Submission Control Number: 116920

All trademark rights used under license (c)2008 JANSSEN-ORTHO Inc.

This product has been approved under the Notice of Compliance with Conditions (NOC/c) policy for one or all of its indicated uses.

What is a Notice of Compliance with Conditions (NOC/c)?

An NOC/c is a form of market approval granted to a product on the basis of promising evidence of clinical effectiveness following review of the submission by Health Canada. Products approved under Health Canada's NOC/c policy are intended for the treatment, prevention or diagnosis of a serious, life-threatening or severely debilitating illness. They have demonstrated promising benefit, are of high quality and possess an acceptable safety profile based on a benefit/risk assessment. In addition, they either respond to a serious unmet medical need in Canada or have demonstrated a significant improvement in the benefit/risk profile over existing therapies. Health Canada has provided access to this product on the condition that sponsors carry out additional clinical trials to verify the anticipated benefit within an agreed upon time frame.

What will be different about this Product Monograph?

The following Product Monograph will contain boxed text at the beginning of each major section clearly stating the nature of the market authorization. Sections for which NOC/c status holds particular significance will be identified in the left margin by the symbol NOC/c. These sections may include, but are not limited to, the following:

• Indications and Clinical Use;

• Action;

• Warnings and Precautions;

• Adverse Reactions;

• Dosage and Administration; and

• Clinical Trials.

CONTRAINDICATIONS

PREZISTA is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see the DOSAGE FORMS, COMPOSITION AND PACKAGING section of the Product Monograph. PREZISTA is contraindicated in patients with severe (Child-Pugh Class C) hepatic insufficiency. Co-administration of PREZISTA/RTV is contraindicated with drugs that are highly dependent on CYP3A4 for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events (narrow therapeutic index). These drugs are listed in Table 1 (also see DRUG INTERACTIONS, Drug-Drug Interactions, Table 4).

Table 1: Drugs That Are Contraindicated With PREZISTA/RTV

Bepridil, astemizole, terfenadine and cisapride are no longer marketed in Canada.

NOC/c

WARNINGS AND PRECAUTIONS

General

PREZISTA (darunavir) must be administered with low-dose ritonavir to ensure its therapeutic effect (see DRUG INTERACTIONS, Drug-Drug Interactions, Table 5; DOSAGE AND ADMINISTRATION; and ACTION AND CLINICAL PHARMACOLOGY,

Pharmacokinetics

). Failure to correctly co-administer PREZISTA with ritonavir will result in reduced plasma levels of PREZISTA that may be insufficient to achieve the desired antiviral effect. Patients should be instructed accordingly. Please refer to the ritonavir Product Monograph for additional information on precautionary measures.

PREZISTA is not a cure for HIV-1 infection or AIDS. Patients receiving darunavir or any other antiretroviral therapy may continue to develop opportunistic infections and other complications of HIV-1 infection. PREZISTA therapy has not been shown to reduce the risk of transmission of HIV-1 to others.

Carcinogenesis and Mutagenesis

Long-term carcinogenicity studies of darunavir have not been completed (see Product Monograph Part II: TOXICOLOGY, Carcinogenesis and Mutagenesis). Darunavir tested negative in the in vitro Ames reverse mutation assay, both in the presence and absence of the metabolic activation system. Darunavir also tested negative in the in vitro chromosomal aberration assay in human lymphocytes, both in the presence and absence of the metabolic activation system. Darunavir did not induce chromosomal damage in the in vivo micronucleus test in mice (see Product Monograph Part II: TOXICOLOGY, Carcinogenesis and Mutagenesis).

Endocrine and Metabolism

Diabetes Mellitus /Hyperglycemia

New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported during postmarketing 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 causal relationships between protease inhibitor therapy and these events have not been established.

Fat Distribution

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.

Hematologic

There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis, in patients with hemophilia type A and 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 reintroduced. A causal relationship between protease inhibitor therapy and these events has not been established; however, the frequency of bleeding episodes should be closely monitored in patients on PREZISTA/RTV.

Hepatic/Biliary/Pancreatic

Hepatic

PREZISTA is contraindicated in patients with severe hepatic insufficiency (Child-Pugh Class C) (see CONTRAINDICATIONS). Patients with mild or moderate hepatic impairment (Child- Pugh Class A or B, respectively) should be closely monitored. Patients with chronic hepatitis B or C and treated with combination antiretroviral therapy are at an increased risk for severe and potentially fatal hepatic adverse events. Limited data are currently available for the use of PREZISTA co-administered with low dose ritonavir, in patients co-infected with hepatitis B or C. Patients with pre-existing liver dysfunction including chronic hepatitis B or C have an increased frequency of liver function abnormalities during combination antiretroviral therapy. Appropriate monitoring should be conducted prior to initiating therapy with PREZISTA/RTV and increased monitoring should be considered in patients with elevated baseline transaminase levels, active hepatitis B or C and in patients with underlying liver disease, especially during the first several months of PREZISTA/RTV treatment. If there is evidence of worsening liver disease in such patients, interruption or discontinuation of treatment should be considered. Drug-induced hepatitis (e.g., acute hepatitis, cytolytic hepatitis) has been reported with PREZISTA/RTV. During the clinical development program (N=3063), hepatitis has been reported in 0.5% of patients receiving combination therapy with PREZISTA/RTV. Post-marketing cases of clinical hepatitis and hepatic decompensation, including some fatalities have been reported. These have generally occurred in patients with advanced HIV disease taking multiple concomitant medications, having co-morbidities including hepatitis B or C co-infection, and/or developing immune reconstitution syndrome. A causal relationship with PREZISTA/RTV therapy has not been established. For information on the multi-dose pharmacokinetics of darunavir in hepatically impaired patients, see ACTION AND CLINICAL PHARMACOLOGY.

Pancreatic

Pancreatitis has been observed in patients receiving PREZISTA/RTV therapy, including those who developed marked triglyceride elevations. Although a causal relationship to PREZISTA has not been established, marked triglyceride elevation is a risk factor for development of pancreatitis (see WARNINGS AND PRECAUTIONS, Lipid Elevations). Patients with advanced HIV disease may be at risk of elevated triglycerides and pancreatitis, and patients with a history of pancreatitis may be at increased risk for recurrence during PREZISTA/RTV therapy.

Immune

Immune Reconstitution Syndrome

During the initial phase of treatment, patients responding to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (such as MAC, CMV, PCP, and TB), which may necessitate further evaluation and treatment.

Lipid Elevations

Treatment with PREZISTA has resulted in increases in the concentration of total cholesterol and triglycerides. Triglyceride and cholesterol testing should be performed prior to initiating PREZISTA therapy and at periodic intervals during therapy. Lipid disorders should be managed as clinically appropriate. See Table 4 and Table 5 for additional information on potential drug interactions with PREZISTA and HMG-CoA reductase inhibitors.

Renal

Renal Impairment

Population pharmacokinetic analysis showed that the pharmacokinetics of darunavir were not significantly affected in HIV infected subjects with moderate renal impairment (CrCL between 30-60 mL/min, n=20). There are no pharmacokinetic data available in HIV-1 infected patients with severe renal impairment or end stage renal disease. However, since the renal clearance of darunavir is limited, a decrease in total body clearance is not expected in patients with renal impairment. As darunavir and ritonavir are highly bound to plasma proteins, it is unlikely that they will be significantly removed by hemodialysis or peritoneal dialysis (see DOSAGE AND ADMINISTRATION and ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Renal Insufficiency). Sensitivity/Resistance Darunavir contains a sulfonamide moiety. PREZISTA (darunavir) should be used with caution in patients with a known sulfonamide allergy. The potential for cross-sensitivity between drugs in the sulfonamide class and darunavir is unknown.

Skin

During the clinical development program, severe skin rash, including erythema multiforme and Stevens-Johnson syndrome, has been reported. In some cases, fever and elevations of transaminases have also been reported. In clinical trials (n=924), rash (all grades, regardless of causality) occurred in 7% of subjects treated with PREZISTA; the discontinuation rate due to rash was 0.3%. Rashes were generally mild-to-moderate, self-limited maculopapular skin eruptions. Treatment with PREZISTA should be discontinued if severe rash develops.

Special Populations

Pregnant Women:

There are no adequate and well-controlled studies with darunavir in pregnant women. Studies in animals have not shown evidence of developmental toxicity or effect on reproductive function and fertility (see Product Monograph Part II: TOXICOLOGY, Reproductive and Developmental Toxicity). PREZISTA should be used during pregnancy only if the potential benefit justifies the potential risk.

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

Nursing Women:

HIV-infected mothers should not breast-feed their infants to avoid risking postnatal transmission of HIV. It is not known whether darunavir is excreted in human milk. Studies in rats have demonstrated that darunavir is excreted into the milk of lactating rats. Because of both the potential for HIV transmission and the potential for serious adverse events in nursing infants, mothers should be instructed not to breast-feed if they are receiving PREZISTA (see Product Monograph Part II: TOXICOLOGY, Reproductive and Developmental Toxicity).

Pediatrics (< 18 years of age):

Safety and effectiveness of PREZISTA/RTV in pediatric patients have not been established.

Geriatrics (> 65 years of age):

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

NOC/c

DRUG INTERACTIONS

Serious Drug Interactions

• Darunavir and ritonavir are both inhibitors of the cytochrome P450 3A4 (CYP3A4) isoform. PREZISTA/RTV should not be co-administered with medicinal products that are highly dependent on CYP3A4 for clearance, and for which increased plasma concentrations are associated with serious and/or life-threatening events (narrow therapeutic index). These medicinal products include amiodarone, bepridil, lidocaine (systemic), quinidine, astemizole, terfenadine, midazolam, triazolam, cisapride, pimozide, and the ergot alkaloids (e.g., ergotamine, dihydroergotamine, ergonovine, and methylergonovine) (see CONTRAINDICATIONS).

Overview

Darunavir and ritonavir are both inhibitors of the cytochrome P450 isoform CYP3A4. Co-administration of darunavir and ritonavir with drugs primarily metabolized by CYP3A4 may result in increased plasma concentrations of such drugs, which could increase or prolong their therapeutic effect and adverse events (see CONTRAINDICATIONS and Drug-Drug Interactions, Tables 4 and 5).

Drug-Drug Interactions

Drugs that are contraindicated and not recommended for co-administration with PREZISTA/RTV 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.

Bepridil, astemizole, terfenadine and cisapride are no longer marketed in Canada.

Other NRTIs:

Based on the different elimination pathways of the other NRTIs (zidovudine, zalcitabine, emtricitabine, stavudine, lamivudine and abacavir) that are primarily renally excreted, no drug interactions are expected for these drugs and PREZISTA/RTV.

Other Protease Inhibitors:

The co-administration of PREZISTA/RTV and PIs other than lopinavir/ritonavir, saquinavir, atazanavir, and indinavir has not been studied. Therefore, such co-administration is not recommended. Drug interaction studies were performed with darunavir and other drugs likely to be co- administered and some drugs commonly used as probes for pharmacokinetic interactions. The effects of co-administration of darunavir on the AUC, Cmax, and Cmin values are summarized in Table 6 and Table 7.

Table 6: Drug Interactions: Pharmacokinetic Parameters for Darunavir in the Presence of Co-administered Drugs

N = number of subjects with data; - = no information available.

a

Ratio based on between-study comparison.

Table 7: Drug Interactions: Pharmacokinetic Parameters for Co-administered Drugs in the Presence of Darunavir/Ritonavir

Table 7: Drug Interactions: Pharmacokinetic Parameters for Co-administered Drugs in the Presence of Darunavir/Ritonavir

N = number of subjects with data; - = no information available.

a

Atorvastatin 10 mg q.d. with darunavir/ritonavir 300/100 mg b.i.d. was compared to atorvastatin 40 mg q.d. alone.

b

Sildenafil 25 mg (single dose) with darunavir/ritonavir 400/100 mg b.i.d. was compared to sildenafil 100 mg alone (single dose).

Drug-Food Interactions

Darunavir, when given as a tablet and co-administered with low-dose ritonavir as a pharmacokinetic enhancer, should be taken with food. The type of food does not affect the exposure to darunavir.

Drug-Herb Interactions

Concomitant use of PREZISTA/RTV and St. John's wort (Hypericum perforatum) or products containing St. John's wort is not recommended. Co-administration of protease inhibitors, including PREZISTA/RTV, with St. John's wort is expected to substantially decrease protease inhibitor concentrations and may result in suboptimal concentrations of darunavir and lead to loss of virologic response and possible resistance to PREZISTA/RTV or to the class of protease inhibitors (see Drug-Drug Interactions, Table 4). Interactions with other herbal products have not been established.

Drug-Laboratory Interactions

Interactions with laboratory tests have not been established.

NOC/c

DOSAGE AND ADMINISTRATION

Dosing Considerations

PREZISTA must always be given with 100 mg ritonavir as a pharmacokinetic enhancer, and in combination with other antiretroviral medicinal products. The prescribing information of ritonavir must, therefore, be consulted prior to initiation of therapy with PREZISTA/RTV.

Recommended Dose and Dosage Adjustment

Adults:

The recommended oral dose of PREZISTA tablets is 600 mg (two 300 mg tablets) twice daily (b.i.d.) taken with ritonavir 100 mg b.i.d. and with food. The type of food does not affect exposure to darunavir. Ritonavir (100 mg b.i.d.) is used as a pharmacokinetic enhancer of PREZISTA (see DRUG INTERACTIONS, Drug-Drug Interactions, and ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics). A further increase in the dose of darunavir or ritonavir is not likely to result in any clinically relevant increase in antiviral activity.

Geriatric Patients:

In general, caution should be exercised in the administration and monitoring of PREZISTA in elderly patients, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy (see INDICATIONS AND CLINICAL USE, WARNINGS AND PRECAUTIONS and ACTION AND CLINICAL PHARMACOLOGY).

Pediatric Patients:

The safety and efficacy of PREZISTA in pediatric patients have not yet been established. There are insufficient data at this time to recommend a dose (see INDICATIONS AND CLINICAL USE, WARNINGS AND PRECAUTIONS and ACTION AND CLINICAL PHARMACOLOGY).

Hepatic Impairment:

The safety and efficacy of PREZISTA have not been established in patients with severe hepatic insufficiency (see CONTRAINDICATIONS). No dose adjustment is required in patients with mild or moderate hepatic impairment (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics).

Renal Impairment:

No dose adjustment is required in patients with renal impairment (see WARNINGS AND PRECAUTIONS, Renal and ACTION AND CLINICAL PHARMACOLOGY,

Pharmacokinetics).

Dosing with Didanosine:

Dosing of enteric-coated didanosine and darunavir, co-administered with low-dose ritonavir, should be separated by at least 2 hours to avoid formulation incompatibility.

Missed Dose

The missed dose should be taken as soon as possible, if the dose was missed by less than 6 hours. The next dose of PREZISTA and ritonavir should be taken at the regularly scheduled time. If the dose of PREZISTA or ritonavir was missed by more than 6 hours, the next dose of PREZISTA or ritonavir should be taken at the regularly scheduled time. Doses should not be doubled.

OVERDOSAGE

For management of a suspected drug overdose, contact your regional Poison Control Centre. Human experience of acute overdose with PREZISTA/RTV is limited. Single doses up to 3200 mg of the oral solution of darunavir alone and up to 1600 mg of the tablet formulation of darunavir co-administered with ritonavir have been administered to healthy volunteers without untoward symptomatic effects. There is no specific antidote for overdose with PREZISTA. Treatment of overdose with PREZISTA consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. Administration of activated charcoal may be used to aid in removal of unabsorbed active substance. Since PREZISTA is highly protein bound, dialysis is unlikely to be beneficial in significant removal of the active substance.

NOC/c

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

Darunavir is an inhibitor of the HIV-1 protease. It selectively inhibits the cleavage of HIV encoded Gag-Pol polyproteins in virus-infected cells, thereby preventing the formation of mature infectious virus particles. Darunavir tightly binds to the HIV-1 protease with a KD of 4.5 x 10-12 M. Darunavir is not an inhibitor of any of 13 tested human cellular proteases.

Pharmacodynamics

The pharmacokinetic properties of darunavir, co-administered with ritonavir, have been evaluated in healthy adult volunteers and in HIV-1 infected patients. Exposure to darunavir was higher in HIV-1 infected patients than in healthy subjects. Darunavir is primarily metabolized by CYP3A. Ritonavir inhibits CYP3A, thereby increasing the plasma concentrations of darunavir considerably.

Table 8: Mean Steady-State Plasma Concentration-Time Profiles of Darunavir and Ritonavir at

600/100 mg b.i.d. at Week 4 (Integrated Data from POWER 1and POWER 2, Primary 24-Week Analysis)

Pharmacokinetics

Absorption:

Darunavir was rapidly absorbed following oral administration. Maximum plasma concentration of darunavir in the presence of low-dose ritonavir is generally achieved within 2.5-4.0 hours. The absolute oral bioavailability of a single 600 mg dose of darunavir alone was approximately 37% and increased to approximately 82% in the presence of 100 mg b.i.d. ritonavir. The overall pharmacokinetic enhancement effect by ritonavir was an approximate 14-fold increase in the systemic exposure of darunavir when a single dose of 600 mg darunavir was given orally co- administered with ritonavir at 100 mg b.i.d. Therefore, PREZISTA should only be co- administered with 100 mg of ritonavir as a pharmacokinetic enhancer.

Table 9: Pharmacokinetic Parameters of Darunavir 600 mg and Darunavir/Rtv at 600/100 mg b.i.d.

Increasing the dose of ritonavir to above 100 mg b.i.d. did not significantly affect darunavir concentrations and is not recommended.

Effects of Food on Oral Absorption:

When administered without food, the relative bioavailability of darunavir in the presence of low- dose ritonavir is 30% lower as compared to intake with food. Therefore, PREZISTA tablets should be taken with ritonavir and with food. The type of food does not affect exposure to darunavir.

Distribution:

Darunavir is approximately 95% bound to plasma proteins. Darunavir binds primarily to plasma AAG (alpha-1-acid glycoprotein).

Metabolism:

In vitro experiments with human liver microsomes (HLMs) indicate that darunavir primarily undergoes oxidative metabolism. Darunavir is extensively metabolized by the hepatic CYP system, and almost exclusively by isozyme CYP3A4. A 14C-darunavir trial in healthy volunteers showed that a majority of the radioactivity in plasma after a single 400/100 mg darunavir/ritonavir dose was due to the parent drug. At least 3 oxidative metabolites of darunavir have been identified in humans; all showed activity that was at least 10-fold less than the activity of darunavir against wild-type HIV.

Excretion:

After a 400/100 mg 14C-darunavir/ritonavir dose, approximately 79.5% and 13.9% of the administered dose of 14C-darunavir could be retrieved in feces and urine, respectively. Unchanged darunavir accounted for approximately 41.2% and 7.7% of the administered dose in feces and urine, respectively. The terminal elimination half-life of darunavir was approximately 15 hours when combined with ritonavir. The intravenous clearance of darunavir alone (150 mg) and in the presence of low-dose ritonavir was 32.8 L/h and 5.9 L/h, respectively.

Special Populations and Conditions:

Pediatrics:

The pharmacokinetics of darunavir co-administered with ritonavir in pediatric patients are under investigation. There are insufficient data at this time to recommend a dose.

Geriatrics:

Population pharmacokinetic analysis in HIV-infected patients showed that darunavir pharmacokinetics are not considerably different in the age range (18 to 75 years) evaluated in HIV-infected patients (n=12, age >= 65) (see WARNINGS AND PRECAUTIONS, Special Populations, Geriatrics).

Gender:

Population pharmacokinetic analysis showed a slightly higher darunavir exposure (16.8%) in HIV-infected females (n=68) compared to males. This difference is not considered clinically relevant.

Race:

Population pharmacokinetic analysis of darunavir in HIV-infected patients indicated that race had no apparent effect on the exposure to darunavir.

Hepatic Insufficiency:

Hepatic Impairment:

Darunavir is primarily metabolized and eliminated by the liver. In a multiple dose study with PREZISTA co-administered with ritonavir (600/100 mg) twice daily, it was demonstrated that the steady-state pharmacokinetic parameters of darunavir in subjects with mild (Child-Pugh Class A, n=8) and moderate (Child-Pugh Class B, n=8) hepatic impairment were comparable with those in healthy subjects. The effect of severe hepatic impairment of on the pharmacokinetics of darunavir has not been studied (see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and DOSAGE AND ADMINISTRATION).

Hepatitis B or Hepatitis C Virus Co-infection:

The primary 24-week analysis of the data from Study TMC114-C213 in 31 HIV-1 infected patients indicated that hepatitis B and/or hepatitis C virus co-infection status had no apparent effect on the exposure to darunavir.

Renal Insufficiency:

Results from a mass balance study with 14C-darunavir/ritonavir showed that approximately 7.7% of the administered dose of darunavir is excreted in the urine as unchanged drug. As darunavir and ritonavir are highly bound to plasma proteins, it is unlikely that they will be significantly removed by hemodialysis or peritoneal dialysis. Although darunavir has not been studied in patients with renal impairment, population pharmacokinetic analysis showed that the pharmacokinetics of darunavir were not significantly affected in HIV-infected patients with moderate renal impairment (CrCL between 30-60 mL/min, n=20) (see WARNINGS AND PRECAUTIONS, Renal and DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage Adjustment, Renal Impairment).

STORAGE AND STABILITY

Store PREZISTA tablets between 15 - 30degC.

DOSAGE FORMS, COMPOSITION AND PACKAGING

PREZISTA is available as an orange, oval-shaped, film-coated tablet for oral administration containing 300 mg of darunavir (corresponding to 325.23 mg of darunavir ethanolate). Each tablet contains the inactive ingredients microcrystalline cellulose, colloidal silicon dioxide, crospovidone, and magnesium stearate. The tablet film coating contains polyethylene glycol, polyvinyl alcohol - partially hydrolyzed, sunset yellow FCF aluminum lake, talc, and titanium dioxide. Each tablet is debossed with "300MG" on one side and "TMC114" on the other side. PREZISTA tablets are packaged in bottles in the following configuration: 300 mg tablets--bottles of 120 tablets

PART II: SCIENTIFIC INFORMATION

PREZISTA, co-administered with 100 mg ritonavir and other antiretroviral agents and indicated for the treatment of human immunodeficiency virus (HIV) infection in antiretroviral treatment- experienced adult patients who have failed prior antiretroviral therapy, has been issued marketing authorization with conditions, pending the results of studies to verify its clinical benefit. Patients should be advised of the nature of the authorization.

