August 17, 2004 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 OLE_LINK2from 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
<mailto:Drugs@FDA> "
<http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm> website at
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/
<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
MedAdvocates Efavirenz Web
|
