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Aug.02.2021

Oseltamivir

Indications/Dosage

Labeled

  • influenza A virus infection
  • influenza B virus infection
  • seasonal influenza prophylaxis

Off-Label

  • avian influenza A virus infection
  • avian influenza prophylaxis
† Off-label indication

For the treatment of acute influenza A virus infection or influenza B virus infection

Oral dosage

Adults

75 mg PO twice daily for 5 days.[31109] May consider extended courses for patients who remain severely ill after 5 days of treatment.[62315] [63866]

Children and Adolescents weighing more than 40 kg

75 mg PO twice daily for 5 days.[31109] May consider extended courses for patients who remain severely ill after 5 days of treatment.[62315] [63866]

Children weighing 24 to 40 kg

60 mg PO twice daily for 5 days.[31109] May consider extended courses for patients who remain severely ill after 5 days of treatment.[62315] [63866]

Children weighing 16 to 23 kg

45 mg PO twice daily for 5 days.[31109] May consider extended courses for patients who remain severely ill after 5 days of treatment.[62315] [63866]

Children weighing 15 kg or less

30 mg PO twice daily for 5 days.[31109] May consider extended courses for patients who remain severely ill after 5 days of treatment.[62315] [63866]

Infants 9 to 11 months

3.5 mg/kg/dose PO twice daily for 5 days is recommended by the American Academy of Pediatrics (AAP) based on pharmacokinetic data indicating that a slightly higher dosage is needed in this age group to achieve target drug exposure.[56854] [63520] The FDA-approved dosage is 3 mg/kg/dose PO twice daily for 5 days.[31109] May consider extended courses for patients who remain severely ill after 5 days of treatment.[62315] [63866]

Infants 1 to 8 months

3 mg/kg/dose PO twice daily for 5 days.[31109] May consider extended courses for patients who remain severely ill after 5 days of treatment.[62315] [63866]

Term Neonates 14 to 29 days

3 mg/kg/dose PO twice daily for 5 days.[31109] May consider extended courses for patients who remain severely ill after 5 days of treatment.[62315] [63866]

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

3 mg/kg/dose PO twice daily for 5 days.[62315] [63520] May consider extended courses for patients who remain severely ill after 5 days of treatment.[62315] [63866]

Premature Neonates 38 to 40 weeks postmenstrual age†

1.5 mg/kg/dose PO twice daily for 5 days.[62315] [63520] May consider extended courses for patients who remain severely ill after 5 days of treatment.[62315] [63866]

Premature Neonates younger than 38 weeks postmenstrual age†

1 mg/kg/dose PO twice daily for 5 days.[62315] [63520] May consider extended courses for patients who remain severely ill after 5 days of treatment.[62315] [63866]

For seasonal influenza prophylaxis

Oral dosage

Adults

75 mg PO once daily for at least 10 days after close contact and for up to 6 weeks during a community outbreak. Safety and efficacy have been demonstrated for up to 6 weeks in immunocompetent patients and safety has been demonstrated for up to 12 weeks in immunocompromised patients (efficacy has not been demonstrated).[25978] [31109] The duration of protection lasts for as long as dosing is continued. The CDC recommends a 7-day course after the last known exposure. For those vaccinated during an outbreak, a 2-week course is recommended. For control of outbreaks in long-term care facilities and hospitals, the CDC recommends chemoprophylaxis for a minimum of 2 weeks and up to 1 week after the last known identified case. High-risk patients may require prophylaxis during the entire influenza season.[62315] [63866] Oseltamivir treatment for 42 days has been efficacious in preventing influenza in 92% of those in residential nursing home settings during a flu outbreak; note that 80% of the residents had previously received influenza vaccination.[31109]

Children weighing more than 40 kg and Adolescents

75 mg PO once daily for at least 10 days after close contact and for up to 6 weeks during a community outbreak.[31109] The duration of protection lasts for as long as dosing is continued. The CDC recommends a 7-day course after the last known exposure. For those vaccinated during an outbreak, a 2-week course is recommended. For control of outbreaks in long-term care facilities and hospitals, the CDC recommends chemoprophylaxis for a minimum of 2 weeks and up to 1 week after the last known identified case. High-risk patients may require prophylaxis during the entire influenza season.[62315] [63866]

Children weighing 24 to 40 kg

60 mg PO once daily for 10 days or for up to 6 weeks during a community outbreak.[31109] The duration of protection lasts for as long as dosing is continued. The CDC recommends a 7-day course after the last known exposure. For those vaccinated during an outbreak, a 2-week course is recommended. For control of outbreaks in long-term care facilities and hospitals, the CDC recommends chemoprophylaxis for a minimum of 2 weeks and up to 1 week after the last identified case. High-risk patients may require prophylaxis during the entire influenza season.[62315] [63866]

Children weighing 16 to 23 kg

45 mg PO once daily for 10 days or for up to 6 weeks during a community outbreak.[31109] The duration of protection lasts for as long as dosing is continued. The CDC recommends a 7-day course after the last known exposure. For those vaccinated during an outbreak, a 2-week course is recommended. For control of outbreaks in long-term care facilities and hospitals, the CDC recommends chemoprophylaxis for a minimum of 2 weeks and up to 1 week after the last identified case. High-risk patients may require prophylaxis during the entire influenza season.[62315] [63866]

Children weighing 15 kg or less

30 mg PO once daily for 10 days or for up to 6 weeks during a community outbreak.[31109] The duration of protection lasts for as long as dosing is continued. The CDC recommends a 7-day course after the last known exposure. For those vaccinated during an outbreak, a 2-week course is recommended. For control of outbreaks in long-term care facilities and hospitals, the CDC recommends chemoprophylaxis for a minimum of 2 weeks and up to 1 week after the last identified case. High-risk patients may require prophylaxis during the entire influenza season.[62315] [63866]

Infants 9 to 11 months†

3.5 mg/kg/dose PO once daily is recommended by the American Academy of Pediatrics (AAP) based on pharmacokinetic data indicating that a slightly higher dosage is needed in this age group to achieve target drug exposure.[56854] [63520] The duration of therapy is dependent on type of exposure: 7 days after the last known exposure; 2 weeks for those vaccinated during an outbreak; a minimum of 2 weeks and up to 1 week after the last-identified case for control of outbreaks in long-term care facilities and hospitals. High-risk patients may require prophylaxis during the entire influenza season.[62315] [63520] [63866]

Infants 3 to 8 months†

3 mg/kg/dose PO once daily.[62315] [63520] The duration of therapy is dependent on type of exposure: 7 days after the last known exposure; 2 weeks for those vaccinated during an outbreak; a minimum of 2 weeks and up to 1 week after the last identified case for control of outbreaks in long-term care facilities and hospitals. High-risk patients may require prophylaxis during the entire influenza season.[62315] [63520] [63866]

Infants 1 to 2 months†

Because of the lack of data in this age group, chemoprophylaxis is not recommended unless the exposure situation is judged to be critical.[62315] [63520] A variety of oseltamivir dosages have been safely used for influenza prophylaxis in infants in limited studies.[43072] [52863] [52865] [52866] A dosage of 1 mg/kg/dose PO twice daily for 10 days was effective in a small study of 13 neonates (mean gestational age 39 weeks [range, 36 to 41 weeks]) exposed to influenza H1N1; no patients developed influenza.[52865]

Neonates†

Because of the lack of data in this age group, chemoprophylaxis is not recommended unless the exposure situation is judged to be critical.[62315] [63520] A variety of oseltamivir dosages have been safely used for influenza prophylaxis in neonates in limited studies.[43072] [52863] [52865] [52866] A dosage of 1 mg/kg/dose PO twice daily for 10 days was effective in a small study of 13 neonates (mean gestational age 39 weeks [range, 36 to 41 weeks]) exposed to influenza H1N1; no patients developed influenza.[52865]

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

Oral dosage

Adults

75 mg PO twice daily for 5 days, with longer courses (e.g., 10 days) considered for severely ill hospitalized patients or immunosuppressed patients. Clinical judgment and virologic testing should guide duration assessment. Oseltamivir is recommended for hospitalized patients as well as outpatients.[62336]

