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Uses

Treatment of Seasonal Influenza A and B Virus Infections

Oseltamivir is used for the treatment of acute, uncomplicated illness caused by influenza A or B viruses in adults, adolescents, and pediatric patients 2 weeks of age or older. Although safety and efficacy have not been established in neonates younger than 2 weeks of age, oseltamivir also is recommended when treatment of influenza is necessary in this age group.

The US Centers for Disease Control and Prevention (CDC), US Public Health Service Advisory Committee on Immunization Practices (ACIP), and American Academy of Pediatrics (AAP) recommend antiviral treatment of seasonal influenza illness as soon as possible in all individuals with suspected or confirmed influenza if they require hospitalization or have severe, complicated, or progressive illness (regardless of vaccination status or underlying illness). These experts also recommend early empiric antiviral treatment in individuals with suspected or confirmed influenza of any severity who are at high risk for influenza-related complications because of age or underlying medical conditions. Individuals at increased risk for influenza-related complications include children younger than 2 years of age; adults 65 years of age or older; individuals of any age with chronic pulmonary (including asthma), cardiovascular (except hypertension alone), renal, hepatic, hematologic (including sickle cell disease), or metabolic disorders (including diabetes mellitus); individuals with neurologic and neurodevelopmental conditions (including disorders of the brain, spinal cord, peripheral nerve, and muscle such as cerebral palsy, epilepsy [seizure disorders], stroke, intellectual disability [mental retardation], moderate to severe developmental delay, muscular dystrophy, or spinal cord injury); individuals with immunosuppression (including that caused by medications or human immunodeficiency virus [HIV] infection); women who are pregnant or up to 2 weeks postpartum; individuals younger than 19 years of age receiving long-term aspirin therapy; American Indians or Alaskan natives; morbidly obese individuals with a body mass index (BMI) of 40 or greater; and residents of any age in nursing homes or other long-term care facilities.

CDC, ACIP, and AAP also state that empiric antiviral treatment can be considered in previously healthy, symptomatic individuals with suspected or confirmed seasonal influenza who are not known to be at increased risk of developing severe or complicated illness if such treatment can be initiated within 48 hours of illness onset. Although these individuals typically do not require treatment, early empiric antiviral treatment might provide some benefit (e.g., shortened duration of illness). The use of antiviral treatment in such individuals should be based on clinical judgment and is not necessary in those who are already beginning to recover. In areas with limited availability of antiviral agents, local public health authorities might provide additional guidance about prioritizing use of antivirals within groups at higher risk for complications.

When treatment of seasonal influenza is indicated, an appropriate antiviral agent should be initiated as soon as possible after illness onset (ideally within 48 hours), and should not be delayed while waiting for laboratory confirmation. The manufacturer states that oseltamivir should be used for the treatment of influenza only in patients who have been symptomatic for no more than 2 days since efficacy of the drug has not been established in those whose symptoms have been present for more than 48 hours. However, although clinical benefit is greatest when oseltamivir is initiated within 48 hours of onset of influenza symptoms, there is some evidence from observational studies of hospitalized patients that antiviral treatment may still be beneficial when initiated up to 4 or 5 days after illness onset. Therefore, CDC, ACIP, and AAP recommend that antiviral treatment be initiated in all patients with severe, complicated, or progressive illness attributable to influenza and all hospitalized patients and patients at increased risk of influenza complications (either hospitalized or outpatient) who have suspected or confirmed influenza, even if it has been more than 48 hours after illness onset. Decisions regarding use of empiric antiviral treatment in outpatients, especially high-risk patients, should be based on disease severity and progression, age, underlying medical conditions, likelihood of influenza, and time since onset of symptoms. If empiric antiviral treatment is considered warranted in previously healthy, symptomatic outpatients not considered at increased risk of influenza complications, such treatment should be initiated within 48 hours after illness onset, but some experts state treatment can be considered in such patients even if it has been more than 48 hours after illness onset.

An age-appropriate neuraminidase inhibitor antiviral agent (oral oseltamivir, IV peramivir, inhaled zanamivir) should be used when treatment of suspected or confirmed acute, uncomplicated influenza is indicated in outpatients. Oseltamivir usually is the preferred neuraminidase inhibitor in hospitalized patients and patients with severe or complicated influenza because of the lack of data regarding use of IV peramivir or inhaled zanamivir in such patients. Although controlled clinical trials evaluating oseltamivir for the treatment of influenza generally only included patients with acute, uncomplicated influenza illness, observational studies indicate that oseltamivir reduces severe clinical outcomes in patients hospitalized with influenza. Limited data suggest that oral oseltamivir usually is well absorbed in critically ill influenza patients, including patients in intensive care units and those requiring continuous renal replacement therapy and/or extracorporeal membrane oxygenation, but there have been rare reports of suspected decreased oral absorption of the drug in patients with decreased gastric motility or GI bleeding. For the treatment of hospitalized patients with severe influenza who cannot tolerate or absorb oral oseltamivir (e.g., because of suspected or known gastric stasis, malabsorption, or GI bleeding), CDC states that use of IV peramivir or investigational IV zanamivir may be considered. Use of investigational IV zanamivir also should be considered for treatment of severe influenza caused by oseltamivir-resistant strains. Oseltamivir is the preferred antiviral agent for treatment of suspected or confirmed influenza in pregnant women.(See Pregnancy under Cautions: Pregnancy, Fertility, and Lactation.)

Viral surveillance data available from local and state health departments and CDC should be considered when selecting an antiviral for treatment of seasonal influenza. Strains of circulating influenza viruses and the antiviral susceptibility of these strains constantly evolve, and the possibility that emergence of oseltamivir-resistant influenza virus may decrease effectiveness of the drug should be considered. Although influenza A and B viruses circulating in the US during the last few years generally have been susceptible to oseltamivir (see Resistance), clinicians should consult the most recent information.

CDC issues recommendations concerning the use of antiviral agents for the treatment of influenza, and these recommendations are updated as needed during each influenza season. Information regarding influenza surveillance and updated recommendations for treatment of seasonal influenza are available from CDC at http://www.cdc.gov/flu.

Clinical Experience

Adults and Adolescents

Efficacy of oseltamivir for the treatment of seasonal influenza in adults 18 years of age or older has been established in randomized placebo-controlled studies in which the predominant influenza infection was influenza A; only a limited number of adults in studies to date have been infected with influenza B. When initiated within 40 hours of onset of symptoms in otherwise healthy adults 18-65 years of age with uncomplicated influenza, the drug has decreased the severity of influenza symptoms (i.e., nasal congestion, sore throat, cough, aches, fatigue, headache, chills/sweats) and shortened the average duration of these symptoms by about 1.3 days. When used in geriatric patients 65 years of age or older, oseltamivir has reduced the time to symptom improvement by 1 day.

Analysis of data from several studies indicated that adults who received oseltamivir for seasonal influenza had a lower incidence of respiratory complications requiring anti-infective therapy and hospitalization. Individuals who initiate therapy sooner (i.e., no later than 24 hours after symptom onset) exhibit greater benefit (e.g., a 2-day decrease in symptom duration). Oseltamivir therapy also has reduced the magnitude and duration of viral replication.

Children 1-12 Years of Age

Efficacy of oseltamivir for the treatment of seasonal influenza in children 1-12 years of age has been established in a placebo-controlled study in children infected with influenza A (67%) or influenza B (33%). When used in these children within 48 hours of symptom onset, the drug reduced influenza symptoms (i.e., cough, coryza, duration of fever) and shortened the average duration of illness by about 1.5 days. Data from this study also indicate that children who received oseltamivir had a lower incidence of newly diagnosed otitis media (a common secondary complication of influenza) than those who received placebo.

