SIDE EFFECTS

The following adverse drug reactions are discussed in other sections of the labeling:

• Lactic Acidosis/Severe Hepatomegaly with Steatosis [See BOXED WARNING, WARNINGS AND PRECAUTIONS].
• Severe Acute Exacerbations of Hepatitis B [See BOXED WARNING, WARNINGS AND PRECAUTIONS].
• New Onset or Worsening Renal Impairment [See WARNINGS AND PRECAUTIONS].
• Decreases in Bone Mineral Density [See WARNINGS AND PRECAUTIONS].
• Immune Reconstitution Syndrome [See WARNINGS AND PRECAUTIONS].

Adverse Reactions from Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the 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.

The safety assessment of STRIBILD is based on pooled data from 1408 subjects in two comparative clinical trials, Study 102 and Study 103, in antiretroviral treatment-naive HIV-1 infected adult subjects. A total of 701 subjects received STRIBILD once daily for at least 48 weeks.

The proportion of subjects who discontinued treatment with STRIBILD, ATRIPLA (efavirenz 600 mg/emtricitabine 200 mg/tenofovir DF 300 mg) or atazanavir + ritonavir + TRUVADA (emtricitabine 200 mg/tenofovir DF 300 mg) due to adverse events, regardless of severity, was 3.7%, 5.1% and 5.1%, respectively. Table 2 displays the frequency of adverse drug reactions greater than or equal to 5%.

Table 2 : Treatment-Emergent Adverse Drug Reactions^a (all grades) Reported in ≥ 5% of Subjects in Any Treatment Arm in Studies 102 and 103 (Week 48 analysis)

See WARNINGS AND PRECAUTIONS, for a discussion of renal adverse events from clinical trials experience with STRIBILD.

Emtricitabine and Tenofovir Disoproxil Fumarate

In addition to the adverse drug reactions observed with STRIBILD, the following adverse drug reactions occurred in at least 5% of treatment-experienced or treatment-naive subjects receiving emtricitabine or tenofovir DF with other antiretroviral agents in other clinical trials: depression, abdominal pain, dyspepsia, vomiting, fever, pain, nasopharyngitis, pneumonia, sinusitis, upper respiratory tract infection, arthralgia, back pain, myalgia, paresthesia, peripheral neuropathy (including peripheral neuritis and neuropathy), anxiety, increased cough, and rhinitis.

Skin discoloration has been reported with higher frequency among emtricitabine-treated subjects; it was manifested by hyperpigmentation on the palms and/or soles and was generally mild and asymptomatic. The mechanism and clinical significance are unknown.

Laboratory Abnormalities

The frequency of treatment-emergent laboratory abnormalities (Grades 3-4) occurring in at least 2% of subjects receiving STRIBILD in Studies 102 and 103 are presented in Table 3.

Table 3 : Laboratory Abnormalities (Grades 3-4) Reported in ≥ 2% of Subjects Receiving STRIBILD in Studies 102 and 103 (Week 48 analysis)

Proteinuria (all grades) occurred in 39% of subjects receiving STRIBILD, 29% of subjects receiving ATRIPLA, and 24% of subjects receiving atazanavir + ritonavir + TRUVADA.

The cobicistat component of STRIBILD has been shown to increase serum creatinine and decrease estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting renal glomerular function. In Studies 102 and 103, increases in serum creatinine and decreases in estimated creatinine clearance occurred early in treatment with STRIBILD, after which they stabilized. The mean ± SD change in serum creatinine after 48 weeks of treatment was 0.14 mg per dL ± 0.13 mg per dL for STRIBILD, 0.01 mg per dL ± 0.12 mg per dL for ATRIPLA, and 0.09 mg per dL ± 0.13 mg per dL for atazanavir + ritonavir + TRUVADA. The mean ± SD change in estimated glomerular filtration rate (eGFR) by Cockcroft-Gault method after 48 weeks of treatment was -13.9 ± 14.9 mL per min for STRIBILD, -1.6 ± 16.5 mL per min for ATRIPLA, and 9.3 ± 15.8 mL per min for atazanavir + ritonavir + TRUVADA. Elevation in serum creatinine (all grades) occurred in 7% of subjects receiving STRIBILD, 1% of subjects receiving ATRIPLA, and 4% of subjects receiving atazanavir + ritonavir + TRUVADA.

Emtricitabine or Tenofovir Disoproxil Fumarate

In addition to the laboratory abnormalities observed with STRIBILD, the following laboratory abnormalities have been previously reported in subjects treated with emtricitabine or tenofovir DF with other antiretroviral agents in other clinical trials: Grades 3 or 4 laboratory abnormalities of ALT (M: greater than 215 U per L; F: greater than 170 U per L), alkaline phosphatase (greater than 550 U per L), bilirubin (greater than 2.5 x ULN), serum glucose (less than 40 or greater than 250 mg per dL), glycosuria (greater than or equal to 3+), neutrophils (less than 750 per mm³ ), fasting cholesterol (greater than 240 mg per dL), and fasting triglycerides (greater than 750 mg per dL).

Serum Lipids

In the clinical trials of STRIBILD, a similar percentage of subjects receiving STRIBILD, ATRIPLA, and atazanavir + ritonavir + TRUVADA were on lipid lowering agents at baseline (11%, 11%, and 12%, respectively). While receiving study drug through Week 48, an additional 4% of STRIBILD subjects were started on lipid lowering agents, compared to 5% of ATRIPLA and 7% of atazanavir + ritonavir + TRUVADA subjects. During the first 48 weeks of study drug exposure, 1% or fewer subjects in any treatment arm experienced Grades 3 or 4 elevations in fasting cholesterol (greater than 300 mg per dL) or fasting triglycerides (greater than 750 mg per dL).

Changes from baseline in total cholesterol, HDL-cholesterol, LDL-cholesterol, and triglycerides are presented in Table 4.

Table 4: Lipid Values, Mean Change from Baseline, Reported in Subjects Receiving STRIBILD or Comparator in Studies 102 and 103

Postmarketing Experience

Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following adverse reactions have been identified during post approval use of tenofovir DF. No additional postmarketing adverse reactions specific for emtricitabine have been identified.

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

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

Renal and Urinary Disorders

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

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.

Read the entire FDA prescribing information for Stribild (Elvitegravir, Cobicistat, Emtricitabine, Tenofovir DF) »