Emtricitabine and Tenofovir Disoproxil Fumarate

INDICATIONS AND USAGE 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.

DOSAGE & ADMINISTRATION • Testing: Prior to or when initiating emtricitabine and tenofovir disoproxil fumarate tablets test for hepatitis B virus infection. Prior to initiation and during use of emtricitabine and tenofovir disoproxil fumarate tablets, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all individuals. In individuals with chronic kidney disease, also assess serum phosphorus. ( 2.1 ) • HIV-1 Screening: Screen all individuals for HIV-1 infection immediately prior to initiating emtricitabine and tenofovir disoproxil fumarate tablets for HIV-1 PrEP and at least once every 3 months while taking Emtricitabine and tenofovir disoproxil fumarate tablets, and upon diagnosis of any other sexually transmitted infections (STIs). ( 2.2 ) Treatment of HIV-1 Infection • Recommended dosage in adults and pediatric patients weighing at least 35 kg: One Emtricitabine and Tenofovir Disoproxil Fumarate Tablets (containing 200 mg of FTC and 300 mg of TDF) once daily taken orally with or without food. ( 2.3 ) • Recommended dosage in pediatric patients weighing at least 17 kg: One emtricitabine and tenofovir disoproxil fumarate tablets 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. ( 2.4 ) • Recommended dosage in renally impaired HIV-1 infected adult patients: o Creatinine clearance (CrCl) 30 to 49 mL/min: 1 tablet every 48 hours. ( 2.6 ) o CrCl below 30 mL/min or hemodialysis: Emtricitabine and tenofovir disoproxil fumarate tablets is not recommended. ( 2.6 ) HIV-1 Pre-Exposure Prophylaxis (PrEP) • Recommended dosage in HIV-1 uninfected adults and adolescents weighing at least 35 kg: One emtricitabine and tenofovir disoproxil fumarate tablets (containing 200 mg of FTC and 300 mg of TDF) once daily taken orally with or without food. ( 2.5 ) • Recommended dosage in renally impaired HIV-uninfected individuals: Emtricitabine and tenofovir disoproxil fumarate tablets is not recommended in HIV-uninfected individuals if CrCl is below 60 mL/min. ( 2.6 ) 2.1 Testing Prior to Initiation of Emtricitabine and Tenofovir Disoproxil Fumarate Tablets for Treatment of HIV-1 Infection or for HIV-1 PrEP Prior to or when initiating emtricitabine and tenofovir disoproxil fumarate tablets, test individuals for hepatitis B virus infection [ see Warnings and Precautions ( 5.1 )]. Prior to initiation and during use of emtricitabine and tenofovir disoproxil fumarate tablets, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose and urine protein in all individuals. In individuals with chronic kidney disease, also assess serum phosphorus [ see Warnings and Precautions ( 5.3 ) ]. 2.2 HIV-1 Screening for Individuals Receiving Emtricitabine and Tenofovir Disoproxil Fumarate Tablets for HIV-1 PrEP Screen all individuals for HIV-1 infection immediately prior to initiating emtricitabine and tenofovir disoproxil fumarate tablets for HIV-1 PrEP and at least once every 3 months while taking emtricitabine and tenofovir disoproxil fumarate tablets, and upon diagnosis of any other sexually transmitted infections (STIs) [see Indications and Usage ( 1.2 ), Contraindications ( 4 ), and Warnings and Precautions ( 5.2 )]. If recent (<1 month) exposures to HIV-1 are suspected or clinical symptoms consistent with acute HIV-1 infection are present, use a test approved or cleared by the FDA as an aid in the diagnosis of acute or primary HIV-1 infection [see Warnings and Precautions ( 5.2 ), Use in Specific Populations ( 8.4 ), and Clinical Studies ( 14.3 and 14.4 )]. 