In a study in children 6-12 years of age with asthma who received oseltamivir or placebo for the treatment of acute influenza virus infection, use of oseltamivir improved pulmonary function and reduced the risk of influenza-induced asthma exacerbations. When initiated within 48 hours of symptom onset, oseltamivir shortened the duration of illness in these children by about 24 hours; however, if initiated within 24 hours of symptom onset, oseltamivir shortened the duration of illness by about 40 hours.

Immunocompromised Individuals

Although the manufacturer states that efficacy of oseltamivir for the treatment of influenza in immunocompromised patients has not been established, oseltamivir has been used to treat seasonal influenza A or B virus infections in bone marrow transplant (BMT) recipients in a prospective, uncontrolled study. This study provides some evidence that oseltamivir treatment (75 mg twice daily for 5 days) may prevent influenza complications and is not associated with any unusual adverse effects in these patients. Oseltamivir also has been used for the treatment of influenza infections in hematopoietic stem cell transplant (HSCT) recipients. Treatment with oseltamivir prevented progression to pneumonia in influenza-infected HSCT recipients in a small study.

Prevention of Seasonal Influenza A and B Virus Infections

Oseltamivir is used for prophylaxis of influenza A or B virus infections in adults, adolescents, and children 1 year of age or older.

Annual vaccination with seasonal influenza virus vaccine, as recommended by ACIP, is the primary means of preventing seasonal influenza and its severe complications. Prophylaxis with an appropriate antiviral agent active against circulating influenza strains is considered an adjunct to vaccination for the control and prevention of influenza.

Decisions regarding use of antivirals for prophylaxis of influenza should be based on the exposed person's risk for influenza complications, vaccination status, the type and duration of contact, recommendations from local or public health authorities, and clinical judgment. In general, postexposure prophylaxis should be used only if it can be initiated within 48 hours of the most recent exposure. Indiscriminate use of antivirals for prophylaxis may promote resistance or reduce availability of antiviral agents for treatment. In areas with limited availability of antiviral agents, local public health authorities might provide additional guidance about prioritizing use of antiviral prophylaxis within groups at higher risk for influenza complications. In certain situations, CDC or local public health authorities might recommend that antiviral agents be reserved for treatment and that prophylaxis be used only in certain limited situations.

When seasonal influenza viruses are circulating in the community, postexposure prophylaxis with oseltamivir or zanamivir can be considered for certain individuals, including those at high risk of developing influenza complications for whom influenza vaccine is contraindicated, unavailable, or expected to have low efficacy (e.g., immunocompromised individuals). Other possible candidates for antiviral postexposure prophylaxis include unvaccinated health care personnel, public health workers, and first responders with unprotected, close-contact exposure to a patient with confirmed, probable, or suspected influenza during the time when the patient was infectious. Antiviral prophylaxis also can be considered for controlling influenza outbreaks in nursing and long-term care facilities or other closed or semi-closed settings with large numbers of individuals at high risk for influenza complications. In individuals at high risk of influenza complications who receive influenza virus vaccine inactivated, use of prophylaxis can be considered during the 2 weeks after vaccination to provide protection until an adequate immune response develops.(See Drug Interactions: Influenza Virus Vaccines.)

Viral surveillance data available from local and state health departments and CDC should be considered when selecting an antiviral for the prophylaxis of influenza. Strains of circulating influenza viruses and the antiviral susceptibility of these strains constantly evolve, and the possibility that emergence of oseltamivir-resistant influenza virus may decrease effectiveness of the drug should be considered. Although influenza A and B viruses circulating in the US during the last few years generally have been susceptible to oseltamivir (see Resistance), clinicians should consult the most recent information.

CDC issues recommendations concerning the use of antiviral agents for prophylaxis of influenza, and these recommendations are updated as needed during each influenza season. Information regarding influenza surveillance and updated recommendations for prevention of seasonal influenza are available from CDC at http://www.cdc.gov/flu.

Clinical Experience

Adults and Adolescents

Results of community studies in healthy, unvaccinated adults indicate that oseltamivir is about 82% effective in preventing febrile, laboratory-confirmed influenza illness. Efficacy of oseltamivir in preventing naturally occurring influenza illness has been demonstrated in seasonal prophylaxis studies and in postexposure prophylaxis studies in households. The primary efficacy parameter for these studies was the incidence of laboratory-confirmed clinical influenza, which was defined as oral temperature exceeding 37.2°C with at least one respiratory symptom (cough, sore throat, nasal congestion) and at least one constitutional symptom (aches and pain, fatigue, headache, chills/sweats) all occurring within a single 24-hour period and either a positive virus isolation or a fourfold increase in virus antibody titer from baseline.

In 2 seasonal prophylaxis studies in healthy, unvaccinated adults and adolescents 13-65 years of age who received oseltamivir (75 mg once daily) or placebo for 42 days during a community outbreak, pooled analysis indicates that the incidence of laboratory-confirmed clinical influenza was 1 or 5% in those receiving oseltamivir or placebo, respectively. In a seasonal prophylaxis study in geriatric residents of skilled nursing facilities (80% vaccinated, 14% with chronic airway obstructive disorders, 43% with cardiac disorders) who received oseltamivir (75 mg once daily) or placebo for 42 days, the incidence of laboratory-confirmed clinical influenza was less than 1 or 4% of those receiving oseltamivir or placebo, respectively.

In a postexposure prophylaxis study in household contacts (13 years of age or older) of influenza-infected index cases (not treated with antivirals) who received oseltamivir (75 mg once daily) or placebo for 7 days within 2 days of onset of symptoms in the index case, the incidence of laboratory-confirmed clinical influenza was 1 or 12% of those receiving oseltamivir or placebo, respectively. In another postexposure prophylaxis study, there was evidence that oseltamivir prophylaxis effectively reduced the secondary spread of influenza within households when given to household contacts of index patients who were receiving the drug for treatment.

Children 1-12 Years of Age

Efficacy of oseltamivir in preventing naturally occurring influenza illness in children 1-12 years of age was evaluated in a randomized, open-label, postexposure prophylaxis study. In this study, oseltamivir prophylaxis was used during a documented community influenza outbreak and was given to adults and children 1 year of age or older residing in households that had an index patient with an influenza-like illness who was receiving oseltamivir for treatment. The primary efficacy parameter for this study was the incidence of laboratory-confirmed clinical influenza (defined as oral temperature 37.8°C or higher with cough and/or coryza occurring within a single 48-hour period and either a positive virus isolation or a fourfold or greater increase in virus antibody titer from baseline). In household contacts 1-12 years of age not shedding virus at baseline, the incidence of laboratory-confirmed clinical influenza was 3 or 17% in those receiving oseltamivir or placebo, respectively. The overall incidence of influenza illness in children who received oseltamivir prophylaxis was higher than that in adults and adolescents 13 years of age or older who received such prophylaxis.

Immunocompromised Individuals

Although the manufacturer states that efficacy of oseltamivir for prevention of influenza in immunocompromised patients has not been established, the drug has been used for prophylaxis of influenza in some immunocompromised individuals, including cancer patients, BMT recipients, HSCT recipients, and solid organ transplant recipients.

