Oseltamivir phosphate is a prodrug of oseltamivir carboxylate, a sialic acid analog and neuraminidase inhibitor antiviral that is pharmacologically related to zanamivir and active against influenza A and B viruses.1, 2, 3, 4, 5, 6, 9, 64
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.1, 2, 4, 5, 15, 65, 105, 112, 116, 120 Although safety and efficacy have not been established in neonates younger than 2 weeks of age†, 1 oseltamivir also is recommended when treatment of influenza is necessary in this age group.112, 120
For the treatment of suspected or confirmed acute, uncomplicated seasonal influenza in otherwise healthy outpatients, the US Centers for Disease Control and Prevention (CDC), Infectious Diseases Society of America (IDSA), and other experts state that any age-appropriate influenza antiviral (oral oseltamivir, inhaled zanamivir, oral baloxavir marboxil, IV peramivir) can be used if not contraindicated.112, 116, 120 CDC states that early empiric antiviral treatment can be considered in outpatients with suspected influenza (e.g., influenza-like illness such as fever with either cough or sore throat) based on clinical judgement if such treatment can be initiated within 48 hours of illness onset.120
For the treatment of suspected or confirmed seasonal influenza in hospitalized patients or outpatients with severe, complicated, or progressive illness (e.g., pneumonia, exacerbation of underlying chronic medical conditions), CDC states that oseltamivir is the preferred influenza antiviral and should be initiated as soon as possible, ideally within 48 hours, without waiting for laboratory confirmation.120 Oseltamivir is the preferred influenza antiviral in hospitalized patients or outpatients with severe, complicated, or progressive influenza because of the lack of data regarding use of other influenza antivirals in such patients.120 Although controlled clinical trials evaluating oseltamivir for the treatment of influenza generally only included patients with acute, uncomplicated influenza illness,1, 161 observational studies indicate that oseltamivir reduces severe clinical outcomes in patients hospitalized with influenza.144 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.161 In patients with severe influenza who cannot tolerate or absorb oseltamivir administered orally or enterically (e.g., because of suspected or known gastric stasis, malabsorption, or GI bleeding), CDC states that use of IV peramivir may be considered.120
CDC 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).105, 112, 120 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 (regardless of vaccination status).105, 112, 116, 120 Individuals at increased risk for influenza-related complications include children younger than 2 years of a 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.112, 116, 120
When treatment of seasonal influenza is indicated, an appropriate antiviral should be initiated as soon as possible after illness onset (ideally within 48 hours), and should not be delayed while waiting for laboratory confirmation.112, 120 The manufacturer states that oseltamivir should be used for the treatment of influenza only in patients who have been symptomatic for no more than 48 hours.1 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.112, 120, 144, 185 Therefore, CDC 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.112, 120 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.112, 120
Influenza and coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have overlapping signs and symptoms and coinfection with influenza A or B viruses and SARS-CoV-2 can occur and should be considered, particularly in hospitalized patients with severe respiratory disease.120 Although laboratory testing can help distinguish between influenza virus infection and SARS-CoV-2 infection, CDC recommends that empiric influenza treatment should be initiated in patients with suspected influenza who are hospitalized, have severe, complicated, or progressive illness, or are at high risk for influenza complication without waiting for results of influenza testing, SARS-CoV-2 testing, or multiplex molecular assays that detect influenza A and B viruses and SARS-CoV- 2.120
Viral surveillance data available from local and state health departments and CDC should be considered when selecting an antiviral for treatment of seasonal influenza.112, 116, 120 Strains of circulating influenza viruses and the antiviral susceptibility of these strains constantly evolve, and emergence of resistant strains may decrease effectiveness of influenza antivirals.1, 120 Although circulating influenza A and B viruses during recent years generally have been susceptible to oseltamivir,120, 195, 198, 199, 200, 201, 202 clinicians should consult the most recent information on susceptibility of circulating viruses when selecting an antiviral for the treatment of influenza.120
CDC issues recommendations concerning the use of antivirals for the treatment of influenza, and these recommendations are updated as needed during each influenza season.120 Information regarding influenza surveillance and updated recommendations for treatment of seasonal influenza are available from CDC at [Web].
Clinical Trials and Experience
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.1, 4, 5 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.1, 4, 5 When used in geriatric patients 65 years of age or older, oseltamivir has reduced the time to symptom improvement by 1 day.1
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.22, 64, 66, 67 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).5, 64 Oseltamivir therapy also has reduced the magnitude and duration of viral replication.2
Efficacy and safety of oseltamivir for the treatment of seasonal influenza in adolescents 13-17 years of age are supported by data from adequate and well-controlled trials in adults, adolescents, and younger pediatric patients and safety data in adolescents.1
Efficacy and safety of oseltamivir for the treatment of seasonal influenza in children 1-12 years of age was established in a double-blind, placebo-controlled study in children infected with influenza A (67%) or influenza B (33%).1, 15 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.1, 15 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.15
The manufacturer states that efficacy could not be established in pediatric patients with asthma.1 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.28 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.28
Infants Younger than 1 Year of Age
Efficacy and safety of oseltamivir for the treatment of seasonal influenza in infants 2 weeks to less than 1 year of age are supported by adequate and well-controlled studies in adults and older pediatric patients and 2 open-label studies in 136 pediatric patients 2 weeks to less than 1 year of age.1 In addition, data from these 2 studies indicate that plasma concentrations of oseltamivir in pediatric patient 2 weeks to less than 1 year of age are similar to or greater than plasma concentrations observed in older pediatric patients and adults.1
Although the manufacturer states that efficacy of oseltamivir for the treatment of influenza in immunocompromised patients has not been established,1 oseltamivir has been used to treat seasonal influenza A or B virus infections in bone marrow transplant (BMT) recipients† in a prospective, uncontrolled study.74 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.74 Oseltamivir also has been used for the treatment of influenza infections in hematopoietic stem cell transplant (HSCT) recipients†.101 Treatment with oseltamivir prevented progression to pneumonia in influenza-infected HSCT recipients in a small study.101
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.1, 16, 30, 105, 112, 116, 120
Annual vaccination with seasonal influenza virus vaccine, as recommended by CDC's Advisory Committee on Immunization Practices (ACIP), is the primary means of preventing seasonal influenza and its severe complications.105, 112, 116, 120, 166 Prophylaxis with an appropriate antiviral active against circulating influenza strains is considered an adjunct to vaccination for the control and prevention of influenza in certain individuals.105, 112, 116, 120, 166
Decisions regarding use of antivirals for prophylaxis of seasonal influenza should be based on the risk of influenza-related complications in the exposed individual, the type and duration of contact, recommendations from local or public health authorities, and clinical judgment.112, 120 In general, antiviral postexposure prophylaxis should be used only if it can be initiated within 48 hours of the most recent exposure.112, 116, 120
CDC and others do not recommend routine use of influenza antivirals for postexposure prophylaxis of seasonal influenza in exposed individuals; however, such prophylaxis can be considered in certain situations in exposed individuals at high risk for influenza-related complications for whom influenza vaccine is contraindicated, unavailable, or expected to have low efficacy (e.g., immunocompromised individuals).116, 120 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.112, 120 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.112, 116, 120 In individuals at high risk of influenza complications who receive influenza virus vaccine inactivated or influenza vaccine recombinant, use of prophylaxis can be considered during the 2 weeks after vaccination to provide protection until an adequate immune response develops.112, 116, 120 (See Influenza Vaccines under Drug Interactions.)
