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b7031b419d55073e6076a1ab0020f52dabfb7516	wikidoc	Radiation	Radiation Radiation is an action or process of throwing or sending out a traveling ray in a line, beam, or stream of small relative cross section. At right is an image of an impact crater on the surface of Venus. It is a likely example of meteor radiation damage. # Rays Def. a beam of light or radiation is called a ray. Def. an action or process of throwing or sending out a traveling ray in a line, beam, or stream of small cross section is called radiation. The term radiation is often used to refer to the ray itself. Def. the shooting forth of anything from a point or surface, like the diverging rays of light; as, the radiation of heat is called radiation. Rays may have a temporal, spectral, or spatial distribution. They may also be dependent on other variables as yet unknown. A delta ray is characterized by very fast electrons produced in quantity by alpha particles or other fast energetic charged particles knocking orbiting electrons out of atoms. Collectively, these electrons are defined as delta radiation when they have sufficient energy to ionize further atoms through subsequent interactions on their own. Epsilon radiation is tertiary radiation caused by secondary radiation (e.g., delta radiation). Epsilon rays are a form of particle radiation and are composed of electrons. The term is very rarely used today. # Radiation theory Def. a theory of the science of the biological, chemical, physical, and logical laws (or principles) with respect to any radiation is called a theory of radiation. Particle radiation consists of a stream of charged or neutral particles, from the size of subatomic elementary particles upwards of rocky and gaseous objects to even larger more loosely bound entities. # Strong forces A "new type of neutron star model (Q stars) high-density, electrically neutral baryonic matter is a coherent classical solution to an effective field theory of strong forces and is bound in the absence of gravity. allows massive compact objects, and has no macroscopic minimum mass." "Compact objects in astronomy are usually analyzed in terms of theoretical characteristics of neutron stars or black holes that are based upon calculations of equations of state for matter at very high densities. At such high densities, the effects of strong forces cannot be neglected. There are several conventional approaches to describing nuclear forces, all of which find that for a baryon number greater than ~250, a nucleus will become energetically unbound. High-density hadronic matter is not stable in these theories until there are enough baryons for gravitational binding to form a neutron star, typically with a minimum mass ≳ 0.1 M⊙ and maximum mass ≲ 3 M⊙." "Another possibility is that in the absence of gravity high-density baryonic matter is bound by purely strong forces. nongravitationally bound bulk hadronic matter is consistent with nuclear physics data and low-energy strong interaction data The effective field theory approach has many successes in nuclear physics suggesting that bulk hadronic matter is just as likely to be a correct description of matter at high densities as conventional, unbound hadronic matter." "The idea behind baryon matter is that a macroscopic state may exist in which a smaller effective baryon mass inside some region makes the state energetically favored over free particles. This state will appear in the limit of large baryon number as an electrically neutral coherent bound state of neutrons, protons, and electrons in β-decay equilibrium." # Meteors Particle radiation upwards in size above that of atomic nuclei may be lumped together as meteor radiation. # Galaxy clusters "Galaxies and clusters of galaxies are not uniformly distributed in the Universe, instead they collect into vast clusters and sheets and walls of galaxies interspersed with large voids in which very few galaxies seem to exist. The map above shows many of these superclusters including the Virgo supercluster - the minor supercluster of which our galaxy is just a minor member. The entire map is approximately 7 percent of the diameter of the entire visible Universe." # High-velocity galaxies "The irregular galaxy NGC 1427A is a spectacular example of the resulting stellar rumble. Under the gravitational grasp of a large gang of galaxies, called the Fornax cluster, the small bluish galaxy is plunging headlong into the group at 600 kilometers per second or nearly 400 miles per second." "Galaxy clusters, like the Fornax cluster, contain hundreds or even thousands of individual galaxies. Within the Fornax cluster, there is a considerable amount of gas lying between the galaxies. When the gas within NGC 1427A collides with the Fornax gas, it is compressed to the point that it starts to collapse under its own gravity. This leads to formation of the myriad of new stars seen across NGC 1427A, which give the galaxy an overall arrowhead shape that appears to point in the direction of the galaxy's high-velocity motion." # Hypervelocity stars "To date, all of the reported hypervelocity stars (HVSs), which are believed to be ejected from the Galactic center, are blue and therefore almost certainly young.” Def. a high-velocity star moving through space with an abnormally high velocity relative to the surrounding interstellar medium is called a runaway star. # Clouds Def. a visible mass of - water droplets suspended in the air ... - dust, - steam ... - smoke ... - a group or swarm is called a cloud. Clouds have been observed on other planets and moons within the Solar System, but, due to their different temperature characteristics, they are composed of other substances such as methane, ammonia, and sulfuric acid. # Aerometeors Def. a discrete unit of air, wind, or mist traveling or falling through or partially through an atmosphere is called an aerometeor. Def. any of the high-speed, high-altitude air currents that circle the Earth in a westerly direction is called a jet stream. # Plasma meteors A coronal cloud is a cloud, or cloud-like, natural astronomical entity, composed of plasma and usually associated with a star or other astronomical object where the temperature is such that X-rays are emitted. While small coronal clouds are above the photosphere of many different visual spectral type stars, others occupy parts of the interstellar medium (ISM), extending sometimes millions of kilometers into space, or thousands of light-years, depending on the size of the associated object such as a galaxy. At left is a radiated object and its associated phenomena. Ultra-violet studies of Mira by NASA's Galaxy Evolution Explorer (Galex) space telescope have revealed that it sheds a trail of material from the outer envelope, leaving a tail 13 light-years in length, formed over tens of thousands of years. It is thought that a hot bow-wave of compressed plasma/gas is the cause of the tail; the bow-wave is a result of the interaction of the stellar wind from Mira A with gas in interstellar space, through which Mira is moving at an extremely high speed of 130 kilometres/second (291,000 miles per hour). The tail consists of material stripped from the head of the bow-wave, which is also visible in ultra-violet observations. Mira's bow-shock will eventually evolve into a planetary nebula, the form of which will be considerably affected by the motion through the interstellar medium (ISM). # Gaseous meteors Gaseous objects have at least one chemical element or compound present in the gaseous state. These gaseous components make up at least 50 % of the detectable portion of the gaseous object. Atmospheric astronomy determines whether gaseous objects have layers or spherical portions predominantly composed of gas. Within these spherical portions may occur various gaseous meteors such as clouds, winds, or streams. # Liquid meteors Liquid water precipitation falls from the atmosphere and reaches the ground, such as drizzle and rain. Suspended liquid water particles may form and remain suspended in the air (damp haze, cloud, fog, and mist), or may be lifted by the wind from the Earth’s surface (blowing spray) causing restrictions to visibility. # Rocky meteors "A skydiver may have captured the first film ever of a meteorite plunging down at terminal velocity, also known as its “dark flight” stage." "The footage was captured in 2012 by a helmet cam worn by Anders Helstrup as he and other members of the Oslo Parachute Club jumped from a small plane that took off from an airport in Hedmark, Norway." “It can’t be anything else. The shape is typical of meteorites -- a fresh fracture surface on one side, while the other side is rounded.” “It has never happened before that a meteorite has been filmed during dark flight; this is the first time in world history.” "Having the rock in hand would certainly help. But despite triangulations and analyses, Helstrup and his recruits still haven’t found it." # Meteoroids Def. a relatively small (sand- to boulder-sized) fragment of debris in a solar system is called a meteoroid. "As of 2011 the International Astronomical Union officially defines a meteoroid as a solid object moving in interplanetary space, of a size considerably smaller than an asteroid and considerably larger than an atom". The visible path of a meteoroid that enters the Earth's atmosphere (or another body's) atmosphere is called a meteor, or colloquially a shooting star or falling star. If a meteoroid reaches the ground and survives impact, then it is called a meteorite. Beech and Steel, writing in Quarterly Journal of the Royal Astronomical Society, proposed a new definition where a meteoroid is between 100 µm and 10 m across. Following the discovery and naming of asteroids below 10 m in size (e.g., 2008 TC3), Rubin and Grossman refined the Beech and Steel definition of meteoroid to objects between 10 µm and 1 m in diameter. The NEO definition includes larger objects, up to 50 m in diameter, in this category. Very small meteoroids are known as micrometeoroids (see also interplanetary dust). The composition of meteoroids can be determined as they pass through Earth's atmosphere from their trajectories and the light spectra of the resulting meteor. Their effects on radio signals also give information, especially useful for daytime meteors which are otherwise very difficult to observe. The light spectra, combined with trajectory and light curve measurements, have yielded various compositions and densities, ranging from fragile snowball-like objects with density about a quarter that of ice, to nickel-iron rich dense rocks. In meteoroid ablation spheres from deep-sea sediments, "he silicate spheres are the most dominant group." From these trajectory measurements, meteoroids have been found to have many different orbits, some clustering in streams (see Meteor showers) often associated with a parent comet, others apparently sporadic. Debris from meteoroid streams may eventually be scattered into other orbits. ... Meteoroids travel around the Sun in a variety of orbits and at various velocities. The fastest ones move at about 26 miles per second (42 kilometers per second) through space in the vicinity of Earth's orbit. The Earth travels at about 18 miles per second (29 kilometers per second). Thus, when meteoroids meet the Earth's atmosphere head-on (which would only occur if the meteors were in a retrograde orbit), the combined speed may reach about 44 miles per second (71 kilometers per second). Meteoroids moving through the earth's orbital space average about 20 km/s. # Fireballs A relatively small percentage of meteoroids hit the Earth's atmosphere and then pass out again: these are termed Earth-grazing fireballs (for example The Great Daylight 1972 Fireball). For 2011 there are 4589 fireball records at the American Meteor Society. "At 66 kilometers (41 miles) per second, they appear as fast streaks, faster by a hair than their sisters, the Eta Aquarids of May. And like the Eta Aquarids, the brightest of family tend to leave long-lasting trains. Fireballs are possible three days after maximum." # Bolides Def. a fireball reaching magnitude −14 or brighter is called a bolide. Def. a fireball reaching an magnitude −17 or brighter is called a superbolide. # Meteor showers Meteors may occur in showers, which arise when the Earth passes through a trail of debris left by a comet, or as "random" or "sporadic" meteors, not associated with a specific single cause. A number of specific meteors have been observed, largely by members of the public and largely by accident. # Cryometeors A megacryometeor is a very large chunk of ice sometimes called huge hailstones, but do not need to form in thunderstorms. # Lithometeors Def. a suspension of dry dust in the atmosphere is called a lithometeor. Def. the solid material thrown into the air by a volcanic eruption that settles on the surrounding areas is called tephra. # Micrometeors A micrometeoroid is a tiny meteoroid; a small particle of rock in space, usually weighing less than a gram. A micrometeorite is such a particle that survives passage through the Earth's atmosphere and reaches the Earth's surface. Micrometeoroids are extremely common in space. particles are a major contributor to space weathering processes. When they hit the surface of the Moon, or any airless body (Mercury, the asteroids, etc.), the resulting melting and vaporization causes darkening and other optical changes in the regolith. Micrometeoroids have less stable orbits than meteoroids, due to their greater surface area to mass ratio. Micrometeoroids pose a significant threat to space exploration. Their velocities relative to a spacecraft in orbit average 10 kilometers per second (22,500 mph), and resistance to micrometeoroid impact is a significant design challenge for spacecraft and space suit designers (See Thermal Micrometeoroid Garment). While the tiny sizes of most micrometeoroids limits the damage incurred, the high velocity impacts will constantly degrade the outer casing of spacecraft in a manner analogous to sandblasting. Long term exposure can threaten the functionality of spacecraft systems. # Hydrometeors Def. precipitation products of the condensation of atmospheric water vapour are called hydrometeors. Def. any or all of the forms of water particles, whether liquid or solid, that fall from the atmosphere are called precipitation. # Particles The Comprehensive Suprathermal and Energetic Particle Analyzer (COSTEP) aboard SOHO "detects and classifies very energetic particle populations of solar, interplanetary, and galactic origin." # Ionizing radiation While large objects may induce the gain or loss of charge from another object, ionizing radiation is usually thought of as on the order of or smaller than an atom. Different types of ionizing radiation behave in different ways, so different shielding techniques are used. - Particle radiation consists of a stream of charged or neutral particles, both charged ions and subatomic elementary particles. This includes solar wind, cosmic radiation, and neutron flux in nuclear reactors. - Alpha particles (helium nuclei) are the least penetrating. Even very energetic alpha particles can be stopped by a single sheet of paper. - Beta particles (electrons) are more penetrating, but still can be absorbed by a few millimeters of aluminum. However, in cases where high energy beta particles are emitted shielding must be accomplished with low density materials, e.g. plastic, wood, water or acrylic glass (Plexiglas, Lucite). This is to reduce generation of Bremsstrahlung X-rays. In the case of beta+ radiation (positrons), the gamma radiation from the electron-positron annihilation reaction poses additional concern. - Neutron radiation is not as readily absorbed as charged particle radiation, which makes this type highly penetrating. Neutrons are absorbed by nuclei of atoms in a nuclear reaction. This most-often creates a secondary radiation hazard, as the absorbing nuclei transmute to the next-heavier isotope, many of which are unstable. - Cosmic radiation is not a common concern, as the Earth's atmosphere absorbs it and the magnetosphere acts as a shield, but it poses a problem for satellites and astronauts and frequent fliers are also at a slight risk. Cosmic radiation is extremely high energy, and is very penetrating. - Electromagnetic radiation consists of emissions of electromagnetic waves, the properties of which depend on the wavelength. - X-ray and gamma radiation are best absorbed by atoms with heavy nuclei; the heavier the nucleus, the better the absorption. In some special applications, depleted uranium is used, but lead is much more common; several centimeters are often required. Barium sulfate is used in some applications too. However, when cost is important, almost any material can be used, but it must be far thicker. Most nuclear reactors use thick concrete shields to create a bioshield with a thin water cooled layer of lead on the inside to protect the porous concrete from the coolant inside. The concrete is also made with heavy aggregates, such as Baryte, to aid in the shielding properties of the concrete. - Ultraviolet (UV) radiation is ionizing but it is not penetrating, so it can be shielded by thin opaque layers such as sunscreen, clothing, and protective eyewear. Protection from UV is simpler than for the other forms of radiation above, so it is often considered separately. In some cases, improper shielding can actually make the situation worse, when the radiation interacts with the shielding material and creates bremsstrahlung secondary radiation that absorbs in the organisms more readily. # Cosmic rays Cosmic rays are energetic charged subatomic particles, originating in outer space. At right is an image indicating the range of cosmic-ray energies. The flux for the lowest energies (yellow zone) is mainly attributed to solar cosmic rays, intermediate energies (blue) to galactic cosmic rays, and highest energies (purple) to extragalactic cosmic rays. "Cosmic rays arise from galactic source accelerators." Cosmic rays may be upwards of a ZeV (1021 eV). About 89% of cosmic rays are simple protons or hydrogen nuclei, 10% are helium nuclei of alpha particles, and 1% are the nuclei of heavier elements. Solitary electrons constitute much of the remaining 1%. Def. cosmic rays that originate from astrophysical sources are called primary cosmic rays. Def. cosmic rays that are created when primary cosmic rays interact with interstellar matter are called secondary cosmic rays. Def. low energy cosmic rays associated with solar flares are called solar cosmic rays. Cosmic rays are not charge balanced; that is, positive ions heavily outnumber electrons. The positive ions are - free protons, - alpha particles (helium nuclei), - lithium nuclei, - beryllium nuclei, and - boron nuclei. # Neutrals Neutrals are usually neutral atoms, or molecules. But they also can be neutral subatomic particles such as the neutron, neutral pions, and the neutrino. # Subatomics Subatomics involves one or more subatomic particles or radiation. The bare nuclei of atoms may qualify as a form of subatomics. Def. - particles that are constituents of the atom, or are smaller than an atom; such as proton, neutron, electron, etc or - any length or mass that is smaller in scale than a the diameter of a hydrogen atom are called subatomics, or subatomic, respectively. As a bare uranium nucleus is smaller than a hydrogen atom in diameter, but much larger in mass, it qualifies as one of the subatomics. Here, subatomic is used to mean smaller than the diameter of a hydrogen atom. # Lithium nuclei The "evidence for the overwhelming majority of the Li-atoms in photospheres has its origin not only in nuclear synthesis near the stellar centers, but also by active processes in stellar atmospheres. the lithium line near 478 keV." "Approximately 90% of lithium atoms originate from α - α reactions for the typical spectra of an accelerated particles on the Sun During impulsive flares, interaction between the accelerated particles and the ambient medium occurs mainly at low altitudes, i.e., close to the footprints of loops." # Alphas About 89% of cosmic rays are simple protons or hydrogen nuclei, 10% are helium nuclei or alpha particles, and 1% are the nuclei of heavier elements. Solitary electrons constitute much of the remaining 1%. # Helions Def. a nucleus of a helium-3 atom" is called a helion. # Tritons Energetic deuterons and tritons have been detected in solar flares. # Deuterons "The flux is found to be 4 ± 1.3 M-2 sec-1 sterad-1". # Baryons In "dense nuclear matter, such as neutron stars has recently been discovered that kaon condensation in nuclear matter at a density of a few times normal nuclear matter may significantly reduce the upper mass limit of neutron stars This clearly has an impact on astronomical observations. By exploiting the electron fermi level, we are able to predict kaon production at reasonable baryon number densities Experimental detection of is a subtle matter there is strong theoretical evidence that such states do exist in nature. the lightest dibaryon is energetically stable against strong decay to by 88 MeV. is bound by 250 MeV." # Radioactivity Def. a spontaneous emission of an α ray, β ray, or γ ray by the disintegration of an atomic nucleus is called radioactivity. Although alpha, beta, and gamma radiations were found most commonly, other types of decay were eventually discovered. Shortly after the discovery of the positron in cosmic ray products, it was realized that the same process that operates in classical beta decay can also produce positrons (positron emission). In an analogous process, instead of emitting positrons and neutrinos, some proton-rich nuclides were found to capture their own atomic electrons (electron capture), and emit only a neutrino (and usually also a gamma ray). Each of these types of decay involves the capture or emission of nuclear electrons or positrons, and acts to move a nucleus toward the ratio of neutrons to protons that has the least energy for a given total number of nucleons (neutrons plus protons). # Hadrons Hadrons are subatomic particles of a type including baryons and mesons that can take part in the strong interaction and may be useful in astronomy. A hadron, like an atomic nucleus, is a composite particle held together by the strong force Hadrons are categorized into two families: baryons (such as protons and neutrons) and mesons. # Radioactivity emissions The nuclei of some atoms spontaneously disintegrate from one form of isotope to another until they reach a stable form. These atoms emit particles (alpha or beta) or electromagnetics (X-ray or gamma) which are different in charge, size, penetrating power and ionization energy. In Template:SubatomicParticle decay, or "positron emission", the weak interaction converts a nucleus into its next-lower neighbor on the periodic table while emitting an positron (Template:SubatomicParticle) and an electron neutrino (Template:SubatomicParticle): ^A_ZN \rightarrow ~ ^{~~~A}_{Z-1}N' + e^+ + \nu_e. Positron emission' or beta plus decay (β+ decay) is a type of beta decay in which a proton is converted, via the weak force, to a neutron, releasing a positron and a neutrino. Isotopes which undergo this decay and thereby emit positrons include carbon-11, potassium-40, nitrogen-13, oxygen-15, fluorine-18, and iodine-121. As an example, the following equation describes the beta plus decay of carbon-11 to boron-11, emitting a positron and a neutrino: ^{11}_{6}C \rightarrow ~ ^{11}_{5}B + e^+ + \nu_e + \gamma {(0.96 MeV)}. # Antimatter Def. a subatomic particle corresponding to another particle with the same mass, spin and mean lifetime but with charge, parity, strangeness and other quantum numbers flipped in sign is called an antiparticle. Def. matter that is composed of antiparticles of those that constitute normal matter is called antimatter. # Annihilations The positron or antielectron is the antiparticle or the antimatter counterpart of the electron. The positron has an electric charge of +1e, a spin of ½, and has the same mass as an electron. When a low-energy positron collides with a low-energy electron, annihilation occurs, resulting in the production of two or more gamma ray photons. Def. the process of a particle and its corresponding antiparticle combining to produce energy is called annihilation. The figure at right shows a positron (e+) emitted from an atomic nucleus together with a neutrino (v). Subsequently, the positron moves randomly through the surrounding matter where it hits several different electrons (e-) until it finally loses enough energy that it interacts with a single electron. This process is called an "annihilation" and results in two diametrically emitted photons with a typical energy of 511 keV each. Under normal circumstances the photons are not emitted exactly diametrically (180 degrees). This is due to the remaining energy of the positron having conservation of momentum. Electron–positron annihilation occurs when an electron (Template:SubatomicParticle) and a positron (Template:SubatomicParticle, the electron's antiparticle) collide. The result of the collision is the annihilation of the electron and positron, and the creation of gamma ray photons or, at higher energies, other particles: The process satisfy a number of conservation laws, including: - Conservation of electric charge. The net charge before and after is zero. - Conservation of linear momentum and total energy. This forbids the creation of a single gamma ray. However, in quantum field theory this process is described; see examples of annihilation. - Conservation of angular momentum. As with any two charged objects, electrons and positrons may also interact with each other without annihilating, in general by elastic scattering. The creation of only one photon can occur for tightly bound atomic electrons. In the most common case, two photons are created, each with energy equal to the rest energy of the electron or positron (511 keV). It is also common for three to be created, since in some angular momentum states, this is necessary to conserve C parity. Any larger number of photons can be created, but the probability becomes lower with each additional photon. When either the electron or positron, or both, have appreciable kinetic energies, other heavier particles can also be produced (such as D mesons), since there is enough kinetic energy in the relative velocities to provide the rest energies of those particles. Photons and other light particles , but they will emerge with higher energies. At energies near and beyond the mass of the carriers of the weak force, the W and Z bosons, the strength of the weak force becomes comparable with electromagnetism. It becomes much easier to produce particles such as neutrinos that interact only weakly. The heaviest particle pairs yet produced by electron–positron annihilation are ] pairs. The heaviest single particle is the Z boson. Annihilation radiation is not monoenergetic, unlike gamma rays produced by radioactive decay. The production mechanism of annihilation radiation introduces Doppler broadening. The annihilation peak produced in a gamma spectrum by annihilation radiation therefore has a higher full width at half maximum (FWHM) than other gamma rays in spectrum. The difference is more apparent with high resolution detectors, such as Germanium detectors, than with low resolution detectors such as Sodium iodide Because of their well-defined energy (511 keV) and characteristic, Doppler-broadened shape, annihilation radiation can often be useful in defining the energy calibration of a gamma ray spectrum. # Positroniums Def. an exotic atom consisting of a positron and an electron, but having no nucleus or an onium consisting of a positron (anti-electron) and an electron, as a particle–anti-particle bound pair is called positronium. Being unstable, the two particles annihilate each other to produce two gamma ray photons after an average lifetime of 125 ps or three gamma ray photons after 142 ns in vacuum, depending on the relative spin states of the positron and electron. The singlet state with antiparallel spins ( S = 0, Ms = 0) is known as para-positronium (p-Ps) and denoted Template:SubatomicParticle. It has a mean lifetime of 125 picoseconds and decays preferentially into two gamma quanta with energy of 511 keV each (in the center of mass frame). Detection of these photons allows for the reconstruction of the vertex of the decay ... Para-positronium can decay into any even number of photons (2, 4, 6, ...), but the probability quickly decreases as the number increases: the branching ratio for decay into 4 photons is 6994143900000000000♠1.439(2)×10−6. para-positronium lifetime (S = 0): The triplet state with parallel spins (S = 1, Ms = −1, 0, 1) is known as ortho-positronium (o-Ps) and denoted 3S1. The triplet state in vacuum has a mean lifetime of 6993142050000000000♠142.05±0.02 ns and the leading mode of decay is three gamma quanta. Other modes of decay are negligible; for instance, the five photons mode has branching ratio of ~6994100000000000000♠1.0×10−6. -rtho-positronium lifetime (S = 1): # Pair production The reverse reaction, electron–positron creation, is a form of pair production governed by two-photon physics. Two-photon physics, also called gamma-gamma physics, the interactions between two photons. If the energy in the center of mass system of the two photons is large enough, matter can be created. In nuclear physics, occurs when a high-energy photon interacts with a nucleus. The photon must have enough energy to create an electron plus a positron. Without a nucleus to absorb momentum, a photon decaying into electron-positron pair (or other pairs for that matter can never conserve energy and momentum simultaneously. These interactions were first observed in Patrick Blackett's counter-controlled cloud chamber. In 2008 the Titan laser aimed at a 1-millimeter-thick gold target was used to generate positron–electron pairs in large numbers.. "The LLNL scientists created the positrons by shooting the lab's high-powered Titan laser onto a one-millimeter-thick piece of gold." # Neutrons "Due to the very low energy of the colliding protons in the Sun, only states with no angular momentum (s-waves) contribute significantly. One can consider it as a head-on collision, so that angular momentum plays no role. Consequently, the total angular momentum is the sum of the spins, and the spins alone control the reaction. Because of Pauli's exclusion principle, the incoming protons must have opposite spins. On the other hand, in the only bound state of deuterium, the spins of the neutron and proton are aligned. Hence a spin flip must take place The strength of the nuclear force which holds the neutron and the proton together depends on the spin of the particles. The force between an aligned proton and neutron is sufficient to give a bound state, but the interaction between two protons does not yield a bound state under any circumstances. Deuterium has only one bound state." The "force acting between the protons and the neutrons the strong force". "A potential of 36 MeV is needed to get just one energy state." The width of a bound proton and neutron is "2.02 x 10-13 cm". # Protons The proton is a subatomic particle with the symbol Template:SubatomicParticle or Template:SubatomicParticle and a positive electric charge of 1 elementary charge. One or more protons are present in the nucleus of each atom, along with neutrons. The number of protons in each atom is its atomic number. Nucleon spin structure describes the partonic structure of proton intrinsic angular momentum (spin). The key question is how the nucleon's spin, whose magnitude is 1/2ħ, is carried by its constituent partons (quarks and gluons). In the late 1980s, the European Muon Collaboration (EMC) conducted experiments that suggested the spin carried by quarks is not sufficient to account for the total spin of . This finding astonished particle physicists at that time, and the problem of where the missing spin lies is sometimes referred to as the "proton spin crisis". Experimental research on these topics has been continued by the Spin Muon Collaboration (SMC) and the COMPASS experiment at CERN, experiments E154 and E155 at SLAC, HERMES at DESY, experiments at JLab and RHIC, and others. Global analysis of data from all major experiments confirmed the original EMC discovery and showed that the quark spin contribute about 30% to the total spin of the nucleon. New measurements performed by European scientists reveal that the radius of the proton is 4 percent smaller than previously estimated. The antiproton (Template:SubatomicParticle, pronounced p-baer) is the antiparticle of the proton. Antiprotons are stable, but they are typically short-lived since any collision with a proton will cause both particles to be annihilated in a burst of energy. Antiprotons have been detected in cosmic rays for over 25 years, first by balloon-borne experiments and more recently by satellite-based detectors. The standard picture for their presence in cosmic rays is that they are produced in collisions of cosmic ray protons with nuclei in the interstellar medium, via the reaction, where A represents a nucleus: The secondary antiprotons (Template:SubatomicParticle) then propagate through the galaxy, confined by the galactic magnetic fields. Their energy spectrum is modified by collisions with other atoms in the interstellar medium. The antiproton cosmic ray energy spectrum is now measured reliably and is consistent with this standard picture of antiproton production by cosmic ray collisions. # Mesons Mesons are hadronic subatomic particles, bound together by the strong interaction. Because mesons are composed of sub-particles, they have a physical size, with a radius roughly one femtometre, which is about 2⁄3 the size of a proton or neutron. Charged mesons decay (sometimes through intermediate particles) to form electrons and neutrinos. Uncharged mesons may decay to photons. Mesons are not produced by radioactive decay, but appear in nature only as short-lived products of very high-energy interactions in matter In cosmic ray interactions, for example, such particles are ordinary protons and neutrons. Mesons are also frequently produced artificially in high-energy particle accelerators that collide protons, anti-protons, or other particles. Mesons are subject to "both the weak and strong interactions. Mesons with net electric charge also participate in the electromagnetic interaction. While no meson is stable, those of lower mass are nonetheless more stable than the most massive mesons, and are easier to observe and study in particle accelerators or in cosmic ray experiments. They are also typically less massive than baryons, meaning that they are more easily produced in experiments, and thus exhibit certain higher energy phenomena more readily than baryons composed of the same quarks would. Potential mesons to be detected astronomically include: π, ρ, η, η′, φ, ω, J/ψ, ϒ, θ, K, B, D, and T. Single π0 production occurs "in neutral current neutrino interactions with water by a 1.3 GeV wide band neutrino beam." "The Gamma-Ray Spectrometer (GRS) on SMM has detected at least two of the flares have spectral properties >40 MeV that require gamma rays from the decay of neutral pions. production can occur early in the impulsive phase as defined by hard X-rays near 100 keV." Gamma-ray "emission matches remarkably well both the position and shape of the inner SNR shocked plasma. Furthermore, the gamma-ray spectrum shows a prominent peak near 1 GeV with a clear decrement at energies below a few hundreds of MeV as expected from neutral pion decay." # Beta-particles Beta particles are high-energy, high-speed electrons or positrons emitted by certain types of radioactive nuclei such as potassium-40. The beta particles emitted are a form of ionizing radiation also known as beta rays. The production of beta particles is termed beta decay. They are designated by the Greek letter beta (β). # Electrons The electron is a subatomic particle with a negative charge, equal to -1.60217646x10-19 C. Current, or the rate of flow of charge, is defined such that one coulomb, so 1/-1.60217646x10-19, or 6.24150974x1018 electrons flowing past a point per second give a current of one ampere. The charge on an electron is often given as -e. note that charge is always considered positive, so the charge of an electron is always negative. The electron has a mass of 9.10938188x10-31 kg, or about 1/1840 that of a proton. The mass of an electron is often written as me. When working, these values can usually be safely approximated to: It has no known components or substructure; in other words, it is generally thought to be an elementary particle. The intrinsic angular momentum (spin) of the electron is a half-integer value in units of ħ, which means that it is a fermion. Def. a quasiparticle produced as a result of electron spin-charge separation is called a chargon. A chargon possesses the charge of an electron without a spin. A spinon, in turn, possesses the spin of an electron without charge. The suggestion is that an elementary particle such as a positron may consist of at least two parts: spin and charge. An electron may be a negative chargon plus a spinon. # Positrons "The two conversions of protons into neutrons are assumed to take place inside the nucleus, and the extra positive charge is emitted as a positron." Def. the antimatter equivalent of an electron, having the same mass but a positive charge is called a positron. # Tauons "For ultrahigh energies the neutrino spectrum at the detector is influenced by neutrino-nucleon interactions and tauon decays during the passage through the interior of the earth." Def. A lepton is a spin 1/2 particle a fermion that does not interact via the strong force. To date there are three known types of leptons. They are the electron, the muon (\mu), and the tauon (\tau) with their corresponding anti-particles that carry opposite charge (+ instead of -). # Muons "TeV muons from γ ray primaries ... are rare because they are only produced by higher energy γ rays whose flux is suppressed by the decreasing flux at the source and by absorption on interstellar light." The muon from the Greek letter mu (μ) used to represent it) is an elementary particle similar to the electron, with unitary negative electric charge (−1) and a spin of 1⁄2. Together with the electron, the tau, and the three neutrinos, it is classified as a lepton. As is the case with other leptons, the muon is not believed to have any sub-structure at all (i.e., is not thought to be composed of any simpler particles). The muon is an unstable subatomic particle with a mean lifetime of 6994220000000000000♠2.2 μs. This comparatively long decay lifetime (the second longest known) is due to being mediated by the weak interaction. The only longer lifetime for an unstable subatomic particle is that for the free neutron, a baryon particle composed of quarks, which also decays via the weak force. Muon decay produces three particles, an electron plus two neutrinos of different types. Like all elementary particles, the muon has a corresponding antiparticle of opposite charge (+1) but equal mass and spin: the antimuon (also called a positive muon). Muons are denoted by Template:SubatomicParticle and antimuons by Template:SubatomicParticle. # Neutrinos A neutrino is an electrically neutral, weakly interacting elementary subatomic particle with half-integer spin. ... Neutrinos do not carry electric charge, which means that they are not affected by the electromagnetic forces that act on charged particles such as electrons and protons. Neutrinos are affected only by the weak sub-atomic force, of much shorter range than electromagnetism, and gravity, which is relatively weak on the subatomic scale. They are therefore able to travel great distances through matter without being affected by it. "If neutrinos have negligible rest mass, the present density expected for relic neutrinos from the big bang is nν = 110 (Tγ/2.7 K)3 cm–3 for each two-component species. This is of order the photon density nγ, differing just by a factor 3/11 (i.e. a factor 3/4 because neutrinos are fermions rather than bosons, multiplied by 4/11, the factor by which the neutrinos are diluted when e+–e– annihilation boosts the photon density). This conclusion holds for non-zero masses, provided that mvc2 is far below the thermal energy (~ 5 MeV) at which neutrinos decoupled from other species and that the neutrinos are stable for the Hubble time. Comparison with the baryon density, related to Ω via nb = 1.5 x 10–5 Ωb h2 cm–3, shows that neutrinos outnumber baryons by such a big factor that they can be dynamically dominant over baryons even if their masses are only a few electron volts. In fact, a single species of neutrino would yield a contribution to Ω of Ωv = 0.01 h–2 (mv)eV, so if h = 0.5, only 25 eV is sufficient to provide the critical density." "Neutrinos of nonzero mass would be dynamically important not only for the expanding universe as a whole but also for large bound systems such as clusters of galaxies. This is because they would now be moving slowly: if the universe had cooled homogeneously, primordial neutrinos would now be moving at around 200 (mv)-1eV km s–1. They would be influenced even by the weak (~ 10–5 c2) gravitational potential fluctuations of galaxies and clusters. If the three (or more) types of neutrinos have different masses, then the heaviest will obviously be gravitationally dominant, since the numbers of each species should be the same." # Electromagnetics Electromagnetics is most familiar as light, or electromagnetic radiation. # Superluminals "The existence of superluminal energy transfer has not been established so far, and one may ask why. There is the possibility that superluminal quanta just do not exist, the vacuum speed of light being the definitive upper bound. There is another explanation, the interaction of superluminal radiation with matter is very small, the quotient of tachyonic and electric fine-structure constants being q2/e2 ≈ 1.4 x 10-11 , and therefore superluminal quanta are hard to detect." # Cherenkovs At right is an example of Cherenkov radiation. Cherenkov radiation (also spelled Čerenkov) is electromagnetic radiation emitted when a charged particle (such as an electron) passes through a dielectric medium at a speed greater than the phase velocity of light in that medium. Cherenkov radiation is an example of medium specific superluminals. # Entities The electron is a subatomic particle with a negative charge, equal to -1.60217646x10-19 C. Current, or the rate of flow of charge, is defined such that one coulomb, so 1/-1.60217646x10-19, or 6.24150974x1018 electrons flowing past a point per second give a current of one ampere. The charge on an electron is often given as -e. note that charge is always considered positive, so the charge of an electron is always negative. # Sources Def. the point of origin of a ray, beam, or stream of small cross section traveling in a line is called a radiation source. The image at right is the first X-ray light image of the Sun by the satellite GOES-15 Solar X-ray Imager (SXI) on June 2, 2010. The surface of the Sun, beneath the coronal cloud layer is dark. The coronal cloud is the actual source of the X-rays. "TeV muons from γ ray primaries ... are rare because they are only produced by higher energy γ rays whose flux is suppressed by the decreasing flux at the source and by absorption on interstellar light." Muon decay produces three particles, an electron plus two neutrinos of different types. Electrons moving along a Birkeland current may be accelerated by a plasma double layer. If the resulting electrons approach relativistic velocities (i.e. if they approach the speed of light) they may subsequently produce a Bennett pinch, which in a magnetic field causes the electrons to spiral and emit synchrotron radiation that may include radio, optical (i.e. visible light), x-rays, and gamma rays. ""Dark" lightning is a type of electrical discharge within a thunderstorm that produces what are called terrestrial gamma-ray flashes." "The fields accelerate electrons to almost the speed of light. Then, the electrons smash into air molecules and produce gamma-rays. The gamma-rays then produce electrons and their antimatter equivalents (positrons). These particles next crash into air molecules, and produce even more gamma-rays." # Objects Electrons "provide remote-sensing observations of distant targets in the heliosphere - the Sun, the Moon, Jupiter, and various heliospheric structures." The image at right is a painting by artist Giorgio Vasari (1511–1574). The main focus is on Cronus (Saturn) castrating Uranus (the Greek sky god). As both Uranus and Cronus are represented by men, this suggests that they were similar in nature. "he ancients’ religions and mythology speak for their knowledge of Uranus; the dynasty of gods had Uranus followed by Saturn, and the latter by Jupiter. ... It is quite possible that the planet Uranus is the very planet known by this name to the ancients. The age of Uranus preceded the age of Saturn; it came to an end with the “removal” of Uranus by Saturn. Saturn is said to have emasculated his father Uranus." # Continua Def. a continuous series or whole, no part of which is noticeably different from its adjacent parts, although the ends or extremes of it are very different from each other is called a continuum. Above is the electromagnetic spectrum. When each wavelength has the same intensity and background, the entire spectrum is a continuum. More generally, the electromagnetic spectrum, is often termed as either continuous (with energy at all wavelengths) or discrete (energy at only certain wavelengths). # Emissions Def. the act of sending or throwing out; the act of sending forth or putting into circulation is called emission. In Draft:physics, emission is the process by which a higher energy quantum mechanical state of a particle becomes converted to a lower one through the emission of a photon, resulting in the production of light. The frequency of light emitted is a function of the energy of the transition. Since energy must be conserved, the energy difference between the two states equals the energy carried off by the photon. The energy states of the transitions can lead to emissions over a very large range of frequencies. For example, visible light is emitted by the coupling of electronic states in atoms and molecules (then the phenomenon is called fluorescence or phosphorescence). On the other hand, nuclear shell transitions can emit high energy gamma rays, while nuclear spin transitions emit low energy radio waves. # Absorptions Def. the act or process of including so that a separate existence is no longer is called absorption. "There are a number of ways to quantify how quickly and effectively radiation is absorbed. The attenuation coefficient is a quantity that characterizes how easily a material or medium can be penetrated by a beam of light, sound, particles, or other energy or matter. The range of a heavy charged particle is approximately proportional to the mass of the particle and the inverse of the density of the medium, and is a function of the initial velocity of the particle. Def. the average energy loss of the particle per unit path length is called stopping power. # Bands Spectral bands are part of optical spectra of polyatomic systems, including condensed materials, large molecules, etc. Each line corresponds to one level in the atom splits in the molecules. When the number of atoms is large, one gets a continuum of energy levels, the so called "spectral bands". They are often labeled in the same way as the monatomic lines. Band spectra is the name given to a group of lines that are closely spaced and arranged in a regular sequence that appears to be a band. It is a colored band, separated by dark spaces on the two sides and arranged in a regular sequence. In one band, there are various sharp and wider color lines, that are closer on one side and wider on other. The intensity in each band falls off from definite limits and indistinct on the other side. In complete band spectra, there is a number lines in a band. The band spectrum is the combination of many different spectral lines, resulting from rotational, vibrational and electronic transition. # Backgrounds Background radiation is the ubiquitous ionizing radiation that the general population is exposed to, including natural and artificial sources. Both natural and artificial background radiation varies by location. The worldwide average natural dose to humans is about 2.4 millisievert (mSv) per year. The biggest source of natural background radiation is airborne radon, a radioactive gas that emanates from the ground. Radon and its isotopes, parent radionuclides, and decay products all contribute to an average inhaled dose of 1.26 mSv/a. Radon is unevenly distributed and variable with weather, such that much higher doses apply to many areas of the world, where it represents a significant health hazard. Concentrations over 500 times higher than the world average have been found inside buildings in Scandinavia, the United States, Iran, and the Czech Republic. Terrestrial radiation usually only includes sources that remain external to the body. The major radionuclides of concern are potassium, uranium and thorium and their decay products, some of which, like radium and radon are intensely radioactive but occur in low concentrations. An average human contains about 30 milligrams of potassium-40 (40K) and about 10 nanograms (10−8 g) of carbon-14 (14C), which has a decay half-life of 5,730 years. Excluding internal contamination by external radioactive material, the largest component of internal radiation exposure from biologically functional components of the human body is from potassium-40. The decay of about 4,000 nuclei of 40K per second makes potassium the largest source of radiation in terms of number of decaying atoms. The energy of beta particles produced by 40K is also about 10 times more powerful than the beta particles from 14C decay. 14C is present in the human body at a level of 3700 Bq with a biological half-life of 40 days. There are about 1,200 beta particles per second produced by the decay of 14C. However, a 14C atom is in the genetic information of about half the cells, while potassium is not a component of DNA. The decay of a 14C atom inside DNA in one person happens about 50 times per second, changing a carbon atom to one of nitrogen. The global average internal dose from radionuclides other than radon and its decay products is 0.29 mSv/a, of which 0.17 mSv/a comes from 40K, 0.12 mSv/a comes from the uranium and thorium series, and 12 μSv/a comes from 14C. Background radiation may simply be any radiation that is pervasive, whether ionizing or not. A particular example of this is the cosmic microwave background radiation, a nearly uniform glow that fills the sky in the microwave part of the spectrum; stars, galaxies and other objects of interest in radio astronomy stand out against this background. In a laboratory, background radiation refers to the measured value from any sources that affect an instrument when a radiation source sample is not being measured. This background rate, which must be established as a stable value by multiple measurements, usually before and after sample measurement, is subtracted from the rate measured when the sample is being measured. # Damages Def. susceptibility of a material to physical or chemical changes induced by radiation is called radiation sensitivity. The radiation effect depends on the type of the irradiating particles, their energy and the number of incident particles per unit volume. Def. harmful changes in the properties of materials caused by interactions with ionizing radiation is called radiation damage. Radiation damage is a term associated with ionizing radiation. Radiation may affect materials and devices in deleterious ways: - By causing the materials to become radioactive (mainly by neutron activation, or in presence of high-energy gamma radiation by photodisintegration). - By nuclear transmutation of the elements within the material including, for example, the production of Hydrogen and Helium which can in turn alter the mechanical properties of the materials and cause swelling and embrittlement. - By radiolysis (breaking chemical bonds) within the material, which can weaken it, cause it to swell, polymerize, promote corrosion, cause belittlements, promote cracking or otherwise change its desirable mechanical, optical, or electronic properties. - By formation of reactive compounds, affecting other materials (e.g. ozone cracking by ozone formed by ionization of air). - By ionization, causing electrical breakdown, particularly in semiconductors employed in electronic equipment, with subsequent currents introducing operation errors or even permanently damaging the devices. Exposure to radiation causes chemical changes in gases. High-intensity ionizing radiation in air can produce a visible ionized air glow of telltale bluish-purplish color. Like gases, liquids lack fixed internal structure; the effects of radiation is therefore mainly limited to radiolysis, altering the chemical composition of the liquids. As with gases, one of the primary mechanisms is formation of free radicals. All liquids are subject to radiation damage, with few exotic exceptions; e.g. molten sodium, where there are no chemical bonds to be disrupted, and liquid hydrogen fluoride, which produces gaseous hydrogen and fluorine, which spontaneously react back to hydrogen fluoride. # Astronomy When any effort to acquire a system of laws or knowledge focusing on an astr, aster, or astro, that is, any natural body in the sky especially at night, succeeds in discovering or exploring radiation even in its smallest measurement, radiation astronomy is the name of the effort and the result. Once an entity, source, or object has been detected as having radiation, it may be necessary to determine what the mechanism is. Usually this information provides understanding of the same entity, source, or object. The formation of radiation on Earth and its initial detection by hominins may be associated primarily with the available senses. # Sun "Energetic photons, ions and electrons from the solar wind, together with galactic and extragalactic cosmic rays, constantly bombard surfaces of planets, planetary satellites, dust particles, comets and asteroids." # Coronal clouds "Coronal clouds, type IIIg, form in space above a spot area and rain streamers upon it." A variety of subatomic particle and γ-ray reactions have been observed during solar flares indicating fusion reactions occurring at or above the photosphere. "There are typically 375 gamma-ray flares per solar cycle ... each releasing on average about 1031 erg of kinetic energy in accelerated ions of energy ≥ 1 MeV per nucleon ." "The solar-flare gamma-ray line emission testifies that fresh nuclei are synthesized in abundance in energetic solar events." "he gamma-ray lines at 478 and 429 keV emitted in the reactions 4He(α,p)7Li and 4He(α,n)7Be, respectively". # Mercury The mosaic image of the rocky-object Mercury at right shows what appears to be meteor damage over a large portion of the surface. "The mosaic consists of 18 images taken at 42 s intervals during a 13 minute period when the spacecraft was 200,000 km (about 6 hours prior to closest approach) from the planet." Mercury's surface is heavily cratered and similar in appearance to Earth's Moon Craters on Mercury range in diameter from small bowl-shaped cavities to multi-ringed impact basins hundreds of kilometers across. They appear in all states of degradation, from relatively fresh rayed craters to highly degraded crater remnants. Mercurian craters differ subtly from lunar craters in that the area blanketed by their ejecta is much smaller, a consequence of Mercury's stronger surface gravity. # Venus In 1967, Venera-4 found the Venusian magnetic field is much weaker than that of Earth. This magnetic field is induced by an interaction between the ionosphere and the solar wind, Venus's small induced magnetosphere provides negligible protection to the atmosphere against cosmic radiation. This radiation may result in cloud-to-cloud lightning discharges. Strong 300 km/h winds at the cloud tops circle the planet about every four to five earth days. Venusian winds move at up to 60 times the speed of the planet's rotation, while Earth's fastest winds are only 10% to 20% rotation speed. While there is little or no water on Venus, there is a phenomenon which is quite similar to snow. The Magellan probe imaged a highly reflective substance at the tops of Venus's highest mountain peaks which bore a strong resemblance to terrestrial snow. This substance arguably formed from a similar process to snow, albeit at a far higher temperature. Too volatile to condense on the surface, it rose in gas form to cooler higher elevations, where it then fell as precipitation. The identity of this substance is not known with certainty, but speculation has ranged from elemental tellurium to lead sulfide (galena). # Earth In the image at left is an aerial view of the Barringer Meteor Crater about 69 km east of Flagstaff, Arizona USA. Although similar to the aerial view of the Soudan crater, the Barringer Meteor Crater appears angular at the farthest ends rather than round. Meteor Crater is a meteorite impact crater approximately 43 miles (69 km) east of Flagstaff, near Winslow in the northern Arizona desert of the United States. Because the US Department of the Interior Division of Names commonly recognizes names of natural features derived from the nearest post office, the feature acquired the name of "Meteor Crater" from the nearby post office named Meteor. The site was formerly known as the Canyon Diablo Crater, and fragments of the meteorite are officially called the Canyon Diablo Meteorite. Scientists refer to the crater as Barringer Crater in honor of Daniel Barringer, who was first to suggest that it was produced by meteorite impact. From space the crater appears almost like a square. The image at right has a resolution of 2 meters per pixel, and illumination is from the right. Layers of exposed limestone and sandstone are visible just beneath the crater rim, as are large stone blocks excavated by the impact. The Holsinger meteorite is the largest discovered fragment of the meteorite that created Meteor Crater and it is exhibited in the crater visitor center. "The Canyon Diablo meteorite comprises many fragments of the asteroid that impacted at Barringer Crater (Meteor Crater), Arizona, USA. Meteorites have been found around the crater rim, and are named for nearby Canyon Diablo, which lies about three to four miles west of the crater. There are fragments in the collections of museums around the world including the Field Museum of Natural History in Chicago. The biggest fragment ever found is the Holsinger Meteorite, weighing 639 kg, now on display in the Meteor Crater Visitor Center on the rim of the crater. # Moon Meteorites have been found on the Moon Lunar origin is established by comparing the mineralogy, the chemical composition, and the isotopic composition between meteorites and samples from the Moon collected by Apollo missions. Cosmic ray exposure history established with noble gas measurements have shown that all lunar meteorites were ejected from the Moon in the past 20 million years. Most left the Moon in the past 100,000 years. In the image at left, twenty degrees of latitude of the Moon's disk is completely covered in the overlapping circles of craters. The illumination angles are from all directions, keeping almost all the crater floors in sunlight, but a set of merged crater floors right at the south pole are completely shadowed. # Mars Martian meteors are thought to be from Mars because they have elemental and isotopic compositions that are similar to rocks and atmosphere gases analyzed by spacecraft on Mars. The image at right is of the Mackinac Island meteorite, discovered on Mars by the NASA Opportunity rover on October 13, 2009. At top left is the first meteorite of any type ever identified on another planet. The pitted, basketball-size object is mostly made of iron and nickel. Readings from spectrometers on the rover determined that composition. Opportunity used its panoramic camera to take the images used in this approximately true-color composite on the rover's 339th martian day, or sol (Jan. 6, 2005). This composite combines images taken through the panoramic camera's 600-nanometer (red), 530-nanometer (green), and 480-nanometer (blue) filters. Comparison of the two meteorites shown here suggests that the left one is a much more recent fall. # Asteroids Notation let the symbol EC denote Earth-crossing asteroids. Notation: let the symbol MB denote the main belt of asteroids. "From the dominant group, the asteroids evolve to intersect the Earth's orbit on a median time scale of about 60 Myr." "The MB group is the most numerous group of MCs. ... 50 % of the MB Mars-crossers become ECs within 59.9 Myr and contribution ... dominates the production of ECs". # Vesta In the full image of Vesta at right, the rocky-object appears to have suffered from meteor damage. Vesta, minor-planet designation 4 Vesta, is one of the largest asteroids in the Solar System. It lost some 1% of its mass less than a billion years ago in a collision that left an enormous crater occupying much of its southern hemisphere. Debris from this event has fallen to Earth as howardite–eucrite–diogenite (HED) meteorites, a rich source of information about the asteroid. # Saturn "rosion from particles making up the icy rings of Saturn are forming rain water that falls on certain parts of the planet. ... tiny ice particles that compose the planet's distinctive rings are sometimes eroded away and then deposited in the planet's upper atmosphere. The droplets then create a kind of rain on the planet. ... charged water molecules rain down only on certain parts of the planet, which show up darker in infrared images. ... The magnetic connection creates a pathway for small ice particles in the rings to slough off into the planet's atmosphere, causing the "ring rain."" "The most surprising element to us was that these dark regions on the planet are found to be linked — via magnetic field lines — to the solid portions of water-ice within Saturn's ring-plane". "Saturn is the first planet to show significant interaction between its atmosphere and ring system ... The main effect of ring rain is that it acts to 'quench' the ionosphere of Saturn. In other words, this rain severely reduces the electron densities in regions in which it falls." "It turns out that a major driver of Saturn's ionospheric environment and climate across vast reaches of the planet are ring particles located some 36,000 miles overhead ... The ring particles affect both what species of particles are in this part of the atmosphere and where it is warm or cool." "Where Jupiter is glowing evenly across its equatorial regions, Saturn has dark bands where the water is falling in, darkening the ionosphere". # Titan "As spring continues to unfold at Saturn, April showers on the planet's largest moon, Titan, have brought methane rain to its equatorial deserts ... Extensive rain from large cloud systems ... has apparently darkened the surface of the moon." “It's amazing to be watching such familiar activity as rainstorms and seasonal changes in weather patterns on a distant, icy satellite". "The Saturn system experienced equinox, when the sun lies directly over a planet's equator and seasons change, in August 2009. (A full Saturn “year” is almost 30 Earth years.)" "Clouds on Titan are formed of methane as part of an Earth-like cycle that uses methane instead of water. On Titan, methane fills lakes on the surface, saturates clouds in the atmosphere, and falls as rain. Though there is evidence that liquids have flowed on the surface at Titan's equator in the past, liquid hydrocarbons, such as methane and ethane, had only been observed on the surface in lakes at polar latitudes. The vast expanses of dunes that dominate Titan's equatorial regions require a predominantly arid climate." "An arrow-shaped storm appeared in the equatorial regions on Sept. 27, 2010 -- the equivalent of early April in Titan's “year” -- and a broad band of clouds appeared the next month. ... A 193,000-square-mile (500,000-square-kilometer) region along the southern boundary of Titan’s Belet dune field, as well as smaller areas nearby, had become darker. ... this change in brightness is most likely the result of surface wetting by methane rain." “These outbreaks may be the Titan equivalent of what creates Earth's tropical rainforest climates, even though the delayed reaction to the change of seasons and the apparently sudden shift is more reminiscent of Earth's behavior over the tropical oceans than over tropical land areas”. At right is an image that shows clouds over the equatorial region of Titan. "Methane clouds in the troposphere, the lowest part of the atmosphere, appear white here and are mostly near Titan's equator. The darkest areas are surface features that have a low albedo, meaning they do not reflect much light. Cassini observations of clouds like these provide evidence of a seasonal shift of Titan's weather systems to low latitudes following the August 2009 equinox in the Saturnian system. (During equinox, the sun lies directly over the equator. See PIA11667 to learn how the sun's illumination of the Saturnian system changed during the equinox transition to spring in the northern hemispheres and to fall in the southern hemispheres of the planet and its moons.)" "In 2004, during Titan's late southern summer, extensive cloud systems were common in Titan's south polar region (see PIA06110, PIA06124 and PIA06241). Since 2005, southern polar systems have been observed infrequently, and one year after the equinox, extensive near-equatorial clouds have been seen. This image was taken on Oct. 18, 2010, a little more than one Earth year after the Saturnian equinox, which happens once in roughly 15 Earth years." "The cloud patterns observed from late southern summer to early southern fall on Titan suggest that Titan's global atmospheric circulation is influenced by both the atmosphere and the surface. The temperature of the surface responds more rapidly to changes in illumination than does the thick atmosphere. Outbreaks such as the clouds seen here may be the Titan equivalent of what creates the Earth's tropical rainforest climates, even though the delayed reaction to the change of seasons and the apparently sudden shift is more reminiscent of the behavior over Earth's tropical oceans than over tropical land areas." "A few clouds can be seen in Titan's southern latitudes here. See PIA12813 for a movie of clouds moving through the middle southern latitudes of Titan. Some clouds are also visible in the high northern latitudes here. See PIA12811 and PIA12812 for movies showing clouds near the moon's north pole. This view looks toward the Saturn-facing side of Titan (5,150 kilometers or 3,200 miles across). North is up. The image appears slightly grainy because it was re-projected to a scale of 6 kilometers (4 miles) per pixel. Scale in the original image was 15 kilometers (9 miles) per pixel. This view consists of an average of three images taken using a filter sensitive to near-infrared light centered at 938 nanometers, which allows for detection of Titan's surface and lower atmosphere, plus an image taken using a filter sensitive to visible light centered at 619 nanometers. The images were taken with the Cassini spacecraft's narrow-angle camera at a distance of approximately 2.5 million kilometers (1.6 million miles) from Titan and at a sun-Titan-spacecraft, or phase, angle of 56 degrees." # Recurrent novas RS Ophiuchi (RS Oph) is a recurrent nova system approximately 5,000 light-years away in the constellation Ophiuchus. In its quiet phase it has an apparent magnitude of about 12.5. It erupted in 1898, 1933, 1958, 1967, 1985, and 2006 and reached about magnitude 5 on average. The recurrent nova is produced by a white dwarf star and a red giant circling about each other in a close orbit. About every 20 years, enough material from the red giant builds up on the surface of the white dwarf to produce a thermonuclear explosion. The white dwarf orbits close to the red giant, with an accretion disc concentrating the overflowing atmosphere of the red giant onto the white dwarf. If the white dwarf accretes enough mass to reach the Chandrasekhar limit, about 1.4 solar mass, it may explode as a Type Ia supernova. # Biology An evolutionary radiation is an increase in taxonomic diversity or morphological disparity, due to adaptive change or the opening of ecospace. Radiations may affect one clade or many, and be rapid or gradual; where they are rapid, and driven by a single lineage's adaptation to their environment, they are termed adaptive radiations. Perhaps the most familiar example of an evolutionary radiation is that of placental mammals immediately after the extinction of the dinosaurs at the end of the Cretaceous, about 65 million years ago. At that time, the placental mammals were mostly small, insect-eating animals similar in size and shape to modern shrews. By the Eocene (58–37 million years ago), they had evolved into such diverse forms as bats, whales, and horses. The Hawaiian lobelioids are a group of flowering plants in the bellflower family, Campanulaceae, all of which are endemic to the Hawaiian Islands. This is the largest plant radiation in the Hawaiian Islands, and indeed the largest on any island archipelago, with over 125 species. # Dose equivalents The equivalent dose to a tissue is found by multiplying the absorbed dose, in gray, by a weighting factor (WR). The relation between absorbed dose D and equivalent dose H is thus: The weighting factor (sometimes referred to as a quality factor) is determined by the radiation type and energy range. where Thus for example, an absorbed dose of 1 Gy by alpha particles will lead to an equivalent dose of 20 Sv. The maximum weight of 30 is obtained for neutrons with L = 100 keV/μm. # Effective doses The effective dose of radiation (E), absorbed by a person is obtained by averaging over all irradiated tissues with weighting factors adding up to 1: # Grays The gray (symbol: Gy) is the SI derived unit of absorbed radiation dose of ionizing radiation (for example, X-rays), and is defined as the absorption of one joule of ionizing radiation by one kilogram of matter (usually human tissue). The rad is equivalent to 0.01 Gy. One gray is the absorption of one joule of energy, in the form of ionizing radiation, per kilogram of matter. For X rays and gamma rays, these are the same units as the sievert (Sv). For alpha particles one sievert is twenty gray. To avoid any risk of confusion between the absorbed dose (by matter) and the equivalent dose (by biological tissues), one must use the corresponding special units, gray is used instead of the joule per kilogram for absorbed dose and the sievert instead of the joule per kilogram for the dose equivalent. The word "gray" is both the singular and plural spelling. # Chemistry Many of the radiation effects on materials are produced by collision cascades and covered by radiation chemistry. Radiation chemistry is a subdivision of nuclear chemistry which is the study of the chemical effects of radiation on matter; this is very different from radiochemistry as no radioactivity needs to be present in the material which is being chemically changed by the radiation. Radiochemistry is the chemistry of radioactive materials, where radioactive isotopes of elements are used to study the properties and chemical reactions of non-radioactive isotopes (often within radiochemistry the absence of radioactivity leads to a substance being described as being inactive as the isotopes are stable). Much of radiochemistry deals with the use of radioactivity to study ordinary chemical reactions. This is very different from radiation chemistry since the radiation levels are kept too low to influence the chemistry. Nuclear chemistry is the subfield of chemistry dealing with radioactivity, nuclear processes and nuclear properties. It is the chemistry of radioactive elements such as the actinides, radium and radon together with the chemistry associated with equipment (such as nuclear reactors) which are designed to perform nuclear processes. This includes the corrosion of surfaces and the behavior under conditions of both normal and abnormal operation (such as during an accident). An important area is the behavior of objects and materials after being placed into a nuclear waste storage or disposal site. # Geography A geographical area is regarded as a natural environment. A species flock may arise when a species penetrates a new geographical area and diversifies to occupy a variety of ecological niches; this process is known as adaptive radiation. The first species flock to be recognized as such was the 13 species of Darwin's finches on the Galápagos Islands described by Charles Darwin. Solar radiation increases significantly as the atmosphere gets thinner with increasing altitude thereby absorbing less ultraviolet radiation. Snow cover reflecting the radiation can amplify the effects by up to 75% increasing the risks and damage from sunburn and snow blindness. Ionization of the ionosphere depends primarily on the Sun and its activity. The amount of ionization in the ionosphere varies greatly with the amount of radiation received from the Sun. Thus there is a diurnal (time of day) effect and a seasonal effect. The local winter hemisphere is tipped away from the Sun, thus there is less received solar radiation. The activity of the Sun is associated with the sunspot cycle, with more radiation occurring with more sunspots. Radiation received also varies with geographical location (polar, auroral zones, mid-latitudes, and equatorial regions). # Geology Granite is a natural source of radiation, like most natural stones. However, some granites have been reported to have higher radioactivity thereby raising some concerns about their safety. Some granites contain around 10 to 20 parts per million of uranium. By contrast, more mafic rocks such as tonalite, gabbro or diorite have 1 to 5 PPM uranium, and limestones and sedimentary rocks usually have equally low amounts. Many large granite plutons are the sources for palaeochannel-hosted or roll front uranium ore deposits, where the uranium washes into the sediments from the granite uplands and associated, often highly radioactive, pegmatites. Granite could be considered a potential natural radiological hazard as, for instance, villages located over granite may be susceptible to higher doses of radiation than other communities. Cellars and basements sunk into soils over granite can become a trap for radon gas, which is formed by the decay of uranium. Radon gas poses significant health concerns, and is the number two cause of lung cancer in the US behind smoking. Thorium occurs in all granites as well. Conway granite has been noted for its relatively high thorium concentration of 56 (±6) PPM. # Ancient history The ancient history period dates from around 8,000 to 3,000 b2k. Meteorites and lunar rocks may contain a record of the ancient radiation history of various stars including our own solar system. The Explorer 3 spacecraft was spin-stabilized and had an on-board tape recorder to provide a complete radiation history for each orbit. The Plutonium Files: America's Secret Medical Experiments in the Cold War is a 1999 book by Eileen Welsome. It is a history of U.S. government-engineered radiation experiments on unwitting Americans, based on the Pulitzer Prize–winning series Welsome wrote for The Albuquerque Tribune. With their closest relatives, the Maluridae (Australian fairy-wrens), Pardalotidae (pardalotes), and Acanthizidae (thornbills, Australian warblers, scrubwrens, etc.) comprise the superfamily Meliphagoidea and originated early in the evolutionary history of the oscine passerine radiation. # Mathematics The Sakuma–Hattori equation is a mathematical model for predicting the amount of thermal radiation, radiometric flux or radiometric power emitted from a perfect blackbody or received by a thermal radiation detector. In its general form it looks like: where: The Stokes parameters are a set of values that describe the polarization state of electromagnetic radiation. The relationship of the Stokes parameters to intensity and polarization ellipse parameters is shown in the equations below and the figure at right. S_0 &= I \\ S_1 &= p I \cos 2\psi \cos 2\chi\\ S_2 &= p I \sin 2\psi \cos 2\chi\\ S_3 &= p I \sin 2\chi. \end{align} Here p I, 2\psi and 2\chi are the spherical coordinates of the three-dimensional vector of cartesian coordinates(S_1, S_2, S_3). I is the total intensity of the beam, and p is the degree of polarization. The factor of two before \psi represents the fact that any polarization ellipse is indistinguishable from one rotated by 180°, while the factor of two before \chi indicates that an ellipse is indistinguishable from one with the semi-axis lengths swapped accompanied by a 90° rotation. The four Stokes parameters are sometimes denoted I, Q, U and V, respectively. If given the Stokes parameters one can solve for the spherical coordinates with the following equations: I &= S_0 \\ p &= \frac{\sqrt{S_1^2 + S_2^2 + S_3^2}}{S_0} \\ 2\psi &= \mathrm{atan} \frac{S_2}{S_1}\\ 2\chi &= \mathrm{atan} \frac{S_3}{\sqrt{S_1^2+S_2^2}}.\\ \end{align} # Physics A particle on the exact design trajectory (or design orbit) of the accelerator only experiences dipole field components, while particles with transverse position deviation \scriptstyle x(s) are re-focused to the design orbit. For preliminary calculations, neglecting all fields components higher than quadrupolar, an inhomogenic Hill differential equation can be used as an approximation, with thus identifying the system as a parametric oscillator. Beam parameters for the accelerator can then be calculated using ray transfer matrix analysis; e.g., a quadrupolar field is analogous to a lens in geometrical optics, having similar properties regarding beam focusing (but obeying Earnshaw's theorem). # Roentgens Def. the radiation exposure equal to the quantity of ionizing radiation that will produce one esu of charge in one cubic centimetre of dry air at 0 °C and a standard atmosphere is called a roentgen. Using an air ionization energy of about 35 J/C, we have 1 Gy ≈ 111 R. # Technology The RHPPC is a radiation hardened processor based on PowerPC 603e technology licensed from Motorola (now Freescale) and manufactured by Honeywell. The RHPPC is equivalent to the commercial PowerPC 603e processor with the minor exceptions of the phase locked loop (PLL) and the processor version register (PVR). The RHPPC processor is compatible with the PowerPC architecture (Book I-III), the PowerPC 603e programmers interface and is also supported by common PowerPC software tools and embedded operating systems, like VxWorks. Demron is a radiation-blocking fabric made by Radiation Shield Technologies. The material is said to have radiation protection similar to lead shielding, while being lightweight and flexible. The composition of Demron is proprietary, but is described as a non-toxic polymer. According to its manufacturer, while Demron shields the wearer from radiation alone, it can be coupled with different protective materials to block chemical and biological threats as well. Demron is roughly three to four times more expensive than a conventional lead apron, but can be treated like a normal fabric for cleaning, storage and disposal. More recent uses for Demron include certified first responder hazmat suits as well as tactical vests. Demron is proven by the United States Department of Energy to significantly reduce high energy alpha and beta radiation, and reduce low energy gamma radiation. When several sheets of Demron are laminated together the result is a much more powerful shield, though Demron cannot completely block all gamma radiation. # Protection Radiation protection, sometimes known as radiological protection, is the protection of people and the environment from the harmful effects of ionizing radiation, which includes both particle radiation and high energy electromagnetic radiation. causes microscopic damage to living tissue, resulting in skin burns and radiation sickness at high exposures and statistically elevated risks of cancer, tumors and genetic damage at low exposures. There are three factors that control the amount, or dose, of radiation received from a source. Radiation exposure can be managed by a combination of these factors: - Time: Reducing the time of an exposure reduces the effective dose proportionally. An example of reducing radiation doses by reducing the time of exposures might be improving operator training to reduce the time they take to handle a source. - Distance: Increasing distance reduces dose due to the inverse square law. Distance can be as simple as handling a source with forceps rather than fingers. - Shielding: The term 'biological shield' refers to a mass of absorbing material placed around a reactor, or other radioactive source, to reduce the radiation to a level safe for humans. # Gloveboxes A glovebox (or glove box) is a sealed container that is designed to allow one to manipulate objects where a separate atmosphere is desired. Built into the sides of the glovebox are gloves arranged in such a way that the user can place their hands into the gloves and perform tasks inside the box without breaking containment. Part or all of the box is usually transparent to allow the user to see what is being manipulated. Two types of gloveboxes exist: one allows a person to work with hazardous substances, such as radioactive materials or infectious disease agents; the other allows manipulation of substances that must be contained within a very high purity inert atmosphere, such as argon or nitrogen. It is also possible to use a glovebox for manipulation of items in a vacuum chamber. Gloveboxes used for hazardous materials generally are maintained at a lower pressure than the surrounding atmosphere, so that microscopic leaks result in air intake rather than hazard outflow. Gloveboxes used for hazardous materials generally incorporate HEPA filters into the exhaust, to keep the hazard contained. # Shield effectiveness The effectiveness of a material as a biological shield is related to its cross-section for scattering and absorption, and to a first approximation is proportional to the total mass of material per unit area interposed along the line of sight between the radiation source and the region to be protected. Hence, shielding strength or "thickness" is conventionally measured in units of g/cm2. The radiation that manages to get through falls exponentially with the thickness of the shield. In X-ray facilities, the plaster on the rooms with the x-ray generator contains barium sulfate and the operators stay behind a leaded glass screen and wear lead aprons. Almost any material can act as a shield from gamma or x-rays if used in sufficient amounts. Practical radiation protection tends to be a job of juggling the three factors to identify the most cost effective solution. # Hypotheses - Radiation has a continuum of speeds.	Radiation Editor-In-Chief: Henry A. Hoff Radiation is an action or process of throwing or sending out a traveling ray in a line, beam, or stream of small relative cross section. At right is an image of an impact crater on the surface of Venus. It is a likely example of meteor radiation damage. # Rays Def. a beam of light or radiation is called a ray. Def. an action or process of throwing or sending out a traveling ray in a line, beam, or stream of small cross section is called radiation. The term radiation is often used to refer to the ray itself. Def. the shooting forth of anything from a point or surface, like the diverging rays of light; as, the radiation of heat is called radiation. Rays may have a temporal, spectral, or spatial distribution. They may also be dependent on other variables as yet unknown. A delta ray is characterized by very fast electrons produced in quantity by alpha particles or other fast energetic charged particles knocking orbiting electrons out of atoms. Collectively, these electrons are defined as delta radiation when they have sufficient energy to ionize further atoms through subsequent interactions on their own. Epsilon radiation is tertiary radiation caused by secondary radiation (e.g., delta radiation). Epsilon rays are a form of particle radiation and are composed of electrons. The term is very rarely used today. # Radiation theory Def. a theory of the science of the biological, chemical, physical, and logical laws (or principles) with respect to any radiation is called a theory of radiation. Particle radiation consists of a stream of charged or neutral particles, from the size of subatomic elementary particles upwards of rocky and gaseous objects to even larger more loosely bound entities. # Strong forces A "new type of neutron star model (Q stars) [is such that] high-density, electrically neutral baryonic matter is a coherent classical solution to an effective field theory of strong forces and is bound in the absence of gravity. [...] allows massive compact objects, [...] and has no macroscopic minimum mass."[1] "Compact objects in astronomy are usually analyzed in terms of theoretical characteristics of neutron stars or black holes that are based upon calculations of equations of state for matter at very high densities. At such high densities, the effects of strong forces cannot be neglected. There are several conventional approaches to describing nuclear forces, all of which find that for a baryon number greater than ~250, a nucleus will become energetically unbound. High-density hadronic matter is not stable in these theories until there are enough baryons for gravitational binding to form a neutron star, typically with a minimum mass ≳ 0.1 M⊙ and maximum mass ≲ 3 M⊙."[1] "Another possibility [called "baryon matter"] is that in the absence of gravity high-density baryonic matter is bound by purely strong forces. [...] nongravitationally bound bulk hadronic matter is consistent with nuclear physics data [...] and low-energy strong interaction data [...] The effective field theory approach has many successes in nuclear physics [...] suggesting that bulk hadronic matter is just as likely to be a correct description of matter at high densities as conventional, unbound hadronic matter."[1] "The idea behind baryon matter is that a macroscopic state may exist in which a smaller effective baryon mass inside some region makes the state energetically favored over free particles. [...] This state will appear in the limit of large baryon number as an electrically neutral coherent bound state of neutrons, protons, and electrons in β-decay equilibrium."[1] # Meteors Particle radiation upwards in size above that of atomic nuclei may be lumped together as meteor radiation. # Galaxy clusters "Galaxies and clusters of galaxies are not uniformly distributed in the Universe, instead they collect into vast clusters and sheets and walls of galaxies interspersed with large voids in which very few galaxies seem to exist. The map above shows many of these superclusters including the Virgo supercluster - the minor supercluster of which our galaxy is just a minor member. The entire map is approximately 7 percent of the diameter of the entire visible Universe."[2] # High-velocity galaxies "The irregular galaxy NGC 1427A is a spectacular example of the resulting stellar rumble. Under the gravitational grasp of a large gang of galaxies, called the Fornax cluster, the small bluish galaxy is plunging headlong into the group at 600 kilometers per second or nearly 400 miles per second."[3] "Galaxy clusters, like the Fornax cluster, contain hundreds or even thousands of individual galaxies. Within the Fornax cluster, there is a considerable amount of gas lying between the galaxies. When the gas within NGC 1427A collides with the Fornax gas, it is compressed to the point that it starts to collapse under its own gravity. This leads to formation of the myriad of new stars seen across NGC 1427A, which give the galaxy an overall arrowhead shape that appears to point in the direction of the galaxy's high-velocity motion."[3] # Hypervelocity stars "To date, all of the reported hypervelocity stars (HVSs), which are believed to be ejected from the Galactic center, are blue and therefore almost certainly young.”[4] Def. a high-velocity star moving through space with an abnormally high velocity relative to the surrounding interstellar medium is called a runaway star. # Clouds Def. a visible mass of - water droplets suspended in the air ... - dust, - steam ... - smoke ... - a group or swarm is called a cloud. Clouds have been observed on other planets and moons within the Solar System, but, due to their different temperature characteristics, they are composed of other substances such as methane, ammonia, and sulfuric acid. # Aerometeors Def. a discrete unit of air, wind, or mist traveling or falling through or partially through an atmosphere is called an aerometeor. Def. any of the high-speed, high-altitude air currents that circle the Earth in a westerly direction is called a jet stream. # Plasma meteors A coronal cloud is a cloud, or cloud-like, natural astronomical entity, composed of plasma and usually associated with a star or other astronomical object where the temperature is such that X-rays are emitted. While small coronal clouds are above the photosphere of many different visual spectral type stars, others occupy parts of the interstellar medium (ISM), extending sometimes millions of kilometers into space, or thousands of light-years, depending on the size of the associated object such as a galaxy. At left is a radiated object and its associated phenomena. Ultra-violet studies of Mira by NASA's Galaxy Evolution Explorer (Galex) space telescope have revealed that it sheds a trail of material from the outer envelope, leaving a tail 13 light-years in length, formed over tens of thousands of years.[5][6] It is thought that a hot bow-wave of compressed plasma/gas is the cause of the tail; the bow-wave is a result of the interaction of the stellar wind from Mira A with gas in interstellar space, through which Mira is moving at an extremely high speed of 130 kilometres/second (291,000 miles per hour).[7][8] The tail consists of material stripped from the head of the bow-wave, which is also visible in ultra-violet observations. Mira's bow-shock will eventually evolve into a planetary nebula, the form of which will be considerably affected by the motion through the interstellar medium (ISM).[9] # Gaseous meteors Gaseous objects have at least one chemical element or compound present in the gaseous state. These gaseous components make up at least 50 % of the detectable portion of the gaseous object. Atmospheric astronomy determines whether gaseous objects have layers or spherical portions predominantly composed of gas. Within these spherical portions may occur various gaseous meteors such as clouds, winds, or streams. # Liquid meteors Liquid water precipitation falls from the atmosphere and reaches the ground, such as drizzle and rain. Suspended liquid water particles may form and remain suspended in the air (damp haze, cloud, fog, and mist), or may be lifted by the wind from the Earth’s surface (blowing spray) causing restrictions to visibility.[10] # Rocky meteors "A skydiver may have captured the first film ever of a meteorite plunging down at terminal velocity, also known as its “dark flight” stage."[11] "The footage was captured in 2012 by a helmet cam worn by Anders Helstrup as he and other members of the Oslo Parachute Club jumped from a small plane that took off from an airport in Hedmark, Norway."[11] “It can’t be anything else. The shape is typical of meteorites -- a fresh fracture surface on one side, while the other side is rounded.”[12] “It has never happened before that a meteorite has been filmed during dark flight; this is the first time in world history.”[12] "Having the rock in hand would certainly help. But despite triangulations and analyses, Helstrup and his recruits still haven’t found it."[11] # Meteoroids Def. a relatively small (sand- to boulder-sized) fragment of debris in a solar system is called a meteoroid. "As of 2011 the International Astronomical Union officially defines a meteoroid as a solid object moving in interplanetary space, of a size considerably smaller than an asteroid and considerably larger than an atom".[13][14] The visible path of a meteoroid that enters the Earth's atmosphere (or another body's) atmosphere is called a meteor, or colloquially a shooting star or falling star. If a meteoroid reaches the ground and survives impact, then it is called a meteorite. Beech and Steel, writing in Quarterly Journal of the Royal Astronomical Society, proposed a new definition where a meteoroid is between 100 µm and 10 m across.[15] Following the discovery and naming of asteroids below 10 m in size (e.g., 2008 TC3), Rubin and Grossman refined the Beech and Steel definition of meteoroid to objects between 10 µm and 1 m in diameter.[16] The [near-Earth object] NEO definition includes larger objects, up to 50 m in diameter, in this category. Very small meteoroids are known as micrometeoroids (see also interplanetary dust). The composition of meteoroids can be determined as they pass through Earth's atmosphere from their trajectories and the light spectra of the resulting meteor. Their effects on radio signals also give information, especially useful for daytime meteors which are otherwise very difficult to observe. The light spectra, combined with trajectory and light curve measurements, have yielded various compositions and densities, ranging from fragile snowball-like objects with density about a quarter that of ice,[17] to nickel-iron rich dense rocks. In meteoroid ablation spheres from deep-sea sediments, "[t]he silicate spheres are the most dominant group."[18] From these trajectory measurements, meteoroids have been found to have many different orbits, some clustering in streams (see Meteor showers) often associated with a parent comet, others apparently sporadic. Debris from meteoroid streams may eventually be scattered into other orbits. ... Meteoroids travel around the Sun in a variety of orbits and at various velocities. The fastest ones move at about 26 miles per second (42 kilometers per second) through space in the vicinity of Earth's orbit. The Earth travels at about 18 miles per second (29 kilometers per second). Thus, when meteoroids meet the Earth's atmosphere head-on (which would only occur if the meteors were in a retrograde orbit), the combined speed may reach about 44 miles per second (71 kilometers per second). Meteoroids moving through the earth's orbital space average about 20 km/s.[19] # Fireballs A relatively small percentage of meteoroids hit the Earth's atmosphere and then pass out again: these are termed Earth-grazing fireballs (for example The Great Daylight 1972 Fireball). For 2011 there are 4589 fireball records at the American Meteor Society.[20] "At 66 kilometers (41 miles) per second, they appear as fast streaks, faster by a hair than their sisters, the Eta Aquarids of May. And like the Eta Aquarids, the brightest of family tend to leave long-lasting trains. Fireballs are possible three days after maximum."[21] # Bolides Def. a fireball reaching magnitude −14 or brighter is called a bolide.[22] Def. a fireball reaching an magnitude −17 or brighter is called a superbolide. # Meteor showers Meteors may occur in showers, which arise when the Earth passes through a trail of debris left by a comet, or as "random" or "sporadic" meteors, not associated with a specific single cause. A number of specific meteors have been observed, largely by members of the public and largely by accident. # Cryometeors A megacryometeor is a very large chunk of ice sometimes called huge hailstones, but do not need to form in thunderstorms. # Lithometeors Def. a suspension of dry dust in the atmosphere is called a lithometeor. Def. the solid material thrown into the air by a volcanic eruption that settles on the surrounding areas is called tephra. # Micrometeors A micrometeoroid is a tiny meteoroid; a small particle of rock in space, usually weighing less than a gram. A micrometeorite is such a particle that survives passage through the Earth's atmosphere and reaches the Earth's surface. Micrometeoroids are extremely common in space. [These tiny] particles are a major contributor to space weathering processes. When they hit the surface of the Moon, or any airless body (Mercury, the asteroids, etc.), the resulting melting and vaporization causes darkening and other optical changes in the regolith. Micrometeoroids have less stable orbits than meteoroids, due to their greater surface area to mass ratio. Micrometeoroids pose a significant threat to space exploration.[23] Their velocities relative to a spacecraft in orbit average 10 kilometers per second (22,500 mph),[23] and resistance to micrometeoroid impact is a significant design challenge for spacecraft and space suit designers (See Thermal Micrometeoroid Garment). While the tiny sizes of most micrometeoroids limits the damage incurred, the high velocity impacts will constantly degrade the outer casing of spacecraft in a manner analogous to sandblasting. Long term exposure can threaten the functionality of spacecraft systems. # Hydrometeors Def. precipitation products of the condensation of atmospheric water vapour are called hydrometeors. Def. any or all of the forms of water particles, whether liquid or solid, that fall from the atmosphere are called precipitation. # Particles The Comprehensive Suprathermal and Energetic Particle Analyzer (COSTEP) aboard SOHO "detects and classifies very energetic particle populations of solar, interplanetary, and galactic origin."[24] # Ionizing radiation While large objects may induce the gain or loss of charge from another object, ionizing radiation is usually thought of as on the order of or smaller than an atom. Different types of ionizing radiation behave in different ways, so different shielding techniques are used. - Particle radiation consists of a stream of charged or neutral particles, both charged ions and subatomic elementary particles. This includes solar wind, cosmic radiation, and neutron flux in nuclear reactors. - Alpha particles (helium nuclei) are the least penetrating. Even very energetic alpha particles can be stopped by a single sheet of paper. - Beta particles (electrons) are more penetrating, but still can be absorbed by a few millimeters of aluminum. However, in cases where high energy beta particles are emitted shielding must be accomplished with low density materials, e.g. plastic, wood, water or acrylic glass (Plexiglas, Lucite). This is to reduce generation of Bremsstrahlung X-rays. In the case of beta+ radiation (positrons), the gamma radiation from the electron-positron annihilation reaction poses additional concern. - Neutron radiation is not as readily absorbed as charged particle radiation, which makes this type highly penetrating. Neutrons are absorbed by nuclei of atoms in a nuclear reaction. This most-often creates a secondary radiation hazard, as the absorbing nuclei transmute to the next-heavier isotope, many of which are unstable. - Cosmic radiation is not a common concern, as the Earth's atmosphere absorbs it and the magnetosphere acts as a shield, but it poses a problem for satellites and astronauts and frequent fliers are also at a slight risk. Cosmic radiation is extremely high energy, and is very penetrating. - Electromagnetic radiation consists of emissions of electromagnetic waves, the properties of which depend on the wavelength. - X-ray and gamma radiation are best absorbed by atoms with heavy nuclei; the heavier the nucleus, the better the absorption. In some special applications, depleted uranium is used, but lead is much more common; several centimeters are often required. Barium sulfate is used in some applications too. However, when cost is important, almost any material can be used, but it must be far thicker. Most nuclear reactors use thick concrete shields to create a bioshield with a thin water cooled layer of lead on the inside to protect the porous concrete from the coolant inside. The concrete is also made with heavy aggregates, such as Baryte, to aid in the shielding properties of the concrete. - Ultraviolet (UV) radiation is ionizing but it is not penetrating, so it can be shielded by thin opaque layers such as sunscreen, clothing, and protective eyewear. Protection from UV is simpler than for the other forms of radiation above, so it is often considered separately. In some cases, improper shielding can actually make the situation worse, when the radiation interacts with the shielding material and creates bremsstrahlung secondary radiation that absorbs in the organisms more readily. # Cosmic rays Cosmic rays are energetic charged subatomic particles, originating in outer space. At right is an image indicating the range of cosmic-ray energies. The flux for the lowest energies (yellow zone) is mainly attributed to solar cosmic rays, intermediate energies (blue) to galactic cosmic rays, and highest energies (purple) to extragalactic cosmic rays.[25] "Cosmic rays arise from galactic source accelerators."[26] Cosmic rays may be upwards of a ZeV (1021 eV). About 89% of cosmic rays are simple protons or hydrogen nuclei, 10% are helium nuclei of alpha particles, and 1% are the nuclei of heavier elements. Solitary electrons constitute much of the remaining 1%. Def. cosmic rays that originate from astrophysical sources are called primary cosmic rays. Def. cosmic rays that are created when primary cosmic rays interact with interstellar matter are called secondary cosmic rays. Def. low energy cosmic rays associated with solar flares are called solar cosmic rays. Cosmic rays are not charge balanced; that is, positive ions heavily outnumber electrons. The positive ions are - free protons, - alpha particles (helium nuclei), - lithium nuclei, - beryllium nuclei, and - boron nuclei. # Neutrals Neutrals are usually neutral atoms, or molecules. But they also can be neutral subatomic particles such as the neutron, neutral pions, and the neutrino. # Subatomics Subatomics involves one or more subatomic particles or radiation. The bare nuclei of atoms may qualify as a form of subatomics. Def. - particles that are constituents of the atom, or are smaller than an atom; such as proton, neutron, electron, etc or - any length or mass that is smaller in scale than a the diameter of a hydrogen atom are called subatomics, or subatomic, respectively. As a bare uranium nucleus is smaller than a hydrogen atom in diameter, but much larger in mass, it qualifies as one of the subatomics. Here, subatomic is used to mean smaller than the diameter of a hydrogen atom. # Lithium nuclei The "evidence for the overwhelming majority of the Li-atoms in photospheres has its origin not only in nuclear synthesis near the stellar centers, but also by active processes in stellar atmospheres. [...] the lithium [resonance] line [is] near 478 keV."[27] "Approximately 90% of lithium atoms originate from α - α reactions for the typical spectra of an accelerated particles on the Sun [...] During impulsive flares, interaction between the accelerated particles and the ambient medium occurs mainly at low altitudes, i.e., close to the footprints of loops."[27] # Alphas About 89% of cosmic rays are simple protons or hydrogen nuclei, 10% are helium nuclei or alpha particles, and 1% are the nuclei of heavier elements. Solitary electrons constitute much of the remaining 1%. # Helions Def. a nucleus of a helium-3 atom" is called a helion. # Tritons Energetic deuterons and tritons have been detected in solar flares.[28] # Deuterons "The flux [of deuterons in cosmic rays at a geomagnetic latitude of 7.6°N] is found to be 4 ± 1.3 M-2 sec-1 sterad-1".[29] # Baryons In "dense nuclear matter, such as neutron stars [it] has recently been discovered that kaon condensation in nuclear matter at a density of a few times normal nuclear matter may significantly reduce the upper mass limit of neutron stars [...] This clearly has an impact on astronomical observations. By exploiting the electron fermi level, we are able to predict kaon production at reasonable baryon number densities [...] Experimental detection of [dibaryons, hyperons] is a subtle matter [...] there is strong theoretical evidence that such states [as the dibaryon] do exist in nature. [...] the lightest dibaryon [...] is energetically stable against strong decay to [ΛΛ baryons] by 88 MeV. [The H dibaryon] is bound by 250 MeV."[30] # Radioactivity Def. a spontaneous emission of an α ray, β ray, or γ ray by the disintegration of an atomic nucleus is called radioactivity.[31] Although alpha, beta, and gamma radiations were found most commonly, other types of decay were eventually discovered. Shortly after the discovery of the positron in cosmic ray products, it was realized that the same process that operates in classical beta decay can also produce positrons (positron emission). In an analogous process, instead of emitting positrons and neutrinos, some proton-rich nuclides were found to capture their own atomic electrons (electron capture), and emit only a neutrino (and usually also a gamma ray). Each of these types of decay involves the capture or emission of nuclear electrons or positrons, and acts to move a nucleus toward the ratio of neutrons to protons that has the least energy for a given total number of nucleons (neutrons plus protons). # Hadrons Hadrons are subatomic particles of a type including baryons and mesons that can take part in the strong interaction and may be useful in astronomy. A hadron, like an atomic nucleus, is a composite particle held together by the strong force Hadrons are categorized into two families: baryons (such as protons and neutrons) and mesons. # Radioactivity emissions The nuclei of some atoms spontaneously disintegrate from one form of isotope to another until they reach a stable form. These atoms emit particles (alpha or beta) or electromagnetics (X-ray or gamma) which are different in charge, size, penetrating power and ionization energy. In Template:SubatomicParticle decay, or "positron emission", the weak interaction converts a nucleus into its next-lower neighbor on the periodic table while emitting an positron (Template:SubatomicParticle) and an electron neutrino (Template:SubatomicParticle): ^A_ZN \rightarrow ~ ^{~~~A}_{Z-1}N' + e^+ + \nu_e. </math> Template:SubatomicParticle decay cannot occur in an isolated proton because it requires energy due to the mass of the neutron being greater than the mass of the proton. Template:SubatomicParticle decay can only happen inside nuclei when the value of the binding energy of the mother nucleus is less than that of the daughter nucleus. The difference between these energies goes into the reaction of converting a proton into a neutron, a positron and a neutrino and into the kinetic energy of these particles. Positron emission' or beta plus decay (β+ decay) is a type of beta decay in which a proton is converted, via the weak force, to a neutron, releasing a positron and a neutrino. Isotopes which undergo this decay and thereby emit positrons include carbon-11, potassium-40, nitrogen-13, oxygen-15, fluorine-18, and iodine-121. As an example, the following equation describes the beta plus decay of carbon-11 to boron-11, emitting a positron and a neutrino: ^{11}_{6}C \rightarrow ~ ^{11}_{5}B + e^+ + \nu_e + \gamma {(0.96 MeV)}. </math> # Antimatter Def. a subatomic particle corresponding to another particle with the same mass, spin and mean lifetime but with charge, parity, strangeness and other quantum numbers flipped in sign is called an antiparticle. Def. matter that is composed of antiparticles of those that constitute normal matter is called antimatter. # Annihilations The positron or antielectron is the antiparticle or the antimatter counterpart of the electron. The positron has an electric charge of +1e, a spin of ½, and has the same mass as an electron. When a low-energy positron collides with a low-energy electron, annihilation occurs, resulting in the production of two or more gamma ray photons. Def. the process of a particle and its corresponding antiparticle combining to produce energy is called annihilation. The figure at right shows a positron (e+) emitted from an atomic nucleus together with a neutrino (v). Subsequently, the positron moves randomly through the surrounding matter where it hits several different electrons (e-) until it finally loses enough energy that it interacts with a single electron. This process is called an "annihilation" and results in two diametrically emitted photons with a typical energy of 511 keV each. Under normal circumstances the photons are not emitted exactly diametrically (180 degrees). This is due to the remaining energy of the positron having conservation of momentum. Electron–positron annihilation occurs when an electron (Template:SubatomicParticle) and a positron (Template:SubatomicParticle, the electron's antiparticle) collide. The result of the collision is the annihilation of the electron and positron, and the creation of gamma ray photons or, at higher energies, other particles: The process [does] satisfy a number of conservation laws, including: - Conservation of electric charge. The net charge before and after is zero. - Conservation of linear momentum and total energy. This forbids the creation of a single gamma ray. However, in quantum field theory this process is described; see examples of annihilation. - Conservation of angular momentum. As with any two charged objects, electrons and positrons may also interact with each other without annihilating, in general by elastic scattering. The creation of only one photon can occur for tightly bound atomic electrons.[32] In the most common case, two photons are created, each with energy equal to the rest energy of the electron or positron (511 keV).[33] It is also common for three to be created, since in some angular momentum states, this is necessary to conserve C parity.[34] Any larger number of photons can be created, but the probability becomes lower with each additional photon. When either the electron or positron, or both, have appreciable kinetic energies, other heavier particles can also be produced (such as D mesons), since there is enough kinetic energy in the relative velocities to provide the rest energies of those particles. Photons and other light particles [may be produced], but they will emerge with higher energies. At energies near and beyond the mass of the carriers of the weak force, the W and Z bosons, the strength of the weak force becomes comparable with electromagnetism.[34] It becomes much easier to produce particles such as neutrinos that interact only weakly. The heaviest particle pairs yet produced by electron–positron annihilation are [[w:W boson\|Template:SubatomicParticle–Template:SubatomicParticle]] pairs. The heaviest single particle is the Z boson. Annihilation radiation is not monoenergetic, unlike gamma rays produced by radioactive decay. The production mechanism of annihilation radiation introduces Doppler broadening.[35] The annihilation peak produced in a gamma spectrum by annihilation radiation therefore has a higher full width at half maximum (FWHM) than other gamma rays in [the] spectrum. The difference is more apparent with high resolution detectors, such as Germanium detectors, than with low resolution detectors such as Sodium iodide Because of their well-defined energy (511 keV) and characteristic, Doppler-broadened shape, annihilation radiation can often be useful in defining the energy calibration of a gamma ray spectrum. # Positroniums Def. an exotic atom consisting of a positron and an electron, but having no nucleus or an onium consisting of a positron (anti-electron) and an electron, as a particle–anti-particle bound pair is called positronium. Being unstable, the two particles annihilate each other to produce two gamma ray photons after an average lifetime of 125 ps or three gamma ray photons after 142 ns in vacuum, depending on the relative spin states of the positron and electron. The singlet state with antiparallel spins ([spin quantum number] S = 0, Ms = 0) is known as para-positronium (p-Ps) and denoted Template:SubatomicParticle. It has a mean lifetime of 125 picoseconds and decays preferentially into two gamma quanta with energy of 511 keV each (in the center of mass frame). Detection of these photons allows for the reconstruction of the vertex of the decay ... Para-positronium can decay into any even number of photons (2, 4, 6, ...), but the probability quickly decreases as the number increases: the branching ratio for decay into 4 photons is 6994143900000000000♠1.439(2)×10−6.[36] para-positronium lifetime (S = 0):[36] The triplet state with parallel spins (S = 1, Ms = −1, 0, 1) is known as ortho-positronium (o-Ps) and denoted 3S1. The triplet state in vacuum has a mean lifetime of 6993142050000000000♠142.05±0.02 ns[37] and the leading mode of decay is three gamma quanta. Other modes of decay are negligible; for instance, the five photons mode has branching ratio of ~6994100000000000000♠1.0×10−6.[38] ortho-positronium lifetime (S = 1):[36] # Pair production The reverse reaction, electron–positron creation, is a form of pair production governed by two-photon physics. Two-photon physics, also called gamma-gamma physics, [studies] the interactions between two photons. If the energy in the center of mass system of the two photons is large enough, matter can be created.[39] In nuclear physics, [the above reaction] occurs when a high-energy photon interacts with a nucleus. The photon must have enough energy [> 2*511 keV, or 1.022 MeV] to create an electron plus a positron. Without a nucleus to absorb momentum, a photon decaying into electron-positron pair (or other pairs for that matter [such as a muon and anti-muon or a tau and anti-tau] can never conserve energy and momentum simultaneously.[40] These interactions were first observed in Patrick Blackett's counter-controlled cloud chamber. In 2008 the Titan laser aimed at a 1-millimeter-thick gold target was used to generate positron–electron pairs in large numbers.[41]. "The LLNL scientists created the positrons by shooting the lab's high-powered Titan laser onto a one-millimeter-thick piece of gold."[41] # Neutrons "Due to the very low energy of the colliding protons in the Sun, only states with no angular momentum (s-waves) contribute significantly. One can consider it as a head-on collision, so that angular momentum plays no role. Consequently, the total angular momentum is the sum of the spins, and the spins alone control the reaction. Because of Pauli's exclusion principle, the incoming protons must have opposite spins. On the other hand, in the only bound state of deuterium, the spins of the neutron and proton are aligned. Hence a spin flip must take place [...] The strength of the nuclear force which holds the neutron and the proton together depends on the spin of the particles. The force between an aligned proton and neutron is sufficient to give a bound state, but the interaction between two protons does not yield a bound state under any circumstances. Deuterium has only one bound state."[42] The "force acting between the protons and the neutrons [is] the strong force".[42] "A potential of 36 MeV is needed to get just one energy state."[42] The width of a bound proton and neutron is "2.02 x 10-13 cm".[42] # Protons The proton is a subatomic particle with the symbol Template:SubatomicParticle or Template:SubatomicParticle and a positive electric charge of 1 elementary charge. One or more protons are present in the nucleus of each atom, along with neutrons. The number of protons in each atom is its atomic number. Nucleon spin structure describes the partonic structure of proton intrinsic angular momentum (spin). The key question is how the nucleon's spin, whose magnitude is 1/2ħ, is carried by its [suggested] constituent partons (quarks and gluons). In the late 1980s, the European Muon Collaboration (EMC) conducted experiments that suggested the spin carried by quarks is not sufficient to account for the total spin of [protons]. This finding astonished particle physicists at that time, and the problem of where the missing spin lies is sometimes referred to as the "proton spin crisis". Experimental research on these topics has been continued by the Spin Muon Collaboration (SMC) and the COMPASS experiment at CERN, experiments E154 and E155 at [SLAC National Accelerator Laboratory] SLAC, HERMES at DESY, experiments at [Thomas Jefferson National Accelerator Facility] JLab and RHIC, and others. Global analysis of data from all major experiments confirmed the original EMC discovery and showed that the quark spin [may] contribute about 30% to the total spin of the nucleon. New measurements performed by European scientists reveal that the radius of the proton is 4 percent smaller than previously estimated.[43] The antiproton (Template:SubatomicParticle, pronounced p-baer) is the antiparticle of the proton. Antiprotons are stable, but they are typically short-lived since any collision with a proton will cause both particles to be annihilated in a burst of energy. Antiprotons have been detected in cosmic rays for over 25 years, first by balloon-borne experiments and more recently by satellite-based detectors. The standard picture for their presence in cosmic rays is that they are produced in collisions of cosmic ray protons with nuclei in the interstellar medium, via the reaction, where A represents a nucleus: The secondary antiprotons (Template:SubatomicParticle) then propagate through the galaxy, confined by the galactic magnetic fields. Their energy spectrum is modified by collisions with other atoms in the interstellar medium. The antiproton cosmic ray energy spectrum is now measured reliably and is consistent with this standard picture of antiproton production by cosmic ray collisions.[44] # Mesons Mesons are hadronic subatomic particles, bound together by the strong interaction. Because mesons are composed of sub-particles, they have a physical size, with a radius roughly one femtometre, which is about 2⁄3 the size of a proton or neutron. Charged mesons decay (sometimes through intermediate particles) to form electrons and neutrinos. Uncharged mesons may decay to photons. Mesons are not produced by radioactive decay, but appear in nature only as short-lived products of very high-energy interactions in matter In cosmic ray interactions, for example, such particles are ordinary protons and neutrons. Mesons are also frequently produced artificially in high-energy particle accelerators that collide protons, anti-protons, or other particles. Mesons are subject to "both the weak and strong interactions. Mesons with net electric charge also participate in the electromagnetic interaction. While no meson is stable, those of lower mass are nonetheless more stable than the most massive mesons, and are easier to observe and study in particle accelerators or in cosmic ray experiments. They are also typically less massive than baryons, meaning that they are more easily produced in experiments, and thus exhibit certain higher energy phenomena more readily than baryons composed of the same quarks would. Potential mesons to be detected astronomically include: π, ρ, η, η′, φ, ω, J/ψ, ϒ, θ, K, B, D, and T. Single π0 production occurs "in neutral current neutrino interactions with water by a 1.3 GeV wide band neutrino beam."[45] "The Gamma-Ray Spectrometer (GRS) on [Solar Maximum Mission] SMM has detected [...] at least two of the flares have spectral properties >40 MeV that require gamma rays from the decay of neutral pions. [Pion] production can occur early in the impulsive phase as defined by hard X-rays near 100 keV."[46] Gamma-ray "emission matches remarkably well both the position and shape of the inner [supernova remnant] SNR shocked plasma. Furthermore, the gamma-ray spectrum shows a prominent peak near 1 GeV with a clear decrement at energies below a few hundreds of MeV as expected from neutral pion decay."[47] # Beta-particles Beta particles are high-energy, high-speed electrons or positrons emitted by certain types of radioactive nuclei such as potassium-40. The beta particles emitted are a form of ionizing radiation also known as beta rays. The production of beta particles is termed beta decay. They are designated by the Greek letter beta (β). # Electrons The electron is a subatomic particle with a negative charge, equal to -1.60217646x10-19 C. Current, or the rate of flow of charge, is defined such that one coulomb, so 1/-1.60217646x10-19, or 6.24150974x1018 electrons flowing past a point per second give a current of one ampere. The charge on an electron is often given as -e. note that charge is always considered positive, so the charge of an electron is always negative. The electron has a mass of 9.10938188x10-31 kg, or about 1/1840 that of a proton. The mass of an electron is often written as me. When working, these values can usually be safely approximated to: It has no known components or substructure; in other words, it is generally thought to be an elementary particle.[48][49] The intrinsic angular momentum (spin) of the electron is a half-integer value in units of ħ, which means that it is a fermion. Def. a quasiparticle produced as a result of electron spin-charge separation is called a chargon. A chargon possesses the charge of an electron without a spin. A spinon, in turn, possesses the spin of an electron without charge. The suggestion is that an elementary particle such as a positron may consist of at least two parts: spin and charge. An electron may be a negative chargon plus a spinon. # Positrons "The two conversions of protons into neutrons are assumed to take place inside the nucleus, and the extra positive charge is emitted as a positron."[42] Def. the antimatter equivalent of an electron, having the same mass but a positive charge is called a positron. # Tauons "For ultrahigh energies the neutrino spectrum at the detector is influenced by neutrino-nucleon interactions and tauon decays during the passage through the interior of the earth."[50] Def. A lepton is a spin 1/2 particle a fermion that does not interact via the strong force. To date there are three known types of leptons. They are the electron, the muon (<math>\mu</math>), and the tauon (<math>\tau</math>) with their corresponding anti-particles that carry opposite charge (<math>+</math> instead of <math>-</math>). # Muons "TeV muons from γ ray primaries ... are rare because they are only produced by higher energy γ rays whose flux is suppressed by the decreasing flux at the source and by absorption on interstellar light."[51] The muon from the Greek letter mu (μ) used to represent it) is an elementary particle similar to the electron, with unitary negative electric charge (−1) and a spin of 1⁄2. Together with the electron, the tau, and the three neutrinos, it is classified as a lepton. As is the case with other leptons, the muon is not believed to have any sub-structure at all (i.e., is not thought to be composed of any simpler particles). The muon is an unstable subatomic particle with a mean lifetime of 6994220000000000000♠2.2 μs. This comparatively long decay lifetime (the second longest known) is due to being mediated by the weak interaction. The only longer lifetime for an unstable subatomic particle is that for the free neutron, a baryon particle composed of quarks, which also decays via the weak force. Muon decay produces three particles, an electron plus two neutrinos of different types. Like all elementary particles, the muon has a corresponding antiparticle of opposite charge (+1) but equal mass and spin: the antimuon (also called a positive muon). Muons are denoted by Template:SubatomicParticle and antimuons by Template:SubatomicParticle. # Neutrinos A neutrino is an electrically neutral, weakly interacting elementary subatomic particle[52] with half-integer spin. ... Neutrinos do not carry electric charge, which means that they are not affected by the electromagnetic forces that act on charged particles such as electrons and protons. Neutrinos are affected only by the weak sub-atomic force, of much shorter range than electromagnetism, and gravity, which is relatively weak on the subatomic scale. They are therefore able to travel great distances through matter without being affected by it. "If neutrinos have negligible rest mass, the present density expected for relic neutrinos from the big bang is nν = 110 (Tγ/2.7 K)3 cm–3 for each two-component species. This is of order the photon density nγ, differing just by a factor 3/11 (i.e. a factor 3/4 because neutrinos are fermions rather than bosons, multiplied by 4/11, the factor by which the neutrinos are diluted when e+–e– annihilation boosts the photon density). This conclusion holds for non-zero masses, provided that mvc2 is far below the thermal energy (~ 5 MeV) at which neutrinos decoupled from other species and that the neutrinos are stable for the Hubble time. Comparison with the baryon density, related to Ω via nb = 1.5 x 10–5 Ωb h2 cm–3, shows that neutrinos outnumber baryons by such a big factor that they can be dynamically dominant over baryons even if their masses are only a few electron volts. In fact, a single species of neutrino would yield a contribution to Ω of Ωv = 0.01 h–2 (mv)eV, so if h = 0.5, only 25 eV is sufficient to provide the critical density."[53] "Neutrinos of nonzero mass would be dynamically important not only for the expanding universe as a whole but also for large bound systems such as clusters of galaxies. This is because they would now be moving slowly: if the universe had cooled homogeneously, primordial neutrinos would now be moving at around 200 (mv)-1eV km s–1. They would be influenced even by the weak (~ 10–5 c2) gravitational potential fluctuations of galaxies and clusters. If the three (or more) types of neutrinos have different masses, then the heaviest will obviously be gravitationally dominant, since the numbers of each species should be the same."[53] # Electromagnetics Electromagnetics is most familiar as light, or electromagnetic radiation. # Superluminals "The existence of superluminal energy transfer has not been established so far, and one may ask why. There is the possibility that superluminal quanta just do not exist, the vacuum speed of light being the definitive upper bound. There is another explanation, the interaction of superluminal radiation with matter is very small, the quotient of tachyonic and electric fine-structure constants being q2/e2 ≈ 1.4 x 10-11 [5], and therefore superluminal quanta are hard to detect."[54] # Cherenkovs At right is an example of Cherenkov radiation. Cherenkov radiation (also spelled Čerenkov) is electromagnetic radiation emitted when a charged particle (such as an electron) passes through a dielectric medium at a speed greater than the phase velocity of light in that medium. Cherenkov radiation is an example of medium specific superluminals. # Entities The electron is a subatomic particle with a negative charge, equal to -1.60217646x10-19 C. Current, or the rate of flow of charge, is defined such that one coulomb, so 1/-1.60217646x10-19, or 6.24150974x1018 electrons flowing past a point per second give a current of one ampere. The charge on an electron is often given as -e. note that charge is always considered positive, so the charge of an electron is always negative. # Sources Def. the point of origin of a ray, beam, or stream of small cross section traveling in a line is called a radiation source. The image at right is the first X-ray light image of the Sun by the satellite GOES-15 Solar X-ray Imager (SXI) on June 2, 2010. The surface of the Sun, beneath the coronal cloud layer is dark. The coronal cloud is the actual source of the X-rays. "TeV muons from γ ray primaries ... are rare because they are only produced by higher energy γ rays whose flux is suppressed by the decreasing flux at the source and by absorption on interstellar light."[51] Muon decay produces three particles, an electron plus two neutrinos of different types. Electrons moving along a Birkeland current may be accelerated by a plasma double layer. If the resulting electrons approach relativistic velocities (i.e. if they approach the speed of light) they may subsequently produce a Bennett pinch, which in a magnetic field causes the electrons to spiral and emit synchrotron radiation that may include radio, optical (i.e. visible light), x-rays, and gamma rays. ""Dark" lightning is a type of electrical discharge within a thunderstorm that produces what are called terrestrial gamma-ray flashes."[55] "The fields accelerate electrons to almost the speed of light. Then, the electrons smash into air molecules and produce gamma-rays. The gamma-rays then produce electrons and their antimatter equivalents (positrons). These particles next crash into air molecules, and produce even more gamma-rays."[55] # Objects Electrons "provide remote-sensing observations of distant targets in the heliosphere - the Sun, the Moon, Jupiter, and various heliospheric structures."[56] The image at right is a painting by artist Giorgio Vasari (1511–1574). The main focus is on Cronus (Saturn) castrating Uranus (the Greek sky god). As both Uranus and Cronus are represented by men, this suggests that they were similar in nature. "[T]he ancients’ religions and mythology speak for their knowledge of Uranus; the dynasty of gods had Uranus followed by Saturn, and the latter by Jupiter. ... It is quite possible that the planet Uranus is the very planet known by this name to the ancients. The age of Uranus preceded the age of Saturn; it came to an end with the “removal” of Uranus by Saturn. Saturn is said to have emasculated his father Uranus."[57] # Continua Def. a continuous series or whole, no part of which is noticeably different from its adjacent parts, although the ends or extremes of it are very different from each other is called a continuum. Above is the electromagnetic spectrum. When each wavelength has the same intensity and background, the entire spectrum is a continuum. More generally, the electromagnetic spectrum, is often termed as either continuous (with energy at all wavelengths) or discrete (energy at only certain wavelengths). # Emissions Def. the act of sending or throwing out; the act of sending forth or putting into circulation is called emission. In Draft:physics, emission is the process by which a higher energy quantum mechanical state of a particle becomes converted to a lower one through the emission of a photon, resulting in the production of light. The frequency of light emitted is a function of the energy of the transition. Since energy must be conserved, the energy difference between the two states equals the energy carried off by the photon. The energy states of the transitions can lead to emissions over a very large range of frequencies. For example, visible light is emitted by the coupling of electronic states in atoms and molecules (then the phenomenon is called fluorescence or phosphorescence). On the other hand, nuclear shell transitions can emit high energy gamma rays, while nuclear spin transitions emit low energy radio waves. # Absorptions Def. the act or process of including so that a separate existence is no longer is called absorption. "There are a number of ways to quantify how quickly and effectively radiation is absorbed. The attenuation coefficient is a quantity that characterizes how easily a material or medium can be penetrated by a beam of light, sound, particles, or other energy or matter. The range of a heavy charged particle is approximately proportional to the mass of the particle and the inverse of the density of the medium, and is a function of the initial velocity of the particle. Def. the average energy loss of the particle per unit path length is called stopping power. # Bands Spectral bands are part of optical spectra of polyatomic systems, including condensed materials, large molecules, etc. Each line corresponds to one level in the atom splits in the molecules. When the number of atoms is large, one gets a continuum of energy levels, the so called "spectral bands". They are often labeled in the same way as the monatomic lines. Band spectra is the name given to a group of lines that are closely spaced and arranged in a regular sequence that appears to be a band. It is a colored band, separated by dark spaces on the two sides and arranged in a regular sequence. In one band, there are various sharp and wider color lines, that are closer on one side and wider on other. The intensity in each band falls off from definite limits and indistinct on the other side. In complete band spectra, there is a number lines in a band. The band spectrum is the combination of many different spectral lines, resulting from rotational, vibrational and electronic transition. # Backgrounds Background radiation is the ubiquitous ionizing radiation that the general population is exposed to, including natural and artificial sources. Both natural and artificial background radiation varies by location. The worldwide average natural dose to humans is about 2.4 millisievert (mSv) per year.[58] The biggest source of natural background radiation is airborne radon, a radioactive gas that emanates from the ground. Radon and its isotopes, parent radionuclides, and decay products all contribute to an average inhaled dose of 1.26 mSv/a. Radon is unevenly distributed and variable with weather, such that much higher doses apply to many areas of the world, where it represents a significant health hazard. Concentrations over 500 times higher than the world average have been found inside buildings in Scandinavia, the United States, Iran, and the Czech Republic.[59] Terrestrial radiation usually only includes sources that remain external to the body. The major radionuclides of concern are potassium, uranium and thorium and their decay products, some of which, like radium and radon are intensely radioactive but occur in low concentrations. An average human contains about 30 milligrams of potassium-40 (40K) and about 10 nanograms (10−8 g) of carbon-14 (14C), which has a decay half-life of 5,730 years. Excluding internal contamination by external radioactive material, the largest component of internal radiation exposure from biologically functional components of the human body is from potassium-40. The decay of about 4,000 nuclei of 40K per second[60] makes potassium the largest source of radiation in terms of number of decaying atoms. The energy of beta particles produced by 40K is also about 10 times more powerful than the beta particles from 14C decay. 14C is present in the human body at a level of 3700 Bq with a biological half-life of 40 days.[61] There are about 1,200 beta particles per second produced by the decay of 14C. However, a 14C atom is in the genetic information of about half the cells, while potassium is not a component of DNA. The decay of a 14C atom inside DNA in one person happens about 50 times per second, changing a carbon atom to one of nitrogen.[62] The global average internal dose from radionuclides other than radon and its decay products is 0.29 mSv/a, of which 0.17 mSv/a comes from 40K, 0.12 mSv/a comes from the uranium and thorium series, and 12 μSv/a comes from 14C.[58] Background radiation may simply be any radiation that is pervasive, whether ionizing or not. A particular example of this is the cosmic microwave background radiation, a nearly uniform glow that fills the sky in the microwave part of the spectrum; stars, galaxies and other objects of interest in radio astronomy stand out against this background. In a laboratory, background radiation refers to the measured value from any sources that affect an instrument when a radiation source sample is not being measured. This background rate, which must be established as a stable value by multiple measurements, usually before and after sample measurement, is subtracted from the rate measured when the sample is being measured. # Damages Def. susceptibility of a material to physical or chemical changes induced by radiation is called radiation sensitivity. The radiation effect depends on the type of the irradiating particles, their energy and the number of incident particles per unit volume. Def. harmful changes in the properties of materials caused by interactions with ionizing radiation is called radiation damage. Radiation damage is a term [usually] associated with ionizing radiation. Radiation may affect materials and devices in deleterious ways: - By causing the materials to become radioactive (mainly by neutron activation, or in [the] presence of high-energy gamma radiation by photodisintegration). - By nuclear transmutation of the elements within the material including, for example, the production of Hydrogen and Helium which can in turn alter the mechanical properties of the materials and cause swelling and embrittlement. - By radiolysis (breaking chemical bonds) within the material, which can weaken it, cause it to swell, polymerize, promote corrosion, cause belittlements, promote cracking or otherwise change its desirable mechanical, optical, or electronic properties. - By formation of reactive compounds, affecting other materials (e.g. ozone cracking by ozone formed by ionization of air). - By ionization, causing electrical breakdown, particularly in semiconductors employed in electronic equipment, with subsequent currents introducing operation errors or even permanently damaging the devices. Exposure to radiation causes chemical changes in gases. High-intensity ionizing radiation in air can produce a visible ionized air glow of telltale bluish-purplish color. Like gases, liquids lack fixed internal structure; the effects of radiation is therefore mainly limited to radiolysis, altering the chemical composition of the liquids. As with gases, one of the primary mechanisms is formation of free radicals. All liquids are subject to radiation damage, with few exotic exceptions; e.g. molten sodium, where there are no chemical bonds to be disrupted, and liquid hydrogen fluoride, which produces gaseous hydrogen and fluorine, which spontaneously react back to hydrogen fluoride. # Astronomy When any effort to acquire a system of laws or knowledge focusing on an astr, aster, or astro, that is, any natural body in the sky especially at night,[31] succeeds in discovering or exploring radiation even in its smallest measurement, radiation astronomy is the name of the effort and the result. Once an entity, source, or object has been detected as having radiation, it may be necessary to determine what the mechanism is. Usually this information provides understanding of the same entity, source, or object. The formation of radiation on Earth and its initial detection by hominins may be associated primarily with the available senses. # Sun "Energetic photons, ions and electrons from the solar wind, together with galactic and extragalactic cosmic rays, constantly bombard surfaces of planets, planetary satellites, dust particles, comets and asteroids."[63] # Coronal clouds "Coronal clouds, type IIIg, form in space above a spot area and rain streamers upon it."[64] A variety of subatomic particle and γ-ray reactions have been observed during solar flares indicating fusion reactions occurring at or above the photosphere. "There are typically 375 gamma-ray flares per solar cycle ... each releasing on average about 1031 erg of kinetic energy in accelerated ions of energy ≥ 1 MeV per nucleon [27]."[65] "The solar-flare gamma-ray line emission testifies that fresh nuclei are synthesized in abundance in energetic solar events."[65] "[T]he gamma-ray lines at 478 and 429 keV [are] emitted in the reactions 4He(α,p)7Li and 4He(α,n)7Be, respectively".[65] # Mercury The mosaic image of the rocky-object Mercury at right shows what appears to be meteor damage over a large portion of the surface. "The mosaic consists of 18 images taken at 42 s intervals during a 13 minute period when the spacecraft was 200,000 km (about 6 hours prior to closest approach) from the planet."[66] Mercury's surface is heavily cratered and similar in appearance to Earth's Moon Craters on Mercury range in diameter from small bowl-shaped cavities to multi-ringed impact basins hundreds of kilometers across. They appear in all states of degradation, from relatively fresh rayed craters to highly degraded crater remnants. Mercurian craters differ subtly from lunar craters in that the area blanketed by their ejecta is much smaller, a consequence of Mercury's stronger surface gravity.[67] # Venus In 1967, Venera-4 found the Venusian magnetic field is much weaker than that of Earth. This magnetic field is induced by an interaction between the ionosphere and the solar wind,[68][69] Venus's small induced magnetosphere provides negligible protection to the atmosphere against cosmic radiation. This radiation may result in cloud-to-cloud lightning discharges.[70] Strong 300 km/h winds at the cloud tops circle the planet about every four to five earth days.[71] Venusian winds move at up to 60 times the speed of the planet's rotation, while Earth's fastest winds are only 10% to 20% rotation speed.[72] While there is little or no water on Venus, there is a phenomenon which is quite similar to snow. The Magellan probe imaged a highly reflective substance at the tops of Venus's highest mountain peaks which bore a strong resemblance to terrestrial snow. This substance arguably formed from a similar process to snow, albeit at a far higher temperature. Too volatile to condense on the surface, it rose in gas form to cooler higher elevations, where it then fell as precipitation. The identity of this substance is not known with certainty, but speculation has ranged from elemental tellurium to lead sulfide (galena).[73] # Earth In the image at left is an aerial view of the Barringer Meteor Crater about 69 km east of Flagstaff, Arizona USA. Although similar to the aerial view of the Soudan crater, the Barringer Meteor Crater appears angular at the farthest ends rather than round. Meteor Crater is a meteorite impact crater approximately 43 miles (69 km) east of Flagstaff, near Winslow in the northern Arizona desert of the United States. Because the US Department of the Interior Division of Names commonly recognizes names of natural features derived from the nearest post office, the feature acquired the name of "Meteor Crater" from the nearby post office named Meteor.[74] The site was formerly known as the Canyon Diablo Crater, and fragments of the meteorite are officially called the Canyon Diablo Meteorite. Scientists refer to the crater as Barringer Crater in honor of Daniel Barringer, who was first to suggest that it was produced by meteorite impact.[75] From space the crater appears almost like a square. The image at right has a resolution of 2 meters per pixel, and illumination is from the right. Layers of exposed limestone and sandstone are visible just beneath the crater rim, as are large stone blocks excavated by the impact. The Holsinger meteorite is the largest discovered fragment of the meteorite that created Meteor Crater and it is exhibited in the crater visitor center. "The Canyon Diablo meteorite comprises many fragments of the asteroid that impacted at Barringer Crater (Meteor Crater), Arizona, USA. Meteorites have been found around the crater rim, and are named for nearby Canyon Diablo, which lies about three to four miles west of the crater. There are fragments in the collections of museums around the world including the Field Museum of Natural History in Chicago. The biggest fragment ever found is the Holsinger Meteorite, weighing 639 kg, now on display in the Meteor Crater Visitor Center on the rim of the crater. # Moon Meteorites have been found on the Moon[76][77] Lunar origin [of lunar meteors] is established by comparing the mineralogy, the chemical composition, and the isotopic composition between meteorites and samples from the Moon collected by Apollo missions. Cosmic ray exposure history established with noble gas measurements have shown that all lunar meteorites were ejected from the Moon in the past 20 million years. Most left the Moon in the past 100,000 years. In the image at left, twenty degrees of latitude of the Moon's disk is completely covered in the overlapping circles of craters. The illumination angles are from all directions, keeping almost all the crater floors in sunlight, but a set of merged crater floors right at the south pole are completely shadowed. # Mars Martian meteors are thought to be from Mars because they have elemental and isotopic compositions that are similar to rocks and atmosphere gases analyzed by spacecraft on Mars.[78] The image at right is of the Mackinac Island meteorite, discovered on Mars by the NASA Opportunity rover on October 13, 2009. At top left is the first meteorite of any type ever identified on another planet. The pitted, basketball-size object is mostly made of iron and nickel. Readings from spectrometers on the rover determined that composition. Opportunity used its panoramic camera to take the images used in this approximately true-color composite on the rover's 339th martian day, or sol (Jan. 6, 2005). This composite combines images taken through the panoramic camera's 600-nanometer (red), 530-nanometer (green), and 480-nanometer (blue) filters. Comparison of the two meteorites shown here suggests that the left one is a much more recent fall. # Asteroids Notation let the symbol EC denote Earth-crossing asteroids. Notation: let the symbol MB denote the main belt of asteroids. "From the dominant group, the asteroids evolve to intersect the Earth's orbit on a median time scale of about 60 Myr."[79] "The MB group is the most numerous group of MCs. ... 50 % of the MB Mars-crossers [MCs] become ECs within 59.9 Myr and [this] contribution ... dominates the production of ECs"[79]. # Vesta In the full image of Vesta at right, the rocky-object appears to have suffered from meteor damage. Vesta, minor-planet designation 4 Vesta, is one of the largest asteroids in the Solar System. It lost some 1% of its mass less than a billion years ago in a collision that left an enormous crater occupying much of its southern hemisphere. Debris from this event has fallen to Earth as howardite–eucrite–diogenite (HED) meteorites, a rich source of information about the asteroid.[80][81] # Saturn "[E]rosion from particles making up the icy rings of Saturn are forming rain water that falls on certain parts of the planet. ... tiny ice particles that compose the planet's distinctive rings are sometimes eroded away and then deposited in the planet's upper atmosphere. The droplets then create a kind of rain on the planet. ... charged water molecules rain down only on certain parts of the planet, which show up darker in infrared images. ... The magnetic connection creates a pathway for small ice particles in the rings to slough off into the planet's atmosphere, causing the "ring rain.""[82] "The most surprising element to us was that these dark regions on the planet are found to be linked — via magnetic field lines — to the solid portions of water-ice within Saturn's ring-plane"[83]. "Saturn is the first planet to show significant interaction between its atmosphere and ring system ... The main effect of ring rain is that it acts to 'quench' the ionosphere of Saturn. In other words, this rain severely reduces the electron densities in regions in which it falls."[84] "It turns out that a major driver of Saturn's ionospheric environment and climate across vast reaches of the planet are ring particles located some 36,000 miles [60,000 kilometers] overhead ... The ring particles affect both what species of particles are in this part of the atmosphere and where it is warm or cool."[85] "Where Jupiter is glowing evenly across its equatorial regions, Saturn has dark bands where the water is falling in, darkening the ionosphere".[86] # Titan "As spring continues to unfold at Saturn, April showers on the planet's largest moon, Titan, have brought methane rain to its equatorial deserts ... Extensive rain from large cloud systems ... has apparently darkened the surface of the moon."[87] “It's amazing to be watching such familiar activity as rainstorms and seasonal changes in weather patterns on a distant, icy satellite".[88] "The Saturn system experienced equinox, when the sun lies directly over a planet's equator and seasons change, in August 2009. (A full Saturn “year” is almost 30 Earth years.)"[87] "Clouds on Titan are formed of methane as part of an Earth-like cycle that uses methane instead of water. On Titan, methane fills lakes on the surface, saturates clouds in the atmosphere, and falls as rain. Though there is evidence that liquids have flowed on the surface at Titan's equator in the past, liquid hydrocarbons, such as methane and ethane, had only been observed on the surface in lakes at polar latitudes. The vast expanses of dunes that dominate Titan's equatorial regions require a predominantly arid climate."[87] "An arrow-shaped storm appeared in the equatorial regions on Sept. 27, 2010 -- the equivalent of early April in Titan's “year” -- and a broad band of clouds appeared the next month. ... A 193,000-square-mile (500,000-square-kilometer) region along the southern boundary of Titan’s Belet dune field, as well as smaller areas nearby, had become darker. ... this change in brightness is most likely the result of surface wetting by methane rain."[87] “These outbreaks may be the Titan equivalent of what creates Earth's tropical rainforest climates, even though the delayed reaction to the change of seasons and the apparently sudden shift is more reminiscent of Earth's behavior over the tropical oceans than over tropical land areas”.[89] At right is an image that shows clouds over the equatorial region of Titan. "Methane clouds in the troposphere, the lowest part of the atmosphere, appear white here and are mostly near Titan's equator. The darkest areas are surface features that have a low albedo, meaning they do not reflect much light. Cassini observations of clouds like these provide evidence of a seasonal shift of Titan's weather systems to low latitudes following the August 2009 equinox in the Saturnian system. (During equinox, the sun lies directly over the equator. See PIA11667 to learn how the sun's illumination of the Saturnian system changed during the equinox transition to spring in the northern hemispheres and to fall in the southern hemispheres of the planet and its moons.)"[90] "In 2004, during Titan's late southern summer, extensive cloud systems were common in Titan's south polar region (see PIA06110, PIA06124 and PIA06241). Since 2005, southern polar systems have been observed infrequently, and one year after the equinox, extensive near-equatorial clouds have been seen. This image was taken on Oct. 18, 2010, a little more than one Earth year after the Saturnian equinox, which happens once in roughly 15 Earth years."[90] "The cloud patterns observed from late southern summer to early southern fall on Titan suggest that Titan's global atmospheric circulation is influenced by both the atmosphere and the surface. The temperature of the surface responds more rapidly to changes in illumination than does the thick atmosphere. Outbreaks such as the clouds seen here may be the Titan equivalent of what creates the Earth's tropical rainforest climates, even though the delayed reaction to the change of seasons and the apparently sudden shift is more reminiscent of the behavior over Earth's tropical oceans than over tropical land areas."[90] "A few clouds can be seen in Titan's southern latitudes here. See PIA12813 for a movie of clouds moving through the middle southern latitudes of Titan. Some clouds are also visible in the high northern latitudes here. See PIA12811 and PIA12812 for movies showing clouds near the moon's north pole. This view looks toward the Saturn-facing side of Titan (5,150 kilometers or 3,200 miles across). North is up. The image appears slightly grainy because it was re-projected to a scale of 6 kilometers (4 miles) per pixel. Scale in the original image was 15 kilometers (9 miles) per pixel. This view consists of an average of three images taken using a filter sensitive to near-infrared light centered at 938 nanometers, which allows for detection of Titan's surface and lower atmosphere, plus an image taken using a filter sensitive to visible light centered at 619 nanometers. The images were taken with the Cassini spacecraft's narrow-angle camera at a distance of approximately 2.5 million kilometers (1.6 million miles) from Titan and at a sun-Titan-spacecraft, or phase, angle of 56 degrees."[90] # Recurrent novas RS Ophiuchi (RS Oph) is a recurrent nova system approximately 5,000 light-years away in the constellation Ophiuchus. In its quiet phase it has an apparent magnitude of about 12.5. It erupted in 1898, 1933, 1958, 1967, 1985, and 2006 and reached about magnitude 5 on average. The recurrent nova is produced by a white dwarf star and a red giant circling about each other in a close orbit. About every 20 years, enough material from the red giant builds up on the surface of the white dwarf to produce a thermonuclear explosion. The white dwarf orbits close to the red giant, with an accretion disc concentrating the overflowing atmosphere of the red giant onto the white dwarf. If the white dwarf accretes enough mass to reach the Chandrasekhar limit, about 1.4 solar mass, it may explode as a Type Ia supernova. # Biology An evolutionary radiation is an increase in taxonomic diversity or morphological disparity, due to adaptive change or the opening of ecospace.[91] Radiations may affect one clade or many, and be rapid or gradual; where they are rapid, and driven by a single lineage's adaptation to their environment, they are termed adaptive radiations.[92] Perhaps the most familiar example of an evolutionary radiation is that of [Eutheria] placental mammals immediately after the extinction of the dinosaurs at the end of the Cretaceous, about 65 million years ago. At that time, the placental mammals were mostly small, insect-eating animals similar in size and shape to modern shrews. By the Eocene (58–37 million years ago), they had evolved into such diverse forms as bats, whales, and horses.[93] The Hawaiian lobelioids are a group of flowering plants in the [Campanula] bellflower family, Campanulaceae, all of which are endemic to the Hawaiian Islands. This is the largest plant radiation in the Hawaiian Islands, and indeed the largest on any island archipelago, with over 125 species. # Dose equivalents The equivalent dose to a tissue is found by multiplying the absorbed dose, in gray, by a weighting factor (WR). The relation between absorbed dose D and equivalent dose H is thus: The weighting factor (sometimes referred to as a quality factor) is determined by the radiation type and energy range.[94] where Thus for example, an absorbed dose of 1 Gy by alpha particles will lead to an equivalent dose of 20 Sv. The maximum weight of 30 is obtained for neutrons with L = 100 keV/μm. # Effective doses The effective dose of radiation (E), absorbed by a person is obtained by averaging over all irradiated tissues with weighting factors adding up to 1:[94][95] # Grays The gray (symbol: Gy) is the SI derived unit of absorbed radiation dose of ionizing radiation (for example, X-rays), and is defined as the absorption of one joule of ionizing radiation by one kilogram of matter (usually human tissue).[96] The rad is equivalent to 0.01 Gy. One gray is the absorption of one joule of energy, in the form of ionizing radiation, per kilogram of matter. For X rays and gamma rays, these are the same units as the sievert (Sv). For alpha particles one sievert is twenty gray. To avoid any risk of confusion between the absorbed dose (by matter) and the equivalent dose (by biological tissues), one must use the corresponding special units, gray is used instead of the joule per kilogram for absorbed dose and the sievert instead of the joule per kilogram for the dose equivalent. The word "gray" is both the singular and plural spelling. # Chemistry Many of the radiation effects on materials are produced by collision cascades and covered by radiation chemistry. Radiation chemistry is a subdivision of nuclear chemistry which is the study of the chemical effects of radiation on matter; this is very different from radiochemistry as no radioactivity needs to be present in the material which is being chemically changed by the radiation. Radiochemistry is the chemistry of radioactive materials, where radioactive isotopes of elements are used to study the properties and chemical reactions of non-radioactive isotopes (often within radiochemistry the absence of radioactivity leads to a substance being described as being inactive as the isotopes are stable). Much of radiochemistry deals with the use of radioactivity to study ordinary chemical reactions. This is very different from radiation chemistry since the radiation levels are kept too low to influence the chemistry. Nuclear chemistry is the subfield of chemistry dealing with radioactivity, nuclear processes and nuclear properties. It is the chemistry of radioactive elements such as the actinides, radium and radon together with the chemistry associated with equipment (such as nuclear reactors) which are designed to perform nuclear processes. This includes the corrosion of surfaces and the behavior under conditions of both normal and abnormal operation (such as during an accident). An important area is the behavior of objects and materials after being placed into a nuclear waste storage or disposal site. # Geography A geographical area is regarded as a natural environment. A species flock may arise when a species penetrates a new geographical area and diversifies to occupy a variety of ecological niches; this process is known as adaptive radiation. The first species flock to be recognized as such was the 13 species of Darwin's finches on the Galápagos Islands described by Charles Darwin. Solar radiation increases significantly as the atmosphere gets thinner with increasing altitude thereby absorbing less ultraviolet radiation.[97][98] Snow cover reflecting the radiation can amplify the effects by up to 75% increasing the risks and damage from sunburn and snow blindness.[98] Ionization of the ionosphere depends primarily on the Sun and its activity. The amount of ionization in the ionosphere varies greatly with the amount of radiation received from the Sun. Thus there is a diurnal (time of day) effect and a seasonal effect. The local winter hemisphere is tipped away from the Sun, thus there is less received solar radiation. The activity of the Sun is associated with the sunspot cycle, with more radiation occurring with more sunspots. Radiation received also varies with geographical location (polar, auroral zones, mid-latitudes, and equatorial regions). # Geology Granite is a natural source of radiation, like most natural stones. However, some granites have been reported to have higher radioactivity thereby raising some concerns about their safety. Some granites contain around 10 to 20 parts per million of uranium. By contrast, more mafic rocks such as tonalite, gabbro or diorite have 1 to 5 PPM uranium, and limestones and sedimentary rocks usually have equally low amounts. Many large granite plutons are the sources for palaeochannel-hosted or roll front uranium ore deposits, where the uranium washes into the sediments from the granite uplands and associated, often highly radioactive, pegmatites. Granite could be considered a potential natural radiological hazard as, for instance, villages located over granite may be susceptible to higher doses of radiation than other communities.[99] Cellars and basements sunk into soils over granite can become a trap for radon gas, which is formed by the decay of uranium.[100] Radon gas poses significant health concerns, and is the number two cause of lung cancer in the US behind smoking.[101] Thorium occurs in all granites as well.[102] Conway granite has been noted for its relatively high thorium concentration of 56 (±6) PPM.[103] # Ancient history The ancient history period dates from around 8,000 to 3,000 b2k. Meteorites and lunar rocks may contain a record of the ancient radiation history of various stars including our own solar system.[104][105][106][107][108][109] The Explorer 3 spacecraft was spin-stabilized and had an on-board tape recorder to provide a complete radiation history for each orbit. The Plutonium Files: America's Secret Medical Experiments in the Cold War is a 1999 book by Eileen Welsome. It is a history of U.S. government-engineered radiation experiments on unwitting Americans, based on the Pulitzer Prize–winning series Welsome wrote for The Albuquerque Tribune.[110][111] With their closest relatives, the Maluridae (Australian fairy-wrens), Pardalotidae (pardalotes), and Acanthizidae (thornbills, Australian warblers, scrubwrens, etc.) [the honeyeaters] comprise the superfamily Meliphagoidea and originated early in the evolutionary history of the oscine passerine radiation.[112] # Mathematics The Sakuma–Hattori equation is a mathematical model for predicting the amount of thermal radiation, radiometric flux or radiometric power emitted from a perfect blackbody or received by a thermal radiation detector. In its general form it looks like:[113] where: The Stokes parameters are a set of values that describe the polarization state of electromagnetic radiation. The relationship of the Stokes parameters to intensity and polarization ellipse parameters is shown in the equations below and the figure at right. S_0 &= I \\ S_1 &= p I \cos 2\psi \cos 2\chi\\ S_2 &= p I \sin 2\psi \cos 2\chi\\ S_3 &= p I \sin 2\chi. \end{align} </math> Here <math>p I</math>, <math>2\psi</math> and <math>2\chi</math> are the spherical coordinates of the three-dimensional vector of cartesian coordinates<math>(S_1, S_2, S_3)</math>. <math>I</math> is the total intensity of the beam, and <math>p</math> is the degree of polarization. The factor of two before <math>\psi</math> represents the fact that any polarization ellipse is indistinguishable from one rotated by 180°, while the factor of two before <math>\chi</math> indicates that an ellipse is indistinguishable from one with the semi-axis lengths swapped accompanied by a 90° rotation. The four Stokes parameters are sometimes denoted I, Q, U and V, respectively. If given the Stokes parameters one can solve for the spherical coordinates with the following equations: I &= S_0 \\ p &= \frac{\sqrt{S_1^2 + S_2^2 + S_3^2}}{S_0} \\ 2\psi &= \mathrm{atan} \frac{S_2}{S_1}\\ 2\chi &= \mathrm{atan} \frac{S_3}{\sqrt{S_1^2+S_2^2}}.\\ \end{align}</math> # Physics A particle on the exact design trajectory (or design orbit) of the accelerator only experiences dipole field components, while particles with transverse position deviation <math>\scriptstyle x(s)</math> are re-focused to the design orbit. For preliminary calculations, neglecting all fields components higher than quadrupolar, an inhomogenic Hill differential equation can be used as an approximation,[115] with thus identifying the system as a parametric oscillator. Beam parameters for the accelerator can then be calculated using ray transfer matrix analysis; e.g., a quadrupolar field is analogous to a lens in geometrical optics, having similar properties regarding beam focusing (but obeying Earnshaw's theorem). # Roentgens Def. the radiation exposure equal to the quantity of ionizing radiation that will produce one esu of charge in one cubic centimetre of dry air at 0 °C and a standard atmosphere is called a roentgen. Using an air ionization energy of about 35 J/C, we have 1 Gy ≈ 111 R. # Technology The RHPPC is a radiation hardened processor based on PowerPC 603e technology licensed from Motorola (now Freescale) and manufactured by Honeywell. The RHPPC is equivalent to the commercial PowerPC 603e processor with the minor exceptions of the phase locked loop (PLL) and the processor version register (PVR). The RHPPC processor is compatible with the PowerPC architecture (Book I-III), the PowerPC 603e programmers interface and is also supported by common PowerPC software tools and embedded operating systems, like VxWorks. Demron is a radiation-blocking fabric made by Radiation Shield Technologies. The material is said to have radiation protection similar to lead shielding, while being lightweight and flexible. The composition of Demron is proprietary, but is described as a non-toxic polymer.[116] According to its manufacturer, while Demron shields the wearer from radiation alone, it can be coupled with different protective materials to block chemical and biological threats as well.[117] Demron is roughly three to four times more expensive than a conventional lead apron, but can be treated like a normal fabric for cleaning, storage and disposal.[116] More recent uses for Demron include certified first responder hazmat suits as well as tactical vests. Demron is proven by the United States Department of Energy to significantly reduce high energy alpha and beta radiation, and reduce low energy gamma radiation. When several sheets of Demron are laminated together the result is a much more powerful shield, though Demron cannot completely block all gamma radiation.[118] # Protection Radiation protection, sometimes known as radiological protection, is the protection of people and the environment from the harmful effects of ionizing radiation, which includes both particle radiation and high energy electromagnetic radiation. [Ionizing radiation] causes microscopic damage to living tissue, resulting in skin burns and radiation sickness at high exposures and statistically elevated risks of cancer, tumors and genetic damage at low exposures. There are three factors that control the amount, or dose, of radiation received from a source. Radiation exposure can be managed by a combination of these factors: - Time: Reducing the time of an exposure reduces the effective dose proportionally. An example of reducing radiation doses by reducing the time of exposures might be improving operator training to reduce the time they take to handle a source. - Distance: Increasing distance reduces dose due to the inverse square law. Distance can be as simple as handling a source with forceps rather than fingers. - Shielding: The term 'biological shield' refers to a mass of absorbing material placed around a reactor, or other radioactive source, to reduce the radiation to a level safe for humans.[119] # Gloveboxes A glovebox (or glove box) is a sealed container that is designed to allow one to manipulate objects where a separate atmosphere is desired. Built into the sides of the glovebox are gloves arranged in such a way that the user can place their hands into the gloves and perform tasks inside the box without breaking containment. Part or all of the box is usually transparent to allow the user to see what is being manipulated. Two types of gloveboxes exist: one allows a person to work with hazardous substances, such as radioactive materials or infectious disease agents; the other allows manipulation of substances that must be contained within a very high purity inert atmosphere, such as argon or nitrogen. It is also possible to use a glovebox for manipulation of items in a vacuum chamber. Gloveboxes used for hazardous materials generally are maintained at a lower pressure than the surrounding atmosphere, so that microscopic leaks result in air intake rather than hazard outflow. Gloveboxes used for hazardous materials generally incorporate HEPA filters into the exhaust, to keep the hazard contained. # Shield effectiveness The effectiveness of a material as a biological shield is related to its cross-section for scattering and absorption, and to a first approximation is proportional to the total mass of material per unit area interposed along the line of sight between the radiation source and the region to be protected. Hence, shielding strength or "thickness" is conventionally measured in units of g/cm2. The radiation that manages to get through falls exponentially with the thickness of the shield. In X-ray facilities, the plaster on the rooms with the x-ray generator contains barium sulfate and the operators stay behind a leaded glass screen and wear lead aprons. Almost any material can act as a shield from gamma or x-rays if used in sufficient amounts. Practical radiation protection tends to be a job of juggling the three factors to identify the most cost effective solution. # Hypotheses - Radiation has a continuum of speeds.	https://www.wikidoc.org/index.php/Radiation
9343aa770682188038fb63d6ff0d42d58bd0c055	wikidoc	Ramelteon	Ramelteon # 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 Ramelteon is a nonbarbiturate hypnotic that is FDA approved for the treatment of insomnia characterized by difficulty with sleep onset. Common adverse reactions include somnolence, dizziness, fatigue, nausea and exacerbated insomnia. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Ramelteon is indicated for the treatment of insomnia characterized by difficulty with sleep onset. - Dosage: - Adult dose: 8 mg taken within 30 minutes of going to bed. - Should not be taken with or immediately after a high-fat meal. - Total daily dose should not exceed 8 mg. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Ramelteon in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Ramelteon in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) Safety and efficacy not established in pediatric patients ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Ramelteon in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Ramelteon in pediatric patients. # Contraindications - Patients who develop angioedema after treatment with ramelteon should not be rechallenged with the drug. - Patients should not take ramelteon in conjunction with fluvoxamine # Warnings ### Severe Anaphylactic and Anaphylactoid Reactions - Rare cases of angioedema involving the tongue, glottis or larynx have been reported in patients after taking the first or subsequent doses of ramelteon. - Some patients have had additional symptoms such as dyspnea, throat closing, or nausea and vomiting that suggest anaphylaxis. Some patients have required medical therapy in the emergency department. - If angioedema involves the tongue, glottis or larynx, airway obstruction may occur and be fatal. - Patients who develop angioedema after treatment with ramelteon should not be rechallenged with the drug. ### Need to Evaluate for Co-morbid Diagnoses - Since sleep disturbances may be the presenting manifestation of a physical and/or psychiatric disorder, symptomatic treatment of insomnia should be initiated only after a careful evaluation of the patient. - The failure of insomnia to remit after 7 to 10 days of treatment may indicate the presence of a primary psychiatric and/or medical illness that should be evaluated. Worsening of insomnia, or the emergence of new cognitive or behavioral abnormalities, may be the result of an unrecognized underlying psychiatric or physical disorder and requires further evaluation of the patient. - Exacerbation of insomnia and emergence of cognitive and behavioral abnormalities were seen with ramelteon during the clinical development program. ### Abnormal Thinking and Behavioral Changes - A variety of cognitive and behavior changes have been reported to occur in association with the use of hypnotics. - In primarily depressed patients, worsening of depression (including suicidal ideation and completed suicides) has been reported in association with the use of hypnotics. - Hallucinations, as well as behavioral changes such as bizarre behavior, agitation and mania have been reported with ramelteon use. Amnesia, anxiety and other neuro-psychiatric symptoms may also occur unpredictably. - Complex behaviors such as "sleep-driving" (i.e., driving while not fully awake after ingestion of a hypnotic) and other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex), with amnesia for the event, have been reported in association with hypnotic use. The use of alcohol and other CNS depressants may increase the risk of such behaviors. These events can occur in hypnotic-naive as well as in hypnotic-experienced persons. Complex behaviors have been reported with the use of ramelteon. Discontinuation of ramelteon should be strongly considered for patients who report any complex sleep behavior. ### CNS Effects - Patients should avoid engaging in hazardous activities that require concentration (such as operating a motor vehicle or heavy machinery) after taking ramelteon. - After taking ramelteon, patients should confine their activities to those necessary to prepare for bed. - Patients should be advised not to consume alcohol in combination with ramelteon as alcohol and ramelteon may have additive effects when used in conjunction. ### Reproductive Effects - Ramelteon has been associated with an effect on reproductive hormones in adults, e.g., decreased testosterone levels and increased prolactin levels. - It is not known what effect chronic or even chronic intermittent use of ramelteon may have on the reproductive axis in developing humans. ### Use in Patients with Concomitant Illness - Ramelteon has not been studied in subjects with severe sleep apnea and is not recommended for use in this population. - Ramelteon should not be used by patients with severe hepatic impairment. ### Laboratory Tests - No standard monitoring is required. - For patients presenting with unexplained amenorrhea, galactorrhea, decreased libido, or problems with fertility, assessment of prolactin levels and testosterone levels should be considered as appropriate. - Ramelteon is not known to interfere with commonly used clinical laboratory tests. - In addition, in vitro data indicate that ramelteon does not cause false-positive results for benzodiazepines, opiates, barbiturates, cocaine, cannabinoids, or amphetamines in two standard urine drug screening methods in vitro. # Adverse Reactions ## Clinical Trials Experience - The data described in this section reflect exposure to ramelteon in 5373 subjects, including 722 exposed for 6 months or longer, and 448 subjects for one year. - Six percent of the 5373 individual subjects exposed to ramelteon in clinical studies discontinued treatment owing to an adverse event, compared with 2% of the 2279 subjects receiving placebo. The most frequent adverse events leading to discontinuation in subjects receiving ramelteon were somnolence, dizziness, nausea, fatigue, headache, and insomnia; all of which occurred in 1% of the patients or less. - Table 1 displays the incidence of adverse events reported by the 2861 patients with chronic insomnia who participated in placebo-controlled trials of ramelteon. - 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 clinical trials of other drugs, and may not reflect the rates observed in practice. - The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates. ## Postmarketing Experience There is limited information regarding Ramelteon Postmarketing Experience in the drug label. # Drug Interactions - Fluvoxamine (strong CYP1A2 inhibitor): AUC0-inf for ramelteon increased approximately 190-fold, and the Cmax increased approximately 70-fold upon coadministration of fluvoxamine and ramelteon, compared to ramelteon administered alone. ramelteon should not be used in combination with fluvoxamine. Other less strong CYP1A2 inhibitors have not been adequately studied. ramelteon should be administered with caution to patients taking less strong CYP1A2 inhibitors. - Rifampin (strong CYP enzyme inducer): Administration of multiple doses of rifampin resulted in a mean decrease of approximately 80% in total exposure to ramelteon and metabolite M-II. Efficacy may be reduced when ramelteon is used in combination with strong CYP enzyme inducers such as rifampin. - Ketoconazole (strong CYP3A4 inhibitor): The AUC0-inf and Cmax of ramelteon increased by approximately 84% and 36% upon coadministration of ketoconazole with ramelteon. ramelteon should be administered with caution in subjects taking strong CYP3A4 inhibitors such as ketoconazole. - Fluconazole (strong CYP2C9 inhibitor): The AUC0-inf and Cmax of ramelteon was increased by approximately 150% when ramelteon was coadministered with fluconazole. ramelteon should be administered with caution in subjects taking strong CYP2C9 inhibitors such as fluconazole. - Donepezil: The AUC0-inf and Cmax of ramelteon increased by approximately 100% and 87%, respectively upon coadministration of donepezil with ramelteon. Patients should be closely monitored when ramelteon is coadministered with donepezil. - Doxepin: The AUC0-inf and Cmax of ramelteon increased by approximately 66% and 69%, respectively, upon coadministration of doxepin with ramelteon. Patients should be closely monitored when ramelteon is coadministered with doxepin. - Ramelteon is not known to interfere with commonly used clinical laboratory tests. In addition, in vitro data indicate that ramelteon does not cause false-positive results for benzodiazepines, opiates, barbiturates, cocaine, cannabinoids, or amphetamines in two standard urine drug screening methods in vitro. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C In animal studies, ramelteon produced evidence of developmental toxicity, including teratogenic effects, in rats at doses much greater than the recommended human dose (RHD) of 8 mg/day. There are no adequate and well-controlled studies in pregnant women. ramelteon should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Oral administration of ramelteon (10, 40, 150 or 600 mg/kg/day) to pregnant rats during the period of organogenesis was associated with increased incidences of fetal structural abnormalities (malformations and variations) at doses greater than 40 mg/kg/day. The no-effect dose is approximately 50 times the RHD on a body surface area (mg/m2) basis. Treatment of pregnant rabbits during the period of organogenesis produced no evidence of embryo-fetal toxicity at oral doses of up to 300 mg/kg/day (or up to 720 times the RHD on a mg/m2 basis. When rats were orally administered ramelteon (30, 100, or 300 mg/kg/day) throughout gestation and lactation, growth retardation, developmental delay, and behavioral changes were observed in the offspring at doses greater than 30 mg/kg/day. The no-effect dose is 36 times the RHD on a mg/m2 basis. Increased incidences of malformation and death among offspring were seen at the highest dose. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ramelteon in women who are pregnant. ### Labor and Delivery The potential effects of ramelteon on the duration of labor and/or delivery, for either the mother or the fetus, have not been studied. ramelteon has no established use in labor and delivery. ### Nursing Mothers It is not known whether ramelteon is secreted into human milk; however ramelteon is secreted into the milk of lactating rats. Because many drugs are excreted into human milk, caution should be exercised when administered to a nursing woman. ### Pediatric Use Safety and effectiveness of ramelteon in pediatric patients have not been established. Further study is needed prior to determining that this product may be used safely in pre-pubescent and pubescent patients. ### Geriatic Use A total of 654 subjects in double-blind, placebo-controlled, efficacy trials who received ramelteon were at least 65 years of age; of these, 199 were 75 years of age or older. No overall differences in safety or efficacy were observed between elderly and younger adult subjects. A double-blind, randomized, placebo-controlled study in elderly subjects with insomnia (n=33) evaluated the effect of a single dose of ramelteon on balance, mobility, and memory functions after middle of the night awakening. There is no information on the effect of multiple dosing. Night time dosing of ramelteon 8 mg did not impair middle of the night balance, mobility, or memory functions relative to placebo. The effects on night balance in the elderly cannot be definitively known from this study. ### Gender There is no FDA guidance on the use of Ramelteon with respect to specific gender populations. ### Race There is no FDA guidance on the use of Ramelteon with respect to specific racial populations. ### Renal Impairment No effects on Cmax and AUC0-t of parent drug or M-II were seen. No adjustment of ramelteon dosage is required in patients with renal impairment. ### Hepatic Impairment Exposure to ramelteon was increased by 4-fold in subjects with mild hepatic impairment and by more than 10-fold in subjects with moderate hepatic impairment. ramelteon should be used with caution in patients with moderate hepatic impairment. Ramelteon is not recommended in patients with severe hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Ramelteon in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Ramelteon in patients who are immunocompromised. ### Sleep Apnea The effects of ramelteon were evaluated after administering a 16 mg dose or placebo in a crossover design to subjects (n=26) with mild to moderate obstructive sleep apnea. Treatment with ramelteon 16 mg for one night showed no difference compared with placebo on the Apnea/Hypopnea Index (the primary outcome variable), apnea index, hypopnea index, central apnea index, mixed apnea index, and obstructive apnea index. Treatment with a single dose of ramelteon does not exacerbate mild to moderate obstructive sleep apnea. There is no available information on the respiratory effects of multiple doses of ramelteon in patients with sleep apnea. The effects on exacerbation in patients with mild to moderate sleep apnea cannot be definitively known from this study. ramelteon has not been studied in subjects with severe obstructive sleep apnea; use of ramelteon is not recommended in such patients. The respiratory depressant effect of ramelteon was evaluated in a crossover design study of subjects (n=26) with mild to moderate COPD after administering a single 16 mg dose or placebo, and in a separate study (n=25), the effects of ramelteon on respiratory parameters were evaluated after administering an 8 mg dose or placebo in a crossover design to patients with moderate to severe COPD, defined as patients who had forced expiratory volume at one second (FEV1)/forced vital capacity ratio of <70%, and a FEV1 <80% of predicted with <12% reversibility to albuterol. Treatment with a single dose of ramelteon has no demonstrable respiratory depressant effects in subjects with mild to severe COPD, as measured by arterial O2 saturation (SaO2). There is no available information on the respiratory effects of multiple doses of ramelteon in patients with COPD. The respiratory depressant effects in patients with COPD cannot be definitively known from this study. # Administration and Monitoring ### Administration Oral ### Monitoring There is limited information regarding Ramelteon Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Ramelteon and IV administrations. # Overdosage - General symptomatic and supportive measures should be used, along with immediate gastric lavage where appropriate. - Intravenous fluids should be administered as needed. - As in all cases of drug overdose, respiration, pulse, blood pressure, and other appropriate vital signs should be monitored, and general supportive measures employed. - Hemodialysis does not effectively reduce exposure to ramelteon. Therefore, the use of dialysis in the treatment of overdosage is not appropriate. # Pharmacology ## Mechanism of Action Ramelteon is a melatonin receptor agonist with both high affinity for melatonin MT1 and MT2 receptors and selectivity over the MT3 receptor. Ramelteon demonstrates full agonist activity in vitro in cells expressing human MT1 or MT2 receptors. The activity of ramelteon at the MT1 and MT2 receptors is believed to contribute to its sleep-promoting properties, as these receptors, acted upon by endogenous melatonin, are thought to be involved in the maintenance of the circadian rhythm underlying the normal sleep-wake cycle. Ramelteon has no appreciable affinity for the GABA receptor complex or for receptors that bind neuropeptides, cytokines, serotonin, dopamine, noradrenaline, acetylcholine, and opiates. Ramelteon also does not interfere with the activity of a number of selected enzymes in a standard panel. The major metabolite of ramelteon, M-II, is active and has approximately one tenth and one fifth the binding affinity of the parent molecule for the human MT1 and MT2 receptors, respectively, and is 17- to 25-fold less potent than ramelteon in in vitro functional assays. Although the potency of M-II at MT1 and MT2 receptors is lower than the parent drug, M-II circulates at higher concentrations than the parent producing 20- to 100-fold greater mean systemic exposure when compared to ramelteon. M-II has weak affinity for the serotonin 5-HT2B receptor, but no appreciable affinity for other receptors or enzymes. Similar to ramelteon, M-II does not interfere with the activity of a number of endogenous enzymes. All other known metabolites of ramelteon are inactive. ## Structure The compound is produced as the (S)-enantiomer, with an empirical formula of C16H21NO2, molecular weight of 259.34, and the following chemical structure: ## Pharmacodynamics There is limited information regarding Ramelteon Pharmacodynamics in the drug label. ## Pharmacokinetics The pharmacokinetic profile of ramelteon has been evaluated in healthy subjects as well as in subjects with hepatic or renal impairment. When administered orally to humans in doses ranging from 4 to 64 mg, ramelteon undergoes rapid, high first-pass metabolism, and exhibits linear pharmacokinetics. Maximal serum concentration (Cmax) and area under the concentration-time curve (AUC) data show substantial intersubject variability, consistent with the high first-pass effect; the coefficient of variation for these values is approximately 100%. Several metabolites have been identified in human serum and urine. Ramelteon is absorbed rapidly, with median peak concentrations occurring at approximately 0.75 hour (range, 0.5 to 1.5 hours) after fasted oral administration. Although the total absorption of ramelteon is at least 84%, the absolute oral bioavailability is only 1.8% due to extensive first-pass metabolism. In vitro protein binding of ramelteon is approximately 82% in human serum, independent of concentration. Binding to albumin accounts for most of that binding, since 70% of the drug is bound in human serum albumin. Ramelteon is not distributed selectively to red blood cells. Ramelteon has a mean volume of distribution after intravenous administration of 73.6 L, suggesting substantial tissue distribution. Metabolism of ramelteon consists primarily of oxidation to hydroxyl and carbonyl derivatives, with secondary metabolism producing glucuronide conjugates. CYP1A2 is the major isozyme involved in the hepatic metabolism of ramelteon; the CYP2C subfamily and CYP3A4 isozymes are also involved to a minor degree. The rank order of the principal metabolites by prevalence in human serum is M-II, M-IV, M-I, and M-III. These metabolites are formed rapidly and exhibit a monophasic decline and rapid elimination. The overall mean systemic exposure of M-II is approximately 20- to 100-fold higher than parent drug. Following oral administration of radiolabeled ramelteon, 84% of total radioactivity was excreted in urine and approximately 4% in feces, resulting in a mean recovery of 88%. Less than 0.1% of the dose was excreted in urine and feces as the parent compound. Elimination was essentially complete by 96 hours post-dose. Repeated once daily dosing with ramelteon does not result in significant accumulation owing to the short elimination half-life of ramelteon (on average, approximately 1 to 2.6 hours). The half-life of M-II is 2 to 5 hours and independent of dose. Serum concentrations of the parent drug and its metabolites in humans are at or below the lower limits of quantitation within 24 hours. When administered with a high-fat meal, the AUC0-inf for a single 16 mg dose of ramelteon was 31% higher and the Cmax was 22% lower than when given in a fasted state. Median Tmax was delayed by approximately 45 minutes when ramelteon was administered with food. Effects of food on the AUC values for M-II were similar. It is therefore recommended that ramelteon not be taken with or immediately after a high-fat meal. ## Nonclinical Toxicology Ramelteon was administered to mice and rats at oral doses of 0, 30, 100, 300, or 1000 mg/kg/day (mice) and 0, 15, 60, 250, or 1000 mg/kg/day (rats). Mice and rats were dosed for two years, except at the high dose (94 weeks for male and female mice and female rats). In mice, dose-related increases in the incidence of hepatic tumors (adenomas, carcinomas, hepatoblastomas) were observed in males and females. The no-effect dose for hepatic tumors in mice (30 mg/kg/day) is approximately 20 times the recommended human dose (RHD) of 8 mg/day on a body surface area (mg/m2) basis. In rats, the incidence of hepatic adenoma and benign Leydig cell tumors of the testis was increased in males at doses ≥250 mg/kg/day. In females, the incidence of hepatic adenoma was increased at doses ≥60 mg/kg/day. The incidence of hepatic carcinoma was increased in males and female rats at 1000 mg/kg/day. The no-effect dose for tumors in rats (15 mg/kg/day) is approximately 20 times the RHD on a mg/m2 basis. Ramelteon was not genotoxic in the in vitro bacterial reverse mutation (Ames) assay, the in vitro mouse lymphoma TK+/- assay, and in in vivo oral micronucleus assays in mouse and rat. Ramelteon was clastogenic in the in vitro chromosomal aberration assay in Chinese hamster lung cells. Separate studies indicated that the concentration of the M-II metabolite formed in the presence of metabolic activation exceeded the concentration of ramelteon; therefore, the genotoxic potential of the M-II metabolite was also assessed in the in vitro studies. # Clinical Studies ### Controlled Clinical Trials Three randomized, double-blind trials in subjects with chronic insomnia employing polysomnography (PSG) were provided as objective support of ramelteon's effectiveness in sleep initiation. One study enrolled younger adults (aged 18 to 64 years, inclusive) with chronic insomnia and employed a parallel design in which the subjects received a single, nightly dose of ramelteon (8 mg or 16 mg) or matching placebo for 35 days. PSG was performed on the first two nights in each of Weeks 1, 3, and 5 of treatment. Ramelteon reduced the average latency to persistent sleep at each of the time points when compared to placebo. The 16 mg dose conferred no additional benefit for sleep initiation. The second study employing PSG was a three-period crossover trial performed in subjects aged 65 years and older with a history of chronic insomnia. Subjects received ramelteon (4 mg or 8 mg) or placebo and underwent PSG assessment in a sleep laboratory for two consecutive nights in each of the three study periods. Both doses of ramelteon reduced latency to persistent sleep when compared to placebo. The third study evaluated long term efficacy and safety in adults with chronic insomnia. Subjects received a single, nightly dose of ramelteon 8 mg or matching placebo for 6 months. PSG was performed on the first two nights of Week 1 and Months 1, 3, 5, and 6. ramelteon reduced sleep latency at each time point when compared to placebo. In this study, when the PSG results from nights 1 and 2 of Month 7 were compared to the results from nights 22 and 23 of Month 6, there was a statistically significant increase in LPS of 33% (9.5 minutes) in the ramelteon group. There was no increase in LPS in the placebo group when the same time periods were compared. A randomized, double-blind, parallel group study was conducted in outpatients aged 65 years and older with chronic insomnia and employed subjective measures of efficacy (sleep diaries). Subjects received ramelteon (4 mg or 8 mg) or placebo for 35 nights. ramelteon reduced patient-reported sleep latency compared to placebo. A similarly designed study performed in younger adults (aged 18 - 64 years) using 8 mg and 16 mg of ramelteon did not replicate this finding of reduced patient-reported sleep latency compared to placebo. While the 16 mg dose was evaluated as a potential treatment for adults, it was shown to confer no additional benefit for sleep initiation and was associated with higher incidences of fatigue, headache and next-day somnolence. In a randomized, double-blind, parallel-group trial using a first-night-effect model, healthy adults received placebo or ramelteon before spending one night in a sleep laboratory and being evaluated with PSG. ramelteon demonstrated a decrease in mean latency to persistent sleep as compared to placebo. ### Studies Pertinent to Safety Concerns for Sleep- promoting Drugs A human laboratory abuse potential study was performed in 14 subjects with a history of sedative/hypnotic or anxiolytic drug abuse. Subjects received single oral doses of ramelteon (16, 80, or 160 mg), triazolam (0.25, 0.50, or 0.75 mg) or placebo. All subjects received each of the 7 treatments separated by a wash-out period and underwent multiple standard tests of abuse potential. No differences in subjective responses indicative of abuse potential were found between ramelteon and placebo at doses up to 20 times the recommended therapeutic dose. The positive control drug, triazolam, consistently showed a dose-response effect on these subjective measures, as demonstrated by the differences from placebo in peak effect and overall 24-hour effect. In order to evaluate potential next-day residual effects, the following scales were used: a Memory Recall Test, a Word List Memory Test, a Visual Analog Mood and Feeling Scale, the Digit-Symbol Substitution Test, and a post-sleep questionnaire to assess alertness and ability to concentrate. There was no evidence of next-day residual effect seen after 2 nights of ramelteon use during the crossover studies. In a 35-night, double-blind, placebo-controlled, parallel-group study in adults with chronic insomnia, measures of residual effects were performed at three time points. Overall, the magnitudes of any observed differences were small. At Week 1, patients who received 8 mg of ramelteon had a mean VAS score (46 mm on a 100 mm scale) indicating more fatigue in comparison to patients who received placebo (42 mm). At Week 3, patients who received 8 mg of ramelteon had a lower mean score for immediate recall (7.5 out of 16 words) compared to patients who received placebo (8.2 words); and the patients treated with ramelteon had a mean VAS score indicating more sluggishness (27 mm on a 100 mm VAS) in comparison to the placebo-treated patients (22 mm). Patients who received ramelteon did not have next-morning residual effects that were different from placebo at Week 5. Potential rebound insomnia and withdrawal effects were assessed in four studies in which subjects received ramelteon or placebo for up to 6 months; 3 were 35-day studies, one was a 6 month study. These studies included a total of 2533 subjects, of whom 854 were elderly. Tyrer Benzodiazepine Withdrawal Symptom Questionnaire (BWSQ): The BWSQ is a self-report questionnaire that solicits specific information on 20 symptoms commonly experienced during withdrawal from benzodiazepine receptor agonists; ramelteon is not a benzodiazepine receptor agonist. In two of the three 35-day insomnia studies, the questionnaire was administered one week after completion of treatment; in the third study, the questionnaire was administered on Days 1 and 2 after completion. In all three of the 35-day studies, subjects receiving ramelteon 4 mg, 8 mg, or 16 mg daily reported BWSQ scores similar to those of subjects receiving placebo. In the 6 month study, there was no evidence of withdrawal from the 8 mg dose as measured by the BWSQ. Rebound Insomnia: Rebound insomnia was assessed in the 35-day studies by measuring sleep latency after abrupt treatment discontinuation. One of these studies employed PSG in younger adult subjects receiving ramelteon 8 mg or 16 mg; the other two studies employed subjective measures of sleep-onset insomnia in elderly subjects receiving ramelteon 4 mg or 8 mg, and in younger adult subjects receiving ramelteon 8 mg or 16 mg. There was no evidence that ramelteon caused rebound insomnia during the post-treatment period. ### Studies to Evaluate Effects on Endocrine Function Two controlled studies evaluated the effects of ramelteon on endocrine function. In the first trial, ramelteon 16 mg once daily or placebo was administered to 99 healthy volunteer subjects for 4 weeks. This study evaluated the thyroid axis, adrenal axis and reproductive axis. No clinically significant endocrinopathies were demonstrated in this study. However, the study was limited in its ability to detect such abnormalities due to its limited duration. In the second trial, ramelteon 16 mg once daily or placebo was administered to 122 subjects with chronic insomnia for 6 months. This study evaluated the thyroid axis, adrenal axis and reproductive axis. There were no significant abnormalities seen in either the thyroid or the adrenal axes. Abnormalities were, however, noted within the reproductive axis. Overall, the mean serum prolactin level change from baseline was 4.9 mcg/L (34% increase) for women in the ramelteon group compared with -0.6 mcg/L (4% decrease) for women in the placebo group (p=0.003). No differences between active- and placebo-treated groups occurred among men. Thirty-two percent of all patients who were treated with ramelteon in this study (women and men) had prolactin levels that increased from normal baseline levels compared to 19% of patients who were treated with placebo. Subject-reported menstrual patterns were similar between the two treatment groups. In a 12-month, open-label study in adult and elderly patients, there were two patients who were noted to have abnormal morning cortisol levels, and subsequent abnormal ACTH stimulation tests. A 29-year-old female patient was diagnosed with a prolactinoma. The relationship of these events to ramelteon therapy is not clear. # How Supplied Ramelteon is supplied in 8 mg tablets - Bottles of 30 (NDC 64764-805-30) - Bottles of 100 (NDC 64764-805-10) - Bottles of 500 (NDC 64764-805-50) ## Storage Store at 25°C (77°F) # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Prescribers or other healthcare professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with hypnotics, should counsel them in their appropriate use and should instruct them to read the accompanying Medication Guide. ### Severe Anaphylactic and Anaphylactoid Reactions - Inform patients that severe anaphylactic and anaphylactoid reactions have occurred with ramelteon. Describe the relevant signs/symptoms and advise seeking immediate medical attention if any such things occur. ### Sleep-driving and other Complex Behaviors - There have been reports of people getting out of bed after taking a sleep medication and driving their cars while not fully awake, often with no memory of the event. If a patient experiences such an episode, it should be reported to his or her doctor immediately, since "sleep-driving" can be dangerous. This behavior is more likely to occur when sleep medications are taken with alcohol or other central nervous system depressants. Other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex) have been reported in patients who are not fully awake after taking a sleep medication. As with sleep-driving, patients usually do not remember these events. ### Endocrine Effects - Patients should consult their health care providers if they experience one of the following: cessation of menses or galactorrhea in females, decreased libido, or problems with fertility. Describe the relevant signs/symptoms and advise seeking medical attention if any such things occur. ### Administration Instructions - Patients should be advised to take ramelteon within 30 minutes prior to going to bed and should confine their activities to those necessary to prepare for bed. - Patients should be advised that they should not take ramelteon with or immediately after a high-fat meal. - Do not break the tablet; it should be swallowed whole. # Precautions with Alcohol Alcohol by itself impairs performance and can cause sleepiness. Since the intended effect of ramelteon is to promote sleep, patients should be cautioned not to consume alcohol when using ramelteon. Use of the products in combination may have an additive effect. # Brand Names - Rozerem # Look-Alike Drug Names There is limited information regarding Ramelteon Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Ramelteon Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gloria Picoy [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 Ramelteon is a nonbarbiturate hypnotic that is FDA approved for the treatment of insomnia characterized by difficulty with sleep onset. Common adverse reactions include somnolence, dizziness, fatigue, nausea and exacerbated insomnia. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Ramelteon is indicated for the treatment of insomnia characterized by difficulty with sleep onset. - Dosage: - Adult dose: 8 mg taken within 30 minutes of going to bed. - Should not be taken with or immediately after a high-fat meal. - Total daily dose should not exceed 8 mg. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Ramelteon in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Ramelteon in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) Safety and efficacy not established in pediatric patients ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Ramelteon in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Ramelteon in pediatric patients. # Contraindications - Patients who develop angioedema after treatment with ramelteon should not be rechallenged with the drug. - Patients should not take ramelteon in conjunction with fluvoxamine # Warnings ### Severe Anaphylactic and Anaphylactoid Reactions - Rare cases of angioedema involving the tongue, glottis or larynx have been reported in patients after taking the first or subsequent doses of ramelteon. - Some patients have had additional symptoms such as dyspnea, throat closing, or nausea and vomiting that suggest anaphylaxis. Some patients have required medical therapy in the emergency department. - If angioedema involves the tongue, glottis or larynx, airway obstruction may occur and be fatal. - Patients who develop angioedema after treatment with ramelteon should not be rechallenged with the drug. ### Need to Evaluate for Co-morbid Diagnoses - Since sleep disturbances may be the presenting manifestation of a physical and/or psychiatric disorder, symptomatic treatment of insomnia should be initiated only after a careful evaluation of the patient. - The failure of insomnia to remit after 7 to 10 days of treatment may indicate the presence of a primary psychiatric and/or medical illness that should be evaluated. Worsening of insomnia, or the emergence of new cognitive or behavioral abnormalities, may be the result of an unrecognized underlying psychiatric or physical disorder and requires further evaluation of the patient. - Exacerbation of insomnia and emergence of cognitive and behavioral abnormalities were seen with ramelteon during the clinical development program. ### Abnormal Thinking and Behavioral Changes - A variety of cognitive and behavior changes have been reported to occur in association with the use of hypnotics. - In primarily depressed patients, worsening of depression (including suicidal ideation and completed suicides) has been reported in association with the use of hypnotics. - Hallucinations, as well as behavioral changes such as bizarre behavior, agitation and mania have been reported with ramelteon use. Amnesia, anxiety and other neuro-psychiatric symptoms may also occur unpredictably. - Complex behaviors such as "sleep-driving" (i.e., driving while not fully awake after ingestion of a hypnotic) and other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex), with amnesia for the event, have been reported in association with hypnotic use. The use of alcohol and other CNS depressants may increase the risk of such behaviors. These events can occur in hypnotic-naive as well as in hypnotic-experienced persons. Complex behaviors have been reported with the use of ramelteon. Discontinuation of ramelteon should be strongly considered for patients who report any complex sleep behavior. ### CNS Effects - Patients should avoid engaging in hazardous activities that require concentration (such as operating a motor vehicle or heavy machinery) after taking ramelteon. - After taking ramelteon, patients should confine their activities to those necessary to prepare for bed. - Patients should be advised not to consume alcohol in combination with ramelteon as alcohol and ramelteon may have additive effects when used in conjunction. ### Reproductive Effects - Ramelteon has been associated with an effect on reproductive hormones in adults, e.g., decreased testosterone levels and increased prolactin levels. - It is not known what effect chronic or even chronic intermittent use of ramelteon may have on the reproductive axis in developing humans. ### Use in Patients with Concomitant Illness - Ramelteon has not been studied in subjects with severe sleep apnea and is not recommended for use in this population. - Ramelteon should not be used by patients with severe hepatic impairment. ### Laboratory Tests - No standard monitoring is required. - For patients presenting with unexplained amenorrhea, galactorrhea, decreased libido, or problems with fertility, assessment of prolactin levels and testosterone levels should be considered as appropriate. - Ramelteon is not known to interfere with commonly used clinical laboratory tests. - In addition, in vitro data indicate that ramelteon does not cause false-positive results for benzodiazepines, opiates, barbiturates, cocaine, cannabinoids, or amphetamines in two standard urine drug screening methods in vitro. # Adverse Reactions ## Clinical Trials Experience - The data described in this section reflect exposure to ramelteon in 5373 subjects, including 722 exposed for 6 months or longer, and 448 subjects for one year. - Six percent of the 5373 individual subjects exposed to ramelteon in clinical studies discontinued treatment owing to an adverse event, compared with 2% of the 2279 subjects receiving placebo. The most frequent adverse events leading to discontinuation in subjects receiving ramelteon were somnolence, dizziness, nausea, fatigue, headache, and insomnia; all of which occurred in 1% of the patients or less. - Table 1 displays the incidence of adverse events reported by the 2861 patients with chronic insomnia who participated in placebo-controlled trials of ramelteon. - 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 clinical trials of other drugs, and may not reflect the rates observed in practice. - The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates. ## Postmarketing Experience There is limited information regarding Ramelteon Postmarketing Experience in the drug label. # Drug Interactions - Fluvoxamine (strong CYP1A2 inhibitor): AUC0-inf for ramelteon increased approximately 190-fold, and the Cmax increased approximately 70-fold upon coadministration of fluvoxamine and ramelteon, compared to ramelteon administered alone. ramelteon should not be used in combination with fluvoxamine. Other less strong CYP1A2 inhibitors have not been adequately studied. ramelteon should be administered with caution to patients taking less strong CYP1A2 inhibitors. - Rifampin (strong CYP enzyme inducer): Administration of multiple doses of rifampin resulted in a mean decrease of approximately 80% in total exposure to ramelteon and metabolite M-II. Efficacy may be reduced when ramelteon is used in combination with strong CYP enzyme inducers such as rifampin. - Ketoconazole (strong CYP3A4 inhibitor): The AUC0-inf and Cmax of ramelteon increased by approximately 84% and 36% upon coadministration of ketoconazole with ramelteon. ramelteon should be administered with caution in subjects taking strong CYP3A4 inhibitors such as ketoconazole. - Fluconazole (strong CYP2C9 inhibitor): The AUC0-inf and Cmax of ramelteon was increased by approximately 150% when ramelteon was coadministered with fluconazole. ramelteon should be administered with caution in subjects taking strong CYP2C9 inhibitors such as fluconazole. - Donepezil: The AUC0-inf and Cmax of ramelteon increased by approximately 100% and 87%, respectively upon coadministration of donepezil with ramelteon. Patients should be closely monitored when ramelteon is coadministered with donepezil. - Doxepin: The AUC0-inf and Cmax of ramelteon increased by approximately 66% and 69%, respectively, upon coadministration of doxepin with ramelteon. Patients should be closely monitored when ramelteon is coadministered with doxepin. - Ramelteon is not known to interfere with commonly used clinical laboratory tests. In addition, in vitro data indicate that ramelteon does not cause false-positive results for benzodiazepines, opiates, barbiturates, cocaine, cannabinoids, or amphetamines in two standard urine drug screening methods in vitro. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C In animal studies, ramelteon produced evidence of developmental toxicity, including teratogenic effects, in rats at doses much greater than the recommended human dose (RHD) of 8 mg/day. There are no adequate and well-controlled studies in pregnant women. ramelteon should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Oral administration of ramelteon (10, 40, 150 or 600 mg/kg/day) to pregnant rats during the period of organogenesis was associated with increased incidences of fetal structural abnormalities (malformations and variations) at doses greater than 40 mg/kg/day. The no-effect dose is approximately 50 times the RHD on a body surface area (mg/m2) basis. Treatment of pregnant rabbits during the period of organogenesis produced no evidence of embryo-fetal toxicity at oral doses of up to 300 mg/kg/day (or up to 720 times the RHD on a mg/m2 basis. When rats were orally administered ramelteon (30, 100, or 300 mg/kg/day) throughout gestation and lactation, growth retardation, developmental delay, and behavioral changes were observed in the offspring at doses greater than 30 mg/kg/day. The no-effect dose is 36 times the RHD on a mg/m2 basis. Increased incidences of malformation and death among offspring were seen at the highest dose. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ramelteon in women who are pregnant. ### Labor and Delivery The potential effects of ramelteon on the duration of labor and/or delivery, for either the mother or the fetus, have not been studied. ramelteon has no established use in labor and delivery. ### Nursing Mothers It is not known whether ramelteon is secreted into human milk; however ramelteon is secreted into the milk of lactating rats. Because many drugs are excreted into human milk, caution should be exercised when administered to a nursing woman. ### Pediatric Use Safety and effectiveness of ramelteon in pediatric patients have not been established. Further study is needed prior to determining that this product may be used safely in pre-pubescent and pubescent patients. ### Geriatic Use A total of 654 subjects in double-blind, placebo-controlled, efficacy trials who received ramelteon were at least 65 years of age; of these, 199 were 75 years of age or older. No overall differences in safety or efficacy were observed between elderly and younger adult subjects. A double-blind, randomized, placebo-controlled study in elderly subjects with insomnia (n=33) evaluated the effect of a single dose of ramelteon on balance, mobility, and memory functions after middle of the night awakening. There is no information on the effect of multiple dosing. Night time dosing of ramelteon 8 mg did not impair middle of the night balance, mobility, or memory functions relative to placebo. The effects on night balance in the elderly cannot be definitively known from this study. ### Gender There is no FDA guidance on the use of Ramelteon with respect to specific gender populations. ### Race There is no FDA guidance on the use of Ramelteon with respect to specific racial populations. ### Renal Impairment No effects on Cmax and AUC0-t of parent drug or M-II were seen. No adjustment of ramelteon dosage is required in patients with renal impairment. ### Hepatic Impairment Exposure to ramelteon was increased by 4-fold in subjects with mild hepatic impairment and by more than 10-fold in subjects with moderate hepatic impairment. ramelteon should be used with caution in patients with moderate hepatic impairment. Ramelteon is not recommended in patients with severe hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Ramelteon in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Ramelteon in patients who are immunocompromised. ### Sleep Apnea The effects of ramelteon were evaluated after administering a 16 mg dose or placebo in a crossover design to subjects (n=26) with mild to moderate obstructive sleep apnea. Treatment with ramelteon 16 mg for one night showed no difference compared with placebo on the Apnea/Hypopnea Index (the primary outcome variable), apnea index, hypopnea index, central apnea index, mixed apnea index, and obstructive apnea index. Treatment with a single dose of ramelteon does not exacerbate mild to moderate obstructive sleep apnea. There is no available information on the respiratory effects of multiple doses of ramelteon in patients with sleep apnea. The effects on exacerbation in patients with mild to moderate sleep apnea cannot be definitively known from this study. ramelteon has not been studied in subjects with severe obstructive sleep apnea; use of ramelteon is not recommended in such patients. The respiratory depressant effect of ramelteon was evaluated in a crossover design study of subjects (n=26) with mild to moderate COPD after administering a single 16 mg dose or placebo, and in a separate study (n=25), the effects of ramelteon on respiratory parameters were evaluated after administering an 8 mg dose or placebo in a crossover design to patients with moderate to severe COPD, defined as patients who had forced expiratory volume at one second (FEV1)/forced vital capacity ratio of <70%, and a FEV1 <80% of predicted with <12% reversibility to albuterol. Treatment with a single dose of ramelteon has no demonstrable respiratory depressant effects in subjects with mild to severe COPD, as measured by arterial O2 saturation (SaO2). There is no available information on the respiratory effects of multiple doses of ramelteon in patients with COPD. The respiratory depressant effects in patients with COPD cannot be definitively known from this study. # Administration and Monitoring ### Administration Oral ### Monitoring There is limited information regarding Ramelteon Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Ramelteon and IV administrations. # Overdosage - General symptomatic and supportive measures should be used, along with immediate gastric lavage where appropriate. - Intravenous fluids should be administered as needed. - As in all cases of drug overdose, respiration, pulse, blood pressure, and other appropriate vital signs should be monitored, and general supportive measures employed. - Hemodialysis does not effectively reduce exposure to ramelteon. Therefore, the use of dialysis in the treatment of overdosage is not appropriate. # Pharmacology ## Mechanism of Action Ramelteon is a melatonin receptor agonist with both high affinity for melatonin MT1 and MT2 receptors and selectivity over the MT3 receptor. Ramelteon demonstrates full agonist activity in vitro in cells expressing human MT1 or MT2 receptors. The activity of ramelteon at the MT1 and MT2 receptors is believed to contribute to its sleep-promoting properties, as these receptors, acted upon by endogenous melatonin, are thought to be involved in the maintenance of the circadian rhythm underlying the normal sleep-wake cycle. Ramelteon has no appreciable affinity for the GABA receptor complex or for receptors that bind neuropeptides, cytokines, serotonin, dopamine, noradrenaline, acetylcholine, and opiates. Ramelteon also does not interfere with the activity of a number of selected enzymes in a standard panel. The major metabolite of ramelteon, M-II, is active and has approximately one tenth and one fifth the binding affinity of the parent molecule for the human MT1 and MT2 receptors, respectively, and is 17- to 25-fold less potent than ramelteon in in vitro functional assays. Although the potency of M-II at MT1 and MT2 receptors is lower than the parent drug, M-II circulates at higher concentrations than the parent producing 20- to 100-fold greater mean systemic exposure when compared to ramelteon. M-II has weak affinity for the serotonin 5-HT2B receptor, but no appreciable affinity for other receptors or enzymes. Similar to ramelteon, M-II does not interfere with the activity of a number of endogenous enzymes. All other known metabolites of ramelteon are inactive. ## Structure The compound is produced as the (S)-enantiomer, with an empirical formula of C16H21NO2, molecular weight of 259.34, and the following chemical structure: ## Pharmacodynamics There is limited information regarding Ramelteon Pharmacodynamics in the drug label. ## Pharmacokinetics The pharmacokinetic profile of ramelteon has been evaluated in healthy subjects as well as in subjects with hepatic or renal impairment. When administered orally to humans in doses ranging from 4 to 64 mg, ramelteon undergoes rapid, high first-pass metabolism, and exhibits linear pharmacokinetics. Maximal serum concentration (Cmax) and area under the concentration-time curve (AUC) data show substantial intersubject variability, consistent with the high first-pass effect; the coefficient of variation for these values is approximately 100%. Several metabolites have been identified in human serum and urine. Ramelteon is absorbed rapidly, with median peak concentrations occurring at approximately 0.75 hour (range, 0.5 to 1.5 hours) after fasted oral administration. Although the total absorption of ramelteon is at least 84%, the absolute oral bioavailability is only 1.8% due to extensive first-pass metabolism. In vitro protein binding of ramelteon is approximately 82% in human serum, independent of concentration. Binding to albumin accounts for most of that binding, since 70% of the drug is bound in human serum albumin. Ramelteon is not distributed selectively to red blood cells. Ramelteon has a mean volume of distribution after intravenous administration of 73.6 L, suggesting substantial tissue distribution. Metabolism of ramelteon consists primarily of oxidation to hydroxyl and carbonyl derivatives, with secondary metabolism producing glucuronide conjugates. CYP1A2 is the major isozyme involved in the hepatic metabolism of ramelteon; the CYP2C subfamily and CYP3A4 isozymes are also involved to a minor degree. The rank order of the principal metabolites by prevalence in human serum is M-II, M-IV, M-I, and M-III. These metabolites are formed rapidly and exhibit a monophasic decline and rapid elimination. The overall mean systemic exposure of M-II is approximately 20- to 100-fold higher than parent drug. Following oral administration of radiolabeled ramelteon, 84% of total radioactivity was excreted in urine and approximately 4% in feces, resulting in a mean recovery of 88%. Less than 0.1% of the dose was excreted in urine and feces as the parent compound. Elimination was essentially complete by 96 hours post-dose. Repeated once daily dosing with ramelteon does not result in significant accumulation owing to the short elimination half-life of ramelteon (on average, approximately 1 to 2.6 hours). The half-life of M-II is 2 to 5 hours and independent of dose. Serum concentrations of the parent drug and its metabolites in humans are at or below the lower limits of quantitation within 24 hours. When administered with a high-fat meal, the AUC0-inf for a single 16 mg dose of ramelteon was 31% higher and the Cmax was 22% lower than when given in a fasted state. Median Tmax was delayed by approximately 45 minutes when ramelteon was administered with food. Effects of food on the AUC values for M-II were similar. It is therefore recommended that ramelteon not be taken with or immediately after a high-fat meal. ## Nonclinical Toxicology Ramelteon was administered to mice and rats at oral doses of 0, 30, 100, 300, or 1000 mg/kg/day (mice) and 0, 15, 60, 250, or 1000 mg/kg/day (rats). Mice and rats were dosed for two years, except at the high dose (94 weeks for male and female mice and female rats). In mice, dose-related increases in the incidence of hepatic tumors (adenomas, carcinomas, hepatoblastomas) were observed in males and females. The no-effect dose for hepatic tumors in mice (30 mg/kg/day) is approximately 20 times the recommended human dose (RHD) of 8 mg/day on a body surface area (mg/m2) basis. In rats, the incidence of hepatic adenoma and benign Leydig cell tumors of the testis was increased in males at doses ≥250 mg/kg/day. In females, the incidence of hepatic adenoma was increased at doses ≥60 mg/kg/day. The incidence of hepatic carcinoma was increased in males and female rats at 1000 mg/kg/day. The no-effect dose for tumors in rats (15 mg/kg/day) is approximately 20 times the RHD on a mg/m2 basis. Ramelteon was not genotoxic in the in vitro bacterial reverse mutation (Ames) assay, the in vitro mouse lymphoma TK+/- assay, and in in vivo oral micronucleus assays in mouse and rat. Ramelteon was clastogenic in the in vitro chromosomal aberration assay in Chinese hamster lung cells. Separate studies indicated that the concentration of the M-II metabolite formed in the presence of metabolic activation exceeded the concentration of ramelteon; therefore, the genotoxic potential of the M-II metabolite was also assessed in the in vitro studies. # Clinical Studies ### Controlled Clinical Trials Three randomized, double-blind trials in subjects with chronic insomnia employing polysomnography (PSG) were provided as objective support of ramelteon's effectiveness in sleep initiation. One study enrolled younger adults (aged 18 to 64 years, inclusive) with chronic insomnia and employed a parallel design in which the subjects received a single, nightly dose of ramelteon (8 mg or 16 mg) or matching placebo for 35 days. PSG was performed on the first two nights in each of Weeks 1, 3, and 5 of treatment. Ramelteon reduced the average latency to persistent sleep at each of the time points when compared to placebo. The 16 mg dose conferred no additional benefit for sleep initiation. The second study employing PSG was a three-period crossover trial performed in subjects aged 65 years and older with a history of chronic insomnia. Subjects received ramelteon (4 mg or 8 mg) or placebo and underwent PSG assessment in a sleep laboratory for two consecutive nights in each of the three study periods. Both doses of ramelteon reduced latency to persistent sleep when compared to placebo. The third study evaluated long term efficacy and safety in adults with chronic insomnia. Subjects received a single, nightly dose of ramelteon 8 mg or matching placebo for 6 months. PSG was performed on the first two nights of Week 1 and Months 1, 3, 5, and 6. ramelteon reduced sleep latency at each time point when compared to placebo. In this study, when the PSG results from nights 1 and 2 of Month 7 were compared to the results from nights 22 and 23 of Month 6, there was a statistically significant increase in LPS of 33% (9.5 minutes) in the ramelteon group. There was no increase in LPS in the placebo group when the same time periods were compared. A randomized, double-blind, parallel group study was conducted in outpatients aged 65 years and older with chronic insomnia and employed subjective measures of efficacy (sleep diaries). Subjects received ramelteon (4 mg or 8 mg) or placebo for 35 nights. ramelteon reduced patient-reported sleep latency compared to placebo. A similarly designed study performed in younger adults (aged 18 - 64 years) using 8 mg and 16 mg of ramelteon did not replicate this finding of reduced patient-reported sleep latency compared to placebo. While the 16 mg dose was evaluated as a potential treatment for adults, it was shown to confer no additional benefit for sleep initiation and was associated with higher incidences of fatigue, headache and next-day somnolence. In a randomized, double-blind, parallel-group trial using a first-night-effect model, healthy adults received placebo or ramelteon before spending one night in a sleep laboratory and being evaluated with PSG. ramelteon demonstrated a decrease in mean latency to persistent sleep as compared to placebo. ### Studies Pertinent to Safety Concerns for Sleep- promoting Drugs A human laboratory abuse potential study was performed in 14 subjects with a history of sedative/hypnotic or anxiolytic drug abuse. Subjects received single oral doses of ramelteon (16, 80, or 160 mg), triazolam (0.25, 0.50, or 0.75 mg) or placebo. All subjects received each of the 7 treatments separated by a wash-out period and underwent multiple standard tests of abuse potential. No differences in subjective responses indicative of abuse potential were found between ramelteon and placebo at doses up to 20 times the recommended therapeutic dose. The positive control drug, triazolam, consistently showed a dose-response effect on these subjective measures, as demonstrated by the differences from placebo in peak effect and overall 24-hour effect. In order to evaluate potential next-day residual effects, the following scales were used: a Memory Recall Test, a Word List Memory Test, a Visual Analog Mood and Feeling Scale, the Digit-Symbol Substitution Test, and a post-sleep questionnaire to assess alertness and ability to concentrate. There was no evidence of next-day residual effect seen after 2 nights of ramelteon use during the crossover studies. In a 35-night, double-blind, placebo-controlled, parallel-group study in adults with chronic insomnia, measures of residual effects were performed at three time points. Overall, the magnitudes of any observed differences were small. At Week 1, patients who received 8 mg of ramelteon had a mean VAS score (46 mm on a 100 mm scale) indicating more fatigue in comparison to patients who received placebo (42 mm). At Week 3, patients who received 8 mg of ramelteon had a lower mean score for immediate recall (7.5 out of 16 words) compared to patients who received placebo (8.2 words); and the patients treated with ramelteon had a mean VAS score indicating more sluggishness (27 mm on a 100 mm VAS) in comparison to the placebo-treated patients (22 mm). Patients who received ramelteon did not have next-morning residual effects that were different from placebo at Week 5. Potential rebound insomnia and withdrawal effects were assessed in four studies in which subjects received ramelteon or placebo for up to 6 months; 3 were 35-day studies, one was a 6 month study. These studies included a total of 2533 subjects, of whom 854 were elderly. Tyrer Benzodiazepine Withdrawal Symptom Questionnaire (BWSQ): The BWSQ is a self-report questionnaire that solicits specific information on 20 symptoms commonly experienced during withdrawal from benzodiazepine receptor agonists; ramelteon is not a benzodiazepine receptor agonist. In two of the three 35-day insomnia studies, the questionnaire was administered one week after completion of treatment; in the third study, the questionnaire was administered on Days 1 and 2 after completion. In all three of the 35-day studies, subjects receiving ramelteon 4 mg, 8 mg, or 16 mg daily reported BWSQ scores similar to those of subjects receiving placebo. In the 6 month study, there was no evidence of withdrawal from the 8 mg dose as measured by the BWSQ. Rebound Insomnia: Rebound insomnia was assessed in the 35-day studies by measuring sleep latency after abrupt treatment discontinuation. One of these studies employed PSG in younger adult subjects receiving ramelteon 8 mg or 16 mg; the other two studies employed subjective measures of sleep-onset insomnia in elderly subjects receiving ramelteon 4 mg or 8 mg, and in younger adult subjects receiving ramelteon 8 mg or 16 mg. There was no evidence that ramelteon caused rebound insomnia during the post-treatment period. ### Studies to Evaluate Effects on Endocrine Function Two controlled studies evaluated the effects of ramelteon on endocrine function. In the first trial, ramelteon 16 mg once daily or placebo was administered to 99 healthy volunteer subjects for 4 weeks. This study evaluated the thyroid axis, adrenal axis and reproductive axis. No clinically significant endocrinopathies were demonstrated in this study. However, the study was limited in its ability to detect such abnormalities due to its limited duration. In the second trial, ramelteon 16 mg once daily or placebo was administered to 122 subjects with chronic insomnia for 6 months. This study evaluated the thyroid axis, adrenal axis and reproductive axis. There were no significant abnormalities seen in either the thyroid or the adrenal axes. Abnormalities were, however, noted within the reproductive axis. Overall, the mean serum prolactin level change from baseline was 4.9 mcg/L (34% increase) for women in the ramelteon group compared with -0.6 mcg/L (4% decrease) for women in the placebo group (p=0.003). No differences between active- and placebo-treated groups occurred among men. Thirty-two percent of all patients who were treated with ramelteon in this study (women and men) had prolactin levels that increased from normal baseline levels compared to 19% of patients who were treated with placebo. Subject-reported menstrual patterns were similar between the two treatment groups. In a 12-month, open-label study in adult and elderly patients, there were two patients who were noted to have abnormal morning cortisol levels, and subsequent abnormal ACTH stimulation tests. A 29-year-old female patient was diagnosed with a prolactinoma. The relationship of these events to ramelteon therapy is not clear. # How Supplied Ramelteon is supplied in 8 mg tablets - Bottles of 30 (NDC 64764-805-30) - Bottles of 100 (NDC 64764-805-10) - Bottles of 500 (NDC 64764-805-50) ## Storage Store at 25°C (77°F) # Images ## Drug Images ## Package and Label Display Panel [[\|thumb\|none\|600px]] # Patient Counseling Information Prescribers or other healthcare professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with hypnotics, should counsel them in their appropriate use and should instruct them to read the accompanying Medication Guide. ### Severe Anaphylactic and Anaphylactoid Reactions - Inform patients that severe anaphylactic and anaphylactoid reactions have occurred with ramelteon. Describe the relevant signs/symptoms and advise seeking immediate medical attention if any such things occur. ### Sleep-driving and other Complex Behaviors - There have been reports of people getting out of bed after taking a sleep medication and driving their cars while not fully awake, often with no memory of the event. If a patient experiences such an episode, it should be reported to his or her doctor immediately, since "sleep-driving" can be dangerous. This behavior is more likely to occur when sleep medications are taken with alcohol or other central nervous system depressants. Other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex) have been reported in patients who are not fully awake after taking a sleep medication. As with sleep-driving, patients usually do not remember these events. ### Endocrine Effects - Patients should consult their health care providers if they experience one of the following: cessation of menses or galactorrhea in females, decreased libido, or problems with fertility. Describe the relevant signs/symptoms and advise seeking medical attention if any such things occur. ### Administration Instructions - Patients should be advised to take ramelteon within 30 minutes prior to going to bed and should confine their activities to those necessary to prepare for bed. - Patients should be advised that they should not take ramelteon with or immediately after a high-fat meal. - Do not break the tablet; it should be swallowed whole. # Precautions with Alcohol Alcohol by itself impairs performance and can cause sleepiness. Since the intended effect of ramelteon is to promote sleep, patients should be cautioned not to consume alcohol when using ramelteon. Use of the products in combination may have an additive effect. # Brand Names - Rozerem [1] # Look-Alike Drug Names There is limited information regarding Ramelteon Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Ramelteon
