Class: Neuraminidase Inhibitors
VA Class: AM800
Chemical Name: [3R-(3α,4β,5α)]-ethyl 4-(acetylamino)-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate phosphate
Molecular Formula: C₁₆H₂₈N₂O₄•H₃PO₄
CAS Number: 204255-11-8
Brands: Tamiflu

Introduction

Antiviral; neuraminidase inhibitor; sialic acid analog.^{1 2 3 4 5 6 9 64 144}

Uses for Oseltamivir Phosphate

Treatment of Seasonal Influenza A and B Virus Infections

Treatment of acute, uncomplicated illness caused by influenza A or B viruses in adults, adolescents, and pediatric patients ≥2 weeks of age.^{1 2 4 5 15 65 105 112 116 144} Although safety and efficacy not established in neonates <2 weeks of age†,¹ also recommended when treatment of influenza considered necessary in this age group.^{112 137}

Although efficacy not established in immunocompromised patients,¹ has been used to treat seasonal influenza A or B virus infections in bone marrow transplant (BMT) recipients†⁷⁴ and to treat seasonal influenza infections in hematopoietic stem cell transplant (HSCT) recipients†.¹⁰¹

CDC, US Public Health Service Advisory Committee on Immunization Practices (ACIP), AAP, and others recommend antiviral treatment of seasonal influenza illness initiated as soon as possible in all individuals with suspected or confirmed influenza who require hospitalization or have severe, complicated, or progressive illness (regardless of vaccination status or underlying illness).^{105 112 116 137 144} Early empiric antiviral treatment also recommended in individuals with suspected or confirmed influenza of any severity if they are at high risk of developing influenza-related complications because of age or underlying medical conditions.^{112 137 144} This includes children <2 years of age, adults ≥65 years of age, individuals of any age with certain chronic medical or immunosuppressive conditions, women who are pregnant women or up to 2 weeks postpartum, individuals <19 years of age receiving long-term aspirin therapy, American Indians, Alaskan natives, morbidly obese individuals with body mass index (BMI) ≥40, and residents of any age in nursing homes or other long-term care facilities.^{112 116 137}

CDC, ACIP, and AAP also state empiric antiviral treatment can be considered in previously healthy, symptomatic individuals with suspected or confirmed influenza who are not known to be at increased risk of developing severe or complicated illness if such treatment can be initiated within 48 hours of illness onset.^{105 112 137 144} Although these individuals typically do not require treatment, early empiric antiviral treatment might provide some benefit (e.g., shortened duration of illness).¹⁴⁴

If indicated, initiate antiviral treatment as soon as possible after illness onset (ideally within 48 hours);^{112 137 144 177} do not delay initiation of treatment while waiting for laboratory confirmation.^{112 137 144 177}

Although manufacturer states use for treatment of influenza only in patients who have been symptomatic for ≤2 days since efficacy not established in those whose symptoms have been present for >48 hours,¹ there is some evidence from observational studies of hospitalized patients that antiviral treatment might still be beneficial when initiated up to 4 or 5 days after illness onset.^{112 137 144 177} CDC, ACIP, and AAP recommend that antiviral treatment be initiated in all patients with severe, complicated, or progressive illness attributable to influenza and all hospitalized patients and patients at increased risk of influenza complications (either hospitalized or outpatient) who have suspected or confirmed influenza, even if it has been >48 hours after illness onset.^{112 137 177} Base decisions regarding use of empiric antiviral treatment in outpatients, especially high-risk patients, on disease severity and progression, age, underlying medical conditions, likelihood of influenza, and time since onset of symptoms.^{137 177} If empiric antiviral treatment considered warranted in previously healthy, symptomatic outpatients not considered at increased risk of influenza complications, initiate within 48 hours after illness onset,^{112 137 177} but some experts state treatment can be considered in such patients even if it has been >48 hours after illness onset.¹¹²

When treatment of suspected or confirmed acute, uncomplicated seasonal influenza indicated, use age-appropriate antiviral (oral oseltamivir, IV peramivir, inhaled zanamivir).^{112 137 144 177} Oseltamivir usually preferred for hospitalized patients and patients with severe or complicated influenza since data are lacking regarding use of IV peramivir or inhaled zanamivir in such patients.^{112 137 161} Oseltamivir also preferred for treatment of suspected or confirmed influenza in pregnant women.¹³⁷ (See Pregnancy under Cautions.)

Consider viral surveillance data available from local and state health departments and CDC when selecting an antiviral for treatment of seasonal influenza.^{112 116 137 144} Strains of circulating influenza viruses and the antiviral susceptibility of these strains constantly evolve;^{116 144} emergence of oseltamivir-resistant influenza virus may decrease effectiveness of the drug.¹ Although influenza A and B viruses circulating in US during last few years generally have been susceptible to oseltamivir, consult most recent information.^{137 144}

CDC issues recommendations concerning use of antiviral agents for treatment of influenza, and these recommendations are updated as needed during each influenza season.^{137 144} Information regarding influenza surveillance and updated recommendations for treatment of seasonal influenza are available from CDC at .

