be administered in a healthcare setting by a healthcare professional prepared to manage anaphylaxis. Patients should be observed for an appropriate period of time after Reslizumab administration. If severe systemic reactions, including anaphylaxis, occur, stop administration of Reslizumab immediately and provide appropriate medical treatment. Prior to discharge, inform patients of the signs and symptoms of anaphylaxis and instruct them to seek immediate medical care if symptoms occur. Discontinue Reslizumab use permanently if the patient experiences signs or symptoms of anaphylaxis.
Reslizumab should not be used to treat acute asthma symptoms or acute exacerbations. Do not use Reslizumab to treat acute bronchospasm or status asthmaticus. Patients should seek medical advice if their asthma remains uncontrolled or worsens after initiation of treatment with Reslizumab.
In placebo-controlled clinical studies, 6/1028 (0.6%) patients receiving 3 mg/kg Reslizumab had at least 1 malignant neoplasm reported compared to 2/730 (0.3%) patients in the placebo group. The observed malignancies in Reslizumab-treated patients were diverse in nature and without clustering of any particular tissue type. The majority of malignancies were diagnosed within less than six months of exposure to Reslizumab.
No clinical studies have been conducted to assess reduction of maintenance corticosteroid dosages following administration of Reslizumab. Do not discontinue systemic or inhaled corticosteroids abruptly upon initiation of therapy with Reslizumab. Reductions in corticosteroid dose, if appropriate, should be gradual and performed under the supervision of a physician. Reduction in corticosteroid dose may be associated with systemic withdrawal symptoms and/or unmask conditions previously suppressed by systemic corticosteroid therapy.
Eosinophils may be involved in the immunological response to some helminth infections. Patients with known parasitic infections were excluded from participation in clinical studies. It is unknown if Reslizumab will influence the immune response against parasitic infections. Treat patients with pre-existing helminth infections before initiating Reslizumab. If patients become infected while receiving treatment with Reslizumab and do not respond to anti-helminth treatment, discontinue treatment with Reslizumab until infection resolves.
# Adverse Reactions
## Clinical Trials Experience
The following adverse reactions are discussed in other sections of the labeling:
- Anaphylaxis
- Malignancy
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
Overall, 2195 subjects received at least 1 dose of Reslizumab. The data described below reflect exposure to Reslizumab in 1611 patients with asthma, including 1120 exposed for up to 16 weeks, 1006 exposed for 6 months, 759 exposed for 1 year, and 249 exposed for longer than 2 years. The above referenced safety exposure for Reslizumab is derived from placebo-controlled studies ranging from 15 to 52 weeks in duration (Reslizumab 0.3 mg/kg and 3 mg/kg [n=1131] and placebo [n=730]) and 480 new Reslizumab 3 mg/kg exposures (previously on placebo) from a single open-label extension study (n=1051). While a lower dose of Reslizumab 0.3 mg/kg (n=103) was included in a clinical trial, 3 mg/kg is the only recommended dose. Of the 1611 patients, 1596 received the 3 mg/kg dose, 1028 of which were in the placebo-controlled studies. In the placebo-controlled asthma studies, the population studied was 12 to 76 years of age, 62% female, and 73% white. While subjects aged 12 to 17 years were included in these trials, Reslizumab is not approved for use in this age group.
Serious adverse reactions that occurred in placebo-controlled studies in more than 1 subject and in a greater percentage of subjects treated with Reslizumab (n=1131) than placebo (n=730) included anaphylaxis (3 subjects vs. 0 subjects, respectively). The 3 subjects who experienced anaphylaxis were discontinued from the clinical studies. Malignancy also occurred more commonly in patients treated with Reslizumab than placebo (0.6% and 0.3%, respectively).
Adverse reactions that occurred at greater than or equal to 2% incidence and more commonly than in the placebo group included 1 event: oropharyngeal pain (2.6% vs. 2.2%).
- CPK elevations and muscle-related adverse reactions
Elevated baseline creatine phosphokinase (CPK) was more frequent in patients randomized to Reslizumab (14%) versus placebo (9%). Transient CPK elevations in patients with normal baseline CPK values were observed more frequently with Reslizumab (20%) versus placebo (18%) during routine laboratory assessments. CPK elevations >10 x ULN, regardless of baseline CPK value, were 0.8% in the Reslizumab group compared to 0.4% in the placebo group. CPK elevations >10 x ULN were asymptomatic and did not lead to treatment discontinuation.
Myalgia was reported in 1% (10/1028) of patients in the Reslizumab 3 mg/kg group compared to 0.5% (4/730) of patients in the placebo group. On the day of infusion, musculoskeletal adverse reactions were reported in 2.2% and 1.5% of patients treated with Reslizumab 3 mg/kg and placebo, respectively. These reactions included (but were not limited to) musculoskeletal chest pain, neck pain, muscle spasms, extremity pain, muscle fatigue, and musculoskeletal pain.
As with all therapeutic proteins, there is a potential for immunogenicity. In placebo-controlled studies, a treatment-emergent anti-reslizumab antibody response developed in 53/983 (5.4%) of Reslizumab-treated patients (3 mg/kg). In the long-term, open-label study, treatment-emergent anti-reslizumab antibodies were detected in 49/1014 (4.8%) of Reslizumab-treated (3 mg/kg) asthma patients over 36 months. The antibody responses were of low titer and often transient. Neutralizing antibodies and product-specific IgE antibodies were not evaluated. There was no detectable impact of the antibodies on the clinical pharmacokinetics, pharmacodynamics, clinical efficacy, and safety of Reslizumab.
The data reflect the percentage of patients whose test results were positive for antibodies to reslizumab in specific assays. The observed incidence of antibody response is highly dependent on several factors, including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medication, and underlying disease. For these reasons, comparison of the incidence of antibodies to reslizumab with the incidence of antibodies to other products may be misleading.
## Postmarketing Experience
There is limited information regarding Reslizumab Postmarketing Experience in the drug label.
# Drug Interactions
No formal clinical drug interaction studies have been performed with Reslizumab.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
N
- Risk Summary
The data on pregnancy exposure from the clinical trials are insufficient to inform on drug-associated risk. Monoclonal antibodies, such as reslizumab, are transported across the placenta in a linear fashion as pregnancy progresses; therefore, potential effects on a fetus are likely to be greater during the second and third trimester of pregnancy. Reslizumab has a long half-life. This should be taken into consideration.
In animal reproduction studies, there was no evidence of embryo-fetal adverse developmental effects with intravenous administration of reslizumab during organogenesis to pregnant mice and rabbits at doses that produced exposures up to approximately 6 times the exposure at the maximum recommended human dose (MRHD) in mice and approximately 17 times the exposure at the MRHD in rabbits.
The estimated background risk of major birth defects and miscarriage for the indicated population(s) are unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
- Clinical Considerations
- Disease-Associated Maternal and/or Embryo-Fetal Risk
In women with poorly or moderately controlled asthma, evidence demonstrates that there is an increased risk of preeclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate. The level of asthma control should be closely monitored in pregnant women and treatment adjusted as necessary to maintain optimal control.
- Data
- Animal Data
In 2 separate embryo-fetal development studies, pregnant mice and rabbits received a single reslizumab dose during the period of organogenesis at 2, 10, and 50 mg/kg (0.4, 1.5, and 6 times the exposures achieved at the MRHD in mice on an AUC basis and 0.67, 3.3, and 17 times the exposures achieved at the MRHD in rabbits on a mg/kg basis). Reslizumab was not teratogenic in mice or rabbits. Embryo-fetal development of interleukin-5 (IL-5) deficient mice has been reported to be generally unaffected relative to wild-type mice.
In a prenatal and postnatal development study, pregnant CD-1 mice received reslizumab during organogenesis on gestation days 6 and 18 and on postnatal day 14 at 10 or 50 mg/kg (1.5 and 6 times the exposures achieved at the MRHD on an AUC basis). Reslizumab did not have any effects on fetal development up to approximately 4 months after birth. Reslizumab crossed the placenta of pregnant mice. Serum concentrations in pups were approximately 6-8% of those in the dams (parental female mice) on postnatal day 14.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Reslizumab in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Reslizumab during labor and delivery.
### Nursing Mothers
- Risk Summary
It is not known whether reslizumab is present in human milk, and the effects of reslizumab on the breast fed infant and on milk production are not known. However, human IgG is known to be present in human milk. Reslizumab was present in the milk of lactating mice following dosing during pregnancy. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Reslizumab and any potential adverse effects on the breast-fed child from Reslizumab or the underlying maternal condition.
- Data
Reslizumab was excreted in milk of lactating CD-1 mice that received reslizumab at 10 or 50 mg/kg (1.5 and 6 times the exposures achieved at the MRHD on an AUC basis) during pregnancy on gestation days 6 and 18 and on postnatal day 14. Levels of reslizumab in milk were approximately 5-7% of maternal serum concentrations.
### Pediatric Use
Reslizumab is not indicated for use in pediatric patients less than 18 years of age. The safety and effectiveness in pediatric patients (aged 17 years and younger) have not been established.
Reslizumab was evaluated in 39 patients aged 12 to less than 18 years with asthma in two 52-week exacerbation studies and one 16-week lung function study. In the exacerbation studies, patients were required to have at least 1 asthma exacerbation requiring systemic corticosteroid use in the year prior to study entry. In these studies, the asthma exacerbation rate was higher in adolescent patients treated with Reslizumab than placebo (Reslizumab n=14, rate 2.86, 95% CI [1.02 to 8.09] and placebo n=11, rate 1.37, 95% CI [0.57 to 3.28]: rate ratio 2.09, 95% CI [0.82 to 5.36]).
### Geriatic Use
Reslizumab was evaluated in 122 patients aged 65 years and older with asthma in two 52-week exacerbation studies and two 16-week lung function studies. No overall differences in safety or effectiveness were observed between these patients and younger patients. Based on available data, no adjustment of the dosage of Reslizumab in geriatric patients is necessary.
### Gender
There is no FDA guidance on the use of Reslizumab with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Reslizumab with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Reslizumab in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Reslizumab in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Reslizumab in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Reslizumab in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Reslizumab is provided as a solution in a single-use vial for intravenous infusion only and should be prepared by a healthcare professional using aseptic technique as follows:
- Remove Reslizumab from the refrigerator. To minimize foaming, do not shake Reslizumab.
- Inspect visually for particulate matter and discoloration prior to administration. Reslizumab solution is clear to slightly hazy/opalescent, colorless to slightly yellow liquid. Since Reslizumab is a protein, proteinaceous particles may be present in the solution that appear as translucent to white, amorphous particulates. Do not administer if discolored or if other foreign particulate matter is present.
- Withdraw the proper volume of Reslizumab from the vial(s), based on the recommended weight-based dosage. Discard any unused portion.
- Dispense syringe contents slowly into an infusion bag containing 50 mL of 0.9% Sodium Chloride Injection, USP to minimize foaming of Reslizumab (Reslizumab is compatible with polyvinylchloride (PVC) or polyolefin infusion bags). Gently invert the bag to mix the solution. Do not shake. Do not mix or dilute with other drugs.
- Administer immediately after preparation. If not used immediately, store diluted solutions of Reslizumab in the refrigerator at 2°C to 8°C (36°F to 46°F) or at room temperature up to 25ºC (77ºF), protected from light, for up to 16 hours. The time between preparation of Reslizumab and administration should not exceed 16 hours.
- Reslizumab should be administered in a healthcare setting by a healthcare professional prepared to manage anaphylaxis.
- If refrigerated prior to administration, allow the diluted Reslizumab solution to reach room temperature.
- Use an infusion set with an in-line, low protein-binding filter (pore size of 0.2 micron). Reslizumab is compatible with polyethersulfone (PES), polyvinylidene fluoride (PVDF), nylon, and cellulose acetate in-line infusion filters.
- Infuse the diluted solution of Reslizumab intravenously, over a 20–50 minute period. Infusion time may vary depending on the total volume to be infused as based upon patient weight.
- Do not infuse Reslizumab concomitantly in the same intravenous line with other agents. No physical or biochemical compatibility studies have been conducted to evaluate the co-administration of Reslizumab with other agents.
- Observe the patient over the infusion and for an appropriate period of time following infusion.
- Upon completion of the infusion, flush the intravenous administration set with 0.9% Sodium Chloride Injection, USP to ensure that all Reslizumab has been administered.
### Monitoring
There is limited information regarding Reslizumab Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Reslizumab and IV administrations.
# Overdosage
Single doses of up to 732 mg have been administered intravenously to subjects in clinical trials without evidence of dose-related toxicities.
There is no specific treatment for an overdose with Reslizumab. If overdose occurs, the patient should be treated supportively with appropriate monitoring as necessary.
# Pharmacology
## Mechanism of Action
Reslizumab is an interleukin-5 antagonist (IgG4, kappa). IL-5 is the major cytokine responsible for the growth and differentiation, recruitment, activation, and survival of eosinophils. Reslizumab binds to IL-5 with a dissociation constant of 81 pM, inhibiting the bioactivity of IL-5 by blocking its binding to the alpha chain of the IL-5 receptor complex expressed on the eosinophil surface. Inflammation is an important component in the pathogenesis of asthma. Multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, cytokines) are involved in inflammation. Reslizumab, by inhibiting IL-5 signaling, reduces the production and survival of eosinophils; however, the mechanism of reslizumab action in asthma has not been definitively established.
## Structure
Reslizumab is a humanized interleukin-5 antagonist monoclonal antibody (IgG4κ). Reslizumab is produced by recombinant DNA technology in murine myeloma non-secreting 0 (NS0) cells. Reslizumab has a molecular weight of approximately 147 kDa.
Reslizumab is a sterile, preservative-free, clear to slightly hazy/opalescent, colorless to slightly yellow solution (injection) for intravenous infusion. Since Reslizumab is a protein, proteinaceous particles may be present in the solution that appear as translucent to white, amorphous particulates. Each single-use vial contains 100 mg reslizumab in 10 mL. Each mL contains 10 mg of reslizumab, glacial acetic acid (0.12 mg), sodium acetate trihydrate (2.45 mg), and sucrose (70 mg), with a pH of 5.5.
## Pharmacodynamics
In clinical studies with Reslizumab 3 mg/kg, reductions in blood eosinophil counts were observed following the first dose and maintained through 52 weeks of treatment with no signs of tachyphylaxis. Mean eosinophil counts were 696 cells/mcL (n=245) and 624 cells/mcL (n=244) at baseline, and were 55 cells/mcL (92% reduction, n=212) and 496 cells /mcL (21% reduction, n=212) at the Week 52 visit for the Reslizumab and placebo treatment groups, respectively. Early eosinophil reduction was apparent in a subset of patients who had blood eosinophil counts assessed at days 2-3: 220 cells/mcL and 610/mcL for Reslizumab (n=35) and placebo (n=32), respectively. Eosinophils returned towards baseline in those Reslizumab-treated patients who completed a 90-day follow-up assessment (n=35, 480 cells/mcL), approximately 120 days after the last dose of Reslizumab.
Reductions of blood eosinophils were related to reslizumab serum levels, i.e., greater reductions of blood eosinophils were observed in subjects with higher reslizumab serum concentrations.
Treatment-emergent anti-reslizumab antibodies did not interfere with the blood eosinophil reduction effect by reslizumab.
## Pharmacokinetics
The pharmacokinetics (PK) of reslizumab were characterized in healthy adults (n=130), in patients with asthma (n=438), and in other patient populations (n=236). The PK characteristics of reslizumab were similar across these populations. Inter-individual variability in peak and overall exposure was approximately 20-30%.
Peak serum concentrations were typically observed at the end of the infusion. Serum reslizumab concentrations generally declined from peak in a biphasic manner. Following multiple doses, serum concentrations of reslizumab accumulated approximately 1.5 to 1.9-fold.
Systemic exposure to reslizumab appeared to be unaffected by the presence of treatment-emergent anti-reslizumab antibodies.
- Distribution
Reslizumab has a volume of distribution of approximately 5 liters, suggesting minimal distribution to the extravascular tissues.
- Metabolism
Similar to other monoclonal antibodies, reslizumab is degraded by enzymatic proteolysis into small peptides and amino acids. As reslizumab binds to a soluble target, it is not expected to go through a target-mediated clearance.
- Elimination
Reslizumab clearance was approximately 7 mL/hour. Reslizumab has a half-life of about 24 days.
- Specific Populations
- Age, Race, and Gender
Population PK analyses demonstrated that there was no significant effect of age, race, or gender on the PK of reslizumab.
- Hepatic Impairment
No clinical studies were conducted to assess the effect of hepatic impairment on the PK of reslizumab. The results of population PK analyses indicated that there was no significant difference in the PK of reslizumab between patients with normal liver function tests (total bilirubin less than or equal to the ULN and aspartate aminotransferase [AST] less than or equal to the ULN) and mildly increased liver function tests (total bilirubin above the ULN and less than or equal to 1.5-times the ULN or AST greater than ULN and total bilirubin less than or equal to the ULN).
- Renal Impairment
No clinical studies have been conducted to assess the effect of renal impairment on the PK of reslizumab. The results of population PK analyses indicated that there was no significant difference in the PK of reslizumab between patients with normal renal function (estimated glomerular filtration rate [eGFR] greater than or equal to 90 mL/min/1.73 m2), mild renal impairment (eGFR 60-89 mL/min/1.73 m2), and moderate renal impairment (eGFR 30-59 mL/min/1.73 m2).
- Drug Interactions
In vitro data indicate that IL-5 and reslizumab are unlikely to affect CYP1A2, 2B6, or 3A4 enzyme activity.
No formal clinical drug interaction studies have been conducted with reslizumab. Population PK analyses indicate that concomitant use of either leukotriene antagonists or corticosteroids does not affect the PK of reslizumab.
## Nonclinical Toxicology
In a 6-month bioassay, reslizumab was administered intravenously once every 2 weeks for 26 consecutive weeks (14 total doses) to Tg.rasH2 mice at doses up to 516 mg/kg/dose. There was no evidence of carcinogenicity.
Published literature using animal models suggests that IL-5 and eosinophils are part of an early inflammatory reaction at the site of tumorigenesis and can promote tumor rejection. However, other reports indicate that eosinophil infiltration into tumors can promote tumor growth. Therefore, the malignancy risk in humans from an antibody to IL-5 such as reslizumab is unknown.
In a fertility study, administration of reslizumab to parental mice at doses up to 50 mg/kg (approximately 6 times the MRHD on an AUC basis) had no effects on male or female mating or fertility.
# Clinical Studies
The asthma development program for Reslizumab 3 mg/kg (administered once every 4 weeks) included 4 randomized, double-blind, placebo-controlled studies (Studies I-IV) 16 to 52 weeks in duration involving 981 patients 12 years of age and older. While patients aged 12 to 17 years were included in these trials, Reslizumab is not approved for use in this age group. All subjects continued their background asthma therapy throughout the duration of the studies.
- Studies I and II
Studies I and II were 52-week studies in 953 patients with asthma who were required to have a blood eosinophil count of at least 400/mcL (within 3 to 4 weeks of dosing), and at least 1 asthma exacerbation requiring systemic corticosteroid use over the past 12 months. The majority of patients (82%) were on medium-high dose inhaled corticosteroids plus a long-acting beta agonist (ICS/LABA) at baseline. Maintenance oral corticosteroids (OCS) (up to 10 mg of prednisone per day or equivalent) were allowed; 106 (11%) patients were on OCS at baseline. Reslizumab 3 mg/kg administered once every 4 weeks for a total of 13 doses was evaluated compared with placebo.
- Study III
Study III was a 16-week study in 315 patients who were required to have a blood eosinophil count of at least 400/mcL at screening (within 3 to 4 weeks of dosing). Maintenance OCS were not allowed. Reslizumab 3 mg/kg or 0.3 mg/kg administered once every 4 weeks for a total of 4 doses was evaluated compared with placebo. While 2 doses of Reslizumab were studied, Reslizumab 3 mg/kg is the only recommended dose.
- Study IV
Study IV was a 16-week study in 496 patients unselected for baseline blood eosinophil levels (approximately 80% of patients had a screening [within 3 to 4 weeks of dosing] blood eosinophil count of less than 400/mcL). Maintenance OCS were not allowed. Reslizumab 3 mg/kg administered once every 4 weeks for a total of 4 doses was evaluated compared with placebo.
The demographics and baseline characteristics of these 4 studies is provided in Table 1.
- Table 1: Demographics and Baseline Characteristics of Patients in Asthma Studies
Exacerbations
The primary endpoint for Studies I and II was the frequency of asthma exacerbations for each patient during the 52-week treatment period. An asthma exacerbation was defined as a worsening of asthma that required at least 1 of the following medical interventions:
1)Either the use of a systemic corticosteroid, or ≥ 2-fold an increase in the use of ICS for 3 or more days, and/or
2)Asthma-related emergency treatment including at least 1 of the following: an unscheduled visit to their healthcare professional for nebulizer treatment or other urgent treatment to prevent worsening of asthma symptoms; a visit to the emergency room for asthma-related treatment; or an asthma-related hospitalization.
The medical intervention had to be corroborated with at least 1 of the following: 1) a decrease in forced expiratory volume in 1 second (FEV 1) by 20% or more from baseline, 2) a decrease in peak expiratory flow rate (PEFR) by 30% or more from baseline on 2 consecutive days, or 3) worsening of symptoms or other clinical signs per physician evaluation of the event.
In Studies I and II, patients receiving Reslizumab 3 mg/kg administered once every 4 weeks had significant reductions in the rate of all asthma exacerbations compared to placebo (Table 2). Exacerbations requiring the use of a systemic corticosteroid (e.g., OCS) as well as exacerbations resulting in hospitalization or an emergency room visit were each reduced with Reslizumab 3 mg/kg.
- Table 2: Frequency of Asthma Exacerbations during the 52-Week Treatment Period in Patients with Severe Asthma with an Eosinophilic Phenotype (Studies I and II)*
CINQAIR: Reslizumab's Brand name
The proportion of patients who did not experience an asthma exacerbation during the 52-week treatment period was higher in the Reslizumab 3 mg/kg group (62% and 75%) compared with the placebo group (46% and 55%), in Studies I and II, respectively. The time to first asthma exacerbation was significantly longer for the groups receiving Reslizumab 3 mg/kg compared with placebo in both Studies I and II. A representative figure from Study I is shown below (Figure 1). Study II showed similar results.
- Figure 1: Time to First Asthma Exacerbation by Treatment Group in Patients with Severe Asthma with an Eosinophilic Phenotype (Study I)
CINQAIR: Reslizumab's Brand name
Lung Function
The effect of Reslizumab 3 mg/kg administered once every 4 weeks on FEV1 over time relative to placebo was assessed in all 4 studies (Table 3). FEV1 was the primary endpoint in the 16-week lung function studies: Study III (Figure 2) and Study IV.
Study III also studied a lower dose, Reslizumab 0.3 mg/kg, that produced significant but numerically smaller changes in FEV1 and blood eosinophil reduction compared with the 3 mg/kg dose. While 2 doses of Reslizumab were studied, Reslizumab 3 mg/kg is the only recommended dose.
Study IV was the only study to test Reslizumab 3 mg/kg in asthma patients unselected for blood eosinophils (measured 3 to 4 weeks prior to dosing); association of treatment effect (i.e., difference between Reslizumab and placebo in the change in FEV1 at Week 16) and baseline blood eosinophils was not observed.
- Table 3: Mean Change (95% CI) from Baseline in FEV1 in mL Over 16 Weeks (Difference from Reslizumab and Placebo) in Patients with Severe Asthma with an Eosinophilic Phenotype
Improvements in FEV1 were observed at 4 weeks following the first dose of Reslizumab for Studies I and II and maintained through Week 52.
- Figure 2: Mean Change from Baseline in FEV1 in Patients with Severe Asthma with an Eosinophilic Phenotype (Study III)
CINQAIR: Reslizumab's Brand name
The Asthma Control Questionnaire-7 (ACQ-7) and Asthma Quality of Life Questionnaire (AQLQ) were both assessed in Studies I, II, and III. The responder rate for both measures was defined as an improvement in score of 0.5 or more as threshold over 16 weeks.
- For ACQ-7, the responder rate for those randomized to Reslizumab vs. placebo was 69% vs. 65% for Study I, 70% vs. 58% for Study II, and 64% vs. 58% for Study III.
- For AQLQ, the responder rate for those randomized to Reslizumab vs. placebo was 66% vs. 58% for Study I, 67% vs. 55% for Study II, and 64% vs. 48% for Study III.
# How Supplied
Reslizumab injection, 100 mg/10 mL (10 mg/mL), is supplied as a preservative-free, sterile, clear to slightly hazy/opalescent, colorless to slightly yellow solution in single-use vials. The following packaging configuration is available:
- NDC 59310-610-31: 100 mg/10 mL (10 mg/mL) single-use vial.
## Storage
Refrigerate at 2 ºC to 8ºC (36°F to 46°F). Do not freeze. Do not shake. Protect the vials from light by storing in the original package until time of use.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
See FDA approved patient labeling (Patient Information).
- Hypersensitivity/Anaphylaxis
Inform patients that hypersensitivity reactions, including anaphylaxis, have occurred with administration of Reslizumab. Educate patients on the signs and symptoms of hypersensitivity reactions and anaphylaxis (e.g., skin or mucosal involvement, airway compromise, reduced blood pressure). Instruct patients to contact their healthcare professional immediately if they experience symptoms of an allergic reaction after they have received their infusion of Reslizumab.
- Not for Acute Symptoms or Deteriorating Disease
Inform patients that Reslizumab does not treat acute asthma symptoms or acute exacerbations. Inform patients to seek medical advice if their asthma remains uncontrolled or worsens after initiation of treatment with Reslizumab.
- Malignancy
Counsel Reslizumab-treated patients about the risk of malignancies.
- Reduction of Corticosteroid Dosage
Inform patients not to discontinue systemic or inhaled corticosteroids except under the direct supervision of a physician. Inform patients that reduction in corticosteroid dose may be associated with systemic withdrawal symptoms and/or unmask conditions previously suppressed by systemic corticosteroid therapy.
# Precautions with Alcohol
Alcohol-Reslizumab interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
CINQAIR®
# Look-Alike Drug Names
There is limited information regarding Reslizumab Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Reslizumab | |
8c894fb557e7c9ba42431f717c5626a3c51c638e | wikidoc | Resolution | Resolution
The term Resolution may refer to:
- Resolution (logic), a rule of inference used for automated theorem proving.
- Resolution (law), a written motion adopted by a deliberative body.
- Resolution (music), a technique in music theory.
- Resolution (meter), the replacement of one longum with two brevia
- New Year's resolution
- Resolution, a Douglas DC-6 aircraft, BCPA Flight 304, which crashed near San Francisco in 1953
# Optics and electronics
- Display resolution, the level of detail on a display device, such as a monitor
- Temporal resolution, for example the sampling frequency of a digital audio device
- Image resolution, the level of detail of an image
- Optical resolution, the capability of an optical system to distinguish, detect, and/or record details
- Angular resolution, the capability of an optical or other sensor to discern small objects
- Sensor resolution
- Spatial resolution, the area on the ground that a single pixel covers.
- Bit resolution, or Bit depth, may refer to Color depth or Audio bit depth
- Printing resolution, the number of individual dots of ink or toner a printer can produce within a unit of distance (e.g., dots per inch)
# Business
- Corporate resolution, a legal document defining which individuals are authorized to act on behalf of a corporation
- Resolution plc, a major manager of in-force UK life funds, part of the FTSE 100 index
- Resolution copper, a copper mining project in Arizona
# Geography
- Resolution Island (Nunavut), in the Arctic region of Canada
- Resolution Island, New Zealand
# Naval vessels
- HMS Resolution, any of several British Royal Navy ships
- HMNZS Resolution (A-14), Royal New Zealand Navy surveillance ship
- Resolution class submarine, British Royal Navy
# Mathematics
- Injective resolution, mathematical series
- Resolution of singularities in algebraic geometry
- Resolution (logic), a proof calculus for propositional logic and first-order logic.
# Literature
- The fictitious "Resolution Island" was the setting of the novel Brown on Resolution by C. S. Forester
# Other uses
- Conflict resolution is the process of attempting to resolve a dispute or a conflict.
- Name resolution, the process of retrieving information from the Domain Name System
- Resolution (electron density), resolution in structural biology
de:Resolution
fa:وضوح
nl:Resolutie | Resolution
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
The term Resolution may refer to:
- Resolution (logic), a rule of inference used for automated theorem proving.
- Resolution (law), a written motion adopted by a deliberative body.
- Resolution (music), a technique in music theory.
- Resolution (meter), the replacement of one longum with two brevia
- New Year's resolution
- Resolution, a Douglas DC-6 aircraft, BCPA Flight 304, which crashed near San Francisco in 1953
# Optics and electronics
- Display resolution, the level of detail on a display device, such as a monitor
- Temporal resolution, for example the sampling frequency of a digital audio device
- Image resolution, the level of detail of an image
- Optical resolution, the capability of an optical system to distinguish, detect, and/or record details
- Angular resolution, the capability of an optical or other sensor to discern small objects
- Sensor resolution
- Spatial resolution, the area on the ground that a single pixel covers.
- Bit resolution, or Bit depth, may refer to Color depth or Audio bit depth
- Printing resolution, the number of individual dots of ink or toner a printer can produce within a unit of distance (e.g., dots per inch)
# Business
- Corporate resolution, a legal document defining which individuals are authorized to act on behalf of a corporation
- Resolution plc, a major manager of in-force UK life funds, part of the FTSE 100 index
- Resolution copper, a copper mining project in Arizona
# Geography
- Resolution Island (Nunavut), in the Arctic region of Canada
- Resolution Island, New Zealand
# Naval vessels
- HMS Resolution, any of several British Royal Navy ships
- HMNZS Resolution (A-14), Royal New Zealand Navy surveillance ship
- Resolution class submarine, British Royal Navy
# Mathematics
- Injective resolution, mathematical series
- Resolution of singularities in algebraic geometry
- Resolution (logic), a proof calculus for propositional logic and first-order logic.
# Literature
- The fictitious "Resolution Island" was the setting of the novel Brown on Resolution by C. S. Forester
# Other uses
- Conflict resolution is the process of attempting to resolve a dispute or a conflict.
- Name resolution, the process of retrieving information from the Domain Name System
- Resolution (electron density), resolution in structural biology
de:Resolution
fa:وضوح
nl:Resolutie
Template:Jb1
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Resolution | |
ac676fc14390eae1ae82d6d361ec3da00ab142ea | wikidoc | Resorcinol | Resorcinol
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
NOTE: Most over the counter (OTC) are not reviewed and approved by the FDA. However, they may be marketed if they comply with applicable regulations and policies. FDA has not evaluated whether this product complies.
# Overview
Resorcinol is an anti acne agent that is FDA approved for the treatment of management of acne. Common adverse reactions include hypersensitivity.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Uses for the management of acne
- Penetrates pores to control acne blemishes, acne pimples, blackheads and whiteheads
- Helps keep skin clear of new acne blemishes, acne pimples, blackheads and whiteheads.
- Shake well
- Cleanse he skin thoroughly before applying the medication
- Cover the entire affected area with a thin layer one to three times daily
- Because excessive drying of the skin may occur, start with one application daily, then gradually increase to two or three times daily if needed or as directed by a doctor
- If bothersome dryness or peeling occurs, reduce application to once a day or every other day.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Resorcinol in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Resorcinol in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Resorcinol in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Resorcinol in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Resorcinol in pediatric patients.
# Contraindications
There is limited information regarding Resorcinol Contraindications in the drug label.
# Warnings
- For external use only
- Flammable, Keep away from fire or flame
- Do not use on broken skin, on large areas of the body
# Adverse Reactions
## Clinical Trials Experience
There is limited information regarding Clinical Trial Experience of Resorcinol in the drug label.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Resorcinol in the drug label.
# Drug Interactions
There is limited information regarding Resorcinol Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Resorcinol in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Resorcinol during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Resorcinol with respect to nursing mothers.
### Pediatric Use
There is no FDA guidance on the use of Resorcinol with respect to pediatric patients.
### Geriatic Use
There is no FDA guidance on the use of Resorcinol with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Resorcinol with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Resorcinol with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Resorcinol in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Resorcinol in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Resorcinol in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Resorcinol in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Topical
### Monitoring
There is limited information regarding Monitoring of Resorcinol in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Resorcinol in the drug label.
# Overdosage
There is limited information regarding Chronic Overdose of Resorcinol in the drug label.
# Pharmacology
## Mechanism of Action
There is limited information regarding Resorcinol Mechanism of Action in the drug label.
## Structure
There is limited information regarding Resorcinol Structure in the drug label.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Resorcinol in the drug label.
## Pharmacokinetics
There is limited information regarding Pharmacokinetics of Resorcinol in the drug label.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Resorcinol in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Resorcinol in the drug label.
# How Supplied
There is limited information regarding Resorcinol How Supplied in the drug label.
## Storage
There is limited information regarding Resorcinol Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Resorcinol in the drug label.
# Precautions with Alcohol
- Alcohol-Resorcinol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- ACNOTEX ACNE TREATMENT®
# Look-Alike Drug Names
There is limited information regarding Resorcinol Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Resorcinol
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
NOTE: Most over the counter (OTC) are not reviewed and approved by the FDA. However, they may be marketed if they comply with applicable regulations and policies. FDA has not evaluated whether this product complies.
# Overview
Resorcinol is an anti acne agent that is FDA approved for the treatment of management of acne. Common adverse reactions include hypersensitivity.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Uses for the management of acne
- Penetrates pores to control acne blemishes, acne pimples, blackheads and whiteheads
- Helps keep skin clear of new acne blemishes, acne pimples, blackheads and whiteheads.
- Shake well
- Cleanse he skin thoroughly before applying the medication
- Cover the entire affected area with a thin layer one to three times daily
- Because excessive drying of the skin may occur, start with one application daily, then gradually increase to two or three times daily if needed or as directed by a doctor
- If bothersome dryness or peeling occurs, reduce application to once a day or every other day.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Resorcinol in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Resorcinol in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Resorcinol in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Resorcinol in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Resorcinol in pediatric patients.
# Contraindications
There is limited information regarding Resorcinol Contraindications in the drug label.
# Warnings
- For external use only
- Flammable, Keep away from fire or flame
- Do not use on broken skin, on large areas of the body
# Adverse Reactions
## Clinical Trials Experience
There is limited information regarding Clinical Trial Experience of Resorcinol in the drug label.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Resorcinol in the drug label.
# Drug Interactions
There is limited information regarding Resorcinol Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Resorcinol in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Resorcinol during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Resorcinol with respect to nursing mothers.
### Pediatric Use
There is no FDA guidance on the use of Resorcinol with respect to pediatric patients.
### Geriatic Use
There is no FDA guidance on the use of Resorcinol with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Resorcinol with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Resorcinol with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Resorcinol in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Resorcinol in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Resorcinol in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Resorcinol in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Topical
### Monitoring
There is limited information regarding Monitoring of Resorcinol in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Resorcinol in the drug label.
# Overdosage
There is limited information regarding Chronic Overdose of Resorcinol in the drug label.
# Pharmacology
## Mechanism of Action
There is limited information regarding Resorcinol Mechanism of Action in the drug label.
## Structure
There is limited information regarding Resorcinol Structure in the drug label.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Resorcinol in the drug label.
## Pharmacokinetics
There is limited information regarding Pharmacokinetics of Resorcinol in the drug label.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Resorcinol in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Resorcinol in the drug label.
# How Supplied
There is limited information regarding Resorcinol How Supplied in the drug label.
## Storage
There is limited information regarding Resorcinol Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Resorcinol in the drug label.
# Precautions with Alcohol
- Alcohol-Resorcinol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- ACNOTEX ACNE TREATMENT®[2]
# Look-Alike Drug Names
There is limited information regarding Resorcinol Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Resorcinol | |
b4ac2ac0e5c4e9600cbed6440c6f189f9a839c2b | wikidoc | Retigabine | Retigabine
# Overview
Retigabine (INN) or ezogabine (USAN), codenamed D-23129, is an anticonvulsant used as a treatment for partial epilepsies. The drug was developed by Valeant Pharmaceuticals and GlaxoSmithKline. It was approved by the European Medicines Agency under the trade name Trobalt on March 28, 2011, and by the United States Food and Drug Administration (FDA), under the trade name Potiga, on June 10, 2011.
Retigabine works primarily as a potassium channel opener—that is, by activating a certain family of voltage-gated potassium channels in the brain. This mechanism of action is unique among antiepileptic drugs, and may hold promise for the treatment of other neurologic conditions, including migraine and neuropathic pain.
# History
Among the newer anticonvulsants, retigabine was one of the most widely studied in the preclinical setting: it was the subject of over 100 published studies before clinical trials began. In preclinical tests, it was found to have a very broad spectrum of activity—being effective in nearly all the animal models of seizures and epilepsy used: retigabine suppresses seizures induced by electroshock, electrical kindling of the amygdala, pentylenetetrazol, kainate, NMDA, and picrotoxin. Researchers hoped this wide-ranging activity would translate to studies in humans as well.
## Clinical trials
In a double-blind, randomized, placebo-controlled Phase II clinical trial, retigabine was added to the treatment regimen of 399 participants with partial seizures that were refractory to therapy with other antiepileptic drugs. The frequency with which seizures occurred was significantly reduced (by 23 to 35%) in participants receiving retigabine, and approximately one fourth to one third of participants had their seizure frequency reduced by more than 50%. Higher doses were associated with a greater response to treatment.
A Phase II trial meant to assess the safety and efficacy of retigabine for treating postherpetic neuralgia was completed in 2009, but failed to meet its primary endpoint. Preliminary results were reported by Valeant as "inconclusive".
## Regulatory approval
The U.S. Food and Drug Administration accepted Valeant's New Drug Application for retigabine on December 30, 2009. The FDA Peripheral and Central Nervous System Drugs Advisory Committee met on August 11, 2010 to discuss the process and unanimously recommended approval of Potiga for the intended indication (add-on treatment of partial seizures in adults). However, the possibility of urinary retention as an adverse effect was considered a significant concern, and the panel's members recommended that some sort of monitoring strategy be used to identify patients at risk of bladder dysfunction. Potiga was approved by the FDA on June 10, 2010, and is set to become available on the U.S. market after scheduling by the Drug Enforcement Administration.
In December 2011, the U.S. Drug Enforcement Administration (DEA) placed the substance into Schedule V of the Controlled Substances Act (CSA), the category for substances with a comparatively low potential for abuse. This became effective 15 December 2011.
# Adverse effects
The adverse effects found in the Phase II trial mainly affected the central nervous system, and appeared to be dose-related. The most common adverse effects were drowsiness, dizziness and vertigo, confusion, and slurred speech. Less common side effects included tremor, memory loss, gait disturbances, and double vision.
Psychiatric symptoms and difficulty urinating have also been reported, with most cases occurring in the first 2 months of treatment.
# Interactions
Retigabine appears to be free of drug interactions with most commonly used anticonvulsants. It may increase metabolism of lamotrigine (Lamictal), whereas phenytoin (Dilantin) and carbamazepine (CBZ, Tegretol) increase the clearance of retigabine.
Concomitant use of retigabine and digoxin may increase serum concentration of the latter. In vitro studies suggest that the main metabolite of retigabine acts as a P-glycoprotein inhibitor, and may thus increase absorption and reduce elimination of digoxin.
# Pharmacokinetics
Retigabine is quickly absorbed, and reaches maximum plasma concentrations between half an hour and 2 hours after a single oral dose. It has a moderately high oral bioavailability (50–60%), a high volume of distribution (6.2 L/kg), and a terminal half-life of 8 to 11 hours. Retigabine requires thrice-daily dosing due to its short half-life.
Retigabine is metabolized in the liver, by N-glucuronidation and acetylation. The cytochrome P450 system is not involved. Retigabine and its metabolites are excreted almost completely (84%) by the kidneys.
# Mechanism of action
Retigabine acts as a neuronal KCNQ/Kv7 potassium channel opener, a mechanism of action markedly different from than of any current anticonvulsants. This mechanism of action is similar to that of flupirtine, which is used mainly for its analgesic properties.
# Name
The International Nonproprietary Name "retigabine" was initially published as being under consideration by WHO in 1996. This was later adopted as the recommended International Nonproprietary Name (rINN) for the drug, and, in 2005 or 2006, the USAN Council—a program sponsored by the American Medical Association, the United States Pharmacopeial Convention, and the American Pharmacists Association that chooses nonproprietary names for drug sold in the United States—adopted the same name. In 2010, however, the USAN Council rescinded its previous decision and assigned "ezogabine" as the United States Adopted Name for the drug. The drug will thus be known as "ezogabine" in the United States and "retigabine" elsewhere. | Retigabine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Retigabine (INN) or ezogabine (USAN), codenamed D-23129, is an anticonvulsant used as a treatment for partial epilepsies. The drug was developed by Valeant Pharmaceuticals and GlaxoSmithKline. It was approved by the European Medicines Agency under the trade name Trobalt on March 28, 2011, and by the United States Food and Drug Administration (FDA), under the trade name Potiga, on June 10, 2011.
Retigabine works primarily as a potassium channel opener—that is, by activating a certain family of voltage-gated potassium channels in the brain.[2][3][4] This mechanism of action is unique among antiepileptic drugs, and may hold promise for the treatment of other neurologic conditions, including migraine and neuropathic pain.
# History
Among the newer anticonvulsants, retigabine was one of the most widely studied in the preclinical setting: it was the subject of over 100 published studies before clinical trials began. In preclinical tests, it was found to have a very broad spectrum of activity—being effective in nearly all the animal models of seizures and epilepsy used: retigabine suppresses seizures induced by electroshock, electrical kindling of the amygdala, pentylenetetrazol, kainate, NMDA, and picrotoxin.[5] Researchers hoped this wide-ranging activity would translate to studies in humans as well.[6]
## Clinical trials
In a double-blind, randomized, placebo-controlled Phase II clinical trial, retigabine was added to the treatment regimen of 399 participants with partial seizures that were refractory to therapy with other antiepileptic drugs. The frequency with which seizures occurred was significantly reduced (by 23 to 35%) in participants receiving retigabine, and approximately one fourth to one third of participants had their seizure frequency reduced by more than 50%. Higher doses were associated with a greater response to treatment.[6][7][8]
A Phase II trial meant to assess the safety and efficacy of retigabine for treating postherpetic neuralgia was completed in 2009, but failed to meet its primary endpoint. Preliminary results were reported by Valeant as "inconclusive".[9]
## Regulatory approval
The U.S. Food and Drug Administration accepted Valeant's New Drug Application for retigabine on December 30, 2009.[10] The FDA Peripheral and Central Nervous System Drugs Advisory Committee met on August 11, 2010 to discuss the process and unanimously recommended approval of Potiga for the intended indication (add-on treatment of partial seizures in adults).[11][12] However, the possibility of urinary retention as an adverse effect was considered a significant concern, and the panel's members recommended that some sort of monitoring strategy be used to identify patients at risk of bladder dysfunction.[11] Potiga was approved by the FDA on June 10, 2010, and is set to become available on the U.S. market after scheduling by the Drug Enforcement Administration.[13]
In December 2011, the U.S. Drug Enforcement Administration (DEA) placed the substance into Schedule V of the Controlled Substances Act (CSA), the category for substances with a comparatively low potential for abuse. This became effective 15 December 2011.[14]
# Adverse effects
The adverse effects found in the Phase II trial mainly affected the central nervous system, and appeared to be dose-related.[6] The most common adverse effects were drowsiness, dizziness and vertigo, confusion, and slurred speech.[8] Less common side effects included tremor, memory loss, gait disturbances, and double vision.[7]
Psychiatric symptoms and difficulty urinating have also been reported, with most cases occurring in the first 2 months of treatment.[13][15]
# Interactions
Retigabine appears to be free of drug interactions with most commonly used anticonvulsants. It may increase metabolism of lamotrigine (Lamictal), whereas phenytoin (Dilantin) and carbamazepine (CBZ, Tegretol) increase the clearance of retigabine.[15][16]
Concomitant use of retigabine and digoxin may increase serum concentration of the latter. In vitro studies suggest that the main metabolite of retigabine acts as a P-glycoprotein inhibitor, and may thus increase absorption and reduce elimination of digoxin.[15]
# Pharmacokinetics
Retigabine is quickly absorbed, and reaches maximum plasma concentrations between half an hour and 2 hours after a single oral dose. It has a moderately high oral bioavailability (50–60%), a high volume of distribution (6.2 L/kg), and a terminal half-life of 8 to 11 hours.[16] Retigabine requires thrice-daily dosing due to its short half-life.[6][8][15]
Retigabine is metabolized in the liver, by N-glucuronidation and acetylation. The cytochrome P450 system is not involved. Retigabine and its metabolites are excreted almost completely (84%) by the kidneys.[16][15]
# Mechanism of action
Retigabine acts as a neuronal KCNQ/Kv7 potassium channel opener, a mechanism of action markedly different from than of any current anticonvulsants.[2][3][4] This mechanism of action is similar to that of flupirtine,[17] which is used mainly for its analgesic properties.
# Name
The International Nonproprietary Name "retigabine" was initially published as being under consideration by WHO in 1996.[18] This was later adopted as the recommended International Nonproprietary Name (rINN) for the drug, and, in 2005 or 2006, the USAN Council—a program sponsored by the American Medical Association, the United States Pharmacopeial Convention, and the American Pharmacists Association that chooses nonproprietary names for drug sold in the United States—adopted the same name.[19] In 2010, however, the USAN Council rescinded its previous decision and assigned "ezogabine" as the United States Adopted Name for the drug.[20] The drug will thus be known as "ezogabine" in the United States and "retigabine" elsewhere. | https://www.wikidoc.org/index.php/Retigabine | |
01ad321f49d1e1d395bfab1389b9eb6bc195520e | wikidoc | Retrovirus | Retrovirus
A retrovirus is any virus belonging to the viral family Retroviridae. They are enveloped viruses possessing an RNA genome, and replicate via a DNA intermediate. Retroviruses rely on the enzyme reverse transcriptase to perform the reverse transcription of its genome from RNA into DNA, which can then be integrated into the host's genome with an integrase enzyme. The virus then replicates as part of the cell's DNA.
# Description of virus
The virus itself stores its nucleic acid, in the form of a +mRNA (including the 5'cap and 3'PolyA inside the virion) genome and serves as a means of delivery of that genome into cells it targets as an obligate parasite, and constitutes the infection. Once in the host's cell, the RNA strands undergo reverse transcription in the cytosol and are integrated into the host's genome, at which point the retroviral DNA is referred to as a provirus.
# Multiplication
When retroviruses have integrated their own genome into the germ line, their genome is passed on to a following generation. These endogenous retroviruses, contrasted with exogenous ones, now make up 5-8% of the human genome. Most insertions have no known function and are often referred to as "junk DNA". However, many endogenous retroviruses play important roles in host biology, such as control of gene transcription, cell fusion during placental development in the course of the germination of an embryo, and resistance to exogenous retroviral infection. Endogenous retroviruses have also received special attention in the research of immunology-related pathologies, such as autoimmune diseases like multiple sclerosis, although endogenous retroviruses have not yet been proven to play any causal role in this class of disease. The role of endogenous retroviruses in human gene evolution is explored in a 2005 peer-reviewed article.
While transcription was classically thought to only occur from DNA to RNA, reverse transcriptase transcribes RNA into DNA. The term "retro" in retrovirus refers to this reversal (making DNA from RNA) of the central dogma of molecular biology. Reverse transcriptase activity outside of retroviruses has been found in almost all eukaryotes, enabling the generation and insertion of new copies of retrotransposons into the host genome. It is important to note that a retrovirus must "bring" its own reverse transcriptase in its capsid, otherwise it is unable to utilize the infected cell's enzymes to carry out the task, due to the unusual nature of producing DNA from RNA.
Because reverse transcription lacks the usual proofreading of DNA replication, this kind of virus mutates very often. This enables the virus to grow resistant to antiviral pharmaceuticals quickly, and impedes, for example, the development of an effective vaccine against the retrovirus HIV.
# Genes
Retrovirus genomes commonly contain these three open reading frames that encode for proteins that can be found in the mature virus:
- group-specific antigen (gag) codes for core and structural proteins of the virus;
- polymerase (pol) codes for reverse transcriptase, protease and integrase; and,
- envelope (env) codes for the retroviral coat proteins.
# Provirus
This DNA can be incoporated into host genome as a provirus that can be passed on to progeny cells. In this way some of retroviruses can convert normal cells into cancer cells.
# Development of retroviruses
Studies of retroviruses led to the first demonstrated synthesis of DNA from RNA templates, a fundamental mode for transferring genetic material that occurs in both eukaryotes and prokaryotes.
It has been speculated that the RNA to DNA transcription processes used by retroviruses may have first caused DNA to be used as genetic material.
In this model, the RNA world hypothesis, cellular organisms adopted the more chemically stable DNA when retroviruses evolved to create DNA from the RNA templates.
# Classification
## Exogenous
The following genera are included here:
- Genus Alpharetrovirus; type species: Avian leukosis virus
- Genus Betaretrovirus; type species: Mouse mammary tumour virus
- Genus Gammaretrovirus; type species: Murine leukemia virus; others include Feline leukemia virus
- Genus Deltaretrovirus; type species: Bovine leukemia virus; others include the cancer-causing Human T-lymphotropic virus
- Genus Epsilonretrovirus; type species: Walleye dermal sarcoma virus
- Genus Lentivirus; type species: Human immunodeficiency virus 1; others include Simian, Feline immunodeficiency viruses
- Genus Spumavirus; type species: Chimpanzee foamy virus
These were previously divided into three subfamilies (Oncovirinae, Lentivirinae, and Spumavirinae), but with current knowledge of retroviruses, this is no longer appropriate. (The term oncovirus is still commonly used, though.)
## Endogenous
Endogenous retroviruses are not formally included in this classification system, and are broadly classified into three classes, on the basis of relatedness to exogenous genera:
- Class I are most similar to the gammaretroviruses
- Class II are most similar to the betaretroviruses and alpharetroviruses
- Class III are most similar to the spumaviruses
# Treatment
Antiretroviral drugs are medications for the treatment of infection by retroviruses, primarily HIV. Different classes of antiretroviral drugs act at different stages of the HIV life cycle. Combination of several (typically three or four) antiretroviral drugs is known as Highly Active Anti-Retroviral Therapy (HAART).
## Genetic barrier
The genetic barrier is loosely defined as the difficulty for retroviruses to evade antiretroviral drugs by mutating into resistant types. | Retrovirus
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
A retrovirus is any virus belonging to the viral family Retroviridae. They are enveloped viruses possessing an RNA genome, and replicate via a DNA intermediate. Retroviruses rely on the enzyme reverse transcriptase to perform the reverse transcription of its genome from RNA into DNA, which can then be integrated into the host's genome with an integrase enzyme. The virus then replicates as part of the cell's DNA.
# Description of virus
The virus itself stores its nucleic acid, in the form of a +mRNA (including the 5'cap and 3'PolyA inside the virion) genome and serves as a means of delivery of that genome into cells it targets as an obligate parasite, and constitutes the infection. Once in the host's cell, the RNA strands undergo reverse transcription in the cytosol and are integrated into the host's genome, at which point the retroviral DNA is referred to as a provirus.
# Multiplication
When retroviruses have integrated their own genome into the germ line, their genome is passed on to a following generation. These endogenous retroviruses, contrasted with exogenous ones, now make up 5-8% of the human genome.[1] Most insertions have no known function and are often referred to as "junk DNA". However, many endogenous retroviruses play important roles in host biology, such as control of gene transcription, cell fusion during placental development in the course of the germination of an embryo, and resistance to exogenous retroviral infection. Endogenous retroviruses have also received special attention in the research of immunology-related pathologies, such as autoimmune diseases like multiple sclerosis, although endogenous retroviruses have not yet been proven to play any causal role in this class of disease. The role of endogenous retroviruses in human gene evolution is explored in a 2005 peer-reviewed article.[2]
While transcription was classically thought to only occur from DNA to RNA, reverse transcriptase transcribes RNA into DNA. The term "retro" in retrovirus refers to this reversal (making DNA from RNA) of the central dogma of molecular biology. Reverse transcriptase activity outside of retroviruses has been found in almost all eukaryotes, enabling the generation and insertion of new copies of retrotransposons into the host genome. It is important to note that a retrovirus must "bring" its own reverse transcriptase in its capsid, otherwise it is unable to utilize the infected cell's enzymes to carry out the task, due to the unusual nature of producing DNA from RNA.
Because reverse transcription lacks the usual proofreading of DNA replication, this kind of virus mutates very often. This enables the virus to grow resistant to antiviral pharmaceuticals quickly, and impedes, for example, the development of an effective vaccine against the retrovirus HIV.
# Genes
Retrovirus genomes commonly contain these three open reading frames that encode for proteins that can be found in the mature virus:
- group-specific antigen (gag) codes for core and structural proteins of the virus;
- polymerase (pol) codes for reverse transcriptase, protease and integrase; and,
- envelope (env) codes for the retroviral coat proteins.
# Provirus
This DNA can be incoporated into host genome as a provirus that can be passed on to progeny cells. In this way some of retroviruses can convert normal cells into cancer cells.
# Development of retroviruses
Studies of retroviruses led to the first demonstrated synthesis of DNA from RNA templates, a fundamental mode for transferring genetic material that occurs in both eukaryotes and prokaryotes.
It has been speculated that the RNA to DNA transcription processes used by retroviruses may have first caused DNA to be used as genetic material.
In this model, the RNA world hypothesis, cellular organisms adopted the more chemically stable DNA when retroviruses evolved to create DNA from the RNA templates.
# Classification
## Exogenous
The following genera are included here:
- Genus Alpharetrovirus; type species: Avian leukosis virus
- Genus Betaretrovirus; type species: Mouse mammary tumour virus
- Genus Gammaretrovirus; type species: Murine leukemia virus; others include Feline leukemia virus
- Genus Deltaretrovirus; type species: Bovine leukemia virus; others include the cancer-causing Human T-lymphotropic virus
- Genus Epsilonretrovirus; type species: Walleye dermal sarcoma virus
- Genus Lentivirus; type species: Human immunodeficiency virus 1; others include Simian, Feline immunodeficiency viruses
- Genus Spumavirus; type species: Chimpanzee foamy virus
These were previously divided into three subfamilies (Oncovirinae, Lentivirinae, and Spumavirinae), but with current knowledge of retroviruses, this is no longer appropriate. (The term oncovirus is still commonly used, though.)
## Endogenous
Endogenous retroviruses are not formally included in this classification system, and are broadly classified into three classes, on the basis of relatedness to exogenous genera:
- Class I are most similar to the gammaretroviruses
- Class II are most similar to the betaretroviruses and alpharetroviruses
- Class III are most similar to the spumaviruses
# Treatment
Antiretroviral drugs are medications for the treatment of infection by retroviruses, primarily HIV. Different classes of antiretroviral drugs act at different stages of the HIV life cycle. Combination of several (typically three or four) antiretroviral drugs is known as Highly Active Anti-Retroviral Therapy (HAART).
## Genetic barrier
The genetic barrier is loosely defined as the difficulty for retroviruses to evade antiretroviral drugs by mutating into resistant types. [3] | https://www.wikidoc.org/index.php/Retroviral | |
1d1dec45756421329db8e0a900a41b7fb8e54414 | wikidoc | Rey Miguel | Rey Miguel
Rey Miguel is a brand of hand-made premium cigar owned by Black Cat Cigar Co. of Philadelphia, Pennsylvania.
# History and Background
The brand was created by José "Pepin" Garcia and is manufactured at the El Rey de los Habanos factory in the Little Havana section of Miami, Florida.
# Description
This is a medium-bodied cigar. The filler is a blend of Nicaraguan tobaccos. The binder is not known. The wrapper is a Connecticut-seed wrapper grown by Silvio & Alfredo Perez in Ecuador. This wrapper tempers the strength and body of the filler blend.
# Models/Vitolas
# Notes
- ↑ Black Cat Cigar Co., in litt., 11/14/2006.,
- ↑ Profile of the Perez family in Cigar Aficionado. | Rey Miguel
Rey Miguel is a brand of hand-made premium cigar owned by Black Cat Cigar Co. of Philadelphia, Pennsylvania.
# History and Background
The brand was created by José "Pepin" Garcia and is manufactured at the El Rey de los Habanos factory[1] in the Little Havana section of Miami, Florida.
# Description
This is a medium-bodied cigar. The filler is a blend of Nicaraguan tobaccos. The binder is not known. The wrapper is a Connecticut-seed wrapper grown by Silvio & Alfredo Perez in Ecuador[2]. This wrapper tempers the strength and body of the filler blend.
# Models/Vitolas
# Notes
- ↑ Black Cat Cigar Co., in litt., 11/14/2006.,
- ↑ Profile of the Perez family in Cigar Aficionado. | https://www.wikidoc.org/index.php/Rey_Miguel | |
57f5ca07b0189414fdadf44ed35680177c057133 | wikidoc | Rhinophyma | Rhinophyma
# Overview
Rhinophyma is a large, bulbous, ruddy nose caused by granulomatous infiltration, commonly due to untreated rosacea.
# Signs and symptoms
Rhinophyma is characterised by prominent pores and a fibrous thickening of the nose, sometimes with papules. It is associated with the common skin condition rosacea. It can carry a strong psychological impact due to its effect on one's personal appearance.
# Causes
Alcoholism is mistakenly attributed as a cause of this disease, but heavy alcohol consumption does aggravate the condition. Rhinophyma may be diagnosed without testing, but a skin biopsy can confirm the diagnosis. Surgical treatment may be beneficial.
Rhinophyma is a slowly progressive condition due to hypertrophy of the sebaceous glands of the tip of the nose often seen in cases of long-standing acne rosacea; it is not a neoplasm. It presents as a pink, lobulated mass over the nose with superficial vascular dilation; it mostly affects men past middle age. Patients seek advice because of the perceived unsightly appearance of the enlargement, or obstruction in breathing and vision.
# Diagnosis
## Physical Examination
### Skin
- Rinofima. Adapted from Dermatology Atlas.
- Rinofima. Adapted from Dermatology Atlas.
- Rinofima. Adapted from Dermatology Atlas.
- Rinofima. Adapted from Dermatology Atlas.
- Rinofima. Adapted from Dermatology Atlas.
- Rinofima. Adapted from Dermatology Atlas.
- Rinofima. Adapted from Dermatology Atlas.
- Rinofima. Adapted from Dermatology Atlas.
- Rinofima. Adapted from Dermatology Atlas.
- Rinofima. Adapted from Dermatology Atlas.
- Rinofima. Adapted from Dermatology Atlas.
- Rinofima. Adapted from Dermatology Atlas.
# Treatment
Treatment consists of paring down the bulk of the tissue with a sharp instrument or carbon dioxide laser and allowing the area to re-epithelialise. Sometimes, the tissue is completely excised and the raw area skin-grafted.
# History
The term rhinophyma is derived from the Greek rhis ('nose') and phyma ('growth'). | Rhinophyma
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kiran Singh, M.D. [2]
# Overview
Rhinophyma is a large, bulbous, ruddy nose caused by granulomatous infiltration, commonly due to untreated rosacea.[1]
# Signs and symptoms
Rhinophyma is characterised by prominent pores and a fibrous thickening of the nose, sometimes with papules.[2] It is associated with the common skin condition rosacea. It can carry a strong psychological impact due to its effect on one's personal appearance.[3]
# Causes
Alcoholism is mistakenly attributed as a cause of this disease, but heavy alcohol consumption does aggravate the condition. Rhinophyma may be diagnosed without testing, but a skin biopsy can confirm the diagnosis. Surgical treatment may be beneficial.[citation needed]
Rhinophyma is a slowly progressive condition due to hypertrophy of the sebaceous glands of the tip of the nose often seen in cases of long-standing acne rosacea; it is not a neoplasm. It presents as a pink, lobulated mass over the nose with superficial vascular dilation; it mostly affects men past middle age. Patients seek advice because of the perceived unsightly appearance of the enlargement, or obstruction in breathing and vision.
# Diagnosis
## Physical Examination
### Skin
- Rinofima. Adapted from Dermatology Atlas.[4]
- Rinofima. Adapted from Dermatology Atlas.[4]
- Rinofima. Adapted from Dermatology Atlas.[4]
- Rinofima. Adapted from Dermatology Atlas.[4]
- Rinofima. Adapted from Dermatology Atlas.[4]
- Rinofima. Adapted from Dermatology Atlas.[4]
- Rinofima. Adapted from Dermatology Atlas.[4]
- Rinofima. Adapted from Dermatology Atlas.[4]
- Rinofima. Adapted from Dermatology Atlas.[4]
- Rinofima. Adapted from Dermatology Atlas.[4]
- Rinofima. Adapted from Dermatology Atlas.[4]
- Rinofima. Adapted from Dermatology Atlas.[4]
# Treatment
Treatment consists of paring down the bulk of the tissue with a sharp instrument or carbon dioxide laser and allowing the area to re-epithelialise. Sometimes, the tissue is completely excised and the raw area skin-grafted.[5]
# History
The term rhinophyma is derived from the Greek rhis ('nose') and phyma ('growth'). | https://www.wikidoc.org/index.php/Rhinophyma | |
83e4d6dfc693f3f0c4b7fcc1dd47cef4bbd9a481 | wikidoc | Rhinorrhea | Rhinorrhea
# Overview
Rhinorrhea, commonly known as a runny nose, is a symptom of the common cold and allergies (hay fever). The term comes from the Greek words "rhinos" meaning "of the nose" and "rhoia" meaning "a flowing." Rhinorrhea can also be a sign of withdrawal, such as from opioids. Symptoms display circadian rhythms.
Cerebrospinal fluid rhinorrhea can indicate basilar skull fracture.
# Overview
Nasal discharge is any mucus-like material that comes out of the nose. Nasal discharges are common, but rarely serious. Drainage from inflamed or infected sinuses may be thick or discolored. Excess mucus production may run down the back of your throat (postnasal drip) or cause a cough that is usually worse at night. A sore throat may also result from excessive mucus drainage. The mucus drainage may plug up the eustachian tube between the nose and the ear, causing an ear infection and pain. The mucus drip may also plug the sinus passages, causing sinus infection and pain.
# Causes
## Common Causes
- Common cold
- Flu
- Allergies
- Hay fever
- Sinusitis
- Head injury
- Bacterial infection
- Foreign body
- Nasal spray
## Causes by Organ System
## Causes in Alphabetical Order
- Acetylandromedol
- Acute upper respiratory infection
- Adenoiditis
- Adenoviridae infections
- Aesculus pollen
- Africanized honeybee
- Airborne allergy
- Alder tree
- Allergic irritability syndrome
- Allergic rhinitis
- Allergic tension-fatigue syndrome
- Allergy-like conditions
- Alternaria
- Amaranthus
- American feverfew
- Amylcinnamic alcohol
- Anaphylaxis
- Andromedotoxin
- Animal allergy
- Anisyl alcohol
- Ant
- Anthrax
- Apomorphine
- Aromatic amino acid decarboxylase deficiency
- Ash juniper tree pollen
- Ash tree
- Aspergillus
- Asrar-facharzt-haque syndrome
- Atrophic rhinitis
- Aureobasidium
- Autonomic dysreflexia
- Baby's breath poisoning
- Basilar skull fracture
- Beech tree
- Beet
- Bent grass
- Benzyl alcohol
- Benzyl salicylate
- Bermuda grass
- Birch tree
- Bird allergy
- Bird flu
- Black fire ant
- Bluegrass
- Bog rosemary poisoning
- Box elder tree
- Brain injury
- Bronchiolitis
- Bronchitis
- Bronchopulmonary dysplasia
- Bumblebee
- Caffeine allergy
- Canary allergy
- Canary grass
- Candida albicans
- Capeweed
- Carcinoma
- Cat allergy
- Catarrh
- Caterpillar complication poisoning
- Charlin's syndrome
- Chemical addiction
- Chemical allergy
- Chemical poisoning
- Chicken allergy
- Chlorine
- Chloroacetophenone
- Chronic infections
- Chronic pneumonitis of infancy
- Chronic rhinitis
- Chronic sinusitis
- Cigarette smoke allergy
- Ciliary dyskinesia
- Cinnamic alcohol
- Cinnamic aldehyde
- Cladosporium
- Clomethiazole
- Cluster headache
- Coastal leucothoe poisoning
- Cocaine abuse
- Cocaine addiction
- Cocklebur
- Cockroach
- Codeine withdrawal
- Common cold
- Congenital nasal abnormality
- Coronavirus-related cold
- Coumarin
- Coxsackievirus-related cold
- Crack addiction
- Cs gas
- Cypress tree
- Daisy
- Dandelion pollen
- Diabetes
- Dilaudid withdrawal
- Dog allergy
- Dopamine beta-hydroxylase deficiency
- Drug allergies
- Duck allergy
- Dust mite allergies
- Eaf
- Echovirus
- Egg hypersensitivity
- Elm tree
- English plantain
- Enterovirus
- Ephedrine
- Epicoccum
- Esthesioneuroblastoma
- Eugenol
- European ash tree
- Fetterbush poisoning
- Florida leucothoe poisoning
- Flu
- Food additive allergy
- Food allergies
- Foreign body
- Fungal infection
- Fusarium
- Gabapentin
- Geraniol
- Glutaraldehyde
- Goose allergy
- Goosefoot
- Granulomatosis with polyangiitis
- Grass pollen allergy
- Grayanotoxin
- Greenhead ant sting
- Guanethidine
- Guayule
- H1n1 flu
- Hay fever
- Hazel tree
- Head injury
- Helminthosporium
- Hemosiderosis
- Hemp
- Heroin withdrawal
- Hickory tree
- Honey bee
- Honey intoxication
- Hop shrub
- Hornbeam tree
- Hornet
- Horse chestnut tree
- House dust allergy
- Hydrocodone withdrawal
- Hydroxycitronellal
- Hypersensitivity reaction
- Hypothyroidism
- Ige mediated gastrointestinal food allergy
- Immotile cilia syndrome
- Inch ant sting
- Isoeugenol
- Jack jumper ant sting
- Japanese andromeda poisoning
- Johnson grass
- Juvenile angiofibroma
- Kartagener syndrome
- Kentucky bluegrass
- Latex allergies
- Leprosy
- Lortab withdrawal
- Lymphomatoid granulomatosis
- Malignant teratocarcinosarcoma
- Maple tree
- Marsh elder
- Mastocytosis
- Measles
- Metapneumovirus
- Methadone withdrawal
- Methyldopa
- Methyldopate
- Midline lethal granuloma
- Mold allergy
- Monteroy pine tree
- Morphine withdrawal
- Mountain andromeda poisoning
- Mountain cedar tree
- Mountain laurel poisoning
- Mucocutaneous leishmaniasis
- Mucopolysaccharidosis type i hurler-scheie syndrome
- Mucor
- Mucormycosis
- Mugwort tree
- Muscarine
- Musk ambrette
- Nasal cancer
- Nasal foreign body
- Nasal mastocytosis
- Nasal obstruction
- Nasal papillomas
- Nasal polyp
- Nasal tumor
- Nasopharyngeal carcinoma
- Nasopharyngitis
- Nasopharynx cancer
- Nettle
- Nitrogen dioxide inhalation
- Oak moss absolute
- Oak tree
- Occupational cancer
- Occupational lung disease
- Olea tree pollen
- Olive tree
- Opioid addiction
- Opioid withdrawal
- Orache
- Orchard grass
- Organophosphates
- Orthomyxovirus
- Otitis media
- Oxycontin addiction
- Ozone inhalation
- Pain killer addiction
- Parainfluenza
- Parakeet allergy
- Paramyxovirus
- Parrot allergy
- Patterson's curse
- Pecan trees
- Penicillium
- Percocet withdrawal
- Perennial rhinitis
- Perfume
- Periorbital cellulitis
- Pernettya poisoning
- Pet allergy
- Phentolamine
- Phoma
- Phosgene inhalation
- Phosgene oxime exposure
- Pigeon allergy
- Pigweed
- Plane tree
- Plantago pollen
- Polychondritis
- Poplar tree pollen
- Prescribed medication addiction
- Primary ciliary dyskinesia
- Pulmonary anthrax
- Ragweed
- Rapeseed oil
- Rasagiline
- Recurring airway infection
- Red fire ant
- Redroot
- Redtop grass
- Relapsing polychondritis
- Reserpine
- Respiratory syncytial virus
- Respiratory tract infections
- Rhinitis medicamentosa
- Rhinocerebral mucormycosis
- Rhinocerebral zygomycosis
- Rhinosporidiosis
- Rhinovirus
- Rhizopus
- Rhodotoxin
- Rice millers' syndrome
- Rodent allergy
- Rosai-dorfman disease
- Rubella
- Ryegrass pollen
- Sagebrush
- Sandalwood oil
- Sarcoidosis
- Scorpion
- Seafood allergy
- Serratia respiratory tract infection
- Sheep laurel poisoning
- Single upper central incisor
- Sinonasal undifferentiated carcinoma
- Sinus infection
- Sinusitis
- Skull fracture
- Slap-cheek syndrome
- Sleeping pill addiction
- Smut
- Sorrel
- Sparrow allergy
- Sphenoid sinusitis
- Spice allergy
- Spicy foods
- Stachybotrys chartarum
- Staggerbush poisoning
- Stress incontinence
- Sulfur dioxide inhalation
- Sunct headache
- Sunflower pollen
- Sweet chestnut tree
- Sweet vernal grass
- Swine flu
- Syphilis
- Systemic capillary leak syndrome
- Teething
- Tilia tree pollen
- Timothy grass
- Ting kung teng
- Tonsilitis
- Toxic mushrooms
- Tranquilizer addiction
- Tree pollen
- Trilostane
- Tropical fire ant
- Tubatoxin poisoning
- Tuberculosis
- Tumble weed
- Turkey allergy
- Type a influenza
- Type b influenza
- Type c influenza
- Type i hypersensitivity
- Upper respiratory tract infection
- Urinary incontinence
- Vasomotor rhinitis
- Velvet grass
- Vicodin withdrawal
- Wall pellitory
- Walnut tree
- Wasp
- Wegener's granulomatosis
- White cedar tree
- Whooping cough
- Willow tree pollen
- Wood tar
- Yellow jacket wasp
- Zotepine
- Zygomycosis
# Treatment
Keep the mucus thin rather than thick and sticky. This helps prevent complications, such as ear and sinus infections, and plugging of your nasal passages. To thin the mucus:
- Drink extra fluids.
- Increase the humidity in the air with a vaporizer or humidifier.
- Antihistamines may reduce the amount of mucus. Be careful, because some antihistamines may make you drowsy.
- Use saline nasal sprays. Don't use over-the-counter nasal sprays more frequently than three days on and three days off, unless ordered by the doctor. | Rhinorrhea
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Alberto Plate [2] Luke Rusowicz-Orazem, B.S.
# Overview
Rhinorrhea, commonly known as a runny nose, is a symptom of the common cold and allergies (hay fever). The term comes from the Greek words "rhinos" meaning "of the nose" and "rhoia" meaning "a flowing." Rhinorrhea can also be a sign of withdrawal, such as from opioids.[1] Symptoms display circadian rhythms.[2]
Cerebrospinal fluid rhinorrhea can indicate basilar skull fracture.
# Overview
Nasal discharge is any mucus-like material that comes out of the nose. Nasal discharges are common, but rarely serious. Drainage from inflamed or infected sinuses may be thick or discolored. Excess mucus production may run down the back of your throat (postnasal drip) or cause a cough that is usually worse at night. A sore throat may also result from excessive mucus drainage. The mucus drainage may plug up the eustachian tube between the nose and the ear, causing an ear infection and pain. The mucus drip may also plug the sinus passages, causing sinus infection and pain.
# Causes
## Common Causes
- Common cold
- Flu
- Allergies
- Hay fever
- Sinusitis
- Head injury
- Bacterial infection
- Foreign body
- Nasal spray
## Causes by Organ System
## Causes in Alphabetical Order
- Acetylandromedol
- Acute upper respiratory infection
- Adenoiditis
- Adenoviridae infections
- Aesculus pollen
- Africanized honeybee
- Airborne allergy
- Alder tree
- Allergic irritability syndrome
- Allergic rhinitis
- Allergic tension-fatigue syndrome
- Allergy-like conditions
- Alternaria
- Amaranthus
- American feverfew
- Amylcinnamic alcohol
- Anaphylaxis
- Andromedotoxin
- Animal allergy
- Anisyl alcohol
- Ant
- Anthrax
- Apomorphine
- Aromatic amino acid decarboxylase deficiency
- Ash juniper tree pollen
- Ash tree
- Aspergillus
- Asrar-facharzt-haque syndrome
- Atrophic rhinitis
- Aureobasidium
- Autonomic dysreflexia
- Baby's breath poisoning
- Basilar skull fracture
- Beech tree
- Beet
- Bent grass
- Benzyl alcohol
- Benzyl salicylate
- Bermuda grass
- Birch tree
- Bird allergy
- Bird flu
- Black fire ant
- Bluegrass
- Bog rosemary poisoning
- Box elder tree
- Brain injury
- Bronchiolitis
- Bronchitis
- Bronchopulmonary dysplasia
- Bumblebee
- Caffeine allergy
- Canary allergy
- Canary grass
- Candida albicans
- Capeweed
- Carcinoma
- Cat allergy
- Catarrh
- Caterpillar complication poisoning
- Charlin's syndrome
- Chemical addiction
- Chemical allergy
- Chemical poisoning
- Chicken allergy
- Chlorine
- Chloroacetophenone
- Chronic infections
- Chronic pneumonitis of infancy
- Chronic rhinitis
- Chronic sinusitis
- Cigarette smoke allergy
- Ciliary dyskinesia
- Cinnamic alcohol
- Cinnamic aldehyde
- Cladosporium
- Clomethiazole
- Cluster headache
- Coastal leucothoe poisoning
- Cocaine abuse
- Cocaine addiction
- Cocklebur
- Cockroach
- Codeine withdrawal
- Common cold
- Congenital nasal abnormality
- Coronavirus-related cold
- Coumarin
- Coxsackievirus-related cold
- Crack addiction
- Cs gas
- Cypress tree
- Daisy
- Dandelion pollen
- Diabetes
- Dilaudid withdrawal
- Dog allergy
- Dopamine beta-hydroxylase deficiency
- Drug allergies
- Duck allergy
- Dust mite allergies
- Eaf
- Echovirus
- Egg hypersensitivity
- Elm tree
- English plantain
- Enterovirus
- Ephedrine
- Epicoccum
- Esthesioneuroblastoma
- Eugenol
- European ash tree
- Fetterbush poisoning
- Florida leucothoe poisoning
- Flu
- Food additive allergy
- Food allergies
- Foreign body
- Fungal infection
- Fusarium
- Gabapentin
- Geraniol
- Glutaraldehyde
- Goose allergy
- Goosefoot
- Granulomatosis with polyangiitis
- Grass pollen allergy
- Grayanotoxin
- Greenhead ant sting
- Guanethidine
- Guayule
- H1n1 flu
- Hay fever
- Hazel tree
- Head injury
- Helminthosporium
- Hemosiderosis
- Hemp
- Heroin withdrawal
- Hickory tree
- Honey bee
- Honey intoxication
- Hop shrub
- Hornbeam tree
- Hornet
- Horse chestnut tree
- House dust allergy
- Hydrocodone withdrawal
- Hydroxycitronellal
- Hypersensitivity reaction
- Hypothyroidism
- Ige mediated gastrointestinal food allergy
- Immotile cilia syndrome
- Inch ant sting
- Isoeugenol
- Jack jumper ant sting
- Japanese andromeda poisoning
- Johnson grass
- Juvenile angiofibroma
- Kartagener syndrome
- Kentucky bluegrass
- Latex allergies
- Leprosy
- Lortab withdrawal
- Lymphomatoid granulomatosis
- Malignant teratocarcinosarcoma
- Maple tree
- Marsh elder
- Mastocytosis
- Measles
- Metapneumovirus
- Methadone withdrawal
- Methyldopa
- Methyldopate
- Midline lethal granuloma
- Mold allergy
- Monteroy pine tree
- Morphine withdrawal
- Mountain andromeda poisoning
- Mountain cedar tree
- Mountain laurel poisoning
- Mucocutaneous leishmaniasis
- Mucopolysaccharidosis type i hurler-scheie syndrome
- Mucor
- Mucormycosis
- Mugwort tree
- Muscarine
- Musk ambrette
- Nasal cancer
- Nasal foreign body
- Nasal mastocytosis
- Nasal obstruction
- Nasal papillomas
- Nasal polyp
- Nasal tumor
- Nasopharyngeal carcinoma
- Nasopharyngitis
- Nasopharynx cancer
- Nettle
- Nitrogen dioxide inhalation
- Oak moss absolute
- Oak tree
- Occupational cancer
- Occupational lung disease
- Olea tree pollen
- Olive tree
- Opioid addiction
- Opioid withdrawal
- Orache
- Orchard grass
- Organophosphates
- Orthomyxovirus
- Otitis media
- Oxycontin addiction
- Ozone inhalation
- Pain killer addiction
- Parainfluenza
- Parakeet allergy
- Paramyxovirus
- Parrot allergy
- Patterson's curse
- Pecan trees
- Penicillium
- Percocet withdrawal
- Perennial rhinitis
- Perfume
- Periorbital cellulitis
- Pernettya poisoning
- Pet allergy
- Phentolamine
- Phoma
- Phosgene inhalation
- Phosgene oxime exposure
- Pigeon allergy
- Pigweed
- Plane tree
- Plantago pollen
- Polychondritis
- Poplar tree pollen
- Prescribed medication addiction
- Primary ciliary dyskinesia
- Pulmonary anthrax
- Ragweed
- Rapeseed oil
- Rasagiline
- Recurring airway infection
- Red fire ant
- Redroot
- Redtop grass
- Relapsing polychondritis
- Reserpine
- Respiratory syncytial virus
- Respiratory tract infections
- Rhinitis medicamentosa
- Rhinocerebral mucormycosis
- Rhinocerebral zygomycosis
- Rhinosporidiosis
- Rhinovirus
- Rhizopus
- Rhodotoxin
- Rice millers' syndrome
- Rodent allergy
- Rosai-dorfman disease
- Rubella
- Ryegrass pollen
- Sagebrush
- Sandalwood oil
- Sarcoidosis
- Scorpion
- Seafood allergy
- Serratia respiratory tract infection
- Sheep laurel poisoning
- Single upper central incisor
- Sinonasal undifferentiated carcinoma
- Sinus infection
- Sinusitis
- Skull fracture
- Slap-cheek syndrome
- Sleeping pill addiction
- Smut
- Sorrel
- Sparrow allergy
- Sphenoid sinusitis
- Spice allergy
- Spicy foods
- Stachybotrys chartarum
- Staggerbush poisoning
- Stress incontinence
- Sulfur dioxide inhalation
- Sunct headache
- Sunflower pollen
- Sweet chestnut tree
- Sweet vernal grass
- Swine flu
- Syphilis
- Systemic capillary leak syndrome
- Teething
- Tilia tree pollen
- Timothy grass
- Ting kung teng
- Tonsilitis
- Toxic mushrooms
- Tranquilizer addiction
- Tree pollen
- Trilostane
- Tropical fire ant
- Tubatoxin poisoning
- Tuberculosis
- Tumble weed
- Turkey allergy
- Type a influenza
- Type b influenza
- Type c influenza
- Type i hypersensitivity
- Upper respiratory tract infection
- Urinary incontinence
- Vasomotor rhinitis
- Velvet grass
- Vicodin withdrawal
- Wall pellitory
- Walnut tree
- Wasp
- Wegener's granulomatosis
- White cedar tree
- Whooping cough
- Willow tree pollen
- Wood tar
- Yellow jacket wasp
- Zotepine
- Zygomycosis
# Treatment
Keep the mucus thin rather than thick and sticky. This helps prevent complications, such as ear and sinus infections, and plugging of your nasal passages. To thin the mucus:
- Drink extra fluids.
- Increase the humidity in the air with a vaporizer or humidifier.
- Antihistamines may reduce the amount of mucus. Be careful, because some antihistamines may make you drowsy.
- Use saline nasal sprays. Don't use over-the-counter nasal sprays more frequently than three days on and three days off, unless ordered by the doctor. | https://www.wikidoc.org/index.php/Rhinorrhea | |
5d6e79b90da1c80e581ae372dd3fb22cabf5a8ad | wikidoc | Rhinovirus | Rhinovirus
Rhinovirus (from the Greek rhin-, which means "nose") is a genus of the Picornaviridae family of viruses.
Rhinoviruses are the most common viral infective agents in humans, and a causative agent of the common cold. There are over 105 serologic virus types that cause cold symptoms, and rhinoviruses are responsible for approximately 50% of all cases.
Rhinoviruses have single-stranded positive sense RNA genomes of between 7.2 and 8.5kb in length. At the 5′ end of the genome is a virus-encoded protein, and like mammalian mRNA, there is a 3′ poly-A tail. Structural proteins are encoded in the 5′ region of the genome and non structural at the end. This is the same for all picornaviruses. The viral particles themselves are not enveloped and are icosahedral in structure.
# Structure
Rhinoviruses are composed of a capsid, that contains four viral proteins VP1, VP2, VP3 and VP4. VP1, VP2, and VP3 form the major part of the protein capsid. The much smaller VP4 protein has a more extended structure and lies at interface between the capsid and the RNA genome. There are 60 copies of each of these proteins assembled as an icosahedron. Antibodies are a major defense against infection with the epitopes lying on the exterior regions of VP1-VP3.
# Transmission and epidemiology
There are two modes of transmission: via aerosols of respiratory droplets and from contaminated surfaces, including direct person-to-person contact.
Rhinoviruses occur worldwide and are the primary cause of common colds. Symptoms include sore throat, runny nose, nasal congestion, sneezing and cough; sometimes accompanied by muscle aches, fatigue, malaise, headache, muscle weakness, or loss of appetite. Fever and extreme exhaustion are more usual in influenza. Children may have six to ten colds a year (and up to 12 colds a year for school children). In the United States, the incidence of colds is higher in the fall and winter, with most infections occurring between September to April. The seasonality may be due to the start of the school year, or due to people spending more time indoors (thus in closer proximity with each other) increasing the chance of transmission of the virus.
# Pathogenesis
The primary route of entry for rhinoviruses is the upper respiratory tract. Afterwards, the virus binds to ICAM-1 (intracellular adhesion molecule -1) receptors on respiratory epithelial cells. As the virus replicates and spreads, infected cells release distress signals known as chemokines and cytokines (which in turn activate inflammatory mediators).
Infection occurs rapidly, with the virus adhering to surface receptors within 15 minutes of entering the respiratory tract. The incubation period is generally 8-10 hours before symptoms begin to occur
Rhinoviruses rarely cause lower respiratory tract disease probably because they grow poorly at 37°C.
# Novel antiviral drugs
Interferon-alpha used intranasally was shown to be protective to rhinovirus infections. However, volunteers treated with this drug experienced some side effects, such as nasal bleeding, and resistance was also developing toward the drug. Hence, all research put into this drug was ceased.
Pleconaril is an orally bioavailable antiviral drug being developed for the treatment of infections caused by picornaviruses. This drug acts by binding to a hydrophobic pocket in VP1 and stabilizes the protein capsid to such an extent that the virus cannot release its RNA genome into the target cell. When tested in volunteers, during the clinical trials, this drug caused a significant decrease in mucus secretions and illness-associated symptoms. Pleconaril is not currently available for treatment of rhinoviral infections, as its efficacy in treating these infections is under further evaluation.
- Note (2): Found in half of children with community-acquired pneumonia; role in pathogenesis unclear (CID 39:681, 2004).
- Note (3): High rate of rhinovirus identified in children with significant lower resp tract infections.
# Vaccine
There are no vaccines against these viruses as there is little-to-no cross-protection between serotypes. | Rhinovirus
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Rhinovirus (from the Greek rhin-, which means "nose") is a genus of the Picornaviridae family of viruses.
Rhinoviruses are the most common viral infective agents in humans, and a causative agent of the common cold. There are over 105 serologic virus types that cause cold symptoms, and rhinoviruses are responsible for approximately 50% of all cases.
Rhinoviruses have single-stranded positive sense RNA genomes of between 7.2 and 8.5kb in length. At the 5′ end of the genome is a virus-encoded protein, and like mammalian mRNA, there is a 3′ poly-A tail. Structural proteins are encoded in the 5′ region of the genome and non structural at the end. This is the same for all picornaviruses. The viral particles themselves are not enveloped and are icosahedral in structure.
# Structure
Rhinoviruses are composed of a capsid, that contains four viral proteins VP1, VP2, VP3 and VP4.[1][2] VP1, VP2, and VP3 form the major part of the protein capsid. The much smaller VP4 protein has a more extended structure and lies at interface between the capsid and the RNA genome. There are 60 copies of each of these proteins assembled as an icosahedron. Antibodies are a major defense against infection with the epitopes lying on the exterior regions of VP1-VP3.
# Transmission and epidemiology
There are two modes of transmission: via aerosols of respiratory droplets and from contaminated surfaces, including direct person-to-person contact.
Rhinoviruses occur worldwide and are the primary cause of common colds. Symptoms include sore throat, runny nose, nasal congestion, sneezing and cough; sometimes accompanied by muscle aches, fatigue, malaise, headache, muscle weakness, or loss of appetite. Fever and extreme exhaustion are more usual in influenza. Children may have six to ten colds a year (and up to 12 colds a year for school children). In the United States, the incidence of colds is higher in the fall and winter, with most infections occurring between September to April. The seasonality may be due to the start of the school year, or due to people spending more time indoors (thus in closer proximity with each other) increasing the chance of transmission of the virus.
# Pathogenesis
The primary route of entry for rhinoviruses is the upper respiratory tract. Afterwards, the virus binds to ICAM-1 (intracellular adhesion molecule -1) receptors on respiratory epithelial cells. As the virus replicates and spreads, infected cells release distress signals known as chemokines and cytokines (which in turn activate inflammatory mediators).
Infection occurs rapidly, with the virus adhering to surface receptors within 15 minutes of entering the respiratory tract. The incubation period is generally 8-10 hours before symptoms begin to occur
[3].
Rhinoviruses rarely cause lower respiratory tract disease probably because they grow poorly at 37°C.
# Novel antiviral drugs
Interferon-alpha used intranasally was shown to be protective to rhinovirus infections. However, volunteers treated with this drug experienced some side effects, such as nasal bleeding, and resistance was also developing toward the drug. Hence, all research put into this drug was ceased.
Pleconaril is an orally bioavailable antiviral drug being developed for the treatment of infections caused by picornaviruses.[4] This drug acts by binding to a hydrophobic pocket in VP1 and stabilizes the protein capsid to such an extent that the virus cannot release its RNA genome into the target cell. When tested in volunteers, during the clinical trials, this drug caused a significant decrease in mucus secretions and illness-associated symptoms. Pleconaril is not currently available for treatment of rhinoviral infections, as its efficacy in treating these infections is under further evaluation.[5]
- Note (2): Found in half of children with community-acquired pneumonia; role in pathogenesis unclear (CID 39:681, 2004).[6]
- Note (3): High rate of rhinovirus identified in children with significant lower resp tract infections.[7]
# Vaccine
There are no vaccines against these viruses as there is little-to-no cross-protection between serotypes. | https://www.wikidoc.org/index.php/Rhinovirus | |
413b738f5404b581ce11d5e52786d42c8b2223e3 | wikidoc | Rho GTPase | Rho GTPase
# Overview
A Rho GTPase is a small (~21 kDa) signaling G protein (more specifically a GTPase) of the Ras superfamily. Rho GTPases have been shown to regulate many aspects of intracellular actin dynamics. Rho GTPases are found in all eukaryotic organisms as well as in yeasts and some plants. Three members of the family have been particularly well-studied: RhoA, Rac1 and Cdc42. Rho GTPase proteins have been described as ‘molecular switches’ and have been described to play a role in cell proliferation, apoptosis, cell division, gene expression and multiple other common cellular functions.
# History
Identification of the Rho family of GTPases began in the late 1980’s. The first report of the cloning and expression of Cdc42 was in 1990 with the Munemitsu et al. paper entitled, “Molecular Cloning and Expression of a G25K cDNA, the human homolog of the yeast cell cycle gene CDC42”. Since the early 1990’s numerous Rho GTPases have been identified and today 22 Rho GTPases have been identified in mammals.
# Categorization
Rho proteins are a member of the ‘Rho’ family. The superfamily, named ‘Ras-like’ proteins, consists of over 150 varieties in mammals. The ‘Ras-like’ superfamily is divided into five categories: Ras, Rho, Rab, Arf and Ran according to intracellular function. The Ras family is generally responsible for cell proliferation, Rho for cell morphology, nuclear transport for Ran and vesicle transport for Rab and Arf.
In mammals, the Rho family contains 22 members. Almost all research involves the three most common members of the Rho family: Rac1, RhoA and Cdc42.
The current 22 members of the Rho family include RhoA, RhoB, RhoC, RhoD, Rif, Rnd1, Rnd2, Rnd3/RhoE, RhoH/TTF, Rac1, Rac2, Rac3, RhoG, Cdc42, TC10 (RhoQ), TCL (RhoJ), Wrch1 (RhoV), Chp/Wrch2 (RhoU), RhoBTB1, RhoBTB2, Miro1 (RhoT1), Miro2 (RhoT2).
# Regulation & Effectors
Three general classes of regulators of rho protein signaling have been identified: guanine nucleotide exchange factor (GEFs), GTPase-activating proteins (GAPs) and guanine nucleotide dissociation inhibitors (GDIs). GEFs control the release of GDP from the rho protein and the replacement with GTP. GAPs control the ability of the GTPase to hydrolyze GTP to GDP, controlling the natural rate of movement from the active conformation to the inactive conformation. GDI proteins form a large complex with the rho protein helping to prevent diffusion within the membrane and into the cytosol, thus acting as an anchor and allowing for very specific spatial control of rho activation.
Each Rho protein affects numerous proteins downstream, all which have roles in various cell processes. In fact, over 60 targets of the three common Rho GTPases have been found. Two molecules which directly stimulate actin polymerization are the WASP/WAVE proteins and the Diaphanous-related formins.
# Functions
Rho/Rac proteins are involved in a wide variety of cellular functions such as cell polarity, vesicular trafficking, the cell cycle and transcriptomal dynamics .
## Morphology
Animal cells form many different shapes based on their function and location in the body. Rho proteins help cells regulate changes in shape throughout their life cycle. Before cells can undergo key processes such as budding, mitosis or locomotion, a certain degree of polarity is required. A ‘polar’ cell is one which has some sort of shape or direction rather than existing as an amorphous, symmetrical shape. For instance, an amoeba becomes polar when it undergoes locomotion and travels from one point to another.
One example of Rho GTPases’ role in cell polarity is seen in the well-studied yeast cell. Before the cell can bud, Cdc42 is used to locate the region of the cell’s membrane which will begin to bulge into the new cell. When Cdc42 is removed from the cell, the cell’s outgrowths still form but form in an unorganized manner.
Much of what is known about cellular morphology changes and the effects of Rho proteins comes from the creation of a ‘constituently active’ mutation of the protein. As early as 1990, Paterson et al. began injecting active rho protein into Swiss 3T3 cells. The proteins were made to be constituently active using recombinant techniques. Essentially by changing one codon of the protein’s DNA, one amino acid is changed and therefore the conformation of the entire protein is altered into one which resembles the GTP bound state. After injection into the 3T3 cells, morphological changes were observed and described as ‘contractions, leaving finger-like projections’.
In the 2006 review article released by Bement et al, the spatial zones of rho activation were explained. Because rho proteins are ‘G proteins’ and plasma-membrane bound, their location can be easily controlled. In each situation, whether it be wound healing, cytokinesis or budding, the location of the rho activation can be imaged and identified. For example, if a circular hole is inflicted in a spherical cell, Cdc42 and other active rhos are seen in highest concentration around the circumference of the circular injury. Bement also mentions two methods of maintaining the spatial zones of activation. The first is through anchoring to the actin cytoskeleton, keeping the membrane bound protein from diffusing away from the region where it is most needed. A second method of maintenance is through the formation of a large complex which is resistant to diffusion and more rigidly bound to the membrane than the rho itself.
One of the most obvious changes to cell morphology controlled by rho proteins is the formation of lamellipodia and filopodia, the processes that look like ‘fingers’ or ‘feet’ and often propel cells across surfaces. As early as the mid-1990’s these processes and the effects of the rho proteins were observed in fibroblasts. Dr. Alan Hall, one of the front-runners in rho protein research, compiled evidence in his 1998 review which showed that it was not only fibroblasts which formed processes based on rho activation, but virtually all eukaryotic cells.
## Movement
In addition to the formation of lamellipodia and filopodia, it has been shown that intracellular concentration and cross-talk between different rho proteins drives the extensions and contractions which cause cellular locomotion. Sakumura et al. proposed a model based on differential equations which helps explain the activity of rhos and their relationship to motion. This model encompassed the three proteins Cdc42, RhoA and Rac. Cdc42 was assumed to encourage filopodia elongation and block actin depolymerization. RhoA was considered to encourage actin retraction. Rac was treated to encourage lamellipodia exentsion but block actin depolymerization. These three proteins, although significantly simplified, covered the key steps in cellular locomotion. Through various mathematical techniques, solutions to the differential equations were found which described various regions of activity based on intracellular activity. The paper concludes by showing that the model predicts that there are a few threshold concentrations which cause interesting effects on the activity of the cell. Below a certain concentration, there is very little activity, causing no extension of the arms and feet of the cell. Above a certain concentration, the rho protein causes a sinusoidal oscillation to occur, much like the extensions and contractions of the lamellipodia and filopodia. Essentially this model predicts that increasing the intracellular concentration of these three key active rho proteins causes an out-of-phase activity of the cell resulting in extensions and contractions which are also out of phase.
## Behavior
One example of behavior which is modulated by Rho GTPase proteins is in the healing of wounds. In 1996, Brock et al. demonstrated this characteristic in chick embryos. Wounds heal differently between young chicks and adult chickens. In young chicks, wounds heal by contraction, much like a draw-string being pulled to close a bag. In older chickens, cells crawl across the wound through locomotion. Brock et al. hypothesized that the actin formation required to close the wounds in young chicks was controlled by Rho GTPase proteins. As they expected, after injection of a bacterial exoenzyme used to block rho and rac activity, the actin polymers did not form and a complete failure of healing was observed.
Another cellular behavior which is affected by rho proteins is phagocytosis. As with most other types of cell membrane modulation, phagocytosis requires the actin cytoskeleton in order to engulf other items. The actin filaments control the formation of the phagocytic cup, and active Rac1 and Cdc42 have been implicated in this signaling cascade.
Yet another major aspect of cellular behavior which is thought to include rho protein signaling is the process of cell division, mitosis. While it was thought for years that rho GTPase activity was restricted only to actin polymerization and therefore only to cytokinesis, new evidence has arisen which shows some activity in microtubule formation and the overall process of mitosis. This topic is still debated and there is evidence both for and against for rho’s importance in mitosis.
# Applications
## Nervous System Regeneration
Because of their implications in cellular motility and shape, rho proteins became a clear target in the study of the growth cones that form during axonal generation and re-generation in the nervous system. Some consider rho proteins to be a potential target for delivery into spinal cord lesions after traumatic injury. Following injury to the spinal cord, the extracellular space becomes inhibitory to the natural efforts neurons undergo to regenerate.
These ‘natural efforts’ include the formation of a growth cone at the proximal end of an injured axon. Newly formed growth cones subsequently attempt to ‘crawl’ across the lesion and are quite sensitive to chemical cues in the extracellular environment. One of the many inhibitory cues includes chondroitin sulfate proteoglycans or CSPGs. In 2004, Jain et al. showed that neurons growing in culture increased in their ability to cross over inhibitory CSPG lanes after administration of constituently active Cdc42, Rac1 and RhoA. This is partly due to the exogenous rho proteins driving cellular locomotion despite the extracellular cues promoting apoptosis and growth cone collapse. It is situations like these that make intracellular modulation of rho proteins the subject of a significant amount of spinal cord research.
## Mental Retardation
Rho proteins have also been implicated in mental retardation. Mental retardation occurs in approximately 3% of the population and is characterized by having an IQ of less than 70. Multiple sources have noticed that mental retardation in some cases shows malformation of the dendritic spines which form the post-synaptic connections between neurons. As expected, the misshapen dendritic spines are sometimes the result of rho protein signaling modulation. After cloning of various genes implicated in X-linked mental retardation, three genes were identified that have effects on rho signaling, including oligophrenin-1 (GAP protein that stimulates GTPase activity of Rac1, Cdc42 and RhoA), PAK3 (involved with the effects of Rac and Cdc42 on the actin cytoskeleton) and αPIX (a GEF which helps activate Rac1 and Cdc42). Because of the effect of rho signaling on the actin cytoskeleton, genetic malfunctions of a rho protein could certainly explain the irregular morphology of neuronal dendrites seen in many cases of mental retardation.
## Cancer
After finding that Ras proteins are mutated in 30% of human cancers, it was suspected that mutated rho proteins were also involved in cancer reproduction, as the signaling pathways involving rho proteins are widely known to play an important role in cancer development. However, Ellenbroek et al. reported in their review that as of August 2007 no mutations have been found in rho proteins and only one has been found to be genetically altered. To explain the role of rho pathways without mutation, researchers have now turned to the regulators of rho activity and the levels of expression of the rho proteins for answers.
Again, one way to explain altered signaling in the absence of mutation is through increased expression. Overexpression of RhoA, RhoB, RhoC, Rac1, Rac2, Rac3, RhoE, RhoG, RhoH and Cdc42 has been shown in multiple types of cancer. This increased presence of so many signaling molecules certainly implies that these proteins promote the cellular functions which become overly active in cancerous cells.
A second target to explain the role of the rho proteins in cancer is their regulatory proteins. Rho proteins are very tightly controlled by a wide variety of sources, and over 60 activators and 70 inactivators have been identified. Multiple GAPs, GDIs and GEFs have been shown to undergo overexpression, downregulation or mutation in different types of cancer. As one can imagine, once an upstream signal is changed, the activity of its targets downstream, i.e. the rho proteins, will change in activity.
More specifically, Ellenbroek et al. outlined a number of different effects of rho activation in cancerous cells. First, in the initiation of the tumor modification of rho activity can suppress apoptosis and therefore contribute to artificial cell longevity. After natural apoptosis is suppressed, abnormal tumor growth can be observed through the loss of polarity in which rho proteins play an integral roll. Next, the growing mass can invade across its normal boundaries through the alteration of adhesion proteins potentially caused by rho proteins. Finally, after inhibition of apoptosis, cell polarity and adhesion molecules, the cancerous mass is free to metastasize and spread to other regions of the body. | Rho GTPase
# Overview
A Rho GTPase is a small (~21 kDa) signaling G protein (more specifically a GTPase) of the Ras superfamily. Rho GTPases have been shown to regulate many aspects of intracellular actin dynamics. Rho GTPases are found in all eukaryotic organisms as well as in yeasts and some plants. Three members of the family have been particularly well-studied: RhoA, Rac1 and Cdc42. Rho GTPase proteins have been described as ‘molecular switches’ and have been described to play a role in cell proliferation, apoptosis, cell division, gene expression and multiple other common cellular functions[1][2].
# History
Identification of the Rho family of GTPases began in the late 1980’s. The first report of the cloning and expression of Cdc42 was in 1990 with the Munemitsu et al. paper entitled, “Molecular Cloning and Expression of a G25K cDNA, the human homolog of the yeast cell cycle gene CDC42”[3]. Since the early 1990’s numerous Rho GTPases have been identified and today 22 Rho GTPases have been identified in mammals[4].
# Categorization
Rho proteins are a member of the ‘Rho’ family. The superfamily, named ‘Ras-like’ proteins, consists of over 150 varieties in mammals. The ‘Ras-like’ superfamily is divided into five categories: Ras, Rho, Rab, Arf and Ran according to intracellular function. The Ras family is generally responsible for cell proliferation, Rho for cell morphology, nuclear transport for Ran and vesicle transport for Rab and Arf[3].
In mammals, the Rho family contains 22 members[4]. Almost all research involves the three most common members of the Rho family: Rac1, RhoA and Cdc42.
The current 22 members of the Rho family include RhoA, RhoB, RhoC, RhoD, Rif, Rnd1, Rnd2, Rnd3/RhoE, RhoH/TTF, Rac1, Rac2, Rac3, RhoG, Cdc42, TC10 (RhoQ), TCL (RhoJ), Wrch1 (RhoV), Chp/Wrch2 (RhoU), RhoBTB1, RhoBTB2, Miro1 (RhoT1), Miro2 (RhoT2)[4].
# Regulation & Effectors
Three general classes of regulators of rho protein signaling have been identified: guanine nucleotide exchange factor (GEFs), GTPase-activating proteins (GAPs) and guanine nucleotide dissociation inhibitors (GDIs)[5]. GEFs control the release of GDP from the rho protein and the replacement with GTP. GAPs control the ability of the GTPase to hydrolyze GTP to GDP, controlling the natural rate of movement from the active conformation to the inactive conformation. GDI proteins form a large complex with the rho protein helping to prevent diffusion within the membrane and into the cytosol, thus acting as an anchor and allowing for very specific spatial control of rho activation[5].
Each Rho protein affects numerous proteins downstream, all which have roles in various cell processes. In fact, over 60 targets of the three common Rho GTPases have been found[6]. Two molecules which directly stimulate actin polymerization are the WASP/WAVE proteins and the Diaphanous-related formins[4].
# Functions
Rho/Rac proteins are involved in a wide variety of cellular functions such as cell polarity, vesicular trafficking, the cell cycle and transcriptomal dynamics [2].
## Morphology
Animal cells form many different shapes based on their function and location in the body. Rho proteins help cells regulate changes in shape throughout their life cycle. Before cells can undergo key processes such as budding, mitosis or locomotion, a certain degree of polarity is required. A ‘polar’ cell is one which has some sort of shape or direction rather than existing as an amorphous, symmetrical shape. For instance, an amoeba becomes polar when it undergoes locomotion and travels from one point to another.
One example of Rho GTPases’ role in cell polarity is seen in the well-studied yeast cell. Before the cell can bud, Cdc42 is used to locate the region of the cell’s membrane which will begin to bulge into the new cell. When Cdc42 is removed from the cell, the cell’s outgrowths still form but form in an unorganized manner[6].
Much of what is known about cellular morphology changes and the effects of Rho proteins comes from the creation of a ‘constituently active’ mutation of the protein. As early as 1990, Paterson et al. began injecting active rho protein into Swiss 3T3 cells. The proteins were made to be constituently active using recombinant techniques. Essentially by changing one codon of the protein’s DNA, one amino acid is changed and therefore the conformation of the entire protein is altered into one which resembles the GTP bound state[7]. After injection into the 3T3 cells, morphological changes were observed and described as ‘contractions, leaving finger-like projections’[7].
In the 2006 review article released by Bement et al, the spatial zones of rho activation were explained. Because rho proteins are ‘G proteins’ and plasma-membrane bound, their location can be easily controlled. In each situation, whether it be wound healing, cytokinesis or budding, the location of the rho activation can be imaged and identified. For example, if a circular hole is inflicted in a spherical cell, Cdc42 and other active rhos are seen in highest concentration around the circumference of the circular injury. Bement also mentions two methods of maintaining the spatial zones of activation. The first is through anchoring to the actin cytoskeleton, keeping the membrane bound protein from diffusing away from the region where it is most needed. A second method of maintenance is through the formation of a large complex which is resistant to diffusion and more rigidly bound to the membrane than the rho itself[8].
One of the most obvious changes to cell morphology controlled by rho proteins is the formation of lamellipodia and filopodia, the processes that look like ‘fingers’ or ‘feet’ and often propel cells across surfaces. As early as the mid-1990’s these processes and the effects of the rho proteins were observed in fibroblasts. Dr. Alan Hall, one of the front-runners in rho protein research, compiled evidence in his 1998 review which showed that it was not only fibroblasts which formed processes based on rho activation, but virtually all eukaryotic cells[9].
## Movement
In addition to the formation of lamellipodia and filopodia, it has been shown that intracellular concentration and cross-talk between different rho proteins drives the extensions and contractions which cause cellular locomotion. Sakumura et al. proposed a model based on differential equations which helps explain the activity of rhos and their relationship to motion. This model encompassed the three proteins Cdc42, RhoA and Rac. Cdc42 was assumed to encourage filopodia elongation and block actin depolymerization. RhoA was considered to encourage actin retraction. Rac was treated to encourage lamellipodia exentsion but block actin depolymerization. These three proteins, although significantly simplified, covered the key steps in cellular locomotion. Through various mathematical techniques, solutions to the differential equations were found which described various regions of activity based on intracellular activity. The paper concludes by showing that the model predicts that there are a few threshold concentrations which cause interesting effects on the activity of the cell. Below a certain concentration, there is very little activity, causing no extension of the arms and feet of the cell. Above a certain concentration, the rho protein causes a sinusoidal oscillation to occur, much like the extensions and contractions of the lamellipodia and filopodia. Essentially this model predicts that increasing the intracellular concentration of these three key active rho proteins causes an out-of-phase activity of the cell resulting in extensions and contractions which are also out of phase[10].
## Behavior
One example of behavior which is modulated by Rho GTPase proteins is in the healing of wounds. In 1996, Brock et al. demonstrated this characteristic in chick embryos. Wounds heal differently between young chicks and adult chickens. In young chicks, wounds heal by contraction, much like a draw-string being pulled to close a bag. In older chickens, cells crawl across the wound through locomotion. Brock et al. hypothesized that the actin formation required to close the wounds in young chicks was controlled by Rho GTPase proteins. As they expected, after injection of a bacterial exoenzyme used to block rho and rac activity, the actin polymers did not form and a complete failure of healing was observed[11].
Another cellular behavior which is affected by rho proteins is phagocytosis. As with most other types of cell membrane modulation, phagocytosis requires the actin cytoskeleton in order to engulf other items. The actin filaments control the formation of the phagocytic cup, and active Rac1 and Cdc42 have been implicated in this signaling cascade[12].
Yet another major aspect of cellular behavior which is thought to include rho protein signaling is the process of cell division, mitosis. While it was thought for years that rho GTPase activity was restricted only to actin polymerization and therefore only to cytokinesis, new evidence has arisen which shows some activity in microtubule formation and the overall process of mitosis. This topic is still debated and there is evidence both for and against for rho’s importance in mitosis[13].
# Applications
## Nervous System Regeneration
Because of their implications in cellular motility and shape, rho proteins became a clear target in the study of the growth cones that form during axonal generation and re-generation in the nervous system. Some consider rho proteins to be a potential target for delivery into spinal cord lesions after traumatic injury. Following injury to the spinal cord, the extracellular space becomes inhibitory to the natural efforts neurons undergo to regenerate.
These ‘natural efforts’ include the formation of a growth cone at the proximal end of an injured axon. Newly formed growth cones subsequently attempt to ‘crawl’ across the lesion and are quite sensitive to chemical cues in the extracellular environment. One of the many inhibitory cues includes chondroitin sulfate proteoglycans or CSPGs. In 2004, Jain et al. showed that neurons growing in culture increased in their ability to cross over inhibitory CSPG lanes after administration of constituently active Cdc42, Rac1 and RhoA[14]. This is partly due to the exogenous rho proteins driving cellular locomotion despite the extracellular cues promoting apoptosis and growth cone collapse. It is situations like these that make intracellular modulation of rho proteins the subject of a significant amount of spinal cord research.
## Mental Retardation
Rho proteins have also been implicated in mental retardation. Mental retardation occurs in approximately 3% of the population and is characterized by having an IQ of less than 70. Multiple sources have noticed that mental retardation in some cases shows malformation of the dendritic spines which form the post-synaptic connections between neurons. As expected, the misshapen dendritic spines are sometimes the result of rho protein signaling modulation. After cloning of various genes implicated in X-linked mental retardation, three genes were identified that have effects on rho signaling, including oligophrenin-1 (GAP protein that stimulates GTPase activity of Rac1, Cdc42 and RhoA), PAK3 (involved with the effects of Rac and Cdc42 on the actin cytoskeleton) and αPIX (a GEF which helps activate Rac1 and Cdc42)[15]. Because of the effect of rho signaling on the actin cytoskeleton, genetic malfunctions of a rho protein could certainly explain the irregular morphology of neuronal dendrites seen in many cases of mental retardation.
## Cancer
After finding that Ras proteins are mutated in 30% of human cancers, it was suspected that mutated rho proteins were also involved in cancer reproduction, as the signaling pathways involving rho proteins are widely known to play an important role in cancer development[5]. However, Ellenbroek et al. reported in their review that as of August 2007 no mutations have been found in rho proteins and only one has been found to be genetically altered[5]. To explain the role of rho pathways without mutation, researchers have now turned to the regulators of rho activity and the levels of expression of the rho proteins for answers.
Again, one way to explain altered signaling in the absence of mutation is through increased expression. Overexpression of RhoA, RhoB, RhoC, Rac1, Rac2, Rac3, RhoE, RhoG, RhoH and Cdc42 has been shown in multiple types of cancer[5]. This increased presence of so many signaling molecules certainly implies that these proteins promote the cellular functions which become overly active in cancerous cells.
A second target to explain the role of the rho proteins in cancer is their regulatory proteins. Rho proteins are very tightly controlled by a wide variety of sources, and over 60 activators and 70 inactivators have been identified[6]. Multiple GAPs, GDIs and GEFs have been shown to undergo overexpression, downregulation or mutation in different types of cancer[5]. As one can imagine, once an upstream signal is changed, the activity of its targets downstream, i.e. the rho proteins, will change in activity.
More specifically, Ellenbroek et al. outlined a number of different effects of rho activation in cancerous cells. First, in the initiation of the tumor modification of rho activity can suppress apoptosis and therefore contribute to artificial cell longevity. After natural apoptosis is suppressed, abnormal tumor growth can be observed through the loss of polarity in which rho proteins play an integral roll. Next, the growing mass can invade across its normal boundaries through the alteration of adhesion proteins potentially caused by rho proteins[5]. Finally, after inhibition of apoptosis, cell polarity and adhesion molecules, the cancerous mass is free to metastasize and spread to other regions of the body. | https://www.wikidoc.org/index.php/Rho_GTP-binding_protein | |
41210976952b9649b072906fcf96ae292b8b4a5f | wikidoc | Ribociclib | Ribociclib
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# Overview
Ribociclib is a kinase inhibitor that is FDA approved for the treatment of pre/perimenopausal or postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer, as initial endocrine-based therapy when given in combination with an aromatase inhibitor; or of postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer, as initial endocrine based therapy or following disease progression on endocrine therapy when given in combination with fulvestrant. Common adverse reactions include neutropenia, nausea, infections, fatigue, diarrhea, leukopenia, vomiting, alopecia, headache, constipation, rash, and cough.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Ribociclib is indicated in combination with:
- an aromatase inhibitor for the treatment of pre/perimenopausal or postmenopausal women, with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer, as initial endocrine-based therapy; or
- fulvestrant for the treatment of postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer, as initial endocrine based therapy or following disease progression on endocrine therapy.
- The recommended dose of Ribociclib is 600 mg (three 200 mg film-coated tablets) taken orally, once daily for 21 consecutive days followed by 7 days off treatment resulting in a complete cycle of 28 days. Ribociclib can be taken with or without food.
- When given with Ribociclib, refer to the Full Prescribing Information for the recommended dose of the aromatase inhibitor being used.
- When given with Ribociclib, the recommended dose of fulvestrant is 500 mg administered on Days 1, 15, 29, and once monthly thereafter. Please refer to the Full Prescribing Information of fulvestrant.
- Pre/perimenopausal women treated with the combination Ribociclib plus an aromatase inhibitor or fulvestrant should be treated with a luteinizing hormone-releasing hormone (LHRH) agonist according to current clinical practice standards.
- Patients should take their dose of Ribociclib at approximately the same time each day, preferably in the morning.
- If the patient vomits after taking the dose, or misses a dose, no additional dose should be taken that day. The next prescribed dose should be taken at the usual time. Ribociclib tablets should be swallowed whole (tablets should not be chewed, crushed or split prior to swallowing). No tablet should be ingested if it is broken, cracked, or otherwise not intact.
Dose Modifications for Adverse Reactions
- The recommended dose modifications for adverse reactions are listed in Table 1.
- Tables 2, 3, 4 and 5 summarize recommendations for dose interruption, reduction, or discontinuation of Ribociclib in the management of specific adverse reactions. Dose modification of Ribociclib is recommended based on individual safety and tolerability.
- Refer to the Full Prescribing Information for the coadministered aromatase inhibitor or fulvestrant for dose modification guidelines in the event of toxicity and other relevant safety information.
- Avoid concomitant use of Ribociclib with strong CYP3A inhibitors and consider an alternative concomitant medication with less potential for CYP3A inhibition. If a strong CYP3A inhibitor must be coadministered, reduce the Ribociclib dose to 400 mg once daily. If the strong inhibitor is discontinued, change the Ribociclib dose (after at least 5 half-lives of the strong CYP3A inhibitor) to the dose used prior to the initiation of the strong CYP3A inhibitor.
- No dose adjustment is necessary in patients with mild hepatic impairment (Child-Pugh class A). The recommended starting dose is 400 mg Ribociclib once daily for patients with moderate (Child-Pugh class B) and severe hepatic impairment (Child-Pugh class C).
- Review the Full Prescribing Information for the coadministered aromatase inhibitor or fulvestrant for dose modifications related to hepatic impairment.
- No dose adjustment is necessary in patients with mild or moderate renal impairment. The recommended starting dose is 200 mg Ribociclib once daily for patients with severe renal impairment.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Ribociclib Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding Ribociclib Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Ribociclib FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Ribociclib Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding Ribociclib Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
# Contraindications
- None
# Warnings
- Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Based on the observed QT prolongation during treatment, Ribociclib may require dose interruption, reduction or discontinuation as described in Table 4.
- Across MONALEESA-2, MONALEESA-7, and MONALEESA-3 in patients with advanced or metastatic breast cancer who received the combination of Ribociclib plus an aromatase inhibitor or fulvestrant, 14 out of 1054 patients (1%) had a > 500 ms post-baseline QTcF value, and 59 out of 1054 patients (6%) had a > 60 ms increase from baseline in QTcF intervals.
- These ECG changes were reversible with dose interruption and the majority occurred within the first four weeks of treatment. There were no reported cases of Torsades de Pointes.
- In MONALEESA-2, on the Ribociclib plus letrozole treatment arm, there was one (0.3%) sudden death in a patient with Grade 3 hypokalemia and Grade 2 QT prolongation. No cases of sudden death were reported in MONALEESA-7 or MONALEESA-3.
- Assess ECG prior to initiation of treatment. Initiate treatment with Ribociclib only in patients with QTcF values less than 450 ms. Repeat ECG at approximately Day 14 of the first cycle and the beginning of the second cycle, and as clinically indicated.
- Monitor serum electrolytes (including potassium, calcium, phosphorous and magnesium) prior to the initiation of treatment, at the beginning of the first 6 cycles, and as clinically indicated. Correct any abnormality before starting Ribociclib therapy.
- Avoid the use of Ribociclib in patients who already have or who are at significant risk of developing QT prolongation, including patients with:
- long QT syndrome.
- uncontrolled or significant cardiac disease including recent myocardial infarction, congestive heart failure, unstable angina and bradyarrhythmias.
- electrolyte abnormalities.
- Avoid using Ribociclib with drugs known to prolong QT interval and/or strong CYP3A inhibitors as this may lead to prolongation of the QTcF interval.
- Ribociclib is not indicated for concomitant use with tamoxifen. In MONALEESA-7, the observed mean QTcF increase from baseline was > 10 ms higher in the tamoxifen plus placebo subgroup compared with the non-steroidal aromatase inhibitors (NSAI) plus placebo subgroup. In the placebo arm, an increase of > 60 ms from baseline occurred in 6/90 (7%) of patients receiving tamoxifen, and in no patients receiving an NSAI. An increase of > 60 ms from baseline in the QTcF interval was observed in 14/87 (16%) of patients in the Ribociclib and tamoxifen combination and in 18/245 (7%) of patients receiving Ribociclib plus an NSAI.
- In MONALEESA-2, MONALEESA-7 and MONALEESA-3, increases in transaminases were observed. Across all studies, Grade 3 or 4 increases in ALT (10% vs. 2%) and AST (7% vs. 2%) were reported in the Ribociclib and placebo arms, respectively.
- Among the patients who had Grade ≥ 3 ALT/AST elevation, the median time-to-onset was 85 days for the Ribociclib plus aromatase inhibitor or fulvestrant treatment group. The median time to resolution to Grade ≤ 2 was 22 days in the Ribociclib plus aromatase inhibitor or fulvestrant treatment group. In MONALEESA-2 and MONALEESA-3, concurrent elevations in ALT or AST greater than three times the ULN and total bilirubin greater than two times the ULN, with normal alkaline phosphatase, in the absence of cholestasis occurred in 6 (1%) patients and all patients recovered after discontinuation of Ribociclib. No cases occurred in MONALEESA-7.
- Perform LFTs before initiating therapy with Ribociclib. Monitor LFTs every 2 weeks for first 2 cycles, at the beginning of each subsequent 4 cycles, and as clinically indicated.
- Based on the severity of the transaminase elevations, Ribociclib may require dose interruption, reduction, or discontinuation as described in Table 3 (Dose Modification and Management for Hepatobiliary Toxicity). Recommendations for patients who have elevated AST/ALT Grade ≥ 3 at baseline have not been established.
- In MONALEESA-2, MONALEESA-7 and MONALEESA-3, neutropenia was the most frequently reported adverse reaction (74%), and a Grade 3/4 decrease in neutrophil count (based on laboratory findings) was reported in 58% of patients receiving Ribociclib plus an aromatase inhibitor or fulvestrant. Among the patients who had Grade 2, 3, or 4 neutropenia, the median time to Grade ≥ 2 neutropenia was 16 days. The median time to resolution of Grade ≥ 3 (to normalization or Grade < 3) was 12 days in the Ribociclib plus aromatase inhibitor or fulvestrant treatment group. Febrile neutropenia was reported in 1% of patients receiving Ribociclib plus an aromatase inhibitor or fulvestrant. Treatment discontinuation due to neutropenia was 0.8%.
- Perform CBC before initiating therapy with Ribociclib. Monitor CBC every 2 weeks for the first 2 cycles, at the beginning of each subsequent 4 cycles, and as clinically indicated.
- Based on the severity of the neutropenia, Ribociclib may require dose interruption, reduction or discontinuation as described in Table 2.
- Based on findings from animal studies and the mechanism of action, Ribociclib can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of Ribociclib to pregnant rats and rabbits during organogenesis caused embryo-fetal toxicities at maternal exposures that were 0.6 and 1.5 times the human clinical exposure, respectively, based on area under the curve (AUC). Advise pregnant women of the potential risk to a fetus. Advise women of reproductive potential to use effective contraception during therapy with Ribociclib and for at least 3 weeks after the last dose.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- Postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer for initial endocrine based therapy.
- The safety data reported below are based on MONALEESA-2, a clinical study of 668 postmenopausal women receiving Ribociclib plus letrozole or placebo plus letrozole. The median duration of exposure to Ribociclib plus letrozole was 13 months with 58% of patients exposed for ≥ 12 months.
- Dose reductions due to adverse reactions (ARs) occurred in 45% of patients receiving Ribociclib plus letrozole and in 3% of patients receiving placebo plus letrozole. Among patients receiving Ribociclib plus letrozole, 7% were reported to have permanently discontinued both Ribociclib and letrozole and 7% were reported to have permanently discontinued Ribociclib alone due to ARs. Among patients receiving placebo plus letrozole, 2% were reported to have permanently discontinued both and 0.9% were reported to have permanently discontinued placebo alone due to ARs. Adverse reactions leading to treatment discontinuation of Ribociclib in patients receiving Ribociclib plus letrozole were ALT increased (4%), AST increased (3%), vomiting (2%). Antiemetics and antidiarrhea medications were used to manage symptoms as clinically indicated.
- On-treatment deaths, regardless of causality, were reported in three cases (0.9%) of Ribociclib plus letrozole treated patients vs. one case (0.3%) of placebo plus letrozole treated patients. Causes of death on Ribociclib plus letrozole included one case each of the following: progressive disease, death (cause unknown), and sudden death (in the setting of Grade 3 hypokalemia and Grade 2 QT prolongation).
- The most common ARs (reported at a frequency ≥ 20% on the Ribociclib arm and ≥ 2% higher than placebo) were neutropenia, nausea, fatigue, diarrhea, leukopenia, alopecia, vomiting, constipation, headache, and back pain.
- The most common Grade 3/4 ARs (reported at a frequency ≥ 5%) were neutropenia, leukopenia, abnormal liver function tests, and lymphopenia.
- In MONALEESA-2, syncope occurred in 9 patients (3%) in the Ribociclib plus letrozole arm vs. 3 (1%) in placebo plus letrozole arm.
- Adverse reactions and laboratory abnormalities occurring in patients in MONALEESA-2 are listed in Table 6 and Table 7, respectively.
- Pre/perimenopausal patients with HR-positive, HER2-negative advanced or metastatic breast cancer for initial endocrine based therapy.
- MONALEESA-7 was conducted in 672 pre/perimenopausal patients with HR-positive, HER2-negative advanced or metastatic breast cancer receiving either Ribociclib plus a non-steroidal aromatase inhibitor (NSAI) or tamoxifen plus goserelin or placebo plus NSAI or tamoxifen plus goserelin. The median duration of exposure on the Ribociclib arm was 15.2 months with 66% of patients exposed for ≥ 12 months. The safety data reported below are based on 495 pre/perimenopausal patients receiving Ribociclib plus NSAI plus goserelin or placebo plus NSAI plus goserelin.
- Dose reductions due to ARs occurred in 33% of patients receiving Ribociclib plus NSAI plus goserelin, and in 4% of patients receiving placebo plus NSAI plus goserelin. Among patients receiving Ribociclib plus NSAI, 3% were reported to have permanently discontinued both Ribociclib and NSAI and 3% were reported to have permanently discontinued Ribociclib alone due to ARs. Among patients receiving placebo plus NSAI, 2% were reported to have permanently discontinued both and 0.8% were reported to have permanently discontinued placebo alone due to ARs. Adverse reactions leading to treatment discontinuation on Ribociclib in patients receiving Ribociclib plus NSAI (as compared to the placebo arm) were ALT increased (2% vs. 0.8%), AST increased (2% vs. 0.8%), drug-induced liver injury (1% vs. 0.4%).
- The most common ARs (reported at a frequency ≥ 20% on the Ribociclib arm and ≥ 2% higher than placebo) were neutropenia, infections, leukopenia, arthralgia, nausea, and alopecia. The most common Grade 3/4 ARs (reported at a frequency ≥ 5%) were neutropenia, leukopenia, and abnormal liver function tests. See Table 8 below.
- Adverse reactions and laboratory abnormalities occurring in patients in MONALEESA-7 are listed in Table 8 and Table 9, respectively.
- Additional adverse reactions in MONALEESA-7 for patients receiving Ribociclib plus NSAI included asthenia (12%), thrombocytopenia (9%), dry skin (8%), oropharyngeal pain (7%), dyspepsia (5%), lacrimation increased (4%), dry eye (4%), vitiligo (3%), hypocalcemia, (2%), blood bilirubin increased (1%) and syncope (0.4%).
- Postmenopausal patients with HR-positive, HER2-negative advanced or metastatic breast cancer for initial endocrine based therapy or after disease progression on endocrine therapy.
- The safety data reported below are based on MONALEESA-3, a clinical study of 724 postmenopausal women receiving Ribociclib plus fulvestrant or placebo plus fulvestrant. The median duration of exposure to Ribociclib plus fulvestrant was 15.8 months with 58% of patients exposed for ≥ 12 months.
- Dose reductions due to ARs occurred in 32% of patients receiving Ribociclib plus fulvestrant and in 3% of patients receiving placebo plus fulvestrant. Among patients receiving Ribociclib plus fulvestrant, 8% were reported to have permanently discontinued both Ribociclib and fulvestrant and 9% were reported to have discontinued Ribociclib alone due to ARs. Among patients receiving placebo plus fulvestrant, 4% were reported to have permanently discontinued both and 2% were reported to have discontinued placebo alone due to ARs. Adverse reactions leading to treatment discontinuation of Ribociclib in patients receiving Ribociclib plus fulvestrant (as compared to the placebo arm) were ALT increased (5% vs. 0%), AST increased (3% vs. 0.6%), and vomiting (1% vs. 0%).
- The most common ARs (reported at a frequency ≥ 20% on the Ribociclib arm and ≥2% higher than placebo) were neutropenia, infections, leukopenia, cough, nausea, diarrhea, vomiting, constipation, pruritus, and rash. The most common Grade 3/4 ARs (reported at a frequency ≥ 5%) were neutropenia, leukopenia, infections, and abnormal liver function tests. See Table 10.
- Adverse reactions and laboratory abnormalities occurring in patients in MONALEESA-3 are listed in Table 10 and Table 11, respectively.
- Additional adverse reactions in MONALEESA-3 for patients receiving Ribociclib plus fulvestrant included asthenia (14%), dyspepsia (10%), thrombocytopenia (9%) dry skin (8%), dysgeusia (7%), dry mouth (5%), vertigo (5%), dry eye (5%), lacrimation increased (4%), erythema (4%), hypocalcemia (4%), blood bilirubin increased (1%), and syncope (1%).
## Postmarketing Experience
There is limited information regarding Ribociclib Postmarketing Experience in the drug label.
# Drug Interactions
- Drugs That May Increase Ribociclib Plasma Concentrations
- Drugs That May Decrease Ribociclib Plasma Concentrations
- Effect of Ribociclib on Other Drugs
- Drugs That Prolong the QT Interval
CYP3A4 Inhibitors
- Coadministration of a strong CYP3A4 inhibitor (ritonavir) increased Ribociclib exposure in healthy subjects by 3.2-fold . Avoid concomitant use of strong CYP3A inhibitors (e.g., boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, and voriconazole) and consider alternative concomitant medications with less potential for CYP3A inhibition.
- If coadministration of Ribociclib with a strong CYP3A inhibitor cannot be avoided, reduce the dose of Ribociclib to 400 mg once daily.
- Instruct patients to avoid grapefruit or grapefruit juice, which are known to inhibit cytochrome CYP3A enzymes and may increase the exposure to Ribociclib.
CYP3A4 Inducers
- Coadministration of a strong CYP3A4 inducer (rifampin) decreased the plasma exposure of Ribociclib in healthy subjects by 89%. Avoid concomitant use of strong CYP3A inducers and consider an alternate concomitant medication with no or minimal potential to induce CYP3A (e.g., phenytoin, rifampin, carbamazepine and St John’s Wort (Hypericum perforatum)).
CYP3A Substrates with Narrow Therapeutic Index
- Coadministration of midazolam (a sensitive CYP3A4 substrate) with multiple doses of Ribociclib (400 mg) increased the midazolam exposure by 3.8-fold in healthy subjects, compared with administration of midazolam alone. Ribociclib given at the clinically relevant dose of 600 mg is predicted to increase the midazolam AUC by 5.2-fold. Therefore, caution is recommended when Ribociclib is administered with CYP3A substrates with a narrow therapeutic index. The dose of a sensitive CYP3A substrate with a narrow therapeutic index, including but not limited to alfentanil, cyclosporine, dihydroergotamine, ergotamine, everolimus, fentanyl, pimozide, quinidine, sirolimus and tacrolimus, may need to be reduced as Ribociclib can increase their exposure.
- Avoid coadministration of Ribociclib with medicinal products with a known potential to prolong QT such as antiarrhythmic medicines (including, but not limited to amiodarone, disopyramide, procainamide, quinidine and sotalol), and other drugs that are known to prolong the QT interval (including, but not limited to, chloroquine, halofantrine, clarithromycin, haloperidol, methadone, moxifloxacin, bepridil, pimozide and ondansetron).
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Risk Summary
- Based on findings from animal studies and the mechanism of action, Ribociclib can cause fetal harm when administered to a pregnant woman.
- There are no available human data informing the drug-associated risk. In animal reproduction studies, administration of Ribociclib to pregnant animals during organogenesis resulted in increased incidences of postimplantation loss and reduced fetal weights in rats and increased incidences of fetal abnormalities in rabbits at exposures 0.6 or 1.5 times the exposure in humans, respectively, at the highest recommended dose of 600 mg/day based on AUC (see Data). Advise pregnant women of the potential risk to a fetus.
- The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk of major birth defects is 2%-4% and of miscarriage is 15%-20% of clinically recognized pregnancies in the U.S. general population.
Data (Animal)
- In embryo-fetal development studies in rats and rabbits, pregnant animals received oral doses of Ribociclib up to 1000 mg/kg/day and 60 mg/kg/day, respectively, during the period of organogenesis.
- In rats, 300 mg/kg/day resulted in reduced maternal body weight gain and reduced fetal weights accompanied by skeletal changes related to the lower fetal weights. There were no significant effects on embryo-fetal viability or fetal morphology at 50 or 300 mg/kg/day.
- In rabbits at doses ≥ 30 mg/kg/day, there were adverse effects on embryo-fetal development including increased incidences of fetal abnormalities (malformations and external, visceral and skeletal variants) and fetal growth (lower fetal weights). These findings included reduced/small lung lobes, additional vessel on the descending aorta, additional vessel on the aortic arch, small eyes, diaphragmatic hernia, absent accessory lobe or (partly) fused lung lobes, reduced/small accessory lung lobe, extra/rudimentary 13th ribs, misshapen hyoid bone, bent hyoid bone alae, and reduced number of phalanges in the pollex. There was no evidence of increased incidence of embryo-fetal mortality. There was no maternal toxicity observed at 30 mg/kg/day.
- At 300 mg/kg/day in rats and 30 mg/kg/day in rabbits, the maternal systemic exposures (AUC) were approximately 0.6 and 1.5 times, respectively, the exposure in patients at the highest recommended dose of 600 mg/day.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ribociclib in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Ribociclib during labor and delivery.
### Nursing Mothers
Risk Summary
- It is not known if Ribociclib is present in human milk. There are no data on the effects of Ribociclib on the breastfed infant or on milk production. Ribociclib and its metabolites readily passed into the milk of lactating rats. Because of the potential for serious adverse reactions in breastfed infants from Ribociclib, advise lactating women not to breastfeed while taking Ribociclib and for at least 3 weeks after the last dose.
Data
- In lactating rats administered a single dose of 50 mg/kg, exposure to Ribociclib was 3.56-fold higher in milk compared to maternal plasma.
### Pediatric Use
- The safety and efficacy of Ribociclib in pediatric patients has not been established.
### Geriatic Use
- Of 334 patients who received Ribociclib in MONALEESA-2, 150 patients (45%) were ≥ 65 years of age and 35 patients (11%) were ≥ 75 years of age. Of 484 patients who received Ribociclib in MONALEESA-3, 226 patients (47%) were ≥ 65 years of age and 65 patients (14%) were ≥ 75 years of age. No overall differences in safety or effectiveness of Ribociclib were observed between these patients and younger patients.
### Gender
There is no FDA guidance on the use of Ribociclib with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Ribociclib with respect to specific racial populations.
### Renal Impairment
- Based on a population pharmacokinetic analysis, no dose adjustment is necessary in patients with mild (60 mL/min/1.73m2 ≤ estimated glomerular filtration rate (eGFR) < 90 mL/min/1.73m2) or moderate (30 mL/min/1.73m2 ≤ eGFR < 60 mL/min/1.73m2) renal impairment. Based on a renal impairment study in healthy subjects and non-cancer subjects with severe renal impairment (eGFR 15 to < 30 mL/min/1.73m2), a starting dose of 200 mg is recommended. Ribociclib has not been studied in breast cancer patients with severe renal impairment.
### Hepatic Impairment
- No dose adjustment is necessary in patients with mild hepatic impairment (Child-Pugh A). A reduced starting dose of 400 mg is recommended in patients with moderate (Child-Pugh B) and severe hepatic impairment (Child-Pugh C). Based on a pharmacokinetic trial in patients with hepatic impairment, mild hepatic impairment had no effect on the exposure of Ribociclib. The mean exposure for Ribociclib was increased less than 2-fold in patients with moderate (geometric mean ratio : 1.44 for Cmax; 1.28 for AUCinf) and severe (GMR: 1.32 for Cmax; 1.29 for AUCinf) hepatic impairment.
### Females of Reproductive Potential and Males
Pregnancy Testing
- Based on animal studies, Ribociclib can cause fetal harm when administered to a pregnant woman. Females of reproductive potential should have a pregnancy test prior to starting treatment with Ribociclib.
Contraception
Females
- Based on animal studies, Ribociclib can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception (methods that result in less than 1% pregnancy rates) during treatment with Ribociclib and for at least 3 weeks after the last dose.
Infertility
- Based on animal studies, Ribociclib may impair fertility in males of reproductive potential.
### Immunocompromised Patients
There is no FDA guidance one the use of Ribociclib in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- If patient vomits or misses a dose, do not give an additional dose that day.
- Give with or without food.
- Give at the same time as the aromatase inhibitor, preferably in the morning.
- Swallow tablets whole, do not chew, crush, or split. Do not ingest any tablet that is broken, cracked, or not in tact.
### Monitoring
- Tumor response may indicate efficacy.
- CBC, including differential: Prior to therapy initiation, every 2 weeks for the first 2 cycles, at the start of each subsequent 4 cycles, and as clinically indicated.
- Liver function tests: Prior to therapy initiation, every 2 weeks for the first 2 cycles, at the start of each subsequent 4 cycles, and as clinically indicated.
- Pregnancy test: Prior to initiation of treatment in females with reproductive potential.
- Serum electrolytes, including potassium, calcium, phosphorus, and magnesium: Prior to therapy initiation, the start of the the first 6 cycles and as clinically indicated.
- ECG: Prior to therapy initiation, at day 14 of the first cycle, at the start of the second cycle, and as clinically indicated.
# IV Compatibility
There is limited information regarding the compatibility of Ribociclib and IV administrations.
# Overdosage
There is limited information regarding Ribociclib overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
- Ribociclib is an inhibitor of cyclin-dependent kinase (CDK) 4 and 6. These kinases are activated upon binding to D-cyclins and play a crucial role in signaling pathways which lead to cell cycle progression and cellular proliferation. The cyclin D-CDK4/6 complex regulates cell cycle progression through phosphorylation of the retinoblastoma protein (pRb).
- In vitro, Ribociclib decreased pRb phosphorylation leading to arrest in the G1 phase of the cell cycle and reduced cell proliferation in breast cancer cell lines. In vivo, treatment with single agent Ribociclib in a rat xenograft model with human tumor cells led to decreased tumor volumes, which correlated with inhibition of pRb phosphorylation. In studies using patient-derived estrogen receptor positive breast cancer xenograft models, combination of Ribociclib and antiestrogen (e.g., letrozole) resulted in increased tumor growth inhibition compared to each drug alone. Additionally, the combination of Ribociclib and fulvestrant resulted in tumor growth inhibition in an estrogen receptor positive breast cancer xenograft model.
## Structure
## Pharmacodynamics
Cardiac Electrophysiology
- Serial, triplicate ECGs were collected following a single dose and at steady-state to evaluate the effect of Ribociclib on the QTcF interval in patients with advanced cancer. A pharmacokinetic-pharmacodynamic analysis included a total of 997 patients treated with Ribociclib at doses ranging from 50 to 1200 mg. The analysis suggested that Ribociclib causes concentration-dependent increases in the QTcF interval. The estimated mean change from baseline in QTcF for Ribociclib 600 mg in combination with aromatase inhibitors or fulvestrant was 22.0 ms (90% CI: 20.6, 23.4) and 23.7 ms (90% CI: 22.3, 25.1), respectively, and was 34.7 ms (90% CI: 31.6, 37.8) in combination with tamoxifen at the geometric mean Cmax at steady-state.
## Pharmacokinetics
- Ribociclib exhibited over-proportional increases in exposure (peak plasma concentrations (Cmax) and area under the time concentration curve (AUC)) across the dose range of 50 mg to 1200 mg following both single dose and repeated doses. Following repeated 600 mg once daily administration, steady-state was generally achieved after 8 days and Ribociclib accumulated with a geometric mean accumulation ratio of 2.51 (range: 0.972 to 6.40).
Absorption
- The time to reach Cmax (Tmax) following Ribociclib administration was between 1 and 4 hours.
- Food Effect: Compared to the fasted state, oral administration of a single 600 mg dose of Ribociclib film-coated tablet with a high-fat, high-calorie meal (approximately 800 to 1000 calories with ~50% calories from fat, ~35% calories from carbohydrates, and ~15% calories from protein) had no effect on the rate and extent of absorption of Ribociclib (Cmax GMR: 1.00; 90% CI: 0.898, 1.11; AUCinf GMR: 1.06; 90% CI: 1.01, 1.12).
Distribution
- Binding of Ribociclib to human plasma proteins in vitro was approximately 70% and independent of concentration (10 to 10,000 ng/mL). Ribociclib was equally distributed between red blood cells and plasma with a mean in vivo blood-to-plasma ratio of 1.04. The apparent volume of distribution at steady-state (Vss/F) was 1090 L based on population PK analysis.
Metabolism
- In vitro and in vivo studies indicated Ribociclib undergoes extensive hepatic metabolism mainly via CYP3A4 in humans. Following oral administration of a single 600 mg dose of radio-labeled Ribociclib to humans, the primary metabolic pathways for Ribociclib involved oxidation (dealkylation, C and/or N-oxygenation, oxidation (-2H)) and combinations thereof. Phase II conjugates of Ribociclib Phase I metabolites involved N-acetylation, sulfation, cysteine conjugation, glycosylation and glucuronidation. Ribociclib was the major circulating drug-derived entity in plasma (44%). The major circulating metabolites included metabolite M13 (CCI284, N-hydroxylation), M4 (LEQ803, N-demethylation), and M1 (secondary glucuronide), each representing an estimated 9%, 9%, and 8% of total radioactivity, and 22%, 20%, and 18% of Ribociclib exposure. Clinical activity (pharmacological and safety) of Ribociclib was due primarily to parent drug, with negligible contribution from circulating metabolites.
- Ribociclib was extensively metabolized with unchanged drug accounting for 17% and 12% in feces and urine, respectively. Metabolite LEQ803 was a significant metabolite in excreta and represented approximately 14% and 4% of the administered dose in feces and urine, respectively. Numerous other metabolites were detected in both feces and urine in minor amounts (≤ 3% of the administered dose).
Elimination
- The geometric mean plasma effective half-life (based on accumulation ratio) was 32.0 hours (63% CV) and the geometric mean apparent oral clearance (CL/F) was 25.5 L/hr (66% CV) at steady-state at 600 mg in patients with advanced cancer. The geometric mean apparent plasma terminal half-life (t ½) of Ribociclib ranged from 29.7 to 54.7 hours and geometric mean CL/F of Ribociclib ranged from 39.9 to 77.5 L/hr at 600 mg across studies in healthy subjects.
- Ribociclib is eliminated mainly via feces, with a small contribution of the renal route. In 6 healthy male subjects, following a single oral dose of radio-labeled Ribociclib, 92% of the total administered radioactive dose was recovered within 22 days; feces was the major route of excretion (69%), with 23% of the dose recovered in urine.
Specific Populations
Patients with Hepatic Impairment
- Based on a pharmacokinetic trial in patients with hepatic impairment, mild (Child-Pugh class A) hepatic impairment had no effect on the exposure of Ribociclib. The mean exposure for Ribociclib was increased less than 2-fold in patients with moderate (Child-Pugh class B; geometric mean ratio : 1.44 for Cmax; 1.28 for AUCinf) and severe (Child-Pugh class C; GMR: 1.32 for Cmax; 1.29 for AUCinf) hepatic impairment. Based on a population pharmacokinetic analysis that included 160 patients with normal hepatic function and 47 patients with mild hepatic impairment, mild hepatic impairment had no effect on the exposure of Ribociclib, further supporting the findings from the dedicated hepatic impairment study.
Patients with Renal Impairment
- Mild (60 mL/min/1.73m2 ≤ eGFR < 90 mL/min/1.73m2) and moderate (30 mL/min/1.73m2 ≤ eGFR < 60 mL/min/1.73m2) renal impairment had no effect on the exposure of Ribociclib based on a population PK analysis.
- The effect of renal impairment on the pharmacokinetics of Ribociclib was assessed in a renal impairment study in non-cancer subjects with normal renal function (eGFR ≥ 90 mL/min/1.73 m2), severe renal impairment (eGFR 15 to < 30 mL/min/1.73 m2), and End Stage Renal Disease (ESRD; eGFR < 15 mL/min/1.73 m2). In subjects with severe renal impairment, AUCinf increased by 1.96 fold, and Cmax increased by 1.51 fold compared to subjects with normal renal function.
Effect of Age, Weight, Gender, and Race
- Population PK analysis showed that there are no clinically relevant effects of age, body weight, gender, or race on the systemic exposure of Ribociclib.
Drug Interaction Studies
Drugs That Affect Ribociclib Plasma Concentrations
- CYP3A Inhibitors: A drug interaction trial in healthy subjects was conducted with ritonavir (a strong CYP3A inhibitor). Compared to Ribociclib alone, ritonavir (100 mg twice a day for 14 days) increased Ribociclib Cmax and AUCinf by 1.7-fold and 3.2-fold, respectively, following a single 400 mg Ribociclib dose. Cmax and AUC for LEQ803 (a prominent metabolite of LEE011, accounting for less than 10% of parent exposure) decreased by 96% and 98%, respectively. A moderate CYP3A4 inhibitor (erythromycin) is predicted to increase Ribociclib Cmax and AUC by 1.3-fold and 1.9-fold, respectively.
- CYP3A Inducers: A drug interaction trial in healthy subjects was conducted with rifampicin (a strong CYP3A4 inducer). Compared to Ribociclib alone, rifampicin (600 mg daily for 14 days) decreased Ribociclib Cmax and AUCinf by 81% and 89%, respectively, following a single 600 mg Ribociclib dose. LEQ803 Cmax increased 1.7-fold and AUCinf decreased by 27%, respectively. A moderate CYP3A inducer (efavirenz) is predicted to decrease Ribociclib Cmax and AUC by 37% and 60%, respectively.
Drugs that are Affected by Ribociclib
- CYP3A4 and CYP1A2 Substrates: A drug interaction trial in healthy subjects was conducted as a cocktail study with midazolam (sensitive CYP3A4 substrate) and caffeine (sensitive CYP1A2 substrate). Compared to midazolam and caffeine alone, multiple doses of Ribociclib (400 mg once daily for 8 days) increased midazolam Cmax and AUCinf by 2.1-fold and 3.8-fold, respectively. Administration of Ribociclib at 600 mg once daily is predicted to increase midazolam Cmax and AUC by 2.4-fold and 5.2-fold, respectively. The effect of multiple doses of 400 mg Ribociclib on caffeine was minimal, with Cmax decreased by 10% and AUCinf increased slightly by 20%. Only weak inhibitory effects on CYP1A2 substrates are predicted at 600 mg Ribociclib once daily dose.
- Gastric pH-elevating Agents: Coadministration of Ribociclib with drugs that elevate the gastric pH was not evaluated in a clinical trial; however, altered Ribociclib absorption was not identified in a population PK analysis and was not predicted using physiology based PK models.
- Letrozole: Data from a clinical trial in patients with breast cancer and population PK analysis indicated no drug interaction between Ribociclib and letrozole following coadministration of the drugs.
- Anastrozole: Data from a clinical trial in patients with breast cancer indicated no clinically relevant drug interaction between Ribociclib and anastrozole following coadministration of the drugs.
- Exemestane: Data from a clinical trial in patients with breast cancer indicated no clinically relevant drug interaction between Ribociclib and exemestane following coadministration of the drugs.
- Fulvestrant: Data from a clinical trial in patients with breast cancer indicated no clinically relevant effect of fulvestrant on Ribociclib exposure following coadministration of the drugs.
- Tamoxifen: Ribociclib is not indicated for concomitant use with tamoxifen. Data from a clinical trial in patients with breast cancer indicated that tamoxifen Cmax and AUC increased approximately 2-fold following coadministration of 600 mg Ribociclib.
In vitro Studies
- Effect of Ribociclib on CYP Enzymes: In vitro, Ribociclib was a reversible inhibitor of CYP1A2, CYP2E1 and CYP3A4/5 and a time-dependent inhibitor of CYP3A4/5, at clinically relevant concentrations. In vitro evaluations indicated that Ribociclib has no potential to inhibit the activities of CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6 at clinically relevant concentrations. It has no potential for time-dependent inhibition of CYP1A2, CYP2C9, and CYP2D6, and no induction of CYP1A2, CYP2B6, CYP2C9 and CYP3A4 at clinically relevant concentrations.
- Effect of Ribociclib on Transporters: In vitro evaluations indicated that Ribociclib has a low potential to inhibit the activities of drug transporters P-gp, OATP1B1/B3, OCT1, MATEK2 at clinically relevant concentrations. Ribociclib may inhibit BCRP, OCT2, MATE1, and human BSEP at clinically relevant concentrations.
- Effect of Transporters on Ribociclib: Based on in vitro data, P-gp and BCRP mediated transport are unlikely to affect the extent of oral absorption of Ribociclib at therapeutic doses. Ribociclib is not a substrate for hepatic uptake transporters OATP1B1/1B3 or OCT-1 in vitro.
## Nonclinical Toxicology
- Carcinogenesis studies have not been conducted with Ribociclib.
- Ribociclib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay or clastogenic in an in vitro human lymphocyte chromosomal aberration assay or an in vivo rat bone marrow micronucleus assay.
- In a fertility and early embryonic development study, female rats received oral doses of Ribociclib for 14 days prior to mating through the first week of pregnancy. Ribociclib did not affect reproductive function, fertility or early embryonic development at doses up to 300 mg/kg/day (approximately 0.6 times the clinical exposure in patients at the highest recommended dose of 600 mg/day based on AUC).
- A fertility study in male rats has not been performed with Ribociclib. In repeat-dose toxicity studies with oral administration of Ribociclib daily for 3 weeks on /1 week off in rats up to 26 weeks duration and dogs up to 39 weeks duration, atrophic changes in testes were reported. Findings included degeneration of seminiferous tubular epithelia in the testes and hypospermia and luminal cellular debris in the epididymides of rats and dogs and vacuolation of epithelia in the epididymides of rats. These findings were observed at doses ≥ 75 mg/kg in rats and ≥ 1 mg/kg in dogs which resulted in systemic exposures that were 1.4 and 0.03 times the human exposure at the highest recommended daily dose of 600 mg/day based on AUC, respectively. These effects can be linked to a direct anti-proliferative effect on the testicular germ cells resulting in atrophy of the seminiferous tubules and showed a trend towards reversibility in rats and dogs after a four-week non-dosing period.
- In vivo cardiac safety studies in dogs demonstrated dose and concentration related QTc interval prolongation at an exposure similar to patients receiving the recommended dose of 600 mg. There is a potential to induce incidences of premature ventricular contractions (PVCs) at elevated exposures (approximately 5-fold the anticipated clinical Cmax).
# Clinical Studies
- Postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer for initial endocrine based therapy.
- MONALEESA-2 was a randomized, double-blind, placebo-controlled, multicenter clinical study of Ribociclib plus letrozole vs. placebo plus letrozole conducted in postmenopausal women with HR-positive, HER2-negative, advanced breast cancer who received no prior therapy for advanced disease.
- A total of 668 patients were randomized to receive either Ribociclib plus letrozole (n = 334) or placebo plus letrozole (n = 334), stratified according to the presence of liver and/or lung metastases. Letrozole 2.5 mg was given orally once daily for 28 days, with either Ribociclib 600 mg or placebo orally once daily for 21 consecutive days followed by 7 days off until disease progression or unacceptable toxicity. The major efficacy outcome measure for the study was investigator-assessed progression-free survival (PFS) using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
- Patients enrolled in MONALEESA-2 had a median age of 62 years (range 23 to 91) and 45% of patients were older than 65. The majority of patients were White (82%), and all patients had an ECOG performance status of 0 or 1. A total of 47% of patients had received chemotherapy and 51% had received antihormonal therapy in the neoadjuvant or adjuvant setting. Thirty-four percent (34%) of patients had de novo metastatic disease, 21% had bone only disease, and 59% had visceral disease.
- The efficacy results from MONALEESA-2 are summarized in Table 12 and Figure 1. The results shown are from a pre-planned interim efficacy analysis of PFS. Results were consistent across patient subgroups of prior adjuvant or neoadjuvant chemotherapy or hormonal therapies, liver and/or lung involvement, and bone-only metastatic disease. The PFS assessment based on a blinded independent central radiological review was consistent with investigator assessment. At the time of the PFS analysis, 6.5% of patients had died, and overall survival data were immature.
- Pre/perimenopausal patients with HR-positive, HER2-negative advanced or metastatic breast cancer for initial endocrine based therapy.
- MONALEESA-7 was a randomized, double-blind, placebo-controlled study of Ribociclib plus either a non-steroidal aromatase inhibitor (NSAI) or tamoxifen and goserelin vs. placebo plus either a NSAI or tamoxifen and goserelin conducted in pre/perimenopausal women with HR-positive, HER2-negative, advanced breast cancer who received no prior endocrine therapy for advanced disease.
- A total of 672 patients were randomized to receive Ribociclib plus NSAI or tamoxifen plus goserelin (n = 335) or placebo plus NSAI or tamoxifen plus goserelin (n = 337), stratified according to the presence of liver and/or lung metastases, prior chemotherapy for advanced disease and endocrine combination partner (tamoxifen and goserelin vs. NSAI and goserelin). NSAI (letrozole 2.5 mg or anastrozole 1 mg) or tamoxifen 20 mg were given orally once daily on a continuous daily schedule, goserelin was administered as a sub-cutaneous injection on Day 1 of each 28 day cycle, with either Ribociclib 600 mg or placebo orally once daily for 21 consecutive days followed by 7 days off until disease progression or unacceptable toxicity. The major efficacy outcome measure for the study was investigator-assessed progression-free survival (PFS) using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
- Patients enrolled in MONALEESA-7 had a median age of 44 years (range 25 to 58) and were primarily Caucasian (58%), Asian (29%), or Black (3%). Nearly all patients (99%) had an ECOG performance status of 0 or 1. Of the 672 patients, 33% had received chemotherapy in the adjuvant vs. 18% in the neoadjuvant setting and 40% had received endocrine therapy in the adjuvant vs. 0.7% in the neoadjuvant setting prior to study entry. Forty percent (40%) of patients had de novo metastatic disease, 24% had bone only disease, and 57% had visceral disease. Demographics and baseline disease characteristics were balanced and comparable between study arms, and endocrine combination partner.
- The efficacy results from a pre-specified subgroup analysis of 495 patients who had received Ribociclib or placebo with NSAI plus goserelin are summarized in Table 13 and Figure 2. Consistent results were observed in stratification factor subgroups of disease site and prior chemotherapy for advanced disease. Overall survival data were immature with 13% deaths.
- Postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer for initial endocrine based therapy or after disease progression on endocrine therapy.
- MONALEESA-3 was a randomized double-blind, placebo-controlled study of Ribociclib in combination with fulvestrant for the treatment of postmenopausal women with hormone receptor positive, HER2-negative, advanced breast cancer who have received no or only one line of prior endocrine treatment.
- A total of 726 patients were randomized in a 2:1 ratio to receive Ribociclib 600 mg and fulvestrant (n = 484) or placebo and fulvestrant (n = 242), stratified according to the presence of liver and/or lung metastases and prior endocrine therapy for advanced or metastatic disease. Fulvestrant 500 mg was administered intramuscularly on Days 1, 15, 29, and once monthly thereafter, with either Ribociclib 600 mg or placebo given orally once daily for 21 consecutive days followed by 7 days off until disease progression or unacceptable toxicity. The major efficacy outcome measure for the study was investigator-assessed progression-free survival (PFS) using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
- Patients enrolled in this study had a median age of 63 years (range 31 to 89). Of the patients enrolled, 47% were 65 years and older, including 14% age 75 years and older. The patients enrolled were primarily Caucasian (85%), Asian (9%), and Black (0.7%). Nearly all patients (99.7%) had an ECOG performance status of 0 or 1. First and second line patients were enrolled in this study (of which 19% had de novo metastatic disease). Forty-three percent (43%) of patients had received chemotherapy in the adjuvant vs. 13% in the neoadjuvant setting and 59% had received endocrine therapy in the adjuvant vs. 1% in the neoadjuvant setting prior to study entry. Twenty-one percent (21%) of patients had bone only disease and 61% had visceral disease. Demographics and baseline disease characteristics were balanced and comparable between study arms.
- The efficacy results from MONALEESA-3 are summarized in Table 14 and Figure 3. Consistent results were observed in stratification factor subgroups of disease site and prior endocrine treatment for advanced disease. At the time of the PFS analysis, 17% of patients had died, and overall survival data were immature.
# How Supplied
- Each film-coated tablet contains 200 mg of Ribociclib free base.
- Light greyish violet, round, curved with beveled edge, debossed with “RIC” on one side and “NVR” on the other side; available in:
- Blister pack (21 tablets) – each blister pack contains 21 tablets (200 mg per tablet) (600 mg daily dose). Outer container - 3 Blister packs per outer container NDC 0078-0874-63
- Blister pack (14 tablets) – each blister pack contains 14 tablets (200 mg per tablet) (400 mg daily dose). Outer container - 3 Blisters packs per outer container NDC 0078-0867-42
- Blister pack (21 tablets) – each blister pack contains 21 tablets (200 mg per tablet) (200 mg daily dose). Outer container – 1 Blister pack per outer container NDC 0078-0860-01
## Storage
- Store at 20°C to 25°C (68°F to 77°F). Store in the original package.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
QT Prolongation
- Inform patients of the signs and symptoms of QT prolongation. Advise patients to contact their healthcare provider immediately for signs or symptoms of QT prolongation.
Hepatobiliary Toxicity
- Inform patients of the signs and symptoms of hepatobiliary toxicity. Advise patients to contact their healthcare provider immediately for signs or symptoms of hepatobiliary toxicity.
Neutropenia
- Advise patients of the possibility of developing neutropenia and to immediately contact their healthcare provider should they develop a fever, particularly in association with any suggestion of infection.
Embryo-Fetal Toxicity
- Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during Ribociclib therapy and for at least 3 weeks after the last dose. Advise females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment with Ribociclib.
Lactation
- Advise lactating women not to breastfeed during treatment with Ribociclib and for at least 3 weeks after the last dose.
Drug Interactions
- Inform patients to avoid grapefruit or grapefruit juice while taking Ribociclib.
- Inform patients to avoid strong CYP3A inhibitors, strong CYP3A inducers, and drugs known to prolong the QT interval.
Dosing
- Instruct patients to take the doses of Ribociclib at approximately the same time every day and to swallow whole (do not chew, crush, or split them prior to swallowing).
- If patient vomits or misses a dose, advise the patient to take the next prescribed dose at the usual time.
- Advise the patient that Ribociclib may be taken with or without food.
# Precautions with Alcohol
Alcohol-Ribociclib interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
- Kisqali
# Look-Alike Drug Names
There is limited information regarding Ribociclib Look-Alike Drug Names in the drug label.
# Drug Shortage Status
Drug Shortage
# Price | Ribociclib
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yashasvi Aryaputra[2];
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# Overview
Ribociclib is a kinase inhibitor that is FDA approved for the treatment of pre/perimenopausal or postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer, as initial endocrine-based therapy when given in combination with an aromatase inhibitor; or of postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer, as initial endocrine based therapy or following disease progression on endocrine therapy when given in combination with fulvestrant. Common adverse reactions include neutropenia, nausea, infections, fatigue, diarrhea, leukopenia, vomiting, alopecia, headache, constipation, rash, and cough.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Ribociclib is indicated in combination with:
- an aromatase inhibitor for the treatment of pre/perimenopausal or postmenopausal women, with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer, as initial endocrine-based therapy; or
- fulvestrant for the treatment of postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer, as initial endocrine based therapy or following disease progression on endocrine therapy.
- The recommended dose of Ribociclib is 600 mg (three 200 mg film-coated tablets) taken orally, once daily for 21 consecutive days followed by 7 days off treatment resulting in a complete cycle of 28 days. Ribociclib can be taken with or without food.
- When given with Ribociclib, refer to the Full Prescribing Information for the recommended dose of the aromatase inhibitor being used.
- When given with Ribociclib, the recommended dose of fulvestrant is 500 mg administered on Days 1, 15, 29, and once monthly thereafter. Please refer to the Full Prescribing Information of fulvestrant.
- Pre/perimenopausal women treated with the combination Ribociclib plus an aromatase inhibitor or fulvestrant should be treated with a luteinizing hormone-releasing hormone (LHRH) agonist according to current clinical practice standards.
- Patients should take their dose of Ribociclib at approximately the same time each day, preferably in the morning.
- If the patient vomits after taking the dose, or misses a dose, no additional dose should be taken that day. The next prescribed dose should be taken at the usual time. Ribociclib tablets should be swallowed whole (tablets should not be chewed, crushed or split prior to swallowing). No tablet should be ingested if it is broken, cracked, or otherwise not intact.
Dose Modifications for Adverse Reactions
- The recommended dose modifications for adverse reactions are listed in Table 1.
- Tables 2, 3, 4 and 5 summarize recommendations for dose interruption, reduction, or discontinuation of Ribociclib in the management of specific adverse reactions. Dose modification of Ribociclib is recommended based on individual safety and tolerability.
- Refer to the Full Prescribing Information for the coadministered aromatase inhibitor or fulvestrant for dose modification guidelines in the event of toxicity and other relevant safety information.
- Avoid concomitant use of Ribociclib with strong CYP3A inhibitors and consider an alternative concomitant medication with less potential for CYP3A inhibition. If a strong CYP3A inhibitor must be coadministered, reduce the Ribociclib dose to 400 mg once daily. If the strong inhibitor is discontinued, change the Ribociclib dose (after at least 5 half-lives of the strong CYP3A inhibitor) to the dose used prior to the initiation of the strong CYP3A inhibitor.
- No dose adjustment is necessary in patients with mild hepatic impairment (Child-Pugh class A). The recommended starting dose is 400 mg Ribociclib once daily for patients with moderate (Child-Pugh class B) and severe hepatic impairment (Child-Pugh class C).
- Review the Full Prescribing Information for the coadministered aromatase inhibitor or fulvestrant for dose modifications related to hepatic impairment.
- No dose adjustment is necessary in patients with mild or moderate renal impairment. The recommended starting dose is 200 mg Ribociclib once daily for patients with severe renal impairment.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Ribociclib Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding Ribociclib Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Ribociclib FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Ribociclib Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding Ribociclib Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
# Contraindications
- None
# Warnings
- Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Based on the observed QT prolongation during treatment, Ribociclib may require dose interruption, reduction or discontinuation as described in Table 4.
- Across MONALEESA-2, MONALEESA-7, and MONALEESA-3 in patients with advanced or metastatic breast cancer who received the combination of Ribociclib plus an aromatase inhibitor or fulvestrant, 14 out of 1054 patients (1%) had a > 500 ms post-baseline QTcF value, and 59 out of 1054 patients (6%) had a > 60 ms increase from baseline in QTcF intervals.
- These ECG changes were reversible with dose interruption and the majority occurred within the first four weeks of treatment. There were no reported cases of Torsades de Pointes.
- In MONALEESA-2, on the Ribociclib plus letrozole treatment arm, there was one (0.3%) sudden death in a patient with Grade 3 hypokalemia and Grade 2 QT prolongation. No cases of sudden death were reported in MONALEESA-7 or MONALEESA-3.
- Assess ECG prior to initiation of treatment. Initiate treatment with Ribociclib only in patients with QTcF values less than 450 ms. Repeat ECG at approximately Day 14 of the first cycle and the beginning of the second cycle, and as clinically indicated.
- Monitor serum electrolytes (including potassium, calcium, phosphorous and magnesium) prior to the initiation of treatment, at the beginning of the first 6 cycles, and as clinically indicated. Correct any abnormality before starting Ribociclib therapy.
- Avoid the use of Ribociclib in patients who already have or who are at significant risk of developing QT prolongation, including patients with:
- long QT syndrome.
- uncontrolled or significant cardiac disease including recent myocardial infarction, congestive heart failure, unstable angina and bradyarrhythmias.
- electrolyte abnormalities.
- Avoid using Ribociclib with drugs known to prolong QT interval and/or strong CYP3A inhibitors as this may lead to prolongation of the QTcF interval.
- Ribociclib is not indicated for concomitant use with tamoxifen. In MONALEESA-7, the observed mean QTcF increase from baseline was > 10 ms higher in the tamoxifen plus placebo subgroup compared with the non-steroidal aromatase inhibitors (NSAI) plus placebo subgroup. In the placebo arm, an increase of > 60 ms from baseline occurred in 6/90 (7%) of patients receiving tamoxifen, and in no patients receiving an NSAI. An increase of > 60 ms from baseline in the QTcF interval was observed in 14/87 (16%) of patients in the Ribociclib and tamoxifen combination and in 18/245 (7%) of patients receiving Ribociclib plus an NSAI.
- In MONALEESA-2, MONALEESA-7 and MONALEESA-3, increases in transaminases were observed. Across all studies, Grade 3 or 4 increases in ALT (10% vs. 2%) and AST (7% vs. 2%) were reported in the Ribociclib and placebo arms, respectively.
- Among the patients who had Grade ≥ 3 ALT/AST elevation, the median time-to-onset was 85 days for the Ribociclib plus aromatase inhibitor or fulvestrant treatment group. The median time to resolution to Grade ≤ 2 was 22 days in the Ribociclib plus aromatase inhibitor or fulvestrant treatment group. In MONALEESA-2 and MONALEESA-3, concurrent elevations in ALT or AST greater than three times the ULN and total bilirubin greater than two times the ULN, with normal alkaline phosphatase, in the absence of cholestasis occurred in 6 (1%) patients and all patients recovered after discontinuation of Ribociclib. No cases occurred in MONALEESA-7.
- Perform LFTs before initiating therapy with Ribociclib. Monitor LFTs every 2 weeks for first 2 cycles, at the beginning of each subsequent 4 cycles, and as clinically indicated.
- Based on the severity of the transaminase elevations, Ribociclib may require dose interruption, reduction, or discontinuation as described in Table 3 (Dose Modification and Management for Hepatobiliary Toxicity). Recommendations for patients who have elevated AST/ALT Grade ≥ 3 at baseline have not been established.
- In MONALEESA-2, MONALEESA-7 and MONALEESA-3, neutropenia was the most frequently reported adverse reaction (74%), and a Grade 3/4 decrease in neutrophil count (based on laboratory findings) was reported in 58% of patients receiving Ribociclib plus an aromatase inhibitor or fulvestrant. Among the patients who had Grade 2, 3, or 4 neutropenia, the median time to Grade ≥ 2 neutropenia was 16 days. The median time to resolution of Grade ≥ 3 (to normalization or Grade < 3) was 12 days in the Ribociclib plus aromatase inhibitor or fulvestrant treatment group. Febrile neutropenia was reported in 1% of patients receiving Ribociclib plus an aromatase inhibitor or fulvestrant. Treatment discontinuation due to neutropenia was 0.8%.
- Perform CBC before initiating therapy with Ribociclib. Monitor CBC every 2 weeks for the first 2 cycles, at the beginning of each subsequent 4 cycles, and as clinically indicated.
- Based on the severity of the neutropenia, Ribociclib may require dose interruption, reduction or discontinuation as described in Table 2.
- Based on findings from animal studies and the mechanism of action, Ribociclib can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of Ribociclib to pregnant rats and rabbits during organogenesis caused embryo-fetal toxicities at maternal exposures that were 0.6 and 1.5 times the human clinical exposure, respectively, based on area under the curve (AUC). Advise pregnant women of the potential risk to a fetus. Advise women of reproductive potential to use effective contraception during therapy with Ribociclib and for at least 3 weeks after the last dose.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- Postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer for initial endocrine based therapy.
- The safety data reported below are based on MONALEESA-2, a clinical study of 668 postmenopausal women receiving Ribociclib plus letrozole or placebo plus letrozole. The median duration of exposure to Ribociclib plus letrozole was 13 months with 58% of patients exposed for ≥ 12 months.
- Dose reductions due to adverse reactions (ARs) occurred in 45% of patients receiving Ribociclib plus letrozole and in 3% of patients receiving placebo plus letrozole. Among patients receiving Ribociclib plus letrozole, 7% were reported to have permanently discontinued both Ribociclib and letrozole and 7% were reported to have permanently discontinued Ribociclib alone due to ARs. Among patients receiving placebo plus letrozole, 2% were reported to have permanently discontinued both and 0.9% were reported to have permanently discontinued placebo alone due to ARs. Adverse reactions leading to treatment discontinuation of Ribociclib in patients receiving Ribociclib plus letrozole were ALT increased (4%), AST increased (3%), vomiting (2%). Antiemetics and antidiarrhea medications were used to manage symptoms as clinically indicated.
- On-treatment deaths, regardless of causality, were reported in three cases (0.9%) of Ribociclib plus letrozole treated patients vs. one case (0.3%) of placebo plus letrozole treated patients. Causes of death on Ribociclib plus letrozole included one case each of the following: progressive disease, death (cause unknown), and sudden death (in the setting of Grade 3 hypokalemia and Grade 2 QT prolongation).
- The most common ARs (reported at a frequency ≥ 20% on the Ribociclib arm and ≥ 2% higher than placebo) were neutropenia, nausea, fatigue, diarrhea, leukopenia, alopecia, vomiting, constipation, headache, and back pain.
- The most common Grade 3/4 ARs (reported at a frequency ≥ 5%) were neutropenia, leukopenia, abnormal liver function tests, and lymphopenia.
- In MONALEESA-2, syncope occurred in 9 patients (3%) in the Ribociclib plus letrozole arm vs. 3 (1%) in placebo plus letrozole arm.
- Adverse reactions and laboratory abnormalities occurring in patients in MONALEESA-2 are listed in Table 6 and Table 7, respectively.
- Pre/perimenopausal patients with HR-positive, HER2-negative advanced or metastatic breast cancer for initial endocrine based therapy.
- MONALEESA-7 was conducted in 672 pre/perimenopausal patients with HR-positive, HER2-negative advanced or metastatic breast cancer receiving either Ribociclib plus a non-steroidal aromatase inhibitor (NSAI) or tamoxifen plus goserelin or placebo plus NSAI or tamoxifen plus goserelin. The median duration of exposure on the Ribociclib arm was 15.2 months with 66% of patients exposed for ≥ 12 months. The safety data reported below are based on 495 pre/perimenopausal patients receiving Ribociclib plus NSAI plus goserelin or placebo plus NSAI plus goserelin.
- Dose reductions due to ARs occurred in 33% of patients receiving Ribociclib plus NSAI plus goserelin, and in 4% of patients receiving placebo plus NSAI plus goserelin. Among patients receiving Ribociclib plus NSAI, 3% were reported to have permanently discontinued both Ribociclib and NSAI and 3% were reported to have permanently discontinued Ribociclib alone due to ARs. Among patients receiving placebo plus NSAI, 2% were reported to have permanently discontinued both and 0.8% were reported to have permanently discontinued placebo alone due to ARs. Adverse reactions leading to treatment discontinuation on Ribociclib in patients receiving Ribociclib plus NSAI (as compared to the placebo arm) were ALT increased (2% vs. 0.8%), AST increased (2% vs. 0.8%), drug-induced liver injury (1% vs. 0.4%).
- The most common ARs (reported at a frequency ≥ 20% on the Ribociclib arm and ≥ 2% higher than placebo) were neutropenia, infections, leukopenia, arthralgia, nausea, and alopecia. The most common Grade 3/4 ARs (reported at a frequency ≥ 5%) were neutropenia, leukopenia, and abnormal liver function tests. See Table 8 below.
- Adverse reactions and laboratory abnormalities occurring in patients in MONALEESA-7 are listed in Table 8 and Table 9, respectively.
- Additional adverse reactions in MONALEESA-7 for patients receiving Ribociclib plus NSAI included asthenia (12%), thrombocytopenia (9%), dry skin (8%), oropharyngeal pain (7%), dyspepsia (5%), lacrimation increased (4%), dry eye (4%), vitiligo (3%), hypocalcemia, (2%), blood bilirubin increased (1%) and syncope (0.4%).
- Postmenopausal patients with HR-positive, HER2-negative advanced or metastatic breast cancer for initial endocrine based therapy or after disease progression on endocrine therapy.
- The safety data reported below are based on MONALEESA-3, a clinical study of 724 postmenopausal women receiving Ribociclib plus fulvestrant or placebo plus fulvestrant. The median duration of exposure to Ribociclib plus fulvestrant was 15.8 months with 58% of patients exposed for ≥ 12 months.
- Dose reductions due to ARs occurred in 32% of patients receiving Ribociclib plus fulvestrant and in 3% of patients receiving placebo plus fulvestrant. Among patients receiving Ribociclib plus fulvestrant, 8% were reported to have permanently discontinued both Ribociclib and fulvestrant and 9% were reported to have discontinued Ribociclib alone due to ARs. Among patients receiving placebo plus fulvestrant, 4% were reported to have permanently discontinued both and 2% were reported to have discontinued placebo alone due to ARs. Adverse reactions leading to treatment discontinuation of Ribociclib in patients receiving Ribociclib plus fulvestrant (as compared to the placebo arm) were ALT increased (5% vs. 0%), AST increased (3% vs. 0.6%), and vomiting (1% vs. 0%).
- The most common ARs (reported at a frequency ≥ 20% on the Ribociclib arm and ≥2% higher than placebo) were neutropenia, infections, leukopenia, cough, nausea, diarrhea, vomiting, constipation, pruritus, and rash. The most common Grade 3/4 ARs (reported at a frequency ≥ 5%) were neutropenia, leukopenia, infections, and abnormal liver function tests. See Table 10.
- Adverse reactions and laboratory abnormalities occurring in patients in MONALEESA-3 are listed in Table 10 and Table 11, respectively.
- Additional adverse reactions in MONALEESA-3 for patients receiving Ribociclib plus fulvestrant included asthenia (14%), dyspepsia (10%), thrombocytopenia (9%) dry skin (8%), dysgeusia (7%), dry mouth (5%), vertigo (5%), dry eye (5%), lacrimation increased (4%), erythema (4%), hypocalcemia (4%), blood bilirubin increased (1%), and syncope (1%).
## Postmarketing Experience
There is limited information regarding Ribociclib Postmarketing Experience in the drug label.
# Drug Interactions
- Drugs That May Increase Ribociclib Plasma Concentrations
- Drugs That May Decrease Ribociclib Plasma Concentrations
- Effect of Ribociclib on Other Drugs
- Drugs That Prolong the QT Interval
CYP3A4 Inhibitors
- Coadministration of a strong CYP3A4 inhibitor (ritonavir) increased Ribociclib exposure in healthy subjects by 3.2-fold [see Clinical Pharmacology (12.3)]. Avoid concomitant use of strong CYP3A inhibitors (e.g., boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, and voriconazole) and consider alternative concomitant medications with less potential for CYP3A inhibition.
- If coadministration of Ribociclib with a strong CYP3A inhibitor cannot be avoided, reduce the dose of Ribociclib to 400 mg once daily.
- Instruct patients to avoid grapefruit or grapefruit juice, which are known to inhibit cytochrome CYP3A enzymes and may increase the exposure to Ribociclib.
CYP3A4 Inducers
- Coadministration of a strong CYP3A4 inducer (rifampin) decreased the plasma exposure of Ribociclib in healthy subjects by 89%. Avoid concomitant use of strong CYP3A inducers and consider an alternate concomitant medication with no or minimal potential to induce CYP3A (e.g., phenytoin, rifampin, carbamazepine and St John’s Wort (Hypericum perforatum)).
CYP3A Substrates with Narrow Therapeutic Index
- Coadministration of midazolam (a sensitive CYP3A4 substrate) with multiple doses of Ribociclib (400 mg) increased the midazolam exposure by 3.8-fold in healthy subjects, compared with administration of midazolam alone. Ribociclib given at the clinically relevant dose of 600 mg is predicted to increase the midazolam AUC by 5.2-fold. Therefore, caution is recommended when Ribociclib is administered with CYP3A substrates with a narrow therapeutic index. The dose of a sensitive CYP3A substrate with a narrow therapeutic index, including but not limited to alfentanil, cyclosporine, dihydroergotamine, ergotamine, everolimus, fentanyl, pimozide, quinidine, sirolimus and tacrolimus, may need to be reduced as Ribociclib can increase their exposure.
- Avoid coadministration of Ribociclib with medicinal products with a known potential to prolong QT such as antiarrhythmic medicines (including, but not limited to amiodarone, disopyramide, procainamide, quinidine and sotalol), and other drugs that are known to prolong the QT interval (including, but not limited to, chloroquine, halofantrine, clarithromycin, haloperidol, methadone, moxifloxacin, bepridil, pimozide and ondansetron).
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Risk Summary
- Based on findings from animal studies and the mechanism of action, Ribociclib can cause fetal harm when administered to a pregnant woman.
- There are no available human data informing the drug-associated risk. In animal reproduction studies, administration of Ribociclib to pregnant animals during organogenesis resulted in increased incidences of postimplantation loss and reduced fetal weights in rats and increased incidences of fetal abnormalities in rabbits at exposures 0.6 or 1.5 times the exposure in humans, respectively, at the highest recommended dose of 600 mg/day based on AUC (see Data). Advise pregnant women of the potential risk to a fetus.
- The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk of major birth defects is 2%-4% and of miscarriage is 15%-20% of clinically recognized pregnancies in the U.S. general population.
Data (Animal)
- In embryo-fetal development studies in rats and rabbits, pregnant animals received oral doses of Ribociclib up to 1000 mg/kg/day and 60 mg/kg/day, respectively, during the period of organogenesis.
- In rats, 300 mg/kg/day resulted in reduced maternal body weight gain and reduced fetal weights accompanied by skeletal changes related to the lower fetal weights. There were no significant effects on embryo-fetal viability or fetal morphology at 50 or 300 mg/kg/day.
- In rabbits at doses ≥ 30 mg/kg/day, there were adverse effects on embryo-fetal development including increased incidences of fetal abnormalities (malformations and external, visceral and skeletal variants) and fetal growth (lower fetal weights). These findings included reduced/small lung lobes, additional vessel on the descending aorta, additional vessel on the aortic arch, small eyes, diaphragmatic hernia, absent accessory lobe or (partly) fused lung lobes, reduced/small accessory lung lobe, extra/rudimentary 13th ribs, misshapen hyoid bone, bent hyoid bone alae, and reduced number of phalanges in the pollex. There was no evidence of increased incidence of embryo-fetal mortality. There was no maternal toxicity observed at 30 mg/kg/day.
- At 300 mg/kg/day in rats and 30 mg/kg/day in rabbits, the maternal systemic exposures (AUC) were approximately 0.6 and 1.5 times, respectively, the exposure in patients at the highest recommended dose of 600 mg/day.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ribociclib in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Ribociclib during labor and delivery.
### Nursing Mothers
Risk Summary
- It is not known if Ribociclib is present in human milk. There are no data on the effects of Ribociclib on the breastfed infant or on milk production. Ribociclib and its metabolites readily passed into the milk of lactating rats. Because of the potential for serious adverse reactions in breastfed infants from Ribociclib, advise lactating women not to breastfeed while taking Ribociclib and for at least 3 weeks after the last dose.
Data
- In lactating rats administered a single dose of 50 mg/kg, exposure to Ribociclib was 3.56-fold higher in milk compared to maternal plasma.
### Pediatric Use
- The safety and efficacy of Ribociclib in pediatric patients has not been established.
### Geriatic Use
- Of 334 patients who received Ribociclib in MONALEESA-2, 150 patients (45%) were ≥ 65 years of age and 35 patients (11%) were ≥ 75 years of age. Of 484 patients who received Ribociclib in MONALEESA-3, 226 patients (47%) were ≥ 65 years of age and 65 patients (14%) were ≥ 75 years of age. No overall differences in safety or effectiveness of Ribociclib were observed between these patients and younger patients.
### Gender
There is no FDA guidance on the use of Ribociclib with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Ribociclib with respect to specific racial populations.
### Renal Impairment
- Based on a population pharmacokinetic analysis, no dose adjustment is necessary in patients with mild (60 mL/min/1.73m2 ≤ estimated glomerular filtration rate (eGFR) < 90 mL/min/1.73m2) or moderate (30 mL/min/1.73m2 ≤ eGFR < 60 mL/min/1.73m2) renal impairment. Based on a renal impairment study in healthy subjects and non-cancer subjects with severe renal impairment (eGFR 15 to < 30 mL/min/1.73m2), a starting dose of 200 mg is recommended. Ribociclib has not been studied in breast cancer patients with severe renal impairment.
### Hepatic Impairment
- No dose adjustment is necessary in patients with mild hepatic impairment (Child-Pugh A). A reduced starting dose of 400 mg is recommended in patients with moderate (Child-Pugh B) and severe hepatic impairment (Child-Pugh C). Based on a pharmacokinetic trial in patients with hepatic impairment, mild hepatic impairment had no effect on the exposure of Ribociclib. The mean exposure for Ribociclib was increased less than 2-fold in patients with moderate (geometric mean ratio [GMR]: 1.44 for Cmax; 1.28 for AUCinf) and severe (GMR: 1.32 for Cmax; 1.29 for AUCinf) hepatic impairment.
### Females of Reproductive Potential and Males
Pregnancy Testing
- Based on animal studies, Ribociclib can cause fetal harm when administered to a pregnant woman. Females of reproductive potential should have a pregnancy test prior to starting treatment with Ribociclib.
Contraception
Females
- Based on animal studies, Ribociclib can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception (methods that result in less than 1% pregnancy rates) during treatment with Ribociclib and for at least 3 weeks after the last dose.
Infertility
- Based on animal studies, Ribociclib may impair fertility in males of reproductive potential.
### Immunocompromised Patients
There is no FDA guidance one the use of Ribociclib in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- If patient vomits or misses a dose, do not give an additional dose that day.
- Give with or without food.
- Give at the same time as the aromatase inhibitor, preferably in the morning.
- Swallow tablets whole, do not chew, crush, or split. Do not ingest any tablet that is broken, cracked, or not in tact.
### Monitoring
- Tumor response may indicate efficacy.
- CBC, including differential: Prior to therapy initiation, every 2 weeks for the first 2 cycles, at the start of each subsequent 4 cycles, and as clinically indicated.
- Liver function tests: Prior to therapy initiation, every 2 weeks for the first 2 cycles, at the start of each subsequent 4 cycles, and as clinically indicated.
- Pregnancy test: Prior to initiation of treatment in females with reproductive potential.
- Serum electrolytes, including potassium, calcium, phosphorus, and magnesium: Prior to therapy initiation, the start of the the first 6 cycles and as clinically indicated.
- ECG: Prior to therapy initiation, at day 14 of the first cycle, at the start of the second cycle, and as clinically indicated.
# IV Compatibility
There is limited information regarding the compatibility of Ribociclib and IV administrations.
# Overdosage
There is limited information regarding Ribociclib overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
- Ribociclib is an inhibitor of cyclin-dependent kinase (CDK) 4 and 6. These kinases are activated upon binding to D-cyclins and play a crucial role in signaling pathways which lead to cell cycle progression and cellular proliferation. The cyclin D-CDK4/6 complex regulates cell cycle progression through phosphorylation of the retinoblastoma protein (pRb).
- In vitro, Ribociclib decreased pRb phosphorylation leading to arrest in the G1 phase of the cell cycle and reduced cell proliferation in breast cancer cell lines. In vivo, treatment with single agent Ribociclib in a rat xenograft model with human tumor cells led to decreased tumor volumes, which correlated with inhibition of pRb phosphorylation. In studies using patient-derived estrogen receptor positive breast cancer xenograft models, combination of Ribociclib and antiestrogen (e.g., letrozole) resulted in increased tumor growth inhibition compared to each drug alone. Additionally, the combination of Ribociclib and fulvestrant resulted in tumor growth inhibition in an estrogen receptor positive breast cancer xenograft model.
## Structure
## Pharmacodynamics
Cardiac Electrophysiology
- Serial, triplicate ECGs were collected following a single dose and at steady-state to evaluate the effect of Ribociclib on the QTcF interval in patients with advanced cancer. A pharmacokinetic-pharmacodynamic analysis included a total of 997 patients treated with Ribociclib at doses ranging from 50 to 1200 mg. The analysis suggested that Ribociclib causes concentration-dependent increases in the QTcF interval. The estimated mean change from baseline in QTcF for Ribociclib 600 mg in combination with aromatase inhibitors or fulvestrant was 22.0 ms (90% CI: 20.6, 23.4) and 23.7 ms (90% CI: 22.3, 25.1), respectively, and was 34.7 ms (90% CI: 31.6, 37.8) in combination with tamoxifen at the geometric mean Cmax at steady-state.
## Pharmacokinetics
- Ribociclib exhibited over-proportional increases in exposure (peak plasma concentrations (Cmax) and area under the time concentration curve (AUC)) across the dose range of 50 mg to 1200 mg following both single dose and repeated doses. Following repeated 600 mg once daily administration, steady-state was generally achieved after 8 days and Ribociclib accumulated with a geometric mean accumulation ratio of 2.51 (range: 0.972 to 6.40).
Absorption
- The time to reach Cmax (Tmax) following Ribociclib administration was between 1 and 4 hours.
- Food Effect: Compared to the fasted state, oral administration of a single 600 mg dose of Ribociclib film-coated tablet with a high-fat, high-calorie meal (approximately 800 to 1000 calories with ~50% calories from fat, ~35% calories from carbohydrates, and ~15% calories from protein) had no effect on the rate and extent of absorption of Ribociclib (Cmax GMR: 1.00; 90% CI: 0.898, 1.11; AUCinf GMR: 1.06; 90% CI: 1.01, 1.12).
Distribution
- Binding of Ribociclib to human plasma proteins in vitro was approximately 70% and independent of concentration (10 to 10,000 ng/mL). Ribociclib was equally distributed between red blood cells and plasma with a mean in vivo blood-to-plasma ratio of 1.04. The apparent volume of distribution at steady-state (Vss/F) was 1090 L based on population PK analysis.
Metabolism
- In vitro and in vivo studies indicated Ribociclib undergoes extensive hepatic metabolism mainly via CYP3A4 in humans. Following oral administration of a single 600 mg dose of radio-labeled Ribociclib to humans, the primary metabolic pathways for Ribociclib involved oxidation (dealkylation, C and/or N-oxygenation, oxidation (-2H)) and combinations thereof. Phase II conjugates of Ribociclib Phase I metabolites involved N-acetylation, sulfation, cysteine conjugation, glycosylation and glucuronidation. Ribociclib was the major circulating drug-derived entity in plasma (44%). The major circulating metabolites included metabolite M13 (CCI284, N-hydroxylation), M4 (LEQ803, N-demethylation), and M1 (secondary glucuronide), each representing an estimated 9%, 9%, and 8% of total radioactivity, and 22%, 20%, and 18% of Ribociclib exposure. Clinical activity (pharmacological and safety) of Ribociclib was due primarily to parent drug, with negligible contribution from circulating metabolites.
- Ribociclib was extensively metabolized with unchanged drug accounting for 17% and 12% in feces and urine, respectively. Metabolite LEQ803 was a significant metabolite in excreta and represented approximately 14% and 4% of the administered dose in feces and urine, respectively. Numerous other metabolites were detected in both feces and urine in minor amounts (≤ 3% of the administered dose).
Elimination
- The geometric mean plasma effective half-life (based on accumulation ratio) was 32.0 hours (63% CV) and the geometric mean apparent oral clearance (CL/F) was 25.5 L/hr (66% CV) at steady-state at 600 mg in patients with advanced cancer. The geometric mean apparent plasma terminal half-life (t ½) of Ribociclib ranged from 29.7 to 54.7 hours and geometric mean CL/F of Ribociclib ranged from 39.9 to 77.5 L/hr at 600 mg across studies in healthy subjects.
- Ribociclib is eliminated mainly via feces, with a small contribution of the renal route. In 6 healthy male subjects, following a single oral dose of radio-labeled Ribociclib, 92% of the total administered radioactive dose was recovered within 22 days; feces was the major route of excretion (69%), with 23% of the dose recovered in urine.
Specific Populations
Patients with Hepatic Impairment
- Based on a pharmacokinetic trial in patients with hepatic impairment, mild (Child-Pugh class A) hepatic impairment had no effect on the exposure of Ribociclib. The mean exposure for Ribociclib was increased less than 2-fold in patients with moderate (Child-Pugh class B; geometric mean ratio [GMR]: 1.44 for Cmax; 1.28 for AUCinf) and severe (Child-Pugh class C; GMR: 1.32 for Cmax; 1.29 for AUCinf) hepatic impairment. Based on a population pharmacokinetic analysis that included 160 patients with normal hepatic function and 47 patients with mild hepatic impairment, mild hepatic impairment had no effect on the exposure of Ribociclib, further supporting the findings from the dedicated hepatic impairment study.
Patients with Renal Impairment
- Mild (60 mL/min/1.73m2 ≤ eGFR < 90 mL/min/1.73m2) and moderate (30 mL/min/1.73m2 ≤ eGFR < 60 mL/min/1.73m2) renal impairment had no effect on the exposure of Ribociclib based on a population PK analysis.
- The effect of renal impairment on the pharmacokinetics of Ribociclib was assessed in a renal impairment study in non-cancer subjects with normal renal function (eGFR ≥ 90 mL/min/1.73 m2), severe renal impairment (eGFR 15 to < 30 mL/min/1.73 m2), and End Stage Renal Disease (ESRD; eGFR < 15 mL/min/1.73 m2). In subjects with severe renal impairment, AUCinf increased by 1.96 fold, and Cmax increased by 1.51 fold compared to subjects with normal renal function.
Effect of Age, Weight, Gender, and Race
- Population PK analysis showed that there are no clinically relevant effects of age, body weight, gender, or race on the systemic exposure of Ribociclib.
Drug Interaction Studies
Drugs That Affect Ribociclib Plasma Concentrations
- CYP3A Inhibitors: A drug interaction trial in healthy subjects was conducted with ritonavir (a strong CYP3A inhibitor). Compared to Ribociclib alone, ritonavir (100 mg twice a day for 14 days) increased Ribociclib Cmax and AUCinf by 1.7-fold and 3.2-fold, respectively, following a single 400 mg Ribociclib dose. Cmax and AUC for LEQ803 (a prominent metabolite of LEE011, accounting for less than 10% of parent exposure) decreased by 96% and 98%, respectively. A moderate CYP3A4 inhibitor (erythromycin) is predicted to increase Ribociclib Cmax and AUC by 1.3-fold and 1.9-fold, respectively.
- CYP3A Inducers: A drug interaction trial in healthy subjects was conducted with rifampicin (a strong CYP3A4 inducer). Compared to Ribociclib alone, rifampicin (600 mg daily for 14 days) decreased Ribociclib Cmax and AUCinf by 81% and 89%, respectively, following a single 600 mg Ribociclib dose. LEQ803 Cmax increased 1.7-fold and AUCinf decreased by 27%, respectively. A moderate CYP3A inducer (efavirenz) is predicted to decrease Ribociclib Cmax and AUC by 37% and 60%, respectively.
Drugs that are Affected by Ribociclib
- CYP3A4 and CYP1A2 Substrates: A drug interaction trial in healthy subjects was conducted as a cocktail study with midazolam (sensitive CYP3A4 substrate) and caffeine (sensitive CYP1A2 substrate). Compared to midazolam and caffeine alone, multiple doses of Ribociclib (400 mg once daily for 8 days) increased midazolam Cmax and AUCinf by 2.1-fold and 3.8-fold, respectively. Administration of Ribociclib at 600 mg once daily is predicted to increase midazolam Cmax and AUC by 2.4-fold and 5.2-fold, respectively. The effect of multiple doses of 400 mg Ribociclib on caffeine was minimal, with Cmax decreased by 10% and AUCinf increased slightly by 20%. Only weak inhibitory effects on CYP1A2 substrates are predicted at 600 mg Ribociclib once daily dose.
- Gastric pH-elevating Agents: Coadministration of Ribociclib with drugs that elevate the gastric pH was not evaluated in a clinical trial; however, altered Ribociclib absorption was not identified in a population PK analysis and was not predicted using physiology based PK models.
- Letrozole: Data from a clinical trial in patients with breast cancer and population PK analysis indicated no drug interaction between Ribociclib and letrozole following coadministration of the drugs.
- Anastrozole: Data from a clinical trial in patients with breast cancer indicated no clinically relevant drug interaction between Ribociclib and anastrozole following coadministration of the drugs.
- Exemestane: Data from a clinical trial in patients with breast cancer indicated no clinically relevant drug interaction between Ribociclib and exemestane following coadministration of the drugs.
- Fulvestrant: Data from a clinical trial in patients with breast cancer indicated no clinically relevant effect of fulvestrant on Ribociclib exposure following coadministration of the drugs.
- Tamoxifen: Ribociclib is not indicated for concomitant use with tamoxifen. Data from a clinical trial in patients with breast cancer indicated that tamoxifen Cmax and AUC increased approximately 2-fold following coadministration of 600 mg Ribociclib.
In vitro Studies
- Effect of Ribociclib on CYP Enzymes: In vitro, Ribociclib was a reversible inhibitor of CYP1A2, CYP2E1 and CYP3A4/5 and a time-dependent inhibitor of CYP3A4/5, at clinically relevant concentrations. In vitro evaluations indicated that Ribociclib has no potential to inhibit the activities of CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6 at clinically relevant concentrations. It has no potential for time-dependent inhibition of CYP1A2, CYP2C9, and CYP2D6, and no induction of CYP1A2, CYP2B6, CYP2C9 and CYP3A4 at clinically relevant concentrations.
- Effect of Ribociclib on Transporters: In vitro evaluations indicated that Ribociclib has a low potential to inhibit the activities of drug transporters P-gp, OATP1B1/B3, OCT1, MATEK2 at clinically relevant concentrations. Ribociclib may inhibit BCRP, OCT2, MATE1, and human BSEP at clinically relevant concentrations.
- Effect of Transporters on Ribociclib: Based on in vitro data, P-gp and BCRP mediated transport are unlikely to affect the extent of oral absorption of Ribociclib at therapeutic doses. Ribociclib is not a substrate for hepatic uptake transporters OATP1B1/1B3 or OCT-1 in vitro.
## Nonclinical Toxicology
- Carcinogenesis studies have not been conducted with Ribociclib.
- Ribociclib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay or clastogenic in an in vitro human lymphocyte chromosomal aberration assay or an in vivo rat bone marrow micronucleus assay.
- In a fertility and early embryonic development study, female rats received oral doses of Ribociclib for 14 days prior to mating through the first week of pregnancy. Ribociclib did not affect reproductive function, fertility or early embryonic development at doses up to 300 mg/kg/day (approximately 0.6 times the clinical exposure in patients at the highest recommended dose of 600 mg/day based on AUC).
- A fertility study in male rats has not been performed with Ribociclib. In repeat-dose toxicity studies with oral administration of Ribociclib daily for 3 weeks on /1 week off in rats up to 26 weeks duration and dogs up to 39 weeks duration, atrophic changes in testes were reported. Findings included degeneration of seminiferous tubular epithelia in the testes and hypospermia and luminal cellular debris in the epididymides of rats and dogs and vacuolation of epithelia in the epididymides of rats. These findings were observed at doses ≥ 75 mg/kg in rats and ≥ 1 mg/kg in dogs which resulted in systemic exposures that were 1.4 and 0.03 times the human exposure at the highest recommended daily dose of 600 mg/day based on AUC, respectively. These effects can be linked to a direct anti-proliferative effect on the testicular germ cells resulting in atrophy of the seminiferous tubules and showed a trend towards reversibility in rats and dogs after a four-week non-dosing period.
