These Highlights Do Not Include All The Information Needed To Use Oseltamivir Phosphate Capsule Safely And Effectively. See Full Prescribing Information For Oseltamivir Phosphate Capsule.

Adults and Adolescents (13 years of age and older)

The recommended oral dosage of Oseltamivir phosphate capsule for treatment of influenza in adults and adolescents 13 years and older is 75 mg twice daily (one 75 mg capsule twice daily) for 5 days.

Store at 20° to 25°C (68° to 77°F); Excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature].

Reports of overdoses with Oseltamivir phosphate 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 capsule [see Adverse Reactions (6)].

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 clinical 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 defects, 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 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 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 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.

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 Oseltamivir Phosphate.

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.

Oseltamivir phosphate, an influenza neuraminidase inhibitor (NAI) is available as capsules containing 75 mg oseltamivir for oral use, in the form of oseltamivir phosphate USP.

In addition to the active ingredient, each capsule contains pregelatinized starch, talc, povidone, croscarmellose sodium, and sodium stearyl fumarate. The 75 mg capsule shell contains gelatin, titanium dioxide, water, Iron oxide yellow, Iron oxide red and Sodium lauryl sulfate.

Imprinting ink contains shellac, black iron oxide, potassium hydroxide.

Oseltamivir phosphate is a White to off-white powder with the chemical name (3R, 4R, 5S) -4-acetylamino-5amino-3(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid, ethyl ester, phosphate (1:1). The chemical formula is C ₁₆H ₂₈N ₂O 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:

Oseltamivir phosphate capsule 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)] .

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)]

Live attenuated influenza vaccine (LAIV), intranasal:

Avoid administration of LAIV within 2 weeks before or 48 hours after Oseltamivir Phosphate Capsule use, unless medically indicated. (7)

Patients with renal impairment had higher blood levels of oseltamivir carboxylate compared to patients with normal renal function which may increase the risk of Oseltamivir phosphate-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 (2.4)].Oseltamivir phosphate is not recommended for patients with ESRD not undergoing dialysis [see Indications and Usage (1.3) and Clinical Pharmacology ( 12.3 )].

• Oseltamivir Phosphate capsule 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 Oseltamivir Phosphate Capsule [see Microbiology (12.4)].
• Oseltamivir Phosphate capsule 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)].

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 ( 12.3 )].

Oseltamivir Phosphate capsule 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)

Oseltamivir is an antiviral drug with activity against influenza virus [see Microbiology ( 12.4)].

Oseltamivir Phosphate capsule 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.

• Serious skin/hypersensitivity reactions such as Stevens-Johnson Syndrome, toxic epidermal necrolysis and erythema multiforme: Discontinue Oseltamivir phosphate capsule and initiate appropriate treatment if allergic-like reactions occur or are suspected. (5.1)
• Neuropsychiatric events: Patients with influenza, including those receiving Oseltamivir phosphate capsule, 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)

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)

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 Oseltamivir phosphate [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 Oseltamivir phosphate usage data. These events were reported primarily among pediatric patients and often had an abrupt onset and rapid resolution. The contribution of Oseltamivir phosphate to these events has not been established. Influenza can be associated with a variety of neurologic and behavioural 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 Oseltamivir phosphate-treated patients with influenza for signs of abnormal behavior. If neuropsychiatric symptoms occur, evaluate the risks and benefits of continuing Oseltamivir phosphate for each patient.

Oseltamivir Phosphate capsule is indicated for the prophylaxis of influenza A and B in patients 1 year and older.

Oseltamivir phosphate capsules:

• 75-mg capsules (75 mg free base equivalent of the phosphate salt): White to off white powder filled in size "2" hard gelatin capsule with cream cap and brown body printed OP on cap and 75 on body in black.

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)]

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.

Efficacy of Oseltamivir phosphate for the treatment or prophylaxis of influenza has not been established in immunocompromised patients [see Clinical Studies (14.2) ]. Safety of Oseltamivir phosphate has been demonstrated for up to 12 weeks for prophylaxis of influenza in immunocompromised patients [see Adverse Reactions (6.1)].

