Continuing Education Activity

Oseltamivir is appropriate for treating acute, uncomplicated influenza A or B illness in adults and pediatric patients, including neonates greater than two weeks of age. Neonates under two weeks of age may also receive oseltamivir to treat influenza, but safety and efficacy in this population have not been established. Nevertheless, multiple national advisory bodies have endorsed using oseltamivir as soon as possible (ideally less than 48 hours after symptom onset) for patients hospitalized with influenza or significant comorbidities, making them at high risk for complications. This activity outlines the indications, mechanism of action, methods of administration, important adverse effects, contraindications, monitoring, and toxicity of oseltamivir so providers can direct patient therapy to optimal outcomes to combat influenza and related viral infections.

Objectives:

• Describe the mechanism of action of oseltamivir.
• Identify the indications for using oseltamivir.
• Summarize the effectiveness of using oseltamivir in influenza infections.
• Review the importance of improving care coordination among the interprofessional team to enhance care delivery for patients who can benefit from therapy with oseltamivir.

Indications

Oseltamivir is appropriate for treating acute, uncomplicated influenza A or B illness in adults and pediatric patients, including neonates older than two weeks of age.[1]

Neonates less than two weeks of age may also receive oseltamivir for the treatment of influenza, but safety and efficacy in this population have not been established.[2]

The American academy of pediatrics guidelines recommends using oseltamivir for treating influenza in preterm infants, but it is not recommended for chemoprophylaxis for preterm infants. Consultation with a pediatric infectious disease physician is recommended in preterm infants < 28 weeks.[3]

Oseltamivir is also useful for influenza prophylaxis within 48 hours of contact with an infected individual in adults and children greater than one year of age. Recommendations endorsing oseltamivir as the drug of choice for treatment and prophylaxis of illness caused by avian influenza strains, including the highly pathogenic avian influenza A (H5N1), come from the Centers for Disease Control and Prevention (CDC) and World Health Organization (WHO).

Empiric treatment with oseltamivir can shorten the duration of illness and is thus recommended for healthy individuals with symptoms suggestive of influenza, even before confirmation testing if treatment can commence within 48 hours of symptoms. Multiple national advisory bodies have endorsed the use of oseltamivir as soon as possible (ideally less than 48 hours after symptom onset) for patients hospitalized with influenza or with significant comorbidities making them at high risk for complications.[4]

There is evidence in hospitalized patients that oseltamivir can have efficacy up to 4 to 5 days after symptoms onset. Hence, recommendations endorse ordering oseltamivir for hospitalized patients with severe or progressive influenza illness or those at high risk of developing complications, regardless of symptom onset.[5] Individuals at increased risk for complications include young children (less than two years of age), those in nursing homes, those 65 years of age or older, obese, pregnant, patients with pulmonary, liver, renal, or cardiovascular disease, malignancy, neurodevelopmental disorders, metabolic disorders, epilepsy, muscular dystrophy, and immunosuppression.

Mechanism of Action

Oseltamivir is an antiviral neuraminidase inhibitor with potent and selective competitive inhibition of the influenza virus neuraminidase, an enzyme necessary for viral replication. Oseltamivir phosphate is an inactive prodrug that exerts pharmacologic activity when hydrolyzed in vivo to the active form, oseltamivir carboxylate. This activated form interferes with the release of progeny influenza virus from infected host cells and thus halts the spread of infection to new host cells. Oseltamivir reduces the duration of shedding and the viral titer and can shorten the length of symptoms by 0.5 to 3 days.[6]

Mechanism of Resistance: The mechanism of resistance of influenza virus is antigenic drift and shift in their surface glycoproteins. Antigenic drift is the process in which minor modifications occur in key viral epitopes through point mutations; antigenic shift results in a complete exchange of hemagglutinin (HA) or neuraminidase (NA) genes. Antigenic shift emerges mainly in influenza A viruses due to their vast animal reservoirs. The consequence of the antigenic shift frequently leads to a pandemic.[7]

Pharmacokinetics

Absorption: Oseltamivir is an orally administrated prodrug. The oral bioavailability of oseltamivir is approximately 80%. Oral intake does not seem to impact the pharmacokinetics of oseltamivir significantly.

Distribution: The volume of distribution is approximately 23 to 26 liters. Oseltamivir is moderately bound to plasma proteins (42%), while oseltamivir carboxylate has poor plasma protein binding.

Metabolism: Hepatic carboxylesterases extensively hydrolyze oseltamivir to the active drug oseltamivir carboxylate (OC). The active metabolite, oseltamivir, is a major circulating component (95%) in plasma, and the prodrug oseltamivir accounts for only 5% of the circulating component.