- In vivo cardiac safety studies in dogs demonstrated dose and concentration related QTc interval prolongation at an exposure similar to patients receiving the recommended dose of 600 mg. There is a potential to induce incidences of premature ventricular contractions (PVCs) at elevated exposures (approximately 5-fold the anticipated clinical Cmax).
# Clinical Studies
- Postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer for initial endocrine based therapy.
- MONALEESA-2 was a randomized, double-blind, placebo-controlled, multicenter clinical study of Ribociclib plus letrozole vs. placebo plus letrozole conducted in postmenopausal women with HR-positive, HER2-negative, advanced breast cancer who received no prior therapy for advanced disease.
- A total of 668 patients were randomized to receive either Ribociclib plus letrozole (n = 334) or placebo plus letrozole (n = 334), stratified according to the presence of liver and/or lung metastases. Letrozole 2.5 mg was given orally once daily for 28 days, with either Ribociclib 600 mg or placebo orally once daily for 21 consecutive days followed by 7 days off until disease progression or unacceptable toxicity. The major efficacy outcome measure for the study was investigator-assessed progression-free survival (PFS) using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
- Patients enrolled in MONALEESA-2 had a median age of 62 years (range 23 to 91) and 45% of patients were older than 65. The majority of patients were White (82%), and all patients had an ECOG performance status of 0 or 1. A total of 47% of patients had received chemotherapy and 51% had received antihormonal therapy in the neoadjuvant or adjuvant setting. Thirty-four percent (34%) of patients had de novo metastatic disease, 21% had bone only disease, and 59% had visceral disease.
- The efficacy results from MONALEESA-2 are summarized in Table 12 and Figure 1. The results shown are from a pre-planned interim efficacy analysis of PFS. Results were consistent across patient subgroups of prior adjuvant or neoadjuvant chemotherapy or hormonal therapies, liver and/or lung involvement, and bone-only metastatic disease. The PFS assessment based on a blinded independent central radiological review was consistent with investigator assessment. At the time of the PFS analysis, 6.5% of patients had died, and overall survival data were immature.
- Pre/perimenopausal patients with HR-positive, HER2-negative advanced or metastatic breast cancer for initial endocrine based therapy.
- MONALEESA-7 was a randomized, double-blind, placebo-controlled study of Ribociclib plus either a non-steroidal aromatase inhibitor (NSAI) or tamoxifen and goserelin vs. placebo plus either a NSAI or tamoxifen and goserelin conducted in pre/perimenopausal women with HR-positive, HER2-negative, advanced breast cancer who received no prior endocrine therapy for advanced disease.
- A total of 672 patients were randomized to receive Ribociclib plus NSAI or tamoxifen plus goserelin (n = 335) or placebo plus NSAI or tamoxifen plus goserelin (n = 337), stratified according to the presence of liver and/or lung metastases, prior chemotherapy for advanced disease and endocrine combination partner (tamoxifen and goserelin vs. NSAI and goserelin). NSAI (letrozole 2.5 mg or anastrozole 1 mg) or tamoxifen 20 mg were given orally once daily on a continuous daily schedule, goserelin was administered as a sub-cutaneous injection on Day 1 of each 28 day cycle, with either Ribociclib 600 mg or placebo orally once daily for 21 consecutive days followed by 7 days off until disease progression or unacceptable toxicity. The major efficacy outcome measure for the study was investigator-assessed progression-free survival (PFS) using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
- Patients enrolled in MONALEESA-7 had a median age of 44 years (range 25 to 58) and were primarily Caucasian (58%), Asian (29%), or Black (3%). Nearly all patients (99%) had an ECOG performance status of 0 or 1. Of the 672 patients, 33% had received chemotherapy in the adjuvant vs. 18% in the neoadjuvant setting and 40% had received endocrine therapy in the adjuvant vs. 0.7% in the neoadjuvant setting prior to study entry. Forty percent (40%) of patients had de novo metastatic disease, 24% had bone only disease, and 57% had visceral disease. Demographics and baseline disease characteristics were balanced and comparable between study arms, and endocrine combination partner.
- The efficacy results from a pre-specified subgroup analysis of 495 patients who had received Ribociclib or placebo with NSAI plus goserelin are summarized in Table 13 and Figure 2. Consistent results were observed in stratification factor subgroups of disease site and prior chemotherapy for advanced disease. Overall survival data were immature with 13% deaths.
- Postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer for initial endocrine based therapy or after disease progression on endocrine therapy.
- MONALEESA-3 was a randomized double-blind, placebo-controlled study of Ribociclib in combination with fulvestrant for the treatment of postmenopausal women with hormone receptor positive, HER2-negative, advanced breast cancer who have received no or only one line of prior endocrine treatment.
- A total of 726 patients were randomized in a 2:1 ratio to receive Ribociclib 600 mg and fulvestrant (n = 484) or placebo and fulvestrant (n = 242), stratified according to the presence of liver and/or lung metastases and prior endocrine therapy for advanced or metastatic disease. Fulvestrant 500 mg was administered intramuscularly on Days 1, 15, 29, and once monthly thereafter, with either Ribociclib 600 mg or placebo given orally once daily for 21 consecutive days followed by 7 days off until disease progression or unacceptable toxicity. The major efficacy outcome measure for the study was investigator-assessed progression-free survival (PFS) using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
- Patients enrolled in this study had a median age of 63 years (range 31 to 89). Of the patients enrolled, 47% were 65 years and older, including 14% age 75 years and older. The patients enrolled were primarily Caucasian (85%), Asian (9%), and Black (0.7%). Nearly all patients (99.7%) had an ECOG performance status of 0 or 1. First and second line patients were enrolled in this study (of which 19% had de novo metastatic disease). Forty-three percent (43%) of patients had received chemotherapy in the adjuvant vs. 13% in the neoadjuvant setting and 59% had received endocrine therapy in the adjuvant vs. 1% in the neoadjuvant setting prior to study entry. Twenty-one percent (21%) of patients had bone only disease and 61% had visceral disease. Demographics and baseline disease characteristics were balanced and comparable between study arms.
- The efficacy results from MONALEESA-3 are summarized in Table 14 and Figure 3. Consistent results were observed in stratification factor subgroups of disease site and prior endocrine treatment for advanced disease. At the time of the PFS analysis, 17% of patients had died, and overall survival data were immature.
# How Supplied
- Each film-coated tablet contains 200 mg of Ribociclib free base.
- Light greyish violet, round, curved with beveled edge, debossed with “RIC” on one side and “NVR” on the other side; available in:
- Blister pack (21 tablets) – each blister pack contains 21 tablets (200 mg per tablet) (600 mg daily dose). Outer container - 3 Blister packs per outer container NDC 0078-0874-63
- Blister pack (14 tablets) – each blister pack contains 14 tablets (200 mg per tablet) (400 mg daily dose). Outer container - 3 Blisters packs per outer container NDC 0078-0867-42
- Blister pack (21 tablets) – each blister pack contains 21 tablets (200 mg per tablet) (200 mg daily dose). Outer container – 1 Blister pack per outer container NDC 0078-0860-01
## Storage
- Store at 20°C to 25°C (68°F to 77°F). Store in the original package.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
QT Prolongation
- Inform patients of the signs and symptoms of QT prolongation. Advise patients to contact their healthcare provider immediately for signs or symptoms of QT prolongation.
Hepatobiliary Toxicity
- Inform patients of the signs and symptoms of hepatobiliary toxicity. Advise patients to contact their healthcare provider immediately for signs or symptoms of hepatobiliary toxicity.
Neutropenia
- Advise patients of the possibility of developing neutropenia and to immediately contact their healthcare provider should they develop a fever, particularly in association with any suggestion of infection.
Embryo-Fetal Toxicity
- Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during Ribociclib therapy and for at least 3 weeks after the last dose. Advise females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment with Ribociclib.
Lactation
- Advise lactating women not to breastfeed during treatment with Ribociclib and for at least 3 weeks after the last dose.
Drug Interactions
- Inform patients to avoid grapefruit or grapefruit juice while taking Ribociclib.
- Inform patients to avoid strong CYP3A inhibitors, strong CYP3A inducers, and drugs known to prolong the QT interval.
Dosing
- Instruct patients to take the doses of Ribociclib at approximately the same time every day and to swallow whole (do not chew, crush, or split them prior to swallowing).
- If patient vomits or misses a dose, advise the patient to take the next prescribed dose at the usual time.
- Advise the patient that Ribociclib may be taken with or without food.
# Precautions with Alcohol
Alcohol-Ribociclib interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
- Kisqali
# Look-Alike Drug Names
There is limited information regarding Ribociclib Look-Alike Drug Names in the drug label.
# Drug Shortage Status
Drug Shortage
# Price | https://www.wikidoc.org/index.php/Ribociclib | |
b8972a8cb02301a527997c1ae5cceede34cde31c | wikidoc | Riboflavin | Riboflavin
# Overview
Riboflavin (E101), also known as vitamin B2, is an easily absorbed micronutrient with a key role in maintaining health in animals. It is the central component of the cofactors FAD and FMN, and is therefore required by all flavoproteins. As such, vitamin B2 is required for a wide variety of cellular processes. Like the other B vitamins, it plays a key role in energy metabolism, and is required for the metabolism of fats, carbohydrates, and proteins.
Milk, cheese, leafy green vegetables, liver, legumes such as mature soybeans , yeast and almonds are good sources of vitamin B2, but exposure to light destroys riboflavin.
# Toxicity
Riboflavin is not toxic when taken orally, as its low solubility keeps it from being absorbed in dangerous amounts from the gut . Although toxic doses can be administered by injection, any excess at nutritionally relevant doses is excreted in the urine, imparting a bright yellow color when in large quantities.
# Industrial synthesis
Various biotechnological processes have been developed for industrial scale riboflavin biosynthesis using different microorganisms, including filamentous fungi such as Ashbya gossypii, Candida famata and Candida flaveri as well as the bacteria Corynebacterium ammoniagenes and Bacillus subtilis. The latter organism has been genetically modified to both increase the bacteria's production of riboflavin and to introduce an antibiotic (ampicillin) resistance marker, and is now successfully employed at a commercial scale to produce riboflavin for feed and food fortification purposes. The chemical company BASF has installed a plant in South Korea, which is specialized on riboflavin production using Ashbya gossypii. The concentrations of riboflavin in their modified strain are so high, that the mycelium has a reddish / brownish color and accumulates riboflavin crystals in the vacuoles, which will eventually burst the mycelium.
# Riboflavin in food
Riboflavin is yellow or orange-yellow in color and in addition to being used as a food coloring it is also used to fortify some foods. It is used in baby foods, breakfast cereals, pastas, sauces, processed cheese, fruit drinks, vitamin-enriched milk products, some energy drinks, and is widely used in vitamin supplements.
Large quantities of riboflavin are often included in multi-vitamins; often, the dose is far more than a normal human can use in a day. The excess is excreted in the urine, causing the urine to be colored bright yellow within a few hours of ingestion of the vitamin.
It is difficult to incorporate riboflavin into many liquid products because it has poor solubility in water. Hence the requirement for riboflavin-5'-phosphate (E101a), a more expensive but more soluble form of riboflavin.
# Nutrition
## Riboflavin deficiency
Riboflavin is continuously excreted in the urine of healthy individuals, making deficiency relatively common when dietary intake is insufficient. However, riboflavin deficiency is always accompanied by deficiency of other vitamins.
A deficiency of riboflavin can be primary - poor vitamin sources in one's daily diet - or secondary, which may be a result of conditions that affect absorption in the intestine, the body not being able to use the vitamin, or an increase in the excretion of the vitamin from the body.
In humans, signs and symptoms of riboflavin deficiency (ariboflavinosis) include cracked and red lips, inflammation of the lining of mouth and tongue, mouth ulcers, cracks at the corners of the mouth (angular cheilitis), and a sore throat. A deficiency may also cause dry and scaling skin, fluid in the mucous membranes, and iron-deficiency anemia. The eyes may also become bloodshot, itchy, watery and sensitive to bright light.
Riboflavin deficiency is classically associated with the oral-ocular-genital syndrome. Angular cheilitis, photophobia, and scrotal dermatitis are the classic remembered signs.
In animals, riboflavin deficiency results in lack of growth, failure to thrive, and eventual death. Experimental riboflavin deficiency in dogs results in growth failure, weakness, ataxia, and inability to stand. The animals collapse, become comatose, and die. During the deficiency state, dermatitis develops together with hair-loss. Other signs include corneal opacity, lenticular cataracts, hemorrhagic adrenals, fatty degeneration of the kidney and liver, and inflammation of the mucus membrane of the gastrointestinal tract. Post-mortem studies in rhesus monkeys fed a riboflavin-deficient diet revealed that about one-third the normal amount of riboflavin was present in the liver, which is the main storage organ for riboflavin in mammals. These overt clinical signs of riboflavin deficiency are rarely seen among inhabitants of the developed countries. However, about 28 million Americans exhibit a common ‘sub-clinical’ stage, characterized by a change in biochemical indices (e.g. reduced plasma erythrocyte glutathione reductase levels). Although the effects of long-term sub-clinical riboflavin deficiency are unknown, in children this deficiency results in reduced growth. Subclinical riboflavin deficiency has also been observed in women taking oral contraceptives, in the elderly, in people with eating disorders, and in disease states such as HIV, inflammatory bowel disease, diabetes and chronic heart disease. The fact that riboflavin deficiency does not immediately lead to gross clinical manifestations indicates that the systemic levels of this essential vitamin are tightly regulated.
## Diagnostic Testing of B2 Deficiency
A positive diagnostic test for measuring levels of riboflavin in serum is ascertained by measuring erythrocyte levels of glutathione reductase.
# Clinical Uses
Riboflavin has been used in several clinical and therapeutic situations. For over 30 years, riboflavin supplements have been used as part of the phototherapy treatment of neonatal jaundice. The light used to irradiate the infants breaks down not only the toxin causing the jaundice, but the naturally occurring riboflavin within the infant's blood as well.
More recently there has been growing evidence that supplemental riboflavin may be a useful additive along with beta-blockers in the treatment of migraine headaches.
Development is underway to use riboflavin to improve the safety of transfused blood by reducing pathogens found in collected blood. Riboflavin attaches itself to the nucleic acids (DNA and RNA) in cells, and when light is applied, the nucleic acids are broken, effectively killing those cells. The technology has been shown to be effective for inactivating pathogens in all three major blood components: (platelets, red blood cells, and plasma). It has been shown to inactivate a broad spectrum of pathogens, including known and emerging viruses, bacteria, and parasites.
Recently riboflavin has been used in a new treatment to slow or stop the progression of the corneal disorder keratoconus. This is called corneal collagen crosslinking (C3R). In corneal crosslinking, riboflavin drops are applied to the patient’s corneal surface. Once the riboflavin has penetrated through the cornea, Ultraviolet A light therapy is applied. This induces collagen crosslinking, which increases the tensile strength of the cornea. The treatment has been shown in several studies to stabilise keratoconus.
## Industrial Uses
Because riboflavin is fluorescent under UV light, dilute solutions (0.015-0.025% w/w) are often used to detect leaks or to demonstrate cleanability in an industrial system such a chemical blend tank or bioreactor. (See the ASME BPE section on Testing and Inspection for additional details.)
## Good sources
Riboflavin is found naturally in asparagus, bananas, okra, chard, cottage cheese, milk, yogurt, meat, eggs, and fish, each of which contain at least 0.1 mg of the vitamin per 3-10.5 oz (85-300 g) serving. | Riboflavin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:
# Overview
Template:Chembox new
Riboflavin (E101), also known as vitamin B2, is an easily absorbed micronutrient with a key role in maintaining health in animals. It is the central component of the cofactors FAD and FMN, and is therefore required by all flavoproteins. As such, vitamin B2 is required for a wide variety of cellular processes. Like the other B vitamins, it plays a key role in energy metabolism, and is required for the metabolism of fats, carbohydrates, and proteins.
Milk, cheese, leafy green vegetables, liver, legumes such as mature soybeans [1], yeast and almonds are good sources of vitamin B2, but exposure to light destroys riboflavin.
# Toxicity
Riboflavin is not toxic when taken orally, as its low solubility keeps it from being absorbed in dangerous amounts from the gut [2]. Although toxic doses can be administered by injection[2], any excess at nutritionally relevant doses is excreted in the urine[3], imparting a bright yellow color when in large quantities.
# Industrial synthesis
Various biotechnological processes have been developed for industrial scale riboflavin biosynthesis using different microorganisms, including filamentous fungi such as Ashbya gossypii, Candida famata and Candida flaveri as well as the bacteria Corynebacterium ammoniagenes and Bacillus subtilis[4]. The latter organism has been genetically modified to both increase the bacteria's production of riboflavin and to introduce an antibiotic (ampicillin) resistance marker, and is now successfully employed at a commercial scale to produce riboflavin for feed and food fortification purposes. The chemical company BASF has installed a plant in South Korea, which is specialized on riboflavin production using Ashbya gossypii. The concentrations of riboflavin in their modified strain are so high, that the mycelium has a reddish / brownish color and accumulates riboflavin crystals in the vacuoles, which will eventually burst the mycelium.
# Riboflavin in food
Riboflavin is yellow or orange-yellow in color and in addition to being used as a food coloring it is also used to fortify some foods. It is used in baby foods, breakfast cereals, pastas, sauces, processed cheese, fruit drinks, vitamin-enriched milk products, some energy drinks, and is widely used in vitamin supplements.
Large quantities of riboflavin are often included in multi-vitamins; often, the dose is far more than a normal human can use in a day. The excess is excreted in the urine, causing the urine to be colored bright yellow within a few hours of ingestion of the vitamin.
It is difficult to incorporate riboflavin into many liquid products because it has poor solubility in water. Hence the requirement for riboflavin-5'-phosphate (E101a), a more expensive but more soluble form of riboflavin.
# Nutrition
## Riboflavin deficiency
Riboflavin is continuously excreted in the urine of healthy individuals[1], making deficiency relatively common when dietary intake is insufficient. However, riboflavin deficiency is always accompanied by deficiency of other vitamins[1].
A deficiency of riboflavin can be primary - poor vitamin sources in one's daily diet - or secondary, which may be a result of conditions that affect absorption in the intestine, the body not being able to use the vitamin, or an increase in the excretion of the vitamin from the body.
In humans, signs and symptoms of riboflavin deficiency (ariboflavinosis) include cracked and red lips, inflammation of the lining of mouth and tongue, mouth ulcers, cracks at the corners of the mouth (angular cheilitis), and a sore throat. A deficiency may also cause dry and scaling skin, fluid in the mucous membranes, and iron-deficiency anemia. The eyes may also become bloodshot, itchy, watery and sensitive to bright light.
Riboflavin deficiency is classically associated with the oral-ocular-genital syndrome. Angular cheilitis, photophobia, and scrotal dermatitis are the classic remembered signs.
In animals, riboflavin deficiency results in lack of growth, failure to thrive, and eventual death. Experimental riboflavin deficiency in dogs results in growth failure, weakness, ataxia, and inability to stand. The animals collapse, become comatose, and die. During the deficiency state, dermatitis develops together with hair-loss. Other signs include corneal opacity, lenticular cataracts, hemorrhagic adrenals, fatty degeneration of the kidney and liver, and inflammation of the mucus membrane of the gastrointestinal tract. Post-mortem studies in rhesus monkeys fed a riboflavin-deficient diet revealed that about one-third the normal amount of riboflavin was present in the liver, which is the main storage organ for riboflavin in mammals. These overt clinical signs of riboflavin deficiency are rarely seen among inhabitants of the developed countries. However, about 28 million Americans exhibit a common ‘sub-clinical’ stage, characterized by a change in biochemical indices (e.g. reduced plasma erythrocyte glutathione reductase levels). Although the effects of long-term sub-clinical riboflavin deficiency are unknown, in children this deficiency results in reduced growth. Subclinical riboflavin deficiency has also been observed in women taking oral contraceptives, in the elderly, in people with eating disorders, and in disease states such as HIV, inflammatory bowel disease, diabetes and chronic heart disease. The fact that riboflavin deficiency does not immediately lead to gross clinical manifestations indicates that the systemic levels of this essential vitamin are tightly regulated.
## Diagnostic Testing of B2 Deficiency
A positive diagnostic test for measuring levels of riboflavin in serum is ascertained by measuring erythrocyte levels of glutathione reductase.
# Clinical Uses
Riboflavin has been used in several clinical and therapeutic situations. For over 30 years, riboflavin supplements have been used as part of the phototherapy treatment of neonatal jaundice. The light used to irradiate the infants breaks down not only the toxin causing the jaundice, but the naturally occurring riboflavin within the infant's blood as well.
More recently there has been growing evidence that supplemental riboflavin may be a useful additive along with beta-blockers in the treatment of migraine headaches.
Development is underway to use riboflavin to improve the safety of transfused blood by reducing pathogens found in collected blood. Riboflavin attaches itself to the nucleic acids (DNA and RNA) in cells, and when light is applied, the nucleic acids are broken, effectively killing those cells. The technology has been shown to be effective for inactivating pathogens in all three major blood components: (platelets, red blood cells, and plasma). It has been shown to inactivate a broad spectrum of pathogens, including known and emerging viruses, bacteria, and parasites.
Recently riboflavin has been used in a new treatment to slow or stop the progression of the corneal disorder keratoconus. This is called corneal collagen crosslinking (C3R). In corneal crosslinking, riboflavin drops are applied to the patient’s corneal surface. Once the riboflavin has penetrated through the cornea, Ultraviolet A light therapy is applied. This induces collagen crosslinking, which increases the tensile strength of the cornea. The treatment has been shown in several studies to stabilise keratoconus.
## Industrial Uses
Because riboflavin is fluorescent under UV light, dilute solutions (0.015-0.025% w/w) are often used to detect leaks or to demonstrate cleanability in an industrial system such a chemical blend tank or bioreactor. (See the ASME BPE section on Testing and Inspection for additional details.)
## Good sources
Riboflavin is found naturally in asparagus, bananas, okra, chard, cottage cheese, milk, yogurt, meat, eggs, and fish, each of which contain at least 0.1 mg of the vitamin per 3-10.5 oz (85-300 g) serving. | https://www.wikidoc.org/index.php/Riboflavin | |
b75cf445952b3c3ca102f41d6c50b51e9e42f8d6 | wikidoc | Rilonacept | Rilonacept
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Rilonacept is an interleukin-1 blocker that is FDA approved for the treatment of cryopyrin-associated periodic syndromes (CAPS), including familial cold auto-inflammatory syndrome (FCAS) and muckle-wells syndrome (MWS) in adults and children 12 and older. Common adverse reactions include injection-site reactions and upper respiratory tract infections.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Treatment should be initiated with a loading dose of 320 mg delivered as two, 2 mL, subcutaneous injections of 160 mg each given on the same day at two different sites. Dosing should be continued with a once-weekly injection of 160 mg administered as a single, 2-mL, subcutaneous injection. ARCALYST should not be given more often than once weekly. Dosage modification is not required based on advanced age or gender.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Rilonacept in adult patients.
### Non–Guideline-Supported Use
- Rilonacept 80 mg subQ once weekly with a 160-mg loading dose for 16 weeks.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Treatment should be initiated with a loading dose of 4.4 mg/kg, up to a maximum of 320 mg, delivered as one or two subcutaneous injections with a maximum single-injection volume of 2 mL. Dosing should be continued with a once-weekly injection of 2.2 mg/kg, up to a maximum of 160 mg, administered as a single subcutaneous injection, up to 2 mL. If the initial dose is given as two injections, they should be given on the same day at two different sites. ARCALYST should not be given more often than once weekly.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Rilonacept in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Rilonacept in pediatric patients.
# Contraindications
- None.
# Warnings
### Precautions
- Infections
- Interleukin -1 (IL-1) blockade may interfere with the immune response to infections. Treatment with another medication that works through inhibition of IL-1 has been associated with an increased risk of serious infections, and serious infections have been reported in patients taking ARCALYST. There was a greater incidence of infections in patients on ARCALYST compared with placebo. In the controlled portion of the study, one infection was reported as severe, which was bronchitis in a patient on ARCALYST.
- In an open-label extension study, one patient developed bacterial meningitis and died. ARCALYST should be discontinued if a patient develops a serious infection. Treatment with ARCALYST should not be initiated in patients with an active or chronic infection.
- In clinical studies, ARCALYST has not been administered concomitantly with tumor necrosis factor (TNF) inhibitors. An increased incidence of serious infections has been associated with administration of an IL-1 blocker in combination with TNF inhibitors. Taking ARCALYST with TNF inhibitors is not recommended because this may increase the risk of serious infections.
- Drugs that affect the immune system by blocking TNF have been associated with an increased risk of reactivation of latent tuberculosis (TB). It is possible that taking drugs such as ARCALYST that block IL-1 increases the risk of TB or other atypical or opportunistic infections. Healthcare providers should follow current CDC guidelines both to evaluate for and to treat possible latent tuberculosis infections before initiating therapy with ARCALYST.
- Immunosuppression
- The impact of treatment with ARCALYST on active and/or chronic infections and the development of malignancies is not known. However, treatment with immunosuppressants, including ARCALYST, may result in an increase in the risk of malignancies.
- Immunizations
- Since no data are available on either the efficacy of live vaccines or on the risks of secondary transmission of infection by live vaccines in patients receiving ARCALYST, live vaccines should not be given concurrently with ARCALYST. In addition, because ARCALYST may interfere with normal immune response to new antigens, vaccinations may not be effective in patients receiving ARCALYST. No data are available on the effectiveness of vaccination with inactivated (killed) antigens in patients receiving ARCALYST.
- Because IL-1 blockade may interfere with immune response to infections, it is recommended that prior to initiation of therapy with ARCALYST adult and pediatric patients receive all recommended vaccinations, as appropriate, including pneumococcal vaccine and inactivated influenza vaccine.
- Lipid Profile Changes
- Patients should be monitored for changes in their lipid profiles and provided with medical treatment if warranted.
- Hypersensitivity
- Hypersensitivity reactions associated with ARCALYST administration in the clinical studies were rare. If a hypersensitivity reaction occurs, administration of ARCALYST should be discontinued and appropriate therapy initiated.
# Adverse Reactions
## Clinical Trials Experience
- Part A of the clinical trial was conducted in patients with CAPS who were naïve to treatment with ARCALYST. Part A of the study was a randomized, double-blind, placebo-controlled, six-week study comparing ARCALYST to placebo. Table 1 reflects the frequency of adverse events reported by at least two patients during Part A.
- Injection-Site Reactions
- In patients with CAPS, the most common and consistently reported adverse event associated with ARCALYST was injection-site reaction (ISR). The ISRs included erythema, swelling, pruritis, mass, bruising, inflammation, pain, edema, dermatitis, discomfort, urticaria, vesicles, warmth and hemorrhage. Most injection-site reactions lasted for one to two days. No ISRs were assessed as severe, and no patient discontinued study participation due to an ISR.
- Infections
- During Part A, the incidence of patients reporting infections was greater with ARCALYST (48%) than with placebo (17%). In Part B, randomized withdrawal, the incidence of infections were similar in the ARCALYST (18%) and the placebo patients (22%). Part A of the trial was initiated in the winter months, while Part B was predominantly performed in the summer months.
- In placebo-controlled studies across a variety of patient populations encompassing 360 patients treated with rilonacept and 179 treated with placebo, the incidence of infections was 34% and 27% (2.15 per patient-exposure year and 1.81 per patient-exposure year), respectively, for rilonacept and placebo.
- Serious Infections: One patient receiving ARCALYST for an unapproved indication in another study developed an infection in his olecranon bursa with Mycobacterium intracellulare. The patient was on chronic glucocorticoid treatment. The infection occurred after an intraarticular glucocorticoid injection into the bursa with subsequent local exposure to a suspected source of mycobacteria. The patient recovered after the administration of the appropriate antimicrobial therapy. One patient treated for another unapproved indication developed bronchitis/sinusitis, which resulted in hospitalization. One patient died in an open-label study of CAPS from Streptococcus pneumoniae meningitis.
- Hematologic Events
- One patient in a study in an unapproved indication developed transient neutropenia (ANC < 1 x 109/L) after receiving a large dose (2000 mg intravenously) of ARCALYST. The patient did not experience any infection associated with the neutropenia.
- Immunogenicity
- Antibodies directed against the receptor domains of rilonacept were detected by an ELISA assay in patients with CAPS after treatment with ARCALYST. Nineteen of 55 patients (35%) who had received ARCALYST for at least 6 weeks tested positive for treatment-emergent binding antibodies on at least one occasion. Of the 19, seven tested positive at the last assessment (Week 18 or 24 of the open-label extension period), and five patients tested positive for neutralizing antibodies on at least one occasion. There was no correlation of antibody activity and either clinical effectiveness or safety.
- The data reflect the percentage of patients whose test results were positive for antibodies to the rilonacept receptor domains in specific assays, and are highly dependent on the sensitivity and specificity of the assays. The observed incidence of antibody (including neutralizing antibody) positivity in an assay is highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to rilonacept with the incidence of antibodies to other products may be misleading.
- Lipid profiles
- Cholesterol and lipid levels may be reduced in patients with chronic inflammation. Patients with CAPS treated with ARCALYST experienced increases in their mean total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides. The mean increases from baseline for total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides were 19 mg/dL, 2 mg/dL, 10 mg/dL, and 57 mg/dL respectively after 6 weeks of open-label therapy. Physicians should monitor the lipid profiles of their patients (for example after 2-3 months) and consider lipid-lowering therapies as needed based upon cardiovascular risk factors and current guidelines.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Rilonacept in the drug label.
# Drug Interactions
- TNF-blocking agent and IL-1 blocking agent
- Specific drug interaction studies have not been conducted with ARCALYST. Concomitant administration of another drug that blocks IL-1 with a TNF-blocking agent in another patient population has been associated with an increased risk of serious infections and an increased risk of neutropenia. The concomitant administration of ARCALYST with TNF-blocking agents may also result in similar toxicities and is not recommended. The concomitant administration of ARCALYST with other drugs that block IL-1 has not been studied. Based upon the potential for pharmacologic interactions between rilonacept and a recombinant IL-1ra, concomitant administration of ARCALYST and other agents that block IL-1 or its receptors is not recommended.
- Cytochrome P450 Substrates
- The formation of CYP450 enzymes is suppressed by increased levels of cytokines (e.g., IL-1) during chronic inflammation. Thus it is expected that for a molecule that binds to IL-1, such as rilonacept, the formation of CYP450 enzymes could be normalized. This is clinically relevant for CYP450 substrates with a narrow therapeutic index, where the dose is individually adjusted (e.g., warfarin). Upon initiation of ARCALYST, in patients being treated with these types of medicinal products, therapeutic monitoring of the effect or drug concentration should be performed and the individual dose of the medicinal product may need to be adjusted as needed.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- There are no adequate and well-controlled studies of ARCALYST in pregnant women. Based on animal data, ARCALYST may cause fetal harm. An embryo-fetal developmental toxicity study was performed in cynomolgus monkeys treated with 0, 5, 15 or 30 mg/kg given twice a week (highest dose is approximately 3.7-fold higher than the human doses of 160 mg based on body surface area). The fetus of the only monkey with exposure to rilonacept during the later period of gestation showed multiple fusion and absence of the ribs and thoracic vertebral bodies and arches. Exposure to rilonacept during this time period was below that expected clinically. Likewise, in the cynomolgus monkey, all doses of rilonacept reduced serum levels of estradiol up to 64% compared to controls and increased the incidence of lumbar ribs compared to both control animals and historical control incidences. In perinatal and postnatal developmental toxicology studies in the mouse model using a murine analog of rilonacept (0, 20, 100 or 200 mg/kg), there was a 3-fold increase in the number of stillbirths in dams treated with 200 mg/kg three times per week (the highest dose is approximately 6-fold higher than the 160 mg maintenance dose based on body surface area). ARCALYST should be used during pregnancy only if the benefit justifies the potential risk to the fetus.
- Nonteratogenic effects. A peri- and post-natal reproductive toxicology study was performed in which mice were subcutaneously administered a murine analogue of rilonacept at doses of 20, 100, 200 mg/kg three times per week (the highest dose is approximately 6-fold higher than the 160 mg maintenance dose based on body surface area). Results indicated an increased incidence in unscheduled deaths of the F1 offspring during maturation at all doses tested.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Rilonacept in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Rilonacept during labor and delivery.
### Nursing Mothers
- It is not known whether rilonacept is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ARCALYST is administered to a nursing woman.
### Pediatric Use
- Six pediatric patients with CAPS between the ages of 12 and 16 were treated with ARCALYST at a weekly, subcutaneous dose of 2.2 mg/kg (up to a maximum of 160 mg) for 24-weeks during the open-label extension phase. These patients showed improvement from baseline in their symptom scores and in objective markers of inflammation (e.g. Serum Amyloid A and C-Reactive Protein). The adverse events included injection site reactions and upper respiratory symptoms as were commonly seen in the adult patients.
- The trough drug levels for four pediatric patients measured at the end of the weekly dose interval (mean 20 mcg/mL, range 3.6 to 33 mcg/mL) were similar to those observed in adult patients with CAPS (mean 24 mcg/mL, range 7 to 56 mcg/mL).
- Safety and effectiveness in pediatric patients below the age of 12 have not been established.
- When administered to pregnant primates, rilonacept treatment may have contributed to alterations in bone ossification in the fetus. It is not known if ARCALYST will alter bone development in pediatric patients. Pediatric patients treated with ARCALYST should undergo appropriate monitoring for growth and development.
### Geriatic Use
- In the placebo-controlled clinical studies in patients with CAPS and other indications, 70 patients randomized to treatment with ARCALYST were ≥ 65 years of age, and 6 were ≥ 75 years of age. In the CAPS clinical trial, efficacy, safety and tolerability were generally similar in elderly patients as compared to younger adults; however, only ten patients ≥ 65 years old participated in the trial. In an open-label extension study of CAPS, a 71 year old woman developed bacterial meningitis and died. Age did not appear to have a significant effect on steady-state trough concentrations in the clinical study.
### Gender
There is no FDA guidance on the use of Rilonacept with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Rilonacept with respect to specific racial populations.
### Renal Impairment
- No formal studies have been conducted to examine the pharmacokinetics of rilonacept administered subcutaneously in patients with renal impairment.
### Hepatic Impairment
- No formal studies have been conducted to examine the pharmacokinetics of rilonacept administered subcutaneously in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Rilonacept in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Rilonacept in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Subcutaneous
### Monitoring
There is limited information regarding Monitoring of Rilonacept in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Rilonacept in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- There have been no reports of overdose with ARCALYST. Maximum weekly doses of up to 320 mg have been administered subcutaneously for up to approximately 18 months in a small number of patients with CAPS and up to 6 months in patients with an unapproved indication in clinical trials without evidence of dose-limiting toxicities. In addition, ARCALYST given intravenously at doses up to 2000 mg monthly in another patient population for up to six months were tolerated without dose-limiting toxicities. The maximum amount of ARCALYST that can be safely administered has not been determined.
### Management
- In case of overdose, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects, and appropriate symptomatic treatment instituted immediately.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Rilonacept in the drug label.
# Pharmacology
## Mechanism of Action
- CAPS refer to rare genetic syndromes generally caused by mutations in the NLRP-3 gene (also known as Cold-Induced Auto-inflammatory Syndrome-1 ). CAPS disorders are inherited in an autosomal dominant pattern with male and female offspring equally affected. Features common to all disorders include fever, urticaria-like rash, arthralgia, myalgia, fatigue, and conjunctivitis.
- In most cases, inflammation in CAPS is associated with mutations in the NLRP-3 gene which encodes the protein cryopyrin, an important component of the inflammasome. Cryopyrin regulates the protease caspase-1 and controls the activation of interleukin-1 beta (IL-1β). Mutations in NLRP-3 result in an overactive inflammasome resulting in excessive release of activated IL-1β that drives inflammation.
- Rilonacept blocks IL-1β signaling by acting as a soluble decoy receptor that binds IL-1β and prevents its interaction with cell surface receptors. Rilonacept also binds IL-1α and IL-1 receptor antagonist (IL-1ra) with reduced affinity. The equilibrium dissociation constants for rilonacept binding to IL-1β, IL-1α and IL-1ra were 0.5 pM, 1.4 pM and 6.1 pM, respectively.
## Structure
- Rilonacept is a dimeric fusion protein consisting of the ligand-binding domains of the extracellular portions of the human interleukin-1 receptor component (IL-1RI) and IL-1 receptor accessory protein (IL-1RAcP) linked in-line to the Fc portion of human IgG1. Rilonacept has a molecular weight of approximately 251 kDa. Rilonacept is expressed in recombinant Chinese hamster ovary (CHO) cells.
- ARCALYST is supplied in single-use, 20-mL glass vials containing a sterile, white to off-white, lyophilized powder. Each vial of ARCALYST is to be reconstituted with 2.3 mL of Sterile Water for Injection. A volume of up to 2 mL can be withdrawn, which is designed to deliver 160 mg for subcutaneous administration only. The resulting solution is viscous, clear, colorless to pale yellow, and essentially free from particulates. Each vial contains 220 mg rilonacept. After reconstitution, each vial contains 80 mg/mL rilonacept, 46 mM histidine, 50 mM arginine, 3.0% (w/v) polyethylene glycol 3350, 2.0% (w/v) sucrose, and 1.0% (w/v) glycine at a pH of 6.5 ± 0.3. No preservatives are present.
## Pharmacodynamics
- C-Reactive Protein (CRP) and Serum Amyloid A (SAA) are indicators of inflammatory disease activity that are elevated in patients with CAPS. Elevated SAA has been associated with the development of systemic amyloidosis in patients with CAPS. Compared to placebo, treatment with ARCALYST resulted in sustained reductions from baseline in mean serum CRP and SAA to normal levels during the clinical trial. ARCALYST also normalized mean SAA from elevated levels.
## Pharmacokinetics
- The average trough levels of rilonacept were approximately 24 mcg/mL at steady-state following weekly subcutaneous doses of 160 mg for up to 48 weeks in patients with CAPS. The steady-state appeared to be reached by 6 weeks.
- No pharmacokinetic data are available in patients with hepatic or renal impairment.
- No study was conducted to evaluate the effect of age, gender, or body weight on rilonacept exposure. Based on limited data obtained from the clinical study, steady state trough concentrations were similar between male and female patients. Age (26-78 years old) and body weight (50-120 kg) did not appear to have a significant effect on trough rilonacept concentrations. The effect of race could not be assessed because only Caucasian patients participated in the clinical study, reflecting the epidemiology of the disease.
## Nonclinical Toxicology
- Long-term animal studies have not been performed to evaluate the carcinogenic potential of rilonacept. The mutagenic potential of rilonacept was not evaluated.
- Male and female fertility was evaluated in a mouse surrogate model using a murine analog of rilonacept. Male mice were treated beginning 8 weeks prior to mating and continuing through female gestation day 15. Female mice were treated for 2 weeks prior to mating and on gestation days 0, 3, and 6. The murine analog of rilonacept did not alter either male or female fertility parameters at doses up to 200 mg/kg (this dose is approximately 6-fold higher than the 160 mg maintenance dose based on body surface area).
# Clinical Studies
- The safety and efficacy of ARCALYST for the treatment of CAPS was demonstrated in a randomized, double-blind, placebo-controlled study with two parts (A and B) conducted sequentially in the same patients with FCAS and MWS.
- Part A was a 6-week, randomized, double-blind, parallel-group period comparing ARCALYST at a dose of 160 mg weekly after an initial loading dose of 320 mg to placebo. Part B followed immediately after Part A and consisted of a 9-week, patient-blind period during which all patients received ARCALYST 160 mg weekly, followed by a 9-week, double-blind, randomized withdrawal period in which patients were randomly assigned to either remain on ARCALYST 160 mg weekly or to receive placebo. Patients were then given the option to enroll in a 24-week, open-label treatment extension phase in which all patients were treated with ARCALYST 160 mg weekly.
- Using a daily diary questionnaire, patients rated the following five signs and symptoms of CAPS: joint pain, rash, feeling of fever/chills, eye redness/pain, and fatigue, each on a scale of 0 (none, no severity) to 10 (very severe). The study evaluated the mean symptom score using the change from baseline to the end of treatment.
- The changes in mean symptom scores for the randomized parallel-group period (Part A) and the randomized withdrawal period (Part B) of the study are shown in Table 2. ARCALYST-treated patients had a larger reduction in the mean symptom score in Part A compared to placebo-treated patients. In Part B, mean symptom scores increased more in patients withdrawn to placebo compared to patients who remained on ARCALYST.
- Improvement in symptom scores was noted within several days of initiation of ARCALYST therapy in most patients.
- In Part A, patients treated with ARCALYST experienced more improvement in each of the five components of the composite endpoint (joint pain, rash, feeling of fever/chills, eye redness/pain, and fatigue) than placebo-treated patients.
- In Part A, a higher proportion of patients in the ARCALYST group experienced improvement from baseline in the composite score by at least 30% (96% vs. 29% of patients), by at least 50% (87% vs. 8%) and by at least 75% (70% vs. 0%) compared to the placebo group.
- Serum Amyloid A (SAA) and C-Reactive Protein (CRP) levels are acute phase reactants that are typically elevated in patients with CAPS with active disease. During Part A, mean levels of CRP decreased versus baseline for the ARCALYST treated patients, while there was no change for those on placebo (Table 3). ARCALYST also led to a decrease in SAA versus baseline to levels within the normal range.
- During the open-label extension, reductions in mean symptom scores, serum CRP, and serum SAA levels were maintained for up to one year.
# How Supplied
- Each 20-mL glass vial of ARCALYST contains a sterile, white to off-white, preservative-free, lyophilized powder. ARCALYST is supplied in a carton containing four vials (NDC 61755-001-01).
- The lyophilized ARCALYST product is to be stored refrigerated at 2° to 8°C (36° to 46°F) inside the original carton to protect from light. Do not use beyond the date stamped on the label. After reconstitution, ARCALYST may be kept at room temperature, should be kept from light, and should be used within three hours of reconstitution. ARCALYST does not contain preservatives; therefore, unused portions of ARCALYST should be discarded. Discard the vial after a single withdrawal of drug.
## Storage
There is limited information regarding Rilonacept Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- The first injection of ARCALYST should be performed under the supervision of a qualified healthcare professional. If a patient or caregiver is to administer ARCALYST, he/she should be instructed on aseptic reconstitution of the lyophilized product and injection technique. The ability to inject subcutaneously should be assessed to ensure proper administration of ARCALYST, including rotation of injection sites. (See Patient Information Leaflet for ARCALYST®). ARCALYST should be reconstituted with preservative-free Sterile Water for Injection to be provided by the pharmacy. A puncture-resistant container for disposal of vials, needles and syringes should be used. Patients or caregivers should be instructed in proper vial, syringe, and needle disposal, and should be cautioned against reuse of these items.
- Injection-site Reactions: Physicians should explain to patients that almost half of the patients in the clinical trials experienced a reaction at the injection site. Injection-site reactions may include pain, erythema, swelling, pruritis, bruising, mass, inflammation, dermatitis, edema, urticaria, vesicles, warmth, and hemorrhage. Patients should be cautioned to avoid injecting into an area that is already swollen or red. Any persistent reaction should be brought to the attention of the prescribing physician.
- Infections: Patients should be cautioned that ARCALYST has been associated with serious, life-threatening infections, and not to initiate treatment with ARCALYST if they have a chronic or active infection. Patients should be counseled to contact their healthcare professional immediately if they develop an infection after starting ARCALYST. Treatment with ARCALYST should be discontinued if a patient develops a serious infection. Patients should be counseled not to take any IL-1 blocking drug, including ARCALYST, if they are also taking a drug that blocks TNF such as etanercept, infliximab, or adalimumab. Use of ARCALYST with other IL-1 blocking agents, such as anakinra, is not recommended.
- Vaccinations: Prior to initiation of therapy with ARCALYST physicians should review with adult and pediatric patients their vaccination history relative to current medical guidelines for vaccine use, including taking into account the potential of increased risk of infection during treatment with ARCALYST.
# Precautions with Alcohol
- Alcohol-Rilonacept interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- ARCALYST®
# Look-Alike Drug Names
There is limited information regarding Rilonacept Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Rilonacept
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2]
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# Overview
Rilonacept is an interleukin-1 blocker that is FDA approved for the treatment of cryopyrin-associated periodic syndromes (CAPS), including familial cold auto-inflammatory syndrome (FCAS) and muckle-wells syndrome (MWS) in adults and children 12 and older. Common adverse reactions include injection-site reactions and upper respiratory tract infections.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Treatment should be initiated with a loading dose of 320 mg delivered as two, 2 mL, subcutaneous injections of 160 mg each given on the same day at two different sites. Dosing should be continued with a once-weekly injection of 160 mg administered as a single, 2-mL, subcutaneous injection. ARCALYST should not be given more often than once weekly. Dosage modification is not required based on advanced age or gender.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Rilonacept in adult patients.
### Non–Guideline-Supported Use
- Rilonacept 80 mg subQ once weekly with a 160-mg loading dose for 16 weeks.[1]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Treatment should be initiated with a loading dose of 4.4 mg/kg, up to a maximum of 320 mg, delivered as one or two subcutaneous injections with a maximum single-injection volume of 2 mL. Dosing should be continued with a once-weekly injection of 2.2 mg/kg, up to a maximum of 160 mg, administered as a single subcutaneous injection, up to 2 mL. If the initial dose is given as two injections, they should be given on the same day at two different sites. ARCALYST should not be given more often than once weekly.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Rilonacept in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Rilonacept in pediatric patients.
# Contraindications
- None.
# Warnings
### Precautions
- Infections
- Interleukin -1 (IL-1) blockade may interfere with the immune response to infections. Treatment with another medication that works through inhibition of IL-1 has been associated with an increased risk of serious infections, and serious infections have been reported in patients taking ARCALYST. There was a greater incidence of infections in patients on ARCALYST compared with placebo. In the controlled portion of the study, one infection was reported as severe, which was bronchitis in a patient on ARCALYST.
- In an open-label extension study, one patient developed bacterial meningitis and died. ARCALYST should be discontinued if a patient develops a serious infection. Treatment with ARCALYST should not be initiated in patients with an active or chronic infection.
- In clinical studies, ARCALYST has not been administered concomitantly with tumor necrosis factor (TNF) inhibitors. An increased incidence of serious infections has been associated with administration of an IL-1 blocker in combination with TNF inhibitors. Taking ARCALYST with TNF inhibitors is not recommended because this may increase the risk of serious infections.
- Drugs that affect the immune system by blocking TNF have been associated with an increased risk of reactivation of latent tuberculosis (TB). It is possible that taking drugs such as ARCALYST that block IL-1 increases the risk of TB or other atypical or opportunistic infections. Healthcare providers should follow current CDC guidelines both to evaluate for and to treat possible latent tuberculosis infections before initiating therapy with ARCALYST.
- Immunosuppression
- The impact of treatment with ARCALYST on active and/or chronic infections and the development of malignancies is not known. However, treatment with immunosuppressants, including ARCALYST, may result in an increase in the risk of malignancies.
- Immunizations
- Since no data are available on either the efficacy of live vaccines or on the risks of secondary transmission of infection by live vaccines in patients receiving ARCALYST, live vaccines should not be given concurrently with ARCALYST. In addition, because ARCALYST may interfere with normal immune response to new antigens, vaccinations may not be effective in patients receiving ARCALYST. No data are available on the effectiveness of vaccination with inactivated (killed) antigens in patients receiving ARCALYST.
- Because IL-1 blockade may interfere with immune response to infections, it is recommended that prior to initiation of therapy with ARCALYST adult and pediatric patients receive all recommended vaccinations, as appropriate, including pneumococcal vaccine and inactivated influenza vaccine.
- Lipid Profile Changes
- Patients should be monitored for changes in their lipid profiles and provided with medical treatment if warranted.
- Hypersensitivity
- Hypersensitivity reactions associated with ARCALYST administration in the clinical studies were rare. If a hypersensitivity reaction occurs, administration of ARCALYST should be discontinued and appropriate therapy initiated.
# Adverse Reactions
## Clinical Trials Experience
- Part A of the clinical trial was conducted in patients with CAPS who were naïve to treatment with ARCALYST. Part A of the study was a randomized, double-blind, placebo-controlled, six-week study comparing ARCALYST to placebo. Table 1 reflects the frequency of adverse events reported by at least two patients during Part A.
- Injection-Site Reactions
- In patients with CAPS, the most common and consistently reported adverse event associated with ARCALYST was injection-site reaction (ISR). The ISRs included erythema, swelling, pruritis, mass, bruising, inflammation, pain, edema, dermatitis, discomfort, urticaria, vesicles, warmth and hemorrhage. Most injection-site reactions lasted for one to two days. No ISRs were assessed as severe, and no patient discontinued study participation due to an ISR.
- Infections
- During Part A, the incidence of patients reporting infections was greater with ARCALYST (48%) than with placebo (17%). In Part B, randomized withdrawal, the incidence of infections were similar in the ARCALYST (18%) and the placebo patients (22%). Part A of the trial was initiated in the winter months, while Part B was predominantly performed in the summer months.
- In placebo-controlled studies across a variety of patient populations encompassing 360 patients treated with rilonacept and 179 treated with placebo, the incidence of infections was 34% and 27% (2.15 per patient-exposure year and 1.81 per patient-exposure year), respectively, for rilonacept and placebo.
- Serious Infections: One patient receiving ARCALYST for an unapproved indication in another study developed an infection in his olecranon bursa with Mycobacterium intracellulare. The patient was on chronic glucocorticoid treatment. The infection occurred after an intraarticular glucocorticoid injection into the bursa with subsequent local exposure to a suspected source of mycobacteria. The patient recovered after the administration of the appropriate antimicrobial therapy. One patient treated for another unapproved indication developed bronchitis/sinusitis, which resulted in hospitalization. One patient died in an open-label study of CAPS from Streptococcus pneumoniae meningitis.
- Hematologic Events
- One patient in a study in an unapproved indication developed transient neutropenia (ANC < 1 x 109/L) after receiving a large dose (2000 mg intravenously) of ARCALYST. The patient did not experience any infection associated with the neutropenia.
- Immunogenicity
- Antibodies directed against the receptor domains of rilonacept were detected by an ELISA assay in patients with CAPS after treatment with ARCALYST. Nineteen of 55 patients (35%) who had received ARCALYST for at least 6 weeks tested positive for treatment-emergent binding antibodies on at least one occasion. Of the 19, seven tested positive at the last assessment (Week 18 or 24 of the open-label extension period), and five patients tested positive for neutralizing antibodies on at least one occasion. There was no correlation of antibody activity and either clinical effectiveness or safety.
- The data reflect the percentage of patients whose test results were positive for antibodies to the rilonacept receptor domains in specific assays, and are highly dependent on the sensitivity and specificity of the assays. The observed incidence of antibody (including neutralizing antibody) positivity in an assay is highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to rilonacept with the incidence of antibodies to other products may be misleading.
- Lipid profiles
- Cholesterol and lipid levels may be reduced in patients with chronic inflammation. Patients with CAPS treated with ARCALYST experienced increases in their mean total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides. The mean increases from baseline for total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides were 19 mg/dL, 2 mg/dL, 10 mg/dL, and 57 mg/dL respectively after 6 weeks of open-label therapy. Physicians should monitor the lipid profiles of their patients (for example after 2-3 months) and consider lipid-lowering therapies as needed based upon cardiovascular risk factors and current guidelines.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Rilonacept in the drug label.
# Drug Interactions
- TNF-blocking agent and IL-1 blocking agent
- Specific drug interaction studies have not been conducted with ARCALYST. Concomitant administration of another drug that blocks IL-1 with a TNF-blocking agent in another patient population has been associated with an increased risk of serious infections and an increased risk of neutropenia. The concomitant administration of ARCALYST with TNF-blocking agents may also result in similar toxicities and is not recommended. The concomitant administration of ARCALYST with other drugs that block IL-1 has not been studied. Based upon the potential for pharmacologic interactions between rilonacept and a recombinant IL-1ra, concomitant administration of ARCALYST and other agents that block IL-1 or its receptors is not recommended.
- Cytochrome P450 Substrates
- The formation of CYP450 enzymes is suppressed by increased levels of cytokines (e.g., IL-1) during chronic inflammation. Thus it is expected that for a molecule that binds to IL-1, such as rilonacept, the formation of CYP450 enzymes could be normalized. This is clinically relevant for CYP450 substrates with a narrow therapeutic index, where the dose is individually adjusted (e.g., warfarin). Upon initiation of ARCALYST, in patients being treated with these types of medicinal products, therapeutic monitoring of the effect or drug concentration should be performed and the individual dose of the medicinal product may need to be adjusted as needed.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- There are no adequate and well-controlled studies of ARCALYST in pregnant women. Based on animal data, ARCALYST may cause fetal harm. An embryo-fetal developmental toxicity study was performed in cynomolgus monkeys treated with 0, 5, 15 or 30 mg/kg given twice a week (highest dose is approximately 3.7-fold higher than the human doses of 160 mg based on body surface area). The fetus of the only monkey with exposure to rilonacept during the later period of gestation showed multiple fusion and absence of the ribs and thoracic vertebral bodies and arches. Exposure to rilonacept during this time period was below that expected clinically. Likewise, in the cynomolgus monkey, all doses of rilonacept reduced serum levels of estradiol up to 64% compared to controls and increased the incidence of lumbar ribs compared to both control animals and historical control incidences. In perinatal and postnatal developmental toxicology studies in the mouse model using a murine analog of rilonacept (0, 20, 100 or 200 mg/kg), there was a 3-fold increase in the number of stillbirths in dams treated with 200 mg/kg three times per week (the highest dose is approximately 6-fold higher than the 160 mg maintenance dose based on body surface area). ARCALYST should be used during pregnancy only if the benefit justifies the potential risk to the fetus.
- Nonteratogenic effects. A peri- and post-natal reproductive toxicology study was performed in which mice were subcutaneously administered a murine analogue of rilonacept at doses of 20, 100, 200 mg/kg three times per week (the highest dose is approximately 6-fold higher than the 160 mg maintenance dose based on body surface area). Results indicated an increased incidence in unscheduled deaths of the F1 offspring during maturation at all doses tested.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Rilonacept in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Rilonacept during labor and delivery.
### Nursing Mothers
- It is not known whether rilonacept is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ARCALYST is administered to a nursing woman.
### Pediatric Use
- Six pediatric patients with CAPS between the ages of 12 and 16 were treated with ARCALYST at a weekly, subcutaneous dose of 2.2 mg/kg (up to a maximum of 160 mg) for 24-weeks during the open-label extension phase. These patients showed improvement from baseline in their symptom scores and in objective markers of inflammation (e.g. Serum Amyloid A and C-Reactive Protein). The adverse events included injection site reactions and upper respiratory symptoms as were commonly seen in the adult patients.
- The trough drug levels for four pediatric patients measured at the end of the weekly dose interval (mean 20 mcg/mL, range 3.6 to 33 mcg/mL) were similar to those observed in adult patients with CAPS (mean 24 mcg/mL, range 7 to 56 mcg/mL).
- Safety and effectiveness in pediatric patients below the age of 12 have not been established.
- When administered to pregnant primates, rilonacept treatment may have contributed to alterations in bone ossification in the fetus. It is not known if ARCALYST will alter bone development in pediatric patients. Pediatric patients treated with ARCALYST should undergo appropriate monitoring for growth and development.
### Geriatic Use
- In the placebo-controlled clinical studies in patients with CAPS and other indications, 70 patients randomized to treatment with ARCALYST were ≥ 65 years of age, and 6 were ≥ 75 years of age. In the CAPS clinical trial, efficacy, safety and tolerability were generally similar in elderly patients as compared to younger adults; however, only ten patients ≥ 65 years old participated in the trial. In an open-label extension study of CAPS, a 71 year old woman developed bacterial meningitis and died. Age did not appear to have a significant effect on steady-state trough concentrations in the clinical study.
### Gender
There is no FDA guidance on the use of Rilonacept with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Rilonacept with respect to specific racial populations.
### Renal Impairment
- No formal studies have been conducted to examine the pharmacokinetics of rilonacept administered subcutaneously in patients with renal impairment.
### Hepatic Impairment
- No formal studies have been conducted to examine the pharmacokinetics of rilonacept administered subcutaneously in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Rilonacept in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Rilonacept in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Subcutaneous
### Monitoring
There is limited information regarding Monitoring of Rilonacept in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Rilonacept in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- There have been no reports of overdose with ARCALYST. Maximum weekly doses of up to 320 mg have been administered subcutaneously for up to approximately 18 months in a small number of patients with CAPS and up to 6 months in patients with an unapproved indication in clinical trials without evidence of dose-limiting toxicities. In addition, ARCALYST given intravenously at doses up to 2000 mg monthly in another patient population for up to six months were tolerated without dose-limiting toxicities. The maximum amount of ARCALYST that can be safely administered has not been determined.
### Management
- In case of overdose, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects, and appropriate symptomatic treatment instituted immediately.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Rilonacept in the drug label.
# Pharmacology
## Mechanism of Action
- CAPS refer to rare genetic syndromes generally caused by mutations in the NLRP-3 [Nucleotide-binding domain, leucine rich family (NLR), pyrin domain containing 3] gene (also known as Cold-Induced Auto-inflammatory Syndrome-1 [CIAS1]). CAPS disorders are inherited in an autosomal dominant pattern with male and female offspring equally affected. Features common to all disorders include fever, urticaria-like rash, arthralgia, myalgia, fatigue, and conjunctivitis.
- In most cases, inflammation in CAPS is associated with mutations in the NLRP-3 gene which encodes the protein cryopyrin, an important component of the inflammasome. Cryopyrin regulates the protease caspase-1 and controls the activation of interleukin-1 beta (IL-1β). Mutations in NLRP-3 result in an overactive inflammasome resulting in excessive release of activated IL-1β that drives inflammation.
- Rilonacept blocks IL-1β signaling by acting as a soluble decoy receptor that binds IL-1β and prevents its interaction with cell surface receptors. Rilonacept also binds IL-1α and IL-1 receptor antagonist (IL-1ra) with reduced affinity. The equilibrium dissociation constants for rilonacept binding to IL-1β, IL-1α and IL-1ra were 0.5 pM, 1.4 pM and 6.1 pM, respectively.
## Structure
- Rilonacept is a dimeric fusion protein consisting of the ligand-binding domains of the extracellular portions of the human interleukin-1 receptor component (IL-1RI) and IL-1 receptor accessory protein (IL-1RAcP) linked in-line to the Fc portion of human IgG1. Rilonacept has a molecular weight of approximately 251 kDa. Rilonacept is expressed in recombinant Chinese hamster ovary (CHO) cells.
- ARCALYST is supplied in single-use, 20-mL glass vials containing a sterile, white to off-white, lyophilized powder. Each vial of ARCALYST is to be reconstituted with 2.3 mL of Sterile Water for Injection. A volume of up to 2 mL can be withdrawn, which is designed to deliver 160 mg for subcutaneous administration only. The resulting solution is viscous, clear, colorless to pale yellow, and essentially free from particulates. Each vial contains 220 mg rilonacept. After reconstitution, each vial contains 80 mg/mL rilonacept, 46 mM histidine, 50 mM arginine, 3.0% (w/v) polyethylene glycol 3350, 2.0% (w/v) sucrose, and 1.0% (w/v) glycine at a pH of 6.5 ± 0.3. No preservatives are present.
## Pharmacodynamics
- C-Reactive Protein (CRP) and Serum Amyloid A (SAA) are indicators of inflammatory disease activity that are elevated in patients with CAPS. Elevated SAA has been associated with the development of systemic amyloidosis in patients with CAPS. Compared to placebo, treatment with ARCALYST resulted in sustained reductions from baseline in mean serum CRP and SAA to normal levels during the clinical trial. ARCALYST also normalized mean SAA from elevated levels.
## Pharmacokinetics
- The average trough levels of rilonacept were approximately 24 mcg/mL at steady-state following weekly subcutaneous doses of 160 mg for up to 48 weeks in patients with CAPS. The steady-state appeared to be reached by 6 weeks.
- No pharmacokinetic data are available in patients with hepatic or renal impairment.
- No study was conducted to evaluate the effect of age, gender, or body weight on rilonacept exposure. Based on limited data obtained from the clinical study, steady state trough concentrations were similar between male and female patients. Age (26-78 years old) and body weight (50-120 kg) did not appear to have a significant effect on trough rilonacept concentrations. The effect of race could not be assessed because only Caucasian patients participated in the clinical study, reflecting the epidemiology of the disease.
## Nonclinical Toxicology
- Long-term animal studies have not been performed to evaluate the carcinogenic potential of rilonacept. The mutagenic potential of rilonacept was not evaluated.
- Male and female fertility was evaluated in a mouse surrogate model using a murine analog of rilonacept. Male mice were treated beginning 8 weeks prior to mating and continuing through female gestation day 15. Female mice were treated for 2 weeks prior to mating and on gestation days 0, 3, and 6. The murine analog of rilonacept did not alter either male or female fertility parameters at doses up to 200 mg/kg (this dose is approximately 6-fold higher than the 160 mg maintenance dose based on body surface area).
# Clinical Studies
- The safety and efficacy of ARCALYST for the treatment of CAPS was demonstrated in a randomized, double-blind, placebo-controlled study with two parts (A and B) conducted sequentially in the same patients with FCAS and MWS.
- Part A was a 6-week, randomized, double-blind, parallel-group period comparing ARCALYST at a dose of 160 mg weekly after an initial loading dose of 320 mg to placebo. Part B followed immediately after Part A and consisted of a 9-week, patient-blind period during which all patients received ARCALYST 160 mg weekly, followed by a 9-week, double-blind, randomized withdrawal period in which patients were randomly assigned to either remain on ARCALYST 160 mg weekly or to receive placebo. Patients were then given the option to enroll in a 24-week, open-label treatment extension phase in which all patients were treated with ARCALYST 160 mg weekly.
- Using a daily diary questionnaire, patients rated the following five signs and symptoms of CAPS: joint pain, rash, feeling of fever/chills, eye redness/pain, and fatigue, each on a scale of 0 (none, no severity) to 10 (very severe). The study evaluated the mean symptom score using the change from baseline to the end of treatment.
- The changes in mean symptom scores for the randomized parallel-group period (Part A) and the randomized withdrawal period (Part B) of the study are shown in Table 2. ARCALYST-treated patients had a larger reduction in the mean symptom score in Part A compared to placebo-treated patients. In Part B, mean symptom scores increased more in patients withdrawn to placebo compared to patients who remained on ARCALYST.
- Improvement in symptom scores was noted within several days of initiation of ARCALYST therapy in most patients.
- In Part A, patients treated with ARCALYST experienced more improvement in each of the five components of the composite endpoint (joint pain, rash, feeling of fever/chills, eye redness/pain, and fatigue) than placebo-treated patients.
- In Part A, a higher proportion of patients in the ARCALYST group experienced improvement from baseline in the composite score by at least 30% (96% vs. 29% of patients), by at least 50% (87% vs. 8%) and by at least 75% (70% vs. 0%) compared to the placebo group.
- Serum Amyloid A (SAA) and C-Reactive Protein (CRP) levels are acute phase reactants that are typically elevated in patients with CAPS with active disease. During Part A, mean levels of CRP decreased versus baseline for the ARCALYST treated patients, while there was no change for those on placebo (Table 3). ARCALYST also led to a decrease in SAA versus baseline to levels within the normal range.
- During the open-label extension, reductions in mean symptom scores, serum CRP, and serum SAA levels were maintained for up to one year.
# How Supplied
- Each 20-mL glass vial of ARCALYST contains a sterile, white to off-white, preservative-free, lyophilized powder. ARCALYST is supplied in a carton containing four vials (NDC 61755-001-01).
- The lyophilized ARCALYST product is to be stored refrigerated at 2° to 8°C (36° to 46°F) inside the original carton to protect from light. Do not use beyond the date stamped on the label. After reconstitution, ARCALYST may be kept at room temperature, should be kept from light, and should be used within three hours of reconstitution. ARCALYST does not contain preservatives; therefore, unused portions of ARCALYST should be discarded. Discard the vial after a single withdrawal of drug.
## Storage
There is limited information regarding Rilonacept Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- The first injection of ARCALYST should be performed under the supervision of a qualified healthcare professional. If a patient or caregiver is to administer ARCALYST, he/she should be instructed on aseptic reconstitution of the lyophilized product and injection technique. The ability to inject subcutaneously should be assessed to ensure proper administration of ARCALYST, including rotation of injection sites. (See Patient Information Leaflet for ARCALYST®). ARCALYST should be reconstituted with preservative-free Sterile Water for Injection to be provided by the pharmacy. A puncture-resistant container for disposal of vials, needles and syringes should be used. Patients or caregivers should be instructed in proper vial, syringe, and needle disposal, and should be cautioned against reuse of these items.
- Injection-site Reactions: Physicians should explain to patients that almost half of the patients in the clinical trials experienced a reaction at the injection site. Injection-site reactions may include pain, erythema, swelling, pruritis, bruising, mass, inflammation, dermatitis, edema, urticaria, vesicles, warmth, and hemorrhage. Patients should be cautioned to avoid injecting into an area that is already swollen or red. Any persistent reaction should be brought to the attention of the prescribing physician.
- Infections: Patients should be cautioned that ARCALYST has been associated with serious, life-threatening infections, and not to initiate treatment with ARCALYST if they have a chronic or active infection. Patients should be counseled to contact their healthcare professional immediately if they develop an infection after starting ARCALYST. Treatment with ARCALYST should be discontinued if a patient develops a serious infection. Patients should be counseled not to take any IL-1 blocking drug, including ARCALYST, if they are also taking a drug that blocks TNF such as etanercept, infliximab, or adalimumab. Use of ARCALYST with other IL-1 blocking agents, such as anakinra, is not recommended.
- Vaccinations: Prior to initiation of therapy with ARCALYST physicians should review with adult and pediatric patients their vaccination history relative to current medical guidelines for vaccine use, including taking into account the potential of increased risk of infection during treatment with ARCALYST.
# Precautions with Alcohol
- Alcohol-Rilonacept interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- ARCALYST®[2]
# Look-Alike Drug Names
There is limited information regarding Rilonacept Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Rilonacept | |
143e21ebe916e585cd054c243c392676942bf063 | wikidoc | Rimexolone | Rimexolone
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Rimexolone is a glucocorticoid that is FDA approved for the treatment of post-operative inflammation and anterior uveitis. Common adverse reactions include hypotension, erythema, pruritus, taste sense altered, headache, blurred vision, discharge from eye, pain in eye, pharyngitis, and rhinitis.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Apply one - two drops of VEXOL® 1% Ophthalmic Suspension into the conjunctival sac of the affected eye four times daily beginning 24 hours after surgery and continuing throughout the first 2 weeks of the postoperative period.
- Apply one - two drops of VEXOL® 1% Ophthalmic Suspension into the conjunctival sac of the affected eye every hour during waking hours for the first week, one drop every two hours during waking hours of the second week, and then taper until uveitis is resolved.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Rimexolone in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Rimexolone in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Rimexolone in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Rimexolone in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Rimexolone in pediatric patients.
# Contraindications
- VEXOL® 1% (rimexolone ophthalmic suspension) is contraindicated in epithelial herpes simplex keratitis (dendritic keratitis), vaccinia, varicella, and most other viral diseases of the cornea and conjunctiva; mycobacterial infection of the eye; fungal diseases of the eye; acute purulent untreated infections which, like other diseases caused by microorganisms, may be masked or enhanced by the presence of the steroid; and in those persons with hypersensitivity to any component of the formulation.
# Warnings
- For topical ophthalmic use only. Not for injection. Use in the treatment of herpes simplex infection requires great caution and frequent slit-lamp examinations. Prolonged use may result in ocular hypertension/glaucoma, damage to the optic nerve, defects in visual acuity and visual fields, and posterior subcapsular cataract formation.
- Prolonged use may also result in secondary ocular infections due to suppression of host response.
- Acute purulent infections of the eye may be masked or exacerbated by the presence of corticosteroid medication. In those diseases causing thinning of the cornea or sclera, perforation has been known to occur with topical steroids. It is advisable that the intraocular pressure be checked frequently.
### Precautions
- Fungal infections of the cornea are particularly prone to develop coincidentally with long-term local steroid application. Fungal invasion must be considered in any persistent corneal ulceration where a steroid has been or is in use.
- For ophthalmic use only. The initial prescription and renewal of the medication order beyond 14 days should be made by a physician only after examination of the patient with the aid of magnification, such as slit lamp biomicroscopy and where appropriate, fluorescein staining. If signs and symptoms fail to improve after two days, the patient should be reevaluated.
- If this product is used for 10 days or longer, intraocular pressure should be monitored even though it may be difficult in children and uncooperative patients.
# Adverse Reactions
## Clinical Trials Experience
- Reactions associated with ophthalmic steroids include elevated intraocular pressure, which may be associated with optic nerve damage, visual acuity and field defects, posterior subcapsular cataract formation, secondary ocular infection from pathogens including herpes simplex, and perforation of the globe where there is thinning of the cornea or sclera.
- Ocular adverse reactions occurring in 1 - 5% of patients in clinical studies of VEXOL® 1% (rimexolone ophthalmic suspension) included blurred vision, discharge, discomfort, ocular pain, increased intraocular pressure, foreign body sensation, hyperemia and pruritus.
- Other ocular adverse reactions occurring in less than 1% of patients included sticky sensation, increased fibrin, dry eye, conjunctival edema, corneal staining, keratitis, tearing, photophobia, edema, irritation, corneal ulcer, browache, lid margin crusting, corneal edema, infiltrate, and corneal erosion.
- Non-ocular adverse reactions occurred in less than 2% of patients. These included headache, hypotension, rhinitis, pharyngitis, and taste perversion.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Rimexolone in the drug label.
# Drug Interactions
There is limited information regarding Rimexolone Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- Rimexolone has been shown to be teratogenic and embryotoxic in rabbits following subcutaneous administration at the lowest dose tested (0.5 mg/kg/day, approximately 2 times the recommended human ophthalmic dose). Corticosteroids are recognized to cause fetal resorptions and malformations in animals. There are no adequate and well-controlled studies in pregnant women. VEXOL® 1% (rimexolone ophthalmic suspension) should be used in pregnant women only if the potential benefit to the mother justifies the potential risk to the fetus.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Rimexolone in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Rimexolone during labor and delivery.
### Nursing Mothers
- It is not known whether topical ophthalmic administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in human breast milk. Nevertheless, caution should be exercised when topical corticosteroids are administered to a nursing woman; a decision should be made whether to discontinue nursing or discontinue therapy, taking into consideration the importance of the drug to the mother.
### Pediatric Use
- Safety and effectiveness in pediatric patients have not been established.
### Geriatic Use
- No overall differences in safety or effectiveness have been observed between elderly and younger patients.
### Gender
There is no FDA guidance on the use of Rimexolone with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Rimexolone with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Rimexolone in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Rimexolone in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Rimexolone in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Rimexolone in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Topical
### Monitoring
There is limited information regarding Monitoring of Rimexolone in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Rimexolone in the drug label.
# Overdosage
## Chronic Overdose
There is limited information regarding Chronic Overdose of Rimexolone in the drug label.
# Pharmacology
## Mechanism of Action
- Corticosteroids suppress the inflammatory response to a variety of inciting agents of a mechanical, chemical, or immunological nature. They inhibit edema, cellular infiltration, capillary dilatation, fibroblastic proliferation, deposition of collagen and scar formation associated with inflammation. Placebo-controlled clinical studies demonstrated that VEXOL® 1% Ophthalmic Suspension is efficacious for the treatment of anterior chamber inflammation following cataract surgery.
## Structure
- VEXOL® 1% Ophthalmic Suspension is a sterile, multi-dose topical ophthalmic suspension containing the corticosteroid, rimexolone. Rimexolone is a white, water-insoluble powder with an empirical formula of C24H34O3 and a molecular weight of 370.53. Its chemical name is 11β-Hydroxy-16α,17α-dimethyl-17-propio nylandrosta-1,4-diene-3-one.The chemical structure of rimexolone is presented below:
- Each mL Contains: Active ingredient: rimexolone 10 mg (1%). Preservative: benzalkonium chloride 0.01%. Inactive ingredients: carbomer 974P, polysorbate 80, sodium chloride, edetate disodium, sodium hydroxide and/or hydrochloric acid (to adjust pH) and purified water.
- The pH of the suspension is 6.0 to 8.0 and the tonicity is 260 to 320 mOsmol/kg.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Rimexolone in the drug label.
## Pharmacokinetics
- In two controlled clinical trials, VEXOL® 1% Ophthalmic Suspension demonstrated clinical equivalence to 1% prednisolone acetate in reducing uveitic inflammation. In a controlled 6-week study of steroid responsive subjects, the time to raise intraocular pressure was similar for VEXOL® 1% Ophthalmic Suspension and 0.1% fluorometholone given four times daily.
- As with other topically administered ophthalmic drugs, VEXOL® 1% (rimexolone ophthalmic suspension) is absorbed systemically. Studies in normal volunteers dosed bilaterally once every hour during waking hours for one week have demonstrated serum concentrations ranging from less than 80 pg/mL to 470 pg/mL. The mean serum concentrations were approximately 130 pg/mL. Serum concentrations were at or near steady state after 5 to 7 hourly doses. After decreasing the dosing frequency to once every two hours while awake during the second week of administration, mean serum concentrations were approximately 100 pg/mL.
- The serum half-life of rimexolone could not be reliably estimated due to the large number of samples below the quantitation limit of the assay (80 pg/mL). However, based on the time required to reach steady-state, the half-life appears to be short (1 - 2 hours).
- Based upon in vivo and in vitro preclinical metabolism studies, and on in vitro results with human liver preparations, rimexolone undergoes extensive metabolism. Following IV administration of radio-labeled rimexolone to rats, greater than 80% of the dose is excreted via the feces as rimexolone and metabolites. Metabolites have been shown to be less active than parent drug, or inactive in human glucocorticoid receptor binding assays.
## Nonclinical Toxicology
- Rimexolone has been shown to be non-mutagenic in a battery of in vitro and in vivo mutagenicity assays.
- Fertility and reproductive capability were not impaired in a study in rats with plasma levels (42 ng/mL) approximately 200 times those obtained in clinical studies after topical administration (<0.2 ng/mL). Long-term studies have not been conducted in animals or humans to evaluate the carcinogenic potential of rimexolone.
# Clinical Studies
There is limited information regarding Clinical Studies of Rimexolone in the drug label.
# How Supplied
- 5 mL and 10 mL in plastic DROP-TAINER® dispensers. VEXOL® 1% Ophthalmic Suspension is supplied in natural (clear) low density polyethylene (LDPE) bottles, with a natural LDPE dispensing plug and pink polypropylene closures. Fill volumes are 5 mL in an 8 mL bottle and 10 mL in a 10 mL bottle.
- 5 mL: NDC 0065-0627-07
- 10 mL: NDC 0065-0627-03
- Storage: Store upright between 2°-25°C (36°-77°F).
- Do not freeze.
- Shake well before using.
## Storage
There is limited information regarding Rimexolone Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Do not touch dropper tip to any surface, as this may contaminate the suspension.
# Precautions with Alcohol
- Alcohol-Rimexolone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- VEXOL®
# Look-Alike Drug Names
- Vosol® — Vexol®
# Drug Shortage Status
# Price | Rimexolone
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Rimexolone is a glucocorticoid that is FDA approved for the treatment of post-operative inflammation and anterior uveitis. Common adverse reactions include hypotension, erythema, pruritus, taste sense altered, headache, blurred vision, discharge from eye, pain in eye, pharyngitis, and rhinitis.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Apply one - two drops of VEXOL® 1% Ophthalmic Suspension into the conjunctival sac of the affected eye four times daily beginning 24 hours after surgery and continuing throughout the first 2 weeks of the postoperative period.
- Apply one - two drops of VEXOL® 1% Ophthalmic Suspension into the conjunctival sac of the affected eye every hour during waking hours for the first week, one drop every two hours during waking hours of the second week, and then taper until uveitis is resolved.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Rimexolone in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Rimexolone in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Rimexolone in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Rimexolone in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Rimexolone in pediatric patients.
# Contraindications
- VEXOL® 1% (rimexolone ophthalmic suspension) is contraindicated in epithelial herpes simplex keratitis (dendritic keratitis), vaccinia, varicella, and most other viral diseases of the cornea and conjunctiva; mycobacterial infection of the eye; fungal diseases of the eye; acute purulent untreated infections which, like other diseases caused by microorganisms, may be masked or enhanced by the presence of the steroid; and in those persons with hypersensitivity to any component of the formulation.
# Warnings
- For topical ophthalmic use only. Not for injection. Use in the treatment of herpes simplex infection requires great caution and frequent slit-lamp examinations. Prolonged use may result in ocular hypertension/glaucoma, damage to the optic nerve, defects in visual acuity and visual fields, and posterior subcapsular cataract formation.
- Prolonged use may also result in secondary ocular infections due to suppression of host response.
- Acute purulent infections of the eye may be masked or exacerbated by the presence of corticosteroid medication. In those diseases causing thinning of the cornea or sclera, perforation has been known to occur with topical steroids. It is advisable that the intraocular pressure be checked frequently.
### Precautions
- Fungal infections of the cornea are particularly prone to develop coincidentally with long-term local steroid application. Fungal invasion must be considered in any persistent corneal ulceration where a steroid has been or is in use.
- For ophthalmic use only. The initial prescription and renewal of the medication order beyond 14 days should be made by a physician only after examination of the patient with the aid of magnification, such as slit lamp biomicroscopy and where appropriate, fluorescein staining. If signs and symptoms fail to improve after two days, the patient should be reevaluated.
- If this product is used for 10 days or longer, intraocular pressure should be monitored even though it may be difficult in children and uncooperative patients.
# Adverse Reactions
## Clinical Trials Experience
- Reactions associated with ophthalmic steroids include elevated intraocular pressure, which may be associated with optic nerve damage, visual acuity and field defects, posterior subcapsular cataract formation, secondary ocular infection from pathogens including herpes simplex, and perforation of the globe where there is thinning of the cornea or sclera.
- Ocular adverse reactions occurring in 1 - 5% of patients in clinical studies of VEXOL® 1% (rimexolone ophthalmic suspension) included blurred vision, discharge, discomfort, ocular pain, increased intraocular pressure, foreign body sensation, hyperemia and pruritus.
- Other ocular adverse reactions occurring in less than 1% of patients included sticky sensation, increased fibrin, dry eye, conjunctival edema, corneal staining, keratitis, tearing, photophobia, edema, irritation, corneal ulcer, browache, lid margin crusting, corneal edema, infiltrate, and corneal erosion.
- Non-ocular adverse reactions occurred in less than 2% of patients. These included headache, hypotension, rhinitis, pharyngitis, and taste perversion.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Rimexolone in the drug label.
# Drug Interactions
There is limited information regarding Rimexolone Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- Rimexolone has been shown to be teratogenic and embryotoxic in rabbits following subcutaneous administration at the lowest dose tested (0.5 mg/kg/day, approximately 2 times the recommended human ophthalmic dose). Corticosteroids are recognized to cause fetal resorptions and malformations in animals. There are no adequate and well-controlled studies in pregnant women. VEXOL® 1% (rimexolone ophthalmic suspension) should be used in pregnant women only if the potential benefit to the mother justifies the potential risk to the fetus.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Rimexolone in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Rimexolone during labor and delivery.
### Nursing Mothers
- It is not known whether topical ophthalmic administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in human breast milk. Nevertheless, caution should be exercised when topical corticosteroids are administered to a nursing woman; a decision should be made whether to discontinue nursing or discontinue therapy, taking into consideration the importance of the drug to the mother.
### Pediatric Use
- Safety and effectiveness in pediatric patients have not been established.
### Geriatic Use
- No overall differences in safety or effectiveness have been observed between elderly and younger patients.
### Gender
There is no FDA guidance on the use of Rimexolone with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Rimexolone with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Rimexolone in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Rimexolone in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Rimexolone in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Rimexolone in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Topical
### Monitoring
There is limited information regarding Monitoring of Rimexolone in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Rimexolone in the drug label.
# Overdosage
## Chronic Overdose
There is limited information regarding Chronic Overdose of Rimexolone in the drug label.
# Pharmacology
## Mechanism of Action
- Corticosteroids suppress the inflammatory response to a variety of inciting agents of a mechanical, chemical, or immunological nature. They inhibit edema, cellular infiltration, capillary dilatation, fibroblastic proliferation, deposition of collagen and scar formation associated with inflammation. Placebo-controlled clinical studies demonstrated that VEXOL® 1% Ophthalmic Suspension is efficacious for the treatment of anterior chamber inflammation following cataract surgery.
## Structure
- VEXOL® 1% Ophthalmic Suspension is a sterile, multi-dose topical ophthalmic suspension containing the corticosteroid, rimexolone. Rimexolone is a white, water-insoluble powder with an empirical formula of C24H34O3 and a molecular weight of 370.53. Its chemical name is 11β-Hydroxy-16α,17α-dimethyl-17-propio nylandrosta-1,4-diene-3-one.The chemical structure of rimexolone is presented below:
- Each mL Contains: Active ingredient: rimexolone 10 mg (1%). Preservative: benzalkonium chloride 0.01%. Inactive ingredients: carbomer 974P, polysorbate 80, sodium chloride, edetate disodium, sodium hydroxide and/or hydrochloric acid (to adjust pH) and purified water.
- The pH of the suspension is 6.0 to 8.0 and the tonicity is 260 to 320 mOsmol/kg.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Rimexolone in the drug label.
## Pharmacokinetics
- In two controlled clinical trials, VEXOL® 1% Ophthalmic Suspension demonstrated clinical equivalence to 1% prednisolone acetate in reducing uveitic inflammation. In a controlled 6-week study of steroid responsive subjects, the time to raise intraocular pressure was similar for VEXOL® 1% Ophthalmic Suspension and 0.1% fluorometholone given four times daily.
- As with other topically administered ophthalmic drugs, VEXOL® 1% (rimexolone ophthalmic suspension) is absorbed systemically. Studies in normal volunteers dosed bilaterally once every hour during waking hours for one week have demonstrated serum concentrations ranging from less than 80 pg/mL to 470 pg/mL. The mean serum concentrations were approximately 130 pg/mL. Serum concentrations were at or near steady state after 5 to 7 hourly doses. After decreasing the dosing frequency to once every two hours while awake during the second week of administration, mean serum concentrations were approximately 100 pg/mL.
- The serum half-life of rimexolone could not be reliably estimated due to the large number of samples below the quantitation limit of the assay (80 pg/mL). However, based on the time required to reach steady-state, the half-life appears to be short (1 - 2 hours).
- Based upon in vivo and in vitro preclinical metabolism studies, and on in vitro results with human liver preparations, rimexolone undergoes extensive metabolism. Following IV administration of radio-labeled rimexolone to rats, greater than 80% of the dose is excreted via the feces as rimexolone and metabolites. Metabolites have been shown to be less active than parent drug, or inactive in human glucocorticoid receptor binding assays.
## Nonclinical Toxicology
- Rimexolone has been shown to be non-mutagenic in a battery of in vitro and in vivo mutagenicity assays.
- Fertility and reproductive capability were not impaired in a study in rats with plasma levels (42 ng/mL) approximately 200 times those obtained in clinical studies after topical administration (<0.2 ng/mL). Long-term studies have not been conducted in animals or humans to evaluate the carcinogenic potential of rimexolone.
# Clinical Studies
There is limited information regarding Clinical Studies of Rimexolone in the drug label.
# How Supplied
- 5 mL and 10 mL in plastic DROP-TAINER® dispensers. VEXOL® 1% Ophthalmic Suspension is supplied in natural (clear) low density polyethylene (LDPE) bottles, with a natural LDPE dispensing plug and pink polypropylene closures. Fill volumes are 5 mL in an 8 mL bottle and 10 mL in a 10 mL bottle.
- 5 mL: NDC 0065-0627-07
- 10 mL: NDC 0065-0627-03
- Storage: Store upright between 2°-25°C (36°-77°F).
- Do not freeze.
- Shake well before using.
## Storage
There is limited information regarding Rimexolone Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Do not touch dropper tip to any surface, as this may contaminate the suspension.
# Precautions with Alcohol
- Alcohol-Rimexolone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- VEXOL®[1]
# Look-Alike Drug Names
- Vosol® — Vexol®[2]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Rimexolone | |
d86330f1077b48d9fc5df483fbc28a045a7598c0 | wikidoc | Rimonabant | Rimonabant
# Overview
Rimonabant (also known as SR141716, Acomplia, Riobant, Slimona, Rimoslim, and Zimulti) is an anorectic anti-obesity drug. It is a CB1 cannabinoid receptor antagonist. Its main avenue of effect is reduction in appetite.
Rimonabant is the first selective CB1 receptor blocker to be approved for use anywhere in the world. In Europe, it is indicated for use in conjunction with diet and exercise for patients with a body mass index greater than 30 kg/m², or patients wih a BMI greater than 27 kg/m² with associated risk factors, such as type 2 diabetes or dyslipidaemia. In the UK, it has been available since the end of July 2006. As of 2007, the drug was available in 38 countries.
# Approval
Despite the FDA issuing an approvable letter in February 2006 for the obesity indication and a non-approvable letter for smoking cessation, the drug did not enter the market in the United States in 2006. The French pharma firm Sanofi-Aventis disclosed that a complete response to the FDA's approvable letter was submitted on October 26, 2006, triggering a Class I (two-month) or Class II (six-month) review process. On June 13, 2007, FDA's Endocrine and Metabolic Drugs Advisory Committee (EMDAC) concluded that the French manufacturer Sanofi-Aventis failed to demonstrate the safety of rimonabant and voted against recommending the anti-obesity treatment for approval. Subsequently, Sanofi-Aventis announced that it was withdrawing the new drug application (NDA) for rimonabant and that it would resubmit an application at some point in the future.
On 21 June 2006, the European Commission approved the sale of rimonabant in the then 25-member European Union. Sanofi announced that the first country in which Acomplia will be sold is the United Kingdom. Sales began in July 2006. Sanofi also announced that it projects that the drug will be sold shortly thereafter in Denmark, Ireland, Germany, Finland and Norway. It is expected in Belgium and Sweden in 2007. Ordinary obesity will, according to official medical recommendations, not be enough to acquire the prescription in Sweden; there are additional requirements concerning abnormal blood lipid levels.
The EU's approval was not a blanket approval, nor did it approve Acomplia for non-obesity related problems such as smoking cessation, although off-label use of the drug is still possible. The approval is in combination with diet and exercise for the treatment of obese patients (BMI greater than or equal to 30), or overweight patients (BMI greater than 27) with associated risk factors, such as type 2 diabetes or dyslipidaemia.
# Side effects
Shortly after market introduction, press reports and independent studies suggest that side effects occur stronger and more commonly than shown by the manufacturer in their clinical studies. Reports of severe depression are frequent. This is deemed to result from the drug being active in the central nervous system, an area of human physiology so complex that drug effects are highly difficult to determine reliably.
Because the drug has the opposite effects of cannabinoid receptor agonists such as tetrahydrocannabinol, which is neuroprotective against excitotoxicity, it can be theorized that Rimonabant promotes the development of neurodegenerative diseases of the central nervous system such as Multiple sclerosis, Alzheimer's disease, Amyotrophic lateral sclerosis (ALS), Parkinson's disease, and Huntington's disease in persons who are susceptible. The reported development of previously clinically silent multiple sclerosis in one patient taking Rimonabant suggests that any patients with an underlying neurological condition should not take Rimonabant, given the neuroprotective role of the endocannabinoid system in many experimental paradigms of neurological disease.
On 15 June 2007 the BBC News reported that a committee advising the US FDA has voted not to recommend the drug's approval because of concerns over suicidality, depression and other related side effects associated with use of the drug.
Similarly, in October 2008 marketing and new prescriptions of Acomplia (Rimonabant, sanofi-aventis) were suspended by the European Medicines Agency (EMEA). While more than 700,000 patients have taken the drug in over 18 countries, the EMEA sited the significant amount of psychiatric side effects and limited clinical effectiveness seen during post-marketing experience as reasons for the recommendation. Sanofi-aventis released a statement indicating both its compliance with the temporary suspension and its commitment to providing more evidence to the EMEA in support of the drug.
## Smoking cessation
Rimonabant may also be found to be effective in assisting some smokers to quit smoking. Sanofi-Aventis is currently conducting studies to determine the possible value of rimonabant in smoking-cessation therapy. The Studies with Rimonabant and Tobacco Use (STRATUS) Program involves more than 6,000 subjects. STRATUS is designed to explore two smoking-related therapies: first, to use rimonabant directly to aid in smoking cessation; second, to help prevent weight gain in former smokers. Initial results apparently suggest that rimonabant is effective for both uses. However, the FDA has explicitly stated to Sanofi-Aventis that without additional studies rimonabant cannot be approved in the United States for smoking cessation therapy.
According to Cochrane review in 2007 Rimonabant "may increase the odds of quitting approximately 1(1/2)-fold".
## Addiction
Rimonabant reduced resumption of cocaine-seeking responses triggered by two of the three most common triggers of relapse in humans, priming and cues. It may also reduce ethanol and opiate seeking behavior.
## Memory
Tetrahydrocannabinol is known to impair short-term memory. It was therefore hypothesised that Rimonabant may improve short-term memory. Indeed in animal studies it significantly improved the performance of rats to encode information in the short-term memory.
## Blockade of Cannabis effects
Rimobants blocks the psychoactive and some of the cardiovascular effects of Δ9-Tetrahydrocannabinol in humans without affecting the pharmacokinetics. | Rimonabant
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Template:Editor help
# Overview
Rimonabant (also known as SR141716, Acomplia, Riobant, Slimona, Rimoslim, and Zimulti)[1] is an anorectic anti-obesity drug. It is a CB1 cannabinoid receptor antagonist. Its main avenue of effect is reduction in appetite.
Rimonabant is the first selective CB1 receptor blocker to be approved for use anywhere in the world. In Europe, it is indicated for use in conjunction with diet and exercise for patients with a body mass index greater than 30 kg/m², or patients wih a BMI greater than 27 kg/m² with associated risk factors, such as type 2 diabetes or dyslipidaemia. In the UK, it has been available since the end of July 2006. As of 2007, the drug was available in 38 countries.
# Approval
Despite the FDA issuing an approvable letter in February 2006 for the obesity indication and a non-approvable letter for smoking cessation, the drug did not enter the market in the United States in 2006. The French pharma firm Sanofi-Aventis disclosed that a complete response to the FDA's approvable letter was submitted on October 26, 2006, triggering a Class I (two-month) or Class II (six-month) review process. On June 13, 2007, FDA's Endocrine and Metabolic Drugs Advisory Committee (EMDAC) concluded that the French manufacturer Sanofi-Aventis failed to demonstrate the safety of rimonabant and voted against recommending the anti-obesity treatment for approval.[2] Subsequently, Sanofi-Aventis announced that it was withdrawing the new drug application (NDA) for rimonabant and that it would resubmit an application at some point in the future.
On 21 June 2006, the European Commission approved the sale of rimonabant in the then 25-member European Union. Sanofi announced that the first country in which Acomplia will be sold is the United Kingdom. Sales began in July 2006. Sanofi also announced that it projects that the drug will be sold shortly thereafter in Denmark, Ireland, Germany, Finland and Norway. It is expected in Belgium[3] and Sweden in 2007. Ordinary obesity will, according to official medical recommendations, not be enough to acquire the prescription in Sweden; there are additional requirements concerning abnormal blood lipid levels.[4]
The EU's approval was not a blanket approval, nor did it approve Acomplia for non-obesity related problems such as smoking cessation, although off-label use of the drug is still possible. The approval is in combination with diet and exercise for the treatment of obese patients (BMI greater than or equal to 30), or overweight patients (BMI greater than 27) with associated risk factors, such as type 2 diabetes or dyslipidaemia.
# Side effects
Shortly after market introduction, press reports and independent studies suggest that side effects occur stronger and more commonly than shown by the manufacturer in their clinical studies. Reports of severe depression are frequent. This is deemed to result from the drug being active in the central nervous system, an area of human physiology so complex that drug effects are highly difficult to determine reliably.[5]
Because the drug has the opposite effects of cannabinoid receptor agonists such as tetrahydrocannabinol, which is neuroprotective against excitotoxicity,[6] it can be theorized that Rimonabant promotes the development of neurodegenerative diseases of the central nervous system such as Multiple sclerosis, Alzheimer's disease, Amyotrophic lateral sclerosis (ALS), Parkinson's disease, and Huntington's disease in persons who are susceptible.[7] The reported development of previously clinically silent multiple sclerosis in one patient taking Rimonabant suggests that any patients with an underlying neurological condition should not take Rimonabant, given the neuroprotective role of the endocannabinoid system in many experimental paradigms of neurological disease.
On 15 June 2007 the BBC News reported [8] that a committee advising the US FDA has voted not to recommend the drug's approval because of concerns over suicidality, depression and other related side effects associated with use of the drug.
Similarly, in October 2008 marketing and new prescriptions of Acomplia (Rimonabant, sanofi-aventis) were suspended by the European Medicines Agency (EMEA). While more than 700,000 patients have taken the drug in over 18 countries, the EMEA sited the significant amount of psychiatric side effects and limited clinical effectiveness seen during post-marketing experience as reasons for the recommendation. Sanofi-aventis released a statement indicating both its compliance with the temporary suspension and its commitment to providing more evidence to the EMEA in support of the drug.[9]
## Smoking cessation
Rimonabant may also be found to be effective in assisting some smokers to quit smoking. Sanofi-Aventis is currently conducting studies to determine the possible value of rimonabant in smoking-cessation therapy. The Studies with Rimonabant and Tobacco Use (STRATUS) Program involves more than 6,000 subjects. STRATUS is designed to explore two smoking-related therapies: first, to use rimonabant directly to aid in smoking cessation; second, to help prevent weight gain in former smokers. Initial results apparently suggest that rimonabant is effective for both uses. However, the FDA has explicitly stated to Sanofi-Aventis that without additional studies rimonabant cannot be approved in the United States for smoking cessation therapy.
According to Cochrane review in 2007 Rimonabant "may increase the odds of quitting approximately 1(1/2)-fold"[10].
## Addiction
Rimonabant reduced resumption of cocaine-seeking responses triggered by two of the three most common triggers of relapse in humans, priming and cues. It may also reduce ethanol and opiate seeking behavior[11].
## Memory
Tetrahydrocannabinol is known to impair short-term memory. It was therefore hypothesised that Rimonabant may improve short-term memory. Indeed in animal studies it significantly improved the performance of rats to encode information in the short-term memory[12].
## Blockade of Cannabis effects
Rimobants blocks the psychoactive and some of the cardiovascular effects of Δ9-Tetrahydrocannabinol in humans without affecting the pharmacokinetics[13]. | https://www.wikidoc.org/index.php/Rimonabant | |
afda3467155eb47bbf7665b7ed16a019b5ec6671 | wikidoc | Rinne test | Rinne test
The Rinne test is a hearing test. It compares perception of sounds, as transmitted by air or by sound conduction through the mastoid. Thus, one can quickly suspect conductive hearing loss.
A Rinne test should always be accompanied by a Weber test to also detect sensorineural hearing loss and thus confirm the nature of hearing loss.
The Rinne test was named after German otologist Heinrich Adolf Rinne (1819-1868); the Weber test was named after Ernst Heinrich Weber (1795 – 1878).
# Procedure
The Rinne test is performed by placing a vibrating tuning fork (512 Hz) initially on the mastoid, then next to the ear and asking which sound is loudest. Air conduction uses the apparatus of the ear (pinna, eardrum and ossicles) to amplify and direct the sound whereas bone conduction bypasses some or all of these and allows the sound to be transmitted directly to the inner ear albeit at a reduced volume, or via the bones of the skull to the opposite ear.
In a normal ear, air conduction (AC) is better than bone conduction (BC)
In conductive hearing loss, bone conduction is better than air
In sensorineural hearing loss, bone conduction and air conduction are both equally depreciated, maintaining the relative difference of
In sensorineural hearing loss patients there may be a false negative Rinne
Note that the words positive and negative are used in a somewhat confusing fashion here, other than their normal use in medical tests. Positive or negative means that a certain parameter that was evaluated was present or not. In this case, that parameter is if air conduction (AC) is better than bone conduction (BC). Thus, a "positive" result indicates the healthy state, in contrast to many other medical tests.
(Images courtesy of Charlie Goldberg, M.D., UCSD School of Medicine and VA Medical Center, San Diego, California)
- Rinne test
- Rinne test
# Hazards
This test, and its complement the Weber test, are quick screening tests and are no replacement for formal audiometry.
# Effect on opposite ear
The effect on the opposite ear, relative to the tuning fork, is reverse to the ear being tested. Here, conduction through the skull to the opposite side is more effective than conduction through room air around the head.
Thus, if the normal ear is not masked, bone conduction could be reported as louder by the patient, even if both ears are normal. | Rinne test
The Rinne test is a hearing test. It compares perception of sounds, as transmitted by air or by sound conduction through the mastoid. Thus, one can quickly suspect conductive hearing loss.
A Rinne test should always be accompanied by a Weber test to also detect sensorineural hearing loss and thus confirm the nature of hearing loss.
The Rinne test was named after German otologist Heinrich Adolf Rinne (1819-1868); the Weber test was named after Ernst Heinrich Weber (1795 – 1878).
# Procedure
The Rinne test is performed by placing a vibrating tuning fork (512 Hz) initially on the mastoid, then next to the ear and asking which sound is loudest. Air conduction uses the apparatus of the ear (pinna, eardrum and ossicles) to amplify and direct the sound whereas bone conduction bypasses some or all of these and allows the sound to be transmitted directly to the inner ear albeit at a reduced volume, or via the bones of the skull to the opposite ear.
In a normal ear, air conduction (AC) is better than bone conduction (BC)
In conductive hearing loss, bone conduction is better than air
In sensorineural hearing loss, bone conduction and air conduction are both equally depreciated, maintaining the relative difference of
In sensorineural hearing loss patients there may be a false negative Rinne
Note that the words positive and negative are used in a somewhat confusing fashion here, other than their normal use in medical tests. Positive or negative means that a certain parameter that was evaluated was present or not. In this case, that parameter is if air conduction (AC) is better than bone conduction (BC). Thus, a "positive" result indicates the healthy state, in contrast to many other medical tests.
(Images courtesy of Charlie Goldberg, M.D., UCSD School of Medicine and VA Medical Center, San Diego, California)
- Rinne test
- Rinne test
# Hazards
This test, and its complement the Weber test, are quick screening tests and are no replacement for formal audiometry.
# Effect on opposite ear
The effect on the opposite ear, relative to the tuning fork, is reverse to the ear being tested. Here, conduction through the skull to the opposite side is more effective than conduction through room air around the head.
Thus, if the normal ear is not masked, bone conduction could be reported as louder by the patient, even if both ears are normal. | https://www.wikidoc.org/index.php/Rinne_test | |
176aec5cb46c9ed9b2d994d2476c4c22c2382c50 | wikidoc | Ristocetin | Ristocetin
Ristocetin is an antibiotic, obtained from Amycolatopsis lurida, previously used to treat staphylococcal infections. It is no longer used clinically because of its toxicity. It causes platelet agglutination and blood coagulation and is used to assay those functions in vitro, e.g. to diagnose von Willebrand disease (vWD) or the Bernard-Soulier syndrome. Platelet agglutination caused by ristocetin can occur only in the presence of large multimers of von Willebrand factor, so if ristocetin is added to blood lacking the factor (or its receptor -- see below), it will not coagulate.
In some types of vWD (types 2B and platelet-type), lower than normal amounts of ristocetin cause platelet aggregation when the patient's platelet-rich plasma is used. This paradox is explained by these types having gain-of-function mutations which cause the vWD high molecular-weight multimers to bind more tightly to their receptors on platelets (the alpha chains of glycoprotein Ib (GPIb) receptors). In the case of type 2B vWD, the gain-of-function mutation involves von Willebrand's factor (VWF gene), and in platelet-type vWD, the receptor is the object of the mutation (GPIb). This increased binding causes vWD because the high-molecular weight multimers are removed from circulation in plasma since they remain attached to the patient's platelets. Thus, if the patient's platelet-poor plasma is used, the ristocetin cofactor assay will not agglutinate "standardized (ie., pooled platelets from normal donors which are fixed in formalin)" platelets, similar to the other types of vWD.
In all forms of the ristocetin assay, the platelets are fixed in formalin prior to the assay to prevent von Willebrand's factor stored in platelet granules from being released and participating in platelet aggregation. Thus, the ristocetin cofactor activity depends only upon high-molecular multimers of the factor present in circulating plasma. | Ristocetin
Ristocetin is an antibiotic, obtained from Amycolatopsis lurida, previously used to treat staphylococcal infections. It is no longer used clinically because of its toxicity. It causes platelet agglutination and blood coagulation and is used to assay those functions in vitro, e.g. to diagnose von Willebrand disease (vWD) or the Bernard-Soulier syndrome. Platelet agglutination caused by ristocetin can occur only in the presence of large multimers of von Willebrand factor, so if ristocetin is added to blood lacking the factor (or its receptor -- see below), it will not coagulate.
In some types of vWD (types 2B and platelet-type), lower than normal amounts of ristocetin cause platelet aggregation when the patient's platelet-rich plasma is used.[1] This paradox is explained by these types having gain-of-function mutations which cause the vWD high molecular-weight multimers to bind more tightly to their receptors on platelets (the alpha chains of glycoprotein Ib (GPIb) receptors). In the case of type 2B vWD, the gain-of-function mutation involves von Willebrand's factor (VWF gene), and in platelet-type vWD, the receptor is the object of the mutation (GPIb). This increased binding causes vWD because the high-molecular weight multimers are removed from circulation in plasma since they remain attached to the patient's platelets. Thus, if the patient's platelet-poor plasma is used, the ristocetin cofactor assay will not agglutinate "standardized (ie., pooled platelets from normal donors which are fixed in formalin)" platelets, similar to the other types of vWD.
In all forms of the ristocetin assay, the platelets are fixed in formalin prior to the assay to prevent von Willebrand's factor stored in platelet granules from being released and participating in platelet aggregation. Thus, the ristocetin cofactor activity depends only upon high-molecular multimers of the factor present in circulating plasma. | https://www.wikidoc.org/index.php/Ristocetin | |
ebe8c8db9b00f657c0ccf195360a085694f21b45 | wikidoc | Rocuronium | Rocuronium
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Rocuronium is a skeletal muscle relaxant, neuromuscular blocking drug that is FDA approved for the {{{indicationType}}} of general anesthesia; adjunct - induction of neuromuscular blockade, during surgery or mechanical ventilation, induction of neuromuscular blockade intubation, routine tracheal, rapid sequence intubation.. Common adverse reactions include cardiovascular: hypertension (0.1% to 2% ), hypotension (0.1% to 2% ), tachycardia (less than 1% to 5.3% )dermatologic: injection site pain, respiratory: Increased pulmonary vascular resistance (24% ).
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosage should be individualized and guided by neuromuscular transmission recovery.
- Induction of neuromuscular blockade, During surgery or mechanical ventilation
- Initial, 0.6 mg/kg IV
- Maintenance, 0.1 to 0.2 mg/kg IV push, repeat as needed or 0.01 to 0.012 mg/kg/minute continuous IV infusion.
- Initial, (regardless of anesthesic technique) 0.6 mg/kg IV; or a lower dose of 0.45 mg/kg IV may be used.
- Initial, (with opioid/nitrous oxide/oxygen anesthesia) 0.9 or 1.2 mg/kg large bolus may be used.
- Maintenance, (only after spontaneous recovery from intubation dose) 0.1 to 0.2 mg/kg IV , repeat as needed or 0.01 to 0.012 mg/kg/minute continuous IV infusion.
- Preinduction defasciculating dose: 0.05 to 0.06 mg/kg IV 1.5-3 min prior to succinylcholine administration.
- Rapid sequence intubation: 0.6 to 1.2 mg/kg IV.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- Premedication for anesthetic procedure, Preinduction defasciculating dose.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Rocuronium in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Induction of neuromuscular blockade, during surgery or mechanical ventilation: 3 mo to 14 yr
- Initial, 0.6 mg/kg/dose IV
- Maintenance, 0.075 to 0.15 mg/kg IV push as needed (anesthetic agent dependent) or 0.012 mg/kg/min continuous IV infusion
- Induction of neuromuscular blockade - Intubation, Routine tracheal: 3 mo to 14 yr
- Initial, 0.6 mg/kg/dose IV
- Initial, (anesthetic technique and age dependent) 0.45 mg/kg IV may be used
- Maintenance, 0.075 to 0.125 mg/kg IV push as needed or 0.012 mg/kg/min continuous IV infusion
- Rapid sequence intubation: not recommended in pediatric patients although 0.6 to 1.2 mg/kg IV have been used in clinical trials
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- Premedication for anesthetic procedure, Preinduction defasciculating dose
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Rocuronium in pediatric patients.
# Contraindications
- Rocuronium is contraindicated in patients known to have hypersensitivity (e.g., anaphylaxis) to rocuronium bromide or other neuromuscular blocking agents.
# Warnings
### Appropriate Administration and Monitoring
- Rocuronium should be administered in carefully adjusted dosages by or under the supervision of experienced clinicians who are familiar with the drug's actions and the possible complications of its use. The drug should not be administered unless facilities for intubation, mechanical ventilation, oxygen therapy, and an antagonist are immediately available. It is recommended that clinicians administering neuromuscular blocking agents such as Rocuronium employ a peripheral nerve stimulator to monitor drug effect, need for additional doses, adequacy of spontaneous recovery or antagonism, and to decrease the complications of overdosage if additional doses are administered.
### Anaphylaxis
- Severe anaphylactic reactions to neuromuscular blocking agents, including Rocuronium, have been reported. These reactions have, in some cases (including cases with Rocuronium), been life threatening and fatal. Due to the potential severity of these reactions, the necessary precautions, such as the immediate availability of appropriate emergency treatment, should be taken. Precautions should also be taken in those patients who have had previous anaphylactic reactions to other neuromuscular blocking agents, since cross-reactivity between neuromuscular blocking agents, both depolarizing and nondepolarizing, has been reported.
### Need for Adequate Anesthesia
- Rocuronium has no known effect on consciousness, pain threshold, or cerebration. Therefore, its administration must be accompanied by adequate anesthesia or sedation.
### Residual Paralysis
- In order to prevent complications resulting from residual paralysis, it is recommended to extubate only after the patient has recovered sufficiently from neuromuscular block. Other factors which could cause residual paralysis after extubation in the post-operative phase (such as drug interactions or patient condition) should also be considered. If not used as part of standard clinical practice the use of a reversal agent should be considered, especially in those cases where residual paralysis is more likely to occur.
### Long-Term Use in an Intensive Care Unit
- Rocuronium has not been studied for long-term use in the intensive care unit (ICU). As with other nondepolarizing neuromuscular blocking drugs, apparent tolerance to Rocuronium may develop during chronic administration in the ICU. While the mechanism for development of this resistance is not known, receptor up-regulation may be a contributing factor. It is strongly recommended that neuromuscular transmission be monitored continuously during administration and recovery with the help of a nerve stimulator. Additional doses of Rocuronium or any other neuromuscular blocking agent should not be given until there is a definite response (one twitch of the train-of-four) to nerve stimulation. Prolonged paralysis and/or skeletal muscle weakness may be noted during initial attempts to wean from the ventilator patients who have chronically received neuromuscular blocking drugs in the ICU.
- Myopathy after long-term administration of other nondepolarizing neuromuscular blocking agents in the ICU alone or in combination with corticosteroid therapy has been reported. Therefore, for patients receiving both neuromuscular blocking agents and corticosteroids, the period of use of the neuromuscular blocking agent should be limited as much as possible and only used in the setting where in the opinion of the prescribing physician, the specific advantages of the drug outweigh the risk.
### Malignant Hyperthermia (MH)
- Rocuronium has not been studied in MH-susceptible patients. Because Rocuronium is always used with other agents, and the occurrence of malignant hyperthermia during anesthesia is possible even in the absence of known triggering agents, clinicians should be familiar with early signs, confirmatory diagnosis, and treatment of malignant hyperthermia prior to the start of any anesthetic.
- In an animal study in MH-susceptible swine, the administration of Rocuronium Injection did not appear to trigger malignant hyperthermia.
### Prolonged Circulation Time
- Conditions associated with an increased circulatory delayed time, e.g., cardiovascular disease or advanced age, may be associated with a delay in onset time .
### QT Interval Prolongation
- The overall analysis of ECG data in pediatric patients indicates that the concomitant use of Rocuronium with general anesthetic agents can prolong the QTc interval .
### Conditions/Drugs Causing Potentiation of, or Resistance to, Neuromuscular Block
- Potentiation: Nondepolarizing neuromuscular blocking agents have been found to exhibit profound neuromuscular blocking effects in cachectic or debilitated patients, patients with neuromuscular diseases, and patients with carcinomatosis.
- Certain inhalation anesthetics, particularly enflurane and isoflurane, antibiotics, magnesium salts, lithium, local anesthetics, procainamide, and quinidine have been shown to increase the duration of neuromuscular block and decrease infusion requirements of neuromuscular blocking agents .
- In these or other patients in whom potentiation of neuromuscular block or difficulty with reversal may be anticipated, a decrease from the recommended initial dose of Rocuronium should be considered .
- Resistance: Resistance to nondepolarizing agents, consistent with up-regulation of skeletal muscle acetylcholine receptors, is associated with burns, disuse atrophy, denervation, and direct muscle trauma. Receptor up-regulation may also contribute to the resistance to nondepolarizing muscle relaxants which sometimes develops in patients with cerebral palsy, patients chronically receiving anticonvulsant agents such as carbamazepine or phenytoin, or with chronic exposure to nondepolarizing agents. When Rocuronium is administered to these patients, shorter durations of neuromuscular block may occur, and infusion rates may be higher due to the development of resistance to nondepolarizing muscle relaxants.
- Potentiation or Resistance: Severe acid-base and/or electrolyte abnormalities may potentiate or cause resistance to the neuromuscular blocking action of Rocuronium. No data are available in such patients and no dosing recommendations can be made.
- Rocuronium-induced neuromuscular blockade was modified by alkalosis and acidosis in experimental pigs. Both respiratory and metabolic acidosis prolonged the recovery time. The potency of Rocuronium was significantly enhanced in metabolic acidosis and alkalosis, but was reduced in respiratory alkalosis. In addition, experience with other drugs has suggested that acute (e.g., diarrhea) or chronic (e.g., adrenocortical insufficiency) electrolyte imbalance may alter neuromuscular blockade. Since electrolyte imbalance and acid-base imbalance are usually mixed, either enhancement or inhibition may occur.
### Incompatibility with Alkaline Solutions
- Rocuronium, which has an acid pH, should not be mixed with alkaline solutions (e.g., barbiturate solutions) in the same syringe or administered simultaneously during intravenous infusion through the same needle.
### Increase in Pulmonary Vascular Resistance
- Rocuronium may be associated with increased pulmonary vascular resistance, so caution is appropriate in patients with pulmonary hypertension or valvular heart disease .
### Use In Patients with Myasthenia
- In patients with myasthenia gravis or myasthenic (Eaton-Lambert) syndrome, small doses of nondepolarizing neuromuscular blocking agents may have profound effects. In such patients, a peripheral nerve stimulator and use of a small test dose may be of value in monitoring the response to administration of muscle relaxants.
### Extravasation
- If extravasation occurs, it may be associated with signs or symptoms of local irritation. The injection or infusion should be terminated immediately and restarted in another vein.
# Adverse Reactions
## Clinical Trials Experience
- In clinical trials, the most common adverse reactions (2%) are transient hypotension and hypertension.
- The following adverse reactions are described, or described in greater detail, in other sections:
- Anaphylaxis
- Residual paralysis
- Myopathy
- Increased pulmonary vascular resistance
### Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- Clinical studies in the US (n=1137) and Europe (n=1394) totaled 2531 patients. The patients exposed in the US clinical studies provide the basis for calculation of adverse reaction rates. The following adverse reactions were reported in patients administered Rocuronium (all events judged by investigators during the clinical trials to have a possible causal relationship):
- Adverse reactions in greater than 1% of patients: None
- Adverse reactions in less than 1% of patients (probably related or relationship unknown):
- Cardiovascular: arrhythmia, abnormal electrocardiogram, tachycardia
- Digestive: nausea, vomiting
- Respiratory: asthma (bronchospasm, wheezing, or rhonchi), hiccup
- Skin and Appendages: rash, injection site edema, pruritus
- In the European studies, the most commonly reported reactions were transient hypotension (2%) and hypertension (2%); these are in greater frequency than the US studies (0.1% and 0.1%). Changes in heart rate and blood pressure were defined differently from in the US studies in which changes in cardiovascular parameters were not considered as adverse events unless judged by the investigator as unexpected, clinically significant, or thought to be histamine related.
- In a clinical study in patients with clinically significant cardiovascular disease undergoing coronary artery bypass graft, hypertension and tachycardia were reported in some patients, but these occurrences were less frequent in patients receiving beta or calcium channel-blocking drugs. In some patients, Rocuronium was associated with transient increases (30% or greater) in pulmonary vascular resistance. In another clinical study of patients undergoing abdominal aortic surgery, transient increases (30% or greater) in pulmonary vascular resistance were observed in about 24% of patients receiving Rocuronium 0.6 or 0.9 mg/kg.
- In pediatric patient studies worldwide (n=704), tachycardia occurred at an incidence of 5.3% (n=37), and it was judged by the investigator as related in 10 cases (1.4%).
## Postmarketing Experience
- In clinical practice, there have been reports of severe allergic reactions (anaphylactic and anaphylactoid reactions and shock) with Rocuronium, including some that have been life-threatening and fatal .
- Because these reactions were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency.
# Drug Interactions
### Antibiotics
- Drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as Rocuronium include certain antibiotics (e.g., aminoglycosides; vancomycin; tetracyclines; bacitracin; polymyxins; colistin; and sodium colistimethate). If these antibiotics are used in conjunction with Rocuronium, prolongation of neuromuscular block may occur.
### Anticonvulsants
- In 2 of 4 patients receiving chronic anticonvulsant therapy, apparent resistance to the effects of Rocuronium was observed in the form of diminished magnitude of neuromuscular block, or shortened clinical duration. As with other nondepolarizing neuromuscular blocking drugs, if Rocuronium is administered to patients chronically receiving anticonvulsant agents such as carbamazepine or phenytoin, shorter durations of neuromuscular block may occur and infusion rates may be higher due to the development of resistance to nondepolarizing muscle relaxants. While the mechanism for development of this resistance is not known, receptor up-regulation may be a contributing factor .
### Inhalation Anesthetics
- Use of inhalation anesthetics has been shown to enhance the activity of other neuromuscular blocking agents (enflurane > isoflurane > halothane).
- Isoflurane and enflurane may also prolong the duration of action of initial and maintenance doses of Rocuronium and decrease the average infusion requirement of Rocuronium by 40% compared to opioid/nitrous oxide/oxygen anesthesia. No definite interaction between Rocuronium and halothane has been demonstrated. In one study, use of enflurane in 10 patients resulted in a 20% increase in mean clinical duration of the initial intubating dose, and a 37% increase in the duration of subsequent maintenance doses, when compared in the same study to 10 patients under opioid/nitrous oxide/oxygen anesthesia. The clinical duration of initial doses of Rocuronium of 0.57 to 0.85 mg/kg under enflurane or isoflurane anesthesia, as used clinically, was increased by 11% and 23%, respectively. The duration of maintenance doses was affected to a greater extent, increasing by 30% to 50% under either enflurane or isoflurane anesthesia.
- Potentiation by these agents is also observed with respect to the infusion rates of Rocuronium required to maintain approximately 95% neuromuscular block. Under isoflurane and enflurane anesthesia, the infusion rates are decreased by approximately 40% compared to opioid/nitrous oxide/oxygen anesthesia. The median spontaneous recovery time (from 25% to 75% of control T1) is not affected by halothane, but is prolonged by enflurane (15% longer) and isoflurane (62% longer). Reversal-induced recovery of Rocuronium neuromuscular block is minimally affected by anesthetic technique .
### Lithium Carbonate
- Lithium has been shown to increase the duration of neuromuscular block and decrease infusion requirements of neuromuscular blocking agents .
### Local Anesthetics
- Local anesthetics have been shown to increase the duration of neuromuscular block and decrease infusion requirements of neuromuscular blocking agents .
### Magnesium
- Magnesium salts administered for the management of toxemia of pregnancy may enhance neuromuscular blockade .
### Nondepolarizing Muscle Relaxants
- There are no controlled studies documenting the use of Rocuronium before or after other nondepolarizing muscle relaxants. Interactions have been observed when other nondepolarizing muscle relaxants have been administered in succession.
### Procainamide
- Procainamide has been shown to increase the duration of neuromuscular block and decrease infusion requirements of neuromuscular blocking agents .
### Propofol
- The use of propofol for induction and maintenance of anesthesia does not alter the clinical duration or recovery characteristics following recommended doses of Rocuronium.
### Quinidine
- Injection of quinidine during recovery from use of muscle relaxants is associated with recurrent paralysis. This possibility must also be considered for Rocuronium .
### Succinylcholine
- The use of Rocuronium before succinylcholine, for the purpose of attenuating some of the side effects of succinylcholine, has not been studied.
- If Rocuronium is administered following administration of succinylcholine, it should not be given until recovery from succinylcholine has been observed. The median duration of action of Rocuronium 0.6 mg/kg administered after a 1 mg/kg dose of succinylcholine when T1 returned to 75% of control was 36 minutes (range: 14-57, n=12) vs. 28 minutes (range: 17-51, n=12) without succinylcholine.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Developmental toxicology studies have been performed with rocuronium bromide in pregnant, conscious, nonventilated rabbits and rats. Inhibition of neuromuscular function was the endpoint for high-dose selection. The maximum tolerated dose served as the high dose and was administered intravenously 3 times a day to rats (0.3 mg/kg, 15%-30% of human intubation dose of 0.6-1.2 mg/kg based on the body surface unit of mg/m2) from Day 6 to 17 and to rabbits (0.02 mg/kg, 25% human dose) from Day 6 to 18 of pregnancy. High-dose treatment caused acute symptoms of respiratory dysfunction due to the pharmacological activity of the drug. Teratogenicity was not observed in these animal species. The incidence of late embryonic death was increased at the high dose in rats, most likely due to oxygen deficiency. Therefore, this finding probably has no relevance for humans because immediate mechanical ventilation of the intubated patient will effectively prevent embryo-fetal hypoxia. However, there are no adequate and well-controlled studies in pregnant women. Rocuronium should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Rocuronium in women who are pregnant.
### Labor and Delivery
- The use of Rocuronium in Cesarean section has been studied in a limited number of patients . Rocuronium is not recommended for rapid sequence induction in Cesarean section patients.
### Nursing Mothers
There is no FDA guidance on the use of Rocuronium in women who are nursing.
### Pediatric Use
- The use of Rocuronium has been studied in pediatric patients 3 months to 14 years of age under halothane anesthesia. Of the pediatric patients anesthetized with halothane who did not receive atropine for induction, about 80% experienced a transient increase (30% or greater) in heart rate after intubation. One of the 19 infants anesthetized with halothane and fentanyl who received atropine for induction experienced this magnitude of change .
- Rocuronium was also studied in pediatric patients up to 17 years of age, including neonates, under sevoflurane (induction) and isoflurane/nitrous oxide (maintenance) anesthesia. Onset time and clinical duration varied with dose, the age of the patient, and anesthetic technique. The overall analysis of ECG data in pediatric patients indicates that the concomitant use of Rocuronium with general anesthetic agents can prolong the QTc interval. The data also suggest that Rocuronium may increase heart rate. However, it was not possible to conclusively identify an effect of Rocuronium independent of that of anesthesia and other factors. Additionally, when examining plasma levels of Rocuronium in correlation to QTc interval prolongation, no relationship was observed .
- Rocuronium is not recommended for rapid sequence intubation in pediatric patients. Recommendations for use in pediatric patients are discussed in other sections .
### Geriatic Use
- Rocuronium was administered to 140 geriatric patients (65 years or greater) in US clinical trials and 128 geriatric patients in European clinical trials. The observed pharmacokinetic profile for geriatric patients (n=20) was similar to that for other adult surgical patients . Onset time and duration of action were slightly longer for geriatric patients (n=43) in clinical trials. Clinical experiences and recommendations for use in geriatric patients are discussed in other sections .
### Gender
There is no FDA guidance on the use of Rocuronium with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Rocuronium with respect to specific racial populations.
### Renal Impairment
- Due to the limited role of the kidney in the excretion of Rocuronium, usual dosing guidelines should be followed. In patients with renal dysfunction, the duration of neuromuscular blockade was not prolonged; however, there was substantial individual variability (range: 22-90 minutes) .
### Hepatic Impairment
- Since Rocuronium is primarily excreted by the liver, it should be used with caution in patients with clinically significant hepatic impairment. Rocuronium 0.6 mg/kg has been studied in a limited number of patients (n=9) with clinically significant hepatic impairment under steady-state isoflurane anesthesia. After Rocuronium 0.6 mg/kg, the median (range) clinical duration of 60 (35-166) minutes was moderately prolonged compared to 42 minutes in patients with normal hepatic function. The median recovery time of 53 minutes was also prolonged in patients with cirrhosis compared to 20 minutes in patients with normal hepatic function. Four of 8 patients with cirrhosis, who received Rocuronium 0.6 mg/kg under opioid/nitrous oxide/oxygen anesthesia, did not achieve complete block. These findings are consistent with the increase in volume of distribution at steady state observed in patients with significant hepatic impairment . If used for rapid sequence induction in patients with ascites, an increased initial dosage may be necessary to assure complete block. Duration will be prolonged in these cases. The use of doses higher than 0.6 mg/kg has not been studied .
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Rocuronium in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Rocuronium in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Rocuronium Administration in the drug label.
### Monitoring
There is limited information regarding Rocuronium Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Rocuronium and IV administrations.
# Overdosage
- Overdosage with neuromuscular blocking agents may result in neuromuscular block beyond the time needed for surgery and anesthesia. The primary treatment is maintenance of a patent airway, controlled ventilation, and adequate sedation until recovery of normal neuromuscular function is assured. Once evidence of recovery from neuromuscular block is observed, further recovery may be facilitated by administration of an anticholinesterase agent in conjunction with an appropriate anticholinergic agent.
- Reversal of Neuromuscular Blockade: Anticholinesterase agents should not be administered prior to the demonstration of some spontaneous recovery from neuromuscular blockade. The use of a nerve stimulator to document recovery is recommended.
- Patients should be evaluated for adequate clinical evidence of neuromuscular recovery, e.g., 5-second head lift, adequate phonation, ventilation, and upper airway patency. Ventilation must be supported while patients exhibit any signs of muscle weakness.
- Recovery may be delayed in the presence of debilitation, carcinomatosis, and concomitant use of certain drugs which enhance neuromuscular blockade or separately cause respiratory depression. Under such circumstances the management is the same as that of prolonged neuromuscular blockade.
# Pharmacology
## Mechanism of Action
- Rocuronium is a nondepolarizing neuromuscular blocking agent with a rapid to intermediate onset depending on dose and intermediate duration. It acts by competing for cholinergic receptors at the motor end-plate. This action is antagonized by acetylcholinesterase inhibitors, such as neostigmine and edrophonium.
## Structure
- Rocuronium (rocuronium bromide) injection is a nondepolarizing neuromuscular blocking agent with a rapid to intermediate onset depending on dose and intermediate duration. Rocuronium bromide is chemically designated as 1--1-(2-propenyl)pyrrolidinium bromide.
- The structural formula is:
- The chemical formula is C32H53BrN2O4 with a molecular weight of 609.70. The partition coefficient of rocuronium bromide in n-octanol/water is 0.5 at 20°C.
- Rocuronium is supplied as a sterile, nonpyrogenic, isotonic solution that is clear, colorless to yellow/orange, for intravenous injection only. Each mL contains 10 mg rocuronium bromide and 2 mg sodium acetate. The aqueous solution is adjusted to isotonicity with sodium chloride and to a pH of 4 with acetic acid and/or sodium hydroxide.
## Pharmacodynamics
- The ED95 (dose required to produce 95% suppression of the first mechanomyographic response of the adductor pollicis muscle to indirect supramaximal train-of-four stimulation of the ulnar nerve) during opioid/nitrous oxide/oxygen anesthesia is approximately 0.3 mg/kg. Patient variability around the ED95 dose suggests that 50% of patients will exhibit T1 depression of 91% to 97%.
Table 4 presents intubating conditions in patients with intubation initiated at 60 to 70 seconds.
- Once spontaneous recovery has reached 25% of control T1, the neuromuscular block produced by Rocuronium is readily reversed with anticholinesterase agents, e.g., edrophonium or neostigmine.
- The median spontaneous recovery from 25% to 75% T1 was 13 minutes in adult patients. When neuromuscular block was reversed in 36 adults at a T1 of 22% to 27%, recovery to a T1 of 89 (50-132)% and T4/T1 of 69 (38-92)% was achieved within 5 minutes. Only 5 of 320 adults reversed received an additional dose of reversal agent. The median (range) dose of neostigmine was 0.04 (0.01-0.09) mg/kg and the median (range) dose of edrophonium was 0.5 (0.3-1.0) mg/kg.
- In geriatric patients (n=51) reversed with neostigmine, the median T4/T1 increased from 40% to 88% in 5 minutes.
- In clinical trials with halothane, pediatric patients (n=27) who received 0.5 mg/kg edrophonium had increases in the median T4/T1 from 37% at reversal to 93% after 2 minutes. Pediatric patients (n=58) who received 1 mg/kg edrophonium had increases in the median T4/T1 from 72% at reversal to 100% after 2 minutes. Infants (n=10) who were reversed with 0.03 mg/kg neostigmine recovered from 25% to 75% T1 within 4 minutes.
- There were no reports of less than satisfactory clinical recovery of neuromuscular function.
- The neuromuscular blocking action of Rocuronium may be enhanced in the presence of potent inhalation anesthetics .
- There were no dose-related effects on the incidence of changes from baseline (30% or greater) in mean arterial blood pressure (MAP) or heart rate associated with Rocuronium administration over the dose range of 0.12 to 1.2 mg/kg (4 × ED95) within 5 minutes after Rocuronium administration and prior to intubation. Increases or decreases in MAP were observed in 2% to 5% of geriatric and other adult patients, and in about 1% of pediatric patients. Heart rate changes (30% or greater) occurred in 0% to 2% of geriatric and other adult patients. Tachycardia (30% or greater) occurred in 12 of 127 pediatric patients. Most of the pediatric patients developing tachycardia were from a single study where the patients were anesthetized with halothane and who did not receive atropine for induction . In US studies, laryngoscopy and tracheal intubation following Rocuronium administration were accompanied by transient tachycardia (30% or greater increases) in about one-third of adult patients under opioid/nitrous oxide/oxygen anesthesia. Animal studies have indicated that the ratio of vagal:neuromuscular block following Rocuronium administration is less than vecuronium but greater than pancuronium. The tachycardia observed in some patients may result from this vagal blocking activity.
- In studies of histamine release, clinically significant concentrations of plasma histamine occurred in 1 of 88 patients. Clinical signs of histamine release (flushing, rash, or bronchospasm) associated with the administration of Rocuronium were assessed in clinical trials and reported in 9 of 1137 (0.8%) patients.
## Pharmacokinetics
- In an effort to maximize the information gathered in the in vivo pharmacokinetic studies, the data from the studies was used to develop population estimates of the parameters for the subpopulations represented (e.g., geriatric, pediatric, renal, and hepatic impairment). These population-based estimates and a measure of the estimate variability are contained in the following section.
- Following intravenous administration of Rocuronium, plasma levels of rocuronium follow a three-compartment open model. The rapid distribution half-life is 1 to 2 minutes and the slower distribution half-life is 14 to 18 minutes. Rocuronium is approximately 30% bound to human plasma proteins. In geriatric and other adult surgical patients undergoing either opioid/nitrous oxide/oxygen or inhalational anesthesia, the observed pharmacokinetic profile was essentially unchanged.
- In general, studies with normal adult subjects did not reveal any differences in the pharmacokinetics of rocuronium due to gender.
- Studies of distribution, metabolism, and excretion in cats and dogs indicate that rocuronium is eliminated primarily by the liver. The rocuronium analog 17-desacetyl-rocuronium, a metabolite, has been rarely observed in the plasma or urine of humans administered single doses of 0.5 to 1 mg/kg with or without a subsequent infusion (for up to 12 hr) of rocuronium. In the cat, 17-desacetyl-rocuronium has approximately one-twentieth the neuromuscular blocking potency of rocuronium. The effects of renal failure and hepatic disease on the pharmacokinetics and pharmacodynamics of rocuronium in humans are consistent with these findings.
- In general, patients undergoing cadaver kidney transplant have a small reduction in clearance which is offset pharmacokinetically by a corresponding increase in volume, such that the net effect is an unchanged plasma half-life. Patients with demonstrated liver cirrhosis have a marked increase in their volume of distribution resulting in a plasma half-life approximately twice that of patients with normal hepatic function. Table 8 shows the pharmacokinetic parameters in subjects with either impaired renal or hepatic function.
- The net result of these findings is that subjects with renal failure have clinical durations that are similar to but somewhat more variable than the duration that one would expect in subjects with normal renal function. Hepatically impaired patients, due to the large increase in volume, may demonstrate clinical durations approaching 1.5 times that of subjects with normal hepatic function. In both populations the clinician should individualize the dose to the needs of the patient .
- Tissue redistribution accounts for most (about 80%) of the initial amount of rocuronium administered. As tissue compartments fill with continued dosing (4-8 hours), less drug is redistributed away from the site of action and, for an infusion-only dose, the rate to maintain neuromuscular blockade falls to about 20% of the initial infusion rate. The use of a loading dose and a smaller infusion rate reduces the need for adjustment of dose.
- Under halothane anesthesia, the clinical duration of effects of Rocuronium did not vary with age in patients 4 months to 8 years of age. The terminal half-life and other pharmacokinetic parameters of rocuronium in these pediatric patients are presented in Table 9.
- Pharmacokinetics of Rocuronium were evaluated using a population analysis of the pooled pharmacokinetic datasets from 2 trials under sevoflurane (induction) and isoflurane/nitrous oxide (maintenance) anesthesia. All pharmacokinetic parameters were found to be linearly proportional to body weight. In patients under the age of 18 years clearance (CL) and volume of distribution (Vss) increase with bodyweight (kg) and age (years). As a result the terminal half-life of Rocuronium decreases with increasing age from 1.1 hour to 0.7-0.8 hour. Table 10 presents the pharmacokinetic parameters in the different age groups in the studies with sevoflurane (induction) and isoflurane/nitrous oxide (maintenance) anesthesia.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
- Studies in animals have not been performed with rocuronium bromide to evaluate carcinogenic potential or impairment of fertility. Mutagenicity studies (Ames test, analysis of chromosomal aberrations in mammalian cells, and micronucleus test) conducted with rocuronium bromide did not suggest mutagenic potential.
# Clinical Studies
- In US clinical studies, a total of 1137 patients received Rocuronium, including 176 pediatric, 140 geriatric, 55 obstetric, and 766 other adults. Most patients (90%) were ASA physical status I or II, about 9% were ASA III, and 10 patients (undergoing coronary artery bypass grafting or valvular surgery) were ASA IV. In European clinical studies, a total of 1394 patients received Rocuronium, including 52 pediatric, 128 geriatric (65 years or greater), and 1214 other adults.
- Intubation using doses of Rocuronium 0.6 to 0.85 mg/kg was evaluated in 203 adults in 11 clinical studies. Excellent to good intubating conditions were generally achieved within 2 minutes and maximum block occurred within 3 minutes in most patients. Doses within this range provide clinical relaxation for a median (range) time of 33 (14-85) minutes under opioid/nitrous oxide/oxygen anesthesia. Larger doses (0.9 and 1.2 mg/kg) were evaluated in 2 studies with 19 and 16 patients under opioid/nitrous oxide/oxygen anesthesia and provided 58 (27-111) and 67 (38-160) minutes of clinical relaxation, respectively.
- In 1 clinical study, 10 patients with clinically significant cardiovascular disease undergoing coronary artery bypass graft received an initial dose of 0.6 mg/kg Rocuronium. Neuromuscular block was maintained during surgery with bolus maintenance doses of 0.3 mg/kg. Following induction, continuous 8 mcg/kg/min infusion of Rocuronium produced relaxation sufficient to support mechanical ventilation for 6 to 12 hours in the surgical intensive care unit (SICU) while the patients were recovering from surgery.
- Intubating conditions were assessed in 230 patients in 6 clinical studies where anesthesia was induced with either thiopental (3-6 mg/kg) or propofol (1.5-2.5 mg/kg) in combination with either fentanyl (2-5 mcg/kg) or alfentanil (1 mg). Most of the patients also received a premedication such as midazolam or temazepam. Most patients had intubation attempted within 60 to 90 seconds of administration of Rocuronium 0.6 mg/kg or succinylcholine 1 to 1.5 mg/kg. Excellent or good intubating conditions were achieved in 119/120 (99% ) patients receiving Rocuronium and in 108/110 (98% ) patients receiving succinylcholine. The duration of action of Rocuronium 0.6 mg/kg is longer than succinylcholine and at this dose is approximately equivalent to the duration of other intermediate-acting neuromuscular blocking drugs.
- Rocuronium was dosed according to actual body weight (ABW) in most clinical studies. The administration of Rocuronium in the 47 of 330 (14%) patients who were at least 30% or more above their ideal body weight (IBW) was not associated with clinically significant differences in the onset, duration, recovery, or reversal of Rocuronium-induced neuromuscular block.
- In 1 clinical study in obese patients, Rocuronium 0.6 mg/kg was dosed according to ABW (n=12) or IBW (n=11). Obese patients dosed according to IBW had a longer time to maximum block, a shorter median (range) clinical duration of 25 (14-29) minutes, and did not achieve intubating conditions comparable to those dosed based on ABW. These results support the recommendation that obese patients be dosed based on actual body weight .
- Rocuronium 0.6 mg/kg was administered with thiopental, 3 to 4 mg/kg (n=13) or 4 to 6 mg/kg (n=42), for rapid sequence induction of anesthesia for Cesarean section. No neonate had APGAR scores greater than 7 at 5 minutes. The umbilical venous plasma concentrations were 18% of maternal concentrations at delivery. Intubating conditions were poor or inadequate in 5 of 13 women receiving 3 to 4 mg/kg thiopental when intubation was attempted 60 seconds after drug injection. Therefore, Rocuronium is not recommended for rapid sequence induction in Cesarean section patients.
- Rocuronium was evaluated in 55 geriatric patients (ages 65-80 years) in 6 clinical studies. Doses of 0.6 mg/kg provided excellent to good intubating conditions in a median (range) time of 2.3 (1-8) minutes. Recovery times from 25% to 75% after these doses were not prolonged in geriatric patients compared to other adult patients .
- Rocuronium 0.45, 0.6, or 1 mg/kg was evaluated under sevoflurane (induction) and isoflurane/nitrous oxide (maintenance) anesthesia for intubation in 326 patients in 2 studies. In 1 of these studies maintenance bolus and infusion requirements were evaluated in 137 patients. In all age groups, doses of 0.6 mg/kg provided time to maximum block in about 1 minute. Across all age groups, median (range) time to reappearance of T3 for doses of 0.6 mg/kg was shortest in the children and longest in infants . For pediatric patients older than 3 months, the time to recovery was shorter after stopping infusion maintenance when compared with bolus maintenance .
- Rocuronium 0.6 or 0.8 mg/kg was evaluated for intubation in 75 pediatric patients (n=28; age 3-12 months, n=47; age 1-12 years) in 3 studies using halothane (1%-5%) and nitrous oxide (60%-70%) in oxygen. Doses of 0.6 mg/kg provided a median (range) time to maximum block of 1 (0.5-3.3) minute(s). This dose provided a median (range) time of clinical relaxation of 41 (24-68) minutes in 3-month to 1-year-old infants and 26 (17-39) minutes in 1- to 12-year-old pediatric patients .
# How Supplied
- Rocuronium (rocuronium bromide) injection is available in the following:
- The packaging of this product contains no natural rubber (latex)
## Storage
- Rocuronium should be stored in a refrigerator, 2-8°C (36-46°F). DO NOT FREEZE. Upon removal from refrigeration to room temperature storage conditions (25°C/77°F), use Rocuronium within 60 days. Use opened vials of Rocuronium within 30 days.
### Safety and Handling
- There is no specific work exposure limit for Rocuronium. In case of eye contact, flush with water for at least 10 minutes.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Obtain information about your patient's medical history, current medications, any history of hypersensitivity to rocuronium bromide or other neuromuscular blocking agents. If applicable, inform your patients that certain medical conditions and medications might influence how Rocuronium works.
- In addition, inform your patient that severe anaphylactic reactions to neuromuscular blocking agents, including Rocuronium, have been reported. Since allergic cross-reactivity has been reported in this class, request information from your patients about previous anaphylactic reactions to other neuromuscular blocking agents.
# Precautions with Alcohol
Alcohol-Rocuronium interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
There is limited information regarding Rocuronium Brand Names in the drug label.
# Look-Alike Drug Names
There is limited information regarding Rocuronium Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Rocuronium
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Chetan Lokhande, M.B.B.S [2]
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# Overview
Rocuronium is a skeletal muscle relaxant, neuromuscular blocking drug that is FDA approved for the {{{indicationType}}} of general anesthesia; adjunct - induction of neuromuscular blockade, during surgery or mechanical ventilation, induction of neuromuscular blockade intubation, routine tracheal, rapid sequence intubation.. Common adverse reactions include cardiovascular: hypertension (0.1% to 2% ), hypotension (0.1% to 2% ), tachycardia (less than 1% to 5.3% )dermatologic: injection site pain, respiratory: Increased pulmonary vascular resistance (24% ).
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosage should be individualized and guided by neuromuscular transmission recovery.
- Induction of neuromuscular blockade, During surgery or mechanical ventilation
- Initial, 0.6 mg/kg IV
- Maintenance, 0.1 to 0.2 mg/kg IV push, repeat as needed or 0.01 to 0.012 mg/kg/minute continuous IV infusion.
- Initial, (regardless of anesthesic technique) 0.6 mg/kg IV; or a lower dose of 0.45 mg/kg IV may be used.
- Initial, (with opioid/nitrous oxide/oxygen anesthesia) 0.9 or 1.2 mg/kg large bolus may be used.
- Maintenance, (only after spontaneous recovery from intubation dose) 0.1 to 0.2 mg/kg IV , repeat as needed or 0.01 to 0.012 mg/kg/minute continuous IV infusion.
- Preinduction defasciculating dose: 0.05 to 0.06 mg/kg IV 1.5-3 min prior to succinylcholine administration.
- Rapid sequence intubation: 0.6 to 1.2 mg/kg IV.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- Premedication for anesthetic procedure, Preinduction defasciculating dose.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Rocuronium in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Induction of neuromuscular blockade, during surgery or mechanical ventilation: 3 mo to 14 yr
- Initial, 0.6 mg/kg/dose IV
- Maintenance, 0.075 to 0.15 mg/kg IV push as needed (anesthetic agent dependent) or 0.012 mg/kg/min continuous IV infusion
- Induction of neuromuscular blockade - Intubation, Routine tracheal: 3 mo to 14 yr
- Initial, 0.6 mg/kg/dose IV
- Initial, (anesthetic technique and age dependent) 0.45 mg/kg IV may be used
- Maintenance, 0.075 to 0.125 mg/kg IV push as needed or 0.012 mg/kg/min continuous IV infusion
- Rapid sequence intubation: not recommended in pediatric patients although 0.6 to 1.2 mg/kg IV have been used in clinical trials
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- Premedication for anesthetic procedure, Preinduction defasciculating dose
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Rocuronium in pediatric patients.
# Contraindications
- Rocuronium is contraindicated in patients known to have hypersensitivity (e.g., anaphylaxis) to rocuronium bromide or other neuromuscular blocking agents.
# Warnings
### Appropriate Administration and Monitoring
- Rocuronium should be administered in carefully adjusted dosages by or under the supervision of experienced clinicians who are familiar with the drug's actions and the possible complications of its use. The drug should not be administered unless facilities for intubation, mechanical ventilation, oxygen therapy, and an antagonist are immediately available. It is recommended that clinicians administering neuromuscular blocking agents such as Rocuronium employ a peripheral nerve stimulator to monitor drug effect, need for additional doses, adequacy of spontaneous recovery or antagonism, and to decrease the complications of overdosage if additional doses are administered.
### Anaphylaxis
- Severe anaphylactic reactions to neuromuscular blocking agents, including Rocuronium, have been reported. These reactions have, in some cases (including cases with Rocuronium), been life threatening and fatal. Due to the potential severity of these reactions, the necessary precautions, such as the immediate availability of appropriate emergency treatment, should be taken. Precautions should also be taken in those patients who have had previous anaphylactic reactions to other neuromuscular blocking agents, since cross-reactivity between neuromuscular blocking agents, both depolarizing and nondepolarizing, has been reported.
### Need for Adequate Anesthesia
- Rocuronium has no known effect on consciousness, pain threshold, or cerebration. Therefore, its administration must be accompanied by adequate anesthesia or sedation.
### Residual Paralysis
- In order to prevent complications resulting from residual paralysis, it is recommended to extubate only after the patient has recovered sufficiently from neuromuscular block. Other factors which could cause residual paralysis after extubation in the post-operative phase (such as drug interactions or patient condition) should also be considered. If not used as part of standard clinical practice the use of a reversal agent should be considered, especially in those cases where residual paralysis is more likely to occur.
### Long-Term Use in an Intensive Care Unit
- Rocuronium has not been studied for long-term use in the intensive care unit (ICU). As with other nondepolarizing neuromuscular blocking drugs, apparent tolerance to Rocuronium may develop during chronic administration in the ICU. While the mechanism for development of this resistance is not known, receptor up-regulation may be a contributing factor. It is strongly recommended that neuromuscular transmission be monitored continuously during administration and recovery with the help of a nerve stimulator. Additional doses of Rocuronium or any other neuromuscular blocking agent should not be given until there is a definite response (one twitch of the train-of-four) to nerve stimulation. Prolonged paralysis and/or skeletal muscle weakness may be noted during initial attempts to wean from the ventilator patients who have chronically received neuromuscular blocking drugs in the ICU.
- Myopathy after long-term administration of other nondepolarizing neuromuscular blocking agents in the ICU alone or in combination with corticosteroid therapy has been reported. Therefore, for patients receiving both neuromuscular blocking agents and corticosteroids, the period of use of the neuromuscular blocking agent should be limited as much as possible and only used in the setting where in the opinion of the prescribing physician, the specific advantages of the drug outweigh the risk.
### Malignant Hyperthermia (MH)
- Rocuronium has not been studied in MH-susceptible patients. Because Rocuronium is always used with other agents, and the occurrence of malignant hyperthermia during anesthesia is possible even in the absence of known triggering agents, clinicians should be familiar with early signs, confirmatory diagnosis, and treatment of malignant hyperthermia prior to the start of any anesthetic.
- In an animal study in MH-susceptible swine, the administration of Rocuronium Injection did not appear to trigger malignant hyperthermia.
### Prolonged Circulation Time
- Conditions associated with an increased circulatory delayed time, e.g., cardiovascular disease or advanced age, may be associated with a delay in onset time [see Dosage and Administration].
### QT Interval Prolongation
- The overall analysis of ECG data in pediatric patients indicates that the concomitant use of Rocuronium with general anesthetic agents can prolong the QTc interval [see Clinical Studies].
### Conditions/Drugs Causing Potentiation of, or Resistance to, Neuromuscular Block
- Potentiation: Nondepolarizing neuromuscular blocking agents have been found to exhibit profound neuromuscular blocking effects in cachectic or debilitated patients, patients with neuromuscular diseases, and patients with carcinomatosis.
- Certain inhalation anesthetics, particularly enflurane and isoflurane, antibiotics, magnesium salts, lithium, local anesthetics, procainamide, and quinidine have been shown to increase the duration of neuromuscular block and decrease infusion requirements of neuromuscular blocking agents [see Drug Interactions].
- In these or other patients in whom potentiation of neuromuscular block or difficulty with reversal may be anticipated, a decrease from the recommended initial dose of Rocuronium should be considered [see Dosage and Administration].
- Resistance: Resistance to nondepolarizing agents, consistent with up-regulation of skeletal muscle acetylcholine receptors, is associated with burns, disuse atrophy, denervation, and direct muscle trauma. Receptor up-regulation may also contribute to the resistance to nondepolarizing muscle relaxants which sometimes develops in patients with cerebral palsy, patients chronically receiving anticonvulsant agents such as carbamazepine or phenytoin, or with chronic exposure to nondepolarizing agents. When Rocuronium is administered to these patients, shorter durations of neuromuscular block may occur, and infusion rates may be higher due to the development of resistance to nondepolarizing muscle relaxants.
- Potentiation or Resistance: Severe acid-base and/or electrolyte abnormalities may potentiate or cause resistance to the neuromuscular blocking action of Rocuronium. No data are available in such patients and no dosing recommendations can be made.
- Rocuronium-induced neuromuscular blockade was modified by alkalosis and acidosis in experimental pigs. Both respiratory and metabolic acidosis prolonged the recovery time. The potency of Rocuronium was significantly enhanced in metabolic acidosis and alkalosis, but was reduced in respiratory alkalosis. In addition, experience with other drugs has suggested that acute (e.g., diarrhea) or chronic (e.g., adrenocortical insufficiency) electrolyte imbalance may alter neuromuscular blockade. Since electrolyte imbalance and acid-base imbalance are usually mixed, either enhancement or inhibition may occur.
### Incompatibility with Alkaline Solutions
- Rocuronium, which has an acid pH, should not be mixed with alkaline solutions (e.g., barbiturate solutions) in the same syringe or administered simultaneously during intravenous infusion through the same needle.
### Increase in Pulmonary Vascular Resistance
- Rocuronium may be associated with increased pulmonary vascular resistance, so caution is appropriate in patients with pulmonary hypertension or valvular heart disease [see Clinical Studies].
### Use In Patients with Myasthenia
- In patients with myasthenia gravis or myasthenic (Eaton-Lambert) syndrome, small doses of nondepolarizing neuromuscular blocking agents may have profound effects. In such patients, a peripheral nerve stimulator and use of a small test dose may be of value in monitoring the response to administration of muscle relaxants.
### Extravasation
- If extravasation occurs, it may be associated with signs or symptoms of local irritation. The injection or infusion should be terminated immediately and restarted in another vein.
# Adverse Reactions
## Clinical Trials Experience
- In clinical trials, the most common adverse reactions (2%) are transient hypotension and hypertension.
- The following adverse reactions are described, or described in greater detail, in other sections:
- Anaphylaxis [see Warnings and Precautions]
- Residual paralysis [see Warnings and Precautions]
- Myopathy [see Warnings and Precautions]
- Increased pulmonary vascular resistance [see Warnings and Precautions]
### Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- Clinical studies in the US (n=1137) and Europe (n=1394) totaled 2531 patients. The patients exposed in the US clinical studies provide the basis for calculation of adverse reaction rates. The following adverse reactions were reported in patients administered Rocuronium (all events judged by investigators during the clinical trials to have a possible causal relationship):
- Adverse reactions in greater than 1% of patients: None
- Adverse reactions in less than 1% of patients (probably related or relationship unknown):
- Cardiovascular: arrhythmia, abnormal electrocardiogram, tachycardia
- Digestive: nausea, vomiting
- Respiratory: asthma (bronchospasm, wheezing, or rhonchi), hiccup
- Skin and Appendages: rash, injection site edema, pruritus
- In the European studies, the most commonly reported reactions were transient hypotension (2%) and hypertension (2%); these are in greater frequency than the US studies (0.1% and 0.1%). Changes in heart rate and blood pressure were defined differently from in the US studies in which changes in cardiovascular parameters were not considered as adverse events unless judged by the investigator as unexpected, clinically significant, or thought to be histamine related.
- In a clinical study in patients with clinically significant cardiovascular disease undergoing coronary artery bypass graft, hypertension and tachycardia were reported in some patients, but these occurrences were less frequent in patients receiving beta or calcium channel-blocking drugs. In some patients, Rocuronium was associated with transient increases (30% or greater) in pulmonary vascular resistance. In another clinical study of patients undergoing abdominal aortic surgery, transient increases (30% or greater) in pulmonary vascular resistance were observed in about 24% of patients receiving Rocuronium 0.6 or 0.9 mg/kg.
- In pediatric patient studies worldwide (n=704), tachycardia occurred at an incidence of 5.3% (n=37), and it was judged by the investigator as related in 10 cases (1.4%).
## Postmarketing Experience
- In clinical practice, there have been reports of severe allergic reactions (anaphylactic and anaphylactoid reactions and shock) with Rocuronium, including some that have been life-threatening and fatal [see Warnings and Precautions (5.2)].
- Because these reactions were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency.
# Drug Interactions
### Antibiotics
- Drugs which may enhance the neuromuscular blocking action of nondepolarizing agents such as Rocuronium include certain antibiotics (e.g., aminoglycosides; vancomycin; tetracyclines; bacitracin; polymyxins; colistin; and sodium colistimethate). If these antibiotics are used in conjunction with Rocuronium, prolongation of neuromuscular block may occur.
### Anticonvulsants
- In 2 of 4 patients receiving chronic anticonvulsant therapy, apparent resistance to the effects of Rocuronium was observed in the form of diminished magnitude of neuromuscular block, or shortened clinical duration. As with other nondepolarizing neuromuscular blocking drugs, if Rocuronium is administered to patients chronically receiving anticonvulsant agents such as carbamazepine or phenytoin, shorter durations of neuromuscular block may occur and infusion rates may be higher due to the development of resistance to nondepolarizing muscle relaxants. While the mechanism for development of this resistance is not known, receptor up-regulation may be a contributing factor [see Warnings and Precautions (5.9)].
### Inhalation Anesthetics
- Use of inhalation anesthetics has been shown to enhance the activity of other neuromuscular blocking agents (enflurane > isoflurane > halothane).
- Isoflurane and enflurane may also prolong the duration of action of initial and maintenance doses of Rocuronium and decrease the average infusion requirement of Rocuronium by 40% compared to opioid/nitrous oxide/oxygen anesthesia. No definite interaction between Rocuronium and halothane has been demonstrated. In one study, use of enflurane in 10 patients resulted in a 20% increase in mean clinical duration of the initial intubating dose, and a 37% increase in the duration of subsequent maintenance doses, when compared in the same study to 10 patients under opioid/nitrous oxide/oxygen anesthesia. The clinical duration of initial doses of Rocuronium of 0.57 to 0.85 mg/kg under enflurane or isoflurane anesthesia, as used clinically, was increased by 11% and 23%, respectively. The duration of maintenance doses was affected to a greater extent, increasing by 30% to 50% under either enflurane or isoflurane anesthesia.
- Potentiation by these agents is also observed with respect to the infusion rates of Rocuronium required to maintain approximately 95% neuromuscular block. Under isoflurane and enflurane anesthesia, the infusion rates are decreased by approximately 40% compared to opioid/nitrous oxide/oxygen anesthesia. The median spontaneous recovery time (from 25% to 75% of control T1) is not affected by halothane, but is prolonged by enflurane (15% longer) and isoflurane (62% longer). Reversal-induced recovery of Rocuronium neuromuscular block is minimally affected by anesthetic technique [see Dosage and Administration (2.5) and Warnings and Precautions].
### Lithium Carbonate
- Lithium has been shown to increase the duration of neuromuscular block and decrease infusion requirements of neuromuscular blocking agents [see Warnings and Precautions].
### Local Anesthetics
- Local anesthetics have been shown to increase the duration of neuromuscular block and decrease infusion requirements of neuromuscular blocking agents [see Warnings and Precautions].
### Magnesium
- Magnesium salts administered for the management of toxemia of pregnancy may enhance neuromuscular blockade [see Warnings and Precautions ].
### Nondepolarizing Muscle Relaxants
- There are no controlled studies documenting the use of Rocuronium before or after other nondepolarizing muscle relaxants. Interactions have been observed when other nondepolarizing muscle relaxants have been administered in succession.
### Procainamide
- Procainamide has been shown to increase the duration of neuromuscular block and decrease infusion requirements of neuromuscular blocking agents [see Warnings and Precautions].
### Propofol
- The use of propofol for induction and maintenance of anesthesia does not alter the clinical duration or recovery characteristics following recommended doses of Rocuronium.
### Quinidine
- Injection of quinidine during recovery from use of muscle relaxants is associated with recurrent paralysis. This possibility must also be considered for Rocuronium [see Warnings and Precautions].
### Succinylcholine
- The use of Rocuronium before succinylcholine, for the purpose of attenuating some of the side effects of succinylcholine, has not been studied.
- If Rocuronium is administered following administration of succinylcholine, it should not be given until recovery from succinylcholine has been observed. The median duration of action of Rocuronium 0.6 mg/kg administered after a 1 mg/kg dose of succinylcholine when T1 returned to 75% of control was 36 minutes (range: 14-57, n=12) vs. 28 minutes (range: 17-51, n=12) without succinylcholine.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Developmental toxicology studies have been performed with rocuronium bromide in pregnant, conscious, nonventilated rabbits and rats. Inhibition of neuromuscular function was the endpoint for high-dose selection. The maximum tolerated dose served as the high dose and was administered intravenously 3 times a day to rats (0.3 mg/kg, 15%-30% of human intubation dose of 0.6-1.2 mg/kg based on the body surface unit of mg/m2) from Day 6 to 17 and to rabbits (0.02 mg/kg, 25% human dose) from Day 6 to 18 of pregnancy. High-dose treatment caused acute symptoms of respiratory dysfunction due to the pharmacological activity of the drug. Teratogenicity was not observed in these animal species. The incidence of late embryonic death was increased at the high dose in rats, most likely due to oxygen deficiency. Therefore, this finding probably has no relevance for humans because immediate mechanical ventilation of the intubated patient will effectively prevent embryo-fetal hypoxia. However, there are no adequate and well-controlled studies in pregnant women. Rocuronium should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Rocuronium in women who are pregnant.
### Labor and Delivery
- The use of Rocuronium in Cesarean section has been studied in a limited number of patients [see Clinical Studies]. Rocuronium is not recommended for rapid sequence induction in Cesarean section patients.
### Nursing Mothers
There is no FDA guidance on the use of Rocuronium in women who are nursing.
### Pediatric Use
- The use of Rocuronium has been studied in pediatric patients 3 months to 14 years of age under halothane anesthesia. Of the pediatric patients anesthetized with halothane who did not receive atropine for induction, about 80% experienced a transient increase (30% or greater) in heart rate after intubation. One of the 19 infants anesthetized with halothane and fentanyl who received atropine for induction experienced this magnitude of change [see Dosage and Administration and Clinical Studies].
- Rocuronium was also studied in pediatric patients up to 17 years of age, including neonates, under sevoflurane (induction) and isoflurane/nitrous oxide (maintenance) anesthesia. Onset time and clinical duration varied with dose, the age of the patient, and anesthetic technique. The overall analysis of ECG data in pediatric patients indicates that the concomitant use of Rocuronium with general anesthetic agents can prolong the QTc interval. The data also suggest that Rocuronium may increase heart rate. However, it was not possible to conclusively identify an effect of Rocuronium independent of that of anesthesia and other factors. Additionally, when examining plasma levels of Rocuronium in correlation to QTc interval prolongation, no relationship was observed [see Dosage and Administration, Warnings and Precautions, and Clinical Studies].
- Rocuronium is not recommended for rapid sequence intubation in pediatric patients. Recommendations for use in pediatric patients are discussed in other sections [see Dosage and Administration and Clinical Pharmacology].
### Geriatic Use
- Rocuronium was administered to 140 geriatric patients (65 years or greater) in US clinical trials and 128 geriatric patients in European clinical trials. The observed pharmacokinetic profile for geriatric patients (n=20) was similar to that for other adult surgical patients [see Clinical Pharmacology]. Onset time and duration of action were slightly longer for geriatric patients (n=43) in clinical trials. Clinical experiences and recommendations for use in geriatric patients are discussed in other sections [see Dosage and Administration (2.5), Clinical Pharmacology , and Clinical Studies].
### Gender
There is no FDA guidance on the use of Rocuronium with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Rocuronium with respect to specific racial populations.
### Renal Impairment
- Due to the limited role of the kidney in the excretion of Rocuronium, usual dosing guidelines should be followed. In patients with renal dysfunction, the duration of neuromuscular blockade was not prolonged; however, there was substantial individual variability (range: 22-90 minutes) [see Clinical Pharmacology ].
### Hepatic Impairment
- Since Rocuronium is primarily excreted by the liver, it should be used with caution in patients with clinically significant hepatic impairment. Rocuronium 0.6 mg/kg has been studied in a limited number of patients (n=9) with clinically significant hepatic impairment under steady-state isoflurane anesthesia. After Rocuronium 0.6 mg/kg, the median (range) clinical duration of 60 (35-166) minutes was moderately prolonged compared to 42 minutes in patients with normal hepatic function. The median recovery time of 53 minutes was also prolonged in patients with cirrhosis compared to 20 minutes in patients with normal hepatic function. Four of 8 patients with cirrhosis, who received Rocuronium 0.6 mg/kg under opioid/nitrous oxide/oxygen anesthesia, did not achieve complete block. These findings are consistent with the increase in volume of distribution at steady state observed in patients with significant hepatic impairment [see Clinical Pharmacology]. If used for rapid sequence induction in patients with ascites, an increased initial dosage may be necessary to assure complete block. Duration will be prolonged in these cases. The use of doses higher than 0.6 mg/kg has not been studied [see Dosage and Administration].
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Rocuronium in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Rocuronium in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Rocuronium Administration in the drug label.
### Monitoring
There is limited information regarding Rocuronium Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Rocuronium and IV administrations.
# Overdosage
- Overdosage with neuromuscular blocking agents may result in neuromuscular block beyond the time needed for surgery and anesthesia. The primary treatment is maintenance of a patent airway, controlled ventilation, and adequate sedation until recovery of normal neuromuscular function is assured. Once evidence of recovery from neuromuscular block is observed, further recovery may be facilitated by administration of an anticholinesterase agent in conjunction with an appropriate anticholinergic agent.
- Reversal of Neuromuscular Blockade: Anticholinesterase agents should not be administered prior to the demonstration of some spontaneous recovery from neuromuscular blockade. The use of a nerve stimulator to document recovery is recommended.
- Patients should be evaluated for adequate clinical evidence of neuromuscular recovery, e.g., 5-second head lift, adequate phonation, ventilation, and upper airway patency. Ventilation must be supported while patients exhibit any signs of muscle weakness.
- Recovery may be delayed in the presence of debilitation, carcinomatosis, and concomitant use of certain drugs which enhance neuromuscular blockade or separately cause respiratory depression. Under such circumstances the management is the same as that of prolonged neuromuscular blockade.
# Pharmacology
## Mechanism of Action
- Rocuronium is a nondepolarizing neuromuscular blocking agent with a rapid to intermediate onset depending on dose and intermediate duration. It acts by competing for cholinergic receptors at the motor end-plate. This action is antagonized by acetylcholinesterase inhibitors, such as neostigmine and edrophonium.
## Structure
- Rocuronium (rocuronium bromide) injection is a nondepolarizing neuromuscular blocking agent with a rapid to intermediate onset depending on dose and intermediate duration. Rocuronium bromide is chemically designated as 1-[17β-(acetyloxy)-3α-hydroxy-2β-(4-morpholinyl)-5α-androstan-16β-yl]-1-(2-propenyl)pyrrolidinium bromide.
- The structural formula is:
- The chemical formula is C32H53BrN2O4 with a molecular weight of 609.70. The partition coefficient of rocuronium bromide in n-octanol/water is 0.5 at 20°C.
- Rocuronium is supplied as a sterile, nonpyrogenic, isotonic solution that is clear, colorless to yellow/orange, for intravenous injection only. Each mL contains 10 mg rocuronium bromide and 2 mg sodium acetate. The aqueous solution is adjusted to isotonicity with sodium chloride and to a pH of 4 with acetic acid and/or sodium hydroxide.
## Pharmacodynamics
- The ED95 (dose required to produce 95% suppression of the first [T1] mechanomyographic [MMG] response of the adductor pollicis muscle [thumb] to indirect supramaximal train-of-four stimulation of the ulnar nerve) during opioid/nitrous oxide/oxygen anesthesia is approximately 0.3 mg/kg. Patient variability around the ED95 dose suggests that 50% of patients will exhibit T1 depression of 91% to 97%.
Table 4 presents intubating conditions in patients with intubation initiated at 60 to 70 seconds.
- Once spontaneous recovery has reached 25% of control T1, the neuromuscular block produced by Rocuronium is readily reversed with anticholinesterase agents, e.g., edrophonium or neostigmine.
- The median spontaneous recovery from 25% to 75% T1 was 13 minutes in adult patients. When neuromuscular block was reversed in 36 adults at a T1 of 22% to 27%, recovery to a T1 of 89 (50-132)% and T4/T1 of 69 (38-92)% was achieved within 5 minutes. Only 5 of 320 adults reversed received an additional dose of reversal agent. The median (range) dose of neostigmine was 0.04 (0.01-0.09) mg/kg and the median (range) dose of edrophonium was 0.5 (0.3-1.0) mg/kg.
- In geriatric patients (n=51) reversed with neostigmine, the median T4/T1 increased from 40% to 88% in 5 minutes.
- In clinical trials with halothane, pediatric patients (n=27) who received 0.5 mg/kg edrophonium had increases in the median T4/T1 from 37% at reversal to 93% after 2 minutes. Pediatric patients (n=58) who received 1 mg/kg edrophonium had increases in the median T4/T1 from 72% at reversal to 100% after 2 minutes. Infants (n=10) who were reversed with 0.03 mg/kg neostigmine recovered from 25% to 75% T1 within 4 minutes.
- There were no reports of less than satisfactory clinical recovery of neuromuscular function.
- The neuromuscular blocking action of Rocuronium may be enhanced in the presence of potent inhalation anesthetics [see Drug Interactions].
- There were no dose-related effects on the incidence of changes from baseline (30% or greater) in mean arterial blood pressure (MAP) or heart rate associated with Rocuronium administration over the dose range of 0.12 to 1.2 mg/kg (4 × ED95) within 5 minutes after Rocuronium administration and prior to intubation. Increases or decreases in MAP were observed in 2% to 5% of geriatric and other adult patients, and in about 1% of pediatric patients. Heart rate changes (30% or greater) occurred in 0% to 2% of geriatric and other adult patients. Tachycardia (30% or greater) occurred in 12 of 127 pediatric patients. Most of the pediatric patients developing tachycardia were from a single study where the patients were anesthetized with halothane and who did not receive atropine for induction [see Clinical Studies (14.3)]. In US studies, laryngoscopy and tracheal intubation following Rocuronium administration were accompanied by transient tachycardia (30% or greater increases) in about one-third of adult patients under opioid/nitrous oxide/oxygen anesthesia. Animal studies have indicated that the ratio of vagal:neuromuscular block following Rocuronium administration is less than vecuronium but greater than pancuronium. The tachycardia observed in some patients may result from this vagal blocking activity.
- In studies of histamine release, clinically significant concentrations of plasma histamine occurred in 1 of 88 patients. Clinical signs of histamine release (flushing, rash, or bronchospasm) associated with the administration of Rocuronium were assessed in clinical trials and reported in 9 of 1137 (0.8%) patients.
## Pharmacokinetics
- In an effort to maximize the information gathered in the in vivo pharmacokinetic studies, the data from the studies was used to develop population estimates of the parameters for the subpopulations represented (e.g., geriatric, pediatric, renal, and hepatic impairment). These population-based estimates and a measure of the estimate variability are contained in the following section.
- Following intravenous administration of Rocuronium, plasma levels of rocuronium follow a three-compartment open model. The rapid distribution half-life is 1 to 2 minutes and the slower distribution half-life is 14 to 18 minutes. Rocuronium is approximately 30% bound to human plasma proteins. In geriatric and other adult surgical patients undergoing either opioid/nitrous oxide/oxygen or inhalational anesthesia, the observed pharmacokinetic profile was essentially unchanged.
- In general, studies with normal adult subjects did not reveal any differences in the pharmacokinetics of rocuronium due to gender.
- Studies of distribution, metabolism, and excretion in cats and dogs indicate that rocuronium is eliminated primarily by the liver. The rocuronium analog 17-desacetyl-rocuronium, a metabolite, has been rarely observed in the plasma or urine of humans administered single doses of 0.5 to 1 mg/kg with or without a subsequent infusion (for up to 12 hr) of rocuronium. In the cat, 17-desacetyl-rocuronium has approximately one-twentieth the neuromuscular blocking potency of rocuronium. The effects of renal failure and hepatic disease on the pharmacokinetics and pharmacodynamics of rocuronium in humans are consistent with these findings.
- In general, patients undergoing cadaver kidney transplant have a small reduction in clearance which is offset pharmacokinetically by a corresponding increase in volume, such that the net effect is an unchanged plasma half-life. Patients with demonstrated liver cirrhosis have a marked increase in their volume of distribution resulting in a plasma half-life approximately twice that of patients with normal hepatic function. Table 8 shows the pharmacokinetic parameters in subjects with either impaired renal or hepatic function.
- The net result of these findings is that subjects with renal failure have clinical durations that are similar to but somewhat more variable than the duration that one would expect in subjects with normal renal function. Hepatically impaired patients, due to the large increase in volume, may demonstrate clinical durations approaching 1.5 times that of subjects with normal hepatic function. In both populations the clinician should individualize the dose to the needs of the patient [see Dosage and Administration].
- Tissue redistribution accounts for most (about 80%) of the initial amount of rocuronium administered. As tissue compartments fill with continued dosing (4-8 hours), less drug is redistributed away from the site of action and, for an infusion-only dose, the rate to maintain neuromuscular blockade falls to about 20% of the initial infusion rate. The use of a loading dose and a smaller infusion rate reduces the need for adjustment of dose.
- Under halothane anesthesia, the clinical duration of effects of Rocuronium did not vary with age in patients 4 months to 8 years of age. The terminal half-life and other pharmacokinetic parameters of rocuronium in these pediatric patients are presented in Table 9.
- Pharmacokinetics of Rocuronium were evaluated using a population analysis of the pooled pharmacokinetic datasets from 2 trials under sevoflurane (induction) and isoflurane/nitrous oxide (maintenance) anesthesia. All pharmacokinetic parameters were found to be linearly proportional to body weight. In patients under the age of 18 years clearance (CL) and volume of distribution (Vss) increase with bodyweight (kg) and age (years). As a result the terminal half-life of Rocuronium decreases with increasing age from 1.1 hour to 0.7-0.8 hour. Table 10 presents the pharmacokinetic parameters in the different age groups in the studies with sevoflurane (induction) and isoflurane/nitrous oxide (maintenance) anesthesia.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
- Studies in animals have not been performed with rocuronium bromide to evaluate carcinogenic potential or impairment of fertility. Mutagenicity studies (Ames test, analysis of chromosomal aberrations in mammalian cells, and micronucleus test) conducted with rocuronium bromide did not suggest mutagenic potential.
# Clinical Studies
- In US clinical studies, a total of 1137 patients received Rocuronium, including 176 pediatric, 140 geriatric, 55 obstetric, and 766 other adults. Most patients (90%) were ASA physical status I or II, about 9% were ASA III, and 10 patients (undergoing coronary artery bypass grafting or valvular surgery) were ASA IV. In European clinical studies, a total of 1394 patients received Rocuronium, including 52 pediatric, 128 geriatric (65 years or greater), and 1214 other adults.
- Intubation using doses of Rocuronium 0.6 to 0.85 mg/kg was evaluated in 203 adults in 11 clinical studies. Excellent to good intubating conditions were generally achieved within 2 minutes and maximum block occurred within 3 minutes in most patients. Doses within this range provide clinical relaxation for a median (range) time of 33 (14-85) minutes under opioid/nitrous oxide/oxygen anesthesia. Larger doses (0.9 and 1.2 mg/kg) were evaluated in 2 studies with 19 and 16 patients under opioid/nitrous oxide/oxygen anesthesia and provided 58 (27-111) and 67 (38-160) minutes of clinical relaxation, respectively.
- In 1 clinical study, 10 patients with clinically significant cardiovascular disease undergoing coronary artery bypass graft received an initial dose of 0.6 mg/kg Rocuronium. Neuromuscular block was maintained during surgery with bolus maintenance doses of 0.3 mg/kg. Following induction, continuous 8 mcg/kg/min infusion of Rocuronium produced relaxation sufficient to support mechanical ventilation for 6 to 12 hours in the surgical intensive care unit (SICU) while the patients were recovering from surgery.
- Intubating conditions were assessed in 230 patients in 6 clinical studies where anesthesia was induced with either thiopental (3-6 mg/kg) or propofol (1.5-2.5 mg/kg) in combination with either fentanyl (2-5 mcg/kg) or alfentanil (1 mg). Most of the patients also received a premedication such as midazolam or temazepam. Most patients had intubation attempted within 60 to 90 seconds of administration of Rocuronium 0.6 mg/kg or succinylcholine 1 to 1.5 mg/kg. Excellent or good intubating conditions were achieved in 119/120 (99% [95% confidence interval: 95%-99.9%]) patients receiving Rocuronium and in 108/110 (98% [94%-99.8%]) patients receiving succinylcholine. The duration of action of Rocuronium 0.6 mg/kg is longer than succinylcholine and at this dose is approximately equivalent to the duration of other intermediate-acting neuromuscular blocking drugs.
- Rocuronium was dosed according to actual body weight (ABW) in most clinical studies. The administration of Rocuronium in the 47 of 330 (14%) patients who were at least 30% or more above their ideal body weight (IBW) was not associated with clinically significant differences in the onset, duration, recovery, or reversal of Rocuronium-induced neuromuscular block.
- In 1 clinical study in obese patients, Rocuronium 0.6 mg/kg was dosed according to ABW (n=12) or IBW (n=11). Obese patients dosed according to IBW had a longer time to maximum block, a shorter median (range) clinical duration of 25 (14-29) minutes, and did not achieve intubating conditions comparable to those dosed based on ABW. These results support the recommendation that obese patients be dosed based on actual body weight [see Dosage and Administration].
- Rocuronium 0.6 mg/kg was administered with thiopental, 3 to 4 mg/kg (n=13) or 4 to 6 mg/kg (n=42), for rapid sequence induction of anesthesia for Cesarean section. No neonate had APGAR scores greater than 7 at 5 minutes. The umbilical venous plasma concentrations were 18% of maternal concentrations at delivery. Intubating conditions were poor or inadequate in 5 of 13 women receiving 3 to 4 mg/kg thiopental when intubation was attempted 60 seconds after drug injection. Therefore, Rocuronium is not recommended for rapid sequence induction in Cesarean section patients.
- Rocuronium was evaluated in 55 geriatric patients (ages 65-80 years) in 6 clinical studies. Doses of 0.6 mg/kg provided excellent to good intubating conditions in a median (range) time of 2.3 (1-8) minutes. Recovery times from 25% to 75% after these doses were not prolonged in geriatric patients compared to other adult patients [see Dosage and Administration and Use in Specific Populations ].
- Rocuronium 0.45, 0.6, or 1 mg/kg was evaluated under sevoflurane (induction) and isoflurane/nitrous oxide (maintenance) anesthesia for intubation in 326 patients in 2 studies. In 1 of these studies maintenance bolus and infusion requirements were evaluated in 137 patients. In all age groups, doses of 0.6 mg/kg provided time to maximum block in about 1 minute. Across all age groups, median (range) time to reappearance of T3 for doses of 0.6 mg/kg was shortest in the children [36.7 (20.1-65.9) minutes] and longest in infants [59.8 (32.3-87.8) minutes]. For pediatric patients older than 3 months, the time to recovery was shorter after stopping infusion maintenance when compared with bolus maintenance [see Dosage and Administration and Use in Specific Populations].
- Rocuronium 0.6 or 0.8 mg/kg was evaluated for intubation in 75 pediatric patients (n=28; age 3-12 months, n=47; age 1-12 years) in 3 studies using halothane (1%-5%) and nitrous oxide (60%-70%) in oxygen. Doses of 0.6 mg/kg provided a median (range) time to maximum block of 1 (0.5-3.3) minute(s). This dose provided a median (range) time of clinical relaxation of 41 (24-68) minutes in 3-month to 1-year-old infants and 26 (17-39) minutes in 1- to 12-year-old pediatric patients [see Dosage and Administration (2.5) and Use in Specific Populations (8.4)].
# How Supplied
- Rocuronium (rocuronium bromide) injection is available in the following:
- The packaging of this product contains no natural rubber (latex)
## Storage
- Rocuronium should be stored in a refrigerator, 2-8°C (36-46°F). DO NOT FREEZE. Upon removal from refrigeration to room temperature storage conditions (25°C/77°F), use Rocuronium within 60 days. Use opened vials of Rocuronium within 30 days.
### Safety and Handling
- There is no specific work exposure limit for Rocuronium. In case of eye contact, flush with water for at least 10 minutes.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Obtain information about your patient's medical history, current medications, any history of hypersensitivity to rocuronium bromide or other neuromuscular blocking agents. If applicable, inform your patients that certain medical conditions and medications might influence how Rocuronium works.
- In addition, inform your patient that severe anaphylactic reactions to neuromuscular blocking agents, including Rocuronium, have been reported. Since allergic cross-reactivity has been reported in this class, request information from your patients about previous anaphylactic reactions to other neuromuscular blocking agents.
# Precautions with Alcohol
Alcohol-Rocuronium interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
There is limited information regarding Rocuronium Brand Names in the drug label.
# Look-Alike Drug Names
There is limited information regarding Rocuronium Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Rocuronium | |
3600237db04cde39578b7ef45b4dfe8227866c34 | wikidoc | Rolapitant | Rolapitant
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# Overview
Rolapitant is a substance P/neurokinin 1 (NK1) receptor antagonist that is FDA approved for the prevention of delayed nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including, but not limited to, highly emetogenic chemotherapy. Common adverse reactions include neutropenia, hiccups, decreased appetite and dizziness.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Rolapitant is indicated in combination with other antiemetic agents in adults for the prevention of delayed nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including, but not limited to, highly emetogenic chemotherapy.
- Prevention of Nausea and Vomiting Associated with Emetogenic Cancer Chemotherapy
The recommended dosage of rolapitant in adults in combination with a 5-HT3 receptor antagonist and dexamethasone is shown in TABLE 1. There is no drug interaction between rolapitant and dexamethasone, so no dosage adjustment for dexamethasone is required. Administer a dexamethasone dose of 20 mg on Day 1.
Administer rolapitant prior to the initiation of each chemotherapy cycle, but at no less than 2 week intervals.
Administer rolapitant without regards to meals.
- Table 1: Recommended Dosing Regimen
VARUBI: Rolapitant's Brand name
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Rolapitant in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Rolapitant in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Safety and efficacy of rolapitant have not been established in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Rolapitant in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Rolapitant in pediatric patients.
# Contraindications
Rolapitant is contraindicated in patients receiving thioridazine, a CYP2D6 substrate. A significant increase in plasma concentrations of thioridazine may result in QT prolongation and Torsades de Pointes.
# Warnings
- Interaction with CYP2D6 Substrates with a Narrow Therapeutic Index
The inhibitory effect of rolapitant on CYP2D6 lasts at least 7 days and may last longer after a single dose administration of rolapitant. Avoid use of rolapitant in patients who are receiving pimozide, a CYP2D6 substrate. An increase in plasma concentrations of pimozide may result in QT prolongation. Monitor for adverse reactions if concomitant use of rolapitant and other CYP2D6 substrates with a narrow therapeutic index cannot be avoided.
# Adverse Reactions
## Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
The safety of rolapitant was evaluated in approximately 2800 patients in 4 controlled clinical trials in patients receiving emetogenic cancer chemotherapy. Rolapitant was given in combination with a 5-HT3 receptor antagonist and dexamethasone. On Day 1 of Cycle 1 of chemotherapy, 1567 patients were treated with rolapitant and 1198 of these patients continued into the optional multiple cycle extension for up to 6 cycles of chemotherapy. The median number of cycles administered 180 mg of rolapitant was four. Rolapitant 180 mg was administered to 1294 patients.
In Cycle 1 adverse reactions were reported in approximately 7% of patients treated with rolapitant compared with approximately 6% of patients treated with control therapy. The most common adverse reactions reported with an incidence of ≥3% and greater than control are listed in TABLE 2 and TABLE 3.
- Table 2: Most Common Adverse Reactions in Patients Receiving Cisplatin-Based Highly Emetogenic Chemotherapy (Cycle 1)*
VARUBI : Rolapitant's Brand name
- Table 3: Most Common Adverse Reactions in Patients Receiving Moderately Emetogenic Chemotherapy and Combinations of Anthracycline and Cyclophosphamide (Cycle 1)*
VARUBI : Rolapitant's Brand name
Adverse reactions in the multiple-cycle extensions of highly and moderately emetogenic chemotherapy studies for up to 6 cycles of chemotherapy were generally similar to that observed in Cycle 1.
## Postmarketing Experience
There is limited information regarding Rolapitant Postmarketing Experience in the drug label.
# Drug Interactions
Rolapitant is not an inhibitor or inducer of CYP3A4. Therefore, no dosage adjustment for dexamethasone (CYP3A4 substrate) is needed when co-administered with rolapitant.
Rolapitant is a moderate CYP2D6 inhibitor, an inhibitor of Breast-Cancer-Resistance Protein (BCRP) and an inhibitor of P-glycoprotein (P-gp).
- CYP2D6 Substrates with a Narrow Therapeutic Index: Increased plasma concentration of CYP2D6 substrates may result in potential adverse reactions. A 3-fold increase in the exposure of dextromethorphan, a CYP2D6 substrate, was observed 7 days after a single dose of rolapitant. The duration of CYP2D6 inhibition was not studied beyond 7 days and may last longer. Concomitant use with Thioridazine is contraindicated. Avoid use of rolapitant with pimozide. Monitor for QT prolongation if concomitant use with pimozide cannot be avoided. Monitor for adverse reactions if concomitant use with CYP2D6 substrates with a narrow therapeutic index cannot be avoided.
- BCRP Substrates with a Narrow Therapeutic Index (e.g., Methotrexate, topotecan, or irinotecan): Increased plasma concentrations of BCRP substrates may result in potential adverse reactions. Monitor for adverse reactions related to the concomitant drug if use of rolapitant cannot be avoided. Use the lowest effective dose of rosuvastatin.
- P-gp Substrates with a Narrow Therapeutic Index: Increased plasma concentrations of digoxin, or other P-gp substrates, may result in potential adverse reactions. Monitor for increased digoxin concentrations. Monitor for adverse reactions if concomitant use of rolapitant with other P-gp substrates with a narrow therapeutic index cannot be avoided.
Strong CYP3A4 Inducers (e.g., rifampin): significantly reduced plasma concentrations of rolapitant can decrease the efficacy of rolapitant; avoid use of rolapitant in patients who require chronic administration of such drugs.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): N
- Risk Summary
There are no available data on rolapitant use in pregnant women to inform any drug-associated risks. In animal reproduction studies, there were no teratogenic or embryo-fetal effects observed with oral administration of rolapitant hydrochloride in rats and rabbits during the period of organogenesis at doses up to 1.2 times and 2.9 times, respectively, the maximum recommended human dose (MRHD). In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
- Data
- Animal Data
The potential embryo-fetal toxicity of rolapitant hydrochloride was assessed in pregnant rats administered oral doses equivalent to up to 22.5 mg/kg per day rolapitant free base throughout organogenesis. Rats administered doses equivalent to 13.5 or 22.5 mg/kg per day rolapitant free base exhibited evidence of maternal toxicity including decreased body weight gain and/or body weight loss and a concomitant decrease in food consumption during the first week of dosing. No teratogenic or embryo-fetal effects were observed at doses equivalent to up to 22.5 mg/kg per day rolapitant free base (approximately 1.2 times the recommended human dose on a body surface area basis). In rabbits administered rolapitant hydrochloride throughout the period of organogenesis, oral doses equivalent to up to 27 mg/kg per day rolapitant free base (approximately 2.9 times the recommended human dose on a body surface area basis) were without effects on the developing fetus.
The pre- and postnatal developmental effects of rolapitant hydrochloride were assessed in rats administered oral doses equivalent to 2.25, 9 or 22.5 mg/kg per day rolapitant free base during the periods of organogenesis and lactation. Maternal toxicity was evident based on mortality/moribund condition, decreased body weight and food consumption, total litter loss, prolonged parturition, decreased length of gestation, and increased number of unaccounted for implantation sites at a dose equivalent to 22.5 mg/kg per day free base (approximately 1.2 times the recommended human dose on a body surface area basis). Effects on offspring at this dose included decreased postnatal survival, and decreased body weights and body weight gain, and may be related to the maternal toxicity observed. At a maternal dose equivalent to 9 mg/kg per day rolapitant free base (approximately 0.5 times the recommended human dose on a body surface area basis), there was a decrease in memory in female pups in a maze test and a decrease in pup body weight.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Rolapitant in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Rolapitant during labor and delivery.
### Nursing Mothers
- Risk Summary
There are no data on the presence of rolapitant in human milk, the effects of rolapitant in the breastfed infant, or the effects of rolapitant on milk production. Rolapitant hydrochloride administered orally to lactating female rats was present in milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for rolapitant and any potential adverse effects on the breastfed infant from rolapitant or from the underlying maternal condition or the use of concomitant chemotherapy.
- Data
Radioactivity from labeled rolapitant hydrochloride was transferred into milk of lactating rats following a single oral dose equivalent to 22.5 mg/kg rolapitant free base, and the maximum radioactivity in milk was observed at 12 hours post-dose. The mean milk/plasma radioactivity concentration ratios in dams at 1 to 48 hours post-dose ranged from 1.24 to 3.25. Based on average daily consumption of milk (2 mL/day) and the maximum milk radioactivity determined, pup exposure is expected to be 0.32% of the orally administered dose.
### Pediatric Use
Safety and efficacy of rolapitant have not been established in pediatric patients.
### Geriatic Use
Of the 1294 subjects treated with rolapitant, 25% were 65 years and over, while 5% were 75 and over. No overall differences in safety or efficacy were reported between the elderly subjects and younger subjects, but greater sensitivity of some older individuals cannot be ruled out.
### Gender
There is no FDA guidance on the use of Rolapitant with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Rolapitant with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Rolapitant in patients with renal impairment.
### Hepatic Impairment
No dosage adjustment is needed in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. There are no clinical or pharmacokinetic data in patients with severe hepatic impairment (Child-Pugh Class C). Avoid use of rolapitant in patients with severe hepatic impairment. If use cannot be avoided, monitor patients for adverse reactions related to rolapitant.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Rolapitant in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Rolapitant in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Prevention of Nausea and Vomiting Associated with Emetogenic Cancer Chemotherapy
The recommended dosage of rolapitant in adults in combination with a 5-HT3 receptor antagonist and dexamethasone is shown in TABLE 1. There is no drug interaction between rolapitant and dexamethasone, so no dosage adjustment for dexamethasone is required. Administer a dexamethasone dose of 20 mg on Day 1.
Administer rolapitant prior to the initiation of each chemotherapy cycle, but at no less than 2 week intervals.
Administer rolapitant without regards to meals.
### Monitoring
There is limited information regarding Rolapitant Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Rolapitant and IV administrations.
# Overdosage
- There are no data on overdose with rolapitant.
- There is no antidote for rolapitant overdose. Discontinue rolapitant in the event of overdose, and institute general supportive measures and close observation.
# Pharmacology
## Mechanism of Action
Rolapitant is a selective and competitive antagonist of human substance P/NK1 receptors. Rolapitant does not have significant affinity for the NK2 or NK3 receptors or for a battery of other receptors, transporters, enzymes and ion channels. Rolapitant is also active in animal models of chemotherapy-induced emesis.
## Structure
Rolapitant hydrochloride is chemically described as (5S,8S)-8- { ethoxy]methyl]}-8-phenyl 1,7-diazaspirodecan-2-one monohydrochloride monohydrate. Its empirical formula is C25H26F6N2O2. HCl.H2O and its structural formula is:
Rolapitant hydrochloride is a white to off-white powder, with a molecular weight of 554.95. Solubility of rolapitant hydrochloride in aqueous solution is pH-dependent and is more soluble at lower pH. Rolapitant hydrochloride has good solubility in common pharmaceutical solvents such as ethanol, propylene glycol, and 40% hydroxypropyl beta cyclodextrin.
Each tablet for oral administration contains 90 mg rolapitant and the following inactive ingredients: lactose monohydrate, pregelatinized starch, microcrystalline cellulose, povidone, croscarmellose sodium, colloidal silicon dioxide and magnesium stearate. The tablets are coated in non-functional blue and clear coats. The tablet coating comprises the following inactive ingredients: polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, FD&C Blue No. 2- Indigo Carmine Lake and polysorbate 80.
## Pharmacodynamics
- NK1 Receptor Occupancy
A human Positron Emission Tomography (PET) study with rolapitant demonstrated that rolapitant crosses the blood brain barrier and occupies brain NK1 receptors. A dose-dependent increase in mean NK1 receptor occupancy was observed in the dose range from 4.5 mg to 180 mg of rolapitant. At the 180 mg dose of rolapitant, the mean NK1 receptor occupancy was 73% in the striatum at 120 hours after a single dose administration in healthy subjects. The relationship between NK1 receptor occupancy and the clinical efficacy of rolapitant has not been established.
- Cardiac Electrophysiology
In a thorough QT study, rolapitant at doses up to 4 times higher than the recommended dose had no significant effects on the QT intervals.
## Pharmacokinetics
- Absorption
Following a single dose administration of 180 mg rolapitant under fasting conditions to healthy subjects, rolapitant was measurable in plasma between 30 minutes and the peak plasma concentration (Cmax) for rolapitant was reached in about 4 hours and mean Cmax was 968 ng/mL (%CV:28%).
Following multiple oral doses 9 to 45 mg once daily of rolapitant, accumulation of rolapitant was approximately 5-fold.
The systemic exposures (Cmax and AUC) to rolapitant increased in a dose-proportional manner when the dose of rolapitant increased from 4.5 mg to 180 mg. With an increase in dose by 4 times from the recommended clinical dose of 180 mg, the Cmax and AUC of rolapitant increased by 3.1 fold and 3.7 fold, respectively.
Concomitant administration of a high fat meal did not significantly affect the pharmacokinetics of rolapitant after administration of 180 mg rolapitant.
- Distribution
Rolapitant was highly protein bound to human plasma (99.8%). The apparent volume of distribution (Vd/F) was 460 L in healthy subjects, indicating an extensive tissue distribution of rolapitant. In a population pharmacokinetic analysis of rolapitant, the Vd/F was 387 L in cancer patients.
- Elimination
Following single oral doses (4.5 to 180 mg) of rolapitant, the mean terminal half-life (t1/2) of rolapitant ranged from 169 to 183 hours (approximately 7 days) and was independent of dose. In a population pharmacokinetic analysis the apparent total clearance (CL/F) of rolapitant was 0.96 L/hour in cancer patients.
- Metabolism
Rolapitant is metabolized primarily by CYP3A4 to form a major active metabolite, M19 (C4- pyrrolidine-hydroxylated rolapitant). In a mass balance study, the metabolite M19 was the major circulating metabolite. The formation of M19 was significantly delayed with the median Tmax of 120 hours (range: 24-168 hours) and the mean half-life of M19 was 158 hours.
The exposure ratio of M19 to rolapitant was approximately 50% in plasma.
- Excretion
Rolapitant is eliminated primarily through the hepatic/biliary route. Following administration of a single oral 180-mg dose of -rolapitant, on average 14.2% (range 9% to 20%) and 73% (range 52% to 89%) of the dose was recovered in the urine and feces, respectively over 6 weeks. In pooled samples collected over 2 weeks, 8.3% of the dose was recovered in the urine primarily as metabolites and 37.8% of the dose was recovered in the feces primarily as unchanged rolapitant. Unchanged rolapitant or M19 were not found in pooled urine sample.
- Specific Populations
- Age, Sex and Race/Ethnicity
Population pharmacokinetic analyses indicated that age, sex and race had no significant impact on the pharmacokinetics of rolapitant.
- Hepatic Impairment
Following administration of a single dose of 180 mg rolapitant to patients with mild hepatic impairment (Child-Pugh Class A), the pharmacokinetics of rolapitant were comparable with those of healthy subjects. In patients with moderate hepatic impairment (Child-Pugh Class B), the mean Cmax was 25% lower while mean AUC of rolapitant was similar compared to those of healthy subjects. The median Tmax for M19 was delayed to 204 hours in patients with mild or moderate hepatic impairment compared to 168 hours in healthy subjects. The pharmacokinetics of rolapitant was not studied in patients with severe hepatic impairment (Child-Pugh Class C).
- Renal Impairment
In population pharmacokinetic analyses, creatinine clearance (CLcr) at baseline did not show a significant effect on rolapitant pharmacokinetics in cancer patients with mild (CLcr: 60 to 90 mL/min) or moderate (CLcr: 30 to 60 mL/min) renal impairment compared to cancer patients with normal kidney function. Information is insufficient for the effect of severe renal impairment. The pharmacokinetics of rolapitant was not studied in patients with end-stage renal disease requiring hemodialysis.
- Drug Interaction Studies
- Effect of Other Drugs on rolapitant
Rolapitant is a substrate for CYP3A4.
- CYP3A4 inducers
Concomitant administration of a CYP3A4 inducer significantly decreased the systemic exposure to rolapitant. When 600 mg rifampin was administered once daily for 7 days before and 7 days after administration of a single dose of 180 mg rolapitant , the mean Cmax of rolapitant was reduced by 30% and the mean AUC was reduced by 85% compared to administration of rolapitant alone. The mean half-life of rolapitant decreased from 176 hours without rifampin to 41 hours with concurrent rifampin.
- CYP3A4 inhibitors
No clinically significant effect was seen on the pharmacokinetics of rolapitant when ketoconazole, a strong CYP3A4 inhibitor was administered with rolapitant. Concurrent administration of 400 mg ketoconazole once daily for 21 days following a single 90 mg dose of rolapitant , did not significantly affect the Cmax of rolapitant while the AUC increased by 21%.
- Effect of rolapitant on Other Drugs
The effect of rolapitant on CYP450 enzymes and transporters is summarized below. See TABLE 4 for a summary of the effects of the clinical dose of rolapitant on the pharmacokinetics of co- administered drugs.
- CYP3A4 substrates
Rolapitant is neither an inhibitor nor an inducer of CYP3A4.
Midazolam: A single dose of 180 mg rolapitant had no significant effects on the pharmacokinetics of midazolam when oral midazolam 3 mg was co-administered on Day 1 and administered alone on Days 6, and 9.
Ondansetron: Rolapitant had no significant effects on the pharmacokinetics of intravenous ondansetron when concomitantly administered with a single 180 mg dose of rolapitant on the same day.
Dexamethasone: Rolapitant had no significant effects on the pharmacokinetics of dexamethasone when oral dexamethasone was administered on Days 1 to 3 after a single 180 mg dose of rolapitant was co-administered on Day 1.
- CYP2D6 substrates
Rolapitant is a moderate inhibitor of CYP2D6.
- BCRP transporter
Rolapitant is an inhibitor of BCRP transporter.
- P-glycoprotein substrates
Rolapitant is an inhibitor of P-gp transporter.
- Substrates for other CYP enzymes
In vitro studies suggest that rolapitant is not an inhibitor of CYP1A2 and CYP2E1. A clinically meaningful drug interaction via an inhibition of CYP2A6 appears unlikely based on in vitro study.
