OSELTAMIVIR PHOSPHATE (Generic for TAMIFLU)

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Oral Administration
-May be taken 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 unable to 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 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.

Oral Liquid Formulations
-Shake well before use.
-Administer using a calibrated measuring device.

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 may vary 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.
-Place an ancillary label on the bottle stating 'Shake Well Before Use', and dispense with the appropriate oral dosing syringe.
-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
-Shake well before use.
-Administer using a calibrated measuring device.

Extemporaneous 6 mg/mL oral suspension (using capsules)
-Compounded suspensions are for use only during emergency situations and should not be used for convenience or when the FDA-approved oral suspension is commercially available.
-The recommended vehicles are Cherry Syrup (Humco), Ora-Sweet SF (Paddock Laboratories), 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.
-The total volume of suspension needed to prepare a full course (5-day treatment course or 10-day course of prophylaxis) is based on 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.
--Oseltamivir dose of 15 mg or less: Prepare 37.5 mL using three (3) 75-mg capsules (225 mg oseltamivir), 2.5 mL of water, and 34.5 mL of recommended vehicle.
-Oseltamivir dose of 30 mg: Prepare 75 mL 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 100 mL 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 125 mL 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 150 mL 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 inert ingredients of the capsules that are insoluble in these vehicles.
-Place an ancillary label on the bottle stating 'Shake Well Before Use', and dispense with the appropriate oral dosing syringe.
-Storage: 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.

The most frequent adverse reaction associated with oseltamivir in children is vomiting. Vomiting was reported more frequently in children who received the twice daily treatment dose compared with the once daily prophylactic dose (16% vs. 8%). Vomiting (9%) and diarrhea (7%) were the most common GI adverse reactions reported in treatment studies in infants younger than 1 year of age. Nausea (8% to 10%) and vomiting (2% to 8%) were also relatively frequent in trials that included adolescents. Oseltamivir may be taken with or without food, but tolerability may be enhanced if it is taken with food. Dyspepsia and diarrhea may occur in patients with hereditary fructose intolerance who take oseltamivir powder for oral suspension because of the sorbitol content. Elevated hepatic enzymes, hepatitis, GI bleeding, and hemorrhagic colitis have been noted in postmarketing reports.

Diaper dermatitis was reported in 7% of infants less than 1 year of age receiving oseltamivir in clinical trials. Other dermatologic reactions observed during clinical practice with oseltamivir include rash, eczema, and urticaria. During the postmarketing surveillance period, rare cases of anaphylactoid reactions such as anaphylactic shock and swelling of face or tongue (laryngeal edema or angioedema) and serious skin reactions such as toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme have been reported. Because these reactions are reported voluntarily, it is impossible to reliably estimate the frequency or establish a causal relationship to oseltamivir. Stop oseltamivir and institute appropriate treatment if an allergic reaction or suspected allergic reaction occurs.

It is unclear whether the use of oseltamivir may be associated with psychiatric adverse reactions; patients or caregivers should report any emotional lability or abnormal behavior while taking oseltamivir. Postmarketing reports of self-injury, delirium (psychosis), hallucinations, agitation, anxiety, altered consciousness, confusion, nightmares, and delusions have been reported with oseltamivir use, mainly in pediatric patients with active influenza infection. These events often had an abrupt onset and rapid resolution. Influenza infection itself may be associated with a variety of neurologic and behavioral symptoms; while symptoms may occur in the setting of encephalitis or encephalopathy, they can occur without obvious severe disease. The relative contribution of oseltamivir to the postmarketing reports of neurological symptoms is not known. A review of data from controlled clinical trials and ongoing surveillance has failed to confirm a link between oseltamivir and psychiatric effects. Seizures have also been noted in postmarketing reports. In a retrospective study in infants younger than 12 months of age, neurologic adverse reactions were not more common with oseltamivir compared with amantadine and rimantadine.

Headache (17%) was commonly reported in oseltamivir prophylaxis studies that included adolescent patients; headache was less frequent (2%) in treatment trials. Generalized pain was reported in up to 4% of patients in prophylaxis studies.

