Oseltamivir

1 INDICATIONS AND USAGE Oseltamivir phosphate capsule is an influenza neuraminidase inhibitor (NAI) indicated for: Treatment of acute, uncomplicated influenza A and B in patients 2 weeks of age and older who have been symptomatic for no more than 48 hours. (1.1) Prophylaxis of influenza A and B in patients 1 year and older. (1.2) Limitations of Use : Not a substitute for annual influenza vaccination. (1.3) Consider available information on influenza drug susceptibility patterns and treatment effects when deciding whether to use. (1.3) Not recommended for patients with end-stage renal disease not undergoing dialysis. (1.3) 1.1 Treatment of Influenza Oseltamivir phosphate capsules are 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. 1.2 Prophylaxis of Influenza Oseltamivir phosphate capsules are indicated for the prophylaxis of influenza A and B in patients 1 year and older. 1.3 Limitations of Use Oseltamivir phosphate capsules are not a substitute for early influenza vaccination on an annual basis as recommended by the Centers for Disease Control and Prevention Advisory Committee on Immunization Practices. Influenza viruses change over time. Emergence of resistance substitutions 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 oseltamivir phosphate capsules [see Microbiology (12.4)] . Oseltamivir phosphate capsules are not recommended for patients with end-stage renal disease not undergoing dialysis [see Dosage and Administration (2.4) and Use in Specific Populations (8.6)].

5 WARNINGS AND PRECAUTIONS Serious skin/hypersensitivity reactions such as Stevens-Johnson Syndrome, toxic epidermal necrolysis and erythema multiforme: Discontinue oseltamivir phosphate capsules and initiate appropriate treatment if allergic-like reactions occur or are suspected. (5.1) Neuropsychiatric events: Patients with influenza, including those receiving oseltamivir phosphate capsules, particularly pediatric patients, may be at an increased risk of confusion or abnormal behavior early in their illness. Monitor for signs of abnormal behavior. (5.2) 5.1 Serious Skin/Hypersensitivity Reactions Cases of anaphylaxis and serious skin reactions including toxic epidermal necrolysis, Stevens-Johnson Syndrome, and erythema multiforme have been reported in postmarketing experience with oseltamivir phosphate capsules. Stop oseltamivir phosphate capsules and institute appropriate treatment if an allergic-like reaction occurs or is suspected. The use of oseltamivir phosphate capsules are contraindicated in patients with known serious hypersensitivity to oseltamivir phosphate capsules [see Contraindications (4) and Adverse Reactions (6.2)] . 5.2 Neuropsychiatric Events 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 phosphate capsules [see Adverse Reactions (6.2)] . Because these events were reported voluntarily during clinical practice, estimates of frequency cannot be made but they appear to be uncommon based on oseltamivir phosphate capsules usage data. These events were reported primarily among pediatric patients and often had an abrupt onset and rapid resolution. The contribution of oseltamivir phosphate capsules 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. Closely monitor oseltamivir phosphate capsules-treated patients with influenza for signs of abnormal behavior. If neuropsychiatric symptoms occur, evaluate the risks and benefits of continuing oseltamivir phosphate capsules for each patient. 5.3 Risk of Bacterial Infections There is no evidence for efficacy of oseltamivir phosphate capsules in any illness caused by pathogens other than influenza viruses. Serious bacterial infections may begin with influenza-like symptoms or may coexist with or occur as complications during the course of influenza. Oseltamivir phosphate capsule has not been shown to prevent such complications. Prescribers should be alert to the potential for secondary bacterial infections and treat them as appropriate.

