Oseltamivir Phosphate (Page 3 of 8)

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.

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 Trails
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 NauseaVomiting 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.

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)]

7 DRUG INTERACTIONS

7.1 Influenza Vaccines

Live Attenuated Influenza Vaccine

The concurrent use of oseltamivir phosphate 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 administration, unless medically indicated.

Inactivated Influenza Vaccine

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)].

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, 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 1,500 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 (1,500 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 (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.

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 and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition.

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