Children weighing more than 40 kg and Adolescents

75 mg PO twice daily for 5 days, with longer courses (e.g., 10 days) considered for severely ill hospitalized patients or immunosuppressed patients. Clinical judgment and virologic testing should guide duration assessment. Oseltamivir is recommended for hospitalized patients as well as outpatients.[62315] [62336]

Children weighing 24 to 40 kg

60 mg PO twice daily for 5 days, with longer courses (e.g., 10 days) considered for severely ill hospitalized patients or immunosuppressed patients. Clinical judgment and virologic testing should guide duration assessment. Oseltamivir is recommended for hospitalized patients as well as outpatients.[62315] [62336]

Children weighing 16 to 23 kg

45 mg PO twice daily for 5 days, with longer courses (e.g., 10 days) considered for severely ill hospitalized patients or immunosuppressed patients. Clinical judgment and virologic testing should guide duration assessment. Oseltamivir is recommended for hospitalized patients as well as outpatients.[62315] [62336]

Children weighing 15 kg or less

30 mg PO twice daily for 5 days, with longer courses (e.g., 10 days) considered for severely ill hospitalized patients or immunosuppressed patients. Clinical judgment and virologic testing should guide duration assessment. Oseltamivir is recommended for hospitalized patients as well as outpatients.[62315] [62336]

Infants

3 mg/kg/dose PO twice daily for 5 days, with longer courses (e.g., 10 days) considered for severely ill hospitalized patients or immunosuppressed patients. The American Academy of Pediatrics (AAP) recommends 3.5 mg/kg/dose PO twice daily for infants 9 to 11 months of age based on pharmacokinetic data indicating that a slightly higher dosage is needed in this age group to achieve target drug exposure. Clinical judgment and virologic testing should guide duration assessment. Oseltamivir is recommended for hospitalized patients as well as outpatients.[56854] [62315] [62336] [63520]

Premature Neonates older than 40 weeks postmenstrual age and Term Neonates

3 mg/kg/dose PO twice daily for 5 days, with longer courses (e.g., 10 days) considered for severely ill hospitalized patients or immunosuppressed patients. Clinical judgment and virologic testing should guide duration assessment. Oseltamivir is recommended for hospitalized patients as well as outpatients.[62315] [62336] [63520]

Premature Neonates 38 to 40 weeks postmenstrual age

1.5 mg/kg/dose PO twice daily for 5 days, with longer courses (e.g., 10 days) considered for severely ill hospitalized patients or immunosuppressed patients. Clinical judgment and virologic testing should guide duration assessment. Oseltamivir is recommended for hospitalized patients as well as outpatients.[62315] [62336] [63520]

Premature Neonates younger than 38 weeks postmenstrual age

1 mg/kg/dose PO twice daily for 5 days, with longer courses (e.g., 10 days) considered for severely ill hospitalized patients or immunosuppressed patients. Clinical judgment and virologic testing should guide duration assessment. Oseltamivir is recommended for hospitalized patients as well as outpatients.[62315] [62336] [63520]

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

Oral dosage

Adults

75 mg PO twice daily. Initiate therapy as soon as possible after first exposure to the confirmed or probable case. If exposure was time-limited and not ongoing, 5 days of treatment from the last known exposure is recommended. If exposure is likely to be ongoing (i.e., household setting), 10 days of treatment is recommended.[62315] [62337] [62338]

Children weighing 40 kg or more and Adolescents

75 mg PO twice daily. Initiate therapy as soon as possible after first exposure to the confirmed or probable case. If exposure was time-limited and not ongoing, 5 days of treatment from the last known exposure is recommended. If exposure is likely to be ongoing (i.e., household setting), 10 days of treatment is recommended.[62315] [62337] [62338]

Children weighing 24 to 40 kg

60 mg PO twice daily. Initiate therapy as soon as possible after first exposure to the confirmed or probable case. If exposure was time-limited and not ongoing, 5 days of treatment from the last known exposure is recommended. If exposure is likely to be ongoing (i.e., household setting), 10 days of treatment is recommended.[62315] [62337] [62338]

Children weighing 16 to 23 kg

45 mg PO twice daily. Initiate therapy as soon as possible after first exposure to the confirmed or probable case. If exposure was time-limited and not ongoing, 5 days of treatment from the last known exposure is recommended. If exposure is likely to be ongoing (i.e., household setting), 10 days of treatment is recommended.[62315] [62337] [62338]

Children weighing 15 kg or less

30 mg PO twice daily. Initiate therapy as soon as possible after first exposure to the confirmed or probable case. If exposure was time-limited and not ongoing, 5 days of treatment from the last known exposure is recommended. If exposure is likely to be ongoing (i.e., household setting), 10 days of treatment is recommended.[62315] [62337] [62338]

Term Neonates and Infants 14 days and older

3 mg/kg/dose PO twice daily.[62315] The American Academy of Pediatrics (AAP) recommends 3.5 mg/kg/dose PO twice daily for infants 9 to 11 months of age based on pharmacokinetic data indicating that a slightly higher dosage is needed in this age group to achieve target drug exposure.[56854] [63520] Initiate therapy as soon as possible after first exposure to the confirmed or probable case. If exposure was time-limited and not ongoing, 5 days of treatment from the last known exposure is recommended. If exposure is likely to be ongoing (i.e., household setting), 10 days of treatment is recommended.[62337] [62338]

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

3 mg/kg/dose PO twice daily. Initiate therapy as soon as possible after first exposure to the confirmed or probable case. If exposure was time-limited and not ongoing, 5 days of treatment from the last known exposure is recommended. If exposure is likely to be ongoing (i.e., household setting), 10 days of treatment is recommended.[62315] [62337] [62338]

Premature Neonates 38 to 40 weeks postmenstrual age

1.5 mg/kg/dose PO twice daily. Initiate therapy as soon as possible after first exposure to the confirmed or probable case. If exposure was time-limited and not ongoing, 5 days of treatment from the last known exposure is recommended. If exposure is likely to be ongoing (i.e., household setting), 10 days of treatment is recommended.[62315] [62337] [62338]

Premature Neonates younger than 38 weeks postmenstrual age

1 mg/kg/dose PO twice daily. Initiate therapy as soon as possible after first exposure to the confirmed or probable case. If exposure was time-limited and not ongoing, 5 days of treatment from the last known exposure is recommended. If exposure is likely to be ongoing (i.e., household setting), 10 days of treatment is recommended.[62315] [62337] [62338]

Therapeutic Drug Monitoring

Maximum Dosage Limits

  • Adults

    75 mg PO twice daily.

  • Geriatric

    75 mg PO twice daily.

  • Adolescents

    75 mg PO twice daily.

  • Children

    weight more than 40 kg: 75 mg PO twice daily.

    weight 24 to 40 kg: 60 mg PO twice daily.

    weight 16 to 23 kg: 45 mg PO twice daily.

    weight 15 kg or less: 30 mg PO twice daily.

  • Infants

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

    1 to 8 months: 3 mg/kg/dose PO twice daily.

  • Neonates

    Term Neonates 14 days and older: 3 mg/kg/dose PO twice daily.

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

    Premature Neonates 38 to 40 weeks postmenstrual age: Safety and efficacy have not been established; however, 1.5 mg/kg/dose PO twice daily has been used off-label.

    Premature Neonates younger than 38 weeks postmenstrual age: Safety and efficacy have not been established; however, 1 mg/kg/dose PO twice daily has been used off-label.

Patients with Hepatic Impairment Dosing

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

Patients with Renal Impairment Dosing

The following dose adjustments are recommended for adult patients with renal impairment. Dose adjustment recommendations are unavailable for pediatric patients; however, similar dose adjustments should be considered, particularly in pediatric patients receiving the adult dosage.[31109]

 

Influenza treatment

CrCl more than 60 mL/minute: No dosage adjustment necessary.

CrCl 31 to 60 mL/minute: 30 mg PO twice daily for 5 days.

