Tenofovir Disoproxil Emtricitabine Mylan 300/200 Tenofovir disoproxil maleate 300 mg and Emtricitabine 200 mg

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1 Tenofovir Disoproxil Emtricitabine Mylan 300/200 Tenofovir disoproxil maleate 300 mg and Emtricitabine 200 mg PRODUCT INFORMATION NAME OF THE MEDICINE The active substances in Tenofovir Disoproxil Emtricitabine Mylan 300/200 tablets are tenofovir disoproxil maleate and emtricitabine. Active ingredient : Tenofovir disoproxil maleate Chemical name : Bis({[propan-2-yloxy) carbonyl)oxy}methyl) ({[(2R)-1-(6-amino-9Hpurin-9- yl)propan-2-yl]joxv} methyl)phosphonate (2Z)-but-2-enedioate. Structural formula: Molecular formula : C 19H 30N 5O 10P.C 4H 4O 4 Molecular weight : CAS Registry no. :

2 Tenofovir Disoproxil Emtricitabine Mylan 300/200 PRODUCT INFORMATION 2 Active ingredient : Emtricitabine Chemical name : 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. Structural formula : H 2 N N O F N O S OH Molecular formula : C 8H 10FN 3O 3S Molecular weight : CAS Registry no. : DESCRIPTION Tenofovir disoproxil maleate 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 is 1.25 and the pka is 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 and the pka is Each Tenofovir Disoproxil Emtricitabine Mylan 300/200 tablet contains 300 mg of tenofovir disoproxil as maleate (equivalent to 245 mg of tenofovir disoproxil) and 200 mg of emtricitabine. The tablets also contain the following ingredients as excipients: Core: microcrystalline cellulose, hyprolose, iron oxide red, colloidal anhydrous silica, lactose monohydrate, magnesium stearate. Coating: Opadry II complete film coating system 31K GREEN (ARTG ). PHARMACOLOGY Tenofovir Disoproxil Emtricitabine Mylan 300/200 tablet contains 200 mg of emtricitabine with 300 mg of tenofovir disoproxil maleate salt as compared to the innovator product which contained 300 mg tenofovir disoproxil fumarate salt. All clinical data in this product information (including Pharmacokinetic, Pharmacodynamic, and Clinical Trial data) relevant to tenofovir are based on tenofovir disoproxil fumarate. Pharmacokinetic bioequivalence has been established between the two salt forms based on tenofovir levels in blood. The results (Test/Reference) were as follows: Tenofovir Geometric Mean Ration (Test/Reference) % 90% Confidence Interval C max AUC t AUC

3 Tenofovir Disoproxil Emtricitabine Mylan 300/200 PRODUCT INFORMATION 3 Tenofovir and emtricitabine belong to the nucleoside and nucleotide reverse transcriptase inhibitors pharmacotherapeutic group (ATC code: J05AF30). Pharmacodynamics Tenofovir Disoproxil Tenofovir disoproxil maleate is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate. Tenofovir disoproxil maleate 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 reverse transcriptase 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,, and mitochondrial DNA polymerase. 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 by competing with the natural substrate deoxycytidine 5'-triphosphate 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. Antiviral activity in vitro Tenofovir disoproxil plus Emtricitabine: In combination studies evaluating the in vitro antiviral activity of tenofovir and emtricitabine together, synergistic antiviral effects were observed. Additive to synergistic effects were observed in combination studies with protease inhibitors, integrase strand transfer inhibitors, and with nucleoside and non-nucleoside analogue inhibitors of HIV-1 reverse transcriptase. Tenofovir disoproxil: The in vitro 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 IC 50 (50% inhibitory concentration) values for tenofovir were in the range of μm. In drug combination studies of tenofovir with nucleoside reverse transcriptase inhibitors (abacavir, didanosine, lamivudine (3TC), stavudine (d4t), zalcitabine, zidovudine (AZT), 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 vitro against HIV-1 clades A, B, C, D, E, F, G and O (IC 50 values ranged from μm). In addition, tenofovir has also been shown to be active in vitro against HIV-2, with similar potency as observed against HIV-1. Emtricitabine: The in vitro 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 IC 50 value for emtricitabine was in the range of μm ( μg/ml). In drug combination studies of emtricitabine with nucleoside reverse transcriptase inhibitors (abacavir, 3TC, d4t, zalcitabine, AZT), 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 vitro against HIV-1 clades A, C, D, E, F, and G (IC 50 values ranged from µm) and showed strain specific activity against HIV-2 (IC 50 values ranged from µm). Prophylactic Activity in a Nonhuman Primate Model of HIV Transmission Emtricitabine and Tenofovir disoproxil: The prophylactic activity of the combination of daily oral emtricitabine and tenofovir disoproxil fumarate 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 emtricitabine and tenofovir disoproxil fumarate 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.

