Control Number: 119561

Table of Contents

PART I : HEALTH PROFESSIONAL INFORMATION

SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 4 WARNINGS AND PRECAUTIONS 4 ADVERSE REACTIONS 12 DRUG INTERACTIONS 20 DOSAGE AND ADMINISTRATION 28 OVERDOSAGE 30 ACTION AND CLINICAL PHARMACOLOGY 31 STORAGE AND STABILITY 36 DOSAGE FORMS, COMPOSITION AND PACKAGING 36

PART II : SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION 37 CLINICAL TRIALS 38 DETAILED PHARMACOLOGY 42 MICROBIOLOGY 49 TOXICOLOGY 50 REFERENCES 52

PART III : CONSUMER INFORMATION

ABOUT THIS MEDICATION 54 WARNINGS AND PRECAUTIONS 55 INTERACTIONS WITH THIS MEDICATION 55 PROPER USE OF THIS MEDICATION 56 SIDE EFFECTS AND WHAT TO DO ABOUT THEM 57 HOW TO STORE IT 58

Pr REYATAZ * (atazanavir sulfate)

PART I : HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION

CONTRAINDICATIONS

Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing see (DOSAGE FORMS, COMPOSITION AND PACKAGING). Coadministration of REYATAZ is contraindicated with drugs that are highly dependent on CYP3A4 and/or UGT1A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events. These drugs are listed in Table 1.

Table 1 : Drugs That Are Contraindicated with REYATAZ *

See Table 11 for more detailed information.

* * Not marketed in Canada

WARNINGS AND PRECAUTIONS

General

ALERT : Find out about medicines that should NOT be taken with REYATAZ.

(See CONTRAINDICATIONS and DRUG INTERACTIONS.)

Atazanavir should always be used in combination with other antiretroviral agents. Atazanavir should not be added as a single agent when antiretrovirals are changed due to loss of virologic response.

Antiretroviral Treatment-Experienced Patients

Atazanavir 400 mg once daily has been shown to be inferior to lopinavir/ritonavir in antiretroviral experienced patients. There are limited safety data from controlled trials for REYATAZ plus ritonavir regimens without tenofovir. (See DRUG INTERACTIONS, DOSAGE AND ADMINISTRATION and CLINICAL TRIALS.)

Carcinogenesis and Mutagenesis

The incidence of benign hepatocellular adenomas was increased in high-dose female mice at systemic exposures approximately 7-fold higher than those in humans at the recommended 400 mg clinical dose. There was no increase in the incidence of tumors in male mice or in male or female rats at any dose tested. The clinical significance of the carcinogenic findings in female mice is unknown as the benign hepatic tumors occurred only at doses that induced liver toxicity. (see TOXICOLOGY - Carcinogenicity and Mutagenicity).

