NORVIR

1 Dosing Considerations Patients should be aware that frequently observed adverse events, such as mild to moderate gastrointestinal disturbances and paresthesias, may diminish as therapy is continued. In addition, patients initiating combination regimens with NORVIR and other antiretroviral agents may improve gastrointestinal tolerance by initiating NORVIR alone and subsequently adding the other antiretroviral agents before completing 2 weeks of NORVIR monotherapy.

The long-term effects of dose escalation on efficacy have not been established. Dose reduction of NORVIR is necessary when used with other protease inhibitors: atazanavir, darunavir, fosamprenavir, saquinavir, and tipranavir. When NORVIR is used as a pharmacokinetic enhancer with other protease inhibitors, see the full prescribing information and clinical study information of that protease inhibitor.

2 Recommended Dose and Dosage Adjustment Adult Patients The recommended dose of NORVIR is 600 mg (6 tablets) twice daily orally and should be taken with a meal. NORVIR tablets should be swallowed whole with water and not chewed, broken, or crushed.

Some patients experience nausea upon initiation of 600 mg twice daily dosing. Use of a dose titration schedule may help to reduce treatment-emergent adverse events while maintaining appropriate ritonavir plasma levels. NORVIR should be started at no less than 300 mg twice daily and increased by 100 mg twice daily increments up to 600 mg twice daily.

The titration period should not exceed 14 days. NORVIR (ritonavir) Page 8 of 65 Pediatric Patients (2 to 16 years of age) NORVIR should be used in combination with other antiretroviral agents. 3 Reconstitution Not applicable. 4 Administration NORVIR is administered orally.

5 Missed Dose If a dose of this medication has been missed, it should be taken as soon as possible. However, if it is almost time for the next dose, skip the missed dose and go back to the regular dosing schedule. Do not double doses.

1 Adverse Reaction Overview When NORVIR is used as a pharmacokinetic enhancer with other protease inhibitors, see the full prescribing information of that protease inhibitor including Adverse Reactions. 2 Clinical Trial Adverse Reactions Clinical trials are conducted under very specific conditions.

The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful for identifying and approximating rates of adverse drug reactions in real-world use.

Adult Patients The safety of NORVIR alone and in combination with nucleoside reverse transcriptase inhibitors was studied in 1270 adult patients. Table 3 lists treatment-emergent adverse events (at least possibly related and of at least moderate intensity) that occurred in 2% or greater of adult patients receiving NORVIR alone or in combination with nucleoside reverse transcriptase inhibitors in Study M94-247 or Study M94-245 and in combination with saquinavir in Study M94-462.

In that study, 141 protease inhibitor-naïve, HIV- infected patients with mean baseline CD4 of 300 cells/microliter were randomized to 1 of 4 regimens of NORVIR + saquinavir, including NORVIR 400 mg twice daily + saquinavir 400 mg twice daily.

Overall, the most frequently reported adverse drug reactions among patients receiving NORVIR alone or in NORVIR (ritonavir) Page 15 of 65 combination with other antiretroviral drugs were gastrointestinal and neurological disturbances including diarrhea, nausea, vomiting, anorexia, abdominal pain (upper and lower), and neurological disturbances (including paresthesia and oral paresthesia), and fatigue/asthenia.

Similar adverse event profiles were reported in adult patients receiving NORVIR in other trials. 8 a. Includes those adverse events at least possibly related to study drug or of unknown relationship and excludes concurrent HIV conditions.

and 9 DRUG INTERACTIONS for co-administration of sildenafil in patients with erectile dysfunction. c. See Table 6 for parenterally administered midazolam. Oral formulation of midazolam is not marketed in Canada. d. See Table 6 for coadministration of the maintenance dose of venetoclax.

NORVIR (ritonavir) Page 7 of 65 3 SERIOUS WARNINGS AND PRECAUTIONS BOX Serious Warnings and Precautions • Pancreatitis should be considered if clinical symptoms (nausea, vomiting, abdominal pain) or abnormalities in laboratory values (such as increased serum lipase or amylase values) suggestive of pancreatitis should occur.

Patients who exhibit these signs or symptoms should be evaluated and NORVIR therapy should be discontinued if a diagnosis of pancreatitis is made (see 7 WARNINGS AND PRECAUTIONS). • Co-administration of NORVIR with certain non-sedating antihistamines, sedative hypnotics, or antiarrhythmics may result in potentially serious and/or life-threatening adverse events due to possible effects of NORVIR on the hepatic metabolism of certain drugs (see 2 CONTRAINDICATIONS and 9 DRUG INTERACTIONS).

1 Serious Drug Interactions. 1 Dosing Considerations Patients should be aware that frequently observed adverse events, such as mild to moderate gastrointestinal disturbances and paresthesias, may diminish as therapy is continued. In addition, patients initiating combination regimens with NORVIR and other antiretroviral agents may improve gastrointestinal tolerance by initiating NORVIR alone and subsequently adding the other antiretroviral agents before completing 2 weeks of NORVIR monotherapy.

The long-term effects of dose escalation on efficacy have not been established. Dose reduction of NORVIR is necessary when used with other protease inhibitors: atazanavir, darunavir, fosamprenavir, saquinavir, and tipranavir. When NORVIR is used as a pharmacokinetic enhancer with other protease inhibitors, see the full prescribing information and clinical study information of that protease inhibitor.

When NORVIR is used as a pharmacokinetic enhancer with other protease inhibitors, see the full prescribing information of that protease inhibitor including contraindication information. , toxic epidermal necrosis (TEN) or Stevens Johnson syndrome (SJS)] to NORVIR or any of its ingredients (see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING).

1 Serious Drug Interactions) because competition for primarily CYP3A by NORVIR could result in inhibition of the metabolism of these drugs and create the potential for serious and/or life-threatening reactions, such as cardiac arrhythmias, prolonged or increased sedation, and respiratory depression.

Voriconazole and St. John’s Wort are exceptions in that co-administration of NORVIR and voriconazole results in a significant reduction in plasma concentrations of voriconazole and possible loss of effect, and co-administration of NORVIR with St.

John’s Wort may lead to loss of virologic response and possible resistance to NORVIR. NORVIR (ritonavir) Page 5 of 65 Table 1 – Drugs that are Contraindicated with NORVIR Drug Class Drugs Within Class that are Contraindicated with NORVIR Clinical Comment Alpha1-Adrenoreceptor Antagonist alfuzosin Potential for serious reactions, such as hypotension (see Table 6).

Antianginal ranolazine Potential for serious and/or life-threatening reactions. Antiarrhythmics amiodarone, bepridila, dronedarone, flecainide, propafenone, quinidine Potential for serious and/or life-threatening reactions, such as cardiac arrhythmias.

Antibiotic fusidic acid Potential of increased fusidic acid-associated adverse events, such as hepatitis or bone marrow suppression. Anticancer apalutamide Apalutamide is a moderate to strong CYP3A4 inducer and this may lead to a decreased exposure of NORVIR and potential loss of virologic response.