TRUVADA

TRUVADA tablets are fixed-dose combination tablets containing emtricitabine and tenofovir disoproxil fumarate. Emtricitabine is a synthetic nucleoside analog of cytidine. Tenofovir DF is converted in vivo to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5′-monophosphate. Both emtricitabine and tenofovir exhibit inhibitory activity against HIV-1 reverse transcriptase. Emtricitabine: The chemical name of emtricitabine is 5-fluoro-1-(2 R ,5 S )-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine. Emtricitabine is the (-) enantiomer of a thio analog of cytidine, which differs from other cytidine analogs in that it has a fluorine in the 5-position. It has a molecular formula of C 8 H 10 FN 3 O 3 S and a molecular weight of 247.24. It has the following structural formula: Emtricitabine is a white to off-white crystalline powder with a solubility of approximately 112 mg/mL in water at 25 °C. The partition coefficient (log p) for emtricitabine is -0.43 and the pKa is 2.65. Chemical Structure Tenofovir Disoproxil Fumarate: Tenofovir disoproxil fumarate is a fumaric acid salt of the bis-isopropoxycarbonyloxymethyl ester derivative of tenofovir. The chemical name of tenofovir disoproxil fumarate is 9-[( R )-2 [[bis[[(isopropoxycarbonyl)oxy]-methoxy]phosphinyl]methoxy]propyl]adenine fumarate (1:1). It has a molecular formula of C 19 H 30 N 5 O 10 P ∙ C 4 H 4 O 4 and a molecular weight of 635.52. It has the following structural formula: Tenofovir disoproxil fumarate is a white to off-white crystalline powder with a solubility of 13.4 mg/mL in water at 25 °C. The partition coefficient (log p) for tenofovir disoproxil is 1.25 and the pKa is 3.75. All dosages are expressed in terms of tenofovir disoproxil fumarate except where otherwise noted. TRUVADA tablets are for oral administration, and are available in the following strengths: Film-coated tablet containing 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate (which is equivalent to 245 mg of tenofovir disoproxil) as active ingredients Film-coated tablet containing 167 mg of emtricitabine and 250 mg of tenofovir disoproxil fumarate (which is equivalent to 204 mg of tenofovir disoproxil) as active ingredients Film-coated tablet containing 133 mg of emtricitabine and 200 mg of tenofovir disoproxil fumarate (which is equivalent to 163 mg of tenofovir disoproxil) as active ingredients Film-coated tablet containing 100 mg of emtricitabine and 150 mg of tenofovir disoproxil fumarate (which is equivalent to 123 mg of tenofovir disoproxil) as active ingredients All strength of TRUVADA tablets also include the following inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and pregelatinized starch (gluten free). The 200 mg/300 mg strength tablets are coated with Opadry II Blue Y-30-10701, which contains FD&C Blue #2 aluminum lake, hypromellose 2910, lactose monohydrate, titanium dioxide, and triacetin. The 167 mg/250 mg, 133 mg/200 mg, and 100 mg/150 mg strength tablets are coated with Opadry II Blue, which contains FD&C Blue #2 aluminum lake, hypromellose 2910, lactose monohydrate, titanium dioxide, and triacetin. Chemical Structure

TRUVADA is a combination of EMTRIVA and VIREAD, both nucleoside analog HIV-1 reverse transcriptase inhibitors. TRUVADA is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients weighing at least 17 kg. ( 1 ) TRUVADA is indicated in combination with safer sex practices for pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 in adults at high risk. ( 1 ) 1.1 Treatment of HIV-1 Infection TRUVADA ® , a combination of EMTRIVA ® and VIREAD ® , is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients weighing at least 17 kg [see Dosage and Administration (2) and Clinical Studies (14) ] . The following points should be considered when initiating therapy with TRUVADA for the treatment of HIV-1 infection:The following points should be considered when initiating therapy with TRUVADA for the treatment of HIV-1 infection: It is not recommended that TRUVADA be used as a component of a triple nucleoside regimen. TRUVADA should not be coadministered with ATRIPLA ® , COMPLERA ® , EMTRIVA, GENVOYA ® , ODEFSEY ® , STRIBILD ® , VIREAD or lamivudine-containing products [see Warnings and Precautions (5.4) ] . In treatment experienced patients, the use of TRUVADA should be guided by laboratory testing and treatment history [see Microbiology (12.4) ] . 1.2 Pre-Exposure Prophylaxis TRUVADA is indicated in combination with safer sex practices for pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 in adults at high risk. This indication is based on clinical trials in men who have sex with men (MSM) at high risk for HIV-1 infection and in heterosexual serodiscordant couples [see Clinical Studies (14.2 , 14.3) ] . When considering TRUVADA for pre-exposure prophylaxis the following factors may help to identify individuals at high risk: has partner(s) known to be HIV-1 infected, or engages in sexual activity within a high prevalence area or social network and one or more of the following: inconsistent or no condom use diagnosis of sexually transmitted infections exchange of sex for commodities (such as money, food, shelter, or drugs) use of illicit drugs or alcohol dependence incarceration partner(s) of unknown HIV-1 status with any of the factors listed above When prescribing TRUVADA for pre-exposure prophylaxis, healthcare providers must: prescribe TRUVADA as part of a comprehensive prevention strategy because TRUVADA is not always effective in preventing the acquisition of HIV-1 infection [see Warnings and Precautions (5.9) ] ; counsel all uninfected individuals to strictly adhere to the recommended TRUVADA dosing schedule because the effectiveness of TRUVADA in reducing the risk of acquiring HIV-1 was strongly correlated with adherence as demonstrated by measurable drug levels in clinical trials [see Warnings and Precautions (5.9) ] ; confirm a negative HIV-1 test immediately prior to initiating TRUVADA for a PrEP indication. If clinical symptoms consistent with acute viral infection are present and recent (<1 month) exposures are suspected, delay starting PrEP for at least one month and reconfirm HIV-1 status or use a test approved by the FDA as an aid in the diagnosis of HIV-1 infection, including acute or primary HIV-1 infection [see Warnings and Precautions (5.9) ] ; and screen for HIV-1 infection at least once every 3 months while taking TRUVADA for PrEP.

