PDR MEMBER LOGIN:
  • PDR Search

    Required field
  • Advertisement
  • CLASSES

    Neuraminidase Inhibitor Antivirals

    DEA CLASS

    Rx

    DESCRIPTION

    Oral neuraminidase inhibitor
    Used for treatment and prevention of uncomplicated infections due to seasonal influenza virus A or B
    Most effective if initiated early (e.g., within 48 hours of symptom onset or exposure)

    COMMON BRAND NAMES

    Tamiflu

    HOW SUPPLIED

    Oseltamivir/Oseltamivir Phosphate/Tamiflu Oral Cap: 30mg, 45mg, 75mg
    Oseltamivir/Oseltamivir Phosphate/Tamiflu Oral Pwd F/Recon: 1mL, 6mg

    DOSAGE & INDICATIONS

    For the treatment of acute influenza A virus infection or influenza B virus infection.
    Oral dosage
    Adults

    75 mg PO twice daily for 5 days. The CDC suggests that longer treatment courses for patients who remain severely ill after 5 days of treatment can be considered.

    Children weighing more than 40 kg and Adolescents

    75 mg PO twice daily for 5 days. The CDC suggests that longer treatment courses for patients who remain severely ill after 5 days of treatment can be considered.

    Children weighing 24 kg to 40 kg

    60 mg PO twice daily for 5 days; extended courses may be considered for patients who remain severely ill after 5 days of treatment.

    Children weighing 16 kg to 23 kg

    45 mg PO twice daily for 5 days; extended courses may be considered for patients who remain severely ill after 5 days of treatment.

    Children weighing 15 kg or less

    30 mg PO twice daily for 5 days; extended courses may be considered for patients who remain severely ill after 5 days of treatment.

    Infants

    3 mg/kg/dose PO twice daily for 5 days; extended courses may be considered for patients who remain severely ill after 5 days of treatment. The American Academy of Pediatrics (AAP) recommends 3.5 mg/kg/dose PO twice daily for infants 9 to 11 months of age based on pharmacokinetic data indicating that a slightly higher dosage is needed in this age group to achieve target drug exposure.

    Term Neonates 14 to 29 days

    3 mg/kg/dose PO twice daily for 5 days; extended courses may be considered for patients who remain severely ill after 5 days of treatment.

    Premature Neonates greater than 40 weeks postmenstrual age† and Term Neonates 0 to 13 days†

    3 mg/kg/dose PO twice daily for 5 days; extended courses may be considered for patients who remain severely ill after 5 days of treatment.

    Premature Neonates 38 to 40 weeks postmenstrual age†

    1.5 mg/kg/dose PO twice daily for 5 days; extended courses may be considered for patients who remain severely ill after 5 days of treatment.

    Premature Neonates younger than 38 weeks postmenstrual age†

    1 mg/kg/dose PO twice daily for 5 days; extended courses may be considered for patients who remain severely ill after 5 days of treatment.

    For seasonal influenza prophylaxis.
    Oral dosage
    Adults

    75 mg PO once daily for at least 10 days after close contact and for up to 6 weeks during a community outbreak. Safety and efficacy have been demonstrated for up to 6 weeks in immunocompetent patients and safety has been demonstrated for up to 12 weeks in immunocompromised patients (efficacy has not been demonstrated). The duration of protection lasts for as long as dosing is continued. High risk patients may require prophylaxis during the entire influenza season. The CDC recommends a 7-day course after the last known exposure. For those vaccinated during an outbreak, a 2-week course is recommended. For control of outbreaks in long-term care facilities and hospitals, the CDC recommends chemoprophylaxis for a minimum of 2 weeks and up to 1 week after the last known identified case. Oseltamivir treatment for 42 days has been efficacious in preventing influenza in 92% of those in residential nursing home settings during a flu outbreak; note that 80% of the residents had previously received influenza vaccination.

    Children weighing more than 40 kg and Adolescents

    75 mg PO once daily for at least 10 days after close contact and for up to 6 weeks during a community outbreak. Safety and efficacy have been demonstrated for up to 6 weeks in immunocompetent patients and safety has been demonstrated for up to 12 weeks in immunocompromised patients (efficacy has not been demonstrated). The duration of protection lasts for as long as dosing is continued. High risk patients may require prophylaxis during the entire influenza season. The CDC recommends a 7-day course after the last known exposure. For those vaccinated during an outbreak, a 2-week course is recommended. For control of outbreaks in long-term care facilities and hospitals, the CDC recommends chemoprophylaxis for a minimum of 2 weeks and up to 1 week after the last known identified case. Oseltamivir treatment for 42 days has been efficacious in preventing influenza in 92% of those in residential nursing home settings during a flu outbreak; note that 80% of the residents had previously received influenza vaccination.

