INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information).Lactic Acidosis and Severe Hepatomegaly: Inform patients that lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported. Treatment with CIMDUO should be suspended in any patient who develops clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity (including nausea, vomiting, unusual or unexpected stomach discomfort, and weakness) [see Warnings and Precautions (5.1)].Post Treatment Acute Exacerbation of Hepatitis in Patients with HBV Co-Infection: Severe acute exacerbations of hepatitis have been reported in patients who are infected with HBV or coinfected with HBV and HIV-1 and have discontinued 3TC and TDF, components of CIMDUO. Test patients with HIV-1 for hepatitis virus (HBV) before initiating antiretroviral therapy. In patients with chronic hepatitis B, it is important to obtain HIV antibody testing prior to initiating 3TC and TDF, components of CIMDUO [see Warnings and Precautions (5.2)].New Onset or Worsening Renal Impairment: Inform patients that renal impairment, including cases of acute renal failure and Fanconi syndrome, has been reported. Advise patients with impaired renal function (i.e., creatinine clearance less than 50 mL/min) or patients with end-stage renal disease (ESRD) requiring hemodialysis to avoid CIMDUO with concurrent or recent use of nephrotoxic agent (e.g., high-dose or multiple NSAIDs) for patients [see Dosage and Administration (2.3), Warnings and Precautions (5.3)].Risk of Hepatic Decompensation in Patients with HIV-1/HCV Co-Infection: Inform patients with HIV-1/HCV co-infection that hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy for HIV-1 and interferon alfa with or without ribavirin [see Warnings and Precautions (5.4)]. Pancreatitis: Advise patients or guardians to monitor pediatric patients for signs and symptoms of pancreatitis [see Warnings and Precautions (5.5)]. Decreases in Bone Mineral Density: Advise patients that decreases in bone mineral density have been observed with the use of 3TC and TDF, components of CIMDUO, in patients with HIV [see Warnings and Precautions (5.6)]. Immune Reconstitution Syndrome: Advise patients to inform their healthcare provider immediately of any symptoms of infection, as in some patients with advanced HIV infection, signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started [see Warnings and Precautions (5.7)]. Fat Redistribution: Inform patients that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy, including CIMDUO, and that the cause and long-term health effects of these conditions are not known at this time [see Warnings and Precautions (5.8)].Administration Instructions: Inform patients that it is important to take CIMDUO once daily on regular dosing schedule and to avoid missing doses as it can result in development of resistance. Advise patients if dose is missed, take it as soon as possible unless it is almost time for the next dose [see Dosage and Administration (2.2)].Pregnancy Registry: Advise patients that there is an antiretroviral pregnancy registry to monitor fetal outcomes in women exposed to CIMDUO [see Use in Specific Populations (8.1)].Lactation: Instruct women 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)].Rx onlyManufactured for: Mylan Specialty L.P. Morgantown, WV 26505 U.S.A.Manufactured by: Mylan Laboratories Limited Hyderabad -- 500 096, India(C) 2021 Viatris Inc.CIMDUO is registered trademark of Mylan Pharmaceuticals Inc., Viatris Company.Other brands listed are the registered trademarks of their respective owners and are not trademarks of Mylan Laboratories Limited or Mylan Pharmaceuticals Inc.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action CIMDUO is fixed-dose combination of antiviral drugs 3TC and TDF with antiviral activity against HIV-1 [see Microbiology (12.4)]. 12.3 Pharmacokinetics Lamivudine. After oral administration of mg/kg of 3TC twice day to adults with HIV-1, the peak serum 3TC concentration (Cmax) was 1.5 +- 0.5 mcg/mL (mean +- SD). The area under the plasma concentration versus time curve (AUC) and Cmax increased in proportion to oral dose over the range from 0.25 to 10 mg/kg and absolute bioavailability in 12 adult patients was 86% +- 16% (mean +- SD) for the 150-mg tablet and 87% +- 13% for the oral solution. Binding of 3TC to human plasma proteins is low (< 36%). Within 12 hours after single oral dose of 3TC in HIV-1-infected adults, 5.2% +- 1.4% (mean +- SD) of the dose was excreted as the trans-sulfoxide metabolite in the urine. The majority of 3TC is eliminated unchanged in urine by active organic cationic secretion and the observed mean elimination half-life (t1/2) ranged from to hours in most single-dose studies with serum sampling for 24 hours after dosing.. Tenofovir Disoproxil Fumarate. Following oral administration of single 300-mg dose of TDF to HIV-1-infected subjects in the fasted state, maximum serum concentrations (Cmax) were achieved in 1.0 +- 0.4 hrs (mean +- SD) and Cmax and AUC values were 296 +- 90 ng/mL and 2287 +- 685 ngohr/mL, respectively. The oral bioavailability of tenofovir from TDF in fasted subjects is approximately 25%. Less than 0.7% of tenofovir binds to human plasma proteins in vitro and the binding is independent of concentration over the range of 0.01 to 25 mcg/mL. Approximately 70 to 80% of the intravenous dose of tenofovir is recovered as unchanged drug in the urine. Tenofovir is eliminated by combination of glomerular filtration and active tubular secretion with renal clearance in adults with normal renal function of 243 +- 33 mL/min (mean +- SD). Following single oral dose, the terminal elimination half-life of tenofovir is approximately 17 hours.. Special Populations. Race Lamivudine. There are no significant or clinically relevant racial differences in lamivudine pharmacokinetics.. Tenofovir Disoproxil Fumarate. There were insufficient numbers from racial and ethnic groups other than Caucasian to adequately determine potential pharmacokinetic differences among these populations.. Gender There are no significant or clinically relevant gender differences in the pharmacokinetics of lamivudine and tenofovir.. Geriatric Patients The pharmacokinetics of lamivudine and tenofovir have not been studied in patients over 65 years of age. Patients with Renal Impairment [See Use in Specific Populations (8.6) .]. Lamivudine. The pharmacokinetics of lamivudine are altered in subjects with renal impairment (Table 3).Table 3. Pharmacokinetic Parameters (Mean +- SD) After Single 300-mg Oral Dose of 3TC in Subjects with Varying Degrees of Renal FunctionParameter Creatinine Clearance Criterion (Number of Subjects)> 60 mL/min(n 6)10-30 mL/min(n 4)< 10 mL/min(n 6)Creatinine clearance (mL/min) 111 +- 1428 +- 86 +- 2Cmax (mcg/mL) 2.6 +- 0.53.6 +- 0.85.8 +- 1.2AUC (mcgoh/mL) 11.0 +- 1.748.0 +- 19157 +- 74Cl/F (mL/min)464 +- 76114 +- 3436 +- 11. Tenofovir Disoproxil Fumarate. The pharmacokinetics of tenofovir are altered in subjects with renal impairment [see Warnings and Precautions (5.3)]. In subjects with creatinine clearance below 50 mL/min or with end-stage renal disease (ESRD) requiring dialysis, Cmax, and AUC0- of tenofovir were increased. Table 4. Pharmacokinetic Parameters (Mean +- SD) of Tenofovir in Subjects After Single 300-mg Oral Dose of TDF in Subjects with Varying Degrees of Renal FunctionBaseline Creatinine Clearance (mL/min) 80(N 3)50-80(N 10)30-49(N 8)12-29(N 11)Cmax (ug/mL) 0.34 +- 0.030.33 +- 0.060.37 +- 0.160.60 +- 0.19AUC0- (ugohr/mL) 2.18 +- 0.263.06 +- 0.936.01 +- 2.5015.98 +- 7.22CL/F (mL/min) 1043.7 +- 115.4807.7 +- 279.2444.4 +- 209.8177.0 +- 97.1CLrenal (mL/min) 243.5 +- 33.3168.6 +- 27.5100.6 +- 27.543.0 +- 31.2. Patients with Hepatic Impairment: Lamivudine. The pharmacokinetics of lamivudine were not altered by diminishing hepatic function. Safety and efficacy of lamivudine have not been established in the presence of decompensated liver disease.. Tenofovir Disoproxil Fumarate. The pharmacokinetics of tenofovir following 300 mg single dose of TDF have been studied in non-HIV-infected subjects with moderate to severe (Child-Pugh to C) hepatic impairment. There were no substantial alterations in tenofovir pharmacokinetics in subjects with hepatic impairment compared with unimpaired subjects. Assessment of Drug Interactions. [See Drug Interactions (7).]. Lamivudine Effect of 3TC on the Pharmacokinetics of Other Agents. Based on in vitro study results, 3TC at therapeutic drug exposures is not expected to affect the pharmacokinetics of drugs that are substrates of the following transporters: organic anion transporter polypeptide 1B1/3 (OATP1B1/3), breast cancer resistance protein (BCRP), P-glycoprotein (P-gp), multidrug and toxin extrusion protein (MATE1), MATE2-K, organic cation transporter (OCT1), OCT2, or OCT3.. Effect of Other Agents on the Pharmacokinetics of 3TC. 3TC is substrate of MATE1, MATE2-K, and OCT2 in vitro. Trimethoprim (an inhibitor of these drug transporters) has been shown to increase 3TC plasma concentrations. This interaction is not considered clinically significant as no dose adjustment of 3TC is needed.3TC is substrate of P-gp and BCRP; however, considering its absolute bioavailability (87%), it is unlikely that these transporters play significant role in the absorption of 3TC. Therefore, coadministration of drugs that are inhibitors of these efflux transporters is unlikely to affect the disposition and elimination of 3TC.. Interferon Alfa. There was no significant pharmacokinetic interaction between 3TC and interferon alfa in trial of 19 healthy male subjects [see Warnings and Precautions (5.4)].. Ribavirin. In vitro data indicate ribavirin reduces phosphorylation of 3TC, stavudine, and zidovudine. However, no pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV-1/HCV virologic suppression) interaction was observed when ribavirin and 3TC (n 18), stavudine (n 10), or zidovudine (n 6) were coadministered as part of multi-drug regimen to HIV-1/HCV co-infected subjects [see Warnings and Precautions (5.4)].. Sorbitol (Excipient). 