July 25, 2016
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Tamiflu

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Tamiflu




Warnings
Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

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 TAMIFLU. Stop TAMIFLU and institute appropriate treatment if an allergic-like reaction occurs or is suspected. The use of TAMIFLU is contraindicated in patients with known serious hypersensitivity to TAMIFLU [see CONTRAINDICATIONS and ADVERSE REACTIONS].

Neuropsychiatric Events

There have been postmarketing reports (mostly from Japan) of delirium and abnormal behavior leading to injury, and in some cases resulting in fatal outcomes, in patients with influenza who were receiving TAMIFLU [see ADVERSE REACTIONS]. Because these events were reported voluntarily during clinical practice, estimates of frequency cannot be made but they appear to be uncommon based on TAMIFLU usage data. These events were reported primarily among pediatric patients and often had an abrupt onset and rapid resolution. The contribution of TAMIFLU 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 TAMIFLU-treated patients with influenza for signs of abnormal behavior. If neuropsychiatric symptoms occur, evaluate the risks and benefits of continuing TAMIFLU for each patient.

Risk Of Bacterial Infections

There is no evidence for efficacy of TAMIFLU 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. TAMIFLU has not been shown to prevent such complications. Prescribers should be alert to the potential for secondary bacterial infections and treat them as appropriate.

Fructose Intolerance In Patients With Hereditary Fructose Intolerance

Fructose can be harmful to patients with hereditary fructose intolerance. One dose of 75 mg TAMIFLU for oral suspension delivers 2 grams of sorbitol. This is above the daily maximum limit of sorbitol for patients with hereditary fructose intolerance, and may cause dyspepsia and diarrhea.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION and Instructions for Use).

Serious Skin/Hypersensitivity Reactions

Advise patients and/or caregivers of the risk of severe allergic reactions (including anaphylaxis) or serious skin reactions. Instruct patients and/or caregiver to stop TAMIFLU and seek immediate medical attention if an allergic-like reaction occurs or is suspected [see WARNINGS AND PRECAUTIONS].

Neuropsychiatric Events

Advise patients and/or caregivers of the risk of neuropsychiatric events in TAMIFLU-treated patients with influenza and instruct patients to contact their physician if they experience signs of abnormal behavior while receiving TAMIFLU [see WARNINGS AND PRECAUTIONS].

Important Dosing Information

Instruct patients to begin treatment with TAMIFLU as soon as possible from the first appearance of flu symptoms, within 48 hours of onset of symptoms. Similarly, instruct patients to start taking TAMIFLU for prevention as soon as possible after exposure [see DOSAGE AND ADMINISTRATION]. Instruct patients to take any missed doses as soon as they remember, except if it is near the next scheduled dose (within 2 hours), and then continue to take TAMIFLU at the usual times.

Influenza Vaccines

Instruct patients that TAMIFLU is not a substitute for receiving an annual flu vaccination. Patients should continue receiving an annual flu vaccination according to guidelines on immunization practices. Because of the potential for TAMIFLU to inhibit replication of live attenuated influenza vaccine (LAIV) and possibly reduce efficacy of LAIV, avoid administration of LAIV within 2 weeks or 48 hours after TAMIFLU administration, unless medically necessary [see DRUG INTERACTIONS].

Fructose Intolerance

Inform patients with hereditary fructose intolerance that one dose of 75 mg TAMIFLU oral suspension (supplied as powder) delivers 2 grams of sorbitol. Inform patients with hereditary fructose intolerance that this is above the daily maximum limit of sorbitol and may cause dyspepsia and diarrhea [see WARNINGS AND PRECAUTIONS].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

In 2-year carcinogenicity studies in mice and rats given daily oral doses of the prodrug oseltamivir phosphate up to 400 mg/kg and 500 mg/kg, respectively, the prodrug and the active form oseltamivir carboxylate induced no statistically significant increases in tumors over controls. The mean maximum daily exposures to the prodrug in mice and rats were approximately 130- and 320-fold, respectively, greater than those in humans at the recommended clinical dose based on AUC comparisons. The respective safety margins of the exposures to the active oseltamivir carboxylate were 15- and 50-fold.

Oseltamivir was found to be non-mutagenic in the Ames test and the human lymphocyte chromosome assay with and without enzymatic activation and negative in the mouse micronucleus test. It was found to be positive in a Syrian Hamster Embryo (SHE) cell transformation test. Oseltamivir carboxylate was non-mutagenic in the Ames test and the L5178Y mouse lymphoma assay with and without enzymatic activation and negative in the SHE cell transformation test.

