Auro-Ritonavir Product Monograph

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TABLE OF CONTENTS

Sections or subsections that are not applicable at the time of authorization are not listed.

RECENT MAJOR LABEL CHANGES ........................................................................................ 2

TABLE OF CONTENTS ........................................................................................................... 2

Part 1: Health Professional Information ................................................................................. 4

1 Indications ................................................................................................................. 4

1.1 Pediatrics ....................................................................................................................... 4

1.2 Geriatrics ....................................................................................................................... 4

2 Contraindications ....................................................................................................... 4

3 Serious Warnings and Precautions Box ....................................................................... 6

4 Dosage and Administration ........................................................................................ 7

4.1 Dosing Considerations ............................................................................................ 7

4.2 Recommended Dose and Dosage Adjustment ....................................................... 7

4.3 Reconstitution ......................................................................................................... 8

4.4 Administration ........................................................................................................ 8

4.5 Missed Dose ............................................................................................................ 8

5 Overdosage ................................................................................................................ 8

6 Dosage forms, Strengths, Composition and Packaging ................................................ 8

7 Warnings and Precautions .......................................................................................... 9

7.1 Special Populations ............................................................................................... 13

7.1.1 Pregnant Women .................................................................................................. 13

7.1.2 Breast-feeding ....................................................................................................... 14

7.1.3 Pediatrics ............................................................................................................... 14

7.1.4 Geriatrics ............................................................................................................... 14

8 Adverse Reactions .................................................................................................... 14

8.1 Adverse Reaction Overview .................................................................................. 14

8.2 Clinical Trial Adverse Reactions ............................................................................ 14

8.2.1 Clinical Trial Adverse Reactions – Pediatrics......................................................... 18

8.3 Less Common Clinical Trial Adverse Reactions ..................................................... 18

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data Clinical Trial Findings ............................................................... 20

8.5 Post-Market Adverse Reactions .................................................................................. 21

9 Drug Interactions ..................................................................................................... 22

9.1 Serious Drug Interactions ..................................................................................... 22

9.2 Drug Interactions Overview .................................................................................. 22

9.3 Drug-Behavioural Interactions .............................................................................. 23

9.4 Drug-Drug Interactions ......................................................................................... 23

9.5 Drug-Food Interactions ......................................................................................... 41

9.6 Drug-Herb Interactions ......................................................................................... 41

9.7 Drug-Laboratory Test Interactions........................................................................ 42

10 Clinical Pharmacology .............................................................................................. 42

10.1 Mechanism of Action ............................................................................................ 42

10.2 Pharmacodynamics ............................................................................................... 42

10.3 Pharmacokinetics .................................................................................................. 42

11 Storage, Stability and Disposal .................................................................................. 45

12 Special Handaling Instructions .................................................................................. 45

Part 2: Scientific Information ............................................................................................... 46

13 Pharmaceutical Information ..................................................................................... 46

14 Clinical Trails ................................................................................................................... 47

14.1 Trial Design and Study Demographics ................................................................... 47

14.2 Study Results ......................................................................................................... 48

14.3 Comparative Bioavailability Studies ...................................................................... 49

15 Microbiology ............................................................................................................ 51

16 Non-Clinical Toxicology ............................................................................................ 52

17 Supporting Product Monographs .................................................................................... 56

Patient Medication Information .......................................................................................... 57

Part 1: Health Professional Information

1 Indications

Auro-Ritonavir (ritonavir) is indicated in combination with other antiretroviral agents for the treatment of HIV infection when therapy is warranted.

1.1 Pediatrics

Pediatrics (2 to 16 years of age): Ritonavir concentrations obtained after 350 to 400 mg/m² twice daily in pediatric patients were comparable to those obtained in adults receiving 600 mg (approximately 330 mg/m²) twice daily (see 10.3 Pharmacokinetics). The safety and effectiveness of Auro-Ritonavir in pediatric patients below the age of 2 years have not been established.

1.2 Geriatrics

Geriatrics (> 65 years of age): Clinical studies of ritonavir did not include sufficient numbers of subjects age 65 and over to determine whether they respond differently from younger subjects. In general, appropriate caution should be exercised in the administration and monitoring of Auro-Ritonavir in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

2 Contraindications

When Auro-Ritonavir is used as a pharmacokinetic enhancer with other protease inhibitors, see the full prescribing information of that protease inhibitor including contraindication information.

Auro-Ritonavir is contraindicated in patients with known hypersensitivity [e.g., toxic epidermal necrosis (TEN) or Stevens Johnson syndrome (SJS)] to ritonavir or any of its ingredients (see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING).

Co-administration of Auro-Ritonavir is contraindicated with the drugs listed in Table 1 (see also 9.1 Serious Drug Interactions) because competition for primarily CYP3A by ritonavir 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 ritonavir and voriconazole results in a significant reduction in plasma concentrations of voriconazole and possible loss of effect, and co-administration of ritonavir with St. John’s Wort may lead to loss of virologic response and possible resistance to ritonavir.

Table 1 – Drugs that are Contraindicated with Auro-Ritonavir

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 Auro-Ritonavir therapy should be discontinued if a diagnosis of pancreatitis is made (see 7 WARNINGS AND PRECAUTIONS).
• Co-administration of ritonavir 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 ritonavir on the hepatic metabolism of certain drugs (see 2 CONTRAINDICATIONS and 9 DRUG INTERACTIONS).
• See 9.1 Serious Drug Interactions.

4 Dosage and Administration

4.1 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 ritonavir and other antiretroviral agents may improve gastrointestinal tolerance by initiating Auro-Ritonavir alone and subsequently adding the other antiretroviral agents before completing 2 weeks of Auro-Ritonavir monotherapy. The long-term effects of dose escalation on efficacy have not been established.

Dose reduction of Auro-Ritonavir is necessary when used with other protease inhibitors: atazanavir, darunavir, fosamprenavir, saquinavir, and tipranavir.

When Auro-Ritonavir is used as a pharmacokinetic enhancer with other protease inhibitors, see the full prescribing information and clinical study information of that protease inhibitor.

4.2 Recommended Dose and Dosage Adjustment

Adult Patients

The recommended dose of Auro-Ritonavir is 600 mg (6 tablets) twice daily orally and should be taken with a meal.

Auro-Ritonavir 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. Auro-Ritonavir 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.

Pediatric Patients (2 to 16 years of age)

Auro-Ritonavir should be used in combination with other antiretroviral agents.

4.3 Reconstitution

Not applicable.

4.4 Administration

Auro-Ritonavir is administered orally.

4.5 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.

5 Overdosage

Acute Overdosage

Human Overdose Experience

Human experience of acute overdose with ritonavir is limited. One patient in clinical trials took ritonavir 1500 mg/day for 2 days. The patient reported paresthesias which resolved after the dose was decreased.

A post-marketing case of renal failure with eosinophilia has been reported with ritonavir overdose.

