Efavirenz, Lamivudine And Tenofovir Disoproxil Fumarate

1 INDICATIONS AND USAGE Efavirenz, lamivudine and tenofovir disoproxil fumarate tablets are indicated as a complete regimen for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adult and pediatric patients weighing at least 40 kg. Efavirenz, lamivudine and tenofovir disoproxil fumarate tablets are three-drug combination of efavirenz (EFV), a non-nucleoside reverse transcriptase inhibitor, and lamivudine (3TC) and tenofovir disoproxil fumarate (TDF), both nucleo(t)side reverse transcriptase inhibitors and are indicated as a complete regimen for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adult and pediatric patients weighing at least 40 kg. ( 1 )

2 DOSAGE AND ADMINISTRATION Testing: Prior to initiation and during treatment with efavirenz, lamivudine and tenofovir disoproxil fumarate tablets, 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 on an empty stomach, preferably at bedtime. ( 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 ) Hepatic Impairment: Not recommended for patients with moderate or severe hepatic impairment. Use caution in patients with mild hepatic impairment. ( 2.4 ) 2.1 Testing Prior to Initiation and During Treatment with Efavirenz, Lamivudine and Tenofovir Disoproxil Fumarate Tablets Prior to initiation of efavirenz, lamivudine and tenofovir disoproxil fumarate tablets, test patients for hepatitis B virus infection [see Warnings and Precautions (5.1) ] . It is recommended that serum creatinine, serum phosphorus, estimated creatinine clearance, urine glucose, and urine protein be assessed before initiating efavirenz, lamivudine and tenofovir disoproxil fumarate tablets and during therapy in all patients as clinically appropriate [see Warnings and Precautions (5.4) ]. Monitor hepatic function prior to and during treatment with efavirenz, lamivudine and tenofovir disoproxil fumarate tablets [see Warnings and Precautions (5.9) ] . 2.2 Recommended Dosage for Adult and Pediatric Patients Weighing at Least 40 kg Efavirenz, lamivudine and tenofovir disoproxil fumarate tablets are a three-drug fixed-dose combination product containing 600 mg of efavirenz (EFV), 300 mg of lamivudine (3TC), and 300 mg of tenofovir disoproxil fumarate (TDF). The recommended dosage of efavirenz, lamivudine and tenofovir disoproxil fumarate tablets in HIV-1-infected adults and pediatric patients who weigh at least 40 kg, and can swallow a solid tablet, is one tablet taken orally once daily. Efavirenz, lamivudine and tenofovir disoproxil fumarate tablets should be taken on an empty stomach, preferably at bedtime. Dosing at bedtime may improve the tolerability of nervous system symptoms [see Warnings and Precautions (5.6) a nd Adverse Reactions (6.1)]. 2.3 Not Recommended in Renal Impairment Because efavirenz, lamivudine and tenofovir disoproxil fumarate tablets are a fixed-dose combination tablet and cannot be dose adjusted, they are 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) ] . 2.4 Not Recommended in Moderate to Severe Hepatic Impairment Efavirenz, lamivudine and tenofovir disoproxil fumarate tablets are not recommended in patients with moderate or severe hepatic impairment (Child-Pugh B or C) [see Warnings and Precautions (5.9) and Use in Specific Populations (8.7)] .