In a prospective, uncontrolled study, oseltamivir was used for prophylaxis of influenza in cancer patients 6.3-23.4 years of age who were immunocompromised because of current or recent chemotherapy or BMT. There were no laboratory-confirmed cases of influenza in the study participants; however, a few patients withdrew from the study because of adverse GI effects.

Safety and efficacy of oseltamivir for prevention of seasonal influenza in immunocompromised patients were evaluated in a double-blind, placebo-controlled study that included 475 immunocompromised adults, adolescents, and pediatric patients 1-12 years of age who had received solid organ transplants (liver, kidney, liver and kidney) or HSCT. The median time since solid organ transplant was 1105 days in those randomized to placebo and 1379 days in those randomized to oseltamivir prophylaxis; the median time since HSCT transplant was 424 days in those randomized to placebo and 367 days in those randomized to oseltamivir. Approximately 40% of patients had received influenza vaccine prior to study entry. The primary efficacy endpoint was the incidence of confirmed clinical influenza, defined as oral temperature exceeding 37.2°C plus cough and/or coryza (all recorded within 24 hours) plus either a positive virus culture or a fourfold increase in virus antibody titers from baseline. The incidence of confirmed clinical influenza was 3% in the placebo group and 2% in the oseltamivir group; this difference was not statistically significant. The safety profile of oseltamivir reported in these immunocompromised patients (up to 12 weeks of prophylaxis) was similar to that reported in other clinical trials evaluating oseltamivir prophylaxis.

Avian Influenza A Virus Infections

Oseltamivir is used for the treatment or prevention of infections caused by susceptible avian influenza A viruses (e.g., H5N1, H7N3, H7N7, H7N9).

Risk of Exposure and Infection

Although avian influenza A viruses usually do not infect humans, infection with these viruses has been reported following exposure to infected poultry. It can be anticipated that human cases of avian influenza A will continue to be detected in countries where these viruses circulate in wild birds, outbreaks occur in poultry, and close human contact with poultry is common (e.g., backyard flocks, markets).

Since 2003, avian influenza A (H5N1) infection in poultry or wild birds has been reported in parts of Asia, Africa, the Pacific, Eastern Europe, and the Middle East. World Health Organization (WHO) data indicate that there were 668 confirmed human cases of highly pathogenic avian influenza A (H5N1) infection (including 393 fatalities) reported in 16 countries from 2003 to October 2014. These human cases occurred in Azerbaijan, Bangladesh, Cambodia, Canada, China, Djibouti, Egypt, Indonesia, Iraq, Laos, Myanmar, Nigeria, Pakistan, Thailand, Turkey, and Vietnam.

In March 2013, a novel avian influenza A (H7N9) virus causing human infection was identified in China. By June 2013, 132 human cases had been confirmed in mainland China and Taiwan. From February 2013 to February 2014, the WHO had received reports of 355 human cases of avian influenza A (H7N9) infection (including 112 fatalities). To date, no cases have been reported in animals or humans in the US. Most reported cases of avian influenza A (H7N9) infection have involved severe respiratory illness, including pneumonia and acute respiratory distress syndrome (ARDS), and approximately 27% of identified cases have been fatal. Many of the infected individuals had close contact with poultry (chickens or ducks) and the source of infection is assumed to be infected poultry or contaminated environments. Preliminary investigations of patients and close contacts have not revealed evidence of sustained human-to-human transmission of influenza A (H7N9), but limited nonsustained human-to-human transmission of the virus could not be excluded in a few family clusters.

In addition, confirmed human cases of H7N2, H7N3, H7N7, and H9N2 avian influenza A infection and illness have been reported, including a few cases in Australia, Canada, Italy, Mexico, the Netherlands, the United Kingdom, and the US. Most of these infections occurred in association with poultry outbreaks and mainly resulted in conjunctivitis and mild upper respiratory symptoms. There was a large outbreak of avian influenza A (H7N7) in commercial poultry farms in the Netherlands in 2003 that resulted in large numbers of human cases of H7N7 infection (principally conjunctivitis and influenza-like illnesses). Human infection with avian influenza A (H10N8) also has been reported rarely in China.

Experience to date indicates that human cases of avian influenza infection are rare and that these viruses do not transmit easily from poultry to humans. Most, but not all, human cases reported to date have been linked to direct contact with infected poultry, uncooked poultry products, or surfaces contaminated with infected poultry feces or respiratory secretions. Sustained person-to-person transmission of avian influenza viruses has not been reported to date, but clustering and limited person-to-person transmission of H5N1 and H7N9 viruses has been reported. Most clusters of human infection with avian influenza A (H5N1) reported to date have included documented exposure to birds. Person-to-person transmission of H7N7 has occurred among household contacts during the outbreak of that virus that occurred in the Netherlands.

In humans, avian influenza A viruses can cause typical influenza illness (fever, cough, sore throat, muscle aches), conjunctivitis, or respiratory disease; however, severe illness can occur, especially with highly pathogenic avian influenza (H5N1) and avian influenza A (H7N9). The fatality rate in patients hospitalized with H5N1 infection has been high (exceeding 50%). In one group of patients in Vietnam with severe H5N1 infections, the median time to death was 9 days (range 6-17 days) with or without treatment.

Avian influenza A virus strains isolated during the past several years (including H5N1 and H7N9 strains causing human illness) generally have been resistant to adamantanes (amantadine, rimantadine). Most avian influenza A virus strains (e.g., H5N1, H7N7, H7N9, H9N2) have been susceptible to oseltamivir and zanamivir in vitro. However, avian influenza A (H5N1) and avian influenza A (H7N9) isolates that have reduced susceptibility or are resistant to oseltamivir in vitro have been reported. (See Spectrum and see Resistance.)

The most recent information regarding avian influenza A infections is available at the WHO website at http://www.who.int/influenza/resources/avian_influenza/en/ and the CDC website at http://www.cdc.gov/flu/avianflu/.

Travelers

CDC does not currently recommend that the general public avoid travel to any of the countries that have had poultry outbreaks or human cases of highly pathogenic avian influenza A (H5N1) or avian influenza A (H7N9). However, CDC recommends that travelers to these areas take certain precautions to reduce the risks. CDC recommends that travelers to countries where highly pathogenic avian influenza A (H5N1) is endemic or countries with known poultry outbreaks of the virus avoid direct contact with all birds (poultry such as chickens and ducks, wild birds), especially contact with sick or dead poultry. Travelers also should avoid places such as poultry farms and markets where live poultry are raised, kept, or sold and avoid contact with surfaces that might be contaminated with poultry feces or secretions. Uncooked (raw) or undercooked poultry or poultry products should not be consumed, and care should be taken when preparing these foods. Because influenza viruses are destroyed by heat, all foods from poultry that comes from these areas (including eggs and poultry blood) should be thoroughly cooked; egg yolks should not be runny or liquid and poultry meat should be cooked to a temperature of 74°C.

Additional information for travelers can be obtained at the CDC website at http://wwwnc.cdc.gov/travel/content/avian-flu-asia.aspx.

Treatment and Prevention of Avian Influenza A Infections

CDC and WHO state that oseltamivir is the drug of choice for the treatment or prophylaxis of infections caused by highly pathogenic avian influenza A (H5N1). Zanamivir is considered an alternative.

Oseltamivir also is considered the drug of choice for the treatment of infections known or presumed to be caused by avian influenza A (H7N9), especially in hospitalized patients and patients with severe or complicated illness. Because of limited data, zanamivir is not recommended for the treatment of severe avian influenza A (H7N9) infections, but may be considered in those with uncomplicated infections. Either oseltamivir or zanamivir can be used for prophylaxis in close contacts of patients with confirmed or probable avian influenza A (H7N9) infections.