Prevention of Seasonal Influenza A and B Virus Infections

Prevention of illness caused by seasonal influenza A or B viruses in adults, adolescents, and children ≥1 year of age.^{1 16 30 105 112 116}

Although efficacy not established in immunocompromised patients,¹ oseltamivir has been used for prophylaxis of seasonal influenza in immunocompromised individuals†, including cancer patients, BMT recipients, HSCT recipients, and solid organ transplant recipients.^{1 75}

Annual vaccination with seasonal influenza virus vaccine, as recommended by ACIP, is the primary means of preventing seasonal influenza and its severe complications.^{105 112 116 137 488} Prophylaxis with an appropriate antiviral active against circulating influenza strains is considered an adjunct to vaccination for control and prevention of influenza.^{1 105 112 116 137 488}

Indiscriminate use of antivirals for prophylaxis may promote resistance or reduce availability of antivirals for treatment.^{137 144} Base decisions regarding use of antivirals for prophylaxis of influenza on exposed person's risk for influenza complications, vaccination status, type and duration of contact, recommendations from local or public health authorities, and clinical judgment.¹⁴⁴ Generally use postexposure prophylaxis only if it can be initiated within 48 hours of most recent exposure.^{137 144}

When seasonal influenza viruses are circulating in the community, postexposure prophylaxis with oseltamivir or zanamivir can be considered for certain individuals, including those at high risk of developing influenza complications for whom influenza vaccine is contraindicated, unavailable, or expected to have low efficacy (e.g., immunocompromised individuals).^{112 116 137 144} Other possible candidates for antiviral prophylaxis include unvaccinated health care personnel, public health workers, and first responders with unprotected, close-contact exposure to a patient with confirmed, probable, or suspected influenza during the time when the patient was infectious.^{112 137 144} Also consider antiviral prophylaxis for controlling influenza outbreaks in nursing and long-term care facilities or other closed or semi-closed settings with large numbers of individuals at high risk for influenza complications.^{112 116 137 144} In individuals at high risk of influenza complications who receive influenza virus vaccine inactivated, prophylaxis can be considered during the 2 weeks after vaccination to provide protection until an adequate immune response develops.^{112 116} (See Specific Drugs under Interactions.)

Consider viral surveillance data available from local and state health departments and CDC when selecting an antiviral for prophylaxis of influenza.^{112 116 137} The most appropriate antiviral for prevention of influenza is based on the likelihood that the influenza strain is susceptible and the known adverse effects of the drug.^{137 144} Strains of circulating influenza viruses and the antiviral susceptibility of these strains constantly evolve;^{116 137 144} emergence of oseltamivir-resistant influenza virus may decrease effectiveness of the drug.¹

CDC issues recommendations concerning use of antivirals for prophylaxis of influenza, and these recommendations are updated as needed during each influenza season.^{137 144} Information regarding influenza surveillance and updated recommendations for prevention of seasonal influenza are available from CDC at .

Avian Influenza A Virus Infections

Treatment or prevention of infections caused by avian influenza A viruses† (e.g., H1N1, H7N3, H7N7, H7N9).^{46 47 50 61 68 94 104 152 169 555 556}

CDC and WHO state that oseltamivir is drug of choice for treatment or prophylaxis of infections caused by highly pathogenic avian influenza A (H5N1);^{50 68 94 104} zanamivir is an alternative.^{50 94}

Oseltamivir also drug of choice for treatment of infections caused by avian influenza A (H7N9), especially in hospitalized patients and patients with severe or complicated illness.^{50 104} Because of limited data, zanamivir not recommended for treatment of severe avian influenza A (H7N9) infections, but may be considered in uncomplicated infections.⁵⁰ Either oseltamivir or zanamivir can be used for prophylaxis in close contacts of patients with confirmed or probable avian influenza A (H7N9) infection.⁵⁰

Most recent information regarding avian influenza A infections is available at WHO website at and CDC website at .

Pandemic Influenza

Treatment or prevention of pandemic influenza† caused by susceptible strains of influenza virus.^{52 151}

Influenza viruses can cause pandemics, during which rates of illness and death from influenza-related complications can increase dramatically worldwide.^{52 104 488}

Most recent influenza pandemic occurred during 2009 and was related to a novel influenza A (H1N1) strain, influenza A (H1N1)pdm09.^{52 134 144 151 488} In the US, the pandemic was characterized by a substantial increase in influenza activity that peaked in late October and early November 2009 and returned to seasonal baseline levels by January 2010.^{123 488} During that time, ≥99% of influenza viruses circulating in the US were influenza A (H1N1)pdm09.^{123 488} In August 2010, the WHO declared that the world was in a post-pandemic period;¹⁴⁸ since that time, influenza A (H1N1)pdm09 has become a seasonal influenza virus and continues to circulate with other seasonal viruses.^{144 551 553}

The spread of the highly pathogenic H5N1 strain of avian influenza A in poultry in Asia and other countries that was first identified in 2003 represents a potential future pandemic threat.^{50 54 55 56 104 147}

Oseltamivir Phosphate Dosage and Administration

Administration

Oral Administration

Administer orally without regard to meals;¹ administration with meals may improve GI tolerability.¹

Commercially available as 30-, 45-, and 75-mg capsules and as a powder for oral suspension that is reconstituted to provide an oral suspension containing 6 mg/mL.¹

