The following adverse 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].
- Bone Effects of Tenofovir DF [See WARNINGS AND PRECAUTIONS].
- Immune Reconstitution Syndrome [See WARNINGS AND PRECAUTIONS].
Adverse Reactions From Clinical Trials Experience In HIV-1 Infected Subjects
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.
Clinical Trials In Adult Subjects
The most common adverse reactions (incidence greater than or equal to 10%, any severity) occurring in Study 934, an active-controlled clinical trial of efavirenz, emtricitabine, and tenofovir disoproxil fumarate, include diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash. See also Table 2 for the frequency of treatment-emergent adverse reactions (Grades 2–4) occurring in greater than or equal to 5% of subjects treated in any treatment group in this trial.
Skin discoloration, manifested by hyperpigmentation on the palms and/or soles, was generally mild and asymptomatic. The mechanism and clinical significance are unknown.
Study 934 -Treatment Emergent Adverse Reactions: In Study 934, 511 antiretroviralnaive subjects received either VIREAD + EMTRIVA administered in combination with efavirenz (N=257) or zidovudine/lamivudine administered in combination with efavirenz (N=254) for 144 weeks. Subjects had a mean age of 40 years (range 20 to 73 years) and were predominantly male (88%). Overall, 65% were White, 17% were Black, and 13% were Hispanic. Adverse reactions observed in this trial were generally consistent with those seen in other trials in treatment-experienced or treatment-naive subjects receiving VIREAD and/or EMTRIVA (Table 2).
Table 2 : Selected Treatment-Emergent Adverse Reactionsa (Grades 2–4) Reported in ≥ 5% in Any Treatment Group in Study 934 (0–144 Weeks)
| FTC + TDF + EFVb N=257 |
AZT/3TC + EFV N=254 |
|
| Gastrointestinal Disorder | ||
| Diarrhea | 9% | 5% |
| Nausea | 9% | 7% |
| Vomiting | 2% | 5% |
| General Disorders and Administration Site Condition | ||
| Fatigue | 9% | 8% |
| Infections and Infestations | ||
| Sinusitis | 8% | 4% |
| Upper respiratory tract infections | 8% | 5% |
| Nasopharyngitis | 5% | 3% |
| Nervous System Disorders | ||
| Headache | 6% | 5% |
| Dizziness | 8% | 7% |
| Psychiatric Disorders | ||
| Depression | 9% | 7% |
| Insomnia | 5% | 7% |
| Skin and Subcutaneous Tissue Disorders | ||
| Rash eventc | 7% | 9% |
| a Frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug. b From Weeks 96 to 144 of the trial, subjects received TRUVADA with efavirenz in place of VIREAD + EMTRIVA with efavirenz. c Rash event includes rash, exfoliative rash, rash generalized, rash macular, rash maculo-papular, rash pruritic, and rash vesicular. |
||
Laboratory Abnormalities: Laboratory abnormalities observed in this trial were generally consistent with those seen in other trials of VIREAD and/or EMTRIVA (Table 3).
Table 3 : Significant Laboratory Abnormalities Reported in ≥ 1% of Subjects in Any Treatment Group in Study 934 (0–144 Weeks)
| FTC + TDF + EFVa N=257 |
AZT/3TC + EFV N=254 |
|
| Any ≥ Grade 3 Laboratory Abnormality | 30% | 26% |
| Fasting Cholesterol ( > 240 mg/dL) | 22% | 24% |
| Creatine Kinase (M: > 990 U/L) (F: > 845 U/L) |
9% | 7% |
| Serum Amylase ( > 175 U/L) | 8% | 4% |
| Alkaline Phosphatase ( > 550 U/L) | 1% | 0% |
| AST (M: > 180 U/L) (F: > 170 U/L) |
3% | 3% |
| ALT (M: > 215 U/L) (F: > 170 U/L) |
2% | 3% |
| Hemoglobin ( < 8.0 mg/dL) | 0% | 4% |
| Hyperglycemia ( > 250 mg/dL) | 2% | 1% |
| Hematuria ( > 75 RBC/HPF) | 3% | 2% |
| Glycosuria ( ≥ 3+) | < 1% | 1% |
| Neutrophils ( < 750/mm³) | 3% | 5% |
| Fasting Triglycerides ( > 750 mg/dL) | 4% | 2% |
| a From Weeks 96 to 144 of the trial, subjects received TRUVADA with efavirenz in place of VIREAD + EMTRIVA with efavirenz. | ||
In addition to the events described above for Study 934, other adverse reactions that occurred in at least 5% of subjects receiving EMTRIVA or VIREAD 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, and rhinitis.