3TC and sorbitol solutions were coadministered to 16 healthy adult subjects in an open-label, randomized sequence, 4-period, crossover trial. Each subject received single 300-mg dose of 3TC oral solution alone or coadministered with single dose of 3.2 grams, 10.2 grams, or 13.4 grams of sorbitol in solution. Coadministration of 3TC with sorbitol resulted in dose-dependent decreases of 20%, 39%, and 44% in the AUC(0-24), 14%, 32%, and 36% in the AUC(), and 28%, 52%, and 55% in the Cmax of lamivudine. Trimethoprim/Sulfamethoxazole. 3TC and TMP/SMX were coadministered to 14 HIV-1-positive subjects in single-center, open-label, randomized, crossover trial. Each subject received treatment with single 300-mg dose of 3TC and TMP 160 mg/SMX 800 mg once day for days with concomitant administration of 3TC 300 mg with the fifth dose in crossover design. Coadministration of TMP/SMX with 3TC resulted in an increase of 43% +- 23% (mean +- SD) in 3TC AUC, decrease of 29% +- 13% in 3TC oral clearance, and decrease of 30% +- 36% in 3TC renal clearance. The pharmacokinetic properties of TMP and SMX were not altered by coadministration with 3TC. There is no information regarding the effect on 3TC pharmacokinetics of higher doses of TMP/SMX such as those used in treating PCP.. Tenofovir Disoproxil Fumarate At concentrations substantially higher (~300-fold) than those observed in vivo, tenofovir did not inhibit in vitro CYP3A4, CYP2D6, CYP2C9, or CYP2E1. However, small (6%) but statistically significant reduction in metabolism of CYP1A substrate was observed. Based on the results of in vitro experiments and the known elimination pathway of tenofovir, the potential for CYP mediated interactions involving TDF with other medicinal products is low.TDF has been evaluated in healthy volunteers in combination with other antiretroviral and potential concomitant drugs. Tables and summarize pharmacokinetic effects of coadministered drug on tenofovir pharmacokinetics and effects of TDF on the pharmacokinetics of coadministered drug. Coadministration of TDF with didanosine results in changes in the pharmacokinetics of didanosine that may be of clinical significance. Concomitant dosing of TDF with didanosine significantly increases the Cmax and AUC of didanosine. When didanosine 250 mg enteric-coated capsules were administered with TDF, systemic exposures of didanosine were similar to those seen with the 400 mg enteric-coated capsules alone under fasted conditions (Table 5). The mechanism of this interaction is unknown.No clinically significant drug interactions have been observed between TDF and efavirenz, methadone, nelfinavir, oral contraceptives, ribavirin, or sofosbuvir.Table 5. Drug Interactions: Changes in Pharmacokinetic Parameters for TenofovirSubjects received TDF 300 mg once daily. in the Presence of the Coadministered DrugCoadministered DrugDose of Coadministered Drug (mg)% Change of Tenofovir Pharmacokinetic ParametersIncrease ; Decrease ; No Effect <->(90% CI)Cmax AUCCmin AtazanavirReyataz(R) (atazanavir) Prescribing Information. 400 once daily 14 days 14( to 20) 24( 21 to 28) 22( 15 to 30)Atazanavir/RitonavirPrezista(R) (darunavir) Prescribing Information. 300/100 once daily 34( 20 to 51) 37( 30 to 45) 29( 21 to 36)Darunavir/Ritonavir 300/100 twice daily 24( to 42) 22( 10 to 35) 37( 19 to 57)Indinavir800 three times daily 7 days 14( to 33)<-><->Ledipasvir/SofosbuvirData generated from simultaneous dosing with HARVONI (ledipasvir/sofosbuvir). Staggered administration (12 hours apart) provide similar results. Comparison based on exposures when administered as atazanavir/ritonavir emtricitabine/TDF. 90/400 once daily 10 days 47( 37 to 58) 35( 29 to 42) 47( 38 to 57)Ledipasvir/Sofosbuvir Comparison based on exposures when administered as darunavir/ritonavir emtricitabine/TDF. 64( 54 to 74) 50( 42 to 59) 59( 49 to 70)Ledipasvir/SofosbuvirStudy conducted with ATRIPLA(R) (efavirenz/emtricitabine/tenofovir DF) coadministered with HARVONI. 90/400 once daily 14 days 79( 56 to 104) 98( 77 to 123) 163( 132 to 197)Ledipasvir/SofosbuvirStudy conducted with COMPLERA(R) (emtricitabine/rilpivirine/tenofovir DF) coadministered with HARVONI. 90/400 once daily 10 days 32( 25 to 39) 40( 31 to 50) 91( 74 to 110)Ledipasvir/SofosbuvirStudy conducted with TRUVADA(R) (emtricitabine/tenofovir DF) dolutegravir coadministered with HARVONI. 90/400 once daily 10 days 61( 51 to 72) 65( 59 to 71) 115( 105 to 126)Lopinavir/Ritonavir 400/100 twice daily 14 days<-> 32( 25 to 38) 51( 37 to 66)Saquinavir/Ritonavir1000/100 twice daily 14 days<-><-> 23( 16 to 30)SofosbuvirStudy conducted with ATRIPLA coadministered with SOVALDI(R) (sofosbuvir). 400 single dose 25 to 45)<-><->Sofosbuvir/VelpatasvirComparison based on exposures when administered as atazanavir/ritonavir emtricitabine/tenofovir DF. 400/100 once daily 55( 43 to 68) 30( 24 to 36) 39( 31 to 48)Sofosbuvir/VelpatasvirComparison based on exposures when administered as darunavir/ritonavir emtricitabine/tenofovir DF. 400/100 once daily 55( 45 to 66) 39( 33 to 44) 52( 45 to 59)Sofosbuvir/VelpatasvirStudy conducted with ATRIPLA coadministered with EPCLUSA (sofosbuvir/velpatasvir). 400/100 once daily 77( 53 to 104) 81( 68 to 94) 121( 100 to 143)Sofosbuvir/VelpatasvirStudy conducted with STRIBILD(R) (elvitegravir/cobicistat/emtricitabine/tenofovir DF) coadministered with EPCLUSA. 400/100 once daily 36( 25 to 47) 35( 29 to 42) 45( 39 to 51)Sofosbuvir/VelpatasvirStudy conducted with COMPLERA coadministered with EPCLUSA. 400/100 once daily 44( 33 to 55) 40( 34 to 46) 84( 76 to 92)Sofosbuvir/VelpatasvirAdministered as raltegravir emtricitabine/tenofovir DF. 400/100 once daily 46( 39 to 54) 40( 34 to 45) 70( 61 to 79)Tacrolimus0.05 mg/kg twice daily 7 days 13( to 27)<-><->Tipranavir/RitonavirAptivus(R) (tipranavir) Prescribing Information. 500/100 twice daily 23( 32 to 13) 2( to 5) 7( to 17)750/200 twice daily (23 doses) 38( 46 to 29) 2( to 10) 14( to 27)No effect on the pharmacokinetic parameters of the following coadministered drugs was observed with TDF: abacavir, didanosine (buffered tablets), emtricitabine, entecavir, and lamivudine.Table 6. Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of TDFCoadministered DrugDose of Coadministered Drug (mg)% Change of Coadministered Drug Pharmacokinetic ParametersIncrease ; Decrease ; No Effect <->; NA Not Applicable(90% CI)Cmax AUCCmin Abacavir300 once 12( to 26)<->NAAtazanavirReyataz (atazanavir) Prescribing Information. 400 once daily 14 days 21( 27 to 14) 25( 30 to 19) 40( 48 to 32)Atazanavir Atazanavir/Ritonavir 300/100 once daily 42 days 28( 50 to 5) 25In HIV-infected subjects, addition of TDF to atazanavir 300 mg plus ritonavir 100 mg, resulted in AUC and Cmin values of atazanavir that were 2.3- and 4-fold higher than the respective values observed for atazanavir 400 mg when given alone. 42 to 3) 23 46 to 10)DarunavirPrezista (darunavir) Prescribing Information. Darunavir/Ritonavir 300/100 once daily 16( to 42) 21( to 54) 24( 10 to 69)DidanosineVidex(R) EC Prescribing Information. Subjects received didanosine enteric-coated capsules. 250 once, simultaneously with VIREAD(R) and light meal373 kcal, 8.2 fat 20Compared with didanosine (enteric-coated) 400 mg administered alone under fasting conditions. 32 to 7)<-> NAEmtricitabine200 once daily 7 days<-><-> 20( 12 to 29)Entecavir1 mg once daily 10 days<-> 13( 11 to 15)<->Indinavir800 three times daily 7 days 11( 30 to 12)<-><->Lamivudine150 twice daily 7 days 24( 34 to 12)<-><->LopinavirRitonavirLopinavir/Ritonavir 400/100 twice daily 14 days<-><-><-><-><-><->SaquinavirSaquinavir/Ritonavir 1000/100 twice daily 14 days 22( to 41) 29Increases in AUC and Cmin are not expected to be clinically relevant; hence no dose adjustments are required when tenofovir DF and ritonavir-boosted saquinavir are coadministered. 12 to 48) 47 23 to 76)Ritonavir<-><-> 23( to 46)Tacrolimus0.05 mg/kg twice daily 7 days<-><-><->TipranavirAptivus (tipranavir) Prescribing Information. Tipranavir/Ritonavir 500/100 twice daily 17( 26 to 6) 18( 25 to 9) 21( 30 to 10)Tipranavir/Ritonavir 750/200 twice daily (23 doses) 11( 16 to 4) 9( 15 to 3) 12( 22 to 0). 12.4Microbiology Mechanism of Action. Lamivudine 3TC is synthetic nucleoside analogue with activity against HIV-1 and HBV. Intracellularly, 3TC is phosphorylated to its active 5-triphosphate metabolite, lamivudine triphosphate (3TC-TP). The principal mode of action of 3TC-TP is inhibition of HIV-1 reverse transcriptase (RT) via DNA chain termination after incorporation of the nucleotide analogue.. Tenofovir Disoproxil Fumarate TDF is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate. TDF requires initial diester hydrolysis for conversion to tenofovir and subsequent phosphorylations by cellular enzymes to form tenofovir diphosphate. Tenofovir diphosphate inhibits the activity of HIV-1 reverse transcriptase and HBV reverse transcriptase 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. Lamivudine The antiviral activity of 3TC against HIV-1 was assessed in number of cell lines (including monocytes and fresh human peripheral blood lymphocytes (PBMCs) using standard susceptibility assays. EC50 values were in the range of to 15,000 nM. (1 uM 0.23 mcg/mL). The median EC50 values of 3TC were 60 nM (range: 20 to 70 nM), 35 nM (range: 30 to 40 nM), 30 nM (range: 20 to 90 nM), 20 nM (range: to 40 nM), 30 nM (range: to 60 nM), 30 nM (range: 20 to 70 nM), 30 nM (range: to 70 nM), and 30 nM (range: 20 to 90 nM) against HIV-1 clades A-G and group viruses (n 3 except = for clade B), respectively. The EC50 values against HIV-2 isolates (n 4) ranged from to 120 nM in PBMCs. 3TC was not antagonistic to all tested anti-HIV agents. Ribavirin (50 uM) used in the treatment of chronic HCV infection decreased the anti-HIV-1 activity of 3TC by 3.5-fold in MT-4 cells. Tenofovir Disoproxil Fumarate The antiviral activity of tenofovir against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, primary monocyte/macrophage cells and peripheral blood lymphocytes. The EC50 (50% effective concentration) values for tenofovir were in the range of 0.04 uM to 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 uM to 2.2 uM) and strain-specific activity against HIV-2 (EC50 values ranged from 1.6 uM to 5.5 uM). Please see the full prescribing information for VIREAD for information regarding the inhibitory activity of TDF against HBV.. Resistance. Lamivudine 3TC-resistant variants of HIV-1 have been selected in cell culture. Genotypic analysis showed that resistance was predominantly due to methionine to valine or isoleucine (M184V/I) substitution in reverse transcriptase. Tenofovir Disoproxil Fumarate HIV-1 isolates with reduced susceptibility to tenofovir have been selected in cell culture. These viruses expressed K65R substitution in reverse transcriptase and showed 2- to 4-fold reduction in susceptibility to tenofovir. In addition, K70E substitution in HIV-1 reverse transcriptase has been selected by tenofovir and results in low-level reduced susceptibility to tenofovir. K65R substitutions developed in some subjects failing tenofovir disoproxil fumarate regimen. Cross-Resistance. Lamivudine Cross-resistance among NRTIs has been observed. 