No clinically significant interaction was seen on the pharmacokinetics of the following drugs when administered with a single dose of 180 mg rolapitant on Day 1 and without rolapitant on Day 8: repaglinide (CYP2C8 substrate; no effect on repaglinide 0.25 mg on Day 1; on Day 8 : 29% and 24% increase in Cmax and AUC, respectively), efavirenz (CYP2B6 substrate; 18% decrease in Cmax and no effect on AUC of efavirenz 600 mg on Day 1; on Day 8: no effect on Cmax and 28% increase in AUC), tolbutamide (CYP2C9 substrate; no effect on tolbutamide 500 mg on Day 1 and on Day 8), or omeprazole (CYP2C19 substrate; 44% increase in Cmax and 23% increase in AUC of omeprazole 40 mg on Day 1; on Day 8: 37% and 15% increase in Cmax and AUC, respectively).
- Table 4: Effect of Rolapitant on the Pharmacokinetics of Co-administered Drugs*
## Nonclinical Toxicology
Carcinogenic potential of rolapitant hydrochloride was assessed in 2-year carcinogenicity studies in CD-1 mice and Sprague-Dawley rats. In mice, there were no drug-related neoplastic findings at doses equivalent to up to 135 mg/kg per day rolapitant free base (approximately 3.6 times the recommended human dose on a body surface area basis). In rats, there were no drug-related neoplastic findings at doses equivalent to up to 90 mg/kg per day rolapitant free base (approximately 4.9 times the recommended human dose on a body surface area basis).
Rolapitant hydrochloride was not genotoxic in an Ames test, a human peripheral blood lymphocyte chromosome aberration test, and a mouse micronucleus test.
In a fertility and early embryonic development study in female rats, rolapitant hydrochloride at an oral dose equivalent to 9 mg/kg per day free base (approximately 0.5 times the recommended human dose on a body surface area basis) caused a transient decrease in maternal body weight gain and increases in the incidence of pre- and post-implantation loss. At a dose equivalent to 4.5 mg/kg per day free base (approximately 0.2 times the recommended human dose on a body surface area basis), there were slight decreases in the number of corpora lutea and implantation sites. Rolapitant hydrochloride did not affect the fertility or general reproductive performance of male rats at doses equivalent to up to 90 mg/kg per day rolapitant free base (approximately 4.9 times the recommended human dose on a body surface area basis).
# Clinical Studies
- Cisplatin-Based Highly Emetogenic Chemotherapy (HEC)
In two multicenter, randomized, double-blind, parallel group, controlled clinical studies (Study 1 and Study 2), the rolapitant regimen (rolapitant, granisetron and dexamethasone) was compared with control therapy (placebo, granisetron and dexamethasone) in patients receiving a chemotherapy regimen that included cisplatin >60 mg/m2. See TABLE 5 for the treatment regimens.
- Table 5: Treatment Regimens in Studies 1 and 2
VARUBI : Rolapitant's Brand name
- Study 1
A total of 532 patients were randomized to either the rolapitant regimen (N =266) or control therapy (N =266). A total of 526 patients were included in the evaluation of efficacy. Of those randomized 42% were women, 58 % men, 67% White, 23% Asian, 1% Black, and 9% multi racial/other/unknown. The proportion of patients from North America was 16%. Patients in this clinical study ranged from 20 to 90 years of age, with a mean age of 57 years. In Study 1, 26% of patients were 65 years or older, with 3% of patients being 75 years or older. The mean cisplatin dose was 77 mg/m2.
During this study, 82% of the patients received a concomitant chemotherapeutic agent in addition to protocol-mandated cisplatin. The most common concomitant chemotherapeutic agents administered during Cycle 1 were: gemcitabine (17%), paclitaxel (12%), fluorouracil (11%), etoposide (10%), vinorelbine (9%), docetaxel (9%), pemetrexed (7%), doxorubicin (6%) and cyclophosphamide (5%).
- Study 2
A total of 555 patients were randomized to either the rolapitant regimen (N =278) or control therapy (N =277). A total of 544 patients were included in the evaluation of efficacy. Of those randomized, 32% were women, 68 % men, 81% White, 14% Asian, 1% Black, and 5% multi racial/other/unknown. The proportion of patients from North America was 7%. Patients in this clinical study ranged from 18 to 83 years of age, with a mean age of 58 years. In this study, 27% of patients were 65 years or older, with 3% of patients being 75 years or older. The mean cisplatin dose was 76 mg/m2.
During this study, 85% of the patients received a concomitant chemotherapeutic agent in addition to protocol-mandated cisplatin. The most common concomitant chemotherapeutic agents administered during Cycle 1 were: vinrorelbine (16%), gemcitabine (15%), fluorouracil (12%), etoposide (11%), pemetrexed (9%), docetaxel (7%), paclitaxel (7%), epirubicin (5%) and capecitabine (4%).
The primary endpoint in both studies was complete response (defined as no emetic episodes and no rescue medication) in the delayed phase (25 to 120 hours) of chemotherapy-induced nausea and vomiting.
- Moderately Emetogenic Chemotherapy (MEC) and Combinations of Anthracycline and Cyclophosphamide Chemotherapy
- Study 3
In Study 3, a multicenter, randomized, double-blind, parallel group, controlled clinical study in moderately emetogenic chemotherapy, the rolapitant regimen (rolapitant, granisetron and dexamethasone) was compared with control therapy (placebo, granisetron and dexamethasone) in patients receiving a moderately emetogenic chemotherapy regimen that included at least 50% of patients receiving a combination of anthracycline and cyclophosphamide. The percentage of patients who received carboplatin in Cycle 1 was 30%. Treatment regimens for the rolapitant and control arms are summarized in TABLE 6.
- Table 6: Treatment Regimens in Study 3
VARUBI : Rolapitant's Brand name
A total of 1369 patients were randomized to either the rolapitant regimen (N = 684) or control therapy (N = 685). A total of 1332 patients were included in the evaluation of efficacy. Of those randomized 80% were women, 20% men, 77% White, 13% Asian, 4% Black, and 6% multi- racial/other/unknown. The proportion of patients from North America was 33%. Patients in this clinical study ranged from 22 to 88 years of age, with a mean age of 57 years. In this study, 28% of patients were 65 years or older, with 7% of patients being 75 years or older.
The primary endpoint was complete response (defined as no emetic episodes and no rescue medication) in the delayed phase (25 to 120 hours) of chemotherapy-induced nausea and vomiting.
A summary of the study results from HEC Studies 1 and 2, and for the MEC Study 3 is shown in TABLE 7.
- Table 7: Percent of Patients Receiving Emetogenic Chemotherapy Responding by Treatment Group for the HEC Studies 1 and 2 and for the MEC Study 3
VARUBI : Rolapitant's Brand name
Multiple-Cycle Extension: In Studies 1, 2, and 3, patients had the option of continuing into a multiple-cycle extension for up to 5 additional cycles of chemotherapy receiving the same treatment as assigned in cycle 1. At day 6 to 8 following initiation of chemotherapy, patients were asked to recall whether they had any episode of vomiting or retching or nausea that interfered with normal daily life. The results are summarized by study and treatment group in the figure below.
- Figure 1: No Emesis and No Nausea Interfering with Daily Life over Cycles 2-6
# How Supplied
Rolapitant is available as film-coated, capsule shaped, blue tablets, debossed with T0101 on one side and 100 on the other side. Each tablet contains 90 mg rolapitant. Rolapitant tablets are packaged in an Aclar blister shell with aluminum foil backing and supplied as follows:
NDC 69656-101-02 A single dose package (2 tablets as one set of twinned blisters)
## Storage
Store at 20°C to 25°C (68°F to 77°F); excursions are permitted between 15°C to 30°C (59°F to 86°F)
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling.
- Drug Interactions
Advise patients to tell their healthcare provider when they start or stop taking any concomitant medications. Rolapitant is a moderate CYP2D6 inhibitor and can increase plasma concentrations of CYP2D6 substrates if they are co-administered. The inhibitory effect of rolapitant on CYP2D6 lasts at least 7 days and may last longer than 7 days after a single dose.
# Precautions with Alcohol
Alcohol-Rolapitant interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
VARUBI™
# Look-Alike Drug Names
There is limited information regarding Rolapitant Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Rolapitant
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Martin Nino [2]
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# Overview
Rolapitant is a substance P/neurokinin 1 (NK1) receptor antagonist that is FDA approved for the prevention of delayed nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including, but not limited to, highly emetogenic chemotherapy. Common adverse reactions include neutropenia, hiccups, decreased appetite and dizziness.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Rolapitant is indicated in combination with other antiemetic agents in adults for the prevention of delayed nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including, but not limited to, highly emetogenic chemotherapy.
- Prevention of Nausea and Vomiting Associated with Emetogenic Cancer Chemotherapy
The recommended dosage of rolapitant in adults in combination with a 5-HT3 receptor antagonist and dexamethasone is shown in TABLE 1. There is no drug interaction between rolapitant and dexamethasone, so no dosage adjustment for dexamethasone is required. Administer a dexamethasone dose of 20 mg on Day 1.
Administer rolapitant prior to the initiation of each chemotherapy cycle, but at no less than 2 week intervals.
Administer rolapitant without regards to meals.
- Table 1: Recommended Dosing Regimen
VARUBI: Rolapitant's Brand name
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Rolapitant in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Rolapitant in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Safety and efficacy of rolapitant have not been established in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Rolapitant in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Rolapitant in pediatric patients.
# Contraindications
Rolapitant is contraindicated in patients receiving thioridazine, a CYP2D6 substrate. A significant increase in plasma concentrations of thioridazine may result in QT prolongation and Torsades de Pointes.
# Warnings
- Interaction with CYP2D6 Substrates with a Narrow Therapeutic Index
The inhibitory effect of rolapitant on CYP2D6 lasts at least 7 days and may last longer after a single dose administration of rolapitant. Avoid use of rolapitant in patients who are receiving pimozide, a CYP2D6 substrate. An increase in plasma concentrations of pimozide may result in QT prolongation. Monitor for adverse reactions if concomitant use of rolapitant and other CYP2D6 substrates with a narrow therapeutic index cannot be avoided.
# Adverse Reactions
## Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
The safety of rolapitant was evaluated in approximately 2800 patients in 4 controlled clinical trials in patients receiving emetogenic cancer chemotherapy. Rolapitant was given in combination with a 5-HT3 receptor antagonist and dexamethasone. On Day 1 of Cycle 1 of chemotherapy, 1567 patients were treated with rolapitant and 1198 of these patients continued into the optional multiple cycle extension for up to 6 cycles of chemotherapy. The median number of cycles administered 180 mg of rolapitant was four. Rolapitant 180 mg was administered to 1294 patients.
In Cycle 1 adverse reactions were reported in approximately 7% of patients treated with rolapitant compared with approximately 6% of patients treated with control therapy. The most common adverse reactions reported with an incidence of ≥3% and greater than control are listed in TABLE 2 and TABLE 3.
- Table 2: Most Common Adverse Reactions in Patients Receiving Cisplatin-Based Highly Emetogenic Chemotherapy (Cycle 1)*
VARUBI : Rolapitant's Brand name
- Table 3: Most Common Adverse Reactions in Patients Receiving Moderately Emetogenic Chemotherapy and Combinations of Anthracycline and Cyclophosphamide (Cycle 1)*
VARUBI : Rolapitant's Brand name
Adverse reactions in the multiple-cycle extensions of highly and moderately emetogenic chemotherapy studies for up to 6 cycles of chemotherapy were generally similar to that observed in Cycle 1.
## Postmarketing Experience
There is limited information regarding Rolapitant Postmarketing Experience in the drug label.
# Drug Interactions
Rolapitant is not an inhibitor or inducer of CYP3A4. Therefore, no dosage adjustment for dexamethasone (CYP3A4 substrate) is needed when co-administered with rolapitant.
Rolapitant is a moderate CYP2D6 inhibitor, an inhibitor of Breast-Cancer-Resistance Protein (BCRP) and an inhibitor of P-glycoprotein (P-gp).
- CYP2D6 Substrates with a Narrow Therapeutic Index: Increased plasma concentration of CYP2D6 substrates may result in potential adverse reactions. A 3-fold increase in the exposure of dextromethorphan, a CYP2D6 substrate, was observed 7 days after a single dose of rolapitant. The duration of CYP2D6 inhibition was not studied beyond 7 days and may last longer. Concomitant use with Thioridazine is contraindicated. Avoid use of rolapitant with pimozide. Monitor for QT prolongation if concomitant use with pimozide cannot be avoided. Monitor for adverse reactions if concomitant use with CYP2D6 substrates with a narrow therapeutic index cannot be avoided.
- BCRP Substrates with a Narrow Therapeutic Index (e.g., Methotrexate, topotecan, or irinotecan): Increased plasma concentrations of BCRP substrates may result in potential adverse reactions. Monitor for adverse reactions related to the concomitant drug if use of rolapitant cannot be avoided. Use the lowest effective dose of rosuvastatin.
- P-gp Substrates with a Narrow Therapeutic Index: Increased plasma concentrations of digoxin, or other P-gp substrates, may result in potential adverse reactions. Monitor for increased digoxin concentrations. Monitor for adverse reactions if concomitant use of rolapitant with other P-gp substrates with a narrow therapeutic index cannot be avoided.
Strong CYP3A4 Inducers (e.g., rifampin): significantly reduced plasma concentrations of rolapitant can decrease the efficacy of rolapitant; avoid use of rolapitant in patients who require chronic administration of such drugs.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): N
- Risk Summary
There are no available data on rolapitant use in pregnant women to inform any drug-associated risks. In animal reproduction studies, there were no teratogenic or embryo-fetal effects observed with oral administration of rolapitant hydrochloride in rats and rabbits during the period of organogenesis at doses up to 1.2 times and 2.9 times, respectively, the maximum recommended human dose (MRHD). In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
- Data
- Animal Data
The potential embryo-fetal toxicity of rolapitant hydrochloride was assessed in pregnant rats administered oral doses equivalent to up to 22.5 mg/kg per day rolapitant free base throughout organogenesis. Rats administered doses equivalent to 13.5 or 22.5 mg/kg per day rolapitant free base exhibited evidence of maternal toxicity including decreased body weight gain and/or body weight loss and a concomitant decrease in food consumption during the first week of dosing. No teratogenic or embryo-fetal effects were observed at doses equivalent to up to 22.5 mg/kg per day rolapitant free base (approximately 1.2 times the recommended human dose on a body surface area basis). In rabbits administered rolapitant hydrochloride throughout the period of organogenesis, oral doses equivalent to up to 27 mg/kg per day rolapitant free base (approximately 2.9 times the recommended human dose on a body surface area basis) were without effects on the developing fetus.
The pre- and postnatal developmental effects of rolapitant hydrochloride were assessed in rats administered oral doses equivalent to 2.25, 9 or 22.5 mg/kg per day rolapitant free base during the periods of organogenesis and lactation. Maternal toxicity was evident based on mortality/moribund condition, decreased body weight and food consumption, total litter loss, prolonged parturition, decreased length of gestation, and increased number of unaccounted for implantation sites at a dose equivalent to 22.5 mg/kg per day free base (approximately 1.2 times the recommended human dose on a body surface area basis). Effects on offspring at this dose included decreased postnatal survival, and decreased body weights and body weight gain, and may be related to the maternal toxicity observed. At a maternal dose equivalent to 9 mg/kg per day rolapitant free base (approximately 0.5 times the recommended human dose on a body surface area basis), there was a decrease in memory in female pups in a maze test and a decrease in pup body weight.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Rolapitant in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Rolapitant during labor and delivery.
### Nursing Mothers
- Risk Summary
There are no data on the presence of rolapitant in human milk, the effects of rolapitant in the breastfed infant, or the effects of rolapitant on milk production. Rolapitant hydrochloride administered orally to lactating female rats was present in milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for rolapitant and any potential adverse effects on the breastfed infant from rolapitant or from the underlying maternal condition or the use of concomitant chemotherapy.
- Data
Radioactivity from labeled [14C] rolapitant hydrochloride was transferred into milk of lactating rats following a single oral dose equivalent to 22.5 mg/kg rolapitant free base, and the maximum radioactivity in milk was observed at 12 hours post-dose. The mean milk/plasma radioactivity concentration ratios in dams at 1 to 48 hours post-dose ranged from 1.24 to 3.25. Based on average daily consumption of milk (2 mL/day) and the maximum milk radioactivity determined, pup exposure is expected to be 0.32% of the orally administered dose.
### Pediatric Use
Safety and efficacy of rolapitant have not been established in pediatric patients.
### Geriatic Use
Of the 1294 subjects treated with rolapitant, 25% were 65 years and over, while 5% were 75 and over. No overall differences in safety or efficacy were reported between the elderly subjects and younger subjects, but greater sensitivity of some older individuals cannot be ruled out.
### Gender
There is no FDA guidance on the use of Rolapitant with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Rolapitant with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Rolapitant in patients with renal impairment.
### Hepatic Impairment
No dosage adjustment is needed in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. There are no clinical or pharmacokinetic data in patients with severe hepatic impairment (Child-Pugh Class C). Avoid use of rolapitant in patients with severe hepatic impairment. If use cannot be avoided, monitor patients for adverse reactions related to rolapitant.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Rolapitant in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Rolapitant in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Prevention of Nausea and Vomiting Associated with Emetogenic Cancer Chemotherapy
The recommended dosage of rolapitant in adults in combination with a 5-HT3 receptor antagonist and dexamethasone is shown in TABLE 1. There is no drug interaction between rolapitant and dexamethasone, so no dosage adjustment for dexamethasone is required. Administer a dexamethasone dose of 20 mg on Day 1.
Administer rolapitant prior to the initiation of each chemotherapy cycle, but at no less than 2 week intervals.
Administer rolapitant without regards to meals.
### Monitoring
There is limited information regarding Rolapitant Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Rolapitant and IV administrations.
# Overdosage
- There are no data on overdose with rolapitant.
- There is no antidote for rolapitant overdose. Discontinue rolapitant in the event of overdose, and institute general supportive measures and close observation.
# Pharmacology
## Mechanism of Action
Rolapitant is a selective and competitive antagonist of human substance P/NK1 receptors. Rolapitant does not have significant affinity for the NK2 or NK3 receptors or for a battery of other receptors, transporters, enzymes and ion channels. Rolapitant is also active in animal models of chemotherapy-induced emesis.
## Structure
Rolapitant hydrochloride is chemically described as (5S,8S)-8- { [(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]methyl]}-8-phenyl 1,7-diazaspiro[4.5]decan-2-one monohydrochloride monohydrate. Its empirical formula is C25H26F6N2O2. HCl.H2O and its structural formula is:
Rolapitant hydrochloride is a white to off-white powder, with a molecular weight of 554.95. Solubility of rolapitant hydrochloride in aqueous solution is pH-dependent and is more soluble at lower pH. Rolapitant hydrochloride has good solubility in common pharmaceutical solvents such as ethanol, propylene glycol, and 40% hydroxypropyl beta cyclodextrin.
Each tablet for oral administration contains 90 mg rolapitant and the following inactive ingredients: lactose monohydrate, pregelatinized starch, microcrystalline cellulose, povidone, croscarmellose sodium, colloidal silicon dioxide and magnesium stearate. The tablets are coated in non-functional blue and clear coats. The tablet coating comprises the following inactive ingredients: polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, FD&C Blue No. 2- Indigo Carmine Lake and polysorbate 80.
## Pharmacodynamics
- NK1 Receptor Occupancy
A human Positron Emission Tomography (PET) study with rolapitant demonstrated that rolapitant crosses the blood brain barrier and occupies brain NK1 receptors. A dose-dependent increase in mean NK1 receptor occupancy was observed in the dose range from 4.5 mg to 180 mg of rolapitant. At the 180 mg dose of rolapitant, the mean NK1 receptor occupancy was 73% in the striatum at 120 hours after a single dose administration in healthy subjects. The relationship between NK1 receptor occupancy and the clinical efficacy of rolapitant has not been established.
- Cardiac Electrophysiology
In a thorough QT study, rolapitant at doses up to 4 times higher than the recommended dose had no significant effects on the QT intervals.
## Pharmacokinetics
- Absorption
Following a single dose administration of 180 mg rolapitant under fasting conditions to healthy subjects, rolapitant was measurable in plasma between 30 minutes and the peak plasma concentration (Cmax) for rolapitant was reached in about 4 hours and mean Cmax was 968 ng/mL (%CV:28%).
Following multiple oral doses 9 to 45 mg once daily of rolapitant, accumulation of rolapitant was approximately 5-fold.
The systemic exposures (Cmax and AUC) to rolapitant increased in a dose-proportional manner when the dose of rolapitant increased from 4.5 mg to 180 mg. With an increase in dose by 4 times from the recommended clinical dose of 180 mg, the Cmax and AUC of rolapitant increased by 3.1 fold and 3.7 fold, respectively.
Concomitant administration of a high fat meal did not significantly affect the pharmacokinetics of rolapitant after administration of 180 mg rolapitant.
- Distribution
Rolapitant was highly protein bound to human plasma (99.8%). The apparent volume of distribution (Vd/F) was 460 L in healthy subjects, indicating an extensive tissue distribution of rolapitant. In a population pharmacokinetic analysis of rolapitant, the Vd/F was 387 L in cancer patients.
- Elimination
Following single oral doses (4.5 to 180 mg) of rolapitant, the mean terminal half-life (t1/2) of rolapitant ranged from 169 to 183 hours (approximately 7 days) and was independent of dose. In a population pharmacokinetic analysis the apparent total clearance (CL/F) of rolapitant was 0.96 L/hour in cancer patients.
- Metabolism
Rolapitant is metabolized primarily by CYP3A4 to form a major active metabolite, M19 (C4- pyrrolidine-hydroxylated rolapitant). In a mass balance study, the metabolite M19 was the major circulating metabolite. The formation of M19 was significantly delayed with the median Tmax of 120 hours (range: 24-168 hours) and the mean half-life of M19 was 158 hours.
The exposure ratio of M19 to rolapitant was approximately 50% in plasma.
- Excretion
Rolapitant is eliminated primarily through the hepatic/biliary route. Following administration of a single oral 180-mg dose of [14C]-rolapitant, on average 14.2% (range 9% to 20%) and 73% (range 52% to 89%) of the dose was recovered in the urine and feces, respectively over 6 weeks. In pooled samples collected over 2 weeks, 8.3% of the dose was recovered in the urine primarily as metabolites and 37.8% of the dose was recovered in the feces primarily as unchanged rolapitant. Unchanged rolapitant or M19 were not found in pooled urine sample.
- Specific Populations
- Age, Sex and Race/Ethnicity
Population pharmacokinetic analyses indicated that age, sex and race had no significant impact on the pharmacokinetics of rolapitant.
- Hepatic Impairment
Following administration of a single dose of 180 mg rolapitant to patients with mild hepatic impairment (Child-Pugh Class A), the pharmacokinetics of rolapitant were comparable with those of healthy subjects. In patients with moderate hepatic impairment (Child-Pugh Class B), the mean Cmax was 25% lower while mean AUC of rolapitant was similar compared to those of healthy subjects. The median Tmax for M19 was delayed to 204 hours in patients with mild or moderate hepatic impairment compared to 168 hours in healthy subjects. The pharmacokinetics of rolapitant was not studied in patients with severe hepatic impairment (Child-Pugh Class C).
- Renal Impairment
In population pharmacokinetic analyses, creatinine clearance (CLcr) at baseline did not show a significant effect on rolapitant pharmacokinetics in cancer patients with mild (CLcr: 60 to 90 mL/min) or moderate (CLcr: 30 to 60 mL/min) renal impairment compared to cancer patients with normal kidney function. Information is insufficient for the effect of severe renal impairment. The pharmacokinetics of rolapitant was not studied in patients with end-stage renal disease requiring hemodialysis.
- Drug Interaction Studies
- Effect of Other Drugs on rolapitant
Rolapitant is a substrate for CYP3A4.
- CYP3A4 inducers
Concomitant administration of a CYP3A4 inducer significantly decreased the systemic exposure to rolapitant. When 600 mg rifampin was administered once daily for 7 days before and 7 days after administration of a single dose of 180 mg rolapitant , the mean Cmax of rolapitant was reduced by 30% and the mean AUC was reduced by 85% compared to administration of rolapitant alone. The mean half-life of rolapitant decreased from 176 hours without rifampin to 41 hours with concurrent rifampin.
- CYP3A4 inhibitors
No clinically significant effect was seen on the pharmacokinetics of rolapitant when ketoconazole, a strong CYP3A4 inhibitor was administered with rolapitant. Concurrent administration of 400 mg ketoconazole once daily for 21 days following a single 90 mg dose of rolapitant , did not significantly affect the Cmax of rolapitant while the AUC increased by 21%.
- Effect of rolapitant on Other Drugs
The effect of rolapitant on CYP450 enzymes and transporters is summarized below. See TABLE 4 for a summary of the effects of the clinical dose of rolapitant on the pharmacokinetics of co- administered drugs.
- CYP3A4 substrates
Rolapitant is neither an inhibitor nor an inducer of CYP3A4.
Midazolam: A single dose of 180 mg rolapitant had no significant effects on the pharmacokinetics of midazolam when oral midazolam 3 mg was co-administered on Day 1 and administered alone on Days 6, and 9.
Ondansetron: Rolapitant had no significant effects on the pharmacokinetics of intravenous ondansetron when concomitantly administered with a single 180 mg dose of rolapitant on the same day.
Dexamethasone: Rolapitant had no significant effects on the pharmacokinetics of dexamethasone when oral dexamethasone was administered on Days 1 to 3 after a single 180 mg dose of rolapitant was co-administered on Day 1.
- CYP2D6 substrates
Rolapitant is a moderate inhibitor of CYP2D6.
- BCRP transporter
Rolapitant is an inhibitor of BCRP transporter.
- P-glycoprotein substrates
Rolapitant is an inhibitor of P-gp transporter.
- Substrates for other CYP enzymes
In vitro studies suggest that rolapitant is not an inhibitor of CYP1A2 and CYP2E1. A clinically meaningful drug interaction via an inhibition of CYP2A6 appears unlikely based on in vitro study.
No clinically significant interaction was seen on the pharmacokinetics of the following drugs when administered with a single dose of 180 mg rolapitant on Day 1 and without rolapitant on Day 8: repaglinide (CYP2C8 substrate; no effect on repaglinide 0.25 mg on Day 1; on Day 8 : 29% and 24% increase in Cmax and AUC, respectively), efavirenz (CYP2B6 substrate; 18% decrease in Cmax and no effect on AUC of efavirenz 600 mg on Day 1; on Day 8: no effect on Cmax and 28% increase in AUC), tolbutamide (CYP2C9 substrate; no effect on tolbutamide 500 mg on Day 1 and on Day 8), or omeprazole (CYP2C19 substrate; 44% increase in Cmax and 23% increase in AUC of omeprazole 40 mg on Day 1; on Day 8: 37% and 15% increase in Cmax and AUC, respectively).
- Table 4: Effect of Rolapitant on the Pharmacokinetics of Co-administered Drugs*
## Nonclinical Toxicology
Carcinogenic potential of rolapitant hydrochloride was assessed in 2-year carcinogenicity studies in CD-1 mice and Sprague-Dawley rats. In mice, there were no drug-related neoplastic findings at doses equivalent to up to 135 mg/kg per day rolapitant free base (approximately 3.6 times the recommended human dose on a body surface area basis). In rats, there were no drug-related neoplastic findings at doses equivalent to up to 90 mg/kg per day rolapitant free base (approximately 4.9 times the recommended human dose on a body surface area basis).
Rolapitant hydrochloride was not genotoxic in an Ames test, a human peripheral blood lymphocyte chromosome aberration test, and a mouse micronucleus test.
In a fertility and early embryonic development study in female rats, rolapitant hydrochloride at an oral dose equivalent to 9 mg/kg per day free base (approximately 0.5 times the recommended human dose on a body surface area basis) caused a transient decrease in maternal body weight gain and increases in the incidence of pre- and post-implantation loss. At a dose equivalent to 4.5 mg/kg per day free base (approximately 0.2 times the recommended human dose on a body surface area basis), there were slight decreases in the number of corpora lutea and implantation sites. Rolapitant hydrochloride did not affect the fertility or general reproductive performance of male rats at doses equivalent to up to 90 mg/kg per day rolapitant free base (approximately 4.9 times the recommended human dose on a body surface area basis).
# Clinical Studies
- Cisplatin-Based Highly Emetogenic Chemotherapy (HEC)
In two multicenter, randomized, double-blind, parallel group, controlled clinical studies (Study 1 and Study 2), the rolapitant regimen (rolapitant, granisetron and dexamethasone) was compared with control therapy (placebo, granisetron and dexamethasone) in patients receiving a chemotherapy regimen that included cisplatin >60 mg/m2. See TABLE 5 for the treatment regimens.
- Table 5: Treatment Regimens in Studies 1 and 2
VARUBI : Rolapitant's Brand name
- Study 1
A total of 532 patients were randomized to either the rolapitant regimen (N =266) or control therapy (N =266). A total of 526 patients were included in the evaluation of efficacy. Of those randomized 42% were women, 58 % men, 67% White, 23% Asian, 1% Black, and 9% multi racial/other/unknown. The proportion of patients from North America was 16%. Patients in this clinical study ranged from 20 to 90 years of age, with a mean age of 57 years. In Study 1, 26% of patients were 65 years or older, with 3% of patients being 75 years or older. The mean cisplatin dose was 77 mg/m2.
During this study, 82% of the patients received a concomitant chemotherapeutic agent in addition to protocol-mandated cisplatin. The most common concomitant chemotherapeutic agents administered during Cycle 1 were: gemcitabine (17%), paclitaxel (12%), fluorouracil (11%), etoposide (10%), vinorelbine (9%), docetaxel (9%), pemetrexed (7%), doxorubicin (6%) and cyclophosphamide (5%).
- Study 2
A total of 555 patients were randomized to either the rolapitant regimen (N =278) or control therapy (N =277). A total of 544 patients were included in the evaluation of efficacy. Of those randomized, 32% were women, 68 % men, 81% White, 14% Asian, 1% Black, and 5% multi racial/other/unknown. The proportion of patients from North America was 7%. Patients in this clinical study ranged from 18 to 83 years of age, with a mean age of 58 years. In this study, 27% of patients were 65 years or older, with 3% of patients being 75 years or older. The mean cisplatin dose was 76 mg/m2.
During this study, 85% of the patients received a concomitant chemotherapeutic agent in addition to protocol-mandated cisplatin. The most common concomitant chemotherapeutic agents administered during Cycle 1 were: vinrorelbine (16%), gemcitabine (15%), fluorouracil (12%), etoposide (11%), pemetrexed (9%), docetaxel (7%), paclitaxel (7%), epirubicin (5%) and capecitabine (4%).
The primary endpoint in both studies was complete response (defined as no emetic episodes and no rescue medication) in the delayed phase (25 to 120 hours) of chemotherapy-induced nausea and vomiting.
- Moderately Emetogenic Chemotherapy (MEC) and Combinations of Anthracycline and Cyclophosphamide Chemotherapy
- Study 3
In Study 3, a multicenter, randomized, double-blind, parallel group, controlled clinical study in moderately emetogenic chemotherapy, the rolapitant regimen (rolapitant, granisetron and dexamethasone) was compared with control therapy (placebo, granisetron and dexamethasone) in patients receiving a moderately emetogenic chemotherapy regimen that included at least 50% of patients receiving a combination of anthracycline and cyclophosphamide. The percentage of patients who received carboplatin in Cycle 1 was 30%. Treatment regimens for the rolapitant and control arms are summarized in TABLE 6.
- Table 6: Treatment Regimens in Study 3
VARUBI : Rolapitant's Brand name
A total of 1369 patients were randomized to either the rolapitant regimen (N = 684) or control therapy (N = 685). A total of 1332 patients were included in the evaluation of efficacy. Of those randomized 80% were women, 20% men, 77% White, 13% Asian, 4% Black, and 6% multi- racial/other/unknown. The proportion of patients from North America was 33%. Patients in this clinical study ranged from 22 to 88 years of age, with a mean age of 57 years. In this study, 28% of patients were 65 years or older, with 7% of patients being 75 years or older.
The primary endpoint was complete response (defined as no emetic episodes and no rescue medication) in the delayed phase (25 to 120 hours) of chemotherapy-induced nausea and vomiting.
A summary of the study results from HEC Studies 1 and 2, and for the MEC Study 3 is shown in TABLE 7.
- Table 7: Percent of Patients Receiving Emetogenic Chemotherapy Responding by Treatment Group for the HEC Studies 1 and 2 and for the MEC Study 3
VARUBI : Rolapitant's Brand name
Multiple-Cycle Extension: In Studies 1, 2, and 3, patients had the option of continuing into a multiple-cycle extension for up to 5 additional cycles of chemotherapy receiving the same treatment as assigned in cycle 1. At day 6 to 8 following initiation of chemotherapy, patients were asked to recall whether they had any episode of vomiting or retching or nausea that interfered with normal daily life. The results are summarized by study and treatment group in the figure below.
- Figure 1: No Emesis and No Nausea Interfering with Daily Life over Cycles 2-6
# How Supplied
Rolapitant is available as film-coated, capsule shaped, blue tablets, debossed with T0101 on one side and 100 on the other side. Each tablet contains 90 mg rolapitant. Rolapitant tablets are packaged in an Aclar blister shell with aluminum foil backing and supplied as follows:
NDC 69656-101-02 A single dose package (2 tablets as one set of twinned blisters)
## Storage
Store at 20°C to 25°C (68°F to 77°F); excursions are permitted between 15°C to 30°C (59°F to 86°F)
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling.
- Drug Interactions
Advise patients to tell their healthcare provider when they start or stop taking any concomitant medications. Rolapitant is a moderate CYP2D6 inhibitor and can increase plasma concentrations of CYP2D6 substrates if they are co-administered. The inhibitory effect of rolapitant on CYP2D6 lasts at least 7 days and may last longer than 7 days after a single dose.
# Precautions with Alcohol
Alcohol-Rolapitant interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
VARUBI™
# Look-Alike Drug Names
There is limited information regarding Rolapitant Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Rolapitant | |
85266ad74921e90612963397913ea95717bd1faa | wikidoc | Romidepsin | Romidepsin
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# Overview
Romidepsin is a histone deacetylase inhibitor that is FDA approved for the treatment of cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphoma (PTCL). Common adverse reactions include EKG ST segment changes, anemia, neutropenia, infectious disease, cutaneous T-cell lymphoma, lymphocytopenia.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Romidepsin is indicated for:
- Treatment of cutaneous T-cell lymphoma (CTCL) in patients who have received at least one prior systemic therapy.
- Treatment of peripheral T-cell lymphoma (PTCL) in patients who have received at least one prior therapy.
- These indications are based on response rate. Clinical benefit such as improvement in overall survival has not been demonstrated.
- The recommended dose of romidepsin is 14 mg/m2 administered intravenously over a 4-hour period on days 1, 8, and 15 of a 28-day cycle. Cycles should be repeated every 28 days provided that the patient continues to benefit from and tolerates the drug.
- Nonhematologic toxicities except alopecia
- Grade 2 or 3 toxicity: Treatment with romidepsin should be delayed until toxicity returns to ≤ Grade 1 or baseline, then therapy may be restarted at 14 mg/m2. If Grade 3 toxicity recurs, treatment with romidepsin should be delayed until toxicity returns to ≤ Grade 1 or baseline and the dose should be permanently reduced to 10 mg/m2.
- Grade 4 toxicity
- Treatment with romidepsin should be delayed until toxicity returns to ≤ Grade 1 or baseline, then the dose should be permanently reduced to 10 mg/m2.
Romidepsin should be discontinued if Grade 3 or 4 toxicities recur after dose reduction.
- Grade 3 or 4 neutropenia or thrombocytopenia: Treatment with romidepsin should be delayed until the specific cytopenia returns to ANC ≥1.5×109/L and platelet count ≥75×109/L or baseline, then therapy may be restarted at 14 mg/m2.
- Grade 4 febrile (≥ 38.5ºC) neutropenia or thrombocytopenia that requires platelet transfusion: Treatment with romidepsin should be delayed until the specific cytopenia returns to ≤ Grade 1 or baseline, and then the dose should be permanently reduced to 10 mg/m2.
- Romidepsin is a cytotoxic drug. Use appropriate handling procedures.
- Romidepsin must be reconstituted with the supplied diluent and further diluted with 0.9% Sodium Chloride Injection, USP before intravenous infusion.
- Each 10 mg single-use vial of Romidepsin must be reconstituted with 2 mL of the supplied diluent. With a suitable syringe, aseptically withdraw 2 mL from the supplied diluent vial, and slowly inject it into the Romidepsin for injection vial. Swirl the contents of the vial until there are no visible particles in the resulting solution. The reconstituted solution will contain Romidepsin 5 mg/mL. The reconstituted Romidepsin solution is chemically stable for up to 8 hours at room temperature.
- Extract the appropriate amount of Romidepsin from the vials to deliver the desired dose, using proper aseptic technique. Before intravenous infusion, further dilute Romidepsin in 500 mL 0.9% Sodium Chloride Injection, USP.
- Infuse over 4 hours.
- The diluted solution is compatible with polyvinyl chloride (PVC), ethylene vinyl acetate (EVA), polyethylene (PE) infusion bags as well as glass bottles, and is chemically stable for up to 24 hours when stored at room temperature. However, it should be administered as soon after dilution as possible.
- Parenteral drug products should be inspected visually for particulate matter and discoloration before administration, whenever solution and container permit.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Romidepsin in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Romidepsin in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Romidepsin FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Romidepsin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Romidepsin in pediatric patients.
# Contraindications
There is limited information regarding Romidepsin Contraindications in the drug label.
# Warnings
- Treatment with Romidepsin can cause thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia. Monitor blood counts regularly during treatment with Romidepsin, and modify the dose as necessary.
- Fatal and serious infections, including pneumonia, sepsis, and viral reactivation, including Epstein Barr and hepatitis B viruses, have been reported in clinical trials with Romidepsin. These can occur during treatment and within 30 days after treatment. The risk of life threatening infections may be greater in patients with a history of prior treatment with monoclonal antibodies directed against lymphocyte antigens and in patients with disease involvement of the bone marrow.
- Reactivation of hepatitis B virus infection has occurred in 1% of PTCL patients in clinical trials in Western populations. In patients with evidence of prior hepatitis B infection, consider monitoring for reactivation, and consider antiviral prophylaxis.
- Reactivation of Epstein Barr viral infection leading to liver failure has occurred in a trial of patients with relapsed or refractory extranodal NK/T-cell lymphoma. In one case, ganciclovir prophylaxis failed to prevent Epstein Barr viral reactivation.
- Several treatment-emergent morphological changes in ECGs (including T-wave and ST-segment changes) have been reported in clinical studies. The clinical significance of these changes is unknown.
- In patients with congenital long QT syndrome, patients with a history of significant cardiovascular disease, and patients taking anti-arrhythmic medicines or medicinal products that lead to significant QT prolongation, consider cardiovascular monitoring of ECGs at baseline and periodically during treatment.
- Confirm that potassium and magnesium levels are within normal range before administration of Romidepsin.
- Tumor lysis syndrome (TLS) has been reported to occur in 1% of patients with tumor stage CTCL and 2% of patients with Stage III/IV PTCL. Patients with advanced stage disease and/or high tumor burden may be at greater risk, should be closely monitored, and managed as appropriate.
- There are no adequate and well-controlled studies of Romidepsin in pregnant women. However, based on its mechanism of action and findings in animals, Romidepsin may cause fetal harm when administered to a pregnant woman. In an animal reproductive study, romidepsin was embryocidal and resulted in adverse effects on the developing fetus at exposures below those in patients at the recommended dose of 14 mg/m2/week. If this drug is used during pregnancy, or if the patient becomes pregnant while taking Romidepsin, the patient should be apprised of the potential hazard to the fetus.
# Adverse Reactions
## Clinical Trials Experience
- Myelosuppression
- Infection
- Electrocardiographic Changes
- Tumor Lysis Syndrome
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- The safety of Romidepsin was evaluated in 185 patients with CTCL in 2 single arm clinical studies in which patients received a starting dose of 14 mg/m2. The mean duration of treatment in these studies was 5.6 months (range: <1 to 83.4 months).
- Table 1 summarizes the most frequent adverse reactions (> 20%) regardless of causality using the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE, Version 3.0). Due to methodological differences between the studies, the AE data are presented separately for Study 1 and Study 2. Adverse reactions are ranked by their incidence in Study 1. Laboratory abnormalities commonly reported (> 20%) as adverse reactions are included in Table 1.
- Infections were the most common type of SAE reported in both studies with 8 patients (8%) in Study 1 and 26 patients (31%) in Study 2 experiencing a serious infection. Serious adverse reactions reported in > 2% of patients in Study 1 were sepsis and pyrexia (3%). In Study 2, serious adverse reactions in > 2% of patients were fatigue (7%), supraventricular arrhythmia, central line infection, neutropenia (6%), hypotension, hyperuricemia, edema (5%), ventricular arrhythmia, thrombocytopenia, nausea, leukopenia, dehydration, pyrexia, aspartate aminotransferase increased, sepsis, catheter related infection, hypophosphatemia and dyspnea (4%).
- Most deaths were due to disease progression. In Study 1, there were two deaths due to cardiopulmonary failure and acute renal failure. In Study 2, there were six deaths due to infection (4), myocardial ischemia, and acute respiratory distress syndrome.
- Discontinuation due to an adverse event occurred in 21% of patients in Study 1 and 11% in Study 2. Discontinuations occurring in at least 2% of patients in either study included infection, fatigue, dyspnea, QT prolongation, and hypomagnesemia.
- The safety of Romidepsin was evaluated in 178 patients with PTCL in a sponsor-conducted pivotal study (Study 3) and a secondary NCI-sponsored study (Study 4) in which patients received a starting dose of 14 mg/m2. The mean duration of treatment and number of cycles were 5.6 months and 6 cycles in Study 3 and 9.6 months and 8 cycles in Study 4.
- Table 2 summarizes the most frequent adverse reactions (≥ 10%) regardless of causality, using the NCI-CTCAE, Version 3.0. The AE data are presented separately for Study 3 and Study 4. Laboratory abnormalities commonly reported (≥ 10%) as adverse reactions are included in Table 2.
- Infections were the most common type of SAE reported. In Study 3, 26 patients (20%) experienced a serious infection, including 6 patients (5%) with serious treatment-related infections. In Study 4, 11 patients (23%) experienced a serious infection, including 8 patients (17%) with serious treatment-related infections. Serious adverse reactions reported in ≥ 2% of patients in Study 3 were pyrexia(8%), pneumonia, sepsis, vomiting (5%), cellulitis, deep vein thrombosis, (4%), febrile neutropenia, abdominal pain (3%), chest pain, neutropenia, pulmonary embolism, dyspnea, and dehydration (2%). In Study 4, serious adverse reactions in ≥ 2 patients were pyrexia (17%), aspartate aminotransferase increased, hypotension (13%), anemia, thrombocytopenia, alanine aminotransferase increased (11%), infection, dehydration, dyspnea (9%), lymphopenia, neutropenia, hyperbilirubinemia, hypocalcemia, hypoxia (6%), febrile neutropenia, leukopenia, ventricular arrhythmia, vomiting, hypersensitivity, catheter related infection, hyperuricemia, hypoalbuminemia, syncope, pneumonitis, packed red blood cell transfusion, and platelet transfusion (4%).
- Reactivation of hepatitis B virus infection has occurred in 1% of patients with PTCL patients in clinical trials in Western population enrolled in Study 3 and Study 4.
- Deaths due to all causes within 30 days of the last dose of Romidepsin occurred in 7% of patients in Study 3 and 17% of patients in Study 4. In Study 3, there were 5 deaths unrelated to disease progression that were due to infections, including multi-organ failure/sepsis, pneumonia, septic shock, candida sepsis, and sepsis/cardiogenic shock. In Study 4, there were 3 deaths unrelated to disease progression that were due to sepsis, aspartate aminotransferase elevation in the setting of Epstein Barr virus reactivation, and death of unknown cause.
- Discontinuation due to an adverse event occurred in 19% of patients in Study 3 and in 28% of patients in Study 4. In Study 3, thrombocytopenia and pneumonia were the only events leading to treatment discontinuation in at least 2% of patients. In Study 4, events leading to treatment discontinuation in ≥ 2 patients were thrombocytopenia (11%), anemia, infection, and alanine aminotransferase increased (4%).
## Postmarketing Experience
- No additional safety signals have been observed from postmarketing experience.
# Drug Interactions
- Prolongation of PT and elevation of INR were observed in a patient receiving Romidepsin concomitantly with warfarin. Although the interaction potential between Romidepsin and warfarin has not been formally studied, monitor PT and INR more frequently in patients concurrently receiving Romidepsin and warfarin.
- Romidepsin is metabolized by CYP3A4. Strong CYP3A4 inhibitors increase concentrations of romidepsin. In a pharmacokinetic drug interaction trial the strong CYP3A4 inhibitor ketoconazole increased romidepsin (AUC0-∞) by approximately 25%.
- Monitor for toxicity related to increased romidepsin exposure and follow the dose modifications for toxicity when romidepsin is initially co-administered with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole).
- Avoid co-administration of Romidepsin with rifampin.
- In a pharmacokinetic drug interaction trial with co-administered rifampin (a strong CYP3A4 inducer), romidepsin exposure was increased by approximately 80% and 60% for AUC0-∞ and Cmax, respectively. Typically, co-administration of CYP3A4 inducers decrease concentrations of drugs metabolized by CYP3A4. The increase in exposure seen after co-administration with rifampin is likely due to rifampin’s inhibition of an undetermined hepatic uptake process that is predominantly responsible for the disposition of Romidepsin.
- It is unknown if other potent CYP3A4 inducers (e.g., dexamethasone, carbamazepine, phenytoin, rifabutin, rifapentine, phenobarbital, St. John’s Wort) would alter the exposure of Romidepsin. Therefore, the use of other potent CYP3A4 inducers should be avoided when possible.
- Romidepsin is a substrate of the efflux transporter P-glycoprotein (P-gp, ABCB1). If Romidepsin is administered with drugs that inhibit P-gp, increased concentrations of romidepsin are likely, and caution should be exercised.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
- There are no adequate and well-controlled studies of Romidepsin in pregnant women. However, based on its mechanism of action and findings in animals, Romidepsin may cause fetal harm when administered to a pregnant woman. In an animal reproductive study, romidepsin was embryocidal and resulted in adverse effects on the developing fetus at exposures below those in patients at the recommended dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking Romidepsin, the patient should be apprised of the potential hazard to the fetus.
- Romidepsin was administered intravenously to rats during the period of organogenesis at doses of 0.1, 0.2, or 0.5 mg/kg/day. Substantial resorption or post-implantation loss was observed at the high-dose of 0.5 mg/kg/day, a maternally toxic dose. Adverse embryo-fetal effects were noted at romidepsin doses of ≥0.1 mg/kg/day, with systemic exposures (AUC) ≥0.2% of the human exposure at the recommended dose of 14 mg/m2/week. Drug-related fetal effects consisted of folded retina, rotated limbs, and incomplete sternal ossification.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Romidepsin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Romidepsin during labor and delivery.
### Nursing Mothers
- It is not known whether romidepsin is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Romidepsin, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
The safety and effectiveness of Romidepsin in pediatric patients has not been established.
### Geriatic Use
- Of the approximately 300 patients with CTCL or PTCL in trials, about 25% were >65 years old. No overall differences in safety or effectiveness were observed between these subjects and younger subjects; however, greater sensitivity of some older individuals cannot be ruled out.
### Gender
There is no FDA guidance on the use of Romidepsin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Romidepsin with respect to specific racial populations.
### Renal Impairment
- No dedicated renal impairment study for Romidepsin has been conducted. Based upon the population pharmacokinetic analysis, renal impairment is not expected to significantly influence drug exposure. The effect of end-stage renal disease on romidepsin pharmacokinetics has not been studied. Thus, patients with end-stage renal disease should be treated with caution.
### Hepatic Impairment
- No dedicated hepatic impairment study for Romidepsin has been conducted. Mild hepatic impairment does not alter pharmacokinetics of romidepsin based on a population pharmacokinetic analysis. Patients with moderate and severe hepatic impairment should be treated with caution.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Romidepsin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Romidepsin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
### Monitoring
- Monitor blood counts regularly during treatment with Romidepsin, and modify the dose as necessary.
- In patients with congenital long QT syndrome, patients with a history of significant cardiovascular disease, and patients taking anti-arrhythmic medicines or medicinal products that lead to significant QT prolongation, consider cardiovascular monitoring of ECGs at baseline and periodically during treatment.
- Carefully monitor prothrombin time (PT) and International Normalized Ratio (INR) in patients concurrently administered Romidepsin and warfarin or coumarin derivatives.
# IV Compatibility
There is limited information regarding the compatibility of Romidepsin and IV administrations.
# Overdosage
- No specific information is available on the treatment of overdosage of Romidepsin.
Toxicities in a single-dose study in rats or dogs, at intravenous romidepsin doses up to 2.2 fold the recommended human dose based on the body surface area, included irregular respiration, irregular heartbeat, staggering gait, tremor, and tonic convulsions.
In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., clinical monitoring and supportive therapy, if required. There is no known antidote for Romidepsin and it is not known if Romidepsin is dialyzable.
# Pharmacology
There is limited information regarding Romidepsin Pharmacology in the drug label.
## Mechanism of Action
- No specific information is available on the treatment of overdosage of Romidepsin.
- Toxicities in a single-dose study in rats or dogs, at intravenous romidepsin doses up to 2.2 fold the recommended human dose based on the body surface area, included irregular respiration, irregular heartbeat, staggering gait, tremor, and tonic convulsions.
- In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., clinical monitoring and supportive therapy, if required. There is no known antidote for Romidepsin and it is not known if Romidepsin is dialyzable.
## Structure
There is limited information regarding Romidepsin Structure in the drug label.
## Pharmacodynamics
- The effect of romidepsin on the heart-rate corrected QTc/QTcF was evaluated in 26 subjects with advanced malignancies given romidepsin at doses of 14 mg/m2 as a 4-hour intravenous infusion, and at doses of 8, 10 or 12 mg/m2 as a 1–hour infusion. Patients received premedications with antiemetics. No large changes in the mean QTc interval (> 20 milliseconds) from baseline based on Fridericia correction method were detected in the trial. Small increase in mean QT interval (< 10 milliseconds) and mean QT interval increase between 10 to 20 milliseconds cannot be excluded because of the limitations in the trial design.
- Romidepsin was associated with a delayed concentration-dependent increase in heart rate in patients with advanced cancer with a maximum mean increase in heart rate of 20 beats per minute occurring at the 6 hour time point after start of romidepsin infusion for patients receiving 14 mg/m2 as a 4-hour infusion.
## Pharmacokinetics
- Romidepsin exhibited linear pharmacokinetics across doses ranging from 1.0 to 24.9 mg/m2 when administered intravenously over 4 hours in patients with advanced cancers.
- In patients with T-cell lymphomas who received 14 mg/m2 of romidepsin intravenously over a 4-hour period on days 1, 8, and 15 of a 28-day cycle, geometric mean values of the maximum plasma concentration (Cmax) and the area under the plasma concentration versus time curve (AUC0-inf) were 377 ng/mL and 1549 ng*hr/mL, respectively.
- Romidepsin is highly protein bound in plasma (92% to 94%) over the concentration range of 50 ng/mL to 1000 ng/mL with α1-acid-glycoprotein (AAG) being the principal binding protein. Romidepsin is a substrate of the efflux transporter P-glycoprotein (P-gp, ABCB1).
- In vitro, romidepsin accumulates into human hepatocytes via an unknown active uptake process. Romidepsin is not a substrate of the following uptake transporters: BCRP, BSEP, MRP2, OAT1, OAT3, OATP1B1, OATP1B3, or OCT2. In addition, romidepsin is not an inhibitor of BCRP, MRP2, MDR1 or OAT3. Although romidepsin did not inhibit OAT1, OCT2, and OATP1B3 at concentrations seen clinically (1 μmol/L), modest inhibition was observed at 10 µmol/L. Romidepsin was found to be an inhibitor of BSEP and OATP1B1.
- Romidepsin undergoes extensive metabolism in vitro primarily by CYP3A4 with minor contribution from CYP3A5, CYP1A1, CYP2B6, and CYP2C19. At therapeutic concentrations, romidepsin did not competitively inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4 in vitro.
- At therapeutic concentrations, romidepsin did not cause notable induction of CYP1A2, CYP2B6 and CYP3A4 in vitro. Therefore, pharmacokinetic drug-drug interactions are unlikely to occur due to CYP450 induction or inhibition by romidepsin when co-administered with CYP450 substrates.
- Following 4-hour intravenous administration of romidepsin at 14 mg/m2 on days 1, 8, and 15 of a 28-day cycle in patients with T-cell lymphomas, the terminal half-life (t½) was approximately 3 hours. No accumulation of plasma concentration of romidepsin was observed after repeated dosing.
- Ketoconazole
- A drug interaction clinical trial with the strong CYP3A4 inhibitor, ketoconazole, was conducted in patients with advanced cancer. Following co-administration of 8 mg/m2 Romidepsin (4-hour infusion) with ketoconazole, the overall romidepsin exposure was increased by approximately 25% and 10% for AUC0-∞ and Cmax, respectively, compared to romidepsin alone, and the difference in AUC0-∞ between the 2 treatments was statistically significant. Co-administration of ketoconazole slightly decreased the romidepsin clearance and volume of distribution, but did not have a statistically significant effect on peak exposure (Cmax).
- Rifampin
- A drug interaction clinical trial with the strong CYP3A4 inducer, rifampin, was conducted in patients with advanced cancer. Following co-administration of 14 mg/m2 Romidepsin (4-hour infusion) with rifampin, the overall romidepsin exposure was unexpectedly increased by approximately 80% and 60% for AUC0-∞ and Cmax, respectively, compared to romidepsin alone, and the difference between the 2 treatments was statistically significant. Co-administration of rifampin decreased the romidepsin clearance and volume of distribution by 44% and 52%, respectively. The increase in exposure seen after co-administration with rifampin is likely due to rifampin's inhibition of an undetermined hepatic uptake process that is predominant for the disposition of Romidepsin.
- The population pharmacokinetic analysis of romidepsin showed that age, gender, or race (white vs. black) did not appear to influence the pharmacokinetics of romidepsin.
- No dedicated hepatic impairment study has been conducted for Romidepsin. The population pharmacokinetic analysis indicates that mild hepatic impairment had no significant influence on romidepsin pharmacokinetics. As the effect of moderate (TB >1.5x - 3x ULN and any AST) and severe (TB >3x ULN and any AST) hepatic impairment on the pharmacokinetics of romidepsin is unknown, patients with moderate and severe hepatic impairment should be treated with caution.
- No dedicated renal impairment study has been conducted for Romidepsin. The population pharmacokinetic analysis showed that romidepsin pharmacokinetics were not affected by mild (estimated creatinine clearance 50 - 80 mL/min), moderate (estimated creatinine clearance 30 - 50 mL/min), or severe (estimated creatinine clearance <30 mL/min) renal impairment. Nonetheless, the effect of end-stage renal disease on romidepsin pharmacokinetics has not been studied. Thus, patients with end-stage renal disease should be treated with caution.
## Nonclinical Toxicology
- Carcinogenicity studies have not been performed with romidepsin. Romidepsin was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test) or the mouse lymphoma assay. Romidepsin was not clastogenic in an in vivo rat bone marrow micronucleus assay when tested to the maximum tolerated dose (MTD) of 1 mg/kg in males and 3 mg/kg in females (6 and 18 mg/m2 in males and females, respectively). These doses were up to 1.3-fold the recommended human dose, based on body surface area.
- Based on nonclinical findings, male and female fertility may be compromised by treatment with Romidepsin. In a 26-week toxicology study, romidepsin administration resulted in testicular degeneration in rats at 0.33 mg/kg/dose (2 mg/m2/dose) following the clinical dosing schedule. This dose resulted in AUC0-inf. values that were approximately 2% the exposure level in patients receiving the recommended dose of 14 mg/m2/dose. A similar effect was seen in mice after 4 weeks of drug administration at higher doses. Seminal vesicle and prostate organ weights were decreased in a separate study in rats after 4 weeks of daily drug administration at 0.1 mg/kg/day (0.6 mg/m2/day), approximately 30% the estimated human daily dose based on body surface area. Romidepsin showed high affinity for binding to estrogen receptors in pharmacology studies. In a 26-week toxicology study in rats, atrophy was seen in the ovary, uterus, vagina and mammary gland of females administered doses as low as 0.1 mg/kg/dose (0.6 mg/m2/dose) following the clinical dosing schedule. This dose resulted in AUC0-inf. values that were 0.3% of those in patients receiving the recommended dose of 14 mg/m2/dose. Maturation arrest of ovarian follicles and decreased weight of ovaries were observed in a separate study in rats after 4 weeks of daily drug administration at 0.1 mg/kg/day (0.6 mg/m2/day). This dose is approximately 30% the estimated human daily dose based on body surface area.
# Clinical Studies
- Romidepsin was evaluated in 2 multicenter, single-arm clinical studies in patients with CTCL. Overall, 167 patients with CTCL were treated in the US, Europe, and Australia. Study 1 included 96 patients with confirmed CTCL after failure of at least 1 prior systemic therapy. Study 2 included 71 patients with a primary diagnosis of CTCL who received at least 2 prior skin directed therapies or one or more systemic therapies. Patients were treated with Romidepsin at a starting dose of 14 mg/m2 infused over 4 hours on days 1, 8, and 15 every 28 days.
- In both studies, patients could be treated until disease progression at the discretion of the investigator and local regulators. Objective disease response was evaluated according to a composite endpoint that included assessments of skin involvement, lymph node and visceral involvement, and abnormal circulating T-cells ("Sézary cells").
- The primary efficacy endpoint for both studies was overall objective disease response rate (ORR) based on the investigator assessments, and defined as the proportion of patients with confirmed complete response (CR) or partial response (PR). CR was defined as no evidence of disease and PR as ≥ 50% improvement in disease. Secondary endpoints in both studies included duration of response and time to response.
- Demographic and disease characteristics of the patients in Study 1 and Study 2 are provided in Table 3.
- Romidepsin was evaluated in a multicenter, single-arm, international clinical study in patients with PTCL who had failed at least 1 prior systemic therapy (Study 3). Patients in US, Europe, and Australia were treated with Romidepsin at a dose of 14 mg/m2 infused over 4 hours on days 1, 8, and 15 every 28 days. Of the 131 patients treated, 130 patients had histological confirmation by independent central review and were evaluable for efficacy (HC Population). Six cycles of treatment were planned; patients who developed progressive disease (PD), significant toxicity, or who met another criterion for study termination were to discontinue treatment. Responding patients had the option of continuing treatment beyond 6 cycles at the discretion of the patient and Investigator until study withdrawal criteria were met.
- Primary assessment of efficacy was based on rate of complete response (CR + CRu) as determined by an Independent Review Committee (IRC) using the International Workshop Response Criteria (IWC). Secondary measures of efficacy included IRC assessment of duration of response and objective disease response (ORR, CR + CRu + PR).
- Demographic and disease characteristics of the PTCL patients are provided in Table 5.
- All patients in both studies had received prior systemic therapy for PTCL. In Study 4, a greater percentage of patients had extensive prior radiation and chemotherapy. Twenty-one patients (16%) in Study 3 and 18 patients (38%) in Study 4 had received prior autologous stem cell transplant and 31 (24%) and 19 (40%) patients, respectively, had received prior radiation therapy.
- Efficacy outcomes for PTCL patients as determined by the IRC are provided in Table 6 for Study 3. The complete response rate was 15% and overall response rate was 26%. Similar complete response rates were observed by the IRC across the 3 major PTCL subtypes (NOS, AITL, and ALK-1 negative ALCL). Median time to objective response was 1.8 months (~2 cycles) for the 34 patients who achieved CR, CRu, or PR and median time to CR was 3.5 months (~4 cycles) for the 20 patients with complete response. The responses in 12 of the 20 patients achieving CR and CRu were known to exceed 11.6 months; the follow-up on the remaining 8 patients was discontinued prior to 8.5 months.
- In a second single-arm clinical study in patients with PTCL who had failed prior therapy (Study 4), patients were treated with Romidepsin at a starting dose of 14 mg/m2 infused over 4 hours on days 1, 8, and 15 every 28 days. Patients could be treated until disease progression at the discretion of the patient and the Investigator. The percentage of patients achieving CR + CRu in Study 4 was similar to that in Study 3.
# How Supplied
- Romidepsin is supplied as a kit including a sterile, lyophilized powder in a single-use vial containing 10 mg of romidepsin and 20 mg of the bulking agent, povidone, USP. In addition, each kit includes one sterile diluent vial containing 2 mL (deliverable volume) of 80% propylene glycol, USP, and 20% dehydrated alcohol, USP.
- NDC 59572-983-01: Romidepsin® KIT containing 1 vial of romidepsin, 10 mg and 1 vial of diluent for romidepsin, 2 mL per carton.
## Storage
- Romidepsin for injection is supplied as a kit containing 2 vials in a single carton. The carton must be stored at 20° to 25°C, excursions permitted between 15° to 30°C.
- Keep out of reach of children.
- Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published1-4.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Romidepsin Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Romidepsin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Romidepsin ®
# Look-Alike Drug Names
There is limited information regarding Romidepsin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Romidepsin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2]
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# Overview
Romidepsin is a histone deacetylase inhibitor that is FDA approved for the treatment of cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphoma (PTCL). Common adverse reactions include EKG ST segment changes, anemia, neutropenia, infectious disease, cutaneous T-cell lymphoma, lymphocytopenia.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Romidepsin is indicated for:
- Treatment of cutaneous T-cell lymphoma (CTCL) in patients who have received at least one prior systemic therapy.
- Treatment of peripheral T-cell lymphoma (PTCL) in patients who have received at least one prior therapy.
- These indications are based on response rate. Clinical benefit such as improvement in overall survival has not been demonstrated.
- The recommended dose of romidepsin is 14 mg/m2 administered intravenously over a 4-hour period on days 1, 8, and 15 of a 28-day cycle. Cycles should be repeated every 28 days provided that the patient continues to benefit from and tolerates the drug.
- Nonhematologic toxicities except alopecia
- Grade 2 or 3 toxicity: Treatment with romidepsin should be delayed until toxicity returns to ≤ Grade 1 or baseline, then therapy may be restarted at 14 mg/m2. If Grade 3 toxicity recurs, treatment with romidepsin should be delayed until toxicity returns to ≤ Grade 1 or baseline and the dose should be permanently reduced to 10 mg/m2.
- Grade 4 toxicity
- Treatment with romidepsin should be delayed until toxicity returns to ≤ Grade 1 or baseline, then the dose should be permanently reduced to 10 mg/m2.
Romidepsin should be discontinued if Grade 3 or 4 toxicities recur after dose reduction.
- Grade 3 or 4 neutropenia or thrombocytopenia: Treatment with romidepsin should be delayed until the specific cytopenia returns to ANC ≥1.5×109/L and platelet count ≥75×109/L or baseline, then therapy may be restarted at 14 mg/m2.
- Grade 4 febrile (≥ 38.5ºC) neutropenia or thrombocytopenia that requires platelet transfusion: Treatment with romidepsin should be delayed until the specific cytopenia returns to ≤ Grade 1 or baseline, and then the dose should be permanently reduced to 10 mg/m2.
- Romidepsin is a cytotoxic drug. Use appropriate handling procedures.
- Romidepsin must be reconstituted with the supplied diluent and further diluted with 0.9% Sodium Chloride Injection, USP before intravenous infusion.
- Each 10 mg single-use vial of Romidepsin must be reconstituted with 2 mL of the supplied diluent. With a suitable syringe, aseptically withdraw 2 mL from the supplied diluent vial, and slowly inject it into the Romidepsin for injection vial. Swirl the contents of the vial until there are no visible particles in the resulting solution. The reconstituted solution will contain Romidepsin 5 mg/mL. The reconstituted Romidepsin solution is chemically stable for up to 8 hours at room temperature.
- Extract the appropriate amount of Romidepsin from the vials to deliver the desired dose, using proper aseptic technique. Before intravenous infusion, further dilute Romidepsin in 500 mL 0.9% Sodium Chloride Injection, USP.
- Infuse over 4 hours.
- The diluted solution is compatible with polyvinyl chloride (PVC), ethylene vinyl acetate (EVA), polyethylene (PE) infusion bags as well as glass bottles, and is chemically stable for up to 24 hours when stored at room temperature. However, it should be administered as soon after dilution as possible.
- Parenteral drug products should be inspected visually for particulate matter and discoloration before administration, whenever solution and container permit.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Romidepsin in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Romidepsin in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Romidepsin FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Romidepsin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Romidepsin in pediatric patients.
# Contraindications
There is limited information regarding Romidepsin Contraindications in the drug label.
# Warnings
- Treatment with Romidepsin can cause thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia. Monitor blood counts regularly during treatment with Romidepsin, and modify the dose as necessary.
- Fatal and serious infections, including pneumonia, sepsis, and viral reactivation, including Epstein Barr and hepatitis B viruses, have been reported in clinical trials with Romidepsin. These can occur during treatment and within 30 days after treatment. The risk of life threatening infections may be greater in patients with a history of prior treatment with monoclonal antibodies directed against lymphocyte antigens and in patients with disease involvement of the bone marrow.
- Reactivation of hepatitis B virus infection has occurred in 1% of PTCL patients in clinical trials in Western populations. In patients with evidence of prior hepatitis B infection, consider monitoring for reactivation, and consider antiviral prophylaxis.
- Reactivation of Epstein Barr viral infection leading to liver failure has occurred in a trial of patients with relapsed or refractory extranodal NK/T-cell lymphoma. In one case, ganciclovir prophylaxis failed to prevent Epstein Barr viral reactivation.
- Several treatment-emergent morphological changes in ECGs (including T-wave and ST-segment changes) have been reported in clinical studies. The clinical significance of these changes is unknown.
- In patients with congenital long QT syndrome, patients with a history of significant cardiovascular disease, and patients taking anti-arrhythmic medicines or medicinal products that lead to significant QT prolongation, consider cardiovascular monitoring of ECGs at baseline and periodically during treatment.
- Confirm that potassium and magnesium levels are within normal range before administration of Romidepsin.
- Tumor lysis syndrome (TLS) has been reported to occur in 1% of patients with tumor stage CTCL and 2% of patients with Stage III/IV PTCL. Patients with advanced stage disease and/or high tumor burden may be at greater risk, should be closely monitored, and managed as appropriate.
- There are no adequate and well-controlled studies of Romidepsin in pregnant women. However, based on its mechanism of action and findings in animals, Romidepsin may cause fetal harm when administered to a pregnant woman. In an animal reproductive study, romidepsin was embryocidal and resulted in adverse effects on the developing fetus at exposures below those in patients at the recommended dose of 14 mg/m2/week. If this drug is used during pregnancy, or if the patient becomes pregnant while taking Romidepsin, the patient should be apprised of the potential hazard to the fetus.
# Adverse Reactions
## Clinical Trials Experience
- Myelosuppression
- Infection
- Electrocardiographic Changes
- Tumor Lysis Syndrome
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- The safety of Romidepsin was evaluated in 185 patients with CTCL in 2 single arm clinical studies in which patients received a starting dose of 14 mg/m2. The mean duration of treatment in these studies was 5.6 months (range: <1 to 83.4 months).
- Table 1 summarizes the most frequent adverse reactions (> 20%) regardless of causality using the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE, Version 3.0). Due to methodological differences between the studies, the AE data are presented separately for Study 1 and Study 2. Adverse reactions are ranked by their incidence in Study 1. Laboratory abnormalities commonly reported (> 20%) as adverse reactions are included in Table 1.
- Infections were the most common type of SAE reported in both studies with 8 patients (8%) in Study 1 and 26 patients (31%) in Study 2 experiencing a serious infection. Serious adverse reactions reported in > 2% of patients in Study 1 were sepsis and pyrexia (3%). In Study 2, serious adverse reactions in > 2% of patients were fatigue (7%), supraventricular arrhythmia, central line infection, neutropenia (6%), hypotension, hyperuricemia, edema (5%), ventricular arrhythmia, thrombocytopenia, nausea, leukopenia, dehydration, pyrexia, aspartate aminotransferase increased, sepsis, catheter related infection, hypophosphatemia and dyspnea (4%).
- Most deaths were due to disease progression. In Study 1, there were two deaths due to cardiopulmonary failure and acute renal failure. In Study 2, there were six deaths due to infection (4), myocardial ischemia, and acute respiratory distress syndrome.
- Discontinuation due to an adverse event occurred in 21% of patients in Study 1 and 11% in Study 2. Discontinuations occurring in at least 2% of patients in either study included infection, fatigue, dyspnea, QT prolongation, and hypomagnesemia.
- The safety of Romidepsin was evaluated in 178 patients with PTCL in a sponsor-conducted pivotal study (Study 3) and a secondary NCI-sponsored study (Study 4) in which patients received a starting dose of 14 mg/m2. The mean duration of treatment and number of cycles were 5.6 months and 6 cycles in Study 3 and 9.6 months and 8 cycles in Study 4.
- Table 2 summarizes the most frequent adverse reactions (≥ 10%) regardless of causality, using the NCI-CTCAE, Version 3.0. The AE data are presented separately for Study 3 and Study 4. Laboratory abnormalities commonly reported (≥ 10%) as adverse reactions are included in Table 2.
- Infections were the most common type of SAE reported. In Study 3, 26 patients (20%) experienced a serious infection, including 6 patients (5%) with serious treatment-related infections. In Study 4, 11 patients (23%) experienced a serious infection, including 8 patients (17%) with serious treatment-related infections. Serious adverse reactions reported in ≥ 2% of patients in Study 3 were pyrexia(8%), pneumonia, sepsis, vomiting (5%), cellulitis, deep vein thrombosis, (4%), febrile neutropenia, abdominal pain (3%), chest pain, neutropenia, pulmonary embolism, dyspnea, and dehydration (2%). In Study 4, serious adverse reactions in ≥ 2 patients were pyrexia (17%), aspartate aminotransferase increased, hypotension (13%), anemia, thrombocytopenia, alanine aminotransferase increased (11%), infection, dehydration, dyspnea (9%), lymphopenia, neutropenia, hyperbilirubinemia, hypocalcemia, hypoxia (6%), febrile neutropenia, leukopenia, ventricular arrhythmia, vomiting, hypersensitivity, catheter related infection, hyperuricemia, hypoalbuminemia, syncope, pneumonitis, packed red blood cell transfusion, and platelet transfusion (4%).
- Reactivation of hepatitis B virus infection has occurred in 1% of patients with PTCL patients in clinical trials in Western population enrolled in Study 3 and Study 4.
- Deaths due to all causes within 30 days of the last dose of Romidepsin occurred in 7% of patients in Study 3 and 17% of patients in Study 4. In Study 3, there were 5 deaths unrelated to disease progression that were due to infections, including multi-organ failure/sepsis, pneumonia, septic shock, candida sepsis, and sepsis/cardiogenic shock. In Study 4, there were 3 deaths unrelated to disease progression that were due to sepsis, aspartate aminotransferase elevation in the setting of Epstein Barr virus reactivation, and death of unknown cause.
- Discontinuation due to an adverse event occurred in 19% of patients in Study 3 and in 28% of patients in Study 4. In Study 3, thrombocytopenia and pneumonia were the only events leading to treatment discontinuation in at least 2% of patients. In Study 4, events leading to treatment discontinuation in ≥ 2 patients were thrombocytopenia (11%), anemia, infection, and alanine aminotransferase increased (4%).
## Postmarketing Experience
- No additional safety signals have been observed from postmarketing experience.
# Drug Interactions
- Prolongation of PT and elevation of INR were observed in a patient receiving Romidepsin concomitantly with warfarin. Although the interaction potential between Romidepsin and warfarin has not been formally studied, monitor PT and INR more frequently in patients concurrently receiving Romidepsin and warfarin.
- Romidepsin is metabolized by CYP3A4. Strong CYP3A4 inhibitors increase concentrations of romidepsin. In a pharmacokinetic drug interaction trial the strong CYP3A4 inhibitor ketoconazole increased romidepsin (AUC0-∞) by approximately 25%.
- Monitor for toxicity related to increased romidepsin exposure and follow the dose modifications for toxicity when romidepsin is initially co-administered with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole).
- Avoid co-administration of Romidepsin with rifampin.
- In a pharmacokinetic drug interaction trial with co-administered rifampin (a strong CYP3A4 inducer), romidepsin exposure was increased by approximately 80% and 60% for AUC0-∞ and Cmax, respectively. Typically, co-administration of CYP3A4 inducers decrease concentrations of drugs metabolized by CYP3A4. The increase in exposure seen after co-administration with rifampin is likely due to rifampin’s inhibition of an undetermined hepatic uptake process that is predominantly responsible for the disposition of Romidepsin.
- It is unknown if other potent CYP3A4 inducers (e.g., dexamethasone, carbamazepine, phenytoin, rifabutin, rifapentine, phenobarbital, St. John’s Wort) would alter the exposure of Romidepsin. Therefore, the use of other potent CYP3A4 inducers should be avoided when possible.
- Romidepsin is a substrate of the efflux transporter P-glycoprotein (P-gp, ABCB1). If Romidepsin is administered with drugs that inhibit P-gp, increased concentrations of romidepsin are likely, and caution should be exercised.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
- There are no adequate and well-controlled studies of Romidepsin in pregnant women. However, based on its mechanism of action and findings in animals, Romidepsin may cause fetal harm when administered to a pregnant woman. In an animal reproductive study, romidepsin was embryocidal and resulted in adverse effects on the developing fetus at exposures below those in patients at the recommended dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking Romidepsin, the patient should be apprised of the potential hazard to the fetus.
- Romidepsin was administered intravenously to rats during the period of organogenesis at doses of 0.1, 0.2, or 0.5 mg/kg/day. Substantial resorption or post-implantation loss was observed at the high-dose of 0.5 mg/kg/day, a maternally toxic dose. Adverse embryo-fetal effects were noted at romidepsin doses of ≥0.1 mg/kg/day, with systemic exposures (AUC) ≥0.2% of the human exposure at the recommended dose of 14 mg/m2/week. Drug-related fetal effects consisted of folded retina, rotated limbs, and incomplete sternal ossification.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Romidepsin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Romidepsin during labor and delivery.
### Nursing Mothers
- It is not known whether romidepsin is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Romidepsin, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
The safety and effectiveness of Romidepsin in pediatric patients has not been established.
### Geriatic Use
- Of the approximately 300 patients with CTCL or PTCL in trials, about 25% were >65 years old. No overall differences in safety or effectiveness were observed between these subjects and younger subjects; however, greater sensitivity of some older individuals cannot be ruled out.
### Gender
There is no FDA guidance on the use of Romidepsin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Romidepsin with respect to specific racial populations.
### Renal Impairment
- No dedicated renal impairment study for Romidepsin has been conducted. Based upon the population pharmacokinetic analysis, renal impairment is not expected to significantly influence drug exposure. The effect of end-stage renal disease on romidepsin pharmacokinetics has not been studied. Thus, patients with end-stage renal disease should be treated with caution.
### Hepatic Impairment
- No dedicated hepatic impairment study for Romidepsin has been conducted. Mild hepatic impairment does not alter pharmacokinetics of romidepsin based on a population pharmacokinetic analysis. Patients with moderate and severe hepatic impairment should be treated with caution.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Romidepsin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Romidepsin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
### Monitoring
- Monitor blood counts regularly during treatment with Romidepsin, and modify the dose as necessary.
- In patients with congenital long QT syndrome, patients with a history of significant cardiovascular disease, and patients taking anti-arrhythmic medicines or medicinal products that lead to significant QT prolongation, consider cardiovascular monitoring of ECGs at baseline and periodically during treatment.
- Carefully monitor prothrombin time (PT) and International Normalized Ratio (INR) in patients concurrently administered Romidepsin and warfarin or coumarin derivatives.
# IV Compatibility
There is limited information regarding the compatibility of Romidepsin and IV administrations.
# Overdosage
- No specific information is available on the treatment of overdosage of Romidepsin.
Toxicities in a single-dose study in rats or dogs, at intravenous romidepsin doses up to 2.2 fold the recommended human dose based on the body surface area, included irregular respiration, irregular heartbeat, staggering gait, tremor, and tonic convulsions.
In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., clinical monitoring and supportive therapy, if required. There is no known antidote for Romidepsin and it is not known if Romidepsin is dialyzable.
# Pharmacology
There is limited information regarding Romidepsin Pharmacology in the drug label.
## Mechanism of Action
- No specific information is available on the treatment of overdosage of Romidepsin.
- Toxicities in a single-dose study in rats or dogs, at intravenous romidepsin doses up to 2.2 fold the recommended human dose based on the body surface area, included irregular respiration, irregular heartbeat, staggering gait, tremor, and tonic convulsions.
- In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., clinical monitoring and supportive therapy, if required. There is no known antidote for Romidepsin and it is not known if Romidepsin is dialyzable.
## Structure
There is limited information regarding Romidepsin Structure in the drug label.
## Pharmacodynamics
- The effect of romidepsin on the heart-rate corrected QTc/QTcF was evaluated in 26 subjects with advanced malignancies given romidepsin at doses of 14 mg/m2 as a 4-hour intravenous infusion, and at doses of 8, 10 or 12 mg/m2 as a 1–hour infusion. Patients received premedications with antiemetics. No large changes in the mean QTc interval (> 20 milliseconds) from baseline based on Fridericia correction method were detected in the trial. Small increase in mean QT interval (< 10 milliseconds) and mean QT interval increase between 10 to 20 milliseconds cannot be excluded because of the limitations in the trial design.
- Romidepsin was associated with a delayed concentration-dependent increase in heart rate in patients with advanced cancer with a maximum mean increase in heart rate of 20 beats per minute occurring at the 6 hour time point after start of romidepsin infusion for patients receiving 14 mg/m2 as a 4-hour infusion.
## Pharmacokinetics
- Romidepsin exhibited linear pharmacokinetics across doses ranging from 1.0 to 24.9 mg/m2 when administered intravenously over 4 hours in patients with advanced cancers.
- In patients with T-cell lymphomas who received 14 mg/m2 of romidepsin intravenously over a 4-hour period on days 1, 8, and 15 of a 28-day cycle, geometric mean values of the maximum plasma concentration (Cmax) and the area under the plasma concentration versus time curve (AUC0-inf) were 377 ng/mL and 1549 ng*hr/mL, respectively.
- Romidepsin is highly protein bound in plasma (92% to 94%) over the concentration range of 50 ng/mL to 1000 ng/mL with α1-acid-glycoprotein (AAG) being the principal binding protein. Romidepsin is a substrate of the efflux transporter P-glycoprotein (P-gp, ABCB1).
- In vitro, romidepsin accumulates into human hepatocytes via an unknown active uptake process. Romidepsin is not a substrate of the following uptake transporters: BCRP, BSEP, MRP2, OAT1, OAT3, OATP1B1, OATP1B3, or OCT2. In addition, romidepsin is not an inhibitor of BCRP, MRP2, MDR1 or OAT3. Although romidepsin did not inhibit OAT1, OCT2, and OATP1B3 at concentrations seen clinically (1 μmol/L), modest inhibition was observed at 10 µmol/L. Romidepsin was found to be an inhibitor of BSEP and OATP1B1.
- Romidepsin undergoes extensive metabolism in vitro primarily by CYP3A4 with minor contribution from CYP3A5, CYP1A1, CYP2B6, and CYP2C19. At therapeutic concentrations, romidepsin did not competitively inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4 in vitro.
- At therapeutic concentrations, romidepsin did not cause notable induction of CYP1A2, CYP2B6 and CYP3A4 in vitro. Therefore, pharmacokinetic drug-drug interactions are unlikely to occur due to CYP450 induction or inhibition by romidepsin when co-administered with CYP450 substrates.
- Following 4-hour intravenous administration of romidepsin at 14 mg/m2 on days 1, 8, and 15 of a 28-day cycle in patients with T-cell lymphomas, the terminal half-life (t½) was approximately 3 hours. No accumulation of plasma concentration of romidepsin was observed after repeated dosing.
- Ketoconazole
- A drug interaction clinical trial with the strong CYP3A4 inhibitor, ketoconazole, was conducted in patients with advanced cancer. Following co-administration of 8 mg/m2 Romidepsin (4-hour infusion) with ketoconazole, the overall romidepsin exposure was increased by approximately 25% and 10% for AUC0-∞ and Cmax, respectively, compared to romidepsin alone, and the difference in AUC0-∞ between the 2 treatments was statistically significant. Co-administration of ketoconazole slightly decreased the romidepsin clearance and volume of distribution, but did not have a statistically significant effect on peak exposure (Cmax).
- Rifampin
- A drug interaction clinical trial with the strong CYP3A4 inducer, rifampin, was conducted in patients with advanced cancer. Following co-administration of 14 mg/m2 Romidepsin (4-hour infusion) with rifampin, the overall romidepsin exposure was unexpectedly increased by approximately 80% and 60% for AUC0-∞ and Cmax, respectively, compared to romidepsin alone, and the difference between the 2 treatments was statistically significant. Co-administration of rifampin decreased the romidepsin clearance and volume of distribution by 44% and 52%, respectively. The increase in exposure seen after co-administration with rifampin is likely due to rifampin's inhibition of an undetermined hepatic uptake process that is predominant for the disposition of Romidepsin.
- The population pharmacokinetic analysis of romidepsin showed that age, gender, or race (white vs. black) did not appear to influence the pharmacokinetics of romidepsin.
- No dedicated hepatic impairment study has been conducted for Romidepsin. The population pharmacokinetic analysis indicates that mild hepatic impairment [total bilirubin (TB) ≤upper limit of normal (ULN) and aspartate aminotransferase (AST) >ULN; or TB >1.0x - 1.5x ULN and any AST] had no significant influence on romidepsin pharmacokinetics. As the effect of moderate (TB >1.5x - 3x ULN and any AST) and severe (TB >3x ULN and any AST) hepatic impairment on the pharmacokinetics of romidepsin is unknown, patients with moderate and severe hepatic impairment should be treated with caution.
- No dedicated renal impairment study has been conducted for Romidepsin. The population pharmacokinetic analysis showed that romidepsin pharmacokinetics were not affected by mild (estimated creatinine clearance 50 - 80 mL/min), moderate (estimated creatinine clearance 30 - 50 mL/min), or severe (estimated creatinine clearance <30 mL/min) renal impairment. Nonetheless, the effect of end-stage renal disease on romidepsin pharmacokinetics has not been studied. Thus, patients with end-stage renal disease should be treated with caution.
## Nonclinical Toxicology
- Carcinogenicity studies have not been performed with romidepsin. Romidepsin was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test) or the mouse lymphoma assay. Romidepsin was not clastogenic in an in vivo rat bone marrow micronucleus assay when tested to the maximum tolerated dose (MTD) of 1 mg/kg in males and 3 mg/kg in females (6 and 18 mg/m2 in males and females, respectively). These doses were up to 1.3-fold the recommended human dose, based on body surface area.
- Based on nonclinical findings, male and female fertility may be compromised by treatment with Romidepsin. In a 26-week toxicology study, romidepsin administration resulted in testicular degeneration in rats at 0.33 mg/kg/dose (2 mg/m2/dose) following the clinical dosing schedule. This dose resulted in AUC0-inf. values that were approximately 2% the exposure level in patients receiving the recommended dose of 14 mg/m2/dose. A similar effect was seen in mice after 4 weeks of drug administration at higher doses. Seminal vesicle and prostate organ weights were decreased in a separate study in rats after 4 weeks of daily drug administration at 0.1 mg/kg/day (0.6 mg/m2/day), approximately 30% the estimated human daily dose based on body surface area. Romidepsin showed high affinity for binding to estrogen receptors in pharmacology studies. In a 26-week toxicology study in rats, atrophy was seen in the ovary, uterus, vagina and mammary gland of females administered doses as low as 0.1 mg/kg/dose (0.6 mg/m2/dose) following the clinical dosing schedule. This dose resulted in AUC0-inf. values that were 0.3% of those in patients receiving the recommended dose of 14 mg/m2/dose. Maturation arrest of ovarian follicles and decreased weight of ovaries were observed in a separate study in rats after 4 weeks of daily drug administration at 0.1 mg/kg/day (0.6 mg/m2/day). This dose is approximately 30% the estimated human daily dose based on body surface area.
# Clinical Studies
- Romidepsin was evaluated in 2 multicenter, single-arm clinical studies in patients with CTCL. Overall, 167 patients with CTCL were treated in the US, Europe, and Australia. Study 1 included 96 patients with confirmed CTCL after failure of at least 1 prior systemic therapy. Study 2 included 71 patients with a primary diagnosis of CTCL who received at least 2 prior skin directed therapies or one or more systemic therapies. Patients were treated with Romidepsin at a starting dose of 14 mg/m2 infused over 4 hours on days 1, 8, and 15 every 28 days.
- In both studies, patients could be treated until disease progression at the discretion of the investigator and local regulators. Objective disease response was evaluated according to a composite endpoint that included assessments of skin involvement, lymph node and visceral involvement, and abnormal circulating T-cells ("Sézary cells").
- The primary efficacy endpoint for both studies was overall objective disease response rate (ORR) based on the investigator assessments, and defined as the proportion of patients with confirmed complete response (CR) or partial response (PR). CR was defined as no evidence of disease and PR as ≥ 50% improvement in disease. Secondary endpoints in both studies included duration of response and time to response.
- Demographic and disease characteristics of the patients in Study 1 and Study 2 are provided in Table 3.
- Romidepsin was evaluated in a multicenter, single-arm, international clinical study in patients with PTCL who had failed at least 1 prior systemic therapy (Study 3). Patients in US, Europe, and Australia were treated with Romidepsin at a dose of 14 mg/m2 infused over 4 hours on days 1, 8, and 15 every 28 days. Of the 131 patients treated, 130 patients had histological confirmation by independent central review and were evaluable for efficacy (HC Population). Six cycles of treatment were planned; patients who developed progressive disease (PD), significant toxicity, or who met another criterion for study termination were to discontinue treatment. Responding patients had the option of continuing treatment beyond 6 cycles at the discretion of the patient and Investigator until study withdrawal criteria were met.
- Primary assessment of efficacy was based on rate of complete response (CR + CRu) as determined by an Independent Review Committee (IRC) using the International Workshop Response Criteria (IWC). Secondary measures of efficacy included IRC assessment of duration of response and objective disease response (ORR, CR + CRu + PR).
- Demographic and disease characteristics of the PTCL patients are provided in Table 5.
- All patients in both studies had received prior systemic therapy for PTCL. In Study 4, a greater percentage of patients had extensive prior radiation and chemotherapy. Twenty-one patients (16%) in Study 3 and 18 patients (38%) in Study 4 had received prior autologous stem cell transplant and 31 (24%) and 19 (40%) patients, respectively, had received prior radiation therapy.
- Efficacy outcomes for PTCL patients as determined by the IRC are provided in Table 6 for Study 3. The complete response rate was 15% and overall response rate was 26%. Similar complete response rates were observed by the IRC across the 3 major PTCL subtypes (NOS, AITL, and ALK-1 negative ALCL). Median time to objective response was 1.8 months (~2 cycles) for the 34 patients who achieved CR, CRu, or PR and median time to CR was 3.5 months (~4 cycles) for the 20 patients with complete response. The responses in 12 of the 20 patients achieving CR and CRu were known to exceed 11.6 months; the follow-up on the remaining 8 patients was discontinued prior to 8.5 months.
- In a second single-arm clinical study in patients with PTCL who had failed prior therapy (Study 4), patients were treated with Romidepsin at a starting dose of 14 mg/m2 infused over 4 hours on days 1, 8, and 15 every 28 days. Patients could be treated until disease progression at the discretion of the patient and the Investigator. The percentage of patients achieving CR + CRu in Study 4 was similar to that in Study 3.
# How Supplied
- Romidepsin is supplied as a kit including a sterile, lyophilized powder in a single-use vial containing 10 mg of romidepsin and 20 mg of the bulking agent, povidone, USP. In addition, each kit includes one sterile diluent vial containing 2 mL (deliverable volume) of 80% propylene glycol, USP, and 20% dehydrated alcohol, USP.
- NDC 59572-983-01: Romidepsin® KIT containing 1 vial of romidepsin, 10 mg and 1 vial of diluent for romidepsin, 2 mL per carton.
## Storage
- Romidepsin for injection is supplied as a kit containing 2 vials in a single carton. The carton must be stored at 20° to 25°C, excursions permitted between 15° to 30°C.
- Keep out of reach of children.
- Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published1-4.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Romidepsin Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Romidepsin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Romidepsin ®[1]
# Look-Alike Drug Names
There is limited information regarding Romidepsin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Romidepsin | |
e5e3942945a456628139b15743d152ec338e32f9 | wikidoc | Roxatidine | Roxatidine
# Overview
Roxatidine acetate is a specific and competitive histamine H2 receptor antagonist drug that is used to treat gastric ulcers, Zollinger–Ellison syndrome, erosive esophagitis, gastro-oesophageal reflux disease, and gastritis.
Pharmacodynamic studies showed that 150 mg of roxatidine acetate were optimal in suppressing gastric acid secretion, and that a single bedtime dose of 150 mg was more effective than a dose of 75 mg twice daily in terms of inhibiting nocturnal acid secretion.
It is available in countries including China, Japan, Korea, Germany, Italy, the Netherlands, Greece and South Africa. | Roxatidine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Roxatidine acetate is a specific and competitive histamine H2 receptor antagonist drug that is used to treat gastric ulcers, Zollinger–Ellison syndrome, erosive esophagitis, gastro-oesophageal reflux disease, and gastritis.[1][2]
Pharmacodynamic studies showed that 150 mg of roxatidine acetate were optimal in suppressing gastric acid secretion, and that a single bedtime dose of 150 mg was more effective than a dose of 75 mg twice daily in terms of inhibiting nocturnal acid secretion.[1]
It is available in countries including China, Japan, Korea, Germany, Italy, the Netherlands, Greece and South Africa.[2] | https://www.wikidoc.org/index.php/Roxatidine | |
a400b355147d6672f96b69549bfa6e713b80c39c | wikidoc | Roy Clauss | Roy Clauss
Dr. Roy H. Clauss, MD (b. 1923, Melrose Park, Illinois - d. July 7, 2007, New York City) was a pioneering cardiovascular and thoracic surgeon.
During his career, Dr. Clauss helped develop and perfect a variety of techniques involved in the performance of open heart surgery and cardiac bypass surgery, and helped pioneer bilateral carotid artery surgery. He authored over 150 medical articles.
In 1971 he co-authored Remedial Arterial Disease with the late Dr. Walter Redisch. Dr. Clauss and his second wife, Pamela Heavey Clauss, a surgical and heart pump nurse, along with Greek surgeon, Dr. George Sanoudos, established the first open heart surgery facility in Athens, Greece in the mid-1970s.
# Personal Life
Dr. Clauss graduated from Northwestern University in 1943 and from its medical school in 1947. Dr. Clauss married Jane Hamden of Oak Park, Illinois in 1945, by whom he had three children. It appears that Jane Clauss predeceased her husband. He was married to his second wife, Pamela Heavey, from 1970 until her death in 2001.
He was a patron of the Metropolitan Opera and the New York Philharmonic. Dr. Clauss was a deacon and elder of the Fifth Avenue Presbyterian Church.
In 1993, he was one of the founding members of The City Church in Manhattan. He died at the age of 84 in 2007. | Roy Clauss
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Dr. Roy H. Clauss, MD (b. 1923, Melrose Park, Illinois - d. July 7, 2007, New York City) was a pioneering cardiovascular and thoracic surgeon.
During his career, Dr. Clauss helped develop and perfect a variety of techniques involved in the performance of open heart surgery and cardiac bypass surgery, and helped pioneer bilateral carotid artery surgery. He authored over 150 medical articles.
In 1971 he co-authored Remedial Arterial Disease with the late Dr. Walter Redisch. Dr. Clauss and his second wife, Pamela Heavey Clauss, a surgical and heart pump nurse, along with Greek surgeon, Dr. George Sanoudos, established the first open heart surgery facility in Athens, Greece in the mid-1970s.[1]
# Personal Life
Dr. Clauss graduated from Northwestern University in 1943 and from its medical school in 1947. Dr. Clauss married Jane Hamden of Oak Park, Illinois in 1945, by whom he had three children. It appears that Jane Clauss predeceased her husband. He was married to his second wife, Pamela Heavey, from 1970 until her death in 2001.
He was a patron of the Metropolitan Opera and the New York Philharmonic. Dr. Clauss was a deacon and elder of the Fifth Avenue Presbyterian Church.
In 1993, he was one of the founding members of The City Church in Manhattan. He died at the age of 84 in 2007. | https://www.wikidoc.org/index.php/Roy_Clauss | |
87e6b9d87bf78ce0b940a1d0c1df2681b085e492 | wikidoc | Ruby laser | Ruby laser
A ruby laser is a solid-state laser that uses a synthetic ruby crystal as its gain medium. It was the first type of laser invented, and was first operated by Theodore H. "Ted" Maiman at Hughes Research Laboratories on 1960-05-16.
The ruby laser produces pulses of visible light at a wavelength of 694.3 nm, which appears as deep red to human eyes. Typical ruby laser pulse lengths are on the order of a millisecond. These short pulses of red light are visible to the human eye, if the viewer carefully watches the target area where the pulse will fire.
# Applications
Ruby lasers have declined in use with the discovery of better lasing media. They are still used in a number of applications where short pulses of red light are required. Holographers around the world produce holographic portraits with ruby lasers, in sizes up to a metre squared. The red 694 nm laser light is preferred to the 532 nm green light of frequency-doubled Nd:YAG. Many non-destructive testing labs use ruby lasers to create holograms of large objects such as aircraft tires to look for weaknesses in the lining. Ruby lasers were used extensively in tattoo and hair removal, but are being replaced by alexandrite lasers and Nd:YAG lasers in this application.
# Design
The ruby laser is a three level solid state laser. The active laser medium (laser gain/amplification medium) is a synthetic ruby rod that is energized through optical pumping, typically by a xenon flash lamp. In early examples, the rod's ends had to be polished with great precision, such that the ends of the rod were flat to within a quarter of a wavelength of the output light, and parallel to each other within a few seconds of arc. The finely polished ends of the rod were silvered: one end completely, the other only partially. The rod with its reflective ends then acts as a Fabry-Pérot etalon (or a Gires-Tournois etalon). Modern lasers often use rods with ends cut and polished at Brewster's angle instead. This eliminates the reflections from the ends of the rod; external dielectric mirrors then are used to form the optical cavity. Curved mirrors are typically used to relax the alignment tolerances. | Ruby laser
A ruby laser is a solid-state laser that uses a synthetic ruby crystal as its gain medium. It was the first type of laser invented, and was first operated by Theodore H. "Ted" Maiman[1] at Hughes Research Laboratories on 1960-05-16[2].
The ruby laser produces pulses of visible light at a wavelength of 694.3 nm, which appears as deep red to human eyes. Typical ruby laser pulse lengths are on the order of a millisecond. These short pulses of red light are visible to the human eye, if the viewer carefully watches the target area where the pulse will fire.
# Applications
Ruby lasers have declined in use with the discovery of better lasing media. They are still used in a number of applications where short pulses of red light are required. Holographers around the world produce holographic portraits with ruby lasers, in sizes up to a metre squared. The red 694 nm laser light is preferred to the 532 nm green light of frequency-doubled Nd:YAG.[citation needed] Many non-destructive testing labs use ruby lasers to create holograms of large objects such as aircraft tires to look for weaknesses in the lining. Ruby lasers were used extensively in tattoo and hair removal, but are being replaced by alexandrite lasers and Nd:YAG lasers in this application.
# Design
Template:Seealso
The ruby laser is a three level solid state laser. The active laser medium (laser gain/amplification medium) is a synthetic ruby rod that is energized through optical pumping, typically by a xenon flash lamp. In early examples, the rod's ends had to be polished with great precision, such that the ends of the rod were flat to within a quarter of a wavelength of the output light, and parallel to each other within a few seconds of arc. The finely polished ends of the rod were silvered: one end completely, the other only partially. The rod with its reflective ends then acts as a Fabry-Pérot etalon (or a Gires-Tournois etalon). Modern lasers often use rods with ends cut and polished at Brewster's angle instead. This eliminates the reflections from the ends of the rod; external dielectric mirrors then are used to form the optical cavity. Curved mirrors are typically used to relax the alignment tolerances. | https://www.wikidoc.org/index.php/Ruby_laser | |
42dfc19bf334f060525e25f558077143e212a5ef | wikidoc | Rufinamide | Rufinamide
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# Overview
Rufinamide is an anti-epileptic drug that is FDA approved for the treatment of lennox-gastaut syndrome (LGS). Common adverse reactions include headache, dizziness, fatigue, somnolence, and nausea.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Treatment should be initiated at a daily dose of 400-800 mg/day administered in two equally divided doses. The dose should be increased by 400-800 mg every other day until a maximum daily dose of 3200 mg/day, administered in two equally divided doses is reached. It is not known whether doses lower than 3200 mg are effective.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Rufinamide in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Rufinamide in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Treatment should be initiated at a daily dose of approximately 10 mg/kg/day administered in two equally divided doses. The dose should be increased by approximately 10 mg/kg increments every other day to a target dose of 45 mg/kg/day or 3200 mg/day, whichever is less, administered in two equally divided doses. It is not known whether doses lower than the target doses are effective.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Rufinamide in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Rufinamide in pediatric patients.
# Contraindications
- BANZEL is contraindicated in patients with Familial Short QT syndrome.
# Warnings
### Precautions
- Suicidal Behavior and Ideation
- Antiepileptic drugs (AEDs), including Banzel, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.
- Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.
- The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
- The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. Table 1 shows absolute and relative risk by indication for all evaluated AEDs.
- The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.
- Anyone considering prescribing Banzel or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.
- Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.
- Central Nervous System Reactions
- Use of BANZEL has been associated with central nervous system-related adverse reactions. The most significant of these can be classified into two general categories:
1) somnolence or fatigue, and 2) coordination abnormalities, dizziness, gait disturbances, and ataxia.
- 1) somnolence or fatigue, and 2) coordination abnormalities, dizziness, gait disturbances, and ataxia.
- QT Shortening
- Formal cardiac ECG studies demonstrated shortening of the QT interval (mean=20 msec, for doses ≥2400 mg twice daily) with BANZEL treatment. In a placebo-controlled study of the QT interval, a higher percentage of BANZEL-treated subjects (46% at 2400 mg, 46% at 3200 mg, and 65% at 4800 mg) had a QT shortening of greater than 20 msec at Tmax compared to placebo (5 - 10%).
- Reductions of the QT interval below 300 msec were not observed in the formal QT studies with doses up to 7200 mg/day. Moreover, there was no signal for drug-induced sudden death or ventricular arrhythmias.
- The degree of QT shortening induced by BANZEL is without any known clinical risk. Familial Short QT syndrome is associated with an increased risk of sudden death and ventricular arrhythmias, particularly ventricular fibrillation. Such events in this syndrome are believed to occur primarily when the corrected QT interval falls below 300 msec. Non-clinical data also indicate that QT shortening is associated with ventricular fibrillation.
- Patients with Familial Short QT syndrome should not be treated with BANZEL. Caution should be used when administering BANZEL with other drugs that shorten the QT interval.
- Multi-organ Hypersensitivity Reactions
- Multi-organ Hypersensitivity Syndrome, a serious condition sometimes induced by antiepileptic drugs, has occurred in association with BANZEL therapy in clinical trials. One patient experienced rash, urticaria, facial edema, fever, elevated eosinophils, stuperous state, and severe hepatitis, beginning on day 29 of Banzel therapy and extending over a course of 30 days of continued Banzel therapy with resolution 11 days after discontinuation. Additional possible cases presented with rash and one or more of the following: fever, elevated liver function studies, hematuria, and lymphadenopathy. These cases occurred in children less than 12 years of age, within four weeks of treatment initiation, and were noted to resolve and/or improve upon BANZEL discontinuation. This syndrome has been reported with other anticonvulsants and typically, although not exclusively, presents with fever and rash associated with other organ system involvement. Because this disorder is variable in its expression, other organ system signs and symptoms not noted here may occur. If this reaction is suspected, BANZEL should be discontinued and alternative treatment started. In addition, rare cases of DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms) and Stevens-Johnson syndrome have been reported in association with rufinamide therapy post marketing. If an antiepileptic drug hypersensitivity syndrome is suspected, rufinamide should be discontinued and alternative treatment started.
- All patients who develop a rash while taking BANZEL must be closely supervised.
- Withdrawal of AEDs
- As with all antiepileptic drugs, BANZEL should be withdrawn gradually to minimize the risk of precipitating seizures, seizure exacerbation, or status epilepticus. If abrupt discontinuation of the drug is medically necessary, the transition to another AED should be made under close medical supervision. In clinical trials, BANZEL discontinuation was achieved by reducing the dose by approximately 25% every two days.
- Status Epilepticus
- Estimates of the incidence of treatment emergent status epilepticus among patients treated with BANZEL are difficult because standard definitions were not employed. In a controlled Lennox-Gastaut Syndrome trial, 3 of 74 (4.1%) BANZEL-treated patients had episodes that could be described as status epilepticus in the BANZEL-treated patients compared with none of the 64 patients in the placebo-treated patients. In all controlled trials that included patients with different epilepsies, 11 of 1240 (0.9%) BANZEL-treated patients had episodes that could be described as status epilepticus compared with none of 635 patients in the placebo-treated patients.
- Laboratory Tests
- Leucopenia (white cell count <3X109 L) was more commonly observed in BANZEL-treated patients 43 of 1171 (3.7%) than placebo-treated patients, 7 of 579 (1.2%) in all controlled trials.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- Placebo-controlled double-blind studies were performed in adults and in pediatric patients, down to age of 4, in other forms of epilepsy, in addition to the trial in Lennox-Gastaut Syndrome. Data on CNS Reactions from the Lennox-Gastaut study are presented first. Because there is no reason to suspect that adverse reactions would substantially differ between these patient populations, safety data from all of these controlled studies are then presented. Most of these adverse reactions were mild to moderate and transient in nature.
- Common central nervous system reactions in the controlled trial of patients 4 years or older with Lennox-Gastaut Syndrome treated with BANZEL as adjunctive therapy.
- Somnolence was reported in 24.3% of BANZEL-treated patients compared to 12.5% of placebo patients and led to study discontinuation in 2.7% of treated patients compared to 0% of placebo patients. Fatigue was reported in 9.5% of BANZEL-treated patients compared to 7.8% of placebo patients. It led to study discontinuation in 1.4% of treated patients and 0% of placebo patients.
- Dizziness was reported in 2.7% of BANZEL-treated patients compared to 0% of placebo patients, and did not lead to study discontinuation.
- Ataxia and gait disturbance were reported in 5.4% and 1.4% of BANZEL-treated patients, respectively, and in no placebo patients. Balance disorder and abnormal coordination were each reported in 0% of BANZEL-treated patients and 1.6% of placebo patients. None of these reactions led to study discontinuation.
- All Adverse Reactions for All Treated Patients with Epilepsy, Double-blind Adjunctive Therapy Studies: The most commonly observed (≥10%) adverse reactions in BANZEL-treated patients, when used as adjunctive therapy at all doses studied (200 to 3200 mg/day) with a higher frequency than in placebo were: headache, dizziness, fatigue, somnolence, and nausea.
- Table 2 lists treatment-emergent adverse reactions that occurred in at least 3% of pediatric patients with epilepsy treated with BANZEL in controlled adjunctive studies and were numerically more common in patients treated with BANZEL than placebo.
- At the target dose of 45 mg/kg/day for adjunctive therapy in children, the most commonly observed (≥3%) adverse reactions with an incidence greater than in placebo, for BANZEL were somnolence, vomiting and headache.
- Table 3 lists treatment-emergent adverse reactions that occurred in at least 3% of adult patients with epilepsy treated with BANZEL (up to 3200 mg/day) in adjunctive controlled studies and were numerically more common in patients treated with BANZEL than placebo. In these studies, either BANZEL or placebo was added to the current AED therapy.
- At all doses studied of up to 3200 mg/day given as adjunctive therapy in adults, the most commonly observed (≥ 3%) adverse reactions, and with the greatest increase in incidence compared to placebo, for BANZEL were dizziness, fatigue, nausea, diplopia, vision blurred, and ataxia.
- Discontinuation in Controlled Clinical Studies
- In controlled double-blind adjunctive clinical studies, 9.0% of patients receiving BANZEL as adjunctive therapy and 4.4% receiving placebo discontinued as a result of an adverse reaction. The adverse reactions most commonly leading to discontinuation of BANZEL (> 1%) used as adjunctive therapy were generally similar in adults and children.
- In pediatric double-blind adjunctive clinical studies, 8.0% of patients receiving BANZEL as adjunctive therapy and 2.2% receiving placebo discontinued as a result of an adverse reaction. The adverse reactions most commonly leading to discontinuation of BANZEL (> 1%) used as adjunctive therapy are presented in Table 4.
- In adult double-blind adjunctive clinical studies (up to 3200 mg/day), 9.5% of patients receiving BANZEL as adjunctive therapy and 5.9% receiving placebo discontinued as a result of an adverse reaction. The adverse reactions most commonly leading to discontinuation of BANZEL (> 1%) used as adjunctive therapy are presented in Table 5.
- Other Adverse Events Observed During Clinical Trials:
- BANZEL has been administered to 1978 individuals during all epilepsy clinical trials (placebo-controlled and open-label). Adverse events occurring during these studies were recorded by the investigators using terminology of their own choosing. To provide a meaningful estimate of the proportion of patients having adverse events, these events were grouped into standardized categories using the MedDRA dictionary. Adverse events occurring at least three times and considered possibly related to treatment are included in the System Organ Class listings below. Terms not included in the listings are those already included in the tables above, those too general to be informative, those related to procedures and terms describing events common in the population. Some events occurring fewer than 3 times are also included based on their medical significance. Because the reports include events observed in open-label, uncontrolled observations, the role of BANZEL in their causation cannot be reliably determined.
- Events are classified by body system and listed in order of decreasing frequency as follows: frequent adverse events- those occurring in at least 1/100 patients; infrequent adverse events- those occurring in 1/100 to 1/1000 patients; rare- those occurring in fewer than 1/1000 patients.
Frequent: anemia. Infrequent: lymphadenopathy, leukopenia, neutropenia, iron deficiency anemia, thrombocytopenia.
Infrequent: bundle branch block right, atrioventricular block first degree.
Frequent: decreased appetite, increased appetite.
Frequent: pollakiuria. Infrequent: urinary incontinence, dysuria, hematuria, nephrolithiasis, polyuria, enuresis, nocturia, incontinence.
## Postmarketing Experience
Decreased weight has been reported in patients receiving rufinamide both in the presence and absence of gastrointestinal symptoms.
# Drug Interactions
- Based on in vitro studies, rufinamide shows little or no inhibition of most cytochrome P450 enzymes at clinically relevant concentrations, with weak inhibition of CYP 2E1. Drugs that are substrates of CYP 2E1 (e.g. chlorzoxazone) may have increased plasma levels in the presence of rufinamide, but this has not been studied.
- Based on in vivo drug interaction studies with triazolam and oral contraceptives, rufinamide is a weak inducer of the CYP 3A4 enzyme and can decrease exposure of drugs that are substrates of CYP 3A4.
- Rufinamide is metabolized by carboxylesterases. Drugs that may induce the activity of carboxylesterases may increase the clearance of rufinamide. Broad-spectrum inducers such as carbamazepine and phenobarbital may have minor effects on rufinamide metabolism via this mechanism. Drugs that are inhibitors of carboxylesterases may decrease metabolism of rufinamide.
- Effects of BANZEL on other AEDs
- Population pharmacokinetic analysis of average concentration at steady state of carbamazepine, lamotrigine, phenobarbital, phenytoin, topiramate, and valproate showed that typical rufinamide Cavss levels had little effect on the pharmacokinetics of other AEDs. Any effects, when they occur, have been more marked in the pediatric population.
- Table 6 summarizes the drug-drug interactions of BANZEL with other AEDs.
- Phenytoin: The decrease in clearance of phenytoin estimated at typical levels of rufinamide (Cavss 15 μg/mL) is predicted to increase plasma levels of phenytoin by 7 to 21%. As phenytoin is known to have non-linear pharmacokinetics (clearance becomes saturated at higher doses), it is possible that exposure will be greater than the model prediction.
- Effects of Other AEDs on BANZEL
- Potent cytochrome P450 enzyme inducers, such as carbamazepine, phenytoin, primidone, and phenobarbital appear to increase the clearance of BANZEL (see Table 6). Given that the majority of clearance of BANZEL is via a non-CYP-dependent route, the observed decreases in blood levels seen with carbamazepine, phenytoin, phenobarbital, and primidone are unlikely to be entirely attributable to induction of a P450 enzyme. Other factors explaining this interaction are not understood. Any effects, where they occurred were likely to be more marked in the pediatric population.
- Valproate: Based on a population pharmacokinetic analysis, rufinamide clearance was decreased by valproate. In children, valproate administration may lead to elevated levels of rufinamide by up to 70%. Patients stabilized on BANZEL before being prescribed valproate should begin valproate therapy at a low dose, and titrate to a clinically effective dose. Similarly, patients on valproate should begin at a BANZEL dose lower than 10 mg/kg/day (children) or 400 mg/day (adults).
- Effects of BANZEL on other Medications
- Hormonal contraceptives: Co-administration of BANZEL (800 mg BID for 14 days) and Ortho-Novum 1/35® resulted in a mean decrease in the ethinyl estradiol AUC0-24 of 22% and Cmax by 31% and norethindrone AUC0-24 by 14% and Cmax by 18%, respectively. The clinical significance of this decrease is unknown. Female patients of childbearing age should be warned that the concurrent use of BANZEL with hormonal contraceptives may render this method of contraception less effective. Additional non-hormonal forms of contraception are recommended when using BANZEL.
- Triazolam: Co-administration and pre-treatment with BANZEL (400 mg bid) resulted in a 37% decrease in AUC and a 23% decrease in Cmax of triazolam, a CYP 3A4 substrate.
- Olanzapine: Co-administration and pre-treatment with BANZEL (400 mg bid) resulted in no change in AUC and Cmax of olanzapine, a CYP 1A2 substrate.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- There are no adequate and well-controlled studies in pregnant women. BANZEL should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Rufinamide produced developmental toxicity when administered orally to pregnant animals at clinically relevant doses.
- Rufinamide was administered orally to rats at doses of 20, 100, and 300 mg/kg/day and to rabbits at doses of 30, 200, and 1000 mg/kg/day during the period of organogenesis (implantation to closure of the hard palate); the high doses are associated with plasma AUCs ≈2 times the human plasma AUC at the maximum recommended human dose (MRHD, 3200 mg/day). Decreased fetal weights and increased incidences of fetal skeletal abnormalities were observed in rats at doses associated with maternal toxicity. In rabbits, embryo-fetal death, decreased fetal body weights, and increased incidences of fetal visceral and skeletal abnormalities occurred at all but the low dose. The highest dose tested in rabbits was associated with abortion. The no-effect doses for adverse effects on rat and rabbit embryo-fetal development (20 and 30 mg/kg/day, respectively) were associated with plasma AUCs ≈ 0.2 times that in humans at the MRHD.
- In a rat pre- and post-natal development study (dosing from implantation through weaning) conducted at oral doses of 5, 30, and 150 mg/kg/day (associated with plasma AUCs up to ≈1.5 times that in humans at the MRHD), decreased offspring growth and survival were observed at all doses tested. A no-effect dose for adverse effects on pre- and post-natal development was not established. The lowest dose tested was associated with plasma AUC <0.1 times that in humans at the MRHD.
- Pregnancy Registry
- To provide information regarding the effects of in utero exposure to BANZEL physicians are advised to recommend that pregnant patients taking BANZEL enroll in the North American Antiepileptic Drug Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website /.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Rufinamide in women who are pregnant.
### Labor and Delivery
- The effect of BANZEL on labor and delivery in humans is not known.
### Nursing Mothers
- Rufinamide is likely to be excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from BANZEL, a decision should be made whether to discontinue nursing or discontinue the drug taking into account the importance of the drug to the mother.
### Pediatric Use
- The safety and effectiveness in patients with Lennox-Gastaut Syndrome have not been established in children less than 4 years. The pharmacokinetics of rufinamide in the pediatric population (age 4-17 years) is similar to that in the adults.
### Geriatic Use
- Clinical studies of BANZEL did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
- Pharmacokinetics of rufinamide in the elderly are similar to that in the young subjects.
### Gender
There is no FDA guidance on the use of Rufinamide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Rufinamide with respect to specific racial populations.
### Renal Impairment
- Rufinamide pharmacokinetics in patients with severe renal impairment (creatinine clearance < 30 mL/min) was similar to that of healthy subjects. Dose adjustment in patients undergoing dialysis should be considered.
### Hepatic Impairment
- There have been no specific studies investigating the effect of hepatic impairment on the pharmacokinetics of rufinamide. Therefore, use in patients with severe hepatic impairment is not recommended. Caution should be exercised in treating patients with mild to moderate hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Rufinamide in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Rufinamide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Rufinamide in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Rufinamide in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Because strategies for the management of overdose are continually evolving, it is advisable to contact a Certified Poison Control Center to determine the latest recommendations for the management of an overdose of any drug.
- One overdose of 7200 mg/day BANZEL was reported in an adult during the clinical trials. The overdose was associated with no major signs or symptoms, no medical intervention was required, and the patient continued in the study at the target dose.
### Management
- There is no specific antidote for overdose with BANZEL. If clinically indicated, elimination of unabsorbed drug should be attempted by induction of emesis or gastric lavage. Usual precautions should be observed to maintain the airway. General supportive care of the patient is indicated including monitoring of vital signs and observation of the clinical status of the patient.
- Hemodialysis: Standard hemodialysis procedures may result in limited clearance of rufinamide. Although there is no experience to date in treating overdose with hemodialysis, the procedure may be considered when indicated by the patient's clinical state.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Rufinamide in the drug label.
# Pharmacology
## Mechanism of Action
- The precise mechanism(s) by which rufinamide exerts its antiepileptic effect is unknown.
- The results of in vitro studies suggest that the principal mechanism of action of rufinamide is modulation of the activity of sodium channels and, in particular, prolongation of the inactive state of the channel. Rufinamide (≥1 μM) significantly slowed sodium channel recovery from inactivation after a prolonged prepulse in cultured cortical neurons, and limited sustained repetitive firing of sodium-dependent action potentials (EC50 of 3.8 μM).
## Structure
- BANZEL (rufinamide) is a triazole derivative structurally unrelated to currently marketed antiepileptic drugs (AEDs). Rufinamide has the chemical name 1--1H-1,2,3-triazole-4 carboxamide. It has an empirical formula of C10H8F2N4O and a molecular weight of 238.2. The drug substance is a white, crystalline, odorless and slightly bitter tasting neutral powder. Rufinamide is practically insoluble in water, slightly soluble in tetrahydrofuran and in methanol, and very slightly soluble in ethanol and in acetonitrile.
- BANZEL is available for oral administration in film-coated tablets, scored on both sides, containing 200 and 400 mg of rufinamide. Inactive ingredients are colloidal silicon dioxide, corn starch, crosscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulphate. The film coating contains hypromellose, iron oxide red, polyethylene glycol, talc, and titanium dioxide.
- BANZEL is also available for oral administration as a liquid containing rufinamide at a concentration of 40 mg/mL. Inactive ingredients include microcrystalline cellulose and carboxymethylcellulose sodium, hydroxyethylcellulose, anhydrous citric acid, simethicone emulsion 30%, poloxamer 188, methylparaben, propylparaben, propylene glycol, potassium sorbate, noncrystallizing sorbitol solution 70%, and an orange flavor.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Rufinamide in the drug label.
## Pharmacokinetics
- BANZEL oral suspension is bioequivalent on a mg per mg basis to BANZEL tablets. BANZEL is well absorbed after oral administration. However, the rate of absorption is relatively slow and the extent of absorption is decreased as dose is increased. The pharmacokinetics does not change with multiple dosing. Most elimination of rufinamide is via metabolism, with the primary metabolite resulting from enzymatic hydrolysis of the carboxamide moiety to form the carboxylic acid. This metabolic route is not cytochrome P450 dependent. There are no known active metabolites. Plasma half-life of rufinamide is approximately 6-10 hours.
- Absorption and Distribution
- Following oral administration of BANZEL, peak plasma concentrations occur between 4 and 6 hours (Tmax) both under fed and fasted conditions. BANZEL tablets display decreasing bioavailability with increasing dose after single and multiple dose administration. Based on urinary excretion, the extent of absorption was at least 85% following oral administration of a single dose of 600 mg rufinamide tablet under fed conditions.
- Multiple dose pharmacokinetics can be predicted from single dose data for both rufinamide and its metabolite. Given the dosing frequency of every 12 hours and the half-life of 6 to 10 hours, the observed steady-state peak concentration of about two to three times the peak concentration after a single dose is expected.
- Food increased the extent of absorption of rufinamide in healthy volunteers by 34% and increased peak exposure by 56% after a single dose of 400 mg tablet, although the Tmax was not elevated. Clinical trials were performed under fed conditions and dosing is recommended with food.
- Only a small fraction of rufinamide (34%) is bound to human serum proteins, predominantly to albumin (27%), giving little risk of displacement drug-drug interactions. Rufinamide was evenly distributed between erythrocytes and plasma. The apparent volume of distribution is dependent upon dose and varies with body surface area. The apparent volume of distribution was about 50 L at 3200 mg/day.
- Metabolism
- Rufinamide is extensively metabolized but has no active metabolites. Following a radiolabeled dose of rufinamide, less than 2% of the dose was recovered unchanged in urine. The primary biotransformation pathway is carboxylesterase(s) mediated hydrolysis of the carboxamide group to the acid derivative CGP 47292. A few minor additional metabolites were detected in urine, which appeared to be acyl-glucuronides of CGP 47292. There is no involvement of oxidizing cytochrome P450 enzymes or glutathione in the biotransformation process.
- Rufinamide is a weak inhibitor of CYP 2E1. It did not show significant inhibition of other CYP enzymes. Rufinamide is a weak inducer of CYP 3A4 enzymes.
- Rufinamide did not show any significant inhibition of P-glycoprotein in an in-vitro study.
- Elimination/Excretion
- Renal excretion is the predominant route of elimination for drug related material, accounting for 85% of the dose based on a radiolabeled study. Of the metabolites identified in urine, at least 66% of the rufinamide dose was excreted as the acid metabolite CGP 47292, with 2% of the dose excreted as rufinamide.
- The plasma elimination half-life is approximately 6-10 hours in healthy subjects and patients with epilepsy.
- Special Populations
- Gender: Population pharmacokinetic analyses of females show a 6-14% lower apparent clearance of rufinamide compared to males. This effect is not clinically important.
- Race: In a population pharmacokinetic analysis of clinical studies, no difference in clearance or volume of distribution of rufinamide was observed between the black and Caucasian subjects, after controlling for body size. Information on other races could not be obtained because of smaller numbers of these subjects.
- Pediatrics: Based on a population analysis in 117 children (age 4-11 years) and 99 adolescents (age 12-17 years), the pharmacokinetics of rufinamide in these patients is similar to the pharmacokinetics in adults.
- Elderly: The results of a study evaluating single-dose (400 mg) and multiple dose (800 mg/day for 6 days) pharmacokinetics of rufinamide in 8 healthy elderly subjects (65-80 years old) and 7 younger healthy subjects (18-45 years old) found no significant age-related differences in the pharmacokinetics of rufinamide.
- Renal Impairment: Rufinamide pharmacokinetics in 9 patients with severe renal impairment (creatinine clearance < 30 mL/min) was similar to that of healthy subjects. Patients undergoing dialysis 3 hours post rufinamide dosing showed a reduction in AUC and Cmax by 29% and 16% respectively. Adjusting rufinamide dose for the loss of drug upon dialysis should be considered.
- Hepatic Impairment: There have been no specific studies investigating the effect of hepatic impairment on the pharmacokinetics of rufinamide. Therefore, use in patients with severe hepatic impairment is not recommended. Caution should be exercised in treating patients with mild to moderate hepatic impairment.
## Nonclinical Toxicology
- Carcinogenesis: Rufinamide was given in the diet to mice at 40, 120, and 400 mg/kg/day and to rats at 20, 60, and 200 mg/kg/day for two years. The doses in mice were associated with plasma AUCs 0.1 to 1 times the human plasma AUC at the maximum recommended human dose (MRHD, 3200 mg/day). Increased incidences of tumors (benign bone tumors (osteomas) and/or hepatocellular adenomas and carcinomas) were observed in mice at all doses. Increased incidences of thyroid follicular adenomas were observed in rats at all but the low dose; the low dose is < 0.1 times the MRHD on a mg/m2 basis.
- Mutagenesis: Rufinamide was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay or the in vitro mammalian cell point mutation assay. Rufinamide was not clastogenic in the in vitro mammalian cell chromosomal aberration assay or the in vivo rat bone marrow micronucleus assay.
- Impairment of Fertility: Oral administration of rufinamide (doses of 20, 60, 200, and 600 mg/kg/day) to male and female rats prior to mating and throughout mating, and continuing in females up to day 6 of gestation resulted in impairment of fertility (decreased conception rates and mating and fertility indices; decreased numbers of corpora lutea, implantations, and live embryos; increased preimplantation loss; decreased sperm count and motility) at all doses tested. Therefore, a no-effect dose was not established. The lowest dose tested was associated with a plasma AUC ≈0.2 times the human plasma AUC at the MRHD.
# Clinical Studies
- The effectiveness of BANZEL as adjunctive treatment for the seizures associated with Lennox-Gastaut Syndrome (LGS) was established in a single multicenter, double-blind, placebo-controlled, randomized, parallel-group study (N=138). Male and female patients (between 4 and 30 years of age) were included if they had a diagnosis of inadequately controlled seizures associated with LGS (including both atypical absence seizures and drop attacks) and were being treated with 1 to 3 concomitant stable dose AEDs. Each patient must have had at least 90 seizures in the month prior to study entry. After completing a 4 week Baseline Phase on stable therapy, patients were randomized to have BANZEL or placebo added to their ongoing therapy during the 12 week Double-blind Phase. The Double-blind Phase consisted of 2 periods: the Titration Period (1 to 2 weeks) and the Maintenance Period (10 weeks). During the Titration Period, the dose was increased to a target dosage of approximately 45 mg/kg/day (3200 mg in adults of ≥ 70 kg), given on a b.i.d. schedule. Dosage reductions were permitted during titration if problems in tolerability were encountered. Final doses at titration were to remain stable during the maintenance period. Target dosage was achieved in 88% of the BANZEL-treated patients. The majority of these patients reached the target dose within 7 days, with the remaining patients achieving the target dose within 14 days.
- The primary efficacy variables were:
- The percent change in total seizure frequency per 28 days;
- The percent change in tonic-atonic (drop attacks) seizure frequency per 28 days;
- Seizure severity from the Parent/Guardian Global Evaluation of the patient's condition. This was a 7-point assessment performed at the end of the Double-blind Phase. A score of +3 indicated that the patient's seizure severity was very much improved, a score of 0 that the seizure severity was unchanged, and a score of -3 that the seizure severity was very much worse.
- The results of the three primary endpoints are shown in Table 7 below.
# How Supplied
- BANZEL 200 mg tablets (containing 200 mg rufinamide) are pink in color, film-coated, oblong-shape tablets, with a score on both sides, imprinted with "Є 262" on one side. They are available in bottles of 120 (NDC 62856-582-52).
- BANZEL 400 mg tablets (containing 400 mg rufinamide) are pink in color, film-coated, oblong-shape tablets, with a score on both sides, imprinted with "Є 263" on one side. They are available in bottles of 120 (NDC 62856-583-52).
- BANZEL Oral Suspension is an orange flavored liquid supplied in a polyethylene terephthalate (PET) bottle with child-resistant closure. The oral suspension is packaged with a dispenser set which contains a calibrated oral dosing syringe and an adapter. Store the oral suspension in an upright position. Use within 90 days of first opening the bottle, then discard any remainder. The oral suspension is available in bottles of 460 mL (NDC 62856-584-46).
- Store the tablets at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F). Protect from moisture. Replace cap securely after opening.
- Store the oral suspension at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F). Replace cap securely after opening. The cap fits properly in place when the adapter is in place.
## Storage
There is limited information regarding Rufinamide Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients should be informed of the availability of a Medication guide and they should be instructed to read the Medication Guide prior to taking BANZEL.
- Patients should be instructed to take BANZEL only as prescribed.
- Suicidal Thinking and Behavior
- Patients, their caregivers, and families should be informed that antiepileptic drugs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.
- As with all centrally acting medications, alcohol in combination with BANZEL may cause additive central nervous system effects.
- Patients should be advised to notify their physician if they experience a rash associated with fever.
- BANZEL should be taken with food.
- Patients should be advised about the potential for somnolence or dizziness and advised not to drive or operate machinery until they have gained sufficient experience on BANZEL to gauge whether it adversely affects their mental and/or motor performance.
- Female patients of childbearing age should be warned that the concurrent use of BANZEL with hormonal contraceptives may render this method of contraception less effective. Additional non-hormonal forms of contraception are recommended when using BANZEL.
- Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy. They should also be encouraged to enroll in the North American Antiepileptic Drug Pregnancy Registry if they become pregnant. To enroll, patients can call the toll free number 1-888-233-2334.
- Patients should be advised to notify their physician if they are breast-feeding or intend to breast-feed.
- Patients who are prescribed the oral suspension should be advised to shake the bottle vigorously before every administration and to use the adaptor and oral dosing syringe.
- When applicable patients should be advised that BANZEL oral suspension does not contain lactose or gluten and is dye-free. The oral suspension does contain carbohydrates.
# Precautions with Alcohol
- Alcohol-Rufinamide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- BANZEL®
# Look-Alike Drug Names
There is limited information regarding Rufinamide Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Rufinamide
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2]
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# Overview
Rufinamide is an anti-epileptic drug that is FDA approved for the treatment of lennox-gastaut syndrome (LGS). Common adverse reactions include headache, dizziness, fatigue, somnolence, and nausea.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Treatment should be initiated at a daily dose of 400-800 mg/day administered in two equally divided doses. The dose should be increased by 400-800 mg every other day until a maximum daily dose of 3200 mg/day, administered in two equally divided doses is reached. It is not known whether doses lower than 3200 mg are effective.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Rufinamide in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Rufinamide in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Treatment should be initiated at a daily dose of approximately 10 mg/kg/day administered in two equally divided doses. The dose should be increased by approximately 10 mg/kg increments every other day to a target dose of 45 mg/kg/day or 3200 mg/day, whichever is less, administered in two equally divided doses. It is not known whether doses lower than the target doses are effective.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Rufinamide in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Rufinamide in pediatric patients.
# Contraindications
- BANZEL is contraindicated in patients with Familial Short QT syndrome.
# Warnings
### Precautions
- Suicidal Behavior and Ideation
- Antiepileptic drugs (AEDs), including Banzel, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.
- Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.
- The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
- The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. Table 1 shows absolute and relative risk by indication for all evaluated AEDs.
- The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.
- Anyone considering prescribing Banzel or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.
- Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.
- Central Nervous System Reactions
- Use of BANZEL has been associated with central nervous system-related adverse reactions. The most significant of these can be classified into two general categories:
1) somnolence or fatigue, and 2) coordination abnormalities, dizziness, gait disturbances, and ataxia.
- 1) somnolence or fatigue, and 2) coordination abnormalities, dizziness, gait disturbances, and ataxia.
- QT Shortening
- Formal cardiac ECG studies demonstrated shortening of the QT interval (mean=20 msec, for doses ≥2400 mg twice daily) with BANZEL treatment. In a placebo-controlled study of the QT interval, a higher percentage of BANZEL-treated subjects (46% at 2400 mg, 46% at 3200 mg, and 65% at 4800 mg) had a QT shortening of greater than 20 msec at Tmax compared to placebo (5 - 10%).
- Reductions of the QT interval below 300 msec were not observed in the formal QT studies with doses up to 7200 mg/day. Moreover, there was no signal for drug-induced sudden death or ventricular arrhythmias.
- The degree of QT shortening induced by BANZEL is without any known clinical risk. Familial Short QT syndrome is associated with an increased risk of sudden death and ventricular arrhythmias, particularly ventricular fibrillation. Such events in this syndrome are believed to occur primarily when the corrected QT interval falls below 300 msec. Non-clinical data also indicate that QT shortening is associated with ventricular fibrillation.
- Patients with Familial Short QT syndrome should not be treated with BANZEL. Caution should be used when administering BANZEL with other drugs that shorten the QT interval.
- Multi-organ Hypersensitivity Reactions
- Multi-organ Hypersensitivity Syndrome, a serious condition sometimes induced by antiepileptic drugs, has occurred in association with BANZEL therapy in clinical trials. One patient experienced rash, urticaria, facial edema, fever, elevated eosinophils, stuperous state, and severe hepatitis, beginning on day 29 of Banzel therapy and extending over a course of 30 days of continued Banzel therapy with resolution 11 days after discontinuation. Additional possible cases presented with rash and one or more of the following: fever, elevated liver function studies, hematuria, and lymphadenopathy. These cases occurred in children less than 12 years of age, within four weeks of treatment initiation, and were noted to resolve and/or improve upon BANZEL discontinuation. This syndrome has been reported with other anticonvulsants and typically, although not exclusively, presents with fever and rash associated with other organ system involvement. Because this disorder is variable in its expression, other organ system signs and symptoms not noted here may occur. If this reaction is suspected, BANZEL should be discontinued and alternative treatment started. In addition, rare cases of DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms) and Stevens-Johnson syndrome have been reported in association with rufinamide therapy post marketing. If an antiepileptic drug hypersensitivity syndrome is suspected, rufinamide should be discontinued and alternative treatment started.
- All patients who develop a rash while taking BANZEL must be closely supervised.
- Withdrawal of AEDs
- As with all antiepileptic drugs, BANZEL should be withdrawn gradually to minimize the risk of precipitating seizures, seizure exacerbation, or status epilepticus. If abrupt discontinuation of the drug is medically necessary, the transition to another AED should be made under close medical supervision. In clinical trials, BANZEL discontinuation was achieved by reducing the dose by approximately 25% every two days.
- Status Epilepticus
- Estimates of the incidence of treatment emergent status epilepticus among patients treated with BANZEL are difficult because standard definitions were not employed. In a controlled Lennox-Gastaut Syndrome trial, 3 of 74 (4.1%) BANZEL-treated patients had episodes that could be described as status epilepticus in the BANZEL-treated patients compared with none of the 64 patients in the placebo-treated patients. In all controlled trials that included patients with different epilepsies, 11 of 1240 (0.9%) BANZEL-treated patients had episodes that could be described as status epilepticus compared with none of 635 patients in the placebo-treated patients.
- Laboratory Tests
- Leucopenia (white cell count <3X109 L) was more commonly observed in BANZEL-treated patients 43 of 1171 (3.7%) than placebo-treated patients, 7 of 579 (1.2%) in all controlled trials.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- Placebo-controlled double-blind studies were performed in adults and in pediatric patients, down to age of 4, in other forms of epilepsy, in addition to the trial in Lennox-Gastaut Syndrome. Data on CNS Reactions from the Lennox-Gastaut study are presented first. Because there is no reason to suspect that adverse reactions would substantially differ between these patient populations, safety data from all of these controlled studies are then presented. Most of these adverse reactions were mild to moderate and transient in nature.
- Common central nervous system reactions in the controlled trial of patients 4 years or older with Lennox-Gastaut Syndrome treated with BANZEL as adjunctive therapy.
- Somnolence was reported in 24.3% of BANZEL-treated patients compared to 12.5% of placebo patients and led to study discontinuation in 2.7% of treated patients compared to 0% of placebo patients. Fatigue was reported in 9.5% of BANZEL-treated patients compared to 7.8% of placebo patients. It led to study discontinuation in 1.4% of treated patients and 0% of placebo patients.
- Dizziness was reported in 2.7% of BANZEL-treated patients compared to 0% of placebo patients, and did not lead to study discontinuation.
- Ataxia and gait disturbance were reported in 5.4% and 1.4% of BANZEL-treated patients, respectively, and in no placebo patients. Balance disorder and abnormal coordination were each reported in 0% of BANZEL-treated patients and 1.6% of placebo patients. None of these reactions led to study discontinuation.
- All Adverse Reactions for All Treated Patients with Epilepsy, Double-blind Adjunctive Therapy Studies: The most commonly observed (≥10%) adverse reactions in BANZEL-treated patients, when used as adjunctive therapy at all doses studied (200 to 3200 mg/day) with a higher frequency than in placebo were: headache, dizziness, fatigue, somnolence, and nausea.
- Table 2 lists treatment-emergent adverse reactions that occurred in at least 3% of pediatric patients with epilepsy treated with BANZEL in controlled adjunctive studies and were numerically more common in patients treated with BANZEL than placebo.
- At the target dose of 45 mg/kg/day for adjunctive therapy in children, the most commonly observed (≥3%) adverse reactions with an incidence greater than in placebo, for BANZEL were somnolence, vomiting and headache.
- Table 3 lists treatment-emergent adverse reactions that occurred in at least 3% of adult patients with epilepsy treated with BANZEL (up to 3200 mg/day) in adjunctive controlled studies and were numerically more common in patients treated with BANZEL than placebo. In these studies, either BANZEL or placebo was added to the current AED therapy.
- At all doses studied of up to 3200 mg/day given as adjunctive therapy in adults, the most commonly observed (≥ 3%) adverse reactions, and with the greatest increase in incidence compared to placebo, for BANZEL were dizziness, fatigue, nausea, diplopia, vision blurred, and ataxia.
- Discontinuation in Controlled Clinical Studies
- In controlled double-blind adjunctive clinical studies, 9.0% of patients receiving BANZEL as adjunctive therapy and 4.4% receiving placebo discontinued as a result of an adverse reaction. The adverse reactions most commonly leading to discontinuation of BANZEL (> 1%) used as adjunctive therapy were generally similar in adults and children.
- In pediatric double-blind adjunctive clinical studies, 8.0% of patients receiving BANZEL as adjunctive therapy and 2.2% receiving placebo discontinued as a result of an adverse reaction. The adverse reactions most commonly leading to discontinuation of BANZEL (> 1%) used as adjunctive therapy are presented in Table 4.
- In adult double-blind adjunctive clinical studies (up to 3200 mg/day), 9.5% of patients receiving BANZEL as adjunctive therapy and 5.9% receiving placebo discontinued as a result of an adverse reaction. The adverse reactions most commonly leading to discontinuation of BANZEL (> 1%) used as adjunctive therapy are presented in Table 5.
- Other Adverse Events Observed During Clinical Trials:
- BANZEL has been administered to 1978 individuals during all epilepsy clinical trials (placebo-controlled and open-label). Adverse events occurring during these studies were recorded by the investigators using terminology of their own choosing. To provide a meaningful estimate of the proportion of patients having adverse events, these events were grouped into standardized categories using the MedDRA dictionary. Adverse events occurring at least three times and considered possibly related to treatment are included in the System Organ Class listings below. Terms not included in the listings are those already included in the tables above, those too general to be informative, those related to procedures and terms describing events common in the population. Some events occurring fewer than 3 times are also included based on their medical significance. Because the reports include events observed in open-label, uncontrolled observations, the role of BANZEL in their causation cannot be reliably determined.
- Events are classified by body system and listed in order of decreasing frequency as follows: frequent adverse events- those occurring in at least 1/100 patients; infrequent adverse events- those occurring in 1/100 to 1/1000 patients; rare- those occurring in fewer than 1/1000 patients.
Frequent: anemia. Infrequent: lymphadenopathy, leukopenia, neutropenia, iron deficiency anemia, thrombocytopenia.
Infrequent: bundle branch block right, atrioventricular block first degree.
Frequent: decreased appetite, increased appetite.
Frequent: pollakiuria. Infrequent: urinary incontinence, dysuria, hematuria, nephrolithiasis, polyuria, enuresis, nocturia, incontinence.
## Postmarketing Experience
Decreased weight has been reported in patients receiving rufinamide both in the presence and absence of gastrointestinal symptoms.
# Drug Interactions
- Based on in vitro studies, rufinamide shows little or no inhibition of most cytochrome P450 enzymes at clinically relevant concentrations, with weak inhibition of CYP 2E1. Drugs that are substrates of CYP 2E1 (e.g. chlorzoxazone) may have increased plasma levels in the presence of rufinamide, but this has not been studied.
- Based on in vivo drug interaction studies with triazolam and oral contraceptives, rufinamide is a weak inducer of the CYP 3A4 enzyme and can decrease exposure of drugs that are substrates of CYP 3A4.
- Rufinamide is metabolized by carboxylesterases. Drugs that may induce the activity of carboxylesterases may increase the clearance of rufinamide. Broad-spectrum inducers such as carbamazepine and phenobarbital may have minor effects on rufinamide metabolism via this mechanism. Drugs that are inhibitors of carboxylesterases may decrease metabolism of rufinamide.
- Effects of BANZEL on other AEDs
- Population pharmacokinetic analysis of average concentration at steady state of carbamazepine, lamotrigine, phenobarbital, phenytoin, topiramate, and valproate showed that typical rufinamide Cavss levels had little effect on the pharmacokinetics of other AEDs. Any effects, when they occur, have been more marked in the pediatric population.
- Table 6 summarizes the drug-drug interactions of BANZEL with other AEDs.
- Phenytoin: The decrease in clearance of phenytoin estimated at typical levels of rufinamide (Cavss 15 μg/mL) is predicted to increase plasma levels of phenytoin by 7 to 21%. As phenytoin is known to have non-linear pharmacokinetics (clearance becomes saturated at higher doses), it is possible that exposure will be greater than the model prediction.
- Effects of Other AEDs on BANZEL
- Potent cytochrome P450 enzyme inducers, such as carbamazepine, phenytoin, primidone, and phenobarbital appear to increase the clearance of BANZEL (see Table 6). Given that the majority of clearance of BANZEL is via a non-CYP-dependent route, the observed decreases in blood levels seen with carbamazepine, phenytoin, phenobarbital, and primidone are unlikely to be entirely attributable to induction of a P450 enzyme. Other factors explaining this interaction are not understood. Any effects, where they occurred were likely to be more marked in the pediatric population.
- Valproate: Based on a population pharmacokinetic analysis, rufinamide clearance was decreased by valproate. In children, valproate administration may lead to elevated levels of rufinamide by up to 70%. Patients stabilized on BANZEL before being prescribed valproate should begin valproate therapy at a low dose, and titrate to a clinically effective dose. Similarly, patients on valproate should begin at a BANZEL dose lower than 10 mg/kg/day (children) or 400 mg/day (adults).
- Effects of BANZEL on other Medications
- Hormonal contraceptives: Co-administration of BANZEL (800 mg BID for 14 days) and Ortho-Novum 1/35® resulted in a mean decrease in the ethinyl estradiol AUC0-24 of 22% and Cmax by 31% and norethindrone AUC0-24 by 14% and Cmax by 18%, respectively. The clinical significance of this decrease is unknown. Female patients of childbearing age should be warned that the concurrent use of BANZEL with hormonal contraceptives may render this method of contraception less effective. Additional non-hormonal forms of contraception are recommended when using BANZEL.
- Triazolam: Co-administration and pre-treatment with BANZEL (400 mg bid) resulted in a 37% decrease in AUC and a 23% decrease in Cmax of triazolam, a CYP 3A4 substrate.
- Olanzapine: Co-administration and pre-treatment with BANZEL (400 mg bid) resulted in no change in AUC and Cmax of olanzapine, a CYP 1A2 substrate.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- There are no adequate and well-controlled studies in pregnant women. BANZEL should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Rufinamide produced developmental toxicity when administered orally to pregnant animals at clinically relevant doses.
- Rufinamide was administered orally to rats at doses of 20, 100, and 300 mg/kg/day and to rabbits at doses of 30, 200, and 1000 mg/kg/day during the period of organogenesis (implantation to closure of the hard palate); the high doses are associated with plasma AUCs ≈2 times the human plasma AUC at the maximum recommended human dose (MRHD, 3200 mg/day). Decreased fetal weights and increased incidences of fetal skeletal abnormalities were observed in rats at doses associated with maternal toxicity. In rabbits, embryo-fetal death, decreased fetal body weights, and increased incidences of fetal visceral and skeletal abnormalities occurred at all but the low dose. The highest dose tested in rabbits was associated with abortion. The no-effect doses for adverse effects on rat and rabbit embryo-fetal development (20 and 30 mg/kg/day, respectively) were associated with plasma AUCs ≈ 0.2 times that in humans at the MRHD.
- In a rat pre- and post-natal development study (dosing from implantation through weaning) conducted at oral doses of 5, 30, and 150 mg/kg/day (associated with plasma AUCs up to ≈1.5 times that in humans at the MRHD), decreased offspring growth and survival were observed at all doses tested. A no-effect dose for adverse effects on pre- and post-natal development was not established. The lowest dose tested was associated with plasma AUC <0.1 times that in humans at the MRHD.
- Pregnancy Registry
- To provide information regarding the effects of in utero exposure to BANZEL physicians are advised to recommend that pregnant patients taking BANZEL enroll in the North American Antiepileptic Drug Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Rufinamide in women who are pregnant.
### Labor and Delivery
- The effect of BANZEL on labor and delivery in humans is not known.
### Nursing Mothers
- Rufinamide is likely to be excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from BANZEL, a decision should be made whether to discontinue nursing or discontinue the drug taking into account the importance of the drug to the mother.
### Pediatric Use
- The safety and effectiveness in patients with Lennox-Gastaut Syndrome have not been established in children less than 4 years. The pharmacokinetics of rufinamide in the pediatric population (age 4-17 years) is similar to that in the adults.
### Geriatic Use
- Clinical studies of BANZEL did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
- Pharmacokinetics of rufinamide in the elderly are similar to that in the young subjects.
### Gender
There is no FDA guidance on the use of Rufinamide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Rufinamide with respect to specific racial populations.
### Renal Impairment
- Rufinamide pharmacokinetics in patients with severe renal impairment (creatinine clearance < 30 mL/min) was similar to that of healthy subjects. Dose adjustment in patients undergoing dialysis should be considered.
### Hepatic Impairment
- There have been no specific studies investigating the effect of hepatic impairment on the pharmacokinetics of rufinamide. Therefore, use in patients with severe hepatic impairment is not recommended. Caution should be exercised in treating patients with mild to moderate hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Rufinamide in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Rufinamide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Rufinamide in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Rufinamide in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Because strategies for the management of overdose are continually evolving, it is advisable to contact a Certified Poison Control Center to determine the latest recommendations for the management of an overdose of any drug.
- One overdose of 7200 mg/day BANZEL was reported in an adult during the clinical trials. The overdose was associated with no major signs or symptoms, no medical intervention was required, and the patient continued in the study at the target dose.
### Management
- There is no specific antidote for overdose with BANZEL. If clinically indicated, elimination of unabsorbed drug should be attempted by induction of emesis or gastric lavage. Usual precautions should be observed to maintain the airway. General supportive care of the patient is indicated including monitoring of vital signs and observation of the clinical status of the patient.
- Hemodialysis: Standard hemodialysis procedures may result in limited clearance of rufinamide. Although there is no experience to date in treating overdose with hemodialysis, the procedure may be considered when indicated by the patient's clinical state.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Rufinamide in the drug label.
# Pharmacology
## Mechanism of Action
- The precise mechanism(s) by which rufinamide exerts its antiepileptic effect is unknown.
- The results of in vitro studies suggest that the principal mechanism of action of rufinamide is modulation of the activity of sodium channels and, in particular, prolongation of the inactive state of the channel. Rufinamide (≥1 μM) significantly slowed sodium channel recovery from inactivation after a prolonged prepulse in cultured cortical neurons, and limited sustained repetitive firing of sodium-dependent action potentials (EC50 of 3.8 μM).
## Structure
- BANZEL (rufinamide) is a triazole derivative structurally unrelated to currently marketed antiepileptic drugs (AEDs). Rufinamide has the chemical name 1-[(2,6-difluorophenyl)methyl]-1H-1,2,3-triazole-4 carboxamide. It has an empirical formula of C10H8F2N4O and a molecular weight of 238.2. The drug substance is a white, crystalline, odorless and slightly bitter tasting neutral powder. Rufinamide is practically insoluble in water, slightly soluble in tetrahydrofuran and in methanol, and very slightly soluble in ethanol and in acetonitrile.
- BANZEL is available for oral administration in film-coated tablets, scored on both sides, containing 200 and 400 mg of rufinamide. Inactive ingredients are colloidal silicon dioxide, corn starch, crosscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulphate. The film coating contains hypromellose, iron oxide red, polyethylene glycol, talc, and titanium dioxide.
- BANZEL is also available for oral administration as a liquid containing rufinamide at a concentration of 40 mg/mL. Inactive ingredients include microcrystalline cellulose and carboxymethylcellulose sodium, hydroxyethylcellulose, anhydrous citric acid, simethicone emulsion 30%, poloxamer 188, methylparaben, propylparaben, propylene glycol, potassium sorbate, noncrystallizing sorbitol solution 70%, and an orange flavor.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Rufinamide in the drug label.
## Pharmacokinetics
- BANZEL oral suspension is bioequivalent on a mg per mg basis to BANZEL tablets. BANZEL is well absorbed after oral administration. However, the rate of absorption is relatively slow and the extent of absorption is decreased as dose is increased. The pharmacokinetics does not change with multiple dosing. Most elimination of rufinamide is via metabolism, with the primary metabolite resulting from enzymatic hydrolysis of the carboxamide moiety to form the carboxylic acid. This metabolic route is not cytochrome P450 dependent. There are no known active metabolites. Plasma half-life of rufinamide is approximately 6-10 hours.
- Absorption and Distribution
- Following oral administration of BANZEL, peak plasma concentrations occur between 4 and 6 hours (Tmax) both under fed and fasted conditions. BANZEL tablets display decreasing bioavailability with increasing dose after single and multiple dose administration. Based on urinary excretion, the extent of absorption was at least 85% following oral administration of a single dose of 600 mg rufinamide tablet under fed conditions.
- Multiple dose pharmacokinetics can be predicted from single dose data for both rufinamide and its metabolite. Given the dosing frequency of every 12 hours and the half-life of 6 to 10 hours, the observed steady-state peak concentration of about two to three times the peak concentration after a single dose is expected.
- Food increased the extent of absorption of rufinamide in healthy volunteers by 34% and increased peak exposure by 56% after a single dose of 400 mg tablet, although the Tmax was not elevated. Clinical trials were performed under fed conditions and dosing is recommended with food.
- Only a small fraction of rufinamide (34%) is bound to human serum proteins, predominantly to albumin (27%), giving little risk of displacement drug-drug interactions. Rufinamide was evenly distributed between erythrocytes and plasma. The apparent volume of distribution is dependent upon dose and varies with body surface area. The apparent volume of distribution was about 50 L at 3200 mg/day.
- Metabolism
- Rufinamide is extensively metabolized but has no active metabolites. Following a radiolabeled dose of rufinamide, less than 2% of the dose was recovered unchanged in urine. The primary biotransformation pathway is carboxylesterase(s) mediated hydrolysis of the carboxamide group to the acid derivative CGP 47292. A few minor additional metabolites were detected in urine, which appeared to be acyl-glucuronides of CGP 47292. There is no involvement of oxidizing cytochrome P450 enzymes or glutathione in the biotransformation process.
- Rufinamide is a weak inhibitor of CYP 2E1. It did not show significant inhibition of other CYP enzymes. Rufinamide is a weak inducer of CYP 3A4 enzymes.
- Rufinamide did not show any significant inhibition of P-glycoprotein in an in-vitro study.
- Elimination/Excretion
- Renal excretion is the predominant route of elimination for drug related material, accounting for 85% of the dose based on a radiolabeled study. Of the metabolites identified in urine, at least 66% of the rufinamide dose was excreted as the acid metabolite CGP 47292, with 2% of the dose excreted as rufinamide.
- The plasma elimination half-life is approximately 6-10 hours in healthy subjects and patients with epilepsy.
- Special Populations
- Gender: Population pharmacokinetic analyses of females show a 6-14% lower apparent clearance of rufinamide compared to males. This effect is not clinically important.
- Race: In a population pharmacokinetic analysis of clinical studies, no difference in clearance or volume of distribution of rufinamide was observed between the black and Caucasian subjects, after controlling for body size. Information on other races could not be obtained because of smaller numbers of these subjects.
- Pediatrics: Based on a population analysis in 117 children (age 4-11 years) and 99 adolescents (age 12-17 years), the pharmacokinetics of rufinamide in these patients is similar to the pharmacokinetics in adults.
- Elderly: The results of a study evaluating single-dose (400 mg) and multiple dose (800 mg/day for 6 days) pharmacokinetics of rufinamide in 8 healthy elderly subjects (65-80 years old) and 7 younger healthy subjects (18-45 years old) found no significant age-related differences in the pharmacokinetics of rufinamide.
- Renal Impairment: Rufinamide pharmacokinetics in 9 patients with severe renal impairment (creatinine clearance < 30 mL/min) was similar to that of healthy subjects. Patients undergoing dialysis 3 hours post rufinamide dosing showed a reduction in AUC and Cmax by 29% and 16% respectively. Adjusting rufinamide dose for the loss of drug upon dialysis should be considered.
- Hepatic Impairment: There have been no specific studies investigating the effect of hepatic impairment on the pharmacokinetics of rufinamide. Therefore, use in patients with severe hepatic impairment is not recommended. Caution should be exercised in treating patients with mild to moderate hepatic impairment.
## Nonclinical Toxicology
- Carcinogenesis: Rufinamide was given in the diet to mice at 40, 120, and 400 mg/kg/day and to rats at 20, 60, and 200 mg/kg/day for two years. The doses in mice were associated with plasma AUCs 0.1 to 1 times the human plasma AUC at the maximum recommended human dose (MRHD, 3200 mg/day). Increased incidences of tumors (benign bone tumors (osteomas) and/or hepatocellular adenomas and carcinomas) were observed in mice at all doses. Increased incidences of thyroid follicular adenomas were observed in rats at all but the low dose; the low dose is < 0.1 times the MRHD on a mg/m2 basis.
- Mutagenesis: Rufinamide was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay or the in vitro mammalian cell point mutation assay. Rufinamide was not clastogenic in the in vitro mammalian cell chromosomal aberration assay or the in vivo rat bone marrow micronucleus assay.
- Impairment of Fertility: Oral administration of rufinamide (doses of 20, 60, 200, and 600 mg/kg/day) to male and female rats prior to mating and throughout mating, and continuing in females up to day 6 of gestation resulted in impairment of fertility (decreased conception rates and mating and fertility indices; decreased numbers of corpora lutea, implantations, and live embryos; increased preimplantation loss; decreased sperm count and motility) at all doses tested. Therefore, a no-effect dose was not established. The lowest dose tested was associated with a plasma AUC ≈0.2 times the human plasma AUC at the MRHD.
# Clinical Studies
- The effectiveness of BANZEL as adjunctive treatment for the seizures associated with Lennox-Gastaut Syndrome (LGS) was established in a single multicenter, double-blind, placebo-controlled, randomized, parallel-group study (N=138). Male and female patients (between 4 and 30 years of age) were included if they had a diagnosis of inadequately controlled seizures associated with LGS (including both atypical absence seizures and drop attacks) and were being treated with 1 to 3 concomitant stable dose AEDs. Each patient must have had at least 90 seizures in the month prior to study entry. After completing a 4 week Baseline Phase on stable therapy, patients were randomized to have BANZEL or placebo added to their ongoing therapy during the 12 week Double-blind Phase. The Double-blind Phase consisted of 2 periods: the Titration Period (1 to 2 weeks) and the Maintenance Period (10 weeks). During the Titration Period, the dose was increased to a target dosage of approximately 45 mg/kg/day (3200 mg in adults of ≥ 70 kg), given on a b.i.d. schedule. Dosage reductions were permitted during titration if problems in tolerability were encountered. Final doses at titration were to remain stable during the maintenance period. Target dosage was achieved in 88% of the BANZEL-treated patients. The majority of these patients reached the target dose within 7 days, with the remaining patients achieving the target dose within 14 days.
- The primary efficacy variables were:
- The percent change in total seizure frequency per 28 days;
- The percent change in tonic-atonic (drop attacks) seizure frequency per 28 days;
- Seizure severity from the Parent/Guardian Global Evaluation of the patient's condition. This was a 7-point assessment performed at the end of the Double-blind Phase. A score of +3 indicated that the patient's seizure severity was very much improved, a score of 0 that the seizure severity was unchanged, and a score of -3 that the seizure severity was very much worse.
- The results of the three primary endpoints are shown in Table 7 below.
# How Supplied
- BANZEL 200 mg tablets (containing 200 mg rufinamide) are pink in color, film-coated, oblong-shape tablets, with a score on both sides, imprinted with "Є 262" on one side. They are available in bottles of 120 (NDC 62856-582-52).
- BANZEL 400 mg tablets (containing 400 mg rufinamide) are pink in color, film-coated, oblong-shape tablets, with a score on both sides, imprinted with "Є 263" on one side. They are available in bottles of 120 (NDC 62856-583-52).
- BANZEL Oral Suspension is an orange flavored liquid supplied in a polyethylene terephthalate (PET) bottle with child-resistant closure. The oral suspension is packaged with a dispenser set which contains a calibrated oral dosing syringe and an adapter. Store the oral suspension in an upright position. Use within 90 days of first opening the bottle, then discard any remainder. The oral suspension is available in bottles of 460 mL (NDC 62856-584-46).
- Store the tablets at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F). Protect from moisture. Replace cap securely after opening.
- Store the oral suspension at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F). Replace cap securely after opening. The cap fits properly in place when the adapter is in place.
## Storage
There is limited information regarding Rufinamide Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients should be informed of the availability of a Medication guide and they should be instructed to read the Medication Guide prior to taking BANZEL.
- Patients should be instructed to take BANZEL only as prescribed.
- Suicidal Thinking and Behavior
- Patients, their caregivers, and families should be informed that antiepileptic drugs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.
- As with all centrally acting medications, alcohol in combination with BANZEL may cause additive central nervous system effects.
- Patients should be advised to notify their physician if they experience a rash associated with fever.
- BANZEL should be taken with food.
- Patients should be advised about the potential for somnolence or dizziness and advised not to drive or operate machinery until they have gained sufficient experience on BANZEL to gauge whether it adversely affects their mental and/or motor performance.
- Female patients of childbearing age should be warned that the concurrent use of BANZEL with hormonal contraceptives may render this method of contraception less effective. Additional non-hormonal forms of contraception are recommended when using BANZEL.
- Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy. They should also be encouraged to enroll in the North American Antiepileptic Drug Pregnancy Registry if they become pregnant. To enroll, patients can call the toll free number 1-888-233-2334.
- Patients should be advised to notify their physician if they are breast-feeding or intend to breast-feed.
- Patients who are prescribed the oral suspension should be advised to shake the bottle vigorously before every administration and to use the adaptor and oral dosing syringe.
- When applicable patients should be advised that BANZEL oral suspension does not contain lactose or gluten and is dye-free. The oral suspension does contain carbohydrates.
# Precautions with Alcohol
- Alcohol-Rufinamide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- BANZEL®[1]
# Look-Alike Drug Names
There is limited information regarding Rufinamide Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Rufinamide | |
d0609737c92a99c2a614e17e951bd53d509b9be2 | wikidoc | Rupatadine | Rupatadine
# Overview
Rupatadine is a second generation antihistamine and PAF antagonist used to treat allergies. It was discovered and developed by J. Uriach y Cia, S. A. and is marketed under several trade names such as Rupafin, Alergoliber, Rinialer, Pafinur, Rupax and Ralif.
# Therapeutic indications approved
Rupatadine fumarate has been approved for the treatment of allergic rhinitis and chronic urticaria in adults and children over 12 years. The defined daily dose (DDD) is 10 mg orally.
## Available form
Rupatadine is available as round, light salmon coloured tablets containing 10 mg of rupatadine (as fumarate) to be administered orally, once a day.
# Side effects
Rupatadine is a non-sedating antihistamine. However, as in other non sedating second-generation antihistamines, the most common side effects in controlled clinical studies were somnolence, headaches and fatigue.
# Mechanism of action
Rupatadine is a second generation, non-sedating, long-acting histamine antagonist with selective peripheral H1 receptor antagonist activity. It further blocks the receptors of the platelet-activating factor (PAF) according to in vitro and in vivo studies.
Rupatadine possesses anti-allergic properties such as the inhibition of the degranulation of mast cells induced by immunological and non-immunological stimuli, and inhibition of the release of cytokines, particularly of the TNF in human mast cells and monocytes.
# Pharmacokinetics
Rupatadine has several active metabolites such as desloratadine, 3-hydroxydesloratadine, 6-hydroxydesloratadine and 5-hydroxydesloratadine.
# History
Rupatadine discovery, pre-clinical and clinical development was performed by J. Uriach y Cia, S. A., a Spanish pharmaceutical company. It was launched in 2003 in Spain by J. Uriach y Cia, S. A., with the brand name of Rupafin. The registration of the product is approved in 23 countries from the EU, 8 Central American countries, Brazil, Argentina, Chile, Turkey and 14 African countries.
# Efficacy in humans
The efficacy of rupatadine as treatment for allergic rhinitis (AR) and chronic idiopathic urticaria (CIU) has been investigated in adults and adolescents (aged over 12 years) in several controlled studies, showing a rapid onset of action and a good safety profile even in prolonged treatment periods of a year. | Rupatadine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Rupatadine is a second generation antihistamine and PAF antagonist used to treat allergies. It was discovered and developed by J. Uriach y Cia, S. A.[1] and is marketed under several trade names such as Rupafin, Alergoliber, Rinialer, Pafinur, Rupax and Ralif.
# Therapeutic indications approved
Rupatadine fumarate has been approved for the treatment of allergic rhinitis and chronic urticaria in adults and children over 12 years. The defined daily dose (DDD) is 10 mg orally.
## Available form
Rupatadine is available as round, light salmon coloured tablets containing 10 mg of rupatadine (as fumarate) to be administered orally, once a day.
# Side effects
Rupatadine is a non-sedating antihistamine. However, as in other non sedating second-generation antihistamines, the most common side effects in controlled clinical studies were somnolence, headaches and fatigue.
# Mechanism of action
Rupatadine is a second generation, non-sedating, long-acting histamine antagonist with selective peripheral H1 receptor antagonist activity. It further blocks the receptors of the platelet-activating factor (PAF) according to in vitro and in vivo studies.[2]
Rupatadine possesses anti-allergic properties such as the inhibition of the degranulation of mast cells induced by immunological and non-immunological stimuli, and inhibition of the release of cytokines, particularly of the TNF in human mast cells and monocytes.[3]
# Pharmacokinetics
Rupatadine has several active metabolites such as desloratadine, 3-hydroxydesloratadine, 6-hydroxydesloratadine and 5-hydroxydesloratadine.
# History
Rupatadine discovery, pre-clinical and clinical development was performed by J. Uriach y Cia, S. A., a Spanish pharmaceutical company. It was launched in 2003 in Spain by J. Uriach y Cia, S. A., with the brand name of Rupafin. The registration of the product is approved in 23 countries from the EU, 8 Central American countries, Brazil, Argentina, Chile, Turkey and 14 African countries.
# Efficacy in humans
The efficacy of rupatadine as treatment for allergic rhinitis (AR) and chronic idiopathic urticaria (CIU) has been investigated in adults and adolescents (aged over 12 years) in several controlled studies, showing a rapid onset of action and a good safety profile even in prolonged treatment periods of a year.[3][4][5] | https://www.wikidoc.org/index.php/Rupatadine | |
d87f40e1ed2c88125f1d63d6515eeb4b84b55452 | wikidoc | SCAT Trial | SCAT Trial
# Objective
To assess the effects of cholesterol lowering and angiotensin-converting enzyme inhibition on coronary atherosclerosis in normocholesterolemic patients.
# Methods
The Simvastatin/Enalapril Coronary Atherosclerosis Trial (SCAT) was a multicentered, randomized, double blinded, placebo-controlled angiographic trial wherein a total of 460 normocholesterolemic patients were enrolled. 230 received simvastatin, 230 a simvastatin placebo, 229 enalapril and 231 an enalapril placebo. All the patients were followed up for an average time period of 47.8 months.
# Results
Less progression was observed in patients receiving simvastatin compared to those receiving placebo. On quantitative coronary angiography the change in mean diameter, minimum diameter, percentage stenosis and the need for angioplasty was less with simvastatin. No additional benefit was observed with enalapril therapy. | SCAT Trial
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Objective
To assess the effects of cholesterol lowering and angiotensin-converting enzyme inhibition on coronary atherosclerosis in normocholesterolemic patients.
# Methods
The Simvastatin/Enalapril Coronary Atherosclerosis Trial (SCAT) was a multicentered, randomized, double blinded, placebo-controlled angiographic trial wherein a total of 460 normocholesterolemic patients were enrolled. 230 received simvastatin, 230 a simvastatin placebo, 229 enalapril and 231 an enalapril placebo. All the patients were followed up for an average time period of 47.8 months.
# Results
Less progression was observed in patients receiving simvastatin compared to those receiving placebo. On quantitative coronary angiography the change in mean diameter, minimum diameter, percentage stenosis and the need for angioplasty was less with simvastatin. No additional benefit was observed with enalapril therapy.[1][2][3] | https://www.wikidoc.org/index.php/SCAT_Trial | |
8ff90b41229015dfee0324388d55d855669051fa | wikidoc | SCM Pharma | SCM Pharma
SCM Pharma was set up to offer specialist manufacturing services - custom designed and adapted to meet specific client requirements, particularly if these involve bespoke needs, short runs or unusual processes products and devices. Their offering is tailored to meet the production demands of formulation development, clinical investigations and commercially available products in niche and low volume markets e.g. orphan drugs and paediatrics.
SCM Pharma is an independently-owned contract development and manufacturing organisation (CDMO) spun-out from The Specials Laboratory, which is an acknowledged leader in the field of unlicensed medicine manufacturing in the UK with an enviable reputation for providing outstanding levels of service and quality products.
Having started life as Specials Clinical Manufacturing, the sister-company to The Specials Laboratory back in 2004, SCM Pharma became its own entity following the sale of The Specials Lab in November 2008. | SCM Pharma
Template:Infobox Company
SCM Pharma was set up to offer specialist manufacturing services - custom designed and adapted to meet specific client requirements, particularly if these involve bespoke needs, short runs or unusual processes products and devices. Their offering is tailored to meet the production demands of formulation development, clinical investigations and commercially available products in niche and low volume markets e.g. orphan drugs and paediatrics.
SCM Pharma is an independently-owned contract development and manufacturing organisation (CDMO) spun-out from The Specials Laboratory, which is an acknowledged leader in the field of unlicensed medicine manufacturing in the UK with an enviable reputation for providing outstanding levels of service and quality products.
Having started life as Specials Clinical Manufacturing, the sister-company to The Specials Laboratory back in 2004, SCM Pharma became its own entity following the sale of The Specials Lab in November 2008.
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/SCM_Pharma | |
614d885ed9ab758adec9697b344a260f41de9bc0 | wikidoc | SF1 (gene) | SF1 (gene)
Splicing factor 1 also known as zinc finger protein 162 (ZFM162) is a protein that in humans is encoded by the SF1 gene.
Splicing factor SF1 is involved in the ATP-dependent formation of the spliceosome complex.SF1 gene is necessary to make the bipotential gonad ; but while SF1 levels decline in the genital ridge of XX mouse embryos,the SF1 gene stays on the developing testes. SF 1 (transcription factor) appears to be active in masculining both the Leydig cells and Steroli cells. In Sterolic cells with the SOX9 protein it elevates the level of AMH transcription. In Leydig cells it activates the gene encoding the enzyme that make testosterone hormone.
# Interactions
SF1 (gene) has been shown to interact with Ewing sarcoma breakpoint region 1, U2AF2, Testis determining factor, and Transcription elongation regulator 1. | SF1 (gene)
Splicing factor 1 also known as zinc finger protein 162 (ZFM162) is a protein that in humans is encoded by the SF1 gene.[1][2][3]
Splicing factor SF1 is involved in the ATP-dependent formation of the spliceosome complex.[4]SF1 gene is necessary to make the bipotential gonad ; but while SF1 levels decline in the genital ridge of XX mouse embryos,the SF1 gene stays on the developing testes. SF 1 (transcription factor) appears to be active in masculining both the Leydig cells and Steroli cells. In Sterolic cells with the SOX9 protein it elevates the level of AMH transcription. In Leydig cells it activates the gene encoding the enzyme that make testosterone hormone.
# Interactions
SF1 (gene) has been shown to interact with Ewing sarcoma breakpoint region 1,[5] U2AF2,[6][7][8] Testis determining factor,[9] and Transcription elongation regulator 1.[10] | https://www.wikidoc.org/index.php/SF1_(gene) | |
9e1adf40b4b57bde0689b9db0e6c6bdf6ac260ce | wikidoc | SH2 domain | SH2 domain
The Src homology 2 domain (or SH2 domain) is a protein domain of about 100 amino acid residues first identified as a conserved sequence region among the oncoproteins Src and Fps.
Similar sequences were later found in many other intracellular proteins involved in signal transduction, such as Abl, ZAP70, STAT proteins,Grb2, and RasGAP.
# Binding and phosphorylation
SH2 domains typically bind a phosphorylated tyrosine residue in the context of a longer peptide motif within a target proteins, and SH2 domains represent the largest class of known pTyr-recognition domains.
Phosphorylation of tyrosine residues in a protein occurs during signal transduction and is carried out by tyrosine kinases. In this way, phosphorylation of a substrate by tyrosine kinases acts as a switch to trigger binding to an SH2 domain-containing protein. The intimate relationship between tyrosine kinases and SH2 domains is supported by their coordinate emergence during eukaryotic evolution.
# Diversity
SH2 domains are not present in yeast and appear at the boundary between protozoa and animalia in organisms such as the social amoeba Dictyostelium discoideum.
A detailed bioinformatic examination of SH2 domains of human and mouse reveals 120 SH2 domains contained within 110 proteins encoded by the human genome, representing a rapid rate of evolutionary expansion among the SH2 domains.
A large number of SH2 domain structures have been solved and many SH2 proteins have been knocked out in mouse.
Proteins with SH2 domains include:
- Abl
- GRB2
- RasGAP
- STAT proteins
- ZAP70
- SHP2
- PI3K
- Phospholipase C γ form
- CRK
- SOCS
- Src
# Functions
Many biological signaling proteins use this mode of regulated protein-protein interactions as a means to localize proteins to various sub-cellular compartments, control enzymatic activities of proteins as well as nucleate multiprotein complexes, to name a few.
The SH2 domain has thus become a prototype for a large number of modular interaction domains that have been since identified.
The discovery of the SH2 domain and its many roles in signal transduction introduced the critical concept of how biology has exploited the use of modular interaction domains to create complex signaling networks. | SH2 domain
The Src homology 2 domain (or SH2 domain) is a protein domain of about 100 amino acid residues first identified as a conserved sequence region among the oncoproteins Src and Fps.
Similar sequences were later found in many other intracellular proteins involved in signal transduction, such as Abl, ZAP70, STAT proteins,Grb2, and RasGAP.
# Binding and phosphorylation
SH2 domains typically bind a phosphorylated tyrosine residue in the context of a longer peptide motif within a target proteins, and SH2 domains represent the largest class of known pTyr-recognition domains[1].
Phosphorylation of tyrosine residues in a protein occurs during signal transduction and is carried out by tyrosine kinases. In this way, phosphorylation of a substrate by tyrosine kinases acts as a switch to trigger binding to an SH2 domain-containing protein. The intimate relationship between tyrosine kinases and SH2 domains is supported by their coordinate emergence during eukaryotic evolution.
# Diversity
SH2 domains are not present in yeast and appear at the boundary between protozoa and animalia in organisms such as the social amoeba Dictyostelium discoideum[2].
A detailed bioinformatic examination of SH2 domains of human and mouse reveals 120 SH2 domains contained within 110 proteins encoded by the human genome[3], representing a rapid rate of evolutionary expansion among the SH2 domains.
A large number of SH2 domain structures have been solved and many SH2 proteins have been knocked out in mouse.[4]
Proteins with SH2 domains include:
- Abl
- GRB2
- RasGAP
- STAT proteins
- ZAP70
- SHP2
- PI3K
- Phospholipase C γ form
- CRK
- SOCS
- Src
# Functions
Many biological signaling proteins use this mode of regulated protein-protein interactions as a means to localize proteins to various sub-cellular compartments, control enzymatic activities of proteins as well as nucleate multiprotein complexes, to name a few.
The SH2 domain has thus become a prototype for a large number of modular interaction domains that have been since identified.
The discovery of the SH2 domain and its many roles in signal transduction introduced the critical concept of how biology has exploited the use of modular interaction domains to create complex signaling networks. | https://www.wikidoc.org/index.php/SH2_domain | |
30b0d56a8195c3f9c0ffa3874059902a00244fb0 | wikidoc | SL-651,498 | SL-651,498
SL-651,498 is an anxiolytic and anticonvulsant drug used in scientific research, with a chemical structure most closely related to β-carboline derivatives such as abecarnil and gedocarnil. It has similar effects to benzodiazepine drugs, but is structurally distinct and so is classed as a nonbenzodiazepine anxiolytic.
SL-651,498 is a subtype-selective GABAA agonist, which acts as a full agonist at α2 and α3 subtypes, and as a partial agonist at α1 and α5 (although its action at α5 subtypes is much weaker than at the others). In animal studies, it has primarily anxiolytic effects, although some sedation, ataxia and muscle relaxant effects are observed at higher doses. It substitutes fully for the anxiolytic benzodiazepine chlordiazepoxide, but only partially substituted for the imidazopyridine hypnotic drug zolpidem and the benzodiazepine hypnotic triazolam. When given repeatedly it failed to produce tolerance or dependence, probably due to its low affinity and efficacy at the α5 subtype.
SL-651,498 has been suggested for development as a novel non-sedating anxiolytic drug for humans, however it has not yet been developed for this use and is currently used only in animal research. | SL-651,498
SL-651,498 is an anxiolytic and anticonvulsant drug used in scientific research, with a chemical structure most closely related to β-carboline derivatives such as abecarnil and gedocarnil.[1] It has similar effects to benzodiazepine drugs, but is structurally distinct and so is classed as a nonbenzodiazepine anxiolytic.
SL-651,498 is a subtype-selective GABAA agonist, which acts as a full agonist at α2 and α3 subtypes, and as a partial agonist at α1 and α5 (although its action at α5 subtypes is much weaker than at the others). In animal studies, it has primarily anxiolytic effects, although some sedation, ataxia and muscle relaxant effects are observed at higher doses.[2] It substitutes fully for the anxiolytic benzodiazepine chlordiazepoxide, but only partially substituted for the imidazopyridine hypnotic drug zolpidem and the benzodiazepine hypnotic triazolam.[3][4] When given repeatedly it failed to produce tolerance or dependence, probably due to its low affinity and efficacy at the α5 subtype.[5]
SL-651,498 has been suggested for development as a novel non-sedating anxiolytic drug for humans, however it has not yet been developed for this use and is currently used only in animal research.[6]
Template:Pharmacology-stub | https://www.wikidoc.org/index.php/SL-651,498 | |
a6de294a396ebc3ed2158b4018478dc684ac4490 | wikidoc | SMS (gene) | SMS (gene)
Spermine synthase is an enzyme that in humans is encoded by the SMS gene.
The protein encoded by this gene belongs to the spermidine/spermine synthases family. This gene encodes a ubiquitous enzyme of polyamine metabolism.
# Model organisms
Model organisms have been used in the study of SMS function. A conditional knockout mouse line, called Smstm1a(EUCOMM)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty three tests were carried out on mutant mice and six significant abnormalities were observed. Hemizygous males were infertile and thus it was not possible to produce homozygous mutant female mice. The remaining tests were therefore carried out on heterozygous mutant females and hemizygous males. Both displayed decreased grip strength while the males also had decreased body weight, length, bone mineral content and atypical peripheral blood lymphocyte counts. | SMS (gene)
Spermine synthase is an enzyme that in humans is encoded by the SMS gene.[1][2][3]
The protein encoded by this gene belongs to the spermidine/spermine synthases family. This gene encodes a ubiquitous enzyme of polyamine metabolism.[3]
# Model organisms
Model organisms have been used in the study of SMS function. A conditional knockout mouse line, called Smstm1a(EUCOMM)Wtsi[12][13] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[14][15][16]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[10][17] Twenty three tests were carried out on mutant mice and six significant abnormalities were observed.[10] Hemizygous males were infertile and thus it was not possible to produce homozygous mutant female mice. The remaining tests were therefore carried out on heterozygous mutant females and hemizygous males. Both displayed decreased grip strength while the males also had decreased body weight, length, bone mineral content and atypical peripheral blood lymphocyte counts.[10] | https://www.wikidoc.org/index.php/SMS_(gene) | |
6b43f0a861cee2fa2052ff72ce6579bdceb954ce | wikidoc | SOFA score | SOFA score
# Overview
The Sequential Organ Failure Assessment score, or just SOFA score, is used to track a patient's status during the stay in an intensive care unit (ICU). It is one of several ICU scoring systems.
The SOFA score is a scoring system to determine the extent of a person's organ function or rate of failure. The score is based on six different scores, one each for the respiratory, cardiovascular, hepatic, coagulation, renal and neurological systems.
# Respiratory System
PaO2/FiO2 (mmHg), SOFA score
< 200 and mechanically ventilated, 3
< 100 and mechanically ventilated, 4
# Nervous System
Glasgow coma score, SOFA score
# Cardio Vascular System
Mean Arterial Pressure OR administration of vasopressors required, SOFA score
MAP < 70 mm/Hg, 1
dop <= 5 or dob (any dose), 2
dop > 5 OR epi <= 0.1 OR nor <= 0.1, 3
dop > 15 OR epi > 0.1 OR nor > 0.1, 4
(vasopressor drug doses are in mcg/kg/min)
# Liver
Bilirubin (mg/dl), SOFA score
# Coagulation
Platelets×103/mcl, SOFA score
# Renal System
Creatinine (mg/dl) (or urine output), SOFA score
3.5 – 4.9 (or < 500 ml/d), 3
5.0 (or < 200 ml/d), 4 | SOFA score
# Overview
The Sequential Organ Failure Assessment score, or just SOFA score, is used to track a patient's status during the stay in an intensive care unit (ICU). It is one of several ICU scoring systems.
The SOFA score is a scoring system to determine the extent of a person's organ function or rate of failure. The score is based on six different scores, one each for the respiratory, cardiovascular, hepatic, coagulation, renal and neurological systems.
# Respiratory System
PaO2/FiO2 (mmHg), SOFA score
< 400, 1
< 300, 2
< 200 and mechanically ventilated, 3
< 100 and mechanically ventilated, 4
# Nervous System
Glasgow coma score, SOFA score
13 – 14, 1
10 – 12, 2
6 – 9, 3
< 6, 4
# Cardio Vascular System
Mean Arterial Pressure OR administration of vasopressors required, SOFA score
MAP < 70 mm/Hg, 1
dop <= 5 or dob (any dose), 2
dop > 5 OR epi <= 0.1 OR nor <= 0.1, 3
dop > 15 OR epi > 0.1 OR nor > 0.1, 4
(vasopressor drug doses are in mcg/kg/min)
# Liver
Bilirubin (mg/dl), SOFA score
1.2 – 1.9, 1
2.0 – 5.9, 2
6.0 – 11.9, 3
> 12.0, 4
# Coagulation
Platelets×103/mcl, SOFA score
< 150, 1
< 100, 2
< 50, 3
< 20, 4
# Renal System
Creatinine (mg/dl) (or urine output), SOFA score
1.2 – 1.9, 1
2.0 – 3.4, 2
3.5 – 4.9 (or < 500 ml/d), 3
> 5.0 (or < 200 ml/d), 4 | https://www.wikidoc.org/index.php/SOFA_score | |
96b484c3948991387d979f1f7abf5109f9c0614e | wikidoc | SON (gene) | SON (gene)
SON protein is a protein that in humans is encoded by the SON gene.
SON is the name that has been given to a large Ser/Arg (SR)-related protein, which is a splicing co-factor that contributes to an efficient splicing within cell cycle progression. It is also known as BASS1 (Bax antagonist selected in saccharomyces 1) or NRE-binding protein (Negative regulatory element-binding protein). The most common gene name of this splicing protein- which is only found in Humans (Homo sapiens)- is SON, but C21orf50, DBP5, KIAA1019 and NREBP can also be used as synonyms.
The protein encoded by SON gene binds to a specific DNA sequence upstream of the upstream regulatory sequence of the core promoter and second enhancer of human hepatitis B virus (HBV). Through this binding, it represses HBV core promoter activity, transcription of HBV genes, and production of HBV virions. The protein shows sequence similarities with other DNA-binding structural proteins such as gallin, oncoproteins of the MYC family, and the oncoprotein MOS. It may also be involved in protecting cells from apoptosis and in pre-mRNA splicing. Mutation in SON gene is associated with ZTTK syndrome.
# Structure
The sequence length of the SON protein consists in 2426 aminoacids and its sequence status is totally completed. Its molecular weight is 263,830 Daltons (Da) and its domain contains 8 types of repeats which are distributed in 3 regions. This protein is found in the 21st chromosome and is mostly located in nuclear speckles. Its higher expression is seen in leukocyte and heart cells.
# Splicing process
SON protein is essential for maintaining the subnuclear organization of the factors that are processed in the nucleus highlighting its direct role in pre-mRNA splicing.
Splicing is known as the process within the maturation of the pre-RNAm takes place. The pre-RNAm which has just been transcript has sequences called introns and exons. Introns are non-active nucleotide sequences that have to be removed in order the exons (active sequences) to get joined. This process must be very controlled. The splicing takes place in the spliceosome, a complex that brings together a pre-RNAm and a variety of the binding proteins. These proteins together with the splicing factors (which are not found in the spliceosome) are in charge of recognizing the intron’s branch point sequence. The SON protein is known to be one of these binding proteins.
Although there is a lack of knowledge about its exact splicing control in the progression of the cell cycle and it has remained largely unexplored, it’s certain that this splicing-associated protein is necessary for the maintenance of the embryonic stem cells because it influences the splicing of pluripotency regulators.
SON plays an important role in the mRNA processing. Nevertheless, this process is still a little uncertain and this is why in a future it will be interesting to understand how exactly this protein interacts with the spliceosomal complex, its exact molecular function in the context of splicing. Not only the SON protein interferes in the splicing but also makes complex mechanisms such as the RNA post-transcriptional to cooperate with the splicing-mRNA processing.
Human embryonic stem cells are able to undergo the process of differentiation into specific and relevant cells. To maintain the pluripotency of the embryonic stem cells, transcription factors and epigenetic modifiers play an important role despite the fact that little is known about the regulation of pluripotency throughout the process of splicing. The factor SON is identified as essential for the maintenance of this pluripotency. It is confirmed that SON regulates the splicing process of transcripts (RNAm) that will encode the gens that are going to regulate the pluripotency of the embryonic human cells.
# Function
On the one hand, SON protein is required to maintain the genome stability in order to ensure an efficient RNA processing of affected genes. It also facilitates the interaction of SR proteins with RNA polymerase II and is required for processing of weak constitutive splice sites, having also strong implications in cancer and other human diseases.
On the other side, a deficiency or knockdown of SON protein causes various and severe defects in mitotic division arrangement, chromosome alignment and microtubule dynamics when spindle pole separation takes place.
But as we could read in the article called “SON protein regulates GATA-2 through transcriptional control of the microRNA 23a-27-24-a clúster”, SON protein has even more functions in the organism. It has been found that these proteins may regulate the hematopoietic cells differentiation. They have a specific job in hematopoietic process, which is based on activating other proteins called GATA. As these ones are finally activated, the cell differentiation starts normally.
# Clinical significance
A recent study suggested that SON may be a novel therapeutic molecular target for pancreatic cancer as the results of a recent study show that this protein is very important as far as proliferation, survival and tumorigenicity of cancer cells are concerned. Specifically, these results revealed that the serine-arginine-rich protein involved in the RNA splicing process, could suppress pancreatic cell tumorigenicity. | SON (gene)
SON protein is a protein that in humans is encoded by the SON gene.[1][2]
SON is the name that has been given to a large Ser/Arg (SR)-related protein, which is a splicing co-factor that contributes to an efficient splicing within cell cycle progression.[3] It is also known as BASS1 (Bax antagonist selected in saccharomyces 1) or NRE-binding protein (Negative regulatory element-binding protein). The most common gene name of this splicing protein- which is only found in Humans (Homo sapiens)- is SON, but C21orf50, DBP5, KIAA1019 and NREBP can also be used as synonyms.[4]
The protein encoded by SON gene binds to a specific DNA sequence upstream of the upstream regulatory sequence of the core promoter and second enhancer of human hepatitis B virus (HBV). Through this binding, it represses HBV core promoter activity, transcription of HBV genes, and production of HBV virions. The protein shows sequence similarities with other DNA-binding structural proteins such as gallin, oncoproteins of the MYC family, and the oncoprotein MOS. It may also be involved in protecting cells from apoptosis and in pre-mRNA splicing.[2] Mutation in SON gene is associated with ZTTK syndrome.[5]
# Structure
The sequence length of the SON protein consists in 2426 aminoacids and its sequence status is totally completed. Its molecular weight is 263,830 Daltons (Da) and its domain contains 8 types of repeats which are distributed in 3 regions. This protein is found in the 21st chromosome and is mostly located in nuclear speckles. Its higher expression is seen in leukocyte and heart cells.[4][6]
# Splicing process
SON protein is essential for maintaining the subnuclear organization of the factors that are processed in the nucleus highlighting its direct role in pre-mRNA splicing.[7][page needed]
Splicing is known as the process within the maturation of the pre-RNAm takes place. The pre-RNAm which has just been transcript has sequences called introns and exons. Introns are non-active nucleotide sequences that have to be removed in order the exons (active sequences) to get joined. This process must be very controlled. The splicing takes place in the spliceosome, a complex that brings together a pre-RNAm and a variety of the binding proteins. These proteins together with the splicing factors (which are not found in the spliceosome) are in charge of recognizing the intron’s branch point sequence. The SON protein is known to be one of these binding proteins.[7][page needed]
Although there is a lack of knowledge about its exact splicing control in the progression of the cell cycle and it has remained largely unexplored, it’s certain that this splicing-associated protein is necessary for the maintenance of the embryonic stem cells because it influences the splicing of pluripotency regulators.[3][8]
SON plays an important role in the mRNA processing. Nevertheless, this process is still a little uncertain and this is why in a future it will be interesting to understand how exactly this protein interacts with the spliceosomal complex, its exact molecular function in the context of splicing. Not only the SON protein interferes in the splicing but also makes complex mechanisms such as the RNA post-transcriptional to cooperate with the splicing-mRNA processing.[9]
Human embryonic stem cells are able to undergo the process of differentiation into specific and relevant cells. To maintain the pluripotency of the embryonic stem cells, transcription factors and epigenetic modifiers play an important role despite the fact that little is known about the regulation of pluripotency throughout the process of splicing. The factor SON is identified as essential for the maintenance of this pluripotency. It is confirmed that SON regulates the splicing process of transcripts (RNAm) that will encode the gens that are going to regulate the pluripotency of the embryonic human cells.[10]
# Function
On the one hand, SON protein is required to maintain the genome stability in order to ensure an efficient RNA processing of affected genes. It also facilitates the interaction of SR proteins with RNA polymerase II and is required for processing of weak constitutive splice sites, having also strong implications in cancer and other human diseases.[3][6]
On the other side, a deficiency or knockdown of SON protein causes various and severe defects in mitotic division arrangement, chromosome alignment and microtubule dynamics when spindle pole separation takes place.[3]
But as we could read in the article called “SON protein regulates GATA-2 through transcriptional control of the microRNA 23a-27-24-a clúster”, SON protein has even more functions in the organism. It has been found that these proteins may regulate the hematopoietic cells differentiation. They have a specific job in hematopoietic process, which is based on activating other proteins called GATA. As these ones are finally activated, the cell differentiation starts normally.[11]
# Clinical significance
A recent study suggested that SON may be a novel therapeutic molecular target for pancreatic cancer as the results of a recent study show that this protein is very important as far as proliferation, survival and tumorigenicity of cancer cells are concerned. Specifically, these results revealed that the serine-arginine-rich protein involved in the RNA splicing process, could suppress pancreatic cell tumorigenicity.[9] | https://www.wikidoc.org/index.php/SON_(gene) | |
9e5e017022c6c6bffb8f23237174dbaaf965689b | wikidoc | SVG Images | SVG Images
# What is an .SVG?
A Scalable Vector Graphic (SVG) is an vector image which is constructed through mathematical expressions rather than a bitmap of RBG colors corresponding to each pixel. Because vector images are mathematically defined, they retain their quality no matter the resolution of the monitor on which they are displayed. This means an .SVG image that is displayed at a size of 2 inches will have lines that are just as crisp as an image that is displayed at 4 inches in size. This makes .SVG images ideal for things like text that will be displayed at various sizes. However, because each element of a .SVG image is represented as a mathematical expression, these images are often larger in size than corresponding raster images.
# When Should I Use an .SVG Image?
Vector images, such as an .SVG, are not always appropriate, especially for certain web applications. The following is a list of times when a .SVG may be more appropriate than a .JPG, .GIF, or .PNG:
- High image quality is required for monitors in a large range of resoltion, such as both on an mobile device and a TV display
- The file size is not critical. E.g., for uses where the user is expected to have a strong internet connection.
- The image involves text and will be viewed on various types of displays
- The text within the image needs to be searchable
# How Do I Place an .SVG on a Page?
The following is a list of steps to allow you place an .SVG in a page on WikiDoc:
- To use an .SVG in WikiDoc, you must first upload the image to the WikiDoc server. Note the name the file on the server was given. For example, Help-1.svg
- Go to www.wikidoc.org/index.php?file: E.g., www.wikidoc.org/index.php?file:Help-1.svg
- Right click on the name of the file extension and choose copy link location or link address. The resulting link is the direct link to the image you have uploaded and should be similar to:
- Insert the following code where you would like to place your image
# How Do I Format an .SVG Image? | SVG Images
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# What is an .SVG?
A Scalable Vector Graphic (SVG) is an vector image which is constructed through mathematical expressions rather than a bitmap of RBG colors corresponding to each pixel. Because vector images are mathematically defined, they retain their quality no matter the resolution of the monitor on which they are displayed. This means an .SVG image that is displayed at a size of 2 inches will have lines that are just as crisp as an image that is displayed at 4 inches in size. This makes .SVG images ideal for things like text that will be displayed at various sizes. However, because each element of a .SVG image is represented as a mathematical expression, these images are often larger in size than corresponding raster images.
# When Should I Use an .SVG Image?
Vector images, such as an .SVG, are not always appropriate, especially for certain web applications. The following is a list of times when a .SVG may be more appropriate than a .JPG, .GIF, or .PNG:
- High image quality is required for monitors in a large range of resoltion, such as both on an mobile device and a TV display
- The file size is not critical. E.g., for uses where the user is expected to have a strong internet connection.
- The image involves text and will be viewed on various types of displays
- The text within the image needs to be searchable
# How Do I Place an .SVG on a Page?
The following is a list of steps to allow you place an .SVG in a page on WikiDoc:
- To use an .SVG in WikiDoc, you must first upload the image to the WikiDoc server. Note the name the file on the server was given. For example, Help-1.svg
- Go to www.wikidoc.org/index.php?file:<Insert file name here> E.g., www.wikidoc.org/index.php?file:Help-1.svg
- Right click on the name of the file extension and choose copy link location or link address. The resulting link is the direct link to the image you have uploaded and should be similar to:
- Insert the following code where you would like to place your image
# How Do I Format an .SVG Image? | https://www.wikidoc.org/index.php/SVG_Images | |
03e6a25a0b93a6dd3d63fc3738766e2061c9aea6 | wikidoc | Vigabatrin | Vigabatrin
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Black Box Warning
# Overview
Vigabatrin is a anticonvulsant, gamma aminobutyric acid transaminase inhibitor that is FDA approved for the treatment of refractory complex partial seizures and infantile spams. There is a Black Box Warning for this drug as shown here. Common adverse reactions include weight increased, arthralgia, confusion, coordination problem, memory impairment, somnolence, tremor, blurred vision, diplopia, nystagmus, infection of ear, otitis media, aggressive behavior, dysmenorrhea, bronchitis, upper respiratory infection and fatigue.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Important Dosing Instructions
- Vigabatrin is given orally with or without food. The Vigabatrin dosing regimen depends on the indication, age group, weight, and dosage form (tablets or powder for oral solution). Patients with impaired renal function require dose adjustment.
- Vigabatrin tablets and powder for oral solution are bioequivalent. Either tablet or powder can be used for CPS. Powder for oral solution should be used for IS; tablets should not be used for IS because of difficulty in the administration of tablets to infants and young children.
- Vigabatrin powder for oral solution should be mixed with water prior to administration.
- If using Vigabatrin powder for oral solution, physicians should review and discuss the Medication Guide and instructions for mixing and giving Vigabatrin with the patient or caregiver(s). Physicians should confirm that patients or caregiver(s) understand how to mix Vigabatrin powder with water and administer the correct daily dose. Empty the entire contents of each 500 mg packet into a clean cup, and dissolve in 10 mL of cold or room temperature water per packet (see Table 2). Administer the resulting solution using the 10 mL oral syringe supplied with the medication. The concentration of the final solution is 50 mg/mL. Discard the resulting solution if it is not clear (or free of particles) and colorless. Each individual dose should be prepared and used immediately. Discard any unused portion of the solution after administering the correct dose. Monitoring of Vigabatrin plasma concentrations to optimize therapy is not helpful. If a decision is made to discontinue Vigabatrin, the dose should be gradually reduced
### Refractory Complex Partial Seizures
- Treatment should be initiated at 1000 mg/day (500 mg twice daily). Total daily dose may be increased in 500 mg increments at weekly intervals depending on response. The recommended dose of Vigabatrin in adults is 3000 mg/day (1500 mg twice daily). A 6000 mg/day dose has not been shown to confer additional benefit compared to the 3000 mg/day dose and is associated with an increased incidence of adverse events. In controlled clinical studies in adults with complex partial seizures, Vigabatrin was tapered by decreasing the daily dose 1000 mg/day on a weekly basis until discontinued.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Vigabatrin in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Vigabatrin in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
### Refractory Complex Partial Seizures
- Treatment is based on body weight as shown in Table 1. Treatment should be initiated at a total daily dose of 500 mg/day (250 mg twice daily) and may be increased weekly to a total maintenance dose of 2000 mg/day (1000 mg twice daily). Patients weighing more than 60 kg should be dosed according to adult recommendations.
### Infantile Spasms
- The initial daily dosing is 50 mg/kg/day given in two divided doses; subsequent dosing can be titrated by 25 mg/kg/day to 50 mg/kg/day increments every 3 days up to a maximum of 150 mg/kg/day given in 2 divided doses.
- Table 2 below describes how many packets and how many milliliters (mL) of water will be needed to prepare each individual dose. The concentration after reconstitution is 50 mg/mL.
- Table 3 provides the volume of the 50 mg/mL dosing solution that should be administered as individual doses in infants of various weights.
- In a controlled clinical study in patients with infantile spasms, Vigabatrin was tapered by decreasing the daily dose at a rate of 25 mg/kg to 50 mg/kg every 3 to 4 days
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Vigabatrin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Vigabatrin in pediatric patients.