Reconstituted oseltamivir oral suspension is the preferred preparation for individuals unable to swallow capsules.¹ Alternatively, if the oral suspension not available, the appropriate dosage of oseltamivir capsules can be administered by opening the appropriate strength of capsules and mixing the contents with a sweet liquid (e.g., regular or sugar-free chocolate syrup, corn syrup, caramel topping, light brown sugar dissolved in water).^{1 141}

If the commercially available powder for oral suspension is not available and the appropriate strength of oseltamivir capsules is not available to mix with sweetened liquids (e.g., shortage during an emergency), a pharmacist can prepare an extemporaneous oral suspension using 75-mg oseltamivir capsules and simple syrup, cherry syrup vehicle (Humco), or Ora-Sweet SF (Paddock).¹ Consult manufacturer's information for specific instructions.¹

Reconstitution

Reconstitute commercially available powder for oral suspension at the time of dispensing.¹ Tap bottle to thoroughly loosen powder and then add the amount of water specified on the bottle; shake well for 15 seconds.¹

Reconstituted oral suspension contains 6 mg/mL; each 12.5 mL contains 75 mg of oseltamivir.¹

Provide an oral dosing device that can accurately measure the appropriate volume in mL;¹ counsel patient and/or caregiver how to use the oral dosing dispenser to correctly measure and administer the appropriate dose.¹

Shake suspension well prior to each dose.¹

Dosage

Available as oseltamivir phosphate; dosage expressed in terms of oseltamivir.¹

Pediatric Patients

Treatment of Seasonal Influenza A and B Virus Infections

Oral

Initiate treatment as soon as possible (preferably within 48 hours of symptom onset).^{1 112 137 144 177} Although efficacy only established when given within 2 days after onset of symptoms,¹ there is some evidence from hospitalized patients that antiviral treatment initiated up to 4 or 5 days after onset of symptoms may still be beneficial.^{112 116 137 144} (See Uses: Treatment of Seasonal Influenza A and B Virus Infections.)

Usual duration of antiviral treatment is 5 days,^{1 112 137 144} but hospitalized patients with severe infections (e.g., those with prolonged infection or admitted into an intensive care unit) or immunosuppressed individuals may require >5 days of treatment.^{137 144}

Infants 2 weeks to <1 year of age: 3 mg/kg twice daily for 5 days recommended by manufacturer.¹

Neonates and infants <1 year of age: AAP recommends 3.5 mg/kg twice daily for 5 days in infants 9 through 11 months of age and 3 mg/kg twice daily for 5 days in full-term neonates and infants through 8 months of age.¹¹² Although safety and efficacy not established in neonates <2 weeks of age†,¹ AAP states the drug can be used for treatment of influenza in neonates from birth† because of its known safety profile.¹¹² (See Pediatric Use under Cautions.)

Dosage recommended for full-term infants may be excessive in preterm neonates.^{112 137 144} Limited data suggest that, if the drug is considered necessary for treatment of influenza in preterm neonates†, dosage should be based on postmenstrual age (i.e., gestational age plus chronological age).^{112 137} CDC and AAP recommend 1 mg/kg twice daily in preterm neonates with postmenstrual age <38 weeks, 1.5 mg/kg twice daily in those with postmenstrual age of 38 through 40 weeks, and 3 mg/kg twice daily in those with postmenstrual age >40 weeks.^{112 137} Consult pediatric infectious disease expert if treatment of influenza considered necessary in extremely premature neonates (postmenstrual age <28 weeks).¹¹²

Children 1–12 years of age: Dosage is based on weight.¹ (See Table 1.)

Adolescents ≥13 years of age: 75 mg twice daily for 5 days.¹

Table 1. Oseltamivir Dosage for Treatment of Seasonal Influenza A and B in Children 1–12 Years of Age1

Weight (kg)	Daily Dosage (mg)	Daily Dosage (Volume of Reconstituted Oral Suspension Containing 6 mg/mL)
≤15	30 mg twice daily for 5 days	5 mL twice daily for 5 day
15.1–23	45 mg twice daily for 5 days	7.5 mL twice daily for 5 day
23.1–40	60 mg twice daily for 5 days	10 mL twice daily for 5 day
≥40.1	75 mg twice daily for 5 days	12.5 mL twice daily for 5 day

Prevention of Seasonal Influenza A and B Virus Infections

Oral

Initiate prophylaxis within 2 days after exposure (e.g., close contact with infected individual).^{1 137} Usual duration is 10 days.¹ CDC recommends prophylaxis be continued for 7 days after last known exposure;¹³⁷ when outbreak is occurring in a long-term care facility or hospital, continue for at least 2 weeks and up to 7 days after last known case is identified.¹³⁷ May be continued for up to 6 weeks during a community influenza outbreak.¹

Although safety and efficacy not established for prophylaxis of influenza in infants <1 year of age†,¹ CDC and ACIP state infants 3 months to <1 year of age† can receive 3 mg/kg once daily for 10 days if considered necessary.^{137 144} AAP recommends 3.5 mg/kg once daily for 10 days in infants 9 through 11 months of age† and 3 mg/kg once daily for 10 days in infants 3 through 8 months of age†.¹¹²

Because of limited safety and efficacy data, CDC, ACIP, and AAP do not recommend use for prophylaxis of influenza in full-term or premature infants <3 months of age† unless situation is judged critical.^{112 137 144}

Children 1–12 years of age: Dosage is based on weight.¹ (See Table 2.)