2.3 Recommended Dosage for Treatment of HIV-1 Infection in Adults and Pediatric Patients Weighing at Least 35 kg Emtricitabine and tenofovir disoproxil fumarate tablets is a two-drug fixed dose combination product containing emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF). The recommended dosage of emtricitabine and tenofovir disoproxil fumarate tablets in adults and in pediatric patients weighing at least 35 kg is one tablet (containing 200 mg of FTC and 300 mg of TDF) once daily taken orally with or without food [see Clinical Pharmacology ( 12.3 )]. 2.4 Recommended Dosage for Treatment of HIV-1 Infection in Pediatric Patients Weighing at Least 17 kg and Able to Swallow a Tablet The recommended oral dosage of emtricitabine and tenofovir disoproxil fumarate tablets for pediatric patients weighing at least 17 kg and who can swallow a tablet is presented in Table 1. Tablets should be taken once daily with or without food. Weight should be monitored periodically and the emtricitabine and tenofovir disoproxil fumarate tablets dose adjusted accordingly. Table 1 Dosing for Treatment of HIV-1 Infection in Pediatric Patients Weighing 17 kg to less than 35 kg Body Weight (kg) Dosing of E mtricitabine and Tenofovir Disoproxil Fumarate Tablets (FTC/TDF) 17 to less than 22 one 100 mg /150 mg tablet once daily 22 to less than 28 one 133 mg /200 mg tablet once daily 28 to less than 35 one 167 mg /250 mg tablet once daily 2.5 Recommended Dosage for HIV-1 PrEP in Adults and Adolescents Weighing at Least 35 kg The dosage of emtricitabine and tenofovir disoproxil fumarate tablets for HIV-1 PrEP is one tablet (containing 200 mg of FTC and 300 mg of TDF) once daily taken orally with or without food in HIV-1 uninfected adults and adolescents weighing at least 35 kg [see Clinical Pharmacology ( 12.3 )]. 2.6 Dosage Adjustment in Individuals with Renal Impairment Treatment of HIV-1 Infection Table 2 provides dosage interval adjustment for patients with renal impairment. No dosage adjustment is necessary for HIV-1 infected patients with mild renal impairment (creatinine clearance 50–80 mL/min). The safety and effectiveness of the dosing interval adjustment recommendations in patients with moderate renal impairment (creatinine clearance 30–49 mL/min) have not been clinically evaluated; therefore, clinical response to treatment and renal function should be closely monitored in these patients [see Warnings and Precautions ( 5.3 )]. No data are available to make dosage recommendations in pediatric patients with renal impairment. Table 2 Dosage Interval Adjustment for HIV-1 Infected Adult Patients with Altered Creatinine Clearance Creatinine Clearance (mL/min) a Recommended Dosing Interval ≥50 30–49 <30 (Including Patients Requiring Hemodialysis) Every 24 hours Every 48 hours Emtricitabine and Tenofovir Disoproxil Fumarate Tablets should not be recommended. a.Calculated using ideal (lean) body weight HIV-1 PrEP Emtricitabine and tenofovir disoproxil fumarate tablets for HIV-1 PrEP is not recommended in HIV-1 uninfected individuals with estimated creatinine clearance below 60 mL/min [ see Warnings and Precautions ( 5.3 )]. If a decrease in estimated creatinine clearance is observed in uninfected individuals while using emtricitabine and tenofovir disoproxil fumarate tablets for HIV-1 PrEP, evaluate potential causes and re-assess potential risks and benefits of continued use [ see Warnings and Precautions ( 5.3 )].

