Oseltamivir Phosphate

Pronunciation

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 7 9

Uses for Oseltamivir Phosphate

Treatment of Seasonal Influenza A and B Virus Infections

Symptomatic treatment of uncomplicated acute illness caused by susceptible influenza A or B virus in adults, adolescents, and children ≥1 year of age who have been symptomatic for ≤2 days.1 2 4 5 9 15 64 65 66 116 149

Although efficacy has not been established in immunocompromised patients,1 oseltamivir has been used to treat seasonal influenza A or B virus infections in bone marrow transplant (BMT) recipients.74 Oseltamivir also has been used for the treatment of seasonal influenza infections in hematopoietic stem cell transplant (HSCT) recipients.101

CDC, AAP, and IDSA recommend treatment of influenza illness 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).116 137 149 Treatment also recommended in individuals with suspected or confirmed influenza who are at high risk of influenza-related complications, including children <2 years of age, adults ≥65 years of age, pregnant women and women up to 2 weeks postpartum (including following pregnancy loss), individuals of any age with certain chronic medical or immunosuppressive conditions, individuals <19 years of age receiving long-term aspirin therapy, American Indians, Alaskan natives, individuals with a body mass index (BMI) ≥40, and residents of any age in nursing homes or other long-term care facilities.116 137 149 If indicated, initiate treatment as early as possible since benefit is greatest if started within 48 hours of symptom onset;116 137 149 do not delay initiation of treatment while waiting for laboratory confirmation.137 149

Consider viral surveillance data available from local and state health departments and the CDC when selecting an antiviral for treatment of seasonal influenza.116 137 149 Strains of circulating influenza viruses and the antiviral susceptibility of these strains constantly evolve,116 144 and emergence of oseltamivir-resistant influenza virus may decrease effectiveness of the drug.1 When treatment of seasonal influenza is indicated, oseltamivir or zanamivir usually is recommended.137 149 Although influenza A and B viruses circulating in the US during the last few years generally have been susceptible to oseltamivir,137 162 consult the most recent information.137

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CDC issues recommendations concerning the use of antiviral agents for the 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 influenza A or B virus in adults, adolescents, and children ≥1 year of age.1 16 30 116 149

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 the US Public Health Service Advisory Committee on Immunization Practices (ACIP), is the primary means of preventing seasonal influenza and its severe complications.116 137 149 161 Prophylaxis with an appropriate antiviral active against circulating influenza strains is considered an adjunct to vaccination for control and prevention of influenza.1 116 137 149 161

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).116 137 149 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.137 149 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.116 137 149 In individuals at high risk of influenza complications who receive influenza virus vaccine inactivated, use of prophylaxis can be considered during the 2 weeks after vaccination to provide protection until an adequate immune response develops.116 149 (See Specific Drugs under Interactions.)

Consider viral surveillance data available from local and state health departments and the CDC when selecting an antiviral for the prophylaxis of influenza.116 137 149 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 and emergence of oseltamivir-resistant influenza virus may decrease effectiveness of the drug.1

CDC issues recommendations concerning the use of antiviral agents 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

Has been used in a limited number of patients for treatment of avian influenza A virus infections (H5N1, H7N3, H7N7).46 47 61 73 152

Drug of choice for treatment of clinically confirmed cases of avian influenza A (H5N1) infection.94 104 Early treatment is likely to provide the greatest clinical benefit.68 104 152 Virus continues to replicate for prolonged periods;104 treatment warranted even in patients who present in later stages of illness.104 152 High doses and prolonged duration of therapy may be needed in some patients.104 152

Concomitant use of a neuraminidase inhibitor (oseltamivir) and an adamantane (amantadine, rimantadine) can be considered in a patient with pneumonic disease or clinical progression if local surveillance data indicate the H5N1 virus is known or likely to be susceptible to an adamantane.94 104

Has been used for prophylaxis of avian influenza A infections (H5N1, H7N7).43 60 61 73 Drug of choice for postexposure prophylaxis in high-risk exposure groups (household or close family contacts of individuals with strongly suspected or confirmed H5N1 illness).94 Can be used for postexposure prophylaxis in moderate-risk exposure groups (individuals with unprotected exposure to infected animals or affected environments; health-care workers with unprotected close contact with individuals with strongly suspected or confirmed H5N1 illness).94

