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Oseltamivir
J05A - Direct acting antiviralsATC J05AH02Small moleculeapproved 1999OralProdrugNatural product
Active form: Oseltamivir Carboxylate.
JFDA label: Tamiflu Oral suspension
Mechanism of Action
Oseltamivir, a prodrug, is hydrolyzed to the active form, oseltamivir carboxylate (OC). OC inhibits influenza virus neuraminidase, an enzyme known to cleave the budding viral progeny from its cellular envelope attachment point (neuraminic acid) just prior to release.
Indications
Approved
Prophylaxis of influenza
The ACIP recommends that prophylaxis be considered for the following
Treatment of influenza
• Persons at higher risk for influenza complications
Off-label
Community-acquired pneumonia (children)
Antimicrobial Spectrum
Expected / intrinsic spectrum (EUCAST breakpoints & labels) — not local resistance. Source: openfda-label.
Viruses
Organism
Activity
MIC
Influenza
Active
—
Influenza A
Active
—
Influenza B
Active
—
Class profile
targetVirus
Influenza A/B
viralClass
Orthomyxoviridae (-ssRNA)
targetStep
Neuraminidase (NA inhibitor, sialic acid analogue)
resistanceBarrier
Low to Moderate (H275Y in H1N1 confers high-level resistance; I223R in H3N2)
crossResistance
Partial cross-resistance with zanamivir depends on NA subtype and mutation
source
DHHS/AASLD/manufacturer-PIL
Contraindications
Source: Lexicomp
Hypersensitivity to oseltamivir or any component of the formulation Absolute
Adverse Reactions
Very Common >10%Common 1–10%Uncommon 0.1–1%Rare 0.01–0.1%Very Rare <0.01%Not Known
Nervous system disorders (3)
Very Common
Headache
Common
Headache · Pain
Gastrointestinal disorders (5)
Very Common
Nausea · Vomiting
Common
Diarrhoea · Nausea · Vomiting
Psychiatric disorders (1)
Very Rare
Neuropsychiatric events (hallucinations, self-harm, in paediatric patients)
Dosing
Source: Lexicomp
Influenza prophylaxis: Oral: 75 mg once daily; initiate prophylaxis within 48 hours of contact with an infected individual; duration of prophylaxis: 10 days (manufacturer recommendation) or alternatively 7 days (CDC [Influenza Antiviral Medications] 2014). During community outbreaks, duration of protection lasts for length of dosing period; safety and efficacy have been demonstrated for use up to 6 weeks in immunocompetent patients and safety has been demonstrated for use up to 12 weeks in patients who are immunocompromised. Prophylaxis, institutional outbreak (CDC [Influenza Antiviral Medications] 2014): Continue for ≥2 weeks and until ~7 days after identification of illness onset in the last patient Influenza treatment: Oral: 75 mg twice daily initiated within 48 hours of onset of symptoms; usual duration of treatment: 5 days. However, optimal duration is uncertain for severe or complicated influenza. Consider longer duration (eg, >5 days) of therapy in severely ill patients who remain severely ill after 5 days of therapy (CDC [Influenza Antiviral Medications] 2014). Note: Data suggest that increased doses (>150 mg daily) in critically ill patients is not necessary since blood concentrations of oseltamivir were comparable or higher compared to ambulatory patients given similar dosing regimens (Ariano 2010; CDC [Influenza Antiviral Medications] 2014). Initiate as early as possible in any hospitalized patient with suspected/confirmed influenza regardless of the time of presentation from symptom onset (even if >48 hours) (CDC [Influenza Antiviral Medications] 2014); may be administered via naso- or orogastric tube in mechanically-ventilated patients (Taylor 2008). Critically ill: Concurrent use of extracorporeal membrane oxygenation (ECMO) alone: No dosage adjustment necessary (Lemaitre 2012; Mulla 2013).