    Children weighing 24 kg to 40 kg

    60 mg PO once daily for 10 days or for up to 6 weeks during a community outbreak. The Centers for Disease Control (CDC) recommends a 7-day course after the last known exposure. For those vaccinated during an outbreak, a 2-week course is recommended. For control of outbreaks in long-term care facilities and hospitals, the CDC recommends chemoprophylaxis for a minimum of 2 weeks and up to 1 week after the last identified case. High-risk patients may require prophylaxis during the entire influenza season.

    Children weighing 16 kg to 23 kg

    45 mg PO once daily for 10 days or for up to 6 weeks during a community outbreak. The Centers for Disease Control (CDC) recommends a 7-day course after the last known exposure. For those vaccinated during an outbreak, a 2-week course is recommended. For control of outbreaks in long-term care facilities and hospitals, the CDC recommends chemoprophylaxis for a minimum of 2 weeks and up to 1 week after the last identified case. High-risk patients may require prophylaxis during the entire influenza season.

    Children weighing 15 kg or less

    30 mg PO once daily for 10 days or for up to 6 weeks during a community outbreak. The Centers for Disease Control (CDC) recommends a 7-day course after the last known exposure. For those vaccinated during an outbreak, a 2-week course is recommended. For control of outbreaks in long-term care facilities and hospitals, the CDC recommends chemoprophylaxis for a minimum of 2 weeks and up to 1 week after the last identified case. High-risk patients may require prophylaxis during the entire influenza season.

    Infants 3 to 11 months†

    3 mg/kg/dose PO once daily. The American Academy of Pediatrics (AAP) recommends 3.5 mg/kg/dose PO once daily for infants 9 to 11 months of age based on pharmacokinetic data indicating that a slightly higher dosage is needed in this age group to achieve target drug exposure. The duration of therapy is dependent on type of exposure: 7 days after the last known exposure; 2 weeks for those vaccinated during an outbreak; a minimum of 2 weeks and up to 1 week after the last identified case for control of outbreaks in long-term care facilities and hospitals. High-risk patients may require prophylaxis during the entire influenza season.

    Infants 1 to 2 months†

    Because of the lack of data in this age group, chemoprophylaxis is not recommended unless the exposure situation is judged to be critical. A variety of oseltamivir dosages have been safely used for influenza prophylaxis in infants in limited studies. A dosage of 1 mg/kg/dose PO twice daily for 10 days was effective in a small study of 13 neonates (mean gestational age 39 weeks [range, 36 to 41 weeks]) exposed to influenza H1N1; no patients developed influenza.

    Neonates†

    Because of the lack of data in this age group, chemoprophylaxis is not recommended unless the exposure situation is judged to be critical. A variety of oseltamivir dosages have been safely used for influenza prophylaxis in neonates in limited studies. A dosage of 1 mg/kg/dose PO twice daily for 10 days was effective in a small study of 13 neonates (mean gestational age 39 weeks [range, 36 to 41 weeks]) exposed to influenza H1N1; no patients developed influenza.

    For the treatment of novel influenza A viruses associated with severe human disease†, including avian influenza A virus infection†.
    Oral dosage
    Adults

    75 mg PO twice daily for 5 days, with longer courses (e.g., 10 days) considered for severely ill hospitalized patients or immunosuppressed patients. Clinical judgement and virologic testing should guide duration assessment. Oseltamivir is recommended for hospitalized patients as well as outpatients.

    Children weighing more than 40 kg and Adolescents

    75 mg PO twice daily for 5 days, with longer courses (e.g., 10 days) considered for severely ill hospitalized patients or immunosuppressed patients. Clinical judgement and virologic testing should guide duration assessment. Oseltamivir is recommended for hospitalized patients as well as outpatients.

    Children weighing 24 kg to 40 kg

    60 mg PO twice daily for 5 days, with longer courses (e.g., 10 days) considered for severely ill hospitalized patients or immunosuppressed patients. Clinical judgement and virologic testing should guide duration assessment. Oseltamivir is recommended for hospitalized patients as well as outpatients.

    Children weighing 16 kg to 23 kg

    45 mg PO twice daily for 5 days, with longer courses (e.g., 10 days) considered for severely ill hospitalized patients or immunosuppressed patients. Clinical judgement and virologic testing should guide duration assessment. Oseltamivir is recommended for hospitalized patients as well as outpatients.

    Children weighing 15 kg or less

    30 mg PO twice daily for 5 days, with longer courses (e.g., 10 days) considered for severely ill hospitalized patients or immunosuppressed patients. Clinical judgement and virologic testing should guide duration assessment. Oseltamivir is recommended for hospitalized patients as well as outpatients.