May be considered for preexposure prophylaxis in certain individuals in high-risk situations (e.g., individuals directly involved in control and eradication of poultry outbreaks).51

Whenever possible, choice of antiviral for treatment or prophylaxis of avian influenza A infections should be based on results of in vitro susceptibility testing; in the absence of such testing, oseltamivir is drug of first choice.51

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.52 161 Most recent influenza pandemic occurred during 2009 and was related to a novel influenza A (H1N1) strain.52 134 144 151

On June 11, 2009, the WHO declared the first global influenza pandemic in 41 years and issued a phase 6 pandemic alert regarding 2009 influenza A (H1N1).134 A phase 6 pandemic is characterized by human-to-human spread of an animal or human-animal reassortant virus and sustained community level outbreaks of the virus in at least 2 countries in a single WHO region and sustained community level outbreaks in at least one other country in a different WHO region.135 Cases of human infection with 2009 influenza A (H1N1) virus were first reported in Mexico and other countries (including the US) beginning in March and April 2009.114 117 118 119 132 134 144 151 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 2010.117 144 During that time, more than 99% of influenza viruses circulating in the US were the 2009 pandemic influenza A (H1N1) virus.117 144 In August 2010, the WHO declared that the world was in a post-pandemic period;148 however, the 2009 influenza A (H1N1) virus continued to circulate during the 2010–2011 influenza season and is expected to continue to circulate during the 2011-2012 season.144 162 163

The spread of the highly pathogenic H5N1 strain of avian influenza A in poultry in Asia and other countries that was identified in 2003 represents a potential future pandemic threat.49 50 54 55 56 77 138 144 147

Oseltamivir Phosphate Dosage and Administration

Administration

Oral Administration

Administer orally without regard to meals;1 administration with meals may improve GI tolerability.1 2

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.1 165

A powder for oral suspension that is reconstituted to provide an oral suspension containing 12 mg/mL was previously available from the manufacturer.164 165 In July 2011, the manufacturer discontinued the 12 mg/kg concentration and began supplying the 6 mg/mL concentration.164 The reconstituted 6 mg/mL preparation is less frothy when shaken (allowing for more accurate dosage measurements) and the oral dosing device provided by the manufacturer with the 6 mg/mL preparation is labeled in volume (mL) instead of dosage (mg).164 Although the manufacturer implemented a voluntary take back program to facilitate removal of the 12 mg/mL preparation from the marketplace, it still may be available from some distributors and still may be in state or national stockpiles.164 There are no quality issues with the 12 mg/mL preparation; any remaining supplies can be used until their expiration date.164 Since both preparations (6 mg/mL and 12 mg/mL) may be available during the 2011–2012 influenza season, healthcare providers should take precautions to avoid potential medication errors.164 Prescribers are encouraged to include the new strength (6 mg/mL) and dosage in mLs on each prescription for oseltamivir for oral suspension.164 Pharmacists should ensure that dosage instructions and oral dosing device provided to the patient are consistent with the concentration of oral suspension (6 mg/mL or 12 mg/mL) that the patient receives.164

Reconstituted oseltamivir oral suspension is the preferred preparation for individuals unable to swallow capsules.1 Alternatively, if the oral suspension is not available, the appropriate dosage of oseltamivir capsules can be administered by opening the 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 (e.g., shortage during an emergency), a pharmacist can prepare an extemporaneous oral suspension using oseltamivir capsules and simple syrup, cherry syrup vehicle (Humco), or Ora-Sweet SF (Paddock).1 Consult the oseltamivir prescribing information for specific instructions.1 Consider that current prescribing information for oseltamivir capsules and powder for suspension (6 mg/mL) includes instructions for emergency compounding of a suspension of the same strength (6 mg/mL).1 164 However, prescribing information for oseltamivir capsules and powder for suspension (12 mg/mL) that still may remain in the marketplace includes instructions for emergency compounding of oseltamivir oral suspension containing 15 mg/mL.164 165

In emergency situations (e.g., pandemic), if oseltamivir is administered as an extemporaneous oral preparation prepared using oseltamivir powder from bulk storage containers (not commercially available in the US), the bitter taste of the drug can be ameliorated by drinking a strongly flavored fruit drink or chewing flavored chewing gum following ingestion of the preparation.43

When dispensing the commercially available oral suspension or an extemporaneous oral suspension, ensure that the units of measure on the oral dosing dispenser provided to the patient match the preparation being dispensed and the patient's dosage and prescription instructions.141 164 (See Reconstitution under Dosage and Administration.)