(For additional information see "Oseltamivir: Pediatric drug information") Community-acquired pneumonia (influenza suspected or confirmed) (off-label use) (IDSA [Bradley 2011]): Oral: Prophylaxis: Infants 3 to 8 months: 3 mg/kg/day once daily Infants ≥9 months to Children ≤23 months: 3.5 mg/kg/day once daily Treatment: Neonates and Infants ≤8 months: 6 mg/kg/day in divided doses twice daily Infants ≥9 months to Children ≤23 months: 7 mg/kg/day in divided doses twice daily Influenza prophylaxis: Oral: Initiate prophylaxis within 48 hours of contact with an infected individual Manufacturer's labeling: Children: 1 to 12 years: ≤15 kg: 30 mg once daily >15 kg to ≤23 kg: 45 mg once daily >23 kg to ≤40 kg: 60 mg once daily >40 kg: 75 mg once daily Adolescents ≥13 years: Refer to adult dosing. Alternate recommendations: American Academy of Pediatrics: Infants 0 to 11 months (off-label dosing; AAP 2013): Note: Do not exceed maximum dose of weight-based dosing; see manufacturer's recommendation. Prophylaxis is not recommended for infants 0 to 8 months: 3 mg/kg/dose once daily 9 to 11 months: 3.5 mg/kg/dose once daily Centers for Disease Control: Infants Note: Do not exceed maximum dose of weight-based dosing; see manufacturer’s recommendation. Prophylaxis is not recommended for infants Infectious Disease Society of America/Pediatric Infectious Disease Society: Infants and Children 3 to 23 months (off-label dosing; Bradley 2011): Note: Do not exceed maximum dose of weight-based dosing; see manufacturer's recommendation. 3 to 8 months: 3 mg/kg/dose once daily 9 to 23 months: 3.5 mg/kg/dose once daily Prophylaxis duration: Individual/household exposure: Manufacturer's labeling: 10 days Alternate recommendations: 7 days (CDC [Influenza Antiviral Medications] 2014); 10 days (AAP 2013) Community/institutional outbreak: Note: The prescribing information states that during community outbreaks, duration of protection lasts for length of dosing period; safety and efficacy have been demonstrated for use up to 6 weeks in immunocompetent patients and safety has been demonstrated for use up to 12 weeks in patients who are immunocompromised. Manufacturer's labeling: May be used for up to 6 weeks Alternate recommendations: Continue for ≥2 weeks and until ~7 days after identification of illness onset in the last patient (CDC [Influenza Antiviral Medications] 2014) or until influenza activity in community subsides or immunity obtained from immunization (Bradley 2011). Influenza treatment: Oral: Initiate treatment within 48 hours of onset of symptoms; usual duration of treatment is 5 days. However, optimal duration is uncertain for severe or complicated influenza. Consider longer duration (eg, >5 days) of therapy in severely ill patients who remain severely ill after 5 days of therapy. Note: Data suggest that increased doses in critically ill patients is not necessary since blood concentrations of oseltamivir were comparable or higher compared to ambulatory patients given s
Refer to adult dosing.
Treatment: Adults: CrCl >60 mL/minute: No dosage adjustment necessary CrCl >30 to 60 mL/minute: 30 mg twice daily CrCl >10 to 30 mL/minute: 30 mg once daily ESRD not undergoing dialysis: Use is not recommended (has not been studied) Prophylaxis: Adults: CrCl >60 mL/minute: No dosage adjustment necessary CrCl >30 to 60 mL/minute: 30 mg once daily CrCl >10 to 30 mL/minute: 30 mg every other day ESRD not undergoing dialysis: Use is not recommended (has not been studied) Intermittent hemodialysis (IHD) (CrCl ≤10 mL/minute): Adults: Treatment: 30 mg immediately and then 30 mg after every hemodialysis session for 5 days. Note: Assumes three hemodialysis sessions in the 5-day period. Alternative recommendations: Treatment (AMMI Canada [Aoki 2012]): Low-flux hemodialysis: 30 mg after each dialysis session for 5 days High-flux hemodialysis: 75 mg after each dialysis session for 5 days Prophylaxis: 30 mg immediately and then 30 mg after every other hemodialysis sessions for the recommended prophylaxis duration. Children >1 year of age (off-label dose; Schreuder 2010): Treatment: ≤15 kg: 7.5 mg after each hemodialysis session >15 kg to ≤23 kg: 10 mg after each hemodialysis session >23 kg to ≤40 kg: 15 mg after each hemodialysis session >40 kg: 30 mg after each hemodialysis session Continuous ambulatory peritoneal dialysis (CAPD): Adults: Treatment: 30 mg immediately as a single dose (single dose provides a 5-day duration) Prophylaxis: 30 mg immediately and then 30 mg once weekly for the recommended prophylaxis duration Note: For patients receiving aggressive automated peritoneal dialysis (APD) with negligible or low residual renal function, a small pharmacokinetic study suggests that 75 mg as a single dose for treatment would produce drug exposure at the upper limit of the safety margin (Patel 2015). Continuous renal replacement therapy (CRRT) (high-flux): Treatment (off-label dose; limited data): 30 mg once daily for 5 days or 75 mg every 48 hours to provide a 5-day duration (AMMI Canada [Aoki 2012]; Ariano 2010) Prophylaxis (off-label): No data (AMMI Canada [Aoki 2012]) Continuous veno-venous hemodialysis (CVVHD): Adults: Note: Limited information available; optimal dosing has not been established: 150 mg twice daily administered via nasogastric or postpyloric feeding tube for suspected or confirmed H1N1 influenza demonstrated supratherapeutic oseltamivir carboxylate concentrations at effluent rates of 3,300 ± 919 mL/hour; the authors determined that the manufacturer recommended dosage of 75 mg once daily for patients with CrCl 10 to 30 mL/minute will likely achieve concentrations necessary to inhibit viral neuraminidase activity at these effluent rates; however, doses >75 mg once daily may be required when using higher effluent rates (Eyler 2012). CVVHD and concurrent use of ECMO: Adults: Lower oseltamivir carboxylate concentrations (~981 ng/mL) were observed as compared to those with the use of CVVHD alone (~2,760 ng/mL) when patients were administered
Mild-to-moderate impairment: No dosage adjustment necessary. Severe impairment: No dosage adjustment provided in manufacturer’s labeling (has not been studied).
