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Table of Contents

PART I: HEALTH PROFESSIONAL INFORMATION 3

SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 4 WARNINGS AND PRECAUTIONS 5 ADVERSE REACTIONS 8 DRUG INTERACTIONS 14 DOSAGE AND ADMINISTRATION 25 OVERDOSAGE 26 ACTION AND CLINICAL PHARMACOLOGY 26 STORAGE AND STABILITY 31 DOSAGE FORMS, COMPOSITION AND PACKAGING 31

PART II: SCIENTIFIC INFORMATION 32

PHARMACEUTICAL INFORMATION 32 CLINICAL TRIALS 33 DETAILED PHARMACOLOGY 37 MICROBIOLOGY 44 TOXICOLOGY 45 REFERENCES 55

PART III: CONSUMER INFORMATION. 57

PrINVIRASE(r) Saquinavir mesylate

PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION

CONTRAINDICATIONS

INVIRASE (saquinavir mesylate) is contraindicated in patients with clinically significant hypersensitivity to saquinavir or to any other component contained in the hard gelatin capsule or film coated tablet (see DOSAGE FORMS, COMPOSITION AND PACKAGING). INVIRASE/ritonavir should not be administered concurrently with terfenadine, cisapride, astemizole, triazolam, midazolam, ergot derivatives, or pimozide. Inhibition of CYP3A4 by saquinavir could result in elevated plasma concentrations of these drugs, potentially causing serious or life-threatening reactions, such as cardiac arrhythmias or prolonged sedation (see DRUG INTERACTIONS). INVIRASE/ritonavir is contraindicated in patients with severe hepatic impairment (see WARNINGS and PRECAUTIONS: Hepatic/Biliary/Pancreatic). INVIRASE/ritonavir should not be given together with rifampin, due to the risk of severe hepatocellular toxicity if the three drugs are taken together (see DRUG INTERACTIONS). INVIRASE/ritonavir should not be administered concurrently with drugs listed in Table 1 (also see DRUG INTERACTIONS, Table 3).

Table 1: Drugs that are Contraindicated with INVIRASE/ritonavir

* No longer marketed in Canada.

Because ritonavir is coadministered with INVIRASE, prescribers should refer to the prescribing information for ritonavir for additional contraindicated drugs.

WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions

INVIRASE (saquinavir mesylate) should only be administered with low dose ritonavir (see INDICATIONS AND CLINICAL USE) Serious or life-threatening drug-drug interactions (see CONTRAINDICATIONS and DRUG INTERACTIONS) INVIRASE/ritonavir is contraindicated in patients with severe hepatic impairment (see Hepatic/Biliary/Pancreatic below)

General

INVIRASE should only be used if it is combined with ritonavir. When INVIRASE is prescribed in combination with other antiretroviral therapies, physicians should refer to the appropriate Product Monographs for safety and prescribing information. If a serious or severe toxicity occurs during treatment with INVIRASE, treatment with the drug should be interrupted until the etiology of the event is identified or the toxicity resolves. At that time, resumption of treatment with full dose may be considered.

Lactose Intolerance:

Each capsule contains lactose (anhydrous) 63.3 mg and each film-coated tablet contains lactose (monohydrate) 38.5 mg. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption (autosomal recessive disorder) should not take this medicine.

Body as a Whole

Fat Redistribution:

Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "Cushingoid appearance" have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

Carcinogenesis and Mutagenesis

No human data is available. For animal data see TOXICOLOGY.

Cardiovascular

Hyperlipidemia:

Elevated cholesterol and/or triglyceride levels have been observed in some patients taking saquinavir in combination with ritonavir. Cholesterol and triglyceride levels should be monitored prior to initiating combination therapy with INVIRASE/ritonavir, and at periodic intervals while on such therapy. In these patients, lipid disorders should be managed as clinically appropriate.

Endocrine and Metabolism

Diabetes Mellitus and Hyperglycemia:

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.

Hematologic

Hemophiliac Patients:

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 saquinavir.

Hepatic/Biliary/Pancreatic

Patients with Hepatic Impairment:

In cases of mild impairment no initial dosage adjustment is necessary at the recommended dose. The use of INVIRASE (alone or in combination with ritonavir) in patients with moderate hepatic impairment has not been studied. In the absence of such studies, caution should be exercised, as increases in saquinavir levels and/or increases in liver enzymes may occur. In patients with underlying hepatitis B or C, cirrhosis, chronic alcoholism and/or other underlying liver abnormalities there have been reports of worsening liver disease and development of portal hypertension after starting saquinavir. Associated symptoms include jaundice, ascites, edema and, in some cases esophageal varices. Several of these patients died. A causal relationship between saquinavir therapy and development of portal hypertension has not been established. Increased monitoring for signs and symptoms of liver toxicity should be considered. INVIRASE/ritonavir is contraindicated in patients with severe hepatic impairment (see CONTRAINDICATIONS).

Pancreatitis:

Elevated cholesterol and/or triglyceride levels have been observed in some patients taking saquinavir in combination with ritonavir. Marked elevation in triglyceride levels is a risk factor for development of pancreatitis (see WARNINGS AND PRECAUTIONS: Cardiovascular).

Immune

Immune Reconstitution Syndrome: Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including INVIRASE. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecil pneumonia (PCP), or tuberculosis), which may necessitate further evaluation and treatment.

Renal

Patients with Renal Impairment:

Renal clearance is only a minor elimination pathway, the principal route of metabolism and excretion for saquinavir is via the liver. Therefore, no initial dose adjustment is necessary for patients with renal impairment. However, patients with severe renal impairment have not been studied and caution should be exercised when prescribing saquinavir in this population.