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 Consider that a powder for oral suspension that is reconstituted to provide 6 mg/mL and a powder for oral suspension that is reconstituted to provide 12 mg/mL both may be available during the 2011–2012 influenza season.164

Use graduated oral dosing dispenser provided by the manufacturer to administer reconstituted oral suspension; alternatively, some other oral dosing device marked with units of measure that correspond to the required dose may be used.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 oseltamivir treatment within 2 days after onset of symptoms.1 Although efficacy not established,1 antiviral treatment initiated >48 hours after onset of symptoms still may be beneficial in those who are hospitalized or have moderate to severe, complicated, or progressive influenza.116 137 149 Although usual duration of antiviral treatment is 5 days, patients hospitalized with severe infections (e.g., those with prolonged infection or admitted into an intensive care unit) may require >5 days of treatment.137

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

12 mg/mL concentration no longer being manufactured, but still may be available from some distributors or may be in state or national stockpiles until current supplies expire.164

Table 1. Oseltamivir Dosage for Treatment of Seasonal Influenza A and B in Children 1–12 Years of Age1149165

Weight (kg)

Daily Dosage (mg)

Daily Dosage (Volume of Reconstituted Oral Suspension Containing 6 mg/mL)

Daily Dosage (Volume of Reconstituted Oral Suspension Containing 12 mg/mL)

≤15

30 mg twice daily for 5 days

5 mL twice daily for 5 day

2.5 mL twice daily for 5 days

16 to 23

45 mg twice daily for 5 days

7.5 mL twice daily for 5 day

3.8 mL twice daily for 5 days

24 to 40

60 mg twice daily for 5 days

10 mL twice daily for 5 day

5 mL twice daily for 5 days

≥41

75 mg twice daily for 5 days

12.5 mL twice daily for 5 day

6.2 mL twice daily for 5 days

Although safety and efficacy not established in infants <1 year of age1 (see Pediatric Use under Cautions), if treatment of influenza is considered necessary in this age group, 3 mg/kg twice daily for 5 days is recommended for full-term infants <1 year of age.137 149

Although weight-based dosage is preferred if oseltamivir is used in infants <1 year of age, dosage for treatment of influenza in full-term infants may be determined based on age, if necessary.149 (See Table 2.)

Data are insufficient to make dosage recommendations for treatment of influenza in premature infants <3 months of age;149 dosage recommended for full-term infants may result in high and variable oseltamivir concentrations in premature infants because of immature renal function.149

Table 2. Age-based Oseltamivir Dosage for Treatment of Seasonal Influenza A or B in Infants <1 Year of Age with Unknown Weight†149168

Age

Daily Dosage (mg)

Daily Dosage (Volume of Reconstituted Oral Suspension Containing 6 mg/mL)

0–3 months (full-term)

12 mg twice daily for 5 days

2 mL twice daily for 5 days

4–5 months

17 mg twice daily for 5 days

2.8 mL twice daily for 5 days

6–11 months

24 mg twice daily for 5 days

4 mL twice daily for 5 days

Prevention of Seasonal Influenza A and B Virus Infections
Oral

Initiate oseltamivir prophylaxis within 2 days after exposure (e.g., close contact with infected individual).1 Usual duration is 10 days.1 May be continued for up to 6 weeks during a community influenza outbreak.1

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

12 mg/mL concentration no longer being manufactured, but still may be available from some distributors or may be in state or national stockpiles until current supplies expire.164

Table 3. Oseltamivir Dosage for Prevention of Seasonal Influenza A and B in Children 1–12 Years of Age1165

Weight (kg)

Daily Dosage (mg)

Daily Dosage (Volume of Reconstituted Oral Suspension Containing 6 mg/mL)