CrCl 11 to 30 mL/minute: 30 mg PO once daily for 5 days.

CrCl 10 mL/minute or less, not undergoing dialysis: Oseltamivir is not recommended.

 

Influenza prophylaxis

CrCl more than 60 mL/minute: No dosage adjustment necessary.

CrCl 31 to 60 mL/minute: 30 mg PO once daily.

CrCl 11 to 30 mL/minute: 30 mg PO every other day.

CrCl 10 mL/minute or less, not undergoing dialysis: Oseltamivir is not recommended.

 

Intermittent hemodialysis (ESRD patients with CrCl 10 mL/minute or less)

For influenza treatment: 30 mg after every hemodialysis cycle; treatment duration not to exceed 5 days. The initial dose may be given immediately, with subsequent doses administered after each dialysis.

For influenza prophylaxis: 30 mg after alternate hemodialysis cycles. The initial dose may be given prior to the start of dialysis.[31109]

 

Continuous ambulatory peritoneal hemodialysis (ESRD patients with CrCl 10 mL/minute or less)

For influenza treatment: A single 30 mg dose given immediately after dialysis exchange.

For influenza prophylaxis: 30 mg once weekly immediately after dialysis exchange.[31109]

† Off-label indication
Revision Date: 08/02/2021, 09:13:34 AM

References

25978 - Hayden FG, Atmar RL, Schilling M, et al. Use of the selective oral neuraminidase inhibitor oseltamivir to prevent influenza. N Engl J Med 1999;341:1336-1343.31109 - Tamiflu (oseltamivir phosphate) package insert. South San Francisco, CA: Genentech; 2019 Aug.43072 - Acosta EP, Jester P, Gal P, et al. Oseltamivir dosing for influenza infection in premature neonates. J Infect Dis 2010;202:563-6.52863 - Standing JF, Nika A, Tsagris V, et al. Oseltamivir pharmacokinetics and clinical experience in neonates and infants during an outbreak of H1N1 influenza A virus infection in a neonatal intensive care unit. Antimicrob Agents Chemother 2012;56:3833-3840.52865 - Maltezou HC, Drakoulis N, Siahanidou T, et al. Safety and pharmacokinetics of oseltamivir for prophylaxis of neonates exposed to influenza H1N1. Pediatr Infect Dis J 2012;31(5):527-529.52866 - Pannaraj PS, Tam B, Akan D. Oseltamivir treatment and prophylaxis in a neonatal intensive care unit during a 2009 H1N1 influenza outbreak. J Perinatol 2011;31:487-493.56854 - Kimberlin DW, Acosta EP, Prichard MN, et al. Oseltamivir pharmacokinetics, dosing, and resistance among children aged < 2 years with influenza. J Infect Dis 2013;207:709-720.62315 - Centers for Disease Control and Prevention (CDC). Influenza antiviral medications: Summary for clinicians, 2020-2021. Retrieved November 5, 2020. Available on the World Wide Web at https://www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm62336 - Centers for Disease Control and Prevention (CDC). Interim guidance on the use of antiviral medications for treatment of human infections with novel influenza A viruses associated with severe human disease. Retrieved September 11, 2017. Available on the World Wide Web at https://www.cdc.gov/flu/avianflu/novel-av-treatment-guidance.htm62337 - Centers for Disease Control and Prevention (CDC). Interim guidance on influenza antiviral chemoprophylaxis of persons exposed to birds with avian influenza A viruses associated with severe human disease or with the potential to cause severe human disease. Retrieved September 11, 2017. Available on the World Wide Web at https://www.cdc.gov/flu/avianflu/guidance-exposed-persons.htm62338 - Centers for Disease Control and Prevention (CDC). Interim guidance on follow-up of close contacts of persons infected with novel influenza A viruses associated with severe human disease and on the use of antiviral medications for chemoprophylaxis. Retrieved September 11, 2017. Available on the World Wide Web at https://www.cdc.gov/flu/avianflu/novel-av-chemoprophylaxis-guidance.htm63520 - American Academy of Pediatrics Committee on Infectious Diseases. Recommendations for Prevention and Control of Influenza in Children, 2020-2021. Pediatrics. 2020;146(4):e202002458863866 - Uyeki TM, Bernstein HH, Bradley JS, et al. Clinical Practice Guidelines by the Infectious Diseases Society of America: 2018 Update on Diagnosis, Treatment, Chemoprophylaxis, and Institutional Management of Seasonal Influenza. Clin Infect Dis 2018 Dec 19 [Epub ahead of print].

How Supplied

Oseltamivir Phosphate Oral capsule

Oseltamivir Phosphate 30mg Capsule (62332-0413) (Alembic Pharmaceuticals, Inc.) null

Oseltamivir Phosphate Oral capsule

Oseltamivir Phosphate 30mg Capsule (47781-0468) (Alvogen, Inc.) nullOseltamivir Phosphate 30mg Capsule package photo

Oseltamivir Phosphate Oral capsule

Oseltamivir Phosphate 30mg Capsule (69238-1264) (Amneal Pharmaceuticals LLC) null

Oseltamivir Phosphate Oral capsule

Oseltamivir Phosphate 30mg Capsule (42291-0666) (AvKARE, Inc.) null

Oseltamivir Phosphate Oral capsule

Oseltamivir Phosphate 30mg Capsule (31722-0630) (Camber Pharmaceuticals Inc) null

Oseltamivir Phosphate Oral capsule

Oseltamivir Phosphate 30mg Capsule (68180-0675) (Lupin Pharmaceuticals, Inc.) null

Oseltamivir Phosphate Oral capsule

Oseltamivir Phosphate 30mg Capsule (33342-0256) (MacLeods Pharma) null

Oseltamivir Phosphate Oral capsule

Oseltamivir Phosphate 30mg Capsule (63739-0038) (McKesson Packaging) (off market)

Oseltamivir Phosphate Oral capsule

Oseltamivir Phosphate 30mg Capsule (16714-0817) (Northstar Rx LLC) null

Oseltamivir Phosphate Oral capsule

Oseltamivir Phosphate 30mg Capsule (72205-0042) (Novadoz Pharmaceuticals LLC) null

Oseltamivir Phosphate Oral capsule

Oseltamivir Phosphate 30mg Capsule (64380-0797) (Strides Pharma., Inc.) null

Oseltamivir Phosphate Oral capsule

Oseltamivir Phosphate 30mg Capsule (70710-1008) (Zydus Pharmaceuticals (USA) Inc.) null

Oseltamivir Phosphate Oral capsule

Tamiflu 30mg Capsule (00004-0802) (Genentech Inc) nullTamiflu 30mg Capsule package photo

Oseltamivir Phosphate Oral capsule

Oseltamivir Phosphate 45mg Capsule (62332-0414) (Alembic Pharmaceuticals, Inc.) null

Oseltamivir Phosphate Oral capsule

Oseltamivir Phosphate 45mg Capsule (47781-0469) (Alvogen, Inc.) nullOseltamivir Phosphate 45mg Capsule package photo

Oseltamivir Phosphate Oral capsule

Oseltamivir Phosphate 45mg Capsule (69238-1265) (Amneal Pharmaceuticals LLC) null

Oseltamivir Phosphate Oral capsule

Oseltamivir Phosphate 45mg Capsule (31722-0631) (Camber Pharmaceuticals Inc) null

Oseltamivir Phosphate Oral capsule

Oseltamivir Phosphate 45mg Capsule (68180-0676) (Lupin Pharmaceuticals, Inc.) null

Oseltamivir Phosphate Oral capsule

Oseltamivir Phosphate 45mg Capsule (33342-0257) (MacLeods Pharma) null

Oseltamivir Phosphate Oral capsule

Oseltamivir Phosphate 45mg Capsule (63739-0044) (McKesson Packaging) (off market)

Oseltamivir Phosphate Oral capsule

Oseltamivir Phosphate 45mg Capsule (16714-0818) (Northstar Rx LLC) null

Oseltamivir Phosphate Oral capsule

Oseltamivir Phosphate 45mg Capsule (72205-0043) (Novadoz Pharmaceuticals LLC) null

