DailyMed Label: Truvada Access

DailyMed Label: Truvada Access

2021

DailyMed Prescription

Truvada Access

EMTRICITABINE and TENOFOVIR DISOPROXIL FUMARATE

Gilead Sciences, Inc

NDC: 61958-0702

NDC: 61958-0702

TRUVADA tablets are fixed-dose combination tablets containing emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF). FTC is a synthetic nucleoside analog of cytidine. TDF is converted in vivo to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5′-monophosphate. Both FTC and tenofovir exhibit inhibitory activity against HIV-1 reverse transcriptase. Emtricitabine: The chemical name of FTC is 5-fluoro-1-(2 R ,5 S )-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine. FTC is the (-) enantiomer of a thio analog of cytidine, which differs from other cytidine analogs in that it has a fluorine in the 5-position. It has a molecular formula of C 8 H 10 FN 3 O 3 S and a molecular weight of 247.24. It has the following structural formula: FTC is a white to off-white crystalline powder with a solubility of approximately 112 mg/mL in water at 25 °C. The partition coefficient (log p) for emtricitabine is −0.43 and the pKa is 2.65. Chemical Structure Tenofovir Disoproxil Fumarate: TDF is a fumaric acid salt of the bis-isopropoxycarbonyloxymethyl ester derivative of tenofovir. The chemical name of tenofovir DF is 9-[( R )-2 [[bis[[(isopropoxycarbonyl)oxy]- methoxy]phosphinyl]methoxy]propyl]adenine fumarate (1:1). It has a molecular formula of C 19 H 30 N 5 O 10 P ∙ C 4 H 4 O 4 and a molecular weight of 635.52. It has the following structural formula: Tenofovir disoproxil fumarate is a white to off-white crystalline powder with a solubility of 13.4 mg/mL in water at 25 °C. The partition coefficient (log p) for tenofovir disoproxil is 1.25 and the pKa is 3.75. All dosages are expressed in terms of TDF except where otherwise noted. TRUVADA tablets are for oral administration. Each film-coated tablet contains 200 mg of emtricitabine and 300 mg of tenofovir DF, (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 Light Blue Y-30-10671-A, which contains FD&C Blue #2 aluminum lake, hydroxypropyl methylcellulose 2910, lactose monohydrate, titanium dioxide, and triacetin. Chemical Structure

HIV-1 Treatment ( 1.1 ) TRUVADA is a two-drug combination of emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF), both HIV-1 nucleoside analog reverse transcriptase inhibitors, and 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. HIV-1 PrEP ( 1.2 ) TRUVADA is indicated in at-risk adults and adolescents weighing at least 35 kg for pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 infection. Individuals must have a negative HIV-1 test immediately prior to intitiating TRUVADA for HIV-1 PrEP. TRUVADA 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 [see Clinical Studies (14) ] . TRUVADA is indicated in at-risk adults and adolescents weighing at least 35 kg for pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 infection. Individuals must have a negative HIV-1 test immediately prior to initiating TRUVADA for HIV-1 PrEP [see Dosage and Administration (2.2) , Warnings and Precautions (5.2) ] .

Testing: Prior to or when initiating TRUVADA test for hepatitis B virus infection. Prior to initiation and during use of TRUVADA, 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 TRUVADA for HIV-1 PrEP and at least once every 3 months while taking TRUVADA, and upon diagnosis of any other sexually transmitted infections (STIs). ( 2.2 ) Treatment of HIV-1 Infection Recommended dosage in adults and pediatric patients (12 years of age and older with a body weight greater than or equal to 35 kg): One TRUVADA tablet (containing 200 mg of FTC and 300 mg of TDF) once daily taken orally with or without food. ( 2.3 ) Recommended dosage in renally impaired HIV-1 infected adult patients: Creatinine clearance (CrCl) 30−49 mL/min: 1 tablet every 48 hours. ( 2.5 ) CrCl below 30 mL/min or hemodialysis: TRUVADA is not recommended. ( 2.5 ) HIV-1 Pre-Exposure Prophylaxis (PrEP) Recommended dosage in HIV-1 uninfected adults and adolescents weighing at least 35 kg: One TRUVADA tablet (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: TRUVADA is not recommended in HIV-uninfected individuals if CrCl is below 60 mL/min. ( 2.5 ) Prior to or when initiating TRUVADA, test individuals for hepatitis B virus infection [see Warnings and Precautions (5.1) ] . Prior to initiation and during use of TRUVADA, 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) ]. Screen all individuals for HIV-1 infection immediately prior to initiating TRUVADA for HIV-1 PrEP and at least once every 3 months while taking TRUVADA, 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) ]. TRUVADA is a two-drug fixed dose combination product containing emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF). The recommended dosage of TRUVADA in adults and in pediatric patients 12 years of age and older with a body weight greater than or equal to 35 kg (greater than or equal to 77 lb) 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) ] . The dosage of TRUVADA 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) ] . Treatment of HIV-1 Infection Table 1 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 1 Dosage Interval Adjustment for HIV-1 Infected Adult Patients with Altered Creatinine Clearance Creatinine Clearance (mL/min) Calculated using ideal (lean) body weight ≥50 30–49 <30 (Including Patients Requiring Hemodialysis) Recommended Dosing Interval Every 24 hours Every 48 hours TRUVADA is not recommended. HIV-1 PrEP TRUVADA 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 TRUVADA for HIV-1 PrEP, evaluate potential causes and re-assess potential risks and benefits of continued use [see Warnings and Precautions (5.3) ] .