Cardiovascular

Cardiac Conduction Abnormalities: Atazanavir has been shown to prolong the PR interval of the electrocardiogram in some patients. In healthy volunteers and in patients, abnormalities in atrioventricular (AV) conduction were asymptomatic and limited to first degree AV block with some exceptions (see OVERDOSAGE). There have been post-marketing reports of second- degree AV block, third-degree AV block, QTc prolongation, Torsades de Pointes and other conduction abnormalities in patients treated with REYATAZ (see ADVERSE REACTIONS - Post-Market Adverse Drug Reactions). In clinical trials, asymptomatic first-degree AV block was observed in 5.9% of atazanavir-treated patients (n = 920), 3.0% of efavirenz treated patients (n = 329), 5.2% of lopinavir/ritonavir treated patients (n = 252) and 10.4% of nelfinavir treated patients (n = 48). In study AI424-045 asymptomatic first degree AV block was observed in 5% (6/118) of REYATAZ/ritonavir-treated patients and 5% (6/116) of lopinavir/ritonavir-treated patients who had on-study electrocardiogram measurements. Because of limited clinical experience, atazanavir should be used with caution in patients with preexisting conduction system disease (e.g., marked first-degree AV block or second or third-degree AV block). Dose related asymptomatic prolongations in PR interval with REYATAZ have been observed in clinical studies. Caution should be used with medicinal products known to induce PR prolongations. In patients with pre-existing conduction problems (second degree or higher atrioventricular or complex bundle-branch block), REYATAZ should be used with caution and only if the benefits exceed the risk. Particular caution should be used when prescribing REYATAZ in association with medicinal products which have the potential to increase the QT interval and/or in patients with pre-existing risk factors (bradycardia, long congenital QT, electrolyte imbalances). (See ACTION AND CLINICAL PHARMACOLOGY.) In a pharmacokinetic study between atazanavir 400 mg once daily and diltiazem 180 mg once daily, a CYP3A substrate, there was a 2-fold increase in the diltiazem plasma concentration and an additive effect on the PR interval. When used in combination with atazanavir, a dose reduction of diltiazem by one half should be considered and ECG monitoring is recommended. In a pharmacokinetic study between atazanavir 400 mg once daily and atenolol 50 mg once daily, there was no substantial additive effect of atazanavir and atenolol on the PR interval. When used in combination with atazanavir, there is no need to adjust the dose of atenolol. (See DRUG INTERACTIONS.) Pharmacokinetic studies between atazanavir and other drugs that prolong the PR interval including beta blockers (other than atenolol), verapamil and digoxin have not been performed. An additive effect of atazanavir and these drugs cannot be excluded; therefore, caution should be exercised when atazanavir is given concurrently with these drugs, especially those that are metabolized by CYP3A4 (e.g., verapamil). (See DRUG INTERACTIONS.)

Endocrine and Metabolism

Diabetes mellitus/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.

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.

Hematologic

Hemophilia

: 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.

Hepatic/Biliary

Hepatic Impairment and Toxicity

: REYATAZ is principally metabolized by the liver; caution should be exercised when administering this drug to patients with hepatic impairment because atazanavir concentrations may be increased (see DOSAGE AND ADMINISTRATION). Patients with underlying hepatitis B or C viral infections or marked elevations in transaminases prior to treatment may be at increased risk for developing further transaminase elevations or hepatic decompensation.

Immune Reconstitution:

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including REYATAZ. During the initial phase of treatment, a patient whose immune system responds to 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.

Hyperbilirubinemia

: Most patients taking atazanavir experience elevations in indirect (unconjugated) bilirubin related to inhibition of UDP-glucuronosyl transferase (UGT). This hyperbilirubinemia is generally reversible upon discontinuation of REYATAZ. If hepatic transaminase elevations occur with hyperbilirubinemia while a patient is receiving atazanavir, consideration should be given to also evaluating alternative etiologies. No long-term safety data are available for patients experiencing persistent elevations in total bilirubin > 5 x ULN. Alternative antiretroviral therapy to REYATAZ may be considered if jaundice or scleral icterus associated with bilirubin elevations present cosmetic concerns for patients. Dose reduction of atazanavir is not recommended since long-term efficacy of reduced doses has not been established. (See ADVERSE REACTIONS.)

There have been post-marketing reports of cholelithiasis, cholecystitis, and cholestasis in patients treated with atazanavir with ritonavir as part of their ART regimen (see ADVERSE REACTIONS - Post-Market Adverse Drug Reactions).

Renal

In healthy subjects, approximately 7% of the dose of atazanavir is eliminated unchanged in the urine. REYATAZ has been studied in adult subjects with severe renal impairment (n=20), including those on hemodialysis, at multiple doses of 400 mg once daily. The impact of renal impairment on atazanavir elimination for patients without hemodialysis is anticipated to be low. Moderate increases in atazanvir clearance and decreased exposure levels were seen in patients managed with hemodialysis. (See DOSAGE AND ADMINISTRATION and ACTION AND CLINICAL PHARMACOLOGY). Cases of nephrolithiasis were reported during post-marketing surveillance in HIV-infected patients receiving atazanavir therapy. Because these events were reported voluntarily during clinical practice, estimates of frequency cannot be made. If signs or symptoms of nephrolithiasis occur, temporary interruption or discontinuation of therapy may be considered.

