Amprenavir

Drug Approvals

INNs in other languages (French, Latin, Spanish): Synonyms: 141W94; Amprenaviiri; Amprenavir; Amprenavirum; KVX-478; VX-478 BAN: Amprenavir USAN: Amprenavir INN: Amprenavir [rINN (en)] INN: Amprenavir [rINN (es)] INN: Amprénavir [rINN (fr)] INN: Amprenavirum [rINN (la)] INN: Ампренавир [rINN (ru)] Chemical name: (3S)-Tetrahydro-3-furyl{(S)-α[(1R)-1-hydroxy-2-(N¹-isobutylsulfanilamido)ethyl]phenethyl}carbamate Molecular formula: C₂₅H₃₅N₃O₆S =505.6 CAS: 161814-49-9 ATC code: J05AE05

Adverse Effects

Adverse effects associated with antiretroviral regimens containing amprenavir are mostly mild to moderate. The most common adverse effects are gastrointestinal disturbances such as diarrhoea, flatulence, nausea, and vomiting. Other commonly reported adverse effects include fatigue, headache, oral paraesthesia, and taste disorders, while the most frequently reported serious adverse effects include peripheral paraesthesias, skin rash, and mood disorders (including depression). Mild to moderate rashes (usually erythematous or maculo-papular and sometimes pruritic), generally occur during the second week of treatment and resolve within 2 weeks. A possible association with Stevens-Johnson syndrome has been reported with amprenavir.

Precautions

Amprenavir (when given with ritonavir) is contra-indicated in patients with severe hepatic impairment, and should be used with caution (and liver enzyme values monitored), in patients with mild to moderate liver disease. Patients co-infected with chronic hepatitis B or C and treated with combination antiretroviral therapy are at increased risk for severe and potentially fatal hepatic adverse events. Caution is advised in treating patients with haemophilia A and B as reports of spontaneous bleeding have been associated with the use of HIV-protease inhibitors. Treatment with amprenavir should be permanently stopped in patients who develop a severe or life-threatening skin rash or a skin rash with associated systemic or allergic symptoms or mucosal involvement. Amprenavir is a sulfonamide and should be used with caution in patients known to be allergic to sulfona-mides. The oral solution and capsule formulations (Agenerase, GlaxoSmithKline) also provide high daily doses of vitamin E. The oral solution has a high content of propylene glycol, present as an excip-ient, and appropriate precautions should be taken; it is contra-indicated in infants and young children, in pregnancy, and in hepatic or renal impairment. For further information on propylene glycol toxicity see Adverse Effects and Precautions.

Pregnancy

Amprenavir has been associated with teratogenicity in animals. The solution is contra-indicated in pregnancy due to the high propylene glycol content.

Interactions

Amprenavir is reported to be metabolised by the cyto-chrome P450 isoenzyme CYP3A4. It is also a modest inhibitor of the cytochrome P450 isoenzymes CYP3 A4 and CYP2C19. Drugs that affect these isoenzymes may modify amprenavir plasma concentrations and amprenavir may alter the pharmacokinetics of other drugs that are metabolized by this enzyme system. Amprenavir is contra-indicated with drugs that are highly dependent on CYP3A4 for clearance and for which elevated plasma concentrations are associated with serious or life-threatening events. These drugs include antiarrhythmics (amiodarone, bepridil, flecainide, propafenone, and quinidine), antihistamines (astemizole and terfenadine), ergot derivatives (dihydroergotamine, ergometrine, ergotamine, methyler-gometrine), gastrointestinal prokinetics (cisapride), antipsychotics (pimozide), sedatives and hypnotics (midazolam and triazolam) and statins (simvastatin and lovastatin). Rifampicin and St John’s wort decrease the concentration of amprenavir; use with the antiretroviral is not recommended due to possible loss of its activity and development of resistance. Agenerase oral solution (GlaxoSmithKline) is contra-indicated in patients taking disulfiram or other products that reduce alcohol metabolism (such as metronidazole) and in those taking alcohol-containing products (such as ritonavir oral solution) because of the potential risk of toxicity from its propylene glycol content.

