Prescription Drug Information: Efavirenz, Lamivudine and Tenofovir Disoproxil Fumarate (Page 5 of 8)

8.3 Females and Males of Reproductive Potential

Because of potential teratogenic effects, pregnancy should be avoided in women receiving efavirenz, lamivudine and tenofovir disoproxil fumarate [see Warnings and Precautions (5.7), Use in Specific Populations (8.1)].

Pregnancy Testing:
Females of reproductive potential should undergo pregnancy testing before initiation of efavirenz, lamivudine and tenofovir disoproxil fumarate.

Contraception: Females of reproductive potential should use effective contraception during treatment with efavirenz, lamivudine and tenofovir disoproxil fumarate and for 12 weeks after discontinuing efavirenz, lamivudine and tenofovir disoproxil fumarate due to the long half-life of EFV. Barrier contraception should always be used in combination with other methods of contraception. Hormonal methods that contain progesterone may have decreased effectiveness [see Drug Interactions (7.5)].

8.4 Pediatric Use

The safety and effectiveness of efavirenz, lamivudine and tenofovir disoproxil fumarate as a 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 (efavirenz, lamivudine, and tenofovir disoproxil fumarate).

8.5 Geriatric Use

Clinical studies of efavirenz, lamivudine and tenofovir disoproxil fumarate 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 3TC in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

8.6 Renal Impairment

Efavirenz, lamivudine and tenofovir disoproxil fumarate 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 a fixed-dose combination formulation that cannot be adjusted [see Dosage and Administration (2.3)].

8.7 Hepatic Impairment

Efavirenz, lamivudine and tenofovir disoproxil fumarate is not recommended for patients with moderate or severe hepatic impairment because there are insufficient data to determine whether dose adjustment is necessary. Patients with mild hepatic impairment may be treated with efavirenz, lamivudine and tenofovir disoproxil fumarate without any adjustment in dose [see Dosage and Administration (2.4),Warnings and Precautions (5.9) and Clinical Pharmacology (12.3)].

10 OVERDOSAGE

If overdose occurs, the patient must be monitored for evidence of toxicity, and standard supportive treatment applied as necessary.

Efavirenz: Some patients accidentally taking 600 mg twice daily have reported increased nervous system symptoms. One patient experienced involuntary muscle contractions.
Treatment of overdose with EFV should consist of general supportive measures, including monitoring of vital signs and observation of the patient’s clinical status. Administration of activated charcoal may be used to aid removal of unabsorbed drug. There is no specific antidote for overdose with efavirenz. Since efavirenz is highly protein bound, dialysis is unlikely to significantly remove the drug from blood.

Lamivudine: There is no known specific treatment for overdose with 3TC. If overdose occurs, the patient should be monitored and standard supportive treatment applied as required because a negligible amount of 3TC was removed via (4-hour) hemodialysis, continuous ambulatory peritoneal dialysis, and automated peritoneal dialysis, it is not known if continuous hemodialysis would provide clinical benefit in a 3TC overdose event.

Tenofovir Disoproxil Fumarate: Limited clinical experience at doses higher than the therapeutic dose of TDF 300 mg is available.
Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%. Following a single 300 mg dose of tenofovir disoproxil fumarate, a 4-hour hemodialysis session removed approximately 10% of the administered tenofovir dose.

11 DESCRIPTION

Efavirenz, lamivudine and tenofovir disoproxil fumarate is a fixed-dose combination tablet for oral administration. Each film coated tablet contains efavirenz USP 400 mg, lamivudine USP 300 mg and tenofovir disoproxil fumarate 300 mg equivalent to tenofovir disoproxil 245 mg. Each tablet contains the following inactive ingredients: croscarmellose sodium, ferric oxide yellow, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, sodium lauryl sulfate, talc and titanium dioxide.

Efavirenz: Efavirenz (EFV) is an HIV-1 specific, non-nucleoside, reverse transcriptase inhibitor (NNRTI). Efavirenz is chemically described as (S)-6-Chloro-4-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H -3,1-benzoxazin-2-one. Its molecular formula is C14 H9 ClF3 NO2 and its structural formula is:

efavirenz-structure

Efavirenz USP is a white to off white powder with a molecular mass of 315.67. It is soluble in methanol and practically insoluble in water (< 10 microgram/mL).

Lamivudine: Lamivudine (also known as 3TC) is a synthetic nucleoside analogue with activity against HIV-1 and HBV.The chemical name of lamivudine is (-)-1-[(2R ,5S)-2-(Hydroxy methyl)-1,3-oxathiolan-5-yl]cytosine. Lamivudine is the (-)enantiomer of a dideoxy analogue of cytidine. Lamivudine has also been referred to as (-)2′,3′-dideoxy, 3′-thiacytidine. It has a molecular formula of C8 H11 N3 O3 S and a molecular weight of 229.26 g per mol. It has the following structural formula:

lamivudine-structure

Lamivudine USP is a white or almost white powder and is soluble in water.

Tenofovir Disoproxil Fumarate: Tenofovir disoproxil fumarate (TDF) (a prodrug of tenofovir) is a fumaric acid salt of bis-isopropoxycarbonyloxymethyl ester derivative of tenofovir. TDF is converted in vivo to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5′ -monophosphate. Tenofovir exhibits activity against HIV-1 reverse transcriptase.

