Lamivudine And Tenofovir Disoproxil Fumarate

1 INDICATIONS AND USAGE CIMDUO ® (lamivudine and tenofovir disoproxil fumarate) is indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adult and pediatric patients weighing at least 35 kg. CIMDUO is a two-drug combination of lamivudine (3TC) and tenofovir disoproxil fumarate (TDF), both nucleo(t)side reverse transcriptase inhibitors and is indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adult and pediatric patients weighing at least 35 kg. ( 1 )

2 DOSAGE AND ADMINISTRATION • Testing: Prior to initiation and during treatment with CIMDUO, patients should be tested for hepatitis B virus infection, and estimated creatinine clearance, urine glucose, and urine protein should be obtained. ( 2.1 ) • Recommended dose: One tablet taken orally once daily with or without food. ( 2.2 ) • Renal Impairment: Not recommended in patients with CrCL less than 50 mL/min or patients with end-stage renal disease requiring hemodialysis. ( 2.3 ) 2.1 Testing Prior to Initiation and During Treatment with CIMDUO Prior to initiation of CIMDUO, test patients for hepatitis B virus infection [see Warnings and Precautions (5.2) ] . It is recommended that serum creatinine, serum phosphorus, estimated creatinine clearance, urine glucose, and urine protein be assessed before initiating CIMDUO and during therapy in all patients as clinically appropriate [see Warnings and Precautions (5.3) ]. 2.2 Recommended Dosage for Adult and Pediatric Patients Weighing at Least 35 kg CIMDUO is a two-drug fixed-dose combination product containing 300 mg of lamivudine (3TC) and 300 mg of tenofovir disoproxil fumarate (TDF). The recommended dosage of CIMDUO in HIV-1-infected adult and pediatric patients weighing at least 35 kg is one tablet taken orally once daily with or without food. 2.3 Not Recommended in Renal Impairment Because CIMDUO is a fixed-dose combination tablet and cannot be dose adjusted, it is not recommended for patients with impaired renal function (creatinine clearance less than 50 mL/min) or patients with end-stage renal disease (ESRD) requiring hemodialysis [see Use in Specific Populations (8.6) ] .

6 ADVERSE REACTIONS The following adverse reactions are discussed in other sections of the labeling: • Lactic Acidosis/Severe Hepatomegaly with Steatosis [see Warnings and Precautions (5.1) ] . • Exacerbations of Hepatitis B [see Boxed Warning , Warnings and Precautions (5.2) ] . • New Onset or Worsening Renal Impairment [see Warnings and Precautions (5.3) ] . • Hepatic Decompensation in Patients Co-infected with HIV-1 and Hepatitis C [see Warnings and Precautions (5.4) ] . • Pancreatitis [see Warnings and Precautions (5.5) ] . • Decreases in Bone Mineral Density [see Warnings and Precautions (5.6) ] . • Immune Reconstitution Syndrome [see Warnings and Precautions (5.7) ] . • Fat Redistribution [see Warnings and Precautions (5.8) ] . • Most 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. 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, the adverse reaction rates observed in clinical trials of a 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-Naïve Patients Study 903 - Adverse Reactions The most common adverse reactions seen in a double-blind comparative controlled study in which 600 treatment-naïve 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 a 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 Reactions Frequencies 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 + EFV d4T + 3TC + EFV N = 299 N = 301 Body as a 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 Lipodystrophy Lipodystrophy represents a variety of investigator-described adverse events not a protocol-defined syndrome. 1% 8% Musculoskeletal Arthralgia 5% 7% Myalgia 3% 5% Nervous System Depression 11% 10% Insomnia 5% 8% Dizziness 3% 6% Peripheral neuropathy Peripheral neuropathy includes peripheral neuritis and neuropathy. 1% 5% Anxiety 6% 6% Respiratory Pneumonia 5% 5% Skin and Appendages Rash event Rash 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. A summary of Grade 3 and 4 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 + EFV d4T + 3TC + EFV N = 299 N = 301 Any ≥ Grade 3 Laboratory Abnormality 36% 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/mm 3 ) 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 a 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 4 subjects in the TDF group and 6 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 C telopeptide, and urinary N telopeptide) and higher serum parathyroid hormone levels and 1,25 Vitamin D 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) ] . 6.2 Postmarketing 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 a 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 a combination of their seriousness, frequency of reporting, or potential causal connection to 3TC and TDF. Lamivudine Body as a 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 B [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 a consequence of proximal renal tubulopathy: rhabdomyolysis, osteomalacia, hypokalemia, muscular weakness, myopathy, hypophosphatemia.

