CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1Mechanism of Action. COMPLERA is fixed-dose combination of the antiretroviral drugs FTC, RPV, and TDF [see Microbiology (12.4)]. 12.2 Pharmacodynamics. Effects on ElectrocardiogramThe effect of RPV at the recommended dose of 25 mg once daily on the QTcF interval was evaluated in randomized, placebo-, and active- (moxifloxacin 400 mg once daily) controlled crossover study in 60 healthy adults, with 13 measurements over 24 hours at steady state. The maximum mean time-matched (95% upper confidence bound) differences in QTcF interval from placebo after baseline correction was 2.0 (5.0) milliseconds (i.e., below the threshold of clinical concern).When doses of 75 mg once daily and 300 mg once daily of RPV (3 times and 12 times the dose in COMPLERA) were studied in healthy adults, the maximum mean time-matched (95% upper confidence bound) differences in QTcF interval from placebo after baseline correction were 10.7 (15.3) and 23.3 (28.4) milliseconds, respectively. Steady-state administration of RPV 75 mg once daily and 300 mg once daily resulted in mean steady-state Cmax approximately 2.6-fold and 6.7-fold, respectively, higher than the mean Cmax observed with the recommended 25 mg once daily dose of RPV [see Warnings and Precautions (5.7)].. 12.3 Pharmacokinetics. COMPLERA: Under fed conditions (total calorie content of the meal was approximately 400 kcal with approximately 13 grams of fat), RPV, FTC, and tenofovir exposures were similar when comparing COMPLERA to EMTRIVA capsules (200 mg) plus Edurant tablets (25 mg) plus VIREAD tablets (300 mg) following single-dose administration to healthy subjects (N=34).Single-dose administration of COMPLERA tablets to healthy subjects under fasted conditions provided approximately 25% higher exposure of RPV compared to administration of EMTRIVA capsules (200 mg) plus Edurant tablets (25 mg) plus VIREAD tablets (300 mg), while exposures of FTC and tenofovir were comparable (N=15).. Absorption, Distribution, Metabolism, and ExcretionThe pharmacokinetic properties of the components of COMPLERA are provided in Table 5. The PK parameters of RPV, FTC, and tenofovir are provided in Table 6.Table 5Pharmacokinetic Properties of the Components of COMPLERARPVFTCTenofovirNC=Not CalculatedAbsorption Tmax (h)4-51-21 Fasted oral bioavailabilityMedian NC9325Oral bioavailability of tenofovir from VIREAD. Effect of light meal (relative to fasting)Values refer to change based on calculated geometric mean ratio [fed/fasted] in AUC.COMPLERA light meal 390 kcal, 12 fat; COMPLERA standard meal 540 kcal, 21 fat. High fat meal not evaluated. Increase ; Decrease ; No Effect= <-> 9%<->28% Effect of standard meal (relative to fasting) 16%<->38%Distribution Bound to human plasma proteins~99<4<0.7 Source of protein binding dataIn vitroIn vitroIn vitroMetabolism MetabolismCYP3ANot significantly metabolizedElimination Major route of eliminationMetabolismGlomerular filtration and active tubular secretion CLrenal Mean +- SD (mL/min)NC213+-89243+-33 t1/2 (h)t1/2 values refer to median terminal plasma half-life. 501017 Of dose excreted in urineDosing in mass balance studies: FTC (single dose administration of [14C] FTC after multiple dosing of FTC for 10 days); RPV (single dose administration of [14C] RPV); mass balance study not conducted for tenofovir. 68670-80 Of dose excreted in feces 85~14NCTable 6Pharmacokinetic Parameters for RPV, FTC, and Tenofovir in HIV-Infected AdultsParameterMean +- SDRPVPopulation PK estimates of RPV 25 mg once daily in antiretroviral treatment-naive HIV-1-infected adult subjects (pooled data from Phase trials through Week 96; n=679) FTCMultiple-dose oral administration of FTC 200 mg to HIV-1-infected subjects (n=20) TenofovirSingle 300 mg dose of TDF to HIV-1-infected subjects in the fasted state NA=Not Applicable; SD=Standard DeviationCmax (ug/mL)NA1.80+-0.72Data presented as steady state values 0.30+-0.09AUCtau (ughr/mL)2.24+-0.85 10.0+-3.12 2.29+-0.69AUC0-24h C0h (ug/mL)0.08+-0.04 0.09+-0.07 NA. Specific Populations. Geriatric PatientsThe pharmacokinetics of FTC, RPV, and tenofovir have not been fully evaluated in the elderly (65 years of age and older) [see Use in Specific Populations (8.5)]. Pediatric PatientsPediatric trials have not been conducted using COMPLERA tablets. Pediatric information is based on trials conducted with the individual components of COMPLERA [see Use in Specific Populations (8.4)].. Emtricitabine: The pharmacokinetics of FTC at steady state were determined in 27 HIV-1-infected pediatric subjects 13 to 17 years of age receiving daily dose of mg/kg up to maximum dose of 240 mg oral solution or 200 mg capsule; 26 of 27 subjects in this age group received the 200 mg FTC capsule. Mean (+- SD) Cmax and AUC were 2.7 +- 0.9 ug/mL and 12.6 +- 5.4 ughr/mL, respectively. Exposures achieved in pediatric subjects 12 to less than 18 years of age were similar to those achieved in adults receiving once daily dose of 200 mg.. Rilpivirine: The pharmacokinetics of RPV in antiretroviral treatment-naive HIV-1- infected pediatric subjects 12 to less than 18 years of age receiving RPV 25 mg once daily were comparable to those in treatment-naive HIV-1-infected adults receiving RPV 25 mg once daily (See Table 7). There was no clinically significant impact of body weight on RPV pharmacokinetics in pediatric subjects in trial C213 (33 to 93 kg).Table 7Population Pharmacokinetic Estimates of RPV 25 mg once daily in Antiretroviral Treatment-Naive HIV-1-Infected Pediatric Subjects aged 12 to less than 18 years (Data from Phase Trial through Week 48)ParameterRPV 25 mg once dailyN=34AUC24h (ngh/mL) Mean +- Standard Deviation2424 +- 1024 Median (Range)2269 (417-5166)C0h (ng/mL) Mean +- Standard Deviation85 +- 40 Median (Range)79 (7-202). Tenofovir DF: Steady-state pharmacokinetics of tenofovir were evaluated in HIV-1-infected pediatric subjects (12 to less than 18 years). Mean (+- SD) Cmax and AUCtau are 0.38 +- 0.13 ug/mL and 3.39 +- 1.22 ughr/mL, respectively. Tenofovir exposure achieved in these pediatric subjects receiving oral daily doses of TDF 300 mg was similar to exposures achieved in adults receiving once-daily doses of TDF 300 mg.. GenderNo clinically relevant pharmacokinetic differences have been observed based on gender for FTC, RPV, and TDF.. Race. Emtricitabine: No pharmacokinetic differences due to race have been identified following the administration of FTC.. Rilpivirine: Population pharmacokinetic analysis of RPV in HIV-1-infected subjects indicated that race had no clinically relevant effect on the exposure to RPV.. Tenofovir DF: There were insufficient numbers from racial and ethnic groups other than Caucasian to adequately determine potential pharmacokinetic differences among these populations following the administration of TDF.. Patients with Renal Impairment. Emtricitabine and Tenofovir DF: The pharmacokinetics of FTC and TDF are altered in subjects with renal impairment. In subjects with creatinine clearance below 50 mL per minute or with end stage renal disease requiring dialysis, Cmax and AUC of FTC and tenofovir were increased [see Warnings and Precautions (5.5) and Use in Specific Populations (8.6)].. Rilpivirine: Population pharmacokinetic analysis indicated that RPV exposure was similar in HIV-1-infected subjects with mild renal impairment relative to HIV-1-infected subjects with normal renal function. There is limited or no information regarding the pharmacokinetics of RPV in patients with moderate or severe renal impairment or in patients with end-stage renal disease, and RPV concentrations may be increased due to alteration of drug absorption, distribution, and metabolism secondary to renal dysfunction [see Use in Specific Populations (8.6)].. Patients with Hepatic Impairment. Emtricitabine: The pharmacokinetics of FTC have not been studied in subjects with hepatic impairment; however, FTC is not significantly metabolized by liver enzymes, so the impact of liver impairment should be limited.. Rilpivirine: RPV is primarily metabolized and eliminated by the liver. In study comparing subjects with mild hepatic impairment (Child-Pugh score A) to matched controls, and subjects with moderate hepatic impairment (Child-Pugh score B) to matched controls, the multiple dose exposure of RPV was 47% higher in subjects with mild hepatic impairment and 5% higher in subjects with moderate hepatic impairment. RPV has not been studied in subjects with severe hepatic impairment (Child-Pugh score C) [see Use in Specific Populations (8.7)]. Tenofovir DF: The pharmacokinetics of tenofovir following 300 mg dose of TDF have been studied in non-HIV-infected subjects with moderate to severe hepatic impairment. There were no substantial alterations in tenofovir pharmacokinetics in subjects with hepatic impairment compared with unimpaired subjects.. Hepatitis and/or Hepatitis Virus CoinfectionThe pharmacokinetics of FTC and TDF have not been fully evaluated in hepatitis and/or virus-coinfected patients. Population pharmacokinetic analysis indicated that hepatitis and/or virus coinfection had no clinically relevant effect on the exposure to RPV.. Pregnancy and PostpartumThe exposure (C0h and AUC24h) to total RPV after intake of RPV 25 mg once daily as part of an antiretroviral regimen was 30 to 40% lower during pregnancy (similar for the second and third trimester), compared with postpartum (see Table 8). However, the exposure during pregnancy was not significantly different from exposures obtained in Phase trials of RPV-containing regimens. Based on the exposure-response relationship for RPV, this decrease is not considered clinically relevant in patients who are virologically suppressed. The protein binding of RPV was similar (>99%) during the second trimester, third trimester, and postpartum.Table 8: Pharmacokinetic Results of Total RPV After Administration of RPV 25 mg Once Daily as Part of an Antiretroviral Regimen, During the 2nd Trimester of Pregnancy, the 3rd Trimester of Pregnancy and PostpartumPharmacokinetics of total RPV(mean +-SD, tmax: median [range])Postpartum(6-12 Weeks)(n=11)2nd Trimester of pregnancy(n=15)3rd Trimester of pregnancy(n=13)C0h, ng/mL111 +- 69.265.0 +- 23.963.5 +- 26.2Cmin, ng/mL84.0 +- 58.854.3 +- 25.852.9 +- 24.4Cmax, ng/mL167 +- 101121 +- 45.9123 +- 47.5tmax, h4.00 (2.03-25.08)4.00 (1.00-9.00)4.00 (2.00-24.93)AUC24h, ngh/mL2,714 +- 1,5351,792 +- 7111,762 +- 662. Drug Interaction Studies. Rilpivirine: RPV is primarily metabolized by cytochrome CYP3A, and drugs that induce or inhibit CYP3A may thus affect the clearance of RPV. Coadministration of COMPLERA and drugs that induce CYP3A may result in decreased plasma concentrations of RPV and loss of virologic response and possible resistance. Coadministration of COMPLERA and drugs that inhibit CYP3A may result in increased plasma concentrations of RPV. Coadministration of COMPLERA with drugs that increase gastric pH may result in decreased plasma concentrations of RPV and loss of virologic response and possible resistance to RPV and to the class of NNRTIs.RPV at dose of 25 mg once daily is not likely to have clinically relevant effect on the exposure of medicinal products metabolized by CYP enzymes.. Emtricitabine and Tenofovir DF: In vitro and clinical pharmacokinetic drug-drug interaction studies have shown that the potential for CYP-mediated interactions involving FTC and tenofovir with other medicinal products is low.FTC and tenofovir are primarily excreted by the kidneys by combination of glomerular filtration and active tubular secretion. No drug-drug interactions due to competition for renal excretion have been observed; however, coadministration of FTC and TDF with drugs that are eliminated by active tubular secretion may increase concentrations of FTC, tenofovir, and/or the coadministered drug [see Drug Interactions (7.4, 7.6)].Drugs that decrease renal function may increase concentrations of FTC and/or tenofovir.The drug interaction studies described in Tables 9-14 were conducted with COMPLERA (RPV/FTC/TDF) or the components of COMPLERA (RPV, FTC, or TDF) administered individually.The effects of coadministration of other drugs on the AUC, Cmax, and Cmin values of RPV, FTC, and TDF are summarized in Tables 9, 10, and 11, respectively. The effect of coadministration of RPV, FTC, and TDF on the AUC, Cmax, and Cmin values of other drugs are summarized in Tables 12, 13, and 14, respectively. For information regarding clinical recommendations, see Drug Interactions (7).Table 9Drug Interactions: Changes in Pharmacokinetic Parameters for RPV in the Presence of the Coadministered DrugsCoadministered DrugDose of Coadministered Drug (mg)RPV Dose (mg)NN=maximum number of subjects for Cmax, AUC, or Cmin Mean Change of RPV Pharmacokinetic ParametersIncrease ; Decrease ; No Effect <-> (90% CI)Cmax AUCCmin NA=not availableAcetaminophen500 single dose150 once dailyThe interaction study has been performed with dose higher than the recommended dose for RPV (25 mg once daily) assessing the maximal effect on the coadministered drug. 169(1 to 18)16(10 to 22)26(16 to 38)Atorvastatin40 once daily150 once daily 169(21 to 6)10(19 to 1)10(16 to 4)Chlorzoxazone500 single dose taken hours after RPV150 once daily 1617(8 to 27)25(16 to 35)18(9 to 28)Ethinyl Estradiol/Norethindrone0.035 once daily/1 once daily25 once daily16<->Study conducted with COMPLERA (RPV/FTC/TDF) coadministered with HARVONI (ledipasvir/sofosbuvir). <-> <-> Famotidine40 single dose taken 12 hours before RPV150 single dose 241(16 to 16)9(22 to 7)NA40 single dose taken hours before RPV150 single dose 2385(88 to 81)76(80 to 72)NA40 single dose taken hours after RPV150 single dose 2421(6 to 39)13(1 to 27)NAKetoconazole400 once daily150 once daily 1530(13 to 48)49(31 to 70)76(57 to 97)Ledipasvir/Sofosbuvir90/400 once daily25 once daily 143(12 to 7)2(6 to 11)12(3 to 21)Methadone60-100 once daily individualized dose25 once daily12<->Comparison based on historic controls. <-> <-> Omeprazole20 once daily150 once daily 1640(52 to 27)40(49 to 29)33(42 to 22)Rifabutin300 once daily25 once daily1831(38 to 24)42(48 to 35)48(54 to 41)300 once daily50 once daily1843(30 to 56)Reference arm for comparison was 25 mg q.d. RPV administered alone. 16(6 to 26) 7(15 to1) Rifampin600 once daily150 once daily 1669(73 to 64)80(82 to 77)89(90 to 87)Simeprevir25 once daily150 once daily23 4( to 13) 12( to 19) 25( 16 to 35)Sildenafil50 single dose75 once daily168(15 to 1)2(8 to 5)4(2 to 9)Sofosbuvir/Velpatasvir400/100 once daily25 once dailyStudy conducted with COMPLERA coadministered with EPCLUSA (sofosbuvir/velpatasvir). 247(12 to 2)5(10 to 0)4(10 to 3)Sofosbuvir/Velpatasvir/VoxilaprevirStudy conducted with ODEFSEY(TM) (FTC/RPV/tenofovir alafenamide). 400/100/100 100 voxilaprevirStudy conducted with additional voxilaprevir 100 mg to achieve voxilaprevir exposures expected in HCV-infected patients. once daily25 once daily3021(26 to 16)20(24 to 15)18(23 to 13)TDF300 once daily150 once daily 164(19 to 13)1(13 to 18)1(17 to 16)Table 10Drug Interactions: Changes in Pharmacokinetic Parameters for FTC in the Presence of the Coadministered DrugsCoadministered DrugDose of Coadministered Drug (mg)FTC Dose (mg)NN=maximum number of subjects for Cmax, AUC, or Cmin Mean Change of FTC Pharmacokinetic ParametersIncrease ; Decrease ; No Effect <-> (90% CI)Cmax AUCCmin NA=not availableFamciclovir500 1200 112<-><->NALedipasvir/Sofosbuvir90/400 once daily200 once dailyStudy conducted with COMPLERA coadministered with HARVONI. 152(2 to 6)5(2 to 8)6(3 to 15)Sofosbuvir/Velpatasvir400/100 once daily200 once dailyStudy conducted with COMPLERA coadministered with EPCLUSA. 245(10 to 0)1(3 to 2)5(1 to 11)Sofosbuvir/Velpatasvir/Voxilaprevir400/100/100 VoxilaprevirStudy conducted with additional voxilaprevir 100 mg to achieve voxilaprevir exposures expected in HCV-infected patients. 100 once daily200 once dailyStudy conducted with ODEFSEY (FTC/RPV/tenofovir alafenamide). 3012(17 to 7)7(10 to 4)7(1 to 14)TDF300 once daily 7 days200 once daily 7 days17<-><-> 20( 12 to 29)Table 11Drug Interactions: Changes in Pharmacokinetic Parameters for Tenofovir in the Presence of the Coadministered DrugsCoadministered DrugDose of Coadministered Drug (mg)TDF Dose (mg)Subjects received VIREAD 300 mg daily. NN=maximum number of subjects for Cmax, AUC, or Cmin Mean Change of Tenofovir Pharmacokinetic ParametersIncrease ; Decrease ; No Effect <-> (90% CI)Cmax AUCCmin NA=not availableEntecavir1 once daily 10 days300 once daily<-><-><->Emtricitabine200 once daily 7 days300 once daily 7 days17<-><-><->Ledipasvir/Sofosbuvir90/400 once daily 10 days300 once dailyStudy conducted with COMPLERA coadministered with HARVONI. 