7f069a32509566808889d8f5d993dbcf383d6917	wikidoc	Sirolimus	Sirolimus # 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 Sirolimus is an immunomodulatory drug that is FDA approved for the prophylaxis of organ rejection in renal transplantation. There is a Black Box Warning for this drug as shown here. Common adverse reactions include lymphedema, pericardial effusion, hepatotoxicity, hypersensitivity, tuberculosis, interstitial lung disease, exfoliative dermatitis, nephrotic syndrome. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Sirolimus is indicated for the prophylaxis of organ rejection in patients aged 13 years or older receiving renal transplants. Therapeutic drug monitoring is recommended for all patients receiving sirolimus. - In patients at low- to moderate-immunologic risk, it is recommended that sirolimus be used initially in a regimen with cyclosporine and corticosteroids; cyclosporine should be withdrawn 2 to 4 months after transplantation. - In patients at high-immunologic risk (defined as Black recipients and/or repeat renal transplant recipients who lost a previous allograft for immunologic reason and/or patients with high panel-reactive antibodies ), it is recommended that sirolimus be used in combination with cyclosporine and corticosteroids for the first year following transplantation. - Cyclosporine withdrawal has not been studied in patients with Banff Grade 3 acute rejection or vascular rejection prior to cyclosporine withdrawal, those who are dialysis-dependent, those with serum creatinine > 4.5 mg/dL, Black patients, patients of multi-organ transplants, secondary transplants, or those with high levels of panel-reactive antibodies. - In patients at high-immunologic risk, the safety and efficacy of sirolimus used in combination with cyclosporine and corticosteroids has not been studied beyond one year; therefore after the first 12 months following transplantation, any adjustments to the immunosuppressive regimen should be considered on the basis of the clinical status of the patient. - In pediatric patients, the safety and efficacy of sirolimus have not been established in patients < 13 years old, or in pediatric (< 18 years) renal transplant patients considered at high-immunologic risk. - The safety and efficacy of de novo use of sirolimus without cyclosporine have not been established in renal transplant patients. - The safety and efficacy of conversion from calcineurin inhibitors to Rapamune in maintenance renal transplant patients have not been established. - Sirolimus is to be administered orally once daily, consistently with or without food. - Tablets should not be crushed, chewed or split. Patients unable to take the tablets should be prescribed the solution and instructed in its use. - The initial dose of sirolimus should be administered as soon as possible after transplantation. It is recommended that sirolimus be taken 4 hours after administration of cyclosporine oral solution (MODIFIED) and or/cyclosporine capsules (MODIFIED). - Frequent sirolimus dose adjustments based on non-steady-state sirolimus concentrations can lead to overdosing or underdosing because sirolimus has a long half-life. - Once sirolimus maintenance dose is adjusted, patients should continue on the new maintenance dose for at least 7 to 14 days before further dosage adjustment with concentration monitoring. In most patients, dose adjustments can be based on simple proportion: new sirolimus dose = current dose x (target concentration/current concentration). - A loading dose should be considered in addition to a new maintenance dose when it is necessary to increase sirolimus trough concentrations: sirolimus loading dose = 3 x (new maintenance dose - current maintenance dose). - The maximum sirolimus dose administered on any day should not exceed 40 mg. If an estimated daily dose exceeds 40 mg due to the addition of a loading dose, the loading dose should be administered over 2 days. - Sirolimus trough concentrations should be monitored at least 3 to 4 days after a loading dose(s). - Two milligrams (2 mg) of Sirolimus Oral Solution have been demonstrated to be clinically equivalent to 2 mg sirolimus Tablets; hence, are interchangeable on a mg-to-mg basis. - However, it is not known if higher doses of sirolimus Oral Solution are clinically equivalent to higher doses of sirolimus Tablets on a mg‑to‑mg basis. ### Patients at Low- to Moderate-Immunologic Risk - For de novo renal transplant patients, it is recommended that sirolimus Oral Solution and Tablets be used initially in a regimen with cyclosporine and corticosteroids. - A loading dose of sirolimus equivalent to 3 times the maintenance dose should be given, i.e. a daily maintenance dose of 2 mg should be preceded with a loading dose of 6 mg. Therapeutic drug monitoring should be used to maintain sirolimus drug concentrations within the target-range. - At 2 to 4 months following transplantation, cyclosporine should be progressively discontinued over 4 to 8 weeks, and the sirolimus dose should be adjusted to obtain sirolimus whole blood trough concentrations within the target-range. - Because cyclosporine inhibits the metabolism and transport of sirolimus, sirolimus concentrations may decrease when cyclosporine is discontinued, unless the sirolimus dose is increased. - In patients with high-immunologic risk, it is recommended that sirolimus be used in combination with cyclosporine and corticosteroids for the first 12 months following transplantation. - The safety and efficacy of this combination in high-immunologic risk patients has not been studied beyond the first 12 months. Therefore, after the first 12 months following transplantation, any adjustments to the immunosuppressive regimen should be considered on the basis of the clinical status of the patient. - For patients receiving sirolimus with cyclosporine, sirolimus therapy should be initiated with a loading dose of up to 15 mg on day 1 post-transplantation. Beginning on day 2, an initial maintenance dose of 5 mg/day should be given. A trough level should be obtained between days 5 and 7, and the daily dose of sirolimus should thereafter be adjusted. - The starting dose of cyclosporine should be up to 7 mg/kg/day in divided doses and the dose should subsequently be adjusted to achieve target whole blood trough concentrations. Prednisone should be administered at a minimum of 5 mg/day. - Antibody induction therapy may be used. - Monitoring of sirolimus trough concentrations is recommended for all patients, especially in those patients likely to have altered drug metabolism, in patients≥ 13 years who weigh less than 40 kg, in patients with hepatic impairment,when a change in the sirolimus dosage form is made, and during concurrent administration of strong CYP3A4 inducers and inhibitors. - Therapeutic drug monitoring should not be the sole basis for adjusting sirolimus therapy. Careful attention should be made to clinical signs/symptoms, tissue biopsy findings, and laboratory parameters. - When used in combination with cyclosporine, sirolimus trough concentrations should be maintained within the target-range. - Following cyclosporine withdrawal in transplant patients at low- to moderate-immunologic risk, the target sirolimus trough concentrations should be 16 to 24 ng/mL for the first year following transplantation. Thereafter, the target sirolimus concentrations should be 12 to 20 ng/mL. - The above recommended 24-hour trough concentration ranges for sirolimus are based on chromatographic methods. On average, chromatographic methods (HPLC UV or LC/MS/MS) yield results that are approximately 20% lower than the immunoassay for whole blood concentration determinations. - Currently in clinical practice, sirolimus whole blood concentrations are being measured by both chromatographic and immunoassay methodologies. Because the measured sirolimus whole blood concentrations depend on the type of assay used, the concentrations obtained by these different methodologies are not interchangeable. - Adjustments to the targeted range should be made according to the assay utilized to determine sirolimus trough concentrations. A discussion of different assay methods is contained in Clinical Therapeutics, Volume 22, Supplement B, April 2000. - The initial dosage in patients ≥ 13 years who weigh less than 40 kg should be adjusted, based on body surface area, to 1 mg/m2/day. The loading dose should be 3 mg/m2. - It is recommended that the maintenance dose of sirolimus be reduced by approximately one third in patients with mild or moderate hepatic impairment and by approximately one half in patients with severe hepatic impairment. It is not necessary to modify the sirolimus loading dose. - Dosage adjustment is not needed in patients with impaired renal function. - The amber oral dose syringe should be used to withdraw the prescribed amount of sirolimus Oral Solution from the bottle. Empty the correct amount of sirolimus from the syringe into only a glass or plastic container holding at least two (2) ounces (1/4 cup, 60 mL) of water or orange juice. No other liquids, including grapefruit juice, should be used for dilution. Stir vigorously and drink at once. Refill the container with an additional volume of water or orange juice, stir vigorously, and drink at once. - Sirolimus Oral Solution contains polysorbate 80, which is known to increase the rate of di‑(2‑ethylhexyl)phthalate (DEHP) extraction from polyvinyl chloride (PVC). This should be considered during the preparation and administration of sirolimus Oral Solution. It is important that these recommendations be followed closely. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Sirolimus in adult patients. ### Non–Guideline-Supported Use - Renal transplant rejection. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Sirolimus in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Sirolimus in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Sirolimus in pediatric patients. # Contraindications - Sirolimus is contraindicated in patients with a hypersensitivity to sirolimus. # Warnings - Increased susceptibility to infection and the possible development of lymphoma and other malignancies, particularly of the skin, may result from immunosuppression. The rates of lymphoma/lymphoproliferative disease observed in Studies 1 and 2 were 0.7-3.2% (for sirolimus-treated patients) versus 0.6-0.8% (azathioprine and placebo control). - Oversuppression of the immune system can also increasesusceptibility to infection, including opportunistic infections such as tuberculosis, fatal infections, and sepsis. Only physicians experienced in immunosuppressive therapy and management of organ transplant patients should use sirolimus. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient. - The use of sirolimus in combination with tacrolimus was associated with excess mortality and graft loss in a study in de novo liver transplant patients (22% in combination versus 9% on tacrolimus alone). Many of these patients had evidence of infection at or near the time of death. - In this and another study in de novo liver transplant patients, the use of sirolimus in combination with cyclosporine or tacrolimus was associated with an increase in HAT (7% in combination versus 2% in the control arm); most cases of HAT occurred within 30 days post-transplantation, and most led to graft loss or death. - The safety and efficacy of sirolimus as immunosuppressive therapy have not been established in liver transplant patients; therefore, such use is not recommended. - Cases of bronchial anastomotic dehiscence, most fatal, have been reported in de novo lung transplant patients when sirolimus has been used as part of an immunosuppressive regimen. - The safety and efficacy of sirolimus as immunosuppressive therapy have not been established in lung transplant patients; therefore, such use is not recommended. - Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, angioedema, exfoliative dermatitis and hypersensitivity vasculitis, have been associated with the administration of sirolimus. - Sirolimus has been associated with the development of angioedema. The concomitant use of sirolimus with other drugs known to cause angioedema, such as ACE-inhibitors, may increase the risk of developing angioedema. - There have been reports of impaired or delayed wound healing in patients receiving sirolimus, including lymphocele and wound dehiscence. - mTOR inhibitors such as sirolimus have been shown in vitro to inhibit production of certain growth factors that may affect angiogenesis, fibroblast proliferation, and vascular permeability. Lymphocele, a known surgical complication of renal transplantation, occurred significantly more often in a dose-related fashion in patients treated with sirolimus. - Appropriate measures should be considered to minimize such complications. Patients with a body mass index (BMI) greater than 30 kg/m2 may be at increased risk of abnormal wound healing based on data from the medical literature. - There have also been reports of fluid accumulation, including peripheral edema, lymphedema, pleural effusion and pericardial effusions (including hemodynamically significant effusions and tamponade requiring intervention in children and adults), in patients receiving sirolimus. - Increased serum cholesterol and triglycerides requiring treatment occurred more frequently in patients treated with sirolimus compared with azathioprine or placebo controls in Studies 1 and 2. - There were increased incidences of hypercholesterolemia (43-46%) and/or hypertriglyceridemia (45-57%) in patients receiving sirolimus compared with placebo controls (each 23%). The risk/benefit should be carefully considered in patients with established hyperlipidemia before initiating an immunosuppressive regimen including sirolimus. - Any patient who is administered sirolimus should be monitored for hyperlipidemia. If detected, interventions such as diet, exercise, and lipid-lowering agents should be initiated as outlined by the National Cholesterol Education Program guidelines. - In clinical trials, the concomitant administration of sirolimus and HMG-CoA reductase inhibitors and/or fibrates appeared to be well-tolerated. - During sirolimus therapy with cyclosporine, patients administered an HMG-CoA reductase inhibitor and/or fibrate should be monitored for the possible development of rhabdomyolysis and other adverse effects, as described in the respective labeling for these agents. - Renal function should be closely monitored during the co-administration of sirolimus with cyclosporine, because long-term administration of the combination has been associated with deterioration of renal function. Patients treated with cyclosporine and sirolimus were noted to have higher serum creatinine levels and lower glomerular filtration rates compared with patients treated with cyclosporine and placebo or azathioprine controls (Studies 1 and 2). The rate of decline in renal function in these studies was greater in patients receiving sirolimus and cyclosporine compared with control therapies. - Appropriate adjustment of the immunosuppressive regimen, including discontinuation of sirolimus and/or cyclosporine, should be considered in patients with elevated or increasing serum creatinine levels. In patients at low- to moderate-immunologic risk, continuation of combination therapy with cyclosporine beyond 4 months following transplantation should only be considered when the benefits outweigh the risks of this combination for the individual patients. Caution should be exercised when using agents (e.g., aminoglycosides and amphotericin B) that are known to have a deleterious effect on renal function. - In patients with delayed graft function, sirolimus may delay recovery of renal function. - Periodic quantitative monitoring of urinary protein excretion is recommended. In a study evaluating conversion from calcineurin inhibitors (CNI) to sirolimus in maintenance renal transplant patients 6-120 months post-transplant, increased urinary protein excretion was commonly observed from 6 through 24 months after conversion to sirolimus compared with CNI continuation. - Patients with the greatest amount of urinary protein excretion prior to sirolimus conversion were those whose protein excretion increased the most after conversion.New onset nephrosis (nephrotic syndrome) was also reported as a treatment-emergent adverse event in 2.2% of the sirolimus conversion group patients in comparison to 0.4% in the CNI continuation group of patients. Nephrotic range proteinuria (defined as urinary protein to creatinine ratio > 3.5) was also reported in 9.2% in the sirolimus conversion group of patients in comparison to 3.7% in the CNI continuation group of patients. In some patients, reduction in the degree of urinary protein excretion was observed for individual patients following discontinuation of sirolimus. - The safety and efficacy of conversion from calcineurin inhibitors to sirolimus in maintenance renal transplant patients have not been established. - Cases of interstitial lung disease (including pneumonitis, bronchiolitis obliterans organizing pneumonia , and pulmonary fibrosis), some fatal, with no identified infectious etiology have occurred in patients receiving immunosuppressive regimens including sirolimus. In some cases, the interstitial lung disease has resolved upon discontinuation or dose reduction of sirolimus. The risk may be increased as the trough sirolimus concentration increases. - The safety and efficacy of de novo use of sirolimus without cyclosporine is not established in renal transplant patients. In a multicenter clinical study, de novo renal transplant patients treated with sirolimus, mycophenolate mofetil (MMF), steroids, and an IL-2 receptor antagonist had significantly higher acute rejection rates and numerically higher death rates compared to patients treated with cyclosporine, MMF, steroids, and IL-2 receptor antagonist. A benefit, in terms of better renal function, was not apparent in the treatment arm with de novo use of sirolimus without cyclosporine. These findings were also observed in a similar treatment group of another clinical trial. - The concomitant use of sirolimus with a calcineurin inhibitor may increase the risk of calcineurin inhibitor-induced hemolytic uremic syndrome/thrombotic thrombocytopenic purpura/thrombotic microangiopathy (HUS/TTP/TMA). - Cases of Pneumocystis carinii pneumonia have been reported in patients not receiving antimicrobial prophylaxis. Therefore, antimicrobial prophylaxis for Pneumocystis carinii pneumonia should be administered for 1 year following transplantation. - Cytomegalovirus (CMV) prophylaxis is recommended for 3 months after transplantation, particularly for patients at increased risk for CMV disease. - The label-recommended 24-hour trough concentration ranges for sirolimus are based on chromatographic methods. Currently in clinical practice, sirolimus whole blood concentrations are being measured by both chromatographic and immunoassay methodologies. These concentration values are not interchangeable. - Patients on immunosuppressive therapy are at increased risk for skin cancer. Exposure to sunlight and ultraviolet (UV) light should be limited by wearing protective clothing and using a sunscreen with a high protection factor. - Co-administration of sirolimus with strong inhibitors of CYP3A4 and/or P-gp (such as ketoconazole, voriconazole, itraconazole, erythromycin, telithromycin, or clarithromycin) or strong inducers of CYP3A4 and/or P-gp (such as rifampin or rifabutin) is not recommended # Adverse Reactions ## Clinical Trials Experience - The following adverse reactions are discussed in greater detail in other sections of the label. - Increased susceptibility to infection, lymphoma, and malignancy - Excess mortality, graft loss, and hepatic artery thrombosis in liver transplant patients. - Bronchial anastomotic dehiscence in lung transplant patients. - Hypersensitivity reactions - Exfoliative dermatitis - Angioedema - Fluid Accumulation and Wound Healing. - Hypertriglyceridemia, hypercholesterolemia - Decline in renal function in long-term combination of cyclosporine with sirolimus - Proteinuria - Interstitial lung disease - Increased risk of calcineurin inhibitor-induced hemolytic uremic syndrome/thrombotic thrombocytopenic purpura/thrombotic microangiopathy (HUS/TTP/TMA). - The most common (≥ 30%) adverse reactions observed with sirolimus in clinical studies are: peripheral edema, hypertriglyceridemia, hypertension, hypercholesterolemia, creatinine increased, constipation, abdominal pain, diarrhea, headache, fever, urinary tract infection, anemia, nausea, arthralgia, pain, and thrombocytopenia. - The following adverse reactions resulted in a rate of discontinuation of > 5% in clinical trials: creatinine increased, hypertriglyceridemia, and thrombotic thrombocytopenic purpura (TTP). - The safety and efficacy of sirolimus Oral Solution for the prevention of organ rejection following renal transplantation were assessed in two randomized, double-blind, multicenter, controlled trials. The safety profiles in the two studies were similar. - The incidence of adverse reactions in the randomized, double-blind, multicenter, placebo-controlled trial (Study 2) in which 219 renal transplant patients received sirolimus Oral Solution 2 mg/day, 208 received sirolimus Oral Solution 5 mg/day, and 124 received placebo is presented in the TABLE below. The study population had a mean age of 46 years (range 15 to 71 years), the distribution was 67% male, and the composition by race was: White (78%), Black (11%), Asian (3%), Hispanic (2%), and Other (5%). All patients were treated with cyclosporine and corticosteroids. Data (≥ 12 months post-transplant) presented in the following TABLE show the adverse reactions that occurred in at least one of the sirolimus treatment groups with an incidence of ≥ 20%. - The safety profile of the tablet did not differ from that of the oral solution formulation. - In general, adverse reactions related to the administration of sirolimus were dependent on dose/concentration. Although a daily maintenance dose of 5 mg, with a loading dose of 15 mg, was shown to be safe and effective, no efficacy advantage over the 2 mg dose could be established for renal transplant patients. - Patients receiving 2 mg of sirolimus Oral Solution per day demonstrated an overall better safety profile than did patients receiving 5 mg of sirolimus Oral Solution per day. - Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in one clinical trial of a drug cannot be directly compared with rates in the clinical trials of the same or another drug and may not reflect the rates observed in practice. - The following adverse reactions were reported less frequently (≥ 3%, but < 20%) - Sepsis, lymphocele, herpes zoster, herpes simplex. - Venous thromboembolism (including pulmonary embolism, deep venous thrombosis), tachycardia). - Stomatitis. - Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), leukopenia. - Abnormal healing, increased lactic dehydrogenase (LDH), hypokalemia. - Bone necrosis. - Pneumonia, epistaxis. - Melanoma, squamous cell carcinoma, basal cell carcinoma. - Pyelonephritis, decline in renal function (creatinine increased) in long-term combination of cyclosporine with sirolimus. - Less frequently (< 3%) occurring adverse reactions included: lymphoma/post-transplant lymphoproliferative disorder, mycobacterial infections (including M. tuberculosis), pancreatitis, cytomegalovirus (CMV), and Epstein-Barr virus. - The use of sirolimus in renal transplant patients was associated with increased serum cholesterol and triglycerides that may require treatment. - In Studies 1 and 2, in de novo renal transplant patients who began the study with fasting, total serum cholesterol 240 mg/dL) or hypertriglyceridemia (fasting serum triglycerides > 500 mg/dL), respectively, in patients receiving both sirolimus 2 mg and sirolimus 5 mg compared with azathioprine and placebo controls. - Treatment of new-onset hypercholesterolemia with lipid-lowering agents was required in 42‑52% of patients enrolled in the sirolimus arms of Studies 1 and 2 compared with 16% of patients in the placebo arm and 22% of patients in the azathioprine arm. - Abnormal healing events following transplant surgery include fascial dehiscence, incisional hernia, and anastomosis disruption (e.g., wound, vascular, airway, ureteral, biliary). - The TABLE below summarizes the incidence of malignancies in the two controlled trials (Studies 1 and 2) for the prevention of acute rejection. - At 24 months (Study 1) and 36 months (Study 2), there were no significant differences among treatment groups. - The incidence of adverse reactions was determined through 36 months in a randomized, multicenter, controlled trial (Study 3) in which 215 renal transplant patients received sirolimus as a maintenance regimen following cyclosporine withdrawal, and 215 patients received sirolimus with cyclosporine therapy. - All patients were treated with corticosteroids. The safety profile prior to randomization (start of cyclosporine withdrawal) was similar to that of the 2 mg sirolimus groups in Studies 1 and 2. - Following randomization (at 3 months), patients who had cyclosporine eliminated from their therapy experienced higher incidences of the following adverse reactions: abnormal liver function tests (including increased AST/SGOT and increased ALT/SGPT), hypokalemia, thrombocytopenia, and abnormal healing. Conversely, the incidence of the following adverse events was higher in patients who remained on cyclosporine than those who had cyclosporine withdrawn from therapy: hypertension, cyclosporine toxicity, increased creatinine, abnormal kidney function, toxic nephropathy, edema, hyperkalemia, hyperuricemia, and gum hyperplasia. Mean systolic and diastolic blood pressure improved significantly following cyclosporine withdrawal. - The incidence of malignancies in Study 3 is presented in the TABLE following. - In Study 3, the incidence of lymphoma/lymphoproliferative disease was similar in all treatment groups. The overall incidence of malignancy was higher in patients receiving sirolimus plus cyclosporine compared with patients who had cyclosporine withdrawn. Conclusions regarding these differences in the incidence of malignancy could not be made because Study 3 was not designed to consider malignancy risk factors or systematically screen subjects for malignancy. In addition, more patients in the sirolimus with cyclosporine group had a pretransplantation history of skin carcinoma. - Safety was assessed in 224 patients who received at least one dose of sirolimus with cyclosporine. Overall, the incidence and nature of adverse events was similar to those seen in previous combination studies with sirolimus. The incidence of malignancy was 1.3% at 12 months. - The safety and efficacy of conversion from calcineurin inhibitors to sirolimus in maintenance renal transplant population have not been established. In an ongoing study evaluating the safety and efficacy of conversion from calcineurin inhibitors to sirolimus (initial target sirolimus concentrations of 12-20 ng/mL, and then 8-20 ng/mL, by chromatographic assay) in maintenance renal transplant patients, enrollment was stopped in the subset of patients (n = 87) with a baseline glomerular filtration rate of less than 40 mL/min. There was a higher rate of serious adverse events, including pneumonia, acute rejection, graft loss and death, in this stratum of the sirolimus treatment arm. - The subset of patients with a baseline glomerular filtration rate of less than 40 mL/min had 2 years of follow-up after randomization. In this population, the rate of pneumonia was 15/58 vs. 4/29, graft loss (excluding death with functioning graft loss) was 13/58 vs. 9/29, and death was 9/58 vs. 1/29 in the sirolimus conversion group and CNI continuation group, respectively. - In the subset of patients with a baseline glomerular filtration rate of greater than 40 mL/min, there was no benefit associated with conversion with regard to improvement in renal function and a greater incidence of proteinuria in the sirolimus conversion arm. - Overall in this study, a 5-fold increase in the reports of tuberculosis among sirolimus (11/551) and comparator (1/273) treatment groups was observed with 2:1 randomization scheme. - Safety was assessed in a controlled clinical trial in pediatric (< 18 years of age) renal transplant patients considered at high-immunologic risk, defined as a history of one or more acute allograft rejection episodes and/or the presence of chronic allograft nephropathy on a renal biopsy. - The use of sirolimus in combination with calcineurin inhibitors and corticosteroids was associated with a higher incidence of deterioration of renal function (creatinine increased) compared to calcineurin inhibitor-based therapy, serum lipid abnormalities (including, but not limited to, increased serum triglycerides and cholesterol), and urinary tract infections. ## Postmarketing Experience - The following adverse reactions have been identified during post-approval use of sirolimus. 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. - Cardiovascular – Pericardial effusion (including hemodynamically significant effusions and tamponade requiring intervention in children and adults). - Hematological/Lymphatic – The concomitant use of sirolimus with a calcineurin inhibitor may increase the risk of calcineurin inhibitor-induced HUS/TTP/TMA; pancytopenia, neutropenia. - Hepatotoxicity, including fatal hepatic necrosis, with elevated sirolimus trough concentrations. - Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, angioedema, and hypersensitivity vasculitis. - Tuberculosis. - Liver function test abnormal, AST/SGOT increased, ALT/SGPT increased, hypophosphatemia, hyperglycemia. - Cases of interstitial lung disease (including pneumonitis, bronchiolitis obliterans organizing pneumonia , and pulmonary fibrosis), some fatal, with no identified infectious etiology have occurred in patients receiving immunosuppressive regimens including sirolimus. In some cases, the interstitial lung disease has resolved upon discontinuation or dose reduction of sirolimus. The risk may be increased as the sirolimus trough concentration increases; pulmonary hemorrhage; pleural effusion; alveolar proteinosis - Exfoliative dermatitis. - Nephrotic syndrome, proteinuria, focal segmental glomerulosclerosis. Azoospermia has been reported with the use of sirolimus and has been reversible upon discontinuation of sirolimus in most cases. # Drug Interactions - Sirolimus is known to be a substrate for both cytochrome P‑450 3A4 (CYP3A4) and p‑glycoprotein (P‑gp). Inducers of CYP3A4 and P‑gp may decrease sirolimus concentrations whereas inhibitors of CYP3A4 and P‑gp may increase sirolimus concentrations. - Cyclosporine, a substrate and inhibitor of CYP3A4 and P‑gp, was demonstrated to increase sirolimus concentrations when co‑administered with sirolimus. In order to diminish the effect of this interaction with cyclosporine, it is recommended that sirolimus be taken 4 hours after administration of cyclosporine oral solution (MODIFIED) and/or cyclosporine capsules (MODIFIED). - If cyclosporine is withdrawn from combination therapy with sirolimus, higher doses of sirolimus are needed to maintain the recommended sirolimus trough concentration ranges. - Strong Inducers and Strong Inhibitors of CYP3A4 and P-gp Avoid concomitant use of sirolimus with strong inducers (e.g., rifampin, rifabutin) and strong inhibitors (e.g., ketoconazole, voriconazole, itraconazole, erythromycin, telithromycin, clarithromycin) of CYP3A4 and P-gp. Alternative agents with lesser interaction potential with sirolimus should be considered. - Because grapefruit juice inhibits the CYP3A4-mediated metabolism of sirolimus, it must not be taken with or be used for dilution of sirolimus. - Exercise caution when using sirolimus with drugs or agents that are modulators of CYP3A4 and P-gp. The dosage of sirolimus and/or the co-administered drug may need to be adjusted. - Drugs that could increase sirolimus blood concentrations: Bromocriptine, cimetidine, cisapride, clotrimazole, danazol, diltiazem, fluconazole, HIV‑protease inhibitors (e.g., ritonavir, indinavir), metoclopramide, nicardipine, troleandomycin, verapamil Drugs and other agents that could decrease sirolimus concentrations: - Carbamazepine, phenobarbital, phenytoin, rifapentine, St. John's Wort (Hypericum perforatum) - Drugs with concentrations that could increase when given with sirolimus: - Verapamil - Immunosuppressants may affect response to vaccination. Therefore, during treatment with sirolimus, vaccination may be less effective. The use of live vaccines should be avoided; live vaccines may include, but are not limited to, the following: measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Sirolimus was embryo/fetotoxic in rats when given in doses approximately 0.2 to 0.5 the human doses (adjusted for body surface area). Embryo/fetotoxicity was manifested as mortality and reduced fetal weights (with associated delays in skeletal ossification). However, no teratogenesis was evident. In combination with cyclosporine, rats had increased embryo/feto mortality compared with sirolimus alone. There were no effects on rabbit development at a maternally toxic dosage approximately 0.3 to 0.8 times the human doses (adjusted for body surface area). There are no adequate and well‑controlled studies in pregnant women. Effective contraception must be initiated before sirolimus therapy, during sirolimus therapy, and for 12 weeks after sirolimus therapy has been stopped. Sirolimus should be used during pregnancy only if the potential benefit outweighs the potential risk to the embryo/fetus. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Sirolimus in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Sirolimus during labor and delivery. ### Nursing Mothers - Sirolimus is excreted in trace amounts in milk of lactating rats. It is not known whether sirolimus is excreted in human milk. The pharmacokinetic and safety profiles of sirolimus in infants are not known. Because many drugs are excreted in human milk, and because of the potential for adverse reactions in nursing infants from sirolimus, 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 efficacy of sirolimus in pediatric patients < 13 years have not been established. - The safety and efficacy of sirolimus Oral Solution and sirolimus Tablets have been established in children ≥ 13 years judged to be at low- to moderate-immunologic risk. Use of sirolimus Oral Solution and sirolimus Tablets in this subpopulation of children ≥ 13 years is supported by evidence from adequate and well-controlled trials of sirolimus Oral Solution in adults with additional pharmacokinetic data in pediatric renal transplantation patients. - Safety and efficacy information from a controlled clinical trial in pediatric and adolescent (< 18 years of age) renal transplant patients judged to be at high-immunologic risk, defined as a history of one or more acute rejection episodes and/or the presence of chronic allograft nephropathy, do not support the chronic use of sirolimus Oral Solution or Tablets in combination with calcineurin inhibitors and corticosteroids, due to the higher incidence of lipid abnormalities and deterioration of renal function associated with these immunosuppressive regimens compared to calcineurin inhibitors, without increased benefit with respect to acute rejection, graft survival, or patient survival. ### Geriatic Use - Clinical studies of sirolimus Oral Solution or Tablets did not include sufficient numbers of patients ≥ 65 years to determine whether they respond differently from younger patients. Data pertaining to sirolimus trough concentrations suggest that dose adjustments based upon age in geriatric renal patients are not necessary. Differences in responses between the elderly and younger patients have not been identified. 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, or cardiac function, and of concomitant disease or other drug therapy. ### Gender There is no FDA guidance on the use of Sirolimus with respect to specific gender populations. ### Race There is no FDA guidance on the use of Sirolimus with respect to specific racial populations. ### Renal Impairment - Dosage adjustment is not required in patients with renal impairment . ### Hepatic Impairment - The maintenance dose of sirolimus should be reduced in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Sirolimus in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Sirolimus in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring - Monitoring of sirolimus trough concentrations is recommended for all patients, especially in those patients likely to have altered drug metabolism, in patients≥ 13 years who weigh less than 40 kg, in patients with hepatic impairment,when a change in the sirolimus dosage form is made, and during concurrent administration of strong CYP3A4 inducers and inhibitors. - Therapeutic drug monitoring should not be the sole basis for adjusting sirolimus therapy. Careful attention should be made to clinical signs/symptoms, tissue biopsy findings, and laboratory parameters. - When used in combination with cyclosporine, sirolimus trough concentrations should be maintained within the target-range. - Following cyclosporine withdrawal in transplant patients at low- to moderate-immunologic risk, the target sirolimus trough concentrations should be 16 to 24 ng/mL for the first year following transplantation. Thereafter, the target sirolimus concentrations should be 12 to 20 ng/mL. - The above recommended 24-hour trough concentration ranges for sirolimus are based on chromatographic methods. On average, chromatographic methods (HPLC UV or LC/MS/MS) yield results that are approximately 20% lower than the immunoassay for whole blood concentration determinations. Currently in clinical practice, sirolimus whole blood concentrations are being measured by both chromatographic and immunoassay methodologies. Because the measured sirolimus whole blood concentrations depend on the type of assay used, the concentrations obtained by these different methodologies are not interchangeable. - Adjustments to the targeted range should be made according to the assay utilized to determine sirolimus trough concentrations. - Therapeutic drug monitoring should be used to maintain sirolimus drug levels within the target-range. - Therapeutic drug monitoring is necessary in all patients with hepatic impairment. - Renal function should be monitored, and appropriate adjustment of the immunosuppressive regimen should be considered in patients with elevated or increasing serum creatinine levels. - Periodic quantitative monitoring of urinary protein excretion is recommended. - During sirolimus therapy with cyclosporine, patients administered an HMG-CoA reductase inhibitor and/or fibrate should be monitored for the possible development of rhabdomyolysis and other adverse effects, as described in the respective labeling for these agents. - Any patient who is administered sirolimus should be monitored for hyperlipidemia. - Monitoring of sirolimus trough concentrations is recommended for all patients, especially in those patients likely to have altered drug metabolism, in patients≥ 13 years who weigh less than 40 kg, in patients with hepatic impairment,when a change in the sirolimus dosage form is made, and during concurrent administration of strong CYP3A4 inducers and inhibitors. - Once sirolimus maintenance dose is adjusted, patients should continue on the new maintenance dose for at least 7 to 14 days before further dosage adjustment with concentration monitoring. # IV Compatibility There is limited information regarding IV Compatibility of Sirolimus in the drug label. # Overdosage - Reports of overdose with sirolimus have been received; however, experience has been limited. In general, the adverse effects of overdose are consistent with those listed in the adverse reactions section. - General supportive measures should be followed in all cases of overdose. Based on the low aqueous solubility and high erythrocyte and plasma protein binding of sirolimus, it is anticipated that sirolimus is not dialyzable to any significant extent. In mice and rats, the acute oral LD50 was greater than 800 mg/kg. # Pharmacology ## Mechanism of Action - Sirolimus inhibits T-lymphocyte activation and proliferation that occurs in response to antigenic and cytokine (Interleukin -2, IL-4, and IL-15) stimulation by a mechanism that is distinct from that of other immunosuppressants. Sirolimus also inhibits antibody production. In cells, sirolimus binds to the immunophilin, FK Binding Protein-12 (FKBP-12), to generate an immunosuppressive complex. The sirolimus:FKBP-12 complex has no effect on calcineurin activity. This complex binds to and inhibits the activation of the mammalian Target Of Rapamycin (mTOR), a key regulatory kinase. This inhibition suppresses cytokine-driven T-cell proliferation, inhibiting the progression from the G1 to the S phase of the cell cycle. - Studies in experimental models show that sirolimus prolongs allograft (kidney, heart, skin, islet, small bowel, pancreatico-duodenal, and bone marrow) survival in mice, rats, pigs, and/or primates. Sirolimus reverses acute rejection of heart and kidney allografts in rats and prolongs the graft survival in presensitized rats. In some studies, the immunosuppressive effect of sirolimus lasts up to 6 months after discontinuation of therapy. This tolerization effect is alloantigen-specific. - In rodent models of autoimmune disease, sirolimus suppresses immune-mediated events associated with systemic lupus erythematosus, collagen-induced arthritis, autoimmune type I diabetes, autoimmune myocarditis, experimental allergic encephalomyelitis, graft-versus-host disease, and autoimmune uveoretinitis. ## Structure - Sirolimus is an immunosuppressive agent. Sirolimus is a macrocyclic lactone produced by Streptomyces hygroscopicus. The chemical name of sirolimus (also known as rapamycin) is (3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-9,10,12,13,14,21,22,23,24,25,26,27,32,33,34, 34a-hexadecahydro-9,27-dihydroxy-3--1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23,27-epoxy-3H-pyrido oxaazacyclohentriacontine-1,5,11,28,29 (4H,6H,31H)-pentone. Its molecular formula is C51H79NO13 and its molecular weight is 914.2. The structural formula of sirolimus is illustrated as follows. - Sirolimus is a white to off-white powder and is insoluble in water, but freely soluble in benzyl alcohol, chloroform, acetone, and acetonitrile. - Sirolimus is available for administration as an oral solution containing 1 mg/mL sirolimus. Sirolimus is also available as a white, triangular-shaped tablet containing 1 mg sirolimus, and as a yellow-to-beige triangular-shaped tablet containing 2 mg sirolimus. - The inactive ingredients in sirolimus Oral Solution are Phosal 50 PG® (phosphatidylcholine, propylene glycol, mono- and di-glycerides, ethanol, soy fatty acids, and ascorbyl palmitate) and polysorbate 80. Sirolimus Oral Solution contains 1.5% - 2.5% ethanol. - The inactive ingredients in sirolimus Tablets include sucrose, lactose, polyethylene glycol 8000, calcium sulfate, microcrystalline cellulose, pharmaceutical glaze, talc, titanium dioxide, magnesium stearate, povidone, poloxamer 188, polyethylene glycol 20,000, glyceryl monooleate, carnauba wax, dl-alpha tocopherol, and other ingredients. The 2 mg dosage strength also contains iron oxide yellow 10 and iron oxide brown 70. ## Pharmacodynamics - Orally-administered sirolimus, at doses of 2 mg/day and 5 mg/day, significantly reduced the incidence of organ rejection in low- to moderate-immunologic risk renal transplant patients at 6 months following transplantation compared with either azathioprine or placebo. There was no demonstrable efficacy advantage of a daily maintenance dose of 5 mg with a loading dose of 15 mg over a daily maintenance dose of 2 mg with a loading dose of 6 mg. Therapeutic drug monitoring should be used to maintain sirolimus drug levels within the target-range. ## Pharmacokinetics - Sirolimus pharmacokinetics activity have been determined following oral administration in healthy subjects, pediatric patients, hepatically impaired patients, and renal transplant patients. - The pharmacokinetic parameters of sirolimus in low- to moderate-immunologic risk adult renal transplant patients following multiple dosing with sirolimus 2 mg daily, in combination with cyclosporine and corticosteroids, is summarized in the following TABLE. - Whole blood trough sirolimus concentrations, as measured by LC/MS/MS in renal transplant patients, were significantly correlated with AUCτ,ss. Upon repeated, twice-daily administration without an initial loading dose in a multiple-dose study, the average trough concentration of sirolimus increases approximately 2- to 3-fold over the initial 6 days of therapy, at which time steady-state is reached. A loading dose of 3 times the maintenance dose will provide near steady-state concentrations within 1 day in most patients. - Following administration of sirolimus Oral Solution, the mean times to peak concentration (tmax) of sirolimus are approximately 1 hour and 2 hours in healthy subjects and renal transplant patients, respectively. The systemic availability of sirolimus is low, and was estimated to be approximately 14% after the administration of sirolimus Oral Solution. In healthy subjects, the mean bioavailability of sirolimus after administration of the tablet is approximately 27% higher relative to the solution. - Sirolimus tablets are not bioequivalent to the solution; however, clinical equivalence has been demonstrated at the 2 mg dose level. Sirolimus concentrations, following the administration of sirolimus Oral Solution to stable renal transplant patients, are dose-proportional between 3 and 12 mg/m2. - To minimize variability in sirolimus concentrations, both sirolimus Oral Solution and Tablets should be taken consistently with or without food. In healthy subjects, a high-fat meal (861.8 kcal, 54.9% kcal from fat) increased the mean total exposure (AUC) of sirolimus by 23 to 35%, compared with fasting. The effect of food on the mean sirolimus Cmax was inconsistent depending on the sirolimus dosage form evaluated. - The mean (± SD) blood-to-plasma ratio of sirolimus was 36 ± 18 in stable renal allograft patients, indicating that sirolimus is extensively partitioned into formed blood elements. The mean volume of distribution (Vss/F) of sirolimus is 12 ± 8 L/kg. Sirolimus is extensively bound (approximately 92%) to human plasma proteins, mainly serum albumin (97%), α1-acid glycoprotein, and lipoproteins. - Sirolimus is a substrate for both CYP3A4 and P-gp. Sirolimus is extensively metabolized in the intestinal wall and liver and undergoes counter-transport from enterocytes of the small intestine into the gut lumen. Inhibitors of CYP3A4 and P-gp increase sirolimus concentrations. Inducers of CYP3A4 and P-gp decrease sirolimus concentrations. - Sirolimus is extensively metabolized by O‑demethylation and/or hydroxylation. Seven (7) major metabolites, including hydroxy, demethyl, and hydroxydemethyl, are identifiable in whole blood. Some of these metabolites are also detectable in plasma, fecal, and urine samples. Sirolimus is the major component in human whole blood and contributes to more than 90% of the immunosuppressive activity. - After a single dose of sirolimus oral solution in healthy volunteers, the majority (91%) of radioactivity was recovered from the feces, and only a minor amount (2.2%) was excreted in urine. The mean ± SD terminal elimination half life (t½) of sirolimus after multiple dosing in stable renal transplant patients was estimated to be about 62 ± 16 hours. - Sirolimus Concentrations (Chromatographic Equivalent) Observed in Phase 3 Clinical Studies - The FOLLOWING sirolimus concentrations (chromatographic equivalent) were observed in phase 3 clinical studies. - The withdrawal of cyclosporine and concurrent increases in sirolimus trough concentrations to steady-state required approximately 6 weeks. Following cyclosporine withdrawal, larger sirolimus doses were required due to the absence of the inhibition of sirolimus metabolism and transport by cyclosporine and to achieve higher target sirolimus trough concentrations during concentration-controlled administration. ### Pharmacokinetics in Specific Populations - Sirolimus was administered as a single, oral dose to subjects with normal hepatic function and to patients with Child-Pugh classification A (mild), B (moderate), or C (severe) hepatic impairment. Compared with the values in the normal hepatic function group, the patients with mild, moderate, and severe hepatic impairment had 43%, 94%, and 189% higher mean values for sirolimus AUC, respectively, with no statistically significant differences in mean Cmax. As the severity of hepatic impairment increased, there were steady increases in mean sirolimus t1/2, and decreases in the mean sirolimus clearance normalized for body weight (CL/F/kg). - The maintenance dose of sirolimus should be reduced by approximately one third in patients with mild‑to‑moderate hepatic impairment and by approximately one half in patients with severe hepatic impairment. - It is not necessary to modify the sirolimus loading dose in patients with mild, moderate, and severe hepatic impairment. Therapeutic drug monitoring is necessary in all patients with hepatic impairment. - The effect of renal impairment on the pharmacokinetics of sirolimus is not known. However, there is minimal (2.2%) renal excretion of the drug or its metabolites in healthy volunteers. The loading and the maintenance doses of sirolimus need not be adjusted in patients with renal impairment. - Sirolimus pharmacokinetic data were collected in concentration-controlled trials of pediatric renal transplant patients who were also receiving cyclosporine and corticosteroids. The target ranges for trough concentrations were either 10-20 ng/mL for the 21 children receiving tablets, or 5-15 ng/mL for the one child receiving oral solution. The children aged 6-11 years (n = 8) received mean ± SD doses of 1.75 ± 0.71 mg/day (0.064 ± 0.018 mg/kg, 1.65 ± 0.43 mg/m2). The children aged 12-18 years (n = 14) received mean ± SD doses of 2.79 ± 1.25 mg/day (0.053 ± 0.0150 mg/kg, 1.86± 0.61 mg/m2). At the time of sirolimus blood sampling for pharmacokinetic evaluation, the majority (80%) of these pediatric patients received the sirolimus dose at 16 hours after the once-daily cyclosporine dose. - Clinical studies of sirolimus did not include a sufficient number of patients > 65 years of age to determine whether they will respond differently than younger patients. After the administration of sirolimus Oral Solution or Tablets, sirolimus trough concentration data in renal transplant patients > 65 years of age were similar to those in the adult population 18 to 65 years of age. - Sirolimus clearance in males was 12% lower than that in females; male subjects had a significantly longer t1/2 than did female subjects (72.3 hours versus 61.3 hours). Dose adjustments based on gender are not recommended. - In the phase 3 trials using sirolimus solution or tablets and cyclosporine oral solution (e.g., Neoral® Oral Solution) and/or cyclosporine capsules (e.g., Neoral® Soft Gelatin Capsules) , there were no significant differences in mean trough sirolimus concentrations over time between Black (n = 190) and non-Black (n = 852) patients during the first 6 months after transplantation. - Sirolimus is known to be a substrate for both cytochrome CYP3A4 and P-gp. The pharmacokinetic interaction between sirolimus and concomitantly administered drugs is discussed below. Drug interaction studies have not been conducted with drugs other than those described below. - Cyclosporine is a substrate and inhibitor of CYP3A4 and P-gp. Sirolimus should be taken 4 hours after administration of cyclosporine oral solution (MODIFIED) and/or cyclosporine capsules (MODIFIED). Sirolimus concentrations may decrease when cyclosporine is discontinued, unless the sirolimus dose is increased. - In a single-dose drug-drug interaction study, 24 healthy volunteers were administered 10 mg sirolimus Tablets either simultaneously or 4 hours after a 300-mg dose of Neoral® Soft Gelatin Capsules (cyclosporine capsules ). For simultaneous administration, mean Cmax and AUC were increased by 512% and 148%, respectively, relative to administration of sirolimus alone. However, when given 4 hours after cyclosporine administration, sirolimus Cmax and AUC were both increased by only 33% compared with administration of sirolimus alone. - In a single dose drug-drug interaction study, 24 healthy volunteers were administered 10 mg sirolimus Oral Solution either simultaneously or 4 hours after a 300 mg dose of Neoral® Soft Gelatin Capsules (cyclosporine capsules ). For simultaneous administration, the mean Cmax and AUC of sirolimus, following simultaneous administration were increased by 116% and 230%, respectively, relative to administration of sirolimus alone. However, when given 4 hours after Neoral® Soft Gelatin Capsules (cyclosporine capsules ) administration, sirolimus Cmax and AUC were increased by only 37% and 80%, respectively, compared with administration of sirolimus alone. - In a single-dose cross-over drug-drug interaction study, 33 healthy volunteers received 5 mg sirolimus Oral Solution alone, 2 hours before, and 2 hours after a 300 mg dose of Neoral® Soft Gelatin Capsules (cyclosporine capsules ). When given 2 hours before Neoral® Soft Gelatin Capsules (cyclosporine capsules ) administration, sirolimus Cmax and AUC were comparable to those with administration of sirolimus alone. However, when given 2 hours after, the mean Cmax and AUC of sirolimus were increased by 126% and 141%, respectively, relative to administration of sirolimus alone. - Mean cyclosporine Cmax and AUC were not significantly affected when sirolimus Oral Solution was given simultaneously or when administered 4 hours after Neoral® Soft Gelatin Capsules (cyclosporine capsules ). However, after multiple-dose administration of sirolimus given 4 hours after Neoral® in renal post-transplant patients over 6 months, cyclosporine oral-dose clearance was reduced, and lower doses of Neoral® Soft Gelatin Capsules (cyclosporine capsules ) were needed to maintain target cyclosporine concentration. - In a multiple-dose study in 150 psoriasis patients, sirolimus 0.5, 1.5, and 3 mg/m2/day was administered simultaneously with Sandimmune® Oral Solution (cyclosporine Oral Solution) 1.25 mg/kg/day. The increase in average sirolimus trough concentrations ranged between 67% to 86% relative to when sirolimus was administered without cyclosporine. The intersubject variability (% CV) for sirolimus trough concentrations ranged from 39.7% to 68.7%. There was no significant effect of multiple-dose sirolimus on cyclosporine trough concentrations following Sandimmune® Oral Solution (cyclosporine oral solution) administration. However, the % CV was higher (range 85.9% - 165%) than those from previous studies. - Diltiazem is a substrate and inhibitor of CYP3A4 and P-gp; sirolimus concentrations should be monitored and a dose adjustment may be necessary. The simultaneous oral administration of 10 mg of sirolimus oral solution and 120 mg of diltiazem to 18 healthy volunteers significantly affected the bioavailability of sirolimus. Sirolimus Cmax, tmax, and AUC were increased 1.4-, 1.3-, and 1.6-fold, respectively. Sirolimus did not affect the pharmacokinetics of either diltiazem or its metabolites desacetyldiltiazem and desmethyldiltiazem. - Erythromycin is a substrate and inhibitor of CYP3A4 and P-gp; co-administration of sirolimus oral solution or tablets and erythromycin is not recommended. The simultaneous oral administration of 2 mg daily of sirolimus oral solution and 800 mg q 8h of erythromycin as erythromycin ethylsuccinate tablets at steady state to 24 healthy volunteers significantly affected the bioavailability of sirolimus and erythromycin. Sirolimus Cmax and AUC were increased 4.4- and 4.2-fold respectively and tmax was increased by 0.4 hr. Erythromycin Cmax and AUC were increased 1.6- and 1.7-fold, respectively, and tmax was increased by 0.3 hr. - Ketoconazole is a strong inhibitor of CYP3A4 and P-gp; co-administration of sirolimus oral solution or tablets and ketoconazole is not recommended. Multiple-dose ketoconazole administration significantly affected the rate and extent of absorption and sirolimus exposure after administration of sirolimus Oral Solution, as reflected by increases in sirolimus Cmax, tmax, and AUC of 4.3-fold, 38%, and 10.9-fold, respectively. However, the terminal t½ of sirolimus was not changed. Single-dose sirolimus did not affect steady-state 12-hour plasma ketoconazole concentrations. - Rifampin is a strong inducer of CYP3A4 and P-gp; co-administration of sirolimus oral solution or tablets and rifampin is not recommended. In patients where rifampin is indicated, alternative therapeutic agents with less enzyme induction potential should be considered. Pretreatment of 14 healthy volunteers with multiple doses of rifampin, 600 mg daily for 14 days, followed by a single 20-mg dose of sirolimus oral solution, greatly decreased sirolimus AUC and Cmax by about 82% and 71%, respectively. - Verapamil is a substrate and inhibitor of CYP3A4 and P-gp; sirolimus concentrations should be monitored and a dose adjustment may be necessary. The simultaneous oral administration of 2 mg daily of sirolimus oral solution and 180 mg q 12h of verapamil at steady state to 26 healthy volunteers significantly affected the bioavailability of sirolimus and verapamil. Sirolimus Cmax and AUC were increased 2.3- and 2.2-fold, respectively, without substantial change in tmax. The Cmax and AUC of the pharmacologically active S(-) enantiomer of verapamil were both increased 1.5-fold and tmax was decreased by 1.2 hr. - Drugs Which May Be Co-administered Without Dose Adjustment Clinically significant pharmacokinetic drug-drug interactions were not observed in studies of drugs listed below. Sirolimus and these drugs may be co-administered without dose adjustments. - Acyclovir - Atorvastatin - Digoxin - Glyburide - Nifedipine - Norgestrel/ethinyl estradiol (Lo/Ovral®) - Prednisolone - Sulfamethoxazole/trimethoprim (Bactrim®) - Co-administration of sirolimus with other known strong inhibitors of CYP3A4 and/or P-gp (such as voriconazole, itraconazole, telithromycin, or clarithromycin) or other known strong inducers of CYP3A4 and/or P-gp (such as rifabutin) is not recommended. In patients in whom strong inhibitors or inducers of CYP3A4 are indicated, alternative therapeutic agents with less potential for inhibition or induction of CYP3A4 should be considered. - Care should be exercised when drugs or other substances that are substrates and/or inhibitors or inducers of CYP3A4 are administered concomitantly with sirolimus. Other drugs that have the potential to increase sirolimus blood concentrations include (but are not limited to): - Calcium channel blockers - Nicardipine. - Antifungal agent - Clotrimazole, fluconazole. - Antibiotics - Troleandomycin. - Gastrointestinal prokinetic agents - Cisapride, metoclopramide. - Other drugs - Bromocriptine, cimetidine, danazol, HIV-protease inhibitors (e.g., ritonavir, indinavir). - Other drugs that have the potential to decrease sirolimus concentrations include (but are not limited to): - Anticonvulsants - Carbamazepine, phenobarbital, phenytoin - Antibiotics - Rifapentine. - Grapefruit juice reduces CYP3A4-mediated drug metabolism. Grapefruit juice must not be taken with or used for dilution of sirolimus. - St. John's Wort (hypericum perforatum) induces CYP3A4 and P-gp. Since sirolimus is a substrate for both cytochrome CYP3A4 and P-gp, there is the potential that the use of St. John's Wort in patients receiving sirolimus could result in reduced sirolimus concentrations. ## Nonclinical Toxicology - Carcinogenicity studies were conducted in mice and rats. In an 86-week female mouse study at sirolimus doses 30 to 120 times higher than the 2 mg daily clinical dose (adjusted for body surface area), there was a statistically significant increase in malignant lymphoma at all dose levels compared with controls. - In a second mouse study at dosages that were approximately 3 to 16 times the clinical dose (adjusted for body surface area), hepatocellular adenoma and carcinoma in males were considered sirolimus-related. In the 104-week rat study at dosages equal to or lower than the clinical dose of 2 mg daily (adjusted for body surface area), there were no significant findings. - Sirolimus was not genotoxic in the in vitro bacterial reverse mutation assay, the Chinese hamster ovary cell chromosomal aberration assay, the mouse lymphoma cell forward mutation assay, or the in vivo mouse micronucleus assay. - Fertility was diminished slightly in both male and female rats following oral administration of sirolimus at doses approximately 10 times or 2 times, respectively, the clinical dose of 2 mg daily (adjusted for body surface area). In male rats, atrophy of testes, epididymides, prostate, seminiferous tubules and/or reduction in sperm counts were observed. In female rats, reduced size of ovaries and uteri was observed. Reduction of sperm count in male rats was reversible upon cessation of dosing in one study. Testicular tubular degeneration was also seen in a 4‑week intravenous study of sirolimus in monkeys at doses that were approximately equal to the clinical dose (adjusted for body surface area). # Clinical Studies ### Prophylaxis of Organ Rejection - The safety and efficacy of sirolimus Oral Solution for the prevention of organ rejection following renal transplantation were assessed in two randomized, double-blind, multicenter, controlled trials. These studies compared two dose levels of sirolimus Oral Solution (2 mg and 5 mg, once daily) with azathioprine (Study 1) or placebo (Study 2) when administered in combination with cyclosporine and corticosteroids. Study 1 was conducted in the United States at 38 sites. Seven hundred nineteen (719) patients were enrolled in this trial and randomized following transplantation; 284 were randomized to receive sirolimus Oral Solution 2 mg/day; 274 were randomized to receive sirolimus Oral Solution 5 mg/day, and 161 to receive azathioprine 2-3 mg/kg/day. Study 2 was conducted in Australia, Canada, Europe, and the United States, at a total of 34 sites. Five hundred seventy-six (576) patients were enrolled in this trial and randomized before transplantation; 227 were randomized to receive sirolimus Oral Solution 2 mg/day; 219 were randomized to receive sirolimus Oral Solution 5 mg/day, and 130 to receive placebo. In both studies, the use of antilymphocyte antibody induction therapy was prohibited. In both studies, the primary efficacy endpoint was the rate of efficacy failure in the first 6 months after transplantation. Efficacy failure was defined as the first occurrence of an acute rejection episode (confirmed by biopsy), graft loss, or death. - The TABLES below summarize the results of the primary efficacy analyses from these trials. Sirolimus Oral Solution, at doses of 2 mg/day and 5 mg/day, significantly reduced the incidence of efficacy failure (statistically significant at the< 0.025 level; nominal significance level adjusted for multiple dose comparisons) at 6 months following transplantation compared with both azathioprine and placebo. - The reduction in the incidence of first biopsy-confirmed acute rejection episodes in patients treated with sirolimus compared with the control groups included a reduction in all grades of rejection. - In Study 1, which was prospectively stratified by race within center, efficacy failure was similar for sirolimus Oral Solution 2 mg/day and lower for sirolimus Oral Solution 5 mg/day compared with azathioprine in Black patients. In Study 2, which was not prospectively stratified by race, efficacy failure was similar for both sirolimus Oral Solution doses compared with placebo in Black patients. The decision to use the higher dose of sirolimus Oral Solution in Black patients must be weighed against the increased risk of dose-dependent adverse events that were observed with the sirolimus Oral Solution 5-mg dose. - Mean glomerular filtration rates (GFR) post-transplant were calculated by using the Nankivell equation at 12 and 24 months for Study 1, and 12 and 36 months for Study 2. Mean GFR was lower in patients treated with cyclosporine and sirolimus Oral Solution compared with those treated with cyclosporine and the respective azathioprine or placebo control. - Within each treatment group in Studies 1 and 2, mean GFR at one-year post-transplant was lower in patients who experienced at least one episode of biopsy-proven acute rejection, compared with those who did not. - Renal function should be monitored, and appropriate adjustment of the immunosuppressive regimen should be considered in patients with elevated or increasing serum creatinine levels. - The safety and efficacy of sirolimus Oral Solution and sirolimus tablets for the prevention of organ rejection following renal transplantation were demonstrated to be clinically equivalent in a randomized, multicenter, controlled trial. - The safety and efficacy of sirolimus as a maintenance regimen were assessed following cyclosporine withdrawal at 3 to 4 months after renal transplantation. Study 3 was a randomized, multicenter, controlled trial conducted at 57 centers in Australia, Canada, and Europe. Five hundred twenty-five (525) patients were enrolled. All patients in this study received the tablet formulation. - This study compared patients who were administered sirolimus, cyclosporine, and corticosteroids continuously with patients who received this same standardized therapy for the first 3 months after transplantation (pre-randomization period) followed by the withdrawal of cyclosporine. During cyclosporine withdrawal, the sirolimus dosages were adjusted to achieve targeted sirolimus whole blood trough concentration ranges (16 to 24 ng/mL until month 12, then 12 to 20 ng/mL thereafter, expressed as chromatographic assay values). At 3 months, 430 patients were equally randomized to either continue sirolimus with cyclosporine therapy or to receive sirolimus as a maintenance regimen following cyclosporine withdrawal. - Eligibility for randomization included no Banff Grade 3 acute rejection or vascular rejection episode in the 4 weeks before random assignment, serum creatinine ≤ 4.5 mg/dL, and adequate renal function to support cyclosporine withdrawal (in the opinion of the investigator). The primary efficacy endpoint was graft survival at 12 months after transplantation. Secondary efficacy endpoints were the rate of biopsy-confirmed acute rejection, patient survival, incidence of efficacy failure (defined as the first occurrence of either biopsy-proven acute rejection, graft loss, or death), and treatment failure (defined as the first occurrence of either discontinuation, acute rejection, graft loss, or death). - The following TABLE summarizes the resulting graft and patient survival at 12, 24, and 36 months for this trial. At 12, 24, and 36 months, graft and patient survival were similar for both groups. - The mean GFR at 12, 24, and 36 months, calculated by the Nankivell equation, was significantly higher for patients receiving sirolimus as a maintenance regimen following cyclosporine withdrawal than for those in the sirolimus with cyclosporine therapy group. Patients who had an acute rejection prior to randomization had a significantly higher GFR following cyclosporine withdrawal compared to those in the sirolimus with cyclosporine group. There was no significant difference in GFR between groups for patients who experienced acute rejection post-randomization. - Although the initial protocol was designed for 36 months, there was a subsequent amendment to extend this study. The results for the cyclosporine withdrawal group at months 48 and 60 were consistent with the results at month 36. Fifty-two percent (112/215) of the patients in the sirolimus with cyclosporine withdrawal group remained on therapy to month 60 and showed sustained GFR. - Sirolimus was studied in a one-year, clinical trial in high risk patients (Study 4) who were defined as Black transplant recipients and/or repeat renal transplant recipients who lost a previous allograft for immunologic reasons and/or patients with high panel-reactive antibodies (PRA; peak PRA level > 80%). Patients received concentration-controlled sirolimus and cyclosporine (MODIFIED), and corticosteroids per local practice. The sirolimus dose was adjusted to achieve target whole blood trough sirolimus concentrationsof 10-15 ng/mL (chromatographic method) throughout the 12-month study period. The cyclosporine dose was adjusted to achieve target whole blood trough concentrations of 200-300 ng/mL through week 2, 150-200 ng/mL from week 2 to week 26, and 100-150 ng/mL from week 26 to week 52 for the observed trough concentrations ranges. Antibody induction was allowed per protocol as prospectively defined at each transplant center, and was used in 88.4% of patients. The study was conducted at 35 centers in the United States. - A total of 224 patients received a transplant and at least one dose of sirolimus and cyclosporine and was comprised of 77.2% Black patients, 24.1% repeat renal transplant recipients, and 13.5% patients with high PRA. Efficacy was assessed with the following endpoints, measured at 12 months: efficacy failure (defined as the first occurrence of biopsy-confirmed acute rejection, graft loss, or death), first occurrence of graft loss or death, and renal function as measured by the calculated GFR using the Nankivell formula. The TABLE below summarizes the result of these endpoints. - Patient survival at 12 months was 94.6%. The incidence of biopsy-confirmed acute rejection was 17.4% and the majority of the episodes of acute rejection were mild in severity. - Conversion from calcineurin inhibitors (CNI) to sirolimus was assessed in maintenance renal transplant patients 6 months to 10 years post‑transplant (Study 5). This study was a randomized, multicenter, controlled trial conducted at 111 centers globally, including US and Europe, and was intended to show that renal function was improved by conversion from CNI to sirolimus. Eight hundred thirty (830) patients were enrolled and stratified by baseline calculated glomerular filtration rate (GFR, 20-40 mL/min vs. greater than 40 mL/min). In this trial there was no benefit associated with conversion with regard to improvement in renal function and a greater incidence of proteinuria in the sirolimus conversion arm. In addition, enrollment of patients with baseline calculated GFR less than 40 mL/min was discontinued due to a higher rate of serious adverse events, including pneumonia, acute rejection, graft loss and death. - This study compared renal transplant patients (6-120 months after transplantation) who were converted from calcineurin inhibitors to sirolimus, with patients who continued to receive calcineurin inhibitors. Concomitant immunosuppressive medications included mycophenolate mofetil (MMF), azathioprine (AZA), and corticosteroids. sirolimus was initiated with a single loading dose of 12-20 mg, after which dosing was adjusted to achieve a target sirolimus whole blood trough concentration of 8-20 ng/mL (chromatographic method). The efficacy endpoint was calculated GFR at 12 months post-randomization. Additional endpoints included biopsy-confirmed acute rejection, graft loss, and death. Findings in the patient stratum with baseline calculated GFR greater than 40 mL/min (sirolimus conversion, n = 497; CNI continuation, n = 246) are summarized BELOW: There was no clinically or statistically significant improvement in Nankivell GFR compared to baseline. - The rates of acute rejection, graft loss, and death were similar at 1 and 2 years. Treatment-emergent adverse events occurred more frequently during the first 6 months after sirolimus conversion. The rates of pneumonia were significantly higher for the sirolimus conversion group. - While the mean and median values for urinary protein to creatinine ratio were similar between treatment groups at baseline, significantly higher mean and median levels of urinary protein excretion were seen in the sirolimus conversion arm at 1 year and at 2 years, as shown in the TABLE below. - In addition, when compared to patients who continued to receive calcineurin inhibitors, a higher percentage of patients had urinary protein to creatinine ratios > 1 at 1 and 2 years after sirolimus conversion. This difference was seen in both patients who had a urinary protein to creatinine ratio ≤ 1 and those who had a protein to creatinine ratio > 1 at baseline. More patients in the sirolimus conversion group developed nephrotic range proteinuria, as defined by a urinary protein to creatinine ratio > 3.5 (46/482 vs. 9/239 ), even when the patients with baseline nephrotic range proteinuria were excluded. The rate of nephrotic range proteinuria was significantly higher in the sirolimus conversion group compared to the calcineurin inhibitor continuation group with baseline urinary protein to creatinine ratio > 1 (13/29 vs. 1/14), excluding patients with baseline nephrotic range proteinuria. - The above information should be taken into account when considering conversion from calcineurin inhibitors to sirolimus in stable renal transplant patients due to the lack of evidence showing that renal function improves following conversion, and the finding of a greater increment in urinary protein excretion, and an increased incidence of treatment-emergent nephrotic range proteinuria following conversion to sirolimus. - This was particularly true among patients with existing abnormal urinary protein excretion prior to conversion. - Sirolimus was evaluated in a 36-month, open-label, randomized, controlled clinical trial at 14 North American centers in pediatric (aged 3 to < 18 years) renal transplant patients considered to be at high-immunologic risk for developing chronic allograft nephropathy, defined as a history of one or more acute allograft rejection episodes and/or the presence of chronic allograft nephropathy on a renal biopsy. Seventy-eight (78) subjects were randomized in a 2:1 ratio to sirolimus (sirolimus target concentrations of 5 to 15 ng/mL, by chromatographic assay, n = 53) in combination with a calcineurin inhibitor and corticosteroids or to continue calcineurin-inhibitor-based immunosuppressive therapy (n = 25). The primary endpoint of the study was efficacy failure as defined by the first occurrence of biopsy-confirmed acute rejection, graft loss, or death, and the trial was designed to show superiority of sirolimus added to a calcineurin-inhibitor-based immunosuppressive regimen compared to a calcineurin-inhibitor-based regimen. - The cumulative incidence of efficacy failure up to 36 months was 45.3% in the sirolimus group compared to 44.0% in the control group, and did not demonstrate superiority. There was one death in each group. The use of sirolimus in combination with calcineurin inhibitors and corticosteroids was associated with an increased risk of deterioration of renal function, serum lipid abnormalities (including, but not limited to, increased serum triglycerides and cholesterol), and urinary tract infections . This study does not support the addition of sirolimus to calcineurin-inhibitor-based immunosuppressive therapy in this subpopulation of pediatric renal transplant patients. # How Supplied - Since sirolimus is not absorbed through the skin, there are no special precautions. However, if direct contact with the skin or mucous membranes occurs, wash thoroughly with soap and water; rinse eyes with plain water. - Each sirolimus Oral Solution carton, NDC 0008-1030-06, contains one 2 oz (60 mL fill) amber glass bottle of sirolimus (concentration of 1 mg/mL), one oral syringe adapter for fitting into the neck of the bottle, sufficient disposable amber oral syringes and caps for daily dosing, and a carrying case. - Sirolimus Oral Solution bottles should be stored protected from light and refrigerated at 2°C to 8°C (36°F to 46°F). Once the bottle is opened, the contents should be used within one month. If necessary, the patient may store the bottles at room temperatures up to 25°C (77°F) for a short period of time (e.g., not more than 15 days for the bottles). - An amber syringe and cap are provided for dosing, and the product may be kept in the syringe for a maximum of 24 hours at room temperatures up to 25°C (77°F) or refrigerated at 2°C to 8°C (36°F to 46°F). The syringe should be discarded after one use. After dilution, the preparation should be used immediately. - Sirolimus Oral Solution provided in bottles may develop a slight haze when refrigerated. If such a haze occurs, allow the product to stand at room temperature and shake gently until the haze disappears. The presence of this haze does not affect the quality of the product. - Sirolimus Tablets are available as follows: - NDC 0008-1041-05, 1 mg, white, triangular-shaped tablets marked"Rapamune 1 mg” on one side; bottle containing 100 tablets. - NDC 0008-1041-10, 1 mg, white, triangular-shaped tablets marked“RAPAMUNE 1 mg” on one side; in Redipak® cartons of 100 tablets (10 blister cards of 10 tablets each). - NDC 0008-1042-05, 2 mg, yellow-to-beige triangular-shaped tablets marked “ Rapamune 2 mg” on one side; bottle containing 100 tablets. ## Storage - Rapamune Tablets should be stored at 20° to 25°C (68° to 77°F). Use cartons to protect blister cards and strips from light. Dispense in a tight, light-resistant container as defined in the USP. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Patients should be given complete dosage instructions. - Patients should be told that exposure to sunlight and ultraviolet (UV) light should be limited by wearing protective clothing and using a sunscreen with a high protection factor because of the increased risk for skin cancer. - Women of childbearing potential should be informed of the potential risks during pregnancy and told that they should use effective contraception prior to initiation of sirolimus therapy, during sirolimus therapy, and for 12 weeks after sirolimus therapy has been stopped. # Precautions with Alcohol - Alcohol-Sirolimus interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Rapamune ® # Look-Alike Drug Names There is limited information regarding Sirolimus Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Sirolimus 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. # Black Box Warning # Overview Sirolimus is an immunomodulatory drug that is FDA approved for the prophylaxis of organ rejection in renal transplantation. There is a Black Box Warning for this drug as shown here. Common adverse reactions include lymphedema, pericardial effusion, hepatotoxicity, hypersensitivity, tuberculosis, interstitial lung disease, exfoliative dermatitis, nephrotic syndrome. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Sirolimus is indicated for the prophylaxis of organ rejection in patients aged 13 years or older receiving renal transplants. Therapeutic drug monitoring is recommended for all patients receiving sirolimus. - In patients at low- to moderate-immunologic risk, it is recommended that sirolimus be used initially in a regimen with cyclosporine and corticosteroids; cyclosporine should be withdrawn 2 to 4 months after transplantation. - In patients at high-immunologic risk (defined as Black recipients and/or repeat renal transplant recipients who lost a previous allograft for immunologic reason and/or patients with high panel-reactive antibodies [PRA; peak PRA level > 80%]), it is recommended that sirolimus be used in combination with cyclosporine and corticosteroids for the first year following transplantation. - Cyclosporine withdrawal has not been studied in patients with Banff Grade 3 acute rejection or vascular rejection prior to cyclosporine withdrawal, those who are dialysis-dependent, those with serum creatinine > 4.5 mg/dL, Black patients, patients of multi-organ transplants, secondary transplants, or those with high levels of panel-reactive antibodies. - In patients at high-immunologic risk, the safety and efficacy of sirolimus used in combination with cyclosporine and corticosteroids has not been studied beyond one year; therefore after the first 12 months following transplantation, any adjustments to the immunosuppressive regimen should be considered on the basis of the clinical status of the patient. - In pediatric patients, the safety and efficacy of sirolimus have not been established in patients < 13 years old, or in pediatric (< 18 years) renal transplant patients considered at high-immunologic risk. - The safety and efficacy of de novo use of sirolimus without cyclosporine have not been established in renal transplant patients. - The safety and efficacy of conversion from calcineurin inhibitors to Rapamune in maintenance renal transplant patients have not been established. - Sirolimus is to be administered orally once daily, consistently with or without food. - Tablets should not be crushed, chewed or split. Patients unable to take the tablets should be prescribed the solution and instructed in its use. - The initial dose of sirolimus should be administered as soon as possible after transplantation. It is recommended that sirolimus be taken 4 hours after administration of cyclosporine oral solution (MODIFIED) and or/cyclosporine capsules (MODIFIED). - Frequent sirolimus dose adjustments based on non-steady-state sirolimus concentrations can lead to overdosing or underdosing because sirolimus has a long half-life. - Once sirolimus maintenance dose is adjusted, patients should continue on the new maintenance dose for at least 7 to 14 days before further dosage adjustment with concentration monitoring. In most patients, dose adjustments can be based on simple proportion: new sirolimus dose = current dose x (target concentration/current concentration). - A loading dose should be considered in addition to a new maintenance dose when it is necessary to increase sirolimus trough concentrations: sirolimus loading dose = 3 x (new maintenance dose - current maintenance dose). - The maximum sirolimus dose administered on any day should not exceed 40 mg. If an estimated daily dose exceeds 40 mg due to the addition of a loading dose, the loading dose should be administered over 2 days. - Sirolimus trough concentrations should be monitored at least 3 to 4 days after a loading dose(s). - Two milligrams (2 mg) of Sirolimus Oral Solution have been demonstrated to be clinically equivalent to 2 mg sirolimus Tablets; hence, are interchangeable on a mg-to-mg basis. - However, it is not known if higher doses of sirolimus Oral Solution are clinically equivalent to higher doses of sirolimus Tablets on a mg‑to‑mg basis. ### Patients at Low- to Moderate-Immunologic Risk - For de novo renal transplant patients, it is recommended that sirolimus Oral Solution and Tablets be used initially in a regimen with cyclosporine and corticosteroids. - A loading dose of sirolimus equivalent to 3 times the maintenance dose should be given, i.e. a daily maintenance dose of 2 mg should be preceded with a loading dose of 6 mg. Therapeutic drug monitoring should be used to maintain sirolimus drug concentrations within the target-range. - At 2 to 4 months following transplantation, cyclosporine should be progressively discontinued over 4 to 8 weeks, and the sirolimus dose should be adjusted to obtain sirolimus whole blood trough concentrations within the target-range. - Because cyclosporine inhibits the metabolism and transport of sirolimus, sirolimus concentrations may decrease when cyclosporine is discontinued, unless the sirolimus dose is increased. - In patients with high-immunologic risk, it is recommended that sirolimus be used in combination with cyclosporine and corticosteroids for the first 12 months following transplantation. - The safety and efficacy of this combination in high-immunologic risk patients has not been studied beyond the first 12 months. Therefore, after the first 12 months following transplantation, any adjustments to the immunosuppressive regimen should be considered on the basis of the clinical status of the patient. - For patients receiving sirolimus with cyclosporine, sirolimus therapy should be initiated with a loading dose of up to 15 mg on day 1 post-transplantation. Beginning on day 2, an initial maintenance dose of 5 mg/day should be given. A trough level should be obtained between days 5 and 7, and the daily dose of sirolimus should thereafter be adjusted. - The starting dose of cyclosporine should be up to 7 mg/kg/day in divided doses and the dose should subsequently be adjusted to achieve target whole blood trough concentrations. Prednisone should be administered at a minimum of 5 mg/day. - Antibody induction therapy may be used. - Monitoring of sirolimus trough concentrations is recommended for all patients, especially in those patients likely to have altered drug metabolism, in patients≥ 13 years who weigh less than 40 kg, in patients with hepatic impairment,when a change in the sirolimus dosage form is made, and during concurrent administration of strong CYP3A4 inducers and inhibitors. - Therapeutic drug monitoring should not be the sole basis for adjusting sirolimus therapy. Careful attention should be made to clinical signs/symptoms, tissue biopsy findings, and laboratory parameters. - When used in combination with cyclosporine, sirolimus trough concentrations should be maintained within the target-range. - Following cyclosporine withdrawal in transplant patients at low- to moderate-immunologic risk, the target sirolimus trough concentrations should be 16 to 24 ng/mL for the first year following transplantation. Thereafter, the target sirolimus concentrations should be 12 to 20 ng/mL. - The above recommended 24-hour trough concentration ranges for sirolimus are based on chromatographic methods. On average, chromatographic methods (HPLC UV or LC/MS/MS) yield results that are approximately 20% lower than the immunoassay for whole blood concentration determinations. - Currently in clinical practice, sirolimus whole blood concentrations are being measured by both chromatographic and immunoassay methodologies. Because the measured sirolimus whole blood concentrations depend on the type of assay used, the concentrations obtained by these different methodologies are not interchangeable. - Adjustments to the targeted range should be made according to the assay utilized to determine sirolimus trough concentrations. A discussion of different assay methods is contained in Clinical Therapeutics, Volume 22, Supplement B, April 2000. - The initial dosage in patients ≥ 13 years who weigh less than 40 kg should be adjusted, based on body surface area, to 1 mg/m2/day. The loading dose should be 3 mg/m2. - It is recommended that the maintenance dose of sirolimus be reduced by approximately one third in patients with mild or moderate hepatic impairment and by approximately one half in patients with severe hepatic impairment. It is not necessary to modify the sirolimus loading dose. - Dosage adjustment is not needed in patients with impaired renal function. - The amber oral dose syringe should be used to withdraw the prescribed amount of sirolimus Oral Solution from the bottle. Empty the correct amount of sirolimus from the syringe into only a glass or plastic container holding at least two (2) ounces (1/4 cup, 60 mL) of water or orange juice. No other liquids, including grapefruit juice, should be used for dilution. Stir vigorously and drink at once. Refill the container with an additional volume [minimum of four (4) ounces (1/2 cup, 120 mL)] of water or orange juice, stir vigorously, and drink at once. - Sirolimus Oral Solution contains polysorbate 80, which is known to increase the rate of di‑(2‑ethylhexyl)phthalate (DEHP) extraction from polyvinyl chloride (PVC). This should be considered during the preparation and administration of sirolimus Oral Solution. It is important that these recommendations be followed closely. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Sirolimus in adult patients. ### Non–Guideline-Supported Use - Renal transplant rejection. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Sirolimus in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Sirolimus in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Sirolimus in pediatric patients. # Contraindications - Sirolimus is contraindicated in patients with a hypersensitivity to sirolimus. # Warnings - Increased susceptibility to infection and the possible development of lymphoma and other malignancies, particularly of the skin, may result from immunosuppression. The rates of lymphoma/lymphoproliferative disease observed in Studies 1 and 2 were 0.7-3.2% (for sirolimus-treated patients) versus 0.6-0.8% (azathioprine and placebo control). - Oversuppression of the immune system can also increasesusceptibility to infection, including opportunistic infections such as tuberculosis, fatal infections, and sepsis. Only physicians experienced in immunosuppressive therapy and management of organ transplant patients should use sirolimus. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient. - The use of sirolimus in combination with tacrolimus was associated with excess mortality and graft loss in a study in de novo liver transplant patients (22% in combination versus 9% on tacrolimus alone). Many of these patients had evidence of infection at or near the time of death. - In this and another study in de novo liver transplant patients, the use of sirolimus in combination with cyclosporine or tacrolimus was associated with an increase in HAT (7% in combination versus 2% in the control arm); most cases of HAT occurred within 30 days post-transplantation, and most led to graft loss or death. - The safety and efficacy of sirolimus as immunosuppressive therapy have not been established in liver transplant patients; therefore, such use is not recommended. - Cases of bronchial anastomotic dehiscence, most fatal, have been reported in de novo lung transplant patients when sirolimus has been used as part of an immunosuppressive regimen. - The safety and efficacy of sirolimus as immunosuppressive therapy have not been established in lung transplant patients; therefore, such use is not recommended. - Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, angioedema, exfoliative dermatitis and hypersensitivity vasculitis, have been associated with the administration of sirolimus. - Sirolimus has been associated with the development of angioedema. The concomitant use of sirolimus with other drugs known to cause angioedema, such as ACE-inhibitors, may increase the risk of developing angioedema. - There have been reports of impaired or delayed wound healing in patients receiving sirolimus, including lymphocele and wound dehiscence. - mTOR inhibitors such as sirolimus have been shown in vitro to inhibit production of certain growth factors that may affect angiogenesis, fibroblast proliferation, and vascular permeability. Lymphocele, a known surgical complication of renal transplantation, occurred significantly more often in a dose-related fashion in patients treated with sirolimus. - Appropriate measures should be considered to minimize such complications. Patients with a body mass index (BMI) greater than 30 kg/m2 may be at increased risk of abnormal wound healing based on data from the medical literature. - There have also been reports of fluid accumulation, including peripheral edema, lymphedema, pleural effusion and pericardial effusions (including hemodynamically significant effusions and tamponade requiring intervention in children and adults), in patients receiving sirolimus. - Increased serum cholesterol and triglycerides requiring treatment occurred more frequently in patients treated with sirolimus compared with azathioprine or placebo controls in Studies 1 and 2. - There were increased incidences of hypercholesterolemia (43-46%) and/or hypertriglyceridemia (45-57%) in patients receiving sirolimus compared with placebo controls (each 23%). The risk/benefit should be carefully considered in patients with established hyperlipidemia before initiating an immunosuppressive regimen including sirolimus. - Any patient who is administered sirolimus should be monitored for hyperlipidemia. If detected, interventions such as diet, exercise, and lipid-lowering agents should be initiated as outlined by the National Cholesterol Education Program guidelines. - In clinical trials, the concomitant administration of sirolimus and HMG-CoA reductase inhibitors and/or fibrates appeared to be well-tolerated. - During sirolimus therapy with cyclosporine, patients administered an HMG-CoA reductase inhibitor and/or fibrate should be monitored for the possible development of rhabdomyolysis and other adverse effects, as described in the respective labeling for these agents. - Renal function should be closely monitored during the co-administration of sirolimus with cyclosporine, because long-term administration of the combination has been associated with deterioration of renal function. Patients treated with cyclosporine and sirolimus were noted to have higher serum creatinine levels and lower glomerular filtration rates compared with patients treated with cyclosporine and placebo or azathioprine controls (Studies 1 and 2). The rate of decline in renal function in these studies was greater in patients receiving sirolimus and cyclosporine compared with control therapies. - Appropriate adjustment of the immunosuppressive regimen, including discontinuation of sirolimus and/or cyclosporine, should be considered in patients with elevated or increasing serum creatinine levels. In patients at low- to moderate-immunologic risk, continuation of combination therapy with cyclosporine beyond 4 months following transplantation should only be considered when the benefits outweigh the risks of this combination for the individual patients. Caution should be exercised when using agents (e.g., aminoglycosides and amphotericin B) that are known to have a deleterious effect on renal function. - In patients with delayed graft function, sirolimus may delay recovery of renal function. - Periodic quantitative monitoring of urinary protein excretion is recommended. In a study evaluating conversion from calcineurin inhibitors (CNI) to sirolimus in maintenance renal transplant patients 6-120 months post-transplant, increased urinary protein excretion was commonly observed from 6 through 24 months after conversion to sirolimus compared with CNI continuation. - Patients with the greatest amount of urinary protein excretion prior to sirolimus conversion were those whose protein excretion increased the most after conversion.New onset nephrosis (nephrotic syndrome) was also reported as a treatment-emergent adverse event in 2.2% of the sirolimus conversion group patients in comparison to 0.4% in the CNI continuation group of patients. Nephrotic range proteinuria (defined as urinary protein to creatinine ratio > 3.5) was also reported in 9.2% in the sirolimus conversion group of patients in comparison to 3.7% in the CNI continuation group of patients. In some patients, reduction in the degree of urinary protein excretion was observed for individual patients following discontinuation of sirolimus. - The safety and efficacy of conversion from calcineurin inhibitors to sirolimus in maintenance renal transplant patients have not been established. - Cases of interstitial lung disease (including pneumonitis, bronchiolitis obliterans organizing pneumonia [BOOP], and pulmonary fibrosis), some fatal, with no identified infectious etiology have occurred in patients receiving immunosuppressive regimens including sirolimus. In some cases, the interstitial lung disease has resolved upon discontinuation or dose reduction of sirolimus. The risk may be increased as the trough sirolimus concentration increases. - The safety and efficacy of de novo use of sirolimus without cyclosporine is not established in renal transplant patients. In a multicenter clinical study, de novo renal transplant patients treated with sirolimus, mycophenolate mofetil (MMF), steroids, and an IL-2 receptor antagonist had significantly higher acute rejection rates and numerically higher death rates compared to patients treated with cyclosporine, MMF, steroids, and IL-2 receptor antagonist. A benefit, in terms of better renal function, was not apparent in the treatment arm with de novo use of sirolimus without cyclosporine. These findings were also observed in a similar treatment group of another clinical trial. - The concomitant use of sirolimus with a calcineurin inhibitor may increase the risk of calcineurin inhibitor-induced hemolytic uremic syndrome/thrombotic thrombocytopenic purpura/thrombotic microangiopathy (HUS/TTP/TMA). - Cases of Pneumocystis carinii pneumonia have been reported in patients not receiving antimicrobial prophylaxis. Therefore, antimicrobial prophylaxis for Pneumocystis carinii pneumonia should be administered for 1 year following transplantation. - Cytomegalovirus (CMV) prophylaxis is recommended for 3 months after transplantation, particularly for patients at increased risk for CMV disease. - The label-recommended 24-hour trough concentration ranges for sirolimus are based on chromatographic methods. Currently in clinical practice, sirolimus whole blood concentrations are being measured by both chromatographic and immunoassay methodologies. These concentration values are not interchangeable. - Patients on immunosuppressive therapy are at increased risk for skin cancer. Exposure to sunlight and ultraviolet (UV) light should be limited by wearing protective clothing and using a sunscreen with a high protection factor. - Co-administration of sirolimus with strong inhibitors of CYP3A4 and/or P-gp (such as ketoconazole, voriconazole, itraconazole, erythromycin, telithromycin, or clarithromycin) or strong inducers of CYP3A4 and/or P-gp (such as rifampin or rifabutin) is not recommended # Adverse Reactions ## Clinical Trials Experience - The following adverse reactions are discussed in greater detail in other sections of the label. - Increased susceptibility to infection, lymphoma, and malignancy - Excess mortality, graft loss, and hepatic artery thrombosis in liver transplant patients. - Bronchial anastomotic dehiscence in lung transplant patients. - Hypersensitivity reactions - Exfoliative dermatitis - Angioedema - Fluid Accumulation and Wound Healing. - Hypertriglyceridemia, hypercholesterolemia - Decline in renal function in long-term combination of cyclosporine with sirolimus - Proteinuria - Interstitial lung disease - Increased risk of calcineurin inhibitor-induced hemolytic uremic syndrome/thrombotic thrombocytopenic purpura/thrombotic microangiopathy (HUS/TTP/TMA). - The most common (≥ 30%) adverse reactions observed with sirolimus in clinical studies are: peripheral edema, hypertriglyceridemia, hypertension, hypercholesterolemia, creatinine increased, constipation, abdominal pain, diarrhea, headache, fever, urinary tract infection, anemia, nausea, arthralgia, pain, and thrombocytopenia. - The following adverse reactions resulted in a rate of discontinuation of > 5% in clinical trials: creatinine increased, hypertriglyceridemia, and thrombotic thrombocytopenic purpura (TTP). - The safety and efficacy of sirolimus Oral Solution for the prevention of organ rejection following renal transplantation were assessed in two randomized, double-blind, multicenter, controlled trials. The safety profiles in the two studies were similar. - The incidence of adverse reactions in the randomized, double-blind, multicenter, placebo-controlled trial (Study 2) in which 219 renal transplant patients received sirolimus Oral Solution 2 mg/day, 208 received sirolimus Oral Solution 5 mg/day, and 124 received placebo is presented in the TABLE below. The study population had a mean age of 46 years (range 15 to 71 years), the distribution was 67% male, and the composition by race was: White (78%), Black (11%), Asian (3%), Hispanic (2%), and Other (5%). All patients were treated with cyclosporine and corticosteroids. Data (≥ 12 months post-transplant) presented in the following TABLE show the adverse reactions that occurred in at least one of the sirolimus treatment groups with an incidence of ≥ 20%. - The safety profile of the tablet did not differ from that of the oral solution formulation. - In general, adverse reactions related to the administration of sirolimus were dependent on dose/concentration. Although a daily maintenance dose of 5 mg, with a loading dose of 15 mg, was shown to be safe and effective, no efficacy advantage over the 2 mg dose could be established for renal transplant patients. - Patients receiving 2 mg of sirolimus Oral Solution per day demonstrated an overall better safety profile than did patients receiving 5 mg of sirolimus Oral Solution per day. - Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in one clinical trial of a drug cannot be directly compared with rates in the clinical trials of the same or another drug and may not reflect the rates observed in practice. - The following adverse reactions were reported less frequently (≥ 3%, but < 20%) - Sepsis, lymphocele, herpes zoster, herpes simplex. - Venous thromboembolism (including pulmonary embolism, deep venous thrombosis), tachycardia). - Stomatitis. - Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), leukopenia. - Abnormal healing, increased lactic dehydrogenase (LDH), hypokalemia. - Bone necrosis. - Pneumonia, epistaxis. - Melanoma, squamous cell carcinoma, basal cell carcinoma. - Pyelonephritis, decline in renal function (creatinine increased) in long-term combination of cyclosporine with sirolimus. - Less frequently (< 3%) occurring adverse reactions included: lymphoma/post-transplant lymphoproliferative disorder, mycobacterial infections (including M. tuberculosis), pancreatitis, cytomegalovirus (CMV), and Epstein-Barr virus. - The use of sirolimus in renal transplant patients was associated with increased serum cholesterol and triglycerides that may require treatment. - In Studies 1 and 2, in de novo renal transplant patients who began the study with fasting, total serum cholesterol< 200 mg/dL or fasting, total serum triglycerides < 200 mg/dL, there was an increased incidence of hypercholesterolemia (fasting serum cholesterol > 240 mg/dL) or hypertriglyceridemia (fasting serum triglycerides > 500 mg/dL), respectively, in patients receiving both sirolimus 2 mg and sirolimus 5 mg compared with azathioprine and placebo controls. - Treatment of new-onset hypercholesterolemia with lipid-lowering agents was required in 42‑52% of patients enrolled in the sirolimus arms of Studies 1 and 2 compared with 16% of patients in the placebo arm and 22% of patients in the azathioprine arm. - Abnormal healing events following transplant surgery include fascial dehiscence, incisional hernia, and anastomosis disruption (e.g., wound, vascular, airway, ureteral, biliary). - The TABLE below summarizes the incidence of malignancies in the two controlled trials (Studies 1 and 2) for the prevention of acute rejection. - At 24 months (Study 1) and 36 months (Study 2), there were no significant differences among treatment groups. - The incidence of adverse reactions was determined through 36 months in a randomized, multicenter, controlled trial (Study 3) in which 215 renal transplant patients received sirolimus as a maintenance regimen following cyclosporine withdrawal, and 215 patients received sirolimus with cyclosporine therapy. - All patients were treated with corticosteroids. The safety profile prior to randomization (start of cyclosporine withdrawal) was similar to that of the 2 mg sirolimus groups in Studies 1 and 2. - Following randomization (at 3 months), patients who had cyclosporine eliminated from their therapy experienced higher incidences of the following adverse reactions: abnormal liver function tests (including increased AST/SGOT and increased ALT/SGPT), hypokalemia, thrombocytopenia, and abnormal healing. Conversely, the incidence of the following adverse events was higher in patients who remained on cyclosporine than those who had cyclosporine withdrawn from therapy: hypertension, cyclosporine toxicity, increased creatinine, abnormal kidney function, toxic nephropathy, edema, hyperkalemia, hyperuricemia, and gum hyperplasia. Mean systolic and diastolic blood pressure improved significantly following cyclosporine withdrawal. - The incidence of malignancies in Study 3 is presented in the TABLE following. - In Study 3, the incidence of lymphoma/lymphoproliferative disease was similar in all treatment groups. The overall incidence of malignancy was higher in patients receiving sirolimus plus cyclosporine compared with patients who had cyclosporine withdrawn. Conclusions regarding these differences in the incidence of malignancy could not be made because Study 3 was not designed to consider malignancy risk factors or systematically screen subjects for malignancy. In addition, more patients in the sirolimus with cyclosporine group had a pretransplantation history of skin carcinoma. - Safety was assessed in 224 patients who received at least one dose of sirolimus with cyclosporine. Overall, the incidence and nature of adverse events was similar to those seen in previous combination studies with sirolimus. The incidence of malignancy was 1.3% at 12 months. - The safety and efficacy of conversion from calcineurin inhibitors to sirolimus in maintenance renal transplant population have not been established. In an ongoing study evaluating the safety and efficacy of conversion from calcineurin inhibitors to sirolimus (initial target sirolimus concentrations of 12-20 ng/mL, and then 8-20 ng/mL, by chromatographic assay) in maintenance renal transplant patients, enrollment was stopped in the subset of patients (n = 87) with a baseline glomerular filtration rate of less than 40 mL/min. There was a higher rate of serious adverse events, including pneumonia, acute rejection, graft loss and death, in this stratum of the sirolimus treatment arm. - The subset of patients with a baseline glomerular filtration rate of less than 40 mL/min had 2 years of follow-up after randomization. In this population, the rate of pneumonia was 15/58 vs. 4/29, graft loss (excluding death with functioning graft loss) was 13/58 vs. 9/29, and death was 9/58 vs. 1/29 in the sirolimus conversion group and CNI continuation group, respectively. - In the subset of patients with a baseline glomerular filtration rate of greater than 40 mL/min, there was no benefit associated with conversion with regard to improvement in renal function and a greater incidence of proteinuria in the sirolimus conversion arm. - Overall in this study, a 5-fold increase in the reports of tuberculosis among sirolimus (11/551) and comparator (1/273) treatment groups was observed with 2:1 randomization scheme. - Safety was assessed in a controlled clinical trial in pediatric (< 18 years of age) renal transplant patients considered at high-immunologic risk, defined as a history of one or more acute allograft rejection episodes and/or the presence of chronic allograft nephropathy on a renal biopsy. - The use of sirolimus in combination with calcineurin inhibitors and corticosteroids was associated with a higher incidence of deterioration of renal function (creatinine increased) compared to calcineurin inhibitor-based therapy, serum lipid abnormalities (including, but not limited to, increased serum triglycerides and cholesterol), and urinary tract infections. ## Postmarketing Experience - The following adverse reactions have been identified during post-approval use of sirolimus. 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. - Cardiovascular – Pericardial effusion (including hemodynamically significant effusions and tamponade requiring intervention in children and adults). - Hematological/Lymphatic – The concomitant use of sirolimus with a calcineurin inhibitor may increase the risk of calcineurin inhibitor-induced HUS/TTP/TMA; pancytopenia, neutropenia. - Hepatotoxicity, including fatal hepatic necrosis, with elevated sirolimus trough concentrations. - Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, angioedema, and hypersensitivity vasculitis. - Tuberculosis. - Liver function test abnormal, AST/SGOT increased, ALT/SGPT increased, hypophosphatemia, hyperglycemia. - Cases of interstitial lung disease (including pneumonitis, bronchiolitis obliterans organizing pneumonia [BOOP], and pulmonary fibrosis), some fatal, with no identified infectious etiology have occurred in patients receiving immunosuppressive regimens including sirolimus. In some cases, the interstitial lung disease has resolved upon discontinuation or dose reduction of sirolimus. The risk may be increased as the sirolimus trough concentration increases; pulmonary hemorrhage; pleural effusion; alveolar proteinosis - Exfoliative dermatitis. - Nephrotic syndrome, proteinuria, focal segmental glomerulosclerosis. Azoospermia has been reported with the use of sirolimus and has been reversible upon discontinuation of sirolimus in most cases. # Drug Interactions - Sirolimus is known to be a substrate for both cytochrome P‑450 3A4 (CYP3A4) and p‑glycoprotein (P‑gp). Inducers of CYP3A4 and P‑gp may decrease sirolimus concentrations whereas inhibitors of CYP3A4 and P‑gp may increase sirolimus concentrations. - Cyclosporine, a substrate and inhibitor of CYP3A4 and P‑gp, was demonstrated to increase sirolimus concentrations when co‑administered with sirolimus. In order to diminish the effect of this interaction with cyclosporine, it is recommended that sirolimus be taken 4 hours after administration of cyclosporine oral solution (MODIFIED) and/or cyclosporine capsules (MODIFIED). - If cyclosporine is withdrawn from combination therapy with sirolimus, higher doses of sirolimus are needed to maintain the recommended sirolimus trough concentration ranges. - Strong Inducers and Strong Inhibitors of CYP3A4 and P-gp Avoid concomitant use of sirolimus with strong inducers (e.g., rifampin, rifabutin) and strong inhibitors (e.g., ketoconazole, voriconazole, itraconazole, erythromycin, telithromycin, clarithromycin) of CYP3A4 and P-gp. Alternative agents with lesser interaction potential with sirolimus should be considered. - Because grapefruit juice inhibits the CYP3A4-mediated metabolism of sirolimus, it must not be taken with or be used for dilution of sirolimus. - Exercise caution when using sirolimus with drugs or agents that are modulators of CYP3A4 and P-gp. The dosage of sirolimus and/or the co-administered drug may need to be adjusted. - Drugs that could increase sirolimus blood concentrations: Bromocriptine, cimetidine, cisapride, clotrimazole, danazol, diltiazem, fluconazole, HIV‑protease inhibitors (e.g., ritonavir, indinavir), metoclopramide, nicardipine, troleandomycin, verapamil Drugs and other agents that could decrease sirolimus concentrations: - Carbamazepine, phenobarbital, phenytoin, rifapentine, St. John's Wort (Hypericum perforatum) - Drugs with concentrations that could increase when given with sirolimus: - Verapamil - Immunosuppressants may affect response to vaccination. Therefore, during treatment with sirolimus, vaccination may be less effective. The use of live vaccines should be avoided; live vaccines may include, but are not limited to, the following: measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Sirolimus was embryo/fetotoxic in rats when given in doses approximately 0.2 to 0.5 the human doses (adjusted for body surface area). Embryo/fetotoxicity was manifested as mortality and reduced fetal weights (with associated delays in skeletal ossification). However, no teratogenesis was evident. In combination with cyclosporine, rats had increased embryo/feto mortality compared with sirolimus alone. There were no effects on rabbit development at a maternally toxic dosage approximately 0.3 to 0.8 times the human doses (adjusted for body surface area). There are no adequate and well‑controlled studies in pregnant women. Effective contraception must be initiated before sirolimus therapy, during sirolimus therapy, and for 12 weeks after sirolimus therapy has been stopped. Sirolimus should be used during pregnancy only if the potential benefit outweighs the potential risk to the embryo/fetus. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Sirolimus in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Sirolimus during labor and delivery. ### Nursing Mothers - Sirolimus is excreted in trace amounts in milk of lactating rats. It is not known whether sirolimus is excreted in human milk. The pharmacokinetic and safety profiles of sirolimus in infants are not known. Because many drugs are excreted in human milk, and because of the potential for adverse reactions in nursing infants from sirolimus, 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 efficacy of sirolimus in pediatric patients < 13 years have not been established. - The safety and efficacy of sirolimus Oral Solution and sirolimus Tablets have been established in children ≥ 13 years judged to be at low- to moderate-immunologic risk. Use of sirolimus Oral Solution and sirolimus Tablets in this subpopulation of children ≥ 13 years is supported by evidence from adequate and well-controlled trials of sirolimus Oral Solution in adults with additional pharmacokinetic data in pediatric renal transplantation patients. - Safety and efficacy information from a controlled clinical trial in pediatric and adolescent (< 18 years of age) renal transplant patients judged to be at high-immunologic risk, defined as a history of one or more acute rejection episodes and/or the presence of chronic allograft nephropathy, do not support the chronic use of sirolimus Oral Solution or Tablets in combination with calcineurin inhibitors and corticosteroids, due to the higher incidence of lipid abnormalities and deterioration of renal function associated with these immunosuppressive regimens compared to calcineurin inhibitors, without increased benefit with respect to acute rejection, graft survival, or patient survival. ### Geriatic Use - Clinical studies of sirolimus Oral Solution or Tablets did not include sufficient numbers of patients ≥ 65 years to determine whether they respond differently from younger patients. Data pertaining to sirolimus trough concentrations suggest that dose adjustments based upon age in geriatric renal patients are not necessary. Differences in responses between the elderly and younger patients have not been identified. 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, or cardiac function, and of concomitant disease or other drug therapy. ### Gender There is no FDA guidance on the use of Sirolimus with respect to specific gender populations. ### Race There is no FDA guidance on the use of Sirolimus with respect to specific racial populations. ### Renal Impairment - Dosage adjustment is not required in patients with renal impairment . ### Hepatic Impairment - The maintenance dose of sirolimus should be reduced in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Sirolimus in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Sirolimus in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring - Monitoring of sirolimus trough concentrations is recommended for all patients, especially in those patients likely to have altered drug metabolism, in patients≥ 13 years who weigh less than 40 kg, in patients with hepatic impairment,when a change in the sirolimus dosage form is made, and during concurrent administration of strong CYP3A4 inducers and inhibitors. - Therapeutic drug monitoring should not be the sole basis for adjusting sirolimus therapy. Careful attention should be made to clinical signs/symptoms, tissue biopsy findings, and laboratory parameters. - When used in combination with cyclosporine, sirolimus trough concentrations should be maintained within the target-range. - Following cyclosporine withdrawal in transplant patients at low- to moderate-immunologic risk, the target sirolimus trough concentrations should be 16 to 24 ng/mL for the first year following transplantation. Thereafter, the target sirolimus concentrations should be 12 to 20 ng/mL. - The above recommended 24-hour trough concentration ranges for sirolimus are based on chromatographic methods. On average, chromatographic methods (HPLC UV or LC/MS/MS) yield results that are approximately 20% lower than the immunoassay for whole blood concentration determinations. Currently in clinical practice, sirolimus whole blood concentrations are being measured by both chromatographic and immunoassay methodologies. Because the measured sirolimus whole blood concentrations depend on the type of assay used, the concentrations obtained by these different methodologies are not interchangeable. - Adjustments to the targeted range should be made according to the assay utilized to determine sirolimus trough concentrations. - Therapeutic drug monitoring should be used to maintain sirolimus drug levels within the target-range. - Therapeutic drug monitoring is necessary in all patients with hepatic impairment. - Renal function should be monitored, and appropriate adjustment of the immunosuppressive regimen should be considered in patients with elevated or increasing serum creatinine levels. - Periodic quantitative monitoring of urinary protein excretion is recommended. - During sirolimus therapy with cyclosporine, patients administered an HMG-CoA reductase inhibitor and/or fibrate should be monitored for the possible development of rhabdomyolysis and other adverse effects, as described in the respective labeling for these agents. - Any patient who is administered sirolimus should be monitored for hyperlipidemia. - Monitoring of sirolimus trough concentrations is recommended for all patients, especially in those patients likely to have altered drug metabolism, in patients≥ 13 years who weigh less than 40 kg, in patients with hepatic impairment,when a change in the sirolimus dosage form is made, and during concurrent administration of strong CYP3A4 inducers and inhibitors. - Once sirolimus maintenance dose is adjusted, patients should continue on the new maintenance dose for at least 7 to 14 days before further dosage adjustment with concentration monitoring. # IV Compatibility There is limited information regarding IV Compatibility of Sirolimus in the drug label. # Overdosage - Reports of overdose with sirolimus have been received; however, experience has been limited. In general, the adverse effects of overdose are consistent with those listed in the adverse reactions section. - General supportive measures should be followed in all cases of overdose. Based on the low aqueous solubility and high erythrocyte and plasma protein binding of sirolimus, it is anticipated that sirolimus is not dialyzable to any significant extent. In mice and rats, the acute oral LD50 was greater than 800 mg/kg. # Pharmacology ## Mechanism of Action - Sirolimus inhibits T-lymphocyte activation and proliferation that occurs in response to antigenic and cytokine (Interleukin [IL]-2, IL-4, and IL-15) stimulation by a mechanism that is distinct from that of other immunosuppressants. Sirolimus also inhibits antibody production. In cells, sirolimus binds to the immunophilin, FK Binding Protein-12 (FKBP-12), to generate an immunosuppressive complex. The sirolimus:FKBP-12 complex has no effect on calcineurin activity. This complex binds to and inhibits the activation of the mammalian Target Of Rapamycin (mTOR), a key regulatory kinase. This inhibition suppresses cytokine-driven T-cell proliferation, inhibiting the progression from the G1 to the S phase of the cell cycle. - Studies in experimental models show that sirolimus prolongs allograft (kidney, heart, skin, islet, small bowel, pancreatico-duodenal, and bone marrow) survival in mice, rats, pigs, and/or primates. Sirolimus reverses acute rejection of heart and kidney allografts in rats and prolongs the graft survival in presensitized rats. In some studies, the immunosuppressive effect of sirolimus lasts up to 6 months after discontinuation of therapy. This tolerization effect is alloantigen-specific. - In rodent models of autoimmune disease, sirolimus suppresses immune-mediated events associated with systemic lupus erythematosus, collagen-induced arthritis, autoimmune type I diabetes, autoimmune myocarditis, experimental allergic encephalomyelitis, graft-versus-host disease, and autoimmune uveoretinitis. ## Structure - Sirolimus is an immunosuppressive agent. Sirolimus is a macrocyclic lactone produced by Streptomyces hygroscopicus. The chemical name of sirolimus (also known as rapamycin) is (3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-9,10,12,13,14,21,22,23,24,25,26,27,32,33,34, 34a-hexadecahydro-9,27-dihydroxy-3-[(1R)-2-[(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-23,27-epoxy-3H-pyrido[2,1-c][1,4] oxaazacyclohentriacontine-1,5,11,28,29 (4H,6H,31H)-pentone. Its molecular formula is C51H79NO13 and its molecular weight is 914.2. The structural formula of sirolimus is illustrated as follows. - Sirolimus is a white to off-white powder and is insoluble in water, but freely soluble in benzyl alcohol, chloroform, acetone, and acetonitrile. - Sirolimus is available for administration as an oral solution containing 1 mg/mL sirolimus. Sirolimus is also available as a white, triangular-shaped tablet containing 1 mg sirolimus, and as a yellow-to-beige triangular-shaped tablet containing 2 mg sirolimus. - The inactive ingredients in sirolimus Oral Solution are Phosal 50 PG® (phosphatidylcholine, propylene glycol, mono- and di-glycerides, ethanol, soy fatty acids, and ascorbyl palmitate) and polysorbate 80. Sirolimus Oral Solution contains 1.5% - 2.5% ethanol. - The inactive ingredients in sirolimus Tablets include sucrose, lactose, polyethylene glycol 8000, calcium sulfate, microcrystalline cellulose, pharmaceutical glaze, talc, titanium dioxide, magnesium stearate, povidone, poloxamer 188, polyethylene glycol 20,000, glyceryl monooleate, carnauba wax, dl-alpha tocopherol, and other ingredients. The 2 mg dosage strength also contains iron oxide yellow 10 and iron oxide brown 70. ## Pharmacodynamics - Orally-administered sirolimus, at doses of 2 mg/day and 5 mg/day, significantly reduced the incidence of organ rejection in low- to moderate-immunologic risk renal transplant patients at 6 months following transplantation compared with either azathioprine or placebo. There was no demonstrable efficacy advantage of a daily maintenance dose of 5 mg with a loading dose of 15 mg over a daily maintenance dose of 2 mg with a loading dose of 6 mg. Therapeutic drug monitoring should be used to maintain sirolimus drug levels within the target-range. ## Pharmacokinetics - Sirolimus pharmacokinetics activity have been determined following oral administration in healthy subjects, pediatric patients, hepatically impaired patients, and renal transplant patients. - The pharmacokinetic parameters of sirolimus in low- to moderate-immunologic risk adult renal transplant patients following multiple dosing with sirolimus 2 mg daily, in combination with cyclosporine and corticosteroids, is summarized in the following TABLE. - Whole blood trough sirolimus concentrations, as measured by LC/MS/MS in renal transplant patients, were significantly correlated with AUCτ,ss. Upon repeated, twice-daily administration without an initial loading dose in a multiple-dose study, the average trough concentration of sirolimus increases approximately 2- to 3-fold over the initial 6 days of therapy, at which time steady-state is reached. A loading dose of 3 times the maintenance dose will provide near steady-state concentrations within 1 day in most patients. - Following administration of sirolimus Oral Solution, the mean times to peak concentration (tmax) of sirolimus are approximately 1 hour and 2 hours in healthy subjects and renal transplant patients, respectively. The systemic availability of sirolimus is low, and was estimated to be approximately 14% after the administration of sirolimus Oral Solution. In healthy subjects, the mean bioavailability of sirolimus after administration of the tablet is approximately 27% higher relative to the solution. - Sirolimus tablets are not bioequivalent to the solution; however, clinical equivalence has been demonstrated at the 2 mg dose level. Sirolimus concentrations, following the administration of sirolimus Oral Solution to stable renal transplant patients, are dose-proportional between 3 and 12 mg/m2. - To minimize variability in sirolimus concentrations, both sirolimus Oral Solution and Tablets should be taken consistently with or without food. In healthy subjects, a high-fat meal (861.8 kcal, 54.9% kcal from fat) increased the mean total exposure (AUC) of sirolimus by 23 to 35%, compared with fasting. The effect of food on the mean sirolimus Cmax was inconsistent depending on the sirolimus dosage form evaluated. - The mean (± SD) blood-to-plasma ratio of sirolimus was 36 ± 18 in stable renal allograft patients, indicating that sirolimus is extensively partitioned into formed blood elements. The mean volume of distribution (Vss/F) of sirolimus is 12 ± 8 L/kg. Sirolimus is extensively bound (approximately 92%) to human plasma proteins, mainly serum albumin (97%), α1-acid glycoprotein, and lipoproteins. - Sirolimus is a substrate for both CYP3A4 and P-gp. Sirolimus is extensively metabolized in the intestinal wall and liver and undergoes counter-transport from enterocytes of the small intestine into the gut lumen. Inhibitors of CYP3A4 and P-gp increase sirolimus concentrations. Inducers of CYP3A4 and P-gp decrease sirolimus concentrations. - Sirolimus is extensively metabolized by O‑demethylation and/or hydroxylation. Seven (7) major metabolites, including hydroxy, demethyl, and hydroxydemethyl, are identifiable in whole blood. Some of these metabolites are also detectable in plasma, fecal, and urine samples. Sirolimus is the major component in human whole blood and contributes to more than 90% of the immunosuppressive activity. - After a single dose of [14C] sirolimus oral solution in healthy volunteers, the majority (91%) of radioactivity was recovered from the feces, and only a minor amount (2.2%) was excreted in urine. The mean ± SD terminal elimination half life (t½) of sirolimus after multiple dosing in stable renal transplant patients was estimated to be about 62 ± 16 hours. - Sirolimus Concentrations (Chromatographic Equivalent) Observed in Phase 3 Clinical Studies - The FOLLOWING sirolimus concentrations (chromatographic equivalent) were observed in phase 3 clinical studies. - The withdrawal of cyclosporine and concurrent increases in sirolimus trough concentrations to steady-state required approximately 6 weeks. Following cyclosporine withdrawal, larger sirolimus doses were required due to the absence of the inhibition of sirolimus metabolism and transport by cyclosporine and to achieve higher target sirolimus trough concentrations during concentration-controlled administration. ### Pharmacokinetics in Specific Populations - Sirolimus was administered as a single, oral dose to subjects with normal hepatic function and to patients with Child-Pugh classification A (mild), B (moderate), or C (severe) hepatic impairment. Compared with the values in the normal hepatic function group, the patients with mild, moderate, and severe hepatic impairment had 43%, 94%, and 189% higher mean values for sirolimus AUC, respectively, with no statistically significant differences in mean Cmax. As the severity of hepatic impairment increased, there were steady increases in mean sirolimus t1/2, and decreases in the mean sirolimus clearance normalized for body weight (CL/F/kg). - The maintenance dose of sirolimus should be reduced by approximately one third in patients with mild‑to‑moderate hepatic impairment and by approximately one half in patients with severe hepatic impairment. - It is not necessary to modify the sirolimus loading dose in patients with mild, moderate, and severe hepatic impairment. Therapeutic drug monitoring is necessary in all patients with hepatic impairment. - The effect of renal impairment on the pharmacokinetics of sirolimus is not known. However, there is minimal (2.2%) renal excretion of the drug or its metabolites in healthy volunteers. The loading and the maintenance doses of sirolimus need not be adjusted in patients with renal impairment. - Sirolimus pharmacokinetic data were collected in concentration-controlled trials of pediatric renal transplant patients who were also receiving cyclosporine and corticosteroids. The target ranges for trough concentrations were either 10-20 ng/mL for the 21 children receiving tablets, or 5-15 ng/mL for the one child receiving oral solution. The children aged 6-11 years (n = 8) received mean ± SD doses of 1.75 ± 0.71 mg/day (0.064 ± 0.018 mg/kg, 1.65 ± 0.43 mg/m2). The children aged 12-18 years (n = 14) received mean ± SD doses of 2.79 ± 1.25 mg/day (0.053 ± 0.0150 mg/kg, 1.86± 0.61 mg/m2). At the time of sirolimus blood sampling for pharmacokinetic evaluation, the majority (80%) of these pediatric patients received the sirolimus dose at 16 hours after the once-daily cyclosporine dose. - Clinical studies of sirolimus did not include a sufficient number of patients > 65 years of age to determine whether they will respond differently than younger patients. After the administration of sirolimus Oral Solution or Tablets, sirolimus trough concentration data in renal transplant patients > 65 years of age were similar to those in the adult population 18 to 65 years of age. - Sirolimus clearance in males was 12% lower than that in females; male subjects had a significantly longer t1/2 than did female subjects (72.3 hours versus 61.3 hours). Dose adjustments based on gender are not recommended. - In the phase 3 trials using sirolimus solution or tablets and cyclosporine oral solution [MODIFIED] (e.g., Neoral® Oral Solution) and/or cyclosporine capsules [MODIFIED] (e.g., Neoral® Soft Gelatin Capsules) [see Clinical Studies (14)], there were no significant differences in mean trough sirolimus concentrations over time between Black (n = 190) and non-Black (n = 852) patients during the first 6 months after transplantation. - Sirolimus is known to be a substrate for both cytochrome CYP3A4 and P-gp. The pharmacokinetic interaction between sirolimus and concomitantly administered drugs is discussed below. Drug interaction studies have not been conducted with drugs other than those described below. - Cyclosporine is a substrate and inhibitor of CYP3A4 and P-gp. Sirolimus should be taken 4 hours after administration of cyclosporine oral solution (MODIFIED) and/or cyclosporine capsules (MODIFIED). Sirolimus concentrations may decrease when cyclosporine is discontinued, unless the sirolimus dose is increased. - In a single-dose drug-drug interaction study, 24 healthy volunteers were administered 10 mg sirolimus Tablets either simultaneously or 4 hours after a 300-mg dose of Neoral® Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]). For simultaneous administration, mean Cmax and AUC were increased by 512% and 148%, respectively, relative to administration of sirolimus alone. However, when given 4 hours after cyclosporine administration, sirolimus Cmax and AUC were both increased by only 33% compared with administration of sirolimus alone. - In a single dose drug-drug interaction study, 24 healthy volunteers were administered 10 mg sirolimus Oral Solution either simultaneously or 4 hours after a 300 mg dose of Neoral® Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]). For simultaneous administration, the mean Cmax and AUC of sirolimus, following simultaneous administration were increased by 116% and 230%, respectively, relative to administration of sirolimus alone. However, when given 4 hours after Neoral® Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]) administration, sirolimus Cmax and AUC were increased by only 37% and 80%, respectively, compared with administration of sirolimus alone. - In a single-dose cross-over drug-drug interaction study, 33 healthy volunteers received 5 mg sirolimus Oral Solution alone, 2 hours before, and 2 hours after a 300 mg dose of Neoral® Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]). When given 2 hours before Neoral® Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]) administration, sirolimus Cmax and AUC were comparable to those with administration of sirolimus alone. However, when given 2 hours after, the mean Cmax and AUC of sirolimus were increased by 126% and 141%, respectively, relative to administration of sirolimus alone. - Mean cyclosporine Cmax and AUC were not significantly affected when sirolimus Oral Solution was given simultaneously or when administered 4 hours after Neoral® Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]). However, after multiple-dose administration of sirolimus given 4 hours after Neoral® in renal post-transplant patients over 6 months, cyclosporine oral-dose clearance was reduced, and lower doses of Neoral® Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]) were needed to maintain target cyclosporine concentration. - In a multiple-dose study in 150 psoriasis patients, sirolimus 0.5, 1.5, and 3 mg/m2/day was administered simultaneously with Sandimmune® Oral Solution (cyclosporine Oral Solution) 1.25 mg/kg/day. The increase in average sirolimus trough concentrations ranged between 67% to 86% relative to when sirolimus was administered without cyclosporine. The intersubject variability (% CV) for sirolimus trough concentrations ranged from 39.7% to 68.7%. There was no significant effect of multiple-dose sirolimus on cyclosporine trough concentrations following Sandimmune® Oral Solution (cyclosporine oral solution) administration. However, the % CV was higher (range 85.9% - 165%) than those from previous studies. - Diltiazem is a substrate and inhibitor of CYP3A4 and P-gp; sirolimus concentrations should be monitored and a dose adjustment may be necessary. The simultaneous oral administration of 10 mg of sirolimus oral solution and 120 mg of diltiazem to 18 healthy volunteers significantly affected the bioavailability of sirolimus. Sirolimus Cmax, tmax, and AUC were increased 1.4-, 1.3-, and 1.6-fold, respectively. Sirolimus did not affect the pharmacokinetics of either diltiazem or its metabolites desacetyldiltiazem and desmethyldiltiazem. - Erythromycin is a substrate and inhibitor of CYP3A4 and P-gp; co-administration of sirolimus oral solution or tablets and erythromycin is not recommended. The simultaneous oral administration of 2 mg daily of sirolimus oral solution and 800 mg q 8h of erythromycin as erythromycin ethylsuccinate tablets at steady state to 24 healthy volunteers significantly affected the bioavailability of sirolimus and erythromycin. Sirolimus Cmax and AUC were increased 4.4- and 4.2-fold respectively and tmax was increased by 0.4 hr. Erythromycin Cmax and AUC were increased 1.6- and 1.7-fold, respectively, and tmax was increased by 0.3 hr. - Ketoconazole is a strong inhibitor of CYP3A4 and P-gp; co-administration of sirolimus oral solution or tablets and ketoconazole is not recommended. Multiple-dose ketoconazole administration significantly affected the rate and extent of absorption and sirolimus exposure after administration of sirolimus Oral Solution, as reflected by increases in sirolimus Cmax, tmax, and AUC of 4.3-fold, 38%, and 10.9-fold, respectively. However, the terminal t½ of sirolimus was not changed. Single-dose sirolimus did not affect steady-state 12-hour plasma ketoconazole concentrations. - Rifampin is a strong inducer of CYP3A4 and P-gp; co-administration of sirolimus oral solution or tablets and rifampin is not recommended. In patients where rifampin is indicated, alternative therapeutic agents with less enzyme induction potential should be considered. Pretreatment of 14 healthy volunteers with multiple doses of rifampin, 600 mg daily for 14 days, followed by a single 20-mg dose of sirolimus oral solution, greatly decreased sirolimus AUC and Cmax by about 82% and 71%, respectively. - Verapamil is a substrate and inhibitor of CYP3A4 and P-gp; sirolimus concentrations should be monitored and a dose adjustment may be necessary. The simultaneous oral administration of 2 mg daily of sirolimus oral solution and 180 mg q 12h of verapamil at steady state to 26 healthy volunteers significantly affected the bioavailability of sirolimus and verapamil. Sirolimus Cmax and AUC were increased 2.3- and 2.2-fold, respectively, without substantial change in tmax. The Cmax and AUC of the pharmacologically active S(-) enantiomer of verapamil were both increased 1.5-fold and tmax was decreased by 1.2 hr. - Drugs Which May Be Co-administered Without Dose Adjustment Clinically significant pharmacokinetic drug-drug interactions were not observed in studies of drugs listed below. Sirolimus and these drugs may be co-administered without dose adjustments. - Acyclovir - Atorvastatin - Digoxin - Glyburide - Nifedipine - Norgestrel/ethinyl estradiol (Lo/Ovral®) - Prednisolone - Sulfamethoxazole/trimethoprim (Bactrim®) - Co-administration of sirolimus with other known strong inhibitors of CYP3A4 and/or P-gp (such as voriconazole, itraconazole, telithromycin, or clarithromycin) or other known strong inducers of CYP3A4 and/or P-gp (such as rifabutin) is not recommended. In patients in whom strong inhibitors or inducers of CYP3A4 are indicated, alternative therapeutic agents with less potential for inhibition or induction of CYP3A4 should be considered. - Care should be exercised when drugs or other substances that are substrates and/or inhibitors or inducers of CYP3A4 are administered concomitantly with sirolimus. Other drugs that have the potential to increase sirolimus blood concentrations include (but are not limited to): - Calcium channel blockers - Nicardipine. - Antifungal agent - Clotrimazole, fluconazole. - Antibiotics - Troleandomycin. - Gastrointestinal prokinetic agents - Cisapride, metoclopramide. - Other drugs - Bromocriptine, cimetidine, danazol, HIV-protease inhibitors (e.g., ritonavir, indinavir). - Other drugs that have the potential to decrease sirolimus concentrations include (but are not limited to): - Anticonvulsants - Carbamazepine, phenobarbital, phenytoin - Antibiotics - Rifapentine. - Grapefruit juice reduces CYP3A4-mediated drug metabolism. Grapefruit juice must not be taken with or used for dilution of sirolimus. - St. John's Wort (hypericum perforatum) induces CYP3A4 and P-gp. Since sirolimus is a substrate for both cytochrome CYP3A4 and P-gp, there is the potential that the use of St. John's Wort in patients receiving sirolimus could result in reduced sirolimus concentrations. ## Nonclinical Toxicology - Carcinogenicity studies were conducted in mice and rats. In an 86-week female mouse study at sirolimus doses 30 to 120 times higher than the 2 mg daily clinical dose (adjusted for body surface area), there was a statistically significant increase in malignant lymphoma at all dose levels compared with controls. - In a second mouse study at dosages that were approximately 3 to 16 times the clinical dose (adjusted for body surface area), hepatocellular adenoma and carcinoma in males were considered sirolimus-related. In the 104-week rat study at dosages equal to or lower than the clinical dose of 2 mg daily (adjusted for body surface area), there were no significant findings. - Sirolimus was not genotoxic in the in vitro bacterial reverse mutation assay, the Chinese hamster ovary cell chromosomal aberration assay, the mouse lymphoma cell forward mutation assay, or the in vivo mouse micronucleus assay. - Fertility was diminished slightly in both male and female rats following oral administration of sirolimus at doses approximately 10 times or 2 times, respectively, the clinical dose of 2 mg daily (adjusted for body surface area). In male rats, atrophy of testes, epididymides, prostate, seminiferous tubules and/or reduction in sperm counts were observed. In female rats, reduced size of ovaries and uteri was observed. Reduction of sperm count in male rats was reversible upon cessation of dosing in one study. Testicular tubular degeneration was also seen in a 4‑week intravenous study of sirolimus in monkeys at doses that were approximately equal to the clinical dose (adjusted for body surface area). # Clinical Studies ### Prophylaxis of Organ Rejection - The safety and efficacy of sirolimus Oral Solution for the prevention of organ rejection following renal transplantation were assessed in two randomized, double-blind, multicenter, controlled trials. These studies compared two dose levels of sirolimus Oral Solution (2 mg and 5 mg, once daily) with azathioprine (Study 1) or placebo (Study 2) when administered in combination with cyclosporine and corticosteroids. Study 1 was conducted in the United States at 38 sites. Seven hundred nineteen (719) patients were enrolled in this trial and randomized following transplantation; 284 were randomized to receive sirolimus Oral Solution 2 mg/day; 274 were randomized to receive sirolimus Oral Solution 5 mg/day, and 161 to receive azathioprine 2-3 mg/kg/day. Study 2 was conducted in Australia, Canada, Europe, and the United States, at a total of 34 sites. Five hundred seventy-six (576) patients were enrolled in this trial and randomized before transplantation; 227 were randomized to receive sirolimus Oral Solution 2 mg/day; 219 were randomized to receive sirolimus Oral Solution 5 mg/day, and 130 to receive placebo. In both studies, the use of antilymphocyte antibody induction therapy was prohibited. In both studies, the primary efficacy endpoint was the rate of efficacy failure in the first 6 months after transplantation. Efficacy failure was defined as the first occurrence of an acute rejection episode (confirmed by biopsy), graft loss, or death. - The TABLES below summarize the results of the primary efficacy analyses from these trials. Sirolimus Oral Solution, at doses of 2 mg/day and 5 mg/day, significantly reduced the incidence of efficacy failure (statistically significant at the< 0.025 level; nominal significance level adjusted for multiple [2] dose comparisons) at 6 months following transplantation compared with both azathioprine and placebo. - The reduction in the incidence of first biopsy-confirmed acute rejection episodes in patients treated with sirolimus compared with the control groups included a reduction in all grades of rejection. - In Study 1, which was prospectively stratified by race within center, efficacy failure was similar for sirolimus Oral Solution 2 mg/day and lower for sirolimus Oral Solution 5 mg/day compared with azathioprine in Black patients. In Study 2, which was not prospectively stratified by race, efficacy failure was similar for both sirolimus Oral Solution doses compared with placebo in Black patients. The decision to use the higher dose of sirolimus Oral Solution in Black patients must be weighed against the increased risk of dose-dependent adverse events that were observed with the sirolimus Oral Solution 5-mg dose. - Mean glomerular filtration rates (GFR) post-transplant were calculated by using the Nankivell equation at 12 and 24 months for Study 1, and 12 and 36 months for Study 2. Mean GFR was lower in patients treated with cyclosporine and sirolimus Oral Solution compared with those treated with cyclosporine and the respective azathioprine or placebo control. - Within each treatment group in Studies 1 and 2, mean GFR at one-year post-transplant was lower in patients who experienced at least one episode of biopsy-proven acute rejection, compared with those who did not. - Renal function should be monitored, and appropriate adjustment of the immunosuppressive regimen should be considered in patients with elevated or increasing serum creatinine levels. - The safety and efficacy of sirolimus Oral Solution and sirolimus tablets for the prevention of organ rejection following renal transplantation were demonstrated to be clinically equivalent in a randomized, multicenter, controlled trial. - The safety and efficacy of sirolimus as a maintenance regimen were assessed following cyclosporine withdrawal at 3 to 4 months after renal transplantation. Study 3 was a randomized, multicenter, controlled trial conducted at 57 centers in Australia, Canada, and Europe. Five hundred twenty-five (525) patients were enrolled. All patients in this study received the tablet formulation. - This study compared patients who were administered sirolimus, cyclosporine, and corticosteroids continuously with patients who received this same standardized therapy for the first 3 months after transplantation (pre-randomization period) followed by the withdrawal of cyclosporine. During cyclosporine withdrawal, the sirolimus dosages were adjusted to achieve targeted sirolimus whole blood trough concentration ranges (16 to 24 ng/mL until month 12, then 12 to 20 ng/mL thereafter, expressed as chromatographic assay values). At 3 months, 430 patients were equally randomized to either continue sirolimus with cyclosporine therapy or to receive sirolimus as a maintenance regimen following cyclosporine withdrawal. - Eligibility for randomization included no Banff Grade 3 acute rejection or vascular rejection episode in the 4 weeks before random assignment, serum creatinine ≤ 4.5 mg/dL, and adequate renal function to support cyclosporine withdrawal (in the opinion of the investigator). The primary efficacy endpoint was graft survival at 12 months after transplantation. Secondary efficacy endpoints were the rate of biopsy-confirmed acute rejection, patient survival, incidence of efficacy failure (defined as the first occurrence of either biopsy-proven acute rejection, graft loss, or death), and treatment failure (defined as the first occurrence of either discontinuation, acute rejection, graft loss, or death). - The following TABLE summarizes the resulting graft and patient survival at 12, 24, and 36 months for this trial. At 12, 24, and 36 months, graft and patient survival were similar for both groups. - The mean GFR at 12, 24, and 36 months, calculated by the Nankivell equation, was significantly higher for patients receiving sirolimus as a maintenance regimen following cyclosporine withdrawal than for those in the sirolimus with cyclosporine therapy group. Patients who had an acute rejection prior to randomization had a significantly higher GFR following cyclosporine withdrawal compared to those in the sirolimus with cyclosporine group. There was no significant difference in GFR between groups for patients who experienced acute rejection post-randomization. - Although the initial protocol was designed for 36 months, there was a subsequent amendment to extend this study. The results for the cyclosporine withdrawal group at months 48 and 60 were consistent with the results at month 36. Fifty-two percent (112/215) of the patients in the sirolimus with cyclosporine withdrawal group remained on therapy to month 60 and showed sustained GFR. - Sirolimus was studied in a one-year, clinical trial in high risk patients (Study 4) who were defined as Black transplant recipients and/or repeat renal transplant recipients who lost a previous allograft for immunologic reasons and/or patients with high panel-reactive antibodies (PRA; peak PRA level > 80%). Patients received concentration-controlled sirolimus and cyclosporine (MODIFIED), and corticosteroids per local practice. The sirolimus dose was adjusted to achieve target whole blood trough sirolimus concentrationsof 10-15 ng/mL (chromatographic method) throughout the 12-month study period. The cyclosporine dose was adjusted to achieve target whole blood trough concentrations of 200-300 ng/mL through week 2, 150-200 ng/mL from week 2 to week 26, and 100-150 ng/mL from week 26 to week 52 for the observed trough concentrations ranges. Antibody induction was allowed per protocol as prospectively defined at each transplant center, and was used in 88.4% of patients. The study was conducted at 35 centers in the United States. - A total of 224 patients received a transplant and at least one dose of sirolimus and cyclosporine and was comprised of 77.2% Black patients, 24.1% repeat renal transplant recipients, and 13.5% patients with high PRA. Efficacy was assessed with the following endpoints, measured at 12 months: efficacy failure (defined as the first occurrence of biopsy-confirmed acute rejection, graft loss, or death), first occurrence of graft loss or death, and renal function as measured by the calculated GFR using the Nankivell formula. The TABLE below summarizes the result of these endpoints. - Patient survival at 12 months was 94.6%. The incidence of biopsy-confirmed acute rejection was 17.4% and the majority of the episodes of acute rejection were mild in severity. - Conversion from calcineurin inhibitors (CNI) to sirolimus was assessed in maintenance renal transplant patients 6 months to 10 years post‑transplant (Study 5). This study was a randomized, multicenter, controlled trial conducted at 111 centers globally, including US and Europe, and was intended to show that renal function was improved by conversion from CNI to sirolimus. Eight hundred thirty (830) patients were enrolled and stratified by baseline calculated glomerular filtration rate (GFR, 20-40 mL/min vs. greater than 40 mL/min). In this trial there was no benefit associated with conversion with regard to improvement in renal function and a greater incidence of proteinuria in the sirolimus conversion arm. In addition, enrollment of patients with baseline calculated GFR less than 40 mL/min was discontinued due to a higher rate of serious adverse events, including pneumonia, acute rejection, graft loss and death. - This study compared renal transplant patients (6-120 months after transplantation) who were converted from calcineurin inhibitors to sirolimus, with patients who continued to receive calcineurin inhibitors. Concomitant immunosuppressive medications included mycophenolate mofetil (MMF), azathioprine (AZA), and corticosteroids. sirolimus was initiated with a single loading dose of 12-20 mg, after which dosing was adjusted to achieve a target sirolimus whole blood trough concentration of 8-20 ng/mL (chromatographic method). The efficacy endpoint was calculated GFR at 12 months post-randomization. Additional endpoints included biopsy-confirmed acute rejection, graft loss, and death. Findings in the patient stratum with baseline calculated GFR greater than 40 mL/min (sirolimus conversion, n = 497; CNI continuation, n = 246) are summarized BELOW: There was no clinically or statistically significant improvement in Nankivell GFR compared to baseline. - The rates of acute rejection, graft loss, and death were similar at 1 and 2 years. Treatment-emergent adverse events occurred more frequently during the first 6 months after sirolimus conversion. The rates of pneumonia were significantly higher for the sirolimus conversion group. - While the mean and median values for urinary protein to creatinine ratio were similar between treatment groups at baseline, significantly higher mean and median levels of urinary protein excretion were seen in the sirolimus conversion arm at 1 year and at 2 years, as shown in the TABLE below. - In addition, when compared to patients who continued to receive calcineurin inhibitors, a higher percentage of patients had urinary protein to creatinine ratios > 1 at 1 and 2 years after sirolimus conversion. This difference was seen in both patients who had a urinary protein to creatinine ratio ≤ 1 and those who had a protein to creatinine ratio > 1 at baseline. More patients in the sirolimus conversion group developed nephrotic range proteinuria, as defined by a urinary protein to creatinine ratio > 3.5 (46/482 [9.5%] vs. 9/239 [3.8%]), even when the patients with baseline nephrotic range proteinuria were excluded. The rate of nephrotic range proteinuria was significantly higher in the sirolimus conversion group compared to the calcineurin inhibitor continuation group with baseline urinary protein to creatinine ratio > 1 (13/29 vs. 1/14), excluding patients with baseline nephrotic range proteinuria. - The above information should be taken into account when considering conversion from calcineurin inhibitors to sirolimus in stable renal transplant patients due to the lack of evidence showing that renal function improves following conversion, and the finding of a greater increment in urinary protein excretion, and an increased incidence of treatment-emergent nephrotic range proteinuria following conversion to sirolimus. - This was particularly true among patients with existing abnormal urinary protein excretion prior to conversion. - Sirolimus was evaluated in a 36-month, open-label, randomized, controlled clinical trial at 14 North American centers in pediatric (aged 3 to < 18 years) renal transplant patients considered to be at high-immunologic risk for developing chronic allograft nephropathy, defined as a history of one or more acute allograft rejection episodes and/or the presence of chronic allograft nephropathy on a renal biopsy. Seventy-eight (78) subjects were randomized in a 2:1 ratio to sirolimus (sirolimus target concentrations of 5 to 15 ng/mL, by chromatographic assay, n = 53) in combination with a calcineurin inhibitor and corticosteroids or to continue calcineurin-inhibitor-based immunosuppressive therapy (n = 25). The primary endpoint of the study was efficacy failure as defined by the first occurrence of biopsy-confirmed acute rejection, graft loss, or death, and the trial was designed to show superiority of sirolimus added to a calcineurin-inhibitor-based immunosuppressive regimen compared to a calcineurin-inhibitor-based regimen. - The cumulative incidence of efficacy failure up to 36 months was 45.3% in the sirolimus group compared to 44.0% in the control group, and did not demonstrate superiority. There was one death in each group. The use of sirolimus in combination with calcineurin inhibitors and corticosteroids was associated with an increased risk of deterioration of renal function, serum lipid abnormalities (including, but not limited to, increased serum triglycerides and cholesterol), and urinary tract infections . This study does not support the addition of sirolimus to calcineurin-inhibitor-based immunosuppressive therapy in this subpopulation of pediatric renal transplant patients. # How Supplied - Since sirolimus is not absorbed through the skin, there are no special precautions. However, if direct contact with the skin or mucous membranes occurs, wash thoroughly with soap and water; rinse eyes with plain water. - Each sirolimus Oral Solution carton, NDC 0008-1030-06, contains one 2 oz (60 mL fill) amber glass bottle of sirolimus (concentration of 1 mg/mL), one oral syringe adapter for fitting into the neck of the bottle, sufficient disposable amber oral syringes and caps for daily dosing, and a carrying case. - Sirolimus Oral Solution bottles should be stored protected from light and refrigerated at 2°C to 8°C (36°F to 46°F). Once the bottle is opened, the contents should be used within one month. If necessary, the patient may store the bottles at room temperatures up to 25°C (77°F) for a short period of time (e.g., not more than 15 days for the bottles). - An amber syringe and cap are provided for dosing, and the product may be kept in the syringe for a maximum of 24 hours at room temperatures up to 25°C (77°F) or refrigerated at 2°C to 8°C (36°F to 46°F). The syringe should be discarded after one use. After dilution, the preparation should be used immediately. - Sirolimus Oral Solution provided in bottles may develop a slight haze when refrigerated. If such a haze occurs, allow the product to stand at room temperature and shake gently until the haze disappears. The presence of this haze does not affect the quality of the product. - Sirolimus Tablets are available as follows: - NDC 0008-1041-05, 1 mg, white, triangular-shaped tablets marked"Rapamune 1 mg” on one side; bottle containing 100 tablets. - NDC 0008-1041-10, 1 mg, white, triangular-shaped tablets marked“RAPAMUNE 1 mg” on one side; in Redipak® cartons of 100 tablets (10 blister cards of 10 tablets each). - NDC 0008-1042-05, 2 mg, yellow-to-beige triangular-shaped tablets marked “ Rapamune 2 mg” on one side; bottle containing 100 tablets. ## Storage - Rapamune Tablets should be stored at 20° to 25°C [USP Controlled Room Temperature] (68° to 77°F). Use cartons to protect blister cards and strips from light. Dispense in a tight, light-resistant container as defined in the USP. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Patients should be given complete dosage instructions. - Patients should be told that exposure to sunlight and ultraviolet (UV) light should be limited by wearing protective clothing and using a sunscreen with a high protection factor because of the increased risk for skin cancer. - Women of childbearing potential should be informed of the potential risks during pregnancy and told that they should use effective contraception prior to initiation of sirolimus therapy, during sirolimus therapy, and for 12 weeks after sirolimus therapy has been stopped. # Precautions with Alcohol - Alcohol-Sirolimus interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Rapamune ®[1] # Look-Alike Drug Names There is limited information regarding Sirolimus Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Rapamune
94e3e1a30955bbd77efde98d7243a7eb5f3c005c	wikidoc	Raspberry	Raspberry The raspberry (plural, raspberries) is the edible fruit of a number of species of the genus Rubus. The name originally refers in particular to the European species Rubus idaeus, and is still used for that species as its standard English name in its native area. Other species, mostly closely related in the same subgenus Idaeobatus, also called raspberries subsequently include: - Rubus strigosus (American Raspberry) (syn. R. idaeus var. strigosus) - Rubus arcticus (Arctic Raspberry) - Rubus crataegifolius (Korean Raspberry) - Rubus occidentalis (Black Raspberry) - Rubus odoratus (Flowering Raspberry) - Rubus phoenicolasius (Wine Raspberry) - Rubus leucodermis (Whitebark or Western Raspberry, native: Blue Raspberry) Raspberries are an important commercial fruit crop, widely grown in all temperate regions of the world. Many of the most important modern commercial raspberry cultivars derive from hybrids between R. idaeus and R. strigosus. # Cultivation Raspberries are grown for the fresh fruit market and for commercial processing into individually quick frozen (IQF) fruit, purée, juice, or as dried fruit used in a variety of grocery products. Traditionally, raspberries were a mid-summer crop, but with new technology, cultivars and transportation, they can now be obtained year-round. Raspberries need ample sun and water for optimal development. While moisture is essential, wet and heavy soils or excess irrigation can bring on Phytophthora root rot which is one of the most serious pest problems facing red raspberry. As a cultivated plant in moist temperate regions, it is easy to grow and has a tendency to spread unless pruned. Escaped raspberries frequently appear as garden weeds, spread by seeds found in bird droppings. Two types are commercially available, the wild-type summer bearing, that produces an abundance of fruit on second-year canes (floricanes) within a relatively short period in mid-summer, and double- or "ever"-bearing plants, which also bear some fruit on first-year canes (primocanes) in the late summer and fall, as well as the summer crop on second-year canes. Raspberries can be cultivated from hardiness zones 3 to 9. Raspberries are traditionally planted in the winter as dormant canes, although planting of tender, plug plants from tissue culture produced plants has become much more common. A specialized production system called "long cane production" involves growing canes for 1 year in a northern climate such as Scotland (UK) or Washington State (US) where the chilling requirement for proper budbreak is met early. These canes are then dug, roots and all, to be replanted in warmer climates such as Spain where they quickly flower and produce a very early season crop. Plants should be spaced 1 m apart in fertile, well drained soil; raspberries are usually planted in raised beds/ridges if there is any question about root rot problems. The flowers can be a major nectar source for honeybees. Raspberries are very vigorous and can be invasive. They propagate using basal shoots (also known as suckers); extended underground shoots that develop roots and individual plants. They can sucker new canes some distance from the main plant. For this reason, raspberries spread well, and can take over gardens if left unchecked. The fruit is harvested when it has turned a deep red and comes off the torus/receptacle easily. This is when the fruits are most ripe and sweetest. Excess fruit can be made into raspberry jam or frozen. The leaves can be used fresh or dried in herbal and medicinal teas. They have an astringent flavour, and in herbal medicine are reputed to be effective in regulating menses. Each raspberry weigh about 4 g each on the average and is made up of around 100 drupelets, which consist of a juicy pulp and a single tiny seed in the center. Raspberry bushes can yield several pounds of fruit (or several hundred berries) a year. Unlike blackberries, raspberries have a hollow core once it is removed from the receptacle. ## Cultivars Numerous cultivars have been selected. Recent breeding has resulted in cultivars that are thornless and more strongly upright, not needing staking. Raspberries have been crossed with black raspberry (Rubus occidentalis) to produce purple raspberies and with species in other subgenera of the genus Rubus, resulting in a number of hybrids, such as boysenberry and loganberry. Cultivars with yellow fruit are sometimes termed "golden raspberry". ## Selected important cultivars Reference: # Nutrients and potential health benefits Raspberries contain significant amounts of polyphenol antioxidants such as anthocyanin pigments linked to potential health protection against several human diseases. The aggregate fruit structure contributes to its nutritional value, as it increases the proportion of dietary fiber, placing it among plant foods with the highest fiber contents known, up to 20% fiber per total weight. Raspberries are a rich source of vitamin C, with 30 mg per serving of 1 cup (about 50% daily value), manganese (about 60% daily value) and dietary fiber (30% daily value). Contents of B vitamins 1-3, folic acid, magnesium, copper and iron are considerable in raspberries. Raspberries rank near the top of all fruits for antioxidant strength, particularly due to their dense contents of ellagic acid (from ellagotannins), quercetin, gallic acid, anthocyanins, cyanidins, pelargonidins, catechins, kaempferol and salicylic acid. All these are polyphenolic antioxidants with promising health benefits under current research. Due to their rich contents of antioxidant vitamin C and the polyphenols mentioned above, raspberries have an ORAC value (oxygen radical absorbance capacity) of about 4900 per 100 grams, including them among the top-ranked ORAC fruits. Cranberries and wild blueberries have around 9000 ORAC units and apples average 2800. The following anti-disease properties have been isolated in experimental models. Although there are no clinical studies to date proving these effects in humans, preliminary medical research shows likely benefit of regularly consuming raspberries against: - inflammation - pain - cancer - cardiovascular disease - diabetes - allergies - age-related cognitive decline - degeneration of eyesight with aging # Diseases and pests Raspberries are sometimes eaten by the larvae of some Lepidoptera species (butterflies and moths). See list of Lepidoptera that feed on Rubus.	Raspberry The raspberry (plural, raspberries) is the edible fruit of a number of species of the genus Rubus. The name originally refers in particular to the European species Rubus idaeus, and is still used for that species as its standard English name in its native area.[1] Other species, mostly closely related in the same subgenus Idaeobatus, also called raspberries subsequently include: - Rubus strigosus (American Raspberry) (syn. R. idaeus var. strigosus) - Rubus arcticus (Arctic Raspberry) - Rubus crataegifolius (Korean Raspberry) - Rubus occidentalis (Black Raspberry) - Rubus odoratus (Flowering Raspberry) - Rubus phoenicolasius (Wine Raspberry) - Rubus leucodermis (Whitebark or Western Raspberry, native: Blue Raspberry) Raspberries are an important commercial fruit crop, widely grown in all temperate regions of the world. Many of the most important modern commercial raspberry cultivars derive from hybrids between R. idaeus and R. strigosus.[2] # Cultivation Raspberries are grown for the fresh fruit market and for commercial processing into individually quick frozen (IQF) fruit, purée, juice, or as dried fruit used in a variety of grocery products. Traditionally, raspberries were a mid-summer crop, but with new technology, cultivars and transportation, they can now be obtained year-round. Raspberries need ample sun and water for optimal development. While moisture is essential, wet and heavy soils or excess irrigation can bring on Phytophthora root rot which is one of the most serious pest problems facing red raspberry. As a cultivated plant in moist temperate regions, it is easy to grow and has a tendency to spread unless pruned. Escaped raspberries frequently appear as garden weeds, spread by seeds found in bird droppings. Two types are commercially available, the wild-type summer bearing, that produces an abundance of fruit on second-year canes (floricanes) within a relatively short period in mid-summer, and double- or "ever"-bearing plants, which also bear some fruit on first-year canes (primocanes) in the late summer and fall, as well as the summer crop on second-year canes. Raspberries can be cultivated from hardiness zones 3 to 9. Raspberries are traditionally planted in the winter as dormant canes, although planting of tender, plug plants from tissue culture produced plants has become much more common. A specialized production system called "long cane production" involves growing canes for 1 year in a northern climate such as Scotland (UK) or Washington State (US) where the chilling requirement for proper budbreak is met early. These canes are then dug, roots and all, to be replanted in warmer climates such as Spain where they quickly flower and produce a very early season crop. Plants should be spaced 1 m apart in fertile, well drained soil; raspberries are usually planted in raised beds/ridges if there is any question about root rot problems. The flowers can be a major nectar source for honeybees. Raspberries are very vigorous and can be invasive. They propagate using basal shoots (also known as suckers); extended underground shoots that develop roots and individual plants. They can sucker new canes some distance from the main plant. For this reason, raspberries spread well, and can take over gardens if left unchecked. The fruit is harvested when it has turned a deep red and comes off the torus/receptacle easily. This is when the fruits are most ripe and sweetest. Excess fruit can be made into raspberry jam or frozen. The leaves can be used fresh or dried in herbal and medicinal teas. They have an astringent flavour, and in herbal medicine are reputed to be effective in regulating menses. Each raspberry weigh about 4 g each on the average [3] and is made up of around 100 drupelets, [4] which consist of a juicy pulp and a single tiny seed in the center. Raspberry bushes can yield several pounds of fruit (or several hundred berries) a year. Unlike blackberries, raspberries have a hollow core once it is removed from the receptacle. ## Cultivars Numerous cultivars have been selected. Recent breeding has resulted in cultivars that are thornless and more strongly upright, not needing staking. Raspberries have been crossed with black raspberry (Rubus occidentalis) to produce purple raspberies and with species in other subgenera of the genus Rubus, resulting in a number of hybrids, such as boysenberry and loganberry. Cultivars with yellow fruit are sometimes termed "golden raspberry". ## Selected important cultivars Reference:[2] # Nutrients and potential health benefits Raspberries contain significant amounts of polyphenol antioxidants such as anthocyanin pigments linked to potential health protection against several human diseases[5]. The aggregate fruit structure contributes to its nutritional value, as it increases the proportion of dietary fiber, placing it among plant foods with the highest fiber contents known, up to 20% fiber per total weight. Raspberries are a rich source of vitamin C, with 30 mg per serving of 1 cup (about 50% daily value), manganese (about 60% daily value) and dietary fiber (30% daily value). Contents of B vitamins 1-3, folic acid, magnesium, copper and iron are considerable in raspberries[6]. Raspberries rank near the top of all fruits for antioxidant strength, particularly due to their dense contents of ellagic acid (from ellagotannins), quercetin, gallic acid, anthocyanins, cyanidins, pelargonidins, catechins, kaempferol and salicylic acid. All these are polyphenolic antioxidants with promising health benefits under current research[7]. Due to their rich contents of antioxidant vitamin C and the polyphenols mentioned above, raspberries have an ORAC value (oxygen radical absorbance capacity) of about 4900 per 100 grams, including them among the top-ranked ORAC fruits. Cranberries and wild blueberries have around 9000 ORAC units and apples average 2800[8]. The following anti-disease properties have been isolated in experimental models. Although there are no clinical studies to date proving these effects in humans, preliminary medical research shows likely benefit of regularly consuming raspberries against:[9][10][11][12] - inflammation - pain - cancer - cardiovascular disease - diabetes - allergies - age-related cognitive decline - degeneration of eyesight with aging # Diseases and pests Template:Sect-stub Raspberries are sometimes eaten by the larvae of some Lepidoptera species (butterflies and moths). See list of Lepidoptera that feed on Rubus.	https://www.wikidoc.org/index.php/Raspberry
706ab45b3907a44f59b03c6e5eeca3d377ae3f88	wikidoc	reCAPTCHA	reCAPTCHA reCAPTCHA is the process of utilizing CAPTCHA to improve the process of digitizing books. It takes scanned words that optical character recognition software reported undetectable and presents them for humans to decipher as CAPTCHA words alongside words recognized by the computer. # How it works In order to verify that humans can decipher these previously undetectable words correctly, two words are displayed instead of the standard one word. One of these words is generated in the usual CAPTCHA form, and only the other word is undetectable. If the users solve the usual test for the first word, it is assumed that they were also correct about the other previously undetected word. Nevertheless, more than one user has to verify the other word in order for it to be considered truly solved. # How it is provided reCAPTCHA tests are taken from the central site of the reCAPTCHA project as they are supplying the undetected words. This is done through a Javascript API with the server making a callback to reCAPTCHA after the request has been submitted. The reCAPTCHA project provides libraries for various programming languages and applications to make this process easier. reCAPTCHA is a free service, except for users who would require a prohibitive amount of bandwidth. # Notes - ↑ The reCAPTCHA project - part of the Carnegie Mellon School of Computer Science at Carnegie Mellon University. - reCAPTCHA has the same goal as Distributed Proofreaders, though DP uses conventional proofreaders - reCAPTCHA press release: "May 24: Carnegie Mellon Project Boosts Book Digitization Efforts - Carnegie Mellon University". Retrieved 2007-06-23..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} - Spam weapon helps preserve books — BBC news report by Paul Rubens, 2007-10-02.	reCAPTCHA reCAPTCHA is the process of utilizing CAPTCHA to improve the process of digitizing books. It takes scanned words that optical character recognition software reported undetectable and presents them for humans to decipher as CAPTCHA words alongside words recognized by the computer. # How it works In order to verify that humans can decipher these previously undetectable words correctly, two words are displayed instead of the standard one word. One of these words is generated in the usual CAPTCHA form, and only the other word is undetectable. If the users solve the usual test for the first word, it is assumed that they were also correct about the other previously undetected word. Nevertheless, more than one user has to verify the other word in order for it to be considered truly solved. # How it is provided reCAPTCHA tests are taken from the central site of the reCAPTCHA project[1] as they are supplying the undetected words. This is done through a Javascript API with the server making a callback to reCAPTCHA after the request has been submitted. The reCAPTCHA project provides libraries for various programming languages and applications to make this process easier. reCAPTCHA is a free service, except for users who would require a prohibitive amount of bandwidth. # Notes - ↑ The reCAPTCHA project - part of the Carnegie Mellon School of Computer Science at Carnegie Mellon University. - reCAPTCHA has the same goal as Distributed Proofreaders, though DP uses conventional proofreaders - reCAPTCHA press release: "May 24: Carnegie Mellon Project Boosts Book Digitization Efforts - Carnegie Mellon University". Retrieved 2007-06-23..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} - Spam weapon helps preserve books — BBC news report by Paul Rubens, 2007-10-02. # External links - The reCAPTCHA project de:Captcha#Weiterentwicklung sk:ReCAPTCHA	https://www.wikidoc.org/index.php/ReCAPTCHA
d7c59bec86f7b073836968d2c5ba4a670d8b229c	wikidoc	Recoverin	Recoverin Recoverin (abbreviated Recov) is a 23 kilodalton (kDa) neuronal calcium-binding protein that is primarily detected in the photoreceptor cells of the eye . It plays a key role in the inhibition of rhodopsin kinase, a molecule which regulates the phosphorylation of rhodopsin. A reduction in this inhibition helps regulate sensory adaptation in the retina, since the light-dependent channel closure in photoreceptors causes calcium levels to decrease, which relieves the inhibition of rhodopsin kinase by calcium-bound recoverin, leading to a more rapid inactivation of metarhodopsin II (activated form of rhodopsin). # Structure & Function Recoverin is involved in the recovery phase of visual excitation and in adaptation to background light. It controls the life span of photoexcited rhodopsin by helping to inhibit rhodopsin kinase. An image of bovine recoverin with 3.00 Å resolution is shown. This three-dimensional structure was determined by X-ray diffraction. Covalently attached at the amino-terminal of recoverin is a myristoyl group. When the protein binds calcium ions, it undergoes a conformational change and brings out the myristoyl group from the binding portion so that the group is able to either interact with the target or the protein can move to a different region. When recoverin is not bound to calcium, it stays in cytosol. When recoverin binds calcium, it migrates to the disc membrane and is embedded into the membrane using the myristoyl group to anchor itself. This calcium-bound form of recoverin slows the activity of rhodopsin kinase, resulting in the prolongation of light sensitivity for rhodopsin. Recent publications point out additional functions for recoverin. For instance, it goes through a light-dependent intracellular translocation to rod synaptic terminals and improves the signal transfer between rods and rod bipolar cells in the retina of mice. In humans, the recoverin protein is encoded by the RCVRN gene.	Recoverin Recoverin (abbreviated Recov) is a 23 kilodalton (kDa) neuronal calcium-binding protein that is primarily detected in the photoreceptor cells of the eye [1]. It plays a key role in the inhibition of rhodopsin kinase, a molecule which regulates the phosphorylation of rhodopsin[2]. A reduction in this inhibition helps regulate sensory adaptation in the retina, since the light-dependent channel closure in photoreceptors causes calcium levels to decrease, which relieves the inhibition of rhodopsin kinase by calcium-bound recoverin, leading to a more rapid inactivation of metarhodopsin II (activated form of rhodopsin). # Structure & Function Recoverin is involved in the recovery phase of visual excitation and in adaptation to background light.[3] It controls the life span of photoexcited rhodopsin by helping to inhibit rhodopsin kinase.[4] An image of bovine recoverin with 3.00 Å resolution is shown.[5] This three-dimensional structure was determined by X-ray diffraction. Covalently attached at the amino-terminal of recoverin is a myristoyl group.[3] When the protein binds calcium ions, it undergoes a conformational change and brings out the myristoyl group from the binding portion so that the group is able to either interact with the target or the protein can move to a different region.[3] When recoverin is not bound to calcium, it stays in cytosol. When recoverin binds calcium, it migrates to the disc membrane and is embedded into the membrane using the myristoyl group to anchor itself. This calcium-bound form of recoverin slows the activity of rhodopsin kinase, resulting in the prolongation of light sensitivity for rhodopsin.[3] Recent publications point out additional functions for recoverin. For instance, it goes through a light-dependent intracellular translocation to rod synaptic terminals and improves the signal transfer between rods and rod bipolar cells in the retina of mice.[5] In humans, the recoverin protein is encoded by the RCVRN gene.[1]	https://www.wikidoc.org/index.php/Recoverin
0c3d35cfc431c4221a7284902307fbec3ffdf81d	wikidoc	Red Alder	Red Alder Red Alder (Alnus rubra) is a deciduous tree native to western North America, from southeast Alaska south to central coastal California, nearly always within about 200 km of the Pacific coast, except for an extension 600 km inland across northern Washington into northernmost Idaho. It is the world's largest species of alder, reaching heights of 20-35 m. The official tallest Red Alder (1979) stands 32 meters tall in Clatsop County, Oregon (USA). The name derives from the bright rusty red color that develops in bruised or scraped bark. Red Alder has ovate leaves 7-15 cm long, with bluntly serrated edges and a distinct point at the end. The leaves turn yellow in the autumn before falling. The bark is mottled, ashy-gray and smooth, often draped with moss. The male flowers are dangling reddish catkins 10-15 cm long in early spring, and female flowers are erect catkins which develop into small, woody, superficially cone-like oval dry fruit 2-3 cm long. The seeds develop between the woody bracts of the 'cones' and are shed in the autumn and winter. In the northwestern Coast Ranges of the USA, Red Alder grows on cool and moist slopes; inland and at the southern end of its range (California) it grows mostly along streams and in swamps. It is associated with Douglas-fir Pseudotsuga menziesii, Western Hemlock Tsuga heterophylla, Grand Fir Abies grandis, Western Redcedar Thuja plicata, and Sitka Spruce Picea sitchensis forests. Along streambanks it is commonly associated with willows Salix spp., Red Osier Dogwood Cornus stolonifera, Oregon Ash Fraxinus latifolia and Bigleaf Maple Acer macrophyllum. In the high mountains it is replaced by the smaller Sitka Alder Alnus viridis subsp. sinuata, and east of the Cascade Mountains by Thinleaf Alder Alnus incana subsp. tenuifolia. In moist forest areas Red Alder will rapidly cover a former burn or clearcut, temporarily preventing the growth of conifers but also improving soil fertility for future growth of conifers. It is a prolific seed producer, but the seeds require an open area of mineral soil to germinate, and so skid trails and other areas disturbed by logging or fire are ideal seedbeds. Such areas may host several hundred thousand to several million seedlings per hectare in the first year after landscape disturbance (Zavitkovski & Stevens 1972). Twigs and buds of alder are only fair browse for wildlife, though deer and elk do browse the twigs in fall and twigs and buds in the winter and spring. Beavers eat the bark. Several finches eat alder seeds, notably Common Redpoll and Pine Siskin, and as do deer mice. Red Alder is also very valuable for playing host to the nitrogen fixing actinomycete Frankia. It is this ability which allows alder to grow in nitrate-poor soils. ## Uses and cultivation A russet dye can be made from a decoction of the bark and was used by Native Americans to dye fishing nets so as to make them less visible underwater. Red Alder is an important forestry tree. Its rapid growth makes it useful in covering disturbed land, such as mine spoils. Alder leaves, shed in the fall, decay readily to form a nitrogen-enriched humus. It is being considered as a rotation crop to discourage the conifer root pathogen Phellinus weirii (Laminated root rot). The vigorous growth has in the past earned it the designation of a "trash tree" by the timber industry. Herbicide spraying of Red Alder over large areas of coastal Oregon and Washington has resulted in a number of lawsuits claiming it caused health problems, including birth defects and other side effects. The increased value of the wood, combined with a better understanding of the species' benefits to other trees, has largely led to a cessation of this practice. The wood is not durable in outdoor use but due to its workability and ease of finishing it is increasingly in use for furniture and cabinetry. Historically it has not been considered of high value for timber but it is now becoming one of the western USA's more important hardwoods. Alder wood ranges from white through pinkish to light brown, is relatively soft, and has medium luster. It is easily worked, glues well, and takes a good finish. Red Alders are not commonly planted as ornamental trees but will do well in wet swales or on stream banks. If used domestically they should be planted well away from drainpipes, sewage pipes, and water lines, as the roots may well invade and clog the lines. Red Alders are also famed for growing easily in burned or destroyed land, and are used as "pioneering" or "reclamation" trees. # References and external links - Zavitkovski, J. & Stevens, R. D. (1972). Primary productivity of red alder ecosystems. Ecology 53(2): 235-242. - Flora of North America - Distribution Map (at Flora of North America): - NRCS: USDA Plants Profile:	Red Alder Template:Globalize/USA Red Alder (Alnus rubra) is a deciduous tree native to western North America, from southeast Alaska south to central coastal California, nearly always within about 200 km of the Pacific coast, except for an extension 600 km inland across northern Washington into northernmost Idaho. It is the world's largest species of alder, reaching heights of 20-35 m. The official tallest Red Alder (1979) stands 32 meters tall in Clatsop County, Oregon (USA). The name derives from the bright rusty red color that develops in bruised or scraped bark. Red Alder has ovate leaves 7-15 cm long, with bluntly serrated edges and a distinct point at the end. The leaves turn yellow in the autumn before falling. The bark is mottled, ashy-gray and smooth, often draped with moss. The male flowers are dangling reddish catkins 10-15 cm long in early spring, and female flowers are erect catkins which develop into small, woody, superficially cone-like oval dry fruit 2-3 cm long. The seeds develop between the woody bracts of the 'cones' and are shed in the autumn and winter. In the northwestern Coast Ranges of the USA, Red Alder grows on cool and moist slopes; inland and at the southern end of its range (California) it grows mostly along streams and in swamps. It is associated with Douglas-fir Pseudotsuga menziesii, Western Hemlock Tsuga heterophylla, Grand Fir Abies grandis, Western Redcedar Thuja plicata, and Sitka Spruce Picea sitchensis forests. Along streambanks it is commonly associated with willows Salix spp., Red Osier Dogwood Cornus stolonifera, Oregon Ash Fraxinus latifolia and Bigleaf Maple Acer macrophyllum. In the high mountains it is replaced by the smaller Sitka Alder Alnus viridis subsp. sinuata, and east of the Cascade Mountains by Thinleaf Alder Alnus incana subsp. tenuifolia. In moist forest areas Red Alder will rapidly cover a former burn or clearcut, temporarily preventing the growth of conifers but also improving soil fertility for future growth of conifers. It is a prolific seed producer, but the seeds require an open area of mineral soil to germinate, and so skid trails and other areas disturbed by logging or fire are ideal seedbeds. Such areas may host several hundred thousand to several million seedlings per hectare in the first year after landscape disturbance (Zavitkovski & Stevens 1972). Twigs and buds of alder are only fair browse for wildlife, though deer and elk do browse the twigs in fall and twigs and buds in the winter and spring. Beavers eat the bark. Several finches eat alder seeds, notably Common Redpoll and Pine Siskin, and as do deer mice. Red Alder is also very valuable for playing host to the nitrogen fixing actinomycete Frankia. It is this ability which allows alder to grow in nitrate-poor soils. ## Uses and cultivation A russet dye can be made from a decoction of the bark and was used by Native Americans to dye fishing nets so as to make them less visible underwater. Red Alder is an important forestry tree. Its rapid growth makes it useful in covering disturbed land, such as mine spoils. Alder leaves, shed in the fall, decay readily to form a nitrogen-enriched humus. It is being considered as a rotation crop to discourage the conifer root pathogen Phellinus weirii (Laminated root rot). The vigorous growth has in the past earned it the designation of a "trash tree" by the timber industry. Herbicide spraying of Red Alder over large areas of coastal Oregon and Washington has resulted in a number of lawsuits claiming it caused health problems, including birth defects and other side effects. The increased value of the wood, combined with a better understanding of the species' benefits to other trees, has largely led to a cessation of this practice. The wood is not durable in outdoor use but due to its workability and ease of finishing it is increasingly in use for furniture and cabinetry. Historically it has not been considered of high value for timber but it is now becoming one of the western USA's more important hardwoods. Alder wood ranges from white through pinkish to light brown, is relatively soft, and has medium luster. It is easily worked, glues well, and takes a good finish. Red Alders are not commonly planted as ornamental trees but will do well in wet swales or on stream banks. If used domestically they should be planted well away from drainpipes, sewage pipes, and water lines, as the roots may well invade and clog the lines. Red Alders are also famed for growing easily in burned or destroyed land, and are used as "pioneering" or "reclamation" trees. # References and external links - Zavitkovski, J. & Stevens, R. D. (1972). Primary productivity of red alder ecosystems. Ecology 53(2): 235-242. - Flora of North America - Distribution Map (at Flora of North America): - NRCS: USDA Plants Profile:	https://www.wikidoc.org/index.php/Red_Alder
3efe1e836eacedc8eee47ceab052c603922e65aa	wikidoc	Red giant	Red giant A red giant is a luminous giant star of low or intermediate mass that is in a late phase of its evolution. The core matter is electron degenerate and extremely compressed, so the outer atmosphere is inflated and tenuous, making the radius immense and the surface temperature low, somewhere from 5,000 K and lower. The appearance of the red giant is from yellow orange to red, including the spectral types K and M, but also class S stars and most carbon stars. The most common red giants are the so-called Red Giant Branch stars (RGB stars) whose shells are still fusing hydrogen, while the core is inactive helium. Another case of red giants of interest are the Asymptotic Giant Branch stars (AGB) that produces carbon by the triple-alpha process from helium. To the AGB stars belong the carbon stars of type C-N and late C-R. Prominent bright red giants in the night sky include Arcturus (Alpha Bootis), Aldebaran (Alpha Tauri), Pollux (Beta Geminorum), and Gamma Crucis (Gacrux). # Overview Red giants are evolved from main sequence stars with masses in the range from about 0.5 solar masses to somewhere between 4 and 6 solar masses . Red giants are stars with radii tens to hundreds of times larger than that of the Sun which have exhausted the supply of hydrogen in their cores and switched to fusing hydrogen in a shell outside the core. Since the inert helium core has no source of energy of its own, it contracts and heats up, and its gravity compresses the hydrogen in the layer immediately above it, thus causing it to fuse faster. This in turn causes the star to become more luminous (from 1,000 to 10,000 times brighter) and expand; the degree of expansion outstrips the increase in luminosity, thus causing the effective temperature to decrease. In stars massive enough to ignite helium fusion, an analogous process occurs when central helium is exhausted and the star switches to fusing helium in a shell, although with the additional complication that in many cases hydrogen fusion will continue in a shell at lesser depth — this puts stars onto the asymptotic giant branch. The decrease in surface temperature shifts the star's visible light output towards the red — hence red giant, even though the color usually is orange. Main sequence stars of spectral types A through K are believed to become red giants. Very low mass stars are thought to be fully convective and thus may not accumulate an inert core of helium, and thus may exhaust all of their fuel without ever becoming red giants. Such stars are commonly referred to as red dwarfs. The predicted lifespan of these stars is much larger than the current age of the universe, and hence there are no actual observations of these stars aging. Very high mass stars instead develop to supergiant stars that wander back and forth horizontally over the HR diagram, at the right end constituting red supergiants. These usually end their life as type II supernovae. If the star is heavier than 0.4 but less than 2.57 solar masses, the addition of helium to the core by shell hydrogen fusing will cause a helium flash — a rapid burst of helium fusing in the core, after which the star will commence a brief period of helium fusing before beginning another ascent of the red giant branch. Stars more massive than 2.5 solar masses, but less than about 4 to 6, enter the helium fusing phase of their lives much more smoothly. The core helium fusing phase of a star's life is called the horizontal branch in metal-poor stars, so named because these stars lie on a nearly horizontal line in the Hertzsprung-Russell diagram of many star clusters. Metal-rich helium-fusing stars do not lie on a horizontal branch, but instead lie in a clump (the red clump) in the Hertzsprung-Russell diagram. Actually, such stars are not big red spheres with sharp limbs (when one is close to it) as displayed on many images. Due to the very low density such stars may not have a sharp photosphere but a star body which gradually transfers into a 'corona'. # The Sun as a red giant The Sun is expected to become a red giant about 7.5 billion years from now. It is calculated that the Sun will become sufficiently large to engulf the current orbits of some of the solar system's inner planets, including Earth. However, the Sun will lose a significant fraction of its mass in the process of becoming a red giant, and all planets but Mercury and Venus are likely to escape as their resulting orbits will widen. Earth's fate is less clear. Earth could technically achieve a widening of its orbit and could potentially maintain a sufficiently high angular velocity to keep it from becoming engulfed. In order to do so, its orbit would increase to 1.7 AU (254,316,600 km). However the results of studies announced in 2008 show that due to tidal interaction between sun and Earth, Earth would actually fall back into a lower orbit, and get engulfed and incorporated inside the sun before sun reaches its largest size, despite the sun losing about 38% of its mass. Before this happens; Earth's biosphere will have long been destroyed by the Sun's steady increase in brightness as its hydrogen supply dwindles and its core contracts, even before the transition to a Red Giant. After just over 1 billion years, the extra solar energy input will cause Earth's oceans to start evaporating and the hydrogen from the water to be lost permanently to space, with total loss of water by 3.5 billion years. Earth's atmosphere and lithosphere will become like that of Venus. Over another billion years, most of the atmosphere will get lost in space as well;, ultimately leaving Earth as a dessicated, dead planet with a surface of molten rock.	Red giant A red giant is a luminous giant star of low or intermediate mass that is in a late phase of its evolution. The core matter is electron degenerate and extremely compressed, so the outer atmosphere is inflated and tenuous, making the radius immense and the surface temperature low, somewhere from 5,000 K and lower. The appearance of the red giant is from yellow orange to red, including the spectral types K and M, but also class S stars and most carbon stars. The most common red giants are the so-called Red Giant Branch stars (RGB stars) whose shells are still fusing hydrogen, while the core is inactive helium. Another case of red giants of interest are the Asymptotic Giant Branch stars (AGB) that produces carbon by the triple-alpha process from helium. To the AGB stars belong the carbon stars of type C-N and late C-R. Prominent bright red giants in the night sky include Arcturus (Alpha Bootis), Aldebaran (Alpha Tauri), Pollux (Beta Geminorum), and Gamma Crucis (Gacrux). # Overview Red giants are evolved from main sequence stars with masses in the range from about 0.5 solar masses to somewhere between 4 and 6 solar masses [1]. Red giants are stars with radii tens to hundreds of times larger than that of the Sun which have exhausted the supply of hydrogen in their cores and switched to fusing hydrogen in a shell outside the core. Since the inert helium core has no source of energy of its own, it contracts and heats up, and its gravity compresses the hydrogen in the layer immediately above it, thus causing it to fuse faster. This in turn causes the star to become more luminous (from 1,000 to 10,000 times brighter) and expand; the degree of expansion outstrips the increase in luminosity, thus causing the effective temperature to decrease. In stars massive enough to ignite helium fusion, an analogous process occurs when central helium is exhausted and the star switches to fusing helium in a shell, although with the additional complication that in many cases hydrogen fusion will continue in a shell at lesser depth — this puts stars onto the asymptotic giant branch.[2][3] The decrease in surface temperature shifts the star's visible light output towards the red — hence red giant, even though the color usually is orange. Main sequence stars of spectral types A through K are believed to become red giants. [4] Very low mass stars are thought to be fully convective[5] and thus may not accumulate an inert core of helium, and thus may exhaust all of their fuel without ever becoming red giants. [6] Such stars are commonly referred to as red dwarfs. The predicted lifespan of these stars is much larger than the current age of the universe, and hence there are no actual observations of these stars aging. Very high mass stars instead develop to supergiant stars that wander back and forth horizontally over the HR diagram, at the right end constituting red supergiants. These usually end their life as type II supernovae. If the star is heavier than 0.4 but less than 2.57 solar masses, the addition of helium to the core by shell hydrogen fusing will cause a helium flash — a rapid burst of helium fusing in the core, after which the star will commence a brief period of helium fusing before beginning another ascent of the red giant branch. Stars more massive than 2.5 solar masses, but less than about 4 to 6, enter the helium fusing phase of their lives much more smoothly. The core helium fusing phase of a star's life is called the horizontal branch in metal-poor stars, so named because these stars lie on a nearly horizontal line in the Hertzsprung-Russell diagram of many star clusters. Metal-rich helium-fusing stars do not lie on a horizontal branch, but instead lie in a clump (the red clump) in the Hertzsprung-Russell diagram.[7] Actually, such stars are not big red spheres with sharp limbs (when one is close to it) as displayed on many images. Due to the very low density such stars may not have a sharp photosphere but a star body which gradually transfers into a 'corona'.[8] [9] # The Sun as a red giant The Sun is expected to become a red giant about 7.5 billion years from now.[10] It is calculated that the Sun will become sufficiently large to engulf the current orbits of some of the solar system's inner planets, including Earth.[11][12][13] However, the Sun will lose a significant fraction of its mass in the process of becoming a red giant, and all planets but Mercury and Venus are likely to escape as their resulting orbits will widen. [14] Earth's fate is less clear. Earth could technically achieve a widening of its orbit and could potentially maintain a sufficiently high angular velocity to keep it from becoming engulfed. In order to do so, its orbit would increase to 1.7 AU (254,316,600 km). However the results of studies announced in 2008 show that due to tidal interaction between sun and Earth, Earth would actually fall back into a lower orbit, and get engulfed and incorporated inside the sun before sun reaches its largest size, despite the sun losing about 38% of its mass. [15] Before this happens; Earth's biosphere will have long been destroyed by the Sun's steady increase in brightness as its hydrogen supply dwindles and its core contracts, even before the transition to a Red Giant. After just over 1 billion years, the extra solar energy input will cause Earth's oceans to start evaporating and the hydrogen from the water to be lost permanently to space, with total loss of water by 3.5 billion years.[16] Earth's atmosphere and lithosphere will become like that of Venus. Over another billion years, most of the atmosphere will get lost in space as well;[17], ultimately leaving Earth as a dessicated, dead planet with a surface of molten rock.[18]	https://www.wikidoc.org/index.php/Red_giant
10969107e6b2c5a901651597bd5e7d8f491562b7	wikidoc	Rehmannia	Rehmannia Rehmannia is a genus of six species of flowering plants in the order Lamiales, endemic to China. The genus was included in the family Scrophulariaceae or Gesneriaceae in some older classifications. The current placement of the genus is uncertain; it belongs to neither Scrophulariaceae s.s. nor Plantaginaceae s.l. (to which many other former Scrophulariaceae have been transferred), nor does it seem to belong with any of the other major clades of Lamiales. Molecular studies suggest that its closest relatives are the genera Lancea and Mazus (Oxelman et al., 2005), which have been included in Phrymaceae (Beardsley & Olmstead, 2002). Sometimes known as Chinese Foxglove due to its superficial resemblance to the genus Digitalis, the species of Rehmannia are perennial herbs. The plants have large flowers and are grown as ornamental garden plants in Europe and North America, and are used medicinally in Asia. Known as dìhuáng (地黄) or gān dìhuáng (干地黄) in Chinese, R. glutinosa is used as a medicinal herb for a variety of ailments such as anemia, dizziness and constipation. Rehmannia contains the vitamins A, B, C, and D, as well as other useful compounds. The name "Rehmannia" has also been given to a genus of Jurassic ammonites belonging to the Reineckeidae family. # Selected species - Rehmannia chingii - Rehmannia elata - Rehmannia glutinosa - Rehmannia henryi - Rehmannia piasezkii - Rehmannia solanifolia	Rehmannia Rehmannia is a genus of six species of flowering plants in the order Lamiales, endemic to China. The genus was included in the family Scrophulariaceae or Gesneriaceae in some older classifications. The current placement of the genus is uncertain; it belongs to neither Scrophulariaceae s.s. nor Plantaginaceae s.l. (to which many other former Scrophulariaceae have been transferred), nor does it seem to belong with any of the other major clades of Lamiales. Molecular studies suggest that its closest relatives are the genera Lancea and Mazus (Oxelman et al., 2005), which have been included in Phrymaceae (Beardsley & Olmstead, 2002). Sometimes known as Chinese Foxglove due to its superficial resemblance to the genus Digitalis, the species of Rehmannia are perennial herbs. The plants have large flowers and are grown as ornamental garden plants in Europe and North America, and are used medicinally in Asia. Known as dìhuáng (地黄) or gān dìhuáng (干地黄) in Chinese, R. glutinosa is used as a medicinal herb for a variety of ailments such as anemia, dizziness and constipation. Rehmannia contains the vitamins A, B, C, and D, as well as other useful compounds. The name "Rehmannia" has also been given to a genus of Jurassic ammonites belonging to the Reineckeidae family. # Selected species - Rehmannia chingii - Rehmannia elata - Rehmannia glutinosa - Rehmannia henryi - Rehmannia piasezkii - Rehmannia solanifolia	https://www.wikidoc.org/index.php/Rehmannia
10dbb1b7b14270fd1e0233643392061c6e8b9dca	wikidoc	Zanamivir	Zanamivir # 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 Zanamivir is a antiviral agent that is FDA approved for the treatment of influenza and prophylaxis of influenza. Common adverse reactions include sinusitis, dizziness, fever and/or chills, arthralgia and articular rheumatism. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - RELENZA is indicated for prophylaxis of influenza in adults and pediatric patients aged 5 years and older. - Dosing Information - Recommended for chemoprophylaxis of influenza in the United States for the 2012 to 2013 influenza season. - 10 mg (2 inhalations) ORALLY once daily for 7 days following exposure; for control of outbreaks in long-term care facilities and hospitals, take for a minimum of 2 weeks, continuing up to 1 week after the last known case OR 10 mg (2 inhalations) ORALLY once daily for 10 days following household exposure; for control of community outbreaks, take for 28 days. - RELENZA® (zanamivir) Inhalation Powder is indicated for treatment of uncomplicated acute illness due to influenza A and B virus in adults and pediatric patients aged 7 years and older who have been symptomatic for no more than 2 days. - Dosing Information - Recommended for treatment of influenza in the United States for the 2012 to 2013 influenza season. - 10 mg (2 inhalations) ORALLY every 12 hours for 5 days; initiate within 2 days of symptom onset and, when possible, administer 2 doses on day 1, at least 2 hours apart. Important Limitations on Use of RELENZA - RELENZA is not recommended for treatment or prophylaxis of influenza in individuals with underlying airways disease (such as asthma or chronic obstructive pulmonary disease) due to risk of serious bronchospasm. - RELENZA has not been proven effective for treatment of influenza in individuals with underlying airways disease. - RELENZA has not been proven effective for prophylaxis of influenza in the nursing home setting. - RELENZA is not a substitute for early influenza vaccination on an annual basis as recommended by the Centers for Disease Control's Immunization Practices Advisory Committee. - Influenza viruses change over time. Emergence of resistance mutations could decrease drug effectiveness. Other factors (for example, changes in viral virulence) might also diminish clinical benefit of antiviral drugs. Prescribers should consider available information on influenza drug susceptibility patterns and treatment effects when deciding whether to use RELENZA. - There is no evidence for efficacy of zanamivir in any illness caused by agents other than influenza virus A and B. - Patients should be advised that the use of RELENZA for treatment of influenza has not been shown to reduce the risk of transmission of influenza to others. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Zanamivir in adult patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of Zanamivir in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Dosing Information - CDC Recommendations: - Zanamivir or oseltamivir is recommended for prophylaxis of influenza in the United States for the 2012 to 2013 influenza season, according to the CDC. - The recommended dose of zanamivir in children 5 years or older is 2 inhalations (5 mg/inhalation) orally once daily. The recommended duration of therapy is for 7 days following last known exposure. In adolescents, the recommended duration of therapy for control of influenza outbreaks in long-term care facilities and hospitals is a minimum of 2 weeks, continuing for up to 1 week after the last known case. For persons receiving zanamivir for antiviral prophylaxis following vaccination with inactivated influenza vaccination, the recommended duration of therapy is until immunity from vaccination develops (eg, antibody development in adults is about 2 weeks; however, it may take longer in children depending on age and vaccination history). Antiviral prophylaxis is generally not recommended if more than 48 hours has elapsed since exposure to an infectious person. - The recommended dose for prophylaxis of influenza (types A and B) in children 5 years or older in a household setting is 2 inhalations (5 mg/inhalation) orally once daily for 10 days. Give the dose at approximately the same time each day and administer under adult supervision and instruction. Data are lacking on the effectiveness of prophylaxis if initiated more than 36 hours after the onset of signs or symptoms. - The recommended dose for prophylaxis of influenza (types A and B) in adolescents in a community setting is 2 inhalations (5 mg/inhalation) orally once daily for 28 days. Give the dose at approximately the same time each day and administer under adult supervision and instruction. Data are lacking on the effectiveness of prophylaxis if initiated more than 36 hours after the onset of signs or symptoms. - Dosing Information - CDC Recommendations: - Oseltamivir or zanamivir should be used for the treatment of influenza in the United States for the 2012 to 2013 influenza season, according to the CDC. - The recommended dose for the treatment of influenza (types A and B) in children 7 years or older is 2 inhalations (5 mg per inhalation) orally twice daily for 5 days. Initiate treatment within 2 days after symptom onset. When possible, on the first day of treatment, administer 2 doses at least 2 hours apart. Administer subsequent doses 12 hours apart. Data are lacking on the effectiveness if treatment is initiated more than 2 days after the onset of signs or symptoms. Administer doses under adult supervision and instruction. - For those patients who remain severely ill following 5 days of treatment, longer treatment courses can be considered. - The safety and efficacy in the treatment of influenza have not been established in children under 7 years of age. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Zanamivir in pediatric patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of Zanamivir in pediatric patients. # Contraindications - Do not use in patients with history of allergic reaction to any ingredient of RELENZA including milk proteins. # Warnings Bronchospasm - RELENZA is not recommended for treatment or prophylaxis of influenza in individuals with underlying airways disease (such as asthma or chronic obstructive pulmonary disease). - Serious cases of bronchospasm, including fatalities, have been reported during treatment with RELENZA in patients with and without underlying airways disease. Many of these cases were reported during postmarketing and causality was difficult to assess. - RELENZA should be discontinued in any patient who develops bronchospasm or decline in respiratory function; immediate treatment and hospitalization may be required. - Some patients without prior pulmonary disease may also have respiratory abnormalities from acute respiratory infection that could resemble adverse drug reactions or increase patient vulnerability to adverse drug reactions. - Bronchospasm was documented following administration of zanamivir in 1 of 13 subjects with mild or moderate asthma (but without acute influenza-like illness) in a Phase I trial. In a Phase III trial in subjects with acute influenza-like illness superimposed on underlying asthma or chronic obstructive pulmonary disease, 10% (24 of 244) of subjects on zanamivir and 9% (22 of 237) on placebo experienced a greater than 20% decline in FEV1 following treatment for 5 days. - If use of RELENZA is considered for a patient with underlying airways disease, the potential risks and benefits should be carefully weighed. If a decision is made to prescribe RELENZA for such a patient, this should be done only under conditions of careful monitoring of respiratory function, close observation, and appropriate supportive care including availability of fast-acting bronchodilators. Allergic Reactions - Allergic-like reactions, including oropharyngeal edema, serious skin rashes, and anaphylaxis have been reported in postmarketing experience with RELENZA. RELENZA should be stopped and appropriate treatment instituted if an allergic reaction occurs or is suspected. Neuropsychiatric Events - Influenza can be associated with a variety of neurologic and behavioral symptoms which can include events such as seizures, hallucinations, delirium, and abnormal behavior, in some cases resulting in fatal outcomes. These events may occur in the setting of encephalitis or encephalopathy but can occur without obvious severe disease. - There have been postmarketing reports (mostly from Japan) of delirium and abnormal behavior leading to injury in patients with influenza who were receiving neuraminidase inhibitors, including RELENZA. Because these events were reported voluntarily during clinical practice, estimates of frequency cannot be made, but they appear to be uncommon based on usage data for RELENZA. These events were reported primarily among pediatric patients and often had an abrupt onset and rapid resolution. The contribution of RELENZA to these events has not been established. Patients with influenza should be closely monitored for signs of abnormal behavior. If neuropsychiatric symptoms occur, the risks and benefits of continuing treatment should be evaluated for each patient. Limitations of Populations Studied - Safety and efficacy have not been demonstrated in patients with high-risk underlying medical conditions. No information is available regarding treatment of influenza in patients with any medical condition sufficiently severe or unstable to be considered at imminent risk of requiring inpatient management. Bacterial Infections - Serious bacterial infections may begin with influenza-like symptoms or may coexist with or occur as complications during the course of influenza. RELENZA has not been shown to prevent such complications. Importance of Proper Route of Administration - RELENZA Inhalation Powder must not be made into an extemporaneous solution for administration by nebulization or mechanical ventilation. There have been reports of hospitalized patients with influenza who received a solution made with RELENZA Inhalation Powder administered by nebulization or mechanical ventilation, including a fatal case where it was reported that the lactose in this formulation obstructed the proper functioning of the equipment. RELENZA Inhalation Powder must only be administered using the device provided. Importance of Proper Use of DISKHALER - Effective and safe use of RELENZA requires proper use of the DISKHALER to inhale the drug. Prescribers should carefully evaluate the ability of young children to use the delivery system if use of RELENZA is considered. # Adverse Reactions ## Clinical Trials Experience - See Warnings and Precautions for information about risk of serious adverse events such as bronchospasm and allergic-like reactions, and for safety information in patients with underlying airways disease. 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 and may not reflect the rates observed in practice. - The placebo used in clinical trials consisted of inhaled lactose powder, which is also the vehicle for the active drug; therefore, some adverse events occurring at similar frequencies in different treatment groups could be related to lactose vehicle inhalation. - Treatment of Influenza: Clinical Trials in Adults and Adolescents: Adverse events that occurred with an incidence ≥1.5% in treatment trials are listed in Table 1. This table shows adverse events occurring in subjects aged 12 years and older receiving RELENZA 10 mg inhaled twice daily, RELENZA in all inhalation regimens, and placebo inhaled twice daily (where placebo consisted of the same lactose vehicle used in RELENZA). - Additional adverse reactions occurring in less than 1.5% of subjects receiving RELENZA included malaise, fatigue, fever, abdominal pain, myalgia, arthralgia, and urticaria. - The most frequent laboratory abnormalities in Phase III treatment trials included elevations of liver enzymes and CPK, lymphopenia, and neutropenia. These were reported in similar proportions of zanamivir and lactose vehicle placebo recipients with acute influenza-like illness. - Clinical Trials in Pediatric Subjects: Adverse events that occurred with an incidence ≥1.5% in children receiving treatment doses of RELENZA in 2 Phase III trials are listed in Table 2. This table shows adverse events occurring in pediatric subjects aged 5 to 12 years receiving RELENZA 10 mg inhaled twice daily and placebo inhaled twice daily (where placebo consisted of the same lactose vehicle used in RELENZA). - In 1 of the 2 trials described in Table 2, some additional information is available from children (aged 5 to 12 years) without acute influenza-like illness who received an investigational prophylaxis regimen of RELENZA; 132 children received RELENZA and 145 children received placebo. Among these children, nasal signs and symptoms (zanamivir 20%, placebo 9%), cough (zanamivir 16%, placebo 8%), and throat/tonsil discomfort and pain (zanamivir 11%, placebo 6%) were reported more frequently with RELENZA than placebo. In a subset with chronic pulmonary disease, lower respiratory adverse events (described as asthma, cough, or viral respiratory infections which could include influenza-like symptoms) were reported in 7 of 7 zanamivir recipients and 5 of 12 placebo recipients. - Prophylaxis of Influenza: Family/Household Prophylaxis Studies: Adverse events that occurred with an incidence of ≥1.5% in the 2 prophylaxis trials are listed in Table 3. This table shows adverse events occurring in subjects aged 5 years and older receiving RELENZA 10 mg inhaled once daily for 10 days. - Community Prophylaxis Trials: Adverse events that occurred with an incidence of ≥1.5% in 2 prophylaxis trials are listed in Table 4. This table shows adverse events occurring in subjects aged 5 years and older receiving RELENZA 10 mg inhaled once daily for 28 days. ## Postmarketing Experience - In addition to adverse events reported from clinical trials, the following events have been identified during postmarketing use of zanamivir (RELENZA). Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to zanamivir (RELENZA). - Allergic Reactions: Allergic or allergic-like reaction, including oropharyngeal edema. - Psychiatric: Delirium, including symptoms such as altered level of consciousness, confusion, abnormal behavior, delusions, hallucinations, agitation, anxiety, nightmares. - Cardiac: Arrhythmias, syncope. - Neurologic: Seizures. Vasovagal-like episodes have been reported shortly following inhalation of zanamivir. - Respiratory: Bronchospasm, dyspnea. - Skin: Facial edema; rash, including serious cutaneous reactions (e.g., erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis); urticaria. # Drug Interactions - Zanamivir is not a substrate nor does it affect cytochrome P450 (CYP) isoenzymes (CYP1A1/2, 2A6, 2C9, 2C18, 2D6, 2E1, and 3A4) in human liver microsomes. No clinically significant pharmacokinetic drug interactions are predicted based on data from in vitro studies. - The concurrent use of RELENZA with live attenuated influenza vaccine (LAIV) intranasal has not been evaluated. However, because of potential interference between these products, LAIV should not be administered within 2 weeks before or 48 hours after administration of RELENZA, unless medically indicated. The concern about possible interference arises from the potential for antiviral drugs to inhibit replication of live vaccine virus. - Trivalent inactivated influenza vaccine can be administered at any time relative to use of RELENZA. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Pregnancy Category C. There are no adequate and well-controlled studies of zanamivir in pregnant women. Zanamivir should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. - Embryo/fetal development studies were conducted in rats (dosed from days 6 to 15 of pregnancy) and rabbits (dosed from days 7 to 19 of pregnancy) using the same IV doses (1, 9, and 90 mg/kg/day). Pre- and post-natal developmental studies were performed in rats (dosed from day 16 of pregnancy until litter day 21 to 23). No malformations, maternal toxicity, or embryotoxicity were observed in pregnant rats or rabbits and their fetuses. Because of insufficient blood sampling timepoints in rat and rabbit reproductive toxicity studies, AUC values were not available. In a subchronic study in rats at the 90 mg/kg/day IV dose, the AUC values were greater than 300 times the human exposure at the proposed clinical dose. - An additional embryo/fetal study, in a different strain of rat, was conducted using subcutaneous administration of zanamivir, 3 times daily, at doses of 1, 9, or 80 mg/kg during days 7 to 17 of pregnancy. There was an increase in the incidence rates of a variety of minor skeleton alterations and variants in the exposed offspring in this study. Based on AUC measurements, the 80 mg/kg dose produced an exposure greater than 1,000 times the human exposure at the proposed clinical dose. However, in most instances, the individual incidence rate of each skeletal alteration or variant remained within the background rates of the historical occurrence in the strain studied. - Zanamivir has been shown to cross the placenta in rats and rabbits. In these animals, fetal blood concentrations of zanamivir were significantly lower than zanamivir concentrations in the maternal blood. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category - There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Zanamivir in women who are pregnant. ### Labor and Delivery - There is no FDA guidance on use of Zanamivir during labor and delivery. ### Nursing Mothers - Studies in rats have demonstrated that zanamivir is excreted in milk. However, nursing mothers should be instructed that it is not known whether zanamivir is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when RELENZA is administered to a nursing mother. ### Pediatric Use - Treatment of Influenza: Safety and effectiveness of RELENZA for treatment of influenza have not been assessed in pediatric patients younger than 7 years, but were studied in a Phase III treatment trial in pediatric subjects, where 471 children aged 5 to 12 years received zanamivir or placebo. Adolescents were included in the 3 principal Phase III adult treatment trials. In these trials, 67 patients were aged 12 to 16 years. No definite differences in safety and efficacy were observed between these adolescent patients and young adults. - In a Phase I trial of 16 children aged 6 to 12 years with signs and symptoms of respiratory disease, 4 did not produce a measurable peak inspiratory flow rate (PIFR) through the DISKHALER (3 with no adequate inhalation on request, 1 with missing data), 9 had measurable PIFR on each of 2 inhalations, and 3 achieved measurable PIFR on only 1 of 2 inhalations. Neither of two 6-year-olds and one of two 7-year-olds produced measurable PIFR. Overall, 8 of the 16 children (including all those younger than 8 years) either did not produce measurable inspiratory flow through the DISKHALER or produced peak inspiratory flow rates below the 60 L/min considered optimal for the device under standardized in vitro testing; lack of measurable flow rate was related to low or undetectable serum concentrations. Prescribers should carefully evaluate the ability of young children to use the delivery system if prescription of RELENZA is considered. - Prophylaxis of Influenza: The safety and effectiveness of RELENZA for prophylaxis of influenza have been studied in 4 Phase III trials where 273 children aged 5 to 11 years and 239 adolescents aged 12 to 16 years received RELENZA. No differences in safety and effectiveness were observed between pediatric and adult subjects. ### Geriatic Use - Of the total number of subjects in 6 clinical trials of RELENZA for treatment of influenza, 59 subjects were aged 65 years and older, while 24 subjects were aged 75 years and older. Of the total number of subjects in 4 clinical trials of RELENZA for prophylaxis of influenza in households and community settings, 954 subjects were aged 65 years and older, while 347 subjects were aged 75 years and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger subjects, but greater sensitivity of some older individuals cannot be ruled out. Elderly patients may need assistance with use of the device. - In 2 additional trials of RELENZA for prophylaxis of influenza in the nursing home setting, efficacy was not demonstrated. ### Gender - There is no FDA guidance on the use of Zanamivir with respect to specific gender populations. ### Race - There is no FDA guidance on the use of Zanamivir with respect to specific racial populations. ### Renal Impairment - There is no FDA guidance on the use of Zanamivir in patients with renal impairment. ### Hepatic Impairment - There is no FDA guidance on the use of Zanamivir in patients with hepatic impairment. ### Females of Reproductive Potential and Males - There is no FDA guidance on the use of Zanamivir in women of reproductive potentials and males. ### Immunocompromised Patients - There is no FDA guidance one the use of Zanamivir in patients who are immunocompromised. # Administration and Monitoring ### Administration Dosing Considerations - RELENZA is for administration to the respiratory tract by oral inhalation only, using the DISKHALER ® device provided. - The 10-mg dose is provided by 2 inhalations (one 5-mg blister per inhalation). - Patients should be instructed in the use of the delivery system. Instructions should include a demonstration whenever possible. If RELENZA is prescribed for children, it should be used only under adult supervision and instruction, and the supervising adult should first be instructed by a healthcare professional. - Patients scheduled to use an inhaled bronchodilator at the same time as RELENZA should use their bronchodilator before taking RELENZA. Treatment of Influenza - The recommended dose of RELENZA for treatment of influenza in adults and pediatric patients aged 7 years and older is 10 mg twice daily (approximately 12 hours apart) for 5 days. - Two doses should be taken on the first day of treatment whenever possible provided there is at least 2 hours between doses. - On subsequent days, doses should be about 12 hours apart (e.g., morning and evening) at approximately the same time each day. - The safety and efficacy of repeated treatment courses have not been studied. Prophylaxis of Influenza - Household Setting: - The recommended dose of RELENZA for prophylaxis of influenza in adults and pediatric patients aged 5 years and older in a household setting is 10 mg once daily for 10 days. - The dose should be administered at approximately the same time each day. - There are no data on the effectiveness of prophylaxis with RELENZA in a household setting when initiated more than 1.5 days after the onset of signs or symptoms in the index case. - Community Outbreaks: - The recommended dose of RELENZA for prophylaxis of influenza in adults and adolescents in a community setting is 10 mg once daily for 28 days. - The dose should be administered at approximately the same time each day. - There are no data on the effectiveness of prophylaxis with RELENZA in a community outbreak when initiated more than 5 days after the outbreak was identified in the community. - The safety and effectiveness of prophylaxis with RELENZA have not been evaluated for longer than 28 days’ duration. DOSAGE FORMS AND STRENGTHS - Blister for oral inhalation: 5 mg. Four 5-mg blisters of powder on a ROTADISK® for oral inhalation via DISKHALER. Packaged in carton containing 5 ROTADISKs (total of 10 doses) and 1 DISKHALER inhalation device . ### Monitoring There is limited information regarding Zanamivir Monitoring in the drug label. # IV Compatibility - There is limited information regarding IV Compatibility of Zanamivir in the drug label. # Overdosage - There have been no reports of overdosage from administration of RELENZA. # Pharmacology ## Mechanism of Action - Zanamivir is an antiviral drug. ## Structure - The active component of RELENZA is zanamivir. The chemical name of zanamivir is 5-(acetylamino)-4--2,6-anhydro-3,4,5-trideoxy-D-glycero-D-galacto-non-2-enonic acid. It has a molecular formula of C12H20N4O7 and a molecular weight of 332.3. It has the following structural formula: - Zanamivir is a white to off-white powder for oral inhalation with a solubility of approximately 18 mg/mL in water at 20°C. - RELENZA is for administration to the respiratory tract by oral inhalation only. Each RELENZA ROTADISK contains 4 regularly spaced double-foil blisters with each blister containing a powder mixture of 5 mg of zanamivir and 20 mg of lactose (which contains milk proteins). The contents of each blister are inhaled using a specially designed breath-activated plastic device for inhaling powder called the DISKHALER. After a RELENZA ROTADISK is loaded into the DISKHALER, a blister that contains medication is pierced and the zanamivir is dispersed into the air stream created when the patient inhales through the mouthpiece. The amount of drug delivered to the respiratory tract will depend on patient factors such as inspiratory flow. Under standardized in vitro testing, RELENZA ROTADISK delivers 4 mg of zanamivir from the DISKHALER device when tested at a pressure drop of 3 kPa (corresponding to a flow rate of about 62 to 65 L/min) for 3 seconds. ## Pharmacodynamics - There is limited information regarding Pharmacodynamics of Zanamivir in the drug label. ## Pharmacokinetics - Absorption and Bioavailability: Pharmacokinetic studies of orally inhaled zanamivir indicate that approximately 4% to 17% of the inhaled dose is systemically absorbed. The peak serum concentrations ranged from 17 to 142 ng/mL within 1 to 2 hours following a 10 mg dose. The area under the serum concentration versus time curve (AUC∞) ranged from 111 to 1,364 ngh/mL. - Distribution: Zanamivir has limited plasma protein binding (<10%). - Metabolism: Zanamivir is renally excreted as unchanged drug. No metabolites have been detected in humans. - Elimination: The serum half-life of zanamivir following administration by oral inhalation ranges from 2.5 to 5.1 hours. It is excreted unchanged in the urine with excretion of a single dose completed within 24 hours. Total clearance ranges from 2.5 to 10.9 L/h. Unabsorbed drug is excreted in the feces. - Impaired Hepatic Function: The pharmacokinetics of zanamivir have not been studied in patients with impaired hepatic function. - Impaired Renal Function: After a single intravenous dose of 4 mg or 2 mg of zanamivir in volunteers with mild/moderate or severe renal impairment, respectively, significant decreases in renal clearance (and hence total clearance: normals 5.3 L/h, mild/moderate 2.7 L/h, and severe 0.8 L/h; median values) and significant increases in half-life (normals 3.1 h, mild/moderate 4.7 h, and severe 18.5 h; median values) and systemic exposure were observed. Safety and efficacy have not been documented in the presence of severe renal insufficiency. Due to the low systemic bioavailability of zanamivir following oral inhalation, no dosage adjustments are necessary in patients with renal impairment. However, the potential for drug accumulation should be considered. - Pediatric Patients: The pharmacokinetics of zanamivir were evaluated in pediatric subjects with signs and symptoms of respiratory illness. Sixteen subjects, aged 6 to 12 years, received a single dose of 10 mg zanamivir dry powder via DISKHALER. Five subjects had either undetectable zanamivir serum concentrations or had low drug concentrations (8.32 to 10.38 ng/mL) that were not detectable after 1.5 hours. Eleven subjects had Cmax median values of 43 ng/mL (range: 15 to 74) and AUC∞ median values of 167 ngh/mL (range: 58 to 279). Low or undetectable serum concentrations were related to lack of measurable PIFR in individual subjects. - Geriatric Patients: The pharmacokinetics of zanamivir have not been studied in subjects older than 65 years. - Gender, Race, and Weight: In a population pharmacokinetic analysis in patient trials, no clinically significant differences in serum concentrations and/or pharmacokinetic parameters (V/F, CL/F, ka, AUC0-3, Cmax, Tmax, CLr, and % excreted in urine) were observed when demographic variables (gender, age, race, and weight) and indices of infection (laboratory evidence of infection, overall symptoms, symptoms of upper respiratory illness, and viral titers) were considered. There were no significant correlations between measures of systemic exposure and safety parameters. Microbiology - Mechanism of Action: Zanamivir is an inhibitor of influenza virus neuraminidase affecting release of viral particles. - Antiviral Activity: The antiviral activity of zanamivir against laboratory and clinical isolates of influenza virus was determined in cell culture assays. The concentrations of zanamivir required for inhibition of influenza virus were highly variable depending on the assay method used and virus isolate tested. The 50% and 90% effective concentrations (EC50 and EC90) of zanamivir were in the range of 0.005 to 16.0 μM and 0.05 to >100 μM, respectively (1 μM = 0.33 mcg/mL). The relationship between the cell culture inhibition of influenza virus by zanamivir and the inhibition of influenza virus replication in humans has not been established. - Resistance: Influenza viruses with reduced susceptibility to zanamivir have been selected in cell culture by multiple passages of the virus in the presence of increasing concentrations of the drug. Genetic analysis of these viruses showed that the reduced susceptibility in cell culture to zanamivir is associated with mutations that result in amino acid changes in the viral neuraminidase or viral hemagglutinin or both. Resistance mutations selected in cell culture which result in neuraminidase amino acid substitutions include E119G/A/D and R292K. Mutations selected in cell culture in hemagglutinin include: K68R, G75E, E114K, N145S, S165N, S186F, N199S, and K222T. - In an immunocompromised patient infected with influenza B virus, a variant virus emerged after treatment with an investigational nebulized solution of zanamivir for 2 weeks. Analysis of this variant showed a hemagglutinin substitution (T198I) which resulted in a reduced affinity for human cell receptors, and a substitution in the neuraminidase active site (R152K) which reduced the enzyme’s activity to zanamivir by 1,000-fold. Insufficient information is available to characterize the risk of emergence of zanamivir resistance in clinical use. - Cross-Resistance: Cross-resistance has been observed between some zanamivir-resistant and some oseltamivir-resistant influenza virus mutants generated in cell culture. However, some of the in cell culture zanamivir-induced resistance mutations, E119G/A/D and R292K, occurred at the same neuraminidase amino acid positions as in the clinical isolates resistant to oseltamivir, E119V and R292K. No trials have been performed to assess risk of emergence of cross-resistance during clinical use. - Influenza Vaccine Interaction Trial: An interaction trial (n = 138) was conducted to evaluate the effects of zanamivir (10 mg once daily) on the serological response to a single dose of trivalent inactivated influenza vaccine, as measured by hemagglutination inhibition titers. There was no difference in hemagglutination inhibition antibody titers at 2 weeks and 4 weeks after vaccine administration between zanamivir and placebo recipients. - Influenza Challenge Trials: Antiviral activity of zanamivir was supported for infection with influenza A virus, and to a more limited extent for infection with influenza B virus, by Phase I trials in volunteers who received intranasal inoculations of challenge strains of influenza virus, and received an intranasal formulation of zanamivir or placebo starting before or shortly after viral inoculation. ## Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility - Carcinogenesis: In 2-year carcinogenicity studies conducted in rats and mice using a powder formulation administered through inhalation, zanamivir induced no statistically significant increases in tumors over controls. The maximum daily exposures in rats and mice were approximately 23 to 25 and 20 to 22 times, respectively, greater than those in humans at the proposed clinical dose based on AUC comparisons. - Mutagenesis: Zanamivir was not mutagenic in in vitro and in vivo genotoxicity assays which included bacterial mutation assays in S. typhimurium and E. coli, mammalian mutation assays in mouse lymphoma, chromosomal aberration assays in human peripheral blood lymphocytes, and the in vivo mouse bone marrow micronucleus assay. - Impairment of Fertility: The effects of zanamivir on fertility and general reproductive performance were investigated in male (dosed for 10 weeks prior to mating, and throughout mating, gestation/lactation, and shortly after weaning) and female rats (dosed for 3 weeks prior to mating through Day 19 of pregnancy, or Day 21 post partum) at IV doses 1, 9, and 90 mg/kg/day. Zanamivir did not impair mating or fertility of male or female rats, and did not affect the sperm of treated male rats. The reproductive performance of the F1 generation born to female rats given zanamivir was not affected. Based on a subchronic study in rats at a 90 mg/kg/day IV dose, AUC values ranged between 142 and 199 mcgh/mL (>300 times the human exposure at the proposed clinical dose). # Clinical Studies Treatment of Influenza - Adults and Adolescents: The efficacy of RELENZA 10 mg inhaled twice daily for 5 days in the treatment of influenza has been evaluated in placebo-controlled trials conducted in North America, the Southern Hemisphere, and Europe during their respective influenza seasons. The magnitude of treatment effect varied between trials, with possible relationships to population-related factors including amount of symptomatic relief medication used. - Populations Studied: The principal Phase III trials enrolled 1,588 subjects aged 12 years and older (median age 34 years, 49% male, 91% Caucasian), with uncomplicated influenza-like illness within 2 days of symptom onset. Influenza was confirmed by culture, hemagglutination inhibition antibodies, or investigational direct tests. Of 1,164 subjects with confirmed influenza, 89% had influenza A and 11% had influenza B. These trials served as the principal basis for efficacy evaluation, with more limited Phase II studies providing supporting information where necessary. Following randomization to either zanamivir or placebo (inhaled lactose vehicle), all subjects received instruction and supervision by a healthcare professional for the initial dose. - Principal Results: The definition of time to improvement in major symptoms of influenza included no fever and self-assessment of “none” or “mild” for headache, myalgia, cough, and sore throat. A Phase II and a Phase III trial conducted in North America (total of over 600 influenza-positive subjects) suggested up to 1 day of shortening of median time to this defined improvement in symptoms in subjects receiving zanamivir compared with placebo, although statistical significance was not reached in either of these trials. In a trial conducted in the Southern Hemisphere (321 influenza-positive subjects), a 1.5-day difference in median time to symptom improvement was observed. Additional evidence of efficacy was provided by the European trial. - Other Findings: There was no consistent difference in treatment effect in subjects with influenza A compared with influenza B; however, these trials enrolled smaller numbers of subjects with influenza B and thus provided less evidence in support of efficacy in influenza B. - In general, subjects with lower temperature (e.g., 38.2°C or less) or investigator-rated as having less severe symptoms at entry derived less benefit from therapy. - No consistent treatment effect was demonstrated in subjects with underlying chronic medical conditions, including respiratory or cardiovascular disease. - No consistent differences in rate of development of complications were observed between treatment groups. - Some fluctuation of symptoms was observed after the primary trial endpoint in both treatment groups. - Pediatric Patients: The efficacy of RELENZA 10 mg inhaled twice daily for 5 days in the treatment of influenza in pediatric patients has been evaluated in a placebo-controlled trial conducted in North America and Europe, enrolling 471 subjects, aged 5 to 12 years (55% male, 90% Caucasian), within 36 hours of symptom onset. Of 346 subjects with confirmed influenza, 65% had influenza A and 35% had influenza B. The definition of time to improvement included no fever and parental assessment of no or mild cough and absent/minimal muscle and joint aches or pains, sore throat, chills/feverishness, and headache. Median time to symptom improvement was 1 day shorter in subjects receiving zanamivir compared with placebo. No consistent differences in rate of development of complications were observed between treatment groups. Some fluctuation of symptoms was observed after the primary trial endpoint in both treatment groups. - Although this trial was designed to enroll children aged 5 to 12 years, the product is indicated only for children aged 7 years and older. This evaluation is based on the combination of lower estimates of treatment effect in 5- and 6-year-olds compared with the overall trial population, and evidence of inadequate inhalation through the DISKHALER in a pharmacokinetic trial. Prophylaxis of Influenza - The efficacy of RELENZA in preventing naturally occurring influenza illness has been demonstrated in 2 post-exposure prophylaxis trials in households and 2 seasonal prophylaxis trials during community outbreaks of influenza. The primary efficacy endpoint in these trials was the incidence of symptomatic, laboratory-confirmed influenza, defined as the presence of 2 or more of the following symptoms: oral temperature ≥100°F/37.8°C or feverishness, cough, headache, sore throat, and myalgia; and laboratory confirmation of influenza A or B by culture, PCR, or seroconversion (defined as a 4-fold increase in convalescent antibody titer from baseline). - Household Prophylaxis Trials: Two trials assessed post-exposure prophylaxis in household contacts of an index case. Within 1.5 days of onset of symptoms in an index case, each household (including all family members aged 5 years and older) was randomized to RELENZA 10 mg inhaled once daily or placebo inhaled once daily for 10 days. In the first trial only, each index case was randomized to RELENZA 10 mg inhaled twice daily for 5 days or inhaled placebo twice daily for 5 days. In this trial, the proportion of households with at least 1 new case of symptomatic laboratory-confirmed influenza was reduced from 19.0% (32 of 168 households) for the placebo group to 4.1% (7 of 169 households) for the group receiving RELENZA. - In the second trial, index cases were not treated. The incidence of symptomatic laboratory-confirmed influenza was reduced from 19.0% (46 of 242 households) for the placebo group to 4.1% (10 of 245 households) for the group receiving RELENZA. - Seasonal Prophylaxis Trials: Two seasonal prophylaxis trials assessed RELENZA 10 mg inhaled once daily versus placebo inhaled once daily for 28 days during community outbreaks. The first trial enrolled subjects aged 18 years or older (mean age: 29 years) from 2 university communities. The majority of subjects were unvaccinated (86%). In this trial, the incidence of symptomatic laboratory-confirmed influenza was reduced from 6.1% (34 of 554) for the placebo group to 2.0% (11 of 553) for the group receiving RELENZA. - The second seasonal prophylaxis trial enrolled subjects aged 12 to 94 years (mean age 60 years) with 56% of them older than 65 years. Sixty-seven percent of the subjects were vaccinated. In this trial, the incidence of symptomatic laboratory-confirmed influenza was reduced from 1.4% (23 of 1,685) for the placebo group to 0.2% (4 of 1,678) for the group receiving RELENZA. # How Supplied - RELENZA is supplied in a circular double-foil pack (a ROTADISK) containing 4 blisters of the drug. Five ROTADISKs are packaged in a white polypropylene tube. The tube is packaged in a carton with 1 blue and gray DISKHALER inhalation device (NDC 0173-0681-01). ## Storage Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) (see USP Controlled Room Temperature). Keep out of reach of children. Do not puncture any RELENZA ROTADISK blister until taking a dose using the DISKHALER. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information # Precautions with Alcohol - Alcohol-Zanamivir interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names Relenza # Look-Alike Drug Names There is limited information regarding Zanamivir Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Zanamivir Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Deepika Beereddy, MBBS [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 Zanamivir is a antiviral agent that is FDA approved for the treatment of influenza and prophylaxis of influenza. Common adverse reactions include sinusitis, dizziness, fever and/or chills, arthralgia and articular rheumatism. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - RELENZA is indicated for prophylaxis of influenza in adults and pediatric patients aged 5 years and older. - Dosing Information - Recommended for chemoprophylaxis of influenza in the United States for the 2012 to 2013 influenza season. - 10 mg (2 inhalations) ORALLY once daily for 7 days following exposure; for control of outbreaks in long-term care facilities and hospitals, take for a minimum of 2 weeks, continuing up to 1 week after the last known case OR 10 mg (2 inhalations) ORALLY once daily for 10 days following household exposure; for control of community outbreaks, take for 28 days. - RELENZA® (zanamivir) Inhalation Powder is indicated for treatment of uncomplicated acute illness due to influenza A and B virus in adults and pediatric patients aged 7 years and older who have been symptomatic for no more than 2 days. - Dosing Information - Recommended for treatment of influenza in the United States for the 2012 to 2013 influenza season. - 10 mg (2 inhalations) ORALLY every 12 hours for 5 days; initiate within 2 days of symptom onset and, when possible, administer 2 doses on day 1, at least 2 hours apart. Important Limitations on Use of RELENZA - RELENZA is not recommended for treatment or prophylaxis of influenza in individuals with underlying airways disease (such as asthma or chronic obstructive pulmonary disease) due to risk of serious bronchospasm. - RELENZA has not been proven effective for treatment of influenza in individuals with underlying airways disease. - RELENZA has not been proven effective for prophylaxis of influenza in the nursing home setting. - RELENZA is not a substitute for early influenza vaccination on an annual basis as recommended by the Centers for Disease Control's Immunization Practices Advisory Committee. - Influenza viruses change over time. Emergence of resistance mutations could decrease drug effectiveness. Other factors (for example, changes in viral virulence) might also diminish clinical benefit of antiviral drugs. Prescribers should consider available information on influenza drug susceptibility patterns and treatment effects when deciding whether to use RELENZA. - There is no evidence for efficacy of zanamivir in any illness caused by agents other than influenza virus A and B. - Patients should be advised that the use of RELENZA for treatment of influenza has not been shown to reduce the risk of transmission of influenza to others. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Zanamivir in adult patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of Zanamivir in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Dosing Information - CDC Recommendations: - Zanamivir or oseltamivir is recommended for prophylaxis of influenza in the United States for the 2012 to 2013 influenza season, according to the CDC. - The recommended dose of zanamivir in children 5 years or older is 2 inhalations (5 mg/inhalation) orally once daily. The recommended duration of therapy is for 7 days following last known exposure. In adolescents, the recommended duration of therapy for control of influenza outbreaks in long-term care facilities and hospitals is a minimum of 2 weeks, continuing for up to 1 week after the last known case. For persons receiving zanamivir for antiviral prophylaxis following vaccination with inactivated influenza vaccination, the recommended duration of therapy is until immunity from vaccination develops (eg, antibody development in adults is about 2 weeks; however, it may take longer in children depending on age and vaccination history). Antiviral prophylaxis is generally not recommended if more than 48 hours has elapsed since exposure to an infectious person. - The recommended dose for prophylaxis of influenza (types A and B) in children 5 years or older in a household setting is 2 inhalations (5 mg/inhalation) orally once daily for 10 days. Give the dose at approximately the same time each day and administer under adult supervision and instruction. Data are lacking on the effectiveness of prophylaxis if initiated more than 36 hours after the onset of signs or symptoms. - The recommended dose for prophylaxis of influenza (types A and B) in adolescents in a community setting is 2 inhalations (5 mg/inhalation) orally once daily for 28 days. Give the dose at approximately the same time each day and administer under adult supervision and instruction. Data are lacking on the effectiveness of prophylaxis if initiated more than 36 hours after the onset of signs or symptoms. - Dosing Information - CDC Recommendations: - Oseltamivir or zanamivir should be used for the treatment of influenza in the United States for the 2012 to 2013 influenza season, according to the CDC. - The recommended dose for the treatment of influenza (types A and B) in children 7 years or older is 2 inhalations (5 mg per inhalation) orally twice daily for 5 days. Initiate treatment within 2 days after symptom onset. When possible, on the first day of treatment, administer 2 doses at least 2 hours apart. Administer subsequent doses 12 hours apart. Data are lacking on the effectiveness if treatment is initiated more than 2 days after the onset of signs or symptoms. Administer doses under adult supervision and instruction. - For those patients who remain severely ill following 5 days of treatment, longer treatment courses can be considered. - The safety and efficacy in the treatment of influenza have not been established in children under 7 years of age. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Zanamivir in pediatric patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of Zanamivir in pediatric patients. # Contraindications - Do not use in patients with history of allergic reaction to any ingredient of RELENZA including milk proteins. # Warnings Bronchospasm - RELENZA is not recommended for treatment or prophylaxis of influenza in individuals with underlying airways disease (such as asthma or chronic obstructive pulmonary disease). - Serious cases of bronchospasm, including fatalities, have been reported during treatment with RELENZA in patients with and without underlying airways disease. Many of these cases were reported during postmarketing and causality was difficult to assess. - RELENZA should be discontinued in any patient who develops bronchospasm or decline in respiratory function; immediate treatment and hospitalization may be required. - Some patients without prior pulmonary disease may also have respiratory abnormalities from acute respiratory infection that could resemble adverse drug reactions or increase patient vulnerability to adverse drug reactions. - Bronchospasm was documented following administration of zanamivir in 1 of 13 subjects with mild or moderate asthma (but without acute influenza-like illness) in a Phase I trial. In a Phase III trial in subjects with acute influenza-like illness superimposed on underlying asthma or chronic obstructive pulmonary disease, 10% (24 of 244) of subjects on zanamivir and 9% (22 of 237) on placebo experienced a greater than 20% decline in FEV1 following treatment for 5 days. - If use of RELENZA is considered for a patient with underlying airways disease, the potential risks and benefits should be carefully weighed. If a decision is made to prescribe RELENZA for such a patient, this should be done only under conditions of careful monitoring of respiratory function, close observation, and appropriate supportive care including availability of fast-acting bronchodilators. Allergic Reactions - Allergic-like reactions, including oropharyngeal edema, serious skin rashes, and anaphylaxis have been reported in postmarketing experience with RELENZA. RELENZA should be stopped and appropriate treatment instituted if an allergic reaction occurs or is suspected. Neuropsychiatric Events - Influenza can be associated with a variety of neurologic and behavioral symptoms which can include events such as seizures, hallucinations, delirium, and abnormal behavior, in some cases resulting in fatal outcomes. These events may occur in the setting of encephalitis or encephalopathy but can occur without obvious severe disease. - There have been postmarketing reports (mostly from Japan) of delirium and abnormal behavior leading to injury in patients with influenza who were receiving neuraminidase inhibitors, including RELENZA. Because these events were reported voluntarily during clinical practice, estimates of frequency cannot be made, but they appear to be uncommon based on usage data for RELENZA. These events were reported primarily among pediatric patients and often had an abrupt onset and rapid resolution. The contribution of RELENZA to these events has not been established. Patients with influenza should be closely monitored for signs of abnormal behavior. If neuropsychiatric symptoms occur, the risks and benefits of continuing treatment should be evaluated for each patient. Limitations of Populations Studied - Safety and efficacy have not been demonstrated in patients with high-risk underlying medical conditions. No information is available regarding treatment of influenza in patients with any medical condition sufficiently severe or unstable to be considered at imminent risk of requiring inpatient management. Bacterial Infections - Serious bacterial infections may begin with influenza-like symptoms or may coexist with or occur as complications during the course of influenza. RELENZA has not been shown to prevent such complications. Importance of Proper Route of Administration - RELENZA Inhalation Powder must not be made into an extemporaneous solution for administration by nebulization or mechanical ventilation. There have been reports of hospitalized patients with influenza who received a solution made with RELENZA Inhalation Powder administered by nebulization or mechanical ventilation, including a fatal case where it was reported that the lactose in this formulation obstructed the proper functioning of the equipment. RELENZA Inhalation Powder must only be administered using the device provided. Importance of Proper Use of DISKHALER - Effective and safe use of RELENZA requires proper use of the DISKHALER to inhale the drug. Prescribers should carefully evaluate the ability of young children to use the delivery system if use of RELENZA is considered. # Adverse Reactions ## Clinical Trials Experience - See Warnings and Precautions for information about risk of serious adverse events such as bronchospasm and allergic-like reactions, and for safety information in patients with underlying airways disease. 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 and may not reflect the rates observed in practice. - The placebo used in clinical trials consisted of inhaled lactose powder, which is also the vehicle for the active drug; therefore, some adverse events occurring at similar frequencies in different treatment groups could be related to lactose vehicle inhalation. - Treatment of Influenza: Clinical Trials in Adults and Adolescents: Adverse events that occurred with an incidence ≥1.5% in treatment trials are listed in Table 1. This table shows adverse events occurring in subjects aged 12 years and older receiving RELENZA 10 mg inhaled twice daily, RELENZA in all inhalation regimens, and placebo inhaled twice daily (where placebo consisted of the same lactose vehicle used in RELENZA). - Additional adverse reactions occurring in less than 1.5% of subjects receiving RELENZA included malaise, fatigue, fever, abdominal pain, myalgia, arthralgia, and urticaria. - The most frequent laboratory abnormalities in Phase III treatment trials included elevations of liver enzymes and CPK, lymphopenia, and neutropenia. These were reported in similar proportions of zanamivir and lactose vehicle placebo recipients with acute influenza-like illness. - Clinical Trials in Pediatric Subjects: Adverse events that occurred with an incidence ≥1.5% in children receiving treatment doses of RELENZA in 2 Phase III trials are listed in Table 2. This table shows adverse events occurring in pediatric subjects aged 5 to 12 years receiving RELENZA 10 mg inhaled twice daily and placebo inhaled twice daily (where placebo consisted of the same lactose vehicle used in RELENZA). - In 1 of the 2 trials described in Table 2, some additional information is available from children (aged 5 to 12 years) without acute influenza-like illness who received an investigational prophylaxis regimen of RELENZA; 132 children received RELENZA and 145 children received placebo. Among these children, nasal signs and symptoms (zanamivir 20%, placebo 9%), cough (zanamivir 16%, placebo 8%), and throat/tonsil discomfort and pain (zanamivir 11%, placebo 6%) were reported more frequently with RELENZA than placebo. In a subset with chronic pulmonary disease, lower respiratory adverse events (described as asthma, cough, or viral respiratory infections which could include influenza-like symptoms) were reported in 7 of 7 zanamivir recipients and 5 of 12 placebo recipients. - Prophylaxis of Influenza: Family/Household Prophylaxis Studies: Adverse events that occurred with an incidence of ≥1.5% in the 2 prophylaxis trials are listed in Table 3. This table shows adverse events occurring in subjects aged 5 years and older receiving RELENZA 10 mg inhaled once daily for 10 days. - Community Prophylaxis Trials: Adverse events that occurred with an incidence of ≥1.5% in 2 prophylaxis trials are listed in Table 4. This table shows adverse events occurring in subjects aged 5 years and older receiving RELENZA 10 mg inhaled once daily for 28 days. ## Postmarketing Experience - In addition to adverse events reported from clinical trials, the following events have been identified during postmarketing use of zanamivir (RELENZA). Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to zanamivir (RELENZA). - Allergic Reactions: Allergic or allergic-like reaction, including oropharyngeal edema. - Psychiatric: Delirium, including symptoms such as altered level of consciousness, confusion, abnormal behavior, delusions, hallucinations, agitation, anxiety, nightmares. - Cardiac: Arrhythmias, syncope. - Neurologic: Seizures. Vasovagal-like episodes have been reported shortly following inhalation of zanamivir. - Respiratory: Bronchospasm, dyspnea. - Skin: Facial edema; rash, including serious cutaneous reactions (e.g., erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis); urticaria. # Drug Interactions - Zanamivir is not a substrate nor does it affect cytochrome P450 (CYP) isoenzymes (CYP1A1/2, 2A6, 2C9, 2C18, 2D6, 2E1, and 3A4) in human liver microsomes. No clinically significant pharmacokinetic drug interactions are predicted based on data from in vitro studies. - The concurrent use of RELENZA with live attenuated influenza vaccine (LAIV) intranasal has not been evaluated. However, because of potential interference between these products, LAIV should not be administered within 2 weeks before or 48 hours after administration of RELENZA, unless medically indicated. The concern about possible interference arises from the potential for antiviral drugs to inhibit replication of live vaccine virus. - Trivalent inactivated influenza vaccine can be administered at any time relative to use of RELENZA. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Pregnancy Category C. There are no adequate and well-controlled studies of zanamivir in pregnant women. Zanamivir should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. - Embryo/fetal development studies were conducted in rats (dosed from days 6 to 15 of pregnancy) and rabbits (dosed from days 7 to 19 of pregnancy) using the same IV doses (1, 9, and 90 mg/kg/day). Pre- and post-natal developmental studies were performed in rats (dosed from day 16 of pregnancy until litter day 21 to 23). No malformations, maternal toxicity, or embryotoxicity were observed in pregnant rats or rabbits and their fetuses. Because of insufficient blood sampling timepoints in rat and rabbit reproductive toxicity studies, AUC values were not available. In a subchronic study in rats at the 90 mg/kg/day IV dose, the AUC values were greater than 300 times the human exposure at the proposed clinical dose. - An additional embryo/fetal study, in a different strain of rat, was conducted using subcutaneous administration of zanamivir, 3 times daily, at doses of 1, 9, or 80 mg/kg during days 7 to 17 of pregnancy. There was an increase in the incidence rates of a variety of minor skeleton alterations and variants in the exposed offspring in this study. Based on AUC measurements, the 80 mg/kg dose produced an exposure greater than 1,000 times the human exposure at the proposed clinical dose. However, in most instances, the individual incidence rate of each skeletal alteration or variant remained within the background rates of the historical occurrence in the strain studied. - Zanamivir has been shown to cross the placenta in rats and rabbits. In these animals, fetal blood concentrations of zanamivir were significantly lower than zanamivir concentrations in the maternal blood. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category - There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Zanamivir in women who are pregnant. ### Labor and Delivery - There is no FDA guidance on use of Zanamivir during labor and delivery. ### Nursing Mothers - Studies in rats have demonstrated that zanamivir is excreted in milk. However, nursing mothers should be instructed that it is not known whether zanamivir is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when RELENZA is administered to a nursing mother. ### Pediatric Use - Treatment of Influenza: Safety and effectiveness of RELENZA for treatment of influenza have not been assessed in pediatric patients younger than 7 years, but were studied in a Phase III treatment trial in pediatric subjects, where 471 children aged 5 to 12 years received zanamivir or placebo. Adolescents were included in the 3 principal Phase III adult treatment trials. In these trials, 67 patients were aged 12 to 16 years. No definite differences in safety and efficacy were observed between these adolescent patients and young adults. - In a Phase I trial of 16 children aged 6 to 12 years with signs and symptoms of respiratory disease, 4 did not produce a measurable peak inspiratory flow rate (PIFR) through the DISKHALER (3 with no adequate inhalation on request, 1 with missing data), 9 had measurable PIFR on each of 2 inhalations, and 3 achieved measurable PIFR on only 1 of 2 inhalations. Neither of two 6-year-olds and one of two 7-year-olds produced measurable PIFR. Overall, 8 of the 16 children (including all those younger than 8 years) either did not produce measurable inspiratory flow through the DISKHALER or produced peak inspiratory flow rates below the 60 L/min considered optimal for the device under standardized in vitro testing; lack of measurable flow rate was related to low or undetectable serum concentrations. Prescribers should carefully evaluate the ability of young children to use the delivery system if prescription of RELENZA is considered. - Prophylaxis of Influenza: The safety and effectiveness of RELENZA for prophylaxis of influenza have been studied in 4 Phase III trials where 273 children aged 5 to 11 years and 239 adolescents aged 12 to 16 years received RELENZA. No differences in safety and effectiveness were observed between pediatric and adult subjects. ### Geriatic Use - Of the total number of subjects in 6 clinical trials of RELENZA for treatment of influenza, 59 subjects were aged 65 years and older, while 24 subjects were aged 75 years and older. Of the total number of subjects in 4 clinical trials of RELENZA for prophylaxis of influenza in households and community settings, 954 subjects were aged 65 years and older, while 347 subjects were aged 75 years and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger subjects, but greater sensitivity of some older individuals cannot be ruled out. Elderly patients may need assistance with use of the device. - In 2 additional trials of RELENZA for prophylaxis of influenza in the nursing home setting, efficacy was not demonstrated. ### Gender - There is no FDA guidance on the use of Zanamivir with respect to specific gender populations. ### Race - There is no FDA guidance on the use of Zanamivir with respect to specific racial populations. ### Renal Impairment - There is no FDA guidance on the use of Zanamivir in patients with renal impairment. ### Hepatic Impairment - There is no FDA guidance on the use of Zanamivir in patients with hepatic impairment. ### Females of Reproductive Potential and Males - There is no FDA guidance on the use of Zanamivir in women of reproductive potentials and males. ### Immunocompromised Patients - There is no FDA guidance one the use of Zanamivir in patients who are immunocompromised. # Administration and Monitoring ### Administration Dosing Considerations - RELENZA is for administration to the respiratory tract by oral inhalation only, using the DISKHALER ® device provided. - The 10-mg dose is provided by 2 inhalations (one 5-mg blister per inhalation). - Patients should be instructed in the use of the delivery system. Instructions should include a demonstration whenever possible. If RELENZA is prescribed for children, it should be used only under adult supervision and instruction, and the supervising adult should first be instructed by a healthcare professional. - Patients scheduled to use an inhaled bronchodilator at the same time as RELENZA should use their bronchodilator before taking RELENZA. Treatment of Influenza - The recommended dose of RELENZA for treatment of influenza in adults and pediatric patients aged 7 years and older is 10 mg twice daily (approximately 12 hours apart) for 5 days. - Two doses should be taken on the first day of treatment whenever possible provided there is at least 2 hours between doses. - On subsequent days, doses should be about 12 hours apart (e.g., morning and evening) at approximately the same time each day. - The safety and efficacy of repeated treatment courses have not been studied. Prophylaxis of Influenza - Household Setting: - The recommended dose of RELENZA for prophylaxis of influenza in adults and pediatric patients aged 5 years and older in a household setting is 10 mg once daily for 10 days. - The dose should be administered at approximately the same time each day. - There are no data on the effectiveness of prophylaxis with RELENZA in a household setting when initiated more than 1.5 days after the onset of signs or symptoms in the index case. - Community Outbreaks: - The recommended dose of RELENZA for prophylaxis of influenza in adults and adolescents in a community setting is 10 mg once daily for 28 days. - The dose should be administered at approximately the same time each day. - There are no data on the effectiveness of prophylaxis with RELENZA in a community outbreak when initiated more than 5 days after the outbreak was identified in the community. - The safety and effectiveness of prophylaxis with RELENZA have not been evaluated for longer than 28 days’ duration. DOSAGE FORMS AND STRENGTHS - Blister for oral inhalation: 5 mg. Four 5-mg blisters of powder on a ROTADISK® for oral inhalation via DISKHALER. Packaged in carton containing 5 ROTADISKs (total of 10 doses) and 1 DISKHALER inhalation device [see How Supplied/Storage and Handling]. ### Monitoring There is limited information regarding Zanamivir Monitoring in the drug label. # IV Compatibility - There is limited information regarding IV Compatibility of Zanamivir in the drug label. # Overdosage - There have been no reports of overdosage from administration of RELENZA. # Pharmacology ## Mechanism of Action - Zanamivir is an antiviral drug. ## Structure - The active component of RELENZA is zanamivir. The chemical name of zanamivir is 5-(acetylamino)-4-[(aminoiminomethyl)-amino]-2,6-anhydro-3,4,5-trideoxy-D-glycero-D-galacto-non-2-enonic acid. It has a molecular formula of C12H20N4O7 and a molecular weight of 332.3. It has the following structural formula: - Zanamivir is a white to off-white powder for oral inhalation with a solubility of approximately 18 mg/mL in water at 20°C. - RELENZA is for administration to the respiratory tract by oral inhalation only. Each RELENZA ROTADISK contains 4 regularly spaced double-foil blisters with each blister containing a powder mixture of 5 mg of zanamivir and 20 mg of lactose (which contains milk proteins). The contents of each blister are inhaled using a specially designed breath-activated plastic device for inhaling powder called the DISKHALER. After a RELENZA ROTADISK is loaded into the DISKHALER, a blister that contains medication is pierced and the zanamivir is dispersed into the air stream created when the patient inhales through the mouthpiece. The amount of drug delivered to the respiratory tract will depend on patient factors such as inspiratory flow. Under standardized in vitro testing, RELENZA ROTADISK delivers 4 mg of zanamivir from the DISKHALER device when tested at a pressure drop of 3 kPa (corresponding to a flow rate of about 62 to 65 L/min) for 3 seconds. ## Pharmacodynamics - There is limited information regarding Pharmacodynamics of Zanamivir in the drug label. ## Pharmacokinetics - Absorption and Bioavailability: Pharmacokinetic studies of orally inhaled zanamivir indicate that approximately 4% to 17% of the inhaled dose is systemically absorbed. The peak serum concentrations ranged from 17 to 142 ng/mL within 1 to 2 hours following a 10 mg dose. The area under the serum concentration versus time curve (AUC∞) ranged from 111 to 1,364 ng•h/mL. - Distribution: Zanamivir has limited plasma protein binding (<10%). - Metabolism: Zanamivir is renally excreted as unchanged drug. No metabolites have been detected in humans. - Elimination: The serum half-life of zanamivir following administration by oral inhalation ranges from 2.5 to 5.1 hours. It is excreted unchanged in the urine with excretion of a single dose completed within 24 hours. Total clearance ranges from 2.5 to 10.9 L/h. Unabsorbed drug is excreted in the feces. - Impaired Hepatic Function: The pharmacokinetics of zanamivir have not been studied in patients with impaired hepatic function. - Impaired Renal Function: After a single intravenous dose of 4 mg or 2 mg of zanamivir in volunteers with mild/moderate or severe renal impairment, respectively, significant decreases in renal clearance (and hence total clearance: normals 5.3 L/h, mild/moderate 2.7 L/h, and severe 0.8 L/h; median values) and significant increases in half-life (normals 3.1 h, mild/moderate 4.7 h, and severe 18.5 h; median values) and systemic exposure were observed. Safety and efficacy have not been documented in the presence of severe renal insufficiency. Due to the low systemic bioavailability of zanamivir following oral inhalation, no dosage adjustments are necessary in patients with renal impairment. However, the potential for drug accumulation should be considered. - Pediatric Patients: The pharmacokinetics of zanamivir were evaluated in pediatric subjects with signs and symptoms of respiratory illness. Sixteen subjects, aged 6 to 12 years, received a single dose of 10 mg zanamivir dry powder via DISKHALER. Five subjects had either undetectable zanamivir serum concentrations or had low drug concentrations (8.32 to 10.38 ng/mL) that were not detectable after 1.5 hours. Eleven subjects had Cmax median values of 43 ng/mL (range: 15 to 74) and AUC∞ median values of 167 ng•h/mL (range: 58 to 279). Low or undetectable serum concentrations were related to lack of measurable PIFR in individual subjects. - Geriatric Patients: The pharmacokinetics of zanamivir have not been studied in subjects older than 65 years. - Gender, Race, and Weight: In a population pharmacokinetic analysis in patient trials, no clinically significant differences in serum concentrations and/or pharmacokinetic parameters (V/F, CL/F, ka, AUC0-3, Cmax, Tmax, CLr, and % excreted in urine) were observed when demographic variables (gender, age, race, and weight) and indices of infection (laboratory evidence of infection, overall symptoms, symptoms of upper respiratory illness, and viral titers) were considered. There were no significant correlations between measures of systemic exposure and safety parameters. Microbiology - Mechanism of Action: Zanamivir is an inhibitor of influenza virus neuraminidase affecting release of viral particles. - Antiviral Activity: The antiviral activity of zanamivir against laboratory and clinical isolates of influenza virus was determined in cell culture assays. The concentrations of zanamivir required for inhibition of influenza virus were highly variable depending on the assay method used and virus isolate tested. The 50% and 90% effective concentrations (EC50 and EC90) of zanamivir were in the range of 0.005 to 16.0 μM and 0.05 to >100 μM, respectively (1 μM = 0.33 mcg/mL). The relationship between the cell culture inhibition of influenza virus by zanamivir and the inhibition of influenza virus replication in humans has not been established. - Resistance: Influenza viruses with reduced susceptibility to zanamivir have been selected in cell culture by multiple passages of the virus in the presence of increasing concentrations of the drug. Genetic analysis of these viruses showed that the reduced susceptibility in cell culture to zanamivir is associated with mutations that result in amino acid changes in the viral neuraminidase or viral hemagglutinin or both. Resistance mutations selected in cell culture which result in neuraminidase amino acid substitutions include E119G/A/D and R292K. Mutations selected in cell culture in hemagglutinin include: K68R, G75E, E114K, N145S, S165N, S186F, N199S, and K222T. - In an immunocompromised patient infected with influenza B virus, a variant virus emerged after treatment with an investigational nebulized solution of zanamivir for 2 weeks. Analysis of this variant showed a hemagglutinin substitution (T198I) which resulted in a reduced affinity for human cell receptors, and a substitution in the neuraminidase active site (R152K) which reduced the enzyme’s activity to zanamivir by 1,000-fold. Insufficient information is available to characterize the risk of emergence of zanamivir resistance in clinical use. - Cross-Resistance: Cross-resistance has been observed between some zanamivir-resistant and some oseltamivir-resistant influenza virus mutants generated in cell culture. However, some of the in cell culture zanamivir-induced resistance mutations, E119G/A/D and R292K, occurred at the same neuraminidase amino acid positions as in the clinical isolates resistant to oseltamivir, E119V and R292K. No trials have been performed to assess risk of emergence of cross-resistance during clinical use. - Influenza Vaccine Interaction Trial: An interaction trial (n = 138) was conducted to evaluate the effects of zanamivir (10 mg once daily) on the serological response to a single dose of trivalent inactivated influenza vaccine, as measured by hemagglutination inhibition titers. There was no difference in hemagglutination inhibition antibody titers at 2 weeks and 4 weeks after vaccine administration between zanamivir and placebo recipients. - Influenza Challenge Trials: Antiviral activity of zanamivir was supported for infection with influenza A virus, and to a more limited extent for infection with influenza B virus, by Phase I trials in volunteers who received intranasal inoculations of challenge strains of influenza virus, and received an intranasal formulation of zanamivir or placebo starting before or shortly after viral inoculation. ## Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility - Carcinogenesis: In 2-year carcinogenicity studies conducted in rats and mice using a powder formulation administered through inhalation, zanamivir induced no statistically significant increases in tumors over controls. The maximum daily exposures in rats and mice were approximately 23 to 25 and 20 to 22 times, respectively, greater than those in humans at the proposed clinical dose based on AUC comparisons. - Mutagenesis: Zanamivir was not mutagenic in in vitro and in vivo genotoxicity assays which included bacterial mutation assays in S. typhimurium and E. coli, mammalian mutation assays in mouse lymphoma, chromosomal aberration assays in human peripheral blood lymphocytes, and the in vivo mouse bone marrow micronucleus assay. - Impairment of Fertility: The effects of zanamivir on fertility and general reproductive performance were investigated in male (dosed for 10 weeks prior to mating, and throughout mating, gestation/lactation, and shortly after weaning) and female rats (dosed for 3 weeks prior to mating through Day 19 of pregnancy, or Day 21 post partum) at IV doses 1, 9, and 90 mg/kg/day. Zanamivir did not impair mating or fertility of male or female rats, and did not affect the sperm of treated male rats. The reproductive performance of the F1 generation born to female rats given zanamivir was not affected. Based on a subchronic study in rats at a 90 mg/kg/day IV dose, AUC values ranged between 142 and 199 mcg•h/mL (>300 times the human exposure at the proposed clinical dose). # Clinical Studies Treatment of Influenza - Adults and Adolescents: The efficacy of RELENZA 10 mg inhaled twice daily for 5 days in the treatment of influenza has been evaluated in placebo-controlled trials conducted in North America, the Southern Hemisphere, and Europe during their respective influenza seasons. The magnitude of treatment effect varied between trials, with possible relationships to population-related factors including amount of symptomatic relief medication used. - Populations Studied: The principal Phase III trials enrolled 1,588 subjects aged 12 years and older (median age 34 years, 49% male, 91% Caucasian), with uncomplicated influenza-like illness within 2 days of symptom onset. Influenza was confirmed by culture, hemagglutination inhibition antibodies, or investigational direct tests. Of 1,164 subjects with confirmed influenza, 89% had influenza A and 11% had influenza B. These trials served as the principal basis for efficacy evaluation, with more limited Phase II studies providing supporting information where necessary. Following randomization to either zanamivir or placebo (inhaled lactose vehicle), all subjects received instruction and supervision by a healthcare professional for the initial dose. - Principal Results: The definition of time to improvement in major symptoms of influenza included no fever and self-assessment of “none” or “mild” for headache, myalgia, cough, and sore throat. A Phase II and a Phase III trial conducted in North America (total of over 600 influenza-positive subjects) suggested up to 1 day of shortening of median time to this defined improvement in symptoms in subjects receiving zanamivir compared with placebo, although statistical significance was not reached in either of these trials. In a trial conducted in the Southern Hemisphere (321 influenza-positive subjects), a 1.5-day difference in median time to symptom improvement was observed. Additional evidence of efficacy was provided by the European trial. - Other Findings: There was no consistent difference in treatment effect in subjects with influenza A compared with influenza B; however, these trials enrolled smaller numbers of subjects with influenza B and thus provided less evidence in support of efficacy in influenza B. - In general, subjects with lower temperature (e.g., 38.2°C or less) or investigator-rated as having less severe symptoms at entry derived less benefit from therapy. - No consistent treatment effect was demonstrated in subjects with underlying chronic medical conditions, including respiratory or cardiovascular disease. - No consistent differences in rate of development of complications were observed between treatment groups. - Some fluctuation of symptoms was observed after the primary trial endpoint in both treatment groups. - Pediatric Patients: The efficacy of RELENZA 10 mg inhaled twice daily for 5 days in the treatment of influenza in pediatric patients has been evaluated in a placebo-controlled trial conducted in North America and Europe, enrolling 471 subjects, aged 5 to 12 years (55% male, 90% Caucasian), within 36 hours of symptom onset. Of 346 subjects with confirmed influenza, 65% had influenza A and 35% had influenza B. The definition of time to improvement included no fever and parental assessment of no or mild cough and absent/minimal muscle and joint aches or pains, sore throat, chills/feverishness, and headache. Median time to symptom improvement was 1 day shorter in subjects receiving zanamivir compared with placebo. No consistent differences in rate of development of complications were observed between treatment groups. Some fluctuation of symptoms was observed after the primary trial endpoint in both treatment groups. - Although this trial was designed to enroll children aged 5 to 12 years, the product is indicated only for children aged 7 years and older. This evaluation is based on the combination of lower estimates of treatment effect in 5- and 6-year-olds compared with the overall trial population, and evidence of inadequate inhalation through the DISKHALER in a pharmacokinetic trial. Prophylaxis of Influenza - The efficacy of RELENZA in preventing naturally occurring influenza illness has been demonstrated in 2 post-exposure prophylaxis trials in households and 2 seasonal prophylaxis trials during community outbreaks of influenza. The primary efficacy endpoint in these trials was the incidence of symptomatic, laboratory-confirmed influenza, defined as the presence of 2 or more of the following symptoms: oral temperature ≥100°F/37.8°C or feverishness, cough, headache, sore throat, and myalgia; and laboratory confirmation of influenza A or B by culture, PCR, or seroconversion (defined as a 4-fold increase in convalescent antibody titer from baseline). - Household Prophylaxis Trials: Two trials assessed post-exposure prophylaxis in household contacts of an index case. Within 1.5 days of onset of symptoms in an index case, each household (including all family members aged 5 years and older) was randomized to RELENZA 10 mg inhaled once daily or placebo inhaled once daily for 10 days. In the first trial only, each index case was randomized to RELENZA 10 mg inhaled twice daily for 5 days or inhaled placebo twice daily for 5 days. In this trial, the proportion of households with at least 1 new case of symptomatic laboratory-confirmed influenza was reduced from 19.0% (32 of 168 households) for the placebo group to 4.1% (7 of 169 households) for the group receiving RELENZA. - In the second trial, index cases were not treated. The incidence of symptomatic laboratory-confirmed influenza was reduced from 19.0% (46 of 242 households) for the placebo group to 4.1% (10 of 245 households) for the group receiving RELENZA. - Seasonal Prophylaxis Trials: Two seasonal prophylaxis trials assessed RELENZA 10 mg inhaled once daily versus placebo inhaled once daily for 28 days during community outbreaks. The first trial enrolled subjects aged 18 years or older (mean age: 29 years) from 2 university communities. The majority of subjects were unvaccinated (86%). In this trial, the incidence of symptomatic laboratory-confirmed influenza was reduced from 6.1% (34 of 554) for the placebo group to 2.0% (11 of 553) for the group receiving RELENZA. - The second seasonal prophylaxis trial enrolled subjects aged 12 to 94 years (mean age 60 years) with 56% of them older than 65 years. Sixty-seven percent of the subjects were vaccinated. In this trial, the incidence of symptomatic laboratory-confirmed influenza was reduced from 1.4% (23 of 1,685) for the placebo group to 0.2% (4 of 1,678) for the group receiving RELENZA. # How Supplied - RELENZA is supplied in a circular double-foil pack (a ROTADISK) containing 4 blisters of the drug. Five ROTADISKs are packaged in a white polypropylene tube. The tube is packaged in a carton with 1 blue and gray DISKHALER inhalation device (NDC 0173-0681-01). ## Storage Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) (see USP Controlled Room Temperature). Keep out of reach of children. Do not puncture any RELENZA ROTADISK blister until taking a dose using the DISKHALER. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information # Precautions with Alcohol - Alcohol-Zanamivir interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names Relenza # Look-Alike Drug Names There is limited information regarding Zanamivir Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Relenza