6 ADVERSE REACTIONS The following adverse reactions are discussed in other sections of the labeling: Exacerbations of Hepatitis B [see Boxed Warning , Warnings and Precautions (5.1 ) ] . Lactic Acidosis/Severe Hepatomegaly with Steatosis [see Warnings and Precautions (5.2) ] . New Onset or Worsening Renal Impairment [see Warnings and Precautions (5.4) ] . Psychiatric Symptoms [see Warnings and Precautions (5.5) ] . Nervous System Symptoms [see Warnings and Precautions (5.6) ] . Skin and Systemic Hypersensitivity Reaction [see Warnings and Precautions (5.8) ] . Hepatotoxicity [see Warnings and Precautions (5.9) ]. Pancreatitis [see Warnings and Precautions (5.10) ] . Bone Loss and Mineralization Effects [see Warnings and Precautions (5.13) ] . Immune Reconstitution Syndrome [see Warnings and Precautions (5.14) ] . Fat Redistribution [see Warnings and Precautions (5.15) ] . Most common adverse reactions are impaired concentration, abnormal dreams, headache, nausea, malaise and fatigue, nasal signs and symptoms, diarrhea, rash, dizziness, insomnia, pain, depression, asthenia, and cough. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Laurus Generics Inc. at 1-833-3-LAURUS (1-833-352-8787) 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. Efavirenz, Lamivudine and Tenofovir Disoproxil Fumarate Clinical Trials in Treatment-Naïve HIV-1 Infected Adult Subjects In Trial 903, 600 antiretroviral-naїve subjects received TDF (N = 299) or stavudine (d4T) (N = 301) administered in combination with 3TC and EFV for 144 weeks. The most common adverse reactions 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. Table 1 provides the treatment-emergent adverse reactions (Grade 2 to 4) occurring in greater than or equal to 5% of subjects treated in any treatment group. Table 1. Selected Adverse Reactions a (Grades 2 to 4) Reported in ≥ 5% in Any Treatment Group in Trial 903 (0 to 144 Weeks) a Frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug. b Rash event includes rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, and pustular rash. c Lipodystrophy represents a variety of investigator-described adverse events not a protocol-defined syndrome. d Peripheral neuropathy includes peripheral neuritis and neuropathy. TDF + 3TC + EFV d4T + 3TC + EFV N = 299 N = 301 Rash event b 18% 12% Headache 14% 17% Pain 13% 12% Diarrhea 11% 13% Depression 11% 10% Back pain 9% 8% Nausea 8% 9% Fever 8% 7% Abdominal pain 7% 12% Asthenia 6% 7% Anxiety 6% 6% Vomiting 5% 9% Insomnia 5% 8% Arthralgia 5% 7% Pneumonia 5% 5% Dyspepsia 4% 5% Dizziness 3% 6% Myalgia 3% 5% Lipodystrophy c 1% 8% Peripheral neuropathy d 1% 5% Laboratory Abnormalities: Table 2 provides a list of laboratory abnormalities (Grades 3 to 4) observed in Trial 903. With the exception of fasting cholesterol and fasting triglyceride elevations that were more common in the d4T group (40% and 9%) compared with the TDF group (19% and 1%) respectively, laboratory abnormalities observed in this trial occurred with similar frequency in the TDF and d4T treatment arms. Table 2. Grade 3 to 4 Laboratory Abnormalities Reported in ≥ 1% of Patients Randomized to Efavirenz, Lamivudine and Tenofovir Disoproxil Fumarate in Study 903 (0 to 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 (5.10) ]. Changes in Bone Mineral Density: In HIV-1-infected adult subjects in Trial 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 to 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 (5.13) ] . 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use for each of the individual components of efavirenz, lamivudine and tenofovir disoproxil fumarate tablets (EFV, 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 EFV, 3TC, and TDF. Efavirenz Body as a Whole: allergic reactions, asthenia, redistribution/accumulation of body fat [see Warnings and Precautions (5.15) ]. Central and Peripheral Nervous System: abnormal coordination, ataxia, encephalopathy, cerebellar coordination and balance disturbances, convulsions, hypoesthesia, paresthesia, neuropathy, tremor, vertigo. Endocrine: gynecomastia. Gastrointestinal: constipation, malabsorption. Cardiovascular: flushing, palpitations. Liver and Biliary System: hepatic enzyme increase, hepatic failure, hepatitis. Metabolic and Nutritional: hypercholesterolemia, hypertriglyceridemia. Musculoskeletal: arthralgia, myalgia, myopathy. Psychiatric: aggressive reactions, agitation, delusions, emotional lability, mania, neurosis, paranoia, psychosis, suicide, catatonia. Respiratory: dyspnea. Skin and Appendages: erythema multiforme, photoallergic dermatitis, Stevens-Johnson syndrome. Special Senses: abnormal vision, tinnitus. Lamivudine Body as a Whole: redistribution/accumulation of body fat [see Warnings and Precautions (5.15) ]. 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 (5.4) ] . 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 The effect of food on efavirenz, lamivudine and tenofovir disoproxil fumarate has not been evaluated. Efavirenz: In HIV-1-infected subjects, time-to-peak plasma concentrations were approximately 3 to 5 hours and steady-state plasma concentrations were reached in 6 to 10 days. EFV is highly bound (approximately 99.5 to 99.75%) to human plasma proteins, predominantly albumin. Following administration of 14 C-labeled EFV, 14 to 34% of the dose was recovered in the urine (mostly as metabolites) and 16 to 61% was recovered in feces (mostly as parent drug). In vitro studies suggest CYP3A and CYP2B6 are the major isozymes responsible for EFV metabolism. EFV has been shown to induce CYP enzymes, resulting in induction of its own metabolism. EFV has a terminal half-life of 52 to 76 hours after single doses and 40 to 55 hours after multiple doses. 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-l-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 2,287 ± 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: Efavirenz and Lamivudine: There are no significant or clinically relevant racial differences in EFV and 3TC 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 EFV, 3TC, and TDF. Geriatric Patients: The pharmacokinetics of 3TC and TDF have not been studied in patients over 65 years of age. Patients with Renal Impairment: [See Use in Specific Populations (8.6) . ] Efavirenz: The pharmacokinetics of EFV have not been studied in patients with renal impairment. Lamivudine: The pharmacokinetics of 3TC are altered in subjects with renal impairment (Table 4). Table 4. 