Because clinical studies are conducted under widely varying conditions, the adverse reaction rates reported cannot be directly compared to rates in other clinical studies and may not reflect the rates observed in clinical practice.
Adverse Reactions in Adults
The most common (>5% in either efavirenz treatment group) adverse reactions of at least moderate severity among patients in Study 006 treated with efavirenz tablets in combination with zidovudine/lamivudine or indinavir were rash, dizziness, nausea, headache, fatigue, insomnia, and vomiting.
Selected clinical adverse reactions of moderate or severe intensity observed in ≥2% of efavirenz tablets-treated patients in two controlled clinical trials are presented in Table 2. Table 2: Selected Treatment-Emergent a Adverse Reactions of Moderate or Severe Intensity Reported in ≥2% of Efavirenz-Treated Patients in Studies 006 and ACTG 364
|Adverse Reactions||Study 006 LAM-, NNRTI-, and Protease Inhibitor-Naive Patients||Study ACTG 364 NRTI-experienced, NNRTI-, and Protease Inhibitor-Naive Patients|
|Efavirenz tablets b + ZDV/LAM (n=412) 180 weeks c||Efavirenz tablets b + Indinavir (n=415) 102 weeks c||Indinavir + ZDV/LAM (n=401) 76 weeks c||Efavirenz tablets b + Nelfinavir + NRTIs (n=64) 71.1 weeks c||Efavirenz tablets b + NRTIs (n=65) 70.9 weeks c||Nelfinavir + NRTIs (n=66) 62.7 weeks c|
|Body as a Whole|
|Central and Peripheral Nervous System|
|Skin & Appendages|
a Includes adverse events at least possibly related to study drug or of unknown relationship for Study 006. Includes all adverse events regardless of relationship to study drug for Study ACTG 364.
b Efavirenz tablets provided as 600 mg once daily.
c Median duration of treatment.
d Includes erythema multiforme, rash, rash erythematous, rash follicular, rash maculopapular, rash petechial, rash pustular, and urticaria for Study 006 and macules, papules, rash, erythema, redness, inflammation, allergic rash, urticaria, welts, hives, itchy, and pruritus for ACTG 364.
— = Not Specified.
ZDV = zidovudine, LAM=lamivudine.
Pancreatitis has been reported, although a causal relationship with efavirenz has not been established. Asymptomatic increases in serum amylase levels were observed in a significantly higher number of patients treated with efavirenz 600 mg than in control patients (see Laboratory Abnormalities).
Nervous System Symptoms
For 1,008 patients treated with regimens containing efavirenz tablets and 635 patients treated with a control regimen in controlled trials, Table 3 lists the frequency of symptoms of different degrees of severity and gives the discontinuation rates for one or more of the following nervous system symptoms: dizziness, insomnia, impaired concentration, somnolence, abnormal dreaming, euphoria, confusion, agitation, amnesia, hallucinations, stupor, abnormal thinking, and depersonalization [see Warnings and Precautions (5.6)].The frequencies of specific central and peripheral nervous system symptoms are provided in Table 2. Table 3: Percent of Patients with One or More Selected Nervous System Symptoms a,b
|Percent of Patients with:||Efavirenz Tablets 600 mg Once Daily (n=1,008) %||Control Groups (n=635) %|
|Symptoms of any severity||52.7||24.6|
|Mild symptoms c||33.3||15.6|
|Moderate symptoms d||17.4||7.7|
|Severe symptoms e||2||1.3|
|Treatment discontinuation as a result of symptoms||2.1||1.1|
a Includes events reported regardless of causality.
b Data from Study 006 and three Phase 2/3 studies.
c “Mild” = Symptoms which do not interfere with patient’s daily activities.
d “Moderate” = Symptoms which may interfere with daily activities.
e “Severe” = Events which interrupt patient’s usual daily activities.
Serious psychiatric adverse experiences have been reported in patients treated with efavirenz tablets. In controlled trials, psychiatric symptoms observed at a frequency greater than 2% among patients treated with efavirenz tablets or control regimens, respectively, were depression (19%, 16%), anxiety (13%, 9%), and nervousness (7%, 2%).
In controlled clinical trials, the frequency of rash (all grades, regardless of causality) was 26% for 1,008 adults treated with regimens containing efavirenz tablets and 17% for 635 adults treated with a control regimen. Most reports of rash were mild or moderate in severity. The frequency of Grade 3 rash was 0.8% for efavirenz tablets-treated patients and 0.3% for control groups, and the frequency of Grade 4 rash was 0.1% for efavirenz tablets and 0 for control groups. The discontinuation rates as a result of rash were 1.7% for efavirenz tablets-treated patients and 0.3% for control groups [see Warnings and Precautions (5.8)].