4 Tenofovir Disoproxil Emtricitabine Mylan 300/200 PRODUCT INFORMATION 4 Anti-Hepatitis B Virus Activity In Vitro Tenofovir disoproxil: Tenofovir inhibits HBV production in HepG with an IC 50 value of 1.1μM. Emtricitabine: Emtricitabine inhibits HBV production against laboratory strains of HBV with IC 50 values in the range of 0.01 to 0.04 μm. Drug Resistance Tenofovir disoproxil: HIV-1 isolates with reduced susceptibility to tenofovir have been selected in vitro. These viruses expressed a K65R mutation in reverse transcriptase and showed a 2-4 fold reduction in susceptibility to tenofovir. In addition, a K70E substitution in HIV-1 reverse transcriptase has been selected by tenofovir and results in low-level reduced susceptibility to abacavir, emtricitabine, tenofovir and lamivudine. Tenofovir-resistant isolates of HIV-1 have also been recovered from some patients treated with tenofovir disoproxil in combination with other antiretroviral agents. In treatment-naïve patients treated with tenofovir disoproxil + lamivudine + efavirenz through 144 weeks, viral isolates from 8/47 (17%) patients with virologic failure showed reduced susceptibility to tenofovir. In treatment-naïve patients treated with emtricitabine + tenofovir disoproxil + efavirenz through 144 weeks, none of the HIV isolates from 19 patients analysed for resistance showed reduced susceptibility to tenofovir or the presence of the K65R mutation. In treatmentexperienced patients, 14/304 (4.6%) of the tenofovir disoproxil treated patients with virologic failure showed reduced susceptibility to tenofovir. Genotypic analysis of the resistant isolates showed the K65R mutation in the HIV-1 reverse transcriptase gene. Emtricitabine: Emtricitabine-resistant isolates of HIV have been selected in vitro. Genotypic analysis of these isolates showed that the reduced susceptibility to emtricitabine was associated with a mutation in the HIV reverse transcriptase gene at codon 184 which resulted in an amino acid substitution of methionine by valine or isoleucine (M184V/I). Emtricitabine-resistant isolates of HIV have been recovered from some patients treated with emtricitabine alone or in combination with other antiretroviral agents. In a clinical study, viral isolates from 37.5% of treatment-naïve patients with virologic failure showed reduced susceptibility to emtricitabine. Genotypic analysis of these isolates showed that the resistance was due to M184V/I mutations in the HIV reverse transcriptase gene. In a second study in treatment-naïve patients, genotyping of viral isolates from 2/12 (17%) patients showed development of the M184V/I mutation. iprex Trial: In a clinical study of HIV-1 seronegative subjects (see CLINICAL TRIALS), no amino acid substitutions associated with resistance to emtricitabine or tenofovir were detected at the time of seroconversion among 48 subjects in the tenofovir/emtricitabine 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 emtricitabine were observed in 3 of the 10 subjects (2 of 2 in the tenofovir/ emtricitabine group and 1 of 8 in the placebo group). One of the two subjects in the tenofovir/ emtricitabine 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 a clinical study of HIV-1 seronegative subjects (see CLINICAL TRIALS), no variants expressing amino acid substitutions associated with resistance to emtricitabine or tenofovir were detected at the time of seroconversion among 12 subjects in the tenofovir/emtricitabine group, 15 subjects in the tenofovir 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 tenofovir/emtricitabine group, 5 in the tenofovir group, and 6 in the placebo group). One of the three subjects in the tenofovir/emtricitabine 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 tenofovir group had tenofovirresistant 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 tenofovir group, 1 in the tenofovir/emtricitabine 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 tenofovir or emtricitabine and may have been present in the infecting virus.

5 Tenofovir Disoproxil Emtricitabine Mylan 300/200 PRODUCT INFORMATION 5 Cross-resistance Cross-resistance among certain reverse transcriptase inhibitors has been recognised. Tenofovir disoproxil: The K65R and K70E substitutions can also be selected by abacavir, or didanosine, and result in reduced susceptibility to, these agents plus abacavir, didanosine, emtricitabine, tenofovir and lamivudine. Patients with HIV-1 expressing three or more thymidine analogue associated mutations (TAMs) that included either the M41L or L210W reverse transcriptase mutation showed reduced susceptibility to tenofovir disoproxil fumarate. Multinucleoside resistant HIV-1 with a T69S double insertion mutation in the reverse transcriptase showed reduced susceptibility to tenofovir. Emtricitabine: Emtricitabine-resistant isolates (M184V/I) were cross-resistant to lamivudine and zalcitabine but retained sensitivity to abacavir, didanosine, d4t, tenofovir, zidovudine, and NNRTIs (delavirdine, efavirenz, and nevirapine). HIV-1 isolates containing the K65R mutation, selected in vivo by abacavir, didanosine, tenofovir, and zalcitabine, demonstrated reduced susceptibility to inhibition by emtricitabine. Viruses harbouring mutations conferring reduced susceptibility to d4t and zidovudine (M41L, D67N, K70R, L210W, T215Y/F, K219Q/E) or didanosine (L74V) remained sensitive to emtricitabine. HIV-1 containing the K103N mutation associated with resistance to NNRTIs was susceptible to emtricitabine. Pharmacokinetics Pharmacokinetics in Adults One tenofovir disoproxil (as fumarate) 300 mg plus emtricitabine200 mg fixed dose combination tablet was bioequivalent to one tenofovir disoproxil (as fumarate) tablet (300 mg) and one emtricitabine capsule (200 mg) following single-dose administration to fasting healthy subjects (N=39). Tenofovir disoproxil The pharmacokinetic properties of tenofovir disoproxil (as fumarate) are summarised in Table 1. Following oral administration of tenofovir disoproxil (as fumarate), 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 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 tenofovir disoproxil (as fumarate), the terminal elimination half-life of tenofovir is approximately 17 hours. Emtricitabine The pharmacokinetic properties of emtricitabine are summarised in Table 1. Following oral administration of emtricitabine, 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 μg/ml. Following administration of radiolabelled emtricitabine approximately 86% is recovered in the urine and 1 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 emtricitabine, the plasma emtricitabine half-life is approximately 10 hours.