Only limited data are available to date regarding treatment of human cases of avian influenza A virus infections. Data from observational studies indicate that early initiation of oseltamivir therapy is associated with a reduction in mortality in influenza A (H5N1)-infected patients. Some data indicate a survival rate of 83% when oseltamivir treatment is initiated within 2 days of symptom onset compared with a survival rate of 21% if initiated 3-8 days after symptom onset. Because this virus continues to replicate for prolonged periods of time, treatment with oseltamivir is warranted even in patients who present for care in the later stages of illness. The optimum dosage and duration of oseltamivir treatment for avian influenza A (H5N1) infections are unknown, but high doses and prolonged duration of therapy may be needed in some patients. Although some individuals with avian influenza A (H5N1) infections who were treated with oseltamivir died, it is unclear whether these deaths were related to a lack of efficacy, a delay in diagnosis and initiation of oseltamivir treatment, or the dosage regimen used.

Pandemic Influenza

Oseltamivir is used for the treatment or prevention of pandemic influenza caused by susceptible strains of influenza virus.

Influenza viruses can cause seasonal epidemics and, occasionally, pandemics during which rates of illness and death from influenza-related complications can increase dramatically worldwide. The most recent influenza pandemic occurred during 2009 and was related to a novel influenza A (H1N1) strain, influenza A (H1N1)pdm09. Influenza A strains also were involved in prior influenza pandemics occurring in 1918 (H1N1), 1957 (H2N2; originated in China), and 1968 (H3N2; originated in Hong Kong).

On June 11, 2009, the WHO declared that the first global influenza pandemic in 41 years was occurring and issued a pandemic alert regarding influenza A (H1N1)pdm09, previously referred to as the novel 2009 influenza A (H1N1) virus or swine-origin influenza A (H1N1) virus. Influenza outbreaks caused by the influenza A (H1N1)pdm09 virus were reported in several countries, including the US, beginning in March and April 2009. The virus is a triple-reassortant swine influenza virus with genes from human, swine, and avian influenza A viruses and contains a unique combination of gene segments not previously reported among human or swine influenza A in the US or elsewhere. The influenza A (H1N1)pdm09 virus is antigenically distinct from previous human influenza A (H1N1) viruses that had been in circulation since 1977, and widespread transmission of the virus occurred since most individuals had no preexisting antibody to the strain. In the US, the 2009 influenza A (H1N1)pdm09 pandemic was characterized by a substantial increase in influenza activity that peaked in late October and early November 2009 and returned to seasonal baseline levels by January 2010. During the pandemic, more than 99% of influenza viruses circulating in the US were the influenza A (H1N1)pdm09 virus; more than 60 million Americans become ill with the virus and more than 270,000 hospitalizations and 12,500 deaths were reported. In August 2010, the WHO declared that the world was in a post-pandemic period. Since that time, influenza A (H1N1)pdm09 has become a seasonal influenza virus and continues to circulate with other seasonal influenza viruses.

The spread of the highly pathogenic H5N1 strain of avian influenza A in poultry in Asia and other countries that has been occurring since 2003 may represent a future pandemic threat.(See Uses: Avian Influenza A Virus Infections.)

Dosage and Administration

Administration

Oseltamivir phosphate is administered orally without regard to meals, although administration with meals may improve GI tolerability.

Oseltamivir phosphate is commercially available as 30-, 45-, and 75-mg capsules and as a powder for oral suspension that is reconstituted to provide an oral suspension containing 6 mg of oseltamivir per mL.

Reconstituted oseltamivir phosphate oral suspension is preferred for patients who cannot swallow capsules or when lower dosage is indicated. Alternatively, if the powder for oral suspension is not available, the appropriate strength of commercially available oseltamivir capsules can be administered by opening the capsules and mixing the contents with a sweet liquid (e.g., regular or sugar-free chocolate syrup, corn syrup, caramel topping, light brown sugar dissolved in water).

If the commercially available powder for oral suspension is not available and the appropriate strength of oseltamivir capsules is not available to mix with sweetened liquids (e.g., a shortage occurs during an emergency situation), an emergency supply of oseltamivir phosphate oral suspension can be prepared extemporaneously by a pharmacist using the commercially available 75-mg capsules of the drug.(See Extemporaneous Oral Suspensions under Dosage and Administration: Administration.)

Reconstitution

The commercially available oseltamivir phosphate powder for oral suspension should be reconstituted at the time of dispensing. The bottle should be tapped to thoroughly loosen the powder and then the amount of water specified on the bottle should be added; the bottle should be shaken for 15 seconds.

The reconstituted oral suspension contains 6 mg/mL; each 12.5 mL of the suspension contains 75 mg of oseltamivir. An oral dosing device that can accurately measure the appropriate volume in mL should be provided with the reconstituted suspension. Patients and/or caregivers should be counseled on how to use the oral dosing dispenser to correctly measure and administer the appropriate dose.

The suspension should be shaken well prior to each dose.

Extemporaneous Oral Suspensions

If necessary for use during emergency situations in patients who cannot swallow capsules, an oral suspension containing 6 mg/mL can be prepared extemporaneously by a pharmacist using 75-mg capsules and simple syrup, cherry syrup vehicle (Humco), or Ora-Sweet SF.

Extemporaneous oral suspensions should be used only if the commercially available powder for oral suspension is not available. The manufacturer's information should be consulted for specific directions on how to prepare extemporaneous oral suspensions of the drug.

Dosage

Dosage of oseltamivir phosphate is expressed in terms of oseltamivir.

Treatment of Seasonal Influenza A and B Virus Infections

When indicated for the treatment of seasonal influenza, oseltamivir should be initiated as soon as possible (preferably within 48 hours of symptom onset). Although efficacy has only been established when oseltamivir treatment is initiated no more than 2 days after onset of symptoms, there is some evidence from observational studies in hospitalized patients that antiviral treatment may still be beneficial when initiated up to 4 or 5 days after illness onset.(See Uses: Treatment of Seasonal Influenza A and B Virus Infections.)

Oseltamivir usually is given for 5 days for the treatment of seasonal influenza. However, hospitalized patients with severe infections (e.g., those with prolonged infection or those admitted into an intensive care unit) or individuals with immunosuppression may require longer than 5 days of treatment.

Adults and Adolescents 13 Years of Age or Older

For the treatment of influenza in adults (including geriatric adults) and adolescents 13 years of age and older, the recommended dosage of oseltamivir is 75 mg twice daily for 5 days.

Children 1-12 Years of Age

Dosage of oseltamivir for the treatment of influenza in children 1-12 years of age is based on weight.(See Table 1.)

Table 1. Oseltamivir Dosage for Treatment of Seasonal Influenza A and B in Children 1-12 Years of Age[1 ]
Weight (kg) Daily Dosage (mg) Daily Dosage (Volume of Reconstituted Oral Suspension Containing 6 mg/mL)
<=15 30 mg twice daily for 5 days 5 mL twice daily for 5 day
15.1-23 45 mg twice daily for 5 days 7.5 mL twice daily for 5 day
23.1-40 60 mg twice daily for 5 days 10 mL twice daily for 5 day
>=40.1 75 mg twice daily for 5 days 12.5 mL twice daily for 5 day

Infants Younger than 1 Year of Age

For the treatment of influenza in infants 2 weeks to less than 1 year of age, the manufacturer recommends that oseltamivir be given in a dosage of 3 mg/kg twice daily for 5 days.

