Efavirenzside effects

The following adverse reactions are discussed in other sections of the labeling: Exacerbations of Hepatitis B. Lactic Acidosis/Severe Hepatomegaly with Steatosis. New Onset or Worsening Renal Impairment. Psychiatric Symptoms. Nervous System Symptoms. Skin and Systemic Hypersensitivity Reaction. Hepatotoxicity. Pancreatitis. Bone Loss and Mineralization Effects. Immune Reconstitution Syndrome. Fat Redistribution. Most common adverse reactions (>5% with efavirenz, lamivudine and tenofovir disoproxil fumarate) are rash and dizziness. To report SUSPECTED ADVERSE REACTIONS, contact Laurus Generics Inc. at 1-833-3-LAURUS (1-833-352-8787) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical

Trials Experience Because clinical studies are conducted under widely varying conditions, the adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Efavirenz, Lamivudine and Tenofovir Disoproxil Fumarate Clinical Trials in Treatment-Naïve HIV-1 Infected Adult Subjects In Trial 903, 600 antiretroviral-naïve subjects received TDF (N = 299) or stavudine (d4T) (N = 301) administered in combination with 3TC and EFV for 144 weeks. The most common adverse reactions were mild to moderate gastrointestinal events and dizziness. Mild adverse reactions (Grade 1) were common with a similar incidence in both arms and included dizziness, diarrhea, and nausea. Table 1 provides the treatment-emergent adverse reactions (Grades 2 to 4) occurring in greater than or equal to 5% of subjects treated in any treatment group. Table 1. Selected Adverse Reactions a (Grades 2 to 4) Reported in ≥ 5% in Any Treatment Group in Trial 903 (0 to 144 Weeks) a Frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug. b Rash event includes rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, and pustular rash. c Lipodystrophy represents a variety of investigator-described adverse events not a protocol-defined syndrome. d Peripheral neuropathy includes peripheral neuritis and neuropathy. TDF + 3TC + EFV d4T + 3TC + EFV N = 299 N = 301 Rash event b 18% 12% Headache 14% 17% Pain 13% 12% Diarrhea 11% 13% Depression 11% 10% Back pain 9% 8% Nausea 8% 9% Fever 8% 7% Abdominal pain 7% 12% Asthenia 6% 7% Anxiety 6% 6% Vomiting 5% 9% Insomnia 5% 8% Arthralgia 5% 7% Pneumonia 5% 5% Dyspepsia 4% 5% Dizziness 3% 6% Myalgia 3% 5% Lipodystrophy c 1% 8% Peripheral neuropathy d 1% 5% ENCORE1 Study - Adverse Reactions: The most common adverse reactions seen in a double-blind comparative controlled study in which 630 treatment-naïve subjects received EFV 400 mg (N = 321) or EFV 600 mg (N = 309) in combination with fixed-dose emtricitabine (FTC)/TDF for 48 weeks were mild to moderate gastrointestinal events, dizziness, abnormal dreams, and rash. Selected clinical adverse reactions of moderate or severe intensity reported in ≥ 2% of treatment-naive patients receiving combination therapy including EFV 400 mg and EFV 600 mg are presented in Table 2. Table 2. Selected Adverse Reactions a (Grades 2 to 4) Reported in ≥ 2% in Either Treatment Group in the ENCORE1 Study through Week 48 a Frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug. b Rash events include dermatitis allergic, drug hypersensitivity, pruritus generalized, eosinophilic pustular folliculitis, rash, rash erythematous, rash generalized, rash macular, rash maculopapular, rash morbilliform, rash papular, rash pruritic, rash vesicular, and urticaria. EFV 400 mg + FTC/TDF EFV 600 mg + FTC/TDF N = 321 N = 309 Rash event b 9% 13% Dizziness 6% 9% Insomnia 3% 4% Abnormal dreams 2% 2% Headache 1% 3% Diarrhea 2% 3% Vomiting 1% 2% Pyrexia 2% 1% Upper respiratory tract infection 3% 1% Nasopharyngitis 3% 2% Herpes zoster 3% 1% Gastroenteritis 2% 2% Laboratory Abnormalities: Table 3 provides a list of laboratory abnormalities (Grades 3 to 4) observed in Trial 903. With the exception of fasting cholesterol and fasting triglyceride elevations that were more common in the d4T group (40% and 9%) compared with the TDF group (19% and 1%) respectively, laboratory abnormalities observed in this trial occurred with similar frequency in the TDF and d4T treatment arms. Table 3. Grade 3 to 4 Laboratory Abnormalities Reported in ≥ 1% of Patients Randomized to Efavirenz, Lamivudine and Tenofovir Disoproxil Fumarate in Study 903 (0 to 144 Weeks) TDF + 3TC + EFV d4T + 3TC + EFV N = 299 N = 301 Any ≥ Grade 3 Laboratory Abnormality 36% 42% Fasting Cholesterol (> 240 mg/dL) 19% 40% Creatine Kinase (M: > 990 U/L;