TRUVADA is available as tablets. Each tablet contains 200 mg of emtricitabine and 300 mg of tenofovir DF (equivalent to 245 mg of tenofovir disoproxil). The tablets are light blue, capsule-shaped, film-coated, debossed with "GILEAD" on one side. Tablets: 200 mg/300 mg emtricitabine and tenofovir disoproxil fumarate, respectively. ( 3 )

TRUVADA for HIV-1 PrEP is contraindicated in individuals with unknown or positive HIV-1 status [see Warnings and Precautions (5.2) ] . TRUVADA for HIV-1 PrEP is contraindicated in individuals with unknown or positive HIV-1 status. ( 4 )

Comprehensive management to reduce the risk of acquiring HIV-1 when TRUVADA 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 TRUVADA 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 TRUVADA 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 TRUVADA in individuals who develop symptoms or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity. ( 5.6 ) All individuals should be tested for the presence of chronic hepatitis B virus (HBV) before or when initiating TRUVADA [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 TRUVADA. Individuals infected with HBV who discontinue TRUVADA 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. Use TRUVADA 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 TRUVADA for HIV-1 PrEP to maximal protection against HIV-1 infection is unknown. Risk for HIV-1acquisition includes behavioral, biological, or epidemiologic factors including but not limited to condomless sex, part 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 TRUVADA 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 TRUVADA, because TRUVADA 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 TRUVADA before confirming the individual is HIV-1 negative. Some HIV-1 testsonly detect anti-HIV antibodies and may not identify HIV-1 during the acute stage of infection. Prior to initiating TRUVADA 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 TRUVADA 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 TRUVADA dosing schedule. The effectiveness of TRUVADA in reducing the risk of acquiring HIV-1 is strongly correlated with adherence, as demonstrated by measurable drug levels in clinical trials of TRUVADA 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) ] . 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 TRUVADA [see Adverse Reactions (6.2) ] . Prior to initiation and during use of TRUVADA, 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. TRUVADA 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 TRUVADA and close monitoring of renal function are recommended in all patients with estimated creatinine clearance 30–49 mL/min [see Dosage and Administration (2.5) ] . 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 is not recommended in patients with estimated creatinine clearance below 30 mL/min or patients requiring hemodialysis. HIV-1 PrEP TRUVADA for HIV-1 PrEP is not recommended in uninfected individuals with estimated creatinine clearance less than 60 mL/min. If a decrease in estimated creatinine clearance is observed while using TRUVADA for HIV-1 PrEP, evaluate potential causes and re-assess potential risks and benefits of continued use [see Dosage and Administration (2.5) ] . Immune reconstitution syndrome has been reported in HIV-1 infected patients treated with combination antiretroviral therapy, including TRUVADA. During the initial phase of combination antiretroviral treatment, HIV-1 infected 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 evaluation and treatment. Autoimmune disorders (such as Graves' disease, polymyositis, Guillain-Barré syndrome, and autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable and can occur many months after initiation of treatment. Bone Mineral Density In clinical trials in HIV-1 infected adults and in a clinical trial of HIV-1 uninfected individuals, TDF (a component of TRUVADA) was associated with slightly greater decreases in bone mineral density (BMD) and increases in biochemical markers of bone metabolism, suggesting increased bone turnover relative to comparators [see Adverse Reactions (6.1) ] . Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher in subjects receiving TDF. Clinical trials evaluating TDF in pediatric and adolescent subjects were conducted. Under normal circumstances, BMD increases rapidly in pediatric patients. In HIV-1 infected subjects aged 2 years to less than 18 years, bone effects were similar to those observed in adult subjects and suggest increased bone turnover. Total body BMD gain was less in the TDF-treated HIV-1 infected pediatric subjects as compared to the control groups. Similar trends were observed in adolescent subjects aged 12 years to less than 18 years treated for chronic hepatitis B. In all pediatric trials, skeletal growth (height) appeared to be unaffected. The effects of TDF-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk are unknown. Assessment of BMD should be considered for adult and pediatric patients 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. If bone abnormalities are suspected, appropriate consultation should be obtained. Mineralization Defects Cases of osteomalacia associated with proximal renal tubulopathy, manifested as bone pain or pain in extremities and which may contribute to fractures, have been reported in association with TDF use [see Adverse Reactions (6.1) ] . Arthralgia and muscle pain or weakness have also been reported in cases of proximal renal tubulopathy. Hypophosphatemia and osteomalacia secondary to proximal renal tubulopathy should be considered in patients at risk of renal dysfunction who present with persistent or worsening bone or muscle symptoms while receiving TDF-containing products [see Warnings and Precautions (5.3) ]. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including FTC and TDF, components of TRUVADA, alone or in combination with other antiretrovirals. Treatment with TRUVADA should be suspended in any individual 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). The concomitant use of TRUVADA and other drugs may result in known or potentially significant drug interactions, some of which may lead to possible clinically significant adverse reactions from greater exposures of concomitant drugs [see Drug Interactions (7.2) ]. See Table 6 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during therapy with TRUVADA; review concomitant medications during therapy with TRUVADA; and monitor for adverse reactions associated with the concomitant drugs.

The following adverse reactions are discussed in other sections of the labeling:

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 TRUVADA, use atazanavir given with ritonavir. ( 7.2 ) Coadministration of TRUVADA 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 ) 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 TRUVADA 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. Table 6 provides a listing of established or clinically significant drug interactions. The drug interactions described are based on studies conducted with either TRUVADA, the components of TRUVADA (FTC and TDF) as individual agents and/or in combination, or are predicted drug interactions that may occur with TRUVADA [see Clinical Pharmacology (12.3) ]. Table 6 Established and Significant This table is not all inclusive. Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Trials Concomitant Drug Class: Drug Name Effect on Concentration ↑=Increase, ↓=Decrease Clinical Comment NRTI: didanosine Indicates that a drug-drug interaction trial was conducted. ↑ didanosine Patients receiving TRUVADA and didanosine should be 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 TRUVADA. Data are not available to recommend a dose adjustment of didanosine for adult or pediatric patients weighing less than 60 kg. When coadministered, TRUVADA and Videx EC may be taken under fasted conditions or with a light meal (less than 400 kcal, 20% fat). HIV-1 Protease Inhibitor s: atazanavir ↓ atazanavir When coadministered with TRUVADA, atazanavir 300 mg should be given with ritonavir 100 mg. lopinavir/ritonavir atazanavir/ritonavir darunavir/ritonavir ↑ tenofovir Monitor patients receiving TRUVADA concomitantly with lopinavir/ritonavir, ritonavir-boosted atazanavir, or ritonavir-boosted darunavir for TDF-associated adverse reactions. Discontinue TRUVADA in patients who develop TDF-associated adverse reactions. Hepatitis C Antiviral Agents: sofosbuvir/velpatasvir sofosbuvir/velpatasvir/voxilaprevir ↑ tenofovir Monitor patients receiving TRUVADA concomitantly with EPCLUSA ® (sofosbuvir/velpatasvir) or VOSEVI ® (sofosbuvir/velpatasvir/voxilaprevir) for adverse reactions associated with TDF. ledipasvir/sofosbuvir Monitor patients receiving TRUVADA 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 TRUVADA concomitantly with HARVONI and an HIV-1 protease inhibitor/ritonavir or an HIV-1 protease inhibitor/cobicistat combination, consider an alternative HCV or antiretroviral therapy, as the safety of increased tenofovir concentrations in this setting has not been established. If coadministration is necessary, monitor for adverse reactions associated with TDF.