    Infants

    3 mg/kg/dose PO twice daily for 5 days, with longer courses (e.g., 10 days) considered for severely ill hospitalized patients or immunosuppressed patients. The American Academy of Pediatrics (AAP) recommends 3.5 mg/kg/dose PO twice daily for infants 9 to 11 months of age based on pharmacokinetic data indicating that a slightly higher dosage is needed in this age group to achieve target drug exposure. Clinical judgement and virologic testing should guide duration assessment. Oseltamivir is recommended for hospitalized patients as well as outpatients.

    Premature Neonates greater than 40 weeks postmenstrual age and Term Neonates

    3 mg/kg/dose PO twice daily for 5 days, with longer courses (e.g., 10 days) considered for severely ill hospitalized patients or immunosuppressed patients. Clinical judgement and virologic testing should guide duration assessment. Oseltamivir is recommended for hospitalized patients as well as outpatients.

    Premature Neonates 38 to 40 weeks postmenstrual age

    1.5 mg/kg/dose PO twice daily for 5 days, with longer courses (e.g., 10 days) considered for severely ill hospitalized patients or immunosuppressed patients. Clinical judgement and virologic testing should guide duration assessment. Oseltamivir is recommended for hospitalized patients as well as outpatients.

    Premature Neonates younger than 38 weeks postmenstrual age

    1 mg/kg/dose PO twice daily for 5 days, with longer courses (e.g., 10 days) considered for severely ill hospitalized patients or immunosuppressed patients. Clinical judgement and virologic testing should guide duration assessment. Oseltamivir is recommended for hospitalized patients as well as outpatients.

    For prophylaxis of novel influenza A viruses associated with severe human disease†, including avian influenza prophylaxis†.
    Oral dosage
    Adults

    75 mg PO twice daily. Initiate therapy as soon as possible after first exposure to the confirmed or probable case. If exposure was time-limited and not ongoing, 5 days of treatment from the last known exposure is recommended. If exposure is likely to be ongoing (i.e., household setting), 10 days of treatment is recommended.

    Children weighing 40 kg or more and Adolescents

    75 mg PO twice daily. Initiate therapy as soon as possible after first exposure to the confirmed or probable case. If exposure was time-limited and not ongoing, 5 days of treatment from the last known exposure is recommended. If exposure is likely to be ongoing (i.e., household setting), 10 days of treatment is recommended.

    Children weighing 24 kg to 40 kg

    60 mg PO twice daily. Initiate therapy as soon as possible after first exposure to the confirmed or probable case. If exposure was time-limited and not ongoing, 5 days of treatment from the last known exposure is recommended. If exposure is likely to be ongoing (i.e., household setting), 10 days of treatment is recommended.

    Children weighing 16 kg to 23 kg

    45 mg PO twice daily. Initiate therapy as soon as possible after first exposure to the confirmed or probable case. If exposure was time-limited and not ongoing, 5 days of treatment from the last known exposure is recommended. If exposure is likely to be ongoing (i.e., household setting), 10 days of treatment is recommended.

    Children weighing 15 kg or less

    30 mg PO twice daily. Initiate therapy as soon as possible after first exposure to the confirmed or probable case. If exposure was time-limited and not ongoing, 5 days of treatment from the last known exposure is recommended. If exposure is likely to be ongoing (i.e., household setting), 10 days of treatment is recommended.

    Term Neonates and Infants 14 days and older

    3 mg/kg/dose PO twice daily. The American Academy of Pediatrics (AAP) recommends 3.5 mg/kg/dose PO twice daily for infants 9 to 11 months of age based on pharmacokinetic data indicating that a slightly higher dosage is needed in this age group to achieve target drug exposure. Initiate therapy as soon as possible after first exposure to the confirmed or probable case. If exposure was time-limited and not ongoing, 5 days of treatment from the last known exposure is recommended. If exposure is likely to be ongoing (i.e., household setting), 10 days of treatment is recommended.

    Premature Neonates greater than 40 weeks postmenstrual age and Term Neonates 0 to 13 days

    3 mg/kg/dose PO twice daily. Initiate therapy as soon as possible after first exposure to the confirmed or probable case. If exposure was time-limited and not ongoing, 5 days of treatment from the last known exposure is recommended. If exposure is likely to be ongoing (i.e., household setting), 10 days of treatment is recommended.

    Premature Neonates 38 to 40 weeks postmenstrual age

    1.5 mg/kg/dose PO twice daily. Initiate therapy as soon as possible after first exposure to the confirmed or probable case. If exposure was time-limited and not ongoing, 5 days of treatment from the last known exposure is recommended. If exposure is likely to be ongoing (i.e., household setting), 10 days of treatment is recommended.

    Premature Neonates younger than 38 weeks postmenstrual age

    1 mg/kg/dose PO twice daily. Initiate therapy as soon as possible after first exposure to the confirmed or probable case. If exposure was time-limited and not ongoing, 5 days of treatment from the last known exposure is recommended. If exposure is likely to be ongoing (i.e., household setting), 10 days of treatment is recommended.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    75 mg PO twice daily is FDA-approved; 300 mg/day PO has been used off-label for avian influenza A (H5N1) treatment.

