Efavirenz (Sustiva generic)
Manufacturer: Bristol-Myers Squibb Indication: This prescription-only agent is used in combination with other medications to treat human immunodeficiency virus (HIV) infection. Reason for FDA Intervention: The product’s labeling has been revised to include safety and efficacy data representing 168 weeks of treatment from Study 006 and other available information.
Label Changes: The following changes appear in the revised labeling:
Microbiology Section. Includes facts on resistance and cross-resistance from clinical studies.
Clinical Pharmacology Section. Includes pharmacokinetic data on the interaction between efavirenz and atazanavir/ritonavir and efavirenz and voriconazole.
Description of Clinical Studies Section. Includes efficacy data through 168 weeks of therapy from Study 006. This randomized, open-label trial compared efavirenz (600 mg once daily) + zidovudine (300 mg twice daily) + lamivudine tablet (150 mg twice daily) versus indinavir (800 mg every eight hours) + zidovudine drug (300 mg twice daily) + lamivudine (150 mg twice daily) versus efavirenz (600 mg once daily) + indinavir (1,000 mg every eight hours). At week 168, the proportion of subjects who achieved and maintained HIV RNA levels below 400 copies/ml (and below 50 copies/ml) was as follows:
- efavirenz + zidovudine + lamivudine = 48% (43%)
- indinavir + zidovudine + lamivudine medication = 29% (23%)
- efavirenz + indinavir = 40% (31%)
Contraindications Section. Efavirenz should not be given concurrently with voriconazole because it significantly decreases plasma concentrations of voriconazole.
Psychiatric Symptoms. Serious psychiatric adverse experiences have been reported with efavirenz. In controlled trials of 1,008 patients treated with regimens containing efavirenz for a mean of 2.1 years and 635 patients treated with control regimens for a mean of 1.5 years, the frequency of specific serious psychiatric events among patients who received efavirenz or control regimens, respectively, was as follows: severe depression (2.4°%, 0.9°%), suicidal ideation (0.7°%, 0.3°%), nonfatal suicide attempts (0.5%, 0), aggressive behavior (0.4%, 0.5%), paranoid reactions (0.4%, 0.3%), and manic reactions (0.2%, 0.3%).
When psychiatric symptoms similar to these were combined and evaluated as a group in a multifactorial analysis of data from Study 006, efavirenz was associated with an increase in these selected symptoms. Other factors associated with increased psychiatric symptoms were a history of injection drug use, a psychiatric history, and receipt of psychiatric medication at study entry. Similar associations were observed in both the efavirenz and control patients.
New serious psychiatric symptoms occurred throughout Study 006 for both groups of patients. Of the efavirenz patients, 1% discontinued or interrupted treatment because of one or more of these symptoms.
Occasional postmarketing reports have included death by suicide, delusions, and psychosis-like behavior, although a causal relationship to the use of efavirenz could not be determined from these reports. Patients with serious adverse psychiatric experiences should seek immediate medical evaluation to determine whether the symptoms might be related to efavirenz. If so, the physician should evaluate whether the risks of continued therapy outweigh the benefits.
Nervous System Symptoms. Analysis of long-term data from Study 006 showed that beyond 24 weeks of therapy, the incidence of new-onset nervous system symptoms among the efavirenz patients was similar to that among those in the indinavir drug containing control arm.
Immune Reconstitution Syndrome. Transient worsening of infection two to three weeks after therapy begins has been reported in patients receiving combination antiretroviral therapy, including efavirenz. During the initial phase of combination antiretroviral treatment, patients with an immune response may experience an augmented inflammatory response to indolent or residual opportunistic infections (e.g., Mycobacterium avium infection, cytomegalovirus, Pneumocystis carinii pneumonia, or tuberculosis), which may necessitate further evaluation and treatment.
(“Drugs That Should Not be Administered with Efavirenz”). Voriconazole has been added.
Table on Established Drug Interactions. When coadminis-tered with efavirenz in treatment-naive patients, the recommended dose of atazanavir is 300 mg with ritonavir 100 mg and efavirenz 600 mg (all once daily). Dosing recommendations for efavirenz and atazanavir in treatment-experienced patients have not been established.
Adverse Reactions Section. Includes 168-week safety data from Study 006.
Table 9 (“Selected Grade 3 and 4 Laboratory Abnormalities”). Includes triglyceride data above 751 mg/dl from Studies 006 and AIDS Clinical Treatment Group (ACTG) 364.
Liver Enzymes and Lipids Subsections
- Liver function tests should be monitored in patients with a history of hepatitis B and/or hepatitis C.
- In the long-term data set from Study 006, 137 patients receiving efavirenz-containing regimens (median duration of therapy, 68 weeks) and 84 subjects given a control regimen (median duration, 56 weeks) were seropositive at screening for hepatitis B (surface antigen-positive) and/or C (hepatitis C antibody-positive).
- Among the co-infected patients, elevations in aspartate transaminase (AST) to greater than five times the upper limit of normal developed in 13% of the efavirenz patients and in 7% of the controls.
- Elevations in alanine transaminase (ALT) to greater than five times the upper limit of normal occurred in 20% of the efavirenz patients and in 7% of the controls.
- Among co-infected patients, 3% of the patients receiving efavirenz-containing regimens and 2% of controls withdrew from the study because of liver or biliary system disorders.
- Increases from baseline in total cholesterol of 10% to 20% were observed in some uninfected volunteers receiving efavirenz.
- In patients treated with efavirenz + zidovudine canadian + lamivu-dine, nonfasting total cholesterol and high-density lipo-protein (HDL) cholesterol levels increased by approximately 20% and 25%, respectively, from baseline values.
- In patients receiving efavirenz + indinavir, nonfasting cholesterol and HDL cholesterol levels increased by approximately 40% and 35%, respectively.
- Nonfasting total cholesterol levels above 240 mg/dl and above 300 mg/dl were reported as follows:
- in 34% and 9%, respectively, of patients treated with efavirenz + zidovudine + generic lamivudine
- in 54% and 20%, respectively, of patients treated with efavirenz + indinavir
- in 28% and 4%, respectively, of patients treated with indinavir + zidovudine + lamivudine
• The effects of efavirenz on triglycerides and low-density lipoprotein (LDL) cholesterol were not well characterized because samples were taken from nonfasting patients. The clinical significance of these findings is unknown.
Conclusion: Efavirenz is an important therapeutic agent for treating acquired immunodeficiency syndrome (AIDS). Even though the agent cannot cure or prevent HIV infection or AIDS, it inhibits the virus from reproducing and appears to slow down the destruction of the immune system.
Efavirenz does not prevent the spread of infection to other people. Patients receiving efavirenz canadian may continue to have some of the problems usually related to AIDS or HIV infection. In deciding whether to use a medication, patients and their physicians must weigh the risks against the benefits.