# Contraindications
- None
# Warnings
- Because of the risk of vision loss, and because, when it is effective, Vigabatrin provides an observable symptomatic benefit, patient response and continued need for treatment should be periodically assessed.
- In patients with refractory complex partial seizures, Vigabatrin should be withdrawn if a substantial clinical benefit is not observed within 3 months of initiating treatment. If, in the clinical judgment of the prescriber, evidence of treatment failure becomes obvious earlier than 3 months, treatment should be discontinued at that time.
- In patients with infantile spasms, Vigabatrin should be withdrawn if a substantial clinical benefit is not observed within 2 to 4 weeks. If, in the clinical judgment of the prescriber, evidence of treatment failure becomes obvious earlier than 2 to 4 weeks, treatment should be discontinued at that time.
- Monitoring of vision by an ophthalmic professional with expertise in visual field interpretation and the ability to perform dilated indirect ophthalmoscopy of the retina is required, unless a patient is formally exempted from periodic ophthalmologic assessment as documented in the Support, Help And Resources for Epilepsy (SHARE) program. Because vision testing in infants is difficult, vision loss may not be detected until it is severe. For patients receiving Vigabatrin who are not exempted, vision assessment is required at baseline (no later than 4 weeks after starting Vigabatrin) and at least every 3 months while on therapy and about 3-6 months after the discontinuation of therapy.
- The diagnostic approach should be individualized for the patient and clinical situation. For all patients, attempts to monitor vision periodically and/or formal exemptions must be documented under the SHARE program. In adults and cooperative pediatric patients, perimetry is recommended, preferably by automated threshold visual field testing. Additional testing may also include electrophysiology (e.g., electroretinography ), retinal imaging (e.g., optical coherence tomography ), and/or other methods appropriate for the patient, but this additional testing is not required. In patients exempted from vision testing, treatment may continue according to clinical judgment, with appropriate patient counseling and with documentation in the SHARE program of the exemption. Because of variability, results from ophthalmic monitoring must be interpreted with caution, and repeat assessment is recommended if results are abnormal or uninterpretable. Repeat assessment in the first few weeks of treatment is recommended to establish if, and to what degree, reproducible results can be obtained, and to guide selection of appropriate ongoing monitoring for the patient.
- The onset and progression of vision loss from Vigabatrin is unpredictable, and it may occur or worsen precipitously between assessments. Once detected, vision loss due to Vigabatrin is not reversible. It is expected that even with frequent monitoring, some Vigabatrin patients will develop severe vision loss. Drug discontinuation should be considered, balancing benefit and risk, if visual loss is documented.
Vigabatrin is available only through a restricted distribution program called the SHARE program, because of the risk of vision loss.
Notable requirements components of the SHARE Program include the following:
- Prescribers must be certified with the program by enrolling and reviewing educational materials and comply with the following:
Assess vision prior to initiating therapy and then every 3 months during therapy.
Remove patients from Vigabatrin therapy if the patients do not experience a meaningful reduction in seizures.
The prescriber may, with appropriate documentation and caregiver counseling, exempt certain patients from vision assessment, using the Ophthalmologic Assessment Form, if:
The patient is blind (subsequent Ophthalmologic Assessment Forms do not need to be submitted to the REMS coordinating center)
The patient’s general neurological and/or mental condition permanently precludes the need for visual assessment (subsequent Ophthalmologic Assessment Forms do not need to be submitted to the REMS coordinating center)
The patient’s general neurological condition temporarily precludes the ability to assess visual function. The evaluation, however, may be performed at a later time as clinically appropriate.
The patient’s medical condition prevents visual assessment being performed safely
For other reasons specified by the prescriber
- Assess vision prior to initiating therapy and then every 3 months during therapy.
- Remove patients from Vigabatrin therapy if the patients do not experience a meaningful reduction in seizures.
- The prescriber may, with appropriate documentation and caregiver counseling, exempt certain patients from vision assessment, using the Ophthalmologic Assessment Form, if:
The patient is blind (subsequent Ophthalmologic Assessment Forms do not need to be submitted to the REMS coordinating center)
The patient’s general neurological and/or mental condition permanently precludes the need for visual assessment (subsequent Ophthalmologic Assessment Forms do not need to be submitted to the REMS coordinating center)
The patient’s general neurological condition temporarily precludes the ability to assess visual function. The evaluation, however, may be performed at a later time as clinically appropriate.
The patient’s medical condition prevents visual assessment being performed safely
For other reasons specified by the prescriber
- The patient is blind (subsequent Ophthalmologic Assessment Forms do not need to be submitted to the REMS coordinating center)
- The patient’s general neurological and/or mental condition permanently precludes the need for visual assessment (subsequent Ophthalmologic Assessment Forms do not need to be submitted to the REMS coordinating center)
- The patient’s general neurological condition temporarily precludes the ability to assess visual function. The evaluation, however, may be performed at a later time as clinically appropriate.
- The patient’s medical condition prevents visual assessment being performed safely
- For other reasons specified by the prescriber
- Patient/parent/legal guardian must understand the risks and benefits and sign a Patient-Prescriber Agreement.
- Pharmacies that dispense Vigabatrin must be certified and agree to comply with the REMS requirements. Certified pharmacies must only dispense Vigabatrin to patients who are enrolled in the program.
- Abnormal MRI signal changes characterized by increased T2 signal and restricted diffusion in a symmetric pattern involving the thalamus, basal ganglia, brain stem, and cerebellum have been observed in some infants treated with vigabatrin for infantile spasms. In a retrospective epidemiologic study in infants with IS (N=205), the prevalence of these changes was 22% in vigabatrin treated patients versus 4% in patients treated with other therapies.
- In the study above, in post marketing experience, and in published literature reports, these changes generally resolved with discontinuation of treatment. In a few patients, the lesion resolved despite continued use. It has been reported that some infants exhibited coincident motor abnormalities, but no causal relationship has been established and the potential for long-term clinical sequelae has not been adequately studied.
- Neurotoxicity (brain histopathology and neurobehavioral abnormalities) was observed in rats exposed to vigabatrin during late gestation and the neonatal and juvenile periods of development. The relationship between these findings and the abnormal MRI findings in infants treated with vigabatrin for infantile spasms is unknown.
- The specific pattern of signal changes observed in IS patients was not observed in older pediatric and adult patients treated with vigabatrin for refractory CPS. In a blinded review of MRI images obtained in prospective clinical trials in patients with refractory CPS 3 years and older (N=656), no difference was observed in anatomic distribution or prevalence of MRI signal changes between vigabatrin treated and placebo treated patients. For adults treated with Vigabatrin, routine MRI surveillance is unnecessary as there is no evidence that vigabatrin causes MRI changes in this population.
- Vacuolation, characterized by fluid accumulation and separation of the outer layers of myelin, has been observed in brain white matter tracts in adult and juvenile rats and adult mice, dogs, and possibly monkeys following administration of vigabatrin. This lesion, referred to as intramyelinic edema (IME), was seen in animals at doses within the human therapeutic range. A no-effect dose was not established in rodents or dogs. In the rat and dog, vacuolation was reversible following discontinuation of vigabatrin treatment, but, in the rat, pathologic changes consisting of swollen or degenerating axons, mineralization, and gliosis were seen in brain areas in which vacuolation had been previously observed. Vacuolation in adult animals was correlated with alterations in MRI and changes in visual and somatosensory evoked potentials (EP).
- Administration of vigabatrin to rats during the neonatal and juvenile periods of development produced vacuolar changes in the brain gray matter (areas including the thalamus, midbrain, deep cerebellar nuclei, substantia nigra, hippocampus, and forebrain) which are considered distinct from the IME observed in vigabatrin treated adult animals. Decreased myelination and evidence of oligodendrocyte injury were additional findings in the brains of vigabatrin-treated rats. An increase in apoptosis was seen in some brain regions following vigabatrin exposure during the early postnatal period. Long-term neurobehavioral abnormalities (convulsions, neuromotor impairment, learning deficits) were also observed following vigabatrin treatment of young rats. These effects in young animals occurred at doses lower than those producing neurotoxicity in adult animals and were associated with plasma vigabatrin levels substantially lower than those achieved clinically in infants and children.
- In a published study, vigabatrin (200, 400 mg/kg/day) induced apoptotic neurodegeneration in the brain of young rats when administered by intraperitoneal injection on postnatal days 5-7.
- Administration of vigabatrin to female rats during pregnancy and lactation at doses below those used clinically resulted in hippocampal vacuolation and convulsions in the mature offspring.
- Abnormal MRI signal changes characterized by increased T2 signal and restricted diffusion in a symmetric pattern involving the thalamus, basal ganglia, brain stem, and cerebellum have been observed in some infants treated for IS with vigabatrin. Studies of the effects of vigabatrin on MRI and EP in adult epilepsy patients have demonstrated no clear-cut abnormalities.
- Antiepileptic drugs (AEDs), including Vigabatrin increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.
- Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI: 1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED treated patients was 0.43%, compared to 0.24% among 16,029 placebo treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug treated patients in the trials and none in placebo treated patients, but the number is too small to allow any conclusion about drug effect on suicide.
- The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
- The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. Table 4 shows absolute and relative risk by indication for all evaluated AEDs.
- The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.
- Anyone considering prescribing Vigabatrin or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.
- Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.
- As with all AEDs, Vigabatrin should be withdrawn gradually. Patients and caregivers should be told not to suddenly discontinue Vigabatrin therapy.
- In controlled clinical studies in adults with complex partial seizures, Vigabatrin was tapered by decreasing the daily dose 1000 mg/day on a weekly basis until discontinued.
- In a controlled study in pediatric patients with complex partial seizures, Vigabatrin was tapered by decreasing the daily dose by one third every week for three weeks.
- In a controlled clinical study in patients with infantile spasms, Vigabatrin was tapered by decreasing the daily dose at a rate of 25-50 mg/kg every 3-4 days.
- In North American controlled trials in adults, 6% of patients (16/280) receiving Vigabatrin and 2% of patients (3/188) receiving placebo had adverse events of anemia and/or met criteria for potentially clinically important hematology changes involving hemoglobin, hematocrit, and/or RBC indices. Across U.S. controlled trials, there were mean decreases in hemoglobin of about 3% and 0% in Vigabatrin and placebo treated patients, respectively, and a mean decrease in hematocrit of about 1% in Vigabatrin treated patients compared to a mean gain of about 1% in patients treated with placebo.
- In controlled and open label epilepsy trials in adults and pediatric patients, 3 Vigabatrin patients (0.06%, 3/4855) discontinued for anemia and 2 Vigabatrin patients experienced unexplained declines in hemoglobin to below 8 g/dL and/or hematocrit below 24%.
- Vigabatrin causes somnolence and fatigue. Patients should be advised not to drive a car or operate other complex machinery until they are familiar with the effects of Vigabatrin on their ability to perform such activities.
- Pooled data from two Vigabatrin controlled trials in adults demonstrated that 24% (54/222) of Vigabatrin patients experienced somnolence compared to 10% (14/135) of placebo patients. In those same studies, 28% of Vigabatrin patients experienced fatigue compared to 15% (20/135) of placebo patients. Almost 1% of Vigabatrin patients discontinued from clinical trials for somnolence and almost 1% discontinued for fatigue.
- Pooled data from three Vigabatrin controlled trials in pediatric patients demonstrated that 6% (10/165) of Vigabatrin patients experienced somnolence compared to 5% (5/104) of placebo patients. In those same studies, 10% (17/165) of Vigabatrin patients experienced fatigue compared to 7% (7/104) of placebo patients. No Vigabatrin patients discontinued from clinical trials due to somnolence or fatigue.
- Vigabatrin causes symptoms of peripheral neuropathy in adults. Pediatric clinical trials were not designed to assess symptoms of peripheral neuropathy, but observed incidence of symptoms based on pooled data from controlled pediatric studies appeared similar for pediatric patients on vigabatrin and placebo. In a pool of North American controlled and uncontrolled epilepsy studies, 4.2% (19/457) of Vigabatrin patients developed signs and/or symptoms of peripheral neuropathy. In the subset of North American placebo-controlled epilepsy trials, 1.4% (4/280) of Vigabatrin treated patients and no (0/188) placebo patients developed signs and/or symptoms of peripheral neuropathy. Initial manifestations of peripheral neuropathy in these trials included, in some combination, symptoms of numbness or tingling in the toes or feet, signs of reduced distal lower limb vibration or position sensation, or progressive loss of reflexes, starting at the ankles. Clinical studies in the development program were not designed to investigate peripheral neuropathy systematically and did not include nerve conduction studies, quantitative sensory testing, or skin or nerve biopsy. There is insufficient evidence to determine if development of these signs and symptoms were related to duration of Vigabatrin treatment, cumulative dose, or if the findings of peripheral neuropathy were completely reversible upon discontinuation of Vigabatrin.
- Vigabatrin causes weight gain in adult and pediatric patients.
- Data pooled from randomized controlled trials in adults found that 17% (77/443) of Vigabatrin patients versus 8% (22/275) of placebo patients gained ≥7% of baseline body weight. In these same trials, the mean weight change among Vigabatrin patients was 3.5 kg compared to 1.6 kg for placebo patients.
- Data pooled from randomized controlled trials in pediatric patients with refractory complex partial seizures found that 47% (77/163) of Vigabatrin patients versus 19% (19/102) of placebo patients gained ≥7% of baseline body weight.
- In all epilepsy trials, 0.6% (31/4855) of Vigabatrin patients discontinued for weight gain. The long term effects of Vigabatrin related weight gain are not known. Weight gain was not related to the occurrence of edema.
- Vigabatrin causes edema in adults. Pediatric clinical trials were not designed to assess edema, but observed incidence of edema based pooled data from controlled pediatric studies appeared similar for pediatric patients on vigabatrin and placebo.
- Pooled data from controlled trials demonstrated increased risk among Vigabatrin patients compared to placebo patients for peripheral edema (Vigabatrin 2%, placebo 1%), and edema (Vigabatrin 1%, placebo 0%). In these studies, one Vigabatrin and no placebo patients discontinued for an edema related AE. In adults, there was no apparent association between edema and cardiovascular adverse events such as hypertension or congestive heart failure. Edema was not associated with laboratory changes suggestive of deterioration in renal or hepatic function.
# Adverse Reactions
## Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- In U.S. and primary non-U.S. clinical studies of 4,079 Vigabatrin treated patients, the most commonly observed (≥5%) adverse reactions associated with the use of Vigabatrin in combination with other AEDs were headache, somnolence, fatigue, dizziness, convulsion, nasopharyngitis, weight increased, upper respiratory tract infection, visual field defect, depression, tremor, nystagmus, nausea, diarrhea, memory impairment, insomnia, irritability, coordination abnormal, vision blurred, diplopia, vomiting, influenza, pyrexia, and rash.
- The adverse reactions most commonly associated with Vigabatrin treatment discontinuation in ≥1% of patients were convulsion and depression.
- In patients with infantile spasms, the adverse reactions most commonly associated with Vigabatrin treatment discontinuation in ≥1% of patients were infections, status epilepticus, developmental coordination disorder, dystonia, hypotonia, hypertonia, weight increased, and insomnia.
### Most Common Adverse Reactions in Controlled Clinical Trials
Table 5 lists the treatment emergent adverse reactions that occurred in ≥2% and more than one patient per Vigabatrin treated group and that occurred more frequently than in placebo patients from 2 U.S. add-on clinical studies of refractory CPS in adults.
Table 6 lists adverse reactions from controlled clinical studies of pediatric patients receiving Vigabatrin or placebo as add-on therapy for refractory complex partial seizures. Adverse reactions that are listed occurred in at least 2% of Vigabatrin treated patients and more frequently than placebo. The median Vigabatrin dose was 49.4 mg/kg, (range of 8.0 – 105.9 mg/kg).
- In a randomized, placebo-controlled IS study with a 5 day double-blind treatment phase (n=40), the adverse events reported by >5% of patients receiving Vigabatrin and that occurred more frequently than in placebo patients, were somnolence (Vigabatrin 45%, placebo 30%), bronchitis (Vigabatrin 30%, placebo 15%), ear infection (Vigabatrin 10%, placebo 5%), and otitis media acute Vigabatrin 10%, placebo 0%).
- In a dose response study of low-dose (18-36 mg/kg/day) versus high-dose (100-148 mg/kg/day) vigabatrin, no clear correlation between dose and incidence of adverse events was observed. The treatment emergent adverse reactions (≥5% in either dose group) are summarized in Table 7.
## Postmarketing Experience
The following adverse reactions have been reported during post approval use of Vigabatrin worldwide. All adverse reactions that are not listed above as adverse reactions reported in clinical trials, that are not relatively common in the population and are not too vague to be useful are listed in this section. These reactions are reported voluntarily from a population of uncertain size; therefore, it is not possible to estimate their frequency or establish a causal relationship to drug exposure. Adverse reactions are categorized by system organ class.
- Congenital cardiac defects
- Congenital external ear anomaly
- Congenital hemangioma
- Congenital hydronephrosis
- Congenital male genital malformation
- Congenital oral malformation
- Congenital vesicoureteric reflux
- Dentofacial anomaly dysmorphism
- Fetal anticonvulsant syndrome
- Hamartomas
- Hip dysplasia
- Limb malformation
- Limb reduction defect
- Low set ears
- Renal aplasia
- Retinitis pigmentosa
- Supernumerary nipple
- Talipes
- Deafness
- Delayed puberty
- Gastrointestinal hemorrhage
- Esophagitis
- Developmental delay
- Facial edema
- Malignant hyperthermia
- Multi-organ failure
- Cholestasis
- Dystonia
- Encephalopathy
- Hypertonia
- Hypotonia
- Muscle spasticity
- Myoclonus
- Optic neuritis
- Dyskinesia
- Acute psychosis
- Apathy
- Delirium
- Hypomania
- Neonatal agitation
- Psychotic disorder
- Laryngeal edema
- Pulmonary embolism
- Respiratory failure
- Stridor
- Angioedema
- Maculo-papular rash
- Pruritus
- Stevens-Johnson syndrome (SJS)
- Toxic epidermal necrolysis (TEN)
# Drug Interactions
### Antiepileptic Drugs
- Although phenytoin dose adjustments are not routinely required, dose adjustment of phenytoin should be considered if clinically indicated, since Vigabatrin may cause a moderate reduction in total phenytoin plasma levels.
- Vigabatrin may moderately increase the Cmax of clonazepam resulting in an increase of clonazepam-associated adverse reactions.
- There are no clinically significant pharmacokinetic interactions between Vigabatrin and either phenobarbital or sodium valproate. Based on population pharmacokinetics, carbamazepine, clorazepate, primidone, and sodium valproate appear to have no effect on plasma concentrations of vigabatrin.
### Oral Contraceptives
- Vigabatrin is unlikely to affect the efficacy of steroid oral contraceptives.
### Drug-Laboratory Test Interactions
- Vigabatrin decreases alanine transaminase (ALT) and aspartate transaminase (AST) plasma activity in up to 90% of patients. In some patients, these enzymes become undetectable. The suppression of ALT and AST activity by Vigabatrin may preclude the use of these markers, especially ALT, to detect early hepatic injury.
- Vigabatrin may increase the amount of amino acids in the urine, possibly leading to a false positive test for certain rare genetic metabolic diseases (e.g., alpha aminoadipic aciduria).
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Vigabatrin produced developmental toxicity, including teratogenic and neurohistopathological effects, when administered to pregnant animals at clinically relevant doses. In addition, developmental neurotoxicity was observed in rats treated with vigabatrin during a period of postnatal development corresponding to the third trimester of human pregnancy. There are no adequate and well-controlled studies in pregnant women. Vigabatrin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Administration of vigabatrin (oral doses of 50 to 200 mg/kg) to pregnant rabbits throughout the period of organogenesis was associated with an increased incidence of malformations (cleft palate) and embryo-fetal death; these findings were observed in two separate studies. The no-effect dose for teratogenicity and embryolethality in rabbits (100 mg/kg) is approximately 1/2 the maximum recommended human dose (MRHD) of 3 g/day on a body surface area (mg/m2) basis. In rats, oral administration of vigabatrin (50, 100, or 150 mg/kg) throughout organogenesis resulted in decreased fetal body weights and increased incidences of fetal anatomic variations. The no-effect dose for embryo-fetal toxicity in rats (50 mg/kg) is approximately 1/5 the MRHD on a mg/m2 basis. Oral administration of vigabatrin (50, 100, 150 mg/kg) to rats from the latter part of pregnancy through weaning produced long-term neurohistopathological (hippocampal vacuolation) and neurobehavioral (convulsions) abnormalities in the offspring. A no-effect dose for developmental neurotoxicity in rats was not established; the low-effect dose (50 mg/kg) is approximately 1/5 the MRHD on a mg/m2 basis.
- In a published study, vigabatrin (300 or 450 mg/kg) was administered by intraperitoneal injection to a mutant mouse strain on a single day during organogenesis (day 7, 8, 9, 10, 11, or 12). An increase in malformations (including cleft palate) was observed at both doses.
- Oral administration of vigabatrin (5, 15, or 50 mg/kg) to young rats during the neonatal and juvenile periods of development (postnatal days 4-65) produced neurobehavioral (convulsions, neuromotor impairment, learning deficits) and neurohistopathological (brain vacuolation, decreased myelination, and retinal dysplasia) abnormalities in treated animals. The early postnatal period in rats is generally thought to correspond to late pregnancy in humans in terms of brain development. The no-effect dose for developmental neurotoxicity in juvenile rats (5 mg/kg) was associated with plasma vigabatrin exposures (AUC) less than 1/30 of those measured in pediatric patients receiving an oral dose of 50 mg/kg.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Vigabatrin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Vigabatrin during labor and delivery.
### Nursing Mothers
- Vigabatrin is excreted in human milk. Because of the potential for serious adverse reactions from vigabatrin in nursing infants a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother
### Pediatric Use
- The safety and effectiveness of Vigabatrin as adjunctive treatment of refractory complex partial seizures in pediatric patients aged 10 to 16 years of age have been established. The dosing recommendation in this population varies according to age group and is weight based. Adverse reactions in this pediatric population are similar to those observed in the adult population.
- The safety and effectiveness of Vigabatrin have not been established in pediatric patients under 10 years of age with refractory complex partial seizures.
- The safety and effectiveness of Vigabatrin as monotherapy for pediatric patients with infantile spasms (1 month to 2 years of age) have been established.
- Duration of therapy for infantile spasms was evaluated in a post hoc analysis of a Canadian Pediatric Epilepsy Network (CPEN) study of developmental outcomes in infantile spasms patients. This analysis suggests that a total duration of 6 months of vigabatrin therapy is adequate for the treatment of infantile spasms. However, prescribers must use their clinical judgment as to the most appropriate duration of use.
- Abnormal MRI signal changes were observed in infants.
- Oral administration of vigabatrin (5, 15, or 50 mg/kg) to young rats during the neonatal and juvenile periods of development (postnatal days 4-65) produced neurobehavioral (convulsions, neuromotor impairment, learning deficits) and neurohistopathological (brain vacuolation, decreased myelination, and retinal dysplasia) abnormalities in treated animals. The no-effect dose for developmental neurotoxicity in juvenile rats (5 mg/kg) was associated with plasma vigabatrin exposures (AUC) less than 1/30 of those measured in pediatric patients receiving an oral dose of 50 mg/kg
### Geriatic Use
- Clinical studies of vigabatrin did not include sufficient numbers of patients aged 65 and over to determine whether they responded differently from younger patients. Vigabatrin is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
- Oral administration of a single dose of 1.5 g of vigabatrin to elderly (>65 years) patients with reduced creatinine clearance (65 years) than in young healthy males. Adjustment of dose or frequency of administration should be considered. Such patients may respond to a lower maintenance dose. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.
### Gender
There is no FDA guidance on the use of Vigabatrin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Vigabatrin with respect to specific racial populations.
### Renal Impairment
Dose adjustment, including initiating treatment with a lower dose, is necessary in pediatric patients 10 years of age and older and adults with mild (creatinine clearance >50-80 mL/min), moderate (creatinine clearance >30-50 mL/min) and severe (creatinine clearance >10-30 mL/min) renal impairment .
- Vigabatrin is primarily eliminated through the kidney.
- Information about how to adjust the dose in infants with renal impairment is unavailable.
- Mild renal impairment (CLcr >50 - 80 mL/min): dose should be decreased by 25%
- Moderate renal impairment (CLcr >30 - 50 mL/min): dose should be decreased by 50%
- Severe renal impairment (CLcr >10 - 30 mL/min): dose should be decreased by 75%.
CLcr in mL/min may be estimated from serum creatinine (mg/dL) using the following formulas:
- Patients 10 to <12 years old: CLcr (mL/min/1.73 m2) = (K × Ht) / Scr
height (Ht) in cm; serum creatinine (Scr) in mg/dL
K (proportionality constant): Female Child (<12 years): K=0.55;
Male Child (<12 years): K=0.70
- height (Ht) in cm; serum creatinine (Scr) in mg/dL
- K (proportionality constant): Female Child (<12 years): K=0.55;
- Male Child (<12 years): K=0.70
- Pediatric patients 12 years or older and adult patients: CLcr (mL/min) = × weight (kg) / (×0.85 for female patients)
### Hepatic Impairment
There is no FDA guidance on the use of Vigabatrin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Vigabatrin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Vigabatrin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Vigabatrin Administration in the drug label.
### Monitoring
There is limited information regarding Vigabatrin Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Vigabatrin and IV administrations.
# Overdosage
- Confirmed and/or suspected vigabatrin overdoses have been reported during clinical trials and in post marketing surveillance. No vigabatrin overdoses resulted in death. When reported, the vigabatrin dose ingested ranged from 3 g to 90 g, but most were between 7.5 g and 30 g. Nearly half the cases involved multiple drug ingestions including carbamazepine, barbiturates, benzodiazepines, lamotrigine, valproic acid, acetaminophen, and/or chlorpheniramine.
- Coma, unconsciousness, and/or drowsiness were described in the majority of cases of vigabatrin overdose. Other less commonly reported symptoms included vertigo, psychosis, apnea or respiratory depression, bradycardia, agitation, irritability, confusion, headache, hypotension, abnormal behavior, increased seizure activity, status epilepticus, and speech disorder. These symptoms resolved with supportive care.
- There is no specific antidote for Vigabatrin overdose. Standard measures to remove unabsorbed drug should be used, including elimination by emesis or gastric lavage. Supportive measures should be employed, including monitoring of vital signs and observation of the clinical status of the patient.
- In an in vitro study, activated charcoal did not significantly adsorb vigabatrin.
- The effectiveness of hemodialysis in the treatment of Vigabatrin overdose is unknown. In isolated case reports in renal failure patients receiving therapeutic doses of vigabatrin, hemodialysis reduced vigabatrin plasma concentrations by 40% to 60%.
# Pharmacology
## Mechanism of Action
- The precise mechanism of vigabatrin’s anti-seizure effect is unknown, but it is believed to be the result of its action as an irreversible inhibitor of γ-aminobutyric acid transaminase (GABA-T), the enzyme responsible for the metabolism of the inhibitory neurotransmitter GABA. This action results in increased levels of GABA in the central nervous system.
No direct correlation between plasma concentration and efficacy has been established. The duration of drug effect is presumed to be dependent on the rate of enzyme re-synthesis rather than on the rate of elimination of the drug from the systemic circulation.
## Structure
- The chemical name of vigabatrin, a racemate consisting of two enantiomers, is (±) 4-amino-5-hexenoic acid. The molecular formula is C6H11NO2 and the molecular weight is 129.16. It has the following structural formula:
## Pharmacodynamics
- There is no indication of a QT/QTc prolonging effect of Vigabatrin in single doses up to 6.0 g. In a randomized, placebo-controlled, crossover study, 58 healthy subjects were administered a single oral dose of Vigabatrin (3 g and 6 g) and placebo. Peak concentrations for 6.0 g Vigabatrin were approximately 2-fold higher than the peak concentrations following the 3.0 g single oral dose.
## Pharmacokinetics
Vigabatrin displayed linear pharmacokinetics after administration of single doses ranging from 0.5 g to 4 g, and after administration of repeated doses of 0.5 g and 2.0 g twice daily. Bioequivalence has been established between the oral solution and tablet formulations. The following PK information (Tmax, half-life, and clearance) of vigabatrin was obtained from stand-alone PK studies and population PK analyses.
- Following oral administration, vigabatrin is essentially completely absorbed. The time to maximum concentration (Tmax) is approximately 1 hour for children (10 years – 16 years) and adults, and approximately 2.5 hours for infants (5 months - 2 years). There was little accumulation with multiple dosing in adult and pediatric patients. A food effect study involving administration of vigabatrin to healthy volunteers under fasting and fed conditions indicated that the Cmax was decreased by 33%, Tmax was increased to 2 hours, and AUC was unchanged under fed conditions.
- Vigabatrin does not bind to plasma proteins. Vigabatrin is widely distributed throughout the body; mean steady-state volume of distribution is 1.1 L/kg (CV = 20%).
- Vigabatrin is not significantly metabolized; it is eliminated primarily through renal excretion. The terminal half-life of vigabatrin is about 5.7 hours for infants (5 months – 2 years), 9.5 hours for children (10 years – 16 years), and 10.5 hours for adults. Following administration of C-vigabatrin to healthy male volunteers, about 95% of total radioactivity was recovered in the urine over 72 hours with the parent drug representing about 80% of this. Vigabatrin induces CYP2C9, but does not induce other hepatic cytochrome P450 enzyme systems.
## Nonclinical Toxicology
There is limited information regarding Vigabatrin Nonclinical Toxicology in the drug label.
# Clinical Studies
### Complex Partial Seizures
- The effectiveness of Vigabatrin as adjunctive therapy in adult patients was established in two U.S. multicenter, double-blind, placebo-controlled, parallel-group clinical studies. A total of 357 adults (age 18 to 60 years) with complex partial seizures, with or without secondary generalization were enrolled (Studies 1 and 2). Patients were required to be on an adequate and stable dose of an anticonvulsant, and have a history of failure on an adequate regimen of carbamazepine or phenytoin. Patients had a history of about 8 seizures per month (median) for about 20 years (median) prior to entrance into the study. These studies were not capable by design of demonstrating direct superiority of Vigabatrin over any other anticonvulsant added to a regimen to which the patient had not adequately responded. Further, in these studies patients had previously been treated with a limited range of anticonvulsants.
- The primary measure of efficacy was the patient’s reduction in mean monthly frequency of complex partial seizures plus partial seizures secondarily generalized at end of study compared to baseline.
- Study 1 (N=174) was a randomized, double-blind, placebo-controlled, dose-response study consisting of an 8-week baseline period followed by an 18-week treatment period. Patients were randomized to receive placebo or 1, 3, or 6 g/day vigabatrin administered twice daily. During the first 6 weeks following randomization, the dose was titrated upward beginning with 1 g/day and increasing by 0.5 g/day on days 1 and 5 of each subsequent week in the 3 g/day and 6 g/day groups, until the assigned dose was reached.
- Results for the primary measure of effectiveness, reduction in monthly frequency of complex partial seizures, are shown in Table 8. The 3 g/day and 6 g/day dose groups were statistically significantly superior to placebo, but the 6 g/day dose was not superior to the 3 g/day dose.
- Figure 1 presents the percentage of patients (X-axis) with a percent reduction in seizure frequency (responder rate) from baseline to the maintenance phase at least as great as that represented on the Y-axis. A positive value on the Y-axis indicates an improvement from baseline (i.e., a decrease in complex partial seizure frequency), while a negative value indicates a worsening from baseline (i.e., an increase in complex partial seizure frequency). Thus, in a display of this type, a curve for an effective treatment is shifted to the left of the curve for placebo. The proportion of patients achieving any particular level of reduction in complex partial seizure frequency was consistently higher for the Vigabatrin 3 and 6 g/day groups compared to the placebo group. For example, 51% of patients randomized to Vigabatrin 3 g/day and 53% of patients randomized to Vigabatrin 6 g/day experienced a 50% or greater reduction in seizure frequency, compared to 9% of patients randomized to placebo. Patients with an increase in seizure frequency >100% are represented on the Y-axis as equal to or greater than -100%.
- Study 2 (N=183 randomized, 182 evaluated for efficacy) was a randomized, double-blind, placebo-controlled, parallel study consisting of an 8-week baseline period and a 16-week treatment period. During the first 4 weeks following randomization, the dose of vigabatrin was titrated upward beginning with 1 g/day and increased by 0.5 g/day on a weekly basis to the maintenance dose of 3 g/day.
- Results for the primary measure of effectiveness, reduction in monthly complex partial seizure frequency, are shown in Table 9. Vigabatrin 3 g/day was statistically significantly superior to placebo in reducing seizure frequency.
- Figure 2 presents the percentage of patients (X-axis) with a percent reduction in seizure frequency (responder rate) from baseline to the maintenance phase at least as great as that represented on the Y-axis. A positive value on the Y-axis indicates an improvement from baseline (i.e., a decrease in complex partial seizure frequency), while a negative value indicates a worsening from baseline (i.e., an increase in complex partial seizure frequency). Thus, in a display of this type, a curve for an effective treatment is shifted to the left of the curve for placebo. The proportion of patients achieving any particular level of reduction in seizure frequency was consistently higher for the Vigabatrin 3 g/day group compared to the placebo group. For example, 39% of patients randomized to Vigabatrin (3 g/day) experienced a 50% or greater reduction in complex partial seizure frequency, compared to 21% of patients randomized to placebo. Patients with an increase in seizure frequency >100% are represented on the Y-axis as equal to or greater than -100%.
- For both studies, there was no difference in the effectiveness of vigabatrin between male and female patients. Analyses of age and race were not possible as nearly all patients were between the ages of 18 to 65 and Caucasian.
### Infantile Spasms
- The effectiveness of Vigabatrin as monotherapy was established for infantile spasms in two multicenter controlled studies. Both studies were similar in terms of disease characteristics and prior treatments of patients and all enrolled infants had a confirmed diagnosis of infantile spasms.
- Study 1 (N=221) was a multicenter, randomized, low-dose high-dose, parallel-group, partially-blind (caregivers knew the actual dose but not whether their child was classified as low or high dose; EEG reader was blinded but investigators were not blinded) study to evaluate the safety and efficacy of vigabatrin in patients <2 years of age with new-onset infantile spasms. Patients with both symptomatic and cryptogenic etiologies were studied. The study was comprised of two phases. The first phase was a 14 to 21 day partially-blind phase in which patients were randomized to receive either low-dose (18-36 mg/kg/day) or high-dose (100-148 mg/kg/day) vigabatrin. Study drug was titrated over 7 days, followed by a constant dose for 7 days. If the patient became spasm-free on or before day 14, another 7 days of constant dose was administered. The primary efficacy endpoint of this study was the proportion of patients who were spasm-free for 7 consecutive days beginning within the first 14 days of vigabatrin therapy. Patients considered spasm-free were defined as those patients who remained free of spasms (evaluated according to caregiver response to direct questioning regarding spasm frequency) and who had no indication of spasms or hypsarrhythmia during 8 hours of CCTV EEG recording (including at least one sleep-wake-sleep cycle) performed within 3 days of the seventh day of spasm freedom and interpreted by a blinded EEG reader. Seventeen patients in the high-dose group achieved spasm freedom compared with 8 patients in the low dose group. This difference was statistically significant (p=0.0375). Primary efficacy results are shown in Table 10.
- Study 2 (N=40) was a multicenter, randomized, double-blind, placebo-controlled, parallel-group study consisting of a pre-treatment (baseline) period of 2-3 days, followed by a 5-day double-blind treatment phase during which patients were treated with vigabatrin (initial dose of 50 mg/kg/day with titration allowed to 150 mg/kg/day) or placebo. The primary efficacy endpoint in this study was the average percent change in daily spasm frequency, assessed during a pre-defined and consistent 2-hour window of evaluation, comparing baseline to the final 2 days of the 5-day double-blind treatment phase. No statistically significant differences were observed in the average frequency of spasms using the 2-hour evaluation window. However, a post-hoc alternative efficacy analysis, using a 24-hour clinical evaluation window found a statistically significant difference in the overall percentage of reductions in spasms between the vigabatrin group (68.9%) and the placebo group (17.0%) (p=0.030).
- Duration of therapy for infantile spasms was evaluated in a post hoc analysis of a Canadian Pediatric Epilepsy Network (CPEN) study of developmental outcomes in infantile spasms patients. The 38/68 infants in the study who had responded to vigabatrin therapy (complete cessation of spasms and hypsarrhythmia) continued vigabatrin therapy for a total duration of 6 months therapy. The 38 infants who responded were then followed for an additional 18 months after discontinuation of vigabatrin to determine their clinical outcome. A post hoc analysis indicated no observed recurrence of infantile spasms in any of these 38 infants.
# How Supplied
- Vigabatrin 500 mg tablets are white, film-coated, oval, biconvex, scored on one side, and debossed with OV 111 on the other. They are supplied as bottles of 100 (NDC 67386-111-01).
- Vigabatrin 500 mg packets contain a white to off-white granular powder. They are supplied in packages of 50 (NDC 67386-211-65).
## Storage
- Store at 20 to 25°C (68 to 77°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Vigabatrin Patient Counseling Information in the drug label.
# Precautions with Alcohol
- Alcohol-Vigabatrin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Sabril
# Look-Alike Drug Names
There is limited information regarding Vigabatrin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Vigabatrin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alberto Plate [2]
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# Black Box Warning
# Overview
Vigabatrin is a anticonvulsant, gamma aminobutyric acid transaminase inhibitor that is FDA approved for the treatment of refractory complex partial seizures and infantile spams. There is a Black Box Warning for this drug as shown here. Common adverse reactions include weight increased, arthralgia, confusion, coordination problem, memory impairment, somnolence, tremor, blurred vision, diplopia, nystagmus, infection of ear, otitis media, aggressive behavior, dysmenorrhea, bronchitis, upper respiratory infection and fatigue.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Important Dosing Instructions
- Vigabatrin is given orally with or without food. The Vigabatrin dosing regimen depends on the indication, age group, weight, and dosage form (tablets or powder for oral solution). Patients with impaired renal function require dose adjustment.
- Vigabatrin tablets and powder for oral solution are bioequivalent. Either tablet or powder can be used for CPS. Powder for oral solution should be used for IS; tablets should not be used for IS because of difficulty in the administration of tablets to infants and young children.
- Vigabatrin powder for oral solution should be mixed with water prior to administration.
- If using Vigabatrin powder for oral solution, physicians should review and discuss the Medication Guide and instructions for mixing and giving Vigabatrin with the patient or caregiver(s). Physicians should confirm that patients or caregiver(s) understand how to mix Vigabatrin powder with water and administer the correct daily dose. Empty the entire contents of each 500 mg packet into a clean cup, and dissolve in 10 mL of cold or room temperature water per packet (see Table 2). Administer the resulting solution using the 10 mL oral syringe supplied with the medication. The concentration of the final solution is 50 mg/mL. Discard the resulting solution if it is not clear (or free of particles) and colorless. Each individual dose should be prepared and used immediately. Discard any unused portion of the solution after administering the correct dose. Monitoring of Vigabatrin plasma concentrations to optimize therapy is not helpful. If a decision is made to discontinue Vigabatrin, the dose should be gradually reduced
### Refractory Complex Partial Seizures
- Treatment should be initiated at 1000 mg/day (500 mg twice daily). Total daily dose may be increased in 500 mg increments at weekly intervals depending on response. The recommended dose of Vigabatrin in adults is 3000 mg/day (1500 mg twice daily). A 6000 mg/day dose has not been shown to confer additional benefit compared to the 3000 mg/day dose and is associated with an increased incidence of adverse events. In controlled clinical studies in adults with complex partial seizures, Vigabatrin was tapered by decreasing the daily dose 1000 mg/day on a weekly basis until discontinued.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Vigabatrin in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Vigabatrin in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
### Refractory Complex Partial Seizures
- Treatment is based on body weight as shown in Table 1. Treatment should be initiated at a total daily dose of 500 mg/day (250 mg twice daily) and may be increased weekly to a total maintenance dose of 2000 mg/day (1000 mg twice daily). Patients weighing more than 60 kg should be dosed according to adult recommendations.
### Infantile Spasms
- The initial daily dosing is 50 mg/kg/day given in two divided doses; subsequent dosing can be titrated by 25 mg/kg/day to 50 mg/kg/day increments every 3 days up to a maximum of 150 mg/kg/day given in 2 divided doses.
- Table 2 below describes how many packets and how many milliliters (mL) of water will be needed to prepare each individual dose. The concentration after reconstitution is 50 mg/mL.
- Table 3 provides the volume of the 50 mg/mL dosing solution that should be administered as individual doses in infants of various weights.
- In a controlled clinical study in patients with infantile spasms, Vigabatrin was tapered by decreasing the daily dose at a rate of 25 mg/kg to 50 mg/kg every 3 to 4 days
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Vigabatrin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Vigabatrin in pediatric patients.
# Contraindications
- None
# Warnings
- Because of the risk of vision loss, and because, when it is effective, Vigabatrin provides an observable symptomatic benefit, patient response and continued need for treatment should be periodically assessed.
- In patients with refractory complex partial seizures, Vigabatrin should be withdrawn if a substantial clinical benefit is not observed within 3 months of initiating treatment. If, in the clinical judgment of the prescriber, evidence of treatment failure becomes obvious earlier than 3 months, treatment should be discontinued at that time.
- In patients with infantile spasms, Vigabatrin should be withdrawn if a substantial clinical benefit is not observed within 2 to 4 weeks. If, in the clinical judgment of the prescriber, evidence of treatment failure becomes obvious earlier than 2 to 4 weeks, treatment should be discontinued at that time.
- Monitoring of vision by an ophthalmic professional with expertise in visual field interpretation and the ability to perform dilated indirect ophthalmoscopy of the retina is required, unless a patient is formally exempted from periodic ophthalmologic assessment as documented in the Support, Help And Resources for Epilepsy (SHARE) program. Because vision testing in infants is difficult, vision loss may not be detected until it is severe. For patients receiving Vigabatrin who are not exempted, vision assessment is required at baseline (no later than 4 weeks after starting Vigabatrin) and at least every 3 months while on therapy and about 3-6 months after the discontinuation of therapy.
- The diagnostic approach should be individualized for the patient and clinical situation. For all patients, attempts to monitor vision periodically and/or formal exemptions must be documented under the SHARE program. In adults and cooperative pediatric patients, perimetry is recommended, preferably by automated threshold visual field testing. Additional testing may also include electrophysiology (e.g., electroretinography [ERG]), retinal imaging (e.g., optical coherence tomography [OCT]), and/or other methods appropriate for the patient, but this additional testing is not required. In patients exempted from vision testing, treatment may continue according to clinical judgment, with appropriate patient counseling and with documentation in the SHARE program of the exemption. Because of variability, results from ophthalmic monitoring must be interpreted with caution, and repeat assessment is recommended if results are abnormal or uninterpretable. Repeat assessment in the first few weeks of treatment is recommended to establish if, and to what degree, reproducible results can be obtained, and to guide selection of appropriate ongoing monitoring for the patient.
- The onset and progression of vision loss from Vigabatrin is unpredictable, and it may occur or worsen precipitously between assessments. Once detected, vision loss due to Vigabatrin is not reversible. It is expected that even with frequent monitoring, some Vigabatrin patients will develop severe vision loss. Drug discontinuation should be considered, balancing benefit and risk, if visual loss is documented.
Vigabatrin is available only through a restricted distribution program called the SHARE program, because of the risk of vision loss.
Notable requirements components of the SHARE Program include the following:
- Prescribers must be certified with the program by enrolling and reviewing educational materials and comply with the following:
Assess vision prior to initiating therapy and then every 3 months during therapy.
Remove patients from Vigabatrin therapy if the patients do not experience a meaningful reduction in seizures.
The prescriber may, with appropriate documentation and caregiver counseling, exempt certain patients from vision assessment, using the Ophthalmologic Assessment Form, if:
The patient is blind (subsequent Ophthalmologic Assessment Forms do not need to be submitted to the REMS coordinating center)
The patient’s general neurological and/or mental condition permanently precludes the need for visual assessment (subsequent Ophthalmologic Assessment Forms do not need to be submitted to the REMS coordinating center)
The patient’s general neurological condition temporarily precludes the ability to assess visual function. The evaluation, however, may be performed at a later time as clinically appropriate.
The patient’s medical condition prevents visual assessment being performed safely
For other reasons specified by the prescriber
- Assess vision prior to initiating therapy and then every 3 months during therapy.
- Remove patients from Vigabatrin therapy if the patients do not experience a meaningful reduction in seizures.
- The prescriber may, with appropriate documentation and caregiver counseling, exempt certain patients from vision assessment, using the Ophthalmologic Assessment Form, if:
The patient is blind (subsequent Ophthalmologic Assessment Forms do not need to be submitted to the REMS coordinating center)
The patient’s general neurological and/or mental condition permanently precludes the need for visual assessment (subsequent Ophthalmologic Assessment Forms do not need to be submitted to the REMS coordinating center)
The patient’s general neurological condition temporarily precludes the ability to assess visual function. The evaluation, however, may be performed at a later time as clinically appropriate.
The patient’s medical condition prevents visual assessment being performed safely
For other reasons specified by the prescriber
- The patient is blind (subsequent Ophthalmologic Assessment Forms do not need to be submitted to the REMS coordinating center)
- The patient’s general neurological and/or mental condition permanently precludes the need for visual assessment (subsequent Ophthalmologic Assessment Forms do not need to be submitted to the REMS coordinating center)
- The patient’s general neurological condition temporarily precludes the ability to assess visual function. The evaluation, however, may be performed at a later time as clinically appropriate.
- The patient’s medical condition prevents visual assessment being performed safely
- For other reasons specified by the prescriber
- Patient/parent/legal guardian must understand the risks and benefits and sign a Patient-Prescriber Agreement.
- Pharmacies that dispense Vigabatrin must be certified and agree to comply with the REMS requirements. Certified pharmacies must only dispense Vigabatrin to patients who are enrolled in the program.
- Abnormal MRI signal changes characterized by increased T2 signal and restricted diffusion in a symmetric pattern involving the thalamus, basal ganglia, brain stem, and cerebellum have been observed in some infants treated with vigabatrin for infantile spasms. In a retrospective epidemiologic study in infants with IS (N=205), the prevalence of these changes was 22% in vigabatrin treated patients versus 4% in patients treated with other therapies.
- In the study above, in post marketing experience, and in published literature reports, these changes generally resolved with discontinuation of treatment. In a few patients, the lesion resolved despite continued use. It has been reported that some infants exhibited coincident motor abnormalities, but no causal relationship has been established and the potential for long-term clinical sequelae has not been adequately studied.
- Neurotoxicity (brain histopathology and neurobehavioral abnormalities) was observed in rats exposed to vigabatrin during late gestation and the neonatal and juvenile periods of development. The relationship between these findings and the abnormal MRI findings in infants treated with vigabatrin for infantile spasms is unknown.
- The specific pattern of signal changes observed in IS patients was not observed in older pediatric and adult patients treated with vigabatrin for refractory CPS. In a blinded review of MRI images obtained in prospective clinical trials in patients with refractory CPS 3 years and older (N=656), no difference was observed in anatomic distribution or prevalence of MRI signal changes between vigabatrin treated and placebo treated patients. For adults treated with Vigabatrin, routine MRI surveillance is unnecessary as there is no evidence that vigabatrin causes MRI changes in this population.
- Vacuolation, characterized by fluid accumulation and separation of the outer layers of myelin, has been observed in brain white matter tracts in adult and juvenile rats and adult mice, dogs, and possibly monkeys following administration of vigabatrin. This lesion, referred to as intramyelinic edema (IME), was seen in animals at doses within the human therapeutic range. A no-effect dose was not established in rodents or dogs. In the rat and dog, vacuolation was reversible following discontinuation of vigabatrin treatment, but, in the rat, pathologic changes consisting of swollen or degenerating axons, mineralization, and gliosis were seen in brain areas in which vacuolation had been previously observed. Vacuolation in adult animals was correlated with alterations in MRI and changes in visual and somatosensory evoked potentials (EP).
- Administration of vigabatrin to rats during the neonatal and juvenile periods of development produced vacuolar changes in the brain gray matter (areas including the thalamus, midbrain, deep cerebellar nuclei, substantia nigra, hippocampus, and forebrain) which are considered distinct from the IME observed in vigabatrin treated adult animals. Decreased myelination and evidence of oligodendrocyte injury were additional findings in the brains of vigabatrin-treated rats. An increase in apoptosis was seen in some brain regions following vigabatrin exposure during the early postnatal period. Long-term neurobehavioral abnormalities (convulsions, neuromotor impairment, learning deficits) were also observed following vigabatrin treatment of young rats. These effects in young animals occurred at doses lower than those producing neurotoxicity in adult animals and were associated with plasma vigabatrin levels substantially lower than those achieved clinically in infants and children.
- In a published study, vigabatrin (200, 400 mg/kg/day) induced apoptotic neurodegeneration in the brain of young rats when administered by intraperitoneal injection on postnatal days 5-7.
- Administration of vigabatrin to female rats during pregnancy and lactation at doses below those used clinically resulted in hippocampal vacuolation and convulsions in the mature offspring.
- Abnormal MRI signal changes characterized by increased T2 signal and restricted diffusion in a symmetric pattern involving the thalamus, basal ganglia, brain stem, and cerebellum have been observed in some infants treated for IS with vigabatrin. Studies of the effects of vigabatrin on MRI and EP in adult epilepsy patients have demonstrated no clear-cut abnormalities.
- Antiepileptic drugs (AEDs), including Vigabatrin increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.
- Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI: 1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED treated patients was 0.43%, compared to 0.24% among 16,029 placebo treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug treated patients in the trials and none in placebo treated patients, but the number is too small to allow any conclusion about drug effect on suicide.
- The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
- The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. Table 4 shows absolute and relative risk by indication for all evaluated AEDs.
- The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.
- Anyone considering prescribing Vigabatrin or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.
- Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.
- As with all AEDs, Vigabatrin should be withdrawn gradually. Patients and caregivers should be told not to suddenly discontinue Vigabatrin therapy.
- In controlled clinical studies in adults with complex partial seizures, Vigabatrin was tapered by decreasing the daily dose 1000 mg/day on a weekly basis until discontinued.
- In a controlled study in pediatric patients with complex partial seizures, Vigabatrin was tapered by decreasing the daily dose by one third every week for three weeks.
- In a controlled clinical study in patients with infantile spasms, Vigabatrin was tapered by decreasing the daily dose at a rate of 25-50 mg/kg every 3-4 days.
- In North American controlled trials in adults, 6% of patients (16/280) receiving Vigabatrin and 2% of patients (3/188) receiving placebo had adverse events of anemia and/or met criteria for potentially clinically important hematology changes involving hemoglobin, hematocrit, and/or RBC indices. Across U.S. controlled trials, there were mean decreases in hemoglobin of about 3% and 0% in Vigabatrin and placebo treated patients, respectively, and a mean decrease in hematocrit of about 1% in Vigabatrin treated patients compared to a mean gain of about 1% in patients treated with placebo.
- In controlled and open label epilepsy trials in adults and pediatric patients, 3 Vigabatrin patients (0.06%, 3/4855) discontinued for anemia and 2 Vigabatrin patients experienced unexplained declines in hemoglobin to below 8 g/dL and/or hematocrit below 24%.
- Vigabatrin causes somnolence and fatigue. Patients should be advised not to drive a car or operate other complex machinery until they are familiar with the effects of Vigabatrin on their ability to perform such activities.
- Pooled data from two Vigabatrin controlled trials in adults demonstrated that 24% (54/222) of Vigabatrin patients experienced somnolence compared to 10% (14/135) of placebo patients. In those same studies, 28% of Vigabatrin patients experienced fatigue compared to 15% (20/135) of placebo patients. Almost 1% of Vigabatrin patients discontinued from clinical trials for somnolence and almost 1% discontinued for fatigue.
- Pooled data from three Vigabatrin controlled trials in pediatric patients demonstrated that 6% (10/165) of Vigabatrin patients experienced somnolence compared to 5% (5/104) of placebo patients. In those same studies, 10% (17/165) of Vigabatrin patients experienced fatigue compared to 7% (7/104) of placebo patients. No Vigabatrin patients discontinued from clinical trials due to somnolence or fatigue.
- Vigabatrin causes symptoms of peripheral neuropathy in adults. Pediatric clinical trials were not designed to assess symptoms of peripheral neuropathy, but observed incidence of symptoms based on pooled data from controlled pediatric studies appeared similar for pediatric patients on vigabatrin and placebo. In a pool of North American controlled and uncontrolled epilepsy studies, 4.2% (19/457) of Vigabatrin patients developed signs and/or symptoms of peripheral neuropathy. In the subset of North American placebo-controlled epilepsy trials, 1.4% (4/280) of Vigabatrin treated patients and no (0/188) placebo patients developed signs and/or symptoms of peripheral neuropathy. Initial manifestations of peripheral neuropathy in these trials included, in some combination, symptoms of numbness or tingling in the toes or feet, signs of reduced distal lower limb vibration or position sensation, or progressive loss of reflexes, starting at the ankles. Clinical studies in the development program were not designed to investigate peripheral neuropathy systematically and did not include nerve conduction studies, quantitative sensory testing, or skin or nerve biopsy. There is insufficient evidence to determine if development of these signs and symptoms were related to duration of Vigabatrin treatment, cumulative dose, or if the findings of peripheral neuropathy were completely reversible upon discontinuation of Vigabatrin.
- Vigabatrin causes weight gain in adult and pediatric patients.
- Data pooled from randomized controlled trials in adults found that 17% (77/443) of Vigabatrin patients versus 8% (22/275) of placebo patients gained ≥7% of baseline body weight. In these same trials, the mean weight change among Vigabatrin patients was 3.5 kg compared to 1.6 kg for placebo patients.
- Data pooled from randomized controlled trials in pediatric patients with refractory complex partial seizures found that 47% (77/163) of Vigabatrin patients versus 19% (19/102) of placebo patients gained ≥7% of baseline body weight.
- In all epilepsy trials, 0.6% (31/4855) of Vigabatrin patients discontinued for weight gain. The long term effects of Vigabatrin related weight gain are not known. Weight gain was not related to the occurrence of edema.
- Vigabatrin causes edema in adults. Pediatric clinical trials were not designed to assess edema, but observed incidence of edema based pooled data from controlled pediatric studies appeared similar for pediatric patients on vigabatrin and placebo.
- Pooled data from controlled trials demonstrated increased risk among Vigabatrin patients compared to placebo patients for peripheral edema (Vigabatrin 2%, placebo 1%), and edema (Vigabatrin 1%, placebo 0%). In these studies, one Vigabatrin and no placebo patients discontinued for an edema related AE. In adults, there was no apparent association between edema and cardiovascular adverse events such as hypertension or congestive heart failure. Edema was not associated with laboratory changes suggestive of deterioration in renal or hepatic function.
# Adverse Reactions
## Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- In U.S. and primary non-U.S. clinical studies of 4,079 Vigabatrin treated patients, the most commonly observed (≥5%) adverse reactions associated with the use of Vigabatrin in combination with other AEDs were headache, somnolence, fatigue, dizziness, convulsion, nasopharyngitis, weight increased, upper respiratory tract infection, visual field defect, depression, tremor, nystagmus, nausea, diarrhea, memory impairment, insomnia, irritability, coordination abnormal, vision blurred, diplopia, vomiting, influenza, pyrexia, and rash.
- The adverse reactions most commonly associated with Vigabatrin treatment discontinuation in ≥1% of patients were convulsion and depression.
- In patients with infantile spasms, the adverse reactions most commonly associated with Vigabatrin treatment discontinuation in ≥1% of patients were infections, status epilepticus, developmental coordination disorder, dystonia, hypotonia, hypertonia, weight increased, and insomnia.
### Most Common Adverse Reactions in Controlled Clinical Trials
Table 5 lists the treatment emergent adverse reactions that occurred in ≥2% and more than one patient per Vigabatrin treated group and that occurred more frequently than in placebo patients from 2 U.S. add-on clinical studies of refractory CPS in adults.
Table 6 lists adverse reactions from controlled clinical studies of pediatric patients receiving Vigabatrin or placebo as add-on therapy for refractory complex partial seizures. Adverse reactions that are listed occurred in at least 2% of Vigabatrin treated patients and more frequently than placebo. The median Vigabatrin dose was 49.4 mg/kg, (range of 8.0 – 105.9 mg/kg).
- In a randomized, placebo-controlled IS study with a 5 day double-blind treatment phase (n=40), the adverse events reported by >5% of patients receiving Vigabatrin and that occurred more frequently than in placebo patients, were somnolence (Vigabatrin 45%, placebo 30%), bronchitis (Vigabatrin 30%, placebo 15%), ear infection (Vigabatrin 10%, placebo 5%), and otitis media acute Vigabatrin 10%, placebo 0%).
- In a dose response study of low-dose (18-36 mg/kg/day) versus high-dose (100-148 mg/kg/day) vigabatrin, no clear correlation between dose and incidence of adverse events was observed. The treatment emergent adverse reactions (≥5% in either dose group) are summarized in Table 7.
## Postmarketing Experience
The following adverse reactions have been reported during post approval use of Vigabatrin worldwide. All adverse reactions that are not listed above as adverse reactions reported in clinical trials, that are not relatively common in the population and are not too vague to be useful are listed in this section. These reactions are reported voluntarily from a population of uncertain size; therefore, it is not possible to estimate their frequency or establish a causal relationship to drug exposure. Adverse reactions are categorized by system organ class.
- Congenital cardiac defects
- Congenital external ear anomaly
- Congenital hemangioma
- Congenital hydronephrosis
- Congenital male genital malformation
- Congenital oral malformation
- Congenital vesicoureteric reflux
- Dentofacial anomaly dysmorphism
- Fetal anticonvulsant syndrome
- Hamartomas
- Hip dysplasia
- Limb malformation
- Limb reduction defect
- Low set ears
- Renal aplasia
- Retinitis pigmentosa
- Supernumerary nipple
- Talipes
- Deafness
- Delayed puberty
- Gastrointestinal hemorrhage
- Esophagitis
- Developmental delay
- Facial edema
- Malignant hyperthermia
- Multi-organ failure
- Cholestasis
- Dystonia
- Encephalopathy
- Hypertonia
- Hypotonia
- Muscle spasticity
- Myoclonus
- Optic neuritis
- Dyskinesia
- Acute psychosis
- Apathy
- Delirium
- Hypomania
- Neonatal agitation
- Psychotic disorder
- Laryngeal edema
- Pulmonary embolism
- Respiratory failure
- Stridor
- Angioedema
- Maculo-papular rash
- Pruritus
- Stevens-Johnson syndrome (SJS)
- Toxic epidermal necrolysis (TEN)
# Drug Interactions
### Antiepileptic Drugs
- Although phenytoin dose adjustments are not routinely required, dose adjustment of phenytoin should be considered if clinically indicated, since Vigabatrin may cause a moderate reduction in total phenytoin plasma levels.
- Vigabatrin may moderately increase the Cmax of clonazepam resulting in an increase of clonazepam-associated adverse reactions.
- There are no clinically significant pharmacokinetic interactions between Vigabatrin and either phenobarbital or sodium valproate. Based on population pharmacokinetics, carbamazepine, clorazepate, primidone, and sodium valproate appear to have no effect on plasma concentrations of vigabatrin.
### Oral Contraceptives
- Vigabatrin is unlikely to affect the efficacy of steroid oral contraceptives.
### Drug-Laboratory Test Interactions
- Vigabatrin decreases alanine transaminase (ALT) and aspartate transaminase (AST) plasma activity in up to 90% of patients. In some patients, these enzymes become undetectable. The suppression of ALT and AST activity by Vigabatrin may preclude the use of these markers, especially ALT, to detect early hepatic injury.
- Vigabatrin may increase the amount of amino acids in the urine, possibly leading to a false positive test for certain rare genetic metabolic diseases (e.g., alpha aminoadipic aciduria).
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Vigabatrin produced developmental toxicity, including teratogenic and neurohistopathological effects, when administered to pregnant animals at clinically relevant doses. In addition, developmental neurotoxicity was observed in rats treated with vigabatrin during a period of postnatal development corresponding to the third trimester of human pregnancy. There are no adequate and well-controlled studies in pregnant women. Vigabatrin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Administration of vigabatrin (oral doses of 50 to 200 mg/kg) to pregnant rabbits throughout the period of organogenesis was associated with an increased incidence of malformations (cleft palate) and embryo-fetal death; these findings were observed in two separate studies. The no-effect dose for teratogenicity and embryolethality in rabbits (100 mg/kg) is approximately 1/2 the maximum recommended human dose (MRHD) of 3 g/day on a body surface area (mg/m2) basis. In rats, oral administration of vigabatrin (50, 100, or 150 mg/kg) throughout organogenesis resulted in decreased fetal body weights and increased incidences of fetal anatomic variations. The no-effect dose for embryo-fetal toxicity in rats (50 mg/kg) is approximately 1/5 the MRHD on a mg/m2 basis. Oral administration of vigabatrin (50, 100, 150 mg/kg) to rats from the latter part of pregnancy through weaning produced long-term neurohistopathological (hippocampal vacuolation) and neurobehavioral (convulsions) abnormalities in the offspring. A no-effect dose for developmental neurotoxicity in rats was not established; the low-effect dose (50 mg/kg) is approximately 1/5 the MRHD on a mg/m2 basis.
- In a published study, vigabatrin (300 or 450 mg/kg) was administered by intraperitoneal injection to a mutant mouse strain on a single day during organogenesis (day 7, 8, 9, 10, 11, or 12). An increase in malformations (including cleft palate) was observed at both doses.
- Oral administration of vigabatrin (5, 15, or 50 mg/kg) to young rats during the neonatal and juvenile periods of development (postnatal days 4-65) produced neurobehavioral (convulsions, neuromotor impairment, learning deficits) and neurohistopathological (brain vacuolation, decreased myelination, and retinal dysplasia) abnormalities in treated animals. The early postnatal period in rats is generally thought to correspond to late pregnancy in humans in terms of brain development. The no-effect dose for developmental neurotoxicity in juvenile rats (5 mg/kg) was associated with plasma vigabatrin exposures (AUC) less than 1/30 of those measured in pediatric patients receiving an oral dose of 50 mg/kg.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Vigabatrin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Vigabatrin during labor and delivery.
### Nursing Mothers
- Vigabatrin is excreted in human milk. Because of the potential for serious adverse reactions from vigabatrin in nursing infants a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother
### Pediatric Use
- The safety and effectiveness of Vigabatrin as adjunctive treatment of refractory complex partial seizures in pediatric patients aged 10 to 16 years of age have been established. The dosing recommendation in this population varies according to age group and is weight based. Adverse reactions in this pediatric population are similar to those observed in the adult population.
- The safety and effectiveness of Vigabatrin have not been established in pediatric patients under 10 years of age with refractory complex partial seizures.
- The safety and effectiveness of Vigabatrin as monotherapy for pediatric patients with infantile spasms (1 month to 2 years of age) have been established.
- Duration of therapy for infantile spasms was evaluated in a post hoc analysis of a Canadian Pediatric Epilepsy Network (CPEN) study of developmental outcomes in infantile spasms patients. This analysis suggests that a total duration of 6 months of vigabatrin therapy is adequate for the treatment of infantile spasms. However, prescribers must use their clinical judgment as to the most appropriate duration of use.
- Abnormal MRI signal changes were observed in infants.
- Oral administration of vigabatrin (5, 15, or 50 mg/kg) to young rats during the neonatal and juvenile periods of development (postnatal days 4-65) produced neurobehavioral (convulsions, neuromotor impairment, learning deficits) and neurohistopathological (brain vacuolation, decreased myelination, and retinal dysplasia) abnormalities in treated animals. The no-effect dose for developmental neurotoxicity in juvenile rats (5 mg/kg) was associated with plasma vigabatrin exposures (AUC) less than 1/30 of those measured in pediatric patients receiving an oral dose of 50 mg/kg
### Geriatic Use
- Clinical studies of vigabatrin did not include sufficient numbers of patients aged 65 and over to determine whether they responded differently from younger patients. Vigabatrin is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
- Oral administration of a single dose of 1.5 g of vigabatrin to elderly (>65 years) patients with reduced creatinine clearance (<50 mL/min) was associated with moderate to severe sedation and confusion in 4 of 5 patients, lasting up to 5 days. The renal clearance of vigabatrin was 36% lower in healthy elderly subjects (>65 years) than in young healthy males. Adjustment of dose or frequency of administration should be considered. Such patients may respond to a lower maintenance dose. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.
### Gender
There is no FDA guidance on the use of Vigabatrin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Vigabatrin with respect to specific racial populations.
### Renal Impairment
Dose adjustment, including initiating treatment with a lower dose, is necessary in pediatric patients 10 years of age and older and adults with mild (creatinine clearance >50-80 mL/min), moderate (creatinine clearance >30-50 mL/min) and severe (creatinine clearance >10-30 mL/min) renal impairment .
- Vigabatrin is primarily eliminated through the kidney.
- Information about how to adjust the dose in infants with renal impairment is unavailable.
- Mild renal impairment (CLcr >50 - 80 mL/min): dose should be decreased by 25%
- Moderate renal impairment (CLcr >30 - 50 mL/min): dose should be decreased by 50%
- Severe renal impairment (CLcr >10 - 30 mL/min): dose should be decreased by 75%.
CLcr in mL/min may be estimated from serum creatinine (mg/dL) using the following formulas:
- Patients 10 to <12 years old: CLcr (mL/min/1.73 m2) = (K × Ht) / Scr******
height (Ht) in cm; serum creatinine (Scr) in mg/dL
K (proportionality constant): Female Child (<12 years): K=0.55;
Male Child (<12 years): K=0.70
- height (Ht) in cm; serum creatinine (Scr) in mg/dL
- K (proportionality constant): Female Child (<12 years): K=0.55;
- Male Child (<12 years): K=0.70
- Pediatric patients 12 years or older and adult patients: CLcr (mL/min) = [140-age (years)] × weight (kg) / [72 × serum creatinine (mg/dL)] (×0.85 for female patients)
### Hepatic Impairment
There is no FDA guidance on the use of Vigabatrin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Vigabatrin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Vigabatrin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Vigabatrin Administration in the drug label.
### Monitoring
There is limited information regarding Vigabatrin Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Vigabatrin and IV administrations.
# Overdosage
- Confirmed and/or suspected vigabatrin overdoses have been reported during clinical trials and in post marketing surveillance. No vigabatrin overdoses resulted in death. When reported, the vigabatrin dose ingested ranged from 3 g to 90 g, but most were between 7.5 g and 30 g. Nearly half the cases involved multiple drug ingestions including carbamazepine, barbiturates, benzodiazepines, lamotrigine, valproic acid, acetaminophen, and/or chlorpheniramine.
- Coma, unconsciousness, and/or drowsiness were described in the majority of cases of vigabatrin overdose. Other less commonly reported symptoms included vertigo, psychosis, apnea or respiratory depression, bradycardia, agitation, irritability, confusion, headache, hypotension, abnormal behavior, increased seizure activity, status epilepticus, and speech disorder. These symptoms resolved with supportive care.
- There is no specific antidote for Vigabatrin overdose. Standard measures to remove unabsorbed drug should be used, including elimination by emesis or gastric lavage. Supportive measures should be employed, including monitoring of vital signs and observation of the clinical status of the patient.
- In an in vitro study, activated charcoal did not significantly adsorb vigabatrin.
- The effectiveness of hemodialysis in the treatment of Vigabatrin overdose is unknown. In isolated case reports in renal failure patients receiving therapeutic doses of vigabatrin, hemodialysis reduced vigabatrin plasma concentrations by 40% to 60%.
# Pharmacology
## Mechanism of Action
- The precise mechanism of vigabatrin’s anti-seizure effect is unknown, but it is believed to be the result of its action as an irreversible inhibitor of γ-aminobutyric acid transaminase (GABA-T), the enzyme responsible for the metabolism of the inhibitory neurotransmitter GABA. This action results in increased levels of GABA in the central nervous system.
No direct correlation between plasma concentration and efficacy has been established. The duration of drug effect is presumed to be dependent on the rate of enzyme re-synthesis rather than on the rate of elimination of the drug from the systemic circulation.
## Structure
- The chemical name of vigabatrin, a racemate consisting of two enantiomers, is (±) 4-amino-5-hexenoic acid. The molecular formula is C6H11NO2 and the molecular weight is 129.16. It has the following structural formula:
## Pharmacodynamics
- There is no indication of a QT/QTc prolonging effect of Vigabatrin in single doses up to 6.0 g. In a randomized, placebo-controlled, crossover study, 58 healthy subjects were administered a single oral dose of Vigabatrin (3 g and 6 g) and placebo. Peak concentrations for 6.0 g Vigabatrin were approximately 2-fold higher than the peak concentrations following the 3.0 g single oral dose.
## Pharmacokinetics
Vigabatrin displayed linear pharmacokinetics after administration of single doses ranging from 0.5 g to 4 g, and after administration of repeated doses of 0.5 g and 2.0 g twice daily. Bioequivalence has been established between the oral solution and tablet formulations. The following PK information (Tmax, half-life, and clearance) of vigabatrin was obtained from stand-alone PK studies and population PK analyses.
- Following oral administration, vigabatrin is essentially completely absorbed. The time to maximum concentration (Tmax) is approximately 1 hour for children (10 years – 16 years) and adults, and approximately 2.5 hours for infants (5 months - 2 years). There was little accumulation with multiple dosing in adult and pediatric patients. A food effect study involving administration of vigabatrin to healthy volunteers under fasting and fed conditions indicated that the Cmax was decreased by 33%, Tmax was increased to 2 hours, and AUC was unchanged under fed conditions.
- Vigabatrin does not bind to plasma proteins. Vigabatrin is widely distributed throughout the body; mean steady-state volume of distribution is 1.1 L/kg (CV = 20%).
- Vigabatrin is not significantly metabolized; it is eliminated primarily through renal excretion. The terminal half-life of vigabatrin is about 5.7 hours for infants (5 months – 2 years), 9.5 hours for children (10 years – 16 years), and 10.5 hours for adults. Following administration of [14]C-vigabatrin to healthy male volunteers, about 95% of total radioactivity was recovered in the urine over 72 hours with the parent drug representing about 80% of this. Vigabatrin induces CYP2C9, but does not induce other hepatic cytochrome P450 enzyme systems.
## Nonclinical Toxicology
There is limited information regarding Vigabatrin Nonclinical Toxicology in the drug label.
# Clinical Studies
### Complex Partial Seizures
- The effectiveness of Vigabatrin as adjunctive therapy in adult patients was established in two U.S. multicenter, double-blind, placebo-controlled, parallel-group clinical studies. A total of 357 adults (age 18 to 60 years) with complex partial seizures, with or without secondary generalization were enrolled (Studies 1 and 2). Patients were required to be on an adequate and stable dose of an anticonvulsant, and have a history of failure on an adequate regimen of carbamazepine or phenytoin. Patients had a history of about 8 seizures per month (median) for about 20 years (median) prior to entrance into the study. These studies were not capable by design of demonstrating direct superiority of Vigabatrin over any other anticonvulsant added to a regimen to which the patient had not adequately responded. Further, in these studies patients had previously been treated with a limited range of anticonvulsants.
- The primary measure of efficacy was the patient’s reduction in mean monthly frequency of complex partial seizures plus partial seizures secondarily generalized at end of study compared to baseline.
- Study 1 (N=174) was a randomized, double-blind, placebo-controlled, dose-response study consisting of an 8-week baseline period followed by an 18-week treatment period. Patients were randomized to receive placebo or 1, 3, or 6 g/day vigabatrin administered twice daily. During the first 6 weeks following randomization, the dose was titrated upward beginning with 1 g/day and increasing by 0.5 g/day on days 1 and 5 of each subsequent week in the 3 g/day and 6 g/day groups, until the assigned dose was reached.
- Results for the primary measure of effectiveness, reduction in monthly frequency of complex partial seizures, are shown in Table 8. The 3 g/day and 6 g/day dose groups were statistically significantly superior to placebo, but the 6 g/day dose was not superior to the 3 g/day dose.
- Figure 1 presents the percentage of patients (X-axis) with a percent reduction in seizure frequency (responder rate) from baseline to the maintenance phase at least as great as that represented on the Y-axis. A positive value on the Y-axis indicates an improvement from baseline (i.e., a decrease in complex partial seizure frequency), while a negative value indicates a worsening from baseline (i.e., an increase in complex partial seizure frequency). Thus, in a display of this type, a curve for an effective treatment is shifted to the left of the curve for placebo. The proportion of patients achieving any particular level of reduction in complex partial seizure frequency was consistently higher for the Vigabatrin 3 and 6 g/day groups compared to the placebo group. For example, 51% of patients randomized to Vigabatrin 3 g/day and 53% of patients randomized to Vigabatrin 6 g/day experienced a 50% or greater reduction in seizure frequency, compared to 9% of patients randomized to placebo. Patients with an increase in seizure frequency >100% are represented on the Y-axis as equal to or greater than -100%.
- Study 2 (N=183 randomized, 182 evaluated for efficacy) was a randomized, double-blind, placebo-controlled, parallel study consisting of an 8-week baseline period and a 16-week treatment period. During the first 4 weeks following randomization, the dose of vigabatrin was titrated upward beginning with 1 g/day and increased by 0.5 g/day on a weekly basis to the maintenance dose of 3 g/day.
- Results for the primary measure of effectiveness, reduction in monthly complex partial seizure frequency, are shown in Table 9. Vigabatrin 3 g/day was statistically significantly superior to placebo in reducing seizure frequency.
- Figure 2 presents the percentage of patients (X-axis) with a percent reduction in seizure frequency (responder rate) from baseline to the maintenance phase at least as great as that represented on the Y-axis. A positive value on the Y-axis indicates an improvement from baseline (i.e., a decrease in complex partial seizure frequency), while a negative value indicates a worsening from baseline (i.e., an increase in complex partial seizure frequency). Thus, in a display of this type, a curve for an effective treatment is shifted to the left of the curve for placebo. The proportion of patients achieving any particular level of reduction in seizure frequency was consistently higher for the Vigabatrin 3 g/day group compared to the placebo group. For example, 39% of patients randomized to Vigabatrin (3 g/day) experienced a 50% or greater reduction in complex partial seizure frequency, compared to 21% of patients randomized to placebo. Patients with an increase in seizure frequency >100% are represented on the Y-axis as equal to or greater than -100%.
- For both studies, there was no difference in the effectiveness of vigabatrin between male and female patients. Analyses of age and race were not possible as nearly all patients were between the ages of 18 to 65 and Caucasian.
### Infantile Spasms
- The effectiveness of Vigabatrin as monotherapy was established for infantile spasms in two multicenter controlled studies. Both studies were similar in terms of disease characteristics and prior treatments of patients and all enrolled infants had a confirmed diagnosis of infantile spasms.
- Study 1 (N=221) was a multicenter, randomized, low-dose high-dose, parallel-group, partially-blind (caregivers knew the actual dose but not whether their child was classified as low or high dose; EEG reader was blinded but investigators were not blinded) study to evaluate the safety and efficacy of vigabatrin in patients <2 years of age with new-onset infantile spasms. Patients with both symptomatic and cryptogenic etiologies were studied. The study was comprised of two phases. The first phase was a 14 to 21 day partially-blind phase in which patients were randomized to receive either low-dose (18-36 mg/kg/day) or high-dose (100-148 mg/kg/day) vigabatrin. Study drug was titrated over 7 days, followed by a constant dose for 7 days. If the patient became spasm-free on or before day 14, another 7 days of constant dose was administered. The primary efficacy endpoint of this study was the proportion of patients who were spasm-free for 7 consecutive days beginning within the first 14 days of vigabatrin therapy. Patients considered spasm-free were defined as those patients who remained free of spasms (evaluated according to caregiver response to direct questioning regarding spasm frequency) and who had no indication of spasms or hypsarrhythmia during 8 hours of CCTV EEG recording (including at least one sleep-wake-sleep cycle) performed within 3 days of the seventh day of spasm freedom and interpreted by a blinded EEG reader. Seventeen patients in the high-dose group achieved spasm freedom compared with 8 patients in the low dose group. This difference was statistically significant (p=0.0375). Primary efficacy results are shown in Table 10.
- Study 2 (N=40) was a multicenter, randomized, double-blind, placebo-controlled, parallel-group study consisting of a pre-treatment (baseline) period of 2-3 days, followed by a 5-day double-blind treatment phase during which patients were treated with vigabatrin (initial dose of 50 mg/kg/day with titration allowed to 150 mg/kg/day) or placebo. The primary efficacy endpoint in this study was the average percent change in daily spasm frequency, assessed during a pre-defined and consistent 2-hour window of evaluation, comparing baseline to the final 2 days of the 5-day double-blind treatment phase. No statistically significant differences were observed in the average frequency of spasms using the 2-hour evaluation window. However, a post-hoc alternative efficacy analysis, using a 24-hour clinical evaluation window found a statistically significant difference in the overall percentage of reductions in spasms between the vigabatrin group (68.9%) and the placebo group (17.0%) (p=0.030).
- Duration of therapy for infantile spasms was evaluated in a post hoc analysis of a Canadian Pediatric Epilepsy Network (CPEN) study of developmental outcomes in infantile spasms patients. The 38/68 infants in the study who had responded to vigabatrin therapy (complete cessation of spasms and hypsarrhythmia) continued vigabatrin therapy for a total duration of 6 months therapy. The 38 infants who responded were then followed for an additional 18 months after discontinuation of vigabatrin to determine their clinical outcome. A post hoc analysis indicated no observed recurrence of infantile spasms in any of these 38 infants.
# How Supplied
- Vigabatrin 500 mg tablets are white, film-coated, oval, biconvex, scored on one side, and debossed with OV 111 on the other. They are supplied as bottles of 100 (NDC 67386-111-01).
- Vigabatrin 500 mg packets contain a white to off-white granular powder. They are supplied in packages of 50 (NDC 67386-211-65).
## Storage
- Store at 20 to 25°C (68 to 77°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Vigabatrin Patient Counseling Information in the drug label.
# Precautions with Alcohol
- Alcohol-Vigabatrin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Sabril
# Look-Alike Drug Names
There is limited information regarding Vigabatrin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Sabril | |
60c70ca56162c796b46a1d4e4be733171df86ac2 | wikidoc | Safe Minds | Safe Minds
The Coalition for SafeMinds (Sensible Action For Ending Mercury-Induced Neurological Disorders) is a non-profit organization dedicated to investigating the risks of exposure to mercury from medical products. Safe Minds, founded in 2000 and led by the parents of autistic children, supports research into what they consider potentially harmful effects of vaccines. The connection between vaccines and neurodevelopmental disorders, asserted by some parent-led advocacy groups, is disputed by mainstream medical groups, who contend no credible evidence supports the possible connection.
SafeMinds claims the symptoms of autism and symptoms of mercury poisoning are virtually identical in young children and include effects on brain cells, eyes, the immune system, the gastrointestinal system, muscular control, and speech.
# Principals
Lyn Redwood, R.N., M.S.N., C.R.N.P, the president and co-founder of Safe Minds, is a nurse practitioner specializing in pediatrics and women's health care for over 25 years. Her son Will was diagnosed with pervasive developmental disorder (PDD), not otherwise specified. Redwood is co-author of Autism: A Novel Form of Mercury Poisoning, and has testified before the United States House of Representatives Government Reform Committee, where she presented 'Mercury in Medicine: Are We Taking Unnecessary Risks?'
Sallie Bernard, based in Summit, New Jersey, is the executive director and co-founder of SafeMinds, and a co-author of research papers on the links between vaccines and neurodevelopmental disorders. Her son Bill was diagnosed with autism in 1993.
Mark Blaxill, a board member of Safe Minds, is a graduate of Princeton University and Harvard, and has an MBA and a public policy degree. Mark's daughter, Michaela, has been diagnosed with autism. As a Director of SafeMinds, Blaxill has testified before the Institute of Medicine (IOM) and published articles in a number of peer-reviewed scientific journals.
# Evidence of Harm
The book Evidence of Harm (2004), by David Kirby, relates the story of SafeMinds parents Lyn Redwood, Sallie Bernard, Liz Birt, Albert Enayati, Heidi Roger, and Mark Blaxill. In the book, Kirby gives credit to these parents for taking on government agencies and the drug companies. The book gives insight into the reasons that such parents look askance at the credibility of evidence put forward by mainstream medical authorities to either explain or falsify the increased number of diagnosed autism cases in recent years. Participant Productions is developing a documentary based on Evidence of Harm. | Safe Minds
The Coalition for SafeMinds (Sensible Action For Ending Mercury-Induced Neurological Disorders) is a non-profit organization dedicated to investigating the risks of exposure to mercury from medical products. Safe Minds, founded in 2000 and led by the parents of autistic children, supports research into what they consider potentially harmful effects of vaccines. The connection between vaccines and neurodevelopmental disorders, asserted by some parent-led advocacy groups, is disputed by mainstream medical groups, who contend no credible evidence supports the possible connection.[1]
SafeMinds claims the symptoms of autism and symptoms of mercury poisoning are virtually identical in young children and include effects on brain cells, eyes, the immune system, the gastrointestinal system, muscular control, and speech.
# Principals
Lyn Redwood, R.N., M.S.N., C.R.N.P, the president and co-founder of Safe Minds, is a nurse practitioner specializing in pediatrics and women's health care for over 25 years. Her son Will was diagnosed with pervasive developmental disorder (PDD), not otherwise specified. Redwood is co-author of Autism: A Novel Form of Mercury Poisoning, and has testified before the United States House of Representatives Government Reform Committee, where she presented 'Mercury in Medicine: Are We Taking Unnecessary Risks?'
Sallie Bernard, based in Summit, New Jersey, is the executive director and co-founder of SafeMinds, and a co-author of research papers on the links between vaccines and neurodevelopmental disorders. Her son Bill was diagnosed with autism in 1993.
Mark Blaxill, a board member of Safe Minds, is a graduate of Princeton University and Harvard, and has an MBA and a public policy degree. Mark's daughter, Michaela, has been diagnosed with autism. As a Director of SafeMinds, Blaxill has testified before the Institute of Medicine (IOM) and published articles in a number of peer-reviewed scientific journals.
# Evidence of Harm
The book Evidence of Harm (2004), by David Kirby, relates the story of SafeMinds parents Lyn Redwood, Sallie Bernard, Liz Birt, Albert Enayati, Heidi Roger, and Mark Blaxill. In the book, Kirby gives credit to these parents for taking on government agencies and the drug companies. The book gives insight into the reasons that such parents look askance at the credibility of evidence put forward by mainstream medical authorities to either explain or falsify the increased number of diagnosed autism cases in recent years. Participant Productions is developing a documentary based on Evidence of Harm. | https://www.wikidoc.org/index.php/Safe_Minds | |
ff102826fb70b1a5f3e4d7fd9af77caf8ce62e47 | wikidoc | Safinamide | Safinamide
# Disclaimer
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# Overview
Safinamide is a monoamine oxidase type B (MAO-B) inhibitor that is FDA approved for the adjunctive treatment of levodopa/carbidopa in patients with Parkinson's disease (PD) experiencing "off" episodes. Common adverse reactions include dyskinesia, fall, nausea, and insomnia.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Safinamide is indicated as adjunctive treatment to levodopa/carbidopa in patients with Parkinson's disease (PD) experiencing "off" episodes.
- The recommended starting dosage of Safinamide is 50 mg administered orally once daily (at the same time of day), without regard to meals. After two weeks, the dosage may be increased to 100 mg once daily, based on individual need and tolerability.
- Daily dosages of Safinamide above 100 mg have not been shown to provide additional benefit, and higher dosages increase the risk for adverse reactions. Safinamide has been shown to be effective only in combination with levodopa/carbidopa.
- If a dose is missed, the next dose should be taken at the same time the next day.
- Safinamide 100 mg should be tapered by decreasing the dose to 50 mg for one week before stopping.
- In patients with moderate hepatic impairment (Child-Pugh B: 7-9), the maximum recommended dosage of Safinamide is 50 mg orally once daily. Safinamide is contraindicated in patients with severe hepatic impairment (Child-Pugh C: 10-15). If a patient taking 50 mg Safinamide progresses from moderate to severe hepatic impairment, discontinue Safinamide.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Safinamide Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding Safinamide Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Safinamide FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Safinamide Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding Safinamide Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
# Contraindications
- Safinamide is contraindicated in patients with:
- Concomitant use of other drugs in the monoamine oxidase inhibitor (MAOI) class or other drugs that are potent inhibitors of monoamine oxidase, including linezolid. The combination may result in increased blood pressure, including hypertensive crisis.
- Concomitant use of opioid drugs (e.g., meperidine and its derivatives, methadone, propoxyphene, or tramadol); serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic, tetracyclic, or triazolopyridine antidepressants; cyclobenzaprine; methylphenidate, amphetamine, and their derivatives; or St John's wort. Concomitant use could result in life-threatening serotonin syndrome.
- Concomitant use of dextromethorphan. The combination of MAO inhibitors and dextromethorphan has been reported to cause episodes of psychosis or abnormal behavior.
- A history of a hypersensitivity to Safinamide. Reactions have included swelling of the tongue and oral mucosa, and dyspnea.
- Severe hepatic impairment (Child-Pugh C: 10-15).
# Warnings
- Safinamide may cause hypertension or exacerbate existing hypertension. In clinical trials, the incidence of hypertension was 7% for Safinamide 50 mg, 5% for Safinamide 100 mg, and 4% for placebo. Monitor patients for new onset hypertension or hypertension that is not adequately controlled after starting Safinamide. Medication adjustment may be necessary if elevation of blood pressure is sustained.
- Monitor for hypertension if Safinamide is prescribed concomitantly with sympathomimetic medications, including prescription or nonprescription nasal, oral, and ophthalmic decongestants and cold remedies.
- Safinamide is a selective inhibitor of MAO-B at the recommended dosages of 50 mg or 100 mg daily. Selectivity for inhibiting MAO-B decreases above the recommended daily dosages. Therefore, Safinamide should not be used at daily dosages exceeding those recommended because of the risks of hypertension, exacerbation of existing hypertension, or hypertensive crisis.
- Dietary tyramine restriction is not required during treatment with recommended doses of Safinamide. However, use with certain foods that contain very high amounts (i.e., more than 150 mg) of tyramine could cause severe hypertension, resulting from an increased sensitivity to tyramine in patients taking recommended dosages of Safinamide, and patients should be advised to avoid such foods.
- Isoniazid has some monoamine oxidase inhibiting activity. Monitor for hypertension and reaction to dietary tyramine in patients treated concomitantly with isoniazid and Safinamide.
- The development of a potentially life-threatening serotonin syndrome has been reported in patients on concomitant treatment with MAO inhibitors (including selective MAO-B inhibitors), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, tetracyclic antidepressants, triazolopyridine antidepressants, cyclobenzaprine, opioid drugs (e.g., meperidine and meperidine derivatives, propoxyphene, tramadol), and methylphenidate, amphetamine, and their derivatives. Concomitant use of Safinamide with these drugs is contraindicated.
- In clinical trials, serotonin syndrome was reported in a patient treated with Safinamide and an SSRI. Use the lowest effective dose of SSRIs in patients treated with concomitant Safinamide.
- Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).
- Patients treated with dopaminergic medications have reported falling asleep while engaged in activities of daily living, including the operation of motor vehicles, which sometimes has resulted in accidents. Patients may not perceive warning signs, such as excessive drowsiness, or they may report feeling alert immediately prior to the event.
- In clinical studies, sleep attacks/sudden onset of sleep were reported in patients treated with Safinamide 100 mg/day.
- If a patient develops daytime sleepiness or episodes of falling asleep during activities that require full attention (e.g., driving a motor vehicle, conversations, eating), Safinamide should ordinarily be discontinued. If a decision is made to continue these patients on Safinamide, advise them to avoid driving and other potentially dangerous activities.
- Safinamide may cause dyskinesia or exacerbate pre-existing dyskinesia.
- In clinical trials, the incidence of dyskinesia was 21% for Safinamide 50 mg, 18% for Safinamide 100 mg, and 9% for placebo. There was a greater incidence of dyskinesia causing study discontinuation in Parkinson's disease patients treated with Safinamide 50 mg or 100 mg (1%), compared to placebo (0%).
- Reducing the patient's daily levodopa dosage or the dosage of another dopaminergic drug may mitigate dyskinesia.
- Patients with a major psychotic disorder should ordinarily not be treated with Safinamide because of the risk of exacerbating the psychosis with an increase in central dopaminergic tone. In addition, treatments for psychosis that antagonize the effects of dopaminergic medications may exacerbate the symptoms of Parkinson's disease.
- Consider dosage reduction or stopping the medication if a patient develops hallucinations or psychotic-like behaviors while taking Safinamide.
- Patients can experience intense urges to gamble, increased sexual urges, intense urges to spend money, binge eating, and/or other intense urges, and the inability to control these urges while taking one or more of the medications, including Safinamide, that increase central dopaminergic tone. In some cases, these urges were reported to have stopped when the dose was reduced or the medication was discontinued. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending or other urges while being treated with Safinamide. Consider dose reduction or stopping the medication if a patient develops such urges while taking Safinamide.
- A symptom complex resembling neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in drugs that increase central dopaminergic tone.
- Retinal degeneration and loss of photoreceptor cells were observed in albino and pigmented rats administered Safinamide orally in toxicity studies of up to 6 months duration. In albino rats administered Safinamide orally for two years, retinal scarring and cataracts were observed at all doses tested.
- Periodically monitor patients for visual changes in patients with a history of retinal/macular degeneration, uveitis, inherited retinal conditions, family history of hereditary retinal disease, albinism, retinitis pigmentosa, or any active retinopathy (e.g., diabetic retinopathy).
# Adverse Reactions
## Clinical Trials Experience
- Clinical trials are conducted under widely varying conditions; therefore, adverse reactions observed in the clinical trials of a drug cannot be directly compared to the incidence in the clinical trials of another drug and may not reflect the incidence observed in clinical practice.
Common Adverse Reactions in Placebo-Controlled Parkinson's Disease Studies
- Table 1 shows the incidence of adverse reactions with an incidence of at least 2% on Safinamide 100 mg/day and greater than placebo in controlled studies in Parkinson's disease (Study 1 and Study 2). The most common adverse reactions associated with Safinamide treatment in which the incidence for Safinamide 100 mg/day was at least 2% greater than the incidence for placebo were dyskinesia, fall, nausea, and insomnia.
Adverse Reactions Reported as Reason for Discontinuation from Study
- In pooled placebo-controlled studies (Study 1 and Study 2) in patients with Parkinson's disease taking a stable dose of carbidopa/levodopa with or without other PD medications, there was an increase in the incidence of Safinamide-treated patients who discontinued from the study because of adverse reactions. The incidence of patients discontinuing from Study 1 and Study 2 for any adverse reaction was 5% for Safinamide 50 mg/day, 6% for Safinamide 100 mg/day, and 4% for placebo. The most frequently reported adverse reaction causing study discontinuation was dyskinesia (1% of patients treated with Safinamide 50 mg/day or Safinamide 100 mg/day vs. 0% for placebo).
Abnormal Laboratory Changes
- In Study 1 and Study 2, the proportion of patients who experienced a shift from normal to above the upper limit of normal for serum alanine aminotransferase (ALT) was 5% for Safinamide 50 mg, 7% for Safinamide 100 mg, and 3% for placebo. No patient treated with Safinamide experienced an increase in ALT that was 3 times the upper limit of normal or higher.
- The proportion of patients with a shift from normal to above the upper limit of normal for serum aspartate aminotransferase (AST) was 7% for Safinamide 50 mg, 6% for Safinamide 100 mg, and 3% for placebo. The incidence of patients with an increase in AST to at least 3 times the upper limit of normal was similar for Safinamide and placebo.
## Postmarketing Experience
- The following adverse reactions have been identified during post-approval of use of Safinamide outside of the United States. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- A postmarketing report describes a patient who developed a hypersensitivity reaction consisting of swelling of the tongue and gingiva, dyspnea and skin rash. The symptoms resolved shortly after Safinamide was discontinued, but reappeared following rechallenge a month later.
# Drug Interactions
- MAO Inhibitors
- Opioid Drugs
- Serotonergic Drugs
- Dextromethorphan
- Sympathomimetic Medications
- Tyramine
- Substrates of Breast Cancer Resistance Protein (BCRP)
- Dopaminergic Antagonists
- Safinamide is contraindicated for use with other drugs in the MAO inhibitor class or other drugs that are potent inhibitors of monoamine oxidase (e.g., linezolid, an oxazolidinone antibacterial, which also has reversible nonselective MAO inhibition activity). Co-administration increases the risk of nonselective MAO inhibition, which may lead to hypertensive crisis. At least 14 days should elapse between discontinuation of Safinamide and initiation of treatment with other MAOIs.
- Isoniazid has some monoamine oxidase inhibiting activity. Monitor for hypertension and reaction to dietary tyramine in patients treated concomitantly with isoniazid and Safinamide.
- Because serious, sometimes fatal reactions have been precipitated with concomitant use of Safinamide with opioid drugs (e.g., meperidine and its derivatives, methadone, propoxyphene, or tramadol) and MAO inhibitors, including selective MAO-B inhibitors, concomitant use of these drugs is contraindicated. At least 14 days should elapse between discontinuation of Safinamide and initiation of treatment with these drugs.
- Concomitant use of Safinamide with SNRIs; triazolopyridine, tricyclic or tetracyclic antidepressants; cyclobenzaprine (a skeletal muscle relaxant that is a tricyclic antidepressant derivative); or St. John's wort is contraindicated. At least 14 days should elapse between discontinuation of Safinamide and initiation of treatment with these drugs.
- Monitor patients for symptoms of serotonin syndrome if selective serotonin re-uptake inhibitors are used by patients treated with Safinamide.
- The combination of MAO inhibitors and dextromethorphan has been reported to cause episodes of psychosis or bizarre behavior. Therefore, in view of Safinamide's MAO inhibitory activity, dextromethorphan is contraindicated for use with Safinamide.
- Severe hypertensive reactions have followed the administration of sympathomimetics and nonselective MAO inhibitors. Hypertensive crisis has been reported in patients taking the recommended doses of selective MAO-B inhibitors and sympathomimetic medications. Concomitant use of Safinamide with methylphenidate, amphetamine, and their derivatives is contraindicated.
- Monitor patients for hypertension if Safinamide is prescribed concomitantly with prescription or nonprescription sympathomimetic medications, including nasal, oral, or ophthalmic decongestants and cold remedies.
- MAO in the gastrointestinal tract and liver (primarily type A) provides protection from exogenous amines (e.g., tyramine). If tyramine were absorbed intact, it could lead to severe hypertension, including hypertensive crisis. Aged, fermented, cured, smoked, and pickled foods containing large amounts of exogenous amines (e.g., aged cheese, pickled herring) may cause release of norepinephrine resulting in a rise in blood pressure (Tyramine Reaction). Patients should be advised to avoid foods containing a large amount of tyramine while taking recommended doses of Safinamide.
- Selectivity for inhibiting MAO-B decreases in a dose-related manner above the highest recommended daily dosage, which may increase the risk for hypertension. In addition, isoniazid has some monoamine oxidase inhibiting activity. Monitor for hypertension and reaction to dietary tyramine in patients treated with isoniazid and Safinamide.
- Safinamide and its major metabolite may inhibit intestinal breast cancer resistance protein (BCRP). Inhibition of BCRP could increase plasma concentrations of BCRP substrates. Examples of substrates of BCRP include methotrexate, mitoxantrone, imatinib, irrinotecan, lapatinib, rosuvastatin, sulfasalazine, and topotecan. Monitor patients for increased pharmacologic or adverse effect of the BCRP substrates if Safinamide is used concomitantly.
- Dopamine antagonists, such as antipsychotics or metoclopramide, may decrease the effectiveness of Safinamide and exacerbate the symptoms of Parkinson's disease.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Pregnancy Category C
- There are no adequate and well-controlled studies of Safinamide in pregnant women. In animals, developmental toxicity, including teratogenic effects, was observed when Safinamide was administered during pregnancy at clinically relevant doses. Developmental toxicity was observed at Safinamide doses lower than those used clinically when Safinamide was administered during pregnancy in combination with levodopa/carbidopa. Safinamide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- In an embryofetal development study in rats, oral administration of Safinamide (0, 50, 100, or 150 mg/kg/day) throughout organogenesis resulted in dose-related increases in fetal abnormalities (primarily urogenital malformations) at all doses. The lowest dose tested is approximately 5 times the maximum recommended human dose (MRHD) of 100 mg on a body surface area (mg/m 2) basis. In a combination embryofetal development study of Safinamide and levodopa (LD)/carbidopa (CD) in rats (80/20 mg/kg/day LD/CD in combination with 0, 25, 50, or 100 mg/kg/day Safinamide or 100 mg/kg/day Safinamide alone) increased incidences of fetal visceral and skeletal malformations and variations were observed at all doses of Safinamide in combination with CD/LD and with Safinamide alone. The lowest dose of Safinamide tested (25 mg/kg/day) is approximately 2 times the MRHD on a mg/m 2 basis.
- In embryofetal development studies in rabbits, no developmental toxicity was observed at up to the highest oral dose of Safinamide tested (100 mg/kg/day). However, when Safinamide (4, 12, or 40 mg/kg/day) was administered throughout organogenesis in a combination study of Safinamide with LD/CD (80/20 mg/kg/day LD/CD) there was an increased incidence of embryofetal death and cardiac and skeletal malformations, compared to LD/CD alone. A no-effect dose for Safinamide was not established; the lowest effect dose of Safinamide tested (4 mg/kg/day) is less than the MRHD on a mg/m 2 basis.
- In a rat pre- and postnatal development study, oral administration of Safinamide (0, 4, 12.5, or 37.5 mg/kg/day) throughout pregnancy and lactation resulted in skin discoloration of the offspring, presumed to be due to hepatobiliary toxicity, at the mid and high doses and decreased body weight and increased postnatal mortality in offspring at the highest dose tested. The no effect dose (4 mg/kg/day) is less than the MRHD on a mg/m 2 basis.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Safinamide in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Safinamide during labor and delivery.
### Nursing Mothers
- Skin discoloration, presumed to be caused by hyperbilirubinemia resulting from hepatobiliary toxicity, was observed in rat pups indirectly exposed to Safinamide through the milk during the lactation period. It is not known whether this drug is present in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Safinamide, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
- The safety and effectiveness of Safinamide in pediatric patients have not been established. No juvenile toxicity studies have been performed in animals.
### Geriatic Use
- Of the 1516 subjects exposed to Safinamide in clinical studies, 38% were 65 and over, while 4% were 75 and over. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
### Gender
There is no FDA guidance on the use of Safinamide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Safinamide with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Safinamide in patients with renal impairment.
### Hepatic Impairment
- Safinamide plasma concentrations are increased in patients with hepatic impairment.
- In patients with moderate hepatic impairment (Child-Pugh B: 7-9), the maximum recommended dosage of Safinamide is 50 mg once daily. Safinamide has not been studied in patients with severe hepatic impairment (Child-Pugh C: 10-15), and is contraindicated in these patients. If patients progress from moderate to severe hepatic impairment, treatment with Safinamide should be stopped.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Safinamide in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Safinamide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Give at the same time each day, with or without meals.
- Avoid consumption of foods high in tyramine.
### Monitoring
- An increase in the total daily "on" time without troublesome dyskinesia associated with Parkinson disease may indicate efficacy.
- Hypertension: New onset of or lack of blood pressure control in hypertensive patients, especially in patients receiving concomitant sympathomimetics, including decongestants and cold remedies.
- New or increased impulse control or compulsive behaviors: Such as gambling, sexual, or spending urges, which may be unrecognizable by the patient as abnormal.
- Visual changes: Periodically in patients with history of retinal or macular degeneration, uveitis, inherited retinal conditions, family history of hereditary retinal disease, albinism, rentinis pigmentosa or any active retinopathy (eg diabetic retinopathy).
# IV Compatibility
There is limited information regarding the compatibility of Safinamide and IV administrations.
# Overdosage
- There is no human experience with Safinamide overdose.
- There is no known antidote to Safinamide nor any specific treatment for Safinamide overdose. If an important overdose occurs, Safinamide treatment should be discontinued and supportive treatment should be administered as clinically indicated. In cases of overdose with Safinamide, dietary tyramine restriction should be observed for several weeks.
- The Poison Control Center should be called at 1-800-222-1222 for the most current treatment guidelines.
# Pharmacology
## Mechanism of Action
- The precise mechanism by which Safinamide exerts its effect in Parkinson's disease is unknown. Safinamide is an inhibitor of monoamine oxidase B (MAO-B). Inhibition of MAO-B activity, by blocking the catabolism of dopamine, is thought to result in an increase in dopamine levels and a subsequent increase in dopaminergic activity in the brain.
## Structure
## Pharmacodynamics
- Safinamide inhibits monoamine oxidase B (MAO-B), with more than 1000-fold selectivity over MAO-A. In clinical studies, complete inhibition (>90%) of MAO-B was measured at doses > 20 mg.
Tyramine Challenge Test
- In an oral tyramine challenge study, Safinamide produced a distinct but relatively small increase in tyramine sensitivity to increase blood pressure. The results suggest that Safinamide at a dose of 50 mg or 100 mg is relatively selective for inhibiting MAO-B and can be used without dietary tyramine restriction. Relative selectivity of XADAGO for inhibiting MAO-B decreases above the highest recommended daily dosage (100 mg).
Cardiac Electrophysiology
- The effect of Safinamide on the QTc interval was evaluated in a randomized placebo and positive controlled double-blind, multiple-dose parallel thorough QTc study in 240 healthy subjects. At a dose of 350 mg (3.5 times the maximum recommended dosage), Safinamide did not prolong the QTc interval.
## Pharmacokinetics
- Pharmacokinetics of Safinamide is linear over a range of 50 mg to 300 mg (3 times the maximum recommended daily dose). Steady state is reached within 5 to 6 days.
Absorption
- After single and multiple oral dosing under fasting conditions, Tmax of Safinamide ranges from 2 to 3 hours. Absolute bioavailability of Safinamide is 95% after oral administration, and first pass metabolism is negligible. A slight delay in Tmax was observed in the fed state relative to the fasted condition, but there was no effect on Safinamide AUC 0−∞ and Cmax.
Distribution
- The volume of distribution (Vss) is approximately 165 L, indicating extensive extravascular distribution. Safinamide is not highly protein bound (unbound fraction is 11 to 12%).
Metabolism and Excretion
- In humans, Safinamide is almost exclusively eliminated via metabolism (~5% of the drug is eliminated unchanged, mainly in urine), through three main metabolic pathways. One pathway involves hydrolytic oxidation of the amide moiety leading to the primary metabolite 'Safinamide acid' (NW-1153). Another pathway is oxidative cleavage of the ether bond forming 'O- debenzylated Safinamide' (NW-1199). Finally, the 'N-dealkylated acid' (NW-1689) is formed by oxidative cleavage of the amine bond of either Safinamide or the primary Safinamide acid metabolite (NW-1153). The 'N-dealkylated acid' (NW-1689) undergoes further conjugation with glucuronic acid yielding its acyl glucuronide. NW-1689 is the main circulating metabolite in human plasma, exceeding the exposure of the parent (161% of parent). NW-1689 AG and NW-1153 account for about 18% and 11% of the parent drug exposure, respectively. None of the metabolites has pharmacological activity.
- Safinamide is predominantly metabolized by non-microsomal enzymes (cytosolic amidases/MAO-A); CYP3A4 and other CYP iso-enzymes play only a minor role in its overall biotransformation.
- The total clearance of Safinamide was determined to be 4.6 L/h. Terminal half-life is 20-26 h. The primary route of excretion is through the kidney (76% of Safinamide dose recovered in the urine, primarily in the form of inactive metabolites).
Specific Populations
- Age: Geriatric Population: There are limited clinical data on the use of Safinamide in the elderly (>75 years). These data suggest that the pharmacokinetics of Safinamide is not affected by age.
- Race: The pharmacokinetics of Safinamide is not influenced by race.
- Sex: The pharmacokinetics of Safinamide is not influenced by sex.
- Hepatic Impairment: The disposition of Safinamide was assessed in subjects with mild and moderate hepatic impairment and compared with subjects with normal hepatic function. A marginal increase in the exposure of Safinamide (approximately 30% increase in AUC) was observed in subjects with mild hepatic impairment (Child-Pugh A). In subjects with moderate hepatic impairment (Child-Pugh B), exposure to Safinamide was increased by about 80% (CI: 154-215%). Safinamide has not been studied in patients with severe hepatic impairment (Child-Pugh C).
- Renal Impairment: The effect of renal impairment on Safinamide pharmacokinetics was investigated in an open-label, parallel-group, single oral dose study in subjects with moderate renal impairment, severe renal impairment, or normal renal function. The pharmacokinetics of Safinamide was not affected by impaired renal function.
Drug Interaction Studies
- In Vitro Studies: In vitro metabolism studies indicate no meaningful inhibition or induction of Cytochrome P450 (CYP) based enzymes by Safinamide and its major metabolites at concentrations that are relevant for dosing. Safinamide or its major metabolites at clinically relevant concentrations are not inhibitors of MAO-A, levodopa decarboxylase or aldehyde dehydrogenase enzymes.
- Safinamide is not a substrate of P-gp. Safinamide and its metabolites did not inhibit P-gp or other transporters OCT2, OATP1B1, OATP1B3, BSEP, OAT1/3/4. Safinamide and NW-1689 may inhibit BCRP at the 100 mg dose.
- In Vivo Studies: Dedicated drug-drug interactions studies conducted with ketoconazole, levodopa (LD) and CYP1A2 and CYP3A4 substrates (caffeine and midazolam, respectively) did not demonstrate any clinically significant effects on the pharmacokinetic profile of Safinamide, or on the pharmacokinetic profile of co-administered levodopa or CYP1A2 and CYP3A4 substrates.
## Nonclinical Toxicology
Carcinogenesis
- In carcinogenicity studies in mice and rats, Safinamide was administered at oral doses of 0, 50, 100 and 200 mg/kg/day, and 0, 25, 50 and 100 mg/kg/day, respectively, for 2 years. The highest doses tested in both species were approximately 10 times the maximum recommended human dose (MRHD) of 100 mg/day on a body surface area (mg/m 2) basis. No evidence of tumorigenic potential was observed in either species.
Mutagenesis
- Safinamide was negative for genotoxicity in in vitro (Ames, mouse lymphoma) and in vivo (mouse micronucleus) assays.
Impairment of Fertility
- In a rat fertility study in which males and females were orally administered Safinamide (0, 50, 100, 150 mg/kg/day) prior to and during mating and continuing through early pregnancy in females, adverse effects on reproductive function were observed in both males (sperm abnormalities) and females (decreased corpora lutea, increased pre-implantation loss). The no-effect dose for reproductive toxicity (50 mg/kg/day) is approximately 5 times the MRHD on a mg/m 2 basis.
Retinal Pathology in Rats
- Degeneration and loss of photoreceptor cells were observed in the retina of both albino and pigmented rats at plasma exposures lower than that in humans at the maximum recommended human dose of 100 mg/kg/day. The findings were dose- and time-dependent and progressed from minimal loss to severe outer nuclear cell layer loss after one year of oral dosing with Safinamide. In a two year study, total retinal atrophy and scarring and lens opacities (cataracts) were seen at all oral doses tested (0, 25, 50, and 100 mg/kg/day).
- In a study in rats dosed orally with Safinamide alone or in combination with pramipexole, pramipexole, at a dose (25 mg/kg/day) that did not cause retinal changes, exacerbated the retinal pathology caused by Safinamide alone (50 mg/kg/day) in both pigmented and albino rats.
- Investigative studies were not able to identify a mechanism underlying the retinal toxicity; the relevance to humans is unknown.
# Clinical Studies
- Two double-blind, placebo-controlled, multi-national, 24-week studies (Study 1 and Study 2) were conducted in PD patients experiencing "OFF" Time during treatment with carbidopa/levodopa and other PD medications, e.g., dopamine agonists, catechol-O-methyl transferase (COMT) inhibitors, anticholinergics, and/or amantadine. In both studies, the primary measure of effectiveness was the change from baseline in total daily "ON" Time without troublesome dyskinesia (i.e., "ON" Time without dyskinesia plus "ON" Time with non- troublesome dyskinesia), based on 18-hour diaries completed by patients for at least 3 days before each of the scheduled visits. Secondary endpoints included "OFF" Time during the diary period and reduction in Uniform Parkinson's Disease Rating Scale (UPDRS) Part III (motor examination).
- In Study 1, patients (n=645) were randomized equally to treatment with Safinamide 50 mg/day (n=217 patients), Safinamide 100 mg/day (n=216 patients), or placebo (n=212 patients), and had at least one post-baseline assessment of "ON" Time.
- The percentages of patients taking stable doses of other classes of PD medications, in addition to levodopa/decarboxylase inhibitor, were: dopamine agonists (61%), COMT inhibitors (24%), anticholinergics (37%), and amantadine (14%). Use of MAO inhibitors was prohibited. The average daily dosage of levodopa was 630 mg. The mean duration of Parkinson's disease was approximately 8 years.
- In Study 1, Safinamide 50 mg/day and 100 mg/day significantly increased "ON" Time compared to placebo (Table 2). The increase in "ON" Time without troublesome dyskinesia was accompanied by a similar significant reduction in "OFF" Time and a reduction in Unified Parkinson's Disease Rating Scale Part III (UPDRS III) scores assessed during "ON" Time (Table 3). Improvement in "ON Time" occurred without an increase in troublesome dyskinesia.
- The effect of Safinamide 100 mg on "ON" Time was only slightly numerically greater than the effect of Safinamide 50 mg. In addition, the time course of improvement in total daily "ON" Time was similar between both doses (Figure 1). The time course of improvement in total daily "ON" Time showed numerically greater improvement with both Safinamide 50mg and 100 mg compared to placebo, at all post-baseline timepoints (Figure 1).
- Figure 2 shows the empirical cumulative distribution functions (CDF) for the change from baseline to Week 24 in total daily "ON" Time in Study 1. The cumulative percentage of patients with a change in "ON" Time was similar for the Safinamide 50 mg and 100 mg groups. The cumulative percentage of patients with an increase in "ON" Time is higher for both Safinamide 50 mg and 100 mg treated patients than for placebo patients.
- Patients who dropped out of the study because of an adverse reaction, lack of efficacy, non-compliance, or withdrawal of consent were treated as treatment failures and assumed to have the smallest change from baseline among all patients. The failure rates are 6.1%, 5.6%, and 6.9% for the placebo group, Safinamide 50 mg/day group, and Safinamide 100 mg/day group, respectively.
- In Study 2, patients (n=549) were randomized to treatment with Safinamide 100 mg daily (n=274 patients) or placebo (n=275 patients) for up to 24 weeks. The percentages of patients taking stable doses of other classes of PD medication, in addition to levodopa/decarboxylase inhibitor, were: dopamine agonists (74%), COMT inhibitors (18%), anticholinergics (17%), and amantadine (30%). Use of MAO inhibitors was prohibited. The average daily dosage of levodopa was 777 mg. The mean duration of Parkinson's disease was approximately 9 years.
- In Study 2, Safinamide was significantly better than placebo for increasing "ON" Time (Table 4). The observed increase in "ON" Time without troublesome dyskinesia was accompanied by a reduction in "OFF" Time of similar magnitude and a reduction in UPDRS III score (assessed during "ON" Time). The time course of effect was similar to that showed in the above figure for Study 1. As in Study 1, the increase in "ON" Time without troublesome dyskinesia was accompanied by a similar significant reduction in "OFF" Time and a reduction in Unified Parkinson's Disease Rating Scale Part III (UPDRS III) scores assessed during "ON" Time (Table 5).
- The time course of improvement in total daily "ON" Time showed numerically greater improvement with Safinamide 100 mg compared to placebo at all post-baseline timepoints (Figure 3).
- Figure 4 shows the empirical cumulative distribution functions (CDF) for the change from baseline to Week 24 in total daily "ON" Time in Study 2. The cumulative percentage of patients with an increase in "ON" Time treated with Safinamide 50 mg to 100 mg is higher than for placebo patients.
# How Supplied
- 50 mg (orange to copper colored with metallic gloss, round film-coated, biconcave shaped tablet embossed with "50" on one side; approximately 7 mm in diameter).
- 100 mg (orange to copper colored with metallic gloss, round film-coated, biconcave shaped tablet embossed with "100" on one side; approximately 9 mm in diameter).
## Storage
- Store at 25°C (77°F); excursions permitted between 15°C to 30°C (59°F to 86°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Hypertension
- Advise patients that treatment with recommended doses of Safinamide may be associated with elevations of blood pressure or onset of hypertension. Tell patients who experience elevation of blood pressure while taking Safinamide to contact their healthcare provider.
- Explain the risk of using higher than recommended daily doses of Safinamide, and provide a brief description of the tyramine associated hypertensive reaction.
- Advise patients to avoid certain foods (e.g., aged cheese) containing a very large amount of tyramine while taking recommended doses of Safinamide because of the potential for large increases in blood pressure. If patients eat foods very rich in tyramine and do not feel well soon after eating, they should contact their healthcare provider.
Serotonin Syndrome
- Tell patients to inform their physician if they are taking, or planning to take, any prescription or over-thecounter drugs, especially antidepressants and over-the-counter cold medications, because there is a potential for interaction with Safinamide. Because patients should not use meperidine or certain other analgesics with Safinamide, they should contact their healthcare provider before taking new medications including antidepressants, analgesics, and prescription or nonprescription decongestants.
Falling Asleep During Activities of Daily Living and Somnolence
- Inform patients about the potential for sedating effects associated with Safinamide and other dopaminergic medications, including somnolence and particularly to the possibility of falling asleep while engaged in activities of daily living. Because somnolence can be a frequent adverse reaction with potentially serious consequences, patients should not operate a motor vehicle or engage in other potentially dangerous activities until they have gained sufficient experience with Safinamide.
- Advise patients that if increased somnolence or new episodes of falling asleep during activities of daily living (e.g., watching television, passenger in a car, etc.) are experienced at any time during treatment, they should not drive or participate in potentially dangerous activities until they have contacted their physician. Patients should not drive, operate machinery, or work at heights during treatment if they have previously experienced somnolence and/or have fallen asleep without warning prior to use of Safinamide.
- Because of possible additive effects, advise patients about the potential for increased somnolence when patients are taking other sedating medications, alcohol, or other central nervous system depressants (e.g., benzodiazepines, antipsychotics, antidepressants) in combination with Safinamide.
Dyskinesia
- Advise patients taking Safinamide as adjunct to levodopa that there is a possibility of dyskinesia or increased dyskinesia.
Hallucinations / Psychotic Behavior
Inform patients that hallucinations or other manifestations of psychotic behavior can occur when taking Safinamide. Advise patients that, if they have a major psychotic disorder, that Safinamide should not ordinarily be used because of the risk of exacerbating the psychosis. Patients with a major psychotic disorder should also be aware that many treatments for psychosis may decrease the effectiveness of Safinamide.
Impulse Control/Compulsive Behaviors
- Advise patients that they may experience intense urges to gamble, increased sexual urges, other intense urges, and the inability to control these urges while taking Safinamide. Although it is not proven that the medications caused these events, these urges were reported to have stopped in some cases when the dose was reduced or the medication was stopped. Prescribers should ask patients about the development of new or increased gambling urges, sexual urges, or other urges while being treated with Safinamide. Patients should inform their physician if they experience these urges while taking Safinamide.
Withdrawal-Emergent Hyperpyrexia and Confusion
- Tell patients to contact their healthcare provider if they wish to discontinue Safinamide and seek guidance for tapering Safinamide instead of abruptly discontinuing Safinamide.
Missing Dose
- Instruct patients to take Safinamide as prescribed. If a dose is missed, instruct patients to take the next dose at the usual time on the following day.
Concomitant Medications
- Advise patients to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter medications because of a potential for interactions.
# Precautions with Alcohol
Alcohol-Safinamide interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
- Xadago
# Look-Alike Drug Names
There is limited information regarding Safinamide Look-Alike Drug Names in the drug label.
# Drug Shortage Status
Drug Shortage
# Price | Safinamide
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yashasvi Aryaputra[2];
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# Overview
Safinamide is a monoamine oxidase type B (MAO-B) inhibitor that is FDA approved for the adjunctive treatment of levodopa/carbidopa in patients with Parkinson's disease (PD) experiencing "off" episodes. Common adverse reactions include dyskinesia, fall, nausea, and insomnia.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Safinamide is indicated as adjunctive treatment to levodopa/carbidopa in patients with Parkinson's disease (PD) experiencing "off" episodes.
- The recommended starting dosage of Safinamide is 50 mg administered orally once daily (at the same time of day), without regard to meals. After two weeks, the dosage may be increased to 100 mg once daily, based on individual need and tolerability.
- Daily dosages of Safinamide above 100 mg have not been shown to provide additional benefit, and higher dosages increase the risk for adverse reactions. Safinamide has been shown to be effective only in combination with levodopa/carbidopa.
- If a dose is missed, the next dose should be taken at the same time the next day.
- Safinamide 100 mg should be tapered by decreasing the dose to 50 mg for one week before stopping.
- In patients with moderate hepatic impairment (Child-Pugh B: 7-9), the maximum recommended dosage of Safinamide is 50 mg orally once daily. Safinamide is contraindicated in patients with severe hepatic impairment (Child-Pugh C: 10-15). If a patient taking 50 mg Safinamide progresses from moderate to severe hepatic impairment, discontinue Safinamide.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Safinamide Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding Safinamide Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Safinamide FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Safinamide Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding Safinamide Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
# Contraindications
- Safinamide is contraindicated in patients with:
- Concomitant use of other drugs in the monoamine oxidase inhibitor (MAOI) class or other drugs that are potent inhibitors of monoamine oxidase, including linezolid. The combination may result in increased blood pressure, including hypertensive crisis.
- Concomitant use of opioid drugs (e.g., meperidine and its derivatives, methadone, propoxyphene, or tramadol); serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic, tetracyclic, or triazolopyridine antidepressants; cyclobenzaprine; methylphenidate, amphetamine, and their derivatives; or St John's wort. Concomitant use could result in life-threatening serotonin syndrome.
- Concomitant use of dextromethorphan. The combination of MAO inhibitors and dextromethorphan has been reported to cause episodes of psychosis or abnormal behavior.
- A history of a hypersensitivity to Safinamide. Reactions have included swelling of the tongue and oral mucosa, and dyspnea.
- Severe hepatic impairment (Child-Pugh C: 10-15).
# Warnings
- Safinamide may cause hypertension or exacerbate existing hypertension. In clinical trials, the incidence of hypertension was 7% for Safinamide 50 mg, 5% for Safinamide 100 mg, and 4% for placebo. Monitor patients for new onset hypertension or hypertension that is not adequately controlled after starting Safinamide. Medication adjustment may be necessary if elevation of blood pressure is sustained.
- Monitor for hypertension if Safinamide is prescribed concomitantly with sympathomimetic medications, including prescription or nonprescription nasal, oral, and ophthalmic decongestants and cold remedies.
- Safinamide is a selective inhibitor of MAO-B at the recommended dosages of 50 mg or 100 mg daily. Selectivity for inhibiting MAO-B decreases above the recommended daily dosages. Therefore, Safinamide should not be used at daily dosages exceeding those recommended because of the risks of hypertension, exacerbation of existing hypertension, or hypertensive crisis.
- Dietary tyramine restriction is not required during treatment with recommended doses of Safinamide. However, use with certain foods that contain very high amounts (i.e., more than 150 mg) of tyramine could cause severe hypertension, resulting from an increased sensitivity to tyramine in patients taking recommended dosages of Safinamide, and patients should be advised to avoid such foods.
- Isoniazid has some monoamine oxidase inhibiting activity. Monitor for hypertension and reaction to dietary tyramine in patients treated concomitantly with isoniazid and Safinamide.
- The development of a potentially life-threatening serotonin syndrome has been reported in patients on concomitant treatment with MAO inhibitors (including selective MAO-B inhibitors), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, tetracyclic antidepressants, triazolopyridine antidepressants, cyclobenzaprine, opioid drugs (e.g., meperidine and meperidine derivatives, propoxyphene, tramadol), and methylphenidate, amphetamine, and their derivatives. Concomitant use of Safinamide with these drugs is contraindicated.
- In clinical trials, serotonin syndrome was reported in a patient treated with Safinamide and an SSRI. Use the lowest effective dose of SSRIs in patients treated with concomitant Safinamide.
- Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).
- Patients treated with dopaminergic medications have reported falling asleep while engaged in activities of daily living, including the operation of motor vehicles, which sometimes has resulted in accidents. Patients may not perceive warning signs, such as excessive drowsiness, or they may report feeling alert immediately prior to the event.
- In clinical studies, sleep attacks/sudden onset of sleep were reported in patients treated with Safinamide 100 mg/day.
- If a patient develops daytime sleepiness or episodes of falling asleep during activities that require full attention (e.g., driving a motor vehicle, conversations, eating), Safinamide should ordinarily be discontinued. If a decision is made to continue these patients on Safinamide, advise them to avoid driving and other potentially dangerous activities.
- Safinamide may cause dyskinesia or exacerbate pre-existing dyskinesia.
- In clinical trials, the incidence of dyskinesia was 21% for Safinamide 50 mg, 18% for Safinamide 100 mg, and 9% for placebo. There was a greater incidence of dyskinesia causing study discontinuation in Parkinson's disease patients treated with Safinamide 50 mg or 100 mg (1%), compared to placebo (0%).
- Reducing the patient's daily levodopa dosage or the dosage of another dopaminergic drug may mitigate dyskinesia.
- Patients with a major psychotic disorder should ordinarily not be treated with Safinamide because of the risk of exacerbating the psychosis with an increase in central dopaminergic tone. In addition, treatments for psychosis that antagonize the effects of dopaminergic medications may exacerbate the symptoms of Parkinson's disease.
- Consider dosage reduction or stopping the medication if a patient develops hallucinations or psychotic-like behaviors while taking Safinamide.
- Patients can experience intense urges to gamble, increased sexual urges, intense urges to spend money, binge eating, and/or other intense urges, and the inability to control these urges while taking one or more of the medications, including Safinamide, that increase central dopaminergic tone. In some cases, these urges were reported to have stopped when the dose was reduced or the medication was discontinued. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending or other urges while being treated with Safinamide. Consider dose reduction or stopping the medication if a patient develops such urges while taking Safinamide.
- A symptom complex resembling neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in drugs that increase central dopaminergic tone.
- Retinal degeneration and loss of photoreceptor cells were observed in albino and pigmented rats administered Safinamide orally in toxicity studies of up to 6 months duration. In albino rats administered Safinamide orally for two years, retinal scarring and cataracts were observed at all doses tested.
- Periodically monitor patients for visual changes in patients with a history of retinal/macular degeneration, uveitis, inherited retinal conditions, family history of hereditary retinal disease, albinism, retinitis pigmentosa, or any active retinopathy (e.g., diabetic retinopathy).
# Adverse Reactions
## Clinical Trials Experience
- Clinical trials are conducted under widely varying conditions; therefore, adverse reactions observed in the clinical trials of a drug cannot be directly compared to the incidence in the clinical trials of another drug and may not reflect the incidence observed in clinical practice.
Common Adverse Reactions in Placebo-Controlled Parkinson's Disease Studies
- Table 1 shows the incidence of adverse reactions with an incidence of at least 2% on Safinamide 100 mg/day and greater than placebo in controlled studies in Parkinson's disease (Study 1 and Study 2). The most common adverse reactions associated with Safinamide treatment in which the incidence for Safinamide 100 mg/day was at least 2% greater than the incidence for placebo were dyskinesia, fall, nausea, and insomnia.
Adverse Reactions Reported as Reason for Discontinuation from Study
- In pooled placebo-controlled studies (Study 1 and Study 2) in patients with Parkinson's disease taking a stable dose of carbidopa/levodopa with or without other PD medications, there was an increase in the incidence of Safinamide-treated patients who discontinued from the study because of adverse reactions. The incidence of patients discontinuing from Study 1 and Study 2 for any adverse reaction was 5% for Safinamide 50 mg/day, 6% for Safinamide 100 mg/day, and 4% for placebo. The most frequently reported adverse reaction causing study discontinuation was dyskinesia (1% of patients treated with Safinamide 50 mg/day or Safinamide 100 mg/day vs. 0% for placebo).
Abnormal Laboratory Changes
- In Study 1 and Study 2, the proportion of patients who experienced a shift from normal to above the upper limit of normal for serum alanine aminotransferase (ALT) was 5% for Safinamide 50 mg, 7% for Safinamide 100 mg, and 3% for placebo. No patient treated with Safinamide experienced an increase in ALT that was 3 times the upper limit of normal or higher.
- The proportion of patients with a shift from normal to above the upper limit of normal for serum aspartate aminotransferase (AST) was 7% for Safinamide 50 mg, 6% for Safinamide 100 mg, and 3% for placebo. The incidence of patients with an increase in AST to at least 3 times the upper limit of normal was similar for Safinamide and placebo.
## Postmarketing Experience
- The following adverse reactions have been identified during post-approval of use of Safinamide outside of the United States. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- A postmarketing report describes a patient who developed a hypersensitivity reaction consisting of swelling of the tongue and gingiva, dyspnea and skin rash. The symptoms resolved shortly after Safinamide was discontinued, but reappeared following rechallenge a month later.
# Drug Interactions
- MAO Inhibitors
- Opioid Drugs
- Serotonergic Drugs
- Dextromethorphan
- Sympathomimetic Medications
- Tyramine
- Substrates of Breast Cancer Resistance Protein (BCRP)
- Dopaminergic Antagonists
- Safinamide is contraindicated for use with other drugs in the MAO inhibitor class or other drugs that are potent inhibitors of monoamine oxidase (e.g., linezolid, an oxazolidinone antibacterial, which also has reversible nonselective MAO inhibition activity). Co-administration increases the risk of nonselective MAO inhibition, which may lead to hypertensive crisis. At least 14 days should elapse between discontinuation of Safinamide and initiation of treatment with other MAOIs.
- Isoniazid has some monoamine oxidase inhibiting activity. Monitor for hypertension and reaction to dietary tyramine in patients treated concomitantly with isoniazid and Safinamide.
- Because serious, sometimes fatal reactions have been precipitated with concomitant use of Safinamide with opioid drugs (e.g., meperidine and its derivatives, methadone, propoxyphene, or tramadol) and MAO inhibitors, including selective MAO-B inhibitors, concomitant use of these drugs is contraindicated. At least 14 days should elapse between discontinuation of Safinamide and initiation of treatment with these drugs.
- Concomitant use of Safinamide with SNRIs; triazolopyridine, tricyclic or tetracyclic antidepressants; cyclobenzaprine (a skeletal muscle relaxant that is a tricyclic antidepressant derivative); or St. John's wort is contraindicated. At least 14 days should elapse between discontinuation of Safinamide and initiation of treatment with these drugs.
- Monitor patients for symptoms of serotonin syndrome if selective serotonin re-uptake inhibitors are used by patients treated with Safinamide.
- The combination of MAO inhibitors and dextromethorphan has been reported to cause episodes of psychosis or bizarre behavior. Therefore, in view of Safinamide's MAO inhibitory activity, dextromethorphan is contraindicated for use with Safinamide.
- Severe hypertensive reactions have followed the administration of sympathomimetics and nonselective MAO inhibitors. Hypertensive crisis has been reported in patients taking the recommended doses of selective MAO-B inhibitors and sympathomimetic medications. Concomitant use of Safinamide with methylphenidate, amphetamine, and their derivatives is contraindicated.
- Monitor patients for hypertension if Safinamide is prescribed concomitantly with prescription or nonprescription sympathomimetic medications, including nasal, oral, or ophthalmic decongestants and cold remedies.
- MAO in the gastrointestinal tract and liver (primarily type A) provides protection from exogenous amines (e.g., tyramine). If tyramine were absorbed intact, it could lead to severe hypertension, including hypertensive crisis. Aged, fermented, cured, smoked, and pickled foods containing large amounts of exogenous amines (e.g., aged cheese, pickled herring) may cause release of norepinephrine resulting in a rise in blood pressure (Tyramine Reaction). Patients should be advised to avoid foods containing a large amount of tyramine while taking recommended doses of Safinamide.
- Selectivity for inhibiting MAO-B decreases in a dose-related manner above the highest recommended daily dosage, which may increase the risk for hypertension. In addition, isoniazid has some monoamine oxidase inhibiting activity. Monitor for hypertension and reaction to dietary tyramine in patients treated with isoniazid and Safinamide.
- Safinamide and its major metabolite may inhibit intestinal breast cancer resistance protein (BCRP). Inhibition of BCRP could increase plasma concentrations of BCRP substrates. Examples of substrates of BCRP include methotrexate, mitoxantrone, imatinib, irrinotecan, lapatinib, rosuvastatin, sulfasalazine, and topotecan. Monitor patients for increased pharmacologic or adverse effect of the BCRP substrates if Safinamide is used concomitantly.
- Dopamine antagonists, such as antipsychotics or metoclopramide, may decrease the effectiveness of Safinamide and exacerbate the symptoms of Parkinson's disease.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Pregnancy Category C
- There are no adequate and well-controlled studies of Safinamide in pregnant women. In animals, developmental toxicity, including teratogenic effects, was observed when Safinamide was administered during pregnancy at clinically relevant doses. Developmental toxicity was observed at Safinamide doses lower than those used clinically when Safinamide was administered during pregnancy in combination with levodopa/carbidopa. Safinamide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- In an embryofetal development study in rats, oral administration of Safinamide (0, 50, 100, or 150 mg/kg/day) throughout organogenesis resulted in dose-related increases in fetal abnormalities (primarily urogenital malformations) at all doses. The lowest dose tested is approximately 5 times the maximum recommended human dose (MRHD) of 100 mg on a body surface area (mg/m 2) basis. In a combination embryofetal development study of Safinamide and levodopa (LD)/carbidopa (CD) in rats (80/20 mg/kg/day LD/CD in combination with 0, 25, 50, or 100 mg/kg/day Safinamide or 100 mg/kg/day Safinamide alone) increased incidences of fetal visceral and skeletal malformations and variations were observed at all doses of Safinamide in combination with CD/LD and with Safinamide alone. The lowest dose of Safinamide tested (25 mg/kg/day) is approximately 2 times the MRHD on a mg/m 2 basis.
- In embryofetal development studies in rabbits, no developmental toxicity was observed at up to the highest oral dose of Safinamide tested (100 mg/kg/day). However, when Safinamide (4, 12, or 40 mg/kg/day) was administered throughout organogenesis in a combination study of Safinamide with LD/CD (80/20 mg/kg/day LD/CD) there was an increased incidence of embryofetal death and cardiac and skeletal malformations, compared to LD/CD alone. A no-effect dose for Safinamide was not established; the lowest effect dose of Safinamide tested (4 mg/kg/day) is less than the MRHD on a mg/m 2 basis.
- In a rat pre- and postnatal development study, oral administration of Safinamide (0, 4, 12.5, or 37.5 mg/kg/day) throughout pregnancy and lactation resulted in skin discoloration of the offspring, presumed to be due to hepatobiliary toxicity, at the mid and high doses and decreased body weight and increased postnatal mortality in offspring at the highest dose tested. The no effect dose (4 mg/kg/day) is less than the MRHD on a mg/m 2 basis.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Safinamide in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Safinamide during labor and delivery.
### Nursing Mothers
- Skin discoloration, presumed to be caused by hyperbilirubinemia resulting from hepatobiliary toxicity, was observed in rat pups indirectly exposed to Safinamide through the milk during the lactation period. It is not known whether this drug is present in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Safinamide, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
- The safety and effectiveness of Safinamide in pediatric patients have not been established. No juvenile toxicity studies have been performed in animals.
### Geriatic Use
- Of the 1516 subjects exposed to Safinamide in clinical studies, 38% were 65 and over, while 4% were 75 and over. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
### Gender
There is no FDA guidance on the use of Safinamide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Safinamide with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Safinamide in patients with renal impairment.
### Hepatic Impairment
- Safinamide plasma concentrations are increased in patients with hepatic impairment.
- In patients with moderate hepatic impairment (Child-Pugh B: 7-9), the maximum recommended dosage of Safinamide is 50 mg once daily. Safinamide has not been studied in patients with severe hepatic impairment (Child-Pugh C: 10-15), and is contraindicated in these patients. If patients progress from moderate to severe hepatic impairment, treatment with Safinamide should be stopped.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Safinamide in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Safinamide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Give at the same time each day, with or without meals.
- Avoid consumption of foods high in tyramine.
### Monitoring
- An increase in the total daily "on" time without troublesome dyskinesia associated with Parkinson disease may indicate efficacy.
- Hypertension: New onset of or lack of blood pressure control in hypertensive patients, especially in patients receiving concomitant sympathomimetics, including decongestants and cold remedies.
- New or increased impulse control or compulsive behaviors: Such as gambling, sexual, or spending urges, which may be unrecognizable by the patient as abnormal.
- Visual changes: Periodically in patients with history of retinal or macular degeneration, uveitis, inherited retinal conditions, family history of hereditary retinal disease, albinism, rentinis pigmentosa or any active retinopathy (eg diabetic retinopathy).
# IV Compatibility
There is limited information regarding the compatibility of Safinamide and IV administrations.
# Overdosage
- There is no human experience with Safinamide overdose.
- There is no known antidote to Safinamide nor any specific treatment for Safinamide overdose. If an important overdose occurs, Safinamide treatment should be discontinued and supportive treatment should be administered as clinically indicated. In cases of overdose with Safinamide, dietary tyramine restriction should be observed for several weeks.
- The Poison Control Center should be called at 1-800-222-1222 for the most current treatment guidelines.
# Pharmacology
## Mechanism of Action
- The precise mechanism by which Safinamide exerts its effect in Parkinson's disease is unknown. Safinamide is an inhibitor of monoamine oxidase B (MAO-B). Inhibition of MAO-B activity, by blocking the catabolism of dopamine, is thought to result in an increase in dopamine levels and a subsequent increase in dopaminergic activity in the brain.
## Structure
## Pharmacodynamics
- Safinamide inhibits monoamine oxidase B (MAO-B), with more than 1000-fold selectivity over MAO-A. In clinical studies, complete inhibition (>90%) of MAO-B was measured at doses > 20 mg.
Tyramine Challenge Test
- In an oral tyramine challenge study, Safinamide produced a distinct but relatively small increase in tyramine sensitivity to increase blood pressure. The results suggest that Safinamide at a dose of 50 mg or 100 mg is relatively selective for inhibiting MAO-B and can be used without dietary tyramine restriction. Relative selectivity of XADAGO for inhibiting MAO-B decreases above the highest recommended daily dosage (100 mg).
Cardiac Electrophysiology
- The effect of Safinamide on the QTc interval was evaluated in a randomized placebo and positive controlled double-blind, multiple-dose parallel thorough QTc study in 240 healthy subjects. At a dose of 350 mg (3.5 times the maximum recommended dosage), Safinamide did not prolong the QTc interval.
## Pharmacokinetics
- Pharmacokinetics of Safinamide is linear over a range of 50 mg to 300 mg (3 times the maximum recommended daily dose). Steady state is reached within 5 to 6 days.
Absorption
- After single and multiple oral dosing under fasting conditions, Tmax of Safinamide ranges from 2 to 3 hours. Absolute bioavailability of Safinamide is 95% after oral administration, and first pass metabolism is negligible. A slight delay in Tmax was observed in the fed state relative to the fasted condition, but there was no effect on Safinamide AUC 0−∞ and Cmax.
Distribution
- The volume of distribution (Vss) is approximately 165 L, indicating extensive extravascular distribution. Safinamide is not highly protein bound (unbound fraction is 11 to 12%).
Metabolism and Excretion
- In humans, Safinamide is almost exclusively eliminated via metabolism (~5% of the drug is eliminated unchanged, mainly in urine), through three main metabolic pathways. One pathway involves hydrolytic oxidation of the amide moiety leading to the primary metabolite 'Safinamide acid' (NW-1153). Another pathway is oxidative cleavage of the ether bond forming 'O- debenzylated Safinamide' (NW-1199). Finally, the 'N-dealkylated acid' (NW-1689) is formed by oxidative cleavage of the amine bond of either Safinamide or the primary Safinamide acid metabolite (NW-1153). The 'N-dealkylated acid' (NW-1689) undergoes further conjugation with glucuronic acid yielding its acyl glucuronide. NW-1689 is the main circulating metabolite in human plasma, exceeding the exposure of the parent (161% of parent). NW-1689 AG and NW-1153 account for about 18% and 11% of the parent drug exposure, respectively. None of the metabolites has pharmacological activity.
- Safinamide is predominantly metabolized by non-microsomal enzymes (cytosolic amidases/MAO-A); CYP3A4 and other CYP iso-enzymes play only a minor role in its overall biotransformation.
- The total clearance of Safinamide was determined to be 4.6 L/h. Terminal half-life is 20-26 h. The primary route of excretion is through the kidney (76% of Safinamide dose recovered in the urine, primarily in the form of inactive metabolites).
Specific Populations
- Age: Geriatric Population: There are limited clinical data on the use of Safinamide in the elderly (>75 years). These data suggest that the pharmacokinetics of Safinamide is not affected by age.
- Race: The pharmacokinetics of Safinamide is not influenced by race.
- Sex: The pharmacokinetics of Safinamide is not influenced by sex.
- Hepatic Impairment: The disposition of Safinamide was assessed in subjects with mild and moderate hepatic impairment and compared with subjects with normal hepatic function. A marginal increase in the exposure of Safinamide (approximately 30% increase in AUC) was observed in subjects with mild hepatic impairment (Child-Pugh A). In subjects with moderate hepatic impairment (Child-Pugh B), exposure to Safinamide was increased by about 80% (CI: 154-215%). Safinamide has not been studied in patients with severe hepatic impairment (Child-Pugh C).
- Renal Impairment: The effect of renal impairment on Safinamide pharmacokinetics was investigated in an open-label, parallel-group, single oral dose study in subjects with moderate renal impairment, severe renal impairment, or normal renal function. The pharmacokinetics of Safinamide was not affected by impaired renal function.
Drug Interaction Studies
- In Vitro Studies: In vitro metabolism studies indicate no meaningful inhibition or induction of Cytochrome P450 (CYP) based enzymes by Safinamide and its major metabolites at concentrations that are relevant for dosing. Safinamide or its major metabolites at clinically relevant concentrations are not inhibitors of MAO-A, levodopa decarboxylase or aldehyde dehydrogenase enzymes.
- Safinamide is not a substrate of P-gp. Safinamide and its metabolites did not inhibit P-gp or other transporters OCT2, OATP1B1, OATP1B3, BSEP, OAT1/3/4. Safinamide and NW-1689 may inhibit BCRP at the 100 mg dose.
- In Vivo Studies: Dedicated drug-drug interactions studies conducted with ketoconazole, levodopa (LD) and CYP1A2 and CYP3A4 substrates (caffeine and midazolam, respectively) did not demonstrate any clinically significant effects on the pharmacokinetic profile of Safinamide, or on the pharmacokinetic profile of co-administered levodopa or CYP1A2 and CYP3A4 substrates.
## Nonclinical Toxicology
Carcinogenesis
- In carcinogenicity studies in mice and rats, Safinamide was administered at oral doses of 0, 50, 100 and 200 mg/kg/day, and 0, 25, 50 and 100 mg/kg/day, respectively, for 2 years. The highest doses tested in both species were approximately 10 times the maximum recommended human dose (MRHD) of 100 mg/day on a body surface area (mg/m 2) basis. No evidence of tumorigenic potential was observed in either species.
Mutagenesis
- Safinamide was negative for genotoxicity in in vitro (Ames, mouse lymphoma) and in vivo (mouse micronucleus) assays.
Impairment of Fertility
- In a rat fertility study in which males and females were orally administered Safinamide (0, 50, 100, 150 mg/kg/day) prior to and during mating and continuing through early pregnancy in females, adverse effects on reproductive function were observed in both males (sperm abnormalities) and females (decreased corpora lutea, increased pre-implantation loss). The no-effect dose for reproductive toxicity (50 mg/kg/day) is approximately 5 times the MRHD on a mg/m 2 basis.
Retinal Pathology in Rats
- Degeneration and loss of photoreceptor cells were observed in the retina of both albino and pigmented rats at plasma exposures lower than that in humans at the maximum recommended human dose of 100 mg/kg/day. The findings were dose- and time-dependent and progressed from minimal loss to severe outer nuclear cell layer loss after one year of oral dosing with Safinamide. In a two year study, total retinal atrophy and scarring and lens opacities (cataracts) were seen at all oral doses tested (0, 25, 50, and 100 mg/kg/day).
- In a study in rats dosed orally with Safinamide alone or in combination with pramipexole, pramipexole, at a dose (25 mg/kg/day) that did not cause retinal changes, exacerbated the retinal pathology caused by Safinamide alone (50 mg/kg/day) in both pigmented and albino rats.
- Investigative studies were not able to identify a mechanism underlying the retinal toxicity; the relevance to humans is unknown.
# Clinical Studies
- Two double-blind, placebo-controlled, multi-national, 24-week studies (Study 1 and Study 2) were conducted in PD patients experiencing "OFF" Time during treatment with carbidopa/levodopa and other PD medications, e.g., dopamine agonists, catechol-O-methyl transferase (COMT) inhibitors, anticholinergics, and/or amantadine. In both studies, the primary measure of effectiveness was the change from baseline in total daily "ON" Time without troublesome dyskinesia (i.e., "ON" Time without dyskinesia plus "ON" Time with non- troublesome dyskinesia), based on 18-hour diaries completed by patients for at least 3 days before each of the scheduled visits. Secondary endpoints included "OFF" Time during the diary period and reduction in Uniform Parkinson's Disease Rating Scale (UPDRS) Part III (motor examination).
- In Study 1, patients (n=645) were randomized equally to treatment with Safinamide 50 mg/day (n=217 patients), Safinamide 100 mg/day (n=216 patients), or placebo (n=212 patients), and had at least one post-baseline assessment of "ON" Time.
- The percentages of patients taking stable doses of other classes of PD medications, in addition to levodopa/decarboxylase inhibitor, were: dopamine agonists (61%), COMT inhibitors (24%), anticholinergics (37%), and amantadine (14%). Use of MAO inhibitors was prohibited. The average daily dosage of levodopa was 630 mg. The mean duration of Parkinson's disease was approximately 8 years.
- In Study 1, Safinamide 50 mg/day and 100 mg/day significantly increased "ON" Time compared to placebo (Table 2). The increase in "ON" Time without troublesome dyskinesia was accompanied by a similar significant reduction in "OFF" Time and a reduction in Unified Parkinson's Disease Rating Scale Part III (UPDRS III) scores assessed during "ON" Time (Table 3). Improvement in "ON Time" occurred without an increase in troublesome dyskinesia.
- The effect of Safinamide 100 mg on "ON" Time was only slightly numerically greater than the effect of Safinamide 50 mg. In addition, the time course of improvement in total daily "ON" Time was similar between both doses (Figure 1). The time course of improvement in total daily "ON" Time showed numerically greater improvement with both Safinamide 50mg and 100 mg compared to placebo, at all post-baseline timepoints (Figure 1).
- Figure 2 shows the empirical cumulative distribution functions (CDF) for the change from baseline to Week 24 in total daily "ON" Time in Study 1. The cumulative percentage of patients with a change in "ON" Time was similar for the Safinamide 50 mg and 100 mg groups. The cumulative percentage of patients with an increase in "ON" Time is higher for both Safinamide 50 mg and 100 mg treated patients than for placebo patients.
- Patients who dropped out of the study because of an adverse reaction, lack of efficacy, non-compliance, or withdrawal of consent were treated as treatment failures and assumed to have the smallest change from baseline among all patients. The failure rates are 6.1%, 5.6%, and 6.9% for the placebo group, Safinamide 50 mg/day group, and Safinamide 100 mg/day group, respectively.
- In Study 2, patients (n=549) were randomized to treatment with Safinamide 100 mg daily (n=274 patients) or placebo (n=275 patients) for up to 24 weeks. The percentages of patients taking stable doses of other classes of PD medication, in addition to levodopa/decarboxylase inhibitor, were: dopamine agonists (74%), COMT inhibitors (18%), anticholinergics (17%), and amantadine (30%). Use of MAO inhibitors was prohibited. The average daily dosage of levodopa was 777 mg. The mean duration of Parkinson's disease was approximately 9 years.
- In Study 2, Safinamide was significantly better than placebo for increasing "ON" Time (Table 4). The observed increase in "ON" Time without troublesome dyskinesia was accompanied by a reduction in "OFF" Time of similar magnitude and a reduction in UPDRS III score (assessed during "ON" Time). The time course of effect was similar to that showed in the above figure for Study 1. As in Study 1, the increase in "ON" Time without troublesome dyskinesia was accompanied by a similar significant reduction in "OFF" Time and a reduction in Unified Parkinson's Disease Rating Scale Part III (UPDRS III) scores assessed during "ON" Time (Table 5).
- The time course of improvement in total daily "ON" Time showed numerically greater improvement with Safinamide 100 mg compared to placebo at all post-baseline timepoints (Figure 3).
- Figure 4 shows the empirical cumulative distribution functions (CDF) for the change from baseline to Week 24 in total daily "ON" Time in Study 2. The cumulative percentage of patients with an increase in "ON" Time treated with Safinamide 50 mg to 100 mg is higher than for placebo patients.
# How Supplied
- 50 mg (orange to copper colored with metallic gloss, round film-coated, biconcave shaped tablet embossed with "50" on one side; approximately 7 mm in diameter).
- 100 mg (orange to copper colored with metallic gloss, round film-coated, biconcave shaped tablet embossed with "100" on one side; approximately 9 mm in diameter).
## Storage
- Store at 25°C (77°F); excursions permitted between 15°C to 30°C (59°F to 86°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Hypertension
- Advise patients that treatment with recommended doses of Safinamide may be associated with elevations of blood pressure or onset of hypertension. Tell patients who experience elevation of blood pressure while taking Safinamide to contact their healthcare provider.
- Explain the risk of using higher than recommended daily doses of Safinamide, and provide a brief description of the tyramine associated hypertensive reaction.
- Advise patients to avoid certain foods (e.g., aged cheese) containing a very large amount of tyramine while taking recommended doses of Safinamide because of the potential for large increases in blood pressure. If patients eat foods very rich in tyramine and do not feel well soon after eating, they should contact their healthcare provider.
Serotonin Syndrome
- Tell patients to inform their physician if they are taking, or planning to take, any prescription or over-thecounter drugs, especially antidepressants and over-the-counter cold medications, because there is a potential for interaction with Safinamide. Because patients should not use meperidine or certain other analgesics with Safinamide, they should contact their healthcare provider before taking new medications including antidepressants, analgesics, and prescription or nonprescription decongestants.
Falling Asleep During Activities of Daily Living and Somnolence
- Inform patients about the potential for sedating effects associated with Safinamide and other dopaminergic medications, including somnolence and particularly to the possibility of falling asleep while engaged in activities of daily living. Because somnolence can be a frequent adverse reaction with potentially serious consequences, patients should not operate a motor vehicle or engage in other potentially dangerous activities until they have gained sufficient experience with Safinamide.
- Advise patients that if increased somnolence or new episodes of falling asleep during activities of daily living (e.g., watching television, passenger in a car, etc.) are experienced at any time during treatment, they should not drive or participate in potentially dangerous activities until they have contacted their physician. Patients should not drive, operate machinery, or work at heights during treatment if they have previously experienced somnolence and/or have fallen asleep without warning prior to use of Safinamide.
- Because of possible additive effects, advise patients about the potential for increased somnolence when patients are taking other sedating medications, alcohol, or other central nervous system depressants (e.g., benzodiazepines, antipsychotics, antidepressants) in combination with Safinamide.
Dyskinesia
- Advise patients taking Safinamide as adjunct to levodopa that there is a possibility of dyskinesia or increased dyskinesia.
Hallucinations / Psychotic Behavior
-
Inform patients that hallucinations or other manifestations of psychotic behavior can occur when taking Safinamide. Advise patients that, if they have a major psychotic disorder, that Safinamide should not ordinarily be used because of the risk of exacerbating the psychosis. Patients with a major psychotic disorder should also be aware that many treatments for psychosis may decrease the effectiveness of Safinamide.
Impulse Control/Compulsive Behaviors
- Advise patients that they may experience intense urges to gamble, increased sexual urges, other intense urges, and the inability to control these urges while taking Safinamide. Although it is not proven that the medications caused these events, these urges were reported to have stopped in some cases when the dose was reduced or the medication was stopped. Prescribers should ask patients about the development of new or increased gambling urges, sexual urges, or other urges while being treated with Safinamide. Patients should inform their physician if they experience these urges while taking Safinamide.
Withdrawal-Emergent Hyperpyrexia and Confusion
- Tell patients to contact their healthcare provider if they wish to discontinue Safinamide and seek guidance for tapering Safinamide instead of abruptly discontinuing Safinamide.
Missing Dose
- Instruct patients to take Safinamide as prescribed. If a dose is missed, instruct patients to take the next dose at the usual time on the following day.
Concomitant Medications
- Advise patients to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter medications because of a potential for interactions.
# Precautions with Alcohol
Alcohol-Safinamide interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
- Xadago
# Look-Alike Drug Names
There is limited information regarding Safinamide Look-Alike Drug Names in the drug label.
# Drug Shortage Status
Drug Shortage
# Price | https://www.wikidoc.org/index.php/Safinamide | |
dcbf9f07b04dff6eb7906d5d39d5a889d9ed2783 | wikidoc | Salmonella | Salmonella
# Overview
Salmonella is a rod-shaped, facultative intracellular, gram-negative enterobacteria. Salmonella species shows motility, produces hydrogen sulfide, and only 1% is able to ferment lactose. It may be isolated from the stool of infected patients, and grown in culture media, such as MacConkey agar and deoxycholate agar. Salmonella enters the body through contaminated food or water, and invades the intestinal epithelial cells, causing inflammation.
This bacterium may be classified into 2 different species: Salmonella enterica and Salmonella bongori. Salmonella enterica is divided in 6 different subspecies, of which I, contains most pathogenic serotypes for humans. Salmonella may be serogrouped into more than 2500 serovars with polyvalent antisera, according to the capsular antigen, polysaccharide O antigens, and flagellar antigens. The bacteria show tropism for the epithelial cells of the gastrointestinal tract, macrophages, dendritic cells, and neutrophils. Different serotypes of Salmonella may have different natural reservoirs, some have humans as their only natural reservoir (serotypes Sendai and Typhi), while others (serotype Dublin) may infect humans and cattle.
# Taxonomy
Cellular organism; Bacteria; Proteobacteria; Gammaproteobacteria; Enterobacteriales; Enterobacteriaceae
# Biology
Salmonella is a gram-negative, facultative intracellular, anaerobic, non-spore-forming bacillus. It measures 2 to 3 by 0.4 to 0.6 μm. Salmonella is a non-lactose fermenting bacterium. It reduces nitrates, produces acid on glucose fermentation and does not produce cytochrome oxidase. Due to the presence of flagella, almost all salmonella species are motile. 1% of the bacteria is able to ferment lactose, which may be responsible for its non-detection in some culture media.
For the isolation of salmonella in culture, freshly passed stool are preferred. Common media for the growth of salmonella include: MacConkey agar, deoxycholate agar, and xylose-lysine-deoxycholate agar.
When the sample has a low number of bacteria, special enrichment broths, such as the selenite-based enrichment broth, may be used to raise the number of bacteria.
## Infectious Cycle
Salmonella enterica enters the body through the mouth, by ingestion of contaminated food and water. For the bacteria to cause disease, an inoculum of about 50 000 pathogens is often required. Once in the intestine, the bacteria will first infect the apical epithelium. Salmonella will then initiate bacterial mechanisms that allow invasion of the host cells, inducing inflammatory changes, such as:
- Diffuse and focal infiltration of PMN
- Crypt abscesses
- Necrosis of the epithelium
- Fluid secretion
- Edema
Different serovars will have different preferable intestinal locations. An example is the enterocolitis at the terminal ileum, cecum, and proximal colon caused by serovar Typhimurium. Intestinal disease is marked by neutrophil migration to the intestinal epithelium. This recruitment is done by the secretion of interleukin-8, induced by Salmonella.
# Classification
Before 1983 Salmonella was classified in several species. However, its genome study has shown high levels of DNA similarities among different types of salmonella, which leads to the actual classification of salmonella in 2 different species:
## Salmonella enterica
- Contains six subspecies - I, II, IIIa, IIIb, IV, and VI:
I - enterica
II - salamae
III - arizonae
IIIb - diarizonae
IV - houtenae
VI - indica
- I - enterica
- II - salamae
- III - arizonae
- IIIb - diarizonae
- IV - houtenae
- VI - indica
- Subspecies I contains most pathogenic serotypes for humans
- Subspecies IIIa and IIIb, formerly belonging to the genus Arizonae, are responsible for rare human infections
## Salmonella bongori
- Formerly subspecies V
## Serovars
Salmonella subspecies may be serogrouped into more than 2500 serovars with polyvalent antisera. For this division the following bacterial structures are considered:
- Capsular antigen
- Polysaccharide O antigens
- Flagellar antigens
Different salmonella serotypes may also be distinguished in culture, according to their different metabolism of sugars. Different serovars may also have different disease manifestations. For example, Salmonella enterica, serovar Typhimurium is the causative agent of typhoid fever, and is not associated with classical salmonellosis.
# Tropism
In vitro, Salmonella is able to interact with different types of cells. However, in vivo, the bacteria was found to enter only certain human cells, namely:
- Epithelial cells of the gastrointestinal tract - first cells to be infected by Salmonella
- Macrophages - where Salmonella survives and replicates
- Dendritic cells - relevant for dissemination of bacteria in the initial stages of infection, yet, they are not considered adequate reservoirs for Salmonella at latter stages
- Neutrophils - interaction is based on the immune response against the bacteria, hence this might not be considered true tropism
# Differential diagnosis
Salmonella gastroenteritis must be differentiated from other causes of viral, bacterial, and parasitic gastroentritis.
8Small bowel diarrhea: watery, voluminous with less than 5 WBC/high power field
Large bowel diarrhea: Mucousy and/or bloody with less volume and more than 10 WBC/high power field
† It could be as high as 1000 based on patient's immunity system.
The table below summarizes the findings that differentiate inflammatory causes of chronic diarrhea
# Natural Reservoir
Different salmonella serovars may have different natural reservoirs. Common types of serovars of salmonella enterica that infect the human gastrointestinal tract include serovars Sendai, Typhi, and Paratyphi. Humans are their only natural reservoir. Other serotypes, such as serotype Dublin, have cattle as their natural reservoir, but has also the capacity to cause infection in humans.
# Drug Side Effect
- Vedolizumab
# Related Chapters
- 1984 Rajneeshee bioterror attack
- List of foodborne illness outbreaks
- Food Testing Strips
# Gallery
- Salmonella bacteria in tetrathionate enrichment broth stained using direct FA staining technique. From Public Health Image Library (PHIL).
- Salmonella bacteria in tetrathionate enrichment broth stained using direct FA staining technique. From Public Health Image Library (PHIL).
- Triple sugar iron agar (TSI) tested for Salmonella (H2S+) and (H2S-); Citrobacter sp. and S. arizonae. From Public Health Image Library (PHIL).
- Gram-negative bacilli, or rod-shaped Salmonella sp. bacteria. From Public Health Image Library (PHIL).
- SEM depicts a number of red-colored Salmonella sp. bacteria invading a mustard-colored ruffled immune cell. From Public Health Image Library (PHIL). | Salmonella
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [2] Jolanta Marszalek, M.D. [3]
# Overview
Salmonella is a rod-shaped, facultative intracellular, gram-negative enterobacteria.[1] Salmonella species shows motility, produces hydrogen sulfide, and only 1% is able to ferment lactose.[2] It may be isolated from the stool of infected patients, and grown in culture media, such as MacConkey agar and deoxycholate agar. Salmonella enters the body through contaminated food or water, and invades the intestinal epithelial cells, causing inflammation.
This bacterium may be classified into 2 different species: Salmonella enterica and Salmonella bongori. Salmonella enterica is divided in 6 different subspecies, of which I, contains most pathogenic serotypes for humans. Salmonella may be serogrouped into more than 2500 serovars with polyvalent antisera, according to the capsular antigen, polysaccharide O antigens, and flagellar antigens. The bacteria show tropism for the epithelial cells of the gastrointestinal tract, macrophages, dendritic cells, and neutrophils. Different serotypes of Salmonella may have different natural reservoirs, some have humans as their only natural reservoir (serotypes Sendai and Typhi), while others (serotype Dublin) may infect humans and cattle.
# Taxonomy
Cellular organism; Bacteria; Proteobacteria; Gammaproteobacteria; Enterobacteriales; Enterobacteriaceae[3]
# Biology
Salmonella is a gram-negative, facultative intracellular, anaerobic, non-spore-forming bacillus. It measures 2 to 3 by 0.4 to 0.6 μm. Salmonella is a non-lactose fermenting bacterium. It reduces nitrates, produces acid on glucose fermentation and does not produce cytochrome oxidase.[5] Due to the presence of flagella, almost all salmonella species are motile. 1% of the bacteria is able to ferment lactose, which may be responsible for its non-detection in some culture media.
For the isolation of salmonella in culture, freshly passed stool are preferred. Common media for the growth of salmonella include: MacConkey agar, deoxycholate agar, and xylose-lysine-deoxycholate agar.[6]
When the sample has a low number of bacteria, special enrichment broths, such as the selenite-based enrichment broth, may be used to raise the number of bacteria.[6]
## Infectious Cycle
Salmonella enterica enters the body through the mouth, by ingestion of contaminated food and water. For the bacteria to cause disease, an inoculum of about 50 000 pathogens is often required. Once in the intestine, the bacteria will first infect the apical epithelium. Salmonella will then initiate bacterial mechanisms that allow invasion of the host cells, inducing inflammatory changes, such as:[7][8][9][10]
- Diffuse and focal infiltration of PMN
- Crypt abscesses
- Necrosis of the epithelium
- Fluid secretion
- Edema
Different serovars will have different preferable intestinal locations. An example is the enterocolitis at the terminal ileum, cecum, and proximal colon caused by serovar Typhimurium. Intestinal disease is marked by neutrophil migration to the intestinal epithelium. This recruitment is done by the secretion of interleukin-8, induced by Salmonella.[11]
# Classification
Before 1983 Salmonella was classified in several species. However, its genome study has shown high levels of DNA similarities among different types of salmonella, which leads to the actual classification of salmonella in 2 different species:
## Salmonella enterica
- Contains six subspecies - I, II, IIIa, IIIb, IV, and VI:[12][13]
I - enterica
II - salamae
III - arizonae
IIIb - diarizonae
IV - houtenae
VI - indica
- I - enterica
- II - salamae
- III - arizonae
- IIIb - diarizonae
- IV - houtenae
- VI - indica
- Subspecies I contains most pathogenic serotypes for humans
- Subspecies IIIa and IIIb, formerly belonging to the genus Arizonae, are responsible for rare human infections
## Salmonella bongori
- Formerly subspecies V[14]
## Serovars
Salmonella subspecies may be serogrouped into more than 2500 serovars with polyvalent antisera. For this division the following bacterial structures are considered:[15]
- Capsular antigen
- Polysaccharide O antigens
- Flagellar antigens
Different salmonella serotypes may also be distinguished in culture, according to their different metabolism of sugars.[16] Different serovars may also have different disease manifestations. For example, Salmonella enterica, serovar Typhimurium is the causative agent of typhoid fever, and is not associated with classical salmonellosis.
# Tropism
In vitro, Salmonella is able to interact with different types of cells. However, in vivo, the bacteria was found to enter only certain human cells, namely:[17]
- Epithelial cells of the gastrointestinal tract - first cells to be infected by Salmonella
- Macrophages - where Salmonella survives and replicates
- Dendritic cells - relevant for dissemination of bacteria in the initial stages of infection, yet, they are not considered adequate reservoirs for Salmonella at latter stages
- Neutrophils - interaction is based on the immune response against the bacteria, hence this might not be considered true tropism
# Differential diagnosis
Salmonella gastroenteritis must be differentiated from other causes of viral, bacterial, and parasitic gastroentritis.
8Small bowel diarrhea: watery, voluminous with less than 5 WBC/high power field
Large bowel diarrhea: Mucousy and/or bloody with less volume and more than 10 WBC/high power field
† It could be as high as 1000 based on patient's immunity system.
The table below summarizes the findings that differentiate inflammatory causes of chronic diarrhea[18][19][20][21][21]
# Natural Reservoir
Different salmonella serovars may have different natural reservoirs. Common types of serovars of salmonella enterica that infect the human gastrointestinal tract include serovars Sendai, Typhi, and Paratyphi. Humans are their only natural reservoir. Other serotypes, such as serotype Dublin, have cattle as their natural reservoir, but has also the capacity to cause infection in humans.[22][23]
# Drug Side Effect
- Vedolizumab
# Related Chapters
- 1984 Rajneeshee bioterror attack
- List of foodborne illness outbreaks
- Food Testing Strips
# Gallery
- Salmonella bacteria in tetrathionate enrichment broth stained using direct FA staining technique. From Public Health Image Library (PHIL). [4]
- Salmonella bacteria in tetrathionate enrichment broth stained using direct FA staining technique. From Public Health Image Library (PHIL). [4]
- Triple sugar iron agar (TSI) tested for Salmonella (H2S+) and (H2S-); Citrobacter sp. and S. arizonae. From Public Health Image Library (PHIL). [4]
- Gram-negative bacilli, or rod-shaped Salmonella sp. bacteria. From Public Health Image Library (PHIL). [4]
- SEM depicts a number of red-colored Salmonella sp. bacteria invading a mustard-colored ruffled immune cell. From Public Health Image Library (PHIL). [4] | https://www.wikidoc.org/index.php/Salmonella | |
5a7bf0992620ebdfaee27a67e40a3f26c3000c68 | wikidoc | Salt gland | Salt gland
The salt gland is an organ for excreting excess salt. It is found in elasmobranchs, marine birds, and some reptiles. In sharks, salt glands are found in the rectum, but in birds and reptiles, they are found in the skull, in the area of the eyes or nostrils. Such glands work by active transport via sodium-potassium pump that moves salt from the blood into the gland, where it can be excreted as a concentrated solution. Salt glands function to keep salt balance, and allow marine reptiles to drink seawater.
The need for salt glands in reptiles and birds stems from the fact that their kidneys are much less efficient than those of mammals. Unlike the skin of amphibians, reptile and bird skin is impermeable to salt, meaning that the transition to a tougher skin meant a loss in salt-releasing ability. The evolution of a salt gland would have allowed early reptiles and birds to eat aquatic plants and animals, who have high salt concentrations. This does not, however, explain the evolution of the gland in the elasmobranchs, suggesting convergent evolution.
Some theories suggest that mammalian tear ducts and sweat glands may be evolutionarily related to salt glands. Human tears are high in potassium, lending support to this theory, however most phylogenists disagree with this idea. | Salt gland
The salt gland is an organ for excreting excess salt. It is found in elasmobranchs, marine birds, and some reptiles. In sharks, salt glands are found in the rectum, but in birds and reptiles, they are found in the skull, in the area of the eyes or nostrils. Such glands work by active transport via sodium-potassium pump that moves salt from the blood into the gland, where it can be excreted as a concentrated solution. Salt glands function to keep salt balance, and allow marine reptiles to drink seawater.[1]
The need for salt glands in reptiles and birds stems from the fact that their kidneys are much less efficient than those of mammals. Unlike the skin of amphibians, reptile and bird skin is impermeable to salt, meaning that the transition to a tougher skin meant a loss in salt-releasing ability. The evolution of a salt gland would have allowed early reptiles and birds to eat aquatic plants and animals, who have high salt concentrations. This does not, however, explain the evolution of the gland in the elasmobranchs, suggesting convergent evolution.
Some theories suggest that mammalian tear ducts and sweat glands may be evolutionarily related to salt glands. Human tears are high in potassium, lending support to this theory, however most phylogenists disagree with this idea.
# External links
- Salt Glands | https://www.wikidoc.org/index.php/Salt_gland | |
c72d29f3529e91c7fe773a5946145225e30631e3 | wikidoc | Sameridine | Sameridine
Sameridine is a 4-phenylpiperidine derivative that is related to the opioid analgesic drug pethidine (meperidine).
Sameridine has an unusual pharmacological profile, being both a local anaesthetic and a μ-opioid partial agonist. It is currently under development for use in surgical anasthesia, mainly administered by intrathecal infusion. It produces less respiratory depression than morphine, even at a high dose, and produces no respiratory depression at a low dose.
Sameridine is not currently a controlled drug, although if approved for medical use it will certainly be a prescription medicine, and it would probably be assigned to one of the controlled drug schedules in more restrictive jurisdictions such as Australia and the USA, especially if it were found to be addictive in animals. | Sameridine
Sameridine is a 4-phenylpiperidine derivative that is related to the opioid analgesic drug pethidine (meperidine).
Sameridine has an unusual pharmacological profile, being both a local anaesthetic and a μ-opioid partial agonist.[1] It is currently under development for use in surgical anasthesia, mainly administered by intrathecal infusion.[2] It produces less respiratory depression than morphine, even at a high dose, and produces no respiratory depression at a low dose.[3]
Sameridine is not currently a controlled drug, although if approved for medical use it will certainly be a prescription medicine, and it would probably be assigned to one of the controlled drug schedules in more restrictive jurisdictions such as Australia and the USA, especially if it were found to be addictive in animals.
Template:Pharm-stub | https://www.wikidoc.org/index.php/Sameridine | |
3a818b814cc879c297386b5968fdadb75597e511 | wikidoc | Sanatorium | Sanatorium
A sanatorium (also sanitorium, sanitarium) is a medical facility for long-term illness, typically tuberculosis. A distinction was sometimes made between a "sanitarium" (a kind of health resort, as in the Battle Creek Sanitarium) and "sanatorium" (a hospital).
According to the Saskatchewan Lung Association, when the National Anti-Tuberculosis Association was founded in 1904, it was felt that a distinction should be made between the health resorts with which people were familiar and the new tuberculosis treatment hospitals: "So they decided to use a new word which instead of being derived from the Latin noun sanitas, meaning health, would emphasize the need for scientific healing or treatment. Accordingly, they took the Latin verb root sano, meaning to heal, and adopted the new word sanatorium" .
The rationale for sanitoriums was that before antibiotic treatments existed, a regime of rest and good nutrition offered the best chance that the sufferer's immune system would "wall off" pockets of pulmonary tuberculosis infection.
In the early twentieth century, tuberculosis sanatoriums (or sanatoria) were common in the United States. The first tuberculosis sanatorium for blacks was Burkeville, Virginia's Piedmont Sanatorium. Waverly Hills Sanatorium, a Louisville, Kentucky tuberculosis sanatorium, was founded in 1911. It has become a mecca for curiosity-seekers who believe it is haunted . A.G. Holley Hospital in Lantana, Florida is the last remaining freestanding tuberculosis sanatorium in the United States .
Switzerland had many sanatoriums, as it was believed that clean mountain air was the best treatment for lung diseases. The ill of Europe were sent to recover there. The Heliantia Sanatorium in Valadares, Portugal was used for the treatment of bone tuberculosis between the 1930s and 1960s.
After 1943, when Albert Schatz, a graduate student at Rutgers University, discovered Streptomycin, the first true cure for tuberculosis, sanatoriums began to close. Around the 1950s, tuberculosis was no longer a major public health threat and so most of the sanatoriums had reached the end of their lives. Most sanatoriums were demolished years ago.
Some, however, have assumed updated medical roles. The Tambaram Sanatorium in south India is now a hospital of excellence for AIDS patients . The state hospital in Sanatorium, Mississippi is now a regional mental retardation center.
# Former Soviet Union
In the former Soviet Union the term has a slightly different meaning. It is mostly a combination of a resort/recreational facility and a medical facility intended to provide short-term complex rest and medical services.
# In literature
The Magic Mountain (Der Zauberberg), a novel by the German author Thomas Mann (1875–1955), is set in a sanatorium. Mann was familiar with this type of setting from 1912 when his wife was hospitalized with lung disease for several months in Dr. Friedrich Jessen's Waldsanatorium in Davos, Switzerland. Der Zauberberg, one of the most influential of all 20th-century novels, is a lengthy work and was first published in two volumes by S. Fischer Verlag in 1924. | Sanatorium
A sanatorium (also sanitorium, sanitarium) is a medical facility for long-term illness, typically tuberculosis. A distinction was sometimes made between a "sanitarium" (a kind of health resort, as in the Battle Creek Sanitarium) and "sanatorium" (a hospital).
According to the Saskatchewan Lung Association, when the National Anti-Tuberculosis Association was founded in 1904, it was felt that a distinction should be made between the health resorts with which people were familiar and the new tuberculosis treatment hospitals: "So they decided to use a new word which instead of being derived from the Latin noun sanitas, meaning health, would emphasize the need for scientific healing or treatment. Accordingly, they took the Latin verb root sano, meaning to heal, and adopted the new word sanatorium" [1].
The rationale for sanitoriums was that before antibiotic treatments existed, a regime of rest and good nutrition offered the best chance that the sufferer's immune system would "wall off" pockets of pulmonary tuberculosis infection.
In the early twentieth century, tuberculosis sanatoriums (or sanatoria) were common in the United States. The first tuberculosis sanatorium for blacks was Burkeville, Virginia's Piedmont Sanatorium. Waverly Hills Sanatorium, a Louisville, Kentucky tuberculosis sanatorium, was founded in 1911. It has become a mecca for curiosity-seekers who believe it is haunted [2]. A.G. Holley Hospital in Lantana, Florida is the last remaining freestanding tuberculosis sanatorium in the United States [3].
Switzerland had many sanatoriums, as it was believed that clean mountain air was the best treatment for lung diseases. The ill of Europe were sent to recover there. The Heliantia Sanatorium in Valadares, Portugal was used for the treatment of bone tuberculosis between the 1930s and 1960s.
After 1943, when Albert Schatz, a graduate student at Rutgers University, discovered Streptomycin, the first true cure for tuberculosis, sanatoriums began to close. Around the 1950s, tuberculosis was no longer a major public health threat and so most of the sanatoriums had reached the end of their lives. Most sanatoriums were demolished years ago.
Some, however, have assumed updated medical roles. The Tambaram Sanatorium in south India is now a hospital of excellence for AIDS patients [4]. The state hospital in Sanatorium, Mississippi is now a regional mental retardation center.
# Former Soviet Union
In the former Soviet Union the term has a slightly different meaning. It is mostly a combination of a resort/recreational facility and a medical facility intended to provide short-term complex rest and medical services.
# In literature
The Magic Mountain (Der Zauberberg), a novel by the German author Thomas Mann (1875–1955), is set in a sanatorium. Mann was familiar with this type of setting from 1912 when his wife was hospitalized with lung disease for several months in Dr. Friedrich Jessen's Waldsanatorium in Davos, Switzerland. Der Zauberberg, one of the most influential of all 20th-century novels, is a lengthy work and was first published in two volumes by S. Fischer Verlag in 1924. | https://www.wikidoc.org/index.php/Sanatorium | |
46b7e49acf678fbc7672950869822bc9ff025829 | wikidoc | Sandbox/07 | Sandbox/07
# Criteria and Definitions of Ventricular Rhythms
- Ventricular premature complex, uniform, fixed coupling
- Ventricular premature complex, uniform, nonfixed coupling
- Ventricular premature complex, multiform
- Ventricular premature complexes, in pairs (2 consecutive)
- Ventricular parasystole
- Ventricular tachycardia (≥3 consecutive beats)
- Accelerated idioventricular rhythm
- Ventricular escape complexes or rhythm
- Ventricular fibrillation
## Ventricular premature complex, uniform, fixed coupling
All of the folowing are required:
Premature in relation to normal cycles, not preceded by P wave (or shorter than expected PR interval or “collapsing PR”)
Coupling interval usually the same for each site or focus (variation usually <0.08 second)
Abnormal QRS configuration that is almost always >0.12 second in duration
Retrograde capture of atria may occur
Initial direction of QRS complex is often different from that observed during sinus rhythm
Usually full compensatory pause is noted
Compensatory pause requires an undisturbed sinus depolarization due to one of the following:
## Ventricular premature complex, uniform, nonfixed coupling
Ventricular premature complexes with variable temporal relationship to regular sinus beats
## Ventricular premature complex, multiform
Two or more morphologic patterns of ventricular premature complexes present
## Ventricular premature complexes, in pairs (2 consecutive)
Two consecutive ventricular premature complexes of not necessarily the same morphology
All of the folowing are required:
Premature in relation to normal cycles, not preceded by P wave (or shorter than expected PR interval or “collapsing PR”)
Coupling interval usually the same for each site or focus (variation usually <0.08 second)
Abnormal QRS configuration that is almost always >0.12 second in duration
Retrograde capture of atria may occur
Initial direction of QRS complex is often different from that observed during sinus rhythm
Usually full compensatory pause is noted
Compensatory pause requires an undisturbed sinus depolarization due to one of the following:
## Ventricular parasystole
An automatic ventricular focus with entrance block and all of the following:
Rates usually 30-56 beats/min
Varying relationship with the preceding sinus beats
All interectopic intervals are a multiple of a constant shortest interval
When fusion beats and lack of fixed coupling are noted, consider parasystole
## Ventricular tachycardia (≥3 consecutive beats)
Rapid succession of ≥3 beats of ventricular origin
Abnormal and wide QRS complexes with secondary ST-T changes (ventricular tachycardia originating in the septum near the normal conduction system may have a narrow QRS complex)
Rate >100 beats/min
Regular or slightly irregular
Abrupt onset and termination
AV dissociation is common. On occasion, retrograde conduction and capture of the atria may occur
Look for ventricular capture and fusion beats as a marker for ventricular tachycardia
QRS complexes like those of ventricular premature complexes
Tachyarrhythmia initiated by ventricular premature complexes
AV dissociation
Capture or fusion beats
QRS ≥0.14 second if RBBB morphology and ≥0.16 second if LBBB morphology when QRS during sinus rhythm <0.12 second
Left or northwest axis deviation
All positive or all negative complexes in precordial leads
In V1, R > r′ (left rabbit ear taller than right)
QRS complex like aberrantly conducted atrial premature complexes or QRS in sinus rhythm
Tachyarrhythmia initiated by atrial premature complexes
RBBB configuration with rSR′ in V1
## Accelerated idioventricular rhythm
Requires all of the following:
Regular rhythm, rate 60-110 beats/min
QRS complexes are abnormal and wide
Usually AV dissociation
Capture and fusion beats are common because of slower rate
## Ventricular escape complexes or rhythm
Requires all of the following:
Rate is usually 30-40 beats/min (can be 20-50 beats/min)
QRS complexes are abnormal and wide
Occurs when the rate of supraventricular impulse arriving at the ventricle is slower than the inherent rate of the ectopic ventricular pacemaker
## Ventricular fibrillation
Chaotic and irregular deflections of varying amplitude and contour
No P waves, QRS complexes, or T waves | Sandbox/07
# Criteria and Definitions of Ventricular Rhythms
- Ventricular premature complex, uniform, fixed coupling
- Ventricular premature complex, uniform, nonfixed coupling
- Ventricular premature complex, multiform
- Ventricular premature complexes, in pairs (2 consecutive)
- Ventricular parasystole
- Ventricular tachycardia (≥3 consecutive beats)
- Accelerated idioventricular rhythm
- Ventricular escape complexes or rhythm
- Ventricular fibrillation
## Ventricular premature complex, uniform, fixed coupling
All of the folowing are required:
■ Premature in relation to normal cycles, not preceded by P wave (or shorter than expected PR interval or “collapsing PR”)
■ Coupling interval usually the same for each site or focus (variation usually <0.08 second)
■ Abnormal QRS configuration that is almost always >0.12 second in duration
■ Retrograde capture of atria may occur
■ Initial direction of QRS complex is often different from that observed during sinus rhythm
■ Usually full compensatory pause is noted
■ Compensatory pause requires an undisturbed sinus depolarization due to one of the following:
## Ventricular premature complex, uniform, nonfixed coupling
■ Ventricular premature complexes with variable temporal relationship to regular sinus beats
## Ventricular premature complex, multiform
■ Two or more morphologic patterns of ventricular premature complexes present
## Ventricular premature complexes, in pairs (2 consecutive)
Two consecutive ventricular premature complexes of not necessarily the same morphology
All of the folowing are required:
■ Premature in relation to normal cycles, not preceded by P wave (or shorter than expected PR interval or “collapsing PR”)
■ Coupling interval usually the same for each site or focus (variation usually <0.08 second)
■ Abnormal QRS configuration that is almost always >0.12 second in duration
■ Retrograde capture of atria may occur
■ Initial direction of QRS complex is often different from that observed during sinus rhythm
■ Usually full compensatory pause is noted
■ Compensatory pause requires an undisturbed sinus depolarization due to one of the following:
## Ventricular parasystole
An automatic ventricular focus with entrance block and all of the following:
■ Rates usually 30-56 beats/min
■ Varying relationship with the preceding sinus beats
■ All interectopic intervals are a multiple of a constant shortest interval
■ When fusion beats and lack of fixed coupling are noted, consider parasystole
## Ventricular tachycardia (≥3 consecutive beats)
Rapid succession of ≥3 beats of ventricular origin
■ Abnormal and wide QRS complexes with secondary ST-T changes (ventricular tachycardia originating in the septum near the normal conduction system may have a narrow QRS complex)
■ Rate >100 beats/min
■ Regular or slightly irregular
■ Abrupt onset and termination
■ AV dissociation is common. On occasion, retrograde conduction and capture of the atria may occur
■ Look for ventricular capture and fusion beats as a marker for ventricular tachycardia
■ QRS complexes like those of ventricular premature complexes
■ Tachyarrhythmia initiated by ventricular premature complexes
■ AV dissociation
■ Capture or fusion beats
■ QRS ≥0.14 second if RBBB morphology and ≥0.16 second if LBBB morphology when QRS during sinus rhythm <0.12 second
■ Left or northwest axis deviation
■ All positive or all negative complexes in precordial leads
■ In V1, R > r′ (left rabbit ear taller than right)
■ QRS complex like aberrantly conducted atrial premature complexes or QRS in sinus rhythm
■ Tachyarrhythmia initiated by atrial premature complexes
■ RBBB configuration with rSR′ in V1
## Accelerated idioventricular rhythm
Requires all of the following:
■ Regular rhythm, rate 60-110 beats/min
■ QRS complexes are abnormal and wide
■ Usually AV dissociation
■ Capture and fusion beats are common because of slower rate
## Ventricular escape complexes or rhythm
Requires all of the following:
■ Rate is usually 30-40 beats/min (can be 20-50 beats/min)
■ QRS complexes are abnormal and wide
■ Occurs when the rate of supraventricular impulse arriving at the ventricle is slower than the inherent rate of the ectopic ventricular pacemaker
## Ventricular fibrillation
■ Chaotic and irregular deflections of varying amplitude and contour
■ No P waves, QRS complexes, or T waves | https://www.wikidoc.org/index.php/Sandbox/07 | |
a5fa218cdf9e95cd438cf73165e408d11c5b6241 | wikidoc | Sandbox/22 | Sandbox/22
# Gas gangrene
# CHF
# Hypertension
- ↑ Cohn JN, Archibald DG, Ziesche S, Franciosa JA, Harston WE, Tristani FE; et al. (1986). "Effect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a Veterans Administration Cooperative Study". N Engl J Med. 314 (24): 1547–52. doi:10.1056/NEJM198606123142404. PMID 3520315.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link) .mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJ, Michelson EL; et al. (2003). "Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme". Lancet. 362 (9386): 759–66. PMID 13678868.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link) Review in: ACP J Club. 2004 Mar-Apr;140(2):32-3
- ↑ Naidu SS (2011). "Novel percutaneous cardiac assist devices: the science of and indications for hemodynamic support". Circulation. 123 (5): 533–43. doi:10.1161/CIRCULATIONAHA.110.945055. PMID 21300961.
- ↑ Birks EJ, Tansley PD, Hardy J, George RS, Bowles CT, Burke M; et al. (2006). "Left ventricular assist device and drug therapy for the reversal of heart failure". N Engl J Med. 355 (18): 1873–84. doi:10.1056/NEJMoa053063. PMID 17079761.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
- ↑ Slaughter MS, Rogers JG, Milano CA, Russell SD, Conte JV, Feldman D; et al. (2009). "Advanced heart failure treated with continuous-flow left ventricular assist device". N Engl J Med. 361 (23): 2241–51. doi:10.1056/NEJMoa0909938. PMID 19920051.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
- ↑ Metra M, Torp-Pedersen C, Cleland JG, Di Lenarda A, Komajda M, Remme WJ, Dei Cas L, Spark P, Swedberg K, Poole-Wilson PA (2007). "Should beta-blocker therapy be reduced or withdrawn after an episode of decompensated heart failure? Results from COMET". European Journal of Heart Failure. 9 (9): 901–9. doi:10.1016/j.ejheart.2007.05.011. PMID 17581778. Retrieved 2012-04-06. Unknown parameter |month= ignored (help)CS1 maint: Multiple names: authors list (link)
- ↑ Gissi-HF Investigators. Tavazzi L, Maggioni AP, Marchioli R, Barlera S, Franzosi MG; et al. (2008). "Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial". Lancet. 372 (9645): 1223–30. doi:10.1016/S0140-6736(08)61239-8. PMID 18757090.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link) Review in: Ann Intern Med. 2009 Jan 20;150(2):JC1-11 | Sandbox/22
# Gas gangrene
# CHF
# Hypertension
- ↑ Cohn JN, Archibald DG, Ziesche S, Franciosa JA, Harston WE, Tristani FE; et al. (1986). "Effect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a Veterans Administration Cooperative Study". N Engl J Med. 314 (24): 1547–52. doi:10.1056/NEJM198606123142404. PMID 3520315.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link) .mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJ, Michelson EL; et al. (2003). "Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme". Lancet. 362 (9386): 759–66. PMID 13678868.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link) Review in: ACP J Club. 2004 Mar-Apr;140(2):32-3
- ↑ Naidu SS (2011). "Novel percutaneous cardiac assist devices: the science of and indications for hemodynamic support". Circulation. 123 (5): 533–43. doi:10.1161/CIRCULATIONAHA.110.945055. PMID 21300961.
- ↑ Birks EJ, Tansley PD, Hardy J, George RS, Bowles CT, Burke M; et al. (2006). "Left ventricular assist device and drug therapy for the reversal of heart failure". N Engl J Med. 355 (18): 1873–84. doi:10.1056/NEJMoa053063. PMID 17079761.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
- ↑ Slaughter MS, Rogers JG, Milano CA, Russell SD, Conte JV, Feldman D; et al. (2009). "Advanced heart failure treated with continuous-flow left ventricular assist device". N Engl J Med. 361 (23): 2241–51. doi:10.1056/NEJMoa0909938. PMID 19920051.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
- ↑ Metra M, Torp-Pedersen C, Cleland JG, Di Lenarda A, Komajda M, Remme WJ, Dei Cas L, Spark P, Swedberg K, Poole-Wilson PA (2007). "Should beta-blocker therapy be reduced or withdrawn after an episode of decompensated heart failure? Results from COMET". European Journal of Heart Failure. 9 (9): 901–9. doi:10.1016/j.ejheart.2007.05.011. PMID 17581778. Retrieved 2012-04-06. Unknown parameter |month= ignored (help)CS1 maint: Multiple names: authors list (link)
- ↑ Gissi-HF Investigators. Tavazzi L, Maggioni AP, Marchioli R, Barlera S, Franzosi MG; et al. (2008). "Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial". Lancet. 372 (9645): 1223–30. doi:10.1016/S0140-6736(08)61239-8. PMID 18757090.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link) Review in: Ann Intern Med. 2009 Jan 20;150(2):JC1-11 | https://www.wikidoc.org/index.php/Sandbox/22 | |
fb0ac70f50982b33399158699d0bdd9c41335cc7 | wikidoc | Sandbox/MS | Sandbox/MS
Abbreviations: CABG: coronary artery bypass graft; ECG: electrocardiogram; LAD: left anterior descending; LBBB: left bundle branch block; MI: myocardial infarction; PCI: percutaneous coronary intervention; S3: third heart sound; S4: fourth heart sound; VSD: ventricular septal defect
Administer ONE of the following antiplatelet agents (before or at the time of PCI):
❑ P2Y12 receptor inhibitors
Prasugrel is contraindicated in case of prior history of strokes or TIAs, active pathological bleeding, age ≥75 years, when urgent coronary artery bypass graft surgery (CABG) is likely, body weight <60 kg, propensity to bleed, concomitant use of medications that increase the risk of bleeding
❑ IV GP IIb/IIIa inhibitors
Administer ONE of the following anticoagulant therapy:
❑ Unfractionated heparin
❑ Bivalirudin
G01=
❑ Ongoing and recurrent ischemia
❑ Cardiogenic shock
❑ Severe heart failure
❑ Other high risk features
# Summary of Recommendations for Mitral Stenosis Intervention
- PMBC is recommended for symptomatic patients with sever mitral stenosis (MVA ≤ 1.5 cm², stage D) and favorabale valve morphology in the absence of contraindications (Class I, level of evidence A)
- Mitral valve surgery is indicated in severely symptomatic patients (NYHA class III/IV) with severe mitral stenosis (MVA ≤ 1.5 cm², stage D) who are not high risk for surgery and who are not candidates for or failed previous PMBC (Class I, level of evidence B)
- Concomitant mitral valve surgery is indicated for patients with severe mitral stenosis (MVA ≤ 1.5 cm², stage C or D) undergoing other cardiac surgery (Class I, level of evidence C)
- PMBC is reasonable for asymptomatic patients with very severe mitral stenosis (MVA ≤ 1 cm², stage C) and favourable valve morphology in the absence of contraindications (Class IIa, level of evidence C)
- Mitral valve surgery is reasonable for severely symptomatic patients with severe mitral stenosis (MVA ≤ 1.5 cm², stage D) provided that there is other operative indications (Class IIa, level of evidence C)
- PMBC may be considered for asymptomatic patients with mitral stenosis (MVA ≤ 1.5 cm², stage C) and favourable valve morphology who have new onset of atrial fibrillation in the absence of contraindications (Class IIb, level of evidence C)
- PMBC may be considered for symptomatic patients with MVA > 1.5 cm² if there is evidence of hemodynamically significant mitral stenosis during exercise (Class IIb, level of evidence C)
- PMBC may be considered for severely symptomatic patients (NYHA III/IV) with severe mitral stenosis (MVA ≤ 1.5 cm², stage D) who have suboptimal valve anatomy and aren't candidates for surgery or at high risk for surgery (Class IIb, level of evidence C)
- Concomitant mitral valve surgery may be considered for patients with moderate mitral stenosis (MVA 1.6 - 2.0 cm²) undergoing other cardiac surgery (Class IIb, level of evidence C)
- Mitral valve surgery and excision of the left atrial appendage may be considered for patients with severe mitral stenosis (MVA ≤ 1.5 cm², stage C and D) who have recurrent embolic events while receiving adequate anticoagulation (Class IIb, level of evidence C)
- ↑ "" (PDF). External link in |title= (help).mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ "" (PDF). External link in |title= (help)
- ↑ Jump up to: 3.0 3.1 "ACC/AHA 2004 guideline update for coronary arter... - PubMed - NCBI".
- ↑ Jump up to: 4.0 4.1 "2008 Focused update incorporated into the ACC/AH... - PubMed - NCBI". | Sandbox/MS
Abbreviations: CABG: coronary artery bypass graft; ECG: electrocardiogram; LAD: left anterior descending; LBBB: left bundle branch block; MI: myocardial infarction; PCI: percutaneous coronary intervention; S3: third heart sound; S4: fourth heart sound; VSD: ventricular septal defect
Administer ONE of the following antiplatelet agents (before or at the time of PCI):
❑ P2Y12 receptor inhibitors
Prasugrel is contraindicated in case of prior history of strokes or TIAs, active pathological bleeding, age ≥75 years, when urgent coronary artery bypass graft surgery (CABG) is likely, body weight <60 kg, propensity to bleed, concomitant use of medications that increase the risk of bleeding
❑ IV GP IIb/IIIa inhibitors
Administer ONE of the following anticoagulant therapy:
❑ Unfractionated heparin
❑ Bivalirudin
G01=
❑ Ongoing and recurrent ischemia
❑ Cardiogenic shock
❑ Severe heart failure
❑ Other high risk features
## Summary of Recommendations for Mitral Stenosis Intervention
- PMBC is recommended for symptomatic patients with sever mitral stenosis (MVA ≤ 1.5 cm², stage D) and favorabale valve morphology in the absence of contraindications (Class I, level of evidence A)
- Mitral valve surgery is indicated in severely symptomatic patients (NYHA class III/IV) with severe mitral stenosis (MVA ≤ 1.5 cm², stage D) who are not high risk for surgery and who are not candidates for or failed previous PMBC (Class I, level of evidence B)
- Concomitant mitral valve surgery is indicated for patients with severe mitral stenosis (MVA ≤ 1.5 cm², stage C or D) undergoing other cardiac surgery (Class I, level of evidence C)
- PMBC is reasonable for asymptomatic patients with very severe mitral stenosis (MVA ≤ 1 cm², stage C) and favourable valve morphology in the absence of contraindications (Class IIa, level of evidence C)
- Mitral valve surgery is reasonable for severely symptomatic patients with severe mitral stenosis (MVA ≤ 1.5 cm², stage D) provided that there is other operative indications (Class IIa, level of evidence C)
- PMBC may be considered for asymptomatic patients with mitral stenosis (MVA ≤ 1.5 cm², stage C) and favourable valve morphology who have new onset of atrial fibrillation in the absence of contraindications (Class IIb, level of evidence C)
- PMBC may be considered for symptomatic patients with MVA > 1.5 cm² if there is evidence of hemodynamically significant mitral stenosis during exercise (Class IIb, level of evidence C)
- PMBC may be considered for severely symptomatic patients (NYHA III/IV) with severe mitral stenosis (MVA ≤ 1.5 cm², stage D) who have suboptimal valve anatomy and aren't candidates for surgery or at high risk for surgery (Class IIb, level of evidence C)
- Concomitant mitral valve surgery may be considered for patients with moderate mitral stenosis (MVA 1.6 - 2.0 cm²) undergoing other cardiac surgery (Class IIb, level of evidence C)
- Mitral valve surgery and excision of the left atrial appendage may be considered for patients with severe mitral stenosis (MVA ≤ 1.5 cm², stage C and D) who have recurrent embolic events while receiving adequate anticoagulation (Class IIb, level of evidence C)
- ↑ "http://eurheartj.oxfordjournals.org/content/32/23/2999.full.pdf" (PDF). External link in |title= (help).mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ "http://eurheartj.oxfordjournals.org/content/32/23/2999.full.pdf" (PDF). External link in |title= (help)
- ↑ Jump up to: 3.0 3.1 "ACC/AHA 2004 guideline update for coronary arter... [Circulation. 2004] - PubMed - NCBI".
