SYMFI (Page 10 of 16)

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 µM) 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 µM) 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 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 Cmax , AUC, and Cmin
Number of Subjects Coadministered Drug (mean % change)
Coadministered Drug Dose Efavirenz Dose Cmax (90% CI) AUC (90% CI) Cmin (90% CI)
↑ Indicates increase ↓ Indicates decrease ↔ Indicates no change or a mean increase or decrease of < 10%.NA = not available.
*
Study conducted with ATRIPLA® coadministered with HARVONI®.
The predominant circulating nucleoside metabolite of sofosbuvir.
Study conducted with ATRIPLA coadministered with SOVALDI® (sofosbuvir).
§
Study conducted with ATRIPLA coadministered with EPCLUSA®.
90% CI not available.
#
Relative to steady-state administration of voriconazole (400 mg for 1 day, then 200 mg po q12h for 2 days).
Þ
Not available because of insufficient data.

Boceprevir

800 mg tid x 6 days

600 mg qd x 16 days

NA

↓ 8%

(↓ 22-↑ 8%)

↓ 19%

(11-25%)

↓ 44%

(26-58%)

Simeprevir

150 mg qd x 14 days

600 mg qd x 14 days

23

↓ 51%

(↓ 46-↓ 56%)

↓ 71%

(↓ 67-↓ 74%)

↓ 91%

(↓ 88-↓ 92%)

Ledipasvir/

Sofosbuvir *

90/400 mg qd x 14 days

600 mg qd x 14 days

15

↓ 34

(↓ 25-↓ 41)

↓ 34

(↓ 25-↓ 41)

↓ 34

(↓ 24-↓ 43)

Ledipasvir

NA

Sofosbuvir

GS-331007

Sofosbuvir

400 mg qd single dose

600 mg qd x 14 days

16

↓ 19

(↓ 40-↑ 10)

NA

GS-331007

↓ 23

(↓ 16-↓ 30)

↓ 16

(↓ 24-↓ 8)

NA

Sofosbuvir/

Velpatasvir §

Sofosbuvir

GS-331007

Velpatasvir

400/100 mg qd x 14 days

600 mg qd x 14 days

14

↑ 38

(↑ 14-↑ 67)

NA

↓ 14

(↓ 20-↓ 7)

↓ 47

(↓ 57-↓ 36)

↓ 53

(↓ 61-↓ 43)

↓ 57

(↓ 64-↓ 48)

Azithromycin

600 mg single dose

400 mg qd x 7 days

14

↑ 22%

(4-42%)

NA

Clarithromycin

500 mg q12h x 7 days

400 mg qd x 7 days

11

↓ 26%

(15-35%)

↓ 39%

(30-46%)

↓ 53%

(42-63%)

14-OH metabolite

↑ 49%

(32-69%)

↑ 34%

(18-53%)

↑ 26%

(9-45%)

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%

(20-51%)

↓ 39%

(21-53%)

↓ 44%

(27-58%)

Hydroxy-itraconazole

↓ 35%

(12-52%)

↓ 37%

(14-55%)

↓ 43%

(18-60%)

Posaconazole

400 mg (oral suspension) bid x 10 and 20 days

400 mg qd x 10 and 20 days

11

↓ 45%

(34-53%)

↓ 50%

(40-57%)

NA

Rifabutin

300 mg qd x 14 days

600 mg qd x 14 days

9

↓ 32%

(15-46%)

↓ 38%

(28-47%)

↓ 45%

(31-56%)

Voriconazole

400 mg po q12h x 1 day, then 200 mg po q12h x 8 days

400 mg qd x 9 days

NA

↓ 61%

↓ 77%

NA

300 mg po q12h days 2‑7

300 mg qd x 7 days

NA

↓ 36%#

(21-49%)

↓ 55%#

(45-62%)

NA

400 mg po q12h days 2‑7

300 mg qd x 7 days

NA

↑ 23%#

(↓ 1-↑ 53%)

↓ 7%#

(↓ 23-↑ 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%

(1-26%)

↓ 43%

(34-50%)

↓ 69%

(49-81%)

Total active (including metabolites)

↓ 15%

(2-26%)

↓ 32%

(21-41%)

↓ 48%

(23-64%)