6 ADVERSE REACTIONS The following important adverse reactions are described below and elsewhere in the labeling: Serious skin and hypersensitivity reactions [see Warnings and Precautions (5.1)] Neuropsychiatric events [see Warnings and Precautions (5.2)] Most common adverse reactions (>1% and more common than with placebo): Treatment studies – Nausea, vomiting, headache. (6.1) Prophylaxis studies – Nausea, vomiting, headache, pain. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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. Adverse Reactions from Treatment and Prophylaxis Trials in Adult and Adolescent Subjects (13 years of age and older) The overall safety profile of oseltamivir phosphate is based on data from 2,646 adult and adolescent subjects that received the recommended dosage of 75 mg orally twice daily for 5 days for treatment of influenza and 1,943 adult and adolescent subjects that received the recommended dosage of 75 mg orally once daily for up to 6 weeks for prophylaxis of influenza in clinical trials. The most common adverse reactions in the pooled treatment and pooled prophylaxis trials in adults and adolescents are displayed in Table 5. The majority of these adverse reactions were reported on a single occasion, occurred on either the first or second treatment day and resolved spontaneously within 1 to 2 days. This summary includes otherwise healthy adults/adolescents and subjects “at risk” (subjects at higher risk of developing complications associated with influenza, e.g., elderly patients and patients with chronic cardiac or respiratory disease). In general, the safety profile in the subjects “at risk” was qualitatively similar to that in otherwise healthy adults/adolescents. Table 5: Adverse Reactions Occurring in ≥1% of Adults and Adolescents (13 years of age and older) in Treatment and Prophylaxis Trials * System Organ Class Adverse Reaction Treatment Trials Prophylaxis Trials Oseltamivir Phosphate 75 mg twice daily (n = 2646) Placebo (n = 1977) Oseltamivir Phosphate 75 mg once daily (n = 1943) Placebo (n = 1586) Gastrointestinal Disorders Nausea 10% 6% 8% 4% Vomiting 8% 3% 2% 1% Nervous System Disorders Headache 2% 1% 17% 16% General Disorders Pain <1% 1% in subjects receiving oseltamivir phosphate (16%) compared to placebo (8%). Amongst the 148 pediatric subjects aged 1 year to 12 years who received oseltamivir phosphate at doses of 30 to 60 mg once daily for 10 days in a post-exposure prophylaxis study in household contacts (n = 99), and in a separate 6-week seasonal influenza prophylaxis safety study (n = 49), vomiting was the most frequent adverse reaction (8% on oseltamivir phosphate versus 2% in the no prophylaxis group). Adverse Reactions from Treatment Trials in Pediatric Subjects (2 weeks to less than 1 year of age) Assessment of adverse reactions in pediatric subjects 2 weeks to less than 1 year of age was based on two open-label studies that included safety data on 135 influenza-infected subjects 2 weeks to less than 1 year of age (including premature infants at least 36 weeks post conceptional age) exposed to oseltamivir phosphate at doses ranging from 2 to 3.5 mg per kg of the formulation for oral suspension twice daily orally for 5 days. The safety profile of oseltamivir phosphate was similar across the age range studied, with vomiting (9%), diarrhea (7%) and diaper rash (7%) being the most frequently reported adverse reactions, and was generally comparable to that observed in older pediatric and adult subjects. Adverse Reactions from the Prophylaxis Trial in Immunocompromised Subjects In a 12-week seasonal prophylaxis study in 475 immunocompromised subjects, including 18 pediatric subjects 1 year to 12 years of age, the safety profile in the 238 subjects receiving oseltamivir phosphate 75 mg once daily was consistent with that previously observed in other oseltamivir phosphate prophylaxis clinical trials [see Clinical Studies (14.2)] . 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of oseltamivir phosphate. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to oseltamivir phosphate exposure. General disorders and administration site conditions: Swelling of the face or tongue, allergy, anaphylactic/anaphylactoid reactions, hypothermia Skin and subcutaneous tissue disorders: Rash, dermatitis, urticaria, eczema, toxic epidermal necrolysis, Stevens-Johnson Syndrome, erythema multiforme [see Warnings and Precautions (5.1)] Gastrointestinal Disorders: Gastrointestinal bleeding, hemorrhagic colitis Cardiac Disorders: Arrhythmia Hepatobiliary Disorders: Hepatitis, abnormal liver function tests Nervous System Disorders: Seizure Metabolism and Nutrition Disorders: Aggravation of diabetes Psychiatric Disorders: Abnormal behavior, delirium, including symptoms such as hallucinations, agitation, anxiety, altered level of consciousness, confusion, nightmares, delusions [see Warnings and Precautions (5.2)]