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Darunavir (as the ethanolate) Chemical name: [(1S,2R)-3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino]-2-hydroxy-1- (phenylmethyl)propyl]-carbamic acid (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl ester ethanolate Molecular formula and molecular mass: Molecular formula: C27H37N3O7S.C2H5OH Molecular mass: 547.66 (593.73 as the ethanolate) Structural formula:

H

O O

O N H H

O O

S N

H

OH

H3C

CH3

C2H5OH Physicochemical properties:

NOC/c

Darunavir ethanolate is a white to off-white powder with a solubility of approximately 0.015 mg/mL in water at 20degC.

CLINICAL TRIALS

Study demographics and trial design

The evidence of efficacy of PREZISTA/RTV is based on the analyses of 24-week data from 2 ongoing, randomized, controlled trials in antiretroviral treatment-experienced HIV-1-infected adult patients (TMC114-C213 and TMC114-C202).

Treatment-Experienced Patients

TMC114-C213 (POWER 1) and TMC114-C202 (POWER 2) are randomized, controlled, Phase 2b trials consisting of 2 parts: an initial partially-blinded, dose-finding part and a second long-term part in which all patients randomized to PREZISTA/RTV received the recommended dose of 600/100 mg b.i.d. HIV-1 infected patients who were eligible for these trials had plasma HIV-1 RNA > 1000 copies/mL, had prior treatment with PI(s), NNRTI(s) and NRTI(s), had at least one primary PI mutation (D30N, M46I/L, G48V, I50L/V, V82A/F/S/T, I84A/C/V, L90M) at screening, and were on a stable PI-containing regimen at screening for at least 8 weeks. Randomization was stratified by the number of PI mutations, screening viral load, and the use of enfuvirtide. This analysis included 318 patients in TMC114-C213 and 319 patients in TMC114-C202 who had completed 24 weeks of treatment or discontinued earlier. At 24 weeks, the virologic response rate was evaluated in patients receiving PREZISTA/RTV plus an optimized background regimen (OBR) versus a control group receiving an investigator- selected PI(s) regimen plus an OBR. The OBR consisted of at least 2 NRTIs with or without enfuvirtide. Based on resistance testing and prior medical history, selected PIs in the control arm included: lopinavir/ritonavir in 36%, (fos)amprenavir in 34%, saquinavir in 35% and atazanavir in 17%; 23% of the control patients used dual-boosted PIs. Approximately 47% of all patients used enfuvirtide (ENF), and 35% of the use was in patients who were ENF-naive. Virologic response was defined as a decrease in plasma HIV-1 RNA viral load of at least 1.0 log10 versus baseline. In the pooled analysis for TMC114-C213 and TMC114-C202, demographics and baseline characteristics were balanced between the PREZISTA/RTV arm and the comparator PI arm. The 131 patients in the PREZISTA/RTV 600/100 mg b.i.d. arm had a median age of 43.9 years (range 27-73), 89% were male, 81% Caucasian, 10% Black, and 7% Hispanic. The median baseline plasma HIV-1 RNA was 4.52 log10 copies/mL (range: 3.0 to 6.4 log10 copies/mL), and the median baseline CD4+ cell count was 153 x 106 cells/L (range: 3 x 106 to 776 x 106 cells/L). 24.4% of patients had a baseline viral load > 100,000 copies/mL, 32.1% had a baseline viral load of <20,000 copies/mL. 33% of patients had a baseline CD4+ cell count > 200 x 106 cells/L, 22% of patients had a baseline CD4+ cell count <50 x 106 cells/L. The median darunavir fold change (FC) was 4.3. Table 10 compares the baseline characteristics between patients in the PREZISTA/RTV 600/100 mg b.i.d. arm and patients in the comparator PI arm.

Table 10: Baseline Demographics of the TMC114-C213, TMC114-C202 Trials and TMC114-C213 & TMC114-C202 (pooled)

a

IAS-USA March 2005: D30N, L33F/I, M46I/L, G48V, 150L/V, V82A/F/L/S/T, 184A/C/V, L90M

b

IAS-USA: L10F/I/R/V, K201/L/M/R/T, L24I, D30N, V32I, L33F/I, M36I/L/V, M46I/L, 147A/V, G48V, 150L/V, F53L, 154A/L/M/S/T/V,

A71V/T, G73A/C/S/T, V77I, V82A/F/L/S/T, 184A/C/V, N88D/S, L90M

c

Based on the IAS-USA list of mutations (March 2005): D30N, L33F/I, M46I/L, G48V, I50L/V, V82A/F/L/S/T, I84A/C/V, L90M

d

Only counting ARVs, excluding low-dose ritonavir, taken for at least 2 months, and for which start and stop dates were available

Study results

The results of the primary efficacy analyses of trials TMC114-C213 and TMC114-C202 demonstrate that, in treatment-experienced subjects, PREZISTA/RTV-containing regimens significantly improve the efficacy benefits obtained with standard of care. These results were robust and consistent across both trials TMC114-C213 and TMC114-C202 for all virologic efficacy parameters studied, and consistent across various statistical sensitivity analyses. Table 11shows that for all efficacy parameters studied, all doses of PREZISTA/RTV used in trials TMC114-C202 and TMC114-C213 were effective and significantly better than control, with the highest dose of PREZISTA/RTV 600/100 mg b.i.d. showing the greatest virologic response at Week 24.

Table 11: Virologic Response Rate Defined as a Decrease of 1.0 log10 or More in Plasma Viral Load Versus Baseline at Week 24 (TMC114-C213 and TMC114-C202) and Logistic Regression Model: Estimated Proportion of Response and Statistical Pairwise Comparisons With Control

a

Percent response estimated from a logistic regression model including treatment and all stratification variables (use of ENF and number of primary mutations as stratified and baseline viral load as a covariate)

b

p-values resulting from pairwise comparison of each darunavir/RTV with Control

Reasserting the observed dose-response trend, there were also statistically significant differences between all the other doses of darunavir/RTV used (400/100 mg q.d., 800/100 mg q.d., 400/100 mg b.i.d.) compared to the comparator PI arm at Week 24 for the secondary efficacy endpoints of a decrease of at least 0.5 log10 viral load (67.0%, 72.3% and 65.0%, respectively vs. 25.5%) and viral load < 50 copies/mL (33.0%, 36.6% and 44.0%, respectively vs. 13.7%). Patients randomized to these dose arms of the TMC114-C213 and TMC114-C202 studies also experienced a mean change in CD4+ cell count versus baseline (x 106 cells/L) at Week 24 of 66.4, 75.0 and 88.1, respectively vs. the comparator PI arm of 16.8. Efficacy data of the 24-week analyses for patients on the recommended dose PREZISTA/RTV 600/100 mg b.i.d. from the TMC114-C213 and TMC114-C202 trials (separate and pooled) are shown in Table 12.

Table 12: Outcomes of Randomized Treatment Through Week 24 of the TMC114-C213 and TMC114- C202 Trials (Separate and Pooled Analyses)

a

Imputations according to the TLOVR algorithm

bPatients who did not achieve at least a confirmed 0.5 log10 HIV-1 RNA drop from baseline at Week 12

cPatients with an initial response (confirmed 1 log10 drop in viral load), but without a confirmed 1 log10 drop in viral load at Week 24

dPatients who never reached a confirmed 1 log10 drop in viral load before Week 24 In the pooled analysis of the TMC114-C213 and TMC114-C202 trials through 24 weeks of therapy, there was a statistically significant higher proportion of patients in the PREZISTA/RTV 600/100 mg b.i.d. arm compared to the comparator PI arm with an HIV-1 RNA decrease of at least 1.0 log10 from baseline (70% vs. 21%, respectively), with HIV-1 RNA < 400 copies/mL (63% vs. 19%, respectively), and with HIV-1 RNA < 50 copies/mL (45% vs. 12%, respectively) (see Table 13).