F: > 845 U/L) 12% 12% Serum Amylase (> 175 U/L) 9% 8% AST (M: > 180 U/L;

F: > 170 U/L) 5% 7% ALT (M: > 215 U/L;

F: > 170 U/L) 4% 5% Hematuria (> 100 RBC/HPF) 7% 7% Neutrophils (< 750/mm 3 ) 3% 1% Fasting Triglycerides (> 750 mg/dL) 1% 9% In ENCORE1 study, a summary of Grade 3 and 4 laboratory abnormalities is provided in Table 4. Table 4. Grades 3 to 4 Laboratory Abnormalities in ≥ 2% in Either Treatment Group Through Week 48 Laboratory Parameter EFV 400 mg + FTC + TDF EFV 600 mg + FTC + TDF N = 321 N = 309 ALT 5% 3% AST 2% 2% Total bilirubin 0.3% 3% Cholesterol 2% 5% Neutrophils 2% 3% Phosphorus 2% 3% Pancreatitis: Pancreatitis, which has been fatal in some cases, has been observed in antiretroviral nucleoside-experienced pediatric subjects receiving 3TC alone or in combination with other antiretroviral agents. Changes in Bone Mineral Density: In HIV-1-infected adult subjects in Trial 903, there was a significantly greater mean percentage decrease from baseline in BMD at the lumbar spine in subjects receiving TDF + 3TC + EFV (-2.2% ± 3.9) compared with subjects receiving d4T + 3TC + EFV (-1.0% ± 4.6) through 144 weeks. Changes in BMD at the hip were similar between the two treatment groups (-2.8% ± 3.5 in the TDF group vs. -2.4% ± 4.5 in the d4T group). In both groups, the majority of the reduction in BMD occurred in the first 24 to 48 weeks of the trial and this reduction was sustained through Week 144. Twenty-eight percent of TDF-treated subjects vs. 21% of the d4T-treated subjects lost at least 5% of BMD at the spine or 7% of BMD at the hip. Clinically relevant fractures (excluding fingers and toes) were reported in 4 subjects in the TDF group and 6 subjects in the d4T group. In addition, there were significant increases in biochemical markers of bone metabolism (serum bone-specific alkaline phosphatase, serum osteocalcin, serum C telopeptide, and urinary N telopeptide) and higher serum parathyroid hormone levels and 1,25 Vitamin D levels in the TDF group relative to the d4T group; however, except for bone-specific alkaline phosphatase, these changes resulted in values that remained within the normal range.

6.2 Postmarketing

Experience The following adverse reactions have been identified during post-approval use for each of the individual components of efavirenz, lamivudine and tenofovir disoproxil fumarate tablets (EFV, 3TC, and TDF). Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure. These reactions have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to EFV, 3TC, and TDF. Efavirenz Body as a Whole: allergic reactions, asthenia, redistribution/accumulation of body fat. Central and Peripheral Nervous System: abnormal coordination, ataxia, encephalopathy, 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.

Metabolic and Nutritional: hypercholesterolemia, hypertriglyceridemia.

Musculoskeletal: arthralgia, myalgia, myopathy.

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

Respiratory: dyspnea.

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

Special Senses: abnormal vision, tinnitus. Lamivudine Body as a Whole: redistribution/accumulation of body fat.

Endocrine and Metabolic: hyperglycemia.

General: weakness.

Hemic and Lymphatic: anemia (including pure red cell aplasia and severe anemias progressing on therapy).

Hepatic and Pancreatic: lactic acidosis and hepatic steatosis, posttreatment exacerbation of hepatitis B.

Hypersensitivity: anaphylaxis, urticaria.

Musculoskeletal: muscle weakness, CPK elevation, rhabdomyolysis.

Skin: Alopecia, pruritus. Tenofovir Disoproxil Fumarate Immune System Disorders: allergic reaction, including angioedema.

Metabolism and Nutrition Disorders: lactic acidosis, hypokalemia, hypophosphatemia. Respiratory, Thoracic, and Mediastinal Disorders: dyspnea.

Gastrointestinal Disorders: pancreatitis, increased amylase, abdominal pain.

Renal and Urinary Disorders: renal insufficiency, acute renal failure, renal failure, acute tubular necrosis, Fanconi syndrome, proximal renal tubulopathy, interstitial nephritis (including acute cases), nephrogenic diabetes insipidus, renal insufficiency, increased creatinine, proteinuria, polyuria.

Hepatobiliary Disorders: hepatic steatosis, hepatitis, increased liver enzymes (most commonly AST, ALT gamma GT). Skin and Subcutaneous Tissue Disorders: rash. Musculoskeletal and Connective Tissue Disorders: rhabdomyolysis, osteomalacia (manifested as bone pain and which may contribute to fractures), muscular weakness, myopathy. General Disorders and Administration Site Conditions: asthenia. The following adverse reactions, listed under the body system headings above, may occur as a consequence of proximal renal tubulopathy: rhabdomyolysis, osteomalacia, hypokalemia, muscular weakness, myopathy, hypophosphatemia.