- ↑ Jump up to: 4.0 4.1 "2008 Focused update incorporated into the ACC/AH... [Circulation. 2008] - PubMed - NCBI". | https://www.wikidoc.org/index.php/Sandbox/MS | |
b25dd71e4050ea424f641edfebc368b6a8dc9522 | wikidoc | Sandbox/am | Sandbox/am
# Overview
Plasma cell myeloma is a monoclonal neoplastic proliferation of plasma cells of bone-marrow derivation, usually multicentric, that eventually infiltrates various organs but rarely produces plasma cell leukaemia. It is characterized by osteolytic lesions, bone pain, hypercalcemia, a
monoclonal gammopathy, and disorders due to depositon of abnormal immunoglobulin chains (amyloid) in various tissues including kidney. It ranges from MGUS to plasmacytoma to multiple myeloma. Solitary plasmacytoma is a rare plasma cell disorder, accounting for 2–10% of plasma cell disorders. It is classified as either solitary extramedullary plasmacytoma (SEP) or solitary bone plasmacytoma. The head and neck are the predominant sites for SEP, and only a small number are associated with serum Most extramedullary plasmacytomas respond to local radiotherapy and have a good prognosis. Although the most common plasma cell dyscrasia is monoclonal gammopathy of undetermined significance (MGUS), closely related disorders include multiple myeloma, solitary plasmacytoma of bone, extramedullary plasmacytoma, waldenstorm's macroglobulinemia, Amyloidosis, light chain deposition disease, paraproteinemia and heavy chain disease. The spectrum of MGUS, solitary plasmacytoma of bone, and asymptomatic and symptomatic multiple myeloma may actually represent a natural progression of the same disease. Prognosis and outcome of PCM, commonly known as multiple myeloma (MM)—the most prevalent and fatal PCN and the second most common hematologic malignancy worldwide—remain grim despite availability of sophisticated conventional treatment protocols (chemotherapy, irradiation, hematopoietic stem cell transplantation) that have been recently supplemented by novel targeted therapies including proteasome inhibitors (bortezomib), immunomodulatory agents (thalidomide, lenalidomide), antibodies to interleukin-6 (IL-6) or its receptor, and a variety of newly emerging inhibitors of cellular signal transduction pathways
Plasma cell neeoplasm can result in several complications:
Impaired immunity. Myeloma cells inhibit the production of antibodies needed for normal immunity. Having multiple myeloma may make you more likely to develop infections, such as pneumonia, sinusitis, bladder or kidney infections, skin infections, and shingles.
Bone problems. Multiple myeloma also can affect your bones, leading to erosion of bone mass and fractures. The condition may cause compression of your spinal cord. Signs of this medical emergency include weakness, or even paralysis, in your legs.
Impaired kidney function. Multiple myeloma may cause problems with kidney function, including kidney failure. Higher calcium levels in the blood related to eroding bones can interfere with your kidneys' ability to filter your blood's waste. The proteins produced by the myeloma cells can cause similar problems, especially if you become dehydrated.
Anemia. As cancerous cells crowd out normal blood cells, multiple myeloma can also cause anemia and other blood problems.
Laboratory findings :
The presence of unexplained anemia, renal dysfunction, a high (ESR), lytic bone lesions, elevated beta globulin, and/or a high serum protein (especially raised globulins or immunoglobulins) may prompt further testing
The screening test for myeloma inlcudes
If symptoms or the results of routine investigations suggest that a patient may have myeloma, then the following investigations should be performed:
FBC.
ESR or plasma viscosity.
Urea, electrolytes and creatinine.
Calcium.
Albumin.
Uric acid.
Protein elctrophoresis: shows the type of paraprotein.
Urine protein electrophoresis: looks for the presence of Bence Jones' protein
Quantitative immunoglobulin levels (eg IgG, IgA, IgM levels): non-myelomatous immunoglobulin can be suppressed. The level of the myeloma paraprotein can also be used to assess response to treatment.
Plain X-ray of symptomatic areas
The classic imaging finding in MM is one or more focal osteolytic lesions seen on radiographs
Osteolytic lesions related to MM are most commonly found in the axial skeleton, skull, shoulder girdle, proximal humeri, ribs, and proximal femurs.2 These lesions are generally investigated by WBXR, which consists of a series of plain X-rays that include the chest, skull, humeri, femurs, and pelvis, as well as antero-posterior and lateral images of the whole spine. According to the current guidelines of the International Myeloma Working Group, WBXR is considered as the gold standard imaging modality.3 However, this technique has significant limitations. First of all, WBXR is insensitive to detect early osteolytic bone lesions and can, therefore, underestimate the extent of BM involvement.4 An experimental study showed that a bone defect in a lumbar vertebra can be seen on lateral X-ray only when 50–75% of the trabecular bone has been destroyed.5 Additionally, because WBXR requires 20 separate films, the patient generally spends a long period of time on the radiographic table. Furthermore, the WBXR cannot be used to assess treatment response, as the appearance of osteolytic lesions may not change following therapy.
PET
Current trends :--
## Toxicity
Treatment-related toxic effects of existing agents pose another challenge.
Peripheral neuropathy is observed in approximately 40% of patients who receive bortezomib (1.3 mg/m) twice weekly, with 14% of patients experiencing grade 3–4 neuropathy, and in approximately 25% of patients who receive the same dose
-nce weekly, including 4% with grade 3–4 sensory neuropathy.46 2 Transplant eligible patient Three-drug induction Two-drug induction Bortezomib–dexamethasone or lenalidomide–dexamethasone Peripheral neuropathy seems to be less frequent and less severe when bortezomib is administered subcutaneously rather than intravenously. In most cases, neuropathy is reversible after discontinuation of bortezomib.
Venous thromboembolism (VTE) is observed inapproximately 1–5% of patients in clinical trials with single-agent thalidomide, which is similar to the backgroundrate of such events in patients with multiple myelom who are not treated with this agent. 47 The reported frequency of thrombotic events has been as high as 26% when thalidomide is used in combination with high-dose dexamethasone. As with thalidomide, the risk of VTE among patients with multiple myeloma who take single-agent lenalidomide does not seem to be higher than that of those who do not take lenalidomide does not seem to be higher than those who take it. 49 . By contrast, the use of lenalidomide in combina- tion with high-dose glucocorticoids is associated with 3 fold increased risk of cotting events.48 43 . Although VTE is the most-common form of thrombosisin this patient population,arterial thrombotic events have also been reported. The International Myeloma Working Group panel recommends the use of aspirin in patients with one risk factor for VTE. 50 Individual risk factors for thrombosis associated with thalidomide or lenalidomide-based therapy include age, history of VTE, central venous catheter, comorbidities (infections, diabetes, cardiac disease), immobilization, surgery and inherited thrombophilia. Myeloma-related risk factors
include diagnosis and hyperviscosity. 49 49 Low-molecularweight heparin (equivalent to enoxaparin 40 mg per day) is recommended for patients with two or more
individual or myeloma-related risk factors for VTE. Heparin is also recommended for all patients receiving thalidomide and lenalidomide in combination with high-dose dexamethasone or doxorubicin. Warfarin given to a therapeutic international normalized ratio of 2–3 is an alternative to heparin, although data in the literature about this strategy are limited. 51 With increasing complexity of drug regimens, the question that remains to be answered is how to individualize the type and intensity of treatment.
VTE is observed inapproximately 1–5% of patients in clinical trials with single-agent thalidomide, which is similar to the background rate of such events in patients with multiple myeloma who are not treated with this agent. 47 The reported frequency of thrombotic events has been as high as 26% when thalidomide is used in combination with high-dose dexamethasone. As with thalidomide, the risk of VTE among patients with multiple myeloma who take single-agent lenalidomide does not seem to be higher than that of those who do not take lenalidomide does not seem to be higher than those who take it. 49 . By contrast, the use of lenalidomide in combination with high-dose glucocorticoids is associated with 3 fold increased risk of cotting events.48 43 | Sandbox/am
Template:Plasma cell neoplasm
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Plasma cell myeloma is a monoclonal neoplastic proliferation of plasma cells of bone-marrow derivation, usually multicentric, that eventually infiltrates various organs but rarely produces plasma cell leukaemia. It is characterized by osteolytic lesions, bone pain, hypercalcemia, a
monoclonal gammopathy, and disorders due to depositon of abnormal immunoglobulin chains (amyloid) in various tissues including kidney. It ranges from MGUS to plasmacytoma to multiple myeloma. Solitary plasmacytoma is a rare plasma cell disorder, accounting for 2–10% of plasma cell disorders. It is classified as either solitary extramedullary plasmacytoma (SEP) or solitary bone plasmacytoma. The head and neck are the predominant sites for SEP, and only a small number are associated with serum Most extramedullary plasmacytomas respond to local radiotherapy and have a good prognosis. Although the most common plasma cell dyscrasia is monoclonal gammopathy of undetermined significance (MGUS), closely related disorders include multiple myeloma, solitary plasmacytoma of bone, extramedullary plasmacytoma, waldenstorm's macroglobulinemia, Amyloidosis, light chain deposition disease, paraproteinemia and heavy chain disease. The spectrum of MGUS, solitary plasmacytoma of bone, and asymptomatic and symptomatic multiple myeloma may actually represent a natural progression of the same disease. Prognosis and outcome of PCM, commonly known as multiple myeloma (MM)—the most prevalent and fatal PCN and the second most common hematologic malignancy worldwide—remain grim despite availability of sophisticated conventional treatment protocols (chemotherapy, irradiation, hematopoietic stem cell transplantation) that have been recently supplemented by novel targeted therapies including proteasome inhibitors (bortezomib), immunomodulatory agents (thalidomide, lenalidomide), antibodies to interleukin-6 (IL-6) or its receptor, and a variety of newly emerging inhibitors of cellular signal transduction pathways
Plasma cell neeoplasm can result in several complications:
Impaired immunity. Myeloma cells inhibit the production of antibodies needed for normal immunity. Having multiple myeloma may make you more likely to develop infections, such as pneumonia, sinusitis, bladder or kidney infections, skin infections, and shingles.
Bone problems. Multiple myeloma also can affect your bones, leading to erosion of bone mass and fractures. The condition may cause compression of your spinal cord. Signs of this medical emergency include weakness, or even paralysis, in your legs.
Impaired kidney function. Multiple myeloma may cause problems with kidney function, including kidney failure. Higher calcium levels in the blood related to eroding bones can interfere with your kidneys' ability to filter your blood's waste. The proteins produced by the myeloma cells can cause similar problems, especially if you become dehydrated.
Anemia. As cancerous cells crowd out normal blood cells, multiple myeloma can also cause anemia and other blood problems.
Laboratory findings :
The presence of unexplained anemia, renal dysfunction, a high (ESR), lytic bone lesions, elevated beta globulin, and/or a high serum protein (especially raised globulins or immunoglobulins) may prompt further testing
The screening test for myeloma inlcudes
If symptoms or the results of routine investigations suggest that a patient may have myeloma, then the following investigations should be performed:[2]
FBC.
ESR or plasma viscosity.
Urea, electrolytes and creatinine.
Calcium.
Albumin.
Uric acid.
Protein elctrophoresis: shows the type of paraprotein.
Urine protein electrophoresis: looks for the presence of Bence Jones' protein
Quantitative immunoglobulin levels (eg IgG, IgA, IgM levels): non-myelomatous immunoglobulin can be suppressed. The level of the myeloma paraprotein can also be used to assess response to treatment.
Plain X-ray of symptomatic areas
The classic imaging finding in MM is one or more focal osteolytic lesions seen on radiographs
Osteolytic lesions related to MM are most commonly found in the axial skeleton, skull, shoulder girdle, proximal humeri, ribs, and proximal femurs.2 These lesions are generally investigated by WBXR, which consists of a series of plain X-rays that include the chest, skull, humeri, femurs, and pelvis, as well as antero-posterior and lateral images of the whole spine. According to the current guidelines of the International Myeloma Working Group, WBXR is considered as the gold standard imaging modality.3 However, this technique has significant limitations. First of all, WBXR is insensitive to detect early osteolytic bone lesions and can, therefore, underestimate the extent of BM involvement.4 An experimental study showed that a bone defect in a lumbar vertebra can be seen on lateral X-ray only when 50–75% of the trabecular bone has been destroyed.5 Additionally, because WBXR requires 20 separate films, the patient generally spends a long period of time on the radiographic table. Furthermore, the WBXR cannot be used to assess treatment response, as the appearance of osteolytic lesions may not change following therapy.
PET
Current trends :--
## Toxicity
Treatment-related toxic effects of existing agents pose another challenge.
Peripheral neuropathy is observed in approximately 40% of patients who receive bortezomib (1.3 mg/m) twice weekly, with 14% of patients experiencing grade 3–4 neuropathy, and in approximately 25% of patients who receive the same dose
once weekly, including 4% with grade 3–4 sensory neuropathy.46 2 Transplant eligible patient Three-drug induction Two-drug induction Bortezomib–dexamethasone or lenalidomide–dexamethasone Peripheral neuropathy seems to be less frequent and less severe when bortezomib is administered subcutaneously rather than intravenously. In most cases, neuropathy is reversible after discontinuation of bortezomib.
Venous thromboembolism (VTE) is observed inapproximately 1–5% of patients in clinical trials with single-agent thalidomide, which is similar to the backgroundrate of such events in patients with multiple myelom who are not treated with this agent. 47 The reported frequency of thrombotic events has been as high as 26% when thalidomide is used in combination with high-dose dexamethasone. As with thalidomide, the risk of VTE among patients with multiple myeloma who take single-agent lenalidomide does not seem to be higher than that of those who do not take lenalidomide does not seem to be higher than those who take it. 49 . By contrast, the use of lenalidomide in combina- tion with high-dose glucocorticoids is associated with 3 fold increased risk of cotting events.48 43 . Although VTE is the most-common form of thrombosisin this patient population,arterial thrombotic events have also been reported. The International Myeloma Working Group panel recommends the use of aspirin in patients with one risk factor for VTE. 50 Individual risk factors for thrombosis associated with thalidomide or lenalidomide-based therapy include age, history of VTE, central venous catheter, comorbidities (infections, diabetes, cardiac disease), immobilization, surgery and inherited thrombophilia. Myeloma-related risk factors
include diagnosis and hyperviscosity. 49 49 Low-molecularweight heparin (equivalent to enoxaparin 40 mg per day) is recommended for patients with two or more
individual or myeloma-related risk factors for VTE. Heparin is also recommended for all patients receiving thalidomide and lenalidomide in combination with high-dose dexamethasone or doxorubicin. Warfarin given to a therapeutic international normalized ratio of 2–3 is an alternative to heparin, although data in the literature about this strategy are limited. 51 With increasing complexity of drug regimens, the question that remains to be answered is how to individualize the type and intensity of treatment.
VTE is observed inapproximately 1–5% of patients in clinical trials with single-agent thalidomide, which is similar to the background rate of such events in patients with multiple myeloma who are not treated with this agent. 47 The reported frequency of thrombotic events has been as high as 26% when thalidomide is used in combination with high-dose dexamethasone. As with thalidomide, the risk of VTE among patients with multiple myeloma who take single-agent lenalidomide does not seem to be higher than that of those who do not take lenalidomide does not seem to be higher than those who take it. 49 . By contrast, the use of lenalidomide in combination with high-dose glucocorticoids is associated with 3 fold increased risk of cotting events.48 43 | https://www.wikidoc.org/index.php/Sandbox/am | |
f132b0d0735da4651d5f5432a21050a1150473b0 | wikidoc | Sandbox:AA | Sandbox:AA
# Differential diagnosis of bacterial meningitis
# classification of bacterial meningitis
Prevention of stroke can work at various levels including:
- primary prevention - the reduction of risk factors across the board, by public health measures such as reducing smoking and the other behaviours that increase risk;
- secondary prevention - actions taken to redrombuce the risk in those who already have disease or risk factors that may have been identified through screening; and
- tertiary prevention - actions taken to reduce the risk of complications (including further strokes) in people who have already had a stroke.
The most important modifiable risk factors for stroke are hypertension, heart disease, diabetes, and cigarette smoking. Other risks include heavy alcohol consumption (see Alcohol consumption and health), high blood cholesterol levels, illicit drug use, and genetic or congenital conditions. Family members may have a genetic tendency for stroke or share a lifestyle that contributes to stroke. Higher levels of Von Willebrand factor are more common amongst people who have had ischemic stroke for the first time. The results of this study found that the only significant genetic factor was the person's blood type. Having had a stroke in the past greatly increases one's risk of future strokes.
One of the most significant stroke risk factors is advanced age. 95% of strokes occur in people age 45 and older, and two-thirds of strokes occur in those over the age of 65. A person's risk of dying if he or she does have a stroke also increases with age. However, stroke can occur at any age, including in fetuses.
Sickle cell anemia, which can cause blood cells to clump up and block blood vessels, also increases stroke risk. Stroke is the second leading killer of people under 20 who suffer from sickle-cell anemia.
Men are 1.25 times more likely to suffer strokes than women, yet 60% of deaths from stroke occur in women. Since women live longer, they are older on average when they have their strokes and thus more often killed (NIMH 2002). Some risk factors for stroke apply only to women. Primary among these are pregnancy, childbirth, menopause and the treatment thereof (HRT).
Prevention is an important public health concern. Identification of patients with treatable risk factors for stroke is paramount. Treatment of risk factors in patients who have already had strokes (secondary prevention) is also very important as they are at high risk of subsequent events compared with those who have never had a stroke. Medication or drug therapy is the most common method of stroke prevention. Aspirin (usually at a low dose of 75 mg) is recommended for the primary and secondary prevention of stroke. Also see Antiplatelet drug treatment. Treating hypertension, diabetes mellitus, smoking cessation, control of hypercholesterolemia, physical exercise, and avoidance of illicit drugs and excessive alcohol consumption are all recommended ways of reducing the risk of stroke.
In patients who have strokes due to abnormalities of the heart, such as atrial fibrillation, anticoagulation with medications such as warfarin is often necessary for stroke prevention.
Procedures such as carotid endarterectomy or carotid angioplasty can be used to remove significant atherosclerotic narrowing (stenosis) of the carotid artery, which supplies blood to the brain. These procedures have been shown to prevent stroke in certain patients, especially where carotid stenosis leads to ischemic events such as transient ischemic attack. (The value and role of carotid artery ultrasound scanning in screening has yet to be established.)
A meta-analysis concluded that lowering homocysteine with folic acid and other supplements may reduce stroke. However, the two largest randomized controlled trials included in the meta-analysis had conflicting results. Lonn reported positve results; whereas the trial by Toole was negative.
Aysha's sandbox
TOAST CLASSIFICATION OF Acute ISCHEMIC STROKE:
- Large artery atherosclerosis
- Cardioembolism
- Small vessel occlusion-Lacunar infarct
- Stroke of other, unusual, determined etiology
- Stroke of undetermined etiology
Based on duration of symptoms:
- Transient ischemic stroke
- Acute ischemic stroke
- Chronic ischemic stroke:
Ischemic stroke due to cause:
- Artherosclerotic
- Non Artherosclerotic
- Systemic hypoperfusion
PATHOPHYSIOLOGY:
Hemodynamic changes:
- Reduction in blood flow due to systemic hypoperfsuion, involves watershed areas
hippocampal pyramidal cells, cerebellar Purkinje cells, and cortical laminar cells
- Thrombosis acutely or chronically, involves extrascranail and intracranial vesssels. Atherosclerotic blood vessels , plts adhere to plaque causing occlusion
- Embolic stroke: clot foms elsewhere in the body and travels to the brain, usually heart in afib, other emboli causing stroke involves tumour, septic embolus, venous clot or fat
- Embolic stroke-cortical undergo hemorrhagic transformation
- Lacunar infarction: involves small penetrating vessels, chronic hypertension causes thickening of media and fibrinoid depositon in the vessel wall causing lumen narrowing and occlusion.
Ususally subcortical but any site can be involved.
Non atherosclerotic causes such as
-Fibromuscular dysplasia
-Vasculitis
-Moyamoya disease
-Sickle cell disease arteriopathy
-Focal cerebral arteriopathy of childhood
Cause Pathogenesis area involved
Cellular changes:
- Focal ischemia-area affected by single blood vessel and its surrounding branches. Central core of tissue die by necrosis as directly supplied by the blood vessel, called infarct.
The cells surrounding the central infarct supplied by collateral vessels receive some oxygen and glucose, at increased risk of infarction but can be salvaged by increase in blood flow to the area called Pneumbra.
Molecular changes:
- Depletion of ATP
- Acidosis, lactate increased
- Ionic imbalance: Na,K, Ca
- Increase in excitatory neurotrasmittor glutamate at synases due to neuronal electrical failure-
Glutamate receptor stimulation NMDA receptors –opening of ion channels, increased calcium and sodium influx and potassium eflux
- Increased Na influx and water-edema and causes decreased uptake of glutamate resulting in excitotoxicity state in the brain
- NMDA receptor activation causes increase NO levels in the brain-excessive levels acts as a free radical-reacts with other free oxygen radicals producing peroxynitirite causing breaks in DNA and DNA damage- Apoptosis
Type of cell death after ischemia
Type of infarct time of initiation of cell death Main mechanism of cell death Area invol
- Global ischemia delayed after 12 hours –several days Apoptosis Hippoca
- Focal ischemia Within 3-4 hours -12 to 24hrs Necrosis central core by necrosis and periphery by apoptosis centre
Loss of brain structural integrity
Cerebral edema:
Vasogenic: Disruption of bbb
Celluar/cytotoxic: ATP dep ion regualtion disrupted
Cerebral autoregulation
Cerebral blood flow determinants
- Cerebral perfusion pressure
- Cerebral blood flow is maintained in the pressure range of 60-150 mmg
- Cerebral blood flow increases in cases of low pressure by vasodilation- nitric oxide release by endothelial cells
- Blood flow decreases by vasoconstriction at high pressures. Smooth muscles in the Bv are the sensors for detection of blood vessels
Pressure below 60 mmhg ischemia
Pressure above 150 mmhg edema
Cerebral autoregulation failure during ischemia:
Low pressures- cerebral vasodilation to increase blood flow-increased oxygen extraction ratio initially to maintain oxygen levels in the brain cells-further dcline in blood presssure- compensatory mechanisms fail-inhibtion of protein synthesis 35ml/100gm/min, increased glucose utilization – 25ml/100gm/minanaerobic glycolysis-tissue acidosis-neuronal electric failure16-18ml/100gm/min-cell membrane dysfunctionml/100gm /min 10-12-cell death (infart)
In hypertension autoregulation set at higher pressures so drop to normal levels may exacerbate ischemia
GENETICS:
-HDAC9 for large vessel disease
-ABO for all ischemic stroke
Prognosis of ischemic stroke
1)a)age, stroke severity, stroke mechanism, infarct location, comorbid conditions, clinical findings, and related complication;
b) interventions such as thrombolysis, stroke unit care, and rehabilitation can play a major role in the outcome of ischemic strok
c)acute phase of stroke, the strongest predictors of outcome are stroke severity and patient age.
2):Bruno A, Biller J, Adams HP Jr, Clarke WR, Woolson RF, Williams LS, et al. Acute blood glucose level and outcome from ischemic stroke.aird TA, Parsons MW, Phanh T, Butcher KS, Desmond PM, Tress BM, et al. Persistent poststroke hyperglycemia is independently associated with infarct expansion and worse clinical outcomeMandelzweig L, Goldbourt U, Boyko V, Tanne D. Perceptual, social, and behavioral factors associated with delays in seeking medical care in patients with symptoms of acute strokeTissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study GroupAcute stroke: usefulness of early CT findings before thrombolytic therapy
3)Poor prognostic factors:
Severe middle cerebral artery infarction
- Large area of brain involvement
- Other co morbid conditons
- Advanced age
- Severe hemiplegia
4)Good prognostic factors:
5)NIHSS score predicts early mortality predicts prognosis; The NIHSS score strongly predicts the likelihood of a patient's recovery after stroke. A score of > or =16 forecasts a high probability of death or severe disability whereas a score of < or =6 forecasts a good recovery.
6)The 1-year mortality in first-time stroke sufferers is 14% to 24% in persons aged 40 to 69 years, and the 1-year mortality increases to 22% to 27% in patients aged 70 years and older. (Find citation)
CDC
Stroke kills almost 130,000 Americans each year—that’s 1 out of every 20 deaths.1
On average, one American dies from stroke every 4 minutes.2
Every year, more than 795,000 people in the United States have a stroke.
About 610,000 of these are first or new strokes.
About 185,00 strokes—nearly one of four—are in people who have had a previous stroke.2
About 87% of all strokes are ischemic strokes, when blood flow to the brain is blocked.2
Stroke costs the United States an estimated $34 billion each year.2 This total includes the cost of health care services, medications to treat stroke, and missed days of work.
Stroke is a leading cause of serious long-term disability.2
Classification of Ischemic Stroke:
According to the causative agent:
- Thrombotic
- Embolic
- Small vessel disease
- Systemic hypoperfusion
- Crytogenic-Undetermined etiology
Toast classification of ischemic stroke:
According to anatomical location:
- Cortical
- Subcortical
- Watershed areas
According to vessel involved:
- Anterial cerebral artery
- Middle cerebral artery
- Posterior cerebral artery
According to duration of symptoms:
- Acute
- subacute
- Chronic
According to clinical presentaion
- Pure Motor
- Pure Sensory
- Mixed
Stroke epidemiology PMID: 26673558
In 2013, stroke fell from the fourth to the fifth leading cause
-f death in the United States, behind diseases of the heart,
cancer, chronic lower respiratory diseases, and unintentional
injury.
●● From 2003 to 2013, the relative rate of stroke death fell
by 33.7% and the actual number of stroke deaths declined by 18.2%. Yet each year, ≈795 000 people continue to
experience a new or recurrent stroke (ischemic or hemorrhagic).
Approximately 610 000 of these are first events
and 185 000 are recurrent stroke events. In 2013, stroke
caused ≈1 of every 20 deaths in the United States. On average,
every 40 seconds, someone in the United States has
a stroke, and someone dies of one approximately every 4
minutes.
●● The decline in stroke mortality over the past decades, a
major improvement in population health observed for
both sexes and all race and age groups, has resulted from
reduced stroke incidence and lower case fatality rates. The
significant improvements in stroke outcomes are concurrent
with cardiovascular risk factor control interventions.
The hypertension control efforts initiated in the 1970s
appear to have had the most substantial influence on the
accelerated decline in stroke mortality, with lower blood
pressure distributions in the population. Control of diabetes
mellitus and high cholesterol and smoking cessation
programs, particularly in combination with hypertension
treatment, also appear to have contributed to the decline in
stroke mortality.
●● Approximately 10% of all strokes occur in people 18 to
50 years of age. Between 1995 and 2008, National Health
Interview Survey data reveal that hospitalizations for
ischemic stroke increased among adolescents and young
adults (aged 5–44 years), whereas subarachnoid hemorrhage
hospitalizations decreased during that same time
period.
●● Stroke death rates declined more among people aged ≥65
years (−54.1%; from 534.1 to 245.2 per 100 000) than
among those aged 45 to 64 years (−53.6%; from 43.5 to
20.2 per 100 000) or those aged 18 to 44 years (−45.9%;
from 3.7 to 2.0 per 100 000).
## Common complications
MRI syphilis 17628376
- 20 mg/kg/dose twice daily (max = 500 mg/dose)
- 10 days
- 30 mg/kg once daily (max = 1 g)
- 10 days
- 7 mg/kg/dose 3 times daily (max = 300 mg/dose)
- 10 days
- 12 mg/kg once daily (max = 500 mg)
- 5 days
- 7.5 mg/kg/dose twice daily (max = 250 mg/dose)
- 10 days
## Postexposure prophylaxis
### Active immunisation
Varicella vaccine is recommended for immunocompetent individuals exposed to varicella infection but did not receive full two dose course of vaccine previously
### Passive immunisation
VZV immunoglobulin
- ↑ Bongers T, de Maat M, van Goor M; et al. (2006). "High von Willebrand factor levels increase the risk of first ischemic stroke: influence of ADAMTS13, inflammation, and genetic variability". Stroke. 37 (11): 2672–7. PMID 16990571.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link) .mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ Jump up to: 2.0 2.1 2.2 2.3 National Institute of Neurological Disorders and Stroke (NINDS) (1999). "Stroke: Hope Through Research". National Institutes of Health.
- ↑ American Heart Association. (2007). Stroke Risk Factors Americanheart.org. Retrieved on January 22, 2007.
- ↑ American Heart Association. (2007). Atrial Fibrillation Americanheart.org. Retrieved on January 22, 2007.
- ↑ Wang X, Qin X, Demirtas H; et al. (2007). "Efficacy of folic acid supplementation in stroke prevention: a meta-analysis". Lancet. 369 (9576): 1876–82. doi:10.1016/S0140-6736(07)60854-X. PMID 17544768.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
- ↑ Lonn E, Yusuf S, Arnold MJ; et al. (2006). "Homocysteine lowering with folic acid and B vitamins in vascular disease". N. Engl. J. Med. 354 (15): 1567–77. doi:10.1056/NEJMoa060900. PMID 16531613.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
- ↑ Toole JF, Malinow MR, Chambless LE; et al. (2004). "Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial". JAMA. 291 (5): 565–75. doi:10.1001/jama.291.5.565. PMID 14762035.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
- ↑ Jump up to: 8.0 8.1 8.2 8.3 Nagaratnam N, Davies D, Chen E (1998). "Clinical effects of anterior cerebral artery infarction". J Stroke Cerebrovasc Dis. 7 (6): 391–7. PMID 17895117.CS1 maint: Multiple names: authors list (link)
- ↑ Jump up to: 9.0 9.1 9.2 Kumral E, Bayulkem G, Evyapan D, Yunten N (2002). "Spectrum of anterior cerebral artery territory infarction: clinical and MRI findings". Eur J Neurol. 9 (6): 615–24. PMID 12453077.CS1 maint: Multiple names: authors list (link)
- ↑ Jump up to: 10.0 10.1 Alexander MP, Schmitt MA (1980). "The aphasia syndrome of stroke in the left anterior cerebral artery territory". Arch Neurol. 37 (2): 97–100. PMID 7356415.
- ↑ Mizuta H, Motomura N (2006). "Memory dysfunction in caudate infarction caused by Heubner's recurring artery occlusion". Brain Cogn. 61 (2): 133–8. doi:10.1016/j.bandc.2005.11.002. PMID 16510225.
- ↑ den Heijer T, Ruitenberg A, Bakker J, Hertzberger L, Kerkhoff H (2007). "Neurological picture. Bilateral caudate nucleus infarction associated with variant in circle of Willis". J Neurol Neurosurg Psychiatry. 78 (11): 1175. doi:10.1136/jnnp.2006.112656. PMC 2117617. PMID 17940169.CS1 maint: Multiple names: authors list (link)
- ↑ Lemieux F, Lanthier S, Chevrier MC, Gioia L, Rouleau I, Cereda C; et al. (2012). "Insular ischemic stroke: clinical presentation and outcome". Cerebrovasc Dis Extra. 2 (1): 80–7. doi:10.1159/000343177. PMC 3492997. PMID 23139684.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
- ↑ Arboix A, Martí-Vilalta JL (2009). "Lacunar stroke". Expert Rev Neurother. 9 (2): 179–96. doi:10.1586/14737175.9.2.179. PMID 19210194.
- ↑ Melo TP, Bogousslavsky J, van Melle G, Regli F (1992). "Pure motor stroke: a reappraisal". Neurology. 42 (4): 789–95. PMID 1565233.CS1 maint: Multiple names: authors list (link)
- ↑ Tei H, Uchiyama S, Maruyama S (1993). "Capsular infarcts: location, size and etiology of pure motor hemiparesis, sensorimotor stroke and ataxic hemiparesis". Acta Neurol Scand. 88 (4): 264–8. PMID 8256570.CS1 maint: Multiple names: authors list (link)
- ↑ Fridriksson J, Fillmore P, Guo D, Rorden C (2015). "Chronic Broca's Aphasia Is Caused by Damage to Broca's and Wernicke's Areas". Cereb Cortex. 25 (12): 4689–96. doi:10.1093/cercor/bhu152. PMC 4669036. PMID 25016386.CS1 maint: Multiple names: authors list (link)
- ↑ Henderson VW (1985). "Lesion localization in Broca's aphasia. Implications from Broca's aphasia without hemiparesis". Arch Neurol. 42 (12): 1210–2. PMID 4062622.
- ↑ Jump up to: 19.0 19.1 Soma Y (1997). "". Rinsho Shinkeigaku. 37 (12): 1117–9. PMID 9577663.
- ↑ Jump up to: 20.0 20.1 Brandt T, Steinke W, Thie A, Pessin MS, Caplan LR (2000). "Posterior cerebral artery territory infarcts: clinical features, infarct topography, causes and outcome. Multicenter results and a review of the literature". Cerebrovasc Dis. 10 (3): 170–82. doi:16053 Check |doi= value (help). PMID 10773642.CS1 maint: Multiple names: authors list (link)
- ↑ Jump up to: 21.0 21.1 Cereda C, Carrera E (2012). "Posterior cerebral artery territory infarctions". Front Neurol Neurosci. 30: 128–31. doi:10.1159/000333610. PMID 22377879.
- ↑ Jump up to: 22.0 22.1 Yamamoto Y, Georgiadis AL, Chang HM, Caplan LR (1999). "Posterior cerebral artery territory infarcts in the New England Medical Center Posterior Circulation Registry". Arch Neurol. 56 (7): 824–32. PMID 10404984.CS1 maint: Multiple names: authors list (link)
- ↑ Jump up to: 23.0 23.1 Fisher CM (1986). "The posterior cerebral artery syndrome". Can J Neurol Sci. 13 (3): 232–9. PMID 3742339.
- ↑ Jump up to: 24.0 24.1 24.2 Caplan LR, Hedley-Whyte T (1974). "Cuing and memory dysfunction in alexia without agraphia. A case report". Brain. 97 (2): 251–62. PMID 4434176.
- ↑ Pessin MS, Lathi ES, Cohen MB, Kwan ES, Hedges TR, Caplan LR (1987). "Clinical features and mechanism of occipital infarction". Ann Neurol. 21 (3): 290–9. doi:10.1002/ana.410210311. PMID 3606035.CS1 maint: Multiple names: authors list (link)
- ↑ Damasio AR, Damasio H, Van Hoesen GW (1982). "Prosopagnosia: anatomic basis and behavioral mechanisms". Neurology. 32 (4): 331–41. PMID 7199655.CS1 maint: Multiple names: authors list (link)
- ↑ Jump up to: 27.0 27.1 Melo TP, Bogousslavsky J (1992). "Hemiataxia-hypesthesia: a thalamic stroke syndrome". J Neurol Neurosurg Psychiatry. 55 (7): 581–4. PMC 489170. PMID 1640235.
- ↑ Jump up to: 28.0 28.1 28.2 Caplan L (2000). "Posterior circulation ischemia: then, now, and tomorrow. The Thomas Willis Lecture-2000". Stroke. 31 (8): 2011–23. PMID 10926972.
- ↑ Nouh A, Remke J, Ruland S (2014). "Ischemic posterior circulation stroke: a review of anatomy, clinical presentations, diagnosis, and current management". Front Neurol. 5: 30. doi:10.3389/fneur.2014.00030. PMC 3985033. PMID 24778625.CS1 maint: Multiple names: authors list (link)
- ↑ Sacco RL, Freddo L, Bello JA, Odel JG, Onesti ST, Mohr JP (1993). "Wallenberg's lateral medullary syndrome. Clinical-magnetic resonance imaging correlations". Arch Neurol. 50 (6): 609–14. PMID 8503798.CS1 maint: Multiple names: authors list (link)
- ↑ Shetty SR, Anusha R, Thomas PS, Babu SG (2012). "Wallenberg's syndrome". J Neurosci Rural Pract. 3 (1): 100–2. doi:10.4103/0976-3147.91980. PMC 3271596. PMID 22346215.CS1 maint: Multiple names: authors list (link)
- ↑ Kim JS, Kim HG, Chung CS (1995). "Medial medullary syndrome. Report of 18 new patients and a review of the literature". Stroke. 26 (9): 1548–52. PMID 7660396.CS1 maint: Multiple names: authors list (link)
- ↑ Kim K, Lee HS, Jung YH, Kim YD, Nam HS, Nam CM; et al. (2012). "Mechanism of medullary infarction based on arterial territory involvement". J Clin Neurol. 8 (2): 116–22. doi:10.3988/jcn.2012.8.2.116. PMC 3391616. PMID 22787495.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
- ↑ Patterson JR, Grabois M (1986). "Locked-in syndrome: a review of 139 cases". Stroke. 17 (4): 758–64. PMID 3738962.
- ↑ Karp JS, Hurtig HI (1974). ""Locked-in" state with bilateral midbrain infarcts". Arch Neurol. 30 (2): 176–8. PMID 4810896.
- ↑ Accessed on October 24, 2016
- ↑ Salzman MB, Garcia C (1998). "Postexposure varicella vaccination in siblings of children with active varicella". Pediatr Infect Dis J. 17 (3): 256–7. PMID 9535260.
- ↑ Asano Y, Nakayama H, Yazaki T, Kato R, Hirose S (1977). "Protection against varicella in family contacts by immediate inoculation with live varicella vaccine". Pediatrics. 59 (1): 3–7. PMID 190583.CS1 maint: Multiple names: authors list (link) | Sandbox:AA
# Differential diagnosis of bacterial meningitis
# classification of bacterial meningitis
Prevention of stroke can work at various levels including:
- primary prevention - the reduction of risk factors across the board, by public health measures such as reducing smoking and the other behaviours that increase risk;
- secondary prevention - actions taken to redrombuce the risk in those who already have disease or risk factors that may have been identified through screening; and
- tertiary prevention - actions taken to reduce the risk of complications (including further strokes) in people who have already had a stroke.
The most important modifiable risk factors for stroke are hypertension, heart disease, diabetes, and cigarette smoking. Other risks include heavy alcohol consumption (see Alcohol consumption and health), high blood cholesterol levels, illicit drug use, and genetic or congenital conditions. Family members may have a genetic tendency for stroke or share a lifestyle that contributes to stroke. Higher levels of Von Willebrand factor are more common amongst people who have had ischemic stroke for the first time.[1] The results of this study found that the only significant genetic factor was the person's blood type. Having had a stroke in the past greatly increases one's risk of future strokes.
One of the most significant stroke risk factors is advanced age. 95% of strokes occur in people age 45 and older, and two-thirds of strokes occur in those over the age of 65.[2] A person's risk of dying if he or she does have a stroke also increases with age. However, stroke can occur at any age, including in fetuses.
Sickle cell anemia, which can cause blood cells to clump up and block blood vessels, also increases stroke risk. Stroke is the second leading killer of people under 20 who suffer from sickle-cell anemia.[2]
Men are 1.25 times more likely to suffer strokes than women,[2] yet 60% of deaths from stroke occur in women. Since women live longer, they are older on average when they have their strokes and thus more often killed (NIMH 2002).[2] Some risk factors for stroke apply only to women. Primary among these are pregnancy, childbirth, menopause and the treatment thereof (HRT).
Prevention is an important public health concern. Identification of patients with treatable risk factors for stroke is paramount. Treatment of risk factors in patients who have already had strokes (secondary prevention) is also very important as they are at high risk of subsequent events compared with those who have never had a stroke. Medication or drug therapy is the most common method of stroke prevention. Aspirin (usually at a low dose of 75 mg) is recommended for the primary and secondary prevention of stroke. Also see Antiplatelet drug treatment. Treating hypertension, diabetes mellitus, smoking cessation, control of hypercholesterolemia, physical exercise, and avoidance of illicit drugs and excessive alcohol consumption are all recommended ways of reducing the risk of stroke.[3]
In patients who have strokes due to abnormalities of the heart, such as atrial fibrillation, anticoagulation with medications such as warfarin is often necessary for stroke prevention.[4]
Procedures such as carotid endarterectomy or carotid angioplasty can be used to remove significant atherosclerotic narrowing (stenosis) of the carotid artery, which supplies blood to the brain. These procedures have been shown to prevent stroke in certain patients, especially where carotid stenosis leads to ischemic events such as transient ischemic attack. (The value and role of carotid artery ultrasound scanning in screening has yet to be established.)
A meta-analysis concluded that lowering homocysteine with folic acid and other supplements may reduce stroke.[5] However, the two largest randomized controlled trials included in the meta-analysis had conflicting results. Lonn reported positve results;[6] whereas the trial by Toole was negative.[7]
Aysha's sandbox
TOAST CLASSIFICATION OF Acute ISCHEMIC STROKE:
- Large artery atherosclerosis
- Cardioembolism
- Small vessel occlusion-Lacunar infarct
- Stroke of other, unusual, determined etiology
- Stroke of undetermined etiology
Based on duration of symptoms:
- Transient ischemic stroke
- Acute ischemic stroke
- Chronic ischemic stroke:
Ischemic stroke due to cause:
- Artherosclerotic
- Non Artherosclerotic
- Systemic hypoperfusion
PATHOPHYSIOLOGY:
Hemodynamic changes:
- Reduction in blood flow due to systemic hypoperfsuion, involves watershed areas
hippocampal pyramidal cells, cerebellar Purkinje cells, and cortical laminar cells
- Thrombosis acutely or chronically, involves extrascranail and intracranial vesssels. Atherosclerotic blood vessels , plts adhere to plaque causing occlusion
- Embolic stroke: clot foms elsewhere in the body and travels to the brain, usually heart in afib, other emboli causing stroke involves tumour, septic embolus, venous clot or fat
- Embolic stroke-cortical undergo hemorrhagic transformation
- Lacunar infarction: involves small penetrating vessels, chronic hypertension causes thickening of media and fibrinoid depositon in the vessel wall causing lumen narrowing and occlusion.
Ususally subcortical but any site can be involved.
Non atherosclerotic causes such as
•Fibromuscular dysplasia
•Vasculitis
•Moyamoya disease
•Sickle cell disease arteriopathy
•Focal cerebral arteriopathy of childhood
Cause Pathogenesis area involved
Cellular changes:
- Focal ischemia-area affected by single blood vessel and its surrounding branches. Central core of tissue die by necrosis as directly supplied by the blood vessel, called infarct.
The cells surrounding the central infarct supplied by collateral vessels receive some oxygen and glucose, at increased risk of infarction but can be salvaged by increase in blood flow to the area called Pneumbra.
Molecular changes:
- Depletion of ATP
- Acidosis, lactate increased
- Ionic imbalance: Na,K, Ca
- Increase in excitatory neurotrasmittor glutamate at synases due to neuronal electrical failure-
Glutamate receptor stimulation NMDA receptors –opening of ion channels, increased calcium and sodium influx and potassium eflux
- Increased Na influx and water-edema and causes decreased uptake of glutamate resulting in excitotoxicity state in the brain
- NMDA receptor activation causes increase NO levels in the brain-excessive levels acts as a free radical-reacts with other free oxygen radicals producing peroxynitirite causing breaks in DNA and DNA damage- Apoptosis
Type of cell death after ischemia
Type of infarct time of initiation of cell death Main mechanism of cell death Area invol
- Global ischemia delayed after 12 hours –several days Apoptosis Hippoca
- Focal ischemia Within 3-4 hours -12 to 24hrs Necrosis central core by necrosis and periphery by apoptosis centre
Loss of brain structural integrity
Cerebral edema:
Vasogenic: Disruption of bbb
Celluar/cytotoxic: ATP dep ion regualtion disrupted
Cerebral autoregulation
Cerebral blood flow determinants
- Cerebral perfusion pressure
- Cerebral blood flow is maintained in the pressure range of 60-150 mmg
- Cerebral blood flow increases in cases of low pressure by vasodilation- nitric oxide release by endothelial cells
- Blood flow decreases by vasoconstriction at high pressures. Smooth muscles in the Bv are the sensors for detection of blood vessels
Pressure below 60 mmhg ischemia
Pressure above 150 mmhg edema
Cerebral autoregulation failure during ischemia:
Low pressures- cerebral vasodilation to increase blood flow-increased oxygen extraction ratio initially to maintain oxygen levels in the brain cells-further dcline in blood presssure- compensatory mechanisms fail-inhibtion of protein synthesis 35ml/100gm/min, increased glucose utilization – 25ml/100gm/minanaerobic glycolysis-tissue acidosis-neuronal electric failure16-18ml/100gm/min-cell membrane dysfunctionml/100gm /min 10-12-cell death (infart)
In hypertension autoregulation set at higher pressures so drop to normal levels may exacerbate ischemia
GENETICS:
•HDAC9 for large vessel disease
•ABO for all ischemic stroke
Prognosis of ischemic stroke
1)a)age, stroke severity, stroke mechanism, infarct location, comorbid conditions, clinical findings, and related complication;
b) interventions such as thrombolysis, stroke unit care, and rehabilitation can play a major role in the outcome of ischemic strok
c)acute phase of stroke, the strongest predictors of outcome are stroke severity and patient age.
2):Bruno A, Biller J, Adams HP Jr, Clarke WR, Woolson RF, Williams LS, et al. Acute blood glucose level and outcome from ischemic stroke.aird TA, Parsons MW, Phanh T, Butcher KS, Desmond PM, Tress BM, et al. Persistent poststroke hyperglycemia is independently associated with infarct expansion and worse clinical outcomeMandelzweig L, Goldbourt U, Boyko V, Tanne D. Perceptual, social, and behavioral factors associated with delays in seeking medical care in patients with symptoms of acute strokeTissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study GroupAcute stroke: usefulness of early CT findings before thrombolytic therapy
3)Poor prognostic factors:
Severe middle cerebral artery infarction
- Large area of brain involvement
- Other co morbid conditons
- Advanced age
- Severe hemiplegia
4)Good prognostic factors:
5)NIHSS score predicts early mortality predicts prognosis; The NIHSS score strongly predicts the likelihood of a patient's recovery after stroke. A score of > or =16 forecasts a high probability of death or severe disability whereas a score of < or =6 forecasts a good recovery.
6)The 1-year mortality in first-time stroke sufferers is 14% to 24% in persons aged 40 to 69 years, and the 1-year mortality increases to 22% to 27% in patients aged 70 years and older. (Find citation)
CDC
Stroke kills almost 130,000 Americans each year—that’s 1 out of every 20 deaths.1
On average, one American dies from stroke every 4 minutes.2
Every year, more than 795,000 people in the United States have a stroke.
About 610,000 of these are first or new strokes.
About 185,00 strokes—nearly one of four—are in people who have had a previous stroke.2
About 87% of all strokes are ischemic strokes, when blood flow to the brain is blocked.2
Stroke costs the United States an estimated $34 billion each year.2 This total includes the cost of health care services, medications to treat stroke, and missed days of work.
Stroke is a leading cause of serious long-term disability.2
Classification of Ischemic Stroke:
According to the causative agent:
- Thrombotic
- Embolic
- Small vessel disease
- Systemic hypoperfusion
- Crytogenic-Undetermined etiology
Toast classification of ischemic stroke:
According to anatomical location:
- Cortical
- Subcortical
- Watershed areas
According to vessel involved:
- Anterial cerebral artery
- Middle cerebral artery
- Posterior cerebral artery
According to duration of symptoms:
- Acute
- subacute
- Chronic
According to clinical presentaion
- Pure Motor
- Pure Sensory
- Mixed
Stroke epidemiology PMID: 26673558
In 2013, stroke fell from the fourth to the fifth leading cause
of death in the United States, behind diseases of the heart,
cancer, chronic lower respiratory diseases, and unintentional
injury.
●● From 2003 to 2013, the relative rate of stroke death fell
by 33.7% and the actual number of stroke deaths declined by 18.2%. Yet each year, ≈795 000 people continue to
experience a new or recurrent stroke (ischemic or hemorrhagic).
Approximately 610 000 of these are first events
and 185 000 are recurrent stroke events. In 2013, stroke
caused ≈1 of every 20 deaths in the United States. On average,
every 40 seconds, someone in the United States has
a stroke, and someone dies of one approximately every 4
minutes.
●● The decline in stroke mortality over the past decades, a
major improvement in population health observed for
both sexes and all race and age groups, has resulted from
reduced stroke incidence and lower case fatality rates. The
significant improvements in stroke outcomes are concurrent
with cardiovascular risk factor control interventions.
The hypertension control efforts initiated in the 1970s
appear to have had the most substantial influence on the
accelerated decline in stroke mortality, with lower blood
pressure distributions in the population. Control of diabetes
mellitus and high cholesterol and smoking cessation
programs, particularly in combination with hypertension
treatment, also appear to have contributed to the decline in
stroke mortality.
●● Approximately 10% of all strokes occur in people 18 to
50 years of age. Between 1995 and 2008, National Health
Interview Survey data reveal that hospitalizations for
ischemic stroke increased among adolescents and young
adults (aged 5–44 years), whereas subarachnoid hemorrhage
hospitalizations decreased during that same time
period.
●● Stroke death rates declined more among people aged ≥65
years (−54.1%; from 534.1 to 245.2 per 100 000) than
among those aged 45 to 64 years (−53.6%; from 43.5 to
20.2 per 100 000) or those aged 18 to 44 years (−45.9%;
from 3.7 to 2.0 per 100 000).
## Common complications
MRI syphilis 17628376
- 20 mg/kg/dose twice daily (max = 500 mg/dose)
- 10 days
- 30 mg/kg once daily (max = 1 g)
- 10 days
- 7 mg/kg/dose 3 times daily (max = 300 mg/dose)
- 10 days
- 12 mg/kg once daily (max = 500 mg)
- 5 days
- 7.5 mg/kg/dose twice daily (max = 250 mg/dose)
- 10 days
## Postexposure prophylaxis
### Active immunisation
Varicella vaccine is recommended for immunocompetent individuals exposed to varicella infection but did not receive full two dose course of vaccine previously[37][38]
### Passive immunisation
VZV immunoglobulin
- ↑ Bongers T, de Maat M, van Goor M; et al. (2006). "High von Willebrand factor levels increase the risk of first ischemic stroke: influence of ADAMTS13, inflammation, and genetic variability". Stroke. 37 (11): 2672–7. PMID 16990571.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link) .mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ Jump up to: 2.0 2.1 2.2 2.3 National Institute of Neurological Disorders and Stroke (NINDS) (1999). "Stroke: Hope Through Research". National Institutes of Health.
- ↑ American Heart Association. (2007). Stroke Risk Factors Americanheart.org. Retrieved on January 22, 2007.
- ↑ American Heart Association. (2007). Atrial Fibrillation Americanheart.org. Retrieved on January 22, 2007.
- ↑ Wang X, Qin X, Demirtas H; et al. (2007). "Efficacy of folic acid supplementation in stroke prevention: a meta-analysis". Lancet. 369 (9576): 1876–82. doi:10.1016/S0140-6736(07)60854-X. PMID 17544768.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
- ↑ Lonn E, Yusuf S, Arnold MJ; et al. (2006). "Homocysteine lowering with folic acid and B vitamins in vascular disease". N. Engl. J. Med. 354 (15): 1567–77. doi:10.1056/NEJMoa060900. PMID 16531613.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
- ↑ Toole JF, Malinow MR, Chambless LE; et al. (2004). "Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial". JAMA. 291 (5): 565–75. doi:10.1001/jama.291.5.565. PMID 14762035.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
- ↑ Jump up to: 8.0 8.1 8.2 8.3 Nagaratnam N, Davies D, Chen E (1998). "Clinical effects of anterior cerebral artery infarction". J Stroke Cerebrovasc Dis. 7 (6): 391–7. PMID 17895117.CS1 maint: Multiple names: authors list (link)
- ↑ Jump up to: 9.0 9.1 9.2 Kumral E, Bayulkem G, Evyapan D, Yunten N (2002). "Spectrum of anterior cerebral artery territory infarction: clinical and MRI findings". Eur J Neurol. 9 (6): 615–24. PMID 12453077.CS1 maint: Multiple names: authors list (link)
- ↑ Jump up to: 10.0 10.1 Alexander MP, Schmitt MA (1980). "The aphasia syndrome of stroke in the left anterior cerebral artery territory". Arch Neurol. 37 (2): 97–100. PMID 7356415.
- ↑ Mizuta H, Motomura N (2006). "Memory dysfunction in caudate infarction caused by Heubner's recurring artery occlusion". Brain Cogn. 61 (2): 133–8. doi:10.1016/j.bandc.2005.11.002. PMID 16510225.
- ↑ den Heijer T, Ruitenberg A, Bakker J, Hertzberger L, Kerkhoff H (2007). "Neurological picture. Bilateral caudate nucleus infarction associated with variant in circle of Willis". J Neurol Neurosurg Psychiatry. 78 (11): 1175. doi:10.1136/jnnp.2006.112656. PMC 2117617. PMID 17940169.CS1 maint: Multiple names: authors list (link)
- ↑ Lemieux F, Lanthier S, Chevrier MC, Gioia L, Rouleau I, Cereda C; et al. (2012). "Insular ischemic stroke: clinical presentation and outcome". Cerebrovasc Dis Extra. 2 (1): 80–7. doi:10.1159/000343177. PMC 3492997. PMID 23139684.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
- ↑ Arboix A, Martí-Vilalta JL (2009). "Lacunar stroke". Expert Rev Neurother. 9 (2): 179–96. doi:10.1586/14737175.9.2.179. PMID 19210194.
- ↑ Melo TP, Bogousslavsky J, van Melle G, Regli F (1992). "Pure motor stroke: a reappraisal". Neurology. 42 (4): 789–95. PMID 1565233.CS1 maint: Multiple names: authors list (link)
- ↑ Tei H, Uchiyama S, Maruyama S (1993). "Capsular infarcts: location, size and etiology of pure motor hemiparesis, sensorimotor stroke and ataxic hemiparesis". Acta Neurol Scand. 88 (4): 264–8. PMID 8256570.CS1 maint: Multiple names: authors list (link)
- ↑ Fridriksson J, Fillmore P, Guo D, Rorden C (2015). "Chronic Broca's Aphasia Is Caused by Damage to Broca's and Wernicke's Areas". Cereb Cortex. 25 (12): 4689–96. doi:10.1093/cercor/bhu152. PMC 4669036. PMID 25016386.CS1 maint: Multiple names: authors list (link)
- ↑ Henderson VW (1985). "Lesion localization in Broca's aphasia. Implications from Broca's aphasia without hemiparesis". Arch Neurol. 42 (12): 1210–2. PMID 4062622.
- ↑ Jump up to: 19.0 19.1 Soma Y (1997). "[Cerebrovascular disorder and the language areas]". Rinsho Shinkeigaku. 37 (12): 1117–9. PMID 9577663.
- ↑ Jump up to: 20.0 20.1 Brandt T, Steinke W, Thie A, Pessin MS, Caplan LR (2000). "Posterior cerebral artery territory infarcts: clinical features, infarct topography, causes and outcome. Multicenter results and a review of the literature". Cerebrovasc Dis. 10 (3): 170–82. doi:16053 Check |doi= value (help). PMID 10773642.CS1 maint: Multiple names: authors list (link)
- ↑ Jump up to: 21.0 21.1 Cereda C, Carrera E (2012). "Posterior cerebral artery territory infarctions". Front Neurol Neurosci. 30: 128–31. doi:10.1159/000333610. PMID 22377879.
- ↑ Jump up to: 22.0 22.1 Yamamoto Y, Georgiadis AL, Chang HM, Caplan LR (1999). "Posterior cerebral artery territory infarcts in the New England Medical Center Posterior Circulation Registry". Arch Neurol. 56 (7): 824–32. PMID 10404984.CS1 maint: Multiple names: authors list (link)
- ↑ Jump up to: 23.0 23.1 Fisher CM (1986). "The posterior cerebral artery syndrome". Can J Neurol Sci. 13 (3): 232–9. PMID 3742339.
- ↑ Jump up to: 24.0 24.1 24.2 Caplan LR, Hedley-Whyte T (1974). "Cuing and memory dysfunction in alexia without agraphia. A case report". Brain. 97 (2): 251–62. PMID 4434176.
- ↑ Pessin MS, Lathi ES, Cohen MB, Kwan ES, Hedges TR, Caplan LR (1987). "Clinical features and mechanism of occipital infarction". Ann Neurol. 21 (3): 290–9. doi:10.1002/ana.410210311. PMID 3606035.CS1 maint: Multiple names: authors list (link)
- ↑ Damasio AR, Damasio H, Van Hoesen GW (1982). "Prosopagnosia: anatomic basis and behavioral mechanisms". Neurology. 32 (4): 331–41. PMID 7199655.CS1 maint: Multiple names: authors list (link)
- ↑ Jump up to: 27.0 27.1 Melo TP, Bogousslavsky J (1992). "Hemiataxia-hypesthesia: a thalamic stroke syndrome". J Neurol Neurosurg Psychiatry. 55 (7): 581–4. PMC 489170. PMID 1640235.
- ↑ Jump up to: 28.0 28.1 28.2 Caplan L (2000). "Posterior circulation ischemia: then, now, and tomorrow. The Thomas Willis Lecture-2000". Stroke. 31 (8): 2011–23. PMID 10926972.
- ↑ Nouh A, Remke J, Ruland S (2014). "Ischemic posterior circulation stroke: a review of anatomy, clinical presentations, diagnosis, and current management". Front Neurol. 5: 30. doi:10.3389/fneur.2014.00030. PMC 3985033. PMID 24778625.CS1 maint: Multiple names: authors list (link)
- ↑ Sacco RL, Freddo L, Bello JA, Odel JG, Onesti ST, Mohr JP (1993). "Wallenberg's lateral medullary syndrome. Clinical-magnetic resonance imaging correlations". Arch Neurol. 50 (6): 609–14. PMID 8503798.CS1 maint: Multiple names: authors list (link)
- ↑ Shetty SR, Anusha R, Thomas PS, Babu SG (2012). "Wallenberg's syndrome". J Neurosci Rural Pract. 3 (1): 100–2. doi:10.4103/0976-3147.91980. PMC 3271596. PMID 22346215.CS1 maint: Multiple names: authors list (link)
- ↑ Kim JS, Kim HG, Chung CS (1995). "Medial medullary syndrome. Report of 18 new patients and a review of the literature". Stroke. 26 (9): 1548–52. PMID 7660396.CS1 maint: Multiple names: authors list (link)
- ↑ Kim K, Lee HS, Jung YH, Kim YD, Nam HS, Nam CM; et al. (2012). "Mechanism of medullary infarction based on arterial territory involvement". J Clin Neurol. 8 (2): 116–22. doi:10.3988/jcn.2012.8.2.116. PMC 3391616. PMID 22787495.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
- ↑ Patterson JR, Grabois M (1986). "Locked-in syndrome: a review of 139 cases". Stroke. 17 (4): 758–64. PMID 3738962.
- ↑ Karp JS, Hurtig HI (1974). ""Locked-in" state with bilateral midbrain infarcts". Arch Neurol. 30 (2): 176–8. PMID 4810896.
- ↑ http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5903a1.htm Accessed on October 24, 2016
- ↑ Salzman MB, Garcia C (1998). "Postexposure varicella vaccination in siblings of children with active varicella". Pediatr Infect Dis J. 17 (3): 256–7. PMID 9535260.
- ↑ Asano Y, Nakayama H, Yazaki T, Kato R, Hirose S (1977). "Protection against varicella in family contacts by immediate inoculation with live varicella vaccine". Pediatrics. 59 (1): 3–7. PMID 190583.CS1 maint: Multiple names: authors list (link) | https://www.wikidoc.org/index.php/Sandbox:AA | |
6103da52cf10f09b23c3ae2eb53df909eb3a0838 | wikidoc | Sandbox:DD | Sandbox:DD
- The table below lists the risk factors for chronic lymphocytic leukmeia development:
- ↑ What are the risk factors for chronic lymphocytic leukemia? American Cancer Society (2015) Accessed on October, 12 2015
- ↑ Chronic Lymphocytic Leukemia. Mayoclinic (2015) Accessed on October, 12 2015 | Sandbox:DD
- The table below lists the risk factors for chronic lymphocytic leukmeia development:[1][2]
- ↑ What are the risk factors for chronic lymphocytic leukemia? American Cancer Society (2015) http://www.cancer.org/cancer/leukemia-chroniclymphocyticcll/detailedguide/leukemia-chronic-lymphocytic-risk-factors Accessed on October, 12 2015
- ↑ Chronic Lymphocytic Leukemia. Mayoclinic (2015) http://www.mayoclinic.org/diseases-conditions/chronic-lymphocytic-leukemia/basics/risk-factors/con-20031195 Accessed on October, 12 2015 | https://www.wikidoc.org/index.php/Sandbox:DD | |
576ae8f138930e012c9bd92221c8e2ae85a6c0f9 | wikidoc | Sandbox:GE | Sandbox:GE
# Overview
Acute gastroenteritis and diarrhea are among the leading causes of seeking medical care. Approximately, 48 million cases occur annually that cost about $150 million for the U.S. health care system. Gastroenteritis is defined as inflammation of the stomach or intestinal mucosa. It typically presents with acute diarrhea, fever, nausea and vomiting, anorexia and crampy abdominal pain and is defined as passage of loose stool for at least 3 times per day for less than 14 days. It may be cause by viruses, bacteria or parasites. Most cases of acute gastroenteritis are caused by viruses and among them, Norovirus is the most common etiology for adults. Other common viral causes include, Rotavirus, Adenovirus and Astrovirus. Common bacterial causes of gastroenteritis include, Escherichia coli sp, Salmonella sp, Yersinia enterocolitica and Vibrio sp that can cause watery diarrhea and Shigella sp and Campylobacter sp that can cause dysenteric diarrhea. Parasites are other causes of gastroenteritis especially in developing countries which Giardia lamblia and Entamoeba histolytica are the most frequent causes. First step in management of this patients is to evaluate the hydration status and vital signs. Once the patient is stabilized proceed to diagnostic evaluation. There are some principles to decrease the risk of acquiring infection which include, using safe water and foods, avoid unsafe foods during traveling and hand washing.
# Classification
Abbreviations:
ETEC: Enterotoxigenic Escherichia coli, EPEC: Enteropathogenic Escherichia coli, EHEC: Enterohemorrhagic Escherichia coli, EAEC: Enteroaggregative Escherichia coli, EIEC: Enteroinvasive Escherichia coli, SARS: severe acute respiratory syndrome
§ EHEC, EIEC, EPEC and EAEC may cause bloody diarrhea, but they are classically associated with watery diarrhea.
† Either Salmonella and Yersinia can cause dysentery.
‡ Entamoeba histolytica may cause dysentery
# Patient Evaluation
## Initial Evaluation:
Shown below is an algorithm depicting the initial management of acute diarrhea is based on the 2001 IDSA practice guidelines for the management of infectious diarrhea.
## Management:
†Illness severity:
- Severe: Total disability due to diarrhea;
- Moderate: Able to function but with forced change in activities due to illness;
- Mild: No change in activities
# Synopsis
∞Small bowel diarrhea: watery, voluminous with less than 5 WBC/high power field
Large bowel diarrhea: Mucousy and/or bloody with less volume and more than 10 WBC/high power field
† It could be as high as 1000 based on patient's immunity system.
# General principles for treatment
- Rehydration with a balanced sodium-glucose solution is The first step for treatment. Oral rehydration solution (ORS) has reduced infant mortality in developing countries by at least 50%. ORS has no effect on disease course however, it's valuable to treat dehydration.
- For infants and the elderly with severe travelers diarrhea (TD) and in anyone who develops profuse cholera-like watery diarrhea, balanced ORS and medical evaluation are advised.
- For most otherwise healthy adults with TD, formal ORS is not needed as they can keep up with fluid losses by taking in salty soups, fruit juices and carbohydrates to provide enough compensation.
- In severe diarrhea, a balanced ORS can usually be found at a local pharmacy with sodium of 60–75 mEq/l and glucose of 75–90 mmol/l for replacing salt and water.
- Bismuth subsalicylates (BSSs) can be administered to control rates of passage of stool and may help travelers function better during bouts of mild to moderate illness. The recommended dose of BSS for therapy of acute diarrhea is 30 ml (525 mg) of liquid formulation or two tablets (263 mg per tablet) chewed well each 30–60 min not to exceed eight doses in 24 h. The drug will cause black stools and black tongues.
- In patients receiving antibiotics for TD, adjunctive loperamide therapy can be administered to decrease duration of diarrhea and increase chance for a cure. The recommended dose of loperamide for therapy for adults with diarrhea is 4 mg initially followed by 2 mg after subsequently passed watery stools not to exceed 8 mg per day. Loperamide is not given for more than 48 h. The most valuable use of loperamide in the self-treatment of TD is as a combination drug with antibacterial drugs where the antimotility drug quickly reduces the number of diarrhea stools passed while the antibiotic cures the enteric infection.
- empiric anti-microbial therapy for routine acute diarrheal infection, except in cases of TD where the likelihood of bacterial pathogens is high enough to justify the potential side effects of antibiotics.
- Use of antibiotics for community-acquired diarrhea should be discouraged as epidemiological studies suggest that most community-acquired diarrhea is viral in origin (norovirus, rotavirus, and adenovirus) and is not shortened by the use of antibiotics.
- Antibiotics shorten the overall duration of moderate-to-severe TD to a little over 24 h and are recommended in TD. The following table summarizes the recommended antibiotics for TD.
# Prevention
## Non travel setting
- Contaminated foods are major causes of foodborne illness in the United states.
- To prevent food preparation chain from contamination, every steps of this process including, products in the farms, packaging industries, stores, restaurants and individuals in the home who are buying and preparing food must be take in to consideration.
- Proper maintaining the filtration systems at water plants is also essential.
- Avoid consuming unpasteurized milk or soft cheeses.
- Frequent and effective hand washing and alcohol-based hand sanitizers.
- Rotavirus vaccination is recommended for all infants unless there is a contraindication for it.
## Travel setting
- A simple rule is, boil it, cook it, peel it, or forget it!
- Use bottled water or boil all drinking water while on outdoor adventures.
- Frequent and effective hand washing and alcohol-based hand sanitizers especially for cruise travelers.
- Chemoprophylaxis with Bismuth subsalicylate (BSS) has been shown to reduce the frequency of TD when used during period of risk for 3 weeks. The recommended dose of BSS for TD prevention is two tablets four daily doses at mealtimes and at bedtime. BSS could be used for trips up to 2 weeks.
- Offer the typhoid vaccine to travelers going to countries with high prevalence of typhoid fever. | Sandbox:GE
# Overview
Acute gastroenteritis and diarrhea are among the leading causes of seeking medical care. Approximately, 48 million cases occur annually that cost about $150 million for the U.S. health care system. [1][2] Gastroenteritis is defined as inflammation of the stomach or intestinal mucosa. It typically presents with acute diarrhea, fever, nausea and vomiting, anorexia and crampy abdominal pain and is defined as passage of loose stool for at least 3 times per day for less than 14 days. It may be cause by viruses, bacteria or parasites. Most cases of acute gastroenteritis are caused by viruses and among them, Norovirus is the most common etiology for adults.[3][4][5] Other common viral causes include, Rotavirus, Adenovirus and Astrovirus. Common bacterial causes of gastroenteritis include, Escherichia coli sp, Salmonella sp, Yersinia enterocolitica and Vibrio sp that can cause watery diarrhea and Shigella sp and Campylobacter sp that can cause dysenteric diarrhea. Parasites are other causes of gastroenteritis especially in developing countries which Giardia lamblia and Entamoeba histolytica are the most frequent causes. First step in management of this patients is to evaluate the hydration status and vital signs. Once the patient is stabilized proceed to diagnostic evaluation. There are some principles to decrease the risk of acquiring infection which include, using safe water and foods, avoid unsafe foods during traveling and hand washing.
# Classification
Abbreviations:
ETEC: Enterotoxigenic Escherichia coli, EPEC: Enteropathogenic Escherichia coli, EHEC: Enterohemorrhagic Escherichia coli, EAEC: Enteroaggregative Escherichia coli, EIEC: Enteroinvasive Escherichia coli, SARS: severe acute respiratory syndrome
§ EHEC, EIEC, EPEC and EAEC may cause bloody diarrhea, but they are classically associated with watery diarrhea.
† Either Salmonella and Yersinia can cause dysentery.
‡ Entamoeba histolytica may cause dysentery
# Patient Evaluation
## Initial Evaluation:
Shown below is an algorithm depicting the initial management of acute diarrhea is based on the 2001 IDSA practice guidelines for the management of infectious diarrhea.[6]
## Management:
†Illness severity:
- Severe: Total disability due to diarrhea;
- Moderate: Able to function but with forced change in activities due to illness;
- Mild: No change in activities
# Synopsis
∞Small bowel diarrhea: watery, voluminous with less than 5 WBC/high power field
Large bowel diarrhea: Mucousy and/or bloody with less volume and more than 10 WBC/high power field
† It could be as high as 1000 based on patient's immunity system.
# General principles for treatment
- Rehydration with a balanced sodium-glucose solution is The first step for treatment. Oral rehydration solution (ORS) has reduced infant mortality in developing countries by at least 50%.[7] ORS has no effect on disease course however, it's valuable to treat dehydration.
- For infants and the elderly with severe travelers diarrhea (TD) and in anyone who develops profuse cholera-like watery diarrhea, balanced ORS and medical evaluation are advised.
- For most otherwise healthy adults with TD, formal ORS is not needed as they can keep up with fluid losses by taking in salty soups, fruit juices and carbohydrates to provide enough compensation. [8]
- In severe diarrhea, a balanced ORS can usually be found at a local pharmacy with sodium of 60–75 mEq/l and glucose of 75–90 mmol/l for replacing salt and water. [9]
- Bismuth subsalicylates (BSSs) can be administered to control rates of passage of stool and may help travelers function better during bouts of mild to moderate illness. The recommended dose of BSS for therapy of acute diarrhea is 30 ml (525 mg) of liquid formulation or two tablets (263 mg per tablet) chewed well each 30–60 min not to exceed eight doses in 24 h. The drug will cause black stools and black tongues.
- In patients receiving antibiotics for TD, adjunctive loperamide therapy can be administered to decrease duration of diarrhea and increase chance for a cure. The recommended dose of loperamide for therapy for adults with diarrhea is 4 mg initially followed by 2 mg after subsequently passed watery stools not to exceed 8 mg per day. Loperamide is not given for more than 48 h. The most valuable use of loperamide in the self-treatment of TD is as a combination drug with antibacterial drugs where the antimotility drug quickly reduces the number of diarrhea stools passed while the antibiotic cures the enteric infection. [10]
- empiric anti-microbial therapy for routine acute diarrheal infection, except in cases of TD where the likelihood of bacterial pathogens is high enough to justify the potential side effects of antibiotics.
- Use of antibiotics for community-acquired diarrhea should be discouraged as epidemiological studies suggest that most community-acquired diarrhea is viral in origin (norovirus, rotavirus, and adenovirus) and is not shortened by the use of antibiotics.
- Antibiotics shorten the overall duration of moderate-to-severe TD to a little over 24 h and are recommended in TD. [11][12] The following table summarizes the recommended antibiotics for TD.
# Prevention
## Non travel setting
- Contaminated foods are major causes of foodborne illness in the United states.[1][2]
- To prevent food preparation chain from contamination, every steps of this process including, products in the farms, packaging industries, stores, restaurants and individuals in the home who are buying and preparing food must be take in to consideration.
- Proper maintaining the filtration systems at water plants is also essential.
- Avoid consuming unpasteurized milk or soft cheeses.
- Frequent and effective hand washing and alcohol-based hand sanitizers.
- Rotavirus vaccination is recommended for all infants unless there is a contraindication for it.[13]
## Travel setting
- A simple rule is, boil it, cook it, peel it, or forget it!
- Use bottled water or boil all drinking water while on outdoor adventures.
- Frequent and effective hand washing and alcohol-based hand sanitizers especially for cruise travelers.
- Chemoprophylaxis with Bismuth subsalicylate (BSS) has been shown to reduce the frequency of TD when used during period of risk for 3 weeks.[14] The recommended dose of BSS for TD prevention is two tablets four daily doses at mealtimes and at bedtime. BSS could be used for trips up to 2 weeks.[15]
- Offer the typhoid vaccine to travelers going to countries with high prevalence of typhoid fever. | https://www.wikidoc.org/index.php/Sandbox:GE | |
757e8d1f568fbb966a186bd9ac8a42227be76116 | wikidoc | Sandbox:MP | Sandbox:MP
Mehdi's sanbox
# Overview
# Historical Perspective
- Hippocrates (460 to 370 BC) was first to describe the phenomenon of sudden paralysis.
- Apoplexy, from the Greek word meaning "struck down with violence,” first appeared in Hippocratic writings to describe this phenomenon.
- The word stroke was used as a synonym for apoplectic seizure as early as 1599, and is a fairly literal translation of the Greek term.
- In 1658, in his Apoplexia, Johann Jacob Wepfer (1620–1695) identified the cause of hemorrhagic stroke when he suggested that people who had died of apoplexy had bleeding in their brains.
- Wepfer also identified the main arteries supplying the brain, the vertebral and carotid arteries, and identified the cause of ischemic stroke when he suggested that apoplexy might be caused by a blockage to those vessels.
# Synopsis
# Imaging Studies
# Prevention
# Epidemiology and Demographics
## Stroke in USA
- Stroke is a leading cause of serious long-term disability
- In USA, the incidence and mortality rates of stroke has significantly decreased compared to previous years.
- From year 2003 to 2013, the mortality rates due to stroke declined by 18.5%.
- In 2013, stroke became the fifth leading cause of death.
- The case fatality rate of stroke is estimated to be 41.7 deaths per 100, 000 population
- The incidence of new (610, 000) or recurrent stroke (185, 000) is estimated to be 795000 people annually or 250 cases per 100, 000.
- It is estimated that one incidence of stroke happens every 4 sec with death occuring every 4 min.
- About 87% of all strokes are ischemic strokes
- Stroke costs the United States an estimated $34 billion each year
## Worldwide
- According to WHO, the incidence of stroke is estimated to be 15 million people annually, worldwide..
- Out of these, 5 million die and 5 million are left permanently disbaled..
## Age
- Stroke can occur in all age groups. However, the incidence of stroke is less among individuals age less than 40 years of age and the risk increases with increasing age.
- According to WHO, stroke also occurs in about 8% of children with sickle cell disease..
- In 2009, 34% of people hospitalized for stroke were younger than 65 years
- The incidence of stroke in people aged 18 to 50 years is estimated to be approximately 10%.
The rate of decline in mortality rates of stroke in different age groups is as follows:
- >65 years of age: from 534.1 to 245.2 per 100,000
- 45-65 years of age: from 43.5 to 20.2 per 100,000
- 18 to 44 years of age: from from 3.7 to 2.0 per 100,000
## Gender
There is increased incidence of stroke in men as compared to women.
## Race
- The risk of incidence of first stroke is twice in african american population as compared to whites with increased mortality rates.
- Hispanics’ risk for stroke falls between that of whites and blacks
## Geographical distribution
- There is increased incidence and mortality rates of stroke in developing countries as compared to developed countries due to low socio economic status and heath facilites.
- In USA, the highest death rates from stroke are in the southeastern United States. | Sandbox:MP
Mehdi's sanbox
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Aysha Anwar, M.B.B.S[2]; Tarek Nafee, M.D. [3]; Sara Mehrsefat, M.D. [4]
# Overview
# Historical Perspective
- Hippocrates (460 to 370 BC) was first to describe the phenomenon of sudden paralysis.
- Apoplexy, from the Greek word meaning "struck down with violence,” first appeared in Hippocratic writings to describe this phenomenon.[3]
- The word stroke was used as a synonym for apoplectic seizure as early as 1599,[4] and is a fairly literal translation of the Greek term.
- In 1658, in his Apoplexia, Johann Jacob Wepfer (1620–1695) identified the cause of hemorrhagic stroke when he suggested that people who had died of apoplexy had bleeding in their brains.[3]
- Wepfer also identified the main arteries supplying the brain, the vertebral and carotid arteries, and identified the cause of ischemic stroke when he suggested that apoplexy might be caused by a blockage to those vessels.
# Synopsis
# Imaging Studies
# Prevention
# Epidemiology and Demographics
## Stroke in USA
- Stroke is a leading cause of serious long-term disability
- In USA, the incidence and mortality rates of stroke has significantly decreased compared to previous years.
- From year 2003 to 2013, the mortality rates due to stroke declined by 18.5%.[5]
- In 2013, stroke became the fifth leading cause of death.
- The case fatality rate of stroke is estimated to be 41.7 deaths per 100, 000 population[5]
- The incidence of new (610, 000) or recurrent stroke (185, 000) is estimated to be 795000 people annually or 250 cases per 100, 000.[5]
- It is estimated that one incidence of stroke happens every 4 sec with death occuring every 4 min.[5]
- About 87% of all strokes are ischemic strokes[6]
- Stroke costs the United States an estimated $34 billion each year[6]
## Worldwide
- According to WHO, the incidence of stroke is estimated to be 15 million people annually, worldwide.[7].
- Out of these, 5 million die and 5 million are left permanently disbaled.[7].
## Age
- Stroke can occur in all age groups. However, the incidence of stroke is less among individuals age less than 40 years of age and the risk increases with increasing age. [6]
- According to WHO, stroke also occurs in about 8% of children with sickle cell disease.[7].
- In 2009, 34% of people hospitalized for stroke were younger than 65 years[6]
- The incidence of stroke in people aged 18 to 50 years is estimated to be approximately 10%. [5]
The rate of decline in mortality rates of stroke in different age groups is as follows:[5]
- >65 years of age: from 534.1 to 245.2 per 100,000
- 45-65 years of age: from 43.5 to 20.2 per 100,000
- 18 to 44 years of age: from from 3.7 to 2.0 per 100,000
## Gender
There is increased incidence of stroke in men as compared to women.
## Race
- The risk of incidence of first stroke is twice in african american population as compared to whites with increased mortality rates.[6]
- Hispanics’ risk for stroke falls between that of whites and blacks [6]
## Geographical distribution
- There is increased incidence and mortality rates of stroke in developing countries as compared to developed countries due to low socio economic status and heath facilites.
- In USA, the highest death rates from stroke are in the southeastern United States.[6] | https://www.wikidoc.org/index.php/Sandbox:MP | |
04854d0bbf4323d254e76072446a8ea451372db8 | wikidoc | Sandbox: H | Sandbox: H
- General symptoms of meningioma include:
- Fatigue
- Loss of appetite
- However, the specific clinical presentation of meningioma is determined by the exact anatomical location of the tumor:
- Neuroblastomas located in the abdomen present may with:
- Abdominal distension
- Constipation
- Neurblasotmas located in the posterior mediastinum present may with:
- Dyspnea
- Cough
- Metastatic neurblasotma lesions located in the bone marrow may present with:
- Bone pain
- Limping
- Neurblasotmas located in the head and neck may present with:
- Facial bruising
- Facial swelling
The first symptoms of neuroblastoma are often vague and may include fatigue and loss of appetite. Later symptoms depend on tumor locations. In the abdomen, a tumor may cause a swollen belly and constipation. A tumor in the chest may cause breathing problems. Tumors pressing on the spinal cord cause a feeling of weakness. A tumor in the head may cause the eyes to start to swell outwards and turn black due to the pressure from behind. Often because symptoms are so unclear, half of all neuroblastomas have already spread (metastasized) to other parts of the body by the time suspicions are raised and a diagnosis is made.
The signs and symptoms of neuroblastoma can vary widely depending on where the disease first started and how much it has spread to other parts of the body. Usual symptoms include:
- Irritability, fatigue, loss of appetite, and fever in infant.
- A swollen stomach, abdominal pain, and decreased appetite in young child.
- Bone pain or soreness, black eyes, bruises, and pale skin
- Weakness, numbness, inability to move a body part, or difficulty walking
- Horner's syndrome: Drooping eyelid, unequal pupils, sweating, and red skin
- Difficulty breathing
The first symptoms of neuroblastoma are often vague making diagnosis difficult. Fatigue, loss of appetite, fever, and joint pain are common. Symptoms depend on primary tumor locations and metastases if present:
In the abdomen, a tumor may cause a swollen belly and constipation.
A tumor in the chest may cause breathing problems.
A tumor pressing on the spinal cord may cause weakness and thus an inability to stand, crawl, or walk.
Bone lesions in the legs and hips may cause pain and limping.
A tumor in the bones around the eyes or orbits may cause distinct bruising and swelling.
Infiltration of the bone marrow may cause pallor from anemia.
Neuroblastoma often spreads to other parts of the body before any symptoms are apparent and 50 to 60% of all neuroblastoma cases present with metastases.
Rare but characteristic presentations include transverse myelopathy (tumor spinal cord compression, 5% of cases), treatment-resistant diarrhea (tumor vasoactive intestinal peptide secretion, 4% of cases), Horner's syndrome (cervical tumor, 2.4% of cases), opsoclonus myoclonus syndrome and ataxia (suspected paraneoplastic cause, 1.3% of cases), and hypertension (catecholamine secretion or renal artery compression, 1.3% of cases).
Clinical presentation is typically with pain or a palpable mass and abdominal distension, although numerous other presentations are encountered due to local mass effect.
Other accompanying syndromes include:
Hutchinson syndrome: bony metastases may present with skeletal pain or a palpable lump or limping and irritability due to skeletal metastases 2
Pepper syndrome: hepatomegaly due to extensive liver metastasis
blueberry muffin syndrome: multiple cutaneous lesions
-psomyoclonus 5: rapid, involuntary conjugate fast eye movements | Sandbox: H
- General symptoms of meningioma include:
- Fatigue
- Loss of appetite
- However, the specific clinical presentation of meningioma is determined by the exact anatomical location of the tumor:
- Neuroblastomas located in the abdomen present may with:
- Abdominal distension
- Constipation
- Neurblasotmas located in the posterior mediastinum present may with:
- Dyspnea
- Cough
- Metastatic neurblasotma lesions located in the bone marrow may present with:
- Bone pain
- Limping
- Neurblasotmas located in the head and neck may present with:
- Facial bruising
- Facial swelling
The first symptoms of neuroblastoma are often vague and may include fatigue and loss of appetite. Later symptoms depend on tumor locations. In the abdomen, a tumor may cause a swollen belly and constipation. A tumor in the chest may cause breathing problems. Tumors pressing on the spinal cord cause a feeling of weakness. A tumor in the head may cause the eyes to start to swell outwards and turn black due to the pressure from behind. Often because symptoms are so unclear, half of all neuroblastomas have already spread (metastasized) to other parts of the body by the time suspicions are raised and a diagnosis is made.
The signs and symptoms of neuroblastoma can vary widely depending on where the disease first started and how much it has spread to other parts of the body. Usual symptoms include:
- Irritability, fatigue, loss of appetite, and fever in infant.
- A swollen stomach, abdominal pain, and decreased appetite in young child.
- Bone pain or soreness, black eyes, bruises, and pale skin
- Weakness, numbness, inability to move a body part, or difficulty walking
- Horner's syndrome: Drooping eyelid, unequal pupils, sweating, and red skin
- Difficulty breathing
The first symptoms of neuroblastoma are often vague making diagnosis difficult. Fatigue, loss of appetite, fever, and joint pain are common. Symptoms depend on primary tumor locations and metastases if present:[8]
In the abdomen, a tumor may cause a swollen belly and constipation.
A tumor in the chest may cause breathing problems.
A tumor pressing on the spinal cord may cause weakness and thus an inability to stand, crawl, or walk.
Bone lesions in the legs and hips may cause pain and limping.
A tumor in the bones around the eyes or orbits may cause distinct bruising and swelling.
Infiltration of the bone marrow may cause pallor from anemia.
Neuroblastoma often spreads to other parts of the body before any symptoms are apparent and 50 to 60% of all neuroblastoma cases present with metastases.[9]
Rare but characteristic presentations include transverse myelopathy (tumor spinal cord compression, 5% of cases), treatment-resistant diarrhea (tumor vasoactive intestinal peptide secretion, 4% of cases), Horner's syndrome (cervical tumor, 2.4% of cases), opsoclonus myoclonus syndrome[11] and ataxia (suspected paraneoplastic cause, 1.3% of cases), and hypertension (catecholamine secretion or renal artery compression, 1.3% of cases).[12]
Clinical presentation is typically with pain or a palpable mass and abdominal distension, although numerous other presentations are encountered due to local mass effect.
Other accompanying syndromes include:
Hutchinson syndrome: bony metastases may present with skeletal pain or a palpable lump or limping and irritability due to skeletal metastases 2
Pepper syndrome: hepatomegaly due to extensive liver metastasis
blueberry muffin syndrome: multiple cutaneous lesions
opsomyoclonus 5: rapid, involuntary conjugate fast eye movements | https://www.wikidoc.org/index.php/Sandbox:_H | |
65fb3322cbdd81ba6d3aaf1383839026510c8420 | wikidoc | Sandbox:ab | Sandbox:ab
Synonyms and keywords: Acute lymphocytic leukemia, Acute myeloid leukemia, ALL, AML
# Overview
Acute Leukemia is a malignancy of bone marrow myeloid and lymphoblastic precursor cells, in which these poorly differentiated hematopoietic cells proliferate rapidly. Hence, their accumulation would disrupt the performance of bone marrow to produce normal blood cells
# Causes
AML and ALL are life-threatening diseases, which would result in death if left untreated. In the majority of cases, etiology is not apparent.
## Common Causes of AML
- Gene mutations:FLT3, IDHI, IDH2, KRAS, DNMT3A, NPM1
- Chromosomal translocations, deletions, and inversions
- Benzene or radiation exposure chronically
## Common Causes of ALL
- Radiation exposure
- Genetic disorders; e.g., Down syndrome, ataxia-telangiectasia, Fanconi anemia
- Certain infections: e.g., HTLV-1
# FIRE
A Focused Initial Rapid Evaluation (FIRE) should be performed to identify patients in need of immediate intervention.
- Focused Initial Rapid Evaluation (FIRE) in AML :
- Focused Initial Rapid Evaluation (FIRE) in ALL:
# Diagnosis
Diagnostic criteria of acute myeloid leukemia and acute lymphoblastic leukemia are similar to one another.
- According to the 2016 WHO criteria observing ≥20% blasts in the bone marrow biopsy or peripheral blood smear is diagnostic for AML. These genetic abnormalities in AML are diagnostic even with less than 20% marrow blasts: inv(16), t(16;16), t(8;21), and t(15;17).
- Presenting ≥20% of leukemic lymphoblasts in bone marrow aspirate and biopsy would prove ALL.
# Treatment
Treatment of acute lymphoblastic leukemia includes three phases:
- Induction therapy, i.e., prednisolone, vincristine, cytarabine
- Administrating Central Nervous System prophylaxis, i.e., methotrexate
- Chemotherapy as a maintenance treatment for two years
- Stem cell transplantation in adults who are eligible while there is a suitable donor
# Do's
- Before starting the therapy, taking a precise history and physical examination have to be done to diagnose any kind of comorbidities ,i.e. heart failure or renal diseases that affect the prognosis and treatment choices.
- HLA-typing evaluation have to be done for all of the AML cases In the pretreatment assessment.
- Seven days after the induction phase of chemotherapy ended, bone marrow biopsy must be done in order to assess the remission situation.
- In the induction chemotherapy process of AML for most of the cases, cytarabine IV infusion should be administrated for seven days consecutively + anthracycline on days one to three.(known as "7+3" regimens)
# Don'ts
- If the patient with AML has a coagulopathy disorder and is susceptible to bleeding, do not have to undergo lumbar puncture in the workup process before correcting that.
- Without the assessment of cardiac symptoms and echocardiogram, chemotherapy medications which are cardiotoxic should not be administrated. | Sandbox:ab
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alieh Behjat, M.D.[2]
Synonyms and keywords: Acute lymphocytic leukemia, Acute myeloid leukemia, ALL, AML
# Overview
Acute Leukemia is a malignancy of bone marrow myeloid and lymphoblastic precursor cells, in which these poorly differentiated hematopoietic cells proliferate rapidly. Hence, their accumulation would disrupt the performance of bone marrow to produce normal blood cells
-
-
# Causes
AML and ALL are life-threatening diseases, which would result in death if left untreated. In the majority of cases, etiology is not apparent.
## Common Causes of AML
- Gene mutations:FLT3, IDHI, IDH2, KRAS, DNMT3A, NPM1
- Chromosomal translocations, deletions, and inversions
- Benzene or radiation exposure chronically[1] [2]
## Common Causes of ALL
- Radiation exposure
- Genetic disorders; e.g., Down syndrome, ataxia-telangiectasia, Fanconi anemia
- Certain infections: e.g., HTLV-1 [3]
# FIRE
A Focused Initial Rapid Evaluation (FIRE) should be performed to identify patients in need of immediate intervention.
- Focused Initial Rapid Evaluation (FIRE) in AML [4][5]:
- Focused Initial Rapid Evaluation (FIRE) in ALL:[3] [6] [7]
# Diagnosis
Diagnostic criteria of acute myeloid leukemia and acute lymphoblastic leukemia are similar to one another.
- According to the 2016 WHO criteria observing ≥20% blasts in the bone marrow biopsy or peripheral blood smear is diagnostic for AML. These genetic abnormalities in AML are diagnostic even with less than 20% marrow blasts: inv(16), t(16;16), t(8;21), and t(15;17).[8]
- Presenting ≥20% of leukemic lymphoblasts in bone marrow aspirate and biopsy would prove ALL.[9]
# Treatment
Treatment of acute lymphoblastic leukemia includes three phases:[13]
- Induction therapy, i.e., prednisolone, vincristine, cytarabine
- Administrating Central Nervous System prophylaxis, i.e., methotrexate
- Chemotherapy as a maintenance treatment for two years
- Stem cell transplantation in adults who are eligible while there is a suitable donor
# Do's
- Before starting the therapy, taking a precise history and physical examination have to be done to diagnose any kind of comorbidities ,i.e. heart failure or renal diseases that affect the prognosis and treatment choices.
- HLA-typing evaluation have to be done for all of the AML cases In the pretreatment assessment.
- Seven days after the induction phase of chemotherapy ended, bone marrow biopsy must be done in order to assess the remission situation.
- In the induction chemotherapy process of AML for most of the cases, cytarabine IV infusion should be administrated for seven days consecutively + anthracycline on days one to three.(known as "7+3" regimens)[14] [4]
# Don'ts
- If the patient with AML has a coagulopathy disorder and is susceptible to bleeding, do not have to undergo lumbar puncture in the workup process before correcting that.
- Without the assessment of cardiac symptoms and echocardiogram, chemotherapy medications which are cardiotoxic should not be administrated. [4] | https://www.wikidoc.org/index.php/Sandbox:ab | |
b327869ee844d7442134fe4be1cc0f38d92eb723 | wikidoc | SandboxTry | SandboxTry
Synonyms / Brand Names: xxxxxx®
# Disclaimer
WikiDoc Drug Project is a constellation of drug information for healthcare providers and patients vigorously vetted on the basis of FDA package insert, MedlinePlus, Practice Guidelines, Scientific Statements, and scholarly medical literature. The information provided is not a medical advice or treatment. WikiDoc does not promote any medication or off-label use of drugs. Please read our full disclaimer here.
# Black Box Warning
# Overview
SandboxTry is an angiotensin converting enzyme inhibitor drug that is FDA approved for the treatment of hypertension. There is a Black Box Warning for this drug as shown here. Common adverse reactions include cough, dizziness, fatigue, and headache.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- Initial dose (not receiving a diuretic): xxxxxx
- Initial dose (concurrent xxxxxx use): xxxxxx (see Warnings). If blood pressure is not controlled with xxxxxx alone, diuretic should be resumed and xxxxxx 5 mg PO qd should be used.
- Maintenance dose: xxxxxx 20—40 mg PO qd or xxxxxx 10—20 mg PO bid (MAX 80 mg/day)
- xxxxxx.
- xxxxxx.
- xxxxxx.
- Dosing Information
- Initial dose (for creatinine clearance 3 mg/dL): xxxxxx 5 mg PO qd
- Dosage may be titrated upward until blood pressure is controlled or to a maximum total daily dose of 40 mg (see Warnings).
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- Developed by: American College of Cardiology (ACC) and American Heart Association (AHA)
- Class of Recommendation: Class I
- Level of Evidence: Level A
- Recommendation
- xxxxxx
- Developed by: American College of Cardiology (ACC) and American Heart Association (AHA)
- Class of Recommendation: Class I
- Level of Evidence: Level A
- Recommendation
- An angiotensin-converting enzyme (ACE) inhibitor should be administered within the first 24 hours to all patients with STEMI with anterior location, HF, or ejection fraction (EF) less than or equal to 0.40, unless contraindicated.
### Non–Guideline-Supported Use
- Dosing Information
- xxxxxx 10 mg PO qd
- Dosing Information
- xxxxxx 10 mg PO qd
- Dosing Information
- xxxxxx 20 mg PO qd for 2 weeks, followed by xxxxxx 40 mg qd or combination of xxxxxx 40 mg PO qd and Amlodipine 5 mg PO qd
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Dosing Information
- Initial dose: xxxxxx 0.2 mg/kg PO qd (for pediatric patients above the age of 6 years)
- xxxxxx is not advised for children below the age of 6 years (see Pediatric Use) and in pediatric patients with glomerular filtration rate <30 mL.
- For pediatric patients who cannot swallow tablets, or for whom the calculated dosage (mg/kg) does not correspond to the available tablet strengths for xxxxxx, follow the suspension preparation instructions to administer xxxxxx HCl as a suspension (see Administration and Monitoring).
- Dosing Information
- Initial dose (for creatinine clearance 3 mg/dL): xxxxxx 5 mg PO qd
- Dosage may be titrated upward until blood pressure is controlled or to a maximum total daily dose of 40 mg (see Warnings).
## Off-Label Use and Dosage (Pediatric)
There is limited information about Off-Label Use and Dosage of xxxxxx tablet in pediatric patients.
# Contraindications
- Hypersensitivity to xxxxxx or to any other ACE inhibitor
- History of angioedema with or without previous ACE inhibitor treatment
# Warnings
- Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including xxxxxx) may be subject to a variety of adverse reactions, some of them serious.
- Head and Neck Angioedema
- Angioedema of the face, extremities, lips, tongue, glottis, and larynx has been reported in patients treated with angiotensin-converting enzyme inhibitors. In U.S. clinical trials, symptoms consistent with angioedema were seen in none of the subjects who received placebo and in about 0.5% of the subjects who received xxxxxx. Angioedema associated with laryngeal edema can be fatal. If laryngeal stridor or angioedema of the face, tongue, or glottis occurs, treatment with xxxxxx should be discontinued and appropriate therapy instituted immediately. Where there is involvement of the tongue, glottis, or larynx, likely to cause airway obstruction, appropriate therapy, e.g., subcutaneous epinephrine injection 1:1000 (0.3 mL to 0.5 mL) should be promptly administered (see Adverse Reactions).
- Black patients receiving ACE inhibitors have been reported to have a higher incidence of angioedema compared to nonblacks.
- Intestinal Angioedema
- Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain.
- Anaphylactoid Reactions During Desensitization
- Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge.
- Anaphylactoid Reactions During Membrane Exposure
- Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption (a procedure dependent upon devices not approved in the United States).
- xxxxxx can cause symptomatic hypotension. Like other ACE inhibitors, xxxxxx has been only rarely associated with hypotension in uncomplicated hypertensive patients. Symptomatic hypotension is most likely to occur in patients who have been volume-and/or salt-depleted as a result of prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting. Volume-and/or salt-depletion should be corrected before initiating therapy with xxxxxx.
- In patients with congestive heart failure, with or without associated renal insufficiency, ACE inhibitor therapy may cause excessive hypotension, which may be associated with oliguria or azotemia and, rarely, with acute renal failure and death. In such patients, xxxxxx therapy should be started under close medical supervision; they should be followed closely for the first 2 weeks of treatment and whenever the dose of xxxxxx or diuretic is increased.
- If hypotension occurs, the patient should be placed in a supine position, and, if necessary, treated with intravenous infusion of physiological saline. xxxxxx treatment usually can be continued following restoration of blood pressure and volume.
- Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue xxxxxx as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus.
- In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue xxxxxx, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to xxxxxx for hypotension, oliguria, and hyperkalemia (see Pediatric Use).
- No teratogenic effects of xxxxxx were seen in studies of pregnant rats, mice, and rabbits. On a mg/m2 basis, the doses used in these studies were 60 times (in rats), 9 times (in mice), and more than 0.8 times (in rabbits) the maximum recommended human dose (assuming a 50-kg woman). On a mg/kg basis these multiples are 300 times (in rats), 90 times (in mice), and more than 3 times (in rabbits) the maximum recommended human dose.
- Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up.
# Adverse Reactions
## Clinical Trials Experience
- xxxxxx has been evaluated for safety in over 6000 patients with hypertension; over 700 of these patients were treated for at least one year. The overall incidence of reported adverse events was comparable in xxxxxx and placebo patients.
- The reported side effects were generally mild and transient, and there was no relation between side effects and age, duration of therapy, or total dosage within the range of 2 to 80 mg. Discontinuation of therapy because of a side effect was required in approximately 5% of U.S. patients treated with xxxxxx and in 3% of patients treated with placebo.
- The most common reasons for discontinuation were headache (0.6%) and cough (0.5%)
- The side effects considered possibly or probably related to study drug that occurred in U.S. placebo-controlled trials in more than 1% of patients treated with xxxxxx are shown below.
- Other adverse experiences reported in controlled clinical trials (in less than 1% of xxxxxx patients or with less than 1% difference in incidence between xxxxxx or placebo treatment), and rarer events seen in post-marketing experience, include the following (in some, a causal relationship to drug use is uncertain):
- Dermatologic
- Stevens-Johnson syndrome, pemphigus, apparent hypersensitivity reactions (manifested by dermatitis, pruritus, or rash), photosensitivity, and flushing.
- Gastrointestinal
- Nausea, pancreatitis, constipation, gastritis, vomiting, and melena.
- Hematologic
- Thrombocytopenia and hemolytic anemia.
- Neurologic and Psychiatric
- Anxiety, decreased libido, hypertonia, insomnia, nervousness, and paresthesia.
- Other
- Fatigue, asthma, bronchitis, dyspnea, sinusitis, urinary tract infection, frequent urination, infection, arthritis, impotence, alopecia, arthralgia, myalgia, asthenia, sweating.
- Another potentially important adverse experience, eosinophilic pneumonitis, has been attributed to other ACE inhibitors.
- Clinical Laboratory Test Findings
- Hemoglobin
- Decreases in hemoglobin (a low value and a decrease of 5 g/dL) were rare, occurring in only 1 of 2,014 patients receiving xxxxxx alone and in 1 of 1,357 patients receiving xxxxxx plus a diuretic. No U.S. patients discontinued treatment because of decreases in hemoglobin.
- Other (causal relationships unknown)
- Elevations of uric acid, blood glucose, serum bilirubin, and liver enzymes (see Warnings) have been reported, as have scattered incidents of hyponatremia, electrocardiographic changes, eosinophilia, and proteinuria.
- Pediatric Patients
- The adverse experience profile for pediatric patients appears to be similar to that seen in adult patients.
## Postmarketing Experience
FDA Package Insert for SandboxTry contains no information regarding Postmarketing Experience.
# Drug Interactions
- Diuretics
- Patients on diuretics, especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with xxxxxx. The possibility of hypotensive effects with xxxxxx can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with xxxxxx. If this is not possible, the starting dose should be reduced (see Adult Indications and Dosage).
- Potassium supplements and potassium-sparing diuretics
- Concomitant use with xxxxxx may effect potassium levels. Monitor potassium periodically.
- Oral anticoagulants
- Interaction studies with warfarin and acenocoumarol failed to identify any clinically important effects on the serum concentrations or clinical effects of these anticoagulants.
- Lithium
- Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors (including xxxxxx) during therapy with lithium. Monitor lithium levels when used concomitantly with xxxxxx.
- Gold
- Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy.
- Anti-diabetics
- In rare cases, diabetic patients receiving an ACE inhibitor (including xxxxxx) concomitantly with insulin or oral anti-diabetics may develop hypoglycemia. Such patients should therefore be advised about the possibility of hypoglycemic reactions and should be monitored accordingly.
- Non-steroidal anti-inflammatory drugs (NSAIDs) including selective cyclooxygenase-2 inhibitors (COX-2 inhibitors)
- In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, including xxxxxx, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving xxxxxx and NSAID therapy.
- The antihypertensive effect of ACE inhibitors, including xxxxxx, may be attenuated by NSAIDs.
- Miscellaneous
- xxxxxx has been used concomitantly with beta-adrenergic-blocking agents, calcium-channel-blocking agents, diuretics, digoxin, and hydralazine, without evidence of clinically important adverse interactions. xxxxxx, like other ACE inhibitors, has had less than additive effects with beta-adrenergic blockers, presumably because both drugs lower blood pressure by inhibiting parts of the renin-angiotensin system.
- The pharmacokinetics of xxxxxx are not affected by the following drugs: hydrochlorothiazide, furosemide, chlorthalidone, digoxin, propranolol, atenolol, nifedipine, amlodipine, naproxen, acetylsalicylic acid, or cimetidine. Likewise the administration of xxxxxx does not substantially affect the pharmacokinetics of these medications (cimetidine kinetics were not studied).
# Use in Specific Populations
### Pregnancy
- Fetal toxicity
- Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue xxxxxx as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus.
- In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue xxxxxx, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to xxxxxx for hypotension, oliguria, and hyperkalemia (see Pediatric Use).
- No teratogenic effects of xxxxxx were seen in studies of pregnant rats, mice, and rabbits. On a mg/m2 basis, the doses used in these studies were 60 times (in rats), 9 times (in mice), and more than 0.8 times (in rabbits) the maximum recommended human dose (assuming a 50-kg woman). On a mg/kg basis these multiples are 300 times (in rats), 90 times (in mice), and more than 3 times (in rabbits) the maximum recommended human dose.
### Labor and Delivery
FDA Package Insert for SandboxTry contains no information regarding Labor and Delivery.
### Nursing Mothers
- Minimal amounts of unchanged xxxxxx and of xxxxxxat are excreted into the breast milk of lactating women treated with xxxxxx. A newborn child ingesting entirely breast milk would receive less than 0.1% of the mg/kg maternal dose of xxxxxx and xxxxxxat.
### Pediatric Use
- Neonates with a history of in utero exposure to xxxxxx
- If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function. xxxxxx, which crosses the placenta, can theoretically be removed from the neonatal circulation by these means; there are occasional reports of benefit from these maneuvers with another ACE inhibitor, but experience is limited.
- The antihypertensive effects of xxxxxx have been evaluated in a double-blind study in pediatric patients 7 to 16 years of age (see Pharmacodynamics). The pharmacokinetics of xxxxxx have been evaluated in pediatric patients 6 to 16 years of age (see Pharmacokinetics) . xxxxxx was generally well tolerated and adverse effects were similar to those described in adults. (See Adverse Reactions). The long-term effects of xxxxxx on growth and development have not been studied. Infants below the age of 1 year should not be given xxxxxx because of the risk of effects on kidney development.
- Treatment with xxxxxx is not recommended in pediatric patients less than 6 years of age (see Adverse Reactions), and in children with glomerular filtration rate <30 mL/min as there are insufficient data available to support a dosing recommendation in these groups. (See Pharmacokinetics.)
### Geriatric Use
- Of the total number of patients who received xxxxxx in U.S. clinical studies of xxxxxx, 18% were 65 or older while 2% were 75 or older. No overall differences in effectiveness or safety were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
- xxxxxx and xxxxxxat are substantially excreted by the kidney. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
### Gender
FDA Package Insert for SandboxTry contains no information regarding Gender.
### Race
FDA Package Insert for SandboxTry contains no information regarding Race.
### Renal Impairment
- As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients with severe congestive heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with angiotensin-converting enzyme inhibitors, including xxxxxx, may be associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death. In a small study of hypertensive patients with renal artery stenosis in a solitary kidney or bilateral renal artery stenosis, treatment with xxxxxx was associated with increases in blood urea nitrogen and serum creatinine; these increases were reversible upon discontinuation of xxxxxx or diuretic therapy, or both. When such patients are treated with ACE inhibitors, renal function should be monitored during the first few weeks of therapy. Some hypertensive patients with no apparent preexisting renal vascular disease have developed increases in blood urea nitrogen and serum creatinine, usually minor and transient, especially when xxxxxx has been given concomitantly with a diuretic. This is more likely to occur in patients with preexisting renal impairment. Dosage reduction of xxxxxx and/or discontinuation of the diuretic may be required. Evaluation of the hypertensive patient should always include assessment of renal function (see Adult Indications and Dosage).
### Hepatic Impairment
- Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up.
### Carcinogenesis, Mutagenesis, Impairment of Fertility
- No evidence of carcinogenicity was found when xxxxxx was administered to rats and mice for up to two years at doses of up to 150 mg/kg/day. When compared on the basis of body weights, this dose is 110 times the maximum recommended human dose. When compared on the basis of body surface areas, this dose is 18 and 9 times (rats and mice, respectively) the maximum recommended human dose (calculations assume a patient weight of 60 kg).
- No mutagenic activity was detected in the Ames test in bacteria (with or without metabolic activation), in an in vitro test for forward mutations in cultured mammalian cells, or in a nucleus anomaly test.
- In doses of 50-500 mg/kg/day (6-60 times the maximum recommended human dose based on mg/m2 comparison and 37-375 times the maximum recommended human dose based on a mg/kg comparison), xxxxxx had no adverse effect on the reproductive performance of male and female rats.
### Immunocompromised Patients
FDA Package Insert for SandboxTry contains no information regarding Immunocompromised Patients.
### Miscellaneous
- Hyperkalemia
- In clinical trials, hyperkalemia (serum potassium at least 0.5 mEq/L greater than the upper limit of normal) occurred in approximately 1% of hypertensive patients receiving xxxxxx. In most cases, these were isolated values which resolved despite continued therapy. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant use of potassium-sparing diuretics, potassium supplements, and/or potassium-containing salt substitutes, which should be used cautiously, if at all, with xxxxxx (see Drug Interactions).
- Cough
- Presumably due to the inhibition of the degradation of endogenous bradykinin, persistent nonproductive cough has been reported with all ACE inhibitors, always resolving after discontinuation of therapy. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough.
- Surgery/Anesthesia
- In patients undergoing surgery or during anesthesia with agents that produce hypotension, xxxxxx will block the angiotensin II formation that could otherwise occur secondary to compensatory renin release. Hypotension that occurs as a result of this mechanism can be corrected by volume expansion.
# Administration and Monitoring
### Administration
- Oral
- Preparation of suspension (for 150 mL of a 2 mg/mL suspension)
- Add 75 mL of Ora-Plus® oral suspending vehicle to an amber polyethylene terephthalate (PET) bottle containing fifteen xxxxxx 20 mg tablets, and shake for at least 2 minutes. Allow the suspension to stand for a minimum of 1 hour. After the standing time, shake the suspension for a minimum of 1 additional minute. Add 75 mL of Ora-Sweet® oral syrup vehicle to the bottle and shake the suspension to disperse the ingredients. The suspension should be refrigerated at 2-8°C (36-46°F) and can be stored for up to 30 days in the PET bottle with a child-resistant screw-cap closure. Shake the suspension before each use.
### Monitoring
- Geriatric Use
- xxxxxx and xxxxxxat are substantially excreted by the kidney. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
- Overdose
- Patients should be closely monitored for blood pressure and clinical symptoms. Supportive management should be employed to ensure adequate hydration and to maintain systemic blood pressure.
- Renal Artery Stenosis
- When hypertensive patients with renal artery stenosis in a solitary kidney or bilateral renal artery stenosis patients are treated with ACE inhibitors, renal function should be monitored during the first few weeks of therapy.
- Use of Potassium Supplements and Potassium-Sparing Diuretics
- Concomitant potassium supplements and potassium-sparing diuretics use with xxxxxx may effect potassium levels. Monitor potassium periodically.
- Use of Lithium
- Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors (including xxxxxx) during therapy with lithium. Monitor lithium levels when used concomitantly with xxxxxx.
- Use of Anti-Diabetics
- In rare cases, diabetic patients receiving an ACE inhibitor (including xxxxxx) concomitantly with insulin or oral anti-diabetics may develop hypoglycemia. Such patients should therefore be advised about the possibility of hypoglycemic reactions and should be monitored accordingly.
- Use of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors)
- In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, including xxxxxx, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving xxxxxx and NSAID therapy.
# IV Compatibility
FDA Package Insert for SandboxTry contains no information regarding IV Compatibility.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Human overdoses of xxxxxx have not been reported, but the most common manifestation of human xxxxxx overdosage is likely to be hypotension, which can be associated with electrolyte disturbances and renal failure.
### Management
- Laboratory determinations of serum levels of xxxxxx and its metabolites are not widely available, and such determinations have, in any event, no established role in the management of xxxxxx overdose.
- No data are available to suggest physiological maneuvers (e.g., maneuvers to change the pH of the urine) that might accelerate elimination of xxxxxx and its metabolites. xxxxxx is only slightly dialyzable, but dialysis might be considered in overdosed patients with severely impaired renal function (see Warnings).
- Angiotensin II could presumably serve as a specific antagonist-antidote in the setting of xxxxxx overdose, but angiotensin II is essentially unavailable outside of scattered research facilities. Because the hypotensive effect of xxxxxx is achieved through vasodilation and effective hypovolemia, it is reasonable to treat xxxxxx overdose by infusion of normal saline solution.
- If ingestion is recent, activated charcoal should be considered. Gastric decontamination (e.g., vomiting, gastric lavage) may be considered in individual cases, in the early period after ingestion.
- Patients should be closely monitored for blood pressure and clinical symptoms. Supportive management should be employed to ensure adequate hydration and to maintain systemic blood pressure.
- In the case of marked hypotension, physiological saline solution should be administered intravenously; depending on the clinical situation the use of vasopressors (e.g., catecholamines i.v.) may be considered.
## Chronic Overdose
### Signs and Symptoms
FDA Package Insert for SandboxTry contains no information regarding Signs and Symptoms in Chronic Overdose.
### Management
FDA Package Insert for SandboxTry contains no information regarding Management in Chronic Overdose.
# Pharmacology
## Mechanism of Action
- xxxxxx and xxxxxxat inhibit angiotensin-converting enzyme (ACE) in human subjects and animals. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex.
- Inhibition of ACE results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and to decreased aldosterone secretion. The latter decrease may result in a small increase of serum potassium. Hypertensive patients treated with xxxxxx alone for up to 52 weeks had elevations of serum potassium of up to 0.2 mEq/L. Similar patients treated with xxxxxx and hydrochlorothiazide for up to 24 weeks had no consistent changes in their serum potassium.
- Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity. In animal studies, xxxxxx had no inhibitory effect on the vasopressor response to angiotensin II and did not interfere with the hemodynamic effects of the autonomic neurotransmitters acetylcholine, epinephrine, and norepinephrine.
- ACE is identical to kininase, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of xxxxxx remains to be elucidated.
- While the mechanism through which xxxxxx lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, xxxxxx has an antihypertensive effect even in patients with low-renin hypertension (see Adult Indications and Dosage).
## Structure
- xxxxxx hydrochloride is a white to off-white crystalline powder, soluble (>100 mg/mL) in water, in ethanol, and in methanol. Its chemical name is xxxxxx 3-amino]-2,3,4,5-tetrahydro-2-oxo-1H-1-(3S)-benzazepine-1-acetic acid monohydrochloride.
- Its empirical formula is C24H28N2O5HCl, and its molecular weight is 460.96.
- xxxxxxat, the active metabolite of xxxxxx, is a non-sulfhydryl angiotensin-converting enzyme inhibitor. xxxxxx is converted to xxxxxxat by hepatic cleavage of the ester group.
- xxxxxx is supplied as tablets containing 5 mg, 10 mg, 20 mg, and 40 mg of xxxxxx hydrochloride for oral administration. The inactive ingredients are colloidal silicon dioxide, crospovidone, hydrogenated castor oil (5-mg, 10-mg, and 20-mg tablets), hypromellose, iron oxides, lactose, magnesium stearate (40-mg tablets), microcrystalline cellulose, polysorbate 80, propylene glycol (5-mg and 40-mg tablets), starch, talc, and titanium dioxide.
## Pharmacodynamics
- Single and multiple doses of 10 mg or more of xxxxxx cause inhibition of plasma ACE activity by at least 80%-90% for at least 24 hours after dosing. Pressor responses to exogenous angiotensin I were inhibited by 60%-90% (up to 4 hours post-dose) at the 10-mg dose.
## Pharmacokinetics
- Following oral administration of xxxxxx, peak plasma concentrations of xxxxxx are reached within 0.5-1.0 hours. The extent of absorption is at least 37% as determined by urinary recovery and is not significantly influenced by the presence of food in the GI tract.
- Cleavage of the ester group (primarily in the liver) converts xxxxxx to its active metabolite, xxxxxxat. Peak plasma concentrations of xxxxxxat are reached 1-2 hours after drug intake in the fasting state and 2-4 hours after drug intake in the nonfasting state. The serum protein binding of xxxxxx is about 96.7% and that of xxxxxxat about 95.3%, as measured by equilibrium dialysis; on the basis of in vitro studies, the degree of protein binding should be unaffected by age, hepatic dysfunction, or concentration (over the concentration range of 0.24-23.6 µmol/L).
- xxxxxx is almost completely metabolized to xxxxxxat, which has much greater ACE inhibitory activity than xxxxxx, and to the glucuronide conjugates of xxxxxx and xxxxxxat. Only trace amounts of an administered dose of xxxxxx can be recovered in the urine as unchanged xxxxxx, while about 20% of the dose is excreted as xxxxxxat, 4% as xxxxxx glucuronide, and 8% as xxxxxxat glucuronide.
- The kinetics of xxxxxx are approximately dose-proportional within the dosage range of 10-80 mg.
- In adults, the effective half-life of accumulation of xxxxxxat following multiple dosing of xxxxxx hydrochloride is 10-11 hours. Thus, steady-state concentrations of xxxxxxat should be reached after 2 or 3 doses of xxxxxx hydrochloride given once daily.
- The kinetics did not change, and there was no significant accumulation during chronic administration (28 days) of once-daily doses between 5 mg and 20 mg. Accumulation ratios based on AUC and urinary recovery of xxxxxxat were 1.19 and 1.27, respectively.
- xxxxxx and xxxxxxat are cleared predominantly by renal excretion in healthy subjects with normal renal function. Nonrenal (i.e., biliary) excretion accounts for approximately 11%-12% of xxxxxxat excretion in healthy subjects. In patients with renal failure, biliary clearance may compensate to an extent for deficient renal clearance.
- In patients with renal insufficiency, the disposition of xxxxxx and xxxxxxat in patients with mild-to-moderate renal insufficiency (creatinine clearance >30 mL/min) is similar to that in patients with normal renal function. In patients with creatinine clearance <30 mL/min, peak xxxxxxat levels and the initial (alpha phase) half-life increase, and time to steady state may be delayed (see Adult Indications and Dosage).
- When dialysis was started 2 hours after ingestion of 10 mg of xxxxxx, approximately 6% of xxxxxxat was removed in 4 hours of dialysis. The parent compound, xxxxxx, was not detected in the dialysate.
- In patients with hepatic insufficiency (due to cirrhosis), the pharmacokinetics of xxxxxxat are essentially unaltered. The pharmacokinetics of xxxxxx and xxxxxxat do not appear to be influenced by age.
- In pediatric patients, (N=45) hypertensive, age 6 to 16 years, given multiple daily doses of xxxxxx (0.1 to 0.5 mg/kg), the clearance of xxxxxxat for children 6 to 12 years old was 0.35 L/hr/kg, more than twice that of healthy adults receiving a single dose of 10 mg (0.13 L/hr/kg). In adolescents, it was 0.17 L/hr/kg, 27% higher than that of healthy adults. The terminal elimination half-life of xxxxxxat in pediatric patients was around 5 hours, one-third that observed in adults.
## Nonclinical Toxicology
FDA Package Insert for SandboxTry contains no information regarding Nonclinical Toxicology.
# Clinical Studies
- xxxxxxx.
- xxxxxxx.
- xxxxxx.
- xxxxxx.
- xxxxxx.
- In a clinical study of 107 pediatric patients, 7 to 16 years of age, with either systolic or diastolic pressure above the 95th percentile, patients were given 0.1 or 0.2 mg/kg then titrated up to 0.3 or 0.6 mg/kg with a maximum dose of 40 mg once daily. After four weeks of treatment, the 85 patients whose blood pressure was reduced on therapy were then randomized to either placebo or xxxxxx and were followed up for an additional two weeks. At the end of two weeks, blood pressure (both systolic and diastolic) in children withdrawn to placebo rose by 4 to 6 mmHg more than in children on xxxxxx. No dose-response was observed for the three doses.
# How Supplied
- xxxxxx is available in tablets of 5 mg, 10 mg, 20 mg, and 40 mg, packaged with a desiccant in bottles of 100 tablets.
- Each tablet is imprinted with xxxxxx on one side and the tablet strength (“5,” “10,” “20,” or “40”) on the other.
- National Drug Code (NDC):
- Storage
- Do not store above 30°C (86°F). Protect from moisture. Dispense in tight container (USP).
- Manufactured by
- Novartis Pharmaceuticals Corporation, Suffern, New York 10901
- Distributed by
- Novartis Pharmaceuticals Corporation, East Hanover, New Jersey 07936
# Images
## Drug Images
## Package and Label Display Panel
# Patient Information
## Patient Information from FDA
- Pregnancy
- Female patients of childbearing age should be told about the consequences of exposure to xxxxxx during pregnancy. Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible.
- Angioedema
- Angioedema, including laryngeal edema, can occur at any time with treatment with ACE inhibitors. Patients should be so advised and told to report immediately any signs or symptoms suggesting angioedema (swelling of face, eyes, lips, or tongue, or difficulty in breathing) and to take no more drug until they have consulted with the prescribing physician.
- Symptomatic Hypotension
- Patients should be cautioned that lightheadedness can occur, especially during the first days of therapy, and it should be reported to the prescribing physician. Patients should be told that if syncope occurs, xxxxxx should be discontinued until the prescribing physician has been consulted.
- All patients should be cautioned that inadequate fluid intake or excessive perspiration, diarrhea, or vomiting can lead to an excessive fall in blood pressure, with the same consequences of lightheadedness and possible syncope.
- Hyperkalemia
- Patients should be told not to use potassium supplements or salt substitutes containing potassium without consulting the prescribing physician.
- Neutropenia
- Patients should be told to promptly report any indication of infection (e.g., sore throat, fever), which could be a sign of neutropenia.
## Patient Information from NLM
For patient information about xxxxxx from NLM, click here.
# Precautions with Alcohol
Alcohol-SandboxTry interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
Lotensin®
# Look-Alike Drug Names
xxxxxx — xxxxxx®
xxxxxx® — xxxxxxx®, xxxxxx®, Lovastatin
# Drug Shortage Status
# Price | SandboxTry
Template:SandboxTry
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Zaghw, M.D. [2]
Synonyms / Brand Names: xxxxxx®
# Disclaimer
WikiDoc Drug Project is a constellation of drug information for healthcare providers and patients vigorously vetted on the basis of FDA package insert, MedlinePlus, Practice Guidelines, Scientific Statements, and scholarly medical literature. The information provided is not a medical advice or treatment. WikiDoc does not promote any medication or off-label use of drugs. Please read our full disclaimer here.
# Black Box Warning
# Overview
SandboxTry is an angiotensin converting enzyme inhibitor drug that is FDA approved for the treatment of hypertension. There is a Black Box Warning for this drug as shown here. Common adverse reactions include cough, dizziness, fatigue, and headache.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- Initial dose (not receiving a diuretic): xxxxxx
- Initial dose (concurrent xxxxxx use): xxxxxx (see Warnings). If blood pressure is not controlled with xxxxxx alone, diuretic should be resumed and xxxxxx 5 mg PO qd should be used.
- Maintenance dose: xxxxxx 20—40 mg PO qd or xxxxxx 10—20 mg PO bid (MAX 80 mg/day)
- xxxxxx.
- xxxxxx.
- xxxxxx.
- Dosing Information
- Initial dose (for creatinine clearance <30 mL/min/1.73 m2 or Cr >3 mg/dL): xxxxxx 5 mg PO qd
- Dosage may be titrated upward until blood pressure is controlled or to a maximum total daily dose of 40 mg (see Warnings).[1]
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- Developed by: American College of Cardiology (ACC) and American Heart Association (AHA)
- Class of Recommendation: Class I
- Level of Evidence: Level A
- Recommendation
- xxxxxx
- Developed by: American College of Cardiology (ACC) and American Heart Association (AHA)
- Class of Recommendation: Class I
- Level of Evidence: Level A
- Recommendation
- An angiotensin-converting enzyme (ACE) inhibitor should be administered within the first 24 hours to all patients with STEMI with anterior location, HF, or ejection fraction (EF) less than or equal to 0.40, unless contraindicated.[2]
### Non–Guideline-Supported Use
- Dosing Information
- xxxxxx 10 mg PO qd[3][4]
- Dosing Information
- xxxxxx 10 mg PO qd[3][4]
- Dosing Information
- xxxxxx 20 mg PO qd for 2 weeks, followed by xxxxxx 40 mg qd or combination of xxxxxx 40 mg PO qd and Amlodipine 5 mg PO qd[5]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Dosing Information
- Initial dose: xxxxxx 0.2 mg/kg PO qd (for pediatric patients above the age of 6 years)
- xxxxxx is not advised for children below the age of 6 years (see Pediatric Use) and in pediatric patients with glomerular filtration rate <30 mL.
- For pediatric patients who cannot swallow tablets, or for whom the calculated dosage (mg/kg) does not correspond to the available tablet strengths for xxxxxx, follow the suspension preparation instructions to administer xxxxxx HCl as a suspension (see Administration and Monitoring).
- Dosing Information
- Initial dose (for creatinine clearance <30 mL/min/1.73 m2 or Cr >3 mg/dL): xxxxxx 5 mg PO qd
- Dosage may be titrated upward until blood pressure is controlled or to a maximum total daily dose of 40 mg (see Warnings).
## Off-Label Use and Dosage (Pediatric)
There is limited information about Off-Label Use and Dosage of xxxxxx tablet in pediatric patients.
# Contraindications
- Hypersensitivity to xxxxxx or to any other ACE inhibitor
- History of angioedema with or without previous ACE inhibitor treatment
# Warnings
- Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including xxxxxx) may be subject to a variety of adverse reactions, some of them serious.
- Head and Neck Angioedema
- Angioedema of the face, extremities, lips, tongue, glottis, and larynx has been reported in patients treated with angiotensin-converting enzyme inhibitors. In U.S. clinical trials, symptoms consistent with angioedema were seen in none of the subjects who received placebo and in about 0.5% of the subjects who received xxxxxx. Angioedema associated with laryngeal edema can be fatal. If laryngeal stridor or angioedema of the face, tongue, or glottis occurs, treatment with xxxxxx should be discontinued and appropriate therapy instituted immediately. Where there is involvement of the tongue, glottis, or larynx, likely to cause airway obstruction, appropriate therapy, e.g., subcutaneous epinephrine injection 1:1000 (0.3 mL to 0.5 mL) should be promptly administered (see Adverse Reactions).
- Black patients receiving ACE inhibitors have been reported to have a higher incidence of angioedema compared to nonblacks.
- Intestinal Angioedema
- Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain.
- Anaphylactoid Reactions During Desensitization
- Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge.
- Anaphylactoid Reactions During Membrane Exposure
- Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption (a procedure dependent upon devices not approved in the United States).
- xxxxxx can cause symptomatic hypotension. Like other ACE inhibitors, xxxxxx has been only rarely associated with hypotension in uncomplicated hypertensive patients. Symptomatic hypotension is most likely to occur in patients who have been volume-and/or salt-depleted as a result of prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting. Volume-and/or salt-depletion should be corrected before initiating therapy with xxxxxx.
- In patients with congestive heart failure, with or without associated renal insufficiency, ACE inhibitor therapy may cause excessive hypotension, which may be associated with oliguria or azotemia and, rarely, with acute renal failure and death. In such patients, xxxxxx therapy should be started under close medical supervision; they should be followed closely for the first 2 weeks of treatment and whenever the dose of xxxxxx or diuretic is increased.
- If hypotension occurs, the patient should be placed in a supine position, and, if necessary, treated with intravenous infusion of physiological saline. xxxxxx treatment usually can be continued following restoration of blood pressure and volume.
- Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue xxxxxx as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus.
- In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue xxxxxx, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to xxxxxx for hypotension, oliguria, and hyperkalemia (see Pediatric Use).
- No teratogenic effects of xxxxxx were seen in studies of pregnant rats, mice, and rabbits. On a mg/m2 basis, the doses used in these studies were 60 times (in rats), 9 times (in mice), and more than 0.8 times (in rabbits) the maximum recommended human dose (assuming a 50-kg woman). On a mg/kg basis these multiples are 300 times (in rats), 90 times (in mice), and more than 3 times (in rabbits) the maximum recommended human dose.
- Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up.
# Adverse Reactions
## Clinical Trials Experience
- xxxxxx has been evaluated for safety in over 6000 patients with hypertension; over 700 of these patients were treated for at least one year. The overall incidence of reported adverse events was comparable in xxxxxx and placebo patients.
- The reported side effects were generally mild and transient, and there was no relation between side effects and age, duration of therapy, or total dosage within the range of 2 to 80 mg. Discontinuation of therapy because of a side effect was required in approximately 5% of U.S. patients treated with xxxxxx and in 3% of patients treated with placebo.
- The most common reasons for discontinuation were headache (0.6%) and cough (0.5%)
- The side effects considered possibly or probably related to study drug that occurred in U.S. placebo-controlled trials in more than 1% of patients treated with xxxxxx are shown below.
- Other adverse experiences reported in controlled clinical trials (in less than 1% of xxxxxx patients or with less than 1% difference in incidence between xxxxxx or placebo treatment), and rarer events seen in post-marketing experience, include the following (in some, a causal relationship to drug use is uncertain):
- Dermatologic
- Stevens-Johnson syndrome, pemphigus, apparent hypersensitivity reactions (manifested by dermatitis, pruritus, or rash), photosensitivity, and flushing.
- Gastrointestinal
- Nausea, pancreatitis, constipation, gastritis, vomiting, and melena.
- Hematologic
- Thrombocytopenia and hemolytic anemia.
- Neurologic and Psychiatric
- Anxiety, decreased libido, hypertonia, insomnia, nervousness, and paresthesia.
- Other
- Fatigue, asthma, bronchitis, dyspnea, sinusitis, urinary tract infection, frequent urination, infection, arthritis, impotence, alopecia, arthralgia, myalgia, asthenia, sweating.
- Another potentially important adverse experience, eosinophilic pneumonitis, has been attributed to other ACE inhibitors.
- Clinical Laboratory Test Findings
- Hemoglobin
- Decreases in hemoglobin (a low value and a decrease of 5 g/dL) were rare, occurring in only 1 of 2,014 patients receiving xxxxxx alone and in 1 of 1,357 patients receiving xxxxxx plus a diuretic. No U.S. patients discontinued treatment because of decreases in hemoglobin.
- Other (causal relationships unknown)
- Elevations of uric acid, blood glucose, serum bilirubin, and liver enzymes (see Warnings) have been reported, as have scattered incidents of hyponatremia, electrocardiographic changes, eosinophilia, and proteinuria.
- Pediatric Patients
- The adverse experience profile for pediatric patients appears to be similar to that seen in adult patients.
## Postmarketing Experience
FDA Package Insert for SandboxTry contains no information regarding Postmarketing Experience.
# Drug Interactions
- Diuretics
- Patients on diuretics, especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with xxxxxx. The possibility of hypotensive effects with xxxxxx can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with xxxxxx. If this is not possible, the starting dose should be reduced (see Adult Indications and Dosage).
- Potassium supplements and potassium-sparing diuretics
- Concomitant use with xxxxxx may effect potassium levels. Monitor potassium periodically.
- Oral anticoagulants
- Interaction studies with warfarin and acenocoumarol failed to identify any clinically important effects on the serum concentrations or clinical effects of these anticoagulants.
- Lithium
- Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors (including xxxxxx) during therapy with lithium. Monitor lithium levels when used concomitantly with xxxxxx.
- Gold
- Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy.
- Anti-diabetics
- In rare cases, diabetic patients receiving an ACE inhibitor (including xxxxxx) concomitantly with insulin or oral anti-diabetics may develop hypoglycemia. Such patients should therefore be advised about the possibility of hypoglycemic reactions and should be monitored accordingly.
- Non-steroidal anti-inflammatory drugs (NSAIDs) including selective cyclooxygenase-2 inhibitors (COX-2 inhibitors)
- In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, including xxxxxx, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving xxxxxx and NSAID therapy.
- The antihypertensive effect of ACE inhibitors, including xxxxxx, may be attenuated by NSAIDs.
- Miscellaneous
- xxxxxx has been used concomitantly with beta-adrenergic-blocking agents, calcium-channel-blocking agents, diuretics, digoxin, and hydralazine, without evidence of clinically important adverse interactions. xxxxxx, like other ACE inhibitors, has had less than additive effects with beta-adrenergic blockers, presumably because both drugs lower blood pressure by inhibiting parts of the renin-angiotensin system.
- The pharmacokinetics of xxxxxx are not affected by the following drugs: hydrochlorothiazide, furosemide, chlorthalidone, digoxin, propranolol, atenolol, nifedipine, amlodipine, naproxen, acetylsalicylic acid, or cimetidine. Likewise the administration of xxxxxx does not substantially affect the pharmacokinetics of these medications (cimetidine kinetics were not studied).
# Use in Specific Populations
### Pregnancy
- Fetal toxicity
- Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue xxxxxx as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus.
- In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue xxxxxx, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to xxxxxx for hypotension, oliguria, and hyperkalemia (see Pediatric Use).
- No teratogenic effects of xxxxxx were seen in studies of pregnant rats, mice, and rabbits. On a mg/m2 basis, the doses used in these studies were 60 times (in rats), 9 times (in mice), and more than 0.8 times (in rabbits) the maximum recommended human dose (assuming a 50-kg woman). On a mg/kg basis these multiples are 300 times (in rats), 90 times (in mice), and more than 3 times (in rabbits) the maximum recommended human dose.
### Labor and Delivery
FDA Package Insert for SandboxTry contains no information regarding Labor and Delivery.
### Nursing Mothers
- Minimal amounts of unchanged xxxxxx and of xxxxxxat are excreted into the breast milk of lactating women treated with xxxxxx. A newborn child ingesting entirely breast milk would receive less than 0.1% of the mg/kg maternal dose of xxxxxx and xxxxxxat.
### Pediatric Use
- Neonates with a history of in utero exposure to xxxxxx
- If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function. xxxxxx, which crosses the placenta, can theoretically be removed from the neonatal circulation by these means; there are occasional reports of benefit from these maneuvers with another ACE inhibitor, but experience is limited.
- The antihypertensive effects of xxxxxx have been evaluated in a double-blind study in pediatric patients 7 to 16 years of age (see Pharmacodynamics). The pharmacokinetics of xxxxxx have been evaluated in pediatric patients 6 to 16 years of age (see Pharmacokinetics) . xxxxxx was generally well tolerated and adverse effects were similar to those described in adults. (See Adverse Reactions). The long-term effects of xxxxxx on growth and development have not been studied. Infants below the age of 1 year should not be given xxxxxx because of the risk of effects on kidney development.
- Treatment with xxxxxx is not recommended in pediatric patients less than 6 years of age (see Adverse Reactions), and in children with glomerular filtration rate <30 mL/min as there are insufficient data available to support a dosing recommendation in these groups. (See Pharmacokinetics.)
### Geriatric Use
- Of the total number of patients who received xxxxxx in U.S. clinical studies of xxxxxx, 18% were 65 or older while 2% were 75 or older. No overall differences in effectiveness or safety were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
- xxxxxx and xxxxxxat are substantially excreted by the kidney. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
### Gender
FDA Package Insert for SandboxTry contains no information regarding Gender.
### Race
FDA Package Insert for SandboxTry contains no information regarding Race.
### Renal Impairment
- As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients with severe congestive heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with angiotensin-converting enzyme inhibitors, including xxxxxx, may be associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death. In a small study of hypertensive patients with renal artery stenosis in a solitary kidney or bilateral renal artery stenosis, treatment with xxxxxx was associated with increases in blood urea nitrogen and serum creatinine; these increases were reversible upon discontinuation of xxxxxx or diuretic therapy, or both. When such patients are treated with ACE inhibitors, renal function should be monitored during the first few weeks of therapy. Some hypertensive patients with no apparent preexisting renal vascular disease have developed increases in blood urea nitrogen and serum creatinine, usually minor and transient, especially when xxxxxx has been given concomitantly with a diuretic. This is more likely to occur in patients with preexisting renal impairment. Dosage reduction of xxxxxx and/or discontinuation of the diuretic may be required. Evaluation of the hypertensive patient should always include assessment of renal function (see Adult Indications and Dosage).
### Hepatic Impairment
- Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up.
### Carcinogenesis, Mutagenesis, Impairment of Fertility
- No evidence of carcinogenicity was found when xxxxxx was administered to rats and mice for up to two years at doses of up to 150 mg/kg/day. When compared on the basis of body weights, this dose is 110 times the maximum recommended human dose. When compared on the basis of body surface areas, this dose is 18 and 9 times (rats and mice, respectively) the maximum recommended human dose (calculations assume a patient weight of 60 kg).
- No mutagenic activity was detected in the Ames test in bacteria (with or without metabolic activation), in an in vitro test for forward mutations in cultured mammalian cells, or in a nucleus anomaly test.
- In doses of 50-500 mg/kg/day (6-60 times the maximum recommended human dose based on mg/m2 comparison and 37-375 times the maximum recommended human dose based on a mg/kg comparison), xxxxxx had no adverse effect on the reproductive performance of male and female rats.
### Immunocompromised Patients
FDA Package Insert for SandboxTry contains no information regarding Immunocompromised Patients.
### Miscellaneous
- Hyperkalemia
- In clinical trials, hyperkalemia (serum potassium at least 0.5 mEq/L greater than the upper limit of normal) occurred in approximately 1% of hypertensive patients receiving xxxxxx. In most cases, these were isolated values which resolved despite continued therapy. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant use of potassium-sparing diuretics, potassium supplements, and/or potassium-containing salt substitutes, which should be used cautiously, if at all, with xxxxxx (see Drug Interactions).
- Cough
- Presumably due to the inhibition of the degradation of endogenous bradykinin, persistent nonproductive cough has been reported with all ACE inhibitors, always resolving after discontinuation of therapy. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough.
- Surgery/Anesthesia
- In patients undergoing surgery or during anesthesia with agents that produce hypotension, xxxxxx will block the angiotensin II formation that could otherwise occur secondary to compensatory renin release. Hypotension that occurs as a result of this mechanism can be corrected by volume expansion.
# Administration and Monitoring
### Administration
- Oral
- Preparation of suspension (for 150 mL of a 2 mg/mL suspension)
- Add 75 mL of Ora-Plus® oral suspending vehicle to an amber polyethylene terephthalate (PET) bottle containing fifteen xxxxxx 20 mg tablets, and shake for at least 2 minutes. Allow the suspension to stand for a minimum of 1 hour. After the standing time, shake the suspension for a minimum of 1 additional minute. Add 75 mL of Ora-Sweet® oral syrup vehicle to the bottle and shake the suspension to disperse the ingredients. The suspension should be refrigerated at 2-8°C (36-46°F) and can be stored for up to 30 days in the PET bottle with a child-resistant screw-cap closure. Shake the suspension before each use.
### Monitoring
- Geriatric Use
- xxxxxx and xxxxxxat are substantially excreted by the kidney. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
- Overdose
- Patients should be closely monitored for blood pressure and clinical symptoms. Supportive management should be employed to ensure adequate hydration and to maintain systemic blood pressure.
- Renal Artery Stenosis
- When hypertensive patients with renal artery stenosis in a solitary kidney or bilateral renal artery stenosis patients are treated with ACE inhibitors, renal function should be monitored during the first few weeks of therapy.
- Use of Potassium Supplements and Potassium-Sparing Diuretics
- Concomitant potassium supplements and potassium-sparing diuretics use with xxxxxx may effect potassium levels. Monitor potassium periodically.
- Use of Lithium
- Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors (including xxxxxx) during therapy with lithium. Monitor lithium levels when used concomitantly with xxxxxx.
- Use of Anti-Diabetics
- In rare cases, diabetic patients receiving an ACE inhibitor (including xxxxxx) concomitantly with insulin or oral anti-diabetics may develop hypoglycemia. Such patients should therefore be advised about the possibility of hypoglycemic reactions and should be monitored accordingly.
- Use of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors)
- In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, including xxxxxx, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving xxxxxx and NSAID therapy.
# IV Compatibility
FDA Package Insert for SandboxTry contains no information regarding IV Compatibility.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Human overdoses of xxxxxx have not been reported, but the most common manifestation of human xxxxxx overdosage is likely to be hypotension, which can be associated with electrolyte disturbances and renal failure.
### Management
- Laboratory determinations of serum levels of xxxxxx and its metabolites are not widely available, and such determinations have, in any event, no established role in the management of xxxxxx overdose.
- No data are available to suggest physiological maneuvers (e.g., maneuvers to change the pH of the urine) that might accelerate elimination of xxxxxx and its metabolites. xxxxxx is only slightly dialyzable, but dialysis might be considered in overdosed patients with severely impaired renal function (see Warnings).
- Angiotensin II could presumably serve as a specific antagonist-antidote in the setting of xxxxxx overdose, but angiotensin II is essentially unavailable outside of scattered research facilities. Because the hypotensive effect of xxxxxx is achieved through vasodilation and effective hypovolemia, it is reasonable to treat xxxxxx overdose by infusion of normal saline solution.
- If ingestion is recent, activated charcoal should be considered. Gastric decontamination (e.g., vomiting, gastric lavage) may be considered in individual cases, in the early period after ingestion.
- Patients should be closely monitored for blood pressure and clinical symptoms. Supportive management should be employed to ensure adequate hydration and to maintain systemic blood pressure.
- In the case of marked hypotension, physiological saline solution should be administered intravenously; depending on the clinical situation the use of vasopressors (e.g., catecholamines i.v.) may be considered.
## Chronic Overdose
### Signs and Symptoms
FDA Package Insert for SandboxTry contains no information regarding Signs and Symptoms in Chronic Overdose.
### Management
FDA Package Insert for SandboxTry contains no information regarding Management in Chronic Overdose.
# Pharmacology
## Mechanism of Action
- xxxxxx and xxxxxxat inhibit angiotensin-converting enzyme (ACE) in human subjects and animals. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex.
- Inhibition of ACE results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and to decreased aldosterone secretion. The latter decrease may result in a small increase of serum potassium. Hypertensive patients treated with xxxxxx alone for up to 52 weeks had elevations of serum potassium of up to 0.2 mEq/L. Similar patients treated with xxxxxx and hydrochlorothiazide for up to 24 weeks had no consistent changes in their serum potassium.
- Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity. In animal studies, xxxxxx had no inhibitory effect on the vasopressor response to angiotensin II and did not interfere with the hemodynamic effects of the autonomic neurotransmitters acetylcholine, epinephrine, and norepinephrine.
- ACE is identical to kininase, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of xxxxxx remains to be elucidated.
- While the mechanism through which xxxxxx lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, xxxxxx has an antihypertensive effect even in patients with low-renin hypertension (see Adult Indications and Dosage).
## Structure
- xxxxxx hydrochloride is a white to off-white crystalline powder, soluble (>100 mg/mL) in water, in ethanol, and in methanol. Its chemical name is xxxxxx 3-[[1-(ethoxy-carbonyl)-3-phenyl-(1S)-propyl]amino]-2,3,4,5-tetrahydro-2-oxo-1H-1-(3S)-benzazepine-1-acetic acid monohydrochloride.
- Its empirical formula is C24H28N2O5•HCl, and its molecular weight is 460.96.
- xxxxxxat, the active metabolite of xxxxxx, is a non-sulfhydryl angiotensin-converting enzyme inhibitor. xxxxxx is converted to xxxxxxat by hepatic cleavage of the ester group.
- xxxxxx is supplied as tablets containing 5 mg, 10 mg, 20 mg, and 40 mg of xxxxxx hydrochloride for oral administration. The inactive ingredients are colloidal silicon dioxide, crospovidone, hydrogenated castor oil (5-mg, 10-mg, and 20-mg tablets), hypromellose, iron oxides, lactose, magnesium stearate (40-mg tablets), microcrystalline cellulose, polysorbate 80, propylene glycol (5-mg and 40-mg tablets), starch, talc, and titanium dioxide.
## Pharmacodynamics
- Single and multiple doses of 10 mg or more of xxxxxx cause inhibition of plasma ACE activity by at least 80%-90% for at least 24 hours after dosing. Pressor responses to exogenous angiotensin I were inhibited by 60%-90% (up to 4 hours post-dose) at the 10-mg dose.
## Pharmacokinetics
- Following oral administration of xxxxxx, peak plasma concentrations of xxxxxx are reached within 0.5-1.0 hours. The extent of absorption is at least 37% as determined by urinary recovery and is not significantly influenced by the presence of food in the GI tract.
- Cleavage of the ester group (primarily in the liver) converts xxxxxx to its active metabolite, xxxxxxat. Peak plasma concentrations of xxxxxxat are reached 1-2 hours after drug intake in the fasting state and 2-4 hours after drug intake in the nonfasting state. The serum protein binding of xxxxxx is about 96.7% and that of xxxxxxat about 95.3%, as measured by equilibrium dialysis; on the basis of in vitro studies, the degree of protein binding should be unaffected by age, hepatic dysfunction, or concentration (over the concentration range of 0.24-23.6 µmol/L).
- xxxxxx is almost completely metabolized to xxxxxxat, which has much greater ACE inhibitory activity than xxxxxx, and to the glucuronide conjugates of xxxxxx and xxxxxxat. Only trace amounts of an administered dose of xxxxxx can be recovered in the urine as unchanged xxxxxx, while about 20% of the dose is excreted as xxxxxxat, 4% as xxxxxx glucuronide, and 8% as xxxxxxat glucuronide.
- The kinetics of xxxxxx are approximately dose-proportional within the dosage range of 10-80 mg.
- In adults, the effective half-life of accumulation of xxxxxxat following multiple dosing of xxxxxx hydrochloride is 10-11 hours. Thus, steady-state concentrations of xxxxxxat should be reached after 2 or 3 doses of xxxxxx hydrochloride given once daily.
- The kinetics did not change, and there was no significant accumulation during chronic administration (28 days) of once-daily doses between 5 mg and 20 mg. Accumulation ratios based on AUC and urinary recovery of xxxxxxat were 1.19 and 1.27, respectively.
- xxxxxx and xxxxxxat are cleared predominantly by renal excretion in healthy subjects with normal renal function. Nonrenal (i.e., biliary) excretion accounts for approximately 11%-12% of xxxxxxat excretion in healthy subjects. In patients with renal failure, biliary clearance may compensate to an extent for deficient renal clearance.
- In patients with renal insufficiency, the disposition of xxxxxx and xxxxxxat in patients with mild-to-moderate renal insufficiency (creatinine clearance >30 mL/min) is similar to that in patients with normal renal function. In patients with creatinine clearance <30 mL/min, peak xxxxxxat levels and the initial (alpha phase) half-life increase, and time to steady state may be delayed (see Adult Indications and Dosage).
- When dialysis was started 2 hours after ingestion of 10 mg of xxxxxx, approximately 6% of xxxxxxat was removed in 4 hours of dialysis. The parent compound, xxxxxx, was not detected in the dialysate.
- In patients with hepatic insufficiency (due to cirrhosis), the pharmacokinetics of xxxxxxat are essentially unaltered. The pharmacokinetics of xxxxxx and xxxxxxat do not appear to be influenced by age.
- In pediatric patients, (N=45) hypertensive, age 6 to 16 years, given multiple daily doses of xxxxxx (0.1 to 0.5 mg/kg), the clearance of xxxxxxat for children 6 to 12 years old was 0.35 L/hr/kg, more than twice that of healthy adults receiving a single dose of 10 mg (0.13 L/hr/kg). In adolescents, it was 0.17 L/hr/kg, 27% higher than that of healthy adults. The terminal elimination half-life of xxxxxxat in pediatric patients was around 5 hours, one-third that observed in adults.
## Nonclinical Toxicology
FDA Package Insert for SandboxTry contains no information regarding Nonclinical Toxicology.
# Clinical Studies
- xxxxxxx.
- xxxxxxx.
- xxxxxx.
- xxxxxx.
- xxxxxx.
- In a clinical study of 107 pediatric patients, 7 to 16 years of age, with either systolic or diastolic pressure above the 95th percentile, patients were given 0.1 or 0.2 mg/kg then titrated up to 0.3 or 0.6 mg/kg with a maximum dose of 40 mg once daily. After four weeks of treatment, the 85 patients whose blood pressure was reduced on therapy were then randomized to either placebo or xxxxxx and were followed up for an additional two weeks. At the end of two weeks, blood pressure (both systolic and diastolic) in children withdrawn to placebo rose by 4 to 6 mmHg more than in children on xxxxxx. No dose-response was observed for the three doses.
# How Supplied
- xxxxxx is available in tablets of 5 mg, 10 mg, 20 mg, and 40 mg, packaged with a desiccant in bottles of 100 tablets.
- Each tablet is imprinted with xxxxxx on one side and the tablet strength (“5,” “10,” “20,” or “40”) on the other.
- National Drug Code (NDC):
- Storage
- Do not store above 30°C (86°F). Protect from moisture. Dispense in tight container (USP).
- Manufactured by
- Novartis Pharmaceuticals Corporation, Suffern, New York 10901
- Distributed by
- Novartis Pharmaceuticals Corporation, East Hanover, New Jersey 07936
# Images
## Drug Images
## Package and Label Display Panel
# Patient Information
## Patient Information from FDA
- Pregnancy
- Female patients of childbearing age should be told about the consequences of exposure to xxxxxx during pregnancy. Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible.
- Angioedema
- Angioedema, including laryngeal edema, can occur at any time with treatment with ACE inhibitors. Patients should be so advised and told to report immediately any signs or symptoms suggesting angioedema (swelling of face, eyes, lips, or tongue, or difficulty in breathing) and to take no more drug until they have consulted with the prescribing physician.
- Symptomatic Hypotension
- Patients should be cautioned that lightheadedness can occur, especially during the first days of therapy, and it should be reported to the prescribing physician. Patients should be told that if syncope occurs, xxxxxx should be discontinued until the prescribing physician has been consulted.
- All patients should be cautioned that inadequate fluid intake or excessive perspiration, diarrhea, or vomiting can lead to an excessive fall in blood pressure, with the same consequences of lightheadedness and possible syncope.
- Hyperkalemia
- Patients should be told not to use potassium supplements or salt substitutes containing potassium without consulting the prescribing physician.
- Neutropenia
- Patients should be told to promptly report any indication of infection (e.g., sore throat, fever), which could be a sign of neutropenia.
## Patient Information from NLM
For patient information about xxxxxx from NLM, click here.
# Precautions with Alcohol
Alcohol-SandboxTry interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
Lotensin®
# Look-Alike Drug Names
xxxxxx — xxxxxx®
xxxxxx® — xxxxxxx®, xxxxxx®, Lovastatin
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/SandboxTry | |
3645ae72d43438bb008be00edcf76b9cefb9e063 | wikidoc | Sandbox CP | Sandbox CP
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Capsule | Sandbox CP
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6e208eec07f630bf8ca3a84d7744becb591095db | wikidoc | Sandbox IE | Sandbox IE
## Endocarditis, treatment ⇧ Return to Top ⇧
- Infective endocarditis
- Culture-negative endocarditis
- Culture-negative, native valve endocarditis
- Preferred regimen: Ampicillin-sulbactam 12 g/24h IV q6h 4–6 weeks AND Gentamicin 3 mg/kg/24h IV/IM q8h for 4–6 weeks
- Alternative regimen: Vancomycin 30 mg/kg/24h IV q12h for 4–6 weeks AND Gentamicin 3 mg/kg/24h IV/IM q8h for 4–6 weeks AND Ciprofloxacin 1000 mg/24h PO or 800 mg/24h IV q12h for 4–6 weeks
- Pediatric dose: Ampicillin-sulbactam 300 mg/kg/24h IV q4–6h; Gentamicin 3 mg/kg/24h IV/IM q8h; Vancomycin 40 mg/kg/24h q8–12h; Ciprofloxacin 20–30 mg/kg/24h IV/PO q12h
- Culture-negative, prosthetic valve endocarditis (early, ≤ 1 year)
- Preferred regimen : Vancomycin 30 mg/kg/24h IV q12h for 6 weeks AND Gentamicin 3 mg/kg/24h IV/IM q8h for 2 weeks AND Cefepime 6 g/24h IV q8h for 6 weeks AND Rifampin 900 mg/24h PO/IV q8h for 6 weeks
- Pediatric dose: Vancomycin 40 mg/kg/24h IV q8–12h; Gentamicin 3 mg/kg/24h IV/IM q8h; Cefepime 150 mg/kg/24h IV q8h; Rifampin 20 mg/kg/24h PO/IV q8h
- Culture-negative, prosthetic valve endocarditis (late, > 1 year)
- Preferred regimen: Ampicillin-sulbactam 12 g/24h IV q6h 6 weeks AND Gentamicin 3 mg/kg/24h IV/IM q8h for 6 weeks
- Alternative regimen: Vancomycin 30 mg/kg/24h IV q12h for 4–6 weeks AND Gentamicin 3 mg/kg/24h IV/IM q8h for 6 weeks AND Ciprofloxacin 1000 mg/24h PO or 800 mg/24h IV q12h for 6 weeks
- Pediatric dose: Ampicillin-sulbactam 300 mg/kg/24h IV q4h; Gentamicin 3 mg/kg/24h IV/IM q8h; Vancomycin 40 mg/kg/24h q8–12h; Ciprofloxacin 20–30 mg/kg/24h IV/PO q12h
- Culture-negative, prosthetic valve endocarditis (early, ≤ 1 year)
- Preferred regimen: Ampicillin-sulbactam 12 g/24h IV q6h 4–6 weeks AND Gentamicin 3 mg/kg/24h IV/IM q8h for 4–6 weeks AND Rifampin 900 mg/24h PO/IV q8h for 6 weeks
- Alternative regimen: Vancomycin 30 mg/kg/24h IV q12h for 4–6 weeks AND Gentamicin 3 mg/kg/24h IV/IM q8h for 4–6 weeks AND Ciprofloxacin 1000 mg/24h PO or 800 mg/24h IV q12h for 4–6 weeks AND Rifampin 900 mg/24h PO/IV q8h for 6 weeks
- Pediatric dose: Ampicillin-sulbactam 300 mg/kg/24h IV q4–6h; Gentamicin 3 mg/kg/24h IV/IM q8h; Vancomycin 40 mg/kg/24h IV q8–12h; Cefepime 150 mg/kg/24h IV q8h; Rifampin 20 mg/kg/24h PO/IV q8h
- Pathogen-directed antimicrobial therapy
- Bartonella
- Suspected Bartonella endocarditis
- Preferred regimen : Ceftriaxone sodium 2 g/24h IV/IM in 1 dose for 6 weeks AND Gentamicin 3 mg/kg/24h IV/IM q8h for 2 weeks ± Doxycycline 200 mg/kg/24h IV/PO q12h for 6 weeks
- Pediatric dose: Ceftriaxone 100 mg/kg/24h IV/IM once daily; Gentamicin 3 mg/kg/24h IV/IM q8h; Doxycycline 2–4 mg/kg/24h IV/PO q12h; Rifampin 20 mg/kg/24h PO/IV q12h
- Documented Bartonella endocarditis
- Preferred regimen: Doxycycline 200 mg/24h IV or PO q12h for 6 weeks AND Gentamicin 3 mg/kg/24h IV/IM q8h for 2 weeks
- Pediatric dose: Ceftriaxone 100 mg/kg/24h IV/IM once daily; Gentamicin 3 mg/kg/24h IV/IM q8h; Doxycycline 2–4 mg/kg/24h IV/PO q12h; Rifampin 20 mg/kg/24h PO/IV q12h
- Enterococcus
- Endocarditis caused by enterococcal strains susceptible to penicillin, gentamicin, and vancomycin
- Preferred regimen : Ampicillin 12 g/24h IV q4h for 4–6 weeks OR Penicillin G 18–30 million U/24h IV either continuously or q4h for 4–6 weeks AND Gentamicin 3 mg/kg/24h IV/IM q8h for 4–6weeks
- Alternative regimen : Vancomycin 30 mg/kg/24h IV q12h for 6 weeks AND Gentamicin 3 mg/kg/24h IV/IM q8h for 6 weeks
- Pediatric dose: Vancomycin 40 mg/kg/24h IV q8–12h; Gentamicin 3 mg/kg/24h IV/IM q8h
- Endocarditis caused by enterococcal strains susceptible to penicillin, streptomycin, and vancomycin and resistant to gentamicin
- Preferred regimen : Ampicillin 12 g/24h IV q4h for 4–6 weeks OR Penicillin G 24 million U/24h IV continuously or q4h for 4–6 weeks AND Streptomycin 15 mg/kg/24h IV/IM q12h for 4–6 weeks
- Alternative regimen : Vancomycin 30 mg/kg/24h IV q12h for 6 weeks AND Streptomycin 15 mg/kg/24h IV/IM q12h for 6 weeks
- Pediatric dose: Ampicillin 300 mg/kg/24h IV q4–6h; Penicillin 300 000 U/kg/24h IV q4–6h; Streptomycin 20–30 mg/kg/24h IV/IM q12h; Vancomycin 40 mg/kg/24h IV q8–12h; Streptomycin 20–30 mg/kg/24h IV/IM q12h
- Endocarditis caused by enterococcal strains resistant to penicillin and susceptible to aminoglycoside and vancomycin
- β-Lactamase–producing strain
- Preferred regimen: Ampicillin-sulbactam 12 g/24h IV q6h for 6 weeks AND Gentamicin 3 mg/kg/24h IV/IM q8h for 6 weeks
- Alternative regimen : Vancomycin 30 mg/kg/24h IV q12h for 6 weeks
- Pediatric dose: Ampicillin-sulbactam 300 mg/kg/24h IV q6h; Gentamicin 3 mg/kg/24h IV/IM q8h
- Intrinsic penicillin resistance
- Preferred regimen: Vancomycin 30 mg/kg/24h IV q12h for 6 weeks AND Gentamicin 3 mg/kg/24h IV/IM q8h for 6 weeks
- Pediatric dose: Vancomycin 40 mg/kg/24h IV q8–12h; Gentamicin 3 mg/kg/24h IV/IM q8h
- Endocarditis caused by enterococcal strains resistant to penicillin, gentamicin, and vancomycin
- Enterococcus faecium
- Preferred regimen : Linezolid 1200 mg/24h IV/PO q12h for ≥ 8 weeks OR Quinupristin-Dalfopristin 22.5 mg/kg/24h IV q8h for 8 weeks
- Enterococcus faecalis
- Preferred regimen : Imipenem/cilastatin 2 g/24h IV q6h for ≥ 8 weeks AND Ampicillin 12 g/24h IV q4h for ≥ 8 weeks OR Ceftriaxone sodium 4 g/24h IV/IM q12h for ≥ 8 weeks AND Ampicillin 12 g/24h IV q4h for ≥ 8 weeks
- Pediatric dose: Linezolid 30 mg/kg/24h IV/PO q8h; Quinupristin-Dalfopristin 22.5 mg/kg/24h IV q8h; Imipenem/cilastatin 60–100 mg/kg/24h IV q6h; Ampicillin 300 mg/kg/24h IV q4–6h; Ceftriaxone 100 mg/kg/24h IV/IM q12h
- HACEK organisms
- Endocarditis caused by Haemophilus, Aggregatibacter (Actinobacillus), Cardiobacterium, Eikenella corrodens, or Kingella
- Preferred regimen : Ceftriaxone sodium 2 g/24h IV/IM in 1 dose for 4 weeks OR Ampicillin 12 g/24h IV q6h for 4 weeks OR Ciprofloxacin 1000 mg/24h PO or 800 mg/24h IV q12h for 4 weeks
- Pediatric dose: Ceftriaxone 100 mg/kg/24h IV/IM once daily; Ampicillin-sulbactam 300 mg/kg/24h IV divided into 4 or 6 equally divided doses; Ciprofloxacin 20–30 mg/kg/24h IV/PO q12h
- Staphylococcus
- Native valve endocarditis caused by oxacillin-susceptible staphylococci
- Preferred regimen (1): Nafcillin or Oxacillin 12 g/24h IV q4–6h for 6 weeks ± Gentamicin 3 mg/kg/24h IV/IM q8–12h for 3–5 days
- Preferred regimen (2): Cefazolin 6 g/24h IV q8h for 6 weeks ± Gentamicin 3 mg/kg/24h IV/IM q8–12h for 3–5 days
- Pediatric dose: Nafcillin or Oxacillin 200 mg/kg/24h IV q4–6h; Gentamicin 3 mg/kg/24h IV/IM q8h; Cefazolin 100 mg/kg/24h IV q8h; Gentamicin 3 mg/kg/24h IV/IM q8h
- Native valve endocarditis caused by oxacillin-resistant staphylococci
- Preferred regimen: Vancomycin 30 mg/kg/24h IV q12h for 6 weeks
- Pediatric dose: Vancomycin 40 mg/kg/24h IV q8–12h
- Prosthetic valve endocarditis caused by oxacillin-susceptible staphylococci
- Preferred regimen: Nafcillin or Oxacillin 12 g/24h IV q4h for ≥ 6 weeks AND Rifampin 900 mg/24h IV/PO q8h for ≥ 6 weeks AND Gentamicin 3 mg/kg/24h IV/IM q8–12h for 2 weeks
- Pediatric dose: Nafcillin or Oxacillin 200 mg/kg/24h IV q4–6h; Rifampin 20 mg/kg/24h IV/PO q8h; Gentamicin 3 mg/kg/24h IV/IM q8h
- Prosthetic valve endocarditis caused by oxacillin-resistant staphylococci
- Preferred regimen: Vancomycin 30 mg/kg 24 h q12h for ≥ 6 weeks AND Rifampin 900 mg/24h IV/PO q8h for ≥ 6 weeks AND Gentamicin 3 mg/kg/24h IV/IM q8–12h for 2 weeks
- Pediatric dose: Vancomycin 40 mg/kg/24h IV q8–12h; Rifampin 20 mg/kg/24h IV/PO q8h (up to adult dose); Gentamicin 3 mg/kg/24h IV or IM q8h
- Viridans group streptococci and Streptococcus bovis
- Native valve endocarditis caused by highly penicillin-susceptible viridans group streptococci and Streptococcus bovis (MIC ≤ 0.12 μg/mL)
- Preferred regimen: Penicillin G 12–18 million U/24h IV either continuously or q4–6h for 4 weeks OR Ceftriaxone 2 g/24h IV/IM in 1 dose for 4 weeks
- Alternative regimen (1): (Penicillin G 12–18 million U/24h IV either continuously or q4h for 2 weeks OR Ceftriaxone 2 g/24h IV/IM in 1 dose for 2 weeks) AND Gentamicin 3 mg/kg/24h IV/IM in 1 dose for 2 weeks
- Alternative regimen (2): Vancomycin 30 mg/kg/24h IV q12h not to exceed 2 g/24h for 4 weeks
- Pediatric dose: Penicillin G 200,000 U/kg/24h IV q4–6h; Ceftriaxone 100 mg/kg/24h IV/IM in 1 dose; Gentamicin 3 mg/kg/24h IV/IM in 1 dose or q8h; Vancomycin 40 mg/kg/24h IV q8–12h
- Native valve endocarditis caused by relatively penicillin-resistant viridans group streptococci and Streptococcus bovis (MIC > 0.12 to ≤ 0.5 μg/mL)
- Preferred regimen (1): (Penicillin G 24 million U/24h IV either continuously or q4–6h for 4 weeks OR Ceftriaxone 2 g/24h IV/IM in 1 dose for 4 weeks) AND Gentamicin 3 mg/kg/24h IV/IM in 1 dose for 2 weeks
- Preferred regimen (2): Vancomycin 30 mg/kg/24h IV q12h not to exceed 2 g/24h for 4 weeks
- Pediatric dose: Penicillin G 200,000 U/kg/24h IV q4–6h; Ceftriaxone 100 mg/kg/24h IV/IM in 1 dose; Gentamicin 3 mg/kg/24h IV/IM in 1 dose or q8h; Vancomycin 40 mg/kg/24h IV q8–12h
- Prosthetic valve endocarditis caused by highly penicillin-susceptible viridans group streptococci and Streptococcus bovis (MIC ≤ 0.12 μg/mL)
- Preferred regimen (1): (Penicillin G 24 million U/24h IV either continuously or q4–6h for 6 weeks OR Ceftriaxone 2 g/24h IV/IM in 1 dose for 6 weeks) ± Gentamicin 3 mg/kg/24h IV/IM in 1 dose for 2 weeks
- Preferred regimen (2): Vancomycin 30 mg/kg/24h IV q12h not to exceed 2 g/24h for 6 weeks
- Pediatric dose: Penicillin G 200,000 U/kg/24h IV q4–6h; Ceftriaxone 100 mg/kg/24h IV/IM in 1 dose; Gentamicin 3 mg/kg/24h IV/IM in 1 dose or q8h; Vancomycin 40 mg/kg/24h IV q8–12h
- Prosthetic valve endocarditis caused by relatively penicillin-resistant viridans group streptococci and Streptococcus bovis (MIC > 0.12 μg/mL)
- Preferred regimen (1): (Penicillin G 24 million U/24h IV either continuously or q4–6h for 6 weeks OR Ceftriaxone 2 g/24h IV/IM in 1 dose for 6 weeks) AND Gentamicin 3 mg/kg/24h IV/IM in 1 dose for 2 weeks
- Preferred regimen (2): Vancomycin 30 mg/kg/24h IV q12h not to exceed 2 g/24h for 6 weeks
- Pediatric dose: Penicillin G 200,000 U/kg/24h IV q4–6h; Ceftriaxone 100 mg/kg/24h IV/IM in 1 dose; Gentamicin 3 mg/kg/24h IV/IM in 1 dose or q8h; Vancomycin 40 mg/kg/24h IV q8–12h
# Endocarditis, prophylaxis
- Antibiotic Prophylactic Regimens for Dental Procedures
- Oral regimen
- Preferred regimen: Amoxicillin 2 g single dose 30-60 minutes before procedure.
- Pediatric dose: Amoxicillin 50 mg/kg single dose 30-60 minutes before procedure.
- Unable to take oral medication
- Preferred regimen: Ampicillin 2 g IM or IV single dose 30-60 minutes before procedure OR Cefazolin 1 g IM or IV single dose 30-60 minutes before procedure OR Ceftriaxone 1 g IM or IV single dose 30-60 minutes before procedure.
- Pediatric dose: Ampicillin 50 mg/kg; Cefazolin 50 mg/kg; Ceftriaxone 50 mg/kg
- Allergic to penicillins or ampicillin— Oral regimen
- Preferred regimen: Cephalexin 2 g single dose 30-60 minutes before procedure OR Clindamycin 600 mg single dose 30-60 minutes before procedure OR Azithromycin 500 mg single dose 30-60 minutes before procedure OR Clarithromycin 500 mg single dose 30-60 minutes before procedure.
- Pediatric dose: Cephalexin 50 mg/kg single; Clindamycin 20 mg/kg; Azithromycin 15 mg/kg OR Clarithromycin 15 mg/kg.
- Allergic to penicillins or ampicillin and unable to take oral medication
- Preferred regimen: Cefazolin 1 g IM or IV single dose 30-60 minutes before procedure OR Ceftriaxone 1 g IM or IV single dose 30-60 minutes before procedure OR Clindamycin 600 mg IM or IV.
- Pediatric dose: Cefazolin 50 mg/kg IM or IV OR Ceftriaxone 20 mg/kg IM or IV.
- Gastrointestinal/Genitourinary Procedures
- Antibiotic prophylaxis solely to prevent IE is no longer recommended for patients who undergo a GI or GU tract procedure.
- Regimens for Respiratory Tract Procedures
- Oral regimen
- Preferred regimen: Amoxicillin 2 g single dose 30-60 minutes before procedure.
- Pediatric dose: Amoxicillin 50 mg/kg single dose 30-60 minutes before procedure.
- Unable to take oral medication
- Preferred regimen: Ampicillin 2 g IM or IV OR Cefazolin 1 g IM or IV OR Ceftriaxone 1 g IM or IV.
- Pediatric dose: Ampicillin 50 mg/kg; Cefazolin 50 mg/kg; Ceftriaxone 50 mg/kg.
- Allergic to penicillins or ampicillin— Oral regimen
- Preferred regimen: Cephalexin 2 g single dose 30-60 minutes before procedure OR Clindamycin 600 mg single dose 30-60 minutes before procedure OR Azithromycin 500 mg single dose 30-60 minutes before procedure OR Clarithromycin 500 mg single dose 30-60 minutes before procedure.
- Pediatric dose: Cephalexin 50 mg/kg single; Clindamycin 20 mg/kg; Azithromycin or Clarithromycin 15 mg/kg.
- Allergic to penicillins or ampicillin and unable to take oral medication
- Preferred regimen: Cefazolin 1 g OR ceftriaxone 1 g IM or IV single dose 30-60 minutes before procedure OR Clindamycin 600 mg IM or IV.
- Pediatric dose: Cefazolin 50 mg/kg IM or IV OR Ceftriaxone 20 mg/kg IM or IV.
- Regimens for Procedures on Infected Skin, Skin Structure, or Musculoskeletal Tissue
- Patients who undergo a surgical procedure that involves infected skin, skin structure, or musculoskeletal tissue, it may be reasonable that the therapeutic regimen administered for treatment of the infection contain an agent active against staphylococci and -hemolytic streptococci, such as an antistaphylococcal penicillin or a cephalosporin.
- ↑ Baddour, Larry M.; Wilson, Walter R.; Bayer, Arnold S.; Fowler, Vance G.; Bolger, Ann F.; Levison, Matthew E.; Ferrieri, Patricia; Gerber, Michael A.; Tani, Lloyd Y.; Gewitz, Michael H.; Tong, David C.; Steckelberg, James M.; Baltimore, Robert S.; Shulman, Stanford T.; Burns, Jane C.; Falace, Donald A.; Newburger, Jane W.; Pallasch, Thomas J.; Takahashi, Masato; Taubert, Kathryn A.; Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease; Council on Cardiovascular Disease in the Young; Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia; American Heart Association; Infectious Diseases Society of America (2005-06-14). "Infective endocarditis: diagnosis, antimicrobial therapy, and management of complications: a statement for healthcare professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, and the Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia, American Heart Association: endorsed by the Infectious Diseases Society of America". Circulation. 111 (23): –394-434. doi:10.1161/CIRCULATIONAHA.105.165564. ISSN 1524-4539. PMID 15956145.CS1 maint: Multiple names: authors list (link) .mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ Nishimura RA, Otto CM, Bonow RO, Carabello BA, Erwin JP, Guyton RA; et al. (2014). "2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines". Circulation. 129 (23): 2440–92. doi:10.1161/CIR.0000000000000029. PMID 24589852.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
- ↑ Vahanian A, Alfieri O, Andreotti F, Antunes MJ, Baron-Esquivias G, Baumgartner H; et al. (2013). "". G Ital Cardiol (Rome). 14 (3): 167–214. doi:10.1714/1234.13659. PMID 23474606.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
- ↑ Wilson W, Taubert KA, Gewitz M, Lockhart PB, Baddour LM, Levison M; et al. (2007). "Prevention of infective endocarditis: guidelines from the American Heart Association: a guideline from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee, Council on Cardiovascular Disease in the Young, and the Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and the Quality of Care and Outcomes Research Interdisciplinary Working Group". Circulation. 116 (15): 1736–54. doi:10.1161/CIRCULATIONAHA.106.183095. PMID 17446442.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link) | Sandbox IE
### Endocarditis, treatment ⇧ Return to Top ⇧
- Infective endocarditis[1]
- Culture-negative endocarditis
- Culture-negative, native valve endocarditis
- Preferred regimen: Ampicillin-sulbactam 12 g/24h IV q6h 4–6 weeks AND Gentamicin 3 mg/kg/24h IV/IM q8h for 4–6 weeks
- Alternative regimen: Vancomycin 30 mg/kg/24h IV q12h for 4–6 weeks AND Gentamicin 3 mg/kg/24h IV/IM q8h for 4–6 weeks AND Ciprofloxacin 1000 mg/24h PO or 800 mg/24h IV q12h for 4–6 weeks
- Pediatric dose: Ampicillin-sulbactam 300 mg/kg/24h IV q4–6h; Gentamicin 3 mg/kg/24h IV/IM q8h; Vancomycin 40 mg/kg/24h q8–12h; Ciprofloxacin 20–30 mg/kg/24h IV/PO q12h
- Culture-negative, prosthetic valve endocarditis (early, ≤ 1 year)
- Preferred regimen : Vancomycin 30 mg/kg/24h IV q12h for 6 weeks AND Gentamicin 3 mg/kg/24h IV/IM q8h for 2 weeks AND Cefepime 6 g/24h IV q8h for 6 weeks AND Rifampin 900 mg/24h PO/IV q8h for 6 weeks
- Pediatric dose: Vancomycin 40 mg/kg/24h IV q8–12h; Gentamicin 3 mg/kg/24h IV/IM q8h; Cefepime 150 mg/kg/24h IV q8h; Rifampin 20 mg/kg/24h PO/IV q8h
- Culture-negative, prosthetic valve endocarditis (late, > 1 year)
- Preferred regimen: Ampicillin-sulbactam 12 g/24h IV q6h 6 weeks AND Gentamicin 3 mg/kg/24h IV/IM q8h for 6 weeks
- Alternative regimen: Vancomycin 30 mg/kg/24h IV q12h for 4–6 weeks AND Gentamicin 3 mg/kg/24h IV/IM q8h for 6 weeks AND Ciprofloxacin 1000 mg/24h PO or 800 mg/24h IV q12h for 6 weeks
- Pediatric dose: Ampicillin-sulbactam 300 mg/kg/24h IV q4h; Gentamicin 3 mg/kg/24h IV/IM q8h; Vancomycin 40 mg/kg/24h q8–12h; Ciprofloxacin 20–30 mg/kg/24h IV/PO q12h
- Culture-negative, prosthetic valve endocarditis (early, ≤ 1 year)
- Preferred regimen: Ampicillin-sulbactam 12 g/24h IV q6h 4–6 weeks AND Gentamicin 3 mg/kg/24h IV/IM q8h for 4–6 weeks AND Rifampin 900 mg/24h PO/IV q8h for 6 weeks
- Alternative regimen: Vancomycin 30 mg/kg/24h IV q12h for 4–6 weeks AND Gentamicin 3 mg/kg/24h IV/IM q8h for 4–6 weeks AND Ciprofloxacin 1000 mg/24h PO or 800 mg/24h IV q12h for 4–6 weeks AND Rifampin 900 mg/24h PO/IV q8h for 6 weeks
- Pediatric dose: Ampicillin-sulbactam 300 mg/kg/24h IV q4–6h; Gentamicin 3 mg/kg/24h IV/IM q8h; Vancomycin 40 mg/kg/24h IV q8–12h; Cefepime 150 mg/kg/24h IV q8h; Rifampin 20 mg/kg/24h PO/IV q8h
- Pathogen-directed antimicrobial therapy
- Bartonella
- Suspected Bartonella endocarditis
- Preferred regimen : Ceftriaxone sodium 2 g/24h IV/IM in 1 dose for 6 weeks AND Gentamicin 3 mg/kg/24h IV/IM q8h for 2 weeks ± Doxycycline 200 mg/kg/24h IV/PO q12h for 6 weeks
- Pediatric dose: Ceftriaxone 100 mg/kg/24h IV/IM once daily; Gentamicin 3 mg/kg/24h IV/IM q8h; Doxycycline 2–4 mg/kg/24h IV/PO q12h; Rifampin 20 mg/kg/24h PO/IV q12h
- Documented Bartonella endocarditis
- Preferred regimen: Doxycycline 200 mg/24h IV or PO q12h for 6 weeks AND Gentamicin 3 mg/kg/24h IV/IM q8h for 2 weeks
- Pediatric dose: Ceftriaxone 100 mg/kg/24h IV/IM once daily; Gentamicin 3 mg/kg/24h IV/IM q8h; Doxycycline 2–4 mg/kg/24h IV/PO q12h; Rifampin 20 mg/kg/24h PO/IV q12h
- Enterococcus
- Endocarditis caused by enterococcal strains susceptible to penicillin, gentamicin, and vancomycin
- Preferred regimen : Ampicillin 12 g/24h IV q4h for 4–6 weeks OR Penicillin G 18–30 million U/24h IV either continuously or q4h for 4–6 weeks AND Gentamicin 3 mg/kg/24h IV/IM q8h for 4–6weeks
- Alternative regimen : Vancomycin 30 mg/kg/24h IV q12h for 6 weeks AND Gentamicin 3 mg/kg/24h IV/IM q8h for 6 weeks
- Pediatric dose: Vancomycin 40 mg/kg/24h IV q8–12h; Gentamicin 3 mg/kg/24h IV/IM q8h
- Endocarditis caused by enterococcal strains susceptible to penicillin, streptomycin, and vancomycin and resistant to gentamicin
- Preferred regimen : Ampicillin 12 g/24h IV q4h for 4–6 weeks OR Penicillin G 24 million U/24h IV continuously or q4h for 4–6 weeks AND Streptomycin 15 mg/kg/24h IV/IM q12h for 4–6 weeks
- Alternative regimen : Vancomycin 30 mg/kg/24h IV q12h for 6 weeks AND Streptomycin 15 mg/kg/24h IV/IM q12h for 6 weeks
- Pediatric dose: Ampicillin 300 mg/kg/24h IV q4–6h; Penicillin 300 000 U/kg/24h IV q4–6h; Streptomycin 20–30 mg/kg/24h IV/IM q12h; Vancomycin 40 mg/kg/24h IV q8–12h; Streptomycin 20–30 mg/kg/24h IV/IM q12h
- Endocarditis caused by enterococcal strains resistant to penicillin and susceptible to aminoglycoside and vancomycin
- β-Lactamase–producing strain
- Preferred regimen: Ampicillin-sulbactam 12 g/24h IV q6h for 6 weeks AND Gentamicin 3 mg/kg/24h IV/IM q8h for 6 weeks
- Alternative regimen : Vancomycin 30 mg/kg/24h IV q12h for 6 weeks
- Pediatric dose: Ampicillin-sulbactam 300 mg/kg/24h IV q6h; Gentamicin 3 mg/kg/24h IV/IM q8h
- Intrinsic penicillin resistance
- Preferred regimen: Vancomycin 30 mg/kg/24h IV q12h for 6 weeks AND Gentamicin 3 mg/kg/24h IV/IM q8h for 6 weeks
- Pediatric dose: Vancomycin 40 mg/kg/24h IV q8–12h; Gentamicin 3 mg/kg/24h IV/IM q8h
- Endocarditis caused by enterococcal strains resistant to penicillin, gentamicin, and vancomycin
- Enterococcus faecium
- Preferred regimen : Linezolid 1200 mg/24h IV/PO q12h for ≥ 8 weeks OR Quinupristin-Dalfopristin 22.5 mg/kg/24h IV q8h for 8 weeks
- Enterococcus faecalis
- Preferred regimen : Imipenem/cilastatin 2 g/24h IV q6h for ≥ 8 weeks AND Ampicillin 12 g/24h IV q4h for ≥ 8 weeks OR Ceftriaxone sodium 4 g/24h IV/IM q12h for ≥ 8 weeks AND Ampicillin 12 g/24h IV q4h for ≥ 8 weeks
- Pediatric dose: Linezolid 30 mg/kg/24h IV/PO q8h; Quinupristin-Dalfopristin 22.5 mg/kg/24h IV q8h; Imipenem/cilastatin 60–100 mg/kg/24h IV q6h; Ampicillin 300 mg/kg/24h IV q4–6h; Ceftriaxone 100 mg/kg/24h IV/IM q12h
- HACEK organisms
- Endocarditis caused by Haemophilus, Aggregatibacter (Actinobacillus), Cardiobacterium, Eikenella corrodens, or Kingella
- Preferred regimen : Ceftriaxone sodium 2 g/24h IV/IM in 1 dose for 4 weeks OR Ampicillin 12 g/24h IV q6h for 4 weeks OR Ciprofloxacin 1000 mg/24h PO or 800 mg/24h IV q12h for 4 weeks
- Pediatric dose: Ceftriaxone 100 mg/kg/24h IV/IM once daily; Ampicillin-sulbactam 300 mg/kg/24h IV divided into 4 or 6 equally divided doses; Ciprofloxacin 20–30 mg/kg/24h IV/PO q12h
- Staphylococcus
- Native valve endocarditis caused by oxacillin-susceptible staphylococci
- Preferred regimen (1): Nafcillin or Oxacillin 12 g/24h IV q4–6h for 6 weeks ± Gentamicin 3 mg/kg/24h IV/IM q8–12h for 3–5 days
- Preferred regimen (2): Cefazolin 6 g/24h IV q8h for 6 weeks ± Gentamicin 3 mg/kg/24h IV/IM q8–12h for 3–5 days
- Pediatric dose: Nafcillin or Oxacillin 200 mg/kg/24h IV q4–6h; Gentamicin 3 mg/kg/24h IV/IM q8h; Cefazolin 100 mg/kg/24h IV q8h; Gentamicin 3 mg/kg/24h IV/IM q8h
- Native valve endocarditis caused by oxacillin-resistant staphylococci
- Preferred regimen: Vancomycin 30 mg/kg/24h IV q12h for 6 weeks
- Pediatric dose: Vancomycin 40 mg/kg/24h IV q8–12h
- Prosthetic valve endocarditis caused by oxacillin-susceptible staphylococci
- Preferred regimen: Nafcillin or Oxacillin 12 g/24h IV q4h for ≥ 6 weeks AND Rifampin 900 mg/24h IV/PO q8h for ≥ 6 weeks AND Gentamicin 3 mg/kg/24h IV/IM q8–12h for 2 weeks
- Pediatric dose: Nafcillin or Oxacillin 200 mg/kg/24h IV q4–6h; Rifampin 20 mg/kg/24h IV/PO q8h; Gentamicin 3 mg/kg/24h IV/IM q8h
- Prosthetic valve endocarditis caused by oxacillin-resistant staphylococci
- Preferred regimen: Vancomycin 30 mg/kg 24 h q12h for ≥ 6 weeks AND Rifampin 900 mg/24h IV/PO q8h for ≥ 6 weeks AND Gentamicin 3 mg/kg/24h IV/IM q8–12h for 2 weeks
- Pediatric dose: Vancomycin 40 mg/kg/24h IV q8–12h; Rifampin 20 mg/kg/24h IV/PO q8h (up to adult dose); Gentamicin 3 mg/kg/24h IV or IM q8h
- Viridans group streptococci and Streptococcus bovis
- Native valve endocarditis caused by highly penicillin-susceptible viridans group streptococci and Streptococcus bovis (MIC ≤ 0.12 μg/mL)
- Preferred regimen: Penicillin G 12–18 million U/24h IV either continuously or q4–6h for 4 weeks OR Ceftriaxone 2 g/24h IV/IM in 1 dose for 4 weeks
- Alternative regimen (1): (Penicillin G 12–18 million U/24h IV either continuously or q4h for 2 weeks OR Ceftriaxone 2 g/24h IV/IM in 1 dose for 2 weeks) AND Gentamicin 3 mg/kg/24h IV/IM in 1 dose for 2 weeks
- Alternative regimen (2): Vancomycin 30 mg/kg/24h IV q12h not to exceed 2 g/24h for 4 weeks
- Pediatric dose: Penicillin G 200,000 U/kg/24h IV q4–6h; Ceftriaxone 100 mg/kg/24h IV/IM in 1 dose; Gentamicin 3 mg/kg/24h IV/IM in 1 dose or q8h; Vancomycin 40 mg/kg/24h IV q8–12h
- Native valve endocarditis caused by relatively penicillin-resistant viridans group streptococci and Streptococcus bovis (MIC > 0.12 to ≤ 0.5 μg/mL)
- Preferred regimen (1): (Penicillin G 24 million U/24h IV either continuously or q4–6h for 4 weeks OR Ceftriaxone 2 g/24h IV/IM in 1 dose for 4 weeks) AND Gentamicin 3 mg/kg/24h IV/IM in 1 dose for 2 weeks
- Preferred regimen (2): Vancomycin 30 mg/kg/24h IV q12h not to exceed 2 g/24h for 4 weeks
- Pediatric dose: Penicillin G 200,000 U/kg/24h IV q4–6h; Ceftriaxone 100 mg/kg/24h IV/IM in 1 dose; Gentamicin 3 mg/kg/24h IV/IM in 1 dose or q8h; Vancomycin 40 mg/kg/24h IV q8–12h
- Prosthetic valve endocarditis caused by highly penicillin-susceptible viridans group streptococci and Streptococcus bovis (MIC ≤ 0.12 μg/mL)
- Preferred regimen (1): (Penicillin G 24 million U/24h IV either continuously or q4–6h for 6 weeks OR Ceftriaxone 2 g/24h IV/IM in 1 dose for 6 weeks) ± Gentamicin 3 mg/kg/24h IV/IM in 1 dose for 2 weeks
- Preferred regimen (2): Vancomycin 30 mg/kg/24h IV q12h not to exceed 2 g/24h for 6 weeks
- Pediatric dose: Penicillin G 200,000 U/kg/24h IV q4–6h; Ceftriaxone 100 mg/kg/24h IV/IM in 1 dose; Gentamicin 3 mg/kg/24h IV/IM in 1 dose or q8h; Vancomycin 40 mg/kg/24h IV q8–12h
- Prosthetic valve endocarditis caused by relatively penicillin-resistant viridans group streptococci and Streptococcus bovis (MIC > 0.12 μg/mL)
- Preferred regimen (1): (Penicillin G 24 million U/24h IV either continuously or q4–6h for 6 weeks OR Ceftriaxone 2 g/24h IV/IM in 1 dose for 6 weeks) AND Gentamicin 3 mg/kg/24h IV/IM in 1 dose for 2 weeks
- Preferred regimen (2): Vancomycin 30 mg/kg/24h IV q12h not to exceed 2 g/24h for 6 weeks
- Pediatric dose: Penicillin G 200,000 U/kg/24h IV q4–6h; Ceftriaxone 100 mg/kg/24h IV/IM in 1 dose; Gentamicin 3 mg/kg/24h IV/IM in 1 dose or q8h; Vancomycin 40 mg/kg/24h IV q8–12h
## Endocarditis, prophylaxis
- Antibiotic Prophylactic Regimens for Dental Procedures[2][3][4]
- Oral regimen
- Preferred regimen: Amoxicillin 2 g single dose 30-60 minutes before procedure.
- Pediatric dose: Amoxicillin 50 mg/kg single dose 30-60 minutes before procedure.
- Unable to take oral medication
- Preferred regimen: Ampicillin 2 g IM or IV single dose 30-60 minutes before procedure OR Cefazolin 1 g IM or IV single dose 30-60 minutes before procedure OR Ceftriaxone 1 g IM or IV single dose 30-60 minutes before procedure.
- Pediatric dose: Ampicillin 50 mg/kg; Cefazolin 50 mg/kg; Ceftriaxone 50 mg/kg
- Allergic to penicillins or ampicillin— Oral regimen
- Preferred regimen: Cephalexin 2 g single dose 30-60 minutes before procedure OR Clindamycin 600 mg single dose 30-60 minutes before procedure OR Azithromycin 500 mg single dose 30-60 minutes before procedure OR Clarithromycin 500 mg single dose 30-60 minutes before procedure.
- Pediatric dose: Cephalexin 50 mg/kg single; Clindamycin 20 mg/kg; Azithromycin 15 mg/kg OR Clarithromycin 15 mg/kg.
- Allergic to penicillins or ampicillin and unable to take oral medication
- Preferred regimen: Cefazolin 1 g IM or IV single dose 30-60 minutes before procedure OR Ceftriaxone 1 g IM or IV single dose 30-60 minutes before procedure OR Clindamycin 600 mg IM or IV.
- Pediatric dose: Cefazolin 50 mg/kg IM or IV OR Ceftriaxone 20 mg/kg IM or IV.
- Gastrointestinal/Genitourinary Procedures
- Antibiotic prophylaxis solely to prevent IE is no longer recommended for patients who undergo a GI or GU tract procedure.
- Regimens for Respiratory Tract Procedures
- Oral regimen
- Preferred regimen: Amoxicillin 2 g single dose 30-60 minutes before procedure.
- Pediatric dose: Amoxicillin 50 mg/kg single dose 30-60 minutes before procedure.
- Unable to take oral medication
- Preferred regimen: Ampicillin 2 g IM or IV OR Cefazolin 1 g IM or IV OR Ceftriaxone 1 g IM or IV.
- Pediatric dose: Ampicillin 50 mg/kg; Cefazolin 50 mg/kg; Ceftriaxone 50 mg/kg.
- Allergic to penicillins or ampicillin— Oral regimen
- Preferred regimen: Cephalexin 2 g single dose 30-60 minutes before procedure OR Clindamycin 600 mg single dose 30-60 minutes before procedure OR Azithromycin 500 mg single dose 30-60 minutes before procedure OR Clarithromycin 500 mg single dose 30-60 minutes before procedure.
- Pediatric dose: Cephalexin 50 mg/kg single; Clindamycin 20 mg/kg; Azithromycin or Clarithromycin 15 mg/kg.
- Allergic to penicillins or ampicillin and unable to take oral medication
- Preferred regimen: Cefazolin 1 g OR ceftriaxone 1 g IM or IV single dose 30-60 minutes before procedure OR Clindamycin 600 mg IM or IV.
- Pediatric dose: Cefazolin 50 mg/kg IM or IV OR Ceftriaxone 20 mg/kg IM or IV.
- Regimens for Procedures on Infected Skin, Skin Structure, or Musculoskeletal Tissue
- Patients who undergo a surgical procedure that involves infected skin, skin structure, or musculoskeletal tissue, it may be reasonable that the therapeutic regimen administered for treatment of the infection contain an agent active against staphylococci and -hemolytic streptococci, such as an antistaphylococcal penicillin or a cephalosporin.
- ↑ Baddour, Larry M.; Wilson, Walter R.; Bayer, Arnold S.; Fowler, Vance G.; Bolger, Ann F.; Levison, Matthew E.; Ferrieri, Patricia; Gerber, Michael A.; Tani, Lloyd Y.; Gewitz, Michael H.; Tong, David C.; Steckelberg, James M.; Baltimore, Robert S.; Shulman, Stanford T.; Burns, Jane C.; Falace, Donald A.; Newburger, Jane W.; Pallasch, Thomas J.; Takahashi, Masato; Taubert, Kathryn A.; Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease; Council on Cardiovascular Disease in the Young; Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia; American Heart Association; Infectious Diseases Society of America (2005-06-14). "Infective endocarditis: diagnosis, antimicrobial therapy, and management of complications: a statement for healthcare professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, and the Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia, American Heart Association: endorsed by the Infectious Diseases Society of America". Circulation. 111 (23): –394-434. doi:10.1161/CIRCULATIONAHA.105.165564. ISSN 1524-4539. PMID 15956145.CS1 maint: Multiple names: authors list (link) .mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ Nishimura RA, Otto CM, Bonow RO, Carabello BA, Erwin JP, Guyton RA; et al. (2014). "2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines". Circulation. 129 (23): 2440–92. doi:10.1161/CIR.0000000000000029. PMID 24589852.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
- ↑ Vahanian A, Alfieri O, Andreotti F, Antunes MJ, Baron-Esquivias G, Baumgartner H; et al. (2013). "[Guidelines on the management of valvular heart disease (version 2012). The Joint Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS)]". G Ital Cardiol (Rome). 14 (3): 167–214. doi:10.1714/1234.13659. PMID 23474606.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
- ↑ Wilson W, Taubert KA, Gewitz M, Lockhart PB, Baddour LM, Levison M; et al. (2007). "Prevention of infective endocarditis: guidelines from the American Heart Association: a guideline from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee, Council on Cardiovascular Disease in the Young, and the Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and the Quality of Care and Outcomes Research Interdisciplinary Working Group". Circulation. 116 (15): 1736–54. doi:10.1161/CIRCULATIONAHA.106.183095. PMID 17446442.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link) | https://www.wikidoc.org/index.php/Sandbox_IE | |
a8c12442bd4756b21dc6f49802faf0821b000361 | wikidoc | Sandbox JA | Sandbox JA
# Test
# Parenchymal lesions
- Tuberculoma
- Single or multiple lesions of > 0.5 cm
- May occur in primary or secundary TB
- Main finding on Chest X-ray in 5% cases of secondary TB
- Results from the surrounding of M. tuberculosis with inflammatory or connective tissue.
- The center of the tuberculoma is often necrotic
- Satellite lesions (80%)
- Nodular or diffused calcifications in 20-30% cases
- Thin-walled cavity
- Present in active and inactive disease
- May regress after treatment
- Air-filled sect may persist
- May be misidentified as an emphysematous bulla or pneumatocelle.
- Cicatrization:
- Common in secondary TB
- Marked fibrosis in ≤40% of secondary TB cases, which may present as:
- Upper love atelectasis
- Compensatory hyperinflation of the lower lobe
- Hilar retraction
- Mediastinal shift
- Unspecific X-Ray findings:
- Parenchymal bands
- Fibrotic cavities
- Fibrotic nodules
- Traction bronchiectasis
- Lung Destruction:
- Common in end-stage of TB
- Involvement of the airways and parenchyma
- May follow primary TB or secondary TB
- Spreads across the lung with cavitation and fibrosis
- Concomitant infection with bacteria or bacteria may occur
- Complicates assessment of TB activity in the lung with the X-ray.
- Aspergilloma
- Mass of hyphae, cell debris and mucus, commonly located in a cavity or bronchus
- Previous history of chronic cavitary TB in 25-55% of cases presenting with aspergilloma
- Frequently courses with hemoptysis (50-90%)
- X-ray shows a mobile mass ringed by an air shadow
- CT shows a mobile mass, generally interspaced with air shadows
- May be calcified
- Bronchogenic carcinoma
- May be misinterpreted as TB progression
- Scar formation in TB may lead to carcinoma
- May cause reactivation of TB
# Airway Lesions
# Differential Diagnosis of Infectious Diarrhea
Acute inflammatory diarrhea may be caused by different pathogens. Bellow is a table describing some of these pathogens in terms of transmission and symptoms: | Sandbox JA
# Test
# Parenchymal lesions
- Tuberculoma
- Single or multiple lesions of > 0.5 cm
- May occur in primary or secundary TB
- Main finding on Chest X-ray in 5% cases of secondary TB[1]
- Results from the surrounding of M. tuberculosis with inflammatory or connective tissue.[2][3][1]
- The center of the tuberculoma is often necrotic
- Satellite lesions (80%)
- Nodular or diffused calcifications in 20-30% cases[2]
- Thin-walled cavity
- Present in active and inactive disease
- May regress after treatment
- Air-filled sect may persist[4]
- May be misidentified as an emphysematous bulla or pneumatocelle.
- Cicatrization:
- Common in secondary TB
- Marked fibrosis in ≤40% of secondary TB cases, which may present as:
- Upper love atelectasis
- Compensatory hyperinflation of the lower lobe
- Hilar retraction
- Mediastinal shift
- Unspecific X-Ray findings:[5]
- Parenchymal bands
- Fibrotic cavities
- Fibrotic nodules
- Traction bronchiectasis
- Lung Destruction:[5]
- Common in end-stage of TB
- Involvement of the airways and parenchyma
- May follow primary TB or secondary TB
- Spreads across the lung with cavitation and fibrosis[2]
- Concomitant infection with bacteria or bacteria may occur
- Complicates assessment of TB activity in the lung with the X-ray.
- Aspergilloma
- Mass of hyphae, cell debris and mucus, commonly located in a cavity or bronchus[6][7][8]
- Previous history of chronic cavitary TB in 25-55% of cases presenting with aspergilloma
- Frequently courses with hemoptysis (50-90%)
- X-ray shows a mobile mass ringed by an air shadow
- CT shows a mobile mass, generally interspaced with air shadows
- May be calcified
- Bronchogenic carcinoma[5]
- May be misinterpreted as TB progression
- Scar formation in TB may lead to carcinoma
- May cause reactivation of TB[9][10]
# Airway Lesions
# Differential Diagnosis of Infectious Diarrhea
Acute inflammatory diarrhea may be caused by different pathogens. Bellow is a table describing some of these pathogens in terms of transmission and symptoms:[11][12] | https://www.wikidoc.org/index.php/Sandbox_JA | |
2d4119e89b237bf3af867664ad14f7c3de471e8b | wikidoc | Sandbox MC | Sandbox MC
# Overview
Alieh Bahjat,M.D.