Table 13: Percentage of Responders with >=1 log10 Drop in Viral Load for TMC114-C213, TMC114-C202 and TMC114-C213 & TMC114-C202 (pooled)

Similarly, at Week 24, the mean changes in plasma HIV-1 RNA from baseline were -1.89 log10 copies/mL in the arm receiving PREZISTA/RTV 600/100 mg b.i.d. and -0.48 log10 copies/mL for the comparator PI arm (see Table 14).

Table 14: Mean (+/- SE) Change in log10 Viral Load (NC=F) for TMC114-C213, TMC114-C202 and POWER 1 & TMC114-C202 (pooled)

The mean increase from baseline in CD4+ cell counts was statistically significantly higher in the arm receiving PREZISTA/RTV 600/100 mg b.i.d. (92 x 106 cells/L) than in the comparator PI arm (17 x 106 cells/L) (see Table 15). Also in both TMC114-C213 and TMC114-C202 trials separately, all response parameters were statistically significantly better in the PREZISTA/RTV 600/100 mg b.i.d. arm compared to the comparator PI arm (p<0.001).

Table 15: Mean (+/- SE) Change in CD4+ count (106/L) for TMC114-C213, TMC114-C202 and TMC114-C213 & TMC114-C202 (pooled)

Additional data on the efficacy of PREZISTA/RTV 600/100 mg b.i.d. have been obtained in 246 treatment-experienced patients participating in the non-randomized POWER 3 trials. Baseline characteristics of the subjects included in the POWER 3 trials were comparable to those subjects in TMC114-C213 and TMC114-C202. In the Week 24 analysis, 65% had a virologic response defined as a decrease of at least 1.0 log10 in plasma viral load versus baseline, 57% of the patients reached less than 400 HIV RNA copies/mL, and 40% of the patients reached less than 50 HIV RNA copies/mL. The mean changes in plasma HIV-1 RNA from baseline were -1.65 log10 copies/mL, and the mean increase in CD4+ cell count versus baseline was 80 x 106 cells/L at Week 20.

DETAILED PHARMACOLOGY

Pharmacokinetics

Absorption

Maximum plasma concentration of darunavir in the presence of low-dose ritonavir is generally achieved within 2.5-4.0 hours. The absolute oral bioavailability of a single 600 mg dose of darunavir alone was approximately 37% and increased to approximately 82% in the presence of 100 mg b.i.d. ritonavir. Increasing the dose of ritonavir to above 100 mg b.i.d. did not significantly affect darunavir concentrations and is not recommended. The population pharmacokinetics derived geometric mean (SD) C0h and AUC12h for darunavir in 119 HIV-1-infected patients (TMC114-C213 and TMC114-C202, Primary 24-Week Analysis) receiving [600/100 mg b.i.d. TRADE NAME] is 3578 (+-1151) ng/mL and 62349 (+-16143) ng.h/mL, respectively.

Effect of food on oral absorption

When administered without food, the relative bioavailability of darunavir in the presence of lowdose ritonavir is 30% lower as compared to intake with food. Therefore, to achieve optimal exposure, PREZISTA tablets should be taken with ritonavir and with food. The type of food does not affect exposure to darunavir. (See DOSAGE AND ADMINISTRATION and DRUG INTERACTIONS; Drug-Food Interactions).

Distribution

Darunavir is approximately 95% bound to plasma proteins. Darunavir binds primarily to plasma AAG (alpha-1-acid glycoprotein).

Metabolism

In vitro

experiments with human liver microsomes indicate that darunavir primarily undergoes oxidative metabolism. Darunavir is extensively metabolized by the hepatic CYP system, and almost exclusively by isozyme CYP3A4. At least 3 oxidative metabolites of darunavir have been identified in humans; all showed activity that was at least 10-fold less than the activity of darunavir against wild-type HIV.

Elimination

The terminal elimination half-life of darunavir was approximately 15 hours when combined with ritonavir. After administration of 14C-darunavir wit low-dose ritonavir, approximately 79.5% and 13.9% of the administered dose of 14C-darunavir could be retrieved in feces and urine, respectively.

Demographics

Population pharmacokinetic analysis in HIV-infected patients showed that darunavir pharmacokinetics is not considerably different in the age range (18 to 75 years) evaluated in HIV-infected patients. The pharmacokinetics of darunavir in children and adolescents are under investigation. Population pharmacokinetic analysis showed a slightly higher darunavir exposure in HIV-infected females compared to males. This difference is not considered clinically relevant. Population pharmacokinetic analysis of darunavir in HIV-infected patients indicated that race had no apparent effect on the exposure to darunavir. The steady-state pharmacokinetic parameters of darunavir in subjects with mild and moderate hepatic impairment were comparable with those in healthy subjects, therefore, no dose adjustment is required in patients with mild or moderate hepatic impairment. PREZISTA has not been studied in subjects with severe hepatic impairment. Population pharmacokinetic analysis showed that the pharmacokinetics of darunavir were not significantly affected in HIV infected subjects with moderate renal impairment. There are no pharmacokinetic data available in HIV-1 infected patients with severe renal impairment or end stage renal disease. However, since the renal clearance of darunavir is limited, a decrease in total body clearance is not expected in patients with renal impairment.

MICROBIOLOGY

Antiviral Activity In Vitro

Darunavir exhibits activity against laboratory strains and clinical isolates of HIV-1 and laboratory strains of HIV-2 in acutely infected T-cell lines, human peripheral blood mononuclear cells and human monocytes/macrophages with median EC50 values ranging from 1.2 to 8.5 nM (0.7 to 5.0 ng/mL). Darunavir demonstrates antiviral activity in vitro against a broad panel of HIV-1 group M (A, B, C, D, E, F, G) and group O primary isolates with EC50 values ranging from < 0.1 to 4.3 nM. These EC50 values are well below the 50% cellular toxicity concentration range of 87 uM to > 100 uM. The EC50 value of darunavir increases by a median factor of 5.4 in the presence of human serum. Darunavir showed synergistic antiviral activity when studied in combination with the protease inhibitors ritonavir, nelfinavir, or amprenavir, and additive antiviral activity when studied in combination with the protease inhibitors indinavir, saquinavir, lopinavir, atazanavir, or tipranavir, the N(t)RTIs zidovudine, lamivudine, zalcitabine, didanosine, stavudine, abacavir, emtricitabine, or tenofovir, the NNRTIs nevirapine, delavirdine, or efavirenz, and the fusion inhibitor enfuvirtide. No antagonism was observed between darunavir and any of these antiretrovirals in vitro.

Resistance In Vitro

In vitro

selection of darunavir-resistant virus from wild-type HIV-1 was lengthy (up to 2 years). The selected viruses were unable to grow in the presence of darunavir concentrations above 220 nM. Viruses selected in these conditions and showing decreased susceptibility to darunavir (range: 6- to 21-fold) harboured 3 to 6 amino acid substitutions in the protease gene.

Identification of determinants of decreased susceptibility to darunavir in those viruses is under investigation. In vitro selection of darunavir resistant HIV-1 (range: 53- to 641-fold change in EC50 values) from 9 HIV-1 strains harbouring multiple PI resistance-associated mutations resulted in the overall emergence of 22 mutations in the protease, of which L10F, V32I, L33F, S37N, M46I, I47V, I50V, L63P, A71V, and I84V were present in more than 50% of the 9 darunavir-resistant isolates. A minimum of 8 of these darunavir in vitro selected mutations, from which at least 2 were already present in the protease prior to selection, were required in the HIV-1 protease to render a virus resistant (fold change (FC) > 10) to darunavir. In 1113 clinical isolates resistant to amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir and/or tipranavir, and in 886 baseline isolates from the patients enrolled in the POWER 1 and POWER 2 trials and in the POWER 3 analysis, only the subgroups with > 10 PI resistance-associated mutations showed a median FC for darunavir > 10.

