Truvada (Page 5 of 9)

Pediatric Patients

TRUVADA should not be administered to pediatric patients less than 12 years of age or weighing less than 35 kg (less than 77 lb).

Emtricitabine: The pharmacokinetics of emtricitabine at steady state were determined in 27 HIV-1-infected pediatric subjects 13 to 17 years of age receiving a daily dose of 6 mg/kg up to a maximum dose of 240 mg oral solution or a 200 mg capsule; 26 of 27 subjects in this age group received the 200 mg EMTRIVA capsule. Mean (± SD) Cmax and AUC were 2.7 ± 0.9 μg/mL and 12.6 ± 5.4 μg•hr/mL, respectively. Exposures achieved in pediatric subjects 12 to less than 18 years of age were similar to those achieved in adults receiving a once daily dose of 200 mg.

Tenofovir Disoproxil Fumarate: Steady-state pharmacokinetics of tenofovir were evaluated in 8 HIV-1 infected pediatric subjects (12 to less than 18 years). Mean (± SD) Cmax and AUCtau are 0.38 ± 0.13 μg/mL and 3.39 ± 1.22 μg•hr/mL, respectively. Tenofovir exposure achieved in these pediatric subjects receiving oral daily doses of VIREAD 300 mg was similar to exposures achieved in adults receiving once-daily doses of VIREAD 300 mg.

Geriatric Patients

Pharmacokinetics of emtricitabine and tenofovir have not been fully evaluated in the elderly (65 years of age and older).

Patients with Impaired Renal Function

The pharmacokinetics of emtricitabine and tenofovir are altered in subjects with renal impairment [See Warnings and Precautions (5.3)]. In adult subjects with creatinine clearance below 50 mL/min, Cmax , and AUC0– of emtricitabine and tenofovir were increased. It is recommended that the dosing interval for TRUVADA be modified in patients with creatinine clearance 30–49 mL/min. TRUVADA should not be used in patients with creatinine clearance below 30 mL/min and in patients with end-stage renal disease requiring dialysis [See Dosage and Administration (2.2)].

Patients with Hepatic Impairment

The pharmacokinetics of tenofovir following a 300 mg dose of VIREAD have been studied in non-HIV infected subjects with moderate to severe hepatic impairment. There were no substantial alterations in tenofovir pharmacokinetics in subjects with hepatic impairment compared with unimpaired subjects. The pharmacokinetics of TRUVADA or emtricitabine have not been studied in subjects with hepatic impairment; however, emtricitabine is not significantly metabolized by liver enzymes, so the impact of liver impairment should be limited.

Assessment of Drug Interactions

The steady state pharmacokinetics of emtricitabine and tenofovir were unaffected when emtricitabine and tenofovir disoproxil fumarate were administered together versus each agent dosed alone.

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

No clinically significant drug interactions have been observed between emtricitabine and famciclovir, indinavir, stavudine, tenofovir disoproxil fumarate, and zidovudine (see Tables 5 and 6). Similarly, no clinically significant drug interactions have been observed between tenofovir disoproxil fumarate and abacavir, efavirenz, emtricitabine, entecavir, indinavir, lamivudine, lopinavir/ritonavir, methadone, nelfinavir, oral contraceptives, ribavirin, saquinavir/ritonavir, and tacrolimus in trials conducted in healthy volunteers (see Tables 7 and 8).

Table 5 Drug Interactions: Changes in Pharmacokinetic Parameters for Emtricitabine in the Presence of the Coadministered Drug *
Coadministered Drug Dose of Coadministered Drug (mg) Emtricitabine Dose (mg) N % Change of Emtricitabine Pharmacokinetic Parameters (90% CI)
Cmax AUC Cmin
*
All interaction trials conducted in healthy volunteers.

↑ = Increase; ↓ = Decrease; Symbol = No Effect; NA = Not Applicable

Tenofovir DF 300 once daily × 7 days 200 once daily × 7 days 17 Symbol Symbol ↑ 20 (↑ 12 to ↑ 29)
Zidovudine 300 twice daily × 7 days 200 once daily × 7 days 27 Symbol Symbol Symbol
Indinavir 800 × 1 200 × 1 12 Symbol Symbol NA
Famciclovir 500 × 1 200 × 1 12 Symbol Symbol NA
Stavudine 40 × 1 200 × 1 6 Symbol Symbol NA
Table 6 Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of Emtricitabine *
Coadministered Drug Dose of Coadministered Drug (mg) Emtricitabine Dose (mg) N % Change of Coadministered Drug Pharmacokinetic Parameters (90% CI)
Cmax AUC Cmin
*
All interaction trials conducted in healthy volunteers.

↑ = Increase; ↓ = Decrease; Symbol = No Effect; NA = Not Applicable

Tenofovir DF 300 once daily × 7 days 200 once daily × 7 days 17 Symbol Symbol Symbol
Zidovudine 300 twice daily × 7 days 200 once daily × 7 days 27 ↑ 17 (↑ 0 to ↑ 38) ↑ 13 (↑ 5 to ↑ 20) Symbol
Indinavir 800 × 1 200 × 1 12 Symbol Symbol NA
Famciclovir 500 × 1 200 × 1 12 Symbol Symbol NA
Stavudine 40 × 1 200 × 1 6 Symbol Symbol NA
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 % Change of Tenofovir Pharmacokinetic Parameters (90% CI)
Cmax AUC Cmin
*
Subjects received VIREAD 300 mg once daily.