6 Tenofovir Disoproxil Emtricitabine Mylan 300/200 PRODUCT INFORMATION 6 Table 1. Single Dose Pharmacokinetic Parameters for Tenofovir and Emtricitabine in Adults 1 Fasted Oral Bioavailability (%) Tenofovir Emtricitabine Plasma Terminal Elimination Half-Life (hr) Cmax (μg/ml) 0.30 ± ± AUC (μg*hr/ml) 2.29 ± ± CL/F (ml/min) 1043 ± ± 94 CLrenal (ml/min) 243 ± ± Data presented as mean values. 2. Data presented as steady state values. Effects of Food on Oral Absorption Administration of tenofovir disoproxil (as fumarate)/ emtricitabine fixed dose combination tablet following a high fat meal (~ kcal containing 40-60% fat) delayed the time of tenofovir C max by approximately 0.75 hour. An increase in tenofovir AUC of approximately 40% and an increase in C max of approximately 14% were observed. Similar findings were observed when tenofovir disoproxil (as fumarate)/ emtricitabine fixed dose combination tablet was administered with a light meal. Emtricitabine systemic exposures (AUC and C max) were unaffected when tenofovir disoproxil (as fumarate)/ emtricitabine fixed dose combination tablet was administered with either a high fat or a light meal. (See DOSAGE AND ADMINISTRATION). Age and gender Children and Geriatric Patients: Pharmacokinetics of tenofovir and emtricitabine have not been fully evaluated in children (<18 years) or in the elderly (>65 years) (see PRECAUTIONS, Paediatric Use, Geriatric Use). Gender: Tenofovir and emtricitabine pharmacokinetics are similar in male and female patients. Patients with Impaired Renal Function The pharmacokinetics of tenofovir and emtricitabine are altered in subjects with renal impairment (See PRECAUTIONS, Renal Impairment). In subjects with creatinine clearance <50 ml/min, or with end-stage renal disease (ESRD) requiring dialysis, C max, and AUC 0- of tenofovir and emtricitabine were increased. It is required that the dosing interval for Tenofovir Disoproxil Emtricitabine Mylan 300/200 be modified in HIV-1 infected patients with creatinine clearance <60 ml/min (see DOSAGE AND ADMINISTRATION). Tenofovir Disoproxil Emtricitabine Mylan 300/200 should not be used in patients with creatinine clearance <30 ml/min and in patients with end-stage renal disease requiring dialysis (See PRECAUTIONS, Renal Impairment). Tenofovir Disoproxil Emtricitabine Mylan 300/200 for a PrEP indication should not be used 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 Tenofovir Disoproxil Emtricitabine Mylan 300/200 for PrEP, evaluate potential causes and re-assess potential risks and benefits of continued use (see DOSAGE AND ADMINISTRATION). Patients with Hepatic Impairment Tenofovir disoproxil/emtricitabine combination tablet: The pharmacokinetics of tenofovir following a 300 mg dose of tenofovir disoproxil (as fumarate) 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 combination tenofovir disoproxil / emtricitabine or emtricitabine alone have not been studied in patients with hepatic impairment; however, emtricitabine is not significantly metabolised by liver enzymes, so the impact of liver impairment should be limited.

7 Tenofovir Disoproxil Emtricitabine Mylan 300/200 PRODUCT INFORMATION 7 Drug Interactions Tenofovir disoproxil/emtricitabine fixed dose combination tablet: The drug interactions described are based on studies conducted with tenofovir disoproxil (as fumarate) or emtricitabine as individual agents; no drug interaction studies have been conducted using tenofovir disoproxil/emtricitabine fixed dose combination tablets. Tenofovir disoproxil and emtricitabine: The steady state pharmacokinetics of tenofovir and emtricitabine were unaffected when tenofovir disoproxil (as fumarate) and emtricitabine were administered together versus each agent dosed alone. In vitro and clinical pharmacokinetic drug-drug interaction studies have shown the potential for CYP450 mediated interactions involving tenofovir disoproxil (as fumarate) and emtricitabine with other medicinal products is low. Tenofovir and emtricitabine 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 tenofovir disoproxil /emtricitabine fixed dose combination tablets with drugs that are eliminated by active tubular secretion may increase serum concentrations of tenofovir, emtricitabine, and/or the co-administered drug. Drugs that decrease renal function may increase serum concentrations of tenofovir and/or emtricitabine. No clinically significant drug interactions have been observed between tenofovir disoproxil (as fumarate) and abacavir, efavirenz, emtricitabine, indinavir, lamivudine, lopinavir/ritonavir, methadone, nelfinavir, saquinavir/ritonavir and oral contraceptives in studies conducted in healthy volunteers. In a study conducted in healthy volunteers dosed with a single 600 mg dose of ribavirin, no clinically significant drug interactions were observed between tenofovir disoproxil (as fumarate) and ribavirin. Similarly, no clinically significant drug interactions have been observed between emtricitabine and famciclovir, indinavir, d4t, zidovudine and tenofovir disoproxil (as fumarate). In drug interaction studies between regimens containing tenofovir disoproxil (as fumarate) and HARVONI (ledipasvir/sofosbuvir) and SOVALDI (sofosbuvir), increases in tenofovir exposure were observed (see PRECAUTIONS, Drug Interactions). When unboosted atazanavir (400 mg) was co-administered with tenofovir disoproxil (as fumarate), atazanavir increased tenofovir C max by 14% and AUC by 24%. Similarly, lopinavir (400 mg)/ritonavir (100 mg) increased tenofovir AUC by 32%. Co-administration of tenofovir disoproxil (as fumarate) with didanosine and atazanavir results in changes in the pharmacokinetics of didanosine and atazanavir that may be of clinical significance. Concomitant dosing of tenofovir disoproxil (as 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. Tenofovir decreases atazanavir concentration. Table 2 summarises the effects of tenofovir disoproxil (as fumarate) on the pharmacokinetics of didanosine and atazanavir.