Cross-Resistance In Vitro

Cross-resistance has been observed among protease inhibitors. Darunavir has a < 10-fold decreased susceptibility against 90% of 3309 clinical isolates resistant to amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir and/or tipranavir showing that viruses resistant to most PIs remain susceptible to darunavir. Seven of the 9 darunavir-resistant viruses selected from PI-resistant viruses had phenotypic data for tipranavir. Six of those showed a FC in EC50 value < 3 for tipranavir, indicative of limited cross-resistance between these 2 protease inhibitors. Cross-resistance between darunavir and the nucleoside/nucleotide reverse transcriptase inhibitors, the non-nucleoside reverse transcriptase inhibitors or the fusion inhibitor, is unlikely because the viral targets for those inhibitors are different.

Antiviral activity of darunavir/ritonavir in treatment-experienced patients

In the Phase 2 trials POWER 1 and 2 and in the POWER 3 analysis, 458 highly treatment- experienced patients received PREZISTA/RTV in their initial regimen at the selected 600/100 mg b.i.d. dose.

In Vivo

Selection of Viral Resistance During Darunavir/Ritonavir Therapy

In the Phase 2 trials POWER 1 and 2, and in the POWER 3 analysis, multiple protease inhibitor- resistant HIV-1 isolates from highly treatment-experienced patients who received PREZISTA/RTV and experienced virologic failure, either by rebound (data available for 50 patients), or by never being suppressed (data available for 70 patients), developed amino acid substitutions that were associated with a decrease in susceptibility to darunavir. The amino acid substitutions that developed on PREZISTA/RTV 600/100 mg b.i.d. in greater than 20% of PREZISTA/RTV virologic failure isolates were V32I and I54L. Other substitutions that developed in 10% to 20% of PREZISTA/RTV virologic failure isolates were L33F, I47V and L89V.

In Vivo

Cross-Resistance with Other Protease Inhibitors

Currently, little information is available on cross-resistance of viruses selected during therapy with darunavir/ritonavir. In viruses isolated from patients experiencing virologic failure by rebound from the PREZISTA/RTV 600/100 mg b.i.d. group, a median darunavir FC increase of 8.14 at endpoint compared to baseline was found. In the same group of patients, no FC increase (median increase of 0.82) at endpoint compared to baseline was found for tipranavir, suggesting limited cross-resistance between these 2 PIs. Patients with resistance to tipranavir (FC > 3) at baseline showed a mean change in viral load at Week 24 of -1.38 log10. The FC increase could not be studied for the other PIs, since the baseline isolates were already resistant to these PIs. Patients with no susceptible commercially available PI at baseline (thus excluding tipranavir) showed a mean change in viral load at Week 24 of -1.57 log10.

Baseline Genotype or Phenotype and Virologic Outcome

Analyses were conducted to evaluate the impact of specific baseline protease inhibitor resistance-associated mutations on virologic response. A diminished virologic response was observed in patients with >= 10 PI resistance-associated mutations (IAS-USA list of mutations - March 2005) at baseline. Nevertheless, the response rate in all subgroups (by type and number of mutations at baseline) was generally higher in the darunavir/RTV groups compared to the response rate in the control group. In a supportive analysis of the POWER-1 and POWER-2 studies and the POWER-3 analysis, the presence at baseline of three or more of the mutations V11I, V32I, L33F, I47V, I50V, I54L or M, G73S, L76V, I84V or L89V was associated with a decreased virologic response to PREZISTA/RTV (the proportion of subjects achieving viral load <50 plasma HIV RNA copies/mL at week 24 was 50%, 22% and 10% when the baseline genotype had 0-2, 3 and >=4 of these mutations, respectively). Substitutions at positions 11 and 89 have only been associated with PI resistance on a very limited basis.

Table 16: Response to PREZISTA/RTV 600/100 mg b.i.d. by baseline genotype *: As-treated analysis of studies POWER-1; POWER-2, and POWER-3

* Number of mutations from the list of mutations associated with a diminished response to PREZISTA/RTV (V11I,

V32I, L33F, I47V, I50V, I54L or M, G73S, L76V, I84V or L89V)

Conclusions regarding the relevance of particular mutations or mutational patterns are subject to change pending additional data. Baseline darunavir phenotype (shift in susceptibility relative to reference) was shown to be the most predictive factor of virologic outcome. Response rates assessed by baseline darunavir phenotype are shown in Table 17. These baseline phenotype groups are based on the select patient populations in the POWER-1 and POWER-2 studies and the POWER-3 analysis and are not meant to represent definitive clinical susceptibility breakpoints. The data are provided to give clinicians information on the likelihood of virologic success based on pre-treatment susceptibility to darunavir in PI-experienced patients.

Table 17: Response to PREZISTA/RTV 600/100 mg b.i.d. by baseline darunavir phenotype: As-treated analysis of studies POWER-1; POWER-2, and POWER-3

In deciding on a new regimen for patients who have failed an antiretroviral regimen, careful consideration should be given to the treatment history and to resistance testing results where available.

TOXICOLOGY

Animal toxicology studies have been conducted with darunavir alone, in mice, rats and dogs and in combination with ritonavir in rats and dogs. In chronic toxicology studies in rats and dogs, there were only limited effects of treatment with darunavir. In the rat the key target organs identified were the hematopoietic system, the blood coagulation system, liver and thyroid, observed at 100 mg/kg/day and above and at exposures below clinical levels. A variable but limited decrease in red blood cell-related parameters was observed, together with increases in activated PTT. The observed liver and thyroid changes were considered to reflect an adaptive response to enzyme induction in the rat rather than an adverse effect. In combination toxicity studies with ritonavir, no additional target organs of toxicity were reported in rats. In the dog, no major toxicity findings or key target organs were identified at doses up to 120 mg/kg/day and exposures equivalent to clinical exposure at the recommended dose.

Carcinogenesis and Mutagenesis

Long-term carcinogenicity studies of darunavir in rodents have not been completed. Darunavir, however, was tested negative in the in vitro Ames reverse mutation assay and in vitro chromosomal aberration assay in human lymphocyte, both tested in the absence and presence of the metabolic activation system. Darunavir did not induce chromosomal damage in the in vivo micronucleous test in mice.

Reproductive and Developmental Toxicity

Investigation of fertility and early embryonic development was performed in rats, teratogenicity studies were conducted in mice, rats and rabbits, and the pre- and post-natal development study was conducted in rats. In the fertility and early embryonic development study, a significant decrease in body weight gain with subsequent related reduction in the number of ovulations resulting in a reduction in the number of live fetuses was observed in female rats treated with 1000 mg/kg. Otherwise, there were no effects on mating or fertility with darunavir treatment up to 1000 mg/kg/day and exposure levels below (AUC 0.5 fold) that in humans at the clinically recommended dose. Up to the same dose levels, there was no teratogenicity with darunavir in rats and rabbits when treated alone nor in mice when treated in combination with ritonavir. The exposure levels were lower than those observed with the recommended clinical dose in humans. In a pre- and post-natal development assessment in rats, darunavir with and without ritonavir caused a transient reduction in body weight gain of the offspring during lactation. This was attributed to drug exposure via the milk. No post-weaning functions were affected with darunavir alone or in combination with ritonavir.

IMPORTANT: PLEASE READ

PREZISTA, for use in patients with human immunodeficiency virus (HIV) infection, has been approved with conditions, pending the results of studies to verify its clinical benefit. For more information, patients are advised to contact their healthcare provider.