Arrhythmia exacerbation, aggravation of diabetes (hyperglycemia), and hypothermia have been noted in postmarketing reports with oseltamivir.

Oseltamivir is contraindicated in any patient with known hypersensitivity to the drug or to any component of the formulation. Cases of anaphylaxis and serious rash, including toxic epidermal necrolysis, Stevens-Johnson Syndrome, and erythema multiforme, have been reported in postmarketing experience with oseltamivir. Discontinue oseltamivir and institute appropriate treatment if an allergic-like reaction occurs or is suspected.

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.

Oseltamivir is not recommended for patients with renal failure (creatinine clearance 10 mL/minute or less) who are not receiving dialysis. Dosage adjustments are recommended in adults with moderate to severe renal impairment (creatinine clearance 60 mL/minute or less); 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.

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.

Use caution in patients with hereditary fructose intolerance as the oseltamivir powder for oral suspension contains 11 g of sorbitol per 13-g bottle. A 75 mg dose of the suspension will deliver 2 g of sorbitol, which is above the daily maximum limit of sorbitol. Dyspepsia and diarrhea may occur in patients with hereditary fructose intolerance.

Serious bacterial infections may begin with influenza-type symptoms, or may coexist with or occur as complications of influenza. There is 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.

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 older pediatric patients with asthma and 'at-risk' adult patients with cardiac disease and chronic obstructive pulmonary disease (COPD) (i.e., chronic bronchitis or emphysema); the incidence of complications in these patient populations did not differ between oseltamivir and placebo. 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.

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.

Description: Oseltamivir is an oral neuraminidase inhibitor (NAI) indicated for the treatment and prevention of acute, uncomplicated seasonal influenza infections. Like other NAIs (zanamivir and peramivir), oseltamivir has activity against both influenza A and B viruses; whereas adamantanes (amantadine and rimantadine) are active against influenza A only. Clinical benefit from antiviral therapy is greatest when initiated early; therefore, the FDA-approved labeling recommends initiating oseltamivir within 48 hours of influenza symptom onset (for treatment) or close contact with an infected individual (post-exposure prophylaxis). However, according to the Centers for Disease Control and Prevention (CDC), specific patients populations (including those with severe, complicated, or progressive illness, those at higher risk for influenza complications, and hospitalized patients) may still receive benefit from antiviral treatment if initiated after 48 hours of illness onset. Oseltamivir is not considered a substitute for annual influenza virus vaccination. Instead, NAI antiviral drugs are considered adjuncts to the prevention and control of influenza; annual influenza vaccination remains the main strategy for reducing the impact of influenza. For influenza treatment, oseltamivir is FDA-approved for use in pediatric patients as young as 2 weeks of age; for influenza prophylaxis, it is approved for patients 1 year of age and older. In addition, the American Academy of Pediatrics (AAP) and the CDC also recommend oseltamivir for treatment of influenza in infants younger than 14 days, and for chemoprophylaxis in infants 3 months to 1 year of age; chemoprophylaxis is not recommended in infants younger than 3 months unless deemed critical by the health care provider.

In a review of randomized controlled trials of oseltamivir in infants and children with laboratory-confirmed influenza, oseltamivir reduced the duration of illness by 36 hours (26%, p less than 0.001). In addition, the administration of oseltamivir reduced the incidence of acute otitis media in children 1 to 5 years of age with laboratory-confirmed influenza (risk difference -0.14; 95% CI, -0.24 to -0.04).

General dosing information:
-Because antiviral resistance patterns can change over time, monitor local antiviral resistance surveillance data. If patients become symptomatic or have worsening symptoms after or during the use of an antiviral agent, a resistant organism is possible.

