Continuing Education Activity

Oseltamivir is an antiviral medication used to manage acute, uncomplicated influenza A or B in adult and pediatric patients, including neonates older than 2 weeks. For neonates younger than 2 weeks, using oseltamivir to treat influenza is considered, although the safety and efficacy in this population remain unestablished. National advisory bodies advocate the initiation of oseltamivir within 48 hours of symptom onset, particularly for individuals hospitalized with influenza or possessing significant comorbidities placing them at heightened risk for complications. This activity explores oseltamivir's indications, mechanism of action, administration protocols, significant adverse effects, contraindications, monitoring strategies, and potential toxicity. The goal is to equip healthcare providers with the necessary knowledge to guide patient therapy effectively, ultimately optimizing outcomes in the combat against influenza and related viral infections.

Objectives:

• Identify the indications for using oseltamivir.

• Evaluate the mechanism of action of oseltamivir.

• Assess the adverse drug reactions of oseltamivir.

• Implement effective collaboration and communication among interprofessional team members to improve outcomes and treatment efficacy for patients who might benefit from oseltamivir treatment.

Indications

Oseltamivir is appropriate for treating acute, uncomplicated influenza A or B illness in adults and pediatric patients, including neonates older than 2 weeks.[1] Neonates younger than 2 weeks may also receive oseltamivir for the treatment of influenza, but safety and efficacy in this population have not been established.[2]

FDA-Approved Indications

Oseltamivir has received approval from the FDA for treating and preventing both influenza A and B infections. They are indicated for managing acute, uncomplicated cases in individuals 2 weeks and older, provided symptoms have emerged within 48 hours. Additionally, oseltamivir is considered suitable for prophylactic use in patients 1 year and older.

The American Academy of Pediatrics guidelines recommend using oseltamivir to treat influenza in preterm infants, but it is not recommended for chemoprophylaxis in preterm infants. Consultation with a pediatric infectious disease physician is recommended in preterm infants younger than 28 weeks.[3] Empiric treatment with oseltamivir can shorten the duration of illness and is recommended for healthy individuals with symptoms suggestive of influenza, even before confirmation testing if treatment is initiated within 48 hours of symptoms. 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, placing them at high risk for complications.[4]

There is evidence that oseltamivir can have efficacy in hospitalized patients up to 4 to 5 days after symptoms onset. Hence, recommendations endorse ordering oseltamivir for hospitalized patients with severe or progressive influenza or those at high risk of developing complications, regardless of symptom onset.[5] Individuals at increased risk for complications include children younger than 2, nursing home residents, adults who are obese or older than 65, pregnant women, and patients with pulmonary, liver, renal, or cardiovascular disease, malignancy, neurodevelopmental disorders, metabolic disorders, epilepsy, muscular dystrophy, and immunosuppression.

Off-Label Uses

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 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 viruses involves 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. Antigenic shift is a process frequently associated with the outbreak of pandemics.[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.

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

Administration

Available Dosage Forms

Oseltamivir phosphate is administered orally, with or without meals, and is available in capsule form of 3 different dosages (30, 45, and 75 mg) and an oral powder for reconstitution to suspension for pediatric patients. Therapy should be initiated 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.

Adult Dosing

Seasonal Influenza A and B Treatment (5-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:
  • <15 kg: 30 mg BID
  • 15 kg to 23 kg: 45 mg BID
  • 23 kg to 40 kg: 60 mg BID
  • >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 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
• Patients on hemodialysis: 30 mg after dialysis x 5 days (assumes 3 HD sessions)

Seasonal Influenza A and B Prophylaxis (7 to 10-day oral course)

• Adults: 75 mg daily [9]
• Infants 0 to 8 months: 3 mg/kg/dose daily (not indicated for under 3 months unless clinically critical)
• Infants 9 to 11 months: 3 mg/kg/dose daily
• Children 1 to 12 yrs old:
  • <15 kg: 30 mg daily
  • 15 kg to 23 kg: 45 mg daily
  • 23 kg to 40 kg: 60 mg daily
  • >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] 