There is no evidence for efficacy of Oseltamivir phosphate 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. Oseltamivir phosphate has not been shown to prevent such complications.

Prescribers should be alert to the potential for secondary bacterial infections and treat them as appropriate.

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

Administer Oseltamivir Phosphate capsule 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:

• Oseltamivir Phosphate capsules

The capsules may be taken with or without food; however, tolerability may be enhanced if Oseltamivir Phosphate capsule is taken with food.

Adjust the Oseltamivir Phosphate capsule 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 andwhen 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)].

Cases of anaphylaxis and serious skin reactions including toxic epidermal necrolysis, Stevens-Johnson Syndrome, and erythema multiforme have been reported in postmarketing experience with Oseltamivir phosphate. Stop Oseltamivir phosphate and institute appropriate treatment if an allergic-like reaction occurs or is suspected. The use of Oseltamivir phosphate is contraindicated in patients with known serious hypersensitivity to Oseltamivir phosphate [see Contraindications (4) and Adverse Reactions (6.2)].

Efficacy of Oseltamivir phosphate 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 ( 14.1 ) ].

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.

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 [ see Use in Specific Population (8.6) and Clinical Pharmacology (12.3) ].

Table 2 Recommended Dosage Modifications for Treatmentand Prophylaxisof Influenza in Adults with Renal Impairment or End Stage Renal Disease (ESRD) on Dialysis

Initiate treatment with Oseltamivir phosphate capsule within 48 hours of influenza symptom onset.

Initiate post-exposure prophylaxis with Oseltamivir phosphate capsule within 48 hours following close contact with an infected individual. Initiate seasonal prophylaxis with Oseltamivir phosphate capsule during a community outbreak.

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 115 times the human systemic exposure (AUC _0-24h) of oseltamivir carboxylate that occurs after administration of the maximum recommended human dose.

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)] .

The following directions are provided for use only during emergency situations andwhen FDA-approved, commercially manufactured Oseltamivir Phosphate for oral suspension is not available from wholesalers or the manufacturer.

The following emergency preparation instructions will provide one patient with enough Oseltamivir Phosphate for a 5-day course of treatment of influenza or a 10-day course of prophylaxis of influenza:

Adults and Adolescents (13 years of age and older)

The recommended oral dosage of Oseltamivir phosphate capsule for treatment of influenza in adults and adolescents 13 years and older is 75 mg twice daily (one 75 mg capsule twice daily) for 5 days.

Store at 20° to 25°C (68° to 77°F); Excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature].

Reports of overdoses with Oseltamivir phosphate 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 capsule [see Adverse Reactions (6)].

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 clinical 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 defects, 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 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 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 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.

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 Oseltamivir Phosphate.

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.

Oseltamivir phosphate, an influenza neuraminidase inhibitor (NAI) is available as capsules containing 75 mg oseltamivir for oral use, in the form of oseltamivir phosphate USP.

In addition to the active ingredient, each capsule contains pregelatinized starch, talc, povidone, croscarmellose sodium, and sodium stearyl fumarate. The 75 mg capsule shell contains gelatin, titanium dioxide, water, Iron oxide yellow, Iron oxide red and Sodium lauryl sulfate.

Imprinting ink contains shellac, black iron oxide, potassium hydroxide.

Oseltamivir phosphate is a White to off-white powder with the chemical name (3R, 4R, 5S) -4-acetylamino-5amino-3(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid, ethyl ester, phosphate (1:1). The chemical formula is C ₁₆H ₂₈N ₂O 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:

Oseltamivir phosphate capsule 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)] .

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)]

Live attenuated influenza vaccine (LAIV), intranasal:

Avoid administration of LAIV within 2 weeks before or 48 hours after Oseltamivir Phosphate Capsule use, unless medically indicated. (7)

Patients with renal impairment had higher blood levels of oseltamivir carboxylate compared to patients with normal renal function which may increase the risk of Oseltamivir phosphate-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 (2.4)].Oseltamivir phosphate is not recommended for patients with ESRD not undergoing dialysis [see Indications and Usage (1.3) and Clinical Pharmacology ( 12.3 )].