3TC-resistant HIV-1 isolates were cross-resistant in cell culture to didanosine (ddI). Cross-resistance is also expected with abacavir and emtricitabine as these select M184V substitutions.. Tenofovir Disoproxil Fumarate Cross-resistance among NRTIs has been observed. The K65R and K70E substitutions selected by tenofovir are also selected in some HIV-1-infected subjects treated with abacavir or didanosine. HIV-1 isolates with the K65R substitution also showed reduced susceptibility to FTC and 3TC. HIV-1 isolates from subjects (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 VIREAD. 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.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS The following adverse reactions are discussed in other sections of the labeling:oLactic Acidosis/Severe Hepatomegaly with Steatosis [see Warnings and Precautions (5.1)].oExacerbations of Hepatitis [see Boxed Warning, Warnings and Precautions (5.2)].oNew Onset or Worsening Renal Impairment [see Warnings and Precautions (5.3)].oHepatic Decompensation in Patients Co-infected with HIV-1 and Hepatitis [see Warnings and Precautions (5.4)].oPancreatitis [see Warnings and Precautions (5.5)].oDecreases in Bone Mineral Density [see Warnings and Precautions (5.6)].oImmune Reconstitution Syndrome [see Warnings and Precautions (5.7)].oFat Redistribution [see Warnings and Precautions (5.8)].. oLactic Acidosis/Severe Hepatomegaly with Steatosis [see Warnings and Precautions (5.1)].. oExacerbations of Hepatitis [see Boxed Warning, Warnings and Precautions (5.2)].. oNew Onset or Worsening Renal Impairment [see Warnings and Precautions (5.3)].. oHepatic Decompensation in Patients Co-infected with HIV-1 and Hepatitis [see Warnings and Precautions (5.4)].. oPancreatitis [see Warnings and Precautions (5.5)].. oDecreases in Bone Mineral Density [see Warnings and Precautions (5.6)].. oImmune Reconstitution Syndrome [see Warnings and Precautions (5.7)].. oFat Redistribution [see Warnings and Precautions (5.8)].. oMost common adverse reactions (> 10% with CIMDUO) are headache, pain, depression, diarrhea, and rash. (6)To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. oMost common adverse reactions (> 10% with CIMDUO) are headache, pain, depression, diarrhea, and rash. (6). 6.1Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, the adverse reaction rates observed in 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.. Lamivudine and Tenofovir Disoproxil Fumarate. Treatment-Naive Patients Study 903 Adverse Reactions The most common adverse reactions seen in double-blind comparative controlled study in which 600 treatment-naive subjects received TDF (N 299) or stavudine (d4T) (N 301) in combination with 3TC and EFV for 144 weeks were mild to moderate gastrointestinal events and dizziness. Mild adverse reactions (Grade 1) were common with similar incidence in both arms, and included dizziness, diarrhea, and nausea. Selected moderate to severe adverse reactions are summarized in Table 1.Table 1. Selected Adverse ReactionsFrequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug. (Grades 2-4) Reported in >= 5% in Any Treatment Group in Study 903 (0-144 Weeks)TDF 3TC EFVd4T 3TC EFVN 299N 301Body as Whole Headache 14%17% Pain 13%12% Fever 8%7% Abdominal pain 7%12% Back pain 9%8% Asthenia 6%7%Digestive System Diarrhea 11%13% Nausea 8%9% Dyspepsia 4%5% Vomiting 5%9%Metabolic Disorders LipodystrophyLipodystrophy represents variety of investigator-described adverse events not protocol-defined syndrome. 1%8%Musculoskeletal Arthralgia 5%7% Myalgia 3%5%Nervous System Depression 11%10% Insomnia 5%8% Dizziness 3%6% Peripheral neuropathyPeripheral neuropathy includes peripheral neuritis and neuropathy. 1%5% Anxiety 6%6%Respiratory Pneumonia 5%5%Skin and Appendages Rash eventRash event includes rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, and pustular rash. 18%12%. Laboratory Abnormalities With the exception of fasting cholesterol and fasting triglyceride elevations that were more common in the stavudine group (40% and 9%) compared with TDF (19% and 1%) respectively, laboratory abnormalities observed in this study occurred with similar frequency in the tenofovir disoproxil fumarate and stavudine treatment arms. summary of Grade and laboratory abnormalities is provided in Table 2.Table 2. Grade 3/4 Laboratory Abnormalities Reported in >= 1% of Tenofovir Disoproxil Fumarate Treated Subjects in Study 903 (0-144 Weeks)TDF 3TC EFVd4T 3TC EFVN 299N 301Any >= Grade Laboratory Abnormality36%42%Fasting Cholesterol (> 240 mg/dL)19%40%Creatine Kinase (M: 990 U/L; F: 845 U/L)12%12%Serum Amylase (> 175 U/L)9%8%AST (M: 180 U/L; F: 170 U/L)5%7%ALT (M: 215 U/L; F: 170 U/L)4%5%Hematuria (> 100 RBC/HPF)7%7%Neutrophils (< 750/mm3)3%1%Fasting Triglycerides (> 750 mg/dL)1%9%. Pancreatitis Pancreatitis, which has been fatal in some cases, has been observed in antiretroviral nucleoside-experienced pediatric subjects receiving 3TC alone or in combination with other antiretroviral agents [see Warnings and Precautions (5.5)]. Changes in Bone Mineral Density In HIV-1-infected adult subjects in Study 903, there was significantly greater mean percentage decrease from baseline in BMD at the lumbar spine in subjects receiving TDF 3TC EFV (-2.2% +- 3.9) compared with subjects receiving d4T 3TC EFV (-1.0% +- 4.6) through 144 weeks. Changes in BMD at the hip were similar between the two treatment groups (-2.8% +- 3.5 in the TDF group vs. -2.4% +- 4.5 in the d4T group). In both groups, the majority of the reduction in BMD occurred in the first 24-48 weeks of the trial and this reduction was sustained through Week 144. Twenty-eight percent of TDF-treated subjects vs. 21% of the d4T-treated subjects lost at least 5% of BMD at the spine or 7% of BMD at the hip. Clinically relevant fractures (excluding fingers and toes) were reported in subjects in the TDF group and subjects in the d4T group. In addition, there were significant increases in biochemical markers of bone metabolism (serum bone-specific alkaline phosphatase, serum osteocalcin, serum telopeptide, and urinary telopeptide) and higher serum parathyroid hormone levels and 1,25 Vitamin levels in the TDF group relative to the d4T group; however, except for bone-specific alkaline phosphatase, these changes resulted in values that remained within the normal range [see Warnings and Precautions (5.6)].. 6.2Postmarketing Experience The following adverse reactions have been identified during post-approval use for each of the individual components of CIMDUO (3TC and TDF). Because these reactions are reported voluntarily from population of unknown size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure. These reactions have been chosen for inclusion due to combination of their seriousness, frequency of reporting, or potential causal connection to 3TC and TDF. Lamivudine. Body as Whole: redistribution/accumulation of body fat [see Warnings and Precautions (5.8)]. Endocrine and Metabolic: hyperglycemia.General: weakness.Hemic and Lymphatic: anemia (including pure red cell aplasia and severe anemias progressing on therapy).Hepatic and Pancreatic: lactic acidosis and hepatic steatosis, posttreatment exacerbation of hepatitis [see Boxed Warning, Warnings and Precautions (5.1, 5.2)].Hypersensitivity: anaphylaxis, urticaria.Musculoskeletal: muscle weakness, CPK elevation, rhabdomyolysis.Skin: Alopecia, pruritus.. Tenofovir Disoproxil Fumarate. Immune System Disorders: allergic reaction, including angioedema.Metabolism and Nutrition Disorders: lactic acidosis, hypokalemia, hypophosphatemia.Respiratory, Thoracic, and Mediastinal Disorders: dyspnea.Gastrointestinal Disorders: pancreatitis, increased amylase, abdominal pain.Renal and Urinary Disorders: renal insufficiency, acute renal failure, renal failure, acute tubular necrosis, Fanconi syndrome, proximal renal tubulopathy, interstitial nephritis (including acute cases), nephrogenic diabetes insipidus, renal insufficiency, increased creatinine, proteinuria, polyuria [see Warnings and Precautions (5.3)].Hepatobiliary Disorders: hepatic steatosis, hepatitis, increased liver enzymes (most commonly AST, ALT gamma GT).Skin and Subcutaneous Tissue Disorders: rash.Musculoskeletal and Connective Tissue Disorders: rhabdomyolysis, osteomalacia (manifested as bone pain and which may contribute to fractures), muscular weakness, myopathy.General Disorders and Administration Site Conditions: asthenia.The 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.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS oAtazanavir: Atazanavir should be coadministered with ritonavir when coadministered with CIMDUO. (7.2) oHIV-1 Protease Inhibitors: Monitor for evidence of tenofovir toxicity when CIMDUO is coadministrated with atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir. (7.2) oSorbitol: Avoid chronic administration of sorbitol with CIMDUO.(7.5). oAtazanavir: Atazanavir should be coadministered with ritonavir when coadministered with CIMDUO. (7.2) oHIV-1 Protease Inhibitors: Monitor for evidence of tenofovir toxicity when CIMDUO is coadministrated with atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir. (7.2) oSorbitol: Avoid chronic administration of sorbitol with CIMDUO.(7.5). 7.1Drugs Affecting Renal Function Since tenofovir is primarily eliminated by the kidneys [see Clinical Pharmacology (12.3)], coadministration of CIMDUO with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of tenofovir and/or increase the concentrations of other renally eliminated drugs. Some examples include, but are not limited to cidofovir, acyclovir, valacyclovir, ganciclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs [see Warnings and Precautions (5.3)].. 