For the treatment of influenza in neonates and infants younger than 1 year of age, the American Academy of Pediatrics (AAP) recommends that oseltamivir be given in a dosage of 3.5 mg/kg twice daily for 5 days in infants 9 through 11 months of age and 3 mg/kg twice daily for 5 days in full-term neonates and infants through 8 months of age. Although safety and efficacy have not been established in neonates younger than 2 weeks of age(see Cautions: Pediatric Precautions), AAP states that, because of the known safety profile of the drug, oseltamivir can be used for the treatment of influenza in neonates from birth if indicated.

Weight-based oseltamivir dosage recommended for full-term infants may be excessive in preterm neonates since clearance of the drug is slower in those with immature renal function. Limited data suggest that, if oseltamivir is considered necessary for treatment of influenza in preterm neonates, dosage should be based on postmenstrual age (i.e., gestational age plus chronological age). AAP and US Centers for Disease Control and Prevention (CDC) recommend an oseltamivir dosage of 1 mg/kg twice daily in preterm neonates with postmenstrual age less than 38 weeks, 1.5 mg/kg twice daily in those with postmenstrual age of 38 through 40 weeks, and 3 mg/kg twice daily in those with postmenstrual age exceeding 40 weeks. For treatment of influenza in extremely premature neonates (postmenstrual age less than 28 weeks), a pediatric infectious disease expert should be consulted.

Prevention of Seasonal Influenza A and B Virus Infections

When indicated for prophylaxis of seasonal influenza, oseltamivir should be initiated within 2 days of exposure. Protection lasts as long as oseltamivir therapy is continued. CDC recommends that antiviral prophylaxis be continued for 7 days after the last known exposure. For prophylaxis of influenza when an outbreak is occurring in a long-term care facility (e.g., nursing home) or hospital, CDC recommends that antiviral prophylaxis be continued for a minimum of 2 weeks and up to 7 days after the last known case of influenza is identified.

Safety and efficacy of oseltamivir prophylaxis was demonstrated for up to 6 weeks in immunocompetent individuals; safety of oseltamivir prophylaxis was demonstrated for up to 12 weeks in immunocompromised individuals.

Adults and Adolescents 13 Years of Age or Older

For prophylaxis of influenza in adults (including geriatric adults) and adolescents 13 years of age or older following close contact with an infected individual or during community outbreaks, the recommended dosage of oseltamivir is 75 mg once daily for at least 10 days.

Children 1-12 Years of Age

Dosage of oseltamivir for prophylaxis of influenza in children 1-12 years of age following close contact with an infected individual or during community outbreaks is based on weight.(See Table 2.)

Table 2. Oseltamivir Dosage for Prevention of Seasonal Influenza A and B in Children 1-12 Years of Age[1 ]
Weight (kg) Daily Dosage (mg) Daily Dosage (Volume of Reconstituted Oral Suspension Containing 6 mg/mL)
<=15 30 mg once daily for 10 days 5 mL once daily for 10 days
15.1-23 45 mg once daily for 10 days 7.5 mL once daily for 10 days
23.1-40 60 mg once daily for 10 days 10 mL once daily for 10 days
>=40.1 75 mg once daily for 10 days 12.5 mL once daily for 10 days

Infants Younger than 1 Year of Age

Although safety and efficacy have not been established for prophylaxis of influenza in infants younger than 1 year of age(see Cautions: Pediatric Precautions), CDC and the US Public Health Service Advisory Committee on Immunization Practices (ACIP) state that infants 3 months to less than 1 year of age can receive oseltamivir in a dosage of 3 mg/kg once daily for 10 days if considered necessary for prevention of influenza. For prophylaxis of influenza, AAP recommends a dosage of 3.5 mg/kg once daily for 10 days in infants 9 through 11 months of age and 3 mg/kg once daily for 10 days in infants 3 through 8 months of age.

Because of limited safety and efficacy data, CDC, ACIP, and AAP state that oseltamivir should not be used for prophylaxis of influenza in full-term or preterm infants younger than 3 months of age unless the situation is judged critical.

Avian Influenza A Virus Infections

Treatment

Only limited data are available to date regarding treatment of infections caused by avian influenza A (H1N1) or avian influenza A (H7N9), and the optimum dosage and duration of oseltamivir for treatment of these infections, especially severe or complicated infections, are unknown.

Some clinicians suggest that the twice-daily oseltamivir dosage usually recommended for the treatment of seasonal influenza A and B virus infection can be used for the treatment of avian influenza A virus infections in adults and pediatric patients.(See Treatment of Seasonal Influenza A and B Virus Infections under Dosage and Administration: Dosage.) Although some experts have suggested that severely ill hospitalized patients or immunocompromised patients may benefit from treatment with a higher oseltamivir dosage (i.e., 150 mg twice daily in adults with normal renal function), oral oseltamivir is adequately absorbed in critically ill patients and limited data from those with severe influenza, including some with avian influenza A (H1N1) infection, suggest that higher dosage may not provide additional clinical benefit. Although 5 days of treatment may be adequate for uncomplicated illness, a longer duration of treatment (i.e., 7-10 days) should be considered in severely ill hospitalized patients and may be necessary in immunosuppressed individuals.

Treatment should be initiated as early as possible and may be most beneficial if initiated within 2 days of symptom onset. However, because the viruses continue to replicate for prolonged periods of time, treatment with oseltamivir is warranted even if initiated more than 48 hours after onset of illness or in patients who present for care in the later stages of illness.

Prevention

If oseltamivir is used for prophylaxis of highly pathogenic avian influenza A (H5N1) infection in close contacts, CDC and WHO state that the once-daily oseltamivir dosage usually recommended for prophylaxis of seasonal influenza A and B virus infections can be used in adults and pediatric patients.(See Prevention of Seasonal Influenza A and B Virus Infections under Dosage and Administration: Dosage.) Prophylaxis should be continued for 7-10 days after the last known exposure.

If oseltamivir is used for prophylaxis of avian influenza virus A (H7N9) infection in close contacts, CDC recommends that the twice-daily oseltamivir dosage usually recommended for treatment of seasonal influenza A and B virus infections be given for 5-10 days.(See Treatment of Seasonal Influenza A and B Virus Infections under Dosage and Administration: Dosage.)

Oseltamivir has been given in a dosage of 75 mg daily for prophylaxis in exposed individuals during an outbreak of avian influenza A (H7N7).

Pandemic Influenza

Oseltamivir dosage usually recommended for the treatment or prophylaxis of seasonal influenza A or B infections is considered the minimum dosage required for the treatment or prophylaxis of influenza in a pandemic situation.(See Treatment of Seasonal Influenza A and B Virus Infections and see Prevention of Seasonal Influenza A and B Virus Infections under Dosage and Administration: Dosage.)

Dosage in Renal and Hepatic Impairment

Renal Impairment

Dosage of oseltamivir for the treatment or prevention of influenza should be adjusted in adults with creatinine clearance of 10-60 mL/minute and in those with end-stage renal disease (ESRD; creatinine clearance 10 mL/minute or less) undergoing hemodialysis or continuous peritoneal dialysis. (See Table 1 and Table 2.)

Oseltamivir is not recommended in adults with ESRD who are not undergoing dialysis.

Although dosage recommendations are not available for pediatric patients with renal impairment, CDC states that oseltamivir dosage recommendations for adults with renal impairment may be useful for treatment or prevention of influenza in children with renal impairment who weigh more than 40 kg.