Adolescents ≥13 years of age: 75 mg once daily for at least 10 days.¹

Table 2. Oseltamivir Dosage for Prevention of Seasonal Influenza A and B in Children 1–12 Years of Age1

Weight (kg)	Daily Dosage (mg)	Daily Dosage (Volume of Reconstituted Oral Suspension Containing 6 mg/mL)
≤15	30 mg once daily for 10 days	5 mL once daily for 10 days
15.1–23	45 mg once daily for 10 days	7.5 mL once daily for 10 days
23.1–40	60 mg once daily for 10 days	10 mL once daily for 10 days
≥40.1	75 mg once daily for 10 days	12.5 mL once daily for 10 days

Avian Influenza A Virus Infection

Treatment of Avian Influenza A Virus Infections†

Oral

Optimum dosage and duration of treatment unknown, especially for severe or complicated infections.^{50 63 68 104}

Dosage usually recommended for treatment of seasonal influenza A and B virus infections has been recommended.^{63 104} (See Treatment of Seasonal Influenza A and B Virus Infections under Dosage and Administration.) Although some experts have suggested that severely ill hospitalized patients or immunocompromised patients may benefit from higher dosage,^{50 63 68 85 104} limited data from those with severe influenza, including some with avian influenza A (H1N1) infection, suggest that higher dosage may not provide additional clinical benefit.^{112 137} Although 5 days of treatment may be adequate for uncomplicated illness, consider longer duration of treatment (i.e., 7–10 days) in severely ill hospitalized patients and immunosuppressed individuals.^{50 63 68 85 104}

Initiate treatment as early as possible.^{50 104 152 555} May be most beneficial if initiated within 2 days of symptom onset,¹⁵² but is warranted even if initiated >48 hours after illness onset or in patients who present for care in later stages of illness.^{50 104 152 555}

Prevention of Avian Influenza A Virus Infections†

Oral

Prophylaxis of highly pathogenic avian influenza A (H5N1) infection in close contacts†: CDC and WHO state that the once-daily dosage usually recommended for prophylaxis of seasonal influenza A and B virus infections can be used.^{50 94} (See Prevention of Seasonal Influenza A and B Virus Infections under Dosage and Administration.) Continue prophylaxis for 7–10 days after last known exposure.^{50 94}

Prophylaxis of avian influenza virus A (H7N9) infection in close contacts†: CDC recommends that the twice-daily dosage usually recommended for treatment of seasonal influenza A and B virus infections be given for 5–10 days.⁵⁰ (See Treatment of Seasonal Influenza A and B Virus Infections under Dosage and Administration.)

Pandemic Influenza†

Oral

Dosage usually recommended for treatment or prophylaxis of seasonal influenza A and B virus infections is considered the minimum dosage required for treatment or prophylaxis of influenza in a pandemic situation.^{43 52}

Adults

Treatment of Seasonal Influenza A and B Virus Infections

Oral

75 mg twice daily for 5 days.¹

Initiate treatment as soon as possible (preferably within 48 hours of symptom onset).^{1 112 137 144 177} Although efficacy only established when given within 2 days after onset of symptoms,¹ there is some evidence from hospitalized patients that antiviral treatment initiated up to 4 or 5 days after onset of symptoms may still be beneficial.^{112 116 137 144} (See Uses: Treatment of Seasonal Influenza A and B Virus Infections.)

Usual duration of antiviral treatment is 5 days, but hospitalized patients with severe infections (e.g., those with prolonged infection or admitted into an intensive care unit) or individuals with immunosuppression may require >5 days of treatment.^{137 144}

Prevention of Seasonal Influenza A and B Virus Infections

Oral

75 mg once daily for at least 10 days.¹

Initiate prophylaxis within 2 days after exposure (e.g., close contact with infected individual).^{1 137} Usual duration is 10 days.¹ CDC recommends prophylaxis be continued for 7 days after last known exposure;¹³⁷ when outbreak is occurring in a long-term care facility (e.g., nursing home) or hospital, continue for at least 2 weeks and up to 7 days after last known case is identified.¹³⁷ Safety and efficacy of prophylaxis demonstrated for up to 6 weeks in immunocompetent individuals;¹ safety of prophylaxis demonstrated for up to 12 weeks in immunocompromised individuals.¹

Avian Influenza A Virus Infections

Treatment of Avian Influenza A Virus Infections†

Oral

Optimum dosage and duration of treatment unknown, especially for severe or complicated infections.^{50 63 68 104}

Dosage usually recommended for treatment of seasonal influenza A and B virus infections has been recommended.^{63 104} (See Treatment of Seasonal Influenza A and B Virus Infections under Dosage and Administration.) Although some experts have suggested that severely ill patients may benefit from higher dosage (i.e., 150 mg twice daily in adults with normal renal function),^{50 63 68 85 104} limited data from those with severe influenza, including some with avian influenza A (H1N1) infection, suggest that higher dosage may not provide additional clinical benefit.^{112 137} Although 5 days may be adequate for uncomplicated illness, consider longer duration of treatment (i.e., 7–10 days) in severely ill hospitalized patients and immunosuppressed individuals.^{50 63 68 85 104}

