Dosing

Dosing: Adult
Influenza prophylaxis: Oral: 75 mg once daily; initiate prophylaxis within 48 hours of contact with an infected individual; duration of prophylaxis: 10 days. During community outbreaks, duration of protection lasts for length of dosing period; safety and efficacy have been demonstrated for use up to 6 weeks in immunocompetent patients and safety has been demonstrated for use up to 12 weeks in patients who are immunocompromised.
Prophylaxis (institutional outbreak, CDC 2011 recommendations): Continue for ≥2 weeks and until ~10 days after identification of illness onset in the last patient
Influenza treatment:
Treatment of influenza: Oral: 75 mg twice daily initiated within 48 hours of onset of symptoms; duration of treatment: 5 days
Note: Hospitalized patients with severe influenza infection may require longer (eg, ≥10 days) treatment courses. Some experts also recommend empirically doubling the treatment dose. Initiate as early as possible in any hospitalized patient with suspected/confirmed influenza (CDC, 2011); may be administered via naso- or orogastric tube in mechanically-ventilated patients (Taylor, 2008).

Dosing: Pediatric
Influenza prophylaxis: Oral: Initiate prophylaxis within 48 hours of contact with an infected individual; duration of prophylaxis: 10 days:
Prophylaxis (institutional outbreak, CDC 2011 recommendations): Continue for ≥2 weeks and until ~10 days after identification of illness onset in the last patient
Children <1 year (unlabeled dosing, CDC 2011): Note: Prophylaxis is not recommended for infants <3 months of age unless clinically critical; weight-based dosing recommendations are not intended for premature neonates:
<12 months: 3 mg/kg/dose once daily
Alternate dosing based on age (use only if weight not available) (unlabeled dosing; AAP, 2010):
3-5 months: 20 mg once daily
6-11 months: 25 mg once daily
Children: 1-12 years: During community outbreaks, prophylaxis may be used for up to 6 weeks.
≤15 kg: 30 mg once daily
>15 kg to ≤23 kg: 45 mg once daily
>23 kg to ≤40 kg: 60 mg once daily
>40 kg: 75 mg once daily
Adolescents ≥13 years: Refer to adult dosing.
Influenza treatment: Oral: Initiate treatment within 48 hours of contact with an infected individual; duration of treatment: 5 days
Note: Hospitalized patients with severe influenza infection may require longer (eg, ≥10 days) treatment courses. Some experts also recommend empirically doubling the treatment dose. Doubling the dose in adult outpatients was not associated with increased adverse events. As no double dose studies have been published in children, use caution. Initiate as early as possible in any hospitalized patient with suspected/confirmed influenza (CDC, 2011); may be administered via naso- or orogastric tube in mechanically-ventilated patients (Taylor, 2008).
Treatment of influenza:
Children <1 year (unlabeled dosing, CDC 2011): Note: Weight-based dosing recommendations are not intended for premature neonates:
<12 months: 3 mg/kg/dose twice daily
Alternate dosing based on age (use only if weight not available) (unlabeled dosing; AAP, 2010):
<3 months: 12 mg twice daily
3-5 months: 20 mg twice daily
6-11 months: 25 mg twice daily
Children: 1-12 years:
≤15 kg: 30 mg twice daily
>15 kg to ≤23 kg: 45 mg twice daily
>23 kg to ≤40 kg: 60 mg twice daily
>40 kg: 75 mg twice daily
Adolescents ≥13 years: Refer to adult dosing.

Dosing: Geriatric
Refer to adult dosing.

Dosing: Renal Impairment
Clcr 10-30 mL/minute: Adults:
Treatment: Reduce dose to 75 mg once daily for 5 days
High-dose treatment (unlabeled [eg, severely-ill hospitalized patients with 2009 H1N1 influenza]): Currently no data are available; consider 150 mg once daily
Prophylaxis: Administer 75 mg every other day or 30 mg once daily.
CAPD (unlabeled dose): Adults: 30 mg once weekly (Robson, 2006)
Hemodialysis:
Children >1 year (unlabeled dose; Schreuder, 2010):
≤15 kg: 7.5 mg after each hemodialysis session
>15 kg to ≤23 kg: 10 mg after each hemodialysis session
>23 kg to ≤40 kg: 15 mg after each hemodialysis session
>40 kg: 30 mg after each hemodialysis session
Adults (unlabeled dose; Robson, 2006): 30 mg after every other session

Dosing: Hepatic Impairment
Mild-to-moderate impairment: No adjustment necessary
Severe impairment: Pharmacokinetics and safety have not been evaluated.