8 Tenofovir Disoproxil Emtricitabine Mylan 300/200 PRODUCT INFORMATION 8 Table 2. Drug Interactions: Changes in Pharmacokinetic Parameters for Didanosine and Atazanavir in the Presence of tenofovir disoproxil. Coadministered Drug Dose of Coadministered Drug (mg) N % Change of Co-administered Drug Pharmacokinetic Parameters 1 (90% CI) Cmax AUC Cmin 400 once / with or without food % ( 25-89) 48-60% ( 31-79) NC Didanosine 3 enteric-coated capsules 250 once / Simultaneously with tenofovir DF, fasted (0 31) NC 250 once / Simultaneously with tenofovir DF, fed 2, ( 39-18) 11 ( 23-2) NC 400 once daily x 14 days ( 27 to 14) 25 ( 30 to 19) 40 ( 48 to 32) Atazanavir 5 Atazanavir/Ritonav ir 6 300/100 once daily x 42 days ( 50 to 5) 6 25 ( 42 to 3) 6 23 ( 46 to 10) 6 1. Increase = ; Decrease = ; No Effect = ; NC = Not Calculated 2. Administration with food was with a light meal (~373 kcal, 20% fat). 3. See PRECAUTIONS regarding use of didanosine with tenofovir disoproxil. 4. Relative to 400 mg alone, fasted. 5. REYATAZ Prescribing Information (Bristol-Myers Squibb) 6. In HIV-infected patients, addition of tenofovir disoproxil 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 (REYATAZ March 2004 United States Package Insert) CLINICAL TRIALS Clinical study 934, which demonstrated the safety and efficacy of emtricitabine and tenofovir disoproxil in combination with efavirenz in treatment-naïve adults, supports the use of emtricitabine and tenofovir disoproxil/emtricitabine fixed dose combination tablets for the treatment of HIV-1 infection. Additional supportive data are derived from study 903, in which lamivudine (3TC) and tenofovir were used in combination in treatment-naïve adults. In clinical study 303 emtricitabine and lamivudine demonstrated comparable efficacy, safety and resistance patterns as part of multidrug regimens. For additional information about these trials, please refer to the Product Information for VIREAD and EMTRIVA. The iprex study and Partners PrEP study support the use of tenofovir disoproxil/emtricitabine fixe dose combination tablets to help reduce the risk of acquiring HIV-1. Combination tenofovir disoproxil and emtricitabine tablets Study 934: Emtricitabine + Tenofovir disoproxil + Efavirenz Compared with COMBIVIR (lamivudine / zidovudine) + Efavirenz Study 934 is a randomised, open-label, active controlled multicentre study comparing two different dosing regimens in 511 antiretroviral-naïve HIV-1 infected patients. Patients were randomised to receive either tenofovir

9 Tenofovir Disoproxil Emtricitabine Mylan 300/200 PRODUCT INFORMATION 9 disoproxil tablet + emtricitabine tablet administered in combination with efavirenz or COMBIVIR (lamivudine/zidovudine) administered in combination with efavirenz. For patients randomised to receive tenofovir disoproxil tablet + emtricitabine tablet the two drugs were administered individually for the first 96 weeks and then switched to tenofovir disoproxil/ emtricitabine (fixed dose combination) during weeks 96 to 144, without regard to food. For inclusion in the study, antiretroviral treatment naïve adult patients ( 18 years) with plasma HIV RNA greater than 10,000 copies/ml, must have an estimated glomerular filtration rate as measured by Cockroft-Gault method of 50 ml/min, adequate haematologic function, hepatic transaminases and alanine aminotransferases 3 ULN, total bilirubin 1.5 mg/dl, serum amylase 1.5 ULN and serum phosphorus 2.2 mg/dl. Exclusion criteria included: a new AIDS defining condition diagnosed within 30 days (except on the basis of CD4 criteria), ongoing therapy with nephrotoxic drugs or agents that interacted with efavirenz, pregnancy/lactation, a history of clinically significant renal / bone disease or malignant disease other than Kaposi s sarcoma or basal-cell carcinoma, or a life expectancy of less than one year. If efavirenz associated central nervous system toxicities occurred, nevirapine could be substituted for efavirenz. Patients who were not receiving their originally assigned treatment regimen after week 48 or 96 and during the 30-day extension study window were not eligible to continue to weeks 96 or 144 respectively. Patients had a mean age of 38 years (range 18 to 80), 86% were male, 59% were Caucasian and 2 were Black. The mean baseline CD4 cell count was 245 cells/mm 3 (range 2 to 1191) and median baseline plasma HIV-1 RNA was 5.01 log 10 copies/ml (range 3.56 to 6.54). Patients were stratified by baseline CD4 count (< or 200 cells/mm 3 ); 41% had CD4 cell counts <200 cells/mm 3 and 51% of patients had baseline viral loads >100,000 copies/ml Treatment outcomes at 48 and 144 weeks for those patients who did not have efavirenz resistance at baseline are presented in Table 3. Table 3. Outcomes of Randomised Treatment at Weeks 48 and 144 (Study 934) in Treatment Naïve Patients WEEK 48 WEEK 144 Outcome at Weeks 48 and 144 Tenofovir disoproxil + emtricitabine administered individually+ EFV (N=244) COMBIVIR + EFV (N=243) Tenofovir disoproxil + emtricitabine (fixed dose combination) 4 + EFV (N=227) COMBIVIR + EFV (N=229) Responder 1 84% 7 71% 58% Virologic failure 2 Rebound Never suppressed Change in antiretroviral regimen 2 % 1 % 0 % 1 % 4% 6% 2% 5% 0% 0% 0% 1% 1% 1% Death 3 <1% 1% 1% 1% 1. Patients achieved and maintained confirmed HIV-1 RNA <400 copies/ml. 2. Includes confirmed viral rebound and failure to achieve confirmed <400 copies/ml. 3. All deaths were unrelated to study drugs 4. Patients received tenofovir disoproxil + emtricitabine administered individually up to week 96 and switched to tenofovir disoproxil + emtricitabine fixed dose combination tablet from week 96 to 144. In this study, tenofovir disoproxil tablet + emtricitabine tablet in combination with efavirenz was statistically significantly superior to lamivudine/zidovudine in combination with efavirenz with regards to the primary and