Resistance/Cross-resistance

Varying degrees of cross-resistance among protease inhibitors have been observed. Continued administration of INVIRASE therapy following loss of viral suppression may increase the likelihood of cross-resistance to other protease inhibitors (see also ACTION AND CLINICAL PHARMACOLOGY: Resistance).

Special Populations

Pregnant Women: .

Reproduction studies with saquinavir in rats have shown no embryotoxicity or teratogenicity at plasma exposures (AUC values) up to 5 times those achieved with human use (1800 mg/day), or in rabbits at dose levels up to 24 times the recommended human dose. There are however, no adequate or well controlled studies of INVIRASE in pregnant women. Because animal reproduction studies are not always predictive of human response, INVIRASE should be used during pregnancy only if the potential benefits are considered to outweigh the potential risks to the fetus

Antiretroviral Pregnancy Registry

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

Nursing Women: Because many drugs are excreted in human milk, it is advisable to caution mothers against breast feeding while taking INVIRASE. Current medical practice advises against breast- feeding by HIV-infected women, due to the possibility of post-natal transmission.

It is not known whether saquinavir is excreted in human milk.

Animal studies indicate that administration of saquinavir to rats through the lactation period at plasma concentrations (AUC values) up to 5 times those achieved with the human-dose (1800 mg/day) had no effect on the survival, growth or development of offspring to weaning. However, the potential for adverse reactions to saquinavir in nursing infants cannot be assessed.

Pediatrics (< 16 years of age):

The safety and efficacy of saquinavir in HIV-infected children has not been established. The safety and efficacy of saquinavir when coadministered with ritonavir to pediatric patients is under investigation.

Geriatrics (> 65 years of age)

: Only limited experience is available in elderly patients. No data are available to establish a dose recommendation in elderly patients.

Monitoring and Laboratory Tests

Clinical chemistry tests, viral load and CD4 count should be performed prior to initiating therapy and at appropriate intervals thereafter. Elevated nonfasting triglyceride levels have been observed in patients in saquinavir trials. Triglyceride levels should be periodically monitored during therapy. Increases in cholesterol have also been observed and should be monitored. For comprehensive information concerning laboratory test alterations associated with the use of other antiretroviral therapies, physicians should refer to the complete product information for these drugs.

DRUG INTERACTIONS

Serious Drug Interactions

• INVIRASE (saquinavir mesylate) should not be administered concurrently with some

antiarrythmics, antihistamines, ergot derivatives, antimycobacterial agents, GI motility agents, neuroleptics, sedatives or hypnotics. For a listing of drugs within each of the above drug classes see CONTRAINDICATIONS. Caution is warranted when coadministering INVIRASE with HMG-CoA reductase inhibitors as there is an increased risk of mypopathy and rhabdomyolysis (see Table 3 and Table 4). In some cases, coadministration of saquinavir and ritonavir has led to severe adverse events, mainly diabetic ketoacidosis and liver disorders, especially with pre-existing liver disease (see Table 4). Unless saquinavir is coadministered with ritonavir, saquinavir should not be used with either rifabutin or efavirenz as the concurrent use results in reduced saquinavir concentrations (see Table 3). Concomitant use of fluticasone propionate and INVIRASE/ritonavir may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Coadministration of fluticasone propionate and INVIRASE/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects (see Tables 3 and 4). Concurrent use of INVIRASE and St. John's Wort or products containing St. John's wort is not recommended (see Drug-Herb Interactions). Garlic capsules should not be used if taking saquinavir without ritonavir (see Drug- Herb Interactions). When coadministering INVIRASE with any agent having a narrow therapeutic margin, such as anticoagulants, anticonvulsants, and antiarrhythmics, special attention is warranted (see Table 3 and Table 4). Co-administration of sildenafil or tadalafil with INVIRASE/ritonavir is expected to substantially increase the concentrations of sildenafil or tadalafil, and may result in associated adverse events such as hypotension, visual changes and priapism. Vardenafil should not be co-administrated with INVIRASE /ritonavir (see Table 4). Caution should be exercised when INVIRASE and digoxin are coadministered; the serum concentration of digoxin should be monitored and the dose of digoxin may need to be reduced. (see Table 4).

Overview

Several drug interaction studies have been completed with both INVIRASE and saquinavir soft gel capsules. Observations from drug interaction studies with saquinavir soft gel capsules may not be predictive for INVIRASE. Because ritonavir is coadministered, prescribers should refer to the prescribing information for ritonavir regarding drug interactions associated with this drug. The metabolism of saquinavir is mediated by cytochrome P450, with the specific isoenzyme CYP3A4 responsible for 90% of the hepatic metabolism. Additionally, saquinavir is a substrate for P-Glycoprotein (Pgp). Therefore, drugs that affect CYP3A4 and/or Pgp, may modify the pharmacokinetics of saquinavir. Similarly, saquinavir might also modify the pharmacokinetics of other drugs that are substrates for CYP3A4 or Pgp.

Drugs that are Mainly Metabolized by CYP3A4:

Compounds that are substrates of CYP3A4

(e.g. alfentanyl, alprazolam, amiodarone, calcium channel blockers, clindamycin, carbamazepine, cyclosporine, dapsone, disopyramide, fentanyl, nefazodone, pimozide, quinidine, quinine, tacrolimus, warfarin) may have elevated plasma concentrations when coadministered with INVIRASE; therefore, these combinations should be used with caution and patients should be monitored for toxicities associated with such drugs. Since INVIRASE is coadministered with ritonavir, the ritonavir product monograph should be reviewed for additional drugs that should not be coadministered.

Substrates of P-gp:

Concomitant use of INVIRASE with drugs that are substrates of P-gp may lead to elevated plasma concentrations of the concomitant drugs. Monitoring for toxicity is therefore recommended. Compounds that are substrates of P-gp include cyclosporine, paclitaxel, and vinblastine.