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no adequate and well-controlled studies with oseltamivir phosphate capsules in pregnant women to inform a drug‐associated risk of adverse developmental outcomes. Available published epidemiological data suggest that oseltamivir phosphate capsule, taken in any trimester, is not associated with an increased risk of birth defects. However, these studies individually are limited by small sample sizes, use of different comparison groups, and some lacked information on dose, which preclude a definitive assessment of the risk [see Data and Clinical Pharmacology (12.3)] . In animal reproduction studies with oseltamivir, no adverse developmental effects were observed at clinically relevant exposures (see Data) . The background risk of major birth defects and miscarriage for the indicated populations 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 miscarriage is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Pregnant women are at higher risk of severe complications from influenza, which may lead to adverse pregnancy and/or fetal outcomes including maternal death, still births, birth defects, preterm delivery, low birth weight and small for gestational age. Data Human Data Published prospective and retrospective observational studies of more than 5,000 women exposed to oseltamivir phosphate capsules during pregnancy, including more than 1,000 women exposed in the first trimester, suggest that the observed rate of congenital malformations was not increased above the rate in the general comparison population, regardless of when therapy was administered during the gestational period. However, individually, none of these studies had adequate sample sizes and some lacked information on dose, which preclude a definitive assessment of the risk. Animal Data Oseltamivir was administered orally during organogenesis to pregnant rats (at 50, 250, or 1500 mg/kg/day on gestation days 6 to 17) and rabbits (at 50, 150, or 500 mg/kg/day on gestation days 6 to 18). In rats, embryo‐fetal effects consisting of an increased incidence of minor skeletal malformations were observed at a maternally toxic dose (1500 mg/kg/day), resulting in systemic drug exposures (based on AUC for oseltamivir carboxylate) 190 times human exposures at the maximum recommended human dose (MRHD) of oseltamivir phosphate capsules (75 mg twice a day). In the rabbit study, embryo‐fetal effects consisting of an increased incidence of minor skeletal abnormalities and variants were observed at maternally toxic doses (≥150 mg/kg/day) resulting in systemic exposures (based on AUC for oseltamivir carboxylate) ≥8 times human exposures at the MRHD of oseltamivir phosphate capsules. In prenatal and postnatal development studies in rats, oseltamivir was administered orally (at 50, 250, 500, or 1500 mg/kg/day) from organogenesis through late gestation, delivery, and lactation (gestation day 6 to postpartum/lactation day 20). Prolonged parturition duration and reduced offspring viability were observed at a maternally toxic dose (1500 mg/kg/day). No adverse maternal or offspring effects were observed at doses ≤500 mg/kg/day, resulting in systemic drug exposures (based on AUC for oseltamivir carboxylate) 44 times human exposures at the MRHD of oseltamivir phosphate capsules. 8.2 Lactation Risk Summary Based on limited published data, oseltamivir and oseltamivir carboxylate have been shown to be present in human milk at low levels considered unlikely to lead to toxicity in the breastfed infant. Postmarketing experience has not reported any information to suggest serious adverse effects of oseltamivir exposure via breast milk in infants. It is not known if oseltamivir affects human milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for oseltamivir phosphate capsules and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition. 8.4 Pediatric Use Treatment of Influenza The safety and efficacy of oseltamivir phosphate for the treatment of influenza in pediatric patients 2 weeks old to 17 years of age has been established [see Dosage and Administration (2.2), Clinical Pharmacology (12.3), and Clinical Studies (14.1)] and is based on: 13 to 17 years of age: Safety and efficacy in adolescent patients 13 to 17 years of age was supported by adequate and well-controlled trials in adults and adolescents and younger pediatric patients and safety data in adolescents treated with oseltamivir phosphate in a study of treatment and prophylaxis. 1 year to 12 years of age: Safety and efficacy in pediatric patients 1 year to 12 years of age was supported by results of one double-blind, placebo-controlled trial in 452 pediatric patients with influenza in whom oseltamivir phosphate 2 mg per kg twice daily or placebo was administered within 48 hours of symptom onset [see Clinical Studies (14.1)]. Additional safety information was provided in a double-blind, placebo-controlled trial in pediatric patients 6 to 12 years of age with known asthma. Efficacy could not be established in pediatric patients with asthma. 