Initiate treatment as early as possible.^{50 104 152 555} May be most beneficial if initiated within 2 days of symptom onset,¹⁵² but is warranted even if initiated >48 hours after illness onset or in patients who present for care in the later stages of illness.^{50 104 152 555}

Prevention of Avian Influenza A Virus Infections†

Oral

Prophylaxis of highly pathogenic avian influenza A (H5N1) infection in close contacts†: CDC and WHO state that the once-daily dosage usually recommended for prophylaxis of seasonal influenza A and B virus infections can be used.^{50 94} (See Prevention of Seasonal Influenza A and B Virus Infections under Dosage and Administration.) Continue prophylaxis for 7–10 days after last known exposure.^{50 94}

Prophylaxis of avian influenza virus A (H7N9) infection in close contacts†: CDC recommends that the twice-daily dosage usually recommended for treatment of seasonal influenza A and B virus infections be given for 5–10 days.⁵⁰ (See Treatment of Seasonal Influenza A and B Virus Infections under Dosage and Administration.)

During avian influenza A (H7N7) outbreaks, 75 mg daily has been used for prophylaxis in exposed individuals.⁶¹

Pandemic Influenza†

Oral

Dosage recommended for treatment or prophylaxis of seasonal influenza A and B virus infections is considered the minimum dosage required for treatment or prophylaxis of influenza in a pandemic situation.⁴³

Special Populations

Hepatic Impairment

Usual dosage can be used in patients with mild to moderate hepatic impairment (Child-Pugh score ≤9).^{1 42} Safety and pharmacokinetics not evaluated in those with severe hepatic impairment.¹

Renal Impairment

Adjust dosage in adults with Cl_cr 10–60 mL/minute and in those with end-stage renal disease (ESRD; Cl_cr ≤10 mL/minute) undergoing hemodialysis or continuous peritoneal dialysis.^{1 137} (See Table 3 and Table 4.)

Not recommended in adults with ESRD who are not undergoing dialysis.^{1 137}

Dosage recommendations not available for pediatric patients with renal impairment; CDC states dosage recommendations for adults with renal impairment may be useful for treatment or prevention of influenza in children with renal impairment who weigh >40 kg.¹³⁷

Dosage assumes 3 hemodialysis sessions in the 5-day period.^{1 137} If influenza symptoms developed during the 48 hours between hemodialysis sessions, give initial oseltamivir dose immediately and give the post-hemodialysis dose regardless of when initial dose was given.^{1 137}

Data derived from studies in patients undergoing CAPD.^{1 137}

Table 3. Oseltamivir Dosage for Treatment of Influenza in Adults with Renal Impairment1137

Clcr (mL/minute)	Dosage
>30 to 60	30 mg twice daily for 5 days
>10 to 30	30 mg once daily for 5 days
≤10 (ESRD receiving hemodialysis)	30 mg given immediately after each hemodialysis cycle for ≤5 days
≤10 (ESRD receiving continuous peritoneal dialysis)	Single 30-mg dose given immediately after a dialysis exchange

An initial dose may be given prior to start of hemodialysis.^{1 137}

Data derived from studies in patients undergoing CAPD.^{1 137}

Table 4. Oseltamivir Dosage for Prevention of Influenza in Adults with Renal Impairment1137

Clcr (mL/minute)	Dosage
>30 to 60	30 mg once daily for ≥10 days
>10 to 30	30 mg once every other day for ≥ 10 days
≤10 (ESRD receiving hemodialysis)	30 mg given immediately after alternate hemodialysis cycles
≤10 (ESRD receiving continuous peritoneal dialysis)	30 mg given once a week immediately following dialysis exchange

Geriatric Patients

No dosage adjustments except those related to renal impairment.¹

Cautions for Oseltamivir Phosphate

Contraindications

• Known hypersensitivity to oseltamivir or any ingredient in the formulations.¹

Warnings/Precautions

Sensitivity Reactions

Dermatologic and Hypersensitivity Reactions

Anaphylaxis and serious skin reactions, including toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme, reported.¹

If an allergic reaction occurs or is suspected, discontinue oseltamivir and institute appropriate therapy.¹

Neuropsychiatric Events

Adverse neuropsychiatric events (e.g., self-injury, delirium, hallucinations, confusion, abnormal behavior, seizures) and death reported.^{1 84 88}

Postmarketing cases of delirium and abnormal behavior leading to injury reported mainly in Japanese children.^{1 84 88} Cases generally had an abrupt onset and rapid resolution.¹ Role of oseltamivir not determined.¹

Influenza itself can be associated with neurologic and behavioral symptoms (e.g., hallucinations, delirium, abnormal behavior) and fatalities can occur.¹ Although such events may occur in the setting of encephalitis or encephalopathy, they can occur without obvious severe disease.¹

Closely monitor patients with influenza for signs of abnormal behavior.¹ If neuropsychiatric symptoms develop, consider risks versus benefits of continued therapy.¹