In addition to the laboratory abnormalities described above for Study 934, Grades 3-4 laboratory abnormalities of increased bilirubin ( > 2.5 x ULN), increased pancreatic amylase ( > 2.0 x ULN), increased or decreased serum glucose ( < 40 or > 250 mg/dL), and increased serum lipase ( > 2.0 x ULN) occurred in up to 3% of subjects treated with EMTRIVA or VIREAD with other antiretroviral agents in clinical trials.
Clinical Trials in Pediatric Subjects 12 Years of Age and Older
Emtricitabine: In addition to the adverse reactions reported in adults, anemia and hyperpigmentation were observed in 7% and 32%, respectively, of pediatric subjects (3 months to less than 18 years of age) who received treatment with EMTRIVA in the larger of two open-label, uncontrolled pediatric trials (N=116). For additional information, please consult the EMTRIVA prescribing information.
Tenofovir Disoproxil Fumarate: In a pediatric clinical trial conducted in subjects 12 to less than 18 years of age, the adverse reactions observed in pediatric subjects who received treatment with VIREAD were consistent with those observed in clinical trials of VIREAD in adults [See WARNINGS AND PRECAUTIONS].
Adverse Reactions From Clinical Trial Experience In HIV-1 Uninfected Adult Subjects
No new adverse reactions to TRUVADA were identified from two randomized placebo-controlled clinical trials (iPrEx, Partners PrEP) in which 2830 HIV-1 uninfected adults received TRUVADA once daily for pre-exposure prophylaxis. Subjects were followed for a median of 71 weeks and 87 weeks, respectively. These trials enrolled HIV-negative individuals ranging in age from 18 to 67 years. The iPrEx trial enrolled only males or transgender females of Hispanic/Latino (72%), White (18%), Black (9%) and Asian (5%) race. The Partners PrEP trial enrolled both males (61-64% across treatment groups) and females in Kenya and Uganda. Table 4 provides a list of all adverse events that occurred ≥ 2% of subjects in any treatment group in the iPrEx and Partners PrEP trials.
Laboratory Abnormalities: Table 5 provides a list of laboratory abnormalities observed in both trials. Six subjects in the TDF-containing arms of the Partners PrEP trial discontinued participation in the study due to an increase in blood creatinine compared with no discontinuations in the placebo group. One subject in the TRUVADA arm of the iPrEx trial discontinued from the study due to an increase in blood creatinine and another due to low phosphorous.
In addition to the laboratory abnormalities described above, Grade 1 proteinuria (1+) occurred in 6% of subjects receiving TRUVADA in the iPrEx trial. Grades 2-3 proteinuria (2-4+) and glycosuria (3+) occurred in less than 1% of subjects treated with TRUVADA in the iPrEx trial and Partners PrEP trial.
