Truvada Drug Information

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 3 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 antiretroviral-naïve 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-naïve subjects receiving VIREAD and/or EMTRIVA (Table 3). Table 3 Selected Treatment-Emergent Adverse Reactions Frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug. (Grades 2–4) Reported in ≥5% in Any Treatment Group in Study 934 (0–144 Weeks) FTC+TDF+EFV From Weeks 96 to 144 of the trial, subjects received TRUVADA with efavirenz in place of VIREAD + EMTRIVA with efavirenz. AZT/3TC+EFV N=257 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 event Rash event includes rash, exfoliative rash, rash generalized, rash macular, rash maculo-papular, rash pruritic, and rash vesicular. 7% 9% Laboratory Abnormalities: Laboratory abnormalities observed in this trial were generally consistent with those seen in other trials of VIREAD and/or EMTRIVA (Table 4). Table 4 Significant Laboratory Abnormalities Reported in ≥1% of Subjects in Any Treatment Group in Study 934 (0–144 Weeks) FTC+TDF+EFV From Weeks 96 to 144 of the trial, subjects received TRUVADA with efavirenz in place of VIREAD + EMTRIVA with efavirenz.

AZT/3TC+EFV N=257 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/mm 3 ) 3% 5% Fasting Triglycerides (>750 mg/dL) 4% 2% 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 × ULN), increased pancreatic amylase (>2.0 × ULN), increased or decreased serum glucose (<40 or >250 mg/dL), and increased serum lipase (>2.0 × 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 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, consult the EMTRIVA prescribing information.

Tenofovir Disoproxil Fumarate: In pediatric clinical trials (Studies 352 and 321) conducted in 184 HIV-1 infected subjects 2 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. Eighty-nine pediatric subjects (2 to less than 12 years of age) received VIREAD in Study 352 for a median exposure of 104 weeks. Of these, 4 subjects discontinued from the trial due to adverse reactions consistent with proximal renal tubulopathy.

Three of these 4 subjects presented with hypophosphatemia and also had decreases in total body or spine BMD Z score. For additional information, consult the VIREAD prescribing information.

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 2,830 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 men or transgender women of Hispanic/Latino (72%), White (18%), Black (9%) and Asian (5%) race. The Partners PrEP trial enrolled both men (61–64% across treatment groups) and women in Kenya and Uganda. Table 5 provides a list of all adverse events that occurred in 2% or more of subjects in any treatment group in the iPrEx and Partners PrEP trials.

Laboratory Abnormalities: Table 6 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 5 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% - Not reported or reported below 2%. - 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% - - Table 6 Laboratory Abnormalities (Highest Toxicity Grade) Reported for Each Subject in the iPrEx Trial and Partners PrEP Trial iPrEx Trial Partners PrEP Trial Grade Grading is per DAIDS criteria.

FTC/TDF (N= 1251) Placebo (N= 1248) FTC/TDF (N=1579) Placebo (N=1584) Creatinine 1 (1.1–1.3 × ULN) 27 (2%) 21 (2%) 18 (1%) 12 (<1%) 2–4 (> 1.4 × ULN) 5 (<1%) 3 (<1%) 2 (<1%) 1 (<1%) Phosphorus 1 (2.5 – 2.6 × ULN) 57 (5%) 61 (5%) 10 (<1%) 4 (<1%) ALT 1 (1.25–<2.5 × ULN) 178 (14%) 194 (16%) 21 (1%) 13 (<1%) 2–4 (> 2.6 × 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/mm 3 ) 23 (2%) 25 (2%) 208 (13%) 163 (10%) 2–4 (<750/mm 3 ) 7 (<1%) 7 (<1%) 73 (5%) 56 (3%) 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 versus 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 . The Partners PrEP trial found similar fracture rates between treatment and placebo groups (0.8% and 0.6%, respectively). No BMD evaluations were performed during this trial .

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.

Didanosine Coadministration of

TRUVADA and didanosine should be undertaken with caution and patients receiving this combination should be monitored closely for didanosine-associated adverse reactions. Didanosine should be discontinued in patients who develop didanosine-associated adverse reactions. When tenofovir disoproxil fumarate was administered with didanosine the C max and AUC of didanosine increased significantly . 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 C min of atazanavir . 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 . Tenofovir disoproxil fumarate is a substrate of P-glycoprotein (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 disoproxil fumarate-associated adverse reactions. TRUVADA should be discontinued in patients who develop tenofovir disoproxil fumarate-associated adverse reactions.

Hepatitis C Antiviral Agents Coadministration of tenofovir disoproxil fumarate and

HARVONI ® (ledipasvir/sofosbuvir) has been shown to increase tenofovir exposure . In patients receiving TRUVADA concomitantly with HARVONI without an HIV-1 protease inhibitor/ritonavir or an HIV-1 protease inhibitor/cobicistat combination, monitor for adverse reactions associated with tenofovir disoproxil fumarate. In patients receiving TRUVADA concomitantly with HARVONI and an HIV-1 protease inhibitor/ritonavir or an HIV-1 protease inhibitor/cobicistat combination, consider an alternative HCV or antiretroviral therapy, as the safety of increased tenofovir concentrations in this setting has not been established. If coadministration is necessary, monitor for adverse reactions associated with tenofovir disoproxil fumarate.