Bacterial Infections

Serious bacterial infections may begin with influenza-like symptoms or may coexist with or occur as complications of influenza.¹ No evidence that oseltamivir prevents such complications.¹

No evidence of efficacy in illness caused by any organisms other than influenza A or B.¹

Concomitant Illness

Efficacy for treatment of influenza in patients with chronic cardiac disease and/or underlying pulmonary disease not established; no evidence to date of increased risk of adverse effects in this population.¹

Although efficacy for treatment or prevention of influenza not established in immunocompromised patients,¹ safety of oseltamivir prophylaxis has been demonstrated for up to 12 weeks in immunocompromised patients.¹ Has been used for treatment or prevention of influenza in some immunocompromised individuals†, including BMT recipients, HSCT recipients, solid organ transplant recipients, and chemotherapy patients.^{1 74 75 101} (See Uses.)

No data available regarding use for treatment of influenza in patients with any medical condition severe or unstable enough to require inpatient care.¹

Influenza Vaccination

Not a substitute for annual vaccination with a seasonal influenza vaccine (influenza virus vaccine inactivated, influenza vaccine live intranasal, influenza vaccine recombinant).^{1 112 144}

Although antivirals used for treatment or prevention of influenza, including oseltamivir, may be used concomitantly with or at any time before or after influenza virus vaccine inactivated,^{1 100} these antivirals may inhibit the vaccine virus contained in influenza vaccine live intranasal.^{1 100} (See Specific Drugs under Interactions.)

Sorbitol

When the commercially available oral suspension containing 6 mg/mL is used, each 75-mg dose of oseltamivir contains 2 g of sorbitol.¹ This amount of sorbitol exceeds the maximum daily limit of sorbitol for individuals with hereditary fructose intolerance and may result in dyspepsia and diarrhea.¹

Specific Populations

Pregnancy

Category C.¹

Pregnant women are at increased risk for severe complications from influenza,^{1 142 144} which may lead to adverse pregnancy and/or fetal outcomes including maternal death, still births, birth defects, preterm delivery, low birthweight, and small size for gestational age.¹

CDC and ACIP state that pregnancy is not a contraindication to use of oseltamivir for treatment or prevention of influenza; oseltamivir regimens recommended in pregnant women are the same as those for other adults.^{142 144}

CDC and ACIP state that oseltamivir may be preferred when a neuraminidase inhibitor is indicated for treatment of influenza in a woman who is pregnant or up to 2 weeks postpartum,^{142 144} but drug of choice for prophylaxis of these infections is less clear.¹⁴² Zanamivir may be preferred by some clinicians for prophylaxis in pregnant women because of its limited systemic absorption; however, consider respiratory complications that may be associated with zanamivir because of its route of administration, especially in women at risk for respiratory problems.^{142 144}

Lactation

Distributed into human milk in low concentrations that are considered unlikely to cause toxicity in nursing infants.¹ Use with caution in nursing women.¹

Pediatric Use

Safety and efficacy for treatment of influenza not established in infants <2 weeks of age.¹

Safety and efficacy for prophylaxis of influenza not established in infants <1 year of age.¹

Young children, especially those <2 years of age, are at increased risk of influenza infection, hospitalization, and complications.^{112 144} During the 2009 influenza A (H1N1)pdm09 pandemic, FDA issued an emergency use authorization (EUA) that temporarily allowed use of oseltamivir for emergency treatment or prevention of these infections in infants <1 year of age†.^{121 150} Although the EUA expired in June 2010,¹⁵⁰ AAP states that, because of the known safety profile of the drug, use for treatment of influenza in full-term or preterm neonates from birth† or for prevention of influenza in infants ≥3 months of age† is appropriate if indicated.¹¹² ACIP and AAP state that oseltamivir not recommended for prevention of influenza in infants <3 months of age† unless situation is judged critical.^{112 144} (See Pediatric Patients under Dosage and Administration.)

Unusual adverse neurologic and/or psychiatric effects (e.g., self-injury, delirium, hallucinations, mental confusion, abnormal behavior, seizures) and deaths reported in Japanese children (≤16 years of age) receiving oseltamivir for treatment of influenza; role of oseltamivir not determined.^{1 83 84} (See Neuropsychiatric Events under Cautions.)

Geriatric Use

No overall differences in safety or efficacy compared with younger adults, but increased sensitivity cannot be ruled out.¹

Hepatic Impairment

Safety and pharmacokinetics not evaluated in patients with severe hepatic impairment.¹

Renal Impairment

Decreased clearance.¹ Dosage adjustments recommended in adults with Cl_cr 10–60 mL/minute and adults with ESRD (Cl_cr ≤10 mL/minute) undergoing dialysis.¹ Not recommended in adults with ESRD not undergoing dialysis.¹ (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

GI effects (nausea, vomiting, diarrhea, abdominal pain), headache, bronchitis, insomnia, vertigo.^{1 2 3 4}

Interactions for Oseltamivir Phosphate

Oseltamivir phosphate and its active metabolite not metabolized by and do not inhibit CYP isoenzymes;^{1 25} drug interactions with drugs that are substrates or inhibitors of these enzymes unlikely.¹

