Tamiflu Drug Information

Dosage and Administration Overview Administer TAMIFLU for the treatment of influenza in patients 2 weeks of age or older or for prophylaxis of influenza in patients 1 year and older using: TAMIFLU capsules or TAMIFLU for oral suspension (supplied as a powder). This is the preferred formulation (6 mg per mL) for patients who cannot swallow capsules. Prior to use, the supplied TAMIFLU powder must be constituted with water by the pharmacist to produce the oral suspension.

The capsules and oral suspension may be taken with or without food; however, tolerability may be enhanced if TAMIFLU is taken with food. Adjust the TAMIFLU dosage in patients with moderate or severe renal impairment. For patients who cannot swallow capsules, TAMIFLU for oral suspension is the preferred formulation.

When TAMIFLU for oral suspension is not available from wholesaler or the manufacturer, TAMIFLU 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 TAMIFLU capsules to mix with sweetened liquids are available, then a pharmacist may prepare an emergency supply of oral suspension from TAMIFLU 75 mg capsules.

Recommended Dosage for Treatment of Influenza

Initiate treatment with TAMIFLU within 48 hours of influenza symptom onset. Pediatric Patients (2 weeks of age through 12 years of age) Table 1 displays the recommended oral dosage of TAMIFLU 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.

Recommended Dosage for Prophylaxis of Influenza

Initiate post-exposure prophylaxis with TAMIFLU within 48 hours following close contact with an infected individual. Initiate seasonal prophylaxis with TAMIFLU during a community outbreak. Adults and Adolescents (13 years of age and older) The recommended dosage of TAMIFLU for prophylaxis of influenza in adults and adolescents 13 years and older is 75 mg orally once daily (one 75 mg capsule or 12.5 mL of oral suspension once daily) for at least 10 days following close contact with an infected individual and up to 6 weeks during a community outbreak.

In immunocompromised patients, TAMIFLU may be continued for up to 12 weeks. The duration of protection lasts for as long as TAMIFLU dosing is continued. Pediatric Patients (1 year to 12 years of age) Table 1 displays the recommended oral dosage of TAMIFLU for prophylaxis of influenza in pediatric patients 1 year to 12 years of age based on body weight and provides information about prescribing the capsule or the formulation for oral suspension.

Table 1 TAMIFLU Dosage Recommendations in Pediatric Patients for Treatment and Prophylaxis of Influenza

Dosage in Patients with Renal Impairment Table 2 displays the dosage recommendations for the treatment and prophylaxis of influenza in adults with various stages of renal impairment (estimated creatinine clearance of less than or equal to 90 mL per minute). Dosage modifications are recommended in adults with an estimated creatinine clearance less than or equal to 60 mL per minute. Table 2 Recommended Dosage Modifications for Treatment and Prophylaxis of Influenza in Adults with Renal Impairment or End Stage Renal Disease (ESRD) on Dialysis

Preparation and Storage of Constituted TAMIFLU Oral Suspension Prior to dispensing to the patient, constitute TAMIFLU for oral suspension (supplied as powder): a Tap the closed bottle containing the supplied TAMIFLU white powder several times to loosen the powder. b Measure 55 mL of water in a graduated cylinder. c Add the total amount of water for constitution to the bottle. d Close bottle with child-resistant cap tightly and shake the closed bottle well for 15 seconds. e Label the bottle with instructions to "Shake Well Before Use". f The constituted oral suspension contains 360 mg of oseltamivir base per 60 mL of volume (6 mg per mL) and is white, tutti-frutti–flavored. Write the expiration date of the constituted oral suspension on the bottle label. g Ensure patients have an oral dosing dispenser that measures the appropriate volume in milliliters. Counsel patients on how to utilize the oral dosing dispenser and correctly measure the oral suspension as prescribed (see Tables 1 and 2 ).