CDC issues recommendations concerning the use of antivirals for prophylaxis of influenza, and these recommendations are updated as needed during each influenza season.120 Information regarding influenza surveillance and updated recommendations for prevention of seasonal influenza are available from CDC at [Web].
Clinical Trials and Experience
Results of community studies in healthy, unvaccinated adults indicate that oseltamivir is about 82% effective in preventing febrile, laboratory-confirmed influenza illness.3 Efficacy of oseltamivir in preventing naturally occurring influenza illness has been demonstrated in seasonal prophylaxis studies and in postexposure prophylaxis studies in household contacts.1, 16, 30, 64 The efficacy end point 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.1
In 2 seasonal prophylaxis studies in healthy, unvaccinated adults 18-65 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.1 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.1, 29
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 48 hours 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.1, 16 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.30
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.1, 30 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.1, 30 The 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).1 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.1 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.30
Although the manufacturer states that efficacy of oseltamivir for prevention of influenza in immunocompromised patients has not been established,1 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.1, 75
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.75 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.75
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.1 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.1 Approximately 40% of patients had received influenza vaccine prior to study entry.1 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.1 The incidence of confirmed clinical influenza was 3% in the placebo group and 2% in the oseltamivir group; this difference was not statistically significant.1 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.1
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).46, 47, 50, 61, 68, 94, 104, 152, 169, 183, 187
Risk of Exposure and Infection
Worldwide, most avian influenza A viruses isolated in wild birds, water fowl, or poultry have been designated as low pathogenic strains; however, highly pathogenic avian influenza (HPAI) strains are occasionally detected.50 Since December 2014, HPAI viruses (H5N1, H5N2, H5N8) have been reported in wild birds, water fowl, and/or domestic poultry (commercial or backyard flocks) in the US (e.g., Arkansas, California, Idaho, Iowa, Minnesota, Missouri, Nebraska, North Dakota, Oregon, South Dakota, Utah, Washington, Wisconsin).50, 180, 184 Although CDC states that the risk of human infection with these HPAI H5 viruses is considered low in the US, human infection is possible since other closely related HPAI H5 viruses in Asia and other countries have caused sporadic cases of human respiratory illness.50, 180, 184 The HPAI (H5N1) strain reported in poultry outbreaks in the US is a new reassortant virus that is genetically different from the highly pathogenic Asian strain of influenza A (H5N1) that has caused human infections in Asia and other countries and has been associated with a high mortality rate.50, 184
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.104, 189 World Health Organization (WHO) data indicate that there were 863 confirmed human cases of highly pathogenic avian influenza A (H5N1) infection (including 456 fatalities; case fatality rate of 53%) reported in 17 countries from January 2003 to August 2021.190 These human cases occurred in Azerbaijan, Bangladesh, Cambodia, Canada, China, Djibouti, Egypt, Indonesia, Iraq, Laos, Myanmar, Nepal, Nigeria, Pakistan, Thailand, Turkey, and Vietnam.181
In March 2013, a novel avian influenza A (H7N9) virus causing human infection was identified in China.104, 183, 186, 187 By June 2013, 132 human cases had been confirmed in mainland China and Taiwan.186 From early 2013 to August 2021, WHO had received reports of 1568human cases of avian influenza A (H7N9) infection (including 616 fatalities; case fatality rate of 39%).190 To date, no cases have been reported in animals or humans in the US.50, 183, 186 Most reported cases of avian influenza A (H7N9) infection have involved severe respiratory illness, including pneumonia and acute respiratory distress syndrome (ARDS).104, 169, 183, 186, 187 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.104, 183, 186 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.104, 183
In addition, confirmed human cases of H5N6, 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.61, 104, 190 Most of these infections occurred in association with poultry outbreaks and mainly resulted in conjunctivitis and mild upper respiratory symptoms.104 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).61 Human infection with avian influenza A (H10N8) also has been reported rarely in China.171
Experience to date indicates that human cases of avian influenza infection are rare and that these viruses do not transmit easily from wild or domestic birds, water fowl, or poultry to humans.35, 43, 50, 68, 104 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.43, 50, 104, 190 Sustained person-to-person transmission of avian influenza viruses has not been reported to date,50, 104, 147, 183 but clustering and limited person-to-person transmission of H5N1 and H7N9 viruses has been reported.69, 73, 104, 147, 183 Most clusters of human infection with avian influenza A (H5N1) reported to date have included documented exposure to birds.147 Person-to-person transmission of H7N7 has occurred among household contacts during the outbreak of that virus that occurred in the Netherlands.61
In humans, avian influenza A viruses can cause typical influenza illness (fever, cough, sore throat, muscle aches), conjunctivitis, or respiratory disease;46, 50, 61, 68, 104 however, severe illness can occur, especially with highly pathogenic avian influenza (H5N1) and avian influenza A (H7N9).46, 50, 63, 68, 104, 104, 183 The fatality rate in patients hospitalized with H5N1 infection has been high (exceeding 50%).63, 68, 152 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.46
Although most avian influenza A virus strains (e.g., H5N1, H7N7, H7N9, H9N2) tested have been susceptible to oseltamivir and zanamivir in vitro,27, 50, 58, 61, 104, 168, 183 avian influenza A (H5N1) and avian influenza A (H7N9) isolates with reduced susceptibility or resistance to oseltamivir in vitro have been reported.50, 68, 73, 81, 168, 169, 197 (See Spectrum and see Resistance.) Avian influenza A virus strains (including H5N1 and H7N9 strains causing human illness) generally have been resistant to adamantanes (amantadine, rimantadine).50, 68, 104, 168, 178, 183
Treatment and Prevention of Avian Influenza A Infections
Although safety and efficacy have not been established, neuraminidase inhibitors (oseltamivir, peramivir, zanamivir) have been used or are recommended for the treatment or prophylaxis of infections caused by susceptible avian influenza A viruses†.50, 68, 94, 104, 178, 179, 180
Appropriate use of a neuraminidase inhibitor antivirals is an important component of response and control measures to treat avian influenza A virus infections and help reduce the risk of additional human infections.50, 178, 179, 180
For the treatment of uncomplicated avian influenza A infections in outpatients, CDC states that oral oseltamivir, IV peramivir, or inhaled zanamivir may be used.178 For the treatment of severe, complicated, or progressive avian influenza A infections in hospitalized patients or outpatients, including infections caused by avian influenza A (H7N9), avian influenza A (H5N1), or novel avian influenza A H5 viruses, oseltamivir is considered the antiviral of choice.50, 104, 178 In those with severe avian influenza A infections who cannot tolerate or absorb oseltamivir administered orally or enterically (e.g., because of suspected or known gastric stasis, malabsorption, or GI bleeding), CDC states that use of IV peramivir may be considered.178 Because of limited data, inhaled zanamivir is not recommended for the treatment of severe avian influenza A infections in hospitalized patients or outpatients.50, 178
When antiviral prophylaxis is indicated in close contacts of individuals with confirmed or probable infection with avian influenza A viruses that have caused or potentially may cause severe disease or indicated in individuals who have been exposed to birds infected with such avian influenza A viruses, CDC recommends oral oseltamivir or inhaled zanamivir.179, 180
Information regarding treatment and prevention of avian influenza A infections is available from CDC at [Web] and WHO at [Web].