Excretion: Osaletmevir carboxylate is eliminated (>99%) through renal excretion by glomerular filtration and active tubular secretion. The half-life of oseltamivir carboxylate is 6–10 hours, while the half-life of oseltamivir is approximately 3 hours.[8]

Administration

Dosing of oseltamivir phosphate is via the oral route, and it can be administered with or without meals. It is available in capsule form of three different dosages (30, 45, and 75 mg) and an oral powder for reconstitution to suspension for pediatric patients. Therapy should initiate as early as possible, and maximum benefit is derived when started within 48 hours of the onset of illness. However, treatment must be initiated before the 48-hour window for severe illness or patients at risk of complications.

Seasonal Influenza A and B Treatment (five-day oral course)[5]

• Adults: 75 mg BID
• Infants 0 to 8 months: 3 mg/kg/dose BID
• Infants 9 to 11 months: 3.5 mg/kg/dose BID
• Children 1 to 12 yrs old:
  • Less than 15 kg: 30 mg BID
  • Greater than 15 kg to less than 23 kg: 45 mg BID
  • Greater than 23 kg to less than 40 kg: 60 mg BID
  • Over 40 kg: 75 mg PO BID

Patients with severe infections admitted to an intensive care unit or immunosuppressed may require oseltamivir treatment for a prolonged indeterminate duration (more than five days).

Treatment Dosing Adjustments for Creatinine Clearance

• CrCl 30 to 60 ml/min: 30 mg BID
• CrCl less than 30 ml/min: 30 mg daily
• Hemodialysis patients: 30 mg after dialysis x 5 days (assumes 3 HD sessions)

Seasonal Influenza A and B Prophylaxis (seven to 10-day oral course)

• Adults: 75 mg daily[9]
• Infants 0 to 8 months: 3 mg/kg/dose daily (not indicated for under three months unless clinically critical)
• Infants 9 to 11 months: 3 mg/kg/dose daily
• Children 1 to 12 yrs old:
  • Less than 15 kg: 30 mg daily
  • Greater than 15 kg to less than 23 kg: 4 5mg daily
  • Greater than 23 kg to less than 40 kg: 60 mg daily
  • Over 40 kg: 75 mg daily

Prophylaxis Dosing Adjustments for Creatinine Clearance

• CrCl 30 to 60 ml/min: 30 mg daily
• CrCl less than 30 ml/min: 30 mg every other day
• End-stage renal disease: use is not recommended

While recommendations for oseltamivir include the treatment of avian influenza infections, the optimum dosage and duration of therapy are unknown for these infections.[10] 

Use in Specific Patient Populations

Patients with Hepatic Impairment: According to the manufacturer's labeling information,  no dosage adjustment is recommended in case of mild to moderate liver disease. According to a pharmacokinetic study, in severe hepatic impairment(Child-Pugh class C), oseltamivir exposure(AUC) is approximately six times increased. Use in severe hepatic impairment is not recommended.[11]

Patients with Renal Impairment: The first dose should be 75 mg for patients with normal body mass. Subsequent doses should be decreased according to the degree of renal impairment.

Pregnancy Considerations:  Complications of influenza during pregnancy include late pregnancy loss and a decrease in mean birth weight.[12] Since pregnant and postpartum women are at increased risk of serious seasonal and pandemic influenza infection complications, CDC recommends treatment and prophylaxis with oseltamivir or zanamivir according to viral strain. Complications of influenza during pregnancy include late pregnancy loss and a decrease in mean birth weight.[13]

Breastfeeding Considerations: Limited clinical information suggests that oseltamivir and its active metabolites are excreted into breast milk in trace amounts. It is a former FDA pregnancy class C. A maternal dose of 150 mg oseltamivir daily produces low levels in milk and is not anticipated to cause adverse drug reactions in breastfed infants.[14]

Adverse Effects

Oseltamivir is generally well tolerated.[15] The most common side effects are nausea (up to 10%), vomiting (2% to 15%), abdominal pain, diarrhea, headache, insomnia, and vertigo. Vomiting is the most frequently reported side effect in children (16% of children aged 1 to 12 years).[16]

Other side effects occurring less than 1% of the time include conjunctivitis, epistaxis, allergy, arrhythmia, GI bleeding, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, confusion, seizures, and neuropsychiatric events.[6][17][18]

Cutaneous adverse drug reactions like erythema multiforme, steven johnson syndrome, and toxic epidermal necrolysis have also been reported.[19][20][21]