    Geriatric

    75 mg PO twice daily.

    Adolescents

    75 mg PO twice daily.

    Children

    Weight more than 40 kg: 75 mg PO twice daily.
    Weight 24 to 40 kg: 60 mg PO twice daily.
    Weight 16 to 23 kg: 45 mg PO twice daily.
    Weight 15 kg or less: 30 mg PO twice daily.

    Infants

    9 to 11 months: 3 mg/kg/dose PO twice daily is FDA-approved; however, 3.5 mg/kg/dose PO twice daily has been used off-label.
    1 to 8 months: 3 mg/kg/dose PO twice daily.

    Neonates

    Term Neonates 14 days and older: 3 mg/kg/dose PO twice daily.
    Premature Neonates older than 40 weeks postmenstrual age and Term Neonates 0 to 13 days: Safety and efficacy have not been established; however, 3 mg/kg/dose PO twice daily has been used off-label.
    Premature Neonates 38 to 40 weeks postmenstrual age: Safety and efficacy have not been established; however, 1.5 mg/kg/dose PO twice daily has been used off-label.
    Premature Neonates younger than 38 weeks postmenstrual age: Safety and efficacy have not been established; however, 1 mg/kg/dose PO twice daily has been used off-label.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    No dosage adjustments are recommended for patients with mild to moderate hepatic impairment (Child-Pugh score 9 or less). The safety and pharmacokinetics of oseltamivir in patients with severe hepatic impairment have not been established.

    Renal Impairment

    The following dose adjustments are recommended for adult patients with renal impairment. Dose adjustment recommendations are unavailable for pediatric patients; however, similar dose adjustments should be considered, particularly in pediatric patients receiving the adult dosage.
     
    Influenza treatment
    CrCl > 60 mL/min: No dosage adjustment necessary.
    CrCl > 30 to 60 mL/min: 30 mg PO twice daily for 5 days.
    CrCl > 10 to 30 mL/min: 30 mg PO once daily for 5 days.
    CrCl <= 10 mL/min, not undergoing dialysis: Oseltamivir is not recommended.
     
    Influenza prophylaxis
    CrCl > 60 mL/min: No dosage adjustment necessary.
    CrCl > 30 to 60 mL/min: 30 mg PO once daily.
    CrCl > 10 to 30 mL/min: 30 mg PO every other day.
    CrCl <= 10 mL/min, not undergoing dialysis: Oseltamivir is not recommended.
     
    Intermittent hemodialysis (ESRD patients with CrCl <= 10 mL/min)
    For influenza treatment: 30 mg after every hemodialysis cycle; treatment duration not to exceed 5 days. The initial dose may be given immediately, with subsequent doses administered after each dialysis.
    For influenza prophylaxis: 30 mg after alternate hemodialysis cycles. The initial dose may be given prior to the start of dialysis.
     
    Continuous ambulatory peritoneal hemodialysis (ESRD patients with CrCl <= 10 mL/min)
    For influenza treatment: A single 30 mg dose given immediately after dialysis exchange.
    For influenza prophylaxis: 30 mg once weekly immediately after dialysis exchange.

    ADMINISTRATION

    Oral Administration

    May be taken orally with or without food; tolerability may be enhanced if taken with food.
    Begin treatment within 48 hours of symptom onset. Begin prophylaxis within 48 hours of exposure.

    Oral Solid Formulations

    For patients who cannot swallow capsules, the commercially available oral suspension is the preferred formulation. However, if the oral suspension is not available, the capsules may be opened and mixed with sweetened liquids such as regular or sugar-free chocolate syrup, corn syrup, caramel topping, or light brown sugar dissolved in water. If the appropriate strengths of capsules are not available to mix with sweetened liquids and the commercially available oral suspension is not available, then a compounded supply of oral suspension can be prepared by the pharmacist (see below).

    Oral Liquid Formulations

    Oral suspension (commercially available 6 mg/mL concentration): Shake well prior to use. Provide the appropriate oral syringe to the patient or caregiver. NOTE: The manufacturer supplies a bottle adapter and a 10 mL oral dispensing syringe with each bottle. For patients heavier than 40 kg, 2 administrations with the 10 mL syringe are required to achieve the full dose (10 mL followed by another 2.5 mL).
     
    Reconstitution of commercially available 6 mg/mL oral suspension:
    Review the reconstitution instructions for the particular product and package size, as the amount of water required for reconstitution varies from manufacturer to manufacturer.
    Loosen powder from sides of the bottle. Add the specified amount of water and shake well for 15 seconds. The final oseltamivir concentration is 6 mg/mL.
    Remove the child-resistant cap and push bottle adapter into the neck of the bottle.
    Close tightly with the child-resistant cap. This will ensure proper sealing of the bottle.
    Storage after reconstitution: Use within 17 days of reconstitution when stored under refrigeration [2 to 8 degrees C (36 to 46 degrees F); DO NOT freeze] or within 10 days if stored at room temperature [15 to 30 degrees C (59 to 86 degree F)]. Write the expiration date on the label.