2 weeks to less than 1 year of age: Safety and efficacy in pediatric patients 2 weeks to less than 1 year of age is supported by adequate and well-controlled trials in adults and older pediatric patients and two open-label trials of oseltamivir phosphate (2 to 3.5 mg per kg twice daily for 5 days) in 136 pediatric subjects 2 weeks to less than 1 year of age. In these two trials, the oseltamivir plasma concentrations in these subjects were similar to or higher than the oseltamivir plasma concentrations observed in older pediatric subjects and adults [see Clinical Pharmacology (12.3) and Clinical Studies (14.1)] . The safety and efficacy of oseltamivir phosphate for treatment of influenza in pediatric patients less than 2 weeks of age have not been established. Prophylaxis of Influenza The safety and efficacy of oseltamivir phosphate for the prophylaxis of influenza in pediatric patients 1 year to 17 years old has been established [see Dosage and Administration (2.3), Clinical Pharmacology (12.3), and Clinical Studies (14.2)] and is based on: 13 to 17 years of age: Prophylaxis in adolescent patients 13 to 17 years of age is supported by one randomized, placebo-controlled post-exposure household prophylaxis trial of oseltamivir phosphate 75 mg taken orally once daily for 7 days in household contacts including 207 adolescents [see Clinical Studies (14.2)]. 1 year to 12 years of age: Oseltamivir phosphate for prophylaxis in pediatric patients 1 year to 12 years of age is supported by one randomized, open-label, post-exposure household prophylaxis trial including pediatric subjects 1 year to 12 years of age who received 30 to 60 mg of oseltamivir phosphate for oral suspension (supplied as powder) taken orally once daily for 10 days [see Clinical Studies (14.2)]. Additional safety information was provided in a 6-week seasonal prophylaxis (community outbreak) safety study in 49 patients 1 year to 12 years of age. The safety and efficacy of oseltamivir phosphate for prophylaxis of influenza have not been established for pediatric patients less than 1 year of age. 8.5 Geriatric Use Treatment of Influenza Of the 4,765 adults in clinical trials of oseltamivir phosphate capsules for the treatment of influenza, 948 (20%) were 65 years and older, while 329 (7%) were 75 years and older. In three double-blind, placebo-controlled trials in the treatment of influenza in patients at least 65 years old, that enrolled 741 subjects (374 received placebo and 362 received oseltamivir phosphate capsules), 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 [see Clinical Studies (14.1)]. Prophylaxis of Influenza Of the 4,603 adults in clinical trials of oseltamivir phosphate capsules for the prophylaxis of influenza, 1,046 (23%) were 65 years and older, while 719 (16%) were 75 years and older. In a randomized, placebo-controlled trial in elderly residents of nursing homes who took oseltamivir phosphate capsules for up to 42 days for the prophylaxis of influenza (oseltamivir phosphate capsules n=276, placebo n=272), 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 [see Clinical Studies (14.2)] . 8.6 Renal Impairment Patients with renal impairment had higher blood levels of oseltamivir carboxylate compared to patients with normal renal function which may increase the risk of oseltamivir phosphate capsules-associated adverse reactions. Therefore, dosage adjustment is recommended for patients with a serum creatinine clearance between 10 and 60 mL/minute and for patients with end-stage renal disease (ESRD) undergoing routine hemodialysis or continuous peritoneal dialysis treatment [see Dosage and Administration (2.4)]. Oseltamivir phosphate capsules are not recommended for patients with ESRD not undergoing dialysis [see Indications and Usage (1.3) and Clinical Pharmacology (12.3)] . 8.7 Hepatic Impairment No dosage adjustment is required in patients with mild to moderate hepatic impairment. The safety and pharmacokinetics in patients with severe hepatic impairment have not been evaluated [see Clinical Pharmacology (12.3)] . 8.8 Use in Patients with Chronic Conditions Efficacy of oseltamivir phosphate capsules in the treatment of influenza in patients with chronic cardiac disease and/or respiratory disease was evaluated in one randomized, placebo-controlled clinical trial. Efficacy in this population, as measured by time to alleviation of all symptoms, was not established, but no new safety signals were identified [see Clinical Studies (14.1) ] . No clinical trial data are available regarding treatment of influenza in patients with any medical condition sufficiently severe or unstable to be considered at imminent risk of requiring hospitalization. 8.9 Immunocompromised Patients Efficacy of oseltamivir phosphate capsules for the treatment or prophylaxis of influenza has not been established in immunocompromised patients [see Clinical Studies (14.2) ] . Safety of oseltamivir phosphate capsules for prophylaxis of influenza has been demonstrated for up to 12 weeks in immunocompromised patients [see Adverse Reactions (6.1) ].