Experience with efavirenz tablets in patients who discontinued other antiretroviral agents of the NNRTI class is limited. Nineteen patients who discontinued nevirapine because of rash have been treated with efavirenz tablets. Nine of these patients developed mild-to-moderate rash while receiving therapy with efavirenz tablets, and two of these patients discontinued because of rash.
Selected Grade 3 to 4 laboratory abnormalities reported in ≥2% of efavirenz tablets-treated patients in two clinical trials are presented in Table 4. Table 4: Selected Grade 3 to 4 Laboratory Abnormalities Reported in ≥2% of Efavirenz-Treated Patients in Studies 006 and ACTG 364
|Study 006 LAM-, NNRTI-, and Protease Inhibitor-Naive Patients||Study ACTG 364 NRTI-experienced, NNRTI-, and Protease Inhibitor-Naive Patients|
|Variable||Limit||Efavirenz tablets a +ZDV/LAM(n=412) 180 weeks b||Efavirenz tablets a +Indinavir (n=415) 102 weeks b||Indinavir +ZDV/LAM (n=401) 76 weeks b||Efavirenz tablets a +Nelfinavir + NRTIs (n=64) 71.1 weeks b||Efavirenz tablets a + NRTIs (n=65) 70.9 weeks b||Nelfinavir + NRTIs (n=66) 62.7 weeks b|
|ALT||>5 x ULN||5%||8%||5%||2%||6%||3%|
|AST||>5 x ULN||5%||6%||5%||6%||8%||8%|
|GGT c||>5 x ULN||8%||7%||3%||5%||0||5%|
|Amylase||>2 x ULN||4%||4%||1%||0||6%||2%|
a Efavirenz tablets provided as 600 mg once daily.
b Median duration of treatment.
c Isolated elevations of GGT in patients receiving efavirenz tablets may reflect enzyme induction not associated with liver toxicity.
ZDV = zidovudine, LAM = lamivudine, ULN = upper limit of normal, ALT = alanine aminotransferase, AST = aspartate aminotransferase, GGT = gamma-glutamyltransferase.
Patients Coinfected with Hepatitis B or C
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 efavirenz tablets-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 coinfected patients, elevations in AST to greater than five times ULN developed in 13% of patients in the efavirenz tablets 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 efavirenz tablets arms and 7% of patients in the control arm. Among coinfected patients, 3% of those treated with efavirenz tablets-containing regimens and 2% in the control arm discontinued from the study because of liver or biliary system disorders [see Warnings and Precautions (5.9)].Lipids
Increases from baseline in total cholesterol of 10 to 20% have been observed in some uninfected volunteers receiving efavirenz. In patients treated with efavirenz tablets + zidovudine + lamivudine, increases from baseline in nonfasting total cholesterol and HDL of approximately 20% and 25%, respectively, were observed. In patients treated with efavirenz tablets + 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 efavirenz tablets + zidovudine + lamivudine; 54% and 20%, respectively, of patients treated with efavirenz tablets + indinavir; and 28% and 4%, respectively, of patients treated with indinavir + zidovudine + lamivudine. The effects of efavirenz tablets on triglycerides and LDL in this study were not well characterized since samples were taken from nonfasting patients. The clinical significance of these findings is unknown [see Warnings and Precautions (5.11)].
Adverse Reactions in Pediatric Patients
Because clinical studies are conducted under widely varying conditions, the adverse reaction rates reported cannot be directly compared to rates in other clinical studies and may not reflect the rates observed in clinical practice. Assessment of adverse reactions is based on three clinical trials in 182 HIV-1 infected pediatric patients (3 months to 21 years of age) who received efavirenz tablets in combination with other antiretroviral agents for a median of 123 weeks. The adverse reactions observed in the three trials were similar to those observed in clinical trials in adults except that rash was more common in pediatric patients (32% for all grades regardless of causality) and more often of higher grade (ie, more severe). Two (1.1%) pediatric patients experienced Grade 3 rash (confluent rash with fever, generalized rash), and four (2.2%) pediatric patients had Grade 4 rash (all erythema multiforme). Five pediatric patients (2.7%) discontinued from the study because of rash [see Warnings and Precautions (5.8)].
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