Oseltamivir Phosphate

Description

11 DESCRIPTION Oseltamivir phosphate capsules, USP, influenza neuraminidase inhibitor (NAI), are available as: Capsules containing 30 mg, 45 mg, or 75 mg of oseltamivir for oral use, in the form of oseltamivir phosphate. In addition to the active ingredient, croscarmellose sodium, povidone K29/32, pregelatinized starch, sodium stearyl fumarate and talc. The 30 mg capsule shell contains: black iron oxide, gelatin, potassium hydroxide and titanium dioxide. The 45 mg capsule shell contains: FD&C Blue#1 Aluminum Lake, gelatin, iron oxide yellow, and titanium dioxide. The 75 mg capsule shell contains: black iron oxide, brilliant blue FCF – FD&C Blue 1, gelatin, potassium hydroxide, quinoline yellow and titanium dioxide. Oseltamivir phosphate is a white or almost 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: Chemical Structure

What Is Oseltamivir Phosphate Used For?

1 INDICATIONS AND USAGE Oseltamivir phosphate capsules are 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) ].

Dosage and Administration

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: 3mg/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 ) 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 ) Community outbreak: Based on weight once daily for up to 6 weeks ( 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) ] . The capsules may be taken with or without food; however, tolerability may be enhanced if oseltamivir phosphate capsules are 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...

Side Effects (Adverse Reactions)

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 Lannett Company, Inc. at 1-844-834-0530 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 capsules 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 1-2 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 Adverse reactions that occurred in ≥1% of oseltamivir phosphate capsules -treated adults and adolescents and ≥1% greater in oseltamivir phosphate capsules -treated subjects compared to placebo-treated subjects in either the treatment or prophylaxis trials. System Organ Class Treatment Trials Prophylaxis Trials Adverse Reaction 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% 4% 3% 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 capsules 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 capsules (16%) compared to placebo (8%). Amongst the 148 pediatric subjects aged 1 year to 12 years who received oseltamivir phosphate capsules 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 capsules versus 2% in the no prophylaxis group). Adverse Reactions from Treatment Trials in Pediatric...

Drug Interactions

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 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 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) ] .

Contraindications

4 CONTRAINDICATIONS Oseltamivir phosphate capsules are 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 capsules ( 4 )

Pregnancy and Breastfeeding

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...

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.

Overdosage

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) ] .

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING Oseltamivir phosphate capsules, USP, 30-mg capsules (30 mg free base equivalent of the phosphate salt): capsule cap and body are opaque white, cap imprinted “S5” with black ink, body without any print; the contents is white or almost white. Available in blister packages of 10 (NDC 0527-4591-13). 45-mg capsules (45 mg free base equivalent of the phosphate salt): capsule cap is buff and printed “S4” with blue ink, body is white and without any imprint; the contents is white or almost white. Available in blister packages of 10 (NDC 0527-4592-13). 75-mg capsules (75 mg free base equivalent of the phosphate salt): capsule cap is light green and printed “S2” with black ink, body is white and without any imprint; the contents is white or almost white. Available in blister packages of 10 (NDC 0527-4593-13). Storage Store oseltamivir phosphate capsules at 20ºC to 25ºC (68ºF to 77ºF); excursions permitted to 15°C and 30°C (59°F to 86°F) [See USP Controlled Room Temperature]. Preserve in well-closed containers as defined in USP.