• Oseltamivir Phosphate capsule 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 Oseltamivir Phosphate Capsule [see Microbiology (12.4)].
• Oseltamivir Phosphate capsule 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)].

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 ( 12.3 )].

Oseltamivir Phosphate capsule 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)

Oseltamivir is an antiviral drug with activity against influenza virus [see Microbiology ( 12.4)].

Oseltamivir Phosphate capsule 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.

• Serious skin/hypersensitivity reactions such as Stevens-Johnson Syndrome, toxic epidermal necrolysis and erythema multiforme: Discontinue Oseltamivir phosphate capsule and initiate appropriate treatment if allergic-like reactions occur or are suspected. (5.1)
• Neuropsychiatric events: Patients with influenza, including those receiving Oseltamivir phosphate capsule, 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)

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)

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 Oseltamivir phosphate [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 Oseltamivir phosphate usage data. These events were reported primarily among pediatric patients and often had an abrupt onset and rapid resolution. The contribution of Oseltamivir phosphate to these events has not been established. Influenza can be associated with a variety of neurologic and behavioural 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 Oseltamivir phosphate-treated patients with influenza for signs of abnormal behavior. If neuropsychiatric symptoms occur, evaluate the risks and benefits of continuing Oseltamivir phosphate for each patient.

Oseltamivir Phosphate capsule is indicated for the prophylaxis of influenza A and B in patients 1 year and older.

Oseltamivir phosphate capsules:

• 75-mg capsules (75 mg free base equivalent of the phosphate salt): White to off white powder filled in size "2" hard gelatin capsule with cream cap and brown body printed OP on cap and 75 on body in black.

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)]

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.

Efficacy of Oseltamivir phosphate for the treatment or prophylaxis of influenza has not been established in immunocompromised patients [see Clinical Studies (14.2) ]. Safety of Oseltamivir phosphate has been demonstrated for up to 12 weeks for prophylaxis of influenza in immunocompromised patients [see Adverse Reactions (6.1)].

There is no evidence for efficacy of Oseltamivir phosphate 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. Oseltamivir phosphate has not been shown to prevent such complications.

Prescribers should be alert to the potential for secondary bacterial infections and treat them as appropriate.

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

Administer Oseltamivir Phosphate capsule 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:

• Oseltamivir Phosphate capsules

The capsules may be taken with or without food; however, tolerability may be enhanced if Oseltamivir Phosphate capsule is taken with food.

Adjust the Oseltamivir Phosphate capsule 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 andwhen 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)].

Cases of anaphylaxis and serious skin reactions including toxic epidermal necrolysis, Stevens-Johnson Syndrome, and erythema multiforme have been reported in postmarketing experience with Oseltamivir phosphate. Stop Oseltamivir phosphate and institute appropriate treatment if an allergic-like reaction occurs or is suspected. The use of Oseltamivir phosphate is contraindicated in patients with known serious hypersensitivity to Oseltamivir phosphate [see Contraindications (4) and Adverse Reactions (6.2)].

Efficacy of Oseltamivir phosphate 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 ( 14.1 ) ].

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.

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 [ see Use in Specific Population (8.6) and Clinical Pharmacology (12.3) ].

Table 2 Recommended Dosage Modifications for Treatmentand Prophylaxisof Influenza in Adults with Renal Impairment or End Stage Renal Disease (ESRD) on Dialysis

Initiate treatment with Oseltamivir phosphate capsule within 48 hours of influenza symptom onset.

Initiate post-exposure prophylaxis with Oseltamivir phosphate capsule within 48 hours following close contact with an infected individual. Initiate seasonal prophylaxis with Oseltamivir phosphate capsule during a community outbreak.

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 115 times the human systemic exposure (AUC _0-24h) of oseltamivir carboxylate that occurs after administration of the maximum recommended human dose.

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)] .

The following directions are provided for use only during emergency situations andwhen FDA-approved, commercially manufactured Oseltamivir Phosphate for oral suspension is not available from wholesalers or the manufacturer.

The following emergency preparation instructions will provide one patient with enough Oseltamivir Phosphate for a 5-day course of treatment of influenza or a 10-day course of prophylaxis of influenza: