ter administration with 350 or 450 mg/m2 twice-daily in children < 2 years of age. Higher ritonavir exposures were not evident with 450 mg/m2 twice-daily compared to the 350 mg/m2 twice-daily. Ritonavir trough concentrations were somewhat lower than those obtained in adults receiving 600 mg twice-daily. The area under the ritonavir plasma concentration-time curve and trough concentrations obtained after administration with 350 or 450 mg/m2 twice-daily in children < 2 years were approximately 16% and 60% lower, respectively, than that obtained in adults receiving 600 mg twice-daily.
Renal Insufficiency
Ritonavir pharmacokinetics have not been studied in patients with renal insufficiency, however, since renal clearance is negligible, a decrease in total body clearance is not expected in patients with renal insufficiency.
Hepatic Insufficiency
Dose-normalized steady-state ritonavir concentrations in subjects with mild hepatic insufficiency (400 mg twice-daily, n = 6) were similar to those in control subjects dosed with 500 mg twice-daily. Dose-normalized steady-state ritonavir exposures in subjects with moderate hepatic impairment (400 mg twice-daily, n= 6) were about 40% lower than those in subjects with normal hepatic function (500 mg twice-daily, n = 6). Protein binding of ritonavir was not statistically significantly affected by mild or moderately impaired hepatic function. No dose adjustment is recommended in patients with mild or moderate hepatic impairment. However, health care providers should be aware of the potential for lower ritonavir concentrations in patients with moderate hepatic impairment and should monitor patient response carefully. Ritonavir has not been studied in patients with severe hepatic impairment.
Drug-Drug Interactions
See also CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS - Drug Interactions.
Table 2 and Table 3 summarize the effects on AUC and Cmax, with 95% confidence intervals (95% CI), of co-administration of ritonavir with a variety of drugs. For information about clinical recommendations see PRECAUTIONS - Drug Interactions.
Table2. Drug Interactions - Pharmacokinetic Parameters for Ritonavir in the Presence of the Co-administered Drug (See PRECAUTIONS - Table6 for Recommended Alterations in Dose or Regimen) Co-administered Drug Dose of Co-administered Drug (mg) Dose of NORVIR (mg) n AUC % (95% CI) Cmax (95% CI) Cmin (95% CI)
Clarithromycin 500 q12h, 4 d 200 q8h, 4 d 22 ↑ 12% (2, 23%) ↑ 15% (2, 28%) ↑ 14% (-3, 36%)
Didanosine 200 q12h, 4 d 600 q12h, 4 d 12 ↔ ↔ ↔
Fluconazole 400 single dose, day1; 200 daily, 4 d 200 q6h, 4 d 8 ↑ 12% (5, 20%) ↑ 15% (7, 22%) ↑ 14% (0, 26%)
Fluoxetine 30 q12h, 8 d 600 single dose, 1 d 16 ↑ 19% (7, 34%) ↔ ND
Ketoconazole 200 daily, 7 d 500 q12h, 10 d 12 ↑ 18% (-3, 52%) ↑ 10% (-11, 36%) ND
Rifampin 600 or 300 daily, 10d 500 q12h, 20 d 7, 9* ↓ 35% (7, 55%) ↓ 25% (-5, 46%) ↓ 49% (-14, 91%)
Voriconazole 400 q12h, 1 d; then 200 q12h, 8 d 400 q12h, 9 d ↔ ↔ ND
Zidovudine 200 q8h, 4 d 300 q6h, 4 d 10 ↔ ↔ ↔
Table3. Drug Interactions - Pharmacokinetic Parameters for Co-administered Drug in the Presence of NORVIR (See PRECAUTIONS - Table 6 for Recommended Alterations in Dose or Regimen) Co-administered Drug Dose of Co-administered Drug (mg) Dose of NORVIR (mg) n AUC % (95% CI) Cmax (95% CI) Cmin (95% CI)
1 Ritonavir and indinavir were co-administered for