Drugs Eliminated by Renal Excretion

Potential pharmacokinetic interaction when used concomitantly with other drugs eliminated by renal tubular secretion (e.g., probenecid);¹ clinically important interactions unlikely.¹

Specific Drugs

Drug	Interaction	Comments
Acetaminophen	No evidence of pharmacokinetic interaction1
Amoxicillin	No evidence of pharmacokinetic interaction1
Antacids (containing magnesium, aluminum, or calcium carbonate)	No clinically important effect on oseltamivir pharmacokinetics1 92
Anticoagulants, oral	No evidence of pharmacokinetic interaction1
Aspirin	Pharmacokinetic interactions unlikely1 33
Cimetidine	No evidence of pharmacokinetic interaction1
Influenza virus vaccines	Influenza virus vaccine inactivated: No specific studies, but interference with antibody response to the vaccine not expected;1 oseltamivir does not interfere with humoral antibody response to influenza infection1 Influenza vaccine live intranasal: No specific studies;1 100 oseltamivir potentially could decrease antibody response to the live vaccine1 100	Influenza virus vaccine inactivated: May be administered simultaneously with or at any time before or after oseltamivir1 112 100 Influenza vaccine live intranasal: Do not administer the live vaccine until at least 48 hours after oseltamivir discontinued; do not administer oseltamivir until at least 2 weeks after the vaccine, unless medically necessary;1 100 if oseltamivir and intranasal live influenza vaccine administered concomitantly, consider revaccination if appropriate; ACIP recommends revaccination if oseltamivir was given within 14 days after the intranasal live vaccine;100 alternatively, if oseltamivir given 2 days before to 14 days after the intranasal live vaccine, revaccinate using parenteral inactivated influenza vaccine or parenteral recombinant influenza vaccine100
Peramivir	No evidence of drug interactions when oral oseltamivir used concomitantly with IV peramivir176
Probenecid	Potential increased systemic exposure to oseltamivir carboxylate because of decreased renal tubular secretion1	Not expected to be clinically important;1 use usual dosages1

Oseltamivir Phosphate Pharmacokinetics

Absorption

Bioavailability

Oseltamivir phosphate readily absorbed following oral administration and then extensively converted to the active metabolite (oseltamivir carboxylate).^{1 24 25}

Absolute bioavailability of oseltamivir carboxylate 80% following oral administration of oseltamivir phosphate;²⁵ peak concentrations of active metabolite attained within 3–4 hours.¹

Food

Administration of oseltamivir phosphate with food has no effect on peak plasma concentrations or AUC of oseltamivir carboxylate.¹

Distribution

Extent

Following oral administration of oseltamivir phosphate, oseltamivir carboxylate distributed throughout body, including upper and lower respiratory tract.^{24 25}

Placental transfer of oseltamivir carboxylate demonstrated in rats and rabbits; not known whether oseltamivir or oseltamivir carboxylate crosses the placenta in humans.¹

Distributed into milk in rats; not known whether oseltamivir or oseltamivir carboxylate distributed into human milk.¹

Plasma Protein Binding

Oseltamivir phosphate 42% bound to plasma proteins; oseltamivir carboxylate 3% bound to plasma proteins.^{1 24}

Elimination

Metabolism

Oseltamivir phosphate extensively (>90%) converted to oseltamivir carboxylate, principally by hepatic esterases.¹ No further metabolism of oseltamivir carboxylate occurs.¹

Oseltamivir phosphate and oseltamivir carboxylate not metabolized by CYP enzymes.^{1 25}

Elimination Route

Oseltamivir carboxylate eliminated (>99%) by renal excretion;^{1 24 25} <20% of dose eliminated in feces.¹

Half-life

Plasma half-life of oseltamivir phosphate is 1–3 hours;^{1 24} half-life of oseltamivir carboxylate is 6–10 hours.^{1 25}

Special Populations

Renal impairment: Systemic exposure to oseltamivir carboxylate increases with declining renal function.¹ In patients undergoing CAPD, peak concentrations following a single 30-mg dose of oseltamivir or once-weekly oseltamivir was approximately threefold higher than peak concentrations in patients with normal renal function receiving 75 mg twice daily.¹

Mild or moderate hepatic impairment: Systemic exposure to oseltamivir carboxylate is comparable to that in individuals without hepatic impairment.^{1 42}

Pediatric patients: Clearance of both oseltamivir phosphate and oseltamivir carboxylate increased in younger pediatric patients compared with adults.¹ Total clearance of oseltamivir carboxylate decreases linearly with increasing age (up to 12 years of age);¹ pharmacokinetics in those >12 years of age similar to adults.¹

Geriatric patients: Exposure to oseltamivir carboxylate at steady state approximately 25–35% higher in those 65–78 years of age compared with younger adults;^{1 3} half-lives in geriatric individuals are similar to those in younger adults.¹

Stability

Storage

Oral

Capsules

25°C (may be exposed to 15–30°C).¹

Powder for Suspension

25°C (may be exposed to 15–30°C).¹

Following reconstitution, store suspension at 2–8°C for up to 17 days.¹ Alternatively, may be stored for up to 10 days at 25°C (may be exposed to 15–30°).¹ Do not freeze.¹

