Oseltamivir Phosphate

RECENT MAJOR CHANGES Warnings and Precautions ( 5.2 ) 04/2018

1 INDICATIONS AND USAGE Oseltamivir Phosphate capsule USP 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 capsule USP 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. 1.2 Prophylaxis of Influenza Oseltamivir Phosphate capsule USP is indicated for the prophylaxis of influenza A and B in patients 1 year and older. 1.3 Limitations of Use • Oseltamivir Phosphate capsule USP is 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 Capsule USP [see Microbiology ( 12.4 )]. • Oseltamivir Phosphate capsule USP is 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 )].

2 DOSAGE AND ADMINISTRATION Treatment of influenza • Adults and adolescents (13 years and older): 75 mg twice daily for 5 days ( 2.2 ) • Pediatric patients 1 to 12 years of age: Based on weight twice daily for 5 days ( 2.2 ) • Pediatric patients 2 weeks to less than 1 year of age: 3 mg/kg twice daily for 5 days ( 2.2 ) • Renally impaired adult patients (creatinine clearance >30-60 mL/min): Reduce to 30 mg twice daily for 5 days (2.4) • Renally impaired adult patients (creatinine clearance >10-30 mL/min): Reduce to 30 mg once daily for 5 days (2.4) • ESRD patients on hemodialysis: Reduce to 30 mg immediately and then 30 mg after every hemodialysis cycle. Treatment duration not to exceed 5 days (2.4) • ESRD patients on CAPD: Reduce to a single 30 mg dose immediately (2.4) Prophylaxis of influenza • Adults and adolescents (13 years and older): 75 mg once daily for at least 10 days ( 2.3 ) o Community outbreak: 75 mg once daily for up to 6 weeks ( 2.3 ) • Pediatric patients 1 to 12 years of age: Based on weight once daily for 10 days ( 2.3 ) o Community outbreak: Based on weight once daily for up to 6weeks ( 2.3 ) • Renally impaired adult patients (creatinine clearance >30-60 mL/min): Reduce to 30 mg once daily (2.4) • Renally impaired adult patients (creatinine clearance >10-30 mL/min): Reduce to 30 mg once every other day (2.4) • ESRD patients on hemodialysis: Reduce to 30 mg immediately and then 30 mg after alternate hemodialysis cycles for the recommended duration of prophylaxis (2.4) • ESRD patients on CAPD: Reduce to 30 mg immediately and then 30 mg once weekly for the recommended duration of prophylaxis (2.4) 2.1 Dosage and Administration Overview Administer oseltamivir phosphate capsules for the treatment of influenza in patients 2 weeks of age or older [see Dosage and Administration (2.2)] or for prophylaxis of influenza in patients 1 year and older [see Dosage and Administration (2.3)] using: • Oseltamivir phosphate capsules The capsules may be taken with or without food; however, tolerability may be enhanced if oseltamivir phosphate capsules is taken with food. Adjust the oseltamivir phosphate capsules dosage in patients with moderate or severe renal impairment [ see Dosage and Administration (2.4)]. For patients who cannot swallow capsules, oseltamivir phosphate for oral suspension is the preferred formulation. When oseltamivir phosphate for oral suspension is not available from wholesaler or the manufacturer, oseltamivir phosphate capsules may be opened and mixed with sweetened liquids such as regular or sugar-free chocolate syrup, corn syrup, caramel topping, or light brown sugar (dissolved in water). During emergency situations and when neither the oral suspension or the age-appropriate strengths of oseltamivir phosphate capsules to mix with sweetened liquids are available, then a pharmacist may prepare an emergency supply of oral suspension from oseltamivir phosphate 75 mg capsules [ see Dosage and Administration (2.6) ]. 2.2 Recommended Dosage for Treatment of Influenza Initiate treatment with oseltamivir phosphate capsules within 48 hours of influenza symptom onset. Adults and Adolescents (13 years of age and older) The recommended oral dosage of oseltamivir phosphate capsules for treatment of influenza in adults and adolescents 13 years and older is 75 mg twice daily (one 75 mg capsule or 12.5 mL of oral suspension twice daily) for 5 days. Pediatric Patients (2 weeks of age through 12 years of age) Table 1 displays the recommended oral dosage of oseltamivir phosphate capsules for treatment of influenza in pediatric patients 2 weeks of age through 12 years of age and provides information about prescribing the capsule or the formulation for oral suspension. 2.3 Recommended Dosage for Prophylaxis of Influenza Initiate post-exposure prophylaxis with oseltamivir phosphate capsules within 48 hours following close contact with an infected individual. Initiate seasonal prophylaxis with oseltamivir phosphate capsules dur …

3 DOSAGE FORMS AND STRENGTHS Oseltamivir Phosphate Capsules, USP: 30-mg capsules (39.40 mg of oseltamivir phosphate is equivalent to 30 mg of oseltamivir (free base)): White to off-white powder filled in Size “4” capsule with yellow color cap imprinted with “30 mg” with blue color ink and yellow color body imprinted with “NAT” with blue color ink. 45-mg capsules (59.10 mg of oseltamivir phosphate is equivalent to 45 mg of oseltamivir (free base)): White to off-white powder filled in Size “4” capsule with grey color cap imprinted with “45 mg” with blue color ink and grey color body imprinted with “NAT” with blue color ink. 75-mg capsules (98.50 mg of oseltamivir phosphate is equivalent to 75 mg of oseltamivir (free base)): White to off-white powder filled in size "2" capsules with yellow color cap imprinted with “75 mg” with blue color ink and grey color body imprinted with “NAT” with blue color ink. Capsules: 30 mg, 45 mg, 75 mg ( 3 )

4 CONTRAINDICATIONS Oseltamivir phosphate capsule is contraindicated in patients with known serious hypersensitivity to oseltamivir or any component of the product. Severe allergic reactions have included anaphylaxis and serious skin reactions including toxic epidermal necrolysis, Stevens - Johnson syndrome, and erythema multiforme [see Warnings and Precautions ( 5.1 )] . Patients with known serious hypersensitivity to oseltamivir or any of the components of Oseltamivir Phosphate Capsule USP ( 4 )

6 ADVERSE REACTIONS The following serious adverse reactions are discussed 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 Amneal Pharmaceuticals at 1-877-835-5472 or 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 = 2,646) Placebo (n = 1,977) Oseltamivir Phosphate 75 mg once daily (n = 1,943) Placebo (n = 1,586) Gastrointestinal Disorders Nausea Vomiting 10% 8% 6% 3% 8% 2% 4% 1% Nervous System Disorders Headache General Disorders Pain 2% < 1% 1% < 1% 17% 4% 16% 3% * Adverse reactions that occurred in ≥ 1% of oseltamivir phosphate-treated adults and adolescents and ≥ 1% greater in oseltamivir phosphate-treated subjects compared to placebo-treated subjects in either the treatment or prophylaxis trials. Adverse Reactions from Treatment and Prophylaxis Trials in Pediatric Subjects (1 year to 12 years of age) A total of 1,481 pediatric subjects (including otherwise healthy pediatric subjects aged 1 year to 12 years and asthmatic pediatric subjects aged 6 to 12 years) participated in clinical trials of oseltamivir phosphate for the treatment of influenza. A total of 859 pediatric subjects received treatment with oseltamivir phosphate for oral suspension either at a 2 mg per kg twice daily for 5 days or weight-band dosing. Vomiting was the only adverse reaction reported at a frequency of ≥ 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) Asses …

7 DRUG INTERACTIONS Live attenuated influenza vaccine (LAIV), intranasal: Avoid administration of LAIV within 2 weeks before or 48 hours after oseltamivir phosphate capsules use, unless medically indicated. ( 7 ) 7.1 Influenza Vaccines Live Attenuated Influenza Vaccine The concurrent use of oseltamivir phosphate capsules with live attenuated influenza vaccine (LAIV) intranasal has not been evaluated. However, because of the potential for oseltamivir phosphate capsules to inhibit replication of live vaccine virus and possibly reduce the efficacy of LAIV, avoid administration of LAIV within 2 weeks before or 48 hours after oseltamivir phosphate capsules administration, unless medically indicated. Inactivated Influenza Vaccine Inactivated influenza vaccine can be administered at any time relative to use of oseltamivir phosphate capsules. 7.2 Drugs Without Clinically Significant Drug Interaction with Oseltamivir Phosphate Capsules No dose adjustments are needed for either oseltamivir or the concomitant drug when coadministering oseltamivir with amoxicillin, acetaminophen, aspirin, cimetidine, antacids (magnesium and aluminum hydroxides and calcium carbonates), rimantadine, amantadine, or warfarin [see Clinical Pharmacology ( 12.3 )] .