12.3 Pharmacokinetics Lamivudine After oral administration of 2 mg/kg of 3TC twice a day to 9 adults with HIV-1, the peak serum 3TC concentration (C max ) was 1.5 ± 0.5 mcg/mL (mean ± SD). The area under the plasma concentration versus time curve (AUC) and C max 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 a single oral dose of 3TC in 6 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 (t 1/2 ) ranged from 5 to 7 hours in most single-dose studies with serum sampling for 24 hours after dosing. Tenofovir Disoproxil Fumarate Following oral administration of a single 300-mg dose of TDF to HIV-1-infected subjects in the fasted state, maximum serum concentrations (C max ) were achieved in 1.0 ± 0.4 hrs (mean ± SD) and C max and AUC values were 296 ± 90 ng/mL and 2287 ± 685 ng•hr/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 a combination of glomerular filtration and active tubular secretion with a renal clearance in adults with normal renal function of 243 ± 33 mL/min (mean ± SD). Following a 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 a Single 300-mg Oral Dose of 3TC in Subjects with Varying Degrees of Renal Function Parameter 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 ± 14 28 ± 8 6 ± 2 C max (mcg/mL) 2.6 ± 0.5 3.6 ± 0.8 5.8 ± 1.2 AUC ∞ (mcg•h/mL) 11.0 ± 1.7 48.0 ± 19 157 ± 74 Cl/F (mL/min) 464 ± 76 114 ± 34 36 ± 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, C max , and AUC 0‑∞ of tenofovir were increased. Table 4. Pharmacokinetic Parameters (Mean ± SD) of Tenofovir in Subjects After a Single 300-mg Oral Dose of TDF in Subjects with Varying Degrees of Renal Function Baseline Creatinine Clearance (mL/min) > 80 (N = 3) 50-80 (N = 10) 30-49 (N = 8) 12-29 (N = 11) C max (µg/mL) 0.34 ± 0.03 0.33 ± 0.06 0.37 ± 0.16 0.60 ± 0.19 AUC 0-∞ (µg • hr/mL) 2.18 ± 0.26 3.06 ± 0.93 6.01 ± 2.50 15.98 ± 7.22 CL/F (mL/min) 1043.7 ± 115.4 807.7 ± 279.2 444.4 ± 209.8 177.0 ± 97.1 CL renal (mL/min) 243.5 ± 33.3 168.6 ± 27.5 100.6 ± 27.5 43.0 ± 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 a 300 mg single dose of TDF have been studied in non-HIV-infected subjects with moderate to severe (Child-Pugh B 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 1 (MATE1), MATE2-K, organic cation transporter 1 (OCT1), OCT2, or OCT3. Effect of Other Agents on the Pharmacokinetics of 3TC 3TC is a 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 a substrate of P-gp and BCRP; however, considering its absolute bioavailability (87%), it is unlikely that these transporters play a 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 a 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 a 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 a single 300-mg dose of 3TC oral solution alone or coadministered with a 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 C max of lamivudine. Trimethoprim/Sulfamethoxazole 3TC and TMP/SMX were coadministered to 14 HIV-1-positive subjects in a single-center, open-label, randomized, crossover trial. Each subject received treatment with a single 300-mg dose of 3TC and TMP 160 mg/SMX 800 mg once a day for 5 days with concomitant administration of 3TC 300 mg with the fifth dose in a crossover design. Coadministration of TMP/SMX with 3TC resulted in an increase of 43% ± 23% (mean ± SD) in 3TC AUC ∞ , a decrease of 29% ± 13% in 3TC oral clearance, and a 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, a 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 5 and 6 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 C max 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 Tenofovir Subjects received TDF 300 mg once daily. in the Presence of the Coadministered Drug Coadministered Drug Dose of Coadministered Drug (mg) % Change of Tenofovir Pharmacokinetic Parameters Increase = ↑; Decrease = ↓; No Effect = ↔ (90% CI) C max AUC C min Atazanavir Reyataz ® (atazanavir) Prescribing Information. 