Variant Influenza Virus Infections
Oseltamivir is used for the treatment of infections cause by variant influenza viruses†.196
Influenza viruses that circulate in swine are called swine influenza viruses when isolated from swine, but are called variant influenza viruses when isolated from humans.194, 196 Human infection with influenza A (H1N1) variant (H1N1v), influenza A (H1N2) variant (H1N2v), and influenza A (H3N2) variant (H3N2v) have been detected in the US.194, 196 Limited data to date indicate that variant influenza viruses are susceptible to neuraminidase inhibitor antivirals (oseltamivir, peramivir, zanamivir).196
CDC states that management of infections caused by variant influenza viruses is similar to management of seasonal influenza virus infections.196 CDC recommends early initiation of oseltamivir for treatment of hospitalized patients, those with severe and progressive illness, and any high-risk patient with suspected or confirmed variant influenza virus infection.196 Antiviral treatment with a neuraminidase inhibitor also is recommended for outpatients with suspected influenza, including variant influenza virus infection, if the individual is considered at high risk for influenza complications.196 CDC states that antiviral treatment also can be considered for any previously healthy, symptomatic outpatient not at high risk who has confirmed or suspected variant virus infection on the basis of clinical judgment, if treatment can be initiated within 48 hours of illness onset.196
Information regarding variant influenza virus infections is available from CDC at [Web].
Oseltamivir is used for the treatment or prevention of pandemic influenza† caused by susceptible strains of influenza virus.52, 151
Influenza viruses can cause seasonal epidemics and, occasionally, pandemics during which rates of illness and death from influenza-related complications can increase dramatically worldwide.52, 166 The most recent influenza pandemic occurred during 2009 and was related to a novel influenza A (H1N1) strain, influenza A (H1N1)pdm09.52, 135, 151, 166 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).35, 43, 166
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.135 Influenza outbreaks caused by the influenza A (H1N1)pdm09 virus were reported in several countries, including the US, beginning in March and April 2009.114, 118, 119, 123, 132, 135, 151 The virus is a triple-reassortant swine influenza virus with genes from human, swine, and avian influenza A viruses and contained a unique combination of gene segments not previously reported among human or swine influenza A in the US or elsewhere.114, 124, 132, 135 The influenza A (H1N1)pdm09 virus was antigenically distinct from previous human influenza A (H1N1) viruses that had been in circulation since 1977,135 and widespread transmission of the virus occurred since most individuals had no preexisting antibody to the strain.100 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 2010.123, 135, 166 During the pandemic, more than 99% of influenza viruses circulating in the US were the influenza A (H1N1)pdm09 virus;123, 166 more than 60 million Americans become ill with the virus and more than 270,000 hospitalizations and 12,500 deaths were reported.166 After the pandemic, influenza A (H1N1)pdm09 became a seasonal influenza virus and continues to circulate with other seasonal influenza viruses.135, 195, 198, 199, 200, 201, 202
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.50, 52, 54, 55, 56, 104, 147 In addition, the novel avian influenza A (H7N9) virus that was first identified in China in March 2013 and has been causing sporadic human infections has pandemic potential.50, 104, 182, 183 (See Avian Influenza A Virus Infections under Uses.)
Information on pandemic influenza, including planning and preparedness resources if an influenza pandemic occurs, is available from CDC at [Web] and WHO at [Web].
Oseltamivir phosphate is administered orally without regard to meals, although administration with meals may improve GI tolerability.1
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.1
Reconstituted oseltamivir phosphate oral suspension is preferred for patients who cannot swallow capsules.1 Alternatively, if the powder for oral suspension is not available from the manufacturer or wholesaler, 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).1, 141
During emergency situations if the powder for oral suspension is not available and the appropriate strength of oseltamivir capsules is not available to mix with sweetened liquids, 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.1 (See Extemporaneous Oral Suspensions under Dosage and Administration.)
The commercially available oseltamivir phosphate powder for oral suspension should be reconstituted at the time of dispensing.1 The bottle should be tapped to thoroughly loosen the white powder and then the amount of water specified on the bottle should be added; the bottle should be shaken for 15 seconds.1
The reconstituted oral suspension contains 6 mg/mL;1 each 12.5 mL of the suspension contains 75 mg of oseltamivir.1 An oral dosing device that can accurately measure the appropriate volume in mL should be provided with the reconstituted suspension.1 Patients and/or caregivers should be counseled on how to use the oral dosing dispenser to correctly measure and administer the appropriate dose.1
The suspension should be shaken well prior to each dose.1
Extemporaneous Oral Suspensions
If necessary for use during emergency situations, 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 (Paddock).1
Extemporaneous oral suspensions should be used only if the commercially available powder for oral suspension and appropriate strength of commercially available oseltamivir capsules are not available from the manufacturer or wholesalers.1 The manufacturer's information should be consulted for specific directions on how to prepare extemporaneous oral suspensions of the drug.1
Dosage of oseltamivir phosphate is expressed in terms of oseltamivir.1
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).1, 112, 120 Although efficacy has only been established when oseltamivir treatment is initiated no more than 48 hours after onset of symptoms,1 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.112, 116, 120 (See Treatment of Seasonal Influenza A and B Virus Infections under Uses.)