Treatment of HIV-1 Infection ( 2.1 ) Recommended dose in adults and pediatric patients weighing greater than or equal to 35 kg: One TRUVADA tablet (containing 200 mg/300 mg of emtricitabine and tenofovir disoproxil fumarate) once daily taken orally with or without food. ( 2.1 ) Recommended dose in pediatric patients weighing greater than or equal to 17 kg and able to swallow a whole tablet: one TRUVADA low strength tablet (100 mg/150 mg, 133 mg/200 mg, or 167 mg/250 mg based on body weight) once daily taken orally with or without food. ( 2.2 ) Recommended dose in renally impaired HIV-1 infected adult patients: Creatinine clearance 30–49 mL/min: 1 tablet every 48 hours. ( 2.4 ) CrCl below 30 mL/min or hemodialysis: Do not use TRUVADA. ( 2.4 ) Pre-exposure Prophylaxis ( 2.3 ) Recommended dose in HIV-1 uninfected adults: One tablet (containing 200 mg/300 mg of emtricitabine and tenofovir disoproxil fumarate) once daily taken orally with or without food. ( 2.3 ) Recommended dose in renally impaired HIV-uninfected individuals: Do not use TRUVADA in HIV-uninfected individuals if CrCl is below 60 mL/min. If a decrease in CrCl is observed in uninfected individuals while using TRUVADA for PrEP, evaluate potential causes and re-assess potential risks and benefits of continued use. ( 2.4 ) 2.1 Recommended Dose for Treatment of HIV-1 Infection in Adults and Pediatric Patients Weighing 35 Kg or More The recommended dose of TRUVADA in adults and in pediatric patients with body weight greater than or equal to 35 kg is one tablet (containing 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate) once daily taken orally with or without food. 2.2 Recommended Dose for Treatment of HIV-1 Infection in Pediatric Patients Weighing at Least 17 kg and Able to Swallow a Whole Tablet The recommended oral dose for pediatric patients weighing greater than or equal to 17 kg and who are able to swallow a whole tablet, is one TRUVADA low strength tablet (emtricitabine [FTC]/tenofovir disoproxil fumarate [TDF]) (167 mg/250 mg, 133 mg/200 mg, or 100 mg/150 mg based on body weight) taken orally once daily with or without food. The recommended oral dosage of TRUVADA low strength tablets is presented in Table 1. Weight should be monitored periodically and the TRUVADA dose adjusted accordingly. Table 1 Dosing for Pediatric Patients Weighing 17 kg to less than 35 kg using TRUVADA Low Strength Tablets Body Weight (kg) Dosing of FTC (mg)/TDF (mg) 17 to less than 22 one 100/150 tablet once daily 22 to less than 28 one 133/200 tablet once daily 28 to less than 35 one 167/250 tablet once daily 2.3 Recommended Dose for Pre-exposure Prophylaxis The dose of TRUVADA in HIV-1 uninfected adults is one tablet (containing 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate) once daily taken orally with or without food. 2.4 Dose Adjustment for Renal Impairment Treatment of HIV-1 Infection Significantly increased drug exposures occurred when EMTRIVA or VIREAD were administered to subjects with moderate to severe renal impairment [see EMTRIVA or VIREAD Package Insert] . Therefore, adjust the dosing interval of TRUVADA in HIV-1 infected adult patients with baseline creatinine clearance 30–49 mL/min using the recommendations in Table 2. These dosing interval recommendations are based on modeling of single-dose pharmacokinetic data in non-HIV infected subjects. The safety and effectiveness of these dosing interval adjustment recommendations have not been clinically evaluated in patients with moderate renal impairment, therefore clinical response to treatment and renal function should be closely monitored in these patients [see Warnings and Precautions (5.3) ] . No dose adjustment is necessary for HIV-1 infected patients with mild renal impairment (creatinine clearance 50–80 mL/min). No data are available to make dose recommendations in pediatric patients with renal impairment. Table 2 Dosage Adjustment for HIV-1 Infected Adult Patients with Altered Creatinine Clearance Creatinine Clearance (mL/min) Calculated using ideal (lean) body weight ≥50 30–49 <30 (Including Patients Requiring Hemodialysis) Recommended Dosing Interval Every 24 hours Every 48 hours TRUVADA should not be administered. Routine monitoring of estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein should be performed in all individuals with mild renal impairment [see Warnings and Precautions (5.3) ] . Pre-exposure Prophylaxis Do not use TRUVADA for a PrEP indication in HIV-1 uninfected individuals with estimated creatinine clearance below 60 mL/min [see Warnings and Precautions (5.3) ] . Routine monitoring of estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein should be performed in all individuals with mild renal impairment. If a decrease in estimated creatinine clearance is observed in uninfected individuals while using TRUVADA for PrEP, evaluate potential causes and re-assess potential risks and benefits of continued use [see Warnings and Precautions (5.3) ] .