Oseltamivir Phosphate Oral capsule

Oseltamivir Phosphate 45mg Capsule (64380-0798) (Strides Pharma., Inc.) null

Oseltamivir Phosphate Oral capsule

Oseltamivir Phosphate 45mg Capsule (70710-1009) (Zydus Pharmaceuticals (USA) Inc.) null

Oseltamivir Phosphate Oral capsule

Tamiflu 45mg Capsule (00004-0801) (Genentech Inc) nullTamiflu 45mg Capsule package photo

Oseltamivir Phosphate Oral capsule

Oseltamivir Phosphate 75mg Capsule (62332-0415) (Alembic Pharmaceuticals, Inc.) null

Oseltamivir Phosphate Oral capsule

Oseltamivir Phosphate 75mg Capsule (47781-0470) (Alvogen, Inc.) nullOseltamivir Phosphate 75mg Capsule package photo

Oseltamivir Phosphate Oral capsule

Oseltamivir Phosphate 75mg Capsule (69238-1266) (Amneal Pharmaceuticals LLC) nullOseltamivir Phosphate 75mg Capsule package photo

Oseltamivir Phosphate Oral capsule

Oseltamivir Phosphate 75mg Capsule (42291-0664) (AvKARE, Inc.) null

Oseltamivir Phosphate Oral capsule

Oseltamivir Phosphate 75mg Capsule (31722-0632) (Camber Pharmaceuticals Inc) null

Oseltamivir Phosphate Oral capsule

Oseltamivir Phosphate 75mg Capsule (68180-0677) (Lupin Pharmaceuticals, Inc.) null

Oseltamivir Phosphate Oral capsule

Oseltamivir Phosphate 75mg Capsule (33342-0258) (MacLeods Pharma) null

Oseltamivir Phosphate Oral capsule

Oseltamivir Phosphate 75mg Capsule (63739-0050) (McKesson Packaging) (off market)

Oseltamivir Phosphate Oral capsule

Oseltamivir Phosphate 75mg Capsule (16714-0819) (Northstar Rx LLC) null

Oseltamivir Phosphate Oral capsule

Oseltamivir Phosphate 75mg Capsule (72205-0044) (Novadoz Pharmaceuticals LLC) null

Oseltamivir Phosphate Oral capsule

Oseltamivir Phosphate 75mg Capsule (64380-0799) (Strides Pharma., Inc.) null

Oseltamivir Phosphate Oral capsule

Oseltamivir Phosphate 75mg Capsule (70710-1010) (Zydus Pharmaceuticals (USA) Inc.) null

Oseltamivir Phosphate Oral capsule

Tamiflu 75mg Capsule (00004-0800) (Genentech Inc) nullTamiflu 75mg Capsule package photo

Oseltamivir Phosphate Powder for oral suspension

Oseltamivir Phosphate 6mg/mL Powder for Suspension (27241-0139) (Ajanta Pharma USA Inc) null

Oseltamivir Phosphate Powder for oral suspension

Oseltamivir Phosphate 6mg/mL Powder for Suspension (47781-0384) (Alvogen, Inc.) nullOseltamivir Phosphate 6mg/mL Powder for Suspension package photo

Oseltamivir Phosphate Powder for oral suspension

Oseltamivir Phosphate 6mg/mL Powder for Suspension (69238-1273) (Amneal Pharmaceuticals LLC) null

Oseltamivir Phosphate Powder for oral suspension

Oseltamivir Phosphate 6mg/mL Powder for Suspension (42291-0567) (AvKARE, Inc.) null

Oseltamivir Phosphate Powder for oral suspension

Oseltamivir Phosphate 6mg/mL Powder for Suspension (68180-0678) (Lupin Pharmaceuticals, Inc.) null

Oseltamivir Phosphate Powder for oral suspension

Oseltamivir Phosphate 6mg/mL Powder for Suspension (00093-8180) (Teva Pharmaceuticals USA) null

Oseltamivir Phosphate Powder for oral suspension

Oseltamivir Phosphate 6mg/mL Powder for Suspension (70710-1165) (Zydus Pharmaceuticals (USA) Inc.) null

Oseltamivir Phosphate Powder for oral suspension

Tamiflu 6mg/mL Powder for Suspension (00004-0820) (Genentech Inc) (off market)Tamiflu 6mg/mL Powder for Suspension package photo

Oseltamivir Phosphate Powder for oral suspension

Tamiflu 6mg/mL Powder for Suspension (00004-0822) (Genentech Inc) nullTamiflu 6mg/mL Powder for Suspension package photo

Oseltamivir Phosphate Powder for oral suspension

Tamiflu 12mg/mL Powder for Suspension (00004-0810) (Genentech Inc) (off market)Tamiflu 12mg/mL Powder for Suspension package photo

Description/Classification

Description

Oseltamivir is an oral neuraminidase inhibitor (NAI) indicated for the treatment and prevention of acute, uncomplicated seasonal influenza infections. Like other NAIs (zanamivir and peramivir), oseltamivir has activity against both influenza A and B viruses; whereas adamantanes (amantadine and rimantadine) are active against influenza A only.[52875] Clinical benefit from antiviral therapy is greatest when initiated early; therefore, the FDA-approved labeling recommends initiating oseltamivir within 48 hours of influenza symptom onset (for treatment) or close contact with an infected individual (post-exposure prophylaxis).[31109] However, according to the Centers for Disease Control and Prevention (CDC), specific patient populations (including those with severe, complicated, or progressive illness, pregnant women of any trimester, and hospitalized patients) may still receive benefit from antiviral treatment if initiated after 48 hours of illness onset. Oseltamivir is not considered a substitute for annual influenza virus vaccination. Instead, NAI antiviral drugs are considered adjuncts to the prevention and control of influenza; annual influenza vaccination remains the main option for reducing the impact of influenza.[62315] [63866]

Classifications

  • General Anti-infectives Systemic
    • Antivirals For Systemic Use
      • Neuraminidase Inhibitor Antivirals
Revision Date: 04/02/2019, 04:28:08 PM

References

31109 - Tamiflu (oseltamivir phosphate) package insert. South San Francisco, CA: Genentech; 2019 Aug.52875 - Moscona A. Neuraminidase inhibitors for influenza. N Engl J Med 2005;353:1363-1373.62315 - Centers for Disease Control and Prevention (CDC). Influenza antiviral medications: Summary for clinicians, 2020-2021. Retrieved November 5, 2020. Available on the World Wide Web at https://www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm63866 - Uyeki TM, Bernstein HH, Bradley JS, et al. Clinical Practice Guidelines by the Infectious Diseases Society of America: 2018 Update on Diagnosis, Treatment, Chemoprophylaxis, and Institutional Management of Seasonal Influenza. Clin Infect Dis 2018 Dec 19 [Epub ahead of print].