Oseltamivir usually is given for 5 days for the treatment of seasonal influenza.1, 112, 116, 120 However, hospitalized patients with severe or prolonged infections or individuals with immunosuppression may require more than 5 days of treatment.116, 120
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.1 Each dose can be given as a single 75-mg capsule or 12.5 mL of oral suspension containing 6 mg/mL.1
Dosage of oseltamivir for the treatment of influenza in children 1-12 years of age is based on weight.1 (See Table 1.)
Weight (kg) | Daily Dosage (mg) | Daily Dosage (Volume of Reconstituted Oral Suspension Containing 6 mg/mL) | Daily Dosage (Capsules) |
|---|---|---|---|
≤15 | 30 mg twice daily for 5 days | 5 mL twice daily for 5 days | One 30-mg capsule twice daily for 5 days |
15.1-23 | 45 mg twice daily for 5 days | 7.5 mL twice daily for 5 days | One 45-mg capsule twice daily for 5 days |
23.1-40 | 60 mg twice daily for 5 days | 10 mL twice daily for 5 days | Two 30-mg capsules twice daily for 5 days |
≥40.1 | 75 mg twice daily for 5 days | 12.5 mL twice daily for 5 days | One 75-mg capsule twice daily for 5 days |
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.1
For the treatment of influenza in neonates and infants younger than 1 year of age, 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.112 Although safety and efficacy have not been established in neonates younger than 2 weeks of age†1 (see Pediatric Precautions under Cautions), 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.112
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.112, 120 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).112, 120 AAP and 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.112, 120 For treatment of influenza in extremely premature neonates (postmenstrual age less than 28 weeks), a pediatric infectious disease expert should be consulted.112
Prevention of Seasonal Influenza A and B Virus Infections
When indicated for prophylaxis of influenza following close contact with an infected individual, oseltamivir should be initiated within 48 hours of exposure.1 Protection lasts as long as oseltamivir is continued.1
CDC recommends that oseltamivir prophylaxis be continued for 7 days after the most recent exposure.120 For prophylaxis of influenza when an outbreak is occurring in institutional settings (e.g., long-term care facilities for elderly individuals and children), CDC recommends that oseltamivir prophylaxis be given for a minimum of 2 weeks and continued for up to 1 week after the last known case of influenza is identified.120
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.1 The manufacturer states that oseltamivir prophylaxis should be continued for at least 10 days following close contact with an infected individual;1 during community outbreaks, the manufacturer states that prophylaxis may be continued for up to 6 weeks in immunocompetent individuals and for up to 12 weeks in immunocompromised individuals.1
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.1 (See Table 2.)
Weight (kg) | Daily Dosage (mg)a | Daily Dosage (Volume of Reconstituted Oral Suspension Containing 6 mg/mL)a | Daily Dosage (Capsules)a |
|---|---|---|---|
≤15 | 30 mg once daily for 10 days | 5 mL once daily for 10 days | One 30-mg capsule once daily for 10 days |
15.1-23 | 45 mg once daily for 10 days | 7.5 mL once daily for 10 days | One 45-mg capsule once daily for 10 days |
23.1-40 | 60 mg once daily for 10 days | 10 mL once daily for 10 days | Two 30-mg capsules once daily for 10 days |
≥40.1 | 75 mg once daily for 10 days | 12.5 mL once daily for 10 days | One 75-mg capsule once daily for 10 days |
aThe manufacturer states that oseltamivir prophylaxis in pediatric patients should be continued for 10 days following close contact with an infected individual;1 during community outbreaks, manufacturer states prophylaxis may be continued for up to 6 weeks in immunocompetent individuals and for up to 12 weeks in immunocompromised individuals.1
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†1 (see Pediatric Precautions under Cautions), CDC states that infants 3 months to less than 1 year of age† can receive oseltamivir in a dosage of 3 mg/kg once daily for 7 days if considered necessary for prevention of influenza.120 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†.112
Because of limited safety and efficacy data, CDC 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.112, 120
Avian Influenza A Virus Infections
Only limited data are available to date regarding treatment of infections caused by avian influenza A (H1N1) or avian influenza A (H7N9)†, 46, 47, 94, 152, 169, 187 and the optimum dosage and duration of oseltamivir for treatment of these infections, especially severe or complicated infections, are unknown.50, 63, 68, 104, 178
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.63, 104, 178 (See Treatment of Seasonal Influenza A and B Virus Infections under Dosage and Administration.) Although some experts have suggested a higher oseltamivir dosage (i.e., 150 mg twice daily in adults with normal renal function) be considered for severely ill or immunocompromised patients,50, 63, 68, 85, 104 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.112, 120, 178
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.50, 63, 68, 85, 104, 178
Treatment should be initiated as early as possible50, 104, 152, 183, 178 and may be most beneficial if initiated within 2 days of symptom onset.152 However, because the viruses continue to replicate for prolonged periods of time,104 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.50, 104, 152, 183
If oseltamivir is used for prophylaxis of avian influenza A infection† in close contacts of individuals with confirmed or probable infection or in individuals who have been exposed to birds infected with such viruses, CDC and WHO state that the twice-daily oseltamivir dosage usually recommended for treatment of seasonal influenza A and B virus infections can be used in adults and pediatric patients.50, 94, 179, 180 (See Treatment of Seasonal Influenza A and B Virus Infections under Dosage and Administration.)
Antiviral prophylaxis for avian influenza A virus infection should be continued for 5-10 days after the last known exposure.50, 94, 180 If exposure was time-limited and not ongoing, CDC states that prophylaxis should be continued for 5 days after the last known exposure.179, 180
Dosage in Renal and Hepatic Impairment
Dosage adjustments are not needed in patients with mild to moderate hepatic impairment (Child-Pugh score 9 or less).1, 42 The safety and pharmacokinetics of the drug have not been evaluated in those with severe hepatic impairment.1
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.1, 120 (See Table 3 and Table 4.)
Oseltamivir is not recommended in adults with ESRD who are not undergoing dialysis.1, 120
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.120
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 and then 30 mg after each hemodialysis cycle for maximum of 5 daysa |
≤10 (ESRD receiving continuous peritoneal dialysis) | Single 30-mg dose given immediatelyb |
ESRD not receiving dialysis | Not recommended |
aDosage assumes 3 hemodialysis sessions in the 5-day period.120 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, 120
bData derived from studies in patients undergoing continuous ambulatory peritoneal dialysis (CAPD).1, 120
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 and then 30 mg after alternate hemodialysis cycles |
≤10 (ESRD receiving continuous peritoneal dialysis) | 30 mg given immediately and then 30 mg once weeklyb |
ESRD not receiving dialysis | Not recommended |
aThe manufacturer states that prophylaxis with oseltamivir during community outbreaks may be continued for up to 6 weeks in immunocompetent individuals and for up to 12 weeks in immunocompromised individuals.1
bData derived from studies in patients undergoing CAPD.1, 120
Dosage adjustments are not needed in geriatric patients.1 (See Geriatric Precautions under Cautions.)