Drugs Affecting Renal Function Emtricitabine and tenofovir are primarily excreted by the

kidneys by a combination of glomerular filtration and active tubular secretion . 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 . Drugs that decrease renal function may increase concentrations of emtricitabine and/or tenofovir.

• Pregnancy Pregnancy Category B Antiretroviral Pregnancy Registry: To monitor fetal outcomes of pregnant women exposed to TRUVADA, an Antiretroviral Pregnancy Registry (APR) has been established. Healthcare providers are encouraged to register patients by calling 1-800-258-4263. Risk Summary TRUVADA has been evaluated in a limited number of women during pregnancy and postpartum. Available human and animal data suggest that TRUVADA does not increase the risk of major birth defects overall compared to the background rate. There are, however, no adequate and well-controlled trials in pregnant women. Because the studies in humans cannot rule out the possibility of harm, TRUVADA should be used during pregnancy only if clearly needed. If an uninfected individual becomes pregnant while taking TRUVADA for a PrEP indication, careful consideration should be given to whether use of TRUVADA should be continued, taking into account the potential increased risk of HIV-1 infection during pregnancy. Clinical Considerations As of July 2011, the APR has received prospective reports of 764 and 1,219 exposures to emtricitabine- and tenofovir-containing regimens, respectively in the first trimester, 321 and 455 exposures, respectively, in second trimester, and 140 and 257 exposures, respectively, in the third trimester. Birth defects occurred in 18 of 764 (2.4%) live births for emtricitabine-containing regimens and 27 of 1219 (2.2%) live births for tenofovir-containing regimens (first trimester exposure) and 10 of 461 (2.2%) live births for emtricitabine-containing regimens and 15 of 714 (2.1%) live births for tenofovir-containing regimens (second/third trimester exposure). Among pregnant women in the U.S. reference population, the background rate of birth defects is 2.7%. There was no association between emtricitabine or tenofovir and overall birth defects observed in the APR.
• Animal Data Emtricitabine: The incidence of fetal variations and malformations was not increased in embryofetal toxicity studies performed with emtricitabine in mice at exposures (AUC) approximately 60-fold higher and in rabbits at approximately 120-fold higher than human exposures at the recommended daily dose.
• Tenofovir Disoproxil Fumarate: Reproduction studies have been performed in rats and rabbits at doses up to 14 and 19 times the human dose based on body surface area comparisons and revealed no evidence of impaired fertility or harm to the fetus due to tenofovir.

Pediatric Use No pediatric clinical trial was conducted to evaluate the safety and efficacy of TRUVADA. Data from previously conducted trials with the individual drug products, EMTRIVA and VIREAD, were relied upon to support dosing recommendations for TRUVADA. For additional information, consult the prescribing information for EMTRIVA and VIREAD. TRUVADA should only be administered to HIV-1 infected pediatric patients with body weight greater than or equal to 17 kg and who are able to swallow a whole tablet. Because it is a fixed-dose combination tablet, TRUVADA cannot be adjusted for patients of lower weight . TRUVADA has not been evaluated for use in pediatric patients weighing less than 17 kg.

Do not use TRUVADA for pre-exposure prophylaxis in individuals with unknown or positive HIV-1 status. TRUVADA should be used in HIV-infected patients only in combination with other antiretroviral agents. Do not use TRUVADA for pre-exposure prophylaxis in individuals with unknown or positive HIV-1 status.

TRUVADA should be used in HIV-infected patients only in combination with other antiretroviral agents.

If overdose occurs, the patient must be monitored for evidence of toxicity, and standard supportive treatment applied as necessary. Emtricitabine: Limited clinical experience is available at doses higher than the therapeutic dose of EMTRIVA. In one clinical pharmacology trial, single doses of emtricitabine 1200 mg were administered to 11 subjects. No severe adverse reactions were reported.

Hemodialysis treatment removes approximately 30% of the emtricitabine dose over a 3-hour dialysis period starting within 1.5 hours of emtricitabine dosing (blood flow rate of 400 mL/min and a dialysate flow rate of 600 mL/min). It is not known whether emtricitabine can be removed by peritoneal dialysis. Tenofovir Disoproxil Fumarate: Limited clinical experience at doses higher than the therapeutic dose of VIREAD 300 mg is available. In one trial, 600 mg tenofovir disoproxil fumarate was administered to 8 subjects orally for 28 days, and no severe adverse reactions were reported.

The effects of higher doses are not known. Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%. Following a single 300 mg dose of VIREAD, a four-hour hemodialysis session removed approximately 10% of the administered tenofovir dose.