Inducers of CYP3A4:

Coadministration with compounds that are potent inducers of CYP3A4 (e.g., phenobarbital, phenytoin, dexamethasone, carbamazepine) may result in decreased plasma levels of saquinavir.

Ritonavir-Boosted INVIRASE and Rifampin:

In a study investigating the drug-drug interaction of rifampin 600 mg/day daily and INVIRASE 1000 mg/ritonavir 100 mg twice daily (ritonavir-boosted INVIRASE) involving 28 healthy volunteers, 11 of 17 healthy volunteers (65%) exposed concomitantly to rifampin and ritonavir-boosted INVIRASE developed severe hepatocellular toxicity presented as increased hepatic transaminases. In some subjects, transaminases increased up to >20-fold the upper limit of normal and were associated with gastrointestinal symptoms including abdominal pain, gastritis, nausea, and vomiting. Following discontinuation of all three drugs, clinical symptoms abated and the increased hepatic transaminases normalized (see CONTRAINDICATIONS).

Drug-Drug Interactions

Information on the kinetics of specific drug combinations are presented in DETAILED PHARMACOLOGY (see Table 9 and Table 10 ). Drugs that are contraindicated or not recommended for coadministration with saquinavir are included in Table 3. Drugs with established and other potentially significant drug interactions are included in Table 4. These recommendations are based on either drug interaction studies or predicted interactions due to the expected magnitude of interaction and potential for serious events or loss of efficacy.

Table 3: Drugs that are Contraindicated or not Recommended for Coadministration with INVIRASE/ritonavir

a

for magnitude of interactions see Tables

9 and 10

b .

No longer marketed in Canada

Since INVIRASE is coadministered with ritonavir, the ritonavir product monograph should be reviewed for additional drugs that should not be coadministered.

Table 4: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction (Information in the table applies to INVIRASE/ritonavir)

a

For magnitude of interactions see Tables

9 and 10

Drug-Food Interactions

Coadministration of 600 mg of saquinavir soft gel capsules and quadruple strength grapefruit juice as a single administration in healthy volunteers resulted in a 54% increase in exposure to saquinavir (see Table 10).

Drug-Herb Interactions

Garlic Capsules

: Garlic capsules should not be used when taking saquinavir without ritonavir due to the risk of decreased saquinavir plasma concentrations (see Table 10). No data are available for the coadministration of INVIRASE/ritonavir and garlic capsules.

St. John's wort (hypericum perforatum):

Concomitant use of INVIRASE and St John's wort or products containing St. John's wort is not recommended due to risk of decreased plasma concentrations of saquinavir which may lead to loss of virologic response and possible resistance to saquinavir or to the class of protease inhibitors.

DOSAGE AND ADMINISTRATION

Dosing Considerations

INVIRASE (saquinavir mesylate) should only be used in combination with ritonavir, because it significantly inhibits saquinavir's metabolism to provide increased plasma saquinavir levels.

Recommended Dose and Dosage Adjustment

For adults or adolescents over the age of 16 years unable to take INVIRASE 500 mg Film- Coated Tablets, INVIRASE should be given in the form of 200 mg capsules.

Adults and adolescents over the age of 16 years:

INVIRASE should only be used in combination with ritonavir. The recommended dosage regimen is INVIRASE 1000 mg (5 x 200 mg capsules or 2 x 500 mg tablets) two times daily with ritonavir 100 mg two times daily, in combination with other antiretroviral agents. Ritonavir should be taken at the same time as INVIRASE, and within 2 hours after a meal.

Concomitant Therapy: INVIRASE with Lopinavir/Ritonavir:

When administered with lopinavir/ritonavir 400/100 mg bid, the appropriate dose of INVIRASE is 1000 mg bid (with no additional ritonavir).

Dose Adjustments for Combination Therapy with INVIRASE:

For serious toxicities that may be associated with saquinavir, the drug should be interrupted. INVIRASE at doses less than 1000 mg with 100 mg ritonavir bid are not recommended since lower doses have not shown antiviral activity. For recipients of combination therapy with INVIRASE and ritonavir, dose adjustments may be necessary. These adjustments should be based on the known toxicity profile of the individual agent and the pharmacokinetic interaction between saquinavir and the coadministered drug (see DRUG INTERACTIONS and DETAILED PHARMACOLOGY). Physicians should refer to the Product Monographs of these drugs for comprehensive dose adjustment recommendations and drug-associated adverse reactions.

Missed Dose

The missed dose should be taken as soon as it is remembered, then the regular dosing schedule should be continued. Two doses should not be taken at the same time.

Administration

Ritonavir should be taken at the same time as INVIRASE, and within 2 hours after a meal. INVIRASE capsules and tablets should be swallowed unchewed, with water or some other non- alcoholic drink. You should avoid excessive consumption of alcohol during your treatment with INVIRASE.

OVERDOSAGE

There is limited experience of overdose with saquinavir. Whereas acute or chronic overdose of saquinavir alone did not result in major complications, in combination with other protease inhibitors, overdose symptoms and signs such as general weakness, fatigue, diarrhea, nausea, vomiting, hair loss, dry mouth, hyponatremia, weight loss and orthostatic hypotension have been observed. There is no specific antidote for overdose with saquinavir. Treatment of overdose with saquinavir, should consist of general supportive measures, including monitoring of vital signs and ECG, and observations of the patient's clinical status. If warranted, patients should be treated with activated charcoal. Since saquinavir is highly protein bound, dialysis is unlikely to be beneficial in significant removal of the active substance.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