    Extemporaneous Compounding-Oral

    Extemporaneous 6 mg/mL oral suspension (using capsules):
    NOTE: This compounded suspension is for use only during emergency situations and should not be used for convenience or when the FDA-approved oral suspension is commercially available.
    NOTE: The recommended vehicles are Cherry Syrup (Humco), Ora-Sweet SF (sugar-free), or simple syrup; other vehicles have not been studied. The final oseltamivir concentration in the compounded suspension is 6 mg/mL, which is the SAME as the commercially available oral suspension.
    NOTE: The total volume of suspension needed to prepare a full course (5-day treatment course or 10-day course of prophylaxis) is based on the patient's dose (see below). If the oseltamivir dose is between the doses listed, the total volume of the oral suspension should default to the next greater dose listed. See Dosage section for specific weight- and age-based dosage recommendations.
    Oseltamivir dose of 15 mg or less: Prepare a 37.5 mL suspension using three (3) 75-mg capsules (225 mg oseltamivir), 2.5 mL of water, and 34.5 mg of recommended vehicle.
    Oseltamivir dose of 30 mg: Prepare a 75 mL suspension using six (6) 75-mg capsules (450 mg oseltamivir), 5 mL of water, and 69 mL of recommended vehicle.
    Oseltamivir dose of 45 mg: Prepare a 100 mL suspension using eight (8) 75-mg capsules (600 mg oseltamivir), 7 mL of water, and 91 mL of recommended vehicle.
    Oseltamivir dose of 60 mg: Prepare a 125 mL suspension using ten (10) 75-mg capsules (750 mg oseltamivir), 8 mL of water, and 115 mL of recommended vehicle.
    Oseltamivir dose of 75 mg: Prepare a 150 mL suspension using twelve (12) 75-mg capsules (900 mg oseltamivir), 10 mL of water, and 137 mL of recommended vehicle.
     
    Compounding the 6 mg/mL oral suspension:
    Add the above specified volume of water to a polyethyleneterephthalate (PET) or glass bottle; a funnel may be used to prevent spillage.
    Carefully open each capsule and transfer contents into the PET or glass bottle.
    Gently swirl the suspension for at least 2 minutes.
    Slowly add the above specified volume of vehicle to the bottle; a funnel may be used to prevent spillage.
    Shake well for 30 seconds to completely dissolve the active drug and to ensure homogenous distribution of the dissolved drug in the resulting suspension. It should be noted that oseltamivir phosphate readily dissolves in the recommended vehicles and that the suspension is due to some of the inert ingredients of the capsules that are insoluble in these vehicles.
    Place an ancillary label on the bottle stating 'Shake Well Before Use'.
    The compounded oral suspension is stable for 5 days when stored at room temperature 25 degrees C (77 degrees F) or for 5 weeks (35 days) under refrigeration at 2 to 8 degrees C (36 to 46 degrees F). However, if pharmacies are preparing batches of the extemporaneously compounded suspension due to high prescription volume, the compounded suspension must be refrigerated until dispensed, stirred thoroughly before dispensing, and refrigerated by the patient at home.
    Dispense with a graduated oral syringe for measuring small amounts of suspension.

    STORAGE

    Tamiflu:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Oseltamivir is contraindicated in any patient who is hypersensitive to the drug or to any component of the formulation.

    Infection, viral infection

    Serious bacterial infections may begin with influenza-type symptoms, or may coexist with or occur as complications of influenza. There are no data to suggest oseltamivir is effective in treating a viral infection other than influenza virus A and B. Data on the treatment of influenza B infection are limited; only 3% of patients in the clinical trials were infected with this virus. Oseltamivir is most effective when initiated within 48 hours of symptom onset or close contact with an infected individual; however, limited data suggest antiviral therapy may still be beneficial to high risk patients when initiated up to 5 days after illness onset.

    Immunosuppression, vaccination

    Antiviral medications with activity against influenza, such as oseltamivir, are not substitutes for receipt of an annual influenza vaccination; these medications should be used as an adjunct to the vaccine in the control of influenza. Oseltamivir does not interfere with the antibody response to the inactivated influenza vaccine; however, there is concern about possible interference with the viral replication necessary after administration of the live attenuated influenza vaccine for the proper development of immunity. Do not administer the live attenuated influenza vaccine within 48 hours after oseltamivir administration, and wait at least 2 weeks after administration of the live attenuated vaccine to begin oseltamivir therapy, unless earlier oseltamivir therapy is medically necessary. According to the manufacturer, efficacy of oseltamivir has not been established in immunocompromised patients or those with immunosuppression. However, the Centers for Disease Control and Prevention (CDC) recommends oseltamivir for the treatment and prevention of influenza in patients with immune deficiencies and those receiving immunosuppressive medications.