Seasonal influenza virus:
-Antiviral therapy with oseltamivir is recommended for patients with suspected or confirmed influenza who are hospitalized; have severe, complicated, or progressive illness; or are at higher risk for complications (e.g., infants and children younger than 2 years of age; patients with chronic conditions; immunosuppressed patients; women who are pregnant or postpartum (less than 2 weeks after delivery); children on long-term aspirin therapy; American Indians/Alaska Natives; morbidly obese patients; and residents of long-term care facilities). Treatment may also be considered for previously healthy, symptomatic patients that are not considered high risk based on clinical judgment if treatment can be initiated within 48 hours of symptom onset.
-When indicated, oseltamivir treatment should be initiated as soon as possible after illness onset, ideally within 48 hours of symptom onset; however, oseltamivir started after 48 hours may still be beneficial in severe, complicated, or progressive illness or hospitalized patients.
-Widespread or routine use of oseltamivir for influenza prevention is discouraged. Preexposure chemoprophylaxis is only recommended for patients at very high risk for influenza-related complications (i.e., immunosuppressed patients). In general, postexposure chemoprophylaxis is only recommended when antivirals can be initiated within 48 hours of exposure. The decision regarding who should receive postexposure prophylaxis is dependent on patient risk factors, type and duration of exposure, clinical judgment, and product availability. Chemoprophylaxis lowers but does not eliminate the risk for influenza infection.
-The 2009 H1N1 influenza virus (swine influenza) is included in seasonal influenza A viruses.

Novel influenza A viruses associated with severe human disease, including avian influenza virus:
-Antiviral therapy is recommended as early as possible for patients with suspected or confirmed cases, even if more than 48 hours have elapsed since illness onset. Treatment is also recommended for any patient with recent or close contact to a confirmed or probable case.
-Postexposure chemoprophylaxis of exposed persons: Postexposure prophylaxis can be considered in all persons in contact with infected sick or dead birds or infected flocks in the past 10 days. Decisions to initiate prophylaxis should be based on clinical judgment, with consideration given to type of exposure and whether the exposed person is at high risk for influenza complications.
-Postexposure chemoprophylaxis of asymptomatic close contacts: Postexposure chemoprophylaxis of asymptomatic close contacts is recommended for high-risk exposure groups (i.e., household or close family member contacts of a confirmed or probable case) and may be considered for moderate-risk exposure groups (i.e., healthcare personnel with unprotected contact with a confirmed or probable case). Chemoprophylaxis is not routinely recommended for low-risk exposure groups (i.e., persons with social contact of short duration with a confirmed or probable case in a non-hospital setting). Decisions to initiate therapy in moderate- and low-risk exposure should be based on clinical judgment, with consideration given to type of exposure and whether the exposed person is at high risk for influenza complications.

Per the manufacturer, this drug has been shown to be active against most strains of the following microorganisms either in vitro and/or in clinical infections: influenza A virus, influenza B virus
NOTE: The safety and effectiveness in treating clinical infections due to organisms with in vitro data only have not been established in adequate and well-controlled clinical trials.

For the treatment of acute influenza A virus infection or influenza B virus infection:
Oral dosage:
Premature Neonates younger than 38 weeks postmenstrual age*: 1 mg/kg/dose PO twice daily for 5 days. May consider extended courses 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. May consider extended courses for patients who remain severely ill after 5 days of treatment.
Premature Neonates older than 40 weeks postmenstrual age* and Term Neonates 0 to 13 days*: 3 mg/kg/dose PO twice daily for 5 days. May consider extended courses for patients who remain severely ill after 5 days of treatment.
Term Neonates 14 to 29 days: 3 mg/kg/dose PO twice daily for 5 days. May consider extended courses for patients who remain severely ill after 5 days of treatment.
Infants 1 to 8 months: 3 mg/kg/dose PO twice daily for 5 days. May consider extended courses for patients who remain severely ill after 5 days of treatment.
Infants 9 to 11 months: 3.5 mg/kg/dose PO twice daily for 5 days is recommended by the American Academy of Pediatrics (AAP) based on pharmacokinetic data indicating that a slightly higher dosage is needed in this age group to achieve target drug exposure. The FDA-approved dosage is 3 mg/kg/dose PO twice daily for 5 days. May consider extended courses 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. May consider extended courses for patients who remain severely ill after 5 days of treatment.
Children weighing 16 to 23 kg: 45 mg PO twice daily for 5 days. May consider extended courses for patients who remain severely ill after 5 days of treatment.
Children weighing 24 to 40 kg: 60 mg PO twice daily for 5 days. May consider extended courses for patients who remain severely ill after 5 days of treatment.
Children and Adolescents weighing more than 40 kg: 75 mg PO twice daily for 5 days. May consider extended courses for patients who remain severely ill after 5 days of treatment.