Administration Information

General Administration Information

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

Route-Specific Administration

Oral Administration

  • May be taken orally with or without food; tolerability may be enhanced if taken with food.
  • Begin treatment within 48 hours of symptom onset. Begin prophylaxis within 48 hours of exposure.[31109]

Oral Solid Formulations

  • For patients who cannot swallow capsules, the commercially available oral suspension is the preferred formulation. However, if the oral suspension is not available, the capsules may be opened and mixed with sweetened liquids such as regular or sugar-free chocolate syrup, corn syrup, caramel topping, or light brown sugar dissolved in water. If the appropriate strengths of capsules are not available to mix with sweetened liquids and the commercially available oral suspension is not available, then a compounded supply of oral suspension can be prepared by the pharmacist (see below).[31109]

Oral Liquid Formulations

  • Shake well before use.
  • Administer using a calibrated measuring device.[31109]

 

Reconstitution of commercially available 6 mg/mL oral suspension:

  • Review the reconstitution instructions for the particular product and package size, as the amount of water required for reconstitution varies from manufacturer to manufacturer.
  • Loosen powder from sides of the bottle. Add the specified amount of water and shake well for 15 seconds. The final oseltamivir concentration is 6 mg/mL.
  • Remove the child-resistant cap and push bottle adapter into the neck of the bottle.
  • Close tightly with the child-resistant cap. This will ensure proper sealing of the bottle.
  • Place an ancillary label on the bottle stating 'Shake Well Before Use', and dispense with the appropriate oral dosing syringe.
  • Storage after reconstitution: Use within 17 days of reconstitution when stored under refrigeration [2 to 8 degrees C (36 to 46 degrees F); DO NOT freeze] or within 10 days if stored at room temperature [15 to 30 degrees C (59 to 86 degree F)]. Write the expiration date on the label.[31109]

Extemporaneous Compounding-Oral

  • Shake well before use.
  • Administer using a calibrated measuring device.[31109]

 

Extemporaneous 6 mg/mL oral suspension (using capsules):

  • Compounded suspensions are for use only during emergency situations and should not be used for convenience or when the FDA-approved oral suspension is commercially available.
  • The recommended vehicles are Cherry Syrup (Humco), Ora-Sweet SF (Paddock Laboratories), or simple syrup; other vehicles have not been studied. The final oseltamivir concentration in the compounded suspension is 6 mg/mL, which is the SAME as the commercially available oral suspension.
  • The total volume of suspension needed to prepare a full course (5-day treatment course or 10-day course of prophylaxis) is based on the patient's dose (see below). If the oseltamivir dose is between the doses listed, the total volume of the oral suspension should default to the next greater dose listed.
    • Oseltamivir dose of 15 mg or less: Prepare a 37.5 mL suspension using three (3) 75-mg capsules (225 mg oseltamivir), 2.5 mL of water, and 34.5 mg of recommended vehicle.
    • Oseltamivir dose of 30 mg: Prepare a 75 mL suspension using six (6) 75-mg capsules (450 mg oseltamivir), 5 mL of water, and 69 mL of recommended vehicle.
    • Oseltamivir dose of 45 mg: Prepare a 100 mL suspension using eight (8) 75-mg capsules (600 mg oseltamivir), 7 mL of water, and 91 mL of recommended vehicle.
    • Oseltamivir dose of 60 mg: Prepare a 125 mL suspension using ten (10) 75-mg capsules (750 mg oseltamivir), 8 mL of water, and 115 mL of recommended vehicle.
    • Oseltamivir dose of 75 mg: Prepare a 150 mL suspension using twelve (12) 75-mg capsules (900 mg oseltamivir), 10 mL of water, and 137 mL of recommended vehicle.[31109]

 

Compounding the 6 mg/mL oral suspension:

  • Add the above specified volume of water to a polyethyleneterephthalate (PET) or glass bottle; a funnel may be used to prevent spillage.
  • Carefully open each capsule and transfer contents into the PET or glass bottle.
  • Gently swirl the suspension for at least 2 minutes.
  • Slowly add the above specified volume of vehicle to the bottle; a funnel may be used to prevent spillage.
  • Shake well for 30 seconds to completely dissolve the active drug and to ensure homogenous distribution of the dissolved drug in the resulting suspension. It should be noted that oseltamivir phosphate readily dissolves in the recommended vehicles and that the suspension is due to some inert ingredients of the capsules that are insoluble in these vehicles.
  • Place an ancillary label on the bottle stating 'Shake Well Before Use', and dispense with the appropriate oral dosing syringe.
  • The compounded oral suspension is stable for 5 days when stored at room temperature 25 degrees C (77 degrees F) or for 5 weeks (35 days) under refrigeration at 2 to 8 degrees C (36 to 46 degrees F). However, if pharmacies are preparing batches of the extemporaneously compounded suspension due to high prescription volume, the compounded suspension must be refrigerated until dispensed, stirred thoroughly before dispensing, and refrigerated by the patient at home.[37104]

Clinical Pharmaceutics Information

From Trissel's 2‚Ñ¢ Clinical Pharmaceutics Database
Revision Date: 11/09/2020, 05:04:25 PMCopyright 2004-2021 by Lawrence A. Trissel. All Rights Reserved.

References

31109 - Tamiflu (oseltamivir phosphate) package insert. South San Francisco, CA: Genentech; 2019 Aug.37104 - Food and Drug Administration. Guidance to pharmacies on advance compounding of Tamiflu oral suspension to provide for multiple pescriptions. Retrieved Nov. 2, 2009. Available on the World Wide Web at http://www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/ucm188629.htm.

Adverse Reactions

Mild

  • agitation
  • anxiety
  • diaper dermatitis
  • diarrhea
  • dyspepsia
  • emotional lability
  • headache
  • hypothermia
  • nausea
  • nightmares
  • rash
  • urticaria
  • vomiting

Severe

  • anaphylactic shock
  • anaphylactoid reactions
  • angioedema
  • arrhythmia exacerbation
  • erythema multiforme
  • GI bleeding
  • laryngeal edema
  • seizures
  • Stevens-Johnson syndrome
  • toxic epidermal necrolysis

Moderate

  • colitis
  • confusion
  • delirium
  • elevated hepatic enzymes
  • hallucinations
  • hepatitis
  • hyperglycemia
  • psychosis

The most frequent adverse effects associated with oseltamivir are nausea and vomiting, which usually occur during the first 2 days of treatment. Vomiting was reported more frequently in both pediatric patients and adults who received the twice daily treatment dose compared with the once daily prophylactic dose. In adults, vomiting was reported in 8% with 75 mg twice daily and 2% with 75 mg once daily; the respective numbers for children were 16% and 8%. Nausea was also reported with treatment doses (10% of adults) and prophylactic doses (8% adults). Vomiting (9%) and diarrhea (7%) were the most common GI adverse reactions reported in treatment studies in infants younger than 1 year of age. Oseltamivir may be taken with or without food, but tolerability may be enhanced if it is taken with food. Dyspepsia and diarrhea may occur in patients with hereditary fructose intolerance and using oseltamivir powder for oral suspension because of the sorbitol content. Elevated hepatic enzymes, hepatitis, GI bleeding, and hemorrhagic colitis have been noted in postmarketing reports.[31109]

Dermatologic reactions observed during clinical practice with oseltamivir include rash, dermatitis, eczema, and urticaria. Diaper dermatitis was reported in 7% of infants less than 1 year of age receiving oseltamivir in clinical trials. During the postmarketing surveillance period, rare cases of anaphylactoid reactions such as anaphylactic shock and swelling of face or tongue (laryngeal edema or angioedema) and serious skin reactions such as toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme have been reported. Because these reactions are reported voluntarily, it is impossible to reliably estimate the frequency or establish a causal relationship to oseltamivir. Stop oseltamivir and institute appropriate treatment if an allergic reaction or suspected allergic reaction occurs.[31109]

It is unclear whether the use of oseltamivir may be associated with psychiatric adverse reactions; patients or caregivers should report any emotional lability or abnormal behavior while taking oseltamivir. Postmarketing reports of self-injury, delirium (psychosis), hallucinations, agitation, anxiety, altered consciousness, confusion, nightmares, and delusions have been reported with oseltamivir use, mainly in pediatric patients with active influenza infection. These events often had an abrupt onset and rapid resolution. Influenza infection itself may be associated with a variety of neurologic and behavioral symptoms; while symptoms may occur in the setting of encephalitis or encephalopathy, they can occur without obvious severe disease. The relative contribution of oseltamivir to the postmarketing reports of neurological symptoms is not known.[31109] A review of data from controlled clinical trials and ongoing surveillance has failed to confirm a link between oseltamivir and psychiatric effects.[63520] Seizures have also been noted in postmarketing reports.[31109]

During clinical trials, 17% of adults receiving the prophylactic dose of oseltamivir (75 mg PO once daily) experienced a headache, compared to 16% of the patients receiving placebo. The incidence of headaches decreased to 2% when the treatment dose (75 mg PO twice daily) was administered. In addition, more patients receiving the prophylactic dose experienced generalized pain when compared to those receiving the higher treatment dose (4% vs. less than 1%).[31109]

Arrhythmia exacerbation, aggravation of diabetes (hyperglycemia), and hypothermia have been noted in postmarketing reports with oseltamivir.[31109]

Revision Date: 11/09/2020, 04:43:16 PM

References

31109 - Tamiflu (oseltamivir phosphate) package insert. South San Francisco, CA: Genentech; 2019 Aug.63520 - American Academy of Pediatrics Committee on Infectious Diseases. Recommendations for Prevention and Control of Influenza in Children, 2020-2021. Pediatrics. 2020;146(4):e2020024588

Contraindications/Precautions

Absolute contraindications are italicized.