636c250433a1793ee414a8dc911b5ca4ed80e456	wikidoc	Reserpine	Reserpine # 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 Reserpine is a catecholamine-depleting sympatholytic that is FDA approved for the {{{indicationType}}} of mild essential hypertension. Common adverse reactions include abdominal pain, diarrhea, nausea, vomiting, xerostomia, dizziness, headache, lethargy, somnolence, vertigo, depression, and nasal congestion. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Dosing Information - Initial Dosage - In the average patient not receiving other antihypertensive agents, the usual initial dosage is 0.5 mg daily for 1 or 2 weeks. - Maintenance Dosage - For maintenance, reduce to 0.1–0.25 mg daily. - Higher dosages should be used cautiously, because occurrence of serious mental depression and other side effects may increase considerably. - Dosing Information - Dosage - The usual initial dosage is 0.5 mg daily, but may range from 0.1 mg to 1.0 mg. Adjust dosage upward or downward according to the patient's response. - Reserpine is also useful as adjunctive therapy with other antihypertensive agents in the more severe forms of hypertension; relief of symptoms in agitated psychotic states (e.g., schizophrenia), primarily in those individuals unable to tolerate phenothiazine derivatives or in those who also require antihypertensive medication. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Reserpine in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Reserpine in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Reserpine is not recommended for use in children. - If it is to be used in treating a child, the usual recommended starting dose is 20 µg/kg daily. The maximum recommended dose is 0.25 mg (total) daily. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Reserpine in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Reserpine in pediatric patients. # Contraindications - Hypersensitivity - Mental depression or history of mental depression (especially with suicidal tendencies) - Active peptic ulcer - Ulcerative colitis - Electroconvulsive therapy # Warnings - Extreme caution should be exercised in treating patients with a history of mental depression. Reserpine may cause mental depression. Recognition of depression may be difficult because this condition may often be disguised by somatic complaints (masked depression). The drug should be discontinued at first signs of depression such as despondency, early morning insomnia, loss of appetite, impotence, or self-deprecation. Drug-induced depression may persist for several months after drug withdrawal and may be severe enough to result in suicide. ### Precautions - General - Since reserpine increases gastrointestinal motility and secretion, it should be used cautiously in patients with a history of peptic ulcer, ulcerative colitis, or gallstones (biliary colic may be precipitated). - Caution should be exercised when treating hypertensive patients with renal insufficiency, since they adjust poorly to lowered blood pressure levels. - Preoperative withdrawal of reserpine does not assure that circulatory instability will not occur. It is important that the anesthesiologist be aware of the patient’s drug intake and consider this in the overall management, since hypotension has occurred in patients receiving rauwolfia preparations. Anticholinergic and/or adrenergic drugs (e.g., metaraminol, norepinephrine) have been employed to treat adverse vagocirculatory effects. # Adverse Reactions ## Clinical Trials Experience There is limited information regarding Clinical Trial Experience of Reserpine in the drug label. ## Postmarketing Experience - The following adverse reactions have been observed with rauwolfia preparations, but there has not been enough systematic collection of data to support an estimate of their frequency. Consequently the reactions are categorized by organ system and are listed in decreasing order of severity and not frequency. Rare parkinsonian syndrome and other extrapyramidal tract symptoms; dizziness; headache; paradoxical anxiety; depression; nervousness; nightmares; dull sensorium; drowsiness. Arrhythmias (particularly when used concurrently with digitalis or quinidine), syncope, angina-like symptoms, bradycardia, edema. Dyspnea, epistaxis, nasal congestion. Vomiting, diarrhea, nausea, anorexia, dryness of mouth, hypersecretion. Muscular aches. Pseudolactation, impotence, dysuria, gynecomastia, decreased libido, breast engorgement. Weight gain. Purpura, rash, pruritus. Deafness, optic atrophy, glaucoma, uveitis, conjunctival injection. # Drug Interactions - MAO inhibitors - MAO inhibitors should be avoided or used with extreme caution. - Tricyclic antidepressants - Concurrent use of tricyclic antidepressants may decrease the antihypertensive effect of reserpine. - Reserpine and sympathomimetics - Concurrent use of reserpine and direct-or-indirect acting sympathomimetics should be closely monitored. The action of direct-acting amines (epinephrine, isoproterenol, phenylephrine, metaraminol) may be prolonged when given to patients taking reserpine. The action of indirect-acting amines (ephedrine, tyramine, amphetamines) is inhibited. - Reserpine should be used cautiously with digitalis and quinidine, since cardiac arrhythmias have occurred with rauwolfia preparations. - Concomitant use of reserpine with other antihypertensive agents necessitates careful titration of dosage with each agent. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - Reserpine administered parenterally has been shown to be teratogenic in rats at doses up to 2 mg/kg and to have an embryocidal effect in guinea pigs given dosages of 0.5 mg daily. - There are no adequate and well-controlled studies of reserpine in pregnant women. Reserpine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. - Nonteratogenic Effects - Reserpine crosses the placental barrier, and increased respiratory tract secretions, nasal congestion, cyanosis, and anorexia may occur in neonates of reserpine-treated mothers. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Reserpine in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Reserpine during labor and delivery. ### Nursing Mothers - Reserpine is excreted in maternal breast milk, and increased respiratory tract secretions, nasal congestion, cyanosis, and anorexia may occur in breast-fed infants. Because of the potential for adverse reactions in nursing infants and the potential for tumorigenicity shown for reserpine in animal studies, 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 - Safety and effectiveness in children have not been established by means of controlled clinical trials, although there is experience with the use of reserpine in children. Because of adverse effects such as emotional depression and lability, sedation, and stuffy nose, reserpine is not usually recommended as a step-2 drug in the treatment of hypertension in children. ### Geriatic Use There is no FDA guidance on the use of Reserpine with respect to geriatric patients. ### Gender There is no FDA guidance on the use of Reserpine with respect to specific gender populations. ### Race There is no FDA guidance on the use of Reserpine with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Reserpine in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Reserpine in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Reserpine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Reserpine in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Reserpine in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Reserpine in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - No deaths due to acute poisoning with reserpine have been reported. - Highest known doses survived: children, 1000 mg (age and sex not specified); young children, 200 mg (20-month-old boy). - Oral LD50's in animals (mg/kg): rat, 2993; mouse, 47 and 500. - The clinical picture of acute poisoning is characterized chiefly by signs and symptoms due to the reflex parasympathomimetic effect of reserpine. - Impairment of consciousness may occur and may range from drowsiness to coma, depending upon the severity of overdosage. Flushing of the skin, conjunctival injection, and pupillary constriction are to be expected. Hypotension, hypothermia, central respiratory depression, and bradycardia may develop in cases of severe overdosage. Increased salivary and gastric secretion and diarrhea may also occur. ### Management - There is no specific antidote. - Stomach contents should be evacuated, taking adequate precautions against aspiration and for protection of the airway. Activated charcoal slurry should be instilled. - The effects of reserpine overdosage should be treated symptomatically. If hypotension is severe enough to require treatment with a vasopressor, one having a direct action upon vascular smooth muscle (e.g., phenylephrine, levarterenol, metaraminol) should be used. Since reserpine is long-acting, the patient should be observed carefully for at least 72 hours, and treatment administered as required. ## Chronic Overdose There is limited information regarding Chronic Overdose of Reserpine in the drug label. # Pharmacology ## Mechanism of Action - Reserpine depletes stores of catecholamines and 5-hydroxytryptamine in many organs, including the brain and adrenal medulla. Most of its pharmacological effects have been attributed to this action. Depletion is slower and less complete in the adrenal medulla than in other tissues. The depression of sympathetic nerve function results in a decreased heart rate and a lowering of arterial blood pressure. The sedative and tranquilizing properties of reserpine are thought to be related to depletion of catecholamines and 5-hydroxytryptamine from the brain. ## Structure - Reserpine, USP is an antihypertensive, available as 0.1 mg and 0.25 mg tablets for oral administration. Its chemical name is methyl 18β-hydroxy-11,17 α-dimethoxy-3β, 20α-yohimban-16β-carboxylate 3,4,5-trimethoxybenzoate (ester) and its structural formula is: - Reserpine USP, a pure crystalline alkaloid of rauwolfia, is a white or pale buff to slightly yellowish, odorless crystalline powder. It darkens slowly on exposure to light, but more rapidly when in solution. It is insoluble in water, freely soluble in acetic acid and in chloroform, slightly soluble in benzene, and very slightly soluble in alcohol and in ether. Its molecular weight is 608.69. - Inactive Ingredients: Acacia, confectioner’s sugar, corn starch, lactose monohydrate, magnesium stearate. ## Pharmacodynamics - Reserpine, like other rauwolfia compounds, is characterized by slow onset of action and sustained effects. Both cardiovascular and central nervous system effects may persist for a period of time following withdrawal of the drug. - Mean maximum plasma levels of plasma concentrations after a single dose of 0.5 mg of reserpine, administered as two 0.25 mg tablets or as an aqueous solution, peaked after 2.5 hours. The mean peak level was approximately 1.1 ng/ml. The two formulations were found to be bioequivalent. Absolute bioavailability of reserpine, as established by comparison to an intravenous dose, has been reported to be approximately 50%. ## Pharmacokinetics - Reserpine is extensively bound (95%) to plasma proteins. Reserpine is almost completely metabolized in the body, and only about 1% is excreted as unchanged drug in the urine. No definitive studies on the human metabolism of reserpine have been made. After oral administration, an initial half-life of approximately 5 hours is followed by a terminal half-life of the order of 200 hours. Plasma levels may be measurable 14 days after a single dose. The clinical significance of the long terminal half-life is unknown. ## Nonclinical Toxicology - Animal Tumorigenicity - Rodent studies have shown that reserpine is an animal tumorigen, causing an increased incidence of mammary fibroadenomas in female mice, malignant tumors of the seminal vesicles in male mice, and malignant adrenal medullary tumors in male rats. These findings arose in 2-year studies in which the drug was administered in the feed at concentrations of 5 to 10 ppm – about 100 to 300 times the usual human dose. The breast neoplasms are thought to be related to reserpine’s prolactin-elevating effect. Several other prolactin-elevating drugs have also been associated with an increased incidence of mammary neoplasia in rodents. - The extent to which these findings indicate a risk to humans is uncertain. Tissue culture experiments show that about one third of human breast tumors are prolactin-dependent in vitro, a factor of considerable importance if the use of the drug is contemplated in a patient with previously detected breast cancer. The possibility of an increased risk of breast cancer in reserpine users has been studied extensively; however, no firm conclusion has emerged. Although a few epidemiologic studies have suggested a slightly increased risk (less than twofold in all studies except one) in women who have used reserpine, other studies of generally similar design have not confirmed this. Epidemiologic studies conducted using other drugs (neuroleptic agents) that, like reserpine, increase prolactin levels and therefore would be considered rodent mammary carcinogens have not shown an association between chronic administration of the drug and human mammary tumorigenesis. While long-term clinical observation has not suggested such as association, the available evidence is considered too limited to be conclusive at this time. An association of reserpine intake with pheochromocytoma or tumors of the seminal vesicles has not been explored. # Clinical Studies There is limited information regarding Clinical Studies of Reserpine in the drug label. # How Supplied - Reserpine Tablets, USP for oral administration are available as: - 0.1 mg: round, white, scored tablets, debossed SZ 71 on one side and plain on the reverse side and supplied as: - 0.25 mg: round, white, scored tablets, debossed SZ 77 on one side and plain on the reverse side and supplied as: - Storage - Store at 20°-25°C (68°-77°F) . Protect from moisture. - Preserve in tight, light-resistant containers. ## Storage There is limited information regarding Reserpine Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Patients should be informed of possible side effects and advised to take the medication regularly and continuously as directed. # Precautions with Alcohol - Alcohol-Reserpine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Resa® - Serpalan® # Look-Alike Drug Names - N/A # Drug Shortage Status # Price	Reserpine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gerald Chi # 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 Reserpine is a catecholamine-depleting sympatholytic that is FDA approved for the {{{indicationType}}} of mild essential hypertension. Common adverse reactions include abdominal pain, diarrhea, nausea, vomiting, xerostomia, dizziness, headache, lethargy, somnolence, vertigo, depression, and nasal congestion. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Dosing Information - Initial Dosage - In the average patient not receiving other antihypertensive agents, the usual initial dosage is 0.5 mg daily for 1 or 2 weeks. - Maintenance Dosage - For maintenance, reduce to 0.1–0.25 mg daily. - Higher dosages should be used cautiously, because occurrence of serious mental depression and other side effects may increase considerably. - Dosing Information - Dosage - The usual initial dosage is 0.5 mg daily, but may range from 0.1 mg to 1.0 mg. Adjust dosage upward or downward according to the patient's response. - Reserpine is also useful as adjunctive therapy with other antihypertensive agents in the more severe forms of hypertension; relief of symptoms in agitated psychotic states (e.g., schizophrenia), primarily in those individuals unable to tolerate phenothiazine derivatives or in those who also require antihypertensive medication. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Reserpine in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Reserpine in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Reserpine is not recommended for use in children. - If it is to be used in treating a child, the usual recommended starting dose is 20 µg/kg daily. The maximum recommended dose is 0.25 mg (total) daily. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Reserpine in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Reserpine in pediatric patients. # Contraindications - Hypersensitivity - Mental depression or history of mental depression (especially with suicidal tendencies) - Active peptic ulcer - Ulcerative colitis - Electroconvulsive therapy # Warnings - Extreme caution should be exercised in treating patients with a history of mental depression. Reserpine may cause mental depression. Recognition of depression may be difficult because this condition may often be disguised by somatic complaints (masked depression). The drug should be discontinued at first signs of depression such as despondency, early morning insomnia, loss of appetite, impotence, or self-deprecation. Drug-induced depression may persist for several months after drug withdrawal and may be severe enough to result in suicide. ### Precautions - General - Since reserpine increases gastrointestinal motility and secretion, it should be used cautiously in patients with a history of peptic ulcer, ulcerative colitis, or gallstones (biliary colic may be precipitated). - Caution should be exercised when treating hypertensive patients with renal insufficiency, since they adjust poorly to lowered blood pressure levels. - Preoperative withdrawal of reserpine does not assure that circulatory instability will not occur. It is important that the anesthesiologist be aware of the patient’s drug intake and consider this in the overall management, since hypotension has occurred in patients receiving rauwolfia preparations. Anticholinergic and/or adrenergic drugs (e.g., metaraminol, norepinephrine) have been employed to treat adverse vagocirculatory effects. # Adverse Reactions ## Clinical Trials Experience There is limited information regarding Clinical Trial Experience of Reserpine in the drug label. ## Postmarketing Experience - The following adverse reactions have been observed with rauwolfia preparations, but there has not been enough systematic collection of data to support an estimate of their frequency. Consequently the reactions are categorized by organ system and are listed in decreasing order of severity and not frequency. Rare parkinsonian syndrome and other extrapyramidal tract symptoms; dizziness; headache; paradoxical anxiety; depression; nervousness; nightmares; dull sensorium; drowsiness. Arrhythmias (particularly when used concurrently with digitalis or quinidine), syncope, angina-like symptoms, bradycardia, edema. Dyspnea, epistaxis, nasal congestion. Vomiting, diarrhea, nausea, anorexia, dryness of mouth, hypersecretion. Muscular aches. Pseudolactation, impotence, dysuria, gynecomastia, decreased libido, breast engorgement. Weight gain. Purpura, rash, pruritus. Deafness, optic atrophy, glaucoma, uveitis, conjunctival injection. # Drug Interactions - MAO inhibitors - MAO inhibitors should be avoided or used with extreme caution. - Tricyclic antidepressants - Concurrent use of tricyclic antidepressants may decrease the antihypertensive effect of reserpine. - Reserpine and sympathomimetics - Concurrent use of reserpine and direct-or-indirect acting sympathomimetics should be closely monitored. The action of direct-acting amines (epinephrine, isoproterenol, phenylephrine, metaraminol) may be prolonged when given to patients taking reserpine. The action of indirect-acting amines (ephedrine, tyramine, amphetamines) is inhibited. - Reserpine should be used cautiously with digitalis and quinidine, since cardiac arrhythmias have occurred with rauwolfia preparations. - Concomitant use of reserpine with other antihypertensive agents necessitates careful titration of dosage with each agent. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - Reserpine administered parenterally has been shown to be teratogenic in rats at doses up to 2 mg/kg and to have an embryocidal effect in guinea pigs given dosages of 0.5 mg daily. - There are no adequate and well-controlled studies of reserpine in pregnant women. Reserpine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. - Nonteratogenic Effects - Reserpine crosses the placental barrier, and increased respiratory tract secretions, nasal congestion, cyanosis, and anorexia may occur in neonates of reserpine-treated mothers. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Reserpine in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Reserpine during labor and delivery. ### Nursing Mothers - Reserpine is excreted in maternal breast milk, and increased respiratory tract secretions, nasal congestion, cyanosis, and anorexia may occur in breast-fed infants. Because of the potential for adverse reactions in nursing infants and the potential for tumorigenicity shown for reserpine in animal studies, 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 - Safety and effectiveness in children have not been established by means of controlled clinical trials, although there is experience with the use of reserpine in children. Because of adverse effects such as emotional depression and lability, sedation, and stuffy nose, reserpine is not usually recommended as a step-2 drug in the treatment of hypertension in children. ### Geriatic Use There is no FDA guidance on the use of Reserpine with respect to geriatric patients. ### Gender There is no FDA guidance on the use of Reserpine with respect to specific gender populations. ### Race There is no FDA guidance on the use of Reserpine with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Reserpine in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Reserpine in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Reserpine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Reserpine in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Reserpine in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Reserpine in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - No deaths due to acute poisoning with reserpine have been reported. - Highest known doses survived: children, 1000 mg (age and sex not specified); young children, 200 mg (20-month-old boy). - Oral LD50's in animals (mg/kg): rat, 2993; mouse, 47 and 500. - The clinical picture of acute poisoning is characterized chiefly by signs and symptoms due to the reflex parasympathomimetic effect of reserpine. - Impairment of consciousness may occur and may range from drowsiness to coma, depending upon the severity of overdosage. Flushing of the skin, conjunctival injection, and pupillary constriction are to be expected. Hypotension, hypothermia, central respiratory depression, and bradycardia may develop in cases of severe overdosage. Increased salivary and gastric secretion and diarrhea may also occur. ### Management - There is no specific antidote. - Stomach contents should be evacuated, taking adequate precautions against aspiration and for protection of the airway. Activated charcoal slurry should be instilled. - The effects of reserpine overdosage should be treated symptomatically. If hypotension is severe enough to require treatment with a vasopressor, one having a direct action upon vascular smooth muscle (e.g., phenylephrine, levarterenol, metaraminol) should be used. Since reserpine is long-acting, the patient should be observed carefully for at least 72 hours, and treatment administered as required. ## Chronic Overdose There is limited information regarding Chronic Overdose of Reserpine in the drug label. # Pharmacology ## Mechanism of Action - Reserpine depletes stores of catecholamines and 5-hydroxytryptamine in many organs, including the brain and adrenal medulla. Most of its pharmacological effects have been attributed to this action. Depletion is slower and less complete in the adrenal medulla than in other tissues. The depression of sympathetic nerve function results in a decreased heart rate and a lowering of arterial blood pressure. The sedative and tranquilizing properties of reserpine are thought to be related to depletion of catecholamines and 5-hydroxytryptamine from the brain. ## Structure - Reserpine, USP is an antihypertensive, available as 0.1 mg and 0.25 mg tablets for oral administration. Its chemical name is methyl 18β-hydroxy-11,17 α-dimethoxy-3β, 20α-yohimban-16β-carboxylate 3,4,5-trimethoxybenzoate (ester) and its structural formula is: - Reserpine USP, a pure crystalline alkaloid of rauwolfia, is a white or pale buff to slightly yellowish, odorless crystalline powder. It darkens slowly on exposure to light, but more rapidly when in solution. It is insoluble in water, freely soluble in acetic acid and in chloroform, slightly soluble in benzene, and very slightly soluble in alcohol and in ether. Its molecular weight is 608.69. - Inactive Ingredients: Acacia, confectioner’s sugar, corn starch, lactose monohydrate, magnesium stearate. ## Pharmacodynamics - Reserpine, like other rauwolfia compounds, is characterized by slow onset of action and sustained effects. Both cardiovascular and central nervous system effects may persist for a period of time following withdrawal of the drug. - Mean maximum plasma levels of plasma concentrations after a single dose of 0.5 mg of reserpine, administered as two 0.25 mg tablets or as an aqueous solution, peaked after 2.5 hours. The mean peak level was approximately 1.1 ng/ml. The two formulations were found to be bioequivalent. Absolute bioavailability of reserpine, as established by comparison to an intravenous dose, has been reported to be approximately 50%. ## Pharmacokinetics - Reserpine is extensively bound (95%) to plasma proteins. Reserpine is almost completely metabolized in the body, and only about 1% is excreted as unchanged drug in the urine. No definitive studies on the human metabolism of reserpine have been made. After oral administration, an initial half-life of approximately 5 hours is followed by a terminal half-life of the order of 200 hours. Plasma levels may be measurable 14 days after a single dose. The clinical significance of the long terminal half-life is unknown. ## Nonclinical Toxicology - Animal Tumorigenicity - Rodent studies have shown that reserpine is an animal tumorigen, causing an increased incidence of mammary fibroadenomas in female mice, malignant tumors of the seminal vesicles in male mice, and malignant adrenal medullary tumors in male rats. These findings arose in 2-year studies in which the drug was administered in the feed at concentrations of 5 to 10 ppm – about 100 to 300 times the usual human dose. The breast neoplasms are thought to be related to reserpine’s prolactin-elevating effect. Several other prolactin-elevating drugs have also been associated with an increased incidence of mammary neoplasia in rodents. - The extent to which these findings indicate a risk to humans is uncertain. Tissue culture experiments show that about one third of human breast tumors are prolactin-dependent in vitro, a factor of considerable importance if the use of the drug is contemplated in a patient with previously detected breast cancer. The possibility of an increased risk of breast cancer in reserpine users has been studied extensively; however, no firm conclusion has emerged. Although a few epidemiologic studies have suggested a slightly increased risk (less than twofold in all studies except one) in women who have used reserpine, other studies of generally similar design have not confirmed this. Epidemiologic studies conducted using other drugs (neuroleptic agents) that, like reserpine, increase prolactin levels and therefore would be considered rodent mammary carcinogens have not shown an association between chronic administration of the drug and human mammary tumorigenesis. While long-term clinical observation has not suggested such as association, the available evidence is considered too limited to be conclusive at this time. An association of reserpine intake with pheochromocytoma or tumors of the seminal vesicles has not been explored. # Clinical Studies There is limited information regarding Clinical Studies of Reserpine in the drug label. # How Supplied - Reserpine Tablets, USP for oral administration are available as: - 0.1 mg: round, white, scored tablets, debossed SZ 71 on one side and plain on the reverse side and supplied as: - 0.25 mg: round, white, scored tablets, debossed SZ 77 on one side and plain on the reverse side and supplied as: - Storage - Store at 20°-25°C (68°-77°F) [see USP Controlled Room Temperature]. Protect from moisture. - Preserve in tight, light-resistant containers. ## Storage There is limited information regarding Reserpine Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Patients should be informed of possible side effects and advised to take the medication regularly and continuously as directed. # Precautions with Alcohol - Alcohol-Reserpine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Resa® - Serpalan®[1] # Look-Alike Drug Names - N/A[2] # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Reserpine
6cc38432033aefeaa28cfe11943ac75fb7be360a	wikidoc	Resistome	Resistome The resistome is a proposed expression by Gerard D. Wright for the collection of all the antibiotic resistance genes and their precursors both in pathogenic and non-pathogenic bacteria. This complete set of antibiotic resistance genes is composed of four different types of genes: 1. Resistance genes found on pathogenic bacteria. These are the fewest but also the most problematic ones at present. 2. Resistance genes found on antibiotic producers. The microorganisms such as soil-dwelling bacteria and fungi that naturally produce antibiotics have their own protection mechanisms to avoid the adverse effects of the antibiotics on them selfs. The genes which code for these resistances are a strong source for the pathogenic bacteria. 3. Cryptic resistance genes. These genes are embedded in the bacterial chromosome but do not obviously confer resistance, because their level of expression is usually low or their not expressed. 4. Precursor genes. These genes do not confer antibiotic resistance. However their proteins confer some kind of basal level activity against the antibiotic molecule or have affinity to the molecule. In both cases this interaction may evolve to a full resistance gene given the appropriate selection pressure. The picture below (extracted from reference 1) demonstrates the proportion amount of this four gene types. Note that this groups are not independent, and some overlapping is expected between them. The bacterial resistome and its components: genes present in pathogenic bacteria and antibiotic producers, cryptic resistance genes and resistance precursors genes. Wright, Gerard D. The antibiotic resistome: the nexus of chemical and genetic diversity. Nature Reviews Microbiology Vol. 5, 175-186 (March 2007) Cundliffe, E. How antibiotic-producing organisms avoid suicide. Annu. Rev. Microbiol. 43, 207–233 (1989). Benveniste, R. & Davies, J. Aminoglycoside antibioticinactivating enzymes in actinomycetes similar to those present in clinical isolates of antibiotic-resistant bacteria. Proc. Natl Acad. Sci. USA 70, 2276–2280 (1973). Fabionic 12:14, 12 May 2007 (UTC)	Resistome The resistome is a proposed expression by Gerard D. Wright[1] for the collection of all the antibiotic resistance genes and their precursors both in pathogenic and non-pathogenic bacteria. This complete set of antibiotic resistance genes is composed of four different types of genes: 1. Resistance genes found on pathogenic bacteria. These are the fewest but also the most problematic ones at present. 2. Resistance genes found on antibiotic producers. The microorganisms such as soil-dwelling bacteria and fungi that naturally produce antibiotics have their own protection mechanisms[2] to avoid the adverse effects of the antibiotics on them selfs. The genes which code for these resistances are a strong source[3] for the pathogenic bacteria. 3. Cryptic resistance genes. These genes are embedded in the bacterial chromosome but do not obviously confer resistance, because their level of expression is usually low or their not expressed. 4. Precursor genes. These genes do not confer antibiotic resistance. However their proteins confer some kind of basal level activity against the antibiotic molecule or have affinity to the molecule. In both cases this interaction may evolve to a full resistance gene given the appropriate selection pressure. The picture below (extracted from reference 1) demonstrates the proportion amount of this four gene types. Note that this groups are not independent, and some overlapping is expected between them. The bacterial resistome and its components: genes present in pathogenic bacteria and antibiotic producers, cryptic resistance genes and resistance precursors genes. [1] Wright, Gerard D. The antibiotic resistome: the nexus of chemical and genetic diversity. Nature Reviews Microbiology Vol. 5, 175-186 (March 2007) [2] Cundliffe, E. How antibiotic-producing organisms avoid suicide. Annu. Rev. Microbiol. 43, 207–233 (1989). [3] Benveniste, R. & Davies, J. Aminoglycoside antibioticinactivating enzymes in actinomycetes similar to those present in clinical isolates of antibiotic-resistant bacteria. Proc. Natl Acad. Sci. USA 70, 2276–2280 (1973). Fabionic 12:14, 12 May 2007 (UTC) Template:WH Template:WS	https://www.wikidoc.org/index.php/Resistome
c48ff5d5995b441a31fd9a22ab3209beaef92d65	wikidoc	Resonance	Resonance # Overview In physics, resonance is the tendency of a system to oscillate at larger amplitude at some frequencies than at others. These are known as the system's resonance frequencies (or resonant frequencies). At these frequencies, even small periodic driving forces can produce large amplitude vibrations, because the system stores vibrational energy. When damping is small, the resonance frequency is approximately equal to the natural frequency of the system, which is the frequency of free vibrations. Resonant phenomena occur with all types of vibrations or waves: there is mechanical resonance, acoustic resonance, electromagnetic resonance, Nuclear Magnetic Resonance (NMR), Electron Spin Resonance (ESR) and resonance of quantum wave functions. Resonant systems can be used to generate vibrations of a specific frequency, or pick out specific frequencies from a complex vibration containing many frequencies. Resonance was discovered by Galileo Galilei with his investigations of pendulums beginning in 1602. # Orbital resonance In celestial mechanics, an orbital resonance occurs when two orbiting bodies exert a regular, periodic gravitational influence on each other, usually due to their orbital periods being related by a ratio of two small integers. Orbital resonances greatly enhance the mutual gravitational influence of the bodies. In most cases, this results in an unstable interaction, in which the bodies exchange momentum and shift orbits until the resonance no longer exists. Under some circumstances, a resonant system can be stable and self correcting, so that the bodies remain in resonance. Examples are the 1:2:4 resonance of Jupiter's moons Ganymede, Europa, and Io, and the 2:3 resonance between Pluto and Neptune. Unstable resonances with Saturn's inner moons give rise to gaps in the rings of Saturn. The special case of 1:1 resonance (between bodies with similar orbital radii) causes large Solar System bodies to clear the neighborhood around their orbits by ejecting nearly everything else around them; this effect is used in the current definition of a planet. # Atomic, particle, and molecular resonance Nuclear magnetic resonance (NMR) is the name given to a physical resonance phenomenon involving the observation of specific quantum mechanical magnetic properties of an atomic nucleus in the presence of an applied, external magnetic field. Many scientific techniques exploit NMR phenomena to study molecular physics, crystals and non-crystalline materials through NMR spectroscopy. NMR is also routinely used in advanced medical imaging techniques, such as in magnetic resonance imaging (MRI). All nuclei that contain odd numbers of nucleons have an intrinsic magnetic moment and angular momentum. A key feature of NMR is that the resonance frequency of a particular substance is directly proportional to the strength of the applied magnetic field. It is this feature that is exploited in imaging techniques; if a sample is placed in a non-uniform magnetic field then the resonance frequencies of the sample's nuclei depend on where in the field they are located. Therefore, the particle can be located quite precisely from its resonance frequency. Electron paramagnetic resonance, otherwise known as Electron Spin Resonance (ESR) is a spectroscopic technique similar to NMR used with unpaired electrons instead. Materials for which this can be applied are much more limited since the material needs to both have an unpaired spin and be paramagnetic. The Mössbauer effect is a physical phenomenon discovered by Rudolf Mößbauer in 1957; it refers to the resonant and recoil-free emission and absorption of gamma ray photons by atoms bound in a solid form. Resonance (particle): In quantum mechanics and quantum field theory resonances may appear in similar circumstances to classical physics. However, they can also be thought of as unstable particles, with the formula above still valid if the \Gamma is the decay rate and \Omega replaced by the particle's mass M. In that case, the formula just comes from the particle's propagator, with its mass replaced by the complex number M+i\Gamma. The formula is further related to the particle's decay rate by the optical theorem.	Resonance # Overview In physics, resonance is the tendency of a system to oscillate at larger amplitude at some frequencies than at others. These are known as the system's resonance frequencies (or resonant frequencies). At these frequencies, even small periodic driving forces can produce large amplitude vibrations, because the system stores vibrational energy. When damping is small, the resonance frequency is approximately equal to the natural frequency of the system, which is the frequency of free vibrations. Resonant phenomena occur with all types of vibrations or waves: there is mechanical resonance, acoustic resonance, electromagnetic resonance, Nuclear Magnetic Resonance (NMR), Electron Spin Resonance (ESR) and resonance of quantum wave functions. Resonant systems can be used to generate vibrations of a specific frequency, or pick out specific frequencies from a complex vibration containing many frequencies. Resonance was discovered by Galileo Galilei with his investigations of pendulums beginning in 1602. # Orbital resonance In celestial mechanics, an orbital resonance occurs when two orbiting bodies exert a regular, periodic gravitational influence on each other, usually due to their orbital periods being related by a ratio of two small integers. Orbital resonances greatly enhance the mutual gravitational influence of the bodies. In most cases, this results in an unstable interaction, in which the bodies exchange momentum and shift orbits until the resonance no longer exists. Under some circumstances, a resonant system can be stable and self correcting, so that the bodies remain in resonance. Examples are the 1:2:4 resonance of Jupiter's moons Ganymede, Europa, and Io, and the 2:3 resonance between Pluto and Neptune. Unstable resonances with Saturn's inner moons give rise to gaps in the rings of Saturn. The special case of 1:1 resonance (between bodies with similar orbital radii) causes large Solar System bodies to clear the neighborhood around their orbits by ejecting nearly everything else around them; this effect is used in the current definition of a planet. # Atomic, particle, and molecular resonance Nuclear magnetic resonance (NMR) is the name given to a physical resonance phenomenon involving the observation of specific quantum mechanical magnetic properties of an atomic nucleus in the presence of an applied, external magnetic field. Many scientific techniques exploit NMR phenomena to study molecular physics, crystals and non-crystalline materials through NMR spectroscopy. NMR is also routinely used in advanced medical imaging techniques, such as in magnetic resonance imaging (MRI). All nuclei that contain odd numbers of nucleons have an intrinsic magnetic moment and angular momentum. A key feature of NMR is that the resonance frequency of a particular substance is directly proportional to the strength of the applied magnetic field. It is this feature that is exploited in imaging techniques; if a sample is placed in a non-uniform magnetic field then the resonance frequencies of the sample's nuclei depend on where in the field they are located. Therefore, the particle can be located quite precisely from its resonance frequency. Electron paramagnetic resonance, otherwise known as Electron Spin Resonance (ESR) is a spectroscopic technique similar to NMR used with unpaired electrons instead. Materials for which this can be applied are much more limited since the material needs to both have an unpaired spin and be paramagnetic. The Mössbauer effect is a physical phenomenon discovered by Rudolf Mößbauer in 1957; it refers to the resonant and recoil-free emission and absorption of gamma ray photons by atoms bound in a solid form. Resonance (particle): In quantum mechanics and quantum field theory resonances may appear in similar circumstances to classical physics. However, they can also be thought of as unstable particles, with the formula above still valid if the <math>\Gamma</math> is the decay rate and <math>\Omega</math> replaced by the particle's mass M. In that case, the formula just comes from the particle's propagator, with its mass replaced by the complex number <math>M+i\Gamma</math>. The formula is further related to the particle's decay rate by the optical theorem.	https://www.wikidoc.org/index.php/Resonance
26152a5549ef17370d72fc018a268400acd0768e	wikidoc	Temazepam	Temazepam # 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 Temazepam is a benzodiazepines that is FDA approved for the treatment of insomnia (generally 7 to 10 days). Common adverse reactions include anorexia, ataxia, equilibrium loss, tremor, increased dreaming, dyspnea, palpitations, vomiting, backache, hyperhidrosis, burning eyes, amnesia, hallucinations, horizontal nystagmus, and paradoxical reactions including restlessness, overstimulation and agitation were rare (less than 0.5%). # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - It is indicated for the short-term treatment of insomnia (generally 7 to 10 days). - For patients with short-term insomnia, instructions in the prescription should indicate that Restoril™ (temazepam) should be used for short periods of time (7 to 10 days). - The clinical trials performed in support of efficacy were 2 weeks in duration with the final formal assessment of sleep latency performed at the end of treatment. - While the recommended usual adult dose is 15 mg before retiring, 7.5 mg may be sufficient for some patients, and others may need 30 mg. In transient insomnia, a 7.5 mg dose may be sufficient to improve sleep latency. In elderly or debilitated patients, it is recommended that therapy be initiated with 7.5 mg until individual responses are determined. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Temazepam in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Temazepam in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Temazepam 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 Temazepam in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Temazepam in pediatric patients. # Contraindications - Benzodiazepines may cause fetal harm when administered to a pregnant woman. - An increased risk of congenital malformations associated with the use of diazepam and chlordiazepoxide during the first trimester of pregnancy has been suggested in several studies. - Transplacental distribution has resulted in neonatal CNS depression following the ingestion of therapeutic doses of a benzodiazepine hypnotic during the last weeks of pregnancy. - Reproduction studies in animals with temazepam were performed in rats and rabbits. - In a perinatal-postnatal study in rats, oral doses of 60 mg/kg/day resulted in increasing nursling mortality. - Teratology studies in rats demonstrated increased fetal resorptions at doses of 30 and 120 mg/kg in one study and increased occurrence of rudimentary ribs, which are considered skeletal variants, in a second study at doses of 240 mg/kg or higher. - In rabbits, occasional abnormalities such as exencephaly and fusion or asymmetry of ribs were reported without dose relationship. - Although these abnormalities were not found in the concurrent control group, they have been reported to occur randomly in historical controls. - At doses of 40 mg/kg or higher, there was an increased incidence of the 13th rib variant when compared to the incidence in concurrent and historical controls. - Restoril is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Patients should be instructed to discontinue the drug prior to becoming pregnant. The possibility that a woman of childbearing potential may be pregnant at the time of institution of therapy should be considered. # Warnings - Sleep disturbance may be the presenting manifestation of an underlying physical and/or psychiatric disorder. - Consequently, a decision to initiate symptomatic treatment of insomnia should only be made after the patient has been carefully evaluated. - The failure of insomnia to remit after 7 to 10 days of treatment may indicate the presence of a primary psychiatric and/or medical illness that should be evaluated. - Worsening of insomnia may be the consequence of an unrecognized psychiatric or physical disorder as may the emergence of new abnormalities of thinking or behavior. Such abnormalities have also been reported to occur in association with the use of drugs with central nervous system depressant activity, including those of the benzodiazepine class. - Because some of the worrisome adverse effects of benzodiazepines, including Restoril, appear to be dose related, it is important to use the lowest possible effective dose. Elderly patients are especially at risk. - Some of these changes may be characterized by decreased inhibition, e.g., aggressiveness and extroversion that seem out of character, similar to that seen with alcohol. - Other kinds of behavioral changes can also occur, for example, bizarre behavior, agitation, hallucinations, and depersonalization. Complex behaviors such as “sleep-driving” (i.e., driving while not fully awake after ingestion of a sedative-hypnotic, with amnesia for the event) have been reported. - These events can occur in sedative-hypnotic-naïve as well as in sedative-hypnotic-experienced persons. - Although behaviors such as sleep-driving may occur with Restoril alone at therapeutic doses, the use of alcohol and other CNS depressants with Restoril appears to increase the risk of such behaviors, as does the use of Restoril at doses exceeding the maximum recommended dose. - Due to the risk to the patient and the community, discontinuation of Restoril should be strongly considered for patients who report a “sleep-driving” episode. Other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex) have been reported in patients who are not fully awake after taking a sedative-hypnotic. As with sleep-driving, patients usually do not remember these events. - Amnesia and other neuro-psychiatric symptoms may occur unpredictably. In primarily depressed patients, worsening of depression, including suicidal thinking has been reported in association with the use of sedative/hypnotics. - It can rarely be determined with certainty whether a particular instance of the abnormal behaviors listed above is drug induced, spontaneous in origin, or a result of an underlying psychiatric or physical disorder. - Nonetheless, the emergence of any new behavioral sign or symptom of concern requires careful and immediate evaluation. - Withdrawal symptoms (of the barbiturate type) have occurred after the abrupt discontinuation of benzodiazepines. ### Severe Anaphylactic and Anaphylactoid Reactions - Rare cases of angioedema involving the tongue, glottis or larynx have been reported in patients after taking the first or subsequent doses of sedative-hypnotics, including Restoril. - Some patients have had additional symptoms such as dyspnea, throat closing, or nausea and vomiting that suggest anaphylaxis. Some patients have required medical therapy in the emergency department. - If angioedema involves the tongue, glottis or larynx, airway obstruction may occur and be fatal. Patients who develop angioedema after treatment with Restoril should not be rechallenged with the drug. # Adverse Reactions ## Clinical Trials Experience There is limited information regarding Temazepam Clinical Trials Experience in the drug label. ## Postmarketing Experience - The following adverse events have been reported less frequently (0.5% to 0.9%): ### Central Nervous System - Anorexia, ataxia, equilibrium loss, tremor, increased dreaming ### Cardiovascular - Dyspnea, palpitations ### Gastrointestinal - Vomiting ### Musculoskeletal - Backache ### Special Senses - Hyperhidrosis, burning eyes ### Psychological - Amnesia, hallucinations, horizontal nystagmus, and paradoxical reactions including restlessness, overstimulation and agitation were rare (less than 0.5%). # Drug Interactions There is limited information regarding Temazepam Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): There is no FDA guidance on usage of Temazepam in women who are pregnant. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Temazepam in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Temazepam during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Temazepam with respect to nursing mothers. ### Pediatric Use There is no FDA guidance on the use of Temazepam with respect to pediatric patients. ### Geriatic Use There is no FDA guidance on the use of Temazepam with respect to geriatric patients. ### Gender There is no FDA guidance on the use of Temazepam with respect to specific gender populations. ### Race There is no FDA guidance on the use of Temazepam with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Temazepam in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Temazepam in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Temazepam in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Temazepam in patients who are immunocompromised. # Administration and Monitoring ### Administration - While the recommended usual adult dose is 15 mg before retiring, 7.5 mg may be sufficient for some patients, and others may need 30 mg. In transient insomnia, a 7.5 mg dose may be sufficient to improve sleep latency. In elderly or debilitated patients, it is recommended that therapy be initiated with 7.5 mg until individual responses are determined. ### Monitoring There is limited information regarding Temazepam Monitoring in the drug label. # IV Compatibility - Intravenous # Overdosage - Manifestations of acute overdosage of Restoril can be expected to reflect the CNS effects of the drug and include somnolence, confusion, and coma, with reduced or absent reflexes, respiratory depression, and hypotension. - The oral LD50 of Restoril was 1963 mg/kg in mice, 1833 mg/kg in rats, and >2400 mg/kg in rabbits. ### Treatment - If the patient is conscious, vomiting should be induced mechanically or with emetics. - Gastric lavage should be employed utilizing concurrently a cuffed endotracheal tube if the patient is unconscious to prevent aspiration and pulmonary complications. - Maintenance of adequate pulmonary ventilation is essential. The use of pressor agents intravenously may be necessary to combat hypotension. - Fluids should be administered intravenously to encourage diuresis. The value of dialysis has not been determined. If excitation occurs, barbiturates should not be used. - It should be borne in mind that multiple agents may have been ingested. Flumazenil (Romazicon®)*, a specific benzodiazepine receptor antagonist, is indicated for the complete or partial reversal of the sedative effects of benzodiazepines and may be used in situations when an overdose with a benzodiazepine is known or suspected. - Prior to the administration of flumazenil, necessary measures should be instituted to secure airway, ventilation, and intravenous access. - Flumazenil is intended as an adjunct to, not as a substitute for, proper management of benzodiazepine overdose. - Patients treated with flumazenil should be monitored for re-sedation, respiratory depression, and other residual benzodiazepine effects for an appropriate period after treatment. - The prescriber should be aware of a risk of seizure in association with flumazenil treatment, particularly in long-term benzodiazepine users and in cyclic antidepressant overdose. - Up-to-date information about the treatment of overdose can often be obtained from a certified Regional Poison Control Center. Telephone numbers of certified Regional Poison Control Centers are listed in the Physicians. ### DOSAGE AND ADMINISTRATION - While the recommended usual adult dose is 15 mg before retiring, 7.5 mg may be sufficient for some patients, and others may need 30 mg. In transient insomnia, a 7.5 mg dose may be sufficient to improve sleep latency. - In elderly or debilitated patients, it is recommended that therapy be initiated with 7.5 mg until individual responses are determined. # Pharmacology ## Mechanism of Action There is limited information regarding Temazepam Mechanism of Action in the drug label. ## Structure There is limited information regarding Temazepam Structure in the drug label. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Temazepam in the drug label. ## Pharmacokinetics - In a single and multiple dose absorption, distribution, metabolism, and excretion (ADME) study, using 3H labeled drug, Restoril was well absorbed and found to have minimal (8%) first pass metabolism. There were no active metabolites formed and the only significant metabolite present in blood was the O-conjugate. - The unchanged drug was 96% bound to plasma proteins. The blood level decline of the parent drug was biphasic with the short half-life ranging from 0.4 to 0.6 hours and the terminal half-life from 3.5 to 18.4 hours (mean 8.8 hours), depending on the study population and method of determination. - Metabolites were formed with a half-life of 10 hours and excreted with a half-life of approximately 2 hours. Thus, formation of the major metabolite is the rate limiting step in the biodisposition of temazepam. - There is no accumulation of metabolites. A dose-proportional relationship has been established for the area under the plasma concentration/time curve over the 15 to 30 mg dose range. - Temazepam was completely metabolized through conjugation prior to excretion; 80% to 90% of the dose appeared in the urine. The major metabolite was the O-conjugate of temazepam (90%); the O-conjugate of N-desmethyl temazepam was a minor metabolite (7%). ### Bioavailability, Induction, and Plasma Levels - Following ingestion of a 30 mg Restoril capsule, measurable plasma concentrations were achieved 10 to 20 minutes after dosing with peak plasma levels ranging from 666 to 982 ng/mL (mean 865 ng/mL) occurring approximately 1.2 to 1.6 hours (mean 1.5 hours) after dosing. - In a 7 day study, in which subjects were given a 30 mg Restoril capsule 1 hour before retiring, steady-state (as measured by the attainment of maximal trough concentrations) was achieved by the third dose. Mean plasma levels of temazepam (for days 2 to 7) were 260±210 ng/mL at 9 hours and 75±80 ng/mL at 24 hours after dosing. A slight trend toward declining 24 hour plasma levels was seen after day 4 in the study, however, the 24 hour plasma levels were quite variable. - At a dose of 30 mg once-a-day for 8 weeks, no evidence of enzyme induction was found in man. - Elimination Rate of Benzodiazepine Hypnotics and Profile of Common Untoward Effects - The type and duration of hypnotic effects and the profile of unwanted effects during administration of benzodiazepine hypnotics may be influenced by the biologic half-life of the administered drug and for some hypnotics, the half-life of any active metabolites formed. Benzodiazepine hypnotics have a spectrum of half-lives from short (20 hours). - When half-lives are long, drug (and for some drugs their active metabolites) may accumulate during periods of nightly administration and be associated with impairments of cognitive and/or motor performance during waking hours; the possibility of interaction with other psychoactive drugs or alcohol will be enhanced. In contrast, if half-lives are shorter, drug (and, where appropriate, its active metabolites) will be cleared before the next dose is ingested, and carry-over effects related to excessive sedation or CNS depression should be minimal or absent. However, during nightly use for an extended period, pharmacodynamic tolerance or adaptation to some effects of benzodiazepine hypnotics may develop. - If the drug has a short elimination half-life, it is possible that a relative deficiency of the drug, or, if appropriate, its active metabolites (i.e., in relationship to the receptor site) may occur at some point in the interval between each night's use. This sequence of events may account for 2 clinical findings reported to occur after several weeks of nightly use of rapidly eliminated benzodiazepine hypnotics, namely, increased wakefulness during the last third of the night, and the appearance of increased signs of daytime anxiety. ### Controlled Trials Supporting Efficacy - Restoril improved sleep parameters in clinical studies. Residual medication effects (“hangover”) were essentially absent. Early morning awakening, a particular problem in the geriatric patient, was significantly reduced. - Patients with chronic insomnia were evaluated in 2 week, placebo controlled sleep laboratory studies with Restoril at doses of 7.5 mg, 15 mg, and 30 mg, given 30 minutes prior to bedtime. There was a linear dose-response improvement in total sleep time and sleep latency, with significant drug-placebo differences at 2 weeks occurring only for total sleep time at the 2 higher doses, and for sleep latency only at the highest dose. - In these sleep laboratory studies, REM sleep was essentially unchanged and slow wave sleep was decreased. No measurable effects on daytime alertness or performance occurred following Restoril treatment or during the withdrawal period, even though a transient sleep disturbance in some sleep parameters was observed following withdrawal of the higher doses. - There was no evidence of tolerance development in the sleep laboratory parameters when patients were given Restoril nightly for at least 2 weeks. - In addition, normal subjects with transient insomnia associated with first night adaptation to the sleep laboratory were evaluated in 24 hour, placebo controlled sleep laboratory studies with Restoril at doses of 7.5 mg, 15 mg, and 30 mg, given 30 minutes prior to bedtime. - There was a linear dose-response improvement in total sleep time, sleep latency and number of awakenings, with significant drug-placebo differences occurring for sleep latency at all doses, for total sleep time at the 2 higher doses and for number of awakenings only at the 30 mg dose. ## Nonclinical Toxicology There is limited information regarding Temazepam Nonclinical Toxicology in the drug label. # Clinical Studies There is limited information regarding Clinical Studies of Temazepam in the drug label. # How Supplied - Restoril™ (temazepam) Capsules USP 7.5 mg - Blue and pink capsules, with the pink body imprinted “FOR SLEEP” on one side and Boxed M on the other side in red, and a blue cap imprinted “RESTORIL 7.5 mg” twice in red. Bottle of 30-NDC 0406-9915-03 Bottle of 100-NDC 0406-9915-01 15 mg - Maroon and pink capsules, with the pink body imprinted “FOR SLEEP” on one side and Boxed M on the other side in red, and a maroon cap imprinted “RESTORIL 15 mg” twice in white. Bottle of 100-NDC 0406-9916-01 22.5 mg - Opaque blue capsules, with the opaque blue body imprinted “FOR SLEEP” on one side and Boxed M on the other side in red, and an opaque blue cap imprinted “RESTORIL 22.5 mg” twice in red. Bottle of 30-NDC 0406-9914-03 30 mg - Maroon and blue capsules, with the blue body imprinted “FOR SLEEP” on one side and Boxed M on the other side in red, and a maroon cap imprinted “RESTORIL 30 mg” twice in white. Bottle of 100-NDC 0406-9917-01 - Dispense in a well-closed, light-resistant container with a child-resistant closure. ## Storage - 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 Temazepam Patient Counseling Information in the drug label. # Precautions with Alcohol Alcohol-Temazepam 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 Temazepam Brand Names in the drug label. # Look-Alike Drug Names There is limited information regarding Temazepam Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Temazepam 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. # Overview Temazepam is a benzodiazepines that is FDA approved for the treatment of insomnia (generally 7 to 10 days). Common adverse reactions include anorexia, ataxia, equilibrium loss, tremor, increased dreaming, dyspnea, palpitations, vomiting, backache, hyperhidrosis, burning eyes, amnesia, hallucinations, horizontal nystagmus, and paradoxical reactions including restlessness, overstimulation and agitation were rare (less than 0.5%). # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - It is indicated for the short-term treatment of insomnia (generally 7 to 10 days). - For patients with short-term insomnia, instructions in the prescription should indicate that Restoril™ (temazepam) should be used for short periods of time (7 to 10 days). - The clinical trials performed in support of efficacy were 2 weeks in duration with the final formal assessment of sleep latency performed at the end of treatment. - While the recommended usual adult dose is 15 mg before retiring, 7.5 mg may be sufficient for some patients, and others may need 30 mg. In transient insomnia, a 7.5 mg dose may be sufficient to improve sleep latency. In elderly or debilitated patients, it is recommended that therapy be initiated with 7.5 mg until individual responses are determined. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Temazepam in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Temazepam in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Temazepam 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 Temazepam in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Temazepam in pediatric patients. # Contraindications - Benzodiazepines may cause fetal harm when administered to a pregnant woman. - An increased risk of congenital malformations associated with the use of diazepam and chlordiazepoxide during the first trimester of pregnancy has been suggested in several studies. - Transplacental distribution has resulted in neonatal CNS depression following the ingestion of therapeutic doses of a benzodiazepine hypnotic during the last weeks of pregnancy. - Reproduction studies in animals with temazepam were performed in rats and rabbits. - In a perinatal-postnatal study in rats, oral doses of 60 mg/kg/day resulted in increasing nursling mortality. - Teratology studies in rats demonstrated increased fetal resorptions at doses of 30 and 120 mg/kg in one study and increased occurrence of rudimentary ribs, which are considered skeletal variants, in a second study at doses of 240 mg/kg or higher. - In rabbits, occasional abnormalities such as exencephaly and fusion or asymmetry of ribs were reported without dose relationship. - Although these abnormalities were not found in the concurrent control group, they have been reported to occur randomly in historical controls. - At doses of 40 mg/kg or higher, there was an increased incidence of the 13th rib variant when compared to the incidence in concurrent and historical controls. - Restoril is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Patients should be instructed to discontinue the drug prior to becoming pregnant. The possibility that a woman of childbearing potential may be pregnant at the time of institution of therapy should be considered. # Warnings - Sleep disturbance may be the presenting manifestation of an underlying physical and/or psychiatric disorder. - Consequently, a decision to initiate symptomatic treatment of insomnia should only be made after the patient has been carefully evaluated. - The failure of insomnia to remit after 7 to 10 days of treatment may indicate the presence of a primary psychiatric and/or medical illness that should be evaluated. - Worsening of insomnia may be the consequence of an unrecognized psychiatric or physical disorder as may the emergence of new abnormalities of thinking or behavior. Such abnormalities have also been reported to occur in association with the use of drugs with central nervous system depressant activity, including those of the benzodiazepine class. - Because some of the worrisome adverse effects of benzodiazepines, including Restoril, appear to be dose related, it is important to use the lowest possible effective dose. Elderly patients are especially at risk. - Some of these changes may be characterized by decreased inhibition, e.g., aggressiveness and extroversion that seem out of character, similar to that seen with alcohol. - Other kinds of behavioral changes can also occur, for example, bizarre behavior, agitation, hallucinations, and depersonalization. Complex behaviors such as “sleep-driving” (i.e., driving while not fully awake after ingestion of a sedative-hypnotic, with amnesia for the event) have been reported. - These events can occur in sedative-hypnotic-naïve as well as in sedative-hypnotic-experienced persons. - Although behaviors such as sleep-driving may occur with Restoril alone at therapeutic doses, the use of alcohol and other CNS depressants with Restoril appears to increase the risk of such behaviors, as does the use of Restoril at doses exceeding the maximum recommended dose. - Due to the risk to the patient and the community, discontinuation of Restoril should be strongly considered for patients who report a “sleep-driving” episode. Other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex) have been reported in patients who are not fully awake after taking a sedative-hypnotic. As with sleep-driving, patients usually do not remember these events. - Amnesia and other neuro-psychiatric symptoms may occur unpredictably. In primarily depressed patients, worsening of depression, including suicidal thinking has been reported in association with the use of sedative/hypnotics. - It can rarely be determined with certainty whether a particular instance of the abnormal behaviors listed above is drug induced, spontaneous in origin, or a result of an underlying psychiatric or physical disorder. - Nonetheless, the emergence of any new behavioral sign or symptom of concern requires careful and immediate evaluation. - Withdrawal symptoms (of the barbiturate type) have occurred after the abrupt discontinuation of benzodiazepines. ### Severe Anaphylactic and Anaphylactoid Reactions - Rare cases of angioedema involving the tongue, glottis or larynx have been reported in patients after taking the first or subsequent doses of sedative-hypnotics, including Restoril. - Some patients have had additional symptoms such as dyspnea, throat closing, or nausea and vomiting that suggest anaphylaxis. Some patients have required medical therapy in the emergency department. - If angioedema involves the tongue, glottis or larynx, airway obstruction may occur and be fatal. Patients who develop angioedema after treatment with Restoril should not be rechallenged with the drug. # Adverse Reactions ## Clinical Trials Experience There is limited information regarding Temazepam Clinical Trials Experience in the drug label. ## Postmarketing Experience - The following adverse events have been reported less frequently (0.5% to 0.9%): ### Central Nervous System - Anorexia, ataxia, equilibrium loss, tremor, increased dreaming ### Cardiovascular - Dyspnea, palpitations ### Gastrointestinal - Vomiting ### Musculoskeletal - Backache ### Special Senses - Hyperhidrosis, burning eyes ### Psychological - Amnesia, hallucinations, horizontal nystagmus, and paradoxical reactions including restlessness, overstimulation and agitation were rare (less than 0.5%). # Drug Interactions There is limited information regarding Temazepam Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): There is no FDA guidance on usage of Temazepam in women who are pregnant. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Temazepam in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Temazepam during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Temazepam with respect to nursing mothers. ### Pediatric Use There is no FDA guidance on the use of Temazepam with respect to pediatric patients. ### Geriatic Use There is no FDA guidance on the use of Temazepam with respect to geriatric patients. ### Gender There is no FDA guidance on the use of Temazepam with respect to specific gender populations. ### Race There is no FDA guidance on the use of Temazepam with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Temazepam in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Temazepam in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Temazepam in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Temazepam in patients who are immunocompromised. # Administration and Monitoring ### Administration - While the recommended usual adult dose is 15 mg before retiring, 7.5 mg may be sufficient for some patients, and others may need 30 mg. In transient insomnia, a 7.5 mg dose may be sufficient to improve sleep latency. In elderly or debilitated patients, it is recommended that therapy be initiated with 7.5 mg until individual responses are determined. ### Monitoring There is limited information regarding Temazepam Monitoring in the drug label. # IV Compatibility - Intravenous # Overdosage - Manifestations of acute overdosage of Restoril can be expected to reflect the CNS effects of the drug and include somnolence, confusion, and coma, with reduced or absent reflexes, respiratory depression, and hypotension. - The oral LD50 of Restoril was 1963 mg/kg in mice, 1833 mg/kg in rats, and >2400 mg/kg in rabbits. ### Treatment - If the patient is conscious, vomiting should be induced mechanically or with emetics. - Gastric lavage should be employed utilizing concurrently a cuffed endotracheal tube if the patient is unconscious to prevent aspiration and pulmonary complications. - Maintenance of adequate pulmonary ventilation is essential. The use of pressor agents intravenously may be necessary to combat hypotension. - Fluids should be administered intravenously to encourage diuresis. The value of dialysis has not been determined. If excitation occurs, barbiturates should not be used. - It should be borne in mind that multiple agents may have been ingested. Flumazenil (Romazicon®)*, a specific benzodiazepine receptor antagonist, is indicated for the complete or partial reversal of the sedative effects of benzodiazepines and may be used in situations when an overdose with a benzodiazepine is known or suspected. - Prior to the administration of flumazenil, necessary measures should be instituted to secure airway, ventilation, and intravenous access. - Flumazenil is intended as an adjunct to, not as a substitute for, proper management of benzodiazepine overdose. - Patients treated with flumazenil should be monitored for re-sedation, respiratory depression, and other residual benzodiazepine effects for an appropriate period after treatment. - The prescriber should be aware of a risk of seizure in association with flumazenil treatment, particularly in long-term benzodiazepine users and in cyclic antidepressant overdose. - Up-to-date information about the treatment of overdose can often be obtained from a certified Regional Poison Control Center. Telephone numbers of certified Regional Poison Control Centers are listed in the Physicians. ### DOSAGE AND ADMINISTRATION - While the recommended usual adult dose is 15 mg before retiring, 7.5 mg may be sufficient for some patients, and others may need 30 mg. In transient insomnia, a 7.5 mg dose may be sufficient to improve sleep latency. - In elderly or debilitated patients, it is recommended that therapy be initiated with 7.5 mg until individual responses are determined. # Pharmacology ## Mechanism of Action There is limited information regarding Temazepam Mechanism of Action in the drug label. ## Structure There is limited information regarding Temazepam Structure in the drug label. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Temazepam in the drug label. ## Pharmacokinetics - In a single and multiple dose absorption, distribution, metabolism, and excretion (ADME) study, using 3H labeled drug, Restoril was well absorbed and found to have minimal (8%) first pass metabolism. There were no active metabolites formed and the only significant metabolite present in blood was the O-conjugate. - The unchanged drug was 96% bound to plasma proteins. The blood level decline of the parent drug was biphasic with the short half-life ranging from 0.4 to 0.6 hours and the terminal half-life from 3.5 to 18.4 hours (mean 8.8 hours), depending on the study population and method of determination. - Metabolites were formed with a half-life of 10 hours and excreted with a half-life of approximately 2 hours. Thus, formation of the major metabolite is the rate limiting step in the biodisposition of temazepam. - There is no accumulation of metabolites. A dose-proportional relationship has been established for the area under the plasma concentration/time curve over the 15 to 30 mg dose range. - Temazepam was completely metabolized through conjugation prior to excretion; 80% to 90% of the dose appeared in the urine. The major metabolite was the O-conjugate of temazepam (90%); the O-conjugate of N-desmethyl temazepam was a minor metabolite (7%). ### Bioavailability, Induction, and Plasma Levels - Following ingestion of a 30 mg Restoril capsule, measurable plasma concentrations were achieved 10 to 20 minutes after dosing with peak plasma levels ranging from 666 to 982 ng/mL (mean 865 ng/mL) occurring approximately 1.2 to 1.6 hours (mean 1.5 hours) after dosing. - In a 7 day study, in which subjects were given a 30 mg Restoril capsule 1 hour before retiring, steady-state (as measured by the attainment of maximal trough concentrations) was achieved by the third dose. Mean plasma levels of temazepam (for days 2 to 7) were 260±210 ng/mL at 9 hours and 75±80 ng/mL at 24 hours after dosing. A slight trend toward declining 24 hour plasma levels was seen after day 4 in the study, however, the 24 hour plasma levels were quite variable. - At a dose of 30 mg once-a-day for 8 weeks, no evidence of enzyme induction was found in man. - Elimination Rate of Benzodiazepine Hypnotics and Profile of Common Untoward Effects - The type and duration of hypnotic effects and the profile of unwanted effects during administration of benzodiazepine hypnotics may be influenced by the biologic half-life of the administered drug and for some hypnotics, the half-life of any active metabolites formed. Benzodiazepine hypnotics have a spectrum of half-lives from short (<4 hours) to long (>20 hours). - When half-lives are long, drug (and for some drugs their active metabolites) may accumulate during periods of nightly administration and be associated with impairments of cognitive and/or motor performance during waking hours; the possibility of interaction with other psychoactive drugs or alcohol will be enhanced. In contrast, if half-lives are shorter, drug (and, where appropriate, its active metabolites) will be cleared before the next dose is ingested, and carry-over effects related to excessive sedation or CNS depression should be minimal or absent. However, during nightly use for an extended period, pharmacodynamic tolerance or adaptation to some effects of benzodiazepine hypnotics may develop. - If the drug has a short elimination half-life, it is possible that a relative deficiency of the drug, or, if appropriate, its active metabolites (i.e., in relationship to the receptor site) may occur at some point in the interval between each night's use. This sequence of events may account for 2 clinical findings reported to occur after several weeks of nightly use of rapidly eliminated benzodiazepine hypnotics, namely, increased wakefulness during the last third of the night, and the appearance of increased signs of daytime anxiety. ### Controlled Trials Supporting Efficacy - Restoril improved sleep parameters in clinical studies. Residual medication effects (“hangover”) were essentially absent. Early morning awakening, a particular problem in the geriatric patient, was significantly reduced. - Patients with chronic insomnia were evaluated in 2 week, placebo controlled sleep laboratory studies with Restoril at doses of 7.5 mg, 15 mg, and 30 mg, given 30 minutes prior to bedtime. There was a linear dose-response improvement in total sleep time and sleep latency, with significant drug-placebo differences at 2 weeks occurring only for total sleep time at the 2 higher doses, and for sleep latency only at the highest dose. - In these sleep laboratory studies, REM sleep was essentially unchanged and slow wave sleep was decreased. No measurable effects on daytime alertness or performance occurred following Restoril treatment or during the withdrawal period, even though a transient sleep disturbance in some sleep parameters was observed following withdrawal of the higher doses. - There was no evidence of tolerance development in the sleep laboratory parameters when patients were given Restoril nightly for at least 2 weeks. - In addition, normal subjects with transient insomnia associated with first night adaptation to the sleep laboratory were evaluated in 24 hour, placebo controlled sleep laboratory studies with Restoril at doses of 7.5 mg, 15 mg, and 30 mg, given 30 minutes prior to bedtime. - There was a linear dose-response improvement in total sleep time, sleep latency and number of awakenings, with significant drug-placebo differences occurring for sleep latency at all doses, for total sleep time at the 2 higher doses and for number of awakenings only at the 30 mg dose. ## Nonclinical Toxicology There is limited information regarding Temazepam Nonclinical Toxicology in the drug label. # Clinical Studies There is limited information regarding Clinical Studies of Temazepam in the drug label. # How Supplied - Restoril™ (temazepam) Capsules USP 7.5 mg - Blue and pink capsules, with the pink body imprinted “FOR SLEEP” on one side and Boxed M on the other side in red, and a blue cap imprinted “RESTORIL 7.5 mg” twice in red. Bottle of 30-NDC 0406-9915-03 Bottle of 100-NDC 0406-9915-01 15 mg - Maroon and pink capsules, with the pink body imprinted “FOR SLEEP” on one side and Boxed M on the other side in red, and a maroon cap imprinted “RESTORIL 15 mg” twice in white. Bottle of 100-NDC 0406-9916-01 22.5 mg - Opaque blue capsules, with the opaque blue body imprinted “FOR SLEEP” on one side and Boxed M on the other side in red, and an opaque blue cap imprinted “RESTORIL 22.5 mg” twice in red. Bottle of 30-NDC 0406-9914-03 30 mg - Maroon and blue capsules, with the blue body imprinted “FOR SLEEP” on one side and Boxed M on the other side in red, and a maroon cap imprinted “RESTORIL 30 mg” twice in white. Bottle of 100-NDC 0406-9917-01 - Dispense in a well-closed, light-resistant container with a child-resistant closure. ## Storage - 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 Temazepam Patient Counseling Information in the drug label. # Precautions with Alcohol Alcohol-Temazepam 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 Temazepam Brand Names in the drug label. # Look-Alike Drug Names There is limited information regarding Temazepam Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Restoril
32c047ef5c8262c50e357331ceec4c501f3a69e9	wikidoc	Restylane	Restylane # Overview Restylane is the trade name for a specific formulation of non-animal sourced hyaluronic acid most commonly used for lip augmentation. In the United States, Restylane has been approved by the FDA for cosmetic injection into subdermal facial tissues. Restylane is injected under wrinkles and aging lines of the face such as the nasolabial folds, melomental folds, "crows feet" and forehead wrinkles. It may also be used for filling aging-related facial hollows and "orbital troughs" (under and around the eyes). The process has a fast recovery time of 2 to 3 days. However, it is not permanent; reapplication is recommended every six months or so. Costs can be anywhere between $300 and $500 per treatment. The effects of Restylane last around six months. Recovery time from an injection takes around three days, as swelling and bruising can be a problem. Some practitioners will ask their patients to return to the practice two or three weeks after treatment for reassessment with view to a "top-up" if required. A new way to use Restylane was described in the August 2007 issue of the Journal of Drugs in Dermatology by Dutch cosmetic doctor Tom van Eijk, whose "fern pattern" injection technique aims to restore dermal elasticity rather than to fill underneath the wrinkles.	Restylane Editors-In-Chief: Martin I. Newman, M.D., FACS, Cleveland Clinic Florida, [1]; Michel C. Samson, M.D., FRCSC, FACS [2] # Overview Restylane is the trade name for a specific formulation of non-animal sourced hyaluronic acid most commonly used for lip augmentation. In the United States, Restylane has been approved by the FDA for cosmetic injection into subdermal facial tissues.[1] Restylane is injected under wrinkles and aging lines of the face such as the nasolabial folds, melomental folds, "crows feet" and forehead wrinkles. It may also be used for filling aging-related facial hollows and "orbital troughs" (under and around the eyes). The process has a fast recovery time of 2 to 3 days. However, it is not permanent; reapplication is recommended every six months or so. Costs can be anywhere between $300 and $500 per treatment. [2] The effects of Restylane last around six months. Recovery time from an injection takes around three days, as swelling and bruising can be a problem. Some practitioners will ask their patients to return to the practice two or three weeks after treatment for reassessment with view to a "top-up" if required. A new way to use Restylane was described in the August 2007 issue of the Journal of Drugs in Dermatology by Dutch cosmetic doctor Tom van Eijk, whose "fern pattern" injection technique aims to restore dermal elasticity rather than to fill underneath the wrinkles. [3]	https://www.wikidoc.org/index.php/Restylane
87468796d164600f5af513d7460d9ffc81604546	wikidoc	Reverting	Reverting # Overview A revert is to undo all changes made to an article page after a specific time in the past. The result will be that the page becomes identical in content to the page saved at that time. However, in the context of the English Wikipedia three revert rule, a revert is defined far more broadly as any change to an article that partially or completely goes back to any older version of an article. A partial revert is accomplished either by an ordinary edit of the current version, or by editing an old version. The former is convenient, for example, for a partial reversion of a recent addition, while the latter is convenient for a partial reversion of a deletion. Below is some Wikipedia-oriented text on reversion. # When to revert ## Do - Reverting is a decision which should be taken seriously. - Reverting is used primarily for fighting vandalism, or anything very similar to the effects of vandalism. - If you are not sure whether a revert is appropriate, discuss it first rather than immediately reverting or deleting it. - If you feel the edit is unsatisfactory, improve it rather than simply reverting or deleting it. ## Do not - Do not simply revert changes that are made as part of a dispute. Be respectful to other editors, their contributions and their points of view. - Do not revert good faith edits. In other words, try to consider the editor "on the other end." If what one is attempting is a positive contribution to Wikipedia, a revert of those contributions is inappropriate unless, and only unless, you as an editor possess firm, substantive, and objective proof to the contrary. Mere disagreement is not such proof. See also Wikipedia:Assume_good_faith. - Generally there are misconceptions that problematic sections of an article or recent changes are the reasons for reverting or deletion. If they contain valid information, these texts should simply be edited and improved accordingly. Reverting is not a decision which should be taken lightly. - There's sometimes trouble determining whether some claim is true or useful, particularly when there are few people "on board" who are knowledgeable about the topic. In such a case, it's a good idea to raise objections on a talk page; if one has some reason to believe that the author of what appears to be biased material will not be induced to change it, editors have sometimes taken the step of transferring the text in question to the talk page itself, thus not deleting it entirely. This action should be taken more or less as a last resort, never as a way of punishing people who have written something biased. See also Wikipedia:Neutral point of view/FAQ - Do not revert changes simply because someone makes an edit you consider problematic, biased, or inaccurate. Improve the edit, rather than reverting it. # How to revert ## Manual method - Go to the page, click on "history" at the top ("Page history" in some skins), and click on the time and date of the earlier version to which you wish to revert. - Then when that page comes up, you'll see something like "(Revision as of 22:19 Aug 15, 2002)" below the title and beneath "From Wikipedia, the free encyclopedia." - Verify that you've selected the correct version, and click to edit the page, as you would normally. Important: in the case of vandalism, take the time to make sure that you are reverting to the last version without the vandalism; there may be multiple consecutive vandal edits. - You'll get a warning, above the edit box, about editing an out-of-date revision. - After heeding the warning, save the page. Be sure to add the word "revert" and a brief explanation for the revert to the edit summary. Some Wikipedians abbreviate "revert" as "rv" and "rvv" when reverting vandalism. A useful addition is to Wikilink the usernames associated with the versions you are reverting from and to. For example, a good edit summary would be rv edits by 219.148.86.36 to last version by David Shear or rvv edits by 219.148.86.36 to last version by David Shear The clickable links are created by entering ] (replacing Username with the real IP address or Username for logged-in users, and replacing Username with their real username). Thus for an edit summary that reverts vandalism you would typed exactly: - Click on "history" again. A new line will have been added, and you will be able to verify (by clicking on "last") that you undid the vandalism plus all subsequent bona fide edits, if any. You are responsible for re-doing all the subsequent edits constructive which you undid. - In a vandalism case where sections of text were simply deleted and then subsequent edits were made by others, it may be easier for you to cut and paste those missing sections of text back in than to revert and then re-do the edits. - Check the contribution history of the user who vandalized the article. (Click on the IP address for anonymous users or the "contribs" for registered users. If this user is vandalizing many articles, please report them to Wikipedia:Administrator intervention against vandalism. ## User Scripts - Sam Hocevar's godmode-light.js script adds functionality similar to the admin rollback links described below. More info at WP:US. - The vandal edit can also be reverted using popups. ## Reverts do not cause edit conflicts Reverts never cause an edit conflict - if between the moment you begin the revert process, and the moment you click Post (or Save page), someone else edits and saves the page, their edits will be silently overwritten by the reverted version (but still appear in the page history). So beware of reverting high-traffic pages! Conversely, if it looks like someone has deleted your edits, consider whether it may be one of these unfortunate revision conflicts. # Undo - WP:UNDO Instead of removing all changes after a certain version, the latest versions of MediaWiki allow a single edit to be undone. To do this, view the diff for the edit, and click on 'undo' above the newer version. The software will attempt to create an edit page with a version of the article in which the undone edit doesn't exist but all later edits are retained. The automatic edit summary added when using the undo feature can be found at MediaWiki:Undo-summary. This feature removes the need to manually redo useful changes since the "undone" edit. However, it will fail if undoing the edit would conflict with later edits. For example, if edit 1000 adds a paragraph and edit 1005 modifies that paragraph, it will be impossible to automatically undo edit 1000. In this case, you must determine how to resolve the problem manually. # Admin features ## Rollback On the user contributions page, admins have the additional "rollback" links at lines which are the last edit made by anybody to that article. Some user scripts (mentioned below) also give users the ability to rollback with an automated edit summary. The rollback link is also shown on the diff page when viewing the difference between any version of the page and the most recent one. Clicking on the link reverts to the previous edit not authored by the last editor, with an automatic edit summary of "Reverted edits by X (talk) to last version by Y," which marks the edit as "minor." If, between loading the User Contributions page and pressing "rollback," someone else edits or rolls back the page, or if there was no previous editor, you will get an error message. The rollback link on the diff page is somewhat misleading because reversion is not necessarily to the old version shown (the diff page may show the combined result of edits including some by other editors, or only part of the edits the rollback button would revert). To see the changes the rollback button would revert, view the corresponding diff page. Rollbacks should be used with caution and restraint, in part because they leave no explanation for the revert in the edit summary. Reverting a good-faith edit may therefore send the message that "I think your edit was no better than vandalism and doesn't deserve even the courtesy of an explanation." It is a slap in the face to a good-faith editor. If you use the rollback feature for anything other than vandalism or for reverting yourself, it's polite to leave an explanation on the article talk page, or on the talk page of the user whose edit(s) you reverted. ## Bot rollback In cases of flood vandalism, admins may choose to hide vandalism from recent changes. To do this, add &bot=1 to the end of the url used to access a user's contributions. For example, :Contributions&target=SomePersistentVandal&bot=1. When the rollback links on the contributions list are clicked, the revert, and the original edit that you are reverting will both be hidden from recent changes unless you click the "bots" link to set hidebots=0. The edits are not hidden from contributions lists, page histories or watchlists. The edits remain in the database and are not removed, but they no longer flood Recentchanges. The aim of this feature is to reduce the annoyance factor of a flood vandal with relatively little effort. This should not be used for reverting a change you just don't like, but is meant only for massive floods of simple vandalism. # Revert wars considered harmful ## Reasons Revert wars are usually considered harmful for the following reasons: - They disrespect the work of the contributor. Being reverted can feel a bit like a slap in the face: "I worked hard on those edits, and someone just rolled it all back" - They cause ill-will between users and negatively destabilize articles - They make the page history less useful, waste space in the database - They make it hard for other people to contribute, and flood recent changes and watchlists ## Three revert rule In consideration of the harm of reverting, Wikipedia policy states that you may not revert any article more than three times in the same day. This is a very strict limit, not a given right; you should not revert any one article more than three times daily. ## Explain reverts When a revert is necessary, it is very important to let people know why you reverted. This helps the reverted person because they can remake their edit, but fixing whatever problem it is that you've identified. Explaining reverts also helps other people. For example, it lets people know whether they need to even view the reverted version (in the case of, eg, "rv page blanking"). Because of the lack of non-verbal communication online, if you don't explain things clearly people will probably assume all kinds of nasty things, and that's one of the possible causes for edit wars. If your reasons for reverting are too complex to explain in the edit summary, drop a note on the Talk page. A nice thing to do is to drop the note on the Talk page first, and then revert, rather than the other way round. Sometimes the other person will agree with you and revert for you before you have a chance. Conversely, if someone reverts your change without apparent explanation, you may wish to wait a few minutes to see if they explain their actions on the article's talk page or your user talk page. ## Exceptions Edits that don't contribute to edit warring are generally considered to be exceptions to the 3-revert rule. Such edits may include reverts of obvious vandalism, reverts of banned users, or removal of potentially libelous text. See Wikipedia:Three-revert rule#Exceptions for a fuller explanation. Please request protection rather than reverting. Violation of this rule may lead to protection of the page on the version preferred by the non-violating party; blocking; or investigation by the Arbitration Committee.	Reverting Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview A revert is to undo all changes made to an article page after a specific time in the past. The result will be that the page becomes identical in content to the page saved at that time. However, in the context of the English Wikipedia three revert rule, a revert is defined far more broadly as any change to an article that partially or completely goes back to any older version of an article. A partial revert is accomplished either by an ordinary edit of the current version, or by editing an old version. The former is convenient, for example, for a partial reversion of a recent addition, while the latter is convenient for a partial reversion of a deletion. Below is some Wikipedia-oriented text on reversion. # When to revert ## Do - Reverting is a decision which should be taken seriously. - Reverting is used primarily for fighting vandalism, or anything very similar to the effects of vandalism. - If you are not sure whether a revert is appropriate, discuss it first rather than immediately reverting or deleting it. - If you feel the edit is unsatisfactory, improve it rather than simply reverting or deleting it. ## Do not - Do not simply revert changes that are made as part of a dispute. Be respectful to other editors, their contributions and their points of view. - Do not revert good faith edits. In other words, try to consider the editor "on the other end." If what one is attempting is a positive contribution to Wikipedia, a revert of those contributions is inappropriate unless, and only unless, you as an editor possess firm, substantive, and objective proof to the contrary. Mere disagreement is not such proof. See also Wikipedia:Assume_good_faith. - Generally there are misconceptions that problematic sections of an article or recent changes are the reasons for reverting or deletion. If they contain valid information, these texts should simply be edited and improved accordingly. Reverting is not a decision which should be taken lightly. - There's sometimes trouble determining whether some claim is true or useful, particularly when there are few people "on board" who are knowledgeable about the topic. In such a case, it's a good idea to raise objections on a talk page; if one has some reason to believe that the author of what appears to be biased material will not be induced to change it, editors have sometimes taken the step of transferring the text in question to the talk page itself, thus not deleting it entirely. This action should be taken more or less as a last resort, never as a way of punishing people who have written something biased. See also Wikipedia:Neutral point of view/FAQ - Do not revert changes simply because someone makes an edit you consider problematic, biased, or inaccurate. Improve the edit, rather than reverting it. # How to revert ## Manual method - Go to the page, click on "history" at the top ("Page history" in some skins), and click on the time and date of the earlier version to which you wish to revert. - Then when that page comes up, you'll see something like "(Revision as of 22:19 Aug 15, 2002)" below the title and beneath "From Wikipedia, the free encyclopedia." - Verify that you've selected the correct version, and click to edit the page, as you would normally. Important: in the case of vandalism, take the time to make sure that you are reverting to the last version without the vandalism; there may be multiple consecutive vandal edits. - You'll get a warning, above the edit box, about editing an out-of-date revision. - After heeding the warning, save the page. Be sure to add the word "revert" and a brief explanation for the revert to the edit summary. Some Wikipedians abbreviate "revert" as "rv" and "rvv" when reverting vandalism. A useful addition is to Wikilink the usernames associated with the versions you are reverting from and to. For example, a good edit summary would be rv edits by 219.148.86.36 to last version by David Shear or rvv edits by 219.148.86.36 to last version by David Shear The clickable links are created by entering [[User:Username\|Username]] (replacing Username with the real IP address or Username for logged-in users, and replacing Username with their real username). Thus for an edit summary that reverts vandalism you would typed exactly: - Click on "history" again. A new line will have been added, and you will be able to verify (by clicking on "last") that you undid the vandalism plus all subsequent bona fide edits, if any. You are responsible for re-doing all the subsequent edits constructive which you undid. - In a vandalism case where sections of text were simply deleted and then subsequent edits were made by others, it may be easier for you to cut and paste those missing sections of text back in than to revert and then re-do the edits. - Check the contribution history of the user who vandalized the article. (Click on the IP address for anonymous users or the "contribs" for registered users. If this user is vandalizing many articles, please report them to Wikipedia:Administrator intervention against vandalism. ## User Scripts - Sam Hocevar's godmode-light.js script adds functionality similar to the admin rollback links described below. More info at WP:US. - The vandal edit can also be reverted using popups. ## Reverts do not cause edit conflicts Reverts never cause an edit conflict - if between the moment you begin the revert process, and the moment you click Post (or Save page), someone else edits and saves the page, their edits will be silently overwritten by the reverted version (but still appear in the page history). So beware of reverting high-traffic pages! Conversely, if it looks like someone has deleted your edits, consider whether it may be one of these unfortunate revision conflicts. # Undo - WP:UNDO Instead of removing all changes after a certain version, the latest versions of MediaWiki allow a single edit to be undone. To do this, view the diff for the edit, and click on 'undo' above the newer version. The software will attempt to create an edit page with a version of the article in which the undone edit doesn't exist but all later edits are retained. The automatic edit summary added when using the undo feature can be found at MediaWiki:Undo-summary. This feature removes the need to manually redo useful changes since the "undone" edit. However, it will fail if undoing the edit would conflict with later edits. For example, if edit 1000 adds a paragraph and edit 1005 modifies that paragraph, it will be impossible to automatically undo edit 1000. In this case, you must determine how to resolve the problem manually. # Admin features ## Rollback On the user contributions page, admins have the additional "rollback" links at lines which are the last edit made by anybody to that article. Some user scripts (mentioned below) also give users the ability to rollback with an automated edit summary. The rollback link is also shown on the diff page when viewing the difference between any version of the page and the most recent one. Clicking on the link reverts to the previous edit not authored by the last editor, with an automatic edit summary of "Reverted edits by X (talk) to last version by Y," which marks the edit as "minor." If, between loading the User Contributions page and pressing "rollback," someone else edits or rolls back the page, or if there was no previous editor, you will get an error message. The rollback link on the diff page is somewhat misleading because reversion is not necessarily to the old version shown (the diff page may show the combined result of edits including some by other editors, or only part of the edits the rollback button would revert). To see the changes the rollback button would revert, view the corresponding diff page. Rollbacks should be used with caution and restraint, in part because they leave no explanation for the revert in the edit summary. Reverting a good-faith edit may therefore send the message that "I think your edit was no better than vandalism and doesn't deserve even the courtesy of an explanation." It is a slap in the face to a good-faith editor. If you use the rollback feature for anything other than vandalism or for reverting yourself, it's polite to leave an explanation on the article talk page, or on the talk page of the user whose edit(s) you reverted. ## Bot rollback In cases of flood vandalism, admins may choose to hide vandalism from recent changes. To do this, add &bot=1 to the end of the url used to access a user's contributions. For example, http://en.wikipedia.org/w/wiki.phtml?title=Special:Contributions&target=SomePersistentVandal&bot=1. When the rollback links on the contributions list are clicked, the revert, and the original edit that you are reverting will both be hidden from recent changes unless you click the "bots" link to set hidebots=0. The edits are not hidden from contributions lists, page histories or watchlists. The edits remain in the database and are not removed, but they no longer flood Recentchanges. The aim of this feature is to reduce the annoyance factor of a flood vandal with relatively little effort. This should not be used for reverting a change you just don't like, but is meant only for massive floods of simple vandalism. # Revert wars considered harmful ## Reasons Revert wars are usually considered harmful for the following reasons: - They disrespect the work of the contributor. Being reverted can feel a bit like a slap in the face: "I worked hard on those edits, and someone just rolled it all back" - They cause ill-will between users and negatively destabilize articles - They make the page history less useful, waste space in the database - They make it hard for other people to contribute, and flood recent changes and watchlists Editors are discouraged to revert because there is disagreement, or the edit is bad or problematic. Users are encouraged to explore alternate methods like raising the objections on a talk page, or following the processes in dispute resolution. ## Three revert rule In consideration of the harm of reverting, Wikipedia policy states that you may not revert any article more than three times in the same day. This is a very strict limit, not a given right; you should not revert any one article more than three times daily. ## Explain reverts When a revert is necessary, it is very important to let people know why you reverted. This helps the reverted person because they can remake their edit, but fixing whatever problem it is that you've identified. Explaining reverts also helps other people. For example, it lets people know whether they need to even view the reverted version (in the case of, eg, "rv page blanking"). Because of the lack of non-verbal communication online, if you don't explain things clearly people will probably assume all kinds of nasty things, and that's one of the possible causes for edit wars. If your reasons for reverting are too complex to explain in the edit summary, drop a note on the Talk page. A nice thing to do is to drop the note on the Talk page first, and then revert, rather than the other way round. Sometimes the other person will agree with you and revert for you before you have a chance. Conversely, if someone reverts your change without apparent explanation, you may wish to wait a few minutes to see if they explain their actions on the article's talk page or your user talk page. ## Exceptions Edits that don't contribute to edit warring are generally considered to be exceptions to the 3-revert rule. Such edits may include reverts of obvious vandalism, reverts of banned users, or removal of potentially libelous text. See Wikipedia:Three-revert rule#Exceptions for a fuller explanation. Please request protection rather than reverting. Violation of this rule may lead to protection of the page on the version preferred by the non-violating party; blocking; or investigation by the Arbitration Committee. Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Reverting
c11ae72af0624d9dcbfa51785864faba24812858	wikidoc	Rhinolith	Rhinolith A rhinolith is a "calculus present in the nasal cavity." It is an uncommon medical phenomenon, not to be confused with dried nasal mucus. Synonyms: Nasal calculi; Concretions in the nose Rhinoliths are rare. They are formed by salts depositing over time on a foreign body in the nostril or paranasal sinus. The foreign body that forms the core for the rhinolith, can originate from within the body (such as a dried blood clot or an ectopic tooth) or outside of it (such as a fruit seed or a bead). The surface of a rhinollith is mulberry like, may be grey or brownish pink in color. Rhinoliths are friable, and they crumble readily under pressure. They are chiefly made of phosphates and carbonates of calcium. Sometimes phosphate of magnesia, chloride of sodium and carbonates of magnesia are also seen. These salts originate from the nasal mucous secretions, tears, and inflammatory exudates. Rhinoliths can cause nasal obstruction, epistaxis, headache, sinusitis and epiphora.	Rhinolith A rhinolith is a "calculus present in the nasal cavity." It is an uncommon medical phenomenon, not to be confused with dried nasal mucus. Synonyms: Nasal calculi; Concretions in the nose Rhinoliths are rare. They are formed by salts depositing over time on a foreign body in the nostril or paranasal sinus. The foreign body that forms the core for the rhinolith, can originate from within the body (such as a dried blood clot or an ectopic tooth) or outside of it (such as a fruit seed or a bead). The surface of a rhinollith is mulberry like, may be grey or brownish pink in color. Rhinoliths are friable, and they crumble readily under pressure. They are chiefly made of phosphates and carbonates of calcium. Sometimes phosphate of magnesia, chloride of sodium and carbonates of magnesia are also seen. These salts originate from the nasal mucous secretions, tears, and inflammatory exudates. Rhinoliths can cause nasal obstruction, epistaxis, headache, sinusitis and epiphora.	https://www.wikidoc.org/index.php/Rhinolith
c936b445a91d8763ab2ae6bf0a546b949c651bea	wikidoc	Rhodamine	Rhodamine Rhodamine (Template:IPAEng) is a family of related chemical compounds, fluorone dyes. Examples are Rhodamine 6G and Rhodamine B. They are used as a dye and as a dye laser gain medium. It is often used as a tracer dye within water to determine the rate and direction of flow and transport. Rhodamine dyes fluoresce and can thus be detected easily and inexpensively with instruments called fluorometers. Rhodamine dyes are used extensively in biotechnology applications such as fluorescence microscopy, flow cytometry, fluorescence correlation spectroscopy and ELISA. Rhodamine dyes are generally toxic, and are soluble in water, methanol and ethanol. # Rhodamine B # Rhodamine 6G # Rhodamine 123 The laser dye rhodamine 123 is also used in biochemistry to inhibit mitochondrion function. Rhodamine 123 seems to bind to the mitochondrion membranes and inhibit transport processes, especially the electron transport chain, thus slowing down inner respiration. It is a substrate of P-glycoprotein (Pgp), which is usually overexpressed in cancer cells. Recent reports indicate that rhodamine 123 may be also a substrate of multidrug resistance-associated protein (MRP), or more specifically, MRP1. # Other Rhodamine Derivatives There are many rhodamine derivatives used for imaging purposes, for example tetramethylrhodamine (TAMRA) and its isothiocyanate derivative (TRITC) and, sulforhodamine 101 (and its sulfonyl chloride form Texas Red) and Rhodamine Red. TRITC is the base rhodamine molecule functionalized with an isothiocyanate group (-N=C=S), replacing a hydrogen atom on the bottom ring of the structure. This derivative is reactive towards amine groups on proteins inside cells. A succinimidyl-ester functional group attached to the rhodamine core, creating NHS-rhodamine, forms another common amine-reactive derivative. Other derivatives of rhodamine include newer fluorophores such as Alexa 546, Alexa 555, Alexa 633, DyLight 549 and DyLight 633, have been tailored for various chemical and biological applications where higher photostability, increased brightness, different spectral characteristics, or different attachment groups are needed.	Rhodamine Rhodamine (Template:IPAEng) is a family of related chemical compounds, fluorone dyes. Examples are Rhodamine 6G and Rhodamine B. They are used as a dye and as a dye laser gain medium. It is often used as a tracer dye within water to determine the rate and direction of flow and transport. Rhodamine dyes fluoresce and can thus be detected easily and inexpensively with instruments called fluorometers. Rhodamine dyes are used extensively in biotechnology applications such as fluorescence microscopy, flow cytometry, fluorescence correlation spectroscopy and ELISA. Rhodamine dyes are generally toxic, and are soluble in water, methanol and ethanol. # Rhodamine B # Rhodamine 6G # Rhodamine 123 The laser dye rhodamine 123 is also used in biochemistry to inhibit mitochondrion function. Rhodamine 123 seems to bind to the mitochondrion membranes and inhibit transport processes, especially the electron transport chain, thus slowing down inner respiration. It is a substrate of P-glycoprotein (Pgp), which is usually overexpressed in cancer cells. Recent reports indicate that rhodamine 123 may be also a substrate of multidrug resistance-associated protein (MRP), or more specifically, MRP1. # Other Rhodamine Derivatives There are many rhodamine derivatives used for imaging purposes, for example tetramethylrhodamine (TAMRA) and its isothiocyanate derivative (TRITC) and, sulforhodamine 101 (and its sulfonyl chloride form Texas Red) and Rhodamine Red. TRITC is the base rhodamine molecule functionalized with an isothiocyanate group (-N=C=S), replacing a hydrogen atom on the bottom ring of the structure. This derivative is reactive towards amine groups on proteins inside cells. A succinimidyl-ester functional group attached to the rhodamine core, creating NHS-rhodamine, forms another common amine-reactive derivative. Other derivatives of rhodamine include newer fluorophores such as Alexa 546, Alexa 555, Alexa 633, DyLight 549 and DyLight 633, have been tailored for various chemical and biological applications where higher photostability, increased brightness, different spectral characteristics, or different attachment groups are needed. # External links - Absorption and Emission Spectra of Rhodamine B - Absorption and Emission Spectra of Rhodamine 6G - Absorption and Emission Spectra of Rhodamine 123 - Berlier et al. 2003 J. Histochem Cytochem refers to Alexa 633 as a rhodamine derivative. de:Rhodamine Template:WH Template:WS	https://www.wikidoc.org/index.php/Rhodamine
3af89bf367963ae391e05eded15c409778d341b5	wikidoc	Rhodopsin	Rhodopsin Rhodopsin (also known as visual purple) is a light-sensitive receptor protein involved in visual phototransduction. It is named after ancient Greek ῥόδον (rhódon) for rose, due to its pinkish color, and ὄψις (ópsis) for sight. Rhodopsin is a biological pigment found in the rods of the retina and is a G-protein-coupled receptor (GPCR). Rhodopsin is extremely sensitive to light, and thus enables vision in low-light conditions. When rhodopsin is exposed to light, it immediately photobleaches. In humans, it is regenerated fully in about 30 minutes, after which rods are more sensitive. Rhodopsin was discovered by Franz Christian Boll in 1876. Its amino acid sequence and physical structure were established in the early 1980s by the laboratories of Yuri Ovchinnikov in Russia and Paul Hargrave in the United States. # Structure Rhodopsin consists of two components, a protein molecule also called scotopsin and a covalently-bound cofactor called retinal. Scotopsin is an opsin, a light-sensitive G protein coupled receptor that embeds in the lipid bilayer of cell membranes using seven protein transmembrane domains. These domains form a pocket where the photoreactive chromophore, retinal, lies horizontally to the cell membrane, linked to a lysine residue in the seventh transmembrane domain of the protein. Thousands of rhodopsin molecules are found in each outer segment disc of the host rod cell. Retinal is produced in the retina from vitamin A, from dietary beta-carotene. Isomerization of 11-cis-retinal into all-trans-retinal by light sets off a series of conformational changes ('bleaching') in the opsin, eventually leading it to a form called metarhodopsin II (Meta II), which activates an associated G protein, transducin, to trigger a cyclic guanosine monophosphate (cGMP) second messenger cascade. Rhodopsin of the rods most strongly absorbs green-blue light and, therefore, appears reddish-purple, which is why it is also called "visual purple". It is responsible for monochromatic vision in the dark. Several closely related opsins differ only in a few amino acids and in the wavelengths of light that they absorb most strongly. Humans have eight other opsins besides rhodopsin, as well as cryptochrome (light-sensitive, but not an opsin). The photopsins are found in the cone cells of the retina and are the basis of color vision. They have absorption maxima for yellowish-green (photopsin I), green (photopsin II), and bluish-violet (photopsin III) light. The remaining opsin, melanopsin, is found in photosensitive ganglion cells and absorbs blue light most strongly. In rhodopsin, the aldehyde group of retinal is covalently linked to the amino group of a lysine residue on the protein in a protonated Schiff base (-NH+=CH-). When rhodopsin absorbs light, its retinal cofactor isomerizes from the 11-cis to the all-trans configuration, and the protein subsequently undergoes a series of relaxations to accommodate the altered shape of the isomerized cofactor. The intermediates formed during this process were first investigated in the laboratory of George Wald, who received the Nobel prize for this research in 1967. The photoisomerization dynamics has been subsequently investigated with time-resolved IR spectroscopy and UV/Vis spectroscopy. A first photoproduct called photorhodopsin forms within 200 femtoseconds after irradiation, followed within picoseconds by a second one called bathorhodopsin with distorted all-trans bonds. This intermediate can be trapped and studied at cryogenic temperatures, and was initially referred to as prelumirhodopsin. In subsequent intermediates lumirhodopsin and metarhodopsin I, the Schiff's base linkage to all-trans retinal remains protonated, and the protein retains its reddish color. The critical change that initiates the neuronal excitation involves the conversion of metarhodopsin I to metarhodopsin II, which is associated with deprotonation of the Schiff's base and change in color from red to yellow. The structure of rhodopsin has been studied in detail via x-ray crystallography on rhodopsin crystals. Several models (e.g., the bicycle-pedal mechanism, hula-twist mechanism) attempt to explain how the retinal group can change its conformation without clashing with the enveloping rhodopsin protein pocket. Recent data support that it is a functional monomer, instead of a dimer, which was the paradigm of G-protein-coupled receptors for many years. # Phototransduction Rhodopsin is an essential G-protein coupled receptor in phototransduction. ## Function The product of light activation, Metarhodopsin II, initiates the visual phototransduction pathway by stimulating the G protein transducin (Gt), resulting in the liberation of its α subunit. This GTP-bound subunit in turn activates cGMP phosphodiesterase. cGMP phosphodiesterase hydrolyzes (breaks down) cGMP, lowering its local concentration so it can no longer activate cGMP-dependent cation channels. This leads to the hyperpolarization of photoreceptor cells, changing the rate at which they release transmitters. ## Deactivation Meta II is deactivated rapidly after activating transducin by rhodopsin kinase and arrestin. Rhodopsin pigment must be regenerated for further phototransduction to occur. This means replacing all-trans-retinal with 11-cis-retinal and the decay of Meta II is crucial in this process. During the decay of Meta II, the Schiff base link that normally holds all-trans-retinal and the apoprotein opsin is hydrolyzed and becomes Meta III. In the rod outer segment, Meta III decays into separate all-trans-retinal and opsin. A second product of Meta II decay is an all-trans-retinal opsin complex in which the all-trans-retinal has been translocated to second binding sites. Whether the Meta II decay runs into Meta III or the all-trans-retinal opsin complex seems to depend on the pH of the reaction. Higher pH tends to drive the decay reaction towards Meta III. # Retinal disease Mutation of the rhodopsin gene is a major contributor to various retinopathies such as retinitis pigmentosa. In general, the disease-causing protein aggregates with ubiquitin in inclusion bodies, disrupts the intermediate filament network, and impairs the ability of the cell to degrade non-functioning proteins, which leads to photoreceptor apoptosis. Other mutations on rhodopsin lead to X-linked congenital stationary night blindness, mainly due to constitutive activation, when the mutations occur around the chromophore binding pocket of rhodopsin. Several other pathological states relating to rhodopsin have been discovered including poor post-Golgi trafficking, dysregulative activation, rod outer segment instability and arrestin binding. # Microbial rhodopsins Some prokaryotes express proton pumps called bacteriorhodopsins, archaerhodopsins, proteorhodopsins, and xanthorhodopsins to carry out phototrophy. Like animal visual pigments, these contain a retinal chromophore (although it is an all-trans, rather than 11-cis form) and have seven transmembrane alpha helices; however, they are not coupled to a G protein. Prokaryotic halorhodopsins are light-activated chloride pumps. Unicellular flagellate algae contain channelrhodopsins that act as light-gated cation channels when expressed in heterologous systems. Many other pro- and eukaryotic organisms (in particular, fungi such as Neurospora) express rhodopsin ion pumps or sensory rhodopsins of yet-unknown function. Very recently, microbial rhodopsins with guanylyl cyclase activity have been discovered. While all microbial rhodopsins have significant sequence homology to one another, they have no detectable sequence homology to the G-protein-coupled receptor (GPCR) family to which animal visual rhodopsins belong. Nevertheless, microbial rhodopsins and GPCRs are possibly evolutionarily related, based on the similarity of their three-dimensional structures. Therefore, they have been assigned to the same superfamily in Structural Classification of Proteins (SCOP).	Rhodopsin Rhodopsin (also known as visual purple) is a light-sensitive receptor protein involved in visual phototransduction. It is named after ancient Greek ῥόδον (rhódon) for rose, due to its pinkish color, and ὄψις (ópsis) for sight.[1] Rhodopsin is a biological pigment found in the rods of the retina and is a G-protein-coupled receptor (GPCR). Rhodopsin is extremely sensitive to light, and thus enables vision in low-light conditions.[2] When rhodopsin is exposed to light, it immediately photobleaches. In humans, it is regenerated fully in about 30 minutes, after which rods are more sensitive.[3] Rhodopsin was discovered by Franz Christian Boll in 1876.[4][5] Its amino acid sequence and physical structure were established in the early 1980s by the laboratories of Yuri Ovchinnikov in Russia and Paul Hargrave in the United States.[6][7][8][9] # Structure Rhodopsin consists of two components, a protein molecule also called scotopsin and a covalently-bound cofactor called retinal. Scotopsin is an opsin, a light-sensitive G protein coupled receptor that embeds in the lipid bilayer of cell membranes using seven protein transmembrane domains. These domains form a pocket where the photoreactive chromophore, retinal, lies horizontally to the cell membrane, linked to a lysine residue in the seventh transmembrane domain of the protein. Thousands of rhodopsin molecules are found in each outer segment disc of the host rod cell. Retinal is produced in the retina from vitamin A, from dietary beta-carotene. Isomerization of 11-cis-retinal into all-trans-retinal by light sets off a series of conformational changes ('bleaching') in the opsin, eventually leading it to a form called metarhodopsin II (Meta II), which activates an associated G protein, transducin, to trigger a cyclic guanosine monophosphate (cGMP) second messenger cascade.[3][10][11] Rhodopsin of the rods most strongly absorbs green-blue light and, therefore, appears reddish-purple, which is why it is also called "visual purple".[12] It is responsible for monochromatic vision in the dark.[3] Several closely related opsins differ only in a few amino acids and in the wavelengths of light that they absorb most strongly. Humans have eight other opsins besides rhodopsin, as well as cryptochrome (light-sensitive, but not an opsin).[13][14] The photopsins are found in the cone cells of the retina and are the basis of color vision. They have absorption maxima for yellowish-green (photopsin I), green (photopsin II), and bluish-violet (photopsin III) light. The remaining opsin, melanopsin, is found in photosensitive ganglion cells and absorbs blue light most strongly. In rhodopsin, the aldehyde group of retinal is covalently linked to the amino group of a lysine residue on the protein in a protonated Schiff base (-NH+=CH-).[15] When rhodopsin absorbs light, its retinal cofactor isomerizes from the 11-cis to the all-trans configuration, and the protein subsequently undergoes a series of relaxations to accommodate the altered shape of the isomerized cofactor. The intermediates formed during this process were first investigated in the laboratory of George Wald, who received the Nobel prize for this research in 1967.[16] The photoisomerization dynamics has been subsequently investigated with time-resolved IR spectroscopy and UV/Vis spectroscopy. A first photoproduct called photorhodopsin forms within 200 femtoseconds after irradiation, followed within picoseconds by a second one called bathorhodopsin with distorted all-trans bonds. This intermediate can be trapped and studied at cryogenic temperatures, and was initially referred to as prelumirhodopsin.[17] In subsequent intermediates lumirhodopsin and metarhodopsin I, the Schiff's base linkage to all-trans retinal remains protonated, and the protein retains its reddish color. The critical change that initiates the neuronal excitation involves the conversion of metarhodopsin I to metarhodopsin II, which is associated with deprotonation of the Schiff's base and change in color from red to yellow.[18] The structure of rhodopsin has been studied in detail via x-ray crystallography on rhodopsin crystals[19]. Several models (e.g., the bicycle-pedal mechanism, hula-twist mechanism) attempt to explain how the retinal group can change its conformation without clashing with the enveloping rhodopsin protein pocket.[20][21][22] Recent data support that it is a functional monomer, instead of a dimer, which was the paradigm of G-protein-coupled receptors for many years.[23] # Phototransduction Rhodopsin is an essential G-protein coupled receptor in phototransduction. ## Function The product of light activation, Metarhodopsin II, initiates the visual phototransduction pathway by stimulating the G protein transducin (Gt), resulting in the liberation of its α subunit. This GTP-bound subunit in turn activates cGMP phosphodiesterase. cGMP phosphodiesterase hydrolyzes (breaks down) cGMP, lowering its local concentration so it can no longer activate cGMP-dependent cation channels. This leads to the hyperpolarization of photoreceptor cells, changing the rate at which they release transmitters. ## Deactivation Meta II is deactivated rapidly after activating transducin by rhodopsin kinase and arrestin.[24] Rhodopsin pigment must be regenerated for further phototransduction to occur. This means replacing all-trans-retinal with 11-cis-retinal and the decay of Meta II is crucial in this process. During the decay of Meta II, the Schiff base link that normally holds all-trans-retinal and the apoprotein opsin is hydrolyzed and becomes Meta III. In the rod outer segment, Meta III decays into separate all-trans-retinal and opsin.[24] A second product of Meta II decay is an all-trans-retinal opsin complex in which the all-trans-retinal has been translocated to second binding sites. Whether the Meta II decay runs into Meta III or the all-trans-retinal opsin complex seems to depend on the pH of the reaction. Higher pH tends to drive the decay reaction towards Meta III.[24] # Retinal disease Mutation of the rhodopsin gene is a major contributor to various retinopathies such as retinitis pigmentosa. In general, the disease-causing protein aggregates with ubiquitin in inclusion bodies, disrupts the intermediate filament network, and impairs the ability of the cell to degrade non-functioning proteins, which leads to photoreceptor apoptosis.[25] Other mutations on rhodopsin lead to X-linked congenital stationary night blindness, mainly due to constitutive activation, when the mutations occur around the chromophore binding pocket of rhodopsin.[26] Several other pathological states relating to rhodopsin have been discovered including poor post-Golgi trafficking, dysregulative activation, rod outer segment instability and arrestin binding.[26] # Microbial rhodopsins Some prokaryotes express proton pumps called bacteriorhodopsins, archaerhodopsins, proteorhodopsins, and xanthorhodopsins to carry out phototrophy.[27] Like animal visual pigments, these contain a retinal chromophore (although it is an all-trans, rather than 11-cis form) and have seven transmembrane alpha helices; however, they are not coupled to a G protein. Prokaryotic halorhodopsins are light-activated chloride pumps.[27] Unicellular flagellate algae contain channelrhodopsins that act as light-gated cation channels when expressed in heterologous systems. Many other pro- and eukaryotic organisms (in particular, fungi such as Neurospora) express rhodopsin ion pumps or sensory rhodopsins of yet-unknown function. Very recently, microbial rhodopsins with guanylyl cyclase activity have been discovered.[28][29][30] While all microbial rhodopsins have significant sequence homology to one another, they have no detectable sequence homology to the G-protein-coupled receptor (GPCR) family to which animal visual rhodopsins belong. Nevertheless, microbial rhodopsins and GPCRs are possibly evolutionarily related, based on the similarity of their three-dimensional structures. Therefore, they have been assigned to the same superfamily in Structural Classification of Proteins (SCOP).[31]	https://www.wikidoc.org/index.php/Rhodopsin
dffe9f9c9bdc14d7685e898ccc7c4789a60607d9	wikidoc	Rhotacism	Rhotacism # Background Rhotacism may refer to several phenomena related to the usage of the consonant r (whether as an alveolar tap, alveolar trill, or the rarer uvular trill). - the excessive or idiosyncratic use of the r; - conversely, the inability or difficulty in pronouncing r. - the conversion of another consonant, e.g., s, into r. The term comes from the Greek letter rho, denoting "r". # Orthoepy In medicine rhotacism is the inability or difficulty in pronouncing the sound "r". The Looney Tunes character, Elmer Fudd (originally voiced by Arthur Q. Bryan and later by Mel Blanc), is notorious for his exaggerated rhotacistic speech ("Be vewwy quiet… I'm hunting wabbits"). Rhotacism is more common among speakers of languages which have a trilled R, such as Swedish, Italian, Polish and Spanish. This sound is usually the last one a child masters. Some people never learn to produce it correctly and substitute other sounds, like a velar or uvular approximant. R may be also realized as an uvular trill—a pronunciation usually known as "French R". It used to be considered prestigious in Poland, but now it's usually believed to be a speech defect too. # Phonetics In Indo-European languages, rhotacism can be seen in a conversion of another consonant — for instance "s" or "d" or "n" to "r" in many words. ## Albanian Albanian rhotacism changes "n" to "r"; - ranë (from the Latin arena) vs rërë (= "sand") - Valona (from the Latin Avlona) vs Vlora (a town in Southern Albania) that change took place in the 13th century in the southern (Tosk) dialects, which now dominate in the literary language. The Northern Gheg dialects, also spoken in Kosovo and Western Macedonia, keep the original "n". Hence "armik" (dictionary entry for "enemy") is "anmik" in Gheg. ## Dutch - vriezen vs gevroren (from Germanic friusana vs fruzenaz) Compare also Gothic dags with Old Norse dagr (from Germanic dagaz) ## English - was vs were (from Germanic was vs wēzun) - lose vs forlorn (from Germanic liusana vs luzenaz) In Scouse, intervocalic dentals are realised as "r" when the stress pattern is STRESSED VOWEL-dental-unstressed vowel. "Got a lot of.." becomes "Gorra lorra...". ## German - war vs gewesen (from Germanic was vs wēzun) In Central German dialects, esp. Rhine-Franconian and Hessian, d is frequently realized as r in intervocalic position. This change also occurs in Mecklenburg dialects. - Borrem (Central Hessian) vs Boden (Standard German) ## Japanese The Japanese language does not have a phoneme equivalent to the English 'l' or 'r'; the closest sound is referred to as an alveolar lateral flap. Loanwords with 'l' or 'r' in the original language are represented using this sound, and in romanized Japanese text the letter 'r' is used, regardless of whether the original was an 'r' or 'l' to begin with. Accordingly, Japanese people are faced with rhotacism-type trouble in pronouncing the letters 'r' and 'l', as well as difficulty in differentiating between the two sounds. ## Latin - flos (nominative) vs florem (accusative) (Old Latin flosem) - genus (nominative) vs generis (genitive) (from geneses, cf Sanskrit janasas) - corroborare vs robustus (verb from *conrobosare) - de iure vs iustus (from de iouse) - ero vs est (from eso) This reflects a highly-regular change in pre-classical Latin. Intervocalic s in the oldest attested Latin documents invariably became r. Intervocalic s in Latin suggests either borrowing, reduction of an earlier ss, or the treatment of d+t into s (videre/visum). Old s was preserved initially (septum), finally, and in consonant clusters. The English word honor is derived from French honour, which in turn was derived from Late Latin honor, earlier honos, which became honor by analogy with honoris (genitive), honorem (accusative) ## Neapolitan In Neapolitan rhotacism is seen in a shift from the sound of "d" to an "r" sound: (Italian vs Neapolitan) - medesimo vs meresemo - diaspora vs riaspro and, to a lesser extent, from the sound of an "l" to an "r" sound: - albero vs arvero - ultimo vs urdemo ## Portuguese In Old Portuguese, rhotacism occurred from the "l" sound to the "r" sound, as in the words obrigado "obliged" and praça "plaza". In contemporary Brazilian Portuguese, rhotacism of "l" in the syllable coda is characteristic of poorly educated speakers. ## Romanesco Rhotacism in Romanesco consists of a shift from "l" to "r" when it is followed by a consonant. Thus, Latin altus (tall) which in Italian is alto in Romanesco becomes arto. In ancient Romanesco it also happened when "l" was preceded by a consonant, as in the word ingrese (english), but the modern way of speaking has lost this characteristic. In Romanesco exists another kind of rhotacism: the shortening of the geminated "r". So the words errore, guerra and marrone (error, war, brown) in Romanesco become erore, guera and marone ## Romanian Romanian rhotacism consists of a shift from intervocalic "l" to "r" and "n" to "r". Thus, Latin caelum became Romanian cer and Latin fenestra becomes Romanian fereastră. Some northern Romanian dialects and Istro-Romanian also further transformed all intervocalic "n" into "r". For example, Latin bonus became Istro-Romanian bur, as compared to standard Daco-Romanian bun. ## Sanskrit In Sanskrit, words ending in -s other than -as become -r in sandhi with a voiced consonant: - naus (before p/t/k) vs naur bharati - agnis (before p/t/k) vs agnir mata This is not a case of rhotacism proper, since r and s are simply allophones in those positions. ## Slovene Slovenian rhotacism consists of shift from Template:IPA (like in English vision) to vibrating Template:IPA: - moreš from možešь - kdor from kъtože Slovenian rhotacism is already visible in the Freising manuscripts, a written document from the 10th century. The same shift occurred in single words in other South Slavic languages.	Rhotacism Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Background Rhotacism may refer to several phenomena related to the usage of the consonant r (whether as an alveolar tap, alveolar trill, or the rarer uvular trill). - the excessive or idiosyncratic use of the r; - conversely, the inability or difficulty in pronouncing r. - the conversion of another consonant, e.g., s, into r. The term comes from the Greek letter rho, denoting "r". # Orthoepy In medicine rhotacism is the inability or difficulty in pronouncing the sound "r". The Looney Tunes character, Elmer Fudd (originally voiced by Arthur Q. Bryan and later by Mel Blanc), is notorious for his exaggerated rhotacistic speech ("Be vewwy quiet… I'm hunting wabbits"). Rhotacism is more common among speakers of languages which have a trilled R, such as Swedish, Italian, Polish and Spanish. This sound is usually the last one a child masters. Some people never learn to produce it correctly and substitute other sounds, like a velar or uvular approximant. R may be also realized as an uvular trill—a pronunciation usually known as "French R". It used to be considered prestigious in Poland, but now it's usually believed to be a speech defect too. # Phonetics In Indo-European languages, rhotacism can be seen in a conversion of another consonant — for instance "s" or "d" or "n" to "r" in many words. ## Albanian Albanian rhotacism changes "n" to "r"; - ranë (from the Latin arena) vs rërë (= "sand") - Valona (from the Latin Avlona) vs Vlora (a town in Southern Albania) that change took place in the 13th century in the southern (Tosk) dialects, which now dominate in the literary language. The Northern Gheg dialects, also spoken in Kosovo and Western Macedonia, keep the original "n". Hence "armik" (dictionary entry for "enemy") is "anmik" in Gheg. ## Dutch - vriezen vs gevroren (from Germanic friusana vs fruzenaz) Compare also Gothic dags with Old Norse dagr (from Germanic dagaz) ## English - was vs were (from Germanic was vs wēzun) - lose vs forlorn (from Germanic liusana vs luzenaz) In Scouse, intervocalic dentals are realised as "r" when the stress pattern is STRESSED VOWEL-dental-unstressed vowel. "Got a lot of.." becomes "Gorra lorra...". ## German - war vs gewesen (from Germanic was vs wēzun) In Central German dialects, esp. Rhine-Franconian and Hessian, d is frequently realized as r in intervocalic position. This change also occurs in Mecklenburg dialects. - Borrem (Central Hessian) vs Boden (Standard German) ## Japanese The Japanese language does not have a phoneme equivalent to the English 'l' or 'r'; the closest sound is referred to as an alveolar lateral flap. Loanwords with 'l' or 'r' in the original language are represented using this sound, and in romanized Japanese text the letter 'r' is used, regardless of whether the original was an 'r' or 'l' to begin with. Accordingly, Japanese people are faced with rhotacism-type trouble in pronouncing the letters 'r' and 'l', as well as difficulty in differentiating between the two sounds. ## Latin - flos (nominative) vs florem (accusative) (Old Latin flosem) - genus (nominative) vs generis (genitive) (from geneses, cf Sanskrit janasas) - corroborare vs robustus (verb from *conrobosare) - de iure vs iustus (from de iouse) - ero vs est (from eso) This reflects a highly-regular change in pre-classical Latin. Intervocalic s in the oldest attested Latin documents invariably became r. Intervocalic s in Latin suggests either borrowing, reduction of an earlier ss, or the treatment of d+t into s (videre/visum). Old s was preserved initially (septum), finally, and in consonant clusters. The English word hono[u]r is derived from French honour, which in turn was derived from Late Latin honor, earlier honos, which became honor by analogy with honoris (genitive), honorem (accusative) ## Neapolitan In Neapolitan rhotacism is seen in a shift from the sound of "d" to an "r" sound: (Italian vs Neapolitan) - medesimo vs meresemo - diaspora vs riaspro and, to a lesser extent, from the sound of an "l" to an "r" sound: - albero vs arvero - ultimo vs urdemo ## Portuguese In Old Portuguese, rhotacism occurred from the "l" sound to the "r" sound, as in the words obrigado "obliged" and praça "plaza". In contemporary Brazilian Portuguese, rhotacism of "l" in the syllable coda is characteristic of poorly educated speakers. ## Romanesco Rhotacism in Romanesco consists of a shift from "l" to "r" when it is followed by a consonant. Thus, Latin altus (tall) which in Italian is alto in Romanesco becomes arto. In ancient Romanesco it also happened when "l" was preceded by a consonant, as in the word ingrese (english), but the modern way of speaking has lost this characteristic. In Romanesco exists another kind of rhotacism: the shortening of the geminated "r". So the words errore, guerra and marrone (error, war, brown) in Romanesco become erore, guera and marone ## Romanian Romanian rhotacism consists of a shift from intervocalic "l" to "r" and "n" to "r". Thus, Latin caelum became Romanian cer and Latin fenestra becomes Romanian fereastră. Some northern Romanian dialects and Istro-Romanian also further transformed all intervocalic "n" into "r". For example, Latin bonus became Istro-Romanian bur, as compared to standard Daco-Romanian bun. ## Sanskrit In Sanskrit, words ending in -s other than -as become -r in sandhi with a voiced consonant: - naus (before p/t/k) vs naur bharati - agnis (before p/t/k) vs agnir mata This is not a case of rhotacism proper, since r and s are simply allophones in those positions. ## Slovene Slovenian rhotacism consists of shift from Template:IPA (like in English vision) to vibrating Template:IPA: - moreš from možešь - kdor from kъtože Slovenian rhotacism is already visible in the Freising manuscripts, a written document from the 10th century. The same shift occurred in single words in other South Slavic languages.	https://www.wikidoc.org/index.php/Rhotacism
87ffb8d05c575799d7ce4babd2c3dd281488685f	wikidoc	Rifaximin	Rifaximin # 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 Rifaximin is a rifamycin antibacterial that is FDA approved for the treatment of travelers’ diarrhea (TD) caused by noninvasive strains of Escherichia coli and reduction in risk of overt hepatic encephalopathy (HE) recurrence in patients ≥ 18 years of age. Common adverse reactions include flatulence, headache, abdominal pain, rectal tenesmus, defecation urgency, nausea, peripheral edema, dizziness, fatigue, and ascites. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Dosing Information - The recommended dose of XIFAXAN is one 200 mg tablet taken orally three times a day for 3 days. XIFAXAN can be administered orally, with or without food. - Dosing Information - The recommended dose of XIFAXAN is one 550 mg tablet taken orally two times a day, with or without food. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Rifaximin in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Rifaximin in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Dosing Information - The recommended dose of XIFAXAN is one 200 mg tablet taken orally three times a day for 3 days (12 years or older). XIFAXAN can be administered orally, with or without food. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Rifaximin in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Rifaximin in pediatric patients. # Contraindications - Hypersensitivity - XIFAXAN is contraindicated in patients with a hypersensitivity to rifaximin, any of the rifamycin antimicrobial agents, or any of the components in XIFAXAN. Hypersensitivity reactions have included exfoliative dermatitis, angioneurotic edema, and anaphylaxis. # Warnings ### Precautions - Travelers’ Diarrhea Not Caused by Escherichia coli - XIFAXAN was not found to be effective in patients with diarrhea complicated by fever and/or blood in the stool or diarrhea due to pathogens other than Escherichia coli. - Discontinue XIFAXAN if diarrhea symptoms get worse or persist more than 24-48 hours and alternative antibiotic therapy should be considered. - XIFAXAN is not effective in cases of travelers’ diarrhea. The effectiveness of XIFAXAN in travelers’ diarrhea caused by spp. and spp. has not been proven. XIFAXAN should not be used in patients where , spp., or spp. may be suspected as causative pathogens. - Clostridium difficile-Associated Diarrhea - Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including XIFAXAN, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon which may lead to overgrowth of Clostridium difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. - If CDAD is suspected or confirmed, ongoing antibiotic use not directed against may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of , and surgical evaluation should be instituted as clinically indicated. - Development of Drug Resistant Bacteria - Prescribing XIFAXAN for travelers’ diarrhea in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. - Severe (Child-Pugh C) Hepatic Impairment - There is increased systemic exposure in patients with severe hepatic impairment. Animal toxicity studies did not achieve systemic exposures that were seen in patients with severe hepatic impairment. The clinical trials were limited to patients with MELD scores <25. Therefore, caution should be exercised when administering XIFAXAN to patients with severe hepatic impairment (Child-Pugh C). - Concomitant use with P-glycoprotein Inhibitors - Concomitant administration of drugs that are P-glycoprotein inhibitors with rifaximin can substantially increase the systemic exposure to rifaximin. Caution should be exercised when concomitant use of rifaximin and a P-glycoprotein inhibitor such as cyclosporine is needed. In patients with hepatic impairment, a potential additive effect of reduced metabolism and concomitant P-glycoprotein inhibitors may further increase the systemic exposure to rifaximin. # 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. - The safety of XIFAXAN 200 mg taken three times a day was evaluated in patients with travelers’ diarrhea consisting of 320 patients in two placebo-controlled clinical trials with 95% of patients receiving three or four days of treatment with XIFAXAN. The population studied had a mean age of 31.3 (18-79) years of which approximately 3% were ≥ 65 years old, 53% were male and 84% were White, 11% were Hispanic. - Discontinuations due to adverse reactions occurred in 0.4% of patients. The adverse reactions leading to discontinuation were taste loss, dysentery, weight loss, anorexia, nausea and nasal passage irritation. - All adverse reactions for XIFAXAN 200 mg three times daily that occurred at a frequency ≥ 2% in the two placebo-controlled trials combined are provided in Table 1. (These include adverse reactions that may be attributable to the underlying disease.) - The following adverse reactions, presented by body system, have also been reported in <2% of patients taking XIFAXAN in the two placebo-controlled clinical trials where the 200 mg tablet was taken three times a day for travelers’ diarrhea. The following includes adverse reactions regardless of causal relationship to drug exposure. Lymphocytosis, monocytosis, neutropenia Ear pain, motion sickness, tinnitus Abdominal distension, diarrhea NOS, dry throat, fecal abnormality NOS, gingival disorder NOS, inguinal hernia NOS, dry lips, stomach discomfort Chest pain, fatigue, malaise, pain NOS, weakness Dysentery NOS, respiratory tract infection NOS, upper respiratory tract infection NOS Aspartate aminotransferase increased, blood in stool, blood in urine, weight decreased Anorexia, dehydration Arthralgia, muscle spasms, myalgia, neck pain Abnormal dreams, dizziness, migraine NOS, syncope, loss of taste Insomnia Choluria, dysuria, hematuria, polyuria, proteinuria, urinary frequency Dyspnea NOS, nasal passage irritation, nasopharyngitis, pharyngitis, pharyngolaryngeal pain, rhinitis NOS, rhinorrhea Clamminess, rash NOS, sweating increased Hot flashes NOS - The data described below reflect exposure to XIFAXAN 550 mg in 348 patients, including 265 exposed for 6 months and 202 exposed for more than a year (mean exposure was 364 days). The safety of XIFAXAN 550 mg taken two times a day for reducing the risk of overt hepatic encephalopathy recurrence in adult patients was evaluated in a 6-month placebo-controlled clinical trial (n = 140) and in a long term follow-up study (n = 280). The population studied had a mean age of 56.26 (range: 21-82) years; approximately 20% of the patients were ≥ 65 years old, 61% were male, 86% were White, and 4% were Black. Ninety-one percent of patients in the trial were taking lactulose concomitantly. All adverse reactions that occurred at an incidence ≥ 5% and at a higher incidence in XIFAXAN 550 mg-treated subjects than in the placebo group in the 6-month trial are provided in Table 2. (These include adverse events that may be attributable to the underlying disease). - The following adverse reactions, presented by body system, have also been reported in the placebo-controlled clinical trial in greater than 2% but less than 5% of patients taking XIFAXAN 550 mg taken orally two times a day for hepatic encephalopathy. The following includes adverse events occurring at a greater incidence than placebo, regardless of causal relationship to drug exposure. Vertigo Lower abdominal pain, abdominal tenderness, dry mouth, esophageal variceal bleed, stomach discomfort Chest pain, generalized edema, influenza like illness, pain NOS Cellulitis, pneumonia, rhinitis, upper respiratory tract infection NOS Contusion, fall, procedural pain Injury Anorexia, dehydration, hyperglycemia, hyperkalemia, hypoglycemia, hyponatremia Myalgia, pain in extremity Amnesia, disturbance in attention, hypoesthesia, memory impairment, tremor Confusional state Epistaxis Hypotension ## Postmarketing Experience - The following adverse reactions have been identified during post approval use of XIFAXAN. Because these reactions are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These reactions have been chosen for inclusion due to either their seriousness, frequency of reporting or causal connection to XIFAXAN. Cases of C. difficile-associated colitis have been reported. Hypersensitivity reactions, including exfoliative dermatitis, rash, angioneurotic edema (swelling of face and tongue and difficulty swallowing), urticaria, flushing, pruritus and anaphylaxis have been reported. These events occurred as early as within 15 minutes of drug administration. # Drug Interactions - Effects of rifaximin on cytochrome P450 enzymes - studies have shown that rifaximin did not inhibit cytochrome P450 isoenzymes 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1 and CYP3A4 at concentrations ranging from 2 to 200 ng/mL. Rifaximin is not expected to inhibit these enzymes in clinical use. - An study has suggested that rifaximin induces CYP3A4. However, in patients with normal liver function, rifaximin at the recommended dosing regimen is not expected to induce CYP3A4. It is unknown whether rifaximin can have a significant effect on the pharmacokinetics of concomitant CYP3A4 substrates in patients with reduced liver function who have elevated rifaximin concentrations. - Concomitant P-glycoprotein inhibitors - An study suggested that rifaximin is a substrate of P-glycoprotein. Co-administration of cyclosporine, a potent P-glycoprotein inhibitor, with rifaximin resulted in 83-fold and 124-fold increases in rifaximin mean C and AUC∞ in healthy subjects. The clinical significance of this increase in systemic exposure is unknown. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - There are no adequate and well controlled studies in pregnant women. Rifaximin has been shown to be teratogenic in rats and rabbits at doses that caused maternal toxicity. XIFAXAN tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. - Administration of rifaximin to pregnant rats and rabbits at dose levels that caused reduced body weight gain resulted in eye malformations in both rat and rabbit fetuses. Additional malformations were observed in fetal rabbits that included cleft palate, lumbar scoliosis, brachygnathia, interventricular septal defect, and large atrium. - The fetal rat malformations were observed in a study of pregnant rats administered a high dose that resulted in 16 times the therapeutic dose to diarrheic patients or 1 times the therapeutic dose to patients with hepatic encephalopathy (based upon plasma AUC comparisons). Fetal rabbit malformations were observed from pregnant rabbits administered mid and high doses that resulted in 1 or 2 times the therapeutic dose to diarrheic patients or less than 0.1 times the dose in patients with hepatic encephalopathy, based upon plasma AUC comparisons. - Post-natal developmental effects were not observed in rat pups from pregnant/lactating female rats dosed during the period from gestation to Day 20 post-partum at the highest dose which resulted in approximately 16 times the human therapeutic dose for travelers’ diarrhea (based upon AUCs) or approximately 1 times the AUCs derived from therapeutic doses to patients with hepatic encephalopathy. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Rifaximin in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Rifaximin during labor and delivery. ### Nursing Mothers - It is not known whether rifaximin is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from XIFAXAN, 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 XIFAXAN 200 mg in pediatric patients with travelers’ diarrhea less than 12 years of age have not been established. - The safety and effectiveness of XIFAXAN 550 mg for HE have not been established in patients < 18 years of age. ### Geriatic Use - Clinical studies with rifaximin 200 mg for travelers’ diarrhea did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger subjects. - In the controlled trial with XIFAXAN 550 mg for hepatic encephalopathy, 19.4% were 65 and over, while 2.3% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, 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 Rifaximin with respect to specific gender populations. ### Race There is no FDA guidance on the use of Rifaximin with respect to specific racial populations. ### Renal Impairment - The pharmacokinetics of rifaximin in patients with impaired renal function has not been studied. ### Hepatic Impairment - Following administration of XIFAXAN 550 mg twice daily to patients with a history of hepatic encephalopathy, the systemic exposure (i.e., AUC ) of rifaximin was about 10-, 13-, and 20-fold higher in those patients with mild (Child-Pugh A), moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment, respectively, compared to that in healthy volunteers. No dosage adjustment is recommended because rifaximin is presumably acting locally. Nonetheless, caution should be exercised when XIFAXAN is administered to patients with severe hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Rifaximin in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Rifaximin in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Rifaximin in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Rifaximin in the drug label. # Overdosage ## Acute Overdose - No specific information is available on the treatment of overdosage with XIFAXAN. In clinical studies at doses higher than the recommended dose (> 600 mg/day for travelers’ diarrhea or > 1100 mg/day for hepatic encephalopathy), adverse reactions were similar in subjects who received doses higher than the recommended dose and placebo. In the case of overdosage, discontinue XIFAXAN, treat symptomatically, and institute supportive measures as required. ## Chronic Overdose There is limited information regarding Chronic Overdose of Rifaximin in the drug label. # Pharmacology ## Mechanism of Action - Rifaximin is a non-aminoglycoside semi-synthetic antibacterial derived from rifamycin SV. Rifaximin acts by binding to the beta-subunit of bacterial DNA-dependent RNA polymerase resulting in inhibition of bacterial RNA synthesis. ## Structure - XIFAXAN tablets contain rifaximin, a non-aminoglycoside semi-synthetic, nonsystemic antibiotic derived from rifamycin SV. Rifaximin is a structural analog of rifampin. The chemical name for rifaximin is (2 ,16 ,18 ,20 ,21 ,22 ,23 ,24 ,25 ,26 ,27 ,28 )-5,6,21,23,25-pentahydroxy-27-methoxy-2,4,11,16,20,22,24,26-octamethyl-2,7-(epoxypentadeca-trienimino)benzofuropyrido-benzimidazole-1,15(2 )-dione,25-acetate. The empirical formula is C H N O and its molecular weight is 785.9. The chemical structure is represented below: SZESSRRRSSSEH4351311 - XIFAXAN tablets for oral administration are film-coated and contain 200 mg or 550 mg of rifaximin. - Inactive ingredients: - Each 200 mg tablet contains colloidal silicon dioxide, disodium edetate, glycerol palmitostearate, hypromellose, microcrystalline cellulose, propylene glycol, red iron oxide, sodium starch glycolate, talc, and titanium dioxide. - Each 550 mg tablet contains colloidal silicon dioxide, glycerol palmitostearate, microcrystalline cellulose, polyethylene glycol/macrogol, polyvinyl alcohol, red iron oxide, sodium starch glycolate, talc, and titanium dioxide. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Rifaximin in the drug label. ## Pharmacokinetics - Absorption - Travelers’ Diarrhea - Systemic absorption of rifaximin (200 mg three times daily) was evaluated in 13 subjects challenged with shigellosis on Days 1 and 3 of a three-day course of treatment. Rifaximin plasma concentrations and exposures were low and variable. There was no evidence of accumulation of rifaximin following repeated administration for 3 days (9 doses). Peak plasma rifaximin concentrations after 3 and 9 consecutive doses ranged from 0.81 to 3.4 ng/mL on Day 1 and 0.68 to 2.26 ng/mL on Day 3. Similarly, AUC estimates were 6.95 ± 5.15 ngh/mL on Day 1 and 7.83 ± 4.94 ngh/mL on Day 3. XIFAXAN is not suitable for treating systemic bacterial infections because of limited systemic exposure after oral administration . - Hepatic Encephalopathy - After a single dose and multiple doses of rifaximin 550 mg in healthy subjects, the mean time to reach peak plasma concentrations was about an hour. The pharmacokinetic (PK) parameters were highly variable and the accumulation ratio based on AUC was 1.37. - The PK of rifaximin in patients with a history of HE was evaluated after administration of XIFAXAN, 550 mg two times a day. The PK parameters were associated with a high variability and mean rifaximin exposure (AUC ) in patients with a history of HE (147 ngh/mL) was approximately 12-fold higher than that observed in healthy subjects following the same dosing regimen (12.3 ngh/mL). When PK parameters were analyzed based on Child-Pugh Class A, B, and C, the mean AUC was 10-, 13-, and 20-fold higher, respectively, compared to that in healthy subjects (Table 3). - Food Effect in Healthy Subjects - A high-fat meal consumed 30 minutes prior to XIFAXAN dosing in healthy subjects delayed the mean time to peak plasma concentration from 0.75 to 1.5 hours and increased the systemic exposure (AUC) of rifaximin by 2-fold (Table 4). - Distribution - Rifaximin is moderately bound to human plasma proteins, the mean protein binding ratio was 67.5% in healthy subjects and 62% in patients with hepatic impairment when XIFAXAN 550 mg was administered. - Metabolism and Excretion - In a mass balance study, after administration of 400 mg C-rifaximin orally to healthy volunteers, of the 96.94% total recovery, 96.62% of the administered radioactivity was recovered in feces almost exclusively as the unchanged drug and 0.32% was recovered in urine mostly as metabolites with 0.03% as the unchanged drug. Rifaximin accounted for 18% of radioactivity in plasma. This suggests that the absorbed rifaximin undergoes metabolism with minimal renal excretion of the unchanged drug. The enzymes responsible for metabolizing rifaximin are unknown. - In a separate study, rifaximin was detected in the bile after cholecystectomy in patients with intact gastrointestinal mucosa, suggesting biliary excretion of rifaximin. - Specific Populations - Hepatic Impairment - The systemic exposure of rifaximin was markedly elevated in patients with hepatic impairment compared to healthy subjects. The mean AUC in patients with Child-Pugh Class C hepatic impairment was 2-fold higher than in patients with Child-Pugh Class A hepatic impairment (see Table 3). - Renal Impairment - The pharmacokinetics of rifaximin in patients with impaired renal function has not been studied. - Drug Interactions - Midazolam - The effect of rifaximin 200 mg administered orally every 8 hours for 3 days and for 7 days on the pharmacokinetics of a single dose of either midazolam 2 mg intravenous or midazolam 6 mg orally was evaluated in healthy subjects. No significant difference was observed in the metrics of systemic exposure or elimination of intravenous or oral midazolam or its major metabolite, 1’-hydroxymidazolam, between midazolam alone or together with rifaximin. Therefore, rifaximin was not shown to significantly affect intestinal or hepatic CYP3A4 activity for the 200 mg three times a day dosing regimen. - After XIFAXAN 550 mg was administered three times a day for 7 days and 14 days to healthy subjects, the mean AUC of single midazolam 2 mg orally was 3.8% and 8.8% lower, respectively, than when midazolam was administered alone. The mean C of midazolam was also decreased by 4-5% when XIFAXAN was administered for 7-14 days prior to midazolam administration. This degree of interaction is not considered clinically meaningful. max - The effect of rifaximin on CYP3A4 in patients with impaired liver function who have elevated systemic exposure is not known. - Oral Contraceptives Containing 0.07 mg Ethinyl Estradiol and 0.5 mg Norgestimate - The oral contraceptive study utilized an open-label, crossover design in 28 healthy female subjects to determine if rifaximin 200 mg orally administered three times a day for 3 days (the dosing regimen for travelers’ diarrhea) altered the pharmacokinetics of a single dose of an oral contraceptive containing 0.07 mg ethinyl estradiol and 0.5 mg norgestimate. Results showed that the pharmacokinetics of single doses of ethinyl estradiol and norgestimate were not altered by rifaximin. - Effect of rifaximin on oral contraceptives was not studied for XIFAXAN 550 mg twice a day, the dosing regimen for hepatic encephalopathy. ## Nonclinical Toxicology - Malignant schwannomas in the heart were significantly increased in male Crl:CD® (SD) rats that received rifaximin by oral gavage for two years at 150 to 250 mg/kg/day (doses equivalent to 2.4 to 4 times the recommended dose of 200 mg three times daily for travelers’ diarrhea, and equivalent to 1.3 to 2.2 times the recommended dose of 550 mg twice daily for hepatic encephalopathy, based on relative body surface area comparisons). There was no increase in tumors in Tg.rasH2 mice dosed orally with rifaximin for 26 weeks at 150 to 2000 mg/kg/day (doses equivalent to 1.2 to 16 times the recommended daily dose for travelers’ diarrhea and equivalent to 0.7 to 9 times the recommended daily dose for hepatic encephalopathy, based on relative body surface area comparisons). - Rifaximin was not genotoxic in the bacterial reverse mutation assay, chromosomal aberration assay, rat bone marrow micronucleus assay, rat hepatocyte unscheduled DNA synthesis assay, or the CHO/HGPRT mutation assay. There was no effect on fertility in male or female rats following the administration of rifaximin at doses up to 300 mg/kg (approximately 5 times the clinical dose of 600 mg/day, and approximately 2.6 times the clinical dose of 1100 mg/day, adjusted for body surface area). # Clinical Studies - The efficacy of XIFAXAN given as 200 mg orally taken three times a day for 3 days was evaluated in 2 randomized, multi‑center, double-blind, placebo-controlled studies in adult subjects with travelers’ diarrhea. One study was conducted at clinical sites in Mexico, Guatemala, and Kenya (Study 1). The other study was conducted in Mexico, Guatemala, Peru, and India (Study 2). Stool specimens were collected before treatment and 1 to 3 days following the end of treatment to identify enteric pathogens. - The clinical efficacy of XIFAXAN was assessed by the time to return to normal, formed stools and resolution of symptoms. The primary efficacy endpoint was time to last unformed stool (TLUS) which was defined as the time to the last unformed stool passed, after which clinical cure was declared. Table 5 displays the median TLUS and the number of patients who achieved clinical cure for the intent to treat (ITT) population of Study 1. The duration of diarrhea was significantly shorter in patients treated with XIFAXAN than in the placebo group. More patients treated with XIFAXAN were classified as clinical cures than were those in the placebo group. - Microbiological eradication (defined as the absence of a baseline pathogen in culture of stool after 72 hours of therapy) rates for Study 1 are presented in Table 6 for patients with any pathogen at baseline and for the subset of patients with at baseline. - Even though XIFAXAN had microbiologic activity similar to placebo, it demonstrated a clinically significant reduction in duration of diarrhea and a higher clinical cure rate than placebo. Therefore, patients should be managed based on clinical response to therapy rather than microbiologic response. - The results of Study 2 supported the results presented for Study 1. In addition, this study provided evidence that subjects treated with XIFAXAN with fever and/or blood in the stool at baseline had prolonged TLUS. These subjects had lower clinical cure rates than those without fever or blood in the stool at baseline. Many of the patients with fever and/or blood in the stool (dysentery-like diarrheal syndromes) had invasive pathogens, primarily ,isolated in the baseline stool. - Also in this study, the majority of the subjects treated with XIFAXAN who had isolated as a sole pathogen at baseline failed treatment and the resulting clinical cure rate for these patients was 23.5% (4/17). In addition to not being different from placebo, the microbiologic eradication rates for subjects with isolated at baseline were much lower than the eradication rates seen. - In an unrelated open-label, pharmacokinetic study of oral XIFAXAN 200 mg taken every 8 hours for 3 days, 15 adult subjects were challenged with 2a, of whom 13 developed diarrhea or dysentery and were treated with XIFAXAN. Although this open-label challenge trial was not adequate to assess the effectiveness of XIFAXAN in the treatment of shigellosis, the following observations were noted: eight subjects received rescue treatment with ciprofloxacin either because of lack of response to XIFAXAN treatment within 24 hours, or because they developed severe dysentery, or because of recurrence of in the stool; five of the 13 subjects received ciprofloxacin although they did not have evidence of severe disease or relapse. - The efficacy of XIFAXAN 550 mg taken orally two times a day was evaluated in a randomized, placebo-controlled, double-blind, multi-center 6-month trial of adult subjects from the U.S., Canada and Russia who were defined as being in remission (Conn score of 0 or 1) from hepatic encephalopathy (HE). Eligible subjects had ³ 2 episodes of HE associated with chronic liver disease in the previous 6 months. - A total of 299 subjects were randomized to receive either XIFAXAN (n=140) or placebo (n=159) in this study. Patients had a mean age of 56 years (range, 21-82 years), 81% 25. Nine percent of the patients were Child-Pugh Class C. Lactulose was concomitantly used by 91% of the patients in each treatment arm of the study. Per the study protocol, patients were withdrawn from the study after experiencing a breakthrough HE episode. Other reasons for early study discontinuation included: adverse reactions (XIFAXAN 6%; placebo 4%), patient request to withdraw (XIFAXAN 4%; placebo 6%) and other (XIFAXAN 7%; placebo 5%). - The primary endpoint was the time to first breakthrough overt HE episode. A breakthrough overt HE episode was defined as a marked deterioration in neurological function and an increase of Conn score to Grade ≥ 2. In patients with a baseline Conn score of 0, a breakthrough overt HE episode was defined as an increase in Conn score of 1 and asterixis grade of 1. - Breakthrough overt HE episodes were experienced by 31 of 140 subjects (22%) in the XIFAXAN group and by 73 of 159 subjects (46%) in the placebo group during the 6-month treatment period. Comparison of Kaplan-Meier estimates of event-free curves showed XIFAXAN significantly reduced the risk of HE breakthrough by 58% during the 6-month treatment period. Presented below in Figure 1 is the Kaplan-Meier event-free curve for all subjects (n = 299) in the study. - Event-free refers to non-occurrence of breakthrough HE. - When the results were evaluated by the following demographic and baseline characteristics, the treatment effect of XIFAXAN 550 mg in reducing the risk of breakthrough overt HE recurrence was consistent for: sex, baseline Conn score, duration of current remission and diabetes. The differences in treatment effect could not be assessed in the following subpopulations due to small sample size: non-White (n=42), baseline MELD > 19 (n=26), Child-Pugh C (n=31), and those without concomitant lactulose use (n=26). - HE-related hospitalizations (hospitalizations directly resulting from HE, or hospitalizations complicated by HE) were reported for 19 of 140 subjects (14%) and 36 of 159 subjects (23%) in the XIFAXAN and placebo groups respectively. Comparison of Kaplan-Meier estimates of event-free curves showed XIFAXAN significantly reduced the risk of HE-related hospitalizations by 50% during the 6-month treatment period. Comparison of Kaplan-Meier estimates of event-free curves is shown in Figure 2. # How Supplied - NDC:68151-4980-0 in a PACKAGE of 1 TABLETS - The 200 mg tablet is a pink-colored, round, biconvex tablet with “Sx” debossed on one side. It is available in the following presentations: - NDC 65649-301-03, bottles of 30 tablets - NDC 65649-301-41, bottles of 100 tablets - NDC 65649-301-05, carton of 100 tablets, Unit Dose - The 550 mg tablet is a pink-colored, oval, biconvex tablet with “rfx” debossed on one side. It is available in the following presentations: - NDC 65649-303-02, bottles of 60 tablets - NDC 65649-303-03, carton of 60 tablets, Unit Dose - Storage - Store XIFAXAN Tablets at 20–25°C (68–77°F); excursions permitted to 15–30°C (59-86°F). ## Storage There is limited information regarding Rifaximin Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Persistent Diarrhea - For those patients being treated for travelers’ diarrhea, discontinue XIFAXAN if diarrhea persists more than 24-48 hours or worsens. Advise the patient to seek medical care for fever and/or blood in the stool. - Clostridium difficile-Associated Diarrhea - Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including XIFAXAN, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibiotics alters the normal flora of the colon which may lead to. Patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If diarrhea occurs after therapy or does not improve or worsens during therapy, advise patients to contact a physician as soon as possible. - Administration with Food - Inform patients that XIFAXAN may be taken with or without food. - Antibacterial Resistance - Counsel patients that antibacterial drugs including XIFAXAN should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When XIFAXAN is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by XIFAXAN or other antibacterial drugs in the future. - Severe Hepatic Impairment - Patients should be informed that in patients with severe hepatic impairment (Child-Pugh C) there is an increase in systemic exposure to XIFAXAN. # Precautions with Alcohol - Alcohol-Rifaximin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - XIFAXAN® # Look-Alike Drug Names - rifaximin® — rifampin® # Drug Shortage Status # Price	Rifaximin 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 Rifaximin is a rifamycin antibacterial that is FDA approved for the treatment of travelers’ diarrhea (TD) caused by noninvasive strains of Escherichia coli and reduction in risk of overt hepatic encephalopathy (HE) recurrence in patients ≥ 18 years of age. Common adverse reactions include flatulence, headache, abdominal pain, rectal tenesmus, defecation urgency, nausea, peripheral edema, dizziness, fatigue, and ascites. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Dosing Information - The recommended dose of XIFAXAN is one 200 mg tablet taken orally three times a day for 3 days. XIFAXAN can be administered orally, with or without food. - Dosing Information - The recommended dose of XIFAXAN is one 550 mg tablet taken orally two times a day, with or without food. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Rifaximin in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Rifaximin in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Dosing Information - The recommended dose of XIFAXAN is one 200 mg tablet taken orally three times a day for 3 days (12 years or older). XIFAXAN can be administered orally, with or without food. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Rifaximin in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Rifaximin in pediatric patients. # Contraindications - Hypersensitivity - XIFAXAN is contraindicated in patients with a hypersensitivity to rifaximin, any of the rifamycin antimicrobial agents, or any of the components in XIFAXAN. Hypersensitivity reactions have included exfoliative dermatitis, angioneurotic edema, and anaphylaxis. # Warnings ### Precautions - Travelers’ Diarrhea Not Caused by Escherichia coli - XIFAXAN was not found to be effective in patients with diarrhea complicated by fever and/or blood in the stool or diarrhea due to pathogens other than Escherichia coli. - Discontinue XIFAXAN if diarrhea symptoms get worse or persist more than 24-48 hours and alternative antibiotic therapy should be considered. - XIFAXAN is not effective in cases of travelers’ diarrhea. The effectiveness of XIFAXAN in travelers’ diarrhea caused by spp. and spp. has not been proven. XIFAXAN should not be used in patients where , spp., or spp. may be suspected as causative pathogens. - Clostridium difficile-Associated Diarrhea - Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including XIFAXAN, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon which may lead to overgrowth of Clostridium difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. - If CDAD is suspected or confirmed, ongoing antibiotic use not directed against may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of , and surgical evaluation should be instituted as clinically indicated. - Development of Drug Resistant Bacteria - Prescribing XIFAXAN for travelers’ diarrhea in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. - Severe (Child-Pugh C) Hepatic Impairment - There is increased systemic exposure in patients with severe hepatic impairment. Animal toxicity studies did not achieve systemic exposures that were seen in patients with severe hepatic impairment. The clinical trials were limited to patients with MELD scores <25. Therefore, caution should be exercised when administering XIFAXAN to patients with severe hepatic impairment (Child-Pugh C). - Concomitant use with P-glycoprotein Inhibitors - Concomitant administration of drugs that are P-glycoprotein inhibitors with rifaximin can substantially increase the systemic exposure to rifaximin. Caution should be exercised when concomitant use of rifaximin and a P-glycoprotein inhibitor such as cyclosporine is needed. In patients with hepatic impairment, a potential additive effect of reduced metabolism and concomitant P-glycoprotein inhibitors may further increase the systemic exposure to rifaximin. # 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. - The safety of XIFAXAN 200 mg taken three times a day was evaluated in patients with travelers’ diarrhea consisting of 320 patients in two placebo-controlled clinical trials with 95% of patients receiving three or four days of treatment with XIFAXAN. The population studied had a mean age of 31.3 (18-79) years of which approximately 3% were ≥ 65 years old, 53% were male and 84% were White, 11% were Hispanic. - Discontinuations due to adverse reactions occurred in 0.4% of patients. The adverse reactions leading to discontinuation were taste loss, dysentery, weight loss, anorexia, nausea and nasal passage irritation. - All adverse reactions for XIFAXAN 200 mg three times daily that occurred at a frequency ≥ 2% in the two placebo-controlled trials combined are provided in Table 1. (These include adverse reactions that may be attributable to the underlying disease.) - The following adverse reactions, presented by body system, have also been reported in <2% of patients taking XIFAXAN in the two placebo-controlled clinical trials where the 200 mg tablet was taken three times a day for travelers’ diarrhea. The following includes adverse reactions regardless of causal relationship to drug exposure. Lymphocytosis, monocytosis, neutropenia Ear pain, motion sickness, tinnitus Abdominal distension, diarrhea NOS, dry throat, fecal abnormality NOS, gingival disorder NOS, inguinal hernia NOS, dry lips, stomach discomfort Chest pain, fatigue, malaise, pain NOS, weakness Dysentery NOS, respiratory tract infection NOS, upper respiratory tract infection NOS Aspartate aminotransferase increased, blood in stool, blood in urine, weight decreased Anorexia, dehydration Arthralgia, muscle spasms, myalgia, neck pain Abnormal dreams, dizziness, migraine NOS, syncope, loss of taste Insomnia Choluria, dysuria, hematuria, polyuria, proteinuria, urinary frequency Dyspnea NOS, nasal passage irritation, nasopharyngitis, pharyngitis, pharyngolaryngeal pain, rhinitis NOS, rhinorrhea Clamminess, rash NOS, sweating increased Hot flashes NOS - The data described below reflect exposure to XIFAXAN 550 mg in 348 patients, including 265 exposed for 6 months and 202 exposed for more than a year (mean exposure was 364 days). The safety of XIFAXAN 550 mg taken two times a day for reducing the risk of overt hepatic encephalopathy recurrence in adult patients was evaluated in a 6-month placebo-controlled clinical trial (n = 140) and in a long term follow-up study (n = 280). The population studied had a mean age of 56.26 (range: 21-82) years; approximately 20% of the patients were ≥ 65 years old, 61% were male, 86% were White, and 4% were Black. Ninety-one percent of patients in the trial were taking lactulose concomitantly. All adverse reactions that occurred at an incidence ≥ 5% and at a higher incidence in XIFAXAN 550 mg-treated subjects than in the placebo group in the 6-month trial are provided in Table 2. (These include adverse events that may be attributable to the underlying disease). - The following adverse reactions, presented by body system, have also been reported in the placebo-controlled clinical trial in greater than 2% but less than 5% of patients taking XIFAXAN 550 mg taken orally two times a day for hepatic encephalopathy. The following includes adverse events occurring at a greater incidence than placebo, regardless of causal relationship to drug exposure. Vertigo Lower abdominal pain, abdominal tenderness, dry mouth, esophageal variceal bleed, stomach discomfort Chest pain, generalized edema, influenza like illness, pain NOS Cellulitis, pneumonia, rhinitis, upper respiratory tract infection NOS Contusion, fall, procedural pain Injury Anorexia, dehydration, hyperglycemia, hyperkalemia, hypoglycemia, hyponatremia Myalgia, pain in extremity Amnesia, disturbance in attention, hypoesthesia, memory impairment, tremor Confusional state Epistaxis Hypotension ## Postmarketing Experience - The following adverse reactions have been identified during post approval use of XIFAXAN. Because these reactions are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These reactions have been chosen for inclusion due to either their seriousness, frequency of reporting or causal connection to XIFAXAN. Cases of C. difficile-associated colitis have been reported. Hypersensitivity reactions, including exfoliative dermatitis, rash, angioneurotic edema (swelling of face and tongue and difficulty swallowing), urticaria, flushing, pruritus and anaphylaxis have been reported. These events occurred as early as within 15 minutes of drug administration. # Drug Interactions - Effects of rifaximin on cytochrome P450 enzymes - studies have shown that rifaximin did not inhibit cytochrome P450 isoenzymes 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1 and CYP3A4 at concentrations ranging from 2 to 200 ng/mL. Rifaximin is not expected to inhibit these enzymes in clinical use. - An study has suggested that rifaximin induces CYP3A4. However, in patients with normal liver function, rifaximin at the recommended dosing regimen is not expected to induce CYP3A4. It is unknown whether rifaximin can have a significant effect on the pharmacokinetics of concomitant CYP3A4 substrates in patients with reduced liver function who have elevated rifaximin concentrations. - Concomitant P-glycoprotein inhibitors - An study suggested that rifaximin is a substrate of P-glycoprotein. Co-administration of cyclosporine, a potent P-glycoprotein inhibitor, with rifaximin resulted in 83-fold and 124-fold increases in rifaximin mean C and AUC∞ in healthy subjects. The clinical significance of this increase in systemic exposure is unknown. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - There are no adequate and well controlled studies in pregnant women. Rifaximin has been shown to be teratogenic in rats and rabbits at doses that caused maternal toxicity. XIFAXAN tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. - Administration of rifaximin to pregnant rats and rabbits at dose levels that caused reduced body weight gain resulted in eye malformations in both rat and rabbit fetuses. Additional malformations were observed in fetal rabbits that included cleft palate, lumbar scoliosis, brachygnathia, interventricular septal defect, and large atrium. - The fetal rat malformations were observed in a study of pregnant rats administered a high dose that resulted in 16 times the therapeutic dose to diarrheic patients or 1 times the therapeutic dose to patients with hepatic encephalopathy (based upon plasma AUC comparisons). Fetal rabbit malformations were observed from pregnant rabbits administered mid and high doses that resulted in 1 or 2 times the therapeutic dose to diarrheic patients or less than 0.1 times the dose in patients with hepatic encephalopathy, based upon plasma AUC comparisons. - Post-natal developmental effects were not observed in rat pups from pregnant/lactating female rats dosed during the period from gestation to Day 20 post-partum at the highest dose which resulted in approximately 16 times the human therapeutic dose for travelers’ diarrhea (based upon AUCs) or approximately 1 times the AUCs derived from therapeutic doses to patients with hepatic encephalopathy. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Rifaximin in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Rifaximin during labor and delivery. ### Nursing Mothers - It is not known whether rifaximin is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from XIFAXAN, 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 XIFAXAN 200 mg in pediatric patients with travelers’ diarrhea less than 12 years of age have not been established. - The safety and effectiveness of XIFAXAN 550 mg for HE have not been established in patients < 18 years of age. ### Geriatic Use - Clinical studies with rifaximin 200 mg for travelers’ diarrhea did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger subjects. - In the controlled trial with XIFAXAN 550 mg for hepatic encephalopathy, 19.4% were 65 and over, while 2.3% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, 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 Rifaximin with respect to specific gender populations. ### Race There is no FDA guidance on the use of Rifaximin with respect to specific racial populations. ### Renal Impairment - The pharmacokinetics of rifaximin in patients with impaired renal function has not been studied. ### Hepatic Impairment - Following administration of XIFAXAN 550 mg twice daily to patients with a history of hepatic encephalopathy, the systemic exposure (i.e., AUC ) of rifaximin was about 10-, 13-, and 20-fold higher in those patients with mild (Child-Pugh A), moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment, respectively, compared to that in healthy volunteers. No dosage adjustment is recommended because rifaximin is presumably acting locally. Nonetheless, caution should be exercised when XIFAXAN is administered to patients with severe hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Rifaximin in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Rifaximin in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Rifaximin in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Rifaximin in the drug label. # Overdosage ## Acute Overdose - No specific information is available on the treatment of overdosage with XIFAXAN. In clinical studies at doses higher than the recommended dose (> 600 mg/day for travelers’ diarrhea or > 1100 mg/day for hepatic encephalopathy), adverse reactions were similar in subjects who received doses higher than the recommended dose and placebo. In the case of overdosage, discontinue XIFAXAN, treat symptomatically, and institute supportive measures as required. ## Chronic Overdose There is limited information regarding Chronic Overdose of Rifaximin in the drug label. # Pharmacology ## Mechanism of Action - Rifaximin is a non-aminoglycoside semi-synthetic antibacterial derived from rifamycin SV. Rifaximin acts by binding to the beta-subunit of bacterial DNA-dependent RNA polymerase resulting in inhibition of bacterial RNA synthesis. ## Structure - XIFAXAN tablets contain rifaximin, a non-aminoglycoside semi-synthetic, nonsystemic antibiotic derived from rifamycin SV. Rifaximin is a structural analog of rifampin. The chemical name for rifaximin is (2 ,16 ,18 ,20 ,21 ,22 ,23 ,24 ,25 ,26 ,27 ,28 )-5,6,21,23,25-pentahydroxy-27-methoxy-2,4,11,16,20,22,24,26-octamethyl-2,7-(epoxypentadeca-[1,11,13]trienimino)benzofuro[4,5-e]pyrido[1,2-á]-benzimidazole-1,15(2 )-dione,25-acetate. The empirical formula is C H N O and its molecular weight is 785.9. The chemical structure is represented below: SZESSRRRSSSEH4351311 - XIFAXAN tablets for oral administration are film-coated and contain 200 mg or 550 mg of rifaximin. - Inactive ingredients: - Each 200 mg tablet contains colloidal silicon dioxide, disodium edetate, glycerol palmitostearate, hypromellose, microcrystalline cellulose, propylene glycol, red iron oxide, sodium starch glycolate, talc, and titanium dioxide. - Each 550 mg tablet contains colloidal silicon dioxide, glycerol palmitostearate, microcrystalline cellulose, polyethylene glycol/macrogol, polyvinyl alcohol, red iron oxide, sodium starch glycolate, talc, and titanium dioxide. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Rifaximin in the drug label. ## Pharmacokinetics - Absorption - Travelers’ Diarrhea - Systemic absorption of rifaximin (200 mg three times daily) was evaluated in 13 subjects challenged with shigellosis on Days 1 and 3 of a three-day course of treatment. Rifaximin plasma concentrations and exposures were low and variable. There was no evidence of accumulation of rifaximin following repeated administration for 3 days (9 doses). Peak plasma rifaximin concentrations after 3 and 9 consecutive doses ranged from 0.81 to 3.4 ng/mL on Day 1 and 0.68 to 2.26 ng/mL on Day 3. Similarly, AUC estimates were 6.95 ± 5.15 ng•h/mL on Day 1 and 7.83 ± 4.94 ng•h/mL on Day 3. XIFAXAN is not suitable for treating systemic bacterial infections because of limited systemic exposure after oral administration . - Hepatic Encephalopathy - After a single dose and multiple doses of rifaximin 550 mg in healthy subjects, the mean time to reach peak plasma concentrations was about an hour. The pharmacokinetic (PK) parameters were highly variable and the accumulation ratio based on AUC was 1.37. - The PK of rifaximin in patients with a history of HE was evaluated after administration of XIFAXAN, 550 mg two times a day. The PK parameters were associated with a high variability and mean rifaximin exposure (AUC ) in patients with a history of HE (147 ng•h/mL) was approximately 12-fold higher than that observed in healthy subjects following the same dosing regimen (12.3 ng•h/mL). When PK parameters were analyzed based on Child-Pugh Class A, B, and C, the mean AUC was 10-, 13-, and 20-fold higher, respectively, compared to that in healthy subjects (Table 3). - Food Effect in Healthy Subjects - A high-fat meal consumed 30 minutes prior to XIFAXAN dosing in healthy subjects delayed the mean time to peak plasma concentration from 0.75 to 1.5 hours and increased the systemic exposure (AUC) of rifaximin by 2-fold (Table 4). - Distribution - Rifaximin is moderately bound to human plasma proteins, the mean protein binding ratio was 67.5% in healthy subjects and 62% in patients with hepatic impairment when XIFAXAN 550 mg was administered. - Metabolism and Excretion - In a mass balance study, after administration of 400 mg C-rifaximin orally to healthy volunteers, of the 96.94% total recovery, 96.62% of the administered radioactivity was recovered in feces almost exclusively as the unchanged drug and 0.32% was recovered in urine mostly as metabolites with 0.03% as the unchanged drug. Rifaximin accounted for 18% of radioactivity in plasma. This suggests that the absorbed rifaximin undergoes metabolism with minimal renal excretion of the unchanged drug. The enzymes responsible for metabolizing rifaximin are unknown. - In a separate study, rifaximin was detected in the bile after cholecystectomy in patients with intact gastrointestinal mucosa, suggesting biliary excretion of rifaximin. - Specific Populations - Hepatic Impairment - The systemic exposure of rifaximin was markedly elevated in patients with hepatic impairment compared to healthy subjects. The mean AUC in patients with Child-Pugh Class C hepatic impairment was 2-fold higher than in patients with Child-Pugh Class A hepatic impairment (see Table 3). - Renal Impairment - The pharmacokinetics of rifaximin in patients with impaired renal function has not been studied. - Drug Interactions - Midazolam - The effect of rifaximin 200 mg administered orally every 8 hours for 3 days and for 7 days on the pharmacokinetics of a single dose of either midazolam 2 mg intravenous or midazolam 6 mg orally was evaluated in healthy subjects. No significant difference was observed in the metrics of systemic exposure or elimination of intravenous or oral midazolam or its major metabolite, 1’-hydroxymidazolam, between midazolam alone or together with rifaximin. Therefore, rifaximin was not shown to significantly affect intestinal or hepatic CYP3A4 activity for the 200 mg three times a day dosing regimen. - After XIFAXAN 550 mg was administered three times a day for 7 days and 14 days to healthy subjects, the mean AUC of single midazolam 2 mg orally was 3.8% and 8.8% lower, respectively, than when midazolam was administered alone. The mean C of midazolam was also decreased by 4-5% when XIFAXAN was administered for 7-14 days prior to midazolam administration. This degree of interaction is not considered clinically meaningful. max - The effect of rifaximin on CYP3A4 in patients with impaired liver function who have elevated systemic exposure is not known. - Oral Contraceptives Containing 0.07 mg Ethinyl Estradiol and 0.5 mg Norgestimate - The oral contraceptive study utilized an open-label, crossover design in 28 healthy female subjects to determine if rifaximin 200 mg orally administered three times a day for 3 days (the dosing regimen for travelers’ diarrhea) altered the pharmacokinetics of a single dose of an oral contraceptive containing 0.07 mg ethinyl estradiol and 0.5 mg norgestimate. Results showed that the pharmacokinetics of single doses of ethinyl estradiol and norgestimate were not altered by rifaximin. - Effect of rifaximin on oral contraceptives was not studied for XIFAXAN 550 mg twice a day, the dosing regimen for hepatic encephalopathy. ## Nonclinical Toxicology - Malignant schwannomas in the heart were significantly increased in male Crl:CD® (SD) rats that received rifaximin by oral gavage for two years at 150 to 250 mg/kg/day (doses equivalent to 2.4 to 4 times the recommended dose of 200 mg three times daily for travelers’ diarrhea, and equivalent to 1.3 to 2.2 times the recommended dose of 550 mg twice daily for hepatic encephalopathy, based on relative body surface area comparisons). There was no increase in tumors in Tg.rasH2 mice dosed orally with rifaximin for 26 weeks at 150 to 2000 mg/kg/day (doses equivalent to 1.2 to 16 times the recommended daily dose for travelers’ diarrhea and equivalent to 0.7 to 9 times the recommended daily dose for hepatic encephalopathy, based on relative body surface area comparisons). - Rifaximin was not genotoxic in the bacterial reverse mutation assay, chromosomal aberration assay, rat bone marrow micronucleus assay, rat hepatocyte unscheduled DNA synthesis assay, or the CHO/HGPRT mutation assay. There was no effect on fertility in male or female rats following the administration of rifaximin at doses up to 300 mg/kg (approximately 5 times the clinical dose of 600 mg/day, and approximately 2.6 times the clinical dose of 1100 mg/day, adjusted for body surface area). # Clinical Studies - The efficacy of XIFAXAN given as 200 mg orally taken three times a day for 3 days was evaluated in 2 randomized, multi‑center, double-blind, placebo-controlled studies in adult subjects with travelers’ diarrhea. One study was conducted at clinical sites in Mexico, Guatemala, and Kenya (Study 1). The other study was conducted in Mexico, Guatemala, Peru, and India (Study 2). Stool specimens were collected before treatment and 1 to 3 days following the end of treatment to identify enteric pathogens. - The clinical efficacy of XIFAXAN was assessed by the time to return to normal, formed stools and resolution of symptoms. The primary efficacy endpoint was time to last unformed stool (TLUS) which was defined as the time to the last unformed stool passed, after which clinical cure was declared. Table 5 displays the median TLUS and the number of patients who achieved clinical cure for the intent to treat (ITT) population of Study 1. The duration of diarrhea was significantly shorter in patients treated with XIFAXAN than in the placebo group. More patients treated with XIFAXAN were classified as clinical cures than were those in the placebo group. - Microbiological eradication (defined as the absence of a baseline pathogen in culture of stool after 72 hours of therapy) rates for Study 1 are presented in Table 6 for patients with any pathogen at baseline and for the subset of patients with at baseline. - Even though XIFAXAN had microbiologic activity similar to placebo, it demonstrated a clinically significant reduction in duration of diarrhea and a higher clinical cure rate than placebo. Therefore, patients should be managed based on clinical response to therapy rather than microbiologic response. - The results of Study 2 supported the results presented for Study 1. In addition, this study provided evidence that subjects treated with XIFAXAN with fever and/or blood in the stool at baseline had prolonged TLUS. These subjects had lower clinical cure rates than those without fever or blood in the stool at baseline. Many of the patients with fever and/or blood in the stool (dysentery-like diarrheal syndromes) had invasive pathogens, primarily ,isolated in the baseline stool. - Also in this study, the majority of the subjects treated with XIFAXAN who had isolated as a sole pathogen at baseline failed treatment and the resulting clinical cure rate for these patients was 23.5% (4/17). In addition to not being different from placebo, the microbiologic eradication rates for subjects with isolated at baseline were much lower than the eradication rates seen. - In an unrelated open-label, pharmacokinetic study of oral XIFAXAN 200 mg taken every 8 hours for 3 days, 15 adult subjects were challenged with 2a, of whom 13 developed diarrhea or dysentery and were treated with XIFAXAN. Although this open-label challenge trial was not adequate to assess the effectiveness of XIFAXAN in the treatment of shigellosis, the following observations were noted: eight subjects received rescue treatment with ciprofloxacin either because of lack of response to XIFAXAN treatment within 24 hours, or because they developed severe dysentery, or because of recurrence of in the stool; five of the 13 subjects received ciprofloxacin although they did not have evidence of severe disease or relapse. - The efficacy of XIFAXAN 550 mg taken orally two times a day was evaluated in a randomized, placebo-controlled, double-blind, multi-center 6-month trial of adult subjects from the U.S., Canada and Russia who were defined as being in remission (Conn score of 0 or 1) from hepatic encephalopathy (HE). Eligible subjects had ³ 2 episodes of HE associated with chronic liver disease in the previous 6 months. - A total of 299 subjects were randomized to receive either XIFAXAN (n=140) or placebo (n=159) in this study. Patients had a mean age of 56 years (range, 21-82 years), 81% < 65 years of age, 61% were male and 86% White. At baseline, 67% of patients had a Conn score of 0 and 68% had an asterixis grade of 0. Patients had MELD scores of either £ 10 (27%) or 11 to 18 (64%) at baseline. No patients were enrolled with a MELD score of > 25. Nine percent of the patients were Child-Pugh Class C. Lactulose was concomitantly used by 91% of the patients in each treatment arm of the study. Per the study protocol, patients were withdrawn from the study after experiencing a breakthrough HE episode. Other reasons for early study discontinuation included: adverse reactions (XIFAXAN 6%; placebo 4%), patient request to withdraw (XIFAXAN 4%; placebo 6%) and other (XIFAXAN 7%; placebo 5%). - The primary endpoint was the time to first breakthrough overt HE episode. A breakthrough overt HE episode was defined as a marked deterioration in neurological function and an increase of Conn score to Grade ≥ 2. In patients with a baseline Conn score of 0, a breakthrough overt HE episode was defined as an increase in Conn score of 1 and asterixis grade of 1. - Breakthrough overt HE episodes were experienced by 31 of 140 subjects (22%) in the XIFAXAN group and by 73 of 159 subjects (46%) in the placebo group during the 6-month treatment period. Comparison of Kaplan-Meier estimates of event-free curves showed XIFAXAN significantly reduced the risk of HE breakthrough by 58% during the 6-month treatment period. Presented below in Figure 1 is the Kaplan-Meier event-free curve for all subjects (n = 299) in the study. - Event-free refers to non-occurrence of breakthrough HE. - When the results were evaluated by the following demographic and baseline characteristics, the treatment effect of XIFAXAN 550 mg in reducing the risk of breakthrough overt HE recurrence was consistent for: sex, baseline Conn score, duration of current remission and diabetes. The differences in treatment effect could not be assessed in the following subpopulations due to small sample size: non-White (n=42), baseline MELD > 19 (n=26), Child-Pugh C (n=31), and those without concomitant lactulose use (n=26). - HE-related hospitalizations (hospitalizations directly resulting from HE, or hospitalizations complicated by HE) were reported for 19 of 140 subjects (14%) and 36 of 159 subjects (23%) in the XIFAXAN and placebo groups respectively. Comparison of Kaplan-Meier estimates of event-free curves showed XIFAXAN significantly reduced the risk of HE-related hospitalizations by 50% during the 6-month treatment period. Comparison of Kaplan-Meier estimates of event-free curves is shown in Figure 2. # How Supplied - NDC:68151-4980-0 in a PACKAGE of 1 TABLETS - The 200 mg tablet is a pink-colored, round, biconvex tablet with “Sx” debossed on one side. It is available in the following presentations: - NDC 65649-301-03, bottles of 30 tablets - NDC 65649-301-41, bottles of 100 tablets - NDC 65649-301-05, carton of 100 tablets, Unit Dose - The 550 mg tablet is a pink-colored, oval, biconvex tablet with “rfx” debossed on one side. It is available in the following presentations: - NDC 65649-303-02, bottles of 60 tablets - NDC 65649-303-03, carton of 60 tablets, Unit Dose - Storage - Store XIFAXAN Tablets at 20–25°C (68–77°F); excursions permitted to 15–30°C (59-86°F). ## Storage There is limited information regarding Rifaximin Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Persistent Diarrhea - For those patients being treated for travelers’ diarrhea, discontinue XIFAXAN if diarrhea persists more than 24-48 hours or worsens. Advise the patient to seek medical care for fever and/or blood in the stool. - Clostridium difficile-Associated Diarrhea - Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including XIFAXAN, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibiotics alters the normal flora of the colon which may lead to. Patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If diarrhea occurs after therapy or does not improve or worsens during therapy, advise patients to contact a physician as soon as possible. - Administration with Food - Inform patients that XIFAXAN may be taken with or without food. - Antibacterial Resistance - Counsel patients that antibacterial drugs including XIFAXAN should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When XIFAXAN is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by XIFAXAN or other antibacterial drugs in the future. - Severe Hepatic Impairment - Patients should be informed that in patients with severe hepatic impairment (Child-Pugh C) there is an increase in systemic exposure to XIFAXAN. # Precautions with Alcohol - Alcohol-Rifaximin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - XIFAXAN®[1] # Look-Alike Drug Names - rifaximin® — rifampin®[2] # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Rifaximin
8b7072184777211078d9ba49f7025f6080eaec53	wikidoc	Riociguat	Riociguat # 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 Riociguat is a cardiovascular agent that is FDA approved for the treatment of persistent,recurrent chronic thromboembolic pulmonary hypertension and pulmonary arterial hypertension. There is a Black Box Warning for this drug as shown here. Common adverse reactions include headache, dyspepsia,gastritis, dizziness, nausea, diarrhea, hypotension, vomiting, anemia, gastroesophageal reflux, and constipation.. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) # Indications Chronic-Thromboembolic Pulmonary Hypertension - Adempas is indicated for the treatment of adults with persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH), (WHO Group 4) after surgical treatment, or inoperable CTEPH, to improve exercise capacity and WHO functional class. Pulmonary Arterial Hypertension - Adempas is indicated for the treatment of adults with pulmonary arterial hypertension (PAH), (WHO Group 1), to improve exercise capacity, WHO functional class and to delay clinical worsening. - Efficacy was shown in patients on Adempas monotherapy or in combination with endothelin receptor antagonists or prostanoids. Studies establishing effectiveness included predominately patients with WHO functional class II–III and etiologies of idiopathic or heritable PAH (61%) or PAH associated with connective tissue diseases (25%). # Dosage Recommended Dosage in Adult Patients - The recommended starting dosage is 1 mg taken 3 times a day. For patients who may not tolerate the hypotensive effect of Adempas, consider a starting dose of 0.5 mg taken three times a day. If systolic blood pressure remains greater than 95 mmHg and the patient has no signs or symptoms of hypotension, up-titrate the dose by 0.5 mg taken three times a day. Dose increases should be no sooner than 2 weeks apart. The dose can be increased to the highest tolerated dosage, up to a maximum of 2.5 mg taken three times a day. If at any time, the patient has symptoms of hypotension, decrease the dosage by 0.5 mg taken three times a day. Dosage Interruption - If a dose is missed, advise patients to continue with the next regularly scheduled dose. - In case Adempas is interrupted for 3 days or more, re-titrate Adempas. Pregnancy Testing in Females of Reproductive Potential - Obtain pregnancy tests prior to initiation and monthly during treatment. Use in Patients who Smoke - Consider titrating to dosages higher than 2.5 mg three times a day, if tolerated, in patients who smoke. A dose decrease may be required in patients who stop smoking. Strong CYP and P-gp/BCRP Inhibitors - Consider a starting dose of 0.5 mg, three times a day when initiating Adempas in patients receiving strong cytochrome P450 (CYP) and P-glycoprotein/breast cancer resistance protein (P-gp/BCRP) inhibitors such as azole antimycotics (for example, ketoconazole, itraconazole) or HIV protease inhibitors (for example, ritonavir). Monitor for signs and symptoms of hypotension on initiation and on treatment with strong CYP and P-gp/BCRP inhibitors. ## DOSAGE FORMS AND STRENGTHS - Tablets: film-coated, round, bi-convex: - 0.5 mg, white, with “BAYER” cross on one side and “0.5” and “R” on the other side - 1 mg, pale-yellow, with “BAYER” cross on one side and “1” and “R” on the other side - 1.5 mg, yellow-orange, with “BAYER” cross on one side and “1.5” and “R” on the other side - 2 mg, pale orange, with “BAYER” cross on one side and “2” and “R” on the other side - 2.5 mg, red-orange, with “BAYER” cross on one side and “2.5” and “R” on the other side ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Riociguat in adult patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of Riociguat in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - There is limited information regarding FDA-Labeled Use of Riociguat in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Riociguat in pediatric patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of Riociguat in pediatric patients. # Contraindications Pregnancy - Adempas may cause fetal harm when administered to a pregnant woman. Adempas is contraindicated in females who are pregnant. Adempas was consistently shown to have teratogenic effects when administered to animals. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus . Nitrates and Nitric Oxide Donors - Co-administration of Adempas with nitrates or nitric oxide donors (such as amyl nitrite) in any form is contraindicated. Phosphodiesterase Inhibitors - Concomitant administration of Adempas with specific PDE-5 inhibitors (such as sildenafil, tadalafil, or vardenafil) or nonspecific PDE inhibitors (such as dipyridamole or theophylline) is contraindicated . # Warnings Embryo-Fetal Toxicity - Adempas may cause fetal harm when administered during pregnancy and is contraindicated for use in women who are pregnant. In females of reproductive potential, exclude pregnancy prior to initiation of therapy, advise use of acceptable contraception and obtain monthly pregnancy tests. For Female, Adempas is only available through a restricted program under the Adempas REMS Program. Adempas REMS Program - Females can only receive Adempas through the Adempas Risk Evaluation and Mitigation Strategy (REMS) Program, a restricted distribution program. - Important requirements of the Adempas REMS Program include the following: - Prescribers must be certified with the program by enrolling and completing training. - All females, regardless of reproductive potential, must enroll in the Adempas REMS Program prior to initiating Adempas. Male patients are not enrolled in the Adempas REMS Program. - Female patients of reproductive potential must comply with the pregnancy testing and contraception requirements. - Pharmacies must be certified with the program and must only dispense to patients who are authorized to receive Adempas. Hypotension - Adempas reduces blood pressure. Consider the potential for symptomatic hypotension or ischemia in patients with hypovolemia, severe left ventricular outflow obstruction, resting hypotension, autonomic dysfunction, or concomitant treatment with antihypertensives or strong CYP and P-gp/BCRP inhibitors. Consider a dose reduction if patient develops signs or symptoms of hypotension. Bleeding - In the placebo-controlled clinical trials, serious bleeding occurred in 2.4% of patients taking Adempas compared to 0% of placebo patients. Serious hemoptysis occurred in 5 (1%) patients taking Adempas compared to 0 placebo patients, including one event with fatal outcome. Serious hemorrhagic events also included 2 patients with vaginal hemorrhage, 2 with catheter site hemorrhage, and 1 each with subdural hematoma, hematemesis, and intra-abdominal hemorrhage. Pulmonary Veno-Occlusive Disease - Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with pulmonary veno-occlusive disease (PVOD). Therefore, administration of Adempas to such patients is not recommended. Should signs of pulmonary edema occur, the possibility of associated PVOD should be considered and, if confirmed, discontinue treatment with Adempas. # Adverse Reactions ## Clinical Trials Experience - The following serious adverse reactions are discussed elsewhere in the labeling: - Embryo-Fetal Toxicity - Hypotension - Bleeding 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. - The safety data described below reflect exposure to Adempas in two, randomized, double blind, placebo-controlled trials in patients with inoperable or recurrent/persistent CTEPH (CHEST-1) and treatment naive or pre-treated PAH patients (PATENT-1). The population (Adempas: n = 490; Placebo: n = 214) was between the age of 18 and 80 years. - The safety profile of Adempas in patients with inoperable or recurrent/persistent CTEPH (CHEST-1) and treatment naive or pre-treated PAH (PATENT-1) were similar. Therefore, adverse drug reactions (ADRs) identified from the 12 and 16 week placebo-controlled trials for PAH and CTEPH respectively were pooled, and those occurring more frequently on Adempas than placebo (≥3%) are displayed in Table 1 below. Most adverse reactions in Table 1 can be ascribed to the vasodilatory mechanism of action of Adempas. - The overall rates of discontinuation due to an adverse event in the pivotal placebo-controlled trials were 2.9% for Adempas and 5.1% for placebo (pooled data). Other events that were seen more frequently in Adempas compared to placebo and potentially related to treatment were: palpitations, nasal congestion, epistaxis, dysphagia, abdominal distension and peripheral edema. With longer observation in uncontrolled long-term extension studies the safety profile was similar to that observed in the placebo controlled phase 3 trials. ## Postmarketing Experience - There is limited information regarding Postmarketing Experience of Riociguat in the drug label. # Drug Interactions Pharmacodynamic Interactions with Adempas Nitrates: Co-administration of Adempas with nitrates or nitric oxide donors (such as amyl nitrite) in any form is contraindicated because of hypotension. PDE Inhibitors: Co-administration of Adempas with specific PDE-5 inhibitors (such as sildenafil, tadalafil, or vardenafil) and nonspecific PDE inhibitors (such as dipyridamole or theophylline), is contraindicated because of hypotension. Clinical experience with co-administration of Adempas and other phosphodiesterase inhibitors (for example, milrinone, cilostazole, roflumilast) is limited. Pharmacokinetic Interactions with Adempas Smoking: Plasma concentrations in smokers are reduced by 50-60% compared to nonsmokers. Based on pharmacokinetic modeling, for patients who are smokers, doses higher than 2.5 mg three times a day may be considered in order to match exposure seen in nonsmoking patients. Safety and effectiveness of Adempas doses higher than 2.5 mg three times a day have not been established. A dose reduction should be considered in patients who stop smoking. Strong CYP and P-gp/BCRP inhibitors: Concomitant use of riociguat with strong cytochrome CYP inhibitors and P-gp/BCRP inhibitors such as azole antimycotics (for example, ketoconazole, itraconazole) or HIV protease inhibitors (such as ritonavir) increase riociguat exposure and may result in hypotension. Consider a starting dose of 0.5 mg 3 times a day when initiating Adempas in patients receiving strong CYP and P-gp/BCRP inhibitors. Monitor for signs and symptoms of hypotension on initiation and on treatment with strong CYP and P-gp/BCRP inhibitors. A dose reduction should be considered in patients who may not tolerate the hypotensive effect of riociguat. Strong CYP3A inducers: Strong inducers of CYP3A (for example, rifampin, phenytoin, carbamazepine, phenobarbital or St. John’s Wort) may significantly reduce riociguat exposure. Data are not available to guide dosing of riociguat when strong CYP3A inducers are co-administered. Antacids: Antacids such as aluminum hydroxide/magnesium hydroxide decrease riociguat absorption and should not be taken within 1 hour of taking Adempas. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): Pregnancy Category X Risk Summary - Adempas may cause fetal harm when administered to a pregnant woman and is contraindicated during pregnancy. Adempas was teratogenic and embryotoxic in rats at doses with exposures to unbound drug that were approximately 8 times and 2 times, respectively, the human exposure. In rabbits, riociguat led to abortions at 4 times the human exposure and fetal toxicity with exposures approximately 13 times the human exposure. If Adempas is used in pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus. Animal Data - In rats administered riociguat orally (1, 5, and 25 mg/kg/day) throughout organogenesis, an increased rate of cardiac ventricular-septal defect was observed at the highest dose tested. The highest dose produced evidence of maternal toxicity (reduced body weight). Post-implantation loss was statistically significantly increased from the mid-dose of 5 mg/kg/day. Plasma exposure at the lowest dose in which no adverse effects were observed is approximately 0.4 times that in humans at the maximally recommended human dose (MRHD) of 2.5 mg three times a day based on area under the time-concentration curve (AUC) for unbound drug in rat and humans. Plasma exposure at the highest dose (25 mg/kg/day) is approximately 8 times that in humans at the MRHD while exposure at the mid-dose (5 mg/kg/day) is approximately 2 times that in humans at the MRHD. In rabbits given doses of 0.5, 1.5 and 5 mg/kg/day, an increase in spontaneous abortions was observed starting at the middle dose of 1.5 mg/kg, and an increase in resorptions was observed at 5 mg/kg/day. Plasma exposures at these doses were 4 times and 13 times, respectively, the human exposure at the MRHD. Pregnancy Category (AUS): - There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Riociguat in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Riociguat during labor and delivery. ### Nursing Mothers - It is not known if Adempas is present in human milk. Riociguat or its metabolites were present in the milk of rats. Because many drugs are present in human milk and because of the potential for serious adverse reactions in nursing infants from riociguat, discontinue nursing or Adempas. ### Pediatric Use - Safety and effectiveness of Adempas in pediatric patients have not been established. ### Geriatic Use - Of the total number of subjects in clinical studies of Adempas, 23% were 65 and over, and 6% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, 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. - Elderly patients showed a higher exposure to Adempas. ### Gender There is no FDA guidance on the use of Riociguat with respect to specific gender populations. ### Race There is no FDA guidance on the use of Riociguat with respect to specific racial populations. ### Renal Impairment - Safety and efficacy have not been demonstrated in patients with creatinine clearance <15 mL/min or on dialysis. ### Hepatic Impairment - Safety and efficacy have not been demonstrated in patients with severe hepatic impairment (Child Pugh C) ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Riociguat in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Riociguat in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Riociguat in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Riociguat in the drug label. # Overdosage - In cases of overdose, blood pressure should be closely monitored and supported as appropriate. Based on extensive plasma protein binding, riociguat is not expected to be dialyzable. # Pharmacology ## Mechanism of Action - Riociguat is a stimulator of soluble guanylate cyclase (sGC), an enzyme in the cardiopulmonary system and the receptor for nitric oxide (NO). - When NO binds to sGC, the enzyme catalyzes synthesis of the signaling molecule cyclic guanosine monophosphate (cGMP). Intracellular cGMP plays an important role in regulating processes that influence vascular tone, proliferation, fibrosis and inflammation. - Pulmonary hypertension is associated with endothelial dysfunction, impaired synthesis of nitric oxide and insufficient stimulation of the NO-sGC-cGMP pathway. - Riociguat has a dual mode of action. It sensitizes sGC to endogenous NO by stabilizing the NO-sGC binding. Riociguat also directly stimulates sGC via a different binding site, independently of NO. - Riociguat stimulates the NO-sGC-cGMP pathway and leads to increased generation of cGMP with subsequent vasodilation. - The active metabolite (M1) of riociguat is 1/3 to 1/10 as potent as riociguat. ## Structure - Adempas (riociguat) is a tablet for oral administration. Riociguat is methyl 4,6-diamino-2-pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate with the following structural formula: - Riociguat is a white to yellowish, crystalline, non-hygroscopic substance with a molecular weight of 422.42 g/mol. In solid form it is stable to temperature, light, and humidity. - The solubility at 25°C in water: 4 mg/L, in ethanol: 800 mg/L, in 0.1 HCl (pH 1): 250 mg/L and in buffer (phosphate) pH 7: 3 mg/L. In the pH range of 2 to 4 the solubility showed strong pH-dependency. Solubility increases at lower pH values. - Each round film-coated tablet contains 0.5 mg (1.0, 1.5, 2.0, 2.5 mg) riociguat. The inactive ingredients are cellulose microcrystalline, crospovidone, hypromellose 5cP, lactose monohydrate, magnesium stearate, sodium laurylsulfate, hydroxypropylcellulose, hypromellose 3cP, propylene glycol, and titanium dioxide. Adempas 1, 1.5, 2 and 2.5 mg tablets contain, in addition, ferric oxide yellow. Adempas 2 and 2.5 mg tablets contain, in addition, ferric oxide red.. ## Pharmacodynamics - There is a direct relationship between riociguat plasma concentration and hemodynamic parameters such as systemic vascular resistance, systolic blood pressure, pulmonary vascular resistance (PVR), and cardiac output. - Hemodynamic parameters were assessed in CTEPH patients in CHEST-1. Right heart catheterization was performed at the beginning and the end of the study period in 233 patients. A statistically significant reduction of PVR (-246 dynscm-5) was shown in the Adempas group vs. placebo. Improvements in other hemodynamic parameters (not pre-specified as endpoints) are displayed in Table 2 below. - Hemodynamic parameters were assessed in PAH patients in PATENT-1. Right heart catheterization was performed at the beginning and the end of the study period in 339 patients. - A statistically significant reduction of PVR (-226 dynseccm-5) was shown in the Adempas individual titration group (to maximum dose of 2.5 mg three times a day) vs. placebo. Improvement in other relevant hemodynamic parameters (not pre-specified as endpoints) for the individual dose titration group versus placebo are displayed in Table 3. Biomarkers - In the CHEST-1 study, Adempas significantly reduced N-terminal prohormone of brain natriuretic peptide (NT-proBNP), placebo-corrected mean change from baseline -444 ng/L, 95% CI -843 to -45. In the PATENT-1 study Adempas demonstrated a statistically significant reduction of NT-proBNP, placebo‑corrected mean change from baseline: -432 ng/L, 95% CI –782 to –82. Pharmacodynamic interactions Nitrates: Riociguat 2.5 mg tablets potentiated the blood pressure lowering effect of sublingual nitroglycerin (0.4 mg) taken 4 and 8 hours after riociguat. Syncope was reported in some patients . Phosphodiesterase-5 inhibitors: In an exploratory interaction study in 7 patients with PAH on stable sildenafil treatment (20 mg three times a day), single doses of riociguat (0.5 mg and 1 mg sequentially) showed additive hemodynamic effects. Among patients with PAH on stable sildenafil treatment (20 mg, three times a day) and riociguat (1 to 2.5 mg, three times a day) there was one death, possibly related to the combination of these drugs, and a high rate of discontinuation for hypotension. Warfarin: Concomitant administration of riociguat and warfarin did not alter prothrombin time. Acetylsalicylic Acid: Concomitant use of riociguat and aspirin did not affect bleeding time or platelet aggregation ## Pharmacokinetics - Riociguat pharmacokinetics are dose proportional from 0.5 to 2.5 mg. Inter-individual variability of riociguat exposure (AUC) across all doses is approximately 60%, and within-subject variability is approximately 30%. Absorption and distribution - The absolute bioavailability of riociguat is about 94%. Peak plasma riociguat concentrations were observed within 1.5 hours after tablet intake. Food does not affect the bioavailability of riociguat. - The volume of distribution at steady state is approximately 30 L. Plasma protein binding in humans is approximately 95%, with serum albumin and α1–acidic glycoprotein being the main binding components. - Riociguat is a substrate of P-gp and BCRP. Metabolism and excretion - Riociguat is mainly cleared by metabolism by CYP1A1, CYP3A, CYP2C8 and CYP2J2. Formation of the major active metabolite, M1, is catalyzed by CYP1A1, which is inducible by polycyclic aromatic hydrocarbons such as those present in cigarette smoke. M1 is further metabolized to the inactive N-glucuronide. Plasma concentrations of M1 in patients with PAH are about half those for riociguat. - Following oral administration of radiolabeled riociguat in healthy individuals, about 40 and 53% of the total radioactivity was recovered in urine and feces, respectively. There appears to be considerable variability in the proportion of metabolites and unchanged riociguat excreted, but metabolites were the major components of the dose excreted in most individuals. - Average systemic clearance of riociguat was about 1.8 L/h in patients with PAH and about 3.4 L/h in healthy subjects. The terminal elimination half-life is about 12 hours in patients and 7 hours in healthy subjects. Specific Populations: The effect of intrinsic factors on riociguat and M1 are shown below in Figure 1. There are no clinically relevant effects of age, sex, weight, or race/ethnicity on the pharmacokinetics of riociguat or M1. No dose adjustment is warranted. Drug interactions: The effect of other extrinsic factors on riociguat and M1 were studied in healthy subjects and are shown in Figure 2 - HIV protease inhibitors are strong CYP3A inhibitors and may increase riociguat plasma concentrations to levels similar to those seen with ketoconazole. AUC only, estimated using population pharmacokinetics methods * AUC only for metabolite, estimated using population pharmacokinetics methods. Monitor for signs and symptoms of hypotension on initiation and on treatment with strong CYP and P-gp/BCRP inhibitors. Strong CYP3A inducers: Data are not available to inform dosing of riociguat when strong CYP3A inducers are co-administered. Effects of Riociguat on other Drugs: Riociguat did not affect the pharmacokinetics of midazolam, warfarin, or sildenafil. ## Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis: Carcinogenicity studies of riociguat were conducted in mice and rats. In mice, oral administration of riociguat (up to 25 mg/kg/day in males and 32 mg/kg/day in females) for up to two years did not demonstrate evidence of carcinogenesis. Plasma exposure (AUC) of unbound riociguat at the highest dose was 6 times the human’s exposure. - In rats, oral administration of riociguat (up to 20 mg/kg/day) for up to two years did not demonstrate evidence of carcinogenesis. Plasma exposure (AUC) of unbound riociguat at the highest dose was 7 times the human exposure Mutagenesis: Riociguat and M1 did not show genotoxic potential in the in vitro bacterial reverse mutation (Ames) assay, the in vitro chromosomal aberration assay in Chinese hamster V79 cells, or the in vivo micronucleus assay in the mouse. - Impairment of fertility: In rats, no effects on male or female fertility were observed. - In male rats, oral administration of riociguat (up to 30 mg/kg/day) prior to and throughout the mating period had no effect on fertility. The no-effect dose for adverse effects is 37 times the human exposure when based on body surface area. - In female rats, oral administration of riociguat (up to 30 mg/kg/day) prior to and during mating and continuing to gestation Day 7 had no effect on fertility. The no-effect dose for adverse effects is 37 times the human exposure when based on body surface area. Animal Toxicology - In growing rats, effects on bone formation were observed, including thickening of the growth plates, disorganized trabecular bone, and diffuse hyperostosis. # Clinical Studies Chronic-Thromboembolic Pulmonary Hypertension - A double-blind, multi-national, multi-center, study (CHEST-1) was conducted in 261 patients with CTEPH. Patients were included if they: - Were technically inoperable for pulmonary endarterectomy, with PVR >300 dynseccm -5 and mean pulmonary artery pressure >25 mmHg measured at least 90 days after the start of full anticoagulation, or - Had recurrent or persisting pulmonary hypertension defined as PVR > 300 dynseccm -5 measured at least 180 days following pulmonary endarterectomy. - Patients were randomized to Adempas titrated up to 2.5 mg three times a day (n=173) or placebo (n=88). All patients were initiated at 1 mg three times a day. Patients with systolic blood pressure < 95 mmHg were excluded from the study. The dose of riociguat was titrated every 2 weeks based on the patient’s systolic blood pressure and signs or symptoms of hypotension. Stable dosages of oral anticoagulants, diuretics, digitalis, calcium channel blockers and oxygen were allowed, but not concomitant therapy with NO donors, endothelin receptor antagonists, prostacyclin analogues (PCA), specific PDE-5 inhibitors (such as, sildenafil, tadalafil, or vardenafil), and nonspecific phosphodiesterase inhibitors (for example, dipyridamole or theophylline). - The primary endpoint of the study was change from baseline in six minute walking distance (6MWD) after 16 weeks. The mean age of the patients enrolled was 59 years (range 18–80 years). In the study, 72% of patients had inoperable CTEPH, 28% had recurrent or persisting pulmonary hypertension following pulmonary endarterectomy. The majority of patients had a World Health Organization (WHO) Functional Class II (31%) or III (64%) at baseline. The mean baseline 6MWD was 347 meters. In the study, 77% of patients were titrated to the maximum dose of 2.5 mg three times a day; 13%, 6%, 4%, and 1% of patients were titrated to riociguat doses of 2, 1.5, 1, and 0.5 mg three times a day, respectively. - Results of the 6MWD over 16 weeks for the CHEST-1 study are shown in Figure 3. - The pre-specified primary endpoint of the study was the change in 6MWD from baseline to week 16 and was based on imputed values. The imputation for missing values included last observed value, not including follow-up for patients who completed the study or withdrew. For deaths or clinical worsening without a termination visit or a measurement at that visit, the imputed worst value (zero) was used. - Improvements in walking distance were apparent from Week 2 onward. At Week 16, the placebo adjusted mean increase in 6MWD within the Adempas group was 46 m (95% confidence interval : 25 m to 67 m; p<0.0001). For CHEST-1, the median difference (Hodges-Lehmann non-parametric estimate) in 6MWD was 39 m (95% CI, 25 m to 54 m). - Figure 4 illustrates the results of the Adempas and placebo treatment groups displayed as a histogram summarizing the treatment effect on the 6MWD. The patients are grouped by change in 20 meters from baseline. Overall this figure shows that patients treated with Adempas benefit compared to those treated with placebo. As demonstrated in Figure 4, 143 patients receiving Adempas (83%) experienced an improvement in 6MWD compared to 50 patients (57%) on placebo. - Placebo-adjusted changes in 6MWD at 16 weeks were evaluated in subgroups (see Figure 5). - WHO Functional Class improvements in the CHEST-1 trial are shown in Table 4. Long Term Treatment of CTEPH - An open-label extension study (CHEST-2) included 237 patients who had completed CHEST-1. At the cut-off date in the CHEST-2 study, the mean treatment duration for the total population was 582 days (± 317). The probability of survival at 1 year and 2 years were 97% and 94%, respectively. Additionally, 6MWD and WHO Functional Class status appeared to further improve in patients taking Adempas. Without a control group, however, these data must be interpreted cautiously. Pulmonary Arterial Hypertension - A double-blind, multi-national, multi-center study (PATENT-1) was conducted in 443 patients with PAH as defined by PVR >300 dynseccm-5 and a PAP mean >25 mmHg. - Patients were randomized to one of three treatment groups: Adempas titrated up to 1.5 mg (n=63), 2.5 mg (n=254) or placebo (n=126) three times a day. Patients with systolic blood pressure < 95 mmHg were excluded from the study. Patients assigned to Adempas were initiated at 1.0 mg three times a day. The dose of Adempas was up-titrated every 2 weeks based on the patient’s systolic blood pressure and signs or symptoms of hypotension. Oral anticoagulants, diuretics, digitalis, calcium channel blockers, and oxygen were allowed. In this study, 50% of the patients were treatment-naive with respect to PAH therapy, 44% were pre-treated with an endothelin receptor antagonist (ERA) and 6% were pre-treated with a PCA (inhaled, oral or subcutaneous). Pre-treated patients were defined as patients on stable treatment for 3 months with either an ERA or PCA; Adempas was added in combination to these background therapies. - The primary endpoint of the study was change from baseline and placebo in 6MWD after 12 weeks in the 2.5 mg group. The mean age of all patients was 51 years and approximately 80% were female. PAH etiologies were either idiopathic (61%) or familial PAH (2%), PAH associated with connective tissue disease (25%), congenital heart disease (8%), portal hypertension (3%), or anorexigen or amphetamine use (1%). The majority of patients had a WHO Functional Class II (42%) or III (54%) at baseline. The overall mean baseline 6MWD was 363 meters. Approximately 75% of patients were up-titrated to receive the maximum dose of 2.5 mg three times a day by week 12; 15%, 6%, 3%, and 2% were titrated to doses of 2 mg, 1.5 mg, 1 mg, and 0.5 mg 3 times a day, respectively. - Results of the 6MWD over 12 weeks for the PATENT-1 study are shown in Figure 6. - The pre-specified primary endpoint of the study was the change in 6MWD from baseline to week 12 and was based on imputed values. The imputation for missing values included last observed value, not including follow-up for patients who completed the study or withdrew. In case of death or clinical worsening without a termination visit or a measurement at that termination visit, the imputed worst value (zero) was used. - Figure 7 illustrates the results of the Adempas and placebo treatment groups displayed as a histogram summarizing the treatment effect on the 6MWD. The patients are grouped by change in 20 meters from baseline. Overall this figure shows that patients treated with Adempas benefit compared to those treated with placebo. As demonstrated in Figure 7, 193 patients receiving Adempas (76%) experienced an improvement in 6MWD compared to 74 patients (59%) on placebo. - Improvements 6MWD were apparent from Week 2 onward. At Week 12, the placebo-adjusted mean increase in 6MWD within the Adempas group was 36 m (95% CI: 20 m to 52 m; p<0.0001). For PATENT-1, the median difference (Hodges-Lehmann non-parametric estimate) in 6MWD was 29 m (95% CI, 17 m to 40 m).There was an exploratory 1.5 mg capped titration arm (n = 63). The data did not suggest incremental benefit from escalating dose from 1.5 mg three times a day to 2.5 mg three times a day. - Placebo-adjusted changes in 6MWD at 12 weeks were evaluated in subgroups (see Figure 8). - WHO Functional Class improvements in the IDT (individual dose titration) arm of the PATENT-1 trial are shown in Table 5 - Time to clinical worsening was a combined endpoint defined as death (all-cause mortality), heart/lung transplantation, atrial septostomy, hospitalization due to persistent worsening of pulmonary hypertension, start of new PAH-specific treatment, persistent decrease in 6MWD and persistent worsening of WHO Functional Class. - Effects of Adempas in PATENT-1 on events of clinical worsening are shown in Table 6. - Adempas-treated patients experienced a significant delay in time to clinical worsening versus placebo-treated patients (p=0.0046; Stratified log-rank test). Significantly fewer events of clinical worsening up to week 12 (last visit) were observed in patients treated with Adempas (1.2%) compared to placebo (6.3%) (p=0.0285, Mantel-Haenszel estimate). - The Kaplan-Meier plot of time to clinical worsening is presented in Figure 9. Long Term Treatment of PAH - An open label extension study (PATENT-2) included 363 patients who had completed PATENT-1. At the cut-off date in the PATENT-2 study, the mean treatment duration for the total population was 663 days (± 319). The probabilities of survival at 1 and 2 years were 97% and 93%, respectively. Without a control group, these data must be interpreted cautiously. # How Supplied - Adempas (riociguat) tablets are film-coated, round, and debossed with the “Bayer cross” on one side. ## Storage - Store at 25°C (77°F); excursions are permitted from 15°C to 30°C (59°F to 86°F). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Embryo-Fetal Toxicity - Instruct patients on the risk of fetal harm when Adempas is used during pregnanc. - Instruct females of reproductive potential to use effective contraception and to contact her physician immediately if they suspect they may be pregnant. Female patients must enroll in the Adempas REMS Program. Adempas REMS Program - For female patients, Adempas is available only through a restricted program called the Adempas REMS Program. Male patients are not enrolled in the Adempas REMS Program. - Inform female patients (and their guardians, if applicable) of the following important requirements: - All female patients must sign an enrollment form. - Advise female patients of reproductive potential that she must comply with the pregnancy testing and contraception requirements. - Educate and counsel females of reproductive potential on the use of emergency contraception in the event of unprotected sex or contraceptive failure. - Advise pre-pubertal females to report any changes in their reproductive status immediately to her prescriber. - Review the Medication Guide and REMS educational materials with female patients. Other Risks Associated with Adempas - Inform patients of the contraindication of Adempas with nitrates or nitric oxide donors or PDE-5 inhibitors. - Advise patients about the potential risks/signs of hemoptysis and to report any potential signs of hemoptysis to their physicians. - Instruct patients on the dosing, titration, and maintenance of Adempas. - Advise patients regarding activities that may impact the pharmacology of Adempas (strong multi pathway CYP inhibitors and P-gp/BCRP inhibitors and smoking). Patients should report all current medications and new medications to their physician. - Advise patients that antacids should not be taken within 1 hour of taking Adempas. - Inform patients that Adempas can cause dizziness, which can affect the ability to drive and use machines. They should be aware of how they react to Adempas, before driving or operating machinery and if needed, consult their physician. # Precautions with Alcohol - Alcohol-Riociguat interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - ADEMPAS ® # Look-Alike Drug Names - A® — B® # Drug Shortage Status # Price	Riociguat Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kiran Singh, 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. # Black Box Warning # Overview Riociguat is a cardiovascular agent that is FDA approved for the treatment of persistent,recurrent chronic thromboembolic pulmonary hypertension and pulmonary arterial hypertension. There is a Black Box Warning for this drug as shown here. Common adverse reactions include headache, dyspepsia,gastritis, dizziness, nausea, diarrhea, hypotension, vomiting, anemia, gastroesophageal reflux, and constipation.. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) # Indications Chronic-Thromboembolic Pulmonary Hypertension - Adempas is indicated for the treatment of adults with persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH), (WHO Group 4) after surgical treatment, or inoperable CTEPH, to improve exercise capacity and WHO functional class. Pulmonary Arterial Hypertension - Adempas is indicated for the treatment of adults with pulmonary arterial hypertension (PAH), (WHO Group 1), to improve exercise capacity, WHO functional class and to delay clinical worsening. - Efficacy was shown in patients on Adempas monotherapy or in combination with endothelin receptor antagonists or prostanoids. Studies establishing effectiveness included predominately patients with WHO functional class II–III and etiologies of idiopathic or heritable PAH (61%) or PAH associated with connective tissue diseases (25%). # Dosage Recommended Dosage in Adult Patients - The recommended starting dosage is 1 mg taken 3 times a day. For patients who may not tolerate the hypotensive effect of Adempas, consider a starting dose of 0.5 mg taken three times a day. If systolic blood pressure remains greater than 95 mmHg and the patient has no signs or symptoms of hypotension, up-titrate the dose by 0.5 mg taken three times a day. Dose increases should be no sooner than 2 weeks apart. The dose can be increased to the highest tolerated dosage, up to a maximum of 2.5 mg taken three times a day. If at any time, the patient has symptoms of hypotension, decrease the dosage by 0.5 mg taken three times a day. Dosage Interruption - If a dose is missed, advise patients to continue with the next regularly scheduled dose. - In case Adempas is interrupted for 3 days or more, re-titrate Adempas. Pregnancy Testing in Females of Reproductive Potential - Obtain pregnancy tests prior to initiation and monthly during treatment. Use in Patients who Smoke - Consider titrating to dosages higher than 2.5 mg three times a day, if tolerated, in patients who smoke. A dose decrease may be required in patients who stop smoking. Strong CYP and P-gp/BCRP Inhibitors - Consider a starting dose of 0.5 mg, three times a day when initiating Adempas in patients receiving strong cytochrome P450 (CYP) and P-glycoprotein/breast cancer resistance protein (P-gp/BCRP) inhibitors such as azole antimycotics (for example, ketoconazole, itraconazole) or HIV protease inhibitors (for example, ritonavir). Monitor for signs and symptoms of hypotension on initiation and on treatment with strong CYP and P-gp/BCRP inhibitors. ## DOSAGE FORMS AND STRENGTHS - Tablets: film-coated, round, bi-convex: - 0.5 mg, white, with “BAYER” cross on one side and “0.5” and “R” on the other side - 1 mg, pale-yellow, with “BAYER” cross on one side and “1” and “R” on the other side - 1.5 mg, yellow-orange, with “BAYER” cross on one side and “1.5” and “R” on the other side - 2 mg, pale orange, with “BAYER” cross on one side and “2” and “R” on the other side - 2.5 mg, red-orange, with “BAYER” cross on one side and “2.5” and “R” on the other side ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Riociguat in adult patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of Riociguat in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - There is limited information regarding FDA-Labeled Use of Riociguat in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Riociguat in pediatric patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of Riociguat in pediatric patients. # Contraindications Pregnancy - Adempas may cause fetal harm when administered to a pregnant woman. Adempas is contraindicated in females who are pregnant. Adempas was consistently shown to have teratogenic effects when administered to animals. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus . Nitrates and Nitric Oxide Donors - Co-administration of Adempas with nitrates or nitric oxide donors (such as amyl nitrite) in any form is contraindicated. Phosphodiesterase Inhibitors - Concomitant administration of Adempas with specific PDE-5 inhibitors (such as sildenafil, tadalafil, or vardenafil) or nonspecific PDE inhibitors (such as dipyridamole or theophylline) is contraindicated . # Warnings Embryo-Fetal Toxicity - Adempas may cause fetal harm when administered during pregnancy and is contraindicated for use in women who are pregnant. In females of reproductive potential, exclude pregnancy prior to initiation of therapy, advise use of acceptable contraception and obtain monthly pregnancy tests. For Female, Adempas is only available through a restricted program under the Adempas REMS Program. Adempas REMS Program - Females can only receive Adempas through the Adempas Risk Evaluation and Mitigation Strategy (REMS) Program, a restricted distribution program. - Important requirements of the Adempas REMS Program include the following: - Prescribers must be certified with the program by enrolling and completing training. - All females, regardless of reproductive potential, must enroll in the Adempas REMS Program prior to initiating Adempas. Male patients are not enrolled in the Adempas REMS Program. - Female patients of reproductive potential must comply with the pregnancy testing and contraception requirements. - Pharmacies must be certified with the program and must only dispense to patients who are authorized to receive Adempas. Hypotension - Adempas reduces blood pressure. Consider the potential for symptomatic hypotension or ischemia in patients with hypovolemia, severe left ventricular outflow obstruction, resting hypotension, autonomic dysfunction, or concomitant treatment with antihypertensives or strong CYP and P-gp/BCRP inhibitors. Consider a dose reduction if patient develops signs or symptoms of hypotension. Bleeding - In the placebo-controlled clinical trials, serious bleeding occurred in 2.4% of patients taking Adempas compared to 0% of placebo patients. Serious hemoptysis occurred in 5 (1%) patients taking Adempas compared to 0 placebo patients, including one event with fatal outcome. Serious hemorrhagic events also included 2 patients with vaginal hemorrhage, 2 with catheter site hemorrhage, and 1 each with subdural hematoma, hematemesis, and intra-abdominal hemorrhage. Pulmonary Veno-Occlusive Disease - Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with pulmonary veno-occlusive disease (PVOD). Therefore, administration of Adempas to such patients is not recommended. Should signs of pulmonary edema occur, the possibility of associated PVOD should be considered and, if confirmed, discontinue treatment with Adempas. # Adverse Reactions ## Clinical Trials Experience - The following serious adverse reactions are discussed elsewhere in the labeling: - Embryo-Fetal Toxicity - Hypotension - Bleeding 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. - The safety data described below reflect exposure to Adempas in two, randomized, double blind, placebo-controlled trials in patients with inoperable or recurrent/persistent CTEPH (CHEST-1) and treatment naive or pre-treated PAH patients (PATENT-1). The population (Adempas: n = 490; Placebo: n = 214) was between the age of 18 and 80 years. - The safety profile of Adempas in patients with inoperable or recurrent/persistent CTEPH (CHEST-1) and treatment naive or pre-treated PAH (PATENT-1) were similar. Therefore, adverse drug reactions (ADRs) identified from the 12 and 16 week placebo-controlled trials for PAH and CTEPH respectively were pooled, and those occurring more frequently on Adempas than placebo (≥3%) are displayed in Table 1 below. Most adverse reactions in Table 1 can be ascribed to the vasodilatory mechanism of action of Adempas. - The overall rates of discontinuation due to an adverse event in the pivotal placebo-controlled trials were 2.9% for Adempas and 5.1% for placebo (pooled data). Other events that were seen more frequently in Adempas compared to placebo and potentially related to treatment were: palpitations, nasal congestion, epistaxis, dysphagia, abdominal distension and peripheral edema. With longer observation in uncontrolled long-term extension studies the safety profile was similar to that observed in the placebo controlled phase 3 trials. ## Postmarketing Experience - There is limited information regarding Postmarketing Experience of Riociguat in the drug label. # Drug Interactions Pharmacodynamic Interactions with Adempas Nitrates: Co-administration of Adempas with nitrates or nitric oxide donors (such as amyl nitrite) in any form is contraindicated because of hypotension. PDE Inhibitors: Co-administration of Adempas with specific PDE-5 inhibitors (such as sildenafil, tadalafil, or vardenafil) and nonspecific PDE inhibitors (such as dipyridamole or theophylline), is contraindicated because of hypotension. Clinical experience with co-administration of Adempas and other phosphodiesterase inhibitors (for example, milrinone, cilostazole, roflumilast) is limited. Pharmacokinetic Interactions with Adempas Smoking: Plasma concentrations in smokers are reduced by 50-60% compared to nonsmokers. Based on pharmacokinetic modeling, for patients who are smokers, doses higher than 2.5 mg three times a day may be considered in order to match exposure seen in nonsmoking patients. Safety and effectiveness of Adempas doses higher than 2.5 mg three times a day have not been established. A dose reduction should be considered in patients who stop smoking. Strong CYP and P-gp/BCRP inhibitors: Concomitant use of riociguat with strong cytochrome CYP inhibitors and P-gp/BCRP inhibitors such as azole antimycotics (for example, ketoconazole, itraconazole) or HIV protease inhibitors (such as ritonavir) increase riociguat exposure and may result in hypotension. Consider a starting dose of 0.5 mg 3 times a day when initiating Adempas in patients receiving strong CYP and P-gp/BCRP inhibitors. Monitor for signs and symptoms of hypotension on initiation and on treatment with strong CYP and P-gp/BCRP inhibitors. A dose reduction should be considered in patients who may not tolerate the hypotensive effect of riociguat. Strong CYP3A inducers: Strong inducers of CYP3A (for example, rifampin, phenytoin, carbamazepine, phenobarbital or St. John’s Wort) may significantly reduce riociguat exposure. Data are not available to guide dosing of riociguat when strong CYP3A inducers are co-administered. Antacids: Antacids such as aluminum hydroxide/magnesium hydroxide decrease riociguat absorption and should not be taken within 1 hour of taking Adempas. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): Pregnancy Category X Risk Summary - Adempas may cause fetal harm when administered to a pregnant woman and is contraindicated during pregnancy. Adempas was teratogenic and embryotoxic in rats at doses with exposures to unbound drug that were approximately 8 times and 2 times, respectively, the human exposure. In rabbits, riociguat led to abortions at 4 times the human exposure and fetal toxicity with exposures approximately 13 times the human exposure. If Adempas is used in pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus. Animal Data - In rats administered riociguat orally (1, 5, and 25 mg/kg/day) throughout organogenesis, an increased rate of cardiac ventricular-septal defect was observed at the highest dose tested. The highest dose produced evidence of maternal toxicity (reduced body weight). Post-implantation loss was statistically significantly increased from the mid-dose of 5 mg/kg/day. Plasma exposure at the lowest dose in which no adverse effects were observed is approximately 0.4 times that in humans at the maximally recommended human dose (MRHD) of 2.5 mg three times a day based on area under the time-concentration curve (AUC) for unbound drug in rat and humans. Plasma exposure at the highest dose (25 mg/kg/day) is approximately 8 times that in humans at the MRHD while exposure at the mid-dose (5 mg/kg/day) is approximately 2 times that in humans at the MRHD. In rabbits given doses of 0.5, 1.5 and 5 mg/kg/day, an increase in spontaneous abortions was observed starting at the middle dose of 1.5 mg/kg, and an increase in resorptions was observed at 5 mg/kg/day. Plasma exposures at these doses were 4 times and 13 times, respectively, the human exposure at the MRHD. Pregnancy Category (AUS): - There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Riociguat in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Riociguat during labor and delivery. ### Nursing Mothers - It is not known if Adempas is present in human milk. Riociguat or its metabolites were present in the milk of rats. Because many drugs are present in human milk and because of the potential for serious adverse reactions in nursing infants from riociguat, discontinue nursing or Adempas. ### Pediatric Use - Safety and effectiveness of Adempas in pediatric patients have not been established. ### Geriatic Use - Of the total number of subjects in clinical studies of Adempas, 23% were 65 and over, and 6% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, 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. - Elderly patients showed a higher exposure to Adempas. ### Gender There is no FDA guidance on the use of Riociguat with respect to specific gender populations. ### Race There is no FDA guidance on the use of Riociguat with respect to specific racial populations. ### Renal Impairment - Safety and efficacy have not been demonstrated in patients with creatinine clearance <15 mL/min or on dialysis. ### Hepatic Impairment - Safety and efficacy have not been demonstrated in patients with severe hepatic impairment (Child Pugh C) ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Riociguat in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Riociguat in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Riociguat in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Riociguat in the drug label. # Overdosage - In cases of overdose, blood pressure should be closely monitored and supported as appropriate. Based on extensive plasma protein binding, riociguat is not expected to be dialyzable. # Pharmacology ## Mechanism of Action - Riociguat is a stimulator of soluble guanylate cyclase (sGC), an enzyme in the cardiopulmonary system and the receptor for nitric oxide (NO). - When NO binds to sGC, the enzyme catalyzes synthesis of the signaling molecule cyclic guanosine monophosphate (cGMP). Intracellular cGMP plays an important role in regulating processes that influence vascular tone, proliferation, fibrosis and inflammation. - Pulmonary hypertension is associated with endothelial dysfunction, impaired synthesis of nitric oxide and insufficient stimulation of the NO-sGC-cGMP pathway. - Riociguat has a dual mode of action. It sensitizes sGC to endogenous NO by stabilizing the NO-sGC binding. Riociguat also directly stimulates sGC via a different binding site, independently of NO. - Riociguat stimulates the NO-sGC-cGMP pathway and leads to increased generation of cGMP with subsequent vasodilation. - The active metabolite (M1) of riociguat is 1/3 to 1/10 as potent as riociguat. ## Structure - Adempas (riociguat) is a tablet for oral administration. Riociguat is methyl 4,6-diamino-2-[1-(2-fluorobenzyl)-1H-pyrazolo [3,4-b]pyridin-3-yl]-5-pyrimidinyl(methyl)carbamate with the following structural formula: - Riociguat is a white to yellowish, crystalline, non-hygroscopic substance with a molecular weight of 422.42 g/mol. In solid form it is stable to temperature, light, and humidity. - The solubility at 25°C in water: 4 mg/L, in ethanol: 800 mg/L, in 0.1 HCl (pH 1): 250 mg/L and in buffer (phosphate) pH 7: 3 mg/L. In the pH range of 2 to 4 the solubility showed strong pH-dependency. Solubility increases at lower pH values. - Each round film-coated tablet contains 0.5 mg (1.0, 1.5, 2.0, 2.5 mg) riociguat. The inactive ingredients are cellulose microcrystalline, crospovidone, hypromellose 5cP, lactose monohydrate, magnesium stearate, sodium laurylsulfate, hydroxypropylcellulose, hypromellose 3cP, propylene glycol, and titanium dioxide. Adempas 1, 1.5, 2 and 2.5 mg tablets contain, in addition, ferric oxide yellow. Adempas 2 and 2.5 mg tablets contain, in addition, ferric oxide red.. ## Pharmacodynamics - There is a direct relationship between riociguat plasma concentration and hemodynamic parameters such as systemic vascular resistance, systolic blood pressure, pulmonary vascular resistance (PVR), and cardiac output. - Hemodynamic parameters were assessed in CTEPH patients in CHEST-1. Right heart catheterization was performed at the beginning and the end of the study period in 233 patients. A statistically significant reduction of PVR (-246 dynscm-5) was shown in the Adempas group vs. placebo. Improvements in other hemodynamic parameters (not pre-specified as endpoints) are displayed in Table 2 below. - Hemodynamic parameters were assessed in PAH patients in PATENT-1. Right heart catheterization was performed at the beginning and the end of the study period in 339 patients. - A statistically significant reduction of PVR (-226 dynseccm-5) was shown in the Adempas individual titration group (to maximum dose of 2.5 mg three times a day) vs. placebo. Improvement in other relevant hemodynamic parameters (not pre-specified as endpoints) for the individual dose titration group versus placebo are displayed in Table 3. Biomarkers - In the CHEST-1 study, Adempas significantly reduced N-terminal prohormone of brain natriuretic peptide (NT-proBNP), placebo-corrected mean change from baseline -444 ng/L, 95% CI -843 to -45. In the PATENT-1 study Adempas demonstrated a statistically significant reduction of NT-proBNP, placebo‑corrected mean change from baseline: -432 ng/L, 95% CI –782 to –82. Pharmacodynamic interactions Nitrates: Riociguat 2.5 mg tablets potentiated the blood pressure lowering effect of sublingual nitroglycerin (0.4 mg) taken 4 and 8 hours after riociguat. Syncope was reported in some patients [see Contraindications (4.2)]. Phosphodiesterase-5 inhibitors: In an exploratory interaction study in 7 patients with PAH on stable sildenafil treatment (20 mg three times a day), single doses of riociguat (0.5 mg and 1 mg sequentially) showed additive hemodynamic effects. Among patients with PAH on stable sildenafil treatment (20 mg, three times a day) and riociguat (1 to 2.5 mg, three times a day) there was one death, possibly related to the combination of these drugs, and a high rate of discontinuation for hypotension. Warfarin: Concomitant administration of riociguat and warfarin did not alter prothrombin time. Acetylsalicylic Acid: Concomitant use of riociguat and aspirin did not affect bleeding time or platelet aggregation ## Pharmacokinetics - Riociguat pharmacokinetics are dose proportional from 0.5 to 2.5 mg. Inter-individual variability of riociguat exposure (AUC) across all doses is approximately 60%, and within-subject variability is approximately 30%. Absorption and distribution - The absolute bioavailability of riociguat is about 94%. Peak plasma riociguat concentrations were observed within 1.5 hours after tablet intake. Food does not affect the bioavailability of riociguat. - The volume of distribution at steady state is approximately 30 L. Plasma protein binding in humans is approximately 95%, with serum albumin and α1–acidic glycoprotein being the main binding components. - Riociguat is a substrate of P-gp and BCRP. Metabolism and excretion - Riociguat is mainly cleared by metabolism by CYP1A1, CYP3A, CYP2C8 and CYP2J2. Formation of the major active metabolite, M1, is catalyzed by CYP1A1, which is inducible by polycyclic aromatic hydrocarbons such as those present in cigarette smoke. M1 is further metabolized to the inactive N-glucuronide. Plasma concentrations of M1 in patients with PAH are about half those for riociguat. - Following oral administration of radiolabeled riociguat in healthy individuals, about 40 and 53% of the total radioactivity was recovered in urine and feces, respectively. There appears to be considerable variability in the proportion of metabolites and unchanged riociguat excreted, but metabolites were the major components of the dose excreted in most individuals. - Average systemic clearance of riociguat was about 1.8 L/h in patients with PAH and about 3.4 L/h in healthy subjects. The terminal elimination half-life is about 12 hours in patients and 7 hours in healthy subjects. Specific Populations: The effect of intrinsic factors on riociguat and M1 are shown below in Figure 1. There are no clinically relevant effects of age, sex, weight, or race/ethnicity on the pharmacokinetics of riociguat or M1. No dose adjustment is warranted. Drug interactions: The effect of other extrinsic factors on riociguat and M1 were studied in healthy subjects and are shown in Figure 2 - HIV protease inhibitors are strong CYP3A inhibitors and may increase riociguat plasma concentrations to levels similar to those seen with ketoconazole. AUC only, estimated using population pharmacokinetics methods * AUC only for metabolite, estimated using population pharmacokinetics methods. **** Monitor for signs and symptoms of hypotension on initiation and on treatment with strong CYP and P-gp/BCRP inhibitors. Strong CYP3A inducers: Data are not available to inform dosing of riociguat when strong CYP3A inducers are co-administered. Effects of Riociguat on other Drugs: Riociguat did not affect the pharmacokinetics of midazolam, warfarin, or sildenafil. ## Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis: Carcinogenicity studies of riociguat were conducted in mice and rats. In mice, oral administration of riociguat (up to 25 mg/kg/day in males and 32 mg/kg/day in females) for up to two years did not demonstrate evidence of carcinogenesis. Plasma exposure (AUC) of unbound riociguat at the highest dose was 6 times the human’s exposure. - In rats, oral administration of riociguat (up to 20 mg/kg/day) for up to two years did not demonstrate evidence of carcinogenesis. Plasma exposure (AUC) of unbound riociguat at the highest dose was 7 times the human exposure Mutagenesis: Riociguat and M1 did not show genotoxic potential in the in vitro bacterial reverse mutation (Ames) assay, the in vitro chromosomal aberration assay in Chinese hamster V79 cells, or the in vivo micronucleus assay in the mouse. - Impairment of fertility: In rats, no effects on male or female fertility were observed. - In male rats, oral administration of riociguat (up to 30 mg/kg/day) prior to and throughout the mating period had no effect on fertility. The no-effect dose for adverse effects is 37 times the human exposure when based on body surface area. - In female rats, oral administration of riociguat (up to 30 mg/kg/day) prior to and during mating and continuing to gestation Day 7 had no effect on fertility. The no-effect dose for adverse effects is 37 times the human exposure when based on body surface area. Animal Toxicology - In growing rats, effects on bone formation were observed, including thickening of the growth plates, disorganized trabecular bone, and diffuse hyperostosis. # Clinical Studies Chronic-Thromboembolic Pulmonary Hypertension - A double-blind, multi-national, multi-center, study (CHEST-1) was conducted in 261 patients with CTEPH. Patients were included if they: - Were technically inoperable for pulmonary endarterectomy, with PVR >300 dynseccm -5 and mean pulmonary artery pressure >25 mmHg measured at least 90 days after the start of full anticoagulation, or - Had recurrent or persisting pulmonary hypertension defined as PVR > 300 dynseccm -5 measured at least 180 days following pulmonary endarterectomy. - Patients were randomized to Adempas titrated up to 2.5 mg three times a day (n=173) or placebo (n=88). All patients were initiated at 1 mg three times a day. Patients with systolic blood pressure < 95 mmHg were excluded from the study. The dose of riociguat was titrated every 2 weeks based on the patient’s systolic blood pressure and signs or symptoms of hypotension. Stable dosages of oral anticoagulants, diuretics, digitalis, calcium channel blockers and oxygen were allowed, but not concomitant therapy with NO donors, endothelin receptor antagonists, prostacyclin analogues (PCA), specific PDE-5 inhibitors (such as, sildenafil, tadalafil, or vardenafil), and nonspecific phosphodiesterase inhibitors (for example, dipyridamole or theophylline). - The primary endpoint of the study was change from baseline in six minute walking distance (6MWD) after 16 weeks. The mean age of the patients enrolled was 59 years (range 18–80 years). In the study, 72% of patients had inoperable CTEPH, 28% had recurrent or persisting pulmonary hypertension following pulmonary endarterectomy. The majority of patients had a World Health Organization (WHO) Functional Class II (31%) or III (64%) at baseline. The mean baseline 6MWD was 347 meters. In the study, 77% of patients were titrated to the maximum dose of 2.5 mg three times a day; 13%, 6%, 4%, and 1% of patients were titrated to riociguat doses of 2, 1.5, 1, and 0.5 mg three times a day, respectively. - Results of the 6MWD over 16 weeks for the CHEST-1 study are shown in Figure 3. - The pre-specified primary endpoint of the study was the change in 6MWD from baseline to week 16 and was based on imputed values. The imputation for missing values included last observed value, not including follow-up for patients who completed the study or withdrew. For deaths or clinical worsening without a termination visit or a measurement at that visit, the imputed worst value (zero) was used. - Improvements in walking distance were apparent from Week 2 onward. At Week 16, the placebo adjusted mean increase in 6MWD within the Adempas group was 46 m (95% confidence interval [CI]: 25 m to 67 m; p<0.0001). For CHEST-1, the median difference (Hodges-Lehmann non-parametric estimate) in 6MWD was 39 m (95% CI, 25 m to 54 m). - Figure 4 illustrates the results of the Adempas and placebo treatment groups displayed as a histogram summarizing the treatment effect on the 6MWD. The patients are grouped by change in 20 meters from baseline. Overall this figure shows that patients treated with Adempas benefit compared to those treated with placebo. As demonstrated in Figure 4, 143 patients receiving Adempas (83%) experienced an improvement in 6MWD compared to 50 patients (57%) on placebo. - Placebo-adjusted changes in 6MWD at 16 weeks were evaluated in subgroups (see Figure 5). - WHO Functional Class improvements in the CHEST-1 trial are shown in Table 4. Long Term Treatment of CTEPH - An open-label extension study (CHEST-2) included 237 patients who had completed CHEST-1. At the cut-off date in the CHEST-2 study, the mean treatment duration for the total population was 582 days (± 317). The probability of survival at 1 year and 2 years were 97% and 94%, respectively. Additionally, 6MWD and WHO Functional Class status appeared to further improve in patients taking Adempas. Without a control group, however, these data must be interpreted cautiously. Pulmonary Arterial Hypertension - A double-blind, multi-national, multi-center study (PATENT-1) was conducted in 443 patients with PAH as defined by PVR >300 dynseccm-5 and a PAP mean >25 mmHg. - Patients were randomized to one of three treatment groups: Adempas titrated up to 1.5 mg (n=63), 2.5 mg (n=254) or placebo (n=126) three times a day. Patients with systolic blood pressure < 95 mmHg were excluded from the study. Patients assigned to Adempas were initiated at 1.0 mg three times a day. The dose of Adempas was up-titrated every 2 weeks based on the patient’s systolic blood pressure and signs or symptoms of hypotension. Oral anticoagulants, diuretics, digitalis, calcium channel blockers, and oxygen were allowed. In this study, 50% of the patients were treatment-naive with respect to PAH therapy, 44% were pre-treated with an endothelin receptor antagonist (ERA) and 6% were pre-treated with a PCA (inhaled, oral or subcutaneous). Pre-treated patients were defined as patients on stable treatment for 3 months with either an ERA or PCA; Adempas was added in combination to these background therapies. - The primary endpoint of the study was change from baseline and placebo in 6MWD after 12 weeks in the 2.5 mg group. The mean age of all patients was 51 years and approximately 80% were female. PAH etiologies were either idiopathic (61%) or familial PAH (2%), PAH associated with connective tissue disease (25%), congenital heart disease (8%), portal hypertension (3%), or anorexigen or amphetamine use (1%). The majority of patients had a WHO Functional Class II (42%) or III (54%) at baseline. The overall mean baseline 6MWD was 363 meters. Approximately 75% of patients were up-titrated to receive the maximum dose of 2.5 mg three times a day by week 12; 15%, 6%, 3%, and 2% were titrated to doses of 2 mg, 1.5 mg, 1 mg, and 0.5 mg 3 times a day, respectively. - Results of the 6MWD over 12 weeks for the PATENT-1 study are shown in Figure 6. - The pre-specified primary endpoint of the study was the change in 6MWD from baseline to week 12 and was based on imputed values. The imputation for missing values included last observed value, not including follow-up for patients who completed the study or withdrew. In case of death or clinical worsening without a termination visit or a measurement at that termination visit, the imputed worst value (zero) was used. - Figure 7 illustrates the results of the Adempas and placebo treatment groups displayed as a histogram summarizing the treatment effect on the 6MWD. The patients are grouped by change in 20 meters from baseline. Overall this figure shows that patients treated with Adempas benefit compared to those treated with placebo. As demonstrated in Figure 7, 193 patients receiving Adempas (76%) experienced an improvement in 6MWD compared to 74 patients (59%) on placebo. - Improvements 6MWD were apparent from Week 2 onward. At Week 12, the placebo-adjusted mean increase in 6MWD within the Adempas group was 36 m (95% CI: 20 m to 52 m; p<0.0001). For PATENT-1, the median difference (Hodges-Lehmann non-parametric estimate) in 6MWD was 29 m (95% CI, 17 m to 40 m).There was an exploratory 1.5 mg capped titration arm (n = 63). The data did not suggest incremental benefit from escalating dose from 1.5 mg three times a day to 2.5 mg three times a day. - Placebo-adjusted changes in 6MWD at 12 weeks were evaluated in subgroups (see Figure 8). - WHO Functional Class improvements in the IDT (individual dose titration) arm of the PATENT-1 trial are shown in Table 5 - Time to clinical worsening was a combined endpoint defined as death (all-cause mortality), heart/lung transplantation, atrial septostomy, hospitalization due to persistent worsening of pulmonary hypertension, start of new PAH-specific treatment, persistent decrease in 6MWD and persistent worsening of WHO Functional Class. - Effects of Adempas in PATENT-1 on events of clinical worsening are shown in Table 6. - Adempas-treated patients experienced a significant delay in time to clinical worsening versus placebo-treated patients (p=0.0046; Stratified log-rank test). Significantly fewer events of clinical worsening up to week 12 (last visit) were observed in patients treated with Adempas (1.2%) compared to placebo (6.3%) (p=0.0285, Mantel-Haenszel estimate). - The Kaplan-Meier plot of time to clinical worsening is presented in Figure 9. Long Term Treatment of PAH - An open label extension study (PATENT-2) included 363 patients who had completed PATENT-1. At the cut-off date in the PATENT-2 study, the mean treatment duration for the total population was 663 days (± 319). The probabilities of survival at 1 and 2 years were 97% and 93%, respectively. Without a control group, these data must be interpreted cautiously. # How Supplied - Adempas (riociguat) tablets are film-coated, round, and debossed with the “Bayer cross” on one side. ## Storage - Store at 25°C (77°F); excursions are permitted from 15°C to 30°C (59°F to 86°F). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Embryo-Fetal Toxicity - Instruct patients on the risk of fetal harm when Adempas is used during pregnanc. - Instruct females of reproductive potential to use effective contraception and to contact her physician immediately if they suspect they may be pregnant. Female patients must enroll in the Adempas REMS Program. Adempas REMS Program - For female patients, Adempas is available only through a restricted program called the Adempas REMS Program. Male patients are not enrolled in the Adempas REMS Program. - Inform female patients (and their guardians, if applicable) of the following important requirements: - All female patients must sign an enrollment form. - Advise female patients of reproductive potential that she must comply with the pregnancy testing and contraception requirements. - Educate and counsel females of reproductive potential on the use of emergency contraception in the event of unprotected sex or contraceptive failure. - Advise pre-pubertal females to report any changes in their reproductive status immediately to her prescriber. - Review the Medication Guide and REMS educational materials with female patients. Other Risks Associated with Adempas - Inform patients of the contraindication of Adempas with nitrates or nitric oxide donors or PDE-5 inhibitors. - Advise patients about the potential risks/signs of hemoptysis and to report any potential signs of hemoptysis to their physicians. - Instruct patients on the dosing, titration, and maintenance of Adempas. - Advise patients regarding activities that may impact the pharmacology of Adempas (strong multi pathway CYP inhibitors and P-gp/BCRP inhibitors and smoking). Patients should report all current medications and new medications to their physician. - Advise patients that antacids should not be taken within 1 hour of taking Adempas. - Inform patients that Adempas can cause dizziness, which can affect the ability to drive and use machines. They should be aware of how they react to Adempas, before driving or operating machinery and if needed, consult their physician. # Precautions with Alcohol - Alcohol-Riociguat interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - ADEMPAS ®[1] # Look-Alike Drug Names - A® — B®[2] # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Riociguat