Resistance / Cross-Resistance Resistance

In vitro HIV-1 isolates with a decreased susceptibility to ATV have been selected in vitro and obtained from patients treated with ATV or atazanavir/ritonavir (ATV/RTV). HIV-1 isolates that were 93- to 183-fold resistant to ATV from three different viral strains were selected in vitro by 5 months. The mutations in these HIV-1 viruses that contributed to ATV resistance included I50L, N88S, I84V, A71V, and M46I. Changes were also observed at the protease cleavage sites following drug selection. Recombinant viruses containing the I50L mutation were growth impaired and displayed increased in vitro susceptibility to other PIs (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir). The I50L and I50V substitutions yielded selective resistance to ATV and amprenavir, respectively, and did not appear to be cross-resistant.

Clinical Studies of Treatment-Naive Patients: ATV-resistant clinical isolates from treatment-naive patients who experienced virologic failure developed an I50L mutation (after an average of 50 weeks of ATV therapy), often in combination with an A71V mutation. In treatment-naive patients, viral isolates that developed the I50L mutation showed phenotypic resistance to ATV but retained in vitro susceptibility to other PIs (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir); however, there are no clinical data available to demonstrate the effect of the I50L mutation on the efficacy of subsequently administered PIs.

Clinical Studies of Treatment-Experienced Patients:

In contrast, from studies of treatment- experienced patients treated with ATV or ATV/RTV, most ATV-resistant isolates from patients who experienced virologic failure developed mutations that were associated with resistance to multiple PIs and displayed decreased susceptibility to multiple PIs. The most common protease mutations to develop in the viral isolates of patients who failed treatment with ATV 300 mg once daily and RTV 100 mg once daily (together with tenofovir and an NRTI) included V32I, L33F/V/I, E35D/G, M46I/L, I50L, F53L/V, I54V, A71V/T/I, G73S/T/C, V82A/T/L, I85V, and L89V/Q/M/T.

Other mutations that developed on ATV/RTV treatment including E34K/A/Q, G48V, I84V, N88S/D/T, and L90M occurred in less than 10% of patient isolates. Generally, if multiple PI resistance mutations were present in the HIV-1 of the patient at baseline, ATV resistance developed through mutations associated with resistance to other PIs and could include the development of the I50L mutation. The I50L mutation has been detected in treatment-experienced patients experiencing virologic failure after long-term treatment. Protease cleavage site changes also emerged on ATV treatment but their presence did not correlate with the level of ATV resistance.

Cross Resistance

Cross-resistance among PIs has been observed. Baseline phenotypic and genotypic analyses of clinical isolates from ATV clinical trials of PI-experienced subjects showed that isolates cross- resistant to multiple PIs were cross-resistant to ATV. Greater than 90% of the isolates with mutations that included I84V or G48V were resistant to ATV. Greater than 60% of isolates containing L90M, G73S/T/C, A71V/T, I54V, M46I/L, or a change at V82 were resistant to ATV, and 38% of isolates containing a D30N mutation in addition to other changes were resistant to ATV. Isolates resistant to ATV were also cross-resistant to other PIs with >90% of the isolates resistant to indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir, and 80% resistant to amprenavir. In treatment-experienced patients, PI-resistant viral isolates that developed the I50L mutation in addition to other PI resistance-associated mutations were also cross-resistant to other PIs. Genotypic and/or phenotypic analysis of baseline virus may aid in determining ATV susceptibility before initiation of ATV/RTV therapy. An association between virologic response at 48 weeks and the number and type of primary PI-resistance-associated mutations detected in baseline HIV-1 isolates from antiretroviral-experienced patients receiving ATV/RTV once daily or lopinavir (LPV)/RTV twice daily in Study AI424-045 is shown in Table 2. Overall, both the number and type of baseline PI mutations affected response rates in treatment- experienced patients. In the ATV/RTV group, patients had lower response rates when 3 or more baseline PI mutations including a mutation at position 36, 71, 77, 82, or 90 were present compared to patients with 1-2 PI mutations including one of these mutations.

