美国FDA批准第一个为减低获得性HIV感染药物Truvada(emtricitabine/tenofovir disoproxil fumarate)新组方。 循证方法加强存在预防战略 2012年7月16日，美国食品药品监督管理局(FDA)批准Truvada(恩曲他滨[emtricitabine]/富马酸替诺福韦酯[tenofovir disoproxil fumarate])，第一个药物被批准对在处在HIV感染高危未感染个体中是和可能与感染艾滋病毒伴侣有性行为的个体减低HIV感染风险。Truvada，在高危成年中每天服用，被为暴露前预防(pre-exposure prophylaxis，缩写PrEP)使用与较安全性行为联用以减低性-获得HIV感染的风险。 FDA既往批准Truvada与其它抗病毒药物联用为治疗HIV-感染成年和儿童12岁或以上使用。 作为PrEP的一部分，处于高危HIV-未感染个体每天服用Truvada降低被暴露于病毒时他们成为感染HIV机会。一个PrEP适应证意味着Truvada被批准使用作为全面HIV预防战略的一部分包括其它预防方法，例如性安全行为规范[safe sex practices]，减少风险咨询，和常规 HIV检验。 FDA负责官员Margaret A. Hamburg, M.D.说“今天批准标志我们与HIV斗争的一个重要里程碑。”“美国每年约50,000成年和青少年被诊断患HIV感染，尽管可得到预防方法和教育战略，检验，和护理与有疾病的人生活。需要新治疗以及预防方法与在这个国家中HIV流行斗争。” 作为这个行动的一部分，FDA正在加强Truvada的黑框警告警告卫生保健专业人员和未感染个体Truvada 对PrEP必须只被用于个体，在处方用药前被确证为HIV-阴性和在使用期间至少每三个月。在有未知或阳性HIV状态个体禁忌药物为PrEP。 FDA强烈建议反对这种使用。 Truvada对PrEP正在与一个风险评估和减灾战略(Risk Evaluation and Mitigation Strategy,缩写REMS)被批准。以求对未感染个体获得HIV感染风险最小和减低发生耐HIV-1变种的风险。The central component of this 这个REMS的核心组成是训练和教育计划帮助开处方者在服用或考虑Truvada为PrEP咨询个体。这个训练和教育计划将不限于Truvada的分配但将提供信息坚持推荐给药方案的重要性和了解当服用Truvada为PrEP适应证时成为HIV感染的严重风险。 FDA的药物评价和研究中心主任Janet Woodcock, M.D. 说：“对Truvada 对PrEP适应证的REMS的目标是教育卫生保健专业人员和未感染个体帮助确保安全使用这个适应证，不增加卫生保健专业人员对和患者不必要的负担”。 在两项大型，随机化，双盲，安慰剂对照临床试验证实Truvada对PrEP的安全性和疗效。这个iPrEx试验在2,499例HIV-阴性男性或变性[transgender]妇女中评价Truvada，这些个体与有高危HIV感染证据，例如与阳性或未知HIV状态伴侣性交时不持续或不用避孕套，高数目性伴侣，和交换日常性用品。结果显示此人群中与安慰剂比较Truvada有效减低HIV感染风险42%。在这个试验中疗效与坚持用药强烈相关。 在4,758例异性伴侣其中一个伴侣为被HIV-感染和另一个没有感染(血清不一致伴侣)进行伴侣PrEP试验。试验评价Truvada和泰诺福韦相比安慰剂在预防HIV感染在未感染男性或女性伴侣的疗效和安全性。结果显示与安慰剂比较 Truvada减低成为感染的风险达75 %。 在临床试验中评价Truvada对PrEP适应证未鉴定新副作用。用Truvada报道最常见副作用包括腹泻，恶心，腹痛，头痛，和体重减轻。严重不良事件一般，以及那些特别是与肾或骨毒性相关是不常见。 作为批准条件, Truvada的制造商，Gilead Sciences, Inc.，被要求从获得性HIV服用Truvada个体采集病毒分离株和评价这厢分离株对耐药性的存在。此外，公司被要求收集为PrEP服用Truvada时成为妊娠妇女的结局和进行一项试验评价监持服药及其与不良事件，和在血清转化风险的相关关系，和血清转化者中耐药性的发展。Gilead已承担义务提供国家药物利用数据为了更好描述利用Truvada为PrEP适应证个体的特征和发展坚持服药的问卷，将有助于开处方者确定低医从性个体的风险。 Gilead Sciences, Inc.是基于加州福斯特市。 TRUVADA(emtricitabine and tenofovir disoproxil fumarate)tabl HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use TRUVADA safely and effectively. See full prescribing information for TRUVADA. TRUVADA® (emtricitabine/tenofovir disoproxil fumarate) tablets Initial U.S. Approval: 2004 WARNINGS: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B See full prescribing information for complete boxed warning. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including VIREAD, a component of TRUVADA. (5.1) TRUVADA is not approved for the treatment of chronic hepatitis B virus (HBV) infection. Severe acute exacerbations of hepatitis B have been reported in patients coinfected with HIV-1 and HBV who have discontinued TRUVADA. Hepatic function should be monitored closely in these patients. If appropriate, initiation of anti-hepatitis B therapy may be warranted. (5.2) RECENT MAJOR CHANGES Indications and Usage (1) 7/2011 Dosage and Administration (2.1, 2.2) 7/2011 Warnings and Precautions  Decreases in Bone Mineral Density (5.5) 7/2011 INDICATIONS AND USAGE TRUVADA, a combination of EMTRIVA and VIREAD, both nucleoside analog HIV-1 reverse transcriptase inhibitors, is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients 12 years of age and older. (1) DOSAGE AND ADMINISTRATION Recommended dose in adults and pediatric patients (12 years of age and older and weighing greater than or equal to 35 kg): One tablet (containing 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate) once daily taken orally with or without food. (2.1) Dose recommended in renal impairment: Creatinine clearance 30–49 mL/min: 1 tablet every 48 hours. (2.2) CrCl below 30 mL/min or hemodialysis: Do not use TRUVADA. (2.2) DOSAGE FORMS AND STRENGTHS Tablets: 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate. (3) CONTRAINDICATIONS None. (4) WARNINGS AND PRECAUTIONS New onset or worsening renal impairment: Can include acute renal failure and Fanconi syndrome. Assess creatinine clearance (CrCl) before initiating treatment with TRUVADA. Monitor CrCl and serum phosphorus in patients at risk. Avoid administering Truvada with concurrent or recent use of nephrotoxic drugs. (5.3) Coadministration with Other Products: Do not use with drugs containing emtricitabine or tenofovir disoproxil fumarate including ATRIPLA, EMTRIVA, VIREAD; or with drugs containing lamivudine. Do not administer in combination with HEPSERA. (5.4) Decreases in bone mineral density (BMD): Consider assessment of BMD in patients with a history of pathologic fracture or other risk factors for osteoporosis or bone loss. (5.5) Redistribution/accumulation of body fat: Observed in patients receiving antiretroviral therapy. (5.6) Immune reconstitution syndrome: May necessitate further eva luation and treatment. (5.7) Triple nucleoside-only regimens: Early virologic failure has been reported in HIV-infected patients. Monitor carefully and consider treatment modification. (5.8) ADVERSE REACTIONS Most common adverse reactions (incidence greater than or equal to 10%) are diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash. (6) To report SUSPECTED ADVERSE REACTIONS, contact Gilead Sciences, Inc. at 1-800-GILEAD-5 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch DRUG INTERACTIONS 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) Atazanavir: Coadministration decreases atazanavir concentrations and increases tenofovir concentrations. Use atazanavir with TRUVADA only with ritonavir; monitor for evidence of tenofovir toxicity. (7.2) Lopinavir/ritonavir: Coadministration increases tenofovir concentrations. Monitor for evidence of tenofovir toxicity. (7.2) USE IN SPECIFIC POPULATIONS Pregnancy: pregnancy registry available: Enroll patients by calling 1-800-258-4263. Nursing mothers: Women infected with HIV should be instructed not to breast feed. (8.3) Pediatrics: Safety and efficacy not established in patients less than 12 years of age. (8.4) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling  Revised: 07/2011 FULL PRESCRIBING INFORMATION: CONTENTS* FULL PRESCRIBING INFORMATION WARNINGS: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including VIREAD, a component of TRUVADA, in combination with other antiretrovirals [See Warnings and Precautions (5.1)]. TRUVADA is not approved for the treatment of chronic hepatitis B virus (HBV) infection and the safety and efficacy of TRUVADA have not been established in patients coinfected with HBV and HIV-1. Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued TRUVADA. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue TRUVADA. If appropriate, initiation of anti-hepatitis B therapy may be warranted [See Warnings and Precautions (5.2)]. 1INDICATIONS AND USAGE TRUVADA®, a combination of EMTRIVA® and VIREAD®, is indicated in combination with other antiretroviral agents (such as non-nucleoside reverse transcriptase inhibitors or protease inhibitors) for the treatment of HIV-1 infection in adults and pediatric patients 12 years of age and older. 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®, EMTRIVA, 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 Clinical Pharmacology (12.4)]. 2 DOSAGE AND ADMINISTRATION 2.1Recommended Dose The dose of TRUVADA for adults and pediatric patients 12 years of age and older with body weight greater than or equal to 35 kg (greater than or equal to 77 lb) is one tablet (containing 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate) once daily taken orally with or without food. 2.2Dose Adjustment for Renal Impairment 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, the dosing interval of TRUVADA should be adjusted in patients with baseline creatinine clearance 30–49 mL/min using the recommendations in Table 1. 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 eva luated 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 patients with mild renal impairment (creatinine clearance 50–80 mL/min). Routine monitoring of calculated creatinine clearance and serum phosphorus should be performed in patients with mild renal impairment [See Warnings and Precautions (5.3)]. Table 1 Dosage Adjustment for Patients with Altered Creatinine Clearance Creatinine Clearance (mL/min)* ≥50 30–49 <30 (Including Patients Requiring Hemodialysis) * Calculated using ideal (lean) body weight Recommended Dosing Interval Every 24 hours Every 48 hours TRUVADA should not be administered. No data are available to make dose recommendations in pediatric patients 12 years of age and older with renal impairment. 3DOSAGE FORMS AND STRENGTHS TRUVADA is available as tablets. Each tablet contains 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate (which is equivalent to 245 mg of tenofovir disoproxil). The tablets are blue, capsule-shaped, film-coated, debossed with "GILEAD" on one side and with "701" on the other side. 4CONTRAINDICATIONS None. 5WARNINGS AND PRECAUTIONS 5.1Lactic Acidosis/Severe Hepatomegaly with Steatosis Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including VIREAD, a component of TRUVADA, in combination with other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering nucleoside analogs to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with TRUVADA should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations). 5.2Patients Coinfected with HIV-1 and HBV It is recommended that all patients with HIV-1 be tested for the presence of chronic hepatitis B virus (HBV) before initiating antiretroviral therapy. TRUVADA is not approved for the treatment of chronic HBV infection and the safety and efficacy of TRUVADA have not been established in patients coinfected with HBV and HIV-1. Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued TRUVADA. In some patients infected with HBV and treated with EMTRIVA, the exacerbations of hepatitis B were associated with liver decompensation and liver failure. Patients who are coinfected with HIV-1 and HBV should be closely monitored with both clinical and laboratory follow up for at least several months after stopping treatment with Truvada. If appropriate, initiation of anti-hepatitis B therapy may be warranted. 5.3New 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 VIREAD [See Adverse Reactions (6.2)]. It is recommended that creatinine clearance be calculated in all patients prior to initiating therapy and as clinically appropriate during therapy with TRUVADA. Routine monitoring of calculated creatinine clearance and serum phosphorus should be performed in patients at risk for renal impairment, including patients who have previously experienced renal events while receiving HEPSERA. Dosing interval adjustment of TRUVADA and close monitoring of renal function are recommended in all patients with creatinine clearance 30–49 mL/min, [See Dosage and Administration (2.2)]. No safety or efficacy data are available in patients with renal impairment who received TRUVADA using these dosing guidelines, so the potential benefit of TRUVADA therapy should be assessed against the potential risk of renal toxicity. TRUVADA should not be administered to patients with creatinine clearance below 30 mL/min or patients requiring hemodialysis. TRUVADA should be avoided with concurrent or recent use of a nephrotoxic agent. 5.4Coadministration with Other Products TRUVADA is a fixed-dose combination of emtricitabine and tenofovir disoproxil fumarate. TRUVADA should not be coadministered with ATRIPLA, EMTRIVA, or VIREAD. Due to similarities between emtricitabine and lamivudine, TRUVADA should not be coadministered with other drugs containing lamivudine, including Combivir (lamivudine/zidovudine), Epivir or Epivir-HBV (lamivudine), Epzicom (abacavir sulfate/lamivudine), or Trizivir (abacavir sulfate/lamivudine/zidovudine). TRUVADA should not be administered with HEPSERA® (adefovir dipivoxil). 5.5Decreases in Bone Mineral Density Assessment of bone mineral density (BMD) should be considered for HIV-1 infected adults and pediatric patients 12 years of age and older who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial for all patients. If bone abnormalities are suspected then appropriate consultation should be obtained. Tenofovir Disoproxil Fumarate: In a 144-week trial of treatment-naive adult subjects, decreases in BMD were seen at the lumbar spine and hip in both arms of the trial. At Week 144, there was a significantly greater mean percentage decrease from baseline in BMD at the lumbar spine in subjects receiving VIREAD + lamivudine + efavirenz compared with subjects receiving stavudine + lamivudine + efavirenz. Changes in BMD at the hip were similar between the two treatment groups. In both groups, the majority of the reduction in BMD occurred in the first 24–48 weeks of the trial and this reduction was sustained through 144 weeks. Twenty-eight percent of VIREAD-treated subjects vs. 21% of the comparator subjects lost at least 5% of BMD at the spine or 7% of BMD at the hip. Clinically relevant fractures (excluding fingers and toes) were reported in 4 subjects in the VIREAD group and 6 subjects in the comparator group. Tenofovir disoproxil fumarate was associated with significant increases in biochemical markers of bone metabolism (serum bone-specific alkaline phosphatase, serum osteocalcin, serum C-telopeptide, and urinary N-telopeptide), suggesting increased bone turnover. Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher in subjects receiving VIREAD. In a clinical trial of HIV-1 infected pediatric subjects 12 years of age and older (Study 321), bone effects were similar to adult subjects. Under normal circumstances BMD increases rapidly in this age group. In this trial, the mean rate of bone gain was less in the VIREAD-treated group compared to the placebo group. Six VIREAD treated subjects and one placebo treated subject had significant (greater than 4%) lumbar spine BMD loss in 48 weeks. Among 28 subjects receiving 96 weeks of VIREAD, Z-scores declined by -0.341 for lumbar spine and -0.458 for total body. Skeletal growth (height) appeared to be unaffected. Markers of bone turnover in VIREAD-treated pediatric subjects 12 years of age and older suggest increased bone turnover, consistent with the effects observed in adults. The effects of VIREAD-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk are unknown. For additional information, please consult the VIREAD prescribing information. Cases of osteomalacia (associated with proximal renal tubulopathy and which may contribute to fractures) have been reported in association with the use of VIREAD [See Adverse Reactions (6.2)]. 5.6Fat Redistribution Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established. 5.7Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including TRUVADA. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections [such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia (PCP), or tuberculosis], which may necessitate further eva luation and treatment. 5.8Early Virologic Failure Clinical trials in HIV-infected subjects have demonstrated that certain regimens that only contain three nucleoside reverse transcriptase inhibitors (NRTI) are generally less effective than triple drug regimens containing two NRTIs in combination with either a non-nucleoside reverse transcriptase inhibitor or a HIV-1 protease inhibitor. In particular, early virological failure and high rates of resistance substitutions have been reported. Triple nucleoside regimens should therefore be used with caution. Patients on a therapy utilizing a triple nucleoside-only regimen should be carefully monitored and considered for treatment modification. 6 ADVERSE REACTIONS 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)]. Decreases in Bone Mineral Density [See Warnings and Precautions (5.5)]. Immune Reconstitution Syndrome [See Warnings and Precautions (5.7)]. 6.1Adverse Reactions from 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. 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 (Grade 2–4) occurring in greater than or equal to 5% of subjects treated with efavirenz, emtricitabine, and tenofovir disoproxil fumarate 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-naive subjects received either VIREAD + EMTRIVA administered in combination with efavirenz (N=257) or zidovudine/lamivudine administered in combination with efavirenz (N=254). 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 Reactions* (Grades 2–4) Reported in ≥5% in Any Treatment Group in Study 934 (0–144 Weeks) FTC + TDF + EFV† AZT/3TC + EFV N=257 N=254   Frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug.   From Weeks 96 to 144 of the trial, subjects received TRUVADA with efavirenz in place of VIREAD + EMTRIVA with efavirenz.   Rash event includes rash, exfoliative rash, rash generalized, rash macular, rash maculo-papular, rash pruritic, and rash vesicular. 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‡ 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 3). Table 3 Significant Laboratory Abnormalities Reported in ≥1% of Subjects in Any Treatment Group in Study 934 (0–144 Weeks) FTC + TDF + EFV* AZT/3TC + EFV N=257 N=254 * From Weeks 96 to 144 of the trial, subjects received TRUVADA with efavirenz in place of VIREAD + EMTRIVA with efavirenz. Any ≥ Grade 3 Laboratory Abnormality 30% 26% Fasting Cholesterol (>240 mg/dL) 22% 24% Creatine Kinase (M: >990 U/L) (F: >845 U/L) 9% 7% Serum Amylase (>175 U/L) 8% 4% Alkaline Phosphatase (>550 U/L) 1% 0% AST (M: >180 U/L) (F: >170 U/L) 3% 3% ALT (M: >215 U/L) (F: >170 U/L) 2% 3% Hemoglobin (<8.0 mg/dL) 0% 4% Hyperglycemia (>250 mg/dL) 2% 1% Hematuria (>75 RBC/HPF) 3% 2% Glycosuria (≥3+) <1% 1% Neutrophils (<750/mm3) 3% 5% Fasting Triglycerides (>750 mg/dL) 4% 2% 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, Grade 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 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 (5.5)]. 6.2Postmarketing 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. 7DRUG INTERACTIONS 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)]. 7.1Didanosine 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 Cmax and AUC of didanosine administered as either the buffered or enteric-coated formulation 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). Coadministration of didanosine buffered tablet formulation with TRUVADA should be under fasted conditions. 7.2Atazanavir Atazanavir has been shown to increase tenofovir concentrations [See Clinical Pharmacology (12.3)]. The mechanism of this interaction is unknown. Patients receiving atazanavir and TRUVADA should be monitored for TRUVADA-associated adverse reactions. TRUVADA should be discontinued in patients who develop TRUVADA-associated adverse reactions. Tenofovir decreases the AUC and Cmin of atazanavir [See Clinical Pharmacology (12.3)]. When coadministered with TRUVADA, it is recommended that atazanavir 300 mg is given with ritonavir 100 mg. Atazanavir without ritonavir should not be coadministered with TRUVADA. 7.3Lopinavir/Ritonavir Lopinavir/ritonavir has been shown to increase tenofovir concentrations [See Clinical Pharmacology (12.3)]. The mechanism of this interaction is unknown. Patients receiving lopinavir/ritonavir and TRUVADA should be monitored for TRUVADA-associated adverse reactions. TRUVADA should be discontinued in patients who develop TRUVADA-associated adverse reactions. 