WARNINGS AND PRECAUTIONS • Comprehensive management to reduce the risk of acquiring HIV-1 when emtricitabine and tenofovir disoproxil fumarate tablet is used for HIV-1 PrEP: Use as part of a comprehensive prevention strategy including other prevention measures; strictly adhere to dosing schedule. ( 5.2 ) • Management to reduce the risk of acquiring HIV-1 drug resistance when emtricitabine and tenofovir disoproxil fumarate tablet is used for HIV-1 PrEP: refer to full prescribing information for additional detail. ( 5.2 ) • New onset or worsening renal impairment: Can include acute renal failure and Fanconi syndrome. Avoid administering emtricitabine and tenofovir disoproxil fumarate with concurrent or recent use of nephrotoxic drugs. ( 5.3 ) • Immune reconstitution syndrome during treatment of HIV-1 infection: May necessitate further evaluation and treatment. ( 5.4 ) • Decreases in bone mineral density (BMD): Consider assessment of BMD in individuals with a history of pathologic fracture or other risk factors for osteoporosis or bone loss. ( 5.5 ) • Lactic acidosis/severe hepatomegaly with steatosis: Discontinue emtricitabine and tenofovir disoproxil fumarate tablets in individuals who develop symptoms or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity. ( 5.6 ) 5.1 Severe Acute Exacerbation of Hepatitis B in Individuals with HBV Infection All individuals should be tested for the presence of chronic hepatitis B virus (HBV) before or when initiating emtricitabine and tenofovir disoproxil fumarate [see Dosage and Administration ( 2.1 )] . Severe acute exacerbations of hepatitis B (e.g., liver decompensation and liver failure) have been reported in HBV-infected individuals who have discontinued emtricitabine and tenofovir disoproxil fumarate. Individuals infected with HBV who discontinue emtricitabine and tenofovir disoproxil fumarate should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. If appropriate, anti-hepatitis B therapy may be warranted, especially in individuals with advanced liver disease or cirrhosis, since posttreatment exacerbation of hepatitis may lead to hepatic decompensation and liver failure. HBV-uninfected individuals should be offered vaccination. 5.2 Comprehensive Management to Reduce the Risk of Sexually Transmitted Infections, Including HIV-1, and Development of HIV-1 Resistance When Emtricitabine and Tenofovir Disoproxil Fumarate Is Used for HIV-1 PrEP Use emtricitabine and tenofovir disoproxil fumarate for HIV-1 PrEP to reduce the risk of HIV-1 infection as part of a comprehensive prevention strategy that includes other prevention measures, including adherence to daily administration and safer sex practices, including condoms, to reduce the risk of sexually transmitted infections (STIs). The time from initiation of emtricitabine and tenofovir disoproxil fumarate for HIV-1 PrEP to maximal protection against HIV-1 infection is unknown. Risk for HIV-1 acquisition includes behavioral, biological, or epidemiologic factors including but not limited to condomless sex, past or current STIs, self-identified HIV risk, having sexual partners of unknown HIV-1 viremic status, or sexual activity in a high prevalence area or network. Counsel individuals on the use of other prevention measures (e.g., consistent and correct condom use, knowledge of partner(s)’ HIV-1 status, including viral suppression status, regular testing for STIs that can facilitate HIV-1 transmission). Inform uninfected individuals about and support their efforts in reducing sexual risk behavior. Use emtricitabine and tenofovir disoproxil fumarate to reduce the risk of acquiring HIV-1 only in individuals confirmed to be HIV-negative. HIV-1 resistance substitutions may emerge in individuals with undetected HIV-1 infection who are taking only emtricitabine and tenofovir disoproxil fumarate, because emtricitabine and tenofovir disoproxil fumarate alone does not constitute a complete regimen for HIV-1 treatment [see Microbiology ( 12.4 )] ; therefore, care should be taken to minimize the risk of initiating or continuing emtricitabine and tenofovir disoproxil fumarate before confirming the individual is HIV-1 negative. • Some HIV-1 tests only detect anti-HIV antibodies and may not identify HIV-1 during the acute stage of infection. Prior to initiating emtricitabine and tenofovir disoproxil fumarate for HIV-1 PrEP, ask seronegative individuals about recent (in past month) potential exposure events (e.g., condomless sex or condom breaking during sex with a partner of unknown HIV-1 status or unknown viremic status, or a recent STI), and