400 once daily × 14 days ↑ 14 (↑ 8 to ↑ 20) ↑ 24 (↑ 21 to ↑ 28) ↑ 22 (↑ 15 to ↑ 30) Atazanavir/ Ritonavir Prezista ® (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 (↑ 8 to ↑ 42) ↑ 22 (↑ 10 to ↑ 35) ↑ 37 (↑ 19 to ↑ 57) Indinavir 800 three times daily × 7 days ↑ 14 (↓ 3 to ↑ 33) ↔ ↔ Ledipasvir/ Sofosbuvir Data 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/ Sofosbuvir Study conducted with ATRIPLA ® (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/ Sofosbuvir Study conducted with COMPLERA ® (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/ Sofosbuvir Study conducted with TRUVADA ® (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/ Ritonavir 1000/100 twice daily × 14 days ↔ ↔ ↑ 23 (↑ 16 to ↑ 30) Sofosbuvir Study conducted with ATRIPLA coadministered with SOVALDI ® (sofosbuvir). 400 single dose ↑ 25 ↑ 8 to ↑ 45) ↔ ↔ Sofosbuvir/ Velpatasvir Comparison 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/ Velpatasvir Comparison 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/ Velpatasvir Study 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/ Velpatasvir Study conducted with STRIBILD ® (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/ Velpatasvir Study conducted with COMPLERA coadministered with EPCLUSA. 400/100 once daily ↑ 44 (↑ 33 to ↑ 55) ↑ 40 (↑ 34 to ↑ 46) ↑ 84 (↑ 76 to ↑ 92) Sofosbuvir/ Velpatasvir Administered as raltegravir + emtricitabine/tenofovir DF. 400/100 once daily ↑ 46 (↑ 39 to ↑ 54) ↑ 40 (↑ 34 to ↑ 45) ↑ 70 (↑ 61 to ↑ 79) Tacrolimus 0.05 mg/kg twice daily × 7 days ↑ 13 (↑ 1 to ↑ 27) ↔ ↔ Tipranavir/ Ritonavir Aptivus ® (tipranavir) Prescribing Information. 500/100 twice daily ↓ 23 (↓ 32 to ↓ 13) ↓ 2 (↓ 9 to ↑ 5) ↑ 7 (↓ 2 to ↑ 17) 750/200 twice daily (23 doses) ↓ 38 (↓ 46 to ↓ 29) ↑ 2 (↓ 6 to ↑ 10) ↑ 14 (↑ 1 to ↑ 27) No effect on the pharmacokinetic parameters of the following coadministered drugs was observed with TDF: abacavir, didanosine (buffered tablets), emtricitabine, entecavir, and lamivudine. Table 6. Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of TDF Coadministered Drug Dose of Coadministered Drug (mg) % Change of Coadministered Drug Pharmacokinetic Parameters Increase = ↑; Decrease = ↓; No Effect = ↔; NA = Not Applicable (90% CI) C max AUC C min Abacavir 300 once ↑ 12 (↓ 1 to ↑ 26) ↔ NA Atazanavir Reyataz (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) ↓ 25 In HIV-infected subjects, addition of TDF to atazanavir 300 mg plus ritonavir 100 mg, resulted in AUC and C min values of atazanavir that were 2.3- and 4-fold higher than the respective values observed for atazanavir 400 mg when given alone. (↓ 42 to ↓ 3) ↓ 23 (↓ 46 to ↑ 10) Darunavir Prezista (darunavir) Prescribing Information. Darunavir/Ritonavir 300/100 once daily ↑ 16 (↓ 6 to ↑ 42) ↑ 21 (↓ 5 to ↑ 54) ↑ 24 (↓ 10 to ↑ 69) Didanosine Videx ® EC Prescribing Information. Subjects received didanosine enteric-coated capsules. 250 once, simultaneously with VIREAD ® and a light meal 373 kcal, 8.2 g fat ↓ 20 Compared with didanosine (enteric-coated) 400 mg administered alone under fasting conditions. (↓ 32 to ↓ 7) ↔ NA Emtricitabine 200 once daily × 7 days ↔ ↔ ↑ 20 (↑ 12 to ↑ 29) Entecavir 1 mg once daily × 10 days ↔ ↑ 13 (↑ 11 to ↑ 15) ↔ Indinavir 800 three times daily × 7 days ↓ 11 (↓ 30 to ↑ 12) ↔ ↔ Lamivudine 150 twice daily × 7 days ↓ 24 (↓ 34 to ↓ 12) ↔ ↔ Lopinavir Ritonavir Lopinavir/Ritonavir 400/100 twice daily × 14 days ↔ ↔ ↔ ↔ ↔ ↔ Saquinavir Saquinavir/Ritonavir 1000/100 twice daily × 14 days ↑ 22 (↑ 6 to ↑ 41) ↑ 29 Increases in AUC and C min are not expected to be clinically relevant; hence no dose adjustments are required when tenofovir DF and ritonavir-boosted saquinavir are coadministered. (↑ 12 to ↑ 48) ↑ 47 (↑ 23 to ↑ 76) Ritonavir ↔ ↔ ↑ 23 (↑ 3 to ↑ 46) Tacrolimus 0.05 mg/kg twice daily × 7 days ↔ ↔ ↔ Tipranavir Aptivus (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)