"Aug. 11, 2011 -- The FDA has approved Gilead's Complera, the second complete HIV treatment in a single, once-daily pill.
Complera is a combination of Truvada (which combines the nucleoside reverse transcriptase inhibitors Emtriva and "...
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.
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
|AZT/3TC + EFV
|General Disorders and Administration Site Condition|
|Infections and Infestations|
|Upper respiratory tract infections||8%||5%|
|Nervous System Disorders|
|Skin and Subcutaneous Tissue Disorders|
|a Frequencies of adverse reactions are based
on all treatment-emergent adverse events, regardless of relationship to study
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
|FTC + TDF + EFVa
|AZT/3TC + EFV
|Any ≥ Grade 3 Laboratory Abnormality||30%||26%|
|Fasting Cholesterol ( > 240 mg/dL)||22%||24%|
(M: > 990 U/L)
(F: > 845 U/L)
|Serum Amylase ( > 175 U/L)||8%||4%|
|Alkaline Phosphatase ( > 550 U/L)||1%||0%|
(M: > 180 U/L)
(F: > 170 U/L)
(M: > 215 U/L)
(F: > 170 U/L)
|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|
|Infections and Infestations|
|Urinary tract infection||2%||2%||5%||7%|
|Musculoskeletal and Connective Tissue Disorders|
|Nervous System Disorders|
|Reproductive System and Breast Disorders|
|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|
|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%)|
||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].
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
Metabolism and Nutrition Disorders
Respiratory, Thoracic, and Mediastinal Disorders
pancreatitis, increased amylase, abdominal pain
Skin and Subcutaneous Tissue Disorders
Musculoskeletal and Connective Tissue Disorders
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
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 Truvada (emtricitabine and tenofovir disoproxil fumarate) Side Effects Center for a complete guide to possible side effects
No drug interaction trials have been conducted using TRUVADA tablets. Drug interaction trials have been conducted with emtricitabine and tenofovir disoproxil fumarate, the components of TRUVADA. This section describes clinically relevant drug interactions observed with emtricitabine and tenofovir disoproxil fumarate [See CLINICAL PHARMACOLOGY].
Coadministration of TRUVADA and didanosine should be undertaken with caution and patients receiving this combination should be monitored closely for didanosineassociated adverse reactions. Didanosine should be discontinued in patients who develop didanosine-associated adverse reactions.
When tenofovir disoproxil fumarate was administered with didanosine the Cmax and AUC of didanosine increased significantly [See CLINICAL PHARMACOLOGY]. The mechanism of this interaction is unknown. Higher didanosine concentrations could potentiate didanosine-associated adverse reactions, including pancreatitis, and neuropathy. Suppression of CD4+ cell counts has been observed in patients receiving tenofovir DF with didanosine 400 mg daily.
In patients weighing greater than 60 kg, the didanosine dose should be reduced to 250 mg when it is coadministered with TRUVADA. Data are not available to recommend a dose adjustment of didanosine for adult or pediatric patients weighing less than 60 kg. When coadministered, TRUVADA and Videx EC may be taken under fasted conditions or with a light meal (less than 400 kcal, 20% fat).
HIV-1 Protease Inhibitors
Tenofovir decreases the AUC and Cmin of atazanavir [See CLINICAL PHARMACOLOGY]. When coadministered with TRUVADA, it is recommended that atazanavir 300 mg is given with ritonavir 100 mg. TRUVADA should not be coadministered with atazanavir without ritonavir.
Lopinavir/ritonavir, atazanavir coadministered with ritonavir, and darunavir coadministered with ritonavir have been shown to increase tenofovir concentrations [See CLINICAL PHARMACOLOGY]. Tenofovir disoproxil fumarate is a substrate of Pglycoprotein (Pgp) and breast cancer resistance protein (BCRP) transporters. When tenofovir disoproxil fumarate is co-administered with an inhibitor of these transporters, an increase in absorption may be observed. Patients receiving TRUVADA concomitantly with lopinavir/ritonavir, ritonavir-boosted atazanavir, or ritonavir-boosted darunavir should be monitored for tenofovir-associated adverse reactions. TRUVADA should be discontinued in patients who develop tenofovir-associated adverse reactions.
Drugs Affecting Renal Function
Emtricitabine and tenofovir are primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion [See CLINICAL PHARMACOLOGY]. No drug-drug interactions due to competition for renal excretion have been observed; however, coadministration of TRUVADA with drugs that are eliminated by active tubular secretion may increase concentrations of emtricitabine, tenofovir, and/or the coadministered drug. Some examples include, but are not limited to acyclovir, adefovir dipivoxil, cidofovir, ganciclovir, valacyclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs [See WARNINGS AND PRECAUTIONS]. Drugs that decrease renal function may increase concentrations of emtricitabine and/or tenofovir.
Read the Truvada Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 12/30/2013
This monograph has been modified to include the generic and brand name in many instances.
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