Table 2: HIV RNA Response by Number and Type of Baseline PI Mutation, Antiretroviral-Experienced Patients in Study AI424-045, As-Treated Analysis

pies/mL

Virologic Response = HIV RNA <400 co b

ATV/RTV

LPV/RTV

Number and Type of Baseline PI Mutations

(n=110)

(n=113)

5 or more PI mutations 0% (0/9) 28% (5/18)

a

Primary mutations include any change at D30, V32, M36, M46, I47, G48, I50, I54, A71, G73, V77, V82, I84, N88, and L90.

b

Results should be interpreted with caution because the subgroups were small.

c

There were insufficient data (n<3) for PI mutations V32I, I47V, G48V, I50V, and F53L.

The response rates of antiretroviral-experienced patients in Study AI424-045 were analyzed by baseline phenotype (shift in in vitro susceptibility relative to reference, Table 3). The analyses are based on a select patient population with 62% of patients receiving an NNRTI-based regimen before study entry compared to 35% receiving a PI-based regimen. Additional data are needed to determine clinically relevant break points for REYATAZ.

Table 3: Baseline Phenotype by Outcome, Antiretroviral-Experienced Patients in Study AI424-045, As-Treated Analysis

pies/mL

Virologic Response = HIV RNA <400 co b

ype

Baseline Phenot a ATV/RTV

LPV/RTV

(n=111) (n=111)

1. Fold change in in vitro susceptibility relative to the wild-type reference.

2. Results should be interpreted with caution because the subgroups were small.

Sexual Function/Reproduction

In a fertility and early embryonic development study in rats, atazanavir altered estrus cycling with no effects on mating, fertility or early embryonic development. Systemic drug exposure levels were equal (in male rats) or two times (in female rats) those at the human clinical dose (400 mg/day).

Skin

Rash

: In controlled clinical trials (n = 1597), rash (all grades, regardless of causality) occurred in 21% of patients treated with REYATAZ. Rashes are usually mild-to-moderate maculopapular skin eruptions that occur within the first 3 weeks of initiating therapy with REYATAZ. In most patients, rash resolves within 2 weeks while continuing REYATAZ therapy. REYATAZ should be discontinued if severe rash develops. Cases of Stevens-Johnson syndrome and erythema multiforme have been reported in patients receiving REYATAZ.

Special Populations

Pregnant Women

: There are no adequate and well-controlled studies in pregnant women. Cases of lactic acidosis, sometimes fatal, and symptomatic hyperlactatemia have been reported in patients (including pregnant women) receiving REYATAZ in combination with nucleoside analogues, which are known to be associated with increased risk of lactic acidosis. Female gender and obesity are also known risk factors for lactic acidosis syndrome. The contribution of REYATAZ to the risk of development of lactic acidosis syndrome has not been established.

Hyperbilirubinemia occurred frequently during treatment with REYATAZ. It is not known whether REYATAZ administered to the mother during pregnancy will exacerbate physiologic hyperbilirubinemia and lead to kernicterus in neonates and young infants. In the prepartum period, additional monitoring and alternative therapy should be considered. REYATAZ has been shown to cross the placenta. No teratogenic effects were observed at maternally toxic doses in rats or rabbits. Systemic drug exposure levels were equal to (in rabbits) or two times (in rats) those at the human clinical dose (400 mg once daily). In the pre-and post-natal development assessment in rats, atazanavir produced a transient reduction in body weight in the offspring at maternally toxic drug exposure levels two times those at the human clinical dose. REYATAZ should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. (See WARNINGS AND PRECAUTIONS : Endocrine and Metabolism.)

Antiretroviral Pregnancy Registry

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

Nursing Women

: It is not known whether atazanavir is secreted in human milk. A study in lactating rats demonstrated that atazanavir is secreted in milk. It is recommended that

HIV-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast-feed if they are receiving REYATAZ.