Table 1. Oseltamivir Dosage for Treatment of Influenza in Adults with Renal Impairment[1 ][137 ]
Creatinine Clearance (mL/minute) Dosage
>30 to 60 30 mg twice daily for 5 days
>10 to 30 30 mg once daily for 5 days
<=10 (ESRD receiving hemodialysis) 30 mg given immediately after each hemodialysis cycle for <=5 days
<=10 (ESRD receiving continuous peritoneal dialysis) Single 30-mg dose given immediately after a dialysis exchange

Dosage assumes 3 hemodialysis sessions in the 5-day period.[1 ][137 ] If influenza symptoms developed during the 48 hours between hemodialysis sessions, give initial oseltamivir dose immediately and give the posthemodialysis dose regardless of when initial dose was given.[1 ][137 ]

Data derived from studies in patients undergoing continuous ambulatory peritoneal dialysis (CAPD).[1 ][137 ]

Table 2. Oseltamivir Dosage for Prevention of Influenza in Adults with Renal Impairment[1 ][137 ]
Creatinine Clearance (mL/minute) Dosage
>30 to 60 30 mg once daily for >=10 days
>10 to 30 30 mg once every other day for >=10 days
<=10 (ESRD receiving hemodialysis) 30 mg given immediately after alternate hemodialysis cycles
<=10 (ESRD receiving continuous peritoneal dialysis) 30 mg given once a week immediately following dialysis exchange

An initial dose may be given prior to start of hemodialysis.[1 ][137 ]

Data derived from studies in patients undergoing CAPD.[1 ][137 ]

Hepatic Impairment

Dosage adjustment is not needed in patients with mild to moderate hepatic impairment (Child-Pugh score 9 or less). The safety and pharmacokinetics of the drug have not been evaluated in those with severe hepatic impairment.

Cautions

Oseltamivir generally is well tolerated. Adverse effects occurring in 1% or more of adults and at an incidence greater than that with placebo include GI effects (nausea, vomiting, diarrhea, abdominal pain), headache, bronchitis, insomnia, and vertigo. In one study in frail older individuals residing in residential homes or sheltered accommodations, the incidence of adverse effects reported in those receiving oseltamivir was similar to that reported in those receiving placebo.

Safety data from dose-ranging studies indicate that a 5-day course of oseltamivir 150 mg twice daily or a 6-week course of oseltamivir 75 mg twice daily are tolerated as well as the usual recommended dosage for treatment or prophylaxis of influenza.

Adverse effects occurring in 1% or more of children receiving oseltamivir for the treatment of influenza include vomiting, abdominal pain, epistaxis, otic disorder, and conjunctivitis. GI effects, especially vomiting, were the most frequently reported adverse effects in children receiving the drug for prophylaxis of influenza.

Dermatologic and Hypersensitivity Reactions

Anaphylaxis and serious dermatologic reactions (toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme) have been reported in patients receiving oseltamivir, including pediatric patients.

Rash, swelling of the face or tongue, allergy, dermatitis, eczema, or urticaria has been reported during postmarketing surveillance.

Nervous System Effects

Headache has occurred in about 2% of adults receiving oseltamivir for treatment of influenza and in about 18% of adults receiving the drug for prophylaxis of influenza. Dizziness, insomnia, vertigo, or fatigue has occurred in up to 2, 1, 1, or 8%, respectively, of adults receiving oseltamivir in clinical studies for the treatment or prevention of influenza. Seizure or confusion has been reported during postmarketing surveillance.

Neuropsychiatric Events

Adverse neurologic and/or psychiatric effects have been reported in patients receiving oseltamivir (principally children in Japan). The contribution of oseltamivir to these events has not been established.

Adverse neuropsychiatric events (e.g., self-injury, delirium, hallucinations, confusion, abnormal behavior, seizures), which occasionally were fatal, have been reported in patients receiving oseltamivir. Cases generally had an abrupt onset and rapid resolution.

Postmarketing reports of self-injury and delirium principally have involved children in Japan. The contribution of oseltamivir to these events has not been established.(See Cautions: Pediatric Precautions.)

Influenza itself can be associated with a variety of neurologic and behavioral symptoms (e.g., hallucinations, delirium, abnormal behavior) and fatalities can occur. Although such events may occur in the setting of encephalitis or encephalopathy, they can occur without obvious severe disease.

Respiratory Effects

Bronchitis or cough has been reported in up to 2 or 5%, respectively, of adults receiving oseltamivir in clinical studies. Pneumonia has occurred in less than 1% of adults receiving oseltamivir. Otitis media, asthma, or epistaxis has occurred in up to 9, 3, or 3% respectively, of oseltamivir-treated pediatric patients. Pneumonia, ear disorder, sinusitis, bronchitis, or tympanic membrane disorder has been reported in less than 2% of pediatric patients receiving oseltamivir for the treatment of influenza.

GI Effects

Nausea, with or without vomiting, has been reported in up to 10% of adults or 15% of children receiving oseltamivir and has resulted in discontinuance in less than 1% of adults. Nausea usually occurs after the initial dose and resolves within 1-2 days; administration of the drug with food improves GI tolerance. Diarrhea or abdominal pain has occurred in up to 7 or 2%, respectively, of adults and in 10 or 5%, respectively, of pediatric patients receiving oseltamivir in clinical studies.

Pseudomembranous colitis has been reported rarely in oseltamivir-treated adults.

Other Adverse Effects

Hepatitis or abnormal liver function test values have been reported during postmarketing surveillance.

Unstable angina, anemia, fracture (humerus), pyrexia, or peritonsillar abscess has been reported in less than 1% of oseltamivir-treated adults.

Conjunctivitis or lymphadenopathy has occurred in 1% of oseltamivir-treated children.

Arrhythmia, hypothermia, or metabolic events (e.g., deterioration in diabetes control) has been reported during postmarketing surveillance.

Precautions and Contraindications

Oseltamivir is contraindicated in patients with known hypersensitivity to the drug or any ingredient in the formulation. If an allergic reaction occurs or is suspected, oseltamivir should be discontinued and appropriate treatment initiated.

Because there have been postmarketing reports of neuropsychiatric events (e.g., self-injury, delirium) in influenza patients receiving oseltamivir (see Neuropsychiatric Events under Cautions: Nervous System Effects), patients with influenza (especially children) should be closely monitored for signs of abnormal behavior during oseltamivir treatment. Patients and/or their caregivers should be instructed to immediately contact a health-care professional if there are any signs of unusual behavior during oseltamivir treatment. If neuropsychiatric symptoms develop, the risks and benefits of continued therapy with oseltamivir should be evaluated.

Efficacy of oseltamivir has not been established in patients with chronic cardiac disease and/or underlying pulmonary disease; however, no difference in incidence of complications between drug and placebo has been observed in these populations. Safety and efficacy have not been established in those with any medical condition severe or unstable enough to require inpatient care. In addition, efficacy of oseltamivir treatment of influenza has not been established in patients whose symptoms have been present for longer than 48 hours.

Although efficacy of oseltamivir for treatment or prevention of influenza in immunocompromised patients has not been established, safety of oseltamivir prophylaxis has been demonstrated for up to 12 weeks in immunocompromised patients. The drug has been used for treatment or prevention of influenza in some immunocompromised individuals, including bone marrow transplant (BMT) recipients, hematopoietic stem cell transplant (HSCT) recipients, solid organ transplant recipients, and chemotherapy patients.(See Uses.)