For seasonal influenza prophylaxis:
Oral dosage:
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.
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.
Infants 3 to 8 months*: 3 mg/kg/dose PO once daily. 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 9 to 11 months*: 3.5 mg/kg/dose PO once daily is recommended by the American Academy of Pediatrics (AAP) 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.
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 duration of protection lasts for as long as dosing is continued. 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 identified case. High-risk patients may require prophylaxis during the entire influenza season.
Children weighing 16 to 23 kg: 45 mg PO once daily for 10 days or for up to 6 weeks during a community outbreak. The duration of protection lasts for as long as dosing is continued. 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 identified case. High-risk patients may require prophylaxis during the entire influenza season.
Children weighing 24 to 40 kg: 60 mg PO once daily for 10 days or for up to 6 weeks during a community outbreak. The duration of protection lasts for as long as dosing is continued. 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 identified case. High-risk patients may require prophylaxis during the entire influenza season.
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. The duration of protection lasts for as long as dosing is continued. 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 identified case. High-risk patients may require prophylaxis during the entire influenza season.

For the treatment of novel influenza A viruses associated with severe human disease*, including avian influenza A virus infection*:
Oral dosage:
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 judgment 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 judgment and virologic testing should guide duration assessment. Oseltamivir is recommended for hospitalized patients as well as outpatients.
Premature Neonates older 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 judgment 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 judgment 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 judgment and virologic testing should guide duration assessment. Oseltamivir is recommended for hospitalized patients as well as outpatients.
Children weighing 16 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 judgment and virologic testing should guide duration assessment. Oseltamivir is recommended for hospitalized patients as well as outpatients.
Children weighing 24 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 judgment 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 judgment 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:
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.
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 older 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.
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.
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.
Children weighing 16 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 24 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 more than 40 kg 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.

Maximum Dosage Limits:
-Neonates
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.
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 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.
Term Neonates 14 days and older: 3 mg/kg/dose PO twice daily.
-Infants
1 to 8 months: 3 mg/kg/dose PO twice daily.
9 to 11 months: 3 mg/kg/dose PO twice daily is the FDA-approved dosage; however, 3.5 mg/kg/dose PO twice daily has been used off-label.
-Children
weight 15 kg or less: 30 mg PO twice daily.
weight 16 to 23 kg: 45 mg PO twice daily.
weight 24 to 40 kg: 60 mg PO twice daily.
weight more than 40 kg: 75 mg PO twice daily.
-Adolescents
75 mg PO twice daily.

Patients with Hepatic Impairment Dosing
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.

Patients with Renal Impairment Dosing
Specific dosage adjustment recommendations are not available for pediatric patients. The following dose adjustments are recommended for adult patients with renal impairment; however, similar dosage adjustments should be considered, particularly in pediatric patients receiving the adult dosage.

Influenza treatment
CrCl more than 60 mL/minute: No dosage adjustment necessary.
CrCl 31 to 60 mL/minute: 30 mg PO twice daily for 5 days.
CrCl 11 to 30 mL/minute: 30 mg PO once daily for 5 days.
CrCl 10 mL/minute or less, not undergoing dialysis: Oseltamivir is not recommended.

Influenza prophylaxis
CrCl more than 60 mL/minute: No dosage adjustment necessary.
CrCl 31 to 60 mL/minute: 30 mg PO once daily.
CrCl 11 to 30 mL/minute: 30 mg PO every other day.
CrCl 10 mL/minute or less, not undergoing dialysis: Oseltamivir is not recommended.

Intermittent hemodialysis (ESRD patients receiving adult doses with CrCl 10 mL/minute or less)
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 receiving adult doses with CrCl 10 mL/minute or less)
For influenza treatment: A single 30 mg dose given immediately after dialysis exchange.
For influenza prophylaxis: 30 mg once weekly immediately after dialysis exchange.

