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).
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. | ||||||
| ||||||
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%) |
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. | |||||||||||||
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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