There is no evidence that oseltamivir is effective for illness caused by any organisms other than influenza A or B. Serious bacterial infections may begin with influenza-like symptoms or may coexist with or occur as complications of influenza. There is no evidence that oseltamivir prevents such complications.

Oseltamivir is not a substitute for annual vaccination with a seasonal influenza vaccine (influenza virus vaccine inactivated, influenza vaccine live intranasal, influenza vaccine recombinant). Although antiviral agents used for treatment or prevention of influenza, including oseltamivir, may be used concomitantly with or at any time before or after influenza virus vaccine inactivated, these antivirals may inhibit the vaccine virus contained in influenza vaccine live intranasal.(See Influenza Virus Vaccines under Drug Interactions.)

When the commercially available oral suspension containing 6 mg/mL is used, each 75-mg dose of oseltamivir contains 2 g of sorbitol. This amount of sorbitol exceeds the maximum daily limit of sorbitol for individuals with hereditary fructose intolerance and may result in dyspepsia and diarrhea.

Safety of oseltamivir has not been systematically evaluated in patients with severe hepatic impairment.

Dosage adjustments are recommended when oseltamivir is used in adults with creatinine clearance of 10-60 mL/minute or adults with end-stage renal disease (ESRD; creatinine clearance 10 mL/minute or less) undergoing hemodialysis or continuous peritoneal dialysis. Oseltamivir is not recommended in adults with ESRD who are not undergoing dialysis.(See Renal Impairment under Dosage and Administration: Dosage in Renal and Hepatic Impairment.)

Pediatric Precautions

Safety and efficacy of oseltamivir for the treatment of influenza have not been established in infants younger than 2 weeks of age.

Safety and efficacy of oseltamivir for prophylaxis of influenza have not been established in infants younger than 1 year of age.

When used for the treatment of influenza, the safety profile of oseltamivir observed in neonates and infants 2 weeks to less than 1 year of age has been consistent with the safety profile for the drug established in adults and pediatric patients older than 1 year of age. Data from open-label studies evaluating oseltamivir for treatment of influenza in infants 2 weeks to less than 1 year of age (including some premature infants with a postconceptional age of at least 36 weeks) indicated that the safety profile was similar across this young age range, and that vomiting, diarrhea, and diaper rash were the most frequently reported adverse effects.

Young children, especially those younger than 2 years of age, are at increased risk of influenza infection, hospitalization, and complications. During the 2009 influenza A (H1N1)pdm09 pandemic, the US Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) that temporarily allowed use of oseltamivir for emergency treatment or prevention of these infections in infants younger than 1 year of age. Although the EUA expired in June 2010, the American Academy of Pediatrics (AAP) states that, because of the known safety profile of the drug, use of oseltamivir for the treatment of influenza in full-term or preterm neonates from birth or for prevention of influenza in infants 3 months of age or older is appropriate if indicated. However, because of limited safety and efficacy data, the US Public Health Service Advisory Committee on Immunization Practices (ACIP) and AAP state that oseltamivir is not recommended for prevention of influenza in infants younger than 3 months of age unless the situation is judged critical. (See Dosage and Administration: Dosage.)

Unusual adverse neurologic and/or psychiatric effects, including self-injury, delirium, hallucinations, mental confusion, abnormal behavior, seizures, and encephalitis, have been reported in children 16 years of age and younger receiving oseltamivir. These effects have been reported principally in children in Japan. There also have been reports of deaths (12 as of November 2005) in Japanese children receiving oseltamivir. These deaths were attributed to sudden death (4), cardiorespiratory arrest (4), suicide (1), pneumonia (1), asphyxiation (1), and acute pancreatitis with cardiopulmonary arrest (1). In many cases, a relationship to oseltamivir was difficult to assess because of concomitantly used drugs, comorbid conditions, and/or lack of adequate detail in reports.

There is no evidence that Japanese patients have a pharmacodynamic predisposition for adverse effects since they do not metabolize oseltamivir differently or achieve higher drug concentrations compared with US patients. However, unusual neurologic manifestations of influenza (influenza-associated encephalitis or encephalopathy) have been documented in Japan, and Japanese pediatricians describe a syndrome of rapid onset of fever accompanied by seizures and altered consciousness that progresses to coma within a few days of flu symptom onset. This syndrome has frequently resulted in death or substantial neurologic sequelae. Currently available information suggests that increased reports of neuropsychiatric events in Japanese children receiving oseltamivir are most likely related to an increased awareness of influenza-associated encephalopathy, increased access to the drug in the Japanese population, and a coincident period of intensive monitoring for potential adverse effects. Therefore, based on available information, the FDA states that it is unable to conclude that a causal relationship exists between oseltamivir and reported pediatric deaths.

Geriatric Precautions

Safety of oseltamivir for the treatment of influenza in geriatric individuals has been established in clinical studies. In addition, safety and efficacy were demonstrated in geriatric individuals (many with cardiac and/or respiratory disease) residing in nursing homes who received oseltamivir for up to 42 days for the prevention of influenza.

When the total number of patients studied in oseltamivir clinical trials is considered, 19% of those in studies evaluating the drug for the treatment of influenza were 65 years of age or older (7% were 75 years of age or older) and 25% of those in studies evaluating the drug for the prevention of influenza were 65 years or older (18% were 75 years of age or older). Although no overall differences in efficacy or safety were observed between geriatric and younger adults, and other clinical experience revealed no evidence of age-related differences, the possibility that some older patients may exhibit increased sensitivity to the drug cannot be ruled out.

Oseltamivir dosage adjustments based solely on age are not necessary for geriatric patients older than 65 years of age.

Mutagenicity and Carcinogenicity

Oseltamivir was not mutagenic in the Ames microbial test, the human lymphocyte chromosome assay, or the mouse micronucleus test; oseltamivir was mutagenic in the Syrian hamster embryo cell transformation assay. Oseltamivir carboxylate was not mutagenic in the Ames microbial test, the L5178Y mouse lymphoma assay, or the Syrian hamster embryo cell transformation assay.

Oseltamivir was not carcinogenic in studies in rats or mice.

Pregnancy, Fertility, and Lactation

Pregnancy

There are no adequate and well-controlled studies using oseltamivir in pregnant women, and the drug should be used during pregnancy only when potential benefits outweigh possible risks to the fetus.

Pregnant women are at increased risk for severe complications from influenza, which may lead to adverse pregnancy and/or fetal outcomes including maternal death, still births, birth defects, preterm delivery, low birthweight, and small size for gestational age.

The US Centers for Disease Control and Prevention (CDC) and ACIP state that pregnancy is not considered a contraindication to use of oseltamivir for treatment or prevention of influenza and that oseltamivir regimens recommended for such infections in pregnant women are the same as those for other adults.

CDC and ACIP state that oseltamivir may be preferred when a neuraminidase inhibitor is indicated for the treatment of suspected or confirmed influenza in women who are pregnant or up to 2 weeks postpartum, but the drug of choice for prophylaxis of influenza is less clear. Zanamivir may be preferred by some clinicians for prophylaxis in pregnant women because of its limited systemic absorption; however, respiratory complications that may be associated with zanamivir because of its route of administration should be considered, especially in women at risk for respiratory problems.

Although data are insufficient to make a definitive assessment of the risk, prospective and retrospective observational studies that included approximately 1500 women exposed to oseltamivir during pregnancy (including approximately 400 women exposed during the first trimester) suggest that the observed rate of congenital malformations following oseltamivir exposures during any trimester was not greater than that reported in the general population. In animal studies, there was a dose-dependent increase in the incidence rates of a variety of minor skeletal abnormalities and variants in offspring of rats and rabbits exposed to maternally toxic dosages (approximately 100 and 50 times the human exposure, respectively), but the individual incidence rate of each skeletal abnormality or variant remained within the background rates of occurrence in the species studied.