Table 4 : Selected Adverse Events (All Grades) Reported in ≥ 2% in Any Treatment Group in the iPrEx Trial and Partners PrEP Trial
| iPrEx Trial | Partners PrEP Trial | |||
| FTC/TDF (N=1251) |
Placebo (N=1248) |
FTC/TDF (N=1579) |
Placebo (N=1584) |
|
| Gastrointestinal Disorders | ||||
| Diarrhea | 7% | 8% | 2% | 3% |
| Abdominal pain | 4% | 2% | -a | - |
| Infections and Infestations | ||||
| Pharyngitis | 13% | 16% | - | - |
| Urethritis | 5% | 7% | - | - |
| Urinary tract infection | 2% | 2% | 5% | 7% |
| Syphilis | 6% | 5% | - | - |
| Secondary syphilis | 6% | 4% | - | - |
| Anogenital warts | 2% | 3% | - | - |
| Musculoskeletal and Connective Tissue Disorders | ||||
| Back pain | 5% | 5% | - | - |
| Nervous System Disorders | ||||
| Headache | 7% | 6% | - | - |
| Psychiatric Disorders | ||||
| Depression | 6% | 7% | - | - |
| Anxiety | 3% | 3% | - | - |
| Reproductive System and Breast Disorders | ||||
| Genital ulceration | 2% | 2% | 2% | 2% |
| Investigations | ||||
| Weight decreased | 3% | 2% | - | - |
| aNot reported or reported below 2%. | ||||
Table 5 : Laboratory Abnormalities (Highest Toxicity Grade) Reported for Each Subject in the iPrEx Trial and Partners PrEP Trial
| Gradeb | iPrEx Trial | Partners PrEP Trial | |||
| FTC/TDF N= 1251 |
Placebo N= 1248 |
FTC/TDF N=1579 |
Placebo N=1584 |
||
| Creatinine | 1(1.1-1.3 X ULN) | 27 (2%) | 21 (2%) | 18 (1%) | 12 ( < 1%) |
| 2-4 ( > 1.4 x ULN) | 5 ( < 1%) | 3 ( < 1%) | 2 ( < 1%) | 1 ( < 1%) | |
| Phosphorus | 1(2.5 -
|
81 (7%) | 110 (9%) | NR a | NRa |
| 2-4( < 2.0 mg/dL) | 123 (10%) | 101 (8%) | 140 (9%) | 136 (9%) | |
| AST | 1(1.25- < 2.5 x ULN) | 175 (14%) | 175 (14%) | 20 (1%) | 25 (2%) |
| 2-4( > 2.6 x ULN) | 57 (5%) | 61 (5%) | 10 ( < 1%) | 4 ( < 1%) | |
| ALT | 1(1.25- < 2.5 x ULN) | 178 (14%) | 194 (16%) | 21 (1%) | 13 ( < 1%) |
| 2-4( > 2.6 x ULN) | 84 (7%) | 82 (7%) | 4 ( < 1%) | 6 ( < 1%) | |
| Hemoglobin | 1(8.5 -10 mg/dL) | 49 (4%) | 62 (5%) | 56 (4%) | 39 (2%) |
| 2-4( < 9.4 mg/dL) | 13 (1%) | 19 (2%) | 28 (2%) | 39 (2%) | |
| Neutrophils | 1(1000-1300/mm³) | 23 (2%) | 25 (2%) | 208 (13%) | 163 (10%) |
| 2-4( < 750/mm³) | 7 ( < 1%) | 7 ( < 1%) | 73 (5%) | 56 (3%) | |
| a Grade 1 phosphorus was not reported for the Partners PrEP trial. b Grading is per DAIDS criteria. |
|||||
Changes in Bone Mineral Density
In clinical trials of HIV-1 uninfected individuals, decreases in BMD were observed. In the iPrEx trial, a substudy of 503 subjects found mean changes from baseline in BMD ranging from -0.4% to -1.0% across total hip, spine, femoral neck, and trochanter in the TRUVADA group compared with the placebo group, which returned toward baseline after discontinuation of treatment. Thirteen percent of subjects receiving TRUVADA vs. 6% of subjects receiving placebo lost at least 5% of BMD at the spine during treatment. Bone fractures were reported in 1.7% of the TRUVADA group compared with 1.4% in the placebo group. No correlation between BMD and fractures was noted [See Clinical Studies]. The Partners PrEP trial found similar fracture rates between treatment and placebo groups (0.8% and 0.6%, respectively). No BMD evaluations were conducted during this trial [See Clinical Studies].
Postmarketing Experience
The following adverse reactions have been identified during postapproval use of VIREAD. No additional adverse reactions have been identified during postapproval use of EMTRIVA. 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.
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.