AIDS Community Research Initiative of America (ACRIA) - Fall 2003 / Winter 2004

Agenerase (amprenavir) and Lexiva (fosamprenavir calcium) are different versions of the same drug. Agenerase was the fifth protease inhibitor to hit the market when the FDA approved it in April 1999. Agenerase's lackluster performance in clinical trials and its high pill count have made it one of the least-prescribed protease inhibitors. In fact, its official Web site contains little text other than the statement that one trial "found Agenerase to be significantly less effective than indinavir [Crixivan]." When even the manufacturer warns you about its drug, you know there's a problem. Lexiva, which received FDA approval in October 2003, lowers the pill count dramatically and has performed better in clinical trials than Agenerase.

Background: Like Invirase (hard-gel saquinavir), Agenerase was a drug waiting for a second life. It was approved in spite of poor showings in clinical trials. In PROAB3001, for example, a study of Agenerase with Epivir (3TC) and Retrovir (AZT) in 232 people who had never taken antiretrovirals, only 41% of people had viral loads below 400 after 11 months. And in PROAB3006, a study of 504 people who had taken NRTIs but no protease inhibitors, only 30% of people who took Agenerase with two NRTIs had viral loads below 400 after 11 months compared to 49% of people who took Crixivan with two NRTIs.

In addition to these poor results, Agenerase capsules are so big that they're sometimes called "horse pills" and the required dose is 16 of them a day! Because of these problems, the manufacturer (GlaxoSmithKline) developed Lexiva, a pro-drug of amprenavir called fosamprenavir. A pro-drug is a compound that changes into the actual drug once it's in the body, sometimes delivering more of the actual drug. Lexiva requires significantly fewer pills than Agenerase, whether it is taken with Norvir or not.

In the SOLO study, 660 people who had never taken antiretrovirals took either Lexiva with low-dose Norvir once a day or Viracept (nelfinavir) twice a day, each with two NRTIs. After 11 months, 58% of those taking Lexiva had viral loads below 50 compared to 55% of those taking Viracept. Also, half of the people on Viracept had developed mutations associated with resistance to protease inhibitors compared to none of those on Lexiva. Similar results were seen when Lexiva was taken twice a day without Norvir - in the NEAT study, 57% of those taking Lexiva had viral loads below 50 compared to 42% of those taking Viracept after 11 months.

For people who have taken protease inhibitors, Lexiva is only approved for twice-a-day dosing. This is because of the CONTEXT study, in which 315 people who had already taken one or two protease inhibitors took either Kaletra (lopinavir/ritonavir) or Lexiva once or twice a day with low-dose Norvir. Everyone also took two NRTIs. After 11 months, 50% of people taking Kaletra had viral loads below 50, compared to only 37% of those taking Lexiva once a day. However, 46% of those taking Lexiva twice a day had viral loads below 50, so the FDA only approved twice-a-day dosing for "experienced" patients and warns that this study was not large enough to prove that Lexiva was as effective as Kaletra.

Side Effects: The most common side effects of both Agenerase and Lexiva are nausea, vomiting, diarrhea, and rash. Users of Agenerase also have reported a tingling feeling around the mouth, and a change in taste sensation. Depression and mood problems have also been reported.

In clinical trials, Lexiva caused fewer gastrointestinal side effects than Agenerase - only 5-9% of people reported nausea or diarrhea. This is probably because Agenerase capsules contain small amounts of propylene glycol (used in deodorants, cosmetics, fat-free ice cream, and other products), while Lexiva doesn't. Rash occurred in only 2-7% of people taking Lexiva in clinical trials - a much lower rate than has been seen with Agenerase.

Drug Interactions: Both Agenerase and Lexiva interact with many other drugs, so anyone taking either drug should be sure that their healthcare provider knows everything they're taking, including over-the-counter drugs and herbal medicines. Check the package insert for a complete list of known drug interactions. The following is a partial list:

Neither Agenerase nor Lexiva should be taken with triazolam (Halcion, Restoril, Dalmane, and others), ergot medicines (used for migraines), Versed (midazolam), or Orap (pimozide). Other drugs that require careful monitoring or dose adjustment include Mycobutin (rifabutin) and Viagra (sildenafil).

Agenerase contains a lot of vitamin E, so avoid taking vitamin E supplements while on Agenerase. Too much vitamin E can lead to blood thinning and worsen already existing blood clotting problems or high blood pressure.