14 32( 25 to 39 40( 31 to 50 91( 74 to 110)Sofosbuvir/Velpatasvir400/100 once daily300 once daily24 44( 33 to 55) 40( 34 to 46) 84( 76 to 92)Tacrolimus0.05 mg/kg twice daily 7 days300 once dailyStudy conducted with COMPLERA coadministered with EPCLUSA. 21 13( to 27)<-><->Table 12Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drugs in the Presence of RPVCoadministered DrugDose of Coadministered Drug (mg)RPV Dose (mg)NN=maximum number of subjects for Cmax, AUC, or Cmin Mean Change of Coadministered Drug Pharmacokinetic ParametersIncrease ; Decrease ; No Effect <-> (90% CI)Cmax AUCCmin NA not availableAcetaminophen500 single dose150 once dailyThe Interaction study has been performed with dose higher than the recommended dose for RPV (25 mg once daily). 16 3( 14 to 10) 8( 15 to 1)NAAtorvastatin40 once daily150 once daily 16 35( to 68) 4( to 12) 15( 31 to 3)2-hydroxy-atorvastatin16 58( 33 to 87) 39( 29 to 50) 32( 10 to 58)4-hydroxy-atorvastatin16 28( 15 to 43) 23( 13 to 33)NAChlorzoxazone500 single dose taken hours after RPV150 once daily 16 2( 15 to 13) 3( to 13)NADigoxin0.5 single dose25 once daily22 6( to 17) 2( to 4)NAEthinyl estradiol0.035 once daily25 once daily17 17( to 30) 14( 10 to 19) 9( to 16)Norethindrone1 mg once daily 6( 17 to 6) 11( 16 to 6) 1( 10 to 8)Ketoconazole400 once daily150 once daily 14 15( 20 to 10) 24( 30 to 18) 66( 75 to 54)Ledipasvir90 once daily25 once daily41 1( to 5) 2( to 6) 2( to 7)R(-) methadone60-100 once daily individualized dose25 once daily13 14( 22 to 5) 16( 26 to 5) 22( 33 to 9)S(+) methadone13 13( 22 to 3) 16( 26 to 4) 21( 33 to 8)Metformin850 single dose25 once daily20 2( to 10) 3( 10 to 6)NAOmeprazole20 once daily150 once daily 15 14( 32 to 9) 14( 24 to 3)NARifampin600 once daily150 once daily 16 2( to 12) 1( to 7)NA25-desacetylrifampin16<->( 13 to 15) 9( 23 to 7)NASimeprevir150 once daily25 once daily21 10( to 26) 6( to 19) 4( 17 to 11)Sildenafil50 single dose75 once daily 16 7( 20 to 8) 3( 13 to 8)NAN-desmethyl-sildenafil 10( 20 to 2) 8( 15 to 1)NASofosbuvir400 once daily25 once daily24 9( to 25) 16( 10 to 24)NAGS-331007The predominant circulating nucleoside metabolite of sofosbuvir. 4( 10 to 1) 4(0 to 7) 12( to 17)Velpatasvir100 once daily25 once daily24 4( 15 to 10) 1( 12 to 11) 2( to 15)Sofosbuvir400 once daily25 once dailyStudy conducted with ODEFSEY. 30 5( 14 to 5) 1( to 6)NAGS-331007 2( to 6) 4( to 6)NAVelpatasvir100 once daily25 once daily 30 5( to 16) 1( to 7) 1( to 9)Voxilaprevir100 100 once daily25 once daily 30 4( 16 to 11) 6( 16 to 5) 2( to 12)TDF300 once daily150 once daily 16 19( to 34) 23( 16 to 31) 24( 10 to 38)Table 13Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drugs in the Presence of FTCCoadministered DrugDose of Coadministered Drug (mg)FTC Dose (mg)NAll interaction trials conducted in healthy volunteers Mean Change of Coadministered Drug Pharmacokinetic ParametersNo Effect <-> (90% CI)Cmax AUCCmin NA=not availableFamciclovir500 1200 112<-><->NATDF300 once daily 7 days200 once daily 7 days17<-><-><->No clinically significant drug interactions have been observed between FTC and indinavir, sofosbuvir/velpatasvir, sofosbuvir/velpatasvir/voxilaprevir, stavudine, and zidovudine.Table 14Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drugs in the Presence of TDFCoadministered DrugDose of Coadministered Drug (mg)TDF Dose (mg)NAll interaction trials conducted in healthy volunteers Mean Change of Coadministered Drug Pharmacokinetic ParametersIncrease ; No Effect <-> (90% CI)Cmax AUCCmin NA=not availableEmtricitabine200 once daily 7 days300 once daily 7 days17<-><-> 20( 12 to 29)Entecavir1 once daily 10 days300 once daily28<-> 13( 11 to 15)<->Tacrolimus0.05 mg/kg twice daily 7 days300 once daily21<-><-><->No effect on the pharmacokinetic parameters of the following coadministered drugs was observed with TDF: methadone, oral contraceptives (ethinyl estradiol/norgestimate), or ribavirin.. 12.4Microbiology. Mechanism of Action. Emtricitabine: FTC, 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 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 weak inhibitor of mammalian DNA polymerases , and mitochondrial DNA polymerase .. Rilpivirine: RPV is diarylpyrimidine non-nucleoside reverse transcriptase inhibitor of HIV-1 and inhibits HIV-1 replication by non-competitive inhibition of HIV-1 RT. RPV does not inhibit the human cellular DNA polymerases , and mitochondrial DNA polymerase .. Tenofovir DF: TDF is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate. TDF requires initial diester hydrolysis for conversion to tenofovir and subsequent phosphorylations by cellular enzymes to form tenofovir diphosphate. 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 weak inhibitor of mammalian DNA polymerases , and mitochondrial DNA polymerase .. Antiviral Activity. Emtricitabine, Rilpivirine, and TDF: The triple combination of FTC, RPV, and TDF was not antagonistic in cell culture.. Emtricitabine: The antiviral activity of FTC against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, the MAGI-CCR5 cell line, and peripheral blood mononuclear cells. The 50% effective concentration (EC50) values for FTC were in the range of 0.0013-0.64 uM. FTC displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, and (EC50 values ranged from 0.007-0.075 uM) and showed strain specific activity against HIV-2 (EC50 values ranged from 0.007-1.5 uM). In drug combination studies of FTC with nucleoside reverse transcriptase inhibitors (abacavir, lamivudine, stavudine, tenofovir, zidovudine), non-nucleoside reverse transcriptase inhibitors (delavirdine, EFV, nevirapine, and RPV), and protease inhibitors (amprenavir, nelfinavir, ritonavir, saquinavir), no antagonistic effects were observed.. Rilpivirine: RPV exhibited activity against laboratory strains of wild-type HIV-1 in an acutely infected T-cell line with median EC50 value for HIV-1IIIB of 0.73 nM. RPV demonstrated limited activity in cell culture against HIV-2 with median EC50 value of 5220 nM (range 2510-10,830 nM). RPV demonstrated antiviral activity against broad panel of HIV-1 group (subtype A, B, C, D, F, G, H) primary isolates with EC50 values ranging from 0.07-1.01 nM and was less active against group primary isolates with EC50 values ranging from 2.88-8.45 nM. The antiviral activity of RPV was not antagonistic when combined with the NNRTIs EFV, etravirine, or nevirapine; the N(t)RTIs abacavir, didanosine, FTC, lamivudine, stavudine, tenofovir, or zidovudine; the PIs amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, or tipranavir; the gp41 fusion inhibitor enfuvirtide; the CCR5 co-receptor antagonist maraviroc; or the integrase strand transfer inhibitor raltegravir.. Tenofovir DF: 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 uM. Tenofovir displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, G, and (EC50 values ranged from 0.5-2.2 uM) and showed strain specific activity against HIV-2 (EC50 values ranged from 1.6-5.5 uM). In drug combination studies of tenofovir with NRTIs (abacavir, didanosine, FTC, lamivudine, stavudine, and zidovudine), NNRTIs (delavirdine, EFV, nevirapine, and RPV), and PIs (amprenavir, indinavir, nelfinavir, ritonavir, saquinavir), no antagonistic effects were observed.. Resistance. In Cell Culture. Emtricitabine and Tenofovir DF: HIV-1 isolates with reduced susceptibility to FTC or tenofovir have been selected in cell culture. Reduced susceptibility to FTC was associated with M184V/I substitutions in HIV-1 RT. HIV-1 isolates selected by tenofovir expressed K65R substitution in HIV-1 RT and showed 2-4 fold reduction in susceptibility to tenofovir. In addition, K70E substitution in HIV-1 RT has been selected by tenofovir and results in low-level reduced susceptibility to abacavir, FTC, lamivudine, and tenofovir.. Rilpivirine: RPV-resistant strains were selected in cell culture starting from wild-type HIV-1 of different origins and subtypes as well as NNRTI-resistant HIV-1. The frequently observed amino acid substitutions that emerged and conferred decreased phenotypic susceptibility to RPV included: L100I, K101E, V106I and A, V108I, E138K and G, Q, R, V179F and I, Y181C and I, V189I, G190E, H221Y, F227C, and M230I and L.. In HIV-1-Infected Adult Subjects With No Antiretroviral Treatment HistoryIn the Week 96 pooled resistance analysis for adult subjects receiving RPV or EFV in combination with FTC/TDF in the Phase clinical trials C209 and C215, the emergence of resistance was greater among subjects viruses in the RPV FTC/TDF arm compared to the EFV FTC/TDF arm and was dependent on baseline viral load. In the pooled resistance analysis, 61% (47/77) of the subjects who qualified for resistance analysis (resistance analysis subjects) in the RPV FTC/TDF arm had virus with genotypic and/or phenotypic resistance to RPV compared to 42% (18/43) of the resistance analysis subjects in the EFV FTC/TDF arm who had genotypic and/or phenotypic resistance to EFV. Moreover, genotypic and/or phenotypic resistance to FTC or tenofovir emerged in viruses from 57% (44/77) of the resistance analysis subjects in the RPV arm compared to 26% (11/43) in the EFV arm.Emerging NNRTI substitutions in the RPV resistance analysis of subjects viruses included V90I, K101E/P/T, E138K/A/Q/G, V179I/L, Y181C/I, V189I, H221Y, F227C/L, and M230L, which were associated with an RPV phenotypic fold change range of 2.6-621. The E138K substitution emerged most frequently during RPV treatment, commonly in combination with the M184I substitution. The FTC and lamivudine resistance-associated substitutions M184I or and NRTI resistance-associated substitutions (K65R/N, A62V, D67N/G, K70E, Y115F, K219E/R) emerged more frequently in the RPV resistance analysis subjects than in EFV resistance analysis subjects (See Table 15).NNRTI- and NRTI-resistance substitutions emerged less frequently in the resistance analysis of viruses from subjects with baseline viral loads of <=100,000 copies/mL compared to viruses from subjects with baseline viral loads of >100,000 copies/mL: 23% (10/44) compared to 77% (34/44) of NNRTI-resistance substitutions and 20% (9/44) compared to 80% (35/44) of NRTI-resistance substitutions. This difference was also observed for the individual FTC/lamivudine and tenofovir resistance substitutions: 22% (9/41) compared to 78% (32/41) for M184I/V and 0% (0/8) compared to 100% (8/8) for K65R/N. Additionally, NNRTI and/or NRTI-resistance substitutions emerged less frequently in the resistance analysis of the viruses from subjects with baseline CD4+ cell counts >=200 cells/mm3 compared to the viruses from subjects with baseline CD4+ cell counts <200 cells/mm3: 32% (14/44) compared to 68% (30/44) of NNRTI-resistance substitutions and 27% (12/44) compared to 73% (32/44) of NRTI-resistance substitutions.Table 15Proportion of Frequently Emerging Reverse Transcriptase Substitutions in the HIV-1 Virus of Resistance Analysis Adult SubjectsSubjects who qualified for resistance analysis Who Received RPV or EFV in Combination with FTC/TDF from Pooled Phase TMC278-C209 and TMC278-C215 Trials in the Week 96 AnalysisC209 and C215N=1096RPV FTC/TDFEFV FTC/TDFN=550N=546Subjects who Qualified for Resistance Analysis14% (77/550)8% (43/546)Subjects with Evaluable Postbaseline Resistance Data7031Emergent NNRTI SubstitutionsV90, L100, K101, K103, V106, V108, E138, V179, Y181, Y188, V189, G190, H221, P225, F227, and M230 Any63% (44/70)55% (17/31)V90I14% (10/70)0K101E/P/T/Q19% (13/70)10% (3/31)K103N1% (1/70)39% (12/31)E138K/A/Q/G40% (28/70)0 E138K+M184IThis combination of NRTI and NNRTI substitutions is subset of those with the E138K. 30% (21/70)0V179I/D6% (4/70)10% (3/31)Y181C/I/S13% (9/70)3% (1/31)V189I9% (6/70)0H221Y10% (7/70)0Emergent NRTI SubstitutionsA62V, K65R/N, D67N/G, K70E, L74I, Y115F, M184V/I, L210F, K219E/R Any63% (44/70)32% (10/31)M184I/V59% (41/70)26% (8/31)K65R/N11% (8/70)6% (2/31)A62V, D67N/G, K70E, Y115F, or K219E/RThese substitutions emerged in addition to the primary substitutions M184V/I or K65R; A62V (n=2), D67N/G (n=3), K70E (n=4), Y115F (n=2), K219E/R (n=8) in RPV resistance analysis subjects. 20% (14/70)3% (1/31). In Virologically Suppressed HIV-1-Infected Adult SubjectsStudy 106: Through Week 48, subjects who switched to COMPLERA (4 of 469 subjects, 0.9%) and subject who maintained their ritonavir-boosted protease inhibitor-based regimen (1 of 159 subjects, 0.6%) developed genotypic and/or phenotypic resistance to study drug. All of the subjects who had resistance emergence on COMPLERA had evidence of FTC resistance and of the subjects had evidence of RPV resistance.. Cross Resistance. Rilpivirine, Emtricitabine, and Tenofovir DF:. In Cell CultureNo significant cross-resistance has been demonstrated between RPV-resistant HIV-1 variants and FTC or tenofovir, or between FTC- or tenofovir-resistant variants and RPV.. Rilpivirine:. Site-Directed NNRTI Mutant VirusCross-resistance has been observed among NNRTIs. The single NNRTI substitutions K101P, Y181I, and Y181V conferred 52-fold, 15-fold, and 12-fold decreased susceptibility to RPV, respectively. The combination of E138K and M184I showed 6.7-fold reduced susceptibility to RPV compared to 2.8-fold for E138K alone. The K103N substitution did not show reduced susceptibility to RPV by itself. However, the combination of K103N and L100I resulted in 7-fold reduced susceptibility to RPV. In another study, the Y188L substitution resulted in reduced susceptibility to RPV of 9-fold for clinical isolates and 6-fold for site-directed mutants. Combinations of or NNRTI resistance-associated substitutions gave decreased susceptibility to RPV (fold change range of 3.7-554) in 38% and 66% of mutants, respectively.. In HIV-1-Infected Adult Subjects With No Antiretroviral Treatment HistoryConsidering all available cell culture and clinical data, any of the following amino acid substitutions, when present at baseline, are likely to decrease the antiviral activity of RPV: K101E, K101P, E138A, E138G, E138K, E138R, E138Q, V179L, Y181C, Y181I, Y181V, Y188L, H221Y, F227C, M230I, M230L, and the combination of L100I+K103N.Cross-resistance to EFV, etravirine, and/or nevirapine is likely after virologic failure and development of RPV resistance. In pooled 96-week analysis for adult subjects receiving RPV in combination with FTC/TDF in the Phase clinical trials TMC278-C209 and TMC278-C215, 43 of the 70 (61%) RPV resistance analysis subjects with postbaseline resistance data had virus with decreased susceptibility to RPV (>=2.5 fold change). Of these, 84% (n=36/43) were resistant to EFV (>=3.3-fold change), 88% (n=38/43) were resistant to etravirine (>=3.2-fold change), and 60% (n=26/43) were resistant to nevirapine (>=6-fold change). In the EFV arm, of the 15 (20%) EFV resistance analysis subjects had viruses with resistance to etravirine and RPV, and 93% (14/15) had resistance to nevirapine. Virus from subjects experiencing virologic failure on RPV in combination with FTC/TDF developed more NNRTI resistance-associated substitutions conferring more cross-resistance to the NNRTI class and had higher likelihood of cross-resistance to all NNRTIs in the class than subjects who failed on EFV.. Emtricitabine: FTC-resistant isolates (M184V/I) were cross-resistant to lamivudine but retained susceptibility in cell culture to didanosine, stavudine, tenofovir, zidovudine, and NNRTIs (delavirdine, EFV, nevirapine, and RPV). HIV-1 isolates containing the K65R substitution, selected in vivo by abacavir, didanosine, and tenofovir, demonstrated reduced susceptibility to inhibition by FTC. Viruses harboring substitutions conferring reduced susceptibility to stavudine and zidovudine (M41L, D67N, K70R, L210W, T215Y/F, K219Q/E), or didanosine (L74V), remained sensitive to FTC. HIV-1 containing the substitutions associated with NNRTI resistance K103N or RPV-associated substitutions were susceptible to FTC.. Tenofovir DF: The K65R and K70E substitutions selected by tenofovir are also selected in some HIV-1-infected patients treated with abacavir or didanosine. HIV-1 isolates with the K65R and K70E substitutions also showed reduced susceptibility to FTC and lamivudine. Therefore, cross-resistance among these NRTIs may occur in patients whose virus harbors the K65R substitution. HIV-1 isolates from patients (N=20) whose HIV-1 expressed mean of zidovudine-associated RT amino acid substitutions (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E/N) showed 3.1-fold decrease in the susceptibility to tenofovir.Subjects whose virus expressed an L74V substitution without zidovudine resistance-associated substitutions (N=8) had reduced response to TDF. Limited data are available for patients whose virus expressed Y115F substitution (N=3), Q151M substitution (N=2), or T69 insertion (N=4), all of whom had reduced response.HIV-1 containing the substitutions associated with NNRTI resistance K103N and Y181C, or RPV-associated substitutions, were susceptible to tenofovir.

