Tamiflu, Oseltamivir

Chemical Structure of Oseltamivir

Adverse Effects

The most commonly reported adverse effects associated with oseltamivir treatment or prophylaxis in adults are nausea and vomiting, abdominal pain, bronchitis, insomnia, and vertigo. Diarrhoea, dizziness, headache, cough, and fatigue may occur, but many adverse effects may be difficult to distinguish from the symptoms of influenza. Other adverse effects occurring less commonly have included unstable angina, anaemia, pseudomembranous colitis, pneumonia, pyrexia, and peritonsillar abscess. There have been occasional reports of anaphylaxis and skin rashes, including toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme. Elevated liver enzymes and hepatitis have been reported rarely. Prophylaxis in adults has also been associated with aches and pains, dyspepsia, rhinorrhoea, and upper respiratory-tract infections.

The most commonly reported adverse effects in children receiving treatment or prophylaxis with oseltamivir are vomiting and other gastrointestinal problems. Other commonly occurring adverse events include asthma, bronchitis, conjunctivitis, dermatitis, epistaxis, ear disorders and otitis media, lymphadenopathy, pneumonia, and sinusitis.

Precautions

Oseltamivir is not recommended in patients with severe renal impairment and it should be given with caution and dosage should be reduced in patients with moderate renal impairment (see Administration in Renal Impairment, ).

Antiviral Action

Oseltamivir has antiviral activity similar to that of zanamivir (). Its active metabolite, oseltamivir carboxylate, selectively blocks the viral surface enzyme neuraminidase, thereby preventing the release of virus particles from infected cells. Oseltamivir is active against influenza A and B viral neuraminidase.

Resistance.

Neuraminidase inhibitors are effective against all strains of influenza and de novo resistance has not been found to date.¹ Some studies^2,3 have described in-vitro resistance to oseltamivir arising during clinical use but it is not yet known if such resistant viruses are transmissible and pathogenic. No resistant viruses have been isolated from immunocompetent people given zanamivir,⁴ although there is a case of resistance in an immunocompromised child.⁵

1. 1. McKimm-Breschkin J, et al. Neuraminidase sequence analysis and susceptibilities of influenza virus clinical isolates to zanamivir and oseltamivir. Antimicrob Agents Chemother 2003; 47: 2264–72. PubMed
2. 2. Whitley RJ, et al. Oral oseltamivir treatment of influenza in children. Pediatr Infect Dis J 2001; 20: 127–33. PubMed
3. 3. Kiso M, et al. Resistant influenza A viruses in children treated with oseltamivir: descriptive study. Lancet 2004; 364: 759–65. PubMed
4. 4. Moscona A. Oseltamivir-resistant influenza? Lancet 2004; 364: 733–4. PubMed
5. 5. Gubareva LV, et al. Evidence for zanamivir resistance in an immunocompromised child infected with influenza B virus. J Infect Dis 1998; 178: 1257–62. PubMed

Pharmacokinetics

Oseltamivir is readily absorbed from the gastrointestinal tract after oral doses and is extensively metabolised in the liver to the active entity, oseltamivir carboxylate. At least 75% of an oral dose reaches the systemic circulation as the carboxylate. Binding to plasma proteins is about 3% for the carboxylate and 42% for the parent drug. Oseltamivir has a plasma half-life of 1 to 3 hours. The carboxylate is not metabolised further and is eliminated in the urine.

Uses and Administration

Oseltamivir is an oral prodrug of oseltamivir carboxylate, an inhibitor of the enzyme neuraminidase (sialidase), which has a role in the infectivity and replication of influenza A and B viruses. It is used in adults and children over 1 year of age for the treatment and postexposure prophylaxis of influenza A and B ().

Oseltamivir is given as the phosphate, but doses are expressed in terms of the base. Oseltamivir phosphate 98.5 mg is equivalent to about 75 mg of oseltamivir. For treatment, doses are given twice daily for 5 days, beginning as soon as possible (within 48 hours) after the onset of symptoms. For postexposure prophylaxis doses are given once daily for 10 days (or longer in adults) and for up to 6 weeks during an epidemic; therapy should begin within 48 hours of exposure.

The following doses may be used for treatment (twice daily) or prophylaxis (once daily):

adults and children over 40 kg: 75 mg

23 to 40 kg: 60 mg

16 to 23 kg: 45 mg

less than 16 kg: 30 mg

Dosage should be reduced in patients with moderate renal impairment (see ).

Reviews.

1. 1. Gubareva LV, et al. Influenza virus neuraminidase inhibitors. Lancet 2000; 355: 827–35. PubMed
2. 2. McClellan K, Perry CM. Oseltamivir: a review of its use in influenza. Drugs 2001; 61: 263–83. PubMed
3. 3. Jefferson T, et al. Neuraminidase inhibitors for preventing and treating influenza in healthy adults. Available in The Cochrane Database of Systematic Reviews; Issue 2. Chichester: John Wiley; 1999 (accessed 26/05/05). PubMed
4. 4. Matheson NJ, et al. Neuraminidase inhibitors for preventing and treating influenza in children. Available in The Cochrane Database of Systematic Reviews; Issue 3. Chichester: John Wiley; 2003 (accessed 26/05/05). PubMed
5. 5. Cooper NJ, et al. Effectiveness of neuraminidase inhibitors in treatment and prevention of influenza A and B: systematic review and meta-analyses of randomised controlled trials. BMJ 2003; 326: 1235–9. PubMed
6. 6. Dutkowski R, et al. Safety and pharmacology of oseltamivir in clinical use. Drug Safety 2003; 26: 787–801. PubMed
7. 7. Ward P, et al. Oseltamivir (Tamiflu) and its potential for use in the event of an influenza pandemic. J Antimicrob Chemother 2005; 55 (suppl 1): i5–i21. PubMed

Administration in renal impairment.

Dosage of oseltamivir should be reduced in patients with moderate renal impairment, according to creatinine clearance (CC):

CC 10 to 30 mL/minute: treatment of influenza: 75 mg once daily or 30 mg twice daily; prevention: 75 mg on alternate days or 30 mg daily

CC less than 10 mL/minute: not recommended

dialysis patients: not recommended