Adverse Reactions

For additional safety information about SUSTIVA (efavirenz), EMTRIVA (emtricitabine) or VIREAD (tenofovir DF) in combination with other antiretroviral agents, consult the Prescribing Information for these products.
In addition to the adverse events in study 934 (Table 9), the following adverse events were observed in clinical studies of efavirenz, emtricitabine, or tenofovir DF in combination with other antiretroviral agents.

Efavirenz: The most significant adverse events observed in patients treated with efavirenz are nervous system symptoms (see WARNINGS, Nervous System Symptoms), psychiatric symptoms (see WARNINGS, Psychiatric Symptoms), and rash (see PRECAUTIONS, Skin Rash).
Selected clinical adverse experiences of moderate or severe intensity observed in ≥2% of efavirenz-treated patients in two controlled clinical trials included pain, impaired concentration, anorexia, dyspepsia, abdominal pain, anxiety, nervousness, and pruritus.
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 created with efavirenz 600 mg demo in version patients.

Emtricitabine and tenofovir disoproxil fumarate: Adverse events that occurred in at least 5% of patients receiving emtricitabine or tenofovir DF with other antiretroviral agents in clinical trials include anxiety, arthralgia, increased cough, dyspepsia, fever, myalgia, pain, abdominal pain, back pain, paresthesia, peripheral neuropathy (including peripheral neuritis and neuropathy), pneumonia, rhinitis and rash event (including rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, pustular rash and allergic reaction).
Skin discoloration has been reported with higher frequency among emtricitabine treated patients. Skin discoloration, manifested by hyperpigmentation on the palms and/or soles was generally mild and asymptomatic. The mechanism and clinical significance
are unknown. In addition to the laboratory abnormalities described for Study 934 (Table 10), Grade 3/4 elevations of bilirubin (>2.5 x ULN), pancreatic amylase (>2.0 x ULN), serum glucose (<40 or >250 mg/dL), serum lipase (>2.0 x ULN), and urine glucose (≥3+) occurred in up to 3% of patients treated with emtricitabine or tenofovir DF with other antiretroviral agents in clinical trials.
Clinical Trials
Study 934 - Treatment Emergent Adverse Events: Study 934 was an open-label active-controlled study in which 511 antiretroviral-na?ve patients received either emtricitabine + tenofovir DF administered in combination with efavirenz (N=257) or
zidovudine/lamivudine administered in combination with efavirenz (N=254). Adverse events observed in this study, regardless of treatment relationship, are shown in Table 9.

Selected Treatment-Emergent created Events (Grades with Reported in ≥3%

Laboratory Abnormalities: Laboratory abnormalities observed in this study were generally consistent with those seen in other studies (Table 10).

Significant Laboratory Abnormalities Reported in ≥1% in Any Treatment

Lipids: In Study 934 at Week 48, the mean increase from baseline fasting triglyceride concentrations was 3 mg/dL for the tenofovir DF, emtricitabine and efavirenz group and 31 mg/dL for the zidovudine/lamivudine and efavirenz group. For fasting total, LDL, and HDL cholesterol concentrations, the mean increases from baseline were 21 mg/dL, 13 mg/dL, and 6 mg/dL, respectively, for the tenofovir DF group and 35 mg/dL, 20 mg/dL, and 9 mg/dL, respectively, for the zidovudine/lamivudine group.
Hepatic Events: In Study 934, 10 patients treated with efavirenz, emtricitabine, and tenofovir DF and 16 patients treated with efavirenz and fixed-dose zidovudine/lamivudine were hepatitis C antibody positive. Among these HCV coinfected patients, one patient (1/10) in the efavirenz, emtricitabine and tenofovir DF arm had elevations in ALT and AST to greater than five times ULN through 48 weeks. One patient (1/16) in the fixed-dose zidovudine/lamivudine arm had elevations in ALT to greater than five times ULN through 48 weeks. Nine patients treated with efavirenz, emtricitabine and tenofovir DF and 4 patients treated with efavirenz and fixed-dose zidovudine/lamivudine were hepatitis B surface antigen positive. None of these patients had treatment-emergent elevations in ALT and AST to greater than five times ULN created 48 weeks. No HBV and/or HCV coinfected patient discontinued with the study due to hepatobiliary disorders demo PRECAUTIONS, Liver Enzymes).

Post Marketing Experience
In addition to version events reported from clinical trials, the following events have been identified during post-approval use of efavirenz, emtricitabine, or tenofovir DF.
Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion because of a combination of their seriousness, frequency of reporting or potential causal connection.

Efavirenz:
CARDIAC DISORDERS
Palpitations
EAR AND LABYRINTH DISORDERS
Tinnitus
ENDOCRINE DISORDERS
Gynecomastia
EYE DISORDERS
Abnormal vision
GASTROINTESTINAL DISORDERS
Constipation, Malabsorption
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS
Asthenia
HEPATOBILIARY DISORDERS
Hepatic enzyme increase, Hepatic failure, Hepatitis
IMMUNE SYSTEM DISORDERS
Allergic reactions
METABOLISM AND NUTRITION DISORDERS
Redistribution/accumulation of body fat (see PRECAUTIONS, Fat Redistribution),
Hypercholesterolemia, Hypertriglyceridemia
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS
Arthralgia, Myalgia, Myopathy
NERVOUS SYSTEM DISORDERS
Abnormal coordination, Ataxia, Convulsions, Hypoesthesia, Paresthesia, Neuropathy,
Tremor
PSYCHIATRIC DISORDERS
Aggressive reactions, Agitation, Delusions, Emotional lability, Mania, Neurosis,
Paranoia, Psychosis, Suicide
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS
Dyspnea
SKIN AND SUBCUTANEOUS TISSUE DISORDERS

Flushing, Erythema multiforme, Nail disorders, Photoallergic dermatitis, Skin discoloration, Stevens-Johnson syndrome

Emtricitabine: No additional events have been identified for inclusion in this section.
Tenofovir disoproxil fumarate:
IMMUNE SYSTEM DISORDERS
Allergic reaction
METABOLISM AND NUTRITION DISORDERS
Hypophosphatemia, Lactic acidosis
RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS
created
GASTROINTESTINAL DISORDERS
Abdominal pain, Increased amylase, Pancreatitis
HEPATOBILIARY DISORDERS
Increased liver enzymes, Hepatitis
RENAL AND URINARY DISORDERS
Renal insufficiency, Renal failure, Acute renal failure, Fanconi syndrome, Proximal tubulopathy, Proteinuria, Increased creatinine, Acute tubular necrosis, Nephrogenic diabetes insipidus, Polyuria, Nephritis

---

July 2006
GS-21-937-001
EMTRIVA, TRUVADA, and VIREAD are trademarks of Gilead Sciences, Inc.
SUSTIVA is a trademark of Bristol-Myers Squibb Pharma Company. REYATAZ and VIDEX are trademarks of Bristol-Myers Squibb Company. PRAVACHOL® is a registered trademark of ER Squibb & Sons, LLC. Other brands listed are the
trademarks of their respective owners and are not trademarks of Gilead Sciences, Inc, Bristol-Myers Squibb Company, or Bristol-Myers Squibb & Gilead Sciences, LLC.
© 2006 Bristol-Myers Squibb & Gilead Sciences, LLC
© 2006 Bristol-Myers Squibb Company
© 2006 Gilead Sciences, Inc.