7.4Drugs 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, and valganciclovir. Drugs that decrease renal function may increase concentrations of emtricitabine and/or tenofovir. 8USE IN SPECIFIC POPULATIONS 8.1Pregnancy Pregnancy Category B 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. There are, however, no adequate and well-controlled trials in pregnant women. Because animal reproduction studies are not always predictive of human response, TRUVADA should be used during pregnancy only if clearly needed. Antiretroviral Pregnancy Registry: To monitor fetal outcomes of pregnant women exposed to TRUVADA, an Antiretroviral Pregnancy Registry has been established. Healthcare providers are encouraged to register patients by calling 1-800-258-4263. 8.3Nursing Mothers Nursing Mothers: The Centers for Disease Control and Prevention recommend that HIV-1 infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV-1. Studies in rats have demonstrated that tenofovir is secreted in milk. It is not known whether tenofovir is excreted in human milk. It is not known whether emtricitabine is excreted in human milk. Because of both the potential for HIV-1 transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast-feed if they are receiving TRUVADA. 8.4Pediatric Use Truvada should only be administered to pediatric patients 12 years of age and older with body weight greater than or equal to 35 kg (greater than or equal to 77 lb) because it is a fixed-dose combination tablet containing a component, VIREAD, for which safety and efficacy have not been established in pediatric patients less than 12 years of age or weighing less than 35 kg (less than 77 lb) [See Warnings and Precautions (5.5), Adverse Reactions (6.1) and Clinical Pharmacology (12.3)]. 8.5Geriatric Use Clinical trials of EMTRIVA or VIREAD did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for the elderly patients should be cautious, keeping in mind the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. 8.6Patients with Impaired Renal Function It is recommended that the dosing interval for TRUVADA be modified in patients with creatinine clearance 30–49 mL/min. TRUVADA should not be used in patients with creatinine clearance below 30 mL/min and in patients with end-stage renal disease requiring dialysis [See Dosage and Administration (2.2)]. 10OVERDOSAGE 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 trials 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. 11DESCRIPTION TRUVADA tablets are fixed dose combination tablets containing emtricitabine and tenofovir disoproxil fumarate. EMTRIVA is the brand name for emtricitabine, a synthetic nucleoside analog of cytidine. Tenofovir disoproxil fumarate (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-(2R,5S)-[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 C8H10FN3O3S 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. 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 C19H30N5O10P • C4H4O4 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. Each film-coated tablet contains 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate, (which is equivalent to 245 mg of tenofovir disoproxil), as active ingredients. The tablets also include the following inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and pregelatinized starch (gluten free). The tablets are coated with Opadry II Blue Y-30-10701, which contains FD&C Blue #2 aluminum lake, hydroxypropyl methylcellulose 2910, lactose monohydrate, titanium dioxide, and triacetin. 12CLINICAL PHARMACOLOGY For additional information on Mechanism of Action, Antiviral Activity, Resistance and Cross Resistance, please consult the EMTRIVA and VIREAD prescribing information. 12.1Mechanism of Action TRUVADA is a fixed-dose combination of antiviral drugs emtricitabine and tenofovir disoproxil fumarate. [See Clinical Pharmacology (12.4)]. 12.3Pharmacokinetics TRUVADA: One TRUVADA tablet was bioequivalent to one EMTRIVA capsule (200 mg) plus one VIREAD tablet (300 mg) following single-dose administration to fasting healthy subjects (N=39). Emtricitabine: The pharmacokinetic properties of emtricitabine are summarized in Table 4. Following oral administration of EMTRIVA, emtricitabine is rapidly absorbed with peak plasma concentrations occurring at 1–2 hours post-dose. Less than 4% of emtricitabine binds to human plasma proteins in vitro and the binding is independent of concentration over the range of 0.02–200 µg/mL. Following administration of radiolabelled emtricitabine, approximately 86% is recovered in the urine and 13% is recovered as metabolites. The metabolites of emtricitabine include 3'-sulfoxide diastereomers and their glucuronic acid conjugate. Emtricitabine is eliminated by a combination of glomerular filtration and active tubular secretion. Following a single oral dose of EMTRIVA, the plasma emtricitabine half-life is approximately 10 hours. Tenofovir Disoproxil Fumarate: The pharmacokinetic properties of tenofovir disoproxil fumarate are summarized in Table 4. Following oral administration of VIREAD, maximum tenofovir serum concentrations are achieved in 1.0 ± 0.4 hour. Less than 0.7% of tenofovir binds to human plasma proteins in vitro and the binding is independent of concentration over the range of 0.01–25 µg/mL. Approximately 70–80% of the intravenous dose of tenofovir is recovered as unchanged drug in the urine. Tenofovir is eliminated by a combination of glomerular filtration and active tubular secretion. Following a single oral dose of VIREAD, the terminal elimination half-life of tenofovir is approximately 17 hours. Table 4 Single Dose Pharmacokinetic Parameters for Emtricitabine and Tenofovir in Adults* Emtricitabine Tenofovir   NC = Not calculated   Median (range)   Mean (± SD)   Data presented as steady state values. Fasted Oral Bioavailability† (%) 92 (83.1–106.4) 25 (NC–45.0) Plasma Terminal Elimination Half-Life† (hr) 10 (7.4–18.0) 17 (12.0–25.7) Cmax‡ (µg/mL) 1.8 ± 0.72§ 0.30 ± 0.09 AUC‡ (µg∙hr/mL) 10.0 ± 3.12§ 2.29 ± 0.69 CL/F‡ (mL/min) 302 ± 94 1043 ± 115 CLrenal‡ (mL/min) 213 ± 89 243 ± 33 Effects of Food on Oral Absorption TRUVADA may be administered with or without food. Administration of TRUVADA following a high fat meal (784 kcal; 49 grams of fat) or a light meal (373 kcal; 8 grams of fat) delayed the time of tenofovir Cmax by approximately 0.75 hour. The mean increases in