MECHANISM OF ACTION SECTION.

12.1Mechanism of Action. COMPLERA is fixed-dose combination of the antiretroviral drugs FTC, RPV, and TDF [see Microbiology (12.4)].

MICROBIOLOGY SECTION.

12.4Microbiology. Mechanism of Action. Emtricitabine: FTC, 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 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 weak inhibitor of mammalian DNA polymerases , and mitochondrial DNA polymerase .. Rilpivirine: RPV is diarylpyrimidine non-nucleoside reverse transcriptase inhibitor of HIV-1 and inhibits HIV-1 replication by non-competitive inhibition of HIV-1 RT. RPV does not inhibit the human cellular DNA polymerases , and mitochondrial DNA polymerase .. Tenofovir DF: TDF is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate. TDF requires initial diester hydrolysis for conversion to tenofovir and subsequent phosphorylations by cellular enzymes to form tenofovir diphosphate. 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 weak inhibitor of mammalian DNA polymerases , and mitochondrial DNA polymerase .. Antiviral Activity. Emtricitabine, Rilpivirine, and TDF: The triple combination of FTC, RPV, and TDF was not antagonistic in cell culture.. Emtricitabine: The antiviral activity of FTC against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, the MAGI-CCR5 cell line, and peripheral blood mononuclear cells. The 50% effective concentration (EC50) values for FTC were in the range of 0.0013-0.64 uM. FTC displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, and (EC50 values ranged from 0.007-0.075 uM) and showed strain specific activity against HIV-2 (EC50 values ranged from 0.007-1.5 uM). In drug combination studies of FTC with nucleoside reverse transcriptase inhibitors (abacavir, lamivudine, stavudine, tenofovir, zidovudine), non-nucleoside reverse transcriptase inhibitors (delavirdine, EFV, nevirapine, and RPV), and protease inhibitors (amprenavir, nelfinavir, ritonavir, saquinavir), no antagonistic effects were observed.. Rilpivirine: RPV exhibited activity against laboratory strains of wild-type HIV-1 in an acutely infected T-cell line with median EC50 value for HIV-1IIIB of 0.73 nM. RPV demonstrated limited activity in cell culture against HIV-2 with median EC50 value of 5220 nM (range 2510-10,830 nM). RPV demonstrated antiviral activity against broad panel of HIV-1 group (subtype A, B, C, D, F, G, H) primary isolates with EC50 values ranging from 0.07-1.01 nM and was less active against group primary isolates with EC50 values ranging from 2.88-8.45 nM. The antiviral activity of RPV was not antagonistic when combined with the NNRTIs EFV, etravirine, or nevirapine; the N(t)RTIs abacavir, didanosine, FTC, lamivudine, stavudine, tenofovir, or zidovudine; the PIs amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, or tipranavir; the gp41 fusion inhibitor enfuvirtide; the CCR5 co-receptor antagonist maraviroc; or the integrase strand transfer inhibitor raltegravir.. Tenofovir DF: 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 uM. Tenofovir displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, G, and (EC50 values ranged from 0.5-2.2 uM) and showed strain specific activity against HIV-2 (EC50 values ranged from 1.6-5.5 uM). In drug combination studies of tenofovir with NRTIs (abacavir, didanosine, FTC, lamivudine, stavudine, and zidovudine), NNRTIs (delavirdine, EFV, nevirapine, and RPV), and PIs (amprenavir, indinavir, nelfinavir, ritonavir, saquinavir), no antagonistic effects were observed.. Resistance. In Cell Culture. Emtricitabine and Tenofovir DF: HIV-1 isolates with reduced susceptibility to FTC or tenofovir have been selected in cell culture. Reduced susceptibility to FTC was associated with M184V/I substitutions in HIV-1 RT. HIV-1 isolates selected by tenofovir expressed K65R substitution in HIV-1 RT and showed 2-4 fold reduction in susceptibility to tenofovir. In addition, K70E substitution in HIV-1 RT has been selected by tenofovir and results in low-level reduced susceptibility to abacavir, FTC, lamivudine, and tenofovir.. Rilpivirine: RPV-resistant strains were selected in cell culture starting from wild-type HIV-1 of different origins and subtypes as well as NNRTI-resistant HIV-1. The frequently observed amino acid substitutions that emerged and conferred decreased phenotypic susceptibility to RPV included: L100I, K101E, V106I and A, V108I, E138K and G, Q, R, V179F and I, Y181C and I, V189I, G190E, H221Y, F227C, and M230I and L.. In HIV-1-Infected Adult Subjects With No Antiretroviral Treatment HistoryIn the Week 96 pooled resistance analysis for adult subjects receiving RPV or EFV in combination with FTC/TDF in the Phase clinical trials C209 and C215, the emergence of resistance was greater among subjects viruses in the RPV FTC/TDF arm compared to the EFV FTC/TDF arm and was dependent on baseline viral load. In the pooled resistance analysis, 61% (47/77) of the subjects who qualified for resistance analysis (resistance analysis subjects) in the RPV FTC/TDF arm had virus with genotypic and/or phenotypic resistance to RPV compared to 42% (18/43) of the resistance analysis subjects in the EFV FTC/TDF arm who had genotypic and/or phenotypic resistance to EFV. Moreover, genotypic and/or phenotypic resistance to FTC or tenofovir emerged in viruses from 57% (44/77) of the resistance analysis subjects in the RPV arm compared to 26% (11/43) in the EFV arm.Emerging NNRTI substitutions in the RPV resistance analysis of subjects viruses included V90I, K101E/P/T, E138K/A/Q/G, V179I/L, Y181C/I, V189I, H221Y, F227C/L, and M230L, which were associated with an RPV phenotypic fold change range of 2.6-621. The E138K substitution emerged most frequently during RPV treatment, commonly in combination with the M184I substitution. The FTC and lamivudine resistance-associated substitutions M184I or and NRTI resistance-associated substitutions (K65R/N, A62V, D67N/G, K70E, Y115F, K219E/R) emerged more frequently in the RPV resistance analysis subjects than in EFV resistance analysis subjects (See Table 15).NNRTI- and NRTI-resistance substitutions emerged less frequently in the resistance analysis of viruses from subjects with baseline viral loads of <=100,000 copies/mL compared to viruses from subjects with baseline viral loads of >100,000 copies/mL: 23% (10/44) compared to 77% (34/44) of NNRTI-resistance substitutions and 20% (9/44) compared to 80% (35/44) of NRTI-resistance substitutions. This difference was also observed for the individual FTC/lamivudine and tenofovir resistance substitutions: 22% (9/41) compared to 78% (32/41) for M184I/V and 0% (0/8) compared to 100% (8/8) for K65R/N. Additionally, NNRTI and/or NRTI-resistance substitutions emerged less frequently in the resistance analysis of the viruses from subjects with baseline CD4+ cell counts >=200 cells/mm3 compared to the viruses from subjects with baseline CD4+ cell counts <200 cells/mm3: 32% (14/44) compared to 68% (30/44) of NNRTI-resistance substitutions and 27% (12/44) compared to 73% (32/44) of NRTI-resistance substitutions.Table 15Proportion of Frequently Emerging Reverse Transcriptase Substitutions in the HIV-1 Virus of Resistance Analysis Adult SubjectsSubjects who qualified for resistance analysis Who Received RPV or EFV in Combination with FTC/TDF from Pooled Phase TMC278-C209 and TMC278-C215 Trials in the Week 96 AnalysisC209 and C215N=1096RPV FTC/TDFEFV FTC/TDFN=550N=546Subjects who Qualified for Resistance Analysis14% (77/550)8% (43/546)Subjects with Evaluable Postbaseline Resistance Data7031Emergent NNRTI SubstitutionsV90, L100, K101, K103, V106, V108, E138, V179, Y181, Y188, V189, G190, H221, P225, F227, and M230 Any63% (44/70)55% (17/31)V90I14% (10/70)0K101E/P/T/Q19% (13/70)10% (3/31)K103N1% (1/70)39% (12/31)E138K/A/Q/G40% (28/70)0 E138K+M184IThis combination of NRTI and NNRTI substitutions is subset of those with the E138K. 30% (21/70)0V179I/D6% (4/70)10% (3/31)Y181C/I/S13% (9/70)3% (1/31)V189I9% (6/70)0H221Y10% (7/70)0Emergent NRTI SubstitutionsA62V, K65R/N, D67N/G, K70E, L74I, Y115F, M184V/I, L210F, K219E/R Any63% (44/70)32% (10/31)M184I/V59% (41/70)26% (8/31)K65R/N11% (8/70)6% (2/31)A62V, D67N/G, K70E, Y115F, or K219E/RThese substitutions emerged in addition to the primary substitutions M184V/I or K65R; A62V (n=2), D67N/G (n=3), K70E (n=4), Y115F (n=2), K219E/R (n=8) in RPV resistance analysis subjects. 20% (14/70)3% (1/31). In Virologically Suppressed HIV-1-Infected Adult SubjectsStudy 106: Through Week 48, subjects who switched to COMPLERA (4 of 469 subjects, 0.9%) and subject who maintained their ritonavir-boosted protease inhibitor-based regimen (1 of 159 subjects, 0.6%) developed genotypic and/or phenotypic resistance to study drug. All of the subjects who had resistance emergence on COMPLERA had evidence of FTC resistance and of the subjects had evidence of RPV resistance.. Cross Resistance. Rilpivirine, Emtricitabine, and Tenofovir DF:. In Cell CultureNo significant cross-resistance has been demonstrated between RPV-resistant HIV-1 variants and FTC or tenofovir, or between FTC- or tenofovir-resistant variants and RPV.. Rilpivirine:. Site-Directed NNRTI Mutant VirusCross-resistance has been observed among NNRTIs. The single NNRTI substitutions K101P, Y181I, and Y181V conferred 52-fold, 15-fold, and 12-fold decreased susceptibility to RPV, respectively. The combination of E138K and M184I showed 6.7-fold reduced susceptibility to RPV compared to 2.8-fold for E138K alone. The K103N substitution did not show reduced susceptibility to RPV by itself. However, the combination of K103N and L100I resulted in 7-fold reduced susceptibility to RPV. In another study, the Y188L substitution resulted in reduced susceptibility to RPV of 9-fold for clinical isolates and 6-fold for site-directed mutants. Combinations of or NNRTI resistance-associated substitutions gave decreased susceptibility to RPV (fold change range of 3.7-554) in 38% and 66% of mutants, respectively.. In HIV-1-Infected Adult Subjects With No Antiretroviral Treatment HistoryConsidering all available cell culture and clinical data, any of the following amino acid substitutions, when present at baseline, are likely to decrease the antiviral activity of RPV: K101E, K101P, E138A, E138G, E138K, E138R, E138Q, V179L, Y181C, Y181I, Y181V, Y188L, H221Y, F227C, M230I, M230L, and the combination of L100I+K103N.Cross-resistance to EFV, etravirine, and/or nevirapine is likely after virologic failure and development of RPV resistance. In pooled 96-week analysis for adult subjects receiving RPV in combination with FTC/TDF in the Phase clinical trials TMC278-C209 and TMC278-C215, 43 of the 70 (61%) RPV resistance analysis subjects with postbaseline resistance data had virus with decreased susceptibility to RPV (>=2.5 fold change). Of these, 84% (n=36/43) were resistant to EFV (>=3.3-fold change), 88% (n=38/43) were resistant to etravirine (>=3.2-fold change), and 60% (n=26/43) were resistant to nevirapine (>=6-fold change). In the EFV arm, of the 15 (20%) EFV resistance analysis subjects had viruses with resistance to etravirine and RPV, and 93% (14/15) had resistance to nevirapine. Virus from subjects experiencing virologic failure on RPV in combination with FTC/TDF developed more NNRTI resistance-associated substitutions conferring more cross-resistance to the NNRTI class and had higher likelihood of cross-resistance to all NNRTIs in the class than subjects who failed on EFV.. Emtricitabine: FTC-resistant isolates (M184V/I) were cross-resistant to lamivudine but retained susceptibility in cell culture to didanosine, stavudine, tenofovir, zidovudine, and NNRTIs (delavirdine, EFV, nevirapine, and RPV). HIV-1 isolates containing the K65R substitution, selected in vivo by abacavir, didanosine, and tenofovir, demonstrated reduced susceptibility to inhibition by FTC. Viruses harboring substitutions conferring reduced susceptibility to stavudine and zidovudine (M41L, D67N, K70R, L210W, T215Y/F, K219Q/E), or didanosine (L74V), remained sensitive to FTC. HIV-1 containing the substitutions associated with NNRTI resistance K103N or RPV-associated substitutions were susceptible to FTC.. Tenofovir DF: The K65R and K70E substitutions selected by tenofovir are also selected in some HIV-1-infected patients treated with abacavir or didanosine. HIV-1 isolates with the K65R and K70E substitutions also showed reduced susceptibility to FTC and lamivudine. Therefore, cross-resistance among these NRTIs may occur in patients whose virus harbors the K65R substitution. HIV-1 isolates from patients (N=20) whose HIV-1 expressed mean of zidovudine-associated RT amino acid substitutions (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E/N) showed 3.1-fold decrease in the susceptibility to tenofovir.Subjects whose virus expressed an L74V substitution without zidovudine resistance-associated substitutions (N=8) had reduced response to TDF. Limited data are available for patients whose virus expressed Y115F substitution (N=3), Q151M substitution (N=2), or T69 insertion (N=4), all of whom had reduced response.HIV-1 containing the substitutions associated with NNRTI resistance K103N and Y181C, or RPV-associated substitutions, were susceptible to tenofovir.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1Carcinogenesis, Mutagenesis, Impairment of Fertility. Emtricitabine: In long-term carcinogenicity studies of FTC, no drug-related increases in tumor incidence were found in mice at doses up to 750 mg per kg per day (26 times the human systemic exposure at the therapeutic dose of 200 mg per day) or in rats at doses up to 600 mg per kg per day (31 times the human systemic exposure at the therapeutic dose).FTC was not genotoxic in the reverse mutation bacterial test (Ames test), or the mouse lymphoma or mouse micronucleus assays.FTC did not affect fertility in male rats at approximately 140-fold or in male and female mice at approximately 60-fold higher exposures (AUC) than in humans given the recommended 200 mg daily dose. Fertility was normal in the offspring of mice exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately 60-fold higher than human exposures at the recommended 200 mg daily dose.. Rilpivirine: RPV was evaluated for carcinogenic potential by oral gavage administration to mice and rats up to 104 weeks. Daily doses of 20, 60, and 160 mg per kg per day were administered to mice and doses of 40, 200, 500, and 1500 mg per kg per day were administered to rats. In rats, there were no drug-related neoplasms. In mice, RPV was positive for hepatocellular neoplasms in both males and females. The observed hepatocellular findings in mice may be rodent-specific. At the lowest tested doses in the carcinogenicity studies, the systemic exposures (based on AUC) to RPV were 21 fold (mice) and fold (rats), relative to those observed in humans at the recommended dose (25 mg once daily).RPV has tested negative in the absence and presence of metabolic activation system, in the in vitro Ames reverse mutation assay and in vitro clastogenicity mouse lymphoma assay. RPV did not induce chromosomal damage in the in vivo micronucleus test in mice. In study conducted in rats, there were no effects on mating or fertility with RPV up to 400 mg per kg per day, dose of RPV that showed maternal toxicity. This dose is associated with an exposure that is approximately 40 times higher than the exposure in humans at the recommended dose of 25 mg once daily.. Tenofovir DF: Long-term oral carcinogenicity studies of TDF in mice and rats were carried out at exposures up to approximately 16 times (mice) and times (rats) those observed in humans at the therapeutic dose for HIV-1 infection. At the high dose in female mice, liver adenomas were increased at exposures 16 times that in humans. In rats, the study was negative for carcinogenic findings at exposures up to times that observed in humans at the therapeutic dose.Tenofovir DF was mutagenic in the in vitro mouse lymphoma assay and negative in an in vitro bacterial mutagenicity test (Ames test). In an in vivo mouse micronucleus assay, TDF was negative when administered to male mice.There were no effects on fertility, mating performance, or early embryonic development when TDF was administered to male rats at 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 of gestation. There was, however, an alteration of the estrous cycle in female rats.. 13.2Animal Toxicology and/or Pharmacology. Tenofovir DF: Tenofovir and TDF administered in toxicology studies to rats, dogs, and monkeys at exposures (based on AUCs) greater than or equal to 6-fold those observed in humans caused bone toxicity. In monkeys the bone toxicity was diagnosed as osteomalacia. Osteomalacia observed in monkeys appeared to be reversible upon dose reduction or discontinuation of tenofovir. In rats and dogs, the bone toxicity manifested as reduced bone mineral density. The mechanism(s) underlying bone toxicity is unknown.Evidence of renal toxicity was noted in 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.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. COMPLERA tablets are white, capsule shaped, film coated, and debossed with GSI on both sides. Each bottle contains 30 tablets, silica gel desiccant, and polyester fiber coil, and is closed with child-resistant closure.. Store below 30 (86 F). Keep container tightly closed.Dispense only in original container.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. COMPLERA(TM) is indicated as complete regimen for the treatment of HIV-1 infection in adults and pediatric patients weighing at least 35 kg:as initial therapy in those with no antiretroviral treatment history with HIV-1 RNA less than or equal to 100,000 copies/mL at the start of therapy orto replace stable antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA less than 50 copies/mL) on stable antiretroviral regimen for at least months with no treatment failure and no known substitutions associated with resistance to the individual components of COMPLERA [see Microbiology (12.4) and Clinical Studies (14)].. as initial therapy in those with no antiretroviral treatment history with HIV-1 RNA less than or equal to 100,000 copies/mL at the start of therapy or. to replace stable antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA less than 50 copies/mL) on stable antiretroviral regimen for at least months with no treatment failure and no known substitutions associated with resistance to the individual components of COMPLERA [see Microbiology (12.4) and Clinical Studies (14)].. COMPLERA, combination of two nucleoside analog HIV-1 reverse transcriptase inhibitors (emtricitabine and tenofovir disoproxil fumarate) and one non-nucleoside reverse transcriptase inhibitor (rilpivirine), is indicated for use as complete regimen for the treatment of HIV-1 infection in patients weighing at least 35 kg (1) as initial therapy in those with no antiretroviral treatment history and with HIV-1 RNA less than or equal to 100,000 copies/mL at the start of therapy, or (2) or to replace stable antiretroviral regiment in those who are virologically suppressed (HIV-1 RNA <50 copies/mL) on stable antiretroviral regimen for at least months with no treatment failure and no known substitutions associated with resistance to the individual components of COMPLERA. (1, 14)Limitations of Use:More rilpivirine-treated subjects with HIV-1 RNA greater than 100,000 copies/mL at the start of therapy experienced virologic failure (HIV-1 RNA >=50 copies/mL) compared to rilpivirine-treated subjects with HIV-1 RNA less than or equal to 100,000 copies/mL. (1, 14). More rilpivirine-treated subjects with HIV-1 RNA greater than 100,000 copies/mL at the start of therapy experienced virologic failure (HIV-1 RNA >=50 copies/mL) compared to rilpivirine-treated subjects with HIV-1 RNA less than or equal to 100,000 copies/mL. (1, 14). Limitations of Use:More rilpivirine-treated subjects with HIV-1 RNA greater than 100,000 copies/mL at the start of therapy experienced virologic failure (HIV-1 RNA >=50 copies/mL) compared to rilpivirine-treated subjects with HIV-1 RNA less than or equal to 100,000 copies/mL [see Clinical Studies (14)].. More rilpivirine-treated subjects with HIV-1 RNA greater than 100,000 copies/mL at the start of therapy experienced virologic failure (HIV-1 RNA >=50 copies/mL) compared to rilpivirine-treated subjects with HIV-1 RNA less than or equal to 100,000 copies/mL [see Clinical Studies (14)].

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the approved patient labeling (Patient Information).. Posttreatment Acute Exacerbation of Hepatitis in Patients Coinfected with HIV-1 and HBVSevere acute exacerbations of hepatitis have been reported in patients who are coinfected with HBV and HIV-1 and who have discontinued products containing FTC or TDF [see Warnings and Precautions (5.1)]. Advise patients to not discontinue COMPLERA without first informing their healthcare provider.. Severe Skin Reactions and HypersensitivityAdvise patients to immediately contact their healthcare provider if they develop rash. Instruct patients to immediately stop taking COMPLERA and seek medical attention if they develop rash associated with any of the following symptoms, as it may be sign of more serious reaction such as DRESS severe hypersensitivity: fever, blisters, mucosal involvement, eye inflammation (conjunctivitis), severe allergic reaction causing swelling of the face, eyes, lips, mouth, tongue, or throat which may lead to difficulty swallowing or breathing, and any signs and symptoms of liver problems, as they may be sign of more serious reaction. Patients should understand that if severe rash occurs, they will be closely monitored, laboratory tests will be performed and appropriate therapy will be initiated [see Warnings and Precautions (5.2)]. HepatotoxicityInform patients that hepatotoxicity has been reported with COMPLERA and that monitoring for hepatotoxicity is recommended [see Warnings and Precautions (5.3)].. Depressive DisordersInform patients that depressive disorders (depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, suicidal ideation) have been reported with COMPLERA. Advise patients to seek immediate medical evaluation if they experience depressive symptoms [see Warnings and Precautions (5.4)]. New Onset or Worsening Renal ImpairmentInform patients that renal impairment, including cases of acute renal failure and Fanconi syndrome, has been reported in association with the use of TDF. COMPLERA should be avoided with concurrent or recent use of nephrotoxic agent (e.g., high-dose or multiple NSAIDs) [see Warnings and Precautions (5.5)].. Bone Loss and Mineralization DefectsInform patients that decreases in bone mineral density have been observed with the use of TDF. Assessment of bone mineral density (BMD) should be considered in patients who have history of pathologic bone fracture or other risk factors for osteoporosis or bone loss [see Warnings and Precautions (5.6)]. Drug InteractionsCOMPLERA may interact with many drugs and is not recommended to be coadministered with numerous drugs. Advise patients to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products, including St. Johns wort [see Contraindications (4), Warnings and Precautions (5.7), and Drug Interactions (7)].For patients receiving rifabutin, an additional 25 mg tablet of RPV (Edurant) once per day is recommended to be taken concomitantly with COMPLERA and with meal for the duration of rifabutin coadministration.. Lactic Acidosis and Severe Hepatomegaly Inform patients that lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported. Treatment with COMPLERA should be suspended in any patient who develops clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity [see Warnings and Precautions (5.8)].. Immune Reconstitution SyndromeInform patients to inform their healthcare provider immediately of any signs and symptoms of inflammation from previous infections, which may occur soon after anti-HIV treatment is started [see Warnings and Precautions (5.9)]. Dosing Instructions Advise patients that it is important to take COMPLERA on regular dosing schedule with food and to avoid missing doses. protein drink is not substitute for food. If the healthcare provider decides to stop COMPLERA and the patient is switched to new medicines to treat HIV that include RPV tablets, the RPV tablets should be taken only with meal.. Pregnancy Registry Inform patients that there is an antiretroviral pregnancy registry to monitor fetal outcomes in those exposed to COMPLERA during pregnancy [see Use in Specific Populations (8.1)]. LactationInstruct patients with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in breast milk [see Use in Specific Populations (8.2)].

