Continuing Education Activity

Oseltamivir is appropriate for the treatment of acute, uncomplicated influenza A or B illness in adults and pediatric patients, including neonates greater than 2 weeks of age. Neonates less than 2 weeks of age may also receive oseltamivir for treatment of influenza, but safety and efficacy in this population have not been established. 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. 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 the delivery of care for patients who can benefit from therapy with oseltamivir.

Indications

Oseltamivir is appropriate for the treatment of acute, uncomplicated influenza A or B illness in adults and pediatric patients, including neonates greater than 2 weeks of age[1]. Neonates less than 2 weeks of age may also receive oseltamivir for treatment of influenza, but safety and efficacy in this population have not been established[2]. 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[3]. There is some evidence in hospitalized patients that oseltamivir can have efficacy up to 4 to 5 days after symptoms onset and hence, recommendations endorse ordering oseltamivir for hospitalized patients with severe or progressive influenza illness or those patients at high risk of developing complications, regardless of the time of symptom onset[4]. Individuals at high 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. 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. Oseltamivir is also useful for influenza prophylaxis within 48 hours of contact with an infected individual in adults and children greater than 1 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). 

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.[5]

Administration

Dosing of oseltamivir phosphate is via the oral route, and it is not necessary to time administration with meals. It is available in capsule form of three different dosages (30, 45, and 75 mg) and as an oral powder for reconstitution to suspension for pediatric patients. Therapy should initiate as early as possible, and maximum benefit is derived when initiated within 48 hours of onset of illness. However, in severe illness or patients at risk of complications, treatment must be initiated even beyond the 48-hour window.

Seasonal Influenza A and B treatment (five-day oral course):

• 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 who are immunosuppressed may require oseltamivir treatment for a prolonged indeterminate duration (more than 5 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)[6]:

• Adults: 75 mg daily
• Infants 0 to 8 months: 3 mg/kg/dose daily (not indicated for under 3 months unless clinically critical)
• Infants 9-11 months: 3 mg/kg/dose daily
• Children 1-12 yrs old:
  • Less than 15 kg: 30 mg daily
  • Greater than 15 kg to less than 23 kg: 45mg daily
  • Greater than 23 kg to less than 40 kg: 60mg daily
  • Over 40 kg: 75 mg daily

While recommendations for oseltamivir include the treatment of avian influenza infections, the optimum dosage and duration of treatment are unknown for these infections.[7]

Adverse Effects

Oseltamivir is generally well tolerated.[8] Most common side effects are nausea (up to 10%), vomiting (2% to 15%), abdominal pain, diarrhea, headache, insomnia, and vertigo. 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, hepatitis, seizures, and neuropsychiatric events.[5][9] Vomiting is the most frequently reported side effect in children (16% of children aged 1 to 12 years).

Contraindications

Known allergies or hypersensitivities to oseltamivir or any component of the drug is a contraindication. It is pregnancy class C. Commercially available oral suspension of oseltamivir contains sorbitol and hence, should be used cautiously in patients with hereditary fructose intolerance. Oseltamivir should not be used in patients with influenza illnesses that are due to strains confirmed as resistant to oseltamivir. It should not be used for diseases that are caused by organisms other than influenza viruses.

Monitoring

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 has correlations with fatalities.[10]

Toxicity

Oseltamivir is generally very well tolerated and has few if any, drug interactions. Multiple animal toxicity studies, both pre and post-marketing of oseltamivir, have indicated respiratory suppression, as a result of 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.[11]

Enhancing Healthcare Team Outcomes

Oseltamivir is used widely across the world for the treatment and prophylaxis of influenza illness, both confirmed and suspected cases.[5] (Level I) However, many practitioners are not aware of the correct indications and uses of oseltamivir as guided by existing scientific evidence. There is a lack of knowledge of the use of oseltamivir in severe or complicated influenza illness, and confusion exists about whether oseltamivir is curative for influenza.[12] (Level I)

When suspicion of influenza illness exists during the viral season in any adult or pediatric patient with chronic conditions or severe illness requiring hospitalization, the treating physician must initiate oseltamivir treatment immediately, regardless of the duration of symptoms.[3] (Level I) The physician needs to make sure that proper specimens are sent to the laboratory promptly for testing, and the pathologists are responsible for rapid testing and confirmatory results, including susceptibility testing to ensure optimal duration of therapy. While the efficacy of oseltamivir in immunocompromised patients is not established, the treating physician must consult with specialists regarding the use of oseltamivir in influenza illness in immunocompromised patients.[13] (Level III)

In both pediatric and geriatric patients, as well as neurodevelopmentally challenged patients, the treating physician must partner with the nursing staff and the family members to find the right preparation of oseltamivir that will be tolerated by the patient without side effects. A pharmacist must also be engaged to dispense the proper preparation of the oral suspension.