tenofovir AUC and Cmax were approximately 35% and 15%, respectively, when administered with a high fat or light meal, compared to administration in the fasted state. In previous safety and efficacy trials, VIREAD (tenofovir) was taken under fed conditions. Emtricitabine systemic exposures (AUC and Cmax) were unaffected when TRUVADA was administered with either a high fat or a light meal. Special Populations Race Emtricitabine: No pharmacokinetic differences due to race have been identified following the administration of EMTRIVA. Tenofovir Disoproxil Fumarate: There were insufficient numbers from racial and ethnic groups other than Caucasian to adequately determine potential pharmacokinetic differences among these populations following the administration of VIREAD. Gender Emtricitabine and Tenofovir Disoproxil Fumarate: Emtricitabine and tenofovir pharmacokinetics are similar in male and female subjects. Pediatric Patients TRUVADA should not be administered to pediatric patients less than 12 years of age or weighing less than 35 kg (less than 77 lb). Emtricitabine: The pharmacokinetics of emtricitabine at steady state were determined in 27 HIV-1-infected pediatric subjects 13 to 17 years of age receiving a daily dose of 6 mg/kg up to a maximum dose of 240 mg oral solution or a 200 mg capsule; 26 of 27 subjects in this age group received the 200 mg EMTRIVA capsule. Mean (± SD) Cmax and AUC were 2.7 ± 0.9 μg/mL and 12.6 ± 5.4 μg•hr/mL, respectively. Exposures achieved in pediatric subjects 12 to less than 18 years of age were similar to those achieved in adults receiving a once daily dose of 200 mg. Tenofovir Disoproxil Fumarate: Steady-state pharmacokinetics of tenofovir were eva luated in 8 HIV-1 infected pediatric subjects (12 to less than 18 years). Mean (± SD) Cmax and AUCtau are 0.38 ± 0.13 μg/mL and 3.39 ± 1.22 μg•hr/mL, respectively. Tenofovir exposure achieved in these pediatric subjects receiving oral daily doses of VIREAD 300 mg was similar to exposures achieved in adults receiving once-daily doses of VIREAD 300 mg. Geriatric Patients Pharmacokinetics of emtricitabine and tenofovir have not been fully eva luated in the elderly (65 years of age and older). Patients with Impaired Renal Function The pharmacokinetics of emtricitabine and tenofovir are altered in subjects with renal impairment [See Warnings and Precautions (5.3)]. In adult subjects with creatinine clearance below 50 mL/min, Cmax, and AUC0–∞ of emtricitabine and tenofovir were increased. It is recommended that the dosing interval for TRUVADA be modified in patients with creatinine clearance 30–49 mL/min. TRUVADA should not be used in patients with creatinine clearance below 30 mL/min and in patients with end-stage renal disease requiring dialysis [See Dosage and Administration (2.2)]. Patients with Hepatic Impairment The pharmacokinetics of tenofovir following a 300 mg dose of VIREAD have been studied in non-HIV infected subjects with moderate to severe hepatic impairment. There were no substantial alterations in tenofovir pharmacokinetics in subjects with hepatic impairment compared with unimpaired subjects. The pharmacokinetics of TRUVADA or emtricitabine have not been studied in subjects with hepatic impairment; however, emtricitabine is not significantly metabolized by liver enzymes, so the impact of liver impairment should be limited. Assessment of Drug Interactions The steady state pharmacokinetics of emtricitabine and tenofovir were unaffected when emtricitabine and tenofovir disoproxil fumarate were administered together versus each agent dosed alone. In vitro studies and clinical pharmacokinetic drug-drug interaction trials have shown that the potential for CYP mediated interactions involving emtricitabine and tenofovir with other medicinal products is low. No clinically significant drug interactions have been observed between emtricitabine and famciclovir, indinavir, stavudine, tenofovir disoproxil fumarate, and zidovudine (see Tables 5 and 6). Similarly, no clinically significant drug interactions have been observed between tenofovir disoproxil fumarate and abacavir, efavirenz, emtricitabine, entecavir, indinavir, lamivudine, lopinavir/ritonavir, methadone, nelfinavir, oral contraceptives, ribavirin, saquinavir/ritonavir, and tacrolimus in trials conducted in healthy volunteers (see Tables 7 and 8). Table 5 Drug Interactions: Changes in Pharmacokinetic Parameters for Emtricitabine in the Presence of the Coadministered Drug* Coadministered Drug Dose of Coadministered Drug (mg) Emtricitabine Dose (mg) N % Change of Emtricitabine Pharmacokinetic Parameters† (90% CI) Cmax AUC Cmin * All interaction trials conducted in healthy volunteers. † ↑ = Increase; ↓ = Decrease; = No Effect; NA = Not Applicable Tenofovir DF 300 once daily × 7 days 200 once daily × 7 days 17 ↑ 20 (↑ 12 to ↑ 29) Zidovudine 300 twice daily × 7 days 200 once daily × 7 days 27 Indinavir 800 × 1 200 × 1 12 NA Famciclovir 500 × 1 200 × 1 12 NA Stavudine 40 × 1 200 × 1 6 NA Table 6 Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of Emtricitabine* Coadministered Drug Dose of Coadministered Drug (mg) Emtricitabine Dose (mg) N % Change of Coadministered Drug Pharmacokinetic Parameters† (90% CI) Cmax AUC Cmin   All interaction trials conducted in healthy volunteers.   ↑ = Increase; ↓ = Decrease; = No Effect; NA = Not Applicable Tenofovir DF 300 once daily × 7 days 200 once daily × 7 days 17 Zidovudine 300 twice daily × 7 days 200 once daily × 7 days 27 ↑ 17 (↑ 0 to ↑ 38) ↑ 13 (↑ 5 to ↑ 20) Indinavir 800 × 1 200 × 1 12 NA Famciclovir 500 × 1 200 × 1 12 NA Stavudine 40 × 1 200 × 1 6 NA Table 7 Drug Interactions: Changes in Pharmacokinetic Parameters for Tenofovir* in the Presence of the Coadministered Drug Coadministered Drug Dose of Coadministered Drug (mg) N % Change of Tenofovir Pharmacokinetic Parameters† (90% CI) Cmax AUC Cmin   Subjects received VIREAD 300 mg once daily.   