7.2HIV-1 Protease Inhibitors TDF decreases the AUC and Cmin of atazanavir [see Clinical Pharmacology (12.3)]. When coadministered with CIMDUO, it is recommended that atazanavir 300 mg is given with ritonavir 100 mg. TDF should not be coadministered with atazanavir without ritonavir.Lopinavir/ritonavir, atazanavir coadministered with ritonavir, and darunavir coadministered with ritonavir have been shown to increase tenofovir concentrations [see Clinical Pharmacology (12.3)]. Patients receiving CIMDUO concomitantly with lopinavir/ritonavir, atazanavir and ritonavir, or darunavir and ritonavir should be monitored for tenofovir-associated adverse reactions. CIMDUO should be discontinued in patients who develop tenofovir-associated adverse reactions.. 7.3Hepatitis Antiviral Agents Coadministration of TDF, component of CIMDUO, and EPCLUSA(R) (sofosbuvir/velpatasvir) or HARVONI(R) (ledipasvir/sofosbuvir) has been shown to increase tenofovir exposure [see Clinical Pharmacology (12.3)]. In patients receiving TDF concomitantly with sofosbuvir/velpatasvir, monitor for adverse reactions associated with TDF.In patients receiving CIMDUO concomitantly with ledipasvir/sofosbuvir without an HIV-1 protease inhibitor/ritonavir or an HIV-1 protease inhibitor/cobicistat combination, monitor for adverse reactions associated with tenofovir. In patients receiving CIMDUO concomitantly with ledipasvir/sofosbuvir and an HIV-1 protease inhibitor/ritonavir or an HIV-1 protease inhibitor/cobicistat combination, consider an alternative HCV or antiretroviral therapy, as the safety of increased tenofovir concentrations in this setting has not been established. If coadministration is necessary, monitor for adverse reactions associated with tenofovir.. 7.4Drugs Inhibiting Organic Cation Transporters 3TC, component of CIMDUO, is predominantly eliminated in the urine by active organic cationic secretion. The possibility of interactions with other drugs administered concurrently should be considered, particularly when their main route of elimination is active renal secretion via the organic cationic transport system (e.g., trimethoprim) [see Clinical Pharmacology (12.3)]. No data are available regarding interactions with other drugs that have renal clearance mechanisms similar to that of 3TC.. 7.5Sorbitol Coadministration of single doses of 3TC and sorbitol resulted in sorbitol dose-dependent reduction in 3TC exposures. When possible, avoid use of sorbitol-containing medicines with 3TC [see Clinical Pharmacology (12.3)].

MICROBIOLOGY SECTION.

12.4Microbiology Mechanism of Action. Lamivudine 3TC is synthetic nucleoside analogue with activity against HIV-1 and HBV. Intracellularly, 3TC is phosphorylated to its active 5-triphosphate metabolite, lamivudine triphosphate (3TC-TP). The principal mode of action of 3TC-TP is inhibition of HIV-1 reverse transcriptase (RT) via DNA chain termination after incorporation of the nucleotide analogue.. Tenofovir Disoproxil Fumarate TDF is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate. TDF requires initial diester hydrolysis for conversion to tenofovir and subsequent phosphorylations by cellular enzymes to form tenofovir diphosphate. Tenofovir diphosphate inhibits the activity of HIV-1 reverse transcriptase and HBV reverse transcriptase 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. Lamivudine The antiviral activity of 3TC against HIV-1 was assessed in number of cell lines (including monocytes and fresh human peripheral blood lymphocytes (PBMCs) using standard susceptibility assays. EC50 values were in the range of to 15,000 nM. (1 uM 0.23 mcg/mL). The median EC50 values of 3TC were 60 nM (range: 20 to 70 nM), 35 nM (range: 30 to 40 nM), 30 nM (range: 20 to 90 nM), 20 nM (range: to 40 nM), 30 nM (range: to 60 nM), 30 nM (range: 20 to 70 nM), 30 nM (range: to 70 nM), and 30 nM (range: 20 to 90 nM) against HIV-1 clades A-G and group viruses (n 3 except = for clade B), respectively. The EC50 values against HIV-2 isolates (n 4) ranged from to 120 nM in PBMCs. 3TC was not antagonistic to all tested anti-HIV agents. Ribavirin (50 uM) used in the treatment of chronic HCV infection decreased the anti-HIV-1 activity of 3TC by 3.5-fold in MT-4 cells. Tenofovir Disoproxil Fumarate The antiviral activity of tenofovir against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, primary monocyte/macrophage cells and peripheral blood lymphocytes. The EC50 (50% effective concentration) values for tenofovir were in the range of 0.04 uM to 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 uM to 2.2 uM) and strain-specific activity against HIV-2 (EC50 values ranged from 1.6 uM to 5.5 uM). Please see the full prescribing information for VIREAD for information regarding the inhibitory activity of TDF against HBV.. Resistance. Lamivudine 3TC-resistant variants of HIV-1 have been selected in cell culture. Genotypic analysis showed that resistance was predominantly due to methionine to valine or isoleucine (M184V/I) substitution in reverse transcriptase. Tenofovir Disoproxil Fumarate HIV-1 isolates with reduced susceptibility to tenofovir have been selected in cell culture. These viruses expressed K65R substitution in reverse transcriptase and showed 2- to 4-fold reduction in susceptibility to tenofovir. In addition, K70E substitution in HIV-1 reverse transcriptase has been selected by tenofovir and results in low-level reduced susceptibility to tenofovir. K65R substitutions developed in some subjects failing tenofovir disoproxil fumarate regimen. Cross-Resistance. Lamivudine Cross-resistance among NRTIs has been observed. 3TC-resistant HIV-1 isolates were cross-resistant in cell culture to didanosine (ddI). Cross-resistance is also expected with abacavir and emtricitabine as these select M184V substitutions.. Tenofovir Disoproxil Fumarate Cross-resistance among NRTIs has been observed. The K65R and K70E substitutions selected by tenofovir are also selected in some HIV-1-infected subjects treated with abacavir or didanosine. HIV-1 isolates with the K65R substitution also showed reduced susceptibility to FTC and 3TC. HIV-1 isolates from subjects (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 VIREAD. 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.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics Lamivudine. After oral administration of mg/kg of 3TC twice day to adults with HIV-1, the peak serum 3TC concentration (Cmax) was 1.5 +- 0.5 mcg/mL (mean +- SD). The area under the plasma concentration versus time curve (AUC) and Cmax increased in proportion to oral dose over the range from 0.25 to 10 mg/kg and absolute bioavailability in 12 adult patients was 86% +- 16% (mean +- SD) for the 150-mg tablet and 87% +- 13% for the oral solution. Binding of 3TC to human plasma proteins is low (< 36%). Within 12 hours after single oral dose of 3TC in HIV-1-infected adults, 5.2% +- 1.4% (mean +- SD) of the dose was excreted as the trans-sulfoxide metabolite in the urine. The majority of 3TC is eliminated unchanged in urine by active organic cationic secretion and the observed mean elimination half-life (t1/2) ranged from to hours in most single-dose studies with serum sampling for 24 hours after dosing.. Tenofovir Disoproxil Fumarate. Following oral administration of single 300-mg dose of TDF to HIV-1-infected subjects in the fasted state, maximum serum concentrations (Cmax) were achieved in 1.0 +- 0.4 hrs (mean +- SD) and Cmax and AUC values were 296 +- 90 ng/mL and 2287 +- 685 ngohr/mL, respectively. The oral bioavailability of tenofovir from TDF in fasted subjects is approximately 25%. Less than 0.7% of tenofovir binds to human plasma proteins in vitro and the binding is independent of concentration over the range of 0.01 to 25 mcg/mL. Approximately 70 to 80% of the intravenous dose of tenofovir is recovered as unchanged drug in the urine. Tenofovir is eliminated by combination of glomerular filtration and active tubular secretion with renal clearance in adults with normal renal function of 243 +- 33 mL/min (mean +- SD). Following single oral dose, the terminal elimination half-life of tenofovir is approximately 17 hours.. Special Populations. Race Lamivudine. There are no significant or clinically relevant racial differences in lamivudine pharmacokinetics.. Tenofovir Disoproxil Fumarate. There were insufficient numbers from racial and ethnic groups other than Caucasian to adequately determine potential pharmacokinetic differences among these populations.. Gender There are no significant or clinically relevant gender differences in the pharmacokinetics of lamivudine and tenofovir.. Geriatric Patients The pharmacokinetics of lamivudine and tenofovir have not been studied in patients over 65 years of age. Patients with Renal Impairment [See Use in Specific Populations (8.6) .]. Lamivudine. The pharmacokinetics of lamivudine are altered in subjects with renal impairment (Table 3).Table 3. Pharmacokinetic Parameters (Mean +- SD) After Single 300-mg Oral Dose of 3TC in Subjects with Varying Degrees of Renal FunctionParameter Creatinine Clearance Criterion (Number of Subjects)> 60 mL/min(n 6)10-30 mL/min(n 4)< 10 mL/min(n 6)Creatinine clearance (mL/min) 111 +- 1428 +- 86 +- 2Cmax (mcg/mL) 2.6 +- 0.53.6 +- 0.85.8 +- 1.2AUC (mcgoh/mL) 11.0 +- 1.748.0 +- 19157 +- 74Cl/F (mL/min)464 +- 76114 +- 3436 +- 11. Tenofovir Disoproxil Fumarate. The pharmacokinetics of tenofovir are altered in subjects with renal impairment [see Warnings and Precautions (5.3)]. In subjects with creatinine clearance below 50 mL/min or with end-stage renal disease (ESRD) requiring dialysis, Cmax, and AUC0- of tenofovir were increased. Table 4. Pharmacokinetic Parameters (Mean +- SD) of Tenofovir in Subjects After Single 300-mg Oral Dose of TDF in Subjects with Varying Degrees of Renal FunctionBaseline Creatinine Clearance (mL/min) 80(N 3)50-80(N 10)30-49(N 8)12-29(N 11)Cmax (ug/mL) 0.34 +- 0.030.33 +- 0.060.37 +- 0.160.60 +- 0.19AUC0- (ugohr/mL) 2.18 +- 0.263.06 +- 0.936.01 +- 2.5015.98 +- 7.22CL/F (mL/min) 1043.7 +- 115.4807.7 +- 279.2444.4 +- 209.8177.0 +- 97.1CLrenal (mL/min) 243.5 +- 33.3168.6 +- 27.5100.6 +- 27.543.0 +- 31.2. Patients with Hepatic Impairment: Lamivudine. The pharmacokinetics of lamivudine were not altered by diminishing hepatic function. Safety and efficacy of lamivudine have not been established in the presence of decompensated liver disease.. Tenofovir Disoproxil Fumarate. The pharmacokinetics of tenofovir following 300 mg single dose of TDF have been studied in non-HIV-infected subjects with moderate to severe (Child-Pugh to C) hepatic impairment. There were no substantial alterations in tenofovir pharmacokinetics in subjects with hepatic impairment compared with unimpaired subjects. Assessment of Drug Interactions. [See Drug Interactions (7).]