Pediatrics (from 6 to 18 years of age) : REYATAZ should not be administered in pediatric patients below the age of 3 months due to the risk of kernicterus. The safety, pharmacokinetic profile, and virologic response of REYATAZ were evaluated in pediatric patients in an open-label, multicenter clinical trial PACTG 1020A (see CLINICAL TRIALS). The safety profile in pediatric patients was comparable to that observed in adults (see ADVERSE REACTIONS). The safety, activity, and pharmacokinetic profiles of REYATAZ in pediatric patients ages 3 months to less than 6 years have not been established.

Geriatrics (> 65 years of age)

: Clinical studies of REYATAZ did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. In general, dose selection for an elderly patient should reflect the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Lactose

: Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Drug Interaction

Atazanavir is an inhibitor of CYP3A and UGT1A1. Coadministration of REYATAZ and drugs primarily metabolized by CYP3A [eg, calcium channel blockers, HMG-CoA reductase inhibitors, immunosuppressants, and phosphodiesterase (PDE5) inhibitors], or UGT1A1 (eg, irinotecan) may result in increased plasma concentrations of the other drug that could increase or prolong its therapeutic and adverse effects. Atazanavir is a weak inhibitor of CYP2C8. Caution should be used when REYATAZ without ritonavir is coadministered with drugs highly dependent on CYP2C8 with narrow therapeutic indicies (eg, paclitaxel, repaglinide). When REYATAZ with ritonavir is coadministered with substrates of CYP2C8, clinically significant interactions are not expected. See the complete prescribing information for NORVIR(r) for information on other potential drug interactions with ritonavir. Clinically significant interactions are not expected between atazanavir and substrates of CYP2C19, CYP2C9, CYP2D6, CYP2B6, CYP2A6, CYP1A2, or CYP2E1 (see DRUG INTERACTIONS).

DRUG INTERACTIONS

Serious Drug Interactions

• Refer to CONTRAINDICATIONS

• Refer to Table 11 for Drugs That Are Contraindicated or Not Recommended for Coadministration with REYATAZ.

• Refer to Table 12 for Established and Other Potentially Significant Drug Interactions