Lactation: Mothers infected with HIV-1 or suspected of having acquired HIV-1 infection should be instructed not to breastfeed due to the potential for HIV transmission. ( 8.2 ) Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to TRUVADA during pregnancy. Healthcare providers are encouraged to register patients on the worldwide Antiretroviral Pregnancy Registry (APR) at http://www.apregistry.com/. Risk Summary Data on the use of TRUVADA during pregnancy from observational studies have shown no increased risk of major birth defects. Available data from the APR show no significant difference in the overall risk of major birth defects with first trimester exposure for emtricitabine (FTC) (2.3%) or tenofovir disoproxil fumarate (TDF) (2.1%) compared with the background rate for major birth defects of 2.7% in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) (see Data ) . The rate of miscarriage for individual drugs is not reported in the APR. In the U.S. general population, the estimated background risk of miscarriage in clinically recognized pregnancies is 15–20%. In animal reproduction studies, no adverse developmental effects were observed when the components of TRUVADA were administered separately at doses/exposures ≥60 (FTC), ≥14 (TDF) and 2.7 (tenofovir) times those of the recommended daily dose of TRUVADA ( see Data ). Clinical Considerations Disease-associated maternal and/or embryo/fetal risk HIV-1 PrEP: Published studies indicate an increased risk of HIV-1 infection during pregnancy and an increased risk of mother to child transmission during acute HIV-1 infection. In women at risk of acquiring HIV-1, consideration should be given to methods to prevent acquisition of HIV, including continuing or initiating TRUVADA for HIV-1 PrEP, during pregnancy. Data Human Data TRUVADA for HIV-1 PrEP: In an observational study based on prospective reports to the APR, 78 HIV-seronegative women exposed to TRUVADA during pregnancy delivered live-born infants with no major malformations. All but one were first trimester exposures, and the median duration of exposure was 10.5 weeks. There were no new safety findings in the women receiving TRUVADA for HIV-1 PrEP compared with HIV-1 infected women treated with other antiretroviral medications. Emtricitabine: Based on prospective reports to the APR of exposures to FTC-containing regimens during pregnancy resulting in live births (including over 3,300 exposed in the first trimester and over 1,300 exposed in the second/third trimester), the prevalence of major birth defects in live births was 2.6% (95% CI: 2.1% to 3.2%) and 2.3% (95% CI: 1.6% to 3.3%) following first and second/third trimester exposure, respectively, to FTC-containing regimens. Tenofovir Disoproxil Fumarate: Based on prospective reports to the APR of exposures to TDF-containing regimens during pregnancy resulting in live births (including over 4,000 exposed in the first trimester and over 1,700 exposed in the second/third trimester), the prevalence of major birth defects in live births was 2.4% (95% CI: 2.0% to 2.9%) and 2.4% (95% CI: 1.7% to 3.2%) following first and second/third trimester exposure, respectively, to TDF-containing regimens. Methodologic limitations of the APR include the use of MACDP as the external comparator group. The MACDP population is not disease-specific, evaluates women and infants from a limited geographic area, and does not include outcomes for births that occurred at <20 weeks gestation. Additionally, published observational studies on emtricitabine and tenofovir exposure in pregnancy have not shown an increased risk for major malformations. Animal Data Emtricitabine: FTC was administered orally to pregnant mice (at 0, 250, 500, or 1,000 mg/kg/day), and rabbits (at 0, 100, 300, or 1,000 mg/kg/day) through organogenesis (on gestation days 6 through 15, and 7 through 19, respectively). No significant toxicological effects were observed in embryo-fetal toxicity studies performed with FTC in mice at exposures (AUC) approximately 60 times higher and in rabbits at approximately 120 times higher than human exposures at the recommended daily dose. In a pre/postnatal development study in mice, FTC was administered orally at doses up to 1,000 mg/kg/day; no significant adverse effects directly related to drug were observed in the offspring exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately 60 times higher than human exposures at the recommended daily dose. Tenofovir Disoproxil Fumarate: TDF was administered orally to pregnant rats (at 0, 50, 150, or 450 mg/kg/day) and rabbits (at 0, 30, 100, or 300 mg/kg/day) through organogenesis (on gestation days 7 through 17, and 6 through 18, respectively). No significant toxicological effects were observed in embryo-fetal toxicity studies performed with TDF in rats at doses up to 14 times the human dose based on body surface area comparisons and in rabbits at doses up to 19 times the human dose based on body surface area comparisons. In a pre/postnatal development study in rats, TDF was administered orally through lactation at doses up to 600 mg/kg/day; no adverse effects were observed in the offspring at tenofovir exposures of approximately 2.7 times higher than human exposures at the recommended daily dose of TRUVADA. Risk Summary Based on published data, FTC and tenofovir have been shown to be present in human breast milk (see Data ). It is not known if the components of TRUVADA affect milk production or have effects on the breastfed child. Treatment of HIV-1 Infection: The Centers for Disease Control and Prevention recommend that HIV-1 infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV-1. Because of the potential for: (1) HIV transmission (in HIV-negative infants); (2) developing viral resistance (in HIV-positive infants); and (3) adverse reactions in a breastfed infant similar to those seen in adults, instruct mothers not to breastfeed if they are taking TRUVADA for the treatment of HIV-1. HIV-1 PrEP: In HIV-uninfected women, the developmental and health benefits of breastfeeding and the mother's clinical need for TRUVADA for HIV-1 PrEP should be considered along with any potential adverse effects on the breastfed child from TRUVADA and the risk of HIV-1 acquisition due to nonadherence and subsequent mother to child transmission. Women should not breastfeed if acute HIV-1 infection is suspected because of the risk of HIV-1 transmission to the infant. Data HIV-1 PrEP: In a study of 50 breastfeeding women who received TRUVADA for HIV-1 PrEP between 1 and 24 weeks postpartum (median 13 weeks), after 7 days of treatment, tenofovir was undetectable but FTC was detectable in the plasma of most infants. In these infants, the average FTC plasma concentration was less than 1% of the FTC C max observed in HIV-infected infants (up to 3 months of age) receiving the therapeutic dose of FTC (3 mg/kg/day). There were no serious adverse events. Two infants (4%) had an adverse event of mild diarrhea which resolved. Treatment of HIV-1 Infection No pediatric clinical trial was conducted to evaluate the safety and efficacy of TRUVADA in patients with HIV-1 infection. Data from previously conducted trials with the individual drug products, FTC and TDF, were relied upon to support dosage recommendations for TRUVADA. For additional information, consult the prescribing information for EMTRIVA and VIREAD. TRUVADA should only be administered to HIV-1 infected pediatric patients 12 years of age and older with body weight greater than or equal to 35 kg and who are able to swallow a tablet. Because it is a fixed-dose combination tablet, TRUVADA cannot be adjusted for patients of lower weight [see Warnings and Precautions (5.5) , Adverse Reactions (6.1) and Clinical Pharmacology (12.3) ] . TRUVADA (200 mg FTC and 300mg TDF) is not approved for use in pediatric patients less than 12 years old weighing less than 35 kg. HIV-1 PrEP The safety and effectiveness of TRUVADA for HIV-1 PrEP in at-risk adolescents weighing at least 35 kg is supported by data from adequate and well-controlled studies of TRUVADA for HIV-1 PrEP in adults with additional data from safety and pharmacokinetic studies in previously conducted trials with the individual drug products, FTC and TDF, in HIV-1 infected adults and pediatric subjects [see Dosage and Administration (2.5) , Adverse Reactions (6.1) , Clinical Pharmacology (12.3 and 12.4) , and Clinical Studies (14.3 and 14.4) ]. Safety, adherence, and resistance were evaluated in a single-arm, open-label clinical trial (ATN113) in which 67 HIV-1 uninfected at-risk adolescent men who have sex with men received TRUVADA once daily for HIV-1 PrEP. The mean age of subjects was 17 years (range 15 to 18 years); 46% were Hispanic, 52% Black, and 37% White. The safety profile of TRUVADA in ATN113 was similar to that observed in the adult HIV-1 PrEP trials [see Adverse Reactions (6.1) ] . In the ATN113 trial, HIV-1 seroconversion occurred in 3 subjects. Tenofovir diphosphate levels in dried blood spot assays indicate that these subjects had poor adherence. No tenofovir- or FTC-associated HIV-1 resistance substitutions were detected in virus isolated from the 3 subjects who seroconverted [see Microbiology (12.4) ]. Adherence to study drug, as demonstrated by tenofovir diphosphate levels in dried blood spot assays, declined markedly after Week 12 once subjects switched from monthly to quarterly visits, suggesting that adolescents may benefit from more frequent visits and counseling [see Warnings and Precautions (5.2) ] . Safety and effectiveness of Truvada for HIV-1 PrEP in pediatric patients weighing less than 35 kg have not been established. Clinical trials of FTC, TDF, or TRUVADA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Treatment of HIV-1 Infection The dosing interval for TRUVADA should be modified in HIV-infected adult individuals with estimated creatinine clearance of 30–49 mL/min. TRUVADA is not recommended in individuals with estimated creatinine clearance below 30 mL/min and in individuals with end-stage renal disease requiring dialysis [see Dosage and Administration (2.5) ] . HIV-1 PrEP TRUVADA for HIV-1 PrEP is not recommended in HIV-1 uninfected individuals with estimated creatinine clearance below 60 mL/min. If a decrease in estimated creatinine clearance is observed in uninfected individuals while using TRUVADA for HIV-1 PrEP, evaluate potential causes and re-assess potential risks and benefits of continued use [see Dosage and Administration (2.5) ] .

TRUVADA tablets are available in bottles containing 30 tablets with child-resistant closure. Each tablet contains 200 mg of emtricitabine and 300 mg of tenofovir DF (equivalent to 245 mg of tenofovir disoproxil). The tablets are light blue, capsule-shaped, film-coated, debossed with "GILEAD" on one side, and are available in unit of use bottles of 30 tablets. Store below 30°C (86°F) Keep container tightly closed Dispense only in original container

TRUVADA is a fixed-dose combination of antiviral drugs FTC and TDF [see Microbiology (12.4) ]. TRUVADA: One TRUVADA tablet was comparable to one FTC capsule (200 mg) plus one TDF tablet (300 mg) following single-dose administration to fasting healthy subjects (N=39). Emtricitabine: The pharmacokinetic properties of FTC are summarized in Table 7. Following oral administration of FTC, FTC is rapidly absorbed with peak plasma concentrations occurring at 1–2 hours postdose. Less than 4% of FTC 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 FTC, approximately 86% is recovered in the urine and 13% is recovered as metabolites. The metabolites of FTC 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 FTC, the plasma FTC half-life is approximately 10 hours. Tenofovir Disoproxil Fumarate: The pharmacokinetic properties of TDF are summarized in Table 7. Following oral administration of TDF, 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 TDF, the terminal elimination half-life of tenofovir is approximately 17 hours. Table 7 Single Dose Pharmacokinetic Parameters for FTC and Tenofovir in Adults NC=Not calculated FTC Tenofovir Fasted Oral Bioavailability Median (range) (%) 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) C max Mean (± SD) (μg/mL) 1.8±0.72 Data presented as steady state values 0.30±0.09 AUC (μg ∙ hr/mL) 10.0±3.12 2.29±0.69 CL/F (mL/min) 302±94 1043±115 CL renal (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 C max by approximately 0.75 hour. The mean increases in tenofovir AUC and C max 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, TDF (tenofovir) was taken under fed conditions. FTC systemic exposures (AUC and C max ) were unaffected when TRUVADA was administered with either a high fat or a light meal. Specific Populations Race Emtricitabine: No pharmacokinetic differences due to race have been identified following the administration of FTC. 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 TDF. Gender Emtricitabine and Tenofovir Disoproxil Fumarate: FTC and tenofovir pharmacokinetics are similar in male and female subjects. Pediatric Patients Treatment of HIV-1 Infection: The pharmacokinetic data for tenofovir and FTC following administration of TRUVADA in pediatric subjects 12 years of age and older with a body weight greater than or equal to 35 kg are not available. The dosage recommendations of TRUVADA in this population are based on the dosage recommendations of FTC and TDF in this population. Refer to the EMTRIVA and VIREAD prescribing information for pharmacokinetic information on the individual products in pediatric. TRUVADA should not be administered to HIV-1 infected pediatric patients less than 12 years of age or weighing less than 35 kg (less than 77 lb). HIV-1 PrEP: The pharmacokinetic data for tenofovir and FTC following administration of TRUVADA in HIV-1 uninfected adolescents weighing 35 kg and above are not available. The dosage recommendations of TRUVADA for HIV-1 PrEP in this population are based on safety and adherence data from the ATN113 trial [see Use in Specific Populations (8.4) ] and known pharmacokinetic information in HIV-infected adolescents taking TDF and FTC for treatment. Geriatric Patients Pharmacokinetics of FTC and tenofovir have not been fully evaluated in the elderly (65 years of age and older). Patients with Renal Impairment The pharmacokinetics of FTC 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, C max and AUC 0–∞ of FTC and tenofovir were increased. No data are available to make dosage recommendations in pediatric patients with renal impairment. Patients with Hepatic Impairment The pharmacokinetics of tenofovir following a 300 mg dose of TDF 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 FTC have not been studied in subjects with hepatic impairment; however, FTC 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 FTC and tenofovir were unaffected when FTC and TDF 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 FTC and tenofovir with other medicinal products is low. TDF is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) transporters. When TDF is coadministered with an inhibitor of these transporters, an increase in absorption may be observed. No clinically significant drug interactions have been observed between FTC and famciclovir, indinavir, stavudine, TDF, and zidovudine (Tables 8 and 9). Similarly, no clinically significant drug interactions have been observed between TDF and efavirenz, methadone, nelfinavir, oral contraceptives, ribavirin, or sofosbuvir in trials conducted in healthy volunteers (Tables 10 and 11). Table 8 Drug Interactions: Changes in Pharmacokinetic Parameters for FTC in the Presence of the Coadministered Drug All interaction trials conducted in healthy volunteers Coadministered Drug Dose of Coadministered Drug (mg) FTC Dose (mg) N % Change of FTC Pharmacokinetic Parameters ↑ = Increase; ⇔ = No Effect; NA = Not Applicable (90% CI) C max AUC C min TDF 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 9 Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of FTC All interaction trials conducted in healthy volunteers Coadministered Drug Dose of Coadministered Drug (mg) FTC Dose (mg) N % Change of Coadministered Drug Pharmacokinetic Parameters ↑ = Increase; ⇔ = No Effect; NA = Not Applicable (90% CI) C max AUC C min TDF 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 10 Drug Interactions: Changes in Pharmacokinetic Parameters for Tenofovir Subjects received VIREAD 300 mg once daily. in the Presence of the Coadministered Drug Coadministered Drug Dose of Coadministered Drug (mg) N % Change of Tenofovir Pharmacokinetic Parameters Increase = ↑; Decrease = ↓; No Effect = ⇔ (90% CI) C max AUC C min Atazanavir Reyataz Prescribing Information. 400 once daily × 14 days 33 ↑ 14 (↑ 8 to ↑ 20) ↑ 24 (↑ 21 to ↑ 28) ↑ 22 (↑ 15 to ↑ 30) Atazanavir/ Ritonavir 300/100 once daily 12 ↑ 34 (↑ 20 to ↑ 51) ↑ 37 (↑ 30 to ↑ 45) ↑ 29 (↑ 21 to ↑ 36) Darunavir/ Ritonavir Prezista Prescribing Information. 