  • breast-feeding
  • cardiac disease
  • hepatic disease
  • hereditary fructose intolerance
  • immunosuppression
  • infection
  • pregnancy
  • psychosis
  • pulmonary disease
  • renal failure
  • renal impairment
  • serious rash
  • vaccination
  • viral infection

Serious bacterial infections may begin with influenza-type symptoms, or may coexist with or occur as complications of influenza. There are no data to suggest oseltamivir is effective in treating a viral infection other than influenza virus A and B. Data on the treatment of influenza B infection are limited; only 3% of patients in the clinical trials were infected with this virus. Oseltamivir is most effective when initiated within 48 hours of symptom onset or close contact with an infected individual; however, limited data suggest antiviral therapy may still be beneficial to high risk patients when initiated up to 5 days after illness onset.[31109] [62315]

Antiviral medications with activity against influenza, such as oseltamivir, are not substitutes for receipt of an annual influenza vaccination; these medications should be used as an adjunct to the vaccine in the control of influenza. Oseltamivir does not interfere with the antibody response to the inactivated influenza vaccine; however, there is concern about possible interference with the viral replication necessary after administration of the live attenuated influenza vaccine for the proper development of immunity. Do not administer the live attenuated influenza vaccine within 48 hours after oseltamivir administration, and wait at least 2 weeks after administration of the live attenuated vaccine to begin oseltamivir therapy, unless earlier oseltamivir therapy is medically necessary. According to the manufacturer, efficacy of oseltamivir has not been established in immunocompromised patients or those with immunosuppression.[31109] However, the Centers for Disease Control and Prevention (CDC) recommends oseltamivir for the treatment and prevention of influenza in patients with immune deficiencies and those receiving immunosuppressive medications.[62315]

Efficacy of oseltamivir, as measured by time to alleviation of all symptoms, has not been established in patients with chronic pulmonary disease or cardiac disease. However, oseltamivir studies have included 'at-risk' adult patients with cardiac disease, adults with chronic obstructive pulmonary disease (COPD) (i.e., chronic bronchitis or emphysema), and older pediatric patients with asthma; the incidence of complications in these patient populations did not differ between oseltamivir and placebo. In addition, studies evaluating safety and efficacy of the drug in elderly (age older than 65 years) and younger adult patients have found no overall difference. Safety and efficacy of oseltamivir have been established in elderly nursing home residents who took oseltamivir for up to 42 days for the prevention of influenza. Many of these individuals had cardiac or respiratory disease, and most had received the influenza vaccine that season. Patients with chronic health conditions are at higher risk for developing complications associated with influenza infection, and the Centers for Disease Control and Prevention (CDC) recommends oseltamivir use in these patient populations for the treatment and prophylaxis of influenza.[62315] No information is available regarding oseltamivir treatment of influenza in patients with any medical condition sufficiently severe or unstable to be considered as having an imminent risk of hospitalization.[31109]

Oseltamivir is not recommended for patients with end stage renal failure (creatinine clearance 10 mL/minute or less) who are not receiving dialysis. Dosage adjustments are recommended in adult patients with moderate to severe renal impairment (creatinine clearance 60 mL/minute or less) and for patients on dialysis; consider similar adjustments in pediatric patients. The active metabolite of oseltamivir is greater than 99% renally eliminated; therefore, patients with renal impairment are at increased risk for drug accumulation and adverse effects.[31109]

The safety and pharmacokinetics of oseltamivir have not been established in patients with severe hepatic disease. During clinical studies, the pharmacokinetics of oseltamivir were not changed in patients with mild or moderate hepatic impairment.[31109]

Neuropsychiatric adverse reactions of self-injury and delirium (psychosis) have been reported during postmarketing use of oseltamivir; some cases resulted in fatal outcomes. These reactions were primarily reported in pediatric patients and often occurred abruptly and resolved rapidly. Since influenza infection itself is associated with a variety of neurologic and behavioral symptoms (e.g., hallucinations, delirium, abnormal behavior), the role of oseltamivir in causing these reactions is unclear. Patients with influenza who are receiving oseltamivir should be closely monitored for signs of abnormal behavior. The risks and benefits of continuing oseltamivir should be evaluated if neuropsychiatric events occur.[31109]

Use caution in patients with hereditary fructose intolerance as the oseltamivir powder for oral suspension contains 11 g of sorbitol per 13-g bottle. A 75 mg dose of the suspension will deliver 2 g of sorbitol, which is above the daily maximum limit of sorbitol. Dyspepsia and diarrhea may occur in patients with hereditary fructose intolerance.[31109]

No adequate and well-controlled studies have been conducted regarding the use of oseltamivir during pregnancy; however, a collection of observational studies have evaluated drug exposure in more than 5,000 pregnant women. Although, individually, these studies lacked adequate sample size, pooled data found no increased risk of congenital malformations when compared to the general population. In addition, the gestational period in which exposure occurred appeared to have no effect on pregnancy outcome, as approximately 1,000 women were exposed during the first trimester. In animal studies, slight and marked maternal toxicities and a dose-dependent increase in skeletal abnormalities in offspring were observed. The manufacturer states that oseltamivir should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus. According to the CDC, pregnant women are known to be at higher risk for complications from influenza infection and severe disease among women has been reported in past pandemics; therefore, guidelines state that the benefits of treatment against the influenza virus likely outweigh the theoretical risks of antiviral use. The CDC considers oseltamivir the preferred antiviral for treatment of influenza in pregnant women.[28647] [31109] [62315]

Limited data suggest oseltamivir and oseltamivir carboxylate are excreted in human breast milk.[31109] The concentration of oseltamivir and oseltamivir carboxylate in breast milk was found to be lower than the concentrations in plasma following a single 75 mg oral dose. The estimated infant exposure to oseltamivir, assuming a 2.75 kg infant receiving 750 mL of breast milk daily, was 0.76 mcg/kg/day.[46321] This dose is much lower than oseltamivir doses used in neonates and infants for treatment of influenza; thus, exposure through breast milk is unlikely to lead to toxicity in the breastfed infant. Postmarketing experience has not reported any information to suggest serious adverse effects of oseltamivir exposure via breast milk in infants. It is not known if oseltamivir affects human milk production. The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for oseltamivir and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition.[31109]

Revision Date: 11/09/2020, 04:13:20 PM

References

28647 - Centers for Disease Control and Prevention (CDC). Antiviral Agents for the Treatment and Chemoprophylaxis of Influenza: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2011;60:1-26.31109 - Tamiflu (oseltamivir phosphate) package insert. South San Francisco, CA: Genentech; 2019 Aug.46321 - Greer LG, Leff RD, Rogers VL, et al. Pharmacokinetics of oseltamivir in breast milk and maternal plasma. Am J Obstet Gynecol 2011;204:524.62315 - Centers for Disease Control and Prevention (CDC). Influenza antiviral medications: Summary for clinicians, 2020-2021. Retrieved November 5, 2020. Available on the World Wide Web at https://www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm

Mechanism of Action

Oseltamivir is an ethyl ester prodrug that requires hydrolysis to the active metabolite, oseltamivir carboxylate. Once in circulation, oseltamivir carboxylate acts extracellularly by selectively binding to an unoccupied area of viral neuraminidase (a surface glycoprotein on influenza A and B that catalyzes the cleavage of the linkage between a terminal sialic acid and adjacent sugar residue), resulting in competitive inhibition of the enzyme. By inhibiting the actions of viral neuraminidase, oseltamivir ultimately prevents the spread of virus in the respiratory tract.[31109][62315]