Pravastatin

40 mg qd x 4 days

600 mg qd x 15 days

13

↓ 32%

(↓ 59-↑ 12%)

↓ 44%

(26-57%)

↓ 19%

(0-35%)

Simvastatin

40 mg qd x 4 days

600 mg qd x 15 days

14

↓ 72%

(63-79%)

↓ 68%

(62-73%)

↓ 45%

(20-62%)

Total active (including metabolites)

↓ 68%

(55-78%)

↓ 60%

(52-68%)

NA Þ

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%

(15-24%)

↓ 27%

(20-33%)

↓ 35%

(24-44%)

Epoxide metabolite

↓ 13%

(↓ 30-↑ 7%)

Cetirizine

10 mg single dose

600 mg qd x 10 days

11

↓ 24%

(18-30%)

NA

Diltiazem

240 mg x 21 days

600 mg qd x 14 days

13

↓ 60%

(50-68%)

↓ 69%

(55-79%)

↓ 63%

(44-75%)

Desacetyl diltiazem

↓ 64%

(57-69%)

↓ 75%

(59-84%)

↓ 62%

(44-75%)

N-monodes-methyl diltiazem

↓ 28%

(7-44%)

↓ 37%

(17-52%)

↓ 37%

(17-52%)

Ethinyl estradiol/ Norgestimate

0.035 mg/0.25 mg x 14 days

600 mg qd x 14 days

Ethinyl estradiol

21

Norelgestromine

21

↓ 46%

(39-52%)

↓ 64%

(62-67%)

↓ 82%

(79-85%)

Levonorgestrel

6

↓ 80%

(77-83%)

↓ 83%

(79-87%)

↓ 86%

(80-90%)

Lorazepam

2 mg single dose

600 mg qd x 10 days

12

↑ 16%

(2-32%)

NA

Methadone

Stable maintenance 35‑100 mg daily

600 mg qd x 14‑21 days

11

↓ 45%

(25-59%)

↓ 52%

(33-66%)

NA

Bupropion

150 mg single dose (sustained-release)

600 mg qd x 14 days

13

↓ 34%

(21-47%)

↓ 55%

(48-62%)

NA

Hydroxy-bupropion

↑ 50%

(20-80%)

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%

(15-40%)

↓ 39%

(27-50%)

↓ 46%

(31-58%)

Table 7. Effect of Coadministered Drug on Efavirenz Plasma Cmax , AUC, and Cmin
Number of Subjects Efavirenz (mean % change)
Coadministered Drug Dose Efavirenz Dose Cmax (90% CI) AUC (90% CI) Cmin (90% CI)
↑ Indicates increase ↓ Indicates decrease ↔ Indicates no change or a mean increase or decrease of < 10%.NA = not available.
*
90% CI not available.
Relative to steady-state administration of efavirenz (600 mg once daily for 9 days).

Boceprevir

800 mg tid x 6 days

600 mg qd x 16 days

NA

↑ 11%

(2-20%)

↑ 20%

(15-26%)

NA

Simeprevir

150 mg qd x 14 days

600 mg qd x 14 days

23

↓ 10%

(5-15%)

↓ 13%

(7-19%)

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%

(3-19%)

Fluconazole

200 mg x 7 days

400 mg qd x 7 days

10

↑ 16%

(6-26%)

↑ 22%

(5-41%)

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-↑ 1%)

Rifampin

600 mg x 7 days

600 mg qd x 7 days

12

↓ 20%

(11-28%)

↓ 26%

(15-36%)

↓ 32%

(15-46%)

Voriconazole

400 mg po q12h x 1 day, then 200 mg po q12h x 8 days

400 mg qd x 9 days

NA

↑ 38%*

↑ 44%*

NA

300 mg po q12h days 2-7

300 mg qd x 7 days

NA

↓ 14%

(7-21%)

NA

400 mg po q12h days 2-7

300 mg qd x 7 days

NA

↑ 17%

(6-29%)

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-↑ 8%)

↓ 12%

(↓ 25-↑ 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%

(15-26%)

↓ 36%

(32-40%)

↓ 47%

(41-53%)

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%

(6-26%)

↑ 11%

(5-18%)

↑ 13%

(1-26%)

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%

(6-16%)

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