Fertility

No effects on fertility, mating performance, or early embryonic development were observed in rats given oseltamivir at doses up to 100 times the human systemic exposure of oseltamivir carboxylate.

Lactation

Limited data indicate that oseltamivir and its active metabolite, oseltamivir carboxylate, are distributed into human milk in low concentrations that are considered unlikely to cause toxicity in nursing infants. Oseltamivir should be used with caution in nursing women.

Drug Interactions

Drugs Affected or Metabolized by Hepatic Microsomal Enzymes

Oseltamivir phosphate and its active metabolite, oseltamivir carboxylate, are not metabolized by and do not inhibit cytochrome P-450 (CYP) isoenzymes; interactions with drugs that are substrates for or inhibitors of these enzymes are unlikely.

Drugs Eliminated by Renal Excretion

Concomitant use of oseltamivir with other drugs eliminated by renal tubular secretion (e.g., probenecid) may result in pharmacokinetic interactions; however, clinically important interactions are unlikely.

Acetaminophen

Oseltamivir does not affect the pharmacokinetics of acetaminophen.

Amoxicillin

Pharmacokinetic interactions are unlikely if oseltamivir is used concomitantly with amoxicillin.

Antacids

Concomitant use of oseltamivir and antacids containing magnesium hydroxide, aluminum hydroxide, or calcium carbonate does not have a clinically important effect on the pharmacokinetics of the antiviral agent.

Anticoagulants

Concomitant use of oseltamivir and warfarin has not revealed any pharmacokinetic interactions between the drugs.

Aspirin

Pharmacokinetic interactions are unlikely if oseltamivir is used concomitantly with aspirin.

Cimetidine

Concomitant use of cimetidine does not affect plasma concentrations of oseltamivir or oseltamivir carboxylate.

Influenza Virus Vaccines

Influenza virus vaccine inactivated (IIV) may be administered concomitantly with or at any time before or after oseltamivir. Although drug interaction studies have not been conducted to evaluate the immune response to IIV in patients receiving oseltamivir, oseltamivir therapy does not appear to impair normal humoral antibody response to infection in patients with naturally or experimentally acquired influenza.

Safety and efficacy of concomitant use of oseltamivir and influenza vaccine live intranasal (LAIV) have not been evaluated. Because influenza antiviral agents, including oseltamivir, reduce replication of influenza viruses, these antivirals potentially could decrease the immune response to the live intranasal vaccine. LAIV should not be administered until at least 48 hours after oseltamivir is discontinued and oseltamivir should not be administered until at least 2 weeks after administration of LAIV. If oseltamivir is administered concomitantly with LAIV, revaccination should be considered if appropriate. The US Public Health Service Advisory Committee on Immunization Practices (ACIP) recommends revaccination with LAIV if an influenza antiviral agent was given within 2 weeks after administration of the vaccine. Alternatively, individuals who received oseltamivir 2 days before to 14 days after LAIV may be revaccinated with either IIV or influenza vaccine recombinant (RIV).

Peramivir

There was no evidence of drug interactions when IV peramivir was used concomitantly with oral oseltamivir.

Probenecid

Concomitant use of oseltamivir with probenecid may result in increased systemic exposure to oseltamivir carboxylate because of decreased renal tubular secretion. However, this pharmacokinetic interaction is not expected to be clinically important and the usual oseltamivir dosage can be used in patients receiving probenecid.

Pharmacokinetics

Absorption

Oseltamivir phosphate is readily absorbed following oral administration and then extensively converted by hepatic esterases to the active metabolite, oseltamivir carboxylate. Following oral administration of oseltamivir 75 mg twice daily for multiple days in healthy adults, peak plasma concentrations of oseltamivir or oseltamivir carboxylate were 65 or 348 ng/mL, respectively. Following oral administration of oseltamivir phosphate, oseltamivir carboxylate is detectable in plasma within 30 minutes; peak concentrations of oseltamivir carboxylate are attained within 3-4 hours. The absolute bioavailability of oseltamivir carboxylate is 80% following oral administration of oseltamivir phosphate. Plasma concentrations of oseltamivir carboxylate are proportional to dosage up to an oseltamivir dosage of 500 mg twice daily.

Administration of oseltamivir phosphate with food has no effect on peak plasma concentrations or area under the plasma concentration-time curve (AUC) of oseltamivir carboxylate.

Pharmacokinetic data indicate that a dosage of 3 mg/kg twice daily in neonates and infants 2 weeks to less than 1 year of age result in oseltamivir concentrations similar to or higher than those reported in adults and children 1 year of age or older receiving usual dosage of the drug.

Following oral administration of oseltamivir phosphate in geriatric individuals (65-78 years of age), systemic exposure to oseltamivir carboxylate at steady-state is about 25-35% higher compared with younger adults receiving the same dosage.

In individuals with varying degrees of renal impairment receiving 100 mg of oseltamivir phosphate twice daily for 5 days, oseltamivir carboxylate exposure increases with declining renal function. In patients undergoing continuous ambulatory peritoneal dialysis (CAPD), peak concentrations of oseltamivir carboxylate following a single 30-mg dose of oseltamivir or once-weekly oseltamivir was approximately threefold higher than peak concentrations in patients with normal renal function receiving 75 mg twice daily.

Limited data in patients with cirrhosis indicate that hepatic carboxylesterase activity in patients with moderate hepatic impairment is sufficient to metabolize oseltamivir phosphate to oseltamivir carboxylate. Systemic exposure to oseltamivir carboxylate in individuals with mild or moderate hepatic impairment is comparable to that in individuals without hepatic impairment.

Distribution

Following oral administration of oseltamivir phosphate, oseltamivir carboxylate is distributed throughout the body, including into the upper and lower respiratory tract.

It is not known whether oseltamivir or oseltamivir carboxylate crosses the placenta in humans; placental transfer of oseltamivir carboxylate has been demonstrated in rats and rabbits.

Oseltamivir and oseltamivir carboxylate are distributed into milk in rats; it is not known whether oseltamivir and oseltamivir carboxylate are distributed into human milk.

Oseltamivir phosphate is 42% bound to plasma proteins; oseltamivir carboxylate is 3% bound to plasma proteins.

Elimination

Oseltamivir phosphate is extensively (greater than 90%) converted to oseltamivir carboxylate, principally by hepatic esterases. Oseltamivir carboxylate is not further metabolized.

Oseltamivir phosphate and oseltamivir carboxylate are not metabolized by cytochrome P-450 (CYP) enzymes.

Oseltamivir carboxylate is eliminated (greater than 99%) by renal excretion; less than 20% of an oral radiolabeled dose of oseltamivir phosphate is eliminated in feces.

The plasma half-life of oseltamivir phosphate is 1-3 hours; half-life of oseltamivir carboxylate is 6-10 hours. Half-lives observed in geriatric individuals are similar to those observed in younger adults.

Clearance of both oseltamivir phosphate and oseltamivir carboxylate is increased in younger pediatric patients compared with adults. Total clearance of oseltamivir carboxylate decreases linearly with increasing age (up to 12 years of age); pharmacokinetics in those 12 years of age or older is similar to that in adults.

Renal clearance of oseltamivir carboxylate decreases linearly with creatinine clearance.

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