8.1 Pregnancy Risk Summary There are no adequate and well-controlled studies with oseltamivir phosphate capsules in pregnant women to inform a drug‐associated risk of adverse developmental outcomes. Available published epidemiological data suggest that oseltamivir phosphate capsule, taken in any trimester, is not associated with an increased risk of birth defects. However, these studies individually are limited by small sample sizes, use of different comparison groups, and some lacked information on dose, which preclude a definitive assessment of the risk [see Data and Clinical Pharmacology (12.3)] . In animal reproduction studies with oseltamivir, no adverse developmental effects were observed at clinically relevant exposures (see Data) . The background risk of major birth defects and miscarriage for the indicated populations 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 miscarriage is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Pregnant women are at higher risk of severe complications from influenza, which may lead to adverse pregnancy and/or fetal outcomes including maternal death, still births, birth defects, preterm delivery, low birth weight and small for gestational age. Data Human Data Published prospective and retrospective observational studies of more than 5,000 women exposed to oseltamivir phosphate capsules during pregnancy, including more than 1,000 women exposed in the first trimester, suggest that the observed rate of congenital malformations was not increased above the rate in the general comparison population, regardless of when therapy was administered during the gestational period. However, individually, none of these studies had adequate sample sizes and some lacked information on dose, which preclude a definitive assessment of the risk. Animal Data Oseltamivir was administered orally during organogenesis to pregnant rats (at 50, 250, or 1500 mg/kg/day on gestation days 6 to 17) and rabbits (at 50, 150, or 500 mg/kg/day on gestation days 6 to 18). In rats, embryo‐fetal effects consisting of an increased incidence of minor skeletal malformations were observed at a maternally toxic dose (1500 mg/kg/day), resulting in systemic drug exposures (based on AUC for oseltamivir carboxylate) 190 times human exposures at the maximum recommended human dose (MRHD) of oseltamivir phosphate capsules (75 mg twice a day). In the rabbit study, embryo‐fetal effects consisting of an increased incidence of minor skeletal abnormalities and variants were observed at maternally toxic doses (≥150 mg/kg/day) resulting in systemic exposures (based on AUC for oseltamivir carboxylate) ≥8 times human exposures at the MRHD of oseltamivir phosphate capsules. In prenatal and postnatal development studies in rats, oseltamivir was administered orally (at 50, 250, 500, or 1500 mg/kg/day) from organogenesis through late gestation, delivery, and lactation (gestation day 6 to postpartum/lactation day 20). Prolonged parturition duration and reduced offspring viability were observed at a maternally toxic dose (1500 mg/kg/day). No adverse maternal or offspring effects were observed at doses ≤500 mg/kg/day, resulting in systemic drug exposures (based on AUC for oseltamivir carboxylate) 44 times human exposures at the MRHD of oseltamivir phosphate capsules.

8.4 Pediatric Use Treatment of Influenza The safety and efficacy of oseltamivir phosphate for the treatment of influenza in pediatric patients 2 weeks old to 17 years of age has been established [see Dosage and Administration (2.2), Clinical Pharmacology (12.3), and Clinical Studies (14.1)] and is based on: 13 to 17 years of age: Safety and efficacy in adolescent patients 13 to 17 years of age was supported by adequate and well-controlled trials in adults and adolescents and younger pediatric patients and safety data in adolescents treated with oseltamivir phosphate in a study of treatment and prophylaxis. 1 year to 12 years of age: Safety and efficacy in pediatric patients 1 year to 12 years of age was supported by results of one double-blind, placebo-controlled trial in 452 pediatric patients with influenza in whom oseltamivir phosphate 2 mg per kg twice daily or placebo was administered within 48 hours of symptom onset [see Clinical Studies (14.1)]. Additional safety information was provided in a double-blind, placebo-controlled trial in pediatric patients 6 to 12 years of age with known asthma. Efficacy could not be established in pediatric patients with asthma. 2 weeks to less than 1 year of age: Safety and efficacy in pediatric patients 2 weeks to less than 1 year of age is supported by adequate and well-controlled trials in adults and older pediatric patients and two open-label trials of oseltamivir phosphate (2 to 3.5 mg per kg twice daily for 5 days) in 136 pediatric subjects 2 weeks to less than 1 year of age. In these two trials, the oseltamivir plasma concentrations in these subjects were similar to or higher than the oseltamivir plasma concentrations observed in older pediatric subjects and adults [see Clinical Pharmacology (12.3) and Clinical Studies (14.1)] . The safety and efficacy of oseltamivir phosphate for treatment of influenza in pediatric patients less than 2 weeks of age have not been established. Prophylaxis of Influenza The safety and efficacy of oseltamivir phosphate for the prophylaxis of influenza in pediatric patients 1 year to 17 years old has been established [see Dosage and Administration (2.3), Clinical Pharmacology (12.3), and Clinical Studies (14.2)] and is based on: 13 to 17 years of age: Prophylaxis in adolescent patients 13 to 17 years of age is supported by one randomized, placebo-controlled post-exposure household prophylaxis trial of oseltamivir phosphate 75 mg taken orally once daily for 7 days in household contacts including 207 adolescents [see Clinical Studies (14.2)]. 1 year to 12 years of age: Oseltamivir phosphate for prophylaxis in pediatric patients 1 year to 12 years of age is supported by one randomized, open-label, post-exposure household prophylaxis trial including pediatric subjects 1 year to 12 years of age who received 30 to 60 mg of oseltamivir phosphate for oral suspension (supplied as powder) taken orally once daily for 10 days [see Clinical Studies (14.2)]. Additional safety information was provided in a 6-week seasonal prophylaxis (community outbreak) safety study in 49 patients 1 year to 12 years of age. The safety and efficacy of oseltamivir phosphate for prophylaxis of influenza have not been established for pediatric patients less than 1 year of age.