Tamiflu - Drug Monograph

Introduction

Oseltamivir phosphate, marketed under the brand name Tamiflu, is an antiviral medication used primarily for the treatment and prophylaxis of influenza infections. Developed by Hoffmann-La Roche, it belongs to the neuraminidase inhibitor class and has been a cornerstone in influenza management since its FDA approval in 1999. Tamiflu is available as oral capsules and oral suspension and remains one of the most prescribed antiviral medications during seasonal influenza outbreaks.

Mechanism of Action

Tamiflu exerts its antiviral effects through selective inhibition of influenza neuraminidase enzymes. Neuraminidase is essential for viral replication and spread, as it cleaves sialic acid residues to facilitate the release of newly formed virions from infected cells and prevents viral aggregation. By inhibiting neuraminidase, oseltamivir effectively:

• Impedes viral release from infected host cells
• Reduces viral spread throughout the respiratory tract
• Decreases viral shedding and transmission

The drug is active against both influenza A and B viruses, though susceptibility varies among strains and subtypes.

Indications

• Treatment of uncomplicated acute influenza in patients 2 weeks and older who have been symptomatic for no more than 48 hours
• Prophylaxis of influenza in patients 1 year and older

• Treatment of influenza in immunocompromised patients beyond 48 hours of symptom onset
• Extended duration prophylaxis during institutional outbreaks
• Treatment of complicated influenza infections (often in combination with other antivirals)

Dosage and Administration

• Treatment: 75 mg twice daily for 5 days
• Prophylaxis: 75 mg once daily for at least 10 days (up to 6 weeks during community outbreaks)

• Renal impairment:

- CrCl 30-60 mL/min: 30 mg twice daily (treatment) or 30 mg once daily (prophylaxis) - CrCl 10-30 mL/min: 30 mg once daily (treatment) or 30 mg every other day (prophylaxis) - ESRD on hemodialysis: 30 mg after each dialysis cycle

• Hepatic impairment: No dosage adjustment necessary
• Pediatric patients:

- Weight-based dosing for children ≥1 year: - ≤15 kg: 30 mg twice daily - >15-23 kg: 45 mg twice daily - >23-40 kg: 60 mg twice daily - >40 kg: 75 mg twice daily

• Geriatric patients: No dosage adjustment required unless renal impairment present

• Take with or without food (food may improve tolerability)
• Oral suspension: shake well before use; use provided measuring device
• For patients unable to swallow capsules, contents may be mixed with sweetened liquids

Pharmacokinetics

• Absorption: Rapidly absorbed from GI tract; prodrug converted to active oseltamivir carboxylate by hepatic esterases
• Bioavailability: ~80% converted to active metabolite
• Tmax: 2-3 hours for active metabolite
• Distribution: Widely distributed throughout body; active metabolite concentrates in respiratory secretions
• Protein binding: <3% (active metabolite)
• Metabolism: Hepatic hydrolysis via esterases to active carboxylate metabolite
• Elimination: Primarily renal excretion (>99% as active metabolite)
• Half-life: 6-10 hours (active metabolite)
• Dialyzable: Yes (hemodialysis removes approximately 15-20% of dose)

Contraindications

• Known hypersensitivity to oseltamivir or any component of the formulation
• Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption (due to capsule excipients)

Warnings and Precautions

• Cases of delirium and abnormal behavior, primarily in pediatric patients, have been reported
• Closely monitor for signs of unusual behavior, especially in children and adolescents

• Serious skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have occurred
• Discontinue immediately if rash or allergic reaction develops

• Influenza may be associated with various neurologic and behavioral symptoms
• Tamiflu does not prevent such events and does not treat bacterial superinfections

• Dose adjustment required in patients with CrCl <60 mL/min
• Monitor for increased adverse effects in renal impairment

Drug Interactions

• Probenecid: Increases exposure to oseltamivir carboxylate by approximately 2-fold
• Live attenuated influenza vaccine: May interfere with vaccine efficacy; separate administration by ≥48 hours
• P-glycoprotein inhibitors: May increase oseltamivir concentrations (clinical significance unknown)

• Warfarin
• Oral contraceptives
• Cimetidine
• Amoxicillin
• Acetaminophen

Adverse Effects

• Nausea (10%)
• Vomiting (8%)
• Headache (2%)
• Diarrhea (5%)
• Abdominal pain (2%)

• Anaphylaxis and serious allergic reactions
• Severe skin reactions
• Hepatotoxicity (elevated transaminases)
• Neuropsychiatric events (hallucinations, delirium)
• Seizures

• Higher incidence of vomiting compared to adults
• Increased reporting of neuropsychiatric events

Monitoring Parameters

• Influenza symptoms resolution
• Signs of bacterial superinfection
• Neuropsychiatric symptoms (especially in children)
• Allergic reactions

• Renal function (baseline and during therapy in at-risk patients)
• Liver function tests (if symptoms suggest hepatotoxicity)
• Not routinely required for most patients

Patient Education

• Start treatment within 48 hours of symptom onset for optimal effectiveness
• Complete full course even if symptoms improve
• Take with food if nausea occurs
• Report any unusual behavior changes, especially in children
• Seek immediate medical attention for allergic reactions (rash, swelling, difficulty breathing)
• Tamiflu is not a substitute for annual influenza vaccination
• Store suspension at room temperature; discard after 10 days

• Take as soon as remembered unless close to next dose
• Do not double dose

References

1. FDA Prescribing Information: Tamiflu (oseltamivir phosphate). 2022 2. Infectious Diseases Society of America Guidelines for Influenza Management. Clin Infect Dis. 2019;68(6):e1-e47 3. Whitley RJ, et al. Oral oseltamivir treatment of influenza in children. Pediatr Infect Dis J. 2001;20(2):127-133 4. Jefferson T, et al. Neuraminidase inhibitors for preventing and treating influenza in adults and children. Cochrane Database Syst Rev. 2014;(4):CD008965 5. Kimberlin DW, et al. Antiviral therapy of influenza: recommendations for the 2022-2023 season. Pediatr Infect Dis J. 2022;41(12):963-968 6. McGeer A, et al. Antiviral therapy and outcomes of influenza requiring hospitalization in Ontario, Canada. Clin Infect Dis. 2007;45(12):1568-1575