. Lamivudine Effect of 3TC on the Pharmacokinetics of Other Agents. Based on in vitro study results, 3TC at therapeutic drug exposures is not expected to affect the pharmacokinetics of drugs that are substrates of the following transporters: organic anion transporter polypeptide 1B1/3 (OATP1B1/3), breast cancer resistance protein (BCRP), P-glycoprotein (P-gp), multidrug and toxin extrusion protein (MATE1), MATE2-K, organic cation transporter (OCT1), OCT2, or OCT3.. Effect of Other Agents on the Pharmacokinetics of 3TC. 3TC is substrate of MATE1, MATE2-K, and OCT2 in vitro. Trimethoprim (an inhibitor of these drug transporters) has been shown to increase 3TC plasma concentrations. This interaction is not considered clinically significant as no dose adjustment of 3TC is needed.3TC is substrate of P-gp and BCRP; however, considering its absolute bioavailability (87%), it is unlikely that these transporters play significant role in the absorption of 3TC. Therefore, coadministration of drugs that are inhibitors of these efflux transporters is unlikely to affect the disposition and elimination of 3TC.. Interferon Alfa. There was no significant pharmacokinetic interaction between 3TC and interferon alfa in trial of 19 healthy male subjects [see Warnings and Precautions (5.4)].. Ribavirin. In vitro data indicate ribavirin reduces phosphorylation of 3TC, stavudine, and zidovudine. However, no pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV-1/HCV virologic suppression) interaction was observed when ribavirin and 3TC (n 18), stavudine (n 10), or zidovudine (n 6) were coadministered as part of multi-drug regimen to HIV-1/HCV co-infected subjects [see Warnings and Precautions (5.4)].. Sorbitol (Excipient). 3TC and sorbitol solutions were coadministered to 16 healthy adult subjects in an open-label, randomized sequence, 4-period, crossover trial. Each subject received single 300-mg dose of 3TC oral solution alone or coadministered with single dose of 3.2 grams, 10.2 grams, or 13.4 grams of sorbitol in solution. Coadministration of 3TC with sorbitol resulted in dose-dependent decreases of 20%, 39%, and 44% in the AUC(0-24), 14%, 32%, and 36% in the AUC(), and 28%, 52%, and 55% in the Cmax of lamivudine. Trimethoprim/Sulfamethoxazole. 3TC and TMP/SMX were coadministered to 14 HIV-1-positive subjects in single-center, open-label, randomized, crossover trial. Each subject received treatment with single 300-mg dose of 3TC and TMP 160 mg/SMX 800 mg once day for days with concomitant administration of 3TC 300 mg with the fifth dose in crossover design. Coadministration of TMP/SMX with 3TC resulted in an increase of 43% +- 23% (mean +- SD) in 3TC AUC, decrease of 29% +- 13% in 3TC oral clearance, and decrease of 30% +- 36% in 3TC renal clearance. The pharmacokinetic properties of TMP and SMX were not altered by coadministration with 3TC. There is no information regarding the effect on 3TC pharmacokinetics of higher doses of TMP/SMX such as those used in treating PCP.. Tenofovir Disoproxil Fumarate At concentrations substantially higher (~300-fold) than those observed in vivo, tenofovir did not inhibit in vitro CYP3A4, CYP2D6, CYP2C9, or CYP2E1. However, small (6%) but statistically significant reduction in metabolism of CYP1A substrate was observed. Based on the results of in vitro experiments and the known elimination pathway of tenofovir, the potential for CYP mediated interactions involving TDF with other medicinal products is low.TDF has been evaluated in healthy volunteers in combination with other antiretroviral and potential concomitant drugs. Tables and summarize pharmacokinetic effects of coadministered drug on tenofovir pharmacokinetics and effects of TDF on the pharmacokinetics of coadministered drug. Coadministration of TDF with didanosine results in changes in the pharmacokinetics of didanosine that may be of clinical significance. Concomitant dosing of TDF with didanosine significantly increases the Cmax and AUC of didanosine. When didanosine 250 mg enteric-coated capsules were administered with TDF, systemic exposures of didanosine were similar to those seen with the 400 mg enteric-coated capsules alone under fasted conditions (Table 5). The mechanism of this interaction is unknown.No clinically significant drug interactions have been observed between TDF and efavirenz, methadone, nelfinavir, oral contraceptives, ribavirin, or sofosbuvir.Table 5. Drug Interactions: Changes in Pharmacokinetic Parameters for TenofovirSubjects received TDF 300 mg once daily. in the Presence of the Coadministered DrugCoadministered DrugDose of Coadministered Drug (mg)% Change of Tenofovir Pharmacokinetic ParametersIncrease ; Decrease ; No Effect <->(90% CI)Cmax AUCCmin AtazanavirReyataz(R) (atazanavir) Prescribing Information. 400 once daily 14 days 14( to 20) 24( 21 to 28) 22( 15 to 30)Atazanavir/RitonavirPrezista(R) (darunavir) Prescribing Information. 300/100 once daily 34( 20 to 51) 37( 30 to 45) 29( 21 to 36)Darunavir/Ritonavir 300/100 twice daily 24( to 42) 22( 10 to 35) 37( 19 to 57)Indinavir800 three times daily 7 days 14( to 33)<-><->Ledipasvir/SofosbuvirData generated from simultaneous dosing with HARVONI (ledipasvir/sofosbuvir). Staggered administration (12 hours apart) provide similar results. Comparison based on exposures when administered as atazanavir/ritonavir emtricitabine/TDF. 90/400 once daily 10 days 47( 37 to 58) 35( 29 to 42) 47( 38 to 57)Ledipasvir/Sofosbuvir Comparison based on exposures when administered as darunavir/ritonavir emtricitabine/TDF. 64( 54 to 74) 50( 42 to 59) 59( 49 to 70)Ledipasvir/SofosbuvirStudy conducted with ATRIPLA(R) (efavirenz/emtricitabine/tenofovir DF) coadministered with HARVONI. 90/400 once daily 14 days 79( 56 to 104) 98( 77 to 123) 163( 132 to 197)Ledipasvir/SofosbuvirStudy conducted with COMPLERA(R) (emtricitabine/rilpivirine/tenofovir DF) coadministered with HARVONI. 90/400 once daily 10 days 32( 25 to 39) 40( 31 to 50) 91( 74 to 110)Ledipasvir/SofosbuvirStudy conducted with TRUVADA(R) (emtricitabine/tenofovir DF) dolutegravir coadministered with HARVONI. 90/400 once daily 10 days 61( 51 to 72) 65( 59 to 71) 115( 105 to 126)Lopinavir/Ritonavir 400/100 twice daily 14 days<-> 32( 25 to 38) 51( 37 to 66)Saquinavir/Ritonavir1000/100 twice daily 14 days<-><-> 23( 16 to 30)SofosbuvirStudy conducted with ATRIPLA coadministered with SOVALDI(R) (sofosbuvir). 400 single dose 25 to 45)<-><->Sofosbuvir/VelpatasvirComparison based on exposures when administered as atazanavir/ritonavir emtricitabine/tenofovir DF. 400/100 once daily 55( 43 to 68) 30( 24 to 36) 39( 31 to 48)Sofosbuvir/VelpatasvirComparison based on exposures when administered as darunavir/ritonavir emtricitabine/tenofovir DF. 400/100 once daily 55( 45 to 66) 39( 33 to 44) 52( 45 to 59)Sofosbuvir/VelpatasvirStudy conducted with ATRIPLA coadministered with EPCLUSA (sofosbuvir/velpatasvir). 400/100 once daily 77( 53 to 104) 81( 68 to 94) 121( 100 to 143)Sofosbuvir/VelpatasvirStudy conducted with STRIBILD(R) (elvitegravir/cobicistat/emtricitabine/tenofovir DF) coadministered with EPCLUSA. 400/100 once daily 36( 25 to 47) 35( 29 to 42) 45( 39 to 51)Sofosbuvir/VelpatasvirStudy conducted with COMPLERA coadministered with EPCLUSA. 400/100 once daily 44( 33 to 55) 40( 34 to 46) 84( 76 to 92)Sofosbuvir/VelpatasvirAdministered as raltegravir emtricitabine/tenofovir DF. 400/100 once daily 46( 39 to 54) 40( 34 to 45) 70( 61 to 79)Tacrolimus0.05 mg/kg twice daily 7 days 13( to 27)<-><->Tipranavir/RitonavirAptivus(R) (tipranavir) Prescribing Information. 500/100 twice daily 23( 32 to 13) 2( to 5) 7( to 17)750/200 twice daily (23 doses) 38( 46 to 29) 2( to 10) 14( to 27)No effect on the pharmacokinetic parameters of the following coadministered drugs was observed with TDF: abacavir, didanosine (buffered tablets), emtricitabine, entecavir, and lamivudine.Table 6. Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of TDFCoadministered DrugDose of Coadministered Drug (mg)% Change of Coadministered Drug Pharmacokinetic ParametersIncrease ; Decrease ; No Effect <->; NA Not Applicable(90% CI)Cmax AUCCmin Abacavir300 once 12( to 26)<->NAAtazanavirReyataz (atazanavir) Prescribing Information. 400 once daily 14 days 21( 27 to 14) 25( 30 to 19) 40( 48 to 32)Atazanavir Atazanavir/Ritonavir 300/100 once daily 42 days 28( 50 to 5) 25In HIV-infected subjects, addition of TDF to atazanavir 300 mg plus ritonavir 100 mg, resulted in AUC and Cmin values of atazanavir that were 2.3- and 4-fold higher than the respective values observed for atazanavir 400 mg when given alone. 42 to 3) 23 46 to 10)DarunavirPrezista (darunavir) Prescribing Information. Darunavir/Ritonavir 300/100 once daily 16( to 42) 21( to 54) 24( 10 to 69)DidanosineVidex(R) EC Prescribing Information. Subjects received didanosine enteric-coated capsules. 250 once, simultaneously with VIREAD(R) and light meal373 kcal, 8.2 fat 20Compared with didanosine (enteric-coated) 400 mg administered alone under fasting conditions. 32 to 7)<-> NAEmtricitabine200 once daily 7 days<-><-> 20( 12 to 29)Entecavir1 mg once daily 10 days<-> 13( 11 to 15)<->Indinavir800 three times daily 7 days 11( 30 to 12)<-><->Lamivudine150 twice daily 7 days 24( 34 to 12)<-><->LopinavirRitonavirLopinavir/Ritonavir 400/100 twice daily 14 days<-><-><-><-><-><->SaquinavirSaquinavir/Ritonavir 1000/100 twice daily 14 days 22( to 41) 29Increases in AUC and Cmin are not expected to be clinically relevant; hence no dose adjustments are required when tenofovir DF and ritonavir-boosted saquinavir are coadministered. 12 to 48) 47 23 to 76)Ritonavir<-><-> 23( to 46)Tacrolimus0.05 mg/kg twice daily 7 days<-><-><->TipranavirAptivus (tipranavir) Prescribing Information. Tipranavir/Ritonavir 500/100 twice daily 17( 26 to 6) 18( 25 to 9) 21( 30 to 10)Tipranavir/Ritonavir 750/200 twice daily (23 doses) 11( 16 to 4) 9( 15 to 3) 12( 22 to 0).