Daily Dosage (Volume of Reconstituted Oral Suspension Containing 12 mg/mL)

≤15

30 mg once daily for 10 days

5 mL once daily for 10 days

2.5 mL once daily for 10 days

16 to 23

45 mg once daily for 10 days

7.5 mL once daily for 10 days

3.8 mL once daily for 10 days

24 to 40

60 mg once daily for 10 days

10 mL once daily for 10 days

5 mL once daily for 10 days

≥41

75 mg once daily for 10 days

12.5 mL once daily for 10 days

6.2 mL once daily for 10 days

Although safety and efficacy not established in infants <1 year of age1 (see Pediatric Use under Cautions), if prevention of influenza is considered necessary in this age group, 3 mg/kg once daily for 10 days is recommended in full-term infants 3 months to <1 year of age.137 149

Although weight-based dosage is preferred if oseltamivir is used in infants <1 year of age, dosage for prevention of influenza in full-term infants 3 months to <1 year of age may be determined based on age, if necessary.149 (See Table 4.)

Data are insufficient to make dosage recommendations for prevention of influenza in full-term or premature infants <3 months of age.149

Table 4. Age-based Oseltamivir Dosage for Prevention of Seasonal Influenza A or B in Infants <1 Year of Age with Unknown Weight†149168

Age

Daily Dosage (mg)

Daily Dosage (Volume of Reconstituted Oral Suspension Containing 6 mg/mL)

0–3 months

Not recommended unless situation judged critical

4–5 months

17 mg once daily for 10 days

2.8 mL once daily for 10 days

6–11 months

24 mg once daily for 10 days

4 mL once daily for 10 days

Treatment of Avian Influenza A Virus Infections
Oral

Dosage usually recommended for treatment of seasonal influenza A and B virus infections has been recommended.104 This dosage may be reasonable for early, mild cases of influenza A (H5N1) infection, but WHO and others state that severely ill patients may benefit from higher dosage and/or longer duration of therapy (i.e., 7–10 days).63 68 85

Initiate treatment as early as possible.104 152 Treatment is most beneficial if initiated within 2 days of symptom onset,152 but is warranted even in patients who present for care in the later stages of illness.104 152

Prevention of Avian Influenza A Virus Infections
Oral

Dosage usually recommended for prophylaxis of seasonal influenza A and B virus infections has been recommended.94

High-risk and moderate-risk exposure groups: Initiate as soon as possible and continue for 7–10 days after last known exposure.94

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 oseltamivir treatment within 2 days after onset of symptoms.1 Although efficacy not established,1 antiviral treatment initiated >48 hours after onset of symptoms may still be beneficial in those with moderate to severe or progressive influenza.116 137 149 Although usual duration of antiviral treatment is 5 days, patients hospitalized with severe infections (e.g., those with prolonged infection or admitted into an intensive care unit) may require >5 days of treatment.137

Prevention of Seasonal Influenza A and B Virus Infections
Oral

75 mg once daily1 given for at least 10 days.1 Initiate prophylaxis within 2 days after exposure (e.g., close contact with infected individual).1 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

Treatment of Avian Influenza A Virus Infections
Oral

75 mg twice daily for 5 days has been recommended.104

Dosage usually recommended for treatment of seasonal influenza A and B virus infections has been recommended.63 104 This dosage may be reasonable for early, mild cases of influenza A (H5N1) infection, but WHO and others state that severely ill patients may benefit from higher dosage (i.e., 150 mg twice daily in adults) and/or longer duration of therapy (i.e., 7–10 days).63 68 85 104

Initiate treatment as early as possible.104 Treatment is most beneficial if initiated within 2 days of symptom onset,152 but is warranted even in patients who present for care in the later stages of illness.104 152

Prevention of Avian Influenza A Virus Infections
Oral

Dosage usually recommended for prophylaxis of seasonal influenza A and B virus infections has been recommended.94

High-risk and moderate-risk exposure groups: Initiate as soon as possible and continue for 7–10 days after last known exposure.94

Preexposure prophylaxis or repeated or continuous postexposure prophylaxis may be necessary in individuals in high-risk situations (e.g., individuals directly involved in control and eradication of poultry outbreaks).51