11125cb2af712936fed05d4ebc83115dc6cf3219	wikidoc	Ritodrine	Ritodrine # Overview Ritodrine (discontinued preparation: Yutopar) is a tocolytic drug, used to stop premature labor. This drug has been removed from the US market, according to FDA Orange Book. It was available in oral tablets or as an injection and was typically used as the hydrochloride salt, ritodrine hydrochloride. # Mechanism Ritodrine is a beta-2 adrenergic receptor agonist - a class of medication used for smooth muscle relaxation (other similar drugs are used in asthma or other pulmonary diseases such as salbutamol). Since ritodrine has a bulky N-substituent, it has high β2-selectivity. Also, the 4'-hydroxy on the benzene ring is important for activity as it is needed to form hydrogen bonds. However, the 4'-hydroxy makes it susceptible to metabolism by COMT. Since it is β2-selective it is used for premature labor. # Side effects and potential contraindications Most side effects of beta-2 agonists result from their concurrent beta-1 activity, and include increase in heart rate, rise in systolic pressure, decrease in diastolic pressure, chest pain secondary to MI, and arrhythmia. Beta agonists may also cause fluid retention secondary to decrease in water clearance, which when added to the tachycardia and increased myocardial work, may result in cardiac failure. In addition, they increase gluconeogenesis in the liver and muscle resulting in hyperglycemia, which increases insulin requirements in diabetic patients. The passage of beta-agonists through the placenta does occur and may be responsible for fetal tachycardia, as well as hypoglycemia or hyperglycemia at birth. Patients with type 2 diabetes, high blood pressure or migraines should bring this to their doctor's attention before receiving care. It has also been associated with post-partum hemorrhage.	Ritodrine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Ritodrine (discontinued preparation: Yutopar) is a tocolytic drug, used to stop premature labor.[1] This drug has been removed from the US market, according to FDA Orange Book. It was available in oral tablets or as an injection and was typically used as the hydrochloride salt, ritodrine hydrochloride. # Mechanism Ritodrine is a beta-2 adrenergic receptor agonist - a class of medication used for smooth muscle relaxation (other similar drugs are used in asthma or other pulmonary diseases such as salbutamol). Since ritodrine has a bulky N-substituent, it has high β2-selectivity. Also, the 4'-hydroxy on the benzene ring is important for activity as it is needed to form hydrogen bonds. However, the 4'-hydroxy makes it susceptible to metabolism by COMT. Since it is β2-selective it is used for premature labor.[2] # Side effects and potential contraindications Most side effects of beta-2 agonists result from their concurrent beta-1 activity, and include increase in heart rate, rise in systolic pressure, decrease in diastolic pressure, chest pain secondary to MI, and arrhythmia. Beta agonists may also cause fluid retention secondary to decrease in water clearance, which when added to the tachycardia and increased myocardial work, may result in cardiac failure. In addition, they increase gluconeogenesis in the liver and muscle resulting in hyperglycemia, which increases insulin requirements in diabetic patients. The passage of beta-agonists through the placenta does occur and may be responsible for fetal tachycardia, as well as hypoglycemia or hyperglycemia at birth. Patients with type 2 diabetes, high blood pressure or migraines should bring this to their doctor's attention before receiving care. It has also been associated with post-partum hemorrhage.[citation needed]	https://www.wikidoc.org/index.php/Ritodrine
a42e0468140f47a0e4b36fd249d6acc8beb7d2a8	wikidoc	Rituximab	Rituximab # 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 Rituximab is a monoclonal antibody that is FDA approved for the treatment of non–hodgkin's lymphoma (nhl), chronic lymphocytic leukemia (CLL), rheumatoid arthritis (RA), granulomatosis with polyangiitis (GPA) (wegener's granulomatosis) and microscopic polyangiitis (MPA),. There is a Black Box Warning for this drug as shown here. Common adverse reactions include hypotension, peripheral edema, night sweats, pruritus, rash, abdominal pain, diarrhea, nausea, vomiting, anemia, arthralgia, backache, myalgia, asthenia, dizziness, headache, sensory neuropathy, increasing frequency of cough, rhinitis, fever, infectious disease, pain, shivering. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Non-Hodgkin's Lymphoma (NHL) - Dosing information - Relapsed or Refractory, Low-Grade or Follicular, CD20-Positive, B-Cell NHL - Administer once weekly for 4 or 8 doses. - Retreatment for Relapsed or Refractory, Low-Grade or Follicular, CD20-Positive, B-Cell NHL - Administer once weekly for 4 doses. - Previously Untreated, Follicular, CD20-Positive, B-Cell NHL - Administer on Day 1 of each cycle of chemotherapy, for up to 8 doses. In patients with complete or partial response, initiate Rituximab maintenance eight weeks following completion of Rituximab in combination with chemotherapy. Administer Rituximab as a single-agent every 8 weeks for 12 doses. - Non-progressing, Low-Grade, CD20-Positive, B-cell NHL, after first-line CVP chemotherapy - Following completion of 6–8 cycles of CVP chemotherapy, administer once weekly for 4 doses at 6-month intervals to a maximum of 16 doses. - Diffuse Large B-Cell NHL - Administer on Day 1 of each cycle of chemotherapy for up to 8 infusions. ### Chronic Lymphocytic Leukemia (CLL) - Dosing information - Recommended dosage: - 375 mg/m2 the day prior to the initiation of FC chemotherapy - 500 mg/m2 on Day 1 of cycles 2–6 (every 28 days). ### Recommended Dose as a Component of Zevalin® - Dosing information - Infuse rituximab 250 mg/m2 within 4 hours prior to the administration of Indium-111-(In-111-) Zevalin and within 4 hours prior to the administration of Yttrium-90- (Y-90-) Zevalin. - Administer Rituximab and In-111-Zevalin 7–9 days prior to Rituximab and Y-90- Zevalin. - Refer to the Zevalin package insert for full prescribing information regarding the Zevalin therapeutic regimen. ### Recommended Dose for Rheumatoid Arthritis (RA) - Dosing information - Administer Rituximab as two-1000 mg intravenous infusions separated by 2 weeks. - Glucocorticoids administered as methylprednisolone 100 mg intravenous or its equivalent 30 minutes prior to each infusion are recommended to reduce the incidence and severity of infusion reactions. - Subsequent courses should be administered every 24 weeks or based on clinical evaluation, but not sooner than every 16 weeks. - Rituximab is given in combination with methotrexate. ### Recommended Dose for Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis) and Microscopic Polyangiitis (MPA) - Dosing information - Administer Rituximab as a 375 mg/m2 intravenous infusion once weekly for 4 weeks. - Glucocorticoids administered as methylprednisolone 1000 mg intravenously per day for 1 to 3 days followed by oral prednisone 1 mg/kg/day (not to exceed 80 mg/day and tapered per clinical need) are recommended to treat severe vasculitis symptoms. This regimen should begin within 14 days prior to or with the initiation of Rituximab and may continue during and after the 4 week course of Rituximab treatment. - Safety and efficacy of treatment with subsequent courses of Rituximab have not been established ### Recommended Concomitant Medications - Dosing information - Premedicate before each infusion with acetaminophen and an antihistamine. For patients administered Rituximab according to the 90-minute infusion rate, the glucocorticoid component of their chemotherapy regimen should be administered prior to infusion - For RA patients, methylprednisolone 100 mg intravenously or its equivalent is recommended 30 minutes prior to each infusion. - For GPA and MPA patients, glucocorticoids are given in combination with Rituximab - Pneumocystis jiroveci pneumonia (PCP) and anti-herpetic viral prophylaxis is recommended for patients with CLL during treatment and for up to 12 months following treatment as appropriate. - PCP prophylaxis is also recommended for patients with GPA and MPA during treatment and for at least 6 months following the last Rituximab infusion. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Rituximab in adult patients. ### Non–Guideline-Supported Use ### Acquired factor VIII deficiency disease - Dosing information - 375 mg/m(2) given once weekly ### Autoimmune hemolytic anemia - Dosing information - 375 mg/m(2) IV weekly for 4 consecutive weeks, ### B-cell lymphoma - Dosing information - 375 mg/m(2) , ### Evans syndrome - Dosing information - 375 mg/m(2) weekly for 2 doses ### Graft-versus-host disease - Dosing information - 375 mg/m(2) IV weekly for 4 consecutive weeks, ### Hairy cell leukemia - Dosing information - 375 mg/m(2) per week ### Hodgkin's disease - Dosing information - 375 mg/m(2) IV once weekly for 4 weeks , ### Idiopathic thrombocytopenic purpura - Dosing information - 375 mg/m(2) once a week for 4 weeks ### Mantle cell lymphoma - Dosing information - 375 mg/m(2) on day 0) every 3 weeks for 6 cycles15668467 - 375 mg/m(2) IV was administered on the first day of cycles 4 and 5 and on the first and ninth day of cycle 6 ### Pemphigus vulgaris - Dosing information - 375 mg/m(2) IV once weekly for a 4-week cycle ### Post-transplant lymphoproliferative disorder - Dosing information - 375 mg/m(2) IV once weekly for 4 weeks - 375 mg/m(2) weekly for 4 weeks every 6 months # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Rituximab 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 Rituximab in pediatric patients. ### Non–Guideline-Supported Use ### Autoimmune hemolytic anemia - Dosing information - 375 mg/m(2), ### Post-transplant lymphoproliferative disorder - Dosing information - 375 mg/m(2) IV once weekly for 4 to 8 cycles # Contraindications None. # Warnings ## Infusion Reactions Rituximab can cause severe, including fatal, infusion reactions. Severe reactions typically occurred during the first infusion with time to onset of 30–120 minutes. Rituximab-induced infusion reactions and sequelae include urticaria, hypotension, angioedema, hypoxia, bronchospasm, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, cardiogenic shock, anaphylactoid events, or death. Premedicate patients with an antihistamine and acetaminophen prior to dosing. For RA patients, methylprednisolone 100 mg intravenously or its equivalent is recommended 30 minutes prior to each infusion. Institute medical management (e.g. glucocorticoids, epinephrine, bronchodilators, or oxygen) for infusion reactions as needed. Depending on the severity of the infusion reaction and the required interventions, temporarily or permanently discontinue Rituximab. Resume infusion at a minimum 50% reduction in rate after symptoms have resolved. Closely monitor the following patients: those with pre-existing cardiac or pulmonary conditions, those who experienced prior cardiopulmonary adverse reactions, and those with high numbers of circulating malignant cells ( ≥ 25,000/mm3). ## Severe Mucocutaneous Reactions Mucocutaneous reactions, some with fatal outcome, can occur in patients treated with Rituximab. These reactions include paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis. The onset of these reactions has been variable and includes reports with onset on the first day of Rituximab exposure. Discontinue Rituximab in patients who experience a severe mucocutaneous reaction. The safety of readministration of Rituximab to patients with severe mucocutaneous reactions has not been determined. ## Hepatitis B Virus Reactivation Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, can occur in patients treated with drugs classified as CD20-directed cytolytic antibodies, including Rituximab. Cases have been reported in patients who are hepatitis B surface antigen (HBsAg) positive and also in patients who are HBsAg negative but are hepatitis B core antibody (anti-HBc) positive. Reactivation also has occurred in patients who appear to have resolved hepatitis B infection (i.e., HBsAg negative, anti-HBc positive and hepatitis B surface antibody positive). HBV reactivation is defined as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level or detection of HBsAg in a person who was previously HBsAg negative and anti-HBc positive. Reactivation of HBV replication is often followed by hepatitis, i.e., increase in transaminase levels. In severe cases increase in bilirubin levels, liver failure, and death can occur. Screen all patients for HBV infection by measuring HBsAg and anti-HBc before initiating treatment with Rituximab. For patients who show evidence of prior hepatitis B infection (HBsAg positive or HBsAg negative but anti-HBc positive), consult with physicians with expertise in managing hepatitis B regarding monitoring and consideration for HBV antiviral therapy before and/or during Rituximab treatment. Monitor patients with evidence of current or prior HBV infection for clinical and laboratory signs of hepatitis or HBV reactivation during and for several months following Rituximab therapy. HBV reactivation has been reported up to 24 months following completion of Rituximab therapy. In patients who develop reactivation of HBV while on Rituximab, immediately discontinue Rituximab and any concomitant chemotherapy, and institute appropriate treatment. Insufficient data exist regarding the safety of resuming Rituximab in patients who develop HBV reactivation. Resumption of Rituximab in patients whose HBV reactivation resolves should be discussed with physicians with expertise in managing hepatitis B. ## Progressive Multifocal Leukoencephalopathy (PML) JC virus infection resulting in PML and death can occur in Rituximab-treated patients with hematologic malignancies or with autoimmune diseases. The majority of patients with hematologic malignancies diagnosed with PML received Rituximab in combination with chemotherapy or as part of a hematopoietic stem cell transplant. The patients with autoimmune diseases had prior or concurrent immunosuppressive therapy. Most cases of PML were diagnosed within 12 months of their last infusion of Rituximab. Consider the diagnosis of PML in any patient presenting with new-onset neurologic manifestations. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture. Discontinue Rituximab and consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML. ## Tumor Lysis Syndrome (TLS) Acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, or hyperphosphatemia from tumor lysis, some fatal, can occur within 12–24 hours after the first infusion of Rituximab in patients with NHL. A high number of circulating malignant cells ( ≥ 25,000/mm3) or high tumor burden, confers a greater risk of TLS. Administer aggressive intravenous hydration and anti-hyperuricemic therapy in patients at high risk for TLS. Correct electrolyte abnormalities, monitor renal function and fluid balance, and administer supportive care, including dialysis as indicated. ## Infections Serious, including fatal, bacterial, fungal, and new or reactivated viral infections can occur during and following the completion of Rituximab-based therapy. Infections have been reported in some patients with prolonged hypogammaglobulinemia (defined as hypogammaglobulinemia >11 months after rituximab exposure). New or reactivated viral infections included cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus, West Nile virus, and hepatitis B and C. Discontinue Rituximab for serious infections and institute appropriate anti-infective therapy. ## Cardiovascular Discontinue infusions for serious or life-threatening cardiac arrhythmias. Perform cardiac monitoring during and after all infusions of Rituximab for patients who develop clinically significant arrhythmias, or who have a history of arrhythmia or angina. ## Renal Severe, including fatal, renal toxicity can occur after Rituximab administration in patients with NHL. Renal toxicity has occurred in patients who experience tumor lysis syndrome and in patients with NHL administered concomitant cisplatin therapy during clinical trials. The combination of cisplatin and Rituximab is not an approved treatment regimen. Monitor closely for signs of renal failure and discontinue Rituximab in patients with a rising serum creatinine or oliguria. ## Bowel Obstruction and Perforation Abdominal pain, bowel obstruction and perforation, in some cases leading to death, can occur in patients receiving Rituximab in combination with chemotherapy. In postmarketing reports, the mean time to documented gastrointestinal perforation was 6 (range 1–77) days in patients with NHL. Evaluate if symptoms of obstruction such as abdominal pain or repeated vomiting occur. ## Immunization The safety of immunization with live viral vaccines following Rituximab therapy has not been studied and vaccination with live virus vaccines is not recommended. For RA patients, physicians should follow current immunization guidelines and administer non-live vaccines at least 4 weeks prior to a course of Rituximab. The effect of Rituximab on immune responses was assessed in a randomized, controlled study in patients with RA treated with Rituximab and methotrexate (MTX) compared to patients treated with MTX alone. A response to pneumococcal vaccination (a T-cell independent antigen) as measured by an increase in antibody titers to at least 6 of 12 serotypes was lower in patients treated with Rituximab plus MTX as compared to patients treated with MTX alone (19% vs. 61%). A lower proportion of patients in the Rituximab plus MTX group developed detectable levels of anti-keyhole limpet hemocyanin antibodies (a novel protein antigen) after vaccination compared to patients on MTX alone (47% vs. 93%). A positive response to tetanus toxoid vaccine (a T-cell dependent antigen with existing immunity) was similar in patients treated with Rituximab plus MTX compared to patients on MTX alone (39% vs. 42%). The proportion of patients maintaining a positive Candida skin test (to evaluate delayed type hypersensitivity) was also similar (77% of patients on Rituximab plus MTX vs. 70% of patients on MTX alone). Most patients in the Rituximab-treated group had B-cell counts below the lower limit of normal at the time of immunization. The clinical implications of these findings are not known. ## Laboratory Monitoring In patients with lymphoid malignancies, during treatment with Rituximab monotherapy, obtain complete blood counts (CBC) and platelet counts prior to each Rituximab course. During treatment with Rituximab and chemotherapy, obtain CBC and platelet counts at weekly to monthly intervals and more frequently in patients who develop cytopenias . In patients with RA, GPA or MPA, obtain CBC and platelet counts at two to four month intervals during Rituximab therapy. The duration of cytopenias caused by Rituximab can extend months beyond the treatment period. ## Concomitant Use with Biologic Agents and DMARDS other than Methotrexate in RA, GPA and MPA Limited data are available on the safety of the use of biologic agents or DMARDs other than methotrexate in RA patients exhibiting peripheral B-cell depletion following treatment with rituximab. Observe patients closely for signs of infection if biologic agents and/or DMARDs are used concomitantly. Use of concomitant immunosuppressants other than corticosteroids has not been studied in GPA or MPA patients exhibiting peripheral B-cell depletion following treatment with Rituximab. ## Use in RA Patients Who Have Not Had Prior Inadequate Response to Tumor Necrosis Factor (TNF) Antagonists While the efficacy of Rituximab was supported in four controlled trials in patients with RA with prior inadequate responses to non-biologic DMARDs, and in a controlled trial in MTX-naïve patients, a favorable risk-benefit relationship has not been established in these populations. The use of Rituximab in patients with RA who have not had prior inadequate response to one or more TNF antagonists is not recommended. ## Retreatment in Patients with Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis) and Microscopic Polyangiitis (MPA) Limited data are available on the safety and efficacy of subsequent courses of Rituximab in patients with GPA and MPA. The safety and efficacy of retreatment with Rituximab have not been established # Adverse Reactions ## Clinical Trials Experience The following serious adverse reactions are discussed in greater detail in other sections of the labeling: - Infusion reactions - Mucocutaneous reactions - Hepatitis B reactivation with fulminant hepatitis - Progressive multifocal leukoencephalopathy - Tumor lysis syndrome - Infections - Cardiac arrhythmias - Renal toxicity - Bowel obstruction and perforation The most common adverse reactions of Rituximab (incidence ≥ 25%) observed in clinical trials of patients with NHL were infusion reactions, fever, lymphopenia, chills, infection, and asthenia. The most common adverse reactions of Rituximab (incidence ≥ 25%) observed in clinical trials of patients with CLL were: infusion reactions and neutropenia. ## Clinical Trials Experience in Lymphoid Malignancies 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 data described below reflect exposure to Rituximab in 2783 patients, with exposures ranging from a single infusion up to 2 years. Rituximab was studied in both single-arm and controlled trials (n=356 and n=2427). The population included 1180 patients with low grade or follicular lymphoma, 927 patients with DLBCL, and 676 patients with CLL. Most NHL patients received Rituximab as an infusion of 375 mg/m2 per infusion, given as a single agent weekly for up to 8 doses, in combination with chemotherapy for up to 8 doses, or following chemotherapy for up to 16 doses. CLL patients received Rituximab 375 mg/m2 as an initial infusion followed by 500 mg/m2 for up to 5 doses, in combination with fludarabine and cyclophosphamide. Seventy-one percent of CLL patients received 6 cycles and 90% received at least 3 cycles of Rituximab-based therapy. Infusion Reactions In the majority of patients with NHL, infusion reactions consisting of fever, chills/rigors, nausea, pruritus, angioedema, hypotension, headache, bronchospasm, urticaria, rash, vomiting, myalgia, dizziness, or hypertension occurred during the first Rituximab infusion. Infusion reactions typically occurred within 30 to 120 minutes of beginning the first infusion and resolved with slowing or interruption of the Rituximab infusion and with supportive care (diphenhydramine, acetaminophen, and intravenous saline). The incidence of infusion reactions was highest during the first infusion (77%) and decreased with each subsequent infusion. In patients with previously untreated follicular NHL or previously untreated DLBCL, who did not experience a Grade 3 or 4 infusion-related reaction in Cycle 1 and received a 90-minute infusion of Rituximab at Cycle 2, the incidence of Grade 3-4 infusion-related reactions on the day of, or day after the infusion was 1.1% (95% CI ). For Cycles 2-8, the incidence of Grade 3-4 infusion reactions on the day of or day after the 90-minute infusion, was 2.8% (95% CI ). Infections Serious infections (NCI CTCAE Grade 3 or 4), including sepsis, occurred in less than 5% of patients with NHL in the single-arm studies. The overall incidence of infections was 31% (bacterial 19%, viral 10%, unknown 6%, and fungal 1%). In randomized, controlled studies where Rituximab was administered following chemotherapy for the treatment of follicular or low-grade NHL, the rate of infection was higher among patients who received Rituximab. In diffuse large B-cell lymphoma patients, viral infections occurred more frequently in those who received Rituximab. Cytopenias and hypogammaglobulinemia In patients with NHL receiving rituximab monotherapy, NCI-CTC Grade 3 and 4 cytopenias were reported in 48% of patients. These included lymphopenia (40%), neutropenia (6%), leukopenia (4%), anemia (3%), and thrombocytopenia (2%). The median duration of lymphopenia was 14 days (range, 1–588 days) and of neutropenia was 13 days (range, 2–116 days). A single occurrence of transient aplastic anemia (pure red cell aplasia) and two occurrences of hemolytic anemia following Rituximab therapy occurred during the single-arm studies. In studies of monotherapy, Rituximab-induced B-cell depletion occurred in 70% to 80% of patients with NHL. Decreased IgM and IgG serum levels occurred in 14% of these patients. In CLL trials, the frequency of prolonged neutropenia and late-onset neutropenia was higher in patients treated with R-FC compared to patients treated with FC. Prolonged neutropenia is defined as Grade 3-4 neutropenia that has not resolved between 24 and 42 days after the last dose of study treatment. Late-onset neutropenia is defined as Grade 3-4 neutropenia starting at least 42 days after the last treatment dose. In patients with previously untreated CLL, the frequency of prolonged neutropenia was 8.5% for patients who received R-FC (n=402) and 5.8% for patients who received FC (n=398). In patients who did not have prolonged neutropenia, the frequency of late-onset neutropenia was 14.8% of 209 patients who received R-FC and 4.3% of 230 patients who received FC. For patients with previously treated CLL, the frequency of prolonged neutropenia was 24.8% for patients who received R-FC (n=274) and 19.1% for patients who received FC (n=274). In patients who did not have prolonged neutropenia, the frequency of late-onset neutropenia was 38.7% in 160 patients who received R-FC and 13.6% of 147 patients who received FC. Relapsed or Refractory, Low-Grade NHL Adverse reactions in Table 1 occurred in 356 patients with relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL treated in single-arm studies of Rituximab administered as a single agent. Most patients received Rituximab 375 mg/m2 weekly for 4 doses. In these single-arm Rituximab studies, bronchiolitis obliterans occurred during and up to 6 months after Rituximab infusion. Previously Untreated, Low-Grade or Follicular, NHL In Study 4, patients in the R-CVP arm experienced a higher incidence of infusional toxicity and neutropenia compared to patients in the CVP arm. The following adverse reactions occurred more frequently ( ≥ 5%) in patients receiving R-CVP compared to CVP alone: rash (17% vs. 5%), cough (15% vs. 6%), flushing (14% vs. 3%), rigors (10% vs. 2%), pruritus (10% vs. 1%), neutropenia (8% vs. 3%), and chest tightness (7% vs. 1%). In Study 5, detailed safety data collection was limited to serious adverse reactions, Grade ≥ 2 infections, and Grade ≥ 3 adverse reactions. In patients receiving Rituximab as single-agent maintenance therapy following Rituximab plus chemotherapy, infections were reported more frequently compared to the observation arm (37% vs. 22%). Grade 3-4 adverse reactions occurring at a higher incidence (≥ 2%) in the Rituximab group were infections (4% vs. 1%) and neutropenia (4% vs. <1%). In Study 6, the following adverse reactions were reported more frequently ( ≥ 5%) in patients receiving Rituximab following CVP compared to patients who received no further therapy: fatigue (39% vs. 14%), anemia (35% vs. 20%), peripheral sensory neuropathy (30% vs. 18%), infections (19% vs. 9%), pulmonary toxicity (18% vs. 10%), hepato-biliary toxicity (17% vs. 7%), rash and/or pruritus (17% vs. 5%), arthralgia (12% vs. 3%), and weight gain (11% vs. 4%). Neutropenia was the only Grade 3 or 4 adverse reaction that occurred more frequently ( ≥ 2%) in the Rituximab arm compared with those who received no further therapy (4% vs. 1%). DLBCL In Studies 7 and 8, the following adverse reactions, regardless of severity, were reported more frequently ( ≥ 5%) in patients age ≥ 60 years receiving R-CHOP as compared to CHOP alone: pyrexia (56% vs. 46%), lung disorder (31% vs. 24%), cardiac disorder (29% vs. 21%), and chills (13% vs. 4%). Detailed safety data collection in these studies was primarily limited to Grade 3 and 4 adverse reactions and serious adverse reactions. In Study 8, a review of cardiac toxicity determined that supraventricular arrhythmias or tachycardia accounted for most of the difference in cardiac disorders (4.5% for R-CHOP vs. 1.0% for CHOP). The following Grade 3 or 4 adverse reactions occurred more frequently among patients in the R-CHOP arm compared with those in the CHOP arm: thrombocytopenia (9% vs. 7%) and lung disorder (6% vs. 3%). Other Grade 3 or 4 adverse reactions occurring more frequently among patients receiving R-CHOP were viral infection (Study 8), neutropenia (Studies 8 and 9), and anemia (Study 9). CLL The data below reflect exposure to Rituximab in combination with fludarabine and cyclophosphamide in 676 patients with CLL in Study 11 or Study 12. The age range was 30–83 years and 71% were men. Detailed safety data collection in Study 11 was limited to Grade 3 and 4 adverse reactions and serious adverse reactions. Infusion-related adverse reactions were defined by any of the following adverse events occurring during or within 24 hours of the start of infusion: nausea, pyrexia, chills, hypotension, vomiting, and dyspnea. In Study 11, the following Grade 3 and 4 adverse reactions occurred more frequently in R-FC-treated patients compared to FC-treated patients: infusion reactions (9% in R-FC arm), neutropenia (30% vs. 19%), febrile neutropenia (9% vs. 6%), leukopenia (23% vs. 12%), and pancytopenia (3% vs. 1%). In Study 12, the following Grade 3 or 4 adverse reactions occurred more frequently in R-FC-treated patients compared to FC-treated patients: infusion reactions (7% in R-FC arm), neutropenia (49% vs. 44%), febrile neutropenia (15% vs. 12%), thrombocytopenia (11% vs. 9%), hypotension (2% vs. 0%), and hepatitis B (2% vs. < 1%). Fifty-nine percent of R-FC-treated patients experienced an infusion reaction of any severity. ## Clinical Trials Experience in Rheumatoid Arthritis Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in 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 data presented below reflect the experience in 2578 RA patients treated with Rituximab in controlled and long-term studies with a total exposure of 5014 patient-years. Among all exposed patients, adverse reactions reported in greater than 10% of patients include infusion-related reactions, upper respiratory tract infection, nasopharyngitis, urinary tract infection, and bronchitis. In placebo-controlled studies, patients received 2 × 500 mg or 2 × 1000 mg intravenous infusions of Rituximab or placebo, in combination with methotrexate, during a 24-week period. From these studies, 938 patients treated with Rituximab (2 × 1000 mg) or placebo have been pooled (see Table 2). Adverse reactions reported in ≥ 5% of patients were hypertension, nausea, upper respiratory tract infection, arthralgia, pyrexia and pruritus (see Table 2). The rates and types of adverse reactions in patients who received Rituximab 2 × 500 mg were similar to those observed in patients who received Rituximab 2 × 1000 mg. Infusion Reactions In the Rituximab RA pooled placebo-controlled studies, 32% of Rituximab-treated patients experienced an adverse reaction during or within 24 hours following their first infusion, compared to 23% of placebo-treated patients receiving their first infusion. The incidence of adverse reactions during the 24-hour period following the second infusion, Rituximab or placebo, decreased to 11% and 13%, respectively. Acute infusion reactions (manifested by fever, chills, rigors, pruritus, urticaria/rash, angioedema, sneezing, throat irritation, cough, and/or bronchospasm, with or without associated hypotension or hypertension) were experienced by 27% of Rituximab-treated patients following their first infusion, compared to 19% of placebo-treated patients receiving their first placebo infusion. The incidence of these acute infusion reactions following the second infusion of Rituximab or placebo decreased to 9% and 11%, respectively. Serious acute infusion reactions were experienced by < 1% of patients in either treatment group. Acute infusion reactions required dose modification (stopping, slowing, or interruption of the infusion) in 10% and 2% of patients receiving rituximab or placebo, respectively, after the first course. The proportion of patients experiencing acute infusion reactions decreased with subsequent courses of Rituximab. The administration of intravenous glucocorticoids prior to Rituximab infusions reduced the incidence and severity of such reactions, however, there was no clear benefit from the administration of oral glucocorticoids for the prevention of acute infusion reactions. Patients in clinical studies also received antihistamines and acetaminophen prior to Rituximab infusions. Infections In the pooled, placebo-controlled studies, 39% of patients in the Rituximab group experienced an infection of any type compared to 34% of patients in the placebo group. The most common infections were nasopharyngitis, upper respiratory tract infections, urinary tract infections, bronchitis, and sinusitis. The incidence of serious infections was 2% in the Rituximab-treated patients and 1% in the placebo group. In the experience with Rituximab in 2578 RA patients, the rate of serious infections was 4.31 per 100 patient years. The most common serious infections ( ≥ 0.5%) were pneumonia or lower respiratory tract infections, cellulitis and urinary tract infections. Fatal serious infections included pneumonia, sepsis and colitis. Rates of serious infection remained stable in patients receiving subsequent courses. In 185 Rituximab-treated RA patients with active disease, subsequent treatment with a biologic DMARD, the majority of which were TNF antagonists, did not appear to increase the rate of serious infection. Thirteen serious infections were observed in 186.1 patient years (6.99 per 100 patient years) prior to exposure and 10 were observed in 182.3 patient years (5.49 per 100 patient years) after exposure. Cardiac Adverse Reactions In the pooled, placebo-controlled studies, the proportion of patients with serious cardiovascular reactions was 1.7% and 1.3% in the Rituximab and placebo treatment groups, respectively. Three cardiovascular deaths occurred during the double-blind period of the RA studies including all rituximab regimens (3/769 = 0.4%) as compared to none in the placebo treatment group (0/389). In the experience with Rituximab in 2578 RA patients, the rate of serious cardiac reactions was 1.93 per 100 patient years. The rate of myocardial infarction (MI) was 0.56 per 100 patient years (28 events in 26 patients), which is consistent with MI rates in the general RA population. These rates did not increase over three courses of Rituximab. Since patients with RA are at increased risk for cardiovascular events compared with the general population, patients with RA should be monitored throughout the infusion and Rituximab should be discontinued in the event of a serious or life-threatening cardiac event. Hypophosphatemia and hyperuricemia In the pooled, placebo-controlled studies, newly-occurring hypophosphatemia ( 10 mg/dl) was observed in 1.5% (8/540) of patients on Rituximab versus 0.3% (1/398) of patients on placebo. In the experience with Rituximab in RA patients, newly-occurring hypophosphatemia was observed in 21% (528/2570) of patients and newly-occurring hyperuricemia was observed in 2% (56/2570) of patients. The majority of the observed hypophosphatemia occurred at the time of the infusions and was transient. Retreatment in Patients with RA In the experience with Rituximab in RA patients, 2578 patients have been exposed to Rituximab and have received up to 10 courses of Rituximab in RA clinical trials, with 1890, 1043, and 425 patients having received at least two, three, and four courses, respectively. Most of the patients who received additional courses did so 24 weeks or more after the previous course and none were retreated sooner than 16 weeks. The rates and types of adverse reactions reported for subsequent courses of Rituximab were similar to rates and types seen for a single course of Rituximab. In RA Study 2, where all patients initially received Rituximab, the safety profile of patients who were retreated with Rituximab was similar to those who were retreated with placebo Clinical Trials Experience in Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis) and Microscopic Polyangiitis (MPA) Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in 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 data presented below reflect the experience in 197 patients with GPA and MPA treated with Rituximab or cyclophosphamide in a single controlled study, which was conducted in two phases: a 6 month randomized, double-blind, double-dummy, active-controlled remission induction phase and an additional 12 month remission maintenance phase. In the 6-month remission induction phase, 197 patients with GPA and MPA were randomized to either Rituximab 375 mg/ m2 once weekly for 4 weeks plus glucocorticoids, or oral cyclophosphamide 2 mg/kg daily (adjusted for renal function, white blood cell count, and other factors) plus glucocorticoids to induce remission. Once remission was achieved or at the end of the 6 month remission induction period, the cyclophosphamide group received azathioprine to maintain remission. The Rituximab group did not receive additional therapy to maintain remission. The primary analysis was at the end of the 6 month remission induction period and the safety results for this period are described below. Adverse reactions presented below in Table 3 were adverse events which occurred at a rate of greater than or equal to 10% in the Rituximab group. This table reflects experience in 99 GPA and MPA patients treated with Rituximab, with a total of 47.6 patient-years of observation and 98 GPA and MPA patients treated with cyclophosphamide, with a total of 47.0 patient-years of observation. Infection was the most common category of adverse events reported (47-62%) and is discussed below. Infusion Reactions Infusion-related reactions in the active-controlled, double-blind study were defined as any adverse event occurring within 24 hours of an infusion and considered to be infusion-related by investigators. Among the 99 patients treated with Rituximab, 12% experienced at least one infusion related reaction, compared with 11% of the 98 patients in the cyclophosphamide group. Infusion-related reactions included cytokine release syndrome, flushing, throat irritation, and tremor. In the Rituximab group, the proportion of patients experiencing an infusion related reaction was 12%, 5%, 4%, and 1% following the first, second, third, and fourth infusions, respectively. Patients were pre-medicated with antihistamine and acetaminophen before each Rituximab infusion and were on background oral corticosteroids which may have mitigated or masked an infusion reaction; however, there is insufficient evidence to determine whether premedication diminishes the frequency or severity of infusion reactions. Infections In the active-controlled, double-blind study, 62% (61/99) of patients in the Rituximab group experienced an infection of any type compared to 47% (46/98) patients in the cyclophosphamide group by Month 6. The most common infections in the Rituximab group were upper respiratory tract infections, urinary tract infections, and herpes zoster. The incidence of serious infections was 11% in the Rituximab-treated patients and 10% in the cyclophosphamide treated patients, with rates of approximately 25 and 28 per 100 patient-years, respectively. The most common serious infection was pneumonia. Hypogammaglobulinemia Hypogammaglobulinemia (IgA, IgG or IgM below the lower limit of normal) has been observed in patients with GPA and MPA treated with Rituximab. At 6 months, in the Rituximab group, 27%, 58% and 51% of patients with normal immunoglobulin levels at baseline, had low IgA, IgG and IgM levels, respectively compared to 25%, 50% and 46% in the cyclophosphamide group. Retreatment in Patients with GPA and MPA In the active-controlled, double-blind study, subsequent courses of Rituximab were allowed for patients experiencing a relapse of disease. The limited data preclude any conclusions regarding the safety of subsequent courses of Rituximab with GPA and MPA. ## Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. 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 Rituximab with the incidence of antibodies to other products may be misleading. Using an ELISA assay, anti-human anti-chimeric antibody (HACA) was detected in 4 of 356 (1.1%) patients with low-grade or follicular NHL receiving single-agent Rituximab. Three of the four patients had an objective clinical response. A total of 273/2578 (11%) patients with RA tested positive for HACA at any time after receiving Rituximab. HACA positivity was not associated with increased infusion reactions or other adverse reactions. Upon further treatment, the proportions of patients with infusion reactions were similar between HACA positive and negative patients, and most reactions were mild to moderate. Four HACA positive patients had serious infusion reactions, and the temporal relationship between HACA positivity and infusion reaction was variable. A total of 23/99 (23%) Rituximab-treated patients with GPA and MPA tested positive for HACA by 18 months. The clinical relevance of HACA formation in Rituximab-treated patients is unclear. ## Postmarketing Experience 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. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to Rituximab. - Hematologic: prolonged pancytopenia, marrow hypoplasia, Grade 3-4 prolonged or late-onset neutropenia, hyperviscosity syndrome in Waldenstrom's macroglobulinemia, prolonged hypogammaglobulinemia - Cardiac: fatal cardiac failure. - Immune/Autoimmune Events: uveitis, “], systemic vasculitis, pleuritis, lupus-like syndrome, serum sickness, polyarticular arthritis, and vasculitis with rash. - Infection: viral infections, including progressive multifocal leukoencephalopathy (PML), increase in fatal infections in HIV-associated lymphoma, and a reported increased incidence of Grade 3 and 4 infections - Neoplasia: disease progression of Kaposi's sarcoma. - Skin: severe mucocutaneous reactions. - Gastrointestinal: bowel obstruction and perforation. - Pulmonary: fatal bronchiolitis obliterans and fatal interstitial lung disease. - Nervous system: Posterior Reversible Encephalopathy Syndrome (PRES) /Reversible Posterior Leukoencephalopathy Syndrome (RPLS). # Drug Interactions Formal drug interaction studies have not been performed with Rituximab. In patients with CLL, Rituximab did not alter systemic exposure to fludarabine or cyclophosphamide. In clinical trials of patients with RA, concomitant administration of methotrexate or cyclophosphamide did not alter the pharmacokinetics of rituximab. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C There are no adequate and well-controlled studies of rituximab in pregnant women. Postmarketing data indicate that B-cell lymphocytopenia generally lasting less than six months can occur in infants exposed to rituximab in-utero. Rituximab was detected postnatally in the serum of infants exposed in-utero. Non-Hodgkin's lymphoma, moderate-severe rheumatoid arthritis, Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis) and Microscopic Polyangiitis are serious conditions that require treatment. Rituximab should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. Reproduction studies in cynomolgus monkeys at maternal exposures similar to human therapeutic exposures showed no evidence of teratogenic effects. However, B-cell lymphoid tissue was reduced in the offspring of treated dams. The B-cell counts returned to normal levels, and immunologic function was restored within 6 months of birth Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Rituximab in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Rituximab during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Rituximab in women who are nursing. ### Pediatric Use FDA has not required pediatric studies in polyarticular juvenile idiopathic arthritis (PJIA) patients ages 0 to 16 due to concerns regarding the potential for prolonged immunosuppression as a result of B-cell depletion in the developing juvenile immune system. Hypogammaglobulinemia has been observed in pediatric patients treated with Rituximab. The safety and effectiveness of Rituximab in pediatric patients have not been established. ### Geriatic Use Diffuse Large B-Cell NHL Among patients with DLBCL evaluated in three randomized, active-controlled trials, 927 patients received Rituximab in combination with chemotherapy. Of these, 396 (43%) were age 65 or greater and 123 (13%) were age 75 or greater. No overall differences in effectiveness were observed between these patients and younger patients. Cardiac adverse reactions, mostly supraventricular arrhythmias, occurred more frequently among elderly patients. Serious pulmonary adverse reactions were also more common among the elderly, including pneumonia and pneumonitis. Low-Grade or Follicular Non-Hodgkin's Lymphoma Patients with previously untreated follicular NHL evaluated in Study 5 were randomized to Rituximab as single-agent maintenance therapy (n=505) or observation (n=513) after achieving a response to Rituximab in combination with chemotherapy. Of these, 123 (24%) patients in the Rituximab arm were age 65 or older. No overall differences in safety or effectiveness were observed between these patients and younger patients. Other clinical studies of Rituximab in low-grade or follicular, CD20-positive, B-cell NHL did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger subjects. Chronic Lymphocytic Leukemia Among patients with CLL evaluated in two randomized active-controlled trials, 243 of 676 Rituximab-treated patients (36%) were 65 years of age or older; of these, 100 Rituximab-treated patients (15%) were 70 years of age or older. In exploratory analyses defined by age, there was no observed benefit from the addition of Rituximab to fludarabine and cyclophosphamide among patients 70 years of age or older in Study 11 or in Study 12; there was also no observed benefit from the addition of Rituximab to fludarabine and cyclophosphamide among patients 65 years of age or older in Study 12. Patients 70 years or older received lower dose intensity of fludarabine and cyclophosphamide compared to younger patients, regardless of the addition of Rituximab. In Study 11, the dose intensity of Rituximab was similar in older and younger patients, however in Study 12 older patients received a lower dose intensity of Rituximab. The incidence of Grade 3 and 4 adverse reactions was higher among patients receiving R-FC who were 70 years or older compared to younger patients for neutropenia , febrile neutropenia , anemia , thrombocytopenia , pancytopenia and infections . Rheumatoid Arthritis Among the 2578 patients in global RA studies completed to date, 12% were 65–75 years old and 2% were 75 years old and older. The incidences of adverse reactions were similar between older and younger patients. The rates of serious adverse reactions, including serious infections, malignancies, and cardiovascular events were higher in older patients. Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis) and Microscopic Polyangiitis Of the 99 Rituximab-treated GPA and MPA patients, 36 (36%) were 65 years old and over, while 8 (8%) were 75 years and over. No overall differences in efficacy were observed between patients that were 65 years old and over and younger patients. The overall incidence and rate of all serious adverse events was higher in patients 65 years old and over. The clinical study did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger subjects. ### Gender There is no FDA guidance on the use of Rituximab with respect to specific gender populations. ### Race There is no FDA guidance on the use of Rituximab with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Rituximab in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Rituximab in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Rituximab in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Rituximab in patients who are immunocompromised. # Administration and Monitoring ### Administration Administer only as an Intravenous Infusion Do not administer as an intravenous push or bolus. Premedicate before each infusion Rituximab should only be administered by a healthcare professional with appropriate medical support to manage severe infusion reactions that can be fatal if they occur. - First Infusion: Initiate infusion at a rate of 50 mg/hr. In the absence of infusion toxicity, increase infusion rate by 50 mg/hr increments every 30 minutes, to a maximum of 400 mg/hr. - Subsequent Infusions: - Standard Infusion: Initiate infusion at a rate of 100 mg/hr. In the absence of infusion toxicity, increase rate by 100 mg/hr increments at 30-minute intervals, to a maximum of 400 mg/hr. - For previously untreated follicular NHL and DLBCL patients: - If patients did not experience a Grade 3 or 4 infusion related adverse event during Cycle 1, a 90-minute infusion can be administered in Cycle 2 with a glucocorticoid-containing chemotherapy regimen. - Initiate at a rate of 20% of the total dose given in the first 30 minutes and the remaining 80% of the total dose given over the next 60 minutes. If the 90-minute infusion is tolerated in Cycle 2, the same rate can be used - when administering the remainder of the treatment regimen (through Cycle 6 or 8). - Patients who have clinically significant cardiovascular disease or who have a circulating lymphocyte count ≥5000/mm3 before Cycle 2 should not be administered the 90-minute infusion. - Interrupt the infusion or slow the infusion rate for infusion reactions. Continue the infusion at one-half the previous rate upon improvement of symptoms. ### Monitoring FDA Package Insert for Rituximab contains no information regarding drug monitoring. # IV Compatibility There is limited information about the IV Compatibility. # Overdosage There has been no experience with overdosage in human clinical trials. Single doses of up to 500 mg/m2 have been administered in clinical trials. # Pharmacology ## Mechanism of Action Rituximab binds specifically to the antigen CD20 (human B-lymphocyte-restricted differentiation antigen, Bp35), a hydrophobic transmembrane protein with a molecular weight of approximately 35 kD located on pre-B and mature B lymphocytes. The antigen is expressed on > 90% of B-cell non-Hodgkin's lymphomas (NHL), but the antigen is not found on hematopoietic stem cells, pro-B-cells, normal plasma cells or other normal tissues. CD20 regulates an early step(s) in the activation process for cell cycle initiation and differentiation, and possibly functions as a calcium ion channel. CD20 is not shed from the cell surface and does not internalize upon antibody binding. Free CD20 antigen is not found in the circulation. B cells are believed to play a role in the pathogenesis of rheumatoid arthritis (RA) and associated chronic synovitis. In this setting, B cells may be acting at multiple sites in the autoimmune/inflammatory process, including through production of rheumatoid factor (RF) and other autoantibodies, antigen presentation, T-cell activation, and/or proinflammatory cytokine production. Mechanism of Action: The Fab domain of rituximab binds to the CD20 antigen on B lymphocytes, and the Fc domain recruits immune effector functions to mediate B-cell lysis in vitro. Possible mechanisms of cell lysis include complement-dependent cytotoxicity (CDC) and antibody-dependent cell mediated cytotoxicity (ADCC). The antibody has been shown to induce apoptosis in the DHL-4 human B-cell lymphoma line. Normal Tissue Cross-reactivity: Rituximab binding was observed on lymphoid cells in the thymus, the white pulp of the spleen, and a majority of B lymphocytes in peripheral blood and lymph nodes. Little or no binding was observed in the non-lymphoid tissues examined. ## Structure Rituximab® (rituximab) is a genetically engineered chimeric murine/human monoclonal IgG1 kappa antibody directed against the CD20 antigen. Rituximab has an approximate molecular weight of 145 kD. Rituximab has a binding affinity for the CD20 antigen of approximately 8.0 nM. Rituximab is produced by mammalian cell (Chinese Hamster Ovary) suspension culture in a nutrient medium containing the antibiotic gentamicin. Gentamicin is not detectable in the final product. Rituximab is a sterile, clear, colorless, preservative-free liquid concentrate for intravenous administration. Rituximab is supplied at a concentration of 10 mg/mL in either 100 mg/10 mL or 500 mg/50 mL single-use vials. The product is formulated in polysorbate 80 (0.7 mg/mL), sodium citrate dihydrate (7.35 mg/mL), sodium chloride (9 mg/mL) and Water for Injection. The pH is 6.5. ## Pharmacodynamics Non-Hodgkin's Lymphoma (NHL) In NHL patients, administration of Rituximab resulted in depletion of circulating and tissue-based B cells. Among 166 patients in Study 1, circulating CD19-positive B cells were depleted within the first three weeks with sustained depletion for up to 6 to 9 months post treatment in 83% of patients. B-cell recovery began at approximately 6 months and median B-cell levels returned to normal by 12 months following completion of treatment. There were sustained and statistically significant reductions in both IgM and IgG serum levels observed from 5 through 11 months following rituximab administration; 14% of patients had IgM and/or IgG serum levels below the normal range. Rheumatoid Arthritis In RA patients, treatment with Rituximab induced depletion of peripheral B lymphocytes, with the majority of patients demonstrating near complete depletion (CD19 counts below the lower limit of quantification, 20 cells/µl) within 2 weeks after receiving the first dose of Rituximab. The majority of patients showed peripheral B-cell depletion for at least 6 months. A small proportion of patients (~4%) had prolonged peripheral B-cell depletion lasting more than 3 years after a single course of treatment. Total serum immunoglobulin levels, IgM, IgG, and IgA were reduced at 6 months with the greatest change observed in IgM. At Week 24 of the first course of Rituximab treatment, small proportions of patients experienced decreases in IgM (10%), IgG (2.8%), and IgA (0.8%) levels below the lower limit of normal (LLN). In the experience with Rituximab in RA patients during repeated Rituximab treatment, 23.3%, 5.5%, and 0.5% of patients experienced decreases in IgM, IgG, and IgA concentrations below LLN at any time after receiving Rituximab, respectively. The clinical consequences of decreases in immunoglobulin levels in RA patients treated with Rituximab are unclear. Treatment with rituximab in patients with RA was associated with reduction of certain biologic markers of inflammation such as interleukin-6 (IL-6), C-reactive protein (CRP), serum amyloid protein (SAA), S100 A8/S100 A9 heterodimer complex (S100 A8/9), anti-citrullinated peptide (anti-CCP), and RF. Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis) and Microscopic Polyangiitis In GPA and MPA patients, peripheral blood CD19 B-cells depleted to less than 10 cells/µl following the first two infusions of Rituximab, and remained at that level in most (84%) patients through Month 6. By Month 12, the majority of patients (81%) showed signs of B-cell return with counts >10 cells/μL. By Month 18, most patients (87%) had counts >10 cells/μL. ## Pharmacokinetics Non-Hodgkin's Lymphoma (NHL) Pharmacokinetics were characterized in 203 NHL patients receiving 375 mg/m2 Rituximab weekly by intravenous infusion for 4 doses. Rituximab was detectable in the serum of patients 3 to 6 months after completion of treatment. The pharmacokinetic profile of rituximab when administered as 6 infusions of 375 mg/m2 in combination with 6 cycles of CHOP chemotherapy was similar to that seen with rituximab alone. Based on a population pharmacokinetic analysis of data from 298 NHL patients who received rituximab once weekly or once every three weeks, the estimated median terminal elimination half-life was 22 days (range, 6.1 to 52 days). Patients with higher CD19-positive cell counts or larger measurable tumor lesions at pretreatment had a higher clearance. However, dose adjustment for pretreatment CD19 count or size of tumor lesion is not necessary. Age and gender had no effect on the pharmacokinetics of rituximab. Pharmacokinetics were characterized in 21 patients with CLL receiving rituximab according to the recommended dose and schedule. The estimated median terminal half-life of rituximab was 32 days (range, 14 to 62 days). Rheumatoid Arthritis Following administration of 2 doses of Rituximab in patients with RA, the mean ( ± S.D.; % CV) concentrations after the first infusion (Cmax first) and second infusion (Cmax second) were 157 ( ± 46; 29%) and 183 ( ± 55; 30%) mcg/mL, and 318 ( ± 86; 27%) and 381 ( ± 98; 26%) mcg/mL for the 2 × 500 mg and 2 × 1000 mg doses, respectively. Based on a population pharmacokinetic analysis of data from 2005 RA patients who received Rituximab, the estimated clearance of rituximab was 0.335 L/day; volume of distribution was 3.1 L and mean terminal elimination half-life was 18.0 days (range, 5.17 to 77.5 days). Age, weight and gender had no effect on the pharmacokinetics of rituximab in RA patients. Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis) and Microscopic Polyangiitis Based on the population pharmacokinetic analysis of data in 97 GPA and MPA patients who received 375 mg/m2 rituximab once weekly by intravenous infusion for four weeks, the estimated median terminal elimination half-life was 23 days (range, 9 to 49 days). Rituximab mean clearance and volume of distribution were 0. 312 L/day (range, 0.115 to 0.728 L/day) and 4.50 L (range, 2.21 to 7.52 L) respectively. Male patients and patients with higher BSA or positive HACA levels have higher clearance. However, further dose adjustment based on gender or HACA status is not necessary. The pharmacokinetics of rituximab have not been studied in children and adolescents. No formal studies were conducted to examine the effects of either renal or hepatic impairment on the pharmacokinetics of rituximab. ## Nonclinical Toxicology ## Carcinogenesis, Mutagenesis, Impairment of Fertility No long-term animal studies have been performed to establish the carcinogenic or mutagenic potential of Rituximab or to determine potential effects on fertility in males or females. ## Animal Toxicology and/or Pharmacology Reproductive Toxicology Studies An embryo-fetal developmental toxicity study was performed on pregnant cynomolgus monkeys. Pregnant animals received rituximab via the intravenous route during early gestation (organogenesis period; post-coitum days 20 through 50). Rituximab was administered as loading doses on post-coitum (PC) days 20, 21 and 22, at 15, 37.5 or 75 mg/kg/day, and then weekly on PC Days 29, 36, 43 and 50, at 20, 50 or 100 mg/kg/week. The 100 mg/kg/week dose resulted in 80% of the exposure (based on AUC) of those achieved following a dose of 2 grams in humans. Rituximab crosses the monkey placenta. Exposed offspring did not exhibit any teratogenic effects but did have decreased lymphoid tissue B cells. A subsequent pre- and postnatal reproductive toxicity study in cynomolgus monkeys was completed to assess developmental effects including the recovery of B cells and immune function in infants exposed to rituximab in utero. Animals were treated with a loading dose of 0, 15, or 75 mg/kg every day for 3 days, followed by weekly dosing with 0, 20, or 100 mg/kg dose. Subsets of pregnant females were treated from PC Day 20 through postpartum Day 78, PC Day 76 through PC Day 134, and from PC Day 132 through delivery and postpartum Day 28. Regardless of the timing of treatment, decreased B cells and immunosuppression were noted in the offspring of rituximab-treated pregnant animals. The B-cell counts returned to normal levels, and immunologic function was restored within 6 months postpartum. # Clinical Studies ## Relapsed or Refractory, Low-Grade or Follicular, CD20-Positive, B-Cell NHL The safety and effectiveness of Rituximab in relapsed, refractory CD20+ NHL were demonstrated in 3 single-arm studies enrolling 296 patients. Study 1 A multicenter, open-label, single-arm study was conducted in 166 patients with relapsed or refractory, low-grade or follicular, B-cell NHL who received 375 mg/m2 of Rituximab given as an intravenous infusion weekly for 4 doses. Patients with tumor masses > 10 cm or with > 5000 lymphocytes/µL in the peripheral blood were excluded from the study. Results are summarized in Table 4. The median time to onset of response was 50 days. Disease-related signs and symptoms (including B-symptoms) resolved in 64% (25/39) of those patients with such symptoms at study entry. Study 2 In a multicenter, single-arm study, 37 patients with relapsed or refractory, low-grade NHL received 375 mg/m2 of Rituximab weekly for 8 doses. Results are summarized in Table 4. Study 3 In a multicenter, single-arm study, 60 patients received 375 mg/m2 of Rituximab weekly for 4 doses. All patients had relapsed or refractory, low-grade or follicular, B-cell NHL and had achieved an objective clinical response to Rituximab administered 3.8–35.6 months (median 14.5 months) prior to retreatment with Rituximab. Of these 60 patients, 5 received more than one additional course of Rituximab. Results are summarized in Table 4. Bulky Disease In pooled data from studies 1 and 3, 39 patients with bulky (single lesion > 10 cm in diameter) and relapsed or refractory, low-grade NHL received Rituximab 375 mg/m2 weekly for 4 doses. Results are summarized in Table 4. ## Previously Untreated, Low-Grade or Follicular, CD20-Positive, B-Cell NHL The safety and effectiveness of Rituximab in previously untreated, low-grade or follicular, CD20+ NHL were demonstrated in 3 randomized, controlled trials enrolling 1,662 patients. Study 4 A total of 322 patients with previously untreated follicular NHL were randomized (1:1) to receive up to eight 3-week cycles of CVP chemotherapy alone (CVP) or in combination with Rituximab 375 mg/m2 on Day 1 of each cycle (R-CVP) in an open-label, multicenter study. The main outcome measure of the study was progression-free survival (PFS) defined as the time from randomization to the first of progression, relapse, or death. Twenty-six percent of the study population was >60 years of age, 99% had Stage III or IV disease, and 50% had an International Prognostic Index (IPI) score ≥2. The results for PFS as determined by a blinded, independent assessment of progression are presented in Table 5. The point estimates may be influenced by the presence of informative censoring. The PFS results based on investigator assessment of progression were similar to those obtained by the independent review assessment. Study 5 An open-label, multicenter, randomized (1:1) study was conducted in 1,018 patients with previously untreated follicular NHL who achieved a response (CR or PR) to Rituximab in combination with chemotherapy. Patients were randomized to Rituximab as single-agent maintenance therapy, 375 mg/m2 every 8 weeks for up to 12 doses or to observation. Rituximab was initiated at 8 weeks following completion of chemotherapy. The main outcome measure of the study was progression-free survival (PFS), defined as the time from randomization in the maintenance/observation phase to progression, relapse, or death, as determined by independent review. Of the randomized patients, 40% were ≥ 60 years of age, 70% had Stage IV disease, 96% had ECOG performance status (PS) 0–1, and 42% had FLIPI scores of 3–5. Prior to randomization to maintenance therapy, patients had received R-CHOP (75%), R-CVP (22%), or R-FCM (3%); 71% had a complete or unconfirmed complete response and 28% had a partial response. PFS was longer in patients randomized to Rituximab as single agent maintenance therapy (HR: 0.54, 95% CI: 0.42, 0.70). The PFS results based on investigator assessment of progression were similar to those obtained by the independent review assessment. Study 6 A total of 322 patients with previously untreated low-grade, B-cell NHL who did not progress after 6 or 8 cycles of \|CVP chemotherapy]] were enrolled in an open-label, multicenter, randomized trial. Patients were randomized (1:1) to receive Rituximab, 375 mg/m2 intravenous infusion, once weekly for 4 doses every 6 months for up to 16 doses or no further therapeutic intervention. The main outcome measure of the study was progression-free survival defined as the time from randomization to progression, relapse, or death. Thirty-seven percent of the study population was >60 years of age, 99% had Stage III or IV disease, and 63% had an IPI score ≥2. There was a reduction in the risk of progression, relapse, or death (hazard ratio estimate in the range of 0.36 to 0.49) for patients randomized to Rituximab as compared to those who received no additional treatment. ## Diffuse Large B-Cell NHL (DLBCL) The safety and effectiveness of Rituximab were evaluated in three randomized, active-controlled, open-label, multicenter studies with a collective enrollment of 1854 patients. Patients with previously untreated diffuse large B-cell NHL received Rituximab in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or other anthracycline-based chemotherapy regimens. Study 7 A total of 632 patients age ≥ 60 years with DLBCL (including primary mediastinal B-cell lymphoma) were randomized in a 1:1 ratio to treatment with CHOP or R-CHOP. Patients received 6 or 8 cycles of CHOP, each cycle lasting 21 days. All patients in the R-CHOP arm received 4 doses of Rituximab 375 mg/m2 on Days –7 and –3 (prior to Cycle 1) and 48–72 hours prior to Cycles 3 and 5. Patients who received 8 cycles of CHOP also received Rituximab prior to Cycle 7. The main outcome measure of the study was progression-free survival, defined as the time from randomization to the first of progression, relapse, or death. Responding patients underwent a second randomization to receive Rituximab or no further therapy. Among all enrolled patients, 62% had centrally confirmed DLBCL histology, 73% had Stage III–IV disease, 56% had IPI scores ≥ 2, 86% had ECOG performance status of < 2, 57% had elevated LDH levels, and 30% had two or more extranodal disease sites involved. Efficacy results are presented in Table 6. These results reflect a statistical approach which allows for an evaluation of Rituximab administered in the induction setting that excludes any potential impact of Rituximab given after the second randomization. Analysis of results after the second randomization in Study 7 demonstrates that for patients randomized to R-CHOP, additional Rituximab exposure beyond induction was not associated with further improvements in progression-free survival or overall survival. Study 8 A total of 399 patients with DLBCL, age ≥ 60 years, were randomized in a 1:1 ratio to receive CHOP or R-CHOP. All patients received up to eight 3-week cycles of CHOP induction; patients in the R-CHOP arm received Rituximab 375 mg/m2 on Day 1 of each cycle. The main outcome measure of the study was event-free survival, defined as the time from randomization to relapse, progression, change in therapy, or death from any cause. Among all enrolled patients, 80% had Stage III or IV disease, 60% of patients had an age-adjusted IPI ≥ 2, 80% had ECOG performance status scores < 2, 66% had elevated LDH levels, and 52% had extranodal involvement in at least two sites. Efficacy results are presented in Table 6. Study 9 A total of 823 patients with DLBCL, aged 18–60 years, were randomized in a 1:1 ratio to receive an anthracycline-containing chemotherapy regimen alone or in combination with Rituximab. The main outcome measure of the study was time to treatment failure, defined as time from randomization to the earliest of progressive disease, failure to achieve a complete response, relapse, or death. Among all enrolled patients, 28% had Stage III–IV disease, 100% had IPI scores of ≤ 1, 99% had ECOG performance status of < 2, 29% had elevated LDH levels, 49% had bulky disease, and 34% had extranodal involvement. Efficacy results are presented in Table 6. In Study 8, overall survival estimates at 5 years were 58% vs. 46% for R-CHOP and CHOP, respectively. ## Ninety-Minute Infusions in Previously Untreated Follicular NHL and DLBCL In Study 10, a total of 363 patients with previously untreated follicular NHL (n=113) or DLBCL (n=250) were evaluated in a prospective, open-label, multi-center, single-arm trial for the safety of 90-minute rituximab infusions. Patients with follicular NHL received rituximab 375 mg/m2 plus CVP chemotherapy. Patients with DLBCL received rituximab 375 mg/m2 plus CHOP chemotherapy. Patients with clinically significant cardiovascular disease were excluded from the study. Patients were eligible for a 90-minute infusion at Cycle 2 if they did not experience a Grade 3-4 infusion-related adverse event with Cycle 1 and had a circulating lymphocyte count ≤ 5000/mm3 before Cycle 2. All patients were pre-medicated with acetaminophen and an antihistamine and received the glucocorticoid component of their chemotherapy prior to Rituximab infusion. The main outcome measure was the development of Grade 3-4 infusion-related reactions on the day of, or day after, the 90-minute infusion at Cycle 2. Eligible patients received their Cycle 2 rituximab infusion over 90 minutes as follows: 20% of the total dose given in the first 30 minutes and the remaining 80% of the total dose given over the next 60 minutes. Patients who tolerated the 90-minute rituximab infusion at Cycle 2 continued to receive subsequent rituximab infusions at the 90-minute infusion rate for the remainder of the treatment regimen (through Cycle 6 or Cycle 8). The incidence of Grade 3-4 infusion-related reactions at Cycle 2 was 1.1% (95% CI ) among all patients, 3.5% (95% CI ) for those patients treated with R-CVP, and 0.0% (95% CI ) for those patients treated with R-CHOP. For Cycles 2-8, the incidence of Grade 3-4 infusion-related reactions was 2.8% (95% CI ). No acute fatal infusion related reactions were observed. ## Chronic Lymphocytic Leukemia (CLL) The safety and effectiveness of Rituximab were evaluated in two randomized (1:1) multicenter open-label studies comparing FC alone or in combination with Rituximab for up to 6 cycles in patients with previously untreated CLL or previously treated CLL . Patients received fludarabine 25 mg/m2/day and cyclophosphamide 250 mg/m2/day on days 1, 2 and 3 of each cycle, with or without Rituximab. In both studies, seventy-one percent of CLL patients received 6 cycles and 90% received at least 3 cycles of Rituximab-based therapy. In Study 11, 30% of patients were 65 years or older, 31% were Binet stage C, 45% had B symptoms, more than 99% had ECOG performance status (PS) 0–1, 74% were male, and 100% were White. In Study 12, 44% of patients were 65 years or older, 28% had B symptoms, 82% received a prior alkylating drug, 18% received prior fludarabine, 100% had ECOG PS 0–1, 67% were male and 98% were White. The main outcome measure in both studies was progression-free survival (PFS), defined as the time from randomization to progression, relapse, or death, as determined by investigators (Study 11) or an independent review committee (Study 12). The investigator assessed results in Study 12 were supportive of those obtained by the independent review committee. Efficacy results are presented in Table 7. Across both studies, 243 of 676 Rituximab-treated patients (36%) were 65 years of age or older and 100 Rituximab-treated patients (15%) were 70 years of age or older. The results of exploratory subset analyses in elderly patients are presented in Table 8. ## Rheumatoid Arthritis (RA) Reducing the Signs and Symptoms: Initial and Re-Treatment Courses The efficacy and safety of Rituximab were evaluated in two randomized, double-blind, placebo-controlled studies of adult patients with moderately to severely active RA who had a prior inadequate response to at least one TNF inhibitor. Patients were 18 years of age or older, diagnosed with active RA according to American College of Rheumatology (ACR) criteria, and had at least 8 swollen and 8 tender joints. In RA Study 1, patients were randomized to receive either Rituximab 2 × 1000 mg + MTX or placebo + MTX for 24 weeks. Further courses of Rituximab 2 × 1000 mg + MTX were administered in an open label extension study at a frequency determined by clinical evaluation, but no sooner than 16 weeks after the preceding course of Rituximab. In addition to the intravenous premedication, glucocorticoids were administered orally on a tapering schedule from baseline through Day 14. The proportions of patients achieving ACR 20, 50, and 70 responses at Week 24 of the placebo-controlled period are shown in Table 9. In RA Study 2, all patients received the first course of Rituximab 2 × 1000 mg + MTX. Patients who experienced ongoing disease activity were randomized to receive a second course of either Rituximab 2 × 1000 mg + MTX or placebo + MTX, the majority between Weeks 24–28. The proportions of patients achieving ACR 20, 50, and 70 responses at Week 24, before the re-treatment course, and at Week 48, after retreatment, are shown in Table 9. Improvement was also noted for all components of ACR response following treatment with Rituximab, as shown in Table 10. The time course of ACR 20 response for Study 1 is shown in Figure 2. Although both treatment groups received a brief course of intravenous and oral glucocorticoids, resulting in similar benefits at Week 4, higher ACR 20 responses were observed for the Rituximab group by Week 8. A similar proportion of patients achieved these responses through Week 24 after a single course of treatment (2 infusions) with Rituximab. Similar patterns were demonstrated for ACR 50 and 70 responses. Radiographic Response In RA Study 1, structural joint damage was assessed radiographically and expressed as changes in Genant-modified Total Sharp Score (TSS) and its components, the erosion score (ES) and the joint space narrowing (JSN) score. Rituximab + MTX slowed the progression of structural damage compared to placebo + MTX after 1 year as shown in Table 11. In RA Study 1 and its open-label extension, 70% of patients initially randomized to Rituximab + MTX and 72% of patients initially randomized to placebo + MTX were evaluated radiographically at Year 2. As shown in Table 11, progression of structural damage in Rituximab + MTX patients was further reduced in the second year of treatment. Following 2 years of treatment with Rituximab + MTX, 57% of patients had no progression of structural damage. During the first year, 60% of Rituximab + MTX treated patients had no progression, defined as a change in TSS of zero or less compared to baseline, compared to 46% of placebo + MTX treated patients. In their second year of treatment with Rituximab + MTX, more patients had no progression than in the first year (68% vs. 60%), and 87% of the Rituximab + MTX treated patients who had no progression in the first year also had no progression in the second year. Lesser Efficacy of 500 Vs. 1000 mg Treatment Courses for Radiographic Outcomes RA Study 3 is a randomized, double-blind, placebo-controlled study which evaluated the effect of placebo + MTX compared to Rituximab 2 × 500 mg + MTX and Rituximab 2 × 1000 mg + MTX treatment courses in MTX-naïve RA patients with moderately to severely active disease. Patients received a first course of two infusions of rituximab or placebo on Days 1 and 15. MTX was initiated at 7.5 mg/week and escalated up to 20 mg/week by Week 8 in all three treatment arms. After a minimum of 24 weeks, patients with ongoing disease activity were eligible to receive re-treatment with additional courses of their assigned treatment. After one year of treatment, the proportion of patients achieving ACR 20/50/70 responses were similar in both Rituximab dose groups and were higher than in the placebo group. However, with respect to radiographic scores, only the Rituximab 1000 mg treatment group demonstrated a statistically significant reduction in TSS: a change of 0.36 units compared to 1.08 units for the placebo group, a 67% reduction. Physical Function Response RA Study 4 is a randomized, double-blind, placebo-controlled study in adult RA patients with moderately to severely active disease with inadequate response to MTX. Patients were randomized to receive an initial course of Rituximab 500 mg, Rituximab 1000 mg, or placebo in addition to background MTX. Physical function was assessed at Weeks 24 and 48 using the Health Assessment Questionnaire Disability Index (HAQ-DI). From baseline to Week 24, a greater proportion of Rituximab-treated patients had an improvement in HAQ-DI of at least 0.22 (a minimal clinically important difference) and a greater mean HAQ-DI improvement compared to placebo, as shown in Table 12. HAQ-DI results for the Rituximab 500 mg treatment group were similar to the Rituximab 1000 mg treatment group; however radiographic responses were not assessed (see Dosing Precaution in the Radiographic Responses section above). These improvements were maintained at 48 weeks. ## Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis) and Microscopic Polyangiitis (MPA) A total of 197 patients with active, severe GPA and MPA (two forms of ANCA Associated Vasculidities) were treated in a randomized, double-blind, active-controlled multicenter, non-inferiority study, conducted in two phases – a 6 month remission induction phase and a 12 month remission maintenance phase. Patients were 15 years of age or older, diagnosed with GPA (75% of patients) or MPA (24% of patients) according to the Chapel Hill Consensus conference criteria (1% of the patients had unknown vasculitis type). All patients had active disease, with a Birmingham Vasculitis Activity Score for Granulomatosis with Polyangiitis (BVAS/GPA) ≥ 3, and their disease was severe, with at least one major item on the BVAS/GPA. Ninety-six (49%) of patients had new disease and 101 (51%) of patients had relapsing disease. Patients in both arms received 1000 mg of pulse intravenous methylprednisolone per day for 1 to 3 days within 14 days prior to initial infusion. Patients were randomized in a 1:1 ratio to receive either Rituximab 375 mg/m2 once weekly for 4 weeks or oral cyclophosphamide 2 mg/kg daily for 3 to 6 months in the remission induction phase. Patients were pre-medicated with antihistamine and acetaminophen prior to Rituximab infusion. Following intravenous corticosteroid administration, all patients received oral prednisone (1 mg/kg/day, not exceeding 80 mg/day) with pre-specified tapering. Once remission was achieved or at the end of the 6 month remission induction period, the cyclophosphamide group received azathioprine to maintain remission. The Rituximab group did not receive additional therapy to maintain remission. The main outcome measure for both GPA and MPA patients was achievement of complete remission at 6 months defined as a BVAS/GPA of 0, and off glucocorticoid therapy. The pre-specified non-inferiority margin was a treatment difference of 20%. As shown in Table 13, the study demonstrated non-inferiority of Rituximab to cyclophosphamide for complete remission at 6 months. Complete Remission (CR) at 12 and 18 months In the Rituximab group, 44% of patients achieved CR at 6 and 12 months, and 38% of patients achieved CR at 6, 12, and 18 months. In patients treated with cyclophosphamide (followed by azathioprine for maintenance of CR), 38% of patients achieved CR at 6 and 12 months, and 31% of patients achieved CR at 6, 12, and 18 months. Retreatment with Rituximab Based upon investigator judgment, 15 patients received a second course of Rituximab therapy for treatment of relapse of disease activity which occurred between 8 and 17 months after the first course of Rituximab. The limited data preclude any conclusions regarding the efficacy of subsequent courses of Rituximab in patients with GPA and MPA. # How Supplied Rituximab vials are stable at 2°C–8°C (36°F–46°F). Do not use beyond expiration date stamped on carton. Rituximab vials should be protected from direct sunlight. Do not freeze or shake. ## Storage Rituximab solutions for infusion may be stored at 2°C–8°C (36°F–46°F) for 24 hours. Rituximab solutions for infusion have been shown to be stable for an additional 24 hours at room temperature. However, since Rituximab solutions do not contain a preservative, diluted solutions should be stored refrigerated (2°C–8°C). No incompatibilities between Rituximab and polyvinylchloride or polyethylene bags have been observed. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Patients should be provided the Rituximab Medication Guide and provided an opportunity to read prior to each treatment session. It is important that the patient's overall health be assessed at each visit and the risks of Rituximab therapy and any questions resulting from the patient's reading of the Medication Guide be discussed. See FDA approved patient labeling (Medication Guide). Rituximab is detectable in serum for up to six months following completion of therapy. Individuals of childbearing potential should use effective contraception during treatment and for 12 months after Rituximab therapy. # Precautions with Alcohol Alcohol-Rituximab 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 Rituximab Brand Names in the drug label. # Look-Alike Drug Names There is limited information regarding Rituximab Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Rituximab Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, M.D. [2]; Aparna Vuppala, M.B.B.S. [3] # 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 Rituximab is a monoclonal antibody that is FDA approved for the treatment of non–hodgkin's lymphoma (nhl), chronic lymphocytic leukemia (CLL), rheumatoid arthritis (RA), granulomatosis with polyangiitis (GPA) (wegener's granulomatosis) and microscopic polyangiitis (MPA),. There is a Black Box Warning for this drug as shown here. Common adverse reactions include hypotension, peripheral edema, night sweats, pruritus, rash, abdominal pain, diarrhea, nausea, vomiting, anemia, arthralgia, backache, myalgia, asthenia, dizziness, headache, sensory neuropathy, increasing frequency of cough, rhinitis, fever, infectious disease, pain, shivering. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Non-Hodgkin's Lymphoma (NHL) - Dosing information - Relapsed or Refractory, Low-Grade or Follicular, CD20-Positive, B-Cell NHL - Administer once weekly for 4 or 8 doses. - Retreatment for Relapsed or Refractory, Low-Grade or Follicular, CD20-Positive, B-Cell NHL - Administer once weekly for 4 doses. - Previously Untreated, Follicular, CD20-Positive, B-Cell NHL - Administer on Day 1 of each cycle of chemotherapy, for up to 8 doses. In patients with complete or partial response, initiate Rituximab maintenance eight weeks following completion of Rituximab in combination with chemotherapy. Administer Rituximab as a single-agent every 8 weeks for 12 doses. - Non-progressing, Low-Grade, CD20-Positive, B-cell NHL, after first-line CVP chemotherapy - Following completion of 6–8 cycles of CVP chemotherapy, administer once weekly for 4 doses at 6-month intervals to a maximum of 16 doses. - Diffuse Large B-Cell NHL - Administer on Day 1 of each cycle of chemotherapy for up to 8 infusions. ### Chronic Lymphocytic Leukemia (CLL) - Dosing information - Recommended dosage: - 375 mg/m2 the day prior to the initiation of FC chemotherapy - 500 mg/m2 on Day 1 of cycles 2–6 (every 28 days). ### Recommended Dose as a Component of Zevalin® - Dosing information - Infuse rituximab 250 mg/m2 within 4 hours prior to the administration of Indium-111-(In-111-) Zevalin and within 4 hours prior to the administration of Yttrium-90- (Y-90-) Zevalin. - Administer Rituximab and In-111-Zevalin 7–9 days prior to Rituximab and Y-90- Zevalin. - Refer to the Zevalin package insert for full prescribing information regarding the Zevalin therapeutic regimen. ### Recommended Dose for Rheumatoid Arthritis (RA) - Dosing information - Administer Rituximab as two-1000 mg intravenous infusions separated by 2 weeks. - Glucocorticoids administered as methylprednisolone 100 mg intravenous or its equivalent 30 minutes prior to each infusion are recommended to reduce the incidence and severity of infusion reactions. - Subsequent courses should be administered every 24 weeks or based on clinical evaluation, but not sooner than every 16 weeks. - Rituximab is given in combination with methotrexate. ### Recommended Dose for Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis) and Microscopic Polyangiitis (MPA) - Dosing information - Administer Rituximab as a 375 mg/m2 intravenous infusion once weekly for 4 weeks. - Glucocorticoids administered as methylprednisolone 1000 mg intravenously per day for 1 to 3 days followed by oral prednisone 1 mg/kg/day (not to exceed 80 mg/day and tapered per clinical need) are recommended to treat severe vasculitis symptoms. This regimen should begin within 14 days prior to or with the initiation of Rituximab and may continue during and after the 4 week course of Rituximab treatment. - Safety and efficacy of treatment with subsequent courses of Rituximab have not been established ### Recommended Concomitant Medications - Dosing information - Premedicate before each infusion with acetaminophen and an antihistamine. For patients administered Rituximab according to the 90-minute infusion rate, the glucocorticoid component of their chemotherapy regimen should be administered prior to infusion - For RA patients, methylprednisolone 100 mg intravenously or its equivalent is recommended 30 minutes prior to each infusion. - For GPA and MPA patients, glucocorticoids are given in combination with Rituximab - Pneumocystis jiroveci pneumonia (PCP) and anti-herpetic viral prophylaxis is recommended for patients with CLL during treatment and for up to 12 months following treatment as appropriate. - PCP prophylaxis is also recommended for patients with GPA and MPA during treatment and for at least 6 months following the last Rituximab infusion. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Rituximab in adult patients. ### Non–Guideline-Supported Use ### Acquired factor VIII deficiency disease - Dosing information - 375 mg/m(2) given once weekly[1] [2] [3] ### Autoimmune hemolytic anemia - Dosing information - 375 mg/m(2) IV weekly for 4 consecutive weeks[4], [5] ### B-cell lymphoma - Dosing information - 375 mg/m(2) [6], [7] ### Evans syndrome - Dosing information - 375 mg/m(2) weekly for 2 doses[8] ### Graft-versus-host disease - Dosing information - 375 mg/m(2) IV weekly for 4 consecutive weeks[9], [10] ### Hairy cell leukemia - Dosing information - 375 mg/m(2) per week[11] ### Hodgkin's disease - Dosing information - 375 mg/m(2) IV once weekly for 4 weeks [12], [13] ### Idiopathic thrombocytopenic purpura - Dosing information - 375 mg/m(2) once a week for 4 weeks [14] ### Mantle cell lymphoma - Dosing information - 375 mg/m(2) on day 0) every 3 weeks for 6 cycles15668467 - 375 mg/m(2) IV was administered on the first day of cycles 4 and 5 and on the first and ninth day of cycle 6 [15] ### Pemphigus vulgaris - Dosing information - 375 mg/m(2) IV once weekly for a 4-week cycle[16] ### Post-transplant lymphoproliferative disorder - Dosing information - 375 mg/m(2) IV once weekly for 4 weeks[17] - 375 mg/m(2) weekly for 4 weeks every 6 months [18] ### # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Rituximab 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 Rituximab in pediatric patients. ### Non–Guideline-Supported Use ### Autoimmune hemolytic anemia - Dosing information - 375 mg/m(2)[19], [20] ### Post-transplant lymphoproliferative disorder - Dosing information - 375 mg/m(2) IV once weekly for 4 to 8 cycles[21] # Contraindications None. # Warnings ## Infusion Reactions Rituximab can cause severe, including fatal, infusion reactions. Severe reactions typically occurred during the first infusion with time to onset of 30–120 minutes. Rituximab-induced infusion reactions and sequelae include urticaria, hypotension, angioedema, hypoxia, bronchospasm, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, cardiogenic shock, anaphylactoid events, or death. Premedicate patients with an antihistamine and acetaminophen prior to dosing. For RA patients, methylprednisolone 100 mg intravenously or its equivalent is recommended 30 minutes prior to each infusion. Institute medical management (e.g. glucocorticoids, epinephrine, bronchodilators, or oxygen) for infusion reactions as needed. Depending on the severity of the infusion reaction and the required interventions, temporarily or permanently discontinue Rituximab. Resume infusion at a minimum 50% reduction in rate after symptoms have resolved. Closely monitor the following patients: those with pre-existing cardiac or pulmonary conditions, those who experienced prior cardiopulmonary adverse reactions, and those with high numbers of circulating malignant cells ( ≥ 25,000/mm3). ## Severe Mucocutaneous Reactions Mucocutaneous reactions, some with fatal outcome, can occur in patients treated with Rituximab. These reactions include paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis. The onset of these reactions has been variable and includes reports with onset on the first day of Rituximab exposure. Discontinue Rituximab in patients who experience a severe mucocutaneous reaction. The safety of readministration of Rituximab to patients with severe mucocutaneous reactions has not been determined. ## Hepatitis B Virus Reactivation Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, can occur in patients treated with drugs classified as CD20-directed cytolytic antibodies, including Rituximab. Cases have been reported in patients who are hepatitis B surface antigen (HBsAg) positive and also in patients who are HBsAg negative but are hepatitis B core antibody (anti-HBc) positive. Reactivation also has occurred in patients who appear to have resolved hepatitis B infection (i.e., HBsAg negative, anti-HBc positive and hepatitis B surface antibody [ anti-HBs ] positive). HBV reactivation is defined as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level or detection of HBsAg in a person who was previously HBsAg negative and anti-HBc positive. Reactivation of HBV replication is often followed by hepatitis, i.e., increase in transaminase levels. In severe cases increase in bilirubin levels, liver failure, and death can occur. Screen all patients for HBV infection by measuring HBsAg and anti-HBc before initiating treatment with Rituximab. For patients who show evidence of prior hepatitis B infection (HBsAg positive [regardless of antibody status] or HBsAg negative but anti-HBc positive), consult with physicians with expertise in managing hepatitis B regarding monitoring and consideration for HBV antiviral therapy before and/or during Rituximab treatment. Monitor patients with evidence of current or prior HBV infection for clinical and laboratory signs of hepatitis or HBV reactivation during and for several months following Rituximab therapy. HBV reactivation has been reported up to 24 months following completion of Rituximab therapy. In patients who develop reactivation of HBV while on Rituximab, immediately discontinue Rituximab and any concomitant chemotherapy, and institute appropriate treatment. Insufficient data exist regarding the safety of resuming Rituximab in patients who develop HBV reactivation. Resumption of Rituximab in patients whose HBV reactivation resolves should be discussed with physicians with expertise in managing hepatitis B. ## Progressive Multifocal Leukoencephalopathy (PML) JC virus infection resulting in PML and death can occur in Rituximab-treated patients with hematologic malignancies or with autoimmune diseases. The majority of patients with hematologic malignancies diagnosed with PML received Rituximab in combination with chemotherapy or as part of a hematopoietic stem cell transplant. The patients with autoimmune diseases had prior or concurrent immunosuppressive therapy. Most cases of PML were diagnosed within 12 months of their last infusion of Rituximab. Consider the diagnosis of PML in any patient presenting with new-onset neurologic manifestations. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture. Discontinue Rituximab and consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML. ## Tumor Lysis Syndrome (TLS) Acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, or hyperphosphatemia from tumor lysis, some fatal, can occur within 12–24 hours after the first infusion of Rituximab in patients with NHL. A high number of circulating malignant cells ( ≥ 25,000/mm3) or high tumor burden, confers a greater risk of TLS. Administer aggressive intravenous hydration and anti-hyperuricemic therapy in patients at high risk for TLS. Correct electrolyte abnormalities, monitor renal function and fluid balance, and administer supportive care, including dialysis as indicated. ## Infections Serious, including fatal, bacterial, fungal, and new or reactivated viral infections can occur during and following the completion of Rituximab-based therapy. Infections have been reported in some patients with prolonged hypogammaglobulinemia (defined as hypogammaglobulinemia >11 months after rituximab exposure). New or reactivated viral infections included cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus, West Nile virus, and hepatitis B and C. Discontinue Rituximab for serious infections and institute appropriate anti-infective therapy. ## Cardiovascular Discontinue infusions for serious or life-threatening cardiac arrhythmias. Perform cardiac monitoring during and after all infusions of Rituximab for patients who develop clinically significant arrhythmias, or who have a history of arrhythmia or angina. ## Renal Severe, including fatal, renal toxicity can occur after Rituximab administration in patients with NHL. Renal toxicity has occurred in patients who experience tumor lysis syndrome and in patients with NHL administered concomitant cisplatin therapy during clinical trials. The combination of cisplatin and Rituximab is not an approved treatment regimen. Monitor closely for signs of renal failure and discontinue Rituximab in patients with a rising serum creatinine or oliguria. ## Bowel Obstruction and Perforation Abdominal pain, bowel obstruction and perforation, in some cases leading to death, can occur in patients receiving Rituximab in combination with chemotherapy. In postmarketing reports, the mean time to documented gastrointestinal perforation was 6 (range 1–77) days in patients with NHL. Evaluate if symptoms of obstruction such as abdominal pain or repeated vomiting occur. ## Immunization The safety of immunization with live viral vaccines following Rituximab therapy has not been studied and vaccination with live virus vaccines is not recommended. For RA patients, physicians should follow current immunization guidelines and administer non-live vaccines at least 4 weeks prior to a course of Rituximab. The effect of Rituximab on immune responses was assessed in a randomized, controlled study in patients with RA treated with Rituximab and methotrexate (MTX) compared to patients treated with MTX alone. A response to pneumococcal vaccination (a T-cell independent antigen) as measured by an increase in antibody titers to at least 6 of 12 serotypes was lower in patients treated with Rituximab plus MTX as compared to patients treated with MTX alone (19% vs. 61%). A lower proportion of patients in the Rituximab plus MTX group developed detectable levels of anti-keyhole limpet hemocyanin antibodies (a novel protein antigen) after vaccination compared to patients on MTX alone (47% vs. 93%). A positive response to tetanus toxoid vaccine (a T-cell dependent antigen with existing immunity) was similar in patients treated with Rituximab plus MTX compared to patients on MTX alone (39% vs. 42%). The proportion of patients maintaining a positive Candida skin test (to evaluate delayed type hypersensitivity) was also similar (77% of patients on Rituximab plus MTX vs. 70% of patients on MTX alone). Most patients in the Rituximab-treated group had B-cell counts below the lower limit of normal at the time of immunization. The clinical implications of these findings are not known. ## Laboratory Monitoring In patients with lymphoid malignancies, during treatment with Rituximab monotherapy, obtain complete blood counts (CBC) and platelet counts prior to each Rituximab course. During treatment with Rituximab and chemotherapy, obtain CBC and platelet counts at weekly to monthly intervals and more frequently in patients who develop cytopenias . In patients with RA, GPA or MPA, obtain CBC and platelet counts at two to four month intervals during Rituximab therapy. The duration of cytopenias caused by Rituximab can extend months beyond the treatment period. ## Concomitant Use with Biologic Agents and DMARDS other than Methotrexate in RA, GPA and MPA Limited data are available on the safety of the use of biologic agents or DMARDs other than methotrexate in RA patients exhibiting peripheral B-cell depletion following treatment with rituximab. Observe patients closely for signs of infection if biologic agents and/or DMARDs are used concomitantly. Use of concomitant immunosuppressants other than corticosteroids has not been studied in GPA or MPA patients exhibiting peripheral B-cell depletion following treatment with Rituximab. ## Use in RA Patients Who Have Not Had Prior Inadequate Response to Tumor Necrosis Factor (TNF) Antagonists While the efficacy of Rituximab was supported in four controlled trials in patients with RA with prior inadequate responses to non-biologic DMARDs, and in a controlled trial in MTX-naïve patients, a favorable risk-benefit relationship has not been established in these populations. The use of Rituximab in patients with RA who have not had prior inadequate response to one or more TNF antagonists is not recommended. ## Retreatment in Patients with Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis) and Microscopic Polyangiitis (MPA) Limited data are available on the safety and efficacy of subsequent courses of Rituximab in patients with GPA and MPA. The safety and efficacy of retreatment with Rituximab have not been established # Adverse Reactions ## Clinical Trials Experience The following serious adverse reactions are discussed in greater detail in other sections of the labeling: - Infusion reactions - Mucocutaneous reactions - Hepatitis B reactivation with fulminant hepatitis - Progressive multifocal leukoencephalopathy - Tumor lysis syndrome - Infections - Cardiac arrhythmias - Renal toxicity - Bowel obstruction and perforation The most common adverse reactions of Rituximab (incidence ≥ 25%) observed in clinical trials of patients with NHL were infusion reactions, fever, lymphopenia, chills, infection, and asthenia. The most common adverse reactions of Rituximab (incidence ≥ 25%) observed in clinical trials of patients with CLL were: infusion reactions and neutropenia. ## Clinical Trials Experience in Lymphoid Malignancies 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 data described below reflect exposure to Rituximab in 2783 patients, with exposures ranging from a single infusion up to 2 years. Rituximab was studied in both single-arm and controlled trials (n=356 and n=2427). The population included 1180 patients with low grade or follicular lymphoma, 927 patients with DLBCL, and 676 patients with CLL. Most NHL patients received Rituximab as an infusion of 375 mg/m2 per infusion, given as a single agent weekly for up to 8 doses, in combination with chemotherapy for up to 8 doses, or following chemotherapy for up to 16 doses. CLL patients received Rituximab 375 mg/m2 as an initial infusion followed by 500 mg/m2 for up to 5 doses, in combination with fludarabine and cyclophosphamide. Seventy-one percent of CLL patients received 6 cycles and 90% received at least 3 cycles of Rituximab-based therapy. Infusion Reactions In the majority of patients with NHL, infusion reactions consisting of fever, chills/rigors, nausea, pruritus, angioedema, hypotension, headache, bronchospasm, urticaria, rash, vomiting, myalgia, dizziness, or hypertension occurred during the first Rituximab infusion. Infusion reactions typically occurred within 30 to 120 minutes of beginning the first infusion and resolved with slowing or interruption of the Rituximab infusion and with supportive care (diphenhydramine, acetaminophen, and intravenous saline). The incidence of infusion reactions was highest during the first infusion (77%) and decreased with each subsequent infusion. In patients with previously untreated follicular NHL or previously untreated DLBCL, who did not experience a Grade 3 or 4 infusion-related reaction in Cycle 1 and received a 90-minute infusion of Rituximab at Cycle 2, the incidence of Grade 3-4 infusion-related reactions on the day of, or day after the infusion was 1.1% (95% CI [0.3%, 2.8%]). For Cycles 2-8, the incidence of Grade 3-4 infusion reactions on the day of or day after the 90-minute infusion, was 2.8% (95% CI [1.3%, 5.0%]). Infections Serious infections (NCI CTCAE Grade 3 or 4), including sepsis, occurred in less than 5% of patients with NHL in the single-arm studies. The overall incidence of infections was 31% (bacterial 19%, viral 10%, unknown 6%, and fungal 1%). In randomized, controlled studies where Rituximab was administered following chemotherapy for the treatment of follicular or low-grade NHL, the rate of infection was higher among patients who received Rituximab. In diffuse large B-cell lymphoma patients, viral infections occurred more frequently in those who received Rituximab. Cytopenias and hypogammaglobulinemia In patients with NHL receiving rituximab monotherapy, NCI-CTC Grade 3 and 4 cytopenias were reported in 48% of patients. These included lymphopenia (40%), neutropenia (6%), leukopenia (4%), anemia (3%), and thrombocytopenia (2%). The median duration of lymphopenia was 14 days (range, 1–588 days) and of neutropenia was 13 days (range, 2–116 days). A single occurrence of transient aplastic anemia (pure red cell aplasia) and two occurrences of hemolytic anemia following Rituximab therapy occurred during the single-arm studies. In studies of monotherapy, Rituximab-induced B-cell depletion occurred in 70% to 80% of patients with NHL. Decreased IgM and IgG serum levels occurred in 14% of these patients. In CLL trials, the frequency of prolonged neutropenia and late-onset neutropenia was higher in patients treated with R-FC compared to patients treated with FC. Prolonged neutropenia is defined as Grade 3-4 neutropenia that has not resolved between 24 and 42 days after the last dose of study treatment. Late-onset neutropenia is defined as Grade 3-4 neutropenia starting at least 42 days after the last treatment dose. In patients with previously untreated CLL, the frequency of prolonged neutropenia was 8.5% for patients who received R-FC (n=402) and 5.8% for patients who received FC (n=398). In patients who did not have prolonged neutropenia, the frequency of late-onset neutropenia was 14.8% of 209 patients who received R-FC and 4.3% of 230 patients who received FC. For patients with previously treated CLL, the frequency of prolonged neutropenia was 24.8% for patients who received R-FC (n=274) and 19.1% for patients who received FC (n=274). In patients who did not have prolonged neutropenia, the frequency of late-onset neutropenia was 38.7% in 160 patients who received R-FC and 13.6% of 147 patients who received FC. Relapsed or Refractory, Low-Grade NHL Adverse reactions in Table 1 occurred in 356 patients with relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL treated in single-arm studies of Rituximab administered as a single agent. Most patients received Rituximab 375 mg/m2 weekly for 4 doses. In these single-arm Rituximab studies, bronchiolitis obliterans occurred during and up to 6 months after Rituximab infusion. Previously Untreated, Low-Grade or Follicular, NHL In Study 4, patients in the R-CVP arm experienced a higher incidence of infusional toxicity and neutropenia compared to patients in the CVP arm. The following adverse reactions occurred more frequently ( ≥ 5%) in patients receiving R-CVP compared to CVP alone: rash (17% vs. 5%), cough (15% vs. 6%), flushing (14% vs. 3%), rigors (10% vs. 2%), pruritus (10% vs. 1%), neutropenia (8% vs. 3%), and chest tightness (7% vs. 1%). In Study 5, detailed safety data collection was limited to serious adverse reactions, Grade ≥ 2 infections, and Grade ≥ 3 adverse reactions. In patients receiving Rituximab as single-agent maintenance therapy following Rituximab plus chemotherapy, infections were reported more frequently compared to the observation arm (37% vs. 22%). Grade 3-4 adverse reactions occurring at a higher incidence (≥ 2%) in the Rituximab group were infections (4% vs. 1%) and neutropenia (4% vs. <1%). In Study 6, the following adverse reactions were reported more frequently ( ≥ 5%) in patients receiving Rituximab following CVP compared to patients who received no further therapy: fatigue (39% vs. 14%), anemia (35% vs. 20%), peripheral sensory neuropathy (30% vs. 18%), infections (19% vs. 9%), pulmonary toxicity (18% vs. 10%), hepato-biliary toxicity (17% vs. 7%), rash and/or pruritus (17% vs. 5%), arthralgia (12% vs. 3%), and weight gain (11% vs. 4%). Neutropenia was the only Grade 3 or 4 adverse reaction that occurred more frequently ( ≥ 2%) in the Rituximab arm compared with those who received no further therapy (4% vs. 1%). DLBCL In Studies 7 and 8, the following adverse reactions, regardless of severity, were reported more frequently ( ≥ 5%) in patients age ≥ 60 years receiving R-CHOP as compared to CHOP alone: pyrexia (56% vs. 46%), lung disorder (31% vs. 24%), cardiac disorder (29% vs. 21%), and chills (13% vs. 4%). Detailed safety data collection in these studies was primarily limited to Grade 3 and 4 adverse reactions and serious adverse reactions. In Study 8, a review of cardiac toxicity determined that supraventricular arrhythmias or tachycardia accounted for most of the difference in cardiac disorders (4.5% for R-CHOP vs. 1.0% for CHOP). The following Grade 3 or 4 adverse reactions occurred more frequently among patients in the R-CHOP arm compared with those in the CHOP arm: thrombocytopenia (9% vs. 7%) and lung disorder (6% vs. 3%). Other Grade 3 or 4 adverse reactions occurring more frequently among patients receiving R-CHOP were viral infection (Study 8), neutropenia (Studies 8 and 9), and anemia (Study 9). CLL The data below reflect exposure to Rituximab in combination with fludarabine and cyclophosphamide in 676 patients with CLL in Study 11 or Study 12. The age range was 30–83 years and 71% were men. Detailed safety data collection in Study 11 was limited to Grade 3 and 4 adverse reactions and serious adverse reactions. Infusion-related adverse reactions were defined by any of the following adverse events occurring during or within 24 hours of the start of infusion: nausea, pyrexia, chills, hypotension, vomiting, and dyspnea. In Study 11, the following Grade 3 and 4 adverse reactions occurred more frequently in R-FC-treated patients compared to FC-treated patients: infusion reactions (9% in R-FC arm), neutropenia (30% vs. 19%), febrile neutropenia (9% vs. 6%), leukopenia (23% vs. 12%), and pancytopenia (3% vs. 1%). In Study 12, the following Grade 3 or 4 adverse reactions occurred more frequently in R-FC-treated patients compared to FC-treated patients: infusion reactions (7% in R-FC arm), neutropenia (49% vs. 44%), febrile neutropenia (15% vs. 12%), thrombocytopenia (11% vs. 9%), hypotension (2% vs. 0%), and hepatitis B (2% vs. < 1%). Fifty-nine percent of R-FC-treated patients experienced an infusion reaction of any severity. ## Clinical Trials Experience in Rheumatoid Arthritis Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in 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 data presented below reflect the experience in 2578 RA patients treated with Rituximab in controlled and long-term studies with a total exposure of 5014 patient-years. Among all exposed patients, adverse reactions reported in greater than 10% of patients include infusion-related reactions, upper respiratory tract infection, nasopharyngitis, urinary tract infection, and bronchitis. In placebo-controlled studies, patients received 2 × 500 mg or 2 × 1000 mg intravenous infusions of Rituximab or placebo, in combination with methotrexate, during a 24-week period. From these studies, 938 patients treated with Rituximab (2 × 1000 mg) or placebo have been pooled (see Table 2). Adverse reactions reported in ≥ 5% of patients were hypertension, nausea, upper respiratory tract infection, arthralgia, pyrexia and pruritus (see Table 2). The rates and types of adverse reactions in patients who received Rituximab 2 × 500 mg were similar to those observed in patients who received Rituximab 2 × 1000 mg. Infusion Reactions In the Rituximab RA pooled placebo-controlled studies, 32% of Rituximab-treated patients experienced an adverse reaction during or within 24 hours following their first infusion, compared to 23% of placebo-treated patients receiving their first infusion. The incidence of adverse reactions during the 24-hour period following the second infusion, Rituximab or placebo, decreased to 11% and 13%, respectively. Acute infusion reactions (manifested by fever, chills, rigors, pruritus, urticaria/rash, angioedema, sneezing, throat irritation, cough, and/or bronchospasm, with or without associated hypotension or hypertension) were experienced by 27% of Rituximab-treated patients following their first infusion, compared to 19% of placebo-treated patients receiving their first placebo infusion. The incidence of these acute infusion reactions following the second infusion of Rituximab or placebo decreased to 9% and 11%, respectively. Serious acute infusion reactions were experienced by < 1% of patients in either treatment group. Acute infusion reactions required dose modification (stopping, slowing, or interruption of the infusion) in 10% and 2% of patients receiving rituximab or placebo, respectively, after the first course. The proportion of patients experiencing acute infusion reactions decreased with subsequent courses of Rituximab. The administration of intravenous glucocorticoids prior to Rituximab infusions reduced the incidence and severity of such reactions, however, there was no clear benefit from the administration of oral glucocorticoids for the prevention of acute infusion reactions. Patients in clinical studies also received antihistamines and acetaminophen prior to Rituximab infusions. Infections In the pooled, placebo-controlled studies, 39% of patients in the Rituximab group experienced an infection of any type compared to 34% of patients in the placebo group. The most common infections were nasopharyngitis, upper respiratory tract infections, urinary tract infections, bronchitis, and sinusitis. The incidence of serious infections was 2% in the Rituximab-treated patients and 1% in the placebo group. In the experience with Rituximab in 2578 RA patients, the rate of serious infections was 4.31 per 100 patient years. The most common serious infections ( ≥ 0.5%) were pneumonia or lower respiratory tract infections, cellulitis and urinary tract infections. Fatal serious infections included pneumonia, sepsis and colitis. Rates of serious infection remained stable in patients receiving subsequent courses. In 185 Rituximab-treated RA patients with active disease, subsequent treatment with a biologic DMARD, the majority of which were TNF antagonists, did not appear to increase the rate of serious infection. Thirteen serious infections were observed in 186.1 patient years (6.99 per 100 patient years) prior to exposure and 10 were observed in 182.3 patient years (5.49 per 100 patient years) after exposure. Cardiac Adverse Reactions In the pooled, placebo-controlled studies, the proportion of patients with serious cardiovascular reactions was 1.7% and 1.3% in the Rituximab and placebo treatment groups, respectively. Three cardiovascular deaths occurred during the double-blind period of the RA studies including all rituximab regimens (3/769 = 0.4%) as compared to none in the placebo treatment group (0/389). In the experience with Rituximab in 2578 RA patients, the rate of serious cardiac reactions was 1.93 per 100 patient years. The rate of myocardial infarction (MI) was 0.56 per 100 patient years (28 events in 26 patients), which is consistent with MI rates in the general RA population. These rates did not increase over three courses of Rituximab. Since patients with RA are at increased risk for cardiovascular events compared with the general population, patients with RA should be monitored throughout the infusion and Rituximab should be discontinued in the event of a serious or life-threatening cardiac event. Hypophosphatemia and hyperuricemia In the pooled, placebo-controlled studies, newly-occurring hypophosphatemia ( < 2.0 mg/dl) was observed in 12% (67/540) of patients on Rituximab versus 10% (39/398) of patients on placebo. Hypophosphatemia was more common in patients who received corticosteroids. Newly-occurring hyperuricemia (>10 mg/dl) was observed in 1.5% (8/540) of patients on Rituximab versus 0.3% (1/398) of patients on placebo. In the experience with Rituximab in RA patients, newly-occurring hypophosphatemia was observed in 21% (528/2570) of patients and newly-occurring hyperuricemia was observed in 2% (56/2570) of patients. The majority of the observed hypophosphatemia occurred at the time of the infusions and was transient. Retreatment in Patients with RA In the experience with Rituximab in RA patients, 2578 patients have been exposed to Rituximab and have received up to 10 courses of Rituximab in RA clinical trials, with 1890, 1043, and 425 patients having received at least two, three, and four courses, respectively. Most of the patients who received additional courses did so 24 weeks or more after the previous course and none were retreated sooner than 16 weeks. The rates and types of adverse reactions reported for subsequent courses of Rituximab were similar to rates and types seen for a single course of Rituximab. In RA Study 2, where all patients initially received Rituximab, the safety profile of patients who were retreated with Rituximab was similar to those who were retreated with placebo Clinical Trials Experience in Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis) and Microscopic Polyangiitis (MPA) Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in 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 data presented below reflect the experience in 197 patients with GPA and MPA treated with Rituximab or cyclophosphamide in a single controlled study, which was conducted in two phases: a 6 month randomized, double-blind, double-dummy, active-controlled remission induction phase and an additional 12 month remission maintenance phase. In the 6-month remission induction phase, 197 patients with GPA and MPA were randomized to either Rituximab 375 mg/ m2 once weekly for 4 weeks plus glucocorticoids, or oral cyclophosphamide 2 mg/kg daily (adjusted for renal function, white blood cell count, and other factors) plus glucocorticoids to induce remission. Once remission was achieved or at the end of the 6 month remission induction period, the cyclophosphamide group received azathioprine to maintain remission. The Rituximab group did not receive additional therapy to maintain remission. The primary analysis was at the end of the 6 month remission induction period and the safety results for this period are described below. Adverse reactions presented below in Table 3 were adverse events which occurred at a rate of greater than or equal to 10% in the Rituximab group. This table reflects experience in 99 GPA and MPA patients treated with Rituximab, with a total of 47.6 patient-years of observation and 98 GPA and MPA patients treated with cyclophosphamide, with a total of 47.0 patient-years of observation. Infection was the most common category of adverse events reported (47-62%) and is discussed below. Infusion Reactions Infusion-related reactions in the active-controlled, double-blind study were defined as any adverse event occurring within 24 hours of an infusion and considered to be infusion-related by investigators. Among the 99 patients treated with Rituximab, 12% experienced at least one infusion related reaction, compared with 11% of the 98 patients in the cyclophosphamide group. Infusion-related reactions included cytokine release syndrome, flushing, throat irritation, and tremor. In the Rituximab group, the proportion of patients experiencing an infusion related reaction was 12%, 5%, 4%, and 1% following the first, second, third, and fourth infusions, respectively. Patients were pre-medicated with antihistamine and acetaminophen before each Rituximab infusion and were on background oral corticosteroids which may have mitigated or masked an infusion reaction; however, there is insufficient evidence to determine whether premedication diminishes the frequency or severity of infusion reactions. Infections In the active-controlled, double-blind study, 62% (61/99) of patients in the Rituximab group experienced an infection of any type compared to 47% (46/98) patients in the cyclophosphamide group by Month 6. The most common infections in the Rituximab group were upper respiratory tract infections, urinary tract infections, and herpes zoster. The incidence of serious infections was 11% in the Rituximab-treated patients and 10% in the cyclophosphamide treated patients, with rates of approximately 25 and 28 per 100 patient-years, respectively. The most common serious infection was pneumonia. Hypogammaglobulinemia Hypogammaglobulinemia (IgA, IgG or IgM below the lower limit of normal) has been observed in patients with GPA and MPA treated with Rituximab. At 6 months, in the Rituximab group, 27%, 58% and 51% of patients with normal immunoglobulin levels at baseline, had low IgA, IgG and IgM levels, respectively compared to 25%, 50% and 46% in the cyclophosphamide group. Retreatment in Patients with GPA and MPA In the active-controlled, double-blind study, subsequent courses of Rituximab were allowed for patients experiencing a relapse of disease. The limited data preclude any conclusions regarding the safety of subsequent courses of Rituximab with GPA and MPA. ## Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. 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 Rituximab with the incidence of antibodies to other products may be misleading. Using an ELISA assay, anti-human anti-chimeric antibody (HACA) was detected in 4 of 356 (1.1%) patients with low-grade or follicular NHL receiving single-agent Rituximab. Three of the four patients had an objective clinical response. A total of 273/2578 (11%) patients with RA tested positive for HACA at any time after receiving Rituximab. HACA positivity was not associated with increased infusion reactions or other adverse reactions. Upon further treatment, the proportions of patients with infusion reactions were similar between HACA positive and negative patients, and most reactions were mild to moderate. Four HACA positive patients had serious infusion reactions, and the temporal relationship between HACA positivity and infusion reaction was variable. A total of 23/99 (23%) Rituximab-treated patients with GPA and MPA tested positive for HACA by 18 months. The clinical relevance of HACA formation in Rituximab-treated patients is unclear. ## Postmarketing Experience 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. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to Rituximab. - Hematologic: prolonged pancytopenia, marrow hypoplasia, Grade 3-4 prolonged or late-onset neutropenia, hyperviscosity syndrome in Waldenstrom's macroglobulinemia, prolonged hypogammaglobulinemia - Cardiac: fatal cardiac failure. - Immune/Autoimmune Events: uveitis, “[optic neuritis]], systemic vasculitis, pleuritis, lupus-like syndrome, serum sickness, polyarticular arthritis, and vasculitis with rash. - Infection: viral infections, including progressive multifocal leukoencephalopathy (PML), increase in fatal infections in HIV-associated lymphoma, and a reported increased incidence of Grade 3 and 4 infections - Neoplasia: disease progression of Kaposi's sarcoma. - Skin: severe mucocutaneous reactions. - Gastrointestinal: bowel obstruction and perforation. - Pulmonary: fatal bronchiolitis obliterans and fatal interstitial lung disease. - Nervous system: Posterior Reversible Encephalopathy Syndrome (PRES) /Reversible Posterior Leukoencephalopathy Syndrome (RPLS). # Drug Interactions Formal drug interaction studies have not been performed with Rituximab. In patients with CLL, Rituximab did not alter systemic exposure to fludarabine or cyclophosphamide. In clinical trials of patients with RA, concomitant administration of methotrexate or cyclophosphamide did not alter the pharmacokinetics of rituximab. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C There are no adequate and well-controlled studies of rituximab in pregnant women. Postmarketing data indicate that B-cell lymphocytopenia generally lasting less than six months can occur in infants exposed to rituximab in-utero. Rituximab was detected postnatally in the serum of infants exposed in-utero. Non-Hodgkin's lymphoma, moderate-severe rheumatoid arthritis, Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis) and Microscopic Polyangiitis are serious conditions that require treatment. Rituximab should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. Reproduction studies in cynomolgus monkeys at maternal exposures similar to human therapeutic exposures showed no evidence of teratogenic effects. However, B-cell lymphoid tissue was reduced in the offspring of treated dams. The B-cell counts returned to normal levels, and immunologic function was restored within 6 months of birth Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Rituximab in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Rituximab during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Rituximab in women who are nursing. ### Pediatric Use FDA has not required pediatric studies in polyarticular juvenile idiopathic arthritis (PJIA) patients ages 0 to 16 due to concerns regarding the potential for prolonged immunosuppression as a result of B-cell depletion in the developing juvenile immune system. Hypogammaglobulinemia has been observed in pediatric patients treated with Rituximab. The safety and effectiveness of Rituximab in pediatric patients have not been established. ### Geriatic Use Diffuse Large B-Cell NHL Among patients with DLBCL evaluated in three randomized, active-controlled trials, 927 patients received Rituximab in combination with chemotherapy. Of these, 396 (43%) were age 65 or greater and 123 (13%) were age 75 or greater. No overall differences in effectiveness were observed between these patients and younger patients. Cardiac adverse reactions, mostly supraventricular arrhythmias, occurred more frequently among elderly patients. Serious pulmonary adverse reactions were also more common among the elderly, including pneumonia and pneumonitis. Low-Grade or Follicular Non-Hodgkin's Lymphoma Patients with previously untreated follicular NHL evaluated in Study 5 were randomized to Rituximab as single-agent maintenance therapy (n=505) or observation (n=513) after achieving a response to Rituximab in combination with chemotherapy. Of these, 123 (24%) patients in the Rituximab arm were age 65 or older. No overall differences in safety or effectiveness were observed between these patients and younger patients. Other clinical studies of Rituximab in low-grade or follicular, CD20-positive, B-cell NHL did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger subjects. Chronic Lymphocytic Leukemia Among patients with CLL evaluated in two randomized active-controlled trials, 243 of 676 Rituximab-treated patients (36%) were 65 years of age or older; of these, 100 Rituximab-treated patients (15%) were 70 years of age or older. In exploratory analyses defined by age, there was no observed benefit from the addition of Rituximab to fludarabine and cyclophosphamide among patients 70 years of age or older in Study 11 or in Study 12; there was also no observed benefit from the addition of Rituximab to fludarabine and cyclophosphamide among patients 65 years of age or older in Study 12. Patients 70 years or older received lower dose intensity of fludarabine and cyclophosphamide compared to younger patients, regardless of the addition of Rituximab. In Study 11, the dose intensity of Rituximab was similar in older and younger patients, however in Study 12 older patients received a lower dose intensity of Rituximab. The incidence of Grade 3 and 4 adverse reactions was higher among patients receiving R-FC who were 70 years or older compared to younger patients for neutropenia [44% vs. 31% (Study 11); 56% vs. 39% (Study 12)], febrile neutropenia [16% vs. 6% (Study 10)], anemia [5% vs. 2% (Study 11); 21% vs. 10% (Study 12)], thrombocytopenia [19% vs. 8% (Study 12)], pancytopenia [7% vs. 2% (Study 11); 7% vs. 2% (Study 12)] and infections [30% vs. 14% (Study 12)]. Rheumatoid Arthritis Among the 2578 patients in global RA studies completed to date, 12% were 65–75 years old and 2% were 75 years old and older. The incidences of adverse reactions were similar between older and younger patients. The rates of serious adverse reactions, including serious infections, malignancies, and cardiovascular events were higher in older patients. Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis) and Microscopic Polyangiitis Of the 99 Rituximab-treated GPA and MPA patients, 36 (36%) were 65 years old and over, while 8 (8%) were 75 years and over. No overall differences in efficacy were observed between patients that were 65 years old and over and younger patients. The overall incidence and rate of all serious adverse events was higher in patients 65 years old and over. The clinical study did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger subjects. ### Gender There is no FDA guidance on the use of Rituximab with respect to specific gender populations. ### Race There is no FDA guidance on the use of Rituximab with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Rituximab in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Rituximab in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Rituximab in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Rituximab in patients who are immunocompromised. # Administration and Monitoring ### Administration Administer only as an Intravenous Infusion Do not administer as an intravenous push or bolus. Premedicate before each infusion Rituximab should only be administered by a healthcare professional with appropriate medical support to manage severe infusion reactions that can be fatal if they occur. - First Infusion: Initiate infusion at a rate of 50 mg/hr. In the absence of infusion toxicity, increase infusion rate by 50 mg/hr increments every 30 minutes, to a maximum of 400 mg/hr. - Subsequent Infusions: - Standard Infusion: Initiate infusion at a rate of 100 mg/hr. In the absence of infusion toxicity, increase rate by 100 mg/hr increments at 30-minute intervals, to a maximum of 400 mg/hr. - For previously untreated follicular NHL and DLBCL patients: - If patients did not experience a Grade 3 or 4 infusion related adverse event during Cycle 1, a 90-minute infusion can be administered in Cycle 2 with a glucocorticoid-containing chemotherapy regimen. - Initiate at a rate of 20% of the total dose given in the first 30 minutes and the remaining 80% of the total dose given over the next 60 minutes. If the 90-minute infusion is tolerated in Cycle 2, the same rate can be used - when administering the remainder of the treatment regimen (through Cycle 6 or 8). - Patients who have clinically significant cardiovascular disease or who have a circulating lymphocyte count ≥5000/mm3 before Cycle 2 should not be administered the 90-minute infusion. - Interrupt the infusion or slow the infusion rate for infusion reactions. Continue the infusion at one-half the previous rate upon improvement of symptoms. ### Monitoring FDA Package Insert for Rituximab contains no information regarding drug monitoring. # IV Compatibility There is limited information about the IV Compatibility. # Overdosage There has been no experience with overdosage in human clinical trials. Single doses of up to 500 mg/m2 have been administered in clinical trials. # Pharmacology ## Mechanism of Action Rituximab binds specifically to the antigen CD20 (human B-lymphocyte-restricted differentiation antigen, Bp35), a hydrophobic transmembrane protein with a molecular weight of approximately 35 kD located on pre-B and mature B lymphocytes. The antigen is expressed on > 90% of B-cell non-Hodgkin's lymphomas (NHL), but the antigen is not found on hematopoietic stem cells, pro-B-cells, normal plasma cells or other normal tissues. CD20 regulates an early step(s) in the activation process for cell cycle initiation and differentiation, and possibly functions as a calcium ion channel. CD20 is not shed from the cell surface and does not internalize upon antibody binding. Free CD20 antigen is not found in the circulation. B cells are believed to play a role in the pathogenesis of rheumatoid arthritis (RA) and associated chronic synovitis. In this setting, B cells may be acting at multiple sites in the autoimmune/inflammatory process, including through production of rheumatoid factor (RF) and other autoantibodies, antigen presentation, T-cell activation, and/or proinflammatory cytokine production. Mechanism of Action: The Fab domain of rituximab binds to the CD20 antigen on B lymphocytes, and the Fc domain recruits immune effector functions to mediate B-cell lysis in vitro. Possible mechanisms of cell lysis include complement-dependent cytotoxicity (CDC) and antibody-dependent cell mediated cytotoxicity (ADCC). The antibody has been shown to induce apoptosis in the DHL-4 human B-cell lymphoma line. Normal Tissue Cross-reactivity: Rituximab binding was observed on lymphoid cells in the thymus, the white pulp of the spleen, and a majority of B lymphocytes in peripheral blood and lymph nodes. Little or no binding was observed in the non-lymphoid tissues examined. ## Structure Rituximab® (rituximab) is a genetically engineered chimeric murine/human monoclonal IgG1 kappa antibody directed against the CD20 antigen. Rituximab has an approximate molecular weight of 145 kD. Rituximab has a binding affinity for the CD20 antigen of approximately 8.0 nM. Rituximab is produced by mammalian cell (Chinese Hamster Ovary) suspension culture in a nutrient medium containing the antibiotic gentamicin. Gentamicin is not detectable in the final product. Rituximab is a sterile, clear, colorless, preservative-free liquid concentrate for intravenous administration. Rituximab is supplied at a concentration of 10 mg/mL in either 100 mg/10 mL or 500 mg/50 mL single-use vials. The product is formulated in polysorbate 80 (0.7 mg/mL), sodium citrate dihydrate (7.35 mg/mL), sodium chloride (9 mg/mL) and Water for Injection. The pH is 6.5. ## Pharmacodynamics Non-Hodgkin's Lymphoma (NHL) In NHL patients, administration of Rituximab resulted in depletion of circulating and tissue-based B cells. Among 166 patients in Study 1, circulating CD19-positive B cells were depleted within the first three weeks with sustained depletion for up to 6 to 9 months post treatment in 83% of patients. B-cell recovery began at approximately 6 months and median B-cell levels returned to normal by 12 months following completion of treatment. There were sustained and statistically significant reductions in both IgM and IgG serum levels observed from 5 through 11 months following rituximab administration; 14% of patients had IgM and/or IgG serum levels below the normal range. Rheumatoid Arthritis In RA patients, treatment with Rituximab induced depletion of peripheral B lymphocytes, with the majority of patients demonstrating near complete depletion (CD19 counts below the lower limit of quantification, 20 cells/µl) within 2 weeks after receiving the first dose of Rituximab. The majority of patients showed peripheral B-cell depletion for at least 6 months. A small proportion of patients (~4%) had prolonged peripheral B-cell depletion lasting more than 3 years after a single course of treatment. Total serum immunoglobulin levels, IgM, IgG, and IgA were reduced at 6 months with the greatest change observed in IgM. At Week 24 of the first course of Rituximab treatment, small proportions of patients experienced decreases in IgM (10%), IgG (2.8%), and IgA (0.8%) levels below the lower limit of normal (LLN). In the experience with Rituximab in RA patients during repeated Rituximab treatment, 23.3%, 5.5%, and 0.5% of patients experienced decreases in IgM, IgG, and IgA concentrations below LLN at any time after receiving Rituximab, respectively. The clinical consequences of decreases in immunoglobulin levels in RA patients treated with Rituximab are unclear. Treatment with rituximab in patients with RA was associated with reduction of certain biologic markers of inflammation such as interleukin-6 (IL-6), C-reactive protein (CRP), serum amyloid protein (SAA), S100 A8/S100 A9 heterodimer complex (S100 A8/9), anti-citrullinated peptide (anti-CCP), and RF. Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis) and Microscopic Polyangiitis In GPA and MPA patients, peripheral blood CD19 B-cells depleted to less than 10 cells/µl following the first two infusions of Rituximab, and remained at that level in most (84%) patients through Month 6. By Month 12, the majority of patients (81%) showed signs of B-cell return with counts >10 cells/μL. By Month 18, most patients (87%) had counts >10 cells/μL. ## Pharmacokinetics Non-Hodgkin's Lymphoma (NHL) Pharmacokinetics were characterized in 203 NHL patients receiving 375 mg/m2 Rituximab weekly by intravenous infusion for 4 doses. Rituximab was detectable in the serum of patients 3 to 6 months after completion of treatment. The pharmacokinetic profile of rituximab when administered as 6 infusions of 375 mg/m2 in combination with 6 cycles of CHOP chemotherapy was similar to that seen with rituximab alone. Based on a population pharmacokinetic analysis of data from 298 NHL patients who received rituximab once weekly or once every three weeks, the estimated median terminal elimination half-life was 22 days (range, 6.1 to 52 days). Patients with higher CD19-positive cell counts or larger measurable tumor lesions at pretreatment had a higher clearance. However, dose adjustment for pretreatment CD19 count or size of tumor lesion is not necessary. Age and gender had no effect on the pharmacokinetics of rituximab. Pharmacokinetics were characterized in 21 patients with CLL receiving rituximab according to the recommended dose and schedule. The estimated median terminal half-life of rituximab was 32 days (range, 14 to 62 days). Rheumatoid Arthritis Following administration of 2 doses of Rituximab in patients with RA, the mean ( ± S.D.; % CV) concentrations after the first infusion (Cmax first) and second infusion (Cmax second) were 157 ( ± 46; 29%) and 183 ( ± 55; 30%) mcg/mL, and 318 ( ± 86; 27%) and 381 ( ± 98; 26%) mcg/mL for the 2 × 500 mg and 2 × 1000 mg doses, respectively. Based on a population pharmacokinetic analysis of data from 2005 RA patients who received Rituximab, the estimated clearance of rituximab was 0.335 L/day; volume of distribution was 3.1 L and mean terminal elimination half-life was 18.0 days (range, 5.17 to 77.5 days). Age, weight and gender had no effect on the pharmacokinetics of rituximab in RA patients. Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis) and Microscopic Polyangiitis Based on the population pharmacokinetic analysis of data in 97 GPA and MPA patients who received 375 mg/m2 rituximab once weekly by intravenous infusion for four weeks, the estimated median terminal elimination half-life was 23 days (range, 9 to 49 days). Rituximab mean clearance and volume of distribution were 0. 312 L/day (range, 0.115 to 0.728 L/day) and 4.50 L (range, 2.21 to 7.52 L) respectively. Male patients and patients with higher BSA or positive HACA levels have higher clearance. However, further dose adjustment based on gender or HACA status is not necessary. The pharmacokinetics of rituximab have not been studied in children and adolescents. No formal studies were conducted to examine the effects of either renal or hepatic impairment on the pharmacokinetics of rituximab. ## Nonclinical Toxicology ## Carcinogenesis, Mutagenesis, Impairment of Fertility No long-term animal studies have been performed to establish the carcinogenic or mutagenic potential of Rituximab or to determine potential effects on fertility in males or females. ## Animal Toxicology and/or Pharmacology Reproductive Toxicology Studies An embryo-fetal developmental toxicity study was performed on pregnant cynomolgus monkeys. Pregnant animals received rituximab via the intravenous route during early gestation (organogenesis period; post-coitum days 20 through 50). Rituximab was administered as loading doses on post-coitum (PC) days 20, 21 and 22, at 15, 37.5 or 75 mg/kg/day, and then weekly on PC Days 29, 36, 43 and 50, at 20, 50 or 100 mg/kg/week. The 100 mg/kg/week dose resulted in 80% of the exposure (based on AUC) of those achieved following a dose of 2 grams in humans. Rituximab crosses the monkey placenta. Exposed offspring did not exhibit any teratogenic effects but did have decreased lymphoid tissue B cells. A subsequent pre- and postnatal reproductive toxicity study in cynomolgus monkeys was completed to assess developmental effects including the recovery of B cells and immune function in infants exposed to rituximab in utero. Animals were treated with a loading dose of 0, 15, or 75 mg/kg every day for 3 days, followed by weekly dosing with 0, 20, or 100 mg/kg dose. Subsets of pregnant females were treated from PC Day 20 through postpartum Day 78, PC Day 76 through PC Day 134, and from PC Day 132 through delivery and postpartum Day 28. Regardless of the timing of treatment, decreased B cells and immunosuppression were noted in the offspring of rituximab-treated pregnant animals. The B-cell counts returned to normal levels, and immunologic function was restored within 6 months postpartum. # Clinical Studies ## Relapsed or Refractory, Low-Grade or Follicular, CD20-Positive, B-Cell NHL The safety and effectiveness of Rituximab in relapsed, refractory CD20+ NHL were demonstrated in 3 single-arm studies enrolling 296 patients. Study 1 A multicenter, open-label, single-arm study was conducted in 166 patients with relapsed or refractory, low-grade or follicular, B-cell NHL who received 375 mg/m2 of Rituximab given as an intravenous infusion weekly for 4 doses. Patients with tumor masses > 10 cm or with > 5000 lymphocytes/µL in the peripheral blood were excluded from the study. Results are summarized in Table 4. The median time to onset of response was 50 days. Disease-related signs and symptoms (including B-symptoms) resolved in 64% (25/39) of those patients with such symptoms at study entry. Study 2 In a multicenter, single-arm study, 37 patients with relapsed or refractory, low-grade NHL received 375 mg/m2 of Rituximab weekly for 8 doses. Results are summarized in Table 4. Study 3 In a multicenter, single-arm study, 60 patients received 375 mg/m2 of Rituximab weekly for 4 doses. All patients had relapsed or refractory, low-grade or follicular, B-cell NHL and had achieved an objective clinical response to Rituximab administered 3.8–35.6 months (median 14.5 months) prior to retreatment with Rituximab. Of these 60 patients, 5 received more than one additional course of Rituximab. Results are summarized in Table 4. Bulky Disease In pooled data from studies 1 and 3, 39 patients with bulky (single lesion > 10 cm in diameter) and relapsed or refractory, low-grade NHL received Rituximab 375 mg/m2 weekly for 4 doses. Results are summarized in Table 4. ## Previously Untreated, Low-Grade or Follicular, CD20-Positive, B-Cell NHL The safety and effectiveness of Rituximab in previously untreated, low-grade or follicular, CD20+ NHL were demonstrated in 3 randomized, controlled trials enrolling 1,662 patients. Study 4 A total of 322 patients with previously untreated follicular NHL were randomized (1:1) to receive up to eight 3-week cycles of CVP chemotherapy alone (CVP) or in combination with Rituximab 375 mg/m2 on Day 1 of each cycle (R-CVP) in an open-label, multicenter study. The main outcome measure of the study was progression-free survival (PFS) defined as the time from randomization to the first of progression, relapse, or death. Twenty-six percent of the study population was >60 years of age, 99% had Stage III or IV disease, and 50% had an International Prognostic Index (IPI) score ≥2. The results for PFS as determined by a blinded, independent assessment of progression are presented in Table 5. The point estimates may be influenced by the presence of informative censoring. The PFS results based on investigator assessment of progression were similar to those obtained by the independent review assessment. Study 5 An open-label, multicenter, randomized (1:1) study was conducted in 1,018 patients with previously untreated follicular NHL who achieved a response (CR or PR) to Rituximab in combination with chemotherapy. Patients were randomized to Rituximab as single-agent maintenance therapy, 375 mg/m2 every 8 weeks for up to 12 doses or to observation. Rituximab was initiated at 8 weeks following completion of chemotherapy. The main outcome measure of the study was progression-free survival (PFS), defined as the time from randomization in the maintenance/observation phase to progression, relapse, or death, as determined by independent review. Of the randomized patients, 40% were ≥ 60 years of age, 70% had Stage IV disease, 96% had ECOG performance status (PS) 0–1, and 42% had FLIPI scores of 3–5. Prior to randomization to maintenance therapy, patients had received R-CHOP (75%), R-CVP (22%), or R-FCM (3%); 71% had a complete or unconfirmed complete response and 28% had a partial response. PFS was longer in patients randomized to Rituximab as single agent maintenance therapy (HR: 0.54, 95% CI: 0.42, 0.70). The PFS results based on investigator assessment of progression were similar to those obtained by the independent review assessment. Study 6 A total of 322 patients with previously untreated low-grade, B-cell NHL who did not progress after 6 or 8 cycles of [[chemotherapy]\|CVP chemotherapy]] were enrolled in an open-label, multicenter, randomized trial. Patients were randomized (1:1) to receive Rituximab, 375 mg/m2 intravenous infusion, once weekly for 4 doses every 6 months for up to 16 doses or no further therapeutic intervention. The main outcome measure of the study was progression-free survival defined as the time from randomization to progression, relapse, or death. Thirty-seven percent of the study population was >60 years of age, 99% had Stage III or IV disease, and 63% had an IPI score ≥2. There was a reduction in the risk of progression, relapse, or death (hazard ratio estimate in the range of 0.36 to 0.49) for patients randomized to Rituximab as compared to those who received no additional treatment. ## Diffuse Large B-Cell NHL (DLBCL) The safety and effectiveness of Rituximab were evaluated in three randomized, active-controlled, open-label, multicenter studies with a collective enrollment of 1854 patients. Patients with previously untreated diffuse large B-cell NHL received Rituximab in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or other anthracycline-based chemotherapy regimens. Study 7 A total of 632 patients age ≥ 60 years with DLBCL (including primary mediastinal B-cell lymphoma) were randomized in a 1:1 ratio to treatment with CHOP or R-CHOP. Patients received 6 or 8 cycles of CHOP, each cycle lasting 21 days. All patients in the R-CHOP arm received 4 doses of Rituximab 375 mg/m2 on Days –7 and –3 (prior to Cycle 1) and 48–72 hours prior to Cycles 3 and 5. Patients who received 8 cycles of CHOP also received Rituximab prior to Cycle 7. The main outcome measure of the study was progression-free survival, defined as the time from randomization to the first of progression, relapse, or death. Responding patients underwent a second randomization to receive Rituximab or no further therapy. Among all enrolled patients, 62% had centrally confirmed DLBCL histology, 73% had Stage III–IV disease, 56% had IPI scores ≥ 2, 86% had ECOG performance status of < 2, 57% had elevated LDH levels, and 30% had two or more extranodal disease sites involved. Efficacy results are presented in Table 6. These results reflect a statistical approach which allows for an evaluation of Rituximab administered in the induction setting that excludes any potential impact of Rituximab given after the second randomization. Analysis of results after the second randomization in Study 7 demonstrates that for patients randomized to R-CHOP, additional Rituximab exposure beyond induction was not associated with further improvements in progression-free survival or overall survival. Study 8 A total of 399 patients with DLBCL, age ≥ 60 years, were randomized in a 1:1 ratio to receive CHOP or R-CHOP. All patients received up to eight 3-week cycles of CHOP induction; patients in the R-CHOP arm received Rituximab 375 mg/m2 on Day 1 of each cycle. The main outcome measure of the study was event-free survival, defined as the time from randomization to relapse, progression, change in therapy, or death from any cause. Among all enrolled patients, 80% had Stage III or IV disease, 60% of patients had an age-adjusted IPI ≥ 2, 80% had ECOG performance status scores < 2, 66% had elevated LDH levels, and 52% had extranodal involvement in at least two sites. Efficacy results are presented in Table 6. Study 9 A total of 823 patients with DLBCL, aged 18–60 years, were randomized in a 1:1 ratio to receive an anthracycline-containing chemotherapy regimen alone or in combination with Rituximab. The main outcome measure of the study was time to treatment failure, defined as time from randomization to the earliest of progressive disease, failure to achieve a complete response, relapse, or death. Among all enrolled patients, 28% had Stage III–IV disease, 100% had IPI scores of ≤ 1, 99% had ECOG performance status of < 2, 29% had elevated LDH levels, 49% had bulky disease, and 34% had extranodal involvement. Efficacy results are presented in Table 6. In Study 8, overall survival estimates at 5 years were 58% vs. 46% for R-CHOP and CHOP, respectively. ## Ninety-Minute Infusions in Previously Untreated Follicular NHL and DLBCL In Study 10, a total of 363 patients with previously untreated follicular NHL (n=113) or DLBCL (n=250) were evaluated in a prospective, open-label, multi-center, single-arm trial for the safety of 90-minute rituximab infusions. Patients with follicular NHL received rituximab 375 mg/m2 plus CVP chemotherapy. Patients with DLBCL received rituximab 375 mg/m2 plus CHOP chemotherapy. Patients with clinically significant cardiovascular disease were excluded from the study. Patients were eligible for a 90-minute infusion at Cycle 2 if they did not experience a Grade 3-4 infusion-related adverse event with Cycle 1 and had a circulating lymphocyte count ≤ 5000/mm3 before Cycle 2. All patients were pre-medicated with acetaminophen and an antihistamine and received the glucocorticoid component of their chemotherapy prior to Rituximab infusion. The main outcome measure was the development of Grade 3-4 infusion-related reactions on the day of, or day after, the 90-minute infusion at Cycle 2. Eligible patients received their Cycle 2 rituximab infusion over 90 minutes as follows: 20% of the total dose given in the first 30 minutes and the remaining 80% of the total dose given over the next 60 minutes. Patients who tolerated the 90-minute rituximab infusion at Cycle 2 continued to receive subsequent rituximab infusions at the 90-minute infusion rate for the remainder of the treatment regimen (through Cycle 6 or Cycle 8). The incidence of Grade 3-4 infusion-related reactions at Cycle 2 was 1.1% (95% CI [0.3%, 2.8%]) among all patients, 3.5% (95% CI [1.0%, 8.8%]) for those patients treated with R-CVP, and 0.0% (95% CI [0.0%, 1.5%]) for those patients treated with R-CHOP. For Cycles 2-8, the incidence of Grade 3-4 infusion-related reactions was 2.8% (95% CI [1.3%, 5.0%]). No acute fatal infusion related reactions were observed. ## Chronic Lymphocytic Leukemia (CLL) The safety and effectiveness of Rituximab were evaluated in two randomized (1:1) multicenter open-label studies comparing FC alone or in combination with Rituximab for up to 6 cycles in patients with previously untreated CLL [Study 11 (n=817)] or previously treated CLL [Study 12 (n=552)]. Patients received fludarabine 25 mg/m2/day and cyclophosphamide 250 mg/m2/day on days 1, 2 and 3 of each cycle, with or without Rituximab. In both studies, seventy-one percent of CLL patients received 6 cycles and 90% received at least 3 cycles of Rituximab-based therapy. In Study 11, 30% of patients were 65 years or older, 31% were Binet stage C, 45% had B symptoms, more than 99% had ECOG performance status (PS) 0–1, 74% were male, and 100% were White. In Study 12, 44% of patients were 65 years or older, 28% had B symptoms, 82% received a prior alkylating drug, 18% received prior fludarabine, 100% had ECOG PS 0–1, 67% were male and 98% were White. The main outcome measure in both studies was progression-free survival (PFS), defined as the time from randomization to progression, relapse, or death, as determined by investigators (Study 11) or an independent review committee (Study 12). The investigator assessed results in Study 12 were supportive of those obtained by the independent review committee. Efficacy results are presented in Table 7. Across both studies, 243 of 676 Rituximab-treated patients (36%) were 65 years of age or older and 100 Rituximab-treated patients (15%) were 70 years of age or older. The results of exploratory subset analyses in elderly patients are presented in Table 8. ## Rheumatoid Arthritis (RA) Reducing the Signs and Symptoms: Initial and Re-Treatment Courses The efficacy and safety of Rituximab were evaluated in two randomized, double-blind, placebo-controlled studies of adult patients with moderately to severely active RA who had a prior inadequate response to at least one TNF inhibitor. Patients were 18 years of age or older, diagnosed with active RA according to American College of Rheumatology (ACR) criteria, and had at least 8 swollen and 8 tender joints. In RA Study 1, patients were randomized to receive either Rituximab 2 × 1000 mg + MTX or placebo + MTX for 24 weeks. Further courses of Rituximab 2 × 1000 mg + MTX were administered in an open label extension study at a frequency determined by clinical evaluation, but no sooner than 16 weeks after the preceding course of Rituximab. In addition to the intravenous premedication, glucocorticoids were administered orally on a tapering schedule from baseline through Day 14. The proportions of patients achieving ACR 20, 50, and 70 responses at Week 24 of the placebo-controlled period are shown in Table 9. In RA Study 2, all patients received the first course of Rituximab 2 × 1000 mg + MTX. Patients who experienced ongoing disease activity were randomized to receive a second course of either Rituximab 2 × 1000 mg + MTX or placebo + MTX, the majority between Weeks 24–28. The proportions of patients achieving ACR 20, 50, and 70 responses at Week 24, before the re-treatment course, and at Week 48, after retreatment, are shown in Table 9. Improvement was also noted for all components of ACR response following treatment with Rituximab, as shown in Table 10. The time course of ACR 20 response for Study 1 is shown in Figure 2. Although both treatment groups received a brief course of intravenous and oral glucocorticoids, resulting in similar benefits at Week 4, higher ACR 20 responses were observed for the Rituximab group by Week 8. A similar proportion of patients achieved these responses through Week 24 after a single course of treatment (2 infusions) with Rituximab. Similar patterns were demonstrated for ACR 50 and 70 responses. Radiographic Response In RA Study 1, structural joint damage was assessed radiographically and expressed as changes in Genant-modified Total Sharp Score (TSS) and its components, the erosion score (ES) and the joint space narrowing (JSN) score. Rituximab + MTX slowed the progression of structural damage compared to placebo + MTX after 1 year as shown in Table 11. In RA Study 1 and its open-label extension, 70% of patients initially randomized to Rituximab + MTX and 72% of patients initially randomized to placebo + MTX were evaluated radiographically at Year 2. As shown in Table 11, progression of structural damage in Rituximab + MTX patients was further reduced in the second year of treatment. Following 2 years of treatment with Rituximab + MTX, 57% of patients had no progression of structural damage. During the first year, 60% of Rituximab + MTX treated patients had no progression, defined as a change in TSS of zero or less compared to baseline, compared to 46% of placebo + MTX treated patients. In their second year of treatment with Rituximab + MTX, more patients had no progression than in the first year (68% vs. 60%), and 87% of the Rituximab + MTX treated patients who had no progression in the first year also had no progression in the second year. Lesser Efficacy of 500 Vs. 1000 mg Treatment Courses for Radiographic Outcomes RA Study 3 is a randomized, double-blind, placebo-controlled study which evaluated the effect of placebo + MTX compared to Rituximab 2 × 500 mg + MTX and Rituximab 2 × 1000 mg + MTX treatment courses in MTX-naïve RA patients with moderately to severely active disease. Patients received a first course of two infusions of rituximab or placebo on Days 1 and 15. MTX was initiated at 7.5 mg/week and escalated up to 20 mg/week by Week 8 in all three treatment arms. After a minimum of 24 weeks, patients with ongoing disease activity were eligible to receive re-treatment with additional courses of their assigned treatment. After one year of treatment, the proportion of patients achieving ACR 20/50/70 responses were similar in both Rituximab dose groups and were higher than in the placebo group. However, with respect to radiographic scores, only the Rituximab 1000 mg treatment group demonstrated a statistically significant reduction in TSS: a change of 0.36 units compared to 1.08 units for the placebo group, a 67% reduction. Physical Function Response RA Study 4 is a randomized, double-blind, placebo-controlled study in adult RA patients with moderately to severely active disease with inadequate response to MTX. Patients were randomized to receive an initial course of Rituximab 500 mg, Rituximab 1000 mg, or placebo in addition to background MTX. Physical function was assessed at Weeks 24 and 48 using the Health Assessment Questionnaire Disability Index (HAQ-DI). From baseline to Week 24, a greater proportion of Rituximab-treated patients had an improvement in HAQ-DI of at least 0.22 (a minimal clinically important difference) and a greater mean HAQ-DI improvement compared to placebo, as shown in Table 12. HAQ-DI results for the Rituximab 500 mg treatment group were similar to the Rituximab 1000 mg treatment group; however radiographic responses were not assessed (see Dosing Precaution in the Radiographic Responses section above). These improvements were maintained at 48 weeks. ## Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis) and Microscopic Polyangiitis (MPA) A total of 197 patients with active, severe GPA and MPA (two forms of ANCA Associated Vasculidities) were treated in a randomized, double-blind, active-controlled multicenter, non-inferiority study, conducted in two phases – a 6 month remission induction phase and a 12 month remission maintenance phase. Patients were 15 years of age or older, diagnosed with GPA (75% of patients) or MPA (24% of patients) according to the Chapel Hill Consensus conference criteria (1% of the patients had unknown vasculitis type). All patients had active disease, with a Birmingham Vasculitis Activity Score for Granulomatosis with Polyangiitis (BVAS/GPA) ≥ 3, and their disease was severe, with at least one major item on the BVAS/GPA. Ninety-six (49%) of patients had new disease and 101 (51%) of patients had relapsing disease. Patients in both arms received 1000 mg of pulse intravenous methylprednisolone per day for 1 to 3 days within 14 days prior to initial infusion. Patients were randomized in a 1:1 ratio to receive either Rituximab 375 mg/m2 once weekly for 4 weeks or oral cyclophosphamide 2 mg/kg daily for 3 to 6 months in the remission induction phase. Patients were pre-medicated with antihistamine and acetaminophen prior to Rituximab infusion. Following intravenous corticosteroid administration, all patients received oral prednisone (1 mg/kg/day, not exceeding 80 mg/day) with pre-specified tapering. Once remission was achieved or at the end of the 6 month remission induction period, the cyclophosphamide group received azathioprine to maintain remission. The Rituximab group did not receive additional therapy to maintain remission. The main outcome measure for both GPA and MPA patients was achievement of complete remission at 6 months defined as a BVAS/GPA of 0, and off glucocorticoid therapy. The pre-specified non-inferiority margin was a treatment difference of 20%. As shown in Table 13, the study demonstrated non-inferiority of Rituximab to cyclophosphamide for complete remission at 6 months. Complete Remission (CR) at 12 and 18 months In the Rituximab group, 44% of patients achieved CR at 6 and 12 months, and 38% of patients achieved CR at 6, 12, and 18 months. In patients treated with cyclophosphamide (followed by azathioprine for maintenance of CR), 38% of patients achieved CR at 6 and 12 months, and 31% of patients achieved CR at 6, 12, and 18 months. Retreatment with Rituximab Based upon investigator judgment, 15 patients received a second course of Rituximab therapy for treatment of relapse of disease activity which occurred between 8 and 17 months after the first course of Rituximab. The limited data preclude any conclusions regarding the efficacy of subsequent courses of Rituximab in patients with GPA and MPA. # How Supplied Rituximab vials [100 mg/10 mL single-use vials (NDC 50242-051-21) and 500 mg/50 mL single-use vials (NDC 50242-053-06)] are stable at 2°C–8°C (36°F–46°F). Do not use beyond expiration date stamped on carton. Rituximab vials should be protected from direct sunlight. Do not freeze or shake. ## Storage Rituximab solutions for infusion may be stored at 2°C–8°C (36°F–46°F) for 24 hours. Rituximab solutions for infusion have been shown to be stable for an additional 24 hours at room temperature. However, since Rituximab solutions do not contain a preservative, diluted solutions should be stored refrigerated (2°C–8°C). No incompatibilities between Rituximab and polyvinylchloride or polyethylene bags have been observed. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Patients should be provided the Rituximab Medication Guide and provided an opportunity to read prior to each treatment session. It is important that the patient's overall health be assessed at each visit and the risks of Rituximab therapy and any questions resulting from the patient's reading of the Medication Guide be discussed. See FDA approved patient labeling (Medication Guide). Rituximab is detectable in serum for up to six months following completion of therapy. Individuals of childbearing potential should use effective contraception during treatment and for 12 months after Rituximab therapy. # Precautions with Alcohol Alcohol-Rituximab 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 Rituximab Brand Names in the drug label. # Look-Alike Drug Names There is limited information regarding Rituximab Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Rituxan
a1d160f524bea5e6e9a614fd9489adb2f71e1d77	wikidoc	Ro15-4513	Ro15-4513 Ro15-4513 is a weak partial inverse agonist of the benzodiazepine class of drugs, developed by Hoffmann–La Roche in 1984, and is structurally related to the benzodiazepine antidote flumazenil. The main interest in Ro15-4513 was as an antidote to alcohol. Flumazenil effectively blocks the effects of benzodiazepine agonists such as alprazolam and diazepam and so is used for treating overdoses of these drugs but is ineffective in blocking alcohol actions. Ro15-4513 was somewhat less effective than flumazenil at blocking the effects of benzodiazepines, but instead selectively blocked the effects of ethanol. This meant that in contrast to flumazenil, which is ineffective at treating alcohol overdoses, Ro15-4513 showed potential as a useful alcohol antidote. It is thought that Ro15-4513 antagonizes the effects of ethanol because the azido group at the 8- position of the benzene ring blocks the binding site for ethanol on the α4β3δ subtype of the GABAA receptor; flumazenil, which has a fluorine at this position, does not block this binding site and so does not counteract the effects of ethanol. Unfortunately Ro15-4513 had several disadvantages that made it unsuitable for development and marketing. Its fairly short half-life means that several repeated doses would have to be given over an extended period, since if only one dose were used it would wear off before the alcohol had been metabolised and the patient would relapse (similar to the problems with renarcotization seen when treating overdoses of long-acting opioids such as methadone with short-acting antagonists such as naloxone). Also because of its GABA antagonist effects, Ro15-4513 causes serious side effects including both anxiety, and at higher doses, convulsions, which would require careful control of dosing and would cause complications in clinical use. Another problem is that alcohol's effects are not purely mediated by GABA receptors, at higher doses alcohol binds to multiple other targets as well, so while Ro15-4513 is an effective antidote against moderate levels of alcohol intoxication, it might be ineffective at treating life-threatening overdoses. Also, Roche was concerned about the legal implications of introducing an alcohol antidote, as Ro15-4513 blocks the effects of ethanol, but does not remove it from the bloodstream, which could lead to potential problems as the effects of the alcohol would only be masked temporarily, so patients might for instance feel that they are sober and discharge themselves from hospital once the drug took effect, then become drunk again once it wore off, possibly crashing their car or having other accidents which might lead to legal consequences for Roche. However the discovery of Ro15-4513 has been important in elucidating the mechanism of action of ethanol as used as a recreational drug, and this compound could now be used as a template to design a more effective and longer lasting antidote for ethanol, or alternatively to develop a selective agonist drug which could replicate the beneficial effects of alcohol but with fewer side effects. # PET Imaging Labelling Ro15-4513 with carbon-11 leads to the possibility of its use in PET imaging of the brain. The specificity of the compound to a small number of GABA receptor sub-types leads to the generation, with accurate modelling, of detailed images with well-defined limbic and cortical structures. These images can be useful in quantitatively analysing conditions such as addiction, that are known to be, at least in part, associated with the GABAergic system. The images produced are similar to those for labelled flumazenil, though the distribution varies especially in regions such as the occipital lobe, cerebellum and basal ganglia, as it does not selectively label the GABRA1 subtype.	Ro15-4513 Ro15-4513 is a weak partial inverse agonist of the benzodiazepine class of drugs, developed by Hoffmann–La Roche in 1984, and is structurally related to the benzodiazepine antidote flumazenil. The main interest in Ro15-4513 was as an antidote to alcohol. Flumazenil effectively blocks the effects of benzodiazepine agonists such as alprazolam and diazepam and so is used for treating overdoses of these drugs but is ineffective in blocking alcohol actions. Ro15-4513 was somewhat less effective than flumazenil at blocking the effects of benzodiazepines, but instead selectively blocked the effects of ethanol. This meant that in contrast to flumazenil, which is ineffective at treating alcohol overdoses, Ro15-4513 showed potential as a useful alcohol antidote. It is thought that Ro15-4513 antagonizes the effects of ethanol because the azido group at the 8- position of the benzene ring blocks the binding site for ethanol on the α4β3δ subtype of the GABAA receptor; flumazenil, which has a fluorine at this position, does not block this binding site and so does not counteract the effects of ethanol. Unfortunately Ro15-4513 had several disadvantages that made it unsuitable for development and marketing. Its fairly short half-life means that several repeated doses would have to be given over an extended period, since if only one dose were used it would wear off before the alcohol had been metabolised and the patient would relapse (similar to the problems with renarcotization seen when treating overdoses of long-acting opioids such as methadone with short-acting antagonists such as naloxone). Also because of its GABA antagonist effects, Ro15-4513 causes serious side effects including both anxiety, and at higher doses, convulsions, which would require careful control of dosing and would cause complications in clinical use. Another problem is that alcohol's effects are not purely mediated by GABA receptors, at higher doses alcohol binds to multiple other targets as well, so while Ro15-4513 is an effective antidote against moderate levels of alcohol intoxication, it might be ineffective at treating life-threatening overdoses. Also, Roche was concerned about the legal implications of introducing an alcohol antidote, as Ro15-4513 blocks the effects of ethanol, but does not remove it from the bloodstream, which could lead to potential problems as the effects of the alcohol would only be masked temporarily, so patients might for instance feel that they are sober and discharge themselves from hospital once the drug took effect, then become drunk again once it wore off, possibly crashing their car or having other accidents which might lead to legal consequences for Roche. However the discovery of Ro15-4513 has been important in elucidating the mechanism of action of ethanol as used as a recreational drug, and this compound could now be used as a template to design a more effective and longer lasting antidote for ethanol, or alternatively to develop a selective agonist drug which could replicate the beneficial effects of alcohol but with fewer side effects. # PET Imaging Labelling Ro15-4513 with carbon-11 leads to the possibility of its use in PET imaging of the brain. The specificity of the compound to a small number of GABA receptor sub-types leads to the generation, with accurate modelling, of detailed images with well-defined limbic and cortical structures. These images can be useful in quantitatively analysing conditions such as addiction, that are known to be, at least in part, associated with the GABAergic system. The images produced are similar to those for labelled flumazenil, though the distribution varies especially in regions such as the occipital lobe, cerebellum and basal ganglia, as it does not selectively label the GABRA1 subtype. Template:Pharma-stub	https://www.wikidoc.org/index.php/Ro15-4513
be3a1b8d7b562dda4f5caf3db35935e42e5c163e	wikidoc	Ro48-6791	Ro48-6791 Ro48-6791 is a drug which is a benzodiazepine derivative developed by Hoffman-LaRoche in the 1990s. Ro48-6791 was developed as an alternative to the short acting imidazobenzodiazepine midazolam, for use in induction of anaesthesia and conscious sedation for minor invasive procedures. Ro48-6791 has similar properties to midazolam, being water soluble, with a fast onset and short duration of action. It is 4-6x more potent than midazolam, and slightly shorter acting, and produces similar side effects such as sedation and amnesia. It was tested up to Phase II human trials, but while it produced less respiratory depression than propofol, it had a longer recovery time and was deemed not to have any significant advantages over the older drug. Similarly when Ro48-6791 was compared to midazolam, it had similar efficacy, higher potency and a shorter recovery time, but produced less of a synergistic effect on opioid-induced analgesia and produced more severe side effects such as dizziness after the procedure. Consequently it was dropped from clinical development, although it is still used in scientific research.	Ro48-6791 Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Ro48-6791 is a drug which is a benzodiazepine derivative developed by Hoffman-LaRoche in the 1990s. Ro48-6791 was developed as an alternative to the short acting imidazobenzodiazepine midazolam, for use in induction of anaesthesia and conscious sedation for minor invasive procedures. Ro48-6791 has similar properties to midazolam, being water soluble, with a fast onset and short duration of action. It is 4-6x more potent than midazolam,[1] and slightly shorter acting,[2] and produces similar side effects such as sedation and amnesia. It was tested up to Phase II human trials, but while it produced less respiratory depression than propofol, it had a longer recovery time and was deemed not to have any significant advantages over the older drug.[3] Similarly when Ro48-6791 was compared to midazolam, it had similar efficacy, higher potency and a shorter recovery time, but produced less of a synergistic effect on opioid-induced analgesia and produced more severe side effects such as dizziness after the procedure.[4] Consequently it was dropped from clinical development,[5] although it is still used in scientific research.[6] Template:Pharma-stub	https://www.wikidoc.org/index.php/Ro48-6791
ba36c4d35c4f4dafefd2f2f3fb1260a53b2c13da	wikidoc	Road rage	Road rage Road rage is behavior by a driver of an automobile or other motor vehicle which causes collisions or incidents on roadways. It can be thought of as an extreme case of aggressive driving. The origins of the phrase can be traced back to when it appeared in an article in the Los Angeles Times. An example of its use in print in 1988 can be found in an article in the Florida's St. Petersburg Times, which reads: "A fit of 'road rage' has landed a man in jail, accused of shooting a woman passenger who's car had 'cut him off' on the highway." # Manifestation The following are common manifestations of road rage: - Generally aggressive driving, including sudden acceleration, braking, and close tailgating. - Cutting others off in a lane, or deliberately preventing someone from merging. - Sounding the vehicle's car horn\|horn or flashing lights excessively. - Rude gestures (such as "Finger (gesture)\|the finger"). - Shouting verbal abuse, obscenities, or threats. - Intentionally causing a collision between vehicles. - Exiting the car to attempt to start a confrontation, including striking someone else's vehicle with an object. - Threatening to use or using a firearm or other deadly weapon. - Throwing projectiles from a moving vehicle with the intent of damaging other vehicles. In the United States\|U.S., more than 300 cases of road rage annually have ended with serious injuries or even fatalities – 1200 incidents per year, according to the AAA Foundation study, and rising yearly throughout the six years of the study that examined police records nationally. # Legal status In some jurisdictions there may be a legal difference between "road rage" and "aggressive driving." In the United States\|U.S., only a few states have enacted special aggressive driving laws, where road rage cases — about 1,200 a year — are normally processed as assault and battery (with or without a vehicle), or "vehicular manslaughter" (if someone is killed). # Road rage as a medical condition As early as 1997, therapists in the United States were working to certify road rage as a medical condition. It is already an official mental disorder in the Diagnostic and Statistical Manual of Mental Disorders. According to an article published by the Associated Press in June 2006, the behaviors typically associated with road rage are the result of intermittent explosive disorder. This conclusion was drawn from surveys of some 9,200 adults in the United States between 2001 and 2003 and was funded by the National Institute of Mental Health. The cause of intermittent explosive disorder has not been described to date. There are many different views on whether "road rage" is a mental issue or not. However, whether it is or isn't, there are many alternative solutions for overcoming this handicap. # Penalties Road rage is a relatively serious act: It may be seen as an endangerment of public safety. It is, however, not possible to judge intent by external observation, so "road ragers" who are stopped by police may be charged only with relatively minor offences such as careless or reckless driving. It is likely that those causing serious injury or death during "road rage" incidents will suffer more serious penalties than those applicable to similar outcomes from simple negligence. In April 2007, a Colorado driver was convicted of first-degree murder for causing the deaths of two motorists in November 2005. He will serve a mandatory sentence of two consecutive life terms. Only 14 U.S. states have passed laws against aggressive driving. Only one state, California, has turned "road rage" into a legal term of art by giving it a particular meaning. # Websites about road rage Due to public concern about road rage and the growth in online forums, several websites have been created for users to share incidents of road rage and share strategies for dealing with it. In 1999, the original Road Rage @ RoadRagers.com began. Originally created by a Canadian, Mark Nelson from Winnipeg, Manitoba, this was the first significant website on the subject and is still referenced in the mainstream media. It continues to provide resources on driving style analysis, a road rage quiz, polls, and advice. It also has provided bad driver and road rage reports allowing visitors to vent and contribute to the database of bad drivers by entering their license plate number and other information. RoadRagers.com remains a complementary foundation to the other sites that followed. In 2000, AboveAverageDriver.com was started as a place to report bad driving by their license plate and vent online. This site allows registered users and unregistered users to report on unsafe drivers around the world but mainly caters to drivers in the US. The site is in its 7th year now, providing a number of statistics to an ever growing community that host a number of reports and search capabilities on good drivers and bad drivers. In 2003, BadDriving.com was launched by a two programmers base in England, Paul Cooper and Gareth Nash. The site provides an outlet for road rage by offering a forum discuss UK related driving issues and also a driving report database to record bad driving incidents on the road. In 2007, the site expanded to the include driving reports in the US. In 2006, PlateWire.com was launched by a Virginia programmer, Mark Buckman. This site offers a communication system for drivers to communicate using their license plate as an identifier. Users can "Flag" bad drivers, "Award" good drivers, warn drivers of vehicle hazards, or send a flirtatious "Wink." PlateWire also offers a toll-free number for members to call in reports. PlateWire has also spawned PlateXchange which enables license plate reporting websites such as PlateWire to share and propagate license plates posted. In 2007, PlateRage.com was launched. It is an online community that allows users from around the world to vent their road rage and report other license plates in a non-physical, non-violent way. Users can also call in their road rage on the go to a 1-800 number "rage line" that uploads to the site. In 2008, YourPlates.com and YourPlates.mobi was launched by programmer Andrew Phipps of Platester.com and PlateState.com and programmer and ex-Iraqi War Veteran Andrew Couch of Las Vegas. It is a license-plate based online social networking and messaging community where drivers can send messages and view messages online as public or private. Members may post a message of road rage to another driver, other members may view those messages to an unclaimed license plate. All license plates are virtually members. Members may search for profiles by license plate or create profiles by license plate. YourPlates.com has created a downloadable widget for MySpace users where they can access the features of license plate messaging directly from their MySpace page. Angry drivers, and Road Ragers use YourPlates.com to share their frustrations in a digital age. # U.S. rankings A 2007 study of the largest U.S. metropolitan areas concluded that the cities with the least courteous drivers (most road rage) are Miami, Phoenix, Arizona\|Phoenix, New York, Los Angeles, and Boston. The cities with the most courteous drivers (least road rage) are Minneapolis, Nashville, Tennessee\|Nashville, St. Louis, Seattle, and Atlanta.	Road rage Road rage is behavior by a driver of an automobile or other motor vehicle which causes collisions or incidents on roadways. It can be thought of as an extreme case of aggressive driving. The origins of the phrase can be traced back to when it appeared in an article in the Los Angeles Times. An example of its use in print in 1988 can be found in an article in the Florida's St. Petersburg Times, which reads: "A fit of 'road rage' has landed a man in jail, accused of shooting a woman passenger who's [sic] car had 'cut him off' on the highway."[1] # Manifestation The following are common manifestations of road rage: - Generally aggressive driving, including sudden acceleration, braking, and close tailgating. - Cutting others off in a lane, or deliberately preventing someone from merging. - Sounding the vehicle's car horn\|horn or flashing lights excessively. - Rude gestures (such as "Finger (gesture)\|the finger"). - Shouting verbal abuse, obscenities, or threats. - Intentionally causing a collision between vehicles. - Exiting the car to attempt to start a confrontation, including striking someone else's vehicle with an object. - Threatening to use or using a firearm or other deadly weapon. - Throwing projectiles from a moving vehicle with the intent of damaging other vehicles. In the United States\|U.S., more than 300 cases of road rage annually have ended with serious injuries or even fatalities[citation needed] – 1200 incidents per year, according to the AAA Foundation study, and rising yearly throughout the six years of the study that examined police records nationally.[citation needed] # Legal status In some jurisdictions there may be a legal difference between "road rage" and "aggressive driving." In the United States\|U.S., only a few states have enacted special aggressive driving laws, where road rage cases — about 1,200 a year — are normally processed as assault and battery (with or without a vehicle), or "vehicular manslaughter" (if someone is killed). # Road rage as a medical condition As early as 1997, therapists in the United States were working to certify road rage as a medical condition. It is already an official mental disorder in the Diagnostic and Statistical Manual of Mental Disorders.[citation needed] According to an article published by the Associated Press in June 2006, the behaviors typically associated with road rage are the result of intermittent explosive disorder.[citation needed] This conclusion was drawn from surveys of some 9,200 adults in the United States between 2001 and 2003 and was funded by the National Institute of Mental Health. The cause of intermittent explosive disorder has not been described to date. There are many different views on whether "road rage" is a mental issue or not. However, whether it is or isn't, there are many alternative solutions for overcoming this handicap. # Penalties Road rage is a relatively serious act: It may be seen as an endangerment of public safety. It is, however, not possible to judge intent by external observation, so "road ragers" who are stopped by police may be charged only with relatively minor offences such as careless or reckless driving.[citation needed] It is likely that those causing serious injury or death during "road rage" incidents will suffer more serious penalties than those applicable to similar outcomes from simple negligence. In April 2007, a Colorado driver was convicted of first-degree murder for causing the deaths of two motorists in November 2005.[2][3] He will serve a mandatory sentence of two consecutive life terms. Only 14 U.S. states have passed laws against aggressive driving. Only one state, California, has turned "road rage" into a legal term of art by giving it a particular meaning.[4] # Websites about road rage Due to public concern about road rage and the growth in online forums, several websites have been created for users to share incidents of road rage and share strategies for dealing with it. In 1999, the original Road Rage @ RoadRagers.com began. Originally created by a Canadian, Mark Nelson from Winnipeg, Manitoba[5], this was the first significant website on the subject and is still referenced in the mainstream media. It continues to provide resources on driving style analysis, a road rage quiz, polls, and advice. It also has provided bad driver and road rage reports allowing visitors to vent and contribute to the database of bad drivers by entering their license plate number and other information. RoadRagers.com remains a complementary foundation to the other sites that followed. In 2000, AboveAverageDriver.com was started as a place to report bad driving by their license plate and vent online. This site allows registered users and unregistered users to report on unsafe drivers around the world but mainly caters to drivers in the US. The site is in its 7th year now, providing a number of statistics to an ever growing community that host a number of reports and search capabilities on good drivers and bad drivers. In 2003, BadDriving.com was launched by a two programmers base in England, Paul Cooper and Gareth Nash. The site provides an outlet for road rage by offering a forum discuss UK related driving issues and also a driving report database to record bad driving incidents on the road. In 2007, the site expanded to the include driving reports in the US. In 2006, PlateWire.com was launched by a Virginia programmer, Mark Buckman. This site offers a communication system for drivers to communicate using their license plate as an identifier. Users can "Flag" bad drivers, "Award" good drivers, warn drivers of vehicle hazards, or send a flirtatious "Wink." PlateWire also offers a toll-free number for members to call in reports. PlateWire has also spawned PlateXchange which enables license plate reporting websites such as PlateWire to share and propagate license plates posted. In 2007, PlateRage.com was launched. It is an online community that allows users from around the world to vent their road rage and report other license plates in a non-physical, non-violent way. Users can also call in their road rage on the go to a 1-800 number "rage line" that uploads to the site. In 2008, YourPlates.com and YourPlates.mobi was launched by programmer Andrew Phipps of Platester.com and PlateState.com and programmer and ex-Iraqi War Veteran Andrew Couch of Las Vegas. It is a license-plate based online social networking and messaging community where drivers can send messages and view messages online as public or private. Members may post a message of road rage to another driver, other members may view those messages to an unclaimed license plate. All license plates are virtually members. Members may search for profiles by license plate or create profiles by license plate. YourPlates.com has created a downloadable widget for MySpace users where they can access the features of license plate messaging directly from their MySpace page. Angry drivers, and Road Ragers use YourPlates.com to share their frustrations in a digital age. # U.S. rankings A 2007 study of the largest U.S. metropolitan areas concluded that the cities with the least courteous drivers (most road rage) are Miami, Phoenix, Arizona\|Phoenix, New York, Los Angeles, and Boston. The cities with the most courteous drivers (least road rage) are Minneapolis, Nashville, Tennessee\|Nashville, St. Louis, Seattle, and Atlanta.[6]	https://www.wikidoc.org/index.php/Road_rage
99bf90a923bc33ee409546b4dea8c4cdbe90faac	wikidoc	Rofecoxib	Rofecoxib # Overview Rofecoxib /ˌrɒfˈkɒksɪb/ is a nonsteroidal anti-inflammatory drug (NSAID) that has now been withdrawn over safety concerns. It was marketed by Merck & Co. to treat osteoarthritis, acute pain conditions, and dysmenorrhoea. Rofecoxib was approved by the Food and Drug Administration (FDA) on May 20, 1999, and was marketed under the brand names Vioxx, Ceoxx, and Ceeoxx. Rofecoxib gained widespread acceptance among physicians treating patients with arthritis and other conditions causing chronic or acute pain. Worldwide, over 80 million people were prescribed rofecoxib at some time. On September 30, 2004, Merck withdrew rofecoxib from the market because of concerns about increased risk of heart attack and stroke associated with long-term, high-dosage use. Merck withdrew the drug after disclosures that it withheld information about rofecoxib's risks from doctors and patients for over five years, resulting in between 88,000 and 140,000 cases of serious heart disease. Rofecoxib was one of the most widely used drugs ever to be withdrawn from the market. In the year before withdrawal, Merck had sales revenue of US$2.5 billion from Vioxx. Merck reserved $970 million to pay for its Vioxx-related legal expenses through 2007, and have set aside $4.85bn for legal claims from US citizens. Rofecoxib was available on prescription in both tablet-form and as an oral suspension. It was available by injection for hospital use. # Mode of action Cyclooxygenase (COX) has two well-studied isoforms, called COX-1 and COX-2. COX-1 mediates the synthesis of prostaglandins responsible for protection of the stomach lining, while COX-2 mediates the synthesis of prostaglandins responsible for pain and inflammation. By creating "selective" NSAIDs that inhibit COX-2, but not COX-1, the same pain relief as traditional NSAIDs is offered, but with greatly reduced risk of fatal or debilitating peptic ulcers. Rofecoxib is a selective COX-2 inhibitor, or "coxib". Others include Merck's etoricoxib (Arcoxia), Pfizer’s celecoxib (Celebrex) and valdecoxib (Bextra). Interestingly, at the time of its withdrawal, rofecoxib was the only coxib with clinical evidence of its superior gastrointestinal adverse effect profile over conventional NSAIDs. This was largely based on the VIGOR (Vioxx GI Outcomes Research) study, which compared the efficacy and adverse effect profiles of rofecoxib and naproxen. ## Pharmacokinetics The therapeutic recommended dosages were 12.5, 25, and 50 mg with an approximate bioavailability of 93%. Rofecoxib crossed the placenta and blood–brain barrier, and took 1–3 hours to reach peak plasma concentration with an effective half-life (based on steady-state levels) of approximately 17 hours. The metabolic products are cis-dihydro and trans-dihydro derivatives of rofecoxib which are primarily excreted through urine. ## Fabricated efficacy studies On March 11, 2009, Scott S. Reuben, former chief of acute pain at Baystate Medical Center, Springfield, Mass., revealed that data for 21 studies he had authored for the efficacy of the drug (along with others such as celecoxib) had been fabricated in order to augment the analgesic effects of the drugs. There is no evidence that Reuben colluded with Merck in falsifying his data. Reuben was also a former paid spokesperson for the drug company Pfizer (which owns the intellectual property rights for marketing celecoxib in the United States). The retracted studies were not submitted to either the FDA or the European Union's regulatory agencies prior to the drug's approval. Drug manufacturer Merck had no comment on the disclosure. # Adverse drug reactions Aside from the reduced incidence of gastric ulceration, rofecoxib exhibits a similar adverse effect profile to other NSAIDs. Prostaglandin is a large family of lipids. Prostaglandin I2/PGI2/prostacyclin is just one member of it. Prostaglandins other than PGI2 (such as PGE2) also play important roles in vascular tone regulation. Prostacyclin/thromboxane are produced by both COX-1 and COX-2, and rofecoxib suppresses just COX-2 enzyme, so there is no reason to believe that prostacyclin levels are significantly reduced by the drug. And there is no reason to believe that only the balance between quantities of prostacyclin and thromboxane is the determinant factor for vascular tone. Indeed Merck has stated that there was no effect on prostacyclin production in blood vessels in animal testing. Other researchers have speculated that the cardiotoxicity may be associated with maleic anhydride metabolites formed when rofecoxib becomes ionized under physiological conditions. (Reddy & Corey, 2005) ## Adverse cardiovascular events ### VIGOR study and publishing controversy The VIGOR (Vioxx GI Outcomes Research) study, conducted by Bombardier, et al., which compared the efficacy and adverse effect profiles of rofecoxib and naproxen, had indicated a significant 4-fold increased risk of acute myocardial infarction (heart attack) in rofecoxib patients when compared with naproxen patients (0.4% vs 0.1%, RR 0.25) over the 12 month span of the study. The elevated risk began during the second month on rofecoxib. There was no significant difference in the mortality from cardiovascular events between the two groups, nor was there any significant difference in the rate of myocardial infarction between the rofecoxib and naproxen treatment groups in patients without high cardiovascular risk. The difference in overall risk was by the patients at higher risk of heart attack, i.e. those meeting the criteria for low-dose aspirin prophylaxis of secondary cardiovascular events (previous myocardial infarction, angina, cerebrovascular accident, transient ischemic attack, or coronary artery bypass). Merck's scientists interpreted the finding as a protective effect of naproxen, telling the FDA that the difference in heart attacks "is primarily due to" this protective effect. Some commentators have noted that naproxen would have to be three times as effective as aspirin to account for all of the difference, and some outside scientists warned Merck that this claim was implausible before VIGOR was published. No evidence has since emerged for such a large cardioprotective effect of naproxen, although a number of studies have found protective effects similar in size to those of aspirin. Though Dr. Topol's 2004 paper criticized Merck's naproxen hypothesis, he himself co-authored a 2001 JAMA article stating "because of the evidence for an antiplatelet effect of naproxen, it is difficult to assess whether the difference in cardiovascular event rates in VIGOR was due to a benefit from naproxen or to a prothrombotic effect from rofecoxib." (Mukherjee, Nissen and Topol, 2001.) The results of the VIGOR study were submitted to the United States Food and Drug Administration (FDA) in February 2001. In September 2001, the FDA sent a warning letter to the CEO of Merck, stating, "Your promotional campaign discounts the fact that in the VIGOR study, patients on Vioxx were observed to have a four to five fold increase in myocardial infarctions (MIs) compared to patients on the comparator non-steroidal anti-inflammatory drug (NSAID), Naprosyn (naproxen)." This led to the introduction, in April 2002, of warnings on Vioxx labeling concerning the increased risk of cardiovascular events (heart attack and stroke). Months after the preliminary version of VIGOR was published in the New England Journal of Medicine, the journal editors learned that certain data reported to the FDA were not included in the NEJM article. Several years later, when they were shown a Merck memo during the depositions for the first federal Vioxx trial, they realized that these data had been available to the authors months before publication. The editors wrote an editorial accusing the authors of deliberately withholding the data. They released the editorial to the media on December 8, 2005, before giving the authors a chance to respond. NEJM editor Gregory Curfman explained that the quick release was due to the imminent presentation of his deposition testimony, which he feared would be misinterpreted in the media. He had earlier denied any relationship between the timing of the editorial and the trial. Although his testimony was not actually used in the December trial, Curfman had testified well before the publication of the editorial. The editors charged that "more than four months before the article was published, at least two of its authors were aware of critical data on an array of adverse cardiovascular events that were not included in the VIGOR article." These additional data included three additional heart attacks, and raised the relative risk of Vioxx from 4.25-fold to 5-fold. All the additional heart attacks occurred in the group at low risk of heart attack (the "aspirin not indicated" group) and the editors noted that the omission "resulted in the misleading conclusion that there was a difference in the risk of myocardial infarction between the aspirin indicated and aspirin not indicated groups." The relative risk for myocardial infarctions among the aspirin not indicated patients increased from 2.25 to 3 (although it remained statitistically insignificant). The editors also noted a statistically significant (2-fold) increase in risk for serious thromboembolic events for this group, an outcome that Merck had not reported in the NEJM, though it had disclosed that information publicly in March 2000, eight months before publication. The authors of the study, including the non-Merck authors, responded by claiming that the three additional heart attacks had occurred after the prespecified cutoff date for data collection and thus were appropriately not included. (Utilizing the prespecified cutoff date also meant that an additional stroke in the naproxen population was not reported.) Furthermore, they said that the additional data did not qualitatively change any of the conclusions of the study, and the results of the full analyses were disclosed to the FDA and reflected on the Vioxx warning label. They further noted that all of the data in the "omitted" table were printed in the text of the article. The authors stood by the original article. NEJM stood by its editorial, noting that the cutoff date was never mentioned in the article, nor did the authors report that the cutoff for cardiovascular adverse events was before that for gastrointestinal adverse events. The different cutoffs increased the reported benefits of Vioxx (reduced stomach problems) relative to the risks (increased heart attacks). Some scientists have accused the NEJM editorial board of making unfounded accusations. Others have applauded the editorial. Renowned research cardiologist Eric Topol, a prominent Merck critic, accused Merck of "manipulation of data" and said "I think now the scientific misconduct trial is really fully backed up". Phil Fontanarosa, executive editor of the prestigious Journal of the American Medical Association, welcomed the editorial, saying "this is another in the long list of recent examples that have generated real concerns about trust and confidence in industry-sponsored studies". On May 15, 2006, the Wall Street Journal reported that a late night email, written by an outside public relations specialist and sent to Journal staffers hours before the Expression of Concern was released, predicted that "the rebuke would divert attention to Merck and induce the media to ignore the New England Journal of Medicine's own role in aiding Vioxx sales." "Internal emails show the New England Journal's expression of concern was timed to divert attention from a deposition in which Executive Editor Gregory Curfman made potentially damaging admissions about the journal's handling of the Vioxx study. In the deposition, part of the Vioxx litigation, Dr. Curfman acknowledged that lax editing might have helped the authors make misleading claims in the article." The Journal stated that NEJM's "ambiguous" language misled reporters into incorrectly believing that Merck had deleted data regarding the three additional heart attacks, rather than a blank table that contained no statistical information; "the New England Journal says it didn't attempt to have these mistakes corrected." ### Alzheimer's studies In 2000 and 2001, Merck conducted several studies of rofecoxib aimed at determining if the drug slowed the onset of Alzheimer's disease. Merck has placed great emphasis on these studies on the grounds that they are relatively large (almost 3000 patients) and compared rofecoxib to a placebo rather than to another pain reliever. These studies found an elevated death rate among rofecoxib patients, although the deaths were not generally heart-related. However, they did not find any elevated cardiovascular risk due to rofecoxib. Before 2004, Merck cited these studies as providing evidence, contrary to VIGOR, of rofecoxib's safety. ### APPROVe study In 2001, Merck commenced the APPROVe (Adenomatous Polyp PRevention On Vioxx) study, a three-year trial with the primary aim of evaluating the efficacy of rofecoxib for the prophylaxis of colorectal polyps. Celecoxib had already been approved for this indication, and it was hoped to add this to the indications for rofecoxib as well. An additional aim of the study was to further evaluate the cardiovascular safety of rofecoxib. The APPROVe study was terminated early when the preliminary data from the study showed an increased relative risk of adverse thrombotic cardiovascular events (including heart attack and stroke), beginning after 18 months of rofecoxib therapy. In patients taking rofecoxib, versus placebo, the relative risk of these events was 1.92 (rofecoxib 1.50 events vs placebo 0.78 events per 100 patient years). The results from the first 18 months of the APPROVe study did not show an increased relative risk of adverse cardiovascular events. Moreover, overall and cardiovascular mortality rates were similar between the rofecoxib and placebo populations. In summary, the APPROVe study suggested that long-term use of rofecoxib resulted in nearly twice the risk of suffering a heart attack or stroke compared to patients receiving a placebo. ### Other studies Pre-approval Phase III clinical trials, like the APPROVe study, showed no increased relative risk of adverse cardiovascular events for the first eighteen months of rofecoxib usage (Merck, 2004). Others have pointed out that "study 090," a pre-approval trial, showed a 3-fold increase in cardiovascular events compared to placebo, a 7-fold increase compared to nabumetone (another ), and an 8-fold increase in heart attacks and strokes combined compared to both control groups. Although this was a relatively small study and only the last result was statistically significant, critics have charged that this early finding should have prompted Merck to quickly conduct larger studies of rofecoxib's cardiovascular safety. Merck notes that it had already begun VIGOR at the time Study 090 was completed. Although VIGOR was primarily designed to demonstrate new uses for rofecoxib, it also collected data on adverse cardiovascular outcomes. Several very large observational studies have also found elevated risk of heart attack from rofecoxib. For example, a recent retrospective study of 113,000 elderly Canadians suggested a borderline statistically significant increased relative risk of heart attacks of 1.24 from Vioxx usage, with a relative risk of 1.73 for higher-dose Vioxx usage. (Levesque, 2005). Another study, using Kaiser Permanente data, found a 1.47 relative risk for low-dose Vioxx usage and 3.58 for high-dose Vioxx usage compared to current use of celecoxib, though the smaller number was not statistically significant, and relative risk compared to other populations was not statistically significant. (Graham, 2005). Furthermore, a more recent meta-study of 114 randomized trials with a total of 116,000+ participants, published in JAMA, showed that Vioxx uniquely increased risk of renal (kidney) disease, and heart arrhythmia. ### Other COX-2 inhibitors Any increased risk of renal and arrhythmia pathologies associated with the class of COX-2 inhibitors, e.g. celecoxib (Celebrex), valdecoxib (Bextra), parecoxib (Dynastat), lumiracoxib, and etoricoxib is not evident, although smaller studies had demonstrated such effects earlier with the use of celecoxib, valdecoxib and parecoxib. Nevertheless, it is likely that trials of newer drugs in the category will be extended in order to supply additional evidence of cardiovascular safety. Examples are some more specific COX-2 inhibitors, including etoricoxib (Arcoxia) and lumiracoxib (Prexige), which are currently (circa 2005) undergoing Phase III/IV clinical trials. Besides, regulatory authorities worldwide now require warnings about cardiovascular risk of COX-2 inhibitors still on the market. For example, in 2005, EU regulators required the following changes to the product information and/or packaging of all COX-2 inhibitors: - Contraindications stating that COX-2 inhibitors must not be used in patients with established ischaemic heart disease and/or cerebrovascular disease (stroke), and also in patients with peripheral arterial disease - Reinforced warnings to healthcare professionals to exercise caution when prescribing COX-2 inhibitors to patients with risk factors for heart disease, such as hypertension, hyperlipidaemia (high cholesterol levels), diabetes and smoking - Given the association between cardiovascular risk and exposure to COX-2 inhibitors, doctors are advised to use the lowest effective dose for the shortest possible duration of treatment ### Other NSAIDs Since the withdrawal of Vioxx it has come to light that there may be negative cardiovascular effects with not only other COX-2 inhibitiors, but even the majority of other NSAIDs. It is only with the recent development of drugs like Vioxx that drug companies have carried out the kind of well executed trials that could establish such effects and these sort of trials have never been carried out in older "trusted" NSAIDs such as ibuprofen, diclofenac and others. The possible exceptions may be aspirin and naproxen due to their anti-platelet aggregation properties. # Withdrawal Due to the findings of its own APPROVe study, Merck publicly announced its voluntary withdrawal of the drug from the market worldwide on September 30, 2004. In addition to its own studies, on September 23, 2004 Merck apparently received information about new research by the FDA that supported previous findings of increased risk of heart attack among rofecoxib users (Grassley, 2004). FDA analysts estimated that Vioxx caused between 88,000 and 139,000 heart attacks, 30 to 40 percent of which were probably fatal, in the five years the drug was on the market. On November 5, the medical journal The Lancet published a meta-analysis of the available studies on the safety of rofecoxib (Jüni et al., 2004). The authors concluded that, owing to the known cardiovascular risk, rofecoxib should have been withdrawn several years earlier. The Lancet published an editorial which condemned both Merck and the FDA for the continued availability of rofecoxib from 2000 until the recall. Merck responded by issuing a rebuttal of the Jüni et al. meta-analysis that noted that Jüni omitted several studies that showed no increased cardiovascular risk. (Merck & Co., 2004). In 2005, advisory panels in both the U.S. and Canada encouraged the return of rofecoxib to the market, stating that rofecoxib's benefits outweighed the risks for some patients. The FDA advisory panel voted 17-15 to allow the drug to return to the market despite being found to increase heart risk. The vote in Canada was 12-1, and the Canadian panel noted that the cardiovascular risks from rofecoxib seemed to be no worse than those from ibuprofen—though the panel recommended that further study was needed for all NSAIDs to fully understand their risk profiles. Notwithstanding these recommendations, Merck has not returned rofecoxib to the market. In 2005, Merck retained Debevoise & Plimpton LLP to investigate Vioxx study results and communications conducted by Merck. Through the report, it was found that Merck's senior management acted in good faith, and that the confusion over the clinical safety of Vioxx was due to the sales team's overzealous behavior. The report that was filed gave a timeline of the events surrounding Vioxx and showed that Merck intended to operate honestly throughout the process. Any mistakes that were made regarding the mishandling of clinical trial results and withholding of information was the result of oversight, not malicious behavior. The Martin Report did conclude that the Merck's marketing team exaggerated the safety of Vioxx and replaced truthful information with sales tactics. The report was published in February 2006, and Merck was satisfied with the findings of the report and promised to consider the recommendations contained in the Martin Report. # Litigation As of March 2006, there had been over 10,000 cases and 190 class actions filed against Merck over adverse cardiovascular events associated with rofecoxib and the adequacy of Merck's warnings. The first wrongful death trial, Rogers v. Merck, was scheduled in Alabama in the spring of 2005, but was postponed after Merck argued that the plaintiff had falsified evidence of rofecoxib use. On August 19, 2005, a jury in Texas voted 10-2 to hold Merck liable for the death of Robert Ernst, a 59-year-old man who allegedly died of a rofecoxib-induced heart attack. The plaintiffs' lead attorney was Mark Lanier. Merck argued that the death was due to cardiac arrhythmia, which had not been shown to be associated with rofecoxib use. The jury awarded Carol Ernst, widow of Robert Ernst, $253.4 million in damages. This award will almost certainly be capped at no more than US$26.1 million because of punitive damages limits under Texas law. As of March 2006, the plaintiff had yet to ask the court to enter a judgment on the verdict; Merck has stated that it will appeal. On November 3, 2005, Merck won the second case Humeston v. Merck, a personal injury case, in Atlantic City, New Jersey. The plaintiff experienced a mild myocardial infarction and claimed that rofecoxib was responsible, after having taken it for two months. Merck argued that there was no evidence that rofecoxib was the cause of Humeston's injury and that there is no scientific evidence linking rofecoxib to cardiac events with short durations of use. The jury ruled that Merck had adequately warned doctors and patients of the drug's risk. The first federal trial on rofecoxib, Plunkett v. Merck, began on November 29, 2005 in Houston. The trial ended in a hung jury and a mistrial was declared on December 12, 2005. According to the Wall Street Journal, the jury hung by an eight to one majority, favoring the defense. Upon retrial in February 2006 in New Orleans, where the Vioxx multidistrict litigation (MDL) is based, a jury found Merck not liable, even though the plaintiffs had the NEJM editor testify as to his objections to the VIGOR study. On January 30, 2006, a New Jersey state court dismissed a case brought by Edgar Lee Boyd, who blamed Vioxx for gastrointestinal bleeding that he experienced after taking the drug. The judge said that Boyd failed to prove the drug caused his stomach pain and internal bleeding. In January 2006, Garza v. Merck began trial in Rio Grande City, Texas. The plaintiff, a 71-year-old smoker with heart disease, had a fatal heart attack three weeks after finishing a one-week sample of rofecoxib. On April 21, 2006 the jury awarded the plaintiff $7 million compensatory and $25 million punitive. The Texas state court of appeals in San Antonio later rules Garza's fatal heart attack probably resulted from pre-existing health conditions unrelated to his taking of Vioxx, thus reversing the $32 million jury award. On April 5, 2006, the jury held Merck liable for the heart attack of 77-year-old John McDarby, and awarded Mr McDarby $4.5 million in compensatory damages based on Merck's failure to properly warn of Vioxx safety risks. After a hearing on April 11, 2006, the jury also awarded Mr McDarby an additional $9 million in punitive damages. The same jury found Merck not liable for the heart attack of 60-year-old Thomas Cona, a second plaintiff in the trial, but was liable for fraud in the sale of the drug to Cona. In March 2010, an Australian class-action lawsuit against Merck ruled that Vioxx doubled the risk of heart attacks, and that Merck had breached the Trade Practices Act by selling a drug which was unfit for sale. In 2010, the national US case against Vioxx and Merck was resolved with a $4.85 billion settlement. After the settlement, the lawyers for the case disputed the $315 million awarded in legal fees. Ultimately, the judge determined how the fees would be awarded to the plaintiff’s attorneys. The judge additionally ordered the plaintiff lawyers to cap their fees at 32% of the settlement amount. The above dispute over lawyer fees has caused scholars and observers to consider tort reform throughout the country. Articles on the subject include The Vioxx Litigation: A Critical Look at Trial Tactics, the Tort System, and the Roles of Lawyers in Mass Tort Litigation and 10 Years of Tort Reform in Texas Bring Fewer Suits, Lower Payouts. In November 2011, Merck announced a civil settlement with the US Attorney's Office for the District of Massachusetts, and individually with 43 US states and the District of Columbia, to resolve civil claims relating to Vioxx. Under the terms of the settlement, Merck agreed to pay two-thirds of a previously recorded $950 million reserve charge in exchange for release from civil liability. Litigation with seven additional states remains outstanding. Under separate criminal proceedings, Merck plead guilty to a federal misdemeanor charge relating to the marketing of the drug across state lines, incurring a fine of $321.6 million. # Other effects Rofecoxib was shown to improve premenstrual acne vulgaris in a placebo controlled study.	Rofecoxib Editor-In-Chief: C. Michael Gibson, M.S., M.D. [13] # Overview Rofecoxib /ˌrɒf[invalid input: 'ɨ']ˈkɒksɪb/ is a nonsteroidal anti-inflammatory drug (NSAID) that has now been withdrawn over safety concerns. It was marketed by Merck & Co. to treat osteoarthritis, acute pain conditions, and dysmenorrhoea. Rofecoxib was approved by the Food and Drug Administration (FDA) on May 20, 1999, and was marketed under the brand names Vioxx, Ceoxx, and Ceeoxx. Rofecoxib gained widespread acceptance among physicians treating patients with arthritis and other conditions causing chronic or acute pain. Worldwide, over 80 million people were prescribed rofecoxib at some time.[1] On September 30, 2004, Merck withdrew rofecoxib from the market because of concerns about increased risk of heart attack and stroke associated with long-term, high-dosage use. Merck withdrew the drug after disclosures that it withheld information about rofecoxib's risks from doctors and patients for over five years, resulting in between 88,000 and 140,000 cases of serious heart disease.[2] Rofecoxib was one of the most widely used drugs ever to be withdrawn from the market. In the year before withdrawal, Merck had sales revenue of US$2.5 billion from Vioxx.[3] Merck reserved $970 million to pay for its Vioxx-related legal expenses through 2007, and have set aside $4.85bn for legal claims from US citizens. Rofecoxib was available on prescription in both tablet-form and as an oral suspension. It was available by injection for hospital use. # Mode of action Cyclooxygenase (COX) has two well-studied isoforms, called COX-1 and COX-2. COX-1 mediates the synthesis of prostaglandins responsible for protection of the stomach lining, while COX-2 mediates the synthesis of prostaglandins responsible for pain and inflammation. By creating "selective" NSAIDs that inhibit COX-2, but not COX-1, the same pain relief as traditional NSAIDs is offered, but with greatly reduced risk of fatal or debilitating peptic ulcers. Rofecoxib is a selective COX-2 inhibitor, or "coxib". Others include Merck's etoricoxib (Arcoxia), Pfizer’s celecoxib (Celebrex) and valdecoxib (Bextra). Interestingly, at the time of its withdrawal, rofecoxib was the only coxib with clinical evidence of its superior gastrointestinal adverse effect profile over conventional NSAIDs. This was largely based on the VIGOR (Vioxx GI Outcomes Research) study, which compared the efficacy and adverse effect profiles of rofecoxib and naproxen.[4] ## Pharmacokinetics The therapeutic recommended dosages were 12.5, 25, and 50 mg with an approximate bioavailability of 93%.[5][6][7] Rofecoxib crossed the placenta and blood–brain barrier,[5][6][8] and took 1–3 hours to reach peak plasma concentration with an effective half-life (based on steady-state levels) of approximately 17 hours.[5][7][9] The metabolic products are cis-dihydro and trans-dihydro derivatives of rofecoxib[5][9] which are primarily excreted through urine. ## Fabricated efficacy studies On March 11, 2009, Scott S. Reuben, former chief of acute pain at Baystate Medical Center, Springfield, Mass., revealed that data for 21 studies he had authored for the efficacy of the drug (along with others such as celecoxib) had been fabricated in order to augment the analgesic effects of the drugs. There is no evidence that Reuben colluded with Merck in falsifying his data. Reuben was also a former paid spokesperson for the drug company Pfizer (which owns the intellectual property rights for marketing celecoxib in the United States). The retracted studies were not submitted to either the FDA or the European Union's regulatory agencies prior to the drug's approval. Drug manufacturer Merck had no comment on the disclosure.[10] # Adverse drug reactions Aside from the reduced incidence of gastric ulceration, rofecoxib exhibits a similar adverse effect profile to other NSAIDs. Prostaglandin is a large family of lipids. Prostaglandin I2/PGI2/prostacyclin is just one member of it. Prostaglandins other than PGI2 (such as PGE2) also play important roles in vascular tone regulation. Prostacyclin/thromboxane are produced by both COX-1 and COX-2, and rofecoxib suppresses just COX-2 enzyme, so there is no reason to believe that prostacyclin levels are significantly reduced by the drug. And there is no reason to believe that only the balance between quantities of prostacyclin and thromboxane is the determinant factor for vascular tone.[11] Indeed Merck has stated that there was no effect on prostacyclin production in blood vessels in animal testing.[12] Other researchers have speculated that the cardiotoxicity may be associated with maleic anhydride metabolites formed when rofecoxib becomes ionized under physiological conditions. (Reddy & Corey, 2005) ## Adverse cardiovascular events ### VIGOR study and publishing controversy The VIGOR (Vioxx GI Outcomes Research) study, conducted by Bombardier, et al., which compared the efficacy and adverse effect profiles of rofecoxib and naproxen, had indicated a significant 4-fold increased risk of acute myocardial infarction (heart attack) in rofecoxib patients when compared with naproxen patients (0.4% vs 0.1%, RR 0.25) over the 12 month span of the study. The elevated risk began during the second month on rofecoxib. There was no significant difference in the mortality from cardiovascular events between the two groups, nor was there any significant difference in the rate of myocardial infarction between the rofecoxib and naproxen treatment groups in patients without high cardiovascular risk. The difference in overall risk was by the patients at higher risk of heart attack, i.e. those meeting the criteria for low-dose aspirin prophylaxis of secondary cardiovascular events (previous myocardial infarction, angina, cerebrovascular accident, transient ischemic attack, or coronary artery bypass). Merck's scientists interpreted the finding as a protective effect of naproxen, telling the FDA that the difference in heart attacks "is primarily due to" this protective effect.[13] Some commentators have noted that naproxen would have to be three times as effective as aspirin to account for all of the difference,[14] and some outside scientists warned Merck that this claim was implausible before VIGOR was published.[15] No evidence has since emerged for such a large cardioprotective effect of naproxen, although a number of studies have found protective effects similar in size to those of aspirin.[16][17] Though Dr. Topol's 2004 paper criticized Merck's naproxen hypothesis, he himself co-authored a 2001 JAMA article stating "because of the evidence for an antiplatelet effect of naproxen, it is difficult to assess whether the difference in cardiovascular event rates in VIGOR was due to a benefit from naproxen or to a prothrombotic effect from rofecoxib." (Mukherjee, Nissen and Topol, 2001.) The results of the VIGOR study were submitted to the United States Food and Drug Administration (FDA) in February 2001. In September 2001, the FDA sent a warning letter to the CEO of Merck, stating, "Your promotional campaign discounts the fact that in the VIGOR study, patients on Vioxx were observed to have a four to five fold increase in myocardial infarctions (MIs) compared to patients on the comparator non-steroidal anti-inflammatory drug (NSAID), Naprosyn (naproxen)."[18] This led to the introduction, in April 2002, of warnings on Vioxx labeling concerning the increased risk of cardiovascular events (heart attack and stroke). Months after the preliminary version of VIGOR was published in the New England Journal of Medicine, the journal editors learned that certain data reported to the FDA were not included in the NEJM article. Several years later, when they were shown a Merck memo during the depositions for the first federal Vioxx trial, they realized that these data had been available to the authors months before publication. The editors wrote an editorial accusing the authors of deliberately withholding the data.[19] They released the editorial to the media on December 8, 2005, before giving the authors a chance to respond. NEJM editor Gregory Curfman explained that the quick release was due to the imminent presentation of his deposition testimony, which he feared would be misinterpreted in the media. He had earlier denied any relationship between the timing of the editorial and the trial. Although his testimony was not actually used in the December trial, Curfman had testified well before the publication of the editorial.[20] The editors charged that "more than four months before the article was published, at least two of its authors were aware of critical data on an array of adverse cardiovascular events that were not included in the VIGOR article." These additional data included three additional heart attacks, and raised the relative risk of Vioxx from 4.25-fold to 5-fold. All the additional heart attacks occurred in the group at low risk of heart attack (the "aspirin not indicated" group) and the editors noted that the omission "resulted in the misleading conclusion that there was a difference in the risk of myocardial infarction between the aspirin indicated and aspirin not indicated groups." The relative risk for myocardial infarctions among the aspirin not indicated patients increased from 2.25 to 3 (although it remained statitistically insignificant). The editors also noted a statistically significant (2-fold) increase in risk for serious thromboembolic events for this group, an outcome that Merck had not reported in the NEJM, though it had disclosed that information publicly in March 2000, eight months before publication.[21] The authors of the study, including the non-Merck authors, responded by claiming that the three additional heart attacks had occurred after the prespecified cutoff date for data collection and thus were appropriately not included. (Utilizing the prespecified cutoff date also meant that an additional stroke in the naproxen population was not reported.) Furthermore, they said that the additional data did not qualitatively change any of the conclusions of the study, and the results of the full analyses were disclosed to the FDA and reflected on the Vioxx warning label. They further noted that all of the data in the "omitted" table were printed in the text of the article. The authors stood by the original article.[22] NEJM stood by its editorial, noting that the cutoff date was never mentioned in the article, nor did the authors report that the cutoff for cardiovascular adverse events was before that for gastrointestinal adverse events. The different cutoffs increased the reported benefits of Vioxx (reduced stomach problems) relative to the risks (increased heart attacks).[21] Some scientists have accused the NEJM editorial board of making unfounded accusations.[23][24] Others have applauded the editorial. Renowned research cardiologist Eric Topol,[25] a prominent Merck critic, accused Merck of "manipulation of data" and said "I think now the scientific misconduct trial is really fully backed up".[26] Phil Fontanarosa, executive editor of the prestigious Journal of the American Medical Association, welcomed the editorial, saying "this is another in the long list of recent examples that have generated real concerns about trust and confidence in industry-sponsored studies".[27] On May 15, 2006, the Wall Street Journal reported that a late night email, written by an outside public relations specialist and sent to Journal staffers hours before the Expression of Concern was released, predicted that "the rebuke would divert attention to Merck and induce the media to ignore the New England Journal of Medicine's own role in aiding Vioxx sales."[28] "Internal emails show the New England Journal's expression of concern was timed to divert attention from a deposition in which Executive Editor Gregory Curfman made potentially damaging admissions about the journal's handling of the Vioxx study. In the deposition, part of the Vioxx litigation, Dr. Curfman acknowledged that lax editing might have helped the authors make misleading claims in the article." The Journal stated that NEJM's "ambiguous" language misled reporters into incorrectly believing that Merck had deleted data regarding the three additional heart attacks, rather than a blank table that contained no statistical information; "the New England Journal says it didn't attempt to have these mistakes corrected."[28] ### Alzheimer's studies In 2000 and 2001, Merck conducted several studies of rofecoxib aimed at determining if the drug slowed the onset of Alzheimer's disease. Merck has placed great emphasis on these studies on the grounds that they are relatively large (almost 3000 patients) and compared rofecoxib to a placebo rather than to another pain reliever. These studies found an elevated death rate among rofecoxib patients, although the deaths were not generally heart-related. However, they did not find any elevated cardiovascular risk due to rofecoxib.[29] Before 2004, Merck cited these studies as providing evidence, contrary to VIGOR, of rofecoxib's safety. ### APPROVe study In 2001, Merck commenced the APPROVe (Adenomatous Polyp PRevention On Vioxx) study, a three-year trial with the primary aim of evaluating the efficacy of rofecoxib for the prophylaxis of colorectal polyps. Celecoxib had already been approved for this indication, and it was hoped to add this to the indications for rofecoxib as well. An additional aim of the study was to further evaluate the cardiovascular safety of rofecoxib. The APPROVe study was terminated early when the preliminary data from the study showed an increased relative risk of adverse thrombotic cardiovascular events (including heart attack and stroke), beginning after 18 months of rofecoxib therapy. In patients taking rofecoxib, versus placebo, the relative risk of these events was 1.92 (rofecoxib 1.50 events vs placebo 0.78 events per 100 patient years). The results from the first 18 months of the APPROVe study did not show an increased relative risk of adverse cardiovascular events. Moreover, overall and cardiovascular mortality rates were similar between the rofecoxib and placebo populations.[30] In summary, the APPROVe study suggested that long-term use of rofecoxib resulted in nearly twice the risk of suffering a heart attack or stroke compared to patients receiving a placebo. ### Other studies Pre-approval Phase III clinical trials, like the APPROVe study, showed no increased relative risk of adverse cardiovascular events for the first eighteen months of rofecoxib usage (Merck, 2004). Others have pointed out that "study 090," a pre-approval trial, showed a 3-fold increase in cardiovascular events compared to placebo, a 7-fold increase compared to nabumetone (another [NSAID]), and an 8-fold increase in heart attacks and strokes combined compared to both control groups.[13][31] Although this was a relatively small study and only the last result was statistically significant, critics have charged that this early finding should have prompted Merck to quickly conduct larger studies of rofecoxib's cardiovascular safety. Merck notes that it had already begun VIGOR at the time Study 090 was completed. Although VIGOR was primarily designed to demonstrate new uses for rofecoxib, it also collected data on adverse cardiovascular outcomes. Several very large observational studies have also found elevated risk of heart attack from rofecoxib. For example, a recent retrospective study of 113,000 elderly Canadians suggested a borderline statistically significant increased relative risk of heart attacks of 1.24 from Vioxx usage, with a relative risk of 1.73 for higher-dose Vioxx usage. (Levesque, 2005). Another study, using Kaiser Permanente data, found a 1.47 relative risk for low-dose Vioxx usage and 3.58 for high-dose Vioxx usage compared to current use of celecoxib, though the smaller number was not statistically significant, and relative risk compared to other populations was not statistically significant. (Graham, 2005). Furthermore, a more recent meta-study of 114 randomized trials with a total of 116,000+ participants, published in JAMA, showed that Vioxx uniquely increased risk of renal (kidney) disease, and heart arrhythmia.[32] ### Other COX-2 inhibitors Any increased risk of renal and arrhythmia pathologies associated with the class of COX-2 inhibitors, e.g. celecoxib (Celebrex), valdecoxib (Bextra), parecoxib (Dynastat), lumiracoxib, and etoricoxib is not evident,[32] although smaller studies[33][34] had demonstrated such effects earlier with the use of celecoxib, valdecoxib and parecoxib. Nevertheless, it is likely that trials of newer drugs in the category will be extended in order to supply additional evidence of cardiovascular safety. Examples are some more specific COX-2 inhibitors, including etoricoxib (Arcoxia) and lumiracoxib (Prexige), which are currently (circa 2005) undergoing Phase III/IV clinical trials. Besides, regulatory authorities worldwide now require warnings about cardiovascular risk of COX-2 inhibitors still on the market. For example, in 2005, EU regulators required the following changes to the product information and/or packaging of all COX-2 inhibitors:[35] - Contraindications stating that COX-2 inhibitors must not be used in patients with established ischaemic heart disease and/or cerebrovascular disease (stroke), and also in patients with peripheral arterial disease - Reinforced warnings to healthcare professionals to exercise caution when prescribing COX-2 inhibitors to patients with risk factors for heart disease, such as hypertension, hyperlipidaemia (high cholesterol levels), diabetes and smoking - Given the association between cardiovascular risk and exposure to COX-2 inhibitors, doctors are advised to use the lowest effective dose for the shortest possible duration of treatment ### Other NSAIDs Since the withdrawal of Vioxx it has come to light that there may be negative cardiovascular effects with not only other COX-2 inhibitiors, but even the majority of other NSAIDs. It is only with the recent development of drugs like Vioxx that drug companies have carried out the kind of well executed trials that could establish such effects and these sort of trials have never been carried out in older "trusted" NSAIDs such as ibuprofen, diclofenac and others. The possible exceptions may be aspirin and naproxen due to their anti-platelet aggregation properties. # Withdrawal Due to the findings of its own APPROVe study, Merck publicly announced its voluntary withdrawal of the drug from the market worldwide on September 30, 2004.[36] In addition to its own studies, on September 23, 2004 Merck apparently received information about new research by the FDA that supported previous findings of increased risk of heart attack among rofecoxib users (Grassley, 2004). FDA analysts estimated that Vioxx caused between 88,000 and 139,000 heart attacks, 30 to 40 percent of which were probably fatal, in the five years the drug was on the market.[37] On November 5, the medical journal The Lancet published a meta-analysis of the available studies on the safety of rofecoxib (Jüni et al., 2004). The authors concluded that, owing to the known cardiovascular risk, rofecoxib should have been withdrawn several years earlier. The Lancet published an editorial which condemned both Merck and the FDA for the continued availability of rofecoxib from 2000 until the recall.[38] Merck responded by issuing a rebuttal of the Jüni et al. meta-analysis that noted that Jüni omitted several studies that showed no increased cardiovascular risk. (Merck & Co., 2004). In 2005, advisory panels in both the U.S. and Canada encouraged the return of rofecoxib to the market, stating that rofecoxib's benefits outweighed the risks for some patients. The FDA advisory panel voted 17-15 to allow the drug to return to the market despite being found to increase heart risk. The vote in Canada was 12-1, and the Canadian panel noted that the cardiovascular risks from rofecoxib seemed to be no worse than those from ibuprofen—though the panel recommended that further study was needed for all NSAIDs to fully understand their risk profiles. Notwithstanding these recommendations, Merck has not returned rofecoxib to the market.[39] In 2005, Merck retained Debevoise & Plimpton LLP to investigate Vioxx study results and communications conducted by Merck. Through the report, it was found that Merck's senior management acted in good faith, and that the confusion over the clinical safety of Vioxx was due to the sales team's overzealous behavior. The report that was filed gave a timeline of the events surrounding Vioxx and showed that Merck intended to operate honestly throughout the process. Any mistakes that were made regarding the mishandling of clinical trial results and withholding of information was the result of oversight, not malicious behavior. The Martin Report did conclude that the Merck's marketing team exaggerated the safety of Vioxx and replaced truthful information with sales tactics.[citation needed] The report was published in February 2006, and Merck was satisfied with the findings of the report and promised to consider the recommendations contained in the Martin Report. # Litigation As of March 2006, there had been over 10,000 cases and 190 class actions filed against Merck[citation needed] over adverse cardiovascular events associated with rofecoxib and the adequacy of Merck's warnings. The first wrongful death trial, Rogers v. Merck, was scheduled in Alabama in the spring of 2005, but was postponed after Merck argued that the plaintiff had falsified evidence of rofecoxib use.[40] On August 19, 2005, a jury in Texas voted 10-2 to hold Merck liable for the death of Robert Ernst, a 59-year-old man who allegedly died of a rofecoxib-induced heart attack. The plaintiffs' lead attorney was Mark Lanier. Merck argued that the death was due to cardiac arrhythmia, which had not been shown to be associated with rofecoxib use. The jury awarded Carol Ernst, widow of Robert Ernst, $253.4 million in damages. This award will almost certainly be capped at no more than US$26.1 million because of punitive damages limits under Texas law.[41] As of March 2006, the plaintiff had yet to ask the court to enter a judgment on the verdict; Merck has stated that it will appeal. On November 3, 2005, Merck won the second case Humeston v. Merck, a personal injury case, in Atlantic City, New Jersey. The plaintiff experienced a mild myocardial infarction and claimed that rofecoxib was responsible, after having taken it for two months. Merck argued that there was no evidence that rofecoxib was the cause of Humeston's injury and that there is no scientific evidence linking rofecoxib to cardiac events with short durations of use. The jury ruled that Merck had adequately warned doctors and patients of the drug's risk.[42] The first federal trial on rofecoxib, Plunkett v. Merck, began on November 29, 2005 in Houston. The trial ended in a hung jury and a mistrial was declared on December 12, 2005. According to the Wall Street Journal, the jury hung by an eight to one majority, favoring the defense. Upon retrial in February 2006 in New Orleans, where the Vioxx multidistrict litigation (MDL) is based, a jury found Merck not liable, even though the plaintiffs had the NEJM editor testify as to his objections to the VIGOR study. On January 30, 2006, a New Jersey state court dismissed a case brought by Edgar Lee Boyd, who blamed Vioxx for gastrointestinal bleeding that he experienced after taking the drug. The judge said that Boyd failed to prove the drug caused his stomach pain and internal bleeding. In January 2006, Garza v. Merck began trial in Rio Grande City, Texas. The plaintiff, a 71-year-old smoker with heart disease, had a fatal heart attack three weeks after finishing a one-week sample of rofecoxib. On April 21, 2006 the jury awarded the plaintiff $7 million compensatory and $25 million punitive. The Texas state court of appeals in San Antonio later rules Garza's fatal heart attack probably resulted from pre-existing health conditions unrelated to his taking of Vioxx, thus reversing the $32 million jury award.[43] On April 5, 2006, the jury held Merck liable for the heart attack of 77-year-old John McDarby, and awarded Mr McDarby $4.5 million in compensatory damages based on Merck's failure to properly warn of Vioxx safety risks. After a hearing on April 11, 2006, the jury also awarded Mr McDarby an additional $9 million in punitive damages. The same jury found Merck not liable for the heart attack of 60-year-old Thomas Cona, a second plaintiff in the trial, but was liable for fraud in the sale of the drug to Cona. In March 2010, an Australian class-action lawsuit against Merck ruled that Vioxx doubled the risk of heart attacks, and that Merck had breached the Trade Practices Act by selling a drug which was unfit for sale.[44] In 2010, the national US case against Vioxx and Merck was resolved with a $4.85 billion settlement.[45] After the settlement, the lawyers for the case disputed the $315 million awarded in legal fees.[45][46] Ultimately, the judge determined how the fees would be awarded to the plaintiff’s attorneys.[47] The judge additionally ordered the plaintiff lawyers to cap their fees at 32% of the settlement amount.[48] The above dispute over lawyer fees has caused scholars and observers to consider tort reform throughout the country. Articles on the subject include The Vioxx Litigation: A Critical Look at Trial Tactics, the Tort System, and the Roles of Lawyers in Mass Tort Litigation [49] and 10 Years of Tort Reform in Texas Bring Fewer Suits, Lower Payouts.[50] In November 2011, Merck announced a civil settlement with the US Attorney's Office for the District of Massachusetts, and individually with 43 US states and the District of Columbia, to resolve civil claims relating to Vioxx.[51] Under the terms of the settlement, Merck agreed to pay two-thirds of a previously recorded $950 million reserve charge in exchange for release from civil liability. Litigation with seven additional states remains outstanding. Under separate criminal proceedings, Merck plead guilty to a federal misdemeanor charge relating to the marketing of the drug across state lines, incurring a fine of $321.6 million.[52] # Other effects Rofecoxib was shown to improve premenstrual acne vulgaris in a placebo controlled study.[53]	https://www.wikidoc.org/index.php/Rofecoxib