Increase = ↑; Decrease = ↓; No Effect = ; NC = Not Calculated   Reyataz Prescribing Information Abacavir 300 once 8 NC Atazanavir‡ 400 once daily × 14 days 33 ↑ 14 (↑ 8 to ↑ 20) ↑ 24 (↑ 21 to ↑ 28) ↑ 22 (↑ 15 to ↑ 30) Didanosine (enteric-coated) 400 once 25 Didanosine (buffered) 250 or 400 once daily × 7 days 14 Efavirenz 600 once daily × 14 days 29 Emtricitabine 200 once daily × 7 days 17 Entecavir 1 mg once daily × 10 days 28 Indinavir 800 three times daily × 7 days 13 ↑ 14 (↓ 3 to ↑ 33) Lamivudine 150 twice daily × 7 days 15 Lopinavir/Ritonavir 400/100 twice daily × 14 days 24 ↑ 32 (↑ 25 to ↑ 38) ↑ 51 (↑ 37 to ↑ 66) Nelfinavir 1250 twice daily × 14 days 29 Saquinavir/Ritonavir 1000/100 twice daily × 14 days 35 ↑ 23 (↑ 16 to ↑ 30) Tacrolimus 0.05 mg/kg twice daily × 7 days 21 ↑ 13 (↑ 1 to ↑ 27) Table 8 Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of Tenofovir Coadministered Drug Dose of Coadministered Drug (mg) N % Change of Coadministered Drug Pharmacokinetic Parameters* (90% CI) Cmax AUC Cmin * Increase = ↑; Decrease = ↓; No Effect = ; NA = Not Applicable   Reyataz Prescribing Information   In HIV-infected subjects, addition of tenofovir DF to atazanavir 300 mg plus ritonavir 100 mg, resulted in AUC and Cmin values of atazanavir that were 2.3 and 4-fold higher than the respective values observed for atazanavir 400 mg when given alone.   R-(active), S- and total methadone exposures were equivalent when dosed alone or with VIREAD.   Individual subjects were maintained on their stable methadone dose. No pharmacodynamic alterations (opiate toxicity or withdrawal signs or symptoms) were reported.   Ethinyl estradiol and 17-deacetyl norgestimate (pharmacologically active metabolite) exposures were equivalent when dosed alone or with VIREAD.   Increases in AUC and Cmin are not expected to be clinically relevant; hence no dose adjustments are required when tenofovir DF and ritonavir-boosted saquinavir are coadministered. Abacavir 300 once 8 ↑ 12 (↓ 1 to ↑ 26) NA Atazanavir† 400 once daily × 14 days 34 ↓ 21 (↓ 27 to ↓ 14) ↓ 25 (↓ 30 to ↓ 19) ↓ 40 (↓ 48 to ↓ 32) Atazanavir† Atazanavir/Ritonavir 300/100 once daily × 42 days 10 ↓ 28 (↓ 50 to ↑ 5) ↓ 25‡ (↓ 42 to ↓ 3) ↓ 23‡ (↓ 46 to ↑ 10) Efavirenz 600 once daily × 14 days 30 Emtricitabine 200 once daily × 7 days 17 ↑ 20 (↑ 12 to ↑ 29) Indinavir 800 three times daily × 7 days 12 ↓ 11 (↓ 30 to ↑ 12) Entecavir 1 mg once daily × 10 days 28 ↑ 13 (↑ 11 to ↑ 15) Lamivudine 150 twice daily × 7 days 15 ↓ 24 (↓ 34 to ↓ 12) Lopinavir Lopinavir/Ritonavir 400/100 twice daily × 14 days 24 Ritonavir Methadone§ 40–110 once daily × 14 days¶ 13 Nelfinavir 1250 twice daily × 14 days 29 M8 metabolite Oral Contraceptives# Ethinyl Estradiol/ Norgestimate (Ortho-Tricyclen) Once daily × 7 days 20 Ribavirin 600 once 22 NA Saquinavir Saquinavir/Ritonavir 1000/100 twice daily × 14 days 32 ↑ 22 (↑ 6 to ↑41) ↑ 29Þ (↑ 12 to ↑ 48) ↑ 47Þ (↑ 23 to ↑ 76) Ritonavir ↑ 23 (↑ 3 to ↑ 46) Tacrolimus 0.05 mg/kg twice daily × 7 days 21 Following multiple dosing to HIV-negative subjects receiving either chronic methadone maintenance therapy or oral contraceptives, or single doses of ribavirin, steady state tenofovir pharmacokinetics were similar to those observed in previous trials, indicating lack of clinically significant drug interactions between these agents and VIREAD. Coadministration of tenofovir disoproxil fumarate with didanosine results in changes in the pharmacokinetics of didanosine that may be of clinical significance. Table 9 summarizes the effects of tenofovir disoproxil fumarate on the pharmacokinetics of didanosine. Concomitant dosing of tenofovir disoproxil fumarate with didanosine buffered tablets or enteric-coated capsules significantly increases the Cmax and AUC of didanosine. When didanosine 250 mg enteric-coated capsules were administered with tenofovir disoproxil fumarate, systemic exposures of didanosine were similar to those seen with the 400 mg enteric-coated capsules alone under fasted conditions. The mechanism of this interaction is unknown. See Drug Interactions (7.1) regarding use of didanosine with VIREAD. Table 9 Drug Interactions: Pharmacokinetic Parameters for Didanosine in the Presence of VIREAD Didanosine* Dose (mg)/Method of Administration* VIREAD Method of Administration* N % Difference (90% CI) vs. Didanosine 400 mg Alone, Fasted† Cmax AUC   Administration with food was with a light meal (~373 kcal, 20% fat).   Increase = ↑; Decrease = ↓; No Effect =   Includes 4 subjects weighing <60 kg receiving ddI 250 mg. Buffered tablets 400 once daily‡ × 7 days Fasted 1 hour after didanosine 14 ↑ 28 (↑ 11 to ↑ 48) ↑ 44 (↑ 31 to ↑ 59) Enteric coated capsules 400 once, fasted With food, 2 hours after didanosine 26 ↑ 48 (↑ 25 to ↑ 76) ↑ 48 (↑ 31 to ↑ 67) 400 once, with food Simultaneously with didanosine 26 ↑ 64 (↑ 41 to ↑ 89) ↑ 60 (↑ 44 to ↑ 79) 250 once, fasted With food, 2 hours after didanosine 28 ↓ 10 (↓ 22 to ↑ 3) 250 once, fasted Simultaneously with didanosine 28 ↑ 14 (0 to ↑ 31) 250 once, with food Simultaneously with didanosine 28 ↓ 29 (↓ 39 to ↓ 18) ↓ 11 (↓ 23 to ↑ 2) 12.4Microbiology Mechanism of Action Emtricitabine: Emtricitabine, a synthetic nucleoside analog of cytidine, is phosphorylated by cellular enzymes to form emtricitabine 5'-triphosphate. Emtricitabine 5'-triphosphate inhibits the activity of the HIV-1 reverse transcriptase (RT) by competing with the natural substrate deoxycytidine 5'-triphosphate and by being incorporated into nascent viral DNA which results in chain termination. Emtricitabine 5'-triphosphate is a weak inhibitor of mammalian DNA polymerase α, β, ε and mitochondrial DNA polymerase γ. Tenofovir Disoproxil Fumarate: Tenofovir disoproxil fumarate is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate. Tenofovir disoproxil fumarate requires initial diester hydrolysis for conversion to tenofovir and subsequent phosphorylations by cellular enzymes to form tenofovir diphosphate. Tenofovir diphosphate inhibits the activity of HIV-1 RT by competing with the natural substrate deoxyadenosine 5'-triphosphate and, after incorporation into DNA, by DNA chain termination. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases α, β, and mitochondrial DNA polymerase γ. Antiviral Activity Emtricitabine and Tenofovir Disoproxil Fumarate: In combination studies eva luating the cell culture antiviral activity of emtricitabine and tenofovir together, synergistic antiviral effects were observed. Emtricitabine: The antiviral activity of emtricitabine against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, the MAGI-CCR5 cell line, and peripheral blood mononuclear cells. The 50% effective concentration (EC50) values for emtricitabine were in the range of 0.0013–0.64 µM (0.0003–0.158 µg/mL). In drug combination studies of emtricitabine with nucleoside reverse transcriptase inhibitors (abacavir, lamivudine, stavudine, zalcitabine, zidovudine), non-nucleoside reverse transcriptase inhibitors (delavirdine, efavirenz, nevirapine), and protease inhibitors (amprenavir, nelfinavir, ritonavir, saquinavir), additive to synergistic effects were observed. Emtricitabine displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, and G (EC50 values ranged from 0.007–0.075 µM) and showed strain specific activity against HIV-2 (EC50 values ranged from 0.007–1.5 µM). Tenofovir Disoproxil Fumarate: The antiviral activity of tenofovir against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, primary monocyte/macrophage cells and peripheral blood lymphocytes. The EC50 values for tenofovir were in the range of 0.04–8.5 µM. In drug combination studies of tenofovir with nucleoside reverse transcriptase inhibitors (abacavir, didanosine, lamivudine, stavudine, zalcitabine, zidovudine), non-nucleoside reverse transcriptase inhibitors (delavirdine, efavirenz, nevirapine), and protease inhibitors (amprenavir, indinavir, nelfinavir, ritonavir, saquinavir), additive to synergistic effects were observed. Tenofovir displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, G and O (EC50 values ranged from 0.5–2.2 µM) and showed strain specific activity against HIV-2 (EC50 values ranged from 1.6 µM to 5.5 µM). Resistance Emtricitabine and Tenofovir Disoproxil Fumarate: HIV-1 isolates with reduced susceptibility to the combination of emtricitabine and tenofovir have been selected in cell culture. Genotypic analysis of these isolates identified the M184V/I and/or K65R amino acid substitutions in the viral RT. In a clinical trial of treatment-naive subjects [Study 934, see Clinical Studies (14.1)], resistance analysis was performed on HIV-1 isolates from all confirmed virologic failure subjects with greater than 400 copies/mL of HIV-1 RNA at Week 144 or early discontinuation. Development of efavirenz resistance-associated substitutions occurred most frequently and was similar between the treatment arms. The M184V amino acid substitution, associated with resistance to EMTRIVA and lamivudine, was observed in 2/19 analyzed subjects isolates in the EMTRIVA + VIREAD group and in 10/29 analyzed subjects isolates in the zidovudine/lamivudine group. Through 144 weeks of Study 934, no subjects have developed a detectable K65R substitution in their HIV-1 as analyzed through standard genotypic analysis. Emtricitabine: Emtricitabine-resistant isolates of HIV-1 have been selected in cell culture and in vivo. Genotypic analysis of these isolates showed that the reduced susceptibility to emtricitabine was associated with a substitution in the HIV-1 RT gene at codon 184 which resulted in an amino acid substitution of methionine by valine or isoleucine (M184V/I). Tenofovir Disoproxil Fumarate: HIV-1 isolates with reduced susceptibility to tenofovir have been selected in cell culture. These viruses expressed a K65R substitution in RT and showed a 2–4 fold reduction in susceptibility to tenofovir. In treatment-naive subjects, isolates from 8/47 (17%) analyzed subjects developed the K65R substitution in the VIREAD arm through 144 weeks; 7 occurred in the first 48 weeks of treatment and 1 at Week 96. In treatment-experienced subjects, 14/304 (5%) isolates from subjects failing VIREAD through Week 96 showed greater than 1.4 fold (median 2.7) reduced susceptibility to tenofovir. Genotypic analysis of the resistant isolates showed a substitution in the HIV-1 RT gene resulting in the K65R amino acid substitution. Cross Resistance Emtricitabine and Tenofovir Disoproxil Fumarate: Cross-resistance among certain nucleoside reverse transcriptase inhibitors (NRTIs) has been recognized. The M184V/I and/or K65R substitutions selected in cell culture by the combination of emtricitabine and tenofovir are also observed in some HIV-1 isolates from subjects failing treatment with tenofovir in combination with either lamivudine or emtricitabine, and either abacavir or didanosine. Therefore, cross-resistance among these drugs may occur in patients whose virus harbors either or both of these amino acid substitutions. Emtricitabine: Emtricitabine-resistant isolates (M184V/I) were cross-resistant to lamivudine and zalcitabine but retained susceptibility in cell culture to didanosine, stavudine, tenofovir, zidovudine, and NNRTIs (delavirdine, efavirenz, and nevirapine). HIV-1 isolates containing the K65R substitution, selected in vivo by abacavir, didanosine, tenofovir, and zalcitabine, demonstrated reduced susceptibility to inhibition by emtricitabine. Viruses harboring substitutions conferring reduced susceptibility to stavudine and zidovudine (M41L, D67N, K70R, L210W, T215Y/F, K219Q/E), or didanosine (L74V) remained sensitive to emtricitabine. HIV-1 containing the K103N substitution associated with resistance to NNRTIs was susceptible to emtricitabine. Tenofovir Disoproxil Fumarate: HIV-1 isolates from subjects (N=20) whose HIV-1 expressed a mean of 3 zidovudine-associated RT amino acid substitutions (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E/N) showed a 3.1-fold decrease in the susceptibility to tenofovir. Subjects whose virus expressed an L74V substitution without zidovudine resistance associated substitutions (N=8) had reduced response to VIREAD. Limited data are available for patients whose virus expressed a Y115F substitution (N=3), Q151M substitution (N=2), or T69 insertion (N=4), all of whom had a reduced response. 13NONCLINICAL TOXICOLOGY 13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Emtricitabine: In long-term oral carcinogenicity studies of emtricitabine, no drug-related increases in tumor incidence were found in mice at doses up to 750 mg/kg/day (26 times the human systemic exposure at the therapeutic dose of 200 mg/day) or in rats at doses up to 600 mg/kg/day (31 times the human systemic exposure at the therapeutic dose). Emtricitabine was not genotoxic in the reverse mutation bacterial test (Ames test), mouse lymphoma or mouse micronucleus assays. Emtricitabine did not affect fertility in male rats at approximately 140-fold or in male and female mice at approximately 60-fold higher exposures (AUC) than in humans given the recommended 200 mg daily dose. Fertility was normal in the offspring of mice exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately 60-fold higher than human exposures at the recommended 200 mg daily dose. Tenofovir Disoproxil Fumarate: Long-term oral