10 Tenofovir Disoproxil Emtricitabine Mylan 300/200 PRODUCT INFORMATION 10 secondary endpoints: achieving and maintaining HIV-1 RNA < 400 copies/ml through 48 and 144 weeks (Table 3). The difference in the proportions of responders between the tenofovir disoproxil tablet + emtricitabine tablet group and the COMBIVIR group was 11.4%, and the 95% CI was 4. to 18.6% (p=0.002) at week 48 and a difference of 12.9% (95% CI was 4.2% to 21.6%, p=0.004) at week 144. Through 48 weeks of therapy, 80% and 70% of patients in the tenofovir disoproxil tablet + emtricitabine tablet and the lamivudine/zidovudine arms, respectively, achieved and maintained HIV-1 RNA <50 copies/ml. The difference in the proportions of responders between tenofovir disoproxil tablet + emtricitabine tablet group and the COMBIVIR group was 9.1%, and the 95% CI was 1.6% to 16.6% (p=0.021) at week 48. The proportion of patients responding at 144 weeks of therapy was higher in the fixed dose combination tenofovir disoproxil/ emtricitabine group (64%) compared with the COMBIVIR group (56%); p=0.082, a difference of 8.1% and the 95% CI was -0.8% to 17.0%. The mean increase from baseline in CD4 cell count was 190 cells/mm 3 and 312 cells/mm 3 for the tenofovir disoproxil tablet + emtricitabine tablet + efavirenz arm, and 158 cells/mm 3 and 271 cells/mm 3 for the COMBIVIR + efavirenz arm (p=0.002 and p = 0.088) at weeks 48 and 144 respectively. Resistance analysis was performed on HIV isolates from all patients with > 400 copies/ml of HIV-1 RNA at week 144 while on study drug or after treatment switch. Genotypic resistance to efavirenz, predominantly the K103N mutation, was the most common form of resistance that developed in both treatment groups. Resistance to efavirenz occurred in 68% (13/19) analysed patients in the fixed dose combination tenofovir disoproxil/emtricitabine group and in 72% (21/29) analysed patients in the COMBIVIR group. The M184V mutation, associated with resistance to emtricitabine and lamivudine developed significantly less in the analysed patients in the fixed dose combination tenofovir disoproxil/emtricitabine group 11% (2/19) compared with the analysed patients in the COMBIVIR group, 34% (10/29). Two patients in the COMBIVIR group developed thymidine analog mutations, specifically D67N or K70R mutations in the reverse transcriptase gene. No patient in either treatment group developed the K65R mutation, which is associated with reduced susceptibility to tenofovir disoproxil. iprex Trial The iprex trial was a randomised double-blind placebo-controlled multinational study evaluating tenofovir disoproxil /emtricitabine fixed dose combination tablet in 2499 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 counselling, condoms and management of sexually transmitted infections. Of the 2499 enrolled, 1251 received tenofovir disoproxil/emtricitabine combination tablet and 1248 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 4237 person-years. The primary outcome measure for the study 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 tenofovir disoproxil/emtricitabine combination tablet group and 83 occurred in the placebo group, indicating a 42% (95% CI: 18% to 60%) reduction in risk. In a post-hoc case control study of plasma and intracellular drug levels in about 10% of study subjects, risk reduction appeared to be the greatest in subjects with detectable intracellular tenofovir. Efficacy was therefore strongly correlated with adherence. Partners PrEP Trial The Partners PrEP trial was a randomised, double-blind, placebo-controlled 3 arm trial conducted in 4758 serodiscordant heterosexual couples in Kenya and Uganda to evaluate the efficacy and safety of tenofovir disoproxil fumarate (TDF) (N=1589) and FTC/TDF (N=1583) versus (parallel comparison) placebo (N=1586),