63579e1597ea66e8bd065a676ea66a3151db76ac	wikidoc	Ron Tripp	Ron Tripp Ron Tripp (born April 1953) Battle Creek, Michigan, is a World sambo (martial art) and Judo champion and the current general secretary of USA Judo. He is also a member of the board of directors of the United States Olympic Committee. His name is well-known in the MMA world, especially among jujutsu and submission grappling enthusiasts, as he is the only person to hold an official victory in competition over veteran Brazilian fighter Rickson Gracie. Tripp was promoted to 10th degree in Sambo in 1995 and became America's first Distinguished Masters of Sport in 1996. He was promoted to 6th dan by USA Judo in November 2006. A native of Lake Orion, Michigan, and graduate of Hillsdale College and Palmer College of Chiropractic, the 6 foot, 205 pound Tripp excelled in both the sports of Judo and Sambo. Trained by Pat Burris, 2 time Judo Olympian and Olympic Judo Coach, Tripp's fight career in judo lasted from 1982 to 1995. He is also a Doctor of Chiropractic. Tripp trained in Japan for six years, and during that time trained under Sensei Takagi at NichiDai University, home of MMA star Makoto Takimoto and 2 Time All Japan Judo Champion Jun Konno. In 2006 he founded C3Fights, a professional MMA company, and still personally trains C3Fighters at the USA Stars Training Center in Oklahoma City, Oklahoma. # Career highlights - 1970-1994: Competed in over 2,000 Judo, Sambo, and Wrestling matches. - 1982-1994: Reportedly compiled a tournament record of 900 wins and 4 defeats. - 1990: Submitted by Rigan Machado in 39 seconds, Pan Am finals - 1993: Defeated Rickson Gracie by Uchimata in 47 seconds. - 1994: At 41, defeated 24 year old Andrew Bourdeau to win the World Heavyweight Championship of Sambo in Montreal, Canada. # The Rickson Gracie fight In 1993 at the U.S. Sambo Championships in Norman, Oklahoma, undefeated Rickson Gracie, of the Gracie Jiu-Jitsu family was matched with multiple Judo and Sambo champion Ron Tripp. The 6 foot, 205 pound Tripp threw the 5 foot 10 inch, 185 pound Gracie to the canvas by "Uchi mata" in 47 seconds and Gracie's shoulders touched the floor, thus giving Tripp "absolute" victory under U.S. Sambo rules. Rickson disputed this loss, claiming he was misinformed of the rules of the event. # Awards and titles - World Sambo Champion - 7-time World Medalist - Distinguished Master of Sports - Olympic Festival Judo Champion Open Division - 8-time Olympic Festival Medal winner - 12-time Judo and Sambo National Champion and Pan American Champion - President of USA Judo 2000-2008 - Member of U.S. Olympic Committee - Co-Founder C3Fights - President of the Oklahoma Board of Chiropractic Examiners (1997–) - District Director, Federation of Chiropractic Licensing Boards (2006–) - Vice-Chairman of the Board of International Oil and Gas Holdings # Footnotes - ↑ USA Judo - ↑ US Judo November 2006 promotions - ↑ Jump up to: 3.0 3.1 3.2 Federation of Chiropractic Licensing Boards - Ron Tripp Bio - ↑ "Rickson Gracie interview: part one" (Reprint). FreeFight magazine. December 12, 2005. Retrieved 2007-07-02..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} - ↑ "Rickson Gracie interview: part two" (Reprint). FreeFight magazine. December 12, 2005. Retrieved 2007-07-02. - ↑ US Judo Media Guide 2005 - ↑ / C3Fights - Management Team - ↑ International Oil & Gas Holdings Corporation - Management Team # Sources - Ron Tripp's International Judo Federation interview - Ron Tripp's Hillsdale College Alumni Bio	Ron Tripp Template:BLP sources Ron Tripp (born April 1953) Battle Creek, Michigan, is a World sambo (martial art) and Judo champion and the current general secretary of USA Judo.[1] He is also a member of the board of directors of the United States Olympic Committee. His name is well-known in the MMA world, especially among jujutsu and submission grappling enthusiasts, as he is the only person to hold an official victory in competition over veteran Brazilian fighter Rickson Gracie. Tripp was promoted to 10th degree in Sambo in 1995 and became America's first Distinguished Masters of Sport in 1996. He was promoted to 6th dan by USA Judo in November 2006.[2] A native of Lake Orion, Michigan, and graduate of Hillsdale College and Palmer College of Chiropractic[3], the 6 foot, 205 pound Tripp excelled in both the sports of Judo and Sambo. Trained by Pat Burris, 2 time Judo Olympian and Olympic Judo Coach, Tripp's fight career in judo lasted from 1982 to 1995. He is also a Doctor of Chiropractic. Tripp trained in Japan for six years, and during that time trained under Sensei Takagi at NichiDai University, home of MMA star Makoto Takimoto and 2 Time All Japan Judo Champion Jun Konno. In 2006 he founded C3Fights, a professional MMA company, and still personally trains C3Fighters at the USA Stars Training Center in Oklahoma City, Oklahoma. # Career highlights - 1970-1994: Competed in over 2,000 Judo, Sambo, and Wrestling matches. - 1982-1994: Reportedly compiled a tournament record of 900 wins and 4 defeats. - 1990: Submitted by Rigan Machado in 39 seconds, Pan Am finals - 1993: Defeated Rickson Gracie by Uchimata in 47 seconds. - 1994: At 41, defeated 24 year old Andrew Bourdeau to win the World Heavyweight Championship of Sambo in Montreal, Canada. # The Rickson Gracie fight In 1993 at the U.S. Sambo Championships in Norman, Oklahoma, undefeated Rickson Gracie, of the Gracie Jiu-Jitsu family was matched with multiple Judo and Sambo champion Ron Tripp. The 6 foot, 205 pound Tripp threw the 5 foot 10 inch, 185 pound Gracie to the canvas by "Uchi mata" in 47 seconds and Gracie's shoulders touched the floor, thus giving Tripp "absolute" victory under U.S. Sambo rules. Rickson disputed this loss, claiming he was misinformed of the rules of the event.[4][5] # Awards and titles - World Sambo Champion[citation needed] - 7-time World Medalist - Distinguished Master of Sports - Olympic Festival Judo Champion Open Division - 8-time Olympic Festival Medal winner - 12-time Judo and Sambo National Champion and Pan American Champion - President of USA Judo 2000-2008[6] - Member of U.S. Olympic Committee - Co-Founder C3Fights[7] - President of the Oklahoma Board of Chiropractic Examiners (1997–)[3] - District Director, Federation of Chiropractic Licensing Boards (2006–)[3] - Vice-Chairman of the Board of International Oil and Gas Holdings[8] # Footnotes - ↑ USA Judo - ↑ US Judo November 2006 promotions - ↑ Jump up to: 3.0 3.1 3.2 Federation of Chiropractic Licensing Boards - Ron Tripp Bio - ↑ "Rickson Gracie interview: part one" (Reprint). FreeFight magazine. December 12, 2005. Retrieved 2007-07-02..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} - ↑ "Rickson Gracie interview: part two" (Reprint). FreeFight magazine. December 12, 2005. Retrieved 2007-07-02. - ↑ US Judo Media Guide 2005 - ↑ http://www.c3fights.com/managementteam/ C3Fights - Management Team - ↑ International Oil & Gas Holdings Corporation - Management Team # Sources - Ron Tripp's International Judo Federation interview - Ron Tripp's Hillsdale College Alumni Bio Template:ATTRIB	https://www.wikidoc.org/index.php/Ron_Tripp
bb14fc8fdf9f4499be8168defdf81aec089741c3	wikidoc	Rootletin	Rootletin Rootletin also known as ciliary rootlet coiled-coil protein (CROCC) is a protein that in humans is encoded by the CROCC gene. Rootletin is a component of the ciliary rootlet, and, together with CEP68 and CEP250, is required for centrosome cohesion. Rootletin is an important protein in the ciliary rootlet, particular for the structure and can be considered an important protein in mitosis as it is a centrosome linker. # Function This protein forms part of the ciliary rootlet structure. It also helps to contribute to the centrosome cohesion before mitosis. Expression of rooletin leads to the formation of fibrous protein. # Structure This protein is part of the structure of a ciliary rootlet. This cytoskeletal-like structure starts from the basal body at one end of the cilium and extends towards nucleus. Its molecular structure consists of a globular head domain and a tail domain made up of coiled-coil structures. # Protein interactions A large coiled-coil protein, C-Nap1, is a docking site for the fibrous tether to proximal ends of centrioles which Rootletin physically interacts with. Furthermore, Rootletin is phosphorylated by Nek2 kinase.	Rootletin Rootletin also known as ciliary rootlet coiled-coil protein (CROCC) is a protein that in humans is encoded by the CROCC gene.[1][2][3] Rootletin is a component of the ciliary rootlet, and, together with CEP68 and CEP250, is required for centrosome cohesion.[4] Rootletin is an important protein in the ciliary rootlet, particular for the structure and can be considered an important protein in mitosis as it is a centrosome linker. # Function This protein forms part of the ciliary rootlet structure. It also helps to contribute to the centrosome cohesion before mitosis.[5] Expression of rooletin leads to the formation of fibrous protein. # Structure This protein is part of the structure of a ciliary rootlet. This cytoskeletal-like structure starts from the basal body at one end of the cilium and extends towards nucleus. Its molecular structure consists of a globular head domain and a tail domain made up of coiled-coil structures.[1] # Protein interactions A large coiled-coil protein, C-Nap1, is a docking site for the fibrous tether to proximal ends of centrioles which Rootletin physically interacts with. Furthermore, Rootletin is phosphorylated by Nek2 kinase.[6]	https://www.wikidoc.org/index.php/Rootletin
d8f6fde9d7a2f369ce4c054b4e71bab963faed69	wikidoc	Rotavirus	Rotavirus # Overview Rotaviruses are a genus of viruses belonging to the Reoviridae family. Seven major groups have been identified, three of which (groups A, B, and C) infect humans, with group A being the most common and widespread one. They cause vomiting and diarrhea and are the most common cause of severe diarrhea in children, killing about 600,000 children every year in developing countries (as of 2005). New vaccines have been shown to be safe and effective in 2006 . # Microbiology ## Structure Rotaviruses have a genome consisting of 11 double-stranded RNA segments surrounded by a distinctive three-layered icosahedral protein capsid. The first layer is formed by the protein VP2, with each vertex having a copy of the proteins VP1 and VP3. The second layer is formed by the protein VP6. The outermost protein layer is composed of the structural glycoprotein VP7 and the spike protein VP4. Viral particles are up to 70nm in diameter and have a buoyant density of 1.36 g/ml in CsCl. By negative staining electron microscopy they resemble 'wheels' from which they derive their name (rota is Latin for wheel). ## Cell Infection Rotaviruses tend to affect gastrointestinal epithelial cells that are at the tip of the villus. Their triple protein coats make them very resistant to the normally prohibitive pH of the stomach, and also digestive enzymes (lipases and proteases) in the gastrointestinal tract. When they infect a cell, they are ingested by the cell in endocytosis in a vesicle known as an endosome. Proteins in the third layer (VP7 and the VP4 spike) disrupt the membrane of the endosome, creating a difference in the Ca2+ concentration. This facilitates the breakdown of VP7 trimers into single protein subunits, leaving the VP2 and VP6 coats around the viral dsRNA, forming a double-layer particle (DLP). While the eleven dsRNA strands are still within the protection of the two protein shells, RNA-dependent RNA polymerase creates viral mRNA transcripts of the double-stranded viral genome. This is more easily done within the environment in the "core" of the virus than in the host cell's aqueous environment, which significantly slows down the detachment of the two RNA strands to begin mRNA synthesis. Encapsidation of the viral RNA may also serve to evade host immune responses that are triggered by the presence of double-stranded RNA. During the infection, rotavirus produces mRNA to support both protein translation and genome replication. Most of the rotavirus proteins accumulate in structures known as viroplasms, where the RNA is replicated and the DLPs are assembled. Viroplasms are electron-dense, perinuclear, punctate structures found as early as 2 hours after virus infection. Viroplasms are viral factories and are thought to be formed by two viral non-structural proteins, NSP5 and NSP2. Expression of certain forms of NSP5, especially one that is tagged at the NH2-terminus, results in the formation of viroplasms. Inhibition of NSP5 using intrabodies or RNA interference results in a profound decrease in rotavirus replication. The DLPs can migrate to the endoplasmic reticulum where they obtain their third, outer layer (formed by VP7 and VP4). # Transmission and associated foods Rotaviruses are transmitted by the fecal-oral route. Person-to-person spread through contaminated hands is probably the most important means by which rotaviruses are transmitted in close communities such as pediatric and geriatric wards, day care centers and family homes. Infected food handlers may contaminate foods that require handling and no further cooking, such as salads, fruits, and hors d'oeuvres. Rotaviruses are quite stable in the environment and have been found in estuary samples at levels as high as 1-5 infectious particles/gal. Sanitary measures adequate for bacteria and parasites seem to be ineffective in endemic control of rotavirus, as similar incidence of rotavirus infection is observed in countries with both high and low health standards. The virus has not been isolated from any food associated with an outbreak, and no satisfactory method is available for routine analysis of food. However, it should be possible to apply procedures that have been used to detect the virus in water and in clinical specimens, of which reverse transcription (RT)-PCR amplification is the most sensitive method to food analysis. # Sources - The Bad Bug Book by the U.S. Food & Drug Administration, 1992. - New vaccines for diarrhoea virus shown effective, New Scientist, 5 January 2006 - Diarrhoea vaccines prove their mettle, [email protected], 5 January 2006	Rotavirus Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Rotaviruses are a genus of viruses belonging to the Reoviridae family. Seven major groups have been identified, three of which (groups A, B, and C) infect humans, with group A being the most common and widespread one. They cause vomiting and diarrhea and are the most common cause of severe diarrhea in children, killing about 600,000 children every year in developing countries (as of 2005). New vaccines have been shown to be safe and effective in 2006 [2]. # Microbiology ## Structure Rotaviruses have a genome consisting of 11 double-stranded RNA segments surrounded by a distinctive three-layered icosahedral protein capsid. The first layer is formed by the protein VP2, with each vertex having a copy of the proteins VP1 and VP3. The second layer is formed by the protein VP6. The outermost protein layer is composed of the structural glycoprotein VP7 and the spike protein VP4. Viral particles are up to 70nm in diameter and have a buoyant density of 1.36 g/ml in CsCl. By negative staining electron microscopy they resemble 'wheels' from which they derive their name (rota is Latin for wheel). ## Cell Infection Rotaviruses tend to affect gastrointestinal epithelial cells that are at the tip of the villus. Their triple protein coats make them very resistant to the normally prohibitive pH of the stomach, and also digestive enzymes (lipases and proteases) in the gastrointestinal tract. When they infect a cell, they are ingested by the cell in endocytosis in a vesicle known as an endosome. Proteins in the third layer (VP7 and the VP4 spike) disrupt the membrane of the endosome, creating a difference in the Ca2+ concentration. This facilitates the breakdown of VP7 trimers into single protein subunits, leaving the VP2 and VP6 coats around the viral dsRNA, forming a double-layer particle (DLP). While the eleven dsRNA strands are still within the protection of the two protein shells, RNA-dependent RNA polymerase creates viral mRNA transcripts of the double-stranded viral genome. This is more easily done within the environment in the "core" of the virus than in the host cell's aqueous environment, which significantly slows down the detachment of the two RNA strands to begin mRNA synthesis. Encapsidation of the viral RNA may also serve to evade host immune responses that are triggered by the presence of double-stranded RNA. During the infection, rotavirus produces mRNA to support both protein translation and genome replication. Most of the rotavirus proteins accumulate in structures known as viroplasms, where the RNA is replicated and the DLPs are assembled. Viroplasms are electron-dense, perinuclear, punctate structures found as early as 2 hours after virus infection. Viroplasms are viral factories and are thought to be formed by two viral non-structural proteins, NSP5 and NSP2. Expression of certain forms of NSP5, especially one that is tagged at the NH2-terminus, results in the formation of viroplasms. Inhibition of NSP5 using intrabodies or RNA interference results in a profound decrease in rotavirus replication. The DLPs can migrate to the endoplasmic reticulum where they obtain their third, outer layer (formed by VP7 and VP4). # Transmission and associated foods Rotaviruses are transmitted by the fecal-oral route. Person-to-person spread through contaminated hands is probably the most important means by which rotaviruses are transmitted in close communities such as pediatric and geriatric wards, day care centers and family homes. Infected food handlers may contaminate foods that require handling and no further cooking, such as salads, fruits, and hors d'oeuvres. Rotaviruses are quite stable in the environment and have been found in estuary samples at levels as high as 1-5 infectious particles/gal. Sanitary measures adequate for bacteria and parasites seem to be ineffective in endemic control of rotavirus, as similar incidence of rotavirus infection is observed in countries with both high and low health standards. The virus has not been isolated from any food associated with an outbreak, and no satisfactory method is available for routine analysis of food. However, it should be possible to apply procedures that have been used to detect the virus in water and in clinical specimens, of which reverse transcription (RT)-PCR amplification is the most sensitive method to food analysis. # Sources - The Bad Bug Book by the U.S. Food & Drug Administration, 1992. - New vaccines for diarrhoea virus shown effective, New Scientist, 5 January 2006 - Diarrhoea vaccines prove their mettle, [email protected], 5 January 2006	https://www.wikidoc.org/index.php/Rotateq
01decc6079758ebebdd656480379ae6fd7e1e300	wikidoc	Rubitecan	Rubitecan # Overview Rubitecan (INN, marketing name Orathecin) is an oral topoisomerase inhibitor, developed by Supergen. # History On January 27, 2004, Supergen announced that it has completed the submission of an NDA for rubitecan to the US FDA, and was accepted for filing on March 2004. On January 2005, Supergen withdrew the NDA for rubitecan, based on feedback indicating that the current data package would not be sufficient to gain US approval, and on January 2006, the Marketing Authorization Application (MAA) filed with the European Medicines Agency (EMA) was also withdrawn.	Rubitecan # Overview Rubitecan (INN, marketing name Orathecin) is an oral topoisomerase inhibitor, developed by Supergen. # History On January 27, 2004, Supergen announced that it has completed the submission of an NDA for rubitecan to the US FDA, [1] and was accepted for filing on March 2004.[2] On January 2005, Supergen withdrew the NDA for rubitecan, based on feedback indicating that the current data package would not be sufficient to gain US approval,[3] and on January 2006, the Marketing Authorization Application (MAA) filed with the European Medicines Agency (EMA) was also withdrawn.[4]	https://www.wikidoc.org/index.php/Rubitecan
e91253bd53e8043563e3313a8c84383915553073	wikidoc	Rudivirus	Rudivirus The Rudivirus or Rudiviridae family consists of a family of viruses that infect archaea bacteria. They share characteristics from the Lipothrixviridae family and both have are filamentous viruses with linear dsDNA genomes that infect thermophilic archaea in the kingdom Crenarchaeota. Rudiviridae are non-enveloped. Replication and topology of the genomes of the members of the family Rudiviridae are similar to those of poxviruses # Literature - ↑ George Rice, Kenneth Stedman, Jamie Snyder, Blake Wiedenheft, Debbie Willits, Susan Brumfield, Timothy McDermott, and Mark J. Young "Viruses from extreme thermal environments" Proc Natl Acad Sci U S A. 2001 November 6; 98(23): 13341–13345. Published online 2001 October 23. - ↑ Zillig, W., Prangishvili, D., Schleper, C., Elferink, M., Holz, I., Albers, S., Janekovic, D. and Götz, D. (1996). Viruses, plasmids and other genetic elements of thermophilic and hyperthermophilic Archaea. FEMS Microbiol. Rev., 18, 225-236 - ↑ Marc Abella, Sonia Rodríguez, Sonia Paytubi, Susana Campoy, Malcolm F. White, and Jordi Barbé "The Sulfolobus solfataricus radA paralogue sso0777 is DNA damage inducible and positively regulated by the Sta1 protein" Nucleic Acids Res. 2007 November; 35(20): 6788–6797. Published online 2007 November. - ↑ Prangishvili, D., Stedman, K. and Zillig, W. (2001). Viruses of the extremely thermophilic archaeon Sulfolobus. Trends Microbiol., 9, 39-43. - ↑ Jenny Keller, Nicolas Leulliot, Christian Cambillau, Valérie Campanacci, Stéphanie Porciero, David Prangishvili, Patrick Forterre, Diego Cortez, Sophie Quevillon-Cheruel, and Herman van Tilbeurgh "Crystal structure of AFV3-109, a highly conserved protein from crenarchaeal viruses" Virol J. 2007; 4: 12. Published online 2007 January 22. doi: 10.1186/1743-422X-4-12. - ↑ Blum, H., Zillig, W., Mallok, S., Domdey, H. and Prangishvili, D. (2001). The genome of the archaeal virus SIRV1 has features in common with genomes of eukaryal viruses. Virology, 281, 6-9. - ↑ Alexandra Kessler, Arie B. Brinkman, John van der Oost, and David Prangishvili "Transcription of the Rod-Shaped Viruses SIRV1 and SIRV2 of the Hyperthermophilic Archaeon Sulfolobus" J Bacteriol. 2004 November; 186(22): 7745–7753. doi: 10.1128/JB.186.22.7745-7753.2004. - ↑ Alexandra Kessler, Guennadi Sezonov, J. Iñaki Guijarro, Nicole Desnoues, Thierry Rose, Muriel Delepierre, Stephen D. Bell, and David Prangishvili "A novel archaeal regulatory protein, Sta1, activates transcription from viral promoters." Nucleic Acids Res. 2006 October; 34(17): 4837–4845. Published online 2006 August 14. de:Rudiviridae	Rudivirus The Rudivirus or Rudiviridae family consists of a family of viruses[1] that infect archaea bacteria[2]. They share characteristics from the Lipothrixviridae family and both have are filamentous viruses with linear dsDNA genomes that infect thermophilic[3] archaea in the kingdom Crenarchaeota[4]. Rudiviridae are non-enveloped[5]. Replication and topology of the genomes of the members of the family Rudiviridae are similar to those of poxviruses[6][7][8] # Literature - ↑ George Rice, Kenneth Stedman, Jamie Snyder, Blake Wiedenheft, Debbie Willits, Susan Brumfield, Timothy McDermott, and Mark J. Young "Viruses from extreme thermal environments" Proc Natl Acad Sci U S A. 2001 November 6; 98(23): 13341–13345. Published online 2001 October 23. - ↑ Zillig, W., Prangishvili, D., Schleper, C., Elferink, M., Holz, I., Albers, S., Janekovic, D. and Götz, D. (1996). Viruses, plasmids and other genetic elements of thermophilic and hyperthermophilic Archaea. FEMS Microbiol. Rev., 18, 225-236 - ↑ Marc Abella, Sonia Rodríguez, Sonia Paytubi, Susana Campoy, Malcolm F. White, and Jordi Barbé "The Sulfolobus solfataricus radA paralogue sso0777 is DNA damage inducible and positively regulated by the Sta1 protein" Nucleic Acids Res. 2007 November; 35(20): 6788–6797. Published online 2007 November. - ↑ Prangishvili, D., Stedman, K. and Zillig, W. (2001). Viruses of the extremely thermophilic archaeon Sulfolobus. Trends Microbiol., 9, 39-43. - ↑ Jenny Keller, Nicolas Leulliot, Christian Cambillau, Valérie Campanacci, Stéphanie Porciero, David Prangishvili, Patrick Forterre, Diego Cortez, Sophie Quevillon-Cheruel, and Herman van Tilbeurgh "Crystal structure of AFV3-109, a highly conserved protein from crenarchaeal viruses" Virol J. 2007; 4: 12. Published online 2007 January 22. doi: 10.1186/1743-422X-4-12. - ↑ Blum, H., Zillig, W., Mallok, S., Domdey, H. and Prangishvili, D. (2001). The genome of the archaeal virus SIRV1 has features in common with genomes of eukaryal viruses. Virology, 281, 6-9. - ↑ Alexandra Kessler, Arie B. Brinkman, John van der Oost, and David Prangishvili "Transcription of the Rod-Shaped Viruses SIRV1 and SIRV2 of the Hyperthermophilic Archaeon Sulfolobus" J Bacteriol. 2004 November; 186(22): 7745–7753. doi: 10.1128/JB.186.22.7745-7753.2004. - ↑ Alexandra Kessler, Guennadi Sezonov, J. Iñaki Guijarro, Nicole Desnoues, Thierry Rose, Muriel Delepierre, Stephen D. Bell, and David Prangishvili "A novel archaeal regulatory protein, Sta1, activates transcription from viral promoters." Nucleic Acids Res. 2006 October; 34(17): 4837–4845. Published online 2006 August 14. Template:Virus-stub de:Rudiviridae	https://www.wikidoc.org/index.php/Rudiviridae
9e39b5f6b2253c8427fa540e6d58fbc85fda37b6	wikidoc	SCH-50911	SCH-50911 SCH-50911 is a selective GABAB antagonist. Its main applications are in pharmacology research, but it has been found to quickly and effectively reverse the symptoms of GHB overdose in mice. In one experiment, mice were given a lethal dose of GHB (7000mg/kg) followed by varying doses of SCH-50911. At the two higher doses of the antagonist (150mg/kg and 300mg/kg), 18 out of 20 of the mice survived (90%), compared to 100% lethality in the control group. SCH-50911 also acts as an anticonvulsant under normal conditions, and so counteracts both the depressant and pro-convulsant effects of GHB overdose. This pharmacological profile makes SCH-50911 a promising candidate as a GHB antidote for human use, and might also make it useful for treating overdoses of other GABAB agonists such as Baclofen. SCH-50911 has never been tested for this purpose in humans and there are no plans at this stage to develop it for these applications. However SCH-50911 induces acute withdrawal syndrome in GHB-dependent rats, similar to the delerium tremens seen in human alcohol withdrawal, and can precipitate convulsions in GHB-dependent animals. This means that while SCH-50911 is likely to be a useful antidote for GHB overdose in non-addicted individuals, its use in people who are dependent on GHB or its analogues could be potentially dangerous as it might precipitate acute withdrawal symptoms, and additional anticonvulsants such as diazepam would most likely be required to counteract the risk of life-threatening seizures. This is similar to the problems seen with opioid antagonists such as naloxone, which are useful antidotes to opiate overdose but may precipitate acute withdrawal syndrome in opiate-addicted individuals.	SCH-50911 Template:Chembox new SCH-50911 is a selective GABAB antagonist.[1] Its main applications are in pharmacology research, but it has been found to quickly and effectively reverse the symptoms of GHB overdose in mice. In one experiment, mice were given a lethal dose of GHB (7000mg/kg) followed by varying doses of SCH-50911. At the two higher doses of the antagonist (150mg/kg and 300mg/kg), 18 out of 20 of the mice survived (90%), compared to 100% lethality in the control group.[2] SCH-50911 also acts as an anticonvulsant under normal conditions, and so counteracts both the depressant and pro-convulsant effects of GHB overdose. This pharmacological profile makes SCH-50911 a promising candidate as a GHB antidote for human use, and might also make it useful for treating overdoses of other GABAB agonists such as Baclofen. SCH-50911 has never been tested for this purpose in humans and there are no plans at this stage to develop it for these applications. However SCH-50911 induces acute withdrawal syndrome in GHB-dependent rats, similar to the delerium tremens seen in human alcohol withdrawal, and can precipitate convulsions in GHB-dependent animals.[3] This means that while SCH-50911 is likely to be a useful antidote for GHB overdose in non-addicted individuals, its use in people who are dependent on GHB or its analogues could be potentially dangerous as it might precipitate acute withdrawal symptoms, and additional anticonvulsants such as diazepam would most likely be required to counteract the risk of life-threatening seizures. This is similar to the problems seen with opioid antagonists such as naloxone, which are useful antidotes to opiate overdose but may precipitate acute withdrawal syndrome in opiate-addicted individuals.	https://www.wikidoc.org/index.php/SCH-50911
c95979d36729d8be5e8c3a416affb93558ef1b8f	wikidoc	SI prefix	SI prefix # Overview An SI prefix (also known as a metric prefix) is a name or associated symbol that precedes a unit of measure (or its symbol) to form a decimal multiple or submultiple. The abbreviation SI is from the French language name Système International d’Unités (also known as International System of Units). SI prefixes are used to reduce the quantity of zeroes in numerical equivalencies. For example, one-billionth of an ampere (a small electrical current) can be written as 0.000 000 001 ampere. In symbol form, this is written as 0.000 000 001 A. Using an SI prefix, these are equivalent to 1 nanoampere or 1 nA. The SI prefixes are governed by the Bureau International des Poids et Mesures (BIPM, also known as the International Bureau of Weights and Measures) and are the product of four resolutions dating from 1960 to 1991. # List of SI prefixes The twenty SI prefixes are shown in the chart below. # Usage ## General use of prefix names and symbols Twenty SI prefixes are available to combine with units of measure. For example, the prefix name kilo denotes a multiple of one thousand, so 1 kilometre equals 1000 metres, 1 kilogram equals 1000 grams, 1 kilowatt equals 1000 watts, and so on. Each SI prefix name has an associated symbol which can be used in combination with the symbols for units of measure. Thus, the “kilo” symbol, k, can be used to produce km, kg, and kW, (kilometre, kilogram, and kilowatt). SI prefixes are internationally recognized and also exist outside the SI (many of them long pre-date SI, going back to the original introduction of the metric system); prefixes may also be used in combination with non-SI units; for example: milligauss (mG), kilofoot (kft) and microinch (µin). ## Prohibition of multiple prefixes The kilogram is the only SI base unit that has an SI prefix as part of its unit name and symbol. Because multiple prefixes may not be used (such as microkilogram or µkg), the prefixes are used with the unit gram and its symbol g (e.g. milligram or mg). ## SI prefixes with symbols for time and angles Officially endorsed policies of the BIPM and the National Institute of Standards and Technology (NIST) vary slightly with respect to the use of the SI prefixes—both between their respective agencies and from real-world practice. For instance, the NIST advises that “…to avoid confusion, prefix symbols (and prefixes) are not used with the time-related unit symbols (names) min (minute), h (hour), d (day); nor with the angle-related symbols (names) ° (degree), ′ (minute), and ″ (second).” The BIPM’s position on the use of SI prefixes with units of time larger than the second is the same as that of the NIST but their position with regard to angles differs: they state “However astronomers use milliarcsecond, which they denote mas, and microarcsecond, µas, which they use as units for measuring very small angles.” ## SI prefixes with °C A similar difference between officially endorsed policy and actual practice exists with regard to the symbol for degree Celsius (°C). The NIST states “Prefix symbols may be used with the unit symbol °C and prefixes may be used with the unit name ‘degree Celsius.’ For example, 12 m°C (12 millidegrees Celsius) is acceptable.” Notwithstanding this official endorsement, the practice of using prefixed forms of “°C” (such as “µ°C”) has not been well-adopted in science and engineering; prefixed forms of the kelvin are usually used instead. # Details Examples: - 5 cm = 5 × 10−2 m = 5 × 0.01 m = 0.05 m - 3 MW = 3 × 106 W = 3 × 1 000 000 W = 3 000 000 W The prefix always takes precedence over any exponentiation; thus "km²" means square kilometre and not kilo–square metre. For example, 3 km² is equal to 3 000 000 m² and not to 3000 m² (nor to 9 000 000 m²). Thus the SI prefixes provide steps of a factor one million instead of one thousand in the case of an exponent 2, of a thousand million in the case of an exponent 3, etc. As a result large numbers may be needed, even if the prefixes are fully used, or intermediate units (like the litre) are introduced. Prefixes where the exponent is divisible by three are often recommended. Hence "100 m" rather than "1 hm". The obsolete prefixes such as myrio- and myria- were dropped before SI was adopted in 1960, probably because they did not fit this pattern, no one-letter symbol was available (M, m, and µ already being used; the two-letter symbols mo and ma were used instead) and were rarely used anyway. The prefix kilo derives from the Greek word χίλια (khilia or chilia) = thousand. Double prefixes such as those formerly used in micromicrofarads (picofarads), hectokilometres (100 kilometres), and millimicrons or micromillimetres (both nanometres) were also dropped with the introduction of the SI. Though in principle legal, many combinations of prefixes with quantities are rarely used. In most contexts only a few, i.e. the most common, standard combination are established: - Mass: hectogram, gram, milligram, microgram, and smaller are common. However, megagram or larger are rarely used; tonnes or scientific notation are used instead. Megagram is sometimes used to disambiguate the (metric) tonne from the various (non-metric) tons. - Volume in litres: litre, decilitre, centilitre, millilitre, microlitre, and smaller are common. Larger volumes are sometimes denoted in hectolitres; otherwise in cubic metres or cubic kilometres. In Australia, large quantities of water are measured in kilolitres, megalitres and gigalitres. - Length: kilometre, metre, decimetre, centimetre, millimetre, and smaller are common. The micrometre is often referred to by the non-SI term micron. In some fields such as chemistry, the angstrom (equal to 0.1 nm) competes with the nanometre. The femtometre, used mainly in particle physics, is usually called a fermi. At large scales, megametre, gigametre, and larger are rarely used. Often used are astronomical units, light years, and parsecs; the astronomical unit is mentioned in the SI standards as an accepted non-SI unit. - Time: second, millisecond, microsecond, and shorter are common. The kilosecond and megasecond also have some use, though for these and longer times one usually uses either scientific notation or minutes, hours, and so on. † the United Kingdom, Ireland, Australia and New Zealand previously used the long scale number name conventions, but have now at least partly switched to the short scale usage. In particular, above a million and below a millionth, the same name has different values in the two naming systems, so billion and trillion (for example) have unfortunately become potentially ambiguous terms internationally. Using the SI prefixes can circumvent this problem. # Pronunciation There are two accepted pronunciations for the prefix giga-: Template:IPA and Template:IPA. According to the American writer Self, in the 1920s a German committee member of the International Electrotechnical Commission proposed giga- as a prefix for 109, drawing on a verse by the humorous poet Christian Morgenstern that appeared in the third (1908) edition of Galgenlieder (Gallows Songs). This suggests a hard German g was originally intended as the pronunciation. Self was unable to ascertain at what point the Template:IPA (soft g) pronunciation became accepted, but as of 1995 current practice had returned to Template:IPA (hard g). When any SI prefix is affixed to a root word, the prefix carries the primary stress, and the root word carries a secondary stress on the same syllable that is stressed when the root word stands alone. For example, the pronunciation and stress of gigabyte is Template:IPA. However, when a word with an SI prefix is also commonly used outside the scientific community, it may adopt other pronunciations that do not follow this rule. For example, kilometre (or in the USA, kilometer) may also be pronounced Template:IPA. # Use outside SI The symbol "K" is often used informally to mean a multiple of (a) thousand, so one may talk of "a 40K salary" (40 000), or the Y2K problem. In these cases an uppercase K is often used, although using an uppercase K is never correct when writing under the rules of the SI. Also, it is often used as a prefix to designate the binary prefix kilo = 210 = 1024, although this is now non-standard. ## Non-SI units - Prefixes go back to the introduction of the metric system in the 1790s, long before the SI was introduced in 1960. The prefixes (including those introduced after the introduction of SI) are used with any metric units, SI or not (e.g. millidynes). - SI prefixes rarely appear coupled with imperial units or English units except in some specialised cases (e.g. microinches, kilofeet, kilopound or 'kip'). - They are also used with other specialized units used in particular fields (e.g. megaelectronvolts, gigaparsecs). - They are also occasionally used with currency units (e.g., gigadollar), mainly by people who are familiar with the prefixes from scientific usage. ## Computing The prefixes k and greater are common in computing, where they are applied to information and storage units like the bit and the byte. Since 210 = 1024, and 103 = 1000, this led to the SI prefix letters being used to denote "binary" powers. Although these are incorrect usages according to the SI standards it seems common to apply base 10 prefixes, when relating to computer memory, as follows: These prefixes, however, usually retain their powers-of-1000 meanings when used to describe either disk storage or rates of data transmission (bit rates): 10 Mbit/s Ethernet runs at 10,000,000 bit/s, not 10,485,760 bit/s. The confusion is compounded by the fact that the units of information (the bit and the byte) are not part of SI, where the bit, byte, octet, baud or symbol rate would rather be given in hertz. Although some use "bit" for the bit and "b" for the byte, "b" is often used for bit and "B" for byte instead. It is recommended by several standards bodies to use bit and B to keep the units very distinct, as in kbit or MiB.Template:Facts French-speakers often use "o" for "octet", today a near synonym for the byte. Consequently, the International Electrotechnical Commission (IEC) adopted new binary prefixes in 1998, formed from the first syllable of the decimal prefix plus 'bi' (pronounced 'bee'). The symbol is the decimal symbol plus 'i'. So now, one kilobyte (1 kB) equals 1000 bytes, whereas one kibibyte (1 KiB) equals 210 = 1024 bytes. Likewise mebi (Mi; 220), gibi (Gi; 230), tebi (Ti; 240), pebi (Pi; 250), and exbi (Ei; 260). Although the IEC standard does not mention them, the sequence can be readily extended to zebi (Zi; 270) and yobi (Yi; 280). The practical use of these binary prefixes is growing only very slowly and is largely limited to expert literature. They remain mostly ignored by marketing literature. # Proposed changes ## Extension Continuing backwards in the alphabet, after zetta and yotta, proposals for the next large number include xenta and xona (among others), the latter as an alteration of the Latin-derived numerical prefix nona-, and the next small number would also start with an ‘x’. One proposed extension is, after zetta and yotta, xona, weka, vunda, uda, and treda. Preserving the rule on abbreviating the prefixes (a Latin capital for the large number and a lower-case letter for the small number), even without consensus on the full name the following prefix symbols could be used without ambiguity: ‘X’, ‘W’, ‘V’, ‘x’, ‘w’, ‘v’. The logically next small prefix symbol, ‘u’, was formerly the accepted substitution for ‘µ’ (now withdrawn), the symbol for “micro”. Another proposal for xenta/xona is novetta, from the Italian nove. This does not have the convenience of backward alphabetic order. Also, the symbol 'n' is already in use for "nano". ## Harmonisation There are also proposals for further harmonisation of the capitalisation. Therefore the symbols for kilo, hecto, and deka would be changed from ‘k’ to ‘K’, from ‘h’ to ‘H’, and from ‘da’ to ‘D’. Likewise some lobby for the removal of prefixes that do not fit the 10±3n scheme, namely hecto, deka, deci, and centi. The CGPM has postponed its decision on both matters for now. An unsolved (and maybe unsolvable) issue is the application of prefixes to units with exponents other than ±1. The prefix is always applied before the exponent. This eventually led to the introduction of special units for area and volume without exponents in the original metric system: - 1 are (a) = 100 m² (10 m × 10 m = 1 dam × 1 dam = 1 dam²) ⇒ 1 ca = 1 m² (1 m × 1 m) ⇒ 1 ha = 10 000 m² (100 m × 100 m = 1 hm × 1 hm = 1 hm²) - ⇒ 1 ca = 1 m² (1 m × 1 m) - ⇒ 1 ha = 10 000 m² (100 m × 100 m = 1 hm × 1 hm = 1 hm²) - 1 stere (st) = 1 m³ - 1 litre (l or L) = 1 dm³ = 1 mst = 0.001 m³ Of these the litre and the hectare are the most ubiquitous in common use: Litre designations are sometimes used to differentiate a volume of liquid (as opposed to a gas, or solid which are usually designated as cubic volumes). Hectares are widely used as a metric alternative to the acre (approximately 2.5 acres to the hectare).	SI prefix # Overview An SI prefix (also known as a metric prefix) is a name or associated symbol that precedes a unit of measure (or its symbol) to form a decimal multiple or submultiple. The abbreviation SI is from the French language name Système International d’Unités (also known as International System of Units). SI prefixes are used to reduce the quantity of zeroes in numerical equivalencies. For example, one-billionth of an ampere (a small electrical current) can be written as 0.000 000 001 ampere. In symbol form, this is written as 0.000 000 001 A. Using an SI prefix, these are equivalent to 1 nanoampere or 1 nA. The SI prefixes are governed by the Bureau International des Poids et Mesures (BIPM, also known as the International Bureau of Weights and Measures) and are the product of four resolutions dating from 1960 to 1991. # List of SI prefixes The twenty SI prefixes are shown in the chart below. Template:SI prefixes # Usage ## General use of prefix names and symbols Twenty SI prefixes are available to combine with units of measure. For example, the prefix name kilo denotes a multiple of one thousand, so 1 kilometre equals 1000 metres, 1 kilogram equals 1000 grams, 1 kilowatt equals 1000 watts, and so on. Each SI prefix name has an associated symbol which can be used in combination with the symbols for units of measure. Thus, the “kilo” symbol, k, can be used to produce km, kg, and kW, (kilometre, kilogram, and kilowatt). SI prefixes are internationally recognized and also exist outside the SI (many of them long pre-date SI, going back to the original introduction of the metric system); prefixes may also be used in combination with non-SI units; for example: milligauss (mG), kilofoot (kft) and microinch (µin). ## Prohibition of multiple prefixes The kilogram is the only SI base unit that has an SI prefix as part of its unit name and symbol. Because multiple prefixes may not be used (such as microkilogram or µkg), the prefixes are used with the unit gram and its symbol g (e.g. milligram or mg). ## SI prefixes with symbols for time and angles Officially endorsed policies of the BIPM and the [American] National Institute of Standards and Technology (NIST) vary slightly with respect to the use of the SI prefixes—both between their respective agencies and from real-world practice. For instance, the NIST advises that “…to avoid confusion, prefix symbols (and prefixes) are not used with the time-related unit symbols (names) min (minute), h (hour), d (day); nor with the angle-related symbols (names) ° (degree), ′ (minute), and ″ (second).” The BIPM’s position on the use of SI prefixes with units of time larger than the second is the same as that of the NIST but their position with regard to angles differs: they state “However astronomers use milliarcsecond, which they denote mas, and microarcsecond, µas, which they use as units for measuring very small angles.” ## SI prefixes with °C A similar difference between officially endorsed policy and actual practice exists with regard to the symbol for degree Celsius (°C). The NIST states “Prefix symbols may be used with the unit symbol °C and prefixes may be used with the unit name ‘degree Celsius.’ For example, 12 m°C (12 millidegrees Celsius) is acceptable.” Notwithstanding this official endorsement, the practice of using prefixed forms of “°C” (such as “µ°C”) has not been well-adopted in science and engineering; prefixed forms of the kelvin are usually used instead. # Details Template:Seealso Examples: - 5 cm = 5 × 10−2 m = 5 × 0.01 m = 0.05 m - 3 MW = 3 × 106 W = 3 × 1 000 000 W = 3 000 000 W The prefix always takes precedence over any exponentiation; thus "km²" means square kilometre and not kilo–square metre. For example, 3 km² is equal to 3 000 000 m² and not to 3000 m² (nor to 9 000 000 m²). Thus the SI prefixes provide steps of a factor one million instead of one thousand in the case of an exponent 2, of a thousand million in the case of an exponent 3, etc. As a result large numbers may be needed, even if the prefixes are fully used, or intermediate units (like the litre) are introduced. Prefixes where the exponent is divisible by three are often recommended. Hence "100 m" rather than "1 hm". The obsolete prefixes such as myrio- and myria- were dropped before SI was adopted in 1960, probably because they did not fit this pattern, no one-letter symbol was available (M, m, and µ already being used; the two-letter symbols mo and ma were used instead) and were rarely used anyway. The prefix kilo derives from the Greek word χίλια (khilia or chilia) = thousand. Double prefixes such as those formerly used in micromicrofarads (picofarads), hectokilometres (100 kilometres), and millimicrons or micromillimetres (both nanometres) were also dropped with the introduction of the SI. Though in principle legal, many combinations of prefixes with quantities are rarely used. In most contexts only a few, i.e. the most common, standard combination are established: - Mass: hectogram, gram, milligram, microgram, and smaller are common. However, megagram or larger are rarely used; tonnes or scientific notation are used instead. Megagram is sometimes used to disambiguate the (metric) tonne from the various (non-metric) tons. - Volume in litres: litre, decilitre, centilitre, millilitre, microlitre, and smaller are common. Larger volumes are sometimes denoted in hectolitres; otherwise in cubic metres or cubic kilometres. In Australia, large quantities of water are measured in kilolitres, megalitres and gigalitres. - Length: kilometre, metre, decimetre, centimetre, millimetre, and smaller are common. The micrometre is often referred to by the non-SI term micron. In some fields such as chemistry, the angstrom (equal to 0.1 nm) competes with the nanometre. The femtometre, used mainly in particle physics, is usually called a fermi. At large scales, megametre, gigametre, and larger are rarely used. Often used are astronomical units, light years, and parsecs; the astronomical unit is mentioned in the SI standards as an accepted non-SI unit. - Time: second, millisecond, microsecond, and shorter are common. The kilosecond and megasecond also have some use, though for these and longer times one usually uses either scientific notation or minutes, hours, and so on. † the United Kingdom, Ireland, Australia and New Zealand previously used the long scale number name conventions, but have now at least partly switched to the short scale usage. In particular, above a million and below a millionth, the same name has different values in the two naming systems, so billion and trillion (for example) have unfortunately become potentially ambiguous terms internationally. Using the SI prefixes can circumvent this problem. # Pronunciation There are two accepted pronunciations for the prefix giga-: Template:IPA and Template:IPA. According to the American writer Self, in the 1920s a German committee member of the International Electrotechnical Commission proposed giga- as a prefix for 109, drawing on a verse by the humorous poet Christian Morgenstern that appeared in the third (1908) edition of Galgenlieder (Gallows Songs). This suggests a hard German g was originally intended as the pronunciation. Self was unable to ascertain at what point the Template:IPA (soft g) pronunciation became accepted, but as of 1995 current practice had returned to Template:IPA (hard g).[1] [2] When any SI prefix is affixed to a root word, the prefix carries the primary stress, and the root word carries a secondary stress on the same syllable that is stressed when the root word stands alone. For example, the pronunciation and stress of gigabyte is Template:IPA. However, when a word with an SI prefix is also commonly used outside the scientific community, it may adopt other pronunciations that do not follow this rule. For example, kilometre (or in the USA, kilometer) may also be pronounced Template:IPA. # Use outside SI The symbol "K" is often used informally to mean a multiple of (a) thousand, so one may talk of "a 40K salary" (40 000), or the Y2K problem. In these cases an uppercase K is often used, although using an uppercase K is never correct when writing under the rules of the SI. Also, it is often used as a prefix to designate the binary prefix kilo = 210 = 1024, although this is now non-standard. ## Non-SI units - Prefixes go back to the introduction of the metric system in the 1790s, long before the SI was introduced in 1960. The prefixes (including those introduced after the introduction of SI) are used with any metric units, SI or not (e.g. millidynes). - SI prefixes rarely appear coupled with imperial units or English units except in some specialised cases (e.g. microinches, kilofeet, kilopound or 'kip'). - They are also used with other specialized units used in particular fields (e.g. megaelectronvolts, gigaparsecs). - They are also occasionally used with currency units (e.g., gigadollar), mainly by people who are familiar with the prefixes from scientific usage. ## Computing The prefixes k and greater are common in computing, where they are applied to information and storage units like the bit and the byte. Since 210 = 1024, and 103 = 1000, this led to the SI prefix letters being used to denote "binary" powers. Although these are incorrect usages according to the SI standards it seems common to apply base 10 prefixes, when relating to computer memory, as follows: These prefixes, however, usually retain their powers-of-1000 meanings when used to describe either disk storage or rates of data transmission (bit rates): 10 Mbit/s Ethernet runs at 10,000,000 bit/s, not 10,485,760 bit/s. The confusion is compounded by the fact that the units of information (the bit and the byte) are not part of SI, where the bit, byte, octet, baud or symbol rate would rather be given in hertz. Although some use "bit" for the bit and "b" for the byte, "b" is often used for bit and "B" for byte instead. It is recommended by several standards bodies to use bit and B to keep the units very distinct, as in kbit or MiB.Template:Facts French-speakers often use "o" for "octet", today a near synonym for the byte. Consequently, the International Electrotechnical Commission (IEC) adopted new binary prefixes in 1998, formed from the first syllable of the decimal prefix plus 'bi' (pronounced 'bee'). The symbol is the decimal symbol plus 'i'. So now, one kilobyte (1 kB) equals 1000 bytes, whereas one kibibyte (1 KiB) equals 210 = 1024 bytes. Likewise mebi (Mi; 220), gibi (Gi; 230), tebi (Ti; 240), pebi (Pi; 250), and exbi (Ei; 260). Although the IEC standard does not mention them, the sequence can be readily extended to zebi (Zi; 270) and yobi (Yi; 280). The practical use of these binary prefixes is growing only very slowly and is largely limited to expert literature. They remain mostly ignored by marketing literature. # Proposed changes ## Extension Continuing backwards in the alphabet, after zetta and yotta, proposals for the next large number include xenta and xona (among others), the latter as an alteration of the Latin-derived numerical prefix nona-, and the next small number would also start with an ‘x’.[citation needed] One proposed extension is, after zetta and yotta, xona, weka, vunda, uda, and treda.[3] Preserving the rule on abbreviating the prefixes (a Latin capital for the large number and a lower-case letter for the small number), even without consensus on the full name the following prefix symbols could be used without ambiguity: ‘X’, ‘W’, ‘V’, ‘x’, ‘w’, ‘v’. The logically next small prefix symbol, ‘u’, was formerly the accepted substitution for ‘µ’ (now withdrawn), the symbol for “micro”.[4][5] Another proposal for xenta/xona is novetta, from the Italian nove.[citation needed] This does not have the convenience of backward alphabetic order. Also, the symbol 'n' is already in use for "nano". ## Harmonisation There are also proposals for further harmonisation of the capitalisation. Therefore the symbols for kilo, hecto, and deka would be changed from ‘k’ to ‘K’, from ‘h’ to ‘H’, and from ‘da’ to ‘D’. Likewise some lobby for the removal of prefixes that do not fit the 10±3n scheme, namely hecto, deka, deci, and centi. The CGPM has postponed its decision on both matters for now. An unsolved (and maybe unsolvable) issue is the application of prefixes to units with exponents other than ±1. The prefix is always applied before the exponent. This eventually led to the introduction of special units for area and volume without exponents in the original metric system: - 1 are (a) = 100 m² (10 m × 10 m = 1 dam × 1 dam = 1 dam²) ⇒ 1 ca = 1 m² (1 m × 1 m) ⇒ 1 ha = 10 000 m² (100 m × 100 m = 1 hm × 1 hm = 1 hm²) - ⇒ 1 ca = 1 m² (1 m × 1 m) - ⇒ 1 ha = 10 000 m² (100 m × 100 m = 1 hm × 1 hm = 1 hm²) - 1 stere (st) = 1 m³ - 1 litre (l or L) = 1 dm³ = 1 mst = 0.001 m³ Of these the litre and the hectare are the most ubiquitous in common use: Litre designations are sometimes used to differentiate a volume of liquid (as opposed to a gas, or solid which are usually designated as cubic volumes). Hectares are widely used as a metric alternative to the acre (approximately 2.5 acres to the hectare).	https://www.wikidoc.org/index.php/SI_prefix
76f373ffdf847e66d9b6c79dbf7a353b741ab1ca	wikidoc	SLAP tear	SLAP tear A SLAP (Superior Labrum from Anterior to Posterior) tear or lesion is an injury to the Glenoid labrum, a part of the shoulder joint. # Overview The shoulder joint is considered a 'ball and socket' joint. However, in bony terms the 'socket' (the glenoid fossa of the scapula) is quite small, covering at most only a third of the 'ball' (the head of the humerus). The socket is somewhat deepened by a circumferential rim of fibrocartilage which is called the glenoidal labrum. Previously there was some argument as to the structure (it is fibrocartilaginous as opposed to the hyaline cartilage found in the remainder of the glenoid fossa) and function (whilst it has previously been considered a redundant evolutionary remnant, it is now considered an integral structure in the shoulder's stability). Currently most authorities agree that the tendon of the long head of the biceps brachii muscle proximally becomes fibrocartilaginous prior to attaching to the superior aspect of the glenoid, and in a similar arrangement the long head of the triceps brachii inserts inferiorly. Together these cartilaginous extensions of the tendon are termed the 'glenoid labrum'. A SLAP (Superior Labrum from Anterior to Posterior) tear or lesion occurs when there is damage to the superior or uppermost area of the labrum. SLAP lesions have come into public awareness with their increasing frequency in overhead and particularly throwing athletes. The increased frequency relates to the relatively recent description of labral injuries in throwing athletes and the initial definitions of the 4 SLAP sub-types all happening in the last 20 years or so. The identification and treatment of these injuries continues to evolve today, however it is safe to say that a baseball pitcher suffering a 'dead arm' caused by a SLAP lesion today is far more likely to recover such that he can return to the game at its highest level than was the case 20 or 30 years ago. ## Sub-types At least ten types of this injury are recognized with varying degrees of damage, seven of which are listed here - Degenerative fraying of the superior portion of the labrum, with the labrum remaining firmly attached to the glenoid rim - Separation of the superior portion of the glenoid labrum and tendon of the biceps brachii muscle from the glenoid rim - Bucket-handle tears of the superior portion of the labrum without involvement of the biceps brachii (long head) attachment - Bucket-handle tears of the superior portion of the labrum extending into the biceps tendon - Anteroinferior Bankart lesion that extends upward to include a separation of the biceps tendon - Unstable radial of flap tears associated with separation of the biceps anchor - Anterior extension of the SLAP lesion beneath the middle glenohumeral ligament # Symptoms There are several symptoms that are common with this type of injury - A dull throbbing ache in the joint. This can be brought on by very strenuous exertion or simple household chores. Sufferers notice that they turn to ice packs more frequently for relief. - Difficulty sleeping due to shoulder discomfort. The SLAP lesion decreases the stability of the joint which when combined with lying in bed causes the shoulder to drop. This in turn pulls on the muscles and ligaments causing discomfort. - For an athlete involved in a throwing sport such as baseball, pain and a catching feeling are prevalent. - Any applied force overhead or pushing directly into the shoulder can result in impingement and catching sensations. # Treatment Very few patients with SLAP lesion injuries return to full capability without surgical intervention. Very rarely physical therapy can strengthen the supporting muscles in the shoulder joint to the point of reestablishing stability. For all other cases the choice is do nothing or have surgery to reattach the labrum to the glenoid. While the surgery can be performed as a traditional open procedure, the recommended course of action is an arthroscopic surgery. This type of procedure is vastly less intrusive to the body and reduces chances of infection. During the procedure the surgeon should check the general health of the shoulder joint. There are at least twenty different items of conditions that he/she should examine or look for. These include: - SLAP lesion – labrum/glenoid separation at the tendon of the biceps muscle - Bankart lesion – labrum/glenoid separation at the inferior glenohumeral ligament - Biceps Tendon - Bone – glenoid, humerus - general surface condition - Ligaments – check for tears and condition ## Procedure The basic procedure is as follows. Following inspection and determination of the extent of the injury the basic labrum repair, be it SLAP or Bankart lesion is as follows. The glenoid and labrum are roughened to increase contact surface area and promote re-growth. Locations for the bone anchors are selected based on number and severity of tear. A really bad tear involving SLAP and Bankart lesions may require seven anchors. Simple tears may only require one. The glenoid is drilled for the anchor implantation. The anchors are inserted in the glenoid. The suture component of the implant is tied through the labrum and knotted such that the labrum is in tight contact with the glenoid surface. # Surgical Recovery Stage one – For the first four weeks the arm is typically kept in a sling. Some surgeons only have the patient in a sling for a week. Patients may find themselves in an immobilizer sling, which adds a waist support to prevent movement. Needless to say, the first stage of recovery is about not stressing the repair site. This is the initial healing phase of the recovery. Stage two – Initial physical therapy. The goal here is to increase range of motion. Load bearing through the joint should be avoided to allow the repair to complete. Stage three – Increased range of motion and initial strength training. At this point, about eight to ten weeks out, the repair should be complete but not ready for full loading yet. Return to day-to-day activities, but not strenuous activity. Stage four – completion. At about six months out the repair should be strong enough for a return to full activity. Note that this timeline will vary according to surgeon preferences and the extent of damage.	SLAP tear A SLAP (Superior Labrum from Anterior to Posterior) tear or lesion is an injury to the Glenoid labrum, a part of the shoulder joint. # Overview The shoulder joint is considered a 'ball and socket' joint. However, in bony terms the 'socket' (the glenoid fossa of the scapula) is quite small, covering at most only a third of the 'ball' (the head of the humerus). The socket is somewhat deepened by a circumferential rim of fibrocartilage which is called the glenoidal labrum. Previously there was some argument as to the structure (it is fibrocartilaginous as opposed to the hyaline cartilage found in the remainder of the glenoid fossa) and function (whilst it has previously been considered a redundant evolutionary remnant, it is now considered an integral structure in the shoulder's stability). Currently most authorities agree that the tendon of the long head of the biceps brachii muscle proximally becomes fibrocartilaginous prior to attaching to the superior aspect of the glenoid, and in a similar arrangement the long head of the triceps brachii inserts inferiorly.[1] Together these cartilaginous extensions of the tendon are termed the 'glenoid labrum'. A SLAP (Superior Labrum from Anterior to Posterior) tear or lesion occurs when there is damage to the superior or uppermost area of the labrum. SLAP lesions have come into public awareness with their increasing frequency in overhead and particularly throwing athletes. The increased frequency relates to the relatively recent description of labral injuries in throwing athletes [2] and the initial definitions of the 4 SLAP sub-types[3] all happening in the last 20 years or so. The identification and treatment of these injuries continues to evolve today, however it is safe to say that a baseball pitcher suffering a 'dead arm' caused by a SLAP lesion today is far more likely to recover such that he can return to the game at its highest level than was the case 20 or 30 years ago. ## Sub-types At least ten types of this injury are recognized with varying degrees of damage,[4] seven of which are listed here - Degenerative fraying of the superior portion of the labrum, with the labrum remaining firmly attached to the glenoid rim - Separation of the superior portion of the glenoid labrum and tendon of the biceps brachii muscle from the glenoid rim - Bucket-handle tears of the superior portion of the labrum without involvement of the biceps brachii (long head) attachment - Bucket-handle tears of the superior portion of the labrum extending into the biceps tendon - Anteroinferior Bankart lesion that extends upward to include a separation of the biceps tendon - Unstable radial of flap tears associated with separation of the biceps anchor - Anterior extension of the SLAP lesion beneath the middle glenohumeral ligament # Symptoms There are several symptoms that are common with this type of injury - A dull throbbing ache in the joint. This can be brought on by very strenuous exertion or simple household chores. Sufferers notice that they turn to ice packs more frequently for relief. - Difficulty sleeping due to shoulder discomfort. The SLAP lesion decreases the stability of the joint which when combined with lying in bed causes the shoulder to drop. This in turn pulls on the muscles and ligaments causing discomfort. - For an athlete involved in a throwing sport such as baseball, pain and a catching feeling are prevalent. - Any applied force overhead or pushing directly into the shoulder can result in impingement and catching sensations. # Treatment Very few patients with SLAP lesion injuries return to full capability without surgical intervention. Very rarely physical therapy can strengthen the supporting muscles in the shoulder joint to the point of reestablishing stability. For all other cases the choice is do nothing or have surgery to reattach the labrum to the glenoid. While the surgery can be performed as a traditional open procedure, the recommended course of action is an arthroscopic surgery. This type of procedure is vastly less intrusive to the body and reduces chances of infection. During the procedure the surgeon should check the general health of the shoulder joint. There are at least twenty different items of conditions that he/she should examine or look for. These include: - SLAP lesion – labrum/glenoid separation at the tendon of the biceps muscle - Bankart lesion – labrum/glenoid separation at the inferior glenohumeral ligament - Biceps Tendon - Bone – glenoid, humerus - general surface condition - Ligaments – check for tears and condition ## Procedure The basic procedure is as follows. Following inspection and determination of the extent of the injury the basic labrum repair, be it SLAP or Bankart lesion is as follows. The glenoid and labrum are roughened to increase contact surface area and promote re-growth. Locations for the bone anchors are selected based on number and severity of tear. A really bad tear involving SLAP and Bankart lesions may require seven anchors. Simple tears may only require one. The glenoid is drilled for the anchor implantation. The anchors are inserted in the glenoid. The suture component of the implant is tied through the labrum and knotted such that the labrum is in tight contact with the glenoid surface. # Surgical Recovery Stage one – For the first four weeks the arm is typically kept in a sling. Some surgeons only have the patient in a sling for a week. Patients may find themselves in an immobilizer sling, which adds a waist support to prevent movement. Needless to say, the first stage of recovery is about not stressing the repair site. This is the initial healing phase of the recovery. Stage two – Initial physical therapy. The goal here is to increase range of motion. Load bearing through the joint should be avoided to allow the repair to complete. Stage three – Increased range of motion and initial strength training. At this point, about eight to ten weeks out, the repair should be complete but not ready for full loading yet. Return to day-to-day activities, but not strenuous activity. Stage four – completion. At about six months out the repair should be strong enough for a return to full activity. Note that this timeline will vary according to surgeon preferences and the extent of damage.	https://www.wikidoc.org/index.php/SLAP_tear
63591a6ef0b9c7a41ddb6f15cac3c6e94e0c5a98	wikidoc	SNOMED CT	SNOMED CT SNOMED (Systematized Nomenclature of Medicine), is a systematically organised computer processable collection of medical terminology covering most areas of clinical information such as diseases, findings, procedures, microorganisms, pharmaceuticals etc. It allows a consistent way to index, store, retrieve, and aggregate clinical data across specialties and sites of care. It also helps organising the content of medical records, reducing the variability in the way data is captured, encoded and used for clinical care of patients and research. # Purpose Clinicians and organizations use different clinical terms that mean the same thing. For example, the terms heart attack, myocardial infarction, and MI may mean the same thing to a cardiologist, but, to a computer, they are all different. There is a need to exchange clinical information consistently between different health care providers, care settings, researchers and others (semantic interoperability), and because medical information is recorded differently from place to place (on paper or electronically), a comprehensive, unified medical terminology system is needed as part of the information infrastructure. # Design SNOMED CT is a compositional concept system, which means that concepts can be specialised by combinations with other concepts. It is based on Description Logic and is designed so that content can be maintained as a dynamic resource. ## Components - Concepts: Basic unit of meaning designated by a unique numeric code, unique name (Fully Specified Name), and descriptions, including a preferred term and one or more synonyms. - Descriptions: Terms or names (synonyms) assigned to a concept. - Hierarchies: 19 higher level hierarchies; each has sub-hierarchies - Relationships: Link concepts either within a hierarchy or across hierarchies - Subsets ## Design fundamentals Local extension of SNOMED CT is achieved by sanctioned specialisation, where new concepts are defined as controlled combinations of those already known. For example, a basic concept such as may be specialised / further qualified with a and a , itself specialised, in order to define a new very detailed clinical concept such as a 'severe burn of the skin of the webspace between the left fourth and fifth toes': Such expressions are said to have been 'post-coordinated' by contrast with the set of entities already included in a given SNOMED CT release, which are normally collectively labelled 'pre-coordinated' concepts, even though the majority (85%) of these pre-coordinated concepts are currently in fact primitive entities. NB: in other contexts or projects 'coordination' may refer not to the specification of a candidate new expression but rather to the subsequent operation of integrating one within the polyhierarchy (ie classifying it). In SNOMED CT terminology, saying that an expression has been 'post-coordinated' does not imply that it has also been classified. Reliable analysis and comparison of any such post-coordinated expressions - with respect to both those concepts already within the SNOMED CT release dataset and any other ad hoc concepts created or yet to be created by its community of endusers - properly requires the application of an appropriate description logic classification algorithm. As of 2007, SNOMED CT content limits itself to a subset of the EL++ formalism, restricting itself to the following operators: The logic may be extended in the near future to include General Concept Inclusion Axioms. In theory, description logic reasoning can be applied to any new candidate post-coordinated expressions in order to assess whether it is a parent or ancestor of, a child or other descendent of, or semantically equivalent to any existing concept from the 370,000 pre-coordinated concepts which are already distributed worldwide. However, partly as the continuing fall-out from the merger with CTV3, SNOMED content in 2007 still contains undiscovered semantically duplicate primitive and defined concepts. Additionally, many concepts remain primitive whilst their semantics can also be legitimately defined in terms of other primitives and roles concurrently in the system. Because of these ommissions and actual or possible redundancies of semantic content, real-world performance of algorithms to infer subsumption or semantic equivalence will be unpredictably imperfect. ## Features Significant features of SNOMED CT by comparison with more traditional and familiar clinical terminologies and classifications (e.g. ICD) are : (1) It contains roughly 3 times as many concepts 'out of the box' as most familiar clinical terminologies (2) The set of entities (or 'concepts') within its list are organised as a polyhierarchy rather than the traditional (statistical) monohierarchy (3) Clinical end users can dynamically and arbitrarily extend the set of concepts within its list so as to include those additionally required but not already included in a particular release. # Use SNOMED CT is one of a suite of designated data standards for use in U.S. Federal Government systems for the electronic exchange of clinical health information. ### Sample Computer Applications Using SNOMED CT - Electronic Medical Records - Computerized Provider Order Entry Such As E-Prescribing Or Laboratory Order Entry - Remote Intensive Care Unit Monitoring - Laboratory Reporting - Emergency Room Charting - Cancer Reporting - Genetic Databases # History In January 2002, SNOMED CT was created by the merger, expansion, and restructuring of SNOMED RT (Reference Terminology) and the UK National Health Service (NHS) Clinical Terms Version 3 (also known as the Read Codes). The historical strength of SNOMED RT was its terminologies for specialty medicine and methods for distributed collaborative development, while the strength of Clinical Terms Version 3 was its terminologies for general practice. By combining these two systems, SNOMED CT is the most comprehensive clinical vocabulary available in any language, covering most aspects of clinical medicine with over 344,000 concepts. SNOMED CT cross maps to such other terminologies as ICD-9-CM, ICD-O3, ICD-10, Laboratory LOINC and OPCS-4. It supports ANSI, DICOM, HL7, and ISO standards. In April 2002, the SNOMED CT Spanish Edition was released, and in April 2003 the SNOMED CT German Edition was released. The National Library of Medicine (NLM), on behalf of the U.S. Department of Health and Human Services, entered into an agreement with College of American Pathologists for a perpetual license for the core SNOMED CT (in Spanish and English) and ongoing updates. The contract provides to NLM a perpetual license to distribute SNOMED within the NLM’s Unified Medical Language System UMLS Metathesaurus for no cost use within the U.S. by both U.S. government (federal, state, local, and territorial) and private organizations. The contract also covers updates to SNOMED CT issued by the College of American Pathologists between June 30, 2003 and June 29, 2008. In April 2007, SNOMED CT was acquired by IHTSDO, The International Healthcare Terminology Standards Development Organisation.	SNOMED CT SNOMED (Systematized Nomenclature of Medicine), is a systematically organised computer processable collection of medical terminology covering most areas of clinical information such as diseases, findings, procedures, microorganisms, pharmaceuticals etc. It allows a consistent way to index, store, retrieve, and aggregate clinical data across specialties and sites of care. It also helps organising the content of medical records, reducing the variability in the way data is captured, encoded and used for clinical care of patients and research. # Purpose Clinicians and organizations use different clinical terms that mean the same thing. For example, the terms heart attack, myocardial infarction, and MI may mean the same thing to a cardiologist, but, to a computer, they are all different. There is a need to exchange clinical information consistently between different health care providers, care settings, researchers and others (semantic interoperability), and because medical information is recorded differently from place to place (on paper or electronically), a comprehensive, unified medical terminology system is needed as part of the information infrastructure. # Design SNOMED CT is a compositional concept system, which means that concepts can be specialised by combinations with other concepts. It is based on Description Logic and is designed so that content can be maintained as a dynamic resource. ## Components - Concepts: Basic unit of meaning designated by a unique numeric code, unique name (Fully Specified Name), and descriptions, including a preferred term and one or more synonyms. - Descriptions: Terms or names (synonyms) assigned to a concept. - Hierarchies: 19 higher level hierarchies; each has sub-hierarchies - Relationships: Link concepts either within a hierarchy or across hierarchies - Subsets [1] ## Design fundamentals Local extension of SNOMED CT is achieved by sanctioned specialisation, where new concepts are defined as controlled combinations of those already known. For example, a basic concept such as [burn] may be specialised / further qualified with a [severity] and a [body site], itself specialised, in order to define a new very detailed clinical concept such as a 'severe burn of the skin of the webspace between the left fourth and fifth toes': Such expressions are said to have been 'post-coordinated' by contrast with the set of entities already included in a given SNOMED CT release, which are normally collectively labelled 'pre-coordinated' concepts, even though the majority (85%) of these pre-coordinated concepts are currently in fact primitive entities. NB: in other contexts or projects 'coordination' may refer not to the specification of a candidate new expression but rather to the subsequent operation of integrating one within the polyhierarchy (ie classifying it). In SNOMED CT terminology, saying that an expression has been 'post-coordinated' does not imply that it has also been classified. Reliable analysis and comparison of any such post-coordinated expressions - with respect to both those concepts already within the SNOMED CT release dataset and any other ad hoc concepts created or yet to be created by its community of endusers - properly requires the application of an appropriate description logic classification algorithm. As of 2007, SNOMED CT content limits itself to a subset of the EL++ formalism, restricting itself to the following operators: The logic may be extended in the near future to include General Concept Inclusion Axioms. In theory, description logic reasoning can be applied to any new candidate post-coordinated expressions in order to assess whether it is a parent or ancestor of, a child or other descendent of, or semantically equivalent to any existing concept from the 370,000 pre-coordinated concepts which are already distributed worldwide. However, partly as the continuing fall-out from the merger with CTV3, SNOMED content in 2007 still contains undiscovered semantically duplicate primitive and defined concepts. Additionally, many concepts remain primitive whilst their semantics can also be legitimately defined in terms of other primitives and roles concurrently in the system. Because of these ommissions and actual or possible redundancies of semantic content, real-world performance of algorithms to infer subsumption or semantic equivalence will be unpredictably imperfect. ## Features Significant features of SNOMED CT by comparison with more traditional and familiar clinical terminologies and classifications (e.g. ICD) are : (1) It contains roughly 3 times as many concepts 'out of the box' as most familiar clinical terminologies (2) The set of entities (or 'concepts') within its list are organised as a polyhierarchy rather than the traditional (statistical) monohierarchy (3) Clinical end users can dynamically and arbitrarily extend the set of concepts within its list so as to include those additionally required but not already included in a particular release. # Use SNOMED CT is one of a suite of designated data standards for use in U.S. Federal Government systems for the electronic exchange of clinical health information. ### Sample Computer Applications Using SNOMED CT - Electronic Medical Records - Computerized Provider Order Entry Such As E-Prescribing Or Laboratory Order Entry - Remote Intensive Care Unit Monitoring - Laboratory Reporting - Emergency Room Charting - Cancer Reporting - Genetic Databases [2] # History In January 2002, SNOMED CT was created by the merger, expansion, and restructuring of SNOMED RT (Reference Terminology) and the UK National Health Service (NHS) Clinical Terms Version 3 (also known as the Read Codes). [3] The historical strength of SNOMED RT was its terminologies for specialty medicine and methods for distributed collaborative development, while the strength of Clinical Terms Version 3 was its terminologies for general practice. [4] By combining these two systems, SNOMED CT is the most comprehensive clinical vocabulary available in any language, covering most aspects of clinical medicine with over 344,000 concepts. [5] SNOMED CT cross maps to such other terminologies as ICD-9-CM, ICD-O3, ICD-10, Laboratory LOINC and OPCS-4. It supports ANSI, DICOM, HL7, and ISO standards. [6] In April 2002, the SNOMED CT Spanish Edition was released, and in April 2003 the SNOMED CT German Edition was released. The National Library of Medicine (NLM), on behalf of the U.S. Department of Health and Human Services, entered into an agreement with College of American Pathologists for a perpetual license for the core SNOMED CT (in Spanish and English) and ongoing updates. The contract provides to NLM a perpetual license to distribute SNOMED within the NLM’s Unified Medical Language System UMLS Metathesaurus for no cost use within the U.S. by both U.S. government (federal, state, local, and territorial) and private organizations. The contract also covers updates to SNOMED CT issued by the College of American Pathologists between June 30, 2003 and June 29, 2008. In April 2007, SNOMED CT was acquired by IHTSDO, The International Healthcare Terminology Standards Development Organisation.	https://www.wikidoc.org/index.php/SNOMED_CT
8a3690d8562c4ad63a96d81e1fa4f6468d56e0f6	wikidoc	Sunitinib	Sunitinib # 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 Sunitinib is a tyrosine kinase inhibitor that is FDA approved for the treatment of gastrointestinal stromal tumor (GIST) after disease progression on or intolerance to imatinib mesylate, advanced renal cell carcinoma (RCC) and Progressive, well-differentiated pancreatic neuroendocrine tumors (pNET) in patients with unresectable locally advanced or metastatic disease. There is a Black Box Warning for this drug as shown here. Common adverse reactions include fatigue, asthenia, fever, diarrhea, nausea, mucositis/stomatitis, vomiting, dyspepsia, abdominal pain, constipation, hypertension, peripheral edema, rash, palmar plantar erythrodysesthesia, skin discoloration, dry skin, hair color changes, altered taste, headache, back pain, arthralgia, extremity pain, cough, dyspnea, anorexia and bleeding. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Gastrointestinal Stromal Tumor (GIST) - Sunitinib is indicated for the treatment of gastrointestinal stromal tumor after disease progression on or intolerance to imatinib mesylate. - Dosage: one 50 mg oral dose taken once daily, on a schedule of 4 weeks on treatment followed by 2 weeks off (Schedule 4/2). - Sunitinib malate may be taken with or without food ### Advanced Renal Cell Carcinoma (RCC) - Sunitinib malate is indicated for the treatment of advanced renal cell carcinoma. - Dosage: one 50 mg oral dose taken once daily, on a schedule of 4 weeks on treatment followed by 2 weeks off (Schedule 4/2). - Sunitinib malate may be taken with or without food ### Advanced Pancreatic Neuroendocrine Tumors (pNET) - Sunitinib malate is indicated for the treatment of progressive, well-differentiated pancreatic neuroendocrine tumors in patients with unresectable locally advanced or metastatic disease. - Dosage: 37.5 mg taken orally once daily continuously without a scheduled off-treatment period. - Sunitinib malate may be taken with or without food. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Sunitinib in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Sunitinib in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Sunitinib 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 Sunitinib in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Sunitinib in pediatric patients. # Contraindications None # Warnings ### Hepatotoxicity Sunitinib malate has been associated with hepatotoxicity, which may result in liver failure or death. Liver failure has been observed in clinical trials (7/2281 ) and post-marketing experience. Liver failure signs include jaundice, elevated transaminases and/or hyperbilirubinemia in conjunction with encephalopathy, coagulopathy, and/or renal failure. Monitor liver function tests (ALT, AST, bilirubin) before initiation of treatment, during each cycle of treatment, and as clinically indicated. Sunitinib malate should be interrupted for Grade 3 or 4 drug-related hepatic adverse events and discontinued if there is no resolution. Do not restart sunitinib malate if patients subsequently experience severe changes in liver function tests or have other signs and symptoms of liver failure. Safety in patients with ALT or AST >2.5 × ULN or, if due to liver metastases, >5.0 × ULN has not been established. ### Pregnancy Sunitinib malate can cause fetal harm when administered to a pregnant woman. As angiogenesis is a critical component of embryonic and fetal development, inhibition of angiogenesis following administration of sunitinib malate should be expected to result in adverse effects on pregnancy. In animal reproductive studies in rats and rabbits, sunitinib was teratogenic, embryotoxic, and fetotoxic. There are no adequate and well-controlled studies of sunitinib malate in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with sunitinib malate. ### Left Ventricular Dysfunction In the presence of clinical manifestations of congestive heart failure (CHF), discontinuation of sunitinib malate is recommended. The dose of sunitinib malate should be interrupted and/or reduced in patients without clinical evidence of CHF but with an ejection fraction 20% below baseline. Cardiovascular events, including heart failure, myocardial disorders and cardiomyopathy, some of which were fatal, have been reported through post-marketing experience. For GIST and RCC, more patients treated with sunitinib malate experienced decline in left ventricular ejection fraction (LVEF) than patients receiving either placebo or interferon-α (IFN-α). In the double-blind treatment phase of GIST Study A, 22/209 patients (11%) on sunitinib malate and 3/102 patients (3%) on placebo had treatment-emergent LVEF values below the lower limit of normal (LLN). Nine of 22 GIST patients on sunitinib malate with LVEF changes recovered without intervention. Five patients had documented LVEF recovery following intervention (dose reduction: one patient; addition of antihypertensive or diuretic medications: four patients). Six patients went off study without documented recovery. Additionally, three patients on sunitinib malate had Grade 3 reductions in left ventricular systolic function to LVEF <40%; two of these patients died without receiving further study drug. No GIST patients on placebo had Grade 3 decreased LVEF. In the double-blind treatment phase of GIST Study A, 1 patient on sunitinib malate and 1 patient on placebo died of diagnosed heart failure; 2 patients on sunitinib malate and 2 patients on placebo died of treatment-emergent cardiac arrest. In the treatment-naïve RCC study, 103/375 (27%) and 54/360 (15%) patients on sunitinib malate and IFN-α, respectively, had an LVEF value below the LLN. Twenty-six patients on sunitinib malate (7%) and seven on IFN-α (2%) experienced declines in LVEF to >20% below baseline and to below 50%. Left ventricular dysfunction was reported in four patients (1%) and CHF in two patients (<1%) who received sunitinib malate. In the Phase 3 pNET study, cardiac failure leading to death was reported in 2/83 (2%) patients on sunitinib malate and no patients on placebo. Patients who presented with cardiac events within 12 months prior to sunitinib malate administration, such as myocardial infarction (including severe/unstable angina), coronary/peripheral artery bypass graft, symptomatic CHF, cerebrovascular accident or transient ischemic attack, or pulmonary embolism were excluded from sunitinib malate clinical studies. It is unknown whether patients with these concomitant conditions may be at a higher risk of developing drug-related left ventricular dysfunction. Physicians are advised to weigh this risk against the potential benefits of the drug. These patients should be carefully monitored for clinical signs and symptoms of CHF while receiving sunitinib malate. Baseline and periodic evaluations of LVEF should also be considered while these patients are receiving sunitinib malate. In patients without cardiac risk factors, a baseline evaluation of ejection fraction should be considered. ### QT Interval Prolongation and Torsade de Pointes Sunitinib malate has been shown to prolong the QT interval in a dose dependent manner, which may lead to an increased risk for ventricular arrhythmias including Torsade de Pointes. Torsade de Pointes has been observed in <0.1% of sunitinib malate-exposed patients. Sunitinib malate should be used with caution in patients with a history of QT interval prolongation, patients who are taking antiarrhythmics, or patients with relevant pre-existing cardiac disease, bradycardia, or electrolyte disturbances. When using sunitinib malate, periodic monitoring with on-treatment electrocardiograms and electrolytes (magnesium, potassium) should be considered. Concomitant treatment with strong CYP3A4 inhibitors, which may increase sunitinib plasma concentrations, should be used with caution and dose reduction of sunitinib malate should be considered. ### Hypertension Patients should be monitored for hypertension and treated as needed with standard anti-hypertensive therapy. In cases of severe hypertension, temporary suspension of sunitinib malate is recommended until hypertension is controlled. Of patients receiving sunitinib malate for treatment-naïve RCC, 127/375 patients (34%) receiving sunitinib malate compared with 13/360 patients (4%) on IFN-α experienced hypertension. Grade 3 hypertension was observed in 50/375 treatment-naïve RCC patients (13%) on sunitinib malate compared to 1/360 patients (200 mmHg systolic or 110 mmHg diastolic) occurred in 8/202 GIST patients on sunitinib malate (4%), 1/102 GIST patients on placebo (1%), in 32/375 treatment-naïve RCC patients (9%) on sunitinib malate, in 3/360 patients (1%) on IFN-α, and in 8/80 pNET patients (10%) on sunitinib malate and 2/76 pNET patients (3%) on placebo. ### Hemorrhagic Events Hemorrhagic events reported through post-marketing experience, some of which were fatal, have included GI, respiratory, tumor, urinary tract and brain hemorrhages. In patients receiving sunitinib malate in a clinical trial for treatment-naïve RCC, 140/375 patients (37%) had bleeding events compared with 35/360 patients (10%) receiving IFN-α. Bleeding events occurred in 37/202 patients (18%) receiving sunitinib malate in the double-blind treatment phase of GIST Study A, compared to 17/102 patients (17%) receiving placebo. Epistaxis was the most common hemorrhagic adverse event reported. Bleeding events, excluding epistaxis, occurred in 18/83 patients (22%) receiving sunitinib malate in the Phase 3 pNET study, compared to 8/82 patients (10%) receiving placebo. Epistaxis was reported in 17/83 patients (20%) receiving sunitinib malate for pNET and 4 patients (5%) receiving placebo. Less common bleeding events in GIST, RCC and pNET patients included rectal, gingival, upper gastrointestinal, genital, and wound bleeding. In the double-blind treatment phase of GIST Study A, 14/202 patients (7%) receiving sunitinib malate and 9/102 patients (9%) on placebo had Grade 3 or 4 bleeding events. In addition, one patient in GIST Study A taking placebo had a fatal gastrointestinal bleeding event during Cycle 2. Most events in RCC patients were Grade 1 or 2; there was one Grade 5 event of gastric bleed in a treatment-naïve patient. In the pNET study, 1/83 patients (1%) receiving sunitinib malate had Grade 3 epistaxis, and no patients had other Grade 3 or 4 bleeding events. In pNET patients receiving placebo, 3/82 patients (4%) had Grade 3 or 4 bleeding events. Tumor-related hemorrhage has been observed in patients treated with sunitinib malate. These events may occur suddenly, and in the case of pulmonary tumors may present as severe and life-threatening hemoptysis or pulmonary hemorrhage. Cases of pulmonary hemorrhage, some with a fatal outcome, have been observed in clinical trials and have been reported in post-marketing experience in patients treated with sunitinib malate for MRCC, GIST and metastatic lung cancer. Sunitinib malate is not approved for use in patients with lung cancer. Treatment-emergent Grade 3 and 4 tumor hemorrhage occurred in 5/202 patients (3%) with GIST receiving sunitinib malate on Study A. Tumor hemorrhages were observed as early as Cycle 1 and as late as Cycle 6. One of these five patients received no further drug following tumor hemorrhage. None of the other four patients discontinued treatment or experienced dose delay due to tumor hemorrhage. No patients with GIST in the Study A placebo arm were observed to undergo intratumoral hemorrhage. Clinical assessment of these events should include serial complete blood counts (CBCs) and physical examinations. Serious, sometimes fatal gastrointestinal complications including gastrointestinal perforation, have occurred rarely in patients with intra-abdominal malignancies treated with sunitinib malate. ### Osteonecrosis of the Jaw (ONJ) ONJ has been observed in clinical trials and has been reported in post-marketing experience in patients treated with sunitinib. Concomitant exposure to other risk factors, such as bisphosphonates or dental disease, may increase the risk of osteonecrosis of the jaw. ### Tumor Lysis Syndrome (TLS) Cases of TLS, some fatal, have been observed in clinical trials and have been reported in post-marketing experience, primarily in patients with RCC or GIST treated with sunitinib malate. Patients generally at risk of TLS are those with high tumor burden prior to treatment. These patients should be monitored closely and treated as clinically indicated. ### Thyroid Dysfunction Baseline laboratory measurement of thyroid function is recommended and patients with hypothyroidism or hyperthyroidism should be treated as per standard medical practice prior to the start of sunitinib malate treatment. All patients should be observed closely for signs and symptoms of thyroid dysfunction, including hypothyroidism, hyperthyroidism, and thyroiditis, on sunitinib malate treatment. Patients with signs and/or symptoms suggestive of thyroid dysfunction should have laboratory monitoring of thyroid function performed and be treated as per standard medical practice. Treatment-emergent acquired hypothyroidism was noted in eight GIST patients (4%) on sunitinib malate versus one (1%) on placebo. Hypothyroidism was reported as an adverse reaction in sixty-one patients (16%) on sunitinib malate in the treatment-naïve RCC study and in three patients (1%) in the IFN-α arm. Hypothyroidism was reported as an adverse reaction in 6/83 patients (7%) on sunitinib malate in the Phase 3 pNET study and in 1/82 patients (1%) in the placebo arm. Cases of hyperthyroidism, some followed by hypothyroidism, have been reported in clinical trials and through post-marketing experience. ### Wound Healing Cases of impaired wound healing have been reported during sunitinib malate therapy. Temporary interruption of sunitinib malate therapy is recommended for precautionary reasons in patients undergoing major surgical procedures. There is limited clinical experience regarding the timing of reinitiation of therapy following major surgical intervention. Therefore, the decision to resume sunitinib malate therapy following a major surgical intervention should be based upon clinical judgment of recovery from surgery. ### Proteinuria Proteinuria and nephrotic syndrome have been reported. Some of these cases have resulted in renal failure and fatal outcomes. Monitor patients for the development or worsening of proteinuria. Perform baseline and periodic urinalyses during treatment, with follow up measurement of 24-hour urine protein as clinically indicated. Interrupt sunitinib malate and dose reduce for 24-hour urine protein ≥ 3 grams. Discontinue sunitinib malate for patients with nephrotic syndrome or repeat episodes of urine protein ≥ 3 grams despite dose reductions. The safety of continued sunitinib malate treatment in patients with moderate to severe proteinuria has not been systematically evaluated. ### Dermatologic Toxicities Severe cutaneous reactions have been reported, including cases of erythema multiforme (EM), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), some of which were fatal. If signs or symptoms of SJS, TEN, or EM (e.g., progressive skin rash often with blisters or mucosal lesions) are present, sunitinib malate treatment should be discontinued. If a diagnosis of SJS or TEN is suspected, sunitinib malate treatment must not be re-started. Necrotizing fasciitis, including fatal cases, has been reported in patients treated with sunitinib malate, including of the perineum and secondary to fistula formation. Discontinue sunitinib malate in patients who develop necrotizing fasciitis. ### Adrenal Function Physicians prescribing sunitinib malate are advised to monitor for adrenal insufficiency in patients who experience stress such as surgery, trauma or severe infection. Adrenal toxicity was noted in non-clinical repeat dose studies of 14 days to 9 months in rats and monkeys at plasma exposures as low as 0.7 times the AUC observed in clinical studies. Histological changes of the adrenal gland were characterized as hemorrhage, necrosis, congestion, hypertrophy and inflammation. In clinical studies, CT/MRI obtained in 336 patients after exposure to one or more cycles of sunitinib malate demonstrated no evidence of adrenal hemorrhage or necrosis. ACTH stimulation testing was performed in approximately 400 patients across multiple clinical trials of sunitinib malate. Among patients with normal baseline ACTH stimulation testing, one patient developed consistently abnormal test results during treatment that are unexplained and may be related to treatment with sunitinib malate. Eleven additional patients with normal baseline testing had abnormalities in the final test performed, with peak cortisol levels of 12–16.4 mcg/dL (normal >18 mcg/dL) following stimulation. None of these patients were reported to have clinical evidence of adrenal insufficiency. ### Laboratory Tests CBCs with platelet count and serum chemistries including phosphate should be performed at the beginning of each treatment cycle for patients receiving treatment with sunitinib malate. # Adverse Reactions ## Clinical Trials Experience The data described below reflect exposure to sunitinib malate in 660 patients who participated in the double-blind treatment phase of a placebo-controlled trial (n=202) for the treatment of GIST, an active-controlled trial (n=375) for the treatment of RCC or a placebo-controlled trial (n=83) for the treatment of pNET. The GIST and RCC patients received a starting oral dose of 50 mg daily on Schedule 4/2 in repeated cycles, and the pNET patients received a starting oral dose of 37.5 mg daily without scheduled off-treatment periods. The most common adverse reactions (≥20%) in patients with GIST, RCC or pNET are fatigue, asthenia, fever, diarrhea, nausea, mucositis/stomatitis, vomiting, dyspepsia, abdominal pain, constipation, hypertension, peripheral edema, rash, palmar-plantar erythrodysesthesia, skin discoloration, dry skin, hair color changes, altered taste, headache, back pain, arthralgia, extremity pain, cough, dyspnea, anorexia and bleeding. The potentially serious adverse reactions are hepatotoxicity, left ventricular dysfunction, QT interval prolongation, hemorrhage, hypertension, thyroid dysfunction, and adrenal function. Other adverse reactions occurring in GIST, RCC and pNET studies are described below. 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. ### Adverse Reactions in GIST Study A Median duration of blinded study treatment was two cycles for patients on sunitinib malate (mean 3.0, range 1–9) and one cycle (mean 1.8, range 1–6) for patients on placebo at the time of the interim analysis. Dose reductions occurred in 23 patients (11%) on sunitinib malate and none on placebo. Dose interruptions occurred in 59 patients (29%) on sunitinib malate and 31 patients (30%) on placebo. The rates of treatment-emergent, non-fatal adverse reactions resulting in permanent discontinuation were 7% and 6% in the sunitinib malate and placebo groups, respectively. Most treatment-emergent adverse reactions in both study arms were Grade 1 or 2 in severity. Grade 3 or 4 treatment-emergent adverse reactions were reported in 56% versus 51% of patients on sunitinib malate versus placebo, respectively, in the double-blind treatment phase of the trial. Table 1 compares the incidence of common (≥10%) treatment-emergent adverse reactions for patients receiving sunitinib malate and reported more commonly in patients receiving sunitinib malate than in patients receiving placebo. In the double-blind treatment phase of GIST Study A, oral pain other than mucositis/stomatitis occurred in 12 patients (6%) on sunitinib malate versus 3 (3%) on placebo. Hair color changes occurred in 15 patients (7%) on sunitinib malate versus 4 (4%) on placebo. Alopecia was observed in 10 patients (5%) on sunitinib malate versus 2 (2%) on placebo. Table 2 provides common (≥10%) treatment-emergent laboratory abnormalities. After an interim analysis, the study was unblinded, and patients on the placebo arm were given the opportunity to receive open-label sunitinib malate treatment. For 241 patients randomized to the sunitinib malate arm, including 139 who received sunitinib malate in both the double-blind and open-label treatment phases, the median duration of sunitinib malate treatment was 6 cycles (mean 8.5, range 1 – 44). For the 255 patients who ultimately received open-label sunitinib malate treatment, median duration of study treatment was 6 cycles (mean 7.8, range 1 – 37) from the time of the unblinding. A total of 118 patients (46%) required dosing interruptions, and a total of 72 patients (28%) required dose reductions. The incidence of treatment-emergent adverse reactions resulting in permanent discontinuation was 20%. The most common Grade 3 or 4 treatment-related adverse reactions experienced by patients receiving sunitinib malate in the open-label treatment phase were fatigue (10%), hypertension (8%), asthenia (5%), diarrhea (5%), palmar-plantar erythrodysesthesia (5%), nausea (4%), abdominal pain (3%), anorexia (3%), mucositis (2%), vomiting (2%), and hypothyroidism (2%). ### Adverse Reactions in the Treatment-Naïve RCC Study The as-treated patient population for the treatment-naive RCC study included 735 patients, 375 randomized to sunitinib malate and 360 randomized to IFN-α. The median duration of treatment was 11.1 months (range: 0.4 – 46.1) for sunitinib malate treatment and 4.1 months (range: 0.1 – 45.6) for IFN-α treatment. Dose interruptions occurred in 202 patients (54%) on sunitinib malate and 141 patients (39%) on IFN-α. Dose reductions occurred in 194 patients (52%) on sunitinib malate and 98 patients (27%) on IFN-α. Discontinuation rates due to adverse reactions were 20% for sunitinib malate and 24% for IFN-α. Most treatment-emergent adverse reactions in both study arms were Grade 1 or 2 in severity. Grade 3 or 4 treatment-emergent adverse reactions were reported in 77% versus 55% of patients on sunitinib malate versus IFN-α, respectively. Table 3 compares the incidence of common (≥10%) treatment-emergent adverse reactions for patients receiving sunitinib malate versus IFN-α. Treatment-emergent Grade 3/4 laboratory abnormalities are presented in Table 4. ### Adverse Reactions in the Phase 3 pNET Study The median number of days on treatment was 139 days (range 13–532 days) for patients on sunitinib malate and 113 days (range 1–614 days) for patients on placebo. Nineteen patients (23%) on sunitinib malate and 4 patients (5%) on placebo were on study for >1 year. Dose interruptions occurred in 25 patients (30%) on sunitinib malate and 10 patients (12%) on placebo. Dose reductions occurred in 26 patients (31%) on sunitinib malate and 9 patients (11%) on placebo. Discontinuation rates due to adverse reactions were 22% for sunitinib malate and 17% for placebo. Most treatment-emergent adverse reactions in both study arms were Grade 1 or 2 in severity. Grade 3 or 4 treatment-emergent adverse reactions were reported in 54% versus 50% of patients on sunitinib malate versus placebo, respectively. Table 5 compares the incidence of common (≥10%) treatment-emergent adverse reactions for patients receiving sunitinib malate and reported more commonly in patients receiving sunitinib malate than in patients receiving placebo. Table 6 provides common (≥10%) treatment-emergent laboratory abnormalities. ### Venous Thromboembolic Events Seven patients (3%) on sunitinib malate and none on placebo in the double-blind treatment phase of GIST Study A experienced venous thromboembolic events; five of the seven were Grade 3 deep venous thrombosis (DVT), and two were Grade 1 or 2. Four of these seven GIST patients discontinued treatment following first observation of DVT. Thirteen (3%) patients receiving sunitinib malate for \|treatment-naïve RCC]] had venous thromboembolic events reported. Seven (2%) of these patients had pulmonary embolism, one was Grade 2 and six were Grade 4, and six (2%) patients had DVT, including three Grade 3. One patient was permanently withdrawn from sunitinib malate due to pulmonary embolism; dose interruption occurred in two patients with pulmonary embolism and one with DVT. In treatment-naïve RCC patients receiving IFN-α, six (2%) venous thromboembolic events occurred; one patient (<1%) experienced a Grade 3 DVT and five patients (1%) had pulmonary embolism, all Grade 4. One patient (1%) receiving sunitinib malate for pNET had a venous thromboembolic events reported compared to 5 patients (6%) receiving placebo. The sunitinib malate patient had Grade 2 thrombosis. Two placebo patients had DVT, one was Grade 3, two placebo patients had pulmonary embolism, one was Grade 3 and one was Grade 4, and one placebo patient had Grade 3 jugular thrombosis. ### Reversible Posterior Leukoencephalopathy Syndrome There have been reports (<1%), some fatal, of subjects presenting with seizures and radiological evidence of reversible posterior leukoencephalopathy syndrome (RPLS). Patients with seizures and signs/symptoms consistent with RPLS, such as hypertension, headache, decreased alertness, altered mental functioning, and visual loss, including cortical blindness should be controlled with medical management including control of hypertension. Temporary suspension of sunitinib malate is recommended; following resolution, treatment may be resumed at the discretion of the treating physician. ### Pancreatic and Hepatic Function If symptoms of pancreatitis or hepatic failure are present, patients should have sunitinib malate discontinued. Pancreatitis was observed in 5 (1%) patients receiving sunitinib malate for treatment-naïve RCC compared to 1 (<1%) patient receiving IFN-α. Pancreatitis was observed in 1 (1%) patient receiving sunitinib malate for pNET and 1 (1%) patient receiving placebo. Hepatotoxicity was observed in patients receiving sunitinib malate. ## Postmarketing Experience The following adverse reactions have been identified during post-approval use of sunitinib malate. 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. ### Blood and lymphatic system disorders - Thrombotic microangiopathy; hemorrhage associated with thrombocytopenia. - Suspension of sunitinib malate is recommended; following resolution, treatment may be resumed at the discretion of the treating physician. ### Gastrointestinal disorders - Esophagitis ### Hepatobiliary disorders - Cholecystitis, particularly acalculous cholecystitis. ### Immune system disorders - Hypersensitivity reactions, including angioedema. ### Infections and infestations - Serious infection (with or without neutropenia) - The infections most commonly observed with sunitinib treatment include respiratory, urinary tract, skin infections, sepsis/septic shock. ### Musculoskeletal and connective tissue disorders - Fistula formation, sometimes associated with tumor necrosis and/or regression; myopathy and/or rhabdomyolysis with or without acute renal failure. - Patients with signs or symptoms of muscle toxicity should be managed as per standard medical practice. ### Renal and urinary disorders - Renal impairment and/or failure ### Respiratory disorders - Pulmonary embolism ### Skin and subcutaneous tissue disorders - Pyoderma gangrenosum, including positive dechallenges. ### Vascular disorders - Arterial thromboembolic events. - The most frequent events included cerebrovascular accident, transient ischemic attack and cerebral infarction. # Drug Interactions ### CYP3A4 Inhibitors strong CYP3A4 inhibitor such as ketoconazole may increase sunitinib plasma concentrations. Selection of an alternate concomitant medication with no or minimal enzyme inhibition potential is recommended. Concurrent administration of sunitinib malate with the strong CYP3A4 inhibitor, ketoconazole, resulted in 49% and 51% increases in the combined (sunitinib + primary active metabolite) Cmax and AUC0–∞ values, respectively, after a single dose of sunitinib malate in healthy volunteers. Co-administration of sunitinib malate with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) may increase sunitinib concentrations. Grapefruit may also increase plasma concentrations of sunitinib. A dose reduction for sunitinib malate should be considered when it must be co-administered with strong CYP3A4 inhibitors. ### CYP3A4 Inducers CYP3A4 inducers such as rifampin may decrease sunitinib plasma concentrations. Selection of an alternate concomitant medication with no or minimal enzyme induction potential is recommended. Concurrent administration of sunitinib malate with the strong CYP3A4 inducer, rifampin, resulted in a 23% and 46% reduction in the combined (sunitinib + primary active metabolite) Cmax and AUC0–∞ values, respectively, after a single dose of sunitinib malate in healthy volunteers. Co-administration of sunitinib malate with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. John's Wort) may decrease sunitinib concentrations. St. John's Wort may decrease sunitinib plasma concentrations unpredictably. Patients receiving sunitinib malate should not take St. John's Wort concomitantly. A dose increase for sunitinib malate should be considered when it must be co-administered with CYP3A4 inducers. ### In Vitro Studies of CYP Inhibition and Induction In vitro studies indicated that sunitinib does not induce or inhibit major CYP enzymes. The in vitro studies in human liver microsomes and hepatocytes of the activity of CYP isoforms CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, and CYP4A9/11 indicated that sunitinib and its primary active metabolite are unlikely to have any clinically relevant drug-drug interactions with drugs that may be metabolized by these enzyme. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): D Sunitinib malate can cause fetal harm when administered to a pregnant woman. As angiogenesis is a critical component of embryonic and fetal development, inhibition of angiogenesis following administration of sunitinib malate should be expected to result in adverse effects on pregnancy. In animal reproductive studies in rats and rabbits, sunitinib was teratogenic, embryotoxic, and fetotoxic. There are no adequate and well-controlled studies of sunitinib malate in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with sunitinib malate. Sunitinib was evaluated in pregnant rats (0.3, 1.5, 3.0, 5.0 mg/kg/day) and rabbits (0.5, 1, 5, 20 mg/kg/day) for effects on the embryo. Significant increases in the incidence of embryolethality and structural abnormalities were observed in rats at the dose of 5 mg/kg/day (approximately 5.5 times the systemic exposure in patients administered the recommended daily doses ). Significantly increased embryolethality was observed in rabbits at 5 mg/kg/day while developmental effects were observed at ≥1 mg/kg/day (approximately 0.3 times the AUC in patients administered the RDD of 50 mg/day). Developmental effects consisted of fetal skeletal malformations of the ribs and vertebrae in rats. In rabbits, cleft lip was observed at 1 mg/kg/day and cleft lip and cleft palate were observed at 5 mg/kg/day (approximately 2.7 times the AUC in patients administered the RDD). Neither fetal loss nor malformations were observed in rats dosed at ≤3 mg/kg/day (approximately 2.3 times the AUC in patients administered the RDD). Sunitinib (0.3, 1.0, 3.0 mg/kg/day) was evaluated in a pre- and postnatal development study in pregnant rats. Maternal body weight gains were reduced during gestation and lactation at doses ≥1 mg/kg/day but no maternal reproductive toxicity was observed at doses up to 3 mg/kg/day (approximately 2.3 times the AUC in patients administered the RDD). At the high dose of 3 mg/kg/day, reduced body weights were observed at birth and persisted for offspring of both sexes during the pre-weaning period and in males during post-weaning period. No other developmental toxicity was observed at doses up to 3 mg/kg/day (approximately 2.3 times the AUC in patients administered the RDD). Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Sunitinib in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Sunitinib during labor and delivery. ### Nursing Mothers Sunitinib and its metabolites are excreted in rat milk. In lactating female rats administered 15 mg/kg, sunitinib and its metabolites were extensively excreted in milk at concentrations up to 12-fold higher than in plasma. It is not known whether this drug or its primary active metabolite are 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 sunitinib malate, 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 efficacy of sunitinib malate in pediatric patients have not been established. Physeal dysplasia was observed in cynomolgus monkeys with open growth plates treated for ≥3 months (3 month dosing 2, 6, 12 mg/kg/day; 8 cycles of dosing 0.3, 1.5, 6.0 mg/kg/day) with sunitinib at doses that were >0.4 times the RDD based on systemic exposure (AUC). In developing rats treated continuously for 3 months (1.5, 5.0 and 15.0 mg/kg) or 5 cycles (0.3, 1.5, and 6.0 mg/kg/day), bone abnormalities consisted of thickening of the epiphyseal cartilage of the femur and an increase of fracture of the tibia at doses ≥5 mg/kg (approximately 10 times the RDD based on AUC). Additionally, caries of the teeth were observed in rats at >5 mg/kg. The incidence and severity of physeal dysplasia were dose-related and were reversible upon cessation of treatment; however, findings in the teeth were not. A no effect level was not observed in monkeys treated continuously for 3 months, but was 1.5 mg/kg/day when treated intermittently for 8 cycles. In rats the no effect level in bones was ≤2 mg/kg/day. ### Geriatic Use Of 825 GIST and RCC patients who received sunitinib malate on clinical studies, 277 (34%) were 65 and over. In the Phase 3 pNET study, 22 (27%) patients who received sunitinib malate were 65 and over. No overall differences in safety or effectiveness were observed between younger and older patients. ### Gender There is no FDA guidance on the use of Sunitinib with respect to specific gender populations. ### Race There is no FDA guidance on the use of Sunitinib with respect to specific racial populations. ### Renal Impairment No adjustment to the starting dose is required when administering sunitinib malate to patients with mild, moderate, and severe renal impairment. Subsequent dose modifications should be based on safety and tolerability. In patients with end-stage renal disease (ESRD) on hemodialysis, no adjustment to the starting dose is required. However, compared to subjects with normal renal function, the sunitinib exposure is 47% lower in subjects with ESRD on hemodialysis. Therefore, the subsequent doses may be increased gradually up to 2 fold based on safety and tolerability. ### Hepatic Impairment No dose adjustment to the starting dose is required when administering sunitinib malate to patients with Child-Pugh Class A or B hepatic impairment. Sunitinib and its primary metabolite are primarily metabolized by the liver. Systemic exposures after a single dose of sunitinib malate were similar in subjects with mild or moderate (Child-Pugh Class A and B) hepatic impairment compared to subjects with normal hepatic function. sunitinib malate was not studied in subjects with severe (Child-Pugh Class C) hepatic impairment. Studies in cancer patients have excluded patients with ALT or AST >2.5 × ULN or, if due to liver metastases, >5.0 × ULN. ### Females of Reproductive Potential and Males Effects on the female reproductive system were identified in a 3-month repeat dose monkey study (2, 6, 12 mg/kg/day), where ovarian changes (decreased follicular development) were noted at 12 mg/kg/day (≥5.1 times the AUC in patients administered the RDD), while uterine changes (endometrial atrophy) were noted at ≥2 mg/kg/day (≥0.4 times the AUC in patients administered the RDD). With the addition of vaginal atrophy, the uterine and ovarian effects were reproduced at 6 mg/kg/day in the 9-month monkey study (0.3, 1.5 and 6 mg/kg/day administered daily for 28 days followed by a 14 day respite; the 6 mg/kg dose produced a mean AUC that was ≥0.8 times the AUC in patients administered the RDD). A no effect level was not identified in the 3 month study; 1.5 mg/kg/day represents a no effect level in monkeys administered sunitinib for 9 months. Although fertility was not affected in rats, sunitinib malate may impair fertility in humans. In female rats, no fertility effects were observed at doses of ≤5.0 mg/kg/day , however significant embryolethality was observed at the 5.0 mg/kg dose. No reproductive effects were observed in male rats dosed (1, 3 or 10 mg/kg/day) for 58 days prior to mating with untreated females. Fertility, copulation, conception indices, and sperm evaluation (morphology, concentration, and motility) were unaffected by sunitinib at doses ≤10 mg/kg/day (the 10 mg/kg/day dose produced a mean AUC that was ≥25.8 times the AUC in patients administered the RDD). ### Immunocompromised Patients There is no FDA guidance one the use of Sunitinib in patients who are immunocompromised. # Administration and Monitoring ### Administration Oral ### Monitoring There is limited information regarding Sunitinib Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Sunitinib and IV administrations. # Overdosage Treatment of overdose with sunitinib malate should consist of general supportive measures. There is no specific antidote for overdosage with sunitinib malate. If indicated, elimination of unabsorbed drug should be achieved by emesis or gastric lavage. A few cases of accidental overdose have been reported; these cases were associated with adverse reactions consistent with the known safety profile of sunitinib malate, or without adverse reactions. A case of intentional overdose involving the ingestion of 1,400 mg of sunitinib malate in an attempted suicide was reported without adverse reaction. In non-clinical studies mortality was observed following as few as 5 daily doses of 400 mg/kg (3000 mg/m2) in rats. At this dose, signs of toxicity included impaired muscle coordination, head shakes, hypoactivity, ocular discharge, piloerection and gastrointestinal distress. Mortality and similar signs of toxicity were observed at lower doses when administered for longer durations. # Pharmacology ## Mechanism of Action Sunitinib is a small molecule that inhibits multiple receptor tyrosine kinases (RTKs), some of which are implicated in tumor growth, pathologic angiogenesis, and metastatic progression of cancer. Sunitinib was evaluated for its inhibitory activity against a variety of kinases (>80 kinases) and was identified as an inhibitor of platelet-derived growth factor receptors (PDGFRα and PDGFRβ), vascular endothelial growth factor receptors (VEGFR1, VEGFR2 and VEGFR3), stem cell factor receptor (KIT), Fms-like tyrosine kinase-3 (FLT3), colony stimulating factor receptor Type 1 (CSF-1R), and the glial cell-line derived neurotrophic factor receptor (RET). Sunitinib inhibition of the activity of these RTKs has been demonstrated in biochemical and cellular assays, and inhibition of function has been demonstrated in cell proliferation assays. The primary metabolite exhibits similar potency compared to sunitinib in biochemical and cellular assays. Sunitinib inhibited the phosphorylation of multiple RTKs (PDGFRβ, VEGFR2, KIT) in tumor xenografts expressing RTK targets in vivo and demonstrated inhibition of tumor growth or tumor regression and/or inhibited metastases in some experimental models of cancer. Sunitinib demonstrated the ability to inhibit growth of tumor cells expressing dysregulated target RTKs (PDGFR, RET, or KIT) in vitro and to inhibit PDGFRβ- and VEGFR2-dependent tumor angiogenesis in vivo. ## Structure Sunitinib malate is described chemically as Butanedioic acid, hydroxy-, (2S)-, compound with N--5--2,4-dimethyl-1H-pyrrole-3-carboxamide (1:1). The molecular formula is C22H27FN4O2 - C4H6O5 and the molecular weight is 532.6 Daltons. The chemical structure of sunitinib malate is: ## Pharmacodynamics There is limited information regarding Sunitinib Pharmacodynamics in the drug label. ## Pharmacokinetics The pharmacokinetics of sunitinib and sunitinib malate have been evaluated in 135 healthy volunteers and in 266 patients with solid tumors. Maximum plasma concentrations (Cmax) of sunitinib are generally observed between 6 and 12 hours (Tmax) following oral administration. Food has no effect on the bioavailability of sunitinib. sunitinib malate may be taken with or without food. Binding of sunitinib and its primary active metabolite to human plasma protein in vitro was 95% and 90%, respectively, with no concentration dependence in the range of 100 – 4000 ng/mL. The apparent volume of distribution (Vd/F) for sunitinib was 2230 L. In the dosing range of 25 – 100 mg, the area under the plasma concentration-time curve (AUC) and Cmax increase proportionately with dose. Sunitinib is metabolized primarily by the cytochrome P450 enzyme, CYP3A4, to produce its primary active metabolite, which is further metabolized by CYP3A4. The primary active metabolite comprises 23 to 37% of the total exposure. Elimination is primarily via feces. In a human mass balance study of sunitinib, 61% of the dose was eliminated in feces, with renal elimination accounting for 16% of the administered dose. Sunitinib and its primary active metabolite were the major drug-related compounds identified in plasma, urine, and feces, representing 91.5%, 86.4% and 73.8% of radioactivity in pooled samples, respectively. Minor metabolites were identified in urine and feces but generally not found in plasma. Total oral clearance (CL/F) ranged from 34 to 62 L/hr with an inter-patient variability of 40%. Following administration of a single oral dose in healthy volunteers, the terminal half-lives of sunitinib and its primary active metabolite are approximately 40 to 60 hours and 80 to 110 hours, respectively. With repeated daily administration, sunitinib accumulates 3- to 4-fold while the primary metabolite accumulates 7- to 10-fold. Steady-state concentrations of sunitinib and its primary active metabolite are achieved within 10 to 14 days. By Day 14, combined plasma concentrations of sunitinib and its active metabolite ranged from 62.9 – 101 ng/mL. No significant changes in the pharmacokinetics of sunitinib or the primary active metabolite were observed with repeated daily administration or with repeated cycles in the dosing regimens tested. The pharmacokinetics were similar in healthy volunteers and in the solid tumor patient populations tested, including patients with GIST and RCC. ## Nonclinical Toxicology ### Carcinogenesis and Mutagenesis The carcinogenic potential of sunitinib has been evaluated in two species: rasH2 transgenic mice and Sprague-Dawley rats. There were similar positive findings in both species. In rasH2 transgenic mice gastroduodenal carcinomas and/or gastric mucosal hyperplasia, as well as an increased incidence of background hemangiosarcomas were observed at doses of ≥25 mg/kg/day following daily dose administration of sunitinib in studies of 1 or 6 months duration. No proliferative changes were observed in rasH2 transgenic mice at 8 mg/kg/day. Similarly, in a 2-year rat carcinogenicity study, administration of sunitinib in 28-day cycles followed by 7-day dose-free periods resulted in findings of duodenal carcinoma at doses as low as 1 mg/kg/day (approximately 0.9 times the AUC in patients given the RDD of 50 mg/day).At the high dose of 3 mg/kg/day (approximately 7.8 times the AUC in patients at the RDD of 50 mg/day) the incidence of duodenal tumors was increased and was accompanied by findings of gastric mucous cell hyperplasia and by an increased incidence of pheochromocytoma and hyperplasia of the adrenal. Sunitinib did not cause genetic damage when tested in in vitro assays (bacterial mutation ]], human lymphocyte chromosome aberration) and an in vivo rat bone marrow micronucleus test. # Clinical Studies ### Gastrointestinal Stromal Tumor Study A was a two-arm, international, randomized, double-blind, placebo-controlled trial of sunitinib malate in patients with GIST who had disease progression during prior imatinib mesylate (imatinib) treatment or who were intolerant of imatinib. The objective was to compare Time-to-Tumor Progression (TTP) in patients receiving sunitinib malate plus best supportive care versus patients receiving placebo plus best supportive care. Other objectives included Progression-Free Survival (PFS), Objective Response Rate (ORR), and Overall Survival (OS). Patients were randomized (2:1) to receive either 50 mg sunitinib malate or placebo orally, once daily, on Schedule 4/2 until disease progression or withdrawal from the study for another reason. Treatment was unblinded at the time of disease progression. Patients randomized to placebo were then offered crossover to open-label sunitinib malate, and patients randomized to sunitinib malate were permitted to continue treatment per investigator judgment. At the time of a pre-specified interim analysis, the intent-to-treat (ITT) population included 312 patients. Two-hundred seven (207) patients were randomized to the sunitinib malate arm, and 105 patients were randomized to the placebo arm. Demographics were comparable between the sunitinib malate and placebo groups with regard to age (69% vs 72% <65 years for sunitinib malate vs. placebo, respectively), gender (Male: 64% vs. 61%), race (White: (88% both arms, Asian: 5% both arms, Black: 4% both arms, remainder not reported), and Performance Status (ECOG 0: 44% vs. 46%, ECOG 1: 55% vs. 52%, and ECOG 2: 1 vs. 2%). Prior treatment included surgery (94% vs. 93%) and radiotherapy (8% vs. 15%). Outcome of prior imatinib treatment was also comparable between arms with intolerance (4% vs. 4%), progression within 6 months of starting treatment (17% vs. 16%), or progression beyond 6 months (78% vs. 80%) balanced. The planned interim efficacy and safety analysis was performed after 149 TTP events had occurred. There was a statistically significant advantage for sunitinib malate over placebo in TTP, meeting the primary endpoint. Efficacy results are summarized in Table 7 and the Kaplan-Meier curve for TTP is in Figure 1. The final ITT population enrolled in the double-blind treatment phase of the study included 243 patients randomized to the sunitinib malate arm and 118 patients randomized to the placebo arm. After the primary endpoint was met at the interim analysis, the study was unblinded, and patients on the placebo arm were offered open-label sunitinib malate treatment. Ninety-nine of the patients initially randomized to placebo crossed over to receive sunitinib malate in the open-label treatment phase. At the protocol specified final analysis of OS, the median OS was 72.7 weeks for the sunitinib malate arm and 64.9 weeks for the placebo arm . Study B was an open-label, multi-center, single-arm, dose-escalation study conducted in patients with GIST following progression on or intolerance to imatinib. Following identification of the recommended Phase 2 regimen (50 mg once daily on Schedule 4/2), 55 patients in this study received the 50 mg dose of sunitinib malate on treatment Schedule 4/2. Partial responses were observed in 5 of 55 patients . ### Renal Cell Carcinoma A multi-center, international randomized study comparing single-agent sunitinib malate with IFN-α was conducted in patients with treatment-naïve RCC. The objective was to compare Progression-Free Survival (PFS) in patients receiving sunitinib malate versus patients receiving IFN-α. Other endpoints included Objective Response Rate (ORR), Overall Survival (OS) and safety. Seven hundred fifty (750) patients were randomized (1:1) to receive either 50 mg sunitinib malate once daily on Schedule 4/2 or to receive IFN-α administered subcutaneously at 9 MIU three times a week. Patients were treated until disease progression or withdrawal from the study. The ITT population included 750 patients, 375 randomized to sunitinib malate and 375 randomized to IFN-α. Demographics were comparable between the sunitinib malate and IFN-α groups with regard to age (59% vs. 67% <65 years for sunitinib malate vs. IFN-α, respectively), gender (Male: 71% vs. 72%), race (White: 94% vs. 91%, Asian: 2% vs. 3%, Black: 1% vs. 2%, remainder not reported), and Performance Status (ECOG 0: 62% vs. 61%, ECOG 1: 38% each arm, ECOG 2: 0 vs. 1%). Prior treatment included nephrectomy (91% vs. 89%) and radiotherapy (14% each arm). The most common site of metastases present at screening was the lung (78% vs. 80%, respectively), followed by the lymph nodes (58% vs. 53%, respectively) and bone (30% each arm); the majority of the patients had multiple (2 or more) metastatic sites at baseline (80% vs. 77%, respectively). There was a statistically significant advantage for sunitinib malate over IFN-α in the endpoint of PFS (see TABLE 8 and FIGURE 2). In the pre-specified stratification factors of LDH (>1.5 ULN vs. ≤1.5 ULN), ECOG performance status (0 vs. 1), and prior nephrectomy (yes vs. no), the hazard ratio favored sunitinib malate over IFN-α. The ORR was higher in the sunitinib malate arm (see TABLE 8). At the protocol-specified final analysis of OS, the median OS was 114.6 weeks for the sunitinib malate arm and 94.9 weeks for the IFN-α arm . The median OS for the IFN-α arm includes 25 patients who discontinued IFN-α treatment because of disease progression and crossed over to treatment with sunitinib malate as well as 121 patients (32%) on the IFN-α arm who received post-study cancer treatment with sunitinib malate. The use of single agent sunitinib malate in the treatment of cytokine-refractory RCC was investigated in two single-arm, multi-center studies. All patients enrolled into these studies experienced failure of prior cytokine-based therapy. In Study 1, failure of prior cytokine therapy was based on radiographic evidence of disease progression defined by RECIST or World Health Organization (WHO) criteria during or within 9 months of completion of 1 cytokine therapy treatment (IFN-α, interleukin-2, or IFN-α plus interleukin-2; patients who were treated with IFN-α alone must have received treatment for at least 28 days). In Study 2, failure of prior cytokine therapy was defined as disease progression or unacceptable treatment-related toxicity. The endpoint for both studies was ORR. Duration of Response (DR) was also evaluated. One hundred six patients (106) were enrolled into Study 1, and 63 patients were enrolled into Study 2. Patients received 50 mg sunitinib malate on Schedule 4/2. Therapy was continued until the patients met withdrawal criteria or had progressive disease. The baseline age, gender, race and ECOG performance statuses of the patients were comparable between Studies 1 and 2. Approximately 86–94% of patients in the two studies were White. Men comprised 65% of the pooled population. The median age was 57 years and ranged from 24 to 87 years in the studies. All patients had an ECOG performance status <2 at the screening visit. The baseline malignancy and prior treatment history of the patients were comparable between Studies 1 and 2. Across the two studies, 95% of the pooled population of patients had at least some component of clear-cell histology. All patients in Study 1 were required to have a histological clear-cell component. Most patients enrolled in the studies (97% of the pooled population) had undergone nephrectomy; prior nephrectomy was required for patients enrolled in Study 1. All patients had received one previous cytokine regimen. Metastatic disease present at the time of study entry included lung metastases in 81% of patients. Liver metastases were more common in Study 1 (27% vs. 16% in Study 2) and bone metastases were more common in Study 2 (51% vs. 25% in Study 1); 52% of patients in the pooled population had at least 3 metastatic sites. Patients with known brain metastases or leptomeningeal disease were excluded from both studies. The ORR and DR data from Studies 1 and 2 are provided in Table 9. There were 36 PRs in Study 1 as assessed by a core radiology laboratory for an ORR of 34.0% (95% CI 25.0, 43.8). There were 23 PRs in Study 2 as assessed by the investigators for an ORR of 36.5% (95% CI 24.7, 49.6). The majority (>90%) of objective disease responses were observed during the first four cycles; the latest reported response was observed in Cycle 10. DR data from Study 1 is premature as only 9 of 36 patients (25%) responding to treatment had experienced disease progression or died at the time of the data cutoff. ### Pancreatic Neuroendocrine Tumors The Phase 3 study was a multi-center, international, randomized, double-blind placebo-controlled study of single-agent sunitinib malate conducted in patients with unresectable pNET. Patients were required to have documented RECIST-defined disease progression within the prior 12 months and were randomized (1:1) to receive either 37.5 mg sunitinib malate (n=86) or placebo (n=85) once daily without a scheduled off-treatment period. The primary objective was to compare Progression-Free Survival (PFS) in patients receiving sunitinib malate versus patients receiving placebo. Other endpoints included Overall Survival (OS), Objective Response Rate (ORR), and safety. Use of somatostatin analogs was allowed in the study. Demographics were comparable between the sunitinib malate and placebo groups. Additionally, 49% of sunitinib malate patients had non-functioning tumors vs 52% of placebo patients, and 92% patients in both arms had liver metastases. A total of 66% of sunitinib malate patients received prior systemic therapy compared with 72% of placebo patients and 35% of sunitinib malate patients had received somatostatin analogs compared with 38% of placebo patients. Patients were treated until disease progression or withdrawal from the study. Upon disease progression, or study closure, patients were offered access to sunitinib malate in a separate extension study. As recommended by the Independent Data Monitoring Committee, the study was terminated prematurely prior to the pre-specified interim analysis. This may have led to an overestimate of the magnitude of PFS effect. A clinically significant improvement for sunitinib malate over placebo in PFS was seen by both investigator and independent assessment. A hazard ratio favoring sunitinib malate was observed in all subgroups of baseline characteristics evaluated. OS data were not mature at the time of the analysis. There were 9 deaths in the sunitinib malate arm and 21 deaths in the placebo arm. A statistically significant difference in ORR favoring sunitinib malate over placebo was observed. Efficacy results are summarized in Table 10 and the Kaplan-Meier curve for PFS is in Figure 3. # How Supplied - 12.5 mg Capsules - Bottles of 28 - NDC 0069-0550-38 - 25 mg Capsules - Bottles of 28 - NDC 0069-0770-38 - 37.5 mg Capsules - Bottles of 28 - NDC 0069-0830-38 - 50 mg Capsules - Bottles of 28 - NDC 0069-0980-38 ## Storage Store at 25°C (77°F) # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information ### Gastrointestinal Disorders Gastrointestinal disorders such as diarrhea, nausea, stomatitis, dyspepsia, and vomiting were the most commonly reported gastrointestinal events occurring in patients who received sunitinib malate. Supportive care for gastrointestinal adverse events requiring treatment may include anti-emetic or anti-diarrheal medication. ### Skin Effects Skin discoloration possibly due to the drug color (yellow) occurred in approximately one third of patients. Patients should be advised that depigmentation of the hair or skin may occur during treatment with sunitinib malate. Other possible dermatologic effects may include dryness, thickness or cracking of skin, blister or rash on the palms of the hands and soles of the feet. Severe dermatologic toxicities including Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis have been reported. Patients should be advised to immediately inform their healthcare provider if severe dermatologic reactions occur. ### Other Common Events Other commonly reported adverse events included fatigue, high blood pressure, bleeding, swelling, mouth pain/irritation and taste disturbance. ### Musculoskeletal Disorders Prior to treatment with sunitinib malate, a dental examination and appropriate preventive dentistry should be considered. In patients being treated with sunitinib malate, who have previously received or are receiving bisphosphonates, invasive dental procedures should be avoided, if possible. ### Concomitant Medications Patients should be advised to inform their healthcare providers of all concomitant medications, including over-the-counter medications and dietary supplements # Precautions with Alcohol Alcohol-Sunitinib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Sutent # Look-Alike Drug Names There is limited information regarding Sunitinib Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Sunitinib Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gloria Picoy [2];Aparna Vuppala, M.B.B.S. [3] # 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 Sunitinib is a tyrosine kinase inhibitor that is FDA approved for the treatment of gastrointestinal stromal tumor (GIST) after disease progression on or intolerance to imatinib mesylate, advanced renal cell carcinoma (RCC) and Progressive, well-differentiated pancreatic neuroendocrine tumors (pNET) in patients with unresectable locally advanced or metastatic disease. There is a Black Box Warning for this drug as shown here. Common adverse reactions include fatigue, asthenia, fever, diarrhea, nausea, mucositis/stomatitis, vomiting, dyspepsia, abdominal pain, constipation, hypertension, peripheral edema, rash, palmar plantar erythrodysesthesia, skin discoloration, dry skin, hair color changes, altered taste, headache, back pain, arthralgia, extremity pain, cough, dyspnea, anorexia and bleeding. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Gastrointestinal Stromal Tumor (GIST) - Sunitinib is indicated for the treatment of gastrointestinal stromal tumor after disease progression on or intolerance to imatinib mesylate. - Dosage: one 50 mg oral dose taken once daily, on a schedule of 4 weeks on treatment followed by 2 weeks off (Schedule 4/2). - Sunitinib malate may be taken with or without food ### Advanced Renal Cell Carcinoma (RCC) - Sunitinib malate is indicated for the treatment of advanced renal cell carcinoma. - Dosage: one 50 mg oral dose taken once daily, on a schedule of 4 weeks on treatment followed by 2 weeks off (Schedule 4/2). - Sunitinib malate may be taken with or without food ### Advanced Pancreatic Neuroendocrine Tumors (pNET) - Sunitinib malate is indicated for the treatment of progressive, well-differentiated pancreatic neuroendocrine tumors in patients with unresectable locally advanced or metastatic disease. - Dosage: 37.5 mg taken orally once daily continuously without a scheduled off-treatment period. - Sunitinib malate may be taken with or without food. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Sunitinib in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Sunitinib in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Sunitinib 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 Sunitinib in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Sunitinib in pediatric patients. # Contraindications None # Warnings ### Hepatotoxicity Sunitinib malate has been associated with hepatotoxicity, which may result in liver failure or death. Liver failure has been observed in clinical trials (7/2281 [0.3%]) and post-marketing experience. Liver failure signs include jaundice, elevated transaminases and/or hyperbilirubinemia in conjunction with encephalopathy, coagulopathy, and/or renal failure. Monitor liver function tests (ALT, AST, bilirubin) before initiation of treatment, during each cycle of treatment, and as clinically indicated. Sunitinib malate should be interrupted for Grade 3 or 4 drug-related hepatic adverse events and discontinued if there is no resolution. Do not restart sunitinib malate if patients subsequently experience severe changes in liver function tests or have other signs and symptoms of liver failure. Safety in patients with ALT or AST >2.5 × ULN or, if due to liver metastases, >5.0 × ULN has not been established. ### Pregnancy Sunitinib malate can cause fetal harm when administered to a pregnant woman. As angiogenesis is a critical component of embryonic and fetal development, inhibition of angiogenesis following administration of sunitinib malate should be expected to result in adverse effects on pregnancy. In animal reproductive studies in rats and rabbits, sunitinib was teratogenic, embryotoxic, and fetotoxic. There are no adequate and well-controlled studies of sunitinib malate in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with sunitinib malate. ### Left Ventricular Dysfunction In the presence of clinical manifestations of congestive heart failure (CHF), discontinuation of sunitinib malate is recommended. The dose of sunitinib malate should be interrupted and/or reduced in patients without clinical evidence of CHF but with an ejection fraction <50% and >20% below baseline. Cardiovascular events, including heart failure, myocardial disorders and cardiomyopathy, some of which were fatal, have been reported through post-marketing experience. For GIST and RCC, more patients treated with sunitinib malate experienced decline in left ventricular ejection fraction (LVEF) than patients receiving either placebo or interferon-α (IFN-α). In the double-blind treatment phase of GIST Study A, 22/209 patients (11%) on sunitinib malate and 3/102 patients (3%) on placebo had treatment-emergent LVEF values below the lower limit of normal (LLN). Nine of 22 GIST patients on sunitinib malate with LVEF changes recovered without intervention. Five patients had documented LVEF recovery following intervention (dose reduction: one patient; addition of antihypertensive or diuretic medications: four patients). Six patients went off study without documented recovery. Additionally, three patients on sunitinib malate had Grade 3 reductions in left ventricular systolic function to LVEF <40%; two of these patients died without receiving further study drug. No GIST patients on placebo had Grade 3 decreased LVEF. In the double-blind treatment phase of GIST Study A, 1 patient on sunitinib malate and 1 patient on placebo died of diagnosed heart failure; 2 patients on sunitinib malate and 2 patients on placebo died of treatment-emergent cardiac arrest. In the treatment-naïve RCC study, 103/375 (27%) and 54/360 (15%) patients on sunitinib malate and IFN-α, respectively, had an LVEF value below the LLN. Twenty-six patients on sunitinib malate (7%) and seven on IFN-α (2%) experienced declines in LVEF to >20% below baseline and to below 50%. Left ventricular dysfunction was reported in four patients (1%) and CHF in two patients (<1%) who received sunitinib malate. In the Phase 3 pNET study, cardiac failure leading to death was reported in 2/83 (2%) patients on sunitinib malate and no patients on placebo. Patients who presented with cardiac events within 12 months prior to sunitinib malate administration, such as myocardial infarction (including severe/unstable angina), coronary/peripheral artery bypass graft, symptomatic CHF, cerebrovascular accident or transient ischemic attack, or pulmonary embolism were excluded from sunitinib malate clinical studies. It is unknown whether patients with these concomitant conditions may be at a higher risk of developing drug-related left ventricular dysfunction. Physicians are advised to weigh this risk against the potential benefits of the drug. These patients should be carefully monitored for clinical signs and symptoms of CHF while receiving sunitinib malate. Baseline and periodic evaluations of LVEF should also be considered while these patients are receiving sunitinib malate. In patients without cardiac risk factors, a baseline evaluation of ejection fraction should be considered. ### QT Interval Prolongation and Torsade de Pointes Sunitinib malate has been shown to prolong the QT interval in a dose dependent manner, which may lead to an increased risk for ventricular arrhythmias including Torsade de Pointes. Torsade de Pointes has been observed in <0.1% of sunitinib malate-exposed patients. Sunitinib malate should be used with caution in patients with a history of QT interval prolongation, patients who are taking antiarrhythmics, or patients with relevant pre-existing cardiac disease, bradycardia, or electrolyte disturbances. When using sunitinib malate, periodic monitoring with on-treatment electrocardiograms and electrolytes (magnesium, potassium) should be considered. Concomitant treatment with strong CYP3A4 inhibitors, which may increase sunitinib plasma concentrations, should be used with caution and dose reduction of sunitinib malate should be considered. ### Hypertension Patients should be monitored for hypertension and treated as needed with standard anti-hypertensive therapy. In cases of severe hypertension, temporary suspension of sunitinib malate is recommended until hypertension is controlled. Of patients receiving sunitinib malate for treatment-naïve RCC, 127/375 patients (34%) receiving sunitinib malate compared with 13/360 patients (4%) on IFN-α experienced hypertension. Grade 3 hypertension was observed in 50/375 treatment-naïve RCC patients (13%) on sunitinib malate compared to 1/360 patients (<1%) on IFN-α. While all-grade hypertension was similar in GIST patients on sunitinib malate compared to placebo, Grade 3 hypertension was reported in 9/202 GIST patients on sunitinib malate (4%), and none of the GIST patients on placebo. Of patients receiving sunitinib malate in the Phase 3 pNET study, 22/83 patients (27%) on sunitinib malate and 4/82 patients (5%) on placebo experienced hypertension. Grade 3 hypertension was reported in 8/83 pNET patients (10%) on sunitinib malate, and 1/82 patient (1%) on placebo. No Grade 4 hypertension was reported. sunitinib malate dosing was reduced or temporarily delayed for hypertension in 21/375 patients (6%) on the treatment-naive RCC study and 7/83 pNET patients (8%). Four treatment-naïve RCC patients, including one with malignant hypertension, one patient with pNET, and no GIST patients discontinued treatment due to hypertension. Severe hypertension (>200 mmHg systolic or 110 mmHg diastolic) occurred in 8/202 GIST patients on sunitinib malate (4%), 1/102 GIST patients on placebo (1%), in 32/375 treatment-naïve RCC patients (9%) on sunitinib malate, in 3/360 patients (1%) on IFN-α, and in 8/80 pNET patients (10%) on sunitinib malate and 2/76 pNET patients (3%) on placebo. ### Hemorrhagic Events Hemorrhagic events reported through post-marketing experience, some of which were fatal, have included GI, respiratory, tumor, urinary tract and brain hemorrhages. In patients receiving sunitinib malate in a clinical trial for treatment-naïve RCC, 140/375 patients (37%) had bleeding events compared with 35/360 patients (10%) receiving IFN-α. Bleeding events occurred in 37/202 patients (18%) receiving sunitinib malate in the double-blind treatment phase of GIST Study A, compared to 17/102 patients (17%) receiving placebo. Epistaxis was the most common hemorrhagic adverse event reported. Bleeding events, excluding epistaxis, occurred in 18/83 patients (22%) receiving sunitinib malate in the Phase 3 pNET study, compared to 8/82 patients (10%) receiving placebo. Epistaxis was reported in 17/83 patients (20%) receiving sunitinib malate for pNET and 4 patients (5%) receiving placebo. Less common bleeding events in GIST, RCC and pNET patients included rectal, gingival, upper gastrointestinal, genital, and wound bleeding. In the double-blind treatment phase of GIST Study A, 14/202 patients (7%) receiving sunitinib malate and 9/102 patients (9%) on placebo had Grade 3 or 4 bleeding events. In addition, one patient in GIST Study A taking placebo had a fatal gastrointestinal bleeding event during Cycle 2. Most events in RCC patients were Grade 1 or 2; there was one Grade 5 event of gastric bleed in a treatment-naïve patient. In the pNET study, 1/83 patients (1%) receiving sunitinib malate had Grade 3 epistaxis, and no patients had other Grade 3 or 4 bleeding events. In pNET patients receiving placebo, 3/82 patients (4%) had Grade 3 or 4 bleeding events. Tumor-related hemorrhage has been observed in patients treated with sunitinib malate. These events may occur suddenly, and in the case of pulmonary tumors may present as severe and life-threatening hemoptysis or pulmonary hemorrhage. Cases of pulmonary hemorrhage, some with a fatal outcome, have been observed in clinical trials and have been reported in post-marketing experience in patients treated with sunitinib malate for MRCC, GIST and metastatic lung cancer. Sunitinib malate is not approved for use in patients with lung cancer. Treatment-emergent Grade 3 and 4 tumor hemorrhage occurred in 5/202 patients (3%) with GIST receiving sunitinib malate on Study A. Tumor hemorrhages were observed as early as Cycle 1 and as late as Cycle 6. One of these five patients received no further drug following tumor hemorrhage. None of the other four patients discontinued treatment or experienced dose delay due to tumor hemorrhage. No patients with GIST in the Study A placebo arm were observed to undergo intratumoral hemorrhage. Clinical assessment of these events should include serial complete blood counts (CBCs) and physical examinations. Serious, sometimes fatal gastrointestinal complications including gastrointestinal perforation, have occurred rarely in patients with intra-abdominal malignancies treated with sunitinib malate. ### Osteonecrosis of the Jaw (ONJ) ONJ has been observed in clinical trials and has been reported in post-marketing experience in patients treated with sunitinib. Concomitant exposure to other risk factors, such as bisphosphonates or dental disease, may increase the risk of osteonecrosis of the jaw. ### Tumor Lysis Syndrome (TLS) Cases of TLS, some fatal, have been observed in clinical trials and have been reported in post-marketing experience, primarily in patients with RCC or GIST treated with sunitinib malate. Patients generally at risk of TLS are those with high tumor burden prior to treatment. These patients should be monitored closely and treated as clinically indicated. ### Thyroid Dysfunction Baseline laboratory measurement of thyroid function is recommended and patients with hypothyroidism or hyperthyroidism should be treated as per standard medical practice prior to the start of sunitinib malate treatment. All patients should be observed closely for signs and symptoms of thyroid dysfunction, including hypothyroidism, hyperthyroidism, and thyroiditis, on sunitinib malate treatment. Patients with signs and/or symptoms suggestive of thyroid dysfunction should have laboratory monitoring of thyroid function performed and be treated as per standard medical practice. Treatment-emergent acquired hypothyroidism was noted in eight GIST patients (4%) on sunitinib malate versus one (1%) on placebo. Hypothyroidism was reported as an adverse reaction in sixty-one patients (16%) on sunitinib malate in the treatment-naïve RCC study and in three patients (1%) in the IFN-α arm. Hypothyroidism was reported as an adverse reaction in 6/83 patients (7%) on sunitinib malate in the Phase 3 pNET study and in 1/82 patients (1%) in the placebo arm. Cases of hyperthyroidism, some followed by hypothyroidism, have been reported in clinical trials and through post-marketing experience. ### Wound Healing Cases of impaired wound healing have been reported during sunitinib malate therapy. Temporary interruption of sunitinib malate therapy is recommended for precautionary reasons in patients undergoing major surgical procedures. There is limited clinical experience regarding the timing of reinitiation of therapy following major surgical intervention. Therefore, the decision to resume sunitinib malate therapy following a major surgical intervention should be based upon clinical judgment of recovery from surgery. ### Proteinuria Proteinuria and nephrotic syndrome have been reported. Some of these cases have resulted in renal failure and fatal outcomes. Monitor patients for the development or worsening of proteinuria. Perform baseline and periodic urinalyses during treatment, with follow up measurement of 24-hour urine protein as clinically indicated. Interrupt sunitinib malate and dose reduce for 24-hour urine protein ≥ 3 grams. Discontinue sunitinib malate for patients with nephrotic syndrome or repeat episodes of urine protein ≥ 3 grams despite dose reductions. The safety of continued sunitinib malate treatment in patients with moderate to severe proteinuria has not been systematically evaluated. ### Dermatologic Toxicities Severe cutaneous reactions have been reported, including cases of erythema multiforme (EM), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), some of which were fatal. If signs or symptoms of SJS, TEN, or EM (e.g., progressive skin rash often with blisters or mucosal lesions) are present, sunitinib malate treatment should be discontinued. If a diagnosis of SJS or TEN is suspected, sunitinib malate treatment must not be re-started. Necrotizing fasciitis, including fatal cases, has been reported in patients treated with sunitinib malate, including of the perineum and secondary to fistula formation. Discontinue sunitinib malate in patients who develop necrotizing fasciitis. ### Adrenal Function Physicians prescribing sunitinib malate are advised to monitor for adrenal insufficiency in patients who experience stress such as surgery, trauma or severe infection. Adrenal toxicity was noted in non-clinical repeat dose studies of 14 days to 9 months in rats and monkeys at plasma exposures as low as 0.7 times the AUC observed in clinical studies. Histological changes of the adrenal gland were characterized as hemorrhage, necrosis, congestion, hypertrophy and inflammation. In clinical studies, CT/MRI obtained in 336 patients after exposure to one or more cycles of sunitinib malate demonstrated no evidence of adrenal hemorrhage or necrosis. ACTH stimulation testing was performed in approximately 400 patients across multiple clinical trials of sunitinib malate. Among patients with normal baseline ACTH stimulation testing, one patient developed consistently abnormal test results during treatment that are unexplained and may be related to treatment with sunitinib malate. Eleven additional patients with normal baseline testing had abnormalities in the final test performed, with peak cortisol levels of 12–16.4 mcg/dL (normal >18 mcg/dL) following stimulation. None of these patients were reported to have clinical evidence of adrenal insufficiency. ### Laboratory Tests CBCs with platelet count and serum chemistries including phosphate should be performed at the beginning of each treatment cycle for patients receiving treatment with sunitinib malate. # Adverse Reactions ## Clinical Trials Experience The data described below reflect exposure to sunitinib malate in 660 patients who participated in the double-blind treatment phase of a placebo-controlled trial (n=202) for the treatment of GIST, an active-controlled trial (n=375) for the treatment of RCC or a placebo-controlled trial (n=83) for the treatment of pNET. The GIST and RCC patients received a starting oral dose of 50 mg daily on Schedule 4/2 in repeated cycles, and the pNET patients received a starting oral dose of 37.5 mg daily without scheduled off-treatment periods. The most common adverse reactions (≥20%) in patients with GIST, RCC or pNET are fatigue, asthenia, fever, diarrhea, nausea, mucositis/stomatitis, vomiting, dyspepsia, abdominal pain, constipation, hypertension, peripheral edema, rash, palmar-plantar erythrodysesthesia, skin discoloration, dry skin, hair color changes, altered taste, headache, back pain, arthralgia, extremity pain, cough, dyspnea, anorexia and bleeding. The potentially serious adverse reactions are hepatotoxicity, left ventricular dysfunction, QT interval prolongation, hemorrhage, hypertension, thyroid dysfunction, and adrenal function. Other adverse reactions occurring in GIST, RCC and pNET studies are described below. 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. ### Adverse Reactions in GIST Study A Median duration of blinded study treatment was two cycles for patients on sunitinib malate (mean 3.0, range 1–9) and one cycle (mean 1.8, range 1–6) for patients on placebo at the time of the interim analysis. Dose reductions occurred in 23 patients (11%) on sunitinib malate and none on placebo. Dose interruptions occurred in 59 patients (29%) on sunitinib malate and 31 patients (30%) on placebo. The rates of treatment-emergent, non-fatal adverse reactions resulting in permanent discontinuation were 7% and 6% in the sunitinib malate and placebo groups, respectively. Most treatment-emergent adverse reactions in both study arms were Grade 1 or 2 in severity. Grade 3 or 4 treatment-emergent adverse reactions were reported in 56% versus 51% of patients on sunitinib malate versus placebo, respectively, in the double-blind treatment phase of the trial. Table 1 compares the incidence of common (≥10%) treatment-emergent adverse reactions for patients receiving sunitinib malate and reported more commonly in patients receiving sunitinib malate than in patients receiving placebo. In the double-blind treatment phase of GIST Study A, oral pain other than mucositis/stomatitis occurred in 12 patients (6%) on sunitinib malate versus 3 (3%) on placebo. Hair color changes occurred in 15 patients (7%) on sunitinib malate versus 4 (4%) on placebo. Alopecia was observed in 10 patients (5%) on sunitinib malate versus 2 (2%) on placebo. Table 2 provides common (≥10%) treatment-emergent laboratory abnormalities. After an interim analysis, the study was unblinded, and patients on the placebo arm were given the opportunity to receive open-label sunitinib malate treatment. For 241 patients randomized to the sunitinib malate arm, including 139 who received sunitinib malate in both the double-blind and open-label treatment phases, the median duration of sunitinib malate treatment was 6 cycles (mean 8.5, range 1 – 44). For the 255 patients who ultimately received open-label sunitinib malate treatment, median duration of study treatment was 6 cycles (mean 7.8, range 1 – 37) from the time of the unblinding. A total of 118 patients (46%) required dosing interruptions, and a total of 72 patients (28%) required dose reductions. The incidence of treatment-emergent adverse reactions resulting in permanent discontinuation was 20%. The most common Grade 3 or 4 treatment-related adverse reactions experienced by patients receiving sunitinib malate in the open-label treatment phase were fatigue (10%), hypertension (8%), asthenia (5%), diarrhea (5%), palmar-plantar erythrodysesthesia (5%), nausea (4%), abdominal pain (3%), anorexia (3%), mucositis (2%), vomiting (2%), and hypothyroidism (2%). ### Adverse Reactions in the Treatment-Naïve RCC Study The as-treated patient population for the treatment-naive RCC study included 735 patients, 375 randomized to sunitinib malate and 360 randomized to IFN-α. The median duration of treatment was 11.1 months (range: 0.4 – 46.1) for sunitinib malate treatment and 4.1 months (range: 0.1 – 45.6) for IFN-α treatment. Dose interruptions occurred in 202 patients (54%) on sunitinib malate and 141 patients (39%) on IFN-α. Dose reductions occurred in 194 patients (52%) on sunitinib malate and 98 patients (27%) on IFN-α. Discontinuation rates due to adverse reactions were 20% for sunitinib malate and 24% for IFN-α. Most treatment-emergent adverse reactions in both study arms were Grade 1 or 2 in severity. Grade 3 or 4 treatment-emergent adverse reactions were reported in 77% versus 55% of patients on sunitinib malate versus IFN-α, respectively. Table 3 compares the incidence of common (≥10%) treatment-emergent adverse reactions for patients receiving sunitinib malate versus IFN-α. Treatment-emergent Grade 3/4 laboratory abnormalities are presented in Table 4. ### Adverse Reactions in the Phase 3 pNET Study The median number of days on treatment was 139 days (range 13–532 days) for patients on sunitinib malate and 113 days (range 1–614 days) for patients on placebo. Nineteen patients (23%) on sunitinib malate and 4 patients (5%) on placebo were on study for >1 year. Dose interruptions occurred in 25 patients (30%) on sunitinib malate and 10 patients (12%) on placebo. Dose reductions occurred in 26 patients (31%) on sunitinib malate and 9 patients (11%) on placebo. Discontinuation rates due to adverse reactions were 22% for sunitinib malate and 17% for placebo. Most treatment-emergent adverse reactions in both study arms were Grade 1 or 2 in severity. Grade 3 or 4 treatment-emergent adverse reactions were reported in 54% versus 50% of patients on sunitinib malate versus placebo, respectively. Table 5 compares the incidence of common (≥10%) treatment-emergent adverse reactions for patients receiving sunitinib malate and reported more commonly in patients receiving sunitinib malate than in patients receiving placebo. Table 6 provides common (≥10%) treatment-emergent laboratory abnormalities. ### Venous Thromboembolic Events Seven patients (3%) on sunitinib malate and none on placebo in the double-blind treatment phase of GIST Study A experienced venous thromboembolic events; five of the seven were Grade 3 deep venous thrombosis (DVT), and two were Grade 1 or 2. Four of these seven GIST patients discontinued treatment following first observation of DVT. Thirteen (3%) patients receiving sunitinib malate for [[RCC]\|treatment-naïve RCC]] had venous thromboembolic events reported. Seven (2%) of these patients had pulmonary embolism, one was Grade 2 and six were Grade 4, and six (2%) patients had DVT, including three Grade 3. One patient was permanently withdrawn from sunitinib malate due to pulmonary embolism; dose interruption occurred in two patients with pulmonary embolism and one with DVT. In treatment-naïve RCC patients receiving IFN-α, six (2%) venous thromboembolic events occurred; one patient (<1%) experienced a Grade 3 DVT and five patients (1%) had pulmonary embolism, all Grade 4. One patient (1%) receiving sunitinib malate for pNET had a venous thromboembolic events reported compared to 5 patients (6%) receiving placebo. The sunitinib malate patient had Grade 2 thrombosis. Two placebo patients had DVT, one was Grade 3, two placebo patients had pulmonary embolism, one was Grade 3 and one was Grade 4, and one placebo patient had Grade 3 jugular thrombosis. ### Reversible Posterior Leukoencephalopathy Syndrome There have been reports (<1%), some fatal, of subjects presenting with seizures and radiological evidence of reversible posterior leukoencephalopathy syndrome (RPLS). Patients with seizures and signs/symptoms consistent with RPLS, such as hypertension, headache, decreased alertness, altered mental functioning, and visual loss, including cortical blindness should be controlled with medical management including control of hypertension. Temporary suspension of sunitinib malate is recommended; following resolution, treatment may be resumed at the discretion of the treating physician. ### Pancreatic and Hepatic Function If symptoms of pancreatitis or hepatic failure are present, patients should have sunitinib malate discontinued. Pancreatitis was observed in 5 (1%) patients receiving sunitinib malate for treatment-naïve RCC compared to 1 (<1%) patient receiving IFN-α. Pancreatitis was observed in 1 (1%) patient receiving sunitinib malate for pNET and 1 (1%) patient receiving placebo. Hepatotoxicity was observed in patients receiving sunitinib malate. ## Postmarketing Experience The following adverse reactions have been identified during post-approval use of sunitinib malate. 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. ### Blood and lymphatic system disorders - Thrombotic microangiopathy; hemorrhage associated with thrombocytopenia. - Suspension of sunitinib malate is recommended; following resolution, treatment may be resumed at the discretion of the treating physician. ### Gastrointestinal disorders - Esophagitis ### Hepatobiliary disorders - Cholecystitis, particularly acalculous cholecystitis. ### Immune system disorders - Hypersensitivity reactions, including angioedema. ### Infections and infestations - Serious infection (with or without neutropenia) - The infections most commonly observed with sunitinib treatment include respiratory, urinary tract, skin infections, sepsis/septic shock. ### Musculoskeletal and connective tissue disorders - Fistula formation, sometimes associated with tumor necrosis and/or regression; myopathy and/or rhabdomyolysis with or without acute renal failure. - Patients with signs or symptoms of muscle toxicity should be managed as per standard medical practice. ### Renal and urinary disorders - Renal impairment and/or failure ### Respiratory disorders - Pulmonary embolism ### Skin and subcutaneous tissue disorders - Pyoderma gangrenosum, including positive dechallenges. ### Vascular disorders - Arterial thromboembolic events. - The most frequent events included cerebrovascular accident, transient ischemic attack and cerebral infarction. # Drug Interactions ### CYP3A4 Inhibitors strong CYP3A4 inhibitor such as ketoconazole may increase sunitinib plasma concentrations. Selection of an alternate concomitant medication with no or minimal enzyme inhibition potential is recommended. Concurrent administration of sunitinib malate with the strong CYP3A4 inhibitor, ketoconazole, resulted in 49% and 51% increases in the combined (sunitinib + primary active metabolite) Cmax and AUC0–∞ values, respectively, after a single dose of sunitinib malate in healthy volunteers. Co-administration of sunitinib malate with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) may increase sunitinib concentrations. Grapefruit may also increase plasma concentrations of sunitinib. A dose reduction for sunitinib malate should be considered when it must be co-administered with strong CYP3A4 inhibitors. ### CYP3A4 Inducers CYP3A4 inducers such as rifampin may decrease sunitinib plasma concentrations. Selection of an alternate concomitant medication with no or minimal enzyme induction potential is recommended. Concurrent administration of sunitinib malate with the strong CYP3A4 inducer, rifampin, resulted in a 23% and 46% reduction in the combined (sunitinib + primary active metabolite) Cmax and AUC0–∞ values, respectively, after a single dose of sunitinib malate in healthy volunteers. Co-administration of sunitinib malate with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. John's Wort) may decrease sunitinib concentrations. St. John's Wort may decrease sunitinib plasma concentrations unpredictably. Patients receiving sunitinib malate should not take St. John's Wort concomitantly. A dose increase for sunitinib malate should be considered when it must be co-administered with CYP3A4 inducers. ### In Vitro Studies of CYP Inhibition and Induction In vitro studies indicated that sunitinib does not induce or inhibit major CYP enzymes. The in vitro studies in human liver microsomes and hepatocytes of the activity of CYP isoforms CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, and CYP4A9/11 indicated that sunitinib and its primary active metabolite are unlikely to have any clinically relevant drug-drug interactions with drugs that may be metabolized by these enzyme. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): D Sunitinib malate can cause fetal harm when administered to a pregnant woman. As angiogenesis is a critical component of embryonic and fetal development, inhibition of angiogenesis following administration of sunitinib malate should be expected to result in adverse effects on pregnancy. In animal reproductive studies in rats and rabbits, sunitinib was teratogenic, embryotoxic, and fetotoxic. There are no adequate and well-controlled studies of sunitinib malate in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with sunitinib malate. Sunitinib was evaluated in pregnant rats (0.3, 1.5, 3.0, 5.0 mg/kg/day) and rabbits (0.5, 1, 5, 20 mg/kg/day) for effects on the embryo. Significant increases in the incidence of embryolethality and structural abnormalities were observed in rats at the dose of 5 mg/kg/day (approximately 5.5 times the systemic exposure [combined AUC of sunitinib + primary active metabolite] in patients administered the recommended daily doses [RDD]). Significantly increased embryolethality was observed in rabbits at 5 mg/kg/day while developmental effects were observed at ≥1 mg/kg/day (approximately 0.3 times the AUC in patients administered the RDD of 50 mg/day). Developmental effects consisted of fetal skeletal malformations of the ribs and vertebrae in rats. In rabbits, cleft lip was observed at 1 mg/kg/day and cleft lip and cleft palate were observed at 5 mg/kg/day (approximately 2.7 times the AUC in patients administered the RDD). Neither fetal loss nor malformations were observed in rats dosed at ≤3 mg/kg/day (approximately 2.3 times the AUC in patients administered the RDD). Sunitinib (0.3, 1.0, 3.0 mg/kg/day) was evaluated in a pre- and postnatal development study in pregnant rats. Maternal body weight gains were reduced during gestation and lactation at doses ≥1 mg/kg/day but no maternal reproductive toxicity was observed at doses up to 3 mg/kg/day (approximately 2.3 times the AUC in patients administered the RDD). At the high dose of 3 mg/kg/day, reduced body weights were observed at birth and persisted for offspring of both sexes during the pre-weaning period and in males during post-weaning period. No other developmental toxicity was observed at doses up to 3 mg/kg/day (approximately 2.3 times the AUC in patients administered the RDD). Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Sunitinib in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Sunitinib during labor and delivery. ### Nursing Mothers Sunitinib and its metabolites are excreted in rat milk. In lactating female rats administered 15 mg/kg, sunitinib and its metabolites were extensively excreted in milk at concentrations up to 12-fold higher than in plasma. It is not known whether this drug or its primary active metabolite are 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 sunitinib malate, 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 efficacy of sunitinib malate in pediatric patients have not been established. Physeal dysplasia was observed in cynomolgus monkeys with open growth plates treated for ≥3 months (3 month dosing 2, 6, 12 mg/kg/day; 8 cycles of dosing 0.3, 1.5, 6.0 mg/kg/day) with sunitinib at doses that were >0.4 times the RDD based on systemic exposure (AUC). In developing rats treated continuously for 3 months (1.5, 5.0 and 15.0 mg/kg) or 5 cycles (0.3, 1.5, and 6.0 mg/kg/day), bone abnormalities consisted of thickening of the epiphyseal cartilage of the femur and an increase of fracture of the tibia at doses ≥5 mg/kg (approximately 10 times the RDD based on AUC). Additionally, caries of the teeth were observed in rats at >5 mg/kg. The incidence and severity of physeal dysplasia were dose-related and were reversible upon cessation of treatment; however, findings in the teeth were not. A no effect level was not observed in monkeys treated continuously for 3 months, but was 1.5 mg/kg/day when treated intermittently for 8 cycles. In rats the no effect level in bones was ≤2 mg/kg/day. ### Geriatic Use Of 825 GIST and RCC patients who received sunitinib malate on clinical studies, 277 (34%) were 65 and over. In the Phase 3 pNET study, 22 (27%) patients who received sunitinib malate were 65 and over. No overall differences in safety or effectiveness were observed between younger and older patients. ### Gender There is no FDA guidance on the use of Sunitinib with respect to specific gender populations. ### Race There is no FDA guidance on the use of Sunitinib with respect to specific racial populations. ### Renal Impairment No adjustment to the starting dose is required when administering sunitinib malate to patients with mild, moderate, and severe renal impairment. Subsequent dose modifications should be based on safety and tolerability. In patients with end-stage renal disease (ESRD) on hemodialysis, no adjustment to the starting dose is required. However, compared to subjects with normal renal function, the sunitinib exposure is 47% lower in subjects with ESRD on hemodialysis. Therefore, the subsequent doses may be increased gradually up to 2 fold based on safety and tolerability. ### Hepatic Impairment No dose adjustment to the starting dose is required when administering sunitinib malate to patients with Child-Pugh Class A or B hepatic impairment. Sunitinib and its primary metabolite are primarily metabolized by the liver. Systemic exposures after a single dose of sunitinib malate were similar in subjects with mild or moderate (Child-Pugh Class A and B) hepatic impairment compared to subjects with normal hepatic function. sunitinib malate was not studied in subjects with severe (Child-Pugh Class C) hepatic impairment. Studies in cancer patients have excluded patients with ALT or AST >2.5 × ULN or, if due to liver metastases, >5.0 × ULN. ### Females of Reproductive Potential and Males Effects on the female reproductive system were identified in a 3-month repeat dose monkey study (2, 6, 12 mg/kg/day), where ovarian changes (decreased follicular development) were noted at 12 mg/kg/day (≥5.1 times the AUC in patients administered the RDD), while uterine changes (endometrial atrophy) were noted at ≥2 mg/kg/day (≥0.4 times the AUC in patients administered the RDD). With the addition of vaginal atrophy, the uterine and ovarian effects were reproduced at 6 mg/kg/day in the 9-month monkey study (0.3, 1.5 and 6 mg/kg/day administered daily for 28 days followed by a 14 day respite; the 6 mg/kg dose produced a mean AUC that was ≥0.8 times the AUC in patients administered the RDD). A no effect level was not identified in the 3 month study; 1.5 mg/kg/day represents a no effect level in monkeys administered sunitinib for 9 months. Although fertility was not affected in rats, sunitinib malate may impair fertility in humans. In female rats, no fertility effects were observed at doses of ≤5.0 mg/kg/day [(0.5, 1.5, 5.0 mg/kg/day) administered for 21 days up to gestational day 7; the 5.0 mg/kg dose produced an AUC that was ≥5 times the AUC in patients administered the RDD], however significant embryolethality was observed at the 5.0 mg/kg dose. No reproductive effects were observed in male rats dosed (1, 3 or 10 mg/kg/day) for 58 days prior to mating with untreated females. Fertility, copulation, conception indices, and sperm evaluation (morphology, concentration, and motility) were unaffected by sunitinib at doses ≤10 mg/kg/day (the 10 mg/kg/day dose produced a mean AUC that was ≥25.8 times the AUC in patients administered the RDD). ### Immunocompromised Patients There is no FDA guidance one the use of Sunitinib in patients who are immunocompromised. # Administration and Monitoring ### Administration Oral ### Monitoring There is limited information regarding Sunitinib Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Sunitinib and IV administrations. # Overdosage Treatment of overdose with sunitinib malate should consist of general supportive measures. There is no specific antidote for overdosage with sunitinib malate. If indicated, elimination of unabsorbed drug should be achieved by emesis or gastric lavage. A few cases of accidental overdose have been reported; these cases were associated with adverse reactions consistent with the known safety profile of sunitinib malate, or without adverse reactions. A case of intentional overdose involving the ingestion of 1,400 mg of sunitinib malate in an attempted suicide was reported without adverse reaction. In non-clinical studies mortality was observed following as few as 5 daily doses of 400 mg/kg (3000 mg/m2) in rats. At this dose, signs of toxicity included impaired muscle coordination, head shakes, hypoactivity, ocular discharge, piloerection and gastrointestinal distress. Mortality and similar signs of toxicity were observed at lower doses when administered for longer durations. # Pharmacology ## Mechanism of Action Sunitinib is a small molecule that inhibits multiple receptor tyrosine kinases (RTKs), some of which are implicated in tumor growth, pathologic angiogenesis, and metastatic progression of cancer. Sunitinib was evaluated for its inhibitory activity against a variety of kinases (>80 kinases) and was identified as an inhibitor of platelet-derived growth factor receptors (PDGFRα and PDGFRβ), vascular endothelial growth factor receptors (VEGFR1, VEGFR2 and VEGFR3), stem cell factor receptor (KIT), Fms-like tyrosine kinase-3 (FLT3), colony stimulating factor receptor Type 1 (CSF-1R), and the glial cell-line derived neurotrophic factor receptor (RET). Sunitinib inhibition of the activity of these RTKs has been demonstrated in biochemical and cellular assays, and inhibition of function has been demonstrated in cell proliferation assays. The primary metabolite exhibits similar potency compared to sunitinib in biochemical and cellular assays. Sunitinib inhibited the phosphorylation of multiple RTKs (PDGFRβ, VEGFR2, KIT) in tumor xenografts expressing RTK targets in vivo and demonstrated inhibition of tumor growth or tumor regression and/or inhibited metastases in some experimental models of cancer. Sunitinib demonstrated the ability to inhibit growth of tumor cells expressing dysregulated target RTKs (PDGFR, RET, or KIT) in vitro and to inhibit PDGFRβ- and VEGFR2-dependent tumor angiogenesis in vivo. ## Structure Sunitinib malate is described chemically as Butanedioic acid, hydroxy-, (2S)-, compound with N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidine)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide (1:1). The molecular formula is C22H27FN4O2 • C4H6O5 and the molecular weight is 532.6 Daltons. The chemical structure of sunitinib malate is: ## Pharmacodynamics There is limited information regarding Sunitinib Pharmacodynamics in the drug label. ## Pharmacokinetics The pharmacokinetics of sunitinib and sunitinib malate have been evaluated in 135 healthy volunteers and in 266 patients with solid tumors. Maximum plasma concentrations (Cmax) of sunitinib are generally observed between 6 and 12 hours (Tmax) following oral administration. Food has no effect on the bioavailability of sunitinib. sunitinib malate may be taken with or without food. Binding of sunitinib and its primary active metabolite to human plasma protein in vitro was 95% and 90%, respectively, with no concentration dependence in the range of 100 – 4000 ng/mL. The apparent volume of distribution (Vd/F) for sunitinib was 2230 L. In the dosing range of 25 – 100 mg, the area under the plasma concentration-time curve (AUC) and Cmax increase proportionately with dose. Sunitinib is metabolized primarily by the cytochrome P450 enzyme, CYP3A4, to produce its primary active metabolite, which is further metabolized by CYP3A4. The primary active metabolite comprises 23 to 37% of the total exposure. Elimination is primarily via feces. In a human mass balance study of [14C]sunitinib, 61% of the dose was eliminated in feces, with renal elimination accounting for 16% of the administered dose. Sunitinib and its primary active metabolite were the major drug-related compounds identified in plasma, urine, and feces, representing 91.5%, 86.4% and 73.8% of radioactivity in pooled samples, respectively. Minor metabolites were identified in urine and feces but generally not found in plasma. Total oral clearance (CL/F) ranged from 34 to 62 L/hr with an inter-patient variability of 40%. Following administration of a single oral dose in healthy volunteers, the terminal half-lives of sunitinib and its primary active metabolite are approximately 40 to 60 hours and 80 to 110 hours, respectively. With repeated daily administration, sunitinib accumulates 3- to 4-fold while the primary metabolite accumulates 7- to 10-fold. Steady-state concentrations of sunitinib and its primary active metabolite are achieved within 10 to 14 days. By Day 14, combined plasma concentrations of sunitinib and its active metabolite ranged from 62.9 – 101 ng/mL. No significant changes in the pharmacokinetics of sunitinib or the primary active metabolite were observed with repeated daily administration or with repeated cycles in the dosing regimens tested. The pharmacokinetics were similar in healthy volunteers and in the solid tumor patient populations tested, including patients with GIST and RCC. ## Nonclinical Toxicology ### Carcinogenesis and Mutagenesis The carcinogenic potential of sunitinib has been evaluated in two species: rasH2 transgenic mice and Sprague-Dawley rats. There were similar positive findings in both species. In rasH2 transgenic mice gastroduodenal carcinomas and/or gastric mucosal hyperplasia, as well as an increased incidence of background hemangiosarcomas were observed at doses of ≥25 mg/kg/day following daily dose administration of sunitinib in studies of 1 or 6 months duration. No proliferative changes were observed in rasH2 transgenic mice at 8 mg/kg/day. Similarly, in a 2-year rat carcinogenicity study, administration of sunitinib in 28-day cycles followed by 7-day dose-free periods resulted in findings of duodenal carcinoma at doses as low as 1 mg/kg/day (approximately 0.9 times the AUC in patients given the RDD of 50 mg/day).At the high dose of 3 mg/kg/day (approximately 7.8 times the AUC in patients at the RDD of 50 mg/day) the incidence of duodenal tumors was increased and was accompanied by findings of gastric mucous cell hyperplasia and by an increased incidence of pheochromocytoma and hyperplasia of the adrenal. Sunitinib did not cause genetic damage when tested in in vitro assays (bacterial mutation [[[AMES test\|AMES Assay]]], human lymphocyte chromosome aberration) and an in vivo rat bone marrow micronucleus test. # Clinical Studies ### Gastrointestinal Stromal Tumor Study A was a two-arm, international, randomized, double-blind, placebo-controlled trial of sunitinib malate in patients with GIST who had disease progression during prior imatinib mesylate (imatinib) treatment or who were intolerant of imatinib. The objective was to compare Time-to-Tumor Progression (TTP) in patients receiving sunitinib malate plus best supportive care versus patients receiving placebo plus best supportive care. Other objectives included Progression-Free Survival (PFS), Objective Response Rate (ORR), and Overall Survival (OS). Patients were randomized (2:1) to receive either 50 mg sunitinib malate or placebo orally, once daily, on Schedule 4/2 until disease progression or withdrawal from the study for another reason. Treatment was unblinded at the time of disease progression. Patients randomized to placebo were then offered crossover to open-label sunitinib malate, and patients randomized to sunitinib malate were permitted to continue treatment per investigator judgment. At the time of a pre-specified interim analysis, the intent-to-treat (ITT) population included 312 patients. Two-hundred seven (207) patients were randomized to the sunitinib malate arm, and 105 patients were randomized to the placebo arm. Demographics were comparable between the sunitinib malate and placebo groups with regard to age (69% vs 72% <65 years for sunitinib malate vs. placebo, respectively), gender (Male: 64% vs. 61%), race (White: (88% both arms, Asian: 5% both arms, Black: 4% both arms, remainder not reported), and Performance Status (ECOG 0: 44% vs. 46%, ECOG 1: 55% vs. 52%, and ECOG 2: 1 vs. 2%). Prior treatment included surgery (94% vs. 93%) and radiotherapy (8% vs. 15%). Outcome of prior imatinib treatment was also comparable between arms with intolerance (4% vs. 4%), progression within 6 months of starting treatment (17% vs. 16%), or progression beyond 6 months (78% vs. 80%) balanced. The planned interim efficacy and safety analysis was performed after 149 TTP events had occurred. There was a statistically significant advantage for sunitinib malate over placebo in TTP, meeting the primary endpoint. Efficacy results are summarized in Table 7 and the Kaplan-Meier curve for TTP is in Figure 1. The final ITT population enrolled in the double-blind treatment phase of the study included 243 patients randomized to the sunitinib malate arm and 118 patients randomized to the placebo arm. After the primary endpoint was met at the interim analysis, the study was unblinded, and patients on the placebo arm were offered open-label sunitinib malate treatment. Ninety-nine of the patients initially randomized to placebo crossed over to receive sunitinib malate in the open-label treatment phase. At the protocol specified final analysis of OS, the median OS was 72.7 weeks for the sunitinib malate arm and 64.9 weeks for the placebo arm [HR= 0.876, 95% CI (0.679, 1.129)]. Study B was an open-label, multi-center, single-arm, dose-escalation study conducted in patients with GIST following progression on or intolerance to imatinib. Following identification of the recommended Phase 2 regimen (50 mg once daily on Schedule 4/2), 55 patients in this study received the 50 mg dose of sunitinib malate on treatment Schedule 4/2. Partial responses were observed in 5 of 55 patients [9.1% PR rate, 95% CI (3.0, 20.0)]. ### Renal Cell Carcinoma A multi-center, international randomized study comparing single-agent sunitinib malate with IFN-α was conducted in patients with treatment-naïve RCC. The objective was to compare Progression-Free Survival (PFS) in patients receiving sunitinib malate versus patients receiving IFN-α. Other endpoints included Objective Response Rate (ORR), Overall Survival (OS) and safety. Seven hundred fifty (750) patients were randomized (1:1) to receive either 50 mg sunitinib malate once daily on Schedule 4/2 or to receive IFN-α administered subcutaneously at 9 MIU three times a week. Patients were treated until disease progression or withdrawal from the study. The ITT population included 750 patients, 375 randomized to sunitinib malate and 375 randomized to IFN-α. Demographics were comparable between the sunitinib malate and IFN-α groups with regard to age (59% vs. 67% <65 years for sunitinib malate vs. IFN-α, respectively), gender (Male: 71% vs. 72%), race (White: 94% vs. 91%, Asian: 2% vs. 3%, Black: 1% vs. 2%, remainder not reported), and Performance Status (ECOG 0: 62% vs. 61%, ECOG 1: 38% each arm, ECOG 2: 0 vs. 1%). Prior treatment included nephrectomy (91% vs. 89%) and radiotherapy (14% each arm). The most common site of metastases present at screening was the lung (78% vs. 80%, respectively), followed by the lymph nodes (58% vs. 53%, respectively) and bone (30% each arm); the majority of the patients had multiple (2 or more) metastatic sites at baseline (80% vs. 77%, respectively). There was a statistically significant advantage for sunitinib malate over IFN-α in the endpoint of PFS (see TABLE 8 and FIGURE 2). In the pre-specified stratification factors of LDH (>1.5 ULN vs. ≤1.5 ULN), ECOG performance status (0 vs. 1), and prior nephrectomy (yes vs. no), the hazard ratio favored sunitinib malate over IFN-α. The ORR was higher in the sunitinib malate arm (see TABLE 8). At the protocol-specified final analysis of OS, the median OS was 114.6 weeks for the sunitinib malate arm and 94.9 weeks for the IFN-α arm [HR= 0.821, 95% CI (0.673, 1.001)]. The median OS for the IFN-α arm includes 25 patients who discontinued IFN-α treatment because of disease progression and crossed over to treatment with sunitinib malate as well as 121 patients (32%) on the IFN-α arm who received post-study cancer treatment with sunitinib malate. The use of single agent sunitinib malate in the treatment of cytokine-refractory RCC was investigated in two single-arm, multi-center studies. All patients enrolled into these studies experienced failure of prior cytokine-based therapy. In Study 1, failure of prior cytokine therapy was based on radiographic evidence of disease progression defined by RECIST or World Health Organization (WHO) criteria during or within 9 months of completion of 1 cytokine therapy treatment (IFN-α, interleukin-2, or IFN-α plus interleukin-2; patients who were treated with IFN-α alone must have received treatment for at least 28 days). In Study 2, failure of prior cytokine therapy was defined as disease progression or unacceptable treatment-related toxicity. The endpoint for both studies was ORR. Duration of Response (DR) was also evaluated. One hundred six patients (106) were enrolled into Study 1, and 63 patients were enrolled into Study 2. Patients received 50 mg sunitinib malate on Schedule 4/2. Therapy was continued until the patients met withdrawal criteria or had progressive disease. The baseline age, gender, race and ECOG performance statuses of the patients were comparable between Studies 1 and 2. Approximately 86–94% of patients in the two studies were White. Men comprised 65% of the pooled population. The median age was 57 years and ranged from 24 to 87 years in the studies. All patients had an ECOG performance status <2 at the screening visit. The baseline malignancy and prior treatment history of the patients were comparable between Studies 1 and 2. Across the two studies, 95% of the pooled population of patients had at least some component of clear-cell histology. All patients in Study 1 were required to have a histological clear-cell component. Most patients enrolled in the studies (97% of the pooled population) had undergone nephrectomy; prior nephrectomy was required for patients enrolled in Study 1. All patients had received one previous cytokine regimen. Metastatic disease present at the time of study entry included lung metastases in 81% of patients. Liver metastases were more common in Study 1 (27% vs. 16% in Study 2) and bone metastases were more common in Study 2 (51% vs. 25% in Study 1); 52% of patients in the pooled population had at least 3 metastatic sites. Patients with known brain metastases or leptomeningeal disease were excluded from both studies. The ORR and DR data from Studies 1 and 2 are provided in Table 9. There were 36 PRs in Study 1 as assessed by a core radiology laboratory for an ORR of 34.0% (95% CI 25.0, 43.8). There were 23 PRs in Study 2 as assessed by the investigators for an ORR of 36.5% (95% CI 24.7, 49.6). The majority (>90%) of objective disease responses were observed during the first four cycles; the latest reported response was observed in Cycle 10. DR data from Study 1 is premature as only 9 of 36 patients (25%) responding to treatment had experienced disease progression or died at the time of the data cutoff. ### Pancreatic Neuroendocrine Tumors The Phase 3 study was a multi-center, international, randomized, double-blind placebo-controlled study of single-agent sunitinib malate conducted in patients with unresectable pNET. Patients were required to have documented RECIST-defined disease progression within the prior 12 months and were randomized (1:1) to receive either 37.5 mg sunitinib malate (n=86) or placebo (n=85) once daily without a scheduled off-treatment period. The primary objective was to compare Progression-Free Survival (PFS) in patients receiving sunitinib malate versus patients receiving placebo. Other endpoints included Overall Survival (OS), Objective Response Rate (ORR), and safety. Use of somatostatin analogs was allowed in the study. Demographics were comparable between the sunitinib malate and placebo groups. Additionally, 49% of sunitinib malate patients had non-functioning tumors vs 52% of placebo patients, and 92% patients in both arms had liver metastases. A total of 66% of sunitinib malate patients received prior systemic therapy compared with 72% of placebo patients and 35% of sunitinib malate patients had received somatostatin analogs compared with 38% of placebo patients. Patients were treated until disease progression or withdrawal from the study. Upon disease progression, or study closure, patients were offered access to sunitinib malate in a separate extension study. As recommended by the Independent Data Monitoring Committee, the study was terminated prematurely prior to the pre-specified interim analysis. This may have led to an overestimate of the magnitude of PFS effect. A clinically significant improvement for sunitinib malate over placebo in PFS was seen by both investigator and independent assessment. A hazard ratio favoring sunitinib malate was observed in all subgroups of baseline characteristics evaluated. OS data were not mature at the time of the analysis. There were 9 deaths in the sunitinib malate arm and 21 deaths in the placebo arm. A statistically significant difference in ORR favoring sunitinib malate over placebo was observed. Efficacy results are summarized in Table 10 and the Kaplan-Meier curve for PFS is in Figure 3. # How Supplied - 12.5 mg Capsules - Bottles of 28 - NDC 0069-0550-38 - 25 mg Capsules - Bottles of 28 - NDC 0069-0770-38 - 37.5 mg Capsules - Bottles of 28 - NDC 0069-0830-38 - 50 mg Capsules - Bottles of 28 - NDC 0069-0980-38 ## Storage Store at 25°C (77°F) # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information ### Gastrointestinal Disorders Gastrointestinal disorders such as diarrhea, nausea, stomatitis, dyspepsia, and vomiting were the most commonly reported gastrointestinal events occurring in patients who received sunitinib malate. Supportive care for gastrointestinal adverse events requiring treatment may include anti-emetic or anti-diarrheal medication. ### Skin Effects Skin discoloration possibly due to the drug color (yellow) occurred in approximately one third of patients. Patients should be advised that depigmentation of the hair or skin may occur during treatment with sunitinib malate. Other possible dermatologic effects may include dryness, thickness or cracking of skin, blister or rash on the palms of the hands and soles of the feet. Severe dermatologic toxicities including Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis have been reported. Patients should be advised to immediately inform their healthcare provider if severe dermatologic reactions occur. ### Other Common Events Other commonly reported adverse events included fatigue, high blood pressure, bleeding, swelling, mouth pain/irritation and taste disturbance. ### Musculoskeletal Disorders Prior to treatment with sunitinib malate, a dental examination and appropriate preventive dentistry should be considered. In patients being treated with sunitinib malate, who have previously received or are receiving bisphosphonates, invasive dental procedures should be avoided, if possible. ### Concomitant Medications Patients should be advised to inform their healthcare providers of all concomitant medications, including over-the-counter medications and dietary supplements # Precautions with Alcohol Alcohol-Sunitinib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Sutent [1] # Look-Alike Drug Names There is limited information regarding Sunitinib Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/SU11248
a9a5965779639f8f1e904725d38c8a2d7a2048df	wikidoc	Semaxanib	Semaxanib # Overview Semaxanib (proposed INN, also semaxinib or SU5416) is a drug intended for use in the treatment of cancer. It is still at an experimental stage and as such has not yet received a licence for use on human patients (except in the setting of a clinical trial). Semaxanib is a potent and selective synthetic inhibitor of the Flk-1/KDR vascular endothelial growth factor (VEGF) receptor tyrosine kinase. It targets the VEGF pathway, and both in vivo and in vitro studies have demonstrated antiangiogenic potential. On February 2002, Pharmacia, the developer of semaxanib, prematurely ended Phase III clinical trials it was conducting on the drug's effectiveness in the treatment of advanced colorectal cancer due to discouraging results. Other studies, at earlier phases, have since been conducted. However, due to the prospect of next-generation tyrosine kinase inhibitors and the ineffaciousness of semaxanib in clinic trials, further development of the drug has been discontinued. # Notes - ↑ World Health Organization (2001). "International Nonproprietary Names for Pharmaceutical Substances (INN). Proposed INN: List 85". WHO Drug Information. 15 (2)..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} Template:PDFlink - ↑ "Pharmacia Announces Closing of SU5416 (semaxanib) Clinical Trials" (Press release). February 8, 2002. Retrieved 2007-03-20. - ↑ O'Donnell A, Padhani A, Hayes C, Kakkar A, Leach M, Trigo J, Scurr M, Raynaud F, Phillips S, Aherne W, Hardcastle A, Workman P, Hannah A, Judson I (2005). "A Phase I study of the angiogenesis inhibitor SU5416 (semaxanib) in solid tumours, incorporating dynamic contrast MR pharmacodynamic end points". Br J Cancer. 93 (8): 876&ndash, 83. PMID 16222321.CS1 maint: Multiple names: authors list (link) - ↑ Lockhart A, Cropp G, Berlin J, Donnelly E, Schumaker R, Schaaf L, Hande K, Fleischer A, Hannah A, Rothenberg M (2006). "Phase I/pilot study of SU5416 (semaxinib) in combination with irinotecan/bolus 5-FU/LV (IFL) in patients with metastatic colorectal cancer". Am J Clin Oncol. 29 (2): 109&ndash, 15. PMID 16601426.CS1 maint: Multiple names: authors list (link) - ↑ Hoff, PM; et al. (2006). "A Phase I Study of Escalating Doses of the Tyrosine Kinase Inhibitor Semaxanib (SU5416) in Combination with Irinotecan in Patients with Advanced Colorectal Carcinoma". Japanese Journal of Clinical Oncology. 36 (2): 100–103.CS1 maint: Explicit use of et al. (link)	Semaxanib # Overview Semaxanib (proposed INN,[1] also semaxinib or SU5416) is a drug intended for use in the treatment of cancer. It is still at an experimental stage and as such has not yet received a licence for use on human patients (except in the setting of a clinical trial). Semaxanib is a potent and selective synthetic inhibitor of the Flk-1/KDR vascular endothelial growth factor (VEGF) receptor tyrosine kinase. It targets the VEGF pathway, and both in vivo and in vitro studies have demonstrated antiangiogenic potential. On February 2002, Pharmacia, the developer of semaxanib, prematurely ended Phase III clinical trials it was conducting on the drug's effectiveness in the treatment of advanced colorectal cancer due to discouraging results.[2] Other studies, at earlier phases, have since been conducted.[3] [4] However, due to the prospect of next-generation tyrosine kinase inhibitors and the ineffaciousness of semaxanib in clinic trials, further development of the drug has been discontinued.[5] # Notes - ↑ World Health Organization (2001). "International Nonproprietary Names for Pharmaceutical Substances (INN). Proposed INN: List 85". WHO Drug Information. 15 (2)..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} Template:PDFlink - ↑ "Pharmacia Announces Closing of SU5416 (semaxanib) Clinical Trials" (Press release). February 8, 2002. Retrieved 2007-03-20. - ↑ O'Donnell A, Padhani A, Hayes C, Kakkar A, Leach M, Trigo J, Scurr M, Raynaud F, Phillips S, Aherne W, Hardcastle A, Workman P, Hannah A, Judson I (2005). "A Phase I study of the angiogenesis inhibitor SU5416 (semaxanib) in solid tumours, incorporating dynamic contrast MR pharmacodynamic end points". Br J Cancer. 93 (8): 876&ndash, 83. PMID 16222321.CS1 maint: Multiple names: authors list (link) - ↑ Lockhart A, Cropp G, Berlin J, Donnelly E, Schumaker R, Schaaf L, Hande K, Fleischer A, Hannah A, Rothenberg M (2006). "Phase I/pilot study of SU5416 (semaxinib) in combination with irinotecan/bolus 5-FU/LV (IFL) in patients with metastatic colorectal cancer". Am J Clin Oncol. 29 (2): 109&ndash, 15. PMID 16601426.CS1 maint: Multiple names: authors list (link) - ↑ Hoff, PM; et al. (2006). "A Phase I Study of Escalating Doses of the Tyrosine Kinase Inhibitor Semaxanib (SU5416) in Combination with Irinotecan in Patients with Advanced Colorectal Carcinoma". Japanese Journal of Clinical Oncology. 36 (2): 100–103.CS1 maint: Explicit use of et al. (link) Template:WH Template:WikiDoc Sources	https://www.wikidoc.org/index.php/SU5416
8d2e55b85ba8ba6c9118e74bedf0730a972cff6a	wikidoc	Salsalate	Salsalate # 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 Salsalate is an analgesic that is FDA approved for the treatment of relief of the signs and symptoms of rheumatoid arthritis, osteoarthritis and related rheumatic disorder. There is a Black Box Warning for this drug as shown here. Common adverse reactions include rash, nausea, vertigo, hearing disorder, tinnitus. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Carefully consider the potential benefits and risks of Salsalate tablets, USP and other treatment options before deciding to use Salsalate tablets, USP. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals. - Salsalate is indicated for relief of the signs and symptoms of rheumatoid arthritis, osteoarthritis and related rheumatic disorder. Carefully consider the potential benefits and risks of Salsalate tablet, USP and other treatment options before deciding to use Salsalate tablet, USP. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals. - After observing the response to initial therapy with Salsalate tablet, USP, the dose and frequency should be adjusted to suit an individual patient's needs. - Salsalate is indicated for relief of the signs and symptoms of rheumatoid arthritis, osteoarthritis and related rheumatic disorder. - Adults - The usual dosage is 3000 mg daily, given in divided doses as follows: 1) two doses of two 750 mg tablets; 2) two doses of three 500 mg tablets; or 3) three doses of two 500 mg tablets. Some patients, e.g., the elderly, may require a lower dosage to achieve therapeutic blood concentrations and to avoid the more common side effects such as auditory. - Alleviation of symptoms is gradual, and full benefit may not be evident for 3 to 4 days, when plasma salicylate levels have achieved steady state. There is no evidence for development of tissue tolerance (tachyphylaxis), but salicylate therapy may induce increased activity of metabolizing liver enzymes, causing a greater rate of salicyluric acid production and excretion, with a resultant increase in dosage requirement for maintenance of therapeutic serum salicylate levels. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Salsalate in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Salsalate in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) Dosage recommendations and indications for salsalate use in children have not been established. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Salsalate in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Salsalate in pediatric patients. # Contraindications - Salsalate tablet, USP is contraindicated in patients with known hypersensitivity to salsalate. - Salsalate tablet, USP should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients. - Salsalate tablet, USP is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery. # Warnings - Reye's Syndrome may develop in individuals who have chicken pox, influenza, or flu symptoms. Some studies suggest a possible association between the development of Reye's Syndrome and the use of medicines containing salicylate or aspirin. Salsalate contains a salicylate and therefore is not recommended for use in patients with chicken pox, influenza, or flu symptoms. # Adverse Reactions ## Clinical Trials Experience There is limited information regarding Clinical Trial Experience of Salsalate in the drug label. ## Postmarketing Experience - In two well-controlled clinical trials, the following reversible adverse experiences characteristic of salicylates were most commonly reported with salsalate (n-280 pts; listed in descending order of frequency): tinnitus, nausea, hearing impairment, rash, and vertigo. These common symptoms of salicylates, i.e., tinnitus or reversible hearing impairment, are often used as a guide to therapy. - Although cause-and-effect relationships have not been established, spontaneous reports over a ten-year period have included the following additional medically significant adverse experiences: abdominal pain, abnormal hepatic function, anaphylactic shock, angioedema, bronchospasm, decreased creatinine clearance, diarrhea, G.I. bleeding, hepatitis, hypotension, nephritis and urticaria. # Drug Interactions There is limited information regarding Salsalate Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Reproductive studies conducted in rats and rabbits have not demonstrated evidence of developmental abnormalities. However, animal reproduction studies are not always predictive of human response. There are no adequate and well-controlled studies in pregnant women. - Because of the known effects of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly late pregnancy) should be avoided. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Salsalate in women who are pregnant. ### Labor and Delivery - There exist no adequate and well-controlled studies in pregnant women. Although adverse effects on mother or infant have not been reported with salsalate use during labor, caution is advised when anti-inflammatory dosage is involved. However, other salicylates have been associated with prolonged gestation and labor, maternal and neonatal bleeding sequelae, potentiation of narcotic and barbiturate effects (respiratory or cardiac arrest in the mother), delivery problems and stillbirth. - In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. The effects of Salsalate tablet, USP on labor and delivery in pregnant women are unknown. ### Nursing Mothers - It is not known whether salsalate per se is excreted in human milk; salicylic acid, the primary metabolite of salsalate, has been shown to appear in human milk in concentrations approximating the maternal blood level. Thus, the infant of a mother on salsalate therapy might ingest in mother’s milk 30 to 80% as much salicylate per kg body weight as the mother is taking. Accordingly, caution should be exercised when salsalate is administered to a nursing woman. ### Pediatric Use Safety and effectiveness of salsalate use in children have not been established. ### Geriatic Use As with any NSAIDs, caution should be exercised in treating the elderly (65 years and older). ### Gender There is no FDA guidance on the use of Salsalate with respect to specific gender populations. ### Race There is no FDA guidance on the use of Salsalate with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Salsalate in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Salsalate in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Salsalate in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Salsalate in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral. - Intravenous. ### Monitoring - Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy. - If Salsalate tablet, USP therapy must be initiated, close monitoring of the patient's renal function is advisable - Patients receiving Salsalate tablet, USP, who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored. # IV Compatibility There is limited information regarding IV Compatibility of Salsalate in the drug label. # Overdosage Death has followed ingestion of 10 to 30 g of salicylates in adults, but much larger amounts have been ingested without fatal outcome. Symptoms The usual symptoms of salicylism tinnitus, vertigo, headache, confusion, drowsiness, sweating, hyperventilation, vomiting and diarrhea will occur. More severe intoxication will lead to disruption of electrolyte balance and blood pH, and hyperthermia and dehydration. Treatment Further absorption of salsalate from the G.I. tract should be prevented by emesis (syrup of ipecac), and, if necessary, by gastric lavage. Fluid and electrolyte imbalance should be corrected by the administration of appropriate I.V. therapy. Adequate renal function should be maintained. Hemodialysis or peritoneal dialysis may be required in extreme cases. # Pharmacology ## Mechanism of Action - Salsalate is a nonsteroidal anti-inflammatory drug (NSAID). The anti-inflammatory property may be attributed to its ability to inhibit prostaglandin synthesis. ## Structure - Salsalate, is a nonsteroidal anti-inflammatory agent for oral administration. Chemically, salsalate (salicylsalicylic acid or 2-hydroxy-benzoic acid, 2- carboxyphenyl ester) is a dimer of salicylic acid; its structural formula is shown below. Each tablet, for oral administration contains 500 mg or 750 mg of salsalate, USP. In addition each tablet contains the following inactive ingredients: Microcrystalline Cellulose, Sodium Starch Glycolate, Povidone, and Stearic Acid. Also contains: Hydroxypropyl Methylcellulose, Polydextrose, Titanium Dioxide, Triacetin, FD&C Blue No. 1 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake and Polyethylene Glycol. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Salsalate in the drug label. ## Pharmacokinetics - Salsalate is insoluble in acid gastric fluids (<0.1 mg/ml at pH 1.0), but readily soluble in the small intestine where it is partially hydrolyzed to two molecules of salicylic acid. A significant portion of the parent compound is absorbed unchanged and undergoes rapid esterase hydrolysis in the body: its half-life is about one hour. About 13% is excreted through the kidneys as a glucuronide conjugate of the parent compound, the remainder as salicylic acid and its metabolites. Thus, the amount of salicylic acid available from salsalate is about 15% less than from aspirin, when the two drugs are administered on a salicylic acid molar equivalent basis (3.6 g salsalate/5 g aspirin). - Salicylic acid biotransformation is saturated at anti-inflammatory doses of salsalate. Such capacity-limited biotransformation results in an increase in the half-life of salicylic acid from 3.5 to 16 or more hours. Thus, dosing with salsalate twice a day will satisfactorily maintain blood levels within the desired therapeutic range (10 to 30 mg/100 ml) throughout the 12-hour intervals. Therapeutic blood levels continue for up to 16 hours after the last dose. The parent compound does not show capacity-limited biotransformation, nor does it accumulate in the plasma on multiple dosing. Food slows the absorption of all salicylates including salsalate. - The mode of anti-inflammatory action of salsalate and other nonsteroidal anti-inflammatory drugs is not fully defined. Although salicylic acid (the primary metabolite of salsalate) is a weak inhibitor of prostaglandin synthesis in vitro, salsalate appears to selectively inhibit prostaglandin synthesis in vivo1, providing anti-inflammatory activity equivalent to aspirin2 and indomethacin3. Unlike aspirin, salsalate does not inhibit platelet aggregation4. - The usefulness of salicylic acid, the active in vivo product of salsalate, in the treatment of arthritic disorders has been established 5,6. In contrast to aspirin, salsalate causes no greater fecal gastrointestinal blood loss than placebo. ## Nonclinical Toxicology There is limited information regarding Nonclinical Toxicology of Salsalate in the drug label. # Clinical Studies There is limited information regarding Salsalate Clinical Studies in the drug label. # How Supplied - Salsalate is insoluble in acid gastric fluids (<0.1 mg/ml at pH 1.0), but readily soluble in the small intestine where it is partially hydrolyzed to two molecules of salicylic acid. A significant portion of the parent compound is absorbed unchanged and undergoes rapid esterase hydrolysis in the body: its half-life is about one hour. About 13% is excreted through the kidneys as a glucuronide conjugate of the parent compound, the remainder as salicylic acid and its metabolites. Thus, the amount of salicylic acid available from salsalate is about 15% less than from aspirin, when the two drugs are administered on a salicylic acid molar equivalent basis (3.6 g salsalate/5 g aspirin). - Salicylic acid biotransformation is saturated at anti-inflammatory doses of salsalate. Such capacity-limited biotransformation results in an increase in the half-life of salicylic acid from 3.5 to 16 or more hours. Thus, dosing with salsalate twice a day will satisfactorily maintain blood levels within the desired therapeutic range (10 to 30 mg/100 ml) throughout the 12-hour intervals. Therapeutic blood levels continue for up to 16 hours after the last dose. The parent compound does not show capacity-limited biotransformation, nor does it accumulate in the plasma on multiple dosing. Food slows the absorption of all salicylates including salsalate. - The mode of anti-inflammatory action of salsalate and other nonsteroidal anti-inflammatory drugs is not fully defined. Although salicylic acid (the primary metabolite of salsalate) is a weak inhibitor of prostaglandin synthesis in vitro, salsalate appears to selectively inhibit prostaglandin synthesis in vivo, providing anti-inflammatory activity equivalent to aspirin2 and indomethacin3. Unlike aspirin, salsalate does not inhibit platelet aggregation. - The usefulness of salicylic acid, the active in vivo product of salsalate, in the treatment of arthritic disorders has been established. In contrast to aspirin, salsalate causes no greater fecal gastrointestinal blood loss than placebo. ## Storage Store at controlled room temperature 15-30°C (59-86°F). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Salsalate Patient Counseling Information in the drug label. # Precautions with Alcohol - Alcohol-Salsalate interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - SALSALATE ® # Look-Alike Drug Names There is limited information regarding Salsalate Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Salsalate 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. # Black Box Warning # Overview Salsalate is an analgesic that is FDA approved for the treatment of relief of the signs and symptoms of rheumatoid arthritis, osteoarthritis and related rheumatic disorder. There is a Black Box Warning for this drug as shown here. Common adverse reactions include rash, nausea, vertigo, hearing disorder, tinnitus. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Carefully consider the potential benefits and risks of Salsalate tablets, USP and other treatment options before deciding to use Salsalate tablets, USP. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals. - Salsalate is indicated for relief of the signs and symptoms of rheumatoid arthritis, osteoarthritis and related rheumatic disorder. Carefully consider the potential benefits and risks of Salsalate tablet, USP and other treatment options before deciding to use Salsalate tablet, USP. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals. - After observing the response to initial therapy with Salsalate tablet, USP, the dose and frequency should be adjusted to suit an individual patient's needs. - Salsalate is indicated for relief of the signs and symptoms of rheumatoid arthritis, osteoarthritis and related rheumatic disorder. - Adults - The usual dosage is 3000 mg daily, given in divided doses as follows: 1) two doses of two 750 mg tablets; 2) two doses of three 500 mg tablets; or 3) three doses of two 500 mg tablets. Some patients, e.g., the elderly, may require a lower dosage to achieve therapeutic blood concentrations and to avoid the more common side effects such as auditory. - Alleviation of symptoms is gradual, and full benefit may not be evident for 3 to 4 days, when plasma salicylate levels have achieved steady state. There is no evidence for development of tissue tolerance (tachyphylaxis), but salicylate therapy may induce increased activity of metabolizing liver enzymes, causing a greater rate of salicyluric acid production and excretion, with a resultant increase in dosage requirement for maintenance of therapeutic serum salicylate levels. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Salsalate in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Salsalate in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) Dosage recommendations and indications for salsalate use in children have not been established. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Salsalate in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Salsalate in pediatric patients. # Contraindications - Salsalate tablet, USP is contraindicated in patients with known hypersensitivity to salsalate. - Salsalate tablet, USP should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients. - Salsalate tablet, USP is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery. # Warnings - Reye's Syndrome may develop in individuals who have chicken pox, influenza, or flu symptoms. Some studies suggest a possible association between the development of Reye's Syndrome and the use of medicines containing salicylate or aspirin. Salsalate contains a salicylate and therefore is not recommended for use in patients with chicken pox, influenza, or flu symptoms. # Adverse Reactions ## Clinical Trials Experience There is limited information regarding Clinical Trial Experience of Salsalate in the drug label. ## Postmarketing Experience - In two well-controlled clinical trials, the following reversible adverse experiences characteristic of salicylates were most commonly reported with salsalate (n-280 pts; listed in descending order of frequency): tinnitus, nausea, hearing impairment, rash, and vertigo. These common symptoms of salicylates, i.e., tinnitus or reversible hearing impairment, are often used as a guide to therapy. - Although cause-and-effect relationships have not been established, spontaneous reports over a ten-year period have included the following additional medically significant adverse experiences: abdominal pain, abnormal hepatic function, anaphylactic shock, angioedema, bronchospasm, decreased creatinine clearance, diarrhea, G.I. bleeding, hepatitis, hypotension, nephritis and urticaria. # Drug Interactions There is limited information regarding Salsalate Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Reproductive studies conducted in rats and rabbits have not demonstrated evidence of developmental abnormalities. However, animal reproduction studies are not always predictive of human response. There are no adequate and well-controlled studies in pregnant women. - Because of the known effects of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during pregnancy (particularly late pregnancy) should be avoided. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Salsalate in women who are pregnant. ### Labor and Delivery - There exist no adequate and well-controlled studies in pregnant women. Although adverse effects on mother or infant have not been reported with salsalate use during labor, caution is advised when anti-inflammatory dosage is involved. However, other salicylates have been associated with prolonged gestation and labor, maternal and neonatal bleeding sequelae, potentiation of narcotic and barbiturate effects (respiratory or cardiac arrest in the mother), delivery problems and stillbirth. - In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. The effects of Salsalate tablet, USP on labor and delivery in pregnant women are unknown. ### Nursing Mothers - It is not known whether salsalate per se is excreted in human milk; salicylic acid, the primary metabolite of salsalate, has been shown to appear in human milk in concentrations approximating the maternal blood level. Thus, the infant of a mother on salsalate therapy might ingest in mother’s milk 30 to 80% as much salicylate per kg body weight as the mother is taking. Accordingly, caution should be exercised when salsalate is administered to a nursing woman. ### Pediatric Use Safety and effectiveness of salsalate use in children have not been established. ### Geriatic Use As with any NSAIDs, caution should be exercised in treating the elderly (65 years and older). ### Gender There is no FDA guidance on the use of Salsalate with respect to specific gender populations. ### Race There is no FDA guidance on the use of Salsalate with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Salsalate in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Salsalate in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Salsalate in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Salsalate in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral. - Intravenous. ### Monitoring - Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy. - If Salsalate tablet, USP therapy must be initiated, close monitoring of the patient's renal function is advisable - Patients receiving Salsalate tablet, USP, who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored. # IV Compatibility There is limited information regarding IV Compatibility of Salsalate in the drug label. # Overdosage Death has followed ingestion of 10 to 30 g of salicylates in adults, but much larger amounts have been ingested without fatal outcome. Symptoms The usual symptoms of salicylism tinnitus, vertigo, headache, confusion, drowsiness, sweating, hyperventilation, vomiting and diarrhea will occur. More severe intoxication will lead to disruption of electrolyte balance and blood pH, and hyperthermia and dehydration. Treatment Further absorption of salsalate from the G.I. tract should be prevented by emesis (syrup of ipecac), and, if necessary, by gastric lavage. Fluid and electrolyte imbalance should be corrected by the administration of appropriate I.V. therapy. Adequate renal function should be maintained. Hemodialysis or peritoneal dialysis may be required in extreme cases. # Pharmacology ## Mechanism of Action - Salsalate is a nonsteroidal anti-inflammatory drug (NSAID). The anti-inflammatory property may be attributed to its ability to inhibit prostaglandin synthesis. ## Structure - Salsalate, is a nonsteroidal anti-inflammatory agent for oral administration. Chemically, salsalate (salicylsalicylic acid or 2-hydroxy-benzoic acid, 2- carboxyphenyl ester) is a dimer of salicylic acid; its structural formula is shown below. Each tablet, for oral administration contains 500 mg or 750 mg of salsalate, USP. In addition each tablet contains the following inactive ingredients: Microcrystalline Cellulose, Sodium Starch Glycolate, Povidone, and Stearic Acid. Also contains: Hydroxypropyl Methylcellulose, Polydextrose, Titanium Dioxide, Triacetin, FD&C Blue No. 1 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake and Polyethylene Glycol. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Salsalate in the drug label. ## Pharmacokinetics - Salsalate is insoluble in acid gastric fluids (<0.1 mg/ml at pH 1.0), but readily soluble in the small intestine where it is partially hydrolyzed to two molecules of salicylic acid. A significant portion of the parent compound is absorbed unchanged and undergoes rapid esterase hydrolysis in the body: its half-life is about one hour. About 13% is excreted through the kidneys as a glucuronide conjugate of the parent compound, the remainder as salicylic acid and its metabolites. Thus, the amount of salicylic acid available from salsalate is about 15% less than from aspirin, when the two drugs are administered on a salicylic acid molar equivalent basis (3.6 g salsalate/5 g aspirin). - Salicylic acid biotransformation is saturated at anti-inflammatory doses of salsalate. Such capacity-limited biotransformation results in an increase in the half-life of salicylic acid from 3.5 to 16 or more hours. Thus, dosing with salsalate twice a day will satisfactorily maintain blood levels within the desired therapeutic range (10 to 30 mg/100 ml) throughout the 12-hour intervals. Therapeutic blood levels continue for up to 16 hours after the last dose. The parent compound does not show capacity-limited biotransformation, nor does it accumulate in the plasma on multiple dosing. Food slows the absorption of all salicylates including salsalate. - The mode of anti-inflammatory action of salsalate and other nonsteroidal anti-inflammatory drugs is not fully defined. Although salicylic acid (the primary metabolite of salsalate) is a weak inhibitor of prostaglandin synthesis in vitro, salsalate appears to selectively inhibit prostaglandin synthesis in vivo1, providing anti-inflammatory activity equivalent to aspirin2 and indomethacin3. Unlike aspirin, salsalate does not inhibit platelet aggregation4. - The usefulness of salicylic acid, the active in vivo product of salsalate, in the treatment of arthritic disorders has been established 5,6. In contrast to aspirin, salsalate causes no greater fecal gastrointestinal blood loss than placebo. ## Nonclinical Toxicology There is limited information regarding Nonclinical Toxicology of Salsalate in the drug label. # Clinical Studies There is limited information regarding Salsalate Clinical Studies in the drug label. # How Supplied - Salsalate is insoluble in acid gastric fluids (<0.1 mg/ml at pH 1.0), but readily soluble in the small intestine where it is partially hydrolyzed to two molecules of salicylic acid. A significant portion of the parent compound is absorbed unchanged and undergoes rapid esterase hydrolysis in the body: its half-life is about one hour. About 13% is excreted through the kidneys as a glucuronide conjugate of the parent compound, the remainder as salicylic acid and its metabolites. Thus, the amount of salicylic acid available from salsalate is about 15% less than from aspirin, when the two drugs are administered on a salicylic acid molar equivalent basis (3.6 g salsalate/5 g aspirin). - Salicylic acid biotransformation is saturated at anti-inflammatory doses of salsalate. Such capacity-limited biotransformation results in an increase in the half-life of salicylic acid from 3.5 to 16 or more hours. Thus, dosing with salsalate twice a day will satisfactorily maintain blood levels within the desired therapeutic range (10 to 30 mg/100 ml) throughout the 12-hour intervals. Therapeutic blood levels continue for up to 16 hours after the last dose. The parent compound does not show capacity-limited biotransformation, nor does it accumulate in the plasma on multiple dosing. Food slows the absorption of all salicylates including salsalate. - The mode of anti-inflammatory action of salsalate and other nonsteroidal anti-inflammatory drugs is not fully defined. Although salicylic acid (the primary metabolite of salsalate) is a weak inhibitor of prostaglandin synthesis in vitro, salsalate appears to selectively inhibit prostaglandin synthesis in vivo, providing anti-inflammatory activity equivalent to aspirin2 and indomethacin3. Unlike aspirin, salsalate does not inhibit platelet aggregation. - The usefulness of salicylic acid, the active in vivo product of salsalate, in the treatment of arthritic disorders has been established. In contrast to aspirin, salsalate causes no greater fecal gastrointestinal blood loss than placebo. ## Storage Store at controlled room temperature 15-30°C (59-86°F). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Salsalate Patient Counseling Information in the drug label. # Precautions with Alcohol - Alcohol-Salsalate interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - SALSALATE ®[1] # Look-Alike Drug Names There is limited information regarding Salsalate Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Salsalate
8bad4148e7b1ca242faef9b7262bd03c985670be	wikidoc	Sanbox:HL	Sanbox:HL # Pathophysiology - The main pathological feature of Hogkin's lymphoma is the Reed-Sternberg cells which is created mainly due to activation of the nuclear factor kappa B (NF-kB) transcription factor-signaling pathway. The improper activation of the (NF-kB) system proteins is correlated with many neoplasms. - NF-kB is degraded normally by "I kappa B (IkB)" family in order to prevent the unwanted stimulation and neoplasm formation. However, there are specific cellular proteins which lead to inactivation of the (IkB). So, by inactivating the (IkB), the NF-kB transcription factors will not be degraded and leads to gene transcriptions activation. - In Hodgkin's lymphoma, there are elevated levels of the NF-kB proteins especially c-REL and REL-A. - Unstopped activation of (NF-kB): Active (NF-kB) will lead to consistent gene activation and eventually no apoptosis takes place. Moreover, uninhibited proliferation of Reed-Sterburg cells. Activation of (NF-kB) occurs due to the following causes: Loss of function Mutation of the IkB protein which is responsible for inhibiting NF-kB Alteration in the NF-kB itself protecting it from inhibition by IkB Gain of function mutation of the MAP3K14 gene which is an activator of NF-kB NF-kB leads to activation of many genes which appear to be related to HL. Some examples of the genes expressed in HL include the following: (ICAM-1) gene GM-CSF gene IL-6 gene IKBA gene - Active (NF-kB) will lead to consistent gene activation and eventually no apoptosis takes place. Moreover, uninhibited proliferation of Reed-Sterburg cells. - Activation of (NF-kB) occurs due to the following causes: Loss of function Mutation of the IkB protein which is responsible for inhibiting NF-kB Alteration in the NF-kB itself protecting it from inhibition by IkB Gain of function mutation of the MAP3K14 gene which is an activator of NF-kB - Loss of function Mutation of the IkB protein which is responsible for inhibiting NF-kB - Alteration in the NF-kB itself protecting it from inhibition by IkB - Gain of function mutation of the MAP3K14 gene which is an activator of NF-kB - NF-kB leads to activation of many genes which appear to be related to HL. Some examples of the genes expressed in HL include the following: (ICAM-1) gene GM-CSF gene IL-6 gene IKBA gene - (ICAM-1) gene - GM-CSF gene - IL-6 gene - IKBA gene - Besides NF-kB signaling pathway, Hodgkin's lymphoma can be caused by mutations in JAK-STAT pathway. Alterations in JAK tyrosine kinases signaling lead to high levels of activated STAT pathway which is considered an observed feature in some cases of HL.	Sanbox:HL # Pathophysiology - The main pathological feature of Hogkin's lymphoma is the Reed-Sternberg cells which is created mainly due to activation of the nuclear factor kappa B (NF-kB) transcription factor-signaling pathway. The improper activation of the (NF-kB) system proteins is correlated with many neoplasms.[1][2] - NF-kB is degraded normally by "I kappa B (IkB)" family in order to prevent the unwanted stimulation and neoplasm formation. However, there are specific cellular proteins which lead to inactivation of the (IkB). So, by inactivating the (IkB), the NF-kB transcription factors will not be degraded and leads to gene transcriptions activation.[1] - In Hodgkin's lymphoma, there are elevated levels of the NF-kB proteins especially c-REL and REL-A.[3] - Unstopped activation of (NF-kB): Active (NF-kB) will lead to consistent gene activation and eventually no apoptosis takes place. Moreover, uninhibited proliferation of Reed-Sterburg cells. Activation of (NF-kB) occurs due to the following causes:[4][5] Loss of function Mutation of the IkB protein which is responsible for inhibiting NF-kB Alteration in the NF-kB itself protecting it from inhibition by IkB Gain of function mutation of the MAP3K14 gene which is an activator of NF-kB NF-kB leads to activation of many genes which appear to be related to HL. Some examples of the genes expressed in HL include the following:[6] (ICAM-1) gene GM-CSF gene IL-6 gene IKBA gene - Active (NF-kB) will lead to consistent gene activation and eventually no apoptosis takes place. Moreover, uninhibited proliferation of Reed-Sterburg cells. - Activation of (NF-kB) occurs due to the following causes:[4][5] Loss of function Mutation of the IkB protein which is responsible for inhibiting NF-kB Alteration in the NF-kB itself protecting it from inhibition by IkB Gain of function mutation of the MAP3K14 gene which is an activator of NF-kB - Loss of function Mutation of the IkB protein which is responsible for inhibiting NF-kB - Alteration in the NF-kB itself protecting it from inhibition by IkB - Gain of function mutation of the MAP3K14 gene which is an activator of NF-kB - NF-kB leads to activation of many genes which appear to be related to HL. Some examples of the genes expressed in HL include the following:[6] (ICAM-1) gene GM-CSF gene IL-6 gene IKBA gene - (ICAM-1) gene - GM-CSF gene - IL-6 gene - IKBA gene - Besides NF-kB signaling pathway, Hodgkin's lymphoma can be caused by mutations in JAK-STAT pathway. Alterations in JAK tyrosine kinases signaling lead to high levels of activated STAT pathway which is considered an observed feature in some cases of HL.[7] - -	https://www.wikidoc.org/index.php/Sanbox:HL
f22bfbeb7541a57cd9ffc240b395e4dfa5c16348	wikidoc	Sandbox/a	Sandbox/a # Overview The symptoms of the middle east respiratory syndrome coronavirus infection include fever, cough, shortness of breath and gatsrointestinal symptoms. # History and Symptoms Suspect MERS-CoV infection in case of: - Fever (≥38°C, 100.4°F) and pneumonia or acute respiratory distress syndrome (based on clinical or radiological evidence); AND EITHER - History of travel from countries in or near the Arabian Peninsula1 within 14 days before symptom onset; OR - Close contact2 with a symptomatic traveler who developed fever and acute respiratory illness (not necessarily pneumonia) within 14 days after traveling from countries in or near the Arabian Peninsula; OR - Is a member of a cluster of patients with severe acute respiratory illness (e.g. fever and pneumonia requiring hospitalization) of unknown etiology in which MERS-CoV is being evaluated, in consultation with state and local health departments. ## Symptoms - Fever (98%) - Cough (83%) - Shortness of breath (72%) - Gastrointestinal symptoms Diarrhea (26%) Vomiting (21%) - Diarrhea (26%) - Vomiting (21%) All but two patients (96%) had one or more chronic medical conditions, including diabetes (68%), hypertension (34%), heart disease (28%), and kidney disease (49%). Thirty-four (72%) had more than one chronic condition. In a retrospective study on 47 patients with MERS-CoV infection, 42 (89%) needed intensive care and 34 (72%) had mechanical ventilation.	Sandbox/a Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview The symptoms of the middle east respiratory syndrome coronavirus infection include fever, cough, shortness of breath and gatsrointestinal symptoms. # History and Symptoms Suspect MERS-CoV infection in case of: - Fever (≥38°C, 100.4°F) and pneumonia or acute respiratory distress syndrome (based on clinical or radiological evidence); AND EITHER - History of travel from countries in or near the Arabian Peninsula1 within 14 days before symptom onset; OR - Close contact2 with a symptomatic traveler who developed fever and acute respiratory illness (not necessarily pneumonia) within 14 days after traveling from countries in or near the Arabian Peninsula; OR - Is a member of a cluster of patients with severe acute respiratory illness (e.g. fever and pneumonia requiring hospitalization) of unknown etiology in which MERS-CoV is being evaluated, in consultation with state and local health departments. ## Symptoms - Fever (98%) - Cough (83%) - Shortness of breath (72%) - Gastrointestinal symptoms Diarrhea (26%) Vomiting (21%) - Diarrhea (26%) - Vomiting (21%) All but two patients (96%) had one or more chronic medical conditions, including diabetes (68%), hypertension (34%), heart disease (28%), and kidney disease (49%). Thirty-four (72%) had more than one chronic condition. In a retrospective study on 47 patients with MERS-CoV infection, 42 (89%) needed intensive care and 34 (72%) had mechanical ventilation.[1]	https://www.wikidoc.org/index.php/Sandbox/a
88d50eb86d988bc65a9eed885c0df295df8cfa0e	wikidoc	Sandbox:1	Sandbox:1 Lymphocytic sclerosing pancreatitis, , Acute Pancreatitis, Benign: Pancreatic atrophy, Pancreatic lipoma, Lymphoepithelial cyst Malignant: Acinar cell carcinoma of pancreas, Adenosquamous carcinoma, Colloid carcinoma, Hepatoid carcinoma, , Pancreatic intraepithelial neoplasia, Pancreatoblastoma, Serous cystadenoma, Signet ring cell carcinoma, Solid-pseudopapillary neoplasm, Undifferentiated carcinoma, Undifferentiated carcinoma with osteoclast-like giant cell, Neuroendocrine tumors, Pancreatic ductal adenocarcinoma, Intraductal papillary mucinous neoplasm (IPMN), Serous cystadenoma, Solid-pseudopapillary tumour of pancreas, Pancreatic lymphangioma, Pancreatic teratoma, Pancreatic lymphoma, Schwannoma, Neurofibroma, Sarcoma, Intraductal tubular neoplasm (ITN), Metastases to pancreas, Von Hippel-Landau (VHL)-associated serous cystic neoplasm Adenocarcinoma of pancreas, Mucinous cystic neoplasm, Insulinoma, Gastrinoma, Glucagonoma, VIPoma, Somatostatinoma, Zollinger-Ellison syndrome, , Pancreatic abscess, pancreatic pseudocyst Intraductal papillary-mucinous neoplasms - Younger women - Constitutional symptoms - Abdominal pain - Highly cellular stromal layer immediately beneath the epithelium is a hallmark finding - Stromal cells express estrogen and progesterone receptors - Columnar epithelium with abundant luminal mucin - Papillary growth pattern and mitoses - Located in the body or tail of the pancreas - Sharply demarcated cystic masses - Thick fibrous wall	Sandbox:1 Lymphocytic sclerosing pancreatitis, , Acute Pancreatitis, Benign: Pancreatic atrophy, Pancreatic lipoma, Lymphoepithelial cyst Malignant: Acinar cell carcinoma of pancreas, Adenosquamous carcinoma, Colloid carcinoma, Hepatoid carcinoma, , Pancreatic intraepithelial neoplasia, Pancreatoblastoma, Serous cystadenoma, Signet ring cell carcinoma, Solid-pseudopapillary neoplasm, Undifferentiated carcinoma, Undifferentiated carcinoma with osteoclast-like giant cell, Neuroendocrine tumors, Pancreatic ductal adenocarcinoma, Intraductal papillary mucinous neoplasm (IPMN), Serous cystadenoma, Solid-pseudopapillary tumour of pancreas, Pancreatic lymphangioma, Pancreatic teratoma, Pancreatic lymphoma, Schwannoma, Neurofibroma, Sarcoma, Intraductal tubular neoplasm (ITN), Metastases to pancreas, Von Hippel-Landau (VHL)-associated serous cystic neoplasm Adenocarcinoma of pancreas, Mucinous cystic neoplasm, Insulinoma, Gastrinoma, Glucagonoma, VIPoma, Somatostatinoma, Zollinger-Ellison syndrome, , Pancreatic abscess, pancreatic pseudocyst Intraductal papillary-mucinous neoplasms - Younger women - Constitutional symptoms - Abdominal pain - Highly cellular stromal layer immediately beneath the epithelium is a hallmark finding - Stromal cells express estrogen and progesterone receptors - Columnar epithelium with abundant luminal mucin - Papillary growth pattern and mitoses - Located in the body or tail of the pancreas - Sharply demarcated cystic masses - Thick fibrous wall	https://www.wikidoc.org/index.php/Sandbox:1
a9bf01b1ee11494e99e9ad3148218876c65bd2a5	wikidoc	SandboxAB	SandboxAB # Overview About 15-25% of hospitalized patients have got a urinary catheter during in-patient management. Catheter associated bacteriuria is the most common infection during hospitalization. however,less than quarter of hospitalized patient develop symptomatic urinary tract infection. # Definition Catheter associated urinary tract infection is defined by the presence of urinary tract infection symptoms or signs in patients with or indwelling or suprapubic catheters with isolation of one or more bacterial strains≥10³cfu/ml from catheter assembled urine specimen or midstream voided urine specimen in patients who had a catheter removed in the last 48 hours. And this is applied after exclusion of other possible sources of infection. ## Catheter associated UTI signs and symptoms General signs and symptoms Non specific presentations are the most common. The new onset or worsening of any of the following : - Fever - Rigors - Altered mental status - Malaise or lethargy After exclusion of alternative diagnosis with thorough evaluation. Urinary tract specific signs and symptom - Flank pain - Costovertebral angel tenderness - Acute hematuria - Pelvic discomfort After catheter removal - Urgency - Frequency - Dysuria - Suprapubic pain or tenderness Patients with spinal cord injury - Increased spasticity - Autonomic dysreflexia - Sence of unease # Pathogenesis and Microbiology Urinary catheterization disturbs the normal uroepithelial barrier, allowing uropathgenes to access through the lamina. ## Microbiology Short-term catheterization E.Coli is the most common isolated organism with about third of all isolates, other isolates include Klebsiella spp, Serratia spp, Citrobacter spp, P.aeruginosa and gram positive cocci(coagulase negative)like staphylococci and Enterococci. Long-term catheterization It is usually polymicrobial, and in addition to the previous organisms, P.mirabilis, Morganella morganii and P.stuartii are also common. # CA-UTI risk reduction ## Avoidance of Unnecessary Catheterization - Indications for indwelling catheters are:30-120-121 1-Significant urinary retention. 2-Urinary incontinence if other less invasive measures fail or contraindicated. 3-Monitoring output for critically ill patients. 4-Anesthetized patients undergoing certain surgical procedures(urological or gynecological). - It's not an indication to use urinary catheters for patients with pressure sacral ulcers. - Using educational methods through hospital or institution guidelines and spreadsheets for indication and contraindication has reduced the inappropriate use of catheters and thereby the rate of CA-UTI. 128 - For post-operation patients, a portable ultrasound for bladder has proven to be accurate assessment for bladder volumes, thus reducing unnecessary catheterization. 131-130 ## Before Catheter Insertion ## Discontinuation of Catheter - Catheter removal should be as soon as possible when it's no longer indicated. Early removal of catheters reduced the risk135-136 and the rate137-138 of catheter associated urinary infections. ## Alternatives to Indwelling Urethral Catheterization ## Infection Intermittent Catheterization Technique ## Insertion Techniques for Indwelling Urethral Catheter # Prevention Before Catheter Insertion ## Infection prevention Health institutions should consider providing screening and preventive programs, which include guidelines and recommendations for catheterization placement procedure, replacement and discontinuation requirements, in addition to feedback of UTI rate to the medical staff. These measurements had significant risk reduction of catheter associated UTIs. 146-151-152 ## Alternatives to Indwelling Catheterization - Condom catheter:an alternative option to short-term and long-term indwelling catheters, to reduce risk of infection for patients with normal post-voiding volume.190-193-195 - Intermittent catheterization:also used as alternative for both short-term and long-term indwelling catheters to reduce CA-UTI risk and its complications 22-24-157-158.It's commonly used with neurogenic bladder and spinal cord injuries.16 - Suprapubic cathterization:an alternative to short-term indwelling catherterization to reduce CA-bacteriuria161. It's preferable more than long-term indwelling catheterization for reduction of catheter associated bacteriuria and infections.It's more comfortable than indwelling catheter with no effect on sexual function, but knowing that it is invasive procedure needs specially trained caregiver has limited its use # Indwelling Catheter Insertion Technique Aseptic technique should be used with sterile equipment, although it's there is no significant difference in rates of infection with clean(non-aseptic)technique199, but it is preferable approach know the multi-drug resistant organism that can cause infection in hospitalized patients.199	SandboxAB # Overview About 15-25% of hospitalized patients have got a urinary catheter during in-patient management. Catheter associated bacteriuria is the most common infection during hospitalization. however,less than quarter of hospitalized patient develop symptomatic urinary tract infection. # Definition Catheter associated urinary tract infection is defined by the presence of urinary tract infection symptoms or signs in patients with or indwelling or suprapubic catheters with isolation of one or more bacterial strains≥10³cfu/ml from catheter assembled urine specimen or midstream voided urine specimen in patients who had a catheter removed in the last 48 hours. And this is applied after exclusion of other possible sources of infection. ## Catheter associated UTI signs and symptoms General signs and symptoms Non specific presentations are the most common. The new onset or worsening of any of the following : - Fever - Rigors - Altered mental status - Malaise or lethargy After exclusion of alternative diagnosis with thorough evaluation. Urinary tract specific signs and symptom - Flank pain - Costovertebral angel tenderness - Acute hematuria - Pelvic discomfort After catheter removal - Urgency - Frequency - Dysuria - Suprapubic pain or tenderness Patients with spinal cord injury - Increased spasticity - Autonomic dysreflexia - Sence of unease # Pathogenesis and Microbiology Urinary catheterization disturbs the normal uroepithelial barrier, allowing uropathgenes to access through the lamina. ## Microbiology Short-term catheterization E.Coli is the most common isolated organism with about third of all isolates, other isolates include Klebsiella spp, Serratia spp, Citrobacter spp, P.aeruginosa and gram positive cocci(coagulase negative)like staphylococci and Enterococci. Long-term catheterization It is usually polymicrobial, and in addition to the previous organisms, P.mirabilis, Morganella morganii and P.stuartii are also common. # CA-UTI risk reduction ## Avoidance of Unnecessary Catheterization - Indications for indwelling catheters are:30-120-121 1-Significant urinary retention. 2-Urinary incontinence if other less invasive measures fail or contraindicated. 3-Monitoring output for critically ill patients. 4-Anesthetized patients undergoing certain surgical procedures(urological or gynecological). - It's not an indication to use urinary catheters for patients with pressure sacral ulcers. - Using educational methods through hospital or institution guidelines and spreadsheets for indication and contraindication has reduced the inappropriate use of catheters and thereby the rate of CA-UTI. 128 - For post-operation patients, a portable ultrasound for bladder has proven to be accurate assessment for bladder volumes, thus reducing unnecessary catheterization. 131-130 ## Before Catheter Insertion ## Discontinuation of Catheter - Catheter removal should be as soon as possible when it's no longer indicated. Early removal of catheters reduced the risk135-136 and the rate137-138 of catheter associated urinary infections. ## Alternatives to Indwelling Urethral Catheterization ## Infection Intermittent Catheterization Technique ## Insertion Techniques for Indwelling Urethral Catheter # Prevention Before Catheter Insertion ## Infection prevention Health institutions should consider providing screening and preventive programs, which include guidelines and recommendations for catheterization placement procedure, replacement and discontinuation requirements, in addition to feedback of UTI rate to the medical staff. These measurements had significant risk reduction of catheter associated UTIs. 146-151-152 ## Alternatives to Indwelling Catheterization - Condom catheter:an alternative option to short-term and long-term indwelling catheters, to reduce risk of infection for patients with normal post-voiding volume.190-193-195 - Intermittent catheterization:also used as alternative for both short-term and long-term indwelling catheters to reduce CA-UTI risk and its complications 22-24-157-158.It's commonly used with neurogenic bladder and spinal cord injuries.16 - Suprapubic cathterization:an alternative to short-term indwelling catherterization to reduce CA-bacteriuria161. It's preferable more than long-term indwelling catheterization for reduction of catheter associated bacteriuria and infections.It's more comfortable than indwelling catheter with no effect on sexual function, but knowing that it is invasive procedure needs specially trained caregiver has limited its use # Indwelling Catheter Insertion Technique Aseptic technique should be used with sterile equipment, although it's there is no significant difference in rates of infection with clean(non-aseptic)technique199, but it is preferable approach know the multi-drug resistant organism that can cause infection in hospitalized patients.199	https://www.wikidoc.org/index.php/SandboxAB