 

Influenza viruses are classified into 3 distinct types, influenza A, influenza B, and influenza C. Influenza A is further divided into subtypes based on their hemagglutinin (H or HA) and neuraminidase (N or NA) activity. At least 16 distinct HAs (H1 to H16) and 9 NAs (N1 to N9) have been described. Influenza infection may be attributed to either influenza A virus or influenza B virus. Influenza A virus subtypes include H1N1 and H3N2. In 2009, a novel influenza A H1N1 virus (previously referred to as swine influenza) was identified; this virus is included in season influenza A viruses. Human cases of influenza illness from the avian H5N1 virus (commonly known as avian flu) have been reported since 1997. Human infections with avian H7N9, H5N2, H5N8, H9N2, H7N7, and H7N3 viruses have also been described.[36906][62337]

 

A neuraminidase assay of clinical isolates identified the median IC50 (50% inhibitory concentration) for oseltamivir carboxylate against influenza A/H1N1, influenza A/H3N2, and influenza B to be 2.5 nM (range 0.93 to 4.16 nM), 0.96 nM (range 0.13 to 7.95 nM), and 60 nM (range 20 to 285 nM), respectively. An evaluation of antiviral activity using laboratory and clinical influenza isolates found the concentrations of oseltamivir carboxylate required for inhibition of influenza virus in cell culture to be highly variable depending on the assay method used and virus testing. Specifically, the EC50 and EC90 (50% and 90% effective inhibitory concentration) of these cell cultures ranged from 0.0008 micromolar to more than 35 micromolar and 0.004 micromolar to more than 100 micromolar, respectively. A relationship between antiviral activity in cell culture, inhibitory activity in neuraminidase assay, and inhibition of influenza virus replication in humans has not been established. Influenza treatment emergent resistance to oseltamivir has been reported, with most cases occurring in influenza A/H1N1 viruses. Genetic analysis shows that reduced susceptibility to oseltamivir carboxylate is associated with mutations that result in amino acid changes in the viral neuraminidase or viral hemagglutinin or both. The prevalence of oseltamivir-resistant viruses varies based on season and geographic location. Severely immunosuppressed persons (e.g., hematopoietic stem cell transplant recipients) are at highest risk for developing an oseltamivir-resistant influenza virus infection during or after antiviral therapy. In addition, selection of influenza A viruses resistant to oseltamivir appears to occur at higher frequencies in pediatric populations. During small pediatric studies, the incidence of oseltamivir treatment-associated resistance for influenza A/H1N1 and influenza A/H3N2 were 27% to 37% and 3% to 18%, respectively. The actual risk of resistance to oseltamivir during clinical use cannot be determined from these small pediatric studies. The CDC Influenza Division is available for consultation regarding resistance testing as needed.[31109][62315]

Revision Date: 07/28/2018, 01:36:38 AM

References

31109 - Tamiflu (oseltamivir phosphate) package insert. South San Francisco, CA: Genentech; 2019 Aug.36906 - Treanor JJ. Influenza viruses (including avian influenza and swine influenza). In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases, 8th ed. New York: Churchhill Livingstone; 2015:2000-2024.62315 - Centers for Disease Control and Prevention (CDC). Influenza antiviral medications: Summary for clinicians, 2020-2021. Retrieved November 5, 2020. Available on the World Wide Web at https://www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm62337 - Centers for Disease Control and Prevention (CDC). Interim guidance on influenza antiviral chemoprophylaxis of persons exposed to birds with avian influenza A viruses associated with severe human disease or with the potential to cause severe human disease. Retrieved September 11, 2017. Available on the World Wide Web at https://www.cdc.gov/flu/avianflu/guidance-exposed-persons.htm

Pharmacokinetics

Oseltamivir is administered orally. Following absorption from the gastrointestinal tract, most of the dose (at least 90%) is hydrolyzed by hepatic esterase to the active metabolite, oseltamivir carboxylate. Oseltamivir carboxylate does not undergo any further metabolism and is only minimally bound to human plasma proteins (3%). The elimination half-life of oseltamivir carboxylate is 6 to 10 hours, with more than 99% being eliminated in the urine via glomerular filtration and active tubular secretion. The elimination half-life of the parent drug is 1 to 3 hours.[31109]

 

Affected cytochrome P450 isoenzymes: none

Neither oseltamivir nor oseltamivir carboxylate are substrates for, or inhibitors of, cytochrome P450 isoenzymes.[31109]

Route-Specific Pharmacokinetics

Oral Route

After oral administration, 75% of the dose reaches systemic circulation as oseltamivir carboxylate; less than 5% of the total dose reaches the systemic circulation as oseltamivir. Administration with food has no effect on the maximum plasma concentration (Cmax) or exposure (AUC) values for oseltamivir carboxylate.[31109]

Special Populations

Hepatic Impairment

In clinical studies, oseltamivir carboxylate systemic exposure was not altered in patients with mild or moderate hepatic impairment; pharmacokinetics in patients with severe hepatic impairment have not been evaluated.[31109]

Renal Impairment

In patients with decreased renal function, oseltamivir carboxylate exposure is inversely proportional to declining renal function. Dosage adjustments are recommended for adults with a creatinine clearance less than 60 mL/minute, including those patients with renal failure (less than 10 mL/minute) who are receiving dialysis. Patients with renal impairment who receive the manufacturer recommended dosage adjustments based on creatinine clearance, have pharmacokinetic exposure parameters (i.e., Cmax, Cmin, AUC) that are similar to those observed in patients with normal renal function. Patients with renal failure (creatinine clearance less than 10 mL/minute) not undergoing dialysis have not been studied; dosage adjustments for these patients are not available.[31109]

Pediatrics

Adolescents

Pharmacokinetics in adolescents are similar to those seen in adults.[31109] Mean oseltamivir carboxylate (active metabolite) clearance and elimination half-life of 5.3 mL/kg/minute and 8.1 hours, respectively, have been reported in adolescents.[52881]

 

Children

Oseltamivir clearance gradually decreases with increasing age (up to 12 years).[31109][52881] In a pharmacokinetic study (n = 12), clearance values for oseltamivir were 259 mL/kg/minute and 170 mL/kg/minute for children 1 to 2 years and 3 to 5 years, respectively. Corresponding values for oseltamivir carboxylate clearance were 12.2 mL/kg/minute and 9.4 mL/kg/minute, respectively.[52872] In pooled data from 2 other pharmacokinetic studies in pediatric patients, mean oseltamivir carboxylate clearance and elimination half-life of 10.5 mL/kg/minute and 7.8 hours, respectively, were reported for children 1 to 12 years.[52881]

 

Infants

Oseltamivir clearance increases with increasing age in infants and pharmacokinetic data in infants 9 to 11 months have shown that a higher weight-based dose is needed in this age group, compared to younger infants, to achieve target drug exposure. A dose of 3.5 mg/kg/dose twice daily was required in infants 9 to 11 months to achieve exposure within the target range (mean oseltamivir carboxylate AUC 2660 to 7700 ng x hour/mL) in a pharmacokinetic study in 87 infants and children < 2 years. Although a dose of 3 mg/kg/dose twice daily resulted in exposures within the target range for infants 0 to 8 months, high interpatient variability was noted. High interpatient variability was also noted among the entire population for oseltamivir carboxylate pharmacokinetic parameters. Clearance values ranged from 1.04 to 13.79 L/hour for infants 0 to 2 months, 1.43 to 6.83 L/hour for infants 3 to 5 months, 2.45 to 15 L/hour for infants 6 to 8 months, and 2.81 to 9.49 L/hour for infants 9 to 11 months. Corresponding elimination half-lives ranged from 4.65 to 28.71 hours for infants 0 to 2 months, 6.25 to 19 hours for infants 3 to 5 months, 1.02 to 78.26 hours for infants 6 to 8 months, and 5.4 to 51.86 hours for infants 9 to 11 months.[56854]

 

