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Oseltamivir
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General dosing information:
Seasonal influenza virus:
Novel influenza A viruses associated with severe human disease, including avian influenza virus:
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
3.5 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.[56854] [62315] [62336] [63520]
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.[56854] [62315] [62336] [63520]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
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]
75 mg PO twice daily.
75 mg PO twice daily.
75 mg PO twice daily.
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.
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.
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.
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.
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
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]
For storage information, see the specific product information within the How Supplied section.
Reconstitution of commercially available 6 mg/mL oral suspension:
Extemporaneous 6 mg/mL oral suspension (using capsules):
Compounding the 6 mg/mL oral suspension:
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]
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]
Oseltamivir is contraindicated in any patient with known hypersensitivity to the drug or to any component of the formulation. Cases of anaphylaxis and serious rash, including toxic epidermal necrolysis, Stevens-Johnson Syndrome, and erythema multiforme, have been reported in postmarketing experience with oseltamivir. Discontinue oseltamivir and institute appropriate treatment if an allergic-like reaction occurs or is suspected.[31109]
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]
Pregnant and postpartum patients are at significantly higher risk for serious complications from influenza infection as compared with nonpregnant people; therefore, timely use of antiviral therapy is recommended for the treatment and post-exposure prevention of influenza. The Centers for Disease Control and Prevention (CDC) and the American College of Obstetricians and Gynecologists (ACOG) consider oseltamivir the preferred antiviral for treatment of influenza in pregnant patients and recommends oseltamivir for postexposure prophylaxis in pregnant patients who have had close contact with infectious individuals. 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 patients. 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 patients 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.[28647] [31109] [62315] [70419]
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]
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: 12/05/2024, 01:30:01 PMOseltamivir 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]
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]
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]
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]
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]
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]
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]
Pregnant and postpartum patients are at significantly higher risk for serious complications from influenza infection as compared with nonpregnant people; therefore, timely use of antiviral therapy is recommended for the treatment and post-exposure prevention of influenza. The Centers for Disease Control and Prevention (CDC) and the American College of Obstetricians and Gynecologists (ACOG) consider oseltamivir the preferred antiviral for treatment of influenza in pregnant patients and recommends oseltamivir for postexposure prophylaxis in pregnant patients who have had close contact with infectious individuals. 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 patients. 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 patients 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.[28647] [31109] [62315] [70419]
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]
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