Oseltamivir generally is well tolerated.1, 2, 3, 4, 5, 28, 29, 30, 31 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.1, 2, 3, 4, 29 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.29
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.4, 43, 65
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.1, 28 GI effects, especially vomiting, were the most frequently reported adverse effects in children receiving the drug for prophylaxis of influenza.1
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.1, 83, 84, 88
Rash, swelling of the face or tongue, allergy, dermatitis, eczema, or urticaria has been reported during postmarketing experience.1
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.1, 3, 29
Adverse neuropsychiatric events (e.g., agitation, anxiety, self-injury, delirium, hallucinations, altered level of consciousness, confusion, nightmares, delusions, abnormal behavior, seizures), which occasionally were fatal, have been reported in patients receiving oseltamivir.1, 83, 84, 88 Cases generally had an abrupt onset and rapid resolution.1 The contribution of oseltamivir to these events has not been established.1 (See Pediatric Precautions under Cautions.)
Influenza itself can be associated with a variety of neurologic and behavioral symptoms (e.g., hallucinations, delirium, abnormal behavior) and fatalities can occur.1 Although such events may occur in the setting of encephalitis or encephalopathy, they can occur without obvious severe disease.1
Nausea, with or without vomiting, has been reported in up to 10% of adults and adolescents 13 years of age or older receiving oseltamivir.1, 2, 3, 4, 28, 29, 30, 31 Nausea usually occurs after the initial dose and resolves within 1-2 days; administration of the drug with food improves GI tolerance.2, 3, 5 In pediatric patients in clinical studies, vomiting was reported in 16% of children 1-12 years of age and diarrhea or vomiting was reported in up to 7 or 9%, respectively, of pediatric patients 2 weeks to less than 1 year of age.1
GI bleeding and hemorrhagic colitis have been reported during postmarketing experience.1
Hepatitis or abnormal liver function test values have been reported during postmarketing experience.1
Arrhythmia, hypothermia, or metabolic events (e.g., deterioration in diabetes control) has been reported during postmarketing experience.1
Precautions and Contraindications
Oseltamivir is contraindicated in patients with known hypersensitivity to the drug or any ingredient in the formulation.1 If an allergic reaction occurs or is suspected, oseltamivir should be discontinued and appropriate treatment initiated.1 Patients and/or their caregivers should be advised of the risk of severe allergic reactions (including anaphylaxis) or serious skin reactions and should be instructed to discontinue oseltamivir and immediately contact a clinician if an allergic-like reaction occurs or is suspected.1
Because there have been postmarketing reports of neuropsychiatric events (e.g., self-injury, delirium) in influenza patients receiving oseltamivir (see Neuropsychiatric Events under Cautions), patients with influenza (especially children) should be closely monitored for signs of abnormal behavior during oseltamivir treatment.1 Patients and/or their caregivers should be instructed to contact a clinician if there are any signs of unusual behavior during oseltamivir treatment.1 If neuropsychiatric symptoms develop, the risks and benefits of continued therapy with oseltamivir should be evaluated.1
Efficacy of oseltamivir has not been established in patients with chronic cardiac disease and/or pulmonary disease; however, no difference in incidence of complications between drug and placebo has been observed in these populations.1 Safety and efficacy have not been established in those with any medical condition severe or unstable enough to require inpatient care.1
Although efficacy of oseltamivir for treatment or prevention of influenza in immunocompromised patients† has not been established,1 safety of oseltamivir prophylaxis has been demonstrated for up to 12 weeks in immunocompromised patients.1 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.1, 74, 75, 101 (See Uses.)
There is no evidence that oseltamivir is effective for illness caused by any organisms other than influenza viruses.1 Serious bacterial infections may begin with influenza-like symptoms or may coexist with or occur as complications of influenza.1 There is no evidence that oseltamivir prevents such complications.1 Clinicians should consider the potential for secondary bacterial infections;1 if such infections occur, they should be treated appropriately.1
Influenza antivirals, including oseltamivir, are important adjuncts to vaccination in the control of influenza but are not a substitute for annual vaccination with a seasonal influenza vaccine (influenza virus vaccine inactivated, influenza vaccine recombinant, influenza vaccine live intranasal).1, 105, 112, 116 Although influenza antivirals 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 or influenza vaccine recombinant, influenza antivirals may inhibit the vaccine virus contained in influenza vaccine live intranasal and decrease efficacy of the live vaccine.1, 100, 134 (See Influenza 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.1 Patients with hereditary fructose intolerance should be informed that this amount of sorbitol exceeds the maximum daily limit of sorbitol for such individuals and may result in dyspepsia and diarrhea.1
Safety and pharmacokinetics of oseltamivir have not been evaluated in patients with severe hepatic impairment.1
Patients with renal impairment (i.e., creatinine clearance of 60 mL/minute or less) may be at increased risk of adverse effects during oseltamivir therapy because of decreased clearance of the drug;1 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.1, 120 Oseltamivir is not recommended in adults with ESRD who are not undergoing dialysis.1, 120 (See Renal Impairment under Dosage and Administration:.)
Safety and efficacy of oseltamivir for the treatment of influenza have not been established in infants younger than 2 weeks of age.1
Safety and efficacy of oseltamivir for prophylaxis of influenza have not been established in infants younger than 1 year of age.1
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.1 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.1 In addition, serum concentrations of oseltamivir in these infants were similar to or greater than those observed in older children and adults.1
Young children, especially those younger than 2 years of age, are at increased risk of influenza infection, hospitalization, and complications.112, 120 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†.121, 150, 144 Although the EUA expired in June 2010,150 the 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.112 However, because of limited safety and efficacy data, CDC 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.112, 120 (See Dosage under Dosage and Administration.)