11 Tenofovir Disoproxil Emtricitabine Mylan 300/200 PRODUCT INFORMATION 11 in preventing HIV-1 acquisition by the uninfected partner. All 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 years. Following 7827 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 randomised to tenofovir disoproxil/emtricitabine combination tablet and placebo, respectively. Two of the 13 seroconversions in the tenofovir disoproxil /emtricitabine combination tablet arm and 3 of the 52 seroconversions in the placebo arm occurred in women during treatment interruptions for pregnancy. The risk reduction for tenofovir disoproxil /emtricitabine combination tablet relative to placebo was 75% (95% CI: 55% to 87%). In a post-hoc case control study of plasma drug levels in about 10% of study subjects, risk reduction appeared to be the greatest in subjects with detectable plasma tenofovir. Efficacy was therefore strongly correlated with adherence. Tenofovir The demonstration of benefit of tenofovir is based on analyses of plasma HIV-1 RNA levels and CD4 cell counts in controlled studies of tenofovir in treatment-naïve adults and in treatment experienced adults. Treatment-Experienced Patients Study 907: Tenofovir + Standard Background Therapy (SBT) Compared With Placebo + SBT Study 907 was a 24 week, double-blind placebo-controlled multicentre study of tenofovir disoproxil tablet added to a stable background regimen of antiretroviral agents in 550 treatment-experienced patients. After 24 weeks of blinded study treatment, all patients continuing on study were offered open label tenofovir disoproxil for an additional 24 weeks. Patients had a mean baseline CD4 cell count of 427 cells/mm 3 (range ), median baseline plasma HIV RNA of 2340 (range 50 75,000) copies/ml, and mean duration of prior HIV treatment was 5.4 years. Mean age of the patients was 42 years, 85% were male and 69% were Caucasian, 17% Black and 12% Hispanic. Changes from baseline in log 10 copies/ml plasma HIV-1 RNA levels over time up to week 48 are presented in Figure 1. Figure 1 Mean Change from Baseline in Plasma HIV-1 RNA (Log 10 Copies/mL) Through Week 48: Study 907 (All Available Data) Tenofovir disoproxil (as fumarate) 300 mg Tenofovir disoproxil fumarate (N=) Placebo (N=) Placebo -> Tenofovir disoproxil fumarate (N=)

12 Tenofovir Disoproxil Emtricitabine Mylan 300/200 PRODUCT INFORMATION 12 Patients on placebo after 24 weeks received tenofovir disoproxil fumarate The percent of patients with HIV RNA <400 copies/ml and outcomes of patients through 48 weeks are summarised in Table 4. Table 4. Outcomes of Randomised Treatment (Study 907) Outcomes 0-24 weeks 0-48 weeks weeks HIV RNA <400 copies/ml 1 TENOFOVIR DISOPROXIL (N=368) % (95% CI) 40% 4 (35% to 45%) Placebo (N=182) % (95% CI) 11% 4 (6% to 16%) TENOFOVIR DISOPROXIL (N=368) % Placebo Crossover to TENOFOVIR DISOPROXIL (N=170) % 28% 30% Virologic failure % 61% 64% Discontinued due to adverse event 5% 5% Discontinued for other reasons 3 5% 1% 1. Patients with HIV RNA < 400 copies/ml and no prior study drug discontinuation at Week 24 and 48 respectively 2. Patients with HIV RNA 400 copies/ml efficacy failure or missing HIV 1 RNA at Week 24 and 48 respectively 3. Includes lost to follow up, patient withdrawal, non-compliance, protocol violation and other reasons. 4. Difference 29% p < At 24 weeks of therapy, there was a higher proportion of patients in the tenofovir disoproxil arm compared to the placebo arm with HIV RNA <50 copies/ml (19% and 1%, respectively). Mean change in absolute CD4 counts by week 24 was +12 cells/mm 3 for the tenofovir group and -5 cells/mm 3 for the placebo group. Mean change in absolute CD4 counts by week 48 was +4 cells/mm 3 for the tenofovir disoproxil group. Treatment-Naïve Patients Study 903: Tenofovir disoproxil+ Lamivudine +Efavirenz Compared to Stavudine + Lamivudine + Efavirenz Data through 144 weeks are reported for Study 903, a double-blind, active-controlled multicentre study comparing tenofovir disoproxil (as fumarate) (300 mg once daily) administered in combination with lamivudine and efavirenz versus d4t, lamivudine, and efavirenz in 600 antiretroviral-naïve patients. Patients had a mean age of 36 years (range 18 64), 74% were male, 64% were Caucasian and 20% were Black. The mean baseline CD4 cell count was 279 cells/mm 3 (range 3 956) and median baseline plasma HIV-1 RNA was 77,600 copies/ml (range 417 5,130,000). Patients were stratified by baseline HIV-1 RNA and CD4 count. Forty-three percent of patients had baseline viral loads >100,000 copies/ml and 39% had CD4 cell counts <200 cells/mm 3. Treatment outcomes through 144 weeks are presented in Table 5. Table 5. Outcomes of Randomised Treatment (Study 903) Outcomes At week 48 At week 144 Tenofovir disoproxil + 3TC+EFV (N=299) d4t +3TC+EFV (N=301) Tenofovir disoproxil + 3TC+EFV (N=299) d4t +3TC+EFV (N=301) % % % % Responder Virologic failure