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following adverse reactions are discussed in other sections of the labeling:Severe Acute Exacerbations of Hepatitis in Patients Coinfected with HIV-1 and HBV [see Warnings and Precautions (5.1)].Skin and Hypersensitivity Reactions [see Warnings and Precautions (5.2)]. Hepatotoxicity [see Warnings and Precautions (5.3)].Depressive Disorders [see Warnings and Precautions (5.4)]. New Onset or Worsening Renal Impairment [see Warnings and Precautions (5.5)].Bone Loss and Mineralization Defects [see Warnings and Precautions (5.6)].Lactic Acidosis/Severe Hepatomegaly with Steatosis [see Warnings and Precautions (5.8)].Immune Reconstitution Syndrome [see Warnings and Precautions (5.9)].. Severe Acute Exacerbations of Hepatitis in Patients Coinfected with HIV-1 and HBV [see Warnings and Precautions (5.1)].. Skin and Hypersensitivity Reactions [see Warnings and Precautions (5.2)]. Hepatotoxicity [see Warnings and Precautions (5.3)].. Depressive Disorders [see Warnings and Precautions (5.4)]. New Onset or Worsening Renal Impairment [see Warnings and Precautions (5.5)].. Bone Loss and Mineralization Defects [see Warnings and Precautions (5.6)].. Lactic Acidosis/Severe Hepatomegaly with Steatosis [see Warnings and Precautions (5.8)].. Immune Reconstitution Syndrome [see Warnings and Precautions (5.9)].. Most common adverse reactions to rilpivirine (incidence greater than or equal to 2%, Grades 2-4) are depressive disorders, insomnia, and headache. (6.1)Most common adverse reactions to emtricitabine and tenofovir disoproxil fumarate (incidence greater than or equal to 10%) are diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Gilead Sciences, Inc. at safetyfcgilead.com or the US FDA at 1-800-FDA-1088 or at www.fda.gov/medwatch. Most common adverse reactions to rilpivirine (incidence greater than or equal to 2%, Grades 2-4) are depressive disorders, insomnia, and headache. (6.1). Most common adverse reactions to emtricitabine and tenofovir disoproxil fumarate (incidence greater than or equal to 10%) are diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash. (6.1). 6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.. Adverse Reactions from Clinical Trials Experience in Adult Subjects. In HIV-1-Infected Adult Subjects With No Antiretroviral Treatment History. Studies C209 and C215The safety assessment of RPV, used in combination with other antiretroviral drugs, is based on the Week 96 pooled data from 1368 subjects in the Phase trials TMC278-C209 (ECHO) and TMC278-C215 (THRIVE) in antiretroviral treatment-naive HIV-1-infected adult subjects. total of 686 subjects received RPV in combination with other antiretroviral drugs as background regimen; most (N=550) received FTC/TDF as background regimen. The number of subjects randomized to the control arm EFV was 682, of which 546 received FTC/TDF as background regimen [see Clinical Studies (14)]. The median duration of exposure for subjects in either treatment arm was 104 weeks.Adverse reactions observed at Week 96 in subjects who received RPV or EFV FTC/TDF as background regimen are shown in Table 1. No new types of adverse reactions were identified between Week 48 and Week 96. The adverse reactions observed in this subset of subjects were generally consistent with those seen for the overall patient population participating in these studies (refer to the prescribing information for Edurant).The proportion of subjects who discontinued treatment with RPV or EFV FTC/TDF due to adverse reactions, regardless of severity, was 2% and 5%, respectively. The most common adverse reactions leading to discontinuation were psychiatric disorders: (1.6%) subjects in the RPV FTC/TDF arm and 12 (2.2%) subjects in the EFV FTC/TDF arm. Rash led to discontinuation in (0.2%) subject in the RPV FTC/TDF arm and 10 (1.8%) subjects in the EFV FTC/TDF arm.. Common Adverse Reactions: Clinical adverse reactions to RPV or EFV of at least moderate intensity (>=Grade 2) reported in at least 2% of adult subjects are shown in Table 1.Table Selected Adverse ReactionsFrequencies of adverse reactions are based on all Grades 2-4 treatment-emergent adverse events assessed to be related to study drug. (Grades 2-4) Reported in >=2% of Adult Subjects Receiving RPV or EFV in Combination with FTC/TDF in Studies C209 and C215 (Week 96 Analysis)Preferred TermRPV FTC/TDFEFV FTC/TDFN=550N=546Depressive disordersIncludes adverse reactions reported as depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, suicide ideation. 2%2%Headache2%2%Insomnia2%2%Abnormal dreams1%3%Dizziness1%7%Nausea1%2%Rash1%5%. Rilpivirine: Adverse reactions of at least moderate intensity (>=Grade 2) that occurred in less than 2% of subjects treated with RPV plus any of the allowed background regimens (N=686) in clinical studies C209 and C215 include (grouped by Body System): vomiting, diarrhea, abdominal discomfort, abdominal pain, fatigue, cholecystitis, cholelithiasis, decreased appetite, somnolence, sleep disorders, anxiety, glomerulonephritis membranous, glomerulonephritis mesangioproliferative, and nephrolithiasis.. In Virologically Suppressed HIV-1-Infected Adult SubjectsNo new adverse reactions to COMPLERA were identified in stable, virologically suppressed subjects switching to COMPLERA from regimen containing ritonavir-boosted protease inhibitor; however, the frequency of adverse reactions increased by 20% (Study 106) after switching to COMPLERA.. Emtricitabine and Tenofovir DF: The most common adverse reactions that occurred in at least 10% of HIV-1-infected treatment-naive adult subjects in Phase clinical trial of FTC and TDF in combination with another antiretroviral agent were diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash. Adverse reactions that occurred in at least 5% of treatment-experienced or treatment-naive subjects receiving FTC or TDF with other antiretroviral agents in clinical trials included abdominal pain, dyspepsia, vomiting, fever, pain, nasopharyngitis, pneumonia, sinusitis, upper respiratory tract infection, arthralgia, back pain, myalgia, paresthesia, peripheral neuropathy (including peripheral neuritis and neuropathy), anxiety, increased cough, and rhinitis.Skin discoloration has been reported with higher frequency among FTC-treated subjects; it was manifested by hyperpigmentation on the palms and/or soles and was generally mild and asymptomatic. The mechanism and clinical significance are unknown.. Laboratory Abnormalities in Adult Subjects The percentage of subjects treated with RPV FTC/TDF or EFV FTC/TDF in studies C209 and C215 with selected laboratory abnormalities (Grades 1-4), representing worst-grade toxicity, is presented in Table 2.Table Selected Laboratory Abnormalities (Grades 1-4) Reported in Adult Subjects Who Received RPV or EFV in Combination with FTC/TDF in Studies C209 and C215 (Week 96 Analysis)Laboratory Parameter AbnormalityDAIDS Toxicity RangeRPV FTC/TDFEFV FTC/TDFN=550N=546N=number of subjects per treatment groupULN=Upper limit of normal value.Note: Percentages were calculated versus the number of subjects in ITT population with FTC TDF as background regimen.BIOCHEMISTRYIncreased Creatinine Grade 11.1-1.3 ULN6%1% Grade 2>1.3-1.8 ULN1%1% Grade 3>1.8-3.4 ULN<1%0 Grade 4>3.4 ULN0<1%Increased AST Grade 11.25-2.5 ULN16%19% Grade 2>2.5-5.0 ULN4%7% Grade 3>5.0-10.0 ULN2%3% Grade 4>10.0 ULN1%1%Increased ALT Grade 11.25-2.5 ULN19%22% Grade 2>2.5-5.0 ULN5%7% Grade 3>5.0-10.0 ULN1%2% Grade 4>10.0 ULN1%1%Increased Total Bilirubin Grade 11.1-1.5 ULN6%<1% Grade 2>1.5-2.5 ULN3%1% Grade 3>2.5-5.0 ULN1%<1%Increased Total Cholesterol (fasted) Grade 1200-239 mg/dL14%31% Grade 2240-300 mg/dL6%18% Grade 3>300 mg/dL<1%2%Increased LDL Cholesterol (fasted) Grade 1130-159 mg/dL13%28% Grade 2160-190 mg/dL5%13% Grade 3>190 mg/dL1%4%Increased Triglycerides (fasted) Grade 2500-750 mg/dL1%2% Grade 3751-1200 mg/dL1%2% Grade 4>1200 mg/dL01%. Emtricitabine or Tenofovir DF: The following Grade or laboratory abnormalities have been previously reported in subjects treated with FTC or TDF with other antiretroviral agents in other clinical trials: increased pancreatic amylase (>2.0 ULN), increased serum amylase (>175 U/L), increased lipase (>3.0 ULN), increased alkaline phosphatase (>550 U/L), increased or decreased serum glucose (<40 or >250 mg/dL), increased glycosuria (>=3+), increased creatine kinase (M: >990 U/L; F: >845 U/L), decreased neutrophils (<750/mm3), and increased hematuria (>75 RBC/HPF).. Adrenal Function: In the pooled Phase trials of C209 and C215, in subjects treated with RPV plus any of the allowed background regimens (N=686), at Week 96 there was an overall mean change from baseline in basal cortisol of -0.69 (-1.12, 0.27) micrograms/dL in the RPV group, and of -0.02 (-0.48, 0.44) micrograms/dL in the EFV group.In the RPV group, 43/588 (7.3%) of subjects with normal 250 micrograms ACTH stimulation test at baseline developed an abnormal 250 micrograms ACTH stimulation test (peak cortisol level <18.1 micrograms/dL) during the trial compared to 18/561 (3.2%) in the EFV group. Of the subjects who developed an abnormal 250 micrograms ACTH stimulation test during the trial, 14 subjects in the RPV group and subjects in the EFV group had an abnormal 250 micrograms ACTH stimulation test at Week 96. Overall, there were no serious adverse events, deaths, or treatment discontinuations that could clearly be attributed to adrenal insufficiency. The clinical significance of the higher abnormal rate of 250 micrograms ACTH stimulation tests in the RPV group is not known.. Serum Creatinine: In the pooled Phase trials of C209 and C215 in subjects treated with RPV plus any of the allowed background regimens (N=686), there was small increase in serum creatinine over 96 weeks of treatment with RPV. Most of this increase occurred within the first weeks of treatment, with mean change of 0.1 mg/dL (range -0.3 to 0.6 mg/dL) observed through Week 96. In subjects who entered the trial with mild or moderate renal impairment, the serum creatinine increase observed was similar to that seen in subjects with normal renal function. These changes are not considered to be clinically relevant, and no subject discontinued treatment due to increases in serum creatinine. Creatinine increases were comparable by background N(t)RTIs.. Serum Lipids: Changes from baseline in total cholesterol, LDL-cholesterol, and triglycerides are presented in Table 3.Table 3Lipid Values Reported in Adult Subjects Receiving RPV or EFV in Combination with FTC/TDF in Studies C209 and C215Excludes subjects who received lipid lowering agents during the treatment period. Pooled Data from the Week 96 Analysis of C209 and C215 TrialsRPV FTC/TDFN=550EFV FTC/TDFN=546NBaselineWeek 96NBaselineWeek 96MeanMean (mg/dL)Mean (mg/dL)Mean ChangeThe change from baseline is the mean of within-patient changes from baseline for patients with both baseline and Week 96 values. (mg/dL)Mean (mg/dL)Mean (mg/dL)Mean Change (mg/dL)N=number of subjects per treatment groupTotal Cholesterol (fasted)430162164240116018626HDL-cholesterol (fasted)42942454399405011LDL-cholesterol (fasted)4279797-13979611014Triglycerides (fasted)430123109-144011271336. Adult Subjects Coinfected with Hepatitis and/or Hepatitis Virus: In adult subjects coinfected with hepatitis or virus receiving RPV in studies C209 and C215, the incidence of hepatic enzyme elevation was higher than in subjects receiving RPV who were not coinfected. The same increase was also observed in the EFV arm. The pharmacokinetic exposure of RPV in coinfected subjects was comparable to that in subjects without coinfection.. Adverse Reactions from Clinical Trials Experience in Pediatric Subjects Emtricitabine: In addition to the adverse reactions reported in adults, anemia and hyperpigmentation were observed in 7% and 32%, respectively, of pediatric subjects (3 months to less than 18 years of age) who received treatment with FTC in the larger of two open-label, uncontrolled pediatric trials (N=116). For additional information, please consult the EMTRIVA(TM) prescribing information.. Rilpivirine: The safety assessment is based on the Week 48 analysis of the single-arm, open-label Phase trial, TMC278-C213, in which 36 antiretroviral treatment-naive HIV-1-infected subjects 12 to less than 18 years of age and weighing at least 32 kg received RPV (25 mg once daily) in combination with other antiretroviral agents. The median duration of exposure for subjects was 63.5 weeks. No subjects discontinued treatment due to adverse reactions. No new adverse reactions were identified compared to those seen in adults.Adverse reactions were reported in 19 pediatric subjects (52.8%). Most adverse reactions were Grade or 2. The most common adverse reactions reported in at least subjects (regardless of severity) include headache (19.4%), depression (19.4%), somnolence (13.9%), nausea (11.1%), dizziness (8.3%), abdominal pain (8.3%), vomiting (5.6%), and rash (5.6%).Observed laboratory abnormalities were comparable to those in adults. For additional information, please consult the Edurant prescribing information.. Adrenal FunctionIn trial TMC278-C213, at Week 48, the overall mean change from baseline in basal cortisol showed an increase of 1.59 (0.24, 2.93) micrograms/dL.Six of 30 (20%) subjects with normal 250 micrograms ACTH stimulation test at baseline developed an abnormal 250 micrograms ACTH stimulation test (peak cortisol level <18.1 micrograms/dL) during the trial. Three of these subjects had an abnormal 250 micrograms ACTH stimulation test at Week 48. Overall, there were no serious adverse events, deaths, or treatment discontinuations that could clearly be attributed to adrenal insufficiency. The clinical significance of the abnormal 250 micrograms ACTH stimulation tests is not known.. Tenofovir DF: In pediatric clinical trial conducted in subjects 12 to less than 18 years of age, the adverse reactions observed in pediatric subjects who received treatment with TDF were consistent with those observed in clinical trials of TDF in adults [see Warnings and Precautions (5.6)]. For additional information, including information on bone mineral density changes, please consult the VIREAD(TM) prescribing information.. 6.2Postmarketing Experience. The following adverse reactions have been identified during postmarketing experience in patients receiving RPV- or TDF-containing regimens. Because postmarketing reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.. COMPLERA:. Metabolism and Nutrition Disordersweight increased. Skin and Subcutaneous Tissue Disorderssevere skin and hypersensitivity reactions including DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms). Rilpivirine:. Renal and Urinary Disordersnephrotic syndrome. Emtricitabine:No postmarketing adverse reactions have been identified for inclusion in this section.. Tenofovir DF:. Immune System Disordersallergic reaction, including angioedema. Metabolism and Nutrition Disorderslactic acidosis, hypokalemia, hypophosphatemia. Respiratory, Thoracic, and Mediastinal Disordersdyspnea. Gastrointestinal Disorderspancreatitis, increased amylase, abdominal pain. Hepatobiliary Disordershepatic steatosis, hepatitis, increased liver enzymes (most commonly AST, ALT, gamma GT). Skin and Subcutaneous Tissue Disordersrash. Musculoskeletal and Connective Tissue Disordersrhabdomyolysis, osteomalacia (manifested as bone pain and which may contribute to fractures), muscular weakness, myopathy. Renal and Urinary Disordersacute renal failure, renal failure, acute tubular necrosis, Fanconi syndrome, proximal renal tubulopathy, interstitial nephritis (including acute cases), nephrogenic diabetes insipidus, renal insufficiency, increased creatinine, proteinuria, polyuria. General Disorders and Administration Site ConditionsastheniaThe following adverse reactions, listed under the body system headings above, may occur as consequence of proximal renal tubulopathy: rhabdomyolysis, osteomalacia, hypokalemia, muscular weakness, myopathy, hypophosphatemia.

ANIMAL PHARMACOLOGY & OR TOXICOLOGY SECTION.

13.2Animal Toxicology and/or Pharmacology. Tenofovir DF: Tenofovir and TDF administered in toxicology studies to rats, dogs, and monkeys at exposures (based on AUCs) greater than or equal to 6-fold those observed in humans caused bone toxicity. In monkeys the bone toxicity was diagnosed as osteomalacia. Osteomalacia observed in monkeys appeared to be reversible upon dose reduction or discontinuation of tenofovir. In rats and dogs, the bone toxicity manifested as reduced bone mineral density. The mechanism(s) underlying bone toxicity is unknown.Evidence of renal toxicity was noted in 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.

BOXED WARNING SECTION.

WARNING: POSTTREATMENT ACUTE EXACERBATION OF HEPATITIS B. Severe acute exacerbations of hepatitis virus (HBV) have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued products containing emtricitabine (FTC) and/or tenofovir disoproxil fumarate (TDF), two of the components of COMPLERA. Closely monitor hepatic function with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue COMPLERA. If appropriate, initiation of anti-hepatitis therapy may be warranted [see Warnings and Precautions (5.1)].. WARNING: POSTTREATMENT ACUTE EXACERBATION OF HEPATITIS BSee full prescribing information for complete boxed warning.Severe acute exacerbations of hepatitis virus (HBV) have been reported in patients coinfected with HIV-1 and HBV who have discontinued products containing emtricitabine (FTC) and/or tenofovir disoproxil fumarate (TDF), two of the components of COMPLERA. Closely monitor hepatic function with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue COMPLERA. If appropriate, initiation of anti-hepatitis therapy may be warranted. (5.1).

LACTATION SECTION.

8.2 Lactation. Risk SummaryThe Centers for Disease Control and Prevention recommend that HIV infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV.Based on published data, FTC and tenofovir have been shown to be present in human milk. There are no data on the presence of RPV in human milk. RPV has been shown to be present in rat milk (see Data).It is not known if the components of COMPLERA affect milk production or have effects on the breastfed child. Because of the potential for: (1) HIV transmission (in HIV-negative infants); (2) developing viral resistance (in HIV-positive infants); and (3) adverse reactions in breastfed infant similar to those seen in adults, instruct mothers not to breastfeed if they are receiving COMPLERA.. Data. Rilpivirine: In animals, no studies have been conducted to assess the excretion of RPV directly; however RPV was measured in rat pups which were exposed through the milk of treated dams (dosed up to 400 mg/kg/day).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility. Emtricitabine: In long-term carcinogenicity studies of FTC, no drug-related increases in tumor incidence were found in mice at doses up to 750 mg per kg per day (26 times the human systemic exposure at the therapeutic dose of 200 mg per day) or in rats at doses up to 600 mg per kg per day (31 times the human systemic exposure at the therapeutic dose).FTC was not genotoxic in the reverse mutation bacterial test (Ames test), or the mouse lymphoma or mouse micronucleus assays.FTC did not affect fertility in male rats at approximately 140-fold or in male and female mice at approximately 60-fold higher exposures (AUC) than in humans given the recommended 200 mg daily dose. Fertility was normal in the offspring of mice exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately 60-fold higher than human exposures at the recommended 200 mg daily dose.. Rilpivirine: RPV was evaluated for carcinogenic potential by oral gavage administration to mice and rats up to 104 weeks. Daily doses of 20, 60, and 160 mg per kg per day were administered to mice and doses of 40, 200, 500, and 1500 mg per kg per day were administered to rats. In rats, there were no drug-related neoplasms. In mice, RPV was positive for hepatocellular neoplasms in both males and females. The observed hepatocellular findings in mice may be rodent-specific. At the lowest tested doses in the carcinogenicity studies, the systemic exposures (based on AUC) to RPV were 21 fold (mice) and fold (rats), relative to those observed in humans at the recommended dose (25 mg once daily).RPV has tested negative in the absence and presence of metabolic activation system, in the in vitro Ames reverse mutation assay and in vitro clastogenicity mouse lymphoma assay. RPV did not induce chromosomal damage in the in vivo micronucleus test in mice. In study conducted in rats, there were no effects on mating or fertility with RPV up to 400 mg per kg per day, dose of RPV that showed maternal toxicity. This dose is associated with an exposure that is approximately 40 times higher than the exposure in humans at the recommended dose of 25 mg once daily.. Tenofovir DF: Long-term oral carcinogenicity studies of TDF in mice and rats were carried out at exposures up to approximately 16 times (mice) and times (rats) those observed in humans at the therapeutic dose for HIV-1 infection. At the high dose in female mice, liver adenomas were increased at exposures 16 times that in humans. In rats, the study was negative for carcinogenic findings at exposures up to times that observed in humans at the therapeutic dose.Tenofovir DF was mutagenic in the in vitro mouse lymphoma assay and negative in an in vitro bacterial mutagenicity test (Ames test). In an in vivo mouse micronucleus assay, TDF was negative when administered to male mice.There were no effects on fertility, mating performance, or early embryonic development when TDF was administered to male rats at 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 of gestation. There was, however, an alteration of the estrous cycle in female rats.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1Adult Subjects. In HIV-1-Infected Adult Subjects With No Antiretroviral Treatment HistoryThe efficacy of COMPLERA is based on the analyses of 48- and 96-week data from two randomized, double-blind, controlled studies (Study C209 [ECHO] and TRUVADA subset of Study C215 [THRIVE]) in treatment-naive, HIV-1-infected subjects (N=1368). The studies are identical in design with the exception of the background regimen (BR). Subjects were randomized in 1:1 ratio to receive either RPV 25 mg (N=686) once daily or EFV 600 mg (N=682) once daily in addition to BR. In Study C209 (N=690), the BR was FTC/TDF. In Study C215 (N=678), the BR consisted of NRTIs: FTC/TDF (60%, n=406), lamivudine/zidovudine (30%, n=204), or abacavir lamivudine (10%, n=68).For subjects who received FTC/TDF (N=1096) in studies C209 and C215, the mean age was 37 years (range 18-78), 78% were male, 62% were White, 24% were Black, and 11% were Asian. The mean baseline CD4+ cell count was 265 cells/mm3 (range 1-888) and 31% had CD4+ cell counts <200 cells/mm3. The median baseline plasma HIV-1 RNA was log10 copies/mL (range 2-7). Subjects were stratified by baseline HIV-1 RNA. Fifty percent of subjects had baseline viral load <=100,000 copies/mL, 39% of subjects had baseline viral load between 100,000 copies/mL to 500,000 copies/mL, and 11% of subjects had baseline viral load >500,000 copies/mL.Treatment outcomes through 96 weeks for the subset of subjects receiving FTC/TDF in studies C209 and C215 (Table 16) are generally consistent with treatment outcomes for all participating subjects (presented in the prescribing information for Edurant). The incidence of virologic failure was higher in the RPV arm than the EFV arm at Week 96. Virologic failures and discontinuations due to adverse events mostly occurred in the first 48 weeks of treatment.Table 16Pooled Virologic Outcome of Randomized Treatment of Studies C209 and C215 at Week 96 in Adult Subjects With No Antiviral Treatment History in Combination with FTC/TDF) at Week 96Analyses were based on the last observed viral load data within the Week 96 window (Week 90-103). RPV FTC/TDFEFV FTC/TDFN=550N=546HIV-1 RNA <50 copies/mLPredicted difference (95% CI) of response rate is 0.5% (-4.5% to 5.5%) at Week 96. 77%77%HIV-1 RNA >=50 copies/mLIncludes subjects who had >=50 copies/mL in the Week 96 window, subjects who discontinued early due to lack or loss of efficacy, subjects who discontinued for reasons other than an adverse event, death, or lack or loss of efficacy and at the time of discontinuation had viral load value of >=50 copies/mL, and subjects who had switch in background regimen that was not permitted by the protocol. 14%8%No Virologic Data at Week 96 Window Reasons Discontinued study due to adverse event or deathIncludes subjects who discontinued due to an adverse event or death if this resulted in no on-treatment virologic data in the Week 96 window. 4%9% Discontinued study for other reasonsIncludes subjects who discontinued for reasons other than an adverse event, death, or lack or loss of efficacy, e.g., withdrew consent, loss to follow-up, etc. and the last available HIV-1 RNA <50 copies/mL (or missing)4%6% Missing data during window but on study<1%<1%HIV-1 RNA <50 copies/mLby Baseline HIV-1 RNA (copies/mL) <=100,00083%80% >100,00071%74%HIV-1 RNA >=50 copies/mL by Baseline HIV-1 RNA (copies/mL) <=100,0007%5% >100,00022%12%HIV-1 RNA <50 copies/mLby Baseline CD4+ Cell Count (cells/mm3) <20068%72% >=20082%79%HIV-1 RNA >=50 copies/mL by Baseline CD4+ Cell Count (cells/mm3) <20027%12% >=2008%7%Based on the pooled data from studies C209 and C215, the mean CD4+ cell count increase from baseline at Week 96 was 226 cells/mm3 for RPV FTC/TDF-treated subjects and 223 cells/mm3 for EFV FTC/TDF-treated subjects.. In Virologically Suppressed HIV-1-Infected Adult Subjects The efficacy and safety of switching from ritonavir-boosted protease inhibitor in combination with two NRTIs to COMPLERA was evaluated in Study 106, randomized, open-label study in virologically suppressed HIV-1-infected adults. Subjects had to be on either their first or second antiretroviral regimen with no history of virologic failure, have no current or past history of resistance to any of the three components of COMPLERA, and must have been suppressed (HIV-1 RNA <50 copies/mL) for at least months prior to screening. Subjects were randomized in 2:1 ratio to either switch to COMPLERA at baseline (COMPLERA arm, N=317), or stay on their baseline antiretroviral regimen for 24 weeks (SBR arm, N=159) and then switch to COMPLERA for an additional 24 weeks (N=52). Subjects had mean age of 42 years (range 19-73), 88% were male, 77% were White, 17% were Black, and 17% were Hispanic/Latino. The mean baseline CD4+ cell count was 584 cells/mm3 (range 42-1484). Randomization was stratified by use of TDF and/or lopinavir/ritonavir in the baseline regimen.Treatment outcomes are presented in Table 17.Table 17Virologic Outcomes of Study GS-US-264-0106 in Virologically Suppressed SubjectsCOMPLERAStayed on Baseline Regimen (SBR)Week 48Week 48 window is between Day 295 and 378 (inclusive). Week 24For subjects in the SBR arm who maintained their baseline regimen for 24 weeks and then switched to COMPLERA, the Week 24 window is between Day 127 and first dose day on COMPLERA. N=317N=159HIV-1 RNA <50 copies/mLPredicted difference (95% CI) of response rate for switching to COMPLERA at Week 48 compared to staying on baseline regimen at Week 24 (in absence of Week 48 results from the SBR group by study design) is -0.7% (-6.4% to 5.1%).89% (283/317)90% (143/159)HIV-1 RNA >=50 copies/mLIncludes subjects who had HIV-1 RNA >=50 copies/mL in the time window, subjects who discontinued early due to lack or loss of efficacy, and subjects who discontinued for reasons other than an adverse event or death and at the time of discontinuation had viral load value of >=50 copies/mL.3% (8/317)5% (8/159)No Virologic Data at Week 24 Window Discontinued study drug due to AE or deathIncludes subjects who discontinued due to adverse event or death at any time point from Day through the time window if this resulted in no virologic data on treatment during the specified window. 2% (7/317)0% Discontinued study drug due to other reasons and last available HIV-1 RNA <50 copies/mLIncludes subjects who discontinued for reasons other than an adverse event, death, or lack or loss of efficacy, e.g., withdrew consent, loss to follow-up, etc. 5% (16/317)3% (5/159) Missing data during window but on study drug1% (3/317)2% (3/159). 14.2Pediatric Subjects. The pharmacokinetics, safety, and efficacy of RPV in combination with other antiretroviral agents was evaluated in single-arm, open-label Phase trial in antiretroviral treatment-naive HIV-1-infected pediatric subjects 12 to less than 18 years of age and weighing at least 32 kg (TMC-C213). Thirty-six (36) subjects were enrolled with median age of 14.5 years (range 12 to 17 years), and were 55.6% female, 88.9% Black, and 11.1% Asian. The majority of subjects (24/36) received RPV in combination with FTC and TDF. Of these 24 subjects, 20 had baseline HIV RNA <=100,000 copies/mL. The baseline characteristics and efficacy outcomes at Week 48 are further described below for the 20 subjects.The median baseline plasma HIV-1 RNA and CD4+ cell count were 49,550 (range 2060 to 92,600 copies/mL) and 437.5 cells/mm3 (range 123 to 983 cells/mm3), respectively. At Week 48, 80% (16/20) of the subjects had HIV RNA <50 copies/mL, 15% (3/20) had HIV RNA >=50 copies/mL, and one subject discontinued therapy prior to Week 48 and before reaching virologic suppression (HIV RNA <50 copies/mL). At Week 48, the mean increase in CD4+ cell count from baseline was 225 cells/mm3.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. COMPLERA is contraindicated when coadministered with the following drugs; coadministration may result in loss of virologic response and possible resistance to COMPLERA or to the class of NNRTIs [see Warnings and Precautions (5.7), Drug Interactions (7), and Clinical Pharmacology (12.3)]: Anticonvulsants: carbamazepine, oxcarbazepine, phenobarbital, phenytoinAntimycobacterials: rifampin, rifapentineGlucocorticoid (systemic): dexamethasone (more than single-dose)Herbal Products: St Johns wort (Hypericum perforatum)Proton Pump Inhibitors: e.g., dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole. Anticonvulsants: carbamazepine, oxcarbazepine, phenobarbital, phenytoin. Antimycobacterials: rifampin, rifapentine. Glucocorticoid (systemic): dexamethasone (more than single-dose). Herbal Products: St Johns wort (Hypericum perforatum). Proton Pump Inhibitors: e.g., dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole. COMPLERA is contraindicated when coadministered with drugs which may result in loss of virologic response and possible resistance to COMPLERA. (4).