Use

Treatment of uncomplicated acute illness due to influenza (A or B) infection in children ≥1 year of age and adults who have been symptomatic for no more than 2 days; prophylaxis against influenza (A or B) infection in children ≥1 year of age and adults
The Advisory Committee on Immunization Practices (ACIP) recommends that treatment be considered for the following:
• Persons with severe, complicated or progressive illness
• Hospitalized persons
• Persons at higher risk for influenza complications:
- Children <2 years of age (highest risk in children <6 months of age)
- Adults ≥65 years of age
- Persons with chronic disorders of the pulmonary (including asthma) or cardiovascular systems (except hypertension)
- Persons with chronic metabolic diseases (including diabetes mellitus), hepatic disease, renal dysfunction, hematologic disorders (including sickle cell disease), or immunosuppression (including immunosuppression caused by medications or HIV)
- Persons with neurologic/neuromuscular conditions (including conditions such as spinal cord injuries, seizure disorders, cerebral palsy, stroke, mental retardation, moderate to severe developmental delay, or muscular dystrophy) which may compromise respiratory function, the handling of respiratory secretions, or that can increase the risk of aspiration
- Pregnant or postpartum women (≤2 weeks after delivery)
- Persons <19 years of age on long-term aspirin therapy
- American Indians and Alaskan Natives
- Persons who are morbidly obese (BMI ≥40)
- Residents of nursing homes or other chronic care facilities
• Use may also be considered for previously healthy, nonhigh-risk outpatients with confirmed or suspected influenza based on clinical judgment when treatment can be started within 48 hours of illness onset.
The ACIP recommends that prophylaxis be considered for the following:
• Postexposure prophylaxis may be considered for family or close contacts of suspected or confirmed cases, who are at higher risk of influenza complications, and who have not been vaccinated against the circulating strain at the time of the exposure.
• Postexposure prophylaxis may be considered for unvaccinated healthcare workers who had occupational exposure without protective equipment.
• Pre-exposure prophylaxis should only be used for persons at very high risk of influenza complications who cannot be otherwise protected at times of high risk for exposure.
• Prophylaxis should also be administered to all eligible residents of institutions that house patients at high risk when needed to control outbreaks.
The ACIP recommends that treatment and prophylaxis be given to children <1 year of age when indicated.

Adverse Reactions

>10%: Gastrointestinal: Vomiting (2% to 15%)
1% to 10%:
Gastrointestinal: Nausea (4% to 10%), abdominal pain (2% to 5%), diarrhea (1% to 3%)
Ocular: Conjunctivitis (1%)
Respiratory: Epistaxis (1%)
<1% (Limited to important or life-threatening): Allergy, anaphylactic/anaphylactoid reaction, angina, arrhythmia, confusion, erythema multiforme, fracture, gastrointestinal bleeding, hemorrhagic colitis, hepatitis, liver function tests abnormal, neuropsychiatric events, pseudomembranous colitis, pyrexia, seizure, Stevens-Johnson syndrome, swelling of face or tongue, toxic epidermal necrolysis

Contraindications

Hypersensitivity to oseltamivir or any component of the formulation

Warnings / Precautions Drug

Concerns related to adverse effects:
• Anaphylaxis/hypersensitivity: Rare but severe hypersensitivity reactions (anaphylaxis, severe dermatologic reactions) have been associated with use.
• Neuropsychiatric events: Rare occurrences of neuropsychiatric events (including confusion, delirium, hallucinations, and/or self-injury) have been reported primarily in pediatric patients from postmarketing surveillance; direct causation is difficult to establish (influenza infection may also be associated with behavioral and neurologic changes). Monitor closely for signs of any unusual behavior.
Disease-related concerns:
• Cardiovascular disease: Use with caution in patients with chronic cardiac disease; efficacy has not been established.
• Hepatic impairment: Use with caution in patients with severe hepatic impairment; safety and efficacy have not been established.
• Renal impairment: Use with caution in patients with renal impairment; dosage adjustment is required for creatinine clearance <30 mL/minute.
• Respiratory disease: Use with caution in patients with respiratory disease; efficacy has not been established.
Special populations:
• Immunocompromised patients: Use with caution in immunocompromised patients; safety and efficacy for treatment or prophylaxis in immunocompromised patients have not been established.
Other warnings/precautions:
• Appropriate use: Oseltamivir is not a substitute for the influenza virus vaccine. It has not been shown to prevent primary or concomitant bacterial infections that may occur with influenza virus. Antiviral treatment should begin within 48 hours of symptom onset. However, the CDC recommends that treatment may still be beneficial and should be started in hospitalized patients with severe, complicated or progressive illness if >48 hours. Nonhospitalized persons who are not at high risk for developing severe or complicated illness and who have a mild disease are not likely to benefit if treatment is started >48 hours after symptom onset. Nonhospitalized persons who are already beginning to recover do not need treatment.