Antiviral Action

Amprenavir is a selective, competitive, reversible inhibitor of HIV-1 and HIV-2 protease. It interferes with the formation of essential viral proteins making them incapable of infecting other cells. Viral resistance develops rapidly when HIV-protease inhibitors are given alone and therefore they are used with other antiretrovirals. Cross-resistance between HIV-protease inhibitors may occur, but cross-resistance between HIV-protease inhibitors and reverse transcriptase inhibitors is considered unlikely. Mechanisms of resistance to amprenavir may differ from those of other HIV-protease inhibitors.

Pharmacokinetics

Amprenavir is rapidly and well absorbed from the gastrointestinal tract after oral doses. Absorption is impaired by ingestion with a high-fat meal. Amprenavir capsules and oral solution are not bioequivalent; oral bioavailability is about 14% lower from the oral solution formulation than from the capsule formulation (Agenerase, GlaxoSmithKline). Peak plasma concentrations are attained 1 to 2 hours after a single dose, ft is about 90% bound to plasma proteins. Amprenavir is metabolised by hepatic cytochrome P450 isoenzyme CYP3A4. ft is excreted mainly in the faeces as metabolites. The plasma elimination half-life is 7.1 to 10.6 hours.

Uses and Administration

Amprenavir is an HIV-protease inhibitor with antiviral activity against HIV. ft is used in the treatment of HIV infection and AIDS. Viral resistance emerges rapidly when amprenavir is used alone, and it is therefore used with other antiretrovirals. Amprenavir is given orally as capsules or solution but the bioavailability of these formulations (Agenerase, GlaxoSmithKline) differ and their doses are not interchangeable.

• In adults and adolescents (13 to 16 years) weighing 50 kg or more the capsules are given in a dose of 1.2 g twice daily; when given with ritonavir (ritonavir-boosted amprenavir) the recommended dose is amprenavir 600 mg with ritonavir 100 mg twice daily or amprenavir 1.2 g with ritonavir 200 mg once daily.
• The oral solution is given in a dose of 17mg/kg three times daily (maximum daily dose 2.8 g) or 1.4 g twice daily.

For details of doses in children and patients weighing less than 50 kg, see below. For dosage in hepatic impairment, also see below. Amprenavir is also used in the form of the prodrug fosamprenavir, which may aid compliance by reducing adverse effects and increasing flexibility of dosing.

Administration in children

For the treatment of HIV infection in children 4 to 12 years of age and in adolescents (13 to 16 years) weighing less than 50 kg, amprenavir is given daily with other antiretroviral drugs.

Doses are based on body-weight:

• the capsules are given in an oral dose of 20 mg/kg twice daily or 15 mg/kg three times daily, to a maximum daily dose of 2.4 g, or
• the solution is given in an oral dose of 22.5 mg/kg twice daily or 17 mg/kg three times daily, to a maximum daily dose of 2.8 g

Administration in hepatic impairment

Amprenavir should be used with caution and in reduced doses in patients with hepatic impairment. Additionally, the oral solution contains propylene glycol and extra restrictions may apply. The following doses have been recommended in UK licensed product information: oral solution:

• do not use capsules:
• moderate impairment: 450 mg twice daily
• severe impairment: 300 mg twice daily

The following doses have been recommended in US product information: oral solution:

• Child-Pugh score 5 to 8: 513 mg twice daily
• Child-Pugh score 9 to 12: 342 mg twice daily
• hepatic failure: do not use capsules:
• Child-Pugh score 5 to 8: 450 mg twice daily
• Child-Pugh score 9 to 12: 300 mg twice daily

Preparations

Proprietary Preparations:

Argentina: Agenerase; Australia: Agenerase; Austria: Agenerase; Belgium: Agenerase; Brazil: Agenerase; Canada: Agenerase; Chile: Agenerase; Czech Republic: Agenerase; Denmark: Agenerase ; Finland: Agenerase; France: Agenerase; Germany: Agenerase; Greece: Agenerase; Ireland: Agenerase; Israel: Agenerase; Italy: Agenerase; Mexico: Agenerase; The Netherlands: Agenerase; Norway: Agenerase ; New Zealand: Agenerase; Poland: Agenerase; Portugal: Agenerase; Russia: Agenerase; Spain: Agenerase; Sweden: Agenerase ; Switzerland: Agenerase; Turkey: Agenerase; United Kingdom: Agenerase ; USA: Agenerase ; Venezuela: Agenerase.