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Clinicians will soon be able to offer HIV-positive patients a protease inhibitor (PI) that combines the convenience of flexible dosing with no restrictions on food or water. The FDA recently approved fosamprenavir (Lexiva, GlaxoSmithKline/Vertex Pharmaceuticals) for the treatment of HIV infection in adults in combination with other antiretroviral agents. Fosamprenavir will be available in pharmacies later this month.
Clinicians will soon be able to offer HIV-positive patients a protease inhibitor (PI) that combines the convenience of flexible dosing with no restrictions on food or water. The Food & Drug Administration recently approved fosamprenavir (Lexiva, GlaxoSmithKline/Vertex Pharmaceuticals) for the treatment of HIV infection in adults in combination with other antiretroviral agents. Fosamprenavir will be available in pharmacies later this month.
Fosamprenavir is a prodrug of amprenavir, said Jeffrey Nadler, M.D., professor of medicine and director of clinical research in infectious diseases at the University of South Florida College of Medicine in Tampa. Fosamprenavir is rapidly hydrolyzed to amprenavir by cellular phosphatases in vivo, he explained.
"Fosamprenavir is water-soluble," Nadler said. "That translates to better absorbability when taken by mouth, so fosamprenavir could be formulated as a tablet and not a capsule.
"During the development of fosamprenavir, researchers demonstrated that many of the side effects associated with PI therapy are related to the excipients," Nadler continued. "When a drug is water soluble, it is easier to concentrate the product, so fosamprenavir can be dosed as two tablets taken twice daily compared with eight large capsules taken twice daily," he added. "Most of the GI side effects associated with amprenavir have been eliminated."
One potential benefit of fosamprenavir, Nadler said, is flexibility in dosing. For therapy-naïve patients, the recommended dosing schedule is two 700-mg fosamprenavir tablets and two 100-mg ritonavir (Norvir, Abbott Laboratories) capsules taken once daily, or one 700-mg fosamprenavir tablet and one 100-mg ritonavir capsule taken twice daily.
According to Nadler, fosamprenavir was studied for use as a boosted PI (PI plus ritonavir). Most clinicians who treat HIV-positive patients lean strongly toward the use of boosted PIs, he said. Unboosted PIs are used only in situations such as hypercholesterolemia. Without ritonavir, the recommended schedule is two 700-mg fosamprenavir tablets taken twice daily.
In PI-experienced patients, the recommended dosing schedule is one 700-mg fosamprenavir tablet plus one 100-mg ritonavir capsule taken twice daily.
GlaxoSmithKline and Vertex recommend that an additional 100 mg per day of ritonavir, for a total of 300 mg ritonavir daily, be administered when efavirenz (Sustiva, Bristol-Myers Squibb) is taken with fosamprenavir plus ritonavir once daily.
The companies advise that fosamprenavir be used at a reduced dosage of 700 mg twice daily in persons with mild to moderate hepatic impairment that are taking fosamprenavir without concurrent ritonavir. They caution that fosamprenavir should not be used in those with severe hepatic impairment.
Fosamprenavir is contraindicated in patients who have previously demonstrated hypersensitivity to any components of the product or to amprenavir. The use of ergot derivatives, cisapride (Propulsid, Janssen Pharmaceuticals), pimozide (Orap, Teva Pharmaceuticals), midazolam, and triazolam are contraindicated with fosamprenavir.
The package insert for fosamprenavir carries a boldfaced warning that serious and/or life-threatening drug interactions could occur between fosamprenavir and amiodarone, lidocaine (systemic), tricyclic antidepressants, and quinidine. GlaxoSmithKline and Vertex caution that rifampin should not be used in combination with fosamprenavir.
Concomitant use of Hypericum perforatum (St. John's Wort) and products containing it are not recommended. In addition, concomitant use of fosamprenavir and lovastatin or simvastatin (Zocor, Merck) is not recommended.
The manufacturers urge caution when prescribing phosphodiesterase (PDE5) inhibitors for erectile dysfunction in patients taking PIs. Fosamprenavir should also be used with caution in those with a known sulfonamide allergy
Fosamprenavir was generally well tolerated in clinical trials, Nadler reported. The most common adverse events were diarrhea, nausea, vomiting, headache, and rash. Severe and life-threatening skin reactions, such as Stevens-Johnson syndrome, have been reported in patients treated with amprenavir.
The following should be considered when initiating therapy with Lexiva plus Norvir in PI-experienced patients:
Charlotte LoBuono. New protease inhibitor offers patients efficacy, convenience. Drug Topics Nov. 17, 2003;147:23.