Specific Patient Populations

Hepatic impairment: According to the manufacturer's labeling information, no dosage adjustment is recommended in case of mild to moderate liver disease. In severe hepatic impairment (Child-Pugh class C), oseltamivir exposure (AUC) is elevated by a factor of 6. Use in severe hepatic impairment is not recommended.[11]

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. In patients on hemodialysis, reduce the oseltamivir dosage by 30 mg and an additional 30 mg after each hemodialysis session, ensuring the treatment duration does not exceed 5 days.[12]

Pregnancy considerations:  Complications of influenza during pregnancy include late pregnancy loss and a decrease in mean birth weight.[13] Since pregnant and postpartum women are at increased risk of severe seasonal and pandemic influenza infection complications, the CDC recommends treatment and prevention with oseltamivir or zanamivir according to viral strain. Complications of influenza during pregnancy include late pregnancy loss and a decrease in mean birth weight.[14]

Breastfeeding considerations: Limited clinical information suggests that oseltamivir and its active metabolites are excreted into breast milk in trace amounts. Oseltamivir is a former FDA pregnancy class C. A maternal dose of 150 mg of oseltamivir daily produces low levels in milk and is not anticipated to cause adverse drug reactions in breastfed infants.[15]

Pediatric patients: For pediatric patients, administer oral suspension (6 mg/mL) based on weight. Ensure accurate dosing for infants. Use oral suspension if swallowing capsules is difficult. Postexposure prophylaxis lasts 10 days, while seasonal prevention is up to 6 weeks (or 12 weeks in immunocompromised cases). A recent study indicates that administering oseltamivir early in hospitalized children led to reduced hospitalization duration and the likelihood of 7-day readmission, ECMO use, and mortality. These results affirm the current guidelines advocating oseltamivir utilization in hospitalized children with influenza.[16]

Older patients: No dose adjustments are needed for older adults in treatment and prevention with oseltamivir, considering drug exposure and tolerability.

Adverse Effects

Oseltamivir is generally well-tolerated.[17] The most common side effects include 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).[18]

Other adverse 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][19][20]

Cutaneous adverse drug reactions like erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis have also been reported.[21][22][23]

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 thought to be 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).[24]

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.[25] 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.[26][27]

Contraindications

Known allergies or hypersensitivities to the drug or excipients are a contraindication to using oseltamivir. Cases of anaphylaxis have been reported.[28]

Warning and Precautions

• Commercially available oral suspension of oseltamivir contains sorbitol and saccharin sodium and should be used cautiously in patients with hereditary fructose intolerance.[29]
• Since the suspension contains sodium benzoate, watch for gasping syndrome in neonates.[30]
• 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, including self-injury, confusion, and delirium, should be monitored, especially in children; reports of these events in children primarily occur in Japan and have also had correlations with fatalities.[31] The influenza risk assessment tool is a systematic approach for evaluating and monitoring threats by influenza viruses.[32]

Toxicity

Oseltamivir is generally very well tolerated and has few drug interactions. Multiple animal toxicity studies, pre-marketing, 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.[33] The oseltamivir-induced liver injury requires discontinuation of the drug and avoidance of reexposure. Most patients recover after discontinuation of oseltamivir without specific interventions.[24]

Enhancing Healthcare Team Outcomes

Oseltamivir is used worldwide for treating and preventing 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. The IDSA (Infectious Diseases Society of America) guidelines recommend oseltamivir as a first-line drug therapy for influenza.[34] The IDSA suggests that clinicians consider extended treatment in patients with immunocompromised conditions or severe lower respiratory tract involvement (acute respiratory distress syndrome or pneumonia). 

If influenza is suspected during the viral season in any patient with chronic conditions or severe disease requiring hospitalization, the treating clinician must initiate oseltamivir treatment immediately, regardless of the duration of symptoms.[4] The clinician must ensure proper specimens are promptly sent to the laboratory 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.[35]

In pediatric and older 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 an 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.[36] Intentional overdose requires referral to a psychiatrist. The responsibility of the entire healthcare team, including clinicians (MDs, DOs, NPs, PAs), nurses, specialists, and pharmacists, is to adopt an interprofessional approach to maximize efficacy, minimize adverse events, and ultimately enhance patient outcomes regarding oseltamivir pharmacotherapy.