Unusual adverse neurologic and/or psychiatric effects, including self-injury, delirium, hallucinations, mental confusion, abnormal behavior, seizures, and encephalitis, have been reported in pediatric patient receiving oseltamivir.1, 83, 84, 88 Adverse neurologic and psychiatric events, including some fatalities, have been reported principally in children in Japan.83, 88 A relationship to oseltamivir was difficult to assess because of concomitantly used drugs, comorbid conditions, and/or lack of adequate detail in reports.88 After reviewing available data, FDA concluded that the increased reports of neuropsychiatric events in Japanese children receiving oseltamivir were most likely related to an increased awareness of influenza-related encephalopathy, increased access to the drug in the Japanese population, and a coincident period of intensive monitoring for potential adverse effects.84, 88 Therefore, based on available information, FDA stated that it was unable to conclude that a causal relationship exists between oseltamivir and the reported pediatric deaths.88
Safety of oseltamivir for the treatment of influenza in geriatric individuals has been established in clinical studies.1 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.1, 29
When the total number of patients studied in oseltamivir clinical trials is considered, 20% 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 23% of those in studies evaluating the drug for the prevention of influenza were 65 years or older (16% were 75 years of age or older).1 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.1
Oseltamivir dosage adjustments based solely on age are not necessary for geriatric patients older than 65 years of age.1
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.1 Oseltamivir carboxylate was not mutagenic in the Ames microbial test, the L5178Y mouse lymphoma assay, or the Syrian hamster embryo cell transformation assay.1
Oseltamivir was not carcinogenic in studies in rats or mice.1
Pregnancy, Fertility, and Lactation
There are no adequate and well-controlled studies using oseltamivir in pregnant women to inform a drug-associated risk of adverse developmental outcomes.1 Available published epidemiological data suggest that oseltamivir administered during any trimester of pregnancy is not associated with an increased risk of birth defects;1 however, these studies had various limitations (e.g., small sample sizes, use of different comparison groups, lack of dosage information) which preclude a definitive assessment of the risk.1 Although data are insufficient to make a definitive assessment of the risk, prospective and retrospective observational studies that included approximately 5000 women exposed to oseltamivir during pregnancy (including approximately 1000 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.1
In animal reproduction studies, no adverse embryofetal effects were observed in pregnant rats and rabbits treated with oral oseltamivir at dosages resulting in clinically relevant exposures.1 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 190 and at least 8 times usual human exposure, respectively).1 No adverse maternal or embryofetal effects were observed in rats exposed to maternally toxic dosages (approximately 44 times usual human exposure).1
Pregnant women are at increased risk for severe complications from influenza,1, 120, 142 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.1
Oseltamivir is the preferred antiviral for the treatment of suspected or confirmed influenza or prevention of influenza in women who are pregnant or up to 2 weeks postpartum.120, 142
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.1
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.1
The benefits of breast-feeding and the importance of oseltamivir to the woman should be considered along with potential adverse effects on the breast-fed child from the drug or from the underlying maternal condition.1
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;1, 25 interactions with drugs that are substrates for or inhibitors of these enzymes are unlikely.1
Concomitant use of acetaminophen and oseltamivir does not result in clinically important pharmacokinetic interactions;1 dosage adjustments are not needed.1
Concomitant use of oseltamivir and amantadine or rimantadine does not result in clinically important pharmacokinetic interactions;1 dosage adjustments are not needed if oseltamivir is used concomitantly with amantadine or rimantadine.1
Concomitant use of amoxicillin and oseltamivir does not result in clinically important pharmacokinetic interactions;1 dosage adjustments are not needed.1
Concomitant use of oseltamivir and antacids containing magnesium hydroxide, aluminum hydroxide, or calcium carbonate does not result in clinically important pharmacokinetic interactions;1, 92 dosage adjustments are not needed.1
Concomitant use of oseltamivir and warfarin does not result in clinically important pharmacokinetic interactions;1 dosage adjustments are not needed.1
Concomitant use of aspirin and oseltamivir does not result in clinically important pharmacokinetic interactions;1 dosage adjustments are not needed.1
Concomitant use of cimetidine and oseltamivir does not affect plasma concentrations of oseltamivir or oseltamivir carboxylate.1, 34 Dosage adjustments are not needed.1
Influenza virus vaccine inactivated (IIV) and influenza vaccine recombinant (RIV) may be administered concomitantly with or at any time before or after oseltamivir.1, 100, 134 Although drug interaction studies have not been conducted to evaluate the immune response to inactivated influenza vaccines in patients receiving oseltamivir,1 oseltamivir therapy does not appear to impair normal humoral antibody response to infection in patients with naturally or experimentally acquired influenza.1, 2, 3
Safety and efficacy of concomitant use of oseltamivir and influenza vaccine live intranasal (LAIV) have not been evaluated.1 Because influenza antivirals, including oseltamivir, inhibit replication of influenza viruses and may inhibit the vaccine virus, these antivirals potentially could decrease the immune response to LAIV and decrease efficacy of the live vaccine.1, 100, 134 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.1, 100, 120 ACIP recommends that individuals who received oseltamivir 48 hours before to 14 days after LAIV should be revaccinated using age-appropriate IIV or RIV.100, 120
There was no evidence of drug interactions when IV peramivir was used concomitantly with oral oseltamivir.176
Concomitant use of oseltamivir with probenecid results in a twofold increase in systemic exposure to oseltamivir carboxylate because of decreased renal tubular secretion.1, 34 However, this pharmacokinetic interaction is not expected to be clinically important and the usual oseltamivir dosage can be used in patients receiving probenecid.1
Oseltamivir phosphate is a prodrug and has little, if any, pharmacologic activity until hydrolyzed in vivo to oseltamivir carboxylate.1, 2, 3, 4, 5, 6, 7, 8, 9 Oseltamivir is pharmacologically related to other neuraminidase inhibitors (e.g., zanamivir, peramivir).1, 2, 3, 4, 5, 6, 7, 8, 9, 120
Oseltamivir carboxylate is a potent selective competitive inhibitor of the influenza virus neuraminidase, an enzyme essential for viral replication in vivo.1, 2, 3, 8, 9 Neuraminidase cleaves terminal sialic acid residues from glycoconjugates to enable the release of virus from infected cells, prevents the formation of viral aggregates after release from host cells, and possibly facilitates viral invasion of the upper airways.1, 2, 7, 9, 64
Neuraminidase inhibitors interfere with the release of progeny influenza virus from infected host cells, thus preventing infection of new host cells and halting the spread of infection.64 Because replication of influenza virus in the respiratory tract reaches its peak between 24 and 72 hours after the onset of illness, neuraminidase inhibitors must be administered as early as possible.64
Oseltamivir (as oseltamivir carboxylate, the active metabolite of oseltamivir phosphate) exhibits potent antiviral activity in vitro against both influenza A and B viruses.1, 2, 3, 7, 25 Oseltamivir appears to be a potent and selective inhibitor of all influenza A neuraminidase subtypes (i.e., N1-N9) tested to date.43
Viral surveillance data indicate that the majority of seasonal influenza A (H1N1)pdm09, influenza A (H3N2), and influenza B viruses circulating during recent influenza seasons, including in the US, have been susceptible to oseltamivir in vitro.120, 192, 193, 194, 195, 198, 199, 200, 201, 202
In vitro studies indicate that oseltamivir is active against avian influenza A (H5N1) and some other avian influenza A viruses (e.g., H7N7, H7N9, H9N2, H10N8).27, 50, 58, 61, 104, 168, 171, 183 However, avian influenza A (H5N1)50, 68, 73, 81, 104 and avian influenza A (H7N9)169, 170, 197 with reduced in vitro susceptibility or resistance to oseltamivir have been reported rarely. (See Resistance.)