13 Tenofovir Disoproxil Emtricitabine Mylan 300/200 PRODUCT INFORMATION 13 Rebound Never suppressed Added an antiretroviral agent Death <1 1 <1 2 Discontinued due to an adverse event Discontinued for other reasons Patients achieved and maintained confirmed HIV-1 RNA <400 copies/ml through Week 48 and Includes confirmed viral rebound and failure to achieve confirmed <400 copies/ml through Week 48 and Includes lost to follow-up, patient s withdrawal, non-compliance, protocol violation and other reasons. 4. Difference -3.0% (-9.2% to 3.1%) p=0.48. The difference and confidence interval are stratum weighted on baseline HIV- 1 RNA and CD4. 5. Difference 6.1% (-1.4% to 13.7%) p=0.11. The difference and confidence interval are stratum weighted on baseline HIV-1 RNA and CD4. Achievement of plasma HIV-1 RNA concentrations of less than 400 copies/ml at week 144 was similar between the two treatment groups for the population stratified at baseline on the basis of HIV-1 RNA concentration ( or >100,000 copies/ml) and CD4 cell count (< or 200 cells/mm 3 ). Through 144 weeks of therapy, 62% and 58% of patients in the tenofovir disoproxil and d4t arms, respectively achieved and maintained confirmed HIV-1 RNA <50 copies/ml. The mean increase from baseline in CD4 cell count was 263 cells/mm 3 for the tenofovir disoproxil arm and 283 cells/mm 3 for the d4t arm. The proportion of patients who achieved and maintained confirmed HIV RNA <400 using intent-to-treat analysis through 144 weeks of treatment in study 903 is presented in Figure 2 below. Genotypic analyses of patients with virologic failure showed development of efavirenz associated and lamivudine-associated mutations to occur most frequently and with no difference between the treatment arms. The K65R mutation occurred in 8 patients on the tenofovir disoproxil arm and in 2 patients on the d4t arm. Of the 8 patients who developed K65R in the tenofovir disoproxil arm through 144 weeks, 7 of these occurred in the first 48 weeks of treatment and the last one at week 96. Among these patients, 5/8 patients subsequently gained full virologic control (<50 copies/ml) upon switching to new regimens that included a protease inhibitor in combination with nucleoside reverse transcriptase inhibitors through a median of 155 weeks of follow-up. From both genotypic and phenotypic analyses there was no evidence for other pathways of resistance to tenofovir. Figure 2: Virologic Response Through W eek 144, Study 903*ǂ 100 Proportion of Patients with HIV-1 RNA <400 copies/ml Tenofovir disoproxil + Lamivudine + Efavirenz (n=299) Stavudine + Lamivudine + Efavirenz (n=301) 0 BL Study Week

14 Tenofovir Disoproxil Emtricitabine Mylan 300/200 PRODUCT INFORMATION 14 * Roche Amplicor HIV-1 Monitor Test. ǂ Responders at each visit are patients who had achieved and maintained HIV-1 RNA<400 copies/ml without discontinuation by that visit. Genotypic Analyses of Tenofovir disoproxil in Patients with Previous Antiretroviral Therapy (Study 902 and 907) The virologic response to tenofovir disoproxil therapy has been evaluated with respect to baseline viral genotype (N=222) in treatment experienced patients participating in trials 902 and 907. In both of these studies, 94% of the participants evaluated had baseline HIV isolates expressing at least one NRTI mutation. These included resistance mutations associated with zidovudine (M41L, D67N, K70R, L210W, T215Y/F or K219Q/E/N), the lamivudine/abacavir-associated mutation (M184V), and others. In addition the majority of participants evaluated had mutations associated with either PI or NNRTI use. Virologic responses for patients in the genotype substudy were similar to the overall results in studies 902 and 907. Several exploratory analyses were conducted to evaluate the effect of specific mutations and mutational patterns on virologic outcome. Descriptions of numerical differences in HIV RNA response are displayed in Table 6. Because of the large number of potential comparisons, statistical testing was not conducted. Varying degrees of cross-resistance to tenofovir disoproxil from pre-existing zidovudine-associated mutations were observed and appeared to depend on the number and type of mutations. Tenofovir disoproxil-treated patients whose HIV expressed 3 or more zidovudine-associated mutations that included either the M41L or L210W reverse transcriptase mutation showed reduced responses to tenofovir disoproxil therapy; however, these responses were still improved compared with placebo. The presence of the D67N, K70R, T215Y/F or K219Q/E/N mutation did not appear to affect responses to tenofovir disoproxil therapy. The HIV RNA responses by number and type of baseline zidovudine-associated mutations are shown in Table 6. Table 6. HIV RNA Response at Week 24 by Number of Baseline Zidovudine-Associated Mutations in Studies 902 and 907 (Intent-To-Treat) 1 Number of baseline zidovudineassociated mutations 2 Tenofovir disoproxil Change in HIV RNA 3 (N) Placebo None (68) (29) Any (154) 0 (81) (55) (33) 3 Including M41L or L210W (57) (29) 3 without M41L or L210W (42) (19) 1. Genotypic testing performed by Virco Laboratories and Visible Genetics TruGene TM Technology 2. M41L, D67N, K70R, L210W, T215Y/F or K219Q/E/N in RT 3. Average HIV RNA change from baseline through week 24 (DAVG24) in log 10 copies/ml In the protocol defined analyses, virologic response to tenofovir disoproxil was not reduced in patients with HIV that expressed the lamivudine/ abacavir-associated M184V mutation. In the absence of zidovudine-associated mutations, patients with the M184V mutation receiving tenofovir disoproxil showed a log 10 copies/ml decrease in their HIV RNA relative to placebo. In the presence of zidovudine-associated mutations, the M184V mutation did not affect the mean HIV RNA responses to tenofovir disoproxil treatment. HIV-1 RNA responses among these patients were durable through week 48. There were limited data on patients expressing some primary nucleoside reverse transcriptase inhibitor mutations and multi-drug resistant mutations at baseline. However, patients expressing mutations at K65R (N=6), or L74V without zidovudine-associated mutations (N=6) appeared to have reduced virologic responses to tenofovir disoproxil.