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no adequate and well-controlled studies with oseltamivir phosphate in pregnant women to inform a drug-associated risk of adverse developmental outcomes. Available published epidemiological data suggest that oseltamivir phosphate capsules, 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 2-4% and 15-20%, 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 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 breastfeedin …

12.1 Mechanism of Action Oseltamivir is an antiviral drug with activity against influenza virus [see Microbiology Error! Hyperlink reference not valid.

11 DESCRIPTION Oseltamivir phosphate, USP, an influenza neuraminidase inhibitor (NAI), is available as capsules containing 30 mg, 45 mg, or 75 mg oseltamivir for oral use. In addition to the active ingredient, each capsule contains croscarmellose sodium, povidone K-30, pregelatinized starch, sodium stearyl fumarate and talc. The 30 mg shell (yellow / yellow) contains gelatin, iron oxide red, iron oxide yellow, purified water and titanium dioxide. The 45 mg shell (grey / grey) contains gelatin, iron oxide black, purified water and titanium dioxide. The 75 mg shell (yellow / grey) contains gelatin, iron oxide black (in body), iron oxide red, iron oxide yellow (in cap), purified water and titanium dioxide. Each capsule is printed with blue ink, which includes butyl alcohol, dehydrated alcohol, FD&C Blue No. 2 aluminum lake, isopropyl alcohol, propylene glycol, shellac and strong ammonium solution. Oseltamivir phosphate, USP is a white to off white powder with the chemical name (3R,4R,5S)-4-acetylamino-5-amino-3(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid, ethyl ester, phosphate (1:1). The chemical formula is C 16 H 28 N 2 O 4 (free base). The molecular weight is 312.4 for oseltamivir free base and 410.4 for oseltamivir phosphate salt. The structural formula is as follows:

10 OVERDOSAGE Reports of overdoses with oseltamivir phosphate capsules 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 phosphate capsules [see Adverse Reactions (6) ] .

16 HOW SUPPLIED/STORAGE AND HANDLING Oseltamivir phosphate capsules USP 30-mg capsules (30 mg free base equivalent of the phosphate salt): White to off white powder filled in size "4" hard gelatin capsule with light yellow opaque cap/body printed 30 on cap and OP on body in black. Available in blister packages of 10 (NDC 85766-144-10 relabeled from NDC 64380-797-01). 45-mg capsules (45 mg free base equivalent of the phosphate salt): White to off white powder filled in size "3" hard gelatin capsule with grey opaque cap/body printed 45 on cap and OP on body in black. Available in blister packages of 10 (NDC 85766-145-10 relabeled from NDC 64380-798-01). 75-mg capsules (75 mg free base equivalent of the phosphate salt): White to off white powder filled in size "2" hard gelatin capsule with cream cap and brown body printed OP on cap and 75 on body in black. Available in blister packages of 10 (NDC 85766-146-10 relabeled from NDC 64380-799-01), HDPE Bottle packages of 30 (NDC 85766-146-30 repackaged from NDC 64380-799-XX), DPE Bottle packages of 30 (NDC 85766-146-60 repackaged from NDC 64380-799-XX), DPE Bottle packages of 30 (NDC 85766-146-90 repackaged from NDC 64380-799-XX), HDPE Bottle packages of 100 (NDC 85766-146-01 relabeled from NDC 64380-799-06) and HDPE Bottle packages of 500 (NDC 85766-146-05 relabeled from NDC 64380-799-07) Storage Store at 20° to 25°C (68° to 77°F); Excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature].