Truvada

Emtricitabine, tenofovir disoproxil fumarate.

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).
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 (VIREAD, also known as 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.
TRUVADA Tablets are for oral administration.
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.
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.
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.
Excipients/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, containing FD&C Blue #2 aluminum lake, hydroxypropyl methylcellulose 2910, lactose monohydrate, titanium dioxide and triacetin.

Pharmacology: 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 evaluating the in 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 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 4.9 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 study of treatment-naïve patients (Study 934, see Description of Clinical Studies under INDICATIONS/USES) resistance analysis was performed on HIV isolates from all virologic failure patients with >400 copies/mL of HIV-1 RNA at Week 48 or early discontinuations. Development of efavirenz resistance-associated mutations 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 2/12 (17%) analyzed patient isolates in the EMTRIVA + VIREAD group and in 7/22 (32%) analyzed patient isolates in the zidovudine/lamivudine group. Through 48 weeks of Study 934, no patients have developed a detectable K65R mutation in their HIV as analyzed through standard genotypic analysis. Insufficient data are available to assess the development of the K65R mutation upon prolonged exposure to this regimen.
Emtricitabine: Emtricitabine-resistant isolates of HIV 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 mutation in the HIV 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 mutation in RT and showed a 2-4 fold reduction in susceptibility to tenofovir.
In treatment-naïve patients, isolates from 8 patients developed the K65R mutation in the VIREAD arm through 144 weeks; 7 occurred in the first 48 weeks of treatment and 1 at Week 96. In treatment-experienced patients, 14/304 (5%) isolates from patients failing VIREAD through Week 96 showed >1.4 fold (median 2.7) reduced susceptibility to tenofovir. Genotypic analysis of the resistant isolates showed a mutation in the HIV-1RT 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 mutations 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 patients (N=20) whose HIV-1expressed 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. Multinucleoside resistant HIV-1 with a T69S double insertion mutation in the RT showed reduced susceptibility to tenofovir.
Pharmacokinetics: Pharmacokinetics in Adults: 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 1. Following oral administration of EMTRIVA, emtricitabine is rapidly absorbed with peak plasma concentrations occurring at 1-2 hours post-dose. In vitro binding of emtricitabine to human plasma proteins is <4% and 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 1. Following oral administration of VIREAD, maximum tenofovir serum concentrations are achieved in 1.0 ± 0.4 hour. In vitro binding of tenofovir to human plasma proteins is <0.7% and 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. (See Table 1.)

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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 hr. 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 studies, VIREAD (tenofovir) was taken under fed conditions. Emtricitabine systemic exposures (AUC and C_max) 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 patients.
Pediatric and Geriatric Patients: Pharmacokinetic studies of tenofovir have not been performed in pediatric patients (<18 years). Pharmacokinetics of emtricitabine and tenofovir have not been fully evaluated in the elderly (>65 years) (see Use in Children and Use in the Elderly under PRECAUTIONS).
Patients with Impaired Renal Function: The pharmacokinetics of emtricitabine and tenofovir are altered in patients with renal impairment (see Renal Impairment under WARNINGS). In patients with creatinine clearance <50 mL/min, C_max, and AUC_0-∞ 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 <30 mL/min and in patients with end-stage renal disease requiring dialysis (see DOSAGE & ADMINISTRATION).
Patients with Hepatic Impairment: The pharmacokinetics of tenofovir following a 300 mg dose of VIREAD have been studied in non-HIV infected patients with moderate to severe hepatic impairment. There were no substantial alterations in tenofovir pharmacokinetics in patients with hepatic impairment compared with unimpaired patients. The pharmacokinetics of TRUVADA or emtricitabine have not been studied in patients with hepatic impairment; however, emtricitabine is not significantly metabolized by liver enzymes, so the impact of liver impairment should be limited.
Pregnancy: (see Use in Pregnancy & Lactation).
Nursing Mothers: (see Use in Pregnancy & Lactation).
Drug Interactions (see Drug Interactions under PRECAUTIONS): TRUVADA: No drug interaction studies have been conducted using TRUVADA Tablets.
Emtricitabine and tenofovir disoproxil fumarate: 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 and clinical pharmacokinetic drug-drug interaction studies have shown that the potential for CYP450 mediated interactions involving emtricitabine and tenofovir with other medicinal products is low.
Emtricitabine and tenofovir are primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion. No drug-drug interactions due to competition for renal excretion have been observed; however, co-administration of TRUVADA with drugs that are eliminated by active tubular secretion may increase concentrations of emtricitabine, tenofovir, and/or the co-administered drug.
Drugs that decrease renal function may increase concentrations of emtricitabine and/or tenofovir.
No clinically significant drug interactions have been observed between emtricitabine and famciclovir, indinavir, stavudine, tenofovir disoproxil fumarate, and zidovudine (see Tables 2 and 3). Similarly, no clinically significant drug interactions have been observed between tenofovir disoproxil fumarate and abacavir, adefovir dipivoxil, efavirenz, emtricitabine, indinavir, lamivudine, lopinavir/ritonavir, methadone, nelfinavir, oral contraceptives, ribavirin, and saquinavir/ritonavir in studies conducted in healthy volunteers (Tables 4 and 5). (See Tables 2, 3, 4, and 5.)

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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 studies, 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 6 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 C_max 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 Table 6.)

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Microbiology: For additional information on Mechanism of Action, Antiviral Activity, Resistance and Cross Resistance, please consult the EMTRIVA and VIREAD prescribing information.

TRUVADA 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.
Additional important information regarding the use of 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).
In treatment-experienced patients, the use of TRUVADA should be guided by laboratory testing and treatment history (see MICROBIOLOGY under Actions).
Description of Clinical 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 were used in combination in treatment-naïve adults, and clinical Study 303 in which EMTRIVA and lamivudine demonstrated comparable efficacy, safety and resistance patterns as part of multidrug regimens. For additional information about these studies, consult the prescribing information for VIREAD and EMTRIVA.
Study 934: EMTRIVA + VIREAD + Efavirenz Compared with zidovudine/lamivudine + Efavirenz: Data through 48 weeks are reported for Study 934, a randomized, open-label, active-controlled multicenter study comparing EMTRIVA + VIREAD administered in combination with efavirenz versus zidovudine/lamivudine fixed-dose combination administered in combination with efavirenz in 511 antiretroviral-naïve patients. Patients 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). Patients were stratified by baseline CD4 count (< or ≥200 cells/mm³); 41% had CD4 cell counts <200 cells/mm3 and 51% of patients had baseline viral loads >100,000 copies/mL. Treatment outcomes through 48 weeks for those patients who did not have efavirenz resistance at baseline are presented in Table 7. (See Table 7.)

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The difference in the proportion of patients 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 study. In addition, 80% and 70% of patients in the EMTRIVA + VIREAD group and the zidovudine/lamivudine group, respectively, achieved and maintained HIV-1 RNA <50 copies/mL. The mean increase from baseline in CD4 cell count was 190 cells/mm³ in the EMTRIVA + VIREAD group and 158 cells/mm³ in the zidovudine/lamivudine group.
Through 48 weeks, 7 patients in the EMTRIVA + VIREAD group and 5 patients in the zidovudine/lamivudine group experienced a new CDC Class C event.

The dose of TRUVADA is one tablet (containing 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate) once daily taken orally with or without food.
Dose Adjustment for Renal Impairment: Significantly increased drug exposures occurred when EMTRIVA or VIREAD were administered to patients 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 8. These dosing interval recommendations are based on modeling of single-dose pharmacokinetic data in non-HIV infected subjects. The safety and effectiveness of these dosing interval adjustment recommendations have not been clinically evaluated in patients with moderate renal impairment, therefore clinical response to treatment and renal function should be closely monitored in these patients (see WARNINGS).
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 for these patients (see WARNINGS). (See Table 8.)

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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 study, single doses of 1200 mg emtricitabine were administered to 11 patients. No severe adverse reactions were reported.
Hemodialysis treatment removes approximately 30% of the emtricitabine dose over a 3-hr dialysis period 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 study, 600 mg tenofovir disoproxil fumarate was administered to 8 patients 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.

TRUVADA is contraindicated in patients with previously demonstrated hypersensitivity to any of the components of the product.

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs alone or in combination with other antiretrovirals (see information as follows).
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. Severe acute exacerbations of Hepatitis B have been reported in patients who have discontinued EMTRIVA or VIREAD, the components of 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 and HBV and discontinue truvada. If appropriate, initiation of anti-hepatitis B therapy may be warranted (see information as follows).
Lactic Acidosis/Severe Hepatomegaly with Steatosis: Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs alone or 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).
Patients Coinfected with HIV and Hepatitis B Virus: It is recommended that all patients with HIV 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. Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV and have discontinued EMTRIVA or VIREAD. In some of these patients treated with EMTRIVA, the exacerbations of hepatitis B were associated with liver decompensation and liver failure. 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 and HBV and discontinue TRUVADA. If appropriate, initiation of anti-hepatitis B therapy may be warranted.
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 in association with the use of VIREAD (see Post Marketing Experience under ADVERSE REACTIONS).
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 phosphorous should be performed in patients at risk for renal impairment.
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 & ADMINISTRATION). No safety or efficacy data are available in patients with renal dysfunction who received TRUVADA using these dosing guidelines, and 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 <30 mL/min or patients requiring hemodialysis.
TRUVADA should be avoided with concurrent or recent use of nephrotoxic agent.
Other: 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).

Drug Interactions: Tenofovir disoproxil fumarate: When tenofovir disoproxil fumarate was administered with didanosine (Videx and Videx EC), the C_max and AUC of didanosine administered as either the buffered or enteric-coated formulation increased significantly (see Table 6 on Pharmacology: Pharmacokinetics under Actions). The mechanism of this interaction is unknown. Higher didanosine concentrations could potentiate didanosine-associated adverse events, including pancreatitis and neuropathy. Suppression of CD4 cell counts has been observed in patients receiving tenofovir DF with didanosine 400 mg daily. In adults weighing >60 kg, the didanosine dose should be reduced to 250 mg when it is co-administered with TRUVADA. Data are not available to recommend a dose adjustment of didanosine for patients weighing <60 kg. When co-administered, TRUVADA and Videx EC may be taken under fasted conditions or with a light meal (<400 kcal, 20% fat).
Co-administration of didanosine buffered tablet formulation with TRUVADA should be under fasted conditions. Co-administration of TRUVADA and didanosine should be undertaken with caution and patients receiving this combination should be monitored closely for didanosine-associated adverse events. Didanosine should be discontinued in patients who develop didanosine-associated adverse events.
Atazanavir and lopinavir/ritonavir have been shown to increase tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving atazanavir and lopinavir/ritonavir and TRUVADA should be monitored for TRUVADA-associated adverse events. TRUVADA should be discontinued in patients who develop TRUVADA-associated adverse events.
Tenofovir decreases the AUC and C_min of atazanavir. When co-administered with TRUVADA, it is recommended that atazanavir 300 mg is given with ritonavir 100 mg. Atazanavir without ritonavir should not be co-administered with TRUVADA.
Emtricitabine and tenofovir disoproxil fumarate: Since emtricitabine and tenofovir are primarily eliminated by the kidneys, co-administration of TRUVADA with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of emtricitabine, tenofovir and/or other renally eliminated drugs. Some examples include, but are not limited to acyclovir, adefovir dipivoxil, cidofovir, ganciclovir, valacyclovir, and valganciclovir.
Bone Effects: Tenofovir disoproxil fumarate: In a 144-week study of treatment naïve patients, decreases in bone mineral density (BMD) were seen at the lumbar spine and hip in both arms of the study. At Week 144, there was a significantly greater mean percentage decrease from baseline in BMD at the lumbar spine in patients receiving VIREAD +lamivudine + efavirenz compared with patients 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 study and this reduction was sustained through 144 weeks. Twenty-eight percent of VIREAD-treated patients vs. 21% of the comparator patients 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 patients in the VIREAD group and 6 patients 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 patients receiving VIREAD. 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) have been reported in association with the use of VIREAD (see Post Marketing Experience under Adverse Reactions).
Bone monitoring should be considered for HIV-infected patients who have a history of pathologic bone fracture or are at risk for osteopenia. 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.
Fat Redistribution: Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral and 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.
Immune Reconstitution Syndrome: Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including EMTRIVA and VIREAD. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (eg, Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia (PCP) or tuberculosis), which may necessitate further evaluation and treatment.
Information for Patients: Truvada is not a cure for HIV infection and patients may continue to experience illnesses associated with HIV infection, including opportunistic infections. Patients should remain under the care of a physician when using TRUVADA.
Patients should be advised that: The use of Truvada has not been shown to reduce the risk of transmission of HIV to others through sexual contact or blood contamination.
The long-term effects of TRUVADA are unknown.
TRUVADA Tablets are for oral ingestion only.
It is important to take TRUVADA with combination therapy on a regular dosing schedule to avoid missing doses.
Redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known.
TRUVADA should not be co-administered with ATRIPLA, EMTRIVA, or VIREAD; or with drugs containing lamivudine, including Combivir (lamivudine/zidovudine), Epivir or Epivir-HBV (lamivudine), Epzicom (abacavir sulfate/lamivudine), or Trizivir (abacavir/lamivudine/zidovudine).
Animal Toxicology: 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.
Carcinogenesis, 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 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.
Use in Pregnancy: 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 studies in pregnant women. Because animal reproduction studies are not always predictive of human response, TRUVADA should be used during pregnancy only if clearly needed.
Use in Lactation: The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breast-feed their infants to avoid risking post-natal transmission of HIV. 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 transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast-feed if they are receiving TRUVADA.
Use in Children: Truvada is not recommended for patients less than 18 years of age because it is a fixed-dose combination tablet containing a component, VIREAD, for which safety and efficacy have not been established in this age group.
Use in the Elderly: Clinical studies 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.

Pregnancy: 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 studies in pregnant women. Because animal reproduction studies are not always predictive of human response, TRUVADA should be used during pregnancy only if clearly needed.
Nursing Mothers: The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breast-feed their infants to avoid risking post-natal transmission of HIV. 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 transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast-feed if they are receiving TRUVADA.

Clinical Trials: TRUVADA: Four hundred and forty-seven HIV-1 infected patients have received combination therapy with EMTRIVA and VIREAD with either a non-nucleoside reverse transcriptase inhibitor or protease inhibitor for 48 weeks in clinical studies.
Study 934 - Treatment Emergent Adverse Events: Adverse events observed in this study were generally consistent with those seen in other studies in treatment experienced or treatment-naïve patients receiving VIREAD and/or EMTRIVA (see Table 9).

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Laboratory Abnormalities: Laboratory abnormalities observed in this study were generally consistent with those seen in other studies of VIREAD and/or EMTRIVA (see Table 10).

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In addition to the events described previously for study 934, other adverse events that occurred in at least 5% of patients 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, rhinitis and rash event (including rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, pustular rash and allergic reaction).
Skin discoloration has been reported with higher frequency among EMTRIVA-treated patients. Skin discoloration, manifested by hyperpigmentation on the palms and/or soles was generally mild and asymptomatic. The mechanism and clinical significance are unknown.
In addition to the laboratory abnormalities described previously for study 934, grade 3/4 elevations of bilirubin (>2.5 x ULN), pancreatic amylase (>2.0 x ULN), serum glucose (<40 or >250 mg/dL), serum lipase (>2.0 x ULN), and urine glucose (≥3+) occurred in up to 3% of patients treated with EMTRIVA or VIREAD with other antiretroviral agents in clinical trials.
For more information, please consult the EMTRIVA and VIREAD package inserts.
Post-Marketing Experience: EMTRIVA: No additional events have been identified for inclusion in this section.
VIREAD: The following events have been identified during post-approval use of VIREAD. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion because of a combination of their seriousness, frequency of reporting or potential causal connection to VIREAD.
Immune System Disorders: Allergic reactions.
Metabolism and Nutritional Disorders: Hypophosphatemia, lactic acidosis.
Respiratory, Thoracic, and Mediastinal Disorders: Dyspnea.
Gastrointestinal Disorders: Abdominal pain, increased amylase, pancreatitis.
Hepatobiliary Disorders: Increased liver enzymes, hepatitis.
Skin and Subcutaneous Tissue Disorders: Rash.
Musculoskeletal and Connective Tissue Disorders: Myopathy, osteomalacia (both associated with proximal renal tubulopathy).
Renal and Urinary Disorders: Renal insufficiency, renal failure, acute renal failure, Fanconi syndrome, proximal tubulopathy, proteinuria, increased creatinine, acute tubular necrosis, nephrogenic diabetes insipidus, polyuria, interstitial nephritis (including acute cases).
General Disorders and Administration Site Conditions: Asthenia.

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Antivirals

J05AR03 - tenofovir disoproxil and emtricitabine ; Belongs to the class of antivirals for treatment of HIV infections, combinations.

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