Management of Overdosage

Administration of activated charcoal may be used to aid in removal of unabsorbed drug. Treatment of overdose with Auro-Ritonavir consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. There is no specific antidote for overdose with Auro-Ritonavir. Since ritonavir is extensively metabolized by the liver and is highly protein-bound, dialysis is unlikely to be beneficial in significant removal of the drug.

For the most recent information in the management of a suspected drug overdose, contact your regional poison control centre or Health Canada’s toll-free number, 1-844 POISON-X (1-844-764- 7669).

6 Dosage forms, Strengths, Composition and Packaging

Table 2 - Dosage Forms, Strengths, Composition and Packaging

Auro-Ritonavir is available as 100 mg film-coated tablets.

Auro-Ritonavir tablets are White to off-white, film-coated, ovaloid tablets, debossed with ‘I’ on one side and ‘100’ on other side. Available in HDPE bottles of 30, 60 and 90 Tablets and Blister Pack of 8x10's

7 Warnings and Precautions

Please see 3 WARNINGS AND PRECAUTIONS BOX.

Drug-Drug Interactions

When Auro-Ritonavir is used as a pharmacokinetic enhancer with other protease inhibitors, see the full prescribing information of that protease inhibitor including Warning and Precautions.

Ritonavir is an inhibitor of cytochrome P450 3A (CYP3A) both in vitro and in vivo. Ritonavir also inhibits CYP2D6 in vitro, but to a lesser extent than CYP3A.

Initiation of Auro-Ritonavir, a CYP3A inhibitor, in patients receiving medications metabolized by CYP3A or initiation of medications metabolized by CYP3A in patients already receiving Auro-Ritonavir, may increase plasma concentrations of medications metabolized by CYP3A. Initiation of medications that inhibit or induce CYP3A may increase or decrease concentrations of Auro-Ritonavir, respectively. These interactions may lead to:

• Clinically significant adverse reactions, potentially leading to severe, life-threatening, or fatal events from greater exposures of concomitant medications.
• Clinically significant adverse reactions from greater exposures of ritonavir.
• Loss of therapeutic effect of ritonavir and possible development of resistance.

Due to inhibition of CYP3A by ritonavir, co-administration of ritonavir with quetiapine may result in increased quetiapine concentrations. Serious and life-threatening quetiapine-related adverse reactions have been reported with CYP3A inhibitors. Auro-Ritonavir should not be used in combination with quetiapine. Monitoring and dose reduction may be required if necessary (see Table 6).

See Table 6 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations (see 9 DRUG INTERACTIONS). Consider the potential for drug interactions prior to and during Auro-Ritonavir therapy; review concomitant medications during Auro-Ritonavir therapy, and monitor for the adverse reactions associated with the concomitant medications (see 2 CONTRAINDICATIONS and 9 DRUG INTERACTIONS).

Allergic Reactions

Allergic reactions including urticaria, skin eruptions, bronchospasm, and angioedema have been reported. Rare cases of anaphylaxis, toxic epidermal necrosis (TEN) and Stevens-Johnson syndrome (SJS) have also been reported. Discontinue treatment if these reactions occur.

Organ Targets for Toxicity

Toxicological studies in laboratory animals identified various organs as targets for toxicity at drug exposures below or approaching those achieved in patients participating in clinical trials with ritonavir. Because no safety margin or a small safety margin has been demonstrated in long-term studies, these organs should be assessed periodically or if clinical signs and symptoms occur during therapy (see 16 NON-CLINICAL TOXICOLOGY).

Carcinogenesis and Mutagenesis

For a brief discussion of pre-clinical carcinogenicity data, see 16 NON-CLINICAL TOXICOLOGY. No evidence of mutagenic or clastogenic activity have been reported in a battery of in vitro and in vivo assays.

Cardiovascular

PR Interval Prolongation

Ritonavir has been shown to cause asymptomatic prolongation of the PR interval in some patients.

Post-marketing reports of second or third degree atrioventricular block have been reported in patients with underlying structural heart disease and pre-existing conduction system abnormalities, ischemic heart disease, cardiomyopathies, as these patients may be at increased risk of cardiac conduction abnormalities, or in patients receiving drugs known to prolong the PR interval (such as calcium channel blockers, beta-adrenergic blockers, digoxin, verapamil or atazanavir).

Co-administration of ritonavir with these drugs should be undertaken with caution, particularly with drugs metabolized by CYP3A4 (see 10.2 Pharmacodynamics). Clinical monitoring is recommended (see 9 DRUG INTERACTIONS).

Endocrine and Metabolism

Diabetes Mellitus/Hyperglycemia

Levels of blood glucose may increase during antiretroviral therapy. Such changes may in part be linked to the treatment per se (e.g., protease inhibitors), and in part to disease control and lifestyle. New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus and hyperglycemia have been reported during post-marketing surveillance in HIV-infected patients receiving protease inhibitor therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases diabetic ketoacidosis has occurred. In those patients who discontinued protease inhibitor therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and a causal relationship between protease inhibitor therapy and these events has not been established. For monitoring of blood glucose, reference is made to established HIV treatment guidelines. Glucose elevations should be managed as clinically appropriate (see 7 WARNINGS AND PRECAUTIONS).

Lipid Disorders

Levels of blood lipids may increase during antiretroviral therapy. Such changes may in part be linked to the treatment per se (e.g., protease inhibitors), and in part to disease control and lifestyle (see Table 5).

Triglycerides and cholesterol testing should be performed prior to initiating ritonavir therapy and at periodic intervals during therapy (see 7 WARNINGS AND PRECAUTIONS). For monitoring of blood lipids, reference is made to established HIV treatment guidelines. Lipid disorders should be managed as clinically appropriate.

Hematologic

There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis, in patients with hemophilia type A and type B treated with protease inhibitors. In some patients, additional Factor VIII was given. In more than half of the reported cases, treatment with protease inhibitors was continued or re-introduced. There is no proven relationship between protease inhibitors and such bleeding; however, the frequency of bleeding episodes should be closely monitored in patients on ritonavir.

Hepatic/Biliary/Pancreatic

Impaired Hepatic Function

Ritonavir is principally metabolized by the liver. Pre-clinical studies have identified the liver as a toxicity target (see 16 NON-CLINICAL TOXICOLOGY). Therefore, appropriate tests should be performed at treatment initiation and at periodic intervals to assess hepatic function.

Caution should be exercised when administering Auro-Ritonavir to patients with impaired hepatic function.

Hepatic Reactions

Hepatic transaminase elevations exceeding 5 times the upper limit of normal, clinical hepatitis, and jaundice have occurred in patients receiving ritonavir alone or in combination with other antiretroviral drugs (see Table 5). There may be an increased risk for transaminase elevations in patients with underlying hepatitis B or C. Therefore, caution should be exercised when administering

Auro-Ritonavir to patients with pre-existing liver disease, liver enzyme abnormalities, or hepatitis. Liver enzyme elevations should be monitored as clinically appropriate (see 7 WARNINGS AND PRECAUTIONS).