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. ( 4 )

The following adverse reactions are discussed in other sections of the labeling: Lactic Acidosis/Severe Hepatomegaly with Steatosis [see Boxed Warning , Warnings and Precautions (5.1) ] . Severe Acute Exacerbations of hepatitis B [see Boxed Warning , Warnings and Precautions (5.2) ] . New Onset or Worsening Renal Impairment [see Warnings and Precautions (5.3) ] . Bone Effects of Tenofovir DF [see Warnings and Precautions (5.5) ] . Immune Reconstitution Syndrome [see Warnings and Precautions (5.7) ] . In HIV-1 infected patients, the most common adverse reactions (incidence greater than or equal to 10%) are diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash. ( 6.1 ) In HIV-1 uninfected individuals in PrEP trials, adverse reactions that were reported by more than 2% of TRUVADA subjects and more frequently than by placebo subjects were headache, abdominal pain and weight decreased. ( 6.2 ) To report SUSPECTED ADVERSE REACTIONS, contact Gilead Sciences, Inc. at 1-800-445-3235 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 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 [see Warnings and Precautions (5.5) ]. For additional information, consult the VIREAD prescribing information. 6.2 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 – <LLN mg/dL) 81 (7%) 110 (9%) NR Grade 1 phosphorus was not reported for the Partners PrEP trial. NR 2–4 (<2.0 mg/dL) 123 (10%) 101 (8%) 140 (9%) 136 (9%) AST 1 (1.25–<2.5 × ULN) 175 (14%) 175 (14%) 20 (1%) 25 (2%) 2–4 (> 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 [see Clinical Studies (14.2) ] . 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 [see Clinical Studies (14.3) ] . 6.3 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.

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 (12.3) ] . Didanosine: Tenofovir disoproxil fumarate increases didanosine concentrations. Use with caution and monitor for evidence of didanosine toxicity (e.g., pancreatitis, neuropathy) when coadministered. Consider dose reductions or discontinuations of didanosine if warranted. ( 7.1 ) HIV-1 protease inhibitors: Coadministration decreases atazanavir concentrations and increases tenofovir concentrations. When coadministered with TRUVADA, use atazanavir given with ritonavir. Coadministration of TRUVADA with atazanavir and ritonavir, darunavir and ritonavir, or lopinavir/ritonavir increases tenofovir concentrations. Monitor for evidence of tenofovir toxicity. ( 7.2 ) 7.1 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 [see Clinical Pharmacology (12.3) ] . 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). 7.2 HIV-1 Protease Inhibitors Tenofovir decreases the AUC and C min of atazanavir [see Clinical Pharmacology (12.3) ] . 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 (12.3) ] . 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 . 7.3 Hepatitis C Antiviral Agents Coadministration of tenofovir disoproxil fumarate and HARVONI ® (ledipasvir/sofosbuvir) has been shown to increase tenofovir exposure [see Clinical Pharmacology (12.3) ] . 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. 7.4 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 (12.3) ] . 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 (5.3) ] . Drugs that decrease renal function may increase concentrations of emtricitabine and/or tenofovir.

Store at 25 °C (77 °F), excursions permitted to 15 °C–30 °C (59 °F–86 °F) (see USP Controlled Room Temperature). Keep container tightly closed Dispense only in original container Do not use if seal over bottle opening is broken or missing