Mitra Chitsazan, M.D.Allahyar
Patients with usually appear . Physical examination of patients with is usually remarkable for , , and .
OR
Common physical examination findings of include , , and .
OR
The presence of on physical examination is diagnostic of .
OR
The presence of on physical examination is highly suggestive of .
File:Snowman-sign-1.jpg
# Physical Examination
Physical examination of ,,,,,,,,, with is usually normal.
OR
Physical examination of patients with is usually remarkable for , , and .
OR
The presence of on physical examination is diagnostic of .
OR
The presence of on physical examination is highly suggestive of .
## Appearance of the Patient
- Patients with PE usually appear normal/toxic.
## Vital Signs
- High-grade
- Tachypnea / bradypnea
- Weak/bounding pulse / pulsus alternans / paradoxical pulse / asymmetric pulse
## Skin
- Cyanosis
## HEENT
- dilated pupils
- icteus
## Neck
- Neck examination of patients with is usually normal.
OR
- Jugular venous distension
- Carotid bruits may be auscultated unilaterally/bilaterally using the bell/diaphragm of the otoscope
- Lymphadenopathy (describe location, size, tenderness, mobility, and symmetry)
- Thyromegaly / thyroid nodules
- Hepatojugular reflux
## Lungs
- Pulmonary examination of patients with is usually normal.
OR
- Asymmetric chest expansion OR decreased chest expansion
- Lungs are hyporesonant OR hyperresonant
- Fine/coarse crackles upon auscultation of the lung bases/apices unilaterally/bilaterally
- Rhonchi
- Vesicular breath sounds OR distant breath sounds
- Expiratory wheezing OR inspiratory wheezing with normal OR delayed expiratory phase
- Wheezing may be present
- Egophony present/absent
- Bronchophony present/absent
- Normal/reduced tactile fremitus
## Heart
- a low grade late systolic murmur
## Abdomen
- Abdominal examination of patients with PE is usually normal.
# =Back
## Genitourinary
- Genitourinary examination of patients with is usually normal.
OR
- A pelvic/adnexal mass may be palpated
- Inflamed mucosa
- Clear/(color), foul-smelling/odorless penile/vaginal discharge
## Neuromuscular
- Neuromuscular examination of patients with is usually normal.
OR
- Patient is usually oriented to persons, place, and time
- Altered mental status
- Glasgow coma scale is ___ / 15
- Clonus may be present
- Hyperreflexia / hyporeflexia / areflexia
- Positive (abnormal) Babinski / plantar reflex unilaterally/bilaterally
- Muscle rigidity
- Proximal/distal muscle weakness unilaterally/bilaterally
- ____ (finding) suggestive of cranial nerve ___ (roman numerical) deficit (e.g. Dilated pupils suggestive of CN III deficit)
- Unilateral/bilateral upper/lower extremity weakness
- Unilateral/bilateral sensory loss in the upper/lower extremity
- Positive straight leg raise test
- Abnormal gait (describe gait: e.g. ataxic (cerebellar) gait / steppage gait / waddling gait / choeiform gait / Parkinsonian gait / sensory gait)
- Positive/negative Trendelenburg sign
- Unilateral/bilateral tremor (describe tremor, e.g. at rest, pill-rolling)
- Normal finger-to-nose test / Dysmetria
- Absent/present dysdiadochokinesia (palm tapping test)
## Extremities
- Extremities examination of patients with is usually normal.
OR
- Clubbing
- Cyanosis
- Pitting/non-pitting edema of the upper/lower extremities
- Muscle atrophy
- Fasciculations in the upper/lower extremity | Sandbox MC
# Overview
Alieh Bahjat,M.D.
[1]Mitra Chitsazan, M.D.[2]Allahyar
[3]
Template:Mitra chitsazan
Patients with [disease name] usually appear [general appearance]. Physical examination of patients with [disease name] is usually remarkable for [finding 1], [finding 2], and [finding 3].
OR
Common physical examination findings of [disease name] include [finding 1], [finding 2], and [finding 3].
OR
The presence of [finding(s)] on physical examination is diagnostic of [disease name].
OR
The presence of [finding(s)] on physical examination is highly suggestive of [disease name].
File:Snowman-sign-1.jpg
# Physical Examination
Physical examination of ,,,,,,,,, with [disease name] is usually normal.
OR
Physical examination of patients with [disease name] is usually remarkable for [finding 1], [finding 2], and [finding 3].
OR
The presence of [finding(s)] on physical examination is diagnostic of [disease name].
OR
The presence of [finding(s)] on physical examination is highly suggestive of [disease name].
## Appearance of the Patient
- Patients with PE usually appear normal/toxic.
## Vital Signs
- High-grade
- Tachypnea / bradypnea
- Weak/bounding pulse / pulsus alternans / paradoxical pulse / asymmetric pulse
## Skin
- Cyanosis
## HEENT
- dilated pupils
- icteus
## Neck
- Neck examination of patients with [disease name] is usually normal.
OR
- Jugular venous distension
- Carotid bruits may be auscultated unilaterally/bilaterally using the bell/diaphragm of the otoscope
- Lymphadenopathy (describe location, size, tenderness, mobility, and symmetry)
- Thyromegaly / thyroid nodules
- Hepatojugular reflux
## Lungs
- Pulmonary examination of patients with [disease name] is usually normal.
OR
- Asymmetric chest expansion OR decreased chest expansion
- Lungs are hyporesonant OR hyperresonant
- Fine/coarse crackles upon auscultation of the lung bases/apices unilaterally/bilaterally
- Rhonchi
- Vesicular breath sounds OR distant breath sounds
- Expiratory wheezing OR inspiratory wheezing with normal OR delayed expiratory phase
- Wheezing may be present
- Egophony present/absent
- Bronchophony present/absent
- Normal/reduced tactile fremitus
## Heart
- a low grade late systolic murmur
## Abdomen
- Abdominal examination of patients with PE is usually normal.
# =Back
## Genitourinary
- Genitourinary examination of patients with [disease name] is usually normal.
OR
- A pelvic/adnexal mass may be palpated
- Inflamed mucosa
- Clear/(color), foul-smelling/odorless penile/vaginal discharge
## Neuromuscular
- Neuromuscular examination of patients with [disease name] is usually normal.
OR
- Patient is usually oriented to persons, place, and time
- Altered mental status
- Glasgow coma scale is ___ / 15
- Clonus may be present
- Hyperreflexia / hyporeflexia / areflexia
- Positive (abnormal) Babinski / plantar reflex unilaterally/bilaterally
- Muscle rigidity
- Proximal/distal muscle weakness unilaterally/bilaterally
- ____ (finding) suggestive of cranial nerve ___ (roman numerical) deficit (e.g. Dilated pupils suggestive of CN III deficit)
- Unilateral/bilateral upper/lower extremity weakness
- Unilateral/bilateral sensory loss in the upper/lower extremity
- Positive straight leg raise test
- Abnormal gait (describe gait: e.g. ataxic (cerebellar) gait / steppage gait / waddling gait / choeiform gait / Parkinsonian gait / sensory gait)
- Positive/negative Trendelenburg sign
- Unilateral/bilateral tremor (describe tremor, e.g. at rest, pill-rolling)
- Normal finger-to-nose test / Dysmetria
- Absent/present dysdiadochokinesia (palm tapping test)
## Extremities
- Extremities examination of patients with [disease name] is usually normal.
OR
- Clubbing
- Cyanosis
- Pitting/non-pitting edema of the upper/lower extremities
- Muscle atrophy
- Fasciculations in the upper/lower extremity | https://www.wikidoc.org/index.php/Sandbox_MC | |
70e405d4cb07b99e94881bc05453e34e4f874478 | wikidoc | Sandbox TA | Sandbox TA
# Overview
Acute bacterial meningitis is a medical emergency; commence empiric treatment after obtaining blood and/or cerebrospinal fluid (CSF) cultures if the possibility of bacterial meningitis becomes evident. Once a bacterial etiology has been identified on a CSF Gram stain, treatment regimen should be optimized accordingly. Further modifications may be required after the culture and/or in vitro susceptibility results are available. Neuroimaging (such as CT scan and MRI) or lumbar puncture must not delay antimicrobial therapy.
# Principles of Therapy for Bacterial Meningitis
### Factors Determining Antimicrobial Activity
- Factors determine the acitivity of antimicrobial agents include pharmacodynamics, pharmacokinetics, penetration into the CSF, and bactericidal activity within the CSF.
- Beta-lactams, aminoglycosides, glycopeptides, linezolid, and daptomycin are considered to have poor penetration into the CSF, while fluoroquinolones, chloramphenicol, aztreonam, and tigecycline generally achieve minimum inhibitory concentration (MIC) in the CSF at standard dosage.
- Aminoglycosides and fluoroquinolones express a concentration-dependent manner of bactericidal activity; beta-lactams typically follow a a time-dependent antimicrobial pattern (i.e., the activity is dependent on the time that CSF concentration exceeds MIC as a proportion of the dosing interval).
- Penetration into the CSF is less prominent for drugs with a high molecular weight, high protein-binding ability, low lipid solubility, and drugs that are subject to active transport in the choroid plexus such as penicillins and cephalosporins. Toxicity due to dose escalation may limit the usage the aminoglycosides, glycopeptides, and polymyxins, thus intrathecal or intraventricular administration might be occasionally required (see table below).
### Duration of Antimicrobial Therapy
- The duration of therapy in patients with bacterial meningitis has not been well-supported by evidence-based data.
- The IDSA Practice Guideline provides recommendations on the duration of antimicrobial agents based on microorganisms (see table below). However, the duration of antimicrobial therapy should be individualized in accordance with patient's clinical response.
- Maximum parenteral dosage should be maintained throughout the recommended duration of therapy to ensure adequate bactericidal concentrations are attained since antimicrobial entry attenuates as meningeal inflammation subsides, especially when dexamethasone is co-administered.
### Adjunctive Dexamethasone Therapy
- Evidences for beneficial effects of dexamethasone are variable. In some studies, adjunctive use of dexamethasone for bacterial meningitis in selected groups are associated with an improved survival or prognosis. However, other studies fail to demonstrate a substantial reduction of death or neurological disability. The occurrence of delayed cerebral thrombosis with dexamethasone therapy has been reported.
- In infants and children with Haemophilus influenzae type b meningitis, the IDSA Practice Guideline supports the use of adjunctive Dexamethasone at 0.15 mg/kg q6h for 2—4 days with the first dose administered 10—20 minutes prior to, or at least concomitant with, the first antimicrobial dose.
- In adults with suspected or proven Streptococcus pneumoniae meningitis, the IDSA also recommends Dexamethasone at 0.15 mg/kg q6h for 2—4 days with the first dose administered 10—20 minutes prior to, or at least concomitant with, the first antimicrobial dose. Dexamethasone should only be continued if the CSF Gram stain reveals Gram-positive diplococci, or if blood or CSF cultures are positive for S. pneumoniae. In this scenario, certain authorities advocate the addition of rifampin to the empirical combination of vancomycin plus a third-generation cephalosporin pending culture results and in vitro susceptibility testing.
- Dexamethasone should not be given to patients who have already received animicrobial therapy because it is unlikely to improve clinical outcome.
# Empiric Therapy
▸ Click on the following categories to expand treatment regimens.
# CSF Gram Stain-Based Therapy
▸ Click on the following categories to expand treatment regimens.
# Pathogen-Based Therapy — Bacteria
▸ Click on the following categories to expand treatment regimens.
# Pathogen-Based Therapy — Fungi, Helminths, and Protozoan
▸ Click on the following categories to expand treatment regimens. | Sandbox TA
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]; Associate Editor(s)-in-Chief: Cafer Zorkun, M.D., Ph.D. [3], Sheng Shi, M.D. [4]
# Overview
Acute bacterial meningitis is a medical emergency; commence empiric treatment after obtaining blood and/or cerebrospinal fluid (CSF) cultures if the possibility of bacterial meningitis becomes evident. Once a bacterial etiology has been identified on a CSF Gram stain, treatment regimen should be optimized accordingly. Further modifications may be required after the culture and/or in vitro susceptibility results are available. Neuroimaging (such as CT scan and MRI) or lumbar puncture must not delay antimicrobial therapy.
# Principles of Therapy for Bacterial Meningitis
### Factors Determining Antimicrobial Activity
- Factors determine the acitivity of antimicrobial agents include pharmacodynamics, pharmacokinetics, penetration into the CSF, and bactericidal activity within the CSF.[1]
- Beta-lactams, aminoglycosides, glycopeptides, linezolid, and daptomycin are considered to have poor penetration into the CSF, while fluoroquinolones, chloramphenicol, aztreonam, and tigecycline generally achieve minimum inhibitory concentration (MIC) in the CSF at standard dosage.[2]
- Aminoglycosides and fluoroquinolones express a concentration-dependent manner of bactericidal activity; beta-lactams typically follow a a time-dependent antimicrobial pattern (i.e., the activity is dependent on the time that CSF concentration exceeds MIC as a proportion of the dosing interval).
- Penetration into the CSF is less prominent for drugs with a high molecular weight, high protein-binding ability, low lipid solubility, and drugs that are subject to active transport in the choroid plexus such as penicillins and cephalosporins. Toxicity due to dose escalation may limit the usage the aminoglycosides, glycopeptides, and polymyxins, thus intrathecal or intraventricular administration might be occasionally required (see table below).
### Duration of Antimicrobial Therapy
- The duration of therapy in patients with bacterial meningitis has not been well-supported by evidence-based data.
- The IDSA Practice Guideline provides recommendations on the duration of antimicrobial agents based on microorganisms (see table below). However, the duration of antimicrobial therapy should be individualized in accordance with patient's clinical response.
- Maximum parenteral dosage should be maintained throughout the recommended duration of therapy to ensure adequate bactericidal concentrations are attained since antimicrobial entry attenuates as meningeal inflammation subsides, especially when dexamethasone is co-administered.
### Adjunctive Dexamethasone Therapy
- Evidences for beneficial effects of dexamethasone are variable. In some studies, adjunctive use of dexamethasone for bacterial meningitis in selected groups are associated with an improved survival or prognosis.[7][8][9][10][11][12] However, other studies fail to demonstrate a substantial reduction of death or neurological disability.[3][13][14][15] The occurrence of delayed cerebral thrombosis with dexamethasone therapy has been reported.[16]
- In infants and children with Haemophilus influenzae type b meningitis, the IDSA Practice Guideline supports the use of adjunctive Dexamethasone at 0.15 mg/kg q6h for 2—4 days with the first dose administered 10—20 minutes prior to, or at least concomitant with, the first antimicrobial dose.[6]
- In adults with suspected or proven Streptococcus pneumoniae meningitis, the IDSA also recommends Dexamethasone at 0.15 mg/kg q6h for 2—4 days with the first dose administered 10—20 minutes prior to, or at least concomitant with, the first antimicrobial dose. Dexamethasone should only be continued if the CSF Gram stain reveals Gram-positive diplococci, or if blood or CSF cultures are positive for S. pneumoniae. In this scenario, certain authorities advocate the addition of rifampin to the empirical combination of vancomycin plus a third-generation cephalosporin pending culture results and in vitro susceptibility testing.[6][17]
- Dexamethasone should not be given to patients who have already received animicrobial therapy because it is unlikely to improve clinical outcome.[6]
# Empiric Therapy
▸ Click on the following categories to expand treatment regimens.[3][18]
# CSF Gram Stain-Based Therapy
▸ Click on the following categories to expand treatment regimens.[6][18]
# Pathogen-Based Therapy — Bacteria
▸ Click on the following categories to expand treatment regimens.[6][18]
# Pathogen-Based Therapy — Fungi, Helminths, and Protozoan
▸ Click on the following categories to expand treatment regimens. | https://www.wikidoc.org/index.php/Sandbox_TA | |
7036a84b39af21a17ee0077af5417e4d9d85df8a | wikidoc | Sandbox TB | Sandbox TB
### Empirical Anti-Tuberculosis Therapy
It should be considered that in developing countries where TB is endemic and in cases with high clinical suspicion of tuberculous pericarditis, starting with empiric antituberculous therapy is appropriate before establishing a definitive diagnosis. In the clinical settings where the diagnosis cannot be established based on bacteriology, histology, or pericardial fluid analysis, clinical response to antituberculous therapy serves as support for a diagnosis of tuberculous pericarditis.In developed countries where TB is not endemic, antituberculous therapy should generally not be initiated empirically in the absence of definitive diagnosis.
### Standard regimens for new TB patients (with presumed, or known, to have drug-susceptible TB)
† WHO no longer recommends omission of ethambutol during the intensive phase of treatment for patients with non-cavitary, smear-negative PTB or EPEPTB who are known to be HIV-negative.
### Standard regimens for new TB patients (with known or suspected high levels of Isoniazid resistance TB)∞
### Dosing Frequency for New TB Adult Patients with Active Tuberculosis caused by Drug-Susceptible Organisms
### Level Of Evidence in Dosing Frequency
The level of evidence of the dosage frequency came from the systematic review showed that equivalent efficacy of daily intensive-phase dosing followed by two times weekly continuation phase, however twice weekly dosing is not recommended on operational grounds. Also showed that the daily (rather than three times weekly) intensive-phase dosing may also help to prevent acquired drug resistance in TB patients starting treatment with isoniazid resistance. The systematic review found that patients with isoniazid resistance treated with a three times weekly intensive phase had significantly higher risks of failure and acquired drug resistance than those treated with daily dosing during the intensive phase.
### Standard Regimens for Previously Treated Patients
The previously treated patients should receive the 8-month regimen with first-line drugs.
# Assessment of Treatment Response
### Definition of Treatment Response₳
### Monitoring the Response to MDR-TB Treatment
- The use of sputum smear microscopy and culture rather than sputum smear microscopy alone is recommended for the monitoring of patients with MDR-TB during treatment
### Rapid drug susceptibility testing for Early start of Appropriate Treatment
Rapid drug susceptibility testing (DST) of isoniazid and rifampicin or of rifampicin alone is recommended over conventional testing or no testing at the time of diagnosis of TB, subject to available resources
### The role of DST in Management
Initial Phase:
Ideally, DST is done for all patients at the start of treatment, so that the most appropriate therapy for each individual can be determined. However, the goal of universal access to DST has not yet been realized for most of the world’s TB patients. While countries are expanding laboratory capacity and implementing new rapid tests (see below), WHO recommends that sputum specimens for testing susceptibility to isoniazid and rifampicin be obtained from the following patient groups at the start of treatment:
- All previously treated patients (17, 21, 22). The highest levels of MDR are found in patients whose prior course of therapy has failed (6).
- All persons living with HIV who are diagnosed with active TB, especially if they live in areas of moderate or high MDR prevalence. It is essential to detect MDR as soon as possible in persons living with HIV, given their high risk of mortality.
Continuation Phase:
In settings where rapid molecular-based DST is available, the results of MDR can be confirmed or excluded within 1-2 days, it should guide the choice of regimen.
In cases if DST is not available, the first-line drugs 2HRZES/1HRZE/5HRE if country-specific data show low or medium levels of MDR in these patients or if such data are not available
Remark: When DST results become available, regimens should be adjusted appropriately.
The Global Plan to Stop TB 2006–2015 sets a target for open accessibility to DST for all previously treated patients at the beginning of treatment by 2015.
### Recommendations For New Patients
- In new patients, if the specimen obtained at the end of the intensive phase 2nd month is smear-positive, sputum smear microscopy should be obtained at the end of the third month (Strong/High grade of evidence).
- In new patients, if the specimen obtained at the end of 3rd month is smear-positive, sputum culture and drug susceptibility testing (DST) should be performed (Strong/High grade of evidence)
- For smear-positive pulmonary TB patients treated with first-line drugs, sputum smear microscopy may be performed at completion of the intensive phase of treatment (Conditional/High or moderate grade of evidence).
- Sputum should be collected after the 1st dose of the intensive phase treatment at the end of the intensive phase is at 2nd month in new patients and 3rd month in previously treated patients receiving the 8-month regimen of first-line drugs. This recommendation also applies to smear-negative patients.
- Sputum specimens should be collected for smear examination at each follow-up sputum check. They should be collected without interrupting treatment and transported to the laboratory as soon as possible.
- Smear status at the end of the intensive phase is a poor predictor of which new patients will relapse.1 However, detection of a positive sputum smear remains important as a trigger for the patient assessment.
- The proportion of sputum smear positive patients converted to negative at the end of the intensive phase is an indicator of TB program performance.
# Treatment Failure
Failure to response to anti-TB drugs means;
- Smear or culture-positivity at the fifth month or later.
- Detection of MDR-TB at any point of therapy.
Treatment failure necessitate to step-wise approach to identify the causes of failure which could be due to:
- Poor supervision of the initial phase.
- Poor patient adherence.
- Poor quality of anti-TB drugs.
- Inappropriate doses of anti-TB drugs {below than recommended range).
- Slow resolution due to extensive cavitation and a heavy initial bacillary load.
- Co-morbid conditions that interfere either with adherence or with response.
- MDR M. tuberculosis with no response to the first-line treatment.
- Non-viable bacteria remain visible by microscopy.
### Drugs Groups for Treatment of MDR-TB
- Anti-TB drugs are grouped according to efficacy, experience of use and drug class.
- All the first-line anti-TB drugs are in (Group 1), except streptomycin, which is classified with the other injectable agents in (Group 2).
- All the drugs in Groups 2–5 (except streptomycin) are second-line, or reserve, drugs.
- The features of the cross-resistance means that resistance mutations (in M. tuberculosis bacteria) to one anti-TB drug may confer resistance to some or all of the members of the drug family of the same group and less commonly to other members of different drug groups (1).
### Guidelines for second-line Anti-TB Regimens for MDR
- In the treatment of patients with MDR-TB, a Fluoroquinolone should be used (strong recommendation,very low quality evidence).
- In the treatment of patients with MDR-TB, a Ethionamide (or prothionamide) should be used (strong recommendation, very low quality evidence).
- In the treatment of patients with MDR-TB, a later-generation fluoroquinolone rather than an earlier-generation fluoroquinolone should be used (conditional recommendation,very low quality evidence).
- In the treatment of patients with MDR-TB, four second-line antituberculosis drugs likely to be effective (including a parenteral agent), as well as pyrazinamide, should be included in the intensive phase3 (conditional recommendation,very low quality evidence).
- In the treatment of patients with MDR-TB, regimens should include at least pyrazinamide, a fluoroquinolone, a parenteral agent, ethionamide (or prothionamide), and either cycloserine or PAS (p-aminosalicylic acid) if cycloserine cannot be used (conditional recommendation,very low quality evidence).
Major changes in recommendation for second-line Anti-TB Regimens for MDR:
- Include at least four second-line Anti-TB drugs likely to be effective as well as pyrazinamide during the intensive phase of treatment.
- No evidence found to support the use of more than four second-line anti-tuberculosis drugs in patients with extensive disease. Increasing the number of second-line drugs in a regimen is permissible if the effectiveness of some of the drugs is uncertain.
- Ethambutol may be used but is not included among the drugs making up the standard regimen.
- Group 5 drugs may be used but are not included among the drugs making up the standard regimen.
### General principles for Designing MDR-TB Treatment Regimens
# Management of Treatment Interruption
# Prevention of Adverse Effects of Drugs
- Isoniazid-induced peripheral neuropathy: Numbness or a tingling or burning sensation of the hands or feet and occurs more commonly in pregnant women and in people with the following conditions: HIV infection, alcohol dependency, malnutrition, diabetes, chronic liver disease, renal failure. Preventive treatment with Pyridoxine, 10 mg/day with anti-TB drugs. Other guidelines recommend 25 mg/day.
# Managing Side-Effects of Anti-TB Drugs
### Hepatitis and Anti-TB medications
The management of Anti-TB induced hepatitis depends on:
- Phase of the therapy (intensive or continuation phase)
- Severity of the liver disease
- Severity of the TB
- Capacity to manage the side-effects of TB drugs
- If TB treatment has been stopped, Wait for liver function tests to normalize and resolution of the clinical symptoms (nausea, abdominal pain) before reintroducing the anti-TB drugs.
- If the liver function tests is not available, it is advisable to wait for extra 2 weeks after resolution of jaundice and upper abdominal tenderness before restarting TB treatment.
- If the signs and symptoms do not resolve and the liver disease is severe, the non-hepatotoxic regimen consisting of streptomycin, ethambutol and a fluoroquinolone should be started (or continued) for a total of 18-24 months.
- Reintroducing one drug at a time is the optimal approach, especially if the patient’s hepatitis was severe.
- Once drug-induced hepatitis has resolved, the drugs are reintroduced one at a time. But if symptoms recur or liver function tests become abnormal again as the drugs are reintroduced, the last drug added should be stopped.
- Some advise starting with rifampicin because it is less likely than isoniazid or pyrazinamide to cause hepatotoxicity and is the most effective agent . After 3–7 days, isoniazid may be reintroduced. In patients who have experienced jaundice but tolerate the reintroduction of rifampicin and isoniazid, it is advisable to avoid pyrazinamide.
It depends on which drug is implicated as the cause of the hepatitis.
- If rifampicin is implicated, a suggested regimen without rifampicin is 2 months of Isoniazid, Ethambutol and Streptomycin followed by 10 months of Isoniazid and Ethambutol.
- If Isoniazid cannot be used, 6-9 months of Rifampicin, Pyrazinamide and Ethambutol can be considered.
- If Pyrazinamide is discontinued before the patient has completed the intensive phase, the total duration of isoniazid and rifampicin therapy may be extended to 9 months.
- If neither isoniazid nor rifampicin can be used, the non-hepatotoxic regimen consisting of Streptomycin, ethambutol and a fluoroquinolone should be continued for a total of 18-24 months.
- Hepatitis during the intensive phase of TB treatment with isoniazid, rifampicin, pyrazinamide and ethambutol: once hepatitis has resolved, restart the same drugs EXCEPT replace pyrazinamide with streptomycin to complete the 2-month course of initial therapy, followed by Rifampicin and Isoniazid for the 6-month continuation phase.
- Hepatitis during the continuation phase: once hepatitis has resolved, restart Isoniazid and Rifampicin to complete the 4-month continuationphase of therapy.
# HIV and Tuberculosis
### Screening for TB in HIV infected patients
Intensified case finding recommendation according to WHO recommendations, lately updated in 2011.
- Adults and adolescents living with HIV should be screened for TB with a clinical algorithm and those who do not report any one of the symptoms of current cough, fever, weight loss or night sweats are unlikely to have active TB and should be offered IPT.(Strong recommendation, moderate quality of evidence)
- Adults and adolescents living with HIV and screened for TB with a clinical algorithm and who report any one of the symptoms of current cough, fever, weight loss or night sweats may have active TB and should be evaluated for TB and other diseases.(Strong recommendation, moderate quality of evidence)
### Detecting Latent TB Infection in Resources Limited Situations
Tuberculin Skin Test (TST) as screening tool for latent TB
- TST is not a requirement for initiating IPT in people living with HIV. People living with HIV who have a positive TST benefit more from IPT;(Strong recommendation, moderate quality of evidence)
- TST can be used where feasible to identify such individuals.(Strong recommendation, high quality of evidence)
Interferon-gamma release assays (IGRA) as screening tool for latent TB
- IGRA has two types; Quantiferon Gold in tube test assay and T-Spot assay.
- Studies showed the ability of IGRA to predict development of TB over time, and reported its sensitivity in children and adults already infected with TB.
- Most of studied showed a significant higher rates of indeterminate test results (non-conclusive results) with Quantiferon Gold in tube test assay in persons with HIV in comparison with non HIV persons. The sensitivity was also markedly reduced among HIV patients with low CD4 counts in comparison with HIV patients with high CD4.
- However, most of studies found no impact of low CD4 cell count on the sensitivity of T-Spot assay.
- Based on the best available evidence considering the fact that IGRA cannot distinguish between active TB disease and latent infection and most of studies were done in low TB prevalence settings, WHO do not recommended IGRA to screen people living with HIV for eligibility to receive IPT.
### Regimen's Efficacy and Duration in Prevention of TB in HIV Patients
- Adults and adolescents living with HIV who have an unknown or positive TST status and who are unlikely to have active TB should receive at least 6 months of IPT as part of a comprehensive package of HIV care. IPT should be given to such individuals irrespective of the degree of immunosuppression, and also to those on ART, those who have previously been treated for TB and pregnant women.(Strong recommendation, high quality of evidence)
- Adults and adolescents living with HIV who have an unknown or positive TST status and are unlikely to have active TB should receive at least 36 months of IPT. IPT should be given to such individuals irrespective of the degree of immunosuppression, and also to those on ART, those who have previously been treated for TB and pregnant women.(Conditional recommendation, moderate quality of evidence)
### IPT and Drug -Resistant TB
- Providing IPT to people living with HIV does not increase the risk of developing INH-resistant TB. Therefore, concerns regarding the development of INH resistance should not be a barrier to providing IPT.(Strong recommendation, moderate quality of evidence)
### Prevention of TB in HIV Patients
HIV is the strongest risk factor for tuberculosis (TB) disease in those with latent or new Mycobacterium tuberculosis infection. The risk of developing TB is about 20-37 times more in people infected with HIV than people non infected HIV. TB is responsible for more than a 25% of deaths in HIV infected people. In response to the dual epidemics of HIV and TB, the World Health Organization (WHO) recommends 12 collaborative TB/HIV activities as part of core HIV and TB prevention, care and treatment services.
- Adults and adolescents living with HIV should be screened for TB with a clinical algorithm and those who do not report any one of the symptoms of current cough, fever, weight loss or night sweats are unlikely to have active TB and should be offered IPT.(Strong recommendation, moderate quality of evidence1)
- Adults and adolescents living with HIV and screened with a clinical algorithm for TB, and who report any one of the symptoms of current cough, fever, weight loss or night sweats may have active TB and should be evaluated for TB and other diseases.(Strong recommendation, moderate quality of evidence)
- Adults and adolescents living with HIV who have an unknown or positive TST status and are unlikely to have active TB should receive at least six months of IPT as part of a comprehensive package of HIV care. IPT should be given to such individuals irrespective of the degree of immunosuppression, and also to those on ART, those who have previously been treated for TB and pregnant women.(Strong recommendation, high quality of evidence)
- Adults and adolescents living with HIV who have an unknown or positive TST status and who are unlikely to have active TB should receive at least 36 months of IPT2. IPT should be given to such individuals irrespective of the degree of immunosuppression, and also to those on ART, those who have previously been treated for TB and pregnant women.(Conditional recommendation, moderate quality of evidence3)
- TST is not a requirement for initiating IPT in people living with HIV.(Strong recommendation, moderate quality of evidence)
- People living with HIV who have a positive TST benefit more from IPT; TST can be used where feasible to identify such individuals.(Strong recommendation, high quality of evidence)
- Providing IPT to people living with HIV does not increase the risk of developing isoniazid (INH)-resistant TB. Therefore, concerns regarding the development of INH resistance should not be a barrier to providing IPT.(Strong recommendation, moderate quality of evidence)
- Children living with HIV who do not have poor weight gain, fever or current cough are unlikely to have active TB.(Strong recommendation, low quality of evidence)
- Children living with HIV who have any one of the following symptoms – poor weight gain, fever, current cough or contact history with a TB case – may have TB and should be evaluated for TB and other conditions. If the evaluation shows no TB, such children should be offered IPT regardless of their age.(Strong recommendation, low quality of evidence)
- Children living with HIV who are more than 12 months of age and who are unlikely to have active TB on symptom-based screening, and have no contact with a TB case should receive six months of IPT (10 mg/kg/day) as part of a comprehensive package of HIV prevention and care services.(Strong recommendation, moderate quality of evidence)
- In children living with HIV who are less than 12 months of age, only those children who have contact with a TB case and who are evaluated for TB (using investigations) should receive six months of IPT if the evaluation shows no TB disease.(Strong recommendation, low quality of evidence)
- All children living with HIV who have successfully completed treatment for TB disease should receive INH for an additional six months.(Conditional recommendation, low quality of evidence)
† Five-day-a-week administration is always given by DOT.
- ↑ Mayosi, BM.; Burgess, LJ.; Doubell, AF. (2005). "Tuberculous pericarditis". Circulation. 112 (23): 3608–16. doi:10.1161/CIRCULATIONAHA.105.543066. PMID 16330703. Unknown parameter |month= ignored (help).mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ Soler-Soler, J.; Sagristà-Sauleda, J.; Permanyer-Miralda, G. (2001). "Management of pericardial effusion". Heart. 86 (2): 235–40. PMID 11454853. Unknown parameter |month= ignored (help)
- ↑ Empty citation (help)CS1 maint: Missing pipe (link)
- ↑ "" (PDF). External link in |title= (help)
- ↑ "" (PDF). External link in |title= (help)
- ↑ Jump up to: 6.0 6.1 6.2 6.3 "Treatment of tuberculosis". MMWR Recomm Rep. 52 (RR-11): 1–77. 2003. PMID 12836625. Unknown parameter |month= ignored (help)
- ↑ "" (PDF). External link in |title= (help)
- ↑ Saukkonen, JJ.; Cohn, DL.; Jasmer, RM.; Schenker, S.; Jereb, JA.; Nolan, CM.; Peloquin, CA.; Gordin, FM.; Nunes, D. (2006). "An official ATS statement: hepatotoxicity of antituberculosis therapy". Am J Respir Crit Care Med. 174 (8): 935–52. doi:10.1164/rccm.200510-1666ST. PMID 17021358. Unknown parameter |month= ignored (help)
- ↑ Aichelburg, MC.; Rieger, A.; Breitenecker, F.; Pfistershammer, K.; Tittes, J.; Eltz, S.; Aichelburg, AC.; Stingl, G.; Makristathis, A. (2009). "Detection and prediction of active tuberculosis disease by a whole-blood interferon-gamma release assay in HIV-1-infected individuals". Clin Infect Dis. 48 (7): 954–62. doi:10.1086/597351. PMID 19245343. Unknown parameter |month= ignored (help)
- ↑ Clark, SA.; Martin, SL.; Pozniak, A.; Steel, A.; Ward, B.; Dunning, J.; Henderson, DC.; Nelson, M.; Gazzard, B. (2007). "Tuberculosis antigen-specific immune responses can be detected using enzyme-linked immunospot technology in human immunodeficiency virus (HIV)-1 patients with advanced disease". Clin Exp Immunol. 150 (2): 238–44. doi:10.1111/j.1365-2249.2007.03477.x. PMID 17672869. Unknown parameter |month= ignored (help)
- ↑ Dheda, K.; van Zyl Smit, R.; Badri, M.; Pai, M. (2009). "T-cell interferon-gamma release assays for the rapid immunodiagnosis of tuberculosis: clinical utility in high-burden vs. low-burden settings". Curr Opin Pulm Med. 15 (3): 188–200. doi:10.1097/MCP.0b013e32832a0adc. PMID 19387262. Unknown parameter |month= ignored (help)
- ↑ Empty citation (help) | Sandbox TB
### Empirical Anti-Tuberculosis Therapy
It should be considered that in developing countries where TB is endemic and in cases with high clinical suspicion of tuberculous pericarditis, starting with empiric antituberculous therapy is appropriate before establishing a definitive diagnosis. In the clinical settings where the diagnosis cannot be established based on bacteriology, histology, or pericardial fluid analysis, clinical response to antituberculous therapy serves as support for a diagnosis of tuberculous pericarditis.[1]In developed countries where TB is not endemic, antituberculous therapy should generally not be initiated empirically in the absence of definitive diagnosis.[2]
### Standard regimens for new TB patients (with presumed, or known, to have drug-susceptible TB)
† WHO no longer recommends omission of ethambutol during the intensive phase of treatment for patients with non-cavitary, smear-negative PTB or EPEPTB who are known to be HIV-negative.
### Standard regimens for new TB patients (with known or suspected high levels of Isoniazid resistance TB)∞
### Dosing Frequency for New TB Adult Patients with Active Tuberculosis caused by Drug-Susceptible Organisms[3]
### Level Of Evidence in Dosing Frequency
The level of evidence of the dosage frequency came from the systematic review showed that equivalent efficacy of daily intensive-phase dosing followed by two times weekly continuation phase, however twice weekly dosing is not recommended on operational grounds. Also showed that the daily (rather than three times weekly) intensive-phase dosing may also help to prevent acquired drug resistance in TB patients starting treatment with isoniazid resistance. The systematic review found that patients with isoniazid resistance treated with a three times weekly intensive phase had significantly higher risks of failure and acquired drug resistance than those treated with daily dosing during the intensive phase.[4]
### Standard Regimens for Previously Treated Patients
The previously treated patients should receive the 8-month regimen with first-line drugs.
# Assessment of Treatment Response
### Definition of Treatment Response₳
### Monitoring the Response to MDR-TB Treatment
- The use of sputum smear microscopy and culture rather than sputum smear microscopy alone is recommended for the monitoring of patients with MDR-TB during treatment
### Rapid drug susceptibility testing for Early start of Appropriate Treatment
Rapid drug susceptibility testing (DST) of isoniazid and rifampicin or of rifampicin alone is recommended over conventional testing or no testing at the time of diagnosis of TB, subject to available resources
### The role of DST in Management
Initial Phase:
Ideally, DST is done for all patients at the start of treatment, so that the most appropriate therapy for each individual can be determined. However, the goal of universal access to DST has not yet been realized for most of the world’s TB patients. While countries are expanding laboratory capacity and implementing new rapid tests (see below), WHO recommends that sputum specimens for testing susceptibility to isoniazid and rifampicin be obtained from the following patient groups at the start of treatment:
• All previously treated patients (17, 21, 22). The highest levels of MDR are found in patients whose prior course of therapy has failed (6).
• All persons living with HIV who are diagnosed with active TB, especially if they live in areas of moderate or high MDR prevalence. It is essential to detect MDR as soon as possible in persons living with HIV, given their high risk of mortality.
Continuation Phase:
In settings where rapid molecular-based DST is available, the results of MDR can be confirmed or excluded within 1-2 days, it should guide the choice of regimen.
In cases if DST is not available, the first-line drugs 2HRZES/1HRZE/5HRE if country-specific data show low or medium levels of MDR in these patients or if such data are not available
Remark: When DST results become available, regimens should be adjusted appropriately.
The Global Plan to Stop TB 2006–2015 sets a target for open accessibility to DST for all previously treated patients at the beginning of treatment by 2015.
### Recommendations For New Patients
- In new patients, if the specimen obtained at the end of the intensive phase 2nd month is smear-positive, sputum smear microscopy should be obtained at the end of the third month (Strong/High grade of evidence).
- In new patients, if the specimen obtained at the end of 3rd month is smear-positive, sputum culture and drug susceptibility testing (DST) should be performed (Strong/High grade of evidence)
- For smear-positive pulmonary TB patients treated with first-line drugs, sputum smear microscopy may be performed at completion of the intensive phase of treatment (Conditional/High or moderate grade of evidence).
- Sputum should be collected after the 1st dose of the intensive phase treatment at the end of the intensive phase is at 2nd month in new patients and 3rd month in previously treated patients receiving the 8-month regimen of first-line drugs. This recommendation also applies to smear-negative patients.
- Sputum specimens should be collected for smear examination at each follow-up sputum check. They should be collected without interrupting treatment and transported to the laboratory as soon as possible.
- Smear status at the end of the intensive phase is a poor predictor of which new patients will relapse.1 However, detection of a positive sputum smear remains important as a trigger for the patient assessment.
- The proportion of sputum smear positive patients converted to negative at the end of the intensive phase is an indicator of TB program performance.
# Treatment Failure
Failure to response to anti-TB drugs means;
- Smear or culture-positivity at the fifth month or later.
- Detection of MDR-TB at any point of therapy.
Treatment failure necessitate to step-wise approach to identify the causes of failure which could be due to[5]:
- Poor supervision of the initial phase.
- Poor patient adherence.
- Poor quality of anti-TB drugs.
- Inappropriate doses of anti-TB drugs {below than recommended range).
- Slow resolution due to extensive cavitation and a heavy initial bacillary load.
- Co-morbid conditions that interfere either with adherence or with response.
- MDR M. tuberculosis with no response to the first-line treatment.
- Non-viable bacteria remain visible by microscopy.
### Drugs Groups for Treatment of MDR-TB
- Anti-TB drugs are grouped according to efficacy, experience of use and drug class.
- All the first-line anti-TB drugs are in (Group 1), except streptomycin, which is classified with the other injectable agents in (Group 2).
- All the drugs in Groups 2–5 (except streptomycin) are second-line, or reserve, drugs.
- The features of the cross-resistance means that resistance mutations (in M. tuberculosis bacteria) to one anti-TB drug may confer resistance to some or all of the members of the drug family of the same group and less commonly to other members of different drug groups (1).
### Guidelines for second-line Anti-TB Regimens for MDR
- In the treatment of patients with MDR-TB, a Fluoroquinolone should be used (strong recommendation,very low quality evidence).
- In the treatment of patients with MDR-TB, a Ethionamide (or prothionamide) should be used (strong recommendation, very low quality evidence).
- In the treatment of patients with MDR-TB, a later-generation fluoroquinolone rather than an earlier-generation fluoroquinolone should be used (conditional recommendation,very low quality evidence).
- In the treatment of patients with MDR-TB, four second-line antituberculosis drugs likely to be effective (including a parenteral agent), as well as pyrazinamide, should be included in the intensive phase3 (conditional recommendation,very low quality evidence).
- In the treatment of patients with MDR-TB, regimens should include at least pyrazinamide, a fluoroquinolone, a parenteral agent, ethionamide (or prothionamide), and either cycloserine or PAS (p-aminosalicylic acid) if cycloserine cannot be used (conditional recommendation,very low quality evidence).
Major changes in recommendation for second-line Anti-TB Regimens for MDR:
- Include at least four second-line Anti-TB drugs likely to be effective as well as pyrazinamide during the intensive phase of treatment.
- No evidence found to support the use of more than four second-line anti-tuberculosis drugs in patients with extensive disease. Increasing the number of second-line drugs in a regimen is permissible if the effectiveness of some of the drugs is uncertain.
- Ethambutol may be used but is not included among the drugs making up the standard regimen.
- Group 5 drugs may be used but are not included among the drugs making up the standard regimen.
### General principles for Designing MDR-TB Treatment Regimens
# Management of Treatment Interruption
# Prevention of Adverse Effects of Drugs
- Isoniazid-induced peripheral neuropathy: Numbness or a tingling or burning sensation of the hands or feet and occurs more commonly in pregnant women and in people with the following conditions: HIV infection, alcohol dependency, malnutrition, diabetes, chronic liver disease, renal failure. Preventive treatment with Pyridoxine, 10 mg/day with anti-TB drugs. Other guidelines recommend 25 mg/day.[6]
# Managing Side-Effects of Anti-TB Drugs[7]
### Hepatitis and Anti-TB medications
The management of Anti-TB induced hepatitis depends on:
- Phase of the therapy (intensive or continuation phase)
- Severity of the liver disease
- Severity of the TB
- Capacity to manage the side-effects of TB drugs
- If TB treatment has been stopped, Wait for liver function tests to normalize and resolution of the clinical symptoms (nausea, abdominal pain) before reintroducing the anti-TB drugs.
- If the liver function tests is not available, it is advisable to wait for extra 2 weeks after resolution of jaundice and upper abdominal tenderness before restarting TB treatment.
- If the signs and symptoms do not resolve and the liver disease is severe, the non-hepatotoxic regimen consisting of streptomycin, ethambutol and a fluoroquinolone should be started (or continued) for a total of 18-24 months.[6]
- Reintroducing one drug at a time is the optimal approach, especially if the patient’s hepatitis was severe.
- Once drug-induced hepatitis has resolved, the drugs are reintroduced one at a time. But if symptoms recur or liver function tests become abnormal again as the drugs are reintroduced, the last drug added should be stopped.
- Some advise starting with rifampicin because it is less likely than isoniazid or pyrazinamide to cause hepatotoxicity and is the most effective agent .[6] [8] After 3–7 days, isoniazid may be reintroduced. In patients who have experienced jaundice but tolerate the reintroduction of rifampicin and isoniazid, it is advisable to avoid pyrazinamide.
It depends on which drug is implicated as the cause of the hepatitis.
- If rifampicin is implicated, a suggested regimen without rifampicin is 2 months of Isoniazid, Ethambutol and Streptomycin followed by 10 months of Isoniazid and Ethambutol.
- If Isoniazid cannot be used, 6-9 months of Rifampicin, Pyrazinamide and Ethambutol can be considered.
- If Pyrazinamide is discontinued before the patient has completed the intensive phase, the total duration of isoniazid and rifampicin therapy may be extended to 9 months.[6]
- If neither isoniazid nor rifampicin can be used, the non-hepatotoxic regimen consisting of Streptomycin, ethambutol and a fluoroquinolone should be continued for a total of 18-24 months.
- Hepatitis during the intensive phase of TB treatment with isoniazid, rifampicin, pyrazinamide and ethambutol: once hepatitis has resolved, restart the same drugs EXCEPT replace pyrazinamide with streptomycin to complete the 2-month course of initial therapy, followed by Rifampicin and Isoniazid for the 6-month continuation phase.
- Hepatitis during the continuation phase: once hepatitis has resolved, restart Isoniazid and Rifampicin to complete the 4-month continuationphase of therapy.
# HIV and Tuberculosis
### Screening for TB in HIV infected patients
Intensified case finding recommendation according to WHO recommendations, lately updated in 2011.
- Adults and adolescents living with HIV should be screened for TB with a clinical algorithm and those who do not report any one of the symptoms of current cough, fever, weight loss or night sweats are unlikely to have active TB and should be offered IPT.(Strong recommendation, moderate quality of evidence)
- Adults and adolescents living with HIV and screened for TB with a clinical algorithm and who report any one of the symptoms of current cough, fever, weight loss or night sweats may have active TB and should be evaluated for TB and other diseases.(Strong recommendation, moderate quality of evidence)
### Detecting Latent TB Infection in Resources Limited Situations
Tuberculin Skin Test (TST) as screening tool for latent TB
- TST is not a requirement for initiating IPT in people living with HIV. People living with HIV who have a positive TST benefit more from IPT;(Strong recommendation, moderate quality of evidence)
- TST can be used where feasible to identify such individuals.(Strong recommendation, high quality of evidence)
Interferon-gamma release assays (IGRA) as screening tool for latent TB
- IGRA has two types; Quantiferon Gold in tube test assay and T-Spot assay.
- Studies showed the ability of IGRA to predict development of TB over time, and reported its sensitivity in children and adults already infected with TB.[9] [10]
- Most of studied showed a significant higher rates of indeterminate test results (non-conclusive results) with Quantiferon Gold in tube test assay in persons with HIV in comparison with non HIV persons. The sensitivity was also markedly reduced among HIV patients with low CD4 counts in comparison with HIV patients with high CD4.
- However, most of studies found no impact of low CD4 cell count on the sensitivity of T-Spot assay.
- Based on the best available evidence considering the fact that IGRA cannot distinguish between active TB disease and latent infection[11] and most of studies were done in low TB prevalence settings, WHO do not recommended IGRA to screen people living with HIV for eligibility to receive IPT.
### Regimen's Efficacy and Duration in Prevention of TB in HIV Patients
- Adults and adolescents living with HIV who have an unknown or positive TST status and who are unlikely to have active TB should receive at least 6 months of IPT as part of a comprehensive package of HIV care. IPT should be given to such individuals irrespective of the degree of immunosuppression, and also to those on ART, those who have previously been treated for TB and pregnant women.(Strong recommendation, high quality of evidence)
- Adults and adolescents living with HIV who have an unknown or positive TST status and are unlikely to have active TB should receive at least 36 months of IPT. IPT should be given to such individuals irrespective of the degree of immunosuppression, and also to those on ART, those who have previously been treated for TB and pregnant women.(Conditional recommendation, moderate quality of evidence)
### IPT and Drug -Resistant TB
- Providing IPT to people living with HIV does not increase the risk of developing INH-resistant TB. Therefore, concerns regarding the development of INH resistance should not be a barrier to providing IPT.(Strong recommendation, moderate quality of evidence)
### Prevention of TB in HIV Patients[12]
HIV is the strongest risk factor for tuberculosis (TB) disease in those with latent or new Mycobacterium tuberculosis infection. The risk of developing TB is about 20-37 times more in people infected with HIV than people non infected HIV. TB is responsible for more than a 25% of deaths in HIV infected people. In response to the dual epidemics of HIV and TB, the World Health Organization (WHO) recommends 12 collaborative TB/HIV activities as part of core HIV and TB prevention, care and treatment services.
- Adults and adolescents living with HIV should be screened for TB with a clinical algorithm and those who do not report any one of the symptoms of current cough, fever, weight loss or night sweats are unlikely to have active TB and should be offered IPT.(Strong recommendation, moderate quality of evidence1)
- Adults and adolescents living with HIV and screened with a clinical algorithm for TB, and who report any one of the symptoms of current cough, fever, weight loss or night sweats may have active TB and should be evaluated for TB and other diseases.(Strong recommendation, moderate quality of evidence)
- Adults and adolescents living with HIV who have an unknown or positive TST status and are unlikely to have active TB should receive at least six months of IPT as part of a comprehensive package of HIV care. IPT should be given to such individuals irrespective of the degree of immunosuppression, and also to those on ART, those who have previously been treated for TB and pregnant women.(Strong recommendation, high quality of evidence)
- Adults and adolescents living with HIV who have an unknown or positive TST status and who are unlikely to have active TB should receive at least 36 months of IPT2. IPT should be given to such individuals irrespective of the degree of immunosuppression, and also to those on ART, those who have previously been treated for TB and pregnant women.(Conditional recommendation, moderate quality of evidence3)
- TST is not a requirement for initiating IPT in people living with HIV.(Strong recommendation, moderate quality of evidence)
- People living with HIV who have a positive TST benefit more from IPT; TST can be used where feasible to identify such individuals.(Strong recommendation, high quality of evidence)
- Providing IPT to people living with HIV does not increase the risk of developing isoniazid (INH)-resistant TB. Therefore, concerns regarding the development of INH resistance should not be a barrier to providing IPT.(Strong recommendation, moderate quality of evidence)
- Children living with HIV who do not have poor weight gain, fever or current cough are unlikely to have active TB.(Strong recommendation, low quality of evidence)
- Children living with HIV who have any one of the following symptoms – poor weight gain, fever, current cough or contact history with a TB case – may have TB and should be evaluated for TB and other conditions. If the evaluation shows no TB, such children should be offered IPT regardless of their age.(Strong recommendation, low quality of evidence)
- Children living with HIV who are more than 12 months of age and who are unlikely to have active TB on symptom-based screening, and have no contact with a TB case should receive six months of IPT (10 mg/kg/day) as part of a comprehensive package of HIV prevention and care services.(Strong recommendation, moderate quality of evidence)
- In children living with HIV who are less than 12 months of age, only those children who have contact with a TB case and who are evaluated for TB (using investigations) should receive six months of IPT if the evaluation shows no TB disease.(Strong recommendation, low quality of evidence)
- All children living with HIV who have successfully completed treatment for TB disease should receive INH for an additional six months.(Conditional recommendation, low quality of evidence)
† Five-day-a-week administration is always given by DOT.
- ↑ Mayosi, BM.; Burgess, LJ.; Doubell, AF. (2005). "Tuberculous pericarditis". Circulation. 112 (23): 3608–16. doi:10.1161/CIRCULATIONAHA.105.543066. PMID 16330703. Unknown parameter |month= ignored (help).mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ Soler-Soler, J.; Sagristà-Sauleda, J.; Permanyer-Miralda, G. (2001). "Management of pericardial effusion". Heart. 86 (2): 235–40. PMID 11454853. Unknown parameter |month= ignored (help)
- ↑ Empty citation (help)CS1 maint: Missing pipe (link)
- ↑ "http://whqlibdoc.who.int/publications/2008/9789241547581_eng.pdf" (PDF). External link in |title= (help)
- ↑ "http://whqlibdoc.who.int/publications/2004/9241546034.pdf" (PDF). External link in |title= (help)
- ↑ Jump up to: 6.0 6.1 6.2 6.3 "Treatment of tuberculosis". MMWR Recomm Rep. 52 (RR-11): 1–77. 2003. PMID 12836625. Unknown parameter |month= ignored (help)
- ↑ "http://whqlibdoc.who.int/publications/2004/9241546034.pdf" (PDF). External link in |title= (help)
- ↑ Saukkonen, JJ.; Cohn, DL.; Jasmer, RM.; Schenker, S.; Jereb, JA.; Nolan, CM.; Peloquin, CA.; Gordin, FM.; Nunes, D. (2006). "An official ATS statement: hepatotoxicity of antituberculosis therapy". Am J Respir Crit Care Med. 174 (8): 935–52. doi:10.1164/rccm.200510-1666ST. PMID 17021358. Unknown parameter |month= ignored (help)
- ↑ Aichelburg, MC.; Rieger, A.; Breitenecker, F.; Pfistershammer, K.; Tittes, J.; Eltz, S.; Aichelburg, AC.; Stingl, G.; Makristathis, A. (2009). "Detection and prediction of active tuberculosis disease by a whole-blood interferon-gamma release assay in HIV-1-infected individuals". Clin Infect Dis. 48 (7): 954–62. doi:10.1086/597351. PMID 19245343. Unknown parameter |month= ignored (help)
- ↑ Clark, SA.; Martin, SL.; Pozniak, A.; Steel, A.; Ward, B.; Dunning, J.; Henderson, DC.; Nelson, M.; Gazzard, B. (2007). "Tuberculosis antigen-specific immune responses can be detected using enzyme-linked immunospot technology in human immunodeficiency virus (HIV)-1 patients with advanced disease". Clin Exp Immunol. 150 (2): 238–44. doi:10.1111/j.1365-2249.2007.03477.x. PMID 17672869. Unknown parameter |month= ignored (help)
- ↑ Dheda, K.; van Zyl Smit, R.; Badri, M.; Pai, M. (2009). "T-cell interferon-gamma release assays for the rapid immunodiagnosis of tuberculosis: clinical utility in high-burden vs. low-burden settings". Curr Opin Pulm Med. 15 (3): 188–200. doi:10.1097/MCP.0b013e32832a0adc. PMID 19387262. Unknown parameter |month= ignored (help)
- ↑ Empty citation (help) | https://www.wikidoc.org/index.php/Sandbox_TB | |
d0c073622a885d9651928902ccb272e804f3ac5e | wikidoc | Sandbox gc | Sandbox gc
# Definition of Multivessel Disease
For AEGIS-II inclusion criteria #5, multivessel disease criteria can be met by findings on the cardiac catheterization for the index MI, a prior cardiac catheterization, or both:
- Index MI cardiac catheterization: 50% or greater stenosis of the left main or at least 2 coronary artery territories (LAD, LCX, RCA) (prior to any interventions performed)
- Prior cardiac catheterization: 50% or greater stenosis of left main or at least 2 coronary artery territories (LAD, LCx, RCA) (prior to any interventions performed)
- Both: Index MI cardiac catheterization with 1 vessel with 50% or greater stenosis (prior to any interventions performed) AND prior PCI of at least 1 vessel different from index MI vessel
- Prior multivessel CABG
Multivessel disease requires a 50% or greater stenosis in at least 2 of the 3 major epicardial artery territories (LAD, LCx, RCA) or the left main vessel. Branch vessel disease may qualify as part of the territory of that branch vessel (for example, a diagonal vessel is considered part of the LAD territory). For the purpose of this study, the ramus is considered part of the Left Circumflex artery territory. If a branch vessel is used as a qualifying vessel, that branch should be of large enough size to potentially undergo revascularization if clinically indicated, e.g. >2mm vessel size.
# MVD Tool | Sandbox gc
# Definition of Multivessel Disease
For AEGIS-II inclusion criteria #5, multivessel disease criteria can be met by findings on the cardiac catheterization for the index MI, a prior cardiac catheterization, or both:
- Index MI cardiac catheterization: 50% or greater stenosis of the left main or at least 2 coronary artery territories (LAD, LCX, RCA) (prior to any interventions performed)
- Prior cardiac catheterization: 50% or greater stenosis of left main or at least 2 coronary artery territories (LAD, LCx, RCA) (prior to any interventions performed)
- Both: Index MI cardiac catheterization with 1 vessel with 50% or greater stenosis (prior to any interventions performed) AND prior PCI of at least 1 vessel different from index MI vessel
- Prior multivessel CABG
Multivessel disease requires a 50% or greater stenosis in at least 2 of the 3 major epicardial artery territories (LAD, LCx, RCA) or the left main vessel. Branch vessel disease may qualify as part of the territory of that branch vessel (for example, a diagonal vessel is considered part of the LAD territory). For the purpose of this study, the ramus is considered part of the Left Circumflex artery territory. If a branch vessel is used as a qualifying vessel, that branch should be of large enough size to potentially undergo revascularization if clinically indicated, e.g. >2mm vessel size.
# MVD Tool | https://www.wikidoc.org/index.php/Sandbox_gc | |
17f5161c265205b52756040bb4fbaa735aa0836d | wikidoc | Sandbox me | Sandbox me
# Toxoplasmosis
- Toxoplasma gondii (treatment)
- 1. Lymphadenopathic toxoplasmosis
- Preferred regimen: Treatment of immunocompetent adults with lymphadenopathic toxoplasmosis is rarely indicated; this form of the disease is usually self-limited.
- 2. Ocular disease
- 2.1 Adults
- Preferred regimen: Pyrimethamine 100 mg PO for 1 day as a loading dose, then 25 to 50 mg/day AND Sulfadiazine 1 g PO qid AND folinic acid (Leucovorin 5-25 mg PO with each dose of Pyrimethamine
- 2.2 Pediatric
- Preferred regimen: Pyrimethamine 2 mg/kg PO first day then 1 mg/kg each day AND Sulfadiazine 50 mg/kg PO bid AND folinic acid (Leucovorin 7.5 mg/day PO ) for 4 to 6 weeks followed by reevaluation of the patient's condition
- Alternative regimen: The fixed combination of Trimethoprim with Sulfamethoxazole has been used as an alternative.
- Note: If the patient has a hypersensitivity reaction to sulfa drugs, Pyrimethamine AND Clindamycin can be used instead.
- 3. Maternal and fetal infection
- 3.1 First and early second trimesters
- Preferred regimen: Spiramycin is recommended
- 3.2 Late second and third trimesters
- Preferred regimen: Pyrimethamine/Sulfadiazine AND Leucovorin for women with acute T. gondii infection diagnosed at a reference laboratory during gestation.
- 3.3 Infant
- Note: If the infant is likely to be infected, then treatment with drugs such as Pyrimethamine, Atovaquone, Sulfadiazine, Leucovorin is typical. Congenitally infected newborns are generally treated with pyrimethamine, a sulfonamide, and leucovorin for 1 year.
- 4. Toxoplasma gondii Encephalitis in AIDS
- 4.1 Treatment for acute infection
- 4.1.1 Patients with weight <60 kg
- Preferred regimen: Pyrimethamine 200 mg PO 1 time, followed by Pyrimethamine 50 mg PO qd AND Atovaquone AND Sulfadiazine 1000 mg PO q6h AND Leucovorin 10–25 mg PO qd,
- 4.1.2 Patients with weight ≥60 kg
- Preferred regimen: Pyrimethamine 200 mg PO 1 time, followed by Pyrimethamine 75 mg PO qd AND Sulfadiazine 1500 mg PO q6h AND Leucovorin 10–25 mg PO qd and Leucovorin dose can be increased to 50 mg qd or bid
- Alternative regimen (1): Pyrimethamine AND Leucovorin AND Clindamycin 600 mg IV/ PO q6h
- Alternative regimen (2): TMP-SMX (TMP 5 mg/kg and SMX 25 mg/kg ) IV/PO bid
- Alternative regimen (3): Atovaquone 1500 mg PO bid AND Pyrimethamine AND Leucovorin
- Alternative regimen (4): Atovaquone1500 mg PO bid AND sulfadiazine 1000–1500 mg PO q6h (weight-based dosing, as in preferred therapy)
- Alternative regimen (5): Atovaquone 1500 mg PO bid
- Alternative regimen (6): Pyrimethamine AND Leucovorin AND Azithromycin 900–1200 mg PO qd
- Note: Treatment for at least 6 weeks; longer duration if clinical or radiologic disease is extensive or response is incomplete at 6 weeks.
- 4.2 Chronic maintenance therapy
- Preferred regimen: Pyrimethamine 25–50 mg PO qd AND sulfadiazine 2000–4000 mg PO qd (in 2–4 divided doses) AND Leucovorin 10–25 mg PO qd
- Alternative regimen (1): Clindamycin 600 mg PO q8h AND (Pyrimethamine 25–50 mg AND Leucovorin 10–25 mg) PO qd
- Alternative regimen (2): TMP-SMX DS 1 tablet bid
- Alternative regimen (3): Atovaquone 750–1500 mg PO bid AND (Pyrimethamine 25 mg AND Leucovorin 10 mg) PO qd
- Alternative regimen (4): Atovaquone 750–1500 mg PO bid
- Alternative regimen (5): Sulfadiazine 2000–4000 mg PO bid/qid
- Alternative regimen (6): Atovaquone 750–1500 mg PO bid Pyrimethamine and Leucovorin doses are the same as for preferred therapy
- Note: Adjunctive corticosteroids (e.g., Dexamethasone) should only be administered when clinically indicated to treat mass effect associated with focal lesions or associated edema; discontinue as soon as clinically feasible. Anticonvulsants should be administered to patients with a history of seizures and continued through acute treatment, but should not be used as seizure prophylaxis . If Clindamycin is used in place of Sulfadiazine, additional therapy must be added to prevent PCP.
- Toxoplasma gondii (prophylaxis)
- 1. Prophylaxis to prevent first episode of encephalitis in AIDS
- 1.1 Indications
- Toxoplasma IgG-positive patients with CD4 count <100 cells/µL
- Seronegative patients receiving PCP prophylaxis not active against toxoplasmosis should have toxoplasma serology retested if CD4 count decline to <100 cells/µL. Prophylaxis should be initiated if seroconversion occurred.
- 1.2 Prophylactic therapy
- Preferred regimen: TMP-SMX 1 DS PO daily
- Alternative regimen (1): TMP-SMX 1 DS PO three times weekly
- Alternative regimen (2): TMP-SMX 1 SS PO qd
- Alternative regimen (3): Dapsone 50 mg PO qd AND (Pyrimethamine 50 mg PO AND Leucovorin 25 mg) PO weekly
- Alternative regimen (4): Dapsone 200 mg PO AND Pyrimethamine 75 mg PO AND Leucovorin 25 mg PO weekly
- Alternative regimen (5): Atovaquone 1500 mg PO qd
- Alternative regimen (6): Atovaquone 1500 mg PO AND Pyrimethamine 25 mg PO AND Leucovorin 10 mg PO qd
# Varicella zoster
- 1. Varicella zoster treatment
- 1.1 Non Immunocompromised person
- Preferred regimen (1): Acyclovir 500 mg PO five times a dayfor 7-10 days
- Preferred regimen (2): Famciclovir 500 mg PO tid for 7 days
- Preferred regimen (3): Valacyclovir 1 g PO tid for 7 days
- Preferred regimen (4): Brivudin 125 mg PO qd for 7 days
- 1.2 Immunocompromised person requiring hospitalization or persons with sever neurologic complications
- Preferred regimen (1): Acyclovir 10 mg/ kg IV q8h for 7-10 days
- Preferred regimen (2): Foscarnet 40 mg/ kg IV q8h until lesions are healed
- Note: Brivudin is not available in USA and has not been approved by FDA. Foscarnet is not approve by FDA
- 2. Treatment of VZV complications
- 2.1 VZV ophthalmicus
- Treatment includes the following
- (1) Famciclovir OR Valacyclovir for 7–10 days, preferably started within 72 h of rash onset (with Acyclovir IV given as needed for retinitis), to resolve acute disease and inhibit late inflammatory recurrences, AND Prednisone 20 mg PO tid for 4 days or bid for 6 days, and then qd for 4 day
- (2) Bacitracin-Polymyxin ophthalmic ointment administered bid ,to protect the ocular surface;
- (3) Topical Prednisolone 0.125%–1% 2–6 times daily prescribed and managed only by an ophthalmologist for corneal immune disease, episcleritis, scleritis, or iritis;
- (4) Homatropine 5% bid as needed for iritis
- (5) Latanaprost qd and/or Timolol maleate ophthalmic gel forming solution every morning)ocular pressure–lowering drugs given as needed for glaucoma
- Note (1): Systemic steroids are indicated in the presence of moderate to severe pain or rash, particularly if there is significant edema, which may cause orbital apex syndrome through pressure on the nerves entering the orbit.
- Note (2): pain medications and cool to tepid wet compresses (if tolerated) and no topical antivirals, because they are ineffective
- 2.2 VZV retinitis
- Preferred regimen: Acyclovir IV 10–15 mg/kg q8h for 10–14 days followed by Valacyclovir PO 1 g tid daily for 4–6 weeks
- 3 Recommendations for treating varicella zoster virus (VZV) Infections in HIV-Infected adults and adolescents
- 3.1 Primary Varicella Infection (Chickenpox)
- 3.1.1 Uncomplicated Cases
- Preferred regimen (1):Valacyclovir 1 g PO tid for 5–7 days
- Preferred regimen (2): Famciclovir 500 mg PO tid for 5–7 days
- Alternative regimen: Acyclovir 800 mg PO 5 times daily for 5–7 days
- 3.1.2 Severe or Complicated Cases
- Preferred regimen: Acyclovir 10–15 mg/kg IV q8h for 7–10 days
- Note: May switch to oral Famciclovir, Valacyclovir, or Acyclovir after defervescence if no evidence of visceral involvement is evident
- 3.2 Herpes Zoster (Shingles)
- 3.2.1 Acute Localized Dermatomal
- Preferred regimen (1): Valacyclovir 1000 mg PO tid for 7–10 days
- Preferred regimen (2): Famciclovir 500 mg PO tid for 7–10 days
- Alternative Therapy: Acyclovir 800 mg PO 5 times daily for 7–10 days
- Note: Longer duration should be considered if lesions resolve slowly
- 3.2.2 Extensive Cutaneous Lesion or Visceral Involvement
- Preferred regimen: Acyclovir 10–15 mg/kg IV q8h until clinical improvement is evident, then switch to (Valacyclovir 1 g PO tid, Famciclovir 500 mg PO tid, or Acyclovir 800 mg PO 5 times daily)—to complete a 10–14 day course, when formation of new lesions has ceased and signs and symptoms of visceral VZV infection are improving
- 3.3 PORN (Progressive outer retinal necrosis)
- Preferred regimen: Ganciclovir 5 mg/kg and/or Foscarnet 90 mg/kg IV q12h AND Ganciclovir 2 mg/0.05mL and/or foscarnet 1.2 mg/0.05mL intravitreal twice weekly.
- Note: Duration of therapy is not well defined and should be determined based on clinical, virologic, and immunologic response in consultation with experienced ophthalmologist and optimize ART regimen.
- Note: Ganciclovir ocular implants are no longer commercially available
- 3.4 ARN (Acute retinal necrosis)
- Preferred regimen: Acyclovir 10-15 mg/kg IV q8h for 10–14 days, followed by Valacyclovir 1 g PO tid for 6 weeks AND Ganciclovir 2 mg/0.05mL intravitreal qd/bid twice weekly
- Note: Duration of therapy is not well defined and should be determined based on clinical, virologic, and immunologic response in consultation with experienced ophthalmologist
- 4 Prevention of varicella zoster virus (VZV) Infections in HIV-Infected Adults and Adolescents
- 4.1 Pre-Exposure Prevention of VZV Primary Infection
- Indications
- Adult and adolescent patients with CD4 count ≥200 cells/mm3 without documentation of vaccination, health-care provider diagnosis or verification of a history of varicella or herpes zoster, laboratory confirmation of disease, or persons who are seronegative for VZV. Routine VZV serologic testing in HIV-infected adults and adolescents is not recommended.
- Vaccination
- Primary varicella vaccination (Varivax™), 2 doses (0.5 mL SQ) administered 3 months apart
- If vaccination results in disease because of vaccine virus, treatment with acyclovir is recommended.
- VZV-susceptible household contacts of susceptible HIV-infected persons should be vaccinated to prevent potential transmission of VZV to their HIV-infected contacts.
- If post-exposure VariZIG has been administered, wait at least 5 months before varicella vaccination.
- If post-exposure acyclovir has been administered, wait at least 3 days before varicella vaccine.
- 4.2 Post-Exposure Prophylaxis
- Indication
- Close contact with a person who has active varicella or herpes zoster, and
- Is susceptible to VZV (i.e., has no history of vaccination or of either condition, or is known to be VZV seronegative)
- Preferred regimen: VariZIG 125 IU /10 kg (maximum of 625 IU) IM, administered as soon as possible and within 10 days after exposure to a person with active varicella or herpes zoster
- Alternative regimen (Begin 7–10 Days After Exposure): Acyclovir 800 mg PO 5 times/day for 5–7 days OR Valacyclovir 1 g PO tid for 5–7 days
- If post-exposure VariZIG has been administered, wait at least 5 months before varicella vaccination.
- Note: Patients receiving monthly high dose IVIG (i.e., >400 mg/kg) are likely to be protected against VZV and probably do not require VariZIG if the last dose of IVIG was administered <3 weeks before VZV exposure.
- Note: Neither these pre-emptive interventions nor post-exposure varicella vaccination have been studied in HIV-infected adults and adolescents.
- If acyclovir or valacyclovir is used, varicella vaccines should not be given until at least 72 hours after the last dose of the antiviral drug.
# Influenza
- Influenza virus Return to Top
- Antiviral Medications Recommended for Treatment of Influenza
- 1. Adults
- Preferred regimen (1): Oseltamivir (Tamiflu®) 75 mg PO bid for 5 days
- Preferred regimen (2): Zanamivir (Relenza®) 10 mg (two 5-mg inhalations) bid for 5 days
- Preferred regimen (3): Peramivir (Rapivab®) 600 mg IV for 15-30 minutes (single dose)
- Note: FDA approved and recommended Peramivir (Rapivab®) for use in adults ≥18 yrs
- 2. Children
- 2.1 Children < 1 yr
- Preferred regimen: Oseltamivir (Tamiflu®) 3 mg/kg/dose PO bid for 5 days
- 2.2 Children > 1 yr
- 2.2.1 Children ≤ 15 kg
- Preferred regimen: Oseltamivir (Tamiflu®) 30 mg PO bid for 5 days
- 2.2.2 Children > 15 to 23 kg
- Preferred regimen: Oseltamivir (Tamiflu®) 45 mg PO bid for 5 days
- 2.2.3 Children > 23 to 40 kg
- Preferred regimen: Oseltamivir (Tamiflu®) 60 mg PO bid for 5 days
- 2.2.4 Children > 40 kg
- Preferred regimen (1): Oseltamivir (Tamiflu®) 75 mg PO bid for 5 days
- Preferred regimen (2): Zanamivir (Relenza®) 10 mg (two 5-mg inhalations) bid for 5 days, may be considered for children > 7 yrs old
- 3. Adult Patients with Renal Impairment or End Stage Renal Disease (ESRD) on Dialysis
- 3.1 Oseltamivir
- Creatinine clearance 61 to 90 mL/min-75 mg PO bid for 5 days
- Creatinine clearance 31 to 60 mL/min-30 mg PO bid for 5 days
- Creatinine clearance 10 to 30 mL/min-30 mg PO qd for 5 days
- ESRD Patients on Hemodialysis
- Creatinine clearance ≤10 mL/min-30 mg after every hemodialysis cycle. Treatment duration not to exceed 5 days
- ESRD Patients on Continuous Ambulatory Peritoneal Dialysis-A single 30 mg dose administered immediately after a dialysis exchange
- 3.2 Peramivir
- Creatinine clearance >50 mL/min-600mg IV single dose
- Creatinine clearance 30 to 49 mL/min-200mg IV single dose
- Creatinine clearance 10 to 29 mL/min-100mg IV single dose
- ESRD Patients on Hemodialysis-Dose administered after dialysis at a dose adjusted based on creatinine clearance
- Note: No dose adjustment is recommended for inhaled zanamivir for a 5-day course of treatment for patients with renal impairment.
- 4. Antiviral Medications Recommended for Chemoprophylaxis of Influenza
- 4.1. Adults
- Preferred regimen (1): Oseltamivir (Tamiflu®) 75 mg PO qd for 7days
- Preferred regimen (2): Zanamivir (Relenza®) 10 mg (two 5-mg inhalations) qd for 7 days
- 4.2. Children
- 4.2.1 Children < 1 yr
- Preferred regimen: Oseltamivir (Tamiflu®) 3 mg/kg/dose PO qd for 7 days
- 4.2.2 Children > 1 yr
- 4.2.2.1 Children ≤ 15 kg
- Preferred regimen: Oseltamivir (Tamiflu®) 30 mg PO qd for 7 days
- 4.2.2.2 Children > 15 to 23 kg
- Preferred regimen: Oseltamivir (Tamiflu®) 45 mg PO qd for 7 days
- 4.2.2.3 Children > 23 to 40 kg
- Preferred regimen: Oseltamivir (Tamiflu®) 60 mg PO qd for 7 days
- 4.2.2.4 Children > 40 kg
- Preferred regimen (1): Oseltamivir (Tamiflu®) 75 mg PO qd for 7 days
- Preferred regimen (2): Zanamivir (Relenza®) 10 mg (two 5-mg inhalations) qd for 7 days, may be considered for children > 7 yrs older
- Note: If child is < 3 months old, use of Oseltamivir for chemoprophylaxis is not recommended unless situation is judged critical due to limited data in this age group.
- ↑ "Parasites - Toxoplasmosis (Toxoplasma infection)"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ "Parasites - Toxoplasmosis (Toxoplasma infection)".
- ↑ "Parasites - Toxoplasmosis (Toxoplasma infection)".
- ↑ "Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents" (PDF).
- ↑ "Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents" (PDF).
- ↑ Cohen JI (2013). "Clinical practice: Herpes zoster". N Engl J Med. 369 (3): 255–63. doi:10.1056/NEJMcp1302674. PMID 23863052.
- ↑ Dworkin RH, Johnson RW, Breuer J, Gnann JW, Levin MJ, Backonja M; et al. (2007). "Recommendations for the management of herpes zoster". Clin Infect Dis. 44 Suppl 1: S1–26. doi:10.1086/510206. PMID 17143845.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
- ↑ "VZV". Text " " ignored (help); Missing or empty |url= (help) | Sandbox me
# Toxoplasmosis
- Toxoplasma gondii (treatment)
- 1. Lymphadenopathic toxoplasmosis[1]
- Preferred regimen: Treatment of immunocompetent adults with lymphadenopathic toxoplasmosis is rarely indicated; this form of the disease is usually self-limited.
- 2. Ocular disease[2]
- 2.1 Adults
- Preferred regimen: Pyrimethamine 100 mg PO for 1 day as a loading dose, then 25 to 50 mg/day AND Sulfadiazine 1 g PO qid AND folinic acid (Leucovorin 5-25 mg PO with each dose of Pyrimethamine
- 2.2 Pediatric
- Preferred regimen: Pyrimethamine 2 mg/kg PO first day then 1 mg/kg each day AND Sulfadiazine 50 mg/kg PO bid AND folinic acid (Leucovorin 7.5 mg/day PO ) for 4 to 6 weeks followed by reevaluation of the patient's condition
- Alternative regimen: The fixed combination of Trimethoprim with Sulfamethoxazole has been used as an alternative.
- Note: If the patient has a hypersensitivity reaction to sulfa drugs, Pyrimethamine AND Clindamycin can be used instead.
- 3. Maternal and fetal infection[3]
- 3.1 First and early second trimesters
- Preferred regimen: Spiramycin is recommended
- 3.2 Late second and third trimesters
- Preferred regimen: Pyrimethamine/Sulfadiazine AND Leucovorin for women with acute T. gondii infection diagnosed at a reference laboratory during gestation.
- 3.3 Infant
- Note: If the infant is likely to be infected, then treatment with drugs such as Pyrimethamine, Atovaquone, Sulfadiazine, Leucovorin is typical. Congenitally infected newborns are generally treated with pyrimethamine, a sulfonamide, and leucovorin for 1 year.
- 4. Toxoplasma gondii Encephalitis in AIDS[4]
- 4.1 Treatment for acute infection
- 4.1.1 Patients with weight <60 kg
- Preferred regimen: Pyrimethamine 200 mg PO 1 time, followed by Pyrimethamine 50 mg PO qd AND Atovaquone AND Sulfadiazine 1000 mg PO q6h AND Leucovorin 10–25 mg PO qd,
- 4.1.2 Patients with weight ≥60 kg
- Preferred regimen: Pyrimethamine 200 mg PO 1 time, followed by Pyrimethamine 75 mg PO qd AND Sulfadiazine 1500 mg PO q6h AND Leucovorin 10–25 mg PO qd and Leucovorin dose can be increased to 50 mg qd or bid
- Alternative regimen (1): Pyrimethamine AND Leucovorin AND Clindamycin 600 mg IV/ PO q6h
- Alternative regimen (2): TMP-SMX (TMP 5 mg/kg and SMX 25 mg/kg ) IV/PO bid
- Alternative regimen (3): Atovaquone 1500 mg PO bid AND Pyrimethamine AND Leucovorin
- Alternative regimen (4): Atovaquone1500 mg PO bid AND sulfadiazine 1000–1500 mg PO q6h (weight-based dosing, as in preferred therapy)
- Alternative regimen (5): Atovaquone 1500 mg PO bid
- Alternative regimen (6): Pyrimethamine AND Leucovorin AND Azithromycin 900–1200 mg PO qd
- Note: Treatment for at least 6 weeks; longer duration if clinical or radiologic disease is extensive or response is incomplete at 6 weeks.
- 4.2 Chronic maintenance therapy
- Preferred regimen: Pyrimethamine 25–50 mg PO qd AND sulfadiazine 2000–4000 mg PO qd (in 2–4 divided doses) AND Leucovorin 10–25 mg PO qd
- Alternative regimen (1): Clindamycin 600 mg PO q8h AND (Pyrimethamine 25–50 mg AND Leucovorin 10–25 mg) PO qd
- Alternative regimen (2): TMP-SMX DS 1 tablet bid
- Alternative regimen (3): Atovaquone 750–1500 mg PO bid AND (Pyrimethamine 25 mg AND Leucovorin 10 mg) PO qd
- Alternative regimen (4): Atovaquone 750–1500 mg PO bid
- Alternative regimen (5): Sulfadiazine 2000–4000 mg PO bid/qid
- Alternative regimen (6): Atovaquone 750–1500 mg PO bid Pyrimethamine and Leucovorin doses are the same as for preferred therapy
- Note: Adjunctive corticosteroids (e.g., Dexamethasone) should only be administered when clinically indicated to treat mass effect associated with focal lesions or associated edema; discontinue as soon as clinically feasible. Anticonvulsants should be administered to patients with a history of seizures and continued through acute treatment, but should not be used as seizure prophylaxis . If Clindamycin is used in place of Sulfadiazine, additional therapy must be added to prevent PCP.
- Toxoplasma gondii (prophylaxis)
- 1. Prophylaxis to prevent first episode of encephalitis in AIDS[5]
- 1.1 Indications
- Toxoplasma IgG-positive patients with CD4 count <100 cells/µL
- Seronegative patients receiving PCP prophylaxis not active against toxoplasmosis should have toxoplasma serology retested if CD4 count decline to <100 cells/µL. Prophylaxis should be initiated if seroconversion occurred.
- 1.2 Prophylactic therapy
- Preferred regimen: TMP-SMX 1 DS PO daily
- Alternative regimen (1): TMP-SMX 1 DS PO three times weekly
- Alternative regimen (2): TMP-SMX 1 SS PO qd
- Alternative regimen (3): Dapsone 50 mg PO qd AND (Pyrimethamine 50 mg PO AND Leucovorin 25 mg) PO weekly
- Alternative regimen (4): Dapsone 200 mg PO AND Pyrimethamine 75 mg PO AND Leucovorin 25 mg PO weekly
- Alternative regimen (5): Atovaquone 1500 mg PO qd
- Alternative regimen (6): Atovaquone 1500 mg PO AND Pyrimethamine 25 mg PO AND Leucovorin 10 mg PO qd
# Varicella zoster
- 1. Varicella zoster treatment[6]
- 1.1 Non Immunocompromised person
- Preferred regimen (1): Acyclovir 500 mg PO five times a dayfor 7-10 days
- Preferred regimen (2): Famciclovir 500 mg PO tid for 7 days
- Preferred regimen (3): Valacyclovir 1 g PO tid for 7 days
- Preferred regimen (4): Brivudin 125 mg PO qd for 7 days
- 1.2 Immunocompromised person requiring hospitalization or persons with sever neurologic complications
- Preferred regimen (1): Acyclovir 10 mg/ kg IV q8h for 7-10 days
- Preferred regimen (2): Foscarnet 40 mg/ kg IV q8h until lesions are healed
- Note: Brivudin is not available in USA and has not been approved by FDA. Foscarnet is not approve by FDA
- 2. Treatment of VZV complications[7]
- 2.1 VZV ophthalmicus
- Treatment includes the following
- (1) Famciclovir OR Valacyclovir for 7–10 days, preferably started within 72 h of rash onset (with Acyclovir IV given as needed for retinitis), to resolve acute disease and inhibit late inflammatory recurrences, AND Prednisone 20 mg PO tid for 4 days or bid for 6 days, and then qd for 4 day
- (2) Bacitracin-Polymyxin ophthalmic ointment administered bid ,to protect the ocular surface;
- (3) Topical Prednisolone 0.125%–1% 2–6 times daily prescribed and managed only by an ophthalmologist for corneal immune disease, episcleritis, scleritis, or iritis;
- (4) Homatropine 5% bid as needed for iritis
- (5) Latanaprost qd and/or Timolol maleate ophthalmic gel forming solution every morning)ocular pressure–lowering drugs given as needed for glaucoma
- Note (1): Systemic steroids are indicated in the presence of moderate to severe pain or rash, particularly if there is significant edema, which may cause orbital apex syndrome through pressure on the nerves entering the orbit.
- Note (2): pain medications and cool to tepid wet compresses (if tolerated) and no topical antivirals, because they are ineffective
- 2.2 VZV retinitis
- Preferred regimen: Acyclovir IV 10–15 mg/kg q8h for 10–14 days followed by Valacyclovir PO 1 g tid daily for 4–6 weeks
- 3 Recommendations for treating varicella zoster virus (VZV) Infections in HIV-Infected adults and adolescents[8]
- 3.1 Primary Varicella Infection (Chickenpox)
- 3.1.1 Uncomplicated Cases
- Preferred regimen (1):Valacyclovir 1 g PO tid for 5–7 days
- Preferred regimen (2): Famciclovir 500 mg PO tid for 5–7 days
- Alternative regimen: Acyclovir 800 mg PO 5 times daily for 5–7 days
- 3.1.2 Severe or Complicated Cases
- Preferred regimen: Acyclovir 10–15 mg/kg IV q8h for 7–10 days
- Note: May switch to oral Famciclovir, Valacyclovir, or Acyclovir after defervescence if no evidence of visceral involvement is evident
- 3.2 Herpes Zoster (Shingles)
- 3.2.1 Acute Localized Dermatomal
- Preferred regimen (1): Valacyclovir 1000 mg PO tid for 7–10 days
- Preferred regimen (2): Famciclovir 500 mg PO tid for 7–10 days
- Alternative Therapy: Acyclovir 800 mg PO 5 times daily for 7–10 days
- Note: Longer duration should be considered if lesions resolve slowly
- 3.2.2 Extensive Cutaneous Lesion or Visceral Involvement
- Preferred regimen: Acyclovir 10–15 mg/kg IV q8h until clinical improvement is evident, then switch to (Valacyclovir 1 g PO tid, Famciclovir 500 mg PO tid, or Acyclovir 800 mg PO 5 times daily)—to complete a 10–14 day course, when formation of new lesions has ceased and signs and symptoms of visceral VZV infection are improving
- 3.3 PORN (Progressive outer retinal necrosis)
- Preferred regimen: Ganciclovir 5 mg/kg and/or Foscarnet 90 mg/kg IV q12h AND Ganciclovir 2 mg/0.05mL and/or foscarnet 1.2 mg/0.05mL intravitreal twice weekly.
- Note: Duration of therapy is not well defined and should be determined based on clinical, virologic, and immunologic response in consultation with experienced ophthalmologist and optimize ART regimen.
- Note: Ganciclovir ocular implants are no longer commercially available
- 3.4 ARN (Acute retinal necrosis)
- Preferred regimen: Acyclovir 10-15 mg/kg IV q8h for 10–14 days, followed by Valacyclovir 1 g PO tid for 6 weeks AND Ganciclovir 2 mg/0.05mL intravitreal qd/bid twice weekly
- Note: Duration of therapy is not well defined and should be determined based on clinical, virologic, and immunologic response in consultation with experienced ophthalmologist
- 4 Prevention of varicella zoster virus (VZV) Infections in HIV-Infected Adults and Adolescents
- 4.1 Pre-Exposure Prevention of VZV Primary Infection
- Indications
- Adult and adolescent patients with CD4 count ≥200 cells/mm3 without documentation of vaccination, health-care provider diagnosis or verification of a history of varicella or herpes zoster, laboratory confirmation of disease, or persons who are seronegative for VZV. Routine VZV serologic testing in HIV-infected adults and adolescents is not recommended.
- Vaccination
- Primary varicella vaccination (Varivax™), 2 doses (0.5 mL SQ) administered 3 months apart
- If vaccination results in disease because of vaccine virus, treatment with acyclovir is recommended.
- VZV-susceptible household contacts of susceptible HIV-infected persons should be vaccinated to prevent potential transmission of VZV to their HIV-infected contacts.
- If post-exposure VariZIG has been administered, wait at least 5 months before varicella vaccination.
- If post-exposure acyclovir has been administered, wait at least 3 days before varicella vaccine.
- 4.2 Post-Exposure Prophylaxis
- Indication
- Close contact with a person who has active varicella or herpes zoster, and
- Is susceptible to VZV (i.e., has no history of vaccination or of either condition, or is known to be VZV seronegative)
- Preferred regimen: VariZIG 125 IU /10 kg (maximum of 625 IU) IM, administered as soon as possible and within 10 days after exposure to a person with active varicella or herpes zoster
- Alternative regimen (Begin 7–10 Days After Exposure): Acyclovir 800 mg PO 5 times/day for 5–7 days OR Valacyclovir 1 g PO tid for 5–7 days
- If post-exposure VariZIG has been administered, wait at least 5 months before varicella vaccination.
- Note: Patients receiving monthly high dose IVIG (i.e., >400 mg/kg) are likely to be protected against VZV and probably do not require VariZIG if the last dose of IVIG was administered <3 weeks before VZV exposure.
- Note: Neither these pre-emptive interventions nor post-exposure varicella vaccination have been studied in HIV-infected adults and adolescents.
- If acyclovir or valacyclovir is used, varicella vaccines should not be given until at least 72 hours after the last dose of the antiviral drug.
# Influenza
- Influenza virus Return to Top
- Antiviral Medications Recommended for Treatment of Influenza
- 1. Adults
- Preferred regimen (1): Oseltamivir (Tamiflu®) 75 mg PO bid for 5 days
- Preferred regimen (2): Zanamivir (Relenza®) 10 mg (two 5-mg inhalations) bid for 5 days
- Preferred regimen (3): Peramivir (Rapivab®) 600 mg IV for 15-30 minutes (single dose)
- Note: FDA approved and recommended Peramivir (Rapivab®) for use in adults ≥18 yrs
- 2. Children
- 2.1 Children < 1 yr
- Preferred regimen: Oseltamivir (Tamiflu®) 3 mg/kg/dose PO bid for 5 days
- 2.2 Children > 1 yr
- 2.2.1 Children ≤ 15 kg
- Preferred regimen: Oseltamivir (Tamiflu®) 30 mg PO bid for 5 days
- 2.2.2 Children > 15 to 23 kg
- Preferred regimen: Oseltamivir (Tamiflu®) 45 mg PO bid for 5 days
- 2.2.3 Children > 23 to 40 kg
- Preferred regimen: Oseltamivir (Tamiflu®) 60 mg PO bid for 5 days
- 2.2.4 Children > 40 kg
- Preferred regimen (1): Oseltamivir (Tamiflu®) 75 mg PO bid for 5 days
- Preferred regimen (2): Zanamivir (Relenza®) 10 mg (two 5-mg inhalations) bid for 5 days, may be considered for children > 7 yrs old
- 3. Adult Patients with Renal Impairment or End Stage Renal Disease (ESRD) on Dialysis
- 3.1 Oseltamivir
- Creatinine clearance 61 to 90 mL/min-75 mg PO bid for 5 days
- Creatinine clearance 31 to 60 mL/min-30 mg PO bid for 5 days
- Creatinine clearance 10 to 30 mL/min-30 mg PO qd for 5 days
- ESRD Patients on Hemodialysis
- Creatinine clearance ≤10 mL/min-30 mg after every hemodialysis cycle. Treatment duration not to exceed 5 days
- ESRD Patients on Continuous Ambulatory Peritoneal Dialysis-A single 30 mg dose administered immediately after a dialysis exchange
- 3.2 Peramivir
- Creatinine clearance >50 mL/min-600mg IV single dose
- Creatinine clearance 30 to 49 mL/min-200mg IV single dose
- Creatinine clearance 10 to 29 mL/min-100mg IV single dose
- ESRD Patients on Hemodialysis-Dose administered after dialysis at a dose adjusted based on creatinine clearance
- Note: No dose adjustment is recommended for inhaled zanamivir for a 5-day course of treatment for patients with renal impairment.
- 4. Antiviral Medications Recommended for Chemoprophylaxis of Influenza
- 4.1. Adults
- Preferred regimen (1): Oseltamivir (Tamiflu®) 75 mg PO qd for 7days
- Preferred regimen (2): Zanamivir (Relenza®) 10 mg (two 5-mg inhalations) qd for 7 days
- 4.2. Children
- 4.2.1 Children < 1 yr
- Preferred regimen: Oseltamivir (Tamiflu®) 3 mg/kg/dose PO qd for 7 days
- 4.2.2 Children > 1 yr
- 4.2.2.1 Children ≤ 15 kg
- Preferred regimen: Oseltamivir (Tamiflu®) 30 mg PO qd for 7 days
- 4.2.2.2 Children > 15 to 23 kg
- Preferred regimen: Oseltamivir (Tamiflu®) 45 mg PO qd for 7 days
- 4.2.2.3 Children > 23 to 40 kg
- Preferred regimen: Oseltamivir (Tamiflu®) 60 mg PO qd for 7 days
- 4.2.2.4 Children > 40 kg
- Preferred regimen (1): Oseltamivir (Tamiflu®) 75 mg PO qd for 7 days
- Preferred regimen (2): Zanamivir (Relenza®) 10 mg (two 5-mg inhalations) qd for 7 days, may be considered for children > 7 yrs older
- Note: If child is < 3 months old, use of Oseltamivir for chemoprophylaxis is not recommended unless situation is judged critical due to limited data in this age group.
- ↑ "Parasites - Toxoplasmosis (Toxoplasma infection)"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ "Parasites - Toxoplasmosis (Toxoplasma infection)".
- ↑ "Parasites - Toxoplasmosis (Toxoplasma infection)".
- ↑ "Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents" (PDF).
- ↑ "Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents" (PDF).
- ↑ Cohen JI (2013). "Clinical practice: Herpes zoster". N Engl J Med. 369 (3): 255–63. doi:10.1056/NEJMcp1302674. PMID 23863052.
- ↑ Dworkin RH, Johnson RW, Breuer J, Gnann JW, Levin MJ, Backonja M; et al. (2007). "Recommendations for the management of herpes zoster". Clin Infect Dis. 44 Suppl 1: S1–26. doi:10.1086/510206. PMID 17143845.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
- ↑ "VZV". Text "https://aidsinfo.nih.gov/guidelines/html/4/adult-and-adolescent-oi-prevention-and-treatment-guidelines/341/vzv " ignored (help); Missing or empty |url= (help) | https://www.wikidoc.org/index.php/Sandbox_me | |
b7adca76dd698478e81d37f8c78352e855935459 | wikidoc | Sandbox mj | Sandbox mj
- Bartonella Return to Top
- Bartonella
- 1. Bartonella quintana
- 1.1 Acute or chronic infections without endocarditis
- Preferred regimen: Doxycycline 200 mg PO qd or 100 mg bid for 4 weeks AND Gentamicin 3 mg/kg IV qd for the first 2 weeks
- 1.2 Endocarditis
- Preferred regimen: Gentamicin 3 mg/kg/day IV q8h for 14 days AND Ceftriaxone 2 g IV q24h for 6 weeks ± Doxycycline 100 mg PO bid for 6 weeks
- 2. Bartonella elizabethae
- 2.1 Endocarditis
- Preferred regimen: Gentamicin 3 mg/kg/day IV q8h for 14 days AND Ceftriaxone 2 g IV q24h for 6 weeks ± Doxycycline 100 mg PO bid for 6 weeks
- 3. Bartonella bacilliformis
- 3.1 Oroya fever
- Preferred regimen: Ciprofloxacin 500 mg PO bid for 14 days
- Note: If severe disease, add Ceftriaxone 1 g IV qd for 14 days
- 3.2 Verruga peruana
- Preferred regimen: Azithromycin 500 mg PO qd for 7 days
- Alternative regimen (1): Rifampin 600 mg PO qd for 14-21 days
- Alternative regimen (2): Ciprofloxacin 500 mg bid for 7-10 days
- 4. Bartonella henselae
- 4.1 Cat scratch disease
- No treatment recommended for typical cat scratch disease, consider treatment if there is an extensive lymphadenopathy
- 4.1.1 If extensive lymphadenopathy
- Preferred regimen (1) (pediatrics): Azithromycin 500 mg PO on day 1 THEN 250 mg PO qd on days 2 to 5
- Preferred regimen (2) (adults): Azithromycin 1 g PO at day 1 THEN 500 mg PO for 4 days
- 4.2 Endocarditis
- Preferred regimen: Gentamicin 3 mg/kg/day IV q8h for 14 days AND Ceftriaxone 2 g/day IV for 6weeks ± Doxycycline 100 mg PO bid for 6 weeks
- 4.3 Retinitis
- Preferred regimen: Doxycycline 100 mg bid AND Rifampin 300 mg bid PO for 4-6 weeks
- 4.4 Bacillary angiomatosis
- Preferred regimen (1): Erythromycin 500 mg PO qid for 2 months at least
- Preferred regimen (2): Doxycycline 100 mg PO bid for 2 months at least
- 4.5 Bacillary Pelliosis
- Preferred regimen (1): Erythromycin 500 mg PO qid for 4 months at least
- Preferred regimen (2): Doxycycline 100 mg PO bid for 4 months at least
# Neurocysticercosis
- Neurocysticercosis Return to Top
- Neurocysticercosis treatment
- 1. Parenchymal neurocysticercosis
- 1.1 Single lesions
- Preferred regimen: Albendazole 15 mg/kg/day PO bid for 3 to 8 days AND Prednisone 1 mg/kg/day PO qid for 8 to 10 days followed by a taper
- 1.2 Multiple cysts
- Preferred regimen: Albendazole 15 mg/kg/day PO bid for 8 to 15 days and high-dose steroids
- Preferred regimen: Praziquantel 50 mg/kg/day PO tid AND Albendazole 15 mg/kg/day PO bid
- 1.3 Cysticercal encephalitis
- Cysticercal encephalitis (diffuse cerebral edema associated with multiple inflamed cysticerci) is a contraindication for antiparasitic therapy, since enhanced parasite killing can exacerbate host inflammatory response and lead to diffuse cerebral edema and potential transtentorial herniation. Most cases of cysticercal encephalitis improve with corticosteroid therapy
- 1.4 Calcified cysts
- Radiographic evidence of parenchymal calcifications is a significant risk factor for recurrent seizure activity; these lesions are present in about 10 percent of individuals in regions where neurocysticercosis is endemic. Seizures in these patients should be treated with antiepileptic therapy.
- 2. Extraparenchymal NCC
- 2.1 Subarachnoid cysts
- Preferred regimen: Albendazole 15 mg/kg/day PO bid for 28 days AND Prednisone up to 60 mg/day PO OR Dexamethasone (up to 24 mg per day) along with the antiparasitic therapy. The dose can often be tapered after a few weeks. However, in cases for which more prolonged steroid therapy is required, methotrexate can be used as a steroid-sparing agent
- 2.2 Giant cysts
- Giant cysticerci are usually accompanied by cerebral edema and mass effect, which should be managed with high-dose corticosteroids (with or without mannitol).
- 2.3 Intraventricular cysts
- Emergent management with CSF diversion via a ventriculostomy or placement of a ventriculo-peritoneal shunt
- Treatment of residual hydrocephalus may be managed with endoscopic foraminotomy and endoscopic third ventriculostomy; this approach may also allow debulking of cisternal cysticerci
- 2.4 Ocular cysticercosis
- Surgical excision is warranted in the setting of intraocular cysts
- Cysticercal involvement of the extraocular muscles should be managed with albendazole and corticosteroids.
- 2.5 Spinal cysticercosis
- Medical therapy with corticosteroids and antiparasitic drugs
### Parasites – Ectoparasites
- Body lice Return to Top
- Body lice
- Pediculus humanus, corporis treatment
- A body lice infestation is treated by improving the personal hygiene of the infested person, including assuring a regular (at least weekly) change of clean clothes.
- Clothing, bedding, and towels used by the infested person should be laundered using hot water (at least 130°F) and machine dried using the hot cycle.
- Sometimes the infested person also is treated with a pediculicide Ivermectin Lotion; however, a pediculicide Ivermectin generally is not necessary if hygiene is maintained and items are laundered appropriately at least once a week. A pediculicide Ivermectin should be applied exactly as directed on the bottle or by your physician.
- Head lice Return to Top
- Head lice
- Pediculus humanus, capitis treatment
- Preferred regimen (1): Permethrin 1% lotion apply to shampooed dried hair for 10 min.; repeat in 9-10 days
- Preferred regimen (2): Malathion 0.5% lotion (Ovide) apply to dry hair for 8–12hrs, then shampoo (2 doses 7-9 days apart)
- Alternative regimen: Ivermectin 200 μg/kg PO once; 3 doses at 7 day intervals reported effective.
- Pubic lice Return to Top
- Pubic lice
- Phthirus pubis treatment
- Preferred regimen (1): Permethrin 1% cream rinse applied to affected areas and washed off after 10 minutes
- Preferred regimen (2): Pyrethrins with piperonyl butoxide applied to the affected area and washed off after 10 minutes
- Alternative regimen (1): Malathion 0.5% lotion applied to affected areas and washed off after 8–12 hours
- Alternative regimen (2): Ivermectin 250 ug/kg PO, repeated in 2 weeks
- Myiasis Return to Top
- Preferred regimen: No medications approved by the FDA are available for treatment
- Note: Fly larvae need to be surgically removed.
- Fly larvae treatment
- Preferred treatment (1): Occlude punctum to prevent gas exchange with petrolatum, fingernail polish, makeup cream or bacon.
- Preferred treatment (2): When larva migrates, manually remove.
- Note (1): Myiasis is due to larvae of flies.
- Note (2): Usually cutaneous/subcutaneous nodule with central punctum.
# Scabies
- Scabies Return to Top
- Sarcoptes scabiei treatment
- 1. Adult
- Preferred regimen (1): Permethrin 5% cream applied to all areas of the body from the neck down and washed off after 8–14 hours
- Preferred regimen (2): Ivermectin 200 ug/kg PO qd and repeated in 2 weeks
- Alternative regimen: Lindane (1%) 1 oz of lotion or 30 g of cream applied in a thin layer to all areas of the body from the neck down and thoroughly washed off after 8 hours
- 2. Infants and young children
- Preferred regimen: Permethrin 5% cream applied to all areas of the body from the neck down and washed off after 8–14 hours
- Note: Infants and young children aged< 10 years should not be treated with lindane.
- 3. Crusted Scabies
- Crusted scabies (i.e., Norwegian scabies) is an aggressive infestation that usually occurs in immunodeficient, debilitated, or malnourished persons, including persons receiving systemic or potent topical glucocorticoids, organ transplant recipients, persons with HIV infection or human T-lymphotrophic virus-1-infection, and persons with hematologic malignancies.
- Preferred regimen: (Topical scabicide 5% topical Benzyl benzoate 5% OR topical Permethrin 5% cream (full-body application to be repeated daily for 7 days then twice weekly until discharge or cure) AND treatment with Ivermectin 200 ug/kg PO on days 1,2,8,9, and 15. Additional Ivermectin treatment on days 22 and 29 might be required for severe cases
- 4.Pregnant or Lactating Women
- Preferred regimen: Permethrin 5% cream applied to all areas of the body from the neck down and washed off after 8–14 hours
- ↑ Bartlett, John (2012). Johns Hopkins ABX guide : diagnosis and treatment of infectious diseases. Burlington, MA: Jones and Bartlett Learning. ISBN 978-1449625580..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ Foucault C, Raoult D, Brouqui P (2003). "Randomized open trial of gentamicin and doxycycline for eradication of Bartonella quintana from blood in patients with chronic bacteremia". Antimicrob Agents Chemother. 47 (7): 2204–7. PMC 161867. PMID 12821469.CS1 maint: Multiple names: authors list (link) CS1 maint: PMC format (link)
- ↑ Jump up to: 3.0 3.1 Baddour LM, Wilson WR, Bayer AS, Fowler VG, Bolger AF, Levison ME; et al. (2005). "Infective endocarditis: diagnosis, antimicrobial therapy, and management of complications: a statement for healthcare professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, and the Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia, American Heart Association: endorsed by the Infectious Diseases Society of America". Circulation. 111 (23): e394–434. doi:10.1161/CIRCULATIONAHA.105.165564. PMID 15956145.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
- ↑ Bradley JS, Jackson MA, Committee on Infectious Diseases, American Academy of Pediatrics. The use of systemic and topical fluoroquinolones. Pediatrics 2011; 128:e1034.
- ↑ Rolain JM, Brouqui P, Koehler JE, Maguina C, Dolan MJ, Raoult D (2004). "Recommendations for treatment of human infections caused by Bartonella species". Antimicrob Agents Chemother. 48 (6): 1921–33. doi:10.1128/AAC.48.6.1921-1933.2004. PMC 415619. PMID 15155180.CS1 maint: Multiple names: authors list (link) CS1 maint: PMC format (link)
- ↑ Jump up to: 6.0 6.1 Spach DH, Koehler JE (1998). "Bartonella-associated infections". Infect Dis Clin North Am. 12 (1): 137–55. PMID 9494835.
- ↑ Jump up to: 7.0 7.1 García HH, Evans CA, Nash TE, Takayanagui OM, White AC, Botero D; et al. (2002). "Current consensus guidelines for treatment of neurocysticercosis". Clin Microbiol Rev. 15 (4): 747–56. PMC 126865. PMID 12364377.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link) CS1 maint: PMC format (link)
- ↑ "body lice".
- ↑ Gilbert, David (2015). The Sanford guide to antimicrobial therapy. Sperryville, Va: Antimicrobial Therapy. ISBN 978-1930808843.
- ↑ Workowski, Kimberly A.; Bolan, Gail A. (2015-06-05). "Sexually transmitted diseases treatment guidelines, 2015". MMWR. Recommendations and reports: Morbidity and mortality weekly report. Recommendations and reports / Centers for Disease Control. 64 (RR-03): 1–137. ISSN 1545-8601. PMID 26042815.
- ↑ "Parasites - Myiasis".
- ↑ Gilbert, David (2014). The Sanford guide to antimicrobial therapy 2014. Sperryville, Va: Antimicrobial Therapy. ISBN 978-1930808782.
- ↑ Workowski, Kimberly A.; Bolan, Gail A. (2015-06-05). "Sexually transmitted diseases treatment guidelines, 2015". MMWR. Recommendations and reports: Morbidity and mortality weekly report. Recommendations and reports / Centers for Disease Control. 64 (RR-03): 1–137. ISSN 1545-8601. PMID 26042815. | Sandbox mj
- Bartonella Return to Top
- Bartonella[1]
- 1. Bartonella quintana
- 1.1 Acute or chronic infections without endocarditis[2]
- Preferred regimen: Doxycycline 200 mg PO qd or 100 mg bid for 4 weeks AND Gentamicin 3 mg/kg IV qd for the first 2 weeks
- 1.2 Endocarditis[3]
- Preferred regimen: Gentamicin 3 mg/kg/day IV q8h for 14 days AND Ceftriaxone 2 g IV q24h for 6 weeks ± Doxycycline 100 mg PO bid for 6 weeks
- 2. Bartonella elizabethae
- 2.1 Endocarditis[3]
- Preferred regimen: Gentamicin 3 mg/kg/day IV q8h for 14 days AND Ceftriaxone 2 g IV q24h for 6 weeks ± Doxycycline 100 mg PO bid for 6 weeks
- 3. Bartonella bacilliformis
- 3.1 Oroya fever
- Preferred regimen: Ciprofloxacin 500 mg PO bid for 14 days
- Note: If severe disease, add Ceftriaxone 1 g IV qd for 14 days
- 3.2 Verruga peruana[4]
- Preferred regimen: Azithromycin 500 mg PO qd for 7 days
- Alternative regimen (1): Rifampin 600 mg PO qd for 14-21 days
- Alternative regimen (2): Ciprofloxacin 500 mg bid for 7-10 days
- 4. Bartonella henselae[5]
- 4.1 Cat scratch disease
- No treatment recommended for typical cat scratch disease, consider treatment if there is an extensive lymphadenopathy
- 4.1.1 If extensive lymphadenopathy
- Preferred regimen (1) (pediatrics): Azithromycin 500 mg PO on day 1 THEN 250 mg PO qd on days 2 to 5
- Preferred regimen (2) (adults): Azithromycin 1 g PO at day 1 THEN 500 mg PO for 4 days
- 4.2 Endocarditis
- Preferred regimen: Gentamicin 3 mg/kg/day IV q8h for 14 days AND Ceftriaxone 2 g/day IV for 6weeks ± Doxycycline 100 mg PO bid for 6 weeks
- 4.3 Retinitis
- Preferred regimen: Doxycycline 100 mg bid AND Rifampin 300 mg bid PO for 4-6 weeks
- 4.4 Bacillary angiomatosis[6]
- Preferred regimen (1): Erythromycin 500 mg PO qid for 2 months at least
- Preferred regimen (2): Doxycycline 100 mg PO bid for 2 months at least
- 4.5 Bacillary Pelliosis[6]
- Preferred regimen (1): Erythromycin 500 mg PO qid for 4 months at least
- Preferred regimen (2): Doxycycline 100 mg PO bid for 4 months at least
# Neurocysticercosis
- Neurocysticercosis Return to Top
- Neurocysticercosis treatment
- 1. Parenchymal neurocysticercosis
- 1.1 Single lesions[7]
- Preferred regimen: Albendazole 15 mg/kg/day PO bid for 3 to 8 days AND Prednisone 1 mg/kg/day PO qid for 8 to 10 days followed by a taper
- 1.2 Multiple cysts
- Preferred regimen: Albendazole 15 mg/kg/day PO bid for 8 to 15 days and high-dose steroids
- Preferred regimen: Praziquantel 50 mg/kg/day PO tid AND Albendazole 15 mg/kg/day PO bid
- 1.3 Cysticercal encephalitis [7]
- Cysticercal encephalitis (diffuse cerebral edema associated with multiple inflamed cysticerci) is a contraindication for antiparasitic therapy, since enhanced parasite killing can exacerbate host inflammatory response and lead to diffuse cerebral edema and potential transtentorial herniation. Most cases of cysticercal encephalitis improve with corticosteroid therapy
- 1.4 Calcified cysts
- Radiographic evidence of parenchymal calcifications is a significant risk factor for recurrent seizure activity; these lesions are present in about 10 percent of individuals in regions where neurocysticercosis is endemic. Seizures in these patients should be treated with antiepileptic therapy.
- 2. Extraparenchymal NCC
- 2.1 Subarachnoid cysts
- Preferred regimen: Albendazole 15 mg/kg/day PO bid for 28 days AND Prednisone up to 60 mg/day PO OR Dexamethasone (up to 24 mg per day) along with the antiparasitic therapy. The dose can often be tapered after a few weeks. However, in cases for which more prolonged steroid therapy is required, methotrexate can be used as a steroid-sparing agent
- 2.2 Giant cysts
- Giant cysticerci are usually accompanied by cerebral edema and mass effect, which should be managed with high-dose corticosteroids (with or without mannitol).
- 2.3 Intraventricular cysts
- Emergent management with CSF diversion via a ventriculostomy or placement of a ventriculo-peritoneal shunt
- Treatment of residual hydrocephalus may be managed with endoscopic foraminotomy and endoscopic third ventriculostomy; this approach may also allow debulking of cisternal cysticerci
- 2.4 Ocular cysticercosis
- Surgical excision is warranted in the setting of intraocular cysts
- Cysticercal involvement of the extraocular muscles should be managed with albendazole and corticosteroids.
- 2.5 Spinal cysticercosis
- Medical therapy with corticosteroids and antiparasitic drugs
### Parasites – Ectoparasites
- Body lice Return to Top
- Body lice
- Pediculus humanus, corporis treatment[8]
- A body lice infestation is treated by improving the personal hygiene of the infested person, including assuring a regular (at least weekly) change of clean clothes.
- Clothing, bedding, and towels used by the infested person should be laundered using hot water (at least 130°F) and machine dried using the hot cycle.
- Sometimes the infested person also is treated with a pediculicide Ivermectin Lotion; however, a pediculicide Ivermectin generally is not necessary if hygiene is maintained and items are laundered appropriately at least once a week. A pediculicide Ivermectin should be applied exactly as directed on the bottle or by your physician.
- Head lice Return to Top
- Head lice
- Pediculus humanus, capitis treatment[9]
- Preferred regimen (1): Permethrin 1% lotion apply to shampooed dried hair for 10 min.; repeat in 9-10 days
- Preferred regimen (2): Malathion 0.5% lotion (Ovide) apply to dry hair for 8–12hrs, then shampoo (2 doses 7-9 days apart)
- Alternative regimen: Ivermectin 200 μg/kg PO once; 3 doses at 7 day intervals reported effective.
- Pubic lice Return to Top
- Pubic lice
- Phthirus pubis treatment[10]
- Preferred regimen (1): Permethrin 1% cream rinse applied to affected areas and washed off after 10 minutes
- Preferred regimen (2): Pyrethrins with piperonyl butoxide applied to the affected area and washed off after 10 minutes
- Alternative regimen (1): Malathion 0.5% lotion applied to affected areas and washed off after 8–12 hours
- Alternative regimen (2): Ivermectin 250 ug/kg PO, repeated in 2 weeks
- Myiasis Return to Top
- Preferred regimen: No medications approved by the FDA are available for treatment[11]
- Note: Fly larvae need to be surgically removed.
- Fly larvae treatment [12]
- Preferred treatment (1): Occlude punctum to prevent gas exchange with petrolatum, fingernail polish, makeup cream or bacon.
- Preferred treatment (2): When larva migrates, manually remove.
- Note (1): Myiasis is due to larvae of flies.
- Note (2): Usually cutaneous/subcutaneous nodule with central punctum.
# Scabies
- Scabies Return to Top
- Sarcoptes scabiei treatment[13]
- 1. Adult
- Preferred regimen (1): Permethrin 5% cream applied to all areas of the body from the neck down and washed off after 8–14 hours
- Preferred regimen (2): Ivermectin 200 ug/kg PO qd and repeated in 2 weeks
- Alternative regimen: Lindane (1%) 1 oz of lotion or 30 g of cream applied in a thin layer to all areas of the body from the neck down and thoroughly washed off after 8 hours
- 2. Infants and young children
- Preferred regimen: Permethrin 5% cream applied to all areas of the body from the neck down and washed off after 8–14 hours
- Note: Infants and young children aged< 10 years should not be treated with lindane.
- 3. Crusted Scabies
- Crusted scabies (i.e., Norwegian scabies) is an aggressive infestation that usually occurs in immunodeficient, debilitated, or malnourished persons, including persons receiving systemic or potent topical glucocorticoids, organ transplant recipients, persons with HIV infection or human T-lymphotrophic virus-1-infection, and persons with hematologic malignancies.
- Preferred regimen: (Topical scabicide 5% topical Benzyl benzoate 5% OR topical Permethrin 5% cream (full-body application to be repeated daily for 7 days then twice weekly until discharge or cure) AND treatment with Ivermectin 200 ug/kg PO on days 1,2,8,9, and 15. Additional Ivermectin treatment on days 22 and 29 might be required for severe cases
- 4.Pregnant or Lactating Women
- Preferred regimen: Permethrin 5% cream applied to all areas of the body from the neck down and washed off after 8–14 hours
- ↑ Bartlett, John (2012). Johns Hopkins ABX guide : diagnosis and treatment of infectious diseases. Burlington, MA: Jones and Bartlett Learning. ISBN 978-1449625580..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ Foucault C, Raoult D, Brouqui P (2003). "Randomized open trial of gentamicin and doxycycline for eradication of Bartonella quintana from blood in patients with chronic bacteremia". Antimicrob Agents Chemother. 47 (7): 2204–7. PMC 161867. PMID 12821469.CS1 maint: Multiple names: authors list (link) CS1 maint: PMC format (link)
- ↑ Jump up to: 3.0 3.1 Baddour LM, Wilson WR, Bayer AS, Fowler VG, Bolger AF, Levison ME; et al. (2005). "Infective endocarditis: diagnosis, antimicrobial therapy, and management of complications: a statement for healthcare professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, and the Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia, American Heart Association: endorsed by the Infectious Diseases Society of America". Circulation. 111 (23): e394–434. doi:10.1161/CIRCULATIONAHA.105.165564. PMID 15956145.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
- ↑ Bradley JS, Jackson MA, Committee on Infectious Diseases, American Academy of Pediatrics. The use of systemic and topical fluoroquinolones. Pediatrics 2011; 128:e1034.
- ↑ Rolain JM, Brouqui P, Koehler JE, Maguina C, Dolan MJ, Raoult D (2004). "Recommendations for treatment of human infections caused by Bartonella species". Antimicrob Agents Chemother. 48 (6): 1921–33. doi:10.1128/AAC.48.6.1921-1933.2004. PMC 415619. PMID 15155180.CS1 maint: Multiple names: authors list (link) CS1 maint: PMC format (link)
- ↑ Jump up to: 6.0 6.1 Spach DH, Koehler JE (1998). "Bartonella-associated infections". Infect Dis Clin North Am. 12 (1): 137–55. PMID 9494835.
- ↑ Jump up to: 7.0 7.1 García HH, Evans CA, Nash TE, Takayanagui OM, White AC, Botero D; et al. (2002). "Current consensus guidelines for treatment of neurocysticercosis". Clin Microbiol Rev. 15 (4): 747–56. PMC 126865. PMID 12364377.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link) CS1 maint: PMC format (link)
- ↑ "body lice".
- ↑ Gilbert, David (2015). The Sanford guide to antimicrobial therapy. Sperryville, Va: Antimicrobial Therapy. ISBN 978-1930808843.
- ↑ Workowski, Kimberly A.; Bolan, Gail A. (2015-06-05). "Sexually transmitted diseases treatment guidelines, 2015". MMWR. Recommendations and reports: Morbidity and mortality weekly report. Recommendations and reports / Centers for Disease Control. 64 (RR-03): 1–137. ISSN 1545-8601. PMID 26042815.
- ↑ "Parasites - Myiasis".
- ↑ Gilbert, David (2014). The Sanford guide to antimicrobial therapy 2014. Sperryville, Va: Antimicrobial Therapy. ISBN 978-1930808782.
- ↑ Workowski, Kimberly A.; Bolan, Gail A. (2015-06-05). "Sexually transmitted diseases treatment guidelines, 2015". MMWR. Recommendations and reports: Morbidity and mortality weekly report. Recommendations and reports / Centers for Disease Control. 64 (RR-03): 1–137. ISSN 1545-8601. PMID 26042815. | https://www.wikidoc.org/index.php/Sandbox_mj | |
03358692169cadca85753ef914198137033bfbb0 | wikidoc | Sandbox mk | Sandbox mk
# Overview
Peptic ulcer disease patient appears in severe stress due to abdominal pain. Common physical examination findings of peptic ulcer disease include epigastric tenderness, tachycardia.Perforated peptic ulcer disease patient presents with classic triad of severe epigastric tenderness, tachycardia, and abdominal rigidity. Clinical signs of perforated peptic ulcer occurs in 3 stages: In the initial stage within first 2 hours, the patient presents with tachycardia, epigastric pain and cool extremities.In next 2 to 12 hours, the patient presents with lower right quadrant tenderness and abdominal rigidity. In more than 12 hours, the patient presents with abdominal distension, hypotension, and pyrexia with acute circulatory collapse.
# Physical Examination
## Appearance of the Patient
- Patient usually appear in severe distress due to severe abdominal pain.
## Vital Signs
- Patient has normal vital signs in initial stages of peptic ulcer.
- In peptic ulcer perforations vital signs may include :
Tachycardia with regular pulse
Weak pulse
low blood pressure with normal pulse pressure
High-grade fever is present at later stage of peptic ulcer perforation
- Tachycardia with regular pulse
- Weak pulse
- low blood pressure with normal pulse pressure
- High-grade fever is present at later stage of peptic ulcer perforation
## Skin
- Pallor is present in patients presents with hematemesis and melena.
- Source- Dr Graham Beards (Own work)
- The hand of a person with severe anemia (on the left) compared to one without (on the right) Source -James Heilman, MD - Own work
## HEENT
- Pallor on the lower conjunctiva can be seen.
## Lungs
- Normal B/L vesicular breath sounds.
## Heart
- S1 and S2 normal ,no murmur/rubs/gallops.
## Abdomen
- Abdominal tenderness at the epigastrium
- Perforated peptic ulcer presents with
Rebound tenderness
Decreased bowel sounds
Lower right quadrant tenderness
Abdominal rigdity
Abdominal distension
- Rebound tenderness
- Decreased bowel sounds
- Lower right quadrant tenderness
- Abdominal rigdity
- Abdominal distension | Sandbox mk
Template:Physical examination of peptic ulcer disease
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Manpreet Kaur, MD [2]
# Overview
Peptic ulcer disease patient appears in severe stress due to abdominal pain. Common physical examination findings of peptic ulcer disease include epigastric tenderness, tachycardia.Perforated peptic ulcer disease patient presents with classic triad of severe epigastric tenderness, tachycardia, and abdominal rigidity. Clinical signs of perforated peptic ulcer occurs in 3 stages: In the initial stage within first 2 hours, the patient presents with tachycardia, epigastric pain and cool extremities.In next 2 to 12 hours, the patient presents with lower right quadrant tenderness and abdominal rigidity. In more than 12 hours, the patient presents with abdominal distension, hypotension, and pyrexia with acute circulatory collapse.[1]
# Physical Examination
## Appearance of the Patient
- Patient usually appear in severe distress due to severe abdominal pain.
## Vital Signs
- Patient has normal vital signs in initial stages of peptic ulcer.
- In peptic ulcer perforations vital signs may include :[2]
Tachycardia with regular pulse
Weak pulse
low blood pressure with normal pulse pressure
High-grade fever is present at later stage of peptic ulcer perforation
- Tachycardia with regular pulse
- Weak pulse
- low blood pressure with normal pulse pressure
- High-grade fever is present at later stage of peptic ulcer perforation
## Skin
- Pallor is present in patients presents with hematemesis and melena.
- Source- Dr Graham Beards (Own work) [3]
- The hand of a person with severe anemia (on the left) compared to one without (on the right) Source -James Heilman, MD - Own work[4]
## HEENT
- Pallor on the lower conjunctiva can be seen.
## Lungs
- Normal B/L vesicular breath sounds.
## Heart
- S1 and S2 normal ,no murmur/rubs/gallops.
## Abdomen
- Abdominal tenderness at the epigastrium
- Perforated peptic ulcer presents with[5]
Rebound tenderness
Decreased bowel sounds
Lower right quadrant tenderness
Abdominal rigdity
Abdominal distension [6]
- Rebound tenderness
- Decreased bowel sounds
- Lower right quadrant tenderness
- Abdominal rigdity
- Abdominal distension [6] | https://www.wikidoc.org/index.php/Sandbox_mk | |
cff2bbbb621bbd962d52c67dc6644cfae8924d35 | wikidoc | Sandbox sc | Sandbox sc
# Mycobacterium terrae
- Mycobacterium terrae
- 1. In vitro susceptibility
- All six of the isolates from a single center and 90% or more of an additional 22 isolates of M. terrae complex were susceptible to Ciprofloxacin and Sulfonamides. Recently, 11 isolates of M. terrae complex were also shown to be susceptible to Linezolid
- 2. Antimicrobial therapy
- Based on in vitro susceptibility results
# Mycobacterium szulgai
- Mycobacterium szulgai
- 1. in vitro susceptibility
- M. szulgai is susceptible in vitro to most antituberculous drugs including Quinolones and newer Macrolides
- 2. Infection
- 2.1 Pulmonary infection
- Three- or four-drug regimen based on susceptibility that includes 12 months of negative sputum cultures while on therapy
- 2.2 Extrapulmonary infection
- Combination anti-tuberculous medications based on in vitro susceptibilities for 4-6 months
# Mycobacterium smegmatis
- Mycobacterium smegmatis
- 1. Mild disease
- Preferred regimen: Doxycycline PO AND Trimethoprim sulfamethoxazole PO
- 2. Severe disease
- Preferred regimen: Amikacin IV OR Imipenem IV
# Mycobacterium mucogenicum
- Mycobacterium mucogenicum
- In vitro susceptible agents: Aminoglycosides, Cefoxitin, Clarithromycin, Minocycline, Doxycycline, Quinolones, Trimethoprim/sulfamethoxazole, and Imipenem
# Mycobacterium malmoense
- Mycobacterium malmoense
- 1. In vitro
- Susceptible: Ethambutol, Ethionamide, Kanamycin, and Cycloserine
- Resistant: INH, Streptomycin, Rifampin, and Capreomycin
- 2. Pulmonary M. malmoense infection
- Preferred regimen: INH AND Rifampin AND Ethambutol ± Quinolones AND Macrolides
# Mycobacterium immunogenum
- Mycobacterium immunogenum
- In vitro
- Susceptible: Amikacin and Clarithromycin
- Resistant: Ciprofloxacin, Doxycycline, Cefoxitin, Tobramycin, and Sulfamethoxazole
- Note: The optimal therapy for this organism is unknown; however, successful therapy is likely difficult due to the extensive antibiotic resistance of the organism
# Mycobacterium leprae
- Mycobacterium leprae
- 1. Multibacillary Leprosy (Skin smear positive)
- 1.1 Adult
- Preferred regimen: Dapsone 100 mg/day PO AND Rifampin 600 mg PO 4 times per week AND Clofazimine 50 mg PO qd for 12-24 months
- Note: Clofazimine should be supplemented by loading dose 300 mg PO monthly
- 1.2 Pediatric
- 1.2.1 < 35 kg
- Preferred regimen: Dapsone 1-2 mg/kg/day PO AND Rifampin 450 mg PO for 12-24 months
- 1.2.2 < 20 kg
- Preferred regimen: Dapsone 1-2 mg/kg/day PO AND Rifampin 300 mg PO for 12-24 months
- 1.2.3 < 12 kg
- Preferred regimen: Dapsone 1-2 mg/kg/day PO AND Rifampin 150 mg PO for 12-24 months
- 2. Paucibacillary Leprosy (Skin Smear negative)
- Preferred regimen: Rifampin 600 mg PO once a month for 6 months AND Dapsone 100 mg PO qd for 6 months
- 3. Erythema Nodosum Leprosum (ENL)
- 3.1 Mild
- Preferred regimen: Rest affect limb, analgesics, follow-up twice a week, check for iridocyclitis; Chloroquine OR Aspirin may be useful
- 3.2 Severe (numerous nodules + fever, ulcerating/pustular ENL, visceral involvement, nodules + neuritis, recurrent ENL)
- Preferred regimen: Prednisolone 30-40 mg/day PO for 1-2 weeks THEN taper over 12 weeks
- Alternative regimen (1): (If unresponsive to corticosteroids or if risk of corticosteroids prevent administration) Start Clofazimine 100 mg PO tid for maximum of 12 weeks THEN 100 mg PO bid for 12 weeks THEN 100 mg qd for 12-24 weeks
- Alternative regimen (2): (if not contraindicated) Thalidomide 200-400 mg/day PO, reduced to 50-100 mg/day after 1-2 weeks
- 4. Reversal Reaction
- Preferred regimen: Prednisolone start with 40 mg/day PO THEN taper by 10 mg twice a week for 12 weeks
# Mycobacterium xenopi
- Mycobacterium xenopi
- 1. The cornerstone of therapy for M. xenopi
- Preferred regimen: Clarithromycin AND Rifampin AND Ethambutol
- Note: Therapy should be continued until the patient has maintained negative sputum cultures while on therapy for 12 months
- 2. Pulmonary disease
- Preferred regimen: INH AND Rifabutin OR Rifampin AND Ethambutol AND Clarithromycin ± Streptomycin
- Note: A quinolone, preferably Moxifloxacin, could be substituted for one of the antituberculous drugs
- 3. Extrapulmonary disease
- Note: Therapy for extrapulmonary disease would include the same agents as for pulmonary disease
# Mycobacterium ulcerans
- Mycobacterium ulcerans
- 1. Preulcerative lesions
- Excision and primary closure, Rifampin monotherapy, or heat therapy
- 2. Established ulcers
- Most antimycobacterial agents are ineffective for the treatment of the ulcer; Surgical debridement combined with skin grafting is the usual treatment of choice
- 3. Control complications of the ulcer
- Preferred regimen: Clarithromycin AND Rifampin
# Swine influenza
- Swine influenza
- 1. Condition1: Patients who have severe or progressive clinical illness
- Preferred regimen: Oseltamivir 150 mg PO bid
- Note(1): Treatment duration depends on clinical response
- Note(2): Where the clinical course remains severe or progressive, despite 5 or more days of antiviral treatment, monitoring of virus replication and shedding, and antiviral drug susceptibility testing is desirable
- Note(3): Antiviral treatment should be maintained without a break until virus infection is resolved or there is satisfactory clinical improvement
- Note(4): Patients who have severe or progressive clinical illness, but who are unable to take oral medication may be treated with Oseltamivir administered by nasogastric or orogastric tube
- 2. Condition2: In situations where oseltamivir is not available, or not possible to use, patients who have severe or progressive clinical illness
- Preferred regimen: Zanamivir inhaled
- Note: Zanamivir IV should be considered where available and is recommended for those with serious or progressive illness. If not available, Peramivir IV may be considered
- 3. Condition3: Severely immunosuppressed patients
- Antiviral chemoprophylaxis would be considered by using Oseltamivir OR Zanamivir
# Mycobacterium simiae
- Mycobacterium simiae
- Preferred regimen: Clarithromycin AND Moxifloxacin AND Trimethoprim/sulfamethoxazole
# Mycobacterium foruitum
- Mycobacterium foruitum
- 1. In vitro isolates
- Susceptible agents: Amikacin (100%), Ciprofloxacin and Ofloxacin (100%), Sulfonamides (100%), Cefoxitin (50%), Imipenem (100%), Clarithromycin (80%), and Doxycycline (50%)
- 2. Disease
- 2.1 M. fortuitum lung disease
- At least two agents with in vitro activity against the clinical isolate should be given for at least 12 months of negative sputum cultures
- 2.2 Serious skin, bone, and soft tissue M fortuitum disease
- At least two agents with in vitro activity against the clinical isolate should be given for a minimum of 4 months; For bone infections, 6 months of therapy is recommended
# Mycobacterium scrofulaceum
- Mycobacterium scrofulaceum
- Susceptibility data are lacking and standard treatment regimens for M. scrofulaceum are controversial, emphasizing the need to perform susceptibility testing on confirmed disease-producing isolates of M. scrofulaceum
# Mycobacterium marinum
- Mycobacterium marinum
- 1. In vitro M. marinum isolates
- Susceptible: Rifampin, Rifabutin, Ethambutol, Clarithromycin, Sulfonamides, and Trimethoprim sulfamethoxazole
- Intermediately susceptible: Streptomycin, Doxycycline, and Minocycline
- Resistant: Isoniazid and Pyrazinamide
- Note: Two active agents for 1 to 2 months after resolution of symptoms, typically 3 to 4 months in total
- 2. Infection
- 2.1 skin and soft tissue infections
- Preferred regimen (1): Clarithromycin AND Ethambutol
- Preferred regimen (2): Ethambutol AND Rifampin
- Note: Azithromycin can replace Clarithromycin
- 2.2 osteomyelitis or deep structure infection
- Preferred regimen: Clarithromycin AND Ethambutol AND Rifampin
# Mycobacterium kansasii
- Mycobacterium kansasii
- 1. pulmonary disease
- Preferred regimen: Rifampin 10 mg/kg/day (Maximum, 600 mg) PO AND Ethambutol 15 mg/kg/ day PO AND Isoniazid 5 mg/kg/day (Maximum 300 mg) PO AND Pyridoxine 50 mg/day PO
- Note: Treatment duration for M. kansasii lung disease should include 12 months of negative sputum cultures
- 2. Rifampin-resistant M. kansasii disease
- Preferred regimen: Clarithromycin OR Azithromycin OR Moxifloxacin OR Ethambutol OR Sulfamethoxazole OR Streptomycin
- Note(1): Use three-drug regimen
- Note(2): Patients undergoing therapy for M. kansasii lung disease should have close clinical monitoring with frequent sputum examinations for mycobacterial culture throughout therapy
- 3. Disseminated M. kansasii disease
- Note: The treatment regimen for disseminated disease should be the same as for pulmonary disease
# Mycobacterium gordonae
- Mycobacterium gordonae
- Preferred regimen: Ethambutol OR Rifabutin OR Clarithromycin OR Linezolid OR Fluoroquinolones
# Mycobacterium genavense
- Mycobacterium genavense
- Susceptibility: Amikacin, Rifamycin, Fluoroquinolones, Streptomycin, and Macrolides
- Note(1): Ethambutol has limited activity
- Note(2): Optimal therapy is not determined, but multidrug therapies including Clarithromycin appear to be more effective than those without Clarithromycin
# Mycobacterium haemophilum
- Mycobacterium haemophilum
- 1. In vitro
- Susceptible: Amikacin, Clarithromycin, Ciprofloxacin, Rifampin, and Rifabutin
- Less susceptible: Doxycycline and Sulfonamides
- 2. Infection
- 2.1 Disseminated disease
- Preferred regimen: Clarithromycin AND Rifampin AND Rifabutin AND Ciprofloxacin
# Mycobacterium chelonae
- Mycobacterium chelonae
- 1. Localized infections
- Preferred regimen: Clarithromycin 500 mg PO bid
- Alternative regimen: Azithromycin
- 2. Disseminated or extensive disease
- 2.1 monotherapy
- Preferred regimen: Clarithromycin 500 mg PO bid for 6 months
- 2.2 multidrug therapy
- preferred regimen: Clarithromycin 500 mg PO bid AND Tobramycin 5 mg/kg IV q24h OR Imipenem 0.5-1 g IV q6h OR Linezolid 600 mg IV/PO q12h/bid for 4-8 weeks
- Alternative regimen: Moxifloxacin 400 mg PO qd AND Linezolid 600 mg PO bid
- Note(1): During initial treatment, multidrug therapy may prevent development of acquired resistance
- Note(2): Total treatment duration is 6 months
- 3. Keratitis (LASIK-related)
- Preferred regimen: Clarithromycin 500 mg PO bid AND Tobramycin 0.3% 2 gtts q4h AND Gatifloxacin 0.3% 1 gtt q4h OR Moxifloxacin 0.5% 1 gtt q4h
# Mycobacterium celatum
- Mycobacterium celatum
- Preferred regimen: Clarithromycin AND Ethambutol AND Ciprofloxacin ± Rifabutin
# Mycobacterium avium complex
- 1. Treatment of MAC pulmonary disease
- 1.1 Patients with nodular/bronchiectatic disease
- Preferreday regimen: Clarithromycin 1,000 mg three times weekly OR Azithromycin 500–600 mg three times weekly AND Ethambutol 25 mg/kg three times weekly AND Rifampin 600 mg three times weekly
- Note: Patients should be treated until culture negative on therapy for 1 year
- 1.2 Patients with fibrocavitary or severe nodular/bronchiectatic disease
- Preferreday regimen: Clarithromycin 500–1,000 mg/day OR Azithromycin 250–300 mg/day OR Rifampin 600 mg/day OR Rifabutin 150–300 mg/day AND Ethambutol 15 mg/kg/day
- Note(1): Amikacin OR Streptomycin threetimes-weekly can be used early in therapy
- Note(2): Patients should be treated until culture negative on therapy for 1 year
- 2. Disseminateday MAC disease
- Preferreday regimen: Clarithromycin 1,000 mg/day OR Azithromycin 250 mg/day AND Ethambutol 15 mg/kg/day ± Rifabutin 150–350 mg/day
# Mycobacterium bovis
- Mycobacterium bovis
- Note: Is intrinsically resistant to Pyrazinamide (PZA). The treatment of M. bovis is extrapolated from experience with the treatment of PZA-resistant M. tuberculosis
- 1. Pulmonary and most extrapulmonary disease
- Preferred regimen: Isoniazid AND Rifampin AND Ethambutol for 2 months, followed by Isoniazid AND Rifampin for 7 months
- 2. Meningitis
- Preferred regimen: Isoniazid AND Rifampin AND Ethambutol for 2 months, followed by Isoniazid AND Rifampin for 10 months
# Mycobacterium abscessus
- 1.Limited, localized extrapulmonary disease
- Preferred regimen: Clarithromycin 500 mg PO bid ± Amikacin 10-15 mg/kg/day IV or 25 mg/kg three times weekly for 4 months
- Alternative regimen (1): Amikacin AND Cefoxitin 12 g/day PO for two weeks
- Note: until clinical improvement in severe cases
- Alternative regimen (2): Amikacin AND Imipenem 500 mg IV q6-8h for two weeks
- Note(1): Until clinical improvement in severe cases
- Note(2): Osteomyelitis should be treated for as least 6 months; Infected foreign bodies should be removed
- 2.Pulmonary or serious extrapulmonary disease
- Preferred regimen: Clarithromycin 500 mg PO bid AND Amikacin 15 mg/kg/day IV AND Cefoxitin 2g IV q4h OR Imipenem 1g IV q6h for at least 2-4 months
- Note: If limited by adverse effects, then switch to Clarithromycin 500 mg PO bid or 1000 mg XR qd OR Azithromycin 250 mg PO qd
- Alternative regimen(1): Tigecycline 100 mg IV loading dose, then 50 mg IV q12h
- Note: could be substituted as one of the injectables
- Alternative regimen(2): Linezolid 600 mg PO bid or 600 mg PO qd AND Clarithromycin
- Note: Could replace parental tx if not tolerated or feasible
# Mycobacterium tuberculosis
- 1. Standard Regimens for new patients
- 1.1 Adult
- 1.1.1 Initial phase
- Preferred regimen: Isoniazid 300 mg PO (5 mg/kg/day) qd for 8 weeks AND Rifampicin 600 mg PO (10 mg/kg/day) qd for 8 weeks AND Pyrazinamide 2 g PO (25 mg/kg/day) qd for 8 weeks AND Ethambutol 1.6 g PO (15 mg/kg/day) qd for 8 weeks
- Alternative regimen (1): Isoniazid 300 mg/day PO for 2 weeks (5 mg/kg/day) AND Rifampicin 600 mg/day PO for 2 weeks (10 mg/kg/day) AND Pyrazinamide 2 g/day PO for 2 weeks (25 mg/kg/day) AND Ethambutol 1.6 g PO for 2 weeks (15 mg/kg/day), followed by Isoniazid 300 mg/day PO twice weekly for 6 weeks (5 mg/kg/day) AND Rifampicin 600 mg/day PO twice weekly for 6 weeks (10 mg/kg/day) AND Pyrazinamide 2 g/day PO twice weekly for 6 weeks AND Ethambutol 1.6 g PO for 2 weeks (15 mg/kg/day)
- Alternative regimen (2): Isoniazid 300 mg/day PO thrice weekly for 8 weeks (5 mg/kg/day) AND Rifampicin 600 mg/day PO thrice weekly for 8 weeks (10 mg/kg/day) AND Pyrazinamide 2g/day PO thrice weekly for 8 week (25 mg/kg/day) AND Ethambutol 1.6 g PO thrice weekly for 8 weeks (15 mg/kg/day)
- 1.1.2 Continuation phase
- Preferred regimen (1): Isoniazid 300 mg PO (5 mg/kg/day) qd AND Rifampicin 600 mg PO (10 mg/kg/day) qd for 18 weeks
- Preferred regimen (2): Isoniazid 300 mg PO twice weekly (5 mg/kg/day) AND Rifampicin 600 mg/day PO twice weekly (10 mg/kg/day) for 18 weeks
- Alternative regimen (1): Isoniazid 300 mg/day PO biweekly for 18 weeks (5 mg/kg/day) AND Rifampicin 600 mg/day PO biweekly for 18 weeks (10 mg/kg/day)
- Alternative regimen (2): Isoniazid 300 mg/day PO thrice weekly for 18 weeks (5 mg/kg/day) AND Rifampicin 600 mg/day PO thrice weekly for 18 weeks (10 mg/kg/day)
- 1.2 Pediatric
- 1.2.1 Initial phase
- Preferred regimen: Isoniazid 10 mg/kg PO (Maximum, 300 mg/day) AND Rifampicin 15 mg/kg PO (Maximum, 600 mg/day) AND Pyrazinamide 35 mg/kg PO (Maximum, 2 g/day) AND Ethambutol 20 mg/kg PO (Maximum, 1.6 g/day), each for 8 weeks
- 1.2.2 Continuation phase
- Preferred regimen: Isoniazid 10 mg/kg PO (Maximum, 300 mg/day) AND Rifampicin 15 mg/kg PO (Maximum, 600 mg/day), each drug daily for 18 weeks
- 2. MDR Tuberculosis
- 2.1 Adult
- Preferred regimen: 4 agents combination
- Agent 1: Pyrazinamide 20–30 mg/kg OR Ethambutol 15–25 mg/kg OR Rifabutin 5 mg/kg
- Agent 2: Capreomycin 15 mg/kg OR Kanamycin 15 mg/kg OR Amikacin 7.5-10 mg/kg OR Streptomycin 12–18 mg/kg
- Agent 3: Levofloxacin 500-1000 mg OR Moxifloxacin 400 mg OR Ofloxacin 400 mg
- Agent 4: Ethionamide 15-20 mg/kg OR Protionamide 15-20 mg/kg OR Cycloserine 10-15 mg/kg OR Terizidone 10-20 mg/kg OR Para-aminosalicylic acid 8-12 g/day IV q8-12h
- 2.2 Pediatric
- Preferred regimen: 4 agents combination
- Agent 1: Pyrazinamide 20-30 mg/kg (Maximum: 600 mg) OR Ethambutol 15-20 mg/kg OR Rifabutin 5 mg/kg
- Agent 2: Capreomycin 15-30 mg/kg (Maximum: 1000 mg) OR Kanamycin 15-30 mg/kg (Maximum: 1000 mg) OR Amikacin 15-22.5 mg/kg (Maximum: 1000 mg) OR Streptomycin 12-18 mg/kg AND
- Agent 3: Levofloxacin 7.5-10 mg/kg OR Moxifloxacin 7.5-10 mg/kg OR Ofloxacin 15-20 mg/kg/day q12h (Maximum: 800 mg)
- Agent 4: Ethionamide 15-20 mg/kg/day q12h (Maximum: 1000 mg) OR Protionamide 15-20 mg/kg/day q12h (Maximum: 1000 mg) OR Cycloserine 10-20 mg/kg (Maximum: 1000 mg) OR Terizidone 10-20 mg/kg (Maximum: 1000 mg) OR Para-aminosalicylic acid 150 mg/kg/day q8-12h(Maximum: 12,000 mg)
- 3. XDR Tuberculosis
- 3.1 Adult
- Preferred regimen: 3 agents combination
- Agent 1: Pyrazinamide 20–30 mg/kg OR Ethambutol 15–25 mg/kg OR Rifabutin 5 mg/kg
- Agent 2: Ethionamide 15-20 mg/kg OR Protionamide 15-20 mg/kg OR Cycloserine 10-15 mg/kg OR Terizidone 10-20 kg/mg OR Para-aminosalicylic acid 8-12 g/day q8-12h
- Agent 3: Clofazimine 50 mg/d AND 300 mg once a month OR Amoxicillin/clavulanate 500 mg/125 mg q12h OR Linezolid 300-600 mg OR Imipenem 500mg q6h OR Clarithromycin 500-1000 mg q12h OR Thioacetazone 2.5 mg/kg OR Isoniazid (high-dose) 16–20 mg/kg
- 3.2 Pediatric
- Preferred regimen: 3 agents combination
- Agent 1: Pyrazinamide 20-30 mg/kg (Maximum: 600 mg) OR Ethambutol 15 mg/kg OR Rifabutin 5 mg/kg
- Agent 2: Ethionamide 15-20 mg/kg (Maximum: 1000 mg) OR Protionamide 15-20 mg/kg (Maximum: 1000 mg) OR Cycloserine 10-20 mg/kg (Maximum: 1000 mg) OR Terizidone 10-20 mg/kg (Maximum: 1000 mg) OR Para-aminosalicylic acid 150 mg/kg/day q8-12h
- Agent 3: Clofazimine 50 mg/d AND 300 mg once a month OR Amoxicillin/clavulanate OR Linezolid 300-600 mg OR Imipenem 500mg q6h OR Clarithromycin 500-1000 mg q12h OR Thioacetazone 2.5 mg/kg OR Isoniazid (high-dose) 16–20 mg/kg
# Bacteroides fragilis
- Bacteroides fragilis
- 1. Monotherapy
- Preferred regimen (1): Imipenem
- Preferred regimen (2): Ertapenem
- Preferred regimen (3): Meropenem
- Preferred regimen (4): Doripenem 0.5-1.0 g IV q6h
- Preferred regimen (5): Piperacillin-tazobactam 3.375 g IV q6h
- Preferred regimen (6): Ampicillin-sulbactam 1-2 g IV q6h
- Preferred regimen (7): Tigecycline 100 mg IV THEN 50 mg IV q12h
- 2. Combination therapy
- Preferred regimen: Metronidazole 0.75-1.0 g IV q12h AND Cefotaxime 1.5-2 g IV q6h OR Aztreonam 1-2 g IV q8h OR Ceftriaxone 1 g IV q12h
# Acinetobacter baumannii
- Acinetobacter baumannii
- Preferred regimen (1): Imipenem 0.5-1 g IV q6h
- Preferred regimen (2): Ampicillin/sulbactam 3 g q4h
- Preferred regimen (3): Cefepime 1-2 g IV q8h
- Preferred regimen (4): Colistin 2.5 mg/kg IV q12h
- Preferred regimen (5): Tigecycline 100 mg IV THEN 50 mg IV q12h
- Preferred regimen (6): Amikacin 7.5 mg/kg q12h IV or 15 mg/kg/day IV
- Alternative regimen (1): Ceftriaxone 1-2g IV every day
- Alternative regimen (2): Cefotaxime 2-3g IV q6-8h
- Alternative regimen (3): Ciprofloxacin 400 mg IV q8-12h or 750 mg PO bid
- Alternative regimen (4): TMP-SMX 15-20 mg (TMP)/kg/day IV q6-8h or 2 DS PO bid
# Vibrio vulnificus
- Vibrio vulnificus
- Note: If V. vulnificus is suspected, treatment should be initiated immediately because antibiotics improve survival
- Preferred regimen: Doxycycline 100 mg PO/IV bid for 7-14 days AND Ceftazidime 1-2 g IV/IM q8h
- Note: A single agent regimen with a fluoroquinolone such as Levofloxacin, Ciprofloxacin or Gatifloxacin, has been reported to be at least as effective in an animal model as combination drug regimens with Doxycycline and a Cephalosporin
- Pediatric regimen: Doxycycline AND Fluoroquinolones; trimethoprim-sulfamethoxazole AND an Aminoglycoside
# Vibrio parahaemolyticus
- Vibrio parahaemolyticus
- 1. Mild to Moderate
- Treatment is not necessary in most cases of V. parahaemolyticus infection
- There is no evidence that antibiotic treatment decreases the severity or the length of the illness
- Patients should drink plenty of liquids to replace fluids lost through diarrhea
- 2. Severe or prolonged illnesses
- Preferred regimen: Tetracycline OR Ciprofloxacin
# Vibrio cholerae
- 1. WHO
- Note: Antibiotic treatment for cholera patients with severe dehydration only
- Adults
- Preferred regimen: Doxycycline 300 mg po single dose
- Alternative regimen: Tetracycline 12.5 mg/kg PO qid for 3 days
- Pediatric
- Under 12 years old
- Preferred regimen: Erythromycin 12.5 mg/kg PO qid for 3 days
- Over 12 years old
- Preferred regimen: Doxycycline 300 mg po single dose
- Alternative regimen: Tetracycline 12.5 mg/kg PO qid for 3 days
- 2. Pan American Health Organization
- Note: Antibiotic treatment for cholera patients with moderate or severe dehydration
- 2.1 Adult
- Preferred regimen: Doxycycline 300 mg po single dose
- Alternative regimen (1): Ciprofloxacin 1 g PO single dose
- Alternative regimen (2): Azithromycin 1 g PO single dose
- 2.2 Pediatric
- 2.2.1 Children over 3 year, who can swallow tablets
- Preferred regimen (1): Erythromycin 12.5 mg/kg/ PO qid for 3 days
- Preferred regimen (2): Azithromycin 20 mg/kg PO in a single dose
- Alternative regimen (1): Ciprofloxacin suspension or tablets 20 mg/kg PO single dose
- Alternative regimen (2): Doxycycline suspension or tablets 2-4 mg/kg PO single dose
- Note: Although doxycycline has been associated with a low risk of yellowing of the teeth in children, its benefits outweigh its risks
- 2.2.2 Children under 3 year, or infants who cannot swallow tablets
- Preferred regimen (1): Erythromycin suspension 12.5 mg/kg/ PO qid for 3 days
- Preferred regimen (2): Azithromycin suspension 20 mg/kg PO single dose
- Alternative regimen (1): Ciprofloxacin suspension 20 mg/kg PO single dose
- Alternative regimen (2): Doxycycline syrup 2-4 mg/kg PO single dose
- 2.3 Pregnancy
- Preferred regimen (!): Erythromycin 500 mg/ PO qid for 3 days
- Preferred regimen (2): Azithromycin 1 g PO single dose
# Treponema pallidum
- 1. Syphilis Among non-HIV-Infected Persons
- 1.1 Primary and Secondary Syphilis
- Preferred regimen: Benzathine penicillin G 2.4 MU IM single dose
- Pediatric regimen: Benzathine penicillin G 50,000 U/kg (Maximum, 2.4 MU) IM single dose
- 1.2 Latent Syphilis
- 1.2.1 Early Latent Syphilis
- Preferred regimen: Benzathine penicillin G 2.4 MU IM in a single dose
- Pediatric regimen: Benzathine penicillin G 50,000 U/kg (Maximum, 2.4 MU) IM single dose
- 1.2.2 Late Latent Syphilis or Latent Syphilis of Unknown Duration
- Preferred regimen: Benzathine penicillin G 7.2 MU total, administered as 3 doses of 2.4 MU IM each at 1 week intervals
- Pediatric regimen: Benzathine penicillin G 50,000 U/kg IM (Maximum, 2.4 MU), administered as 3 doses at 1 week intervals (total 150,000 U/kg up to the adult total dose of 7.2 MU)
- 1.3 Tertiary Syphilis
- Preferred regimen: Benzathine penicillin G 7.2 MU total, administered as 3 doses of 2.4 MU IM each at 1 week intervals
- 1.4 Neurosyphilis and ocular syphilis
- Preferred regimen: Aqueous crystalline penicillin G 18-24 MU per day, administered as 3-4 MU IV q4h or continuous infusion, for 10-14 days
- Alternative regimen: Procaine penicillin 2.4 MU IM q24h AND Probenecid 500 mg PO qid for 10-14 days
- 2. Syphilis Among HIV-Infected Persons
- 2.1 Primary and Secondary Syphilis Among HIV-Infected Persons
- Preferred regimen: Benzathine penicillin G 2.4 MU IM single dose
- 2.2 Latent Syphilis Among HIV-Infected Persons
- 2.2.1 early latent
- Preferred regimen: Benzathine penicillin G 2.4 MU IM single dose
- 2.2.2 late latent
- Preferred regimen: Benzathine penicillin G 2.4 MU once a week for 3 weeks
- 2.3 Neurosyphilis Among HIV-Infected Persons
- Preferred regimen: Aqueous crystalline penicillin G 18-24 MU per day, administered as 3-4 MU IV q4h or continuous infusion, for 10-14 days
- Alternative regimen: Procaine penicillin 2.4 MU IM q24h AND Probenecid 500 mg PO qid for 10-14 days
- 3. Syphilis During Pregnancy
- Pregnant women should be treated with the penicillin regimen appropriate for their stage of infection
- 4. Congenital Syphilis in neonates
- 4.1 condition1: Infants with proven or highly probable disease and (1) an abnormal physical examination that is consistent with congenital syphilis;（2）a serum quantitative nontreponemal serologic titer that is fourfold higher than the mother's titer; or（3）a positive darkfield test of body fluid(s).
- Preferred regimen (1): Aqueous crystalline penicillin G 100,000-150,000 U/kg/day, administered as 50,000 U/kg/dose IV q12h during the first 7 days of life and q8h thereafter for a total of 10 days
- Preferred regimen (2): Procaine penicillin G 50,000 U/kg/dose IM q24h for 10 days
- Note: If more than 1 day of therapy is missed, the entire course should be restarted. Data are insufficient regarding the use of other antimicrobial agents (e.g., ampicillin). When possible, a full 10-day course of penicillin is preferred, even if ampicillin was initially provided for possible sepsis. The use of agents other than penicillin requires close serologic follow-up to assess adequacy of therapy. In all other situations, the maternal history of infection with T. pallidum and treatment for syphilis must be considered when evaluating and treating the infant.
- 4.2 condition2: Infants who have a normal physical examination and a serum quantitive nontreponemal serologic titer the same or less than fourfold the maternal titer and the (1) mother was not treated, inadequately treated, or has no documentation of having received treatment; (2) mother was treated with erythromycin or another nonpenicillin regimen; or (3) mother received treatment <4 weeks before delivery.
- Preferred regimen (1): Aqueous crystalline penicillin G 100,000-150,000 U/kg/day, administered as 50,000 U/kg/dose IV q12h during the first 7 days of life and q8h thereafter for a total of 10 days
- Preferred regimen (2): Procaine penicillin G 50,000 U/kg/dose IM q24h for 10 days
- Preferred regimen (3): Benzathine penicillin G 50,000 U/kg/dose IM single dose
- Note: If the mother has untreated early syphilis at delivery, 10 days of parenteral therapy can be considered
- 4.3 condition3: Infants who have a normal physical examination and a serum quantitative nontreponemal serologic titer the same or less than fourfold the maternal titer and the (1) mother was treated during pregnancy, treatment was appropriate for the stage of infection, and treatment was administered >4 weeks before delivery and (2) mother has no evidence of reinfection or relapse.
- Preferred regimen: Benzathine penicillin G 50,000 U/kg/dose IM single dose
- 4.4 condition4: Infants who have a normal physical examination and a serum quantitative nontreponemal serologic titer the same or less than fourfold the maternal titer and the (1) mother's treatment was adequate before pregnancy; and (2) mother's nontreponemal serologic titer remained low and stable before and during pregnancy and at delivery (VDRL <1:2; RPR <1:4).
- No treatment is required
- Benzathine penicillin G 50,000 U/kg IM single dose might be considered, particularly if follow-up is uncertain.
- 5. Congenital Syphilis in infants and children
- Preferred regimen: Aqueous crystalline penicillin G 50,000 U/kg q4–6h for 10 days
# Leptospira
- Leptospira
- Preferred regimen: Doxycycline 200 mg PO once a week
# Borrelia recurrentis
- 1. Tick-Borne Relapsing Fever
- Preferred regimen: Doxycycline 100 mg PO bid for 5-10 days
- Alternative regimen: Erythromycin 500 mg PO qid for 5-10 days
- Note: If meningitis/encephalitis present, use Ceftriaxone 2 g IV q12h for 14 days
- 2. Louse-Borne Relapsing Fever
- Preferred regimen: Tetracycline 500 mg PO single dose
- Alternative regimen: Erythromycin 500 mg PO single dose
# Borrelia burgdorferi
- Lyme disease
- 1. Early Lyme Disease
- 1.1 Erythema migrans
- 1.1.1 Adult
- Preferred regimen (1): Doxycycline 100 mg PO bid for 10-21 days
- Preferred regimen (2): Amoxicillin 500 mg PO tid for 14-21 days
- Preferred regimen (3): Cefuroxime axetil 500 mg bid for 14-21 days
- Alternatie regimen (1): Azithromycin 500 mg PO qd for 7–10 days
- Alternatie regimen (2): Clarithromycin 500 mg PO bid for 14–21 days (if the patient is not pregnant)
- Alternatie regimen (3): Erythromycin 500 mg PO qid for 14–21 days
- 1.1.2 Pediatric
- 1.1.2.1 children <8 years of age
- Preferred regimen (1): Amoxicillin 50 mg/kg/day PO q8h (Maximum of 500 mg per dose)
- Preferred regimen (2): Cefuroxime axetil 30 mg/kg/day PO q12h（Maximum, 500 mg per dose)
- 1.1.2.2 children ≥8 years of age
- Preferred regimen (1): Doxycycline 4 mg/kg/day PO q12h（Maximum, 100 mg per dose）
- Preferred regimen (2): Azithromycin 10 mg/kg PO qd (Maximum, 500 mg qd)
- Preferred regimen (3): Clarithromycin 7.5 mg/kg PO bid (Maximum, 500 mg per dose)
- Preferred regimen (4): Erythromycin 12.5 mg/kg PO qid (Maximum, 500 mg per dose)
- 1.2 When erythema migrans cannot be reliably distinguished from community-acquired bacterial cellulitis
- Preferred regimen: Amoxicillin-Clavulanate 500 mg PO tid
- Pediatric regimen: Amoxicillin-Clavulanate 50 mg/kg/day q8h (Maximum, 500 mg per dose)
- 1.3 Lyme meningitis and other manifestations of early neurologic Lyme disease
- 1.3.1 Adult
- Preferred regimen: Ceftriaxone 2 g IV q24h for 10–28 days
- Alternative regimen (1): Cefotaxime 2 g IV q8h
- Alternative regimen (2): Penicillin G 18–24 MU q4h (for patients with normal renal function)
- Alternative regimen (3): Doxycycline 200–400 mg/day PO bid for 10–28 days
- 1.3.2 Pediatric
- Preferred regimen (1): Ceftriaxone 50–75 mg/kg IV single dose (Maximum, 2 g)
- Preferred regimen (2): Cefotaxime 150–200 mg/kg/day IV q6-8h (Maximum, 6 g per day)
- Alternative regimen (1): Penicillin G 200,000–400,000 units/kg/day IV q4h (for normal renal function) (maximum, 18–24 MU per day)
- Alternative regimen (2): Doxycycline 4–8 mg/kg/day PO bid (maximum, 100–200 mg per dose) (≥8 years old)
- 1.4 Lyme carditis
- Preferred regimen: Ceftriaxone 2 g IV q24h for 10–28 days
- Note: patients with advanced heart block, a temporary pacemaker may be required; expert consultation with a cardiologist is recommended; Use of the pacemaker may be discontinued when the advanced heart block has resolved; An oral antibiotic treatment regimen should be used for completion of therapy and for outpatients, as is used for patients with erythema migrans without carditis (see above)
- 1.5 Borrelial lymphocytoma
- Preferred regimen: The same regimens used to treat patients with erythema migrans (see above)
- 2. Late Lyme Disease
- 2.1 Lyme arthritis
- Preferred regimen (1): Doxycycline 100 mg PO bid
- Preferred regimen (2): Amoxicillin 500 mg PO tid
- Alternative regimen: Cefuroxime axetil 500 mg PO bid for 28 days
- Pediatric regimen: Amoxicillin 50 mg/kg/day tid (Maximum, 500 mg per dose); Cefuroxime axetil 30 mg/kg/day bid (Maximum,500 mg per dose); (≥8 years of age) Doxycycline 4 mg/kg/day bid (Maximum, 100 mg per dose)
- Note: For patients who have persistent or recurrent joint swelling after a recommended course of oral antibiotic therapy, we recommend re-treatment with another 4-week course of oral antibiotics or with a 2–4 weeks course of Ceftriaxone IV
- 2.2 patients with arthritis and objective evidence of neurologic disease
- Preferred regimen: Ceftriaxone IV for 2–4 weeks
- Alternative regimen (1): Cefotaxime IV
- Alternative regimen (1): Penicillin G IV
- Pediatric regime: Ceftriaxone; Cefotaxime; Penicillin G IV
- 2.3 Late neurologic Lyme disease
- Preferred regimen: Ceftriaxone IV for 2 to 4 weeks
- Alternative regimen (1): Cefotaxime IV
- Alternative regimen (2): Penicillin G IV
- Pediatric regimen: Ceftriaxone; Cefotaxime; Penicillin G
- 2.4 Acrodermatitis chronica atrophicans
- Preferred regimen (1): Doxycycline 100 mg PO bid for 21 days
- Preferred regimen (2): Amoxicillin 500 mg PO tid for 21 days
- Preferred regimen (3): Cefuroxime axetil 500 mg PO bid for 21 days
- 3. Post–Lyme Disease Syndromes
- Preferred regimen: Further antibiotic therapy for Lyme disease should not be given unless there are objective findings of active disease (including physical findings, abnormalities on cerebrospinal or synovial fluid analysis, or changes on formal neuropsychologic testing)
# Pasteurella multocida
- Pasteurella multocida
- Preferred regimen (1): Amoxicillin clavulanate 500 mg PO tid or 875 mg PO bid with food
- Note: Its also a preferred empirical coverage of animal bite wounds
- Preferred regimen (2): Ampicillin sulbactam 3 g IV q6h
- Preferred regimen (3): Ciprofloxacin 500 mg PO bid or 400 mg IV q12h
- Preferred regimen (4): Levofloxacin 500 mg PO qd or IV q24h
- Alternative regimen (1): Doxycycline 100 mg PO bid
- Alternative regimen (2): TMP-SMX DS PO bid (for beta-lactam allergic patients )
- Alternative regimen (3): Penicillin 500 mg PO qid or 4 MU IV q4h (use only if isolate known to be susceptible)
# Moraxella catarrhalis
- Moraxella catarrhalis
- Preferred regimen(1): TMP-SMX 1DS PO bid
- Preferred regimen(2): Erythromycin 500 mg PO qid
- Preferred regimen(3): Clarithromycin 500 mg PO bid or XL 1 g PO qd
- Preferred regimen(4): Azithromycin 500 mg PO single dose THEN 250 mg PO qd
- Preferred regimen(5): Doxycycline 100 mg PO/IV bid/q12h
- Preferred regimen(6): Cefprozil 200-500 mg PO bid
- Preferred regimen(7): Cefpodoxime 200-400 mg PO bid
- Preferred regimen(8): Cefuroxime 250-500 mg PO bid
- Preferred regimen(9): Cefdinir 300 mg PO bid
- Preferred regimen(10): Moxifloxacin 400 mg IV/PO qd
- Preferred regimen(11): Levofloxacin 500 mg IV/PO qd
- Preferred regimen(12): Amoxicillin clavulanate 875/125 mg PO bid or XL 2000/125 PO bid
# Eikenella corrodens
- 1. Human bite/soft tissue infections
- 1.1 Severe
- Preferred regimen: Ampicillin sulbactam 1.5-3 g IV q6h
- Alternative regimen (1): Doxycycline 100 mg IV bid
- Alternative regimen (2): Moxifloxacin 400 mg IV q24h
- Alternative regimen (3): Levofloxacin 500 mg IV q24h
- 1.2 Mild
- Preferred regimen: Amoxicillin clavulanate 250-500 mg tid or 875/125 mg PO bid
- Alternative regimen (1): Doxycycline 100 mg PO bid
- Alternative regimen (2): Moxifloxacin 400 mg PO qd
- Alternative regimen (3): Levofloxacin 500 mg PO qd
- 2. Head and neck infections
- 2.1 Severe
- Preferred regimen: Ampicillin sulbactam 1.5-3 g IV q6h
- Alternative regimen (1): Doxycycline 100 mg IV bid
- Alternative regimen (2): Moxifloxacin 400 mg IV q24h
- Alternative regimen (3): Levofloxacin 500 mg IV q24h
- 2.2 Mild
- Preferred regimen: Amoxicillin clavulanate 250-500 mg tid or 875/125 mg PO bid
- Alternative regimen (1): Doxycycline 100 mg PO bid
- Alternative regimen (2): Moxifloxacin 400 mg PO qd
- Alternative regimen (3): Levofloxacin 500 mg PO qd
- 3. Endocarditis
- Preferred regimen (1): Ceftriaxone 1 g IV q12h
- Preferred regimen (1): Cefotaxime 1-2 g IV q8h
- Preferred regimen (1): Cefepime 1-2g IV q8h
# Rickettsia rickettsii
- 1. Adult
- Preferred regimen: Doxycycline 100 mg q12h
- Note: Patients should be treated for at least 3 days after the fever subsides and until there is evidence of clinical improvement. Standard duration of treatment is 7-14 days
- Alternative regimen: Chloramphenicol 500 mg PO qid for 7 days or stop 3 days after defervescence
- 2. Pediatric (under 45 kg (100 lbs))
- Preferred regimen: Doxycycline 2.2 mg/kg bid
- Note: The recommended dose and duration of medication needed to treat RMSF has not been shown to cause staining of permanent teeth, even when five courses are given before the age of eight. Healthcare providers should use doxycycline as the first-line treatment for suspected Rocky Mountain spotted fever in patients of all ages
# Rhodococcus equi
- Rhodococcus equi
- First line:
- Preferred regimen: Vancomycin 1 g IV q12h (15 mg/kg q12 for >70 kg) OR Imipenem 500 mg IV q6h AND Rifampin 600 mg PO qd OR Ciprofloxacin 750 mg PO bid OR Erythromycin 500 mg PO qid for at least 4 weeks or until infiltrate disappears
- Note: Should be administrated at least 8 weeks in immunocompromised patients
- Oral/maintenance therapy (after infiltrate clears):
- Preferred regimen (1): Ciprofloxacin 750 mg PO bid
- Preferred regimen (2): Erythromycin 500 mg PO qid
- Alternative regimen: Azithromycin OR TMP-SMX OR Chloramphenicol OR Clindamycin
- Note: Avoid Penicillins/Cephalosporins due to development of resistance; Linezolid effective in vitro, but no clinical reports of use
# Propionibacterium acnes
- Propiobacterium acnes
- 1. Systemic infection
- Preferred regimen: Penicillin G 2 MU IV q4h for 2-4 weeks
- Alternative regimen (1): Clindamycin 600 mg IV q8h for 2-4 weeks
- Alternative regimen (2): Vancomycin 15 mg/kg IV q12h for 2-4 weeks
- 2. Shoulder prosthesis infection
- Preferred regimen: Amoxicillin AND Rifampin for 3-6 months
- 3. Acne vulgaris
- Topical antibiotics: Erythromycin OR Clindamycin
- Systemic antibiotics: Minocycline OR Doxycycline OR Trimethoprim-Sulfamethoxazole
# Nocardia
- 1. Sulfonamide-based therapies
- 1.1 Pulmonary
- Preferred regimen: TMP-SMX 10 mg/kg/day (TMP) IV q6-12h for 3-6 weeks, then 2 DS PO bid for at least 5 months
- 1.2 Pulmonary alternatives
- Preferred regimen: Sulfisoxazole OR Sulfadiazine OR Trisulfapyrimidine 3-6 g/day PO bid-qid OR TMP-SMX 2 DS bid up to 2 DS tid
- 1.3 CNS (AIDS, severe or disseminated disease)
- Preferred regimen: TMP-SMX 15 mg/kg/day (TMP) IV for 3-6 weeks, then PO (3 DS bid) for 6-12 months
- 1.4 CNS alternatives
- Preferred regimen: Imipenem 1000 mg IV q8h OR Ceftriaxone 2 g IV q12h OR Cefotaxime 2-3 g IV q6h AND Amikacin
- 1.5 Severe disease, compromised host, multiple sites
- Preferred regimen: TMP-SMX 15 mg/kg/day (TMP) IV AND Amikacin 7.5 mg/kg q12h OR Sulfonamide 6-12 mg/day PO
- 1.6 Sporotrichoid (cutaneous)
- Preferred regimen: TMP-SMX 1 DS bid for 4-6 months
- Note (1): Immunocompetent medicine use for 6 months; Immunosuppressed medicine for 12 months
- Note (2): Treat based on host, site of disease and in vitro activity; Sulfonamide usually preferred, must treat for 6-12 months; Preferred drugs for resistant strains are Amikacin and/or Imipenem
- Note (3): Seriously ill usually treated with IV Imipenem or Sulfonamide or Cefotaxime all potentially combined with Amikacin; less seriously ill treated with oral agents— especially TMP-SMX or Minocycline
- 2. Sulfonamide alternatives
- 2.1 Severe
- Preferred regimen (1): (For AIDS) (Imipenem 1000 mg IV q8h OR Meropenem 2 g q8h AND Amikacin 7.5 mg/kg q12h IV
- Preferred regimen (2): Cefotaxime 2-3 g q6-8h OR Ceftriaxone 2 g/day IV ± Amikacin
- 2.2 Mild
- Preferred regimen: Minocycline 100 mg bid for at least 6 months (initial treatment of local disease or maintenance)
- Alternative regimen: Amoxicillin clavulanate 875/125 mg bid OR Doxycycline OR Erythromycin OR Clarithromycin OR Linezolid OR Fluoroquinolone OR combinations for at least 6 months
# Leuconostoc
- Leuconostoc
- Preferred regimen (1): Penicillin G
- Preferred regimen (2): Ampicillin
- Alternative regimen (1): Clindamycin
- Alternative regimen (2): Erythromycin
- Alternative regimen (3): Minocycline
# Lactobacillus
- 1. Endovascular Infection
- Preferred regiemn (1): Penicillin G 20 MU/day for 6 weeks
- Preferred regiemn (2): Gentamicin 1.3 mg/kg IV q8h (trough <1.5 mg/L) AND Polychlorinated naphthalene
- 2. Odontogenic Infection
- Preferred regiemn: Clindamycin 450 mg PO qid
- 3. Intrabdominal Abscess
- Preferred regiemn: Clindamycin 450 mg PO qid
# Listeria monocytogenes
- 1. Meningitis
- Preferred regimen: Ampicillin 2g IV q4-6h ± Gentamicin 1.7 mg/kg IV q8h for more than 3 weeks
- Alternative regimen: TMP-SMX 3-5 mg/kg (trimethoprim) IV q6h for more than 3 weeks
- 2. Bacteremia
- Preferred regimen: Ampicillin 2g IV q4-6h ± Gentamicin 1.7 mg/kg IV q8h for 2 weeks
- Alternative regimen: TMP-SMX 3-5 mg/kg (trimethoprim) q6h IV for 2 weeks
- 3. Brain abscess or rhomboencephalitis
- Preferred regimen: Ampicillin 2g IV q4-6h ± Gentamicin 1.7 mg/kg IV q8h for 4-6 weeks
- Alternative regimen: TMP-SMX 3-5 mg/kg (trimethoprim) q6h IV for 4-6 weeks
- 4. Gastroenteritis
- Preferred regimen (1): Amoxicillin 2g IV q4-6h
- Preferred regimen (2): TMP-SMX 3-5 mg/kg (trimethoprim) q6h IV for 7 days
# Erysipelothrix rhusiopathiae
- Erysipelothrix rhusiopathiae
- 1. Erysipeloid of Rosenbach (localized cutaneous infection)
- Preferred regimen (1): Penicillin G benzathine 1.2 MU IV single dose
- Preferred regimen (2): Penicillin VK 250 mg PO qid for 5-7 days
- Preferred regimen (3): Procaine penicillin 0.6-1.2 MU IM qd for 5-7 days
- Alternative regimen (1): Erythromycin 250 mg PO qid for 5-7 days
- Alternative regimen (2): Doxycycline 100 mg PO bid for 5-7 days
- 2. Diffuse cutaneous infection
- Preferred regimen: See localized infection
- 3. Bacteremia or endocarditis
- Preferred regimen: Penicillin G benzathine 2-4 MU IV q4h for 4-6 weeks
- Alternative regimen (1): Ceftriaxone 2 g IV q24h for 4-6 weeks
- Alternative regimen (2): Imipenem 500 mg IV q6h for 4-6 weeks
- Alternative regimen (3): Ciprofloxacin 400 mg IV q12h for 4-6 weeks
- Alternative regimen (4): Daptomycin 6 mg/kg IV q24h for 4-6 weeks
- Note: Recommended duration of therapy for endocarditis is 4 to 6 weeks, although shorter courses consisting of 2 weeks of intravenous therapy followed by 2 to 4 weeks of oral therapy have been successful
# Ehrlichia
- 1. Human Monocytic Ehrlichiosis or Human Granulocytic Anaplasmosis (adult)
- Preferred regimen: Doxycycline 100 mg PO/IV q12h for 7-14 days
- Note: Patients should be treated for at least 3 days after the fever subsides and until there is evidence of clinical improvement
- Alternative regimen (1): Chloramphenicol 500mg PO qid
- Alternative regimen (2): Rifampin 600 mg PO/IV qd for 7-10 days
- 2. Human Monocytic Ehrlichiosis or Human Granulocytic Anaplasmosis (pediatric)
- 2.1 ≥ 8 years old
- Preferred regimen: Doxycycline 2 mg/kg IV/PO q12h (Maximum, 200 mg/day) for 10 days
- 2.2 < 8 years old without Lyme disease
- Preferred regimen: Doxycycline 2 mg/kg IV/PO q12h (Maximum, 200 mg/day) for 4-5 days (or 3 days after resolution of fever)
- 2.3 co-infected with Lyme disease
- Preferred regimen: Doxycycline (see above) THEN Amoxicillin 50 mg/kg/day tid (Maximum, 500 mg/dose) OR Cefuroxime 30 mg/kg/day bid (Maximum, 500 mg/dose) for 14 days
# Coxiella burnetii
- 1. Acute Q fever
- 1.1 Adults
- Preferred Regimen: Doxycycline 100 mg PO bid for 14 days
- 1.2 Pediatric
- 1.2.1 ≥ 8 years old
- Preferred regimen:Doxycycline 2.2 mg/kg PO bid for 14 days (Maximum, 100 mg per dose)
- 1.2.2 < 8 years old with high risk criteria
- Preferred regimen:Doxycycline 2.2 mg/kg PO bid for 14 days (Maximum, 100 mg per dose)
- 1.2.3 < 8 years old with mild or uncomplicated illness
- Preferred regimen:Doxycycline 2.2 mg/kg PO bid for 5 days (Maximum, 100 mg per dose)
- Alternative regimen: (If patient remains febrile past 5 days of treatment) Trimethoprim/Sulfamethoxazole 4-20 mg/kg PO bid for 14 days (Maximum, 800 mg per dose)
- 1.3 Pregnant women
- Preferred regimen: Trimethoprim/sulfamethoxazole 160 mg/800 mg PO bid
- Note: Should be given throughout pregnancy
- 2. Chronic Q fever
- 2.1 Endocarditis or vascular infection
- Preferred regimen: Doxycycline 100 mg PO bid AND hydroxychloroquine 200 mg PO tid for ≥18 months
- Note: Childern and pregnant women consultation recommended
- 2.2 Non-cardiac organ disease
- Preferred regimen: Doxycycline 100 mg PO bid AND hydroxychloroquine 200 mg PO tid
- Note: childern and pregnant women consultation recommended
- 2.3 Postpartumwith serologic profile for chronic Q fever
- Preferred regimen: Doxycycline 100 mg PO bid AND hydroxychloroquine 200 mg PO tid for 12 months
- Note (1): Women should only be treated postpartum if serologic titers remain elevated >12 months after delivery (immunoglobulin G phase I titer ≥1:1024); Women treated during pregnancy for acute Q fever should be monitored similarly to other patients who are at high risk for progression to chronic disease (e.g., serologic monitoring at 3, 6, 12, 18, and 24 months after delivery)
- Note (2): Post-Q fever fatigue syndrome- no current recommendation
# Corynebacterium diphtheriae
- Diphtheria treatment
- 1. Antitoxin
- 1.1 Pharyngeal disease <48 hrs
- Preferred regimen: 20,000-40,000 U IV/IM
- 1.2 Nasopharyngeal
- Preferred regimen: 40-60,000 U IV/IM
- 1.3 Extensive disease, or >72 hrs
- Preferred regimen: 80-120,000 U IV/IM
- Note: IV administration for severe disease
- 2. Antibiotics
- Preferred regimen: Erythromycin 40 mg/kg/day (Maximum, 2 gm/day) PO/IV for 14 days
- Alternative regimen: Procaine penicillin G 600,000 U/day IM qd for 14 days
- Note: Procaine penicillin G 300,000 U/day for those weighing 10 kg or less
- 3. Preventive antibiotic use
- Note: For close contacts, especially household contacts, a diphtheria booster, appropriate for age, should be given
- Preferred regimen: Benzathine penicillin G
- younger than 6 years old: 600,000 U IM
- 6 years old and older: 1,200,000 U IM
- Alternative regimen: Erythromycin
- Adult: 1 g/day PO 7-10 days
- Pediatric: 40 mg/kg/day PO 7-10 days
- Note (1): If surveillance of contacts cannot be maintained, they should receive benzathine penicillin G
- Note (2): Maintain close surveillance and begin antitoxin at the first signs of illness
# Swine influenza
- Swine influenza
- 1. Condition1: Patients who have severe or progressive clinical illness
- Preferred regimen: Oseltamivir 150 mg PO bid
- Note (1): Treatment duration depends on clinical response
- Note (2): Where the clinical course remains severe or progressive, despite 5 or more days of antiviral treatment, monitoring of virus replication and shedding, and antiviral drug susceptibility testing is desirable
- Note (3): Antiviral treatment should be maintained without a break until virus infection is resolved or there is satisfactory clinical improvement
- Note (4): Patients who have severe or progressive clinical illness, but who are unable to take oral medication may be treated with oseltamivir administered by nasogastric or orogastric tube
- 2. Condition2: In situations where oseltamivir is not available, or not possible to use, patients who have severe or progressive clinical illness
- Preferred regimen: Zanamivir inhaled
- Note: Zanamivir IV should be considered where available and is recommended for those with serious or progressive illness. If not available, Peramivir IV may be considered
- 3. Condition3: Severely immunosuppressed patients
- Preferred regimen: Antiviral chemoprophylaxis by using Oseltamivir OR Zanamivir
# Trichinella spiralis
- Trichinella spiralis
- Preferred regimen (1): Albendazole 400 mg PO bid for 8-14 days
- Preferred regimen (2): Mebendazole 200-400 mg PO tid for 3 days THEN 400-500 mg PO tid for 10 days
- Note (1): Both treatment schemes are suitable for adult and pediatric dosages
- Note (1): Albendazole and Mebendazole are contraindicated during pregnancy and not recommended in children aged 2 years.
- Alternative regimen (1): (severe symptoms) Prednisone 30 mg/day-60 mg/day for 10-15 days
- Alternative regimen (2): Pyrantel 10-20 mg/kg single dose for 2-3 days | Sandbox sc
# Mycobacterium terrae
- Mycobacterium terrae [1]
- 1. In vitro susceptibility
- All six of the isolates from a single center and 90% or more of an additional 22 isolates of M. terrae complex were susceptible to Ciprofloxacin and Sulfonamides. Recently, 11 isolates of M. terrae complex were also shown to be susceptible to Linezolid
- 2. Antimicrobial therapy
- Based on in vitro susceptibility results
# Mycobacterium szulgai
- Mycobacterium szulgai [2][3]
- 1. in vitro susceptibility
- M. szulgai is susceptible in vitro to most antituberculous drugs including Quinolones and newer Macrolides
- 2. Infection
- 2.1 Pulmonary infection
- Three- or four-drug regimen based on susceptibility that includes 12 months of negative sputum cultures while on therapy
- 2.2 Extrapulmonary infection
- Combination anti-tuberculous medications based on in vitro susceptibilities for 4-6 months
# Mycobacterium smegmatis
- Mycobacterium smegmatis [4]
- 1. Mild disease
- Preferred regimen: Doxycycline PO AND Trimethoprim sulfamethoxazole PO
- 2. Severe disease
- Preferred regimen: Amikacin IV OR Imipenem IV
# Mycobacterium mucogenicum
- Mycobacterium mucogenicum [5]
- In vitro susceptible agents: Aminoglycosides, Cefoxitin, Clarithromycin, Minocycline, Doxycycline, Quinolones, Trimethoprim/sulfamethoxazole, and Imipenem
# Mycobacterium malmoense
- Mycobacterium malmoense[6]
- 1. In vitro
- Susceptible: Ethambutol, Ethionamide, Kanamycin, and Cycloserine
- Resistant: INH, Streptomycin, Rifampin, and Capreomycin
- 2. Pulmonary M. malmoense infection
- Preferred regimen: INH AND Rifampin AND Ethambutol ± Quinolones AND Macrolides
# Mycobacterium immunogenum
- Mycobacterium immunogenum [7]
- In vitro
- Susceptible: Amikacin and Clarithromycin
- Resistant: Ciprofloxacin, Doxycycline, Cefoxitin, Tobramycin, and Sulfamethoxazole
- Note: The optimal therapy for this organism is unknown; however, successful therapy is likely difficult due to the extensive antibiotic resistance of the organism
# Mycobacterium leprae
- Mycobacterium leprae [8]
- 1. Multibacillary Leprosy (Skin smear positive)
- 1.1 Adult
- Preferred regimen: Dapsone 100 mg/day PO AND Rifampin 600 mg PO 4 times per week AND Clofazimine 50 mg PO qd for 12-24 months
- Note: Clofazimine should be supplemented by loading dose 300 mg PO monthly
- 1.2 Pediatric
- 1.2.1 < 35 kg
- Preferred regimen: Dapsone 1-2 mg/kg/day PO AND Rifampin 450 mg PO for 12-24 months
- 1.2.2 < 20 kg
- Preferred regimen: Dapsone 1-2 mg/kg/day PO AND Rifampin 300 mg PO for 12-24 months
- 1.2.3 < 12 kg
- Preferred regimen: Dapsone 1-2 mg/kg/day PO AND Rifampin 150 mg PO for 12-24 months
- 2. Paucibacillary Leprosy (Skin Smear negative)
- Preferred regimen: Rifampin 600 mg PO once a month for 6 months AND Dapsone 100 mg PO qd for 6 months
- 3. Erythema Nodosum Leprosum (ENL)
- 3.1 Mild
- Preferred regimen: Rest affect limb, analgesics, follow-up twice a week, check for iridocyclitis; Chloroquine OR Aspirin may be useful
- 3.2 Severe (numerous nodules + fever, ulcerating/pustular ENL, visceral involvement, nodules + neuritis, recurrent ENL)
- Preferred regimen: Prednisolone 30-40 mg/day PO for 1-2 weeks THEN taper over 12 weeks
- Alternative regimen (1): (If unresponsive to corticosteroids or if risk of corticosteroids prevent administration) Start Clofazimine 100 mg PO tid for maximum of 12 weeks THEN 100 mg PO bid for 12 weeks THEN 100 mg qd for 12-24 weeks
- Alternative regimen (2): (if not contraindicated) Thalidomide 200-400 mg/day PO, reduced to 50-100 mg/day after 1-2 weeks
- 4. Reversal Reaction
- Preferred regimen: Prednisolone start with 40 mg/day PO THEN taper by 10 mg twice a week for 12 weeks
# Mycobacterium xenopi
- Mycobacterium xenopi [9]
- 1. The cornerstone of therapy for M. xenopi
- Preferred regimen: Clarithromycin AND Rifampin AND Ethambutol
- Note: Therapy should be continued until the patient has maintained negative sputum cultures while on therapy for 12 months
- 2. Pulmonary disease
- Preferred regimen: INH AND Rifabutin OR Rifampin AND Ethambutol AND Clarithromycin ± Streptomycin
- Note: A quinolone, preferably Moxifloxacin, could be substituted for one of the antituberculous drugs
- 3. Extrapulmonary disease
- Note: Therapy for extrapulmonary disease would include the same agents as for pulmonary disease
# Mycobacterium ulcerans
- Mycobacterium ulcerans [10]
- 1. Preulcerative lesions
- Excision and primary closure, Rifampin monotherapy, or heat therapy
- 2. Established ulcers
- Most antimycobacterial agents are ineffective for the treatment of the ulcer; Surgical debridement combined with skin grafting is the usual treatment of choice
- 3. Control complications of the ulcer
- Preferred regimen: Clarithromycin AND Rifampin
# Swine influenza
- Swine influenza [11]
- 1. Condition1: Patients who have severe or progressive clinical illness
- Preferred regimen: Oseltamivir 150 mg PO bid
- Note(1): Treatment duration depends on clinical response
- Note(2): Where the clinical course remains severe or progressive, despite 5 or more days of antiviral treatment, monitoring of virus replication and shedding, and antiviral drug susceptibility testing is desirable
- Note(3): Antiviral treatment should be maintained without a break until virus infection is resolved or there is satisfactory clinical improvement
- Note(4): Patients who have severe or progressive clinical illness, but who are unable to take oral medication may be treated with Oseltamivir administered by nasogastric or orogastric tube
- 2. Condition2: In situations where oseltamivir is not available, or not possible to use, patients who have severe or progressive clinical illness
- Preferred regimen: Zanamivir inhaled
- Note: Zanamivir IV should be considered where available and is recommended for those with serious or progressive illness. If not available, Peramivir IV may be considered
- 3. Condition3: Severely immunosuppressed patients
- Antiviral chemoprophylaxis would be considered by using Oseltamivir OR Zanamivir
# Mycobacterium simiae
- Mycobacterium simiae [12]
- Preferred regimen: Clarithromycin AND Moxifloxacin AND Trimethoprim/sulfamethoxazole
# Mycobacterium foruitum
- Mycobacterium foruitum [13]
- 1. In vitro isolates
- Susceptible agents: Amikacin (100%), Ciprofloxacin and Ofloxacin (100%), Sulfonamides (100%), Cefoxitin (50%), Imipenem (100%), Clarithromycin (80%), and Doxycycline (50%)
- 2. Disease
- 2.1 M. fortuitum lung disease
- At least two agents with in vitro activity against the clinical isolate should be given for at least 12 months of negative sputum cultures
- 2.2 Serious skin, bone, and soft tissue M fortuitum disease
- At least two agents with in vitro activity against the clinical isolate should be given for a minimum of 4 months; For bone infections, 6 months of therapy is recommended
# Mycobacterium scrofulaceum
- Mycobacterium scrofulaceum [14]
- Susceptibility data are lacking and standard treatment regimens for M. scrofulaceum are controversial, emphasizing the need to perform susceptibility testing on confirmed disease-producing isolates of M. scrofulaceum
# Mycobacterium marinum
- Mycobacterium marinum [15]
- 1. In vitro M. marinum isolates
- Susceptible: Rifampin, Rifabutin, Ethambutol, Clarithromycin, Sulfonamides, and Trimethoprim sulfamethoxazole
- Intermediately susceptible: Streptomycin, Doxycycline, and Minocycline
- Resistant: Isoniazid and Pyrazinamide
- Note: Two active agents for 1 to 2 months after resolution of symptoms, typically 3 to 4 months in total
- 2. Infection
- 2.1 skin and soft tissue infections
- Preferred regimen (1): Clarithromycin AND Ethambutol
- Preferred regimen (2): Ethambutol AND Rifampin
- Note: Azithromycin can replace Clarithromycin
- 2.2 osteomyelitis or deep structure infection
- Preferred regimen: Clarithromycin AND Ethambutol AND Rifampin
# Mycobacterium kansasii
- Mycobacterium kansasii [16]
- 1. pulmonary disease
- Preferred regimen: Rifampin 10 mg/kg/day (Maximum, 600 mg) PO AND Ethambutol 15 mg/kg/ day PO AND Isoniazid 5 mg/kg/day (Maximum 300 mg) PO AND Pyridoxine 50 mg/day PO
- Note: Treatment duration for M. kansasii lung disease should include 12 months of negative sputum cultures
- 2. Rifampin-resistant M. kansasii disease
- Preferred regimen: Clarithromycin OR Azithromycin OR Moxifloxacin OR Ethambutol OR Sulfamethoxazole OR Streptomycin
- Note(1): Use three-drug regimen
- Note(2): Patients undergoing therapy for M. kansasii lung disease should have close clinical monitoring with frequent sputum examinations for mycobacterial culture throughout therapy
- 3. Disseminated M. kansasii disease
- Note: The treatment regimen for disseminated disease should be the same as for pulmonary disease
# Mycobacterium gordonae
- Mycobacterium gordonae [17]
- Preferred regimen: Ethambutol OR Rifabutin OR Clarithromycin OR Linezolid OR Fluoroquinolones
# Mycobacterium genavense
- Mycobacterium genavense [18]
- Susceptibility: Amikacin, Rifamycin, Fluoroquinolones, Streptomycin, and Macrolides
- Note(1): Ethambutol has limited activity
- Note(2): Optimal therapy is not determined, but multidrug therapies including Clarithromycin appear to be more effective than those without Clarithromycin
# Mycobacterium haemophilum
- Mycobacterium haemophilum [19]
- 1. In vitro
- Susceptible: Amikacin, Clarithromycin, Ciprofloxacin, Rifampin, and Rifabutin
- Less susceptible: Doxycycline and Sulfonamides
- 2. Infection
- 2.1 Disseminated disease
- Preferred regimen: Clarithromycin AND Rifampin AND Rifabutin AND Ciprofloxacin
# Mycobacterium chelonae
- Mycobacterium chelonae [20]
- 1. Localized infections
- Preferred regimen: Clarithromycin 500 mg PO bid
- Alternative regimen: Azithromycin
- 2. Disseminated or extensive disease
- 2.1 monotherapy
- Preferred regimen: Clarithromycin 500 mg PO bid for 6 months
- 2.2 multidrug therapy
- preferred regimen: Clarithromycin 500 mg PO bid AND Tobramycin 5 mg/kg IV q24h OR Imipenem 0.5-1 g IV q6h OR Linezolid 600 mg IV/PO q12h/bid for 4-8 weeks
- Alternative regimen: Moxifloxacin 400 mg PO qd AND Linezolid 600 mg PO bid
- Note(1): During initial treatment, multidrug therapy may prevent development of acquired resistance
- Note(2): Total treatment duration is 6 months
- 3. Keratitis (LASIK-related)
- Preferred regimen: Clarithromycin 500 mg PO bid AND Tobramycin 0.3% 2 gtts q4h AND Gatifloxacin 0.3% 1 gtt q4h OR Moxifloxacin 0.5% 1 gtt q4h
# Mycobacterium celatum
- Mycobacterium celatum [21]
- Preferred regimen: Clarithromycin AND Ethambutol AND Ciprofloxacin ± Rifabutin
# Mycobacterium avium complex
- 1. Treatment of MAC pulmonary disease [22]
- 1.1 Patients with nodular/bronchiectatic disease
- Preferreday regimen: Clarithromycin 1,000 mg three times weekly OR Azithromycin 500–600 mg three times weekly AND Ethambutol 25 mg/kg three times weekly AND Rifampin 600 mg three times weekly
- Note: Patients should be treated until culture negative on therapy for 1 year
- 1.2 Patients with fibrocavitary or severe nodular/bronchiectatic disease
- Preferreday regimen: Clarithromycin 500–1,000 mg/day OR Azithromycin 250–300 mg/day OR Rifampin 600 mg/day OR Rifabutin 150–300 mg/day AND Ethambutol 15 mg/kg/day
- Note(1): Amikacin OR Streptomycin threetimes-weekly can be used early in therapy
- Note(2): Patients should be treated until culture negative on therapy for 1 year
- 2. Disseminateday MAC disease
- Preferreday regimen: Clarithromycin 1,000 mg/day OR Azithromycin 250 mg/day AND Ethambutol 15 mg/kg/day ± Rifabutin 150–350 mg/day
# Mycobacterium bovis
- Mycobacterium bovis [23]
- Note: Is intrinsically resistant to Pyrazinamide (PZA). The treatment of M. bovis is extrapolated from experience with the treatment of PZA-resistant M. tuberculosis
- 1. Pulmonary and most extrapulmonary disease
- Preferred regimen: Isoniazid AND Rifampin AND Ethambutol for 2 months, followed by Isoniazid AND Rifampin for 7 months
- 2. Meningitis
- Preferred regimen: Isoniazid AND Rifampin AND Ethambutol for 2 months, followed by Isoniazid AND Rifampin for 10 months
# Mycobacterium abscessus
- 1.Limited, localized extrapulmonary disease [24]
- Preferred regimen: Clarithromycin 500 mg PO bid ± Amikacin 10-15 mg/kg/day IV or 25 mg/kg three times weekly for 4 months
- Alternative regimen (1): Amikacin AND Cefoxitin 12 g/day PO for two weeks
- Note: until clinical improvement in severe cases
- Alternative regimen (2): Amikacin AND Imipenem 500 mg IV q6-8h for two weeks
- Note(1): Until clinical improvement in severe cases
- Note(2): Osteomyelitis should be treated for as least 6 months; Infected foreign bodies should be removed
- 2.Pulmonary or serious extrapulmonary disease
- Preferred regimen: Clarithromycin 500 mg PO bid AND Amikacin 15 mg/kg/day IV AND Cefoxitin 2g IV q4h OR Imipenem 1g IV q6h for at least 2-4 months
- Note: If limited by adverse effects, then switch to Clarithromycin 500 mg PO bid or 1000 mg XR qd OR Azithromycin 250 mg PO qd
- Alternative regimen(1): Tigecycline 100 mg IV loading dose, then 50 mg IV q12h
- Note: could be substituted as one of the injectables
- Alternative regimen(2): Linezolid 600 mg PO bid or 600 mg PO qd AND Clarithromycin
- Note: Could replace parental tx if not tolerated or feasible
# Mycobacterium tuberculosis
- 1. Standard Regimens for new patients [25]
- 1.1 Adult
- 1.1.1 Initial phase
- Preferred regimen: Isoniazid 300 mg PO (5 mg/kg/day) qd for 8 weeks AND Rifampicin 600 mg PO (10 mg/kg/day) qd for 8 weeks AND Pyrazinamide 2 g PO (25 mg/kg/day) qd for 8 weeks AND Ethambutol 1.6 g PO (15 mg/kg/day) qd for 8 weeks
- Alternative regimen (1): Isoniazid 300 mg/day PO for 2 weeks (5 mg/kg/day) AND Rifampicin 600 mg/day PO for 2 weeks (10 mg/kg/day) AND Pyrazinamide 2 g/day PO for 2 weeks (25 mg/kg/day) AND Ethambutol 1.6 g PO for 2 weeks (15 mg/kg/day), followed by Isoniazid 300 mg/day PO twice weekly for 6 weeks (5 mg/kg/day) AND Rifampicin 600 mg/day PO twice weekly for 6 weeks (10 mg/kg/day) AND Pyrazinamide 2 g/day PO twice weekly for 6 weeks AND Ethambutol 1.6 g PO for 2 weeks (15 mg/kg/day)
- Alternative regimen (2): Isoniazid 300 mg/day PO thrice weekly for 8 weeks (5 mg/kg/day) AND Rifampicin 600 mg/day PO thrice weekly for 8 weeks (10 mg/kg/day) AND Pyrazinamide 2g/day PO thrice weekly for 8 week (25 mg/kg/day) AND Ethambutol 1.6 g PO thrice weekly for 8 weeks (15 mg/kg/day)
- 1.1.2 Continuation phase
- Preferred regimen (1): Isoniazid 300 mg PO (5 mg/kg/day) qd AND Rifampicin 600 mg PO (10 mg/kg/day) qd for 18 weeks
- Preferred regimen (2): Isoniazid 300 mg PO twice weekly (5 mg/kg/day) AND Rifampicin 600 mg/day PO twice weekly (10 mg/kg/day) for 18 weeks
- Alternative regimen (1): Isoniazid 300 mg/day PO biweekly for 18 weeks (5 mg/kg/day) AND Rifampicin 600 mg/day PO biweekly for 18 weeks (10 mg/kg/day)
- Alternative regimen (2): Isoniazid 300 mg/day PO thrice weekly for 18 weeks (5 mg/kg/day) AND Rifampicin 600 mg/day PO thrice weekly for 18 weeks (10 mg/kg/day)
- 1.2 Pediatric
- 1.2.1 Initial phase
- Preferred regimen: Isoniazid 10 mg/kg PO (Maximum, 300 mg/day) AND Rifampicin 15 mg/kg PO (Maximum, 600 mg/day) AND Pyrazinamide 35 mg/kg PO (Maximum, 2 g/day) AND Ethambutol 20 mg/kg PO (Maximum, 1.6 g/day), each for 8 weeks
- 1.2.2 Continuation phase
- Preferred regimen: Isoniazid 10 mg/kg PO (Maximum, 300 mg/day) AND Rifampicin 15 mg/kg PO (Maximum, 600 mg/day), each drug daily for 18 weeks
- 2. MDR Tuberculosis [26]
- 2.1 Adult
- Preferred regimen: 4 agents combination
- Agent 1: Pyrazinamide 20–30 mg/kg OR Ethambutol 15–25 mg/kg OR Rifabutin 5 mg/kg
- Agent 2: Capreomycin 15 mg/kg OR Kanamycin 15 mg/kg OR Amikacin 7.5-10 mg/kg OR Streptomycin 12–18 mg/kg
- Agent 3: Levofloxacin 500-1000 mg OR Moxifloxacin 400 mg OR Ofloxacin 400 mg
- Agent 4: Ethionamide 15-20 mg/kg OR Protionamide 15-20 mg/kg OR Cycloserine 10-15 mg/kg OR Terizidone 10-20 mg/kg OR Para-aminosalicylic acid 8-12 g/day IV q8-12h
- 2.2 Pediatric
- Preferred regimen: 4 agents combination
- Agent 1: Pyrazinamide 20-30 mg/kg (Maximum: 600 mg) OR Ethambutol 15-20 mg/kg OR Rifabutin 5 mg/kg
- Agent 2: Capreomycin 15-30 mg/kg (Maximum: 1000 mg) OR Kanamycin 15-30 mg/kg (Maximum: 1000 mg) OR Amikacin 15-22.5 mg/kg (Maximum: 1000 mg) OR Streptomycin 12-18 mg/kg AND
- Agent 3: Levofloxacin 7.5-10 mg/kg OR Moxifloxacin 7.5-10 mg/kg OR Ofloxacin 15-20 mg/kg/day q12h (Maximum: 800 mg)
- Agent 4: Ethionamide 15-20 mg/kg/day q12h (Maximum: 1000 mg) OR Protionamide 15-20 mg/kg/day q12h (Maximum: 1000 mg) OR Cycloserine 10-20 mg/kg (Maximum: 1000 mg) OR Terizidone 10-20 mg/kg (Maximum: 1000 mg) OR Para-aminosalicylic acid 150 mg/kg/day q8-12h(Maximum: 12,000 mg)
- 3. XDR Tuberculosis [27]
- 3.1 Adult
- Preferred regimen: 3 agents combination
- Agent 1: Pyrazinamide 20–30 mg/kg OR Ethambutol 15–25 mg/kg OR Rifabutin 5 mg/kg
- Agent 2: Ethionamide 15-20 mg/kg OR Protionamide 15-20 mg/kg OR Cycloserine 10-15 mg/kg OR Terizidone 10-20 kg/mg OR Para-aminosalicylic acid 8-12 g/day q8-12h
- Agent 3: Clofazimine 50 mg/d AND 300 mg once a month OR Amoxicillin/clavulanate 500 mg/125 mg q12h OR Linezolid 300-600 mg OR Imipenem 500mg q6h OR Clarithromycin 500-1000 mg q12h OR Thioacetazone 2.5 mg/kg OR Isoniazid (high-dose) 16–20 mg/kg
- 3.2 Pediatric
- Preferred regimen: 3 agents combination
- Agent 1: Pyrazinamide 20-30 mg/kg (Maximum: 600 mg) OR Ethambutol 15 mg/kg OR Rifabutin 5 mg/kg
- Agent 2: Ethionamide 15-20 mg/kg (Maximum: 1000 mg) OR Protionamide 15-20 mg/kg (Maximum: 1000 mg) OR Cycloserine 10-20 mg/kg (Maximum: 1000 mg) OR Terizidone 10-20 mg/kg (Maximum: 1000 mg) OR Para-aminosalicylic acid 150 mg/kg/day q8-12h
- Agent 3: Clofazimine 50 mg/d AND 300 mg once a month OR Amoxicillin/clavulanate OR Linezolid 300-600 mg OR Imipenem 500mg q6h OR Clarithromycin 500-1000 mg q12h OR Thioacetazone 2.5 mg/kg OR Isoniazid (high-dose) 16–20 mg/kg
# Bacteroides fragilis
- Bacteroides fragilis [28]
- 1. Monotherapy
- Preferred regimen (1): Imipenem
- Preferred regimen (2): Ertapenem
- Preferred regimen (3): Meropenem
- Preferred regimen (4): Doripenem 0.5-1.0 g IV q6h
- Preferred regimen (5): Piperacillin-tazobactam 3.375 g IV q6h
- Preferred regimen (6): Ampicillin-sulbactam 1-2 g IV q6h
- Preferred regimen (7): Tigecycline 100 mg IV THEN 50 mg IV q12h
- 2. Combination therapy
- Preferred regimen: Metronidazole 0.75-1.0 g IV q12h AND Cefotaxime 1.5-2 g IV q6h OR Aztreonam 1-2 g IV q8h OR Ceftriaxone 1 g IV q12h
# Acinetobacter baumannii
- Acinetobacter baumannii [29]
- Preferred regimen (1): Imipenem 0.5-1 g IV q6h
- Preferred regimen (2): Ampicillin/sulbactam 3 g q4h
- Preferred regimen (3): Cefepime 1-2 g IV q8h
- Preferred regimen (4): Colistin 2.5 mg/kg IV q12h
- Preferred regimen (5): Tigecycline 100 mg IV THEN 50 mg IV q12h
- Preferred regimen (6): Amikacin 7.5 mg/kg q12h IV or 15 mg/kg/day IV
- Alternative regimen (1): Ceftriaxone 1-2g IV every day
- Alternative regimen (2): Cefotaxime 2-3g IV q6-8h
- Alternative regimen (3): Ciprofloxacin 400 mg IV q8-12h or 750 mg PO bid
- Alternative regimen (4): TMP-SMX 15-20 mg (TMP)/kg/day IV q6-8h or 2 DS PO bid
# Vibrio vulnificus
- Vibrio vulnificus [30]
- Note: If V. vulnificus is suspected, treatment should be initiated immediately because antibiotics improve survival
- Preferred regimen: Doxycycline 100 mg PO/IV bid for 7-14 days AND Ceftazidime 1-2 g IV/IM q8h
- Note: A single agent regimen with a fluoroquinolone such as Levofloxacin, Ciprofloxacin or Gatifloxacin, has been reported to be at least as effective in an animal model as combination drug regimens with Doxycycline and a Cephalosporin
- Pediatric regimen: Doxycycline AND Fluoroquinolones; trimethoprim-sulfamethoxazole AND an Aminoglycoside
# Vibrio parahaemolyticus
- Vibrio parahaemolyticus [31]
- 1. Mild to Moderate
- Treatment is not necessary in most cases of V. parahaemolyticus infection
- There is no evidence that antibiotic treatment decreases the severity or the length of the illness
- Patients should drink plenty of liquids to replace fluids lost through diarrhea
- 2. Severe or prolonged illnesses
- Preferred regimen: Tetracycline OR Ciprofloxacin
# Vibrio cholerae
- 1. WHO [32] [33]
- Note: Antibiotic treatment for cholera patients with severe dehydration only
- Adults
- Preferred regimen: Doxycycline 300 mg po single dose
- Alternative regimen: Tetracycline 12.5 mg/kg PO qid for 3 days
- Pediatric
- Under 12 years old
- Preferred regimen: Erythromycin 12.5 mg/kg PO qid for 3 days
- Over 12 years old
- Preferred regimen: Doxycycline 300 mg po single dose
- Alternative regimen: Tetracycline 12.5 mg/kg PO qid for 3 days
- 2. Pan American Health Organization [34]
- Note: Antibiotic treatment for cholera patients with moderate or severe dehydration
- 2.1 Adult
- Preferred regimen: Doxycycline 300 mg po single dose
- Alternative regimen (1): Ciprofloxacin 1 g PO single dose
- Alternative regimen (2): Azithromycin 1 g PO single dose
- 2.2 Pediatric
- 2.2.1 Children over 3 year, who can swallow tablets
- Preferred regimen (1): Erythromycin 12.5 mg/kg/ PO qid for 3 days
- Preferred regimen (2): Azithromycin 20 mg/kg PO in a single dose
- Alternative regimen (1): Ciprofloxacin suspension or tablets 20 mg/kg PO single dose
- Alternative regimen (2): Doxycycline suspension or tablets 2-4 mg/kg PO single dose
- Note: Although doxycycline has been associated with a low risk of yellowing of the teeth in children, its benefits outweigh its risks
- 2.2.2 Children under 3 year, or infants who cannot swallow tablets
- Preferred regimen (1): Erythromycin suspension 12.5 mg/kg/ PO qid for 3 days
- Preferred regimen (2): Azithromycin suspension 20 mg/kg PO single dose
- Alternative regimen (1): Ciprofloxacin suspension 20 mg/kg PO single dose
- Alternative regimen (2): Doxycycline syrup 2-4 mg/kg PO single dose
- 2.3 Pregnancy
- Preferred regimen (!): Erythromycin 500 mg/ PO qid for 3 days
- Preferred regimen (2): Azithromycin 1 g PO single dose
# Treponema pallidum
- 1. Syphilis Among non-HIV-Infected Persons [35]
- 1.1 Primary and Secondary Syphilis
- Preferred regimen: Benzathine penicillin G 2.4 MU IM single dose
- Pediatric regimen: Benzathine penicillin G 50,000 U/kg (Maximum, 2.4 MU) IM single dose
- 1.2 Latent Syphilis
- 1.2.1 Early Latent Syphilis
- Preferred regimen: Benzathine penicillin G 2.4 MU IM in a single dose
- Pediatric regimen: Benzathine penicillin G 50,000 U/kg (Maximum, 2.4 MU) IM single dose
- 1.2.2 Late Latent Syphilis or Latent Syphilis of Unknown Duration
- Preferred regimen: Benzathine penicillin G 7.2 MU total, administered as 3 doses of 2.4 MU IM each at 1 week intervals
- Pediatric regimen: Benzathine penicillin G 50,000 U/kg IM (Maximum, 2.4 MU), administered as 3 doses at 1 week intervals (total 150,000 U/kg up to the adult total dose of 7.2 MU)
- 1.3 Tertiary Syphilis
- Preferred regimen: Benzathine penicillin G 7.2 MU total, administered as 3 doses of 2.4 MU IM each at 1 week intervals
- 1.4 Neurosyphilis and ocular syphilis
- Preferred regimen: Aqueous crystalline penicillin G 18-24 MU per day, administered as 3-4 MU IV q4h or continuous infusion, for 10-14 days
- Alternative regimen: Procaine penicillin 2.4 MU IM q24h AND Probenecid 500 mg PO qid for 10-14 days
- 2. Syphilis Among HIV-Infected Persons
- 2.1 Primary and Secondary Syphilis Among HIV-Infected Persons
- Preferred regimen: Benzathine penicillin G 2.4 MU IM single dose
- 2.2 Latent Syphilis Among HIV-Infected Persons
- 2.2.1 early latent
- Preferred regimen: Benzathine penicillin G 2.4 MU IM single dose
- 2.2.2 late latent
- Preferred regimen: Benzathine penicillin G 2.4 MU once a week for 3 weeks
- 2.3 Neurosyphilis Among HIV-Infected Persons
- Preferred regimen: Aqueous crystalline penicillin G 18-24 MU per day, administered as 3-4 MU IV q4h or continuous infusion, for 10-14 days
- Alternative regimen: Procaine penicillin 2.4 MU IM q24h AND Probenecid 500 mg PO qid for 10-14 days
- 3. Syphilis During Pregnancy
- Pregnant women should be treated with the penicillin regimen appropriate for their stage of infection
- 4. Congenital Syphilis in neonates
- 4.1 condition1: Infants with proven or highly probable disease and (1) an abnormal physical examination that is consistent with congenital syphilis;（2）a serum quantitative nontreponemal serologic titer that is fourfold higher than the mother's titer; or（3）a positive darkfield test of body fluid(s).