SPL PATIENT PACKAGE INSERT SECTION.

Patient Information CIMDUO(R) (sim-DEW-oh)(lamivudine and tenofovir disoproxil fumarate) tablets What is the most important information should know about CIMDUOCIMDUO can cause serious side effects, including:oToo much lactic acid in your blood (lactic acidosis). Lactic acidosis is serious medical emergency that can lead to death. Tell your healthcare provider right away if you get any of the following symptoms that could be signs of lactic acidosis:ofeel very weak or tired ounusual (not normal) muscle pain otrouble breathingostomach pain with nausea or vomitingofeel cold, especially in your arms and legs ofeel dizzy or lightheaded ohave fast or irregular heartbeatoSevere liver problems. In some cases, severe liver problems can lead to death. Your liver may become large (hepatomegaly) and you may develop fat in your liver (steatosis). Call your healthcare provider right away if you get any of the following signs or symptoms of liver problems: oyour skin or the white part of your eyes turns yellow (jaundice)odark or tea-colored urineolight-colored stools (bowel movements)oloss of appetite for several days or longeronausea and vomiting opain, aching, or tenderness on the right side of your stomach-areaoWorsening of hepatitis infection. If you have Human Immunodeficiency Virus type (HIV-1) and hepatitis Virus (HBV) infection, your HBV may get worse (flare-up) if you stop taking CIMDUO. flare-up is when your HBV infection suddenly returns in worse way than before. Your healthcare provider will test you for HBV infection before you start treatment with CIMDUO. oIt is not known if CIMDUO is safe and effective in people who have both HIV-1 and HBV infection.oDo not run out of CIMDUO. Refill your prescription or talk to your healthcare provider before your CIMDUO is all gone.oDo not stop CIMDUO without first talking to your healthcare provider. If you stop taking CIMDUO, your healthcare provider will need to check your health often and do blood tests regularly for several months to check your liver. oNew or worse kidney problems, including kidney failure. Your healthcare provider may do blood and urine tests to check your kidneys before and during treatment with CIMDUO. Tell your healthcare provider if you get signs and symptoms of kidney problems, including bone pain that does not go away or worsening bone pain, pain in your arms, hands, legs or feet, broken (fractured) bones, muscle pain or weakness. For more information about side effects, see What are the possible side effects of CIMDUOWhat is CIMDUOCIMDUO is prescription medicine that is used with other antiretroviral medicines to treat Human Immunodeficiency Virus-1 (HIV-1) in adults and children weighing at least 35 kg. HIV-1 is the virus that causes AIDS (Acquired Immune Deficiency Syndrome).CIMDUO contains the prescription medicines lamivudine and tenofovir disoproxil fumarate.Do not take CIMDUO if you:oare allergic to lamivudine, tenofovir disoproxil fumarate, or any of the ingredients in CIMDUO. See the end of this Patient Information leaflet for complete list of ingredients in CIMDUO.Before you take CIMDUO, tell your healthcare provider about all of your medical conditions, including if you:ohave liver problems, including hepatitis or infectionohave kidney problems, including end-stage renal disease (ESRD) that requires dialysis ohave bone problems, including history of bone fractures oare pregnant or plan to become pregnant. It is not known if CIMDUO will harm your unborn baby. There is pregnancy registry for women who take CIMDUO during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk to your healthcare provider about how you can take part in this registry.oare breastfeeding or plan to breastfeed. Do not breastfeed if you take CIMDUO. oYou should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby.oTalk to your healthcare provider about the best way to feed your baby. 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 CIMDUO. CIMDUO may affect the way other medicines work, and other medicines may affect how CIMDUO works. Keep list of your medicines and show it to your healthcare provider and pharmacist when you get new medicine. oYou can ask your healthcare provider or pharmacist for list of medicines that interact with CIMDUO.oDo not start taking new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take CIMDUO with other medicines. How should take CIMDUOoTake CIMDUO exactly as your healthcare provider tells you to take it.oTake CIMDUO time each day with or without food. oDo not miss dose of CIMDUO. If you miss dose, take the missed dose as soon as you remember. If it is almost time for your next dose of CIMDUO, do not take the missed dose. Take the next dose at your regular time.oStay under the care of your healthcare provider during treatment with CIMDUO. oDo not run out of CIMDUO. The virus in your blood may increase and the virus may become harder to treat. When your supply starts to run low, get more from your healthcare provider or pharmacy. oIf you take too much CIMDUO, go to the nearest hospital emergency room right away.What should avoid while taking CIMDUOYou should avoid taking medicines that contain sorbitol during treatment with CIMDUO.What are the possible side effects of CIMDUOCIMDUO may cause serious side effects, including: oSee What is the most important information should know about CIMDUOoUse with interferon- and ribavirin-based regimens. Worsening of liver disease that has caused death has happened in people infected with HIV-1 and hepatitis virus who were taking antiretroviral medicines for HIV-1 and were also being treated for hepatitis with interferon alfa with or without ribavirin. If you are taking CIMDUO and interferon alfa with or without ribavirin, tell your healthcare provider if you have any new symptoms.oRisk of inflammation of the pancreas (pancreatitis). Children may be at risk for developing pancreatitis during treatment with CIMDUO if they:ohave taken nucleoside analogue medicines in the pastohave history of pancreatitisohave other risk factors for pancreatitis Call your healthcare provider right away if your child develops signs and symptoms of pancreatitis including severe upper stomach-area pain, with or without nausea and vomiting. Your healthcare provider may tell you to stop giving CIMDUO to your child if their symptoms and blood test results show that your child may have pancreatitis.oBone problems can happen in some people who take CIMDUO. Bone problems include bone pain, softening or thinning (which may lead to fractures). Your healthcare provider may need to do tests to check your bones. Tell your healthcare provider if you have any bone pain, pain in your hands or feet, or muscle pain or weakness during treatment with CIMDUO.oChanges 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 if you start having new symptoms after starting your HIV-1 medicine.oChanges in body fat can happen in some people who take HIV-1 medicines. These changes may include increased amount of fat in the upper back and neck (buffalo hump), breast, and around the main part of your body (trunk). Loss of fat from the legs, arms, and face may also happen. The cause and long-term health effects of these conditions are not known.The most common side effects of CIMDUO include:oheadacheopainodepressionodiarrheaorashTell your healthcare provider if you have any side effect that bothers you or that does not go away.These are not all the possible side effects of CIMDUO. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should store CIMDUOoStore CIMDUO tablets at room temperature between 68F to 77F (20C to 25C). oKeep CIMDUO tablets in the original container.Keep CIMDUO and all medicines out of the reach of children.General information about the safe and effective use of CIMDUO.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use CIMDUO for condition for which it was not prescribed. Do not give CIMDUO to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about CIMDUO that is written for health professionals.What are the ingredients in CIMDUOActive ingredient: lamivudine and tenofovir disoproxil fumarate Inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate and microcrystalline cellulose. The tablet coating contains polyethylene glycol, titanium dioxide, polyvinyl alcohol and talc. Manufactured for: Mylan Specialty L.P. Morgantown, WV 26505 U.S.A.Manufactured by: Mylan Laboratories Limited Hyderabad -- 500 096, India (C) 2021 Viatris Inc. CIMDUO is registered trademark of Mylan Pharmaceuticals Inc., Viatris Company. Other brands listed are the registered trademarks of their respective owners and are not trademarks of Mylan Laboratories Limited or Mylan Pharmaceuticals Inc. 75078442MS:TLDT:R2For more information, call Mylan at 1-877-446-3679 (1-877-4-INFO-RX).This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 2/2021 oToo much lactic acid in your blood (lactic acidosis). Lactic acidosis is serious medical emergency that can lead to death. Tell your healthcare provider right away if you get any of the following symptoms that could be signs of lactic acidosis:. ofeel very weak or tired ounusual (not normal) muscle pain otrouble breathing. ostomach pain with nausea or vomiting. ofeel cold, especially in your arms and legs ofeel dizzy or lightheaded ohave fast or irregular heartbeat. oSevere liver problems. In some cases, severe liver problems can lead to death. Your liver may become large (hepatomegaly) and you may develop fat in your liver (steatosis). Call your healthcare provider right away if you get any of the following signs or symptoms of liver problems: oyour skin or the white part of your eyes turns yellow (jaundice). odark or tea-colored urine. olight-colored stools (bowel movements). oloss of appetite for several days or longer. onausea and vomiting opain, aching, or tenderness on the right side of your stomach-area. oWorsening of hepatitis infection. If you have Human