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Clinical Trials Experience in Adults

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.

The most significant adverse reactions observed in patients treated with SUSTIVA are:

  • psychiatric symptoms [see WARNINGS AND PRECAUTIONS],
  • nervous system symptoms [see WARNINGS AND PRECAUTIONS],
  • rash [see WARNINGS AND PRECAUTIONS].

The most common ( > 5% in either efavirenz treatment group) adverse reactions of at least moderate severity among patients in Study 006 treated with SUSTIVA 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 SUSTIVA-treated patients in two controlled clinical trials are presented in Table 2.

Table 2: Selected Treatment-Emergenta Adverse Reactions of Moderate or Severe Intensity Reported in ≥ 2% of SUSTIVA-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
SUSTIVAb+ ZDV/LAM
(n=412)
SUSTIVAb+ Indinavir
(n=415)
Indinavir + ZDV/LAM
(n=401)
SUSTIVAb+ Nelfinavir + NRTIs
(n=64)
SUSTIVAb+ NRTIs
(n=65)
Nelfinavir +NRTIs
(n=66)
180 weeksc 102 weeksc 76 weeksc 71.1 weeksc 70.9 weeksc 62.7 weeksc
Body as a Whole
  Fatigue 8% 5% 9% 0 2% 3%
  Pain 1% 2% 8% 13% 6% 17%
Central and Peripheral Nervous System
  Dizziness 9% 9% 2% 2% 6% 6%
  Headache 8% 5% 3% 5% 2% 3%
  Insomnia 7% 7% 2% 0 0 2%
  Concentration impaired 5% 3% < 1% 0 0 0
  Abnormal dreams 3% 1% 0
  Somnolence 2% 2% < 1% 0 0 0
  Anorexia 1% < 1% < 1% 0 2% 2%
Gastrointestinal
  Nausea 10% 6% 24% 3% 2% 2%
  Vomiting 6% 3% 14%
  Diarrhea 3% 5% 6% 14% 3% 9%
  Dyspepsia 4% 4% 6% 0 0 2%
  Abdominal pain 2% 2% 5% 3% 3% 3%
Psychiatric
  Anxiety 2% 4% < 1%
  Depression 5% 4% < 1% 3% 0 5%
  Nervousness 2% 2% 0 2% 0 2%
  Skin & Appendages Rashd 11% 16% 5% 9% 5% 9%
  Pruritus < 1% 1% 1% 9% 5% 9%
aIncludes 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.
bSUSTIVA provided as 600 mg once daily.
cMedian duration of treatment.
dIncludes 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 1008 patients treated with regimens containing SUSTIVA 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]. 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 Symptomsa,b

Percent of Patients with: SUSTIVA 600 mg Once Daily
(n=1008) %
Control Groups
(n=635) %
Symptoms of any severity 52.7 24.6
Mild symptomsc 33.3 15.6
Moderate symptomsd 17.4 7.7
Severe symptomse 2.0 1.3
Treatment discontinuation as a result of symptoms 2.1 1.1
aIncludes events reported regardless of causality.
bData 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.

Psychiatric Symptoms

Serious psychiatric adverse experiences have been reported in patients treated with SUSTIVA. In controlled trials, psychiatric symptoms observed at a frequency greater than 2% among patients treated with SUSTIVA or control regimens, respectively, were depression (19%, 16%), anxiety (13%, 9%), and nervousness (7%, 2%).

Rash

In controlled clinical trials, the frequency of rash (all grades, regardless of causality) was 26% for 1008 adults treated with regimens containing SUSTIVA 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 SUSTIVA-treated patients and 0.3% for control groups, and the frequency of Grade 4 rash was 0.1% for SUSTIVA and 0 for control groups. The discontinuation rates as a result of rash were 1.7% for SUSTIVA-treated patients and 0.3% for control groups [see WARNINGS AND PRECAUTIONS].

Experience with SUSTIVA 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 SUSTIVA. Nine of these patients developed mild-to-moderate rash while receiving therapy with SUSTIVA, and two of these patients discontinued because of rash.

Laboratory Abnormalities

Selected Grade 3-4 laboratory abnormalities reported in ≥ 2% of SUSTIVA-treated patients in two clinical trials are presented in Table 4.

Table 4: Selected Grade 3-4 Laboratory Abnormalities Reported in ≥ 2% of SUSTIVA-Treated Patients in Studies 006 and ACTG 364

Variable Limit Study 006 LAM-, NNRTI-, and Protease Inhibitor-Naive Patients Study ACTG 364 NRTI-experienced, NNRTI-, and Protease Inhibitor-Naive Patients
SUSTIVAa+ ZDV/LAM
(n=412) b180 weeks
SUSTIVAa + Indinavir
(n=415) b102 weeks
Indinavir + ZDV/LAM
(n=401) 76 weeks
SUSTIVAa + Nelfinavir + NRTIs
(n=64) b71.1 weeks
SUSTIVAa + NRTIs
(n=65) b 70.9 weeks
Nelfinavir + NRTIs
(n=66) b 62.7 weeks
Chemistry
  ALT > 5 x ULN 5% 8% 5% 2% 6% 3%
  AST > 5 x ULN 5% 6% 5% 6% 8% 8%
  GGTc > 5 x ULN 8% 7% 3% 5% 0 5%
  Amylase > 2 x ULN 4% 4% 1% 0 6% 2%
  Glucose > 250 mg/dL 3% 3% 3% 5% 2% 3%
  Triglyceridesd > 751 mg/dL 9% 6% 6% 11% 8% 17%
Hematology
  Neutrophils 3 < 750/mm³ 10% 3% 5% 2% 3% 2%
aSUSTIVA provided as 600 mg once daily.
b Median duration of treatment.
c Isolated elevations of GGT in patients receiving SUSTIVA may reflect enzyme induction not associated with liver toxicity.
dNonfasting.
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 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 coinfected 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 coinfected 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 [see WARNINGS AND PRECAUTIONS].

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 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].

Clinical Trial Experience 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 SUSTIVA 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].

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of SUSTIVA. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Body as a Whole: allergic reactions, asthenia, redistribution/accumulation of body fat [see WARNINGS AND PRECAUTIONS]

Central and Peripheral Nervous System: abnormal coordination, ataxia, cerebellar coordination and balance disturbances, convulsions, hypoesthesia, paresthesia, neuropathy, tremor, vertigo

Endocrine: gynecomastia

Gastrointestinal: constipation, malabsorption

Cardiovascular: flushing, palpitations

Liver and Biliary System: hepatic enzyme increase, hepatic failure, hepatitis. A few of the postmarketing reports of hepatic failure, including cases in patients with no pre-existing hepatic disease or other identifiable risk factors, were characterized by a fulminant course, progressing in some cases to transplantation or death.

Metabolic and Nutritional: hypercholesterolemia, hypertriglyceridemia

Musculoskeletal: arthralgia, myalgia, myopathy

Psychiatric: aggressive reactions, agitation, delusions, emotional lability, mania, neurosis, paranoia, psychosis, suicide

Respiratory: dyspnea

Skin and Appendages: erythema multiforme, photoallergic dermatitis, Stevens-Johnson syndrome

Special Senses: abnormal vision, tinnitus