Increase = ↑; Decrease = ↓; No Effect = Symbol; NC = Not Calculated

Reyataz Prescribing Information
Abacavir 300 once 8 Symbol Symbol NC
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 Symbol Symbol Symbol
Didanosine (buffered) 250 or 400 once daily × 7 days 14 Symbol Symbol Symbol
Efavirenz 600 once daily × 14 days 29 Symbol Symbol Symbol
Emtricitabine 200 once daily × 7 days 17 Symbol Symbol Symbol
Entecavir 1 mg once daily × 10 days 28 Symbol Symbol Symbol
Indinavir 800 three times daily × 7 days 13 ↑ 14 (↓ 3 to ↑ 33) Symbol Symbol
Lamivudine 150 twice daily × 7 days 15 Symbol Symbol Symbol
Lopinavir/Ritonavir 400/100 twice daily × 14 days 24 Symbol ↑ 32 (↑ 25 to ↑ 38) ↑ 51 (↑ 37 to ↑ 66)
Nelfinavir 1250 twice daily × 14 days 29 Symbol Symbol Symbol
Saquinavir/Ritonavir 1000/100 twice daily × 14 days 35 Symbol Symbol ↑ 23 (↑ 16 to ↑ 30)
Tacrolimus 0.05 mg/kg twice daily × 7 days 21 ↑ 13(↑ 1 to ↑ 27) Symbol Symbol
Table 8 Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of Tenofovir
Coadministered Drug Dose of Coadministered Drug (mg) N % Change of Coadministered Drug Pharmacokinetic Parameters * (90% CI)
Cmax AUC Cmin
*

Increase = ↑; Decrease = ↓; No Effect = Symbol; NA = Not Applicable

Reyataz Prescribing Information
In HIV-infected subjects, 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.
§
R-(active), S- and total methadone exposures were equivalent when dosed alone or with VIREAD.
Individual subjects were maintained on their stable methadone dose. No pharmacodynamic alterations (opiate toxicity or withdrawal signs or symptoms) were reported.
#
Ethinyl estradiol and 17-deacetyl norgestimate (pharmacologically active metabolite) exposures were equivalent when dosed alone or with VIREAD.
Þ
Increases in AUC and Cmin are not expected to be clinically relevant; hence no dose adjustments are required when tenofovir DF and ritonavir-boosted saquinavir are coadministered.
Abacavir 300 once 8 ↑ 12 (↓ 1 to ↑ 26) Symbol NA
Atazanavir 400 once daily × 14 days 34 ↓ 21 (↓ 27 to ↓ 14) ↓ 25 (↓ 30 to ↓ 19) ↓ 40 (↓ 48 to ↓ 32)
Atazanavir Atazanavir/Ritonavir 300/100 once daily × 42 days 10 ↓ 28 (↓ 50 to ↑ 5) ↓ 25 (↓ 42 to ↓ 3) ↓ 23 (↓ 46 to ↑ 10)
Efavirenz 600 once daily × 14 days 30 Symbol Symbol Symbol
Emtricitabine 200 once daily × 7 days 17 Symbol Symbol ↑ 20 (↑ 12 to ↑ 29)
Indinavir 800 three times daily × 7 days 12 ↓ 11 (↓ 30 to ↑ 12) Symbol Symbol
Entecavir 1 mg once daily × 10 days 28 Symbol ↑ 13(↑ 11 to ↑ 15) Symbol
Lamivudine 150 twice daily × 7 days 15 ↓ 24 (↓ 34 to ↓ 12) Symbol Symbol
Lopinavir Lopinavir/Ritonavir 400/100 twice daily × 14 days 24 Symbol Symbol Symbol
Ritonavir Symbol Symbol Symbol
Methadone § 40–110 once daily × 14 days 13 Symbol Symbol Symbol
Nelfinavir 1250 twice daily × 14 days 29 Symbol Symbol Symbol
M8 metabolite Symbol Symbol Symbol
Oral Contraceptives # Ethinyl Estradiol/ Norgestimate (Ortho-Tricyclen) Once daily × 7 days 20 Symbol Symbol Symbol
Ribavirin 600 once 22 Symbol Symbol NA
Saquinavir Saquinavir/Ritonavir 1000/100 twice daily × 14 days 32 ↑ 22 (↑ 6 to ↑41) ↑ 29Þ (↑ 12 to ↑ 48) ↑ 47Þ (↑ 23 to ↑ 76)
Ritonavir Symbol Symbol ↑ 23 (↑ 3 to ↑ 46)
Tacrolimus 0.05 mg/kg twice daily × 7 days 21 Symbol Symbol Symbol

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

Coadministration of tenofovir disoproxil fumarate with didanosine results in changes in the pharmacokinetics of didanosine that may be of clinical significance. Table 9 summarizes the effects of tenofovir disoproxil fumarate on the pharmacokinetics of didanosine. Concomitant dosing of tenofovir disoproxil fumarate 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 disoproxil fumarate, 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. See Drug Interactions (7.1) regarding use of didanosine with VIREAD.

Table 9 Drug Interactions: Pharmacokinetic Parameters for Didanosine in the Presence of VIREAD
Didanosine * Dose (mg)/Method of Administration * VIREAD Method of Administration * N % Difference (90% CI) vs. Didanosine 400 mg Alone, Fasted
Cmax AUC
*
Administration with food was with a light meal (~373 kcal, 20% fat).

Increase = ↑; Decrease = ↓; No Effect = Symbol

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 hours 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 hours after didanosine 28 ↓ 10 (↓ 22 to ↑ 3) Symbol
250 once, fasted Simultaneously with didanosine 28 Symbol ↑ 14 (0 to ↑ 31)
250 once, with food Simultaneously with didanosine 28 ↓ 29 (↓ 39 to ↓ 18) ↓ 11 (↓ 23 to ↑ 2)

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