The chemical name of tenofovir disoproxil fumarateis 9-[(R)-2- [[bis[[(isopropoxycarbonyl)oxy]methoxy]phosphinyl]methoxy]propyl]adenine fumarate (1:1). It has a molecular formula of C19 H30 N5 O10 P•C4 H4 O4 and a molecular weight of 635.52. It has the following structural formula:

tenofovir-structure

Tenofovir disoproxil fumarate is a white to off white powder freely soluble in dimethyl formamide, soluble in methanol and slightly soluble in water at 25°C. It has a partition coefficient (log p) of 0.75.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Efavirenz, lamivudine and tenofovir disoproxil fumarate tablets are a fixed-dose combination of antiviral drugs EFV, 3TC, and TDF with antiviral activity against HIV-1 [see Microbiology (12.4)].

12.2 Pharmacodynamics

Cardiac Electrophysiology: The effect of EFV on the QTc interval was evaluated in an open- label, positive and placebo-controlled, fixed single sequence 3-period, 3-treatment crossover QT study in 58 healthy subjects enriched for CYP2B6 polymorphisms. The mean Cmax of EFV in subjects with CYP2B6 *6/*6 genotype following the administration of 600 mg daily dose for 14 days was 2.25-fold the mean Cmax observed in subjects with CYP2B6 *1/*1 genotype. A positive relationship between EFV concentration and QTc prolongation was observed. Based on the concentration-QTc relationship, the mean QTc prolongation and its upper bound 90% confidence interval are 8.7 ms and 11.3 ms in subjects with CYP2B6*6/*6 genotype following the administration of 600 mg daily dose for 14 days [see Warnings and Precautions (5.16)].

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 14C-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 (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 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 (t1/2) 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 (Cmax) were achieved in 1.0 ± 0.4 hrs (mean ± SD) and Cmax 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 6).

Table 6. 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
Cmax (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, Cmax, and AUC0-∞ of tenofovir were increased.

Table 7. 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)
Cmax (mcg/mL) 0.34 ± 0.03 0.33 ± 0.06 0.37 ± 0.16 0.60 ± 0.19
AUC0-∞ (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
CLrenal (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 Ki 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 (Ki 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 Cmax, AUC, and Cmin are summarized in Table 8 (effect of EFV on other drugs) and Table 9 (effect of other drugs on EFV). For information regarding clinical recommendations see Drug Interactions (7.5).

Table 8. Effect of Efavirenz on Coadministered Drug Plasma Cmax , AUC, and Cmin
↑ 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/ SofosbuvirdLedipasvirSofosbuvir GS-331007e 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
SofosbuvirfGS-331007e 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/ VelpatasvirgSofosbuvir GS-331007eVelpatasvir 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
Clarithromycin14-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 10and 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 120mg 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%) NAc
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 9. Effect of Coadministered Drug on Efavirenz Plasma Cmax , AUC, and Cmin
↑ 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 poq12h days 2 to 7 300 mg qd x 7 days NA ↓ 14%b(7 to 21%) ↔b NA
400 mg poq12h days 2 to 7 300 mg qd x 7 days NA ↔b ↑ 17%b(6 to 29%) NA
Artemether/ Lumefantrine Artemether 20 mg/ lumefantrine120 mg tablets(6 4-tabletdoses 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, magnesiumhydroxide 400 mg,plus simethicone 40 mg 30 mL single dose 400 mg single dose 17 NA
Carbamazepine 200 mg qd x 3days, 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 Cmax 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 10 summarizes pharmacokinetic effects of coadministered drug on tenofovir pharmacokinetics. No clinically significant drug interactions have been observed between tenofovir and ribavirin.

Table 10. Drug Interactions: Changes in Pharmacokinetic Parameters for Tenofovira in the Presence of the Coadministered Drug
a Subjects received tenofovir disoproxil fumarate 300 mg once daily.b Increase = ↑; Decrease = ↓; No Effect = ↔; NC = Not Calculatedc 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 Parametersb (90% CI)
C max AUC C min
Ledipasvir/ Sofosbuvire,f 90/400 once daily x 10 days 24 ↑ 47(↑ 37 to ↑ 58) ↑ 35(↑ 29 to ↑ 42) ↑ 47(↑ 38 to ↑ 57)
Ledipasvir/ Sofosbuvire,g 23 ↑ 64(↑ 54 to ↑ 74) ↑ 50(↑ 42 to ↑ 59) ↑ 59(↑ 49 to ↑ 70)
Ledipasvir/ Sofosbuvirc 90/400 once daily x 14 days 15 ↑ 79(↑ 56 to ↑104) ↑ 98(↑ 77 to ↑123) ↑ 163(↑ 132 to ↑ 197)
Sofosbuvir/Velpatasvirh 400/100 once daily 24 ↑ 44(↑ 33 to ↑55) ↑ 40(↑ 34 to↑46) ↑ 84(↑ 76 to ↑ 92)
Sofosbuvir/Velpatasviri 400/100 once daily 30 ↑ 46(↑ 39 to ↑54) ↑ 40(↑ 34 to ↑45) ↑70(↑61 to ↑ 79)
Sofosbuvir/Velpatasvir/Voxilaprevirj 400/100/100 + Voxilaprevirk 100 once daily 29 ↑ 48(↑ 36 to ↑61) ↑ 39(↑ 32 to ↑46) ↑47(↑38 to ↑ 56)
Sofosbuvird 400 single dose 16 ↑ 25(↑ 8 to ↑ 45)
Tacrolimus 0.05 mg/kg twice daily x 7 days 21 ↑ 13(↑ 1 to ↑ 27)

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