*non-FDA-approved indication

Monograph content under development

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 the 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 have 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. After 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 drug is widely distributed into body tissues and fluids, including saliva, nasal mucosa, lung, and middle-ear fluid. 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.


-Route-Specific Pharmacokinetics
Oral Route
Oseltamivir is readily absorbed from the gastrointestinal tract. At least 75% of an oral dose reaches the systemic circulation as oseltamivir carboxylate; less than 5% of the total dose reaches the systemic circulation as oseltamivir. In infants and young children, peak concentrations of oseltamivir and oseltamivir carboxylate are reached approximately 1 to 2 hours and 4 to 6 hours after administration, respectively. Food has no significant effect on oseltamivir exposure. Oseltamivir suspension and capsules have been found to be bioequivalent for the active metabolite in healthy adults.


-Special Populations
Pediatrics
Neonates
Premature neonates eliminate oseltamivir more slowly than term neonates and infants and, therefore, require lower dosages. Data from several small pharmacokinetic trials in premature neonates suggest that oseltamivir 1 mg/kg/dose PO twice daily achieves similar oseltamivir carboxylate (active metabolite) exposure to that seen in infants and young children receiving the recommended dose of 3 mg/kg/dose twice daily; however, some trials found significant inter-patient variability. Interestingly, the clearance of oseltamivir, which represents the conversion of parent drug to active metabolite, is higher in neonates compared to older infants and children. However, elimination of the active metabolite is slower in neonates compared to older children due to immature renal function.

Infants
Oseltamivir clearance increases with increasing age in infants and pharmacokinetic data in infants 9 to 11 months have shown that a higher weight-based dose is needed in this age group, compared to younger infants, to achieve target drug exposure. A dose of 3.5 mg/kg/dose twice daily was required in infants 9 to 11 months to achieve exposure within the target range (mean oseltamivir carboxylate AUC 2,660 to 7,700 ng x hr/mL) in a pharmacokinetic study in 87 infants and children younger than 2 years. Although a dose of 3 mg/kg/dose twice daily resulted in exposures within the target range for infants 0 to 8 months, high interpatient variability was noted. High interpatient variability was also noted among the entire population for oseltamivir carboxylate pharmacokinetic parameters. Clearance values ranged from 1.04 to 13.79 L/hr for infants 0 to 2 months, 1.43 to 6.83 L/hr for infants 3 to 5 months, 2.45 to 15 L/hr for infants 6 to 8 months, and 2.81 to 9.49 L/hr for infants 9 to 11 months. Corresponding elimination half-lives ranged from 4.65 to 28.71 hours for infants 0 to 2 months, 6.25 to 19 hours for infants 3 to 5 months, 1.02 to 78.26 hours for infants 6 to 8 months, and 5.4 to 51.86 hours for infants 9 to 11 months.

Children
Oseltamivir clearance gradually decreases with increasing age (up to 12 years). In a pharmacokinetic study (n = 12), clearance values for oseltamivir were 259 mL/kg/min and 170 mL/kg/min for children 1 to 2 years and 3 to 5 years, respectively. Corresponding values for oseltamivir carboxylate clearance were 12.2 mL/kg/min and 9.4 mL/kg/min, respectively. In pooled data from 2 other pharmacokinetic studies in pediatric patients, mean oseltamivir carboxylate clearance and elimination half-life of 10.5 mL/kg/min and 7.8 hours, respectively, were reported for children 1 to 12 years.

Adolescents
Pharmacokinetic parameters in adolescents are similar to those seen in adults. Mean oseltamivir carboxylate clearance and elimination half-life of 5.3 mL/kg/min and 8.1 hours, respectively, have been reported in adolescents.

Hepatic Impairment
Pharmacokinetic data are unavailable in pediatric patients with hepatic impairment. However, in adult patients with mild or moderate hepatic impairment, oseltamivir carboxylate exposure is unaltered.

Renal Impairment
Pharmacokinetic data are unavailable in pediatric patients with renal impairment. However, adult data have shown that oseltamivir carboxylate exposure is inversely proportional to declining renal function. Dose adjustments are recommended in patients with moderate to severe renal impairment.