DESCRIPTION SECTION.

11 DESCRIPTION. COMPLERA is fixed-dose combination tablet containing FTC, rilpivirine hydrochloride, and TDF. Emtricitabine (FTC) is synthetic nucleoside analog of cytidine. Rilpivirine (RPV) is non-nucleoside reverse transcriptase inhibitor. Tenofovir disoproxil fumarate (TDF) is converted in vivo to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5-monophosphate.COMPLERA tablets are for oral administration. Each tablet contains 200 mg of FTC, 27.5 mg of rilpivirine hydrochloride (equivalent to 25 mg of RPV), and 300 mg of TDF (equivalent to 245 mg of tenofovir disoproxil) as active ingredients. The tablets include the following inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polysorbate 20, povidone, pregelatinized starch. The tablets are film coated with coating material containing hypromellose, lactose monohydrate, polyethylene glycol, titanium dioxide, triacetin.. Emtricitabine: The chemical name of FTC is 5-fluoro-1-[(2R,5S)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine. Emtricitabine is the (-) enantiomer of thio analog of cytidine, which differs from other cytidine analogs in that it has fluorine in the 5-position.It has molecular formula of C8H10FN3O3S and molecular weight of 247.24. It has the following structural formula:FTC is white to off-white crystalline powder with solubility of approximately 112 mg per mL in water at 25 C.. Chemical Structure. Rilpivirine: RPV is available as the hydrochloride salt. The chemical name for rilpivirine hydrochloride is 4-[[4-[[4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile monohydrochloride. Its molecular formula is C22H18N6 HCl and its molecular weight is 402.88. Rilpivirine hydrochloride has the following structural formula:Rilpivirine hydrochloride is white to almost white powder. Rilpivirine hydrochloride is practically insoluble in water over wide pH range.. Chemical Structure. Tenofovir DF: TDF is fumaric acid salt of the bis-isopropoxycarbonyloxymethyl ester derivative of tenofovir. The chemical name of TDF is 9-[(R)-2 [[bis[[(isopropoxycarbonyl)oxy]- methoxy]phosphinyl]methoxy]propyl]adenine fumarate (1:1). It has molecular formula of C19H30N5O10P C4H4O4 and molecular weight of 635.52. It has the following structural formula:TDF is white to off-white crystalline powder with solubility of 13.4 mg per mL in water at 25 C. All dosages are expressed in terms of TDF except where otherwise noted.. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Testing: Prior to or when initiating COMPLERA, test for hepatitis virus infection. Prior to initiation and during treatment with COMPLERA, on clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus. (2.1)Recommended dosage in adults and pediatric patients weighing at least 35 kg: One tablet taken orally once daily with food. (2.2) For pregnant patients who are already on COMPLERA prior to pregnancy and who are virologically suppressed (HIV-1 RNA less than 50 copies per mL), one tablet taken once daily may be continued. Lower exposures of rilpivirine were observed during pregnancy; therefore, viral load should be monitored closely. (2.3)Renal impairment: Not recommended in patients with estimated creatinine clearance below 50 mL per minute. (2.4)Recommended dosage with rifabutin coadministration: an additional 25 mg tablet of rilpivirine (Edurant) once per day taken concomitantly with COMPLERA and with meal for the duration of the rifabutin coadministration. (2.5, 7.6, 12.3). Testing: Prior to or when initiating COMPLERA, test for hepatitis virus infection. Prior to initiation and during treatment with COMPLERA, on clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus. (2.1). Recommended dosage in adults and pediatric patients weighing at least 35 kg: One tablet taken orally once daily with food. (2.2). For pregnant patients who are already on COMPLERA prior to pregnancy and who are virologically suppressed (HIV-1 RNA less than 50 copies per mL), one tablet taken once daily may be continued. Lower exposures of rilpivirine were observed during pregnancy; therefore, viral load should be monitored closely. (2.3). Renal impairment: Not recommended in patients with estimated creatinine clearance below 50 mL per minute. (2.4). Recommended dosage with rifabutin coadministration: an additional 25 mg tablet of rilpivirine (Edurant) once per day taken concomitantly with COMPLERA and with meal for the duration of the rifabutin coadministration. (2.5, 7.6, 12.3). 2.1Testing Prior to Initiation and During Treatment with COMPLERA. Prior to or when initiating COMPLERA, test patients for hepatitis virus infection [see Warnings and Precautions (5.1)]. Prior to initiation of COMPLERA, and during treatment with COMPLERA, on clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus [see Warnings and Precautions (5.5)]. 2.2Recommended Dosage COMPLERA is three-drug fixed dose combination product containing 200 mg of emtricitabine (FTC), 25 mg of rilpivirine (RPV), and 300 mg of tenofovir disoproxil fumarate (TDF). The recommended dosage of COMPLERA in adult and pediatric patients weighing at least 35 kg is one tablet taken orally once daily with food [see Use in Specific Populations (8.4) and Clinical Pharmacology (12.3)]. 2.3Recommended Dosage During Pregnancy. For pregnant patients who are already on COMPLERA prior to pregnancy and are virologically suppressed (HIV-1 RNA less than 50 copies per mL), one tablet of COMPLERA taken once daily may be continued. Lower exposures of rilpivirine, component of COMPLERA, were observed during pregnancy, therefore viral load should be monitored closely [see Use in Specific Populations (8.1) and Clinical Pharmacology (12.3)].. 2.4Not Recommended in Patients with Moderate or Severe Renal Impairment. COMPLERA is not recommended in patients with moderate or severe renal impairment (estimated creatinine clearance below 50 mL per minute) [see Warnings and Precautions (5.5) and Use in Specific Populations (8.6)].. 2.5Recommended Dosage with Rifabutin Coadministration. If COMPLERA is coadministered with rifabutin, take an additional 25 mg tablet of rilpivirine (Edurant) with COMPLERA once daily with meal for the duration of the rifabutin coadministration [see Drug Interactions (7.6) and Clinical Pharmacology (12.3)].

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Each COMPLERA tablet contains 200 mg of emtricitabine (FTC), 27.5 mg of rilpivirine hydrochloride (equivalent to 25 mg of rilpivirine [RPV]), and 300 mg of tenofovir disoproxil fumarate (TDF, equivalent to 245 mg of tenofovir disoproxil).The tablets are white, capsule shaped, film coated and debossed with GSI on both sides. Tablets: 200 mg of emtricitabine, 25 mg of rilpivirine, and 300 mg of tenofovir disoproxil fumarate. (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. COMPLERA is complete regimen for the treatment of HIV-1 infection; therefore, coadministration with other antiretroviral medications for treatment of HIV-1 infection is not recommended. (7.1)Consult the Full Prescribing Information prior to and during treatment for important drug interactions. (4, 5.7, 7). COMPLERA is complete regimen for the treatment of HIV-1 infection; therefore, coadministration with other antiretroviral medications for treatment of HIV-1 infection is not recommended. (7.1). Consult the Full Prescribing Information prior to and during treatment for important drug interactions. (4, 5.7, 7). 7.1Not Recommended with Other Antiretroviral Medications Because COMPLERA is complete regimen, coadministration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended. Comprehensive information regarding potential drug-drug interactions with other antiretroviral medications is not provided.This section describes clinically relevant drug interactions with COMPLERA. Drug interaction studies were conducted with the components of COMPLERA (FTC, RPV, and TDF as single agents) or with COMPLERA as combination product [see Dosage and Administration (2), Contraindications (4), and Clinical Pharmacology (12.3)].. 7.2Drugs Inducing or Inhibiting CYP3A Enzymes. Rilpivirine is primarily metabolized by cytochrome P450 (CYP) 3A, and drugs that induce or inhibit CYP3A may thus affect the clearance of RPV [see Contraindications (4), Warnings and Precautions (5.7), and Clinical Pharmacology (12.3)]. Coadministration of RPV and drugs that induce CYP3A may result in decreased plasma concentrations of RPV and loss of virologic response and possible resistance to RPV or to the class of NNRTIs. Coadministration of RPV and drugs that inhibit CYP3A may result in increased plasma concentrations of RPV.. 7.3Drugs Increasing Gastric pH. Coadministration of RPV with drugs that increase gastric pH may decrease plasma concentrations of RPV and loss of virologic response and possible resistance to RPV or to the class of NNRTIs. Use of RPV with proton pump inhibitors is contraindicated and use of RPV with H2-receptor antagonists requires staggered administration [see Contraindications (4) and Clinical Pharmacology (12.3)].. 7.4Drugs Affecting Renal Function. Because FTC and tenofovir are primarily eliminated by the kidneys through combination of glomerular filtration and active tubular secretion, coadministration of COMPLERA with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of FTC, tenofovir, and/or other renally eliminated drugs. Some examples of drugs that are eliminated by active tubular secretion include, but are not limited to, acyclovir, adefovir dipivoxil, cidofovir, ganciclovir, valacyclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs [see Warnings and Precautions (5.5)].. 7.5QT Prolonging Drugs. There is limited information available on the potential for pharmacodynamic interaction between RPV and drugs that prolong the QTc interval of the electrocardiogram. In study of healthy subjects, 75 mg once daily and 300 mg once daily doses of RPV (3 times and 12 times the dose in COMPLERA) have been shown to prolong the QTc interval of the electrocardiogram [see Warnings and Precautions (5.7) and Clinical Pharmacology (12.2)]. Consider alternatives to COMPLERA when coadministered with drug with known risk of Torsade de Pointes.. 7.6 Significant Drug Interactions. Important drug interaction information for COMPLERA is summarized in Table 4. The drug interactions described are based on studies conducted with FTC, RPV, or TDF as individual medications or with COMPLERA as combination product, or are potential drug interactions [see Clinical Pharmacology (12.3) Tables 9-14]. For list of contraindicated drugs, [see Contraindications (4)]. Table 4SignificantThis table is not all inclusive. Drug InteractionsConcomitant Drug Class: Drug NameEffect on ConcentrationIncrease ; Decrease ; No Effect <-> Clinical CommentAntacids: antacids (e.g., aluminum, magnesium hydroxide, or calcium carbonate)<-> RPV(antacids taken at least hours before or at least hours after RPV) RPV (concomitant intake)Administer antacids at least hours before or at least hours after COMPLERA.Anticonvulsants: carbamazepine oxcarbazepine phenobarbital phenytoin RPVCoadministration is contraindicated due to potential for loss of virologic response and development of resistance.Antimycobacterials: rifampin rifapentine RPVCoadministration is contraindicated due to potential for loss of virologic response and development of resistance. rifabutin RPVThe interaction was evaluated in clinical study. All other drug-drug interactions shown are predicted. If COMPLERA is coadministered with rifabutin, an additional 25 mg tablet of RPV (Edurant) once per day is recommended to be taken concomitantly with COMPLERA and with meal for the duration of rifabutin coadministration.Azole Antifungal Agents: fluconazole itraconazole ketoconazole posaconazole voriconazole RPV This interaction study has been performed with dose higher than the recommended dose for RPV assessing the maximal effect on the coadministered drug. The dosing recommendation is applicable to the recommended dose of RPV 25 mg once daily. ketoconazole No dose adjustment is required when COMPLERA is coadministered with azole antifungal agents. Clinically monitor for breakthrough fungal infections when azole antifungals are coadministered with COMPLERA.Glucocorticoid (systemic): dexamethasone (more than single-dose treatment) RPVCoadministration is contraindicated due to potential for loss of virologic response and development of resistance.Hepatitis Antiviral Agents: ledipasvir/sofosbuvir sofosbuvir/velpatasvir sofosbuvir/velpatasvir/voxilaprevir tenofovir Patients receiving COMPLERA concomitantly with HARVONI(TM) (ledipasvir/sofosbuvir), EPCLUSA(TM) (sofosbuvir/velpatasvir), or VOSEVI(TM) (sofosbuvir/velpatasvir/voxilaprevir) should be monitored for adverse reactions associated with TDF.H2-Receptor Antagonists: cimetidine famotidine nizatidine ranitidine<-> RPV (famotidine taken 12 hours before RPV or hours after RPV) RPV (famotidine taken hours before RPV)Administer H2-receptor antagonists at least 12 hours before or at least hours after COMPLERA.Herbal Products: St Johns wort (Hypericum perforatum) RPVCoadministration is contraindicated due to potential for loss of virologic response and development of resistance.Macrolide or Ketolide Antibiotics: clarithromycin erythromycin telithromycin RPV<-> clarithromycin<-> erythromycin<-> telithromycinWhere possible, alternatives such as azithromycin should be considered.Narcotic Analgesics: methadone R(-) methadone S(+) methadone <-> RPV <-> methadone (when used with tenofovir)No dose adjustments are required when initiating coadministration of methadone with COMPLERA. However, clinical monitoring is recommended as methadone maintenance therapy may need to be adjusted in some patients.Proton Pump Inhibitors: e.g., dexlansoprazole esomeprazole lansoprazole omeprazole pantoprazole rabeprazole RPVCoadministration is contraindicated due to potential for loss of virologic response and development of resistance.. 7.7Drugs with No Observed Interactions with COMPLERA. No clinically significant drug interactions have been observed between FTC and the following medications: famciclovir, ledipasvir/sofosbuvir, sofosbuvir/velpatasvir, sofosbuvir/velpatasvir/voxilaprevir, or TDF.No clinically significant drug interactions have been observed between TDF and the following medications: entecavir, methadone, oral contraceptives, ribavirin, sofosbuvir, or tacrolimus in studies conducted in healthy subjects.No clinically significant drug interactions have been observed between RPV and the following medications: acetaminophen, atorvastatin, chlorzoxazone, ethinyl estradiol, ledipasvir/sofosbuvir, norethindrone, sildenafil, simeprevir, sofosbuvir, sofosbuvir/velpatasvir, sofosbuvir/velpatasvir/voxilaprevir, or TDF. RPV did not have clinically significant effect on the pharmacokinetics of digoxin or metformin.

GERIATRIC USE SECTION.

8.5 Geriatric Use. Clinical studies of FTC, RPV, or TDF 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 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 [see Clinical Pharmacology (12.3)].

HEPATIC IMPAIRMENT SUBSECTION.

8.7Hepatic Impairment. No dose adjustment of COMPLERA is required in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. COMPLERA has not been studied in patients with severe hepatic impairment (Child-Pugh Class C) [see Clinical Pharmacology (12.3)].

OVERDOSAGE SECTION.

10 OVERDOSAGE. If overdose occurs the patient must be monitored for evidence of toxicity. Treatment of overdose with COMPLERA consists of general supportive measures, including monitoring of vital signs and ECG (QT interval) as well as observation of the clinical status of the patient.. Emtricitabine: Hemodialysis treatment removes approximately 30% of the FTC dose over 3-hour dialysis period starting within 1.5 hours of FTC dosing (blood flow rate of 400 mL per minute and dialysate flow rate of 600 mL per minute). It is not known whether FTC can be removed by peritoneal dialysis.. Rilpivirine: There is no specific antidote for overdose with RPV. Human experience of overdose with RPV is limited. Since RPV is highly bound to plasma protein, dialysis is unlikely to result in significant removal of RPV.. Tenofovir DF: Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%. Following single 300 mg dose of TDF, 4-hour hemodialysis session removed approximately 10% of the administered tenofovir dose.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 30 Tablet Bottle Label. 61958-1102-530 tabletsCOMPLERA(TM)(emtricitabine, rilpivirine, tenofovir disoproxil fumarate) tablets 200 mg 25 mg 300 mgGILEAD ACCESS PROGRAMNote to pharmacist: Do not cover ALERT box with pharmacy label.ALERT: Find out about medicines that should NOT be taken with COMPLERARx onlyPOM. PRINCIPAL DISPLAY PANEL 30 Tablet Bottle Label.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectiveness of COMPLERA as complete regimen for the treatment of HIV-1 infection was established in pediatric subjects 12 years of age and older with body weight greater than or equal to 35 kg [see Dosage and Administration (2.2)]. Use of COMPLERA in this age group weighing at least 35 kg is supported by adequate and well-controlled studies of RPV+FTC+TDF in adults with HIV-1 infection as well as data from pediatric studies of the individual components of COMPLERA (RPV, FTC, and TDF) [see Clinical Pharmacology (12.3), and Clinical Studies (14.2)]. COMPLERA should only be administered to pediatric patients with body weight greater than or equal to 35 kg. Because COMPLERA is fixed-dose combination tablet, the dose of COMPLERA cannot be adjusted for patients of lower weight. Safety and effectiveness for COMPLERA have not been established in pediatric patients weighing less than 35 kg [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3)].

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Effects on ElectrocardiogramThe effect of RPV at the recommended dose of 25 mg once daily on the QTcF interval was evaluated in randomized, placebo-, and active- (moxifloxacin 400 mg once daily) controlled crossover study in 60 healthy adults, with 13 measurements over 24 hours at steady state. The maximum mean time-matched (95% upper confidence bound) differences in QTcF interval from placebo after baseline correction was 2.0 (5.0) milliseconds (i.e., below the threshold of clinical concern).When doses of 75 mg once daily and 300 mg once daily of RPV (3 times and 12 times the dose in COMPLERA) were studied in healthy adults, the maximum mean time-matched (95% upper confidence bound) differences in QTcF interval from placebo after baseline correction were 10.7 (15.3) and 23.3 (28.4) milliseconds, respectively. Steady-state administration of RPV 75 mg once daily and 300 mg once daily resulted in mean steady-state Cmax approximately 2.6-fold and 6.7-fold, respectively, higher than the mean Cmax observed with the recommended 25 mg once daily dose of RPV [see Warnings and Precautions (5.7)].