Neonates

Premature neonates eliminate oseltamivir more slowly than term neonates and infants and, therefore, require lower dosages. Data from several small pharmacokinetic trials in premature neonates suggest that oseltamivir 1 mg/kg/dose PO twice daily achieves similar oseltamivir carboxylate exposure to that seen in infants and young children receiving the recommended dose of 3 mg/kg/dose twice daily; however, some trials found significant interpatient variability.[43072][52862][52863][52865][56854] Interestingly, the clearance of oseltamivir, which represents the conversion of parent drug to active metabolite, is higher in neonates compared to older infants and children. However, elimination of the active metabolite is slower in neonates compared to older children due to immature renal function.[52865]

Geriatric

In elderly patients (age 65 to 78 years), oseltamivir carboxylate exposures at the steady-state AUC were 25% to 35% higher than values observed in younger patients given comparable oseltamivir doses. However, the observed half-lives were similar between the two groups, and no dosage adjustments were required.[31109]

Other

Pregnancy

Although data are insufficient to recommend dosage adjustments, an analysis of pooled pharmacokinetic parameters found exposure to the active metabolite of oseltamivir to be lower in pregnant women (n = 59) than in non-pregnant women (n = 33). Drug exposures in pregnant women are expected to be high enough to maintain activity against susceptible influenza virus strains.[31109]

Revision Date: 07/17/2018, 01:47:48 PM

References

31109 - Tamiflu (oseltamivir phosphate) package insert. South San Francisco, CA: Genentech; 2019 Aug.43072 - Acosta EP, Jester P, Gal P, et al. Oseltamivir dosing for influenza infection in premature neonates. J Infect Dis 2010;202:563-6.52862 - McPherson C, Warner B, Hunstad DA, et al. Oseltamivir dosing in premature infants. JID 2012;206:847-850.52863 - Standing JF, Nika A, Tsagris V, et al. Oseltamivir pharmacokinetics and clinical experience in neonates and infants during an outbreak of H1N1 influenza A virus infection in a neonatal intensive care unit. Antimicrob Agents Chemother 2012;56:3833-3840.52865 - Maltezou HC, Drakoulis N, Siahanidou T, et al. Safety and pharmacokinetics of oseltamivir for prophylaxis of neonates exposed to influenza H1N1. Pediatr Infect Dis J 2012;31(5):527-529.52872 - Oo C, Hill G, Dorr A, et al. Pharmacokinetics of anti-influenza prodrug oseltamivir in children aged 1-5 years. Eur J Clin Pharmacol 2003;59:411-415.52881 - Oo C, Barrett J, Hill G, et al. Pharmacokinetics and dosage recommendations for an oseltamivir oral suspension for the treatment of influenza in children. Paediatr Drugs 2001;3:229-236.56854 - Kimberlin DW, Acosta EP, Prichard MN, et al. Oseltamivir pharmacokinetics, dosing, and resistance among children aged < 2 years with influenza. J Infect Dis 2013;207:709-720.

Pregnancy/Breast-feeding

pregnancy

No adequate and well-controlled studies have been conducted regarding the use of oseltamivir during pregnancy; however, a collection of observational studies have evaluated drug exposure in more than 5,000 pregnant women. Although, individually, these studies lacked adequate sample size, pooled data found no increased risk of congenital malformations when compared to the general population. In addition, the gestational period in which exposure occurred appeared to have no effect on pregnancy outcome, as approximately 1,000 women were exposed during the first trimester. In animal studies, slight and marked maternal toxicities and a dose-dependent increase in skeletal abnormalities in offspring were observed. The manufacturer states that oseltamivir should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus. According to the CDC, pregnant women are known to be at higher risk for complications from influenza infection and severe disease among women has been reported in past pandemics; therefore, guidelines state that the benefits of treatment against the influenza virus likely outweigh the theoretical risks of antiviral use. The CDC considers oseltamivir the preferred antiviral for treatment of influenza in pregnant women.[28647] [31109] [62315]

breast-feeding

Limited data suggest oseltamivir and oseltamivir carboxylate are excreted in human breast milk.[31109] The concentration of oseltamivir and oseltamivir carboxylate in breast milk was found to be lower than the concentrations in plasma following a single 75 mg oral dose. The estimated infant exposure to oseltamivir, assuming a 2.75 kg infant receiving 750 mL of breast milk daily, was 0.76 mcg/kg/day.[46321] This dose is much lower than oseltamivir doses used in neonates and infants for treatment of influenza; thus, exposure through breast milk is unlikely to lead to toxicity in the breastfed infant. Postmarketing experience has not reported any information to suggest serious adverse effects of oseltamivir exposure via breast milk in infants. It is not known if oseltamivir affects human milk production. The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for oseltamivir and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition.[31109]

Revision Date: 11/09/2020, 04:13:20 PM

References

28647 - Centers for Disease Control and Prevention (CDC). Antiviral Agents for the Treatment and Chemoprophylaxis of Influenza: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2011;60:1-26.31109 - Tamiflu (oseltamivir phosphate) package insert. South San Francisco, CA: Genentech; 2019 Aug.46321 - Greer LG, Leff RD, Rogers VL, et al. Pharmacokinetics of oseltamivir in breast milk and maternal plasma. Am J Obstet Gynecol 2011;204:524.62315 - Centers for Disease Control and Prevention (CDC). Influenza antiviral medications: Summary for clinicians, 2020-2021. Retrieved November 5, 2020. Available on the World Wide Web at https://www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm

Interactions

Level 2 (Major)

  • Dichlorphenamide
  • Live Attenuated Influenza Vaccine (intranasal)

Level 4 (Minor)

  • Colchicine; Probenecid
  • Probenecid
Colchicine; Probenecid: (Minor) Coadministration of oseltamivir and probenecid results in a two-fold increase in exposure to oseltamivir carboxylate due to a decrease in active anionic tubular secretion in the kidney. However, due to the safety margin of oseltamivir carboxylate, no dosage adjustments are required when oseltamivir is given concomitantly with probenecid. [31109] Dichlorphenamide: (Major) Concomitant use of dichlorphenamide and oseltamivir is not recommended because of an increased risk of oseltamivir-related adverse effects. Monitor closely for signs of drug toxicity if coadministration cannot be avoided. Increased oseltamivir exposure is possible. Dichlorphenamide inhibits OAT1. Oseltamivir is a sensitive OAT1 substrate. Consider if an alternative to oseltamivir would be appropriate for the patient. [56579] [60122] Live Attenuated Influenza Vaccine (intranasal): (Major) Do not administer intranasal live attenuated influenza vaccine (LAIV) 2 weeks before or 48 hours after administration of oseltamivir, unless medically indicated. Inactivated influenza vaccines may be used, as appropriate. Because of its antiviral properties, oseltamivir may interfere with the efficacy of live attenuated influenza vaccines. Therefore, live influenza virus vaccines are not recommended during treatment with oseltamivir. Consult currently recommended guidance on the use of antiviral drugs against influenza. [31109] [63436] Probenecid: (Minor) Coadministration of oseltamivir and probenecid results in a two-fold increase in exposure to oseltamivir carboxylate due to a decrease in active anionic tubular secretion in the kidney. However, due to the safety margin of oseltamivir carboxylate, no dosage adjustments are required when oseltamivir is given concomitantly with probenecid. [31109]
Revision Date: 10/14/2020, 02:50:00 AM

References

31109 - Tamiflu (oseltamivir phosphate) package insert. South San Francisco, CA: Genentech; 2019 Aug.56579 - Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. Updated Mar 10, 2020. Retrieved from the World Wide Web at www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm60122 - Keveyis (dichlorphenamide) tablets package insert. Trevose, PA: Strongbridge US Inc.; 2019 Nov.63436 - Grohskopf LA, Alyanak E, Broder KR, et al. Prevention and Control of Seasonal Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization Practices - United States, 2020-2021 Influenza Season. MMWR 2020;69(No. RR-8):1-24.

Monitoring Parameters

  • laboratory monitoring not necessary

US Drug Names

  • Tamiflu
;