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 to 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 TDF are altered in subjects with renal impairment [see Warnings and Precautions (5.4) ] . 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 5. Pharmacokinetic Parameters (Mean ± SD) of Tenofovir 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 to 80 (N = 10) 30 to 49 (N = 8) 12 to 29 (N = 11) C max (mcg/mL) 0.34 ± 0.03 0.33 ± 0.06 0.37 ± 0.16 0.60 ± 0.19 AUC 0-∞ (mcg • 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: Efavirenz: A multiple-dose study showed no significant effect on EFV pharmacokinetics in patients with mild hepatic impairment (Child-Pugh Class A) compared with controls. There were insufficient data to determine whether moderate or severe hepatic impairment (Child-Pugh Class B or C) affects EFV pharmacokinetics. Lamivudine: The pharmacokinetic properties of 3TC have been determined in adults with impaired hepatic function. Pharmacokinetic parameters were not altered by diminishing hepatic function. Safety and efficacy of 3TC 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) .] Efavirenz: EFV has been shown in vivo to cause hepatic enzyme induction, thus increasing the biotransformation of some drugs metabolized by CYP3A and CYP2B6. In vitro studies have shown that EFV inhibited CYP isozymes 2C9, 2C19, and 3A4 with K i values (8.5 to 17 mcM) in the range of observed EFV plasma concentrations. In in vitro studies, EFV did not inhibit CYP2E1 and inhibited CYP2D6 and CYP1A2 (K i values 82 to 160 mcM) only at concentrations well above those achieved clinically. Coadministration of EFV with drugs primarily metabolized by 2C9, 2C19, and 3A isozymes may result in altered plasma concentrations of the coadministered drug. Drugs which induce CYP3A activity would be expected to increase the clearance of EFV resulting in lowered plasma concentrations. Drug interaction studies were performed with EFV and other drugs likely to be coadministered or drugs commonly used as probes for pharmacokinetic interaction. The effects of coadministration of EFV on the C max , AUC, and C min are summarized in Table 6 (effect of EFV on other drugs) and Table 7 (effect of other drugs on EFV). For information regarding clinical recommendations see Drug Interactions (7.5) . Table 6. Effect of Efavirenz on Coadministered Drug Plasma C max , AUC, and C min ↑ Indicates increase ↓ Indicates decrease ↔ Indicates no change or a mean increase or decrease of < 10%. a 90% CI not available. b Relative to steady-state administration of voriconazole (400 mg for 1 day, then 200 mg po q12h for 2 days). c Not available because of insufficient data. d Study conducted with ATRIPLA ® coadministered with HARVONI ® . e The predominant circulating