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 those with mild to moderate hepatic impairment (Child-Pugh score ≤9).1 42

Renal Impairment

Treatment of influenza A or B virus infections in patients with Clcr 10–30 mL/minute: 75 mg once daily for 5 days.1

Prevention of influenza A or B virus infections in patients with Clcr 10–30 mL/minute: 75 mg once every other day or 30 mg once daily for 10 days after last known exposure to a confirmed case.1

Dosage recommendations not available for patients with end-stage renal disease (Clcr <10 mL/minute) or for those undergoing routine hemodialysis or CAPD.1

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 97

Postmarketing reports of delirium and abnormal behavior leading to injury mainly involved children from Japan.1 84 88 97 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

Oseltamivir is not a substitute for annual vaccination with seasonal influenza virus vaccine inactivated or seasonal influenza virus vaccine live intranasal.1 137 144

Antiviral agents used for treatment or prevention of influenza (amantadine, oseltamivir, rimantadine, zanamivir) may be used concomitantly with parenteral inactivated seasonal influenza virus vaccine.1 144

Intranasal live influenza virus vaccine should not be administered until at least 48 hours after influenza antiviral agents are discontinued and these antiviral agents should not be administered until at least 2 weeks after administration of an intranasal live influenza virus vaccine, unless medically indicated.1 144 (See Influenza Virus Vaccines under Interactions.)

Sorbitol

When the commercially available oral suspension 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 and death from influenza.144

CDC states that pregnancy is not considered a contraindication to use of oseltamivir for treatment or prevention of influenza; oseltamivir regimens recommended for such infections in pregnant women are the same as those for other adults.127 137 142

Because of its systemic absorption, CDC states that oseltamivir may be preferred when a neuraminidase inhibitor is indicated for treatment of influenza in a pregnant woman, but the drug of choice for prophylaxis of these infections is less clear.127 142 Zanamivir may be preferred for prophylaxis in pregnant women because of its limited systemic absorption; however, respiratory complications that may be associated with zanamivir because of its route of administration should be considered, especially in women at risk for respiratory problems.127 142

Lactation

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

Use with caution and only if potential benefits justify possible risks to breast-fed infant.1

CDC states that antiviral treatment or prophylaxis is not a contraindication for breastfeeding.127

Pediatric Use

Safety and efficacy not established in infants <1 year of age.1 12

Manufacturer states oseltamivir is not indicated for treatment or prevention of influenza in infants <1 year of age because it is not known whether toxicology data reported in animals are clinically relevant for human infants.1 23

Young children, especially those <2 years of age, are at increased risk of influenza infection, hospitalization, and complications.144 149 During the 2009 influenza A (H1N1) pandemic, FDA issued an emergency use authorization (EUA) that temporarily allowed use of oseltamivir for emergency treatment or prevention of 2009 influenza A (H1N1) infection in infants <1 year of age.121 150 Although the EUA expired in June 2010,150 the AAP states that use of oseltamivir in infants <1 year of age is appropriate when indicated.149 (See Pediatric Patients under Dosage.)

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 adjustment is recommended if Clcr is 10–30 mL/minute.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

Parenteral inactivated influenza vaccine: Oseltamivir does not interfere with the antibody response to the vaccine1

Intranasal live influenza vaccine: Potential interference with antibody response to the live vaccine; no specific studies1 144

Parenteral inactivated influenza vaccine: May be administered concomitantly with or at any interval before or after oseltamivir1 144

Intranasal live influenza vaccine: Do not administer the live intranasal vaccine until at least 48 hours after oseltamivir is discontinued; do not administer oseltamivir until at least 2 weeks after administration of the live intranasal vaccine;1 144 repeat vaccination if influenza antiviral is given 2 days before to 14 days after the vaccine144

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 converted to oseltamivir carboxylate, principally by hepatic esterases.1

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

Elimination Route

Oseltamivir phosphate principally (>90%) eliminated by conversion to oseltamivir carboxylate.1 25 No further metabolism.1

Oseltamivir carboxylate principally eliminated by glomerular filtration and tubular secretion;1 24 25 <20% of dose eliminated in feces.1