15 Tenofovir Disoproxil Emtricitabine Mylan 300/200 PRODUCT INFORMATION 15 The presence of at least one HIV protease inhibitor or non-nucleoside reverse transcriptase inhibitor mutation at baseline did not appear to affect the virologic response to tenofovir disoproxil. Cross resistance between tenofovir disoproxil and HIV protease inhibitors is unlikely because of the different enzyme targets involved. Phenotypic Analyses of Tenofovir in Patients with Previous Antiretroviral Therapy (Study 902 and 907) The virologic response to tenofovir disoproxil therapy has been evaluated with respect to baseline phenotype (N=100) in treatment experienced patients participating in trials 902 and 907. Phenotypic analysis of baseline HIV from patients in Studies 902 and 907 demonstrated a correlation between baseline susceptibility to tenofovir and response to tenofovir disoproxil therapy. Table 7 summarises the HIV RNA response by baseline tenofovir susceptibility. Table 7. HIV RNA Response at Week 24 by Baseline Tenofovir Susceptibility in Studies 902 and 907 (Intent-To-Treat) 1 Baseline Tenofovir disoproxil Susceptibility 2 Change in HIV RNA 3 (N) < (35) > 1 and < (49) > 3 and < (7) < (91) > (9) 1. Tenofovir susceptibility was determined by recombinant phenotypic Antivirogram TM assay (Virco) 2. Fold change in susceptibility from wild-type 3. Average HIV RNA change from baseline through week 24 (DAVG 24 ) in log 10 copies/ml Emtricitabine Treatment-Experienced Patients Study 303: Emtricitabine once daily + Stable Background Therapy (SBT) Compared to Lamivudine twice daily + SBT Study 303 was a 48 week, open-label, active-controlled multicentre study comparing emtricitabine (200 mg once daily) to lamivudine, in combination with d4t or zidovudine and a protease inhibitor or NNRTI in 440 patients who were on a lamivudine-containing triple antiretroviral drug regimen for at least 12 weeks prior to study entry and had HIV RNA 400 copies/ml. Patients were randomised 1:2 to continue therapy with lamivudine (150 mg twice daily) or to switch to emtricitabine (200 mg once daily). All patients were maintained on their stable background regimen. Patients had a mean age of 42 years (range 22-80), 86% were male, 64% Caucasian, 21% African-American and 1 Hispanic. Patients had a mean baseline CD4 cell count of 527 cells/mm 3 (range ), and a median baseline plasma HIV RNA of 1.7 log 10 copies/ml (range ). The median duration of prior antiretroviral therapy was 27.6 months. Treatment outcomes through 48 weeks are presented in Table 8. Table 8. Outcomes of randomised treatment at week 48 (Study 303) Outcome at Week 48 Emtricitabine + ZDV/d4T + NNRTI/PI (N=294) Lamivudine + ZDV/d4T + NNRTI/PI (N=146) Responder 1 77% (67%) 82% (72%) Virologic Failure 2 7% 8% Death 0% <1%

16 Tenofovir Disoproxil Emtricitabine Mylan 300/200 PRODUCT INFORMATION 16 Study Discontinuation Due to Adverse Event 4% 0% Study Discontinuation For Other Reasons 3 12% 10% 1. Patients achieved and maintained confirmed HIV RNA <400 copies/ml (<50 ml) through week Includes patients who failed to achieve virologic suppression or rebounded after achieving virologic suppression. 3. Includes lost to follow-up, patient withdrawal, non-compliance, protocol violation and other reasons. The mean increase from baseline in CD4 cell count was 29 cells/mm 3 for the emtricitabine arm and 61 cells/mm 3 for the lamivudine arm. Treatment- Naïve Patients Study 301A: Emtricitabine once daily + Didanosine once daily + Efavirenz once daily Compared to Stavudine twice daily + Didanosine once daily + Efavirenz once daily Study 301A was a 48 week double-blind, active-controlled multicentre study comparing emtricitabine (200 mg once daily) administered in combination with didanosine and efavirenz versus d4t, didanosine and efavirenz in 571 antiretroviral naïve patients. Patients had a mean age of 36 years (range 18-69), 85% were male, 52% Caucasian, 16% African-American and 26% Hispanic. Patients had a mean baseline CD4 cell count of 318 cells/mm 3 (range ) and a median baseline plasma HIV RNA of 4.9 log 10 copies/ml (range ). Thirtyeight percent of patients had baseline viral loads >100,000 copies/ml and 31% had CD4 cell counts <200 cells/ml. Treatment outcomes through 48 weeks are presented in Table 9. Table 9. Outcomes of randomised treatment at week 48 (Study 301A) Outcome at Week 48 Emtricitabine + Didanosine + Efavirenz (N=286) d4t + Didanosine + Efavirenz (N=285) Responder 1 81% (78%) 68% (59%) Virologic Failure 2 11% Death 0% <1% Study Discontinuation Due to Adverse Event 7% 1 Study Discontinuation For Other Reasons 3 9% 8% 1. Patients achieved and maintained confirmed HIV RNA <400 copies/ml (<50 copies/ml) through week Includes patients who failed to achieve virologic suppression or rebounded after achieving virologic suppression 3. Includes lost to follow-up, patient withdrawal, non-compliance, protocol violation and other reasons. The mean increase from baseline in CD4 cell count was 168 cells/mm 3 for the emtricitabine arm and 134 cells/mm 3 for the d4t arm. INDICATIONS Treatment of HIV-1 infection Tenofovir Disoproxil Emtricitabine Mylan 300/200 is indicated for the treatment of HIV infected adults over the age of 18 years, in combination with other antiretroviral agents. Pre-Exposure Prophylaxis Tenofovir Disoproxil Emtricitabine Mylan 300/200 is indicated in combination with safer sex practices for preexposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 in adults at high risk. This indication is based on clinical trials in men who have sex with men (MSM) at high risk for HIV-1 infection and in heterosexual serodiscordant couples (see CLINICAL STUDIES).