Saquinavir is a selective inhibitor of the viral pol-encoded aspartic protease which cleaves precursor molecules into the structural proteins of the mature virion core and activates reverse transcriptase during the HIV growth cycle. Because of these functions, this protease is essential for the release of infectious virus (as proved by active site mutagenesis). Saquinavir is a potent (Ki <= 0.12 nM) inhibitor of HIV proteases. No inhibition of human aspartyl or other proteases has been seen even at a concentration of 10mM, indicating high selectivity (at least 50,000 fold). Saquinavir is active in lymphoblastoid and monocytic lines and in primary cultures of lymphocytes and monocytes infected with laboratory strains or clinical isolates of HIV-1, typically displaying antiviral IC50 and IC90 values in the range 1-10 nM and 5-50 nM, respectively, depending on the cell type and virus isolate, in acutely infected cells. In common with other protease inhibitors, saquinavir binds extensively to plasma proteins, and its in vitro antiviral potency is markedly attenuated in the presence of human serum or its constituent proteins. Addition of 50% human serum or alpha-1 acid glycoprotein (1 mg/ml) to the cell culture resulted in 25-fold and 14-fold reductions, respectively, in activity against wild- type HIV, as well as 33-fold and 7-fold reductions, respectively, in activity against mutant HIV strains. Experiments in cell culture indicate that saquinavir produces an additive to synergistic effect against HIV in double and triple combination with various reverse transcriptase inhibitors (including zidovudine, didanosine, zalcitabine, lamivudine, stavudine and nevirapine), without enhanced cytotoxicity.

Potential for resistance and cross-resistance to saquinavir

There are two primary protease mutations - L90M and G48V - associated with resistance to unboosted saquinavir. The G48V and L90M mutations give modest (typically less than 10-fold) reductions in susceptibility to saquinavir measured in vitro.

Selection of viral resistance during boosted saquinavir therapy:

In the MaxCmin1 and MaxCmin2 studies of 309 antiretroviral-naive, PI-naive and PI- experienced patients, isolates from 41 patients treated with saquinavir/r 1000/100 mg bid for >= 12 weeks with quantifiable (>= 200 copies/ml) viral load and a matched baseline sample (or a missing baseline sample if PI naive) were subjected to protease gene sequencing tests. This revealed an increase in the prevalence of primary PI mutations (at codons 30, 46, 48, 50, 82, 84 or 90) from 27% (11/41) at baseline to 32% (13/41) following boosted saquinavir therapy. New primary PI mutations (predominantly at codons 84, 90 or 46) were observed in 2/19 of PI-naive patients and 5/22 of PI-experienced patients. The risk of developing a new primary PI mutation during ritonavir-boosted saquinavir treatment was positively correlated with the number of primary PI mutations present at baseline. Saquinavir mutations (mutations at codons 10, 48, 54, 71, 73, 77, 82, 84 or 90) developed on boosted saquinavir therapy in 17% (7/41) of patients overall (predominantly at codons 84, 10, 90 or 71). Antiviral activity of boosted saquinavir in patients failing protease inhibitor therapy: In a study of 139 PI-experienced patients experiencing virological failure, subsequent virological response to treatment with soft-capsule saquinavir/r 1000/100 mg bid at 12, 24 and 48 weeks was dependent on a threshold of five PI resistance mutations at baseline. Overall, 80% of patients with <= 5 PI resistance mutations achieved a virological response (< 50 copies/ml or > 1 log10- fold reduction in HIV RNA at week 24) with boosted saquinavir therapy, compared with 29% of patients who had > 5 such mutations. In a retrospective analysis of 138 PI-experienced patients receiving a saquinavir/r 1000/100 mg bid-based regimen, the following nine baseline PI mutations were detected in more than 5% of patients and were identified as most strongly associated with reduced virological response: 10F/I/M/R/V, 15A/V, 20I/M/R/T, 24I, 62V, 73S/T, 82A/F/S/T, 84V and 90M. Among these PI- experienced patients, a significantly reduced virological response to boosted saquinavir therapy was predicted by isolates that had at least three to four of the nine mutations in this resistance score. In a clinical study of 32 individuals pre-treated with indinavir or ritonavir but naive to saquinavir, 81% showed reduced susceptibility to indinavir, 59% showed reduced susceptibility to ritonavir and 40% showed reduced susceptibility to saquinavir at baseline. Following 24 weeks of therapy with Invirase/r 1000/100 mg bid, efavirenz and nucleoside analogues, the median decrease in plasma HIV-RNA was 0.9 log10 copies/ml for patients with phenotypic resistance to saquinavir versus 1.52 log10 copies/ml for those without resistance (p=0.03). HIV RNA levels < 50 copies/ml were achieved at week 24 for 58 % of those patients carrying saquinavir-sensitive virus and for 25 % of those carrying virus with reduced (> 10 fold) sensitivity to saquinavir. The median number of resistance mutations in the protease gene in individuals with phenotypic resistance to saquinavir was 5.5 (range 4-8), whereas it was 3 (range 0-6) in those sensitive to saquinavir (p=0.0003). Using a linear regression model to analyse baseline phenotypic resistance and virological response from clinical observations derived from various clinical trials and patient cohorts, and following validation by bootstrapping, a baseline fold-change in saquinavir IC50 of 7.1 and 26.5, relative to wild type, was predicted to be associated with a 20% and 80% loss in maximum virological response at week 8, respectively, to boosted saquinavir therapy.

Pharmacokinetics

The pharmacokinetic properties of saquinavir have been evaluated in healthy volunteers and in HIV-infected patients after single and multiple oral doses of 25, 75, 200 and 600 mg TID; and in healthy volunteers after intravenous infusion doses of 12 mg administered over 1 hour, and 6, 36 and 72 mg administered over 3 hours.

Absorption:

Absorption and absolute bioavailability are improved when the drug is taken after a meal. Similarly, the presence of food increases the time required to achieve maximum concentration.

