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How amprenavir works

Amprenavir is a member of the group of drugs referred to as protease inhibitors (PIs). This class of drug combats viral replication of HIV by blocking HIV's protease protein. This protein or enzyme is used by HIV to break up large viral proteins into smaller particles from which new HIV particles can be formed.

Protease inhibitors ensure that these new particles are immature and incapable of infecting new cells, thus inhibiting the HIV replication process.

History

Amprenavir was formerly known as 141W94 or VX-478.
Amprenavir was first licensed in the US in April 1999 for adults and children over the age of four. The European licence was granted in October 2000 for the use of amprenavir with other antiretrovirals for the treatment of HIV-1 in adults and children over the age of four who have antiretroviral treatment experience. It is not approved for first line HIV treatment.

Combination therapy

Amprenavir is established as an effective component of combination antiretroviral therapy with modest antiviral effect for those who have prior antiretroviral treatment experience.

Amprenavir is absorbed into the blood, brain, lymph tissues and also penetrates the male genital tract; this enables reduction of viral load in seminal fluid.

Careful consideration needs to be applied when incorporating amprenavir into combination therapy, as there are several known interactions with other antiretrovirals. Amprenavir levels are reduced by about a third if it is used in combination with the non-nucleoside reverse transcriptase inhibitor efavirenz; either increasing the amprenavir dose or boosting amprenavir with low dose ritonavir or nelfinavir can counteract this. Ritonavir can also boost amprenavir's efficacy in the absence of efavirenz.

When amprenavir is used in combination with lopinavir/ritonavir, the levels of lopinavir and amprenavir in the blood can be significantly reduced. Studies investigating this complex interaction have shown wide levels of variation in their results. As this specific combination is a complex issue, decisions relating to whether patients will benefit from its inclusion into their regime should be fully discussed with a physician.

Dosing

Amprenavir is white-cream coloured and produced in 50mg and 150mg strengths. Each capsule also contains vitamin E, the 150mg capsule contains 109IU.

The recommended adult daily dose of amprenavir is 1200mg (eight 150mg capsules) twice daily in combination with other antiretrovirals. Amprenavir is also produced as an oral solution.

The recommended paediatric dose is weight-based as follows: 17mg amprenavir per kg body weight, three times daily, up to a maximum of 2,800 mg.

Dosing restrictions

Amprenavir capsules may be taken with or without food. High fat food decreases the absorption of amprenavir and is not recommended. Vitamin E should not be taken with amprenavir capsules as they exceed the recommended daily intake.

There are several drug interactions with amprenavir that should be noted these include the following:

• St. John's wort reduces the efficacy of amprenavir
• Amprenavir should be taken at least one hour before ddI or any antacid medication
• Levels of Viagra in the body are increased in the presence of amprenavir, a reduced dose of Viagra (25mg) is recommended
• Amprenavir and rifampicin (TB medication) should not be prescribed together
• Amprenavir increases levels of rifabutin (TB medication) in the blood, dosage adjustment of rifabutin will be necessary
• Amprenavir should not be administered alongside triazolam, cisapride, atemizole
  or midazolam

There are several specific considerations relating to amprenavir oral solution. Patients should be aware that an accumulation of propylene glyocol, necessary to ensure stability of the solution, may lead to seizures, stupor, increased heart rate and various blood disorders. For this reason pregnant women, children under the age of four, and those with either kidney or liver failure should not take amprenavir oral solution. Those taking oral solution should avoid alcohol. The alcohol withdrawal drug disulfiram and the antibiotic metronidazole are contraindicated for use with amprenavir solution.

Side effects

The most common side effects of amprenavir are those related to gastro-intestinal disturbances. These are likely to occur in the first few weeks after commencing treatment and include:

• Nausea
• Abdominal pain
• Vomiting
• Diarrhoea

Other common side effects include:

• Rash
• Numbness/tingling around the mouth
• Numbness/tingling in feet and/or hands
• Altered taste
• Fatigue
• Headache
• Depression or mood disorders

Other side effects associated with amprenavir and common to all the protease inhibitors include:

• Lipodystrophy (although incidence and degree varies between all PIs)
• Joint inflammation
• Blood clots
• Increased bleeding in those with bleeding disorders
• Increase in blood fats
• Diabetes

In about 1% of patients taking amprenavir, a severe and life-threatening rash has been experienced. There have been reports of Stevens-Johnson syndrome.

Pre-existing conditions

Amprenavir capsules and oral solution are contraindicated for use in patients with liver or renal failure.

All protease inhibitors, including amprenavir, have been associated with increased bleeding in patients with bleeding disorders, these patients may require additional clotting agents if protease inhibitors are included in their antiretroviral combination therapy.

Patients currently treated for TB and prescribed rifampicin should not also take amprenavir, those prescribed rifabutin for TB will need the rifabutin dose adjusted to 150mg per day or 300mg taken two or three times weekly.

Paediatric use

Amprenavir is licensed for use in children over four years of age. An oral solution is produced and is prescribed according to body weight.

Use during pregnancy

There are no adequate and well-controlled studies of amprenavir in pregnant women. Therefore, amprenavir is not recommended for use during pregnancy. Also, mothers should be advised not to breastfeed their infants if receiving amprenavir.

Amprenavir-resistant HIV

It is widely accepted that all protease inhibitors experience an element of cross-resistance within the group. However, amprenavir has a slightly different resistance profile and may be suitable for those who have experience of protease inhibitor resistance; once again a matter for consultation with a physician.

Future developments

A new version of amprenavir is currently in development. It is hoped that as a 'pro-drug' it will reduce pill burden and achieve improved therapeutic drug levels. An expanded access programme for this new formulation operates - anyone interested in this programme should consult with their clinician.