There have been post-marketing reports of hepatic dysfunction, including some fatalities. These have generally occurred in patients taking multiple concomitant medications and/or with advanced AIDS.

Pancreatitis

Pancreatitis has been observed in patients receiving ritonavir therapy, including those who developed hypertriglyceridemia. In some cases fatalities have been observed. Patients with advanced HIV disease may be at increased risk of elevated triglycerides and pancreatitis.

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 Auro-Ritonavir therapy should be discontinued if a diagnosis of pancreatitis is made.

Immune

Immune Reconstitution Inflammatory Syndrome

Immune reconstitution inflammatory syndrome has been reported in HIV-infected patients treated with combination antiretroviral therapy, including ritonavir. During the initial phase of treatment, patients responding to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia, or tuberculosis), which may necessitate further evaluation and treatment.

Autoimmune disorders (such as Graves’ disease, polymyositis, Guillain-Barré syndrome, and autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution, however, the time to onset is more variable, and can occur many months after initiation of treatment.

Monitoring and Laboratory Tests

Ritonavir has been associated with elevations in cholesterol, triglycerides, SGOT (AST), SGPT (ALT), GGT, CK, and uric acid. Appropriate laboratory testing should be performed prior to initiating ritonavir therapy and at periodic intervals or if any clinical signs or symptoms occur during therapy. For monitoring of liver enzymes, blood lipids, and glucose refer to established HIV treatment guidelines. For comprehensive information concerning laboratory test alterations associated with other antiretroviral agents, physicians should refer to the complete product information for each of these drugs.

Neurologic

Central nervous system (CNS) penetration of ritonavir has not been established.

Sensitivity/Resistance

Resistance

Mutations associated with the HIV viral protease in isolates obtained from 41 patients appeared to occur in a stepwise and ordered fashion.

The clinical relevance of phenotypic and genotypic changes associated with ritonavir therapy has not been established (see 15 MICROBIOLOGY).

Cross-Resistance

Serial HIV isolates obtained from 6 patients during ritonavir therapy showed a decrease in ritonavir susceptibility in vitro to indinavir (8-fold), nelfinavir (12- to 14-fold), and none to amprenavir. One zidovudine (ZDV)-resistant HIV isolate tested in vitro retained full susceptibility to ritonavir (see 15 MICROBIOLOGY).

7.2 Special Populations

7.2.1 Pregnant Women

There are no adequate and well-controlled studies in pregnant women. Prospective pregnancy data from the Antiretroviral Pregnancy Registry (APR) are not sufficient to adequately assess the risk of birth defects or miscarriage. Based on approximately 6100 live births following exposure to ritonavir- containing regimens (including over 2800 live births exposed in the first trimester and over 3200 live births exposed in the second and third trimesters) in the APR, there was no difference in the rate of overall birth defects for ritonavir compared with the background birth defect rate of 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). The prevalence of birth defects in live births was 2.3% (95% CI: 1.7% to 2.9%) following first-trimester exposure to ritonavir-containing regimens and 2.9% (95% CI: 2.3% to 3.5%) following second and third trimester exposure to ritonavir-containing regimens. The prevalence of birth defects after any trimester exposure to ritonavir is comparable to the prevalence observed in the general population.

Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

In rat fertility studies, hepatic toxicity precluded drug exposures equal to those achieved with the proposed human therapeutic dose. No effects on fertility in rats were produced at drug exposures approximately 40% (male) and 60% (female) of that achieved with the proposed human therapeutic dose.

No treatment-related malformations were observed when ritonavir was administered to pregnant rats or rabbits. Developmental toxicity observed in rats (early resorptions, decreased fetal body weight and ossification delays and developmental variations) occurred at a maternally toxic dosage at an exposure equivalent to approximately 30% of that achieved with the proposed therapeutic dose. A slight increase in the incidence of cryptorchidism was also noted in rats at an exposure approximately 22% of that achieved with the proposed therapeutic dose.

Developmental toxicity observed in rabbits (resorptions, decreased litter size and decreased fetal weights) also occurred at a maternally toxic dosage equivalent to 1.8 times the proposed therapeutic dose based on a body surface area conversion factor.

Antiretroviral Pregnancy Registry

To monitor maternal-fetal outcomes of pregnant women exposed to Auro-Ritonavir, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.

7.2.2 Breast-feeding

HIV-infected mothers should not breast-feed their infants to avoid risking postnatal transmission of HIV. Limited published data reports that ritonavir is present in human milk. There is no information on the effects of ritonavir on the breast-fed infant or the effects of the drug on milk production. Because of the potential for (1) HIV transmission (in HIV-negative infants), (2) developing viral resistance (in HIV- positive infants) and (3) serious adverse reactions in a breast-fed infant, instruct mothers not to breast- feed if they are receiving Auro-Ritonavir.

7.2.3 Pediatrics

Pediatrics (2 to 16 years of age): The safety and effectiveness of ritonavir in pediatric patients below the age of 2 years have not been established. Although the database in HIV-infected patients age 2 to 16 years is much smaller, the adverse event profile seen during a clinical trial and post-marketing experience was similar to that observed for adult patients.

7.2.4 Geriatrics

Geriatrics (> 65 years of age): Clinical studies of ritonavir did not include sufficient numbers of subjects age 65 and over to determine whether they respond differently from younger subjects. In general, appropriate caution should be exercised in the administration and monitoring of ritonavir in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

8 Adverse Reactions

8.2 Adverse Reaction Overview

When ritonavir is used as a pharmacokinetic enhancer with other protease inhibitors, see the full prescribing information of that protease inhibitor including Adverse Reactions.

8.3 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 ritonavir 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 ritonavir 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 ritonavir + saquinavir, including ritonavir 400 mg twice daily + saquinavir 400 mg twice daily. Overall, the most frequently reported adverse drug reactions among patients receiving ritonavir alone or in 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 ritonavir in other trials.

Table 3 - Percentage of Patients with Treatment-Emergent Adverse Events^a of Moderate or Severe Intensity Occurring in ≥ 2% of Adult Patients Receiving Ritonavir

Other Common Clinical Trial Adverse Drug Reactions

Table 4 includes other treatment-emergent adverse reactions (with possible or probable relationship to study drug) occurring in ≥ 1% of adult patients receiving ritonavir derived from cumulative data from combined Phase 2 to 4 studies.

Table 4 - Treatment-Emergent Adverse Reactions (With Possible or Probable Relationship to Study Drug) Occurring in ≥ 1% of Adult Patients Receiving ritonavir in Combined Phase 2 to 4 Studies (N = 1,755)

Adverse Reactions

8.3.1 Clinical Trial Adverse Reactions – Pediatrics

The safety and pharmacokinetic profiles of ritonavir in pediatric patients below the age of 2 have not been studied. Although the database in HIV-infected patients age 2 to 16 years is much smaller, the adverse event profile seen during a clinical trial and post-marketing experience was similar to that observed for adult patients.

8.4 Less Common Clinical Trial Adverse Reactions

Adverse events occurring in less than 2% of adult patients receiving ritonavir in all Phase 2/Phase 3 studies and considered at least possibly related or of unknown relationship to treatment and of at least moderate intensity are listed below by body system.

8.5 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data Clinical Trial Findings

Table 5 shows the percentage of adult patients who developed marked laboratory abnormalities.

Table 5 - Percentage of Adult Patients, by Study and Treatment Group, with Chemistry and

Hematology Abnormalities Occurring in ≥ 2% of Patients Receiving ritonavir

8.5 Post-Market Adverse Reactions

The following adverse events have been reported during post-marketing use of ritonavir. Because these reactions are reported voluntarily from a population of unknown size, it is not possible to reliably estimate their frequency or establish a causal relationship to ritonavir exposure.

9 Drug Interactions

9.2 Serious Drug Interactions

Serious Drug Interactions

• Co-administration (saquinavir/ ritonavir): The recommended dose of Auro-Ritonavir is 100 mg twice daily when used with saquinavir. Higher doses of ritonavir when given with saquinavir have been associated with severe adverse events mainly diabetic ketoacidosis and liver disorders, especially in patients with pre-existing liver disease
• Co-administration (saquinavir/rifampin/ ritonavir): Saquinavir/ Ritonavir should not be given together with rifampin, due to the risk of severe hepatotoxicity (presenting as increased hepatic transaminases) if the 3 drugs are given together.
• Co-administration (tipranavir/ ritonavir): Tipranavir co-administered with 200 mg of ritonavir has been associated with reports of clinical hepatitis and hepatic decompensation including some fatalities. Extra vigilance is warranted in patients with chronic hepatitis B or hepatitis C co-infection, as these patients have an increased risk of hepatotoxicity

9.3 Drug Interactions Overview

When Auro-Ritonavir is used as a pharmacokinetic enhancer with other protease inhibitors, see the full prescribing information of that protease inhibitor including information on drug interactions.

These examples are a guide and not considered a comprehensive list of all possible drugs that may interact with ritonavir. The healthcare provider should consult appropriate references for comprehensive information.

Potential for Ritonavir to Affect Other Drugs

Ritonavir is an inhibitor of cytochrome P450 3A (CYP3A) and may increase plasma concentrations of agents that are primarily metabolized by CYP3A. Agents that are extensively metabolized by CYP3A and have high first pass metabolism appear to be the most susceptible to large increases in AUC (> 3-fold) when co-administered with ritonavir. Thus, co-administration of ritonavir with drugs highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated. Co-administration with other CYP3A substrates may require a dose adjustment or additional monitoring as shown in Table 6.

Ritonavir also inhibits CYP2D6 to a lesser extent. Co-administration of substrates of CYP2D6 with ritonavir could result in increases (up to 2-fold) in the AUC of the other agent, possibly requiring a proportional dosage reduction. Ritonavir also appears to induce CYP3A, CYP1A2, CYP2C9, CYP2C19, and CYP2B6 as well as other enzymes, including glucuronosyl transferase. Therefore, decreased plasma concentrations of the co-administered drugs and potential loss of therapeutic effects may signify the need for dosage alteration of these agents.

When co-administering Auro-Ritonavir with any agent having a narrow therapeutic margin, such as anticoagulants, anticonvulsants, and antiarrhythmics, special attention is warranted.

Potential for Other Drugs to Affect Ritonavir

Agents which increase CYP3A activity (e.g., phenobarbital, carbamazepine, dexamethasone, phenytoin, rifampin, and rifabutin) would be expected to increase the clearance of ritonavir resulting in decreased ritonavir plasma concentrations. Tobacco use is associated with an 18% decrease in the area under the concentration-time curve (AUC) of ritonavir.

9.4 Drug-Behavioural Interactions

Not applicable.

9.5 Drug-Drug Interactions

Table 6 lists the established and other potentially significant drug interactions. Alteration in dose or regimen may be recommended based on drug interaction studies or predicted interaction (see also 2 CONTRAINDICATIONS and Table 7 and Table 8 for magnitude of interaction).

The drugs listed in this table are based on either drug interaction case reports or studies, or potential interactions due to the expected magnitude and seriousness of the interaction (i.e., those identified as contraindicated).

Table 6 - Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen Recommended Based on Drug Interaction Studies or Predicted Interaction

Assessment of Drug Interactions

For details regarding the ritonavir pharmacokinetics refer to section (10.3 Pharmacokinetics).

The effects of co-administration of ritonavir on the AUC, C_max, and C_min are summarized in Table 7 and Table 8.

Table 7 - Drug Interactions: Pharmacokinetic Parameters for Ritonavir in the Presence of the Co-administered Drug (See Table 6 for Recommended Alterations in Dose or Regimen)

Table 8 - Drug Interactions: Pharmacokinetic Parameters for Co-administered Drug in the Presence of ritonavir (See Table 6 for Recommended Alterations in Dose or Regimen)

9.5 Drug-Food Interactions

It is recommended that ritonavir be taken with meals, if possible. Refer to 10.3 Pharmacokinetics and to 14 CLINICAL TRIALS for information on the effect of food on ritonavir pharmacokinetics.

9.6 Drug-Herb Interactions

Concomitant use of ritonavir and St. John’s wort (Hypericum perforatum) or products containing St. John’s wort is contraindicated. Co-administration of protease inhibitors, including ritonavir, with St.

John’s wort is expected to substantially decrease protease inhibitor concentrations and may result in sub-optimal levels of ritonavir and lead to loss of virologic response and possible resistance to ritonavir or to the class of protease inhibitors (see 2 CONTRAINDICATIONS).

9.7 Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.

10 Clinical Pharmacology

10.1 Mechanism of Action

Ritonavir is an inhibitor of HIV protease with activity against the Human Immunodeficiency Virus (HIV).

Ritonavir is an orally active peptidomimetic inhibitor of both the HIV-1 and HIV-2 proteases. Inhibition of HIV protease renders the enzyme incapable of processing the gag-pol polyprotein precursor which leads to the production of HIV particles with immature morphology that are unable to initiate new rounds of infection. Ritonavir has selective affinity for the HIV protease and has little inhibitory activity against human aspartyl proteases.

10.2 Pharmacodynamics

In vitro data indicate that ritonavir is active against all strains of HIV tested in a variety of transformed and primary human cell lines. The concentration of drug that inhibits 50% and 90% (EC₅₀, EC₉₀) of viral replication is approximately 0.02 and 0.11 microM, respectively. Studies which measured direct cell toxicity of ritonavir on several cell lines showed no direct toxicity at concentrations up to 25 microM, with a resulting in vitro therapeutic index of at least 1000.