carcinogenicity studies of tenofovir disoproxil fumarate in mice and rats were carried out at exposures up to approximately 16 times (mice) and 5 times (rats) those observed in humans at the therapeutic dose for HIV-1 infection. At the high dose in female mice, liver adenomas were increased at exposures 16 times that in humans. In rats, the study was negative for carcinogenic findings at exposures up to 5 times that observed in humans at the therapeutic dose. Tenofovir disoproxil fumarate was mutagenic in the in vitro mouse lymphoma assay and negative in an in vitro bacterial mutagenicity test (Ames test). In an in vivo mouse micronucleus assay, tenofovir disoproxil fumarate was negative when administered to male mice. There were no effects on fertility, mating performance or early embryonic development when tenofovir disoproxil fumarate was administered to male rats at a dose equivalent to 10 times the human dose based on body surface area comparisons for 28 days prior to mating and to female rats for 15 days prior to mating through day seven of gestation. There was, however, an alteration of the estrous cycle in female rats. 13.2Animal Toxicology and/or Pharmacology Tenofovir and tenofovir disoproxil fumarate administered in toxicology studies to rats, dogs and monkeys at exposures (based on AUCs) greater than or equal to 6-fold those observed in humans caused bone toxicity. In monkeys the bone toxicity was diagnosed as osteomalacia. Osteomalacia observed in monkeys appeared to be reversible upon dose reduction or discontinuation of tenofovir. In rats and dogs, the bone toxicity manifested as reduced bone mineral density. The mechanism(s) underlying bone toxicity is unknown. Evidence of renal toxicity was noted in 4 animal species. Increases in serum creatinine, BUN, glycosuria, proteinuria, phosphaturia, and/or calciuria and decreases in serum phosphate were observed to varying degrees in these animals. These toxicities were noted at exposures (based on AUCs) 2–20 times higher than those observed in humans. The relationship of the renal abnormalities, particularly the phosphaturia, to the bone toxicity is not known. 14CLINICAL STUDIES Clinical Study 934 supports the use of TRUVADA tablets for the treatment of HIV-1 infection. Additional data in support of the use of TRUVADA are derived from Study 903, in which lamivudine and tenofovir disoproxil fumarate (tenofovir DF) were used in combination in treatment-naive adults, and clinical Study 303 in which emtricitabine and lamivudine demonstrated comparable efficacy, safety and resistance patterns as part of multidrug regimens. For additional information about these trials, please consult the prescribing information for tenofovir DF and emtricitabine. 14.1Study 934 Data through 144 weeks are reported for Study 934, a randomized, open-label, active-controlled multicenter trial comparing emtricitabine + tenofovir DF administered in combination with efavirenz versus zidovudine/lamivudine fixed-dose combination administered in combination with efavirenz in 511 antiretroviral-naive subjects. From Weeks 96 to 144 of the trial, subjects received TRUVADA with efavirenz in place of emtricitabine + tenofovir DF with efavirenz. Subjects had a mean age of 38 years (range 18–80), 86% were male, 59% were Caucasian and 23% were Black. The mean baseline CD4+ cell count was 245 cells/mm3 (range 2–1191) and median baseline plasma HIV-1 RNA was 5.01 log10 copies/mL (range 3.56–6.54). Subjects were stratified by baseline CD4+ cell count (< or ≥200 cells/mm3); 41% had CD4+ cell counts <200 cells/mm3 and 51% of subjects had baseline viral loads >100,000 copies/mL. Treatment outcomes through 48 and 144 weeks for those subjects who did not have efavirenz resistance at baseline are presented in Table 10. Table 10 Outcomes of Randomized Treatment at Week 48 and 144 (Study 934) Outcomes At Week 48 At Week 144 FTC + TDF + EFV (N=244) AZT/3TC + EFV (N=243) FTC + TDF + EFV (N=227)* AZT/3TC + EFV (N=229)*   Subjects who were responders at Week 48 or Week 96 (HIV-1 RNA <400 copies/mL) but did not consent to continue trial after Week 48 or Week 96 were excluded from analysis.   Subjects achieved and maintained confirmed HIV-1 RNA <400 copies/mL through Weeks 48 and 144.   Includes confirmed viral rebound and failure to achieve confirmed <400 copies/mL through Weeks 48 and 144.   Includes lost to follow-up, subject withdrawal, noncompliance, protocol violation and other reasons. Responder† 84% 73% 71% 58% Virologic failure‡ 2% 4% 3% 6% Rebound 1% 3% 2% 5% Never suppressed 0% 0% 0% 0% Change in antiretroviral regimen 1% 1% 1% 1% Death <1% 1% 1% 1% Discontinued due to adverse event 4% 9% 5% 12% Discontinued for other reasons§ 10% 14% 20% 22% Through Week 48, 84% and 73% of subjects in the emtricitabine + tenofovir DF group and the zidovudine/lamivudine group, respectively, achieved and maintained HIV-1 RNA <400 copies/mL (71% and 58% through Week 144). The difference in the proportion of subjects who achieved and maintained HIV-1 RNA <400 copies/mL through 48 weeks largely results from the higher number of discontinuations due to adverse events and other reasons in the zidovudine/lamivudine group in this open-label trial. In addition, 80% and 70% of subjects in the emtricitabine + tenofovir DF group and the zidovudine/lamivudine group, respectively, achieved and maintained HIV-1 RNA <50 copies/mL through Week 48 (64% and 56% through Week 144). The mean increase from baseline in CD4+ cell count was 190 cells/mm3 in the emtricitabine + tenofovir DF group and 158 cells/mm3 in the zidovudine/lamivudine group at Week 48 (312 and 271 cells/mm3 at Week 144). Through 48 weeks, 7 subjects in the emtricitabine + tenofovir DF group and 5 subjects in the zidovudine/lamivudine group experienced a new CDC Class C event (10 and 6 subjects through 144 weeks). 16HOW SUPPLIED/STORAGE AND HANDLING The blue, capsule-shaped, film-coated, tablets contain 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate (which is equivalent to 245 mg of tenofovir disoproxil), are debossed with "GILEAD" on one side and with "701" on the other side, and are available in unit of use bottles (containing a dessicant [silica gel canister or sachet] and closed with a child-resistant closure) of: 30 tablets (NDC 61958-0701-1) Store at 25 °C (77 °F), excursions permitted to 15–30 °C (59–86 °F) (see USP Controlled Room Temperature).