Immunodeficiency Virus type (HIV-1) and hepatitis Virus (HBV) infection, your HBV may get worse (flare-up) if you stop taking CIMDUO. flare-up is when your HBV infection suddenly returns in worse way than before. Your healthcare provider will test you for HBV infection before you start treatment with CIMDUO. oIt is not known if CIMDUO is safe and effective in people who have both HIV-1 and HBV infection.oDo not run out of CIMDUO. Refill your prescription or talk to your healthcare provider before your CIMDUO is all gone.oDo not stop CIMDUO without first talking to your healthcare provider. If you stop taking CIMDUO, your healthcare provider will need to check your health often and do blood tests regularly for several months to check your liver. oIt is not known if CIMDUO is safe and effective in people who have both HIV-1 and HBV infection.. oDo not run out of CIMDUO. Refill your prescription or talk to your healthcare provider before your CIMDUO is all gone.. oDo not stop CIMDUO without first talking to your healthcare provider. If you stop taking CIMDUO, your healthcare provider will need to check your health often and do blood tests regularly for several months to check your liver. oNew or worse kidney problems, including kidney failure. Your healthcare provider may do blood and urine tests to check your kidneys before and during treatment with CIMDUO. Tell your healthcare provider if you get signs and symptoms of kidney problems, including bone pain that does not go away or worsening bone pain, pain in your arms, hands, legs or feet, broken (fractured) bones, muscle pain or weakness. oare allergic to lamivudine, tenofovir disoproxil fumarate, or any of the ingredients in CIMDUO. See the end of this Patient Information leaflet for complete list of ingredients in CIMDUO.. ohave liver problems, including hepatitis or infection. ohave kidney problems, including end-stage renal disease (ESRD) that requires dialysis ohave bone problems, including history of bone fractures oare pregnant or plan to become pregnant. It is not known if CIMDUO will harm your unborn baby. There is pregnancy registry for women who take CIMDUO during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk to your healthcare provider about how you can take part in this registry.. oare breastfeeding or plan to breastfeed. Do not breastfeed if you take CIMDUO. oYou should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby.oTalk to your healthcare provider about the best way to feed your baby. oYou should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby.. oTalk to your healthcare provider about the best way to feed your baby. oYou can ask your healthcare provider or pharmacist for list of medicines that interact with CIMDUO.. oDo not start taking new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take CIMDUO with other medicines. oTake CIMDUO exactly as your healthcare provider tells you to take it.. oTake CIMDUO time each day with or without food. oDo not miss dose of CIMDUO. If you miss dose, take the missed dose as soon as you remember. If it is almost time for your next dose of CIMDUO, do not take the missed dose. Take the next dose at your regular time.. oStay under the care of your healthcare provider during treatment with CIMDUO. oDo not run out of CIMDUO. The virus in your blood may increase and the virus may become harder to treat. When your supply starts to run low, get more from your healthcare provider or pharmacy. oIf you take too much CIMDUO, go to the nearest hospital emergency room right away.. oSee What is the most important information should know about CIMDUO. oUse with interferon- and ribavirin-based regimens. Worsening of liver disease that has caused death has happened in people infected with HIV-1 and hepatitis virus who were taking antiretroviral medicines for HIV-1 and were also being treated for hepatitis with interferon alfa with or without ribavirin. If you are taking CIMDUO and interferon alfa with or without ribavirin, tell your healthcare provider if you have any new symptoms.. oRisk of inflammation of the pancreas (pancreatitis). Children may be at risk for developing pancreatitis during treatment with CIMDUO if they:ohave taken nucleoside analogue medicines in the pastohave history of pancreatitisohave other risk factors for pancreatitis. ohave taken nucleoside analogue medicines in the past. ohave history of pancreatitis. ohave other risk factors for pancreatitis. Call your healthcare provider right away if your child develops signs and symptoms of pancreatitis including severe upper stomach-area pain, with or without nausea and vomiting. Your healthcare provider may tell you to stop giving CIMDUO to your child if their symptoms and blood test results show that your child may have pancreatitis.. oBone problems can happen in some people who take CIMDUO. Bone problems include bone pain, softening or thinning (which may lead to fractures). Your healthcare provider may need to do tests to check your bones. Tell your healthcare provider if you have any bone pain, pain in your hands or feet, or muscle pain or weakness during treatment with CIMDUO.. oChanges 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 if you start having new symptoms after starting your HIV-1 medicine.. oChanges in body fat can happen in some people who take HIV-1 medicines. These changes may include increased amount of fat in the upper back and neck (buffalo hump), breast, and around the main part of your body (trunk). Loss of fat from the legs, arms, and face may also happen. The cause and long-term health effects of these conditions are not known.. oheadache. opain. odepression. odiarrhea. orash. oStore CIMDUO tablets at room temperature between 68F to 77F (20C to 25C). oKeep CIMDUO tablets in the original container.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS oLactation: Breastfeeding not recommended due to potential for HIV transmission. (8.2). oLactation: Breastfeeding not recommended due to potential for HIV transmission. (8.2). 8.1 Pregnancy Pregnancy Exposure Registry. There is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to CIMDUO during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.. Risk Summary. Available data from the APR show no difference in the risk of overall major birth defects for 3TC compared to the background rate for major birth defects of 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) (see Data). 3TC produced embryonic toxicity in rabbits at dose that produced similar human exposures as the recommended clinical dose. The relevance of animal findings to human pregnancy registry data is not known. There are no adequate and well-controlled studies with TDF in pregnant women. Because animal reproduction studies are not always predictive of human response, TDF should be used during pregnancy only if clearly needed.. Human Data. Lamivudine Based on prospective reports from the APR of over 11,000 exposures to 3TC during pregnancy resulting in live births (including over 4,300 exposed in the first trimester), there was no difference between 3TC and overall birth defects compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of defects in the first trimester was 3.1% (95% CI: 2.6% to 3.7%).3TC pharmacokinetics were studied in pregnant women during clinical trials conducted in South Africa. The trials assessed pharmacokinetics in 16 women at 36 weeks gestation using 150 mg 3TC twice daily with zidovudine, 10 women at 38 weeks gestation using 150 mg 3TC twice daily with zidovudine, and 10 women at 38 weeks gestation using 3TC 300 mg twice daily without other antiretrovirals. These trials were not designed or powered to provide efficacy information.3TC pharmacokinetics in pregnant women were similar to those seen in non-pregnant adults and in postpartum women. 3TC concentrations were generally similar in maternal, neonatal, and umbilical cord serum samples. In subset of subjects, amniotic fluid specimens were collected following natural rupture of membranes and confirmed that lamivudine crosses the placenta in humans. Amniotic fluid concentrations of lamivudine were typically times greater than maternal serum levels and ranged from 1.2 to 2.5 mcg per mL (150 mg twice daily) and 2.1 to 5.2 mcg per mL (300 mg twice daily). Animal Data. Lamivudine Studies in pregnant rats showed that 3TC is transferred to the fetus through the placenta. Reproduction studies with orally administered 3TC have been performed in rats and rabbits at doses producing plasma levels up to approximately 35 times that for the recommended adult HIV dose. No evidence of teratogenicity due to 3TC was observed. Evidence of embryo-lethality was seen in the rabbit at exposure levels similar to those observed in humans but there was no indication of this effect in the rat at exposure levels up to 35 times those in humans.. Tenofovir Disoproxil Fumarate Reproduction studies have been performed in rats and rabbits at doses up to 14 and 19 times the human dose based on body surface area comparisons and revealed no evidence of impaired fertility or harm to the fetus due to tenofovir. 8.2 Lactation The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. Lamivudine. 3TC is excreted into human milk. Samples of breast milk obtained from 20 mothers receiving 3TC monotherapy, 300 mg twice daily (2 times the dose in CIMDUO), had measurable concentrations of 3TC. There is no information on the effects of 3TC on the breastfed infant, or the effects of 3TC on milk production.. Tenofovir Disoproxil Fumarate. Samples of breast milk obtained from five HIV-1-infected mothers in the first postpartum week show that tenofovir is excreted in human milk at low levels. The impact of this exposure in breastfed infants is unknown and the effects of TDF on milk production is unknown.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 CIMDUO. 8.4 Pediatric Use The safety and effectiveness of CIMDUO as fixed-dose tablet in pediatric patients infected with HIV-1 and weighing at least 35 kg have been established based on clinical studies using the individual components (lamivudine and tenofovir disoproxil fumarate).. 8.5 Geriatric Use Clinical studies of CIMDUO did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, caution should be exercised in the administration of CIMDUO in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.. 