300/100 twice daily 12 ↑ 24 (↑ 8 to ↑ 42) ↑ 22 (↑ 10 to ↑ 35) ↑ 37 (↑ 19 to ↑ 57) Indinavir 800 three times daily × 7 days 13 ↑ 14 (↓ 3 to ↑ 33) ⇔ ⇔ Ledipasvir/ Sofosbuvir Data generated from simultaneous dosing with HARVONI (ledipasvir/sofosbuvir). Staggered administration (12 hours apart) provided similar results. , Comparison based on exposures when administered as atazanavir/ritonavir + FTC/TDF. 90/400 once daily × 10 days 24 ↑ 47 (↑ 37 to ↑ 58) ↑ 35 (↑ 29 to ↑42 ) ↑ 47 (↑ 38 to ↑ 57) Ledipasvir/ Sofosbuvir , Comparison based on exposures when administered as darunavir/ritonavir + FTC/TDF. 23 ↑ 64 (↑ 54 to ↑ 74) ↑ 50 (↑ 42 to ↑ 59) ↑ 59 (↑ 49 to ↑ 70) Ledipasvir/ Sofosbuvir Study conducted with ATRIPLA (efavirenz/FTC/TDF) coadministered with HARVONI. 90/400 once daily × 14 days 15 ↑ 79 (↑ 56 to ↑ 104) ↑ 98 (↑ 77 to ↑ 123) ↑ 163 (↑ 132 to ↑ 197) Ledipasvir/ Sofosbuvir Study conducted with COMPLERA (FTC/rilpivirine/TDF) coadministered with HARVONI. 90/400 once daily × 10 days 14 ↑ 32 (↑ 25 to ↑ 39 ) ↑ 40 (↑ 31 to ↑ 50 ) ↑ 91 (↑ 74 to ↑ 110) Ledipasvir/ Sofosbuvir Study conducted with TRUVADA (FTC/TDF) + dolutegravir coadministered with HARVONI. 90/400 once daily × 10 days 29 ↑ 61 (↑ 51 to ↑ 72) ↑ 65 (↑ 59 to ↑ 71) ↑ 115 (↑ 105 to ↑ 126) Lopinavir/ Ritonavir 400/100 twice daily × 14 days 24 ⇔ ↑ 32 (↑ 25 to ↑ 38) ↑ 51 (↑ 37 to ↑ 66) Saquinavir/ Ritonavir 1000/100 twice daily × 14 days 35 ⇔ ⇔ ↑ 23 (↑ 16 to ↑ 30) Sofosbuvir Study conducted with ATRIPLA coadministered with SOVALDI ® (sofosbuvir). 400 single dose 16 ↑ 25 (↑ 8 to ↑ 45) ⇔ ⇔ Sofosbuvir/ Velpatasvir Study conducted with COMPLERA coadministered with EPCLUSA; coadministration with EPCLUSA also results in comparable increases in tenofovir exposures when TDF is administered as ATRIPLA, STRIBILD, TRUVADA + atazanavir/ritonavir, or TRUVADA + darunavir/ritonavir. 400/100 once daily 24 ↑ 44 (↑ 33 to ↑ 55) ↑ 40 (↑ 34 to ↑ 46) ↑ 84 (↑ 76 to ↑ 92) Sofosbuvir/ Velpatasvir Administered as raltegravir + FTC/TDF. 400/100 once daily 30 ↑ 46 (↑ 39 to ↑ 54) ↑ 40 (↑ 34 to ↑ 45) ↑ 70 (↑ 61 to ↑ 79) Sofosbuvir/ Velpatasvir/Voxilaprevir Comparison based on exposures when administered as darunavir + ritonavir + FTC/TDF. 400/100/100 + Voxilaprevir Study conducted with additional voxilaprevir 100 mg to achieve voxilaprevir exposures expected in HCV-infected patients 100 once daily 29 ↑ 48 (↑ 36 to ↑ 61) ↑ 39 (↑ 32 to ↑ 46) ↑ 47 (↑ 38 to ↑ 56) Tacrolimus 0.05 mg/kg twice daily × 7 days 21 ↑ 13 (↑ 1 to ↑ 27) ⇔ ⇔ Tipranavir/ Ritonavir Aptivus Prescribing Information. 500/100 twice daily 22 ↓ 23 (↓ 32 to ↓ 13) ↓ 2 (↓ 9 to ↑ 5) ↑ 7 (↓ 2 to ↑ 17) 750/200 twice daily (23 doses) 20 ↓ 38 (↓ 46 to ↓ 29) ↑ 2 (↓ 6 to ↑ 10) ↑ 14 (↑ 1 to ↑ 27) No effect on the pharmacokinetic parameters of the following coadministered drugs was observed with TRUVADA: abacavir, didanosine (buffered tablets), FTC, entecavir, and lamivudine. Table 11 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 Increase = ↑; Decrease = ↓; No Effect = ⇔; NA = Not Applicable (90% CI) C max AUC C min Abacavir 300 once 8 ↑ 12 (↓ 1 to ↑ 26) ⇔ NA Atazanavir Reyataz Prescribing Information. 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 In HIV-infected subjects, addition of TDF to atazanavir 300 mg plus ritonavir 100 mg resulted in AUC and C min values of atazanavir that were 2.3- and 4-fold higher than the respective values observed for atazanavir 400 mg when given alone. (↓ 42 to ↓ 3) ↓ 23 (↓ 46 to ↑ 10) Darunavir Prezista Prescribing Information. Darunavir/Ritonavir 300/100 once daily 12 ↑ 16 (↓ 6 to ↑ 42) ↑ 21 (↓ 5 to ↑ 54) ↑ 24 (↓ 10 to ↑ 69) Didanosine Videx EC Prescribing Information. Subjects received didanosine enteric-coated capsules. When didanosine 250 mg enteric-coated capsules were administered with TDF, systemic exposures of didanosine were similar to those seen with the 400 mg enteric-coated capsules alone under fasted conditions. 250 once, simultaneously with TDF and a light meal 373 kcal, 8.2 g fat 33 ↓ 20 Compared with didanosine (enteric-coated) 400 mg administered alone under fasting conditions. (↓ 32 to ↓ 7) ⇔ NA 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 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 ⇔ ⇔ ⇔ Saquinavir Saquinavir/Ritonavir 1000/100 twice daily × 14 days 32 ↑ 22 (↑ 6 to ↑41) ↑ 29 Increases in AUC and C min are not expected to be clinically relevant; hence, no dose adjustments are required when TDF and ritonavir-boosted saquinavir are coadministered. (↑ 12 to ↑ 48) ↑ 47 (↑ 23 to ↑ 76) Ritonavir ⇔ ⇔ ↑ 23 (↑ 3 to ↑ 46) Tacrolimus 0.05 mg/kg twice daily × 7 days 21 ⇔ ⇔ ⇔ Tipranavir Aptivus Prescribing Information. Tipranavir/Ritonavir 500/100 twice daily 22 ↓ 17 (↓ 26 to ↓ 6) ↓ 18 (↓ 25 to ↓ 9) ↓ 21 (↓ 30 to ↓ 10) Tipranavir/Ritonavir 750/200 twice daily (23 doses) 20 ↓ 11 (↓ 16 to ↓ 4) ↓ 9 (↓ 15 to ↓ 3) ↓ 12 (↓ 22 to 0) Mechanism of Action Emtricitabine: FTC, a synthetic nucleoside analog of cytidine, is phosphorylated by cellular enzymes to form emtricitabine 5'-triphosphate (FTC-TP), which 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. FTC-TP is a weak inhibitor of mammalian DNA polymerases α, β, ε and mitochondrial DNA polymerase γ. Tenofovir Disoproxil Fumarate: TDF is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate. TDF requires initial diester hydrolysis for conversion to tenofovir and subsequent phosphorylations by cellular enzymes to form tenofovir diphosphate (TFV-DP), which 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. TFV-DP is a weak inhibitor of mammalian DNA polymerases α, β, and mitochondrial DNA polymerase γ. Antiviral Activity Emtricitabine and Tenofovir Disoproxil Fumarate: No antagonism was observed in combination studies evaluating the cell culture antiviral activity of FTC and tenofovir together. Emtricitabine: The antiviral activity of FTC 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 (EC 50 ) values for FTC were in the range of 0.0013–0.64 µM (0.0003–0.158 µg/mL). In drug combination studies of FTC with nucleoside RT inhibitors (abacavir, lamivudine, stavudine, zidovudine), non-nucleoside RT inhibitors (delavirdine, efavirenz, nevirapine), and protease inhibitors (amprenavir, nelfinavir, ritonavir, saquinavir), no antagonism was observed. Emtricitabine displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, and G (EC 50 values ranged from 0.007–0.075 µM) and showed strain-specific activity against HIV-2 (EC 50 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 EC 50 values for tenofovir were in the range of 0.04–8.5 µM. In drug combination studies of tenofovir with nucleoside RT inhibitors (abacavir, didanosine, lamivudine, stavudine, zidovudine), non-nucleoside RT inhibitors (delavirdine, efavirenz, nevirapine), and protease inhibitors (amprenavir, indinavir, nelfinavir, ritonavir, saquinavir), no antagonism was observed. Tenofovir displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, G, and O (EC 50 values ranged from 0.5–2.2 µM) and showed strain-specific activity against HIV-2 (EC 50 values ranged from 1.6 µM to 5.5 µM). Prophylactic Activity in a Nonhuman Primate Model of HIV-1 Transmission Emtricitabine and Tenofovir Disoproxil Fumarate: The prophylactic activity of the combination of daily oral FTC and TDF was evaluated in a controlled study of macaques inoculated once weekly for 14 weeks with SIV/HIV-1 chimeric virus (SHIV) applied to the rectal surface. Of the 18 control animals, 17 became infected after a median of 2 weeks. In contrast, 4 of the 6 animals treated daily with oral FTC and TDF remained uninfected and the two infections that did occur were significantly delayed until 9 and 12 weeks and exhibited reduced viremia. An M184I-expressing FTC-resistant variant emerged in 1 of the 2 macaques after 3 weeks of continued drug exposure. Resistance Emtricitabine and Tenofovir Disoproxil Fumarate: HIV-1 isolates with reduced susceptibility to the combination of FTC 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 addition, a K70E substitution in the HIV-1 RT has been selected by tenofovir and results in reduced susceptibility to tenofovir. In Study 934, a clinical trial of treatment-naïve subjects [see Clinical Studies (14.2) ] , 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 FTC and lamivudine, was observed in 2/19 analyzed subject isolates in the FTC+TDF group and in 10/29 analyzed subject isolates in the zidovudine/lamivudine group. Through 144 weeks of Study 934, no subjects have developed a detectable K65R or K70E substitution in their HIV-1 as analyzed through standard genotypic analysis. Emtricitabine: FTC-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 FTC 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- to 4-fold reduction in susceptibility to tenofovir. In treatment-naïve subjects, isolates from 8/47 (17%) analyzed subjects developed the K65R substitution in the TDF 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 TDF through Week 96 showed greater than 1.4-fold (median 2.7) reduced susceptibility to tenofovir. Genotypic analysis of the resistant isolates showed a K65R amino acid substitution in the HIV-1 RT. iPrEx Trial: In the iPrEx trial, a clinical trial of HIV-1 seronegative adult subjects [see Clinical Studies (14.3) ] , no amino acid substitutions associated with resistance to FTC or TDF were detected at the time of seroconversion among 48 subjects in the TRUVADA group and 83 subjects in the placebo group who became infected with HIV-1 during the trial. Ten subjects were observed to be HIV-1 infected at time of enrollment. The M184V/I substitutions associated with resistance to FTC were observed in 3 of the 10 subjects (2 of 2 in the TRUVADA group and 1 of 8 in the placebo group). One of the two subjects in the TRUVADA group harbored wild type virus at enrollment and developed the M184V substitution 4 weeks after enrollment. The other subject had indeterminate resistance at enrollment but was found to have the M184I substitution 4 weeks after enrollment. Partners PrEP Trial: In the Partners PrEP trial, a clinical trial of HIV-1 seronegative adult subjects [see Clinical Studies (14.4) ], no variants expressing amino acid substitutions associated with resistance to FTC or TDF were detected at the time of seroconversion among 12 subjects in the TRUVADA group, 15 subjects in the TDF group, and 51 subjects in the placebo group. Fourteen subjects were observed to be HIV-1 infected at the time of enrollment (3 in the TRUVADA group, 5 in the TDF group, and 6 in the placebo group). One of the three subjects in the TRUVADA group who was infected with wild type virus at enrollment selected an M184V expressing virus by Week 12. Two of the five subjects in the TDF group had tenofovir-resistant viruses at the time of seroconversion; one subject infected with wild type virus at enrollment developed a K65R substitution by Week 16, while the second subject had virus expressing the combination of D67N and K70R substitutions upon seroconversion at Week 60, although baseline virus was not genotyped and it is unclear if the resistance emerged or was transmitted. Following enrollment, 4 subjects (2 in the TDF group, 1 in the TRUVADA group, and 1 in the placebo group) had virus expressing K103N or V106A substitutions, which confer high-level resistance to NNRTIs but have not been associated with FTC or TDF and may have been present in the infecting virus. ATN113 Trial: In ATN113, a clinical trial of HIV-1 seronegative adolescent subjects [see Use in Specific Populations (8.4) ], no amino acid substitutions associated with resistance to FTC or TDF were detected at the time of seroconversion from any of the 3 subjects who became infected with HIV-1 during the trial. All 3 subjects who seroconverted were nonadherent to the recommended TRUVADA dosage. Cross Resistance Emtricitabine and Tenofovir Disoproxil Fumarate: Cross-resistance among certain NRTIs has been recognized. The M184V/I and/or K65R substitutions selected in cell culture by the combination of FTC and tenofovir are also observed in some HIV-1 isolates from subjects failing treatment with tenofovir in combination with either FTC or lamivudine, 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: FTC-resistant isolates (M184V/I) were cross-resistant to lamivudine but retained susceptibility in cell culture to the NRTIs didanosine, stavudine, tenofovir, and zidovudine, and to NNRTIs (delavirdine, efavirenz, and nevirapine). HIV-1 isolates containing the K65R substitution, selected in vivo by abacavir, didanosine, and tenofovir, demonstrated reduced susceptibility to inhibition by FTC. Viruses harboring substitutions conferring reduced susceptibility to stavudine and zidovudine (M41L, D67N, K70R, L210W, T215Y/F, K219Q/E), or didanosine (L74V) remained sensitive to FTC. HIV-1 containing the K103N substitution associated with resistance to NNRTIs was susceptible to FTC. Tenofovir Disoproxil Fumarate: The K65R and K70E substitutions selected by tenofovir are also selected in some HIV-1 infected patients treated with abacavir or didanosine. HIV-1 isolates with the K65R and K70E substitutions also showed reduced susceptibility to FTC and lamivudine. Therefore, cross-resistance among these NRTIs may occur in patients whose virus harbors the K65R or K70E substitutions. 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 TDF. 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.