Serum aminotransferase elevations have been reported in 2% of clinical trials, but enzyme elevation in patients was transient and asymptomatic. The mechanism of hepatotoxicity is possibly immunoallergic. Rare cases of liver injury and jaundice have been reported, but influenza infection can also lead to serum enzyme elevations and jaundice. Consequently, the likelihood score is D(possible rare cause of clinically apparent liver injury).[22]

Drug-Drug Interactions

Influenza antiviral medications may decrease the efficacy of LAIV4 (live attenuated influenza vaccine) if administered within 48 hours to 14 days after LAIV4.[23] Oseltamivir is an ester prodrug, and oseltamivir carboxylate contributes to the antiviral activity. Hydrolytic activation is mediated by human carboxylesterase (HCE) 1. In the presence of clopidogrel, the hydrolysis of oseltamivir is inhibited, leading to reduced antiviral efficacy.[24][25]

Contraindications

• Known allergies or hypersensitivities to the drug or excipients are a contraindication to using oseltamivir. Cases of anaphylaxis have been reported.[26]
• Commercially available oral suspension of oseltamivir contains sorbitol and saccharin sodium and should be used cautiously in patients with hereditary fructose intolerance.[27]
• Since the suspension contains sodium benzoate, watch for gasping syndrome in neonates.[28]
• Oseltamivir should not be used in patients with influenza illnesses due to strains confirmed as resistant to oseltamivir. In addition, it should not be used for diseases caused by organisms other than influenza viruses.[7]

Monitoring

• Repeat RT-PCR or viral culture can determine the viral load in critically ill patients.
• Neuropsychiatric events such as self-injury, confusion, and delirium should be monitored, especially in children; this has mainly been reported in children in Japan and has also had correlations with fatalities.[29]
• The influenza risk assessment tool is a systematic approach for evaluating and monitoring threats by influenza viruses.[30]

Toxicity

Oseltamivir is generally very well tolerated and has few drug interactions. Multiple animal toxicity studies, pre, and post-marketing of oseltamivir, have indicated respiratory suppression resulting from central nervous system suppression, hypothermia, hypoactivity, and sudden death. This adverse event correlates with sudden-onset type neuropsychiatric reactions in human patients (especially children from Japan), but no definitive link has been established.[31] 

Oseltamivir-induced liver injury requires discontinuation of the drug and avoidance of reexposure. The majority of the patients recover on discontinuation of oseltamivir without specific interventions.[22]

Enhancing Healthcare Team Outcomes

Oseltamivir is used widely worldwide for the treatment and prophylaxis of influenza illness, both confirmed and suspected cases.[6] Consequently, clinicians should know the correct indications and uses of oseltamivir as guided by existing scientific evidence. IDSA (Infectious Diseases Society of America) guidelines include oseltamivir as one of the first-line drug therapy for influenza in their recommendations.[32][level I] IDSA suggests that clinicians consider the extended duration treatment in patients with immunocompromised conditions or severe lower respiratory tract involvement (acute respiratory distress syndrome or pneumonia). 

When suspicion of influenza illness exists during the viral season in any adult or pediatric patient with chronic conditions or severe disease requiring hospitalization, the treating clinician must initiate oseltamivir treatment immediately, regardless of the duration of symptoms.[4] (Level I) The clinician must ensure that proper specimens are sent to the laboratory promptly for testing. Pathologists and clinical microbiologists are responsible for rapid testing and confirmatory results, including susceptibility testing, to ensure the optimal duration of therapy. If an immunocompromised condition is suspected, the treating clinician should consult an infectious disease specialist regarding the use of oseltamivir in influenza illness in an immunocompromised patient.[33] (Level III)

In pediatric and geriatric patients and neurodevelopmentally challenged patients, the treating clinician must partner with the nursing staff and family members to prepare the proper oseltamivir that the patient will tolerate without side effects. In addition, a pharmacist must perform medication reconciliation and dispense the appropriate dosage form of oseltamivir. In overdose, a medical toxicologist should be consulted. Intensivist and pulmonologist consultation is vital in case of respiratory failure to deliver optimal ventilatory support in critically ill patients.[34] Intentional overdose requires referral to a psychiatrist. Thus it is the responsibility of the entire healthcare team, such as clinicians (MDs, DOs, NPs, PAs), nurses, specialists, and pharmacists, to work with an interprofessional team approach that would maximize efficacy, minimize adverse events and translate to enhanced patient outcomes related to oseltamivir therapy.[Level 5]