PART III: CONSUMER INFORMATION

What is a Notice of Compliance with Conditions (NOC/c)?

An NOC/c is a form of market approval granted to a

product on the basis of promising evidence of clinical effectiveness following review of the submission by Health Canada.

Products approved under Health Canada's NOC/c policy are intended for the treatment, prevention or diagnosis of a serious, life-threatening or severely debilitating illness. They have demonstrated promising benefit, are of high quality and possess an acceptable safety profile based on a benefit/risk assessment. In addition, they either respond to a serious unmet medical need in Canada or have demonstrated a significant improvement in the benefit/risk profile over existing therapies. Health Canada has provided access to this product on the condition that sponsors carry out additional clinical trials to verify the anticipated benefit within an agreed upon time frame.

PREZISTA *

darunavir

This leaflet is Part III of a three-part "Product Monograph" published when PREZISTA was approved for sale in Canada and is designed specifically for Consumers. This leaflet is a summary and will not tell you everything about PREZISTA. Contact your doctor or pharmacist if you have any questions about the drug.

ABOUT THIS MEDICATION

What the medication is used for:

using a latex or polyurethane condom or other barrier method to lower the chance of sexual contact with any body fluids such as semen, vaginal secretions, or blood. Never use or share dirty needles.

Ask your doctor if you have any questions on how to prevent passing HIV to other people.

What it does:

PREZISTA blocks HIV protease, an enzyme which is

needed for HIV to multiply. When used with other anti- HIV medicines, PREZISTA may reduce the amount of HIV in your blood (called "viral load") and increase your CD4+ (T) cell count. HIV infection destroys CD4+

(T) cells, which are important to the immune system. The immune system helps fight infection. Reducing the amount of HIV and increasing the CD4+ (T) cell count may improve your immune system.

PREZISTA is always taken with and at the same time as 100 mg of ritonavir (NORVIR(r)), in combination with other anti-HIV medicines.

PREZISTA does not cure HIV infection or AIDS. At present, there is no cure for HIV infection. People taking PREZISTA may still develop infections or other conditions associated with HIV infection. Because of this, it is very important for you to remain under the care of a doctor.

When it should not be used:

Together with your doctor, you need to decide whether taking PREZISTA is right for you.

Do not take PREZISTA:

if you are allergic to darunavir or any of the other ingredients in PREZISTA (see What the nonmedicinal ingredients are)

if you are allergic to ritonavir (NORVIR(r))

if you have severe liver disease

if you take any of the following types of medicines because you could experience serious side effects:

Type of Drug Examples of Generic

Names (Brand Names)

PREZISTA is an oral tablet used for the treatment of

HIV (Human Immunodeficiency Virus) infection in adults, when co-administered with ritonavir and other antiretroviral medications. HIV is the virus that causes AIDS (Acquired Immune Deficiency Syndrome). PREZISTA is a type of anti-HIV drug called a protease (PRO-tee-ase) inhibitor.

PREZISTA does not reduce the risk of passing HIV to others through sexual contact, sharing needles, or being exposed to your blood. For your health and the health of others, it is important to always practice safer sex by

Antiarrhythmics

(to treat abnormal heart rhythms)

Antihistamines (to treat allergy symptoms)

bepridil1

lidocaine quinidine

amiodarone (Cordarone(r))

astemizole1 terfenadine1

Type of Drug Examples of Generic Names (Brand Names)

doctor about how you can be included in the Antiretroviral Pregnancy Registry.

Ergot Derivatives

(to treat migraine and headaches)

Gastrointestinal Motility Agents (to treat some

digestive conditions)

Neuroleptics

(to treat psychiatric

conditions)

Sedatives/Hypnotics (to treat trouble with sleeping and/or anxiety)

dihydroergotamine (Migranal(r)) ergonovine

ergotamine (Cafergot(r)) methylergonovine cisapride1

pimozide (Orap(r))

midazolam triazolam (Halcion(r))

• are breast-feeding. Do not breast-feed if you are taking PREZISTA. You should not breast-feed if you have HIV because of the chance of passing HIV to your baby. Talk with your doctor about the best way to feed your baby.

INTERACTIONS WITH THIS MEDICATION

Tell your doctor about all the medicines you take including prescription and nonprescription medicines, vitamins, and herbal supplements, including St. John's wort (Hypericum perforatum). PREZISTA and many other medicines can interact. Sometimes serious side effects will happen if PREZISTA is taken with certain other medicines (see "When it should not be used").

PREZISTA should not be combined with phenobarbital, phenytoin, carbamazepine, rifampin or St. John's wort

Bepridil, astemizole, terfenadine and cisapride are

no longer marketed in Canada.

What the medicinal ingredient is:

The active substance is darunavir. Each 300 mg tablet contains 325.23 mg of darunavir ethanolate,

corresponding to 300 mg of darunavir.

What the nonmedicinal ingredients are:

The other ingredients are colloidal anhydrous silica, crospovidone, magnesium stearate, and microcrystalline

cellulose. The tablet film coating contains polyethylene glycol, polyvinyl alcohol - partially hydrolyzed, sunset

yellow FCF aluminum lake, talc, and titanium dioxide.

What dosage forms it comes in:

300 mg tablets

WARNINGS AND PRECAUTIONS

BEFORE you use PREZISTA talk to your doctor or pharmacist if you:

have diabetes. In general, anti-HIV medicines, such

because the combination may significantly lower the amount of PREZISTA in your blood and reduce the effects of PREZISTA.

PREZISTA should not be combined with vardenafil, because you may be at increased risk of side effects of vardenafil such as low blood pressure, visual changes and penile erection lasting more than 4 hours.

Tell your doctor if you are taking estrogen-based contraceptives. PREZISTA might reduce the effectiveness of estrogen-based contraceptives. You must take additional precautions for birth control such as a condom.

Tell your doctor if you take other anti-HIV medicines. PREZISTA can be combined with some other anti-HIV medicines while other combinations are not recommended.

Tell your doctor if you are taking any of the following medicines:

Type of Drug Examples of Generic

Names (Brand Names)

as PREZISTA, might increase sugar levels in the blood.

have liver problems, including hepatitis B or C.

have hemophilia. Anti-HIV medicines, such as PREZISTA, might increase the risk of bleeding.

are pregnant or planning to become pregnant. It is not known if PREZISTA can harm your unborn baby. You and your doctor will need to decide if taking PREZISTA is right for you. If you take PREZISTA while you are pregnant, talk to your

Antiarrythmics

(to treat to abnormal heart rhythms)

Anticoagulants

(to prevent the clotting of

red blood cells)

digoxin (Lanoxin(r))

warfarin (Coumadin(r))

Type of Drug Examples of Generic Names (Brand Names)

This is not a complete list of medicines that you should tell your doctor that you are taking. Know and keep

Anticonvulsants

(to treat epilepsy and prevent seizures)

Anti-infectives (to treat bacterial infections)

Antifungals

(to treat fungal infections)

Antimycobacterials (to treat bacterial infections)

Calcium Channel Blockers

(to treat heart disease)

Corticosteroids

(to treat inflammation or

asthma)

HMG-CoA Reductase Inhibitors

(to lower cholesterol

levels)

Immunosuppressants

(to prevent organ transplant

rejection)

carbamazepine (Tegretol(r)) phenobarbital phenytoin (Dilantin(r))

clarithromycin (Biaxin(r))

ketoconazole (Nizoral(r)) itraconazole (Sporanox(r)) voriconazole (Vfend(r))

rifabutin (Mycobutin(r)) rifampin (Rifadin(r), Rifater(r))

felodipine nifedipine (Adalat(r)) nicardipine

dexamethasone fluticasone propionate (Advair Diskus(r), Cutivate(r), Flonase(r), Flovent Diskus(r))

atorvastatin (Lipitor(r)) lovastatin (Mevacor(r)) pravastatin (Pravachol(r)) simvastatin (Zocor(r))

cyclosporine (Sandimmune(r), Neoral(r)) tacrolimus (Prograf(r)) sirolimus (Rapamune(r))

track of all the medicines you take and have a list of

them with you. Show this list to all of your doctors and pharmacists any time you get a new medicine. Both your doctor and your pharmacist can tell you if you can take these other medicines with PREZISTA. Do not start any new medicines while you are taking PREZISTA without first talking with your doctor or pharmacist. You can ask your doctor or pharmacist for a list of medicines that can interact with PREZISTA.