cff6545bd0d28118988f7c697b08a41323b19a39	wikidoc	Sandbox 2	Sandbox 2 Lower GI bleeding is defined as any bleed that occurs distal to the ligament of Treitz. # Incidence - In the United States the incidence of LGIB ranges from 20.5 to 27 per 100,000 persons per year. # Age - There is a greater than 200 fold increase from the third to the ninth decade of life. # Classification - Lower GI bleeding can be classified into 3 groups based on the severity of bleeding: Occult lower GI bleeding Moderate lower GI bleeding Severe lower GI bleeding - Occult lower GI bleeding - Moderate lower GI bleeding - Severe lower GI bleeding # Blood supply - The SMA and IMA are connected by the marginal artery of Drummond. - This vascular arcade runs in the mesentery close to the bowel. - As patients age, there is increased incidence of occlusion of the IMA. - The left colon stays perfused, primarily because of the marginal artery. ## Pathogenesis Diverticulosis is the most common etiology of lower GI bleeding accounting for 30% of all cases, followed by anorectal disease, ischemia, inflammatory bowel disease (IBD), neoplasia and arteriovenous (AV) malformations. - Diverticulosis The colonic wall weakens with age and results in the formation of saclike protrusions known as diverticula. These protrusions generally occur at the junction of blood vessel penetrating through the mucosa and circular muscle fibers of the colon. Diverticula are most common in the descending and sigmoid colon. Despite the majority of diverticula being on the left side of the colon, diverticular bleeding originates from the right side of the colon in 50% to 90% of instances. Most of the time bleeding from diverticulosis stops spontaneously, however, in about 5% of patients, the bleeding can be massive and life-threatening. - The colonic wall weakens with age and results in the formation of saclike protrusions known as diverticula. - These protrusions generally occur at the junction of blood vessel penetrating through the mucosa and circular muscle fibers of the colon. - Diverticula are most common in the descending and sigmoid colon. - Despite the majority of diverticula being on the left side of the colon, diverticular bleeding originates from the right side of the colon in 50% to 90% of instances. - Most of the time bleeding from diverticulosis stops spontaneously, however, in about 5% of patients, the bleeding can be massive and life-threatening. - Anorectal disease - Hemorrhoids and anal fissures are the most common disease under anorectal disease responsible for GI bleeding. - Hemorrhoids are engorged vessels in the normal anal cushions. When swollen, this tissue is very friable and susceptible to trauma, which leads to painless, bright red bleeding. - Anal fissures are defined as a tear in the anal mucosa. With the passage of stool, the mucosa continues to tear and leads to bright red bleeding. - Mesenteric Ischemia - Mesenteric ischemia results when there is inadequate blood supply at the level of the small intestine. - 2 or more vessels (celiac, SMA, or IMA) must be involved for symptoms to occur. - Non occlusive mesenetric ischemia affects critically ill patients who are vasopressor-dependent. - Venous thrombosis of the visceral vessels can also precipitate an acute ischemic event. - Ischemic Colitis - Ischemic colitis is caused by poor perfusion of the colon, which results in the inability of that area of the colon to meet its metabolic demands. - It can be gangrenous or nongangrenous, acute, transient, or chronic. - The left colon is predominantly affected, with the splenic flexure having increased susceptibility. - Intraluminal hemorrhage occurs as the mucosa becomes necrotic, sloughs, and bleeds. - Damage to the tissue is caused both with the ischemic insult as well as reperfusion injury. - Inflammatory Bowel Disease - In Crohn's disease T cell activation stimulates interleukin (IL)-12 and tumor necrosis factor (TNF)-a, which causes chronic inflammation and tissue injury. - Initially, inflammation starts focally around the crypts, followed by superficial ulceration of the mucosa. - The deep mucosal layers are then invaded in a noncontinuous fashion, and noncaseating granulomas form, which can invade through the entire thickness of the bowel and into the mesentery and surrounding structures. - In ulcerative colitis T cells cytotoxic to the colonic epithelium accumulate in the lamina propria, accompanied by B cells that secrete immunoglobulin G (IgG) and IgE. - This results in inflammation of the crypts of Lieberkuhn, with abscesses and pseudopolyps. - Ulcerative colitis generally begins at the rectum and is a continuous process confined exclusively to the colon. - Neoplasia - Colon carcinoma follows a distinct progression from polyp to cancer. - Mutations of multiple genes are required for the formation of adenocarcinoma, including the APC gene, Kras, DCC, and p53. - Certain hereditary syndromes are also classified by defects in DNA mismatch repair genes and microsatellite instability. - These tumors tend to bleed slowly, and patients present with hemocult positive stools and microcytic anemia. - Although cancers of the small bowel are much less common than colorectal cancers, they should be ruled out in cases of lower GI bleeding in which no other source is identified. - AV Malformation/Angiodysplasia - In AV malformation direct connections between arteries and veins occur in the colonic submucosa. - The lack of capillary buffers causes high pressure blood to enter directly into the venous system, making these vessels at high risk of rupture into the bowel lumen. - In Angiodysplasia over time, previously healthy blood vessels of the cecum and ascending colon degenerate and become prone to bleeding. - Although 75% of angiodysplasia cases involve the right colon, they are a significant cause of obscure bleeding and the most common cause of bleeding from the small bowel in the elderly. # Epidemiology ## Prevalence - Approximately 20 patients/100,000 population in the U.S. ## Incidence - The estimated annual incidence of lower GI bleeding is approximately 0.03% in the adult population as a whole. # Demographics ## Gender - More common in men than women ## Age - Rare in children - The incidence of lower GI bleeding increases with age with a 200-fold increase from the second to eighth decades of life la. Largely due to the increase in the prevalence of diverticular disease and angiodysplasia with age. - Largely due to the increase in the prevalence of diverticular disease and angiodysplasia with age. # Symptoms - Occult LGIB may present with symptoms of iron deficiency anemia such as fatigue, palpitations, and dyspnea. - Patients with intussusception may present with pallor and vomiting in addition to LGIB - Associated symptoms, such as abdominal pain or change in bowel habits, may also aide in the diagnosis - Bloody diarrhea associated with abdominal pain may suggest an infectious cause or IBD in a younger patient and ischemic colitis in an older patient with vascular disease - Painless bleeding usually suggests angiodysplasia, diverticular disease, or internal hemorrhoids - Perianal pain suggests a perianal fissure or fistula # History - A detailed description of the nature of the blood loss can help in pinpointing the likely source of bleeding. ## Past Medical History - The clinical history should identify whether this is a recurrent bleed. - Bleeding from angiodysplasia is usually recurrent and chronic, but severe bleeding resulting in hemodynamic instability can occur. - Associated weight loss suggests malignancy. - The presence of systemic diseases such as atherosclerotic disease, IBD, coagulopathies, and HIV, and a history of pelvic irradiation for malignancy should be considered ## Past Surgical History - A history of recent colonic polypectomy or biopsy indicates iatrogenic bleeding. This is usually low grade and limited, although it can be severe if an underlying artery is involved or if there is an inadequate coagulation of the polypectomy stalk. In 1.5% of polypectomies bleeding occurs immediately. However, delayed bleeding can occur several hours or days following the procedure - This is usually low grade and limited, although it can be severe if an underlying artery is involved or if there is an inadequate coagulation of the polypectomy stalk. - In 1.5% of polypectomies bleeding occurs immediately. However, delayed bleeding can occur several hours or days following the procedure - It is essential to establish the presence of comorbid diseases, as these not only help in diagnosis but may also influence treatment. ## Family history - A family history of diseases such as IBD or colorectal malignancy is relevant. # Symptoms - The clinical presentation of LGIB varies with the anatomic source of the bleeding. - Commonly, LGIB from the right side of the colon can manifest as maroon stools, whereas a left-sided bleeding source may be evidenced by bright red blood per rectum. - The presentation of LGIB can also vary depending on the etiology. A young patient may present with fever, dehydration, abdominal cramps, and hematochezia caused by infectious or noninfectious (idiopathic) colitis. An older patient may present with painless bleeding and minimal symptoms caused by diverticular bleeding or angiodysplasia. LGIB can be mild and intermittent, as often is the case with angiodysplasia, or it may be moderate or severe, as may be the situation in diverticula-related bleeding. Young patients may present with abdominal pain, rectal bleeding, diarrhea, and mucous discharge that may be associated with IBD. Elderly patients presenting with abdominal pain, rectal bleeding, and diarrhea may have ischemic colitis. Elderly patients with atherosclerotic heart disease may present with intermittent LGIB and syncope that may be due to angiodysplastic lesions. Stools streaked with blood, perianal pain, and blood drops on the toilet paper or in the toilet bowl may be associated with perianal pathology, such as anal fissure or hemorrhoidal bleeding. The passage of maroon stools or bright red blood from the rectum is usually indicative of massive lower GI hemorrhage. - A young patient may present with fever, dehydration, abdominal cramps, and hematochezia caused by infectious or noninfectious (idiopathic) colitis. - An older patient may present with painless bleeding and minimal symptoms caused by diverticular bleeding or angiodysplasia. - LGIB can be mild and intermittent, as often is the case with angiodysplasia, or it may be moderate or severe, as may be the situation in diverticula-related bleeding. - Young patients may present with abdominal pain, rectal bleeding, diarrhea, and mucous discharge that may be associated with IBD. - Elderly patients presenting with abdominal pain, rectal bleeding, and diarrhea may have ischemic colitis. - Elderly patients with atherosclerotic heart disease may present with intermittent LGIB and syncope that may be due to angiodysplastic lesions. - Stools streaked with blood, perianal pain, and blood drops on the toilet paper or in the toilet bowl may be associated with perianal pathology, such as anal fissure or hemorrhoidal bleeding. - The passage of maroon stools or bright red blood from the rectum is usually indicative of massive lower GI hemorrhage. - Massive LGIB is a life-threatening condition in which patients present with a systolic blood pressure (SBP) of below 90 mm Hg and a hemoglobin (Hb) level of 6 g/dL or less. ## Common causes - Colonic diverticulosis Colonic diverticulosisis the most common cause of acute LGIB in the western world, accounting for 15% to 55% of all LGIB Diverticula can occur anywhere in the gastrointestinal tract, but are most common in the sigmoid colon. However, approximately 60% of diverticular bleeds arise from diverticula in the right colon, highlighting a tendency for right-sided diverticula to bleed Hemorrhage results from rupture of the intramural branches (vasa recta) of the marginal artery at the dome of a diverticulum and can give rise to a massive, life-threatening LGIB This is by far the most common cause of bleeding in the elderly, as the prevalence of diverticular disease increases with age, being as high as 85% by the age of 85 years - Colonic diverticulosisis the most common cause of acute LGIB in the western world, accounting for 15% to 55% of all LGIB - Diverticula can occur anywhere in the gastrointestinal tract, but are most common in the sigmoid colon. However, approximately 60% of diverticular bleeds arise from diverticula in the right colon, highlighting a tendency for right-sided diverticula to bleed - Hemorrhage results from rupture of the intramural branches (vasa recta) of the marginal artery at the dome of a diverticulum and can give rise to a massive, life-threatening LGIB - This is by far the most common cause of bleeding in the elderly, as the prevalence of diverticular disease increases with age, being as high as 85% by the age of 85 years - Obesity has recently been recognized as a risk factor in the development of diverticular disease, and the risk of diverticular bleeding in this group of patients is higher than that in patients who are not obese - Vascular ectasias (angiodysplasias/angioectasias): Tortuous dilated submucosal vessels that account for approximately 10% of LGIB. They appear endoscopically as small, flat lesions (5-10 mm) with ectatic capillaries radiating from a central vessel (Fig. 1) The prevalence of angiodysplasia in the gastrointestinal tract is not well known, but a pooled analysis of three colonoscopic cancer screening studies detected angiodysplasia in 0.8% of the patients The prevalence of angiodysplasia is higher in older populations and, in the past, has been linked to certain conditions such as end-stage renal disease, Von Willebrand disease , and aortic stenosis In one series, 37% of colonic dysplasias were found in the cecum, 17% in the ascending colon, 7% in the transverse colon, 7% in the descending colon, and 32% in rectosigmoid area Angiodysplasia can also be found throughout the small bowel and is responsible for up to 40% of small intestinal bleeding in patients older than 40 years. Angiodysplasia of the stomach and duodenum is responsible for up to 7% of UGIB I - Tortuous dilated submucosal vessels that account for approximately 10% of LGIB. - They appear endoscopically as small, flat lesions (5-10 mm) with ectatic capillaries radiating from a central vessel (Fig. 1) - The prevalence of angiodysplasia in the gastrointestinal tract is not well known, but a pooled analysis of three colonoscopic cancer screening studies detected angiodysplasia in 0.8% of the patients The prevalence of angiodysplasia is higher in older populations and, in the past, has been linked to certain conditions such as end-stage renal disease, Von Willebrand disease , and aortic stenosis In one series, 37% of colonic dysplasias were found in the cecum, 17% in the ascending colon, 7% in the transverse colon, 7% in the descending colon, and 32% in rectosigmoid area - Angiodysplasia can also be found throughout the small bowel and is responsible for up to 40% of small intestinal bleeding in patients older than 40 years. - Angiodysplasia of the stomach and duodenum is responsible for up to 7% of UGIB I - Iatrogenic: Bleeding is recognized as the most common complication of colonoscopy and polypectomy, occurring in 0.3% to 6.1% of polypectomies Risk factors for bleeding include polyp size greater than 1 cm, patient age older than 65 years, presence of comorbid disease, and polypectomy using the cutting mode of current The risk is also greater in patients taking anticoagulant or antiplatelet agents - Bleeding is recognized as the most common complication of colonoscopy and polypectomy, occurring in 0.3% to 6.1% of polypectomies - Risk factors for bleeding include polyp size greater than 1 cm, patient age older than 65 years, presence of comorbid disease, and polypectomy using the cutting mode of current - The risk is also greater in patients taking anticoagulant or antiplatelet agents - Ischemic colitis: Ischemic colitis accounts for approximately 20% of LGIB Ischemia results from a sudden reduction in blood flow to the mesenteric vessels as a result of hypotension, occlusion, or spasm of the mesenteric vessels Nonocclusive disease typically affects the watershed areas of the bowels, such as the splenic flexure and adjacent transverse colon due to the poor blood supply from the marginal artery. Occlusive disease is rarer but can occur as a result of thrombus formation or embolus. It is a recognized complication of aortic surgery Elderly patients with comorbid disease are at higher risk of developing ischemic colitis. There may be a history of ischemic heart disease The majority of patients with ischemic colitis improve following conservative management; however, approximately 20% will progress to develop colonic gangrene Other complications include chronic colitis and stricture formation Diagnosis requires a high index of suspicion - Ischemic colitis accounts for approximately 20% of LGIB - Ischemia results from a sudden reduction in blood flow to the mesenteric vessels as a result of hypotension, occlusion, or spasm of the mesenteric vessels - Nonocclusive disease typically affects the watershed areas of the bowels, such as the splenic flexure and adjacent transverse colon due to the poor blood supply from the marginal artery. - Occlusive disease is rarer but can occur as a result of thrombus formation or embolus. - It is a recognized complication of aortic surgery - Elderly patients with comorbid disease are at higher risk of developing ischemic colitis. - There may be a history of ischemic heart disease - The majority of patients with ischemic colitis improve following conservative management; however, approximately 20% will progress to develop colonic gangrene - Other complications include chronic colitis and stricture formation - Diagnosis requires a high index of suspicion - Colorectal malignancy: Colorectal cancer accounts for approximately 10% of bleeds, either as occult bleeding presenting with anemia or as frank blood loss per rectum A family history of colorectal cancer is important to establish - Colorectal cancer accounts for approximately 10% of bleeds, either as occult bleeding presenting with anemia or as frank blood loss per rectum - A family history of colorectal cancer is important to establish - Anorectal abnormalities: Hemorrhoids, fissures, fistulae, and polyps can all present with bright red rectal bleeding, which may be intermittent in nature Hemorrhoids are the most common cause of rectal bleeding in adults younger than 50 years The finding of hemorrhoids in older patients with LGIB should not preclude further investigation, as hemorrhoids are an extremely common finding and may not be the cause of bleeding - Hemorrhoids, fissures, fistulae, and polyps can all present with bright red rectal bleeding, which may be intermittent in nature - Hemorrhoids are the most common cause of rectal bleeding in adults younger than 50 years - The finding of hemorrhoids in older patients with LGIB should not preclude further investigation, as hemorrhoids are an extremely common finding and may not be the cause of bleeding - Inflammatory bowel disease (IBD): IBD refers to both Crohn disease and ulcerative colitis Accounts for 5% to 10% of bleeds. It is by far the most common cause of LGIB in Asian populations in whom the prevalence of diverticular disease is much lower A previous history of IBD in patients with LGIB is important, as these patients have a higher risk of developing colorectal malignancy than do the general population - IBD refers to both Crohn disease and ulcerative colitis Accounts for 5% to 10% of bleeds. - It is by far the most common cause of LGIB in Asian populations in whom the prevalence of diverticular disease is much lower - A previous history of IBD in patients with LGIB is important, as these patients have a higher risk of developing colorectal malignancy than do the general population - Infectious colitis: The most common organisms in the U.S. are species ofSalmonella,Campylobacter,Shigella, andYersinia - The most common organisms in the U.S. are species ofSalmonella,Campylobacter,Shigella, andYersinia ## Rare causes - Colonic polyps: These can occur in isolation or as part of an inherited polyposis syndrome Can cause occult or overt LGIB - These can occur in isolation or as part of an inherited polyposis syndrome - Can cause occult or overt LGIB - Radiation proctitis: This usually occurs a few months following ionizing radiation for pelvic malignancies (Fig. 2). In one study of patients with radiation proctitis following pelvic irradiation, 69% presented with bleeding within 1 year and 96% within 2 years - This usually occurs a few months following ionizing radiation for pelvic malignancies (Fig. 2). In one study of patients with radiation proctitis following pelvic irradiation, 69% presented with bleeding within 1 year and 96% within 2 years - Rectal varices: Associated with portal hypertension; may result in massive bleeding Stercoral ulceration: Can cause significant fresh rectal bleeding in elderly constipated patients - Associated with portal hypertension; may result in massive bleeding - Stercoral ulceration: - Can cause significant fresh rectal bleeding in elderly constipated patients - Meckel diverticulum: These small bowel diverticula may contain ectopic gastric mucosa that can ulcerate and cause bleeding They are the most common cause of massive LGIB in young children, and can be diagnosed with angiography, Meckel scans, and radionuclide imaging - These small bowel diverticula may contain ectopic gastric mucosa that can ulcerate and cause bleeding - They are the most common cause of massive LGIB in young children, and can be diagnosed with angiography, Meckel scans, and radionuclide imaging - Intussusception : More common in children, with the highest incidence between the ages of 6 months and 2 years - More common in children, with the highest incidence between the ages of 6 months and 2 years - Henoch-Schönlein purpura (HSP): Most commonly affects children Bleeding may be a direct result of vasculitis or secondary to intussusception, which is associated with HSP - Most commonly affects children - Bleeding may be a direct result of vasculitis or secondary to intussusception, which is associated with HSP - Aortoenteric fistula: - Abdominal aortic aneurysms, especially those of the inflammatory type, may fistulate into the small bowel, giving rise to a massive, life-threatening hemorrhage - Peutz-Jeghers syndrome: Polyps may give rise to frank or occult bleeding - Polyps may give rise to frank or occult bleeding - Klippel-Trenaunay-Weber syndrome: Hemangiomas in the colon can cause significant bleeding - Hemangiomas in the colon can cause significant bleeding - Hereditary hemorrhagic telangiectasia: Blood loss from mucosal telangiectasia can be chronic or acute - Blood loss from mucosal telangiectasia can be chronic or acute - Neurofibromatosis : Neurofibromas within the lumen of the bowel can ulcerate, causing bleeding - Neurofibromas within the lumen of the bowel can ulcerate, causing bleeding - Blue rubber bleb syndrome: Bleeding can arise from hemangiomas in the bowel Usually occult in nature - Bleeding can arise from hemangiomas in the bowel Usually occult in nature ## Risk factors Common risk factors in the development of lower GI bleeding include: - Advancing age - Previous history of gastrointestinal bleed - Chronic constipation - Hematologic disorders - Anticoagulants medications - Nonsteroidal anti-inflammatory drugs - Human immunodeficiency virus # Management ## Initial Evaluation - In patients with acute lower gastrointestinal bleeding who are unstable rapid assessment and resuscitation should be initiated even before diagnostic evaluation. - The initial steps in the management of a patient with lower gastrointestinal bleeding are to assess the severity of bleeding, and then institute fluid and blood resuscitation as needed. - Once hemodynamic stability is achieved, nasogastric lavage should be performed to rule of upper GI source. - Equilibration between the intravascular and extravascular volumes cannot be achieved until 24 to 72 hours after bleeding has occurred. ## Role of Nasogastric tube (NGT) - Nasogastric tube (NGT) lavage is recommended in all patients with lower gastrointestinal bleeding once the patient is stabilized. - A carefully placed nasogastric tube (NGT) with irrigation and aspiration of bile is necessary to ensure sampling of duodenal contents. - If there is a bloody NGT aspirate then an esophagogastroduodenoscopy (EGD) is warranted (11 to 15% of patients despite “negative” NGT aspirates are due to upper GI bleeding). - Obtaining clear fluid favors a lower GI source of bleeding. ## Assessment of severity of bleeding ## Fluid resuscitation - Two large caliber (16-gauge) peripheral catheters or a central venous line should be inserted in patients who are hemodynamically unstable. - The rate of fluid resuscitation is proportional to the severity of bleeding with the goal of restoring and maintaining the patient’s blood pressure. - Infusion of 500 mL of normal saline or lactated Ringer's solution over 30 minutes is preferred treatment for patients with active bleeding before blood type matching and blood transfusion. - Intensive monitoring with a pulmonary artery catheter is recommended to monitor the response of initial resuscitation efforts and any complications of fluid overload. - If the blood pressure fails to respond to initial resuscitation, the rate of fluid administration should be increased and urgent intervention (eg, angiography) considered. ## Blood transfusion - Patients with severe bleeding need to be transfused. - Fresh frozen plasma, platelets, or both should be given to patients with coagulopathy who are actively bleeding and to those who have received more than 10 units of packed erythrocytes. ## Triage and consultations - All patients with visible rectal bleeding warrants an immediate evaluation in all cases. The timing and setting of the evaluation depends upon the severity of bleeding and the patient's comorbid illnesses. - A gastroenterology consultation should be obtained early in the hospital course of patients with acute lower GI bleeding. ## Risk stratification Clinical features can predict the risk of complications in patients with presumed acute lower GI bleeding. These features can also be used to categorize patients as either low or high risk. The number of high-risk features present correlates with the likelihood of a poor outcome. High-risk features include: # Pharmacotherapy Epinephrine is used alone or in conjunction with other surgical techniques to treat a variety of causes of LGIB. Local injection of epinephrine stops bleeding by both pressure tamponade and the vasoconstrictor effect. In patients with rebleeding, surgery should be considered. Pharmacotherapy is only used as an adjuvant therapy for all patients with LGIB. - Preferred regimen (1): Local injection of 1:10,000 to 20,000 solution (Intra-arterial vasopressin infusions begin at a rate of 0.2 U/min. If the bleeding persists, the rate of the infusion is increased to 0.4-0.6 U/min). - Note:- The bleeding stops in about 91% of patients receiving intra-arterial vasopressin but recurs in up to 50% of patients when the infusion is stopped. ## Major contraindications - Closed-angle glaucoma - Labor - Shock - Sulfite hypersensitivity - CAD, PAD ## Complications During vasopressin infusion, monitor patients for: - Recurrent hemorrhage - Myocardial ischemia (Nitroglycerine drip can be used to overcome cardiac complications). - Arrhythmias - Hypertension - Volume overload with hyponatremia. # Colonoscopy - Colonoscopy is considered as the initial diagnostic modality of choice in patients presenting with lower GI bleeding. Colonoscopy can identify the origin of severe LGI bleeding in 74% to 82% of patients. - As long as patients remain stable during the bowel preparation and sedation, colonoscopy has the advantage of not only localizing the source of bleeding, but also allowing intervention via clips, epinephrine injection, thermoregulation, or laser photocoagulation. - In patients with massive lower GI bleeding, colonoscopic hemostasis is an effective means of controlling bleeding from a diverticular source when appropriately skilled providers are available. - In cases in which no source of bleeding is seen on colonoscopy, esophagogastroduodenoscopy should be undertaken, as occasionally, brisk UGIB increases transit time and presents as blood per rectum. - If a patient has pain associated with bleeding, ischemic bowel disease should be considered. CTA may be a more appropriate first-line investigation in patients with abdominal pain or suspected peritonitis. ## Timing of colonoscopy - In patients with ongoing bleeding or high-risk clinical features, a colonoscopy should be performed within 24 hours of presentation after adequate colon preparation to potentially improve diagnostic and therapeutic yield. ## Bowel preparation - In a patient who is not actively bleeding, rapid bowel preparation can be administered with 3 to 4 L of polyethylene glycol. - This can be administered orally or via a nasogastric tube to avoid nausea and reduce the potential risk of aspiration. - However, there is the potential risk of fluid overload in the acutely ill patient receiving rapid bowel preparation this way. - Metoclopramide, 10 to 20 mg, can be administered with the bowel preparation as a prokinetic agent to facilitate gastric emptying and reduce the risk of vomiting. - Some have advocated colonoscopy following limited bowel preparation using polyethylene glycol purges supplemented with rectal enemas. - Blood is cathartic to the colon and tends to facilitate the emptying of colonic residue. ## Complications - Perforation of the luminal wall, resulting in peritonitis and sepsis. - Poor visualization in an unprepared colon. ## Non surgical options - Once the bleeding site is localized, therapeutic options include coagulation and injection with vasoconstrictors or sclerosing agents. - In cases of diverticular bleeding, bipolar probe coagulation, epinephrine injection, and metallic clips may be used. - If recurrent bleeding is present, the affected bowel segment can be resected. - In cases of angiodysplasia, thermal therapy, such as electrocoagulation or argon plasma coagulation, is generally successful. - Angiodysplastic lesions may be missed at colonoscopy if the lesions are small or covered with blood clots. - Endoscopic hemostasis therapy is a safe and effective method to control high-risk indications of hemorrhage: active bleeding, nonbleeding visible vessel, or adherent clot. - It is also effective for diverticular bleeding, angioectasia bleeding, and post-polypectomy bleeding. - In patients with brisk, active lower gastrointestinal bleeding, obtain a surgical consultation. ## CXXX - Diverticula are most common in the descending and sigmoid colon. - Most of the time bleeding from diverticulosis stops spontaneously, however, in about 5% of patients, the bleeding can be massive and life-threatening.	Sandbox 2 Lower GI bleeding is defined as any bleed that occurs distal to the ligament of Treitz. # Incidence - In the United States the incidence of LGIB ranges from 20.5 to 27 per 100,000 persons per year. # Age - There is a greater than 200 fold increase from the third to the ninth decade of life. # Classification - Lower GI bleeding can be classified into 3 groups based on the severity of bleeding: Occult lower GI bleeding Moderate lower GI bleeding Severe lower GI bleeding - Occult lower GI bleeding - Moderate lower GI bleeding - Severe lower GI bleeding # Blood supply - The SMA and IMA are connected by the marginal artery of Drummond. - This vascular arcade runs in the mesentery close to the bowel. - As patients age, there is increased incidence of occlusion of the IMA. - The left colon stays perfused, primarily because of the marginal artery. ## Pathogenesis Diverticulosis is the most common etiology of lower GI bleeding accounting for 30% of all cases, followed by anorectal disease, ischemia, inflammatory bowel disease (IBD), neoplasia and arteriovenous (AV) malformations. - Diverticulosis The colonic wall weakens with age and results in the formation of saclike protrusions known as diverticula. These protrusions generally occur at the junction of blood vessel penetrating through the mucosa and circular muscle fibers of the colon. Diverticula are most common in the descending and sigmoid colon. Despite the majority of diverticula being on the left side of the colon, diverticular bleeding originates from the right side of the colon in 50% to 90% of instances. Most of the time bleeding from diverticulosis stops spontaneously, however, in about 5% of patients, the bleeding can be massive and life-threatening. - The colonic wall weakens with age and results in the formation of saclike protrusions known as diverticula. - These protrusions generally occur at the junction of blood vessel penetrating through the mucosa and circular muscle fibers of the colon. - Diverticula are most common in the descending and sigmoid colon. - Despite the majority of diverticula being on the left side of the colon, diverticular bleeding originates from the right side of the colon in 50% to 90% of instances. - Most of the time bleeding from diverticulosis stops spontaneously, however, in about 5% of patients, the bleeding can be massive and life-threatening. - Anorectal disease - Hemorrhoids and anal fissures are the most common disease under anorectal disease responsible for GI bleeding. - Hemorrhoids are engorged vessels in the normal anal cushions. When swollen, this tissue is very friable and susceptible to trauma, which leads to painless, bright red bleeding. - Anal fissures are defined as a tear in the anal mucosa. With the passage of stool, the mucosa continues to tear and leads to bright red bleeding. - Mesenteric Ischemia - Mesenteric ischemia results when there is inadequate blood supply at the level of the small intestine. - 2 or more vessels (celiac, SMA, or IMA) must be involved for symptoms to occur. - Non occlusive mesenetric ischemia affects critically ill patients who are vasopressor-dependent. - Venous thrombosis of the visceral vessels can also precipitate an acute ischemic event. - Ischemic Colitis - Ischemic colitis is caused by poor perfusion of the colon, which results in the inability of that area of the colon to meet its metabolic demands. - It can be gangrenous or nongangrenous, acute, transient, or chronic. - The left colon is predominantly affected, with the splenic flexure having increased susceptibility. - Intraluminal hemorrhage occurs as the mucosa becomes necrotic, sloughs, and bleeds. - Damage to the tissue is caused both with the ischemic insult as well as reperfusion injury. - Inflammatory Bowel Disease - In Crohn's disease T cell activation stimulates interleukin (IL)-12 and tumor necrosis factor (TNF)-a, which causes chronic inflammation and tissue injury. - Initially, inflammation starts focally around the crypts, followed by superficial ulceration of the mucosa. - The deep mucosal layers are then invaded in a noncontinuous fashion, and noncaseating granulomas form, which can invade through the entire thickness of the bowel and into the mesentery and surrounding structures. - In ulcerative colitis T cells cytotoxic to the colonic epithelium accumulate in the lamina propria, accompanied by B cells that secrete immunoglobulin G (IgG) and IgE. - This results in inflammation of the crypts of Lieberkuhn, with abscesses and pseudopolyps. - Ulcerative colitis generally begins at the rectum and is a continuous process confined exclusively to the colon. - Neoplasia - Colon carcinoma follows a distinct progression from polyp to cancer. - Mutations of multiple genes are required for the formation of adenocarcinoma, including the APC gene, Kras, DCC, and p53. - Certain hereditary syndromes are also classified by defects in DNA mismatch repair genes and microsatellite instability. - These tumors tend to bleed slowly, and patients present with hemocult positive stools and microcytic anemia. - Although cancers of the small bowel are much less common than colorectal cancers, they should be ruled out in cases of lower GI bleeding in which no other source is identified. - AV Malformation/Angiodysplasia - In AV malformation direct connections between arteries and veins occur in the colonic submucosa. - The lack of capillary buffers causes high pressure blood to enter directly into the venous system, making these vessels at high risk of rupture into the bowel lumen. - In Angiodysplasia over time, previously healthy blood vessels of the cecum and ascending colon degenerate and become prone to bleeding. - Although 75% of angiodysplasia cases involve the right colon, they are a significant cause of obscure bleeding and the most common cause of bleeding from the small bowel in the elderly. # Epidemiology ## Prevalence - Approximately 20 patients/100,000 population in the U.S. ## Incidence - The estimated annual incidence of lower GI bleeding is approximately 0.03% in the adult population as a whole. # Demographics ## Gender - More common in men than women ## Age - Rare in children - The incidence of lower GI bleeding increases with age with a 200-fold increase from the second to eighth decades of life la. Largely due to the increase in the prevalence of diverticular disease and angiodysplasia with age. - Largely due to the increase in the prevalence of diverticular disease and angiodysplasia with age. # Symptoms - Occult LGIB may present with symptoms of iron deficiency anemia such as fatigue, palpitations, and dyspnea. - Patients with intussusception may present with pallor and vomiting in addition to LGIB - Associated symptoms, such as abdominal pain or change in bowel habits, may also aide in the diagnosis - Bloody diarrhea associated with abdominal pain may suggest an infectious cause or IBD in a younger patient and ischemic colitis in an older patient with vascular disease - Painless bleeding usually suggests angiodysplasia, diverticular disease, or internal hemorrhoids - Perianal pain suggests a perianal fissure or fistula # History - A detailed description of the nature of the blood loss can help in pinpointing the likely source of bleeding. ## Past Medical History - The clinical history should identify whether this is a recurrent bleed. - Bleeding from angiodysplasia is usually recurrent and chronic, but severe bleeding resulting in hemodynamic instability can occur. - Associated weight loss suggests malignancy. - The presence of systemic diseases such as atherosclerotic disease, IBD, coagulopathies, and HIV, and a history of pelvic irradiation for malignancy should be considered ## Past Surgical History - A history of recent colonic polypectomy or biopsy indicates iatrogenic bleeding. This is usually low grade and limited, although it can be severe if an underlying artery is involved or if there is an inadequate coagulation of the polypectomy stalk. In 1.5% of polypectomies bleeding occurs immediately. However, delayed bleeding can occur several hours or days following the procedure - This is usually low grade and limited, although it can be severe if an underlying artery is involved or if there is an inadequate coagulation of the polypectomy stalk. - In 1.5% of polypectomies bleeding occurs immediately. However, delayed bleeding can occur several hours or days following the procedure - It is essential to establish the presence of comorbid diseases, as these not only help in diagnosis but may also influence treatment. ## Family history - A family history of diseases such as IBD or colorectal malignancy is relevant. # Symptoms - The clinical presentation of LGIB varies with the anatomic source of the bleeding. - Commonly, LGIB from the right side of the colon can manifest as maroon stools, whereas a left-sided bleeding source may be evidenced by bright red blood per rectum. - The presentation of LGIB can also vary depending on the etiology. A young patient may present with fever, dehydration, abdominal cramps, and hematochezia caused by infectious or noninfectious (idiopathic) colitis. An older patient may present with painless bleeding and minimal symptoms caused by diverticular bleeding or angiodysplasia. LGIB can be mild and intermittent, as often is the case with angiodysplasia, or it may be moderate or severe, as may be the situation in diverticula-related bleeding. Young patients may present with abdominal pain, rectal bleeding, diarrhea, and mucous discharge that may be associated with IBD. Elderly patients presenting with abdominal pain, rectal bleeding, and diarrhea may have ischemic colitis. Elderly patients with atherosclerotic heart disease may present with intermittent LGIB and syncope that may be due to angiodysplastic lesions. Stools streaked with blood, perianal pain, and blood drops on the toilet paper or in the toilet bowl may be associated with perianal pathology, such as anal fissure or hemorrhoidal bleeding. The passage of maroon stools or bright red blood from the rectum is usually indicative of massive lower GI hemorrhage. - A young patient may present with fever, dehydration, abdominal cramps, and hematochezia caused by infectious or noninfectious (idiopathic) colitis. - An older patient may present with painless bleeding and minimal symptoms caused by diverticular bleeding or angiodysplasia. - LGIB can be mild and intermittent, as often is the case with angiodysplasia, or it may be moderate or severe, as may be the situation in diverticula-related bleeding. - Young patients may present with abdominal pain, rectal bleeding, diarrhea, and mucous discharge that may be associated with IBD. - Elderly patients presenting with abdominal pain, rectal bleeding, and diarrhea may have ischemic colitis. - Elderly patients with atherosclerotic heart disease may present with intermittent LGIB and syncope that may be due to angiodysplastic lesions. - Stools streaked with blood, perianal pain, and blood drops on the toilet paper or in the toilet bowl may be associated with perianal pathology, such as anal fissure or hemorrhoidal bleeding. - The passage of maroon stools or bright red blood from the rectum is usually indicative of massive lower GI hemorrhage. - Massive LGIB is a life-threatening condition in which patients present with a systolic blood pressure (SBP) of below 90 mm Hg and a hemoglobin (Hb) level of 6 g/dL or less. ## Common causes - Colonic diverticulosis Colonic diverticulosisis the most common cause of acute LGIB in the western world, accounting for 15% to 55% of all LGIB Diverticula can occur anywhere in the gastrointestinal tract, but are most common in the sigmoid colon. However, approximately 60% of diverticular bleeds arise from diverticula in the right colon, highlighting a tendency for right-sided diverticula to bleed Hemorrhage results from rupture of the intramural branches (vasa recta) of the marginal artery at the dome of a diverticulum and can give rise to a massive, life-threatening LGIB This is by far the most common cause of bleeding in the elderly, as the prevalence of diverticular disease increases with age, being as high as 85% by the age of 85 years - Colonic diverticulosisis the most common cause of acute LGIB in the western world, accounting for 15% to 55% of all LGIB - Diverticula can occur anywhere in the gastrointestinal tract, but are most common in the sigmoid colon. However, approximately 60% of diverticular bleeds arise from diverticula in the right colon, highlighting a tendency for right-sided diverticula to bleed - Hemorrhage results from rupture of the intramural branches (vasa recta) of the marginal artery at the dome of a diverticulum and can give rise to a massive, life-threatening LGIB - This is by far the most common cause of bleeding in the elderly, as the prevalence of diverticular disease increases with age, being as high as 85% by the age of 85 years - Obesity has recently been recognized as a risk factor in the development of diverticular disease, and the risk of diverticular bleeding in this group of patients is higher than that in patients who are not obese - Vascular ectasias (angiodysplasias/angioectasias): Tortuous dilated submucosal vessels that account for approximately 10% of LGIB. They appear endoscopically as small, flat lesions (5-10 mm) with ectatic capillaries radiating from a central vessel (Fig. 1) The prevalence of angiodysplasia in the gastrointestinal tract is not well known, but a pooled analysis of three colonoscopic cancer screening studies detected angiodysplasia in 0.8% of the patients The prevalence of angiodysplasia is higher in older populations and, in the past, has been linked to certain conditions such as end-stage renal disease, Von Willebrand disease , and aortic stenosis In one series, 37% of colonic dysplasias were found in the cecum, 17% in the ascending colon, 7% in the transverse colon, 7% in the descending colon, and 32% in rectosigmoid area Angiodysplasia can also be found throughout the small bowel and is responsible for up to 40% of small intestinal bleeding in patients older than 40 years. Angiodysplasia of the stomach and duodenum is responsible for up to 7% of UGIB I - Tortuous dilated submucosal vessels that account for approximately 10% of LGIB. - They appear endoscopically as small, flat lesions (5-10 mm) with ectatic capillaries radiating from a central vessel (Fig. 1) - The prevalence of angiodysplasia in the gastrointestinal tract is not well known, but a pooled analysis of three colonoscopic cancer screening studies detected angiodysplasia in 0.8% of the patients The prevalence of angiodysplasia is higher in older populations and, in the past, has been linked to certain conditions such as end-stage renal disease, Von Willebrand disease , and aortic stenosis In one series, 37% of colonic dysplasias were found in the cecum, 17% in the ascending colon, 7% in the transverse colon, 7% in the descending colon, and 32% in rectosigmoid area - Angiodysplasia can also be found throughout the small bowel and is responsible for up to 40% of small intestinal bleeding in patients older than 40 years. - Angiodysplasia of the stomach and duodenum is responsible for up to 7% of UGIB I - Iatrogenic: Bleeding is recognized as the most common complication of colonoscopy and polypectomy, occurring in 0.3% to 6.1% of polypectomies Risk factors for bleeding include polyp size greater than 1 cm, patient age older than 65 years, presence of comorbid disease, and polypectomy using the cutting mode of current The risk is also greater in patients taking anticoagulant or antiplatelet agents - Bleeding is recognized as the most common complication of colonoscopy and polypectomy, occurring in 0.3% to 6.1% of polypectomies - Risk factors for bleeding include polyp size greater than 1 cm, patient age older than 65 years, presence of comorbid disease, and polypectomy using the cutting mode of current - The risk is also greater in patients taking anticoagulant or antiplatelet agents - Ischemic colitis: Ischemic colitis accounts for approximately 20% of LGIB Ischemia results from a sudden reduction in blood flow to the mesenteric vessels as a result of hypotension, occlusion, or spasm of the mesenteric vessels Nonocclusive disease typically affects the watershed areas of the bowels, such as the splenic flexure and adjacent transverse colon due to the poor blood supply from the marginal artery. Occlusive disease is rarer but can occur as a result of thrombus formation or embolus. It is a recognized complication of aortic surgery Elderly patients with comorbid disease are at higher risk of developing ischemic colitis. There may be a history of ischemic heart disease The majority of patients with ischemic colitis improve following conservative management; however, approximately 20% will progress to develop colonic gangrene Other complications include chronic colitis and stricture formation Diagnosis requires a high index of suspicion - Ischemic colitis accounts for approximately 20% of LGIB - Ischemia results from a sudden reduction in blood flow to the mesenteric vessels as a result of hypotension, occlusion, or spasm of the mesenteric vessels - Nonocclusive disease typically affects the watershed areas of the bowels, such as the splenic flexure and adjacent transverse colon due to the poor blood supply from the marginal artery. - Occlusive disease is rarer but can occur as a result of thrombus formation or embolus. - It is a recognized complication of aortic surgery - Elderly patients with comorbid disease are at higher risk of developing ischemic colitis. - There may be a history of ischemic heart disease - The majority of patients with ischemic colitis improve following conservative management; however, approximately 20% will progress to develop colonic gangrene - Other complications include chronic colitis and stricture formation - Diagnosis requires a high index of suspicion - Colorectal malignancy: Colorectal cancer accounts for approximately 10% of bleeds, either as occult bleeding presenting with anemia or as frank blood loss per rectum A family history of colorectal cancer is important to establish - Colorectal cancer accounts for approximately 10% of bleeds, either as occult bleeding presenting with anemia or as frank blood loss per rectum - A family history of colorectal cancer is important to establish - Anorectal abnormalities: Hemorrhoids, fissures, fistulae, and polyps can all present with bright red rectal bleeding, which may be intermittent in nature Hemorrhoids are the most common cause of rectal bleeding in adults younger than 50 years The finding of hemorrhoids in older patients with LGIB should not preclude further investigation, as hemorrhoids are an extremely common finding and may not be the cause of bleeding - Hemorrhoids, fissures, fistulae, and polyps can all present with bright red rectal bleeding, which may be intermittent in nature - Hemorrhoids are the most common cause of rectal bleeding in adults younger than 50 years - The finding of hemorrhoids in older patients with LGIB should not preclude further investigation, as hemorrhoids are an extremely common finding and may not be the cause of bleeding - Inflammatory bowel disease (IBD): IBD refers to both Crohn disease and ulcerative colitis Accounts for 5% to 10% of bleeds. It is by far the most common cause of LGIB in Asian populations in whom the prevalence of diverticular disease is much lower A previous history of IBD in patients with LGIB is important, as these patients have a higher risk of developing colorectal malignancy than do the general population - IBD refers to both Crohn disease and ulcerative colitis Accounts for 5% to 10% of bleeds. - It is by far the most common cause of LGIB in Asian populations in whom the prevalence of diverticular disease is much lower - A previous history of IBD in patients with LGIB is important, as these patients have a higher risk of developing colorectal malignancy than do the general population - Infectious colitis: The most common organisms in the U.S. are species ofSalmonella,Campylobacter,Shigella, andYersinia - The most common organisms in the U.S. are species ofSalmonella,Campylobacter,Shigella, andYersinia ## Rare causes - Colonic polyps: These can occur in isolation or as part of an inherited polyposis syndrome Can cause occult or overt LGIB - These can occur in isolation or as part of an inherited polyposis syndrome - Can cause occult or overt LGIB - Radiation proctitis: This usually occurs a few months following ionizing radiation for pelvic malignancies (Fig. 2). In one study of patients with radiation proctitis following pelvic irradiation, 69% presented with bleeding within 1 year and 96% within 2 years - This usually occurs a few months following ionizing radiation for pelvic malignancies (Fig. 2). In one study of patients with radiation proctitis following pelvic irradiation, 69% presented with bleeding within 1 year and 96% within 2 years - Rectal varices: Associated with portal hypertension; may result in massive bleeding Stercoral ulceration: Can cause significant fresh rectal bleeding in elderly constipated patients - Associated with portal hypertension; may result in massive bleeding - Stercoral ulceration: - Can cause significant fresh rectal bleeding in elderly constipated patients - Meckel diverticulum: These small bowel diverticula may contain ectopic gastric mucosa that can ulcerate and cause bleeding They are the most common cause of massive LGIB in young children, and can be diagnosed with angiography, Meckel scans, and radionuclide imaging - These small bowel diverticula may contain ectopic gastric mucosa that can ulcerate and cause bleeding - They are the most common cause of massive LGIB in young children, and can be diagnosed with angiography, Meckel scans, and radionuclide imaging - Intussusception : More common in children, with the highest incidence between the ages of 6 months and 2 years - More common in children, with the highest incidence between the ages of 6 months and 2 years - Henoch-Schönlein purpura (HSP): Most commonly affects children Bleeding may be a direct result of vasculitis or secondary to intussusception, which is associated with HSP - Most commonly affects children - Bleeding may be a direct result of vasculitis or secondary to intussusception, which is associated with HSP - Aortoenteric fistula: - Abdominal aortic aneurysms, especially those of the inflammatory type, may fistulate into the small bowel, giving rise to a massive, life-threatening hemorrhage - Peutz-Jeghers syndrome: Polyps may give rise to frank or occult bleeding - Polyps may give rise to frank or occult bleeding - Klippel-Trenaunay-Weber syndrome: Hemangiomas in the colon can cause significant bleeding - Hemangiomas in the colon can cause significant bleeding - Hereditary hemorrhagic telangiectasia: Blood loss from mucosal telangiectasia can be chronic or acute - Blood loss from mucosal telangiectasia can be chronic or acute - Neurofibromatosis : Neurofibromas within the lumen of the bowel can ulcerate, causing bleeding - Neurofibromas within the lumen of the bowel can ulcerate, causing bleeding - Blue rubber bleb syndrome: Bleeding can arise from hemangiomas in the bowel Usually occult in nature - Bleeding can arise from hemangiomas in the bowel Usually occult in nature - ## Risk factors Common risk factors in the development of lower GI bleeding include:[1][2][3][4] - Advancing age - Previous history of gastrointestinal bleed - Chronic constipation - Hematologic disorders - Anticoagulants medications - Nonsteroidal anti-inflammatory drugs - Human immunodeficiency virus # Management ## Initial Evaluation - In patients with acute lower gastrointestinal bleeding who are unstable rapid assessment and resuscitation should be initiated even before diagnostic evaluation. - The initial steps in the management of a patient with lower gastrointestinal bleeding are to assess the severity of bleeding, and then institute fluid and blood resuscitation as needed. - Once hemodynamic stability is achieved, nasogastric lavage should be performed to rule of upper GI source. - Equilibration between the intravascular and extravascular volumes cannot be achieved until 24 to 72 hours after bleeding has occurred. ## Role of Nasogastric tube (NGT) - Nasogastric tube (NGT) lavage is recommended in all patients with lower gastrointestinal bleeding once the patient is stabilized. - A carefully placed nasogastric tube (NGT) with irrigation and aspiration of bile is necessary to ensure sampling of duodenal contents. - If there is a bloody NGT aspirate then an esophagogastroduodenoscopy (EGD) is warranted (11 to 15% of patients despite “negative” NGT aspirates are due to upper GI bleeding). - Obtaining clear fluid favors a lower GI source of bleeding. ## Assessment of severity of bleeding ## Fluid resuscitation - Two large caliber (16-gauge) peripheral catheters or a central venous line should be inserted in patients who are hemodynamically unstable. - The rate of fluid resuscitation is proportional to the severity of bleeding with the goal of restoring and maintaining the patient’s blood pressure. - Infusion of 500 mL of normal saline or lactated Ringer's solution over 30 minutes is preferred treatment for patients with active bleeding before blood type matching and blood transfusion. - Intensive monitoring with a pulmonary artery catheter is recommended to monitor the response of initial resuscitation efforts and any complications of fluid overload. - If the blood pressure fails to respond to initial resuscitation, the rate of fluid administration should be increased and urgent intervention (eg, angiography) considered. ## Blood transfusion - Patients with severe bleeding need to be transfused.[5][6] - Fresh frozen plasma, platelets, or both should be given to patients with coagulopathy who are actively bleeding and to those who have received more than 10 units of packed erythrocytes. ## Triage and consultations - All patients with visible rectal bleeding warrants an immediate evaluation in all cases. The timing and setting of the evaluation depends upon the severity of bleeding and the patient's comorbid illnesses. - A gastroenterology consultation should be obtained early in the hospital course of patients with acute lower GI bleeding. ## Risk stratification Clinical features can predict the risk of complications in patients with presumed acute lower GI bleeding. These features can also be used to categorize patients as either low or high risk. The number of high-risk features present correlates with the likelihood of a poor outcome. High-risk features include: # Pharmacotherapy Epinephrine is used alone or in conjunction with other surgical techniques to treat a variety of causes of LGIB. Local injection of epinephrine stops bleeding by both pressure tamponade and the vasoconstrictor effect. In patients with rebleeding, surgery should be considered. Pharmacotherapy is only used as an adjuvant therapy for all patients with LGIB. - Preferred regimen (1): Local injection of 1:10,000 to 20,000 solution (Intra-arterial vasopressin infusions begin at a rate of 0.2 U/min. If the bleeding persists, the rate of the infusion is increased to 0.4-0.6 U/min). - Note:- The bleeding stops in about 91% of patients receiving intra-arterial vasopressin but recurs in up to 50% of patients when the infusion is stopped. ## Major contraindications - Closed-angle glaucoma - Labor - Shock - Sulfite hypersensitivity - CAD, PAD ## Complications During vasopressin infusion, monitor patients for: - Recurrent hemorrhage - Myocardial ischemia (Nitroglycerine drip can be used to overcome cardiac complications). - Arrhythmias - Hypertension - Volume overload with hyponatremia. # Colonoscopy - Colonoscopy is considered as the initial diagnostic modality of choice in patients presenting with lower GI bleeding. Colonoscopy can identify the origin of severe LGI bleeding in 74% to 82% of patients. - As long as patients remain stable during the bowel preparation and sedation, colonoscopy has the advantage of not only localizing the source of bleeding, but also allowing intervention via clips, epinephrine injection, thermoregulation, or laser photocoagulation. - In patients with massive lower GI bleeding, colonoscopic hemostasis is an effective means of controlling bleeding from a diverticular source when appropriately skilled providers are available. - In cases in which no source of bleeding is seen on colonoscopy, esophagogastroduodenoscopy should be undertaken, as occasionally, brisk UGIB increases transit time and presents as blood per rectum. - If a patient has pain associated with bleeding, ischemic bowel disease should be considered. CTA may be a more appropriate first-line investigation in patients with abdominal pain or suspected peritonitis. ## Timing of colonoscopy - In patients with ongoing bleeding or high-risk clinical features, a colonoscopy should be performed within 24 hours of presentation after adequate colon preparation to potentially improve diagnostic and therapeutic yield. ## Bowel preparation - In a patient who is not actively bleeding, rapid bowel preparation can be administered with 3 to 4 L of polyethylene glycol. - This can be administered orally or via a nasogastric tube to avoid nausea and reduce the potential risk of aspiration. - However, there is the potential risk of fluid overload in the acutely ill patient receiving rapid bowel preparation this way. - Metoclopramide, 10 to 20 mg, can be administered with the bowel preparation as a prokinetic agent to facilitate gastric emptying and reduce the risk of vomiting. - Some have advocated colonoscopy following limited bowel preparation using polyethylene glycol purges supplemented with rectal enemas. - Blood is cathartic to the colon and tends to facilitate the emptying of colonic residue. ## Complications - Perforation of the luminal wall, resulting in peritonitis and sepsis. - Poor visualization in an unprepared colon. ## Non surgical options - Once the bleeding site is localized, therapeutic options include coagulation and injection with vasoconstrictors or sclerosing agents. - In cases of diverticular bleeding, bipolar probe coagulation, epinephrine injection, and metallic clips may be used. - If recurrent bleeding is present, the affected bowel segment can be resected. - In cases of angiodysplasia, thermal therapy, such as electrocoagulation or argon plasma coagulation, is generally successful. - Angiodysplastic lesions may be missed at colonoscopy if the lesions are small or covered with blood clots. - Endoscopic hemostasis therapy is a safe and effective method to control high-risk indications of hemorrhage: active bleeding, nonbleeding visible vessel, or adherent clot. - It is also effective for diverticular bleeding, angioectasia bleeding, and post-polypectomy bleeding. - In patients with brisk, active lower gastrointestinal bleeding, obtain a surgical consultation. ## CXXX - Diverticula are most common in the descending and sigmoid colon. - Most of the time bleeding from diverticulosis stops spontaneously, however, in about 5% of patients, the bleeding can be massive and life-threatening.	https://www.wikidoc.org/index.php/Sandbox_2
8b4dc79cb72db03cd4ec16e74f70f75e0fdc6f74	wikidoc	Sandbox m	Sandbox m # Overview Both type I and type II varieties of complex regional pain syndrome share a common diagnostic criteria. They both consist of having a spontaneous onset of pain that is not limited to the distribution of a single nerve, a history of edema, or abnormal sweating. The only difference lies in the nature of the inciting event. # Diagnostic Criteria CRPS types I and II share the common diagnostic criteria shown below. - Spontaneous pain or allodynia/hyperalgesia is not limited to the territory of a single peripheral nerve, and is disproportionate to the inciting event. - There is a history of edema, skin blood flow abnormality, or abnormal sweating in the region of the pain since the inciting event. - No other conditions can account for the degree of pain and dysfunction. The two types differ only in the nature of the inciting event. Type I CRPS develops following an initiating noxious event that may or may not have been traumatic, while type II CRPS develops after a nerve injury.	Sandbox m Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Both type I and type II varieties of complex regional pain syndrome share a common diagnostic criteria. They both consist of having a spontaneous onset of pain that is not limited to the distribution of a single nerve, a history of edema, or abnormal sweating. The only difference lies in the nature of the inciting event. # Diagnostic Criteria CRPS types I and II share the common diagnostic criteria shown below. - Spontaneous pain or allodynia/hyperalgesia is not limited to the territory of a single peripheral nerve, and is disproportionate to the inciting event. - There is a history of edema, skin blood flow abnormality, or abnormal sweating in the region of the pain since the inciting event. - No other conditions can account for the degree of pain and dysfunction. The two types differ only in the nature of the inciting event. Type I CRPS develops following an initiating noxious event that may or may not have been traumatic, while type II CRPS develops after a nerve injury.	https://www.wikidoc.org/index.php/Sandbox_m
025e118aa0abeaa583276177355825f1e2d88dc7	wikidoc	Sandboxak	Sandboxak For information about (Generic Name), click here. # 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 Sandboxak 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) ### Heart failure - Dosing Information ### Atrial fibrillation - Dosing Information ## 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 - Developed by: (Organisation) - Class of Recommendation: (Class) (Link) - Strength of Evidence: (Category A/B/C) (Link) - Dosing Information ### Non–Guideline-Supported Use - Dosing Information - Dosing Information - Dosing Information # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Dosing Information - Dosing Information ## 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 - Developed by: (Organisation) - Class of Recommendation: (Class) (Link) - Strength of Evidence: (Category A/B/C) (Link) - Dosing Information ### Non–Guideline-Supported Use - Dosing Information - Dosing Information - Dosing Information # Contraindications - Condition 1 - Condition 2 - Condition 3 - Condition 4 - Condition 5 # Warnings Because digoxin slows sinoatrial and AV conduction, the drug commonly prolongs the PR interval. The drug may cause severe sinus bradycardia or sinoatrial block in patients with pre-existing sinus node disease and may cause advanced or complete heart block in patients with pre-existing incomplete AV block. In such patients consideration should be given to the insertion of a pacemaker before treatment with digoxin. After intravenous digoxin therapy, some patients with paroxysmal atrial fibrillation or flutter and a coexisting accessory AV pathway have developed increased antegrade conduction across the accessory pathway bypassing the AV node, leading to a very rapid ventricular response or ventricular fibrillation. Unless conduction down the accessory pathway has been blocked (either pharmacologically or by surgery), digoxin should not be used in such patients. The treatment of paroxysmal supraventricular tachycardia in such patients is usually direct-current cardioversion. Patients with certain disorders involving heart failure associated with preserved left ventricular ejection fraction may be particularly susceptible to toxicity of the drug. Such disorders include restrictive cardiomyopathy, constrictive pericarditis, amyloid heart disease, and acute cor pulmonale. Patients with idiopathic hypertrophic subaortic stenosis may have worsening of the outflow obstruction due to the inotropic effects of digoxin. Digoxin should generally be avoided in these patients, although it has been used for ventricular rate control in the subgroup of patients with atrial fibrillation. # Adverse Reactions ## Clinical Trials Experience The side effects of digoxin in infants and children differ from those seen in adults in several respects. Although digoxin may produce anorexia, nausea, vomiting, diarrhea, and CNS disturbances in young patients, these are rarely the initial symptoms of overdosage. Rather, the earliest and most frequent manifestation of excessive dosing with digoxin in infants and children is the appearance of cardiac arrhythmias, including sinus bradycardia. In children, the use of digoxin may produce any arrhythmia. The most common are conduction disturbances or supraventricular tachyarrhythmias, such as atrial tachycardia (with or without block) and junctional (nodal) tachycardia. Ventricular arrhythmias are less common. Sinus bradycardia may be a sign of impending digoxin intoxication, especially in infants, even in the absence of first-degree heart block. Any arrhythmia or alteration in cardiac conduction that develops in a child taking digoxin should be assumed to be caused by digoxin, until further evaluation proves otherwise. ## Postmarketing Experience FDA Package Insert for Lanoxin tablet contains no information regarding 'Postmarketing Experience'. # Drug Interactions - Drug 1 - Drug 2 - Drug 3 - Drug 4 - Drug 5 (Description) (Description) (Description) (Description) (Description) # Use in Specific Populations ### Pregnancy ### Labor and Delivery (Description) ### Nursing Mothers Studies have shown that digoxin concentrations in the mother’s serum and milk are similar. However, the estimated exposure of a nursing infant to digoxin via breastfeeding will be far below the usual infant maintenance dose. Therefore, this amount should have no pharmacologic effect upon the infant. Nevertheless, caution should be exercised when digoxin is administered to a nursing woman. ### Pediatric Use Newborn infants display considerable variability in their tolerance to digoxin. Premature and immature infants are particularly sensitive to the effects of digoxin, and the dosage of the drug must not only be reduced but must be individualized according to their degree of maturity. Digitalis glycosides can cause poisoning in children due to accidental ingestion. ### Geriatric Use The majority of clinical experience gained with digoxin has been in the elderly population. This experience has not identified differences in response or adverse effects between the elderly and younger patients. However, this drug 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, which should be based on renal function, and it may be useful to monitor renal function (see DOSAGE AND ADMINISTRATION). ### Gender (Description) ### Race (Description) ### Renal Impairment (Description) ### Hepatic Impairment (Description) ### Females of Reproductive Potential and Males (Description) ### Immunocompromised Patients (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 (PillBox 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-Sandboxak interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # 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	Sandboxak Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] For information about (Generic Name), click here. # 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 Sandboxak 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) ### Heart failure - Dosing Information ### Atrial fibrillation - Dosing Information ## 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 - Developed by: (Organisation) - Class of Recommendation: (Class) (Link) - Strength of Evidence: (Category A/B/C) (Link) - Dosing Information ### Non–Guideline-Supported Use - Dosing Information - Dosing Information - Dosing Information # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Dosing Information - Dosing Information ## 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 - Developed by: (Organisation) - Class of Recommendation: (Class) (Link) - Strength of Evidence: (Category A/B/C) (Link) - Dosing Information ### Non–Guideline-Supported Use - Dosing Information - Dosing Information - Dosing Information # Contraindications - Condition 1 - Condition 2 - Condition 3 - Condition 4 - Condition 5 # Warnings Because digoxin slows sinoatrial and AV conduction, the drug commonly prolongs the PR interval. The drug may cause severe sinus bradycardia or sinoatrial block in patients with pre-existing sinus node disease and may cause advanced or complete heart block in patients with pre-existing incomplete AV block. In such patients consideration should be given to the insertion of a pacemaker before treatment with digoxin. After intravenous digoxin therapy, some patients with paroxysmal atrial fibrillation or flutter and a coexisting accessory AV pathway have developed increased antegrade conduction across the accessory pathway bypassing the AV node, leading to a very rapid ventricular response or ventricular fibrillation. Unless conduction down the accessory pathway has been blocked (either pharmacologically or by surgery), digoxin should not be used in such patients. The treatment of paroxysmal supraventricular tachycardia in such patients is usually direct-current cardioversion. Patients with certain disorders involving heart failure associated with preserved left ventricular ejection fraction may be particularly susceptible to toxicity of the drug. Such disorders include restrictive cardiomyopathy, constrictive pericarditis, amyloid heart disease, and acute cor pulmonale. Patients with idiopathic hypertrophic subaortic stenosis may have worsening of the outflow obstruction due to the inotropic effects of digoxin. Digoxin should generally be avoided in these patients, although it has been used for ventricular rate control in the subgroup of patients with atrial fibrillation. # Adverse Reactions ## Clinical Trials Experience The side effects of digoxin in infants and children differ from those seen in adults in several respects. Although digoxin may produce anorexia, nausea, vomiting, diarrhea, and CNS disturbances in young patients, these are rarely the initial symptoms of overdosage. Rather, the earliest and most frequent manifestation of excessive dosing with digoxin in infants and children is the appearance of cardiac arrhythmias, including sinus bradycardia. In children, the use of digoxin may produce any arrhythmia. The most common are conduction disturbances or supraventricular tachyarrhythmias, such as atrial tachycardia (with or without block) and junctional (nodal) tachycardia. Ventricular arrhythmias are less common. Sinus bradycardia may be a sign of impending digoxin intoxication, especially in infants, even in the absence of first-degree heart block. Any arrhythmia or alteration in cardiac conduction that develops in a child taking digoxin should be assumed to be caused by digoxin, until further evaluation proves otherwise. ## Postmarketing Experience FDA Package Insert for Lanoxin tablet contains no information regarding 'Postmarketing Experience'. # Drug Interactions - Drug 1 - Drug 2 - Drug 3 - Drug 4 - Drug 5 (Description) (Description) (Description) (Description) (Description) # Use in Specific Populations ### Pregnancy ### Labor and Delivery (Description) ### Nursing Mothers Studies have shown that digoxin concentrations in the mother’s serum and milk are similar. However, the estimated exposure of a nursing infant to digoxin via breastfeeding will be far below the usual infant maintenance dose. Therefore, this amount should have no pharmacologic effect upon the infant. Nevertheless, caution should be exercised when digoxin is administered to a nursing woman. ### Pediatric Use Newborn infants display considerable variability in their tolerance to digoxin. Premature and immature infants are particularly sensitive to the effects of digoxin, and the dosage of the drug must not only be reduced but must be individualized according to their degree of maturity. Digitalis glycosides can cause poisoning in children due to accidental ingestion. ### Geriatric Use The majority of clinical experience gained with digoxin has been in the elderly population. This experience has not identified differences in response or adverse effects between the elderly and younger patients. However, this drug 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, which should be based on renal function, and it may be useful to monitor renal function (see DOSAGE AND ADMINISTRATION). ### Gender (Description) ### Race (Description) ### Renal Impairment (Description) ### Hepatic Impairment (Description) ### Females of Reproductive Potential and Males (Description) ### Immunocompromised Patients (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 (PillBox 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-Sandboxak interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # 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/Sandboxak
a021917f3d80879d35000e1b124de9d3f95ad7b0	wikidoc	Sarcomere	Sarcomere # Overview A sarcomere is the basic unit of a muscle's cross-striated myofibril. Sarcomeres are multi-protein complexes composed of three different filament systems. - The thick filament system is composed of myosin protein which is connected from the M-line to the Z-disc by Titin - The thin filaments are assembled by actin monomers bound to Nebulin. - Nebulin and Titin gives stability and structure to the sarcomere. A muscle cell, from a biceps, may contain 100,000 sarcomeres. The myofibrils of smooth muscle cells are not arranged into sarcomeres. # Bands The sarcomeres are what give skeletal and cardiac muscles their striated appearance. - A sarcomere is defined as the segment between two neighbouring Z-lines (or Z-discs, or Z bodies). In electron micrographs of cross striated muscle the Z-line (from the German "Zwischen", between the I bands) appears as a series of dark lines. - Surrounding the Z-line is the region of the I-band (for isotropic). - Following the I-band is the A-band (for anisotropic). Named for their properties under a polarizing microscope. - Within the A-band is a paler region called the H-band (from the German "Heller", bright). Named for their properties under a polarization microscope. - Finally, inside the H-band is a thin M-line (from the German "Mittel", middle of the sarcomere). The relationship between the proteins and the regions of the sarcomere are as follows: - Actin filaments are the major component of the I-band and extend into the A-band. - Myosin filaments extend throughout the A-band and are thought to overlap in the M-band. - The giant protein titin (connectin) extends from the Z-line of the sarcomere, where it binds to the thin filament system, to the M-band, where it is thought to interact with the thick filaments. Titin (and its splice isoforms) is the biggest single protein found in nature. It provides binding sites for numerous proteins and is thought to play an important role as sarcomeric ruler and as blueprint for the assembly of the sarcomere. - Several proteins important for the stability of the sarcomeric structure are found in the Z-line as well as in the M-band of the sarcomere. - Actin filaments and Titin molecules are cross-linked in the Z-disc via the Z-line protein alpha-Actinin. - The M-band proteins myomesin as well as M-protein crosslink the thick filament system (myosins) and the M-band part of titin (the elastic filaments). - The interaction between actin and myosin filaments in the A-band of the sarcomere is responsible for the muscle contraction (sliding filament model). # Contraction Upon muscle contraction, the A-bands maintain their length (1.6 micrometer in mammalian skeletal muscle) whereas the I-bands shorten. The A-band, I-band and Z-line are the only components visible at the light-microscope level. The protein tropomyosin covers the myosin binding sites of the actin molecules in the muscle cell. To allow the muscle cell to contract, tropomyosin must be moved to uncover the binding sites on the actin. Calcium ions bind with troponin molecules (which are dispersed throughout the tropomyosin protein) and alter the structure of the tropomyosin, forcing it to reveal the cross bridge binding site on the actin. The concentration of calcium within muscle cells is controlled by the sarcoplasmic reticulum, a unique form of endoplasmic reticulum. Muscle contraction ends when calcium ions are pumped back out of the sarcomere. Skeletal muscle only contracts when an impulse is received from a motor neuron. During stimulation of the muscle cell, the motor neuron releases the neurotransmitter acetylcholine which travels across the neuromuscular junction (the synapse between the terminal bouton of the neuron and the muscle cell). The action potential then travels along T (transverse) tubules until it reaches the sarcoplasmic reticulum; the action potential from the motor neuron changes the permeability of the sarcoplasmic reticulum, allowing the flow of calcium ions into the sarcomere. The outflow of calcium allows the myosin heads access to the actin cross bridge binding sites, permitting muscle contraction. # Rest At rest, the myosin head is bound to an ATP molecule in a low-energy configuration and is unable to access the cross bridge binding sites on the actin. However, the myosin head can hydrolyze ATP into ADP and an inorganic phosphate ion. A portion of the energy released in this reaction changes the shape of the myosin head and promotes it to a high-energy configuration. Through the process of binding to the actin, the myosin head releases ADP and inorganic phosphate ion, changing its configuration back to one of low energy. The myosin remains attached to actin in a state known as Rigor, until an new ATP binds the myosin head. This binding of ATP to myosin releases the actin by cross-bridge dissociation. The ATP associated myosin is ready for another cycle, beginning with hydrolysis of the ATP. # Storage Most muscle cells only store enough ATP for a small number of muscle contractions. While muscle cells also store glycogen, most of the energy required for contraction is derived from phosphagens. One such phosphagen is creatine phosphate, which is used to provide ADP with a phosphate group for ATP synthesis in vertebrates.	Sarcomere Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview A sarcomere is the basic unit of a muscle's cross-striated myofibril. Sarcomeres are multi-protein complexes composed of three different filament systems. - The thick filament system is composed of myosin protein which is connected from the M-line to the Z-disc by Titin - The thin filaments are assembled by actin monomers bound to Nebulin. - Nebulin and Titin gives stability and structure to the sarcomere. A muscle cell, from a biceps, may contain 100,000 sarcomeres. The myofibrils of smooth muscle cells are not arranged into sarcomeres. # Bands The sarcomeres are what give skeletal and cardiac muscles their striated appearance. - A sarcomere is defined as the segment between two neighbouring Z-lines (or Z-discs, or Z bodies). In electron micrographs of cross striated muscle the Z-line (from the German "Zwischen", between the I bands) appears as a series of dark lines. - Surrounding the Z-line is the region of the I-band (for isotropic). - Following the I-band is the A-band (for anisotropic). Named for their properties under a polarizing microscope. - Within the A-band is a paler region called the H-band (from the German "Heller", bright). Named for their properties under a polarization microscope. - Finally, inside the H-band is a thin M-line (from the German "Mittel", middle of the sarcomere). The relationship between the proteins and the regions of the sarcomere are as follows: - Actin filaments are the major component of the I-band and extend into the A-band. - Myosin filaments extend throughout the A-band and are thought to overlap in the M-band. - The giant protein titin (connectin) extends from the Z-line of the sarcomere, where it binds to the thin filament system, to the M-band, where it is thought to interact with the thick filaments. Titin (and its splice isoforms) is the biggest single protein found in nature. It provides binding sites for numerous proteins and is thought to play an important role as sarcomeric ruler and as blueprint for the assembly of the sarcomere. - Several proteins important for the stability of the sarcomeric structure are found in the Z-line as well as in the M-band of the sarcomere. - Actin filaments and Titin molecules are cross-linked in the Z-disc via the Z-line protein alpha-Actinin. - The M-band proteins myomesin as well as M-protein crosslink the thick filament system (myosins) and the M-band part of titin (the elastic filaments). - The interaction between actin and myosin filaments in the A-band of the sarcomere is responsible for the muscle contraction (sliding filament model). # Contraction Upon muscle contraction, the A-bands maintain their length (1.6 micrometer in mammalian skeletal muscle) whereas the I-bands shorten. The A-band, I-band and Z-line are the only components visible at the light-microscope level. The protein tropomyosin covers the myosin binding sites of the actin molecules in the muscle cell. To allow the muscle cell to contract, tropomyosin must be moved to uncover the binding sites on the actin. Calcium ions bind with troponin molecules (which are dispersed throughout the tropomyosin protein) and alter the structure of the tropomyosin, forcing it to reveal the cross bridge binding site on the actin. The concentration of calcium within muscle cells is controlled by the sarcoplasmic reticulum, a unique form of endoplasmic reticulum. Muscle contraction ends when calcium ions are pumped back out of the sarcomere. Skeletal muscle only contracts when an impulse is received from a motor neuron. During stimulation of the muscle cell, the motor neuron releases the neurotransmitter acetylcholine which travels across the neuromuscular junction (the synapse between the terminal bouton of the neuron and the muscle cell). The action potential then travels along T (transverse) tubules until it reaches the sarcoplasmic reticulum; the action potential from the motor neuron changes the permeability of the sarcoplasmic reticulum, allowing the flow of calcium ions into the sarcomere. The outflow of calcium allows the myosin heads access to the actin cross bridge binding sites, permitting muscle contraction. # Rest At rest, the myosin head is bound to an ATP molecule in a low-energy configuration and is unable to access the cross bridge binding sites on the actin. However, the myosin head can hydrolyze ATP into ADP and an inorganic phosphate ion. A portion of the energy released in this reaction changes the shape of the myosin head and promotes it to a high-energy configuration. Through the process of binding to the actin, the myosin head releases ADP and inorganic phosphate ion, changing its configuration back to one of low energy. The myosin remains attached to actin in a state known as Rigor, until an new ATP binds the myosin head. This binding of ATP to myosin releases the actin by cross-bridge dissociation. The ATP associated myosin is ready for another cycle, beginning with hydrolysis of the ATP. # Storage Most muscle cells only store enough ATP for a small number of muscle contractions. While muscle cells also store glycogen, most of the energy required for contraction is derived from phosphagens. One such phosphagen is creatine phosphate, which is used to provide ADP with a phosphate group for ATP synthesis in vertebrates. # External links - Template:McGrawHillAnimation - Template:UIUCHistologySubject - Histology image: 21601ooa – Histology Learning System at Boston University - "Ultrastructure of the Cell: sarcoplasm of skeletal muscle" - Template:MedicalMnemonics - Images created by antibody to striations - model of a sarcomere de:Sarkomer sv:Sarkomer Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Sarcomere
737ca04fabb33f9a5d7f112c24592daa2dda8eda	wikidoc	Sarilumab	Sarilumab # 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 Sarilumab is a interleukin-6 (IL-6) receptor antagonist that is FDA approved for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to one or more disease-modifying antirheumatic drugs (DMARDs). There is a Black Box Warning for this drug as shown here. Common adverse reactions include neutropenia, increased ALT, injection site erythema, upper respiratory infections and urinary tract infections. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Sarilumab is indicated for treatment of adult patients with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response or intolerance to one or more disease-modifying antirheumatic drugs (DMARDs). - Sarilumab may be used as monotherapy or in combination with methotrexate (MTX) or other conventional DMARDs. - The recommended dosage of Sarilumab is 200 mg once every two weeks given as a subcutaneous injection. - Reduce dose to 150 mg once every two weeks for management of neutropenia, thrombocytopenia and elevated liver enzymes. - If a patient develops a serious infection, hold treatment with Sarilumab until the infection is controlled. - Modify dosage in case of neutropenia, thrombocytopenia or liver enzyme elevations (see TABLE 1). ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Sarilumab Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding Sarilumab 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 Sarilumab FDA-Labeled Indications and Dosage (Pediatric) in the drug label. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Sarilumab Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding Sarilumab Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label. # Contraindications - Sarilumab is contraindicated in patients with known hypersensitivity to Sarilumab or any of the inactive ingredients. # Warnings - Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in patients receiving immunosuppressive agents including Sarilumab for rheumatoid arthritis (RA). The most frequently observed serious infections with Sarilumab included pneumonia and cellulitis. Among opportunistic infections, tuberculosis, candidiasis, and pneumocystis were reported with Sarilumab. Some patients presented with disseminated rather than localized disease and were often taking concomitant immunosuppressants such as methotrexate or corticosteroids, which in addition to RA may predispose them to infections. While not reported in Sarilumab clinical studies, other serious infections (e.g., histoplasmosis, cryptococcus, aspergillosis) have been reported in patients receiving other immunosuppressive agents for the treatment of RA. - Avoid use of Sarilumab in patients with an active infection, including localized infections. Consider the risks and benefits of treatment prior to initiating Sarilumab in patients who have: - chronic or recurrent infection; - a history of serious or opportunistic infections; - underlying conditions, in addition to RA, that may predispose them to infection; - been exposed to tuberculosis; or - lived in or traveled to areas of endemic tuberculosis or endemic mycoses. - Closely monitor patients for the development of signs and symptoms of infection during treatment with Sarilumab, as signs and symptoms of acute inflammation may be lessened due to suppression of the acute phase reactants. - Hold treatment with Sarilumab if a patient develops a serious infection or an opportunistic infection. - Perform prompt and complete diagnostic testing appropriate for an immunocompromised patient who develops a new infection during treatment with Sarilumab; initiate appropriate antimicrobial therapy, and closely monitor the patient. Tuberculosis - Evaluate patients for tuberculosis (TB) risk factors and test for latent infection prior to initiating treatment with Sarilumab. Treat patients with latent TB with standard antimycobacterial therapy before initiating Sarilumab. Consider anti-TB therapy prior to initiation of Sarilumab in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent TB but having risk factors for TB infection. When considering anti-TB therapy, consultation with a physician with expertise in TB may be appropriate. - Closely monitor patients for the development of signs and symptoms of TB including patients who tested negative for latent TB infection prior to initiating therapy. Viral Reactivation - Viral reactivation has been reported with immunosuppressive biologic therapies. Cases of herpes zoster were observed in clinical studies with Sarilumab. The risk of Hepatitis B reactivation with Sarilumab is unknown since patients who were at risk for reactivation were excluded. Neutropenia - Treatment with Sarilumab was associated with a higher incidence of decrease in absolute neutrophil count (ANC), including neutropenia. - Assess neutrophil count prior to initiation of Sarilumab and monitor neutrophil count 4 to 8 weeks after start of therapy and every 3 months thereafter. - Based on the pharmacodynamics of the changes in ANC, use results obtained at the end of the dosing interval when considering dose modification. Thrombocytopenia - Treatment with Sarilumab was associated with a reduction in platelet counts in clinical studies. - Assess platelet count prior to initiation of Sarilumab and monitor platelets 4 to 8 weeks after start of therapy and every 3 months thereafter. Elevated Liver Enzymes - Treatment with Sarilumab was associated with a higher incidence of transaminase elevations. These elevations were transient and did not result in any clinically evident hepatic injury in clinical studies. Increased frequency and magnitude of these elevations were observed when potentially hepatotoxic drugs (e.g., MTX) were used in combination with Sarilumab. - Assess ALT/AST levels prior to initiation of Sarilumab and monitor ALT and AST levels 4 to 8 weeks after start of therapy and every 3 months thereafter. When clinically indicated, consider other liver function tests such as bilirubin. Lipid Abnormalities - Treatment with Sarilumab was associated with increases in lipid parameters such as LDL cholesterol, HDL cholesterol and/or triglycerides. - Assess lipid parameters approximately 4 to 8 weeks following initiation of treatment with Sarilumab, then at approximately 6 month intervals. - Manage patients according to clinical guidelines for the management of hyperlipidemia. - Gastrointestinal perforations have been reported in clinical studies, primarily as complications of diverticulitis. GI perforation risk may be increased with concurrent diverticulitis or concomitant use of NSAIDs or corticosteroids. Promptly evaluate patients presenting with new onset abdominal symptoms. - Treatment with immunosuppressants may result in an increased risk of malignancies. The impact of treatment with Sarilumab on the development of malignancies is not known but malignancies were reported in clinical studies. - Hypersensitivity reactions have been reported in association with Sarilumab. Hypersensitivity reactions that required treatment discontinuation were reported in 0.3% of patients in controlled RA trials. Injection site rash, rash, and urticaria were the most frequent hypersensitivity reactions. Advise patients to seek immediate medical attention if they experience any symptoms of a hypersensitivity reaction. If anaphylaxis or other hypersensitivity reaction occurs, stop administration of Sarilumab immediately. Do not administer Sarilumab to patients with known hypersensitivity to Sarilumab. - Treatment with Sarilumab is not recommended in patients with active hepatic disease or hepatic impairment, as treatment with Sarilumab was associated with transaminase elevations. - Avoid concurrent use of live vaccines during treatment with Sarilumab due to potentially increased risk of infections; clinical safety of live vaccines during Sarilumab treatment has not been established. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving Sarilumab. The interval between live vaccinations and initiation of Sarilumab therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents. # Adverse Reactions ## Clinical Trials Experience - Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. - All patients in the safety data described below had moderately to severely active rheumatoid arthritis. - The safety of Sarilumab in combination with conventional DMARDs was evaluated based on data from seven studies, of which two were placebo-controlled, consisting of 2887 patients (long-term safety population). Of these, 2170 patients received Sarilumab for at least 24 weeks, 1546 for at least 48 weeks, 1020 for at least 96 weeks, and 624 for at least 144 weeks. - The pre-rescue placebo-controlled population includes patients from the two Phase 3 efficacy studies (Studies 1 and 2) from weeks 0 to 16 for Study 1 and weeks 0 to 12 for Study 2, and was used to assess common adverse reactions and laboratory abnormalities prior to patients being permitted to switch from placebo to Sarilumab. In this population, 582 patients, 579 patients, and 579 patients received Sarilumab 200 mg, Sarilumab 150 mg, or placebo once every two weeks, respectively, in combination with conventional DMARDs. - The 52-week placebo-controlled population includes patients from one Phase 2 study of 12 week duration and two Phase 3 efficacy studies (one of 24 week duration and the other of 52 week duration). This placebo-controlled population includes all subjects from the double-blind, placebo-controlled periods from each study and was analyzed under their original randomization assignment. In this population, 661 patients, 660 patients, and 661 patients received Sarilumab 200 mg, Sarilumab 150 mg, or placebo once every two weeks, respectively, in combination with conventional DMARDs. - Most safety data are described for the pre-rescue population. For rarer events, the 52-week placebo-controlled population is used. - The most common serious adverse reactions were infections. - The most frequent adverse reactions (occurring in at least 3% of patients treated with Sarilumab in combination with DMARDs) observed with Sarilumab in the clinical studies were neutropenia, increased ALT, injection site erythema, upper respiratory infections, and urinary tract infections. - In the pre-rescue placebo-controlled population, premature discontinuation due to adverse reactions occurred in 8%, 6% and 3% of patients treated with Sarilumab 200 mg, Sarilumab 150 mg, and placebo, respectively. - The most common adverse reaction (greater than 1%) that resulted in discontinuation of therapy with Sarilumab was neutropenia. - The use of Sarilumab as monotherapy was assessed in 132 patients, of which 67 received Sarilumab 200 mg and 65 patients received Sarilumab 150 mg without concomitant DMARDs. The safety profile was generally consistent with that in the population receiving concomitant DMARDs. Overall Infections - In the pre-rescue placebo-controlled population, the rate of infections in the 200 mg and 150 mg Sarilumab + DMARD group was 110 and 105 events per 100 patient-years, respectively, compared to 81 events per 100 patient-years in the placebo + DMARD group. The most commonly reported infections (2% to 4% of patients) were upper respiratory tract infections, urinary tract infections, and nasopharyngitis. - In the 52-week placebo-controlled population, 0.8% of patients (5 patients) treated with Sarilumab 200 mg + DMARD, 0.6% (4 patients) treated with Sarilumab 150 mg + DMARD and 0.5% (3 patients) treated with placebo + DMARD had an event of herpes zoster. - The overall rate of infections with Sarilumab + DMARD in the long-term safety population was consistent with rates in the controlled periods of the studies. Serious Infections - In the pre-rescue population, the rate of serious infections in the 200 mg and 150 mg Sarilumab + DMARD group was 3.8 and 4.4 events per 100 patient-years, respectively, compared to 2.5 events per 100 patient-years in the placebo + DMARD group. In the 52-week placebo-controlled population, the rate of serious infections in the 200 mg and 150 mg Sarilumab + DMARD group was 4.3 and 3.0 events per 100 patient-years, respectively, compared to 3.1 events per 100 patient-years in the placebo + DMARD group. - In the long-term safety population, the overall rate of serious infections was consistent with rates in the controlled periods of the studies. The most frequently observed serious infections included pneumonia and cellulitis. Cases of opportunistic infection have been reported. Gastrointestinal Perforation - In the 52-week placebo-controlled population, one patient on Sarilumab therapy experienced a gastrointestinal (GI) perforation (0.11 events per 100 patient-years). - In the long-term safety population, the overall rate of GI perforation was consistent with rates in the controlled periods of the studies. Reports of GI perforation were primarily reported as complications of diverticulitis including lower GI perforation and abscess. Most patients who developed GI perforations were taking concomitant nonsteroidal anti-inflammatory medications (NSAIDs) or corticosteroids. The contribution of these concomitant medications relative to Sarilumab in the development of GI perforations is not known. Hypersensitivity Reactions - In the pre-rescue placebo-controlled population, the proportion of patients who discontinued treatment due to hypersensitivity reactions was higher among those treated with Sarilumab (0.3% in 200 mg, 0.2% in 150 mg) than placebo (0%). The rate of discontinuations due to hypersensitivity in the long-term safety population was consistent with the placebo-controlled period. Injection Site Reactions - In the pre-rescue placebo-controlled population, injection site reactions were reported in 7% of patients receiving Sarilumab 200 mg, 6% receiving Sarilumab 150 mg, and 1% receiving placebo. These injection site reactions (including erythema and pruritus) were mild in severity for the majority of patients and necessitated drug discontinuation in 2 (0.2%) patients receiving Sarilumab. Laboratory Abnormalities Decreased neutrophil count - In the pre-rescue placebo-controlled population, decreases in neutrophil counts less than 1000 per mm3 occurred in 6% and 4% of patients in the 200 mg Sarilumab + DMARD and 150 mg Sarilumab + DMARD group, respectively, compared to no patients in the placebo + DMARD groups. Decreases in neutrophil counts less than 500 per mm3 occurred in 0.7% of patients in both the 200 mg Sarilumab + DMARD and 150 mg Sarilumab + DMARD groups. Decrease in ANC was not associated with the occurrence of infections, including serious infections. - In the long-term safety population, the observations on neutrophil counts were consistent with what was seen in the placebo-controlled clinical studies. Decreased platelet count - In the pre-rescue placebo-controlled population, decreases in platelet counts less than 100,000 per mm3 occurred in 1% and 0.7% of patients on 200 mg and 150 mg Sarilumab + DMARD, respectively, compared to no patients on placebo + DMARD, without associated bleeding events. - In the long-term safety population, the observations on platelet counts were consistent with what was seen in the placebo-controlled clinical studies. Elevated liver enzymes - Liver enzyme elevations in the pre-rescue placebo-controlled population (Sarilumab + DMARD or placebo + DMARD) are summarized in Table 2. In patients experiencing liver enzyme elevation, modification of treatment regimen, such as interruption of Sarilumab or reduction in dose, resulted in decrease or normalization of liver enzymes. These elevations were not associated with clinically relevant increases in direct bilirubin, nor were they associated with clinical evidence of hepatitis or hepatic impairment. Lipid Abnormalities - Lipid parameters (LDL, HDL, and triglycerides) were first assessed at 4 weeks following initiation of Sarilumab + DMARDs in the placebo-controlled population. Increases were observed at this time point with no additional increases observed thereafter. Changes in lipid parameters from baseline to Week 4 are summarized below: - Mean LDL increased by 12 mg/dL in the Sarilumab 150 mg every two weeks + DMARD group and 16 mg/dL in the Sarilumab 200 mg every two weeks + DMARD group. - Mean triglycerides increased by 20 mg/dL in the Sarilumab 150 mg every two weeks + DMARD group and 27 mg/dL in the Sarilumab 200 mg every two weeks + DMARD group. - Mean HDL increased by 3 mg/dL in both the Sarilumab 150 mg every two weeks + DMARD and Sarilumab 200 mg every two weeks + DMARD groups. - In the long-term safety population, the observations in lipid parameters were consistent with what was observed in the placebo-controlled clinical studies. Malignancies - In the 52-week placebo-controlled population, 9 malignancies (exposure-adjusted event rate of 1.0 event per 100 patient-years) were diagnosed in patients receiving Sarilumab+ DMARD compared to 4 malignancies in patients in the control group (exposure-adjusted event rate of 1.0 event per 100 patient-years). - In the long-term safety population, the rate of malignancies was consistent with the rate observed in the placebo-controlled period. Other Adverse Reactions - Adverse reactions occurring in 2% or more of patients on Sarilumab + DMARD and greater than those observed in patients on placebo + DMARD are summarized in Table 3. - Medically relevant adverse reactions occurring at an incidence less than 2% in patients with rheumatoid arthritis treated with Sarilumab in controlled studies was oral herpes. - As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Sarilumab in the studies described below with the incidence of antibodies in other studies or to other products may be misleading. - In the pre-rescue population, 4.0% of patients treated with Sarilumab 200 mg + DMARD, 5.7% of patients treated with Sarilumab 150 mg + DMARD and 1.9% of patients treated with placebo + DMARD, exhibited an anti-drug antibody (ADA) response. Neutralizing antibodies (NAb) were detected in 1.0% of patients on Sarilumab 200 mg + DMARD, 1.6% of patients on Sarilumab 150 mg + DMARD, and 0.2% of patients on placebo + DMARD. - In patients treated with Sarilumab monotherapy, 9.2% of patients exhibited an ADA response with 6.9% of patients also exhibiting NAbs. Prior to administration of Sarilumab, 2.3% of patients exhibited an ADA response. - No correlation was observed between ADA development and either loss of efficacy or adverse reactions. ## Postmarketing Experience There is limited information regarding Sarilumab Postmarketing Experience in the drug label. # Drug Interactions - Use with Other Drugs for Treatment of Rheumatoid Arthritis - Interactions with CYP450 Substrates - Live Vaccines - Population pharmacokinetic analyses did not detect any effect of methotrexate (MTX) on Sarilumab clearance. Sarilumab has not been investigated in combination with JAK inhibitors or biological DMARDs such as TNF antagonists. - Various in vitro and limited in vivo human studies have shown that cytokines and cytokine modulators can influence the expression and activity of specific cytochrome P450 (CYP) enzymes and therefore have the potential to alter the pharmacokinetics of concomitantly administered drugs that are substrates of these enzymes. Elevated interleukin-6 (IL-6) concentration may down-regulate CYP activity such as in patients with RA and hence increase drug levels compared to subjects without RA. Blockade of IL-6 signaling by IL-6Rα antagonists such as Sarilumab might reverse the inhibitory effect of IL-6 and restore CYP activity, leading to altered drug concentrations. - The modulation of IL-6 effect on CYP enzymes by Sarilumab may be clinically relevant for CYP substrates with a narrow therapeutic index, where the dose is individually adjusted. Upon initiation or discontinuation of Sarilumab, in patients being treated with CYP substrate medicinal products, perform therapeutic monitoring of effect (e.g., warfarin) or drug concentration (e.g., theophylline) and adjust the individual dose of the medicinal product as needed. - Exercise caution when coadministering Sarilumab with CYP3A4 substrate drugs where decrease in effectiveness is undesirable, e.g., oral contraceptives, lovastatin, atorvastatin, etc. The effect of Sarilumab on CYP450 enzyme activity may persist for several weeks after stopping therapy. - Avoid concurrent use of live vaccines during treatment with Sarilumab. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): Pregnancy Exposure Registry - There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Sarilumab during pregnancy. Physicians are encouraged to register patients and pregnant women are encouraged to register themselves by calling 1-877-311-8972. Risk Summary - The limited human data with Sarilumab in pregnant women are not sufficient to inform drug-associated risk for major birth defects and miscarriage. Monoclonal antibodies, such as Sarilumab, are actively transported across the placenta during the third trimester of pregnancy and may affect immune response in the in utero exposed infant. From animal data, and consistent with the mechanism of action, levels of IgG, in response to antigen challenge, may be reduced in the fetus/infant of treated mothers. In an animal reproduction study, consisting of a combined embryo-fetal and pre- and postnatal development study with monkeys that received intravenous administration of Sarilumab, there was no evidence of embryotoxicity or fetal malformations with exposures up to approximately 84 times the maximum recommended human dose (MRHD). The literature suggests that inhibition of IL-6 signaling may interfere with cervical ripening and dilatation and myometrial contractile activity leading to potential delays of parturition. - The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Sarilumab should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus. Clinical Considerations (Fetal/Neonatal Adverse Reactions) - Monoclonal antibodies are increasingly transported across the placenta as pregnancy progresses, with the largest amount transferred during the third trimester. Risks and benefits should be considered prior to administering live or live-attenuated vaccines to infants exposed to Sarilumab in utero. From the animal data, and consistent with the mechanism of action, levels of IgG, in response to antigen challenge, may be reduced in the fetus/infant of treated mothers. Data (Animal) - In a combined embryo-fetal and pre- and postnatal development study, pregnant cynomolgus monkeys received Sarilumab at intravenous doses of 0, 5, 15, or 50 mg/kg/week from confirmation of pregnancy at gestation day (GD) 20, throughout the period of organogenesis (up to approximately GD 50), and continuing to natural birth of infants at around GD 165. Maintenance of pregnancy was not affected at any doses. Sarilumab was not embryotoxic or teratogenic with exposures up to approximately 84 times the MRHD (based on AUC with maternal intravenous doses up to 50 mg/kg/week). Sarilumab had no effect on neonatal growth and development evaluated up to one month after birth. Sarilumab was detected in the serum of neonates up to one month after birth, suggesting that the antibody had crossed the placenta. - Following antigen challenge, decreased IgG titers attributed to the immunosuppressive action of Sarilumab were evident in studies with older monkeys, with exposures up to approximately 80 times the MRHD (based on AUC with intravenous doses up to 50 mg/kg/week) and juvenile mice treated with an analogous antibody, which binds to murine IL-6Rα to inhibit IL-6 mediated signaling, at subcutaneous doses up to 200 mg/kg/week. These findings suggest the potential for decreased IgG titers, following antigen challenge, in infants of mothers treated with Sarilumab. - Parturition is associated with significant increases of IL-6 in the cervix and myometrium. The literature suggests that inhibition of IL-6 signaling may interfere with cervical ripening and dilatation and myometrial contractile activity leading to potential delays of parturition. For mice deficient in IL-6 (ll6-/- null mice), parturition was delayed relative to wild-type (ll6+/+) mice. Administration of recombinant IL-6 to ll6-/- null mice restored the normal timing of delivery. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Sarilumab in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Sarilumab during labor and delivery. ### Nursing Mothers Risk Summary - No information is available on the presence of Sarilumab in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. Maternal IgG is present in human milk. If Sarilumab is transferred into human milk, the effects of local exposure in the gastrointestinal tract and potential limited systemic exposure in the infant to Sarilumab are unknown. The lack of clinical data during lactation precludes clear determination of the risk of Sarilumab to an infant during lactation; therefore, the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Sarilumab and the potential adverse effects on the breastfed child from Sarilumab or from the underlying maternal condition. ### Pediatric Use - Safety and efficacy of Sarilumab in pediatric patients have not been established. ### Geriatic Use - Of the total number of patients in clinical studies of Sarilumab, 15% were 65 years of age and over, while 1.6% were 75 years and over. In clinical studies, no overall differences in safety and efficacy were observed between older and younger patients. The frequency of serious infection among Sarilumab and placebo-treated patients 65 years of age and older was higher than those under the age of 65. As there is a higher incidence of infections in the elderly population in general, caution should be used when treating the elderly. ### Gender There is no FDA guidance on the use of Sarilumab with respect to specific gender populations. ### Race There is no FDA guidance on the use of Sarilumab with respect to specific racial populations. ### Renal Impairment - No dose adjustment is required in patients with mild to moderate renal impairment. Sarilumab has not been studied in patients with severe renal impairment. ### Hepatic Impairment - The safety and efficacy of Sarilumab have not been studied in patients with hepatic impairment, including patients with positive HBV or HCV serology. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Sarilumab in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Sarilumab in patients who are immunocompromised. # Administration and Monitoring ### Administration - Allow to sit at room temperature for 30 minutes prior to administration or 60 minutes if using a pre-filled pen; do not warm any other way. - Rotate injection sites; do not inject where skin is tender, damaged, bruised, or scarred. - Inject full amount of pre-filled syringe or pen. - Missed dose: If 3 days or less since missed dose, take as soon as possible; take next dose at regularly scheduled time. ### Monitoring - Improvement in the signs or symptoms of rheumatoid arthritis may indicate efficacy. - Neutrophils and platelets: 4 to 8 weeks after treatment initiation and approximately every 3 months thereafter. - ALT and AST levels: 4 to 8 weeks after treatment initiation and approximately every 3 months thereafter; other liver function tests if clinically indicated. - Lipid parameters: Approximately 4 to 8 weeks after treatment initiation, and at 6 month intervals thereafter. - Latent TB: Prior to initiation. - Active TB: Monitor all patients for active TB during treatment, even if initial latent TB test was negative. - Signs and symptoms of infection: During and after therapy. # IV Compatibility There is limited information regarding the compatibility of Sarilumab and IV administrations. # Overdosage There is limited information regarding Sarilumab overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately. # Pharmacology ## Mechanism of Action - Sarilumab binds to both soluble and membrane-bound IL-6 receptors (sIL-6R and mIL-6R), and has been shown to inhibit IL-6-mediated signaling through these receptors. IL-6 is a pleiotropic pro-inflammatory cytokine produced by a variety of cell types including T- and B-cells, lymphocytes, monocytes, and fibroblasts. IL-6 has been shown to be involved in diverse physiological processes such as T-cell activation, induction of immunoglobulin secretion, initiation of hepatic acute phase protein synthesis, and stimulation of hematopoietic precursor cell proliferation and differentiation. IL-6 is also produced by synovial and endothelial cells leading to local production of IL-6 in joints affected by inflammatory processes such as rheumatoid arthritis. ## Structure There is limited information regarding Sarilumab Structure in the drug label. ## Pharmacodynamics - Following single-dose subcutaneous administration of Sarilumab 200-mg and 150-mg in patients with RA, rapid reduction of CRP levels was observed. Levels were reduced to normal within 2 weeks after treatment initiation. Following single-dose Sarilumab administration, in patients with RA, absolute neutrophil counts decreased to the nadir between 3 to 4 days and thereafter recovered towards baseline. Treatment with Sarilumab resulted in decreases in fibrinogen and serum amyloid A, and increases in hemoglobin and serum albumin. ## Pharmacokinetics Absorption - The pharmacokinetics of Sarilumab were characterized in 1770 patients with rheumatoid arthritis (RA) treated with Sarilumab which included 631 patients treated with 150 mg and 682 patients treated with 200 mg doses by subcutaneous injection every two weeks for up to 52 weeks. The median tmax was observed in 2 to 4 days. - At steady state, exposure over the dosing interval measured by area under curve (AUC) increased 2-fold with an increase in dose from 150 to 200 mg every two weeks. Steady state was reached in 14 to 16 weeks with a 2- to 3-fold accumulation compared to single dose exposure. - For the 150 mg every two weeks dose regimen, the estimated mean (± SD) steady-state AUC, Cmin and Cmax of Sarilumab were 202 ± 120 mg.day/L, 6.35 ± 7.54 mg/L, and 20.0 ± 9.20 mg/L, respectively. - For the 200 mg every two weeks dose regimen, the estimated mean (± SD) steady-state AUC, Cmin and Cmax of Sarilumab were 395 ± 207 mg.day/L, 16.5 ± 14.1 mg/L, and 35.6 ± 15.2 mg/L, respectively. Distribution - In patients with RA, the apparent volume of distribution at steady state was 7.3 L. Elimination - Sarilumab is eliminated by parallel linear and non-linear pathways. At higher concentrations, the elimination is predominantly through the linear, non-saturable proteolytic pathway, while at lower concentrations, non-linear saturable target-mediated elimination predominates. The half-life of Sarilumab is concentration-dependent. At 200 mg every 2 weeks, the concentration-dependent half-life is up to 10 days in patients with RA at steady state. At 150 mg every 2 weeks, the concentration-dependent half-life is up to 8 days in patients with RA at steady state. - After the last steady state dose of 150 mg and 200 mg Sarilumab, the median times to non-detectable concentration are 28 and 43 days, respectively. - Population pharmacokinetic analyses in patients with RA revealed that there was a trend toward higher apparent clearance of Sarilumab in the presence of anti-Sarilumab antibodies. Metabolism - The metabolic pathway of Sarilumab has not been characterized. As a monoclonal antibody Sarilumab is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG. Excretion - Monoclonal antibodies, including Sarilumab, are not eliminated via renal or hepatic pathways. Specific Populations - Population pharmacokinetic analyses in adult patients with rheumatoid arthritis showed that age, gender and race did not meaningfully influence the pharmacokinetics of Sarilumab. Although body weight influenced the pharmacokinetics of Sarilumab, no dose adjustments are recommended for any of these demographics. Hepatic impairment - No formal study of the effect of hepatic impairment on the pharmacokinetics of Sarilumab was conducted. Renal impairment - No formal study of the effect of renal impairment on the pharmacokinetics of Sarilumab was conducted. Based on population pharmacokinetic analysis of data from 1770 patients with RA, including patients with mild (creatinine clearance (CLcr): 60 to 90 mL/min; N=471 at baseline) or moderate (CLcr: 30 to 60 mL/min; N=74 at baseline) renal impairment, CLcr was correlated with Sarilumab exposure. However, the effect of CLcr on exposure is not sufficient to warrant a dose adjustment. Patients with severe renal impairment were not studied. Drug-Drug Interactions CYP450 substrates - Simvastatin is a CYP3A4 and OATP1B1 substrate. In 17 patients with RA, one week following a single 200-mg subcutaneous administration of Sarilumab, exposure of simvastatin and simvastatin acid decreased by 45% and 36%, respectively. ## Nonclinical Toxicology - No long-term animal studies have been performed to establish the carcinogenicity potential of Sarilumab. Literature indicates that the IL-6 pathway can mediate anti-tumor responses by promoting increased immune cell surveillance of the tumor microenvironment. However, available published evidence also supports that IL-6 signaling through the IL-6 receptor may be involved in pathways that lead to tumorigenesis. The malignancy risk in humans from an antibody that disrupts signaling through the IL-6 receptor, such as Sarilumab, is presently unknown. - Fertility and reproductive performance were unaffected in male and female mice treated with an analogous antibody, which binds to murine IL-6Rα to inhibit IL-6 mediated signaling, at subcutaneous doses of 10, 25, and 100 mg/kg twice per week. # Clinical Studies - The efficacy and safety of Sarilumab were assessed in two randomized, double-blind, placebo-controlled multicenter studies (Study 1 and Study 2) in patients older than 18 years with moderately to severely active rheumatoid arthritis (RA) diagnosed according to American College of Rheumatology (ACR) criteria. Patients had at least 8 tender and 6 swollen joints at baseline. - Study 1 evaluated 1197 patients with moderately to severely active rheumatoid arthritis who had inadequate clinical response to methotrexate (MTX). Patients received subcutaneous Sarilumab 200 mg, Sarilumab 150 mg, or placebo every two weeks with concomitant MTX. After Week 16 in Study 1, patients with an inadequate response could have been rescued with Sarilumab 200 mg every two weeks. - Study 2 evaluated 546 patients with moderately to severely active rheumatoid arthritis who had an inadequate clinical response or were intolerant to one or more TNF-α antagonists. Patients received subcutaneous Sarilumab 200 mg, Sarilumab 150 mg, or placebo every two weeks with concomitant conventional DMARDs (MTX, sulfasalazine, leflunomide, and/or hydroxychloroquine). After Week 12 in Study 2, patients with an inadequate response could have been rescued with Sarilumab 200 mg every two weeks. - In Studies 1 and 2, the primary endpoint was the proportion of patients who achieved an ACR20 response at Week 24. Other key endpoints evaluated included change from baseline in HAQ-DI at Week 16 in Study 1 and at Week 12 in Study 2, and change from baseline in van der Heijde-modified Total Sharp Score (mTSS) at Week 52 in Study 1. - The percentages of Sarilumab every two weeks + MTX/DMARD-treated patients achieving ACR20, ACR50 and ACR70 responses in Studies 1 and 2 are shown Table 4. In both studies, patients treated with either 200 mg or 150 mg of Sarilumab every two weeks + MTX/DMARD had higher ACR20, ACR50, and ACR70 response rates versus placebo + MTX/DMARD-treated patients at Week 24. - In Studies 1 and 2, a greater proportion of patients treated with Sarilumab 200 mg or 150 mg every two weeks plus MTX/DMARD achieved a low level of disease activity as measured by a Disease Activity Score 28-C-Reactive Protein (DAS28-CRP) <2.6 compared with placebo + MTX/DMARD at the end of the studies (Table 4). In Study 1, the proportion of patients achieving DAS28-CRP <2.6 who had at least 3 or more active joints at the end of Week 24 was 33.1%, 37.8% and 20%, in the Sarilumab 200 mg + MTX/DMARD arm, Sarilumab 150 mg + MTX/DMARD arm, and placebo arm respectively. - The percent ACR20 response by visit in Study 1 is shown in Figure 1. A similar response curve was observed in Study 2. - The results of the components of the ACR response criteria at Week 12 for Studies 1 and 2 are shown in Table 5. - In Study 1, structural joint damage was assessed radiographically and expressed as the van der Heijde-modified Total Sharp Score (mTSS) and its components, the erosion score and joint space narrowing score. Radiographs of hands and feet were obtained at baseline, 24 weeks, and 52 weeks and scored independently by at least two well-trained readers who were blinded to treatment group and visit number. - Both doses of Sarilumab + MTX were superior to placebo + MTX in the change from baseline in mTSS over 52 weeks. Less progression of both erosion and joint space narrowing scores over 52 weeks was reported in the Sarilumab + MTX treatment groups compared to the placebo + MTX group. - Treatment with Sarilumab + MTX was associated with significantly less radiographic progression of structural damage as compared with placebo + MTX. At Week 52, 55.6% of patients receiving Sarilumab 200 mg + MTX and 47.8% of patients receiving Sarilumab 150 mg + MTX had no progression of structural damage (as defined by a change in the Total Sharp Score of zero or less) compared with 38.7% of patients receiving placebo. - In Studies 1 and 2, physical function and disability were assessed by the Health Assessment Questionnaire Disability Index (HAQ-DI). Patients receiving Sarilumab 200 mg every two weeks + MTX/DMARD and Sarilumab 150 mg every two weeks + MTX/DMARD demonstrated greater improvement from baseline in physical function compared to placebo + MTX/DMARD at Week 16 and Week 12 in Studies 1 and 2, respectively (Table 7). - General health status was assessed by the Short Form health survey (SF-36) in Studies 1 and 2. Patients receiving Sarilumab 200 mg every two weeks + MTX/DMARD demonstrated greater improvement from baseline compared to placebo + MTX/DMARD in the physical component summary (PCS) at Week 24, but there was no evidence of a difference between the treatment groups in the mental component summary (MCS) at Week 24. Patients receiving Sarilumab 200 mg + MTX/DMARD reported greater improvement relative to placebo in the domains of Physical Functioning, Role Physical, Bodily Pain, General Health Perception, Vitality, Social Functioning and Mental Health, but not in the Role Emotional domain. # How Supplied - Sarilumab injection is supplied as a colorless to pale yellow solution in a single-dose pre-filled syringes and single-dose pre-filled pens. ## Storage - Refrigerate at 36°F to 46°F (2°C to 8°C) in original carton to protect from light. Do not freeze. Do not shake. - If needed, patients/caregivers may store Sarilumab at room temperature up to 77°F (25°C) up to 14 days in the outer carton. Do not store above 77°F (25°C). After removal from the refrigerator, use Sarilumab within 14 days or discard. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Inform patients that Sarilumab may lower their resistance to infections. Instruct patients to contact their physician immediately when symptoms suggesting infection appear, to ensure rapid evaluation and appropriate treatment. - Inform patients that some patients, particularly those also taking NSAIDS, and/or steroids, have had tears (perforations) of the stomach or intestines. Inform patients that gastrointestinal perforations have been reported in Sarilumab-treated patients in clinical studies, primarily as a complication of diverticulitis. Instruct patients to contact their physician immediately when symptoms of severe, persistent abdominal pain appear to ensure rapid evaluation and appropriate treatment. - Assess patient suitability for home use for SC injection. Inform patients that some patients who have been treated with Sarilumab have developed serious allergic reactions. Advise patients to seek immediate medical attention if they experience any symptom of serious allergic reactions. - There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Sarilumab during pregnancy. Encourage participation in the registry. - Instruct patients and caregivers to read the Instructions for Use before the patient starts using Sarilumab, and each time the patient gets a refill as there may be new information they need to know. - Provide guidance to patients and caregivers on proper subcutaneous injection technique, including aseptic technique, and how to use the pre-filled syringe or pre-filled pen correctly. - The pre-filled syringe or pre-filled pen should be left at room temperature for 30 minutes or 60 minutes respectively prior to use. The syringe or pen should be used within 14 days after being taken out of the refrigerator. A puncture-resistant container should be used to dispose the used pre-filled syringes or pre-filled pens and should be kept out of the reach of children. Instruct patients or caregivers in the technique as well as proper pre-filled syringe or pre-filled pen disposal, and caution against reuse of these items. # Precautions with Alcohol Alcohol-Sarilumab interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names - Kevzara # Look-Alike Drug Names There is limited information regarding Sarilumab Look-Alike Drug Names in the drug label. # Drug Shortage Status Drug Shortage # Price	Sarilumab Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yashasvi Aryaputra[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 Sarilumab is a interleukin-6 (IL-6) receptor antagonist that is FDA approved for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to one or more disease-modifying antirheumatic drugs (DMARDs). There is a Black Box Warning for this drug as shown here. Common adverse reactions include neutropenia, increased ALT, injection site erythema, upper respiratory infections and urinary tract infections. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Sarilumab is indicated for treatment of adult patients with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response or intolerance to one or more disease-modifying antirheumatic drugs (DMARDs). - Sarilumab may be used as monotherapy or in combination with methotrexate (MTX) or other conventional DMARDs. - The recommended dosage of Sarilumab is 200 mg once every two weeks given as a subcutaneous injection. - Reduce dose to 150 mg once every two weeks for management of neutropenia, thrombocytopenia and elevated liver enzymes. - If a patient develops a serious infection, hold treatment with Sarilumab until the infection is controlled. - Modify dosage in case of neutropenia, thrombocytopenia or liver enzyme elevations (see TABLE 1). ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Sarilumab Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding Sarilumab 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 Sarilumab FDA-Labeled Indications and Dosage (Pediatric) in the drug label. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Sarilumab Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding Sarilumab Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label. # Contraindications - Sarilumab is contraindicated in patients with known hypersensitivity to Sarilumab or any of the inactive ingredients. # Warnings - Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in patients receiving immunosuppressive agents including Sarilumab for rheumatoid arthritis (RA). The most frequently observed serious infections with Sarilumab included pneumonia and cellulitis. Among opportunistic infections, tuberculosis, candidiasis, and pneumocystis were reported with Sarilumab. Some patients presented with disseminated rather than localized disease and were often taking concomitant immunosuppressants such as methotrexate or corticosteroids, which in addition to RA may predispose them to infections. While not reported in Sarilumab clinical studies, other serious infections (e.g., histoplasmosis, cryptococcus, aspergillosis) have been reported in patients receiving other immunosuppressive agents for the treatment of RA. - Avoid use of Sarilumab in patients with an active infection, including localized infections. Consider the risks and benefits of treatment prior to initiating Sarilumab in patients who have: - chronic or recurrent infection; - a history of serious or opportunistic infections; - underlying conditions, in addition to RA, that may predispose them to infection; - been exposed to tuberculosis; or - lived in or traveled to areas of endemic tuberculosis or endemic mycoses. - Closely monitor patients for the development of signs and symptoms of infection during treatment with Sarilumab, as signs and symptoms of acute inflammation may be lessened due to suppression of the acute phase reactants. - Hold treatment with Sarilumab if a patient develops a serious infection or an opportunistic infection. - Perform prompt and complete diagnostic testing appropriate for an immunocompromised patient who develops a new infection during treatment with Sarilumab; initiate appropriate antimicrobial therapy, and closely monitor the patient. Tuberculosis - Evaluate patients for tuberculosis (TB) risk factors and test for latent infection prior to initiating treatment with Sarilumab. Treat patients with latent TB with standard antimycobacterial therapy before initiating Sarilumab. Consider anti-TB therapy prior to initiation of Sarilumab in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent TB but having risk factors for TB infection. When considering anti-TB therapy, consultation with a physician with expertise in TB may be appropriate. - Closely monitor patients for the development of signs and symptoms of TB including patients who tested negative for latent TB infection prior to initiating therapy. Viral Reactivation - Viral reactivation has been reported with immunosuppressive biologic therapies. Cases of herpes zoster were observed in clinical studies with Sarilumab. The risk of Hepatitis B reactivation with Sarilumab is unknown since patients who were at risk for reactivation were excluded. Neutropenia - Treatment with Sarilumab was associated with a higher incidence of decrease in absolute neutrophil count (ANC), including neutropenia. - Assess neutrophil count prior to initiation of Sarilumab and monitor neutrophil count 4 to 8 weeks after start of therapy and every 3 months thereafter. - Based on the pharmacodynamics of the changes in ANC, use results obtained at the end of the dosing interval when considering dose modification. Thrombocytopenia - Treatment with Sarilumab was associated with a reduction in platelet counts in clinical studies. - Assess platelet count prior to initiation of Sarilumab and monitor platelets 4 to 8 weeks after start of therapy and every 3 months thereafter. Elevated Liver Enzymes - Treatment with Sarilumab was associated with a higher incidence of transaminase elevations. These elevations were transient and did not result in any clinically evident hepatic injury in clinical studies. Increased frequency and magnitude of these elevations were observed when potentially hepatotoxic drugs (e.g., MTX) were used in combination with Sarilumab. - Assess ALT/AST levels prior to initiation of Sarilumab and monitor ALT and AST levels 4 to 8 weeks after start of therapy and every 3 months thereafter. When clinically indicated, consider other liver function tests such as bilirubin. Lipid Abnormalities - Treatment with Sarilumab was associated with increases in lipid parameters such as LDL cholesterol, HDL cholesterol and/or triglycerides. - Assess lipid parameters approximately 4 to 8 weeks following initiation of treatment with Sarilumab, then at approximately 6 month intervals. - Manage patients according to clinical guidelines for the management of hyperlipidemia. - Gastrointestinal perforations have been reported in clinical studies, primarily as complications of diverticulitis. GI perforation risk may be increased with concurrent diverticulitis or concomitant use of NSAIDs or corticosteroids. Promptly evaluate patients presenting with new onset abdominal symptoms. - Treatment with immunosuppressants may result in an increased risk of malignancies. The impact of treatment with Sarilumab on the development of malignancies is not known but malignancies were reported in clinical studies. - Hypersensitivity reactions have been reported in association with Sarilumab. Hypersensitivity reactions that required treatment discontinuation were reported in 0.3% of patients in controlled RA trials. Injection site rash, rash, and urticaria were the most frequent hypersensitivity reactions. Advise patients to seek immediate medical attention if they experience any symptoms of a hypersensitivity reaction. If anaphylaxis or other hypersensitivity reaction occurs, stop administration of Sarilumab immediately. Do not administer Sarilumab to patients with known hypersensitivity to Sarilumab. - Treatment with Sarilumab is not recommended in patients with active hepatic disease or hepatic impairment, as treatment with Sarilumab was associated with transaminase elevations. - Avoid concurrent use of live vaccines during treatment with Sarilumab due to potentially increased risk of infections; clinical safety of live vaccines during Sarilumab treatment has not been established. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving Sarilumab. The interval between live vaccinations and initiation of Sarilumab therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents. # Adverse Reactions ## Clinical Trials Experience - Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. - All patients in the safety data described below had moderately to severely active rheumatoid arthritis. - The safety of Sarilumab in combination with conventional DMARDs was evaluated based on data from seven studies, of which two were placebo-controlled, consisting of 2887 patients (long-term safety population). Of these, 2170 patients received Sarilumab for at least 24 weeks, 1546 for at least 48 weeks, 1020 for at least 96 weeks, and 624 for at least 144 weeks. - The pre-rescue placebo-controlled population includes patients from the two Phase 3 efficacy studies (Studies 1 and 2) from weeks 0 to 16 for Study 1 and weeks 0 to 12 for Study 2, and was used to assess common adverse reactions and laboratory abnormalities prior to patients being permitted to switch from placebo to Sarilumab. In this population, 582 patients, 579 patients, and 579 patients received Sarilumab 200 mg, Sarilumab 150 mg, or placebo once every two weeks, respectively, in combination with conventional DMARDs. - The 52-week placebo-controlled population includes patients from one Phase 2 study of 12 week duration and two Phase 3 efficacy studies (one of 24 week duration and the other of 52 week duration). This placebo-controlled population includes all subjects from the double-blind, placebo-controlled periods from each study and was analyzed under their original randomization assignment. In this population, 661 patients, 660 patients, and 661 patients received Sarilumab 200 mg, Sarilumab 150 mg, or placebo once every two weeks, respectively, in combination with conventional DMARDs. - Most safety data are described for the pre-rescue population. For rarer events, the 52-week placebo-controlled population is used. - The most common serious adverse reactions were infections. - The most frequent adverse reactions (occurring in at least 3% of patients treated with Sarilumab in combination with DMARDs) observed with Sarilumab in the clinical studies were neutropenia, increased ALT, injection site erythema, upper respiratory infections, and urinary tract infections. - In the pre-rescue placebo-controlled population, premature discontinuation due to adverse reactions occurred in 8%, 6% and 3% of patients treated with Sarilumab 200 mg, Sarilumab 150 mg, and placebo, respectively. - The most common adverse reaction (greater than 1%) that resulted in discontinuation of therapy with Sarilumab was neutropenia. - The use of Sarilumab as monotherapy was assessed in 132 patients, of which 67 received Sarilumab 200 mg and 65 patients received Sarilumab 150 mg without concomitant DMARDs. The safety profile was generally consistent with that in the population receiving concomitant DMARDs. Overall Infections - In the pre-rescue placebo-controlled population, the rate of infections in the 200 mg and 150 mg Sarilumab + DMARD group was 110 and 105 events per 100 patient-years, respectively, compared to 81 events per 100 patient-years in the placebo + DMARD group. The most commonly reported infections (2% to 4% of patients) were upper respiratory tract infections, urinary tract infections, and nasopharyngitis. - In the 52-week placebo-controlled population, 0.8% of patients (5 patients) treated with Sarilumab 200 mg + DMARD, 0.6% (4 patients) treated with Sarilumab 150 mg + DMARD and 0.5% (3 patients) treated with placebo + DMARD had an event of herpes zoster. - The overall rate of infections with Sarilumab + DMARD in the long-term safety population was consistent with rates in the controlled periods of the studies. Serious Infections - In the pre-rescue population, the rate of serious infections in the 200 mg and 150 mg Sarilumab + DMARD group was 3.8 and 4.4 events per 100 patient-years, respectively, compared to 2.5 events per 100 patient-years in the placebo + DMARD group. In the 52-week placebo-controlled population, the rate of serious infections in the 200 mg and 150 mg Sarilumab + DMARD group was 4.3 and 3.0 events per 100 patient-years, respectively, compared to 3.1 events per 100 patient-years in the placebo + DMARD group. - In the long-term safety population, the overall rate of serious infections was consistent with rates in the controlled periods of the studies. The most frequently observed serious infections included pneumonia and cellulitis. Cases of opportunistic infection have been reported. Gastrointestinal Perforation - In the 52-week placebo-controlled population, one patient on Sarilumab therapy experienced a gastrointestinal (GI) perforation (0.11 events per 100 patient-years). - In the long-term safety population, the overall rate of GI perforation was consistent with rates in the controlled periods of the studies. Reports of GI perforation were primarily reported as complications of diverticulitis including lower GI perforation and abscess. Most patients who developed GI perforations were taking concomitant nonsteroidal anti-inflammatory medications (NSAIDs) or corticosteroids. The contribution of these concomitant medications relative to Sarilumab in the development of GI perforations is not known. Hypersensitivity Reactions - In the pre-rescue placebo-controlled population, the proportion of patients who discontinued treatment due to hypersensitivity reactions was higher among those treated with Sarilumab (0.3% in 200 mg, 0.2% in 150 mg) than placebo (0%). The rate of discontinuations due to hypersensitivity in the long-term safety population was consistent with the placebo-controlled period. Injection Site Reactions - In the pre-rescue placebo-controlled population, injection site reactions were reported in 7% of patients receiving Sarilumab 200 mg, 6% receiving Sarilumab 150 mg, and 1% receiving placebo. These injection site reactions (including erythema and pruritus) were mild in severity for the majority of patients and necessitated drug discontinuation in 2 (0.2%) patients receiving Sarilumab. Laboratory Abnormalities Decreased neutrophil count - In the pre-rescue placebo-controlled population, decreases in neutrophil counts less than 1000 per mm3 occurred in 6% and 4% of patients in the 200 mg Sarilumab + DMARD and 150 mg Sarilumab + DMARD group, respectively, compared to no patients in the placebo + DMARD groups. Decreases in neutrophil counts less than 500 per mm3 occurred in 0.7% of patients in both the 200 mg Sarilumab + DMARD and 150 mg Sarilumab + DMARD groups. Decrease in ANC was not associated with the occurrence of infections, including serious infections. - In the long-term safety population, the observations on neutrophil counts were consistent with what was seen in the placebo-controlled clinical studies. Decreased platelet count - In the pre-rescue placebo-controlled population, decreases in platelet counts less than 100,000 per mm3 occurred in 1% and 0.7% of patients on 200 mg and 150 mg Sarilumab + DMARD, respectively, compared to no patients on placebo + DMARD, without associated bleeding events. - In the long-term safety population, the observations on platelet counts were consistent with what was seen in the placebo-controlled clinical studies. Elevated liver enzymes - Liver enzyme elevations in the pre-rescue placebo-controlled population (Sarilumab + DMARD or placebo + DMARD) are summarized in Table 2. In patients experiencing liver enzyme elevation, modification of treatment regimen, such as interruption of Sarilumab or reduction in dose, resulted in decrease or normalization of liver enzymes. These elevations were not associated with clinically relevant increases in direct bilirubin, nor were they associated with clinical evidence of hepatitis or hepatic impairment. Lipid Abnormalities - Lipid parameters (LDL, HDL, and triglycerides) were first assessed at 4 weeks following initiation of Sarilumab + DMARDs in the placebo-controlled population. Increases were observed at this time point with no additional increases observed thereafter. Changes in lipid parameters from baseline to Week 4 are summarized below: - Mean LDL increased by 12 mg/dL in the Sarilumab 150 mg every two weeks + DMARD group and 16 mg/dL in the Sarilumab 200 mg every two weeks + DMARD group. - Mean triglycerides increased by 20 mg/dL in the Sarilumab 150 mg every two weeks + DMARD group and 27 mg/dL in the Sarilumab 200 mg every two weeks + DMARD group. - Mean HDL increased by 3 mg/dL in both the Sarilumab 150 mg every two weeks + DMARD and Sarilumab 200 mg every two weeks + DMARD groups. - In the long-term safety population, the observations in lipid parameters were consistent with what was observed in the placebo-controlled clinical studies. Malignancies - In the 52-week placebo-controlled population, 9 malignancies (exposure-adjusted event rate of 1.0 event per 100 patient-years) were diagnosed in patients receiving Sarilumab+ DMARD compared to 4 malignancies in patients in the control group (exposure-adjusted event rate of 1.0 event per 100 patient-years). - In the long-term safety population, the rate of malignancies was consistent with the rate observed in the placebo-controlled period. Other Adverse Reactions - Adverse reactions occurring in 2% or more of patients on Sarilumab + DMARD and greater than those observed in patients on placebo + DMARD are summarized in Table 3. - Medically relevant adverse reactions occurring at an incidence less than 2% in patients with rheumatoid arthritis treated with Sarilumab in controlled studies was oral herpes. - As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Sarilumab in the studies described below with the incidence of antibodies in other studies or to other products may be misleading. - In the pre-rescue population, 4.0% of patients treated with Sarilumab 200 mg + DMARD, 5.7% of patients treated with Sarilumab 150 mg + DMARD and 1.9% of patients treated with placebo + DMARD, exhibited an anti-drug antibody (ADA) response. Neutralizing antibodies (NAb) were detected in 1.0% of patients on Sarilumab 200 mg + DMARD, 1.6% of patients on Sarilumab 150 mg + DMARD, and 0.2% of patients on placebo + DMARD. - In patients treated with Sarilumab monotherapy, 9.2% of patients exhibited an ADA response with 6.9% of patients also exhibiting NAbs. Prior to administration of Sarilumab, 2.3% of patients exhibited an ADA response. - No correlation was observed between ADA development and either loss of efficacy or adverse reactions. ## Postmarketing Experience There is limited information regarding Sarilumab Postmarketing Experience in the drug label. # Drug Interactions - Use with Other Drugs for Treatment of Rheumatoid Arthritis - Interactions with CYP450 Substrates - Live Vaccines - Population pharmacokinetic analyses did not detect any effect of methotrexate (MTX) on Sarilumab clearance. Sarilumab has not been investigated in combination with JAK inhibitors or biological DMARDs such as TNF antagonists. - Various in vitro and limited in vivo human studies have shown that cytokines and cytokine modulators can influence the expression and activity of specific cytochrome P450 (CYP) enzymes and therefore have the potential to alter the pharmacokinetics of concomitantly administered drugs that are substrates of these enzymes. Elevated interleukin-6 (IL-6) concentration may down-regulate CYP activity such as in patients with RA and hence increase drug levels compared to subjects without RA. Blockade of IL-6 signaling by IL-6Rα antagonists such as Sarilumab might reverse the inhibitory effect of IL-6 and restore CYP activity, leading to altered drug concentrations. - The modulation of IL-6 effect on CYP enzymes by Sarilumab may be clinically relevant for CYP substrates with a narrow therapeutic index, where the dose is individually adjusted. Upon initiation or discontinuation of Sarilumab, in patients being treated with CYP substrate medicinal products, perform therapeutic monitoring of effect (e.g., warfarin) or drug concentration (e.g., theophylline) and adjust the individual dose of the medicinal product as needed. - Exercise caution when coadministering Sarilumab with CYP3A4 substrate drugs where decrease in effectiveness is undesirable, e.g., oral contraceptives, lovastatin, atorvastatin, etc. The effect of Sarilumab on CYP450 enzyme activity may persist for several weeks after stopping therapy. - Avoid concurrent use of live vaccines during treatment with Sarilumab. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): Pregnancy Exposure Registry - There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Sarilumab during pregnancy. Physicians are encouraged to register patients and pregnant women are encouraged to register themselves by calling 1-877-311-8972. Risk Summary - The limited human data with Sarilumab in pregnant women are not sufficient to inform drug-associated risk for major birth defects and miscarriage. Monoclonal antibodies, such as Sarilumab, are actively transported across the placenta during the third trimester of pregnancy and may affect immune response in the in utero exposed infant. From animal data, and consistent with the mechanism of action, levels of IgG, in response to antigen challenge, may be reduced in the fetus/infant of treated mothers. In an animal reproduction study, consisting of a combined embryo-fetal and pre- and postnatal development study with monkeys that received intravenous administration of Sarilumab, there was no evidence of embryotoxicity or fetal malformations with exposures up to approximately 84 times the maximum recommended human dose (MRHD). The literature suggests that inhibition of IL-6 signaling may interfere with cervical ripening and dilatation and myometrial contractile activity leading to potential delays of parturition. - The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Sarilumab should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus. Clinical Considerations (Fetal/Neonatal Adverse Reactions) - Monoclonal antibodies are increasingly transported across the placenta as pregnancy progresses, with the largest amount transferred during the third trimester. Risks and benefits should be considered prior to administering live or live-attenuated vaccines to infants exposed to Sarilumab in utero. From the animal data, and consistent with the mechanism of action, levels of IgG, in response to antigen challenge, may be reduced in the fetus/infant of treated mothers. Data (Animal) - In a combined embryo-fetal and pre- and postnatal development study, pregnant cynomolgus monkeys received Sarilumab at intravenous doses of 0, 5, 15, or 50 mg/kg/week from confirmation of pregnancy at gestation day (GD) 20, throughout the period of organogenesis (up to approximately GD 50), and continuing to natural birth of infants at around GD 165. Maintenance of pregnancy was not affected at any doses. Sarilumab was not embryotoxic or teratogenic with exposures up to approximately 84 times the MRHD (based on AUC with maternal intravenous doses up to 50 mg/kg/week). Sarilumab had no effect on neonatal growth and development evaluated up to one month after birth. Sarilumab was detected in the serum of neonates up to one month after birth, suggesting that the antibody had crossed the placenta. - Following antigen challenge, decreased IgG titers attributed to the immunosuppressive action of Sarilumab were evident in studies with older monkeys, with exposures up to approximately 80 times the MRHD (based on AUC with intravenous doses up to 50 mg/kg/week) and juvenile mice treated with an analogous antibody, which binds to murine IL-6Rα to inhibit IL-6 mediated signaling, at subcutaneous doses up to 200 mg/kg/week. These findings suggest the potential for decreased IgG titers, following antigen challenge, in infants of mothers treated with Sarilumab. - Parturition is associated with significant increases of IL-6 in the cervix and myometrium. The literature suggests that inhibition of IL-6 signaling may interfere with cervical ripening and dilatation and myometrial contractile activity leading to potential delays of parturition. For mice deficient in IL-6 (ll6-/- null mice), parturition was delayed relative to wild-type (ll6+/+) mice. Administration of recombinant IL-6 to ll6-/- null mice restored the normal timing of delivery. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Sarilumab in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Sarilumab during labor and delivery. ### Nursing Mothers Risk Summary - No information is available on the presence of Sarilumab in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. Maternal IgG is present in human milk. If Sarilumab is transferred into human milk, the effects of local exposure in the gastrointestinal tract and potential limited systemic exposure in the infant to Sarilumab are unknown. The lack of clinical data during lactation precludes clear determination of the risk of Sarilumab to an infant during lactation; therefore, the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Sarilumab and the potential adverse effects on the breastfed child from Sarilumab or from the underlying maternal condition. ### Pediatric Use - Safety and efficacy of Sarilumab in pediatric patients have not been established. ### Geriatic Use - Of the total number of patients in clinical studies of Sarilumab, 15% were 65 years of age and over, while 1.6% were 75 years and over. In clinical studies, no overall differences in safety and efficacy were observed between older and younger patients. The frequency of serious infection among Sarilumab and placebo-treated patients 65 years of age and older was higher than those under the age of 65. As there is a higher incidence of infections in the elderly population in general, caution should be used when treating the elderly. ### Gender There is no FDA guidance on the use of Sarilumab with respect to specific gender populations. ### Race There is no FDA guidance on the use of Sarilumab with respect to specific racial populations. ### Renal Impairment - No dose adjustment is required in patients with mild to moderate renal impairment. Sarilumab has not been studied in patients with severe renal impairment. ### Hepatic Impairment - The safety and efficacy of Sarilumab have not been studied in patients with hepatic impairment, including patients with positive HBV or HCV serology. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Sarilumab in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Sarilumab in patients who are immunocompromised. # Administration and Monitoring ### Administration - Allow to sit at room temperature for 30 minutes prior to administration or 60 minutes if using a pre-filled pen; do not warm any other way. - Rotate injection sites; do not inject where skin is tender, damaged, bruised, or scarred. - Inject full amount of pre-filled syringe or pen. - Missed dose: If 3 days or less since missed dose, take as soon as possible; take next dose at regularly scheduled time. ### Monitoring - Improvement in the signs or symptoms of rheumatoid arthritis may indicate efficacy. - Neutrophils and platelets: 4 to 8 weeks after treatment initiation and approximately every 3 months thereafter. - ALT and AST levels: 4 to 8 weeks after treatment initiation and approximately every 3 months thereafter; other liver function tests if clinically indicated. - Lipid parameters: Approximately 4 to 8 weeks after treatment initiation, and at 6 month intervals thereafter. - Latent TB: Prior to initiation. - Active TB: Monitor all patients for active TB during treatment, even if initial latent TB test was negative. - Signs and symptoms of infection: During and after therapy. # IV Compatibility There is limited information regarding the compatibility of Sarilumab and IV administrations. # Overdosage There is limited information regarding Sarilumab overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately. # Pharmacology ## Mechanism of Action - Sarilumab binds to both soluble and membrane-bound IL-6 receptors (sIL-6R and mIL-6R), and has been shown to inhibit IL-6-mediated signaling through these receptors. IL-6 is a pleiotropic pro-inflammatory cytokine produced by a variety of cell types including T- and B-cells, lymphocytes, monocytes, and fibroblasts. IL-6 has been shown to be involved in diverse physiological processes such as T-cell activation, induction of immunoglobulin secretion, initiation of hepatic acute phase protein synthesis, and stimulation of hematopoietic precursor cell proliferation and differentiation. IL-6 is also produced by synovial and endothelial cells leading to local production of IL-6 in joints affected by inflammatory processes such as rheumatoid arthritis. ## Structure There is limited information regarding Sarilumab Structure in the drug label. ## Pharmacodynamics - Following single-dose subcutaneous administration of Sarilumab 200-mg and 150-mg in patients with RA, rapid reduction of CRP levels was observed. Levels were reduced to normal within 2 weeks after treatment initiation. Following single-dose Sarilumab administration, in patients with RA, absolute neutrophil counts decreased to the nadir between 3 to 4 days and thereafter recovered towards baseline. Treatment with Sarilumab resulted in decreases in fibrinogen and serum amyloid A, and increases in hemoglobin and serum albumin. ## Pharmacokinetics Absorption - The pharmacokinetics of Sarilumab were characterized in 1770 patients with rheumatoid arthritis (RA) treated with Sarilumab which included 631 patients treated with 150 mg and 682 patients treated with 200 mg doses by subcutaneous injection every two weeks for up to 52 weeks. The median tmax was observed in 2 to 4 days. - At steady state, exposure over the dosing interval measured by area under curve (AUC) increased 2-fold with an increase in dose from 150 to 200 mg every two weeks. Steady state was reached in 14 to 16 weeks with a 2- to 3-fold accumulation compared to single dose exposure. - For the 150 mg every two weeks dose regimen, the estimated mean (± SD) steady-state AUC, Cmin and Cmax of Sarilumab were 202 ± 120 mg.day/L, 6.35 ± 7.54 mg/L, and 20.0 ± 9.20 mg/L, respectively. - For the 200 mg every two weeks dose regimen, the estimated mean (± SD) steady-state AUC, Cmin and Cmax of Sarilumab were 395 ± 207 mg.day/L, 16.5 ± 14.1 mg/L, and 35.6 ± 15.2 mg/L, respectively. Distribution - In patients with RA, the apparent volume of distribution at steady state was 7.3 L. Elimination - Sarilumab is eliminated by parallel linear and non-linear pathways. At higher concentrations, the elimination is predominantly through the linear, non-saturable proteolytic pathway, while at lower concentrations, non-linear saturable target-mediated elimination predominates. The half-life of Sarilumab is concentration-dependent. At 200 mg every 2 weeks, the concentration-dependent half-life is up to 10 days in patients with RA at steady state. At 150 mg every 2 weeks, the concentration-dependent half-life is up to 8 days in patients with RA at steady state. - After the last steady state dose of 150 mg and 200 mg Sarilumab, the median times to non-detectable concentration are 28 and 43 days, respectively. - Population pharmacokinetic analyses in patients with RA revealed that there was a trend toward higher apparent clearance of Sarilumab in the presence of anti-Sarilumab antibodies. Metabolism - The metabolic pathway of Sarilumab has not been characterized. As a monoclonal antibody Sarilumab is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG. Excretion - Monoclonal antibodies, including Sarilumab, are not eliminated via renal or hepatic pathways. Specific Populations - Population pharmacokinetic analyses in adult patients with rheumatoid arthritis showed that age, gender and race did not meaningfully influence the pharmacokinetics of Sarilumab. Although body weight influenced the pharmacokinetics of Sarilumab, no dose adjustments are recommended for any of these demographics. Hepatic impairment - No formal study of the effect of hepatic impairment on the pharmacokinetics of Sarilumab was conducted. Renal impairment - No formal study of the effect of renal impairment on the pharmacokinetics of Sarilumab was conducted. Based on population pharmacokinetic analysis of data from 1770 patients with RA, including patients with mild (creatinine clearance (CLcr): 60 to 90 mL/min; N=471 at baseline) or moderate (CLcr: 30 to 60 mL/min; N=74 at baseline) renal impairment, CLcr was correlated with Sarilumab exposure. However, the effect of CLcr on exposure is not sufficient to warrant a dose adjustment. Patients with severe renal impairment were not studied. Drug-Drug Interactions CYP450 substrates - Simvastatin is a CYP3A4 and OATP1B1 substrate. In 17 patients with RA, one week following a single 200-mg subcutaneous administration of Sarilumab, exposure of simvastatin and simvastatin acid decreased by 45% and 36%, respectively. ## Nonclinical Toxicology - No long-term animal studies have been performed to establish the carcinogenicity potential of Sarilumab. Literature indicates that the IL-6 pathway can mediate anti-tumor responses by promoting increased immune cell surveillance of the tumor microenvironment. However, available published evidence also supports that IL-6 signaling through the IL-6 receptor may be involved in pathways that lead to tumorigenesis. The malignancy risk in humans from an antibody that disrupts signaling through the IL-6 receptor, such as Sarilumab, is presently unknown. - Fertility and reproductive performance were unaffected in male and female mice treated with an analogous antibody, which binds to murine IL-6Rα to inhibit IL-6 mediated signaling, at subcutaneous doses of 10, 25, and 100 mg/kg twice per week. # Clinical Studies - The efficacy and safety of Sarilumab were assessed in two randomized, double-blind, placebo-controlled multicenter studies (Study 1 and Study 2) in patients older than 18 years with moderately to severely active rheumatoid arthritis (RA) diagnosed according to American College of Rheumatology (ACR) criteria. Patients had at least 8 tender and 6 swollen joints at baseline. - Study 1 evaluated 1197 patients with moderately to severely active rheumatoid arthritis who had inadequate clinical response to methotrexate (MTX). Patients received subcutaneous Sarilumab 200 mg, Sarilumab 150 mg, or placebo every two weeks with concomitant MTX. After Week 16 in Study 1, patients with an inadequate response could have been rescued with Sarilumab 200 mg every two weeks. - Study 2 evaluated 546 patients with moderately to severely active rheumatoid arthritis who had an inadequate clinical response or were intolerant to one or more TNF-α antagonists. Patients received subcutaneous Sarilumab 200 mg, Sarilumab 150 mg, or placebo every two weeks with concomitant conventional DMARDs (MTX, sulfasalazine, leflunomide, and/or hydroxychloroquine). After Week 12 in Study 2, patients with an inadequate response could have been rescued with Sarilumab 200 mg every two weeks. - In Studies 1 and 2, the primary endpoint was the proportion of patients who achieved an ACR20 response at Week 24. Other key endpoints evaluated included change from baseline in HAQ-DI at Week 16 in Study 1 and at Week 12 in Study 2, and change from baseline in van der Heijde-modified Total Sharp Score (mTSS) at Week 52 in Study 1. - The percentages of Sarilumab every two weeks + MTX/DMARD-treated patients achieving ACR20, ACR50 and ACR70 responses in Studies 1 and 2 are shown Table 4. In both studies, patients treated with either 200 mg or 150 mg of Sarilumab every two weeks + MTX/DMARD had higher ACR20, ACR50, and ACR70 response rates versus placebo + MTX/DMARD-treated patients at Week 24. - In Studies 1 and 2, a greater proportion of patients treated with Sarilumab 200 mg or 150 mg every two weeks plus MTX/DMARD achieved a low level of disease activity as measured by a Disease Activity Score 28-C-Reactive Protein (DAS28-CRP) <2.6 compared with placebo + MTX/DMARD at the end of the studies (Table 4). In Study 1, the proportion of patients achieving DAS28-CRP <2.6 who had at least 3 or more active joints at the end of Week 24 was 33.1%, 37.8% and 20%, in the Sarilumab 200 mg + MTX/DMARD arm, Sarilumab 150 mg + MTX/DMARD arm, and placebo arm respectively. - The percent ACR20 response by visit in Study 1 is shown in Figure 1. A similar response curve was observed in Study 2. - The results of the components of the ACR response criteria at Week 12 for Studies 1 and 2 are shown in Table 5. - In Study 1, structural joint damage was assessed radiographically and expressed as the van der Heijde-modified Total Sharp Score (mTSS) and its components, the erosion score and joint space narrowing score. Radiographs of hands and feet were obtained at baseline, 24 weeks, and 52 weeks and scored independently by at least two well-trained readers who were blinded to treatment group and visit number. - Both doses of Sarilumab + MTX were superior to placebo + MTX in the change from baseline in mTSS over 52 weeks. Less progression of both erosion and joint space narrowing scores over 52 weeks was reported in the Sarilumab + MTX treatment groups compared to the placebo + MTX group. - Treatment with Sarilumab + MTX was associated with significantly less radiographic progression of structural damage as compared with placebo + MTX. At Week 52, 55.6% of patients receiving Sarilumab 200 mg + MTX and 47.8% of patients receiving Sarilumab 150 mg + MTX had no progression of structural damage (as defined by a change in the Total Sharp Score of zero or less) compared with 38.7% of patients receiving placebo. - In Studies 1 and 2, physical function and disability were assessed by the Health Assessment Questionnaire Disability Index (HAQ-DI). Patients receiving Sarilumab 200 mg every two weeks + MTX/DMARD and Sarilumab 150 mg every two weeks + MTX/DMARD demonstrated greater improvement from baseline in physical function compared to placebo + MTX/DMARD at Week 16 and Week 12 in Studies 1 and 2, respectively (Table 7). - General health status was assessed by the Short Form health survey (SF-36) in Studies 1 and 2. Patients receiving Sarilumab 200 mg every two weeks + MTX/DMARD demonstrated greater improvement from baseline compared to placebo + MTX/DMARD in the physical component summary (PCS) at Week 24, but there was no evidence of a difference between the treatment groups in the mental component summary (MCS) at Week 24. Patients receiving Sarilumab 200 mg + MTX/DMARD reported greater improvement relative to placebo in the domains of Physical Functioning, Role Physical, Bodily Pain, General Health Perception, Vitality, Social Functioning and Mental Health, but not in the Role Emotional domain. # How Supplied - Sarilumab injection is supplied as a colorless to pale yellow solution in a single-dose pre-filled syringes and single-dose pre-filled pens. ## Storage - Refrigerate at 36°F to 46°F (2°C to 8°C) in original carton to protect from light. Do not freeze. Do not shake. - If needed, patients/caregivers may store Sarilumab at room temperature up to 77°F (25°C) up to 14 days in the outer carton. Do not store above 77°F (25°C). After removal from the refrigerator, use Sarilumab within 14 days or discard. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Inform patients that Sarilumab may lower their resistance to infections. Instruct patients to contact their physician immediately when symptoms suggesting infection appear, to ensure rapid evaluation and appropriate treatment. - Inform patients that some patients, particularly those also taking NSAIDS, and/or steroids, have had tears (perforations) of the stomach or intestines. Inform patients that gastrointestinal perforations have been reported in Sarilumab-treated patients in clinical studies, primarily as a complication of diverticulitis. Instruct patients to contact their physician immediately when symptoms of severe, persistent abdominal pain appear to ensure rapid evaluation and appropriate treatment. - Assess patient suitability for home use for SC injection. Inform patients that some patients who have been treated with Sarilumab have developed serious allergic reactions. Advise patients to seek immediate medical attention if they experience any symptom of serious allergic reactions. - There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Sarilumab during pregnancy. Encourage participation in the registry. - Instruct patients and caregivers to read the Instructions for Use before the patient starts using Sarilumab, and each time the patient gets a refill as there may be new information they need to know. - Provide guidance to patients and caregivers on proper subcutaneous injection technique, including aseptic technique, and how to use the pre-filled syringe or pre-filled pen correctly. - The pre-filled syringe or pre-filled pen should be left at room temperature for 30 minutes or 60 minutes respectively prior to use. The syringe or pen should be used within 14 days after being taken out of the refrigerator. A puncture-resistant container should be used to dispose the used pre-filled syringes or pre-filled pens and should be kept out of the reach of children. Instruct patients or caregivers in the technique as well as proper pre-filled syringe or pre-filled pen disposal, and caution against reuse of these items. # Precautions with Alcohol Alcohol-Sarilumab interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names - Kevzara # Look-Alike Drug Names There is limited information regarding Sarilumab Look-Alike Drug Names in the drug label. # Drug Shortage Status Drug Shortage # Price	https://www.wikidoc.org/index.php/Sarilumab
19cd204aa75a4c91be0ddb2b40f4d4d056c93f1b	wikidoc	Sassafras	Sassafras Sassafras is a genus of three species of deciduous trees in the family Lauraceae, native to eastern North America and eastern Asia. Sassafras trees grow from 15-35 m (50-120 feet) tall and 70-150 cm (2.5-6 feet) in diameter, with many slender branches, and smooth, orange-brown bark. The branching is sympodial. The bark of the mature trunk is thick, red-brown, and deeply furrowed. The wood is light, soft, weak, and brittle. All parts of the plants are very fragrant. The species are unusual in having three distinct leaf patterns on the same plant, unlobed oval, bilobed (mitten-shaped), and trilobed (three pronged; rarely the leaves can be five-lobed). They have smooth margins and grow 7-20 cm long by 5-10 cm broad. The young leaves and twigs are quite mucilaginous, and produce a scent similar to lemons when crushed. The tiny, yellow flowers are five-petaled and bloom in the spring; they are dioecious, with male and female flowers on separate trees. The fruit are blue-black, egg-shaped, 1 cm long, produced on long, red-stalked cups, and mature in late summer. The name "Sassafras", applied by the botanist Nicolas Monardes in the sixteenth century, is said to be a corruption of the Spanish word for saxifrage. # Species - Sassafras albidum (Nuttall) Nees - Sassafras, White Sassafras, Red Sassafras or Silky Sassafras. Eastern North America, from southernmost Ontario, Canada through the eastern United States south to central Florida, and west to southern Iowa and eastern Texas. - Sassafras tzumu (Hemsl.) Hemsl. - Chinese Sassafras or Tzumu. Central and southwestern China. It differs from S. albidum in the leaves being more frequently three-lobed, the lobes having a tapered acuminate apex (not rounded to weakly acute). - Sassafras randaiense (Hayata) Rehd. - Taiwan Sassafras. Taiwan. Treated by some botanists in a distinct genus as Yushunia randaiensis (Hayata) Kamikoti, though this is not supported by recent genetic evidence which shows the genus to be monophyletic. # Uses Essential oil distilled from the root-bark or the fruit was used as a fragrance in perfumes and soaps, food (sassafras tea and candy flavoring) and for aromatherapy. The dried and ground leaves are used to make filé powder, a spice used in the making of some types of gumbo.	Sassafras Template:Otheruses4 Sassafras is a genus of three species of deciduous trees in the family Lauraceae, native to eastern North America and eastern Asia.[1] Sassafras trees grow from 15-35 m (50-120 feet) tall and 70-150 cm (2.5-6 feet) in diameter, with many slender branches, and smooth, orange-brown bark. The branching is sympodial. The bark of the mature trunk is thick, red-brown, and deeply furrowed. The wood is light, soft, weak, and brittle. All parts of the plants are very fragrant. The species are unusual in having three distinct leaf patterns on the same plant, unlobed oval, bilobed (mitten-shaped), and trilobed (three pronged; rarely the leaves can be five-lobed[2]). They have smooth margins and grow 7-20 cm long by 5-10 cm broad. The young leaves and twigs are quite mucilaginous, and produce a scent similar to lemons when crushed. The tiny, yellow flowers are five-petaled and bloom in the spring; they are dioecious, with male and female flowers on separate trees. The fruit are blue-black, egg-shaped, 1 cm long, produced on long, red-stalked cups, and mature in late summer.[3] The name "Sassafras", applied by the botanist Nicolas Monardes in the sixteenth century, is said to be a corruption of the Spanish word for saxifrage. # Species - Sassafras albidum (Nuttall) Nees - Sassafras, White Sassafras, Red Sassafras or Silky Sassafras. Eastern North America, from southernmost Ontario, Canada through the eastern United States south to central Florida, and west to southern Iowa and eastern Texas. - Sassafras tzumu (Hemsl.) Hemsl. - Chinese Sassafras or Tzumu. Central and southwestern China. It differs from S. albidum in the leaves being more frequently three-lobed,[4] the lobes having a tapered acuminate apex (not rounded to weakly acute). - Sassafras randaiense (Hayata) Rehd. - Taiwan Sassafras. Taiwan. Treated by some botanists in a distinct genus as Yushunia randaiensis (Hayata) Kamikoti,[5] though this is not supported by recent genetic evidence which shows the genus to be monophyletic.[1] # Uses Essential oil distilled from the root-bark or the fruit was used as a fragrance in perfumes and soaps, food (sassafras tea and candy flavoring) and for aromatherapy. The dried and ground leaves are used to make filé powder, a spice used in the making of some types of gumbo.	https://www.wikidoc.org/index.php/Sassafras
fd674489af1753acad95608fbc04ab2bc6e26619	wikidoc	Saussurea	Saussurea Saussurea is a genus of about 300 species of flowering plants in the family Asteraceae, native to cool temperate and arctic regions of Asia, Europe, and North America, with the highest diversity in alpine habitats in the Himalaya and central Asia. Common names include saw-wort and snow lotus, the latter used for a number of high altitude species in central Asia. They are perennial herbaceous plants, ranging in height from dwarf alpine species 5-10 cm tall, to tall thistle-like plants up to 3 m tall. The leaves are produced in a dense basal rosette, and then spirally up the flowering stem. The flowers form in a dense head of small capitula, often completely surrounded in dense white to purple woolly hairs; the individual florets are also white to purple. The wool is densest in the high altitude species, and aid in thermoregulation of the flowers, minimising frost damage at night, and also preventing ultraviolet light damage from the intense high altitude sunlight. De Candolle named the genus after Nicolas-Théodore de Saussure (1767-1845). ## Uses A number of the high alpine Himalayan species are grown as ornamental plants for their decorative dense woolly flowerheads; they are among the most challenging plants to grow, being adapted to harsh climates from 3500-5000 m altitude, demanding cool temperatures, a very long (up to 8-10 months) winter rest period, and very good soil drainage in humus-rich gravel soils. Costi amari radix or costus root was an important item of Roman trade with India, and is believed to have been the dried root of Saussurea lappa. Saussurea lappa is used as an anti-inflammatory drug, and a component of the traditional Tibetan medicine Padma 28, and has been shown to inhibit the mRNA expression of iNOS by lipopolysaccharide stimulated macrophages, thus reducing nitric oxide production. In rats, 50-200 milligrams per kilogram of crude ethanolic extract reduced observed inflammation in standard laboratory tests, and 25-100 milligrams per kilogram of the sesquiterpene fraction of the extract reduced several molecular markers of inflammation. Saussurea involucrata flowers and stems have long been used in traditional Chinese medicine for the treatment of rheumatoid arthritis, cough with cold, stomachache, dysmenorrhea, and altitude sickness, and has been found to have antiinflammatory, cardiotonic, abortifacient, anticancer, and antifatigue actions. Ethanol extracts were shown to have analgesic and antiinflammatory effects at doses of 75-300 milligrams per kilogram. As the slow-growing wild plant is endangered by collections, a substitute grown in tissue culture has been suggested, which is mostly equivalent. Generally the analgesic and antiinflammatory effects of the plant are much inferior to those of 10 milligrams of indomethacin. - Saussurea abnormis. Himalaya. - Saussurea acrophila. China. - Saussurea albescens. Western Himalaya. - Saussurea alpina. Common Saw-wort. Northern and central Europe, northwest Asia. - Saussurea amara. China, Russia. - Saussurea americana. American Saw-wort. Western North America. - Saussurea amurensis. China. - Saussurea angustifolia. Narrowleaf Saw-wort. Arctic northeast Asia, Alaska, Canada. - Saussurea auriculata. Himalaya, western China. - Saussurea bhutkesh. Himalaya. - Saussurea bodinieri. China. - Saussurea bullockii. China. - Saussurea cana. China. - Saussurea candolleana. Himalaya. - Saussurea ceratocarpa. Kashmir. - Saussurea chinnampoensis. China. - Saussurea chrysotricha. Himalaya. - Saussurea controversa. Russia. - Saussurea cordifolia. China. - Saussurea costus. Eastern Himalaya. - Saussurea crispa. Himalaya. - Saussurea deltoidea. Himalaya, China, Taiwan. - Saussurea densa. Clustered Saw-wort. Arctic northeast Asia, Canada, Montana. - Saussurea dhwojii. Himalaya. - Saussurea discolor. Alpine central Europe. - Saussurea dolichopoda. China. - Saussurea donkiah. Himalaya. - Saussurea dutaillyana. China. - Saussurea dzeurensis. China. - Saussurea elegans. Caucasus. - Saussurea epilobioides. China. - Saussurea fastuosa. Himalaya, western China. - Saussurea formosana. Taiwan. - Saussurea forrestii. Himalaya. - Saussurea frondosa. China. - Saussurea glandulosa. Taiwan. - Saussurea globosa. China. - Saussurea gnaphalodes. Himalaya, western China. - Saussurea gossypiphora. Himalaya. - Saussurea graminea. China. - Saussurea graminifolia. Himalaya. - Saussurea grandiflora. China. - Saussurea heteromalla. Himalaya. - Saussurea hieracioides. Himalaya, western China. - Saussurea hookeri. Himalaya. - Saussurea involucrata. Snow Lotus, Himalaya, China. - Saussurea iodostegia. China. - Saussurea japonica. Japan, Korea, northern China. - Saussurea kanaii. Himalaya. - Saussurea kanzanensis. Taiwan. - Saussurea kingii. China. - Saussurea kiraisanensis. Taiwan. - Saussurea laminamaensis. Himalaya. - Saussurea laniceps. China. - Saussurea lanuginosa. China. - Saussurea lappa. Himalaya. - Saussurea leontodontoides. Himalaya. - Saussurea licentiana. China. - Saussurea likiangensis. Southwest China. - Saussurea linearifolia. Himalaya. - Saussurea longifolia. China. - Saussurea manshurica. Northern China. - Saussurea medusa. China. - Saussurea mongolica. Western China, Mongolia. - Saussurea namikawae. Himalaya. - Saussurea neofranchetii. China. - Saussurea nepalensis. Himalaya. - Saussurea nigrescens. China. - Saussurea nishiokae. Himalaya. - Saussurea nivea. China. - Saussurea nuda. Nutty Saw-wort. Alaska. - Saussurea obvallata. Brahma Kamal. Himalaya, northern Burma and south-west China. - Saussurea oligantha. China. - Saussurea otophylla. China. - Saussurea pachyneura. Himalaya. - Saussurea parviflora. Russia, China. - Saussurea pectinata. China. - Saussurea peguensis. China. - Saussurea phaeantha. China. - Saussurea pinetorum. China. - Saussurea piptathera. Himalaya. - Saussurea platyphyllaria. Himalaya. - Saussurea polycephala. China. - Saussurea polystichoides. Himalaya. - Saussurea populifolia. China. - Saussurea porcii. Carpathians. - Saussurea pulchella. Japan, Korea, northern China, eastern Siberia. - Saussurea pygmaea. Alps, Carpathians. - Saussurea quercifolia. China. - Saussurea romuleifolia. China. - Saussurea roylei. Himalaya. - Saussurea runcinata. China. - Saussurea salsa. Russia, China. - Saussurea simpsoniana. Himalaya. - Saussurea sobarocephala. China. - Saussurea spicata. Himalaya. - Saussurea stafleuana. Himalaya. - Saussurea stella. China. - Saussurea stracheyana. Himalaya. - Saussurea sughoo. Himalaya. - Saussurea taraxacifolia. Himalaya. - Saussurea tangutica. Western Asia. - Saussurea topkegolensis. Himalaya. - Saussurea tridactyla. Himalaya. - Saussurea turgaiensis. Russia. - Saussurea uniflora. Himalaya. - Saussurea ussuriensis. China, eastern Russia. - Saussurea veitchiana. Central China. - Saussurea velutina. China. - Saussurea viscida. Sticky Saw-wort. Alaska. - Saussurea weberi. Weber's Saw-wort. Rocky Mountains. - Saussurea werneroides. Himalaya. - Saussurea yakla. Himalaya. # References and external links - ↑ PMID 11100933 - ↑ PMID 12916066 - ↑ PMID 12222664 - ↑ PMID 16141525 - Chinese plant names: Saussurea - Checklist of the plants of Nepal: Saussurea - Jintu: Snow Lotus - Law W, Salick J (2005). "Human-induced dwarfing of Himalayan snow lotus, Saussurea laniceps (Asteraceae)". Proceedings of the National Academy of Sciences. 109 (29): 10218–10220. PMID 16006524. Unknown parameter \|quotes= 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} de:Alpenscharten	Saussurea Saussurea is a genus of about 300 species of flowering plants in the family Asteraceae, native to cool temperate and arctic regions of Asia, Europe, and North America, with the highest diversity in alpine habitats in the Himalaya and central Asia. Common names include saw-wort and snow lotus, the latter used for a number of high altitude species in central Asia. They are perennial herbaceous plants, ranging in height from dwarf alpine species 5-10 cm tall, to tall thistle-like plants up to 3 m tall. The leaves are produced in a dense basal rosette, and then spirally up the flowering stem. The flowers form in a dense head of small capitula, often completely surrounded in dense white to purple woolly hairs; the individual florets are also white to purple. The wool is densest in the high altitude species, and aid in thermoregulation of the flowers, minimising frost damage at night, and also preventing ultraviolet light damage from the intense high altitude sunlight. De Candolle named the genus after Nicolas-Théodore de Saussure (1767-1845). ## Uses A number of the high alpine Himalayan species are grown as ornamental plants for their decorative dense woolly flowerheads; they are among the most challenging plants to grow, being adapted to harsh climates from 3500-5000 m altitude, demanding cool temperatures, a very long (up to 8-10 months) winter rest period, and very good soil drainage in humus-rich gravel soils. Costi amari radix or costus root was an important item of Roman trade with India, and is believed to have been the dried root of Saussurea lappa.[1] Saussurea lappa is used as an anti-inflammatory drug, and a component of the traditional Tibetan medicine Padma 28, and has been shown to inhibit the mRNA expression of iNOS by lipopolysaccharide stimulated macrophages, thus reducing nitric oxide production. In rats, 50-200 milligrams per kilogram of crude ethanolic extract reduced observed inflammation in standard laboratory tests, and 25-100 milligrams per kilogram of the sesquiterpene fraction of the extract reduced several molecular markers of inflammation.[2][3] Saussurea involucrata flowers and stems have long been used in traditional Chinese medicine for the treatment of rheumatoid arthritis, cough with cold, stomachache, dysmenorrhea, and altitude sickness, and has been found to have antiinflammatory, cardiotonic, abortifacient, anticancer, and antifatigue actions.[4] Ethanol extracts were shown to have analgesic and antiinflammatory effects at doses of 75-300 milligrams per kilogram. As the slow-growing wild plant is endangered by collections, a substitute grown in tissue culture has been suggested, which is mostly equivalent. Generally the analgesic and antiinflammatory effects of the plant are much inferior to those of 10 milligrams of indomethacin. - Saussurea abnormis. Himalaya. - Saussurea acrophila. China. - Saussurea albescens. Western Himalaya. - Saussurea alpina. Common Saw-wort. Northern and central Europe, northwest Asia. - Saussurea amara. China, Russia. - Saussurea americana. American Saw-wort. Western North America. - Saussurea amurensis. China. - Saussurea angustifolia. Narrowleaf Saw-wort. Arctic northeast Asia, Alaska, Canada. - Saussurea auriculata. Himalaya, western China. - Saussurea bhutkesh. Himalaya. - Saussurea bodinieri. China. - Saussurea bullockii. China. - Saussurea cana. China. - Saussurea candolleana. Himalaya. - Saussurea ceratocarpa. Kashmir. - Saussurea chinnampoensis. China. - Saussurea chrysotricha. Himalaya. - Saussurea controversa. Russia. - Saussurea cordifolia. China. - Saussurea costus. Eastern Himalaya. - Saussurea crispa. Himalaya. - Saussurea deltoidea. Himalaya, China, Taiwan. - Saussurea densa. Clustered Saw-wort. Arctic northeast Asia, Canada, Montana. - Saussurea dhwojii. Himalaya. - Saussurea discolor. Alpine central Europe. - Saussurea dolichopoda. China. - Saussurea donkiah. Himalaya. - Saussurea dutaillyana. China. - Saussurea dzeurensis. China. - Saussurea elegans. Caucasus. - Saussurea epilobioides. China. - Saussurea fastuosa. Himalaya, western China. - Saussurea formosana. Taiwan. - Saussurea forrestii. Himalaya. - Saussurea frondosa. China. - Saussurea glandulosa. Taiwan. - Saussurea globosa. China. - Saussurea gnaphalodes. Himalaya, western China. - Saussurea gossypiphora. Himalaya. - Saussurea graminea. China. - Saussurea graminifolia. Himalaya. - Saussurea grandiflora. China. - Saussurea heteromalla. Himalaya. - Saussurea hieracioides. Himalaya, western China. - Saussurea hookeri. Himalaya. - Saussurea involucrata. Snow Lotus, Himalaya, China. - Saussurea iodostegia. China. - Saussurea japonica. Japan, Korea, northern China. - Saussurea kanaii. Himalaya. - Saussurea kanzanensis. Taiwan. - Saussurea kingii. China. - Saussurea kiraisanensis. Taiwan. - Saussurea laminamaensis. Himalaya. - Saussurea laniceps. China. - Saussurea lanuginosa. China. - Saussurea lappa. Himalaya. - Saussurea leontodontoides. Himalaya. - Saussurea licentiana. China. - Saussurea likiangensis. Southwest China. - Saussurea linearifolia. Himalaya. - Saussurea longifolia. China. - Saussurea manshurica. Northern China. - Saussurea medusa. China. - Saussurea mongolica. Western China, Mongolia. - Saussurea namikawae. Himalaya. - Saussurea neofranchetii. China. - Saussurea nepalensis. Himalaya. - Saussurea nigrescens. China. - Saussurea nishiokae. Himalaya. - Saussurea nivea. China. - Saussurea nuda. Nutty Saw-wort. Alaska. - Saussurea obvallata. Brahma Kamal. Himalaya, northern Burma and south-west China. - Saussurea oligantha. China. - Saussurea otophylla. China. - Saussurea pachyneura. Himalaya. - Saussurea parviflora. Russia, China. - Saussurea pectinata. China. - Saussurea peguensis. China. - Saussurea phaeantha. China. - Saussurea pinetorum. China. - Saussurea piptathera. Himalaya. - Saussurea platyphyllaria. Himalaya. - Saussurea polycephala. China. - Saussurea polystichoides. Himalaya. - Saussurea populifolia. China. - Saussurea porcii. Carpathians. - Saussurea pulchella. Japan, Korea, northern China, eastern Siberia. - Saussurea pygmaea. Alps, Carpathians. - Saussurea quercifolia. China. - Saussurea romuleifolia. China. - Saussurea roylei. Himalaya. - Saussurea runcinata. China. - Saussurea salsa. Russia, China. - Saussurea simpsoniana. Himalaya. - Saussurea sobarocephala. China. - Saussurea spicata. Himalaya. - Saussurea stafleuana. Himalaya. - Saussurea stella. China. - Saussurea stracheyana. Himalaya. - Saussurea sughoo. Himalaya. - Saussurea taraxacifolia. Himalaya. - Saussurea tangutica. Western Asia. - Saussurea topkegolensis. Himalaya. - Saussurea tridactyla. Himalaya. - Saussurea turgaiensis. Russia. - Saussurea uniflora. Himalaya. - Saussurea ussuriensis. China, eastern Russia. - Saussurea veitchiana. Central China. - Saussurea velutina. China. - Saussurea viscida. Sticky Saw-wort. Alaska. - Saussurea weberi. Weber's Saw-wort. Rocky Mountains. - Saussurea werneroides. Himalaya. - Saussurea yakla. Himalaya. # References and external links - ↑ PMID 11100933 - ↑ PMID 12916066 - ↑ PMID 12222664 - ↑ PMID 16141525 - Chinese plant names: Saussurea - Checklist of the plants of Nepal: Saussurea - Jintu: Snow Lotus - Law W, Salick J (2005). "Human-induced dwarfing of Himalayan snow lotus, Saussurea laniceps (Asteraceae)". Proceedings of the National Academy of Sciences. 109 (29): 10218–10220. PMID 16006524. 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fd17cd9c6f2f1b1a3600cfd6576bf388dd6faa7f	wikidoc	Saxitoxin	Saxitoxin Saxitoxin (STX) is a cyanotoxin found in marine dinoflagellates (algae). It is a neurotoxin that is a selective sodium channel blocker. The United States military isolated saxitoxin and assigned it the chemical weapon designation TZ. It is unique among toxins in that it acts in a matter of minutes. The median lethal dose (LCt50) of TZ is 5 mg·min/m³. The medical importance of saxitoxin is in relation to red tide in shellfish and causes the paralytic shellfish poisoning (PSP) food poisoning. The blocking of the sodium channel produces a flaccid paralysis that leaves its victim calm and conscious through the progression of symptoms. Death is from respiratory failure. It is listed in schedule 1 of the Chemical Weapons Convention. Though its early isolation and characterization were related to military efforts, saxitoxin has been more important to cellular research in delineating the function of the sodium channel. In episode 22 of the television series "Prison Break", a "glycoside saxitoxin hybrid" is used to cause cardiac arrest of a public official.	Saxitoxin Template:OrganicBox small Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Saxitoxin (STX) is a cyanotoxin found in marine dinoflagellates (algae). It is a neurotoxin that is a selective sodium channel blocker. The United States military isolated saxitoxin and assigned it the chemical weapon designation TZ. It is unique among toxins in that it acts in a matter of minutes. The median lethal dose (LCt50) of TZ is 5 mg·min/m³. The medical importance of saxitoxin is in relation to red tide in shellfish and causes the paralytic shellfish poisoning (PSP) food poisoning. The blocking of the sodium channel produces a flaccid paralysis that leaves its victim calm and conscious through the progression of symptoms. Death is from respiratory failure. It is listed in schedule 1 of the Chemical Weapons Convention. Though its early isolation and characterization were related to military efforts, saxitoxin has been more important to cellular research in delineating the function of the sodium channel. In episode 22 of the television series "Prison Break", a "glycoside saxitoxin hybrid" is used to cause cardiac arrest of a public official.	https://www.wikidoc.org/index.php/Saxitoxin
1cf227e2e0f7374b1ea34e39b389b93d83d4584e	wikidoc	Treeshrew	Treeshrew The treeshrews (or tree shrews) are small mammals native to the tropical forests of Southeast Asia. They make up the families Tupaiidae and Ptilocercidae and the entire order Scandentia. There are 20 species in 5 genera. Treeshrews have a higher brain to body mass ratio than humans, though this is not uncommon for animals weighing less than a kilogram. Although called treeshrews, they are not true shrews (although they were previously classified in the Insectivora), and are not all arboreal. Among other things, they eat Rafflesia fruit. They have no clear fossil record. # Characteristics Treeshrews are slender animals with long tails and soft, greyish to reddish-brown fur. The terrestrial species tend to be larger than the arboreal forms, and to have larger claws, which they use for digging up insect prey. They are omnivorous, feeding on insects, small vertebrates, fruit, and seeds. They have poorly developed canine teeth and unspecialised molars, with an overall dental formula of:Template:Dentition2 Treeshrews have good vision, which is binocular in the case of the more arboreal species. Most are diurnal, although the Pen-tailed Treeshrew is nocturnal. Female treeshrews give birth to up to three young after a gestation period of 45-50 days, in nests lined with dry leaves inside tree hollows. The young are born blind and hairless, but are able to leave the nest after about a month. During this period, the mother provides relatively little maternal care, visiting her young only for a few minutes every other day to suckle them. Treeshrews reach sexual maturity after around four months, and breed for much of the year, with no clear breeding season in most species. These animals live in small family groups, which defend their territory from intruders. They mark their territories using various scent glands, or urine, depending on the particular species. The name Tupaia is derived from tupai the Malay word for squirrel and was provided by Sir Stamford Raffles. # Classification Treeshrews were moved from Insectivora to the Primates order, because of certain internal similarities to the latter (for example, similarities in the brain anatomy, highlighted by Sir Wilfred Le Gros Clark), and classified as a primitive prosimian. However, recent molecular phylogenetic studies have strongly suggested that treeshrews should be given the same rank (order) as the primates and, with the primates and the flying lemurs, belong to the clade Euarchonta. According to this classification, the Euarchonta are sister to the Glires (lagomorphs and rodents), and the two groups are combined into the clade Euarchontoglires. Other arrangements of these orders have been proposed. - ORDER SCANDENTIA Family Tupaiidae Genus Anathana Madras Treeshrew, Anathana ellioti Genus Dendrogale Bornean Smooth-tailed Treeshrew, Dendrogale melanura Northern Smooth-tailed Treeshrew, Dendrogale murina Genus Tupaia Northern Treeshrew, Tupaia belangeri Golden-bellied Treeshrew, Tupaia chrysogaster Striped Treeshrew, Tupaia dorsalis Common Treeshrew, Tupaia glis Slender Treeshrew, Tupaia gracilis Horsfield's Treeshrew, Tupaia javanica Long-footed Treeshrew, Tupaia longipes Pygmy Treeshrew, Tupaia minor Calamian Treeshrew, Tupaia moellendorffi Mountain Treeshrew, Tupaia montana Nicobar Treeshrew, Tupaia nicobarica Palawan Treeshrew, Tupaia palawanensis Painted Treeshrew, Tupaia picta Ruddy Treeshrew, Tupaia splendidula Large Treeshrew, Tupaia tana Genus Urogale Mindanao Treeshrew, Urogale evereti Family Ptilocercidae Genus Ptilocercus Pen-tailed Treeshrew, Ptilocercus lowii - Family Tupaiidae Genus Anathana Madras Treeshrew, Anathana ellioti Genus Dendrogale Bornean Smooth-tailed Treeshrew, Dendrogale melanura Northern Smooth-tailed Treeshrew, Dendrogale murina Genus Tupaia Northern Treeshrew, Tupaia belangeri Golden-bellied Treeshrew, Tupaia chrysogaster Striped Treeshrew, Tupaia dorsalis Common Treeshrew, Tupaia glis Slender Treeshrew, Tupaia gracilis Horsfield's Treeshrew, Tupaia javanica Long-footed Treeshrew, Tupaia longipes Pygmy Treeshrew, Tupaia minor Calamian Treeshrew, Tupaia moellendorffi Mountain Treeshrew, Tupaia montana Nicobar Treeshrew, Tupaia nicobarica Palawan Treeshrew, Tupaia palawanensis Painted Treeshrew, Tupaia picta Ruddy Treeshrew, Tupaia splendidula Large Treeshrew, Tupaia tana Genus Urogale Mindanao Treeshrew, Urogale evereti - Genus Anathana Madras Treeshrew, Anathana ellioti - Madras Treeshrew, Anathana ellioti - Genus Dendrogale Bornean Smooth-tailed Treeshrew, Dendrogale melanura Northern Smooth-tailed Treeshrew, Dendrogale murina - Bornean Smooth-tailed Treeshrew, Dendrogale melanura - Northern Smooth-tailed Treeshrew, Dendrogale murina - Genus Tupaia Northern Treeshrew, Tupaia belangeri Golden-bellied Treeshrew, Tupaia chrysogaster Striped Treeshrew, Tupaia dorsalis Common Treeshrew, Tupaia glis Slender Treeshrew, Tupaia gracilis Horsfield's Treeshrew, Tupaia javanica Long-footed Treeshrew, Tupaia longipes Pygmy Treeshrew, Tupaia minor Calamian Treeshrew, Tupaia moellendorffi Mountain Treeshrew, Tupaia montana Nicobar Treeshrew, Tupaia nicobarica Palawan Treeshrew, Tupaia palawanensis Painted Treeshrew, Tupaia picta Ruddy Treeshrew, Tupaia splendidula Large Treeshrew, Tupaia tana - Northern Treeshrew, Tupaia belangeri - Golden-bellied Treeshrew, Tupaia chrysogaster - Striped Treeshrew, Tupaia dorsalis - Common Treeshrew, Tupaia glis - Slender Treeshrew, Tupaia gracilis - Horsfield's Treeshrew, Tupaia javanica - Long-footed Treeshrew, Tupaia longipes - Pygmy Treeshrew, Tupaia minor - Calamian Treeshrew, Tupaia moellendorffi - Mountain Treeshrew, Tupaia montana - Nicobar Treeshrew, Tupaia nicobarica - Palawan Treeshrew, Tupaia palawanensis - Painted Treeshrew, Tupaia picta - Ruddy Treeshrew, Tupaia splendidula - Large Treeshrew, Tupaia tana - Genus Urogale Mindanao Treeshrew, Urogale evereti - Mindanao Treeshrew, Urogale evereti - Family Ptilocercidae Genus Ptilocercus Pen-tailed Treeshrew, Ptilocercus lowii - Genus Ptilocercus Pen-tailed Treeshrew, Ptilocercus lowii - Pen-tailed Treeshrew, Ptilocercus lowii	Treeshrew The treeshrews (or tree shrews) are small mammals native to the tropical forests of Southeast Asia. They make up the families Tupaiidae and Ptilocercidae and the entire order Scandentia. There are 20 species in 5 genera. Treeshrews have a higher brain to body mass ratio than humans, though this is not uncommon for animals weighing less than a kilogram.[citation needed] Although called treeshrews, they are not true shrews (although they were previously classified in the Insectivora), and are not all arboreal. Among other things, they eat Rafflesia fruit. They have no clear fossil record. # Characteristics Treeshrews are slender animals with long tails and soft, greyish to reddish-brown fur. The terrestrial species tend to be larger than the arboreal forms, and to have larger claws, which they use for digging up insect prey. They are omnivorous, feeding on insects, small vertebrates, fruit, and seeds. They have poorly developed canine teeth and unspecialised molars, with an overall dental formula of:[2]Template:Dentition2 Treeshrews have good vision, which is binocular in the case of the more arboreal species. Most are diurnal, although the Pen-tailed Treeshrew is nocturnal. Female treeshrews give birth to up to three young after a gestation period of 45-50 days, in nests lined with dry leaves inside tree hollows. The young are born blind and hairless, but are able to leave the nest after about a month. During this period, the mother provides relatively little maternal care, visiting her young only for a few minutes every other day to suckle them. Treeshrews reach sexual maturity after around four months, and breed for much of the year, with no clear breeding season in most species.[2] These animals live in small family groups, which defend their territory from intruders. They mark their territories using various scent glands, or urine, depending on the particular species. The name Tupaia is derived from tupai the Malay word for squirrel[3] and was provided by Sir Stamford Raffles.[4] # Classification Treeshrews were moved from Insectivora to the Primates order, because of certain internal similarities to the latter (for example, similarities in the brain anatomy, highlighted by Sir Wilfred Le Gros Clark), and classified as a primitive prosimian. However, recent molecular phylogenetic studies have strongly suggested that treeshrews should be given the same rank (order) as the primates and, with the primates and the flying lemurs, belong to the clade Euarchonta. According to this classification, the Euarchonta are sister to the Glires (lagomorphs and rodents), and the two groups are combined into the clade Euarchontoglires.[5] Other arrangements of these orders have been proposed.[6] Template:Clade - ORDER SCANDENTIA Family Tupaiidae Genus Anathana Madras Treeshrew, Anathana ellioti Genus Dendrogale Bornean Smooth-tailed Treeshrew, Dendrogale melanura Northern Smooth-tailed Treeshrew, Dendrogale murina Genus Tupaia Northern Treeshrew, Tupaia belangeri Golden-bellied Treeshrew, Tupaia chrysogaster Striped Treeshrew, Tupaia dorsalis Common Treeshrew, Tupaia glis Slender Treeshrew, Tupaia gracilis Horsfield's Treeshrew, Tupaia javanica Long-footed Treeshrew, Tupaia longipes Pygmy Treeshrew, Tupaia minor Calamian Treeshrew, Tupaia moellendorffi Mountain Treeshrew, Tupaia montana Nicobar Treeshrew, Tupaia nicobarica Palawan Treeshrew, Tupaia palawanensis Painted Treeshrew, Tupaia picta Ruddy Treeshrew, Tupaia splendidula Large Treeshrew, Tupaia tana Genus Urogale Mindanao Treeshrew, Urogale evereti Family Ptilocercidae Genus Ptilocercus Pen-tailed Treeshrew, Ptilocercus lowii - Family Tupaiidae Genus Anathana Madras Treeshrew, Anathana ellioti Genus Dendrogale Bornean Smooth-tailed Treeshrew, Dendrogale melanura Northern Smooth-tailed Treeshrew, Dendrogale murina Genus Tupaia Northern Treeshrew, Tupaia belangeri Golden-bellied Treeshrew, Tupaia chrysogaster Striped Treeshrew, Tupaia dorsalis Common Treeshrew, Tupaia glis Slender Treeshrew, Tupaia gracilis Horsfield's Treeshrew, Tupaia javanica Long-footed Treeshrew, Tupaia longipes Pygmy Treeshrew, Tupaia minor Calamian Treeshrew, Tupaia moellendorffi Mountain Treeshrew, Tupaia montana Nicobar Treeshrew, Tupaia nicobarica Palawan Treeshrew, Tupaia palawanensis Painted Treeshrew, Tupaia picta Ruddy Treeshrew, Tupaia splendidula Large Treeshrew, Tupaia tana Genus Urogale Mindanao Treeshrew, Urogale evereti - Genus Anathana Madras Treeshrew, Anathana ellioti - Madras Treeshrew, Anathana ellioti - Genus Dendrogale Bornean Smooth-tailed Treeshrew, Dendrogale melanura Northern Smooth-tailed Treeshrew, Dendrogale murina - Bornean Smooth-tailed Treeshrew, Dendrogale melanura - Northern Smooth-tailed Treeshrew, Dendrogale murina - Genus Tupaia Northern Treeshrew, Tupaia belangeri Golden-bellied Treeshrew, Tupaia chrysogaster Striped Treeshrew, Tupaia dorsalis Common Treeshrew, Tupaia glis Slender Treeshrew, Tupaia gracilis Horsfield's Treeshrew, Tupaia javanica Long-footed Treeshrew, Tupaia longipes Pygmy Treeshrew, Tupaia minor Calamian Treeshrew, Tupaia moellendorffi Mountain Treeshrew, Tupaia montana Nicobar Treeshrew, Tupaia nicobarica Palawan Treeshrew, Tupaia palawanensis Painted Treeshrew, Tupaia picta Ruddy Treeshrew, Tupaia splendidula Large Treeshrew, Tupaia tana - Northern Treeshrew, Tupaia belangeri - Golden-bellied Treeshrew, Tupaia chrysogaster - Striped Treeshrew, Tupaia dorsalis - Common Treeshrew, Tupaia glis - Slender Treeshrew, Tupaia gracilis - Horsfield's Treeshrew, Tupaia javanica - Long-footed Treeshrew, Tupaia longipes - Pygmy Treeshrew, Tupaia minor - Calamian Treeshrew, Tupaia moellendorffi - Mountain Treeshrew, Tupaia montana - Nicobar Treeshrew, Tupaia nicobarica - Palawan Treeshrew, Tupaia palawanensis - Painted Treeshrew, Tupaia picta - Ruddy Treeshrew, Tupaia splendidula - Large Treeshrew, Tupaia tana - Genus Urogale Mindanao Treeshrew, Urogale evereti - Mindanao Treeshrew, Urogale evereti - Family Ptilocercidae Genus Ptilocercus Pen-tailed Treeshrew, Ptilocercus lowii - Genus Ptilocercus Pen-tailed Treeshrew, Ptilocercus lowii - Pen-tailed Treeshrew, Ptilocercus lowii	https://www.wikidoc.org/index.php/Scandentia
9e3a293eaafb5077f711c5f439d9dffce89f9fb9	wikidoc	Scatology	Scatology # Overview In medicine and biology, scatology or coprology is the study of feces. Scatological studies allow one to determine a wide range of biological information about a creature, including its diet (and thus where it has been), healthiness, and diseases such as tapeworms. The word derives from the Greek σκώρ (genitive σκατός, modern σκατό, pl. σκατά) meaning "feces". In psychology, a scatology is an obsession with excretion or excrement, or the study of such obsessions. (See also coprophilia). In sexual context scatology refers to sexual acts conducted with human (or other) excrement. In literature, "scatological" is a common incorrect term to denote the literary trope of the grotesque body. It is used to describe works that make particular reference to excretion or excrement, as well as to toilet humor.	Scatology # Overview In medicine and biology, scatology or coprology is the study of feces. Scatological studies allow one to determine a wide range of biological information about a creature, including its diet (and thus where it has been), healthiness, and diseases such as tapeworms. The word derives from the Greek σκώρ (genitive σκατός, modern σκατό, pl. σκατά) meaning "feces". In psychology, a scatology is an obsession with excretion or excrement, or the study of such obsessions. (See also coprophilia). In sexual context scatology refers to sexual acts conducted with human (or other) excrement. In literature, "scatological" is a common incorrect term to denote the literary trope of the grotesque body. It is used to describe works that make particular reference to excretion or excrement, as well as to toilet humor. # External links and references - Jae Num Lee "Swift and Scatological Satire" UNIVERSITY OF NEW MEXICO PRESS 1971 ISBN 0826301967 jstor review - Bakhtin, Mikhail, "Rabelais and his World" - Lee, Jae Num. "Scatology in Continental Satirical Writings from Aristophanes to Rabelais" and "English Scatological Writings from Skelton to Pope." Swift and Scatological Satire. Albuquerque: U of New Mexico P, 1971. 7-22; 23-53. - Susan Gubar "The Female Monster in Augustan Satire" Signs, Vol. 3, No. 2 (Winter, 1977), pp. 380-394 - Maledicta: The International Journal of Verbal Aggression (Template:ISSN) - Scatology: The Last Taboo - An analysis of scatology in Malachi 2:3 # Further reading Probably the most comprehensive study of scatology was that documented by John Gregory Bourke under the title Scatalogic Rites of All Nations (1891). An abbreviated version of the work was published as The Portable Scatalog, edited by Louis P. Kaplan and with a foreword by Sigmund Freud; New York: William Morrow and Company (1994) ISBN 0688132065 - Henderson, Jeffrey The Maculate Muse: Obscene Language in Attic Comedy 1991 Oxford University Press ISBN 0195066855 - Slater, W. J. review of The Maculate Muse: Obscene Language in Attic Comedy by Jeffrey Henderson. Phoenix, Vol. 30, No. 3 (Autumn, 1976), pp. 291-293 doi:10.2307/1087300 da:Skatologi hu:Szkatológia fi:Skatologia Template:WH Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Scatology
41e5aaabc7e09cdffb5cb0c448a1d99475417323	wikidoc	Scientist	Scientist A scientist, in the broadest sense, refers to any person that engages in a systematic activity to acquire knowledge or an individual that engages in such practices and traditions that are linked to schools of thought or philosophy. In a more restricted sense, scientist refers to individuals who use the scientific method. The person may be an expert in one or more areas of science. This article focuses on the more restricted use of the word. # Etymology Historically, scientists were termed "natural philosophers" or "men of science"; they were men of knowledge. Science and philosophy were roughly synonymous. William Whewell coined the term scientist in 1833 to describe an expert in the study of nature, but this term did not gain wide acceptance till the turn of the 19th century. By the twentieth century, the modern notion of science as a special brand of information about the world, practiced by a distinct group and pursued through a unique method, was essentially in place. # Description Science and technology have continually modified human existence. As a profession, the scientist of today is widely recognised. Scientists include theoreticians who mainly develop new models to explain existing data, and experimentalists who mainly test models by making measurements — though in practice the division between these activities is not clear-cut, and many scientists perform both. Mathematics is often grouped with the sciences. Like other scientists, mathematicians start with hunches (hypotheses) and then conduct symbolic or computational experiments to test them. Some of the greatest physicists have also been creative mathematicians. There is a continuum from the most theoretical to the most empirical scientists with no distinct boundaries. By personality, interests, training and professional activity, there is little difference between applied mathematicians and theoretical physicists. Scientists can be motivated in several ways. Many have a desire to understand why the world is as we see it and how it came to be. They exhibit a strong curiosity about reality. Other motivations are recognition by their peers and prestige, or the desire to apply scientific knowledge for the benefit of peoples health, the nations, the world, nature or industries. Only few scientists count generating personal wealth as an important driving force behind their science. ## Scientists versus Engineers Engineers and scientists are often confused in the minds of the general public, with the former being closer to applied science. While scientists explore nature in order to discover general principles, engineers apply established principles drawn from mathematics and science in order to develop economical solutions to technical problems. In short, scientists study things whereas engineers build things. But there are plenty of instances where significant accomplishments are made in both fields by the same individual. Scientists often perform engineering tasks in designing experimental equipment and building prototypes, and some engineers do first-rate scientific research. Mechanical, electrical, chemical and aerospace engineers are often at the forefront of scientific investigation of new phenomena and materials. Peter Debye received a degree in electrical engineering and a doctorate in physics before eventually winning a Nobel Prize in chemistry. Similarly, Paul Dirac, one of the founders of quantum mechanics, began his academic career as an electrical engineer before proceeding to mathematics and later theoretical physics. Claude Shannon, a theoretical engineer, founded modern information theory. # Historical Scientists An early scientific method which emphasized experimentation was first used by the Iraqi Arab physicist and polymath Ibn al-Haytham (Alhazen), circa 1021 AD, in his Book of Optics, and he has been described as the "first scientist" for this reason. There are notable examples of people who have moved back and forth among disciplines. Such polymaths were common during the Islamic Golden Age and European Renaissance. Many of these early polymath scientists were also religious priests and theologians: for example, the polymath scientists Alhazen and al-Biruni were mutakallimiin; the polymath physician Avicenna was a hafiz; the polymath physician Ibn al-Nafis was a hafiz, muhaddith and ulema; the astronomer and physician Nicolaus Copernicus was a priest; and Gregor Mendel, whose discoveries on inheritance founded modern genetics and provides a mechanism to explain Charles Darwin's observations about evolution, was also a priest. Descartes was not only a pioneer of analytic geometry but formulated a theory of mechanics and advanced ideas about the origins of animal movement and perception. Vision interested the physicists Young and Helmholtz, who also studied optics, hearing and music. Newton extended Descartes' mathematics by inventing calculus (contemporaneously with Leibniz). He provided a comprehensive formulation of classical mechanics and investigated light and optics. Fourier founded a new branch of mathematics — infinite, periodic series — studied heat flow and infrared radiation, and discovered the greenhouse effect. Von Neumann, Turing, Khinchin, Markov and Wiener, all mathematicians, made major contributions to science and probability theory, including the ideas behind computers, and some of the foundations of statistical mechanics and quantum mechanics. Many mathematically inclined scientists, including Galileo, were also musicians. In the late 19th century, Louis Pasteur, an organic chemist, discovered that microorganisms can cause disease. A few years earlier, Oliver Wendell Holmes, Sr., the American physician, poet and essayist, noted that sepsis in women following childbirth was spread by the hands of doctors and nurses, four years before Semmelweis in Europe. There are many compelling stories in medicine and biology, such as the development of ideas about the circulation of blood from Galen to Harvey. The flowering of genetics and molecular biology in the 20th century is replete with famous names. Ramón y Cajal won the Nobel Prize in 1906 for his remarkable observations in neuroanatomy. Some see a dichotomy between experimental sciences and purely "observational" sciences such as astronomy, meteorology, oceanography and seismology. But astronomers have done basic research in optics, developed charge-coupled devices, and in recent decades have sent space probes to study other planets in addition to using the Hubble Telescope to probe the origins of the Universe some 14 billion years ago. Microwave spectroscopy has now identified dozens of organic molecules in interstellar space, requiring laboratory experimentation and computer simulation to confirm the observational data and starting a new branch of chemistry. Computer modeling and numerical methods are techniques required of students in every field of quantitative science. Those considering science as a career often look to the frontiers. These include cosmology and biology, especially molecular biology and the human genome project. Other areas of active research include the exploration of matter at the scale of elementary particles as described by high-energy physics, and nanotechnology, which hopes to develop electronics including microscopic computers, and perhaps artificial intelligence. Although there have been remarkable discoveries with regard to brain function and neurotransmitters, the nature of the mind and human thought still remain. # Types of scientists	Scientist A scientist, in the broadest sense, refers to any person that engages in a systematic activity to acquire knowledge or an individual that engages in such practices and traditions that are linked to schools of thought or philosophy. In a more restricted sense, scientist refers to individuals who use the scientific method.[1] The person may be an expert in one or more areas of science.[2] This article focuses on the more restricted use of the word. # Etymology Historically, scientists were termed "natural philosophers" or "men of science"[3][4][5][6]; they were men of knowledge. Science and philosophy were roughly synonymous. William Whewell coined the term scientist in 1833 to describe an expert in the study of nature, but this term did not gain wide acceptance till the turn of the 19th century.[7][8] By the twentieth century, the modern notion of science as a special brand of information about the world, practiced by a distinct group and pursued through a unique method, was essentially in place. # Description Science and technology have continually modified human existence. As a profession, the scientist of today is widely recognised. Scientists include theoreticians who mainly develop new models to explain existing data, and experimentalists who mainly test models by making measurements — though in practice the division between these activities is not clear-cut, and many scientists perform both. Mathematics is often grouped with the sciences. Like other scientists, mathematicians start with hunches (hypotheses) and then conduct symbolic or computational experiments to test them. Some of the greatest physicists have also been creative mathematicians. There is a continuum from the most theoretical to the most empirical scientists with no distinct boundaries. By personality, interests, training and professional activity, there is little difference between applied mathematicians and theoretical physicists. Scientists can be motivated in several ways. Many have a desire to understand why the world is as we see it and how it came to be. They exhibit a strong curiosity about reality. Other motivations are recognition by their peers and prestige, or the desire to apply scientific knowledge for the benefit of peoples health, the nations, the world, nature or industries. Only few scientists count generating personal wealth as an important driving force behind their science. ## Scientists versus Engineers Engineers and scientists are often confused in the minds of the general public, with the former being closer to applied science. While scientists explore nature in order to discover general principles, engineers apply established principles drawn from mathematics and science in order to develop economical solutions to technical problems.[9][10] In short, scientists study things whereas engineers build things. But there are plenty of instances where significant accomplishments are made in both fields by the same individual. Scientists often perform engineering tasks in designing experimental equipment and building prototypes, and some engineers do first-rate scientific research. Mechanical, electrical, chemical and aerospace engineers are often at the forefront of scientific investigation of new phenomena and materials. Peter Debye received a degree in electrical engineering and a doctorate in physics before eventually winning a Nobel Prize in chemistry. Similarly, Paul Dirac, one of the founders of quantum mechanics, began his academic career as an electrical engineer before proceeding to mathematics and later theoretical physics. Claude Shannon, a theoretical engineer, founded modern information theory. # Historical Scientists An early scientific method which emphasized experimentation was first used by the Iraqi Arab physicist and polymath Ibn al-Haytham (Alhazen), circa 1021 AD, in his Book of Optics, and he has been described as the "first scientist" for this reason.[11] There are notable examples of people who have moved back and forth among disciplines. Such polymaths were common during the Islamic Golden Age and European Renaissance. Many of these early polymath scientists were also religious priests and theologians: for example, the polymath scientists Alhazen and al-Biruni were mutakallimiin; the polymath physician Avicenna was a hafiz; the polymath physician Ibn al-Nafis was a hafiz, muhaddith and ulema; the astronomer and physician Nicolaus Copernicus was a priest; and Gregor Mendel, whose discoveries on inheritance founded modern genetics and provides a mechanism to explain Charles Darwin's observations about evolution, was also a priest. Descartes was not only a pioneer of analytic geometry but formulated a theory of mechanics and advanced ideas about the origins of animal movement and perception. Vision interested the physicists Young and Helmholtz, who also studied optics, hearing and music. Newton extended Descartes' mathematics by inventing calculus (contemporaneously with Leibniz). He provided a comprehensive formulation of classical mechanics and investigated light and optics. Fourier founded a new branch of mathematics — infinite, periodic series — studied heat flow and infrared radiation, and discovered the greenhouse effect. Von Neumann, Turing, Khinchin, Markov and Wiener, all mathematicians, made major contributions to science and probability theory, including the ideas behind computers, and some of the foundations of statistical mechanics and quantum mechanics. Many mathematically inclined scientists, including Galileo, were also musicians. In the late 19th century, Louis Pasteur, an organic chemist, discovered that microorganisms can cause disease. A few years earlier, Oliver Wendell Holmes, Sr., the American physician, poet and essayist, noted that sepsis in women following childbirth was spread by the hands of doctors and nurses, four years before Semmelweis in Europe. There are many compelling stories in medicine and biology, such as the development of ideas about the circulation of blood from Galen to Harvey. The flowering of genetics and molecular biology in the 20th century is replete with famous names. Ramón y Cajal won the Nobel Prize in 1906 for his remarkable observations in neuroanatomy. Some see a dichotomy between experimental sciences and purely "observational" sciences such as astronomy, meteorology, oceanography and seismology. But astronomers have done basic research in optics, developed charge-coupled devices, and in recent decades have sent space probes to study other planets in addition to using the Hubble Telescope to probe the origins of the Universe some 14 billion years ago. Microwave spectroscopy has now identified dozens of organic molecules in interstellar space, requiring laboratory experimentation and computer simulation to confirm the observational data and starting a new branch of chemistry. Computer modeling and numerical methods are techniques required of students in every field of quantitative science. Those considering science as a career often look to the frontiers. These include cosmology and biology, especially molecular biology and the human genome project. Other areas of active research include the exploration of matter at the scale of elementary particles as described by high-energy physics, and nanotechnology, which hopes to develop electronics including microscopic computers, and perhaps artificial intelligence. Although there have been remarkable discoveries with regard to brain function and neurotransmitters, the nature of the mind and human thought still remain. # Types of scientists	https://www.wikidoc.org/index.php/Scientist
dd2a9541a6d3a3271431714245014754cb19ac61	wikidoc	Scleraxis	Scleraxis The scleraxis protein is a member of the basic helix-loop-helix (bHLH) superfamily of transcription factors. Currently two genes (SCXA and SCXB respectively) have been identified to code for identical scleraxis proteins. # Function It is thought that early scleraxis-expressing progenitor cells lead to the eventual formation of tendon tissue and other muscle attachments. Scleraxis is involved in mesoderm formation and is expressed in the syndetome (a collection of embryonic tissue that develops into tendon and blood vessels) of developing somites (primitive segments or compartments of embryos). # Inducing scleraxis expression The syndetome location within the somite is determined by FGF secreted from the center of the myotome (a collection of embryonic tissue that develops into skeletal muscle)- the FGF then induces the adjacent anterior and posterior sclerotome (a collection of embryonic tissue that develops into the axial skeleton) to adopt a tendon cell fate. This ultimately places future scleraxis-expressing cells between the two tissue types they will ultimately join. Scleraxis expression will be seen throughout the entire sclerotome (rather than just the sclerotome directly anterior and posterior to the myotome) with an overexpression of FGF8, demonstrating that all sclerotome cells are capable of expressing scleraxis in response to FGF signaling. While the FGF interaction has been shown to be necessary for scleraxis expression, it is still unclear as to whether the FGF signaling pathway directly induces the syndetome to secrete scleraxis, or indirectly through a secondary signaling pathway. Most likely, the syndetomal cells, through careful reading of the FGF concentration (coming from the myotome), can precisely determine their location and begin expressing scleraxis. Much of embryonic development follows this model of inducing specific cell fates through the reading of surrounding signaling molecule concentration gradients. # Background bHLH transcription factors have been shown to have a wide array of functions in developmental processes. More precisely, they have critical roles in the control of cellular differentiation, proliferation and regulation of oncogenesis. To date, 242 eukaryotic proteins belonging to the HLH superfamily have been reported. They have varied expression patterns in all eukaryotes from yeast to humans. Structurally, bHLH proteins are characterised by a “highly conserved domain containing a stretch of basic amino acids adjacent to two amphipathic α-helices separated by a loop”. These helices have important functional properties, forming part of the DNA binding and transcription activating domains. With respect to scleraxis, the bHLH region spans amino acid residues 78 to 131. A proline rich region is also predicted to lie between residues 161-170. A stretch of basic residues, which aids in DNA binding, is found closer to the N terminal end of scleraxis. HLH proteins that lack this basic domain have been shown to negatively regulate the activities of bHLH proteins and are called inhibitors of differentiation (Id). Basic HLH proteins function normally as dimers and bind to a specific hexanucleotide DNA sequence (CAANTG) known as an E-box thus switching on the expression of various genes involved in cellular development and survival.	Scleraxis The scleraxis protein is a member of the basic helix-loop-helix (bHLH) superfamily of transcription factors.[1] Currently two genes (SCXA and SCXB respectively) have been identified to code for identical scleraxis proteins. # Function It is thought that early scleraxis-expressing progenitor cells lead to the eventual formation of tendon tissue and other muscle attachments.[1] Scleraxis is involved in mesoderm formation and is expressed in the syndetome (a collection of embryonic tissue that develops into tendon and blood vessels) of developing somites (primitive segments or compartments of embryos).[2] # Inducing scleraxis expression The syndetome location within the somite is determined by FGF secreted from the center of the myotome (a collection of embryonic tissue that develops into skeletal muscle)- the FGF then induces the adjacent anterior and posterior sclerotome (a collection of embryonic tissue that develops into the axial skeleton) to adopt a tendon cell fate. This ultimately places future scleraxis-expressing cells between the two tissue types they will ultimately join. [3] Scleraxis expression will be seen throughout the entire sclerotome (rather than just the sclerotome directly anterior and posterior to the myotome) with an overexpression of FGF8, demonstrating that all sclerotome cells are capable of expressing scleraxis in response to FGF signaling. While the FGF interaction has been shown to be necessary for scleraxis expression, it is still unclear as to whether the FGF signaling pathway directly induces the syndetome to secrete scleraxis, or indirectly through a secondary signaling pathway. Most likely, the syndetomal cells, through careful reading of the FGF concentration (coming from the myotome), can precisely determine their location and begin expressing scleraxis.[3] Much of embryonic development follows this model of inducing specific cell fates through the reading of surrounding signaling molecule concentration gradients. # Background bHLH transcription factors have been shown to have a wide array of functions in developmental processes.[4] More precisely, they have critical roles in the control of cellular differentiation, proliferation and regulation of oncogenesis.[4][5][6] To date, 242 eukaryotic proteins belonging to the HLH superfamily have been reported. They have varied expression patterns in all eukaryotes from yeast to humans.[7] Structurally, bHLH proteins are characterised by a “highly conserved domain containing a stretch of basic amino acids adjacent to two amphipathic α-helices separated by a loop”.[8][9] These helices have important functional properties, forming part of the DNA binding and transcription activating domains. With respect to scleraxis, the bHLH region spans amino acid residues 78 to 131. A proline rich region is also predicted to lie between residues 161-170. A stretch of basic residues, which aids in DNA binding, is found closer to the N terminal end of scleraxis.[1][10] HLH proteins that lack this basic domain have been shown to negatively regulate the activities of bHLH proteins and are called inhibitors of differentiation (Id).[11] Basic HLH proteins function normally as dimers and bind to a specific hexanucleotide DNA sequence (CAANTG) known as an E-box thus switching on the expression of various genes involved in cellular development and survival.	https://www.wikidoc.org/index.php/Scleraxis
f19628350cfb99ae76a5d62a116f165c0c7bacc6	wikidoc	Scleritis	Scleritis # Scleral Anatomy The word "sclera" is derived from Greek word, "sklēros" meaning hard. It consists of the posterior five-sixths part of the fibrous outer tunic of the eye. The outer scleral surface is in contact with Tenon’s capsule and the bulbar conjunctiva. The sclera is covered by a thin layer of loose tissue called episclera. It is separated from the choroid by the suprachoroidal space. The extraocular muscles are also inserted in the sclera. The thickness of the sclera varies from place to place. The thickest part is at the posterior pole and the thinnest underneath the insertion of rectus muscles. At the point of entrance for the optic nerve in the orbit, the sclera is consists of a sieve-like membrane, the lamina cribrosa, which allows the passage of fasciculi of the nerve. The sclera receives the circulation of two long and ten to twelve short posterior ciliary arteries around the optic nerve. Slightly posterior to the equator, four vortex veins (venae vorticosae) drain the sclera. The anterior ciliary arteries and veins penetrate the sclera nearly 3 to 4 mm away from the limbus. The histology of the sclera consists of three layers - episcleral tissue, sclera proper and lamina fusca. The episcleral tissue comprises fine loose elastic tissue fibers and contains a large number of small vessels. The sclera proper is formed by dense bands of parallel and interlacing collagen fibers. The collagen fiber bundles are arranged in concentric circles at the limbus and around the entrance of the optic nerve, elsewhere the arrangement is quite complicated. The lamina fusca has a brown color owing to the presence of a large number of branched chromatophores. The sclera is almost avascular and its histological structure resembles that of the cornea. However, sclera is opaque due to the hydration and irregular arrangement of its lamellae. The nerve supply of sclera comes through the ciliary nerves. # Scleritis Scleritis is a serious inflammatory disease that affects the sclera. The disease is often contracted through association with other diseases of the body, such as Wegener's granulomatosis or rheumatoid arthritis; it can also be attained through disorders of menstruation. For this reason, scleritis occurs frequently among young women. There are three types of scleritis: diffuse scleritis (the most common), nodular scleritis, and necrotizing scleritis (the most severe). Scleritis may be the first symptom of onset connective tissue disease. The term "Episcleritis" refers to inflammation of the episclera. # Classification Inflammation of the sclera is classified by its location and severity using the system devised by Watson. # Pathophysiology AUTOIMMUNE DISEASE Systemic autoimmune disease is a common finding in patients with scleritis,2 and scleral and episcleral tissues appear to be particularly at risk in a wide range of autoimmune disorders. Why this should be the case is not clear. It is possible that everyday exposure to irritants and pathogens provokes minor episodes of inflammation that in some way prime the autoimmune-mediated inflammation. The following description includes details of histology -f some cases where precise information concerning aetiology was not provided, but it has been assumed that the cases were of autoimmune aetiology. The detailed pathogenesis of this heterogeneous group of conditions remains uncertain although it is agreed that autoimmunity plays an important role. Immune complex deposition may be a feature1–3 and, interestingly, one case of scleritis following treatment with a mouse monoclonal antibody has been reported.4 Immune complex formation has also been described in at least -ne pathological report.5 In conditions such as relapsing polychondritis, autoantibodies, in this instance to type II collagen, may have a role to play. It has been proposed that the presence of higher levels of complement C1 in the anterior sclera may explain the increased incidence of immune complex disease-associated scleritis at the front of the eye.6 Necrotizing and non-necrotizing vasculitis (especially arteritis) have been seen in some cases.2,7 The early involvement of sclera adjacent to anterior and posterior ciliary vessels has been used to support the notion that vasculitis is an important component in the pathogenesis of scleritis,8 but non-vasculitic inflammatory diseases, such as multiple sclerosis, are also characterized by perivascular pathology. In addition, in many cases vasculitis is not found and, although this may to a degree reflect problems with sampling, it seems probable that vasculitis is not a universal finding. Interestingly, other vascular changes, in the absence of inflammation, vasculitic or otherwise, have been reported. These include vascular closure,9 which might be anticipated to lead to ischaemic necrosis in the absence of vasculitis. There has been relatively little analysis of the detailed phenotype -f the inflammatory cell infiltrate. In one study of two cases there was a predominance of CD4 positive T cells with clusters of B cells in a perivascular location.10 In this study no evidence of vasculitis was seen. Relatively few of the T cells appeared activated as # Signs and symptoms Symptoms of the disease include: - Redness of the sclera and conjunctiva, sometimes changing to a purple hue - Severe ocular pain (not present in episcleritis) which may radiate to the temple or jaw - Increased light sensitivity and tearing - Decrease in visual acuity, possibly leading to blindness # Diagnosis Scleritis is best detected by examining the sclera in daylight; retracting the lids helps determine the extent of involvement. Other aspects of the eye exam (i.e. visual acuity testing, slit lamp examination, etc) can be normal. Ancillary tests CT scans, MRIs, and ultrasonographies can be helpful, but do not replace the physical examination. # Treatment In very severe cases of necrotizing scleritis, eye surgery must be performed to repair damaged corneal tissue in the eye and preserve the patient's vision. For less severe cases, nonsteroidal anti-inflammatory drugs, such as ibuprofen, are prescribed for pain relief. Scleritis itself is treated with an oral medication containing corticosteroids and an eye solution. In some cases, antibiotics are prescribed. Simply using eye drops will not treat scleritis. If not treated, scleritis can cause blindness.	Scleritis Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Rohan Bir Singh, M.B.B.S.[2] # Scleral Anatomy The word "sclera" is derived from Greek word, "sklēros" meaning hard. It consists of the posterior five-sixths part of the fibrous outer tunic of the eye. The outer scleral surface is in contact with Tenon’s capsule and the bulbar conjunctiva. The sclera is covered by a thin layer of loose tissue called episclera. It is separated from the choroid by the suprachoroidal space. The extraocular muscles are also inserted in the sclera. The thickness of the sclera varies from place to place. The thickest part is at the posterior pole and the thinnest underneath the insertion of rectus muscles. At the point of entrance for the optic nerve in the orbit, the sclera is consists of a sieve-like membrane, the lamina cribrosa, which allows the passage of fasciculi of the nerve. The sclera receives the circulation of two long and ten to twelve short posterior ciliary arteries around the optic nerve. Slightly posterior to the equator, four vortex veins (venae vorticosae) drain the sclera. The anterior ciliary arteries and veins penetrate the sclera nearly 3 to 4 mm away from the limbus. The histology of the sclera consists of three layers - episcleral tissue, sclera proper and lamina fusca. The episcleral tissue comprises fine loose elastic tissue fibers and contains a large number of small vessels. The sclera proper is formed by dense bands of parallel and interlacing collagen fibers. The collagen fiber bundles are arranged in concentric circles at the limbus and around the entrance of the optic nerve, elsewhere the arrangement is quite complicated. The lamina fusca has a brown color owing to the presence of a large number of branched chromatophores. The sclera is almost avascular and its histological structure resembles that of the cornea. However, sclera is opaque due to the hydration and irregular arrangement of its lamellae. The nerve supply of sclera comes through the ciliary nerves. # Scleritis Scleritis is a serious inflammatory disease that affects the sclera. The disease is often contracted through association with other diseases of the body, such as Wegener's granulomatosis or rheumatoid arthritis; it can also be attained through disorders of menstruation. For this reason, scleritis occurs frequently among young women. There are three types of scleritis: diffuse scleritis (the most common), nodular scleritis, and necrotizing scleritis (the most severe). Scleritis may be the first symptom of onset connective tissue disease[3]. The term "Episcleritis" refers to inflammation of the episclera. # Classification Inflammation of the sclera is classified by its location and severity using the system devised by Watson.[1] # Pathophysiology AUTOIMMUNE DISEASE Systemic autoimmune disease is a common finding in patients with scleritis,2 and scleral and episcleral tissues appear to be particularly at risk in a wide range of autoimmune disorders. Why this should be the case is not clear. It is possible that everyday exposure to irritants and pathogens provokes minor episodes of inflammation that in some way prime the autoimmune-mediated inflammation. The following description includes details of histology of some cases where precise information concerning aetiology was not provided, but it has been assumed that the cases were of autoimmune aetiology. The detailed pathogenesis of this heterogeneous group of conditions remains uncertain although it is agreed that autoimmunity plays an important role. Immune complex deposition may be a feature1–3 and, interestingly, one case of scleritis following treatment with a mouse monoclonal antibody has been reported.4 Immune complex formation has also been described in at least one pathological report.5 In conditions such as relapsing polychondritis, autoantibodies, in this instance to type II collagen, may have a role to play. It has been proposed that the presence of higher levels of complement C1 in the anterior sclera may explain the increased incidence of immune complex disease-associated scleritis at the front of the eye.6 Necrotizing and non-necrotizing vasculitis (especially arteritis) have been seen in some cases.2,7 The early involvement of sclera adjacent to anterior and posterior ciliary vessels has been used to support the notion that vasculitis is an important component in the pathogenesis of scleritis,8 but non-vasculitic inflammatory diseases, such as multiple sclerosis, are also characterized by perivascular pathology. In addition, in many cases vasculitis is not found and, although this may to a degree reflect problems with sampling, it seems probable that vasculitis is not a universal finding. Interestingly, other vascular changes, in the absence of inflammation, vasculitic or otherwise, have been reported. These include vascular closure,9 which might be anticipated to lead to ischaemic necrosis in the absence of vasculitis. There has been relatively little analysis of the detailed phenotype of the inflammatory cell infiltrate. In one study of two cases there was a predominance of CD4 positive T cells with clusters of B cells in a perivascular location.10 In this study no evidence of vasculitis was seen. Relatively few of the T cells appeared activated as # Signs and symptoms Symptoms of the disease include: - Redness of the sclera and conjunctiva, sometimes changing to a purple hue - Severe ocular pain (not present in episcleritis) which may radiate to the temple or jaw - Increased light sensitivity and tearing - Decrease in visual acuity, possibly leading to blindness # Diagnosis Scleritis is best detected by examining the sclera in daylight; retracting the lids helps determine the extent of involvement. Other aspects of the eye exam (i.e. visual acuity testing, slit lamp examination, etc) can be normal. Ancillary tests CT scans, MRIs, and ultrasonographies can be helpful, but do not replace the physical examination. # Treatment In very severe cases of necrotizing scleritis, eye surgery must be performed to repair damaged corneal tissue in the eye and preserve the patient's vision. For less severe cases, nonsteroidal anti-inflammatory drugs, such as ibuprofen, are prescribed for pain relief. Scleritis itself is treated with an oral medication containing corticosteroids and an eye solution. In some cases, antibiotics are prescribed. Simply using eye drops will not treat scleritis. If not treated, scleritis can cause blindness.	https://www.wikidoc.org/index.php/Scleritis
fa95f84ff1935d80cad31f110c154378d3325f8f	wikidoc	Scombroid	Scombroid # Overview Scombroid is a foodborne illness poisoning associated with eating seafood that has been stored improperly. It is the second most common type of seafood poisoning, second only to ciguatera. However it is often missed because it resembles an allergic reaction. # Causes Unlike many types of food poisonings, this form is not produced by an organism or virus. Histidine exists naturally on many types of fish, and at temperatures above 60 degrees Fahrenheit it converts to the biogenic amine histamine (this is one reason why fish should be stored at low temperatures). Histamine is not destroyed by normal cooking temperatures, so even properly cooked fish can be affected. Histamine is a mediator of allergic reactions, so the symptoms produced are those one would expect to see in severe allergic responses. # Symptoms Symptoms consist of skin flushing, throbbing headache, oral burning, abdominal cramps, nausea, diarrhea, palpitations, a sense of unease, and, rarely prostration or loss of vision. Symptoms usually occur within 10-30 minutes of ingesting the fish and generally are self-limited. Physical signs may include a diffuse blanching erythema, tachycardia, wheezing, and hypotension or hypertension. People with asthma are more vulnerable to respiratory problems such as wheezing or bronchospasms. # Treatment Treatment is in the form of supportive care such as fluids and oxygen. H1 and H2 receptor (histamine receptors) blocking medications can also be given with some success. # Related Chapters - Scombroid food poisoning	Scombroid Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Scombroid is a foodborne illness poisoning associated with eating seafood that has been stored improperly. It is the second most common type of seafood poisoning, second only to ciguatera. However it is often missed because it resembles an allergic reaction. # Causes Unlike many types of food poisonings, this form is not produced by an organism or virus. Histidine exists naturally on many types of fish, and at temperatures above 60 degrees Fahrenheit it converts to the biogenic amine histamine (this is one reason why fish should be stored at low temperatures). Histamine is not destroyed by normal cooking temperatures, so even properly cooked fish can be affected. Histamine is a mediator of allergic reactions, so the symptoms produced are those one would expect to see in severe allergic responses. # Symptoms Symptoms consist of skin flushing, throbbing headache, oral burning, abdominal cramps, nausea, diarrhea, palpitations, a sense of unease, and, rarely prostration or loss of vision. Symptoms usually occur within 10-30 minutes of ingesting the fish and generally are self-limited. Physical signs may include a diffuse blanching erythema, tachycardia, wheezing, and hypotension or hypertension. People with asthma are more vulnerable to respiratory problems such as wheezing or bronchospasms. # Treatment Treatment is in the form of supportive care such as fluids and oxygen. H1 and H2 receptor (histamine receptors) blocking medications can also be given with some success. # Related Chapters - Scombroid food poisoning Template:Poisoning and toxicity Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Scombroid
942c6b5b1b7aecc24476d41009794e75f5c0bb63	wikidoc	Searching	Searching # Searching WikiDoc - In order to search for a particular article with a given word in it, simply type the word or topic you are looking for into the search box on the left hand side of the screen and press the Search button. - You will also notice there is also a Go button next to the Search button. The Go button only displays pages with the title that you type in. Using GO is a much more restricted search listing only pages with that name! On the other hand, if you know the exact name of the page you want, the GO button allows you to go directly to the page without following links. - Another way to search is through categories. You can click on a category such as Pulmonary or Nephrology on the Main Home Page and you will see a list of all articles that are filed underneath that particular category. To see a list all all of the categories click Special:categories # How Can I See A List of All the Pages in WikiDoc? 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An apostrophe is identical to a single quote, therefore Mu'ammar can be found searching for exactly that (and not otherwise). A word with apostrophe s is an exception in that it can be found also searching for the word without the apostrophe and the s. ## Don't use the Underline Character _ as a Space Note that the underscore (_) is not equivalent to a space: putting it in the URL results in a search for a word containing actual underscores at those positions. ## Be Patient! There is a Delay in Updating the Search Index For reasons of efficiency and priority, very recent changes to pages are not always immediately taken into account in searches. # Search Options ## How do I Browse Through Filenames of the Images? Searching the image namespace means searching the image descriptions, i.e. the first parts of the image pages. For searching the titles, use Special:Imagelist. ## The wikitext is searched The wikitext (source text, what one sees in the edit box) is searched. This distinction is relevant for piped links, for interlanguage links, special characters (if ê is coded as ê it is found searching for ecirc), etc. ## Highlighting Some portions of matching pages that contain the searched-for terms are shown, with the terms highlighted in red. You can set the number of lines extracted and the amount of text per line shown in your preferences. If you search e.g. for "book" you get only pages with that word, not pages with "books" only. However, on pages with "book" and "books", also the part "book" of the word "books" is highlighted.	Searching Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Searching WikiDoc - In order to search for a particular article with a given word in it, simply type the word or topic you are looking for into the search box on the left hand side of the screen and press the Search button. - You will also notice there is also a Go button next to the Search button. 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a3a1ca485b797c719e4eaf14a4f069e2885ca321	wikidoc	Secretion	Secretion # Overview Secretion is the process of segregating, elaborating, and releasing chemicals from a cell, or a secreted chemical substance or amount of substance. In contrast to excretion, the substance may have a certain function, rather than being a waste product. # In humans Secretion in humans include e.g.: - gastrointestinal tract digestive enzymes gastric acid - digestive enzymes - gastric acid - pulmonary surfactant - surfactant ## Mechanism In humans, just as in all eukaryotic cells, there is a highly evolved process of secretion. Proteins targeted for the outside are synthesized by ribosomes docked to the rough endoplasmic reticulum. As they are synthesized, these proteins translocate into the ER lumen, where they are glycosylated and where molecular chaperones aid protein folding. Misfolded proteins are usually identified here and retrotranslocated by ER-associated degradation to the cytosol, where they are degraded by a proteasome. The vesicles containing the properly-folded proteins then enter the Golgi apparatus. In the Golgi apparatus, the glycosylation of the proteins is modified and further posttranslational modifications, including cleavage and functionalization, may occur. The proteins are then moved into secretory vesicles which travel along the cytoskeleton to the edge of the cell. More modification can occur in the secretory vesicles (for example insulin is cleaved from proinsulin in the secretory vesicles). Eventually, the vesicle fuses with the cell membrane in a process called exocytosis, dumping its contents out of the cell's environment. Strict biochemical control is maintained over this sequence by usage of a pH gradient: the pH of the cytosol is 7.4, the ER's pH is 7.0, and the cis-golgi has a pH of 6.5. Secretory vesicles have pHs ranging between 5.0 and 6.0; some secretory vesicles evolve into lysosomes, which have a pH of 4.8. ### Nonclassical secretion There are many proteins like FGF1 (aFGF), FGF2 (bFGF), interleukin1 (IL1) etc which do not have a signal sequence. They do not use the classical ER-golgi pathway. These are secreted through various nonclassical pathways. ## Secretory cells Many human cell types have the ability to be secretory cells. They have a well deloped endoplasmic reticulum and Golgi apparatus to fulfill their function. # Secretion in Gram negative bacteria Secretion is not unique to eukaryotes alone, it is present in bacteria and archaea as well. ATP binding cassette (ABC) type transporters are common to all the three domains of life. The Sec system is also another conserved secretion system which is homologous to the translocon in the eukaryotic endoplasmic reticulum consisting of Sec 61 translocon complex in yeast and Sec Y-E-G complex in bacteria. Gram negative bacteria have two membranes, thus making secretion topologically more complex. So there are at least six specialized secretion system in Gram negative bacteria: ## Type I secretion system It is similar to the ABC transporter, however it has additional proteins that, together with the ABC protein, form a contiguous channel traversing the inner and outer membranes of Gram-negative bacteria. It is a simple system, which consists of only three protein subunits: the ABC protein, membrane fusion protein (MFP), and outer membrane protein (OMP). Type I secretion system transports various molecules, from ions, drugs, to proteins of various sizes (20 - 100 kDa). ## Type II secretion system Proteins secreted through the type II system, or main terminal branch of the general secretory pathway, depend on the Sec system for initial transport into the periplasm. Once there, they pass through the outer membrane via a multimeric complex of secretin proteins. In addition to the secretin protein, 10-15 other inner and outer membrane proteins compose the full secretion apparatus, many with as yet unknown function. Gram-negative type IV pili use a modified version of the type II system for their biogenesis, and in some cases certain proteins are shared between a pilus complex and type II system within a single bacterial species. ## Type III secretion system (T3SS) It is homologous to bacterial flagellar basal body. It is like a molecular syringe through which a bacterium (e.g. certain types of Salmonella, Shigella, Yersinia) can inject proteins into eukaryotic cells. The low Ca2+ concentration in the cytosol opens the gate that regulates T3SS. One such mechanism to detect low calcium concentration has been illustrated by the lcrV (Low Calcium Response) antigen ulitized by Y. pestis, which is used to detect low calcium concentrations and elicits T3SS attachment. The Hrp system in plant pathogens inject harpins through similar mechanisms into plants. This secretion system was first discovered in Y. pestis and showed that toxins could be injected directly from the bacterial cytoplasm into the cytoplasm of its host's cells rather than simply into the extracellular medium. ## Type IV secretion system It is homologous to conjugation machinery of bacteria (and archaeal flagella). It is capable of transporting both DNA and proteins. It was discovered in Agrobacterium tumefaciens, which uses this system to introduce the Ti plasmid and proteins into the host which develops the crown gall (tumor). Helicobactor pylori uses a type IV secretion system to inject Cag A into gastric epithelial cells. Bordetella pertussis, the causative agent of whooping cough, secretes the pertussis toxin partly through the type IV system. ## Type V secretion system Also called the autotransporter system, type V secretion involves use of the sec system for crossing the inner membrane. Proteins which use this pathway have the capability to form a beta-barrel with their C-terminus which inserts into the outer membrane, allowing the rest of the peptide (the passenger domain) to reach the outside of the cell. Often, autotransporters are cleaved, leaving the beta-barrel domain in the outer membrane and freeing the passenger domain. Some people believe remnants of the autotransporters gave rise to the porins which form similar beta-barrel structures. ## Type VI secretion system Secretion of several proteins by the Type VI secretion system from Vibrio cholerae and Pseudomonas aeruginosa was recently described. Proteins secreted by the type VI system lack N-terminal signal sequences. ## Twin-arginine translocation Bacteria as well as mitochondria and chloroplasts also use many other special transport systems such as the twin-arginine translocation (Tat) pathway which, in contrast to Sec-depedendent export, transports fully folded proteins across the membrane. The name of the system comes from the requirement for two consecutive arginines in the signal sequence required for targeting to this system. ## Release of outer membrane vesicles In addition to the use of the multiprotein complexes listed above, Gram-negative bacteria possess another method for release of material: the formation of outer membrane vesicles . Portions of the outer membrane pinch off, forming spherical structures made of a lipid bilayer enclosing periplasmic materials. Vesicles from a number of bacterial species have been found to contain virulence factors, some have immunomodulatory effects, and some can directly adhere to and intoxicate host cells. While release of vesicles has been demonstrated as a general response to stress conditions, the process of loading cargo proteins seems to be selective	Secretion Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Secretion is the process of segregating, elaborating, and releasing chemicals from a cell, or a secreted chemical substance or amount of substance. In contrast to excretion, the substance may have a certain function, rather than being a waste product. # In humans Secretion in humans include e.g.: - gastrointestinal tract digestive enzymes gastric acid - digestive enzymes - gastric acid - pulmonary surfactant - surfactant ## Mechanism In humans, just as in all eukaryotic cells, there is a highly evolved process of secretion. Proteins targeted for the outside are synthesized by ribosomes docked to the rough endoplasmic reticulum. As they are synthesized, these proteins translocate into the ER lumen, where they are glycosylated and where molecular chaperones aid protein folding. Misfolded proteins are usually identified here and retrotranslocated by ER-associated degradation to the cytosol, where they are degraded by a proteasome. The vesicles containing the properly-folded proteins then enter the Golgi apparatus. In the Golgi apparatus, the glycosylation of the proteins is modified and further posttranslational modifications, including cleavage and functionalization, may occur. The proteins are then moved into secretory vesicles which travel along the cytoskeleton to the edge of the cell. More modification can occur in the secretory vesicles (for example insulin is cleaved from proinsulin in the secretory vesicles). Eventually, the vesicle fuses with the cell membrane in a process called exocytosis, dumping its contents out of the cell's environment. Strict biochemical control is maintained over this sequence by usage of a pH gradient: the pH of the cytosol is 7.4, the ER's pH is 7.0, and the cis-golgi has a pH of 6.5. Secretory vesicles have pHs ranging between 5.0 and 6.0; some secretory vesicles evolve into lysosomes, which have a pH of 4.8. ### Nonclassical secretion There are many proteins like FGF1 (aFGF), FGF2 (bFGF), interleukin1 (IL1) etc which do not have a signal sequence. They do not use the classical ER-golgi pathway. These are secreted through various nonclassical pathways. ## Secretory cells Many human cell types have the ability to be secretory cells. They have a well deloped endoplasmic reticulum and Golgi apparatus to fulfill their function. # Secretion in Gram negative bacteria Secretion is not unique to eukaryotes alone, it is present in bacteria and archaea as well. ATP binding cassette (ABC) type transporters are common to all the three domains of life. The Sec system is also another conserved secretion system which is homologous to the translocon in the eukaryotic endoplasmic reticulum consisting of Sec 61 translocon complex in yeast and Sec Y-E-G complex in bacteria. Gram negative bacteria have two membranes, thus making secretion topologically more complex. So there are at least six specialized secretion system in Gram negative bacteria: ## Type I secretion system It is similar to the ABC transporter, however it has additional proteins that, together with the ABC protein, form a contiguous channel traversing the inner and outer membranes of Gram-negative bacteria. It is a simple system, which consists of only three protein subunits: the ABC protein, membrane fusion protein (MFP), and outer membrane protein (OMP). Type I secretion system transports various molecules, from ions, drugs, to proteins of various sizes (20 - 100 kDa). ## Type II secretion system Proteins secreted through the type II system, or main terminal branch of the general secretory pathway, depend on the Sec system for initial transport into the periplasm. Once there, they pass through the outer membrane via a multimeric complex of secretin proteins. In addition to the secretin protein, 10-15 other inner and outer membrane proteins compose the full secretion apparatus, many with as yet unknown function. Gram-negative type IV pili use a modified version of the type II system for their biogenesis, and in some cases certain proteins are shared between a pilus complex and type II system within a single bacterial species. ## Type III secretion system (T3SS) It is homologous to bacterial flagellar basal body. It is like a molecular syringe through which a bacterium (e.g. certain types of Salmonella, Shigella, Yersinia) can inject proteins into eukaryotic cells. The low Ca2+ concentration in the cytosol opens the gate that regulates T3SS. One such mechanism to detect low calcium concentration has been illustrated by the lcrV (Low Calcium Response) antigen ulitized by Y. pestis, which is used to detect low calcium concentrations and elicits T3SS attachment. The Hrp system in plant pathogens inject harpins through similar mechanisms into plants. This secretion system was first discovered in Y. pestis and showed that toxins could be injected directly from the bacterial cytoplasm into the cytoplasm of its host's cells rather than simply into the extracellular medium.[1] ## Type IV secretion system It is homologous to conjugation machinery of bacteria (and archaeal flagella). It is capable of transporting both DNA and proteins. It was discovered in Agrobacterium tumefaciens, which uses this system to introduce the Ti plasmid and proteins into the host which develops the crown gall (tumor). Helicobactor pylori uses a type IV secretion system to inject Cag A into gastric epithelial cells. Bordetella pertussis, the causative agent of whooping cough, secretes the pertussis toxin partly through the type IV system. ## Type V secretion system Also called the autotransporter system[2], type V secretion involves use of the sec system for crossing the inner membrane. Proteins which use this pathway have the capability to form a beta-barrel with their C-terminus which inserts into the outer membrane, allowing the rest of the peptide (the passenger domain) to reach the outside of the cell. Often, autotransporters are cleaved, leaving the beta-barrel domain in the outer membrane and freeing the passenger domain. Some people believe remnants of the autotransporters gave rise to the porins which form similar beta-barrel structures. ## Type VI secretion system Secretion of several proteins by the Type VI secretion system from Vibrio cholerae and Pseudomonas aeruginosa was recently described.[3][4] Proteins secreted by the type VI system lack N-terminal signal sequences. ## Twin-arginine translocation Bacteria as well as mitochondria and chloroplasts also use many other special transport systems such as the twin-arginine translocation (Tat) pathway which, in contrast to Sec-depedendent export, transports fully folded proteins across the membrane. The name of the system comes from the requirement for two consecutive arginines in the signal sequence required for targeting to this system. ## Release of outer membrane vesicles In addition to the use of the multiprotein complexes listed above, Gram-negative bacteria possess another method for release of material: the formation of outer membrane vesicles [5]. Portions of the outer membrane pinch off, forming spherical structures made of a lipid bilayer enclosing periplasmic materials. Vesicles from a number of bacterial species have been found to contain virulence factors, some have immunomodulatory effects, and some can directly adhere to and intoxicate host cells. While release of vesicles has been demonstrated as a general response to stress conditions, the process of loading cargo proteins seems to be selective [6]	https://www.wikidoc.org/index.php/Secrete
ce5256dcac14635fa885a589118383f02e0b7b14	wikidoc	Segrosome	Segrosome # Overview Segrosomes are protein complexes that ensure accurate segregation (partitioning) of plasmids or chromosomes during bacterial cell division. Just as higher forms of life have evolved a complex mitotic apparatus to partition duplicated DNA during cell division, bacteria require a specialized apparatus to partition their duplicated DNA. In bacteria, segrosomes perform the function similar to that performed by mitotic spindle. Therefore, segrosomes can be thought of as minimalist spindles. Segrosomes are usually composed of three basic components- the DNA (plasmid or chromosome) that needs to be segregated into daughter cells, a motor protein that provides the necessary physical forces for accomplishing the segregation and a DNA binding protein that connects the DNA and the motor protein, to form the complete segrosome complex. # Motor proteins present in bacterial segrosomal complexes The majority of motor proteins participating in plasmid segrosomes is comprised of Walker-type or ParM type ATPases. Segrosome formation could be a highly regulated and ordered process to ensure its coupling with the other events of the bacterial cell cycle. Recently segrosomal complexes derived from the tubulin family of cytoskeletal proteins, which are GTPases have been discovered in megaplasmids found in Bacillus species.	Segrosome Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Segrosomes are protein complexes that ensure accurate segregation (partitioning) of plasmids or chromosomes during bacterial cell division. Just as higher forms of life have evolved a complex mitotic apparatus to partition duplicated DNA during cell division, bacteria require a specialized apparatus to partition their duplicated DNA. In bacteria, segrosomes perform the function similar to that performed by mitotic spindle. Therefore, segrosomes can be thought of as minimalist spindles. Segrosomes are usually composed of three basic components- the DNA (plasmid or chromosome) that needs to be segregated into daughter cells, a motor protein that provides the necessary physical forces for accomplishing the segregation and a DNA binding protein that connects the DNA and the motor protein, to form the complete segrosome complex. # Motor proteins present in bacterial segrosomal complexes The majority of motor proteins participating in plasmid segrosomes is comprised of Walker-type or ParM type ATPases. Segrosome formation could be a highly regulated and ordered process to ensure its coupling with the other events of the bacterial cell cycle. Recently segrosomal complexes derived from the tubulin family of cytoskeletal proteins, which are GTPases have been discovered in megaplasmids found in Bacillus species.	https://www.wikidoc.org/index.php/Segrosome