Videx (ddI) and antacids should be taken at least an hour before or after taking Agenerase. Rescriptor (delavirdine), rifampin, the oral contraceptives norethindrone and ethinyl estradiol, and St. John's wort (hypericum) may lower blood levels of Agenerase or Lexiva and shouldn't be taken with either drug. Sustiva (efavirenz) lowers levels of Agenerase, so the two drugs shouldn't be combined unless Agenerase is boosted with Norvir. If Lexiva is taken with Norvir once a day in a regimen that includes Sustiva, the Norvir dose should be increased from 200 mg to 300 mg.

Anyone using the liquid formulation of Agenerase shouldn't take Antabuse (disulfiram) or Flagyl (metronidazole). Alcohol should also be avoided if the liquid formulation is used.

Since Lexiva is often taken with Norvir, even more drug interactions can be expected. Be sure to check out the drug interactions associated with Norvir before combining it with either Agenerase or Lexiva. Serious interactions could occur between Agenerase or Lexiva and amiodarone (Cordarone, Pacerone), systemic lidocaine, tricyclic antidepressants, and quinidine. Careful monitoring is required if any of these are taken with Agenerase or Lexiva.

When To Consider It: The Department of Health and Human Services treatment guidelines do not recommend Agenerase as part of a preferred first regimen. It's included as part of an alternative regimen, but only when combined with low-dose Norvir to reduce the number of pills. There's no recommendation regarding Lexiva since the guidelines haven't been updated since its approval.

One of the mutations (changes) found in HIV that's resistant to Agenerase (I50V) does not seem to cause cross-resistance to other protease inhibitors, but other mutations (I84V, M46I) do. ACTG 373, a study of people who had previously taken Agenerase, found that 59% of the participants had viral loads below 500 after 11 months on Crixivan, Viramune (nevirapine), and two NRTIs. So it's possible to switch to another protease inhibitor after taking Agenerase - at least it was for many people in this study.

Other than the CONTEXT study, there have been few trials of Lexiva or Agenerase in people who have taken other protease inhibitors. CNA 2007, a study of Agenerase, Sustiva, and Ziagen (abacavir) in people resistant to at least one protease inhibitor, had poor results - only 26% of people had viral loads below 400 after four months. But that was probably due to the interaction between Agenerase and Sustiva, which lowers Agenerase levels. As mentioned above, the CONTEXT study had better results with Lexiva, but it was too small to prove whether Lexiva is as effective as Kaletra in people with resistance to other protease inhibitors.

Pregnancy: Agenerase and Lexiva are FDA pregnancy category C drugs. The Antiretroviral Pregnancy Registry only contains information on 24 infants exposed to Agenerase in the womb. One child was born with a birth defect, but since there's only data on 24 infants, it's impossible to know whether this was a result of Agenerase exposure or something else. Agenerase should be used during pregnancy only if the potential benefit justifies the potential risk to the mother and fetus. The liquid form of Agenerase should not be used during pregnancy because it contains propylene glycol, which could be toxic to the fetus. There's no information yet on the use of Lexiva during pregnancy.

Dose:

• Lexiva comes in 700-mg tablets. For people who have never taken antiretrovirals, the dose is 1,400 mg twice a day (two tablets twice a day). If taken with Norvir, the dose is either 700 mg Lexiva with 100 mg Norvir twice a day, or 1,400 mg Lexiva with 200 mg Norvir once a day. For people who have taken protease inhibitors, the only approved dose is 700 mg Lexiva with 100 mg Norvir twice a day. Lexiva can be taken with or without food. It is not yet approved for pediatric use.
• Agenerase comes in 150-mg capsules. The dose is 1,200 mg twice a day without Norvir or 600 mg twice a day with 100 mg of Norvir. It can also be taken once a day at a dose of 1,200 mg with 200 mg of Norvir. Agenerase can be taken with or without food, but not with a high fat meal, as this will lower blood levels of the drug.
  
  Agenerase is also available as a liquid (15 mg/mL), but children under age 4 should not use it due to the risk of side effects from the propylene glycol it contains. The liquid should only be used if the Agenerase capsules or Lexiva tablets can't be swallowed.
  
  The pediatric dose is based on weight. For children 4 to 12 years old (and adolescents 13 to 16 years old who weigh less than 110 pounds), the dose is 20 mg/kg twice a day or 15 mg/kg three times a day, up to a maximum of 2,400 mg a day.

FDA Approval: Agenerase 1999; Lexiva 2003

Manufacturer: GlaxoSmithKline

Patient Assistance Program: 866-728-4368

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