PROPER USE OF THIS MEDICATION

Always use PREZISTA exactly as your doctor has told you. You must check with your doctor if you are not sure.

Usual adult dose:

Take PREZISTA tablets every day exactly as prescribed by your doctor. You must take ritonavir (NORVIR(r)) at the same time as PREZISTA. The usual dose is 600 mg (two 300 mg tablets) of PREZISTA, together with 100 mg (one 100 mg capsule) of ritonavir (NORVIR(r)), twice daily every day. It may be easier to remember to take PREZISTA and ritonavir (NORVIR(r)) if you take them at the same time every day. If you have questions about when to take PREZISTA and ritonavir (NORVIR(r)), your doctor can help you decide which schedule works for you.

You should always take PREZISTA and ritonavir (NORVIR(r)) together with food. The type of food is not important.

Continue taking PREZISTA and ritonavir (NORVIR(r)) unless your doctor tells you to stop. Take the exact amount of PREZISTA and ritonavir (NORVIR(r)) that

Narcotic Analgesics methadone, meperidine

your doctor tells you to take, right from the very start. To help make sure you will benefit from PREZISTA

PDE-5 Inhibitors (to treat erectile dysfunction)

Selective Serotonin Reuptake Inhibitors (SSRIs)

(to treat depression, anxiety, or panic disorder)

sildenafil (Viagra(r)) vardenafil (Levitra(r)) tadalafil (Cialis(r))

paroxetine (Paxil(r)) sertraline (Zoloft(r))

and ritonavir (NORVIR(r)), you must not skip doses or interrupt therapy. If you don't take PREZISTA and ritonavir (NORVIR(r)) as prescribed, the beneficial

effects of PREZISTA and ritonavir (NORVIR(r)) may be

reduced or even lost.

If you have also been prescribed enteric-coated didanosine as well as PREZISTA and ritonavir, take didanosine 2 hours before or after the PREZISTA/ritonavir combination.

Tell your doctor if you are taking any medicines that you obtained without a prescription.

Overdose:

Contact your doctor or pharmacist immediately.

Missed dose:

If you miss a dose of PREZISTA or ritonavir (NORVIR(r)) by more than 6 hours, wait and then take the next dose of PREZISTA and ritonavir (NORVIR(r)) at the regularly scheduled time. If you miss a dose of PREZISTA or ritonavir (NORVIR(r)) by less than 6 hours, take your missed dose of PREZISTA and ritonavir (NORVIR(r)) immediately. Then take your next dose of PREZISTA and ritonavir (NORVIR(r)) at the regularly scheduled time.

If a dose of PREZISTA or ritonavir (NORVIR(r)) is skipped, do not double the next dose. Do not take more or less than your prescribed dose of PREZISTA or ritonavir (NORVIR(r)) at any one time.

Do not stop using PREZISTA without talking to your doctor first.

SIDE EFFECTS AND WHAT TO DO ABOUT THEM

Like all prescription drugs, PREZISTA can cause side effects. The following is not a complete list of side effects reported with PREZISTA when taken either alone or with other anti-HIV medicines. Do not rely on this leaflet alone for information about side effects. Your doctor can discuss with you a more complete list of side effects.

Mild to moderate rash has been reported in 7% of subjects receiving PREZISTA. In some patients, PREZISTA has been reported to cause a severe or life- threatening rash. Contact your doctor if you develop a rash. Your doctor will advise you whether your symptoms can be managed on therapy or whether PREZISTA should be stopped.

The most common side effects include diarrhea, nausea, headache, abdominal pain, constipation, and vomiting.

As with other protease inhibitors, PREZISTA may cause side effects, including:

• high blood sugar (hyperglycemia) and diabetes.

This can happen in patients taking PREZISTA or other protease inhibitor medicines. Some patients have diabetes before starting treatment with PREZISTA, which gets worse. Some patients get diabetes during treatment with PREZISTA. Some patients will need changes in their diabetes medicine. Some patients may need new diabetes medicine.

increased bleeding in patients with hemophilia.

This may happen in patients taking PREZISTA as it has been reported with other protease inhibitor medicines.

changes in body fat. These changes can happen in patients taking anti-HIV medicines. The changes may include an increased amount of fat in the upper back and neck, breast, and around the back, chest, and stomach area. Loss of fat from the legs, arms, and face may also happen. The exact cause and long-term health effects of these conditions are not known.

increases in triglycerides and cholesterol (forms of fat that are found in your blood). Your doctor may order blood testing for you.

development of pancreatitis (inflammation of the pancreas) with symptoms such as abdominal pain, nausea and vomiting. If you suffer these symptoms while taking PREZISTA, contact your doctor.

immune reconstitution syndrome. In some patients with advanced HIV infection (AIDS) and a history of opportunistic infection, signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started. It is believed that these symptoms are due to an improvement in the body's immune response, enabling the body to fight infections that may have been present with no obvious symptoms.

Tell your doctor promptly about these or any other unusual symptoms. If the condition persists or worsens, seek medical attention.

HOW TO STORE IT

Keep out of the reach and sight of children.

Store PREZISTA tablets at room temperature between 15-30degC. Ask your doctor or pharmacist if you have any questions about storing your tablets.

This medication is prescribed for your particular condition. Do not use it for any other condition or give it to anybody else. Keep PREZISTA and all of your medicines out of the reach of children. If you suspect that more than the prescribed dose of this medicine has been taken, contact your local poison control centre or emergency room immediately.

This leaflet provides a summary of information about PREZISTA. If you have any questions or concerns about either PREZISTA or HIV, talk to your doctor.

REPORTING SUSPECTED SIDE EFFECTS

To monitor drug safety, Health Canada through the Canada Vigilance Program collects information on serious and unexpected side effects of drugs. If you suspect you have had a serious or unexpected reaction to this drug you may notify Canada Vigilance:

By toll-free telephone: 866-234-2345 By toll-free fax: 866-678-6789 Online: www.healthcanada.gc.ca/medeffect By email: CanadaVigilance @hc-sc.gc.ca

By regular mail:

Canada Vigilance National Office

Marketed Health Products Safety and Effectiveness Bureau

Marketed Health Products Directorate Health Products and Food Branch

Health Canada

Tunney's Pasture, AL 0701C Ottawa, ON K1A 0K9

NOTE: Should your require information related to the management of the side effect, please contact your health care provider before notifying Canada Vigilance. The Canada Vigilance Program does not provide medical advice.

MORE INFORMATION

This document plus the full product monograph, prepared for health professionals can be found at: http://www.janssen-ortho.com

or by contacting the sponsor, Janssen-Ortho Inc., at: 1-800-567-3331

This leaflet was prepared by Janssen-Ortho Inc.

Toronto, Ontario M3C 1L9

Last revised: June 12, 2008

*All trademark rights used under license NORVIR(r) is a registered trademark of Abbott

Laboratories Ltd.

All listed brand names are registered trademarks of their respective manufacturers.