Extemporaneous Oral Suspension

Extemporaneous oral suspensions prepared according to manufacturer's directions using 75-mg oseltamivir capsules and simple syrup, cherry syrup vehicle, or Ora-Sweet SF are stable for 5 weeks (35 days) at 2–8°C or 5 days at 25°C.¹

Actions and Spectrum

• Oseltamivir phosphate is prodrug and is inactive until hydrolyzed by hepatic esterases to oseltamivir carboxylate, the active metabolite.^{1 2 3 4 5 6 7 8 9}

• Oseltamivir carboxylate is a potent selective competitive inhibitor of influenza virus neuraminidase, an enzyme essential for viral replication;^{1 2 3 8 9} possibly alters virus particle aggregation and release.¹

• Active against influenza A and B viruses, including amantadine- and rimantadine-resistant isolates.^{1 2 3 7 8} The majority of seasonal influenza A (H3N2), influenza A (H1N1)pdm09, and influenza B viruses circulating during recent influenza seasons have been susceptible to oseltamivir.^{551 552 557 559}

• Beginning in the 2007–2008 influenza season, a significant increase in the prevalence of oseltamivir-resistant seasonal influenza A (H1N1) was reported worldwide;^{144 153 488} almost all seasonal influenza A (H1N1) strains tested in the US in 2008, 2009, and beginning of 2010 were resistant to oseltamivir.⁴⁸⁸ During the 2010–2011 influenza season, the former seasonal influenza A (H1N1) was rarely detected; almost all circulating influenza A (H1N1) reported since that time have been the 2009 pandemic influenza A (H1N1)pdm09 virus.^{163 551 552}

• Although almost all isolates of influenza A (H1N1)pdm09 virus have been susceptible to oseltamivir in vitro,^{144 163 167 551 552 557 559} resistance has been reported rarely.^{123 144 155 156 157 163 167 172 551 552 557 559} Oseltamivir-resistant influenza A (H1N1)pdm09 have emerged during oseltamivir treatment or prophylaxis, including in immunosuppressed individuals receiving oseltamivir treatment and in individuals who developed influenza illness while receiving oseltamivir prophylaxis.¹⁴⁴

• Active in vitro against some avian influenza A viruses, including avian influenza A (H5N1) and other avian influenza A viruses (e.g., H7N2, H7N9, H9N2, H10N8).^{26 27 50 58 61 104 555 168 171} However, avian influenza A (H5N1)^{50 68 73 81 104 168} and influenza A (H7N9)^{169 170} with reduced in vitro susceptibility or resistance to oseltamivir have been reported rarely.

• Cross-resistance between oseltamivir and other neuraminidase inhibitors (e.g., peramivir, zanamivir) reported in influenza A and B viruses.^{1 9 36 37 38 43 62 172 173 175 176} However, because oseltamivir, peramivir, and zanamivir bind to different sites on the neuraminidase enzyme or interact differently with binding sites, cross-resistance among the drugs is variable.^{9 36 37 43 62 173 175} Reduced in vitro susceptibility to all 3 drugs (oseltamivir, peramivir, zanamivir) reported in some influenza A and influenza B strains with certain resistance-associated neuraminidase substitutions.^{1 176} Some influenza A or B strains may have reduced in vitro susceptibility to oseltamivir and/or peramivir, but are susceptible to zanamivir;^{1 38 44 144 163 167 176 552} other strains may have reduced in vitro susceptibility to zanamivir, but are susceptible to oseltamivir and/or peramivir.^{1 176} To date, influenza A (H1N1)pdm09 isolates with the H275Y mutation are cross-resistant to oseltamivir and peramivir, but susceptible to zanamivir in vitro.^{172 174 559} Avian influenza A (H5N1) with the H274Y mutation that are resistant to oseltamivir have been susceptible to zanamivir in vitro.^{73 94}

Advice to Patients

• Importance of using the appropriate graduated oral dosing dispenser to measure and administer dose of reconstituted oral suspension.¹

• Importance of initiating oseltamivir treatment as soon as possible after appearance of influenza symptoms (within 2 days after symptom onset);¹ efficacy not established if treatment begins >48 hours after symptoms have been established.¹

• Importance of initiating oseltamivir prophylaxis as soon as possible after exposure to influenza (within 2 days after exposure).¹

• Importance of complying with the entire drug regimen.¹ Importance of taking missed dose as soon as remembered, except if within 2 hours of the next scheduled dose.¹

• Importance of informing clinician if signs of unusual behavior develop.¹

• Advise patients that oseltamivir is not a substitute for annual vaccination with influenza virus vaccine.¹

• Importance of informing clinicians of existing or contemplated therapy, including prescription and OTC drugs, as well as any concomitant illnesses.¹

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹

• Importance of advising patients of other important precautionary information.¹ (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Oseltamivir Phosphate

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Capsules	30 mg (of oseltamivir)	Tamiflu	Genentech
		45 mg (of oseltamivir)	Tamiflu	Genentech
		75 mg (of oseltamivir)	Tamiflu	Genentech
	For suspension	6 mg (of oseltamivir) per mL	Tamiflu	Genentech