Oseltamivir

312.4

312.40

1308068-626-2

20O93L6F9H

DTXSID9044291

C62061

J05AH02|J - Antiinfectives for systemic use

90.6

1

Solid

1.08±0.1 g/cm3(Predicted)

107-108 °C

473.3±45.0 °C(Predicted)

223.2±31.5 °C

1.529

H2O: soluble

Store the capsules at 25 deg C (77 deg F); excursions permitted to 15 deg to 30 deg C (59 deg to 86 deg F).

1.3X10-8 mm Hg at 25 deg C (est)

Henry's Law constant = 2.9X10-16 atm-cu m/mol at 25 °C (est)

pKa = 7.7 at 25 °C (primary amine)

180.7 Ų [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]

Mol wt: 410.40. White crystalline solid /Phosphate/|Hydroxyl radical reaction rate constant = 1.3X10-10 cu cm/molecule-sec at 25 °C (est)

SRP: The most favorable course of action is to use an alternative chemical product with less inherent propensity for occupational exposure or environmental contamination. Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in soil or water; effects on animal, aquatic, and plant life; and conformance with environmental and public health regulations.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl oseltamivir phosphate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Oseltamivir phosphate/

Reports of overdoses with oseltamivir have been received from clinical trials and during postmarketing experience. In the majority of cases reporting overdose, no adverse reactions were reported. Adverse reactions reported following overdose were similar in nature to those observed with therapeutic doses of oseltamivir.

In clinical trials of oseltamivir, serum aminotransferase elevations occurred in 2% of treated subjects, but were asymptomatic and transient in all and there were no reports of clinically apparent liver injury with jaundice. The rates of ALT elevations with oseltamivir were generally similar to those treated with placebo or with a comparative agents. Since its approval in 1999, oseltamivir has been widely used during influenza seasonal outbreaks. There have been a few, isolated reports of mild liver injury in patients receiving oseltamivir, but the relationship of the injury with oseltamivir has not always been very convincingly shown. There have been no reports of acute liver failure or chronic liver disease attributed to oseltamivir use. Furthermore, a proportion of patients with influenza have serum enzyme elevations and even mild jaundice during the acute illness, independent of any therapy.

Concomitant administration /with probenecid/ results in an approximate two-fold increase in the active metabolite due to a decrease in active anionic tubular secretion in the kidney.|In vitro studies demonstrate that neither oseltamivir nor oseltamivir carboxylate is a good substrate for P450 mixed-function oxidases or for glucuronyl transferases. Cimetidine, a non-specific inhibitor of cytochrome P450 isoforms and competitor for renal tubular secretion of basic or cationic drugs, has no effect on plasma levels of oseltamivir or oseltamivir carboxylate.|Coadministration with amoxicillin does not alter plasma levels of either compound, indicating that competition for the anionic secretion pathway is weak.

The binding of the active oseltamivir carboxylate metabolite to human plasma protein is negligible at approximately 3 % while the binding of oseltamivir to human plasma protein is 42%, which is insufficient to cause significant displacement-based drug interactions.

Oseltamivir's production and use as an antiviral drug for the treatment of individuals with influenza(1) may result in its release to the environment through various waste streams(SRC).

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 340(SRC), determined from a structure estimation method(2), indicates that oseltamivir is expected to have moderate mobility in soil(SRC). The pKa of oseltamivir is 7.7 (primary amine)(3), indicating that this compound will exist partially as a cation in the environment and cations generally have lower mobility in soil than their neutral counterparts(4). Volatilization of oseltamivir from moist soil surfaces is not expected to be an important fate process(SRC) because cations do not volatilize and based on an estimated Henry's Law constant of 2.9X10-16 atm-cu m/mole(SRC), calculated using a fragment constant estimation method(5). Oseltamivir is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.3X10-8 mm Hg(SRC), determined from a fragment constant method(6). Biodegradation data were not available(SRC, 2006).|AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 340(SRC), determined from a structure estimation method(2), indicates that oseltamivir is expected to adsorb slightly to suspended solids and sediment(SRC). The pKa of oseltamivir is 7.7 (primary amine)(3), indicating that this compound will exist partially as a cation in the environment and cations generally adsorb to sediment more strongly than their neutral counterparts(4). Volatilization from water surfaces is not expected(5) because cations do not volatilize and based upon an estimated Henry's Law constant of 2.9X10-16 atm-cu m/mole(SRC), developed using a fragment constant estimation method(6). According to a classification scheme(7), an estimated BCF of 3(SRC), from an estimated log Kow of 0.95(8), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation data were not available(SRC, 2006).|ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), oseltamivir, which has an estimated vapor pressure of 1.3X10-8 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase oseltamivir may be removed from the air by wet or dry deposition(SRC). Oseltamivir does not contain chromophores that absorb at wavelengths >290 nm and therefore is not expected to be susceptible to direct photolysis by sunlight(SRC).

A base-catalyzed second-order hydrolysis rate constant of 2.0X10-3 L/mole-sec(SRC) was estimated using a structure estimation method(1); this corresponds to half-lives of 110 and 10 years at pH values of 7 and 8, respectively(1). Oseltamivir does not contain chromophores that absorb at wavelengths >290 nm and therefore is not expected to be susceptible to direct photolysis by sunlight(SRC).

An estimated BCF of 3 was calculated for oseltamivir(SRC), using an estimated log Kow of 0.95(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).

Using a structure estimation method based on molecular connectivity indices(1), the Koc of oseltamivir can be estimated to be 340(SRC). According to a classification scheme(2), this estimated Koc value suggests that oseltamivir is expected to have moderate mobility in soil. The pKa of oseltamivir is 7.7 (primary amine)(3), indicating that this compound will exist partially as a cation in the environment and cations generally adsorb to soil and sediment more strongly than their neutral counterparts(4).

The Henry's Law constant for oseltamivir is estimated as 2.9X10-16 atm-cu m/mole(SRC) using a fragment constant estimation method(1). The pKa of oseltamivir is 7.7 (primary amine)(2), indicating that this compound will exist partially as a cation in the environment. Based on this Henry's Law constant and the fact that cations do not volatilize, oseltamivir is expected to be essentially nonvolatile from moist soil and water surfaces(3). Oseltamivir is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.3X10-8 mm Hg(SRC), determined from a fragment constant method(4).

While data specific to oseltamivir were not located(SRC, 2006), the literature suggests that some pharmaceutically active compounds originating from human and veterinary therapy are not eliminated completely in municipal sewage treatment plants and are therefore discharged into receiving waters(1). Wastewater treatment processes often were not designed to remove them from the effluent(2). Selected organic waste compounds may be degrading to new and more persistent compounds that may be released instead of or in addition to the parent compound(2).

It is not known whether oseltamivir is distributed into human breast milk. Oseltamivir and oseltamivir carboxylate are distributed into the milk of lactating rats.

Occupational exposure to oseltamivir may occur through inhalation and dermal contact with this compound at workplaces where oseltamivir is produced or used. Exposure to oseltamivir among the general population may be limited to those administered this substance as a drug. (SRC)

According to FDA prescribing information, oseltamivir is indicated for the treatment of acute, uncomplicated illness due to influenza A and B infection in patients 2 weeks of age and older who have been symptomatic for no more than 48 hours. In particular, this agent is indicated in adults and children including full-term neonates who present with symptoms typical of influenza when influenza virus is circulating in the community. Efficacy has been demonstrated when treatment is initiated within two days of the first onset of symptoms. Oseltamivir is also indicated for the prophylaxis of influenza in patients one year and older. Specifically, post-exposure prevention in individuals one year of age or older following contact with a clinically diagnosed influenza case when influenza virus is circulating in the community qualifies for such prophylactic therapy. Oseltamivir would only be indicated for post-exposure prevention of influenza in infants less than 1 year of age during a pandemic influenza outbreak.|Treatment of influenzaTamiflu is indicated in adults and children including full term neonates who present with symptoms typical of influenza, when influenza virus is circulating in the community. Efficacy has been demonstrated when treatment is initiated within two days of first onset of symptoms.Prevention of influenzaPost-exposure prevention in individuals one year of age or older following contact with a clinically diagnosed influenza case when influenza virus is circulating in the community.The appropriate use of Tamiflu for prevention of influenza should be determined on a case-by-case basis by the circumstances and the population requiring protection. In exceptional situations (e.g. in case of a mismatch between the circulating and vaccine virus strains, and a pandemic situation) seasonal prevention could be considered in individuals one year of age or older.Tamiflu is indicated for post-exposure prevention of influenza in infants less than 1 year of age during a pandemic-influenza outbreak.Tamiflu is not a substitute for influenza vaccination.The use of antivirals for the treatment and prevention of influenza should be determined on the basis of official recommendations. Decisions regarding the use of oseltamivir for treatment and prophylaxis should take into consideration what is known about the characteristics of the circulating influenza viruses, available information on influenza drug susceptibility patterns for each season and the impact of the disease in different geographical areas and patient populations.|Treatment of influenzaIn patients one year of age and older who present with symptoms typical of influenza, when influenza virus is circulating in the community.Ebilfumin is indicated for the treatment of infants less than 1 year of age during a pandemic influenza outbreak (see section 5.2 of the SmPC). The treating physician should take into account the pathogenicity of the circulating strain and the underlying condition of the patient to ensure there is a potential benefit to the child.Prevention of influenzaPost-exposure prevention in individuals 1 year of age or older following contact with a clinically diagnosed influenza case when influenza virus is circulating in the community.The appropriate use of Ebilfumin for prevention of influenza should be determined on a case by case basis by the circumstances and the population requiring protection. In exceptional situations (e.g. in case of a mismatch between the circulating and vaccine virus strains, and a pandemic situation) seasonal prevention could be considered in individuals one year of age or older.Ebilfumin is indicated for post-exposure prevention of influenza in infants less than 1 year of age during a pandemic influenza outbreak (see section 5.2 of the SmPC).Ebilfumin is not a substitute for influenza vaccination.

Oseltamivir is an inhibitor of the influenza neuraminidase enzyme and is used as therapy and prophylaxis against influenza A and B. Oseltamivir has not been associated with clinically apparent liver injury.

Antiviral Agents

Oseltamivir has known transformation products that include Oseltamivir acid.

Antiviral Agents; Enzyme Inhibitors|At this time, CDC recommends the use of oseltamivir or zanamivir for the treatment of infection with swine influenza (H1N1) viruses.|MEDICATION: Antiviral; Orally active inhibitor of influenza virus neuraminidase; converted in vivo to the active acid metabolite, GS-4071.|Oseltamivir is indicated for the treatment of uncomplicated acute infection caused by influenza A virus in patients older than 1 year of age who have been symptomatic for no more than 2 days. /Included in US product labeling/|For more Therapeutic Uses (Complete) data for OSELTAMIVIR (8 total), please visit the HSDB record page.

Swine influenza (H1N1) viruses contain a unique combination of gene segments that have not been reported previously among swine or human influenza viruses in the US or elsewhere. The H1N1 viruses are resistant to amantadine and rimantadine but not to oseltamivir or zanamivir.|Adverse effects occurring in 1% or more of adults and at an incidence greater than that with placebo include nausea, vomiting, bronchitis, insomnia, and vertigo. Nausea, with or without vomiting, was most common, usually occurring after the initial dose and resolving within 1-2 days, but resulting in drug discontinuance in less than 1% of adults. Adverse effects occurring in 1% or more of children and at an incidence greater than with placebo include vomiting, abdominal pain, epistaxis, otic disorder, and conjunctivitis. Unlike amantadine and rimantadine, neuraminidase inhibitors like oseltamivir do not appear to adversely affect the CNS.|FDA Pregnancy Risk Category: C /RISK CANNOT BE RULED OUT. Adequate, well controlled human studies are lacking, and animal studies have shown risk to the fetus or are lacking as well. There is a chance of fetal harm if the drug is given during pregnancy; but the potential benefits may outweigh the potential risk./|Serious bacterial infections may begin with influenza-like symptoms or may coexist with or occur as complications during the course of influenza. /Oseltamivir/ has not been shown to prevent such complications.|For more Drug Warnings (Complete) data for OSELTAMIVIR (7 total), please visit the HSDB record page.

There have been postmarketing reports of delirium and abnormal behavior leading to injury, and in some cases resulting in fatal outcomes, in patients with influenza who were receiving oseltamivir. Because these events were reported voluntarily during clinical practice, estimates of frequency cannot be made but they appear to be uncommon based on oseltamivir. These events were reported primarily among pediatric patients and often had an abrupt onset and rapid resolution. The contribution of oseltamivir to these events has not been established. Influenza can be associated with a variety of neurologic and behavioral symptoms that can include events such as 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.

Agents used in the prophylaxis or therapy of VIRUS DISEASES. Some of the ways they may act include preventing viral replication by inhibiting viral DNA polymerase; binding to specific cell-surface receptors and inhibiting viral penetration or uncoating; inhibiting viral protein synthesis; or blocking late stages of virus assembly. (See all compounds classified as Antiviral Agents.)|Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. (See all compounds classified as Enzyme Inhibitors.)

Oseltamivir is readily absorbed from the gastrointestinal tract after oral administration of oseltamivir phosphate and is extensively converted by predominantly hepatic esterases to the active metabolite oseltamivir carboxylate. At least 75 % of an oral dose reaches the systemic circulation as the active metabolite. Exposure to the pro-drug is less than 5 % relative to the active metabolite. Plasma concentrations of both pro-drug and active metabolite are proportional to dose and are unaffected by co-administration with food. Pharmacokinetic parameters following twice daily dosing of oseltamivir 75mg capsules are as follows: Cmax of oseltamivir and oseltamivir carboxylate were found to be 65ng/mL and 348ng/mL, respectively, while AUC (0-12h) of oseltamivir and oseltamivir carboxylate were found to be 112ng·h/mL and 2719ng·h/mL, respectively.|Following absorption, oseltamivir is more than 90 % eliminated through conversion to oseltamivir carboxylate and subsequent elimination entirely through renal excretion. During clinical studies, less than 20 % of oral radiolabelled dose was found to be eliminated in faeces.|The mean volume of distribution at steady state of the oseltamivir carboxylate ranges approximately between 23 and 26 liters in humans, a volume that is roughly equivalent to extracellular body fluid. Since neuraminidase activity is extracellular, oseltamivir carboxylate distributes to all sites of influenza virus spread.|Renal clearance (18.8 l/h) of the drug exceeds glomerular filtration rate (7.5 l/h) indicating that tubular secretion occurs in addition to glomerular filtration.|Protein binding: Oseltamivir phosphate: Moderate (42%). Oseltamivir carboxylate: Very low < 3%.|Oseltamivir carboxylate: Volume of distribution is 23 to 26 liters following intravenous administration in 24 subjects.|Oral oseltamivir phosphate is readily absorbed then extensively converted to oseltamivir carboxylate, the active form, predominantly by hepatic esterases. At least 75% of an oral dose reaches the systemic circulation as oseltamivir carboxylate. Less than 5% of an oral dose reaches the systemic circulation as oseltamivir phosphate.|Elimination: Renal: Oseltamivir carboxylate is extensively eliminated by renal excretion (> 99%). Renal clearance (18.8 L/hr) exceeds glomerular filtration rate (7.5 L/hr), indicating that tubular secretion occurs. Fecal: Elimination of an oral radiolabeled dose in < 20% in the feces.|For more Absorption, Distribution and Excretion (Complete) data for OSELTAMIVIR (8 total), please visit the HSDB record page.

Oseltamivir is extensively converted to the active metabolite, oseltamivir carboxylate, by esterases located predominantly in the liver. Oseltamivir carboxylate is not further metabolized. Neither oseltamivir nor oseltamivir carboxylate is a substrate for, or inhibitor of, cytochrome P450 isoforms. No phase 2 conjugates of either compound have been identified in vivo.|Oseltamivir is extensively converted to oseltamivir carboxylate by esterases located predominantly in the liver. Neither oseltamivir nor oseltamivir carboxylate is a substrate for, or inhibitor of, cytochrome p450 isoforms.|Biotransformation: Hepatic; oseltamivir, ethyl ester prodrug, undergoes extensive hydrolysis to the active aster form, oseltamivir carboxylate.

Plasma concentrations of oseltamivir declined with a half-life of 1 to 3 hours in most subjects after oral administration, although plasma concentrations of oseltamivir carboxylate declined with a half-life of 6 to 10 hours in most subjects after oral administration.|Elimination: 1 to 3 hours for oseltamivir and 6 to 10 hours for oseltamivir carboxylate.

Oseltamivir phosphate is a pro-drug of the active metabolite (oseltamivir carboxylate) which is a potent and selective inhibitor of influenza virus neuraminidase enzymes, which are glycoproteins found on the virion surface. Viral neuraminidase enzyme activity is important for viral entry into uninfected cells, for the release of recently formed virus particles from infected cells, and for the further spread of the infectious virus in the body. Oseltamivir activity reduces viral shedding and infectivity. Oseltamivir is effective agaisnt viral neuraminidases of influenza A (including pandemic H1N1) and influenza B.|Oseltamivir is an ethyl ester prodrug requiring ester hydrolysis for conversion to the active form, oseltamivir carboxylate. The proposed mechanism of action of oseltamivir is inhibition of influenza virus neuraminidase with the possibility of alteration of virus particle aggregation and release.

/SRP:/ Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poison A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in respiratory arrest. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poison A and B/

GS 4071

Oral: Capsules: 75 mg (of oseltamivir) (Tamiflu), (Roche); For Suspension: 12 mg (of oseltamivir) per mL (Tamiflu), (Roche). /Oseltamivir phosphate/

Human drugs -> Tamiflu -> EMA Drug Category|Antivirals for systemic use -> Human pharmacotherapeutic group|Human drugs -> Ebilfumin -> EMA Drug Category|Antivirals for systemic use, Neuraminidase inhibitors -> Human pharmacotherapeutic group|Pharmaceuticals -> Antiinfectives for systemic use -> Antivirals for systemic use -> Direct acting antivirals -> Neuraminidase inhibitors