The extent of absorption (as reflected by AUC) after a 600 mg oral dose in fasting healthy volunteers was substantially increased (from 24 ng[? ]h/mL to 161 ng[? ]h/mL) when given following a heavy breakfast (48g protein, 60g carbohydrate, 57g fat; 1006 kcal). The presence of food also increased the time taken to achieve maximum concentration from 2.4 hours to 3.8 hours, and substantially increased the mean maximum plasma concentrations (Cmax) from 3.0 ng/mL to 35.5 ng/mL. The effect of food has been shown to be present for up to 2 hours. Therefore, INVIRASE (saquinavir mesylate) should be taken within 2 hours after a meal. Gastric pH has been shown not to play a major role in this increased bioavailability which is associated with food. Additionally, exposure to saquinavir was doubled (AUC(0-12) increased from 183.2 ng[? ]h/mL to 374.4 ng[? ]h/mL) when INVIRASE was coadministered with "double-strength" grapefruit juice; and increased by 30% (AUC(0-12) from 183.2 ng[? ]h/mL to 238.1 ng[? ]h/mL) when taken with normal strength grapefruit juice in a single dose study. HIV-infected patients administered saquinavir 600 mg TID, with the instructions to take their doses after a meal or substantial snack, had AUC and Cmax which were about twice those observed in healthy volunteers receiving the same treatment regimen (AUC = 757.2 vs. 359.0 ng[? ]h/mL; Cmax = 253.3 vs. 90.39 ng/mL). Following administration of a 600 mg (3 x 200 mg) oral dose to 8 healthy volunteers in the presence of food (heavy breakfast, as defined above), the mean absolute bioavailability is 4% (range: 1% to 9%). This low bioavailability is thought to be due to a combination of incomplete absorption (30%) and extensive first pass metabolism. After single and multiple oral doses as capsules (25 to 600 mg TID) in the presence of food, the increase in exposure (50-fold) was greater than directly proportional to the increase in dose (24- fold). Accumulation following multiple dosing (600 mg TID) in HIV-infected patients is modest: AUC was increased 150% at steady state compared to single doses. No food effect data are available for INVIRASE in combination with ritonavir. Saquinavir exposure was similar when saquinavir soft gel capsules plus ritonavir (1000 mg/100 mg bid) were administered following a high-fat (45 g fat) or moderate-fat (20 g fat) breakfast.

Table 5Pharmacokinetic Parameters of Saquinavir at Steady-State After Administration of Different Regimens in HIV-Infected Patients

:

Arithmetic Mean +- Standard Deviation

t

is the dosing interval (ie, 8h if tid and 12h if bid)

Distribution:

The mean steady-state volume of distribution following intravenous administration of a 12 mg dose of saquinavir is 700 L (CV 39%), indicating extensive partitioning into tissues. Saquinavir shows a high degree of protein binding (~98%), which is independent of concentration over the range 15-700 ng/mL.

In two patients treated with saquinavir (600 mg TID), cerebrospinal fluid concentrations were negligible when compared to concentrations from matching plasma samples.

Metabolism:

Greater than 96% of a radiolabelled I.V. dose appears in the feces within 48 hours, indicating extensive hepatic clearance. Hepatic metabolism is P450-mediated, of which >90% is the work of one isozyme (CYP3A4). The metabolic profile of saquinavir has been investigated in bile, plasma and microsomes in rats and in microsomes from other species, including man. Saquinavir is rapidly metabolized to a range of mono- and di-hydroxylated inactive compounds. Following intravenous administration, 66% of circulating saquinavir is present as unchanged drug and the remainder as metabolites, suggesting that saquinavir undergoes extensive first-pass metabolism.

Excretion:

Renal excretion is a very minor route of elimination for saquinavir (<4%). Systemic clearance is rapid, 80 L/h, which is close to hepatic plasma flow. Systemic clearance was constant after intravenous doses of 6, 36 and 72 mg infused over 3 hours. The mean residence time of the drug was found to be 7 hours.

In a mass balance study using 14C-saquinavir (n=8), 88% and 1% of the orally administered radioactivity was recovered in feces and urine, respectively, within 4 days of dosing. In an additional four subjects administered 10.5 mg 14C-saquinavir intravenously, 81% and 3% of the intravenously administered radioactivity was recovered in the feces and urine, respectively, within 4 days of dosing. In mass-balance studies, 13% of circulating saquinavir in plasma was present as unchanged drug after oral administration and the remainder present as metabolites.

Special Populations and Conditions

Pediatrics:

The pharmacokinetics of saquinavir when administered as INVIRASE have not been sufficiently investigated in pediatric patients.

Geriatrics:

The pharmacokinetics of saquinavir when administered as INVIRASE have not been sufficiently investigated in patients >65 years of age.

Gender: A gender difference was observed, with females showing a higher saquinavir exposure than males (mean AUC increase of 56%, mean Cmax increase of 26%), in the bioequivalence study comparing INVIRASE 500 mg film coated tablets to the INVIRASE 200 mg capsules in combination with ritonavir (see CLINICAL TRIALS: Comparative Bioavailability Studies). There was no evidence that age and body weight explained the gender difference in this study. A clinically significant difference in safety and efficacy between men and women has not been reported with the 1000 mg INVIRASE / 100 mg ritonavir b.i.d. dosage regimen.

Race:

The influence of race on the pharmacokinetics of INVIRASE has not been determined.

Hepatic Insufficiency:

In cases of mild impairment no initial dosage adjustment is necessary at the recommended dose. The use of INVIRASE (alone or in combination with ritonavir) in patients with moderate hepatic impairment has not been studied. In the absence of such studies, caution should be exercised, as increases in saquinavir levels and/or increases in liver enzymes may occur. In patients with underlying hepatitis B or C, cirrhosis, chronic alcoholism and/or other underlying liver abnormalities there have been reports of worsening liver disease and development of portal hypertension after starting saquinavir. Associated symptoms include jaundice, ascites, edema and, in some cases esophageal varices. Several of these patients died. A causal relationship between saquinavir therapy and development of portal hypertension has not been established. Increased monitoring for signs and symptoms of liver toxicity should be considered (see CONTRAINDICATIONS).