evaluate for current or recent signs or symptoms consistent with acute HIV-1 infection (e.g., fever, fatigue, myalgia, skin rash). • If recent (<1 month) exposures to HIV-1 are suspected or clinical symptoms consistent with acute HIV-1 infection are present, use a test approved or cleared by the FDA as an aid in the diagnosis of acute or primary HIV-1 infection. While using emtricitabine and tenofovir disoproxil fumarate for HIV-1 PrEP, HIV-1 testing should be repeated at least every 3 months, and upon diagnosis of any other STIs. • If an HIV-1 test indicates possible HIV-1 infection, or if symptoms consistent with acute HIV-1 infection develop following a potential exposure event, convert the HIV-1 PrEP regimen to an HIV treatment regimen until negative infection status is confirmed using a test approved or cleared by the FDA as an aid in the diagnosis of acute or primary HIV-1 infection. Counsel HIV-1 uninfected individuals to strictly adhere to the once daily emtricitabine and tenofovir disoproxil fumarate dosing schedule. The effectiveness of emtricitabine and tenofovir disoproxil fumarate in reducing the risk of acquiring HIV-1 is strongly correlated with adherence, as demonstrated by measurable drug levels in clinical trials of emtricitabine and tenofovir disoproxil fumarate for HIV-1 PrEP. Some individuals, such as adolescents, may benefit from more frequent visits and counseling to support adherence [see Use in Specific Populations ( 8.4 ), Microbiology ( 12.4 ), and Clinical Studies ( 14.3 and 14.4 )]. 5.3 New Onset or Worsening Renal Impairment Emtricitabine and tenofovir are principally eliminated by the kidney. Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of TDF, a component of emtricitabine and tenofovir disoproxil fumarate tablets [see Adverse Reactions ( 6.2 )] . Prior to initiation and during use of emtricitabine and tenofovir disoproxil fumarate, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all individuals. In individuals with chronic kidney disease, also assess serum phosphorus. Emtricitabine and tenofovir disoproxil fumarate should be avoided with concurrent or recent use of a nephrotoxic agent (e.g., high-dose or multiple non-steroidal anti-inflammatory drugs [NSAIDs]) [see Drug Interactions ( 7.1 )] . Cases of acute renal failure after initiation of high-dose or multiple NSAIDs have been reported in HIV-infected patients with risk factors for renal dysfunction who appeared stable on TDF. Some patients required hospitalization and renal replacement therapy. Alternatives to NSAIDs should be considered, if needed, in patients at risk for renal dysfunction. Persistent or worsening bone pain, pain in extremities, fractures, and/or muscular pain or weakness may be manifestations of proximal renal tubulopathy and should prompt an evaluation of renal function in individuals at risk of renal dysfunction. Treatment of HIV-1 Infection Dosing interval adjustment of emtricitabine and tenofovir disoproxil fumarate and close monitoring of renal function are recommended in all patients with estimated creatinine clearance 30 to 49 mL/min [see Do

CONTRAINDICATIONS 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 )

DRUG INTERACTIONS • Tenofovir disoproxil fumarate increases didanosine concentrations. Dose reduction and close monitoring for didanosine toxicity are warranted. ( 7.2 ) • Coadministration decreases atazanavir concentrations. When coadministered with emtricitabine and tenofovir disoproxil fumarate tablets, use atazanavir given with ritonavir. ( 7.2 ) • Coadministration of emtricitabine and tenofovir disoproxil fumarate tablets with certain HIV-1 protease inhibitors or certain drugs to treat HCV increases tenofovir concentrations. Monitor for evidence of tenofovir toxicity. ( 7.2 ) • Consult Full Prescribing Information prior to and during treatment for important drug interactions. ( 7.2 ) 7.1 Drugs Affecting Renal Function FTC 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 emtricitabine and tenofovir disoproxil fumarate tablets with drugs that are eliminated by active tubular secretion may increase concentrations of FTC, 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 FTC and/or tenofovir. 