Half-life

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

Special Populations

Renal clearance decreased in patients with impaired renal function.1 25

Systemic exposure to oseltamivir carboxylate in individuals with mild or moderate hepatic impairment is comparable to that in individuals without hepatic impairment.1 42

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

Exposure to oseltamivir carboxylate at steady-state approximately 25–35% higher in geriatric individuals (65–78 years of age) compared with younger adults;1 3 similar plasma half-life.1

Stability

Storage

Oral

Capsules

25°C (may be exposed to 15–30°C).1

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 by dissolving contents of oseltamivir capsules in 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

Powder in Bulk Storage Containers

Extemporaneous oral preparations, prepared by dissolving oseltamivir powder from bulk storage containers (not commercially available in the US) in water at a concentration of 15 mg of oseltamivir per mL and adding sodium benzoate as a preservative, are stable for 3 weeks at 25°C or for 6 weeks at 5°C.43

Actions and Spectrum

  • Oseltamivir phosphate is an inactive prodrug 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

  • Active in vitro and in vivo in animal studies against some avian influenza A viruses (some strains of H5N1, H7N2, H9N2); active against influenza A (H5N1) isolated from patients in Vietnam and Thailand during 2004.26 27 However, avian influenza A (H5N1) with reduced in vitro susceptibility or resistance to oseltamivir have been isolated from a few oseltamivir-treated patients;72 73 81 some of these isolates remained susceptible to zanamivir.73

  • Beginning in the 2007–2008 influenza season, a significant increase in the prevalence of oseltamivir-resistant seasonal influenza A (H1N1) was reported worldwide;144 153 161 almost all seasonal influenza A (H1N1) strains tested in the US in 2008, 2009, and beginning of 2010 were resistant to oseltamivir.144 161 During the 2010–2011 influenza season, the former seasonal influenza A (H1N1) was rarely detected and almost all circulating influenza A (H1N1) were the 2009 pandemic influenza A (H1N1) virus.162 163

  • Although most isolates of the 2009 pandemic influenza A (H1N1) virus (>99% of isolates from the 2010–2011 influenza season) have been susceptible to oseltamivir in vitro,137 144 162 163 167 oseltamivir-resistance has been reported rarely.117 155 156 157 162 163 167 These oseltamivir-resistant strains generally were susceptible to zanamivir.117 137 162 163 167

  • Influenza strains cross-resistant to zanamivir and oseltamivir have been generated in cell culture; only limited data available regarding possible emergence of clinical isolates with cross-resistance to both drugs.1 9 36 37 62

Advice to Patients

  • Importance of using the appropriate graduated oral dosing dispenser for the strength of powder for oral suspension being dispensed.1 164 Importance of informing patient of appropriate dosage for the strength of oseltamivir suspension being dispensed.164

  • 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.97

  • 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.

Oseltamivir phosphate powder for oral suspension that is reconstituted to provide an oral suspension containing 12 mg of oseltamivir per mL was previously available from the manufacturer.164 165 In July 2011, the manufacturer discontinued the 12 mg/mL preparation and began supplying a powder for oral suspension that is reconstituted to provide an oral suspension containing 6 mg/mL.164 Although the manufacturer implemented a voluntary take back program during July and August 2011 to facilitate removal of the 12 mg/mL preparation from the marketplace, it still may be available from some distributors and still may be in state or national stockpiles.164 There are no quality issues with the 12 mg/mL preparation; any remaining supplies can be used until their expiration date.164 Since both strengths (6 mg/mL and 12 mg/mL) may be available during the 2011–2012 influenza season and since dosage recommendations for these preparations differ (i.e., volume of reconstituted oral suspension), precautions should be taken to avoid potential medication errors.164 (See Dosage and Administration.)

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

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2013. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Tamiflu 12MG/ML Suspension (GENENTECH): 25/$53.54 or 75/$145.91

Tamiflu 30MG Capsules (GENENTECH): 10/$110.08 or 30/$321.51

Tamiflu 45MG Capsules (GENENTECH): 10/$110.08 or 30/$321.51

Tamiflu 75MG Capsules (GENENTECH): 10/$110.99 or 30/$321.98

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2013, Selected Revisions November 3, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

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