Renal Insufficiency:

Renal clearance is only a minor elimination pathway, the principal route of metabolism and excretion for saquinavir is via the liver. Therefore, no initial dose adjustment is necessary for patients with renal impairment. However, patients with severe renal impairment have not been studied and caution should be exercised when prescribing saquinavir in this population.

STORAGE AND STABILITY

INVIRASE (saquinavir mesylate) tablets and capsules should be kept in a tightly closed container and stored between 15 and 30oC.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Hard Gelatin Capsule

Composition: Each hard gelatin capsule contains 200 mg saquinavir, present as saquinavir mesylate; the light brown and green, opaque shells are imprinted with "Roche" and "0245". The non-medicinal ingredients are lactose, magnesium stearate, microcrystalline cellulose, povidone, sodium starch glycolate, and talc. The capsule shells contain gelatin, indigotine, iron oxide, and titanium dioxide. Availability: INVIRASE (saquinavir mesylate) hard gelatin capsules are available in either glass or plastic (HDPE) bottles, each containing 270 capsules.

Film Coated Tablet

Composition: INVIRASE 500 mg film coated tablets are light orange to greyish- or brownish-orange, oval cylindrical, biconvex tablets with ROCHE and SQV 500 imprinted on the tablet face. Each film coated tablet contains 500 mg saquinavir, present as saquinavir mesylate. Each tablet also contains the inactive ingredients croscarmellose sodium, lactose, magnesium stearate, microcrystalline cellulose, and povidone K30. Each film coat contains hypromellose, iron oxide red, iron oxide yellow, talc, titanium dioxide, and triacetin. Availability: INVIRASE film coated tablets are available in plastic (HDPE) bottles, each containing 120 tablets.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: saquinavir mesylate Chemical name: cis-N-tert-butyl-decahydro-2-[2(R)-hydroxy-4-phenyl-3(S)-[[N-2- quinolylcarbonyl-L-asparaginyl]amino]butyl]-(4aS,8aS)-isoquinoline- 3(S)-carboxamide methanesulphonate Molecular formula: C38H50N6O5 1:1 CH4O3S Molecular mass: 766.96 (free base 670.86) Structural formula: Physicochemical properties: Description: Saquinavir mesylate is a white crystalline solid Melting Point: 245-249oC Solubility: Solubility in water at 25oC is 0.22 g/100 mL pH: Approximately 5 in 1% aqueous suspension

CLINICAL TRIALS

In a randomized, double-blind clinical study (NV14256) in ZDV-experienced, HIV-infected patients, INVIRASE (saquinavir mesylate) in combination with zalcitabine was shown to be superior to either INVIRASE or zalcitabine monotherapy in decreasing the cumulative incidence of clinical disease progression to AIDS-defining events or death. Furthermore, in a randomized study (ACTG229/NV14255), patients with advanced HIV infection with history of prolonged ZDV treatment and who were given INVIRASE 600 mg tid + ZDV + zalcitabine experienced greater increases in CD4 cell counts as compared to those who received INVIRASE + ZDV or zalcitabine + ZDV. It should be noted that HIV treatment regimens that were used in these initial clinical studies of INVIRASE are no longer considered standard of care. No large, controlled clinical trial has been performed with the INVIRASE/ritonavir 1000mg /100mg dosage regimen. INVIRASE in combination with low dose ritonavir, provides increased saquinavir plasma levels (see ACTION AND CLINICAL PHARMACOLOGY: Pharmacokinetics).

Study Demographics and Trial Design

Table 6: Summary of Patient Demographics for the MaxCmin 2 Clinical Trial

Study Results

MaxCmin 2 Study: Saquinavir soft gel capsule/ritonavir versus lopinavir/ritonavir

In the MaxCmin 2 study, the safety and efficacy of saquinavir soft gel capsules/ritonavir 1000/100 mg bid plus 2 NRTIs/NNRTIs was compared with lopinavir/ritonavir 400/100 mg bid plus 2 NRTIs/NNRTIs in over 324 subjects. Values for median baseline CD4 count and median baseline plasma HIV RNA were 241 cells/mm3 and 4.4 log10 copies/ml in the saquinavir/ritonavir arm, and 239 cells/mm3 and 4.6 log10 copies/ml in the lopinavir/ritonavir arm, respectively. In the primary efficacy analysis, incidence of virologic failure, including all subjects that took at least one dose of the study medication (ITT/exposed population), fewer failures were observed in the lopinavir/ritonavir arm compared to the saquinavir/ritonavir arm (hazard ratio (HR) of lopinavir/ritonavir versus saquinavir/ritonavir: 0.5 (95% confidence intervals (CI): 0.3 - 0.8). This better outcome in the lopinavir/ritonavir arm was associated with lower failure rate among subjects no longer taking their assigned treatment and better compliance with the protocols intention to use antiretroviral treatment strategies aimed at suppressing viral replication at all times. At 48 weeks, the proportion of subjects with HIV RNA below the limit of detection (< 50 copies/ml) was 53% (N=161) for the saquinavir arm versus 60% (N=163) for the lopinavir arm in the intent-to-treat, switch equals failure analysis, and 74% (N=114) for the saquinavir arm versus 70% (N=141) for the lopinavir arm in the on-treatment analysis (p = ns for both comparisons). The combination of saquinavir and ritonavir exhibited comparable virological activity with the lopinavir and ritonavir arm when switch from the assigned treatment was counted as virological failure. Over 48 weeks a similar strong immunological response was seen in both arms with median increases in CD4 count of 106 cells/mm3 for the lopinavir/ritonavir arm, and 110 cells/mm3 for the saquinavir/ritonavir arm. No difference in the incidence of adverse events of grade 3 and/or 4 was seen between the two arms.

