Atripla (Page 8 of 12)

Emtricitabine and Tenofovir Disoproxil Fumarate: The steady-state pharmacokinetics of emtricitabine and tenofovir were unaffected when emtricitabine and tenofovir DF were administered together versus each agent dosed alone.

In vitro and clinical pharmacokinetic drug-drug interaction studies have shown that the potential for CYP mediated interactions involving emtricitabine and tenofovir with other medicinal products is low.

Emtricitabine and tenofovir are primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion. No drug-drug interactions due to competition for renal excretion have been observed; however, coadministration of emtricitabine and tenofovir DF with drugs that are eliminated by active tubular secretion may increase concentrations of emtricitabine, tenofovir, and/or the coadministered drug.

Drugs that decrease renal function may increase concentrations of emtricitabine and/or tenofovir.

No clinically significant drug interactions have been observed between emtricitabine and famciclovir, indinavir, stavudine, tenofovir DF and zidovudine. Similarly, no clinically significant drug interactions have been observed between tenofovir DF and abacavir, efavirenz, emtricitabine, entecavir, indinavir, lamivudine, lopinavir/ritonavir, methadone, nelfinavir, oral contraceptives, ribavirin, saquinavir/ritonavir or tacrolimus in studies conducted in healthy volunteers.

Following multiple dosing to HIV-negative subjects receiving either chronic methadone maintenance therapy, oral contraceptives, or single doses of ribavirin, steady-state tenofovir pharmacokinetics were similar to those observed in previous studies, indicating a lack of clinically significant drug interactions between these agents and tenofovir DF.

The effects of coadministered drugs on the Cmax , AUC, and Cmin of tenofovir are shown in Table 7. The effects of coadministration of tenofovir DF on Cmax , AUC, and Cmin of coadministered drugs are shown in Table 8 and Table 9.

Table 7 Drug Interactions: Changes in Pharmacokinetic Parameters for Tenofovir in the Presence of the Coadministered Drug *,
Coadministered Drug Dose of Coadministered Drug (mg) N Mean % Change of Tenofovir Pharmacokinetic Parameters (90% CI)
Cmax AUC Cmin
*
All interaction studies conducted in healthy volunteers.
Subjects received tenofovir DF 300 mg once daily.
Increase = ↑; Decrease = ↓; No Effect = ↔
§
Reyataz Prescribing Information
Atazanavir § 400 once daily × 14 days 33 ↑ 14 (↑ 8 to ↑ 20) ↑ 24 (↑ 21 to ↑ 28) ↑ 22 (↑ 15 to ↑ 30)
Didanosine (enteric-coated) 400 once 25
Didanosine (buffered) 250 or 400 once daily × 7 days 14
Lopinavir/ ritonavir 400/100 twice daily × 14 days 24 ↑ 32 (↑ 25 to ↑ 38) ↑ 51 (↑ 37 to ↑ 66)
Table 8 Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of Tenofovir Disoproxil Fumarate *,
Coadministered Drug Dose of Coadministered Drug (mg) N Mean % Change of Coadministered Drug Pharmacokinetic Parameters (90% CI)
Cmax AUC Cmin
*
All interaction studies conducted in healthy volunteers.
Subjects received tenofovir DF 300 mg once daily.
Increase = ↑; Decrease = ↓; No Effect = ↔
§
Reyataz Prescribing Information
In HIV-infected patients, addition of tenofovir DF to atazanavir 300 mg plus ritonavir 100 mg, resulted in AUC and Cmin values of atazanavir that were 2.3- and 4-fold higher than the respective values observed for atazanavir 400 mg when given alone.
Atazanavir § 400 once daily × 14 days 34 ↓ 21 (↓ 27 to ↓ 14) ↓ 25 (↓ 30 to ↓ 19) ↓ 40 (↓ 48 to ↓ 32)
Atazanavir/ritonavir 300/100 once daily × 42 days 10 ↓ 28 (↓ 50 to ↑ 5) ↓ 25 (↓ 42 to ↓ 3) ↓ 23 (↓ 46 to ↑ 10)
Lopinavir Lopinavir/ritonavir 400/100 twice daily × 14 days 24
Ritonavir Lopinavir/ritonavir 400/100 twice daily × 14 days 24

Coadministration of tenofovir DF with didanosine results in changes in the pharmacokinetics of didanosine that may be of clinical significance. Table 9 summarizes the effects of tenofovir DF on the pharmacokinetics of didanosine. Concomitant dosing of tenofovir DF with didanosine buffered tablets or enteric-coated capsules significantly increases the Cmax and AUC of didanosine. When didanosine 250 mg enteric-coated capsules were administered with tenofovir DF, systemic exposures of didanosine were similar to those seen with the 400 mg enteric-coated capsules alone under fasted conditions. The mechanism of this interaction is unknown [for didanosine dosing adjustment recommendations see Drug Interactions (7.3), Table 4].

Table 9 Drug Interactions: Changes in Pharmacokinetic Parameters for Didanosine in the Presence of Tenofovir Disoproxil Fumarate *,
Didanosine Dose (mg)/Method of Administration Tenofovir DF Method of Administration , N Mean % Change (90% CI) vs. Didanosine 400 mg Alone, Fasted §
Cmax AUC
*
All interaction studies conducted in healthy volunteers.
Subjects received tenofovir DF 300 mg once daily.
Administration with food was with a light meal (~373 kcal, 20% fat).
§
Increase = ↑; Decrease = ↓; No Effect = ↔
Includes 4 subjects weighing <60 kg receiving ddI 250 mg.
Buffered tablets
400 once daily × 7 days Fasted 1 hour after didanosine 14 ↑ 28 (↑ 11 to ↑ 48) ↑ 44 (↑ 31 to ↑ 59)
Enteric coated capsules
400 once, fasted With food, 2 hr after didanosine 26 ↑ 48 (↑ 25 to ↑ 76) ↑ 48 (↑ 31 to ↑ 67)
400 once, with food Simultaneously with didanosine 26 ↑ 64 (↑ 41 to ↑ 89) ↑ 60 (↑ 44 to ↑ 79)
250 once, fasted With food, 2 hr after didanosine 28 ↓ 10 (↓ 22 to ↑ 3)
250 once, fasted Simultaneously with didanosine 28 ↑ 14 (0 to ↑ 31)
250 once, with food Simultaneously with didanosine 28 ↓ 29 (↓ 39 to ↓ 18) ↓ 11 (↓ 23 to ↑ 2)

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