In a fertility and early embryonic development study in rats, doses of oseltamivir at 50, 250, and 1500 mg/kg/day were administered to females for 2 weeks before mating, during mating and until day 6 of pregnancy. Males were dosed for 4 weeks before mating, during mating, and for 2 weeks after mating. There were no effects on fertility, mating performance or early embryonic development at any dose level. The highest dose in this study was approximately 100 times the human systemic exposure (AUC0-24h) of oseltamivir carboxylate that occurs after administration of the maximum recommended human dose.

Use In Specific Populations

Pregnancy

Pregnancy Category C

Risk Summary

There are no adequate and well-controlled studies with TAMIFLU in pregnant women. Available published epidemiological data suggest that TAMIFLU, 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. In animal studies, there was a dose-dependent increase in the incidence rates of a variety of minor skeletal abnormalities and variants in offspring of rats and rabbits exposed at maternally toxic doses 100 and 50 times human exposures, respectively. TAMIFLU should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus [see CLINICAL PHARMACOLOGY].

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 approximately 1,500 women exposed to TAMIFLU during pregnancy, including approximately 400 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

Studies for effects on embryo-fetal development were conducted in rats (50, 250, and 1500 mg/kg/day) and rabbits (50, 150, and 500 mg/kg/day) by the oral route. Relative exposures at these doses were, respectively, 2, 13, and 100 times human exposure in the rat and 4, 8, and 50 times human exposure in the rabbit, based on AUC. Pharmacokinetic studies indicated that there was fetal exposure in both species. In the rat study, minimal maternal toxicity was reported in the 1500 mg/kg/day group. In the rabbit study, slight and marked maternal toxicities were observed, respectively, in the 150 and 500 mg/kg/day groups. At the maternally toxic doses, statistically significant increases in the incidence rates of a variety of minor skeletal abnormalities and variants were observed in the exposed offspring. However, the individual incidence rate of each skeletal abnormality or variant remained within the background rates of occurrence in the species studied.

Nursing Mothers

Risk Summary

Based on limited published data, oseltamivir and oseltamivir carboxylate are present in human milk at low levels considered unlikely to lead to toxicity in the breastfed infant. Exercise caution when TAMIFLU is administered to a nursing woman.

Pediatric Use

Treatment Of Influenza

The safety and efficacy of TAMIFLU for the treatment of influenza in pediatric patients 2 weeks old to 17 years of age has been established [see DOSAGE AND ADMINISTRATION, CLINICAL PHARMACOLOGY, and Clinical Studies] 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 TAMIFLU 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 TAMIFLU 2 mg per kg twice daily or placebo was administered within 48 hours of symptom onset [see Clinical Studies]. 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 TAMIFLU (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 and Clinical Studies].

The safety and efficacy of TAMIFLU 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 TAMIFLU for the prophylaxis of influenza in pediatric patients 1 year to 17 years old has been established [see DOSAGE AND ADMINISTRATION, CLINICAL PHARMACOLOGY, and Clinical Studies] 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 TAMIFLU 75 mg taken orally once daily for 7 days in household contacts including 207 adolescents [see Clinical Studies].
  • 1 year to 12 years of age: TAMIFLU 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 TAMIFLU for oral suspension (supplied as powder) taken orally once daily for 10 days [see Clinical Studies]. 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 TAMIFLU for prophylaxis of influenza have not been established for pediatric patients less than 1 year of age.

Geriatric Use

Treatment Of Influenza

Of the 4,765 adults in clinical trials of TAMIFLU 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 TAMIFLU), 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].

Prophylaxis Of Influenza

Of the 4,603 adults in clinical trials of TAMIFLU 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 TAMIFLU for up to 42 days for the prophylaxis of influenza (TAMIFLU 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].

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 TAMIFLU-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]. TAMIFLU is not recommended for patients with ESRD not undergoing dialysis [see INDICATIONS AND USAGE and CLINICAL PHARMACOLOGY].

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].

Use In Patients With Chronic Conditions

Efficacy of TAMIFLU 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].

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.

Immunocompromised Patients

Efficacy of TAMIFLU for the treatment or prophylaxis of influenza has not been established in immunocompromised patients [see Clinical Studies]. Safety of TAMIFLU for prophylaxis of influenza has been demonstrated for up to 12 weeks in immunocompromised patients [see ADVERSE REACTIONS].

This monograph has been modified to include the generic and brand name in many instances.

Last reviewed on RxList: 6/30/2016

Warnings
Precautions

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