Effects on the Electrocardiogram

A Phase 1, multiple-dose, open-label, placebo and active controlled (moxifloxacin 400 mg once daily), randomized crossover study was conducted in healthy volunteers. NORVIR was dosed at 400 mg twice daily and on Day 3, ritonavir concentrations were approximately 1.5 fold higher than that observed with the 600 mg twice daily dose at steady state. At these increased concentrations, the maximum increase in QTcF was 5.5 msec. This increase is not clinically significant. No subject experienced an increase in QTcF of ≥ 60 msec from baseline or a QTcF interval exceeding the potentially clinically relevant threshold of 500 msec. Maximum PR interval was 252 msec and no second or third degree heart block was observed. Exposure-response analysis predicted that the PR effect of ritonavir plateaus around 20 msec, thus ritonavir 600 mg twice daily is unlikely to result in clinically significant PR prolongation (see 7 WARNINGS AND PRECAUTIONS).

10.3 Pharmacokinetics

The pharmacokinetics of ritonavir have been studied in healthy volunteers and HIV-infected patients (CD₄ ≥ 50 cells/microliter). See Table 9 for ritonavir pharmacokinetic characteristics.

Table 9 - Ritonavir Pharmacokinetic Characteristics

Absorption

Ritonavir tablets are not bioequivalent to ritonavir capsules. Under moderate fat conditions (857 kcal; 31% fat, 13% protein, 56% carbohydrates), when a single 100 mg ritonavir dose was administered as a tablet compared with a capsule, AUC_(0-∞) met equivalence criteria but mean C_max was increased by 26% (92.8% confidence intervals: +15 to +39%).

Effect of Food on Oral Absorption

A food effect is observed for ritonavir tablets. Food decreased the bioavailability of the ritonavir tablets when a single 100 mg dose of ritonavir was administered. Under high fat conditions (907 kcal; 52% fat, 15% protein, 33% carbohydrates), a 23% decrease in mean AUC_(0-∞) [90% confidence intervals: -30 to -15%], and a 23% decrease in mean C_max [90% confidence intervals: -34 to -11%] was observed relative to fasting conditions. Under moderate fat conditions, a 21% decrease in mean AUC_(0-∞) [90% confidence intervals: -28 to -13%], and a 22% decrease in mean C_max [90% confidence intervals: -33 to -9%] was observed relative to fasting conditions.

However, the type of meal administered did not change ritonavir tablet bioavailability when high fat was compared to moderate fat meals.

Distribution

The protein binding of ritonavir in human plasma was noted to be approximately 98 to 99%. Ritonavir binds to both human α-1-acid glycoprotein (AAG) and human serum albumin (HSA) with comparable affinities. Total plasma protein binding is constant over the concentration range of 1 to 100 mcg/mL.

Tissue distribution studies with ¹⁴C-labeled ritonavir in rats showed the liver, adrenals, pancreas, kidneys and thyroid to have the highest concentrations of drug. Tissue to plasma ratios of approximately one, measured in rat lymph nodes, suggest that ritonavir distributes into lymphatic tissue. Ritonavir penetrates minimally into the brain.

Metabolism

Nearly all of the plasma radioactivity after a single oral 600 mg dose of ¹⁴C-ritonavir oral solution (n = 5) was attributed to unchanged ritonavir. Five ritonavir metabolites have been identified in human urine and feces. The isopropyl thiazole oxidation metabolite (M-2) is the major metabolite and has antiviral activity similar to that of parent drug; however, the concentrations of this metabolite in plasma are low. Studies utilizing human liver microsomes have demonstrated that cytochrome P450 3A (CYP3A) is the major isoform involved in ritonavir metabolism, although CYP2D6 also contributes to the formation of

M-2.

Elimination

In a study of 5 subjects receiving a 600 mg dose of ¹⁴C-ritonavir oral solution, 11.3 ± 2.8% of the dose was excreted into the urine, with 3.5 ± 1.8% of the dose excreted as unchanged parent drug. In that study, 86.4 ± 2.9% of the dose was excreted in the feces with 33.8 ± 10.8% of the dose excreted as unchanged parent drug. Upon multiple dosing, ritonavir accumulation is less than predicted from a single dose possibly due to a time and dose-related increase in clearance.

Special Populations and Conditions

• Pediatrics

  The pharmacokinetic profile of ritonavir in pediatric patients below the age of 2 years has not been established. Steady-state pharmacokinetics were evaluated in 37 HIV-infected patients ages 2 to 14 years receiving doses ranging from 250 mg/m² twice daily to 400 mg/m² twice daily. Across dose groups, ritonavir steady-state oral clearance (CL/F/m²) was approximately 1.5 times faster in pediatric patients than in adult subjects. Ritonavir concentrations obtained after 350 to 400 mg/m² twice daily in pediatric patients were comparable to those obtained in adults receiving 600 mg (approximately 330 mg/m²) twice daily.

• Geriatrics

  No age-related pharmacokinetic differences have been observed in adult patients (18 to 63 years). Ritonavir pharmacokinetics have not been studied in older patients.

• Sex

  A study of ritonavir pharmacokinetics in healthy males and females showed no statistically significant differences in the pharmacokinetics of ritonavir.

• Ethnic origin

  Pharmacokinetic differences due to race have not been identified.

• Hepatic Insufficiency

  In 6 HIV-infected adult subjects with mild hepatic insufficiency dosed with ritonavir 400 mg twice daily, ritonavir exposures were similar to control subjects dosed with 500 mg twice daily. Results indicate that dose adjustment is not required in patients with mild hepatic impairment.

  Adequate pharmacokinetic data are not available for patients with moderate hepatic impairment. Protein binding of ritonavir was not statistically significantly affected by mildly or moderately impaired hepatic function.

• 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.

  Because ritonavir is highly protein bound it is unlikely that it will be significantly removed by dialysis (see 5 OVERDOSAGE).

• Obesity

  Ritonavir pharmacokinetic parameters were not statistically significantly associated with body weight or lean body mass.

11 Storage, Stability and Disposal

Temperature:

Store between 15°C to 30°C. Dispense in original container, exposure of the product to high humidity outside the original tight container is not recommended.

Others:

Keep out of reach and sight of children.

12 Special Handling Instructions

Not applicable.

Part 2: Scientific Information

13 Pharmaceutical Information

Drug Substance

Proper name: Ritonavir

Chemical name: Thiazol-5-ylmethyl [1S,2S,4S)-1-benzyl-2-hydroxy-4-[[(2S)-3-methyl-2-[[methyl[[2-(1-methylethyl)thiazol-4-yl]methyl]carbamoyl]amino] butanoyl]amino]-5-phenylpentyl]carbamate

Molecular form ula: C₃₇H₄₈N₆O₅S₂

Molecular mass: 721 g/mol

Structural formula:

Physicochemical properties: White or almost white powder

Solubility: Freely soluble in methanol and in methylene chloride, very slightly soluble in acetonitrile, practically insoluble in water

14 Clinical Trails

14.1 Trial Design and Study Demographics

The activity of ritonavir (ritonavir) as monotherapy or in combination with nucleoside reverse transcriptase inhibitors has been evaluated in 1446 patients enrolled in 2 double-blind, randomized trials. Ritonavir therapy in combination with zidovudine and zalcitabine was also evaluated in an open- label, non-comparative study of 32 patients.

