Oseltamivir Phosphate

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

Special Alerts:

[Posted 07/11/2011] ISSUE: Labeling changes are being made to oseltamivir phosphate (Tamiflu) oral suspension to reduce the possibility of prescribing and dosing confusion that can lead to medication errors. The changes to the product label include:

• 
  

  A change in the concentration of oseltamivir from 12 mg/mL to 6 mg/mL. The lower concentration of oseltamivir is less likely to become frothy when shaken, which helps to ensure an accurate measurement. A change in the measurements of the oral dosing device from milligrams (mg = weight) to milliliters (mL = volume).

  
  


• 
  

  A change in the dosing table for oseltamivir to include a column for the volume (mL) based on the new 6 mg/mL concentration. Revised container labels and carton packaging. Revised compounding instructions for pharmacies to prepare a 6 mg/mL oral suspension from oseltamivir capsules in an emergency situation only if the commercially manufactured oseltamivir for oral suspension is unavailable.

  
  

BACKGROUND: Oseltamivir is in a class of medications called neuraminidase inhibitors. These drugs work by stopping the spread of the influenza (flu) virus in the body. Genentech, the manufacturer of oseltamivir for oral suspension, plans to begin distribution of the new 6 mg/mL product in July 2011. The company has instituted a voluntary Take Back Program for wholesale buyers, distributors and pharmacies to remove the 12 mg/mL product from the marketplace. The 12 mg/mL product will remain in the marketplace and in state or national stockpiles until current supplies expire.

RECOMMENDATION: It is important for healthcare professionals to be aware that a patient may potentially receive either concentration (6 mg/mL or 12 mg/mL) from their pharmacy during the next influenza season (2011-2012). Steps should be taken to avoid the potential for a medication error due to confusion between the two concentrations. Prescribers should include the new concentration (6 mg/mL) and dose in milliliters on all prescriptions for oseltamivir for oral suspension. For more information visit the FDA website at: and .

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 (regardless of vaccination status or underlying illness)^{116 137 149} and in individuals with suspected or confirmed influenza who are at high risk of developing complications (regardless of vaccination status or influenza severity).^{116 149} Early empiric treatment also should be considered for individuals with suspected or confirmed influenza who are at increased risk for 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 who are receiving long-term aspirin therapy, and residents of any age in nursing homes or other long-term care facilities.^{116 137} 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} If viral surveillance indicates that influenza strains resistant to oseltamivir are circulating and treatment is indicated, zanamivir should be used.¹³⁷

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.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.^{116 144 149 161} Prophylaxis with an appropriate antiviral active against circulating influenza strains is considered an adjunct to vaccination for control and prevention of influenza.^{1 116 144 149 161}

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.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} As of August 2010, the WHO declared that the world was in a post-pandemic period;¹⁴⁸ however, the 2009 influenza A (H1N1) virus is expected to continue to circulate during the 2010–2011 influenza season.^{144 162}

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

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

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 12 mg/mL.¹

Oseltamivir oral suspension is the preferred preparation for individuals who are unable to swallow capsules.¹ Alternatively, if the oral suspension is not available, each dose can be administered by opening the appropriate capsules corresponding to the dose and mixing the contents with a sweet liquid (e.g., regular or sugar-free chocolate syrup).^{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 either cherry syrup vehicle (Humco) or Ora-Sweet SF (Paddock).¹ Consult the oseltamivir prescribing information for specific instructions.¹ The oral dosing dispenser (oral syringe) provided with the commercially available powder for oral suspension should not be used to administer the extemporaneous preparation (extemporaneous suspension contains 15 mg/mL; suspension prepared using the powder for oral suspension contains 12 mg/mL).¹

In the event of a pandemic, if oseltamivir is administered as an extemporaneous oral preparation prepared from bulk storage containers of the drug (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 (oral syringe) provided to the patient match the patient’s dosage and prescription instructions.¹⁴¹ (See Reconstitution under Dosage and Administration.)

Reconstitution

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

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

Children ≥1 year of age: Use graduated oral dosing dispenser (oral syringe) provided by the manufacturer to administer reconstituted oral suspension; alternatively, some other oral dosing syringe or similar device may be used.¹

Shake suspension well prior to each dose.¹

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

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

Systemic availability of oseltamivir carboxylate from an extemporaneous oral preparation prepared from a bulk storage containers of the drug (not commercially available in the US) is expected to be the same as that from the commercially available preparations.⁴³

Pediatric Patients

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

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 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

Adolescents ≥13 years of age: 75 mg twice daily for 5 days.^{1 149}

Table 1. Dosage for Treatment of Seasonal Influenza A and B in Children 1–12 Years of Age1149

Weight (kg)	Daily Dosage	Daily Dosage (Volume of Reconstituted Commercially Available Suspension Containing Oseltamivir 12 mg/mL)
≤15	30 mg twice daily for 5 days	2.5 mL twice daily for 5 days
>15 to 23	45 mg twice daily for 5 days	3.8 mL twice daily for 5 days
>23 to 40	60 mg twice daily for 5 days	5 mL twice daily for 5 days
>40	75 mg twice daily for 5 days	6.2 mL twice daily for 5 days

Although safety and efficacy not established in infants <1 year of age†¹ (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†.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 Dosage for Treatment of Seasonal Influenza A or B in Infants <1 Year of Age with Unknown Weight†149

Age	Daily Dosage	Daily Dosage (Volume of Reconstituted Commercially Available Suspension Containing Oseltamivir 12 mg/mL)
<3 months (full-term)	12 mg twice daily for 5 days	1 mL twice daily for 5 days
3–5 months	20 mg twice daily for 5 days	1.6 mL twice daily for 5 days
6–11 months	25 mg twice daily for 5 days	2 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

Table 3. Dosage for Prevention of Seasonal Influenza A and B in Children 1–12 Years of Age1

Weight (kg)	Daily Dosage	Daily Dosage (Volume of Reconstituted Commercially Available Suspension Containing Oseltamivir 12 mg/mL)
≤15	30 mg once daily for 10 days	2.5 mL once daily for 10 days
>15 to 23	45 mg once daily for 10 days	3.8 mL once daily for 10 days
>23 to 40	60 mg once daily for 10 days	5 mL once daily for 10 days
>40	75 mg once daily for 10 days	6.2 mL once daily for 10 days

Although safety and efficacy not established in infants <1 year of age†¹ (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†.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 Dosage for Prevention of Seasonal Influenza A or B in Infants <1 Year of Age with Unknown Weight†149

Age	Daily Dosage	Daily Dosage (Volume of Reconstituted Commercially Available Suspension Containing Oseltamivir 12 mg/mL)
<3 months	Not recommended unless situation judged critical
3–5 months	20 mg once daily for 10 days	1.6 mL once daily for 10 days
6–11 months	25 mg once daily for 10 days	2 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 Has been given for up to 6 weeks during a community outbreak of influenza.¹ Safety of prophylaxis was demonstrated for up to 12 weeks in immunocompromised adults and adolescents.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 Cl_cr 10–30 mL/minute: 75 mg once daily for 5 days.¹

Prevention of influenza A or B virus infections in patients with Cl_cr 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 (Cl_cr <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

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

Differential Diagnosis

When making treatment decisions in patients with suspected influenza, consider the possibility of primary or concomitant bacterial infection for which oseltamivir would be ineffective.^{1 13}

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

Influenza Vaccination

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

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 Cl_cr 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 unlikely33
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 oseltamivir144 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.