nucleoside metabolite of sofosbuvir. f Study conducted with ATRIPLA coadministered with SOVALDI ® (sofosbuvir). g Study conducted with ATRIPLA coadministered with EPCLUSA ® . NA = not available. Number of Subjects Coadministered Drug (mean % change) Coadministered Drug Dose Efavirenz Dose C max (90% CI) AUC (90% CI) C min (90% CI) Boceprevir 800 mg tid x 6 days 600 mg qd x 16 days NA ↓ 8% (↓ 22 to ↑ 8%) ↓ 19% (11 to 25%) ↓ 44% (26 to 58%) Simeprevir 150 mg qd x 14 days 600 mg qd x 14 days 23 ↓ 51% (↓ 46 to ↓ 56%) ↓ 71% (↓ 67 to ↓ 74%) ↓ 91% (↓ 88 to ↓ 92%) Ledipasvir/ Sofosbuvir d Ledipasvir Sofosbuvir GS-331007 e 90/400 mg qd x 14 days 600 mg qd x 14 days 15 ↓ 34 (↓ 25 to ↓ 41) ↓ 34 (↓ 25 to ↓ 41) ↓ 34 (↓ 24 to ↓ 43) ↔ ↔ NA ↔ ↔ ↔ Sofosbuvir f GS-331007 e 400 mg qd single dose 600 mg qd x 14 days 16 ↓ 19 (↓ 40 to ↑10) ↔ NA ↓ 23 (↓ 16 to ↓ 30) ↓ 16 (↓ 24 to ↓ 8) NA Sofosbuvir/ Velpatasvir g Sofosbuvir GS-331007 e Velpatasvir 400/100 mg qd x 14 days 600 mg qd x 14 days 14 ↑ 38 (↑14 to ↑67) ↔ NA ↓ 14 (↓ 20 to ↓ 7) ↔ ↔ ↓ 47 (↓ 57 to ↓ 36) ↓ 53 (↓ 61 to ↓ 43) ↓ 57 (↓ 64 to ↓ 48) Azithromycin 600 mg single dose 400 mg qd x 7 days 14 ↑ 22% (4 to 42%) ↔ NA Clarithromycin 14-OH metabolite 500 mg q12h x 7 days 400 mg qd x 7 days 11 ↓ 26% (15 to 35%) ↓ 39% (30 to 46%) ↓ 53% (42 to 63%) ↑ 49% (32 to 69%) ↑ 34% (18 to 53%) ↑ 26% (9 to 45%) Fluconazole 200 mg x 7 days 400 mg qd x 7 days 10 ↔ ↔ ↔ Itraconazole 200 mg q12h x 28 days 600 mg qd x 14 days 18 ↓ 37% (20 to 51%) ↓ 39% (21 to 53%) ↓ 44% (27 to 58%) Hydroxy-itraconazole ↓ 35% (12 to 52%) ↓ 37% (14 to 55%) ↓ 43% (18 to 60%) Posaconazole 400 mg (oral suspension) bid x 10 and 20 days 400 mg qd x 10 and 20 days 11 ↓ 45% (34 to 53%) ↓ 50% (40 to 57%) NA Rifabutin 300 mg qd x 14 days 600 mg qd x 14 days 9 ↓ 32% (15 to 46%) ↓ 38% (28 to 47%) ↓ 45% (31 to 56%) Voriconazole 400 mg po q12h x 1 day, then 200 mg po q12h x 8 days 400 mg qd x 9 days NA ↓ 61% a ↓ 77% a NA 300 mg po q12h days 2 to 7 300 mg qd x 7 days NA ↓ 36% b (21 to 49%) ↓ 55% b (45 to 62%) NA 400 mg po q12h days 2 to 7 300 mg qd x 7 days NA ↑ 23% b (↓ 1 to ↑ 53%) ↓ 7% b (↓ 23 to ↑ 13%) NA Artemether/ lumefantrine Artemether 20 mg/ lumefantrine 120 mg tablets (6 4- tablet doses over 3 days) 600 mg qd x 26 days 12 Artemether ↓ 21% ↓ 51% NA dihydroartemisinin ↓ 38% ↓ 46% NA lumefantrine ↔ ↓ 21% NA Atorvastatin 10 mg qd x 4 days 600 mg qd x 15 days 14 ↓ 14% (1 to 26%) ↓ 43% (34 to 50%) ↓ 69% (49 to 81%) Total active (including metabolites) ↓ 15% (2 to 26%) ↓ 32% (21 to 41%) ↓ 48% (23 to 64%) Pravastatin 40 mg qd x 4 days 600 mg qd x 15 days 13 ↓ 32% (↓ 59 to ↑ 12%) ↓ 44% (26 to 57%) ↓ 19% (0 to 35%) Simvastatin 40 mg qd x 4 days 600 mg qd x 15 days 14 ↓ 72% (63 to 79%) ↓ 68% (62 to 73%) ↓ 45% (20 to 62%) Total active (including metabolites) ↓ 68% (55 to 78%) ↓ 60% (52 to 68%) NA c Carbamazepine 200 mg qd x 3 days, 200 mg bid x 3 days, then 400 mg qd x 29 days 600 mg qd x 14 days 12 ↓ 20% (15 to 24%) ↓ 27% (20 to 33%) ↓ 35% (24 to 44%) Epoxide metabolite ↔ ↔ ↓ 13% (↓ 30 to ↑ 7%) Cetirizine 10 mg single dose 600 mg qd x 10 days 11 ↓ 24% (18 to 30%) ↔ NA Diltiazem 240 mg x 21 days 600 mg qd x 14 days 13 ↓ 60% (50 to 68%) ↓ 69% (55 to 79%) ↓ 63% (44 to 75%) Desacetyl diltiazem ↓ 64% (57 to 69%) ↓ 75% (59 to 84%) ↓ 62% (44 to 75%) N-monodes-methyl diltiazem ↓ 28% (7 to 44%) ↓ 37% (17 to 52%) ↓ 37% (17 to 52%) Ethinyl estradiol/ Norgestimate 0.035 mg/0.25 mg x 14 days 600 mg qd x 14 days Ethinyl estradiol 21 ↔ ↔ ↔ Norelgestromine 21 ↓ 46% (39 to 52%) ↓ 64% (62 to 67%) ↓ 82% (79 to 85%) Levonorgestrel 6 ↓ 80% (77 to 83%) ↓ 83% (79 to 87%) ↓ 86% (80 to 90%) Lorazepam 2 mg single dose 600 mg qd x 10 days 12 ↑ 16% (2 to 32%) ↔ NA Methadone Stable maintenance 35 to 100 mg daily 600 mg qd x 14 to 21 days 11 ↓ 45% (25 to 59%) ↓ 52% (33 to 66%) NA Bupropion 150 mg single dose (sustained-release) 600 mg qd x 14 days 13 ↓ 34% (21 to 47%) ↓ 55% (48 to 62%) NA Hydroxy-bupropion ↑ 50% (20 to 80%) ↔ NA Paroxetine 20 mg qd x 14 days 600 mg qd x 14 days 16 ↔ ↔ ↔ Sertraline 50 mg qd x 14 days 600 mg qd x 14 days 13 ↓ 29% (15 to 40%) ↓ 39% (27 to 50%) ↓ 46% (31 to 58%) Table 7. Effect of Coadministered Drug on Efavirenz Plasma C max , AUC, and C min ↑ Indicates increase ↓ Indicates decrease ↔ Indicates no change or a mean increase or decrease of < 10%. a 90% CI not available. b Relative to steady-state administration of efavirenz (600 mg once daily for 9 days). NA = not available. Number of Subjects Efavirez (mean % change) Coadministered Drug Dose Efavirenz Dose C max (90% CI) AUC (90% CI) C min (90% CI) Boceprevir 800 mg tid x 6 days 600 mg qd x 16 days NA ↑ 11% (2 to 20%) ↑ 20% (15 to 26%) NA Simeprevir 150 mg qd x 14 days 600 mg qd x 14 days 23 ↔ ↓ 10% (5 to 15%) ↓ 13% (7 to 19%) Azithromycin 600 mg single dose 400 mg qd x 7 days 14 ↔ ↔ ↔ Clarithromycin 500 mg q12h x 7 days 400 mg qd x 7 days 12 ↑ 11% (3 to 19%) ↔ ↔ Fluconazole 200 mg x 7 days 400 mg qd x 7 days 10 ↔ ↑ 16% (6 to 26%) ↑ 22% (5 to 41%) Itraconazole 200 mg q12h x 14 days 600 mg qd x 28 days 16 ↔ ↔ ↔ Rifabutin 300 mg qd x 14 days 600 mg qd x 14 days 11 ↔ ↔ ↓ 12% (↓ 24 to ↑ 1%) Rifampin 600 mg x 7 days 600 mg qd x 7 days 12 ↓ 20% (11 to 28%) ↓ 26% (15 to 36%) ↓ 32% (15 to 46%) Voriconazole 400 mg po q12h x 1 day, then 200 mg po q12h x 8 days 400 mg qd x 9 days NA ↑ 38% a ↑ 44% a NA 300 mg po q12h days 2 to 7 300 mg qd x 7 days NA ↓ 14% b (7 to 21%) ↔ b NA 400 mg po q12h days 2 to 7 300 mg qd x 7 days NA ↔ b ↑ 17% b (6 to 29%) NA Artemether/ Lumefantrine Artemether 20 mg/lumefantrine 120 mg tablets (6 4-tablet doses over 3 days) 600 mg qd x 26 days 12 ↔ ↓ 17% NA Atorvastatin 10 mg qd x 4 days 600 mg qd x 15 days 14 ↔ ↔ ↔ Pravastatin 40 mg qd x 4 days 600 mg qd x 15 days 11 ↔ ↔ ↔ Simvastatin 40 mg qd x 4 days 600 mg qd x 15 days 14 ↓ 12% (↓ 28 to ↑ 8%) ↔ ↓ 12% (↓ 25 to ↑ 3%) Aluminum hydroxide 400 mg, magnesium hydroxide 400 mg, plus simethicone 40 mg 30 mL single dose 400 mg single dose 17 ↔ ↔ NA Carbamazepine 200 mg qd x 3 days, 200 mg bid x 3 days, then 400 mg qd x 15 days 600 mg qd x 35 days 14 ↓ 21% (15 to 26%) ↓ 36% (32 to 40%) ↓ 47% (41 to 53%) Cetirizine 10 mg single dose 600 mg qd x 10 days 11 ↔ ↔ ↔ Diltiazem 240 mg x 14 days 600 mg qd x 28 days 12 ↑ 16% (6 to 26%) ↑ 11% (5 to 18%) ↑ 13% (1 to 26%) Famotidine 40 mg single dose 400 mg single dose 17 ↔ ↔ NA Paroxetine 20 mg qd x 14 days 600 mg qd x 14 days 12 ↔ ↔ ↔ Sertraline 50 mg qd x 14 days 600 mg qd x 14 days 13 ↑ 11% (6 to 16%) ↔ ↔ 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. 