Comparative Bioavailability Studies

Study BP17359 was a two-center, open-label, randomized, two-treatment, two-sequence, four period, replicated crossover study conducted in healthy male and female subjects (87 males, 7 females) to establish bioequivalence between INVIRASE Film-Coated Tablet (FCT) 500 mg and INVIRASE HC 200 mg, administered at a single dose of 1000 mg of saquinavir combined with multiple dose ritonavir 100 mg bid under fed conditions. Study BP17359 results are summarized in the table below.

Saquinavir (1000 mg dose)

From measured data

Geometric Mean Arithmetic Mean (CV %)

*

INVIRASE 500 mg Film Coated Tablet administered as a 1000 mg dose (2 x 500 mg).

+

INVIRASE 200 mg Hard Gelatin Capsules [F. Hoffmann-La Roche, Basle, Switzerland] is identical to INVIRASE 200 mg Hard Gelatin Capsules commercially available in Canada and was administered as a

1000 mg dose (5 x 200 mg).

SS

Expressed as the median (range) only.

Expressed as the arithmetic mean (CV%) only.

The following table presents the pharmacokinetic data split for gender and treatment in study BP17359. While tmax was in the same range for male and female subjects, t1/2,b was increased in female subjects following both treatments. Moreover, AUC0-[?] and Cmax were higher in female subjects than in male subjects.

Arithmatic means (arithmatic CV%) followed by geometric means (geometric CV%) are reported for AUC0-[? ], Cmax, t1/2,ss, and CL/F. Median values (min-max) are reported for tmax. A similar gender difference was observed in Study BP17653 when INVIRASE 500 mg Film- Coated Tablets were administered at a single dose of 1000 mg of saquinavir (without ritonavir) under fed conditions.

DETAILED PHARMACOLOGY

Animal Pharmacology:

Saquinavir produced only minor effects in general pharmacology studies when administered orally at a dose level of 30 mg/kg either as a single dose or daily for five days. No pharmacodynamic effects were seen in the test models used when a single intravenous dose of the drug was given at a dose level of 1 mg/kg. A transient reduction in response to a painful stimulus, and an acute anti-convulsant effect to leptazol were observed in mice after oral administration of saquinavir. These effects however, were not confirmed in either the same models following IV dosing, or after oral dosing in other models used to investigate neuropharmacological or analgesic properties of the drug. A stimulation of respiration was seen in two of four anesthetized cats following intraduodenal administration of saquinavir. However, this effect was seen neither in anesthetized cats when the drug was given IV, nor in conscious cats following either IV or oral administration of saquinavir. Furthermore, no gross changes in respiration were seen during preclinical toxicity testing of saquinavir.

Table 7: Single-Dose General Pharmacology

Table 8: Five-Day Multiple Dose General Pharmacology

Drug-Drug Interactions:

Table 9 summarizes the effects of saquinavir on the geometric mean AUC and Cmax of coadministered drugs, and Table 10 summarizes the effect of coadministered drugs on the geometric mean AUC and Cmax of saquinavir.

Table 9: Effects of Saquinavir on the Pharmacokinetics of Coadministered Drugs

- Denotes no statistically significant change in exposure

| Denotes an average increase in exposure by percentage indicated

| Denotes an average decrease in exposure by percentage indicated

[?]

90% Confidence Interval

SS

Did not reach statistical significance

* * INVIRASE should not be coadministered (see Contraindications)

# No longer marketed in Canada

P Patient

V Healthy Volunteers

M Methadone-dependent, HIV negative patients NA Not Available

Table 10: Effect of Coadministered Drugs on Saquinavir Pharmacokinetics

- Mean change < 10%

| Denotes an average increase in exposure by percentage indicated

| Denotes an average decrease in exposure by percentage indicated

+ % change for described regimen versus historical data for standard saquinavir soft gel capsule 1200 mg tid regimen

++

% change for described regimen versus historical data for standard INVIRASE 600 mg tid regimen

SS Did not reach statistical significance

^ 90% Confidence Interval

# No longer marketed in Canada P Patient

V Healthy Volunteers

MICROBIOLOGY

The relationship between the in vitro susceptibility of HIV infection to saquinavir and the inhibition of HIV in humans or the clinical response to therapy has not been established. Western blot analysis has shown that saquinavir can block viral protein cleavage in infected cells at concentrations as low as 3.0 nM. Its mode of action has been confirmed by direct observation of virus maturation by electron microscopy: mature virus particles are replaced by immature forms within 24 h of treatment of chronically-infected CEM cells with 10 nM saquinavir. Viral yields from such treated cultures proved, as predicted, non-infectious on further passage on to fresh cells in the absence of drug, although there may be some late breakthrough on continued culture. Saquinavir has shown consistently potent antiviral activity in primary monocytes and monocytic lung cell lines, and in lymphocytes or lymphoblastoid cells. Unlike nucleoside analogues (zidovudine, etc., which act only in early infection), saquinavir acts directly on its viral target enzyme. As a consequence of this direct action and because it does not require metabolic activation, the antiviral potential of saquinavir is retained against resting (non-dividing), chronically infected cultures (as well as acutely infected cultures). In vitro antiviral activity of saquinavir was assessed in lymphoblastoid and monocytic cell lines and in peripheral blood lymphocytes. Saquinavir inhibited HIV activity in both acutely and chronically infected cells. IC50 and IC90 values (50% and 90% inhibitory concentrations) were in the range of 1 to 30 nM and 5 to 80 nM, respectively. In the presence of 40% human serum, the mean IC50 of saquinavir against laboratory strain HIV-1 RF in MT4 cells was 37.7 +- 5 nM representing a 4-fold increase in the IC50 value. In cell culture, saquinavir demonstrated additive to synergistic effects against HIV-1 in combination with reverse transcriptase inhibitors (didanosine, lamivudine, nevirapine, stavudine, zalcitabine and zidovudine) without enhanced cytotoxicity. Saquinavir in combination with the protease inhibitors amprenavir, atazanavir, or lopinavir resulted in synergistic antiviral activity. Saquinavir displayed antiviral activity in vitro against HIV-1 clades A-H (IC50 ranged from 0.9 to 2.5 nM). The IC50 and IC90 values of saquinavir against HIV-2 isolates in vitro ranged from 0.25 nM to 14.6 nM and 4.65 nM to 28.6 nM, respectively. Evidence of saquinavir cytotoxicity has been found only at mM concentrations (typically 5-100 mM), affording a high in vitro therapeutic index of >1000. This lack of cytotoxicity has allowed long-term administration of the compound without detriment to host cells, in consequence of which studies have indicated the disappearance of HIV-1 (infectivity and DNA) from infected MT-2 cell cultures after some 80 days of drug treatment at 100 nM, and without rebound infection after 35 days from drug removal; this has been explained by outgrowth of healthy cells following the progressive death of the infected component.