- Preferred regimen (1): Aqueous crystalline penicillin G 100,000-150,000 U/kg/day, administered as 50,000 U/kg/dose IV q12h during the first 7 days of life and q8h thereafter for a total of 10 days
- Preferred regimen (2): Procaine penicillin G 50,000 U/kg/dose IM q24h for 10 days
- Note: If more than 1 day of therapy is missed, the entire course should be restarted. Data are insufficient regarding the use of other antimicrobial agents (e.g., ampicillin). When possible, a full 10-day course of penicillin is preferred, even if ampicillin was initially provided for possible sepsis. The use of agents other than penicillin requires close serologic follow-up to assess adequacy of therapy. In all other situations, the maternal history of infection with T. pallidum and treatment for syphilis must be considered when evaluating and treating the infant.
- 4.2 condition2: Infants who have a normal physical examination and a serum quantitive nontreponemal serologic titer the same or less than fourfold the maternal titer and the (1) mother was not treated, inadequately treated, or has no documentation of having received treatment; (2) mother was treated with erythromycin or another nonpenicillin regimen; or (3) mother received treatment <4 weeks before delivery.
- Preferred regimen (1): Aqueous crystalline penicillin G 100,000-150,000 U/kg/day, administered as 50,000 U/kg/dose IV q12h during the first 7 days of life and q8h thereafter for a total of 10 days
- Preferred regimen (2): Procaine penicillin G 50,000 U/kg/dose IM q24h for 10 days
- Preferred regimen (3): Benzathine penicillin G 50,000 U/kg/dose IM single dose
- Note: If the mother has untreated early syphilis at delivery, 10 days of parenteral therapy can be considered
- 4.3 condition3: Infants who have a normal physical examination and a serum quantitative nontreponemal serologic titer the same or less than fourfold the maternal titer and the (1) mother was treated during pregnancy, treatment was appropriate for the stage of infection, and treatment was administered >4 weeks before delivery and (2) mother has no evidence of reinfection or relapse.
- Preferred regimen: Benzathine penicillin G 50,000 U/kg/dose IM single dose
- 4.4 condition4: Infants who have a normal physical examination and a serum quantitative nontreponemal serologic titer the same or less than fourfold the maternal titer and the (1) mother's treatment was adequate before pregnancy; and (2) mother's nontreponemal serologic titer remained low and stable before and during pregnancy and at delivery (VDRL <1:2; RPR <1:4).
- No treatment is required
- Benzathine penicillin G 50,000 U/kg IM single dose might be considered, particularly if follow-up is uncertain.
- 5. Congenital Syphilis in infants and children
- Preferred regimen: Aqueous crystalline penicillin G 50,000 U/kg q4–6h for 10 days
# Leptospira
- Leptospira [36]
- Preferred regimen: Doxycycline 200 mg PO once a week
# Borrelia recurrentis
- 1. Tick-Borne Relapsing Fever [37]
- Preferred regimen: Doxycycline 100 mg PO bid for 5-10 days
- Alternative regimen: Erythromycin 500 mg PO qid for 5-10 days
- Note: If meningitis/encephalitis present, use Ceftriaxone 2 g IV q12h for 14 days
- 2. Louse-Borne Relapsing Fever
- Preferred regimen: Tetracycline 500 mg PO single dose
- Alternative regimen: Erythromycin 500 mg PO single dose
# Borrelia burgdorferi
- Lyme disease [38]
- 1. Early Lyme Disease
- 1.1 Erythema migrans
- 1.1.1 Adult
- Preferred regimen (1): Doxycycline 100 mg PO bid for 10-21 days
- Preferred regimen (2): Amoxicillin 500 mg PO tid for 14-21 days
- Preferred regimen (3): Cefuroxime axetil 500 mg bid for 14-21 days
- Alternatie regimen (1): Azithromycin 500 mg PO qd for 7–10 days
- Alternatie regimen (2): Clarithromycin 500 mg PO bid for 14–21 days (if the patient is not pregnant)
- Alternatie regimen (3): Erythromycin 500 mg PO qid for 14–21 days
- 1.1.2 Pediatric
- 1.1.2.1 children <8 years of age
- Preferred regimen (1): Amoxicillin 50 mg/kg/day PO q8h (Maximum of 500 mg per dose)
- Preferred regimen (2): Cefuroxime axetil 30 mg/kg/day PO q12h（Maximum, 500 mg per dose)
- 1.1.2.2 children ≥8 years of age
- Preferred regimen (1): Doxycycline 4 mg/kg/day PO q12h（Maximum, 100 mg per dose）
- Preferred regimen (2): Azithromycin 10 mg/kg PO qd (Maximum, 500 mg qd)
- Preferred regimen (3): Clarithromycin 7.5 mg/kg PO bid (Maximum, 500 mg per dose)
- Preferred regimen (4): Erythromycin 12.5 mg/kg PO qid (Maximum, 500 mg per dose)
- 1.2 When erythema migrans cannot be reliably distinguished from community-acquired bacterial cellulitis
- Preferred regimen: Amoxicillin-Clavulanate 500 mg PO tid
- Pediatric regimen: Amoxicillin-Clavulanate 50 mg/kg/day q8h (Maximum, 500 mg per dose)
- 1.3 Lyme meningitis and other manifestations of early neurologic Lyme disease
- 1.3.1 Adult
- Preferred regimen: Ceftriaxone 2 g IV q24h for 10–28 days
- Alternative regimen (1): Cefotaxime 2 g IV q8h
- Alternative regimen (2): Penicillin G 18–24 MU q4h (for patients with normal renal function)
- Alternative regimen (3): Doxycycline 200–400 mg/day PO bid for 10–28 days
- 1.3.2 Pediatric
- Preferred regimen (1): Ceftriaxone 50–75 mg/kg IV single dose (Maximum, 2 g)
- Preferred regimen (2): Cefotaxime 150–200 mg/kg/day IV q6-8h (Maximum, 6 g per day)
- Alternative regimen (1): Penicillin G 200,000–400,000 units/kg/day IV q4h (for normal renal function) (maximum, 18–24 MU per day)
- Alternative regimen (2): Doxycycline 4–8 mg/kg/day PO bid (maximum, 100–200 mg per dose) (≥8 years old)
- 1.4 Lyme carditis
- Preferred regimen: Ceftriaxone 2 g IV q24h for 10–28 days
- Note: patients with advanced heart block, a temporary pacemaker may be required; expert consultation with a cardiologist is recommended; Use of the pacemaker may be discontinued when the advanced heart block has resolved; An oral antibiotic treatment regimen should be used for completion of therapy and for outpatients, as is used for patients with erythema migrans without carditis (see above)
- 1.5 Borrelial lymphocytoma
- Preferred regimen: The same regimens used to treat patients with erythema migrans (see above)
- 2. Late Lyme Disease
- 2.1 Lyme arthritis
- Preferred regimen (1): Doxycycline 100 mg PO bid
- Preferred regimen (2): Amoxicillin 500 mg PO tid
- Alternative regimen: Cefuroxime axetil 500 mg PO bid for 28 days
- Pediatric regimen: Amoxicillin 50 mg/kg/day tid (Maximum, 500 mg per dose); Cefuroxime axetil 30 mg/kg/day bid (Maximum,500 mg per dose); (≥8 years of age) Doxycycline 4 mg/kg/day bid (Maximum, 100 mg per dose)
- Note: For patients who have persistent or recurrent joint swelling after a recommended course of oral antibiotic therapy, we recommend re-treatment with another 4-week course of oral antibiotics or with a 2–4 weeks course of Ceftriaxone IV
- 2.2 patients with arthritis and objective evidence of neurologic disease
- Preferred regimen: Ceftriaxone IV for 2–4 weeks
- Alternative regimen (1): Cefotaxime IV
- Alternative regimen (1): Penicillin G IV
- Pediatric regime: Ceftriaxone; Cefotaxime; Penicillin G IV
- 2.3 Late neurologic Lyme disease
- Preferred regimen: Ceftriaxone IV for 2 to 4 weeks
- Alternative regimen (1): Cefotaxime IV
- Alternative regimen (2): Penicillin G IV
- Pediatric regimen: Ceftriaxone; Cefotaxime; Penicillin G
- 2.4 Acrodermatitis chronica atrophicans
- Preferred regimen (1): Doxycycline 100 mg PO bid for 21 days
- Preferred regimen (2): Amoxicillin 500 mg PO tid for 21 days
- Preferred regimen (3): Cefuroxime axetil 500 mg PO bid for 21 days
- 3. Post–Lyme Disease Syndromes
- Preferred regimen: Further antibiotic therapy for Lyme disease should not be given unless there are objective findings of active disease (including physical findings, abnormalities on cerebrospinal or synovial fluid analysis, or changes on formal neuropsychologic testing)
# Pasteurella multocida
- Pasteurella multocida [39]
- Preferred regimen (1): Amoxicillin clavulanate 500 mg PO tid or 875 mg PO bid with food
- Note: Its also a preferred empirical coverage of animal bite wounds
- Preferred regimen (2): Ampicillin sulbactam 3 g IV q6h
- Preferred regimen (3): Ciprofloxacin 500 mg PO bid or 400 mg IV q12h
- Preferred regimen (4): Levofloxacin 500 mg PO qd or IV q24h
- Alternative regimen (1): Doxycycline 100 mg PO bid
- Alternative regimen (2): TMP-SMX DS PO bid (for beta-lactam allergic patients )
- Alternative regimen (3): Penicillin 500 mg PO qid or 4 MU IV q4h (use only if isolate known to be susceptible)
# Moraxella catarrhalis
- Moraxella catarrhalis [40]
- Preferred regimen(1): TMP-SMX 1DS PO bid
- Preferred regimen(2): Erythromycin 500 mg PO qid
- Preferred regimen(3): Clarithromycin 500 mg PO bid or XL 1 g PO qd
- Preferred regimen(4): Azithromycin 500 mg PO single dose THEN 250 mg PO qd
- Preferred regimen(5): Doxycycline 100 mg PO/IV bid/q12h
- Preferred regimen(6): Cefprozil 200-500 mg PO bid
- Preferred regimen(7): Cefpodoxime 200-400 mg PO bid
- Preferred regimen(8): Cefuroxime 250-500 mg PO bid
- Preferred regimen(9): Cefdinir 300 mg PO bid
- Preferred regimen(10): Moxifloxacin 400 mg IV/PO qd
- Preferred regimen(11): Levofloxacin 500 mg IV/PO qd
- Preferred regimen(12): Amoxicillin clavulanate 875/125 mg PO bid or XL 2000/125 PO bid
# Eikenella corrodens
- 1. Human bite/soft tissue infections [41]
- 1.1 Severe
- Preferred regimen: Ampicillin sulbactam 1.5-3 g IV q6h
- Alternative regimen (1): Doxycycline 100 mg IV bid
- Alternative regimen (2): Moxifloxacin 400 mg IV q24h
- Alternative regimen (3): Levofloxacin 500 mg IV q24h
- 1.2 Mild
- Preferred regimen: Amoxicillin clavulanate 250-500 mg tid or 875/125 mg PO bid
- Alternative regimen (1): Doxycycline 100 mg PO bid
- Alternative regimen (2): Moxifloxacin 400 mg PO qd
- Alternative regimen (3): Levofloxacin 500 mg PO qd
- 2. Head and neck infections
- 2.1 Severe
- Preferred regimen: Ampicillin sulbactam 1.5-3 g IV q6h
- Alternative regimen (1): Doxycycline 100 mg IV bid
- Alternative regimen (2): Moxifloxacin 400 mg IV q24h
- Alternative regimen (3): Levofloxacin 500 mg IV q24h
- 2.2 Mild
- Preferred regimen: Amoxicillin clavulanate 250-500 mg tid or 875/125 mg PO bid
- Alternative regimen (1): Doxycycline 100 mg PO bid
- Alternative regimen (2): Moxifloxacin 400 mg PO qd
- Alternative regimen (3): Levofloxacin 500 mg PO qd
- 3. Endocarditis
- Preferred regimen (1): Ceftriaxone 1 g IV q12h
- Preferred regimen (1): Cefotaxime 1-2 g IV q8h
- Preferred regimen (1): Cefepime 1-2g IV q8h
# Rickettsia rickettsii
- 1. Adult [42] [43]
- Preferred regimen: Doxycycline 100 mg q12h
- Note: Patients should be treated for at least 3 days after the fever subsides and until there is evidence of clinical improvement. Standard duration of treatment is 7-14 days
- Alternative regimen: Chloramphenicol 500 mg PO qid for 7 days or stop 3 days after defervescence
- 2. Pediatric (under 45 kg (100 lbs))
- Preferred regimen: Doxycycline 2.2 mg/kg bid
- Note: The recommended dose and duration of medication needed to treat RMSF has not been shown to cause staining of permanent teeth, even when five courses are given before the age of eight. Healthcare providers should use doxycycline as the first-line treatment for suspected Rocky Mountain spotted fever in patients of all ages
# Rhodococcus equi
- Rhodococcus equi [44]
- First line:
- Preferred regimen: Vancomycin 1 g IV q12h (15 mg/kg q12 for >70 kg) OR Imipenem 500 mg IV q6h AND Rifampin 600 mg PO qd OR Ciprofloxacin 750 mg PO bid OR Erythromycin 500 mg PO qid for at least 4 weeks or until infiltrate disappears
- Note: Should be administrated at least 8 weeks in immunocompromised patients
- Oral/maintenance therapy (after infiltrate clears):
- Preferred regimen (1): Ciprofloxacin 750 mg PO bid
- Preferred regimen (2): Erythromycin 500 mg PO qid
- Alternative regimen: Azithromycin OR TMP-SMX OR Chloramphenicol OR Clindamycin
- Note: Avoid Penicillins/Cephalosporins due to development of resistance; Linezolid effective in vitro, but no clinical reports of use
# Propionibacterium acnes
- Propiobacterium acnes [45]
- 1. Systemic infection
- Preferred regimen: Penicillin G 2 MU IV q4h for 2-4 weeks
- Alternative regimen (1): Clindamycin 600 mg IV q8h for 2-4 weeks
- Alternative regimen (2): Vancomycin 15 mg/kg IV q12h for 2-4 weeks
- 2. Shoulder prosthesis infection
- Preferred regimen: Amoxicillin AND Rifampin for 3-6 months
- 3. Acne vulgaris
- Topical antibiotics: Erythromycin OR Clindamycin
- Systemic antibiotics: Minocycline OR Doxycycline OR Trimethoprim-Sulfamethoxazole
# Nocardia
- 1. Sulfonamide-based therapies [46]
- 1.1 Pulmonary
- Preferred regimen: TMP-SMX 10 mg/kg/day (TMP) IV q6-12h for 3-6 weeks, then 2 DS PO bid for at least 5 months
- 1.2 Pulmonary alternatives
- Preferred regimen: Sulfisoxazole OR Sulfadiazine OR Trisulfapyrimidine 3-6 g/day PO bid-qid OR TMP-SMX 2 DS bid up to 2 DS tid
- 1.3 CNS (AIDS, severe or disseminated disease)
- Preferred regimen: TMP-SMX 15 mg/kg/day (TMP) IV for 3-6 weeks, then PO (3 DS bid) for 6-12 months
- 1.4 CNS alternatives
- Preferred regimen: Imipenem 1000 mg IV q8h OR Ceftriaxone 2 g IV q12h OR Cefotaxime 2-3 g IV q6h AND Amikacin
- 1.5 Severe disease, compromised host, multiple sites
- Preferred regimen: TMP-SMX 15 mg/kg/day (TMP) IV AND Amikacin 7.5 mg/kg q12h OR Sulfonamide 6-12 mg/day PO
- 1.6 Sporotrichoid (cutaneous)
- Preferred regimen: TMP-SMX 1 DS bid for 4-6 months
- Note (1): Immunocompetent medicine use for 6 months; Immunosuppressed medicine for 12 months
- Note (2): Treat based on host, site of disease and in vitro activity; Sulfonamide usually preferred, must treat for 6-12 months; Preferred drugs for resistant strains are Amikacin and/or Imipenem
- Note (3): Seriously ill usually treated with IV Imipenem or Sulfonamide or Cefotaxime all potentially combined with Amikacin; less seriously ill treated with oral agents— especially TMP-SMX or Minocycline
- 2. Sulfonamide alternatives
- 2.1 Severe
- Preferred regimen (1): (For AIDS) (Imipenem 1000 mg IV q8h OR Meropenem 2 g q8h AND Amikacin 7.5 mg/kg q12h IV
- Preferred regimen (2): Cefotaxime 2-3 g q6-8h OR Ceftriaxone 2 g/day IV ± Amikacin
- 2.2 Mild
- Preferred regimen: Minocycline 100 mg bid for at least 6 months (initial treatment of local disease or maintenance)
- Alternative regimen: Amoxicillin clavulanate 875/125 mg bid OR Doxycycline OR Erythromycin OR Clarithromycin OR Linezolid OR Fluoroquinolone OR combinations for at least 6 months
# Leuconostoc
- Leuconostoc [47]
- Preferred regimen (1): Penicillin G
- Preferred regimen (2): Ampicillin
- Alternative regimen (1): Clindamycin
- Alternative regimen (2): Erythromycin
- Alternative regimen (3): Minocycline
# Lactobacillus
- 1. Endovascular Infection [48]
- Preferred regiemn (1): Penicillin G 20 MU/day for 6 weeks
- Preferred regiemn (2): Gentamicin 1.3 mg/kg IV q8h (trough <1.5 mg/L) AND Polychlorinated naphthalene
- 2. Odontogenic Infection
- Preferred regiemn: Clindamycin 450 mg PO qid
- 3. Intrabdominal Abscess
- Preferred regiemn: Clindamycin 450 mg PO qid
# Listeria monocytogenes
- 1. Meningitis [49]
- Preferred regimen: Ampicillin 2g IV q4-6h ± Gentamicin 1.7 mg/kg IV q8h for more than 3 weeks
- Alternative regimen: TMP-SMX 3-5 mg/kg (trimethoprim) IV q6h for more than 3 weeks
- 2. Bacteremia
- Preferred regimen: Ampicillin 2g IV q4-6h ± Gentamicin 1.7 mg/kg IV q8h for 2 weeks
- Alternative regimen: TMP-SMX 3-5 mg/kg (trimethoprim) q6h IV for 2 weeks
- 3. Brain abscess or rhomboencephalitis
- Preferred regimen: Ampicillin 2g IV q4-6h ± Gentamicin 1.7 mg/kg IV q8h for 4-6 weeks
- Alternative regimen: TMP-SMX 3-5 mg/kg (trimethoprim) q6h IV for 4-6 weeks
- 4. Gastroenteritis
- Preferred regimen (1): Amoxicillin 2g IV q4-6h
- Preferred regimen (2): TMP-SMX 3-5 mg/kg (trimethoprim) q6h IV for 7 days
# Erysipelothrix rhusiopathiae
- Erysipelothrix rhusiopathiae [50]
- 1. Erysipeloid of Rosenbach (localized cutaneous infection)
- Preferred regimen (1): Penicillin G benzathine 1.2 MU IV single dose
- Preferred regimen (2): Penicillin VK 250 mg PO qid for 5-7 days
- Preferred regimen (3): Procaine penicillin 0.6-1.2 MU IM qd for 5-7 days
- Alternative regimen (1): Erythromycin 250 mg PO qid for 5-7 days
- Alternative regimen (2): Doxycycline 100 mg PO bid for 5-7 days
- 2. Diffuse cutaneous infection
- Preferred regimen: See localized infection
- 3. Bacteremia or endocarditis
- Preferred regimen: Penicillin G benzathine 2-4 MU IV q4h for 4-6 weeks
- Alternative regimen (1): Ceftriaxone 2 g IV q24h for 4-6 weeks
- Alternative regimen (2): Imipenem 500 mg IV q6h for 4-6 weeks
- Alternative regimen (3): Ciprofloxacin 400 mg IV q12h for 4-6 weeks
- Alternative regimen (4): Daptomycin 6 mg/kg IV q24h for 4-6 weeks
- Note: Recommended duration of therapy for endocarditis is 4 to 6 weeks, although shorter courses consisting of 2 weeks of intravenous therapy followed by 2 to 4 weeks of oral therapy have been successful
# Ehrlichia
- 1. Human Monocytic Ehrlichiosis or Human Granulocytic Anaplasmosis (adult) [51]
- Preferred regimen: Doxycycline 100 mg PO/IV q12h for 7-14 days
- Note: Patients should be treated for at least 3 days after the fever subsides and until there is evidence of clinical improvement
- Alternative regimen (1): Chloramphenicol 500mg PO qid
- Alternative regimen (2): Rifampin 600 mg PO/IV qd for 7-10 days
- 2. Human Monocytic Ehrlichiosis or Human Granulocytic Anaplasmosis (pediatric)
- 2.1 ≥ 8 years old
- Preferred regimen: Doxycycline 2 mg/kg IV/PO q12h (Maximum, 200 mg/day) for 10 days
- 2.2 < 8 years old without Lyme disease
- Preferred regimen: Doxycycline 2 mg/kg IV/PO q12h (Maximum, 200 mg/day) for 4-5 days (or 3 days after resolution of fever)
- 2.3 co-infected with Lyme disease
- Preferred regimen: Doxycycline (see above) THEN Amoxicillin 50 mg/kg/day tid (Maximum, 500 mg/dose) OR Cefuroxime 30 mg/kg/day bid (Maximum, 500 mg/dose) for 14 days
# Coxiella burnetii
- 1. Acute Q fever [52]
- 1.1 Adults
- Preferred Regimen: Doxycycline 100 mg PO bid for 14 days
- 1.2 Pediatric
- 1.2.1 ≥ 8 years old
- Preferred regimen:Doxycycline 2.2 mg/kg PO bid for 14 days (Maximum, 100 mg per dose)
- 1.2.2 < 8 years old with high risk criteria
- Preferred regimen:Doxycycline 2.2 mg/kg PO bid for 14 days (Maximum, 100 mg per dose)
- 1.2.3 < 8 years old with mild or uncomplicated illness
- Preferred regimen:Doxycycline 2.2 mg/kg PO bid for 5 days (Maximum, 100 mg per dose)
- Alternative regimen: (If patient remains febrile past 5 days of treatment) Trimethoprim/Sulfamethoxazole 4-20 mg/kg PO bid for 14 days (Maximum, 800 mg per dose)
- 1.3 Pregnant women
- Preferred regimen: Trimethoprim/sulfamethoxazole 160 mg/800 mg PO bid
- Note: Should be given throughout pregnancy
- 2. Chronic Q fever
- 2.1 Endocarditis or vascular infection
- Preferred regimen: Doxycycline 100 mg PO bid AND hydroxychloroquine 200 mg PO tid for ≥18 months
- Note: Childern and pregnant women consultation recommended
- 2.2 Non-cardiac organ disease
- Preferred regimen: Doxycycline 100 mg PO bid AND hydroxychloroquine 200 mg PO tid
- Note: childern and pregnant women consultation recommended
- 2.3 Postpartumwith serologic profile for chronic Q fever
- Preferred regimen: Doxycycline 100 mg PO bid AND hydroxychloroquine 200 mg PO tid for 12 months
- Note (1): Women should only be treated postpartum if serologic titers remain elevated >12 months after delivery (immunoglobulin G phase I titer ≥1:1024); Women treated during pregnancy for acute Q fever should be monitored similarly to other patients who are at high risk for progression to chronic disease (e.g., serologic monitoring at 3, 6, 12, 18, and 24 months after delivery)
- Note (2): Post-Q fever fatigue syndrome- no current recommendation
# Corynebacterium diphtheriae
- Diphtheria treatment [53] [54]
- 1. Antitoxin
- 1.1 Pharyngeal disease <48 hrs
- Preferred regimen: 20,000-40,000 U IV/IM
- 1.2 Nasopharyngeal
- Preferred regimen: 40-60,000 U IV/IM
- 1.3 Extensive disease, or >72 hrs
- Preferred regimen: 80-120,000 U IV/IM
- Note: IV administration for severe disease
- 2. Antibiotics
- Preferred regimen: Erythromycin 40 mg/kg/day (Maximum, 2 gm/day) PO/IV for 14 days
- Alternative regimen: Procaine penicillin G 600,000 U/day IM qd for 14 days
- Note: Procaine penicillin G 300,000 U/day for those weighing 10 kg or less
- 3. Preventive antibiotic use
- Note: For close contacts, especially household contacts, a diphtheria booster, appropriate for age, should be given
- Preferred regimen: Benzathine penicillin G
- younger than 6 years old: 600,000 U IM
- 6 years old and older: 1,200,000 U IM
- Alternative regimen: Erythromycin
- Adult: 1 g/day PO 7-10 days
- Pediatric: 40 mg/kg/day PO 7-10 days
- Note (1): If surveillance of contacts cannot be maintained, they should receive benzathine penicillin G
- Note (2): Maintain close surveillance and begin antitoxin at the first signs of illness
# Swine influenza
- Swine influenza [55]
- 1. Condition1: Patients who have severe or progressive clinical illness
- Preferred regimen: Oseltamivir 150 mg PO bid
- Note (1): Treatment duration depends on clinical response
- Note (2): Where the clinical course remains severe or progressive, despite 5 or more days of antiviral treatment, monitoring of virus replication and shedding, and antiviral drug susceptibility testing is desirable
- Note (3): Antiviral treatment should be maintained without a break until virus infection is resolved or there is satisfactory clinical improvement
- Note (4): Patients who have severe or progressive clinical illness, but who are unable to take oral medication may be treated with oseltamivir administered by nasogastric or orogastric tube
- 2. Condition2: In situations where oseltamivir is not available, or not possible to use, patients who have severe or progressive clinical illness
- Preferred regimen: Zanamivir inhaled
- Note: Zanamivir IV should be considered where available and is recommended for those with serious or progressive illness. If not available, Peramivir IV may be considered
- 3. Condition3: Severely immunosuppressed patients
- Preferred regimen: Antiviral chemoprophylaxis by using Oseltamivir OR Zanamivir
# Trichinella spiralis
- Trichinella spiralis[56]
- Preferred regimen (1): Albendazole 400 mg PO bid for 8-14 days
- Preferred regimen (2): Mebendazole 200-400 mg PO tid for 3 days THEN 400-500 mg PO tid for 10 days
- Note (1): Both treatment schemes are suitable for adult and pediatric dosages
- Note (1): Albendazole and Mebendazole are contraindicated during pregnancy and not recommended in children aged 2 years.
- Alternative regimen (1): (severe symptoms) Prednisone 30 mg/day-60 mg/day for 10-15 days
- Alternative regimen (2): Pyrantel 10-20 mg/kg single dose for 2-3 days | https://www.wikidoc.org/index.php/Sandbox_sc | |
b4be1c1e9af523cc416d47f8188ff08363a14fab | wikidoc | Sandboxrx1 | Sandboxrx1
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- Dosing Information/Recommendation
- (Dosage)
### Non–Guideline-Supported Use
- Dosing Information
- There is limited information about Off-Label Non–Guideline-Supported Use of Sandboxrx1 in adult patients.
- Dosing Information
- (Dosage)
- Dosing Information
- (Dosage)
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Dosing Information
- (Dosage)
- Dosing Information
- (Dosage)
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- Developed by: (Organisation)
- Class of Recommendation: (Class) (Link)
- Strength of Evidence: (Category A/B/C) (Link)
- Dosing Information/Recommendation
- (Dosage)
- Developed by: (Organisation)
- Class of Recommendation: (Class) (Link)
- Strength of Evidence: (Category A/B/C) (Link)
- Dosing Information/Recommendation
- (Dosage)
### Non–Guideline-Supported Use
- Dosing Information
- (Dosage)
- Dosing Information
- (Dosage)
- Dosing Information
- (Dosage)
# Contraindications
- Condition 1
- Condition 2
- Condition 3
- Condition 4
- Condition 5
# Warnings
(Description)
(Description)
(Description)
# Adverse Reactions
## Clinical Trials Experience
## Postmarketing Experience
(Description)
# Drug Interactions
- Drug 1
- Drug 2
- Drug 3
- Drug 4
- Drug 5
(Description)
(Description)
(Description)
(Description)
(Description)
# Use in Specific Populations
### Pregnancy
- Pregnancy Category (FDA): X
- Pregnancy Category (AUS): Sandboxrx1 is not included in Australian Drug Evaluation Committee (ADEC) Pregnancy Categories.
(Description)
### Labor and Delivery
(Description)
### Nursing Mothers
(Description)
### Pediatric Use
(Description)
### Geriatric Use
(Description)
### Gender
(Description)
### Race
(Description)
### Renal Impairment
(Description)
### Hepatic Impairment
(Description)
### Carcinogenesis, Mutagenesis, Impairment of Fertility
(Description)
### Immunocompromised Patients
(Description)
### Miscellaneous
(Description)
# Administration and Monitoring
### Administration
(Oral/Intravenous/etc)
### Monitoring
(Description regarding monitoring, from Warnings section)
(Description regarding monitoring, from Warnings section)
(Description regarding monitoring, from Warnings section)
# IV Compatibility
## Solution
### Compatible
- Solution 1
- Solution 2
- Solution 3
### Not Tested
- Solution 1
- Solution 2
- Solution 3
### Variable
- Solution 1
- Solution 2
- Solution 3
### Incompatible
- Solution 1
- Solution 2
- Solution 3
## Y-Site
### Compatible
- Solution 1
- Solution 2
- Solution 3
### Not Tested
- Solution 1
- Solution 2
- Solution 3
### Variable
- Solution 1
- Solution 2
- Solution 3
### Incompatible
- Solution 1
- Solution 2
- Solution 3
## Admixture
### Compatible
- Solution 1
- Solution 2
- Solution 3
### Not Tested
- Solution 1
- Solution 2
- Solution 3
### Variable
- Solution 1
- Solution 2
- Solution 3
### Incompatible
- Solution 1
- Solution 2
- Solution 3
## Syringe
### Compatible
- Solution 1
- Solution 2
- Solution 3
### Not Tested
- Solution 1
- Solution 2
- Solution 3
### Variable
- Solution 1
- Solution 2
- Solution 3
### Incompatible
- Solution 1
- Solution 2
- Solution 3
## TPN/TNA
### Compatible
- Solution 1
- Solution 2
- Solution 3
### Not Tested
- Solution 1
- Solution 2
- Solution 3
### Variable
- Solution 1
- Solution 2
- Solution 3
### Incompatible
- Solution 1
- Solution 2
- Solution 3
# Overdosage
## Acute Overdose
### Signs and Symptoms
(Description)
### Management
(Description)
## Chronic Overdose
### Signs and Symptoms
(Description)
### Management
(Description)
# Pharmacology
## Mechanism of Action
(Description)
## Structure
(Description with picture)
## Pharmacodynamics
(Description)
## Pharmacokinetics
(Description)
## Nonclinical Toxicology
(Description)
# Clinical Studies
(Description)
(Description)
(Description)
# How Supplied
(Description)
- National Drug Code (NDC):
- Storage:
- Manufactured by:
- Distributed by:
# Images
## Drug Images
## Package and Label Display Panel
(Package Images)
(Display Panel Images)
# Patient Information
## Patient Information from FDA
(Patient Counseling Information)
## Patient Information from NLM
(Link to patient information page)
# Precautions with Alcohol
Alcohol-Sandboxrx1 interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
Brand Names®
# Look-Alike Drug Names
- (Paired Confused Name 1a) — (Paired Confused Name 1b)
- (Paired Confused Name 2a) — (Paired Confused Name 2b)
- (Paired Confused Name 3a) — (Paired Confused Name 3b)
# Drug Shortage Status
# Price | Sandboxrx1
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
For information about (Generic Name), click here.
Synonyms / Brand Names:
# Disclaimer
WikiDoc Drug Project is a constellation of drug information for healthcare providers and patients vigorously vetted on the basis of FDA package insert, MedlinePlus, Practice Guidelines, Scientific Statements, and scholarly medical literature. The information provided is not a medical advice or treatment. WikiDoc does not promote any medication or off-label use of drugs. Please read our full disclaimer here.
# Black Box Warning
FDA Package Insert for Sandboxrx1 contains no information regarding Black Box Warning.
# Overview
Sandboxrx1 is a _______ drug that is FDA approved for the treatment of _______. There is a Black Box Warning for this drug as shown here. Common adverse reactions include _______.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- (Dosage)
- Dosing Information
- (Dosage)
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- Developed by: (Organisation)
- Class of Recommendation: (Class) (Link)
- Strength of Evidence: (Category A/B/C) (Link)
- Dosing Information/Recommendation
- (Dosage)
- Developed by: (Organisation)
- Class of Recommendation: (Class) (Link)
- Strength of Evidence: (Category A/B/C) (Link)
- Dosing Information/Recommendation
- (Dosage)
### Non–Guideline-Supported Use
- Dosing Information
- There is limited information about Off-Label Non–Guideline-Supported Use of Sandboxrx1 in adult patients.
- Dosing Information
- (Dosage)
- Dosing Information
- (Dosage)
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Dosing Information
- (Dosage)
- Dosing Information
- (Dosage)
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- Developed by: (Organisation)
- Class of Recommendation: (Class) (Link)
- Strength of Evidence: (Category A/B/C) (Link)
- Dosing Information/Recommendation
- (Dosage)
- Developed by: (Organisation)
- Class of Recommendation: (Class) (Link)
- Strength of Evidence: (Category A/B/C) (Link)
- Dosing Information/Recommendation
- (Dosage)
### Non–Guideline-Supported Use
- Dosing Information
- (Dosage)
- Dosing Information
- (Dosage)
- Dosing Information
- (Dosage)
# Contraindications
- Condition 1
- Condition 2
- Condition 3
- Condition 4
- Condition 5
# Warnings
(Description)
(Description)
(Description)
# Adverse Reactions
## Clinical Trials Experience
## Postmarketing Experience
(Description)
# Drug Interactions
- Drug 1
- Drug 2
- Drug 3
- Drug 4
- Drug 5
(Description)
(Description)
(Description)
(Description)
(Description)
# Use in Specific Populations
### Pregnancy
- Pregnancy Category (FDA): X
- Pregnancy Category (AUS): Sandboxrx1 is not included in Australian Drug Evaluation Committee (ADEC) Pregnancy Categories.
(Description)
### Labor and Delivery
(Description)
### Nursing Mothers
(Description)
### Pediatric Use
(Description)
### Geriatric Use
(Description)
### Gender
(Description)
### Race
(Description)
### Renal Impairment
(Description)
### Hepatic Impairment
(Description)
### Carcinogenesis, Mutagenesis, Impairment of Fertility
(Description)
### Immunocompromised Patients
(Description)
### Miscellaneous
(Description)
# Administration and Monitoring
### Administration
(Oral/Intravenous/etc)
### Monitoring
(Description regarding monitoring, from Warnings section)
(Description regarding monitoring, from Warnings section)
(Description regarding monitoring, from Warnings section)
# IV Compatibility
## Solution
### Compatible
- Solution 1
- Solution 2
- Solution 3
### Not Tested
- Solution 1
- Solution 2
- Solution 3
### Variable
- Solution 1
- Solution 2
- Solution 3
### Incompatible
- Solution 1
- Solution 2
- Solution 3
## Y-Site
### Compatible
- Solution 1
- Solution 2
- Solution 3
### Not Tested
- Solution 1
- Solution 2
- Solution 3
### Variable
- Solution 1
- Solution 2
- Solution 3
### Incompatible
- Solution 1
- Solution 2
- Solution 3
## Admixture
### Compatible
- Solution 1
- Solution 2
- Solution 3
### Not Tested
- Solution 1
- Solution 2
- Solution 3
### Variable
- Solution 1
- Solution 2
- Solution 3
### Incompatible
- Solution 1
- Solution 2
- Solution 3
## Syringe
### Compatible
- Solution 1
- Solution 2
- Solution 3
### Not Tested
- Solution 1
- Solution 2
- Solution 3
### Variable
- Solution 1
- Solution 2
- Solution 3
### Incompatible
- Solution 1
- Solution 2
- Solution 3
## TPN/TNA
### Compatible
- Solution 1
- Solution 2
- Solution 3
### Not Tested
- Solution 1
- Solution 2
- Solution 3
### Variable
- Solution 1
- Solution 2
- Solution 3
### Incompatible
- Solution 1
- Solution 2
- Solution 3
# Overdosage
## Acute Overdose
### Signs and Symptoms
(Description)
### Management
(Description)
## Chronic Overdose
### Signs and Symptoms
(Description)
### Management
(Description)
# Pharmacology
## Mechanism of Action
(Description)
## Structure
(Description with picture)
## Pharmacodynamics
(Description)
## Pharmacokinetics
(Description)
## Nonclinical Toxicology
(Description)
# Clinical Studies
(Description)
(Description)
(Description)
# How Supplied
(Description)
- National Drug Code (NDC):
- Storage:
- Manufactured by:
- Distributed by:
# Images
## Drug Images
## Package and Label Display Panel
(Package Images)
(Display Panel Images)
# Patient Information
## Patient Information from FDA
(Patient Counseling Information)
## Patient Information from NLM
(Link to patient information page)
# Precautions with Alcohol
Alcohol-Sandboxrx1 interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
Brand Names®
# Look-Alike Drug Names
- (Paired Confused Name 1a) — (Paired Confused Name 1b)
- (Paired Confused Name 2a) — (Paired Confused Name 2b)
- (Paired Confused Name 3a) — (Paired Confused Name 3b)
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Sandboxrx1 | |
cccf03c3e599c091e82ef1e464eae760513807f9 | wikidoc | Sanitation | Sanitation
Sanitation is the hygienic means of preventing human contact from the hazards of wastes to promote health. Hazards can be either physical, microbiological, biological or chemical agents of disease. Wastes that can cause health problems are human and animal feces, solid wastes, domestic wastewater (sewage, urine, sullage, greywater), industrial wastes, and agricultural wastes. Hygienic means of prevention can be by using engineering solutions (e.g. sewerage and wastewater treatment), simple technologies (e.g.latrines, septic tanks), or even by personal hygiene practices (e.g. simple handwashing with soap).
The term "sanitation" can be applied to a specific aspect, concept, location, or strategy, such as:
Basic sanitation - refers to the management of human feces at the household level. This terminology is the indicator used to describe the target of the Millennium Development Goal on sanitation.
On-site sanitation - the collection and teatment of waste is done where it is deposited. Examples are the use of pit latrines, septic tanks, and imhoff tanks.
Food sanitation - refers to the hygienic measures for ensuring food safety.
Environmental sanitation - the control of environmental factors that form links in disease transmission. Subsets of this category are solid waste management, water and wastewater treatment, industrial waste treatment and noise and pollution control.
Ecological sanitation - a concept and an approach of recycling to nature the nutrients from human and animal wastes.
# Sanitation and wastewater
### Wastewater collection
The standard sanitation technology in urban areas is the collection of wastewater in sewers, its treatment in wastewater treatment plants for reuse or disposal in rivers, lakes or the sea. Sewers are either combined with storm drains or separated from them as sanitary sewers. Combined sewers are usually found in the central, older parts or urban areas. Heavy rainfall and inadequate maintenance can lead to combined sewer overflows or sanitary sewer overflows, i.e. more or less diluted raw sewage being discharged into the environment. Industries often discharge wastewater into municipal sewers, which can complicate wastewater treatment unless industries pre-treat their discharges.
The high investment cost of conventional wastewater collection systems are difficult to afford for many developing countries. Some countries have therefore promoted alternative wastewater collection systems such as condominial sewerage, which uses smaller diameter pipes at lower depth with different network layouts from conventional sewerage.
### Wastewater treatment
In developed countries treatment of municipal wastewater is now widespread, but not yet universal (for an overview of technologies see wastewater treatment). In developing countries most wastewater is still discharge untreated into the environment. For example, in Latin America only about 15% of collected sewerage is being treated (see water and sanitation in Latin America)
### Reuse of wastewater
The reuse of untreated wastewater in irrigated agriculture is common in developing countries. The reuse of treated wastewater in landscaping (esp. on golf courses), irrigated agriculture and for industrial use is becoming increasingly widespread.
In many peri-urban and rural areas households are not connected to sewers. They discharge their wastewater into septic tanks or other types of on-site sanitation.
### Ecological sanitation
Ecological sanitation is sometimes presented as a radical alternative to conventional sanitation systems. Ecological sanitation is based on the separation of urine and feces at the source for sanitization and recycling. It thus eliminates fecal pathogens from the wastewater flow. If ecological sanitation is practiced municipal wastewater consists of greywater, which can be recycled for gardening. However, in most cases greywater continues to be discharged to sewers.
## Sanitation and public health
The importance of waste isolation lies in an effort to prevent water and sanitation related diseases, which afflicts both developed countries as well as developing countries to differing degrees. It is estimated that up to 5 million people die each year from preventable water-borne disease, as a result of inadequate sanitation and hygiene practices.
## Global access to improved sanitation
The Joint Monitoring Program for water and sanitation of WHO and UNICEF has defined improved sanitation as
- connection to a public sewer
- connection to a septic system
- pour-flush latrine
- simple pit latrine
- ventilated improved pit latrine
According to that definition, 59% of the world population had access to improved sanitation in 2004. Only slightly more than half of them or 31% of the world population lived in houses connected to a sewer. Overall, 2.6 billion people lacked access to improved sanitation and thus had to resort to open defecation or other unsanitary forms of defecation, such as public latrines or open pit latrines. This outcome presents substantial public health risks as the waste could contaminate drinking water and cause life threatening forms of diarrhea to infants.
In developed countries, where less than 20% of the world population lives, 99% of the population has access to improved sanitation and 81% were connected to sewers.
# Solid waste disposal
Disposal of solid waste is most commonly conducted in landfills, but incineration, recycling, composting and conversion to biofuels are also avenues. In the case of landfills, advanced countries typically have rigid protocols for daily cover with topsoil, where underdeveloped countries customarily rely upon less stringent proocols. The importance of daily cover lies in the reduction of vector contact and spreading of pathogens. Daily cover also minimises odour emissions and reduces windblown litter. Likewise, developed countries typically have requirements for perimeter sealing of the landfill with clay-type soils to minimize migration of leachate that could contaminate groundwater (and hence jeopardize some drinking water supplies).
For incineration options, the release of air pollutants, including certain toxic components is an attendant adverse outcome. Recycling and biofuel conversion are the sustainable options that generally have superior life cycle costs, particularly when total ecological consequences are considered. Composting value will ultimately be limited by the market demand for compost product.
# Sanitation in the food industry
Sanititation within the food industry means to the adequate treatment of food-contact surfaces by a
process that is effective in destroying vegetative cells of microorganisms of public health significance, and in substantially reducing numbers of other undesirable microorganisms, but without
adversely affecting the product or its safety for the consumer (FDA, Code of Federal Regulations, 21CFR110, USA).
Additionally, in the food and Biopharmaceutical industries, the term sanitary equipment means equipment that is fully cleanable using Clean-in-place (CIP), and Sterilization in place (SIP) procedures: that is fully drainable from cleaning solutions and other liquids. The design should have a minimum amount of deadleg or areas where the turbulence during cleaning is not enough to remove product deposits. In general, to improve cleanability, this equipment is made from Stainless Steel 316L, (an alloy containing small amounts of molybdenum). The surface is usually electropolished to an effective surface roughness of less than 0.5 micrometre, to reduce the possibility of bacterial adhesion to the surface.
# History
The earliest evidence of urban sanitation was seen in Harappa, Mohenjo-daro and the recently discovered Rakhigarhi of Indus Valley civilisation. This urban plan included the world's first urban sanitation systems. Within the city, individual homes or groups of homes obtained water from wells. From a room that appears to have been set aside for bathing, waste water was directed to covered drains, which lined the major streets. Houses opened only to inner courtyards and smaller lanes.
Although the Romans had some elements of sanitation systems, especially related to wastewater collection and transport away from populated areas, there is little record of sanitation in Europe until the High Middle Ages. Unsanitary conditions were widespread throughout Europe and Asia throughout the Middle Ages, but there were no cataclysmic results until the 1300s when overpopulation of some regions created overcrowding and magnified the impacts of lack of sanitation. Between 1348 and 1351 the plague killed 25 million Europeans or almost one third of the entire population.
Very high infant and child mortality prevailed in Europe throughout medieval times, due not only to deficiencies in sanitation but to insufficient food for the population that had expanded faster than agriculture. Thus sanitation and food supply are looked upon as the balances of rapidly population in the period 1300 to 1600 in most of Europe, especially for the towns. | Sanitation
Sanitation is the hygienic means of preventing human contact from the hazards of wastes to promote health. Hazards can be either physical, microbiological, biological or chemical agents of disease. Wastes that can cause health problems are human and animal feces, solid wastes, domestic wastewater (sewage, urine, sullage, greywater), industrial wastes, and agricultural wastes. Hygienic means of prevention can be by using engineering solutions (e.g. sewerage and wastewater treatment), simple technologies (e.g.latrines, septic tanks), or even by personal hygiene practices (e.g. simple handwashing with soap).
The term "sanitation" can be applied to a specific aspect, concept, location, or strategy, such as:
Basic sanitation - refers to the management of human feces at the household level. This terminology is the indicator used to describe the target of the Millennium Development Goal on sanitation.
On-site sanitation - the collection and teatment of waste is done where it is deposited. Examples are the use of pit latrines, septic tanks, and imhoff tanks.
Food sanitation - refers to the hygienic measures for ensuring food safety.
Environmental sanitation - the control of environmental factors that form links in disease transmission. Subsets of this category are solid waste management, water and wastewater treatment, industrial waste treatment and noise and pollution control.
Ecological sanitation - a concept and an approach of recycling to nature the nutrients from human and animal wastes.
# Sanitation and wastewater
### Wastewater collection
The standard sanitation technology in urban areas is the collection of wastewater in sewers, its treatment in wastewater treatment plants for reuse or disposal in rivers, lakes or the sea. Sewers are either combined with storm drains or separated from them as sanitary sewers. Combined sewers are usually found in the central, older parts or urban areas. Heavy rainfall and inadequate maintenance can lead to combined sewer overflows or sanitary sewer overflows, i.e. more or less diluted raw sewage being discharged into the environment. Industries often discharge wastewater into municipal sewers, which can complicate wastewater treatment unless industries pre-treat their discharges.[1]
The high investment cost of conventional wastewater collection systems are difficult to afford for many developing countries. Some countries have therefore promoted alternative wastewater collection systems such as condominial sewerage, which uses smaller diameter pipes at lower depth with different network layouts from conventional sewerage.
### Wastewater treatment
In developed countries treatment of municipal wastewater is now widespread,[2] but not yet universal (for an overview of technologies see wastewater treatment). In developing countries most wastewater is still discharge untreated into the environment. For example, in Latin America only about 15% of collected sewerage is being treated (see water and sanitation in Latin America)
### Reuse of wastewater
The reuse of untreated wastewater in irrigated agriculture is common in developing countries. The reuse of treated wastewater in landscaping (esp. on golf courses), irrigated agriculture and for industrial use is becoming increasingly widespread.
In many peri-urban and rural areas households are not connected to sewers. They discharge their wastewater into septic tanks or other types of on-site sanitation.
### Ecological sanitation
Ecological sanitation is sometimes presented as a radical alternative to conventional sanitation systems. Ecological sanitation is based on the separation of urine and feces at the source for sanitization and recycling. It thus eliminates fecal pathogens from the wastewater flow. If ecological sanitation is practiced municipal wastewater consists of greywater, which can be recycled for gardening. However, in most cases greywater continues to be discharged to sewers.
## Sanitation and public health
The importance of waste isolation lies in an effort to prevent water and sanitation related diseases, which afflicts both developed countries as well as developing countries to differing degrees. It is estimated that up to 5 million people die each year from preventable water-borne disease[3], as a result of inadequate sanitation and hygiene practices.
## Global access to improved sanitation
The Joint Monitoring Program for water and sanitation of WHO and UNICEF has defined improved sanitation as
- connection to a public sewer
- connection to a septic system
- pour-flush latrine
- simple pit latrine
- ventilated improved pit latrine
According to that definition, 59% of the world population had access to improved sanitation in 2004. [1] Only slightly more than half of them or 31% of the world population lived in houses connected to a sewer. Overall, 2.6 billion people lacked access to improved sanitation and thus had to resort to open defecation or other unsanitary forms of defecation, such as public latrines or open pit latrines. This outcome presents substantial public health risks as the waste could contaminate drinking water and cause life threatening forms of diarrhea to infants.
In developed countries, where less than 20% of the world population lives, 99% of the population has access to improved sanitation and 81% were connected to sewers.
# Solid waste disposal
Disposal of solid waste is most commonly conducted in landfills, but incineration, recycling, composting and conversion to biofuels are also avenues. In the case of landfills, advanced countries typically have rigid protocols for daily cover with topsoil, where underdeveloped countries customarily rely upon less stringent proocols[4]. The importance of daily cover lies in the reduction of vector contact and spreading of pathogens. Daily cover also minimises odour emissions and reduces windblown litter. Likewise, developed countries typically have requirements for perimeter sealing of the landfill with clay-type soils to minimize migration of leachate that could contaminate groundwater (and hence jeopardize some drinking water supplies).
For incineration options, the release of air pollutants, including certain toxic components is an attendant adverse outcome. Recycling and biofuel conversion are the sustainable options that generally have superior life cycle costs, particularly when total ecological consequences are considered[5]. Composting value will ultimately be limited by the market demand for compost product.
# Sanitation in the food industry
Sanititation within the food industry means to the adequate treatment of food-contact surfaces by a
process that is effective in destroying vegetative cells of microorganisms of public health significance, and in substantially reducing numbers of other undesirable microorganisms, but without
adversely affecting the product or its safety for the consumer (FDA, Code of Federal Regulations, 21CFR110, USA).
Additionally, in the food and Biopharmaceutical industries, the term sanitary equipment means equipment that is fully cleanable using Clean-in-place (CIP), and Sterilization in place (SIP) procedures: that is fully drainable from cleaning solutions and other liquids. The design should have a minimum amount of deadleg[6] or areas where the turbulence during cleaning is not enough to remove product deposits. In general, to improve cleanability, this equipment is made from Stainless Steel 316L, (an alloy containing small amounts of molybdenum). The surface is usually electropolished to an effective surface roughness of less than 0.5 micrometre, to reduce the possibility of bacterial adhesion to the surface.
# History
The earliest evidence of urban sanitation was seen in Harappa, Mohenjo-daro and the recently discovered Rakhigarhi of Indus Valley civilisation. This urban plan included the world's first urban sanitation systems. Within the city, individual homes or groups of homes obtained water from wells. From a room that appears to have been set aside for bathing, waste water was directed to covered drains, which lined the major streets. Houses opened only to inner courtyards and smaller lanes.
Although the Romans had some elements of sanitation systems, especially related to wastewater collection and transport away from populated areas, there is little record of sanitation in Europe until the High Middle Ages. Unsanitary conditions were widespread throughout Europe and Asia throughout the Middle Ages, but there were no cataclysmic results until the 1300s when overpopulation of some regions created overcrowding and magnified the impacts of lack of sanitation.[7] Between 1348 and 1351 the plague killed 25 million Europeans or almost one third of the entire population.
Very high infant and child mortality prevailed in Europe throughout medieval times, due not only to deficiencies in sanitation but to insufficient food for the population that had expanded faster than agriculture[8]. Thus sanitation and food supply are looked upon as the balances of rapidly population in the period 1300 to 1600 in most of Europe, especially for the towns. | https://www.wikidoc.org/index.php/Sanitation | |
e5bd90b774dd07fcb54a472a5eb61b6b34ce77d3 | wikidoc | Saquinavir | Saquinavir
# Overview
Saquinavir is an antiretroviral drug used in HIV therapy. It falls in the protease inhibitor class. Two formulations have been marketed:
- a hard-gel capsule formulation of the mesylate, with trade name Invirase, which requires combination with ritonavir to increase the saquinavir bioavailability;
- a soft-gel capsule formulation of saquinavir (microemulsion, orally-administered formulation), with trade name Fortovase.
Both formulations are generally used as a component of highly active antiretroviral therapy (HAART).
Saquinavir was developed by the pharmaceutical company Roche. Saquinavir was the first protease inhibitor (and sixth antiretroviral) approved by the Food and Drug Administration (FDA). Within 2 years of its approval, and that of ritonavir 4 months later, annual deaths from AIDS in the United States fell from over 50,000 to approximately 18,000
. It was approved on December 6, 1995, as Invirase, a poorly-absorbed hard gel capsule which quickly led to viral resistance in many of the pioneer patients. The manufacturer, Roche, requested and received approval of Invirase via the FDA's "Accelerated Approval" program, a process designed to speed drugs to market for the treatment of serious diseases. This decision was controversial, amid disagreement between AIDS activists over the benefits of thorough testing versus early access to new drugs.
It was approved again on Nov 7, 1997 as Fortovase, a soft gel capsule reformulated for improved bioavailability. Roche announced in May 2005 that, owing to reduction in demand, Fortovase would cease being marketed early in 2006 in favour of Invirase boosted with ritonavir.
# Category
Protease inhibitor
# US Brand Names
INVIRASE®
# FDA Package Insert
Description
# Mechanism of Action
Saquinavir is a protease inhibitor. Proteases are enzymes that cleave protein molecules into smaller fragments. HIV protease is vital for both viral replication within the cell and release of mature viral particles from an infected cell. Saquinavir binds to the active site of the viral protease and prevents cleavage of viral polyproteins, preventing maturation of the virus. Saquinavir inhibits both HIV-1 and HIV-2 proteases. | Saquinavir
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Chetan Lokhande, M.B.B.S [2]
# Overview
Saquinavir is an antiretroviral drug used in HIV therapy. It falls in the protease inhibitor class. Two formulations have been marketed:
- a hard-gel capsule formulation of the mesylate, with trade name Invirase, which requires combination with ritonavir to increase the saquinavir bioavailability;
- a soft-gel capsule formulation of saquinavir (microemulsion,[1] orally-administered formulation), with trade name Fortovase.
Both formulations are generally used as a component of highly active antiretroviral therapy (HAART).
Saquinavir was developed by the pharmaceutical company Roche. Saquinavir was the first protease inhibitor (and sixth antiretroviral) approved by the Food and Drug Administration (FDA). Within 2 years of its approval, and that of ritonavir 4 months later, annual deaths from AIDS in the United States fell from over 50,000 to approximately 18,000 [2]
. It was approved on December 6, 1995, as Invirase, a poorly-absorbed hard gel capsule which quickly led to viral resistance in many of the pioneer patients.[citation needed] The manufacturer, Roche, requested and received approval of Invirase via the FDA's "Accelerated Approval" program, a process designed to speed drugs to market for the treatment of serious diseases. This decision was controversial, amid disagreement between AIDS activists over the benefits of thorough testing versus early access to new drugs.[3]
It was approved again on Nov 7, 1997 as Fortovase, a soft gel capsule reformulated for improved bioavailability. Roche announced in May 2005 that, owing to reduction in demand, Fortovase would cease being marketed early in 2006 in favour of Invirase boosted with ritonavir.[4]
# Category
Protease inhibitor
# US Brand Names
INVIRASE®
# FDA Package Insert
Description
# Mechanism of Action
Saquinavir is a protease inhibitor. Proteases are enzymes that cleave protein molecules into smaller fragments. HIV protease is vital for both viral replication within the cell and release of mature viral particles from an infected cell. Saquinavir binds to the active site of the viral protease and prevents cleavage of viral polyproteins, preventing maturation of the virus. Saquinavir inhibits both HIV-1 and HIV-2 proteases. | https://www.wikidoc.org/index.php/Saquinavir | |
5806cd8902bc9031401b4f5c1fc33df67dafddb5 | wikidoc | Sarcolipin | Sarcolipin
Sarcolipin is a micropeptide protein that in humans is encoded by the SLN gene.
# Function
Sarcoplasmic reticulum Ca2+-ATPases are transmembrane proteins that catalyze the ATP-dependent transport of Ca2+ from the cytosol into the lumen of the sarcoplasmic reticulum in muscle cells. The SLN gene encodes a small transmembrane proteolipid that regulates several sarcoplasmic reticulum Ca2+-ATPases by reducing the accumulation of Ca2+ in the sarcoplasmic reticulum without affecting the rate of ATP hydrolysis.
Ablation of sarcolipin increases atrial Ca2+ transient amplitudes and enhanced atrial contractility. Furthermore, atria from sarcolipin-null mice have blunted response to isoproterenol stimulation, implicating sarcolipin as a mediator of beta-adrenergic responses in atria.
Recently it has been shown that SLN is an important mediator of muscle based thermogenesis and loss of sarcolipin predisposes mice to diet-induced obesity thus suggesting its role in energy metabolism and regulation of weight gain
# Interactions
SLN (gene) has been shown to interact with PLN and ATP2A1. | Sarcolipin
Sarcolipin is a micropeptide protein that in humans is encoded by the SLN gene.[1][2]
# Function
Sarcoplasmic reticulum Ca2+-ATPases are transmembrane proteins that catalyze the ATP-dependent transport of Ca2+ from the cytosol into the lumen of the sarcoplasmic reticulum in muscle cells. The SLN gene encodes a small transmembrane proteolipid that regulates several sarcoplasmic reticulum Ca2+-ATPases by reducing the accumulation of Ca2+ in the sarcoplasmic reticulum without affecting the rate of ATP hydrolysis.[2]
Ablation of sarcolipin increases atrial Ca2+ transient amplitudes and enhanced atrial contractility. Furthermore, atria from sarcolipin-null mice have blunted response to isoproterenol stimulation, implicating sarcolipin as a mediator of beta-adrenergic responses in atria.[3]
Recently it has been shown that SLN is an important mediator of muscle based thermogenesis and loss of sarcolipin predisposes mice to diet-induced obesity thus suggesting its role in energy metabolism and regulation of weight gain [4]
# Interactions
SLN (gene) has been shown to interact with PLN[5][6] and ATP2A1.[5][6] | https://www.wikidoc.org/index.php/Sarcolipin | |
acb24dd5f5934b84e84e83b204e6e9eb67315fce | wikidoc | Sarcopenia | Sarcopenia
# Introduction
Sarcopenia (from the Greek meaning "poverty of flesh") is the degenerative loss of skeletal muscle mass and strength in senescence. About a third of muscle mass is lost in old age. This loss of mass reduces the performance of muscles. Due to the increasing number of elderly people, sarcopenia is an increasing health issue in the developed world. The level of sarcopenia can be so severe that it prevents an elderly person from living an independent life and they require constant assistance and care. Sarcopenia is an important independent predictor of disability in population-based studies, linked to poor balance, gait speed, falls, and fractures.
Sarcopenia can be thought of as analogous to "osteoporosis", which is the age-related loss of bone. The combination of osteoporosis and sarcopenia results in the significant frailty often seen in the elderly population.
# Natural history
Strength losses with aging are similar for men and women on a relative bases. They are greater for lower than upper extremity muscles. Strength generally peaks in mid twenties and declines thereafter. The decline is precipitous after 65 years of age, though few longitudinal studies exist on this topic.
# Diagnosis
Making the clinical diagnosis of sarcopenia is difficult for the following reasons. There is no absolute level of lean mass, body cell mass, or muscle mass for comparison. There is no generally accepted clinical test to diagnose sarcopenia. Finally, there is no accepted threshold of functional decline at which sarcopenia is implied.
# Mechanism
The biological mechanism of sarcopenia appears to be in the decreased ability of satellite cells to propagate themselves. Satellite cells are required to fuse into skeletal muscle fibers, and help in settings where repair and regeneration are required. Therefore aging muscle loses its ability to respond to anabolic stimuli, such as insulin, growth hormone, and amino acids. Catabolic stimuli may also play a role: the inflammatory IL-6, IL1-Ra, and TNF-alpha are elevated in elderly people with significant sarcopenia. Many anabolic stimuli are withdrawn in the elderly population. Decreased protein intake in the elderly plays a role: 1/3 of men over the age of 60 eat less than the RDA of 0.8 g/kg. A decline in exercise, a potent stimulus to protein synthesis, also contributes. Hormonal factors may be involved, such as decreased levels of sex hormones, growth hormones, and decreased insulin.
Depleted muscles atrophy and are replaced by connective tissue, though the mechanism in sarcopenia may be different than that seen in other settings of "muscle atrophy", since in younger individuals there is not an obvious problem with the satellite cells. Type II muscle fibers atrophy more so than type I.
# Management
Possible therapeutic strategies include increased protein intake and aggressive resistance-based exercise programs, but long-term randomized controlled trials are needed to evaluate the efficacy of these modalities. Hormonal supplementation may help if levels are low. Countermeasures should have the goals of maintaining adequate total body mass and protein intake. Physical activity incorporating resistance training is probably the most effective countermeasure to sarcopenia. | Sarcopenia
Template:AB
# Introduction
Sarcopenia (from the Greek meaning "poverty of flesh") is the degenerative loss of skeletal muscle mass and strength in senescence. About a third of muscle mass is lost in old age. This loss of mass reduces the performance of muscles. Due to the increasing number of elderly people, sarcopenia is an increasing health issue in the developed world. The level of sarcopenia can be so severe that it prevents an elderly person from living an independent life and they require constant assistance and care. Sarcopenia is an important independent predictor of disability in population-based studies, linked to poor balance, gait speed, falls, and fractures.
Sarcopenia can be thought of as analogous to "osteoporosis", which is the age-related loss of bone. The combination of osteoporosis and sarcopenia results in the significant frailty often seen in the elderly population.
# Natural history
Strength losses with aging are similar for men and women on a relative bases. They are greater for lower than upper extremity muscles. Strength generally peaks in mid twenties and declines thereafter. The decline is precipitous after 65 years of age, though few longitudinal studies exist on this topic.
# Diagnosis
Making the clinical diagnosis of sarcopenia is difficult for the following reasons. There is no absolute level of lean mass, body cell mass, or muscle mass for comparison. There is no generally accepted clinical test to diagnose sarcopenia. Finally, there is no accepted threshold of functional decline at which sarcopenia is implied.
# Mechanism
The biological mechanism of sarcopenia appears to be in the decreased ability of satellite cells to propagate themselves. Satellite cells are required to fuse into skeletal muscle fibers, and help in settings where repair and regeneration are required. Therefore aging muscle loses its ability to respond to anabolic stimuli, such as insulin, growth hormone, and amino acids. Catabolic stimuli may also play a role: the inflammatory IL-6, IL1-Ra, and TNF-alpha are elevated in elderly people with significant sarcopenia. Many anabolic stimuli are withdrawn in the elderly population. Decreased protein intake in the elderly plays a role: 1/3 of men over the age of 60 eat less than the RDA of 0.8 g/kg. A decline in exercise, a potent stimulus to protein synthesis, also contributes. Hormonal factors may be involved, such as decreased levels of sex hormones, growth hormones, and decreased insulin.
Depleted muscles atrophy and are replaced by connective tissue, though the mechanism in sarcopenia may be different than that seen in other settings of "muscle atrophy", since in younger individuals there is not an obvious problem with the satellite cells. Type II muscle fibers atrophy more so than type I.
# Management
Possible therapeutic strategies include increased protein intake and aggressive resistance-based exercise programs, but long-term randomized controlled trials are needed to evaluate the efficacy of these modalities. Hormonal supplementation may help if levels are low. Countermeasures should have the goals of maintaining adequate total body mass and protein intake. Physical activity incorporating resistance training is probably the most effective countermeasure to sarcopenia. | https://www.wikidoc.org/index.php/Sarcopenia | |
9410a8f1190abdbdfb80d939edaed82b5dd18afd | wikidoc | Saturation | Saturation
In chemistry, saturation has five different meanings:
- In physical chemistry, saturation is the point at which a solution of a substance can dissolve no more of that substance and additional amounts of that substance will appear as a precipitate. This point of maximum concentration, the saturation point, depends on the temperature of the liquid as well as the chemical nature of the substances involved. This can be used in the process of recrystallisation to purify a chemical: it is dissolved to the point of saturation in hot solvent, then as the solvent cools and the solubility decreases, excess solute precipitates. Impurities, being present in much lower concentration, do not saturate the solvent and so remain dissolved in the liquid. If a change in conditions (e.g. cooling) means that the concentration is actually higher than the saturation point, the solution has become supersaturated.
- In physical chemistry, when referring to surface processes, saturation denotes the degree of which a binding site is fully occupied. For example, base saturation refers to the fraction of exchangeable cations that are base cations. Similarly, in environmental soil science, nitrogen saturation means that an ecosystem, such as a soil, can not store any more nitrogen.
- In organic chemistry, a saturated compound has no double or triple bonds. In saturated linear hydrocarbons, every carbon atom is attached to two hydrogen atoms, except those at the ends of the chain, which bear three hydrogen atoms. In the case of saturated methane, four hydrogen atoms are attached to the single, central carbon atom. Of simple hydrocarbons, alkanes are saturated, and alkenes are unsaturated. The degree of unsaturation specifies the amount of hydrogen that a compound can bind. The term is applied similarly to the fatty acid constituents of lipids, where the fat is described as saturated or unsaturated, depending on whether the constituent fatty acids contain carbon-carbon double bonds. Unsaturated is used when any carbon structure contains double or occasionally triple bonds. Many vegetable oils contain fatty acids with one (monounsaturated) or more (polyunsaturated) double bonds in them. The bromine number is an index of unsaturation.
- In organometallic chemistry, an unsaturated complex has fewer than 18 valence electrons and thus is susceptible to oxidative addition or coordination of an additional ligand. Unsaturation is characteristic of many catalysts because it is usually a requirement for substrate activation.
- In biochemistry, the term saturation refers to the fraction of total protein binding sites that are occupied at any given time. | Saturation
In chemistry, saturation has five different meanings:
- In physical chemistry, saturation is the point at which a solution of a substance can dissolve no more of that substance and additional amounts of that substance will appear as a precipitate. This point of maximum concentration, the saturation point, depends on the temperature of the liquid as well as the chemical nature of the substances involved. This can be used in the process of recrystallisation to purify a chemical: it is dissolved to the point of saturation in hot solvent, then as the solvent cools and the solubility decreases, excess solute precipitates. Impurities, being present in much lower concentration, do not saturate the solvent and so remain dissolved in the liquid. If a change in conditions (e.g. cooling) means that the concentration is actually higher than the saturation point, the solution has become supersaturated.
- In physical chemistry, when referring to surface processes, saturation denotes the degree of which a binding site is fully occupied. For example, base saturation refers to the fraction of exchangeable cations that are base cations. Similarly, in environmental soil science, nitrogen saturation means that an ecosystem, such as a soil, can not store any more nitrogen.
- In organic chemistry, a saturated compound has no double or triple bonds. In saturated linear hydrocarbons, every carbon atom is attached to two hydrogen atoms, except those at the ends of the chain, which bear three hydrogen atoms. In the case of saturated methane, four hydrogen atoms are attached to the single, central carbon atom. Of simple hydrocarbons, alkanes are saturated, and alkenes are unsaturated. The degree of unsaturation specifies the amount of hydrogen that a compound can bind. The term is applied similarly to the fatty acid constituents of lipids, where the fat is described as saturated or unsaturated, depending on whether the constituent fatty acids contain carbon-carbon double bonds. Unsaturated is used when any carbon structure contains double or occasionally triple bonds. Many vegetable oils contain fatty acids with one (monounsaturated) or more (polyunsaturated) double bonds in them. The bromine number is an index of unsaturation.
- In organometallic chemistry, an unsaturated complex has fewer than 18 valence electrons and thus is susceptible to oxidative addition or coordination of an additional ligand. Unsaturation is characteristic of many catalysts because it is usually a requirement for substrate activation.
- In biochemistry, the term saturation refers to the fraction of total protein binding sites that are occupied at any given time. | https://www.wikidoc.org/index.php/Saturation | |
228b37a407193310fce3c43d7817a49df22ccafa | wikidoc | Sauerkraut | Sauerkraut
Sauerkraut is finely sliced cabbage fermented by various lactic acid bacteria including Leuconostoc, Lactobacillus, and Pediococcus.
It has good keeping qualities and a distinctive sour flavour, both of which result from the lactic acid that forms when bacteria ferment the sugars in the fresh cabbage.
The word comes directly from the German Template:Audio, which literally translates to sour cabbage. Sauerkraut is a typical dish of traditional Dutch (Zuurkool), and Central Europe cuisine. It is also a prominent feature of cuisines from most of the cold regions of Europe, and it is eaten in many parts of Northeast China, the USA and Canada as well.
# History
Fermentation of cabbages in salt and acid liquids dates back to prehistoric times and was probably first described by Pliny the Elder during the first century AD. Modern preparation techniques are thought to have been developed between 1550 and 1750 AD.
In his 1772 "Treatise on Scurvy", James Lind discussed the ability of Dutch seamen to withstand long sea voyages without succumbing to scurvy, compared to seamen from other countries, and pointed to their consumption of fermented cabbage as a defining difference.
In 1776, Captain James Cook was awarded the Copley Medal for demonstrating that sauerkraut could be used to allay scurvy in British crews on long sea voyages.
# Preparation
## Container
The correct choice of container is critical to successful preparation of sauerkraut.
Traditionally the container is a stoneware crock and the seal is created with a piece of wet linen cloth, a board, and a heavy stone. This arrangement is not fully airtight and will lead to spoiled sauerkraut unless the surface of the brine is skimmed daily to remove molds and other aerobic contaminants that grow on the surface where there is contact with air.
An alternative that avoids this problem is a type of ceramic jar that has a trough around its lid. When this trough is filled with water the result is an airtight seal. One such product is the Harsch crock, which is sold by natural-health retailers especially for home sauerkraut production.
Glass canning jars with clamped threadless lids can also be used.
Commercial-scale sauerkraut production typically employs large airtight plastic barrels fitted with one-way valves for gas escape.
Whatever kind of vessel is used, it must allow the escape of fermentation gases.
## Fermentation
Sauerkraut is made by a process of pickling called lacto-fermentation that is analogous to how traditional (not heat-treated) pickled cucumbers are made.
Fully cured sauerkraut keeps for several months in an airtight container stored at or below 15°C. Neither refrigeration nor pasteurization is required, though these treatments can prolong storage life. In the United States during the Great Depression years (1930s), some nearly-starving farm families lived through winters by eating sauerkraut exclusively because it was easy to grow and preserve and, being both pickled and canned, was not susceptible to invasion by mice or to rot or mildew.
No special culture of lactic acid bacteria is needed because these bacteria are already present on raw cabbage. Yeasts are also present, and can cause soft sauerkraut of poor flavor when the fermentation temperature is too high. The fermentation process has three phases. In the first phase, anaerobic bacteria such as Klebsiella and Enterobacter lead the fermentation, and begin producing an acid environment that favours later bacteria. The second phase starts as the acid levels become too high for many bacteria, and Leuconostoc mesenteroides and other Leuconostoc spp. take dominance. In the third phase, various Lactobacillus species including L. brevis and L. plantarum ferment any remaining sugars, further lowering the pH.
Salt (sodium chloride) is a major component in both the fermentation process and the flavour profile of sauerkraut, and is typically added in proportions between 0.6% and 2% relative to the amount of cabbage. For preparation at home, the USDA recommends a greater amount of salt than is traditional, making the sauerkraut unpalatably salty unless rinsed before eating. Such rinsing removes much of the nutrient content and flavor. When traditional amounts of salt are used, temperature control is critical, because spoilage leading to food poisoning can occur if the fermentation temperature is too high. However, once made, sauerkraut is a very safe food, because its high acidity prevents spoilage. USDA also recommends pasteurizing sauerkraut for storage, though this is not necessary if the raw sauerkraut has been properly made and stored. To be safe, do not eat any sauerkraut that has a slimy or excessively soft texture, or a discoloration or off-flavor, any of which can indicate spoilage....
## Variations
Variations include sauerkraut prepared from whole cabbages or leaves instead of shredded strips. Sometimes other vegetables are added, such as carrots. Spices may be added; caraway and juniper berries are traditional. Sometimes wine is added. Red cabbage can be used to make a red sauerkraut. When sauerkraut is made from turnips or rutabagas, the product is called Sauerrüben. In Russia, sour berries such as cranberry, or bits of finely chopped vegetables or fruit, such as carrots or apples, may be added prior to fermenting to enhance flavour. Beets may also be added to give the cabbage a red colour.
# Serving
Sauerkraut is a common and traditional ingredient in Bulgarian cuisine, Austrian cuisine, German cuisine, Russian cuisine, Alsatian French cuisine, Dutch cuisine, Romanian cuisine, Polish cuisine and other cuisines of Northern and Eastern Europe, as well as in Manchuria. It is also eaten in the Friuli and Trentino Alto Adige regions of Italy, where it is called capuzi garbi and crauti, respectively.
Sauerkraut can be eaten raw and unadorned; in this form it is often eaten as a relish with meat dishes, for example,
as condiment on bratwurst or North American hot dogs. Raw sauerkraut dressed with oil and onions is served as a salad.
However, sauerkraut is commonly served hot.
A popular German dish involves serving cooked sauerkraut with Schupfnudeln (potato noodles, the German equivalent of gnocchi).
In Polish cooking, sauerkraut is known as kiszona kapusta. Preparations including sauerkraut include soups and stews, such as bigos and kapusniak (sauerkraut soup) or shchi ; filled dumplings (pierogi); and seasoned kapusta served as a hot vegetable side dish.
In Alsace (a region of France that was part of Germany until 1678 and again from 1870 until 1919), the traditional sauerkraut dish is choucroute garnie (garnished sauerkraut): a one-dish meal of sauerkraut, sausages, pieces of meat such as ham knuckle, and perhaps potatoes, all cooked together in goose fat. Typical accompaniment beverages are beer or white wine (Riesling).
Common ingredients in cooked sauerkraut dishes (besides those already mentioned) are bacon, caraway, and apples.
Kraut juice is a regional beverage in the USA that consists of the liquid in which sauerkraut is cured.
In North America, sauerkraut is a key ingredient in the Reuben sandwich.
In Bulgaria, it is used in various dishes, especially in chicken and pork stews. Sauerkraut (Template:Lang-bg) is sometimes served when cold in salads, usually seasoned with oil and paprika. Kraut juice is believed to help against hangovers and is often said to work even in severe situations.
# Other varieties
Sauerkraut is similar to many ancient Northeastern Asian dishes, including Korean kimchi and other fermented vegetables. In Manchuria, people make a similar dish suan cai, which also literally translates to "sour vegetable".
It has long been associated with German cuisine although other Europeans consume a large amount of sauerkraut and it has long been a staple of the diet in, e.g., the Netherlands, Russia, and Poland (raw as kiszona kapusta or in a dish as bigos), France (the popularity of the dish in Alsace has spread sauerkraut (choucroute in French) to other regions of the country), Latvia (popularly known as skābi kāposti), Estonia (known as hapukapsas and often prepared with cumin or cranberries), as well as in Lithuania (rauginti kopūstai).
Immigrants to America from Germany (e.g. the Pennsylvania Dutch) and other European regions brought their traditional preparation methods and appreciation of this food. Pork and Sauerkraut is an extremely popular meal for New Year's Day in Pennsylvania, an example of the culture left from the Pennsylvania Dutch. Sauerkraut's popularity in Europe and America continues today, though in somewhat reduced measure due to the convenience of modern alternative preserving methods. Many people in Argentina also eat sauerkraut, and in Chile, as "chucrut", is part of the popular "completo", a hot dog that (usually, but ingredients may vary) combines it with mayonnaise and tomato.
In the USA there is an annual sauerkraut festival held in Phelps, NY.; also in Waynesville, Ohio
The area of Europe where Sauerkraut is probably the most typical regional dish is around Leinfelden-Echterdingen. The town, where Stuttgart Airport is located, holds an annual "Krautfest" around the middle of October. The event has taken place since 1978 and attracts up to 40,000 visitors.
# Health Benefits
Raw sauerkraut is an extremely healthy food. It is an excellent source of vitamin C, lactobacilli (even more than yoghurt), and other nutrients. However, the low pH and over-abundance of lactobacilli can easily upset the stomach of people who are not used to eating raw sauerkraut. Sauerkraut provided a vital source for these nutrients during the winter, especially before frozen foods and importation of foods from southern countries became generally available in northern and central Europe. Captain James Cook always took a store of sauerkraut on his sea voyages, since experience had taught him that it was an effective remedy against scurvy. It is now known that the preservation of sauerkraut in an anaerobic environment (under the brine) keeps the vitamin C in it from being oxidized. There is some evidence that indicates that kimchi and by extension sauerkraut may be used to treat avian influenza in birds. There is currently no evidence of its effects on human cases.
Sauerkraut is also a source of biogenic amines such as tyramine, which in sensitive people can cause adverse reactions .
# Similar foods
There are many other vegetables that are preserved by a similar process.
- Korean kimchi
- Japanese tsukemono
- Filipino atchara
- Manchurian suan cai
Also silage, a feed for cattle, is made the same way.
There is a dessert known as sauerkraut candy which is a penuche made with coconut flakes. While it visually resembles sauerkraut, it does not always contain actual sauerkraut as an ingredient.
# Cultural References
The American soldiers in World War 2 referred to German soldiers as "Krauts", in reference to the sauerkraut which, as German soldiers were seen at that time by the allied forces, was typically bitter and sour. The word is still used as an ethnic slur against people of German descent. | Sauerkraut
Template:Nutritionalvalue
Sauerkraut is finely sliced cabbage fermented by various lactic acid bacteria including Leuconostoc, Lactobacillus, and Pediococcus.[1][2]
It has good keeping qualities and a distinctive sour flavour, both of which result from the lactic acid that forms when bacteria ferment the sugars in the fresh cabbage.
The word comes directly from the German Template:Audio, which literally translates to sour cabbage.[1] Sauerkraut is a typical dish of traditional Dutch (Zuurkool), and Central Europe cuisine. It is also a prominent feature of cuisines from most of the cold regions of Europe, and it is eaten in many parts of Northeast China, the USA and Canada as well.
# History
Fermentation of cabbages in salt and acid liquids dates back to prehistoric times and was probably first described by Pliny the Elder during the first century AD.[1] Modern preparation techniques are thought to have been developed between 1550 and 1750 AD.[1]
In his 1772 "Treatise on Scurvy", James Lind discussed the ability of Dutch seamen to withstand long sea voyages without succumbing to scurvy, compared to seamen from other countries, and pointed to their consumption of fermented cabbage as a defining difference.[3]
In 1776, Captain James Cook was awarded the Copley Medal for demonstrating that sauerkraut could be used to allay scurvy in British crews on long sea voyages.[1]
# Preparation
## Container
The correct choice of container is critical to successful preparation of sauerkraut.
Traditionally the container is a stoneware crock and the seal is created with a piece of wet linen cloth, a board, and a heavy stone. This arrangement is not fully airtight and will lead to spoiled sauerkraut unless the surface of the brine is skimmed daily to remove molds and other aerobic contaminants that grow on the surface where there is contact with air.
An alternative that avoids this problem is a type of ceramic jar that has a trough around its lid. When this trough is filled with water the result is an airtight seal. One such product is the Harsch crock, which is sold by natural-health retailers especially for home sauerkraut production.
Glass canning jars with clamped threadless lids can also be used.
Commercial-scale sauerkraut production typically employs large airtight plastic barrels fitted with one-way valves for gas escape.
Whatever kind of vessel is used, it must allow the escape of fermentation gases.
## Fermentation
Sauerkraut is made by a process of pickling called lacto-fermentation that is analogous to how traditional (not heat-treated) pickled cucumbers are made.
Fully cured sauerkraut keeps for several months in an airtight container stored at or below 15°C. Neither refrigeration nor pasteurization is required, though these treatments can prolong storage life. In the United States during the Great Depression years (1930s), some nearly-starving farm families lived through winters by eating sauerkraut exclusively because it was easy to grow and preserve and, being both pickled and canned, was not susceptible to invasion by mice or to rot or mildew[citation needed].
No special culture of lactic acid bacteria is needed because these bacteria are already present on raw cabbage. Yeasts are also present, and can cause soft sauerkraut of poor flavor when the fermentation temperature is too high. The fermentation process has three phases. In the first phase, anaerobic bacteria such as Klebsiella and Enterobacter lead the fermentation, and begin producing an acid environment that favours later bacteria. The second phase starts as the acid levels become too high for many bacteria, and Leuconostoc mesenteroides and other Leuconostoc spp. take dominance. In the third phase, various Lactobacillus species including L. brevis and L. plantarum ferment any remaining sugars, further lowering the pH.[1][2]
Salt (sodium chloride) is a major component in both the fermentation process and the flavour profile of sauerkraut, and is typically added in proportions between 0.6% and 2% relative to the amount of cabbage.[1] For preparation at home, the USDA recommends a greater amount of salt than is traditional, making the sauerkraut unpalatably salty unless rinsed before eating. Such rinsing removes much of the nutrient content and flavor. When traditional amounts of salt are used, temperature control is critical, because spoilage leading to food poisoning can occur if the fermentation temperature is too high. However, once made, sauerkraut is a very safe food, because its high acidity prevents spoilage. USDA also recommends pasteurizing sauerkraut for storage, though this is not necessary if the raw sauerkraut has been properly made and stored. To be safe, do not eat any sauerkraut that has a slimy or excessively soft texture, or a discoloration or off-flavor, any of which can indicate spoilage....
## Variations
Variations include sauerkraut prepared from whole cabbages or leaves instead of shredded strips. Sometimes other vegetables are added, such as carrots. Spices may be added; caraway and juniper berries are traditional. Sometimes wine is added. Red cabbage can be used to make a red sauerkraut. When sauerkraut is made from turnips or rutabagas, the product is called Sauerrüben. In Russia, sour berries such as cranberry, or bits of finely chopped vegetables or fruit, such as carrots or apples, may be added prior to fermenting to enhance flavour. Beets may also be added to give the cabbage a red colour.
# Serving
Sauerkraut is a common and traditional ingredient in Bulgarian cuisine, Austrian cuisine, German cuisine, Russian cuisine, Alsatian French cuisine, Dutch cuisine, Romanian cuisine, Polish cuisine and other cuisines of Northern and Eastern Europe, as well as in Manchuria. It is also eaten in the Friuli and Trentino Alto Adige regions of Italy, where it is called capuzi garbi and crauti, respectively.
Sauerkraut can be eaten raw and unadorned; in this form it is often eaten as a relish with meat dishes, for example,
as condiment on bratwurst or North American hot dogs. Raw sauerkraut dressed with oil and onions is served as a salad.
However, sauerkraut is commonly served hot.
A popular German dish involves serving cooked sauerkraut with Schupfnudeln (potato noodles, the German equivalent of gnocchi).
In Polish cooking, sauerkraut is known as kiszona kapusta. Preparations including sauerkraut include soups and stews, such as bigos and kapusniak (sauerkraut soup) or shchi ; filled dumplings (pierogi); and seasoned kapusta served as a hot vegetable side dish.
In Alsace (a region of France that was part of Germany until 1678 and again from 1870 until 1919), the traditional sauerkraut dish is choucroute garnie (garnished sauerkraut): a one-dish meal of sauerkraut, sausages, pieces of meat such as ham knuckle, and perhaps potatoes, all cooked together in goose fat. Typical accompaniment beverages are beer or white wine (Riesling).
Common ingredients in cooked sauerkraut dishes (besides those already mentioned) are bacon, caraway, and apples.
Kraut juice is a regional beverage in the USA that consists of the liquid in which sauerkraut is cured.
In North America, sauerkraut is a key ingredient in the Reuben sandwich.
In Bulgaria, it is used in various dishes, especially in chicken and pork stews. Sauerkraut (Template:Lang-bg) is sometimes served when cold in salads, usually seasoned with oil and paprika. Kraut juice is believed to help against hangovers and is often said to work even in severe situations.
# Other varieties
Sauerkraut is similar to many ancient Northeastern Asian dishes, including Korean kimchi and other fermented vegetables. In Manchuria, people make a similar dish suan cai, which also literally translates to "sour vegetable".
It has long been associated with German cuisine although other Europeans consume a large amount of sauerkraut and it has long been a staple of the diet in, e.g., the Netherlands, Russia, and Poland (raw as kiszona kapusta or in a dish as bigos), France (the popularity of the dish in Alsace has spread sauerkraut (choucroute in French) to other regions of the country), Latvia (popularly known as skābi kāposti), Estonia (known as hapukapsas and often prepared with cumin or cranberries), as well as in Lithuania (rauginti kopūstai).
Immigrants to America from Germany (e.g. the Pennsylvania Dutch) and other European regions brought their traditional preparation methods and appreciation of this food. Pork and Sauerkraut is an extremely popular meal for New Year's Day in Pennsylvania, an example of the culture left from the Pennsylvania Dutch. Sauerkraut's popularity in Europe and America continues today, though in somewhat reduced measure due to the convenience of modern alternative preserving methods. Many people in Argentina also eat sauerkraut, and in Chile, as "chucrut", is part of the popular "completo", a hot dog that (usually, but ingredients may vary) combines it with mayonnaise and tomato.
In the USA there is an annual sauerkraut festival held in Phelps, NY.; also in Waynesville, Ohio
The area of Europe where Sauerkraut is probably the most typical regional dish is around Leinfelden-Echterdingen. The town, where Stuttgart Airport is located, holds an annual "Krautfest" around the middle of October. The event has taken place since 1978 and attracts up to 40,000 visitors.
# Health Benefits
Raw sauerkraut is an extremely healthy food. It is an excellent source of vitamin C, lactobacilli (even more than yoghurt), and other nutrients. However, the low pH and over-abundance of lactobacilli can easily upset the stomach of people who are not used to eating raw sauerkraut. Sauerkraut provided a vital source for these nutrients during the winter, especially before frozen foods and importation of foods from southern countries became generally available in northern and central Europe. Captain James Cook always took a store of sauerkraut on his sea voyages, since experience had taught him that it was an effective remedy against scurvy. It is now known that the preservation of sauerkraut in an anaerobic environment (under the brine) keeps the vitamin C in it from being oxidized. There is some evidence [1] that indicates that kimchi and by extension sauerkraut may be used to treat avian influenza in birds. There is currently no evidence of its effects on human cases.
Sauerkraut is also a source of biogenic amines such as tyramine, which in sensitive people can cause adverse reactions [2] [3].
# Similar foods
There are many other vegetables that are preserved by a similar process.
- Korean kimchi
- Japanese tsukemono
- Filipino atchara
- Manchurian suan cai
Also silage, a feed for cattle, is made the same way.
There is a dessert known as sauerkraut candy which is a penuche made with coconut flakes. While it visually resembles sauerkraut, it does not always contain actual sauerkraut as an ingredient. [4]
# Cultural References
The American soldiers in World War 2 referred to German soldiers as "Krauts", in reference to the sauerkraut which, as German soldiers were seen at that time by the allied forces, was typically bitter and sour. The word is still used as an ethnic slur against people of German descent.
Template:Herbs & spices | https://www.wikidoc.org/index.php/Sauerkraut | |
5cf8e80a020374f6642f20d045c715779fe5720a | wikidoc | Schizotypy | Schizotypy
# Overview
Schizotypy is a psychological concept which describes a continuum of personality characteristics and experiences related to psychosis and in particular, schizophrenia.
This is in contrast to a categorical view of psychosis, where psychosis is considered to be a particular (usually pathological) state, that someone either has, or has not.
# Development of the concept
The categorical view of psychosis is most associated with Emil Kraepelin, who created criteria for the medical diagnosis and classification of different forms of psychotic illness. Particularly, he made the distinction between dementia praecox (now called schizophrenia), manic depressive insanity and non-psychotic states. Modern diagnostic systems used in psychiatry (such as the DSM) maintain this categorical view.
In contrast, psychiatrist Eugene Bleuler did not believe there was a clear separation between sanity and madness, and that psychosis was simply an extreme expression of thoughts and behaviours that could be present to varying degrees through the population.
This was picked up by psychologists such as Hans Eysenck and Gordon Claridge who sought to understand this variation in unusual thought and behaviour in terms of personality theory. This was conceptualised by Eysenck as a single personality trait named psychoticism.
Claridge named his concept schizotypy and by examining unusual experiences in the general population and the clustering of symptoms in diagnosed schizophrenia, Claridge's work suggested that this personality trait was much more complex, and could break down into four factors.
- Unusual experiences: The disposition to have unusual perceptual and other cognitive experiences, such as hallucinations, magical or superstitious belief and interpretation of events (see also delusions).
- Cognitive disorganisation: A tendency for thoughts to become derailed, disorganised or tangential (see also formal thought disorder).
- Introverted anhedonia: A tendency to introverted, emotionally flat and asocial behaviour, associated with a deficiency in the ability to feel pleasure from social and physical stimulation.
- Impulsive nonconformity: The disposition to unstable mood and behaviour particularly with regard to rules and social conventions.
# The relationship between schizotypy and mental illness
Although aiming to reflect some of the features present in diagnosable mental illness, schizotypy does not necessarily imply that someone who is more schizotypal than someone else is more ill. For example, certain aspects of schizotypy may be beneficial. Both the Unusual experiences and Cognitive disorganisation aspects have been linked to creativity and academic achievement.Jackson proposed the concept of ‘benign schizotypy’ in relation to certain classes of religious experience, which he suggested might be regarded as a form of problem-solving and therefore of adaptive value.
However, the exact nature of the relationship between schizotypy and diagnosable psychotic illness is still controversial. One of the key concerns that researchers have had is that questionnaire-based measures of schizotypy, when analysed using factor analysis, do not suggest that schizotypy is a unified, homogeneous concept. The three main approaches have been labelled as the 'quasi-dimensional', the ‘dimensional’ and the ‘fully dimensional’.
Each approach is sometimes used to imply that schizotypy reflects a cognitive or biological vulnerability to psychosis, although this may remain dormant and never express itself, unless triggered by appropriate environmental events or conditions (such as certain doses of drugs or high levels of stress).
## Quasi-dimensional approach
The quasi-dimensional model may be traced back to Bleuler (the inventor of the term ‘schizophrenia’), who commented on two types of continuity between normality and psychosis: that between the schizophrenic and his or her relatives, and that between the patient’s pre- and post-morbid personalities (i.e. their personality before and after the onset of overt psychosis).
On the first score he commented: ‘If one observes the relatives of our patients, one often finds in them peculiarities which are qualitatively identical with those of the patients themselves, so that the disease appears to be only a quantitative increase of the anomalies seen in the parents and siblings.’
On the second point, Bleuler discusses in a number of places whether peculiarities displayed by the patient before admission to hospital should be regarded as premonitory symptoms of the disease or merely indications of a predisposition to develop it.
Despite these observations of continuity Bleuler himself remained an advocate of the disease model of schizophrenia. To this end he invoked a concept of latent schizophrenia, writing: ‘In form, we can see in nuce all the symptoms and all the combinations of symptoms which are present in the manifest types of the disease.’
Later advocates of the quasi-dimensional view of schizotypy are Rado and Meehl, according to both of whom schizotypal symptoms merely represent less explicitly expressed manifestations of the underlying disease process which is schizophrenia. Rado proposed the term ‘schizotype’ to describe the person whose genetic make-up gave him or her a life-long predisposition to schizophrenia.
The quasi-dimensional model is so called because the only dimension it postulates is that of gradations of severity or explicitness in relation to the symptoms of a disease process: namely schizophrenia.
## Dimensional approach
The dimensional approach, influenced by personality theory, argues that full blown psychotic illness is just the most extreme end of the schizotypy spectrum and there is a natural continuum between people with low and high levels of schizotypy. This model is most closely associated with the work of Hans Eysenck, who regarded the person exhibiting the full-blown manifestations of psychosis as simply someone occupying the extreme upper end of his ‘psychoticism’ dimension.
Support for the dimensional model comes from the fact that high-scorers on measures of schizotypy may meet, or partially fulfill, the diagnostic criteria for schizotypal disorders, such as schizophrenia, schizoaffective disorder, schizoid personality disorder and schizotypal personality disorder. Similarly, when analyzed, schizotypy traits often break down into similar groups as do symptoms from schizophrenia (although they are typically present in much less intense forms).
## Fully dimensional approach
Claridge calls the latest version of his model ‘the fully dimensional approach’. However, it might also be characterised as the hybrid or composite approach, as it incorporates elements of both the disease model and the dimensional one.
On this latest Claridge model schizotypy is regarded as a dimension of personality, normally distributed throughout the population, as in the Eysenck model. However, schizophrenia itself is regarded as a breakdown process, quite distinct from the continuously distributed trait of schizotypy, and forming a second, graded continuum, ranging from schizotypal personality disorder to full-blown schizophrenic psychosis.
The model is characterised as fully-dimensional because, not only is the personality trait of schizotypy continuously graded, but the independent continuum of the breakdown processes is also graded rather than categorical.
The fully-dimensional approach argues that full blown psychosis is not just high schizotypy, but must involve other factors that make it qualitatively different and pathological.
# Possible biological bases of schizotypy
## Anhedonia
Anhedonia, or a reduced ability to experience pleasure, is a feature of full-blown schizophrenia that was commented on by both Kraepelin and Bleuler. However, they regarded it as just one among a number of features that tended to characterise the ‘deterioration’, as they saw it, of the schizophrenic’s emotional life. In other words, it was an effect, rather than a cause, of the disease process.
Rado reversed this way of thinking, and ascribed anhedonia a causal role. He considered that the crucial neural deficit in the schizotype was an ‘integrative pleasure deficiency’, i.e. an innate deficiency in the ability to experience pleasure. Meehl took on this view, and attempted to relate this deficiency to abnormality in the dopamine system in the brain, which is implicated in the human reward system.
Questionnaire research on schizotypy in normal subjects is ambiguous with regard to the causal role, if any, of anhedonia. Nettle and McCreery and Claridge found that high schizotypes as measured by factor 1 (above) scored lower than controls on the introverted anhedonia factor, as if they were particularly enjoying life.
Various writers, including Kelley and Coursey and L.J. and J.P. Chapman suggest that anhedonia, if present as a pre-existent trait in a person, may act as a potentiating factor, whereas a high capacity for hedonic enjoyment might act as a protecting one.
## Weakness of inhibitory mechanisms
Various lines of evidence from experimental psychology have suggested a relative weakness of inhibitory mechanisms may be a characteristic of the schizotypal nervous system.
### Negative priming
A number of studies have found that high schizotypes, as measured by questionnaire, show less negative priming than controls. Negative priming is said to occur when a person reacts more slowly than usual to a stimulus which has previously been presented as a distractor and which has therefore had to be ignored. Beech interprets the relative weakness of the negative priming effect in schizotypes as a sign that ‘inhibition of distracting information is reduced in schizophrenia and high schizotypes’.
The reduced negative priming shown by high schizotypes has the interesting effect that they actually perform better on certain tasks (those that require them to respond to previously ignored stimuli) than low schizotypes. This phenomenon may be of significance in the relation to the question of why schizotypy, and indeed schizophrenia itself, is not progressively ‘weeded out’ by the process of natural selection.
### SAWCI
The phenomenon of semantic activation without conscious identification (SAWCI) is said to be displayed when a person shows a priming effect from the processing of consciously undetectable words. For example, a person who has just been shown the word ‘giraffe’, but at a speed at which he or she was not able consciously to report what it was, may nevertheless identify more quickly than usual another animal word on the next trial. Evans found that high schizotypes showed a greater priming effect than controls in such a situation. She argued that this could be accounted for by a relative weakness of inhibitory mechanisms in the semantic networks of high schizotypes.
## Abnormalities of arousal
Claridge suggested that one consequence of a weakness of inhibitory mechanisms in high schizotypes and schizophrenics might be a relative failure of homeostasis in the central nervous system. This, it was proposed, could lead, both to lability of arousal, and to dissociation of arousal in different parts of the nervous system.
### Dissociation of different arousal systems
Claridge and co-workers have found various types of abnormal co-variation between different psychophysiological variables in schizotypes, including between measures of cortical and autonomic arousal.
McCreery and Claridge found evidence of a relative activation of the right cerebral hemisphere as compared with the left in high schizotypes attempting to induce a hallucinatory episode in the laboratory. This suggested a relative dissociation of arousal between the two hemispheres in such people as compared with controls.
### Hyperarousal
A failure of homeostasis in the central nervous system could lead to episodes of hyper-arousal. Oswald has pointed out that extreme stress and hyper-arousal can lead to sleep as a provoked reaction. McCreery has suggested that this could account for the phenomenological similarities between Stage 1 sleep and psychosis, which include hallucinations, delusions, and flattened or inappropriate affect (emotions). On this model, high schizotypes and schizophrenics are people who are liable to what Oswald calls ‘micro-sleeps’, or intrusions of Stage 1 sleep phenomena into waking consciousness, on account of their tendency to high arousal.
In support of this view McCreery points to the high correlation that has been found to exist between scores on the Chapmans’ Perceptual Aberration scale, which measures proneness to perceptual anomalies such as hallucinations, and the Chapmans’ Hypomania scale, which measures a tendency to episodes of heightened arousal. This correlation is found despite the fact that there is no overlap of item content between the two scales.
In the clinical field there is also the paradoxical finding of Stevens and Darbyshire, that schizophrenic patients exhibiting the symptom of catatonia can be aroused from their apparent stupor by the administration of sedative rather than stimulant drugs. They wrote: ‘The psychic state in catatonic schizophrenia can be described as one of great excitement (i.e., hyperalertness) The inhibition of activity apparently does not alter the inner seething excitement.'
It is argued that such a view would be consistent with the model that suggests schizophrenics and high schizotypes are people with a tendency to hyper-arousal. | Schizotypy
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Schizotypy is a psychological concept which describes a continuum of personality characteristics and experiences related to psychosis and in particular, schizophrenia.
This is in contrast to a categorical view of psychosis, where psychosis is considered to be a particular (usually pathological) state, that someone either has, or has not.
# Development of the concept
The categorical view of psychosis is most associated with Emil Kraepelin, who created criteria for the medical diagnosis and classification of different forms of psychotic illness. Particularly, he made the distinction between dementia praecox (now called schizophrenia), manic depressive insanity and non-psychotic states. Modern diagnostic systems used in psychiatry (such as the DSM) maintain this categorical view.[1]
In contrast, psychiatrist Eugene Bleuler did not believe there was a clear separation between sanity and madness, and that psychosis was simply an extreme expression of thoughts and behaviours that could be present to varying degrees through the population.[2]
This was picked up by psychologists such as Hans Eysenck and Gordon Claridge who sought to understand this variation in unusual thought and behaviour in terms of personality theory. This was conceptualised by Eysenck as a single personality trait named psychoticism.[3]
Claridge named his concept schizotypy and by examining unusual experiences in the general population and the clustering of symptoms in diagnosed schizophrenia, Claridge's work suggested that this personality trait was much more complex, and could break down into four factors.[4][5]
- Unusual experiences: The disposition to have unusual perceptual and other cognitive experiences, such as hallucinations, magical or superstitious belief and interpretation of events (see also delusions).
- Cognitive disorganisation: A tendency for thoughts to become derailed, disorganised or tangential (see also formal thought disorder).
- Introverted anhedonia: A tendency to introverted, emotionally flat and asocial behaviour, associated with a deficiency in the ability to feel pleasure from social and physical stimulation.
- Impulsive nonconformity: The disposition to unstable mood and behaviour particularly with regard to rules and social conventions.
# The relationship between schizotypy and mental illness
Although aiming to reflect some of the features present in diagnosable mental illness, schizotypy does not necessarily imply that someone who is more schizotypal than someone else is more ill. For example, certain aspects of schizotypy may be beneficial. Both the Unusual experiences and Cognitive disorganisation aspects have been linked to creativity and academic achievement.[6]Jackson[7] proposed the concept of ‘benign schizotypy’ in relation to certain classes of religious experience, which he suggested might be regarded as a form of problem-solving and therefore of adaptive value.
However, the exact nature of the relationship between schizotypy and diagnosable psychotic illness is still controversial. One of the key concerns that researchers have had is that questionnaire-based measures of schizotypy, when analysed using factor analysis, do not suggest that schizotypy is a unified, homogeneous concept. The three main approaches have been labelled as the 'quasi-dimensional', the ‘dimensional’ and the ‘fully dimensional’.[8]
Each approach is sometimes used to imply that schizotypy reflects a cognitive or biological vulnerability to psychosis, although this may remain dormant and never express itself, unless triggered by appropriate environmental events or conditions (such as certain doses of drugs or high levels of stress).
## Quasi-dimensional approach
The quasi-dimensional model may be traced back to Bleuler[9] (the inventor of the term ‘schizophrenia’), who commented on two types of continuity between normality and psychosis: that between the schizophrenic and his or her relatives, and that between the patient’s pre- and post-morbid personalities (i.e. their personality before and after the onset of overt psychosis).
On the first score he commented: ‘If one observes the relatives of our patients, one often finds in them peculiarities which are qualitatively identical with those of the patients themselves, so that the disease appears to be only a quantitative increase of the anomalies seen in the parents and siblings.’[10]
On the second point, Bleuler discusses in a number of places whether peculiarities displayed by the patient before admission to hospital should be regarded as premonitory symptoms of the disease or merely indications of a predisposition to develop it.
Despite these observations of continuity Bleuler himself remained an advocate of the disease model of schizophrenia. To this end he invoked a concept of latent schizophrenia, writing: ‘In [the latent] form, we can see in nuce [in a nutshell] all the symptoms and all the combinations of symptoms which are present in the manifest types of the disease.’[11]
Later advocates of the quasi-dimensional view of schizotypy are Rado[12] and Meehl,[13] according to both of whom schizotypal symptoms merely represent less explicitly expressed manifestations of the underlying disease process which is schizophrenia. Rado proposed the term ‘schizotype’ to describe the person whose genetic make-up gave him or her a life-long predisposition to schizophrenia.
The quasi-dimensional model is so called because the only dimension it postulates is that of gradations of severity or explicitness in relation to the symptoms of a disease process: namely schizophrenia.
## Dimensional approach
The dimensional approach, influenced by personality theory, argues that full blown psychotic illness is just the most extreme end of the schizotypy spectrum and there is a natural continuum between people with low and high levels of schizotypy. This model is most closely associated with the work of Hans Eysenck, who regarded the person exhibiting the full-blown manifestations of psychosis as simply someone occupying the extreme upper end of his ‘psychoticism’ dimension.[14]
Support for the dimensional model comes from the fact that high-scorers on measures of schizotypy may meet, or partially fulfill, the diagnostic criteria for schizotypal disorders, such as schizophrenia, schizoaffective disorder, schizoid personality disorder and schizotypal personality disorder. Similarly, when analyzed, schizotypy traits often break down into similar groups as do symptoms from schizophrenia[15] (although they are typically present in much less intense forms).
## Fully dimensional approach
Claridge calls the latest version of his model ‘the fully dimensional approach’.[16] However, it might also be characterised as the hybrid or composite approach, as it incorporates elements of both the disease model and the dimensional one.
On this latest Claridge model schizotypy is regarded as a dimension of personality, normally distributed throughout the population, as in the Eysenck model. However, schizophrenia itself is regarded as a breakdown process, quite distinct from the continuously distributed trait of schizotypy, and forming a second, graded continuum, ranging from schizotypal personality disorder to full-blown schizophrenic psychosis.
The model is characterised as fully-dimensional because, not only is the personality trait of schizotypy continuously graded, but the independent continuum of the breakdown processes is also graded rather than categorical.
The fully-dimensional approach argues that full blown psychosis is not just high schizotypy, but must involve other factors that make it qualitatively different and pathological.
# Possible biological bases of schizotypy
## Anhedonia
Anhedonia, or a reduced ability to experience pleasure, is a feature of full-blown schizophrenia that was commented on by both Kraepelin[17] and Bleuler.[18] However, they regarded it as just one among a number of features that tended to characterise the ‘deterioration’, as they saw it, of the schizophrenic’s emotional life. In other words, it was an effect, rather than a cause, of the disease process.
Rado[19] reversed this way of thinking, and ascribed anhedonia a causal role. He considered that the crucial neural deficit in the schizotype was an ‘integrative pleasure deficiency’, i.e. an innate deficiency in the ability to experience pleasure. Meehl[20] took on this view, and attempted to relate this deficiency to abnormality in the dopamine system in the brain, which is implicated in the human reward system.
Questionnaire research on schizotypy in normal subjects is ambiguous with regard to the causal role, if any, of anhedonia. Nettle[21] and McCreery and Claridge[22] found that high schizotypes as measured by factor 1 (above) scored lower than controls on the introverted anhedonia factor, as if they were particularly enjoying life.
Various writers, including Kelley and Coursey[23] and L.J. and J.P. Chapman[24] suggest that anhedonia, if present as a pre-existent trait in a person, may act as a potentiating factor, whereas a high capacity for hedonic enjoyment might act as a protecting one.
## Weakness of inhibitory mechanisms
Various lines of evidence from experimental psychology have suggested a relative weakness of inhibitory mechanisms may be a characteristic of the schizotypal nervous system.
### Negative priming
A number of studies have found that high schizotypes, as measured by questionnaire, show less negative priming than controls.[25] Negative priming is said to occur when a person reacts more slowly than usual to a stimulus which has previously been presented as a distractor and which has therefore had to be ignored. Beech interprets the relative weakness of the negative priming effect in schizotypes as a sign that ‘inhibition of distracting information is reduced in schizophrenia and high schizotypes’.[26]
The reduced negative priming shown by high schizotypes has the interesting effect that they actually perform better on certain tasks (those that require them to respond to previously ignored stimuli) than low schizotypes. This phenomenon may be of significance in the relation to the question of why schizotypy, and indeed schizophrenia itself, is not progressively ‘weeded out’ by the process of natural selection.
### SAWCI
The phenomenon of semantic activation without conscious identification (SAWCI) is said to be displayed when a person shows a priming effect from the processing of consciously undetectable words. For example, a person who has just been shown the word ‘giraffe’, but at a speed at which he or she was not able consciously to report what it was, may nevertheless identify more quickly than usual another animal word on the next trial. Evans[27] found that high schizotypes showed a greater priming effect than controls in such a situation. She argued that this could be accounted for by a relative weakness of inhibitory mechanisms in the semantic networks of high schizotypes.
## Abnormalities of arousal
Claridge[28] suggested that one consequence of a weakness of inhibitory mechanisms in high schizotypes and schizophrenics might be a relative failure of homeostasis in the central nervous system. This, it was proposed, could lead, both to lability of arousal, and to dissociation of arousal in different parts of the nervous system.
### Dissociation of different arousal systems
Claridge and co-workers[29][30][31] have found various types of abnormal co-variation between different psychophysiological variables in schizotypes, including between measures of cortical and autonomic arousal.
McCreery and Claridge[32] found evidence of a relative activation of the right cerebral hemisphere as compared with the left in high schizotypes attempting to induce a hallucinatory episode in the laboratory. This suggested a relative dissociation of arousal between the two hemispheres in such people as compared with controls.
### Hyperarousal
A failure of homeostasis in the central nervous system could lead to episodes of hyper-arousal. Oswald[33] has pointed out that extreme stress and hyper-arousal can lead to sleep as a provoked reaction. McCreery[34][35] has suggested that this could account for the phenomenological similarities between Stage 1 sleep and psychosis, which include hallucinations, delusions, and flattened or inappropriate affect (emotions). On this model, high schizotypes and schizophrenics are people who are liable to what Oswald calls ‘micro-sleeps’, or intrusions of Stage 1 sleep phenomena into waking consciousness, on account of their tendency to high arousal.
In support of this view McCreery points to the high correlation that has been found to exist[36] between scores on the Chapmans’ Perceptual Aberration scale,[37] which measures proneness to perceptual anomalies such as hallucinations, and the Chapmans’ Hypomania scale,[38] which measures a tendency to episodes of heightened arousal. This correlation is found despite the fact that there is no overlap of item content between the two scales.
In the clinical field there is also the paradoxical finding of Stevens and Darbyshire,[39] that schizophrenic patients exhibiting the symptom of catatonia can be aroused from their apparent stupor by the administration of sedative rather than stimulant drugs. They wrote: ‘The psychic state in catatonic schizophrenia can be described as one of great excitement (i.e., hyperalertness)[…] The inhibition of activity apparently does not alter the inner seething excitement.'
It is argued that such a view would be consistent with the model that suggests schizophrenics and high schizotypes are people with a tendency to hyper-arousal. | https://www.wikidoc.org/index.php/Schizotypy | |
350376a74169147de4ce6b87cb73792bf26f5ee0 | wikidoc | School run | School run
The School Run is a modern phenomenon associated with parents taking their children to school by car. Outside most British schools parents park cars near the school gates and drop off and pick up their children at the appropriate times.
In the past it was not unusual for most children to walk to school, either on their own, with friends, or accompanied by an adult. Walking to school has fallen from 61% of primary school pupils in 1992/4 to 50% in 2004.
Walking to school is being replaced by parents using cars, sometimes in a rota with other parents.
The reasons for this are manyfold. Firstly, in many cases both parents work and do not have time to walk their children to school, and do not know any other parents who have the time either. Secondly, even if the children are old enough to walk on their own (or cycle), most parents are worried that something may happen to them, e.g. abduction, car accidents etc. Some schools do not offer bus service and can be too far to walk to school anyway, forcing the school run.
Ironically, the risk of children being run over near their schools is much higher than in the past due to all the parents driving their own children to school and parking in unsafe places near the school gates. It is not unusual to see cars parking in bus stops, on pedestrian crossings or facing the wrong way, with children getting in or out of the car.
The fear that something may happen to the children has perhaps more to do with media coverage of isolated (but tragic) cases than any real threat.
Some schools now have a 20 mph (~30 km/h) speed limit operating when the children are about, though traffic congestion often necessitates a lower speed.
A further problem in recent times has been an increasing level of choice by parents as to which school their children go to. Obviously the inevitable result is that kids may have further to travel and are more likely to require a bus or a lift in the car.
It is claimed that the school run is responsible for a large amount of the traffic problems in the morning rush hour. However, the often dramatic reduction in congestion at the start of school holidays, is also because many parents have to go on holiday at this time.
The decreasing amount of exercise and associated increase in obesity are also partly blamed on the school run.
In the United Kingdom, the school run has become a popular target for some politicians and campaigners against the use of cars for journeys which could be better walked or cycled. One of the campaigns promoting this alternative is the walk to school campaign. | School run
Template:Globalize/UK
The School Run is a modern phenomenon associated with parents taking their children to school by car. Outside most British schools parents park cars near the school gates and drop off and pick up their children at the appropriate times.
In the past it was not unusual for most children to walk to school, either on their own, with friends, or accompanied by an adult. Walking to school has fallen from 61% of primary school pupils in 1992/4 to 50% in 2004. [1]
Walking to school is being replaced by parents using cars, sometimes in a rota with other parents.
The reasons for this are manyfold. Firstly, in many cases both parents work and do not have time to walk their children to school, and do not know any other parents who have the time either. Secondly, even if the children are old enough to walk on their own (or cycle), most parents are worried that something may happen to them, e.g. abduction, car accidents etc. Some schools do not offer bus service and can be too far to walk to school anyway, forcing the school run.
Ironically, the risk of children being run over near their schools is much higher than in the past due to all the parents driving their own children to school and parking in unsafe places near the school gates. It is not unusual to see cars parking in bus stops, on pedestrian crossings or facing the wrong way, with children getting in or out of the car.
The fear that something may happen to the children has perhaps more to do with media coverage of isolated (but tragic) cases than any real threat.
Some schools now have a 20 mph (~30 km/h) speed limit operating when the children are about, though traffic congestion often necessitates a lower speed.
A further problem in recent times has been an increasing level of choice by parents as to which school their children go to. Obviously the inevitable result is that kids may have further to travel and are more likely to require a bus or a lift in the car.
It is claimed that the school run is responsible for a large amount of the traffic problems in the morning rush hour. However, the often dramatic reduction in congestion at the start of school holidays, is also because many parents have to go on holiday at this time.
The decreasing amount of exercise and associated increase in obesity are also partly blamed on the school run.
In the United Kingdom, the school run has become a popular target for some politicians and campaigners against the use of cars for journeys which could be better walked or cycled. One of the campaigns promoting this alternative is the walk to school campaign. | https://www.wikidoc.org/index.php/School_run | |
85c9a1f8868b04375c9b35753069aaefaf03a0f8 | wikidoc | Sciencenet | Sciencenet
"Sciencenet" is an experimental search engine at KIT (Karlsruhe Institute of Technology - Liebel-Lab) for scientific knowledge.
The Sciencenet software (YaCy) is based on p2p technology developed by Michael Christen in collaboration with Liebel-lab at Karlsruhe Institute of Technology.
# Background
Scientific knowledge is spread across many database, research institutes, educational websites and literature repositories. Today's search engines success is often based on popularity ranking.
Popularity ranking is a powerful method for general search strategies, but less efficient for scientific knowledge. The Sciencenet search engine is especially for scientific websites and scientific content. Its index is a collection of educational (e.g. of ".edu" / ".ac.uk" /".ac.au") and research dedicated sites (e.g. the german Helmholtz society, Max Planck institutes or Swiss and Austrian universities). This is the major difference to the global YaCy search engine ("Freeworld"), which serves as a global search engine.
# Sciencenet architecture
Sciencenet is a network of Linux PCs running "YaCy" software. The "Sciencenet core cluster" is located at the Institute of Toxicology and Genetics (Liebel-Lab), KIT Karlsruhe (Karlsruhe Institute of Technology).
Sciencenet-YaCy software has been designed and tested to run in a network with at least 2000 CPUs, with up to 10 Mio webpages per single CPU, allowing to search large and/or distributed information repositories.
# Mission
Any university / research institute is encouraged to use the software and contribute to the scientific network. The software automatically connects to the "core cluster" and contributes its search engine to the distributed sciencenet network. A high speed internet broadband connection (> 2 Mbit/s) and dedicated PCs are required.
Ideally every research institute runs the free YaCy-Sciencenet software on 1-2 local PCs and provides its webpages to the network.
As a side effect, wasted bandwidth from external search engines is reduced to a minimum.
The sciencenet ideally provides a free, open scientific search engine index to the community.
# Sciencenet current status
- Currently (April, 2008) 45 low cost Linux-PCs running Java and YaCy software share ~105.000.000 documents in a distributed peer2peer network. | Sciencenet
Template:Infobox Software
"Sciencenet" is an experimental search engine at KIT (Karlsruhe Institute of Technology - Liebel-Lab) for scientific knowledge.
The Sciencenet software (YaCy) is based on p2p technology developed by Michael Christen in collaboration with Liebel-lab at Karlsruhe Institute of Technology.
# Background
Scientific knowledge is spread across many database, research institutes, educational websites and literature repositories. Today's search engines success is often based on popularity ranking.
Popularity ranking is a powerful method for general search strategies, but less efficient for scientific knowledge. The Sciencenet search engine is especially for scientific websites and scientific content. Its index is a collection of educational (e.g. of ".edu" / ".ac.uk" /".ac.au") and research dedicated sites (e.g. the german Helmholtz society, Max Planck institutes or Swiss and Austrian universities). This is the major difference to the global YaCy search engine ("Freeworld"), which serves as a global search engine.
# Sciencenet architecture
Sciencenet is a network of Linux PCs running "YaCy" software. The "Sciencenet core cluster" is located at the Institute of Toxicology and Genetics (Liebel-Lab), KIT Karlsruhe (Karlsruhe Institute of Technology).
Sciencenet-YaCy software has been designed and tested to run in a network with at least 2000 CPUs, with up to 10 Mio webpages per single CPU, allowing to search large and/or distributed information repositories.
# Mission
Any university / research institute is encouraged to use the software and contribute to the scientific network. The software automatically connects to the "core cluster" and contributes its search engine to the distributed sciencenet network. A high speed internet broadband connection (> 2 Mbit/s) and dedicated PCs are required.
Ideally every research institute runs the free YaCy-Sciencenet software on 1-2 local PCs and provides its webpages to the network.
As a side effect, wasted bandwidth from external search engines is reduced to a minimum.
The sciencenet ideally provides a free, open scientific search engine index to the community.
# Sciencenet current status
- Currently (April, 2008) 45 low cost Linux-PCs running Java and YaCy software share ~105.000.000 documents in a distributed peer2peer network. | https://www.wikidoc.org/index.php/Sciencenet | |
94237d7aca9dd473d6b0822f3002b1b6676a23ad | wikidoc | Sclerology | Sclerology
Sclerology is a non-invasive alternative medicine practice in which the sclera is examined for information about a patient's systemic health.
According to advocates, examination of the sclera reveals a great number of disease processes and is capable of showing data that is more current (to within days), while iridology is better at showing genetic tendency. They claim sclerology requires no clinical tools and is an inexpensive, non-invasive method to enhance the evaluation of patients' health.
# History
Sclerology has been used perennially by indigenous cultures for at least a millennia. Ancient Chinese medical texts (Secrets of the Bronze Man, written 1046AD in the Song Dynasty, translated by Stuart Mauro of Dallas TX) show that the method was used in China over 1000 years ago. American Indians (Nez Percé and Blackfoot) practiced it but kept no written records.
# Criticism
Similar to criticism which has been leveled at iridology and other alternative practices, skeptics point out that sclerology is founded in pseudoscience, claiming that there is no reason to assume that the condition of the sclera has any causal relation to a patient's condition in general. They also claim it is ineffective and may be harmful to patients if it delays the diagnosis and treatment of a true medical problem. | Sclerology
Sclerology is a non-invasive alternative medicine practice in which the sclera is examined for information about a patient's systemic health.
According to advocates, examination of the sclera reveals a great number of disease processes and is capable of showing data that is more current (to within days), while iridology is better at showing genetic tendency.[1] They claim sclerology requires no clinical tools and is an inexpensive, non-invasive method to enhance the evaluation of patients' health.[1]
# History
Sclerology has been used perennially by indigenous cultures for at least a millennia.[citation needed] Ancient Chinese medical texts (Secrets of the Bronze Man, written 1046AD in the Song Dynasty, translated by Stuart Mauro of Dallas TX) show that the method was used in China over 1000 years ago. American Indians (Nez Percé and Blackfoot) practiced it but kept no written records.[citation needed]
# Criticism
Similar to criticism which has been leveled at iridology and other alternative practices, skeptics point out that sclerology is founded in pseudoscience, claiming that there is no reason to assume that the condition of the sclera has any causal relation to a patient's condition in general.[citation needed] They also claim it is ineffective and may be harmful to patients if it delays the diagnosis and treatment of a true medical problem.[citation needed] | https://www.wikidoc.org/index.php/Sclerology | |
bdb0c09eed609f80ceee1e47f6caa19b48cb3ea4 | wikidoc | Sclerostin | Sclerostin
Sclerostin is a protein that in humans is encoded by the SOST gene.
Sclerostin is a secreted glycoprotein with a C-terminal cysteine knot-like (CTCK) domain and sequence similarity to the DAN (differential screening-selected gene aberrative in neuroblastoma) family of bone morphogenetic protein (BMP) antagonists. Sclerostin is produced primarily by the osteocyte but is also expressed in other tissues, and has anti-anabolic effects on bone formation.
# Structure
The sclerostin protein, with a length of 213 residues, has a secondary structure that has been determined by protein NMR to be 28% beta sheet (6 strands; 32 residues).
# Function
Sclerostin, the product of the SOST gene, located on chromosome 17q12–q21 in humans, was originally believed to be a non-classical bone morphogenetic protein (BMP) antagonist. More recently, sclerostin has been identified as binding to LRP5/6 receptors and inhibiting the Wnt signaling pathway. The inhibition of the Wnt pathway leads to decreased bone formation. Although the underlying mechanisms are unclear, it is believed that the antagonism of BMP-induced bone formation by sclerostin is mediated by Wnt signaling, but not BMP signaling pathways. Sclerostin is expressed in osteocytes and some chondrocytes and it inhibits bone formation by osteoblasts.
Sclerostin production by osteocytes is inhibited by parathyroid hormone, mechanical loading and cytokines including prostaglandin E2, oncostatin M, cardiotrophin-1 and leukemia inhibitory factor. Sclerostin production is increased by calcitonin. Thus, osteoblast activity is self regulated by a negative feedback system.
# Clinical significance
Mutations in the gene that encodes the sclerostin protein are associated with disorders associated with high bone mass, sclerosteosis and van Buchem disease.
van Buchem disease is also an autosomal recessive skeletal disease characterized by bone overgrowth. It was first described in 1955 as "hyperostosis corticalis generalisata familiaris", but was given the current name in 1968. Excessive bone formation is most prominent in the skull, mandible, clavicle, ribs and diaphyses of long bones and bone formation occurs throughout life. It is a very rare condition with about 30 known cases in 2002. In 1967 van Buchem characterized the disease in 15 patients of Dutch origin. Patients with sclerosteosis are distinguished from those with van Buchem disease because they are often taller and have hand malformations. In the late 1990s, scientists at the company Chiroscience and the University of Cape Town determined that a "single mutation" in the gene was responsible for the disorder.
An antibody for sclerostin is being developed because of the protein’s specificity to bone. Its use has increased bone growth in preclinical trials in osteoporotic rats and monkeys. In a Phase I study, a single dose of anti-sclerostin antibody from Amgen (Romosozumab) increased bone density in the hip and spine in healthy men and postmenopausal women and the drug was well tolerated. In a Phase II trial, one year of the antibody treatment in osteoporotic women increased bone density more than bisphosphonate and teriparatide treatment; it had mild injection side effects. A Phase II trial of a monoclonal human antibody to sclerostin from Eli Lilly had positive effects on post-menopausal women. Monthly treatments of the antibody for one year increased the bone mineral density of the spine and hip by 18 percent and 6 percent, respectively, compared to the placebo group. In a Phase III trial, one year of Romosozumab treatment in post-menopausal women reduced the risk of vertebral fractures compared to the placebo group. It also increased the bone mineral density in the lumbar spine (13.3% versus 0.0%), femoral neck (5.2% versus -0.7%) and total hip (6.8% versus 0.0%) compared to the placebo group. Adverse events were balanced between the groups. | Sclerostin
Sclerostin is a protein that in humans is encoded by the SOST gene.[1][2]
Sclerostin is a secreted glycoprotein with a C-terminal cysteine knot-like (CTCK) domain and sequence similarity to the DAN (differential screening-selected gene aberrative in neuroblastoma) family of bone morphogenetic protein (BMP) antagonists. Sclerostin is produced primarily by the osteocyte but is also expressed in other tissues,[3] and has anti-anabolic effects on bone formation.[4]
# Structure
The sclerostin protein, with a length of 213 residues, has a secondary structure that has been determined by protein NMR to be 28% beta sheet (6 strands; 32 residues).[5]
# Function
Sclerostin, the product of the SOST gene, located on chromosome 17q12–q21 in humans,[6] was originally believed to be a non-classical bone morphogenetic protein (BMP) antagonist.[7] More recently, sclerostin has been identified as binding to LRP5/6 receptors and inhibiting the Wnt signaling pathway.[8][9] The inhibition of the Wnt pathway leads to decreased bone formation.[8] Although the underlying mechanisms are unclear, it is believed that the antagonism of BMP-induced bone formation by sclerostin is mediated by Wnt signaling, but not BMP signaling pathways.[10][11] Sclerostin is expressed in osteocytes and some chondrocytes and it inhibits bone formation by osteoblasts.[12][13][14]
Sclerostin production by osteocytes is inhibited by parathyroid hormone,[14][15] mechanical loading[16] and cytokines including prostaglandin E2,[17] oncostatin M, cardiotrophin-1 and leukemia inhibitory factor.[18] Sclerostin production is increased by calcitonin.[19] Thus, osteoblast activity is self regulated by a negative feedback system.[20]
# Clinical significance
Mutations in the gene that encodes the sclerostin protein are associated with disorders associated with high bone mass, sclerosteosis and van Buchem disease.[6]
van Buchem disease is also an autosomal recessive skeletal disease characterized by bone overgrowth.[21] It was first described in 1955 as "hyperostosis corticalis generalisata familiaris", but was given the current name in 1968.[21][22] Excessive bone formation is most prominent in the skull, mandible, clavicle, ribs and diaphyses of long bones and bone formation occurs throughout life.[21] It is a very rare condition with about 30 known cases in 2002.[21] In 1967 van Buchem characterized the disease in 15 patients of Dutch origin.[21] Patients with sclerosteosis are distinguished from those with van Buchem disease because they are often taller and have hand malformations.[23] In the late 1990s, scientists at the company Chiroscience and the University of Cape Town determined that a "single mutation" in the gene was responsible for the disorder.[24]
An antibody for sclerostin is being developed because of the protein’s specificity to bone.[12] Its use has increased bone growth in preclinical trials in osteoporotic rats and monkeys.[25][26] In a Phase I study, a single dose of anti-sclerostin antibody from Amgen (Romosozumab) increased bone density in the hip and spine in healthy men and postmenopausal women and the drug was well tolerated.[27] In a Phase II trial, one year of the antibody treatment in osteoporotic women increased bone density more than bisphosphonate and teriparatide treatment; it had mild injection side effects.[13][28] A Phase II trial of a monoclonal human antibody to sclerostin from Eli Lilly had positive effects on post-menopausal women. Monthly treatments of the antibody for one year increased the bone mineral density of the spine and hip by 18 percent and 6 percent, respectively, compared to the placebo group.[29] In a Phase III trial, one year of Romosozumab treatment in post-menopausal women reduced the risk of vertebral fractures compared to the placebo group. It also increased the bone mineral density in the lumbar spine (13.3% versus 0.0%), femoral neck (5.2% versus -0.7%) and total hip (6.8% versus 0.0%) compared to the placebo group. Adverse events were balanced between the groups.[30] | https://www.wikidoc.org/index.php/Sclerosteosis | |
12b2f2656563c7d8f888b1bf778689cd3700164a | wikidoc | Seismology | Seismology
Seismology (from the Greek seismos(σεισμός) = earthquake and λόγος,logos = knowledge ) is the scientific study of earthquakes and the propagation of elastic waves through the Earth. The field also includes studies of earthquake effects, such as tsunamis as well as diverse seismic sources such as volcanic, tectonic, oceanic, atmospheric, and artificial processes (such as explosions). A related field that uses geology to infer information regarding past earthquakes is paleoseismology. A recording of earth motion as a function of time is called a seismogram.
# Seismic Waves
Earthquakes, and other sources, produce different types of seismic waves which travel through rock, and provide an effective way to image both sources and structures deep within the Earth. There are three basic types of seismic waves in solids: P-waves, S-waves (both body waves) and surface waves. The two basic kinds of surface waves (Rayleigh and Love), can be fundamentally explained in terms of interacting P- and/or S-waves.
Pressure waves (P-waves), are longitudinal waves that travel at maximum velocity within solids and are therefore the first waves to appear on a seismogram.
S-waves, also called Shear waves or secondary waves, are transverse waves that travel more slowly than P-waves and thus appear later than P-waves on a seismogram. Particle motion is perpendicular to the direction of wave propagation. Shear waves do not exist in fluids such as air or water.
Surface waves travel more slowly than P-waves and S-waves, but because they are guided by the surface of the Earth (and their energy is thus trapped near the Earth's surface) they can be much larger in amplitude than body waves, and can be the largest signals seen in earthquake seismograms. They are particularly strongly excited when the seismic source is close to the surface of the Earth, such as the case of a shallow earthquake.
For large enough earthquakes, one can observe the normal modes of the Earth. These modes are excited as discrete frequencies and can be observed for days after the generating event. The first observations were made in the 1960s as the advent of higher fidelity instruments coincided with two of the largest earthquakes of the 20th century - the 1960 Great Chilean earthquake and the 1964 Great Alaskan earthquake. Since then, the normal modes of the Earth have given us some of the strongest constraints on the deep structure of the Earth.
One of the earliest important discoveries (suggested by Richard Dixon Oldham in 1906 and definitively shown by Harold Jeffreys in 1926) was that the outer core of the Earth is liquid. Pressure waves (P-waves) pass through the core. Transverse or shear waves (S-waves) that shake side-to-side require rigid material so they do not pass through the outer core. Thus, the liquid core causes a "shadow" on the side of the planet opposite of the earthquake where no direct S-waves are observed. The reduction in P-wave velocity of the outer core also causes a substantial delay for P waves penetrating the core from the (seismically faster velocity) mantle.
Seismic waves produced by explosions or vibrating controlled sources are the primary method of underground exploration. Controlled source seismology has been used to map salt domes, faults, anticlines and other geologic traps in petroleum-bearing rocks, geological faults, rock types, and long-buried giant meteor craters. For example, the Chicxulub impactor, which is believed to have killed the dinosaurs, was localized to Central America by analyzing ejecta in the cretaceous boundary, and then physically proven to exist using seismic maps from oil exploration.
Using seismic tomography with earthquake waves, the interior of the Earth has been completely mapped to a resolution of several hundred kilometers. This process has enabled scientists to identify convection cells, mantle plumes and other large-scale features of the inner Earth.
Seismographs are instruments that sense and record the motion of the Earth. Networks of seismographs today continuously monitor the seismic environment of the planet, allowing for the monitoring and analysis of global earthquakes and tsunami warnings, as well as recording a variety of seismic signals arising from non-earthquake sources ranging from explosions (nuclear and chemical), to pressure variations on the ocean floor induced by ocean waves (the global microseism), to cryospheric events associated with large icebergs and glaciers. Above-ocean meteor strikes as large as ten kilotons of TNT, (equivalent to about 4.2 × 1013 J of effective explosive force) have been recorded by seismographs. A major motivation for the global instrumentation of the Earth with seismographs has been for the monitoring of nuclear testing.
One of the first attempts at the scientific study of earthquakes followed the 1755 Lisbon earthquake. Other especially notable earthquakes that spurred major developments in the science of seismology include the 1906 San Francisco earthquake, the 1964 Alaska earthquake and the 2004 Sumatra-Andaman earthquake. An extensive list of famous earthquakes can be found on the earthquake page.
# Earthquake prediction
Most seismologists do not believe that a system to provide timely warnings for individual earthquakes has yet to be developed, and many believe that such a system would be unlikely to give significant warning of impending seismic events. More general forecasts, however, are routinely used to establish seismic hazard. Such forecasts estimate the probability of an earthquake of a particular size affecting a particular location within a particular time span.
Various attempts have been made by seismologists and others to create effective systems for precise earthquake predictions, including the VAN method. Such methods have yet to be generally accepted in the seismology community.
# Notable seismologists
- Aki, Keiiti
- Beroza, Gregory
- Bolt, Bruce
- Dziewonski, Adam Marian
- Galitzine, Boris Borisovich
- Gamburtsev, Grigory A.
- Gutenberg, Beno
- Hutton, Kate
- Jordan, Thomas
- Jeffreys, Harold
- Kanamori, Hiroo
- Keilis-Borok, Vladimir
- Knopoff, Leon
- Lehmann, Inge
- Mercalli, Giuseppe
- Hanks, Thomas C.
- Milne, John
- Mohorovičić, Andrija
- Oldham, Richard Dixon
- Sebastião de Melo, Marquis of Pombal
- Press, Frank
- Richter, Charles Francis
- Zhang Heng | Seismology
Template:Cleanup
Seismology (from the Greek seismos(σεισμός) = earthquake and λόγος,logos = knowledge ) is the scientific study of earthquakes and the propagation of elastic waves through the Earth. The field also includes studies of earthquake effects, such as tsunamis as well as diverse seismic sources such as volcanic, tectonic, oceanic, atmospheric, and artificial processes (such as explosions). A related field that uses geology to infer information regarding past earthquakes is paleoseismology. A recording of earth motion as a function of time is called a seismogram.
# Seismic Waves
Earthquakes, and other sources, produce different types of seismic waves which travel through rock, and provide an effective way to image both sources and structures deep within the Earth. There are three basic types of seismic waves in solids: P-waves, S-waves (both body waves) and surface waves. The two basic kinds of surface waves (Rayleigh and Love), can be fundamentally explained in terms of interacting P- and/or S-waves.
Pressure waves (P-waves), are longitudinal waves that travel at maximum velocity within solids and are therefore the first waves to appear on a seismogram.
S-waves, also called Shear waves or secondary waves, are transverse waves that travel more slowly than P-waves and thus appear later than P-waves on a seismogram. Particle motion is perpendicular to the direction of wave propagation. Shear waves do not exist in fluids such as air or water.
Surface waves travel more slowly than P-waves and S-waves, but because they are guided by the surface of the Earth (and their energy is thus trapped near the Earth's surface) they can be much larger in amplitude than body waves, and can be the largest signals seen in earthquake seismograms. They are particularly strongly excited when the seismic source is close to the surface of the Earth, such as the case of a shallow earthquake.
For large enough earthquakes, one can observe the normal modes of the Earth. These modes are excited as discrete frequencies and can be observed for days after the generating event. The first observations were made in the 1960s as the advent of higher fidelity instruments coincided with two of the largest earthquakes of the 20th century - the 1960 Great Chilean earthquake and the 1964 Great Alaskan earthquake. Since then, the normal modes of the Earth have given us some of the strongest constraints on the deep structure of the Earth.
One of the earliest important discoveries (suggested by Richard Dixon Oldham in 1906 and definitively shown by Harold Jeffreys in 1926) was that the outer core of the Earth is liquid. Pressure waves (P-waves) pass through the core. Transverse or shear waves (S-waves) that shake side-to-side require rigid material so they do not pass through the outer core. Thus, the liquid core causes a "shadow" on the side of the planet opposite of the earthquake where no direct S-waves are observed. The reduction in P-wave velocity of the outer core also causes a substantial delay for P waves penetrating the core from the (seismically faster velocity) mantle.
Seismic waves produced by explosions or vibrating controlled sources are the primary method of underground exploration. Controlled source seismology has been used to map salt domes, faults, anticlines and other geologic traps in petroleum-bearing rocks, geological faults, rock types, and long-buried giant meteor craters. For example, the Chicxulub impactor, which is believed to have killed the dinosaurs, was localized to Central America by analyzing ejecta in the cretaceous boundary, and then physically proven to exist using seismic maps from oil exploration.
Using seismic tomography with earthquake waves, the interior of the Earth has been completely mapped to a resolution of several hundred kilometers. This process has enabled scientists to identify convection cells, mantle plumes and other large-scale features of the inner Earth.
Seismographs are instruments that sense and record the motion of the Earth. Networks of seismographs today continuously monitor the seismic environment of the planet, allowing for the monitoring and analysis of global earthquakes and tsunami warnings, as well as recording a variety of seismic signals arising from non-earthquake sources ranging from explosions (nuclear and chemical), to pressure variations on the ocean floor induced by ocean waves (the global microseism), to cryospheric events associated with large icebergs and glaciers. Above-ocean meteor strikes as large as ten kilotons of TNT, (equivalent to about 4.2 × 1013 J of effective explosive force) have been recorded by seismographs. A major motivation for the global instrumentation of the Earth with seismographs has been for the monitoring of nuclear testing.
One of the first attempts at the scientific study of earthquakes followed the 1755 Lisbon earthquake. Other especially notable earthquakes that spurred major developments in the science of seismology include the 1906 San Francisco earthquake, the 1964 Alaska earthquake and the 2004 Sumatra-Andaman earthquake. An extensive list of famous earthquakes can be found on the earthquake page.
# Earthquake prediction
Most seismologists do not believe that a system to provide timely warnings for individual earthquakes has yet to be developed, and many believe that such a system would be unlikely to give significant warning of impending seismic events. More general forecasts, however, are routinely used to establish seismic hazard. Such forecasts estimate the probability of an earthquake of a particular size affecting a particular location within a particular time span.
Various attempts have been made by seismologists and others to create effective systems for precise earthquake predictions, including the VAN method. Such methods have yet to be generally accepted in the seismology community.
# Notable seismologists
- Aki, Keiiti
- Beroza, Gregory
- Bolt, Bruce
- Dziewonski, Adam Marian
- Galitzine, Boris Borisovich
- Gamburtsev, Grigory A.
- Gutenberg, Beno
- Hutton, Kate
- Jordan, Thomas
- Jeffreys, Harold
- Kanamori, Hiroo
- Keilis-Borok, Vladimir
- Knopoff, Leon
- Lehmann, Inge
- Mercalli, Giuseppe
- Hanks, Thomas C.
- Milne, John
- Mohorovičić, Andrija
- Oldham, Richard Dixon
- Sebastião de Melo, Marquis of Pombal
- Press, Frank
- Richter, Charles Francis
- Zhang Heng | https://www.wikidoc.org/index.php/Seismology | |
65d0cd347df81b6a69a4c421e372b157062ba7a1 | wikidoc | Self-worth | Self-worth
In psychology, self-esteem reflects a person's overall evaluation or appraisal of his or her own worth.
Self-esteem encompasses beliefs (for example, "I am competent/incompetent") and emotions (for example, triumph/despair, pride/shame). Behavior may reflect self-esteem (for example, assertiveness/shyness, confidence/caution).
Psychologists usually regard self-esteem as an enduring personality characteristic (trait self-esteem), though normal, short-term variations (state self-esteem) occur.
Self-esteem can apply specifically to a particular dimension (for example, "I believe I am a good writer, and feel proud of that in particular") or have global extent (for example, "I believe I am a good person, and feel proud of myself in general").
Synonyms or near-synonyms of self-esteem include: self-worth, self-regard, self-respect, self-love (which can express overtones of self-promotion), self-integrity. Self-esteem is distinct from self-confidence and self-efficacy, which involve beliefs about ability and future performance.
# History of the concept
The Oxford English Dictionary
traces the use of the word "self-esteem" in English back as far as 1657. ]
After a career in the proto-psychological lore of phrenology in the 19th century
the term entered more mainstream psychological use in the work of the American psychologists and philosophers Lorne Park and William James in 1890.
Self-esteem has become the third most frequently occurring theme in psychological literature: as of 2003 over 25,000 articles, chapters, and books referred to the topic.
# Definitions
Given a long and varied history, the term has, unsurprisingly, no less than three major types of definitions in the field, each of which has generated its own tradition of research, findings, and practical applications:
- The original definition presents self-esteem as a ratio found by dividing one’s successes in areas of life of importance to a given individual by the failures in them or one’s “success / pretensions”. Problems with this approach come from making self-esteem contingent upon success: this implies inherent instability because failure can occur at any moment.
- In the mid 1960s Morris Rosenberg and social-learning theorists defined self-esteem in terms of a stable sense of personal worth or worthiness, (see Rosenberg self esteem scale). This became the most frequently used definition for research, but involves problems of boundary-definition, making self-esteem indistinguishable from such things as narcissism or simple bragging.
- Nathaniel Branden in 1969 briefly defined self-esteem as "...the experience of being competent to cope with the basic challenges of life and being worthy of happiness". This two-factor approach, as some have also called it, provides a balanced definition that seems to be capable of dealing with limits of defining self-esteem primarily in terms of competence or worth alone.
Branden’s (1969) description of self-esteem includes the following primary properties:
- self-esteem as a basic human need, i.e., "...it makes an essential contribution to the life process", "...is indispensable to normal and healthy self-development, and has a value for survival."
- self-esteem as an automatic and inevitable consequence of the sum of individuals' choices in using their consciousness
- something experienced as a part of, or background to, all of the individuals thoughts, feelings and actions.
Self esteem is a concept of personality, for it to grow, we need to have self worthy, and this self worthy will be sought from embracing challenges that result in the showing of success.
Compare the usage of terms such as self-love or self-confidence.
Implicit self-esteem refers to a person's disposition to evaluate themselves positively or negatively in a spontaneous, automatic, or unconscious manner. It contrasts with explicit self-esteem, which entails more conscious and reflective self-evaluation. Both explicit and implicit self-esteem are subtypes of self-esteem proper.
Implicit self-esteem is assessed using indirect measures of cognitive processing. These include the Name Letter Task and the Implicit Association Test. Such indirect measures are designed to reduce awareness of, or control of, the process of assessment. When used to assess implicit self-esteem, they feature stimuli designed to represent the self, such as personal pronouns (e.g., "I") or letters in one's name.
# Measurement
For the purposes of empirical research, psychologists typically assess self-esteem by a self-report inventory yielding a quantitative result. They establish the validity and reliability of the questionnaire prior to its use. Researchers are becoming more interested in measures of implicit self-esteem.
Popular lore recognizes just "high" self-esteem and "low" self-esteem.
The Rosenberg Self-Esteem Scale (1965) and the Coopersmith Self-Esteem Inventory (1967/1981) feature among the most widely used systems for measuring self-esteem. The Rosenberg test usually uses a ten-question battery scored on a four-point response-system that requires participants to indicate their level of agreement with a series of statements about themselves. The Coopersmith Inventory uses a 50-question battery over a variety of topics and asks subjects whether they rate positive or negative characteristics of someone as similar or dissimilar to themselves.
# Theories
Many early theories suggested that self-esteem is a basic human need or motivation. American psychologist Abraham Maslow, for example, included self-esteem in his hierarchy of needs. He described two different forms of esteem: the need for respect from others and the need for self-respect, or inner self-esteem. Respect from others entails recognition, acceptance, status, and appreciation, and was believed to be more fragile and easily lost than inner self-esteem. According to Maslow, without the fulfillment of the self-esteem need, individuals will be driven to seek it and unable to grow and obtain self-actualization.
Modern theories of self-esteem explore the reasons why humans are motivated to maintain a high regard for themselves. Sociometer theory maintains that self-esteem evolved to check one's level of status and acceptance in ones' social group. According to terror management theory, self esteem serves a protective function and reduces anxiety about life and death.
# Quality and level of self-esteem
Level and quality of self-esteem, though correlated, remain distinct. Level-wise, one can exhibit high but fragile self-esteem (as in narcissism) or low but stable self-esteem (as in humility). However, investigators can indirectly assess the quality of self-esteem in several ways:
- in terms of its constancy over time (stability)
- in terms of its independence of meeting particular conditions (non-contingency)
- in terms of its ingrained nature at a basic psychological level (implicitness or automatized).
Humans have portrayed the dangers of excessive self-esteem and the advantages of more humility since at least the development of Greek tragedy, which typically showed the results of hubris.
# Self-esteem, grades and relationships
From the late 1970s to the early 1990s many Americans assumed as a matter of course that students' self-esteem acted as a critical factor in the grades that they earn in school, in their relationships with their peers, and in their later success in life. Given this assumption, some American groups created programs which aimed to increase the self-esteem of students. Until the 1990s little peer-reviewed and controlled research took place on this topic.
Peer-reviewed research undertaken since then has not validated previous assumptions. Recent research indicates that inflating students' self-esteem in and of itself has no positive effect on grades. One study has shown that inflating self-esteem by itself can actually decrease grades.
High self-esteem correlates highly with self-reported happiness. However, it is not clear which, if either, necessarily leads to the other. Additionally, self-esteem has been found to be related to forgiveness in close relationships, in that people with high self-esteem will be more forgiving than people with low self-esteem.
The relationship involving self-esteem and academic results does not signify that high self-esteem contributes to high academic results. It simply means that high self- esteem may be accomplished due to high academic performance.
# Bullying, violence and murder
Some of the most interesting results of recent studies center on the relationships between bullying, violence, and self-esteem. People used to assume that bullies acted violently towards others because they suffered from low self-esteem (although supporters of this position offered no controlled studies to back up this belief).
In contrast to old beliefs, recent research indicates that bullies act the way that they do because they suffer from unearned high self-esteem.
The presence of superiority-complexes can be seen both in individual cases, such as the criminals Roy Baumeister studied, and in whole societies, such as Germany under the Nazi regime.
The findings of this research do not take into account that the concept of self-esteem lacks a clear definition and that differing views exist of the precise definition of self-esteem. In his own work, Baumeister often uses a "common use" definition: self-esteem is how you regard yourself (or how you appear to regard yourself) regardless of how this view was cultivated. Other psychologists believe that a "self esteem" that depends on external validation of the self (or other people's approval), such as what seems relevant in the discussion of violent people, does not, in fact, equate to "true" self-esteem. Nathaniel Branden labeled external validation as "pseudo self-esteem", arguing that "true self-esteem" comes from internal sources, such as self-responsibility, self-sufficiency and the knowledge of one's own competence and capability to deal with obstacles and adversity, regardless of what other people think.
Psychologists who agree with Branden's view dismiss Baumeister's findings. Such psychologistsTemplate:Who say that Baumeister mistakes narcissism as "high self-esteem" in criminals. They see such narcissism as an inflated opinion of self, built on shaky grounds, and opine that violence comes when that opinion comes under threat. Those with "true" self-esteem who valued themselves and believed wholly in their own competence and worth would have no need to resort to violence or indeed have any need to believe in their superiority or to prove their superiority.
# Contingencies of self-worth
Contingencies of self-worth comprise those qualities a person believes he or she must have in order to class as a person of value; proponents claim the contingencies as the core of self-esteem.
According to the "Contingencies of Self-Worth model" (Crocker & Wolfe, 2001) people differ in their bases of self-esteem. Their beliefs — beliefs about what they think they need to do or who they need to "be" in order to class as a person of worth — form these bases. Crocker and her colleagues (2001) identified seven "domains" in which people frequently derive their self-worth:
- Virtue
- God's love
- Support of family
- Academic competence
- Physical attractiveness
- Gaining others' approval
- Outdoing others in competition
Individuals who base their self-worth in a specific domain (such as, for example, academic success) leave themselves much more vulnerable to having their self-esteem threatened when negative events happen to them within that domain (such as when they fail a test at school). A 2003 study by Crocker found that students who based their contingency of self-worth on academic criteria had a greater likelihood of experiencing lower-state self-esteem, greater negative affect, and negative self-evaluative thoughts when they did not perform well on academic tasks, when they received poor grades, or when graduate schools rejected them (Crocker, Karpinski, Quinn, & Chase, 2003; Crocker, Sommers, & Luhtanen, 2002).
Crocker and her colleagues (2003) have constructed the "Contingencies of Self-Worth Scale", which measures the seven domains mentioned above that previous research had hypothesized as providing important internal and external sources of self-esteem. Crocker argues that the domains on which people base self-worth play a greater role than whether self-worth is actually contingent or not. Contingencies of self-worth can function internally, externally, or somewhere in between. Some research has shown that external contingencies of self-worth, such as physical appearance and academic success, correlate negatively to well-being, even promoting depression and eating-disorders (Jambekar, Quinn, & Crocker, 2001). Other work has found internal contingencies, on the other hand, unrelated or even positively related to well-being (Sargent, Crocker, & Luhtanen, 2006).
Research by Crocker and her colleagues also suggests that contingencies of self-worth have self-regulatory properties (Crocker, Luhtanen, Cooper, & Bouvrette, 2003). Crocker et al. define successful self-regulation as “the willingness to exert effort toward one’s most important goals, while taking setbacks and failures as opportunities to learn, identify weaknesses and address them, and develop new strategies toward achieving those goals” (Crocker, Brook, & Niiya, 2006). Since many individuals strive for a feeling of value, it makes sense that those people would experience special motivation to succeed and actively to avoid failure in the domains on which they base their own self-worth. Accordingly, successful self-regulation can prove difficult for people aiming to maintain and enhance their self-esteem, because they would have to actually embrace failure or criticism as a learning opportunity, rather than avoid it. Instead, when a task which individuals see as fundamental to their self-worth proves difficult and failure seems probable, contingencies of self-worth lead to stress, feelings of pressure, and a loss of intrinsic motivation. In these cases, highly contingent people may withdraw from the situation. On the other hand, the positive emotional affect following success in a domain of contingency may become addictive for the highly contingent individual (Baumeister & Vohs, 2001). Over time, these people may require even greater successes to achieve the same satisfaction or emotional “high”. Therefore, the goal to succeed can become a relentless quest for these individuals (Crocker & Nuer, 2004).
Researchers such as Crocker believe that people confuse the boosts to self-esteem resulting from successes with true human needs, such as learning, mutually supportive relationships, autonomy, and safety (Crocker & Nuer, 2004; Crocker & Park, 2004; Deci & Ryan, 2000). Crocker claims that people do not seek "self-esteem", but basic human needs, and that the contingencies on which they base their self-esteem has more importance than the level of self-esteem itself.
# Criticism and controversy
The concept of self-esteem has been criticized by different camps but notably by figures like Dalai Lama, Carl Rogers, Paul Tillich, Alfred Korzybski and George Carlin.
Perhaps one of the strongest theoretical and operational critiques of the concept of self-esteem has come from American psychologist Albert Ellis who on numerous occasions criticized the philosophy as essentially self-defeating and ultimately destructive. Although acknowledging the human propensity and tendency to ego rating as innate, he has claimed that the philosophy of self-esteem in the last analysis is both unrealistic, illogical and self- and socially destructive – often doing more harm than good. Questioning the foundations and usefulness of generalized ego strength, he has claimed that self-esteem is based on arbitrary definitional premises, over-generalized, perfectionistic and grandiose thinking. Acknowledging that rating and valuing behaviours and characteristics is functional and even necessary, he sees rating and valuing human beings totality and total selves as irrational, unethical and absolutistic. The more healthy alternative to self-esteem according to him is unconditional self-acceptance and unconditional other-acceptance and these concepts are incorporated in his therapeutic system Rational Emotive Behavior Therapy. In 2005 he released a book with a detailed analysis of the concept of self-esteem titled "The Myth of Self-esteem". | Self-worth
In psychology, self-esteem reflects a person's overall evaluation or appraisal of his or her own worth.
Self-esteem encompasses beliefs (for example, "I am competent/incompetent") and emotions (for example, triumph/despair, pride/shame). Behavior may reflect self-esteem (for example, assertiveness/shyness, confidence/caution).
Psychologists usually regard self-esteem as an enduring personality characteristic (trait self-esteem), though normal, short-term variations (state self-esteem) occur.
Self-esteem can apply specifically to a particular dimension (for example, "I believe I am a good writer, and feel proud of that in particular") or have global extent (for example, "I believe I am a good person, and feel proud of myself in general").
Synonyms or near-synonyms of self-esteem include: self-worth,[1] self-regard,[2] self-respect,[3][4] self-love (which can express overtones of self-promotion),[5] self-integrity. Self-esteem is distinct from self-confidence and self-efficacy, which involve beliefs about ability and future performance.
# History of the concept
The Oxford English Dictionary[6]
traces the use of the word "self-esteem" in English back as far as 1657. [John Milton is argued to have first coined this term.[7]]
After a career in the proto-psychological lore of phrenology in the 19th century[8]
the term entered more mainstream psychological use in the work of the American psychologists and philosophers Lorne Park[citation needed] and William James in 1890.
Self-esteem has become the third most frequently occurring theme in psychological literature: as of 2003 over 25,000 articles, chapters, and books referred to the topic.[9]
# Definitions
Given a long and varied history, the term has, unsurprisingly, no less than three major types of definitions in the field, each of which has generated its own tradition of research, findings, and practical applications:
- The original definition presents self-esteem as a ratio found by dividing one’s successes in areas of life of importance to a given individual by the failures in them or one’s “success / pretensions”.[10] Problems with this approach come from making self-esteem contingent upon success: this implies inherent instability because failure can occur at any moment.[11]
- In the mid 1960s Morris Rosenberg and social-learning theorists defined self-esteem in terms of a stable sense of personal worth or worthiness, (see Rosenberg self esteem scale). This became the most frequently used definition for research, but involves problems of boundary-definition, making self-esteem indistinguishable from such things as narcissism or simple bragging.[12]
- Nathaniel Branden in 1969 briefly defined self-esteem as "...the experience of being competent to cope with the basic challenges of life and being worthy of happiness". This two-factor approach, as some have also called it, provides a balanced definition that seems to be capable of dealing with limits of defining self-esteem primarily in terms of competence or worth alone.[13]
Branden’s (1969) description of self-esteem includes the following primary properties:
- self-esteem as a basic human need, i.e., "...it makes an essential contribution to the life process", "...is indispensable to normal and healthy self-development, and has a value for survival."
- self-esteem as an automatic and inevitable consequence of the sum of individuals' choices in using their consciousness
- something experienced as a part of, or background to, all of the individuals thoughts, feelings and actions.
Self esteem is a concept of personality, for it to grow, we need to have self worthy, and this self worthy will be sought from embracing challenges that result in the showing of success.
Compare the usage of terms such as self-love or self-confidence.
Implicit self-esteem refers to a person's disposition to evaluate themselves positively or negatively in a spontaneous, automatic, or unconscious manner. It contrasts with explicit self-esteem, which entails more conscious and reflective self-evaluation. Both explicit and implicit self-esteem are subtypes of self-esteem proper.
Implicit self-esteem is assessed using indirect measures of cognitive processing. These include the Name Letter Task[14] and the Implicit Association Test.[15] Such indirect measures are designed to reduce awareness of, or control of, the process of assessment. When used to assess implicit self-esteem, they feature stimuli designed to represent the self, such as personal pronouns (e.g., "I") or letters in one's name.
# Measurement
For the purposes of empirical research, psychologists typically assess self-esteem by a self-report inventory yielding a quantitative result. They establish the validity and reliability of the questionnaire prior to its use. Researchers are becoming more interested in measures of implicit self-esteem.
Popular lore recognizes just "high" self-esteem and "low" self-esteem.
The Rosenberg Self-Esteem Scale (1965) and the Coopersmith Self-Esteem Inventory (1967/1981) feature among the most widely used systems for measuring self-esteem. The Rosenberg test usually uses a ten-question battery scored on a four-point response-system that requires participants to indicate their level of agreement with a series of statements about themselves. The Coopersmith Inventory uses a 50-question battery over a variety of topics and asks subjects whether they rate positive or negative characteristics of someone as similar or dissimilar to themselves.[16]
# Theories
Many early theories suggested that self-esteem is a basic human need or motivation. American psychologist Abraham Maslow, for example, included self-esteem in his hierarchy of needs. He described two different forms of esteem: the need for respect from others and the need for self-respect, or inner self-esteem.[17] Respect from others entails recognition, acceptance, status, and appreciation, and was believed to be more fragile and easily lost than inner self-esteem. According to Maslow, without the fulfillment of the self-esteem need, individuals will be driven to seek it and unable to grow and obtain self-actualization.
Modern theories of self-esteem explore the reasons why humans are motivated to maintain a high regard for themselves. Sociometer theory maintains that self-esteem evolved to check one's level of status and acceptance in ones' social group. According to terror management theory, self esteem serves a protective function and reduces anxiety about life and death.[18]
# Quality and level of self-esteem
Level and quality of self-esteem, though correlated, remain distinct. Level-wise, one can exhibit high but fragile self-esteem (as in narcissism) or low but stable self-esteem (as in humility). However, investigators can indirectly assess the quality of self-esteem in several ways:
- in terms of its constancy over time (stability)
- in terms of its independence of meeting particular conditions (non-contingency)
- in terms of its ingrained nature at a basic psychological level (implicitness or automatized).
Humans have portrayed the dangers of excessive self-esteem and the advantages of more humility since at least the development of Greek tragedy, which typically showed the results of hubris.
# Self-esteem, grades and relationships
From the late 1970s to the early 1990s many Americans assumed as a matter of course that students' self-esteem acted as a critical factor in the grades that they earn in school, in their relationships with their peers, and in their later success in life. Given this assumption, some American groups created programs which aimed to increase the self-esteem of students. Until the 1990s little peer-reviewed and controlled research took place on this topic.
Peer-reviewed research undertaken since then has not validated previous assumptions. Recent research indicates that inflating students' self-esteem in and of itself has no positive effect on grades. One study has shown that inflating self-esteem by itself can actually decrease grades.[19]
High self-esteem correlates highly with self-reported happiness. However, it is not clear which, if either, necessarily leads to the other.[20] Additionally, self-esteem has been found to be related to forgiveness in close relationships, in that people with high self-esteem will be more forgiving than people with low self-esteem.[21]
The relationship involving self-esteem and academic results does not signify that high self-esteem contributes to high academic results. It simply means that high self- esteem may be accomplished due to high academic performance.[22]
# Bullying, violence and murder
Some of the most interesting results of recent studies center on the relationships between bullying, violence, and self-esteem. People used to assume that bullies acted violently towards others because they suffered from low self-esteem (although supporters of this position offered no controlled studies to back up this belief).
In contrast to old beliefs, recent research indicates that bullies act the way that they do because they suffer from unearned high self-esteem.
The presence of superiority-complexes can be seen both in individual cases, such as the criminals Roy Baumeister studied, and in whole societies, such as Germany under the Nazi regime.
The findings of this research do not take into account that the concept of self-esteem lacks a clear definition and that differing views exist of the precise definition of self-esteem. In his own work, Baumeister often uses a "common use" definition: self-esteem is how you regard yourself (or how you appear to regard yourself) regardless of how this view was cultivated. Other psychologists believe that a "self esteem" that depends on external validation of the self (or other people's approval), such as what seems relevant in the discussion of violent people, does not, in fact, equate to "true" self-esteem. Nathaniel Branden labeled external validation as "pseudo self-esteem", arguing that "true self-esteem" comes from internal sources, such as self-responsibility, self-sufficiency and the knowledge of one's own competence and capability to deal with obstacles and adversity, regardless of what other people think.
Psychologists who agree with Branden's view dismiss Baumeister's findings. Such psychologistsTemplate:Who say that Baumeister mistakes narcissism as "high self-esteem" in criminals. They see such narcissism as an inflated opinion of self, built on shaky grounds, and opine that violence comes when that opinion comes under threat. Those with "true" self-esteem who valued themselves and believed wholly in their own competence and worth would have no need to resort to violence or indeed have any need to believe in their superiority or to prove their superiority.
# Contingencies of self-worth
Contingencies of self-worth comprise those qualities a person believes he or she must have in order to class as a person of value; proponents claim the contingencies as the core of self-esteem.[citation needed]
According to the "Contingencies of Self-Worth model" (Crocker & Wolfe, 2001) people differ in their bases of self-esteem. Their beliefs — beliefs about what they think they need to do or who they need to "be" in order to class as a person of worth — form these bases. Crocker and her colleagues (2001) identified seven "domains" in which people frequently derive their self-worth:
- Virtue
- God's love
- Support of family
- Academic competence
- Physical attractiveness
- Gaining others' approval
- Outdoing others in competition
Individuals who base their self-worth in a specific domain (such as, for example, academic success) leave themselves much more vulnerable to having their self-esteem threatened when negative events happen to them within that domain (such as when they fail a test at school). A 2003 study by Crocker found that students who based their contingency of self-worth on academic criteria had a greater likelihood of experiencing lower-state self-esteem, greater negative affect, and negative self-evaluative thoughts when they did not perform well on academic tasks, when they received poor grades, or when graduate schools rejected them (Crocker, Karpinski, Quinn, & Chase, 2003; Crocker, Sommers, & Luhtanen, 2002).
Crocker and her colleagues (2003) have constructed the "Contingencies of Self-Worth Scale", which measures the seven domains mentioned above that previous research[citation needed] had hypothesized as providing important internal and external sources of self-esteem. Crocker argues that the domains on which people base self-worth play a greater role than whether self-worth is actually contingent or not. Contingencies of self-worth can function internally, externally, or somewhere in between. Some research has shown that external contingencies of self-worth, such as physical appearance and academic success, correlate negatively to well-being, even promoting depression and eating-disorders (Jambekar, Quinn, & Crocker, 2001). Other work has found internal contingencies, on the other hand, unrelated or even positively related to well-being (Sargent, Crocker, & Luhtanen, 2006).
Research by Crocker and her colleagues also suggests that contingencies of self-worth have self-regulatory properties (Crocker, Luhtanen, Cooper, & Bouvrette, 2003). Crocker et al. define successful self-regulation as “the willingness to exert effort toward one’s most important goals, while taking setbacks and failures as opportunities to learn, identify weaknesses and address them, and develop new strategies toward achieving those goals” (Crocker, Brook, & Niiya, 2006). Since many individuals strive for a feeling of value, it makes sense that those people would experience special motivation to succeed and actively to avoid failure in the domains on which they base their own self-worth. Accordingly, successful self-regulation can prove difficult for people aiming to maintain and enhance their self-esteem, because they would have to actually embrace failure or criticism as a learning opportunity, rather than avoid it. Instead, when a task which individuals see as fundamental to their self-worth proves difficult and failure seems probable, contingencies of self-worth lead to stress, feelings of pressure, and a loss of intrinsic motivation.[citation needed] In these cases, highly contingent people may withdraw from the situation.[citation needed] On the other hand, the positive emotional affect following success in a domain of contingency may become addictive for the highly contingent individual (Baumeister & Vohs, 2001). Over time, these people may require even greater successes to achieve the same satisfaction or emotional “high”. Therefore, the goal to succeed can become a relentless quest for these individuals (Crocker & Nuer, 2004).
Researchers such as Crocker believe that people confuse the boosts to self-esteem resulting from successes with true human needs, such as learning, mutually supportive relationships, autonomy, and safety (Crocker & Nuer, 2004; Crocker & Park, 2004; Deci & Ryan, 2000). Crocker claims that people do not seek "self-esteem", but basic human needs, and that the contingencies on which they base their self-esteem has more importance than the level of self-esteem itself.
# Criticism and controversy
The concept of self-esteem has been criticized by different camps but notably by figures like Dalai Lama, Carl Rogers, Paul Tillich, Alfred Korzybski and George Carlin.
Perhaps one of the strongest theoretical and operational critiques of the concept of self-esteem has come from American psychologist Albert Ellis who on numerous occasions criticized the philosophy as essentially self-defeating and ultimately destructive.[23] Although acknowledging the human propensity and tendency to ego rating as innate, he has claimed that the philosophy of self-esteem in the last analysis is both unrealistic, illogical and self- and socially destructive – often doing more harm than good. Questioning the foundations and usefulness of generalized ego strength, he has claimed that self-esteem is based on arbitrary definitional premises, over-generalized, perfectionistic and grandiose thinking.[24] Acknowledging that rating and valuing behaviours and characteristics is functional and even necessary, he sees rating and valuing human beings totality and total selves as irrational, unethical and absolutistic. The more healthy alternative to self-esteem according to him is unconditional self-acceptance and unconditional other-acceptance and these concepts are incorporated in his therapeutic system Rational Emotive Behavior Therapy. In 2005 he released a book with a detailed analysis of the concept of self-esteem titled "The Myth of Self-esteem". | https://www.wikidoc.org/index.php/Self-worth | |
5609c91edd8d28a584e745f9b25a28e9c6c69357 | wikidoc | Semorphone | Semorphone
Semorphone (Mr 2264) is an opiate analogue that is an N-substituted derivative of oxymorphone.
Semorphone is a partial agonist at μ-opioid receptors. It is around twice the potency of morphine, but with a ceiling effect on both analgesia and respiratory depression which means that these effects stop becoming any stronger after a certain maximum dose.
It is not currently used in medicine, and is not a controlled drug, although it might be considered to be a controlled substance analogue of oxymorphone on the grounds of its related chemical structure in some jurisdictions such as the USA, Canada, Australia and New Zealand. | Semorphone
Semorphone (Mr 2264) is an opiate analogue that is an N-substituted derivative of oxymorphone.
Semorphone is a partial agonist at μ-opioid receptors. It is around twice the potency of morphine, but with a ceiling effect on both analgesia and respiratory depression[1] which means that these effects stop becoming any stronger after a certain maximum dose.
It is not currently used in medicine, and is not a controlled drug, although it might be considered to be a controlled substance analogue of oxymorphone on the grounds of its related chemical structure in some jurisdictions such as the USA, Canada, Australia and New Zealand. | https://www.wikidoc.org/index.php/Semorphone | |
40e032430268872f562831966db6640b2cf306e2 | wikidoc | Sequestrum | Sequestrum
A sequestrum is a piece of dead bone that has become separated during the process of necrosis from normal/sound bone.
It is a complication (sequelae) of osteomyelitis. The pathological process is as follows:
- infection in the bone leads to an increase in intramedullary pressure due to inflammatory exudates
- the periosteum becomes stripped from the osteum, leading to vascular thrombosis
- bone necrosis follows due to lack of blood supply
- sequestra are formed
The sequestra are surrounded by sclerotic bone which for all intents and purposes is relatively avascular (without a blood supply). Within the bone itself, the haversian canals become blocked with scar tissue, and the bone becomes surrounded by thickened periosteum.
Due to the avascular nature of this bone, antibiotics which travel to sites of infection via the bloodstream, poorly penetrate these tissues. Hence the difficulty in treating chronic osteomyelitis.
At the same time as this, new bone is forming (known as involucrum). Opening in this involucrum allow debris and exudates (including pus) to pass from the sequestrum via sinus tracts to the skin. | Sequestrum
A sequestrum is a piece of dead bone that has become separated during the process of necrosis from normal/sound bone.
It is a complication (sequelae) of osteomyelitis. The pathological process is as follows:
- infection in the bone leads to an increase in intramedullary pressure due to inflammatory exudates
- the periosteum becomes stripped from the osteum, leading to vascular thrombosis
- bone necrosis follows due to lack of blood supply
- sequestra are formed
The sequestra are surrounded by sclerotic bone which for all intents and purposes is relatively avascular (without a blood supply). Within the bone itself, the haversian canals become blocked with scar tissue, and the bone becomes surrounded by thickened periosteum.
Due to the avascular nature of this bone, antibiotics which travel to sites of infection via the bloodstream, poorly penetrate these tissues. Hence the difficulty in treating chronic osteomyelitis.
At the same time as this, new bone is forming (known as involucrum). Opening in this involucrum allow debris and exudates (including pus) to pass from the sequestrum via sinus tracts to the skin.
Template:WH
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Sequestrum | |
462b396917687cbadeb11da11deef26b1d3aeb94 | wikidoc | Sermorelin | Sermorelin
# Overview
Sermorelin is a Growth hormone releasing hormone analogue.
# Clinical use
Sermorelin is used as a test for growth hormone secretion.
# Sermorelin: A better approach to management of adult growth hormone insufficiency
Richard F Walker, PHD
International Society for Applied Research in Aging (SARA)
Growth hormone replacement therapy (GHRT) using recombinant human growth hormone (rhGH) has been embraced by many age management practitioners as one of the most effective methods for opposing somatic senescence currently available. However, its routine use has been controversial because few clinical studies have been performed to determine the potential risks of long-term therapy. Also, certain medical and legal issues have not been resolved causing some practitioners to restrict their use of the product. Some of these issues include the fact that:
- Improper dosing can lead to side effects that may be serious in some patients,
- Injection of hGH creates unnatural conditions of exposure to the hormone that may erode normal physiology,
- The Code of Federal Regulations specifically forbids the use of rhGH in adults except for treatment of AIDS wasting or human growth hormone deficiency (GHD) diagnosed pursuant to regularly accepted guidelines.
While there is a wealth of information showing that long-term administration of rhGH reduces intrinsic disease and extends life in adults suffering pathogenic GHD, consensus on whether extrapolation of those data to the aging condition is justified has not been reached (Perls et al 2005). Most of the major concerns derive from the fact that rhGH is mitogenic and may awaken latent cancers, that improper dose selection may promote metabolic disorders such as diabetes, and perhaps that pharmacological presentation may exacerbate decline of endocrine function by distorting essential hormonal interactions. Of course, all these concerns are speculative and will not be resolved until sufficient scientific evidence for or against GHRT eventually accumulate. In the interim, the value of rhGH in GHRT will continue to be debated; unfortunately based more upon personal prejudice than objective information.
Despite the eventual outcome to the "Great Hormone Debate" as it has been titled in media articles (Landsmann 2006), certain negative aspects of GHRT using rhGH cannot be disputed and justify searching for a better alternative. For example, "square wave" or pharmacological presentation of the exogenous hormone cannot be avoided since it is administered as a bolus, subcutaneous injection. Since the amount of rhGH entering the general circulation is not controlled by normal feedback mechanisms, tissue exposure to elevated concentrations is persistent and eventually may lead to tachyphylaxis and reduced efficacy. Also, because the body cannot modulate tissue exposure to rhGH, the practitioner is required to "best guess" the appropriate dosage based upon little other than serum measurements of insulin-like growth factor-1 (IGF-1) and subjective comments from the patient about perceived responses to the hormone. Thus, it would seem that an alternative method(s) of GHRT that circumvented these problems would be of great value so long as it retained the positive attributes of rhGH.
One possibility that is receiving growing attention is the use of GH secretagogues to promote pituitary health and function during aging. An example of such molecules is growth hormone releasing factor 1-29 NH2-acetate, or sermorelin, that recently became available to practitioners for use in longevity medicine (Merriam et al 2001). Other alternatives include orally active growth hormone-releasing peptides (GHRP) that are currently being developed by pharmaceutical companies. Some of these have been reported to be effective at improving physical performance in the elderly (Fahy 2006). However, it is unlikely that they will be marketed for several years. On the other hand, sermorelin, an analog of naturally occurring growth hormone-releasing hormone (GHRH) whose activity declines during aging, may presently offer a more immediate and better alternative to rhGH for GHRT in aging (Russell-Aulet et al 2001). The molecule was commercially produced and marketed for many years as an alternative to rhGH for use in children with growth retardation, but it could not compete with rhGH and was withdrawn as a therapeutic entity by the manufacturer. Paradoxically sermorelin failed as a growthpromoting agent in children for the very reason that it is a better alternative for GHRT in aging adults. Growthdeficient children need higher doses of growth hormone than can be achieved by stimulating production of their own hormone, whereas the beneficial effects of sermorelin on pituitary function and simulation of youthful growth hormone secretory dynamics in aging adults have little effect on growth rate in children. Unlike exogenous rhGH that causes production of the bioactive hormone IGF-1 from the liver, sermorelin simulates the patients own pituitary gland by binding to specific receptors to increase production and secretion of endogenous hGH. Because sermorelin increases endogenous hGH by stimulating the pituitary gland, it has certain physiological and clinical advantages over hGH that include:
Effects are regulated by negative feedback involving the inhibitory neurohormone, somatostatin, so that unlike administration of exogenous rhGH, overdoses of endogenous hGH are difficult if not impossible to achieve,
Because of the interactive effects of sermorelin and somatostain, release of hGH by the pituitary is episodic or intermittent rather than constant as with injected rhGH.
Tachyphylaxis is avoided because sermorelin-induced release of pituitary hGH is not "square wave", but instead simulates more normal physiology,
Sermorelin stimulates pituitary gene transcription of hGH messenger RNA, increasing pituitary reserve and thereby preserving more of the growth hormone neuroendocrine axis, which is the first to fail during aging (Walker et al 1994).
Pituitary recrudescence resulting from sermorelin helps slow the cascade of hypophyseal hormone failure that occurs during aging thereby preserving not only youthful anatomy but also youthful physiology (Villalobos et al 1997).
Finally, there is the question of lawful practice. Unlike rhGH which has legal restrictions on its clinical use, the off-label prescribing of sermorelin is not prohibited by federal law. Thus, it can be carefully employed and evaluated by the practitioner to objectively determine whether it provides greater benefits with less risk to his/her patients. In support of this effort, the Society for Applied Research in Aging will be providing sermorelin free of cost on a competitive basis to practitioners willing to study its effects under protocol conditions and to report the outcomes in a peer-reviewed journal such as Clinical Interventions in Aging. Hopefully, through such efforts we can contribute to development of a paradigm for evidence-based GHRT in clinical age management. For more information on this effort and to participate in the protocol, please contact [email protected].
# Resources
Richard Walker, PHD
Health-Forum.info topic about Sermorelin | Sermorelin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Sermorelin is a Growth hormone releasing hormone analogue.
# Clinical use
Sermorelin is used as a test for growth hormone secretion. [1]
# Sermorelin: A better approach to management of adult growth hormone insufficiency
[2] Richard F Walker, PHD
International Society for Applied Research in Aging (SARA)
Growth hormone replacement therapy (GHRT) using recombinant human growth hormone (rhGH) has been embraced by many age management practitioners as one of the most effective methods for opposing somatic senescence currently available. However, its routine use has been controversial because few clinical studies have been performed to determine the potential risks of long-term therapy. Also, certain medical and legal issues have not been resolved causing some practitioners to restrict their use of the product. Some of these issues include the fact that:
- Improper dosing can lead to side effects that may be serious in some patients,
- Injection of hGH creates unnatural conditions of exposure to the hormone that may erode normal physiology,
- The Code of Federal Regulations specifically forbids the use of rhGH in adults except for treatment of AIDS wasting or human growth hormone deficiency (GHD) diagnosed pursuant to regularly accepted guidelines.
While there is a wealth of information showing that long-term administration of rhGH reduces intrinsic disease and extends life in adults suffering pathogenic GHD, consensus on whether extrapolation of those data to the aging condition is justified has not been reached (Perls et al 2005). Most of the major concerns derive from the fact that rhGH is mitogenic and may awaken latent cancers, that improper dose selection may promote metabolic disorders such as diabetes, and perhaps that pharmacological presentation may exacerbate decline of endocrine function by distorting essential hormonal interactions. Of course, all these concerns are speculative and will not be resolved until sufficient scientific evidence for or against GHRT eventually accumulate. In the interim, the value of rhGH in GHRT will continue to be debated; unfortunately based more upon personal prejudice than objective information.
Despite the eventual outcome to the "Great Hormone Debate" as it has been titled in media articles (Landsmann 2006), certain negative aspects of GHRT using rhGH cannot be disputed and justify searching for a better alternative. For example, "square wave" or pharmacological presentation of the exogenous hormone cannot be avoided since it is administered as a bolus, subcutaneous injection. Since the amount of rhGH entering the general circulation is not controlled by normal feedback mechanisms, tissue exposure to elevated concentrations is persistent and eventually may lead to tachyphylaxis and reduced efficacy. Also, because the body cannot modulate tissue exposure to rhGH, the practitioner is required to "best guess" the appropriate dosage based upon little other than serum measurements of insulin-like growth factor-1 (IGF-1) and subjective comments from the patient about perceived responses to the hormone. Thus, it would seem that an alternative method(s) of GHRT that circumvented these problems would be of great value so long as it retained the positive attributes of rhGH.
One possibility that is receiving growing attention is the use of GH secretagogues to promote pituitary health and function during aging. An example of such molecules is growth hormone releasing factor 1-29 NH2-acetate, or sermorelin, that recently became available to practitioners for use in longevity medicine (Merriam et al 2001). Other alternatives include orally active growth hormone-releasing peptides (GHRP) that are currently being developed by pharmaceutical companies. Some of these have been reported to be effective at improving physical performance in the elderly (Fahy 2006). However, it is unlikely that they will be marketed for several years. On the other hand, sermorelin, an analog of naturally occurring growth hormone-releasing hormone (GHRH) whose activity declines during aging, may presently offer a more immediate and better alternative to rhGH for GHRT in aging (Russell-Aulet et al 2001). The molecule was commercially produced and marketed for many years as an alternative to rhGH for use in children with growth retardation, but it could not compete with rhGH and was withdrawn as a therapeutic entity by the manufacturer. Paradoxically sermorelin failed as a growthpromoting agent in children for the very reason that it is a better alternative for GHRT in aging adults. Growthdeficient children need higher doses of growth hormone than can be achieved by stimulating production of their own hormone, whereas the beneficial effects of sermorelin on pituitary function and simulation of youthful growth hormone secretory dynamics in aging adults have little effect on growth rate in children. Unlike exogenous rhGH that causes production of the bioactive hormone IGF-1 from the liver, sermorelin simulates the patients own pituitary gland by binding to specific receptors to increase production and secretion of endogenous hGH. Because sermorelin increases endogenous hGH by stimulating the pituitary gland, it has certain physiological and clinical advantages over hGH that include:
Effects are regulated by negative feedback involving the inhibitory neurohormone, somatostatin, so that unlike administration of exogenous rhGH, overdoses of endogenous hGH are difficult if not impossible to achieve,
Because of the interactive effects of sermorelin and somatostain, release of hGH by the pituitary is episodic or intermittent rather than constant as with injected rhGH.
Tachyphylaxis is avoided because sermorelin-induced release of pituitary hGH is not "square wave", but instead simulates more normal physiology,
Sermorelin stimulates pituitary gene transcription of hGH messenger RNA, increasing pituitary reserve and thereby preserving more of the growth hormone neuroendocrine axis, which is the first to fail during aging (Walker et al 1994).
Pituitary recrudescence resulting from sermorelin helps slow the cascade of hypophyseal hormone failure that occurs during aging thereby preserving not only youthful anatomy but also youthful physiology (Villalobos et al 1997).
Finally, there is the question of lawful practice. Unlike rhGH which has legal restrictions on its clinical use, the off-label prescribing of sermorelin is not prohibited by federal law. Thus, it can be carefully employed and evaluated by the practitioner to objectively determine whether it provides greater benefits with less risk to his/her patients. In support of this effort, the Society for Applied Research in Aging will be providing sermorelin free of cost on a competitive basis to practitioners willing to study its effects under protocol conditions and to report the outcomes in a peer-reviewed journal such as Clinical Interventions in Aging. Hopefully, through such efforts we can contribute to development of a paradigm for evidence-based GHRT in clinical age management. For more information on this effort and to participate in the protocol, please contact [email protected].
# Resources
[3] Richard Walker, PHD
[4] Health-Forum.info topic about Sermorelin | https://www.wikidoc.org/index.php/Sermorelin | |
b1b0bc8949d00b63f2226cf2ac21585d4608d4cd | wikidoc | Sertindole | Sertindole
# Overview
Sertindole (brand names: Serdolect, and Serlect) is an antipsychotic medication. Sertindole was developed by the Danish pharmaceutical company H. Lundbeck and marketed under license by Abbott Labs. Like other atypical antipsychotics, it has activity at dopamine and serotonin receptors in the brain. It is used in the treatment of schizophrenia. It is classified chemically as a phenylindole derivative.
Sertindole is not approved for use in the United States.
# Medical Uses
Sertindole appears effective as an antipsychotic in schizophrenia.