Emtricitabine: In long-term oral carcinogenicity studies of FTC, 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). FTC was not genotoxic in the reverse mutation bacterial test (Ames test), or the mouse lymphoma or mouse micronucleus assays. FTC 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 TDF 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. TDF 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, TDF was negative when administered to male mice. There were no effects on fertility, mating performance, or early embryonic development when TDF 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 7 of gestation. There was, however, an alteration of the estrous cycle in female rats. Tenofovir and TDF 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 four 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.

The efficacy and safety of TRUVADA have been evaluated in the studies summarized in Table 12. Table 12 Trials Conducted with TRUVADA for HIV-1 Treatment and HIV-1 PrEP Trial Population Study Arms (N) Randomized and dosed. Timepoint Study 934 Randomized, open label, active-controlled trial. (NCT00112047) HIV-infected, treatment-naïve adults FTC+TDF + efavirenz (257) zidovudine/lamivudine + efavirenz (254) 48 Weeks iPrEx Randomized, double-blind, placebo-controlled trial. (NCT00458393) HIV-seronegative men or transgender women who have sex with men TRUVADA (1,251) Placebo (1,248) 4,237 person-years Partners PrEP (NCT00557245) HIV serodiscordant heterosexual couples TRUVADA (1,583) Placebo (1,586) 7,827 person-years Data through 144 weeks are reported for Study 934, a randomized, open-label, active-controlled multicenter trial comparing FTC+TDF administered in combination with efavirenz (EFV) versus zidovudine (AZT)/lamivudine (3TC) fixed-dose combination administered in combination with EFV in 511 antiretroviral-naïve adult subjects. From Weeks 96 to 144 of the trial, subjects received TRUVADA with EFV in place of FTC+TDF with EFV. 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/mm 3 (range 2–1,191) and median baseline plasma HIV-1 RNA was 5.01 log 10 copies/mL (range 3.56–6.54). Subjects were stratified by baseline CD4+ cell count (< or ≥200 cells/mm 3 ); 41% had CD4+ cell counts <200 cells/mm 3 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 EFV resistance at baseline are presented in Table 13. Table 13 Virologic Outcomes of Randomized Treatment at Weeks 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) 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. AZT/3TC +EFV (N=229) Responder Subjects achieved and maintained confirmed HIV-1 RNA <400 copies/mL through Weeks 48 and 144. 84% 73% 71% 58% Virologic failure Includes confirmed viral rebound and failure to achieve confirmed <400 copies/mL through Weeks 48 and 144. 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 Includes lost to follow-up, subject withdrawal, noncompliance, protocol violation, and other reasons. 10% 14% 20% 22% Through Week 48, 84% and 73% of subjects in the FTC+TDF group and the AZT/3TC 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 is largely due to the higher number of discontinuations due to adverse events and other reasons in the AZT/3TC group in this open-label trial. In addition, 80% and 70% of subjects in the FTC+TDF group and the AZT/3TC 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/mm 3 in the FTC+TDF group and 158 cells/mm 3 in the AZT/3TC group at Week 48 (312 and 271 cells/mm 3 at Week 144). Through 48 weeks, 7 subjects in the FTC+TDF group and 5 subjects in the AZT/3TC group experienced a new CDC Class C event (10 and 6 subjects through 144 weeks). The iPrEx trial was a randomized, double-blind, placebo-controlled multinational study evaluating TRUVADA in 2,499 HIV-seronegative men or transgender women who have sex with men and with evidence of high-risk behavior for HIV-1 infection. Evidence of high-risk behavior included any one of the following reported to have occurred up to six months prior to study screening: no condom use during anal intercourse with an HIV-1 positive partner or a partner of unknown HIV status; anal intercourse with more than 3 sex partners; exchange of money, gifts, shelter, or drugs for anal sex; sex with male partner and diagnosis of sexually transmitted infection; no consistent use of condoms with sex partner known to be HIV-1 positive. All subjects received monthly HIV-1 testing, risk-reduction counseling, condoms, and management of sexually transmitted infections. Of the 2,499 enrolled subjects, 1,251 received TRUVADA and 1,248 received placebo. The mean age of subjects was 27 years; 5% were Asian, 9% Black, 18% White, and 72% Hispanic/Latino. Subjects were followed for 4,237 person-years. The primary outcome measure was the incidence of documented HIV seroconversion. At the end of treatment, emergent HIV-1 seroconversion was observed in 131 subjects, of which 48 occurred in the TRUVADA group and 83 occurred in the placebo group, indicating a 42% (95% CI: 18–60%) reduction in risk. Risk reduction was found to be higher (53%; 95% CI: 34–72%) among subjects who reported previous unprotected anal intercourse (URAI) at screening (732 and 753 subjects reported URAI within the last 12 weeks at screening in the TRUVADA and placebo groups, respectively). In a post-hoc case control study of plasma and intracellular drug levels in about 10% of study subjects, risk reduction appeared to be greatest in subjects with detectable intracellular tenofovir diphosphate concentrations. Efficacy was therefore strongly correlated with adherence. The Partners PrEP trial was a randomized, double-blind, placebo-controlled 3-arm trial conducted in 4,758 HIV-1 serodiscordant heterosexual couples in Kenya and Uganda to evaluate the efficacy and safety of TDF (N=1,589) and FTC/TDF (N=1,583) versus (parallel comparison) placebo (N=1,586) in preventing HIV-1 acquisition by the uninfected partner. All uninfected partner subjects received monthly HIV-1 testing, evaluation of adherence, assessment of sexual behavior, and safety evaluations. Women were also tested monthly for pregnancy. Women who became pregnant during the trial had study drug interrupted for the duration of the pregnancy and while breastfeeding. The uninfected partner subjects were predominantly male (61–64% across study drug groups) and had a mean age of 33–34 years. Following 7,827 person-years of follow-up, 82 emergent HIV-1 seroconversions were reported, with an overall observed seroincidence rate of 1.05 per 100 person-years. Of the 82 seroconversions, 13 and 52 occurred in partner subjects randomized to TRUVADA and placebo, respectively. Two of the 13 seroconversions in the TRUVADA arm and 3 of the 52 seroconversions in the placebo arm occurred in women during treatment interruptions for pregnancy. The risk reduction for TRUVADA relative to placebo was 75% (95% CI: 55–87%). In a post-hoc case control study of plasma drug levels in about 10% of study subjects, risk reduction appeared to be greatest in subjects with detectable plasma tenofovir concentrations. Efficacy was therefore strongly correlated with adherence.

Truvada™ (emtricitabine and tenofovir disoproxil fumarate) Tablets GILEAD ACCESS PROGRAM 30 tablets Rx only POM PRINCIPAL DISPLAY PANEL - 30 Tablet Bottle Label