Hypersusceptibility to Mutant Virus:

Hypersusceptibility of some resistant viruses to inhibition with saquinavir has been described for example in the presence of the 30N substitution (with or without additional substitutions at residues 46, 71 or 88). This was also observed in complexes of substitutions showing resistance to amprenavir including 50V in presence or absence of 46I and 47V. Indeed, recently it was found that a high proportion of viruses with substitutions at residue 82 either retain susceptibility (37%) or show enhanced activity (8%) to saquinavir. The clinical significance of hypersusceptibility to saquinavir has not been established.

TOXICOLOGY

Oral toxicity and toxicokinetic studies in the rat and marmoset of up to six months duration have demonstrated excellent tolerance to high plasma levels of saquinavir. Increased susceptibility to saquinavir, as a result of gastrointestinal irritancy, was seen in neonatal rats. After weaning, juvenile animals tolerated the drug with no indications of toxicity. No reproductive, teratogenic, developmental or mutagenic effects have been seen with saquinavir. A four-week oral combination study of saquinavir and zidovudine was conducted in mice; no toxic or toxicokinetic interactions were observed between these two drugs. A small toxicity and toxicokinetic program was also conducted to evaluate the intravenous use of saquinavir. Administration to rats and marmosets for up to four weeks produced mild to severe effects at the injection site. Only minor systemic findings were observed that were considered related to treatment with saquinavir.

Carcinogenesis:

In the rat and mouse carcinogenicity studies with saquinavir, animals were administered Ro 31-8959/008 which is the mesylate salt. Carcinogenicity studies found no indication of carcinogenic activity in rats and mice administered saquinavir for approximately 2 years. The plasma exposures (AUC values) in the respective species were up to approximately 29% of (using rat) and 65% of (using mouse) those obtained in humans at the recommended clinical dose boosted with ritonavir.

Table 11: Plasma Exposure Data from the Rat and Mouse Carcinogenicity Studies Conducted with Saquinavir in Relation to Saquinavir Plasma Levels Obtained in Patients Following the Boosted Dose Regimen (1000 mg saquinavir/100 mg ritonavir b.i.d.)

* Ratios are based on exposure seen in patients receiving saquinavir soft gel capsules/ritonavir 1000 mg/100 mg

b.i.d.

Mutagenesis: Mutagenicity and genotoxicity studies, with and without metabolic activation where appropriate, have shown that saquinavir has no mutagenic activity in vitro in either bacterial (Ames test) or mammalian cells (Chinese hamster lung V79/HPRT test). Saquinavir does not induce chromosomal damage in vivo in the mouse micronucleus assay or in vitro in human peripheral blood lymphocytes and does not induce primary DNA damage in vitro in the unscheduled DNA synthesis test.

Impairment of Fertility:

Fertility and reproductive performance were not affected in rats at plasma exposures (AUC values) up to 26% of those obtained in humans at the recommended clinical dose boosted with ritonavir.

Table 12: Plasma Exposure Data from the Rat Fertility, Rat Embryotoxicity/ Teratogenicity and Rabbit Embryotoxicity/Teratogenicity Studies Conducted with Saquinavir in Relation to Saquinavir Plasma Levels Obtained in Patients Following the Boosted Dose Regimen (1000 mg saquinavir/100 mg ritonavir b.i.d.)

*Ratios are based on exposure seen in patients receiving saquinavir soft gel capsules/ritonavir 1000 mg/100 mg

b.i.d.

a: AUC data from separate TK study in pregnant rats (report W-141963)

b: AUC data from separate general tolerance and TK study in non-pregnant rabbits (reported in B-154991) NM = Not measured

ND = Not determined due to insufficient data

Teratogenicity:

Embryotoxic/teratogenic effects were not observed in rats or rabbits at plasma exposures (AUC values) approximately 32% of those achieved in humans at the recommended clinical dose of INVIRASE (1000 mg BID) boosted with ritonavir (100 mg BID).

Table 13: Acute Toxicity

Table 14: Multiple-Dose Toxicity

*

equivalent to approximately 0, 220, 700, 2100, 5500 and 10000 mg/kg/day

Table 14 (continued): Multiple-Dose Toxicity

Table 14 (continued): Multiple-Dose Toxicity

*

equivalent to approximately 0, 85. 230, 815, 2200 and 3600 mg/kg/day

Table 14 (continued): Multiple-Dose Toxicity

Table 15: Dermal Toxicity

Table 16: Teratology and Reproductive Toxicity

Table 17: Mutagenicity and Genotoxicity

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