    Asthma, bronchitis, cardiac disease, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary disease

    Efficacy of oseltamivir, as measured by time to alleviation of all symptoms, has not been established in patients with chronic pulmonary disease or cardiac disease. However, oseltamivir studies have included 'at-risk' adult patients with cardiac disease, adults with chronic obstructive pulmonary disease (COPD) (i.e., chronic bronchitis or emphysema), and older pediatric patients with asthma; the incidence of complications in these patient populations did not differ between oseltamivir and placebo. In addition, studies evaluating safety and efficacy of the drug in elderly (age older than 65 years) and younger adult patients have found no overall difference. Safety and efficacy of oseltamivir have been established in elderly nursing home residents who took oseltamivir for up to 42 days for the prevention of influenza. Many of these individuals had cardiac or respiratory disease, and most had received the influenza vaccine that season. Patients with chronic health conditions are at higher risk for developing complications associated with influenza infection, and the Centers for Disease Control and Prevention (CDC) recommends oseltamivir use in these patient populations for the treatment and prophylaxis of influenza. No information is available regarding oseltamivir treatment of influenza in patients with any medical condition sufficiently severe or unstable to be considered as having an imminent risk of hospitalization.

    Renal failure, renal impairment

    Oseltamivir is not recommended for patients with end stage renal failure (creatinine clearance 10 mL/min or less) who are not receiving dialysis. Dosage adjustments are recommended in adult patients with moderate to severe renal impairment (creatinine clearance 60 mL/min or less) and for patients on dialysis; consider similar adjustments in pediatric patients. The active metabolite of oseltamivir is greater than 99% renally eliminated; therefore, patients with renal impairment are at increased risk for drug accumulation and adverse effects.

    Hepatic disease

    The safety and pharmacokinetics of oseltamivir have not been established in patients with severe hepatic disease. During clinical studies, the pharmacokinetics of oseltamivir were not changed in patients with mild or moderate hepatic impairment.

    Psychosis

    Neuropsychiatric adverse reactions of self-injury and delirium (psychosis) have been reported during postmarketing use of oseltamivir; some cases resulted in fatal outcomes. These reactions were primarily reported in pediatric patients and often occurred abruptly and resolved rapidly. Since influenza infection itself is associated with a variety of neurologic and behavioral symptoms (e.g., hallucinations, delirium, abnormal behavior), the role of oseltamivir in causing these reactions is unclear. Patients with influenza who are receiving oseltamivir should be closely monitored for signs of abnormal behavior. The risks and benefits of continuing oseltamivir should be evaluated if neuropsychiatric events occur.

    Children, infants, neonates, Reye's syndrome

    Neuropsychiatric adverse reactions of self-injury and delirium have been reported during postmarketing use of oseltamivir. These reactions were primarily reported in children; monitor patients for signs of abnormal behavior. Dosing in children is typically weight-based; the drug requires dosage adjustment for children younger than 13 years of age weighing less than 40 kg. In clinical trials, pediatric patients 1 year and older who were treated with oseltamivir within 2 days of symptom onset experienced a reduction in the duration of flu of about 1.5 days. Based on these trials and trials in adults, oseltamivir was approved for treatment of influenza in children, infants, and neonates 14 days and older. The drug is also effective in preventing the spread of influenza in close contacts in children at least 1 year of age. However, prophylactic use of oseltamivir beyond 10 days duration has not been evaluated in children 1 to 12 years old. Safety and efficacy of oseltamivir prophylaxis have not been established in infants and neonates; however, the CDC has issued recommendations for infants as well as treatment recommendations for neonates and premature neonates.. According to the manufacturer, animal studies have identified high blood and brain concentrations of oseltamivir and associated deaths in very young animals; immature blood-brain barriers might be susceptible to increased oseltamivir penetration and adverse events may result. A single dose of 1,000 mg/kg oseltamivir phosphate (about 250-times the recommended human pediatric dose) in 7-day-old rats resulted in deaths associated with unusually high exposure to both oseltamivir and oseltamivir phosphate; concentrations in the brain were roughly 1,500-times those seen in adult rats that received the same dose. No adverse effects were noted after 7 to 21 day old rats received doses of 500 mg/kg/day. The clinical significance of these preclinical data to human infants is uncertain. It is generally recommended that the drug not be administered to infants prior to the maturation of the blood-brain-barrier (i.e. approximately 1 year of age). Aspirin has been associated with the occurrence of Reye's syndrome when given to children with varicella (i.e., chickenpox) or influenza. Although a causal relationship has not been confirmed, most authorities advise against the use of aspirin in children with varicella, influenza, or other viral infection.