7.2 Established and Significant Interactions Table 7 provides a listing of established or clinically significant drug interactions. The drug interactions described are based on studies conducted with either emtricitabine and tenofovir disoproxil fumarate tablets, the components of emtricitabine and tenofovir disoproxil fumarate tablets (FTC and TDF) as individual agents and/or in combination, or are predicted drug interactions that may occur with emtricitabine and tenofovir disoproxil fumarate tablets [see Clinical Pharmacology ( 12.3 )]. Table 7 Established and Significant a Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Trials Concomitant Drug Class: Drug Name Effect on Concentration Clinical Comment NRTI didanosine c ↑ didanosine Patients receiving emtricitabine and tenofovir disoproxil fumarate tablets and didanosine should be didanosinec monitored closely for didanosine-associated adverse reactions. Discontinue didanosine in patients who develop didanosine-associated adverse reactions. Higher didanosine concentrations could potentiate didanosine-associated adverse reactions, including pancreatitis, and neuropathy. Suppression of CD4+ cell counts has been observed in patients receiving TDF with didanosine 400 mg daily. In patients weighing greater than 60 kg, reduce the didanosine dose to 250 mg when it is coadministered with emtricitabine and tenofovir disoproxil fumarate tablets. Data are not available to recommend a dose adjustment of didanosine for adult or pediatric patients weighing less than 60 kg. When coadministered, emtricitabine and tenofovir disoproxil fumarate tablets and Videx EC may be taken under fasted conditions or with a light meal (less than 400 kcal, 20% fat). HIV-1 Protease Inhibitors: atazanavir c lopinavir/ritonavir c atazanavir/ritonavir c darunavir /ritonavir c ↓ atazanavir ↑ tenofovir When coadministered with emtricitabine and tenofovir disoproxil fumarate tablets, atazanavir 300 mg should be given with ritonavir 100 mg. Monitor patients receiving emtricitabine and tenofovir disoproxil fumarate tablets concomitantly with lopinavir/ritonavir, ritonavir-boosted atazanavir, or ritonavir boosted darunavir for TDF-associated adverse reactions Discontinue emtricitabine and tenofovir disoproxil fumarate tablets in patients who develop TDF-associated adverse reactions. Hepatitis C Antiviral Agents: sofosbuvir/velpatasvir c sofosbuvir/velpatasvir/ voxilaprevir c ledipasvir/sofosbuvir c ↑ tenofovir Monitor patients receiving emtricitabine and tenofovir disoproxil fumarate tablets concomitantly with EPCLUSA® (sofosbuvir/velpatasvir) or VOSEVI® (sofosbuvir/velpatasvir/voxilaprevir) for adverse reactions associated with TDF. Monitor patients receiving emtricitabine and tenofovir disoproxil fumarate tablets concomitantly with HARVONI® (ledipasvir/sofosbuvir) without an HIV-1 protease inhibitor/ritonavir or an HIV-1 protease inhibitor/cobicistat combination for adverse reactions associated with TDF. In patients receiving emtricitabine and tenofovir disoproxil fumarate tablets 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 TDF. a. This table is not all inclusive. b. ↑=Increase, ↓=Decrease c. Indicates that a drug-drug interaction trial was conducted.

ADVERSE REACTIONS The following adverse reactions are discussed in other sections of the labeling: • Severe Acute Exacerbations of Hepatitis B in Patients with HBV Infection [see Warnings and Precautions ( 5.1 )] . • New Onset or Worsening Renal Impairment [see Warnings and Precautions ( 5.3 )] . • Immune Reconstitution Syndrome [see Warnings and Precautions ( 5.4 )] . • Bone Loss and Mineralization Defects [see Warnings and Precautions ( 5.5 )]. • Lactic Acidosis/Severe Hepatomegaly with Steatosis [see Warnings and Precautions ( 5.6 )] . • 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 adults in PrEP trials, adverse reactions that were reported by more than 2% of emtricitabine and tenofovir disoproxil fumarate participants and more frequently than by placebo participants were headache, abdominal pain, and weight decreased. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Hetero Labs Limited at 1-866-495-1995 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 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. Adverse Reactions from Clinical Trials Experience in HIV-1 Infected Subjects Clinical Trials in Adult Subjects In Study 934, 511 antiretroviral-naïve subjects received efavirenz (EFV) administered in combination with either FTC+TDF (N=257) or zidovudine (AZT)/lamivudine (3TC) (N=254) for 144 weeks. The most common adverse reactions (incidence greater than or equal to 10%, all grades) included diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash. Table 3 provides the treatment-emergent adverse reactions (Grades 2 to 4) occurring in greater than or equal to 5% of subjects treated in any treatment group. Skin discoloration, manifested by hyperpigmentation, occurred in 3% of subjects taking