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. 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 to 24) , 14%, 32%, and 36% in the AUC (∞) , and 28%, 52%, and 55% in the C max of lamivudine, respectively. 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. Table 8 summarizes pharmacokinetic effects of coadministered drug on tenofovir pharmacokinetics. No clinically significant drug interactions have been observed between tenofovir and ribavirin. Table 8. Drug Interactions: Changes in Pharmacokinetic Parameters for Tenofovir a in the Presence of the Coadministered Drug a Subjects received tenofovir disoproxil fumarate 300 mg once daily. b Increase = ↑; Decrease = ↓; No Effect = ↔; NC = Not Calculated c Study conducted with efavirenz/emtricitabine/tenofovir disoproxil fumarate coadministered with ledipasvir/sofosbuvir. d Study conducted with efavirenz/emtricitabine/tenofovir disoproxil fumarate coadministered with sofosbuvir. e Data generated from simultaneous dosing with ledipasvir/sofosbuvir. Staggered administration (12 hours apart) provide similar results. f Comparison based on exposures when administered as atazanavir/ritonavir + emtricitabine/tenofovir DF. g Comparison based on exposures when administered as darunavir/ritonavir + emtricitabine/tenofovir DF. h Study conducted with COMPLERA coadministered with EPCLUSA; coadministration with EPCLUSA also results in comparable increases in tenofovir exposures when TDF is administered as ATRIPLA, STRIBILD ® (elvitegravir/cobicistat/FTC/TDF), TRUVADA + atazanavir/ritonavir, or TRUVADA + darunavir/ritonavir. i Administered as raltegravir + FTC/TDF. j Comparison based on exposures when administered as darunavir + ritonavir + FTC/TDF. k Study conducted with additional voxilaprevir 100 mg to achieve voxilaprevir exposures expected in HCV-infected patients. Coadministered Drug Dose of Coadministered Drug (mg) N % Change of Tenofovir Pharmacokinetic Parameters b (90% CI) C max AUC C min Ledipasvir/ Sofosbuvir e,f 90/400 once daily x 10 days 24 ↑ 47 (↑ 37 to ↑ 58) ↑ 35 (↑ 29 to ↑ 42) ↑ 47 (↑ 38 to ↑ 57) Ledipasvir/ Sofosbuvir e,g 23 ↑ 64 (↑ 54 to ↑ 74) ↑ 50 (↑ 42 to ↑ 59) ↑ 59 (↑ 49 to ↑ 70) Ledipasvir/ Sofosbuvir c 90/400 once daily x 14 days 15 ↑ 79 (↑ 56 to ↑104) ↑ 98 (↑ 77 to ↑123) ↑ 163 (↑ 132 to ↑ 197) Sofosbuvir/ Velpatasvir h 400/100 once daily 24 ↑ 44 (↑ 33 to ↑55) ↑ 40 (↑ 34 to ↑46) ↑ 84 (↑ 76 to ↑ 92) Sofosbuvir/ Velpatasvir i 400/100 once daily 30 ↑ 46 (↑ 39 to ↑54) ↑ 40 (↑ 34 to ↑45) ↑ 70 (↑ 61 to ↑ 79) Sofosbuvir/ Velpatasvir/ Voxilaprevir j 400/100/100 + Voxilaprevir k 100 once daily 29 ↑ 48 (↑ 36 to ↑61) ↑ 39 (↑32 to ↑46) ↑47 (↑ 38 to ↑ 56) Sofosbuvir d 400 single dose 16 ↑ 25 (↑ 8 to ↑ 45) ↔ ↔ Tacrolimus 0.05 mg/kg twice daily x 7 days 21 ↑ 13 (↑ 1 to ↑ 27) ↔ ↔