September 18, 1998
"Drug development for serious and life-threatening diseases, including AIDS, is one of our highest agency priorities," said Dr. Michael A. Friedman, FDA Acting Commissioner. "Each approval of antiretroviral agents offers people with HIV and AIDS more opportunities to maintain meaningful quality of life. This treatment is taken once a day, which can be beneficial to people who generally take several drugs concurrently."
Efavirenz is the third non-nucleoside, reverse transcriptase inhibitor FDA has approved. The results of three adequate and well-controlled trials conducted in 928 adults and an uncontrolled open-label study conducted in 57 pediatric patients (some as young as age 3) support the safety and efficacy of efavirenz. Additional supportive information on safety and activity is provided by the results of phase I and phase II trials and the sponsor's expanded access program.
Drug labeling recommends that patients take 600 mg of efavirenz once daily in combination with a protease inhibitor and/or nucleoside analogue reverse transcriptase inhibitors. Although the drug may be taken with or without food, as desired, the label suggests that patients avoid high-fat meals. Health care providers should consult the drug labeling for a discussion of drug interactions with efavirenz.
Nervous system symptoms, such as dizziness, insomnia, impaired concentration, abnormal dreams, and drowsiness have been reported in more than half of patients treated with efavirenz. These symptoms generally occur in the first or second day of treatment and usually resolve as treatment continues. Additionally, bedtime dosing may make these symptoms more tolerable. Patients should avoid potentially hazardous tasks such as driving or operating machinery, if they experience these symptoms. Reports of delusions and severe acute depression have also occurred, predominantly in patients with a history of mental illness or substance abuse. Efavirenz should be discontinued in patients with these more severe symptoms.
During clinical trials, approximately 27 percent of patients treated with efavirenz experienced a skin rash, compared to 17 percent of patients in control groups. Severe rash, requiring stopping efavirenz, was infrequently seen in clinical trials.
The labeling also recommends that health care providers monitor patients' liver enzymes, especially in those infected with hepatitis B or C viruses. Cholesterol levels should also be monitored because clinical studies could not distinguish whether this drug contributed to elevated levels or not. Several AIDS drugs have been associated with increased cholesterol and liver enzyme levels.
Adverse reactions in pediatric patients have been similar to those seen in adults, with a higher incidence of, and more severe rash than in adults.
Information from some preclinical studies showed that efavirenz appears to cause birth defects, so women should be screened for pregnancy before starting treatment and should be encouraged to use effective contraception. The sponsor has established a pregnancy registry to track fetal exposures to the drug.
FDA's approval of the efavirenz marketing application was granted as an accelerated approval, a regulatory mechanism that speeds approvals of drugs for people with serious or life-threatening illnesses. The agency bases early approval for a product on laboratory markers such as CD4 cell counts and viral load, rather than on clinical endpoints such as delay in death or reduction in opportunistic infections. FDA may withdraw the approval of products granted accelerated approval if post-marketing studies fail to verify clinical benefits.
DuPont Pharmaceuticals of Wilmington, Delaware, manufacturers efavirenz under the trade name Sustiva.
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