Emergency Preparation of Oral Suspension from 75 mg TAMIFLU Capsules The following directions are provided for use only during emergency situations and when FDA-approved, commercially manufactured TAMIFLU for oral suspension is not available from wholesalers or the manufacturer. The following emergency preparation instructions will provide one patient with enough TAMIFLU for a 5-day course of treatment of influenza or a 10-day course of prophylaxis of influenza: Step #1: Determine the dosage of TAMIFLU for the patient then determine the total volume of oral suspension needed to be prepared (see Table 3 ). Table 3 Emergency Preparation: Volume of Prepared Oral Suspension (6 mg per mL) Based Upon TAMIFLU Dose Step #2: Preparation must be performed with only one of the following vehicles (other vehicles have not been studied): Cherry Syrup (Humco ® ), Ora-Sweet ® SF (sugar-free) (Paddock Laboratories), or simple syrup.

Determine the number of capsules and the amount of water and vehicle needed to prepare the total volume (see Table 3 ) of prepared oral suspension (6 mg per mL) for a complete treatment or prophylaxis course (see Table 4 ). Table 4 Emergency Preparation: Number of TAMIFLU 75 mg Capsules and Amount of Water and Vehicle Needed to Prepare the Total Volume of a Prepared Oral Suspension (6 mg per mL) Step #3: Follow the instructions below for preparing the 75 mg TAMIFLU capsules to produce the oral suspension (6 mg per mL): Place the specified amount of water into a polyethyleneterephthalate (PET) or glass bottle (see Table 4 ). Constitution in other bottle types is not recommended because there is no stability data with other bottle types.

Carefully separate the capsule body and cap and pour the contents of the required number of TAMIFLU 75 mg capsules into the PET or glass bottle. Gently swirl the suspension to ensure adequate wetting of the TAMIFLU powder for at least 2 minutes. Slowly add the specified amount of vehicle to the bottle.

Close the bottle using a child-resistant cap and shake well for 30 seconds to completely dissolve the active drug and to ensure homogeneous distribution of the dissolved drug in the resulting suspension. The active drug, oseltamivir phosphate, readily dissolves in the specified vehicles. The suspension is caused by inert ingredients of TAMIFLU capsules which are insoluble in these vehicles.

Put an ancillary label on the bottle indicating "Shake Well Before Use." Instruct the parent or caregiver that any unused suspension remaining in the bottle following completion of therapy must be discarded by either affixing an ancillary label to the bottle or adding a statement to the pharmacy label instructions. Place a pharmacy label on the bottle that includes the patient's name, dosing instructions, drug name and any other required information to be in compliance with all State and Federal Pharmacy Regulations. Place an appropriate expiration date on the label according to storage conditions below.

Include the recommended dosage on the pharmacy label as per Tables 1 and 2. Store the prepared oral suspension in glass or PET bottles either: In a refrigerator: Stable for 5 weeks when stored in a refrigerator. At room temperature: Stable for 5 days when stored at room temperature.

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 TAMIFLU 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.

A total of 859 pediatric subjects received treatment with TAMIFLU 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 TAMIFLU (16%) compared to placebo (8%). The safety profile of TAMIFLU 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 TAMIFLU 75 mg once daily was consistent with that previously observed in other TAMIFLU prophylaxis clinical trials.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of TAMIFLU. 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 TAMIFLU 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 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

Influenza Vaccines Live Attenuated Influenza Vaccine

The concurrent use of TAMIFLU with live attenuated influenza vaccine (LAIV) intranasal has not been evaluated. However, because of the potential for TAMIFLU 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 TAMIFLU administration, unless medically indicated. Inactivated Influenza Vaccine Inactivated influenza vaccine can be administered at any time relative to use of TAMIFLU.

Drugs Without Clinically Significant Drug Interaction with TAMIFLU 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.

Pregnancy Risk Summary There are no adequate and well-controlled studies with TAMIFLU in pregnant women to inform a drug-associated risk of adverse developmental outcomes. 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 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 TAMIFLU 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. 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 TAMIFLU (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 TAMIFLU.

In prenatal and postnatal development studies in rats, oseltamivir was administered orally (at 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 TAMIFLU.

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 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. Additional safety information was provided in a double-blind, placebo-controlled trial in pediatric patients 6 to 12 years of age with known asthma. 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.

The safety and efficacy of TAMIFLU for treatment of influenza in pediatric patients less than 2 weeks of age have not been established. 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.

TAMIFLU 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.

Reports of overdoses with TAMIFLU 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 TAMIFLU.