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. COMPLERA: Under fed conditions (total calorie content of the meal was approximately 400 kcal with approximately 13 grams of fat), RPV, FTC, and tenofovir exposures were similar when comparing COMPLERA to EMTRIVA capsules (200 mg) plus Edurant tablets (25 mg) plus VIREAD tablets (300 mg) following single-dose administration to healthy subjects (N=34).Single-dose administration of COMPLERA tablets to healthy subjects under fasted conditions provided approximately 25% higher exposure of RPV compared to administration of EMTRIVA capsules (200 mg) plus Edurant tablets (25 mg) plus VIREAD tablets (300 mg), while exposures of FTC and tenofovir were comparable (N=15).. Absorption, Distribution, Metabolism, and ExcretionThe pharmacokinetic properties of the components of COMPLERA are provided in Table 5. The PK parameters of RPV, FTC, and tenofovir are provided in Table 6.Table 5Pharmacokinetic Properties of the Components of COMPLERARPVFTCTenofovirNC=Not CalculatedAbsorption Tmax (h)4-51-21 Fasted oral bioavailabilityMedian NC9325Oral bioavailability of tenofovir from VIREAD. Effect of light meal (relative to fasting)Values refer to change based on calculated geometric mean ratio [fed/fasted] in AUC.COMPLERA light meal 390 kcal, 12 fat; COMPLERA standard meal 540 kcal, 21 fat. High fat meal not evaluated. Increase ; Decrease ; No Effect= <-> 9%<->28% Effect of standard meal (relative to fasting) 16%<->38%Distribution Bound to human plasma proteins~99<4<0.7 Source of protein binding dataIn vitroIn vitroIn vitroMetabolism MetabolismCYP3ANot significantly metabolizedElimination Major route of eliminationMetabolismGlomerular filtration and active tubular secretion CLrenal Mean +- SD (mL/min)NC213+-89243+-33 t1/2 (h)t1/2 values refer to median terminal plasma half-life. 501017 Of dose excreted in urineDosing in mass balance studies: FTC (single dose administration of [14C] FTC after multiple dosing of FTC for 10 days); RPV (single dose administration of [14C] RPV); mass balance study not conducted for tenofovir. 68670-80 Of dose excreted in feces 85~14NCTable 6Pharmacokinetic Parameters for RPV, FTC, and Tenofovir in HIV-Infected AdultsParameterMean +- SDRPVPopulation PK estimates of RPV 25 mg once daily in antiretroviral treatment-naive HIV-1-infected adult subjects (pooled data from Phase trials through Week 96; n=679) FTCMultiple-dose oral administration of FTC 200 mg to HIV-1-infected subjects (n=20) TenofovirSingle 300 mg dose of TDF to HIV-1-infected subjects in the fasted state NA=Not Applicable; SD=Standard DeviationCmax (ug/mL)NA1.80+-0.72Data presented as steady state values 0.30+-0.09AUCtau (ughr/mL)2.24+-0.85 10.0+-3.12 2.29+-0.69AUC0-24h C0h (ug/mL)0.08+-0.04 0.09+-0.07 NA. Specific Populations. Geriatric PatientsThe pharmacokinetics of FTC, RPV, and tenofovir have not been fully evaluated in the elderly (65 years of age and older) [see Use in Specific Populations (8.5)]. Pediatric PatientsPediatric trials have not been conducted using COMPLERA tablets. Pediatric information is based on trials conducted with the individual components of COMPLERA [see Use in Specific Populations (8.4)].. Emtricitabine: The pharmacokinetics of FTC at steady state were determined in 27 HIV-1-infected pediatric subjects 13 to 17 years of age receiving daily dose of mg/kg up to maximum dose of 240 mg oral solution or 200 mg capsule; 26 of 27 subjects in this age group received the 200 mg FTC capsule. Mean (+- SD) Cmax and AUC were 2.7 +- 0.9 ug/mL and 12.6 +- 5.4 ughr/mL, respectively. Exposures achieved in pediatric subjects 12 to less than 18 years of age were similar to those achieved in adults receiving once daily dose of 200 mg.. Rilpivirine: The pharmacokinetics of RPV in antiretroviral treatment-naive HIV-1- infected pediatric subjects 12 to less than 18 years of age receiving RPV 25 mg once daily were comparable to those in treatment-naive HIV-1-infected adults receiving RPV 25 mg once daily (See Table 7). There was no clinically significant impact of body weight on RPV pharmacokinetics in pediatric subjects in trial C213 (33 to 93 kg).Table 7Population Pharmacokinetic Estimates of RPV 25 mg once daily in Antiretroviral Treatment-Naive HIV-1-Infected Pediatric Subjects aged 12 to less than 18 years (Data from Phase Trial through Week 48)ParameterRPV 25 mg once dailyN=34AUC24h (ngh/mL) Mean +- Standard Deviation2424 +- 1024 Median (Range)2269 (417-5166)C0h (ng/mL) Mean +- Standard Deviation85 +- 40 Median (Range)79 (7-202). Tenofovir DF: Steady-state pharmacokinetics of tenofovir were evaluated in HIV-1-infected pediatric subjects (12 to less than 18 years). Mean (+- SD) Cmax and AUCtau are 0.38 +- 0.13 ug/mL and 3.39 +- 1.22 ughr/mL, respectively. Tenofovir exposure achieved in these pediatric subjects receiving oral daily doses of TDF 300 mg was similar to exposures achieved in adults receiving once-daily doses of TDF 300 mg.. GenderNo clinically relevant pharmacokinetic differences have been observed based on gender for FTC, RPV, and TDF.. Race. Emtricitabine: No pharmacokinetic differences due to race have been identified following the administration of FTC.. Rilpivirine: Population pharmacokinetic analysis of RPV in HIV-1-infected subjects indicated that race had no clinically relevant effect on the exposure to RPV.. Tenofovir DF: There were insufficient numbers from racial and ethnic groups other than Caucasian to adequately determine potential pharmacokinetic differences among these populations following the administration of TDF.. Patients with Renal Impairment. Emtricitabine and Tenofovir DF: The pharmacokinetics of FTC and TDF are altered in subjects with renal impairment. In subjects with creatinine clearance below 50 mL per minute or with end stage renal disease requiring dialysis, Cmax and AUC of FTC and tenofovir were increased [see Warnings and Precautions (5.5) and Use in Specific Populations (8.6)].. Rilpivirine: Population pharmacokinetic analysis indicated that RPV exposure was similar in HIV-1-infected subjects with mild renal impairment relative to HIV-1-infected subjects with normal renal function. There is limited or no information regarding the pharmacokinetics of RPV in patients with moderate or severe renal impairment or in patients with end-stage renal disease, and RPV concentrations may be increased due to alteration of drug absorption, distribution, and metabolism secondary to renal dysfunction [see Use in Specific Populations (8.6)].. Patients with Hepatic Impairment. Emtricitabine: The pharmacokinetics of FTC have not been studied in subjects with hepatic impairment; however, FTC is not significantly metabolized by liver enzymes, so the impact of liver impairment should be limited.. Rilpivirine: RPV is primarily metabolized and eliminated by the liver. In study comparing subjects with mild hepatic impairment (Child-Pugh score A) to matched controls, and subjects with moderate hepatic impairment (Child-Pugh score B) to matched controls, the multiple dose exposure of RPV was 47% higher in subjects with mild hepatic impairment and 5% higher in subjects with moderate hepatic impairment. RPV has not been studied in subjects with severe hepatic impairment (Child-Pugh score C) [see Use in Specific Populations (8.7)]. Tenofovir DF: The pharmacokinetics of tenofovir following 300 mg dose of TDF have been studied in non-HIV-infected subjects with moderate to severe hepatic impairment. There were no substantial alterations in tenofovir pharmacokinetics in subjects with hepatic impairment compared with unimpaired subjects.. Hepatitis and/or Hepatitis Virus CoinfectionThe pharmacokinetics of FTC and TDF have not been fully evaluated in hepatitis and/or virus-coinfected patients. Population pharmacokinetic analysis indicated that hepatitis and/or virus coinfection had no clinically relevant effect on the exposure to RPV.. Pregnancy and PostpartumThe exposure (C0h and AUC24h) to total RPV after intake of RPV 25 mg once daily as part of an antiretroviral regimen was 30 to 40% lower during pregnancy (similar for the second and third trimester), compared with postpartum (see Table 8). However, the exposure during pregnancy was not significantly different from exposures obtained in Phase trials of RPV-containing regimens. Based on the exposure-response relationship for RPV, this decrease is not considered clinically relevant in patients who are virologically suppressed. The protein binding of RPV was similar (>99%) during the second trimester, third trimester, and postpartum.Table 8: Pharmacokinetic Results of Total RPV After Administration of RPV 25 mg Once Daily as Part of an Antiretroviral Regimen, During the 2nd Trimester of Pregnancy, the 3rd Trimester of Pregnancy and PostpartumPharmacokinetics of total RPV(mean +-SD, tmax: median [range])Postpartum(6-12 Weeks)(n=11)2nd Trimester of pregnancy(n=15)3rd Trimester of pregnancy(n=13)C0h, ng/mL111 +- 69.265.0 +- 23.963.5 +- 26.2Cmin, ng/mL84.0 +- 58.854.3 +- 25.852.9 +- 24.4Cmax, ng/mL167 +- 101121 +- 45.9123 +- 47.5tmax, h4.00 (2.03-25.08)4.00 (1.00-9.00)4.00 (2.00-24.93)AUC24h, ngh/mL2,714 +- 1,5351,792 +- 7111,762 +- 662. Drug Interaction Studies. Rilpivirine: RPV is primarily metabolized by cytochrome CYP3A, and drugs that induce or inhibit CYP3A may thus affect the clearance of RPV. Coadministration of COMPLERA and drugs that induce CYP3A may result in decreased plasma concentrations of RPV and loss of virologic response and possible resistance. Coadministration of COMPLERA and drugs that inhibit CYP3A may result in increased plasma concentrations of RPV. Coadministration of COMPLERA with drugs that increase gastric pH may result in decreased plasma concentrations of RPV and loss of virologic response and possible resistance to RPV and to the class of NNRTIs.RPV at dose of 25 mg once daily is not likely to have clinically relevant effect on the exposure of medicinal products metabolized by CYP enzymes.. Emtricitabine and Tenofovir DF: In vitro and clinical pharmacokinetic drug-drug interaction studies have shown that the potential for CYP-mediated interactions involving FTC and tenofovir with other medicinal products is low.FTC and tenofovir are primarily excreted by the kidneys by combination of glomerular filtration and active tubular secretion. No drug-drug interactions due to competition for renal excretion have been observed; however, coadministration of FTC and TDF with drugs that are eliminated by active tubular secretion may increase concentrations of FTC, tenofovir, and/or the coadministered drug [see Drug Interactions (7.4, 7.6)].Drugs that decrease renal function may increase concentrations of FTC and/or tenofovir.The drug interaction studies described in Tables 9-14 were conducted with COMPLERA (RPV/FTC/TDF) or the components of COMPLERA (RPV, FTC, or TDF) administered individually.The effects of coadministration of other drugs on the AUC, Cmax, and Cmin values of RPV, FTC, and TDF are summarized in Tables 9, 10, and 11, respectively. The effect of coadministration of RPV, FTC, and TDF on the AUC, Cmax, and Cmin values of other drugs are summarized in Tables 12, 13, and 14, respectively. For information regarding clinical recommendations, see Drug Interactions (7).Table 9Drug Interactions: Changes in Pharmacokinetic Parameters for RPV in the Presence of the Coadministered DrugsCoadministered DrugDose of Coadministered Drug (mg)RPV Dose (mg)NN=maximum number of subjects for Cmax, AUC, or Cmin Mean Change of RPV Pharmacokinetic ParametersIncrease ; Decrease ; No Effect <-> (90% CI)Cmax AUCCmin NA=not availableAcetaminophen500 single dose150 once dailyThe interaction study has been performed with dose higher than the recommended dose for RPV (25 mg once daily) assessing the maximal effect on the coadministered drug. 169(1 to 18)16(10 to 22)26(16 to 38)Atorvastatin40 once daily150 once daily 169(21 to 6)10(19 to 1)10(16 to 4)Chlorzoxazone500 single dose taken hours after RPV150 once daily 1617(8 to 27)25(16 to 35)18(9 to 28)Ethinyl Estradiol/Norethindrone0.035 once daily/1 once daily25 once daily16<->Study conducted with COMPLERA (RPV/FTC/TDF) coadministered with HARVONI (ledipasvir/sofosbuvir). <-> <-> Famotidine40 single dose taken 12 hours before RPV150 single dose 241(16 to 16)9(22 to 7)NA40 single dose taken hours before RPV150 single dose 2385(88 to 81)76(80 to 72)NA40 single dose taken hours after RPV150 single dose 2421(6 to 39)13(1 to 27)NAKetoconazole400 once daily150 once daily 1530(13 to 48)49(31 to 70)76(57 to 97)Ledipasvir/Sofosbuvir90/400 once daily25 once daily 143(12 to 7)2(6 to 11)12(3 to 21)Methadone60-100 once daily individualized dose25 once daily12<->Comparison based on historic controls. <-> <-> Omeprazole20 once daily150 once daily 1640(52 to 27)40(49 to 29)33(42 to 22)Rifabutin300 once daily25 once daily1831(38 to 24)42(48 to 35)48(54 to 41)300 once daily50 once daily1843(30 to 56)Reference arm for comparison was 25 mg q.d. RPV administered alone. 16(6 to 26) 7(15 to1) Rifampin600 once daily150 once daily 1669(73 to 64)80(82 to 77)89(90 to 87)Simeprevir25 once daily150 once daily23 4( to 13) 12( to 19) 25( 16 to 35)Sildenafil50 single dose75 once daily168(15 to 1)2(8 to 5)4(2 to 9)Sofosbuvir/Velpatasvir400/100 once daily25 once dailyStudy conducted with COMPLERA coadministered with EPCLUSA (sofosbuvir/velpatasvir). 247(12 to 2)5(10 to 0)4(10 to 3)Sofosbuvir/Velpatasvir/VoxilaprevirStudy conducted with ODEFSEY(TM) (FTC/RPV/tenofovir alafenamide). 400/100/100 100 voxilaprevirStudy conducted with additional voxilaprevir 100 mg to achieve voxilaprevir exposures expected in HCV-infected patients. once daily25 once daily3021(26 to 16)20(24 to 15)18(23 to 13)TDF300 once daily150 once daily 164(19 to 13)1(13 to 18)1(17 to 16)Table 10Drug Interactions: Changes in Pharmacokinetic Parameters for FTC in the Presence of the Coadministered DrugsCoadministered DrugDose of Coadministered Drug (mg)FTC Dose (mg)NN=maximum number of subjects for Cmax, AUC, or Cmin Mean Change of FTC Pharmacokinetic ParametersIncrease ; Decrease ; No Effect <-> (90% CI)Cmax AUCCmin NA=not availableFamciclovir500 1200 112<-><->NALedipasvir/Sofosbuvir90/400 once daily200 once dailyStudy conducted with COMPLERA coadministered with HARVONI. 152(2 to 6)5(2 to 8)6(3 to 15)Sofosbuvir/Velpatasvir400/100 once daily200 once dailyStudy conducted with COMPLERA coadministered with EPCLUSA. 245(10 to 0)1(3 to 2)5(1 to 11)Sofosbuvir/Velpatasvir/Voxilaprevir400/100/100 VoxilaprevirStudy conducted with additional voxilaprevir 100 mg to achieve voxilaprevir exposures expected in HCV-infected patients. 100 once daily200 once dailyStudy conducted with ODEFSEY (FTC/RPV/tenofovir alafenamide). 3012(17 to 7)7(10 to 4)7(1 to 14)TDF300 once daily 7 days200 once daily 7 days17<-><-> 20( 12 to 29)Table 11Drug Interactions: Changes in Pharmacokinetic Parameters for Tenofovir in the Presence of the Coadministered DrugsCoadministered DrugDose of Coadministered Drug (mg)TDF Dose (mg)Subjects received VIREAD 300 mg daily. NN=maximum number of subjects for Cmax, AUC, or Cmin Mean Change of Tenofovir Pharmacokinetic ParametersIncrease ; Decrease ; No Effect <-> (90% CI)Cmax AUCCmin NA=not availableEntecavir1 once daily 10 days300 once daily<-><-><->Emtricitabine200 once daily 7 days300 once daily 7 days17<-><-><->Ledipasvir/Sofosbuvir90/400 once daily 10 days300 once dailyStudy conducted with COMPLERA coadministered with HARVONI. 14 32( 25 to 39 40( 31 to 50 91( 74 to 110)Sofosbuvir/Velpatasvir400/100 once daily300 once daily24 44( 33 to 55) 40( 34 to 46) 84( 76 to 92)Tacrolimus0.05 mg/kg twice daily 7 days300 once dailyStudy conducted with COMPLERA coadministered with EPCLUSA. 21 13( to 27)<-><->Table 12Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drugs in the Presence of RPVCoadministered DrugDose of Coadministered Drug (mg)RPV Dose (mg)NN=maximum number of subjects for Cmax, AUC, or Cmin Mean Change of Coadministered Drug Pharmacokinetic ParametersIncrease ; Decrease ; No Effect <-> (90% CI)Cmax AUCCmin NA not availableAcetaminophen500 single dose150 once dailyThe Interaction study has been performed with dose higher than the recommended dose for RPV (25 mg once daily). 16 3( 14 to 10) 8( 15 to 1)NAAtorvastatin40 once daily150 once daily 16 35( to 68) 4( to 12) 15( 31 to 3)2-hydroxy-atorvastatin16 58( 33 to 87) 39( 29 to 50) 32( 10 to 58)4-hydroxy-atorvastatin16 28( 15 to 43) 23( 13 to 33)NAChlorzoxazone500 single dose taken hours after RPV150 once daily 16 2( 15 to 13) 3( to 13)NADigoxin0.5 single dose25 once daily22 6( to 17) 2( to 4)NAEthinyl estradiol0.035 once daily25 once daily17 17( to 30) 14( 10 to 19) 9( to 16)Norethindrone1 mg once daily 6( 17 to 6) 11( 16 to 6) 1( 10 to 8)Ketoconazole400 once daily150 once daily 14 15( 20 to 10) 24( 30 to 18) 66( 75 to 54)Ledipasvir90 once daily25 once daily41 1( to 5) 2( to 6) 2( to 7)R(-) methadone60-100 once daily individualized dose25 once daily13 14( 22 to 5) 16( 26 to 5) 22( 33 to 9)S(+) methadone13 13( 22 to 3) 16( 26 to 4) 21( 33 to 8)Metformin850 single dose25 once daily20 2( to 10) 3( 10 to 6)NAOmeprazole20 once daily150 once daily 15 14( 32 to 9) 14( 24 to 3)NARifampin600 once daily150 once daily 16 2( to 12) 1( to 7)NA25-desacetylrifampin16<->( 13 to 15) 9( 23 to 7)NASimeprevir150 once daily25 once daily21 10( to 26) 6( to 19) 4( 17 to 11)Sildenafil50 single dose75 once daily 16 7( 20 to 8) 3( 13 to 8)NAN-desmethyl-sildenafil 10( 20 to 2) 8( 15 to 1)NASofosbuvir400 once daily25 once daily24 9( to 25) 16( 10 to 24)NAGS-331007The predominant circulating nucleoside metabolite of sofosbuvir. 4( 10 to 1) 4(0 to 7) 12( to 17)Velpatasvir100 once daily25 once daily24 4( 15 to 10) 1( 12 to 11) 2( to 15)Sofosbuvir400 once daily25 once dailyStudy conducted with ODEFSEY. 30 5( 14 to 5) 1( to 6)NAGS-331007 2( to 6) 4( to 6)NAVelpatasvir100 once daily25 once daily 30 5( to 16) 1( to 7) 1( to 9)Voxilaprevir100 100 once daily25 once daily 30 4( 16 to 11) 6( 16 to 5) 2( to 12)TDF300 once daily150 once daily 16 19( to 34) 23( 16 to 31) 24( 10 to 38)Table 13Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drugs in the Presence of FTCCoadministered DrugDose of Coadministered Drug (mg)FTC Dose (mg)NAll interaction trials conducted in healthy volunteers Mean Change of Coadministered Drug Pharmacokinetic ParametersNo Effect <-> (90% CI)Cmax AUCCmin NA=not availableFamciclovir500 1200 112<-><->NATDF300 once daily 7 days200 once daily 7 days17<-><-><->No clinically significant drug interactions have been observed between FTC and indinavir, sofosbuvir/velpatasvir, sofosbuvir/velpatasvir/voxilaprevir, stavudine, and zidovudine.Table 14Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drugs in the Presence of TDFCoadministered DrugDose of Coadministered Drug (mg)TDF Dose (mg)NAll interaction trials conducted in healthy volunteers Mean Change of Coadministered Drug Pharmacokinetic ParametersIncrease ; No Effect <-> (90% CI)Cmax AUCCmin NA=not availableEmtricitabine200 once daily 7 days300 once daily 7 days17<-><-> 20( 12 to 29)Entecavir1 once daily 10 days300 once daily28<-> 13( 11 to 15)<->Tacrolimus0.05 mg/kg twice daily 7 days300 once daily21<-><-><->No effect on the pharmacokinetic parameters of the following coadministered drugs was observed with TDF: methadone, oral contraceptives (ethinyl estradiol/norgestimate), or ribavirin.

PREGNANCY SECTION.

