Food and Drug Administration - August 18, 2004
Richard Klein, Kimberly Struble

Sustiva labeling has been revised to include safety and efficacy data representing 168 weeks of treatment from Study 006 ( efavirenz + lamivudine + zidovudine vs indinavir + lamivudine + zidovudine vs efavirenz + indinavir) and other available data.

The following changes appear in the revised labeling:

• The Microbiology section was updated to include resistance information from clinical studies and cross-resistance data.
• The Clinical Pharmacology section was updated to include pharmacokinetic data on the interaction between efavirenz and atazanavir/ritonavir and efavirenz and voriconazole
• The Description of Clinical Studies section was updated to efficacy data through 168 weeks of therapy from study 006. Study 006 was a randomized, open-label trial, compared SUSTIVA (600 mg once daily) + zidovudine (300 mg twice daily) + lamivudine (150 mg twice daily) vs indinavir (800 mg every 8 hours) + zidovudine (300 mg twice daily) + lamivudine (150 mg twice daily) vs SUSTIVA (600 mg once daily) + indinavir (1000 mg every 8 hours). At week 168, the proportion of subjects who achieved and maintained HIV RNA < 400 copies/mL (and < 50 copies/mL) was the following:
• SUSTIVA + zidovudine + lamivudine = 48% (43%)
• Indinavir + zidovudine + lamivudine = 29% (23%)
• SUSTIVA + indinavir = 40% (31%)
• The Contraindications section was updated to include the following:
• SUSTIVA should not be administered concurrently with voriconazole because SUSTIVA significantly decreases voriconazole plasma concentrations
• The Warnings - Psychiatric Symptoms and Nervous System subsections were updated as follows:

Psychiatric Symptoms: Serious psychiatric adverse experiences have been reported in patients treated with SUSTIVA. In controlled trials of 1008 patients treated with regimens containing SUSTIVA 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 SUSTIVA or control regimens, respectively, were: 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 those noted above were combined and evaluated as a group in a multifactorial analysis of data from Study 006, treatment with efavirenz was associated with an increase in the occurrence of these selected psychiatric symptoms. Other factors associated with an increase in the occurrence of these psychiatric symptoms were history of injection drug use, psychiatric history, and receipt of psychiatric medication at study entry; similar associations were observed in both the SUSTIVA and control treatment groups. In Study 006, onset of new serious psychiatric symptoms occurred throughout the study for both SUSTIVA-treated and control-treated patients. One percent of SUSTIVA-treated patients discontinued or interrupted treatment because of one or more of these selected psychiatric symptoms. There have also been occasional postmarketing reports of death by suicide, delusions, and psychosis-like behavior, although a causal relationship to the use of SUSTIVA cannot be determined from these reports. Patients with serious psychiatric adverse experiences should seek immediate medical evaluation to assess the possibility that the symptoms may be related to the use of SUSTIVA, and if so, to determine whether the risks of continued therapy outweigh the benefits.

Nervous System Symptoms: Analysis of long-term data from Study 006 (median follow-up 180 weeks, 102 weeks, and 76 weeks for patients treated with SUSTIVA + zidovudine + lamivudine, SUSTIVA + indinavir, and indinavir + zidovudine + lamivudine, respectively) showed that, beyond 24 weeks of therapy, the incidences of new-onset nervous system symptoms among SUSTIVA-treated patients were generally similar to those in the indinavir-containing control arm.

• The Precautions section was updated to include information on Immune Reconstitution Syndrome and update Table 5: Drugs That Should Not Be Coadministered with SUSTIVA and the Established Drug Interaction Table as follows:
• Immune Reconstitution Syndrome: Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including SUSTIVA. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis carinii pneumonia, or tuberculosis), which may necessitate further evaluation and treatment.
• Voriconazole was added to Table 5: Drugs That Should Not Be Coadministered with SUSTIVA


• The Established Drug Interaction table includes the following information regarding atazanavir:
• When coadministered with SUSTIVA in treatment-naive patients, the recommended dose of atazanavir is 300 mg with ritonavir 100 mg and SUSTIVA 600 mg (all once daily). Dosing recommendations for SUSTIVA and atazanavir in treatment-experienced patients have not been established.
• The Adverse Reactions section was updated to include the 168 week safety data (adverse reactions and laboratory abnormalities) from study 006
  • Table 9: Selected Grade 3 and 4 laboratory abnormality table was also updated to include triglyceride data > 751 mg/dL from studies 006 and ACTG 364

  • The Liver Enzymes and Lipids subsection were revised to include the following information from study 006
  
  
  • Liver function tests should be monitored in patients with a history of hepatitis B and/or C. In the long-term data set from Study 006, 137 patients treated with SUSTIVA-containing regimens (median duration of therapy, 68 weeks) and 84 treated with 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 these co-infected patients, elevations in AST to greater than five times ULN developed in 13% of patients in the SUSTIVA arms and 7% of those in the control arm, and elevations in ALT to greater than five times ULN developed in 20% of patients in the SUSTIVA arms and 7% of patients in the control arm. Among co-infected patients, 3% of those treated with SUSTIVA-containing regimens and 2% in the control arm discontinued from the study because of liver or biliary system disorders

  • Lipids: Increases from baseline in total cholesterol of 10-20% have been observed in some uninfected volunteers receiving SUSTIVA. In patients treated with SUSTIVA + zidovudine + lamivudine, increases from baseline in nonfasting total cholesterol and HDL of approximately 20% and 25%, respectively, were observed. In patients treated with SUSTIVA + indinavir, increases from baseline in nonfasting cholesterol and HDL of approximately 40% and 35%, respectively, were observed. Nonfasting total cholesterol levels > 240 mg/dL and > 300 mg/dL were reported in 34% and 9%, respectively, of patients treated with SUSTIVA + zidovudine + lamivudine, 54% and 20%, respectively, of patients treated with SUSTIVA + indinavir, and 28% and 4%, respectively, of patients treated with indinavir + zidovudine + lamivudine. The effects of SUSTIVA on triglycerides and LDL were not well characterized since samples were taken from nonfasting patients. The clinical significance of these findings is unknown.

The complete revised label will be available soon on the Drugs@FDA website at: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/

Richard Klein, Office of Special Health Issues - Food and Drug Administration

Kimberly Struble, Division of Antiviral Drug Products - Food and Drug Administration

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FD040803

SOURCE: Food and Drug Administration (FDA).

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