5e212be7b3b6330e7825d55619eeac05f78effb8	wikidoc	Selexipag	Selexipag # 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 Selexipag is a prostacyclin receptor agonist that is FDA approved for the treatment of patients with pulmonary arterial hypertension (PAH, WHO Group I) to delay disease progression and reduce the risk of hospitalization for PAH. Common adverse reactions include headache, diarrhea, jaw pain, nausea, myalgia, vomiting, pain in extremity, and flushing (≥5%).. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Selexipag is indicated for the treatment of pulmonary arterial hypertension (PAH, WHO Group I) to delay disease progression and reduce the risk of hospitalization for PAH. Effectiveness was established in a long-term study in PAH patients with WHO Functional Class II-III symptoms. Patients had idiopathic and heritable PAH (58%), PAH associated with connective tissue disease (29%), PAH associated with congenital heart disease with repaired shunts (10%) - Recommended Dosage The recommended starting dose of Selexipag is 200 micrograms (mcg) given twice daily. Tolerability may be improved when taken with food. Increase the dose in increments of 200 mcg twice daily, usually at weekly intervals, to the highest tolerated dose up to 1600 mcg twice daily. If a patient reaches a dose that cannot be tolerated, the dose should be reduced to the previous tolerated dose. Do not split, crush, or chew tablets. - Interruptions and Discontinuations If a dose of medication is missed, patients should take a missed dose as soon as possible unless the next dose is within the next 6 hours. If treatment is missed for 3 days or more, restart Selexipag at a lower dose and then retitrate. - Dosage Adjustment in Patients with Hepatic Impairment No dose adjustment of Selexipag is necessary for patients with mild hepatic impairment (Child-Pugh class A). For patients with moderate hepatic impairment (Child-Pugh class B), the starting dose of Selexipag is 200 mcg once daily. Increase in increments of 200 mcg once daily at weekly intervals, as tolerated. Avoid use of Selexipag in patients with severe hepatic impairment (Child-Pugh class C). ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Selexipagin adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Selexipag in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) Safety and effectiveness in pediatric patients have not been established. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Selexipag in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Selexipag in pediatric patients. # Contraindications None # Warnings - Pulmonary Veno-Occlusive Disease (PVOD) Should signs of pulmonary edema occur, consider the possibility of associated PVOD. If confirmed, discontinue Selexipag. # 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. The safety of Selexipag has been evaluated in a long-term, placebo-controlled study enrolling 1156 patients with symptomatic PAH (GRIPHON study). The exposure to Selexipag in this trial was up to 4.2 years with median duration of exposure of 1.4 years. TABLE1 presents adverse reactions more frequent on Selexipag than on placebo by ≥3%. - Table 1 Adverse Reactions UPTRAVI: Selexipag's Brand name These adverse reactions are more frequent during the dose titration phase. Hyperthyroidism was observed in 1% (n=8) of patients on Selexipag and in none of the patients on placebo. - Laboratory Test Abnormalities - Hemoglobin In a Phase 3 placebo-controlled study in patients with PAH, mean absolute changes in hemoglobin at regular visits compared to baseline ranged from −0.34 to −0.02 g/dL in the selexipag group compared to −0.05 to 0.25 g/dL in the placebo group. A decrease in hemoglobin concentration to below 10 g/dL was reported in 8.6% of patients treated with selexipag and 5.0% of placebo-treated patients. - Thyroid function tests In a Phase 3 placebo-controlled study in patients with PAH, a reduction (up to −0.3 MU/L from a baseline median of 2.5 MU/L) in median thyroid-stimulating hormone (TSH) was observed at most visits in the selexipag group. In the placebo group, little change in median values was apparent. There were no mean changes in triiodothyronine or thyroxine in either group. ## Postmarketing Experience There is limited information regarding Selexipag Postmarketing Experience in the drug label. # Drug Interactions Strong CYP2C8 Inhibitors: Concomitant administration with strong inhibitors of CYP2C8 may result in a significant increase in exposure to selexipag and its active metabolite. Avoid concomitant administration of Selexipag with strong inhibitors of CYP2C8 (e.g., gemfibrozil). # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Risk Summary There are no adequate and well-controlled studies with Selexipag in pregnant women. Animal reproduction studies performed with selexipag showed no clinically relevant effects on embryofetal development and survival. A slight reduction in maternal as well as in fetal body weight was observed when pregnant rats were administered selexipag during organogenesis at a dose producing an exposure approximately 47 times that in humans at the maximum recommended human dose. No adverse developmental outcomes were observed with oral administration of selexipag to pregnant rabbits during organogenesis at exposures up to 50 times the human exposure at the maximum recommended human dose. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. - Data - Animal Data Pregnant rats were treated with selexipag using oral doses of 2, 6, and 20 mg/kg/day (up to 47 times the exposure at the maximum recommended human dose of 1600 mcg twice daily on an area under the curve basis) during the period of organogenesis (gestation days 7 to 17). Selexipag did not cause adverse developmental effects to the fetus in this study. A slight reduction in fetal body weight was observed in parallel with a slight reduction in maternal body weight at the high dose. Pregnant rabbits were treated with selexipag using oral doses of 3, 10, and 30 mg/kg (up to 50 times the exposure to the active metabolite at the maximum recommended human dose of 1600 mcg twice daily on an AUC basis) during the period of organogenesis (gestation days 6 to 18). Selexipag did not cause adverse developmental effects to the fetus in this study. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Selexipag in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Selexipag during labor and delivery. ### Nursing Mothers It is not known if Selexipag is present in human milk. Selexipag or its metabolites were present in the milk of rats. Because many drugs are present in the human milk and because of the potential for serious adverse reactions in nursing infants, discontinue nursing or discontinue Selexipag. ### Pediatric Use Safety and effectiveness in pediatric patients have not been established. ### Geriatic Use Of the 1368 subjects in clinical studies of Selexipag 248 subjects were 65 years of age and older, while 19 were 75 and older. No overall differences were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity cannot be ruled out. ### Gender There is no FDA guidance on the use of Selexipag with respect to specific gender populations. ### Race There is no FDA guidance on the use of Selexipag with respect to specific racial populations. ### Renal Impairment No adjustment to the dosing regimen is needed in patients with estimated glomerular filtration rate > 15 mL/min/1.73 m2. There is no clinical experience with Selexipag in patients undergoing dialysis or in patients with glomerular filtration rates < 15 mL/min/1.73 m2. ### Hepatic Impairment No adjustment to the dosing regimen is needed in patients with mild hepatic impairment (Child-Pugh class A). A once-daily regimen is recommended in patients with moderate hepatic impairment (Child-Pugh class B) due to the increased exposure to selexipag and its active metabolite. There is no experience with Selexipag in patients with severe hepatic impairment (Child-Pugh class C). Avoid use of Selexipag in patients with severe hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Selexipag in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Selexipag in patients who are immunocompromised. # Administration and Monitoring ### Administration There is limited information regarding Selexipag Administration in the drug label. ### Monitoring There is limited information regarding Selexipag Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Selexipag and IV administrations. # Overdosage Isolated cases of overdose up to 3200 mcg were reported. Mild, transient nausea was the only reported consequence. In the event of overdose, supportive measures must be taken as required. Dialysis is unlikely to be effective because selexipag and its active metabolite are highly protein-bound. # Pharmacology ## Mechanism of Action Selexipag is an oral prostacyclin receptor (IP receptor) agonist that is structurally distinct from prostacyclin. Selexipag is hydrolyzed by carboxylesterase 1 to yield its active metabolite, which is approximately 37-fold as potent as selexipag. Selexipag and the active metabolite are selective for the IP receptor versus other prostanoid receptors (EP(1-4), DP, FP and TP). ## Structure Selexipag is a selective non-prostanoid IP prostacyclin receptor agonist. The chemical name of selexipag is 2-{4-butoxy}-N-(methylsulfonyl) acetamide. It has a molecular formula of C26H32N4O4S and a molecular weight of 496.62. Selexipag has the following structural formula: Selexipag is a pale yellow crystalline powder that is practically insoluble in water. In the solid state selexipag is very stable, is not hygroscopic, and is not light sensitive. Depending on the dose strength, each round film-coated tablet for oral administration contains 200, 400, 600, 800, 1000, 1200, 1400, or 1600 mcg of selexipag. The tablets include the following inactive ingredients: D-mannitol, corn starch, low substituted hydroxypropylcellulose, hydroxypropylcellulose, and magnesium stearate. The tablets are film coated with a coating material containing hypromellose, propylene glycol, titanium dioxide, carnauba wax along with mixtures of iron oxide red, iron oxide yellow or iron oxide black. ## Pharmacodynamics - Cardiac electrophysiology: At the maximum tolerated dose of 1600 mcg twice daily, selexipag does not prolong the QT interval to any clinically relevant extent. - Platelet aggregation: Both selexipag and its active metabolite caused concentration-dependent inhibition of platelet aggregation in vitro with an IC50 of 5.5 µM and 0.21 µM, respectively. However, at clinically relevant concentrations, there was no effect on platelet aggregation test parameters as seen following multiple-dose administrations of selexipag in healthy subjects from 400 mcg up to 1800 mcg twice daily. - Pulmonary hemodynamics: A Phase 2 clinical study assessed hemodynamic variables after 17 weeks of treatment in patients with PAH WHO Functional Class II–III and concomitantly receiving endothelin receptor antagonists (ERAs) and/or phosphodiesterase type 5 (PDE-5) inhibitors. Patients titrating selexipag to an individually tolerated dose (200 mcg twice daily increments up to 800 mcg twice daily) (N=33) achieved a statistically-significant mean reduction in pulmonary vascular resistance of 30.3% (95% confidence interval −44.7%, −12.2%) and an increase in cardiac index (median treatment effect) of 0.41 L/min/m2 (95% CI 0.10, 0.71) compared to placebo (N=10). - Drug interaction: In a study in healthy subjects, selexipag (400 mcg twice a day) did not influence the pharmacodynamic effect of warfarin on the international normalized ratio. ## Pharmacokinetics The pharmacokinetics of selexipag and its active metabolite have been studied primarily in healthy subjects. The pharmacokinetics of selexipag and the active metabolite, after both single- and multiple-dose administration, were dose-proportional up to a single dose of 800 mcg and multiple doses of up to 1800 mcg twice daily. No accumulation in plasma, either of parent compound or active metabolite, occurred after multiple-dose administration. In healthy subjects, inter-subject variability in exposure (area under the curve over a dosing interval, AUC) at steady-state was 43% and 39% for selexipag and the active metabolite, respectively. Intra-subject variability in exposure was 24% and 19% for selexipag and the active metabolite, respectively. Exposures to selexipag and the active metabolite at steady-state in PAH patients and healthy subjects were similar. The pharmacokinetics of selexipag and the active metabolite in PAH patients were not influenced by the severity of the disease and did not change with time. Both in healthy subjects and PAH patients, exposure at steady-state to the active metabolite is approximately 3- to 4-fold that of selexipag. - Absorption Upon oral administration, maximum observed plasma concentrations of selexipag and its active metabolite after oral administration are reached within about 1–3 hours and 3–4 hours, respectively. In the presence of food, the absorption of selexipag was prolonged resulting in a delayed time to peak concentration (Tmax) and ~30% lower peak plasma concentration (Cmax). The exposure to selexipag and the active metabolite (AUC) did not significantly change in the presence of food. - Distribution Selexipag and its active metabolite are highly bound to plasma proteins (approximately 99% in total and to the same extent to albumin and alpha1-acid glycoprotein). - Metabolism Selexipag undergoes enzymatic hydrolysis of the acylsulfonamide by hepatic carboxylesterase 1, to yield the active metabolite. Oxidative metabolism catalyzed by CYP3A4 and CYP2C8 leads to the formation of hydroxylated and dealkylated products. UGT1A3 and UGT2B7 are involved in the glucuronidation of the active metabolite. Except for the active metabolite, none of the circulating metabolites in human plasma exceeds 3% of the total drug-related material. - Elimination Elimination of selexipag is predominately via metabolism with a mean terminal half-life of 0.8-2.5 hours. The active metabolite has a terminal half-life of 6.2-13.5 hours. The apparent oral clearance of selexipag is on average 35 L/hour. - Excretion In a study in healthy subjects with radiolabeled selexipag, approximately 93% of radioactive drug material was eliminated in feces and only 12% in urine. Neither selexipag nor its active metabolite were found in urine. - Specific Populations: No clinically relevant effects of sex, race, age or body weight on the pharmacokinetics of selexipag and its active metabolite have been observed in healthy subjects or PAH patients. - Age: The pharmacokinetic variables (Cmax and AUC) were similar in adult and elderly subjects up to 75 years of age. There was no effect of age on the pharmacokinetics of selexipag and the active metabolite in PAH patients. - Hepatic Impairment: In subjects with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, exposure to selexipag was 2- and 4-fold that seen in healthy subjects. Exposure to the active metabolite of selexipag remained almost unchanged in subjects with mild hepatic impairment and was doubled in subjects with moderate hepatic impairment. Based on pharmacokinetic modeling of data from a study in subjects with hepatic impairment, the exposure to the active metabolite at steady state in subjects with moderate hepatic impairment (Child-Pugh class B) after a once daily regimen is expected to be similar to that in healthy subjects receiving a twice daily regimen. The exposure to selexipag at steady state in these patients during a once daily regimen is predicted to be approximately 2-fold that seen in healthy subjects receiving a twice-daily regimen. - Renal Impairment: A 40-70% increase in exposure (maximum plasma concentration and area under the plasma concentration-time curve) to selexipag and its active metabolite was observed in subjects with severe renal impairment (estimated glomerular filtration rate ≥ 15 mL/min/1.73 m2 and < 30 mL/min/1.73 m2). - Drug Interaction Studies: - In vitro studies Selexipag is hydrolyzed to its active metabolite by hepatic carboxylesterase 1. Selexipag and its active metabolite both undergo oxidative metabolism by CYP2C8 and CYP3A4. The glucuronidation of the active metabolite is catalyzed by UGT1A3 and UGT2B7. Selexipag and its active metabolite are substrates of OATP1B1 and OATP1B3. Selexipag is a substrate of P-gp, and the active metabolite is a substrate of the transporter of breast cancer resistance protein (BCRP). Selexipag and its active metabolite do not inhibit or induce hepatic cytochrome P450 enzymes at clinically relevant concentrations. Selexipag and its active metabolite do not inhibit hepatic or renal transport proteins. The effect of strong inhibitors of CYP2C8 (such as gemfibrozil) on the exposure to selexipag or its active metabolite has not been studied. Concomitant administration with strong inhibitors of CYP2C8 may result in a significant increase in exposure to selexipag and its active metabolite. The results on in vivo drug interaction studies are presented in FIGURE 1. - Figure 1 Effect of Other Drugs on Selexipag and its Active Metabolite (A) and Effect of Selexipag on Warfarin (B) ## Nonclinical Toxicology - Carcinogenesis: In the 2-year carcinogenicity studies, chronic oral administration of selexipag revealed no evidence of carcinogenic potential in rats at 100 mg/kg/day and mice at 500 mg/kg/day. The exposures were more than 25-fold human exposure. - Mutagenesis: Selexipag and the active metabolite are not genotoxic on the basis of the overall evidence of conducted genotoxicity studies. - Fertility: The no effect dose for effects on fertility was 60 mg/kg/day in a study in which rats were administered selexipag orally. This dose corresponded to an exposure of 175-times (active metabolite) the human therapeutic exposure. # Clinical Studies The effect of selexipag on progression of PAH was demonstrated in a multi-center, double-blind, placebo-controlled, parallel group, event-driven study (GRIPHON) in 1156 patients with symptomatic (WHO Functional Class I , II , III , and IV ) PAH. Patients were randomized to either placebo (N = 582), or Selexipag (N = 574). The dose was increased in weekly intervals by increments of 200 mcg twice a day to the highest tolerated dose up to 1600 mcg twice a day. The primary study endpoint was the time to first occurrence up to end-of-treatment of: a) death, b) hospitalization for PAH, c) PAH worsening resulting in need for lung transplantation, or balloon atrial septostomy, d) initiation of parenteral prostanoid therapy or chronic oxygen therapy, or e) other disease progression based on a 15% decrease from baseline in 6MWD plus worsening of Functional Class or need for additional PAH-specific therapy. The mean age was 48 years, the majority of patients were white (65%) and female (80%). Nearly all patients were in WHO Functional Class II and III at baseline. Idiopathic or heritable PAH was the most common etiology in the study population (58%) followed by PAH associated with connective tissue disease (29%), PAH associated with congenital heart disease with repaired shunts (10%), drugs and toxins (2%), and HIV (1%). At baseline, the majority of enrolled patients (80%) were being treated with a stable dose of an endothelin receptor antagonist (15%), a PDE-5 inhibitor (32%), or both (33%). Patients on selexipag achieved doses within the following groups: 200 - 400 mcg (23%), 600 - 1000 mcg (31%) and 1200 - 1600 mcg (43%). Treatment with Selexipag resulted in a 40% reduction (99% CI: 22 to 54%; two-sided log-rank p-value < 0.0001) of the occurrence of primary endpoint events compared to placebo (TABLE 2; FIGURE 2). The beneficial effect of Selexipag was primarily attributable to a reduction in hospitalization for PAH and a reduction in other disease progression events (TABLE 2). The observed benefit of Selexipag was similar regardless of the dose achieved when patients are titrated to their highest tolerated dose. - Figure 2 Kaplan-Meier Estimates of the First Morbidity-Mortality Event in GRIPHON UPTRAVI: Selexipag's Brand name - Table 2 Primary Endpoints and Related Components in GRIPHON UPTRAVI: Selexipag's Brand name It is not known if the excess number of deaths in the selexipag group is drug-related because there were so few deaths and the imbalance was not observed until 18 months into GRIPHON. FIGURES 3A, B and C show time to first event analyses for primary endpoint components of hospitalization for PAH (A), other disease progression (B), and death (C)—all censored 7 days after any primary end point event (because many patients on placebo transitioned to open-label Selexipag at this point). - Figure 3A Hospitalization for PAH as the First Endpoint in GRIPHON UPTRAVI: Selexipag's Brand name - Figure 3B Disease Progression as the First Endpoint in GRIPHON UPTRAVI: Selexipag's Brand name - Figure 3C Death as the First Endpoint in GRIPHON UPTRAVI: Selexipag's Brand name The treatment effect of Selexipag on time to first primary event was consistent irrespective of background PAH therapy (i.e., in combination with ERA, PDE5i, or both, or without background therapy) (FIGURE 4). - Figure 4 Subgroup Analyses of the Primary Endpoint in GRIPHON UPTRAVI: Selexipag's Brand name - 6-Minute Walk Distance (6MWD): Exercise capacity was evaluated as a secondary endpoint. Median absolute change from baseline to week 26 in 6MWD measured at trough (i.e. at approximately 12 hours post-dose) was +4 meters with Selexipag and -9 meters in the placebo group. This resulted in a placebo-corrected median treatment effect of 12 meters (99% CI: 1, 24 meters;two-sided p = 0.005). # How Supplied Selexipag film-coated, round tablets are supplied in the following configurations: Selexipag is also supplied in a Titration Pack that includes a 140 count bottle of 200 mcg tablets and a 60 count bottle of 800 mcg tablets. ## Storage Store at 20°C to 25°C (68°F to 77°F). Excursions are permitted between 15°C and 30°C (59°F and 86°F). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Advise the patient to read the FDA-approved patient labeling (Patient Package Insert). Inform patients: - what to do if they miss a dose - not to split, crush, or chew tablets. # Precautions with Alcohol Alcohol-Selexipag interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names UPTRAVI® # Look-Alike Drug Names There is limited information regarding Selexipag Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Selexipag 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. # Overview Selexipag is a prostacyclin receptor agonist that is FDA approved for the treatment of patients with pulmonary arterial hypertension (PAH, WHO Group I) to delay disease progression and reduce the risk of hospitalization for PAH. Common adverse reactions include headache, diarrhea, jaw pain, nausea, myalgia, vomiting, pain in extremity, and flushing (≥5%).. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Selexipag is indicated for the treatment of pulmonary arterial hypertension (PAH, WHO Group I) to delay disease progression and reduce the risk of hospitalization for PAH. Effectiveness was established in a long-term study in PAH patients with WHO Functional Class II-III symptoms. Patients had idiopathic and heritable PAH (58%), PAH associated with connective tissue disease (29%), PAH associated with congenital heart disease with repaired shunts (10%) - Recommended Dosage The recommended starting dose of Selexipag is 200 micrograms (mcg) given twice daily. Tolerability may be improved when taken with food. Increase the dose in increments of 200 mcg twice daily, usually at weekly intervals, to the highest tolerated dose up to 1600 mcg twice daily. If a patient reaches a dose that cannot be tolerated, the dose should be reduced to the previous tolerated dose. Do not split, crush, or chew tablets. - Interruptions and Discontinuations If a dose of medication is missed, patients should take a missed dose as soon as possible unless the next dose is within the next 6 hours. If treatment is missed for 3 days or more, restart Selexipag at a lower dose and then retitrate. - Dosage Adjustment in Patients with Hepatic Impairment No dose adjustment of Selexipag is necessary for patients with mild hepatic impairment (Child-Pugh class A). For patients with moderate hepatic impairment (Child-Pugh class B), the starting dose of Selexipag is 200 mcg once daily. Increase in increments of 200 mcg once daily at weekly intervals, as tolerated. Avoid use of Selexipag in patients with severe hepatic impairment (Child-Pugh class C). ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Selexipagin adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Selexipag in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) Safety and effectiveness in pediatric patients have not been established. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Selexipag in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Selexipag in pediatric patients. # Contraindications None # Warnings - Pulmonary Veno-Occlusive Disease (PVOD) Should signs of pulmonary edema occur, consider the possibility of associated PVOD. If confirmed, discontinue Selexipag. # 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. The safety of Selexipag has been evaluated in a long-term, placebo-controlled study enrolling 1156 patients with symptomatic PAH (GRIPHON study). The exposure to Selexipag in this trial was up to 4.2 years with median duration of exposure of 1.4 years. TABLE1 presents adverse reactions more frequent on Selexipag than on placebo by ≥3%. - Table 1 Adverse Reactions UPTRAVI: Selexipag's Brand name These adverse reactions are more frequent during the dose titration phase. Hyperthyroidism was observed in 1% (n=8) of patients on Selexipag and in none of the patients on placebo. - Laboratory Test Abnormalities - Hemoglobin In a Phase 3 placebo-controlled study in patients with PAH, mean absolute changes in hemoglobin at regular visits compared to baseline ranged from −0.34 to −0.02 g/dL in the selexipag group compared to −0.05 to 0.25 g/dL in the placebo group. A decrease in hemoglobin concentration to below 10 g/dL was reported in 8.6% of patients treated with selexipag and 5.0% of placebo-treated patients. - Thyroid function tests In a Phase 3 placebo-controlled study in patients with PAH, a reduction (up to −0.3 MU/L from a baseline median of 2.5 MU/L) in median thyroid-stimulating hormone (TSH) was observed at most visits in the selexipag group. In the placebo group, little change in median values was apparent. There were no mean changes in triiodothyronine or thyroxine in either group. ## Postmarketing Experience There is limited information regarding Selexipag Postmarketing Experience in the drug label. # Drug Interactions Strong CYP2C8 Inhibitors: Concomitant administration with strong inhibitors of CYP2C8 may result in a significant increase in exposure to selexipag and its active metabolite. Avoid concomitant administration of Selexipag with strong inhibitors of CYP2C8 (e.g., gemfibrozil). # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Risk Summary There are no adequate and well-controlled studies with Selexipag in pregnant women. Animal reproduction studies performed with selexipag showed no clinically relevant effects on embryofetal development and survival. A slight reduction in maternal as well as in fetal body weight was observed when pregnant rats were administered selexipag during organogenesis at a dose producing an exposure approximately 47 times that in humans at the maximum recommended human dose. No adverse developmental outcomes were observed with oral administration of selexipag to pregnant rabbits during organogenesis at exposures up to 50 times the human exposure at the maximum recommended human dose. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. - Data - Animal Data Pregnant rats were treated with selexipag using oral doses of 2, 6, and 20 mg/kg/day (up to 47 times the exposure at the maximum recommended human dose of 1600 mcg twice daily on an area under the curve [AUC] basis) during the period of organogenesis (gestation days 7 to 17). Selexipag did not cause adverse developmental effects to the fetus in this study. A slight reduction in fetal body weight was observed in parallel with a slight reduction in maternal body weight at the high dose. Pregnant rabbits were treated with selexipag using oral doses of 3, 10, and 30 mg/kg (up to 50 times the exposure to the active metabolite at the maximum recommended human dose of 1600 mcg twice daily on an AUC basis) during the period of organogenesis (gestation days 6 to 18). Selexipag did not cause adverse developmental effects to the fetus in this study. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Selexipag in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Selexipag during labor and delivery. ### Nursing Mothers It is not known if Selexipag is present in human milk. Selexipag or its metabolites were present in the milk of rats. Because many drugs are present in the human milk and because of the potential for serious adverse reactions in nursing infants, discontinue nursing or discontinue Selexipag. ### Pediatric Use Safety and effectiveness in pediatric patients have not been established. ### Geriatic Use Of the 1368 subjects in clinical studies of Selexipag 248 subjects were 65 years of age and older, while 19 were 75 and older. No overall differences were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity cannot be ruled out. ### Gender There is no FDA guidance on the use of Selexipag with respect to specific gender populations. ### Race There is no FDA guidance on the use of Selexipag with respect to specific racial populations. ### Renal Impairment No adjustment to the dosing regimen is needed in patients with estimated glomerular filtration rate > 15 mL/min/1.73 m2. There is no clinical experience with Selexipag in patients undergoing dialysis or in patients with glomerular filtration rates < 15 mL/min/1.73 m2. ### Hepatic Impairment No adjustment to the dosing regimen is needed in patients with mild hepatic impairment (Child-Pugh class A). A once-daily regimen is recommended in patients with moderate hepatic impairment (Child-Pugh class B) due to the increased exposure to selexipag and its active metabolite. There is no experience with Selexipag in patients with severe hepatic impairment (Child-Pugh class C). Avoid use of Selexipag in patients with severe hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Selexipag in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Selexipag in patients who are immunocompromised. # Administration and Monitoring ### Administration There is limited information regarding Selexipag Administration in the drug label. ### Monitoring There is limited information regarding Selexipag Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Selexipag and IV administrations. # Overdosage Isolated cases of overdose up to 3200 mcg were reported. Mild, transient nausea was the only reported consequence. In the event of overdose, supportive measures must be taken as required. Dialysis is unlikely to be effective because selexipag and its active metabolite are highly protein-bound. # Pharmacology ## Mechanism of Action Selexipag is an oral prostacyclin receptor (IP receptor) agonist that is structurally distinct from prostacyclin. Selexipag is hydrolyzed by carboxylesterase 1 to yield its active metabolite, which is approximately 37-fold as potent as selexipag. Selexipag and the active metabolite are selective for the IP receptor versus other prostanoid receptors (EP(1-4), DP, FP and TP). ## Structure Selexipag is a selective non-prostanoid IP prostacyclin receptor agonist. The chemical name of selexipag is 2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl) acetamide. It has a molecular formula of C26H32N4O4S and a molecular weight of 496.62. Selexipag has the following structural formula: Selexipag is a pale yellow crystalline powder that is practically insoluble in water. In the solid state selexipag is very stable, is not hygroscopic, and is not light sensitive. Depending on the dose strength, each round film-coated tablet for oral administration contains 200, 400, 600, 800, 1000, 1200, 1400, or 1600 mcg of selexipag. The tablets include the following inactive ingredients: D-mannitol, corn starch, low substituted hydroxypropylcellulose, hydroxypropylcellulose, and magnesium stearate. The tablets are film coated with a coating material containing hypromellose, propylene glycol, titanium dioxide, carnauba wax along with mixtures of iron oxide red, iron oxide yellow or iron oxide black. ## Pharmacodynamics - Cardiac electrophysiology: At the maximum tolerated dose of 1600 mcg twice daily, selexipag does not prolong the QT interval to any clinically relevant extent. - Platelet aggregation: Both selexipag and its active metabolite caused concentration-dependent inhibition of platelet aggregation in vitro with an IC50 of 5.5 µM and 0.21 µM, respectively. However, at clinically relevant concentrations, there was no effect on platelet aggregation test parameters as seen following multiple-dose administrations of selexipag in healthy subjects from 400 mcg up to 1800 mcg twice daily. - Pulmonary hemodynamics: A Phase 2 clinical study assessed hemodynamic variables after 17 weeks of treatment in patients with PAH WHO Functional Class II–III and concomitantly receiving endothelin receptor antagonists (ERAs) and/or phosphodiesterase type 5 (PDE-5) inhibitors. Patients titrating selexipag to an individually tolerated dose (200 mcg twice daily increments up to 800 mcg twice daily) (N=33) achieved a statistically-significant mean reduction in pulmonary vascular resistance of 30.3% (95% confidence interval [CI] −44.7%, −12.2%) and an increase in cardiac index (median treatment effect) of 0.41 L/min/m2 (95% CI 0.10, 0.71) compared to placebo (N=10). - Drug interaction: In a study in healthy subjects, selexipag (400 mcg twice a day) did not influence the pharmacodynamic effect of warfarin on the international normalized ratio. ## Pharmacokinetics The pharmacokinetics of selexipag and its active metabolite have been studied primarily in healthy subjects. The pharmacokinetics of selexipag and the active metabolite, after both single- and multiple-dose administration, were dose-proportional up to a single dose of 800 mcg and multiple doses of up to 1800 mcg twice daily. No accumulation in plasma, either of parent compound or active metabolite, occurred after multiple-dose administration. In healthy subjects, inter-subject variability in exposure (area under the curve over a dosing interval, AUC) at steady-state was 43% and 39% for selexipag and the active metabolite, respectively. Intra-subject variability in exposure was 24% and 19% for selexipag and the active metabolite, respectively. Exposures to selexipag and the active metabolite at steady-state in PAH patients and healthy subjects were similar. The pharmacokinetics of selexipag and the active metabolite in PAH patients were not influenced by the severity of the disease and did not change with time. Both in healthy subjects and PAH patients, exposure at steady-state to the active metabolite is approximately 3- to 4-fold that of selexipag. - Absorption Upon oral administration, maximum observed plasma concentrations of selexipag and its active metabolite after oral administration are reached within about 1–3 hours and 3–4 hours, respectively. In the presence of food, the absorption of selexipag was prolonged resulting in a delayed time to peak concentration (Tmax) and ~30% lower peak plasma concentration (Cmax). The exposure to selexipag and the active metabolite (AUC) did not significantly change in the presence of food. - Distribution Selexipag and its active metabolite are highly bound to plasma proteins (approximately 99% in total and to the same extent to albumin and alpha1-acid glycoprotein). - Metabolism Selexipag undergoes enzymatic hydrolysis of the acylsulfonamide by hepatic carboxylesterase 1, to yield the active metabolite. Oxidative metabolism catalyzed by CYP3A4 and CYP2C8 leads to the formation of hydroxylated and dealkylated products. UGT1A3 and UGT2B7 are involved in the glucuronidation of the active metabolite. Except for the active metabolite, none of the circulating metabolites in human plasma exceeds 3% of the total drug-related material. - Elimination Elimination of selexipag is predominately via metabolism with a mean terminal half-life of 0.8-2.5 hours. The active metabolite has a terminal half-life of 6.2-13.5 hours. The apparent oral clearance of selexipag is on average 35 L/hour. - Excretion In a study in healthy subjects with radiolabeled selexipag, approximately 93% of radioactive drug material was eliminated in feces and only 12% in urine. Neither selexipag nor its active metabolite were found in urine. - Specific Populations: No clinically relevant effects of sex, race, age or body weight on the pharmacokinetics of selexipag and its active metabolite have been observed in healthy subjects or PAH patients. - Age: The pharmacokinetic variables (Cmax and AUC) were similar in adult and elderly subjects up to 75 years of age. There was no effect of age on the pharmacokinetics of selexipag and the active metabolite in PAH patients. - Hepatic Impairment: In subjects with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, exposure to selexipag was 2- and 4-fold that seen in healthy subjects. Exposure to the active metabolite of selexipag remained almost unchanged in subjects with mild hepatic impairment and was doubled in subjects with moderate hepatic impairment. Based on pharmacokinetic modeling of data from a study in subjects with hepatic impairment, the exposure to the active metabolite at steady state in subjects with moderate hepatic impairment (Child-Pugh class B) after a once daily regimen is expected to be similar to that in healthy subjects receiving a twice daily regimen. The exposure to selexipag at steady state in these patients during a once daily regimen is predicted to be approximately 2-fold that seen in healthy subjects receiving a twice-daily regimen. - Renal Impairment: A 40-70% increase in exposure (maximum plasma concentration and area under the plasma concentration-time curve) to selexipag and its active metabolite was observed in subjects with severe renal impairment (estimated glomerular filtration rate ≥ 15 mL/min/1.73 m2 and < 30 mL/min/1.73 m2). - Drug Interaction Studies: - In vitro studies Selexipag is hydrolyzed to its active metabolite by hepatic carboxylesterase 1. Selexipag and its active metabolite both undergo oxidative metabolism by CYP2C8 and CYP3A4. The glucuronidation of the active metabolite is catalyzed by UGT1A3 and UGT2B7. Selexipag and its active metabolite are substrates of OATP1B1 and OATP1B3. Selexipag is a substrate of P-gp, and the active metabolite is a substrate of the transporter of breast cancer resistance protein (BCRP). Selexipag and its active metabolite do not inhibit or induce hepatic cytochrome P450 enzymes at clinically relevant concentrations. Selexipag and its active metabolite do not inhibit hepatic or renal transport proteins. The effect of strong inhibitors of CYP2C8 (such as gemfibrozil) on the exposure to selexipag or its active metabolite has not been studied. Concomitant administration with strong inhibitors of CYP2C8 may result in a significant increase in exposure to selexipag and its active metabolite. The results on in vivo drug interaction studies are presented in FIGURE 1. - Figure 1 Effect of Other Drugs on Selexipag and its Active Metabolite (A) and Effect of Selexipag on Warfarin (B) ## Nonclinical Toxicology - Carcinogenesis: In the 2-year carcinogenicity studies, chronic oral administration of selexipag revealed no evidence of carcinogenic potential in rats at 100 mg/kg/day and mice at 500 mg/kg/day. The exposures were more than 25-fold human exposure. - Mutagenesis: Selexipag and the active metabolite are not genotoxic on the basis of the overall evidence of conducted genotoxicity studies. - Fertility: The no effect dose for effects on fertility was 60 mg/kg/day in a study in which rats were administered selexipag orally. This dose corresponded to an exposure of 175-times (active metabolite) the human therapeutic exposure. # Clinical Studies The effect of selexipag on progression of PAH was demonstrated in a multi-center, double-blind, placebo-controlled, parallel group, event-driven study (GRIPHON) in 1156 patients with symptomatic (WHO Functional Class I [0.8%], II [46%], III [53%], and IV [1%] ) PAH. Patients were randomized to either placebo (N = 582), or Selexipag (N = 574). The dose was increased in weekly intervals by increments of 200 mcg twice a day to the highest tolerated dose up to 1600 mcg twice a day. The primary study endpoint was the time to first occurrence up to end-of-treatment of: a) death, b) hospitalization for PAH, c) PAH worsening resulting in need for lung transplantation, or balloon atrial septostomy, d) initiation of parenteral prostanoid therapy or chronic oxygen therapy, or e) other disease progression based on a 15% decrease from baseline in 6MWD plus worsening of Functional Class or need for additional PAH-specific therapy. The mean age was 48 years, the majority of patients were white (65%) and female (80%). Nearly all patients were in WHO Functional Class II and III at baseline. Idiopathic or heritable PAH was the most common etiology in the study population (58%) followed by PAH associated with connective tissue disease (29%), PAH associated with congenital heart disease with repaired shunts (10%), drugs and toxins (2%), and HIV (1%). At baseline, the majority of enrolled patients (80%) were being treated with a stable dose of an endothelin receptor antagonist (15%), a PDE-5 inhibitor (32%), or both (33%). Patients on selexipag achieved doses within the following groups: 200 - 400 mcg (23%), 600 - 1000 mcg (31%) and 1200 - 1600 mcg (43%). Treatment with Selexipag resulted in a 40% reduction (99% CI: 22 to 54%; two-sided log-rank p-value < 0.0001) of the occurrence of primary endpoint events compared to placebo (TABLE 2; FIGURE 2). The beneficial effect of Selexipag was primarily attributable to a reduction in hospitalization for PAH and a reduction in other disease progression events (TABLE 2). The observed benefit of Selexipag was similar regardless of the dose achieved when patients are titrated to their highest tolerated dose. - Figure 2 Kaplan-Meier Estimates of the First Morbidity-Mortality Event in GRIPHON UPTRAVI: Selexipag's Brand name - Table 2 Primary Endpoints and Related Components in GRIPHON UPTRAVI: Selexipag's Brand name It is not known if the excess number of deaths in the selexipag group is drug-related because there were so few deaths and the imbalance was not observed until 18 months into GRIPHON. FIGURES 3A, B and C show time to first event analyses for primary endpoint components of hospitalization for PAH (A), other disease progression (B), and death (C)—all censored 7 days after any primary end point event (because many patients on placebo transitioned to open-label Selexipag at this point). - Figure 3A Hospitalization for PAH as the First Endpoint in GRIPHON UPTRAVI: Selexipag's Brand name - Figure 3B Disease Progression as the First Endpoint in GRIPHON UPTRAVI: Selexipag's Brand name - Figure 3C Death as the First Endpoint in GRIPHON UPTRAVI: Selexipag's Brand name The treatment effect of Selexipag on time to first primary event was consistent irrespective of background PAH therapy (i.e., in combination with ERA, PDE5i, or both, or without background therapy) (FIGURE 4). - Figure 4 Subgroup Analyses of the Primary Endpoint in GRIPHON UPTRAVI: Selexipag's Brand name - 6-Minute Walk Distance (6MWD): Exercise capacity was evaluated as a secondary endpoint. Median absolute change from baseline to week 26 in 6MWD measured at trough (i.e. at approximately 12 hours post-dose) was +4 meters with Selexipag and -9 meters in the placebo group. This resulted in a placebo-corrected median treatment effect of 12 meters (99% CI: 1, 24 meters;two-sided p = 0.005). # How Supplied Selexipag film-coated, round tablets are supplied in the following configurations: Selexipag is also supplied in a Titration Pack [NDC 66215-628-20] that includes a 140 count bottle of 200 mcg tablets and a 60 count bottle of 800 mcg tablets. ## Storage Store at 20°C to 25°C (68°F to 77°F). Excursions are permitted between 15°C and 30°C (59°F and 86°F). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Advise the patient to read the FDA-approved patient labeling (Patient Package Insert). Inform patients: - what to do if they miss a dose - not to split, crush, or chew tablets. # Precautions with Alcohol Alcohol-Selexipag interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names UPTRAVI® # Look-Alike Drug Names There is limited information regarding Selexipag Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Selexipag
4fae1b51704ac2b7fe1987b82fc2a1b5f36f4807	wikidoc	Serelaxin	Serelaxin # Overview Serelaxin (RLX030) is an investigational drug for the treatment of acute heart failure (AHF), targeting the relaxin receptor. Serelaxin is a recombinant form of human relaxin-2, a hormone that (among other functions) is produced during pregnancy and mediates the haemodynamic changes that occur during this time, such as increased blood output of the heart and blood flow in the kidney. Human-relaxin-2 mediates vasodilation (widening of blood vessels) by increasing the production of nitric oxide (NO), a potent vasodilator. Activation of the relaxin receptor RXFP1 activates several enzymes in a phosphorylation cascade that eventually results in the activation of NO synthase in endothelial cells and the subsequent production of NO. Relaxin can also bind to a secondary receptor, endothelial B receptor, which is upregulated as a result of the previous pathway. Relaxin binding to endothelial B receptor on endothelial cells also induces vasodilation. Relaxin causes vasodilation by an indirect mechanism, where it inhibits the potent vasoconstrictors angiotensin II and endothelin. In addition to vasodilation, the effects of relaxin are also seen in the kidneys, by significantly increasing creatinine clearance, which is a measure of kidney function, as well as increased renal blood flow. Relaxin also functions as a cardiac stimulant. Studies have demonstrated that relaxin increases calcium sensitivity of cardiac myofilaments as well as increasing phosphorylation of the myofilaments by protein kinase C (PKC). These modifications both function to increase the force generated by the myofilaments without increasing the energy consumption of the cardiac myocytes. Thus relaxin and serelaxin can increase stroke volume, the amount of blood pumped per heart beat, without increasing the energy demand on the already strained heart of acute heart failure patients. # Acute heart failure Serelaxin is currently undergoing clinical trials in patients with acute heart failure, and is being developed by Novartis. Serelaxin has completed several clinical trials as a therapy for AHF. Phase I trials examined safety and tolerability, while phase II trials evaluated its haemodynamic effects and symptom relief. The Pre-RELAX-AHF phase II trial administered a dose of 30 µg/kg/day and showed a decrease in blood pressure, improved dyspnoea, and increased renal blood flow. In phase III the RELAX-AHF trial gave a 48hr intravenous infusion of the same dose. It significantly improved patients' dyspnoea, resulted in a 30% reduction in worsening of heart failure symptoms, a decreased hospital stay and a reduction in signs and symptoms of congestion. The FDA has granted serelaxin "breakthrough therapy" designation, meant to expedite the development and review of drugs for life threatening conditions and is set to be reviewed in February 2014.	Serelaxin Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kiran Singh, M.D. [2] # Overview Serelaxin (RLX030) is an investigational drug for the treatment of acute heart failure (AHF), targeting the relaxin receptor. Serelaxin is a recombinant form of human relaxin-2, a hormone that (among other functions) is produced during pregnancy and mediates the haemodynamic changes that occur during this time, such as increased blood output of the heart and blood flow in the kidney. Human-relaxin-2 mediates vasodilation (widening of blood vessels) by increasing the production of nitric oxide (NO), a potent vasodilator. Activation of the relaxin receptor RXFP1 activates several enzymes in a phosphorylation cascade that eventually results in the activation of NO synthase in endothelial cells and the subsequent production of NO. Relaxin can also bind to a secondary receptor, endothelial B receptor, which is upregulated as a result of the previous pathway. Relaxin binding to endothelial B receptor on endothelial cells also induces vasodilation. Relaxin causes vasodilation by an indirect mechanism, where it inhibits the potent vasoconstrictors angiotensin II and endothelin. In addition to vasodilation, the effects of relaxin are also seen in the kidneys, by significantly increasing creatinine clearance, which is a measure of kidney function, as well as increased renal blood flow. Relaxin also functions as a cardiac stimulant. Studies have demonstrated that relaxin increases calcium sensitivity of cardiac myofilaments as well as increasing phosphorylation of the myofilaments by protein kinase C (PKC). These modifications both function to increase the force generated by the myofilaments without increasing the energy consumption of the cardiac myocytes. Thus relaxin and serelaxin can increase stroke volume, the amount of blood pumped per heart beat, without increasing the energy demand on the already strained heart of acute heart failure patients. # Acute heart failure Serelaxin is currently undergoing clinical trials in patients with acute heart failure, and is being developed by Novartis. Serelaxin has completed several clinical trials as a therapy for AHF. Phase I trials examined safety and tolerability, while phase II trials evaluated its haemodynamic effects and symptom relief. The Pre-RELAX-AHF phase II trial administered a dose of 30 µg/kg/day and showed a decrease in blood pressure, improved dyspnoea, and increased renal blood flow. In phase III the RELAX-AHF trial gave a 48hr intravenous infusion of the same dose. It significantly improved patients' dyspnoea, resulted in a 30% reduction in worsening of heart failure symptoms, a decreased hospital stay and a reduction in signs and symptoms of congestion. The FDA has granted serelaxin "breakthrough therapy" designation, meant to expedite the development and review of drugs for life threatening conditions and is set to be reviewed in February 2014.	https://www.wikidoc.org/index.php/Serelaxin
326d6f48351afdce7386908066aada48896ac0d7	wikidoc	Set point	Set point Set point or setpoint might mean one of: - Set point (tennis), a tennis term meaning one player is one point away from winning a set - Set point (electronics), a term which refers to the point at which an electrical circuit is either activated or de-activated - Set point (medicine), a term referring to any one of a number of quantities (e.g. body weight, body temperature) which the body tries to keep at a particular value (see also homeostasis) - Setpoint (control system), the target value that an automatic control system, for example PID controller, will aim to reach - SetPoint, the driver suite for Logitech mice	Set point Set point or setpoint might mean one of: - Set point (tennis), a tennis term meaning one player is one point away from winning a set - Set point (electronics), a term which refers to the point at which an electrical circuit is either activated or de-activated - Set point (medicine), a term referring to any one of a number of quantities (e.g. body weight, body temperature) which the body tries to keep at a particular value (see also homeostasis) - Setpoint (control system), the target value that an automatic control system, for example PID controller, will aim to reach - SetPoint, the driver suite for Logitech mice Template:Disambig Template:WS	https://www.wikidoc.org/index.php/Set_point
5f9f6e7892985a1a70fc61b4f5ebe917c5dec83f	wikidoc	Sevelamer	Sevelamer # 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 Sevelamer is a phosphate binder that is FDA approved for the {{{indicationType}}} of chronic kidney disease on dialysis. Common adverse reactions include nausea, vomiting, diarrhea, dyspepsia, abdominal pain, flatulence and constipation. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Dosing Information - Renvela should be given three times a day with meals. - Patients Not Taking a Phosphate Binder. The recommended starting dose of Renvela is 0.8 to 1.6 g with meals based on serum phosphorus level. Table 1 provides recommended starting doses of Renvela for patients not taking a phosphate binder. - Switching from Sevelamer Hydrochloride Tablets. For patients switching from sevelamer hydrochloride tablets to sevelamer carbonate tablets or powder, use the same dose in grams. Further titration may be necessary to achieve desired phosphorus levels. The highest daily dose of sevelamer carbonate studied was 14 grams in CKD patients on dialysis. - Switching between Sevelamer Carbonate Tablets and Powder. Use the same dose in grams. Further titration may be necessary to achieve desired phosphorus levels. - Switching from Calcium Acetate. In a study in 84 CKD patients on hemodialysis, a similar reduction in serum phosphorus was seen with equivalent doses (approximately mg for mg) of sevelamer hydrochloride and calcium acetate. Table 2 gives recommended starting doses of Renvela based on a patient’s current calcium acetate dose. - Dose Titration for All Patients Taking Renvela. Titrate the Renvela dose by 0.8 g three times per day with meals at two-week intervals as necessary with the goal of controlling serum phosphorus within the target range. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Sevelamer in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Sevelamer in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Sevelamer in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Sevelamer in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Sevelamer in pediatric patients. # Contraindications - Renvela is contraindicated in patients with bowel obstruction. # Warnings ### Precautions - Gastrointestinal Adverse Events - Cases of dysphagia and esophageal tablet retention have been reported in association with use of the tablet formulation of sevelamer, some requiring hospitalization and intervention. Consider using sevelamer suspension in patients with a history of swallowing disorders. - Cases of bowel obstruction and perforation have also been reported with sevelamer use. - Patients with dysphagia, swallowing disorders, severe gastrointestinal (GI) motility disorders including severe constipation, or major GI tract surgery were not included in the Renvela clinical studies. - Monitor Serum Chemistries - Bicarbonate and chloride levels should be monitored. - Monitor for Reduced Vitamins D, E, K (clotting factors) and Folic Acid Levels - In preclinical studies in rats and dogs, sevelamer hydrochloride, which contains the same active moiety as sevelamer carbonate, reduced vitamins D, E, and K (coagulation parameters) and folic acid levels at doses of 6‑10 times the recommended human dose. In short-term clinical trials, there was no evidence of reduction in serum levels of vitamins. However, in a one-year clinical trial, 25-hydroxyvitamin D (normal range 10 to 55 ng/mL) fell from 39 ± 22 ng/mL to 34 ± 22 ng/mL (p<0.01) with sevelamer hydrochloride treatment. Most (approximately 75%) patients in sevelamer hydrochloride clinical trials received vitamin supplements, which is typical of patients on dialysis. # 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 can not be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. - There are limited data on the safety of Renvela. However, based on the fact that it contains the same active ingredient as the hydrochloride salt, the adverse event profiles of the two salts should be similar. In a cross-over study in hemodialysis patients with treatment durations of eight weeks each and no washout the adverse reactions on sevelamer carbonate tablets were similar to those reported for sevelamer hydrochloride. In another cross-over study in hemodialysis patients, with treatment durations of four weeks each and no washout between treatment periods, the adverse reactions on sevelamer carbonate powder were similar to those reported for sevelamer hydrochloride. - In a parallel design study of sevelamer hydrochloride with treatment duration of 52 weeks, adverse reactions reported for sevelamer hydrochloride (n=99) were similar to those reported for the active-comparator group (n=101). Overall adverse reactions among those treated with sevelamer hydrochloride occurring in > 5% of patients included: vomiting (22%), nausea (20%), diarrhea (19%), dyspepsia (16%), abdominal pain (9%), flatulence (8%) and constipation (8%). A total of 27 patients treated with sevelamer and 10 patients treated with comparator withdrew from the study due to adverse reactions. - Based on studies of 8-52 weeks, the most common reason for withdrawal from sevelamer hydrochloride was gastrointestinal adverse reactions (3-16%). - In one hundred and forty-three peritoneal dialysis patients studied for 12 weeks using sevelamer hydrochloride, most adverse reactions were similar to adverse reactions observed in hemodialysis patients. The most frequently occurring treatment emergent serious adverse reaction was peritonitis (8 reactions in 8 patients in the sevelamer group and 2 reactions in 2 patients on active-control). Thirteen patients (14%) in the sevelamer group and 9 patients (20%) in the active-control group discontinued, mostly for gastrointestinal adverse reactions. Patients on peritoneal dialysis should be closely monitored to ensure the reliable use of appropriate aseptic technique with the prompt recognition and management of any signs and symptoms associated with peritonitis. ## Postmarketing Experience - Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or to establish a causal relationship to drug exposure. - The following adverse reactions have been identified during post-approval use of sevelamer hydrochloride, which has the same active moiety as sevelamer carbonate: pruritus, rash, abdominal pain, fecal impaction, and uncommon cases of ileus, intestinal obstruction, and intestinal perforation. Appropriate medical management should be given to patients who develop constipation or have worsening of existing constipation to avoid severe complications. # Drug Interactions - Ciprofloxacin - In a study of 15 healthy subjects, a co-administered single dose of 2.8 grams of sevelamer hydrochloride decreased the bioavailability of ciprofloxacin by approximately 50%. - Digoxin - In 19 healthy subjects receiving 2.4 grams of sevelamer hydrochloride three times a day with meals for 2 days, sevelamer did not alter the pharmacokinetics of a single dose of digoxin. - In 18 healthy subjects receiving 9.6 grams of sevelamer carbonate once daily with a meal, sevelamer did not alter the pharmacokinetics of a single dose of digoxin. - Warfarin - In 14 healthy subjects receiving 2.4 g of sevelamer hydrochloride three times a day with meals for two days sevelamer did not alter the pharmacokinetics of a single dose of warfarin. - In 14 healthy subjects receiving 9.6 grams of sevelamer carbonate once daily with a meal, sevelamer did not alter the pharmacokinetics of a single dose of warfarin. - Enalapril - In 28 healthy subjects a single 2.4 gram dose of sevelamer hydrochloride did not alter the pharmacokinetics of a single dose of enalapril. - Metoprolol - In 31 healthy subjects a single 2.4 gram dose of sevelamer hydrochloride did not alter the pharmacokinetics of a single dose of metoprolol. - Iron - In 23 healthy subjects, a single 2.8 gram dose of sevelamer hydrochloride did not alter the absorption of a single oral dose of iron as 200 mg exsiccated ferrous sulfate tablet. - Other Concomitant Drug Therapy - There are no empirical data on avoiding drug interactions between Renvela and most concomitant drugs. During postmarketing experience, very rare cases of increased thyroid stimulating hormone (TSH) levels have been reported in patients co-administered sevelamer hydrochloride and levothyroxine. Monitor TSH levels and signs of hypothyroidism in patients receiving both medications. - When administering an oral medication where a reduction in the bioavailability of that medication would have a clinically significant effect on its safety or efficacy, there is no information that suggests a dosing regimen that would be universally appropriate for all drugs. One may, however, administer the drug one hour before or three hours after Renvela, and monitor blood levels of the drug. Patients taking anti-arrhythmic medications for the control of arrhythmias and anti-seizure medications for the control of seizure disorders were excluded from the clinical trials. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - There are no adequate and well-controlled studies in pregnant women. Sevelamer products should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. - The effect of sevelamer hydrochloride on the absorption of vitamins and other nutrients has not been studied in pregnant women. Requirements for vitamins and other nutrients are increased in pregnancy. In pregnant rats given doses of sevelamer hydrochloride during organogenesis, reduced or irregular ossification of fetal bones, probably due to a reduced absorption of fat-soluble vitamin D, occurred at a dose approximately equal to the maximum clinical trial dose of 13 g on a body surface area basis. In pregnant rabbits given oral doses of sevelamer hydrochloride by gavage during organogenesis, an increase of early resorptions occurred at dose approximately twice the maximum clinical trial dose on a body surface area basis. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Sevelamer in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Sevelamer during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Sevelamer with respect to nursing mothers. ### Pediatric Use There is no FDA guidance on the use of Sevelamer with respect to pediatric patients. ### Geriatic Use There is no FDA guidance on the use of Sevelamer with respect to geriatric patients. ### Gender There is no FDA guidance on the use of Sevelamer with respect to specific gender populations. ### Race There is no FDA guidance on the use of Sevelamer with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Sevelamer in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Sevelamer in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Sevelamer in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Sevelamer in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring - Bicarbonate and chloride levels should be monitored. - Patients on peritoneal dialysis should be closely monitored to ensure the reliable use of appropriate aseptic technique with the prompt recognition and management of any signs and symptoms associated with peritonitis. - Monitor TSH levels and signs of hypothyroidism in patients receiving both sevelamer and levothyroxine. # IV Compatibility There is limited information regarding IV Compatibility of Sevelamer in the drug label. # Overdosage ## Chronic Overdose There is limited information regarding Chronic Overdose of Sevelamer in the drug label. # Pharmacology ## Mechanism of Action - Renvela contains sevelamer carbonate, a non-absorbed phosphate binding crosslinked polymer, free of metal and calcium. It contains multiple amines separated by one carbon from the polymer backbone. These amines exist in a protonated form in the intestine and interact with phosphate molecules through ionic and hydrogen bonding. By binding phosphate in the gastrointestinal tract and decreasing absorption, sevelamer carbonate lowers the phosphate concentration in the serum (serum phosphorus). ## Structure - The active ingredient in Renvela is sevelamer carbonate, a polymeric amine that binds phosphate and is meant for oral administration. It was developed as a pharmaceutical alternative to sevelamer hydrochloride (Renagel®). Sevelamer carbonate is an anion exchange resin, with the same polymeric structure as sevelamer hydrochloride, in which carbonate replaces chloride as the counterion. While the counterions differ for the two salts, the polymer itself, the active moiety involved in phosphate binding, is the same. - Renvela (sevelamer carbonate) is known chemically as poly(allylamine-co-N,N’-diallyl-1,3-diamino-2-hydroxypropane) carbonate salt. Sevelamer carbonate is hygroscopic, but insoluble in water. The structure is represented in Figure 1. ## Pharmacodynamics - In addition to effects on serum phosphorus levels, sevelamer hydrochloride has been shown to bind bile acids in vitro and in vivo in experimental animal models. Bile acid binding by ion exchange resins is a well-established method of lowering blood cholesterol. Because sevelamer binds bile acids, it may interfere with normal fat absorption and thus may reduce absorption of fat soluble vitamins such as A, D and K. In clinical trials of sevelamer hydrochloride, both the mean total and LDL cholesterol declined by 15-31%. This effect is observed after 2 weeks. Triglycerides, HDL cholesterol and albumin did not change. ## Pharmacokinetics - A mass balance study using 14C-sevelamer hydrochloride, in 16 healthy male and female volunteers showed that sevelamer hydrochloride is not systemically absorbed. No absorption studies have been performed in patients with renal disease. ## Nonclinical Toxicology - Carcinogenesis, Mutagenesis, Impairment of Fertility - Standard lifetime carcinogenicity bioassays were conducted in mice and rats. Rats were given sevelamer hydrochloride by diet at 0.3, 1, or 3 g/kg/day. There was an increased incidence of urinary bladder transitional cell papilloma in male rats of the high dose group (human equivalent dose twice the maximum clinical trial dose of 13 g). Mice received dietary administration of sevelamer hydrochloride at doses of up to 9 g/kg/day (human equivalent dose 3 times the maximum clinical trial dose). There was no increased incidence of tumors observed in mice. - In an in vitro mammalian cytogenetic test with metabolic activation, sevelamer hydrochloride caused a statistically significant increase in the number of structural chromosome aberrations. Sevelamer hydrochloride was not mutagenic in the Ames bacterial mutation assay. - Sevelamer hydrochloride did not impair the fertility of male or female rats in a dietary administration study in which the females were treated from 14 days prior to mating through gestation and the males were treated for 28 days prior to mating. The highest dose in this study was 4.5 g/kg/day (human equivalent dose 3 times the maximum clinical trial dose of 13 g). - Developmental Toxicity - In pregnant rats given dietary doses of 0.5, 1.5 or 4.5 g/kg/day of sevelamer hydrochloride during organogenesis, reduced or irregular ossification of fetal bones, probably due to a reduced absorption of fat-soluble vitamin D, occurred in mid- and high-dose groups (human equivalent doses approximately equal to 3-4 times the maximum clinical trial dose of 13 g). In pregnant rabbits given oral doses of 100, 500 or 1000 mg/kg/day of sevelamer hydrochloride by gavage during organogenesis, an increase of early resorptions occurred in the high-dose group (human equivalent dose twice the maximum clinical trial dose). # Clinical Studies - The ability of sevelamer to control serum phosphorus in CKD patients on dialysis was predominantly determined from the effects of the hydrochloride salt to bind phosphate. Six clinical trials used sevelamer hydrochloride and three clinical trials used sevelamer carbonate. The sevelamer hydrochloride studies include one double-blind, placebo-controlled 2-week study (sevelamer N=24); two open-label, uncontrolled, 8-week studies (sevelamer N=220) and three active-controlled open-label studies with treatment durations of 8 to 52 weeks (sevelamer N=256). The sevelamer carbonate studies include one double-blind, active-controlled, cross-over study with two 8-week treatment periods using sevelamer carbonate tablets (N=79), one open-label, active-controlled, cross-over study with two 4-week treatment periods using sevelamer carbonate powder (N=31) and one randomized, parallel, open-label study using sevelamer carbonate powder (N=144) dosed once daily or sevelamer hydrochloride tablets (N=73) dosed three times daily for 24 weeks. Six of the active-controlled studies are described here (three sevelamer carbonate and three sevelamer hydrochloride studies). - Stage 5 CKD patients on hemodialysis were entered into a five-week sevelamer hydrochloride run-in period and 79 patients received, in random order, sevelamer carbonate 800 mg tablets and sevelamer hydrochloride 800 mg tablets for eight weeks each, with no intervening washout. Study dose during the cross-over period was determined based on the sevelamer hydrochloride dose during the run-in period on a gram per gram basis. The phosphorus levels at the end of each of the two cross-over periods were similar. Average actual daily dose was 6 g/day divided among meals for both treatments. Thirty-nine of those completing the cross-over portion of the study were entered into a two-week washout period during which patients were instructed not to take any phosphate binders; this confirmed the activity of sevelamer in this study. - Stage 5 CKD patients on hemodialysis were entered into a four-week sevelamer hydrochloride run-in period and 31 patients received, in random order, sevelamer carbonate powder and sevelamer hydrochloride tablets for four weeks each with no intervening washout. Study dose during the cross-over period was determined based on the sevelamer hydrochloride dose during the run-in period on a gram per gram basis. The phosphorus levels at the end of each of the two cross-over periods were similar. Average actual daily dose was 6.0 g/day divided among meals for sevelamer carbonate powder and 6.4 g/day divided among meals for sevelamer hydrochloride tablets. - Eighty-four CKD patients on hemodialysis who were hyperphosphatemic (serum phosphorus > 6.0 mg/dL) following a two-week phosphate binder washout period were randomized in a cross-over design to receive in random order sevelamer hydrochloride and active-control for eight weeks each. Treatment periods were separated by a two-week phosphate binder washout period. Patients started on treatment three times per day with meals. Over each eight-week treatment period, at three separate time points the dose of sevelamer hydrochloride could be titrated up to control serum phosphorus, the dose of active-control could also be altered to attain phosphorus control. Both treatments significantly decreased mean serum phosphorus by about 2 mg/dL (Table 4). - The distribution of responses is shown in Figure 2. The distributions are similar for sevelamer hydrochloride and active control. The median response is a reduction of about 2 mg/dL in both groups. About 50% of subjects have reductions between 1 and 3 mg/dL. - Average daily sevelamer hydrochloride dose at the end of treatment was 4.9 g (range of 0.0 to 12.6 g). - Two hundred CKD patients on hemodialysis who were hyperphosphatemic (serum phosphorus > 5.5 mg/dL) following a two-week phosphate binder washout period were randomized to receive sevelamer hydrochloride 800 mg tablets (N=99) or an active-control (N=101). At week 52, using last-observation-carried-forward, sevelamer and active-control both significantly decreased mean serum phosphorus (Table 5). - Sixty-one percent of sevelamer hydrochloride patients and 73% of the control patients completed the full 52 weeks of treatment. - Figure 3, a plot of the phosphorus change from baseline for the completers, illustrates the durability of response for patients who are able to remain on treatment. - Average daily sevelamer hydrochloride dose at the end of treatment was 6.5 g (range of 0.8 to 13 g). - One hundred and forty-three patients on peritoneal dialysis who were hyperphosphatemic (serum phosphorus > 5.5 mg/dL) following a two-week phosphate binder washout period were randomized to receive sevelamer hydrochloride (N=97) or active-control (N=46) open label for 12 weeks. Average daily sevelamer hydrochloride dose at the end of treatment was 5.9 g (range 0.8 to 14.3 g). Thirteen patients (14%) in the sevelamer group and 9 patients (20%) in the active-control group discontinued, mostly for gastrointestinal adverse reactions. There were statistically significant changes in serum phosphorus (p<0.001) for sevelamer hydrochloride (-1.6 mg/dL from baseline of 7.5 mg/dL), similar to the active-control. - Stage 5 CKD patients on hemodialysis with a serum phosphate level of > 5.5 mg/dL after washout from baseline therapies were randomized in a 2:1 ratio to receive either sevelamer carbonate powder once-daily (N=144) or sevelamer hydrochloride as a tablet with the dose divided three times per day (N=73) for 24 weeks. The initial dose for the two groups was 4.8 g/day. At the end of the study, the total daily dose was 6.2 g/day of sevelamer carbonate powder once daily and 6.7 g/day of sevelamer hydrochloride tablets three times per day. A greater percentage of subjects on the once daily dose than three times per day regimen discontinued therapy prematurely, 35% versus 15%. The reasons for discontinuation were largely driven by adverse events and withdrawal of consent in the once daily dosing regimen. Serum phosphate levels and calcium-phosphate product were better controlled on the three times per day regimen than on the once daily regimen. Mean serum phosphorus decreased 2.0 mg/dL for sevelamer carbonate powder once daily and 2.9 mg/dL for sevelamer hydrochloride tablets three times per day. # How Supplied - Tablets: Renvela® 800 mg Tablets are supplied as white oval, film-coated, compressed tablets, imprinted with “RENVELA 800”, containing 800 mg of sevelamer carbonate on an anhydrous basis, microcrystalline cellulose, hypromellose, diacetylated monoglycerides, sodium chloride, and zinc stearate. - 1 Bottle of 30 ct 800 mg Tablets (NDC 58468-0130-2) - 1 Bottle of 270 ct 800 mg Tablets (NDC 58468-0130-1) - Powder: Renvela® for Oral Suspension is supplied as opaque, foil lined, heat sealed, packets containing 0.8 g or 2.4 g of sevelamer carbonate on an anhydrous basis, natural and artificial citrus flavor, propylene glycol alginate, sodium chloride, sucralose, and ferric oxide (yellow). - 1 Box (NDC 58468-0131-2) of 90 ct 2.4 g packets (NDC 58468-0131-1) - 1 Box (NDC 58468-0132-2) of 90 ct 0.8 g packets (NDC 58468-0132-1) - 1 Sample Box (NDC 58468-0131-4) of 90 ct 2.4 g packets (NDC 58468-0131-3) - 1 Sample Box (NDC 58468-0131-5) of 15 ct 2.4 g packets (NDC 58468-0131-3) - Storage: Store at 25°C (77°F): excursions permitted to 15-30°C (59-86°F). - Protect from moisture. ## Storage There is limited information regarding Sevelamer Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Dosing - Inform patients to take Renvela as directed with meals and adhere to their prescribed diets. - For patients using an oral medication where a reduction in the bioavailability of that medication would have a clinically significant effect on its safety or efficacy, advise the patient to take the oral medication at least one hour before or three hours after Renvela. Blood levels of the oral medication should be monitored, if applicable, to determine if there is a significant interaction between the oral medication and Renvela. - For Renvela powder, brief the patient on preparation of the powder in water. - Sevelamer Carbonate Powder Preparation Instructions - The entire contents of each 0.8 or 2.4 g packet should be placed in a cup and mixed thoroughly with the amount of water described in Table 6 . - Multiple packets may be mixed together with the appropriate amount of water. Patients should be instructed that the powder does not dissolve and therefore it should be stirred vigorously just before drinking. The entire preparation should be consumed within 30 minutes. # Precautions with Alcohol - Alcohol-Sevelamer interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Renvela® # Look-Alike Drug Names - Renvela® — Renagel® # Drug Shortage Status # Price	Sevelamer 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 Sevelamer is a phosphate binder that is FDA approved for the {{{indicationType}}} of chronic kidney disease on dialysis. Common adverse reactions include nausea, vomiting, diarrhea, dyspepsia, abdominal pain, flatulence and constipation. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Dosing Information - Renvela should be given three times a day with meals. - Patients Not Taking a Phosphate Binder. The recommended starting dose of Renvela is 0.8 to 1.6 g with meals based on serum phosphorus level. Table 1 provides recommended starting doses of Renvela for patients not taking a phosphate binder. - Switching from Sevelamer Hydrochloride Tablets. For patients switching from sevelamer hydrochloride tablets to sevelamer carbonate tablets or powder, use the same dose in grams. Further titration may be necessary to achieve desired phosphorus levels. The highest daily dose of sevelamer carbonate studied was 14 grams in CKD patients on dialysis. - Switching between Sevelamer Carbonate Tablets and Powder. Use the same dose in grams. Further titration may be necessary to achieve desired phosphorus levels. - Switching from Calcium Acetate. In a study in 84 CKD patients on hemodialysis, a similar reduction in serum phosphorus was seen with equivalent doses (approximately mg for mg) of sevelamer hydrochloride and calcium acetate. Table 2 gives recommended starting doses of Renvela based on a patient’s current calcium acetate dose. - Dose Titration for All Patients Taking Renvela. Titrate the Renvela dose by 0.8 g three times per day with meals at two-week intervals as necessary with the goal of controlling serum phosphorus within the target range. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Sevelamer in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Sevelamer in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Sevelamer in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Sevelamer in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Sevelamer in pediatric patients. # Contraindications - Renvela is contraindicated in patients with bowel obstruction. # Warnings ### Precautions - Gastrointestinal Adverse Events - Cases of dysphagia and esophageal tablet retention have been reported in association with use of the tablet formulation of sevelamer, some requiring hospitalization and intervention. Consider using sevelamer suspension in patients with a history of swallowing disorders. - Cases of bowel obstruction and perforation have also been reported with sevelamer use. - Patients with dysphagia, swallowing disorders, severe gastrointestinal (GI) motility disorders including severe constipation, or major GI tract surgery were not included in the Renvela clinical studies. - Monitor Serum Chemistries - Bicarbonate and chloride levels should be monitored. - Monitor for Reduced Vitamins D, E, K (clotting factors) and Folic Acid Levels - In preclinical studies in rats and dogs, sevelamer hydrochloride, which contains the same active moiety as sevelamer carbonate, reduced vitamins D, E, and K (coagulation parameters) and folic acid levels at doses of 6‑10 times the recommended human dose. In short-term clinical trials, there was no evidence of reduction in serum levels of vitamins. However, in a one-year clinical trial, 25-hydroxyvitamin D (normal range 10 to 55 ng/mL) fell from 39 ± 22 ng/mL to 34 ± 22 ng/mL (p<0.01) with sevelamer hydrochloride treatment. Most (approximately 75%) patients in sevelamer hydrochloride clinical trials received vitamin supplements, which is typical of patients on dialysis. # 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 can not be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. - There are limited data on the safety of Renvela. However, based on the fact that it contains the same active ingredient as the hydrochloride salt, the adverse event profiles of the two salts should be similar. In a cross-over study in hemodialysis patients with treatment durations of eight weeks each and no washout the adverse reactions on sevelamer carbonate tablets were similar to those reported for sevelamer hydrochloride. In another cross-over study in hemodialysis patients, with treatment durations of four weeks each and no washout between treatment periods, the adverse reactions on sevelamer carbonate powder were similar to those reported for sevelamer hydrochloride. - In a parallel design study of sevelamer hydrochloride with treatment duration of 52 weeks, adverse reactions reported for sevelamer hydrochloride (n=99) were similar to those reported for the active-comparator group (n=101). Overall adverse reactions among those treated with sevelamer hydrochloride occurring in > 5% of patients included: vomiting (22%), nausea (20%), diarrhea (19%), dyspepsia (16%), abdominal pain (9%), flatulence (8%) and constipation (8%). A total of 27 patients treated with sevelamer and 10 patients treated with comparator withdrew from the study due to adverse reactions. - Based on studies of 8-52 weeks, the most common reason for withdrawal from sevelamer hydrochloride was gastrointestinal adverse reactions (3-16%). - In one hundred and forty-three peritoneal dialysis patients studied for 12 weeks using sevelamer hydrochloride, most adverse reactions were similar to adverse reactions observed in hemodialysis patients. The most frequently occurring treatment emergent serious adverse reaction was peritonitis (8 reactions in 8 patients [8%] in the sevelamer group and 2 reactions in 2 patients [4%] on active-control). Thirteen patients (14%) in the sevelamer group and 9 patients (20%) in the active-control group discontinued, mostly for gastrointestinal adverse reactions. Patients on peritoneal dialysis should be closely monitored to ensure the reliable use of appropriate aseptic technique with the prompt recognition and management of any signs and symptoms associated with peritonitis. ## Postmarketing Experience - Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or to establish a causal relationship to drug exposure. - The following adverse reactions have been identified during post-approval use of sevelamer hydrochloride, which has the same active moiety as sevelamer carbonate: pruritus, rash, abdominal pain, fecal impaction, and uncommon cases of ileus, intestinal obstruction, and intestinal perforation. Appropriate medical management should be given to patients who develop constipation or have worsening of existing constipation to avoid severe complications. # Drug Interactions - Ciprofloxacin - In a study of 15 healthy subjects, a co-administered single dose of 2.8 grams of sevelamer hydrochloride decreased the bioavailability of ciprofloxacin by approximately 50%. - Digoxin - In 19 healthy subjects receiving 2.4 grams of sevelamer hydrochloride three times a day with meals for 2 days, sevelamer did not alter the pharmacokinetics of a single dose of digoxin. - In 18 healthy subjects receiving 9.6 grams of sevelamer carbonate once daily with a meal, sevelamer did not alter the pharmacokinetics of a single dose of digoxin. - Warfarin - In 14 healthy subjects receiving 2.4 g of sevelamer hydrochloride three times a day with meals for two days sevelamer did not alter the pharmacokinetics of a single dose of warfarin. - In 14 healthy subjects receiving 9.6 grams of sevelamer carbonate once daily with a meal, sevelamer did not alter the pharmacokinetics of a single dose of warfarin. - Enalapril - In 28 healthy subjects a single 2.4 gram dose of sevelamer hydrochloride did not alter the pharmacokinetics of a single dose of enalapril. - Metoprolol - In 31 healthy subjects a single 2.4 gram dose of sevelamer hydrochloride did not alter the pharmacokinetics of a single dose of metoprolol. - Iron - In 23 healthy subjects, a single 2.8 gram dose of sevelamer hydrochloride did not alter the absorption of a single oral dose of iron as 200 mg exsiccated ferrous sulfate tablet. - Other Concomitant Drug Therapy - There are no empirical data on avoiding drug interactions between Renvela and most concomitant drugs. During postmarketing experience, very rare cases of increased thyroid stimulating hormone (TSH) levels have been reported in patients co-administered sevelamer hydrochloride and levothyroxine. Monitor TSH levels and signs of hypothyroidism in patients receiving both medications. - When administering an oral medication where a reduction in the bioavailability of that medication would have a clinically significant effect on its safety or efficacy, there is no information that suggests a dosing regimen that would be universally appropriate for all drugs. One may, however, administer the drug one hour before or three hours after Renvela, and monitor blood levels of the drug. Patients taking anti-arrhythmic medications for the control of arrhythmias and anti-seizure medications for the control of seizure disorders were excluded from the clinical trials. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - There are no adequate and well-controlled studies in pregnant women. Sevelamer products should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. - The effect of sevelamer hydrochloride on the absorption of vitamins and other nutrients has not been studied in pregnant women. Requirements for vitamins and other nutrients are increased in pregnancy. In pregnant rats given doses of sevelamer hydrochloride during organogenesis, reduced or irregular ossification of fetal bones, probably due to a reduced absorption of fat-soluble vitamin D, occurred at a dose approximately equal to the maximum clinical trial dose of 13 g on a body surface area basis. In pregnant rabbits given oral doses of sevelamer hydrochloride by gavage during organogenesis, an increase of early resorptions occurred at dose approximately twice the maximum clinical trial dose on a body surface area basis. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Sevelamer in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Sevelamer during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Sevelamer with respect to nursing mothers. ### Pediatric Use There is no FDA guidance on the use of Sevelamer with respect to pediatric patients. ### Geriatic Use There is no FDA guidance on the use of Sevelamer with respect to geriatric patients. ### Gender There is no FDA guidance on the use of Sevelamer with respect to specific gender populations. ### Race There is no FDA guidance on the use of Sevelamer with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Sevelamer in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Sevelamer in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Sevelamer in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Sevelamer in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring - Bicarbonate and chloride levels should be monitored. - Patients on peritoneal dialysis should be closely monitored to ensure the reliable use of appropriate aseptic technique with the prompt recognition and management of any signs and symptoms associated with peritonitis. - Monitor TSH levels and signs of hypothyroidism in patients receiving both sevelamer and levothyroxine. # IV Compatibility There is limited information regarding IV Compatibility of Sevelamer in the drug label. # Overdosage ## Chronic Overdose There is limited information regarding Chronic Overdose of Sevelamer in the drug label. # Pharmacology ## Mechanism of Action - Renvela contains sevelamer carbonate, a non-absorbed phosphate binding crosslinked polymer, free of metal and calcium. It contains multiple amines separated by one carbon from the polymer backbone. These amines exist in a protonated form in the intestine and interact with phosphate molecules through ionic and hydrogen bonding. By binding phosphate in the gastrointestinal tract and decreasing absorption, sevelamer carbonate lowers the phosphate concentration in the serum (serum phosphorus). ## Structure - The active ingredient in Renvela is sevelamer carbonate, a polymeric amine that binds phosphate and is meant for oral administration. It was developed as a pharmaceutical alternative to sevelamer hydrochloride (Renagel®). Sevelamer carbonate is an anion exchange resin, with the same polymeric structure as sevelamer hydrochloride, in which carbonate replaces chloride as the counterion. While the counterions differ for the two salts, the polymer itself, the active moiety involved in phosphate binding, is the same. - Renvela (sevelamer carbonate) is known chemically as poly(allylamine-co-N,N’-diallyl-1,3-diamino-2-hydroxypropane) carbonate salt. Sevelamer carbonate is hygroscopic, but insoluble in water. The structure is represented in Figure 1. ## Pharmacodynamics - In addition to effects on serum phosphorus levels, sevelamer hydrochloride has been shown to bind bile acids in vitro and in vivo in experimental animal models. Bile acid binding by ion exchange resins is a well-established method of lowering blood cholesterol. Because sevelamer binds bile acids, it may interfere with normal fat absorption and thus may reduce absorption of fat soluble vitamins such as A, D and K. In clinical trials of sevelamer hydrochloride, both the mean total and LDL cholesterol declined by 15-31%. This effect is observed after 2 weeks. Triglycerides, HDL cholesterol and albumin did not change. ## Pharmacokinetics - A mass balance study using 14C-sevelamer hydrochloride, in 16 healthy male and female volunteers showed that sevelamer hydrochloride is not systemically absorbed. No absorption studies have been performed in patients with renal disease. ## Nonclinical Toxicology - Carcinogenesis, Mutagenesis, Impairment of Fertility - Standard lifetime carcinogenicity bioassays were conducted in mice and rats. Rats were given sevelamer hydrochloride by diet at 0.3, 1, or 3 g/kg/day. There was an increased incidence of urinary bladder transitional cell papilloma in male rats of the high dose group (human equivalent dose twice the maximum clinical trial dose of 13 g). Mice received dietary administration of sevelamer hydrochloride at doses of up to 9 g/kg/day (human equivalent dose 3 times the maximum clinical trial dose). There was no increased incidence of tumors observed in mice. - In an in vitro mammalian cytogenetic test with metabolic activation, sevelamer hydrochloride caused a statistically significant increase in the number of structural chromosome aberrations. Sevelamer hydrochloride was not mutagenic in the Ames bacterial mutation assay. - Sevelamer hydrochloride did not impair the fertility of male or female rats in a dietary administration study in which the females were treated from 14 days prior to mating through gestation and the males were treated for 28 days prior to mating. The highest dose in this study was 4.5 g/kg/day (human equivalent dose 3 times the maximum clinical trial dose of 13 g). - Developmental Toxicity - In pregnant rats given dietary doses of 0.5, 1.5 or 4.5 g/kg/day of sevelamer hydrochloride during organogenesis, reduced or irregular ossification of fetal bones, probably due to a reduced absorption of fat-soluble vitamin D, occurred in mid- and high-dose groups (human equivalent doses approximately equal to 3-4 times the maximum clinical trial dose of 13 g). In pregnant rabbits given oral doses of 100, 500 or 1000 mg/kg/day of sevelamer hydrochloride by gavage during organogenesis, an increase of early resorptions occurred in the high-dose group (human equivalent dose twice the maximum clinical trial dose). # Clinical Studies - The ability of sevelamer to control serum phosphorus in CKD patients on dialysis was predominantly determined from the effects of the hydrochloride salt to bind phosphate. Six clinical trials used sevelamer hydrochloride and three clinical trials used sevelamer carbonate. The sevelamer hydrochloride studies include one double-blind, placebo-controlled 2-week study (sevelamer N=24); two open-label, uncontrolled, 8-week studies (sevelamer N=220) and three active-controlled open-label studies with treatment durations of 8 to 52 weeks (sevelamer N=256). The sevelamer carbonate studies include one double-blind, active-controlled, cross-over study with two 8-week treatment periods using sevelamer carbonate tablets (N=79), one open-label, active-controlled, cross-over study with two 4-week treatment periods using sevelamer carbonate powder (N=31) and one randomized, parallel, open-label study using sevelamer carbonate powder (N=144) dosed once daily or sevelamer hydrochloride tablets (N=73) dosed three times daily for 24 weeks. Six of the active-controlled studies are described here (three sevelamer carbonate and three sevelamer hydrochloride studies). - Stage 5 CKD patients on hemodialysis were entered into a five-week sevelamer hydrochloride run-in period and 79 patients received, in random order, sevelamer carbonate 800 mg tablets and sevelamer hydrochloride 800 mg tablets for eight weeks each, with no intervening washout. Study dose during the cross-over period was determined based on the sevelamer hydrochloride dose during the run-in period on a gram per gram basis. The phosphorus levels at the end of each of the two cross-over periods were similar. Average actual daily dose was 6 g/day divided among meals for both treatments. Thirty-nine of those completing the cross-over portion of the study were entered into a two-week washout period during which patients were instructed not to take any phosphate binders; this confirmed the activity of sevelamer in this study. - Stage 5 CKD patients on hemodialysis were entered into a four-week sevelamer hydrochloride run-in period and 31 patients received, in random order, sevelamer carbonate powder and sevelamer hydrochloride tablets for four weeks each with no intervening washout. Study dose during the cross-over period was determined based on the sevelamer hydrochloride dose during the run-in period on a gram per gram basis. The phosphorus levels at the end of each of the two cross-over periods were similar. Average actual daily dose was 6.0 g/day divided among meals for sevelamer carbonate powder and 6.4 g/day divided among meals for sevelamer hydrochloride tablets. - Eighty-four CKD patients on hemodialysis who were hyperphosphatemic (serum phosphorus > 6.0 mg/dL) following a two-week phosphate binder washout period were randomized in a cross-over design to receive in random order sevelamer hydrochloride and active-control for eight weeks each. Treatment periods were separated by a two-week phosphate binder washout period. Patients started on treatment three times per day with meals. Over each eight-week treatment period, at three separate time points the dose of sevelamer hydrochloride could be titrated up to control serum phosphorus, the dose of active-control could also be altered to attain phosphorus control. Both treatments significantly decreased mean serum phosphorus by about 2 mg/dL (Table 4). - The distribution of responses is shown in Figure 2. The distributions are similar for sevelamer hydrochloride and active control. The median response is a reduction of about 2 mg/dL in both groups. About 50% of subjects have reductions between 1 and 3 mg/dL. - Average daily sevelamer hydrochloride dose at the end of treatment was 4.9 g (range of 0.0 to 12.6 g). - Two hundred CKD patients on hemodialysis who were hyperphosphatemic (serum phosphorus > 5.5 mg/dL) following a two-week phosphate binder washout period were randomized to receive sevelamer hydrochloride 800 mg tablets (N=99) or an active-control (N=101). At week 52, using last-observation-carried-forward, sevelamer and active-control both significantly decreased mean serum phosphorus (Table 5). - Sixty-one percent of sevelamer hydrochloride patients and 73% of the control patients completed the full 52 weeks of treatment. - Figure 3, a plot of the phosphorus change from baseline for the completers, illustrates the durability of response for patients who are able to remain on treatment. - Average daily sevelamer hydrochloride dose at the end of treatment was 6.5 g (range of 0.8 to 13 g). - One hundred and forty-three patients on peritoneal dialysis who were hyperphosphatemic (serum phosphorus > 5.5 mg/dL) following a two-week phosphate binder washout period were randomized to receive sevelamer hydrochloride (N=97) or active-control (N=46) open label for 12 weeks. Average daily sevelamer hydrochloride dose at the end of treatment was 5.9 g (range 0.8 to 14.3 g). Thirteen patients (14%) in the sevelamer group and 9 patients (20%) in the active-control group discontinued, mostly for gastrointestinal adverse reactions. There were statistically significant changes in serum phosphorus (p<0.001) for sevelamer hydrochloride (-1.6 mg/dL from baseline of 7.5 mg/dL), similar to the active-control. - Stage 5 CKD patients on hemodialysis with a serum phosphate level of > 5.5 mg/dL after washout from baseline therapies were randomized in a 2:1 ratio to receive either sevelamer carbonate powder once-daily (N=144) or sevelamer hydrochloride as a tablet with the dose divided three times per day (N=73) for 24 weeks. The initial dose for the two groups was 4.8 g/day. At the end of the study, the total daily dose was 6.2 g/day of sevelamer carbonate powder once daily and 6.7 g/day of sevelamer hydrochloride tablets three times per day. A greater percentage of subjects on the once daily dose than three times per day regimen discontinued therapy prematurely, 35% versus 15%. The reasons for discontinuation were largely driven by adverse events and withdrawal of consent in the once daily dosing regimen. Serum phosphate levels and calcium-phosphate product were better controlled on the three times per day regimen than on the once daily regimen. Mean serum phosphorus decreased 2.0 mg/dL for sevelamer carbonate powder once daily and 2.9 mg/dL for sevelamer hydrochloride tablets three times per day. # How Supplied - Tablets: Renvela® 800 mg Tablets are supplied as white oval, film-coated, compressed tablets, imprinted with “RENVELA 800”, containing 800 mg of sevelamer carbonate on an anhydrous basis, microcrystalline cellulose, hypromellose, diacetylated monoglycerides, sodium chloride, and zinc stearate. - 1 Bottle of 30 ct 800 mg Tablets (NDC 58468-0130-2) - 1 Bottle of 270 ct 800 mg Tablets (NDC 58468-0130-1) - Powder: Renvela® for Oral Suspension is supplied as opaque, foil lined, heat sealed, packets containing 0.8 g or 2.4 g of sevelamer carbonate on an anhydrous basis, natural and artificial citrus flavor, propylene glycol alginate, sodium chloride, sucralose, and ferric oxide (yellow). - 1 Box (NDC 58468-0131-2) of 90 ct 2.4 g packets (NDC 58468-0131-1) - 1 Box (NDC 58468-0132-2) of 90 ct 0.8 g packets (NDC 58468-0132-1) - 1 Sample Box (NDC 58468-0131-4) of 90 ct 2.4 g packets (NDC 58468-0131-3) - 1 Sample Box (NDC 58468-0131-5) of 15 ct 2.4 g packets (NDC 58468-0131-3) - Storage: Store at 25°C (77°F): excursions permitted to 15-30°C (59-86°F). - Protect from moisture. ## Storage There is limited information regarding Sevelamer Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Dosing - Inform patients to take Renvela as directed with meals and adhere to their prescribed diets. - For patients using an oral medication where a reduction in the bioavailability of that medication would have a clinically significant effect on its safety or efficacy, advise the patient to take the oral medication at least one hour before or three hours after Renvela. Blood levels of the oral medication should be monitored, if applicable, to determine if there is a significant interaction between the oral medication and Renvela. - For Renvela powder, brief the patient on preparation of the powder in water. - Sevelamer Carbonate Powder Preparation Instructions - The entire contents of each 0.8 or 2.4 g packet should be placed in a cup and mixed thoroughly with the amount of water described in Table 6 . - Multiple packets may be mixed together with the appropriate amount of water. Patients should be instructed that the powder does not dissolve and therefore it should be stirred vigorously just before drinking. The entire preparation should be consumed within 30 minutes. # Precautions with Alcohol - Alcohol-Sevelamer interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Renvela®[1] # Look-Alike Drug Names - Renvela® — Renagel®[2] # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Sevelamer
8447a3034e9764f3df7473acde58c760808d5613	wikidoc	Sfumatura	Sfumatura The sfumatura or slow-folding process is a traditional technique for manually extracting the essential oils from citrus peel using sponges. Dating back to 18th-century Italy, the process is still carried out in Sicily today, although it is increasingly rare. Despite the modern array of sophisticated machines for extracting citrus oil, even the best machinery does not approach the quality of sfumatura-produced oil. Using a rastrello, a special spoon-shaped knife, the fresh peel is de-pulped. It is then thoroughly washed with limewater and drip-dried on woven mats or special baskets for 3 to 24 hours, depending on the ripeness of the fruit, the temperature, and the humidity. These steps harden the peel, causing the oil to spurt from the oil glands more easily, and the lime helps neutralize the acidity of the peel. A series of natural sponges is fixed upon a terracotta basin or concolina and held in place with a wooden bar laid across the rim. The dried peel is folded and pressed against the sponges several times in a circular motion, causing a mixture of essential oil and peel liquids to pass into the concolina. After finishing with the peel, the sponges are squeezed to recover additional oil and liquids. Finally, the oil is decanted away from the heavier watery phase, which contains detritus from breaking the peel.	Sfumatura The sfumatura or slow-folding process is a traditional technique for manually extracting the essential oils from citrus peel using sponges. Dating back to 18th-century Italy, the process is still carried out in Sicily today, although it is increasingly rare.[1] Despite the modern array of sophisticated machines for extracting citrus oil, even the best machinery does not approach the quality of sfumatura-produced oil.[2] Using a rastrello, a special spoon-shaped knife, the fresh peel is de-pulped. It is then thoroughly washed with limewater and drip-dried on woven mats or special baskets for 3 to 24 hours, depending on the ripeness of the fruit, the temperature, and the humidity. These steps harden the peel, causing the oil to spurt from the oil glands more easily, and the lime helps neutralize the acidity of the peel.[3] A series of natural sponges is fixed upon a terracotta basin or concolina and held in place with a wooden bar laid across the rim. The dried peel is folded and pressed against the sponges several times in a circular motion, causing a mixture of essential oil and peel liquids to pass into the concolina. After finishing with the peel, the sponges are squeezed to recover additional oil and liquids. Finally, the oil is decanted away from the heavier watery phase, which contains detritus from breaking the peel.[3]	https://www.wikidoc.org/index.php/Sfumatura
dca04eaf6478a76959927c47790e714146c765f4	wikidoc	Sheep dip	Sheep dip The term sheep dip refers to a liquid formulation of insecticide and fungicide which shepherds and farmers may use to protect their sheep from infestation against external parasites such as scab mite, blow-fly, ticks, keds and lice. The dip is available as wettable powders, pastes, solutions or suspensions which are used to prepare diluted solutions, suspensions or active substances. The term is used both for the formulation itself, and the trough in which the sheep is dipped. The sheep are completely immersed in the preparation. The world's first sheep dip was invented and produced by Mr George Wilson of Coldstream, Scotland in 1830. That dip was based on arsenic powder and was exported by Package Steamer from nearby Berwick Upon Tweed. There are two broad classes of sheep dip - organophosphorus compounds, which were developed from chemical warfare, and synthetic pyrethroids. Organophosphorous compounds are very toxic to humans, as they travel easily through the skin. When traveling over water, containers for these sheep dips are subject to United Nations regulations which state that they must remain legible after immersion in water. Sheep dips have been found to contaminate surrounding soil, creating environmental problems. # Other meanings The term is used colloquially in business to refer to the process of training all employees in an organization in a general subject of wide applicability. The term is also used in information security. It refers to a computer that is isolated from a business core network used to screen incoming digital devices. They will often contain multiple malware scanners and egress packet detection. As it is used in the documentary The Men Who Killed Kennedy, the term also refers to the intentional broadcast of misleading details about oneself for the purposes of generating a cover prior to engaging in covert information gathering. The name is also used to refer to some brands of originally-bootleg whisky, the best-known of which is probably Original Oldbury. When confronted by authorities, it was called "sheep dip" by sellers to escape liquor taxes (see moonshine). # Other Uses In the Monty Python Bruces sketch, Bruce (Michael Palin) is said to teach logical positivism, as well as being in charge of the sheep dip. Sheepdip is a rock and roll band based in Rindge, New Hampshire. Sheep Dip is the name of a brand of Scotch whisky.	Sheep dip The term sheep dip refers to a liquid formulation of insecticide and fungicide which shepherds and farmers may use to protect their sheep from infestation against external parasites such as scab mite, blow-fly, ticks, keds and lice. The dip is available as wettable powders, pastes, solutions or suspensions which are used to prepare diluted solutions, suspensions or active substances. The term is used both for the formulation itself, and the trough in which the sheep is dipped. The sheep are completely immersed in the preparation. The world's first sheep dip was invented and produced by Mr George Wilson of Coldstream, Scotland in 1830. That dip was based on arsenic powder and was exported by Package Steamer from nearby Berwick Upon Tweed. There are two broad classes of sheep dip - organophosphorus compounds, which were developed from chemical warfare, and synthetic pyrethroids. Organophosphorous compounds are very toxic to humans, as they travel easily through the skin. When traveling over water, containers for these sheep dips are subject to United Nations regulations which state that they must remain legible after immersion in water. Sheep dips have been found to contaminate surrounding soil, creating environmental problems. [1] # Other meanings The term is used colloquially in business to refer to the process of training all employees in an organization in a general subject of wide applicability. The term is also used in information security. It refers to a computer that is isolated from a business core network used to screen incoming digital devices. They will often contain multiple malware scanners and egress packet detection. As it is used in the documentary The Men Who Killed Kennedy, the term also refers to the intentional broadcast of misleading details about oneself for the purposes of generating a cover prior to engaging in covert information gathering. The name is also used to refer to some brands of originally-bootleg whisky, the best-known of which is probably Original Oldbury. When confronted by authorities, it was called "sheep dip" by sellers to escape liquor taxes (see moonshine). # Other Uses In the Monty Python Bruces sketch, Bruce (Michael Palin) is said to teach logical positivism, as well as being in charge of the sheep dip. Sheepdip is a rock and roll band based in Rindge, New Hampshire.[2] Sheep Dip is the name of a brand of Scotch whisky.	https://www.wikidoc.org/index.php/Sheep_dip
81feff580d403a8ae1235b98a16109a812f90dee	wikidoc	Shivering	Shivering Lua error in Module:Redirect at line 65: could not parse redirect on page "Shiver". Shivering is a bodily function in response to early hypothermia in warm-blooded animals. When the core body temperature drops, the shivering reflex is triggered. Muscle groups around the vital organs begin to shake in small movements in an attempt to create warmth by expending energy. Shivering can also be a response to a fever as a person may feel cold, though their core temperature is already elevated. Located in the dorsomedial portion of the hypothalamus near the wall of the third ventricle is an area called the primary motor center for shivering. This area is normally inhibited by signals from the heat center in the anterior hypothalamic-preoptic area but is excited by cold signals from the skin and spinal cord. Therefore, this center becomes activated when the body temperature falls even a fraction of a degree below a critical temperature level. # Causes ## Causes by Organ System ## Causes in Alphabetical Order ## Drug Side Effect BCG vaccine, Tretinoin	Shivering Lua error in Module:Redirect at line 65: could not parse redirect on page "Shiver". Shivering is a bodily function in response to early hypothermia in warm-blooded animals. When the core body temperature drops, the shivering reflex is triggered. Muscle groups around the vital organs begin to shake in small movements in an attempt to create warmth by expending energy. Shivering can also be a response to a fever as a person may feel cold, though their core temperature is already elevated. Located in the dorsomedial portion of the hypothalamus near the wall of the third ventricle is an area called the primary motor center for shivering. This area is normally inhibited by signals from the heat center in the anterior hypothalamic-preoptic area but is excited by cold signals from the skin and spinal cord. Therefore, this center becomes activated when the body temperature falls even a fraction of a degree below a critical temperature level. Template:Med-stub # Causes ## Causes by Organ System ## Causes in Alphabetical Order ## Drug Side Effect BCG vaccine, Tretinoin	https://www.wikidoc.org/index.php/Shiver
5d3f9d776ae0e3f6ab9dd8b427e807d52fca15bf	wikidoc	Sialidase	Sialidase Sialidase, accession number PF02973 is a widespread enzyme that catalyzes the hydrolysis of terminal acylneuraminic residues from oligosaccharides, glycolipids and glycoproteins. Also called neuraminidase. It is present as a surface antigen in myxo viruses, hence sialidase inhibitors are used in anti-viral drugs. Deficiency of this enzyme, an autosomal recessive trait, causes sialidosis; enzyme activity is also lacking in galactosialidosis. The EC nomenclature is exo-α-sialidase. # Genes - NEU1, NEU2, NEU3, NEU4	Sialidase Sialidase, accession number PF02973 is a widespread enzyme that catalyzes the hydrolysis of terminal acylneuraminic residues from oligosaccharides, glycolipids and glycoproteins. Also called neuraminidase. It is present as a surface antigen in myxo viruses, hence sialidase inhibitors are used in anti-viral drugs.[1] Deficiency of this enzyme, an autosomal recessive trait, causes sialidosis; enzyme activity is also lacking in galactosialidosis. The EC nomenclature is exo-α-sialidase. # Genes - NEU1, NEU2, NEU3, NEU4	https://www.wikidoc.org/index.php/Sialidase
79d0f5c7eedee3dcba3dd038c5b872ff16e3f9d1	wikidoc	Sialogram	Sialogram # Overview Sialogram or sialography is imaging of the salivary glands using x-ray # Technique A baseline radiograph of the required salivary gland would be taken , a cannula then is inserted in this salivary gland duct's opening in the mouth, a Radio-opaque fluid (Contrast medium) then is injected in the duct. A series of radigraphs would then be taken to determine the flow of the fluid , identify any obstructions and its location , the rate of fluid excretion from the gland. Usually the radiographs taken are lateral oplique views of the face as Orthopantomogram's are not useful for the purpose of locating the area due to superimpositions and the way they are taken to put the teeth in the main field. # Indications - Salivary gland's stones - Salivary duct calculus - Sjogren syndrome - salivary gland tumours - Salivary gland narrowing or obstruction # Contraindications - Allergy to the contrast medium , mainly to Iodine. - Acute salivary gland infections	Sialogram Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Sialogram or sialography is imaging of the salivary glands using x-ray[1] # Technique A baseline radiograph of the required salivary gland would be taken , a cannula then is inserted in this salivary gland duct's opening in the mouth, a Radio-opaque fluid (Contrast medium) then is injected in the duct. A series of radigraphs would then be taken to determine the flow of the fluid , identify any obstructions and its location , the rate of fluid excretion from the gland. Usually the radiographs taken are lateral oplique views of the face [2]as Orthopantomogram's are not useful for the purpose of locating the area due to superimpositions and the way they are taken to put the teeth in the main field. # Indications - Salivary gland's stones - Salivary duct calculus - Sjogren syndrome - salivary gland tumours - Salivary gland narrowing or obstruction # Contraindications - Allergy to the contrast medium , mainly to Iodine. - Acute salivary gland infections	https://www.wikidoc.org/index.php/Sialogram
1f5b2ae817aa2def69669af8a55cb352f0eb8005	wikidoc	Sideburns	Sideburns Sideburns (known colloquially as side-whiskers, or sideboards in the United Kingdom) are patches of facial hair grown on the sides of a man's face, in front of the ears. The term “sideburns” is a 19th century bastardization of the original burnsides, named after Ambrose Burnside, a man known for his unusual facial hairstyle that connected thick sideburns by way of a moustache but left the chin clean-shaven. ## Variations Sideburns are hardly restricted to any particular length or shape, and a number of variations can be found throughout history- they can be thin or wide, voluptuous or neatly-trimmed; be cropped flat, flare out, or end in a point; end at mid-ear or further down the jawline. The word 'Sideburns' is also a broad term that encompasses several other distinct types of facial hair, such as Mutton Chops and Friendly Mutton Chops. Mutton Chops are sideburns named for their mutton-like shape as they extend down to the corner of the mouth, while Friendly Mutton Chops connect both sideburns with a "friendly" moustache- a style of facial hair not unlike the one worn by Burnside himself. Sideburns can be worn in combination with other styles of facial hair, such as the moustache or goatee, but once they extend from ear to ear via the chin they cease to be sideburns and become a beard, or chin curtain. ## History After the clean-shaven period of the eighteenth century, sideburns, like beards, began to grow in popularity during the early nineteenth century, a trend that eventually made its way to Japan. Nineteenth century sideburns were often far more extravagant than those seen today, appearing more along the lines of what we know as modern-day mutton chops. As with beards, sideburns went quickly out of fashion in the early twentieth century, but made a comeback in the 1960s and 1970s among the younger generation. Pointed sideburns, more specifically, became a symbol of the gay club scenes of San Francisco and Sydney, Australia. Because of their multifarious history, sideburns may be seen as either stuffily Victorian and ultra-conservative, or as a sign of 1970s-style rebelliousness. Today sideburns enjoy an intermediate level of popularity, though groups of sideburn and beard afficionados have formed and flourished with the introduction of the internet. Indigenous men of Mexico, who shave their heads and wear their sideburns long, as well as Colombians, who wear their sideburns long and typically do not have any other facial hair, are said to be wearing "balcarrotas". # Gallery of interesting sideburns - Henrik Ibsen (1828-1906) Henrik Ibsen (1828-1906) - Franz Joseph I of Austria (1830-1916) Franz Joseph I of Austria (1830-1916) - Miguel Grau Seminario (1834-1879) Miguel Grau Seminario (1834-1879) - W. S. Gilbert (1836-1911) W. S. Gilbert (1836-1911)	Sideburns Sideburns (known colloquially as side-whiskers, or sideboards[1] in the United Kingdom) are patches of facial hair grown on the sides of a man's face, in front of the ears. The term “sideburns” is a 19th century bastardization of the original burnsides, named after Ambrose Burnside[2], a man known for his unusual facial hairstyle that connected thick sideburns by way of a moustache but left the chin clean-shaven. ## Variations Sideburns are hardly restricted to any particular length or shape, and a number of variations can be found throughout history- they can be thin or wide, voluptuous or neatly-trimmed; be cropped flat, flare out, or end in a point; end at mid-ear or further down the jawline. The word 'Sideburns' is also a broad term that encompasses several other distinct types of facial hair, such as Mutton Chops and Friendly Mutton Chops. Mutton Chops are sideburns named for their mutton-like shape as they extend down to the corner of the mouth, while Friendly Mutton Chops connect both sideburns with a "friendly" moustache- a style of facial hair not unlike the one worn by Burnside himself. Sideburns can be worn in combination with other styles of facial hair, such as the moustache or goatee, but once they extend from ear to ear via the chin they cease to be sideburns and become a beard, or chin curtain. ## History After the clean-shaven period of the eighteenth century, sideburns, like beards, began to grow in popularity during the early nineteenth century, a trend that eventually made its way to Japan. Nineteenth century sideburns were often far more extravagant than those seen today, appearing more along the lines of what we know as modern-day mutton chops. As with beards, sideburns went quickly out of fashion in the early twentieth century, but made a comeback in the 1960s and 1970s among the younger generation. Pointed sideburns, more specifically, became a symbol of the gay club scenes of San Francisco and Sydney, Australia. Because of their multifarious history, sideburns may be seen as either stuffily Victorian and ultra-conservative, or as a sign of 1970s-style rebelliousness. Today sideburns enjoy an intermediate level of popularity, though groups of sideburn and beard afficionados have formed and flourished with the introduction of the internet. Indigenous men of Mexico, who shave their heads and wear their sideburns long, as well as Colombians, who wear their sideburns long and typically do not have any other facial hair, are said to be wearing "balcarrotas". # Gallery of interesting sideburns - Henrik Ibsen (1828-1906) Henrik Ibsen (1828-1906) - Franz Joseph I of Austria (1830-1916) Franz Joseph I of Austria (1830-1916) - Miguel Grau Seminario (1834-1879) Miguel Grau Seminario (1834-1879) - W. S. Gilbert (1836-1911) W. S. Gilbert (1836-1911)	https://www.wikidoc.org/index.php/Sideburn
c46a3c21e43988529f8b77f81b7f920c5f4bcb6a	wikidoc	Silibinin	Silibinin # Overview Silibinin (INN), also known as silybin (both from Silybum, the generic name of the plant from which it is extracted), is the major active constituent of silymarin, a standardized extract of the milk thistle seeds, containing a mixture of flavonolignans consisting of silibinin, isosilibinin, silicristin, silidianin and others. Silibinin itself is mixture of two diastereomers, silybin A and silybin B, in approximately equimolar ratio.Both in vitro and animal research suggest that silibinin has hepatoprotective (antihepatotoxic) properties that protect liver cells against toxins. Silibinin has also demonstrated in vitro anti-cancer effects against human prostate adenocarcinoma cells, estrogen-dependent and -independent human breast carcinoma cells, human ectocervical carcinoma cells, human colon cancer cells, and both small and nonsmall human lung carcinoma cells. Chemically modified silibinin, silibinin dihydrogen disuccinate disodium (trade name Legalon SIL), a solution for injection, is currently being tested as a treatment of severe intoxications with hepatotoxic substances, such as death cap (Amanita phalloides) poisoning.There is also clinical evidence for the use of silibinin as a supportive element in alcoholic and child grade 'A' liver cirrhosis. # Pharmacology Poor water solubility and bioavailability of silymarin led to the development of enhanced formulations. Silipide (trade name Siliphos), a complex of silymarin and phosphatidylcholine (lecithin), is about 10 times more bioavailable than silymarin. It has been also reported that silymarin inclusion complex with β-cyclodextrin is much more soluble than silymarin itself.There have also been prepared glycosides of silybin, which show better water solubility and even stronger hepatoprotective effect. Silymarin is the first ingredient in several products sold as herbal telomerase activators, though the research demonstrating silymarin's effectiveness in this regard is proprietary and unpublished. Silymarin, as other flavonoids, has been shown to inhibit P-glycoprotein-mediated cellular efflux. The modulation of P-glycoprotein activity may result in altered absorption and bioavailability of drugs that are P-glycoprotein substrates. It has been reported that silymarin inhibits cytochrome P450 enzymes and an interaction with drugs primarily cleared by P450s cannot be excluded. # Toxicity A phase I clinical trial in humans with prostate cancer designed to study the effects of high dose silibinin found 13 grams daily to be well tolerated in patients with advanced prostate cancer with asymptomatic liver toxicity (hyperbilirubinemia and elevation of alanine aminotransferase) being the most commonly seen adverse event. The compound is also devoid of embryotoxic potential in animal models. # Potential medical uses A recent study suggested that silymarin may help patients with type II diabetes by assisting in blood sugar control. Lab experiments on mice showed that silibinin protects the hepatic cells against the toxin alpha-amanitin which causes Amanita phalloides mushroom poisoning. # Biotechnology Silymarin can be produced in callus and cells suspensions of Silybum marianum and substituted pyrazinecarboxamides can be used as abiotic elicitors of flavolignan production.	Silibinin Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Silibinin (INN), also known as silybin (both from Silybum, the generic name of the plant from which it is extracted), is the major active constituent of silymarin, a standardized extract of the milk thistle seeds, containing a mixture of flavonolignans consisting of silibinin, isosilibinin, silicristin, silidianin and others. Silibinin itself is mixture of two diastereomers, silybin A and silybin B, in approximately equimolar ratio.Both in vitro and animal research suggest that silibinin has hepatoprotective (antihepatotoxic) properties that protect liver cells against toxins. Silibinin has also demonstrated in vitro anti-cancer effects against human prostate adenocarcinoma cells, estrogen-dependent and -independent human breast carcinoma cells, human ectocervical carcinoma cells, human colon cancer cells, and both small and nonsmall human lung carcinoma cells. Chemically modified silibinin, silibinin dihydrogen disuccinate disodium (trade name Legalon SIL), a solution for injection, is currently being tested as a treatment of severe intoxications with hepatotoxic substances, such as death cap (Amanita phalloides) poisoning.There is also clinical evidence for the use of silibinin as a supportive element in alcoholic and child grade 'A' liver cirrhosis. # Pharmacology Poor water solubility and bioavailability of silymarin led to the development of enhanced formulations. Silipide (trade name Siliphos), a complex of silymarin and phosphatidylcholine (lecithin), is about 10 times more bioavailable than silymarin. It has been also reported that silymarin inclusion complex with β-cyclodextrin is much more soluble than silymarin itself.There have also been prepared glycosides of silybin, which show better water solubility and even stronger hepatoprotective effect. Silymarin is the first ingredient in several products sold as herbal telomerase activators, though the research demonstrating silymarin's effectiveness in this regard is proprietary and unpublished. Silymarin, as other flavonoids, has been shown to inhibit P-glycoprotein-mediated cellular efflux. The modulation of P-glycoprotein activity may result in altered absorption and bioavailability of drugs that are P-glycoprotein substrates. It has been reported that silymarin inhibits cytochrome P450 enzymes and an interaction with drugs primarily cleared by P450s cannot be excluded. # Toxicity A phase I clinical trial in humans with prostate cancer designed to study the effects of high dose silibinin found 13 grams daily to be well tolerated in patients with advanced prostate cancer with asymptomatic liver toxicity (hyperbilirubinemia and elevation of alanine aminotransferase) being the most commonly seen adverse event. The compound is also devoid of embryotoxic potential in animal models. # Potential medical uses A recent study suggested that silymarin may help patients with type II diabetes by assisting in blood sugar control. Lab experiments on mice showed that silibinin protects the hepatic cells against the toxin alpha-amanitin which causes Amanita phalloides mushroom poisoning. # Biotechnology Silymarin can be produced in callus and cells suspensions of Silybum marianum and substituted pyrazinecarboxamides can be used as abiotic elicitors of flavolignan production.	https://www.wikidoc.org/index.php/Silibinin
86edf66c7c0f8fb99912b9885fff2003e605445a	wikidoc	Silodosin	Silodosin # 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 Silodosin is an alpha-1 adrenergic antagonist that is FDA approved for the treatment of the signs and symptoms of benign prostatic hyperplasia (BPH). Common adverse reactions include retrograde ejaculation, dizziness, diarrhea, orthostatic hypotension, headache, nasopharyngitis, and nasal congestion. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Silodosin is indicated for the treatment of the signs and symptoms of benign prostatic hyperplasia (BPH) - Dosage: 8 mg orally once daily with a meal. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Silodosin in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Silodosin in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) Safety and efficacy not established in pediatric patients ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Silodosin in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Silodosin in pediatric patients. # Contraindications - Severe renal impairment (CCr < 30 mL/min). - Severe hepatic impairment (Child-Pugh score > 10). - Concomitant administration with strong Cytochrome P450 3A4 (CYP3A4) inhibitors (e.g., ketoconazole, clarithromycin, itraconazole, ritonavir). - Patients with a history of hypersensitivity to silodosin or any of the ingredients of silodosin. # Warnings Postural hypotension, with or without symptoms (e.g., dizziness) may develop when beginning silodosin treatment. As with other alpha-blockers, there is potential for syncope. Patients should be cautioned about driving, operating machinery, or performing hazardous tasks when initiating therapy. Silodosin has not been tested in patients with severe hepatic impairment, and therefore, should not be prescribed to such patients. In a drug interaction study, co-administration of a single 8 mg dose of silodosin with 400 mg ketoconazole, a strong CYP3A4 inhibitor, caused a 3.8-fold increase in maximum plasma silodosin concentrations and 3.2-fold increase in silodosin exposure (i.e., AUC). Concomitant use of ketoconazole or other strong CYP3A4 inhibitors (e.g., itraconazole, clarithromycin, ritonavir) is therefore contraindicated. The pharmacodynamic interactions between silodosin and other alpha-blockers have not been determined. However, interactions may be expected, and silodosin should not be used in combination with other alpha-blockers. A specific pharmacodynamic interaction study between silodosin and antihypertensive agents has not been performed. However, patients in the Phase 3 clinical studies taking concomitant antihypertensive medications with silodosin did not experience a significant increase in the incidence of syncope, dizziness, or orthostasis. Nevertheless, exercise caution during concomitant use with antihypertensives and monitor patients for possible adverse events. Caution is also advised when alpha-adrenergic blocking agents including silodosin are co-administered with PDE5 inhibitors. Alpha-adrenergic blockers and PDE5 inhibitors are both vasodilators that can lower blood pressure. Concomitant use of these two drug classes can potentially cause symptomatic hypotension. Carcinoma of the prostate and BPH cause many of the same symptoms. These two diseases frequently co-exist. Therefore, patients thought to have BPH should be examined prior to starting therapy with silodosin to rule out the presence of carcinoma of the prostate. Intraoperative Floppy Iris Syndrome has been observed during cataract surgery in some patients on alpha-1 blockers or previously treated with alpha-1 blockers. This variant of small pupil syndrome is characterized by the combination of a flaccid iris that billows in response to intraoperative irrigation currents; progressive intraoperative miosis despite preoperative dilation with standard mydriatic drugs; and potential prolapse of the iris toward the phacoemulsification incisions. Patients planning cataract surgery should be told to inform their ophthalmologist that they are taking silodosin. # 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. In U.S. clinical trials, 897 patients with BPH were exposed to 8 mg silodosin daily. This includes 486 patients exposed for 6 months and 168 patients exposed for 1 year. The population was 44 to 87 years of age, and predominantly Caucasian. Of these patients, 42.8% were 65 years of age or older and 10.7% were 75 years of age or older. In double-blind, placebo controlled, 12-week clinical trials, 466 patients were administered silodosin and 457 patients were administered placebo. At least one treatment-emergent adverse reaction was reported by 55.2% of silodosin treated patients (36.8% for placebo treated). The majority (72.1%) of adverse reactions for the silodosin treated patients (59.8% for placebo treated) were qualified by the investigator as mild. A total of 6.4% of silodosin treated patients (2.2% for placebo treated) discontinued therapy due to an adverse reaction (treatment-emergent), the most common reaction being retrograde ejaculation (2.8%) for silodosin treated patients. Retrograde ejaculation is reversible upon discontinuation of treatment. The incidence of treatment-emergent adverse reactions listed in the following table were derived from two 12-week, multicenter, double-blind, placebo-controlled clinical studies of silodosin 8 mg daily in BPH patients. Adverse reactions that occurred in at least 2% of patients treated with silodosin and more frequently than with placebo are shown in Table 1. In the two 12-week, placebo-controlled clinical trials, the following adverse events were reported by between 1% and 2% of patients receiving silodosin and occurred more frequently than with placebo: insomnia, PSA increased, sinusitis, abdominal pain, asthenia, and rhinorrhea. One case of syncope in a patient taking prazosin concomitantly and one case of priapism were reported in the silodosin treatment group. In a 9-month open-label safety study of silodosin, one case of Intraoperative Floppy Iris Syndrome (IFIS) was reported. ## Postmarketing Experience The following adverse reactions have been identified during post approval use of silodosin. 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: - Skin and subcutaneous tissue disorders: toxic skin eruption, purpura, skin rash, pruritus, and urticaria. - Hepatobiliary disorders: jaundice, impaired hepatic function associated with increased transaminase values. - Immune system disorders: allergic-type reactions, not limited to skin reactions including swollen tongue and pharyngeal edema resulting in serious outcomes. # Drug Interactions In a clinical metabolic inhibition study, a 3.8-fold increase in silodosin maximum plasma concentrations and 3.2-fold increase in silodosin exposure were observed with concurrent administration of a strong CYP3A4 inhibitor, 400 mg ketoconazole. Use of strong CYP3A4 inhibitors such as itraconazole or ritonavir may cause plasma concentrations of silodosin to increase. Concomitant administration of strong CYP3A4 inhibitors and silodosin is contraindicated. The effect of moderate CYP3A4 inhibitors on the pharmacokinetics of silodosin has not been evaluated. Concomitant administration with moderate CYP3A4 inhibitors (e.g., diltiazem, erythromycin, verapamil) may increase concentration of silodosin. Exercise caution and monitor patients for adverse events when co-administering silodosin with moderate CYP3A4 inhibitors. In vitro studies indicated that silodosin is a P-gp substrate. Ketoconazole, a CYP3A4 inhibitor that also inhibits P-gp, caused significant increase in exposure to silodosin. Inhibition of P-gp may lead to increased silodosin concentration. Silodosin is therefore not recommended in patients taking strong P-gp inhibitors such as cyclosporine. The pharmacodynamic interactions between silodosin and other alpha-blockers have not been determined. However, interactions may be expected, and silodosin should not be used in combination with other alpha-blockers. The effect of co-administration of silodosin and digoxin 0.25 mg/day for 7 days was evaluated in a clinical trial in 16 healthy males, aged 18 to 45 years. Concomitant administration of silodosin and digoxin did not significantly alter the steady state pharmacokinetics of digoxin. No dose adjustment is required. Co-administration of silodosin with a single dose of 100 mg sildenafil or 20 mg tadalafil was evaluated in a placebo-controlled clinical study that included 24 healthy male subjects, 45 to 78 years of age. Orthostatic vital signs were monitored in the 12-hour period following concomitant dosing. During this period, the total number of positive orthostatic test results was greater in the group receiving silodosin plus a PDE5 inhibitor compared with silodosin alone. No events of symptomatic orthostasis or dizziness were reported in subjects receiving silodosin with a PDE5 inhibitor. The pharmacodynamic interactions between silodosin and antihypertensives have not been rigorously investigated in a clinical study. However, approximately one-third of the patients in clinical studies used concomitant antihypertensive medications with silodosin. The incidence of dizziness and orthostatic hypotension in these patients was higher than in the general silodosin population (4.6% versus 3.8% and 3.4% versus 3.2%, respectively). Exercise caution during concomitant use with antihypertensives and monitor patients for possible adverse events. In vitro data indicate that silodosin does not have the potential to inhibit or induce cytochrome P450 enzyme systems. The effect of a moderate fat, moderate calorie meal on silodosin pharmacokinetics was variable and decreased silodosin maximum plasma concentration (Cmax) by approximately 18 to 43% and exposure (AUC) by 4 to 49% across three different studies. Safety and efficacy clinical trials for silodosin were always conducted in the presence of food intake. Patients should be instructed to take silodosin with a meal to reduce risk of adverse events. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): B An embryo/fetal study in rabbits showed decreased maternal body weight at 200 mg/kg/day (approximately 13 to 25 times the maximum recommended human exposure or MRHE of silodosin via AUC). No statistically significant teratogenicity was observed at this dose. Silodosin was not teratogenic when administered to pregnant rats during organogenesis at 1000 mg/kg/day (estimated to be approximately 20 times the MRHE). No maternal or fetal effects were observed at this dose. Rats and rabbits do not produce glucuronidated silodosin, which is present in human serum at approximately 4 times the level of circulating silodosin and which has similar pharmacological activity to silodosin. No effects on physical or behavioral development of offspring were observed when rats were treated during pregnancy and lactation at up to 300 mg/kg/day. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Silodosin in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Silodosin during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Silodosin in women who are nursing. ### Pediatric Use Silodosin is not indicated for use in pediatric patients. Safety and effectiveness in pediatric patients have not been established. ### Geriatic Use In double-blind, placebo-controlled, 12-week clinical studies of silodosin, 259 (55.6%) were under 65 years of age, 207 (44.4%) patients were 65 years of age and over, while 60 (12.9%) patients were 75 years of age and over. Orthostatic hypotension was reported in 2.3% of silodosin patients 65 years of age (1.9% for placebo), and 5.0% of patients > 75 years of age (0% for placebo). There were otherwise no significant differences in safety or effectiveness between older and younger patients. ### Gender There is no FDA guidance on the use of Silodosin with respect to specific gender populations. ### Race No clinical studies specifically investigating the effects of race have been performed. ### Renal Impairment The effect of renal impairment on silodosin pharmacokinetics was evaluated in a single dose study of six male patients with moderate renal impairment and seven male subjects with normal renal function. Plasma concentrations of silodosin were approximately three times higher in subjects with moderate renal impairment compared with subjects with normal renal function. Silodosin should be reduced to 4 mg per day in patients with moderate renal impairment. Exercise caution and monitor patients for adverse events. Silodosin has not been studied in patients with severe renal impairment. silodosin is contraindicated in patients with severe renal impairment. ### Hepatic Impairment In a study comparing nine male patients with moderate hepatic impairment (Child-Pugh scores 7 to 9), to nine healthy male subjects, the single dose pharmacokinetics of silodosin were not significantly altered in patients with hepatic impairment. No dosing adjustment is required in patients with mild or moderate hepatic impairment. Silodosin has not been studied in patients with severe hepatic impairment. Silodosin is contraindicated in patients with severe hepatic impairment. ### Females of Reproductive Potential and Males Treatment of male rats with silodosin for 15 days resulted in decreased fertility at the high dose of 20 mg/kg/day (about twice the MRHE) which was reversible following a two week recovery period. No effect was observed at 6 mg/kg/day. The clinical relevance of this finding is not known. In a fertility study in female rats, the high dose of 20 mg/kg/day (about 1 to 4 times the MRHE) resulted in estrus cycle changes, but no effect on fertility. No effect on the estrus cycle was observed at 6 mg/kg/day. In a male rat fertility study, sperm viability and count were significantly lower after administration of 600 mg/kg/day (about 65 times the MRHE) for one month. Histopathological examination of infertile males revealed changes in the testes and epididymides at 200 mg/kg/day (about 30 times the MRHE). ### Immunocompromised Patients There is no FDA guidance one the use of Silodosin in patients who are immunocompromised. # Administration and Monitoring ### Administration Oral ### Monitoring There is limited information regarding Silodosin Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Silodosin and IV administrations. # Overdosage Silodosin was evaluated at doses of up to 48 mg/day in healthy male subjects. The dose-limiting adverse event was postural hypotension. Should overdose of silodosin lead to hypotension, support of the cardiovascular system is of first importance. Restoration of blood pressure and normalization of heart rate may be accomplished by maintaining the patient in the supine position. If this measure is inadequate, administration of intravenous fluid should be considered. If necessary, vasopressors could be used, and renal function should be monitored and supported as needed. Dialysis is unlikely to be of significant benefit since silodosin is highly (97%) protein bound. # Pharmacology ## Mechanism of Action Silodosin is a selective antagonist of post-synaptic alpha-1 adrenoreceptors, which are located in the human prostate, bladder base, bladder neck, prostatic capsule, and prostatic urethra. Blockade of these alpha-1 adrenoreceptors can cause smooth muscle in these tissues to relax, resulting in an improvement in urine flow and a reduction in BPH symptoms. An in vitro study examining binding affinity of silodosin to the three subtypes of the alpha-1 adrenoreceptors (alpha-1A, alpha-1B, and alpha-1D) was conducted. The results of the study demonstrated that silodosin binds with high affinity to the alpha-1A subtype. ## Structure The molecular formula is C25H32F3N3O4 with a molecular weight of 495.53. The structural formula of silodosin is: ## Pharmacodynamics A test for postural hypotension was conducted 2 to 6 hours after the first dose in the two 12-week, double-blind, placebo-controlled clinical studies. After the patient had been at rest in a supine position for 5 minutes, the patient was asked to stand. Blood pressure and heart rate were assessed at 1 minute and 3 minutes after standing. A positive result was defined as a > 30 mmHg decrease in systolic blood pressure, or a > 20 mmHg decrease in diastolic blood pressure, or a > 20 bpm increase in heart rate. The effect of silodosin on QT interval was evaluated in a double-blind, randomized, active- (moxifloxacin) and placebo-controlled, parallel-group study in 189 healthy male subjects aged 18 to 45 years. Subjects received either silodosin 8 mg, silodosin 24 mg, or placebo once daily for five days, or a single dose of moxifloxacin 400 mg on Day 5 only. The 24 mg dose of silodosin was selected to achieve blood levels of silodosin that may be seen in a “worst-case” scenario exposure (i.e., in the setting of concomitant renal disease or use of strong CYP3A4 inhibitors). QT interval was measured during a 24-hour period following dosing on Day 5 (at silodosin steady state). Silodosin was not associated with an increase in individual corrected (QTcI) QT interval at any time during steady state measurement, while moxifloxacin, the active control, was associated with a maximum 9.59 msec increase in QTcI. There has been no signal of Torsade de Pointes in the post-marketing experience with silodosin outside the United States. ## Pharmacokinetics The pharmacokinetics of silodosin have been evaluated in adult male subjects with doses ranging from 0.1 mg to 24 mg per day. The pharmacokinetics of silodosin are linear throughout this dosage range. The pharmacokinetic characteristics of silodosin 8 mg once daily were determined in a multi-dose, open-label, 7-day pharmacokinetic study completed in 19 healthy, target-aged (> 45 years of age) male subjects. Table 3 presents the steady state pharmacokinetics of this study. The maximum effect of food (i.e., co-administration with a high fat, high calorie meal) on the PK of silodosin was not evaluated. The effect of a moderate fat, moderate calorie meal was variable and decreased silodosin Cmax by approximately 18 to 43% and AUC by 4 to 49% across three different studies. In a single-center, open-label, single-dose, randomized, two-period crossover study in twenty healthy male subjects age 21 to 43 years under fed conditions, a study was conducted to evaluate the relative bioavailability of the contents of an 8 mg capsule (size #1) of silodosin sprinkled on applesauce compared to the product administered as an intact capsule. Based on AUC0-24 and Cmax, silodosin administered by sprinkling the contents of a silodosin capsule onto a tablespoonful of applesauce was found to be bioequivalent to administering the capsule whole. Silodosin has an apparent volume of distribution of 49.5 L and is approximately 97% protein bound. Silodosin undergoes extensive metabolism through glucuronidation, alcohol and aldehyde dehydrogenase, and cytochrome P450 3A4 (CYP3A4) pathways. The main metabolite of silodosin is a glucuronide conjugate (KMD-3213G) that is formed via direct conjugation of silodosin by UDP-glucuronosyltransferase 2B7 (UGT2B7). Co-administration with inhibitors of UGT2B7 (e.g., probenecid, valproic acid, fluconazole) may potentially increase exposure to silodosin. KMD-3213G, which has been shown in vitro to be active, has an extended half-life (approximately 24 hours) and reaches plasma exposure (AUC) approximately four times greater than that of silodosin. The second major metabolite (KMD-3293) is formed via alcohol and aldehyde dehydrogenases and reaches plasma exposures similar to that of silodosin. KMD-3293 is not expected to contribute significantly to the overall pharmacologic activity of silodosin. Following oral administration of 14C-labeled silodosin, the recovery of radioactivity after 10 days was approximately 33.5% in urine and 54.9% in feces. After intravenous administration, the plasma clearance of silodosin was approximately 10 L/hour. ## Nonclinical Toxicology In a 2-year oral carcinogenicity study in rats administered doses up to 150 mg/kg/day , an increase in thyroid follicular cell tumor incidence was seen in male rats receiving doses of 150 mg/kg/day. Silodosin induced stimulation of thyroid stimulating hormone (TSH) secretion in the male rat as a result of increased metabolism and decreased circulating levels of thyroxine (T4). These changes are believed to produce specific morphological and functional changes in the rat thyroid including hypertrophy, hyperplasia, and neoplasia. Silodosin did not alter TSH or T4 levels in clinical trials and no effects based on thyroid examinations were noted. The relevance to human risk of these thyroid tumors in rats is not known. In a 2-year oral carcinogenicity study in mice administered doses up to 100 mg/kg/day in males (about nine times the MRHE based on AUC of silodosin) and 400 mg/kg/day in females (about 72 times the MRHE based on AUC), there were no significant tumor findings in male mice. Female mice treated for 2 years with doses of 150 mg/kg/day (about 29 times the MRHE based on AUC) or greater had statistically significant increases in the incidence of mammary gland adenoacanthomas and adenocarcinomas. The increased incidence of mammary gland neoplasms in female mice was considered secondary to silodosin-induced hyperprolactinemia measured in the treated mice. Elevated prolactin levels were not observed in clinical trials. The relevance to human risk of prolactin-mediated endocrine tumors in mice is not known. Rats and mice do not produce glucuronidated silodosin, which is present in human serum at approximately four times the level of circulating silodosin and which has similar pharmacological activity to silodosin. Silodosin produced no evidence of mutagenic or genotoxic potential in the in vitro Ames assay, mouse lymphoma assay, unscheduled DNA synthesis assay and the in vivo mouse micronucleus assay. A weakly positive response was obtained in two in vitro Chinese Hamster Lung (CHL) tests for chromosomal aberration assays at high, cytotoxic concentrations. # Clinical Studies Two 12-week, randomized, double-blind, placebo-controlled, multicenter studies were conducted with 8 mg daily of silodosin. In these two studies, 923 patients were randomized and 466 patients received silodosin 8 mg daily. The two studies were identical in design except for the inclusion of pharmacokinetic sampling in Study 1. The primary efficacy assessment was the International Prostate Symptom Score (IPSS) which evaluated irritative (frequency, urgency, and nocturia), and obstructive (hesitancy, incomplete emptying, intermittency, and weak stream) symptoms. Maximum urine flow rate (Qmax) was a secondary efficacy measure. Mean changes from baseline to last assessment (Week 12) in total IPSS score were statistically significantly greater for groups treated with silodosin than those treated with placebo in both studies (Table 4 and Figures 2 and 3). Mean IPSS total score for silodosin once daily groups showed a decrease starting at the first scheduled observation and remained decreased through the 12 weeks of treatment in both studies. Silodosin produced statistically significant increases in maximum urinary flow rates from baseline to last assessment (Week 12) versus placebo in both studies (Table 5 and Figures 4 and 5). Mean peak flow rate increased starting at the first scheduled observation at Day 1 and remained greater than the baseline flow rate through the 12 weeks of treatment for both studies. # How Supplied Silodosin capsules 8 mg - Bottle of 30 capsules (NDC 52544-152-30) - Bottle of 90 capsules (NDC 52544-152-19) Silodosin capsules 4 mg - Bottle of 30 capsules (NDC 52544-151-30) - Bottle of 90 capsules (NDC 52544-151-19) ## Storage Store at 25°C (77°F) # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Patients should be instructed to take silodosin once daily with a meal. - Patients should be instructed about the possible occurrence of symptoms related to postural hypotension (such as dizziness), and should be cautioned about driving, operating machinery, or performing hazardous tasks until they know how silodosin will affect them. This is especially important for those with low blood pressure or who are taking antihypertensive medications. - The most common side effect seen with silodosin is an orgasm with reduced or no semen. This side effect does not pose a safety concern and is reversible with discontinuation of the product. - The patient should be instructed to tell his ophthalmologist about the use of silodosin before cataract surgery or other procedures involving the eyes, even if the patient is no longer taking silodosin. # Precautions with Alcohol Alcohol-Silodosin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Rapaflo # Look-Alike Drug Names There is limited information regarding Silodosin Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Silodosin Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gloria Picoy [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 Silodosin is an alpha-1 adrenergic antagonist that is FDA approved for the treatment of the signs and symptoms of benign prostatic hyperplasia (BPH). Common adverse reactions include retrograde ejaculation, dizziness, diarrhea, orthostatic hypotension, headache, nasopharyngitis, and nasal congestion. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Silodosin is indicated for the treatment of the signs and symptoms of benign prostatic hyperplasia (BPH) - Dosage: 8 mg orally once daily with a meal. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Silodosin in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Silodosin in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) Safety and efficacy not established in pediatric patients ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Silodosin in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Silodosin in pediatric patients. # Contraindications - Severe renal impairment (CCr < 30 mL/min). - Severe hepatic impairment (Child-Pugh score > 10). - Concomitant administration with strong Cytochrome P450 3A4 (CYP3A4) inhibitors (e.g., ketoconazole, clarithromycin, itraconazole, ritonavir). - Patients with a history of hypersensitivity to silodosin or any of the ingredients of silodosin. # Warnings Postural hypotension, with or without symptoms (e.g., dizziness) may develop when beginning silodosin treatment. As with other alpha-blockers, there is potential for syncope. Patients should be cautioned about driving, operating machinery, or performing hazardous tasks when initiating therapy. Silodosin has not been tested in patients with severe hepatic impairment, and therefore, should not be prescribed to such patients. In a drug interaction study, co-administration of a single 8 mg dose of silodosin with 400 mg ketoconazole, a strong CYP3A4 inhibitor, caused a 3.8-fold increase in maximum plasma silodosin concentrations and 3.2-fold increase in silodosin exposure (i.e., AUC). Concomitant use of ketoconazole or other strong CYP3A4 inhibitors (e.g., itraconazole, clarithromycin, ritonavir) is therefore contraindicated. The pharmacodynamic interactions between silodosin and other alpha-blockers have not been determined. However, interactions may be expected, and silodosin should not be used in combination with other alpha-blockers. A specific pharmacodynamic interaction study between silodosin and antihypertensive agents has not been performed. However, patients in the Phase 3 clinical studies taking concomitant antihypertensive medications with silodosin did not experience a significant increase in the incidence of syncope, dizziness, or orthostasis. Nevertheless, exercise caution during concomitant use with antihypertensives and monitor patients for possible adverse events. Caution is also advised when alpha-adrenergic blocking agents including silodosin are co-administered with PDE5 inhibitors. Alpha-adrenergic blockers and PDE5 inhibitors are both vasodilators that can lower blood pressure. Concomitant use of these two drug classes can potentially cause symptomatic hypotension. Carcinoma of the prostate and BPH cause many of the same symptoms. These two diseases frequently co-exist. Therefore, patients thought to have BPH should be examined prior to starting therapy with silodosin to rule out the presence of carcinoma of the prostate. Intraoperative Floppy Iris Syndrome has been observed during cataract surgery in some patients on alpha-1 blockers or previously treated with alpha-1 blockers. This variant of small pupil syndrome is characterized by the combination of a flaccid iris that billows in response to intraoperative irrigation currents; progressive intraoperative miosis despite preoperative dilation with standard mydriatic drugs; and potential prolapse of the iris toward the phacoemulsification incisions. Patients planning cataract surgery should be told to inform their ophthalmologist that they are taking silodosin. # 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. In U.S. clinical trials, 897 patients with BPH were exposed to 8 mg silodosin daily. This includes 486 patients exposed for 6 months and 168 patients exposed for 1 year. The population was 44 to 87 years of age, and predominantly Caucasian. Of these patients, 42.8% were 65 years of age or older and 10.7% were 75 years of age or older. In double-blind, placebo controlled, 12-week clinical trials, 466 patients were administered silodosin and 457 patients were administered placebo. At least one treatment-emergent adverse reaction was reported by 55.2% of silodosin treated patients (36.8% for placebo treated). The majority (72.1%) of adverse reactions for the silodosin treated patients (59.8% for placebo treated) were qualified by the investigator as mild. A total of 6.4% of silodosin treated patients (2.2% for placebo treated) discontinued therapy due to an adverse reaction (treatment-emergent), the most common reaction being retrograde ejaculation (2.8%) for silodosin treated patients. Retrograde ejaculation is reversible upon discontinuation of treatment. The incidence of treatment-emergent adverse reactions listed in the following table were derived from two 12-week, multicenter, double-blind, placebo-controlled clinical studies of silodosin 8 mg daily in BPH patients. Adverse reactions that occurred in at least 2% of patients treated with silodosin and more frequently than with placebo are shown in Table 1. In the two 12-week, placebo-controlled clinical trials, the following adverse events were reported by between 1% and 2% of patients receiving silodosin and occurred more frequently than with placebo: insomnia, PSA increased, sinusitis, abdominal pain, asthenia, and rhinorrhea. One case of syncope in a patient taking prazosin concomitantly and one case of priapism were reported in the silodosin treatment group. In a 9-month open-label safety study of silodosin, one case of Intraoperative Floppy Iris Syndrome (IFIS) was reported. ## Postmarketing Experience The following adverse reactions have been identified during post approval use of silodosin. 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: - Skin and subcutaneous tissue disorders: toxic skin eruption, purpura, skin rash, pruritus, and urticaria. - Hepatobiliary disorders: jaundice, impaired hepatic function associated with increased transaminase values. - Immune system disorders: allergic-type reactions, not limited to skin reactions including swollen tongue and pharyngeal edema resulting in serious outcomes. # Drug Interactions In a clinical metabolic inhibition study, a 3.8-fold increase in silodosin maximum plasma concentrations and 3.2-fold increase in silodosin exposure were observed with concurrent administration of a strong CYP3A4 inhibitor, 400 mg ketoconazole. Use of strong CYP3A4 inhibitors such as itraconazole or ritonavir may cause plasma concentrations of silodosin to increase. Concomitant administration of strong CYP3A4 inhibitors and silodosin is contraindicated. The effect of moderate CYP3A4 inhibitors on the pharmacokinetics of silodosin has not been evaluated. Concomitant administration with moderate CYP3A4 inhibitors (e.g., diltiazem, erythromycin, verapamil) may increase concentration of silodosin. Exercise caution and monitor patients for adverse events when co-administering silodosin with moderate CYP3A4 inhibitors. In vitro studies indicated that silodosin is a P-gp substrate. Ketoconazole, a CYP3A4 inhibitor that also inhibits P-gp, caused significant increase in exposure to silodosin. Inhibition of P-gp may lead to increased silodosin concentration. Silodosin is therefore not recommended in patients taking strong P-gp inhibitors such as cyclosporine. The pharmacodynamic interactions between silodosin and other alpha-blockers have not been determined. However, interactions may be expected, and silodosin should not be used in combination with other alpha-blockers. The effect of co-administration of silodosin and digoxin 0.25 mg/day for 7 days was evaluated in a clinical trial in 16 healthy males, aged 18 to 45 years. Concomitant administration of silodosin and digoxin did not significantly alter the steady state pharmacokinetics of digoxin. No dose adjustment is required. Co-administration of silodosin with a single dose of 100 mg sildenafil or 20 mg tadalafil was evaluated in a placebo-controlled clinical study that included 24 healthy male subjects, 45 to 78 years of age. Orthostatic vital signs were monitored in the 12-hour period following concomitant dosing. During this period, the total number of positive orthostatic test results was greater in the group receiving silodosin plus a PDE5 inhibitor compared with silodosin alone. No events of symptomatic orthostasis or dizziness were reported in subjects receiving silodosin with a PDE5 inhibitor. The pharmacodynamic interactions between silodosin and antihypertensives have not been rigorously investigated in a clinical study. However, approximately one-third of the patients in clinical studies used concomitant antihypertensive medications with silodosin. The incidence of dizziness and orthostatic hypotension in these patients was higher than in the general silodosin population (4.6% versus 3.8% and 3.4% versus 3.2%, respectively). Exercise caution during concomitant use with antihypertensives and monitor patients for possible adverse events. In vitro data indicate that silodosin does not have the potential to inhibit or induce cytochrome P450 enzyme systems. The effect of a moderate fat, moderate calorie meal on silodosin pharmacokinetics was variable and decreased silodosin maximum plasma concentration (Cmax) by approximately 18 to 43% and exposure (AUC) by 4 to 49% across three different studies. Safety and efficacy clinical trials for silodosin were always conducted in the presence of food intake. Patients should be instructed to take silodosin with a meal to reduce risk of adverse events. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): B An embryo/fetal study in rabbits showed decreased maternal body weight at 200 mg/kg/day (approximately 13 to 25 times the maximum recommended human exposure or MRHE of silodosin via AUC). No statistically significant teratogenicity was observed at this dose. Silodosin was not teratogenic when administered to pregnant rats during organogenesis at 1000 mg/kg/day (estimated to be approximately 20 times the MRHE). No maternal or fetal effects were observed at this dose. Rats and rabbits do not produce glucuronidated silodosin, which is present in human serum at approximately 4 times the level of circulating silodosin and which has similar pharmacological activity to silodosin. No effects on physical or behavioral development of offspring were observed when rats were treated during pregnancy and lactation at up to 300 mg/kg/day. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Silodosin in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Silodosin during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Silodosin in women who are nursing. ### Pediatric Use Silodosin is not indicated for use in pediatric patients. Safety and effectiveness in pediatric patients have not been established. ### Geriatic Use In double-blind, placebo-controlled, 12-week clinical studies of silodosin, 259 (55.6%) were under 65 years of age, 207 (44.4%) patients were 65 years of age and over, while 60 (12.9%) patients were 75 years of age and over. Orthostatic hypotension was reported in 2.3% of silodosin patients < 65 years of age (1.2% for placebo), 2.9% of silodosin patients > 65 years of age (1.9% for placebo), and 5.0% of patients > 75 years of age (0% for placebo). There were otherwise no significant differences in safety or effectiveness between older and younger patients. ### Gender There is no FDA guidance on the use of Silodosin with respect to specific gender populations. ### Race No clinical studies specifically investigating the effects of race have been performed. ### Renal Impairment The effect of renal impairment on silodosin pharmacokinetics was evaluated in a single dose study of six male patients with moderate renal impairment and seven male subjects with normal renal function. Plasma concentrations of silodosin were approximately three times higher in subjects with moderate renal impairment compared with subjects with normal renal function. Silodosin should be reduced to 4 mg per day in patients with moderate renal impairment. Exercise caution and monitor patients for adverse events. Silodosin has not been studied in patients with severe renal impairment. silodosin is contraindicated in patients with severe renal impairment. ### Hepatic Impairment In a study comparing nine male patients with moderate hepatic impairment (Child-Pugh scores 7 to 9), to nine healthy male subjects, the single dose pharmacokinetics of silodosin were not significantly altered in patients with hepatic impairment. No dosing adjustment is required in patients with mild or moderate hepatic impairment. Silodosin has not been studied in patients with severe hepatic impairment. Silodosin is contraindicated in patients with severe hepatic impairment. ### Females of Reproductive Potential and Males Treatment of male rats with silodosin for 15 days resulted in decreased fertility at the high dose of 20 mg/kg/day (about twice the MRHE) which was reversible following a two week recovery period. No effect was observed at 6 mg/kg/day. The clinical relevance of this finding is not known. In a fertility study in female rats, the high dose of 20 mg/kg/day (about 1 to 4 times the MRHE) resulted in estrus cycle changes, but no effect on fertility. No effect on the estrus cycle was observed at 6 mg/kg/day. In a male rat fertility study, sperm viability and count were significantly lower after administration of 600 mg/kg/day (about 65 times the MRHE) for one month. Histopathological examination of infertile males revealed changes in the testes and epididymides at 200 mg/kg/day (about 30 times the MRHE). ### Immunocompromised Patients There is no FDA guidance one the use of Silodosin in patients who are immunocompromised. # Administration and Monitoring ### Administration Oral ### Monitoring There is limited information regarding Silodosin Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Silodosin and IV administrations. # Overdosage Silodosin was evaluated at doses of up to 48 mg/day in healthy male subjects. The dose-limiting adverse event was postural hypotension. Should overdose of silodosin lead to hypotension, support of the cardiovascular system is of first importance. Restoration of blood pressure and normalization of heart rate may be accomplished by maintaining the patient in the supine position. If this measure is inadequate, administration of intravenous fluid should be considered. If necessary, vasopressors could be used, and renal function should be monitored and supported as needed. Dialysis is unlikely to be of significant benefit since silodosin is highly (97%) protein bound. # Pharmacology ## Mechanism of Action Silodosin is a selective antagonist of post-synaptic alpha-1 adrenoreceptors, which are located in the human prostate, bladder base, bladder neck, prostatic capsule, and prostatic urethra. Blockade of these alpha-1 adrenoreceptors can cause smooth muscle in these tissues to relax, resulting in an improvement in urine flow and a reduction in BPH symptoms. An in vitro study examining binding affinity of silodosin to the three subtypes of the alpha-1 adrenoreceptors (alpha-1A, alpha-1B, and alpha-1D) was conducted. The results of the study demonstrated that silodosin binds with high affinity to the alpha-1A subtype. ## Structure The molecular formula is C25H32F3N3O4 with a molecular weight of 495.53. The structural formula of silodosin is: ## Pharmacodynamics A test for postural hypotension was conducted 2 to 6 hours after the first dose in the two 12-week, double-blind, placebo-controlled clinical studies. After the patient had been at rest in a supine position for 5 minutes, the patient was asked to stand. Blood pressure and heart rate were assessed at 1 minute and 3 minutes after standing. A positive result was defined as a > 30 mmHg decrease in systolic blood pressure, or a > 20 mmHg decrease in diastolic blood pressure, or a > 20 bpm increase in heart rate. The effect of silodosin on QT interval was evaluated in a double-blind, randomized, active- (moxifloxacin) and placebo-controlled, parallel-group study in 189 healthy male subjects aged 18 to 45 years. Subjects received either silodosin 8 mg, silodosin 24 mg, or placebo once daily for five days, or a single dose of moxifloxacin 400 mg on Day 5 only. The 24 mg dose of silodosin was selected to achieve blood levels of silodosin that may be seen in a “worst-case” scenario exposure (i.e., in the setting of concomitant renal disease or use of strong CYP3A4 inhibitors). QT interval was measured during a 24-hour period following dosing on Day 5 (at silodosin steady state). Silodosin was not associated with an increase in individual corrected (QTcI) QT interval at any time during steady state measurement, while moxifloxacin, the active control, was associated with a maximum 9.59 msec increase in QTcI. There has been no signal of Torsade de Pointes in the post-marketing experience with silodosin outside the United States. ## Pharmacokinetics The pharmacokinetics of silodosin have been evaluated in adult male subjects with doses ranging from 0.1 mg to 24 mg per day. The pharmacokinetics of silodosin are linear throughout this dosage range. The pharmacokinetic characteristics of silodosin 8 mg once daily were determined in a multi-dose, open-label, 7-day pharmacokinetic study completed in 19 healthy, target-aged (> 45 years of age) male subjects. Table 3 presents the steady state pharmacokinetics of this study. The maximum effect of food (i.e., co-administration with a high fat, high calorie meal) on the PK of silodosin was not evaluated. The effect of a moderate fat, moderate calorie meal was variable and decreased silodosin Cmax by approximately 18 to 43% and AUC by 4 to 49% across three different studies. In a single-center, open-label, single-dose, randomized, two-period crossover study in twenty healthy male subjects age 21 to 43 years under fed conditions, a study was conducted to evaluate the relative bioavailability of the contents of an 8 mg capsule (size #1) of silodosin sprinkled on applesauce compared to the product administered as an intact capsule. Based on AUC0-24 and Cmax, silodosin administered by sprinkling the contents of a silodosin capsule onto a tablespoonful of applesauce was found to be bioequivalent to administering the capsule whole. Silodosin has an apparent volume of distribution of 49.5 L and is approximately 97% protein bound. Silodosin undergoes extensive metabolism through glucuronidation, alcohol and aldehyde dehydrogenase, and cytochrome P450 3A4 (CYP3A4) pathways. The main metabolite of silodosin is a glucuronide conjugate (KMD-3213G) that is formed via direct conjugation of silodosin by UDP-glucuronosyltransferase 2B7 (UGT2B7). Co-administration with inhibitors of UGT2B7 (e.g., probenecid, valproic acid, fluconazole) may potentially increase exposure to silodosin. KMD-3213G, which has been shown in vitro to be active, has an extended half-life (approximately 24 hours) and reaches plasma exposure (AUC) approximately four times greater than that of silodosin. The second major metabolite (KMD-3293) is formed via alcohol and aldehyde dehydrogenases and reaches plasma exposures similar to that of silodosin. KMD-3293 is not expected to contribute significantly to the overall pharmacologic activity of silodosin. Following oral administration of 14C-labeled silodosin, the recovery of radioactivity after 10 days was approximately 33.5% in urine and 54.9% in feces. After intravenous administration, the plasma clearance of silodosin was approximately 10 L/hour. ## Nonclinical Toxicology In a 2-year oral carcinogenicity study in rats administered doses up to 150 mg/kg/day [about 8 times the exposure of the maximum recommended human dose (MRHE) based on AUC of silodosin], an increase in thyroid follicular cell tumor incidence was seen in male rats receiving doses of 150 mg/kg/day. Silodosin induced stimulation of thyroid stimulating hormone (TSH) secretion in the male rat as a result of increased metabolism and decreased circulating levels of thyroxine (T4). These changes are believed to produce specific morphological and functional changes in the rat thyroid including hypertrophy, hyperplasia, and neoplasia. Silodosin did not alter TSH or T4 levels in clinical trials and no effects based on thyroid examinations were noted. The relevance to human risk of these thyroid tumors in rats is not known. In a 2-year oral carcinogenicity study in mice administered doses up to 100 mg/kg/day in males (about nine times the MRHE based on AUC of silodosin) and 400 mg/kg/day in females (about 72 times the MRHE based on AUC), there were no significant tumor findings in male mice. Female mice treated for 2 years with doses of 150 mg/kg/day (about 29 times the MRHE based on AUC) or greater had statistically significant increases in the incidence of mammary gland adenoacanthomas and adenocarcinomas. The increased incidence of mammary gland neoplasms in female mice was considered secondary to silodosin-induced hyperprolactinemia measured in the treated mice. Elevated prolactin levels were not observed in clinical trials. The relevance to human risk of prolactin-mediated endocrine tumors in mice is not known. Rats and mice do not produce glucuronidated silodosin, which is present in human serum at approximately four times the level of circulating silodosin and which has similar pharmacological activity to silodosin. Silodosin produced no evidence of mutagenic or genotoxic potential in the in vitro Ames assay, mouse lymphoma assay, unscheduled DNA synthesis assay and the in vivo mouse micronucleus assay. A weakly positive response was obtained in two in vitro Chinese Hamster Lung (CHL) tests for chromosomal aberration assays at high, cytotoxic concentrations. # Clinical Studies Two 12-week, randomized, double-blind, placebo-controlled, multicenter studies were conducted with 8 mg daily of silodosin. In these two studies, 923 patients were randomized and 466 patients received silodosin 8 mg daily. The two studies were identical in design except for the inclusion of pharmacokinetic sampling in Study 1. The primary efficacy assessment was the International Prostate Symptom Score (IPSS) which evaluated irritative (frequency, urgency, and nocturia), and obstructive (hesitancy, incomplete emptying, intermittency, and weak stream) symptoms. Maximum urine flow rate (Qmax) was a secondary efficacy measure. Mean changes from baseline to last assessment (Week 12) in total IPSS score were statistically significantly greater for groups treated with silodosin than those treated with placebo in both studies (Table 4 and Figures 2 and 3). Mean IPSS total score for silodosin once daily groups showed a decrease starting at the first scheduled observation and remained decreased through the 12 weeks of treatment in both studies. Silodosin produced statistically significant increases in maximum urinary flow rates from baseline to last assessment (Week 12) versus placebo in both studies (Table 5 and Figures 4 and 5). Mean peak flow rate increased starting at the first scheduled observation at Day 1 and remained greater than the baseline flow rate through the 12 weeks of treatment for both studies. # How Supplied Silodosin capsules 8 mg - Bottle of 30 capsules (NDC 52544-152-30) - Bottle of 90 capsules (NDC 52544-152-19) Silodosin capsules 4 mg - Bottle of 30 capsules (NDC 52544-151-30) - Bottle of 90 capsules (NDC 52544-151-19) ## Storage Store at 25°C (77°F) # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Patients should be instructed to take silodosin once daily with a meal. - Patients should be instructed about the possible occurrence of symptoms related to postural hypotension (such as dizziness), and should be cautioned about driving, operating machinery, or performing hazardous tasks until they know how silodosin will affect them. This is especially important for those with low blood pressure or who are taking antihypertensive medications. - The most common side effect seen with silodosin is an orgasm with reduced or no semen. This side effect does not pose a safety concern and is reversible with discontinuation of the product. - The patient should be instructed to tell his ophthalmologist about the use of silodosin before cataract surgery or other procedures involving the eyes, even if the patient is no longer taking silodosin. # Precautions with Alcohol Alcohol-Silodosin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Rapaflo [1] # Look-Alike Drug Names There is limited information regarding Silodosin Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Silodosin
482ac3f109d16b7301556bfc188b2fcb6dbad8ab	wikidoc	Sincalide	Sincalide # 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 Sincalide is a hormone analog that is FDA approved for the treatment of gallbladder contraction, stimulate pancreatic secretion. Common adverse reactions include vomiting, flushing, sweating, rash, hypotension, hypertension, shortness of breath, urge to defecate, headache, diarrhea, sneezing, and numbness. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Kinevac (Sincalide for Injection) may be used: (1) to stimulate gallbladder contraction, as may be assessed by various methods of diagnostic imaging, or to obtain by duodenal aspiration a sample of concentrated bile for analysis of cholesterol, bile salts, phospholipids, and crystals; (2) to stimulate pancreatic secretion (especially in conjunction with secretin) prior to obtaining a duodenal aspirate for analysis of enzyme activity, composition, and cytology; (3) to accelerate the transit of a barium meal through the small bowel, thereby decreasing the time and extent of radiation associated with fluoroscopy and x-ray examination of the intestinal tract. - Sincalide for Injection may be stored at room temperature prior to reconstitution. - To reconstitute, aseptically add 5 mL of Sterile Water for Injection USP to the vial. This solution may be kept at room temperature and should be used within 8 hours of reconstitution, after which time any unused portion should be discarded. - Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. - For prompt contraction of the gallbladder, a dose of 0.02 mcg sincalide per kg (1.4 mcg/70 kg) is injected intravenously over a 30- to 60-second interval; if satisfactory contraction of the gallbladder does not occur in 15 minutes, a second dose, 0.04 mcg sincalide per kg, may be administered. - To reduce the intestinal side effects, an intravenous infusion may be prepared at a dose of 0.12 mcg/kg in 100 mL of Sodium Chloride Injection USP and given at a rate of 2 mL per minute; alternatively, an intramuscular dose of 0.1 mcg/kg may be given. When Kinevac (Sincalide for Injection) is used in cholecystography, roentgenograms are usually taken at five-minute intervals after the injection. For visualization of the cystic duct, it may be necessary to take roentgenograms at one-minute intervals during the first five minutes after the injection. - For the Secretin-Kinevac test of pancreatic function, the patient receives a dose of 0.25 units secretin per kg by intravenous infusion over a 60-minute period. Thirty minutes after the initiation of the secretin infusion, a separate IV infusion of Kinevac at a total dose of 0.02 mcg per kg is administered over a 30-minute interval. For example, the total dose for a 70 kg patient is 1.4 mcg of sincalide; therefore, dilute 1.4 mL of reconstituted Kinevac solution to 30 mL with Sodium Chloride Injection USP and administer at a rate of 1 mL per minute. - To accelerate the transit time of a barium meal through the small bowel, administer Kinevac after the barium meal is beyond the proximal jejunum. (Sincalide, like cholecystokinin, may cause pyloric contraction.) The recommended dose is 0.04 mcg sincalide per kg (2.8 mcg/70 kg) injected intravenously over a 30- to 60- second interval; if satisfactory transit of the barium meal has not occurred in 30 minutes, a second dose of 0.04 mcg sincalide per kg may be administered. For reduction of side effects, a 30-minute IV infusion of sincalide may be administered. - Sodium Chloride Injection dilutions may be kept at room temperature and should be used within one hour of dilution. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Sincalide in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Sincalide in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Sincalide in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Sincalide in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Sincalide in pediatric patients. # Contraindications - The preparation is contraindicated in patients hypersensitive to sincalide and in patients with intestinal obstruction. # Warnings - Because of Kinevac’s effect on smooth muscle, pregnant patients should be advised that spontaneous abortion or premature induction of labor may occur # Adverse Reactions ## Clinical Trials Experience There is limited information regarding Clinical Trial Experience of Sincalide in the drug label. ## Postmarketing Experience - Reactions to sincalide are generally mild and of short duration. The most frequent adverse reactions were abdominal discomfort or pain, and nausea; rapid intravenous injection of 0.04 mcg sincalide per kg expectably causes transient abdominal cramping. These phenomena are usually manifestations of the physiologic action of the drug, including delayed gastric emptying and increased intestinal motility. These reactions occurred in approximately 20 percent of patients; they are not to be construed as necessarily indicating an abnormality of the billiary tract unless there is other clinical or radiologic evidence of disease. - The incidence of other adverse reactions, including vomiting, flushing, sweating, rash, hypotension, hypertension, shortness of breath, urge to defecate, headache, diarrhea, sneezing, and numbness was less than 1 percent; dizziness was reported in approximately 2 percent of patients. These manifestations are usually lessened by slower injection rate. # Drug Interactions There is limited information regarding Sincalide Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): B - Reproduction studies in rats in which sincalide was administered subcutaneously at doses up to 12.5 times the maximum recommended human dose revealed no evidence of harm to the fetus due to sincalide. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Sincalide in women who are pregnant. ### Labor and Delivery - Reproduction studies in rats in which sincalide was administered subcutaneously at doses up to 12.5 times the maximum recommended human dose revealed no evidence of harm to the fetus due to sincalide. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. ### Nursing Mothers - 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 sincalide is administered to a nursing woman. ### Pediatric Use Safety and effectiveness in children have not been established. ### Geriatic Use There is no FDA guidance on the use of Sincalide with respect to geriatric patients. ### Gender There is no FDA guidance on the use of Sincalide with respect to specific gender populations. ### Race There is no FDA guidance on the use of Sincalide with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Sincalide in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Sincalide in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Sincalide in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Sincalide in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral - Intravenous ### Monitoring There is limited information regarding Monitoring of Sincalide in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Sincalide in the drug label. # Overdosage - Although no overdosage reports have been received, gastrointestinal symptoms (abdominal cramps, nausea, vomiting and diarrhea) would be expected. Hypotension with dizziness or fainting might also occur. - Overdosage symptoms should be treated symptomatically and should be of short duration. Starting with single bolus i.v. injection comparable to the human does of 0.4 mg/kg, sincalide caused hypotension and bradycardia in dogs. Higher doses injected once or repeatedly in dogs caused syncope and ECG changes in addition. These effects were attributed to sincalide-induced vagal stimulation in that all were prevented by pretreatment with atropine or bilateral vagotomy. # Pharmacology ## Mechanism of Action - When injected intravenously, sincalide produces a substantial reduction in gallbladder size by causing this organ to contract. The evacuation of bile that results is similar to that which occurs physiologically in response to endogenous cholecystokinin. The intravenous (bolus) administration of sincalide causes a prompt contraction of the gallbladder that becomes maximal in 5 to 15 minutes, as compared with the stimulus of a fatty meal which causes a progressive contraction that becomes maximal after approximately 40 minutes. Generally, a 40 percent reduction in radiographic area of the gallbladder is considered satisfactory contraction, although some patients will show area reduction of 60 to 70 percent. - Like cholecystokinin, sincalide stimulates pancreatic secretion; concurrent administration with secretin increases both the volume of pancreatic secretion and the out-put of bicarbonate and protein (enzymes) by the gland. This combined effect of secretin and sincalide permits the assessment of specific pancreatic function through measurement and analysis of the duodenal aspirate. The parameters usually determined are: volume of the secretion; bicarbonate concentration; and amylase content (which parallels the content of trypsin and total protein). - Both cholecystokinin and sincalide stimulate intestinal motility, and may cause pyloric contraction which retards gastric emptying. ## Structure - Kinevac (Sincalide for Injection) is a cholecystopancreatic-gastrointestinal hormone peptide for parenteral administration. The agent is a synthetically-prepared C-terminal octapeptide of cholecystokinin. Each vial of sincalide provides a sterile nonpyrogenic lyophillized white powder consisting of 5 mcg sincalide with 170 mg mannitol, 30 mg arginine hydrochloride, 15 mg lysine hydrochloride, 9 mg potassium phosphate dibasic, 4 mg methionine, 2 mg pentetic acid, 0.04 mg sodium metabisulfite, and 0.005 mcg polysorbate 20. The pH is adjusted to 6.0 - 8.0 with hydrochloric acid and/or sodium hydroxide prior to lyophilization. Sincalide is designated chemically as L-α-aspartyl-O-sulfo-L-tyrosyl-L-methionylglycyl-L-tryptophyl-L-methionyl- L-α-aspartyl-L-phenylalaninamide. Graphic formula: ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Sincalide in the drug label. ## Pharmacokinetics There is limited information regarding Pharmacokinetics of Sincalide in the drug label. ## Nonclinical Toxicology There is limited information regarding Nonclinical Toxicology of Sincalide in the drug label. # Clinical Studies There is limited information regarding Clinical Studies of Sincalide in the drug label. # How Supplied - Kinevac (Sincalide for Injection) is supplied in packages of 10 vials containing 5 mcg of sincalide per vial (NDC 0270-0556-15). ## Storage - Store at 25° C (77° F); excursions permitted to 15-30° C (59-86° F). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Patient Counseling Information of Sincalide in the drug label. # Precautions with Alcohol - Alcohol-Sincalide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - KINEVAC ® # Look-Alike Drug Names - A® — B® # Drug Shortage Status # Price	Sincalide 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. # Overview Sincalide is a hormone analog that is FDA approved for the treatment of gallbladder contraction, stimulate pancreatic secretion. Common adverse reactions include vomiting, flushing, sweating, rash, hypotension, hypertension, shortness of breath, urge to defecate, headache, diarrhea, sneezing, and numbness. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Kinevac (Sincalide for Injection) may be used: (1) to stimulate gallbladder contraction, as may be assessed by various methods of diagnostic imaging, or to obtain by duodenal aspiration a sample of concentrated bile for analysis of cholesterol, bile salts, phospholipids, and crystals; (2) to stimulate pancreatic secretion (especially in conjunction with secretin) prior to obtaining a duodenal aspirate for analysis of enzyme activity, composition, and cytology; (3) to accelerate the transit of a barium meal through the small bowel, thereby decreasing the time and extent of radiation associated with fluoroscopy and x-ray examination of the intestinal tract. - Sincalide for Injection may be stored at room temperature prior to reconstitution. - To reconstitute, aseptically add 5 mL of Sterile Water for Injection USP to the vial. This solution may be kept at room temperature and should be used within 8 hours of reconstitution, after which time any unused portion should be discarded. - Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. - For prompt contraction of the gallbladder, a dose of 0.02 mcg sincalide per kg (1.4 mcg/70 kg) is injected intravenously over a 30- to 60-second interval; if satisfactory contraction of the gallbladder does not occur in 15 minutes, a second dose, 0.04 mcg sincalide per kg, may be administered. * To reduce the intestinal side effects, an intravenous infusion may be prepared at a dose of 0.12 mcg/kg in 100 mL of Sodium Chloride Injection USP and given at a rate of 2 mL per minute; alternatively, an intramuscular dose of 0.1 mcg/kg may be given. When Kinevac (Sincalide for Injection) is used in cholecystography, roentgenograms are usually taken at five-minute intervals after the injection. For visualization of the cystic duct, it may be necessary to take roentgenograms at one-minute intervals during the first five minutes after the injection. - For the Secretin-Kinevac test of pancreatic function, the patient receives a dose of 0.25 units secretin per kg by intravenous infusion over a 60-minute period. Thirty minutes after the initiation of the secretin infusion, a separate IV infusion of Kinevac at a total dose of 0.02 mcg per kg is administered over a 30-minute interval. For example, the total dose for a 70 kg patient is 1.4 mcg of sincalide; therefore, dilute 1.4 mL of reconstituted Kinevac solution to 30 mL with Sodium Chloride Injection USP and administer at a rate of 1 mL per minute. - To accelerate the transit time of a barium meal through the small bowel, administer Kinevac after the barium meal is beyond the proximal jejunum. (Sincalide, like cholecystokinin, may cause pyloric contraction.) The recommended dose is 0.04 mcg sincalide per kg (2.8 mcg/70 kg) injected intravenously over a 30- to 60- second interval; if satisfactory transit of the barium meal has not occurred in 30 minutes, a second dose of 0.04 mcg sincalide per kg may be administered. For reduction of side effects, a 30-minute IV infusion of sincalide [0.12 mcg per kg (8.4 mcg/70 kg) diluted to approximately 100 mL with Sodium Chloride Injection USP] may be administered. - Sodium Chloride Injection dilutions may be kept at room temperature and should be used within one hour of dilution. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Sincalide in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Sincalide in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Sincalide in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Sincalide in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Sincalide in pediatric patients. # Contraindications - The preparation is contraindicated in patients hypersensitive to sincalide and in patients with intestinal obstruction. # Warnings - Because of Kinevac’s effect on smooth muscle, pregnant patients should be advised that spontaneous abortion or premature induction of labor may occur # Adverse Reactions ## Clinical Trials Experience There is limited information regarding Clinical Trial Experience of Sincalide in the drug label. ## Postmarketing Experience - Reactions to sincalide are generally mild and of short duration. The most frequent adverse reactions were abdominal discomfort or pain, and nausea; rapid intravenous injection of 0.04 mcg sincalide per kg expectably causes transient abdominal cramping. These phenomena are usually manifestations of the physiologic action of the drug, including delayed gastric emptying and increased intestinal motility. These reactions occurred in approximately 20 percent of patients; they are not to be construed as necessarily indicating an abnormality of the billiary tract unless there is other clinical or radiologic evidence of disease. - The incidence of other adverse reactions, including vomiting, flushing, sweating, rash, hypotension, hypertension, shortness of breath, urge to defecate, headache, diarrhea, sneezing, and numbness was less than 1 percent; dizziness was reported in approximately 2 percent of patients. These manifestations are usually lessened by slower injection rate. # Drug Interactions There is limited information regarding Sincalide Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): B - Reproduction studies in rats in which sincalide was administered subcutaneously at doses up to 12.5 times the maximum recommended human dose revealed no evidence of harm to the fetus due to sincalide. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Sincalide in women who are pregnant. ### Labor and Delivery - Reproduction studies in rats in which sincalide was administered subcutaneously at doses up to 12.5 times the maximum recommended human dose revealed no evidence of harm to the fetus due to sincalide. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. ### Nursing Mothers - 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 sincalide is administered to a nursing woman. ### Pediatric Use Safety and effectiveness in children have not been established. ### Geriatic Use There is no FDA guidance on the use of Sincalide with respect to geriatric patients. ### Gender There is no FDA guidance on the use of Sincalide with respect to specific gender populations. ### Race There is no FDA guidance on the use of Sincalide with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Sincalide in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Sincalide in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Sincalide in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Sincalide in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral - Intravenous ### Monitoring There is limited information regarding Monitoring of Sincalide in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Sincalide in the drug label. # Overdosage - Although no overdosage reports have been received, gastrointestinal symptoms (abdominal cramps, nausea, vomiting and diarrhea) would be expected. Hypotension with dizziness or fainting might also occur. * Overdosage symptoms should be treated symptomatically and should be of short duration. Starting with single bolus i.v. injection comparable to the human does of 0.4 mg/kg, sincalide caused hypotension and bradycardia in dogs. Higher doses injected once or repeatedly in dogs caused syncope and ECG changes in addition. These effects were attributed to sincalide-induced vagal stimulation in that all were prevented by pretreatment with atropine or bilateral vagotomy. # Pharmacology ## Mechanism of Action - When injected intravenously, sincalide produces a substantial reduction in gallbladder size by causing this organ to contract. The evacuation of bile that results is similar to that which occurs physiologically in response to endogenous cholecystokinin. The intravenous (bolus) administration of sincalide causes a prompt contraction of the gallbladder that becomes maximal in 5 to 15 minutes, as compared with the stimulus of a fatty meal which causes a progressive contraction that becomes maximal after approximately 40 minutes. Generally, a 40 percent reduction in radiographic area of the gallbladder is considered satisfactory contraction, although some patients will show area reduction of 60 to 70 percent. - Like cholecystokinin, sincalide stimulates pancreatic secretion; concurrent administration with secretin increases both the volume of pancreatic secretion and the out-put of bicarbonate and protein (enzymes) by the gland. This combined effect of secretin and sincalide permits the assessment of specific pancreatic function through measurement and analysis of the duodenal aspirate. The parameters usually determined are: volume of the secretion; bicarbonate concentration; and amylase content (which parallels the content of trypsin and total protein). - Both cholecystokinin and sincalide stimulate intestinal motility, and may cause pyloric contraction which retards gastric emptying. ## Structure - Kinevac (Sincalide for Injection) is a cholecystopancreatic-gastrointestinal hormone peptide for parenteral administration. The agent is a synthetically-prepared C-terminal octapeptide of cholecystokinin. Each vial of sincalide provides a sterile nonpyrogenic lyophillized white powder consisting of 5 mcg sincalide with 170 mg mannitol, 30 mg arginine hydrochloride, 15 mg lysine hydrochloride, 9 mg potassium phosphate dibasic, 4 mg methionine, 2 mg pentetic acid, 0.04 mg sodium metabisulfite, and 0.005 mcg polysorbate 20. The pH is adjusted to 6.0 - 8.0 with hydrochloric acid and/or sodium hydroxide prior to lyophilization. Sincalide is designated chemically as L-α-aspartyl-O-sulfo-L-tyrosyl-L-methionylglycyl-L-tryptophyl-L-methionyl- L-α-aspartyl-L-phenylalaninamide. Graphic formula: ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Sincalide in the drug label. ## Pharmacokinetics There is limited information regarding Pharmacokinetics of Sincalide in the drug label. ## Nonclinical Toxicology There is limited information regarding Nonclinical Toxicology of Sincalide in the drug label. # Clinical Studies There is limited information regarding Clinical Studies of Sincalide in the drug label. # How Supplied - Kinevac (Sincalide for Injection) is supplied in packages of 10 vials containing 5 mcg of sincalide per vial (NDC 0270-0556-15). ## Storage - Store at 25° C (77° F); excursions permitted to 15-30° C (59-86° F). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Patient Counseling Information of Sincalide in the drug label. # Precautions with Alcohol - Alcohol-Sincalide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - KINEVAC ®[1] # Look-Alike Drug Names - A® — B®[2] # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Sincalide
28a368235601583a9f7a355e5fc19ffe51a91c21	wikidoc	Sirtuin 1	Sirtuin 1 Sirtuin 1, also known as NAD-dependent deacetylase sirtuin-1, is a protein that in humans is encoded by the SIRT1 gene. SIRT1 stands for sirtuin (silent mating type information regulation 2 homolog) 1 (S. cerevisiae), referring to the fact that its sirtuin homolog (biological equivalent across species) in yeast (S. cerevisiae) is Sir2. SIRT1 is an enzyme that deacetylates proteins that contribute to cellular regulation (reaction to stressors, longevity). # Function Sirtuin 1 is a member of the sirtuin family of proteins, homologs of the Sir2 gene in S. cerevisiae. Members of the sirtuin family are characterized by a sirtuin core domain and grouped into four classes. The functions of human sirtuins have not yet been determined; however, yeast sirtuin proteins are known to regulate epigenetic gene silencing and suppress recombination of rDNA. Studies suggest that the human sirtuins may function as intracellular regulatory proteins with mono-ADP-ribosyltransferase activity. The protein encoded by this gene is included in class I of the sirtuin family. Sirtuin 1 is downregulated in cells that have high insulin resistance and inducing its expression increases insulin sensitivity, suggesting the molecule is associated with improving insulin sensitivity. Furthermore, SIRT1 was shown to de-acetylate and affect the activity of both members of the PGC1-alpha/ERR-alpha complex, which are essential metabolic regulatory transcription factors. In mammals, SIRT1 has been shown to deacetylate and thereby deactivate the p53 protein. SIRT1 also stimulates autophagy by preventing acetylation of proteins (via deacetylation) required for autophagy as demonstrated in cultured cells and embryonic and neonatal tissues. This function provides a link between sirtuin expression and the cellular response to limited nutrients due to caloric restriction. Furthermore, SIRT1 was shown to de-acetylate and affect the activity of both members of the PGC1-alpha/ERR-alpha complex, which are essential metabolic regulatory transcription factors. Human aging is characterized by a chronic, low-grade inflammation level and NF-κB is the main transcriptional regulator of genes related to inflammation. SIRT1 inhibits NF-κB-regulated gene expression by deacetylating the RelA/p65 subunit of NF-κB at lysine 310. SIRT1 plays a role in activating T helper 17 cells, which contribute to autoimmune disease; efforts to activate SIRT1 therapeutically may trigger or exacerbate autoimmune disease. # Selective ligands ## Activators - Lamin A is a protein that had been identified as a direct activator of Sirtuin 1 during a study on progeria. - Resveratrol has been claimed to be an activator of Sirtuin 1, but this effect has been disputed based on the fact that the initially used activity assay, using a non-physiological substrate peptide, can produce artificial results. Resveratrol increases the expression of SIRT1, meaning that it does increase the activity of SIRT1, though not necessarily by direct activation. However, resveratrol was later shown to directly activate Sirtuin 1 against non-modified peptide substrates. Resveratrol also enhances the binding between Sirtuin 1 and Lamin A. In addition to resveratrol, a range of other plant-derived polyphenols have also been shown to interact with SIRT1. - SRT-1720 was also claimed to be an activator, but this now has been questioned. - Methylene blue by increasing NAD+/NADH ratio. - Metformin activates both PRKA and SIRT1. # Interactions Sirtuin 1 has been shown to interact with HEY2, PGC1-alpha, ERR-alpha, and AIRE. Mir-132 microRNA has been reported to interact with Sirtuin 1 mRNA, so as to reduce protein expression. This has been linked to insulin resistance in the obese. Human Sirt1 has been reported having 136 direct interactions in Interactomic studies involved in numerous processes. # Sir2 Sir2 (whose homolog in mammals is known as SIRT1) was the first gene of the sirtuin genes to be found. It was found in budding yeast, and, since then, members of this highly conserved family have been found in nearly all organisms studied. Sirtuins are hypothesized to play a key role in an organism's response to stresses (such as heat or starvation) and to be responsible for the lifespan-extending effects of calorie restriction. The three letter yeast gene symbol Sir stands for Silent Information Regulator while the number 2 is representative of the fact that it was the second SIR gene discovered and characterized. In the roundworm, Caenorhabditis elegans, Sir-2.1 is used to denote the gene product most similar to yeast Sir2 in structure and activity. ## Method of action and observed effects Sirtuins act primarily by removing acetyl groups from lysine residues within proteins in the presence of NAD+; thus, they are classified as "NAD+-dependent deacetylases" and have EC number 3.5.1. They add the acetyl group from the protein to the ADP-ribose component of NAD+ to form O-acetyl-ADP-ribose. The HDAC activity of Sir2 results in tighter packaging of chromatin and a reduction in transcription at the targeted gene locus. The silencing activity of Sir2 is most prominent at telomeric sequences, the hidden MAT loci (HM loci), and the ribosomal DNA (rDNA) locus (RDN1) from which ribosomal RNA is transcribed. Limited overexpression of the Sir2 gene results in a lifespan extension of about 30%, if the lifespan is measured as the number of cell divisions the mother cell can undergo before cell death. Concordantly, deletion of Sir2 results in a 50% reduction in lifespan. In particular, the silencing activity of Sir2, in complex with Sir3 and Sir4, at the HM loci prevents simultaneous expression of both mating factors which can cause sterility and shortened lifespan. Additionally, Sir2 activity at the rDNA locus is correlated with a decrease in the formation of rDNA circles. Chromatin silencing, as a result of Sir2 activity, reduces homologous recombination between rDNA repeats, which is the process leading to the formation of rDNA circles. As accumulation of these rDNA circles is the primary way in which yeast are believed to "age", then the action of Sir2 in preventing accumulation of these rDNA circles is a necessary factor in yeast longevity. Starving of yeast cells leads to a similarly extended lifespan, and indeed starving increases the available amount of NAD+ and reduces nicotinamide, both of which have the potential to increase the activity of Sir2. Furthermore, removing the Sir2 gene eliminates the life-extending effect of caloric restriction. Experiments in the nematode Caenorhabditis elegans and in the fruit fly Drosophila melanogaster support these findings. As of 2006, experiments in mice are underway. However, some other findings call the above interpretation into question. If one measures the lifespan of a yeast cell as the amount of time it can live in a non-dividing stage, then silencing the Sir2 gene actually increases lifespan Furthermore, calorie restriction can substantially prolong reproductive lifespan in yeast even in the absence of Sir2. In organisms more complicated than yeast, it appears that Sir2 acts by deacetylation of several other proteins besides histones. Resveratrol is a substance that has been shown through experiment to have a number of life-extending and health benefits in various species; it also increases the activity of Sir2, which is the postulated reason for its beneficial effects. Resveratrol is produced by plants when they are stressed, and it is possible that plants use the substance to increase their own Sir2 activity in order to survive periods of stress. Although there is mounting evidence for this hypothesis, its validity is debated. In the fruit fly Drosophilia melanogaster, the Sir2 gene does not seem to be essential; loss of a sirtuin gene has only very subtle effects. However, mice lacking the SIRT1 gene (the sir2 biological equivalent) were smaller than normal at birth, often died early or became sterile. # Activation of SIRT1 in mice Increased expression of SIRT1 protein, when induced by a synthetic small molecule activator of SIRT1 (SRT2104), extended both the mean and maximal lifespan of mice. In these mice health was also improved as well as bone and muscle mass. Another SIRT1 activator (SRT1720) also extended lifespan and improved the health of mice. # Homologous recombination SIRT1 protein actively promotes homologous recombination (HR) in human cells, and likely promotes recombinational repair of DNA breaks. SIRT1 mediated HR requires the WRN protein. WRN protein functions in double-strand break repair by HR. WRN protein is a RecQ helicase, and in its mutated form gives rise to Werner syndrome, a genetic condition in humans characterized by numerous features of premature aging. These findings link SIRT1 function to HR, a DNA repair process that is likely necessary for maintaining the integrity of the genome during aging.	Sirtuin 1 Sirtuin 1, also known as NAD-dependent deacetylase sirtuin-1, is a protein that in humans is encoded by the SIRT1 gene.[1][2][3] SIRT1 stands for sirtuin (silent mating type information regulation 2 homolog) 1 (S. cerevisiae), referring to the fact that its sirtuin homolog (biological equivalent across species) in yeast (S. cerevisiae) is Sir2. SIRT1 is an enzyme that deacetylates proteins that contribute to cellular regulation (reaction to stressors, longevity).[4] # Function Sirtuin 1 is a member of the sirtuin family of proteins, homologs of the Sir2 gene in S. cerevisiae. Members of the sirtuin family are characterized by a sirtuin core domain and grouped into four classes. The functions of human sirtuins have not yet been determined; however, yeast sirtuin proteins are known to regulate epigenetic gene silencing and suppress recombination of rDNA. Studies suggest that the human sirtuins may function as intracellular regulatory proteins with mono-ADP-ribosyltransferase activity. The protein encoded by this gene is included in class I of the sirtuin family.[2] Sirtuin 1 is downregulated in cells that have high insulin resistance and inducing its expression increases insulin sensitivity, suggesting the molecule is associated with improving insulin sensitivity.[5] Furthermore, SIRT1 was shown to de-acetylate and affect the activity of both members of the PGC1-alpha/ERR-alpha complex, which are essential metabolic regulatory transcription factors.[6][7][8][9][10][11] In mammals, SIRT1 has been shown to deacetylate and thereby deactivate the p53 protein.[12] SIRT1 also stimulates autophagy by preventing acetylation of proteins (via deacetylation) required for autophagy as demonstrated in cultured cells and embryonic and neonatal tissues. This function provides a link between sirtuin expression and the cellular response to limited nutrients due to caloric restriction.[13] Furthermore, SIRT1 was shown to de-acetylate and affect the activity of both members of the PGC1-alpha/ERR-alpha complex, which are essential metabolic regulatory transcription factors.[6][7][8][9][10][11] Human aging is characterized by a chronic, low-grade inflammation level[14] and NF-κB is the main transcriptional regulator of genes related to inflammation.[15] SIRT1 inhibits NF-κB-regulated gene expression by deacetylating the RelA/p65 subunit of NF-κB at lysine 310.[16][17] SIRT1 plays a role in activating T helper 17 cells, which contribute to autoimmune disease; efforts to activate SIRT1 therapeutically may trigger or exacerbate autoimmune disease.[18] # Selective ligands ## Activators - Lamin A is a protein that had been identified as a direct activator of Sirtuin 1 during a study on progeria.[19] - Resveratrol has been claimed to be an activator of Sirtuin 1,[20] but this effect has been disputed based on the fact that the initially used activity assay, using a non-physiological substrate peptide, can produce artificial results.[21][22] Resveratrol increases the expression of SIRT1, meaning that it does increase the activity of SIRT1, though not necessarily by direct activation.[5] However, resveratrol was later shown to directly activate Sirtuin 1 against non-modified peptide substrates.[23][24] Resveratrol also enhances the binding between Sirtuin 1 and Lamin A.[19] In addition to resveratrol, a range of other plant-derived polyphenols have also been shown to interact with SIRT1.[25] - SRT-1720 was also claimed to be an activator,[20] but this now has been questioned.[26] - Methylene blue [27] by increasing NAD+/NADH ratio. - Metformin activates both PRKA and SIRT1.[28] # Interactions Sirtuin 1 has been shown to interact with HEY2,[29] PGC1-alpha,[8] ERR-alpha,[6] and AIRE.[30] Mir-132 microRNA has been reported to interact with Sirtuin 1 mRNA, so as to reduce protein expression. This has been linked to insulin resistance in the obese.[31] Human Sirt1 has been reported having 136 direct interactions in Interactomic studies involved in numerous processes.[32] # Sir2 Sir2 (whose homolog in mammals is known as SIRT1) was the first gene of the sirtuin genes to be found. It was found in budding yeast, and, since then, members of this highly conserved family have been found in nearly all organisms studied.[33] Sirtuins are hypothesized to play a key role in an organism's response to stresses (such as heat or starvation) and to be responsible for the lifespan-extending effects of calorie restriction.[34][35] The three letter yeast gene symbol Sir stands for Silent Information Regulator while the number 2 is representative of the fact that it was the second SIR gene discovered and characterized.[36][37] In the roundworm, Caenorhabditis elegans, Sir-2.1 is used to denote the gene product most similar to yeast Sir2 in structure and activity.[38][39] ## Method of action and observed effects Sirtuins act primarily by removing acetyl groups from lysine residues within proteins in the presence of NAD+; thus, they are classified as "NAD+-dependent deacetylases" and have EC number 3.5.1.[40] They add the acetyl group from the protein to the ADP-ribose component of NAD+ to form O-acetyl-ADP-ribose. The HDAC activity of Sir2 results in tighter packaging of chromatin and a reduction in transcription at the targeted gene locus. The silencing activity of Sir2 is most prominent at telomeric sequences, the hidden MAT loci (HM loci), and the ribosomal DNA (rDNA) locus (RDN1) from which ribosomal RNA is transcribed. Limited overexpression of the Sir2 gene results in a lifespan extension of about 30%,[41] if the lifespan is measured as the number of cell divisions the mother cell can undergo before cell death. Concordantly, deletion of Sir2 results in a 50% reduction in lifespan.[41] In particular, the silencing activity of Sir2, in complex with Sir3 and Sir4, at the HM loci prevents simultaneous expression of both mating factors which can cause sterility and shortened lifespan.[42] Additionally, Sir2 activity at the rDNA locus is correlated with a decrease in the formation of rDNA circles. Chromatin silencing, as a result of Sir2 activity, reduces homologous recombination between rDNA repeats, which is the process leading to the formation of rDNA circles. As accumulation of these rDNA circles is the primary way in which yeast are believed to "age", then the action of Sir2 in preventing accumulation of these rDNA circles is a necessary factor in yeast longevity.[42] Starving of yeast cells leads to a similarly extended lifespan, and indeed starving increases the available amount of NAD+ and reduces nicotinamide, both of which have the potential to increase the activity of Sir2. Furthermore, removing the Sir2 gene eliminates the life-extending effect of caloric restriction.[43] Experiments in the nematode Caenorhabditis elegans and in the fruit fly Drosophila melanogaster[44] support these findings. As of 2006[update], experiments in mice are underway.[34] However, some other findings call the above interpretation into question. If one measures the lifespan of a yeast cell as the amount of time it can live in a non-dividing stage, then silencing the Sir2 gene actually increases lifespan [45] Furthermore, calorie restriction can substantially prolong reproductive lifespan in yeast even in the absence of Sir2.[46] In organisms more complicated than yeast, it appears that Sir2 acts by deacetylation of several other proteins besides histones. Resveratrol is a substance that has been shown through experiment to have a number of life-extending and health benefits in various species; it also increases the activity of Sir2, which is the postulated reason for its beneficial effects. Resveratrol is produced by plants when they are stressed, and it is possible that plants use the substance to increase their own Sir2 activity in order to survive periods of stress.[34] Although there is mounting evidence for this hypothesis, its validity is debated.[26][21][47][22] In the fruit fly Drosophilia melanogaster, the Sir2 gene does not seem to be essential; loss of a sirtuin gene has only very subtle effects.[43] However, mice lacking the SIRT1 gene (the sir2 biological equivalent) were smaller than normal at birth, often died early or became sterile.[48] # Activation of SIRT1 in mice Increased expression of SIRT1 protein, when induced by a synthetic small molecule activator of SIRT1 (SRT2104), extended both the mean and maximal lifespan of mice.[49] In these mice health was also improved as well as bone and muscle mass. Another SIRT1 activator (SRT1720) also extended lifespan and improved the health of mice.[50] # Homologous recombination SIRT1 protein actively promotes homologous recombination (HR) in human cells, and likely promotes recombinational repair of DNA breaks.[51] SIRT1 mediated HR requires the WRN protein.[51] WRN protein functions in double-strand break repair by HR.[52] WRN protein is a RecQ helicase, and in its mutated form gives rise to Werner syndrome, a genetic condition in humans characterized by numerous features of premature aging. These findings link SIRT1 function to HR, a DNA repair process that is likely necessary for maintaining the integrity of the genome during aging.[51]	https://www.wikidoc.org/index.php/Sirtuin_1
143f62e4122fe074f2acfb6757baf1f0ea129a5e	wikidoc	Sirtuin 2	Sirtuin 2 NAD-dependent deacetylase sirtuin 2 is an enzyme that in humans is encoded by the SIRT2 gene. SIRT2 is an NAD+ (nicotinamide adenine dinucleotide)-dependent deacetylase. Studies of this protein have often been divergent, highlighting the dependence of pleiotropic effects of SIRT2 on cellular context. The natural polyphenol resveratrol is known to exert opposite actions on neural cells according to their normal or cancerous status. Similar to other sirtuin family members, SIRT2 displays a ubiquitous distribution. SIRT2 is expressed in a wide range of tissues and organs and has been detected particularly in metabolically relevant tissues, including the brain, muscle, liver, testes, pancreas, kidney, and adipose tissue of mice. Of note, SIRT2 expression is much higher in the brain than all other organs studied, particularly in the cortex, striatum, hippocampus, and spinal cord. # Function Studies suggest that the human sirtuins may function as intracellular regulatory proteins with mono-ADP-ribosyltransferase activity. Cytosolic functions of SIRT2 include the regulation of microtubule acetylation, control of myelination in the central and peripheral nervous system and gluconeogenesis. There is growing evidence for additional functions of SIRT2 in the nucleus. During the G2/M transition, nuclear SIRT2 is responsible for global deacetylation of H4K16, facilitating H4K20 methylation and subsequent chromatin compaction. In response to DNA damage, SIRT2 was also found to deacetylate H3K56 in vivo. Finally, SIRT2 negatively regulates the acetyltransferase activity of the transcriptional co-activator p300 via deacetylation of an automodification loop within its catalytic domain. # Structure ## Gene Human SIRT2 gene has 18 exons resides on chromosome 19 at q13. For SIRT2, four different human splice variants are deposited in the GenBank sequence database. ## Protein SIRT2 gene encodes a member of the sirtuin family of proteins, homologs to the yeast Sir2 protein. Members of the sirtuin family are characterized by a sirtuin core domain and grouped into four classes. The protein encoded by this gene is included in class I of the sirtuin family. Several transcript variants are resulted from alternative splicing of this gene. Only transcript variants 1 and 2 have confirmed protein products of physiological relevance. A leucine-rich nuclear export signal (NES) within the N-terminal region of these two isoforms is identified. Since deletion of the NES led to nucleocytoplasmic distribution, it is suggested to mediate their cytosolic localization. # Selective ligands ## Inhibitors - Benzamide compound # 64 - (S)-2-Pentyl-6-chloro,8-bromo-chroman-4-one: IC50 of 1.5 μM, highly selective over SIRT2 and SIRT3 - 3′-Phenethyloxy-2-anilinobenzamide (33i): IC50 of 0.57 μM # Model organisms The functions of human sirtuins have not yet been determined; however, model organisms have been used in the study of SIRT2 function. Yeast sirtuin proteins are known to regulate epigenetic gene silencing and suppress recombination of rDNA. A conditional knockout mouse line, called Sirt2tm1a(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 — at the Wellcome Trust Sanger Institute. Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty five tests were carried out on homozygous mutant adult mice, however no significant abnormalities were observed. # Animal studies ## Metabolic actions SIRT2 suppresses inflammatory responses in mice through p65 deacetylation and inhibition of NF-κB activity. SIRT2 is responsible for the deacetylation and activation of G6PD, stimulating pentose phosphate pathway to supply cytosolic NADPH to counteract oxidative damage and protect mouse erythrocytes. ## Neurodegeneration Several studies in cell and invertebrate models of Parkinson's disease (PD) and Huntington's disease (HD) suggested potential neuroprotective effects of SIRT2 inhibition, in striking contrast with other sirtuin family members. In addition, recent evidence shows that inhibition of SIRT2 protects against MPTP-induced neuronal loss in vivo. # Clinical significance ## Metabolic actions Several SIRT2 deacetylation targets play important roles in metabolic homeostasis. SIRT2 inhibits adipogenesis by deacetylating FOXO1 and thus may protect against insulin resistance. SIRT2 sensitizes cells to the action of insulin by physically interacting with and activating Akt and downstream targets. SIRT2 mediates mitochondrial biogenesis by deacetylating PGC-1α, upregulates antioxidant enzyme expression by deacetylating FOXO3a, and thereby reduces ROS levels. ## Cell cycle regulation Although preferentially cytosolic, SIRT2 transiently shuttles to the nucleus during the G2/M transition of the cell cycle, where it has a strong preference for histone H4 lysine 16 (H4K16Ac), thereby regulating chromosomal condensation during mitosis. During the cell cycle, SIRT2 associates with several mitotic structures including the centrosome, mitotic spindle, and midbody, presumably to ensure normal cell division. Finally, cells with SIRT2 overexpression exhibit marked prolongation of the cell cycle. ## Tumorigenesis Mounting evidence implies a role for SIRT2 in tumorigenesis. SIRT2 may suppress or promote tumor growth in a context-dependent manner. SIRT2 has been proposed to act as a tumor suppressor by preventing chromosomal instability during mitosis. SIRT2-specific inhibitors exhibits broad anticancer activity. # Interactions SIRT2 has been shown to interact with: - α-tubulin, - TUG, - β-catenin, - PGAM2, - TIAM1, - ApoE4, - p53, - PEPCK, - FOXO1, - p300, - 14-3-3 protein, - G6PD, and - CBP.	Sirtuin 2 NAD-dependent deacetylase sirtuin 2 is an enzyme that in humans is encoded by the SIRT2 gene.[1][2][3] SIRT2 is an NAD+ (nicotinamide adenine dinucleotide)-dependent deacetylase. Studies of this protein have often been divergent, highlighting the dependence of pleiotropic effects of SIRT2 on cellular context. The natural polyphenol resveratrol is known to exert opposite actions on neural cells according to their normal or cancerous status.[4] Similar to other sirtuin family members, SIRT2 displays a ubiquitous distribution. SIRT2 is expressed in a wide range of tissues and organs and has been detected particularly in metabolically relevant tissues, including the brain, muscle, liver, testes, pancreas, kidney, and adipose tissue of mice. Of note, SIRT2 expression is much higher in the brain than all other organs studied, particularly in the cortex, striatum, hippocampus, and spinal cord.[5] # Function Studies suggest that the human sirtuins may function as intracellular regulatory proteins with mono-ADP-ribosyltransferase activity.[3] Cytosolic functions of SIRT2 include the regulation of microtubule acetylation, control of myelination in the central and peripheral nervous system[citation needed] and gluconeogenesis.[6] There is growing evidence for additional functions of SIRT2 in the nucleus. During the G2/M transition, nuclear SIRT2 is responsible for global deacetylation of H4K16, facilitating H4K20 methylation and subsequent chromatin compaction.[7] In response to DNA damage, SIRT2 was also found to deacetylate H3K56 in vivo.[8] Finally, SIRT2 negatively regulates the acetyltransferase activity of the transcriptional co-activator p300 via deacetylation of an automodification loop within its catalytic domain.[9] # Structure ## Gene Human SIRT2 gene has 18 exons resides on chromosome 19 at q13.[3] For SIRT2, four different human splice variants are deposited in the GenBank sequence database.[10] ## Protein SIRT2 gene encodes a member of the sirtuin family of proteins, homologs to the yeast Sir2 protein. Members of the sirtuin family are characterized by a sirtuin core domain and grouped into four classes. The protein encoded by this gene is included in class I of the sirtuin family. Several transcript variants are resulted from alternative splicing of this gene.[3] Only transcript variants 1 and 2 have confirmed protein products of physiological relevance. A leucine-rich nuclear export signal (NES) within the N-terminal region of these two isoforms is identified.[10] Since deletion of the NES led to nucleocytoplasmic distribution, it is suggested to mediate their cytosolic localization.[11] # Selective ligands ## Inhibitors - Benzamide compound # 64[12] - (S)-2-Pentyl-6-chloro,8-bromo-chroman-4-one: IC50 of 1.5 μM, highly selective over SIRT2 and SIRT3[13] - 3′-Phenethyloxy-2-anilinobenzamide (33i): IC50 of 0.57 μM[14] # Model organisms The functions of human sirtuins have not yet been determined; however, model organisms have been used in the study of SIRT2 function. Yeast sirtuin proteins are known to regulate epigenetic gene silencing and suppress recombination of rDNA. A conditional knockout mouse line, called Sirt2tm1a(EUCOMM)Wtsi[16][17] 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 — at the Wellcome Trust Sanger Institute.[18][19][20] Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[15][21] Twenty five tests were carried out on homozygous mutant adult mice, however no significant abnormalities were observed.[15] # Animal studies ## Metabolic actions SIRT2 suppresses inflammatory responses in mice through p65 deacetylation and inhibition of NF-κB activity.[22] SIRT2 is responsible for the deacetylation and activation of G6PD, stimulating pentose phosphate pathway to supply cytosolic NADPH to counteract oxidative damage and protect mouse erythrocytes.[23] ## Neurodegeneration Several studies in cell and invertebrate models of Parkinson's disease (PD) and Huntington's disease (HD) suggested potential neuroprotective effects of SIRT2 inhibition, in striking contrast with other sirtuin family members.[24][25] In addition, recent evidence shows that inhibition of SIRT2 protects against MPTP-induced neuronal loss in vivo.[26] # Clinical significance ## Metabolic actions Several SIRT2 deacetylation targets play important roles in metabolic homeostasis. SIRT2 inhibits adipogenesis by deacetylating FOXO1 and thus may protect against insulin resistance. SIRT2 sensitizes cells to the action of insulin by physically interacting with and activating Akt and downstream targets. SIRT2 mediates mitochondrial biogenesis by deacetylating PGC-1α, upregulates antioxidant enzyme expression by deacetylating FOXO3a, and thereby reduces ROS levels. ## Cell cycle regulation Although preferentially cytosolic, SIRT2 transiently shuttles to the nucleus during the G2/M transition of the cell cycle, where it has a strong preference for histone H4 lysine 16 (H4K16Ac),[27] thereby regulating chromosomal condensation during mitosis.[28] During the cell cycle, SIRT2 associates with several mitotic structures including the centrosome, mitotic spindle, and midbody, presumably to ensure normal cell division.[11] Finally, cells with SIRT2 overexpression exhibit marked prolongation of the cell cycle.[29] ## Tumorigenesis Mounting evidence implies a role for SIRT2 in tumorigenesis. SIRT2 may suppress or promote tumor growth in a context-dependent manner. SIRT2 has been proposed to act as a tumor suppressor by preventing chromosomal instability during mitosis.[30] SIRT2-specific inhibitors exhibits broad anticancer activity.[31][32] # Interactions SIRT2 has been shown to interact with: - α-tubulin,[33] - TUG,[34] - β-catenin,[35] - PGAM2,[36] - TIAM1,[37] - ApoE4,[38] - p53,[39] - PEPCK,[40] - FOXO1,[41] - p300,[42] - 14-3-3 protein,[43] - G6PD,[23][32] and - CBP.[44]	https://www.wikidoc.org/index.php/Sirtuin_2
38192c59abc05736b1711c6c3926417efc3b6ecf	wikidoc	Sirtuin 3	Sirtuin 3 NAD-dependent deacetylase sirtuin-3, mitochondrial also known as SIRT3 is a protein that in humans is encoded by the SIRT3 gene . SIRT3 is member of the mammalian sirtuin family of proteins, which are homologs to the yeast Sir2 protein. SIRT3 exhibits NAD+-dependent deacetylase activity. Members of the sirtuin family are characterized by a sirtuin core domain and grouped into four classes, and the protein encoded by this gene is included in class I of the sirtuin family. The human sirtuins have a range of molecular functions and have emerged as important proteins in aging, stress resistance and metabolic regulation. Yeast sirtuin proteins are known to regulate epigenetic gene silencing and suppress recombination of rDNA. In addition to protein deacetylation, studies have shown that the human sirtuins may also function as intracellular regulatory proteins with mono ADP ribosyltransferase activity. # Structure SIRT3 is a soluble protein located in the mitochondrial matrix, and contains a mitochondrial processing peptide at the N-terminus. A set of crystal structures of human SIRT3 have been solved, including an apo-structure with no substrate, a structure with a peptide containing acetyl lysine of its natural substrate acetyl-CoA synthetase 2, a reaction intermediate structure trapped by a thioacetyl peptide and a structure with the dethioacetylated peptide bond. These structures show the conformational changes induced by the two substrates required for the reaction, the acetylated substrate peptide and NAD+. In addition, a binding study by isothermal titration calorimetry suggests that the acetylated peptide is the first substrate to bind to SIRT3, prior to NAD+. # Function ## Mitochondrial Three sirtuins, SIRT3, SIRT4 and SIRT5, are located in mitochondria and have been implicated in regulating metabolic processes. Endogenous SIRT3 is a soluble protein located in the mitochondrial matrix. Overexpression of SIRT3 in cultured cells increases respiration and decreases the production of reactive oxygen species. Fasting increases SIRT3 expression in white and brown adipose tissue (WAT and BAT, respectively) and overexpression of SIRT3 in HIB1B brown adipocytes increases the expression of PGC-1α and UCP1, suggesting a role for SIRT3 in adaptive thermogenesis BAT. BAT is different from WAT because it harbors large numbers of mitochondria and is important for thermogenesis in rodents. Thermogenesis in BAT is mediated by the uncoupling protein 1 (UCP1), which induces proton leakage and thereby generates heat instead of ATP. Mechanistic insights into how SIRT3 affects thermogenesis in BAT is lacking and whether SIRT3 affects UCP1 activity directly is not known. In addition to controlling metabolism at the transcriptional level, sirtuins also directly control the activity of metabolic enzymes. In Salmonella enterica, the bacterial sirtuin CobB regulates the activity of the enzyme acetyl-coenzyme A (acetyl-CoA) synthetase. As mentioned above, orthologs of acetyl-CoA synthetase exist in the cytoplasm (AceCS1) and in mitochondria (AceCS2) in mammals. The presence of the sirtuin deacetylase SIRT3 in the mitochondrial matrix suggests the existence of lysine acetylated mitochondrial proteins. Indeed, SIRT3 deacetylates and activates the mammalian mitochondrial acetyl-coA synthetase (AceCS2). Furthermore, SIRT3 and AceCS2 are found complexed with one another, suggesting a critical role for control of AceCS2 activity by SIRT3. ## Nuclear In addition to its reported mitochondrial function, some researchers have proposed a very small pool of active nuclear SIRT3 exists. This pool is reported to consist of the long form of SIRT3 and has been suggested to have histone deacetylase activity. The observation that SIRT3 has nuclear activity came from a report that SIRT3 protected cardiomyocytes from stress mediated cell death and that this effect was due to deacetylation of a nuclear factor, Ku-70. # Clinical significance There is a strong association between SIRT3 alleles and longevity in males. ## Aging and carcinogenesis There is also a significant body of published literature suggesting a strong mechanistic link between mitochondrial function, aging, and carcinogenesis. Sirt3 functions as a mitochondrial tumor suppressor protein. Although some evidence attributes SIRT3 activity in bypassing growth arrest in bladder carcinoma cells via regulation of p53 in the mitochondria. Damaged and aberrant mitochondrial function, similar to gene mutations, may be an early event that ultimately leads to the development of cancers. Mice genetically altered to delete Sirt3 develop estrogen and progesterone receptor (ER/PR) positive breast mammary tumors. In tumor samples from women with breast cancer, SIRT3 expression was decreased, as compared to normal breast tissues. Thus, the Sirt3 knockout model may be used to investigate ER/PR positive breast tumor development.	Sirtuin 3 NAD-dependent deacetylase sirtuin-3, mitochondrial also known as SIRT3 is a protein that in humans is encoded by the SIRT3 gene [sirtuin (silent mating type information regulation 2 homolog) 3 (S. cerevisiae)].[1][2] SIRT3 is member of the mammalian sirtuin family of proteins, which are homologs to the yeast Sir2 protein. SIRT3 exhibits NAD+-dependent deacetylase activity. Members of the sirtuin family are characterized by a sirtuin core domain and grouped into four classes, and the protein encoded by this gene is included in class I of the sirtuin family.[1] The human sirtuins have a range of molecular functions and have emerged as important proteins in aging, stress resistance and metabolic regulation. Yeast sirtuin proteins are known to regulate epigenetic gene silencing and suppress recombination of rDNA. In addition to protein deacetylation, studies have shown that the human sirtuins may also function as intracellular regulatory proteins with mono ADP ribosyltransferase activity. # Structure SIRT3 is a soluble protein located in the mitochondrial matrix, and contains a mitochondrial processing peptide at the N-terminus. A set of crystal structures of human SIRT3 have been solved, including an apo-structure with no substrate, a structure with a peptide containing acetyl lysine of its natural substrate acetyl-CoA synthetase 2, a reaction intermediate structure trapped by a thioacetyl peptide and a structure with the dethioacetylated peptide bond.[3] These structures show the conformational changes induced by the two substrates required for the reaction, the acetylated substrate peptide and NAD+. In addition, a binding study by isothermal titration calorimetry suggests that the acetylated peptide is the first substrate to bind to SIRT3, prior to NAD+. # Function ## Mitochondrial Three sirtuins, SIRT3, SIRT4 and SIRT5, are located in mitochondria and have been implicated in regulating metabolic processes. Endogenous SIRT3 is a soluble protein located in the mitochondrial matrix.[4] Overexpression of SIRT3 in cultured cells increases respiration and decreases the production of reactive oxygen species. Fasting increases SIRT3 expression in white and brown adipose tissue (WAT and BAT, respectively) and overexpression of SIRT3 in HIB1B brown adipocytes increases the expression of PGC-1α and UCP1, suggesting a role for SIRT3 in adaptive thermogenesis BAT. BAT is different from WAT because it harbors large numbers of mitochondria and is important for thermogenesis in rodents. Thermogenesis in BAT is mediated by the uncoupling protein 1 (UCP1), which induces proton leakage and thereby generates heat instead of ATP. Mechanistic insights into how SIRT3 affects thermogenesis in BAT is lacking and whether SIRT3 affects UCP1 activity directly is not known. In addition to controlling metabolism at the transcriptional level, sirtuins also directly control the activity of metabolic enzymes. In Salmonella enterica, the bacterial sirtuin CobB regulates the activity of the enzyme acetyl-coenzyme A (acetyl-CoA) synthetase. As mentioned above, orthologs of acetyl-CoA synthetase exist in the cytoplasm (AceCS1) and in mitochondria (AceCS2) in mammals. The presence of the sirtuin deacetylase SIRT3 in the mitochondrial matrix suggests the existence of lysine acetylated mitochondrial proteins. Indeed, SIRT3 deacetylates and activates the mammalian mitochondrial acetyl-coA synthetase (AceCS2). Furthermore, SIRT3 and AceCS2 are found complexed with one another, suggesting a critical role for control of AceCS2 activity by SIRT3. ## Nuclear In addition to its reported mitochondrial function, some researchers have proposed a very small pool of active nuclear SIRT3 exists. This pool is reported to consist of the long form of SIRT3 and has been suggested to have histone deacetylase activity.[5] The observation that SIRT3 has nuclear activity came from a report that SIRT3 protected cardiomyocytes from stress mediated cell death and that this effect was due to deacetylation of a nuclear factor, Ku-70.[6] # Clinical significance There is a strong association between SIRT3 alleles and longevity in males.[7] ## Aging and carcinogenesis There is also a significant body of published literature suggesting a strong mechanistic link between mitochondrial function, aging, and carcinogenesis.[7] Sirt3 functions as a mitochondrial tumor suppressor protein. Although some evidence attributes SIRT3 activity in bypassing growth arrest in bladder carcinoma cells via regulation of p53 in the mitochondria.[8] Damaged and aberrant mitochondrial function, similar to gene mutations, may be an early event that ultimately leads to the development of cancers. Mice genetically altered to delete Sirt3 develop estrogen and progesterone receptor (ER/PR) positive breast mammary tumors. In tumor samples from women with breast cancer, SIRT3 expression was decreased, as compared to normal breast tissues. Thus, the Sirt3 knockout model may be used to investigate ER/PR positive breast tumor development.[9]	https://www.wikidoc.org/index.php/Sirtuin_3
86812be3f49b645e528ed2e35968f0e4cd90e88b	wikidoc	Sirtuin 4	Sirtuin 4 Sirtuin 4, also known as SIRT4, is a protein which in humans is encoded by the SIRT4 gene. # Function This gene encodes a member of the sirtuin family of proteins which are homologs of the Sir2 gene in budding yeast. Members of the sirtuin family are characterized by a sirtuin core domain and grouped into four classes. The functions of human sirtuins have not yet been fully determined; however, yeast sirtuin proteins are known to regulate epigenetic gene silencing and suppress recombination of rDNA. Studies suggest that the human sirtuins may function as intracellular regulatory proteins with mono-ADP-ribosyltransferase activity. The protein encoded by this gene is included in class IV of the sirtuin family. SIRT4 is a mitochondrial ADP-ribosyltransferase that inhibits mitochondrial glutamate dehydrogenase 1 activity, thereby downregulating insulin secretion in response to amino acids. It has been shown that SIRT4 regulates fatty acid oxidation and mitochondrial gene expression in liver and muscle cells.	Sirtuin 4 Sirtuin 4, also known as SIRT4, is a protein which in humans is encoded by the SIRT4 gene.[1][2] # Function This gene encodes a member of the sirtuin family of proteins which are homologs of the Sir2 gene in budding yeast. Members of the sirtuin family are characterized by a sirtuin core domain and grouped into four classes. The functions of human sirtuins have not yet been fully determined; however, yeast sirtuin proteins are known to regulate epigenetic gene silencing and suppress recombination of rDNA.[3] Studies suggest that the human sirtuins may function as intracellular regulatory proteins with mono-ADP-ribosyltransferase activity.[1][3] The protein encoded by this gene is included in class IV of the sirtuin family.[2] SIRT4 is a mitochondrial ADP-ribosyltransferase that inhibits mitochondrial glutamate dehydrogenase 1 activity, thereby downregulating insulin secretion in response to amino acids.[4] It has been shown that SIRT4 regulates fatty acid oxidation and mitochondrial gene expression in liver and muscle cells.[5]	https://www.wikidoc.org/index.php/Sirtuin_4
006771a657c35a3ef8322cf07ccffa3f201d29bf	wikidoc	Sirtuin 5	Sirtuin 5 Sirtuin (silent mating type information regulation 2 homolog) 5 (S. cerevisiae), also known as SIRT5 is a protein which in humans in encoded by the SIRT5 gene and in other species by the orthologous Sirt5 gene. This gene encodes a member of the sirtuin family of proteins, homologs to the yeast Sir2 protein. Members of the sirtuin family are characterized by a sirtuin core domain and belong to the class III of the superfamily, and are dependent on NAD+ as co-factor of enzymatic activities. SIRT5 is one of the three sirtuins localized primarily to the mitochondrion. # Structure Alternative splicing of this gene results in two transcript variants. The protein structure of SIRT5 has been resolved and shows high degrees of structural conservation with other sirtuins, such as the ancestral yeast protein and human SIRT2. # Function SIRT5 has been found to exhibit enzymatic activities as a deacetylase, desuccinylase, and demalonylase, capable of removing acetyl, succinyl, and malonyl groups from the lysine residues of proteins. SIRT5 deacetylases and regulates carbamoyl phosphate synthetase (CPS1), the rate-limiting and initiating step of the urea cycle in liver mitochondria. Deacetylation of CPS1 stimulates its enzymatic activity. Mice with deletion of SIRT5 show elevated ammonia levels after a prolonged fast, whereas in contrast, mice overexpressing SIRT5 show increased CPS1 activity, suggesting one of the functions of SIRT5 may be to regulate the urea cycle. SIRT5 also interacts with and deacetylates cytochrome c. Large-scale profiling studies of SIRT5 deacetylase activity have uncovered over 700 protein substrates, including proteins localized to the mitochondria, the cytosol and other sub cellular localization. The identities of SIRT5 desuccinylation substrates suggest that SIRT5-mediated desuccinylation may be involved in energy metabolism. The physiological consequences of SIRT5 molecular functions in human is under investigation but may involved regulations of mitochondrial metabolism. # Interactions NAD+ Cytochrome c Carbamoyl phosphate synthetase (CPS1)	Sirtuin 5 Sirtuin (silent mating type information regulation 2 homolog) 5 (S. cerevisiae), also known as SIRT5 is a protein which in humans in encoded by the SIRT5 gene and in other species by the orthologous Sirt5 gene.[1] This gene encodes a member of the sirtuin family of proteins, homologs to the yeast Sir2 protein. Members of the sirtuin family are characterized by a sirtuin core domain and belong to the class III of the [histone deacetylase] superfamily, and are dependent on NAD+ as co-factor of enzymatic activities. SIRT5 is one of the three sirtuins localized primarily to the mitochondrion. # Structure Alternative splicing of this gene results in two transcript variants.[1] The protein structure of SIRT5 has been resolved and shows high degrees of structural conservation with other sirtuins, such as the ancestral yeast protein and human SIRT2. # Function SIRT5 has been found to exhibit enzymatic activities as a deacetylase, desuccinylase, and demalonylase, capable of removing acetyl, succinyl, and malonyl groups from the lysine residues of proteins.[2] SIRT5 deacetylases and regulates carbamoyl phosphate synthetase (CPS1), the rate-limiting and initiating step of the urea cycle in liver mitochondria. Deacetylation of CPS1 stimulates its enzymatic activity. Mice with deletion of SIRT5 show elevated ammonia levels after a prolonged fast, whereas in contrast, mice overexpressing SIRT5 show increased CPS1 activity, suggesting one of the functions of SIRT5 may be to regulate the urea cycle.[3] SIRT5 also interacts with and deacetylates cytochrome c.[4] Large-scale profiling studies of SIRT5 deacetylase activity have uncovered over 700 protein substrates, including proteins localized to the mitochondria, the cytosol and other sub cellular localization. The identities of SIRT5 desuccinylation substrates suggest that SIRT5-mediated desuccinylation may be involved in energy metabolism.[5] The physiological consequences of SIRT5 molecular functions in human is under investigation but may involved regulations of mitochondrial metabolism.[6] # Interactions NAD+ Cytochrome c [7] Carbamoyl phosphate synthetase (CPS1)	https://www.wikidoc.org/index.php/Sirtuin_5
84600b28be2e9bd221ee048374e901ca35513329	wikidoc	Sirtuin 6	Sirtuin 6 Sirtuin 6 (SIRT6 or Sirt6) is a stress responsive protein deacetylase and mono-ADP ribosyltransferase enzyme encoded by the SIRT6 gene. SIRT6 functions in multiple molecular pathways related to aging, including DNA repair, telomere maintenance, glycolysis and inflammation. # Function Studies in mice have revealed that Sirt6 is essential for post-natal development and survival. Sirt6 knock-out mice, in which the gene encoding Sirt6 has been disrupted, exhibit a severe progeria, or premature aging syndrome, characterized by spinal curvature, greying of the fur, lymphopenia and low levels of blood glucose. The lifespan of Sirt6 knock-out mice is typically one to three months, dependent upon the strain in which the Sirt6 gene has been deleted. By contrast, wild type mice, which retain expression of Sirt6, exhibit a maximum lifespan of two to four years. Mice which have been genetically engineered to overexpress, or produce more, Sirt6 protein exhibit an extended maximum lifespan. This lifespan extension, of about 15–16 percent, is observed only in male mice. Reciprocal regulation between SIRT6 and miRNA-122 controls liver metabolism and Predicts Hepatocarcinoma prognosis by study of Haim Cohen's lab with mice. they found that SIRT6 and miR-122 negatively regulate each other's expression. The study found SIRT6 was shown to act as a tumor suppressor that blocks the Warburg effect in cancer cells. # DNA repair SIRT6 is a chromatin-associated protein that is required for normal base excision repair of DNA damage in mammalian cells. Deficiency of SIRT6 in mice leads to abnormalities that overlap with aging-associated degenerative processes. SIRT6 also promotes the repair of DNA double-strand breaks by the process of non-homologous end joining. SIRT6 stabilizes the repair protein DNA-PKcs (DNA-dependent protein kinase catalytic subunit) at chromatin sites of damage. As normal human fibroblasts replicate and progress towards replicative senescence the capability to undergo homologous recombinational repair (HRR) declines. However, over-expression of SIRT6 in “middle-aged” and pre-senescent cells strongly stimulates HRR. This effect depends on the mono-ADP ribosylation activity of poly(ADP-ribose) polymerase (PARP1). SIRT6 also rescues the decline in base excision repair of aged human fibroblasts in a PARP1 dependent manner. These findings suggest that SIRT6 expression may slow the aging process by facilitating DNA repair (see DNA damage theory of aging). # Clinical relevance The medical and therapeutic relevance of SIRT6 in humans remains unclear. SIRT6 may be an attractive drug target for pharmocological activation in several diseases. Because SIRT6 attenuates glycolysis and inflammation, the gene is of medical interest in the context of several diseases, including diabetes and arthritis. Additionally, SIRT6 may be relevant in the context of cancer. Several studies have indicated that SIRT6 is selectively inactivated during oncogenesis in a variety of tumor types; a separate study demonstrated that SIRT6 overexpression was selectively cytotoxic to cancer cells. Neurodegenerative diseases in seniors (including Alzheimer's) appear concurrently with low levels of SIRT6. # Activators Sirt6 deacetylation activity can be stimulated by high concentrations (several hundred micromolar) of fatty acids, and more potently by a first series of synthetic activators based on a pyrroloquinoxaline scaffold. Crystal structures of Sirt6/activator complexes show that the compounds exploit a SIRT6 specific pocket in the enzyme's substrate acyl binding channel.	Sirtuin 6 Sirtuin 6 (SIRT6 or Sirt6) is a stress responsive protein deacetylase and mono-ADP ribosyltransferase enzyme encoded by the SIRT6 gene.[1][2] SIRT6 functions in multiple molecular pathways related to aging, including DNA repair, telomere maintenance, glycolysis and inflammation.[1] # Function Studies in mice have revealed that Sirt6 is essential for post-natal development and survival. Sirt6 knock-out mice, in which the gene encoding Sirt6 has been disrupted, exhibit a severe progeria, or premature aging syndrome, characterized by spinal curvature, greying of the fur, lymphopenia and low levels of blood glucose.[3] The lifespan of Sirt6 knock-out mice is typically one to three months, dependent upon the strain in which the Sirt6 gene has been deleted. By contrast, wild type mice, which retain expression of Sirt6, exhibit a maximum lifespan of two to four years.[3] Mice which have been genetically engineered to overexpress, or produce more, Sirt6 protein exhibit an extended maximum lifespan. This lifespan extension, of about 15–16 percent, is observed only in male mice.[4] Reciprocal regulation between SIRT6 and miRNA-122 controls liver metabolism and Predicts Hepatocarcinoma prognosis by study of Haim Cohen's lab with mice. they found that SIRT6 and miR-122 negatively regulate each other's expression. The study found SIRT6 was shown to act as a tumor suppressor that blocks the Warburg effect in cancer cells.[5] # DNA repair SIRT6 is a chromatin-associated protein that is required for normal base excision repair of DNA damage in mammalian cells.[6] Deficiency of SIRT6 in mice leads to abnormalities that overlap with aging-associated degenerative processes.[6] SIRT6 also promotes the repair of DNA double-strand breaks by the process of non-homologous end joining. SIRT6 stabilizes the repair protein DNA-PKcs (DNA-dependent protein kinase catalytic subunit) at chromatin sites of damage.[7] As normal human fibroblasts replicate and progress towards replicative senescence the capability to undergo homologous recombinational repair (HRR) declines.[8] However, over-expression of SIRT6 in “middle-aged” and pre-senescent cells strongly stimulates HRR.[8] This effect depends on the mono-ADP ribosylation activity of poly(ADP-ribose) polymerase (PARP1). SIRT6 also rescues the decline in base excision repair of aged human fibroblasts in a PARP1 dependent manner.[9] These findings suggest that SIRT6 expression may slow the aging process by facilitating DNA repair (see DNA damage theory of aging). # Clinical relevance The medical and therapeutic relevance of SIRT6 in humans remains unclear. SIRT6 may be an attractive drug target for pharmocological activation in several diseases.[10] Because SIRT6 attenuates glycolysis and inflammation, the gene is of medical interest in the context of several diseases, including diabetes and arthritis.[11] Additionally, SIRT6 may be relevant in the context of cancer. Several studies have indicated that SIRT6 is selectively inactivated during oncogenesis in a variety of tumor types; a separate study demonstrated that SIRT6 overexpression was selectively cytotoxic to cancer cells.[12] Neurodegenerative diseases in seniors (including Alzheimer's) appear concurrently with low levels of SIRT6.[13] # Activators Sirt6 deacetylation activity can be stimulated by high concentrations (several hundred micromolar) of fatty acids,[14] and more potently by a first series of synthetic activators based on a pyrrolo[1,2-a]quinoxaline scaffold.[15] Crystal structures of Sirt6/activator complexes show that the compounds exploit a SIRT6 specific pocket in the enzyme's substrate acyl binding channel.[15]	https://www.wikidoc.org/index.php/Sirtuin_6
059b498d2369178c59cc009a8fd5535ea185a549	wikidoc	Sirtuin 7	Sirtuin 7 NAD-dependent deacetylase sirtuin 7 is an enzyme that in humans is encoded by the SIRT7 gene. # Function This gene encodes a member of the sirtuin family of proteins, homologs to the yeast Sir2 protein. Members of the sirtuin family are characterized by a sirtuin core domain and grouped into four classes. The functions of human sirtuins have not yet been determined; however, yeast sirtuin proteins are known to regulate epigenetic gene silencing and suppress recombination of rDNA. Studies suggest that the human sirtuins may function as intracellular regulatory proteins with mono-ADP-ribosyltransferase activity. The protein encoded by this gene is included in class IV of the sirtuin family. In humans cells, SIRT7 has only been shown to interact with two other molecules: RNA polymerase I (RNA Pol I) and upstream binding factor (UBF). SIRT7 is localized to the nucleolus and interacts with RNA Pol I. Chromatin immunoprecipitation studies demonstrate that SIRT7 localizes to rDNA, and coimmunoprecipitation shows that SIRT7 binds RNA Pol I. In addition SIRT7 interacts with UBF, a major component of the RNA Pol I initiation complex. It is not known whether or not SIRT7 is modifying RNA Pol I and/or UBF, and if so, what those modifications are. SIRT7 is expressed more in metabolically active tissues, such as liver and spleen, and less in non-proliferating tissues, such as heart and brain. Furthermore, it has been shown that SIRT7 is necessary for rDNA transcription. Knock down of SIRT7 in HEK293 cells resulted in decreased rRNA levels. This same study found that this SIRT3 knockdown decreased the amount of RNA Pol I associated with rDNA, suggesting that SIRT7 may be required for rDNA transcription. Knock down SIRT7 led to reduced RNA Pol I levels, but RNA Pol I mRNA levels did not change. This suggests that SIRT7 plays a crucial role in connecting the function of chromatin remodeling complexes to RNA Pol I machinery during transcription. SIRT7 may help attenuate DNA damage and thereby promoting cellular survival under conditions of genomic stress. ## DNA repair Depletion of SIRT7 results in impaired repair of DNA double-strand breaks (DSBs) by the process of non-homologous end joining (NHDJ). DSBs are one of the most significant types of DNA damage leading to genome instability. SIRT7 is recruited to DSBs where it specifically deacylates histone H3 at lysine 18. This affects the focal accumulation of the DNA damage response factor 53BP1, a protein that promotes NHEJ by protecting DNA from end resection. ## Accelerated aging Sirt7 mutant mice show phenotypic and molecular features of accelerated aging. These features include premature curvature of the spine, reduced weight and fat content, compromised hematopoietic stem cell function and leukopenia, and multiple organ disfunction. # Clinical relevance This gene has been found to be involved in maintenance of oncogenic transformation.	Sirtuin 7 NAD-dependent deacetylase sirtuin 7 is an enzyme that in humans is encoded by the SIRT7 gene.[1][2][3] # Function This gene encodes a member of the sirtuin family of proteins, homologs to the yeast Sir2 protein. Members of the sirtuin family are characterized by a sirtuin core domain and grouped into four classes. The functions of human sirtuins have not yet been determined; however, yeast sirtuin proteins are known to regulate epigenetic gene silencing and suppress recombination of rDNA. Studies suggest that the human sirtuins may function as intracellular regulatory proteins with mono-ADP-ribosyltransferase activity. The protein encoded by this gene is included in class IV of the sirtuin family.[3] In humans cells, SIRT7 has only been shown to interact with two other molecules: RNA polymerase I (RNA Pol I) and upstream binding factor (UBF).[2] SIRT7 is localized to the nucleolus and interacts with RNA Pol I. Chromatin immunoprecipitation studies demonstrate that SIRT7 localizes to rDNA, and coimmunoprecipitation shows that SIRT7 binds RNA Pol I. In addition SIRT7 interacts with UBF, a major component of the RNA Pol I initiation complex.[4] It is not known whether or not SIRT7 is modifying RNA Pol I and/or UBF, and if so, what those modifications are. SIRT7 is expressed more in metabolically active tissues, such as liver and spleen, and less in non-proliferating tissues, such as heart and brain.[2] Furthermore, it has been shown that SIRT7 is necessary for rDNA transcription. Knock down of SIRT7 in HEK293 cells resulted in decreased rRNA levels. This same study found that this SIRT3 knockdown decreased the amount of RNA Pol I associated with rDNA, suggesting that SIRT7 may be required for rDNA transcription. Knock down SIRT7 led to reduced RNA Pol I levels, but RNA Pol I mRNA levels did not change. This suggests that SIRT7 plays a crucial role in connecting the function of chromatin remodeling complexes to RNA Pol I machinery during transcription.[5] SIRT7 may help attenuate DNA damage and thereby promoting cellular survival under conditions of genomic stress.[6] ## DNA repair Depletion of SIRT7 results in impaired repair of DNA double-strand breaks (DSBs) by the process of non-homologous end joining (NHDJ).[7] DSBs are one of the most significant types of DNA damage leading to genome instability. SIRT7 is recruited to DSBs where it specifically deacylates histone H3 at lysine 18. This affects the focal accumulation of the DNA damage response factor 53BP1, a protein that promotes NHEJ by protecting DNA from end resection.[7][8] ## Accelerated aging Sirt7 mutant mice show phenotypic and molecular features of accelerated aging.[7] These features include premature curvature of the spine, reduced weight and fat content, compromised hematopoietic stem cell function and leukopenia, and multiple organ disfunction.[7][8] # Clinical relevance This gene has been found to be involved in maintenance of oncogenic transformation.[9]	https://www.wikidoc.org/index.php/Sirtuin_7