8.1 Pregnancy. Pregnancy Exposure RegistryThere is pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to COMPLERA during pregnancy. Healthcare providers are encouraged to register patients on the worldwide Antiretroviral Pregnancy Registry (APR) at www.apregistry.com/.. Risk SummaryAvailable data from the APR show no increase in the overall risk of major birth defects with first trimester exposure for emtricitabine (FTC), rilpivirine (RPV), or tenofovir (TDF) compared with the background rate for major birth defects of 2.7% in U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) (see Data). In clinical trial, total rilpivirine exposures were generally lower during pregnancy compared to the postpartum period [see Clinical Pharmacology (12.3)]. The rate of miscarriage for individual drugs is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15-20%.Based on the experience of HIV-1-infected pregnant individuals who completed clinical trial through the postpartum period with an RPV-based regimen, no dose adjustments are required for pregnant patients who are already on stable RPV-containing regimen prior to pregnancy and who are virologically suppressed (HIV-1 RNA less than 50 copies per mL). Lower exposures of RPV were observed during pregnancy, therefore viral load should be monitored closely [see Data and Clinical Pharmacology (12.3)].In animal studies, no adverse developmental effects were observed when the components of COMPLERA were administered separately during the period of organogenesis at exposures up to 60 and 120 times (mice and rabbits, respectively, FTC) and 15 and 70 times (rats and rabbits, respectively; RPV) the exposure of these components in COMPLERA and at 14 and 19 times (rats and rabbits, respectively) the human dose of TDF based on body surface area comparisons (see Data). Likewise, no adverse developmental effects were seen when FTC was administered to mice and RPV was administered to rats through lactation at exposures up to approximately 60 and 63 times, respectively, the exposure at the recommended daily dose of these components in COMPLERA. No adverse effects were observed in the offspring of rats when TDF was administered through lactation at tenofovir exposures of approximately 14 times the exposure at the recommended daily dosage of COMPLERA.. Data. Human DataProspective reports from the APR of overall major birth defects in pregnancies exposed to drug components of COMPLERA are compared with U.S. background major birth defect rate. Methodological limitations of the APR include the use of MACDP as the external comparator group. Limitations of using an external comparator include differences in methodology and populations, as well as confounding due to the underlying disease.. Emtricitabine: Based on prospective reports to the APR of exposures to FTC-containing regimens during pregnancy resulting in live births (including over 2,750 exposed in the first trimester and over 1,200 exposed in the second/third trimester), there was no increase in overall major birth defects with FTC compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of major birth defects in live births was 2.4% (95% CI: 1.9% to 3.1%) with first trimester exposure to FTC-containing regimens and 2.3% (95% CI: 1.5% to 3.3%) with the second/third trimester exposure to FTC-containing regimens.. Rilpivirine: RPV in combination with background regimen was evaluated in clinical trial of 19 HIV-1 infected pregnant subjects on an RPV-based regimen during the second and third trimesters and postpartum. Each of the subjects were on an RPV-based regimen at the time of enrollment. Twelve subjects completed the trial through the postpartum period (6-12 weeks after delivery) and pregnancy outcomes are missing for six subjects. The exposure (C0h and AUC) of total RPV was approximately 30 to 40% lower during pregnancy compared with postpartum (6 to 12 weeks). The protein binding of RPV was similar (>99%) during second trimester, third trimester, and postpartum period [see Clinical Pharmacology (12.3)]. One subject discontinued the trial following fetal death at 25 weeks gestation due to suspected premature rupture of membranes. Among the 12 subjects who were virologically suppressed at baseline (less than 50 copies/mL), virologic response was preserved in 10 subjects (83.3%) through the third trimester visit and in subjects (75%) through the 6-12 week postpartum visit. Virologic outcomes during the third trimester visit were missing for two subjects who were withdrawn (one subject was nonadherent to the study drug and one subject withdrew consent). Among the 10 infants with available HIV test results, all were negative for HIV-1 at the time of delivery and up to 16 weeks postpartum (all 10 infants received prophylactic treatment with zidovudine). RPV was well tolerated during pregnancy and postpartum. There were no new safety findings compared with the known safety profile of RPV in HIV-1-infected adults.Based on prospective reports to the APR of exposures to RPV-containing regimens during pregnancy (including over 290 exposed during first trimester and over 160 exposed in the second/third trimester), there was no significant increase in overall risk of major birth defects with RPV compared to the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of major birth defects in live births was 1.0% (95% CI: 0.2% to 2.9%) and 1.2% (95% CI: 0.2% to 4.4%) following first and second/third trimester exposure, respectively, to RPV-containing regimens.. Tenofovir DF: Based on prospective reports to the APR of exposures to TDF-containing regimens during pregnancy resulting in live births (including over 3,500 exposed in the first trimester and over 1,500 exposed in the second/third trimester), there was no increase in overall risk of major birth defects compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of major birth defects in live births was 2.3% (95% CI: 1.8% to 2.9%) with first trimester exposure to TDF-containing regimens, and 2.2% (95% CI: 1.6% to 3.1%) with the second/third trimester exposure to TDF-containing regimens.. Animal Data. Emtricitabine: FTC was administered orally to pregnant mice (at 0, 250, 500, or 1,000 mg/kg/day), and rabbits (at 0, 100, 300, or 1,000 mg/kg/day) through organogenesis (on gestation days through 15, and through 19, respectively). No significant toxicological effects were observed in embryo-fetal toxicity studies performed with FTC in mice at exposures (AUC) approximately 60 times higher and in rabbits at approximately 120 times higher than human exposures at the recommended daily dose. In pre/postnatal development study in mice, FTC was administered orally at doses up to 1,000 mg/kg/day; no significant adverse effects directly related to drug were observed in the offspring exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately 60 times higher than human exposures at the recommended daily dose.. Rilpivirine: RPV was administered orally to pregnant rats (40, 120, or 400 mg/kg/day) and rabbits (5, 10, or 20 mg/kg/day) through organogenesis (on gestation days through 17, and through 19, respectively). No significant toxicological effects were observed in embryo-fetal toxicity studies performed with RPV in rats and rabbits at exposures 15 (rats) and 70 (rabbits) times higher than the exposure in humans at the recommended dose of 25 mg once daily. In pre/postnatal development study with RPV, where rats were administered up to 400 mg/kg/day through lactation, no significant adverse effects directly related to drug were noted in the offspring.. Tenofovir DF: TDF was administered orally to pregnant rats (at 0, 50, 150, or 450 mg/kg/day) and rabbits (at 0, 30, 100, or 300 mg/kg/day) through organogenesis (on gestation days through 17, and through 18, respectively). No significant toxicological effects were observed in embryo-fetal toxicity studies performed with TDF in rats at doses up to 14 times the human dose based on body surface area comparisons and in rabbits at doses up to 19 times the human dose based on body surface area comparisons. In pre/postnatal development study in rats, TDF was administered orally through lactation at doses up to 600 mg/kg/day; no adverse effects were observed in the offspring at tenofovir exposures of approximately 2.7 times higher than human exposures at the recommended daily dose of COMPLERA.

RECENT MAJOR CHANGES SECTION.

Warnings and PrecautionsImmune Reconstituition Syndrome (5.9)11/2019.

RENAL IMPAIRMENT SUBSECTION.

8.6Renal Impairment. Because COMPLERA is fixed-dose combination, and cannot be dose adjusted, it is not recommended in patients with moderate, severe, or end-stage renal impairment (estimated creatinine clearance below 50 mL per minute) or that require dialysis [see Warnings and Precautions (5.5) and Clinical Pharmacology (12.3)].

SPL PATIENT PACKAGE INSERT SECTION.

This Patient Information has been approved by the U.S. Food and Drug Administration.Revised: 11/2019Patient InformationCOMPLERA(TM) (kom-PLEH-rah)(emtricitabine, rilpivirine, tenofovir disoproxil fumarate)tabletsImportant: Ask your healthcare provider or pharmacist about medicines that should not be taken with COMPLERA. For more information, see the section What should tell my healthcare provider before taking COMPLERAWhat is the most important information should know about COMPLERACOMPLERA can cause serious side effects, including:Worsening of Hepatitis virus (HBV) infection. Your healthcare provider will test you for HBV before starting treatment with COMPLERA. If you have HBV infection and take COMPLERA, your HBV may get worse (flare-up) if you stop taking COMPLERA. flare-up is when your HBV infection suddenly returns in worse way than before.Do not stop taking COMPLERA without first talking to your healthcare provider.Do not run out of COMPLERA. Refill your prescription or talk to your healthcare provider before your COMPLERA is all gone.If you stop taking COMPLERA, your healthcare provider will need to check your health often and do blood tests regularly for several months to check your HBV infection. Tell your healthcare provider about any new or unusual symptoms you may have after you stop taking COMPLERA.For more information about side effects, see the section What are the possible side effects of COMPLERA.What is COMPLERACOMPLERA is prescription medicine that is used to treat Human Immunodeficiency Virus-1 (HIV-1) in people weighing at least 77 lb (35 kg) who:have never taken HIV-1 medicines before, and who have an amount of HIV-1 in their blood (this is called viral load) that is no more than 100,000 copies/mL before they start taking COMPLERA, or in certain people who have viral load that is less than 50 copies/mL when they start taking COMPLERA, to replace their current HIV-1 medicines.HIV-1 is the virus that causes AIDS (Acquired Immune Deficiency Syndrome). COMPLERA does not cure HIV-1 or AIDS.COMPLERA contains medicines (emtricitabine, rilpivirine, tenofovir disoproxil fumarate) combined in one tablet. Emtricitabine (EMTRIVA(R)) and tenofovir disoproxil fumarate (VIREAD(R)) are HIV-1 nucleoside analog reverse transcriptase inhibitors (NRTIs). Rilpivirine (Edurant(R)) is an HIV-1 non-nucleoside analog reverse transcriptase inhibitor (NNRTI).It is not known if COMPLERA is safe and effective in children less than 12 years of age or who weigh less than 77 lb (35 kg).Who should not take COMPLERADo not take COMPLERA if you also take:anti-seizure medicines:carbamazepineoxcarbazepinephenobarbitalphenytoin anti-tuberculosis (anti-TB) medicines:rifampinrifapentine proton pump inhibitor (PPI) medicine for certain stomach or intestinal problems:dexlansoprazoleesomeprazolelansoprazoleomeprazolepantoprazole sodiumrabeprazole more than dose of the steroid medicine dexamethasone or dexamethasone sodium phosphateSt. Johns wort (Hypericum perforatum)What should tell my healthcare provider before taking COMPLERABefore taking COMPLERA, tell your healthcare provider about all your medical conditions, including if you:have liver problems, including hepatitis or virus infectionhave kidney problemshave history of depression or suicidal thoughtshave bone problemsare pregnant or plan to become pregnant. It is not known if COMPLERA can harm your unborn child. Tell your healthcare provider if you become pregnant during treatment with COMPLERA. Pregnancy Registry. There is pregnancy registry for those who take COMPLERA during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk with your healthcare provider about how you can take part in this registry.are breastfeeding or plan to breastfeed. Do not breastfeed if you are taking COMPLERA.You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby.At least two of the medicines contained in COMPLERA can be passed to your baby in your breast milk.Talk with your healthcare provider about the best way to feed your baby during treatment with COMPLERA. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.Some medicines interact with COMPLERA. Keep list of your medicines to show your healthcare provider and pharmacist when you get new medicine.You can ask your healthcare provider or pharmacist for list of medicines that can interact with COMPLERA.Do not start taking new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take COMPLERA with other medicines.How should take COMPLERATake COMPLERA exactly as your healthcare provider tells you to take it.Take COMPLERA with food. Taking COMPLERA with food is important to help get the right amount of medicine in your body. protein drink does not replace food. If your healthcare provider decides to stop COMPLERA and you are switched to new medicines to treat HIV-1 that include rilpivirine tablets, the rilpivirine tablets should be taken only with meal.Do not change your dose or stop taking COMPLERA without first talking with your healthcare provider. Stay under the care of your healthcare provider during treatment with COMPLERA.If you miss dose of COMPLERA within 12 hours of the time you usually take it, take your dose of COMPLERA with food as soon as possible. Then, take your next dose of COMPLERA at the regularly scheduled time. If you miss dose of COMPLERA by more than 12 hours of the time you usually take it, wait and then take the next dose of COMPLERA at the regularly scheduled time.Do not take more than your prescribed dose to make up for missed dose.If you take too much COMPLERA, contact your local poison control center or go to the nearest hospital emergency room right away.When your COMPLERA supply starts to run low, get more from your healthcare provider or pharmacy. It is very important not to run out of COMPLERA. The amount of virus in your blood may increase if the medicine is stopped for even short time.What are the possible side effects of COMPLERACOMPLERA can cause serious side effects, including:See What is the most important information should know about COMPLERASevere skin rash and allergic reactions. Skin rash is common side effect of COMPLERA. Rash can be serious. Call your healthcare provider right away if you get rash. In some cases, rash and allergic reaction may need to be treated in hospital. If you get rash with any of the following symptoms, stop taking COMPLERA and call your healthcare provider or get medical help right away: feverskin blistersmouth soresredness or swelling of the eyes (conjunctivitis)swelling of the face, lips, mouth, tongue or throattrouble breathing or swallowingpain on the right side of the stomach (abdominal) areadark or tea colored urineSevere liver problems. In rare cases, severe liver problems can happen that can lead to death. Tell your healthcare provider right away if you get these symptoms: skin or the white part of your eyes turns yellow, dark tea-colored urine, light-colored stools, loss of appetite for several days or longer, nausea, or stomach-area pain.Change in liver enzymes. People with history of hepatitis or virus infection or who have certain liver enzyme changes may have an increased risk of developing new or worsening liver problems during treatment with COMPLERA. Liver problems can also happen during treatment with COMPLERA in people without history of liver disease. Your healthcare provider may need to do tests to check your liver enzymes before and during treatment with COMPLERA.Depression or mood changes. Tell your healthcare provider right away if you have any of the following symptoms:feel sad or hopelessfeel anxious or restlesshave thoughts of hurting yourself (suicide) or have tried to hurt yourselfNew or worse kidney problems, including kidney failure, can happen in some people who take COMPLERA. Your healthcare provider should do blood tests to check your kidneys before starting treatment with COMPLERA. If you have had kidney problems in the past or need to take another medicine that can cause kidney problems, your healthcare provider may need to do blood tests to check your kidneys during your treatment with COMPLERA.Bone problems can happen in some people who take COMPLERA. Bone problems include bone pain, softening, or thinning (which may lead to fractures). Your healthcare provider may need to do additional tests to check your bones.Too much lactic acid in your blood (lactic acidosis). Too much lactic acid is serious but rare medical emergency that can lead to death. Tell your healthcare provider right away if you get these symptoms: weakness or being more tired than usual, unusual muscle pain, being short of breath or fast breathing, stomach pain with nausea and vomiting, cold or blue hands and feet, feel dizzy or lightheaded, or fast or abnormal heartbeat.Changes in your immune system (Immune Reconstitution Syndrome) can happen when you start taking HIV-1 medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for long time. Tell your healthcare provider right away if you start having new symptoms after starting your HIV-1 medicine.The most common side effects of rilpivirine, one of the medicines in COMPLERA, include:depressiontrouble sleepingheadacheThe most common side effects of emtricitabine and tenofovir disoproxil fumarate, two of the medicines in COMPLERA, include:diarrheanauseatirednessheadachedizzinessdepressiontrouble sleepingabnormal dreamsrashThese are not all the possible side effects of COMPLERA.Call your healthcare provider for medical advice about side effects. You may report side effects to US FDA at 1-800-FDA-1088.How should store COMPLERAStore COMPLERA at room temperature below 30 (86 F).Keep COMPLERA in its original container and keep the container tightly closed.Do not use COMPLERA if the seal over the bottle opening is broken or missing.Keep COMPLERA and all other medicines out of reach of children.General information about safe and effective use of COMPLERAMedicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use COMPLERA for condition for which it was not prescribed. Do not give COMPLERA to other people, even if they have the same symptoms you have. It may harm them. You can ask your healthcare provider or pharmacist for information about COMPLERA that is written for health professionals.For more information, go to www.COMPLERA.com.What are the ingredients of COMPLERAActive ingredients: emtricitabine, rilpivirine hydrochloride, and tenofovir disoproxil fumarate. Inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polysorbate 20, povidone, pregelatinized starch. The tablet film coating contains hypromellose, lactose monohydrate, polyethylene glycol, titanium dioxide, triacetin.Manufactured and distributed for: Gilead Sciences, Inc. Foster City, CA 94404COMPLERA, EMTRIVA, and VIREAD are trademarks of Gilead Sciences, Inc., or its related companies. All other trademarks referenced herein are the property of their respective owners.(C) 2019 Gilead Sciences, Inc. All rights reserved.202123-GS-013A. Do not stop taking COMPLERA without first talking to your healthcare provider.. Do not run out of COMPLERA. Refill your prescription or talk to your healthcare provider before your COMPLERA is all gone.. If you stop taking COMPLERA, your healthcare provider will need to check your health often and do blood tests regularly for several months to check your HBV infection. Tell your healthcare provider about any new or unusual symptoms you may have after you stop taking COMPLERA.. have never taken HIV-1 medicines before, and who have an amount of HIV-1 in their blood (this is called viral load) that is no more than 100,000 copies/mL before they start taking COMPLERA, or in certain people who have viral load that is less than 50 copies/mL when they start taking COMPLERA, to replace their current HIV-1 medicines.. anti-seizure medicines:carbamazepineoxcarbazepinephenobarbitalphenytoin carbamazepine. oxcarbazepine. phenobarbital. phenytoin. anti-tuberculosis (anti-TB) medicines:rifampinrifapentine rifampin. rifapentine. proton pump inhibitor (PPI) medicine for certain stomach or intestinal problems:dexlansoprazoleesomeprazolelansoprazoleomeprazolepantoprazole sodiumrabeprazole dexlansoprazole. esomeprazole. lansoprazole. omeprazole. pantoprazole sodium. rabeprazole. more than dose of the steroid medicine dexamethasone or dexamethasone sodium phosphate. St. Johns wort (Hypericum perforatum). have liver problems, including hepatitis or virus infection. have kidney problems. have history of depression or suicidal thoughts. have bone problems. are pregnant or plan to become pregnant. It is not known if COMPLERA can harm your unborn child. Tell your healthcare provider if you become pregnant during treatment with COMPLERA. Pregnancy Registry. There is pregnancy registry for those who take COMPLERA during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk with your healthcare provider about how you can take part in this registry.. are breastfeeding or plan to breastfeed. Do not breastfeed if you are taking COMPLERA.You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby.At least two of the medicines contained in COMPLERA can be passed to your baby in your breast milk.Talk with your healthcare provider about the best way to feed your baby during treatment with COMPLERA. You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby.. At least two of the medicines contained in COMPLERA can be passed to your baby in your breast milk.. Talk with your healthcare provider about the best way to feed your baby during treatment with COMPLERA.. You can ask your healthcare provider or pharmacist for list of medicines that can interact with COMPLERA.. Do not start taking new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take COMPLERA with other medicines.. Take COMPLERA exactly as your healthcare provider tells you to take it.. Take COMPLERA with food. Taking COMPLERA with food is important to help get the right amount of medicine in your body. protein drink does not replace food. If your healthcare provider decides to stop COMPLERA and you are switched to new medicines to treat HIV-1 that include rilpivirine tablets, the rilpivirine tablets should be taken only with meal.. Do not change your dose or stop taking COMPLERA without first talking with your healthcare provider. Stay under the care of your healthcare provider during treatment with COMPLERA.. If you miss dose of COMPLERA within 12 hours of the time you usually take it, take your dose of COMPLERA with food as soon as possible. Then, take your next dose of COMPLERA at the regularly scheduled time. If you miss dose of COMPLERA by more than 12 hours of the time you usually take it, wait and then take the next dose of COMPLERA at the regularly scheduled time.. Do not take more than your prescribed dose to make up for missed dose.. If you take too much COMPLERA, contact your local poison control center or go to the nearest hospital emergency room right away.. When your COMPLERA supply starts to run low, get more from your healthcare provider or pharmacy. It is very important not to run out of COMPLERA. The amount of virus in your blood may increase if the medicine is stopped for even short time.. See What is the most important information should know about COMPLERASevere skin rash and allergic reactions. Skin rash is common side effect of COMPLERA. Rash can be serious. Call your healthcare provider right away if you get rash. In some cases, rash and allergic reaction may need to be treated in hospital. If you get rash with any of the following symptoms, stop taking COMPLERA and call your healthcare provider or get medical help right away: fever. skin blisters. mouth sores. redness or swelling of the eyes (conjunctivitis). swelling of the face, lips, mouth, tongue or throat. trouble breathing or swallowing. pain on the right side of the stomach (abdominal) area. dark or tea colored urine. Severe liver problems. In rare cases, severe liver problems can happen that can lead to death. Tell your healthcare provider right away if you get these symptoms: skin or the white part of your eyes turns yellow, dark tea-colored urine, light-colored stools, loss of appetite for several days or longer, nausea, or stomach-area pain.. Change in liver enzymes. People with history of hepatitis or virus infection or who have certain liver enzyme changes may have an increased risk of developing new or worsening liver problems during treatment with COMPLERA. Liver problems can also happen during treatment with COMPLERA in people without history of liver disease. Your healthcare provider may need to do tests to check your liver enzymes before and during treatment with COMPLERA.. Depression or mood changes. Tell your healthcare provider right away if you have any of the following symptoms:feel sad or hopelessfeel anxious or restlesshave thoughts of hurting yourself (suicide) or have tried to hurt yourself. feel sad or hopeless. feel anxious or restless. have thoughts of hurting yourself (suicide) or have tried to hurt yourself. New or worse kidney problems, including kidney failure, can happen in some people who take COMPLERA. Your healthcare provider should do blood tests to check your kidneys before starting treatment with COMPLERA. If you have had kidney problems in the past or need to take another medicine that can cause kidney problems, your healthcare provider may need to do blood tests to check your kidneys during your treatment with COMPLERA.. Bone problems can happen in some people who take COMPLERA. Bone problems include bone pain, softening, or thinning (which may lead to fractures). Your healthcare provider may need to do additional tests to check your bones.. Too much lactic acid in your blood (lactic acidosis). Too much lactic acid is serious but rare medical emergency that can lead to death. Tell your healthcare provider right away if you get these symptoms: weakness or being more tired than usual, unusual muscle pain, being short of breath or fast breathing, stomach pain with nausea and vomiting, cold or blue hands and feet, feel dizzy or lightheaded, or fast or abnormal heartbeat.. Changes in your immune system (Immune Reconstitution Syndrome) can happen when you start taking HIV-1 medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for long time. Tell your healthcare provider right away if you start having new symptoms after starting your HIV-1 medicine.. depression. trouble sleeping. headache. diarrhea. nausea. tiredness. headache. dizziness. depression. trouble sleeping. abnormal dreams. rash. Store COMPLERA at room temperature below 30 (86 F).. Keep COMPLERA in its original container and keep the container tightly closed.. Do not use COMPLERA if the seal over the bottle opening is broken or missing.