    Hereditary fructose intolerance

    Patients with hereditary fructose intolerance should be warned that oseltamivir powder for oral suspension contains 11 g of sorbitol per 13-g bottle. This results in a 75 mg dose of the suspension delivering 2 g of sorbitol, which is above the daily maximum limit of sorbitol. Dyspepsia and diarrhea may occur in patients with hereditary fructose intolerance.

    Pregnancy

    Oseltamivir is classified as FDA pregnancy risk category C. No adequate and well-controlled studies have been conducted in pregnant women; however, a collection of observational studies have evaluated drug exposure in approximately 1,500 pregnant women. Although, individually, these studies lacked adequate sample size, pooled data found no increased risk of congenital malformations when compared to the general population. In addition, the gestational period in which exposure occurred appeared to have no effect on pregnancy outcome, as approximately 400 women were exposed during the first trimester. In animal studies, slight and marked maternal toxicities and a dose-dependent increase in skeletal abnormalities in offspring were observed. The manufacturer states that oseltamivir should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus. According to the CDC, pregnant women are known to be at higher risk for complications from influenza infection and severe disease among women has been reported in past pandemics; therefore, guidelines state that the benefits of treatment against the influenza virus likely outweigh the theoretical risks of antiviral use. The CDC considers oseltamivir the preferred antiviral for treatment of influenza in pregnant women.

    Breast-feeding

    According to the manufacturer, limited data suggest oseltamivir and oseltamivir carboxylate are excreted in human breast milk. The concentration of oseltamivir and oseltamivir carboxylate in breast milk was found to be lower than the concentrations in plasma following a single 75 mg oral dose. The estimated infant exposure to oseltamivir, assuming a 2.75 kg infant receiving 750 ml of breast milk daily, was 0.76 mcg/kg/day. This dose is much lower than oseltamivir doses used in neonates and infants for treatment of influenza; thus, exposure through breast milk is unlikely to cause fetal toxicity. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    ADVERSE REACTIONS

    Severe

    laryngeal edema / Rapid / Incidence not known
    anaphylactic shock / Rapid / Incidence not known
    GI bleeding / Delayed / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known
    seizures / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known

    Moderate

    hepatitis / Delayed / Incidence not known
    colitis / Delayed / Incidence not known
    hyperglycemia / Delayed / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known
    psychosis / Early / Incidence not known
    hallucinations / Early / Incidence not known
    confusion / Early / Incidence not known
    delirium / Early / Incidence not known

    Mild

    headache / Early / 2.0-17.0
    vomiting / Early / 2.0-16.0
    nausea / Early / 8.0-10.0
    diarrhea / Early / 7.0-7.0
    dyspepsia / Early / Incidence not known
    urticaria / Rapid / Incidence not known
    rash / Early / Incidence not known
    hypothermia / Delayed / Incidence not known
    emotional lability / Early / Incidence not known
    agitation / Early / Incidence not known
    nightmares / Early / Incidence not known
    anxiety / Delayed / Incidence not known

    DRUG INTERACTIONS

    Intranasal Influenza Vaccine: (Major) Avoid the use of live attenuated influenza vaccine (LAIV) within 2 weeks before or 48 hours after administration of oseltamivir unless medically indicated. Although concurrent use has not been evaluated, antiviral drugs, such as oseltamivir, may inhibit viral replication and reduce vaccine efficacy. Inactivated influenza vaccines may be used, as appropriate. Consult currently recommended guidance on the use of antiviral drugs against influenza.
    Probenecid: (Minor) Coadministration of oseltamivir and probenecid results in a two-fold increase in exposure to oseltamivir carboxylate due to a decrease in active anionic tubular secretion in the kidney. However, due to the safety margin of oseltamivir carboxylate, no dosage adjustments are required when oseltamivir is given concomitantly with probenecid.

    PREGNANCY AND LACTATION

    Pregnancy

    Oseltamivir is classified as FDA pregnancy risk category C. No adequate and well-controlled studies have been conducted in pregnant women; however, a collection of observational studies have evaluated drug exposure in approximately 1,500 pregnant women. Although, individually, these studies lacked adequate sample size, pooled data found no increased risk of congenital malformations when compared to the general population. In addition, the gestational period in which exposure occurred appeared to have no effect on pregnancy outcome, as approximately 400 women were exposed during the first trimester. In animal studies, slight and marked maternal toxicities and a dose-dependent increase in skeletal abnormalities in offspring were observed. The manufacturer states that oseltamivir should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus. According to the CDC, pregnant women are known to be at higher risk for complications from influenza infection and severe disease among women has been reported in past pandemics; therefore, guidelines state that the benefits of treatment against the influenza virus likely outweigh the theoretical risks of antiviral use. The CDC considers oseltamivir the preferred antiviral for treatment of influenza in pregnant women.