7c4097ad9436e7057a0008d314ab8c62639601bd	wikidoc	Sisomicin	Sisomicin # Overview Sisomicin (bactoCeaze or Ensamycin) is an aminoglycoside antibiotic, isolated from the fermentation broth of a new species of the genus Micromonospora. It is a newer broad-spectrum aminoglycoside most structurally related to gentamicin. Sisomicin is the most predictably active aminoglycoside against gram-positive bacteria. Like most other aminoglycosides, Sisomicin is bactericidal for sensitive clinical isolates. The minimum bactericidal concentrations (MBC) have been found to be equivalent or very close to the minimum inhibitory concentrations (MIC). Like other aminoglycosides, most clinical isolates of Pseudomonas aeruginosa remain susceptible to sisomicin. Resistance to sisomicin may enzymatically or non-enzymatically be mediated. Sisomicin is inactivated by the same enzymes as gentamicin but it is active against many, not all, organisms that resist gentamicin by non-enzymatic mechanisms. Some studies show that sisomicin has been effective in the treatment of infections that either had failed to respond to other drugs or were due to microorganisms resistant in vitro to other aminoglycosides.	Sisomicin Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Sisomicin (bactoCeaze or Ensamycin) is an aminoglycoside antibiotic, isolated from the fermentation broth of a new species of the genus Micromonospora.[1] It is a newer broad-spectrum aminoglycoside most structurally related to gentamicin. Sisomicin is the most predictably active aminoglycoside against gram-positive bacteria.[2] Like most other aminoglycosides, Sisomicin is bactericidal for sensitive clinical isolates. The minimum bactericidal concentrations (MBC) have been found to be equivalent or very close to the minimum inhibitory concentrations (MIC).[2] Like other aminoglycosides, most clinical isolates of Pseudomonas aeruginosa remain susceptible to sisomicin. Resistance to sisomicin may enzymatically or non-enzymatically be mediated. Sisomicin is inactivated by the same enzymes as gentamicin but it is active against many, not all, organisms that resist gentamicin by non-enzymatic mechanisms.[3] Some studies show that sisomicin has been effective in the treatment of infections that either had failed to respond to other drugs or were due to microorganisms resistant in vitro to other aminoglycosides.[4][5]	https://www.wikidoc.org/index.php/Sisomicin
113420f6625e72525b7c99cf570094d0b72c7fe5	wikidoc	Sleep log	Sleep log # Overview A sleep log is a record of an individual's sleeping and waking times, usually over a period of several weeks. It is used to diagnose circadian rhythm sleep disorders, and to monitor whether treatment of those disorders is successful. # Components A sleep log usually includes: - The time the person tried to fall asleep - The time the person thinks they fell asleep - The number, time, and length of any nighttime awakenings - The time the person woke up - The time the person got out of bed - The time the person had wanted to wake up, before trying to fall asleep - Whether the person woke up by themselves, by an alarm clock, or because of being disturbed - Whether the person got out of bed by themselves, by an alarm clock, or because of being disturbed - A few words about how the person felt during the day - The start and end times of any daytime naps - What, if any, medications the person was using # Data collection Sleep logs are often hand-drawn on graph paper. Specialized software for creating sleep logs is also freely available. A spreadsheet or database software can also be used. Sleep logs may be used in conjunction with actigraphy.	Sleep log Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview A sleep log is a record of an individual's sleeping and waking times, usually over a period of several weeks. It is used to diagnose circadian rhythm sleep disorders, and to monitor whether treatment of those disorders is successful. # Components A sleep log usually includes: - The time the person tried to fall asleep - The time the person thinks they fell asleep - The number, time, and length of any nighttime awakenings - The time the person woke up - The time the person got out of bed - The time the person had wanted to wake up, before trying to fall asleep - Whether the person woke up by themselves, by an alarm clock, or because of being disturbed - Whether the person got out of bed by themselves, by an alarm clock, or because of being disturbed - A few words about how the person felt during the day - The start and end times of any daytime naps - What, if any, medications the person was using # Data collection Sleep logs are often hand-drawn on graph paper. Specialized software for creating sleep logs is also freely available. A spreadsheet or database software can also be used. Sleep logs may be used in conjunction with actigraphy.	https://www.wikidoc.org/index.php/Sleep_log
9ee35a7c8524f066843b3f7bc61bde1ad26efcc1	wikidoc	Sleep sex	Sleep sex # Overview Sleep sex or sexsomnia is a form of non-rapid eye movement (NREM) parasomnia (similar to sleepwalking) that causes people to commit sexual acts while they are asleep. The first doctor to coin the term "Sleep sex" was Dr. David Saul Rosenfeld, a neurologist and sleep doctor from Los Angeles, California. The proposed medical diagnosis is NREM Arousal Parasomnia - Sexual Behaviour in Sleep, and is considered to be a distinct variant of sleepwalking/confusional arousals (ICSD 2). The condition was defined by three researchers from the University of Toronto and the University of Ottawa in a paper called "Sexsomnia — A New Parasomnia?" published in the Canadian Journal of Psychiatry in June 2003. Sufferers are often aware of their behavior for a long time before they seek help, often because they are not aware that it is a medical disorder or for fear that others will judge it as willful behavior rather than a medical disorder. However, the reality of the condition has been confirmed by sleep disorder researchers who have made sound and video recordings of patients with the condition and observed unusual brain wave activity during the episodes similar to that experienced by other parasomniacs. It is a mind/body disconnect that occurs during sleep. In many cases it is a pre-cursor to neuromuscular disease and is treated with muscle relaxants and other medications. The first research paper that suggested that sexual behavior during sleep may be a new type of parasomnia was published in 1996. Later, several papers were published describing the problem and suggested that problematic forms of sleep sex are medically treatable "conditions" (see external links). Sexsomnia is not always problematic or extreme for those who experience it or for their partners. There is a great variety in both the frequency and levels to which people are affected by this disorder. # Cases reported in the press On 30 November 2005, a Toronto court acquitted a man of sexual assault after he was diagnosed with sleep sex disorder, although prosecutors have filed an appeal of the acquittal as of February 2006. In Britain a man from York was cleared of three counts of rape on 19 December 2005. In Australia, a woman was reported as leaving her house at night and having sex with strangers while sleepwalking. On 8 August 2007, a British RAF mechanic was cleared of a rape charge after the jury found him not responsible of his actions when he had sex with a 15-year-old girl. # Fictional cases A case of this disorder is found in the episode "Role Model" of the television series House.	Sleep sex Editor-In-Chief: C. Michael Gibson, M.S., M.D. [5] # Overview Sleep sex or sexsomnia is a form of non-rapid eye movement (NREM) parasomnia (similar to sleepwalking) that causes people to commit sexual acts while they are asleep. The first doctor to coin the term "Sleep sex" was Dr. David Saul Rosenfeld, a neurologist and sleep doctor from Los Angeles, California. The proposed medical diagnosis is NREM Arousal Parasomnia - Sexual Behaviour in Sleep, and is considered to be a distinct variant of sleepwalking/confusional arousals (ICSD 2). The condition was defined by three researchers from the University of Toronto and the University of Ottawa in a paper called "Sexsomnia — A New Parasomnia?" published in the Canadian Journal of Psychiatry in June 2003. Sufferers are often aware of their behavior for a long time before they seek help, often because they are not aware that it is a medical disorder or for fear that others will judge it as willful behavior rather than a medical disorder. However, the reality of the condition has been confirmed by sleep disorder researchers who have made sound and video recordings of patients with the condition and observed unusual brain wave activity during the episodes similar to that experienced by other parasomniacs. It is a mind/body disconnect that occurs during sleep. In many cases it is a pre-cursor to neuromuscular disease[citation needed] and is treated with muscle relaxants and other medications. The first research paper that suggested that sexual behavior during sleep may be a new type of parasomnia was published in 1996. Later, several papers were published describing the problem and suggested that problematic forms of sleep sex are medically treatable "conditions" (see external links). Sexsomnia is not always problematic or extreme for those who experience it or for their partners. There is a great variety in both the frequency and levels to which people are affected by this disorder. # Cases reported in the press On 30 November 2005, a Toronto court acquitted a man of sexual assault after he was diagnosed with sleep sex disorder, although prosecutors have filed an appeal of the acquittal as of February 2006.[1] In Britain a man from York was cleared of three counts of rape on 19 December 2005.[2] In Australia, a woman was reported as leaving her house at night and having sex with strangers while sleepwalking.[3] On 8 August 2007, a British RAF mechanic was cleared of a rape charge after the jury found him not responsible of his actions when he had sex with a 15-year-old girl.[4] # Fictional cases A case of this disorder is found in the episode "Role Model" of the television series House.	https://www.wikidoc.org/index.php/Sleep_sex
544e0d19724f283b92ac82f25c9b8602610e95fa	wikidoc	Slit lamp	Slit lamp The slit lamp is an instrument consisting of a high-intensity light source that can be focused to shine as a slit. It is used in conjunction with a microscope. The lamp facilitates an examination which looks at anterior segment, or frontal structures, of the human eye, which includes the eyelid, sclera, conjunctiva, iris, natural crystalline lens, and cornea. The binocular slit-lamp examination provides stereoscopic magnified view of the eye structures in striking detail, enabling exact anatomical diagnoses to be made for a variety of eye conditions. Combined with special lenses like Goldmann 3-mirror lens, Gonioscopy single-mirror/ Zeiss 4-mirror lens for angle structures and +90D lens, +78D lens, +66D lens & Hruby (-56D) lens, the examination of retinal structures is accomplished in detail. While a patient is seated in the examination chair, he rests his chin and forehead on a support to steady the head. Using the biomicroscope, the ophthalmologist then proceeds to examine the patient's eye. A fine strip of paper, stained with fluorescein, an orange-colored dye, may be touched to the side of the eye; this stains the tear film on the surface of the eye to aid examination. The dye is naturally rinsed out of the eye by tears. The subsequent test may involve placing drops in the eye in order to dilate the pupils. The drops take about 15 to 20 minutes to work, after which the examination is repeated, allowing the back of the eye to be examined. Patients will experience some light sensitivity for a few hours after this exam, and the dilating drops may also cause increased pressure in the eye, leading to nausea and pain; although this is very rare, patients experiencing these symptoms are advised to immediately seek medical attention. Adults need no special preparation for the test, however children may need some preparation, depending on age, interests, previous experiences, and level of trust. The slit lamp exam may detect many diseases of the eye, including: - Cataract - Conjunctivitis - Corneal injury - Fuchs' dystrophy - Keratoconus - Macular degeneration - Presbyopia - Retinal detachment - Retinal vessel occlusion - Retinitis pigmentosa - Sjögren's syndrome - Uveitis - Wilson's disease (Kayser-Fleischer ring) de:Spaltlampe hr:Procjepna svjetiljka it:Lampada a fessura no:Spaltelampe	Slit lamp The slit lamp is an instrument consisting of a high-intensity light source that can be focused to shine as a slit. It is used in conjunction with a microscope. The lamp facilitates an examination which looks at anterior segment, or frontal structures, of the human eye, which includes the eyelid, sclera, conjunctiva, iris, natural crystalline lens, and cornea. The binocular slit-lamp examination provides stereoscopic magnified view of the eye structures in striking detail, enabling exact anatomical diagnoses to be made for a variety of eye conditions. Combined with special lenses like Goldmann 3-mirror lens, Gonioscopy single-mirror/ Zeiss 4-mirror lens for angle structures and +90D lens, +78D lens, +66D lens & Hruby (-56D) lens, the examination of retinal structures is accomplished in detail. While a patient is seated in the examination chair, he rests his chin and forehead on a support to steady the head. Using the biomicroscope, the ophthalmologist then proceeds to examine the patient's eye. A fine strip of paper, stained with fluorescein, an orange-colored dye, may be touched to the side of the eye; this stains the tear film on the surface of the eye to aid examination. The dye is naturally rinsed out of the eye by tears. The subsequent test may involve placing drops in the eye in order to dilate the pupils. The drops take about 15 to 20 minutes to work, after which the examination is repeated, allowing the back of the eye to be examined. Patients will experience some light sensitivity for a few hours after this exam, and the dilating drops may also cause increased pressure in the eye, leading to nausea and pain; although this is very rare, patients experiencing these symptoms are advised to immediately seek medical attention. Adults need no special preparation for the test, however children may need some preparation, depending on age, interests, previous experiences, and level of trust. The slit lamp exam may detect many diseases of the eye, including: - Cataract - Conjunctivitis - Corneal injury - Fuchs' dystrophy - Keratoconus - Macular degeneration - Presbyopia - Retinal detachment - Retinal vessel occlusion - Retinitis pigmentosa - Sjögren's syndrome - Uveitis - Wilson's disease (Kayser-Fleischer ring) de:Spaltlampe hr:Procjepna svjetiljka it:Lampada a fessura no:Spaltelampe Template:WH Template:WS	https://www.wikidoc.org/index.php/Slit-lamp
79720b3129667a32cca7edeaef48d52ff91d5e7e	wikidoc	Slow Food	Slow Food # The Slow Food organization Slow Food began in Italy with the foundation of its forerunner organization, Arcigola, in 1986. The Slow Food organization spawned by the movement has expanded to include over 80,000 members in over 100 countries, every country with its own chapters. All totaled, 800 local convivia chapters exist. 360 convivia in Italy — to which the name condotta (singular) / condotte (plural) applies — are composed of 35,000 members, along with 450 other regional chapters around the world. The organizational structure is decentralized: each convivium has a leader who is responsible for promoting local artisans, local farmers, and local flavors through regional events such as Taste Workshops, wine tastings, and farmers' markets. Offices have been opened in Switzerland (1995), Germany (1998), New York (2000), France (2003), Japan (2005), and most recently in the United Kingdom. The head offices are located in Bra, northern Italy. Numerous publications are put out by the organization, in several languages. In the US, the Snail is the quarterly of choice, while Slow Food puts out literature in several other European nations. Recent efforts at publicity include the world's largest food and wine fair, the Salone del Gusto, a biennial cheese fair in Bra called Cheese, the Genoan fish festival called SlowFish, and Turin's Terra Madre ("Mother Earth") world meeting of food communities. In 2004 Slow Food opened a University of Gastronomic Sciences at Pollenzo, in Piedmont, and Colorno, in Emilia-Romagna, Italy. Carlo Petrini and Massimo Montanari are the leading figures in the creation of the University, whose goal is to promote awareness of good food and nutrition. ## Objectives The Slow Food movement incorporates a series of objectives within its mission, including: - forming and sustaining seed banks to preserve heirloom varieties in cooperation with local food systems - developing an "ark of taste" for each ecoregion, where local culinary traditions and foods are celebrated - preserving and promoting local and traditional food products, along with their lore and preparation - organizing small-scale processing (including facilities for slaughtering and short run products) - organizing celebrations of local cuisine within regions (for example, the Feast of Fields held in some cities in Canada) - promoting "taste education" - educating consumers about the risks of fast food - educating citizens about the drawbacks of commercial agribusiness and factory farms - educating citizens about the risks of monoculture and reliance on too few genomes or varieties - developing various political programs to preserve family farms - Lobbying for the inclusion of organic farming concerns within agricultural policy - Lobbying against government funding of genetic engineering - Lobbying against the use of pesticides - Teaching gardening skills to students and prisoners - Encouraging ethical buying in local marketplaces From time to time, Slow Food intervenes directly in market transactions; for example, Slow Food was able to preserve four varieties of native American turkey by ordering 4,000 of their eggs and commissioning their raising and slaughtering and delivery to market. ## Impact It is difficult to gauge the extent of the success of the Slow Food movement, considering that the organization itself is still very young. The current grassroots nature of Slow Food is such that few people in Europe and especially the United States are aware of it. Statistics show that Europe, and Germany in particular, is a much bigger consumer of organics than the US. Slow Food has contributed to the growing awareness of health concerns in Europe, as evidenced by this fact, but on society as a whole, Slow Food has had little effect. An example of this is the fact that tourists visit Slow Food restaurants more than locals, but Slow Food and its sister movements are still young. In an effort to spread the ideals of anti-fast food, Slow Food has targeted the youth of the nations in primary and secondary schools. Volunteers help build structural frameworks for school gardens and put on workshops to introduce the new generation to the art of farming. # Criticism Critics of the organization have charged it with being elitist, as it discourages nominally cheaper alternative methods of growing or preparing food. Slow Food responds by claiming to be working towards local production and consumption which will exploit "best practices" of science and professions worldwide but ultimately prove cheaper due to less reliance on transport and energy and chemical and technology intensive methods. These arguments parallel those of the anti-globalization movement, Greenpeace and green parties against global export of monocultured foodstuffs, especially GMOs. A central point related to these arguments is that transport prices are artificially low because the true cost of fuel (including the protection of shipping lanes and other military interventions around the world) are not factored into the price of goods, and are instead paid for indirectly through personal taxes.	Slow Food # The Slow Food organization Slow Food began in Italy with the foundation of its forerunner organization, Arcigola, in 1986.[1] The Slow Food organization spawned by the movement has expanded to include over 80,000 members in over 100 countries, every country with its own chapters. All totaled, 800 local convivia chapters exist. 360 convivia in Italy — to which the name condotta (singular) / condotte (plural) applies — are composed of 35,000 members, along with 450 other regional chapters around the world. The organizational structure is decentralized: each convivium has a leader who is responsible for promoting local artisans, local farmers, and local flavors through regional events such as Taste Workshops, wine tastings, and farmers' markets. Offices have been opened in Switzerland (1995), Germany (1998), New York (2000), France (2003), Japan (2005), and most recently in the United Kingdom. The head offices are located in Bra, northern Italy. Numerous publications are put out by the organization, in several languages. In the US, the Snail is the quarterly of choice, while Slow Food puts out literature in several other European nations. Recent efforts at publicity include the world's largest food and wine fair, the Salone del Gusto, a biennial cheese fair in Bra called Cheese, the Genoan fish festival called SlowFish, and Turin's Terra Madre ("Mother Earth") world meeting of food communities. In 2004 Slow Food opened a University of Gastronomic Sciences[2] at Pollenzo, in Piedmont, and Colorno, in Emilia-Romagna, Italy. Carlo Petrini and Massimo Montanari are the leading figures in the creation of the University, whose goal is to promote awareness of good food and nutrition. ## Objectives The Slow Food movement incorporates a series of objectives within its mission, including: - forming and sustaining seed banks to preserve heirloom varieties in cooperation with local food systems - developing an "ark of taste" for each ecoregion, where local culinary traditions and foods are celebrated - preserving and promoting local and traditional food products, along with their lore and preparation - organizing small-scale processing (including facilities for slaughtering and short run products) - organizing celebrations of local cuisine within regions (for example, the Feast of Fields held in some cities in Canada) - promoting "taste education" - educating consumers about the risks of fast food - educating citizens about the drawbacks of commercial agribusiness and factory farms - educating citizens about the risks of monoculture and reliance on too few genomes or varieties - developing various political programs to preserve family farms - Lobbying for the inclusion of organic farming concerns within agricultural policy - Lobbying against government funding of genetic engineering - Lobbying against the use of pesticides - Teaching gardening skills to students and prisoners - Encouraging ethical buying in local marketplaces From time to time, Slow Food intervenes directly in market transactions; for example, Slow Food was able to preserve four varieties of native American turkey by ordering 4,000 of their eggs and commissioning their raising and slaughtering and delivery to market[citation needed]. ## Impact It is difficult to gauge the extent of the success of the Slow Food movement, considering that the organization itself is still very young. The current grassroots nature of Slow Food is such that few people in Europe and especially the United States are aware of it. Statistics show that Europe, and Germany in particular, is a much bigger consumer of organics than the US.[3] Slow Food has contributed to the growing awareness of health concerns in Europe, as evidenced by this fact, but on society as a whole, Slow Food has had little effect. An example of this is the fact that tourists visit Slow Food restaurants more than locals, but Slow Food and its sister movements are still young. In an effort to spread the ideals of anti-fast food, Slow Food has targeted the youth of the nations in primary and secondary schools. Volunteers help build structural frameworks for school gardens and put on workshops to introduce the new generation to the art of farming. # Criticism Critics of the organization have charged it with being elitist, as it discourages nominally cheaper alternative methods of growing or preparing food. Slow Food responds by claiming to be working towards local production and consumption which will exploit "best practices" of science and professions worldwide but ultimately prove cheaper due to less reliance on transport and energy and chemical and technology intensive methods. These arguments parallel those of the anti-globalization movement, Greenpeace and green parties against global export of monocultured foodstuffs, especially GMOs. A central point related to these arguments is that transport prices are artificially low because the true cost of fuel (including the protection of shipping lanes and other military interventions around the world) are not factored into the price of goods, and are instead paid for indirectly through personal taxes.	https://www.wikidoc.org/index.php/Slow_Food
40b79e3deec3810d6701d056ae5f44bcb050f987	wikidoc	Soapberry	Soapberry # Overview Soapberry is a common name for several plants and may refer to: - Plants in the genus Sapindus, native to warm temperate to tropical regions in both the Old World and the New World. The Berry (botany)\|berries of these plants contain a natural, low-sudsing detergent called saponin. - Canada buffaloberry (Shepherdia canadensis) is also known as "soapberry" and is native to North America. This shrub bears bitter yet edible red berries.	Soapberry Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Soapberry is a common name for several plants and may refer to: - Plants in the genus Sapindus, native to warm temperate to tropical regions in both the Old World and the New World. The Berry (botany)\|berries of these plants contain a natural, low-sudsing detergent called saponin. - Canada buffaloberry (Shepherdia canadensis) is also known as "soapberry" and is native to North America. This shrub bears bitter yet edible red berries.	https://www.wikidoc.org/index.php/Soapberry
4db89291f6dacd6232476153304dda5a77931c1d	wikidoc	Socionics	Socionics Socionics (Russian: соционика) is a model of personality based on Carl Jung's work on Psychological Types, Freud's theory of the conscious and subconscious mind, and Antoni Kępiński's theory of information metabolism. The model was founded mainly by the Lithuanian researcher Aušra Augustinavičiūtė in the 1970s, and is evolving rapidly. The name socionics is derived from the word "society", since Augustinavičiūtė believed that each personality type has a distinct societal role, which can be specified and explained by socionics. Socionics is based upon the idea that a person's character acts like a set of blocks called "psychological functions". Different combinations of these functions result in different ways of accepting and producing information, which in turn results in distinct behavioral patterns and thus different character types. Socionics also includes an intertype relations theory, based on the interaction of these functions among different character types. The International Institute of Socionics (IIS) - was founded in 1991 in Kiev, Ukraine. The organization's director is Dr. Alexander Boukalov. Some Socionics sources also believe in a form of physiognomy which correlates physical traits such as weight, shape of nose and so on with particular types. One very popular website for Socionics, , espouses this view, beginning the description of each type with statements like "ENTps normally have a long, slim figure. Other parts of the body are also stretched, especially the legs and fingers. They often have rounded shoulders. Sometimes ENTps have a characteristic inwardly sloping chin." These VI proponents believe they can type people through a process called V.I. (Visual Identification) which it is claimed "is the fastest and most reliable method of Type identification of today." This subset of Socionists believe they can identify type without any other information, and group pictures of particular "types" as examples or training materials. Other proponents of Socionics strongly disagree with this view. # Jung's psychological types Carl Jung describes four basic psychological functions that are capable of becoming conscious: - Sensation - all perceptions by means of the sense organs - Intuition - perception by way of the unconscious, or perception of unconscious events - Thinking (logic) - interpretation of information based on whether it is correct or incorrect - Feeling (ethics) - interpretation of information based on its ethical aspects Sensation and intuition are called perceiving or irrational functions, and are thus named because unlike the rational or judging functions (i.e., thinking and feeling), they deal with the perception of reality rather than the interpretation of it. One function dominates consciousness, while its opposite characterizes unconsciousness. There are dominant (primary) functions and auxiliary (secondary) functions. It is common to refer to both dominant and auxiliary functions, e.g., intuitive-thinking or sensation-feeling. Attitude of consciousness refers to the basic direction of conscious energy flow. Two possible directions of flow are introversion (inward to subjective, psychological experience) or extroversion (outward to the environment of objects, other people and collective norms). Opposite attitudes would characterize unconsciousness. Hence the dominant function of consciousness can be either introverted or extroverted, which allows for 8 different major psychological types. Mixed types would include auxiliary functions. # Socionics functions The basic premise of socionics is that the complete information about any given individual can be described by 8 categories, called socionics functions. Augustinavičiūtė introduced special symbols for each of this functions, to simplify their discussion. # The 16 types Classical socionics theory contains 16 different psychological types. These types are described by their two strongest functions, where Jung's functions are used. While Jung described only 8 types, considering the most dominant function of the personality, socionics, like the MBTI describes the different types based on pairs of functions - dominant and secondary functions. The secondary function is opposite to the dominant function in extroversion and rationality. For example, if the dominant function is introverted thinking (a rational and introverted function), the secondary function must be irrational and extroverted, which means the only two functions that could complement introverted thinking are extroverted sensing or extroverted intuition. Augustinavičiūtė usually used names like sensory logical introvert to refer to the type. In this example the first function is introverted sensing and the secondary is logic (which must be extroverted). Besides this, Augustinavičiūtė introduced the use of names of famous people as a moniker for each type. For example, she called the type of sensory logical introvert Gabin or sensory ethical introvert Dumas. Some later researchers believed that using names of famous people is not quite appropriate and used instead such names as Craftsman or Mediator. Such names were selected to describe the social role of each particular type as precisely as possible. In Russian, to keep the text brief, the types are labeled with three-letter acronyms, which are also used to specify the types in English, e.g., ILE, which stands for "intuitive logical extravert". However, some authors in socionics specify socionic types using MBTI abbreviations, given the similarities present in the two theories. In order to distinguish between socionics and MBTI types using this nomenclature, a tradition of leaving the last letter uncapitalized has been established among some groups. For example, an MBTI extroverted sensing feeling judging type is often referred to as an ESFJ, while a socionics ethical sensory extravert is referred to as an ESFj. The following tables provide a list of types with names most commonly used in socionics: # Model A Aušra Augustinavičiūtė developed a model of personality called Model A, which includes all eight socionic functions. A function's position in Model A reflects the nature of its usage by a particular type. The following diagram is an example of the positions of the functions as expressed in Model A. Note that, although often these functions are numbered 1 to 8, this does not mean that the functions are ordinal in strength, as is the case in MBTI. ## Nature of functions - Function 1 - leading, program, primary, base, or dominant function. This is the strongest conscious function, and the most utilized function of the psyche. A person's outlook and role in life is largely determined by the nature of this function. One is generally very confident in the use of this function, and may defend it when challenged. - Function 2 - creative or secondary function, is second in influence only to the dominant function. It assists the dominant function in achieving its goal. One may be somewhat less confident with the use of this function than with his dominant function. As a result, the creative function is sometimes less instrumental when a person is challenged or threatened. - Function 3 - role function, is a weak but conscious function. One generally tries to be at least adequate in areas where use of the role function is necessary. However, generally one has very little control or confidence over the role function, and criticism is painfully acknowledged with respect to it. Tactful assistance is required from one's dual-seeking function to overcome the problems associated with the role function. - Function 4 - place of least resistance or the painful function, is a weak and conscious function, in addition to being the weakest function of the psyche. One painfully perceives his complete inability to use this function, and reacts negatively to its imposition upon him. Tactful assistance is required from one's hidden agenda to overcome the problems associated with this function. - Function 5 - suggestive, or inspired function, is a weak and unconscious function which is largely lacked. One requires assistance from somebody confident in this function in order to overcome the difficulties it presents. - Function 6 - actualization, the hidden agenda or estimative function. This is a weak and unconscious function which one often understands poorly. Nonetheless, this function has a strong influence over one's activities, and one requires assistance from someone who uses it confidently in order to understand it. - Function 7 - observant function, the function of personal knowledge. This is a strong but unconscious function. One generally has a good grasp of this function, but attempts to limit its use considerably. Arguments calling for restraint are often used to overlook this function. - Function 8 - demonstrative function. This is the strongest of the unconscious functions. As a result, it is so deeply rooted into the psyche that one is usually not even aware of its existence or utilization. ## Blocks of the psyche According to Augustinavičiūtė, there are four blocks of the psyche: the ego block, the super-ego block, the id block, and the super-id block. The ego block contains the dominant and creative functions, the super-ego block contains the role and PoLR functions, the super-id block contains the dual-seeking function and the hidden agenda, while the id block contains the seventh and eighth functions. The functions within the ego and super-ego blocks are said to be conscious functions, while those within the id and super-id blocks are said to be unconscious. Similarly, the functions presiding within the ego and id blocks are said to be strong functions which are expressed easily or naturally, while the functions of the super-ego and super-id blocks are weak and expressed with difficulty or support, or are not expressed at all. ## The 16 types in Model A # Intertype Relations The field of Intertype Relations within Socionics attempts to describe the nature of relations between two different people based on their Socionics type. ## Identity Relations of Identity describe relations between two individuals of the same type. Often, both partners will perceive similar situations and problems, and will take similar actions. Partners usually understand the motivations behind the other's actions. A relationship between identity partners is characterized by mutual understanding, self-development, and learning. Each is interested in the other's ideas, and sees their value. ## Duality Duality is a fundamental concept in Socionics. Dual relations are characterized by mutual benefit and support. Duality occurs between two members of the same quadra who are both either rational or irrational. So duality partners share the same function blocks, but their dominance is reversed. In a sense, they are opposite sides of the same coin. The 8 duality pairs are as follows: - LII-ESE - ILE-SEI - LSI-EIE - SLE-IEI - ESI-LIE - SEE-ILI - EII-LSE - IEE-SLI In dual relations, the super-id functions of both partners are the ego functions of the other. As the super-id functions are generally the areas in which a person needs assistance from somebody skilled in these areas, duality interaction is quite rewarding and satisfying for both parties. ## Activity Activity relations occur between two members of the same quadra who share either introversion or extroversion. Relations of activity can resemble duality since the super-id functions are both present in the ego functions of the other partner. However, activity relations are somewhat less fulfilling than dual relations. Each partner's dominant function is the others Hidden Agenda function. Activity relations are better suited to friendly correspondence. ## Mirror Mirror relations occur between types who share the same ego functions, yet place different emphases on them; the dominant function of one partner is the creative function of the other. Mirror relations are characterized by similar actions and motivations between partners, and mutual understanding. Interactions usually result in a drawn out dialogue, as each partner seems to keep opening up avenues of thought which the other needs to now clarify verbally. An important source of dissension between mirror types is the opposing temperament, as all mirror relations occur between EJ and IP temperaments, or between EP and IJ temperaments. EJs find the passive, unstable IP behavior to be a severe hindrance in getting things done, while IPs find the restless and proactive actions of EJ types paranoid and stifling. Similarly, EP types find IJ types to be somewhat dull and boring, while IJ types see EP types as wildly unpredictable and impetuous. ## Comparative Comparative relations occur between types who share the same dominant function but possess different creative functions. Comparative partners often see each other as interesting people and are often able to see each other's motivations, but often tailor their actions towards areas in which the other partner is unskilled or uninterested, as the creative function for one partner is the place of least resistance of the other. ## Semi-duality Relations of semi-duality are similar to relations of duality. Semi-duality occurs between partners who share each other's dual-seeking (5th) functions but lack each other's actualization (hidden agenda) functions. As a result, both partners often perceive elements of duality from the relationship but feel the other partner is misplacing the correct emphasis; as semi-duals will be able to help their partners with their dual seeking functions but both have the least confidence in the same area of the psyche (thinking, feeling, sensing, or intuition). ## Look-a-like / Cooperation Look-a-like relations occur between partners who have the same creative function but differing dominant functions. As a result, look-a-like partners may often perform similar activities or have similar fields of interest, but often do not understand each other's internal motivations. Look-a-like relations for this reason can become very formal and business like. ## Illusionary Relations of Illusion occur between partners whose creative functions are the other partners' hidden agenda, but whose dual seeking functions are part of the id block of the other partner. Relations of illusion can resemble duality, but neither partner is particularly satisfied, as they receive no assistance in their dual-seeking functions from this relation. ## Benefit / Instruction / Order Relations of Benefit are asymmetrical relations; one type benefits another. Relations of benefit are characterized by the beneficiary's attempt to draw in the benefactor to a world where the benefactor clearly does not belong. The beneficiary's dual seeking function is the benefactor's creative function, and as a result the beneficiary often takes an interest in the benefactor. However, the benefactor's dual seeking function is the beneficiary's place of least resistance, and the benefactor finds the beneficiary a highly uninteresting person. Relations of benefit frequently end with the departure of the benefactor... often to the utter bewilderment of the beneficiary. ## Supervision Relations of supervision are asymmetrical; one type supervises another. Relations of supervision are characterized by the supervisor's attempt to introduce his base function into the supervisee's life. The supervisor often perceives the supervisee as an interesting person and understands the supervisee's lifestyle, since the supervisor's creative function is the supervisee's base function. Nonetheless, the supervisee is often on the defensive since the supervisor's base function is the supervisee's point of least resistance (the function most vulnerable to criticism). The supervisee often perceives the supervisor to be the evil incarnate, while the bewildered supervisor wonders why the supervisee reacts so poorly to his benevolent assistance. ## Contrary / Contrast Contrary relations occur between types confident in the same area of the psyche but who place different emphases on each function. For example, the relation between an EIE and an EII, who possess in the ego block extroverted feeling with introverted intuition and introverted feeling with extroverted intuition, respectively, is a contrary relation. Contrary relations often consist of similar lifestyles with lack of mutual understanding and differing thought processes. ## Super-ego Super-ego relations occur between types whose ego functions are the other partners' super-ego functions. Super-ego relations are generally characterized by open conflict, discomfort, differing values, and lack of true understanding of partners' motivations. ## Quasi-Identity Relations of Quasi-Identity are characterized by mutual misunderstanding. One partner's ego functions are the other partner's demonstrative and observant functions. As quasi-identicals have opposite functions, they will often have similar interests and become involved in similar activities, but they rarely understand each other's motivations or ideas. ## Conflict Relations of Conflict are, unsurprisingly, characterized by constantly escalating conflict. Conflictors are the types with the most dissimilar values, and they rarely understand anything regarding each other's motivations or lifestyles. Conflictors may take for granted truths that their partners will dismiss as absurd. Sometimes they understand each other so little that the conflict is not well understood, but prevails under the surface, discomfiting both partners to no end. Conflictors also are of opposite temperaments, a fact which both partners often find irritating. # Temperaments There are four temperaments in socionics; namely, the extroverted rational (EJ), introverted rational (IJ), extroverted irrational (EP), and introverted irrational (IP) temperaments. ## Extroverted Rational Temperament Extroverted rational types, namely the ESE, EIE, LIE, and LSE, are characterized by energetic and proactive behavior. ## Introverted Rational Temperament Introverted rational types, namely the LII, LSI, ESI, and EII, are characterized by slow and methodical behavior. ## Extroverted Irrational Temperament Extroverted irrational types, namely the ILE, SLE, SEE, and IEE, are characterized by impulsive and unpredictable behavior. ## Introverted Irrational Temperament Introverted irrational types, namely the SEI, IEI, ILI, and SLI, are characterized by lack of motivation, inertia, and unstable moods and energy levels. # Quadras A quadra is a group of four sociotypes in which mirror, activity, and dual relations are experienced by each member of the group. The unique feature of the quadra is that it offers the greatest degree of psychological comfort among all groups containing four types in which functional interaction is symmetrical. The feeling of comfort and harmony produced by the quadra is due to the fact that all types in the quadra are alike in that they seek to give expression to the shared set of information elements in their ego and super-id blocks and to de-emphasize the information elements in their super-ego and id blocks. # Cultural Influence of Socionics Socionics, having originated in Vilnius, has developed extensively in the former Soviet Union in the past 30 years. In the Russian-speaking world (primarily Russia and Ukraine, but also the Baltic States, Central Asia, and Russian communities abroad) socionics has grown significantly in popularity, and is now a topic of discussion among large numbers of amateurs, as well as a group of a few hundred professionals whose experience and discoveries in socionics are highly regarded. Clubs for socializing and/or theoretical discussion exist in many large cities across the former USSR., A couple journals exist, as well as a number of organizations which periodically hold conferences in Kiev, Moscow, St. Petersburg, and other cities. In the West, however, socionics exists as little more than an internet phenomenon due to its novelty. (It was first introduced in English on the Internet in the mid 90s.) Although there do exist English discussion forums where some significant discussion of the theoretical and practical aspects of socionics does occur, little understanding of Socionics has dispersed beyond them.	Socionics Socionics (Russian: соционика) is a model of personality based on Carl Jung's work on Psychological Types, Freud's theory of the conscious and subconscious mind, and Antoni Kępiński's theory of information metabolism. The model was founded mainly by the Lithuanian researcher Aušra Augustinavičiūtė in the 1970s, and is evolving rapidly.[citation needed] The name socionics is derived from the word "society", since Augustinavičiūtė believed that each personality type has a distinct societal role, which can be specified and explained by socionics.[1] Socionics is based upon the idea that a person's character acts like a set of blocks called "psychological functions". Different combinations of these functions result in different ways of accepting and producing information, which in turn results in distinct behavioral patterns and thus different character types. Socionics also includes an intertype relations theory, based on the interaction of these functions among different character types. The International Institute of Socionics (IIS) - was founded in 1991 in Kiev, Ukraine. The organization's director is Dr. Alexander Boukalov. Some Socionics sources also believe in a form of physiognomy which correlates physical traits such as weight, shape of nose and so on with particular types. One very popular website for Socionics, http://www.socionics.com, espouses this view, beginning the description of each type with statements like "ENTps normally have a long, slim figure. Other parts of the body are also stretched, especially the legs and fingers. They often have rounded shoulders. Sometimes ENTps have a characteristic inwardly sloping chin." These VI proponents believe they can type people through a process called V.I. (Visual Identification) which it is claimed "is the fastest and most reliable method of Type identification of today." This subset of Socionists believe they can identify type without any other information, and group pictures of particular "types" as examples or training materials. Other proponents of Socionics strongly disagree with this view. # Jung's psychological types Carl Jung describes four basic psychological functions that are capable of becoming conscious:[2] - Sensation - all perceptions by means of the sense organs - Intuition - perception by way of the unconscious, or perception of unconscious events - Thinking (logic) - interpretation of information based on whether it is correct or incorrect - Feeling (ethics) - interpretation of information based on its ethical aspects Sensation and intuition are called perceiving or irrational functions, and are thus named because unlike the rational or judging functions (i.e., thinking and feeling), they deal with the perception of reality rather than the interpretation of it. One function dominates consciousness, while its opposite characterizes unconsciousness. There are dominant (primary) functions and auxiliary (secondary) functions. It is common to refer to both dominant and auxiliary functions, e.g., intuitive-thinking or sensation-feeling. Attitude of consciousness refers to the basic direction of conscious energy flow. Two possible directions of flow are introversion (inward to subjective, psychological experience) or extroversion (outward to the environment of objects, other people and collective norms). Opposite attitudes would characterize unconsciousness. Hence the dominant function of consciousness can be either introverted or extroverted, which allows for 8 different major psychological types. Mixed types would include auxiliary functions. # Socionics functions The basic premise of socionics is that the complete information about any given individual can be described by 8 categories, called socionics functions. Augustinavičiūtė introduced special symbols for each of this functions, to simplify their discussion. # The 16 types Classical socionics theory contains 16 different psychological types. These types are described by their two strongest functions, where Jung's functions are used. While Jung described only 8 types, considering the most dominant function of the personality, socionics, like the MBTI describes the different types based on pairs of functions - dominant and secondary functions. The secondary function is opposite to the dominant function in extroversion and rationality. For example, if the dominant function is introverted thinking (a rational and introverted function), the secondary function must be irrational and extroverted, which means the only two functions that could complement introverted thinking are extroverted sensing or extroverted intuition. Augustinavičiūtė usually used names like sensory logical introvert to refer to the type. In this example the first function is introverted sensing and the secondary is logic (which must be extroverted). Besides this, Augustinavičiūtė introduced the use of names of famous people as a moniker for each type. For example, she called the type of sensory logical introvert Gabin or sensory ethical introvert Dumas. Some later researchers believed that using names of famous people is not quite appropriate and used instead such names as Craftsman or Mediator. Such names were selected to describe the social role of each particular type as precisely as possible. In Russian, to keep the text brief, the types are labeled with three-letter acronyms, which are also used to specify the types in English, e.g., ILE, which stands for "intuitive logical extravert". However, some authors in socionics specify socionic types using MBTI abbreviations, given the similarities present in the two theories. In order to distinguish between socionics and MBTI types using this nomenclature, a tradition of leaving the last letter uncapitalized has been established among some groups.[citation needed] For example, an MBTI extroverted sensing feeling judging type is often referred to as an ESFJ, while a socionics ethical sensory extravert is referred to as an ESFj. The following tables provide a list of types with names most commonly used in socionics:[3] # Model A Aušra Augustinavičiūtė developed a model of personality called Model A, which includes all eight socionic functions.[4] A function's position in Model A reflects the nature of its usage by a particular type. The following diagram is an example of the positions of the functions as expressed in Model A. Note that, although often these functions are numbered 1 to 8, this does not mean that the functions are ordinal in strength, as is the case in MBTI. ## Nature of functions - Function 1 - leading, program, primary, base, or dominant function. This is the strongest conscious function, and the most utilized function of the psyche. A person's outlook and role in life is largely determined by the nature of this function. One is generally very confident in the use of this function, and may defend it when challenged. - Function 2 - creative or secondary function, is second in influence only to the dominant function. It assists the dominant function in achieving its goal. One may be somewhat less confident with the use of this function than with his dominant function. As a result, the creative function is sometimes less instrumental when a person is challenged or threatened. - Function 3 - role function, is a weak but conscious function. One generally tries to be at least adequate in areas where use of the role function is necessary. However, generally one has very little control or confidence over the role function, and criticism is painfully acknowledged with respect to it. Tactful assistance is required from one's dual-seeking function to overcome the problems associated with the role function. - Function 4 - place of least resistance or the painful function, is a weak and conscious function, in addition to being the weakest function of the psyche. One painfully perceives his complete inability to use this function, and reacts negatively to its imposition upon him. Tactful assistance is required from one's hidden agenda to overcome the problems associated with this function. - Function 5 - suggestive, or inspired function, is a weak and unconscious function which is largely lacked. One requires assistance from somebody confident in this function in order to overcome the difficulties it presents. - Function 6 - actualization, the hidden agenda or estimative function. This is a weak and unconscious function which one often understands poorly. Nonetheless, this function has a strong influence over one's activities, and one requires assistance from someone who uses it confidently in order to understand it. - Function 7 - observant function, the function of personal knowledge. This is a strong but unconscious function. One generally has a good grasp of this function, but attempts to limit its use considerably. Arguments calling for restraint are often used to overlook this function. - Function 8 - demonstrative function. This is the strongest of the unconscious functions. As a result, it is so deeply rooted into the psyche that one is usually not even aware of its existence or utilization. ## Blocks of the psyche According to Augustinavičiūtė, there are four blocks of the psyche: the ego block, the super-ego block, the id block, and the super-id block. The ego block contains the dominant and creative functions, the super-ego block contains the role and PoLR functions, the super-id block contains the dual-seeking function and the hidden agenda, while the id block contains the seventh and eighth functions. The functions within the ego and super-ego blocks are said to be conscious functions, while those within the id and super-id blocks are said to be unconscious. Similarly, the functions presiding within the ego and id blocks are said to be strong functions which are expressed easily or naturally, while the functions of the super-ego and super-id blocks are weak and expressed with difficulty or support, or are not expressed at all. ## The 16 types in Model A Template:Socionics table # Intertype Relations The field of Intertype Relations within Socionics attempts to describe the nature of relations between two different people based on their Socionics type. ## Identity Relations of Identity describe relations between two individuals of the same type. Often, both partners will perceive similar situations and problems, and will take similar actions. Partners usually understand the motivations behind the other's actions. A relationship between identity partners is characterized by mutual understanding, self-development, and learning. Each is interested in the other's ideas, and sees their value. ## Duality Duality is a fundamental concept in Socionics. Dual relations are characterized by mutual benefit and support. Duality occurs between two members of the same quadra who are both either rational or irrational. So duality partners share the same function blocks, but their dominance is reversed. In a sense, they are opposite sides of the same coin. The 8 duality pairs are as follows: - LII-ESE - ILE-SEI - LSI-EIE - SLE-IEI - ESI-LIE - SEE-ILI - EII-LSE - IEE-SLI In dual relations, the super-id functions of both partners are the ego functions of the other. As the super-id functions are generally the areas in which a person needs assistance from somebody skilled in these areas, duality interaction is quite rewarding and satisfying for both parties. ## Activity Activity relations occur between two members of the same quadra who share either introversion or extroversion. Relations of activity can resemble duality since the super-id functions are both present in the ego functions of the other partner. However, activity relations are somewhat less fulfilling than dual relations. Each partner's dominant function is the others Hidden Agenda function. Activity relations are better suited to friendly correspondence. ## Mirror Mirror relations occur between types who share the same ego functions, yet place different emphases on them; the dominant function of one partner is the creative function of the other. Mirror relations are characterized by similar actions and motivations between partners, and mutual understanding. Interactions usually result in a drawn out dialogue, as each partner seems to keep opening up avenues of thought which the other needs to now clarify verbally. An important source of dissension between mirror types is the opposing temperament, as all mirror relations occur between EJ and IP temperaments, or between EP and IJ temperaments. EJs find the passive, unstable IP behavior to be a severe hindrance in getting things done, while IPs find the restless and proactive actions of EJ types paranoid and stifling. Similarly, EP types find IJ types to be somewhat dull and boring, while IJ types see EP types as wildly unpredictable and impetuous. ## Comparative Comparative relations occur between types who share the same dominant function but possess different creative functions. Comparative partners often see each other as interesting people and are often able to see each other's motivations, but often tailor their actions towards areas in which the other partner is unskilled or uninterested, as the creative function for one partner is the place of least resistance of the other. ## Semi-duality Relations of semi-duality are similar to relations of duality. Semi-duality occurs between partners who share each other's dual-seeking (5th) functions but lack each other's actualization (hidden agenda) functions. As a result, both partners often perceive elements of duality from the relationship but feel the other partner is misplacing the correct emphasis; as semi-duals will be able to help their partners with their dual seeking functions but both have the least confidence in the same area of the psyche (thinking, feeling, sensing, or intuition). ## Look-a-like / Cooperation Look-a-like relations occur between partners who have the same creative function but differing dominant functions. As a result, look-a-like partners may often perform similar activities or have similar fields of interest, but often do not understand each other's internal motivations. Look-a-like relations for this reason can become very formal and business like. ## Illusionary Relations of Illusion occur between partners whose creative functions are the other partners' hidden agenda, but whose dual seeking functions are part of the id block of the other partner. Relations of illusion can resemble duality, but neither partner is particularly satisfied, as they receive no assistance in their dual-seeking functions from this relation. ## Benefit / Instruction / Order Relations of Benefit are asymmetrical relations; one type benefits another. Relations of benefit are characterized by the beneficiary's attempt to draw in the benefactor to a world where the benefactor clearly does not belong. The beneficiary's dual seeking function is the benefactor's creative function, and as a result the beneficiary often takes an interest in the benefactor. However, the benefactor's dual seeking function is the beneficiary's place of least resistance, and the benefactor finds the beneficiary a highly uninteresting person. Relations of benefit frequently end with the departure of the benefactor... often to the utter bewilderment of the beneficiary. ## Supervision Relations of supervision are asymmetrical; one type supervises another. Relations of supervision are characterized by the supervisor's attempt to introduce his base function into the supervisee's life. The supervisor often perceives the supervisee as an interesting person and understands the supervisee's lifestyle, since the supervisor's creative function is the supervisee's base function. Nonetheless, the supervisee is often on the defensive since the supervisor's base function is the supervisee's point of least resistance (the function most vulnerable to criticism). The supervisee often perceives the supervisor to be the evil incarnate, while the bewildered supervisor wonders why the supervisee reacts so poorly to his benevolent assistance. ## Contrary / Contrast Contrary relations occur between types confident in the same area of the psyche but who place different emphases on each function. For example, the relation between an EIE and an EII, who possess in the ego block extroverted feeling with introverted intuition and introverted feeling with extroverted intuition, respectively, is a contrary relation. Contrary relations often consist of similar lifestyles with lack of mutual understanding and differing thought processes. ## Super-ego Super-ego relations occur between types whose ego functions are the other partners' super-ego functions. Super-ego relations are generally characterized by open conflict, discomfort, differing values, and lack of true understanding of partners' motivations. ## Quasi-Identity Relations of Quasi-Identity are characterized by mutual misunderstanding. One partner's ego functions are the other partner's demonstrative and observant functions. As quasi-identicals have opposite functions, they will often have similar interests and become involved in similar activities, but they rarely understand each other's motivations or ideas. ## Conflict Relations of Conflict are, unsurprisingly, characterized by constantly escalating conflict. Conflictors are the types with the most dissimilar values, and they rarely understand anything regarding each other's motivations or lifestyles. Conflictors may take for granted truths that their partners will dismiss as absurd. Sometimes they understand each other so little that the conflict is not well understood, but prevails under the surface, discomfiting both partners to no end. Conflictors also are of opposite temperaments, a fact which both partners often find irritating. # Temperaments There are four temperaments in socionics; namely, the extroverted rational (EJ), introverted rational (IJ), extroverted irrational (EP), and introverted irrational (IP) temperaments. ## Extroverted Rational Temperament Extroverted rational types, namely the ESE, EIE, LIE, and LSE, are characterized by energetic and proactive behavior. ## Introverted Rational Temperament Introverted rational types, namely the LII, LSI, ESI, and EII, are characterized by slow and methodical behavior. ## Extroverted Irrational Temperament Extroverted irrational types, namely the ILE, SLE, SEE, and IEE, are characterized by impulsive and unpredictable behavior. ## Introverted Irrational Temperament Introverted irrational types, namely the SEI, IEI, ILI, and SLI, are characterized by lack of motivation, inertia, and unstable moods and energy levels. # Quadras A quadra is a group of four sociotypes in which mirror, activity, and dual relations are experienced by each member of the group. The unique feature of the quadra is that it offers the greatest degree of psychological comfort among all groups containing four types in which functional interaction is symmetrical. The feeling of comfort and harmony produced by the quadra is due to the fact that all types in the quadra are alike in that they seek to give expression to the shared set of information elements in their ego and super-id blocks and to de-emphasize the information elements in their super-ego and id blocks. # Cultural Influence of Socionics Socionics, having originated in Vilnius, has developed extensively[citation needed] in the former Soviet Union in the past 30 years. In the Russian-speaking world (primarily Russia and Ukraine, but also the Baltic States, Central Asia, and Russian communities abroad) socionics has grown significantly in popularity, and is now a topic of discussion among large numbers of amateurs, as well as a group of a few hundred professionals whose experience and discoveries in socionics are highly regarded.[citation needed] Clubs for socializing and/or theoretical discussion exist in many large cities across the former USSR.[5],[6] A couple journals exist, as well as a number of organizations which periodically hold conferences in Kiev, Moscow, St. Petersburg, and other cities.[7] In the West, however, socionics exists as little more than an internet phenomenon due to its novelty. (It was first introduced in English on the Internet in the mid 90s.[citation needed]) Although there do exist English discussion forums[8][9] where some significant[citation needed] discussion of the theoretical and practical aspects of socionics does occur, little understanding of Socionics has dispersed beyond them.[citation needed]	https://www.wikidoc.org/index.php/Socionics
1ee3c95c79156c696cfd1a6103da527246cdc036	wikidoc	Solvation	Solvation Solvation, commonly called dissolution, is the process of attraction and association of molecules of a solvent with molecules or ions of a solute. As ions dissolve in a solvent they spread out and become surrounded by solvent molecules. The bigger the ion, the more solvent molecules are able to surround it and the more it becomes solvated. # Distinction between solvation, dissolution and solubility By an IUPAC definition, solvation is an interaction of a solute with the solvent which leads to stabilization of the solute species in the solution. One may also refer to the solvated state, whereby an ion in a solution is complexed by solvent molecules. The concept of the solvation interaction can also be applied to an insoluble material, for example, solvation of functional groups on a surface of ion-exchange resin. Solvation should be conceptually separated from dissolution and solubility. Dissolution is a kinetic process and it is quantified by its rate. Solubility quantifies the dynamic equilibrium state achieved when the rate of dissolution equals the rate of precipitation. The consideration of the units makes the distinction clearer. Complexation can be described by coordination number and the complex stability constants. The typical unit for dissolution rate is mol/s. The unit for solubility can be mol/kg. # Solvents and intermolecular interactions Solvents that are Polar are ones with a molecular structure that contains polar bonds. Such compounds are often found to have a high dielectric constant. Examples of polar solvents include water and acetonitrile. These polar molecules can solvate ions because they can orient the appropriate partially charged portion of the molecule towards the ion in response to electrostatic attraction. This stabilizes the system. Water represents the most common and well-studied polar solvent, but others exist, such as acetonitrile, dimethyl sulfoxide, methanol, propylene carbonate, ammonia, ethanol, and acetone, among others. These solvents can be used to dissolve inorganic compounds such as salts. Solvation involves different types of intermolecular interactions: hydrogen bonding, ion-dipole and dipole-dipole attractions or van der Waals forces. The hydrogen bonding, ion-dipole, and dipole-dipole interactions occur only in polar solvents. Ion-ion interactions occur only in ionic solvents. The solvation process will only be thermodynamically favored if the overall Gibbs energy of the solution is decreased compared to the Gibbs energy of the separated solvent and solid (or gas or liquid). This means that the change in enthalpy minus the change in entropy (multiplied by the absolute temperature) is a negative value, or that the Gibbs free energy of the system decreases. # Thermodynamic considerations For solvation to occur, energy is required to release individual ions from the crystal lattices in which they are present. This is necessary to break the attractions the ions have with each other and is equal to the solid's lattice free energy (the energy released at the formation of the lattice as the ions bonded with each other). The energy for this comes from the energy released when ions of the lattice associate with molecules of the solvent. Energy released in this form is called the free energy of solvation. The enthalpy of solution is the solution enthalpy minus the enthalpy of the separate systems, while the entropy is the corresponding difference in entropy. Most gases have a negative enthalpy of solution. A negative enthalpy of solution means that the solute is less soluble at high temperatures. Although early thinking was that a higher ratio of a cation's ion charge to the size, or the charge density, resulted in more solvation, this does not stand up to scrutiny for ions like Iron(III) or lanthanides and actinides, which are readily hydrolyzed to form insoluble (hydrous)oxides. As solids, these are obviously not solvated. Enthalpy of solvation can help explain why solvation occurs with some ionic lattices but not with others. The difference in energy between that which is necessary to release an ion from its lattice and the energy given off when it combines with a solvent molecule is called the enthalpy change of solution. A negative value for the enthalpy change of solution corresponds to an ion that is likely to dissolve, whereas a high positive value means that solvation will not occur. It is possible that an ion will dissolve even if it has a positive enthalpy value. The extra energy required comes from the increase in entropy that results when the ion dissolves. The introduction of entropy makes it harder to determine by calculation alone whether a substance will dissolve or not. A quantitative measure for solvation power of solvents is given by donor numbers. Note that solvation does not mean a reaction takes place. Adding NaCl(s) to water, for example, will only create a solution of sodium and chloride ions; you would only have solvation of the salt's ions. Adding the weak base ammonia to water, on the other hand, would be a reaction.	Solvation Solvation, commonly called dissolution, is the process of attraction and association of molecules of a solvent with molecules or ions of a solute. As ions dissolve in a solvent they spread out and become surrounded by solvent molecules. The bigger the ion, the more solvent molecules are able to surround it and the more it becomes solvated. # Distinction between solvation, dissolution and solubility By an IUPAC definition[1], solvation is an interaction of a solute with the solvent which leads to stabilization of the solute species in the solution. One may also refer to the solvated state, whereby an ion in a solution is complexed by solvent molecules. The concept of the solvation interaction can also be applied to an insoluble material, for example, solvation of functional groups on a surface of ion-exchange resin. Solvation should be conceptually separated from dissolution and solubility. Dissolution is a kinetic process and it is quantified by its rate. Solubility quantifies the dynamic equilibrium state achieved when the rate of dissolution equals the rate of precipitation. The consideration of the units makes the distinction clearer. Complexation can be described by coordination number and the complex stability constants. The typical unit for dissolution rate is mol/s. The unit for solubility can be mol/kg. # Solvents and intermolecular interactions Solvents that are Polar are ones with a molecular structure that contains polar bonds. Such compounds are often found to have a high dielectric constant. Examples of polar solvents include water and acetonitrile. These polar molecules can solvate ions because they can orient the appropriate partially charged portion of the molecule towards the ion in response to electrostatic attraction. This stabilizes the system. Water represents the most common and well-studied polar solvent, but others exist, such as acetonitrile, dimethyl sulfoxide, methanol, propylene carbonate, ammonia, ethanol, and acetone, among others. These solvents can be used to dissolve inorganic compounds such as salts. Solvation involves different types of intermolecular interactions: hydrogen bonding, ion-dipole and dipole-dipole attractions or van der Waals forces. The hydrogen bonding, ion-dipole, and dipole-dipole interactions occur only in polar solvents. Ion-ion interactions occur only in ionic solvents. The solvation process will only be thermodynamically favored if the overall Gibbs energy of the solution is decreased compared to the Gibbs energy of the separated solvent and solid (or gas or liquid). This means that the change in enthalpy minus the change in entropy (multiplied by the absolute temperature) is a negative value, or that the Gibbs free energy of the system decreases. # Thermodynamic considerations For solvation to occur, energy is required to release individual ions from the crystal lattices in which they are present. This is necessary to break the attractions the ions have with each other and is equal to the solid's lattice free energy (the energy released at the formation of the lattice as the ions bonded with each other). The energy for this comes from the energy released when ions of the lattice associate with molecules of the solvent. Energy released in this form is called the free energy of solvation. The enthalpy of solution is the solution enthalpy minus the enthalpy of the separate systems, while the entropy is the corresponding difference in entropy. Most gases have a negative enthalpy of solution. A negative enthalpy of solution means that the solute is less soluble at high temperatures. Although early thinking was that a higher ratio of a cation's ion charge to the size, or the charge density, resulted in more solvation, this does not stand up to scrutiny for ions like Iron(III) or lanthanides and actinides, which are readily hydrolyzed to form insoluble (hydrous)oxides. As solids, these are obviously not solvated. Enthalpy of solvation can help explain why solvation occurs with some ionic lattices but not with others. The difference in energy between that which is necessary to release an ion from its lattice and the energy given off when it combines with a solvent molecule is called the enthalpy change of solution. A negative value for the enthalpy change of solution corresponds to an ion that is likely to dissolve, whereas a high positive value means that solvation will not occur. It is possible that an ion will dissolve even if it has a positive enthalpy value. The extra energy required comes from the increase in entropy that results when the ion dissolves. The introduction of entropy makes it harder to determine by calculation alone whether a substance will dissolve or not. A quantitative measure for solvation power of solvents is given by donor numbers. Note that solvation does not mean a reaction takes place. Adding NaCl(s) to water, for example, will only create a solution of sodium and chloride ions; you would only have solvation of the salt's ions. Adding the weak base ammonia to water, on the other hand, would be a reaction.	https://www.wikidoc.org/index.php/Solvate
be06474c8b829e47e6b672e72521c4bd6ebbcb78	wikidoc	Sonidegib	Sonidegib # 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 Sonidegib is a hedgehog pathway inhibitor that is FDA approved for the treatment of adult patients with locally advanced basal cell carcinoma (BCC) that has recurred following surgery or radiation therapy, or those who are not candidates for surgery or radiation therapy. There is a Black Box Warning for this drug as shown here. Common adverse reactions include muscle spasms, alopecia, dysgeusia, fatigue, nausea, musculoskeletal pain, diarrhea, decreased weight, decreased appetite, myalgia, abdominal pain, headache, pain, vomiting, and pruritus (≥10%). # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Sonidegib is indicated for the treatment of adult patients with locally advanced basal cell carcinoma (BCC) that has recurred following surgery or radiation therapy, or those who are not candidates for surgery or radiation therapy. The recommended dose of Sonidegib is 200 mg taken orally once daily on an empty stomach, at least 1 hour before or 2 hours after a meal, administered until disease progression or unacceptable toxicity. Verify the pregnancy status of females of reproductive potential prior to initiating Sonidegib. Obtain serum creatine kinase (CK) levels and renal function tests prior to initiating Sonidegib in all patients. If a dose of Sonidegib is missed, resume dosing with the next scheduled dose. - Dose Modifications Interrupt Sonidegib for: - Severe or intolerable musculoskeletal adverse reactions. - First occurrence of serum CK elevation between 2.5 and 10 times upper limit of normal (ULN). - Recurrent serum CK elevation between 2.5 and 5 times ULN. Resume Sonidegib at 200 mg daily upon resolution of clinical signs and symptoms. Permanently discontinue Sonidegib for: - Serum CK elevation greater than 2.5 times ULN with worsening renal function. - Serum CK elevation greater than 10 times ULN. - Recurrent serum CK elevation greater than 5 times ULN. - Recurrent severe or intolerable musculoskeletal adverse reactions. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Pimavanserin in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Pimavanserin in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) The safety and effectiveness of Sonidegib 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 Pimavanserin in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Pimavanserin in pediatric patients. # Contraindications None # Warnings Sonidegib can cause embryo-fetal death or severe birth defects when administered to a pregnant woman. In animal reproduction studies, Sonidegib was embryotoxic, fetotoxic, and teratogenic at maternal exposures below the recommended human dose of 200 mg. Advise pregnant women of the potential risk to a fetus. - Females of Reproductive Potential Verify pregnancy status of females of reproductive potential prior to initiating Sonidegib treatment. Advise females to use effective contraception during treatment with Sonidegib and for at least 20 months after the last dose. - Males Advise male patients with female partners to use condoms, even after a vasectomy, during treatment with Sonidegib and for at least 8 months after the last dose to avoid potential drug exposure in pregnant females or females of reproductive potential. - Blood Donation Advise patients not to donate blood or blood products while taking Sonidegib and for at least 20 months after the last dose of Sonidegib because their blood or blood products might be given to a female of reproductive potential. Musculoskeletal adverse reactions, which may be accompanied by serum creatine kinase (CK) elevations, occur with Sonidegib and other drugs which inhibit the hedgehog pathway. In a pooled safety analysis of 12 clinical studies involving 571 patients with various advanced cancers treated with Sonidegib at doses ranging from 100 mg to 3000 mg, rhabdomyolysis (defined as serum CK increase of more than ten times the baseline value with a concurrent 1.5-fold or greater increase in serum creatinine above baseline value) occurred in one patient (0.2%) treated with Sonidegib 800 mg. In Study 1, musculoskeletal adverse reactions occurred in 68% (54/79) of patients treated with Sonidegib 200 mg daily with 9% (7/79) reported as Grade 3 or 4. The most frequent manifestations of musculoskeletal adverse reactions reported as an adverse event were muscle spasms (54%), musculoskeletal pain (32%), and myalgia (19%). Increased serum CK laboratory values occurred in 61% (48/79) of patients with 8% (6/79) of patients having Grade 3 or 4 serum CK elevations. Musculoskeletal pain and myalgia usually preceded serum CK elevation. Among patients with Grade 2 or higher CK elevations, the median time to onset was 12.9 weeks (range: 2 to 39 weeks) and the median time to resolution (to ≤ Grade 1) was 12 days (95% CI: 8 to 14 days). Sonidegib was temporarily interrupted in 8% of patients or permanently discontinued in 8% of patients for musculoskeletal adverse reactions. The incidence of musculoskeletal adverse reactions requiring medical intervention (magnesium supplementation, muscle relaxants, and analgesics or narcotics) was 29%, including four patients (5%) who received intravenous hydration or were hospitalized. Obtain baseline serum CK and creatinine levels prior to initiating Sonidegib, periodically during treatment, and as clinically indicated (e.g., if muscle symptoms are reported). Obtain serum creatinine and CK levels at least weekly in patients with musculoskeletal adverse reactions with concurrent serum CK elevation greater than 2.5 times ULN until resolution of clinical signs and symptoms. Depending on the severity of symptoms, temporary dose interruption or discontinuation may be required for musculoskeletal adverse reactions or serum CK elevation. Advise patients starting therapy with Sonidegib of the risk of muscle-related adverse reactions. Advise patients to report promptly any new unexplained muscle pain, tenderness or weakness occurring during treatment or that persists after discontinuing Sonidegib. # 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 Sonidegib was evaluated in Study 1, a randomized, double-blind, multiple cohort trial in which 229 patients received Sonidegib at either 200 mg (n=79) or 800 mg (n=150) daily. The frequency of common adverse reactions including muscle spasms, alopecia, dysgeusia, fatigue, nausea, decreased weight, decreased appetite, myalgia, pain, and vomiting was greater in patients treated with Sonidegib 800 mg as compared to 200 mg. The data described below reflect exposure to Sonidegib 200 mg daily in 79 patients with locally advanced BCC (laBCC; n=66) or metastatic BCC (mBCC; n=13) enrolled in Study 1. Patients were followed for at least 18 months unless discontinued earlier. The median duration of treatment with Sonidegib was 11.0 months (range 1.3 to 33.5 months). The study population characteristics were: median age of 67 years (range 25 to 92; 59% were ≥65 years), 61% male, and 90% white. The majority of patients had prior surgery (75%), radiotherapy (24%), systemic chemotherapy (4%), or topical or photodynamic therapies (18%) for treatment of BCC. No patient had prior exposure to a hedgehog pathway inhibitor. Sonidegib was permanently discontinued in 34% of patients or temporarily interrupted in 20% of patients for adverse reactions. Adverse reactions reported in at least two patients that led to discontinuation of the drug were: muscle spasms and dysgeusia (each 5%), asthenia, increased lipase, and nausea (each 4%), fatigue, decreased appetite, alopecia, and decreased weight (each 3%). Serious adverse reactions occurred in 18% of patients. The most common adverse reactions occurring in ≥10% of patients treated with Sonidegib 200 mg were muscle spasms, alopecia, dysgeusia, fatigue, nausea, musculoskeletal pain, diarrhea, decreased weight, decreased appetite, myalgia, abdominal pain, headache, pain, vomiting, and pruritus (Table 1). The key laboratory abnormalities are described in Table 2. - Table 1: Adverse Reactions Occurring in ≥10% of Patients in Study 1 ODOMZO: Sonidegib's Brand name - Table 2: Key Laboratory Abnormalities(a) ODOMZO: Sonidegib's Brand name - Amenorrhea Amenorrhea lasting for at least 18 months occurred in two of 14 pre-menopausal women treated with Sonidegib 200 mg or 800 mg once daily. ## Postmarketing Experience There is limited information regarding Sonidegib Postmarketing Experience in the drug label. # Drug Interactions - Strong and Moderate CYP3A Inhibitors Avoid concomitant administration of Sonidegib with strong CYP3A inhibitors, including but not limited to saquinavir, telithromycin, ketoconazole, itraconazole, voriconazole, posaconazole and nefazodone. Avoid concomitant administration of Sonidegib with moderate CYP3A inhibitors, including but not limited to atazanavir, diltiazem, and fluconazole. If a moderate CYP3A inhibitor must be used, administer the moderate CYP3A inhibitor for less than 14 days and monitor closely for adverse reactions particularly musculoskeletal adverse reactions. - Strong and Moderate CYP3A Inducers Avoid concomitant administration of Sonidegib with strong and moderate CYP3A inducers, including but not limited to carbamazepine, efavirenz, modafinil, phenobarbital, phenytoin, rifabutin, rifampin and St. John’s Wort (Hypericum perforatum). # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): N - Risk Summary Based on its mechanism of action and data from animal reproduction studies, Sonidegib can cause fetal harm when administered to a pregnant woman. There are no available data on the use of Sonidegib in pregnant women. In animal reproduction studies, oral administration of Sonidegib during organogenesis at doses below the recommended human dose of 200 mg resulted in embryotoxicity, fetotoxicity, and teratogenicity in rabbits. Teratogenic effects observed included severe midline defects, missing digits, and other irreversible malformations. Advise pregnant women of the potential risk to a fetus. Report pregnancies to Novartis Pharmaceuticals Corporation at 1-888-669-6682. The background risk of major birth defects and miscarriage for the indicated population is unknown; however, the background risk in the U.S. general population of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies. - Data - Animal Data Daily oral administration of Sonidegib to pregnant rabbits resulted in abortion, complete resorption of fetuses, or severe malformations at ≥ 5 mg/kg/day (approximately 0.05 times the recommended human dose based on AUC). Teratogenic effects included vertebral, distal limb and digit malformations, severe craniofacial malformations, and other severe midline defects. Skeletal variations were observed when maternal exposure to Sonidegib was below the limit of detection. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Sonidegib in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Sonidegib during labor and delivery. ### Nursing Mothers No data are available regarding the presence of Sonidegib in human milk, the effects of the drug on the breast fed infant, or the effects of the drug on milk production. Because of the potential for serious adverse reactions in breastfed infants from Sonidegib, advise a nursing woman not to breastfeed during treatment with Sonidegib and for 20 months after the last dose. ### Pediatric Use The safety and effectiveness of Sonidegib have not been established in pediatric patients. - Juvenile Animal Data In a 5-week juvenile rat toxicology study, effects of Sonidegib were observed in bone, teeth, reproductive tissues, and nerves at doses ≥10 mg/kg/day (approximately 1.2 times the recommended human dose based on AUC). Bone findings included thinning/closure of bone growth plate, decreased bone length and width, and hyperostosis. Findings in teeth included missing or fractured teeth, and atrophy. Reproductive tissue toxicity was evidenced by atrophy of testes, ovaries, and uterus, partial development of the prostate gland and seminal vesicles, and inflammation and aspermia of the epididymis. Nerve degeneration was also noted. ### Geriatic Use Of the 229 patients who received Sonidegib (79 patients receiving 200 mg daily and 150 patients receiving 800 mg daily) in Study 1, 54% were 65 years and older, while 28% were 75 years and older. No overall differences in effectiveness were observed between these patients and younger patients. There was a higher incidence of serious adverse events, Grade 3 and 4 adverse events, and adverse events requiring dose interruption or discontinuation in patients ≥65 years compared with younger patients; this was not attributable to an increase in any specific adverse event. ### Gender There is no FDA guidance on the use of Sonidegib with respect to specific gender populations. ### Race There is no FDA guidance on the use of Sonidegib with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Sonidegib in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Sonidegib in patients with hepatic impairment. ### Females of Reproductive Potential and Males Based on its mechanism of action and animal data, Sonidegib can cause fetal harm when administered to a pregnant woman. - Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating Sonidegib treatment. - Contraception - Females Advise females of reproductive potential to use effective contraception during treatment with Sonidegib and for at least 20 months after the last dose. - Males It is not known if Sonidegib is present in semen. Advise male patients to use condoms, even after a vasectomy, to avoid potential drug exposure to pregnant partners and female partners of reproductive potential during treatment with Sonidegib and for at least 8 months after the last dose. Advise males not to donate semen during treatment with Sonidegib and for at least 8 months after the last dose. - Infertility Based on findings from animal studies, female fertility may be compromised with Sonidegib. ### Immunocompromised Patients There is no FDA guidance one the use of Sonidegib in patients who are immunocompromised. # Administration and Monitoring ### Administration The recommended dose of Sonidegib is 200 mg taken orally once daily on an empty stomach, at least 1 hour before or 2 hours after a meal, administered until disease progression or unacceptable toxicity. ### Monitoring There is limited information regarding Sonidegib Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Sonidegib and IV administrations. # Overdosage There are no recommendations regarding management of overdosage. # Pharmacology ## Mechanism of Action Sonidegib is an inhibitor of the Hedgehog pathway. Sonidegib binds to and inhibits Smoothened, a transmembrane protein involved in Hedgehog signal transduction. ## Structure There is limited information regarding Sonidegib Structure in the drug label. ## Pharmacodynamics There is limited information regarding Sonidegib Pharmacodynamics in the drug label. ## Pharmacokinetics Absorption Less than 10% of an oral dose of Sonidegib is absorbed. Following the administration of a single Sonidegib dose (100 mg to 3000 mg) under fasted conditions in patients with cancer, the median time-to-peak concentration (Tmax) was 2 to 4 hours. Sonidegib exhibited dose-proportional increases in the area under the curve (AUC) and the maximal concentration (Cmax) over the dose range of 100 mg to 400 mg, but less than dose-proportional increases at doses greater than 400 mg. Steady-state was reached approximately 4 months after starting Sonidegib and the estimated accumulation at steady-state was 19-fold. Following a dose of 200 mg once daily, the estimated mean steady-state Cmax is 1030 ng/mL, AUC(0-24h) is 22 μg*h/mL and minimal concentration (Cmin) is 890 ng/mL. A high-fat meal (approximately 1000 calories with 50% of calories from fat) increased exposure to Sonidegib (geometric mean AUC(inf) and Cmax) by 7.4- to 7.8-fold. Distribution The estimated apparent steady-state volume of distribution (Vss/F) was 9,166 L. Sonidegib was greater than 97% bound to human plasma proteins in vitro and the binding was concentration independent. In vitro studies suggested that sonidegib is not a substrate of P-glycoprotein, MRP2 or BCRP. Elimination The elimination half-life (t1/2) of Sonidegib estimated from population pharmacokinetic (PK) modeling was approximately 28 days. - Metabolism Sonidegib is primarily metabolized by CYP3A. The main circulating compound was unchanged sonidegib (36% of circulating radioactivity). - Excretion Sonidegib and its metabolites are eliminated primarily by the hepatic route. Of the absorbed dose, approximately 70% was eliminated in the feces and 30% was eliminated in the urine. Unchanged Sonidegib was not detectable in the urine. Specific Populations - Hepatic Impairment Mild (Child-Pugh class A), moderate (Child-Pugh class B), or severe (Child-Pugh class C) hepatic impairment had no clinically meaningful effect on Sonidegib exposure as compared to subjects with normal hepatic function. - Renal Impairment Mild (CLcr 60 to 89 mL/min) and moderate (CLcr 30 to 59 mL/min) renal impairment had no effect on Sonidegib steady-state exposure as compared to patients with normal renal function (CLcr ≥90 mL/min). - Age, Sex, Weight and Race Age, body weight, or sex had no clinically meaningful effect on Sonidegib steady-state exposure. A cross study comparison suggests that geometric mean AUCinf of Sonidegib is 1.7-fold higher in Japanese healthy subjects compared to Western healthy subjects (Whites and Blacks) following a single 200 mg dose of Sonidegib. Drug Interaction Studies - Effects of CYP3A Inhibitors on Sonidegib Strong CYP3A inhibitor: The geometric mean Sonidegib AUC(0-10d) increased by 2.2-fold and the Cmax increased by 1.5-fold when Sonidegib at a dose of 800 mg was taken with ketoconazole compared to Sonidegib alone. The geometric mean sonidegib steady-state AUC(0-24h) would similarly increase in cancer patients taking Sonidegib 200 mg once daily when coadministered with a strong CYP3A inhibitor for 14 days. Moderate CYP3A inhibitor: The geometric mean sonidegib steady-state AUC(0-24h) would increase 1.8-fold when Sonidegib 200 mg once daily is coadministered with a moderate CYP3A inhibitor (erythromycin) for 14 days and would increase 2.8-fold when Sonidegib 200 mg once daily is coadministered with a moderate CYP3A inhibitor (erythromycin) for 4 months. - Effects of CYP3A Inducers on Sonidegib Strong CYP3A inducer: The geometric mean Sonidegib AUC(0-10d) decreased by 72% and the Cmax decreased by 54% when Sonidegib at a dose of 800 mg was taken with rifampicin compared to Sonidegib alone. Moderate CYP3A inducer: The geometric mean Sonidegib steady-state AUC(0-24h) would decrease 56% in cancer patients taking Sonidegib 200 mg once daily when coadministered with a moderate CYP3A inducer (efavirenz) for 14 days and would decrease 69% when coadministered with a moderate CYP3A inducer (efavirenz) for 4 months. - Effect of Sonidegib on Cytochrome P450 Enzymes and Transporters In vitro studies suggested that Sonidegib inhibits CYP2B6 and CYP2C9 and it does not induce CYP1A2, CYP2B6 or CYP3A expression or activity. In vitro studies suggested that Sonidegib inhibits BCRP, but not P-glycoprotein, MRP2, OATP1B1, OATP1B3, OAT1, OAT3, OCT1 or OCT2. - Effect of Acid Reducing Agents on Sonidegib No clinically meaningful effect on Sonidegib exposure was observed when Sonidegib at dose of 200 mg was coadministered with esomeprazole, a proton pump inhibitor. ## Nonclinical Toxicology Carcinogenicity studies with Sonidegib have not been performed. Sonidegib was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay and was not clastogenic or aneugenic in the in vitro human chromosome aberration assay or in vivo rat bone marrow micronucleus assay. Sonidegib resulted in a lack of fertility when administered to female rats at ≥20 mg/kg/day (approximately 1.3 times the recommended human dose based on body surface area (BSA). A reduction of the number of pregnant females, an increase in the number of early resorptions, and a decrease in the number of viable fetuses was also noted at 2 mg/kg/day (approximately 0.12 times the recommended human dose based on BSA). In addition, in a 6 month repeat-dose toxicology study in rats, effects on female reproductive organs included atrophy of the uterus and ovaries at doses of 10 mg/kg (approximately ≥2 times the exposure in humans at the recommended dose of 200 mg based on AUC). No adverse effects on fertility were noted when male rats were administered Sonidegib at doses up to 20 mg/kg/day, the highest dose tested. Body tremors along with significant increases in creatine kinase were observed in rats administered oral Sonidegib for 13 weeks or longer at ≥10 mg/kg/day (approximately ≥2 times the recommended human dose based on AUC). # Clinical Studies The safety and effectiveness of Sonidegib were evaluated in a single, multicenter, double-blind, multiple cohort clinical trial conducted in patients with locally advanced basal cell carcinoma (laBCC) (n=194) or metastatic basal cell carcinoma (mBCC) (n=36) (Study 1). Patients were randomized (2:1) to receive either Sonidegib 800 mg or 200 mg orally, once daily, until disease progression or intolerable toxicity. Randomization was stratified by stage of disease (locally advanced or metastatic), laBCC disease histology (aggressive vs. non-aggressive), and geographic region. Patients with laBCC were required to have lesions for which radiotherapy was contraindicated or inappropriate (e.g., Gorlin syndrome or limitations because of location of tumor), that had recurred after radiotherapy, that were unresectable or for which surgical resection would result in substantial deformity, or that had recurred after prior surgical resection. The major efficacy outcome measure of the trial was objective response rate (ORR) as determined by blinded central review according to modified Response Evaluation Criteria in Solid Tumors (mRECIST) for patients with laBCC or RECIST version 1.1 for patients with mBCC. Duration of response (DoR), determined by blinded central review, was a key secondary outcome measure. For patients with laBCC, the evaluation of tumor response was based on a composite assessment that integrated tumor measurements obtained by radiographic assessments of target lesions (per RECIST 1.1), digital clinical photography, and histopathology assessments (via punch biopsies). All modalities used must have demonstrated absence of tumor to achieve a composite assessment of complete response (CR). Response by digital clinical photography was evaluated by World Health Organization (WHO) adapted criteria . Multiple punch biopsies of target lesions were performed to confirm a CR or when a response assessment was confounded by presence of lesion ulceration, cyst, and or scarring/fibrosis. A total of 66 patients randomized to Sonidegib 200 mg daily had laBCC. Three of these patients had a diagnosis of Gorlin Syndrome. The demographic characteristics of the 66 patients with laBCC were: median age of 67 years (range: 25 to 92 years; 58% were ≥65 years); 58% male, 89% white, and ECOG performance status of 0 (67%). Seventy-six percent of patients had prior therapy for treatment of BCC; this included surgery (73%), radiotherapy (18%), and topical/photodynamic therapies (21%). Approximately half of these patients (56%) had aggressive histology. Patients with laBCC randomized to receive Sonidegib 200 mg daily were followed for at least 12 months unless discontinued earlier. The ORR was 58% (95% confidence interval: 45, 70), consisting of 3 (5%) complete responses and 35 (53%) partial responses. A pre-specified sensitivity analysis using an alternative definition for complete response, defined as at least a PR according to MRI and/or photography and no evidence of tumor on biopsy of the residual lesion, yielded a CR rate of 20%. Among the 38 patients with an objective response, 7 (18%) patients experienced subsequent disease progression with 4 of these 7 patients having maintained a response of 6 months or longer. The remaining 31 patients (82%) have ongoing responses ranging from to 1.9+ to 18.6+ months and the median duration of response has not been reached. A total of 128 patients randomized to Sonidegib 800 mg daily had laBCC. Twelve of these patients had a diagnosis of Gorlin Syndrome. There was no evidence of better antitumor activity (ORR) among patients with laBCC randomized to receive Sonidegib 800 mg daily and followed for at least 12 months unless discontinued earlier. # How Supplied Each Sonidegib capsule has an opaque pink color with ‘SONIDEGIB 200MG’ printed on the capsule body and ‘NVR’ printed on the cap in black ink. Sonidegib capsules are supplied as follows: Bottle of 30 capsules (NDC 0078-0645-15) ## Storage Store at 25°C (77°F); excursions permitted to 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. Embryo-Fetal Toxicity - Advise female patients of the potential risk to a fetus. - Advise females of reproductive potential to use effective contraception during treatment with Sonidegib and for at least 20 months after the last dose. - Advise males, even those with prior vasectomy, to use condoms, to avoid potential drug exposure in both pregnant partners and female partners of reproductive potential during treatment with Sonidegib and for at least 8 months after the last dose. - Advise female patients and female partners of male patients to contact their healthcare provider with a known or suspected pregnancy. - Advise females who may have been exposed to Sonidegib during pregnancy, either directly or through seminal fluid, to contact the Novartis Pharmaceuticals Corporation at 1-888-669-6682. Blood Donation Advise patients not to donate blood or blood products while taking Sonidegib and for 20 months after stopping treatment. Musculoskeletal Adverse Reactions Advise patients to contact their healthcare provider immediately for new or worsening signs or symptoms of muscle toxicity, dark urine, decreased urine output, or the inability to urinate. Administration Instructions Advise patients to take Sonidegib on an empty stomach, at least 1 hour before or 2 hours after a meal. Lactation Advise women not to breastfeed during treatment with Sonidegib and for up to 20 months after the last dose. # Precautions with Alcohol Alcohol-Sonidegib interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names ODOMZO® # Look-Alike Drug Names There is limited information regarding Sonidegib Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Sonidegib 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 Sonidegib is a hedgehog pathway inhibitor that is FDA approved for the treatment of adult patients with locally advanced basal cell carcinoma (BCC) that has recurred following surgery or radiation therapy, or those who are not candidates for surgery or radiation therapy. There is a Black Box Warning for this drug as shown here. Common adverse reactions include muscle spasms, alopecia, dysgeusia, fatigue, nausea, musculoskeletal pain, diarrhea, decreased weight, decreased appetite, myalgia, abdominal pain, headache, pain, vomiting, and pruritus (≥10%). # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Sonidegib is indicated for the treatment of adult patients with locally advanced basal cell carcinoma (BCC) that has recurred following surgery or radiation therapy, or those who are not candidates for surgery or radiation therapy. The recommended dose of Sonidegib is 200 mg taken orally once daily on an empty stomach, at least 1 hour before or 2 hours after a meal, administered until disease progression or unacceptable toxicity. Verify the pregnancy status of females of reproductive potential prior to initiating Sonidegib. Obtain serum creatine kinase (CK) levels and renal function tests prior to initiating Sonidegib in all patients. If a dose of Sonidegib is missed, resume dosing with the next scheduled dose. - Dose Modifications Interrupt Sonidegib for: - Severe or intolerable musculoskeletal adverse reactions. - First occurrence of serum CK elevation between 2.5 and 10 times upper limit of normal (ULN). - Recurrent serum CK elevation between 2.5 and 5 times ULN. Resume Sonidegib at 200 mg daily upon resolution of clinical signs and symptoms. Permanently discontinue Sonidegib for: - Serum CK elevation greater than 2.5 times ULN with worsening renal function. - Serum CK elevation greater than 10 times ULN. - Recurrent serum CK elevation greater than 5 times ULN. - Recurrent severe or intolerable musculoskeletal adverse reactions. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Pimavanserin in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Pimavanserin in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) The safety and effectiveness of Sonidegib 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 Pimavanserin in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Pimavanserin in pediatric patients. # Contraindications None # Warnings Sonidegib can cause embryo-fetal death or severe birth defects when administered to a pregnant woman. In animal reproduction studies, Sonidegib was embryotoxic, fetotoxic, and teratogenic at maternal exposures below the recommended human dose of 200 mg. Advise pregnant women of the potential risk to a fetus. - Females of Reproductive Potential Verify pregnancy status of females of reproductive potential prior to initiating Sonidegib treatment. Advise females to use effective contraception during treatment with Sonidegib and for at least 20 months after the last dose. - Males Advise male patients with female partners to use condoms, even after a vasectomy, during treatment with Sonidegib and for at least 8 months after the last dose to avoid potential drug exposure in pregnant females or females of reproductive potential. - Blood Donation Advise patients not to donate blood or blood products while taking Sonidegib and for at least 20 months after the last dose of Sonidegib because their blood or blood products might be given to a female of reproductive potential. Musculoskeletal adverse reactions, which may be accompanied by serum creatine kinase (CK) elevations, occur with Sonidegib and other drugs which inhibit the hedgehog pathway. In a pooled safety analysis of 12 clinical studies involving 571 patients with various advanced cancers treated with Sonidegib at doses ranging from 100 mg to 3000 mg, rhabdomyolysis (defined as serum CK increase of more than ten times the baseline value with a concurrent 1.5-fold or greater increase in serum creatinine above baseline value) occurred in one patient (0.2%) treated with Sonidegib 800 mg. In Study 1, musculoskeletal adverse reactions occurred in 68% (54/79) of patients treated with Sonidegib 200 mg daily with 9% (7/79) reported as Grade 3 or 4. The most frequent manifestations of musculoskeletal adverse reactions reported as an adverse event were muscle spasms (54%), musculoskeletal pain (32%), and myalgia (19%). Increased serum CK laboratory values occurred in 61% (48/79) of patients with 8% (6/79) of patients having Grade 3 or 4 serum CK elevations. Musculoskeletal pain and myalgia usually preceded serum CK elevation. Among patients with Grade 2 or higher CK elevations, the median time to onset was 12.9 weeks (range: 2 to 39 weeks) and the median time to resolution (to ≤ Grade 1) was 12 days (95% CI: 8 to 14 days). Sonidegib was temporarily interrupted in 8% of patients or permanently discontinued in 8% of patients for musculoskeletal adverse reactions. The incidence of musculoskeletal adverse reactions requiring medical intervention (magnesium supplementation, muscle relaxants, and analgesics or narcotics) was 29%, including four patients (5%) who received intravenous hydration or were hospitalized. Obtain baseline serum CK and creatinine levels prior to initiating Sonidegib, periodically during treatment, and as clinically indicated (e.g., if muscle symptoms are reported). Obtain serum creatinine and CK levels at least weekly in patients with musculoskeletal adverse reactions with concurrent serum CK elevation greater than 2.5 times ULN until resolution of clinical signs and symptoms. Depending on the severity of symptoms, temporary dose interruption or discontinuation may be required for musculoskeletal adverse reactions or serum CK elevation. Advise patients starting therapy with Sonidegib of the risk of muscle-related adverse reactions. Advise patients to report promptly any new unexplained muscle pain, tenderness or weakness occurring during treatment or that persists after discontinuing Sonidegib. # 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 Sonidegib was evaluated in Study 1, a randomized, double-blind, multiple cohort trial in which 229 patients received Sonidegib at either 200 mg (n=79) or 800 mg (n=150) daily. The frequency of common adverse reactions including muscle spasms, alopecia, dysgeusia, fatigue, nausea, decreased weight, decreased appetite, myalgia, pain, and vomiting was greater in patients treated with Sonidegib 800 mg as compared to 200 mg. The data described below reflect exposure to Sonidegib 200 mg daily in 79 patients with locally advanced BCC (laBCC; n=66) or metastatic BCC (mBCC; n=13) enrolled in Study 1. Patients were followed for at least 18 months unless discontinued earlier. The median duration of treatment with Sonidegib was 11.0 months (range 1.3 to 33.5 months). The study population characteristics were: median age of 67 years (range 25 to 92; 59% were ≥65 years), 61% male, and 90% white. The majority of patients had prior surgery (75%), radiotherapy (24%), systemic chemotherapy (4%), or topical or photodynamic therapies (18%) for treatment of BCC. No patient had prior exposure to a hedgehog pathway inhibitor. Sonidegib was permanently discontinued in 34% of patients or temporarily interrupted in 20% of patients for adverse reactions. Adverse reactions reported in at least two patients that led to discontinuation of the drug were: muscle spasms and dysgeusia (each 5%), asthenia, increased lipase, and nausea (each 4%), fatigue, decreased appetite, alopecia, and decreased weight (each 3%). Serious adverse reactions occurred in 18% of patients. The most common adverse reactions occurring in ≥10% of patients treated with Sonidegib 200 mg were muscle spasms, alopecia, dysgeusia, fatigue, nausea, musculoskeletal pain, diarrhea, decreased weight, decreased appetite, myalgia, abdominal pain, headache, pain, vomiting, and pruritus (Table 1). The key laboratory abnormalities are described in Table 2. - Table 1: Adverse Reactions Occurring in ≥10% of Patients in Study 1 ODOMZO: Sonidegib's Brand name - Table 2: Key Laboratory Abnormalities(a) ODOMZO: Sonidegib's Brand name - Amenorrhea Amenorrhea lasting for at least 18 months occurred in two of 14 pre-menopausal women treated with Sonidegib 200 mg or 800 mg once daily. ## Postmarketing Experience There is limited information regarding Sonidegib Postmarketing Experience in the drug label. # Drug Interactions - Strong and Moderate CYP3A Inhibitors Avoid concomitant administration of Sonidegib with strong CYP3A inhibitors, including but not limited to saquinavir, telithromycin, ketoconazole, itraconazole, voriconazole, posaconazole and nefazodone. Avoid concomitant administration of Sonidegib with moderate CYP3A inhibitors, including but not limited to atazanavir, diltiazem, and fluconazole. If a moderate CYP3A inhibitor must be used, administer the moderate CYP3A inhibitor for less than 14 days and monitor closely for adverse reactions particularly musculoskeletal adverse reactions. - Strong and Moderate CYP3A Inducers Avoid concomitant administration of Sonidegib with strong and moderate CYP3A inducers, including but not limited to carbamazepine, efavirenz, modafinil, phenobarbital, phenytoin, rifabutin, rifampin and St. John’s Wort (Hypericum perforatum). # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): N - Risk Summary Based on its mechanism of action and data from animal reproduction studies, Sonidegib can cause fetal harm when administered to a pregnant woman. There are no available data on the use of Sonidegib in pregnant women. In animal reproduction studies, oral administration of Sonidegib during organogenesis at doses below the recommended human dose of 200 mg resulted in embryotoxicity, fetotoxicity, and teratogenicity in rabbits. Teratogenic effects observed included severe midline defects, missing digits, and other irreversible malformations. Advise pregnant women of the potential risk to a fetus. Report pregnancies to Novartis Pharmaceuticals Corporation at 1-888-669-6682. The background risk of major birth defects and miscarriage for the indicated population is unknown; however, the background risk in the U.S. general population of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies. - Data - Animal Data Daily oral administration of Sonidegib to pregnant rabbits resulted in abortion, complete resorption of fetuses, or severe malformations at ≥ 5 mg/kg/day (approximately 0.05 times the recommended human dose based on AUC). Teratogenic effects included vertebral, distal limb and digit malformations, severe craniofacial malformations, and other severe midline defects. Skeletal variations were observed when maternal exposure to Sonidegib was below the limit of detection. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Sonidegib in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Sonidegib during labor and delivery. ### Nursing Mothers No data are available regarding the presence of Sonidegib in human milk, the effects of the drug on the breast fed infant, or the effects of the drug on milk production. Because of the potential for serious adverse reactions in breastfed infants from Sonidegib, advise a nursing woman not to breastfeed during treatment with Sonidegib and for 20 months after the last dose. ### Pediatric Use The safety and effectiveness of Sonidegib have not been established in pediatric patients. - Juvenile Animal Data In a 5-week juvenile rat toxicology study, effects of Sonidegib were observed in bone, teeth, reproductive tissues, and nerves at doses ≥10 mg/kg/day (approximately 1.2 times the recommended human dose based on AUC). Bone findings included thinning/closure of bone growth plate, decreased bone length and width, and hyperostosis. Findings in teeth included missing or fractured teeth, and atrophy. Reproductive tissue toxicity was evidenced by atrophy of testes, ovaries, and uterus, partial development of the prostate gland and seminal vesicles, and inflammation and aspermia of the epididymis. Nerve degeneration was also noted. ### Geriatic Use Of the 229 patients who received Sonidegib (79 patients receiving 200 mg daily and 150 patients receiving 800 mg daily) in Study 1, 54% were 65 years and older, while 28% were 75 years and older. No overall differences in effectiveness were observed between these patients and younger patients. There was a higher incidence of serious adverse events, Grade 3 and 4 adverse events, and adverse events requiring dose interruption or discontinuation in patients ≥65 years compared with younger patients; this was not attributable to an increase in any specific adverse event. ### Gender There is no FDA guidance on the use of Sonidegib with respect to specific gender populations. ### Race There is no FDA guidance on the use of Sonidegib with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Sonidegib in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Sonidegib in patients with hepatic impairment. ### Females of Reproductive Potential and Males Based on its mechanism of action and animal data, Sonidegib can cause fetal harm when administered to a pregnant woman. - Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating Sonidegib treatment. - Contraception - Females Advise females of reproductive potential to use effective contraception during treatment with Sonidegib and for at least 20 months after the last dose. - Males It is not known if Sonidegib is present in semen. Advise male patients to use condoms, even after a vasectomy, to avoid potential drug exposure to pregnant partners and female partners of reproductive potential during treatment with Sonidegib and for at least 8 months after the last dose. Advise males not to donate semen during treatment with Sonidegib and for at least 8 months after the last dose. - Infertility Based on findings from animal studies, female fertility may be compromised with Sonidegib. ### Immunocompromised Patients There is no FDA guidance one the use of Sonidegib in patients who are immunocompromised. # Administration and Monitoring ### Administration The recommended dose of Sonidegib is 200 mg taken orally once daily on an empty stomach, at least 1 hour before or 2 hours after a meal, administered until disease progression or unacceptable toxicity. ### Monitoring There is limited information regarding Sonidegib Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Sonidegib and IV administrations. # Overdosage There are no recommendations regarding management of overdosage. # Pharmacology ## Mechanism of Action Sonidegib is an inhibitor of the Hedgehog pathway. Sonidegib binds to and inhibits Smoothened, a transmembrane protein involved in Hedgehog signal transduction. ## Structure There is limited information regarding Sonidegib Structure in the drug label. ## Pharmacodynamics There is limited information regarding Sonidegib Pharmacodynamics in the drug label. ## Pharmacokinetics Absorption Less than 10% of an oral dose of Sonidegib is absorbed. Following the administration of a single Sonidegib dose (100 mg to 3000 mg) under fasted conditions in patients with cancer, the median time-to-peak concentration (Tmax) was 2 to 4 hours. Sonidegib exhibited dose-proportional increases in the area under the curve (AUC) and the maximal concentration (Cmax) over the dose range of 100 mg to 400 mg, but less than dose-proportional increases at doses greater than 400 mg. Steady-state was reached approximately 4 months after starting Sonidegib and the estimated accumulation at steady-state was 19-fold. Following a dose of 200 mg once daily, the estimated mean steady-state Cmax is 1030 ng/mL, AUC(0-24h) is 22 μg*h/mL and minimal concentration (Cmin) is 890 ng/mL. A high-fat meal (approximately 1000 calories with 50% of calories from fat) increased exposure to Sonidegib (geometric mean AUC(inf) and Cmax) by 7.4- to 7.8-fold. Distribution The estimated apparent steady-state volume of distribution (Vss/F) was 9,166 L. Sonidegib was greater than 97% bound to human plasma proteins in vitro and the binding was concentration independent. In vitro studies suggested that sonidegib is not a substrate of P-glycoprotein, MRP2 or BCRP. Elimination The elimination half-life (t1/2) of Sonidegib estimated from population pharmacokinetic (PK) modeling was approximately 28 days. - Metabolism Sonidegib is primarily metabolized by CYP3A. The main circulating compound was unchanged sonidegib (36% of circulating radioactivity). - Excretion Sonidegib and its metabolites are eliminated primarily by the hepatic route. Of the absorbed dose, approximately 70% was eliminated in the feces and 30% was eliminated in the urine. Unchanged Sonidegib was not detectable in the urine. Specific Populations - Hepatic Impairment Mild (Child-Pugh class A), moderate (Child-Pugh class B), or severe (Child-Pugh class C) hepatic impairment had no clinically meaningful effect on Sonidegib exposure as compared to subjects with normal hepatic function. - Renal Impairment Mild (CLcr 60 to 89 mL/min) and moderate (CLcr 30 to 59 mL/min) renal impairment had no effect on Sonidegib steady-state exposure as compared to patients with normal renal function (CLcr ≥90 mL/min). - Age, Sex, Weight and Race Age, body weight, or sex had no clinically meaningful effect on Sonidegib steady-state exposure. A cross study comparison suggests that geometric mean AUCinf of Sonidegib is 1.7-fold higher in Japanese healthy subjects compared to Western healthy subjects (Whites and Blacks) following a single 200 mg dose of Sonidegib. Drug Interaction Studies - Effects of CYP3A Inhibitors on Sonidegib Strong CYP3A inhibitor: The geometric mean Sonidegib AUC(0-10d) increased by 2.2-fold and the Cmax increased by 1.5-fold when Sonidegib at a dose of 800 mg was taken with ketoconazole compared to Sonidegib alone. The geometric mean sonidegib steady-state AUC(0-24h) would similarly increase in cancer patients taking Sonidegib 200 mg once daily when coadministered with a strong CYP3A inhibitor for 14 days. Moderate CYP3A inhibitor: The geometric mean sonidegib steady-state AUC(0-24h) would increase 1.8-fold when Sonidegib 200 mg once daily is coadministered with a moderate CYP3A inhibitor (erythromycin) for 14 days and would increase 2.8-fold when Sonidegib 200 mg once daily is coadministered with a moderate CYP3A inhibitor (erythromycin) for 4 months. - Effects of CYP3A Inducers on Sonidegib Strong CYP3A inducer: The geometric mean Sonidegib AUC(0-10d) decreased by 72% and the Cmax decreased by 54% when Sonidegib at a dose of 800 mg was taken with rifampicin compared to Sonidegib alone. Moderate CYP3A inducer: The geometric mean Sonidegib steady-state AUC(0-24h) would decrease 56% in cancer patients taking Sonidegib 200 mg once daily when coadministered with a moderate CYP3A inducer (efavirenz) for 14 days and would decrease 69% when coadministered with a moderate CYP3A inducer (efavirenz) for 4 months. - Effect of Sonidegib on Cytochrome P450 Enzymes and Transporters In vitro studies suggested that Sonidegib inhibits CYP2B6 and CYP2C9 and it does not induce CYP1A2, CYP2B6 or CYP3A expression or activity. In vitro studies suggested that Sonidegib inhibits BCRP, but not P-glycoprotein, MRP2, OATP1B1, OATP1B3, OAT1, OAT3, OCT1 or OCT2. - Effect of Acid Reducing Agents on Sonidegib No clinically meaningful effect on Sonidegib exposure was observed when Sonidegib at dose of 200 mg was coadministered with esomeprazole, a proton pump inhibitor. ## Nonclinical Toxicology Carcinogenicity studies with Sonidegib have not been performed. Sonidegib was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay and was not clastogenic or aneugenic in the in vitro human chromosome aberration assay or in vivo rat bone marrow micronucleus assay. Sonidegib resulted in a lack of fertility when administered to female rats at ≥20 mg/kg/day (approximately 1.3 times the recommended human dose based on body surface area (BSA). A reduction of the number of pregnant females, an increase in the number of early resorptions, and a decrease in the number of viable fetuses was also noted at 2 mg/kg/day (approximately 0.12 times the recommended human dose based on BSA). In addition, in a 6 month repeat-dose toxicology study in rats, effects on female reproductive organs included atrophy of the uterus and ovaries at doses of 10 mg/kg (approximately ≥2 times the exposure in humans at the recommended dose of 200 mg based on AUC). No adverse effects on fertility were noted when male rats were administered Sonidegib at doses up to 20 mg/kg/day, the highest dose tested. Body tremors along with significant increases in creatine kinase were observed in rats administered oral Sonidegib for 13 weeks or longer at ≥10 mg/kg/day (approximately ≥2 times the recommended human dose based on AUC). # Clinical Studies The safety and effectiveness of Sonidegib were evaluated in a single, multicenter, double-blind, multiple cohort clinical trial conducted in patients with locally advanced basal cell carcinoma (laBCC) (n=194) or metastatic basal cell carcinoma (mBCC) (n=36) (Study 1). Patients were randomized (2:1) to receive either Sonidegib 800 mg or 200 mg orally, once daily, until disease progression or intolerable toxicity. Randomization was stratified by stage of disease (locally advanced or metastatic), laBCC disease histology (aggressive vs. non-aggressive), and geographic region. Patients with laBCC were required to have lesions for which radiotherapy was contraindicated or inappropriate (e.g., Gorlin syndrome or limitations because of location of tumor), that had recurred after radiotherapy, that were unresectable or for which surgical resection would result in substantial deformity, or that had recurred after prior surgical resection. The major efficacy outcome measure of the trial was objective response rate (ORR) as determined by blinded central review according to modified Response Evaluation Criteria in Solid Tumors (mRECIST) for patients with laBCC or RECIST version 1.1 for patients with mBCC. Duration of response (DoR), determined by blinded central review, was a key secondary outcome measure. For patients with laBCC, the evaluation of tumor response was based on a composite assessment that integrated tumor measurements obtained by radiographic assessments of target lesions (per RECIST 1.1), digital clinical photography, and histopathology assessments (via punch biopsies). All modalities used must have demonstrated absence of tumor to achieve a composite assessment of complete response (CR). Response by digital clinical photography was evaluated by World Health Organization (WHO) adapted criteria [partial response (PR): ≥50% decrease in the sum of the product of perpendicular diameters (SPD) of the lesions, CR: disappearance of all lesions, progressive disease (PD): ≥25% increase in the SPD of the lesions]. Multiple punch biopsies of target lesions were performed to confirm a CR or when a response assessment was confounded by presence of lesion ulceration, cyst, and or scarring/fibrosis. A total of 66 patients randomized to Sonidegib 200 mg daily had laBCC. Three of these patients had a diagnosis of Gorlin Syndrome. The demographic characteristics of the 66 patients with laBCC were: median age of 67 years (range: 25 to 92 years; 58% were ≥65 years); 58% male, 89% white, and ECOG performance status of 0 (67%). Seventy-six percent of patients had prior therapy for treatment of BCC; this included surgery (73%), radiotherapy (18%), and topical/photodynamic therapies (21%). Approximately half of these patients (56%) had aggressive histology. Patients with laBCC randomized to receive Sonidegib 200 mg daily were followed for at least 12 months unless discontinued earlier. The ORR was 58% (95% confidence interval: 45, 70), consisting of 3 (5%) complete responses and 35 (53%) partial responses. A pre-specified sensitivity analysis using an alternative definition for complete response, defined as at least a PR according to MRI and/or photography and no evidence of tumor on biopsy of the residual lesion, yielded a CR rate of 20%. Among the 38 patients with an objective response, 7 (18%) patients experienced subsequent disease progression with 4 of these 7 patients having maintained a response of 6 months or longer. The remaining 31 patients (82%) have ongoing responses ranging from to 1.9+ to 18.6+ months and the median duration of response has not been reached. A total of 128 patients randomized to Sonidegib 800 mg daily had laBCC. Twelve of these patients had a diagnosis of Gorlin Syndrome. There was no evidence of better antitumor activity (ORR) among patients with laBCC randomized to receive Sonidegib 800 mg daily and followed for at least 12 months unless discontinued earlier. # How Supplied Each Sonidegib capsule has an opaque pink color with ‘SONIDEGIB 200MG’ printed on the capsule body and ‘NVR’ printed on the cap in black ink. Sonidegib capsules are supplied as follows: Bottle of 30 capsules (NDC 0078-0645-15) ## Storage Store at 25°C (77°F); excursions permitted to 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. Embryo-Fetal Toxicity - Advise female patients of the potential risk to a fetus. - Advise females of reproductive potential to use effective contraception during treatment with Sonidegib and for at least 20 months after the last dose. - Advise males, even those with prior vasectomy, to use condoms, to avoid potential drug exposure in both pregnant partners and female partners of reproductive potential during treatment with Sonidegib and for at least 8 months after the last dose. - Advise female patients and female partners of male patients to contact their healthcare provider with a known or suspected pregnancy. - Advise females who may have been exposed to Sonidegib during pregnancy, either directly or through seminal fluid, to contact the Novartis Pharmaceuticals Corporation at 1-888-669-6682. Blood Donation Advise patients not to donate blood or blood products while taking Sonidegib and for 20 months after stopping treatment. Musculoskeletal Adverse Reactions Advise patients to contact their healthcare provider immediately for new or worsening signs or symptoms of muscle toxicity, dark urine, decreased urine output, or the inability to urinate. Administration Instructions Advise patients to take Sonidegib on an empty stomach, at least 1 hour before or 2 hours after a meal. Lactation Advise women not to breastfeed during treatment with Sonidegib and for up to 20 months after the last dose. # Precautions with Alcohol Alcohol-Sonidegib interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names ODOMZO® # Look-Alike Drug Names There is limited information regarding Sonidegib Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Sonidegib
06480c96d7aefa3b6be6619a77a1903eb84679f9	wikidoc	Sparteine	Sparteine # Overview Sparteine is a class 1a antiarrhythmic agent; a sodium channel blocker. It is an alkaloid and can be extracted from scotch broom. It is the predominant alkaloid in Lupinus mutabilis, and is thought to chelate the bivalents calcium and magnesium. It is not FDA approved for human use as an antiarrhythmic agent, and it is not included in the Vaughn Williams classification of antiarrhythmic drugs. It is also used as a chiral base in organic chemistry, and as a ligand in organic chemical synthesis. # Biosynthesis Sparteine is a lupin alkaloid containing a tetracyclic bis-quinolizidine ring system derived from three C5 chains of lysine, or more specifically, L-lysine. The first intermediate in the biosynthesis is cadaverine, the decarboxylation product of lysine catalyzed by the enzyme lysine decarboxylase (LDC). Three units of cadaverine are used to form the quinolizidine skeleton. The mechanism of formation has been studied enzymatically, as well as with tracer experiments, but the exact route of synthesis still remains unclear. Tracer studies using 13C-15N-doubly labeled cadaverine have shown three units of cadaverine are incorporated into sparteine and two of the C-N bonds from two of the cadaverine units remain intact. The observations have also been confirmed using 2H NMR labeling experiments. Enzymatic evidence then showed that the three molecules of cadaverine are transformed to the quinolizidine ring via enzyme bound intermediates, without the generation of any free intermediates. Originally, it was thought that conversion of cadaverine to the corresponding aldehyde, 5-aminopentanal, was catalyzed by the enzyme diamine oxidase. The aldehyde then spontaneously converts to the corresponding Schiff base, Δ1-piperideine. Coupling of two molecules occurs between the two tautomers of Δ1-piperideine in an aldol-type reaction. The imine is then hydrolyzed to the corresponding aldehyde/amine. The primary amine is then oxidized to an aldehyde followed by formation of the imine to yield the quinolizidine ring. The breakdown of this mechanism is shown in figure 1; however, the intermediates, as mentioned before, were not isolated. More recent enzymatic evidence has indicated the presence of 17-oxosparteine synthase (OS), a transaminase enzyme. The deaminated cadaverine is not released from the enzyme, thus is can be assumed that the enzyme catalyzes the formation of the quinolizidine skeleton in a channeled fashion (Figure 2)., 7-oxosparteine requires four units of pyruvate as the NH2 acceptors and produces four molecules of alanine (Figure 3). Both lysine decarboxylase and the quinolizidine skeleton-forming enzyme are localized in chloroplasts.	Sparteine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Sparteine is a class 1a antiarrhythmic agent; a sodium channel blocker. It is an alkaloid and can be extracted from scotch broom. It is the predominant alkaloid in Lupinus mutabilis, and is thought to chelate the bivalents calcium and magnesium. It is not FDA approved for human use as an antiarrhythmic agent, and it is not included in the Vaughn Williams classification of antiarrhythmic drugs. It is also used as a chiral base in organic chemistry, and as a ligand in organic chemical synthesis. # Biosynthesis Sparteine is a lupin alkaloid containing a tetracyclic bis-quinolizidine ring system derived from three C5 chains of lysine, or more specifically, L-lysine.[1] The first intermediate in the biosynthesis is cadaverine, the decarboxylation product of lysine catalyzed by the enzyme lysine decarboxylase (LDC).[2] Three units of cadaverine are used to form the quinolizidine skeleton. The mechanism of formation has been studied enzymatically, as well as with tracer experiments, but the exact route of synthesis still remains unclear. Tracer studies using 13C-15N-doubly labeled cadaverine have shown three units of cadaverine are incorporated into sparteine and two of the C-N bonds from two of the cadaverine units remain intact.[3] The observations have also been confirmed using 2H NMR labeling experiments.[4] Enzymatic evidence then showed that the three molecules of cadaverine are transformed to the quinolizidine ring via enzyme bound intermediates, without the generation of any free intermediates. Originally, it was thought that conversion of cadaverine to the corresponding aldehyde, 5-aminopentanal, was catalyzed by the enzyme diamine oxidase.[5] The aldehyde then spontaneously converts to the corresponding Schiff base, Δ1-piperideine. Coupling of two molecules occurs between the two tautomers of Δ1-piperideine in an aldol-type reaction. The imine is then hydrolyzed to the corresponding aldehyde/amine. The primary amine is then oxidized to an aldehyde followed by formation of the imine to yield the quinolizidine ring.[5] The breakdown of this mechanism is shown in figure 1; however, the intermediates, as mentioned before, were not isolated. More recent enzymatic evidence has indicated the presence of 17-oxosparteine synthase (OS), a transaminase enzyme.[6][7][8][9][10][11] The deaminated cadaverine is not released from the enzyme, thus is can be assumed that the enzyme catalyzes the formation of the quinolizidine skeleton in a channeled fashion (Figure 2)., [9][10][11] 7-oxosparteine requires four units of pyruvate as the NH2 acceptors and produces four molecules of alanine (Figure 3). Both lysine decarboxylase and the quinolizidine skeleton-forming enzyme are localized in chloroplasts.[12]	https://www.wikidoc.org/index.php/Sparteine
3719b38e9bcd7abf4b1ae5159bd462c0c8111da8	wikidoc	Spermatid	Spermatid # Overview The term spermatid refers to the haploid male gametid that results from division of secondary spermatocytes. As a result of meiosis, each spermatid contains only half of the genetic material present in the original primary spermatocyte. Spermatids are connected together by cytoplasmic material and have superfluous cytoplasmic material around their nuclei. When formed, early round spermatids must undergo further maturational events in order to develop into spermatozoa, a process termed spermiogenesis (also termed spermeteliosis). The spermatids begin to grow a tail, develop a thickened mid-piece where the mitochondria become localised and form an acrosome. Spermatid DNA also undergoes packaging, becoming highly condensed. The DNA is packaged firstly with specific nuclear basic proteins, which are subsequently replaced with protamines during spermatid elongation. The resultant tightly packed chromatin is transcriptionally inactive. # Additional images - Scheme showing analogies in the process of maturation of the ovum and the development of the spermatids (young spermatozoa).	Spermatid Template:Infobox Anatomy # Overview The term spermatid refers to the haploid male gametid that results from division of secondary spermatocytes. As a result of meiosis, each spermatid contains only half of the genetic material present in the original primary spermatocyte. Spermatids are connected together by cytoplasmic material and have superfluous cytoplasmic material around their nuclei. When formed, early round spermatids must undergo further maturational events in order to develop into spermatozoa, a process termed spermiogenesis (also termed spermeteliosis). The spermatids begin to grow a tail, develop a thickened mid-piece where the mitochondria become localised and form an acrosome. Spermatid DNA also undergoes packaging, becoming highly condensed. The DNA is packaged firstly with specific nuclear basic proteins, which are subsequently replaced with protamines during spermatid elongation. The resultant tightly packed chromatin is transcriptionally inactive. # Additional images - Scheme showing analogies in the process of maturation of the ovum and the development of the spermatids (young spermatozoa). # External links - Histology image: 17804loa – Histology Learning System at Boston University - "Male Reproductive System: testis, early spermatids" - Histology image: 17805loa – Histology Learning System at Boston University - "Male Reproductive System: testis, late spermatids" - Histology at okstate.edu Template:Male reproductive system ar:نطفة أرومية Template:WH Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Spermatid
856c3b5612315a6b9887fd92543150174de3956b	wikidoc	Sphincter	Sphincter A sphincter is a structure, usually a circular muscle, that normally maintains constriction of a natural body passage or orifice and which relaxes as required by normal physiological functioning. There are over 40 different sphincters in the human body; some of these sphincters are microscopic in size. Many sphincters are used every day in the normal course of digestion. For example, the epiglottis is used to seal off the windpipe when swallowing, so as to ensure that no food or liquid enters the lungs. The use of the epiglottis is a typical example of an involuntary action by the body. # Examples of sphincters - The sphincter pupillae, or pupillary sphincter, belonging to the iris in the eye. - The orbicularis oris muscle, a muscle around the mouth. - The upper esophageal sphincter - The cardia/lower esophageal sphincter, or cardiac sphincter at the upper portion of the stomach. This sphincter prevents the acidic contents of the stomach from moving upward into the esophagus. - The pyloric sphincter, at the lower end of the stomach. - The Ileocecal sphincter, which prevents the backup of non-digested material into the small intestine. - The sphincter of Oddi, or Glisson's sphincter, controlling secretions from the liver, pancreas and gall bladder into the duodenum. - The sphincter urethrae, or urethral sphincter, controlling the exit of urine from the body. - At the anus, there are two sphincters which control the exit of feces from the body (see internal anal sphincter and external anal sphincter). The inner sphincter is involuntary and the outer voluntary. Sphincters prove effective in the mediation of the entrance or release of liquids and fluids; this is evident in the blowholes of numerous marine mammals, for example. # Sphincter Video - Video on Sphincter Control ca:Esfínter de:Schließmuskel it:Sfintere ku:Miçînik nl:Sluitspier	Sphincter Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] A sphincter is a structure, usually a circular muscle, that normally maintains constriction of a natural body passage or orifice and which relaxes as required by normal physiological functioning. There are over 40 different sphincters in the human body; some of these sphincters are microscopic in size. Many sphincters are used every day in the normal course of digestion. For example, the epiglottis is used to seal off the windpipe when swallowing, so as to ensure that no food or liquid enters the lungs. The use of the epiglottis is a typical example of an involuntary action by the body. # Examples of sphincters - The sphincter pupillae, or pupillary sphincter, belonging to the iris in the eye. - The orbicularis oris muscle, a muscle around the mouth. - The upper esophageal sphincter - The cardia/lower esophageal sphincter, or cardiac sphincter at the upper portion of the stomach. This sphincter prevents the acidic contents of the stomach from moving upward into the esophagus. - The pyloric sphincter, at the lower end of the stomach. - The Ileocecal sphincter, which prevents the backup of non-digested material into the small intestine. - The sphincter of Oddi, or Glisson's sphincter, controlling secretions from the liver, pancreas and gall bladder into the duodenum. - The sphincter urethrae, or urethral sphincter, controlling the exit of urine from the body. - At the anus, there are two sphincters which control the exit of feces from the body (see internal anal sphincter and external anal sphincter). The inner sphincter is involuntary and the outer voluntary. Sphincters prove effective in the mediation of the entrance or release of liquids and fluids; this is evident in the blowholes of numerous marine mammals, for example. # Sphincter Video - Video on Sphincter Control ca:Esfínter de:Schließmuskel it:Sfintere ku:Miçînik nl:Sluitspier Template:Jb1 Template:WH Template:WS	https://www.wikidoc.org/index.php/Sphincter
5e7bb81180b3f90ade9fce911c00842c53015471	wikidoc	Spirapril	Spirapril # Overview Spirapril hydrochloride (Renormax) is an ACE inhibitor antihypertensive drug used to treat hypertension. It belongs to dicarboxy group of ace inhibitor. Like many ACE inhibitors, this is a prodrug which is converted to the active metabolite spiraprilat following oral administration. Unlike other members of the group, it is eliminated both by renal and hepatic routes which may allow for greater use in patients with renal impairment. However data on its effect upon the renal function is conflicting. It is produced synthetically by combining the following two pharmaceutical intermediates: (S)-1,4-Dithia-7-azaspiro(4,4)-nonane-8-carboxylic acid hydrobromide CAS 75776-79-3 and N- # Footnotes - ↑ Shohat J, Wittenberg C, Erman A, Rosenfeld J, Boner G (1999). "Acute and chronic effects of spirapril, alone or in combination with isradipine on kidney function and blood pressure in patients with reduced kidney function and hypertension". Scand J Urol Nephrol. 33 (1): 57&ndash, 62. doi:10.1080/003655999750016294. PMID 10100366.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} - ↑ Noble S, Sorkin E (1995). "Spirapril. A preliminary review of its pharmacology and therapeutic efficacy in the treatment of hypertension". Drugs. 49 (5): 750&ndash, 66. doi:10.2165/00003495-199549050-00008. PMID 7601014.	Spirapril Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Spirapril hydrochloride (Renormax) is an ACE inhibitor antihypertensive drug used to treat hypertension. It belongs to dicarboxy group of ace inhibitor. Like many ACE inhibitors, this is a prodrug which is converted to the active metabolite spiraprilat following oral administration. Unlike other members of the group, it is eliminated both by renal and hepatic routes which may allow for greater use in patients with renal impairment.[1] However data on its effect upon the renal function is conflicting.[2] It is produced synthetically by combining the following two pharmaceutical intermediates: (S)-1,4-Dithia-7-azaspiro(4,4)-nonane-8-carboxylic acid hydrobromide CAS 75776-79-3 and N-[1-(S)-ethoxycarbonyl-3-phenylpropyl)-L-Alanine (ECPPA) [2] # Footnotes - ↑ Shohat J, Wittenberg C, Erman A, Rosenfeld J, Boner G (1999). "Acute and chronic effects of spirapril, alone or in combination with isradipine on kidney function and blood pressure in patients with reduced kidney function and hypertension". Scand J Urol Nephrol. 33 (1): 57&ndash, 62. doi:10.1080/003655999750016294. PMID 10100366.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} - ↑ Noble S, Sorkin E (1995). "Spirapril. A preliminary review of its pharmacology and therapeutic efficacy in the treatment of hypertension". Drugs. 49 (5): 750&ndash, 66. doi:10.2165/00003495-199549050-00008. PMID 7601014.	https://www.wikidoc.org/index.php/Spirapril
31b0ef22ac5807f8cd3c293a2f51480b060ac454	wikidoc	Spirurida	Spirurida Spirurida is an order of spirurian nematodes. Like all their relatives, they have neither a circulatory a or respiratory system. The Camallanida are sometimes included herein as a suborder, and the Drilonematida are sometimes placed here as a superfamily. Some Spirurida, like the genus Gongylonema, can cause disease in humans.	Spirurida Spirurida is an order of spirurian nematodes. Like all their relatives, they have neither a circulatory a or respiratory system. The Camallanida are sometimes included herein as a suborder, and the Drilonematida are sometimes placed here as a superfamily. Some Spirurida, like the genus Gongylonema, can cause disease in humans. Template:Wikispecies Template:WH Template:WS	https://www.wikidoc.org/index.php/Spirurida
cc0c12fbed5cf4fbedf46908aa3a487e23e6bec0	wikidoc	Sucralose	Sucralose Sucralose is an artificial sweetener. In the European Union, it is also known under the E number (additive code) E955. Sucralose was originally sold under the trade name Splenda. It is now also supplied by a variety of manufacturers and brands. Sucralose is approximately 600 times as sweet as sucrose (table sugar), twice as sweet as saccharin, and four times as sweet as aspartame. Unlike aspartame, it is stable under heat and over a broad range of pH conditions and can be used in baking or in products that require a longer shelf life. Sucralose also does not promote tooth decay. Since its introduction in 1999, sucralose has overtaken Equal in the $1.5 billion artificial sweetener market, holding a 62% market share. According to market research firm IRI, as reported in the Wall Street Journal, Splenda sold $212 million in 2006 in the U.S. while Equal sold $48.7 million. # History Sucralose was discovered in 1976 by scientists from Tate & Lyle, working with researchers Leslie Hough and Shashikant Phadnis at Queen Elizabeth College (now part of King's College London). The duo were trying to test chlorinated sugars as chemical intermediates. On a late-summer day, Phadnis was told to test the powder. Phadnis thought that Hough asked him to taste it, so he did. He found the compound to be exceptionally sweet (the final formula was 600 times as sweet as sugar). They worked with Tate & Lyle for a year before settling down on the final formula. It was first approved for use in Canada (marketed as Splenda) in 1991. Subsequent approvals came in Australia in 1993, in New Zealand in 1996, in the United States in 1998, and in the European Union in 2004. As of 2008, it had been approved in over 80 countries, including Mexico, Brazil, China, India and Japan. Tate & Lyle manufactures sucralose at a plant in McIntosh, Alabama, with additional capacity under construction in Jurong, Singapore. It is manufactured by the selective chlorination of sucrose, in which three of the hydroxyl groups are replaced with chlorine atoms to produce sucralose. An alternative pathway is to selectively chlorinate raffinose. It is used in products such as candy, breakfast bars and soft drinks. It is also used in canned fruits wherein water and sucralose take the place of much higher calorie corn syrup based additives. Sucralose mixed with maltodextrin and dextrose (both made from corn) as a filler is sold internationally by McNeil Nutritionals under the Splenda brand name. In the United States and Canada, this blend is increasingly found in restaurants, including McDonalds and Starbucks, in yellow packets, in contrast to the pink packets commonly used by saccharin sweeteners and the blue packets used by those containing aspartame; though in Canada yellow packets are also associated with the SugarTwin brand of cyclamate sweetener. # Packaging and storage Most products that contain sucralose add fillers and additional sweetener to bring the product to the approximate volume and texture of an equivalent amount of sugar. This is because sucralose is nearly 600 times as sweet as sucrose (table sugar). Pure sucralose is sold in bulk, but not in quantities suitable for individual use, although some highly concentrated sucralose-water blends are available online, using 1/4 tsp per 1 cup of sweetness or roughly 1 part sucralose to 2 parts water. Pure dry sucralose undergoes some decomposition at elevated temperatures. When it is in solution or blended with maltodextrin, it is slightly more stable. # Energy (caloric) content Though marketed in the U.S. as a “No calorie sweetener,” Splenda actually contains about 86% of the calories as the same mass of sugar (331 calories per 100 g vs. 387 calories per 100 g for sugar). However, since Splenda is about 14.5% as dense as sugar, a given volume of Splenda has 12.4% the energy of the same volume of sugar. When sucralose is added directly to commercial products, the filler is omitted and no energy is added. Note too that although the “nutritional facts” label on Splenda’s retail packaging states that a single serving of 0.5 gram (1 teaspoon or 5 milliliters) contains zero calories, Splenda actually contains 1.66 calories per teaspoon. Note that the individual, tear-open packages are double-size, one-gram servings, which contain 3.31 calories. Such labeling is appropriate in the U.S. because the FDA’s regulations permit a product to be labeled as “zero calories” if the “food contains less than 5 calories per reference amount customarily consumed and per labeled serving.” Because Splenda contains a relatively small amount of sucralose, little of which is metabolized, virtually all of Splenda’s caloric content derives from the highly fluffed dextrose or maltodextrin filler, or carrier, that gives Splenda its volume. Like other carbohydrates, dextrose and maltodextrin have 3.75 calories per gram. # Use in branded products Sucralose can be found in more than 4,500 food and beverage products. Sucralose is used as a replacement for, or in combination with, other artificial or natural sweeteners such as aspartame, acesulfame potassium or high-fructose corn syrup. Sucralose is marketed in India by Zydus Cadila under the brand name Sugar free Natura and by Hexagon Group under brand name Kal Tame. # Cooking Sucralose is a highly heat-stable artificial sweetener, allowing it to be used in many recipes without any use of sugar. Sucralose is available in a granulated form that allows for volume-for-volume substitution with sugar. This mix of sucralose and fillers rapidly dissolves in liquids. However, while it provides volume-for-volume sweetness, the texture may be noticeably different. # Safety Sucralose has been accepted by several national and international food safety regulatory bodies, including the U.S. Food and Drug Administration (FDA), Joint Food and Agriculture Organization/World Health Organization Expert Committee on Food Additives, The European Union's Scientific Committee on Food, Health Protection Branch of Health and Welfare Canada and Food Standards Australia-New Zealand (FSANZ). According to the Canadian Diabetes Association, one can consume 15 mg/kg/day of Sucralose "on a daily basis over a ... lifetime without any adverse effects". For a 150 lb person, 15 mg/kg is about 1000 mg, equivalent to about 75 packets of Splenda or the sweetness of 612 gm or 2500 kcal of sugar. “In determining the safety of sucralose, the FDA reviewed data from more than 110 studies in humans and animals. Many of the studies were designed to identify possible toxic effects including carcinogenic, reproductive and neurological effects. No such effects were found, and FDA's approval is based on the finding that sucralose is safe for human consumption.” For example, McNeil Nutritional LLC studies submitted as part of its U.S. FDA Food Additive Petition 7A3987, indicated that "in the 2-year rodent bioassays...there was no evidence of carcinogenic activity for either sucralose or its hydrolysis products...." After FDA approval, a study published in the Journal of Head and Face Pain reported sucralose as a possible trigger for migraine patients. Another study published in the Journal of Mutation Research linked high doses (2000 mg per kg; equal to 10,000 packets per day for the 150 lb person in the above example) of sucralose to DNA damage in mice. Concerns have been raised about the effect of sucralose on the thymus, an organ that is important to the immune system. A report from NICNAS cites two studies on rats, both of which found "a significant decrease in mean thymus weight" at a certain dose. The sucralose dosages which caused the thymus gland effects referenced in the NICNAS report was 3000 mg/kg bw/day for 28 days. For an 80 kg (176 lb) human, this would mean a 28-day intake of 240 grams of sucralose, which is equivalent to more than 20,000 individual Splenda packets/day for approximately one month. The dose required to provoke any immunological response was 750 mg/kg bw/day, or 60 grams of sucralose per day, which is more than 5,000 Splenda packets/day (there are 11.9 mg of sucralose in a 1g retail packet of Splenda). These and other studies were considered by regulators before concluding that sucralose was safe. However, because some ingested sucralose is broken down and absorbed by the body there is concern that chronic consumption may lead to thymus shrinkage or other side-effects. There have been anecdotal reports of "allergic" reactions and other adverse reactions to Splenda. The bulk of sucralose ingested does not leave the gastrointestinal tract and is directly excreted in the feces while 11-27% of it is absorbed. The amount that is absorbed from the GI tract is largely removed from the blood stream by the kidneys and excreted in the urine with 20-30% of the absorbed sucralose being metabolized. According to one study, sucralose is digestible by a number of microorganisms and is broken down once released into the environment. However, measurements by the Swedish Environmental Research Institute have shown that wastewater treatment has little effect on sucralose, which is present in wastewater effluents at levels of several μg/l. There are no known eco-toxicological effects at such levels, but the Swedish Environmental Protection Agency warns that there may be a continuous increase in levels if the compound is only slowly degraded in nature. Splenda usually contains 95% dextrose (the "right-handed" isomer of glucose - see dextrorotation and chirality), which the body readily metabolizes. The safety information that many specialists and the media give to consumers is that Splenda is safe to ingest as a diabetic sugar substitute. ## Natural alternatives Critics of sucralose often favor natural alternatives, including xylitol, maltitol, thaumatin, isomalt and stevia. However, those substances raise other health concerns, and natural products generally do not undergo controlled trials before being allowed in food. ## Organochlorides The basis for concern about the safety of sucralose derives from the class of chemical to which it belongs. The sucralose molecule is an organochloride (or chlorocarbon). Since some organochlorides are known to cause adverse health effects in extremely small concentrations, critics of sucralose feel the extra-high burden of proof is warranted. Although some chlorocarbons are toxic, sucralose is not known to be toxic in small quantities and is extremely insoluble in fat; it can not accumulate in fat like chlorinated hydrocarbons. In addition, sucralose does not break down or dechlorinate. In contrast to these concerns, many organochlorides occur naturally in food sources such as seaweed. ## Effect on weight gain Artificial sweetners including sucralose have been identified as possible factors in raising population obesity levels by making the consumer take up more calories later, because it confuses the brain and body responses about sugary substances and calories - associating sweet foods with fewer calories. # Marketing controversy In 2006 Merisant, the maker of Equal, filed suit against McNeil Nutritionals in federal court in Philadelphia alleging that Splenda's tagline "Made from sugar, so it tastes like sugar" is false and misleading and Merisant's website calls it an urban myth. McNeil argued during the trial that it had never deceived consumers or set out to deceive them, since the product did in fact start out with sugar. Merisant asked that McNeil be ordered to surrender profits and modify its advertising. The case ended with an agreement reached outside of court, with undisclosed settlement conditions. The lawsuit was the latest move in a long-simmering dispute. In 2004, Merisant filed a complaint with the Better Business Bureau regarding McNeil's advertising. McNeil alleged that Merisant's complaint was in retaliation for a ruling in federal court in Puerto Rico, which forced Merisant to stop packaging Equal in packages resembling Splenda's. McNeil filed suit in Puerto Rico seeking a ruling which would declare its advertising to not be misleading. Following Merisant's lawsuit in Philadelphia, McNeil agreed to a jury trial and to the dismissal of its lawsuit in Puerto Rico. In 2007, Merisant France won a significant victory in the Commercial Court of Paris against subsidiaries of McNeil Nutritionals LLC, the American company that markets Splenda. The court awarded Merisant $54,000 in damages and ordered the defendants to cease advertising claims found to violate French consumer protection laws. The advertising claims found to violate French law and which McNeil must cease include: "Because it comes from sugar, sucralose tastes like sugar" and "With sucralose: Comes from sugar and tastes like sugar". The ruling orders McNeil to amend all advertising and promotions of Splenda that contain these misleading claims and to amend all packaging. The Court prohibited the distribution of any products under the trademark Splenda with unchanged packaging after a period of four months after serving this ruling. A Sugar Association complaint to the Federal Trade Commission points out that "Splenda is not a natural product. It is not cultivated or grown and it does not occur in nature." McNeil Nutritionals, the manufacturer of Splenda, has responded that its "advertising represents the products in an accurate and informative manner and complies with applicable advertising rules in the countries where Splenda brand products are marketed." The U.S. Sugar Association has also started a web site where they put forward their criticism of sucralose.	Sucralose Template:Chembox new Sucralose is an artificial sweetener. In the European Union, it is also known under the E number (additive code) E955. Sucralose was originally sold under the trade name Splenda. It is now also supplied by a variety of manufacturers and brands. Sucralose is approximately 600 times as sweet as sucrose (table sugar),[1] twice as sweet as saccharin, and four times as sweet as aspartame. Unlike aspartame, it is stable under heat and over a broad range of pH conditions and can be used in baking or in products that require a longer shelf life. Sucralose also does not promote tooth decay.[2] Since its introduction in 1999, sucralose has overtaken Equal in the $1.5 billion artificial sweetener market, holding a 62% market share.[3] According to market research firm IRI, as reported in the Wall Street Journal, Splenda sold $212 million in 2006 in the U.S. while Equal sold $48.7 million.[4] # History Sucralose was discovered in 1976 by scientists from Tate & Lyle, working with researchers Leslie Hough and Shashikant Phadnis at Queen Elizabeth College (now part of King's College London).[5] The duo were trying to test chlorinated sugars as chemical intermediates. On a late-summer day, Phadnis was told to test the powder. Phadnis thought that Hough asked him to taste it, so he did. He found the compound to be exceptionally sweet (the final formula was 600 times as sweet as sugar). They worked with Tate & Lyle for a year before settling down on the final formula. It was first approved for use in Canada (marketed as Splenda) in 1991. Subsequent approvals came in Australia in 1993, in New Zealand in 1996, in the United States in 1998, and in the European Union in 2004. As of 2008, it had been approved in over 80 countries, including Mexico, Brazil, China, India and Japan.[6] Tate & Lyle manufactures sucralose at a plant in McIntosh, Alabama, with additional capacity under construction in Jurong, Singapore. It is manufactured by the selective chlorination of sucrose, in which three of the hydroxyl groups are replaced with chlorine atoms to produce sucralose. An alternative pathway is to selectively chlorinate raffinose. It is used in products such as candy, breakfast bars and soft drinks. It is also used in canned fruits wherein water and sucralose take the place of much higher calorie corn syrup based additives. Sucralose mixed with maltodextrin and dextrose (both made from corn) as a filler is sold internationally by McNeil Nutritionals under the Splenda brand name. In the United States and Canada, this blend is increasingly found in restaurants, including McDonalds and Starbucks, in yellow packets, in contrast to the pink packets commonly used by saccharin sweeteners and the blue packets used by those containing aspartame; though in Canada yellow packets are also associated with the SugarTwin brand of cyclamate sweetener. # Packaging and storage Most products that contain sucralose add fillers and additional sweetener to bring the product to the approximate volume and texture of an equivalent amount of sugar. This is because sucralose is nearly 600 times as sweet as sucrose (table sugar). Pure sucralose is sold in bulk, but not in quantities suitable for individual use, although some highly concentrated sucralose-water blends are available online, using 1/4 tsp per 1 cup of sweetness or roughly 1 part sucralose to 2 parts water.[7] Pure dry sucralose undergoes some decomposition at elevated temperatures. When it is in solution or blended with maltodextrin, it is slightly more stable. # Energy (caloric) content Though marketed in the U.S. as a “No calorie sweetener,” Splenda actually contains about 86% of the calories as the same mass of sugar (331 calories per 100 g vs. 387 calories per 100 g for sugar).[8] However, since Splenda is about 14.5% as dense as sugar, a given volume of Splenda has 12.4% the energy of the same volume of sugar.[9] When sucralose is added directly to commercial products, the filler is omitted and no energy is added. Note too that although the “nutritional facts” label on Splenda’s retail packaging states that a single serving of 0.5 gram (1 teaspoon or 5 milliliters) contains zero calories, Splenda actually contains 1.66 calories per teaspoon.[10] Note that the individual, tear-open packages are double-size, one-gram servings, which contain 3.31 calories. Such labeling is appropriate in the U.S. because the FDA’s regulations permit a product to be labeled as “zero calories” if the “food contains less than 5 calories per reference amount customarily consumed and per labeled serving.”[11] Because Splenda contains a relatively small amount of sucralose, little of which is metabolized, virtually all of Splenda’s caloric content derives from the highly fluffed dextrose or maltodextrin filler, or carrier, that gives Splenda its volume. Like other carbohydrates, dextrose and maltodextrin have 3.75 calories per gram. # Use in branded products Sucralose can be found in more than 4,500 food and beverage products. Sucralose is used as a replacement for, or in combination with, other artificial or natural sweeteners such as aspartame, acesulfame potassium or high-fructose corn syrup. Sucralose is marketed in India by Zydus Cadila under the brand name Sugar free Natura and by Hexagon Group under brand name Kal Tame. # Cooking Template:Expand-section Sucralose is a highly heat-stable artificial sweetener, allowing it to be used in many recipes without any use of sugar. Sucralose is available in a granulated form that allows for volume-for-volume substitution with sugar. This mix of sucralose and fillers rapidly dissolves in liquids. However, while it provides volume-for-volume sweetness, the texture may be noticeably different. # Safety Template:Double image stack Sucralose has been accepted by several national and international food safety regulatory bodies, including the U.S. Food and Drug Administration (FDA), Joint Food and Agriculture Organization/World Health Organization Expert Committee on Food Additives, The European Union's Scientific Committee on Food, Health Protection Branch of Health and Welfare Canada and Food Standards Australia-New Zealand (FSANZ). According to the Canadian Diabetes Association, one can consume 15 mg/kg/day of Sucralose "on a daily basis over a ... lifetime without any adverse effects".[12] For a 150 lb person, 15 mg/kg is about 1000 mg, equivalent to about 75 packets of Splenda or the sweetness of 612 gm or 2500 kcal of sugar. “In determining the safety of sucralose, the FDA reviewed data from more than 110 studies in humans and animals. Many of the studies were designed to identify possible toxic effects including carcinogenic, reproductive and neurological effects. No such effects were found, and FDA's approval is based on the finding that sucralose is safe for human consumption.”[13] For example, McNeil Nutritional LLC studies submitted as part of its U.S. FDA Food Additive Petition 7A3987, indicated that "in the 2-year rodent bioassays...there was no evidence of carcinogenic activity for either sucralose or its hydrolysis products...."[14] After FDA approval, a study published in the Journal of Head and Face Pain reported sucralose as a possible trigger for migraine patients.[15] Another study published in the Journal of Mutation Research linked high doses (2000 mg per kg; equal to 10,000 packets per day for the 150 lb person in the above example) of sucralose to DNA damage in mice.[16] Concerns have been raised about the effect of sucralose on the thymus, an organ that is important to the immune system. A report from NICNAS cites two studies on rats, both of which found "a significant decrease in mean thymus weight" at a certain dose.[17] The sucralose dosages which caused the thymus gland effects referenced in the NICNAS report was 3000 mg/kg bw/day for 28 days. For an 80 kg (176 lb) human, this would mean a 28-day intake of 240 grams of sucralose, which is equivalent to more than 20,000 individual Splenda packets/day for approximately one month. The dose required to provoke any immunological response was 750 mg/kg bw/day,[18] or 60 grams of sucralose per day, which is more than 5,000 Splenda packets/day (there are 11.9 mg of sucralose in a 1g retail packet of Splenda). These and other studies were considered by regulators before concluding that sucralose was safe. However, because some ingested sucralose is broken down and absorbed by the body there is concern that chronic consumption may lead to thymus shrinkage or other side-effects. There have been anecdotal reports of "allergic" reactions and other adverse reactions to Splenda. [19][20] The bulk of sucralose ingested does not leave the gastrointestinal tract and is directly excreted in the feces while 11-27% of it is absorbed.[1] The amount that is absorbed from the GI tract is largely removed from the blood stream by the kidneys and excreted in the urine with 20-30% of the absorbed sucralose being metabolized.[1] According to one study, sucralose is digestible by a number of microorganisms and is broken down once released into the environment.[21] However, measurements by the Swedish Environmental Research Institute have shown that wastewater treatment has little effect on sucralose, which is present in wastewater effluents at levels of several μg/l. [22]There are no known eco-toxicological effects at such levels, but the Swedish Environmental Protection Agency warns that there may be a continuous increase in levels if the compound is only slowly degraded in nature.[23] Splenda usually contains 95% dextrose (the "right-handed" isomer of glucose - see dextrorotation and chirality), which the body readily metabolizes. The safety information that many specialists and the media give to consumers is that Splenda is safe to ingest as a diabetic sugar substitute.[24] ## Natural alternatives Critics of sucralose often favor natural alternatives, including xylitol, maltitol, thaumatin, isomalt and stevia. However, those substances raise other health concerns,[25][26][27] and natural products generally do not undergo controlled trials before being allowed in food.[28] ## Organochlorides The basis for concern about the safety of sucralose derives from the class of chemical to which it belongs. The sucralose molecule is an organochloride (or chlorocarbon). Since some organochlorides are known to cause adverse health effects in extremely small concentrations, critics of sucralose feel the extra-high burden of proof is warranted. Although some chlorocarbons are toxic, sucralose is not known to be toxic in small quantities and is extremely insoluble in fat; it can not accumulate in fat like chlorinated hydrocarbons. In addition, sucralose does not break down or dechlorinate.[29] In contrast to these concerns, many organochlorides occur naturally in food sources such as seaweed.[30] ## Effect on weight gain Artificial sweetners including sucralose have been identified as possible factors in raising population obesity levels by making the consumer take up more calories later, because it confuses the brain and body responses about sugary substances and calories - associating sweet foods with fewer calories.[31] # Marketing controversy In 2006 Merisant, the maker of Equal, filed suit against McNeil Nutritionals in federal court in Philadelphia alleging that Splenda's tagline "Made from sugar, so it tastes like sugar" is false and misleading and Merisant's website calls it an urban myth. McNeil argued during the trial that it had never deceived consumers or set out to deceive them, since the product did in fact start out with sugar. Merisant asked that McNeil be ordered to surrender profits and modify its advertising. The case ended with an agreement reached outside of court, with undisclosed settlement conditions.[32] The lawsuit was the latest move in a long-simmering dispute. In 2004, Merisant filed a complaint with the Better Business Bureau regarding McNeil's advertising. McNeil alleged that Merisant's complaint was in retaliation for a ruling in federal court in Puerto Rico, which forced Merisant to stop packaging Equal in packages resembling Splenda's. McNeil filed suit in Puerto Rico seeking a ruling which would declare its advertising to not be misleading. Following Merisant's lawsuit in Philadelphia, McNeil agreed to a jury trial and to the dismissal of its lawsuit in Puerto Rico.[4] In 2007, Merisant France won a significant victory in the Commercial Court of Paris against subsidiaries of McNeil Nutritionals LLC, the American company that markets Splenda. The court awarded Merisant $54,000 in damages and ordered the defendants to cease advertising claims found to violate French consumer protection laws. The advertising claims found to violate French law and which McNeil must cease include: "Because it comes from sugar, sucralose tastes like sugar" and "With sucralose: Comes from sugar and tastes like sugar". The ruling orders McNeil to amend all advertising and promotions of Splenda that contain these misleading claims and to amend all packaging. The Court prohibited the distribution of any products under the trademark Splenda with unchanged packaging after a period of four months after serving this ruling.[33] A Sugar Association complaint to the Federal Trade Commission points out that "Splenda is not a natural product. It is not cultivated or grown and it does not occur in nature."[34] McNeil Nutritionals, the manufacturer of Splenda, has responded that its "advertising represents the products in an accurate and informative manner and complies with applicable advertising rules in the countries where Splenda brand products are marketed."[35] The U.S. Sugar Association has also started a web site where they put forward their criticism of sucralose.[36]	https://www.wikidoc.org/index.php/Splenda
5891b045e2cddca41ccf72ab74a29c7aaf9b321e	wikidoc	Stability	Stability Stability can refer to: - Aircraft flight Stability (aircraft) - Atmospheric stability, a measure of the turbulence in the ambient atmosphere - BIBO stability (Bounded Input, Bounded Output stability), in signal processing and control theory, part of electrical engineering - Directional stability, and the tendency for a body moving with respect to a medium to point in the direction of motion. In the context of arrows, darts, rockets and missiles this is also known as 'weathercock stability'. - Chemical stability, occurring when a substance is in a dynamic chemical equilibrium with its environment - Ecological stability, measure of the probability of a population returning quickly to a previous state, or not going extinct - Economic stability - Numerical stability, a property of numerical algorithms which describes how errors in the input data propagate through the algorithm - Plasma stability, a measure of how likely a perturbation in a plasma is to be damped out - Relaxed stability, the property of inherently unstable aircraft - Stability conditions of waterborne vessels. - Stability (probability), a property of probability distributions - Stability radius, a property of continuous polynomial functions - Stability theory, the study of the stability of solutions to differential equations and dynamical systems Lyapunov stability Structural stability - Lyapunov stability - Structural stability - Stability (computer software), the degree to which software can be run over periods of time without crashing or otherwise malfunctioning. - The Stability E.P., a 2002 three song EP by Death Cab for Cutie - Network stability, the tendency of maximum delay and backlog in a network to grow indefinitely over time or to stay bounded See also: - Stable (disambiguation) - Homeostasis - Equilibrium (disambiguation) - Balance - Instability - Fault-tolerant system - Bicycle and motorcycle dynamics ar:مفهوم الاستقرار cs:Stabilita de:Stabilität nl:Stabiliteit	Stability Stability can refer to: - Aircraft flight Stability (aircraft) - Atmospheric stability, a measure of the turbulence in the ambient atmosphere - BIBO stability (Bounded Input, Bounded Output stability), in signal processing and control theory, part of electrical engineering - Directional stability, and the tendency for a body moving with respect to a medium to point in the direction of motion. In the context of arrows, darts, rockets and missiles this is also known as 'weathercock stability'. - Chemical stability, occurring when a substance is in a dynamic chemical equilibrium with its environment - Ecological stability, measure of the probability of a population returning quickly to a previous state, or not going extinct - Economic stability - Numerical stability, a property of numerical algorithms which describes how errors in the input data propagate through the algorithm - Plasma stability, a measure of how likely a perturbation in a plasma is to be damped out - Relaxed stability, the property of inherently unstable aircraft - Stability conditions of waterborne vessels. - Stability (probability), a property of probability distributions - Stability radius, a property of continuous polynomial functions - Stability theory, the study of the stability of solutions to differential equations and dynamical systems Lyapunov stability Structural stability - Lyapunov stability - Structural stability - Stability (computer software), the degree to which software can be run over periods of time without crashing or otherwise malfunctioning. - The Stability E.P., a 2002 three song EP by Death Cab for Cutie - Network stability, the tendency of maximum delay and backlog in a network to grow indefinitely over time or to stay bounded See also: - Stable (disambiguation) - Homeostasis - Equilibrium (disambiguation) - Balance - Instability - Fault-tolerant system - Bicycle and motorcycle dynamics Template:Mathdab ar:مفهوم الاستقرار cs:Stabilita de:Stabilität nl:Stabiliteit Template:WS	https://www.wikidoc.org/index.php/Stability
25c525f629f62ae17e257060dc110da08f14a253	wikidoc	Stannosis	Stannosis Synonyms and keywords: Synonym 1; Synonym 2; Synonym 3 # Overview Stannosis is a benign non-fibrotic pneumoconiosis caused by exposure to tin oxides including stannous oxide (SnO) and stannic oxide (SnO2) # Historical Perspective - was first discovered by , a , in during/following . - In , mutations were first identified in the pathogenesis of . - In , the first was developed by to treat/diagnose . # Classification - may be classified according to into subtypes/groups: - Other variants of include , , and . # Pathophysiology - The pathogenesis of is characterized by , , and . - The gene/Mutation in has been associated with the development of , involving the pathway. - On gross pathology, , , and are characteristic findings of . - On microscopic histopathological analysis, , , and are characteristic findings of . # Causes - may be caused by either , , or . - is caused by a mutation in the , , or gene. - There are no established causes for . # Differentiating from other Diseases - must be differentiated from other diseases that cause , , and , such as: # Epidemiology and Demographics - The prevalence of is approximately per 100,000 individuals worldwide. - In , the incidence of was estimated to be cases per 100,000 individuals in . ## Age - Patients of all age groups may develop . - is more commonly observed among patients aged years old. - is more commonly observed among . ## Gender - affects men and women equally. - are more commonly affected with than . - The to ratio is approximately to 1. ## Race - There is no racial predilection for . - usually affects individuals of the race. - individuals are less likely to develop . # Risk Factors - Common risk factors in the development of are , , , and . # Natural History, Complications and Prognosis - The majority of patients with remain asymptomatic for . - Early clinical features include , , and . - If left untreated, of patients with may progress to develop , , and . - Common complications of include , , and . - Prognosis is generally , and the of patients with is approximately . # Diagnosis ## Diagnostic Criteria - The diagnosis of is made when at least of the following diagnostic criteria are met: ## Symptoms - is usually asymptomatic. - Symptoms of may include the following: ## Physical Examination - Patients with usually appear . - Physical examination may be remarkable for: ## Laboratory Findings - There are no specific laboratory findings associated with . - A is diagnostic of . - An concentration of is diagnostic of . - Other laboratory findings consistent with the diagnosis of include , , and . ## Imaging Findings - There are no findings associated with . - is the imaging modality of choice for . - On , is characterized by , , and . - may demonstrate , , and . ## Other Diagnostic Studies - may also be diagnosed using . - Findings on include , , and . # Treatment ## Medical Therapy - There is no treatment for ; the mainstay of therapy is supportive care. - The mainstay of therapy for is and . - acts by . - Response to can be monitored with every . ## Surgery - Surgery is the mainstay of therapy for . - in conjunction with is the most common approach to the treatment of . - can only be performed for patients with . ## Prevention - There are no primary preventive measures available for . - Effective measures for the primary prevention of include , , and . - Once diagnosed and successfully treated, patients with are followed-up every . Follow-up testing includes , , and .	Stannosis Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Your Name Synonyms and keywords: Synonym 1; Synonym 2; Synonym 3 # Overview Stannosis is a benign non-fibrotic pneumoconiosis caused by exposure to tin oxides including stannous oxide (SnO) and stannic oxide (SnO2) # Historical Perspective - [Disease name] was first discovered by [scientist name], a [nationality + occupation], in [year] during/following [event]. - In [year], [gene] mutations were first identified in the pathogenesis of [disease name]. - In [year], the first [discovery] was developed by [scientist] to treat/diagnose [disease name]. # Classification - [Disease name] may be classified according to [classification method] into [number] subtypes/groups: - [group1] - [group2] - [group3] - Other variants of [disease name] include [disease subtype 1], [disease subtype 2], and [disease subtype 3]. # Pathophysiology - The pathogenesis of [disease name] is characterized by [feature1], [feature2], and [feature3]. - The [gene name] gene/Mutation in [gene name] has been associated with the development of [disease name], involving the [molecular pathway] pathway. - On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name]. - On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name]. # Causes - [Disease name] may be caused by either [cause1], [cause2], or [cause3]. - [Disease name] is caused by a mutation in the [gene1], [gene2], or [gene3] gene[s]. - There are no established causes for [disease name]. # Differentiating [disease name] from other Diseases - [Disease name] must be differentiated from other diseases that cause [clinical feature 1], [clinical feature 2], and [clinical feature 3], such as: - [Differential dx1] - [Differential dx2] - [Differential dx3] # Epidemiology and Demographics - The prevalence of [disease name] is approximately [number or range] per 100,000 individuals worldwide. - In [year], the incidence of [disease name] was estimated to be [number or range] cases per 100,000 individuals in [location]. ## Age - Patients of all age groups may develop [disease name]. - [Disease name] is more commonly observed among patients aged [age range] years old. - [Disease name] is more commonly observed among [elderly patients/young patients/children]. ## Gender - [Disease name] affects men and women equally. - [Gender 1] are more commonly affected with [disease name] than [gender 2]. - The [gender 1] to [Gender 2] ratio is approximately [number > 1] to 1. ## Race - There is no racial predilection for [disease name]. - [Disease name] usually affects individuals of the [race 1] race. - [Race 2] individuals are less likely to develop [disease name]. # Risk Factors - Common risk factors in the development of [disease name] are [risk factor 1], [risk factor 2], [risk factor 3], and [risk factor 4]. # Natural History, Complications and Prognosis - The majority of patients with [disease name] remain asymptomatic for [duration/years]. - Early clinical features include [manifestation 1], [manifestation 2], and [manifestation 3]. - If left untreated, [#%] of patients with [disease name] may progress to develop [manifestation 1], [manifestation 2], and [manifestation 3]. - Common complications of [disease name] include [complication 1], [complication 2], and [complication 3]. - Prognosis is generally [excellent/good/poor], and the [1/5/10year mortality/survival rate] of patients with [disease name] is approximately [#%]. # Diagnosis ## Diagnostic Criteria - The diagnosis of [disease name] is made when at least [number] of the following [number] diagnostic criteria are met: - [criterion 1] - [criterion 2] - [criterion 3] - [criterion 4] ## Symptoms - [Disease name] is usually asymptomatic. - Symptoms of [disease name] may include the following: - [symptom 1] - [symptom 2] - [symptom 3] - [symptom 4] - [symptom 5] - [symptom 6] ## Physical Examination - Patients with [disease name] usually appear [general appearance]. - Physical examination may be remarkable for: - [finding 1] - [finding 2] - [finding 3] - [finding 4] - [finding 5] - [finding 6] ## Laboratory Findings - There are no specific laboratory findings associated with [disease name]. - A [positive/negative] [test name] is diagnostic of [disease name]. - An [elevated/reduced] concentration of [serum/blood/urinary/CSF/other] [lab test] is diagnostic of [disease name]. - Other laboratory findings consistent with the diagnosis of [disease name] include [abnormal test 1], [abnormal test 2], and [abnormal test 3]. ## Imaging Findings - There are no [imaging study] findings associated with [disease name]. - [Imaging study 1] is the imaging modality of choice for [disease name]. - On [imaging study 1], [disease name] is characterized by [finding 1], [finding 2], and [finding 3]. - [Imaging study 2] may demonstrate [finding 1], [finding 2], and [finding 3]. ## Other Diagnostic Studies - [Disease name] may also be diagnosed using [diagnostic study name]. - Findings on [diagnostic study name] include [finding 1], [finding 2], and [finding 3]. # Treatment ## Medical Therapy - There is no treatment for [disease name]; the mainstay of therapy is supportive care. - The mainstay of therapy for [disease name] is [medical therapy 1] and [medical therapy 2]. - [Medical therapy 1] acts by [mechanism of action 1]. - Response to [medical therapy 1] can be monitored with [test/physical finding/imaging] every [frequency/duration]. ## Surgery - Surgery is the mainstay of therapy for [disease name]. - [Surgical procedure] in conjunction with [chemotherapy/radiation] is the most common approach to the treatment of [disease name]. - [Surgical procedure] can only be performed for patients with [disease stage] [disease name]. ## Prevention - There are no primary preventive measures available for [disease name]. - Effective measures for the primary prevention of [disease name] include [measure1], [measure2], and [measure3]. - Once diagnosed and successfully treated, patients with [disease name] are followed-up every [duration]. Follow-up testing includes [test 1], [test 2], and [test 3].	https://www.wikidoc.org/index.php/Stannosis
2fc3ce47dedb38128024304b8e17af3ac8a71f1a	wikidoc	Stavudine	Stavudine # 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 Stavudine is a nucleoside reverse transcriptase inhibitor that is FDA approved for the treatment of human immunodeficiency virus (HIV)-1 infection. There is a Black Box Warning for this drug as shown here. Common adverse reactions include headache, diarrhea, peripheral neuropathy, rash, nausea, and vomiting. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Stavudine capsules, in combination with other antiretroviral agents, are indicated for the treatment of human immunodeficiency virus (HIV)-1 infection. - Dosage: - For patients weighing less than 60 kg: 30 mg every 12 hours. - For patients weighing at least 60 kg: 40 mg every 12 hours. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Stavudine in adult patients. ### Non–Guideline-Supported Use Prophylaxis of occupational exposure to HIV - Dosage - Lamivudine: 300 mg once daily or 150 mg twice daily, AND - Stavudine: 40 mg twice daily for 4 weeks. If body weight is less than 60 kg, 30 mg twice daily for 4 weeks; if toxicity occurs, lower doses of 20 to 30 mg twice daily for 4 weeks can be used. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) Stavudine capsules, in combination with other antiretroviral agents, are indicated for the treatment of human immunodeficiency virus (HIV)-1 infection. - Dosage: - For newborns from birth to 13 days old: 0.5 mg/kg given every 12 hours. - For pediatric patients at least 14 days old and weighing less than 30 kg: 1 mg/kg given every 12 hours. - For pediatric patients weighing at least 30 kg: use the recommended adult dosage. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Stavudine in pediatric patients. ### Non–Guideline-Supported Use Prophylaxis of occupational exposure to HIV - Dosage - Lamivudine: 300 mg once daily or 150 mg twice daily, AND - Stavudine: 40 mg twice daily for 4 weeks. If body weight is less than 60 kg, 30 mg twice daily for 4 weeks; if toxicity occurs, lower doses of 20 to 30 mg twice daily for 4 weeks can be used. # Contraindications Stavudine capsules are contraindicated in patients with clinically significant hypersensitivity to stavudine or to any of the components contained in the formulation. # Warnings Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including stavudine and other antiretrovirals. Although relative rates of lactic acidosis have not been assessed in prospective well-controlled trials, longitudinal cohort and retrospective studies suggest that this infrequent event may be more often associated with antiretroviral combinations containing stavudine. Female gender, obesity, and prolonged nucleoside exposure may be risk factors. Fatal lactic acidosis has been reported in pregnant women who received the combination of stavudine and didanosine with other antiretroviral agents. The combination of stavudine and didanosine should be used with caution during pregnancy and is recommended only if the potential benefit clearly outweighs the potential risk. Particular caution should be exercised when administering stavudine to any patient with known risk factors for liver disease; however, cases of lactic acidosis have also been reported in patients with no known risk factors. Generalized fatigue, digestive symptoms (nausea, vomiting, abdominal pain, and unexplained weight loss); respiratory symptoms (tachypnea and dyspnea); or neurologic symptoms, including motor weakness might be indicative of the development of symptomatic hyperlactatemia or lactic acidosis syndrome. Treatment with stavudine should be suspended in any patient who develops clinical or laboratory findings suggestive of symptomatic hyperlactatemia, lactic acidosis, or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations). Permanent discontinuation of stavudine should be considered for patients with confirmed lactic acidosis. The safety and efficacy of stavudine have not been established in HIV-infected patients with significant underlying liver disease. During combination antiretroviral therapy, patients with preexisting liver dysfunction, including chronic active hepatitis, have an increased frequency of liver function abnormalities, including severe and potentially fatal hepatic adverse events, and should be monitored according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment must be considered. Hepatotoxicity and hepatic failure resulting in death were reported during postmarketing surveillance in HIV-infected patients treated with hydroxyurea and other antiretroviral agents. Fatal hepatic events were reported most often in patients treated with the combination of hydroxyurea, didanosine, and stavudine. This combination should be avoided. In vitro studies have shown ribavirin can reduce the phosphorylation of pyrimidine nucleoside analogues such as stavudine. Although no evidence of a pharmacokinetic or pharmacodynamic (e.g., loss of HIV-1/HCV virologic suppression) interaction was seen when ribavirin was coadministered with stavudine in HIV-1/HCV co-infected patients, hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy for HIV-1 and interferon and ribavirin. Patients receiving interferon with or without ribavirin and stavudine should be closely monitored for treatment-associated toxicities, especially hepatic decompensation. Discontinuation of stavudine should be considered as medically appropriate. Dose reduction or discontinuation of interferon, ribavirin, or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh >6) (see the full prescribing information for interferon and ribavirin). Motor weakness has been reported rarely in patients receiving combination antiretroviral therapy including stavudine. Most of these cases occurred in the setting of lactic acidosis. The evolution of motor weakness may mimic the clinical presentation of Guillain-Barré syndrome (including respiratory failure). If motor weakness develops, stavudine should be discontinued. Symptoms may continue or worsen following discontinuation of therapy. Peripheral sensory neuropathy, manifested by numbness, tingling, or pain in the hands or feet, has been reported in patients receiving stavudine therapy. Peripheral neuropathy, which can be severe, is dose related and occurs more frequently in patients with advanced HIV-1 disease, a history of peripheral neuropathy, or in patients receiving other drugs that have been associated with neuropathy, including didanosine. Patients should be monitored for the development of peripheral neuropathy. Stavudine-related peripheral neuropathy may resolve if therapy is withdrawn promptly. If peripheral neuropathy develops permanent discontinuation of stavudine should be considered. In some cases, symptoms may worsen temporarily following discontinuation of therapy. Fatal and nonfatal pancreatitis have occurred during therapy when stavudine was part of a combination regimen that included didanosine in both treatment-naive and treatment-experienced patients, regardless of degree of immunosuppression. The combination of stavudine and didanosine and any other agents that are toxic to the pancreas should be suspended in patients with suspected pancreatitis. Reinstitution of stavudine after a confirmed diagnosis of pancreatitis should be undertaken with particular caution and close patient monitoring; avoid use in combination with didanosine. Fat redistribution including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. In randomized controlled trials of treatment-naive patients, clinical lipoatrophy or lipodystrophy developed in a higher proportion of patients treated with stavudine compared to other nucleosides (tenofovir or abacavir). Dual energy x-ray absorptiometry (DEXA) scans demonstrated overall limb fat loss in stavudine-treated patients compared to limb fat gain or no gain in patients treated with other nucleosides (abacavir, tenofovir, or zidovudine). The incidence and severity of lipoatrophy or lipodystrophy are cumulative over time with stavudine-containing regimens. In clinical trials, switching from stavudine to other nucleosides (tenofovir or abacavir) resulted in increases in limb fat with modest to no improvements in clinical lipoatrophy. Patients receiving stavudine should be monitored for symptoms or signs of lipoatrophy or lipodystrophy and questioned about body changes related to lipoatrophy or lipodystrophy. Given the potential risks of using stavudine including lipoatrophy or lipodystrophy, a benefit-risk assessment for each patient should be made and an alternative antiretroviral should be considered. Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including stavudine. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia (PCP), or tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment. # 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. Selected adverse reactions that occurred in adult patients receiving stavudine in a controlled monotherapy study (Study AI455-019) are provided in Table 2. Pancreatitis was observed in 3 of the 412 adult patients who received stavudine in study AI455-019. Selected adverse reactions that occurred in antiretroviral-naive adult patients receiving stavudine from two controlled combination studies are provided in Table 3. Selected laboratory abnormalities reported in a controlled monotherapy study (Study AI455-019) are provided in Table 4. Selected laboratory abnormalities reported in two controlled combination studies are provided in Tables 5 and 6. Selected laboratory abnormalities reported in two controlled combination studies are provided in Tables 5 and 6. Adverse reactions and serious laboratory abnormalities reported in pediatric patients from birth through adolescence during clinical trials were similar in type and frequency to those seen in adult patients. ## Postmarketing Experience The following adverse reactions have been identified during postmarketing use of stavudine. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These reactions have been chosen for inclusion due to their seriousness, frequency of reporting, causal connection to stavudine, or a combination of these factors. - Body as a Whole: abdominal pain, allergic reaction, chills/fever, and redistribution/accumulation of body fat. - Digestive Disorders: anorexia. - Exocrine Gland Disorders: pancreatitis, including fatal cases. - Hematologic Disorders: anemia, leukopenia, thrombocytopenia, neutropenia, and macrocytosis. - Liver: symptomatic hyperlactatemia/lactic acidosis and hepatic steatosis, hepatitis and liver failure. - Metabolic Disorders: lipoatrophy, lipodystrophy, diabetes mellitus and hyperglycemia. - Musculoskeletal: myalgia. - Nervous System: insomnia, severe motor weakness (most often reported in the setting of lactic acidosis) # Drug Interactions Stavudine is unlikely to interact with drugs metabolized by cytochrome P450 isoenzymes. - Zidovudine: Zidovudine competitively inhibits the intracellular phosphorylation of stavudine. Therefore, use of zidovudine in combination with stavudine should be avoided. - Doxorubicin: In vitro data indicate that the phosphorylation of stavudine is inhibited at relevant concentrations by doxorubicin. The clinical significance of this interaction is unknown; therefore, concomitant use of stavudine with doxorubicin should be undertaken with caution. - Ribavirin: In vitro data indicate ribavirin reduces phosphorylation of lamivudine, stavudine, and zidovudine. The clinical significance of the interaction with stavudine is unknown; therefore, concomitant use of stavudine with ribavirin should be undertaken with caution. No pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV-1/HCV virologic suppression) interaction was observed when ribavirin and lamivudine (n=18), stavudine (n=10), or zidovudine (n=6) were coadministered as part of a multi-drug regimen to HIV-1/HCV co-infected patients. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C Reproduction studies have been performed in rats and rabbits with exposures (based on Cmax) up to 399 and 183 times, respectively, of that seen at a clinical dosage of 1 mg/kg/day and have revealed no evidence of teratogenicity. The incidence in fetuses of a common skeletal variation, unossified or incomplete ossification of sternebra, was increased in rats at 399 times human exposure, while no effect was observed at 216 times human exposure. A slight post-implantation loss was noted at 216 times the human exposure with no effect noted at approximately 135 times the human exposure. An increase in early rat neonatal mortality (birth to 4 days of age) occurred at 399 times the human exposure, while survival of neonates was unaffected at approximately 135 times the human exposure. A study in rats showed that stavudine is transferred to the fetus through the placenta. The concentration in fetal tissue was approximately one-half the concentration in maternal plasma. Animal reproduction studies are not always predictive of human response. There are no adequate and well-controlled studies of stavudine in pregnant women. Stavudine should be used during pregnancy only if the potential benefit justifies the potential risk. Fatal lactic acidosis has been reported in pregnant women who received the combination of stavudine and didanosine with other antiretroviral agents. It is unclear if pregnancy augments the risk of lactic acidosis/hepatic steatosis syndrome reported in nonpregnant individuals receiving nucleoside analogues. The combination of stavudine and didanosine should be used with caution during pregnancy and is recommended only if the potential benefit clearly outweighs the potential risk. Healthcare providers caring for HIV-infected pregnant women receiving stavudine should be alert for early diagnosis of lactic acidosis/hepatic steatosis syndrome. Pregnancy Category (AUS): B3 There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Stavudine in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Stavudine during labor and delivery. ### Nursing Mothers The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV. Studies in lactating rats demonstrated that stavudine is excreted in milk. Although it is not known whether stavudine is excreted in human milk, there exists the potential for adverse effects from stavudine in nursing infants. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving stavudine. ### Pediatric Use Use of stavudine in pediatric patients from birth through adolescence is supported by evidence from adequate and well-controlled studies of stavudine in adults with additional pharmacokinetic and safety data in pediatric patients. Adverse reactions and laboratory abnormalities reported to occur in pediatric patients in clinical studies were generally consistent with the safety profile of stavudine in adults. These studies include ACTG 240, where 105 pediatric patients ages 3 months to 6 years received stavudine 2 mg/kg/day for a median of 6.4 months; a controlled clinical trial where 185 newborns received stavudine 2 mg/kg/day either alone or in combination with didanosine from birth through 6 weeks of age; and a clinical trial where 8 newborns received stavudine 2 mg/kg/day in combination with didanosine and nelfinavir from birth through 4 weeks of age. Stavudine pharmacokinetics have been evaluated in 25 HIV-1-infected pediatric patients ranging in age from 5 weeks to 15 years and in weight from 2 to 43 kg after IV or oral administration of single doses and twice-daily regimens and in 30 HIV-1-exposed or -infected newborns ranging in age from birth to 4 weeks after oral administration of twice-daily regimens. ### Geriatic Use Clinical studies of stavudine did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently than younger patients. Greater sensitivity of some older individuals to the effects of stavudine cannot be ruled out. In a monotherapy Expanded Access Program for patients with advanced HIV-1 infection, peripheral neuropathy or peripheral neuropathic symptoms were observed in 15 of 40 (38%) elderly patients receiving 40 mg twice daily and 8 of 51 (16%) elderly patients receiving 20 mg twice daily. Of the approximately 12,000 patients enrolled in the Expanded Access Program, peripheral neuropathy or peripheral neuropathic symptoms developed in 30% of patients receiving 40 mg twice daily and 25% of patients receiving 20 mg twice daily. Elderly patients should be closely monitored for signs and symptoms of peripheral neuropathy. Stavudine 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, it may be useful to monitor renal function. Dose adjustment is recommended for patients with renal impairment. ### Gender A population pharmacokinetic analysis of data collected during a controlled clinical study in HIV-1-infected patients showed no clinically important differences between males (n=291) and females (n=27). ### Race A population pharmacokinetic analysis of data collected during a controlled clinical study in HIV-1-infected patients showed no clinically important differences between races (n=233 Caucasian, 39 African-American, 41 Hispanic, 1 Asian, and 4 other). ### Renal Impairment Data from two studies in adults indicated that the apparent oral clearance of stavudine decreased and the terminal elimination half-life increased as creatinine clearance decreased. Based on these observations, it is recommended that the stavudine dosage be modified in patients with reduced creatinine clearance and in patients receiving maintenance hemodialysis. ### Hepatic Impairment Stavudine pharmacokinetics were not altered in five non-HIV-infected patients with hepatic impairment secondary to cirrhosis (Child-Pugh classification B or C) following the administration of a single 40 mg dose. ### Females of Reproductive Potential and Males No evidence of impaired fertility was seen in rats with exposures (based on Cmax) up to 216 times that observed following a clinical dosage of 1 mg/kg/day. ### Immunocompromised Patients There is no FDA guidance one the use of Stavudine in patients who are immunocompromised. # Administration and Monitoring ### Administration Oral ### Monitoring There is limited information regarding Stavudine Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Stavudine and IV administrations. # Overdosage Experience with adults treated with 12 to 24 times the recommended daily dosage revealed no acute toxicity. Complications of chronic overdosage include peripheral neuropathy and hepatic toxicity. Stavudine can be removed by hemodialysis; the mean ± SD hemodialysis clearance of stavudine is 120 ± 18 mL/min. Whether stavudine is eliminated by peritoneal dialysis has not been studied. # Pharmacology ## Mechanism of Action Stavudine, a nucleoside analogue of thymidine, is phosphorylated by cellular kinases to the active metabolite stavudine triphosphate. Stavudine triphosphate inhibits the activity of HIV-1 reverse transcriptase (RT) by competing with the natural substrate thymidine triphosphate (Ki=0.0083 to 0.032 μM) and by causing DNA chain termination following its incorporation into viral DNA. Stavudine triphosphate inhibits cellular DNA polymerases β and γ and markedly reduces the synthesis of mitochondrial DNA. ## Structure Stavudine has the following structural formula: ## Pharmacodynamics There is limited information regarding Stavudine Pharmacodynamics in the drug label. ## Pharmacokinetics The pharmacokinetics of stavudine have been evaluated in HIV-1-infected adult and pediatric patients (Tables 7, 8, and 9). Peak plasma concentrations (Cmax) and area under the plasma concentration-time curve (AUC) increased in proportion to dose after both single and multiple doses ranging from 0.03 to 4 mg/kg. There was no significant accumulation of stavudine with repeated administration every 6, 8, or 12 hours. Following oral administration, stavudine is rapidly absorbed, with peak plasma concentrations occurring within 1 hour after dosing. The systemic exposure to stavudine is the same following administration as capsules or solution. Steady-state pharmacokinetic parameters of stavudine in HIV-1-infected adults are shown in Table 7. Binding of stavudine to serum proteins was negligible over the concentration range of 0.01 to 11.4 mcg/mL. Stavudine distributes equally between red blood cells and plasma. Volume of distribution is shown in Table 8. Metabolism plays a limited role in the clearance of stavudine. Unchanged stavudine was the major drug-related component circulating in plasma after an 80 mg dose of 14C-stavudine, while metabolites constituted minor components of the circulating radioactivity. Minor metabolites include oxidized stavudine, glucuronide conjugates of stavudine and its oxidized metabolite, and an N-acetylcysteine conjugate of the ribose after glycosidic cleavage, suggesting that thymine is also a metabolite of stavudine. Following an 80 mg dose of 14C-stavudine to healthy subjects, approximately 95% and 3% of the total radioactivity was recovered in urine and feces, respectively. Radioactivity due to parent drug in urine and feces was 73.7% and 62%, respectively. The mean terminal elimination half-life is approximately 2.3 hours following single oral doses. Mean renal clearance of the parent compound is approximately 272 mL/min, accounting for approximately 67% of the apparent oral clearance. In HIV-1-infected patients, renal elimination of unchanged drug accounts for about 40% of the overall clearance regardless of the route of administration (Table 8). The mean renal clearance was about twice the average endogenous creatinine clearance, indicating active tubular secretion in addition to glomerular filtration. ## Nonclinical Toxicology The cell culture antiviral activity of stavudine was measured in peripheral blood mononuclear cells, monocytic cells, and lymphoblastoid cell lines. The concentration of drug necessary to inhibit HIV-1 replication by 50% (EC50) ranged from 0.009 to 4 μM against laboratory and clinical isolates of HIV-1. In cell culture, stavudine exhibited additive to antagonistic activity in combination with zidovudine. Stavudine in combination with either abacavir, didanosine, tenofovir, or zalcitabine exhibited additive to synergistic anti-HIV-1 activity. Ribavirin, at the 9 to 45 μM concentrations tested, reduced the anti-HIV-1 activity of stavudine by 2.5- to 5-fold. The relationship between cell culture susceptibility of HIV-1 to stavudine and the inhibition of HIV-1 replication in humans has not been established. HIV-1 isolates with reduced susceptibility to stavudine have been selected in cell culture (strain-specific) and were also obtained from patients treated with stavudine. Phenotypic analysis of HIV-1 isolates from 61 patients receiving prolonged (6 to 29 months) stavudine monotherapy showed that post-therapy isolates from four patients exhibited EC50 values more than 4-fold (range 7- to 16-fold) higher than the average pretreatment susceptibility of baseline isolates. Of these, HIV-1 isolates from one patient contained the zidovudine-resistance-associated substitutions T215Y and K219E, and isolates from another patient contained the multiple-nucleoside-resistance-associated substitution Q151M. Mutations in the RT gene of HIV-1 isolates from the other two patients were not detected. The genetic basis for stavudine susceptibility changes has not been identified. Cross-resistance among HIV-1 reverse transcriptase inhibitors has been observed. Several studies have demonstrated that prolonged stavudine treatment can select and/or maintain thymidine analogue mutations (TAMs; M41L, D67N, K70R, L210W, T215Y/F, K219Q/E) associated with zidovudine resistance. HIV-1 isolates with one or more TAMs exhibited reduced susceptibility to stavudine in cell culture. These TAMs are seen at a similar frequency with stavudine and zidovudine in virological treatment. The clinical relevance of these findings suggests that stavudine should be avoided in the presence of thymidine analogue mutations. In 2-year carcinogenicity studies in mice and rats, stavudine was noncarcinogenic at doses which produced exposures (AUC) 39 and 168 times, respectively, human exposure at the recommended clinical dose. Benign and malignant liver tumors in mice and rats and malignant urinary bladder tumors in male rats occurred at levels of exposure 250 (mice) and 732 (rats) times human exposure at the recommended clinical dose. Stavudine was not mutagenic in the Ames, E. coli reverse mutation, or the CHO/HGPRT mammalian cell forward gene mutation assays, with and without metabolic activation. Stavudine produced positive results in the in vitro human lymphocyte clastogenesis and mouse fibroblast assays, and in the in vivo mouse micronucleus test. In the in vitro assays, stavudine elevated the frequency of chromosome aberrations in human lymphocytes (concentrations of 25 to 250 mcg/mL, without metabolic activation) and increased the frequency of transformed foci in mouse fibroblast cells (concentrations of 25 to 2500 mcg/mL, with and without metabolic activation). In the in vivo micronucleus assay, stavudine was clastogenic in bone marrow cells following oral stavudine administration to mice at dosages of 600 to 2000 mg/kg/day for 3 days. # Clinical Studies The combination use of stavudine is based on the results of clinical studies in HIV-1-infected patients in double- and triple-combination regimens with other antiretroviral agents. One of these studies (START 1) was a multicenter, randomized, open-label study comparing stavudine (40 mg twice daily) plus lamivudine plus indinavir to zidovudine plus lamivudine plus indinavir in 202 treatment-naive patients. Both regimens resulted in a similar magnitude of inhibition of HIV-1 RNA levels and increases in CD4+cell counts through 48 weeks. The efficacy of stavudine was demonstrated in a randomized, double-blind study (AI455-019, conducted 1992 to 1994) comparing stavudine with zidovudine in 822 patients with a spectrum of HIV-1-related symptoms. The outcome in terms of progression of HIV-1 disease and death was similar for both drugs. # How Supplied - Stavudine Capsules 15 mg - Bottle of 60 Capsules - NDC 65862-111-60 - Stavudine Capsules 20 mg - Bottle of 60 Capsules - NDC 65862-112-60 - Stavudine Capsules 30 mg - Bottle of 60 Capsules - NDC 65862-046-60 - Stavudine Capsules 40 mg - Bottle of 60 Capsules - NDC 65862-047-60 ## Storage Store at 20° to 25°C (68° to 77°F) # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Patients should be advised that stavudine is not a cure for HIV-1 infection, and that they may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections. Patients should be advised to remain under the care of a physician when using stavudine and the importance of adherence to any antiretroviral regimen including those that contain stavudine. Patients should be advised to avoid doing things that can spread HIV-1 infection to others. - Do not share needles or other injection equipment. - Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades. - Do not have any kind of sex without protection. Always practice safe sex by using a latex or polyurethane condom or other barrier method to lower the chance of sexual contact with semen, vaginal secretions, or blood. - Do not breastfeed. It is not known if stavudine can be passed to your baby in your breast milk and whether it could harm your baby. Also, mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in breast milk. Patients should be informed that when stavudine is used in combination with other agents with similar toxicities, the incidence of adverse reactions may be higher than when stavudine is used alone. Patients should be instructed that if they miss a dose, to take it as soon as possible. If it is almost time for the next dose, skip the missed dose and continue the regular dosing schedule. Patients should be instructed if they take too much stavudine, they should contact a poison control center or emergency room right away. Patients should be informed that the Centers for Disease Control and Prevention (CDC) recommend that HIV-infected mothers not nurse newborn infants to reduce the risk of postnatal transmission of HIV infection. Patients should be informed of the importance of early recognition of symptoms of symptomatic hyperlactatemia or lactic acidosis syndrome, which include unexplained weight loss, abdominal discomfort, nausea, vomiting, fatigue, dyspnea, and motor weakness. Patients in whom these symptoms develop should seek medical attention immediately. Discontinuation of stavudine therapy may be required. Patients should be informed that an increased risk of hepatotoxicity, which may be fatal, may occur in patients treated with stavudine in combination with didanosine and hydroxyurea. This combination should be avoided. Patients should be informed that an important toxicity of stavudine is peripheral neuropathy. Patients should be aware that peripheral neuropathy is manifested by numbness, tingling, or pain in hands or feet, and that these symptoms should be reported to their physicians. Patients should be counseled that peripheral neuropathy occurs with greatest frequency in patients who have advanced HIV-1 disease or a history of peripheral neuropathy, and discontinuation of stavudine may be required if toxicity develops. Caregivers of young children receiving stavudine therapy should be instructed regarding detection and reporting of peripheral neuropathy. Patients should be informed that an increased risk of pancreatitis, which may be fatal, may occur in patients treated with the combination of stavudine and didanosine. This combination should be avoided. Patients should be closely monitored for symptoms of pancreatitis. The patient should be instructed to avoid alcohol while taking stavudine. Alcohol may increase the patient’s risk of pancreatitis or liver damage. Patients should be informed that redistribution or accumulation of body fat may occur in individuals receiving antiretroviral therapy including stavudine. Patients receiving stavudine should be monitored for clinical signs and symptoms of lipoatrophy/lipodystrophy. Patients should be routinely questioned about body changes related to lipoatrophy/lipodystrophy. # Precautions with Alcohol Alcohol-Stavudine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Zerit # Look-Alike Drug Names There is limited information regarding Stavudine Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Stavudine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gloria Picoy [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 Stavudine is a nucleoside reverse transcriptase inhibitor that is FDA approved for the treatment of human immunodeficiency virus (HIV)-1 infection. There is a Black Box Warning for this drug as shown here. Common adverse reactions include headache, diarrhea, peripheral neuropathy, rash, nausea, and vomiting. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Stavudine capsules, in combination with other antiretroviral agents, are indicated for the treatment of human immunodeficiency virus (HIV)-1 infection. - Dosage: - For patients weighing less than 60 kg: 30 mg every 12 hours. - For patients weighing at least 60 kg: 40 mg every 12 hours. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Stavudine in adult patients. ### Non–Guideline-Supported Use Prophylaxis of occupational exposure to HIV - Dosage [1] - Lamivudine: 300 mg once daily or 150 mg twice daily, AND - Stavudine: 40 mg twice daily for 4 weeks. If body weight is less than 60 kg, 30 mg twice daily for 4 weeks; if toxicity occurs, lower doses of 20 to 30 mg twice daily for 4 weeks can be used. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) Stavudine capsules, in combination with other antiretroviral agents, are indicated for the treatment of human immunodeficiency virus (HIV)-1 infection. - Dosage: - For newborns from birth to 13 days old: 0.5 mg/kg given every 12 hours. - For pediatric patients at least 14 days old and weighing less than 30 kg: 1 mg/kg given every 12 hours. - For pediatric patients weighing at least 30 kg: use the recommended adult dosage. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Stavudine in pediatric patients. ### Non–Guideline-Supported Use Prophylaxis of occupational exposure to HIV - Dosage [1] - Lamivudine: 300 mg once daily or 150 mg twice daily, AND - Stavudine: 40 mg twice daily for 4 weeks. If body weight is less than 60 kg, 30 mg twice daily for 4 weeks; if toxicity occurs, lower doses of 20 to 30 mg twice daily for 4 weeks can be used. # Contraindications Stavudine capsules are contraindicated in patients with clinically significant hypersensitivity to stavudine or to any of the components contained in the formulation. # Warnings Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including stavudine and other antiretrovirals. Although relative rates of lactic acidosis have not been assessed in prospective well-controlled trials, longitudinal cohort and retrospective studies suggest that this infrequent event may be more often associated with antiretroviral combinations containing stavudine. Female gender, obesity, and prolonged nucleoside exposure may be risk factors. Fatal lactic acidosis has been reported in pregnant women who received the combination of stavudine and didanosine with other antiretroviral agents. The combination of stavudine and didanosine should be used with caution during pregnancy and is recommended only if the potential benefit clearly outweighs the potential risk. Particular caution should be exercised when administering stavudine to any patient with known risk factors for liver disease; however, cases of lactic acidosis have also been reported in patients with no known risk factors. Generalized fatigue, digestive symptoms (nausea, vomiting, abdominal pain, and unexplained weight loss); respiratory symptoms (tachypnea and dyspnea); or neurologic symptoms, including motor weakness might be indicative of the development of symptomatic hyperlactatemia or lactic acidosis syndrome. Treatment with stavudine should be suspended in any patient who develops clinical or laboratory findings suggestive of symptomatic hyperlactatemia, lactic acidosis, or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations). Permanent discontinuation of stavudine should be considered for patients with confirmed lactic acidosis. The safety and efficacy of stavudine have not been established in HIV-infected patients with significant underlying liver disease. During combination antiretroviral therapy, patients with preexisting liver dysfunction, including chronic active hepatitis, have an increased frequency of liver function abnormalities, including severe and potentially fatal hepatic adverse events, and should be monitored according to standard practice. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment must be considered. Hepatotoxicity and hepatic failure resulting in death were reported during postmarketing surveillance in HIV-infected patients treated with hydroxyurea and other antiretroviral agents. Fatal hepatic events were reported most often in patients treated with the combination of hydroxyurea, didanosine, and stavudine. This combination should be avoided. In vitro studies have shown ribavirin can reduce the phosphorylation of pyrimidine nucleoside analogues such as stavudine. Although no evidence of a pharmacokinetic or pharmacodynamic (e.g., loss of HIV-1/HCV virologic suppression) interaction was seen when ribavirin was coadministered with stavudine in HIV-1/HCV co-infected patients, hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy for HIV-1 and interferon and ribavirin. Patients receiving interferon with or without ribavirin and stavudine should be closely monitored for treatment-associated toxicities, especially hepatic decompensation. Discontinuation of stavudine should be considered as medically appropriate. Dose reduction or discontinuation of interferon, ribavirin, or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh >6) (see the full prescribing information for interferon and ribavirin). Motor weakness has been reported rarely in patients receiving combination antiretroviral therapy including stavudine. Most of these cases occurred in the setting of lactic acidosis. The evolution of motor weakness may mimic the clinical presentation of Guillain-Barré syndrome (including respiratory failure). If motor weakness develops, stavudine should be discontinued. Symptoms may continue or worsen following discontinuation of therapy. Peripheral sensory neuropathy, manifested by numbness, tingling, or pain in the hands or feet, has been reported in patients receiving stavudine therapy. Peripheral neuropathy, which can be severe, is dose related and occurs more frequently in patients with advanced HIV-1 disease, a history of peripheral neuropathy, or in patients receiving other drugs that have been associated with neuropathy, including didanosine. Patients should be monitored for the development of peripheral neuropathy. Stavudine-related peripheral neuropathy may resolve if therapy is withdrawn promptly. If peripheral neuropathy develops permanent discontinuation of stavudine should be considered. In some cases, symptoms may worsen temporarily following discontinuation of therapy. Fatal and nonfatal pancreatitis have occurred during therapy when stavudine was part of a combination regimen that included didanosine in both treatment-naive and treatment-experienced patients, regardless of degree of immunosuppression. The combination of stavudine and didanosine and any other agents that are toxic to the pancreas should be suspended in patients with suspected pancreatitis. Reinstitution of stavudine after a confirmed diagnosis of pancreatitis should be undertaken with particular caution and close patient monitoring; avoid use in combination with didanosine. Fat redistribution including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. In randomized controlled trials of treatment-naive patients, clinical lipoatrophy or lipodystrophy developed in a higher proportion of patients treated with stavudine compared to other nucleosides (tenofovir or abacavir). Dual energy x-ray absorptiometry (DEXA) scans demonstrated overall limb fat loss in stavudine-treated patients compared to limb fat gain or no gain in patients treated with other nucleosides (abacavir, tenofovir, or zidovudine). The incidence and severity of lipoatrophy or lipodystrophy are cumulative over time with stavudine-containing regimens. In clinical trials, switching from stavudine to other nucleosides (tenofovir or abacavir) resulted in increases in limb fat with modest to no improvements in clinical lipoatrophy. Patients receiving stavudine should be monitored for symptoms or signs of lipoatrophy or lipodystrophy and questioned about body changes related to lipoatrophy or lipodystrophy. Given the potential risks of using stavudine including lipoatrophy or lipodystrophy, a benefit-risk assessment for each patient should be made and an alternative antiretroviral should be considered. Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including stavudine. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia (PCP), or tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment. # 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. Selected adverse reactions that occurred in adult patients receiving stavudine in a controlled monotherapy study (Study AI455-019) are provided in Table 2. Pancreatitis was observed in 3 of the 412 adult patients who received stavudine in study AI455-019. Selected adverse reactions that occurred in antiretroviral-naive adult patients receiving stavudine from two controlled combination studies are provided in Table 3. Selected laboratory abnormalities reported in a controlled monotherapy study (Study AI455-019) are provided in Table 4. [[\|thumb\|none\|500px]] Selected laboratory abnormalities reported in two controlled combination studies are provided in Tables 5 and 6. Selected laboratory abnormalities reported in two controlled combination studies are provided in Tables 5 and 6. Adverse reactions and serious laboratory abnormalities reported in pediatric patients from birth through adolescence during clinical trials were similar in type and frequency to those seen in adult patients. ## Postmarketing Experience The following adverse reactions have been identified during postmarketing use of stavudine. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These reactions have been chosen for inclusion due to their seriousness, frequency of reporting, causal connection to stavudine, or a combination of these factors. - Body as a Whole: abdominal pain, allergic reaction, chills/fever, and redistribution/accumulation of body fat. - Digestive Disorders: anorexia. - Exocrine Gland Disorders: pancreatitis, including fatal cases. - Hematologic Disorders: anemia, leukopenia, thrombocytopenia, neutropenia, and macrocytosis. - Liver: symptomatic hyperlactatemia/lactic acidosis and hepatic steatosis, hepatitis and liver failure. - Metabolic Disorders: lipoatrophy, lipodystrophy, diabetes mellitus and hyperglycemia. - Musculoskeletal: myalgia. - Nervous System: insomnia, severe motor weakness (most often reported in the setting of lactic acidosis) # Drug Interactions Stavudine is unlikely to interact with drugs metabolized by cytochrome P450 isoenzymes. - Zidovudine: Zidovudine competitively inhibits the intracellular phosphorylation of stavudine. Therefore, use of zidovudine in combination with stavudine should be avoided. - Doxorubicin: In vitro data indicate that the phosphorylation of stavudine is inhibited at relevant concentrations by doxorubicin. The clinical significance of this interaction is unknown; therefore, concomitant use of stavudine with doxorubicin should be undertaken with caution. - Ribavirin: In vitro data indicate ribavirin reduces phosphorylation of lamivudine, stavudine, and zidovudine. The clinical significance of the interaction with stavudine is unknown; therefore, concomitant use of stavudine with ribavirin should be undertaken with caution. No pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV-1/HCV virologic suppression) interaction was observed when ribavirin and lamivudine (n=18), stavudine (n=10), or zidovudine (n=6) were coadministered as part of a multi-drug regimen to HIV-1/HCV co-infected patients. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C Reproduction studies have been performed in rats and rabbits with exposures (based on Cmax) up to 399 and 183 times, respectively, of that seen at a clinical dosage of 1 mg/kg/day and have revealed no evidence of teratogenicity. The incidence in fetuses of a common skeletal variation, unossified or incomplete ossification of sternebra, was increased in rats at 399 times human exposure, while no effect was observed at 216 times human exposure. A slight post-implantation loss was noted at 216 times the human exposure with no effect noted at approximately 135 times the human exposure. An increase in early rat neonatal mortality (birth to 4 days of age) occurred at 399 times the human exposure, while survival of neonates was unaffected at approximately 135 times the human exposure. A study in rats showed that stavudine is transferred to the fetus through the placenta. The concentration in fetal tissue was approximately one-half the concentration in maternal plasma. Animal reproduction studies are not always predictive of human response. There are no adequate and well-controlled studies of stavudine in pregnant women. Stavudine should be used during pregnancy only if the potential benefit justifies the potential risk. Fatal lactic acidosis has been reported in pregnant women who received the combination of stavudine and didanosine with other antiretroviral agents. It is unclear if pregnancy augments the risk of lactic acidosis/hepatic steatosis syndrome reported in nonpregnant individuals receiving nucleoside analogues. The combination of stavudine and didanosine should be used with caution during pregnancy and is recommended only if the potential benefit clearly outweighs the potential risk. Healthcare providers caring for HIV-infected pregnant women receiving stavudine should be alert for early diagnosis of lactic acidosis/hepatic steatosis syndrome. Pregnancy Category (AUS): B3 There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Stavudine in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Stavudine during labor and delivery. ### Nursing Mothers The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV. Studies in lactating rats demonstrated that stavudine is excreted in milk. Although it is not known whether stavudine is excreted in human milk, there exists the potential for adverse effects from stavudine in nursing infants. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving stavudine. ### Pediatric Use Use of stavudine in pediatric patients from birth through adolescence is supported by evidence from adequate and well-controlled studies of stavudine in adults with additional pharmacokinetic and safety data in pediatric patients. Adverse reactions and laboratory abnormalities reported to occur in pediatric patients in clinical studies were generally consistent with the safety profile of stavudine in adults. These studies include ACTG 240, where 105 pediatric patients ages 3 months to 6 years received stavudine 2 mg/kg/day for a median of 6.4 months; a controlled clinical trial where 185 newborns received stavudine 2 mg/kg/day either alone or in combination with didanosine from birth through 6 weeks of age; and a clinical trial where 8 newborns received stavudine 2 mg/kg/day in combination with didanosine and nelfinavir from birth through 4 weeks of age. Stavudine pharmacokinetics have been evaluated in 25 HIV-1-infected pediatric patients ranging in age from 5 weeks to 15 years and in weight from 2 to 43 kg after IV or oral administration of single doses and twice-daily regimens and in 30 HIV-1-exposed or -infected newborns ranging in age from birth to 4 weeks after oral administration of twice-daily regimens. ### Geriatic Use Clinical studies of stavudine did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently than younger patients. Greater sensitivity of some older individuals to the effects of stavudine cannot be ruled out. In a monotherapy Expanded Access Program for patients with advanced HIV-1 infection, peripheral neuropathy or peripheral neuropathic symptoms were observed in 15 of 40 (38%) elderly patients receiving 40 mg twice daily and 8 of 51 (16%) elderly patients receiving 20 mg twice daily. Of the approximately 12,000 patients enrolled in the Expanded Access Program, peripheral neuropathy or peripheral neuropathic symptoms developed in 30% of patients receiving 40 mg twice daily and 25% of patients receiving 20 mg twice daily. Elderly patients should be closely monitored for signs and symptoms of peripheral neuropathy. Stavudine 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, it may be useful to monitor renal function. Dose adjustment is recommended for patients with renal impairment. ### Gender A population pharmacokinetic analysis of data collected during a controlled clinical study in HIV-1-infected patients showed no clinically important differences between males (n=291) and females (n=27). ### Race A population pharmacokinetic analysis of data collected during a controlled clinical study in HIV-1-infected patients showed no clinically important differences between races (n=233 Caucasian, 39 African-American, 41 Hispanic, 1 Asian, and 4 other). ### Renal Impairment Data from two studies in adults indicated that the apparent oral clearance of stavudine decreased and the terminal elimination half-life increased as creatinine clearance decreased. Based on these observations, it is recommended that the stavudine dosage be modified in patients with reduced creatinine clearance and in patients receiving maintenance hemodialysis. ### Hepatic Impairment Stavudine pharmacokinetics were not altered in five non-HIV-infected patients with hepatic impairment secondary to cirrhosis (Child-Pugh classification B or C) following the administration of a single 40 mg dose. ### Females of Reproductive Potential and Males No evidence of impaired fertility was seen in rats with exposures (based on Cmax) up to 216 times that observed following a clinical dosage of 1 mg/kg/day. ### Immunocompromised Patients There is no FDA guidance one the use of Stavudine in patients who are immunocompromised. # Administration and Monitoring ### Administration Oral ### Monitoring There is limited information regarding Stavudine Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Stavudine and IV administrations. # Overdosage Experience with adults treated with 12 to 24 times the recommended daily dosage revealed no acute toxicity. Complications of chronic overdosage include peripheral neuropathy and hepatic toxicity. Stavudine can be removed by hemodialysis; the mean ± SD hemodialysis clearance of stavudine is 120 ± 18 mL/min. Whether stavudine is eliminated by peritoneal dialysis has not been studied. # Pharmacology ## Mechanism of Action Stavudine, a nucleoside analogue of thymidine, is phosphorylated by cellular kinases to the active metabolite stavudine triphosphate. Stavudine triphosphate inhibits the activity of HIV-1 reverse transcriptase (RT) by competing with the natural substrate thymidine triphosphate (Ki=0.0083 to 0.032 μM) and by causing DNA chain termination following its incorporation into viral DNA. Stavudine triphosphate inhibits cellular DNA polymerases β and γ and markedly reduces the synthesis of mitochondrial DNA. ## Structure Stavudine has the following structural formula: ## Pharmacodynamics There is limited information regarding Stavudine Pharmacodynamics in the drug label. ## Pharmacokinetics The pharmacokinetics of stavudine have been evaluated in HIV-1-infected adult and pediatric patients (Tables 7, 8, and 9). Peak plasma concentrations (Cmax) and area under the plasma concentration-time curve (AUC) increased in proportion to dose after both single and multiple doses ranging from 0.03 to 4 mg/kg. There was no significant accumulation of stavudine with repeated administration every 6, 8, or 12 hours. Following oral administration, stavudine is rapidly absorbed, with peak plasma concentrations occurring within 1 hour after dosing. The systemic exposure to stavudine is the same following administration as capsules or solution. Steady-state pharmacokinetic parameters of stavudine in HIV-1-infected adults are shown in Table 7. Binding of stavudine to serum proteins was negligible over the concentration range of 0.01 to 11.4 mcg/mL. Stavudine distributes equally between red blood cells and plasma. Volume of distribution is shown in Table 8. Metabolism plays a limited role in the clearance of stavudine. Unchanged stavudine was the major drug-related component circulating in plasma after an 80 mg dose of 14C-stavudine, while metabolites constituted minor components of the circulating radioactivity. Minor metabolites include oxidized stavudine, glucuronide conjugates of stavudine and its oxidized metabolite, and an N-acetylcysteine conjugate of the ribose after glycosidic cleavage, suggesting that thymine is also a metabolite of stavudine. Following an 80 mg dose of 14C-stavudine to healthy subjects, approximately 95% and 3% of the total radioactivity was recovered in urine and feces, respectively. Radioactivity due to parent drug in urine and feces was 73.7% and 62%, respectively. The mean terminal elimination half-life is approximately 2.3 hours following single oral doses. Mean renal clearance of the parent compound is approximately 272 mL/min, accounting for approximately 67% of the apparent oral clearance. In HIV-1-infected patients, renal elimination of unchanged drug accounts for about 40% of the overall clearance regardless of the route of administration (Table 8). The mean renal clearance was about twice the average endogenous creatinine clearance, indicating active tubular secretion in addition to glomerular filtration. ## Nonclinical Toxicology The cell culture antiviral activity of stavudine was measured in peripheral blood mononuclear cells, monocytic cells, and lymphoblastoid cell lines. The concentration of drug necessary to inhibit HIV-1 replication by 50% (EC50) ranged from 0.009 to 4 μM against laboratory and clinical isolates of HIV-1. In cell culture, stavudine exhibited additive to antagonistic activity in combination with zidovudine. Stavudine in combination with either abacavir, didanosine, tenofovir, or zalcitabine exhibited additive to synergistic anti-HIV-1 activity. Ribavirin, at the 9 to 45 μM concentrations tested, reduced the anti-HIV-1 activity of stavudine by 2.5- to 5-fold. The relationship between cell culture susceptibility of HIV-1 to stavudine and the inhibition of HIV-1 replication in humans has not been established. HIV-1 isolates with reduced susceptibility to stavudine have been selected in cell culture (strain-specific) and were also obtained from patients treated with stavudine. Phenotypic analysis of HIV-1 isolates from 61 patients receiving prolonged (6 to 29 months) stavudine monotherapy showed that post-therapy isolates from four patients exhibited EC50 values more than 4-fold (range 7- to 16-fold) higher than the average pretreatment susceptibility of baseline isolates. Of these, HIV-1 isolates from one patient contained the zidovudine-resistance-associated substitutions T215Y and K219E, and isolates from another patient contained the multiple-nucleoside-resistance-associated substitution Q151M. Mutations in the RT gene of HIV-1 isolates from the other two patients were not detected. The genetic basis for stavudine susceptibility changes has not been identified. Cross-resistance among HIV-1 reverse transcriptase inhibitors has been observed. Several studies have demonstrated that prolonged stavudine treatment can select and/or maintain thymidine analogue mutations (TAMs; M41L, D67N, K70R, L210W, T215Y/F, K219Q/E) associated with zidovudine resistance. HIV-1 isolates with one or more TAMs exhibited reduced susceptibility to stavudine in cell culture. These TAMs are seen at a similar frequency with stavudine and zidovudine in virological treatment. The clinical relevance of these findings suggests that stavudine should be avoided in the presence of thymidine analogue mutations. In 2-year carcinogenicity studies in mice and rats, stavudine was noncarcinogenic at doses which produced exposures (AUC) 39 and 168 times, respectively, human exposure at the recommended clinical dose. Benign and malignant liver tumors in mice and rats and malignant urinary bladder tumors in male rats occurred at levels of exposure 250 (mice) and 732 (rats) times human exposure at the recommended clinical dose. Stavudine was not mutagenic in the Ames, E. coli reverse mutation, or the CHO/HGPRT mammalian cell forward gene mutation assays, with and without metabolic activation. Stavudine produced positive results in the in vitro human lymphocyte clastogenesis and mouse fibroblast assays, and in the in vivo mouse micronucleus test. In the in vitro assays, stavudine elevated the frequency of chromosome aberrations in human lymphocytes (concentrations of 25 to 250 mcg/mL, without metabolic activation) and increased the frequency of transformed foci in mouse fibroblast cells (concentrations of 25 to 2500 mcg/mL, with and without metabolic activation). In the in vivo micronucleus assay, stavudine was clastogenic in bone marrow cells following oral stavudine administration to mice at dosages of 600 to 2000 mg/kg/day for 3 days. # Clinical Studies The combination use of stavudine is based on the results of clinical studies in HIV-1-infected patients in double- and triple-combination regimens with other antiretroviral agents. One of these studies (START 1) was a multicenter, randomized, open-label study comparing stavudine (40 mg twice daily) plus lamivudine plus indinavir to zidovudine plus lamivudine plus indinavir in 202 treatment-naive patients. Both regimens resulted in a similar magnitude of inhibition of HIV-1 RNA levels and increases in CD4+cell counts through 48 weeks. The efficacy of stavudine was demonstrated in a randomized, double-blind study (AI455-019, conducted 1992 to 1994) comparing stavudine with zidovudine in 822 patients with a spectrum of HIV-1-related symptoms. The outcome in terms of progression of HIV-1 disease and death was similar for both drugs. # How Supplied - Stavudine Capsules 15 mg - Bottle of 60 Capsules - NDC 65862-111-60 - Stavudine Capsules 20 mg - Bottle of 60 Capsules - NDC 65862-112-60 - Stavudine Capsules 30 mg - Bottle of 60 Capsules - NDC 65862-046-60 - Stavudine Capsules 40 mg - Bottle of 60 Capsules - NDC 65862-047-60 ## Storage Store at 20° to 25°C (68° to 77°F) # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Patients should be advised that stavudine is not a cure for HIV-1 infection, and that they may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections. Patients should be advised to remain under the care of a physician when using stavudine and the importance of adherence to any antiretroviral regimen including those that contain stavudine. Patients should be advised to avoid doing things that can spread HIV-1 infection to others. - Do not share needles or other injection equipment. - Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades. - Do not have any kind of sex without protection. Always practice safe sex by using a latex or polyurethane condom or other barrier method to lower the chance of sexual contact with semen, vaginal secretions, or blood. - Do not breastfeed. It is not known if stavudine can be passed to your baby in your breast milk and whether it could harm your baby. Also, mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in breast milk. Patients should be informed that when stavudine is used in combination with other agents with similar toxicities, the incidence of adverse reactions may be higher than when stavudine is used alone. Patients should be instructed that if they miss a dose, to take it as soon as possible. If it is almost time for the next dose, skip the missed dose and continue the regular dosing schedule. Patients should be instructed if they take too much stavudine, they should contact a poison control center or emergency room right away. Patients should be informed that the Centers for Disease Control and Prevention (CDC) recommend that HIV-infected mothers not nurse newborn infants to reduce the risk of postnatal transmission of HIV infection. Patients should be informed of the importance of early recognition of symptoms of symptomatic hyperlactatemia or lactic acidosis syndrome, which include unexplained weight loss, abdominal discomfort, nausea, vomiting, fatigue, dyspnea, and motor weakness. Patients in whom these symptoms develop should seek medical attention immediately. Discontinuation of stavudine therapy may be required. Patients should be informed that an increased risk of hepatotoxicity, which may be fatal, may occur in patients treated with stavudine in combination with didanosine and hydroxyurea. This combination should be avoided. Patients should be informed that an important toxicity of stavudine is peripheral neuropathy. Patients should be aware that peripheral neuropathy is manifested by numbness, tingling, or pain in hands or feet, and that these symptoms should be reported to their physicians. Patients should be counseled that peripheral neuropathy occurs with greatest frequency in patients who have advanced HIV-1 disease or a history of peripheral neuropathy, and discontinuation of stavudine may be required if toxicity develops. Caregivers of young children receiving stavudine therapy should be instructed regarding detection and reporting of peripheral neuropathy. Patients should be informed that an increased risk of pancreatitis, which may be fatal, may occur in patients treated with the combination of stavudine and didanosine. This combination should be avoided. Patients should be closely monitored for symptoms of pancreatitis. The patient should be instructed to avoid alcohol while taking stavudine. Alcohol may increase the patient’s risk of pancreatitis or liver damage. Patients should be informed that redistribution or accumulation of body fat may occur in individuals receiving antiretroviral therapy including stavudine. Patients receiving stavudine should be monitored for clinical signs and symptoms of lipoatrophy/lipodystrophy. Patients should be routinely questioned about body changes related to lipoatrophy/lipodystrophy. # Precautions with Alcohol Alcohol-Stavudine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Zerit [2] # Look-Alike Drug Names There is limited information regarding Stavudine Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Stavudine
ac0d157c24089e2ee9771f675c7d1c0a506e47e8	wikidoc	Steatosis	Steatosis # Overview In cellular pathology, steatosis (also called fatty change) is the process describing the abnormal retention of lipids within a cell. It reflects an impairment of the normal processes of synthesis and breakdown of triglyceride fat. Excess lipid accumulates in vesicles that displace the cytoplasm. When the vesicles are large enough to distort the nucleus, the condition is known as macrovesicular steatosis, otherwise the condition is known as microvesicular steatosis. Whilst not particularly detrimental to the cell in mild cases, large accumulations can disrupt cell constituents, and in severe cases the cell may even burst. The risk factors associated with steatosis are varied, and include diabetes mellitus, protein malnutrition, hypertension cell toxins, obesity, and anoxia. As the liver is the primary organ of lipid metabolism it is most often associated with steatosis, however it may occur in any organ, commonly the kidneys, heart, and muscle. # Historical Perspective # Classification # Pathophysiology ## Pathogenesis No single mechanism leading to steatosis exists, rather a varied multitude of pathologies disrupt normal lipid movement through the cell and cause accumulation. These mechanisms can be separated on whether they ultimately cause an oversupply of lipid which can not be removed quickly enough (too much in), or whether they cause a failure in lipid breakdown (not enough being utilised). Oversupply of lipid may occur due to obesity, insulin resistance, or alcoholism. Nutrient malnutrition may also cause the mobilisation of fat from adipocytes and create a local oversupply in the liver where lipid metabolism occurs. Excess alcohol over a long period of time can induce steatosis. The breakdown of large amounts of ethanol in alcoholic drinks produces large amounts of chemical energy, in the form of NADH, signalling to the cell to inhibit the breakdown of fatty acids (which also produces energy) and simultaneously increase the synthesis of fatty acids. This "false sense of energy" results in more lipid being created than is needed. Failure of lipid metabolism can also lead to the mechanisms which would normally utilise or remove lipids becoming impaired, resulting in the accumulation of unused lipids in the cell. Certain toxins, such as alcohols, carbon tetrachloride, aspirin, and diphtheria toxin, interfere with cellular machinery involved in lipid metabolism. In those with Gaucher's disease, the lysosomes fail to degrade lipids and steatosis arises from the accumulation of glycolipids. Protein malnutrition, such as that seen in kwashiorkor, results in a lack of precursor apoproteins within the cell, therefore unused lipids which would normally participate in lipoprotein synthesis begin to accumulate. # Causes ## Drug Side Effect - Adefovir - Telbivudine - Zidovudine # Differentiating Steatosis from Other Diseases # Epidemiology and Demographics ## Appearance Histologically, steatosis is physically apparent as lipid within membrane bound liposomes of parenchymal cells. When this tissue is fixed and stained to be better viewed under a microscope, the lipid is usually dissolved by the solvents used to prepare the sample. As such, samples prepared this way will appear to have empty holes within the cells where the lipid has been cleared. Special lipid stains, such as Sudan stains and osmium tetroxide are able to retain and show up lipid droplets, hence more conclusively indicating the presence of lipids. Other intracellular accumulations, such as water or glycogen, can also appear as clear vacuoles, therefore it becomes necessary to use stains to better decide what is accumulating. Grossly, steatosis causes organ enlargement and lightning in colour. This is due to the high lipid content increasing the organ's volume and becoming visible to the unaided eye. In severe cases, the organ may become vastly enlarged, greasy, and yellow in appearance. # Risk Factors # Screening # Natural History, Complications, and Prognosis # Diagnosis ## Diagnosis Criteria ## History and Symptoms ## Physical Examination ## Laboratory Findings ## Imaging Findings ## Other Diagnostic Studies # Treatment ## Medical Therapy ## Surgery ## Prevention # Related Chapters - Fatty liver - Lipid metabolism - Non-alcoholic fatty liver disease	Steatosis Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: # Overview In cellular pathology, steatosis (also called fatty change) is the process describing the abnormal retention of lipids within a cell. It reflects an impairment of the normal processes of synthesis and breakdown of triglyceride fat. Excess lipid accumulates in vesicles that displace the cytoplasm. When the vesicles are large enough to distort the nucleus, the condition is known as macrovesicular steatosis, otherwise the condition is known as microvesicular steatosis. Whilst not particularly detrimental to the cell in mild cases, large accumulations can disrupt cell constituents, and in severe cases the cell may even burst. The risk factors associated with steatosis are varied, and include diabetes mellitus,[1] protein malnutrition,[2] hypertension[3] cell toxins, obesity,[4] and anoxia.[5] As the liver is the primary organ of lipid metabolism it is most often associated with steatosis, however it may occur in any organ, commonly the kidneys, heart, and muscle.[5] # Historical Perspective # Classification # Pathophysiology ## Pathogenesis No single mechanism leading to steatosis exists, rather a varied multitude of pathologies disrupt normal lipid movement through the cell and cause accumulation. These mechanisms can be separated on whether they ultimately cause an oversupply of lipid which can not be removed quickly enough (too much in), or whether they cause a failure in lipid breakdown (not enough being utilised). Oversupply of lipid may occur due to obesity, insulin resistance, or alcoholism. Nutrient malnutrition may also cause the mobilisation of fat from adipocytes and create a local oversupply in the liver where lipid metabolism occurs. Excess alcohol over a long period of time can induce steatosis. The breakdown of large amounts of ethanol in alcoholic drinks produces large amounts of chemical energy, in the form of NADH, signalling to the cell to inhibit the breakdown of fatty acids (which also produces energy) and simultaneously increase the synthesis of fatty acids. This "false sense of energy" results in more lipid being created than is needed. Failure of lipid metabolism can also lead to the mechanisms which would normally utilise or remove lipids becoming impaired, resulting in the accumulation of unused lipids in the cell. Certain toxins, such as alcohols, carbon tetrachloride, aspirin, and diphtheria toxin, interfere with cellular machinery involved in lipid metabolism. In those with Gaucher's disease, the lysosomes fail to degrade lipids and steatosis arises from the accumulation of glycolipids. Protein malnutrition, such as that seen in kwashiorkor, results in a lack of precursor apoproteins within the cell, therefore unused lipids which would normally participate in lipoprotein synthesis begin to accumulate. # Causes ## Drug Side Effect - Adefovir - Telbivudine - Zidovudine # Differentiating Steatosis from Other Diseases # Epidemiology and Demographics ## Appearance Histologically, steatosis is physically apparent as lipid within membrane bound liposomes of parenchymal cells[5]. When this tissue is fixed and stained to be better viewed under a microscope, the lipid is usually dissolved by the solvents used to prepare the sample. As such, samples prepared this way will appear to have empty holes within the cells where the lipid has been cleared. Special lipid stains, such as Sudan stains and osmium tetroxide are able to retain and show up lipid droplets, hence more conclusively indicating the presence of lipids. Other intracellular accumulations, such as water or glycogen, can also appear as clear vacuoles, therefore it becomes necessary to use stains to better decide what is accumulating. Grossly, steatosis causes organ enlargement and lightning in colour[5]. This is due to the high lipid content increasing the organ's volume and becoming visible to the unaided eye. In severe cases, the organ may become vastly enlarged, greasy, and yellow in appearance. # Risk Factors # Screening # Natural History, Complications, and Prognosis # Diagnosis ## Diagnosis Criteria ## History and Symptoms ## Physical Examination ## Laboratory Findings ## Imaging Findings ## Other Diagnostic Studies # Treatment ## Medical Therapy ## Surgery ## Prevention # Related Chapters - Fatty liver - Lipid metabolism - Non-alcoholic fatty liver disease	https://www.wikidoc.org/index.php/Steatosis

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