By Ronald Baker, PhD

The FDA approved on February 1, 2002 a new formulation of the anti-HIV drug Sustiva (efavirenz). Sustiva is a non nucleoside reverse transcriptase inhibitor (nNRTI) that is FDA-approved for the treatment of HIV infection in adults, adolescents and children, when used in combination with other antiretroviral drugs.

By late February 2002, Sustiva will be available by prescription in a 600 mg tablet to be taken once-daily instead of three 200 mg capsules once-daily, in combination with a protease inhibitor (PI) and/or with nucleoside analogue reverse transcriptase inhibitors (NRTIs). The US government-recommended HIV treatment guidelines list Sustiva as the only nNRTI "strongly recommended" for use in first-line combination with NRTIs for the treatment of HIV infection.

Sustiva will continue to be available in the 50 mg, 100 and 200 mg capsules in addition to the new 600 mg tablet. The 600 mg tablet is approximately the same size as one Sustiva 200 mg capsule.

In approving the new formulation of Sustiva, the FDA also revised the drug's label to include new statements in the DOSAGE AND ADMINISTRATION section. The revised statements are shown below within > < symbols:

"Adults: The recommended dosage of Sustiva is 600 mg orally, once daily, in combination with a protease inhibitor and/or nucleoside analogue reverse transcriptase inhibitors (NRTIs). >It is recommended that Sustiva be taken on an empty stomach, preferably at bedtime. The increased efavirenz concentrations observed following administration of Sustiva with food may lead to an increase in frequency of adverse events. Dosing at bedtime may improve the tolerability of nervous system symptoms.<"

In addition, the CLINICAL PHARMAOLOGY and PRECAUTIONS sections have been updated to include drug interaction information on Sustiva with the following medications: St. John's wort, lorazepam, methadone, cetirizine and rifabutin. The ADVERSE REACTION section was also revised to update the incidences of adverse events and laboratory abnormalities seen in clinical trials. The revised label is hyper linked below in PDF format http://www.fda.gov/cder/foi/label/2002/21360lbl.pdf

"As physicians look to prescribe easier-to-use regimens to treat patients with HIV, the availability of Sustiva as a one-tablet, once-daily component is a welcome addition to the treatment armamentarium," said Brian Boyle, MD, Assistant Professor, Cornell University Medical College, attending physician, New York-Presbyterian Hospital, and medical editor of HIV and Hepatitis.com. "As we move towards once-daily treatment regimens with low numbers of pills for our patients, products like Sustiva will be the cornerstone that we build these regimens around."

Bristol-Myers Squibb (BMS) took over the manufacturing and marketing of Sustiva in the US when it acquired DuPont Pharmaceuticals in late 2001 for $7 billion. Considered the "crown jewel" of the DuPont portfolio, Sustiva brought in greater than $300 million in annual sales in the US alone. With its friendly acquisition of DuPont, BMS also inherited the DuPont pipeline that included PIs and nNRTIS in various stages of pre-clinical development. The ultimate fate of these experimental compounds and their future development remains uncertain at this time.

With Videx (didanosine; ddI) and Sustiva now both FDA-approved as once-daily drugs, with a new, once-daily formulation of Zerit (stavudine; d4T) nearing FDA approval, and with atazanavir, the first truly once-daily protease inhibitor, expected to win FDA approval in late 2002, BMS clearly has taken a big lead among AIDS drug manufacturers in moving toward significantly simplified, once-daily regimens utilizing several drug classes. Because these simpler, once-daily regimens will require far fewer pills, tablets or capsules, BMS is counting on physician and patient preference for them, and expecting that the low pill burden and simplification also likely will increase patient adherence.

Sustiva is generally well tolerated, but many patients experience dizziness, trouble sleeplessness, drowsiness, concentration difficulties, and/or unusual dreams. These feelings tend to go away after taking Sustiva for a few weeks. Rash is a potential, but uncommon side effect. A small number of patients taking Sustiva have reported severe depression, strange thoughts, or angry behavior. There have been a few reports of possible drug-related suicide, but Sustiva has not been established as the cause.

Sustiva should not be taken with herbal products (particularly St. John's wort), Hismanal® (astemizole), Propulsid® (cisapride), Versed® (midazolam), Halcion® (triazolam) or ergot derivatives. Tell your doctor about any medication or herbal products that you are taking. Women should not become pregnant or breastfeed while taking Sustiva.

02/05/02

Sources
PK Stauffer. Update from FDA about Sustiva and new formulation and labeling changes. FDA HIV/AIDS Electronic E-Mail Service. February 4, 2002.

D Rosen. Bristol-Myers Squibb announces approval of new one tablet, once-daily formulation of Sustiva. Press Release from Bristol-Myers Squibb. February 4, 2002.

B Boyle. Managing Sustiva Side Effects. HIV and Hepatitis.com.