    According to the manufacturer, limited data suggest oseltamivir and oseltamivir carboxylate are excreted in human breast milk. The concentration of oseltamivir and oseltamivir carboxylate in breast milk was found to be lower than the concentrations in plasma following a single 75 mg oral dose. The estimated infant exposure to oseltamivir, assuming a 2.75 kg infant receiving 750 ml of breast milk daily, was 0.76 mcg/kg/day. This dose is much lower than oseltamivir doses used in neonates and infants for treatment of influenza; thus, exposure through breast milk is unlikely to cause fetal toxicity. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Oseltamivir is an ethyl ester prodrug that requires hydrolysis to the active metabolite, oseltamivir carboxylate. Once in circulation, oseltamivir carboxylate acts extracellularly by selectively binding to an unoccupied area of viral neuraminidase (a surface glycoprotein on influenza A and B that catalyzes the cleavage of the linkage between a terminal sialic acid and adjacent sugar residue), resulting in competitive inhibition of the enzyme. By inhibiting the actions of viral neuraminidase, oseltamivir ultimately prevents the spread of virus in the respiratory tract.
     
    Influenza viruses are classified into 3 distinct types, influenza A, influenza B, and influenza C. Influenza A is further divided into subtypes based on their hemagglutinin (H or HA) and neuraminidase (N or NA) activity. At least 16 distinct HAs (H1 to H16) and 9 NAs (N1 to N9) have been described. Influenza infection may be attributed to either influenza A virus or influenza B virus. Influenza A virus subtypes include H1N1 and H3N2. In 2009, a novel influenza A H1N1 virus (previously referred to as swine influenza) was identified; this virus is included in season influenza A viruses. Human cases of influenza illness from the avian H5N1 virus (commonly known as avian flu) have been reported since 1997. Human infections with avian H7N9, H5N2, H5N8, H9N2, H7N7, and H7N3 viruses have also been described.
     
    A neuraminidase assay of clinical isolates identified the median IC50 (50% inhibitory concentration) for oseltamivir carboxylate against influenza A/H1N1, influenza A/H3N2, and influenza B to be 2.5 nM (range 0.93 to 4.16 nM), 0.96 nM (range 0.13 to 7.95 nM), and 60 nM (range 20 to 285 nM), respectively. An evaluation of antiviral activity using laboratory and clinical influenza isolates found the concentrations of oseltamivir carboxylate required for inhibition of influenza virus in cell culture to be highly variable depending on the assay method used and virus testing. Specifically, the EC50 and EC90 (50% and 90% effective inhibitory concentration) of these cell cultures ranged from 0.0008 micromolar to more than 35 micromolar and 0.004 micromolar to more than 100 micromolar, respectively. A relationship between antiviral activity in cell culture, inhibitory activity in neuraminidase assay, and inhibition of influenza virus replication in humans has not been established. Influenza treatment emergent resistance to oseltamivir has been reported, with most cases occurring in influenza A/H1N1 viruses. Genetic analysis shows that reduced susceptibility to oseltamivir carboxylate is associated with mutations that result in amino acid changes in the viral neuraminidase or viral hemagglutinin or both. The prevalence of oseltamivir-resistant viruses varies based on season and geographic location. Severely immunosuppressed persons (e.g., hematopoietic stem cell transplant recipients) are at highest risk for developing an oseltamivir-resistant influenza virus infection during or after antiviral therapy. In addition, selection of influenza A viruses resistant to oseltamivir appears to occur at higher frequencies in pediatric populations. During small pediatric studies, the incidence of oseltamivir treatment-associated resistance for influenza A/H1N1 and influenza A/H3N2 were 27% to 37% and 3% to 18%, respectively. The actual risk of resistance to oseltamivir during clinical use cannot be determined from these small pediatric studies. The CDC Influenza Division is available for consultation regarding resistance testing as needed.

    PHARMACOKINETICS

    Oseltamivir is administered orally. Following absorption from the gastrointestinal tract, most of the dose (at least 90%) is hydrolyzed by hepatic esterase to the active metabolite, oseltamivir carboxylate. Oseltamivir carboxylate does not undergo any further metabolism and is only minimally bound to human plasma proteins (3%). The elimination half-life of oseltamivir carboxylate is 6 to 10 hours, with more than 99% being eliminated in the urine via glomerular filtration and active tubular secretion. The elimination half-life of the parent drug is 1 to 3 hours.
     
    Affected cytochrome P450 isoenzymes: none
    Neither oseltamivir nor oseltamivir carboxylate are substrates for, or inhibitors of, cytochrome P450 isoenzymes.

    Oral Route

    After oral administration, 75% of the dose reaches systemic circulation as oseltamivir carboxylate; less than 5% of the total dose reaches the systemic circulation as oseltamivir. Administration with food has no effect on the maximum plasma concentration (Cmax) or exposure (AUC) values for oseltamivir carboxylate.