FTC+TDF, and was generally mild and asymptomatic. The mechanism and clinical significance are unknown. Table 3 Selected Adverse Reactions a (Grades 2 to 4) Reported in ≥5% in Any Treatment Group in Study 934 (0 to 144 Weeks) FTC+TDF+EFV b AZT/3TC+EFV N=257 N=254 Fatigue Depression Nausea Diarrhea Dizziness Upper respiratory tract infections Sinusitis Rash event c Headache Insomnia Nasopharyngitis Vomiting 9% 9% 9% 9% 8% 8% 8% 7% 6% 5% 5% 2% 8% 7% 7% 5% 7% 5% 4% 9% 5% 7% 3% 5% 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 emtricitabine and tenofovir disoproxil fumarate with efavirenz in place of FTC+TDF 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 TDF and/or FTC (Table 4). Table 4 Significant Laboratory Abnormalities Reported in ≥1% of Subjects in Any Treatment Group in Study 934 (0 to 144 Weeks) FTC+TDF+EFV a 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% a. From Weeks 96 to 144 of the trial, subjects received emtricitabine and tenofovir disoproxil fumarate with efavirenz in place of FTC+TDF with efavirenz. 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 FTC in the larger of two open-label, uncontrolled pediatric trials (N=116). 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 TDF were consistent with those observed in clinical trials of TDF in adults. In Study 352 (2 to less than 12 years of age), 89 pediatric subjects received TDF 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 had decreases in total body or spine BMD Z-score [see Warnings and Precautions ( 5.5 )] . Total body BMD gain at Week 48 was less in the TDF group compared to the stavudine (d4T) or zidovudine (AZT) treatment groups. The mean rate of BMD gain in lumbar spine was similar between treatment groups. One TDF-treated subject and none of the d4T- or AZT-treated subjects experienced significant (greater than 4%) lumbar spine BMD loss at Week 48. Changes from baseline in BMD Z-scores were −0.012 for lumbar spine and −0.338 for total body in the 64 subjects who were treated with TDF for 96 weeks. In Study 321 (12 to less than 18 years of age), the mean rate of BMD gain at Week 48 was less in the TDF compared to the placebo treatment group. Six TDF-treated subjects and one placebo-treated subject had significant (greater than 4%) lumbar spine BMD loss at Week 48. Changes from baseline BMD Z-scores were −0.341 for lumbar spine and −0.458 for total body in the 28 subjects who were treated with TDF for 96 weeks. In both trials, skeletal growth (height) appeared to be unaffected. Adverse Reactions from Clinical Trial Experience in Uninfected Subjects Taking Emtricitabine and Tenofovir Disoproxil Fumarate for HIV-1 PrEP Clinical Trials in Adult Subjects The safety profile of emtricitabine and tenofovir disoproxil fumarate for HIV-1 PrEP was comparable to that observed in clinical trials of HIV-infected subjects based on two randomized placebo-controlled clinical trials (iPrEx, Partners PrEP) in which 2,830 HIV-1 uninfected adults received emtricitabine and tenofovir disoproxil fumarate once daily for HIV-1 PrEP. Subjects were followed for a median of 71 weeks and 87 weeks, respectively. Table 5 provides a list of selected adverse events that occurred in 2% or more of subjects in any treatment group in the iPrEx trial, with an incidence greater than placebo. Table 5 Selected Adverse Events (All Grades) Reported in ≥2% in Any Treatment Group in the iPrEx Trial and Greater than Placebo FTC/TDF Placebo (N=1251) (N=1248) Headache 7% 6% Abdominal pain 4% 2% Weight decreased 3% 2% In the Partners PrEP trial, the frequency of adverse events in the emtricitabine and tenofovir disoproxil fumarate treatment group was generally either less than or the same as in the placebo group. Laboratory Abnormalities: Table 6 provides a list of Grade 2 to 4 laboratory abnormalities observed in the iPrEx and Partners PrEP trials. Six subjects in the TDF-containing arms of the Partners PrEP trial discontinued from the trial due to an increase in serum creatinine compared with no discontinuations in the placebo group. One subject in the emtricitabine and tenofovir disoproxil fumarate arm of the iPrEx trial discontinued from the trial due to an increase in serum creatinine and another subject discontinued due to low serum phosphorus. Grades 2 to 3 proteinuria (2 to 4+) and/or glycosuria (3+) occurred in less than 1% of subjects treated with emtricitabine and tenofovir disoproxil f

Mechanism of Action Emtricitabine and tenofovir disoproxil fumarate tablets are a fixed-dose combination of antiviral drugs FTC and TDF [see Microbiology ( 12.4 ) ].