SPL UNCLASSIFIED SECTION.

Limitations of Use:More rilpivirine-treated subjects with HIV-1 RNA greater than 100,000 copies/mL at the start of therapy experienced virologic failure (HIV-1 RNA >=50 copies/mL) compared to rilpivirine-treated subjects with HIV-1 RNA less than or equal to 100,000 copies/mL [see Clinical Studies (14)].. More rilpivirine-treated subjects with HIV-1 RNA greater than 100,000 copies/mL at the start of therapy experienced virologic failure (HIV-1 RNA >=50 copies/mL) compared to rilpivirine-treated subjects with HIV-1 RNA less than or equal to 100,000 copies/mL [see Clinical Studies (14)].

STORAGE AND HANDLING SECTION.

Store below 30 (86 F). Keep container tightly closed.Dispense only in original container.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Pregnancy: Monitor viral load closely during pregnancy as rilpivirine exposures were generally lower during pregnancy. (2.3, 8.1, 12.3)Lactation: Breastfeeding not recommended due to the potential for HIV-1 transmission. (8.2)Pediatrics: Not recommended for patients weighing less than 35 kg. (8.4). Pregnancy: Monitor viral load closely during pregnancy as rilpivirine exposures were generally lower during pregnancy. (2.3, 8.1, 12.3). Lactation: Breastfeeding not recommended due to the potential for HIV-1 transmission. (8.2). Pediatrics: Not recommended for patients weighing less than 35 kg. (8.4). 8.1 Pregnancy. Pregnancy Exposure RegistryThere is pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to COMPLERA during pregnancy. Healthcare providers are encouraged to register patients on the worldwide Antiretroviral Pregnancy Registry (APR) at www.apregistry.com/.. Risk SummaryAvailable data from the APR show no increase in the overall risk of major birth defects with first trimester exposure for emtricitabine (FTC), rilpivirine (RPV), or tenofovir (TDF) compared with the background rate for major birth defects of 2.7% in U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) (see Data). In clinical trial, total rilpivirine exposures were generally lower during pregnancy compared to the postpartum period [see Clinical Pharmacology (12.3)]. The rate of miscarriage for individual drugs is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15-20%.Based on the experience of HIV-1-infected pregnant individuals who completed clinical trial through the postpartum period with an RPV-based regimen, no dose adjustments are required for pregnant patients who are already on stable RPV-containing regimen prior to pregnancy and who are virologically suppressed (HIV-1 RNA less than 50 copies per mL). Lower exposures of RPV were observed during pregnancy, therefore viral load should be monitored closely [see Data and Clinical Pharmacology (12.3)].In animal studies, no adverse developmental effects were observed when the components of COMPLERA were administered separately during the period of organogenesis at exposures up to 60 and 120 times (mice and rabbits, respectively, FTC) and 15 and 70 times (rats and rabbits, respectively; RPV) the exposure of these components in COMPLERA and at 14 and 19 times (rats and rabbits, respectively) the human dose of TDF based on body surface area comparisons (see Data). Likewise, no adverse developmental effects were seen when FTC was administered to mice and RPV was administered to rats through lactation at exposures up to approximately 60 and 63 times, respectively, the exposure at the recommended daily dose of these components in COMPLERA. No adverse effects were observed in the offspring of rats when TDF was administered through lactation at tenofovir exposures of approximately 14 times the exposure at the recommended daily dosage of COMPLERA.. Data. Human DataProspective reports from the APR of overall major birth defects in pregnancies exposed to drug components of COMPLERA are compared with U.S. background major birth defect rate. Methodological limitations of the APR include the use of MACDP as the external comparator group. Limitations of using an external comparator include differences in methodology and populations, as well as confounding due to the underlying disease.. Emtricitabine: Based on prospective reports to the APR of exposures to FTC-containing regimens during pregnancy resulting in live births (including over 2,750 exposed in the first trimester and over 1,200 exposed in the second/third trimester), there was no increase in overall major birth defects with FTC compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of major birth defects in live births was 2.4% (95% CI: 1.9% to 3.1%) with first trimester exposure to FTC-containing regimens and 2.3% (95% CI: 1.5% to 3.3%) with the second/third trimester exposure to FTC-containing regimens.. Rilpivirine: RPV in combination with background regimen was evaluated in clinical trial of 19 HIV-1 infected pregnant subjects on an RPV-based regimen during the second and third trimesters and postpartum. Each of the subjects were on an RPV-based regimen at the time of enrollment. Twelve subjects completed the trial through the postpartum period (6-12 weeks after delivery) and pregnancy outcomes are missing for six subjects. The exposure (C0h and AUC) of total RPV was approximately 30 to 40% lower during pregnancy compared with postpartum (6 to 12 weeks). The protein binding of RPV was similar (>99%) during second trimester, third trimester, and postpartum period [see Clinical Pharmacology (12.3)]. One subject discontinued the trial following fetal death at 25 weeks gestation due to suspected premature rupture of membranes. Among the 12 subjects who were virologically suppressed at baseline (less than 50 copies/mL), virologic response was preserved in 10 subjects (83.3%) through the third trimester visit and in subjects (75%) through the 6-12 week postpartum visit. Virologic outcomes during the third trimester visit were missing for two subjects who were withdrawn (one subject was nonadherent to the study drug and one subject withdrew consent). Among the 10 infants with available HIV test results, all were negative for HIV-1 at the time of delivery and up to 16 weeks postpartum (all 10 infants received prophylactic treatment with zidovudine). RPV was well tolerated during pregnancy and postpartum. There were no new safety findings compared with the known safety profile of RPV in HIV-1-infected adults.Based on prospective reports to the APR of exposures to RPV-containing regimens during pregnancy (including over 290 exposed during first trimester and over 160 exposed in the second/third trimester), there was no significant increase in overall risk of major birth defects with RPV compared to the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of major birth defects in live births was 1.0% (95% CI: 0.2% to 2.9%) and 1.2% (95% CI: 0.2% to 4.4%) following first and second/third trimester exposure, respectively, to RPV-containing regimens.. Tenofovir DF: Based on prospective reports to the APR of exposures to TDF-containing regimens during pregnancy resulting in live births (including over 3,500 exposed in the first trimester and over 1,500 exposed in the second/third trimester), there was no increase in overall risk of major birth defects compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of major birth defects in live births was 2.3% (95% CI: 1.8% to 2.9%) with first trimester exposure to TDF-containing regimens, and 2.2% (95% CI: 1.6% to 3.1%) with the second/third trimester exposure to TDF-containing regimens.. Animal Data. Emtricitabine: FTC was administered orally to pregnant mice (at 0, 250, 500, or 1,000 mg/kg/day), and rabbits (at 0, 100, 300, or 1,000 mg/kg/day) through organogenesis (on gestation days through 15, and through 19, respectively). No significant toxicological effects were observed in embryo-fetal toxicity studies performed with FTC in mice at exposures (AUC) approximately 60 times higher and in rabbits at approximately 120 times higher than human exposures at the recommended daily dose. In pre/postnatal development study in mice, FTC was administered orally at doses up to 1,000 mg/kg/day; no significant adverse effects directly related to drug were observed in the offspring exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately 60 times higher than human exposures at the recommended daily dose.. Rilpivirine: RPV was administered orally to pregnant rats (40, 120, or 400 mg/kg/day) and rabbits (5, 10, or 20 mg/kg/day) through organogenesis (on gestation days through 17, and through 19, respectively). No significant toxicological effects were observed in embryo-fetal toxicity studies performed with RPV in rats and rabbits at exposures 15 (rats) and 70 (rabbits) times higher than the exposure in humans at the recommended dose of 25 mg once daily. In pre/postnatal development study with RPV, where rats were administered up to 400 mg/kg/day through lactation, no significant adverse effects directly related to drug were noted in the offspring.. Tenofovir DF: TDF was administered orally to pregnant rats (at 0, 50, 150, or 450 mg/kg/day) and rabbits (at 0, 30, 100, or 300 mg/kg/day) through organogenesis (on gestation days through 17, and through 18, respectively). No significant toxicological effects were observed in embryo-fetal toxicity studies performed with TDF in rats at doses up to 14 times the human dose based on body surface area comparisons and in rabbits at doses up to 19 times the human dose based on body surface area comparisons. In pre/postnatal development study in rats, TDF was administered orally through lactation at doses up to 600 mg/kg/day; no adverse effects were observed in the offspring at tenofovir exposures of approximately 2.7 times higher than human exposures at the recommended daily dose of COMPLERA.. 8.2 Lactation. Risk SummaryThe Centers for Disease Control and Prevention recommend that HIV infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV.Based on published data, FTC and tenofovir have been shown to be present in human milk. There are no data on the presence of RPV in human milk. RPV has been shown to be present in rat milk (see Data).It is not known if the components of COMPLERA affect milk production or have effects on the breastfed child. Because of the potential for: (1) HIV transmission (in HIV-negative infants); (2) developing viral resistance (in HIV-positive infants); and (3) adverse reactions in breastfed infant similar to those seen in adults, instruct mothers not to breastfeed if they are receiving COMPLERA.. Data. Rilpivirine: In animals, no studies have been conducted to assess the excretion of RPV directly; however RPV was measured in rat pups which were exposed through the milk of treated dams (dosed up to 400 mg/kg/day).. 8.4 Pediatric Use. The safety and effectiveness of COMPLERA as complete regimen for the treatment of HIV-1 infection was established in pediatric subjects 12 years of age and older with body weight greater than or equal to 35 kg [see Dosage and Administration (2.2)]. Use of COMPLERA in this age group weighing at least 35 kg is supported by adequate and well-controlled studies of RPV+FTC+TDF in adults with HIV-1 infection as well as data from pediatric studies of the individual components of COMPLERA (RPV, FTC, and TDF) [see Clinical Pharmacology (12.3), and Clinical Studies (14.2)]. COMPLERA should only be administered to pediatric patients with body weight greater than or equal to 35 kg. Because COMPLERA is fixed-dose combination tablet, the dose of COMPLERA cannot be adjusted for patients of lower weight. Safety and effectiveness for COMPLERA have not been established in pediatric patients weighing less than 35 kg [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3)].. 8.5 Geriatric Use. Clinical studies of FTC, RPV, or TDF 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 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 [see Clinical Pharmacology (12.3)]. 8.6Renal Impairment. Because COMPLERA is fixed-dose combination, and cannot be dose adjusted, it is not recommended in patients with moderate, severe, or end-stage renal impairment (estimated creatinine clearance below 50 mL per minute) or that require dialysis [see Warnings and Precautions (5.5) and Clinical Pharmacology (12.3)].. 8.7Hepatic Impairment. No dose adjustment of COMPLERA is required in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. COMPLERA has not been studied in patients with severe hepatic impairment (Child-Pugh Class C) [see Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Skin and Hypersensitivity Reactions: Severe skin and hypersensitivity reactions have been reported during postmarketing experience, including cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS). Immediately discontinue treatment if hypersensitivity or rash with systemic symptoms or elevations in hepatic serum biochemistries develops and closely monitor clinical status, including hepatic serum biochemistries. (5.2)Hepatotoxicity: Hepatic adverse events have been reported in patients receiving rilpivirine-containing regimen. Monitor liver-associated tests before and during treatment with COMPLERA in patients with underlying hepatic disease or marked elevations in liver-associated tests. Also consider monitoring liver-associated tests in patients without risk factors. (5.3)Depressive disorders: Severe depressive disorders have been reported. Immediate medical evaluation is recommended for severe depressive disorders. (5.4)New onset or worsening renal impairment: Can include acute renal failure and Fanconi syndrome. Avoid administering COMPLERA with concurrent or recent use of nephrotoxic drugs. (5.5)Decreases in bone mineral density (BMD): Consider monitoring BMD in patients with history of pathologic fracture or other risk factors of osteoporosis or bone loss. (5.6)Concomitant use of COMPLERA with drugs with known risk to prolong the QTc interval of the electrocardiogram may increase the risk of Torsade de Pointes. (5.7)Lactic acidosis/severe hepatomegaly with steatosis: Discontinue treatment in patients who develop symptoms or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity. (5.8) Immune reconstitution syndrome: May necessitate further evaluation and treatment. (5.9). Skin and Hypersensitivity Reactions: Severe skin and hypersensitivity reactions have been reported during postmarketing experience, including cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS). Immediately discontinue treatment if hypersensitivity or rash with systemic symptoms or elevations in hepatic serum biochemistries develops and closely monitor clinical status, including hepatic serum biochemistries. (5.2). Hepatotoxicity: Hepatic adverse events have been reported in patients receiving rilpivirine-containing regimen. Monitor liver-associated tests before and during treatment with COMPLERA in patients with underlying hepatic disease or marked elevations in liver-associated tests. Also consider monitoring liver-associated tests in patients without risk factors. (5.3). Depressive disorders: Severe depressive disorders have been reported. Immediate medical evaluation is recommended for severe depressive disorders. (5.4). New onset or worsening renal impairment: Can include acute renal failure and Fanconi syndrome. Avoid administering COMPLERA with concurrent or recent use of nephrotoxic drugs. (5.5). Decreases in bone mineral density (BMD): Consider monitoring BMD in patients with history of pathologic fracture or other risk factors of osteoporosis or bone loss. (5.6). Concomitant use of COMPLERA with drugs with known risk to prolong the QTc interval of the electrocardiogram may increase the risk of Torsade de Pointes. (5.7). Lactic acidosis/severe hepatomegaly with steatosis: Discontinue treatment in patients who develop symptoms or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity. (5.8). Immune reconstitution syndrome: May necessitate further evaluation and treatment. (5.9). 5.1Severe Acute Exacerbation of Hepatitis in Patients Coinfected with HIV-1 and HBV. Test all patients with HIV-1 for the presence of chronic hepatitis virus (HBV) before or when initiating antiretroviral therapy [see Dosage and Administration (2.1)].Severe acute exacerbations of hepatitis (e.g., liver decompensation and liver failure) have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued products containing FTC and/or TDF, two of the components of COMPLERA. Patients coinfected with HIV-1 and HBV who discontinue COMPLERA should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment with COMPLERA. If appropriate, initiation of anti-hepatitis therapy may be warranted, especially in patients with advanced liver disease or cirrhosis, since posttreatment exacerbation of hepatitis may lead to hepatic decompensation and liver failure.. 5.2Skin and Hypersensitivity Reactions. Severe skin and hypersensitivity reactions have been reported during the postmarketing experience, including cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) with RPV-containing regimens. While some skin reactions were accompanied by constitutional symptoms such as fever, other skin reactions were associated with organ dysfunctions, including elevations in hepatic serum biochemistries. During the Phase clinical trials, treatment-related rashes with at least Grade severity were reported in 1% of subjects receiving RPV plus FTC/TDF. Overall, most rashes were Grade or and occurred in the first four to six weeks of therapy [see Adverse Reactions (6.1 and 6.2)].Discontinue COMPLERA immediately if signs or symptoms of severe skin or hypersensitivity reactions develop, including but not limited to, severe rash or rash accompanied by fever, blisters, mucosal involvement, conjunctivitis, facial edema, angioedema, hepatitis, or eosinophilia. Clinical status including laboratory parameters should be monitored and appropriate therapy should be initiated.. 5.3Hepatotoxicity. Hepatic adverse events have been reported in patients receiving an RPV-containing regimen. Patients with underlying hepatitis or virus infection, or marked elevations in liver-associated tests prior to treatment, may be at increased risk for worsening or development of liver-associated test elevations with use of COMPLERA. few cases of hepatic toxicity have been reported in adult patients receiving an RPV-containing regimen who had no pre-existing hepatic disease or other identifiable risk factors. Appropriate laboratory testing prior to initiating therapy and monitoring for hepatotoxicity during therapy with COMPLERA is recommended in patients with underlying hepatic disease such as hepatitis or C, or in patients with marked elevations in liver-associated tests prior to treatment initiation. Liver-associated test monitoring should also be considered for patients without pre-existing hepatic dysfunction or other risk factors.. 5.4Depressive Disorders. The adverse reaction depressive disorders (depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, suicidal ideation) has been reported with RPV. Patients with severe depressive symptoms should seek immediate medical evaluation to assess the possibility that the symptoms are related to COMPLERA, and if so, to determine whether the risks of continued therapy outweigh the benefits.During the Phase trials in adults (N=1368) through 96 weeks, the incidence of depressive disorders (regardless of causality, severity) reported among RPV (n=686) or efavirenz (EFV, n=682) was 9% and 8%, respectively. Most events were mild or moderate in severity. The incidence of Grades and depressive disorders (regardless of causality) was 1% for both RPV and EFV. The incidence of discontinuation due to depressive disorders among RPV or EFV was 1% in each arm. Suicidal ideation was reported in subjects in each arm while suicide attempt was reported in subjects in the RPV arm.During the Phase trial in pediatric subjects 12 to less than 18 years of age (N=36) receiving RPV through 48 weeks, the incidence of depressive disorders (regardless of causality, severity) was 19.4% (7/36). Most events were mild or moderate in severity. The incidence of Grade and depressive disorders (regardless of causality) was 5.6% (2/36). None of the subjects discontinued due to depressive disorders. Suicidal ideation and suicide attempt were reported in subject.. 5.5New Onset or Worsening Renal Impairment. Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of TDF [see Adverse Reactions (6.2)].Prior to initiation of COMPLERA, and during treatment with COMPLERA, on clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus.COMPLERA should be avoided with concurrent or recent use of nephrotoxic agent (e.g., high-dose or multiple nonsteroidal anti-inflammatory drugs [NSAIDs]) [see Drug Interactions (7.4)]. Cases of acute renal failure after initiation of high-dose or multiple NSAIDs have been reported in HIV-infected patients with risk factors for renal dysfunction who appeared stable on TDF. Some patients required hospitalization and renal replacement therapy. Alternatives to NSAIDs should be considered, if needed, in patients at risk for renal dysfunction.Persistent or worsening bone pain, pain in extremities, fractures, and/or muscular pain or weakness may be manifestations of proximal renal tubulopathy and should prompt an evaluation of renal function in at-risk patients.Emtricitabine and TDF are principally eliminated by the kidney; however, RPV is not. Since COMPLERA is combination product and the dose of the individual components cannot be altered, COMPLERA is not recommended in patients with estimated creatinine clearance below 50 mL per minute [see Use in Specific Populations (8.6)].. 5.6Bone Loss and Mineralization Defects. Bone Mineral DensityIn clinical trials in HIV-1-infected adults, TDF, component of COMPLERA, was associated with slightly greater decreases in bone mineral density (BMD) and increases in biochemical markers of bone metabolism, suggesting increased bone turnover relative to comparators. Serum parathyroid hormone levels and 1,25 Vitamin levels were also higher in subjects receiving TDF.Clinical trials evaluating TDF in pediatric and adolescent subjects were conducted. Under normal circumstances, BMD increases rapidly in pediatric patients. In HIV-1-infected subjects aged years to less than 18 years, bone effects were similar to those observed in adult subjects and suggest increased bone turnover. Total body BMD gain was less in the TDF-treated HIV-1-infected pediatric subjects as compared to the control groups. Similar trends were observed in chronic hepatitis B-infected adolescent subjects aged 12 years to less than 18 years. In all pediatric trials, skeletal growth (height) appeared to be unaffected.The effects of TDF-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk are unknown. Assessment of BMD should be considered for adult and pediatric patients who have history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. Although the effect of supplementation with calcium and Vitamin was not studied, such supplementation may be beneficial for all patients. If bone abnormalities are suspected, then appropriate consultation should be obtained.. Mineralization DefectsCases of osteomalacia associated with proximal renal tubulopathy, manifested as bone pain or pain in extremities and which may contribute to fractures, have been reported in association with the use of TDF [see Adverse Reactions (6.2)]. Arthralgias and muscle pain or weakness have also been reported in cases of proximal renal tubulopathy. Hypophosphatemia and osteomalacia secondary to proximal renal tubulopathy should be considered in patients at risk of renal dysfunction who present with persistent or worsening bone or muscle symptoms while receiving products containing TDF [See Warnings and Precautions (5.5)]. 5.7Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions. The concomitant use of COMPLERA and other drugs may result in potentially significant drug interactions, some of which may lead to [see Dosage and Administration (2.5), Contraindications (4), and Drug Interactions (7)]:Loss of therapeutic effect of COMPLERA and possible development of resistance due to reduced exposure to RPV.Possible clinically significant adverse reaction from greater exposures of components of COMPLERA.In healthy subjects, 75 mg once daily and 300 mg once daily doses of RPV (3 times and 12 times the dose in COMPLERA) have been shown to prolong the QTc interval of the electrocardiogram. Consider alternatives to COMPLERA when coadministered with drug that is known to have risk of Torsade de Pointes [see Drug Interactions (7) and Clinical Pharmacology (12.2)].See Table for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during COMPLERA therapy and review concomitant medications during COMPLERA therapy.. Loss of therapeutic effect of COMPLERA and possible development of resistance due to reduced exposure to RPV.. Possible clinically significant adverse reaction from greater exposures of components of COMPLERA.. 5.8Lactic Acidosis/Severe Hepatomegaly with Steatosis. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including TDF and FTC, components of COMPLERA, alone or in combination with other antiretrovirals. Treatment with COMPLERA should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).. 5.9Immune Reconstitution Syndrome. Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including the components of COMPLERA. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment.Autoimmune disorders (such as Graves disease, polymyositis, Guillain-Barre syndrome, and autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable and can occur many months after initiation of treatment.