Interactions

Influenza Virus Vaccine (Live/Attenuated): Antiviral Agents (Influenza A and B) may diminish the therapeutic effect of Influenza Virus Vaccine (Live/Attenuated). Management: Avoid anti-influenza antivirals during the period beginning 48 hours prior to and ending 2 weeks after vaccine administration. Persons receiving these agents within 2 weeks of the live intranasal spray vaccine should receive a repeat vaccine dose. Risk D: Consider therapy modification
Probenecid: May increase serum concentrations of the active metabolite(s) of Oseltamivir. Management: Consider a change in therapy when using oseltamivir together with probenecid; reduced oseltamivir dose may be necessary. Increase monitoring for adverse events, such as thrombocytopenia. Risk D: Consider therapy modification

Pregnancy

C
Pregnancy Implications
In animal reproduction studies, a dose-dependent increase in the rates of minor skeleton abnormalities was found in exposed offspring; therefore, the manufacturer classifies oseltamivir as pregnancy category C. The rate of each abnormality remained within the background rate of occurrence in the species studied. In an in vitro study, placental transfer of oseltamivir phosphate and its active metabolite oseltamivir carboxylate was found to be incomplete, resulting in minimal accumulation in the fetus. An increased risk of adverse neonatal outcomes has not been observed following maternal use of oseltamivir during pregnancy. Untreated influenza infection is associated with an increased risk of adverse events to the fetus and an increased risk of complications or death to the mother. Oseltamivir and zanamivir are currently recommended for the treatment or prophylaxis of influenza in pregnant women and women up to 2 weeks postpartum. Oseltamivir and zanamivir are currently recommended as an adjunct to vaccination and should not be used as a substitute for vaccination in pregnant women (consult current CDC guidelines).

Lactation

Enters breast milk/not recommended
Breast-Feeding Considerations
Small amounts of oseltamivir and oseltamivir carboxylate have been detected in breast milk. Breast milk samples were obtained from a single patient (~9 months postpartum) over the course of 5 days of treatment. Using a maximum total milk concentration of oseltamivir (expressed as parent drug and metabolite) of 81.6 ng/mL, the estimated exposure to the breast-feeding infant would be ~0.5% of the weight-adjusted maternal dose (in a 60 kg woman). Breast-feeding is not recommended by the manufacturer. According to the CDC, breast-feeding while taking oseltamivir can be continued. The CDC recommends that women infected with the influenza virus follow general precautions (eg, frequent hand washing) to decrease viral transmission to the child. Mothers with influenza-like illnesses at delivery should consider avoiding close contact with the infant until they have received 48 hours of antiviral medication, fever has resolved, and cough and secretions can be controlled. These measures may help decrease (but not eliminate) the risk of transmitting influenza to the newborn. During this time, breast milk can be expressed and bottle-fed to the infant by another person who is well. Protective measures, such as wearing a face mask, changing into a clean gown or clothing, and strict hand hygiene should be continued by the mother for ≥7 days after the onset of symptoms or until symptom-free for 24 hours. Infant care should be performed by a noninfected person when possible (consult current CDC guidelines).

Mechanism of Action

Oseltamivir, a prodrug, is hydrolyzed to the active form, oseltamivir carboxylate (OC). OC inhibits influenza virus neuraminidase, an enzyme known to cleave the budding viral progeny from its cellular envelope attachment point (neuraminic acid) just prior to release.

Pharmacodynamics / Kinetics

Absorption: Well absorbed
Distribution: Vd: 23-26 L (oseltamivir carboxylate)
Protein binding, plasma: Oseltamivir carboxylate: 3%; Oseltamivir: 42%
Metabolism: Hepatic (90%) to oseltamivir carboxylate; neither the parent drug nor active metabolite has any effect on the cytochrome P450 system
Bioavailability: 75% as oseltamivir carboxylate
Half-life elimination: Oseltamivir: 1-3 hours; Oseltamivir carboxylate: 6-10 hours
Excretion: Urine (>90% as oseltamivir carboxylate); feces