The major mechanisms of resistance to neuraminidase inhibitors (i.e., oseltamivir, zanamivir) that have been identified in vitro are viral neuraminidase (NA) mutations that affect the ability of the drugs to inhibit the enzyme and hemagglutinin (HA) mutations that reduce viral dependence on neuraminidase activity.35, 43
Influenza A and B viruses with decreased susceptibility to oseltamivir have been produced in vitro by serial passage of virus in cell culture in the presence of increasing concentrations of oseltamivir carboxylate and reduced in vitro susceptibility have been observed in clinical isolates.1, 4, 36, 43
HA substitutions selected in cell culture and associated with reduced susceptibility to oseltamivir include A11T, K173E, and R453M in influenza A (H3N2) and H99Q in influenza B (Yamagata lineage).1 In some cases, HA substitutions were selected in conjunction with known NA resistance substitutions and may contribute to reduced susceptibility to oseltamivir; however, the impact of HA substitutions on antiviral activity of oseltamivir in humans is unknown and likely depends on the influenza strain.1
Influenza A virus variants with reduced susceptibility to oseltamivir include substitutions in neuraminidase N1 (i.e., I117V, E119V, R152K, Y155H, F174V, D199G/N, I223K/R/T/V, S247G/N, G249R+I267V, H275Y, N295S, Q313R+I427T, N325K, R368K) and in neuraminidase N2 (i.e., E41G, E119I/V, D151V, I222L/V, N294S, Q226H, R292K, SASG245-248 deletion, S247P).1, 36, 37, 43 Influenza B virus variants with reduced susceptibility to oseltamivir recovered from patients receiving the drug or identified during viral surveillance include E117A, P139S, G140R, R150K, I221L/T/V, D197E/N/Y, A245D/S/T, H273Y, N294S, R374K, and G407S.1 The H275Y substitution in influenza A (H1N1) has been the major substitution associated with resistance to oseltamivir.1, 52, 153, 154, 155, 157, 167 In the event of an H5N1 pandemic, the N1 mutation at position 274 would be important because this is associated with a greater than 600-fold increase in inhibitory concentrations for oseltamivir in enzyme inhibition assays.35, 44 Viruses that have neuraminidase mutations generally have reduced virulence.35, 36, 43, 62, 64 Although it has been suggested that these mutant viruses may have some degree of compromised infectivity and transmissibility compared with wild-type viruses, person-to-person transmission of oseltamivir-resistant variants of influenza A (H1N1) has been documented.162
Strains of seasonal influenza with reduced in vitro susceptibility to oseltamivir have emerged in posttreatment isolates obtained from 1.3% of adults and adolescents and 8.6% of pediatric patients 1-12 years of age who received the drug in clinical studies of naturally acquired influenza infection.4, 36 In pediatric treatment studies, the rate of treatment-emergent resistance to oseltamivir was 27-37% in children with influenza A (H1N1) and 3-18% in children with influenza A (H3N2).1 In one group of Japanese children who received oseltamivir for the treatment of seasonal influenza, oseltamivir-resistant mutants were detected in 18% of patients posttreatment.70 Resistant strains of influenza A and influenza B viruses have emerged in immunocompromised patients who received oseltamivir therapy,93 and there is evidence that influenza viruses resistant to oseltamivir may be selected at higher frequencies in immunocompromised adults and pediatric patients than in otherwise healthy individuals.1 In a study evaluating oseltamivir for treatment of influenza in immunocompromised patients, the rate of treatment-emergent resistance to oseltamivir was 27% in immunocompromised patients infected with influenza A (H1N1) and 12% in those infected with influenza A (H3N2);1 the rate of treatment-emergent resistance to oseltamivir was 32% in hematopoietic stem cell transplant (HSCT) recipients.1
The frequency of resistance selection to oseltamivir and the prevalence of such resistant virus vary seasonally and geographically.1 Viral surveillance data from recent influenza seasons indicate that reduced in vitro susceptibility or resistance to oseltamivir was reported rarely in circulating strains of influenza A (H1N1)pdm09, influenza A (H3N2), influenza B (Yamagata lineage), and influenza B (Victoria lineage).195, 199, 200, 201, 202
Avian influenza A (H5N1) and avian influenza A (H7N9) isolates with reduced in vitro susceptibility or resistance to oseltamivir have been reported.50, 68, 73, 81, 168, 169, 197 In a patient with influenza A (H5N1) infection who received prophylaxis with oseltamivir (75 mg once daily for 3 days) immediately followed by oseltamivir treatment (75 mg twice daily for 7 days), isolates obtained on the third day of oseltamivir prophylaxis had mutations associated with oseltamivir resistance (these isolates remained susceptible to zanamivir).73 In 2 patients in Vietnam who received oseltamivir for treatment of avian influenza A (H5N1) infection, isolates had an amino acid substitution (H274Y) associated with high-level oseltamivir resistance; both patients subsequently died.81 In a few patients with avian influenza A (H7N9) infection who were receiving oseltamivir for treatment, oseltamivir resistance emerged and was associated with treatment failure and adverse clinical outcomes.169 Genetic analyses of isolates from an ongoing epidemic of avian influenza A (H7N9) that has been occurring in China since October 2016 indicate that approximately 7-9% of isolates tested (many may have been collected after antiviral treatment was started) have known or suspected markers for reduced susceptibility to one or more neuraminidase inhibitor antivirals.197
Cross-resistance between oseltamivir and other neuraminidase inhibitors (e.g., peramivir, zanamivir) has been reported in influenza A and B viruses.1, 9, 36, 37, 38, 43, 62, 172, 173, 175, 176, 195, 199, 200, 201, 202 However, because oseltamivir, peramivir, and zanamivir bind to different sites on the neuraminidase enzyme or interact differently with the binding sites, cross-resistance among the drugs is variable.9, 36, 37, 43, 62, 173, 175
Some influenza A strains may have reduced susceptibility to oseltamivir and/or peramivir, but are susceptible to zanamivir;1, 38, 44, 144, 163, 167, 176 other strains may have reduced susceptibility to zanamivir, but are susceptible to oseltamivir and/or peramivir.1, 176, 201 Circulating influenza B (Victoria lineage) with reduced susceptibility to both oseltamivir and peramivir have been reported.195 Avian influenza A (H5N1) with the H274Y mutation that are resistant to oseltamivir have been susceptible to zanamivir in vitro.73, 94
