Norvir (Ritonavir) - Indications and Dosage

INDICATIONS AND USAGE

NORVIR is indicated in combination with other antiretroviral agents for the treatment of HIV-infection. This indication is based on the results from a study in patients with advanced HIV disease that showed a reduction in both mortality and AIDS-defining clinical events for patients who received NORVIR either alone or in combination with nucleoside analogues. Median duration of follow-up in this study was 13.5 months.

Description of Clinical Studies

The activity of NORVIR as monotherapy or in combination with nucleoside reverse transcriptase inhibitors has been evaluated in 1446 patients enrolled in two double-blind, randomized trials.

Advanced Patients with Prior Antiretroviral Therapy

Study 247 was a randomized, double-blind trial (with open-label follow-up) conducted in HIV-infected patients with at least nine months of prior antiretroviral therapy and baseline CD₄ cell counts ≤ 100 cells/µL. NORVIR 600 mg twice-daily or placebo was added to each patient's baseline antiretroviral therapy regimen, which could have consisted of up to two approved antiretroviral agents. The study accrued 1090 patients, with mean baseline CD₄ cell count at study entry of 32 cells/µL. After the clinical benefit of NORVIR therapy was demonstrated, all patients were eligible to switch to open-label NORVIR for the duration of the follow-up period. Median duration of double-blind therapy with NORVIR and placebo was 6 months. The median duration of follow-up through the end of the open-label phase was 13.5 months for patients randomized to NORVIR and 14 months for patients randomized to placebo.

The cumulative incidence of clinical disease progression or death during the double-blind phase of Study 247 was 26% for patients initially randomized to NORVIR compared to 42% for patients initially randomized to placebo. This difference in rates was statistically significant (see Figure 1).

Figure 1. Time to Disease Progression or Death During the Double-blind Phase of Study 247

The cumulative mortality through the end of the open-label follow-up phase for patients enrolled in Study 247 was 18% for patients initially randomized to NORVIR compared to 26% for patients initially randomized to placebo. This difference in rates was statistically significant (see Figure 2). Since the analysis at the end of the open-label phase includes patients in the placebo arm who were switched from placebo to NORVIR therapy, the survival benefit of NORVIR cannot be precisely estimated.

Figure 2. Survival of Patients by Randomized Treatment Regimen in Study 247

Figure 3 and Figure 4 summarize the mean change from baseline for CD₄ cell count and plasma HIV RNA (copies/mL), respectively, during the first 24 weeks for the double-blind phase of Study 247.

Figure 3. Mean Change from Baseline in CD₄ Cell Count (cells/µL) During the Double-blind Phase of Study 247

Figure 4. Mean Change from Baseline in HIV RNA (log copies/mL) During the Double-blind Phase of Study 247

Patients Without Prior Antiretroviral Therapy

In Study 245, 356 antiretroviral-naive HIV-infected patients (mean baseline CD₄ = 364 cells/µL) were randomized to receive either NORVIR 600 mg twice-daily, zidovudine 200 mg three-times-daily, or a combination of these drugs. Figure 5 and Figure 6 summarize the mean change from baseline for CD₄ cell count and plasma HIV RNA (copies/mL), respectively, during the first 24 weeks for the double-blind phase of Study 245.

Figure 5. Mean Change from Baseline in CD₄ Cell Count (cells/µL) During Study 245

Figure 6. Mean Change from Baseline in HIV RNA (log copies/mL) During Study 245

DOSAGE AND ADMINISTRATION

NORVIR is administered orally. It is recommended that NORVIR be taken with meals if possible. Patients may improve the taste of NORVIR oral solution by mixing with chocolate milk, Ensure^®, or Advera^® within one hour of dosing. The effects of antacids on the absorption of ritonavir have not been studied.

Adults

Recommended Dosage

The recommended dosage of ritonavir is 600 mg twice daily by mouth. Use of a dose titration schedule may help to reduce treatment-emergent adverse events while maintaining appropriate ritonavir plasma levels. Ritonavir should be started at no less than 300 mg twice daily and increased at 2 to 3 day intervals by 100 mg twice daily.

Pediatric Patients

Ritonavir should be used in combination with other antiretroviral agents (see General Dosing Guidelines). The recommended dosage of ritonavir in children > 1 month is 350 to 400 mg/m² twice daily by mouth and should not exceed 600 mg twice daily. Ritonavir should be started at 250 mg/m² and increased at 2 to 3 day intervals by 50 mg/m² twice daily. If patients do not tolerate 400 mg/m² twice daily due to adverse events, the highest tolerated dose may be used for maintenance therapy in combination with other antiretroviral agents, however, alternative therapy should be considered. When possible, dose should be administered using a calibrated dosing syringe.

Pediatric Dosage Guidelines¹

Body Surface Area* (m2)	Twice Daily Dose 250 mg/m2	Twice Daily Dose 300 mg/m2	Twice Daily Dose 350 mg/m2	Twice Daily Dose 400 mg/m2
*   Body surface area can be calculated with the following equation:
0.20	0.6 mL (50 mg)	0.75 mL (60 mg)	0.9 mL (70 mg)	1.0 mL (80 mg)
0.25	0.8 mL (62.5 mg)	0.9 mL (75 mg)	1.1 mL (87.5 mg)	1.25 mL (100 mg)
0.50	1.6 mL (125 mg)	1.9 mL (150 mg)	2.2 mL (175 mg)	2.5 mL (200 mg)
0.75	2.3 mL (187.5 mg)	2.8 mL (225 mg)	3.3 mL (262.5 mg)	3.75 mL (300 mg)
1.00	3.1 mL (250 mg)	3.75 mL (300 mg)	4.4 mL (350 mg)	5 mL (400 mg)
1.25	3.9 mL (312.5 mg)	4.7 mL (375 mg)	5.5 mL (437.5 mg)	6.25 mL (500 mg)
1.50	4.7 mL (375 mg)	5.6 mL (450 mg)	6.6 mL (525 mg)	7.5 mL (600 mg)

General Dosing Guidelines

Patients should be aware that frequently observed adverse events, such as mild to moderate gastrointestinal disturbances and paraesthesias, may diminish as therapy is continued. In addition, patients initiating combination regimens with NORVIR and reverse transcriptase inhibitors may improve gastrointestinal tolerance by initiating NORVIR alone and subsequently adding reverse transcriptase inhibitors before completing two weeks of NORVIR monotherapy.

HOW SUPPLIED

NORVIR (ritonavir capsules) soft gelatin are white capsules imprinted with the corporate Abbott“A” logo, 100 and the Abbo-Code DS, available in the following package size:

Bottles of 120 capsules each (NDC 0074-6633-22).
Bottles of 30 capsules each (NDC 0074-6633-30).

Recommended Storage

Store soft gelatin capsules in the refrigerator between 36-46°F (2-8°C) until dispensed. Refrigeration of NORVIR soft gelatin capsules by the patient is recommended, but not required if used within 30 days and stored below 77°F (25°C). Protect from light. Avoid exposure to excessive heat.

NORVIR (ritonavir oral solution) is an orange-colored liquid, supplied in amber-colored, multi-dose bottles containing 600 mg ritonavir per 7.5 mL marked dosage cup (80 mg/mL) in the following size:

240 mL bottles (NDC 0074-1940-63).

Recommended Storage

Store NORVIR oral solution at room temperature 68°F to 77°F (20°C to 25°C). Do not refrigerate. Shake well before each use. Use by product expiration date.

Product should be stored and dispensed in the original container.

Avoid exposure to excessive heat. Keep cap tightly closed.