Table 10 - Summary of Patient Demographics for Clinical Trials in Specific Indication

14.2 Study Results

Advanced Patients with Prior Antiretroviral Therapy

Study M94-247 was a randomized, double-blind trial conducted in HIV-infected patients with at least 9 months of prior antiretroviral therapy and baseline CD₄ cells counts ≤ 100 cells/microliter. Ritonavir 600 mg twice daily or placebo was added to each patient's baseline antiretroviral therapy regimen, which could have consisted of up to 2 approved antiretroviral agents. The study accrued 1090 patients, with mean baseline CD₄ cell count at study entry of 32 cells/microliter. Median duration of follow-up was 6 months.

The 6-month cumulative incidence of clinical disease progression or death was 17% for patients randomized to ritonavir compared to 34% for patients randomized to placebo. This difference in rates was statistically significant.

The 6-month cumulative mortality was 5.8% for patients randomized to ritonavir and 10.1% for patients randomized to placebo. This difference in rates was statistically significant.

In addition, analyses of mean CD₄ cell count changes from baseline over the first 16 weeks of study for the first 211 patients enrolled (mean baseline CD4 cell count = 29 cells/microliter) showed that ritonavir was associated with larger increases in CD₄ cell counts than was placebo. Compared to placebo, ritonavir also produced a greater mean decrease in HIV RNA levels from baseline.

Patients Without Prior Antiretroviral Therapy

In Study M94-245, 356 antiretroviral-naïve HIV-infected patients (mean baseline CD₄ = 364 cells/microliter) were randomized to receive either ritonavir 600 mg twice daily, zidovudine 200 mg three times daily, or a combination of these drugs. In analyses of average CD₄ cell count changes from baseline over the first 16 weeks of study, both ritonavir monotherapy and combination therapy produced greater mean increases in CD₄ cell count than did zidovudine monotherapy. The CD₄ cell count increases for ritonavir monotherapy were larger than the increases for combination therapy. Similarly, the mean decreases in HIV RNA level from baseline were larger with ritonavir monotherapy than with combination therapy or zidovudine monotherapy.

Combination Therapy with ritonavir, Zidovudine, and Zalcitabine in Antiretroviral-Naïve Patients

In Study M94-208, an open-label uncontrolled trial, 32 antiretroviral- naïve HIV-infected patients initially received ritonavir 600 mg twice daily monotherapy. Zidovudine 200 mg three times daily and zalcitabine 0.75 mg three times daily were added after 14 days of ritonavir monotherapy. Results of combination therapy for the first 20 weeks of this study show median increases in CD₄ cell counts from baseline levels of 83 to 106 cells/microliter over the treatment period. Mean decreases from baseline in HIV RNA particle levels ranged from 1.69 to 1.92 logs.

14.3 Comparative Bioavailability Studies

Fasting Study

A double blinded, randomized, two-treatment, two-sequence, two-period, crossover, single dose oral bioequivalence study of Auro-Ritonavir tablets, 100 mg (Auro Pharma Inc.) versus ^PrNorvir^® tablets, 100 mg (AbbVie Corporation) was conducted in 48 healthy, adult, human subjects under fasting conditions. A summary of the bioavailability data of 46 subjects who completed the study is presented in the following table.

SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA

¹Auro-Ritonavir (Ritonavir) Tablets, 100 mg (Auro Pharma Inc.).

^{2 Pr}Norvir^® (Ritonavir) Tablets, 100 mg (AbbVie Corporation) were purchased from Canada.

³ Expressed as the median (range) only.

⁴ Expressed as arithmetic mean (% CV) only

Fed Study

A double blinded, randomized, two-treatment, two-sequence, two-period, cross-over, single-dose, oral bioequivalence study of Auro-Ritonavir tablets, 100 mg (Auro Pharma Inc.) versus ^PrNorvir^® tablets, 100 mg (AbbVie Corporation) was conducted in 54 healthy, adult, human subjects under fed conditions. A summary of the bioavailability data of 50 subjects who completed the study is presented in the following table.

SUMMARY TABLE OF THE COMPARATIVE BIO-AVAILABILITY DATA

¹Auro-Ritonavir (Ritonavir) Tablets, 100 mg (Auro Pharma Inc.).

^{2 Pr}Norvir^® (Ritonavir) Tablets, 100 mg (AbbVie Corporation) were purchased from Canada.

³ Expressed as the median (range) only.

⁴ Expressed as arithmetic mean (% CV) only.

15 Microbiology

Resistance

HIV-1 isolates with reduced susceptibility to ritonavir have been selected in vitro. The clinical relevance of phenotypic and genotypic changes associated with ritonavir therapy has not been established (see 7 WARNINGS AND PRECAUTIONS and 15 MICROBIOLOGY). Genotypic analysis of these isolates showed mutations in the HIV protease gene at amino acid positions 84 (Ile to Val), 82 (Val to Phe), 71 (Ala to Val), and 46 (Met to Ile). Phenotypic (n = 18) and genotypic (n = 44) changes in HIV isolates from selected patients treated with ritonavir were monitored in Phase 1/2 trials over a period of 3 to 32 weeks. Mutations associated with the HIV viral protease in isolates obtained from 41 patients appeared to occur in a stepwise and ordered fashion; in sequence, these mutations were position 82 (Val to Ala/Phe), 54 (Ile to Val), 71 (Ala to Val/Thr), and 36 (Ile to Leu), followed by combinations of mutations at an additional 5 specific amino acid positions.

Of 18 patients for which both phenotypic and genotypic analysis were performed on free virus isolated from plasma, 12 showed reduced susceptibility to ritonavir in vitro. All 18 patients possessed one or more mutations in the viral protease gene. The 82 mutation appeared to be necessary but not sufficient to confer phenotypic resistance. Phenotypic resistance was defined as a ≥ 5-fold decrease in viral sensitivity in vitro from baseline. The clinical relevance of phenotypic and genotypic changes associated with ritonavir therapy has not been established.

Cross-resistance to Other Antiretrovirals

Among protease inhibitors variable cross-resistance has been recognized (see 7 WARNINGS AND PRECAUTIONS and 15 MICROBIOLOGY). Serial HIV isolates obtained from 6 patients during ritonavir therapy showed a decrease in ritonavir susceptibility in vitro but did not demonstrate a concordant decrease in susceptibility to saquinavir in vitro when compared to matched baseline isolates. However, isolates from 2 of these patients demonstrated decreased susceptibility to indinavir in vitro (8-fold). Isolates from 5 patients were also tested for cross-resistance to amprenavir and nelfinavir; isolates from two patients had a decrease in susceptibility to nelfinavir (12- to 14-fold), and none to amprenavir. Cross-resistance between ritonavir and reverse transcriptase inhibitors is unlikely because of the different enzyme targets involved. One ZDV-resistant HIV isolate tested in vitro retained full susceptibility to ritonavir.

Cross-resistance between ritonavir and reverse transcriptase inhibitors is unlikely because of the different enzyme targets involved. One ZDV-resistant HIV isolate tested in vitro retained full susceptibility to ritonavir.

Antiviral Activity in vitro

The activity of ritonavir was assessed in vitro in acutely infected lymphoblastoid cell lines and in peripheral blood lymphocytes. The concentration of drug that inhibits 50% (EC₅₀) of viral replication ranged from 3.8 to 153 nM depending upon the HIV-1 isolate and the cells employed. The average EC₅₀ for low passage clinical isolates was 22 nM (n = 13). In MT₄ cells, ritonavir demonstrated additive effects against HIV-1 in combination with either zidovudine (ZDV) or didanosine (ddI). Studies which measured cytotoxicity of ritonavir on several cell lines showed that > 20 microM was required to inhibit cellular growth by 50% resulting in an in vitro therapeutic index of at least 1000.

16 Non-Clinical Toxicology

The toxicology of ritonavir has been assessed in mice, rats, dogs and rabbits in studies ranging in duration from a single dose to 6 months of oral administration. All phases of the reproductive process have been evaluated for potential adverse effects, and a generally accepted battery of in vitro and in vivo mutagenicity studies has been conducted. The following section summarizes the findings from these studies. The most significant target organs in the toxicity studies have been the liver and retina. Retinal changes secondary to phospholipidosis were limited to rodents only and were considered not to pose any undue risk to humans. Dogs appeared to be less sensitive than the rodent to the hepatotoxic effects of ritonavir. Human clinical studies have not disclosed a high incidence of hepatic complications (see 8 ADVERSE REACTIONS).

Pharmacodynamics

Ritonavir was administered orally to mice or rats at doses of 5 to 50 mg/kg to determine potential effects on various neuropharmacological endpoints. In mice, ritonavir had no meaningful effect on rotarod performance, ethanol-induced sleep time or pentobarbital-induced sleep time. In rats, no effect was observed on spontaneous motor activity or rotarod performance.

Ritonavir produced no pharmacologically significant effects on heart rate or blood pressure when administered orally to unanesthetized rats at doses of 20 or 50 mg/kg. The compound was also infused intravenously in a vehicle consisting of 20% ethanol and 15% propylene glycol in 5% dextrose water to pentobarbital-anesthetized dogs instrumented to measure various cardiovascular parameters.

Mean peak plasma levels of ritonavir were as high as 15.11 mcg/mL. Although the vehicle itself produced hemodynamic changes consistent with cardiac depression, ritonavir produced no consistent additional effects on systemic or pulmonary pressures or resistance, central venous pressure, cardiac output, left ventricular dP/dt or end-diastolic pressure.

Ritonavir had no effect on isolated guinea pig ileum basal tone or on carbachol-induced contractions.

Acute Toxicity

Ritonavir has a low order of acute toxicity in rodents by oral route but is more toxic when given intravenously. The difference is probably due to the fact that the acute toxicity produced by ritonavir is more related to plasma C_max than AUC values, and C_max is most likely considerably higher following intravenous injection. When given orally in a vehicle of propylene glycol and ethyl alcohol (95:5, v/v) containing 2 molar equivalents of p-toluene sulfonic acid monohydrate, the median lethal dose (LD₅₀) generally exceeds the limited dose of 2500 mg/kg for both mice and rats. Toxic signs for both species consisted of decreased activity, ataxia, dyspnea, squinting, prostration, and tremors.

When administered intravenously, the approximately lethal dose (ALD) ranged from 35 to 80 mg/kg for both species. Signs of toxicity included decreased activity, ataxia, dyspnea, exophthalmos, and clonic convulsions.

Sub-chronic Toxicity

Rat

Ritonavir has been studied in rats at study durations for 1-month (0, 15, 50 and 150/100 mg/kg/day), 13-weeks (0, 25, 75, and 175/125 mg/kg/day) and 6-months (0, 25, 75, and 175/125 mg/kg/day). Consistent findings across all studies included treatment-related clinical signs consisting of decreased activity, emaciation, hunched posture, weakness, and rough hair coat along with some indications of ataxia, lower body weight and food consumption at higher dosages. Target organs of toxicity were liver, eye (retina), kidney and thyroid.

Hepatic changes include multinucleated hepatocytes, single cell necrosis, histiocytic granulomas and chronic pericholangitis. Changes in laboratory parameters consistent with these findings were observed in serum for ALT, AST, GGT, ALP, total bilirubin, and cholesterol.

Retinal changes included observation of pale choroidal vasculature, with hypertrophy and cytoplasmic granularity in the retinal pigment epithelium, with reduced or absent photoreceptor outer segments. Electroretinograms (ERGs) revealed decreases in A- and B–wave amplitudes, with primary findings associated with rods. Recovery was not observed following treatment discontinuation.

Mild epithelial hypertrophy in the thyroid gland was associated with increased TSH and lower T₄. Kidney changes were consisted of tubular degeneration and were only observed in the 6-month study.

The no-toxic effect dosage was considered to be 15 mg/kg/day and corresponded to systemic exposure of 3.6 to 4.7 mcg·h/mL in male rats and 5.3 to 8.9 mcg·h/mL in female rats (approximately 1/25^th of the expected human exposure of 150 mcg·h/mL from a dose of 600 mg twice daily).

Dog

Ritonavir has been studied in dogs at study durations for 1-month (0, 10, 50 and 200 mg/kg/day), 13- weeks (0, 10, 50, and 200/100 mg/kg/day) and 6-months (0, 10, 50 and 125 mg/kg/day). Consistent findings across all studies included treatment-related clinical signs consisting of emesis and abnormal stool/diarrhea; at higher dosages decreased activity, ataxia, weakness, tremor, and posture difficulties were observed along with decreased body weight and food intake. Target organs of toxicity were liver and thymus. Due to pronounced clinical adversity and moribundity the high dosage was reduced from 200 to 100 mg/kg/day in the 13-week study.

Hepatic changes included histopathological findings of hydropic degeneration, with pericholangitis, biliary hyperplasia, fibrosis becoming evident as the dose duration increased. Associated changes in serum markers included ALT, ALLP, GGT, and bile acids.

Decreased thymic weight and atrophy were observed at the highest dosages.

The no-toxic effect dosage was dependent on the test formulation used and ranged from 10 to 50 mg/kg/day that corresponded to systemic exposure of 18 to 25 mcg·h/mL (approximately one-seventh of the expected human exposure of 150 mcg·h/mL). However, it is important to note that histopathological changes in liver were only observed in a single female dog at the highest dosage (125 mg/kg/day) at a plasma drug exposure of 482 mcg·h/mL.

Carcinogenicity

Carcinogenicity studies with ritonavir have been conducted in mice and rats. In male mice, at dosage levels of 50, 100, or 200 mg/kg/day, there was a dose dependent increase in the incidence of both adenomas and combined adenomas and carcinomas in the liver. Based on the drug exposure (AUC) measurements, the exposure at the high dosage was approximately 0.3-fold for males that of exposure in humans with the recommended therapeutic dose (600 mg twice daily). There were no carcinogenic effects seen in females at the dosages tested. The exposure at the high dosage was approximately 0.6-fold for the females that of the exposure in humans. In rats dosed at levels of 7, 15 or 30 mg/kg/day there were no carcinogenic effects. In this study the exposure at the high dose was approximately 5% that of the exposure in humans with the 600 mg twice daily regimen. Based on the exposures achieved in the animal studies, the significance of the observed effects is not known.

Mutagenicity

Ritonavir was not found to be mutagenic or clastogenic in a battery of in vitro and in vivo assays including the Ames bacterial reverse mutation assay using S. Typhimurium and E. coli, the mouse lymphoma assay, the mouse micronucleus test, and chromosomal aberration assays in human lymphocytes.

Reproductive and Developmental Toxicology

Fertility and General Reproductive Performance

Rats

Ritonavir was administered orally by gavage to female rats at dosages of 0, 20, 40, and 75 mg/kg/day beginning at 14 days prior to mating with males that were treated at dosages of 0, 20, 40, and 125 mg/kg/day beginning at 28 days prior to mating. The treatment in female rats was continued through mating until gestation Day 9. The group mean plasma AUC values for males near the end of the premating period were 8.2, 19.7 and 61.0 mcg·h/mL, respectively, for the 20, 40, and 125 mg/kg/day treatment groups. The corresponding values for females were 14.6, 33.1 and 90.5 mcg·h/mL, respectively, for the 20, 40 and 75 mg/kg/day treatment groups. There were no treatment-related deaths in the study. Maternal toxicity consisted of adverse clinical signs and decreases in mean body weights and food intake in the mid and high dosage groups.

There were no treatment-related effects on the estrous cycle or male and female reproductive indices. Maternal survival and pregnancy status of the ritonavir-treated groups were also comparable to the controls. No treatment-related effects were seen in the number of corpora lutea, implantation sites, viable and nonviable embryos. There were no increases in the incidence of preimplantation and postimplantation losses. The no-toxic-effect level for systemic toxicity in F₀ generation rats was 20 mg/kg/day. However, there were no adverse effects on male or female reproduction or early embryonic development up to the highest dosage (125/75 mg/kg/day) tested.

Developmental Toxicity

Rats

Ritonavir was administered orally to mated female rats at dosages of 0, 15, 35, and 75 mg/kg/day from Gestation Day 6 to 17. Three high dosage rats were euthanized in moribund condition during the study. The group mean plasma AUC values on Gestation Day 16 were 17.3, 34.3 and 45.2 mcg·h/mL at dosages of 15, 35 and 75 mg/kg/day, respectively. Decreased activity, emaciation, dehydration, rough coat and/or matted coat, hunched posture, tremors, and noisy respiration were observed in rats at the high dosage level. Marked decreases in body weights and food consumption were evident in the high dosage group. Reduction in food consumption accompanied by a reduction in body weight gain was also noted for the mid dosage group during Gestation Days 6 to 9. No effects were found in the number of corpora lutes or implantation sites. Developmental toxicity in the high dosage group was characterized by increased postimplantation loss, decreased fetal body weights, and an increased incidence of ossification delays and developmental variations (enlarged fontanelles, cryptorchidism, and wavy ribs). Developmental toxicity at the 35 mg/kg/day dosage level was characterized by a slight increase in cryptorchidism. No treatment-related malformations were observed in this study.

Developmental toxicity occurred only at maternally toxic dosages. The no-effect level for maternal and developmental toxicity was 15 mg/kg/day corresponding to a systemic exposure of 17.3 mcg·h/mL.

Rabbits

Ritonavir was administered to mated female rabbits by oral gavage at dosages of 0, 25, 50, and

110 mg/kg/day from Gestation Day 6 to 19. The group mean plasma AUC values on Gestation Day 20 were 1.30 and 28.55 mcg·h/mL at dosages of 25 and 50 mg/kg/day, respectively. Plasma AUC values were not calculated for the 110 mg/kg/day group because plasma samples were obtained from the 3 surviving rabbits at only 2 time points. Four deaths in rabbits given 110 mg/kg/day were considered to be possibly drug-related. There was an increased incidence of decreased defecation and soft stool in all drug-treated groups. The observation of no stool was noted in mid and high dosage groups; rales and mucoid stool occurred only at the high dosage. Marked decreases in body weights, body weight gain and food consumption were noted in the high dosage group. Developmental toxicity was evident at the high dosage level with 4 whole litter resorptions and in surviving litters a significant increase in postimplantation losses, decreased litter size and decreased uterine and fetal weights. There were no drug-related fetal malformations in this study.

The no-observable-effect level was 50 mg/kg/day with respect to maternal and developmental toxicity.

Special Toxicology Studies

Dietary administration of ritonavir was provided to mice and rats for 13-weeks in preparation for 2-year carcinogenicity studies in these species. Dosages were 0, 200, 400, 600, and 1000 mg/kg/day for mice and 0 50, 100, 160, and 200 mg/kg/day for male rats and 0, 30, 75, 125, and 175 mg/kg/day for female rats. In both species target organ toxicity was similar to that noted in the 3-month rat study using oral gavage administration, with target organ toxicities in liver, eye (retina), and thyroid (rat only). Systemic plasma exposure (AUC) associated with target organ toxicity was similar to plasma exposures in the 3- month study in rats.

Ritonavir was evaluated for the potential to produce delayed contact hypersensitivity in guinea pigs. The Maximization Method was used in this study and the data generated indicated that ritonavir did not induce delayed contact hypersensitivity in guinea pigs.

Peri-/Postnatal Toxicity

Rats

Mated female rats were administered ritonavir orally at dosages of 0, 15, 35, or 60 mg/kg/day beginning on Gestation Day (GD) 6. Treatment continued throughout gestation, parturition, and lactation; the final dosage was given on Postpartum Day (PD) 20. Plasma drug levels were not determined in this study. No deaths or treatment-related clinical signs were observed among the F₀ dams. Dams in the 60 mg/kg/day group gained less weight and consumed less food during GD 6 to 9. Gestation length, litter size at birth, and F₁ pup growth and survival were unaffected. No effects on the time of appearance of developmental landmarks or learning as measured by a passive avoidance test were evident. The ontogeny of various reflexes was unaffected. The reproductive competence of the F₁ generation was unaffected. Therefore, the no-observed-effect level for developmental toxicity was considered to be 60 mg/kg/day, the highest dosage tested.

17 Supporting Product Monographs

1. 1. NORVIR®, Tablets, 100 mg, Submission Control Number: 291456, Product Monograph, AbbVie Corporation, Date of revision: March 19, 2025.