Overview

Atazanavir is a metabolism-dependent CYP3A inhibitor, with a Kinact value of 0.05 to 0.06 min-1 and Ki value of 0.84 to 1.0 uM. Atazanavir is also a direct inhibitor for UGT1A1 (Ki=1.9 uM). Co-administration of atazanavir and drugs primarily metabolized by CYP3A4 (e.g., calcium channel blockers, HMG CoA reductase inhibitors, immunosuppressants and phosphodiesterase (PDE5) inhibitors) or UGT1A1 (e.g., irinotecan) may result in increased plasma concentrations of the other drug that could increase or prolong both its therapeutic and adverse effects. Co-administration of atazanavir and drugs that induce CYP3A4, such as rifampin, may decrease atazanavir plasma concentrations and reduce its therapeutic effect. Co-administration of atazanavir and drugs that inhibit CYP3A4 may increase atazanavir plasma concentrations. (See Tables 11 and 12, DRUG INTERACTIONS.) Atazanavir competitively inhibits CYP1A2 and CYP2C9 with Ki values of 12 mM and a Cmax/Ki ratio of approximately 0.25. There is a potential drug-drug interaction between atazanavir and CYP1A2 or CYP2C19 substrates. Atazanavir does not inhibit CYP2C19 or CYP2El at clinically relevant concentrations. Atazanavir should not be administered concurrently with medications with narrow therapeutic windows that are substrates of CYP3A or UGT1A1 (see CONTRAINDICATIONS). Atazanavir solubility decreases as pH increases. Reduced plasma concentrations of atazanavir are expected if antacids, buffered medications, H2- receptor antagonists, and proton-pump inhibitors are administered with atazanavir. Particular caution should be used when prescribing phosphodiesterase (PDE5) inhibitors for erectile dysfunction (eg, sildenafil, tadalafil) in patients receiving protease inhibitors, including REYATAZ. Coadministration of a protease inhibitor with a PDE5 inhibitor is expected to substantially increase PDE5 inhibitor concentrations and may result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, visual changes, and priapism. (See PRECAUTIONS, Information for Patients, and the complete Product Monograph for sildenafil, and tadalafil. ). Vardenafil should not be coadministered with REYATAZ (with and without ritonavir) (see Tables 11 and 12). Simvastatin and lovastatin are contraindicated with REYATAZ (see Table 11). Caution should be exercised if HIV protease inhibitors, including REYATAZ, are used concurrently with other HMG-CoA reductase inhibitors that are also metabolized by the CYP3A pathway. Use the lowest possible dose of atorvastatin or rosuvastatin with careful monitoring, or consider other HMG- CoA reductase inhibitors such as pravastatin or fluvastatin in combination with REYATAZ (with and without ritonavir). The risk of myopathy, including rhabdomyolysis, may be increased when HIV protease inhibitors, including REYATAZ, are used in combination with these drugs. Concomitant use of REYATAZ and St. John's wort (Hypericum perforatum), or products containing St. John's wort, is not recommended. Coadministration of protease inhibitors, including REYATAZ, with St. John's wort is expected to substantially decrease concentrations of the protease inhibitor and may result in suboptimal levels of atazanavir and lead to loss of virologic response and possible resistance to atazanavir or to the class of protease inhibitors. The magnitude of CYP3A4-mediated drug interactions (effect on atazanavir or effect on coadministered drug) may change when REYATAZ is coadministered with ritonavir, a potent CYP3A4 inhibitor. The Product Monograph for ritonavir should be consulted for information on drug interactions with ritonavir. Atazanavir has the potential to prolong the PR interval of the electrocardiogram in some patients. Caution should be used when co-administering REYATAZ with medicinal products known to induce PR interval prolongation (eg, atenolol, diltiazem). The exposure to buprenorphine and the active metabolite, norbuprenorphine, were significantly increased when co-administered with atazanavir (with or without ritonavir). Co-administration of buprenorphine and REYATAZ (with or without ritonavir) warrants clinical monitoring for sedation and cognitive effects. A dose reduction of buprenorphine may be considered. A drug interaction study in healthy subjects has shown that ritonavir significantly increases plasma fluticasone propionate exposures, resulting in significantly decreased serum cortisol concentrations. Concomitant use of REYATAZ with ritonavir and fluticasone propionate is expected to produce the same effects. Systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, have been reported during post-marketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Therefore, coadministration of fluticasone propionate and REYATAZ/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects. Drugs that are contraindicated or not recommended for coadministration with REYATAZ are included in Table 11. Drugs with established and other potentially significant drug interactions are included in Table 12. 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 11 : Drugs That Are Contraindicated or Not Recommended for Coadministration with REYATAZ

Not marketed in Canada.

Table 12 : Established and Other Potentially Significant Drug Interactions : Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interactionsa

• didanosine buffered formulations

• didanosine EC formulation

• efavirenz

• nevirapine

• saquinavir (soft gelatin capsules)

• ritonavir

• Other protease inhibitors

• ketoconazole, itraconazole

• voriconazole

• REYATAZ 300 mg with ritonavir 100 mg once daily (all

• REYATAZ 400 mg with ritonavir 100 mg once daily (all

a

For magnitude of interactions see DETAILED PHARMACOLOGY : Drug-Drug Interactions.

Based on known metabolic profiles, clinically significant drug interactions are not expected between REYATAZ and fluvastatin, pravastatin, dapsone, trimethoprim/sulfamethoxazole, azithromycin, erythromycin, or itraconazole. Coadministration of methadone and REYATAZ in subjects chronically treated with methadone did not result in clinically relevant interactions. REYATAZ does not interact with substrates of CYP2D6 (eg, nortriptyline, desipramine, metoprolol). Additionally, no clinically significant drug interaction was observed when REYATAZ was coadministered with methadone, fluconazole or acetaminophen. Refer to Norvir(r) Product Monograph for drug interaction of ritonavir with these drugs before prescribing REYATAZ 300 mg with ritonavir 100 mg.