# Adverse Effects
Very common (>10% incidence) adverse effects include:
- Headache
- Ejaculation failure
- Insomnia
- Dizziness
Common (1-10% incidence) adverse effects include:
- Urine that tests positive for red and/or white blood cells
- Sedation (causes less sedation than most antipsychotic drugs according to a recent meta-analysis of the efficacy and tolerability of 15 antipsychotic drugs. Causes only slightly more sedation than amisulpride and paliperidone)
- Ejaculation disorder
- Erectile dysfunction
- Orthostatic hypotension
- Weight gain (which it seems to possess a similar propensity for causing as quetiapine)
Uncommon (0.1-1% incidence) adverse effects include:
- Substernal chest pain
- Face oedema
- Flu syndrome
- Neck rigidity
- Pallor
- Peripheral vascular disorder
- Syncope
- Torsades de Pointes
- Vasodilation
- Suicide attempt
- Amnesia
- Anxiety
- Ataxia
- Confusion
- Incoordination
- Libido decreased
- Libido increased
- Miosis
- Nystagmus
- Personality disorder
- Psychosis
- Reflexes decreased
- Reflexes increased
- Stupor
- Suicidal tendency
- Urinary retention
- Vertigo
- Diabetes mellitus
- Abnormal stools
- Gastritis
- Gingivitis
- Glossitis
- Increased appetite
- Mouth ulceration
- Rectal disorder
- Rectal haemorrhage
- Stomatitis
- Tongue disorder
- Ulcerative stomatitis
- Anaemia
- Ecchymosis
- Hypochromic anaemia
- Leukopenia
- Hyperglycaemia
- Hyperlipemia
- Oedema
- Bone pain
- Myasthenia
- Twitching
- Bronchitis
- Hyperventilation
- Pneumonia
- Sinusitis
- Furunculosis
- Herpes simplex
- Nail disorder
- Psoriasis
- Pustular Rash
- Skin discolouration
- Skin hypertrophy
- Skin ulcer
- Abnormal vision
- Keratoconjunctivitis
- Lacrimation disorder
- Otitis externa
- Pupillary disorder
- Taste perversion
- Anorgasmia
- Penis disorder (gs)
- Urinary urgency
- Hyperprolactinaemia (which it seems to cause with a higher propensity than most other atypical antipsychotics do)
- Seizures
- Galactorrhoea
Rare (<0.1% incidence) adverse effects include:
- Neuroleptic malignant syndrome
- Tardive dyskinesia
Unknown frequency adverse events include:
- Extrapyramidal side effects (EPSE; e.g. dystonia, akathisia, muscle rigidity, parkinsonism, etc. These adverse effects are probably uncommon/rare according to a recent meta-analysis of the efficacy and tolerability of 15 antipsychotic drugs which found it had the 2nd lowest effect size for causing EPSE)
- Venous thromboembolism
- QT interval prolongation (probably common; in a recent meta-analysis of the efficacy and tolerability of 15 antipsychotic drugs it was found to be the most prone to causing QT interval prolongation)
# Pharmacology
# Safety and status
## USA
Abbott Labs first applied for U.S. Food and Drug Administration (FDA) approval for sertindole in 1996, but withdrew this application in 1998 following concerns over the increased risk of sudden death from QTc prolongation. In a trial of 2000 patients on taking sertindole, 27 patients died unexpectedly, including 13 sudden deaths. Lundbeck cites the results of the Sertindole Cohort Prospective (SCoP) study of 10,000 patients to support its claim that although sertindole does increase the QTc interval, this is not associated with increased rates of cardiac arrhythmias, and that patients on sertindole had the same overall mortality rate as those on risperidone. Nevertheless in April 2009 an FDA advisory panel voted 13-0 that sertindole was effective in the treatment of schizophrenia but 12-1 that it had not been shown to be acceptably safe. As of October 2010, the drug has not been approved by the FDA for use in the USA.
## Europe
In Europe, sertindole was approved and marketed in 19 countries from 1996, but its marketing authorization was suspended by the European Medicines Agency in 1998 and the drug was withdrawn from the market. In 2002, based on new data, the EMA's CHMP suggested that Sertindole could be reintroduced for restricted use in clinical trials, with strong safeguards including extensive contraindications and warnings for patients at risk of cardiac dysrhythmias, a recommended reduction in maximum dose from 24 mg to 20 mg in all but exceptional cases, and extensive ECG monitoring requirement before and during treatment.
# Synthesis | Sertindole
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]
# Overview
Sertindole (brand names: Serdolect, and Serlect) is an antipsychotic medication. Sertindole was developed by the Danish pharmaceutical company H. Lundbeck and marketed under license by Abbott Labs. Like other atypical antipsychotics, it has activity at dopamine and serotonin receptors in the brain. It is used in the treatment of schizophrenia. It is classified chemically as a phenylindole derivative.
Sertindole is not approved for use in the United States.
# Medical Uses
Sertindole appears effective as an antipsychotic in schizophrenia.[4]
# Adverse Effects
Very common (>10% incidence) adverse effects include:[1]
- Headache
- Ejaculation failure
- Insomnia
- Dizziness
Common (1-10% incidence) adverse effects include:[1]
- Urine that tests positive for red and/or white blood cells
- Sedation (causes less sedation than most antipsychotic drugs according to a recent meta-analysis of the efficacy and tolerability of 15 antipsychotic drugs. Causes only slightly [and non-significantly] more sedation than amisulpride and paliperidone[5][6])
- Ejaculation disorder
- Erectile dysfunction
- Orthostatic hypotension[5]
- Weight gain (which it seems to possess a similar propensity for causing as quetiapine[6])
Uncommon (0.1-1% incidence) adverse effects include:[1]
- Substernal chest pain
- Face oedema
- Flu syndrome
- Neck rigidity
- Pallor
- Peripheral vascular disorder
- Syncope
- Torsades de Pointes
- Vasodilation
- Suicide attempt
- Amnesia
- Anxiety
- Ataxia
- Confusion
- Incoordination
- Libido decreased
- Libido increased
- Miosis
- Nystagmus
- Personality disorder
- Psychosis
- Reflexes decreased
- Reflexes increased
- Stupor
- Suicidal tendency
- Urinary retention
- Vertigo
- Diabetes mellitus
- Abnormal stools
- Gastritis
- Gingivitis
- Glossitis
- Increased appetite
- Mouth ulceration
- Rectal disorder
- Rectal haemorrhage
- Stomatitis
- Tongue disorder
- Ulcerative stomatitis
- Anaemia
- Ecchymosis
- Hypochromic anaemia
- Leukopenia
- Hyperglycaemia
- Hyperlipemia
- Oedema
- Bone pain
- Myasthenia
- Twitching
- Bronchitis
- Hyperventilation
- Pneumonia
- Sinusitis
- Furunculosis
- Herpes simplex
- Nail disorder
- Psoriasis
- Pustular Rash
- Skin discolouration
- Skin hypertrophy
- Skin ulcer
- Abnormal vision
- Keratoconjunctivitis
- Lacrimation disorder
- Otitis externa
- Pupillary disorder
- Taste perversion
- Anorgasmia
- Penis disorder (gs)
- Urinary urgency
- Hyperprolactinaemia (which it seems to cause with a higher propensity than most other atypical antipsychotics do[6])
- Seizures
- Galactorrhoea
Rare (<0.1% incidence) adverse effects include:[1]
- Neuroleptic malignant syndrome
- Tardive dyskinesia
Unknown frequency adverse events include:[1]
- Extrapyramidal side effects (EPSE; e.g. dystonia, akathisia, muscle rigidity, parkinsonism, etc. These adverse effects are probably uncommon/rare according to a recent meta-analysis of the efficacy and tolerability of 15 antipsychotic drugs which found it had the 2nd lowest effect size for causing EPSE[6])
- Venous thromboembolism
- QT interval prolongation (probably common; in a recent meta-analysis of the efficacy and tolerability of 15 antipsychotic drugs it was found to be the most prone to causing QT interval prolongation[6])
# Pharmacology
# Safety and status
## USA
Abbott Labs first applied for U.S. Food and Drug Administration (FDA) approval for sertindole in 1996,[9] but withdrew this application in 1998 following concerns over the increased risk of sudden death from QTc prolongation.[10] In a trial of 2000 patients on taking sertindole, 27 patients died unexpectedly, including 13 sudden deaths.[11] Lundbeck cites the results of the Sertindole Cohort Prospective (SCoP) study of 10,000 patients to support its claim that although sertindole does increase the QTc interval, this is not associated with increased rates of cardiac arrhythmias, and that patients on sertindole had the same overall mortality rate as those on risperidone.[12] Nevertheless in April 2009 an FDA advisory panel voted 13-0 that sertindole was effective in the treatment of schizophrenia but 12-1 that it had not been shown to be acceptably safe.[13] As of October 2010[update], the drug has not been approved by the FDA for use in the USA.[14]
## Europe
In Europe, sertindole was approved and marketed in 19 countries from 1996,[11] but its marketing authorization was suspended by the European Medicines Agency in 1998[15] and the drug was withdrawn from the market. In 2002, based on new data, the EMA's CHMP suggested that Sertindole could be reintroduced for restricted use in clinical trials, with strong safeguards including extensive contraindications and warnings for patients at risk of cardiac dysrhythmias, a recommended reduction in maximum dose from 24 mg to 20 mg in all but exceptional cases, and extensive ECG monitoring requirement before and during treatment.[16][17]
# Synthesis | https://www.wikidoc.org/index.php/Sertindole | |
2f845026366a58dfb0379102697a5a7c110385be | wikidoc | Sertraline | Sertraline
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Black Box Warning
# Overview
Sertraline is a serotonin reuptake inhibitor that is FDA approved for the {{{indicationType}}} of major depressive disorder, obsessive-compulsive disorder, panic disorder, posttraumatic stress disorder, premenstrual dysphoric disorder and social phobia. There is a Black Box Warning for this drug as shown here. Common adverse reactions include constipation, diarrhea, indigestion, nausea and vomiting, dizziness, headache, insomnia, somnolence, tremor, abnormal ejaculation, reduced libido, and fatigue.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Sertraline hydrochloride treatment should be administered at a dose of 50 mg once daily.
- Maintenance/Continuation/Extended Treatment
- It is generally agreed that acute episodes of major depressive disorder require several months or longer of sustained pharmacologic therapy beyond response to the acute episode. Systematic evaluation of sertraline hydrochloride has demonstrated that its antidepressant efficacy is maintained for periods of up to 44 weeks following 8 weeks of initial treatment at a dose of 50-200 mg/day (mean dose of 70 mg/day). It is not known whether the dose of sertraline hydrochloride needed for maintenance treatment is identical to the dose needed to achieve an initial response. Patients should be periodically reassessed to determine the need for maintenance treatment.
- Sertraline hydrochloride treatment should be administered at a dose of 50 mg once daily.
- Maintenance/Continuation/Extended Treatment
- It is generally agreed that OCD require several months or longer of sustained pharmacological therapy beyond response to initial treatment. Systematic evaluation of continuing sertraline hydrochloride for periods of up to 28 weeks in patients with OCD who have responded while taking sertraline hydrochloride during initial treatment phases of 24 to 52 weeks of treatment at a dose range of 50-200 mg/day has demonstrated a benefit of such maintenance treatment. It is not known whether the dose of sertraline hydrochloride needed for maintenance treatment is identical to the dose needed to achieve an initial response. Nevertheless, patients should be periodically reassessed to determine the need for maintenance treatment.
- Sertraline hydrochloride treatment should be initiated with a dose of 25 mg once daily. After one week, the dose should be increased to 50 mg once daily.
- While a relationship between dose and effect has not been established for major depressive disorder, OCD, panic disorder, PTSD or social anxiety disorder, patients were dosed in a range of 50-200 mg/day in the clinical trials demonstrating the effectiveness of sertraline hydrochloride for the treatment of these indications. Consequently, a dose of 50 mg, administered once daily, is recommended as the initial therapeutic dose. Patients not responding to a 50 mg dose may benefit from dose increases up to a maximum of 200 mg/day. Given the 24 hour elimination half-life of sertraline hydrochloride, dose changes should not occur at intervals of less than 1 week.
- Maintenance/Continuation/Extended Treatment
- It is generally agreed that Panic Disorder require several months or longer of sustained pharmacological therapy beyond response to initial treatment. Systematic evaluation of continuing sertraline hydrochloride for periods of up to 28 weeks in patients with OCD who have responded while taking sertraline hydrochloride during initial treatment phases of 24 to 52 weeks of treatment at a dose range of 50-200 mg/day has demonstrated a benefit of such maintenance treatment. It is not known whether the dose of sertraline hydrochloride needed for maintenance treatment is identical to the dose needed to achieve an initial response. Nevertheless, patients should be periodically reassessed to determine the need for maintenance treatment.
- Sertraline hydrochloride treatment should be initiated with a dose of 25 mg once daily. After one week, the dose should be increased to 50 mg once daily.
- While a relationship between dose and effect has not been established for major depressive disorder, OCD, panic disorder, PTSD or social anxiety disorder, patients were dosed in a range of 50-200 mg/day in the clinical trials demonstrating the effectiveness of sertraline hydrochloride for the treatment of these indications. Consequently, a dose of 50 mg, administered once daily, is recommended as the initial therapeutic dose. Patients not responding to a 50 mg dose may benefit from dose increases up to a maximum of 200 mg/day. Given the 24 hour elimination half-life of sertraline hydrochloride, dose changes should not occur at intervals of less than 1 week.
- Maintenance/Continuation/Extended Treatment
- It is generally agreed that PTSD requires several months or longer of sustained pharmacological therapy beyond response to initial treatment. Systematic evaluation of sertraline hydrochloride has demonstrated that its efficacy in PTSD is maintained for periods of up to 28 weeks following 24 weeks of treatment at a dose of 50-200 mg/day. It is not known whether the dose of sertraline hydrochloride needed for maintenance treatment is identical to the dose needed to achieve an initial response. Patients should be periodically reassessed to determine the need for maintenance treatment.
- Sertraline hydrochloride treatment should be initiated with a dose of 50 mg/day, either daily throughout the menstrual cycle or limited to the luteal phase of the menstrual cycle, depending on physician assessment.
- While a relationship between dose and effect has not been established for PMDD, patients were dosed in the range of 50-150 mg/day with dose increases at the onset of each new menstrual cycle. Patients not responding to a 50 mg/day dose may benefit from dose increases (at 50 mg increments/menstrual cycle) up to 150 mg/day when dosing daily throughout the menstrual cycle, or 100 mg/day when dosing during the luteal phase of the menstrual cycle. If a 100 mg/day dose has been established with luteal phase dosing, a 50 mg/day titration step for three days should be utilized at the beginning of each luteal phase dosing period.
- Sertraline hydrochloride should be administered once daily, either in the morning or evening.
- Maintenance/Continuation/Extended Treatment
- The effectiveness of sertraline hydrochloride in long-term use, that is, for more than 3 menstrual cycles, has not been systematically evaluated in controlled trials. However, as women commonly report that symptoms worsen with age until relieved by the onset of menopause, it is reasonable to consider continuation of a responding patient. Dosage adjustments, which may include changes between dosage regimens (e.g., daily throughout the menstrual cycle versus during the luteal phase of the menstrual cycle), may be needed to maintain the patient on the lowest effective dosage and patients should be periodically reassessed to determine the need for continued treatment.
- Sertraline hydrochloride treatment should be initiated with a dose of 25 mg once daily. After one week, the dose should be increased to 50 mg once daily.
- While a relationship between dose and effect has not been established for major depressive disorder, OCD, panic disorder, PTSD or social anxiety disorder, patients were dosed in a range of 50-200 mg/day in the clinical trials demonstrating the effectiveness of sertraline hydrochloride for the treatment of these indications. Consequently, a dose of 50 mg, administered once daily, is recommended as the initial therapeutic dose. Patients not responding to a 50 mg dose may benefit from dose increases up to a maximum of 200 mg/day. Given the 24 hour elimination half-life of sertraline hydrochloride, dose changes should not occur at intervals of less than 1 week.
- Maintenance/Continuation/Extended Treatment
- Social anxiety disorder is a chronic condition that may require several months or longer of sustained pharmacological therapy beyond response to initial treatment. Systematic evaluation of sertraline hydrochloride has demonstrated that its efficacy in social anxiety disorder is maintained for periods of up to 24 weeks following 20 weeks of treatment at a dose of 50-200 mg/day. Dosage adjustments should be made to maintain patients on the lowest effective dose and patients should be periodically reassessed to determine the need for long-term treatment.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Sertraline in adult patients.
### Non–Guideline-Supported Use
- Sertraline 50 to 200 mg/day.
- Sertraline 50 milligrams (mg) daily.
- Sertraline 50 mg daily.
- Sertraline 50 mg/day.
- Sertraline 25 mg/day initially for 1 week with increases in 50-mg increments at weeks 2, 3, 4, and 7, up to a maximum of 200 mg/day.
- Sertraline 50 milligrams orally once daily for 8 weeks.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Sertraline hydrochloride treatment should be initiated with a dose of 25 mg once daily in children (ages 6-12) and at a dose of 50 mg once daily in adolescents (ages 13-17).
- While a relationship between dose and effect has not been established for OCD, patients were dosed in a range of 25-200 mg/day in the clinical trials demonstrating the effectiveness of sertraline hydrochloride for pediatric patients (6-17 years) with OCD. Patients not responding to an initial dose of 25 or 50 mg/day may benefit from dose increases up to a maximum of 200 mg/day. For children with OCD, their generally lower body weights compared to adults should be taken into consideration in advancing the dose, in order to avoid excess dosing. Given the 24 hour elimination half-life of sertraline hydrochloride, dose changes should not occur at intervals of less than 1 week.
- Sertraline hydrochloride should be administered once daily, either in the morning or evening.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Sertraline in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Sertraline in pediatric patients.
# Contraindications
- The use of MAOIs intended to treat psychiatric disorders with sertraline hydrochloride or within 14 days of stopping treatment with sertraline hydrochloride is contraindicated because of an increased risk of serotonin syndrome. The use of sertraline hydrochloride within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated.
- Starting sertraline hydrochloride in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome.
- Concomitant use in patients taking pimozide is contraindicated.
- Sertraline hydrochloride is contraindicated in patients with a hypersensitivity to sertraline or any of the inactive ingredients in sertraline hydrochloride tablets, USP.
# Warnings
- Clinical Worsening and Suicide Risk
- Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.
- The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1.
- No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.
- It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.
- All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.
- The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.
- Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.
- If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms.
- Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for sertraline hydrochloride should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.
- Screening Patients for Bipolar Disorder: A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that sertraline hydrochloride is not approved for use in treating bipolar depression.
- Serotonin Syndrome
- The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including sertraline hydrochloride, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John's Wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
- Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome.
- The concomitant use of sertraline hydrochloride with MAOIs intended to treat psychiatric disorders is contraindicated. Sertraline hydrochloride should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with a MAOI such as linezolid or intravenous methylene blue in a patient taking sertraline hydrochloride. Sertraline hydrochloride should be discontinued before initiating treatment with the MAOI.
- If concomitant use of sertraline hydrochloride with other serotonergic drugs including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John's Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases.
- Treatment with sertraline hydrochloride and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.
- Angle-Closure Glaucoma
- The pupillary dilation that occurs following use of many antidepressant drugs including sertraline hydrochloride may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.
### Precautions
- Activation of Mania/Hypomania
- During premarketing testing, hypomania or mania occurred in approximately 0.4% of sertraline hydrochloride treated patients.
- Weight Loss
- Significant weight loss may be an undesirable result of treatment with sertraline for some patients, but on average, patients in controlled trials had minimal, 1 to 2 pound weight loss, versus smaller changes on placebo. Only rarely have sertraline patients been discontinued for weight loss.
- Seizure
- Sertraline hydrochloride has not been evaluated in patients with a seizure disorder. These patients were excluded from clinical studies during the product's premarket testing. No seizures were observed among approximately 3000 patients treated with sertraline hydrochloride in the development program for major depressive disorder. However, 4 patients out of approximately 1800 (220 <;<18 years of age) exposed during the development program for obsessive-compulsive disorder experienced seizures, representing a crude incidence of 0.2%. Three of these patients were adolescents, two with a seizure disorder and one with a family history of seizure disorder, none of whom were receiving anticonvulsant medication. Accordingly, sertraline hydrochloride should be introduced with care in patients with a seizure disorder.
- Discontinuation of Treatment with sertraline hydrochloride
- During marketing of sertraline hydrochloride and other SSRIs and SNRIs (Serotonin and Norepinephrine Reuptake Inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g. paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms.
- Patients should be monitored for these symptoms when discontinuing treatment with sertraline hydrochloride. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate.
- Abnormal Bleeding
- SSRIs and SNRIs, including sertraline hydrochloride, may increase the risk of bleeding events ranging from ecchymoses, hematomas, epistaxis, petechiae, and gastrointestinal hemorrhage to life-threatening hemorrhage. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anticoagulants or other drugs known to affect platelet function may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding.
- Patients should be cautioned about the risk of bleeding associated with the concomitant use of sertraline hydrochloride and NSAIDs, aspirin, or other drugs that affect coagulation.
- Weak Uricosuric Effect
- Sertraline hydrochloride is associated with a mean decrease in serum uric acid of approximately 7%. The clinical significance of this weak uricosuric effect is unknown.
- Use in Patients with Concomitant Illness
- Clinical experience with sertraline hydrochloride in patients with certain concomitant systemic illness is limited. Caution is advisable in using sertraline hydrochloride in patients with diseases or conditions that could affect metabolism or hemodynamic responses.
- Patients with a recent history of myocardial infarction or unstable heart disease were excluded from clinical studies during the product's premarket testing. However, the electrocardiograms of 774 patients who received sertraline hydrochloride in double-blind trials were evaluated and the data indicate that sertraline hydrochloride is not associated with the development of significant ECG abnormalities.
- Sertraline hydrochloride administered in a flexible dose range of 50 to 200 mg/day (mean dose of 89 mg/day) was evaluated in a post-marketing, placebo-controlled trial of 372 randomized subjects with a DSM-IV diagnosis of major depressive disorder and recent history of myocardial infarction or unstable angina requiring hospitalization. Exclusions from this trial included, among others, patients with uncontrolled hypertension, need for cardiac surgery, history of CABG within 3 months of index event, severe or symptomatic bradycardia, non-atherosclerotic cause of angina, clinically significant renal impairment (creatinine > 2.5 mg/dl), and clinically significant hepatic dysfunction. Sertraline hydrochloride treatment initiated during the acute phase of recovery (within 30 days post-MI or post-hospitalization for unstable angina) was indistinguishable from placebo in this study on the following week 16 treatment endpoints: left ventricular ejection fraction, total cardiovascular events (angina, chest pain, edema, palpitations, syncope, postural dizziness, CHF, MI, tachycardia, bradycardia, and changes in BP), and major cardiovascular events involving death or requiring hospitalization (for MI, CHF, stroke, or angina).
- Sertraline hydrochloride is extensively metabolized by the liver. In patients with chronic mild liver impairment, sertraline clearance was reduced, resulting in increased AUC, Cmax and elimination half-life. The effects of sertraline in patients with moderate and severe hepatic impairment have not been studied. The use of sertraline in patients with liver disease must be approached with caution. If sertraline is administered to patients with liver impairment, a lower or less frequent dose should be used.
- Since sertraline hydrochloride is extensively metabolized, excretion of unchanged drug in urine is a minor route of elimination. A clinical study comparing sertraline pharmacokinetics in healthy volunteers to that in patients with renal impairment ranging from mild to severe (requiring dialysis) indicated that the pharmacokinetics and protein binding are unaffected by renal disease. Based on the pharmacokinetic results, there is no need for dosage adjustment in patients with renal impairment.
- Interference with Cognitive and Motor Performance
- In controlled studies, sertraline hydrochloride did not cause sedation and did not interfere with psychomotor performance.
- Hyponatremia
- Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including sertraline hydrochloride. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk. Discontinuation of sertraline hydrochloride should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted.
- Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death.
- Platelet Function
- There have been rare reports of altered platelet function and/or abnormal results from laboratory studies in patients taking sertraline hydrochloride. While there have been reports of abnormal bleeding or purpura in several patients taking sertraline hydrochloride, it is unclear whether sertraline hydrochloride had a causative role.
# Adverse Reactions
## Clinical Trials Experience
- During its premarketing assessment, multiple doses of sertraline hydrochloride were administered to over 4000 adult subjects as of February 18, 2000. The conditions and duration of exposure to sertraline hydrochloride varied greatly, and included (in overlapping categories) clinical pharmacology studies, open and double-blind studies, uncontrolled and controlled studies, inpatient and outpatient studies, fixed-dose and titration studies, and studies for multiple indications, including major depressive disorder, OCD, panic disorder, PTSD, PMDD and social anxiety disorder.
- Untoward events associated with this exposure were recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of untoward events into a smaller number of standardized event categories.
- In the tabulations that follow, a World Health Organization dictionary of terminology has been used to classify reported adverse events. The frequencies presented, therefore, represent the proportion of the over 4000 adult individuals exposed to multiple doses of sertraline hydrochloride who experienced a treatment-emergent adverse event of the type cited on at least one occasion while receiving sertraline hydrochloride. An event was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. It is important to emphasize that events reported during therapy were not necessarily caused by it.
- The prescriber should be aware that the figures in the tables and tabulations cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and non-drug factors to the side effect incidence rate in the population studied.
- Incidence in Placebo-Controlled Trials–Table 2 enumerates the most common treatment-emergent adverse events associated with the use of sertraline hydrochloride (incidence of at least 5% for sertraline hydrochloride and at least twice that for placebo within at least one of the indications) for the treatment of adult patients with major depressive disorder/other*, OCD, panic disorder, PTSD, PMDD and social anxiety disorder in placebo-controlled clinical trials. Most patients in major depressive disorder/other*, OCD, panic disorder, PTSD and social anxiety disorder studies received doses of 50 to 200 mg/day. Patients in the PMDD study with daily dosing throughout the menstrual cycle received doses of 50 to 150 mg/day, and in the PMDD study with dosing during the luteal phase of the menstrual cycle received doses of 50 to 100 mg/day. Table 3 enumerates treatment-emergent adverse events that occurred in 2% or more of adult patients treated with sertraline hydrochloride and with incidence greater than placebo who participated in controlled clinical trials comparing sertraline hydrochloride with placebo in the treatment of major depressive disorder/other*, OCD, panic disorder, PTSD, PMDD and social anxiety disorder. Table 3 provides combined data for the pool of studies that are provided separately by indication in Table 2.
- Associated with Discontinuation in Placebo-Controlled Clinical Trials
- Table 4 lists the adverse events associated with discontinuation of sertraline hydrochloride treatment (incidence at least twice that for placebo and at least 1% for sertraline hydrochloride in clinical trials) in major depressive disorder/other*, OCD, panic disorder, PTSD, PMDD and social anxiety disorder.
- Male and Female Sexual Dysfunction with SSRIs
- Although changes in sexual desire, sexual performance and sexual satisfaction often occur as manifestations of a psychiatric disorder, they may also be a consequence of pharmacologic treatment. In particular, some evidence suggests that selective serotonin reuptake inhibitors (SSRIs) can cause such untoward sexual experiences. Reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance and satisfaction are difficult to obtain, however, in part because patients and physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance cited in product labeling, are likely to underestimate their actual incidence.
- Table 5 below displays the incidence of sexual side effects reported by at least 2% of patients taking sertraline hydrochloride in placebo-controlled trials.
- There are no adequate and well-controlled studies examining sexual dysfunction with sertraline treatment.
- Priapism has been reported with all SSRIs.
- While it is difficult to know the precise risk of sexual dysfunction associated with the use of SSRIs, physicians should routinely inquire about such possible side effects.
- Other Adverse Events in Pediatric Patients–In over 600 pediatric patients treated with sertraline hydrochloride, the overall profile of adverse events was generally similar to that seen in adult studies. However, the following adverse events, from controlled trials, not appearing in Tables 2 and 3, were reported at an incidence of at least 2% and occurred at a rate of at least twice the placebo rate (N=281 patients treated with sertraline hydrochloride): fever, hyperkinesia, urinary incontinence, aggressive reaction, sinusitis, epistaxis and purpura.
- Other Events Observed During the Premarketing Evaluation of Sertraline hydrochloride–Following is a list of treatment-emergent adverse events reported during premarketing assessment of sertraline hydrochloride in clinical trials (over 4000 adult subjects) except those already listed in the previous tables or elsewhere in labeling.
- In the tabulations that follow, a World Health Organization dictionary of terminology has been used to classify reported adverse events. The frequencies presented, therefore, represent the proportion of the over 4000 adult individuals exposed to multiple doses of sertraline hydrochloride who experienced an event of the type cited on at least one occasion while receiving sertraline hydrochloride. All events are included except those already listed in the previous tables or elsewhere in labeling and those reported in terms so general as to be uninformative and those for which a causal relationship to sertraline hydrochloride treatment seemed remote. It is important to emphasize that although the events reported occurred during treatment with sertraline hydrochloride, they were not necessarily caused by it.
- Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring on one or more occasions in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients. Events of major clinical importance are also described in the PRECAUTIONS section.
Frequent: impotence; Infrequent: flushing, increased saliva, cold clammy skin, mydriasis; Rare: pallor, glaucoma, priapism, vasodilation.
Rare: allergic reaction, allergy.
Frequent: palpitations, chest pain; Infrequent: hypertension, tachycardia, postural dizziness, postural hypotension, periorbital edema, peripheral edema, hypotension, peripheral ischemia, syncope, edema, dependent edema; Rare: precordial chest pain, substernal chest pain, aggravated hypertension, myocardial infarction, cerebrovascular disorder.
Frequent: hypertonia, hypoesthesia; Infrequent: twitching, confusion, hyperkinesia, vertigo, ataxia, migraine, abnormal coordination, hyperesthesia, leg cramps, abnormal gait, nystagmus, hypokinesia; Rare: dysphonia, coma, dyskinesia, hypotonia, ptosis, choreoathetosis, hyporeflexia.
Infrequent: pruritus, acne, urticaria, alopecia, dry skin, erythematous rash, photosensitivity reaction, maculopapular rash; Rare: follicular rash, eczema, dermatitis, contact dermatitis, bullous eruption, hypertrichosis, skin discoloration, pustular rash.
Rare: exophthalmos, gynecomastia.
Frequent: appetite increased; Infrequent: dysphagia, tooth caries aggravated, eructation, esophagitis, gastroenteritis; Rare: melena, glossitis, gum hyperplasia, hiccup, stomatitis, tenesmus, colitis, diverticulitis, fecal incontinence, gastritis, rectum hemorrhage, hemorrhagic peptic ulcer, proctitis, ulcerative stomatitis, tongue edema, tongue ulceration.
Frequent: back pain, asthenia, malaise, weight increase; Infrequent: fever, rigors, generalized edema; Rare: face edema, aphthous stomatitis.
Rare: hyperacusis, labyrinthine disorder.
Rare: anemia, anterior chamber eye hemorrhage.
Rare: abnormal hepatic function.
Infrequent: thirst; Rare: hypoglycemia, hypoglycemia reaction.
Frequent: myalgia; Infrequent: arthralgia, dystonia, arthrosis, muscle cramps, muscle weakness.
Frequent: yawning, other male sexual dysfunction, other female sexual dysfunction; Infrequent: depression, amnesia, paroniria, teeth-grinding, emotional lability, apathy, abnormal dreams, euphoria, paranoid reaction, hallucination, aggressive reaction, aggravated depression, delusions; Rare: withdrawal syndrome, suicide ideation, libido increased, somnambulism, illusion.
Infrequent: menstrual disorder, dysmenorrhea, intermenstrual bleeding, vaginal hemorrhage, amenorrhea, leukorrhea; Rare: female breast pain, menorrhagia, balanoposthitis, breast enlargement, atrophic vaginitis, acute female mastitis.
Frequent: rhinitis; Infrequent: coughing, dyspnea, upper respiratory tract infection, epistaxis, bronchospasm, sinusitis; Rare: hyperventilation, bradypnea, stridor, apnea, bronchitis, hemoptysis, hypoventilation, laryngismus, laryngitis.
Frequent: tinnitus; Infrequent: conjunctivitis, earache, eye pain, abnormal accommodation; Rare: xerophthalmia, photophobia, diplopia, abnormal lacrimation, scotoma, visual field defect.
Infrequent: micturition frequency, polyuria, urinary retention, dysuria, nocturia, urinary incontinence; Rare: cystitis, oliguria, pyelonephritis, hematuria, renal pain, strangury.
- In man, asymptomatic elevations in serum transaminases (SGOT and SGPT ) have been reported infrequently (approximately 0.8%) in association with sertraline hydrochloride administration. These hepatic enzyme elevations usually occurred within the first 1 to 9 weeks of drug treatment and promptly diminished upon drug discontinuation.
- Sertraline hydrochloride therapy was associated with small mean increases in total cholesterol (approximately 3%) and triglycerides (approximately 5%), and a small mean decrease in serum uric acid (approximately 7%) of no apparent clinical importance.
- The safety profile observed with sertraline hydrochloride treatment in patients with major depressive disorder, OCD, panic disorder, PTSD, PMDD and social anxiety disorder is similar.
## Postmarketing Experience
- Reports of adverse events temporally associated with sertraline hydrochloride that have been received since market introduction, that are not listed above and that may have no causal relationship with the drug, include the following: acute renal failure, anaphylactoid reaction, angioedema, blindness, optic neuritis, cataract, increased coagulation times, bradycardia, AV block, atrial arrhythmias, QT-interval prolongation, ventricular tachycardia (including Torsade de Pointes arrhythmias), cerebrovascular spasm (including reversible cerebral vasconstriction syndrome and Call-Fleming syndrome), hypothyroidism, agranulocytosis, aplastic anemia and pancytopenia, leukopenia, thrombocytopenia, lupus-like syndrome, serum sickness, diabetes mellitus, hyperglycemia, galactorrhea, hyperprolactinemia, extrapyramidal symptoms, oculogyric crisis, serotonin syndrome, psychosis, pulmonary hypertension, severe skin reactions, which potentially can be fatal, such as Stevens-Johnson syndrome, vasculitis, photosensitivity and other severe cutaneous disorders, rare reports of pancreatitis, and liver events—clinical features (which in the majority of cases appeared to be reversible with discontinuation of sertraline hydrochloride) occurring in one or more patients include: elevated enzymes, increased bilirubin, hepatomegaly, hepatitis, jaundice, abdominal pain, vomiting, liver failure and death.
# Drug Interactions
- Potential Effects of Coadministration of Drugs Highly Bound to Plasma Proteins
- Because sertraline is tightly bound to plasma protein, the administration of sertraline hydrochloride to a patient taking another drug which is tightly bound to protein (e.g., warfarin, digitoxin) may cause a shift in plasma concentrations potentially resulting in an adverse effect. Conversely, adverse effects may result from displacement of protein bound sertraline hydrochloride by other tightly bound drugs.
- In a study comparing prothrombin time AUC (0-120 hr) following dosing with warfarin (0.75 mg/kg) before and after 21 days of dosing with either sertraline hydrochloride (50-200 mg/day) or placebo, there was a mean increase in prothrombin time of 8% relative to baseline for sertraline hydrochloride compared to a 1% decrease for placebo (p<0.02). The normalization of prothrombin time for the sertraline hydrochloride group was delayed compared to the placebo group. The clinical significance of this change is unknown. Accordingly, prothrombin time should be carefully monitored when sertraline hydrochloride therapy is initiated or stopped.
- Cimetidine
- In a study assessing disposition of sertraline hydrochloride (100 mg) on the second of 8 days of cimetidine administration (800 mg daily), there were significant increases in sertraline hydrochloride mean AUC (50%), Cmax (24%) and half-life (26%) compared to the placebo group. The clinical significance of these changes is unknown.
- CNS Active Drugs
- In a study comparing the disposition of intravenously administered diazepam before and after 21 days of dosing with either sertraline hydrochloride (50 to 200 mg/day escalating dose) or placebo, there was a 32% decrease relative to baseline in diazepam clearance for the sertraline hydrochloride group compared to a 19% decrease relative to baseline for the placebo group (p<0.03). There was a 23% increase in Tmax for desmethyldiazepam in the sertraline hydrochloride group compared to a 20% decrease in the placebo group (p<;<0.03). The clinical significance of these changes is unknown.
- In a placebo-controlled trial in normal volunteers, the administration of two doses of sertraline hydrochloride did not significantly alter steady-state lithium levels or the renal clearance of lithium.
- Nonetheless, at this time, it is recommended that plasma lithium levels be monitored following initiation of sertraline hydrochloride therapy with appropriate adjustments to the lithium dose.
- In a controlled study of a single dose (2 mg) of pimozide, 200 mg sertraline (q.d.) co-administration to steady state was associated with a mean increase in pimozide AUC and Cmax of about 40%, but was not associated with any changes in EKG. Since the highest recommended pimozide dose (10 mg) has not been evaluated in combination with sertraline, the effect on QT interval and PK parameters at doses higher than 2 mg at this time are not known. While the mechanism of this interaction is unknown, due to the narrow therapeutic index of pimozide and due to the interaction noted at a low dose of pimozide, concomitant administration of sertraline hydrochloride and pimozide should be contraindicated.
- Results of a placebo-controlled trial in normal volunteers suggest that chronic administration of sertraline 200 mg/day does not produce clinically important inhibition of phenytoin metabolism. Nonetheless, at this time, it is recommended that plasma phenytoin concentrations be monitored following initiation of sertraline hydrochloride therapy with appropriate adjustments to the phenytoin dose, particularly in patients with multiple underlying medical conditions and/or those receiving multiple concomitant medications.
- The effect of sertraline hydrochloride on valproate levels has not been evaluated in clinical trials. In the absence of such data, it is recommended that plasma valproate levels be monitored following initiation of sertraline hydrochloride therapy with appropriate adjustments to the valproate dose.
- The risk of using sertraline hydrochloride in combination with other CNS active drugs has not been systematically evaluated. Consequently, caution is advised if the concomitant administration of sertraline hydrochloride and such drugs is required.
- There is limited controlled experience regarding the optimal timing of switching from other drugs effective in the treatment of major depressive disorder, obsessive-compulsive disorder, panic disorder, posttraumatic stress disorder, premenstrual dysphoric disorder and social anxiety disorder to sertraline hydrochloride. Care and prudent medical judgment should be exercised when switching, particularly from long-acting agents. The duration of an appropriate washout period which should intervene before switching from one selective serotonin reuptake inhibitor (SSRI) to another has not been established.
- Drugs Metabolized by P450 3A4
- In three separate in vivo interaction studies, sertraline was co-administered with cytochrome P450 3A4 substrates, terfenadine, carbamazepine, or cisapride under steady-state conditions. The results of these studies indicated that sertraline did not increase plasma concentrations of terfenadine, carbamazepine, or cisapride. These data indicate that sertraline's extent of inhibition of P450 3A4 activity is not likely to be of clinical significance. Results of the interaction study with cisapride indicate that sertraline 200 mg (q.d.) induces the metabolism of cisapride (cisapride AUC and Cmax were reduced by about 35%).
- Drugs Metabolized by P450 2D6
- Many drugs effective in the treatment of major depressive disorder, e.g., the SSRIs, including sertraline, and most tricyclic antidepressant drugs effective in the treatment of major depressive disorder inhibit the biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase), and, thus, may increase the plasma concentrations of co-administered drugs that are metabolized by P450 2D6. The drugs for which this potential interaction is of greatest concern are those metabolized primarily by 2D6 and which have a narrow therapeutic index, e.g., the tricyclic antidepressant drugs effective in the treatment of major depressive disorder and the Type 1C antiarrhythmics propafenone and flecainide. The extent to which this interaction is an important clinical problem depends on the extent of the inhibition of P450 2D6 by the antidepressant and the therapeutic index of the co-administered drug. There is variability among the drugs effective in the treatment of major depressive disorder in the extent of clinically important 2D6 inhibition, and in fact sertraline at lower doses has a less prominent inhibitory effect on 2D6 than some others in the class. Nevertheless, even sertraline has the potential for clinically important 2D6 inhibition. Consequently, concomitant use of a drug metabolized by P450 2D6 with sertraline hydrochloride may require lower doses than usually prescribed for the other drug. Furthermore, whenever sertraline hydrochloride is withdrawn from co-therapy, an increased dose of the co-administered drug may be required.
- Triptans
- There have been rare post marketing reports of serotonin syndrome with use of an SNRI or an SSRI and a triptan. If concomitant treatment of SNRIs and SSRIs, including sertraline hydrochloride, with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases.
- Sumatriptan
- There have been rare post marketing reports describing patients with weakness, hyperreflexia, and incoordination following the use of a selective serotonin reuptake inhibitor (SSRI) and sumatriptan. If concomitant treatment with sumatriptan and an SSRI (e.g., citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) is clinically warranted, appropriate observation of the patient is advised.
- Tricyclic Antidepressant Drugs Effective in the Treatment of Major Depressive Disorder (TCAs)
- The extent to which SSRI–TCA interactions may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is indicated in the co-administration of TCAs with sertraline hydrochloride, because sertraline may inhibit TCA metabolism. Plasma TCA concentrations may need to be monitored, and the dose of TCA may need to be reduced, if a TCA is co-administered with sertraline hydrochloride.
- Hypoglycemic Drugs
- In a placebo-controlled trial in normal volunteers, administration of sertraline hydrochloride for 22 days (including 200 mg/day for the final 13 days) caused a statistically significant 16% decrease from baseline in the clearance of tolbutamide following an intravenous 1000 mg dose. Sertraline hydrochloride administration did not noticeably change either the plasma protein binding or the apparent volume of distribution of tolbutamide, suggesting that the decreased clearance was due to a change in the metabolism of the drug. The clinical significance of this decrease in tolbutamide clearance is unknown.
- Atenolol
- Sertraline hydrochloride (100 mg) when administered to 10 healthy male subjects had no effect on the beta-adrenergic blocking ability of atenolol.
- Digoxin
- In a placebo-controlled trial in normal volunteers, administration of sertraline hydrochloride for 17 days (including 200 mg/day for the last 10 days) did not change serum digoxin levels or digoxin renal clearance.
- Microsomal Enzyme Induction
- Preclinical studies have shown sertraline hydrochloride to induce hepatic microsomal enzymes. In clinical studies, sertraline hydrochloride was shown to induce hepatic enzymes minimally as determined by a small (5%) but statistically significant decrease in antipyrine half-life following administration of 200 mg/day for 21 days. This small change in antipyrine half-life reflects a clinically insignificant change in hepatic metabolism.
- Drugs That Interfere With Hemostasis (Non-selective NSAIDs, Aspirin, Warfarin, etc.)-Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs or SNRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when sertraline hydrochloride is initiated or discontinued.
- Electroconvulsive Therapy
- There are no clinical studies establishing the risks or benefits of the combined use of electroconvulsive therapy (ECT) and sertraline hydrochloride.
- Alcohol
- Although sertraline hydrochloride did not potentiate the cognitive and psychomotor effects of alcohol in experiments with normal subjects, the concomitant use of sertraline hydrochloride and alcohol is not recommended.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- Reproduction studies have been performed in rats and rabbits at doses up to 80 mg/kg/day and 40 mg/kg/day, respectively. These doses correspond to approximately 4 times the maximum recommended human dose (MRHD) on a mg/m2 basis. There was no evidence of teratogenicity at any dose level. When pregnant rats and rabbits were given sertraline during the period of organogenesis, delayed ossification was observed in fetuses at doses of 10 mg/kg (0.5 times the MRHD on a mg/m2 basis) in rats and 40 mg/kg (4 times the MRHD on a mg/m2 basis) in rabbits. When female rats received sertraline during the last third of gestation and throughout lactation, there was an increase in the number of stillborn pups and in the number of pups dying during the first 4 days after birth. Pup body weights were also decreased during the first four days after birth. These effects occurred at a dose of 20 mg/kg (1 times the MRHD on a mg/m2 basis). The no effect dose for rat pup mortality was 10 mg/kg (0.5 times the MRHD on a mg/m2 basis). The decrease in pup survival was shown to be due to in utero exposure to sertraline. The clinical significance of these effects is unknown. There are no adequate and well-controlled studies in pregnant women. Sertraline hydrochloride should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Pregnancy-Nonteratogenic Effects
- Neonates exposed to sertraline hydrochloride and other SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs), late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome.
- Infants exposed to SSRIs in pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1 – 2 per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. Several recent epidemiologic studies suggest a positive statistical association between SSRI use (including sertraline hydrochloride) in pregnancy and PPHN. Other studies do not show a significant statistical association.
- Physicians should also note the results of a prospective longitudinal study of 201 pregnant women with a history of major depression, who were either on antidepressants or had received antidepressants less than 12 weeks prior to their last menstrual period, and were in remission. Women who discontinued antidepressant medication during pregnancy showed a significant increase in relapse of their major depression compared to those women who remained on antidepressant medication throughout pregnancy.
- When treating a pregnant woman with sertraline hydrochloride, the physician should carefully consider both the potential risks of taking an SSRI, along with the established benefits of treating depression with an antidepressant. This decision can only be made on a case by case basis.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Sertraline in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Sertraline during labor and delivery.
### Nursing Mothers
- It is not known whether, and if so in what amount, sertraline or its metabolites are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when sertraline hydrochloride is administered to a nursing woman.
### Pediatric Use
- The efficacy of sertraline hydrochloride for the treatment of obsessive-compulsive disorder was demonstrated in a 12-week, multicenter, placebo-controlled study with 187 outpatients ages 6-17. Safety and effectiveness in the pediatric population other than pediatric patients with OCD have not been established. Two placebo controlled trials (n=373) in pediatric patients with MDD have been conducted with sertraline hydrochloride, and the data were not sufficient to support a claim for use in pediatric patients. Anyone considering the use of sertraline hydrochloride in a child or adolescent must balance the potential risks with the clinical need.
- The safety of sertraline hydrochloride use in children and adolescents with OCD, ages 6-18, was evaluated in a 12-week, multicenter, placebo-controlled study with 187 outpatients, ages 6-17, and in a flexible dose, 52 week open extension study of 137 patients, ages 6-18, who had completed the initial 12-week, double-blind, placebo- controlled study. Sertraline hydrochloride was administered at doses of either 25 mg/day (children, ages 6-12) or 50 mg/day (adolescents, ages 13-18) and then titrated in weekly 25 mg/day or 50 mg/day increments, respectively, to a maximum dose of 200 mg/day based upon clinical response. The mean dose for completers was 157 mg/day. In the acute 12 week pediatric study and in the 52 week study, sertraline hydrochloride had an adverse event profile generally similar to that observed in adults.
- Sertraline pharmacokinetics were evaluated in 61 pediatric patients between 6 and 17 years of age with major depressive disorder or OCD and revealed similar drug exposures to those of adults when plasma concentration was adjusted for weight.
- Approximately 600 patients with major depressive disorder or OCD between 6 and 17 years of age have received sertraline hydrochloride in clinical trials, both controlled and uncontrolled. The adverse event profile observed in these patients was generally similar to that observed in adult studies with sertraline hydrochloride. As with other SSRIs, decreased appetite and weight loss have been observed in association with the use of sertraline hydrochloride. In a pooled analysis of two 10-week, double-blind, placebo-controlled, flexible dose (50-200 mg) outpatient trials for major depressive disorder (n=373), there was a difference in weight change between sertraline and placebo of roughly 1 kilogram, for both children (ages 6-11) and adolescents (ages 12-17), in both cases representing a slight weight loss for sertraline compared to a slight gain for placebo. At baseline the mean weight for children was 39.0 kg for sertraline and 38.5 kg for placebo. At baseline the mean weight for adolescents was 61.4 kg for sertraline and 62.5 kg for placebo. There was a bigger difference between sertraline and placebo in the proportion of outliers for clinically important weight loss in children than in adolescents. For children, about 7% had a weight loss > 7% of body weight compared to none of the placebo patients; for adolescents, about 2% had a weight loss > 7% of body weight compared to about 1% of the placebo patients. A subset of these patients who completed the randomized controlled trials (sertraline n=99, placebo n=122) were continued into a 24-week, flexible-dose, open-label, extension study. A mean weight loss of approximately 0.5 kg was seen during the first eight weeks of treatment for subjects with first exposure to sertraline during the open-label extension study, similar to mean weight loss observed among sertraline treated subjects during the first eight weeks of the randomized controlled trials. The subjects continuing in the open label study began gaining weight compared to baseline by week 12 of sertraline treatment. Those subjects who completed 34 weeks of sertraline treatment (10 weeks in a placebo controlled trial + 24 weeks open label, n=68) had weight gain that was similar to that expected using data from age-adjusted peers. Regular monitoring of weight and growth is recommended if treatment of a pediatric patient with an SSRI is to be continued long term. Safety and effectiveness in pediatric patients below the age of 6 have not been established.
- The risks, if any, that may be associated with sertraline hydrochloride's use beyond 1 year in children and adolescents with OCD or major depressive disorder have not been systematically assessed. The prescriber should be mindful that the evidence relied upon to conclude that sertraline is safe for use in children and adolescents derives from clinical studies that were 10 to 52 weeks in duration and from the extrapolation of experience gained with adult patients. In particular, there are no studies that directly evaluate the effects of long-term sertraline use on the growth, development, and maturation of children and adolescents. Although there is no affirmative finding to suggest that sertraline possesses a capacity to adversely affect growth, development or maturation, the absence of such findings is not compelling evidence of the absence of the potential of sertraline to have adverse effects in chronic use
### Geriatic Use
- U.S. geriatric clinical studies of sertraline hydrochloride in major depressive disorder included 663 sertraline hydrochloride-treated subjects ≥ 65 years of age, of those, 180 were ≥ 75 years of age. No overall differences in the pattern of adverse reactions were observed in the geriatric clinical trial subjects relative to those reported in younger subjects, and other reported experience has not identified differences in safety patterns between the elderly and younger subjects. As with all medications, greater sensitivity of some older individuals cannot be ruled out. There were 947 subjects in placebo-controlled geriatric clinical studies of sertraline hydrochloride in major depressive disorder. No overall differences in the pattern of efficacy were observed in the geriatric clinical trial subjects relative to those reported in younger subjects.
- Other Adverse Events in Geriatric Patients. In 354 geriatric subjects treated with sertraline hydrochloride in placebo-controlled trials, the overall profile of adverse events was generally similar to that shown in Tables 2 and 3. Urinary tract infection was the only adverse event not appearing in Tables 2 and 3 and reported at an incidence of at least 2% and at a rate greater than placebo in placebo-controlled trials.
- SSRIs and SNRIs, including sertraline hydrochloride, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event.
### Gender
There is no FDA guidance on the use of Sertraline with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Sertraline with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Sertraline in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Sertraline in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Sertraline in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Sertraline in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Sertraline in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Sertraline in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Of 1,027 cases of overdose involving sertraline hydrochloride worldwide, alone or with other drugs, there were 72 deaths (circa 1999).
- Among 634 overdoses in which sertraline hydrochloride was the only drug ingested, 8 resulted in fatal outcome, 75 completely recovered, and 27 patients experienced sequelae after overdosage to include alopecia, decreased libido, diarrhea, ejaculation disorder, fatigue, insomnia, somnolence and serotonin syndrome. The remaining 524 cases had an unknown outcome. The most common signs and symptoms associated with non-fatal sertraline hydrochloride overdosage were somnolence, vomiting, tachycardia, nausea, dizziness, agitation and tremor.
- The largest known ingestion was 13.5 grams in a patient who took sertraline hydrochloride alone and subsequently recovered. However, another patient who took 2.5 grams of sertraline hydrochloride alone experienced a fatal outcome.
- Other important adverse events reported with sertraline hydrochloride overdose (single or multiple drugs) include bradycardia, bundle branch block, coma, convulsions, delirium, hallucinations, hypertension, hypotension, manic reaction, pancreatitis, QT-interval prolongation, serotonin syndrome, stupor, syncope and Torsade de Pointes.
### Management
- Treatment should consist of those general measures employed in the management of overdosage with any antidepressant.
- Ensure an adequate airway, oxygenation and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion, or in symptomatic patients.
- Activated charcoal should be administered. Due to large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion and exchange transfusion are unlikely to be of benefit. No specific antidotes for sertraline are known.
- In managing overdosage, consider the possibility of multiple drug involvement. The physician should consider contacting a poison control center on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physicians' Desk Reference (PDR ).
## Chronic Overdose
There is limited information regarding Chronic Overdose of Sertraline in the drug label.
# Pharmacology
## Mechanism of Action
- The mechanism of action of sertraline is presumed to be linked to its inhibition of CNS neuronal uptake of serotonin (5HT). Studies at clinically relevant doses in man have demonstrated that sertraline blocks the uptake of serotonin into human platelets.
## Structure
- Sertraline hydrochloride is a selective serotonin reuptake inhibitor (SSRI) for oral administration. It has a molecular weight of 342.7. Sertraline hydrochloride has the following chemical name: (1S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine hydrochloride. The empirical formula C17H17NCl2HCl is represented by the following structural formula:
- Sertraline hydrochloride is a white crystalline powder that is slightly soluble in water and isopropyl alcohol, and sparingly soluble in ethanol.
- Sertraline hydrochloride tablets, USP are supplied for oral administration as tablets containing sertraline hydrochloride equivalent to 25, 50 and 100 mg of sertraline and the following inactive ingredients: corn starch, D&C yellow no. 10 aluminum lake (in 25 mg), FD&C blue no. 2 aluminum lake (in 25 mg and 50 mg), FD&C yellow no. 6 aluminum lake (in 25 mg), hypromellose, iron oxide yellow (in 100 mg), magnesium stearate, microcrystalline cellulose, polyethylene glycol, sodium starch glycolate and titanium dioxide.
## Pharmacodynamics
- The mechanism of action of sertraline is presumed to be linked to its inhibition of CNS neuronal uptake of serotonin (5HT). Studies at clinically relevant doses in man have demonstrated that sertraline blocks the uptake of serotonin into human platelets. In vitro studies in animals also suggest that sertraline is a potent and selective inhibitor of neuronal serotonin reuptake and has only very weak effects on norepinephrine and dopamine neuronal reuptake. In vitro studies have shown that sertraline has no significant affinity for adrenergic (alpha1, alpha2, beta), cholinergic, GABA, dopaminergic, histaminergic, serotonergic (5HT1A, 5HT1B, 5HT2), or benzodiazepine receptors; antagonism of such receptors has been hypothesized to be associated with various anticholinergic, sedative, and cardiovascular effects for other psychotropic drugs. The chronic administration of sertraline was found in animals to down regulate brain norepinephrine receptors, as has been observed with other drugs effective in the treatment of major depressive disorder. Sertraline does not inhibit monoamine oxidase.
## Pharmacokinetics
- Systemic Bioavailability
- In man, following oral once-daily dosing over the range of 50 to 200 mg for 14 days, mean peak plasma concentrations (Cmax) of sertraline occurred between 4.5 to 8.4 hours post-dosing. The average terminal elimination half-life of plasma sertraline is about 26 hours. Based on this pharmacokinetic parameter, steady-state sertraline plasma levels should be achieved after approximately one week of once-daily dosing. Linear dose-proportional pharmacokinetics were demonstrated in a single dose study in which the Cmax and area under the plasma concentration time curve (AUC) of sertraline were proportional to dose over a range of 50 to 200 mg. Consistent with the terminal elimination half-life, there is an approximately two-fold accumulation, compared to a single dose, of sertraline with repeated dosing over a 50 to 200 mg dose range. The single dose bioavailability of sertraline tablets is approximately equal to an equivalent dose of solution.
- In a relative bioavailability study comparing the pharmacokinetics of 100 mg sertraline as the oral solution to a 100 mg sertraline tablet in 16 healthy adults, the solution to tablet ratio of geometric mean AUC and Cmax values were 114.8% and 120.6%, respectively. 90% confidence intervals (CI) were within the range of 80-125% with the exception of the upper 90% CI limit for Cmax which was 126.5%.
- The effects of food on the bioavailability of the sertraline tablet and oral concentrate were studied in subjects administered a single dose with and without food. For the tablet, AUC was slightly increased when drug was administered with food but the Cmax was 25% greater, while the time to reach peak plasma concentration (Tmax) decreased from 8 hours post-dosing to 5.5 hours. For the oral concentrate, Tmax was slightly prolonged from 5.9 hours to 7.0 hours with food.
- Metabolism
- Sertraline undergoes extensive first pass metabolism. The principal initial pathway of metabolism for sertraline is N-demethylation. N-desmethylsertraline has a plasma terminal elimination half-life of 62 to 104 hours. Both in vitro biochemical and in vivo pharmacological testing have shown N-desmethylsertraline to be substantially less active than sertraline. Both sertraline and N-desmethylsertraline undergo oxidative deamination and subsequent reduction, hydroxylation, and glucuronide conjugation. In a study of radiolabeled sertraline involving two healthy male subjects, sertraline accounted for less than 5% of the plasma radioactivity. About 40-45% of the administered radioactivity was recovered in urine in 9 days. Unchanged sertraline was not detectable in the urine. For the same period, about 40-45% of the administered radioactivity was accounted for in feces, including 12-14% unchanged sertraline.
- Desmethylsertraline exhibits time-related, dose dependent increases in AUC (0-24 hour), Cmax and Cmin, with about a 5-9 fold increase in these pharmacokinetic parameters between day 1 and day 14.
- Protein Binding
- In vitro protein binding studies performed with radiolabeled 3H-sertraline showed that sertraline is highly bound to serum proteins (98%) in the range of 20 to 500 ng/mL. However, at up to 300 and 200 ng/mL concentrations, respectively, sertraline and N-desmethylsertraline did not alter the plasma protein binding of two other highly protein bound drugs, viz., warfarin and propranolol.
- Pediatric Pharmacokinetics
- Sertraline pharmacokinetics were evaluated in a group of 61 pediatric patients (29 aged 6-12 years, 32 aged 13-17 years) with a DSM-III-R diagnosis of major depressive disorder or obsessive-compulsive disorder. Patients included both males (N=28) and females (N=33). During 42 days of chronic sertraline dosing, sertraline was titrated up to 200 mg/day and maintained at that dose for a minimum of 11 days. On the final day of sertraline 200 mg/day, the 6-12 year old group exhibited a mean sertraline AUC (0-24 hr) of 3107 ng-hr/mL, mean Cmax of 165 ng/mL, and mean half-life of 26.2 hr. The 13-17 year old group exhibited a mean sertraline AUC (0-24 hr) of 2296 ng-hr/mL, mean Cmax of 123 ng/mL, and mean half-life of 27.8 hr. Higher plasma levels in the 6-12 year old group were largely attributable to patients with lower body weights. No gender associated differences were observed. By comparison, a group of 22 separately studied adults between 18 and 45 years of age (11 male, 11 female) received 30 days of 200 mg/day sertraline and exhibited a mean sertraline AUC (0-24 hr) of 2570 ng-hr/mL, mean Cmax of 142 ng/mL, and mean half-life of 27.2 hr. Relative to the adults, both the 6-12 year olds and the 13-17 year olds showed about 22% lower AUC (0-24 hr) and Cmax values when plasma concentration was adjusted for weight. These data suggest that pediatric patients metabolize sertraline with slightly greater efficiency than adults. Nevertheless, lower doses may be advisable for pediatric patients given their lower body weights, especially in very young patients, in order to avoid excessive plasma levels.
- Age
- Sertraline plasma clearance in a group of 16 (8 male, 8 female) elderly patients treated for 14 days at a dose of 100 mg/day was approximately 40% lower than in a similarly studied group of younger (25 to 32 y.o.) individuals. Steady-state, therefore, should be achieved after 2 to 3 weeks in older patients. The same study showed a decreased clearance of desmethylsertraline in older males, but not in older females.
- Liver Disease
- As might be predicted from its primary site of metabolism, liver impairment can affect the elimination of sertraline. In patients with chronic mild liver impairment (N=10, 8 patients with Child-Pugh scores of 5-6 and 2 patients with Child-Pugh scores of 7-8) who received 50 mg sertraline per day maintained for 21 days, sertraline clearance was reduced, resulting in approximately 3-fold greater exposure compared to age-matched volunteers with no hepatic impairment (N=10). The exposure to desmethylsertraline was approximately 2-fold greater compared to age-matched volunteers with no hepatic impairment. There were no significant differences in plasma protein binding observed between the two groups. The effects of sertraline in patients with moderate and severe hepatic impairment have not been studied. The results suggest that the use of sertraline in patients with liver disease must be approached with caution. If sertraline is administered to patients with liver impairment, a lower or less frequent dose should be used.
- Renal Disease
- Sertraline is extensively metabolized and excretion of unchanged drug in urine is a minor route of elimination. In volunteers with mild to moderate (CLcr=30-60 mL/min), moderate to severe (CLcr=10-29 mL/min) or severe (receiving hemodialysis) renal impairment (N=10 each group), the pharmacokinetics and protein binding of 200 mg sertraline per day maintained for 21 days were not altered compared to age-matched volunteers (N=12) with no renal impairment. Thus sertraline multiple dose pharmacokinetics appear to be unaffected by renal impairment.
## Nonclinical Toxicology
- Carcinogenesis
- Lifetime carcinogenicity studies were carried out in CD-1 mice and Long-Evans rats at doses up to 40 mg/kg/day. These doses correspond to 1 times (mice) and 2 times (rats) the maximum recommended human dose (MRHD) on a mg/m2 basis. There was a dose-related increase of liver adenomas in male mice receiving sertraline at 10-40 mg/kg (0.25-1.0 times the MRHD on a mg/m2 basis). No increase was seen in female mice or in rats of either sex receiving the same treatments, nor was there an increase in hepatocellular carcinomas. Liver adenomas have a variable rate of spontaneous occurrence in the CD-1 mouse and are of unknown significance to humans. There was an increase in follicular adenomas of the thyroid in female rats receiving sertraline at 40 mg/kg (2 times the MRHD on a mg/m2 basis); this was not accompanied by thyroid hyperplasia. While there was an increase in uterine adenocarcinomas in rats receiving sertraline at 10-40 mg/kg (0.5-2.0 times the MRHD on a mg/m2 basis) compared to placebo controls, this effect was not clearly drug related.
- Mutagenesis
- Sertraline had no genotoxic effects, with or without metabolic activation, based on the following assays: bacterial mutation assay; mouse lymphoma mutation assay; and tests for cytogenetic aberrations in vivo in mouse bone marrow and in vitro in human lymphocytes.
- Impairment of Fertility
- A decrease in fertility was seen in one of two rat studies at a dose of 80 mg/kg (4 times the maximum recommended human dose on a mg/m2 basis).
# Clinical Studies
- The efficacy of sertraline hydrochloride as a treatment for major depressive disorder was established in two placebo-controlled studies in adult outpatients meeting DSM-III criteria for major depressive disorder. Study 1 was an 8-week study with flexible dosing of sertraline hydrochloride in a range of 50 to 200 mg/day; the mean dose for completers was 145 mg/day. Study 2 was a 6-week fixed-dose study, including sertraline hydrochloride doses of 50, 100, and 200 mg/day. Overall, these studies demonstrated sertraline hydrochloride to be superior to placebo on the Hamilton Depression Rating Scale and the Clinical Global Impression Severity and Improvement scales. Study 2 was not readily interpretable regarding a dose response relationship for effectiveness.
- Study 3 involved depressed outpatients who had responded by the end of an initial 8-week open treatment phase on sertraline hydrochloride 50-200 mg/day. These patients (N=295) were randomized to continuation for 44 weeks on double-blind sertraline hydrochloride 50-200 mg/day or placebo. A statistically significantly lower relapse rate was observed for patients taking sertraline hydrochloride compared to those on placebo. The mean dose for completers was 70 mg/day.
- Analyses for gender effects on outcome did not suggest any differential responsiveness on the basis of sex.
- The effectiveness of sertraline hydrochloride in the treatment of OCD was demonstrated in three multicenter placebo-controlled studies of adult outpatients (Studies 1-3). Patients in all studies had moderate to severe OCD (DSM-III or DSM-III-R) with mean baseline ratings on the Yale–Brown Obsessive-Compulsive Scale (YBOCS) total score ranging from 23 to 25.
- Study 1 was an 8-week study with flexible dosing of sertraline hydrochloride in a range of 50 to 200 mg/day; the mean dose for completers was 186 mg/day. Patients receiving sertraline hydrochloride experienced a mean reduction of approximately 4 points on the YBOCS total score which was significantly greater than the mean reduction of 2 points in placebo-treated patients.
- Study 2 was a 12-week fixed-dose study, including sertraline hydrochloride doses of 50, 100, and 200 mg/day. Patients receiving sertraline hydrochloride doses of 50 and 200 mg/day experienced mean reductions of approximately 6 points on the YBOCS total score which were significantly greater than the approximately 3 point reduction in placebo-treated patients.
- Study 3 was a 12-week study with flexible dosing of sertraline hydrochloride in a range of 50 to 200 mg/day; the mean dose for completers was 185 mg/day. Patients receiving sertraline hydrochloride experienced a mean reduction of approximately 7 points on the YBOCS total score which was significantly greater than the mean reduction of approximately 4 points in placebo-treated patients.
- Analyses for age and gender effects on outcome did not suggest any differential responsiveness on the basis of age or sex.
- The effectiveness of sertraline hydrochloride for the treatment of OCD was also demonstrated in a 12-week, multicenter, placebo-controlled, parallel group study in a pediatric outpatient population (children and adolescents, ages 6-17). Patients receiving sertraline hydrochloride in this study were initiated at doses of either 25 mg/day (children, ages 6-12) or 50 mg/day (adolescents, ages 13-17), and then titrated over the next four weeks to a maximum dose of 200 mg/day, as tolerated. The mean dose for completers was 178 mg/day. Dosing was once a day in the morning or evening. Patients in this study had moderate to severe OCD (DSM-III-R) with mean baseline ratings on the Children's Yale-Brown Obsessive-Compulsive Scale (CYBOCS) total score of 22. Patients receiving sertraline experienced a mean reduction of approximately 7 units on the CYBOCS total score which was significantly greater than the 3 unit reduction for placebo patients. Analyses for age and gender effects on outcome did not suggest any differential responsiveness on the basis of age or sex.
- In a longer-term study, patients meeting DSM-III-R criteria for OCD who had responded during a 52-week single-blind trial on sertraline hydrochloride 50-200 mg/day (n=224) were randomized to continuation of sertraline hydrochloride or to substitution of placebo for up to 28 weeks of observation for discontinuation due to relapse or insufficient clinical response. Response during the single-blind phase was defined as a decrease in the YBOCS score of ≥ 25% compared to baseline and a CGII of 1 (very much improved), 2 (much improved) or 3 (minimally improved). Relapse during the double-blind phase was defined as the following conditions being met (on three consecutive visits for 1 and 2, and for visit 3 for condition 3): (1) YBOCS score increased by ≥ 5 points, to a minimum of 20, relative to baseline; (2) CGI-I increased by ≥ one point; and (3) worsening of the patient's condition in the investigator's judgment, to justify alternative treatment. Insufficient clinical response indicated a worsening of the patient's condition that resulted in study discontinuation, as assessed by the investigator. Patients receiving continued sertraline hydrochloride treatment experienced a significantly lower rate of discontinuation due to relapse or insufficient clinical response over the subsequent 28 weeks compared to those receiving placebo. This pattern was demonstrated in male and female subjects.
- The effectiveness of sertraline hydrochloride in the treatment of panic disorder was demonstrated in three double-blind, placebo-controlled studies (Studies 1-3) of adult outpatients who had a primary diagnosis of panic disorder (DSM-III-R), with or without agoraphobia.
- Studies 1 and 2 were 10-week flexible dose studies. Sertraline hydrochloride was initiated at 25 mg/day for the first week, and then patients were dosed in a range of 50-200 mg/day on the basis of clinical response and toleration. The mean sertraline hydrochloride doses for completers to 10 weeks were 131 mg/day and 144 mg/day, respectively, for Studies 1 and 2. In these studies, sertraline hydrochloride was shown to be significantly more effective than placebo on change from baseline in panic attack frequency and on the Clinical Global Impression Severity of Illness and Global Improvement scores. The difference between sertraline hydrochloride and placebo in reduction from baseline in the number of full panic attacks was approximately 2 panic attacks per week in both studies.
- Study 3 was a 12-week fixed-dose study, including sertraline hydrochloride doses of 50, 100, and 200 mg/day. Patients receiving sertraline hydrochloride experienced a significantly greater reduction in panic attack frequency than patients receiving placebo. Study 3 was not readily interpretable regarding a dose response relationship for effectiveness.
- Subgroup analyses did not indicate that there were any differences in treatment outcomes as a function of age, race, or gender.
- In a longer-term study, patients meeting DSM-III-R criteria for Panic Disorder who had responded during a 52-week open trial on sertraline hydrochloride 50-200 mg/day (n=183) were randomized to continuation of sertraline hydrochloride or to substitution of placebo for up to 28 weeks of observation for discontinuation due to relapse or insufficient clinical response. Response during the open phase was defined as a CGI-I score of 1(very much improved) or 2 (much improved). Relapse during the double-blind phase was defined as the following conditions being met on three consecutive visits: (1) CGI-I ≥ 3; (2) meets DSM-III-R criteria for Panic Disorder; (3) number of panic attacks greater than at baseline. Insufficient clinical response indicated a worsening of the patient's condition that resulted in study discontinuation, as assessed by the investigator. Patients receiving continued sertraline hydrochloride treatment experienced a significantly lower rate of discontinuation due to relapse or insufficient clinical response over the subsequent 28 weeks compared to those receiving placebo. This pattern was demonstrated in male and female subjects.
- The effectiveness of sertraline hydrochloride in the treatment of PTSD was established in two multicenter placebo-controlled studies (Studies 1-2) of adult outpatients who met DSM-III-R criteria for PTSD. The mean duration of PTSD for these patients was 12 years (Studies 1 and 2 combined) and 44% of patients (169 of the 385 patients treated) had secondary depressive disorder.
- Studies 1 and 2 were 12-week flexible dose studies. Sertraline hydrochloride was initiated at 25 mg/day for the first week, and patients were then dosed in the range of 50-200 mg/day on the basis of clinical response and toleration. The mean sertraline hydrochloride dose for completers was 146 mg/day and 151 mg/day, respectively for Studies 1 and 2. Study outcome was assessed by the Clinician-Administered PTSD Scale Part 2 (CAPS) which is a multi-item instrument that measures the three PTSD diagnostic symptom clusters of reexperiencing/intrusion, avoidance/numbing, and hyperarousal as well as the patient-rated Impact of Event Scale (IES) which measures intrusion and avoidance symptoms. Sertraline hydrochloride was shown to be significantly more effective than placebo on change from baseline to endpoint on the CAPS, IES and on the Clinical Global Impressions (CGI) Severity of Illness and Global Improvement scores. In two additional placebo-controlled PTSD trials, the difference in response to treatment between patients receiving sertraline hydrochloride and patients receiving placebo was not statistically significant. One of these additional studies was conducted in patients similar to those recruited for Studies 1 and 2, while the second additional study was conducted in predominantly male veterans.
- As PTSD is a more common disorder in women than men, the majority (76%) of patients in these trials were women (152 and 139 women on sertraline and placebo versus 39 and 55 men on sertraline and placebo; Studies 1 and 2 combined). Post hoc exploratory analyses revealed a significant difference between sertraline hydrochloride and placebo on the CAPS, IES and CGI in women, regardless of baseline diagnosis of comorbid major depressive disorder, but essentially no effect in the relatively smaller number of men in these studies. The clinical significance of this apparent gender interaction is unknown at this time. There was insufficient information to determine the effect of race or age on outcome.
- In a longer-term study, patients meeting DSM-III-R criteria for PTSD who had responded during a 24-week open trial on sertraline hydrochloride 50-200 mg/day (n=96) were randomized to continuation of sertraline hydrochloride or to substitution of placebo for up to 28 weeks of observation for relapse. Response during the open phase was defined as a CGI-I of 1 (very much improved) or 2 (much improved), and a decrease in the CAPS-2 score of > 30% compared to baseline. Relapse during the double-blind phase was defined as the following conditions being met on two consecutive visits: (1) CGI-I ≥ 3; (2) CAPS-2 score increased by ≥ 30% and by ≥ 15 points relative to baseline; and (3) worsening of the patient's condition in the investigator's judgment. Patients receiving continued sertraline hydrochloride treatment experienced significantly lower relapse rates over the subsequent 28 weeks compared to those receiving placebo. This pattern was demonstrated in male and female subjects.
- The effectiveness of sertraline hydrochloride for the treatment of PMDD was established in two double-blind, parallel group, placebo-controlled flexible dose trials (Studies 1 and 2) conducted over 3 menstrual cycles. Patients in Study 1 met DSM-III-R criteria for Late Luteal Phase Dysphoric Disorder (LLPDD), the clinical entity now referred to as Premenstrual Dysphoric Disorder (PMDD) in DSM-IV. Patients in Study 2 met DSM-IV criteria for PMDD. Study 1 utilized daily dosing throughout the study, while Study 2 utilized luteal phase dosing for the 2 weeks prior to the onset of menses. The mean duration of PMDD symptoms for these patients was approximately 10.5 years in both studies. Patients on oral contraceptives were excluded from these trials; therefore, the efficacy of sertraline in combination with oral contraceptives for the treatment of PMDD is unknown.
- Efficacy was assessed with the Daily Record of Severity of Problems (DRSP), a patient-rated instrument that mirrors the diagnostic criteria for PMDD as identified in the DSM-IV, and includes assessments for mood, physical symptoms, and other symptoms. Other efficacy assessments included the Hamilton Depression Rating Scale (HAMD-17), and the Clinical Global Impression Severity of Illness (CGI-S) and Improvement (CGI-I) scores.
- In Study 1, involving n=251 randomized patients; sertraline hydrochloride treatment was initiated at 50 mg/day and administered daily throughout the menstrual cycle. In subsequent cycles, patients were dosed in the range of 50-150 mg/day on the basis of clinical response and toleration. The mean dose for completers was 102 mg/day. Sertraline hydrochloride administered daily throughout the menstrual cycle was significantly more effective than placebo on change from baseline to endpoint on the DRSP total score, the HAMD-17 total score, and the CGI-S score, as well as the CGI-I score at endpoint.
- In Study 2, involving n=281 randomized patients, sertraline hydrochloride treatment was initiated at 50 mg/day in the late luteal phase (last 2 weeks) of each menstrual cycle and then discontinued at the onset of menses. In subsequent cycles, patients were dosed in the range of 50-100 mg/day in the luteal phase of each cycle, on the basis of clinical response and toleration. Patients who were titrated to 100 mg/day received 50 mg/day for the first 3 days of the cycle, then 100 mg/day for the remainder of the cycle. The mean sertraline hydrochloride dose for completers was 74 mg/day. Sertraline hydrochloride administered in the late luteal phase of the menstrual cycle was significantly more effective than placebo on change from baseline to endpoint on the DRSP total score and the CGI-S score, as well as the CGI-I score at endpoint.
- There was insufficient information to determine the effect of race or age on outcome in these studies.
- The effectiveness of sertraline hydrochloride in the treatment of social anxiety disorder (also known as social phobia) was established in two multicenter placebo-controlled studies (Study 1 and 2) of adult outpatients who met DSM-IV criteria for social anxiety disorder.
- Study 1 was a 12-week, multicenter, flexible dose study comparing sertraline hydrochloride (50-200 mg/day) to placebo, in which sertraline hydrochloride was initiated at 25 mg/day for the first week. Study outcome was assessed by (a) the Liebowitz Social Anxiety Scale (LSAS), a 24-item clinician administered instrument that measures fear, anxiety and avoidance of social and performance situations, and by (b) the proportion of responders as defined by the Clinical Global Impression of Improvement (CGI-I) criterion of CGI-I ≤ 2 (very much or much improved). Sertraline hydrochloride was statistically significantly more effective than placebo as measured by the LSAS and the percentage of responders.
- Study 2 was a 20-week, multicenter, flexible dose study that compared sertraline hydrochloride (50-200 mg/day) to placebo. Study outcome was assessed by the (a) Duke Brief Social Phobia Scale (BSPS), a multi-item clinician-rated instrument that measures fear, avoidance and physiologic response to social or performance situations, (b) the Marks Fear Questionnaire Social Phobia Subscale (FQ-SPS), a 5-item patient-rated instrument that measures change in the severity of phobic avoidance and distress, and (c) the CGI-I responder criterion of ≤ 2. Sertraline hydrochloride was shown to be statistically significantly more effective than placebo as measured by the BSPS total score and fear, avoidance and physiologic factor scores, as well as the FQ-SPS total score, and to have significantly more responders than placebo as defined by the CGI-I.
- Subgroup analyses did not suggest differences in treatment outcome on the basis of gender. There was insufficient information to determine the effect of race or age on outcome.
- In a longer-term study, patients meeting DSM-IV criteria for social anxiety disorder who had responded while assigned to sertraline hydrochloride (CGI-I of 1 or 2) during a 20-week placebo-controlled trial on sertraline hydrochloride 50-200 mg/day were randomized to continuation of sertraline hydrochloride or to substitution of placebo for up to 24 weeks of observation for relapse. Relapse was defined as ≥ 2 point increase in the Clinical Global Impression – Severity of Illness (CGI-S) score compared to baseline or study discontinuation due to lack of efficacy. Patients receiving sertraline hydrochloride continuation treatment experienced a statistically significantly lower relapse rate over this 24week study than patients randomized to placebo substitution.
# How Supplied
- Sertraline hydrochloride tablets, USP are supplied in capsule-shaped tablets containing sertraline hydrochloride equivalent to 25, 50 and 100 mg of sertraline, are packaged in bottles.
- Sertraline hydrochloride tablets USP, 25 mg: Light green coloured, capsule shaped, biconvex, film coated tablets with debossing "C155" on one side and scored on the other side.
- NDC 69097-155-02 Bottles of 30
- NDC 69097-155-05 Bottles of 90
- NDC 69097-155-12 Bottles of 500
- Sertraline hydrochloride tablets USP, 50 mg: Blue coloured, capsule shaped, biconvex, film coated tablets with debossing "C156" on one side and scored on the other side.
- NDC 69097-156-02 Bottles of 30
- NDC 69097-156-05 Bottles of 90
- NDC 69097-156-12 Bottles of 500
- Sertraline hydrochloride tablets USP, 100 mg: Yellow coloured, capsule shaped, biconvex, film coated tablets with debossing "C157" on one side and scored on the other side.
- NDC 69097-157-02 Bottles of 30
- NDC 69097-157-05 Bottles of 90
- NDC 69097-157-12 Bottles of 500
- Storage
- Store at 20°C-25°C (68°F-77°F).
## Storage
There is limited information regarding Sertraline Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with sertraline hydrochloride and should counsel them in its appropriate use. A patient Medication Guide about "Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions: is available for sertraline hydrochloride. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document.
- Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking sertraline hydrochloride.
- Clinical Worsening and Suicide Risk: Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.
- Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of SNRIs and SSRIs, including sertraline hydrochloride, and triptans, tramadol, or other serotonergic agents.
- Patients should be advised that taking sertraline hydrochloride can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible.
- Patients should be told that although sertraline hydrochloride has not been shown to impair the ability of normal subjects to perform tasks requiring complex motor and mental skills in laboratory experiments, drugs that act upon the central nervous system may affect some individuals adversely. Therefore, patients should be told that until they learn how they respond to sertraline hydrochloride they should be careful doing activities when they need to be alert, such as driving a car or operating machinery.
- Patients should be cautioned about the concomitant use of sertraline hydrochloride and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding.
- Patients should be told that although sertraline hydrochloride has not been shown in experiments with normal subjects to increase the mental and motor skill impairments caused by alcohol, the concomitant use of sertraline hydrochloride and alcohol is not advised.
- Patients should be told that while no adverse interaction of sertraline hydrochloride with over-the-counter (OTC) drug products is known to occur, the potential for interaction exists. Thus, the use of any OTC product should be initiated cautiously according to the directions of use given for the OTC product.
- Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy.
- Patients should be advised to notify their physician if they are breast feeding an infant.
# Precautions with Alcohol
- Alcohol-Sertraline interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- SERTRALINE HYDROCHLORIDE®
# Look-Alike Drug Names
- sertraline® — cetirizine®
- sertraline® — Soriatane®
# Drug Shortage Status
# Price | Sertraline
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2]
# Disclaimer
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# Black Box Warning
# Overview
Sertraline is a serotonin reuptake inhibitor that is FDA approved for the {{{indicationType}}} of major depressive disorder, obsessive-compulsive disorder, panic disorder, posttraumatic stress disorder, premenstrual dysphoric disorder and social phobia. There is a Black Box Warning for this drug as shown here. Common adverse reactions include constipation, diarrhea, indigestion, nausea and vomiting, dizziness, headache, insomnia, somnolence, tremor, abnormal ejaculation, reduced libido, and fatigue.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Sertraline hydrochloride treatment should be administered at a dose of 50 mg once daily.
- Maintenance/Continuation/Extended Treatment
- It is generally agreed that acute episodes of major depressive disorder require several months or longer of sustained pharmacologic therapy beyond response to the acute episode. Systematic evaluation of sertraline hydrochloride has demonstrated that its antidepressant efficacy is maintained for periods of up to 44 weeks following 8 weeks of initial treatment at a dose of 50-200 mg/day (mean dose of 70 mg/day). It is not known whether the dose of sertraline hydrochloride needed for maintenance treatment is identical to the dose needed to achieve an initial response. Patients should be periodically reassessed to determine the need for maintenance treatment.
- Sertraline hydrochloride treatment should be administered at a dose of 50 mg once daily.
- Maintenance/Continuation/Extended Treatment
- It is generally agreed that OCD require several months or longer of sustained pharmacological therapy beyond response to initial treatment. Systematic evaluation of continuing sertraline hydrochloride for periods of up to 28 weeks in patients with OCD who have responded while taking sertraline hydrochloride during initial treatment phases of 24 to 52 weeks of treatment at a dose range of 50-200 mg/day has demonstrated a benefit of such maintenance treatment. It is not known whether the dose of sertraline hydrochloride needed for maintenance treatment is identical to the dose needed to achieve an initial response. Nevertheless, patients should be periodically reassessed to determine the need for maintenance treatment.
- Sertraline hydrochloride treatment should be initiated with a dose of 25 mg once daily. After one week, the dose should be increased to 50 mg once daily.
- While a relationship between dose and effect has not been established for major depressive disorder, OCD, panic disorder, PTSD or social anxiety disorder, patients were dosed in a range of 50-200 mg/day in the clinical trials demonstrating the effectiveness of sertraline hydrochloride for the treatment of these indications. Consequently, a dose of 50 mg, administered once daily, is recommended as the initial therapeutic dose. Patients not responding to a 50 mg dose may benefit from dose increases up to a maximum of 200 mg/day. Given the 24 hour elimination half-life of sertraline hydrochloride, dose changes should not occur at intervals of less than 1 week.
- Maintenance/Continuation/Extended Treatment
- It is generally agreed that Panic Disorder require several months or longer of sustained pharmacological therapy beyond response to initial treatment. Systematic evaluation of continuing sertraline hydrochloride for periods of up to 28 weeks in patients with OCD who have responded while taking sertraline hydrochloride during initial treatment phases of 24 to 52 weeks of treatment at a dose range of 50-200 mg/day has demonstrated a benefit of such maintenance treatment. It is not known whether the dose of sertraline hydrochloride needed for maintenance treatment is identical to the dose needed to achieve an initial response. Nevertheless, patients should be periodically reassessed to determine the need for maintenance treatment.
- Sertraline hydrochloride treatment should be initiated with a dose of 25 mg once daily. After one week, the dose should be increased to 50 mg once daily.
- While a relationship between dose and effect has not been established for major depressive disorder, OCD, panic disorder, PTSD or social anxiety disorder, patients were dosed in a range of 50-200 mg/day in the clinical trials demonstrating the effectiveness of sertraline hydrochloride for the treatment of these indications. Consequently, a dose of 50 mg, administered once daily, is recommended as the initial therapeutic dose. Patients not responding to a 50 mg dose may benefit from dose increases up to a maximum of 200 mg/day. Given the 24 hour elimination half-life of sertraline hydrochloride, dose changes should not occur at intervals of less than 1 week.
- Maintenance/Continuation/Extended Treatment
- It is generally agreed that PTSD requires several months or longer of sustained pharmacological therapy beyond response to initial treatment. Systematic evaluation of sertraline hydrochloride has demonstrated that its efficacy in PTSD is maintained for periods of up to 28 weeks following 24 weeks of treatment at a dose of 50-200 mg/day. It is not known whether the dose of sertraline hydrochloride needed for maintenance treatment is identical to the dose needed to achieve an initial response. Patients should be periodically reassessed to determine the need for maintenance treatment.
- Sertraline hydrochloride treatment should be initiated with a dose of 50 mg/day, either daily throughout the menstrual cycle or limited to the luteal phase of the menstrual cycle, depending on physician assessment.
- While a relationship between dose and effect has not been established for PMDD, patients were dosed in the range of 50-150 mg/day with dose increases at the onset of each new menstrual cycle. Patients not responding to a 50 mg/day dose may benefit from dose increases (at 50 mg increments/menstrual cycle) up to 150 mg/day when dosing daily throughout the menstrual cycle, or 100 mg/day when dosing during the luteal phase of the menstrual cycle. If a 100 mg/day dose has been established with luteal phase dosing, a 50 mg/day titration step for three days should be utilized at the beginning of each luteal phase dosing period.
- Sertraline hydrochloride should be administered once daily, either in the morning or evening.
- Maintenance/Continuation/Extended Treatment
- The effectiveness of sertraline hydrochloride in long-term use, that is, for more than 3 menstrual cycles, has not been systematically evaluated in controlled trials. However, as women commonly report that symptoms worsen with age until relieved by the onset of menopause, it is reasonable to consider continuation of a responding patient. Dosage adjustments, which may include changes between dosage regimens (e.g., daily throughout the menstrual cycle versus during the luteal phase of the menstrual cycle), may be needed to maintain the patient on the lowest effective dosage and patients should be periodically reassessed to determine the need for continued treatment.
- Sertraline hydrochloride treatment should be initiated with a dose of 25 mg once daily. After one week, the dose should be increased to 50 mg once daily.
- While a relationship between dose and effect has not been established for major depressive disorder, OCD, panic disorder, PTSD or social anxiety disorder, patients were dosed in a range of 50-200 mg/day in the clinical trials demonstrating the effectiveness of sertraline hydrochloride for the treatment of these indications. Consequently, a dose of 50 mg, administered once daily, is recommended as the initial therapeutic dose. Patients not responding to a 50 mg dose may benefit from dose increases up to a maximum of 200 mg/day. Given the 24 hour elimination half-life of sertraline hydrochloride, dose changes should not occur at intervals of less than 1 week.
- Maintenance/Continuation/Extended Treatment
- Social anxiety disorder is a chronic condition that may require several months or longer of sustained pharmacological therapy beyond response to initial treatment. Systematic evaluation of sertraline hydrochloride has demonstrated that its efficacy in social anxiety disorder is maintained for periods of up to 24 weeks following 20 weeks of treatment at a dose of 50-200 mg/day. Dosage adjustments should be made to maintain patients on the lowest effective dose and patients should be periodically reassessed to determine the need for long-term treatment.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Sertraline in adult patients.
### Non–Guideline-Supported Use
- Sertraline 50 to 200 mg/day.
- Sertraline 50 milligrams (mg) daily.
- Sertraline 50 mg daily.
- Sertraline 50 mg/day.
- Sertraline 25 mg/day initially for 1 week with increases in 50-mg increments at weeks 2, 3, 4, and 7, up to a maximum of 200 mg/day.
- Sertraline 50 milligrams orally once daily for 8 weeks.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Sertraline hydrochloride treatment should be initiated with a dose of 25 mg once daily in children (ages 6-12) and at a dose of 50 mg once daily in adolescents (ages 13-17).
- While a relationship between dose and effect has not been established for OCD, patients were dosed in a range of 25-200 mg/day in the clinical trials demonstrating the effectiveness of sertraline hydrochloride for pediatric patients (6-17 years) with OCD. Patients not responding to an initial dose of 25 or 50 mg/day may benefit from dose increases up to a maximum of 200 mg/day. For children with OCD, their generally lower body weights compared to adults should be taken into consideration in advancing the dose, in order to avoid excess dosing. Given the 24 hour elimination half-life of sertraline hydrochloride, dose changes should not occur at intervals of less than 1 week.
- Sertraline hydrochloride should be administered once daily, either in the morning or evening.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Sertraline in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Sertraline in pediatric patients.
# Contraindications
- The use of MAOIs intended to treat psychiatric disorders with sertraline hydrochloride or within 14 days of stopping treatment with sertraline hydrochloride is contraindicated because of an increased risk of serotonin syndrome. The use of sertraline hydrochloride within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated.
- Starting sertraline hydrochloride in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome.
- Concomitant use in patients taking pimozide is contraindicated.
- Sertraline hydrochloride is contraindicated in patients with a hypersensitivity to sertraline or any of the inactive ingredients in sertraline hydrochloride tablets, USP.
# Warnings
- Clinical Worsening and Suicide Risk
- Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.
- The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1.
- No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.
- It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.
- All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.
- The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.
- Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.
- If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms.
- Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for sertraline hydrochloride should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.
- Screening Patients for Bipolar Disorder: A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that sertraline hydrochloride is not approved for use in treating bipolar depression.
- Serotonin Syndrome
- The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including sertraline hydrochloride, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John's Wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
- Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome.
- The concomitant use of sertraline hydrochloride with MAOIs intended to treat psychiatric disorders is contraindicated. Sertraline hydrochloride should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with a MAOI such as linezolid or intravenous methylene blue in a patient taking sertraline hydrochloride. Sertraline hydrochloride should be discontinued before initiating treatment with the MAOI.
- If concomitant use of sertraline hydrochloride with other serotonergic drugs including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John's Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases.
- Treatment with sertraline hydrochloride and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.
- Angle-Closure Glaucoma
- The pupillary dilation that occurs following use of many antidepressant drugs including sertraline hydrochloride may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.
### Precautions
- Activation of Mania/Hypomania
- During premarketing testing, hypomania or mania occurred in approximately 0.4% of sertraline hydrochloride treated patients.
- Weight Loss
- Significant weight loss may be an undesirable result of treatment with sertraline for some patients, but on average, patients in controlled trials had minimal, 1 to 2 pound weight loss, versus smaller changes on placebo. Only rarely have sertraline patients been discontinued for weight loss.
- Seizure
- Sertraline hydrochloride has not been evaluated in patients with a seizure disorder. These patients were excluded from clinical studies during the product's premarket testing. No seizures were observed among approximately 3000 patients treated with sertraline hydrochloride in the development program for major depressive disorder. However, 4 patients out of approximately 1800 (220 <;<18 years of age) exposed during the development program for obsessive-compulsive disorder experienced seizures, representing a crude incidence of 0.2%. Three of these patients were adolescents, two with a seizure disorder and one with a family history of seizure disorder, none of whom were receiving anticonvulsant medication. Accordingly, sertraline hydrochloride should be introduced with care in patients with a seizure disorder.
- Discontinuation of Treatment with sertraline hydrochloride
- During marketing of sertraline hydrochloride and other SSRIs and SNRIs (Serotonin and Norepinephrine Reuptake Inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g. paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms.
- Patients should be monitored for these symptoms when discontinuing treatment with sertraline hydrochloride. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate.
- Abnormal Bleeding
- SSRIs and SNRIs, including sertraline hydrochloride, may increase the risk of bleeding events ranging from ecchymoses, hematomas, epistaxis, petechiae, and gastrointestinal hemorrhage to life-threatening hemorrhage. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anticoagulants or other drugs known to affect platelet function may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding.
- Patients should be cautioned about the risk of bleeding associated with the concomitant use of sertraline hydrochloride and NSAIDs, aspirin, or other drugs that affect coagulation.
- Weak Uricosuric Effect
- Sertraline hydrochloride is associated with a mean decrease in serum uric acid of approximately 7%. The clinical significance of this weak uricosuric effect is unknown.
- Use in Patients with Concomitant Illness
- Clinical experience with sertraline hydrochloride in patients with certain concomitant systemic illness is limited. Caution is advisable in using sertraline hydrochloride in patients with diseases or conditions that could affect metabolism or hemodynamic responses.
- Patients with a recent history of myocardial infarction or unstable heart disease were excluded from clinical studies during the product's premarket testing. However, the electrocardiograms of 774 patients who received sertraline hydrochloride in double-blind trials were evaluated and the data indicate that sertraline hydrochloride is not associated with the development of significant ECG abnormalities.
- Sertraline hydrochloride administered in a flexible dose range of 50 to 200 mg/day (mean dose of 89 mg/day) was evaluated in a post-marketing, placebo-controlled trial of 372 randomized subjects with a DSM-IV diagnosis of major depressive disorder and recent history of myocardial infarction or unstable angina requiring hospitalization. Exclusions from this trial included, among others, patients with uncontrolled hypertension, need for cardiac surgery, history of CABG within 3 months of index event, severe or symptomatic bradycardia, non-atherosclerotic cause of angina, clinically significant renal impairment (creatinine > 2.5 mg/dl), and clinically significant hepatic dysfunction. Sertraline hydrochloride treatment initiated during the acute phase of recovery (within 30 days post-MI or post-hospitalization for unstable angina) was indistinguishable from placebo in this study on the following week 16 treatment endpoints: left ventricular ejection fraction, total cardiovascular events (angina, chest pain, edema, palpitations, syncope, postural dizziness, CHF, MI, tachycardia, bradycardia, and changes in BP), and major cardiovascular events involving death or requiring hospitalization (for MI, CHF, stroke, or angina).
- Sertraline hydrochloride is extensively metabolized by the liver. In patients with chronic mild liver impairment, sertraline clearance was reduced, resulting in increased AUC, Cmax and elimination half-life. The effects of sertraline in patients with moderate and severe hepatic impairment have not been studied. The use of sertraline in patients with liver disease must be approached with caution. If sertraline is administered to patients with liver impairment, a lower or less frequent dose should be used.
- Since sertraline hydrochloride is extensively metabolized, excretion of unchanged drug in urine is a minor route of elimination. A clinical study comparing sertraline pharmacokinetics in healthy volunteers to that in patients with renal impairment ranging from mild to severe (requiring dialysis) indicated that the pharmacokinetics and protein binding are unaffected by renal disease. Based on the pharmacokinetic results, there is no need for dosage adjustment in patients with renal impairment.
- Interference with Cognitive and Motor Performance
- In controlled studies, sertraline hydrochloride did not cause sedation and did not interfere with psychomotor performance.
- Hyponatremia
- Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including sertraline hydrochloride. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk. Discontinuation of sertraline hydrochloride should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted.
- Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death.
- Platelet Function
- There have been rare reports of altered platelet function and/or abnormal results from laboratory studies in patients taking sertraline hydrochloride. While there have been reports of abnormal bleeding or purpura in several patients taking sertraline hydrochloride, it is unclear whether sertraline hydrochloride had a causative role.
# Adverse Reactions
## Clinical Trials Experience
- During its premarketing assessment, multiple doses of sertraline hydrochloride were administered to over 4000 adult subjects as of February 18, 2000. The conditions and duration of exposure to sertraline hydrochloride varied greatly, and included (in overlapping categories) clinical pharmacology studies, open and double-blind studies, uncontrolled and controlled studies, inpatient and outpatient studies, fixed-dose and titration studies, and studies for multiple indications, including major depressive disorder, OCD, panic disorder, PTSD, PMDD and social anxiety disorder.
- Untoward events associated with this exposure were recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of untoward events into a smaller number of standardized event categories.
- In the tabulations that follow, a World Health Organization dictionary of terminology has been used to classify reported adverse events. The frequencies presented, therefore, represent the proportion of the over 4000 adult individuals exposed to multiple doses of sertraline hydrochloride who experienced a treatment-emergent adverse event of the type cited on at least one occasion while receiving sertraline hydrochloride. An event was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. It is important to emphasize that events reported during therapy were not necessarily caused by it.
- The prescriber should be aware that the figures in the tables and tabulations cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and non-drug factors to the side effect incidence rate in the population studied.
- Incidence in Placebo-Controlled Trials–Table 2 enumerates the most common treatment-emergent adverse events associated with the use of sertraline hydrochloride (incidence of at least 5% for sertraline hydrochloride and at least twice that for placebo within at least one of the indications) for the treatment of adult patients with major depressive disorder/other*, OCD, panic disorder, PTSD, PMDD and social anxiety disorder in placebo-controlled clinical trials. Most patients in major depressive disorder/other*, OCD, panic disorder, PTSD and social anxiety disorder studies received doses of 50 to 200 mg/day. Patients in the PMDD study with daily dosing throughout the menstrual cycle received doses of 50 to 150 mg/day, and in the PMDD study with dosing during the luteal phase of the menstrual cycle received doses of 50 to 100 mg/day. Table 3 enumerates treatment-emergent adverse events that occurred in 2% or more of adult patients treated with sertraline hydrochloride and with incidence greater than placebo who participated in controlled clinical trials comparing sertraline hydrochloride with placebo in the treatment of major depressive disorder/other*, OCD, panic disorder, PTSD, PMDD and social anxiety disorder. Table 3 provides combined data for the pool of studies that are provided separately by indication in Table 2.
- Associated with Discontinuation in Placebo-Controlled Clinical Trials
- Table 4 lists the adverse events associated with discontinuation of sertraline hydrochloride treatment (incidence at least twice that for placebo and at least 1% for sertraline hydrochloride in clinical trials) in major depressive disorder/other*, OCD, panic disorder, PTSD, PMDD and social anxiety disorder.
- Male and Female Sexual Dysfunction with SSRIs
- Although changes in sexual desire, sexual performance and sexual satisfaction often occur as manifestations of a psychiatric disorder, they may also be a consequence of pharmacologic treatment. In particular, some evidence suggests that selective serotonin reuptake inhibitors (SSRIs) can cause such untoward sexual experiences. Reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance and satisfaction are difficult to obtain, however, in part because patients and physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance cited in product labeling, are likely to underestimate their actual incidence.
- Table 5 below displays the incidence of sexual side effects reported by at least 2% of patients taking sertraline hydrochloride in placebo-controlled trials.
- There are no adequate and well-controlled studies examining sexual dysfunction with sertraline treatment.
- Priapism has been reported with all SSRIs.
- While it is difficult to know the precise risk of sexual dysfunction associated with the use of SSRIs, physicians should routinely inquire about such possible side effects.
- Other Adverse Events in Pediatric Patients–In over 600 pediatric patients treated with sertraline hydrochloride, the overall profile of adverse events was generally similar to that seen in adult studies. However, the following adverse events, from controlled trials, not appearing in Tables 2 and 3, were reported at an incidence of at least 2% and occurred at a rate of at least twice the placebo rate (N=281 patients treated with sertraline hydrochloride): fever, hyperkinesia, urinary incontinence, aggressive reaction, sinusitis, epistaxis and purpura.
- Other Events Observed During the Premarketing Evaluation of Sertraline hydrochloride–Following is a list of treatment-emergent adverse events reported during premarketing assessment of sertraline hydrochloride in clinical trials (over 4000 adult subjects) except those already listed in the previous tables or elsewhere in labeling.
- In the tabulations that follow, a World Health Organization dictionary of terminology has been used to classify reported adverse events. The frequencies presented, therefore, represent the proportion of the over 4000 adult individuals exposed to multiple doses of sertraline hydrochloride who experienced an event of the type cited on at least one occasion while receiving sertraline hydrochloride. All events are included except those already listed in the previous tables or elsewhere in labeling and those reported in terms so general as to be uninformative and those for which a causal relationship to sertraline hydrochloride treatment seemed remote. It is important to emphasize that although the events reported occurred during treatment with sertraline hydrochloride, they were not necessarily caused by it.
- Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring on one or more occasions in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients. Events of major clinical importance are also described in the PRECAUTIONS section.
Frequent: impotence; Infrequent: flushing, increased saliva, cold clammy skin, mydriasis; Rare: pallor, glaucoma, priapism, vasodilation.
Rare: allergic reaction, allergy.
Frequent: palpitations, chest pain; Infrequent: hypertension, tachycardia, postural dizziness, postural hypotension, periorbital edema, peripheral edema, hypotension, peripheral ischemia, syncope, edema, dependent edema; Rare: precordial chest pain, substernal chest pain, aggravated hypertension, myocardial infarction, cerebrovascular disorder.
Frequent: hypertonia, hypoesthesia; Infrequent: twitching, confusion, hyperkinesia, vertigo, ataxia, migraine, abnormal coordination, hyperesthesia, leg cramps, abnormal gait, nystagmus, hypokinesia; Rare: dysphonia, coma, dyskinesia, hypotonia, ptosis, choreoathetosis, hyporeflexia.
Infrequent: pruritus, acne, urticaria, alopecia, dry skin, erythematous rash, photosensitivity reaction, maculopapular rash; Rare: follicular rash, eczema, dermatitis, contact dermatitis, bullous eruption, hypertrichosis, skin discoloration, pustular rash.
Rare: exophthalmos, gynecomastia.
Frequent: appetite increased; Infrequent: dysphagia, tooth caries aggravated, eructation, esophagitis, gastroenteritis; Rare: melena, glossitis, gum hyperplasia, hiccup, stomatitis, tenesmus, colitis, diverticulitis, fecal incontinence, gastritis, rectum hemorrhage, hemorrhagic peptic ulcer, proctitis, ulcerative stomatitis, tongue edema, tongue ulceration.
Frequent: back pain, asthenia, malaise, weight increase; Infrequent: fever, rigors, generalized edema; Rare: face edema, aphthous stomatitis.
Rare: hyperacusis, labyrinthine disorder.
Rare: anemia, anterior chamber eye hemorrhage.
Rare: abnormal hepatic function.
Infrequent: thirst; Rare: hypoglycemia, hypoglycemia reaction.
Frequent: myalgia; Infrequent: arthralgia, dystonia, arthrosis, muscle cramps, muscle weakness.
Frequent: yawning, other male sexual dysfunction, other female sexual dysfunction; Infrequent: depression, amnesia, paroniria, teeth-grinding, emotional lability, apathy, abnormal dreams, euphoria, paranoid reaction, hallucination, aggressive reaction, aggravated depression, delusions; Rare: withdrawal syndrome, suicide ideation, libido increased, somnambulism, illusion.
Infrequent: menstrual disorder, dysmenorrhea, intermenstrual bleeding, vaginal hemorrhage, amenorrhea, leukorrhea; Rare: female breast pain, menorrhagia, balanoposthitis, breast enlargement, atrophic vaginitis, acute female mastitis.
Frequent: rhinitis; Infrequent: coughing, dyspnea, upper respiratory tract infection, epistaxis, bronchospasm, sinusitis; Rare: hyperventilation, bradypnea, stridor, apnea, bronchitis, hemoptysis, hypoventilation, laryngismus, laryngitis.
Frequent: tinnitus; Infrequent: conjunctivitis, earache, eye pain, abnormal accommodation; Rare: xerophthalmia, photophobia, diplopia, abnormal lacrimation, scotoma, visual field defect.
Infrequent: micturition frequency, polyuria, urinary retention, dysuria, nocturia, urinary incontinence; Rare: cystitis, oliguria, pyelonephritis, hematuria, renal pain, strangury.
- In man, asymptomatic elevations in serum transaminases (SGOT [or AST] and SGPT [or ALT]) have been reported infrequently (approximately 0.8%) in association with sertraline hydrochloride administration. These hepatic enzyme elevations usually occurred within the first 1 to 9 weeks of drug treatment and promptly diminished upon drug discontinuation.
- Sertraline hydrochloride therapy was associated with small mean increases in total cholesterol (approximately 3%) and triglycerides (approximately 5%), and a small mean decrease in serum uric acid (approximately 7%) of no apparent clinical importance.
- The safety profile observed with sertraline hydrochloride treatment in patients with major depressive disorder, OCD, panic disorder, PTSD, PMDD and social anxiety disorder is similar.
## Postmarketing Experience
- Reports of adverse events temporally associated with sertraline hydrochloride that have been received since market introduction, that are not listed above and that may have no causal relationship with the drug, include the following: acute renal failure, anaphylactoid reaction, angioedema, blindness, optic neuritis, cataract, increased coagulation times, bradycardia, AV block, atrial arrhythmias, QT-interval prolongation, ventricular tachycardia (including Torsade de Pointes arrhythmias), cerebrovascular spasm (including reversible cerebral vasconstriction syndrome and Call-Fleming syndrome), hypothyroidism, agranulocytosis, aplastic anemia and pancytopenia, leukopenia, thrombocytopenia, lupus-like syndrome, serum sickness, diabetes mellitus, hyperglycemia, galactorrhea, hyperprolactinemia, extrapyramidal symptoms, oculogyric crisis, serotonin syndrome, psychosis, pulmonary hypertension, severe skin reactions, which potentially can be fatal, such as Stevens-Johnson syndrome, vasculitis, photosensitivity and other severe cutaneous disorders, rare reports of pancreatitis, and liver events—clinical features (which in the majority of cases appeared to be reversible with discontinuation of sertraline hydrochloride) occurring in one or more patients include: elevated enzymes, increased bilirubin, hepatomegaly, hepatitis, jaundice, abdominal pain, vomiting, liver failure and death.
# Drug Interactions
- Potential Effects of Coadministration of Drugs Highly Bound to Plasma Proteins
- Because sertraline is tightly bound to plasma protein, the administration of sertraline hydrochloride to a patient taking another drug which is tightly bound to protein (e.g., warfarin, digitoxin) may cause a shift in plasma concentrations potentially resulting in an adverse effect. Conversely, adverse effects may result from displacement of protein bound sertraline hydrochloride by other tightly bound drugs.
- In a study comparing prothrombin time AUC (0-120 hr) following dosing with warfarin (0.75 mg/kg) before and after 21 days of dosing with either sertraline hydrochloride (50-200 mg/day) or placebo, there was a mean increase in prothrombin time of 8% relative to baseline for sertraline hydrochloride compared to a 1% decrease for placebo (p<0.02). The normalization of prothrombin time for the sertraline hydrochloride group was delayed compared to the placebo group. The clinical significance of this change is unknown. Accordingly, prothrombin time should be carefully monitored when sertraline hydrochloride therapy is initiated or stopped.
- Cimetidine
- In a study assessing disposition of sertraline hydrochloride (100 mg) on the second of 8 days of cimetidine administration (800 mg daily), there were significant increases in sertraline hydrochloride mean AUC (50%), Cmax (24%) and half-life (26%) compared to the placebo group. The clinical significance of these changes is unknown.
- CNS Active Drugs
- In a study comparing the disposition of intravenously administered diazepam before and after 21 days of dosing with either sertraline hydrochloride (50 to 200 mg/day escalating dose) or placebo, there was a 32% decrease relative to baseline in diazepam clearance for the sertraline hydrochloride group compared to a 19% decrease relative to baseline for the placebo group (p<0.03). There was a 23% increase in Tmax for desmethyldiazepam in the sertraline hydrochloride group compared to a 20% decrease in the placebo group (p<;<0.03). The clinical significance of these changes is unknown.
- In a placebo-controlled trial in normal volunteers, the administration of two doses of sertraline hydrochloride did not significantly alter steady-state lithium levels or the renal clearance of lithium.
- Nonetheless, at this time, it is recommended that plasma lithium levels be monitored following initiation of sertraline hydrochloride therapy with appropriate adjustments to the lithium dose.
- In a controlled study of a single dose (2 mg) of pimozide, 200 mg sertraline (q.d.) co-administration to steady state was associated with a mean increase in pimozide AUC and Cmax of about 40%, but was not associated with any changes in EKG. Since the highest recommended pimozide dose (10 mg) has not been evaluated in combination with sertraline, the effect on QT interval and PK parameters at doses higher than 2 mg at this time are not known. While the mechanism of this interaction is unknown, due to the narrow therapeutic index of pimozide and due to the interaction noted at a low dose of pimozide, concomitant administration of sertraline hydrochloride and pimozide should be contraindicated.
- Results of a placebo-controlled trial in normal volunteers suggest that chronic administration of sertraline 200 mg/day does not produce clinically important inhibition of phenytoin metabolism. Nonetheless, at this time, it is recommended that plasma phenytoin concentrations be monitored following initiation of sertraline hydrochloride therapy with appropriate adjustments to the phenytoin dose, particularly in patients with multiple underlying medical conditions and/or those receiving multiple concomitant medications.
- The effect of sertraline hydrochloride on valproate levels has not been evaluated in clinical trials. In the absence of such data, it is recommended that plasma valproate levels be monitored following initiation of sertraline hydrochloride therapy with appropriate adjustments to the valproate dose.
- The risk of using sertraline hydrochloride in combination with other CNS active drugs has not been systematically evaluated. Consequently, caution is advised if the concomitant administration of sertraline hydrochloride and such drugs is required.
- There is limited controlled experience regarding the optimal timing of switching from other drugs effective in the treatment of major depressive disorder, obsessive-compulsive disorder, panic disorder, posttraumatic stress disorder, premenstrual dysphoric disorder and social anxiety disorder to sertraline hydrochloride. Care and prudent medical judgment should be exercised when switching, particularly from long-acting agents. The duration of an appropriate washout period which should intervene before switching from one selective serotonin reuptake inhibitor (SSRI) to another has not been established.
- Drugs Metabolized by P450 3A4
- In three separate in vivo interaction studies, sertraline was co-administered with cytochrome P450 3A4 substrates, terfenadine, carbamazepine, or cisapride under steady-state conditions. The results of these studies indicated that sertraline did not increase plasma concentrations of terfenadine, carbamazepine, or cisapride. These data indicate that sertraline's extent of inhibition of P450 3A4 activity is not likely to be of clinical significance. Results of the interaction study with cisapride indicate that sertraline 200 mg (q.d.) induces the metabolism of cisapride (cisapride AUC and Cmax were reduced by about 35%).
- Drugs Metabolized by P450 2D6
- Many drugs effective in the treatment of major depressive disorder, e.g., the SSRIs, including sertraline, and most tricyclic antidepressant drugs effective in the treatment of major depressive disorder inhibit the biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase), and, thus, may increase the plasma concentrations of co-administered drugs that are metabolized by P450 2D6. The drugs for which this potential interaction is of greatest concern are those metabolized primarily by 2D6 and which have a narrow therapeutic index, e.g., the tricyclic antidepressant drugs effective in the treatment of major depressive disorder and the Type 1C antiarrhythmics propafenone and flecainide. The extent to which this interaction is an important clinical problem depends on the extent of the inhibition of P450 2D6 by the antidepressant and the therapeutic index of the co-administered drug. There is variability among the drugs effective in the treatment of major depressive disorder in the extent of clinically important 2D6 inhibition, and in fact sertraline at lower doses has a less prominent inhibitory effect on 2D6 than some others in the class. Nevertheless, even sertraline has the potential for clinically important 2D6 inhibition. Consequently, concomitant use of a drug metabolized by P450 2D6 with sertraline hydrochloride may require lower doses than usually prescribed for the other drug. Furthermore, whenever sertraline hydrochloride is withdrawn from co-therapy, an increased dose of the co-administered drug may be required.
- Triptans
- There have been rare post marketing reports of serotonin syndrome with use of an SNRI or an SSRI and a triptan. If concomitant treatment of SNRIs and SSRIs, including sertraline hydrochloride, with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases.
- Sumatriptan
- There have been rare post marketing reports describing patients with weakness, hyperreflexia, and incoordination following the use of a selective serotonin reuptake inhibitor (SSRI) and sumatriptan. If concomitant treatment with sumatriptan and an SSRI (e.g., citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) is clinically warranted, appropriate observation of the patient is advised.
- Tricyclic Antidepressant Drugs Effective in the Treatment of Major Depressive Disorder (TCAs)
- The extent to which SSRI–TCA interactions may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is indicated in the co-administration of TCAs with sertraline hydrochloride, because sertraline may inhibit TCA metabolism. Plasma TCA concentrations may need to be monitored, and the dose of TCA may need to be reduced, if a TCA is co-administered with sertraline hydrochloride.
- Hypoglycemic Drugs
- In a placebo-controlled trial in normal volunteers, administration of sertraline hydrochloride for 22 days (including 200 mg/day for the final 13 days) caused a statistically significant 16% decrease from baseline in the clearance of tolbutamide following an intravenous 1000 mg dose. Sertraline hydrochloride administration did not noticeably change either the plasma protein binding or the apparent volume of distribution of tolbutamide, suggesting that the decreased clearance was due to a change in the metabolism of the drug. The clinical significance of this decrease in tolbutamide clearance is unknown.
- Atenolol
- Sertraline hydrochloride (100 mg) when administered to 10 healthy male subjects had no effect on the beta-adrenergic blocking ability of atenolol.
- Digoxin
- In a placebo-controlled trial in normal volunteers, administration of sertraline hydrochloride for 17 days (including 200 mg/day for the last 10 days) did not change serum digoxin levels or digoxin renal clearance.
- Microsomal Enzyme Induction
- Preclinical studies have shown sertraline hydrochloride to induce hepatic microsomal enzymes. In clinical studies, sertraline hydrochloride was shown to induce hepatic enzymes minimally as determined by a small (5%) but statistically significant decrease in antipyrine half-life following administration of 200 mg/day for 21 days. This small change in antipyrine half-life reflects a clinically insignificant change in hepatic metabolism.
- Drugs That Interfere With Hemostasis (Non-selective NSAIDs, Aspirin, Warfarin, etc.)-Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs or SNRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when sertraline hydrochloride is initiated or discontinued.
- Electroconvulsive Therapy
- There are no clinical studies establishing the risks or benefits of the combined use of electroconvulsive therapy (ECT) and sertraline hydrochloride.
- Alcohol
- Although sertraline hydrochloride did not potentiate the cognitive and psychomotor effects of alcohol in experiments with normal subjects, the concomitant use of sertraline hydrochloride and alcohol is not recommended.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- Reproduction studies have been performed in rats and rabbits at doses up to 80 mg/kg/day and 40 mg/kg/day, respectively. These doses correspond to approximately 4 times the maximum recommended human dose (MRHD) on a mg/m2 basis. There was no evidence of teratogenicity at any dose level. When pregnant rats and rabbits were given sertraline during the period of organogenesis, delayed ossification was observed in fetuses at doses of 10 mg/kg (0.5 times the MRHD on a mg/m2 basis) in rats and 40 mg/kg (4 times the MRHD on a mg/m2 basis) in rabbits. When female rats received sertraline during the last third of gestation and throughout lactation, there was an increase in the number of stillborn pups and in the number of pups dying during the first 4 days after birth. Pup body weights were also decreased during the first four days after birth. These effects occurred at a dose of 20 mg/kg (1 times the MRHD on a mg/m2 basis). The no effect dose for rat pup mortality was 10 mg/kg (0.5 times the MRHD on a mg/m2 basis). The decrease in pup survival was shown to be due to in utero exposure to sertraline. The clinical significance of these effects is unknown. There are no adequate and well-controlled studies in pregnant women. Sertraline hydrochloride should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Pregnancy-Nonteratogenic Effects
- Neonates exposed to sertraline hydrochloride and other SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs), late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome.
- Infants exposed to SSRIs in pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1 – 2 per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. Several recent epidemiologic studies suggest a positive statistical association between SSRI use (including sertraline hydrochloride) in pregnancy and PPHN. Other studies do not show a significant statistical association.
- Physicians should also note the results of a prospective longitudinal study of 201 pregnant women with a history of major depression, who were either on antidepressants or had received antidepressants less than 12 weeks prior to their last menstrual period, and were in remission. Women who discontinued antidepressant medication during pregnancy showed a significant increase in relapse of their major depression compared to those women who remained on antidepressant medication throughout pregnancy.
- When treating a pregnant woman with sertraline hydrochloride, the physician should carefully consider both the potential risks of taking an SSRI, along with the established benefits of treating depression with an antidepressant. This decision can only be made on a case by case basis.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Sertraline in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Sertraline during labor and delivery.
### Nursing Mothers
- It is not known whether, and if so in what amount, sertraline or its metabolites are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when sertraline hydrochloride is administered to a nursing woman.
### Pediatric Use
- The efficacy of sertraline hydrochloride for the treatment of obsessive-compulsive disorder was demonstrated in a 12-week, multicenter, placebo-controlled study with 187 outpatients ages 6-17. Safety and effectiveness in the pediatric population other than pediatric patients with OCD have not been established. Two placebo controlled trials (n=373) in pediatric patients with MDD have been conducted with sertraline hydrochloride, and the data were not sufficient to support a claim for use in pediatric patients. Anyone considering the use of sertraline hydrochloride in a child or adolescent must balance the potential risks with the clinical need.
- The safety of sertraline hydrochloride use in children and adolescents with OCD, ages 6-18, was evaluated in a 12-week, multicenter, placebo-controlled study with 187 outpatients, ages 6-17, and in a flexible dose, 52 week open extension study of 137 patients, ages 6-18, who had completed the initial 12-week, double-blind, placebo- controlled study. Sertraline hydrochloride was administered at doses of either 25 mg/day (children, ages 6-12) or 50 mg/day (adolescents, ages 13-18) and then titrated in weekly 25 mg/day or 50 mg/day increments, respectively, to a maximum dose of 200 mg/day based upon clinical response. The mean dose for completers was 157 mg/day. In the acute 12 week pediatric study and in the 52 week study, sertraline hydrochloride had an adverse event profile generally similar to that observed in adults.
- Sertraline pharmacokinetics were evaluated in 61 pediatric patients between 6 and 17 years of age with major depressive disorder or OCD and revealed similar drug exposures to those of adults when plasma concentration was adjusted for weight.
- Approximately 600 patients with major depressive disorder or OCD between 6 and 17 years of age have received sertraline hydrochloride in clinical trials, both controlled and uncontrolled. The adverse event profile observed in these patients was generally similar to that observed in adult studies with sertraline hydrochloride. As with other SSRIs, decreased appetite and weight loss have been observed in association with the use of sertraline hydrochloride. In a pooled analysis of two 10-week, double-blind, placebo-controlled, flexible dose (50-200 mg) outpatient trials for major depressive disorder (n=373), there was a difference in weight change between sertraline and placebo of roughly 1 kilogram, for both children (ages 6-11) and adolescents (ages 12-17), in both cases representing a slight weight loss for sertraline compared to a slight gain for placebo. At baseline the mean weight for children was 39.0 kg for sertraline and 38.5 kg for placebo. At baseline the mean weight for adolescents was 61.4 kg for sertraline and 62.5 kg for placebo. There was a bigger difference between sertraline and placebo in the proportion of outliers for clinically important weight loss in children than in adolescents. For children, about 7% had a weight loss > 7% of body weight compared to none of the placebo patients; for adolescents, about 2% had a weight loss > 7% of body weight compared to about 1% of the placebo patients. A subset of these patients who completed the randomized controlled trials (sertraline n=99, placebo n=122) were continued into a 24-week, flexible-dose, open-label, extension study. A mean weight loss of approximately 0.5 kg was seen during the first eight weeks of treatment for subjects with first exposure to sertraline during the open-label extension study, similar to mean weight loss observed among sertraline treated subjects during the first eight weeks of the randomized controlled trials. The subjects continuing in the open label study began gaining weight compared to baseline by week 12 of sertraline treatment. Those subjects who completed 34 weeks of sertraline treatment (10 weeks in a placebo controlled trial + 24 weeks open label, n=68) had weight gain that was similar to that expected using data from age-adjusted peers. Regular monitoring of weight and growth is recommended if treatment of a pediatric patient with an SSRI is to be continued long term. Safety and effectiveness in pediatric patients below the age of 6 have not been established.
- The risks, if any, that may be associated with sertraline hydrochloride's use beyond 1 year in children and adolescents with OCD or major depressive disorder have not been systematically assessed. The prescriber should be mindful that the evidence relied upon to conclude that sertraline is safe for use in children and adolescents derives from clinical studies that were 10 to 52 weeks in duration and from the extrapolation of experience gained with adult patients. In particular, there are no studies that directly evaluate the effects of long-term sertraline use on the growth, development, and maturation of children and adolescents. Although there is no affirmative finding to suggest that sertraline possesses a capacity to adversely affect growth, development or maturation, the absence of such findings is not compelling evidence of the absence of the potential of sertraline to have adverse effects in chronic use
### Geriatic Use
- U.S. geriatric clinical studies of sertraline hydrochloride in major depressive disorder included 663 sertraline hydrochloride-treated subjects ≥ 65 years of age, of those, 180 were ≥ 75 years of age. No overall differences in the pattern of adverse reactions were observed in the geriatric clinical trial subjects relative to those reported in younger subjects, and other reported experience has not identified differences in safety patterns between the elderly and younger subjects. As with all medications, greater sensitivity of some older individuals cannot be ruled out. There were 947 subjects in placebo-controlled geriatric clinical studies of sertraline hydrochloride in major depressive disorder. No overall differences in the pattern of efficacy were observed in the geriatric clinical trial subjects relative to those reported in younger subjects.
- Other Adverse Events in Geriatric Patients. In 354 geriatric subjects treated with sertraline hydrochloride in placebo-controlled trials, the overall profile of adverse events was generally similar to that shown in Tables 2 and 3. Urinary tract infection was the only adverse event not appearing in Tables 2 and 3 and reported at an incidence of at least 2% and at a rate greater than placebo in placebo-controlled trials.
- SSRIs and SNRIs, including sertraline hydrochloride, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event.
### Gender
There is no FDA guidance on the use of Sertraline with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Sertraline with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Sertraline in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Sertraline in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Sertraline in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Sertraline in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Sertraline in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Sertraline in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Of 1,027 cases of overdose involving sertraline hydrochloride worldwide, alone or with other drugs, there were 72 deaths (circa 1999).
- Among 634 overdoses in which sertraline hydrochloride was the only drug ingested, 8 resulted in fatal outcome, 75 completely recovered, and 27 patients experienced sequelae after overdosage to include alopecia, decreased libido, diarrhea, ejaculation disorder, fatigue, insomnia, somnolence and serotonin syndrome. The remaining 524 cases had an unknown outcome. The most common signs and symptoms associated with non-fatal sertraline hydrochloride overdosage were somnolence, vomiting, tachycardia, nausea, dizziness, agitation and tremor.
- The largest known ingestion was 13.5 grams in a patient who took sertraline hydrochloride alone and subsequently recovered. However, another patient who took 2.5 grams of sertraline hydrochloride alone experienced a fatal outcome.
- Other important adverse events reported with sertraline hydrochloride overdose (single or multiple drugs) include bradycardia, bundle branch block, coma, convulsions, delirium, hallucinations, hypertension, hypotension, manic reaction, pancreatitis, QT-interval prolongation, serotonin syndrome, stupor, syncope and Torsade de Pointes.
### Management
- Treatment should consist of those general measures employed in the management of overdosage with any antidepressant.
- Ensure an adequate airway, oxygenation and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion, or in symptomatic patients.
- Activated charcoal should be administered. Due to large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion and exchange transfusion are unlikely to be of benefit. No specific antidotes for sertraline are known.
- In managing overdosage, consider the possibility of multiple drug involvement. The physician should consider contacting a poison control center on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physicians' Desk Reference (PDR ).
## Chronic Overdose
There is limited information regarding Chronic Overdose of Sertraline in the drug label.
# Pharmacology
## Mechanism of Action
- The mechanism of action of sertraline is presumed to be linked to its inhibition of CNS neuronal uptake of serotonin (5HT). Studies at clinically relevant doses in man have demonstrated that sertraline blocks the uptake of serotonin into human platelets.
## Structure
- Sertraline hydrochloride is a selective serotonin reuptake inhibitor (SSRI) for oral administration. It has a molecular weight of 342.7. Sertraline hydrochloride has the following chemical name: (1S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine hydrochloride. The empirical formula C17H17NCl2•HCl is represented by the following structural formula:
- Sertraline hydrochloride is a white crystalline powder that is slightly soluble in water and isopropyl alcohol, and sparingly soluble in ethanol.
- Sertraline hydrochloride tablets, USP are supplied for oral administration as tablets containing sertraline hydrochloride equivalent to 25, 50 and 100 mg of sertraline and the following inactive ingredients: corn starch, D&C yellow no. 10 aluminum lake (in 25 mg), FD&C blue no. 2 aluminum lake (in 25 mg and 50 mg), FD&C yellow no. 6 aluminum lake (in 25 mg), hypromellose, iron oxide yellow (in 100 mg), magnesium stearate, microcrystalline cellulose, polyethylene glycol, sodium starch glycolate and titanium dioxide.
## Pharmacodynamics
- The mechanism of action of sertraline is presumed to be linked to its inhibition of CNS neuronal uptake of serotonin (5HT). Studies at clinically relevant doses in man have demonstrated that sertraline blocks the uptake of serotonin into human platelets. In vitro studies in animals also suggest that sertraline is a potent and selective inhibitor of neuronal serotonin reuptake and has only very weak effects on norepinephrine and dopamine neuronal reuptake. In vitro studies have shown that sertraline has no significant affinity for adrenergic (alpha1, alpha2, beta), cholinergic, GABA, dopaminergic, histaminergic, serotonergic (5HT1A, 5HT1B, 5HT2), or benzodiazepine receptors; antagonism of such receptors has been hypothesized to be associated with various anticholinergic, sedative, and cardiovascular effects for other psychotropic drugs. The chronic administration of sertraline was found in animals to down regulate brain norepinephrine receptors, as has been observed with other drugs effective in the treatment of major depressive disorder. Sertraline does not inhibit monoamine oxidase.
## Pharmacokinetics
- Systemic Bioavailability
- In man, following oral once-daily dosing over the range of 50 to 200 mg for 14 days, mean peak plasma concentrations (Cmax) of sertraline occurred between 4.5 to 8.4 hours post-dosing. The average terminal elimination half-life of plasma sertraline is about 26 hours. Based on this pharmacokinetic parameter, steady-state sertraline plasma levels should be achieved after approximately one week of once-daily dosing. Linear dose-proportional pharmacokinetics were demonstrated in a single dose study in which the Cmax and area under the plasma concentration time curve (AUC) of sertraline were proportional to dose over a range of 50 to 200 mg. Consistent with the terminal elimination half-life, there is an approximately two-fold accumulation, compared to a single dose, of sertraline with repeated dosing over a 50 to 200 mg dose range. The single dose bioavailability of sertraline tablets is approximately equal to an equivalent dose of solution.
- In a relative bioavailability study comparing the pharmacokinetics of 100 mg sertraline as the oral solution to a 100 mg sertraline tablet in 16 healthy adults, the solution to tablet ratio of geometric mean AUC and Cmax values were 114.8% and 120.6%, respectively. 90% confidence intervals (CI) were within the range of 80-125% with the exception of the upper 90% CI limit for Cmax which was 126.5%.
- The effects of food on the bioavailability of the sertraline tablet and oral concentrate were studied in subjects administered a single dose with and without food. For the tablet, AUC was slightly increased when drug was administered with food but the Cmax was 25% greater, while the time to reach peak plasma concentration (Tmax) decreased from 8 hours post-dosing to 5.5 hours. For the oral concentrate, Tmax was slightly prolonged from 5.9 hours to 7.0 hours with food.
- Metabolism
- Sertraline undergoes extensive first pass metabolism. The principal initial pathway of metabolism for sertraline is N-demethylation. N-desmethylsertraline has a plasma terminal elimination half-life of 62 to 104 hours. Both in vitro biochemical and in vivo pharmacological testing have shown N-desmethylsertraline to be substantially less active than sertraline. Both sertraline and N-desmethylsertraline undergo oxidative deamination and subsequent reduction, hydroxylation, and glucuronide conjugation. In a study of radiolabeled sertraline involving two healthy male subjects, sertraline accounted for less than 5% of the plasma radioactivity. About 40-45% of the administered radioactivity was recovered in urine in 9 days. Unchanged sertraline was not detectable in the urine. For the same period, about 40-45% of the administered radioactivity was accounted for in feces, including 12-14% unchanged sertraline.
- Desmethylsertraline exhibits time-related, dose dependent increases in AUC (0-24 hour), Cmax and Cmin, with about a 5-9 fold increase in these pharmacokinetic parameters between day 1 and day 14.
- Protein Binding
- In vitro protein binding studies performed with radiolabeled 3H-sertraline showed that sertraline is highly bound to serum proteins (98%) in the range of 20 to 500 ng/mL. However, at up to 300 and 200 ng/mL concentrations, respectively, sertraline and N-desmethylsertraline did not alter the plasma protein binding of two other highly protein bound drugs, viz., warfarin and propranolol.
- Pediatric Pharmacokinetics
- Sertraline pharmacokinetics were evaluated in a group of 61 pediatric patients (29 aged 6-12 years, 32 aged 13-17 years) with a DSM-III-R diagnosis of major depressive disorder or obsessive-compulsive disorder. Patients included both males (N=28) and females (N=33). During 42 days of chronic sertraline dosing, sertraline was titrated up to 200 mg/day and maintained at that dose for a minimum of 11 days. On the final day of sertraline 200 mg/day, the 6-12 year old group exhibited a mean sertraline AUC (0-24 hr) of 3107 ng-hr/mL, mean Cmax of 165 ng/mL, and mean half-life of 26.2 hr. The 13-17 year old group exhibited a mean sertraline AUC (0-24 hr) of 2296 ng-hr/mL, mean Cmax of 123 ng/mL, and mean half-life of 27.8 hr. Higher plasma levels in the 6-12 year old group were largely attributable to patients with lower body weights. No gender associated differences were observed. By comparison, a group of 22 separately studied adults between 18 and 45 years of age (11 male, 11 female) received 30 days of 200 mg/day sertraline and exhibited a mean sertraline AUC (0-24 hr) of 2570 ng-hr/mL, mean Cmax of 142 ng/mL, and mean half-life of 27.2 hr. Relative to the adults, both the 6-12 year olds and the 13-17 year olds showed about 22% lower AUC (0-24 hr) and Cmax values when plasma concentration was adjusted for weight. These data suggest that pediatric patients metabolize sertraline with slightly greater efficiency than adults. Nevertheless, lower doses may be advisable for pediatric patients given their lower body weights, especially in very young patients, in order to avoid excessive plasma levels.
- Age
- Sertraline plasma clearance in a group of 16 (8 male, 8 female) elderly patients treated for 14 days at a dose of 100 mg/day was approximately 40% lower than in a similarly studied group of younger (25 to 32 y.o.) individuals. Steady-state, therefore, should be achieved after 2 to 3 weeks in older patients. The same study showed a decreased clearance of desmethylsertraline in older males, but not in older females.
- Liver Disease
- As might be predicted from its primary site of metabolism, liver impairment can affect the elimination of sertraline. In patients with chronic mild liver impairment (N=10, 8 patients with Child-Pugh scores of 5-6 and 2 patients with Child-Pugh scores of 7-8) who received 50 mg sertraline per day maintained for 21 days, sertraline clearance was reduced, resulting in approximately 3-fold greater exposure compared to age-matched volunteers with no hepatic impairment (N=10). The exposure to desmethylsertraline was approximately 2-fold greater compared to age-matched volunteers with no hepatic impairment. There were no significant differences in plasma protein binding observed between the two groups. The effects of sertraline in patients with moderate and severe hepatic impairment have not been studied. The results suggest that the use of sertraline in patients with liver disease must be approached with caution. If sertraline is administered to patients with liver impairment, a lower or less frequent dose should be used.
- Renal Disease
- Sertraline is extensively metabolized and excretion of unchanged drug in urine is a minor route of elimination. In volunteers with mild to moderate (CLcr=30-60 mL/min), moderate to severe (CLcr=10-29 mL/min) or severe (receiving hemodialysis) renal impairment (N=10 each group), the pharmacokinetics and protein binding of 200 mg sertraline per day maintained for 21 days were not altered compared to age-matched volunteers (N=12) with no renal impairment. Thus sertraline multiple dose pharmacokinetics appear to be unaffected by renal impairment.
## Nonclinical Toxicology
- Carcinogenesis
- Lifetime carcinogenicity studies were carried out in CD-1 mice and Long-Evans rats at doses up to 40 mg/kg/day. These doses correspond to 1 times (mice) and 2 times (rats) the maximum recommended human dose (MRHD) on a mg/m2 basis. There was a dose-related increase of liver adenomas in male mice receiving sertraline at 10-40 mg/kg (0.25-1.0 times the MRHD on a mg/m2 basis). No increase was seen in female mice or in rats of either sex receiving the same treatments, nor was there an increase in hepatocellular carcinomas. Liver adenomas have a variable rate of spontaneous occurrence in the CD-1 mouse and are of unknown significance to humans. There was an increase in follicular adenomas of the thyroid in female rats receiving sertraline at 40 mg/kg (2 times the MRHD on a mg/m2 basis); this was not accompanied by thyroid hyperplasia. While there was an increase in uterine adenocarcinomas in rats receiving sertraline at 10-40 mg/kg (0.5-2.0 times the MRHD on a mg/m2 basis) compared to placebo controls, this effect was not clearly drug related.
- Mutagenesis
- Sertraline had no genotoxic effects, with or without metabolic activation, based on the following assays: bacterial mutation assay; mouse lymphoma mutation assay; and tests for cytogenetic aberrations in vivo in mouse bone marrow and in vitro in human lymphocytes.
- Impairment of Fertility
- A decrease in fertility was seen in one of two rat studies at a dose of 80 mg/kg (4 times the maximum recommended human dose on a mg/m2 basis).
# Clinical Studies
- The efficacy of sertraline hydrochloride as a treatment for major depressive disorder was established in two placebo-controlled studies in adult outpatients meeting DSM-III criteria for major depressive disorder. Study 1 was an 8-week study with flexible dosing of sertraline hydrochloride in a range of 50 to 200 mg/day; the mean dose for completers was 145 mg/day. Study 2 was a 6-week fixed-dose study, including sertraline hydrochloride doses of 50, 100, and 200 mg/day. Overall, these studies demonstrated sertraline hydrochloride to be superior to placebo on the Hamilton Depression Rating Scale and the Clinical Global Impression Severity and Improvement scales. Study 2 was not readily interpretable regarding a dose response relationship for effectiveness.
- Study 3 involved depressed outpatients who had responded by the end of an initial 8-week open treatment phase on sertraline hydrochloride 50-200 mg/day. These patients (N=295) were randomized to continuation for 44 weeks on double-blind sertraline hydrochloride 50-200 mg/day or placebo. A statistically significantly lower relapse rate was observed for patients taking sertraline hydrochloride compared to those on placebo. The mean dose for completers was 70 mg/day.
- Analyses for gender effects on outcome did not suggest any differential responsiveness on the basis of sex.
- The effectiveness of sertraline hydrochloride in the treatment of OCD was demonstrated in three multicenter placebo-controlled studies of adult outpatients (Studies 1-3). Patients in all studies had moderate to severe OCD (DSM-III or DSM-III-R) with mean baseline ratings on the Yale–Brown Obsessive-Compulsive Scale (YBOCS) total score ranging from 23 to 25.
- Study 1 was an 8-week study with flexible dosing of sertraline hydrochloride in a range of 50 to 200 mg/day; the mean dose for completers was 186 mg/day. Patients receiving sertraline hydrochloride experienced a mean reduction of approximately 4 points on the YBOCS total score which was significantly greater than the mean reduction of 2 points in placebo-treated patients.
- Study 2 was a 12-week fixed-dose study, including sertraline hydrochloride doses of 50, 100, and 200 mg/day. Patients receiving sertraline hydrochloride doses of 50 and 200 mg/day experienced mean reductions of approximately 6 points on the YBOCS total score which were significantly greater than the approximately 3 point reduction in placebo-treated patients.
- Study 3 was a 12-week study with flexible dosing of sertraline hydrochloride in a range of 50 to 200 mg/day; the mean dose for completers was 185 mg/day. Patients receiving sertraline hydrochloride experienced a mean reduction of approximately 7 points on the YBOCS total score which was significantly greater than the mean reduction of approximately 4 points in placebo-treated patients.
- Analyses for age and gender effects on outcome did not suggest any differential responsiveness on the basis of age or sex.
- The effectiveness of sertraline hydrochloride for the treatment of OCD was also demonstrated in a 12-week, multicenter, placebo-controlled, parallel group study in a pediatric outpatient population (children and adolescents, ages 6-17). Patients receiving sertraline hydrochloride in this study were initiated at doses of either 25 mg/day (children, ages 6-12) or 50 mg/day (adolescents, ages 13-17), and then titrated over the next four weeks to a maximum dose of 200 mg/day, as tolerated. The mean dose for completers was 178 mg/day. Dosing was once a day in the morning or evening. Patients in this study had moderate to severe OCD (DSM-III-R) with mean baseline ratings on the Children's Yale-Brown Obsessive-Compulsive Scale (CYBOCS) total score of 22. Patients receiving sertraline experienced a mean reduction of approximately 7 units on the CYBOCS total score which was significantly greater than the 3 unit reduction for placebo patients. Analyses for age and gender effects on outcome did not suggest any differential responsiveness on the basis of age or sex.
- In a longer-term study, patients meeting DSM-III-R criteria for OCD who had responded during a 52-week single-blind trial on sertraline hydrochloride 50-200 mg/day (n=224) were randomized to continuation of sertraline hydrochloride or to substitution of placebo for up to 28 weeks of observation for discontinuation due to relapse or insufficient clinical response. Response during the single-blind phase was defined as a decrease in the YBOCS score of ≥ 25% compared to baseline and a CGII of 1 (very much improved), 2 (much improved) or 3 (minimally improved). Relapse during the double-blind phase was defined as the following conditions being met (on three consecutive visits for 1 and 2, and for visit 3 for condition 3): (1) YBOCS score increased by ≥ 5 points, to a minimum of 20, relative to baseline; (2) CGI-I increased by ≥ one point; and (3) worsening of the patient's condition in the investigator's judgment, to justify alternative treatment. Insufficient clinical response indicated a worsening of the patient's condition that resulted in study discontinuation, as assessed by the investigator. Patients receiving continued sertraline hydrochloride treatment experienced a significantly lower rate of discontinuation due to relapse or insufficient clinical response over the subsequent 28 weeks compared to those receiving placebo. This pattern was demonstrated in male and female subjects.
- The effectiveness of sertraline hydrochloride in the treatment of panic disorder was demonstrated in three double-blind, placebo-controlled studies (Studies 1-3) of adult outpatients who had a primary diagnosis of panic disorder (DSM-III-R), with or without agoraphobia.
- Studies 1 and 2 were 10-week flexible dose studies. Sertraline hydrochloride was initiated at 25 mg/day for the first week, and then patients were dosed in a range of 50-200 mg/day on the basis of clinical response and toleration. The mean sertraline hydrochloride doses for completers to 10 weeks were 131 mg/day and 144 mg/day, respectively, for Studies 1 and 2. In these studies, sertraline hydrochloride was shown to be significantly more effective than placebo on change from baseline in panic attack frequency and on the Clinical Global Impression Severity of Illness and Global Improvement scores. The difference between sertraline hydrochloride and placebo in reduction from baseline in the number of full panic attacks was approximately 2 panic attacks per week in both studies.
- Study 3 was a 12-week fixed-dose study, including sertraline hydrochloride doses of 50, 100, and 200 mg/day. Patients receiving sertraline hydrochloride experienced a significantly greater reduction in panic attack frequency than patients receiving placebo. Study 3 was not readily interpretable regarding a dose response relationship for effectiveness.
- Subgroup analyses did not indicate that there were any differences in treatment outcomes as a function of age, race, or gender.
- In a longer-term study, patients meeting DSM-III-R criteria for Panic Disorder who had responded during a 52-week open trial on sertraline hydrochloride 50-200 mg/day (n=183) were randomized to continuation of sertraline hydrochloride or to substitution of placebo for up to 28 weeks of observation for discontinuation due to relapse or insufficient clinical response. Response during the open phase was defined as a CGI-I score of 1(very much improved) or 2 (much improved). Relapse during the double-blind phase was defined as the following conditions being met on three consecutive visits: (1) CGI-I ≥ 3; (2) meets DSM-III-R criteria for Panic Disorder; (3) number of panic attacks greater than at baseline. Insufficient clinical response indicated a worsening of the patient's condition that resulted in study discontinuation, as assessed by the investigator. Patients receiving continued sertraline hydrochloride treatment experienced a significantly lower rate of discontinuation due to relapse or insufficient clinical response over the subsequent 28 weeks compared to those receiving placebo. This pattern was demonstrated in male and female subjects.
- The effectiveness of sertraline hydrochloride in the treatment of PTSD was established in two multicenter placebo-controlled studies (Studies 1-2) of adult outpatients who met DSM-III-R criteria for PTSD. The mean duration of PTSD for these patients was 12 years (Studies 1 and 2 combined) and 44% of patients (169 of the 385 patients treated) had secondary depressive disorder.
- Studies 1 and 2 were 12-week flexible dose studies. Sertraline hydrochloride was initiated at 25 mg/day for the first week, and patients were then dosed in the range of 50-200 mg/day on the basis of clinical response and toleration. The mean sertraline hydrochloride dose for completers was 146 mg/day and 151 mg/day, respectively for Studies 1 and 2. Study outcome was assessed by the Clinician-Administered PTSD Scale Part 2 (CAPS) which is a multi-item instrument that measures the three PTSD diagnostic symptom clusters of reexperiencing/intrusion, avoidance/numbing, and hyperarousal as well as the patient-rated Impact of Event Scale (IES) which measures intrusion and avoidance symptoms. Sertraline hydrochloride was shown to be significantly more effective than placebo on change from baseline to endpoint on the CAPS, IES and on the Clinical Global Impressions (CGI) Severity of Illness and Global Improvement scores. In two additional placebo-controlled PTSD trials, the difference in response to treatment between patients receiving sertraline hydrochloride and patients receiving placebo was not statistically significant. One of these additional studies was conducted in patients similar to those recruited for Studies 1 and 2, while the second additional study was conducted in predominantly male veterans.
- As PTSD is a more common disorder in women than men, the majority (76%) of patients in these trials were women (152 and 139 women on sertraline and placebo versus 39 and 55 men on sertraline and placebo; Studies 1 and 2 combined). Post hoc exploratory analyses revealed a significant difference between sertraline hydrochloride and placebo on the CAPS, IES and CGI in women, regardless of baseline diagnosis of comorbid major depressive disorder, but essentially no effect in the relatively smaller number of men in these studies. The clinical significance of this apparent gender interaction is unknown at this time. There was insufficient information to determine the effect of race or age on outcome.
- In a longer-term study, patients meeting DSM-III-R criteria for PTSD who had responded during a 24-week open trial on sertraline hydrochloride 50-200 mg/day (n=96) were randomized to continuation of sertraline hydrochloride or to substitution of placebo for up to 28 weeks of observation for relapse. Response during the open phase was defined as a CGI-I of 1 (very much improved) or 2 (much improved), and a decrease in the CAPS-2 score of > 30% compared to baseline. Relapse during the double-blind phase was defined as the following conditions being met on two consecutive visits: (1) CGI-I ≥ 3; (2) CAPS-2 score increased by ≥ 30% and by ≥ 15 points relative to baseline; and (3) worsening of the patient's condition in the investigator's judgment. Patients receiving continued sertraline hydrochloride treatment experienced significantly lower relapse rates over the subsequent 28 weeks compared to those receiving placebo. This pattern was demonstrated in male and female subjects.
- The effectiveness of sertraline hydrochloride for the treatment of PMDD was established in two double-blind, parallel group, placebo-controlled flexible dose trials (Studies 1 and 2) conducted over 3 menstrual cycles. Patients in Study 1 met DSM-III-R criteria for Late Luteal Phase Dysphoric Disorder (LLPDD), the clinical entity now referred to as Premenstrual Dysphoric Disorder (PMDD) in DSM-IV. Patients in Study 2 met DSM-IV criteria for PMDD. Study 1 utilized daily dosing throughout the study, while Study 2 utilized luteal phase dosing for the 2 weeks prior to the onset of menses. The mean duration of PMDD symptoms for these patients was approximately 10.5 years in both studies. Patients on oral contraceptives were excluded from these trials; therefore, the efficacy of sertraline in combination with oral contraceptives for the treatment of PMDD is unknown.
- Efficacy was assessed with the Daily Record of Severity of Problems (DRSP), a patient-rated instrument that mirrors the diagnostic criteria for PMDD as identified in the DSM-IV, and includes assessments for mood, physical symptoms, and other symptoms. Other efficacy assessments included the Hamilton Depression Rating Scale (HAMD-17), and the Clinical Global Impression Severity of Illness (CGI-S) and Improvement (CGI-I) scores.
- In Study 1, involving n=251 randomized patients; sertraline hydrochloride treatment was initiated at 50 mg/day and administered daily throughout the menstrual cycle. In subsequent cycles, patients were dosed in the range of 50-150 mg/day on the basis of clinical response and toleration. The mean dose for completers was 102 mg/day. Sertraline hydrochloride administered daily throughout the menstrual cycle was significantly more effective than placebo on change from baseline to endpoint on the DRSP total score, the HAMD-17 total score, and the CGI-S score, as well as the CGI-I score at endpoint.
- In Study 2, involving n=281 randomized patients, sertraline hydrochloride treatment was initiated at 50 mg/day in the late luteal phase (last 2 weeks) of each menstrual cycle and then discontinued at the onset of menses. In subsequent cycles, patients were dosed in the range of 50-100 mg/day in the luteal phase of each cycle, on the basis of clinical response and toleration. Patients who were titrated to 100 mg/day received 50 mg/day for the first 3 days of the cycle, then 100 mg/day for the remainder of the cycle. The mean sertraline hydrochloride dose for completers was 74 mg/day. Sertraline hydrochloride administered in the late luteal phase of the menstrual cycle was significantly more effective than placebo on change from baseline to endpoint on the DRSP total score and the CGI-S score, as well as the CGI-I score at endpoint.
- There was insufficient information to determine the effect of race or age on outcome in these studies.
- The effectiveness of sertraline hydrochloride in the treatment of social anxiety disorder (also known as social phobia) was established in two multicenter placebo-controlled studies (Study 1 and 2) of adult outpatients who met DSM-IV criteria for social anxiety disorder.
- Study 1 was a 12-week, multicenter, flexible dose study comparing sertraline hydrochloride (50-200 mg/day) to placebo, in which sertraline hydrochloride was initiated at 25 mg/day for the first week. Study outcome was assessed by (a) the Liebowitz Social Anxiety Scale (LSAS), a 24-item clinician administered instrument that measures fear, anxiety and avoidance of social and performance situations, and by (b) the proportion of responders as defined by the Clinical Global Impression of Improvement (CGI-I) criterion of CGI-I ≤ 2 (very much or much improved). Sertraline hydrochloride was statistically significantly more effective than placebo as measured by the LSAS and the percentage of responders.
- Study 2 was a 20-week, multicenter, flexible dose study that compared sertraline hydrochloride (50-200 mg/day) to placebo. Study outcome was assessed by the (a) Duke Brief Social Phobia Scale (BSPS), a multi-item clinician-rated instrument that measures fear, avoidance and physiologic response to social or performance situations, (b) the Marks Fear Questionnaire Social Phobia Subscale (FQ-SPS), a 5-item patient-rated instrument that measures change in the severity of phobic avoidance and distress, and (c) the CGI-I responder criterion of ≤ 2. Sertraline hydrochloride was shown to be statistically significantly more effective than placebo as measured by the BSPS total score and fear, avoidance and physiologic factor scores, as well as the FQ-SPS total score, and to have significantly more responders than placebo as defined by the CGI-I.
- Subgroup analyses did not suggest differences in treatment outcome on the basis of gender. There was insufficient information to determine the effect of race or age on outcome.
- In a longer-term study, patients meeting DSM-IV criteria for social anxiety disorder who had responded while assigned to sertraline hydrochloride (CGI-I of 1 or 2) during a 20-week placebo-controlled trial on sertraline hydrochloride 50-200 mg/day were randomized to continuation of sertraline hydrochloride or to substitution of placebo for up to 24 weeks of observation for relapse. Relapse was defined as ≥ 2 point increase in the Clinical Global Impression – Severity of Illness (CGI-S) score compared to baseline or study discontinuation due to lack of efficacy. Patients receiving sertraline hydrochloride continuation treatment experienced a statistically significantly lower relapse rate over this 24week study than patients randomized to placebo substitution.
# How Supplied
- Sertraline hydrochloride tablets, USP are supplied in capsule-shaped tablets containing sertraline hydrochloride equivalent to 25, 50 and 100 mg of sertraline, are packaged in bottles.
- Sertraline hydrochloride tablets USP, 25 mg: Light green coloured, capsule shaped, biconvex, film coated tablets with debossing "C155" on one side and scored on the other side.
- NDC 69097-155-02 Bottles of 30
- NDC 69097-155-05 Bottles of 90
- NDC 69097-155-12 Bottles of 500
- Sertraline hydrochloride tablets USP, 50 mg: Blue coloured, capsule shaped, biconvex, film coated tablets with debossing "C156" on one side and scored on the other side.
- NDC 69097-156-02 Bottles of 30
- NDC 69097-156-05 Bottles of 90
- NDC 69097-156-12 Bottles of 500
- Sertraline hydrochloride tablets USP, 100 mg: Yellow coloured, capsule shaped, biconvex, film coated tablets with debossing "C157" on one side and scored on the other side.
- NDC 69097-157-02 Bottles of 30
- NDC 69097-157-05 Bottles of 90
- NDC 69097-157-12 Bottles of 500
- Storage
- Store at 20°C-25°C (68°F-77°F).
## Storage
There is limited information regarding Sertraline Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with sertraline hydrochloride and should counsel them in its appropriate use. A patient Medication Guide about "Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions: is available for sertraline hydrochloride. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document.
- Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking sertraline hydrochloride.
- Clinical Worsening and Suicide Risk: Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.
- Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of SNRIs and SSRIs, including sertraline hydrochloride, and triptans, tramadol, or other serotonergic agents.
- Patients should be advised that taking sertraline hydrochloride can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible.
- Patients should be told that although sertraline hydrochloride has not been shown to impair the ability of normal subjects to perform tasks requiring complex motor and mental skills in laboratory experiments, drugs that act upon the central nervous system may affect some individuals adversely. Therefore, patients should be told that until they learn how they respond to sertraline hydrochloride they should be careful doing activities when they need to be alert, such as driving a car or operating machinery.
- Patients should be cautioned about the concomitant use of sertraline hydrochloride and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding.
- Patients should be told that although sertraline hydrochloride has not been shown in experiments with normal subjects to increase the mental and motor skill impairments caused by alcohol, the concomitant use of sertraline hydrochloride and alcohol is not advised.
- Patients should be told that while no adverse interaction of sertraline hydrochloride with over-the-counter (OTC) drug products is known to occur, the potential for interaction exists. Thus, the use of any OTC product should be initiated cautiously according to the directions of use given for the OTC product.
- Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy.
- Patients should be advised to notify their physician if they are breast feeding an infant.
# Precautions with Alcohol
- Alcohol-Sertraline interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- SERTRALINE HYDROCHLORIDE®[4]
# Look-Alike Drug Names
- sertraline® — cetirizine®[5]
- sertraline® — Soriatane®[5]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Sertraline | |
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The medical laboratory test for serum iron measures the amount of circulating iron that is bound to transferrin.
Clinicians order this laboratory test when they are concerned about iron deficiency, which can cause anemia and other problems.
65% of the iron in the body is bound up in hemoglobin molecules in red blood cells. About 4% is bound up in myoglobin molecules. Around 30% of the iron in the body is stored as ferritin or hemosiderin in the spleen, the bone marrow and the liver. Small amounts of iron can be found in other molecules in cells throughout the body. None of this iron is directly accessible by testing the serum.
However, some iron is circulating in the serum. Transferrin is a molecule produced by the liver that binds one or two iron(III) ions; transferrin is essential if stored iron is to be moved and used.
Most of the time, about 30% of the available sites on the transferrin molecule are filled. The test for serum iron uses blood drawn from veins to measure the iron molecules that are bound to transferrin, and circulating in the blood.
The extent to which sites on transferrin molecules are filled by iron ions can be another helpful clinical indicator, known as percent transferrin saturation. Another lab test saturates the sample to measure the total amount of transferrin; this test is called total iron-binding capacity (TIBC). These three tests are generally done at the same time, and taken together are an important part of the diagnostic process for anemia, iron deficiency, iron deficiency anemia and Haemochromatosis.
# Normal values
- Serum Iron (SI):
Men: 65 to 176 µg/dL
Women: 50 to 170 µg/dL
Newborns: 100 to 250 µg/dL
Children: 50 to 120 µg/dL
- Men: 65 to 176 µg/dL
- Women: 50 to 170 µg/dL
- Newborns: 100 to 250 µg/dL
- Children: 50 to 120 µg/dL
- TIBC: 240-450 µg/dL
- Transferrin saturation: 20-50%
µg/dL = micrograms per deciliter.
Laboratories often use different units and "normal" may vary by population and the lab techniques used; look at the individual laboratory reference values to interpret a specific test (for instance, your own). | Serum iron
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
The medical laboratory test for serum iron measures the amount of circulating iron that is bound to transferrin.
Clinicians order this laboratory test when they are concerned about iron deficiency, which can cause anemia and other problems.
65% of the iron in the body is bound up in hemoglobin molecules in red blood cells. About 4% is bound up in myoglobin molecules. Around 30% of the iron in the body is stored as ferritin or hemosiderin in the spleen, the bone marrow and the liver. Small amounts of iron can be found in other molecules in cells throughout the body. None of this iron is directly accessible by testing the serum.
However, some iron is circulating in the serum. Transferrin is a molecule produced by the liver that binds one or two iron(III) ions; transferrin is essential if stored iron is to be moved and used.
Most of the time, about 30% of the available sites on the transferrin molecule are filled. The test for serum iron uses blood drawn from veins to measure the iron molecules that are bound to transferrin, and circulating in the blood.
The extent to which sites on transferrin molecules are filled by iron ions can be another helpful clinical indicator, known as percent transferrin saturation. Another lab test saturates the sample to measure the total amount of transferrin; this test is called total iron-binding capacity (TIBC). These three tests are generally done at the same time, and taken together are an important part of the diagnostic process for anemia, iron deficiency, iron deficiency anemia and Haemochromatosis.
# Normal values
- Serum Iron (SI):
Men: 65 to 176 µg/dL
Women: 50 to 170 µg/dL
Newborns: 100 to 250 µg/dL
Children: 50 to 120 µg/dL
- Men: 65 to 176 µg/dL
- Women: 50 to 170 µg/dL
- Newborns: 100 to 250 µg/dL
- Children: 50 to 120 µg/dL
- TIBC: 240-450 µg/dL
- Transferrin saturation: 20-50%
µg/dL = micrograms per deciliter.
Laboratories often use different units and "normal" may vary by population and the lab techniques used; look at the individual laboratory reference values to interpret a specific test (for instance, your own). | https://www.wikidoc.org/index.php/Serum_iron | |
6bc485b2445bb5a656806fe05faa474a62a6a0ce | wikidoc | Sesame oil | Sesame oil
Sesame oil (a/k/a "gingelly oil" or "til oil") is an edible vegetable oil derived from sesame seeds. Besides being used as a cooking oil in South India, it is often used as a flavor enhancer in Southeast Asian cuisine.
# Composition
Sesame oil is composed of the following fatty acids:
# History
Sesame seeds were one of the first crops processed for oil as well as one of the earliest condiments. In fact, the word ennai that means oil in Tamil has its roots in the Tamil words eL(எள்ளு) and nei(னெய்), which mean sesame and fat.
Prior to 600 BC, the Assyrians used sesame oil as a food, salve, and medication, primarily by the rich, as the difficulty of obtaining it made it expensive. Hindus use til oil in votive lamps, and consider the oil sacred. According to Hindu belief, lighting lamp filled with til oil in front of Lord Hanuman removes obstacles and difficulties in life.
## Nomenclature
In the Tamil language of India, Sesame Oil is called "Nalla Ennai"(நல்லெண்ணெய்), which literal translation in English is "good oil". In the Telugu language of India, Sesame Oil is called "Nuvvula Noona" (from "Nuvvulu" for sesame). In the Kannada language of India, Sesame Oil is called "yellenne" (from "yellu" for sesame). It is also called as Gingelly Oil in India.
# Manufacture of sesame oil
## Manufacturing process
The extraction of sesame oil from the sesame seed is not a completely automated process. In the fairy tale “Ali Baba and the Forty Thieves” the sesame fruit serves as a symbol for wealth. When the fruit capsule opens, it releases a real treasure - the sesame seeds. However, a great deal of manual work is necessary before this point is reached. That is why sesame is hardly ever cultivated in Western industrialised agricultural areas.
The sesame seeds are protected by a capsule, which does not burst open until the seeds are completely ripe. The ripening time tends to vary. For this reason, the farmers cut plants by hand and place them together in upright position to carry on ripening for a few days. The seeds are only shaken out onto a cloth after all the capsules have opened.
The discovery of an indehiscent (nonshattering) mutant by Langham in 1943 began the work towards development of a high yielding, shatter-resistant variety. Although researchers have made significant progress in sesame breeding, harvest losses due to shattering continue to limit domestic US production.
## Sesame seed market
As of 2007, sesame is being imported into the US at a price of US$0.43/lb. This relatively high price reflects a world-wide shortage. Though the market for sesame seed is strong, domestic US production awaits the development of high-yielding nonshattering varieties. It is advisable to establish a market before planting.
## Varieties
There are many variations in the colour of sesame oil: cold-pressed sesame oil is almost colourless, while Indian sesame oil (gingelly or til oil) is golden and Chinese sesame oil is commonly a dark brown colour.
East Asian sesame oil derives its dark colour and flavour from toasted hulled sesame seeds. Cold pressed sesame oil has less flavour than the toasted oil, since it is produced directly from raw, rather than toasted seeds.
Sesame oil is traded in any of the forms described above: Cold-pressed sesame oil is available in Western health shops. In most Asian countries, different kinds of hot-pressed sesame oil are preferred.
# Uses
## Cooking
Sesame oil carries a premium relative to other cooking oils and is considered more stable than most vegetable oils due to antioxidants in the oil. Sesame oil is least prone, among cooking oils, to turn rancid. This is because it has a very high boiling point. In effect, sesame oil retains its natural structure and does not break down even when heated to a very high temperature.
Sesame oil is most popular in Asia, including the South Indian state of Tamil Nadu, where its widespread use is similar to that of olive oil in the Mediterranean.
## Body massage
Sesame oil is reputed to penetrate the skin easily, and is used in India for oil massage.
## Hair treatment
Applying sesame oil to the hair is said to result in darker hair. It may be used for hair and scalp massage.
It is believed to reduce the heat of the body and thus helps in preventing hair
## Food manufacture
Sesame oil is used in the manufacture of pickles.
Refined sesame oil is used to make margarine in Western countries.
## Drug manufacture
Sesame oil is used in the manufacture of Ayurvedic drugs.
## Worship
Sesame or Til oil is used in brass or silver lamps kept in front of gods and goddess of Hindus. Sesame oil is used for performing puja in Hindu temples.
## Industrial uses
In industry, sesame oil may be used as:
- a solvent in injected drugs or intravenous drip solutions,
- a cosmetics carrier oil,
- coating stored grains to prevent weevil attacks. The oil also has synergy with some insecticides.
# Alternative medicine
## Vitamins and Minerals
Sesame oil is a source of vitamin E. Vitamin E is an anti-oxidant, which means it helps lower cholesterol. As with most plant based condiments, sesame oil contains magnesium, copper, calcium, iron, zinc and vitamin B6. Copper provides relief for rheumatoid arthritis. Magnesium supports vascular and respiratory health. Calcium helps prevent colon cancer, osteoporosis, migraine and PMS. Zinc promotes bone health.
Besides being rich in Vitamin E, there is insufficient research on the medicinal properties of sesame oil. However, the following claims have been made.
## Blood pressure
Sesame oil has a high percentage of polyunsaturated fatty acids.
It is suggested that due to the presence of high levels of Polyunsaturated fatty acids in sesame oil, it may help to control blood pressure. It could be used in cooking in place of other edible oils and to help reduce high blood pressure and lower the amount of medication needed to control hypertension.
Sesame oil is unique in that it has one of the highest concentrations of omega-6 fatty acids. At the same time, the oil contains two natural-occurring preservatives, sesamol and sesamin. Therefore, sesame oil is the only oil which has a high percentage of polyunsaturates and also keeps at room temperature. (Comparatively, olive oil also keeps at room temperature, but is predominately composed of the omega-9 monounsaturated oil.)
The effect of the oil on blood pressure may be due to polyunsaturated fatty acids (PUFA), and the compound sesamin – a lignan present in sesame oil. There is evidence suggesting that both compounds reduce blood pressure in hypertensive rats. Sesame lignans also inhibit the synthesis and absorption of cholesterol in these rats.
## Oil pulling
Sesame oil is one of the few oils recommended for use in oil pulling. (sunflower oil is the other oil recommended).
## Stress and tension
Various constituents present in the sesame oil have anti-oxidant and anti-depressant properties. Therefore proponents encourage its use to help fight senile changes and bring about a sense of well being.
Adherents for its therapeutic use reports claims of feeling better than when not using it.
## General claims
While not approved by the Food and Drug Administration (FDA), sesame oil is reputed to have a number of therapeutic uses.
As with cure-all claims of other folk and therapeutic medicines, it is suggested that regular topical application and/or consumption of sesame oil should mitigate effects of anxiety, nerve and bone disorders, poor circulation, lowered immunity and bowel problems. It is suggested such use would also relieve lethargy, fatigue and insomnia, while promoting strength and vitality, enhancing blood circulation. There are claims that its use has relaxing properties which eases pain and muscle spasm, such as sciatica, dysmenorrhoea, colic, backache and joint pain. There are claims similar to other therapeutic medicines, that its having antioxidants explains beliefs that it slows the aging process and promotes longevity.
It is suggested that sesame oil, when consumed and/or topically applied, should relieve dryness both externally and internally. Sesame oil is sometimes recommended to alleviate the dryness associated with menopause. It is believed that its use "restores moisture to the skin, keeping it soft, flexible and young looking". It is suggested that it relieves "dryness of joints" and bowels, and eases symptoms of dryness such as irritating coughs, cracking joints and hard stools. Since "dryness of joints" is not a medically classifiable condition, it would be difficult to medically comprehend or verify these claims of panacea.
Other uses include as a laxative, as a remedy for toothaches and gum disease and in the treatment of blurred vision, dizziness, and headaches.
It is suggested that sesame oil could be used in the treatment of dry nose, reduction of cholestrol levels (due to presence of Lignans which are phytoestrogens), anti-bacterial effects, and even slowing down certain types of cancer(due to the anti-oxidant properties of the Lignans).
# Adverse effects
Sesame oil is not known to be harmful when taken in recommended dosages, though the long-term effects of taking sesame-derived remedies (in any amount) have not been investigated. Due to lack of sufficient medical study, sesame oil should be used with caution in children, women who are pregnant or breast-feeding, and people with liver or kidney disease.
Because of its laxative effects, sesame oil should not be used by people who have diarrhea.
No more than 10% of a person's total caloric intake should be derived from polyunsaturated fats such as those found in sesame oil, according to the American Heart Association.
Oil massage should be avoided immediately after administering enemas, emetics or purgatives, during the first stages of fever or if suffering from indigestion.
People who are allergic to Peanuts are likely to be more susceptible to Sesame allergy. Allergy to Peanuts is one of the most common allergies, and can lead to anaphylactic shock which can be fatal. Persons allergic to Sesame seeds should be cautious about using Sesame oil. | Sesame oil
Sesame oil (a/k/a "gingelly oil" or "til oil") is an edible vegetable oil derived from sesame seeds. Besides being used as a cooking oil in South India, it is often used as a flavor enhancer in Southeast Asian cuisine.
# Composition
Sesame oil is composed of the following fatty acids:[1]
# History
Sesame seeds were one of the first crops processed for oil as well as one of the earliest condiments. In fact, the word ennai that means oil in Tamil has its roots in the Tamil words eL(எள்ளு) and nei(னெய்), which mean sesame and fat.
Prior to 600 BC, the Assyrians used sesame oil as a food, salve, and medication, primarily by the rich, as the difficulty of obtaining it made it expensive. Hindus use til oil in votive lamps, and consider the oil sacred. According to Hindu belief, lighting lamp filled with til oil in front of Lord Hanuman removes obstacles and difficulties in life.[2]
## Nomenclature
In the Tamil language of India, Sesame Oil is called "Nalla Ennai"(நல்லெண்ணெய்), which literal translation in English is "good oil". In the Telugu language of India, Sesame Oil is called "Nuvvula Noona" (from "Nuvvulu" for sesame). In the Kannada language of India, Sesame Oil is called "yellenne" (from "yellu" for sesame). It is also called as Gingelly Oil in India.
# Manufacture of sesame oil
## Manufacturing process
The extraction of sesame oil from the sesame seed is not a completely automated process. In the fairy tale “Ali Baba and the Forty Thieves” the sesame fruit serves as a symbol for wealth. When the fruit capsule opens, it releases a real treasure - the sesame seeds. However, a great deal of manual work is necessary before this point is reached. That is why sesame is hardly ever cultivated in Western industrialised agricultural areas.[3]
The sesame seeds are protected by a capsule, which does not burst open until the seeds are completely ripe. The ripening time tends to vary. For this reason, the farmers cut plants by hand and place them together in upright position to carry on ripening for a few days. The seeds are only shaken out onto a cloth after all the capsules have opened.
The discovery of an indehiscent (nonshattering) mutant by Langham in 1943 began the work towards development of a high yielding, shatter-resistant variety. Although researchers have made significant progress in sesame breeding, harvest losses due to shattering continue to limit domestic US production.[4]
## Sesame seed market
As of 2007, sesame is being imported into the US at a price of US$0.43/lb. This relatively high price reflects a world-wide shortage. Though the market for sesame seed is strong, domestic US production awaits the development of high-yielding nonshattering varieties. It is advisable to establish a market before planting.
## Varieties
There are many variations in the colour of sesame oil: cold-pressed sesame oil is almost colourless, while Indian sesame oil (gingelly or til oil) is golden and Chinese sesame oil is commonly a dark brown colour.
East Asian sesame oil derives its dark colour and flavour from toasted hulled sesame seeds. Cold pressed sesame oil has less flavour than the toasted oil, since it is produced directly from raw, rather than toasted seeds.
Sesame oil is traded in any of the forms described above: Cold-pressed sesame oil is available in Western health shops. In most Asian countries, different kinds of hot-pressed sesame oil are preferred.[5]
# Uses
## Cooking
Sesame oil carries a premium relative to other cooking oils and is considered more stable than most vegetable oils due to antioxidants in the oil.[6] Sesame oil is least prone, among cooking oils, to turn rancid. This is because it has a very high boiling point. In effect, sesame oil retains its natural structure and does not break down even when heated to a very high temperature.
Sesame oil is most popular in Asia, including the South Indian state of Tamil Nadu, where its widespread use is similar to that of olive oil in the Mediterranean.
## Body massage
Sesame oil is reputed to penetrate the skin easily, and is used in India for oil massage.[7]
## Hair treatment
Applying sesame oil to the hair is said to result in darker hair. It may be used for hair and scalp massage.[8]
It is believed to reduce the heat of the body and thus helps in preventing hair
## Food manufacture
Sesame oil is used in the manufacture of pickles.[9]
Refined sesame oil is used to make margarine in Western countries.
## Drug manufacture
Sesame oil is used in the manufacture of Ayurvedic drugs.[10]
## Worship
Sesame or Til oil is used in brass or silver lamps kept in front of gods and goddess of Hindus. Sesame oil is used for performing puja in Hindu temples.[11]
## Industrial uses
In industry, sesame oil may be used as:
- a solvent in injected drugs or intravenous drip solutions,
- a cosmetics carrier oil,
- coating stored grains to prevent weevil attacks. The oil also has synergy with some insecticides.[12]
# Alternative medicine
## Vitamins and Minerals
Sesame oil is a source of vitamin E.[13] Vitamin E is an anti-oxidant, which means it helps lower cholesterol. As with most plant based condiments, sesame oil contains magnesium, copper, calcium, iron, zinc and vitamin B6. Copper provides relief for rheumatoid arthritis. Magnesium supports vascular and respiratory health. Calcium helps prevent colon cancer, osteoporosis, migraine and PMS. Zinc promotes bone health.
Besides being rich in Vitamin E, there is insufficient research on the medicinal properties of sesame oil. However, the following claims have been made.
## Blood pressure
Sesame oil has a high percentage of polyunsaturated fatty acids.[14]
It is suggested that due to the presence of high levels of Polyunsaturated fatty acids in sesame oil, it may help to control blood pressure. It could be used in cooking in place of other edible oils and to help reduce high blood pressure and lower the amount of medication needed to control hypertension.[15]
Sesame oil is unique in that it has one of the highest concentrations of omega-6 fatty acids. At the same time, the oil contains two natural-occurring preservatives, sesamol and sesamin. Therefore, sesame oil is the only oil which has a high percentage of polyunsaturates and also keeps at room temperature. (Comparatively, olive oil also keeps at room temperature, but is predominately composed of the omega-9 monounsaturated oil.)
The effect of the oil on blood pressure may be due to polyunsaturated fatty acids (PUFA), and the compound sesamin – a lignan present in sesame oil. There is evidence suggesting that both compounds reduce blood pressure in hypertensive rats. Sesame lignans also inhibit the synthesis and absorption of cholesterol in these rats.
## Oil pulling
Sesame oil is one of the few oils recommended for use in oil pulling. [16] (sunflower oil is the other oil recommended).
## Stress and tension
Various constituents present in the sesame oil have anti-oxidant and anti-depressant properties. Therefore proponents encourage its use to help fight senile changes and bring about a sense of well being.[17]
Adherents for its therapeutic use reports claims of feeling better than when not using it.
## General claims
While not approved by the Food and Drug Administration (FDA), sesame oil is reputed to have a number of therapeutic uses.
As with cure-all claims of other folk and therapeutic medicines, it is suggested that regular topical application and/or consumption of sesame oil should mitigate effects[18] of anxiety, nerve and bone disorders, poor circulation, lowered immunity and bowel problems. It is suggested such use would also relieve lethargy, fatigue and insomnia, while promoting strength and vitality, enhancing blood circulation. There are claims that its use has relaxing properties which eases pain and muscle spasm, such as sciatica, dysmenorrhoea, colic, backache and joint pain. There are claims similar to other therapeutic medicines, that its having antioxidants explains beliefs that it slows the aging process and promotes longevity.
It is suggested that sesame oil, when consumed and/or topically applied, should relieve dryness both externally and internally. Sesame oil is sometimes recommended to alleviate the dryness associated with menopause.[19] It is believed that its use "restores moisture to the skin, keeping it soft, flexible and young looking". It is suggested that it relieves "dryness of joints" and bowels, and eases symptoms of dryness such as irritating coughs, cracking joints and hard stools. Since "dryness of joints" is not a medically classifiable condition, it would be difficult to medically comprehend or verify these claims of panacea.
Other uses include as a laxative, as a remedy for toothaches and gum disease[20] and in the treatment of blurred vision, dizziness, and headaches.[21]
It is suggested that sesame oil could be used in the treatment of dry nose, reduction of cholestrol levels (due to presence of Lignans which are phytoestrogens), anti-bacterial effects, and even slowing down certain types of cancer(due to the anti-oxidant properties of the Lignans).[22]
# Adverse effects
Sesame oil is not known to be harmful when taken in recommended dosages, though the long-term effects of taking sesame-derived remedies (in any amount) have not been investigated. Due to lack of sufficient medical study, sesame oil should be used with caution in children, women who are pregnant or breast-feeding, and people with liver or kidney disease.
Because of its laxative effects, sesame oil should not be used by people who have diarrhea.
No more than 10% of a person's total caloric intake should be derived from polyunsaturated fats such as those found in sesame oil, according to the American Heart Association.[23]
Oil massage should be avoided immediately after administering enemas, emetics or purgatives, during the first stages of fever or if suffering from indigestion.[24]
People who are allergic to Peanuts are likely to be more susceptible to Sesame allergy. Allergy to Peanuts is one of the most common allergies, and can lead to anaphylactic shock which can be fatal. Persons allergic to Sesame seeds should be cautious about using Sesame oil. | https://www.wikidoc.org/index.php/Sesame_oil | |
42e18d719c8611990ef396d09cda67926d914457 | wikidoc | Sexdactyly | Sexdactyly
Sexadactyly or hexadactyly is a genetic condition in which a person has six fingers on one or both hands, or six toes on one or both feet. This is a genetically inheritable condition; it is actually autosomal-dominant; and some populations feature a larger proportion of six-fingered people.
Sexadactyly, or hexadactyly, is not merely defined as having six finger per hand or six toes per foot. It requires that each of the six fingers have its own ray, so that no two fingers would be more "merged" than on a normal hand on X-rays (as in most forms of polydactyly). Nonspecialists and the media however use the terms interchangeably.
It has been rumored that Anne Boleyn, wife of King Henry VIII of England and mother of Queen Elizabeth I of England, had six fingers on one hand. In fiction, Thomas Harris' character Hannibal Lecter has sexadactyly of the left hand, with mid-ray duplication.
The biblical giant Goliath is said to have had six fingers on each hand and six toes on each foot:
2 Samuel 21:20
And there was yet a battle in Gath, where was a man of great stature, that had on every hand six fingers, and on every foot six toes, four and twenty in number; and he also was born to the giant. - Authorized King James Version|KJV
1 Chronicles 20:6
And yet again there was war at Gath, where was a man of great stature, whose fingers and toes were four and twenty, six on each hand, and six on each foot and he also was the son of the giant. - KJV | Sexdactyly
Sexadactyly or hexadactyly is a genetic condition in which a person has six fingers on one or both hands, or six toes on one or both feet. This is a genetically inheritable condition; it is actually autosomal-dominant; and some populations feature a larger proportion of six-fingered people.
Sexadactyly, or hexadactyly, is not merely defined as having six finger per hand or six toes per foot. It requires that each of the six fingers have its own ray, so that no two fingers would be more "merged" than on a normal hand on X-rays (as in most forms of polydactyly). Nonspecialists and the media however use the terms interchangeably.
It has been rumored that Anne Boleyn, wife of King Henry VIII of England and mother of Queen Elizabeth I of England, had six fingers on one hand. In fiction, Thomas Harris' character Hannibal Lecter has sexadactyly of the left hand, with mid-ray duplication.
The biblical giant Goliath is said to have had six fingers on each hand and six toes on each foot:
2 Samuel 21:20
And there was yet a battle in Gath, where was a man of great stature, that had on every hand six fingers, and on every foot six toes, four and twenty in number; and he also was born to the giant. - Authorized King James Version|KJV
1 Chronicles 20:6
And yet again there was war at Gath, where was a man of great stature, whose fingers and toes were four and twenty, six on each hand, and six on each foot and he also was the son of the giant. - KJV | https://www.wikidoc.org/index.php/Sexdactyly | |
927e222d85735265cf0951fab8cd6e436401bd8e | wikidoc | Sfdasfasdf | Sfdasfasdf
# Disclaimer
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# Overview
Sfdasfasdf is {{{aOrAn}}} {{{drugClass}}} that is FDA approved for the {{{indicationType}}} of {{{indication}}}. Common adverse reactions include {{{adverseReactions}}}.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Condition 1
- Dosing Information
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
Condition 1
- Developed by: (Organization)
- Class of Recommendation: (Class) (Link)
- Strength of Evidence: (Category A/B/C) (Link)
- Dosing Information/Recommendation
- (Dosage)
### Non–Guideline-Supported Use
Condition 1
- Dosing Information
- There is limited information about Off-Label Non–Guideline-Supported Use of Sfdasfasdf in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Condition 1
- Dosing Information
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
Condition 1
- Developed by: (Organization)
- Class of Recommendation: (Class) (Link)
- Strength of Evidence: (Category A/B/C) (Link)
- Dosing Information/Recommendation
- (Dosage)
### Non–Guideline-Supported Use
Condition 1
- Dosing Information
- There is limited information about Off-Label Non–Guideline-Supported Use of Sfdasfasdf in pediatric patients.
# Contraindications
- Condition 1
- Condition 2
- Condition 3
- Condition 4
- Condition 5
# Warnings
Conidition 1
(Description)
# Adverse Reactions
## Clinical Trials Experience
Central Nervous System
Cardiovascular
Respiratory
Gastrointestinal
Hypersensitive Reactions
Miscellaneous
## Postmarketing Experience
Central Nervous System
Cardiovascular
Respiratory
Gastrointestinal
Hypersensitive Reactions
Miscellaneous
# Drug Interactions
- (Drug 1)
- (Description)
- (Drug 2)
- (Description)
- (Drug 3)
- (Description)
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
There is no FDA guidance on usage of Sfdasfasdf in women who are pregnant.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Sfdasfasdf in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Sfdasfasdf during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Sfdasfasdf in women who are nursing.
### Pediatric Use
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### Geriatic Use
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### Gender
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### Race
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### Renal Impairment
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### Hepatic Impairment
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### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Sfdasfasdf in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Sfdasfasdf in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Sfdasfasdf Administration in the drug label.
### Monitoring
There is limited information regarding Sfdasfasdf Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Sfdasfasdf and IV administrations.
# Overdosage
There is limited information regarding Sfdasfasdf overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
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## Mechanism of Action
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## Structure
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## Pharmacodynamics
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## Pharmacokinetics
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## Nonclinical Toxicology
There is limited information regarding Sfdasfasdf Nonclinical Toxicology in the drug label.
# Clinical Studies
There is limited information regarding Sfdasfasdf Clinical Studies in the drug label.
# How Supplied
There is limited information regarding Sfdasfasdf How Supplied in the drug label.
## Storage
There is limited information regarding Sfdasfasdf Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Sfdasfasdf Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Sfdasfasdf interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
There is limited information regarding Sfdasfasdf Brand Names in the drug label.
# Look-Alike Drug Names
There is limited information regarding Sfdasfasdf Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Sfdasfasdf
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Sfdasfasdf is {{{aOrAn}}} {{{drugClass}}} that is FDA approved for the {{{indicationType}}} of {{{indication}}}. Common adverse reactions include {{{adverseReactions}}}.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Condition 1
- Dosing Information
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
Condition 1
- Developed by: (Organization)
- Class of Recommendation: (Class) (Link)
- Strength of Evidence: (Category A/B/C) (Link)
- Dosing Information/Recommendation
- (Dosage)
### Non–Guideline-Supported Use
Condition 1
- Dosing Information
- There is limited information about Off-Label Non–Guideline-Supported Use of Sfdasfasdf in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Condition 1
- Dosing Information
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
Condition 1
- Developed by: (Organization)
- Class of Recommendation: (Class) (Link)
- Strength of Evidence: (Category A/B/C) (Link)
- Dosing Information/Recommendation
- (Dosage)
### Non–Guideline-Supported Use
Condition 1
- Dosing Information
- There is limited information about Off-Label Non–Guideline-Supported Use of Sfdasfasdf in pediatric patients.
# Contraindications
- Condition 1
- Condition 2
- Condition 3
- Condition 4
- Condition 5
# Warnings
Conidition 1
(Description)
# Adverse Reactions
## Clinical Trials Experience
Central Nervous System
Cardiovascular
Respiratory
Gastrointestinal
Hypersensitive Reactions
Miscellaneous
## Postmarketing Experience
Central Nervous System
Cardiovascular
Respiratory
Gastrointestinal
Hypersensitive Reactions
Miscellaneous
# Drug Interactions
- (Drug 1)
- (Description)
- (Drug 2)
- (Description)
- (Drug 3)
- (Description)
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
There is no FDA guidance on usage of Sfdasfasdf in women who are pregnant.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Sfdasfasdf in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Sfdasfasdf during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Sfdasfasdf in women who are nursing.
### Pediatric Use
There is no FDA guidance on the use of Sfdasfasdf in pediatric settings.
### Geriatic Use
There is no FDA guidance on the use of Sfdasfasdf in geriatric settings.
### Gender
There is no FDA guidance on the use of Sfdasfasdf with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Sfdasfasdf with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Sfdasfasdf in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Sfdasfasdf in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Sfdasfasdf in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Sfdasfasdf in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Sfdasfasdf Administration in the drug label.
### Monitoring
There is limited information regarding Sfdasfasdf Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Sfdasfasdf and IV administrations.
# Overdosage
There is limited information regarding Sfdasfasdf overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
There is limited information regarding Sfdasfasdf Pharmacology in the drug label.
## Mechanism of Action
There is limited information regarding Sfdasfasdf Mechanism of Action in the drug label.
## Structure
There is limited information regarding Sfdasfasdf Structure in the drug label.
## Pharmacodynamics
There is limited information regarding Sfdasfasdf Pharmacodynamics in the drug label.
## Pharmacokinetics
There is limited information regarding Sfdasfasdf Pharmacokinetics in the drug label.
## Nonclinical Toxicology
There is limited information regarding Sfdasfasdf Nonclinical Toxicology in the drug label.
# Clinical Studies
There is limited information regarding Sfdasfasdf Clinical Studies in the drug label.
# How Supplied
There is limited information regarding Sfdasfasdf How Supplied in the drug label.
## Storage
There is limited information regarding Sfdasfasdf Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Sfdasfasdf Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Sfdasfasdf interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
There is limited information regarding Sfdasfasdf Brand Names in the drug label.
# Look-Alike Drug Names
There is limited information regarding Sfdasfasdf Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Sfdasfasdf | |
9641b6629d287d12ed794e302e395e9d242a5390 | wikidoc | Shift work | Shift work
# Overview
Shift work is an employment practice designed to make use of the 24 hours of the clock, rather than a standard working day. The term shift work includes both long-term night shifts and work schedules in which employees change or rotate shifts.
A related yet different concept, the work shift, is the time period during which a person is at work.
# Practice
A day may be divided into three shifts, each of eight hours, and each employee works just one of those shifts; they might for example be 00:00 to 08:00, 08:00 to 16:00, 16:00 to 24:00. Generally, "first shift" refers to the day shift, with "second shift" running from late afternoon to midnight or so, and "third shift" being the night shift. On occasion, more complex schedules are used, sometimes involving employees changing shifts, in order to operate during weekends as well, in which case there will be four or more sets of employees.
Twelve-hour work shifts are also in use. In a modern steelworks, four sets of personnel are used, working consecutive days in one twelve hour shift (06:00-18:00 and vice-versa). Shift A will work days, and shift B nights, over a 48-hour period, before handing over to shifts C and D and taking 48 hours off. In the offshore petroleum industry, employees may work 14 consecutive days or nights, 06:00-18:00 or 18:00-06:00, followed by three or four weeks free.
Shift work was once characteristic primarily of manufacturing industry, where it has a clear effect of increasing the use that can be made of capital equipment and allows for up to three times the production compared to just a day shift. It contrasts with the use of overtime to increase production at the margin. Both approaches incur higher wage costs. In general, requiring workers to live on a time-shifted schedule for extended periods, is unpopular, and this typically must be paid for at a premium. It is common in heavy industry, particularly automobile and textile manufacturing and is becoming more common in locations where a shut-down of equipment would incur an extensive restart process. Food manufacturing plants, in particular, have extensive cleaning programs that are required before any restart. The use of shift work in manufacturing varies greatly from country to country. Shift work has been traditional in law enforcement and the armed forces: for example sailors must be available to handle a vessel around the clock, and a system of naval watches organised to ensure enough hands are on duty at any time. This is shift work by another name.
Service industries now increasingly operate on some shift system; for example a restaurant or convenience store will normally each day be open for much longer than a working day. Shift work is also the norm in governmental and private employment in fields related to public safety and healthcare, such as police, fire prevention, security, emergency medical transportation and hospitals. Companies working in the field of meteorology, such as the National Weather Service and private forecasting companies, also utilize shift work, as constant monitoring of the weather is necessary.
# Shift Patterns
- In some areas, the swing shift, also known as "second shift", is scheduled during the afternoon and evening, such as 16:00 to 24:00 or 15:00 to 22:00. Some shift work expertsTemplate:Who consider this swing shift to be the least desirable of the three possibilities in an 8-hour shift schedule. The swing shift (svingskift) in the offshore petroleum industry in Norway refers to a two week tour where one works 12-hour days the first seven days and 12-hour nights the second, or vice versa.
- The graveyard shift, also known as "third shift", means a shift of work running through the early hours of the morning, especially one from midnight until 08:00. There is no certainty as to the origin of this phrase; according to Michael Quinion it is little more than "an evocative term for the night shift ... when ... your skin is clammy, there's sand behind your eyeballs, and the world is creepily silent, like the graveyard."
- In the 7 day fortnight shift pattern, employees do their allotted hours within 7 days rather than 10. Therefore, 41 hours per week equate to 82 hours per fortnight (fourteen days and nights), which will be done in seven days by working 11-12 hours per shift. This shift structure is used in the broadcast television industry.
7 day fortnight shift example
# Health consequences
The February 15, 2005 issue of American Family Physician noted that shift work has been associated with cluster headaches. The consequences of disturbing natural circadian rhythms has been investigated also. A study by Knutsson et al in 1986 found that shift workers who had worked in that method for 15 years or more were 300% more likely to develop ischaemic heart disease.
In 1978 Cohen et al proposed that reduced production of the hormone melatonin might increase the risk of breast cancer and citing "environmental lighting" as a possible causal factor.
In 1987, working the night shift first became associated with higher rates of cancer. This may be due to alterations in circadian rhythm: melatonin, a known tumor suppressant, is generally produced at night and late shifts may disrupt its production. Multiple studies have documented a link between night shift work and the increased incidence of breast cancer.
In 2007, "shiftwork that involves circadian disruption" was listed as a probable carcinogen by the World Health Organization's International Agency for Research on Cancer. (IARC Press release No. 180).
A good review of current knowledge of the health consequences of exposure to artificial light at night and an explanation of the causal mechanisms has been published in the Journal of Pineal Research in 2007.
# Fatigue countermeasures and shift worker lifestyle training
The behaviors and decisions made by people who work shift work affect their alertness, safety, and performance (and possibly their short-term and long-term health, although that has not been adequately studied at this time). There are a number of areas in which shift workers can implement certain fatigue countermeasures and other ways in which they can modify their lifestyles to better adapt to the realities of their work schedules. These include managing what and how much they eat, managing their use of caffeine and other substances to increase alertness or induce sleep, creating a sleep-friendly environment for sleeping during the day time, avoiding drowsy driving, how to nap effectively, and tips for maintaining family and social life.
# Shift work management practices
The practices and policies put in place by managers of round-the-clock or 24/7 operations can significantly influence shiftworker alertness (and hence safety) and performance.
These practices and policies can be fairly obvious: selecting an appropriate shift schedule or rota, setting the length of shifts, managing overtime, increasing lighting levels, or providing shiftworker lifestyle training to help shiftworkers better handle issues such as understanding basic circadian physiology, sleep and napping, caffeine usage, social life issues, diet and nutrition, etc. They may also be more indirect: retirement compensation based on salary in the last few years of employment (which can encourage excessive overtime among older workers who may be less able to obtain adequate sleep), or screening and hiring of new shiftworkers that assesses adaptability to a shift work schedule. | Shift work
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Shift work is an employment practice designed to make use of the 24 hours of the clock, rather than a standard working day. The term shift work includes both long-term night shifts and work schedules in which employees change or rotate shifts.[1][2]
A related yet different concept, the work shift, is the time period during which a person is at work.
# Practice
A day may be divided into three shifts, each of eight hours, and each employee works just one of those shifts; they might for example be 00:00 to 08:00, 08:00 to 16:00, 16:00 to 24:00. Generally, "first shift" refers to the day shift, with "second shift" running from late afternoon to midnight or so, and "third shift" being the night shift. On occasion, more complex schedules are used, sometimes involving employees changing shifts, in order to operate during weekends as well, in which case there will be four or more sets of employees.
Twelve-hour work shifts are also in use. In a modern steelworks, four sets of personnel are used, working consecutive days in one twelve hour shift (06:00-18:00 and vice-versa). Shift A will work days, and shift B nights, over a 48-hour period, before handing over to shifts C and D and taking 48 hours off. In the offshore petroleum industry, employees may work 14 consecutive days or nights, 06:00-18:00 or 18:00-06:00, followed by three or four weeks free.
Shift work was once characteristic primarily of manufacturing industry, where it has a clear effect of increasing the use that can be made of capital equipment and allows for up to three times the production compared to just a day shift. It contrasts with the use of overtime to increase production at the margin. Both approaches incur higher wage costs. In general, requiring workers to live on a time-shifted schedule for extended periods, is unpopular, and this typically must be paid for at a premium. It is common in heavy industry, particularly automobile and textile manufacturing and is becoming more common in locations where a shut-down of equipment would incur an extensive restart process. Food manufacturing plants, in particular, have extensive cleaning programs that are required before any restart. The use of shift work in manufacturing varies greatly from country to country. Shift work has been traditional in law enforcement and the armed forces: for example sailors must be available to handle a vessel around the clock, and a system of naval watches organised to ensure enough hands are on duty at any time. This is shift work by another name.
Service industries now increasingly operate on some shift system; for example a restaurant or convenience store will normally each day be open for much longer than a working day. Shift work is also the norm in governmental and private employment in fields related to public safety and healthcare, such as police, fire prevention, security, emergency medical transportation and hospitals. Companies working in the field of meteorology, such as the National Weather Service and private forecasting companies, also utilize shift work, as constant monitoring of the weather is necessary.
# Shift Patterns
- In some areas, the swing shift, also known as "second shift", is scheduled during the afternoon and evening, such as 16:00 to 24:00 or 15:00 to 22:00. Some shift work expertsTemplate:Who consider this swing shift to be the least desirable of the three possibilities in an 8-hour shift schedule. The swing shift (svingskift) in the offshore petroleum industry in Norway refers to a two week tour where one works 12-hour days the first seven days and 12-hour nights the second, or vice versa.
- The graveyard shift, also known as "third shift", means a shift of work running through the early hours of the morning, especially one from midnight until 08:00. There is no certainty as to the origin of this phrase; according to Michael Quinion it is little more than "an evocative term for the night shift ... when ... your skin is clammy, there's sand behind your eyeballs, and the world is creepily silent, like the graveyard."[3]
- In the 7 day fortnight shift pattern, employees do their allotted hours within 7 days rather than 10. Therefore, 41 hours per week equate to 82 hours per fortnight (fourteen days and nights), which will be done in seven days by working 11-12 hours per shift. This shift structure is used in the broadcast television industry.
7 day fortnight shift example
# Health consequences
The February 15, 2005 issue of American Family Physician noted that shift work has been associated with cluster headaches. The consequences of disturbing natural circadian rhythms has been investigated also. A study by Knutsson et al in 1986 found that shift workers who had worked in that method for 15 years or more were 300% more likely to develop ischaemic heart disease.
In 1978 Cohen et al proposed that reduced production of the hormone melatonin might increase the risk of breast cancer and citing "environmental lighting" as a possible causal factor.[4]
In 1987, working the night shift first became associated with higher rates of cancer. This may be due to alterations in circadian rhythm: melatonin, a known tumor suppressant, is generally produced at night and late shifts may disrupt its production. Multiple studies have documented a link between night shift work and the increased incidence of breast cancer.[5][6][7][8]
In 2007, "shiftwork that involves circadian disruption" was listed as a probable carcinogen by the World Health Organization's International Agency for Research on Cancer. (IARC Press release No. 180).[9][10]
A good review of current knowledge of the health consequences of exposure to artificial light at night and an explanation of the causal mechanisms has been published in the Journal of Pineal Research in 2007.[11]
# Fatigue countermeasures and shift worker lifestyle training
The behaviors and decisions made by people who work shift work affect their alertness, safety, and performance (and possibly their short-term and long-term health, although that has not been adequately studied at this time). There are a number of areas in which shift workers can implement certain fatigue countermeasures and other ways in which they can modify their lifestyles to better adapt to the realities of their work schedules.[12] These include managing what and how much they eat, managing their use of caffeine and other substances to increase alertness or induce sleep, creating a sleep-friendly environment for sleeping during the day time, avoiding drowsy driving,[13] how to nap effectively, and tips for maintaining family and social life.
# Shift work management practices
The practices and policies[14] put in place by managers of round-the-clock or 24/7 operations can significantly influence shiftworker alertness (and hence safety) and performance.
These practices and policies can be fairly obvious: selecting an appropriate shift schedule or rota, setting the length of shifts, managing overtime, increasing lighting levels, or providing shiftworker lifestyle training to help shiftworkers better handle issues such as understanding basic circadian physiology, sleep and napping, caffeine usage, social life issues, diet and nutrition, etc. They may also be more indirect: retirement compensation based on salary in the last few years of employment (which can encourage excessive overtime among older workers who may be less able to obtain adequate sleep), or screening and hiring of new shiftworkers that assesses adaptability to a shift work schedule. | https://www.wikidoc.org/index.php/Shift_work |
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