Reduced in vitro susceptibility to all 3 drugs (oseltamivir, peramivir, zanamivir) has been observed in some circulating seasonal influenza A and influenza B viruses.1, 176, 195, 200 Cross-resistance to both oseltamivir and zanamivir has been reported in vitro in influenza B with I222T, D198E/N, R371K, or G402S resistance-associated neuraminidase substitutions.1 The H275Y (N1 numbering) or N294S (N2 numbering) oseltamivir resistance-associated substitutions observed in the N1 neuraminidase subtype and the E119V or N294S oseltamivir resistance-associated substitutions observed in the N2 subtype (N2 numbering) are associated with reduced in vitro susceptibility to oseltamivir, but not zanamivir.1 The Q136K and K150T zanamivir resistance-associated substitutions observed in N1 neuraminidase or the S250G zanamivir resistance-associated substitutions observed in influenza B virus neuraminidase confer reduced in vitro susceptibility to zanamivir, but not oseltamivir.1 Influenza A (H1N1)pdm09 with the H275Y N1 amino acid substitution are cross-resistant to oseltamivir and peramivir, but susceptible to zanamivir in vitro.172, 174, 189 Avian influenza A (H5N1) isolates with the H274Y mutation that are resistant to oseltamivir have been susceptible to zanamivir in vitro.73, 94
An amino acid substitution that confers cross-resistance between neuraminidase inhibitors (oseltamivir, peramivir, zanamivir) and adamantane derivatives (M2 ion channel inhibitors; amantadine, rimantadine) has not been identified.1, 176 However, influenza strains that have a neuraminidase substitution that confers resistance to neuraminidase inhibitors and also have an M2 substitution that confers resistance to M2 ion channel inhibitors may be resistant to both classes of influenza antivirals.1, 176 The clinical relevance of phenotypic cross-resistance evaluations has not been established.1, 176
Oseltamivir phosphate is readily absorbed following oral administration and then extensively converted by hepatic esterases to the active metabolite, oseltamivir carboxylate.1, 24, 25 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.1 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.25 The absolute bioavailability of oseltamivir carboxylate is 80% following oral administration of oseltamivir phosphate.25 Plasma concentrations of oseltamivir carboxylate are proportional to dosage up to an oseltamivir dosage of 500 mg twice daily.1
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.1
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.1
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.1, 25
In individuals with varying degrees of renal impairment receiving 100 mg of oseltamivir phosphate twice daily (about 1.3 times the maximum recommended dosage) for 5 days, oseltamivir carboxylate exposure increases with declining renal function.1 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.1
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.42 Systemic exposure to oseltamivir carboxylate in individuals with mild or moderate hepatic impairment is comparable to that in individuals without hepatic impairment.1, 42
Following oral administration of oseltamivir phosphate, oseltamivir carboxylate is distributed throughout the body, including into the upper and lower respiratory tract.24, 25
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.1
Oseltamivir and oseltamivir carboxylate are distributed into milk.1
Oseltamivir phosphate is 42% bound to plasma proteins; oseltamivir carboxylate is 3% bound to plasma proteins.1, 24
Oseltamivir phosphate is extensively (greater than 90%) converted to oseltamivir carboxylate (the active metabolite), principally by hepatic esterases.1, 25 Oseltamivir carboxylate is not further metabolized.1
Oseltamivir phosphate and oseltamivir carboxylate are not metabolized by cytochrome P-450 (CYP) enzymes.1, 25
Oseltamivir carboxylate is eliminated (greater than 99%) by renal excretion;1, 24, 25 less than 20% of an oral radiolabeled dose of oseltamivir phosphate is eliminated in feces.1
The plasma half-life of oseltamivir phosphate is 1-3 hours;1, 24 half-life of oseltamivir carboxylate is 6-10 hours.1, 25 Half-lives observed in geriatric individuals are similar to those observed in younger adults.1
Clearance of both oseltamivir phosphate and oseltamivir carboxylate is increased in younger pediatric patients compared with adults.1, 39, 40 Total clearance of oseltamivir carboxylate decreases linearly with increasing age (up to 12 years of age);1, 39, 40 pharmacokinetics in those 12 years of age or older is similar to that in adults.1
Renal clearance of oseltamivir carboxylate decreases linearly with creatinine clearance.1, 25
Oseltamivir phosphate is a carbocyclic transition state sialic acid analog.1, 2, 3, 4, 5, 6, 7, 8, 9 Oseltamivir differs structurally from zanamivir (another sialic acid analog) by the absence of glycerol and guanidino groups.9 These structural modifications in oseltamivir result in a compound with substantially improved oral bioavailability compared with that of zanamivir.1, 9
Oseltamivir phosphate occurs as a white, crystalline solid1 with a bitter taste.35, 43 Oseltamivir phosphate has an aqueous solubility of 588 mg/mL at 25°C.12
Oseltamivir phosphate capsules should be stored at 25°C, but may be exposed to temperatures ranging from 15-30°C.1
Oseltamivir phosphate powder for oral suspension should be stored at 25°C, but may be exposed to temperatures ranging from 15-30°C.1 The reconstituted oral suspension should be stored at 2-8°C for up to 17 days.1 Alternatively, the reconstituted suspension may be stored for up to 10 days at 25°C and may be exposed to temperatures ranging from 15-30°C during this time.1 The reconstituted oral suspension should not be frozen.1
Extemporaneous oral suspensions of oseltamivir phosphate prepared according to the manufacturer's directions using commercially available 75-mg capsules of the drug are stable for 5 weeks when refrigerated at 2-8°C or for 5 days when stored at room temperature (25°C).1
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Capsules | 30 mg (of oseltamivir)* | Oseltamivir Capsules | |
45 mg (of oseltamivir)* | Oseltamivir Capsules | |||
Tamiflu® | Genentech | |||
75 mg (of oseltamivir)* | Oseltamivir Capsules | |||
Tamiflu® | Genentech | |||
For suspension | 6 mg (of oseltamivir) per mL* | Oseltamivir for Suspension | ||
Tamiflu® | Genentech |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
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