8.6Renal Impairment CIMDUO is not recommended for patients with impaired renal function (i.e., creatinine clearance less than 50 mL/min) or patients with end-stage renal disease (ESRD) requiring hemodialysis because it is fixed-dose combination formulation that cannot be adjusted [see Dosage and Administration (2.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS oLactic Acidosis/Severe Hepatomegaly with Steatosis: Discontinue treatment in patients who develop symptoms or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity. (5.1)oNew Onset or Worsening Renal Impairment: Can include acute renal failure and Fanconi syndrome. Assess estimated creatinine clearance before initiating treatment with tenofovir disoproxil fumarate, component of CIMDUO. In patients at risk for renal dysfunction, assess estimated creatinine clearance, serum phosphorus, urine glucose and urine protein before initiating treatment with tenofovir and periodically during treatment. Avoid administering CIMDUO with concurrent or recent use of nephrotoxic drugs. (5.3)oHepatic decompensation, some fatal, has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy and interferon- and ribavirin-based regimens. Monitor for treatment-associated toxicities. Discontinue CIMDUO, as medically appropriate, and consider dose reduction or discontinuation of interferon alfa, ribavirin, or both. (5.4)oPancreatitis: Use with caution in pediatric patients with history of pancreatitis or other significant risk factors for pancreatitis. Discontinue CIMDUO as clinically appropriate. (5.5)oDecreases in Bone Mineral Density (BMD): Observed in HIV-infected patients. Consider assessment of BMD in patients with history of pathologic fracture or other risk factors for osteoporosis or bone loss. (5.6)oImmune Reconstitution Syndrome: Observed in HIV-infected patients. May necessitate further evaluation and treatment. (5.7) oRedistribution/Accumulation of Body Fat: Observed in HIV-infected patients receiving antiretroviral combination therapy. (5.8)oTriple Nucleoside-Only Regimens: Early virologic failure has been reported in HIV-infected patients. Monitor carefully and consider treatment modification. (5.9) oLactic Acidosis/Severe Hepatomegaly with Steatosis: Discontinue treatment in patients who develop symptoms or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity. (5.1). oNew Onset or Worsening Renal Impairment: Can include acute renal failure and Fanconi syndrome. Assess estimated creatinine clearance before initiating treatment with tenofovir disoproxil fumarate, component of CIMDUO. In patients at risk for renal dysfunction, assess estimated creatinine clearance, serum phosphorus, urine glucose and urine protein before initiating treatment with tenofovir and periodically during treatment. Avoid administering CIMDUO with concurrent or recent use of nephrotoxic drugs. (5.3). oHepatic decompensation, some fatal, has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy and interferon- and ribavirin-based regimens. Monitor for treatment-associated toxicities. Discontinue CIMDUO, as medically appropriate, and consider dose reduction or discontinuation of interferon alfa, ribavirin, or both. (5.4). oPancreatitis: Use with caution in pediatric patients with history of pancreatitis or other significant risk factors for pancreatitis. Discontinue CIMDUO as clinically appropriate. (5.5). oDecreases in Bone Mineral Density (BMD): Observed in HIV-infected patients. Consider assessment of BMD in patients with history of pathologic fracture or other risk factors for osteoporosis or bone loss. (5.6). oImmune Reconstitution Syndrome: Observed in HIV-infected patients. May necessitate further evaluation and treatment. (5.7) oRedistribution/Accumulation of Body Fat: Observed in HIV-infected patients receiving antiretroviral combination therapy. (5.8). oTriple Nucleoside-Only Regimens: Early virologic failure has been reported in HIV-infected patients. Monitor carefully and consider treatment modification. (5.9) 5.1Lactic Acidosis and Severe Hepatomegaly with Steatosis Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs and other antiretrovirals. Treatment 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). 5.2Severe Acute Exacerbation of Hepatitis in Patients Coinfected with HIV-1 and HBV Posttreatment Exacerbations of Hepatitis. All patients with HIV-1 should be tested for the presence of chronic hepatitis virus (HBV) before initiating antiretroviral therapy. Discontinuation of anti-HBV therapy, including 3TC and TDF, may be associated with severe acute exacerbations of hepatitis. Patients infected with HBV who discontinue CIMDUO should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. If appropriate, resumption of anti-hepatitis therapy may be warranted.. Important Differences Among Lamivudine-Containing Products. CIMDUO tablets contain higher dose of the same active ingredient, 3TC, than EPIVIR-HBV(R) tablets. EPIVIR-HBV was developed for patients with chronic hepatitis B. The formulation and dosage of 3TC in EPIVIR-HBV are not appropriate for patients co-infected with HIV-1 and HBV. Safety and efficacy of 3TC have not been established for treatment of chronic hepatitis in patients co-infected with HIV-1 and HBV. If treatment with EPIVIR-HBV, TDF, or tenofovir alafenamide (TAF)-containing product is prescribed for chronic hepatitis for patient with unrecognized or untreated HIV-1 infection, rapid emergence of HIV-1 resistance is likely to result because of the subtherapeutic dose and the inappropriateness of monotherapy HIV-1 treatment. 5.3New Onset or Worsening Renal Impairment TDF, component of CIMDUO is principally eliminated by the kidney. Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of TDF [see Adverse Reactions (6.2)].It is recommended that estimated creatinine clearance be assessed in all patients prior to initiating therapy and as clinically appropriate during therapy with TDF. In patients at risk of renal dysfunction, it is recommended that estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein be assessed prior to initiation of tenofovir disoproxil fumarate, and periodically during TDF therapy.Avoid CIMDUO with concurrent or recent use of nephrotoxic agent (e.g., high-dose or multiple non-steroidal anti-inflammatory drugs (NSAIDs)) [see Drug Interactions (7.1)]. Cases of acute renal failure after initiation of high dose or multiple NSAIDs have been reported in HIV-infected patients with risk factors for renal dysfunction who appeared stable on TDF. Some patients required hospitalization and renal replacement therapy. Alternatives to NSAIDs should be considered, if needed, in patients at risk for renal dysfunction. Persistent or worsening bone pain, pain in extremities, fractures and/or muscular pain or weakness may be manifestations of proximal renal tubulopathy and should prompt an evaluation of renal function in at-risk patients.. 5.4Risk of Hepatic Decompensation When Used with Interferon- and Ribavirin-Based Regimens In vitro studies have shown ribavirin can reduce the phosphorylation of pyrimidine nucleoside analogues such as 3TC, component of CIMDUO. Although no evidence of pharmacokinetic or pharmacodynamic interaction (e.g., loss of HIV-1/HCV virologic suppression) was seen when ribavirin was coadministered with 3TC in HIV-1/HCV co-infected patients [see Clinical Pharmacology (12.3)], hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy for HIV-1 and interferon alfa with or without ribavirin. Patients receiving interferon alfa with or without ribavirin and 3TC should be closely monitored for treatment-associated toxicities, especially hepatic decompensation. Discontinuation of 3TC should be considered as medically appropriate. Dose reduction or discontinuation of interferon alfa, ribavirin, or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh 6). See the full prescribing information for interferon and ribavirin.. 5.5Pancreatitis In pediatric patients with history of prior antiretroviral nucleoside exposure, history of pancreatitis, or other significant risk factors for the development of pancreatitis, 3TC, component of CIMDUO, should be used with caution. Treatment with CIMDUO should be stopped immediately if clinical signs, symptoms, or laboratory abnormalities suggestive of pancreatitis occur [see Adverse Reactions (6.1)].. 5.6Bone Effects Bone Mineral Density (BMD). In clinical trials in HIV-1-infected adults, TDF was associated with slightly greater decreases in 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 [see Adverse Reactions (6.1)].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 adults 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 Defects. Cases of osteomalacia associated with proximal renal tubulopathy, manifested as bone pain or pain in extremities and which may contribute to fractures, have been reported in association with 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 (5.3)]. 5.7Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in HIV-infected patients treated with combination antiretroviral therapy, including 3TC and TDF. 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, and Guillain-Barre syndrome) 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.. 5.8Fat Redistribution In HIV-infected patients, redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and cushingoid appearance have been observed in patients receiving combination antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. causal relationship has not been established.. 5.9Early Virologic Failure Clinical trials in HIV-infected subjects have demonstrated that certain regimens that only contain three nucleoside reverse transcriptase inhibitors (NRTI) are generally less effective than triple drug regimens containing two NRTIs in combination with either non-nucleoside reverse transcriptase inhibitor or HIV-1 protease inhibitor. In particular, early virological failure and high rates of resistance substitutions have been reported. Triple nucleoside regimens should therefore be used with caution. Patients on therapy utilizing triple nucleoside-only regimen should be carefully monitored and considered for treatment modification.