Tamiflu

1 INDICATIONS AND USAGE TAMIFLU 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 TAMIFLU 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 TAMIFLU is indicated for the prophylaxis of influenza A and B in patients 1 year and older. 1.3 Limitations of Use TAMIFLU 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 TAMIFLU [see Microbiology (12.4) ] . TAMIFLU 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: 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 TAMIFLU 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: 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 [see Dosage and Administration (2.5) ]. 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 [see Dosage and Administration (2.4) ]. 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 [see Dosage and Administration (2.6) ]. 2.2 Recommended Dosage for Treatment of Influenza Initiate treatment with TAMIFLU within 48 hours of influenza symptom onset. Adults and Adolescents (13 years of age and older) The recommended oral dosage of TAMIFLU 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 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. 2.3 Recommended Dosage for Prophylaxis of Influenza Initiate post-exposure prophylaxis with TAMIFLU within 48 hours following close contact with an infected individual…

5 WARNINGS AND PRECAUTIONS Serious skin/hypersensitivity reactions such as Stevens-Johnson Syndrome, toxic epidermal necrolysis and erythema multiforme: Discontinue TAMIFLU and initiate appropriate treatment if allergic-like reactions occur or are suspected. ( 5.1 ) Neuropsychiatric events: Patients with influenza, including those receiving TAMIFLU, particularly pediatric patients, may be at an increased risk of confusion or abnormal behavior early in their illness. Monitor for signs of abnormal behavior. ( 5.2 ) 5.1 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 (4) and Adverse Reactions (6.2) ] . 5.2 Neuropsychiatric Events There have been postmarketing reports 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 (6.2) ] . 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. 5.3 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. 5.4 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.

4 CONTRAINDICATIONS 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 [see Warnings and Precautions (5.1) ] . Patients with known serious hypersensitivity to oseltamivir or any of the components of TAMIFLU ( 4 )

7 DRUG INTERACTIONS Live attenuated influenza vaccine (LAIV), intranasal: Avoid administration of LAIV within 2 weeks before or 48 hours after TAMIFLU use, unless medically indicated. ( 7 ) 7.1 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. 7.2 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 [see Clinical Pharmacology (12.3) ] .

8.1 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 [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 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. 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 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 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 TAMIFLU.

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 Genentech at 1-888-835-2555 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 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. 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 TAMIFLU-treated adults and adolescents and ≥1% greater in TAMIFLU-treated subjects compared to placebo-treated subjects in either the treatment or prophylaxis trials. System Organ Class Treatment Trials Prophylaxis Trials Adverse Reaction TAMIFLU 75 mg twice daily (n = 2646) Placebo (n = 1977) TAMIFLU 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 TAMIFLU for the treatment of influenza. 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%). Amongst the 148 pediatric subjects aged 1 year to 12 years who received TAMIFLU 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 TAMIFLU versus 2% in the no prophylaxis group). Adverse Reactions from Treatment Trials in Pediatric Subjects (2 weeks to less than 1 year of age) Assessment of adverse reactions in pediatric subjects 2 weeks to less than 1 year of age was based on two open-label studies that included safety data on 135 influenza-infe…