Warnings & Precautions
Source: Lexicomp
Anaphylaxis/hypersensitivity
Rare but severe hypersensitivity reactions, including anaphylaxis and severe dermatologic reactions (eg, toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme), have been associated with use. Discontinue use immediately if hypersensitivity occurs or is suspected and treat appropriately.
Neuropsychiatric events
Rare occurrences of neuropsychiatric events (including confusion, delirium, hallucinations, and/or self-injury) have been reported primarily in pediatric patients from postmarketing surveillance; direct causation is difficult to establish (influenza infection may also be associated with behavioral and neurologic changes, in some cases resulting in fatal outcomes). These events may occur in the setting of encephalitis or encephalopathy but can occur without obvious severe disease. Monitor closely for signs of any unusual behavior. Disease-related concerns:
Cardiovascular disease
Use with caution in patients with chronic cardiac disease.
Hepatic impairment
Use with caution in patients with severe hepatic impairment; safety and efficacy have not been established.
Renal impairment
Use with caution; dosage adjustment is required for patients with renal impairment. Not recommended for patients with end stage renal disease (ESRD) not undergoing dialysis.
Respiratory disease
Use with caution in patients with respiratory disease. Dosage form specific issues:
Benzyl alcohol and derivatives
Some dosage forms may contain sodium benzoate/benzoic acid; benzoic acid (benzoate) is a metabolite of benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC, 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol derivative with caution in neonates. See manufacturer's labeling.
Sorbitol
Oral suspension contains sorbitol (delivers ~2 g sorbitol per 75 mg dose) which is greater than the maximum daily limit for patients with hereditary fructose intolerance; may cause diarrhea and dyspepsia; use with caution. Other warnings/precautions:
Appropriate use
Oseltamivir is not a substitute for the influenza virus vaccine. It has not been shown to prevent primary or concomitant bacterial infections that may occur with influenza virus. Antiviral treatment should begin within 48 hours of symptom onset. However, the CDC recommends that treatment may still be beneficial and should be started in hospitalized patients with severe, complicated or progressive illness if >48 hours. Treatment should not be delayed while awaiting results of laboratory tests for influenza. Nonhospitalized persons who are not at high risk for developing severe or complicated illness and who have a mild disease are not likely to benefit if treatment is started >48 hours after symptom onset. Nonhospitalized persons who are already beginning to recover do not need treatment.
Pregnancy & Lactation
Pregnancy
FDA category C
Safe
Treatment and prophylaxis of influenza recommended in pregnancy — risk of severe maternal disease (ICU admission, death) greatly exceeds drug risk. Treatment within 48 h of symptom onset
Lactation
RID 0.5%
Oseltamivir and oseltamivir carboxylate (OC) are present in breast milk.
The relative infant dose (RID) of oseltamivir is 0.5% when calculated using the highest breast milk concentration located and compared to a weight-adjusted maternal dose of 2.5 mg/kg/day.
In general, breastfeeding is considered acceptable when the RID of a medication is The RID of oseltamivir was calculated by the authors of a study using a total milk concentration of oseltamivir plus OC (expressed as equivalent of osel
Monitoring
Efficacy
Viral load (undetectable = success); CD4 count (HIV); hepatic enzymes and HBV/HCV DNA (hepatitis); clinical resolution of acute viral illness
Toxicity
Renal function (most antivirals are renally cleared); LFTs; resistance testing if virological failure; CBC
Clinical pearl
For HIV, undetectable viral load at 6 months predicts long-term treatment success. Resistance testing is mandatory at virological failure.
Counseling
Do not miss doses — even brief interruptions can cause viral rebound and resistance selection. Report any side effects early rather than stopping independently.