DOSAGE AND ADMINISTRATION

Recommended Adult Dose

The recommended dose of REYATAZ is 400 mg (two 200-mg capsules) once daily taken with food; 300 mg (one 300-mg capsule or two 150-mg capsules) once daily taken with ritonavir 100 mg once daily taken with food. Capsules should not be opened, they should be swallowed whole with water.

Recommended Pediatric Dose (from 6 to 18 years of age)

The recommended dosage of REYATAZ for pediatric patients (6 to less than 18 years of age) is based on body weight and should not exceed the recommended adult dosage. REYATAZ Capsules must be taken with food. The data are insufficient to recommend dosing of REYATAZ for any of the following: (1) patients less than 6 years of age, (2) without ritonavir in patients less than 13 years of age, and (3) treatment-experienced pediatric patients with body weight less than 25 kg.

Therapy-Naive Pediatric Patients

The recommended dosage of REYATAZ with ritonavir in treatment-naive patients at least 6 years of age is shown in Table 13. For treatment-naive patients at least 13 years of age and at least 39 kg, who are unable to tolerate ritonavir, the recommended dose is REYATAZ 400 mg (without ritonavir) once daily with food.

Table 13: Dosage for Treatment-Naive Pediatric Patients (6 to less than 18 years of age) for REYATAZ Capsules with ritonavir

a

The recommended dosage of REYATAZ can be achieved using a combination of commercially available capsule strengths.

b

The dosage of REYATAZ and ritonavir was calculated as follows:

• 15 kg to less than 20 kg: REYATAZ 8.5 mg/kg with ritonavir 4 mg/kg once daily with food.

• at least 20 kg: REYATAZ 7 mg/kg with ritonavir 4 mg/kg once daily with food not to exceed REYATAZ 300 mg and ritonavir 100 mg.

c

Ritonavir liquid.

d

Ritonavir capsule or liquid.

Therapy-Experienced Pediatric Patients

The recommended dosage of REYATAZ with ritonavir in treatment-experienced patients at least 6 years of age is shown in Table 14.

Table 14: Dosage for Treatment-Experienced Pediatric Patients (6 to less than 18 years of age) for REYATAZ Capsules with ritonavir

a

The recommended dosage of REYATAZ can be achieved using a combination of commercially available capsule strengths.

b

The dosage was calculated as REYATAZ 7 mg/kg with ritonavir 4 mg/kg once daily with food not to exceed REYATAZ 300 mg and ritonavir 100 mg.

c

Ritonavir capsule or liquid.

Dosing Considerations

Concomitant Therapy

: (See ACTION AND CLINICAL PHARMACOLOGY : Drug-Drug Interactions, WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS.)

Ritonavir

: There are limited safety data from controlled trials for REYATAZ plus ritonavir regimens without tenofovir. (See WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS.)

Efavirenz : Treatment-Naive patients: If coadministered with efavirenz, it is recommended that 300 mg of REYATAZ and ritonavir 100 mg be given with efavirenz 600 mg. REYATAZ, ritonavir and efavirenz are all administered as single daily doses with efavirenz administered 2 hours after atazanavir and ritonavir (given with food). REYATAZ without ritonavir should not be coadministered with efavirenz. The safety and efficacy of regimens containing REYATAZ, ritonavir and efavirenz has not been established. (See DRUG INTERACTIONS.) Treatment-Experienced patients: Dosing recommendations for efavirenz and REYATAZ have not been established.

Didanosine

: When coadministered with didanosine buffered formulations, REYATAZ should be given (with food) two hours before or one hour after didanosine.

Tenofovir DF

: If coadministered with tenofovir DF, it is recommended that 300 mg of REYATAZ and ritonavir 100 mg be given with tenofovir 300 mg (together as single daily doses with food). There are limited safety data from controlled trials for REYATAZ plus ritonavir regimens without tenofovir. REYATAZ without ritonavir should not be coadministered with tenofovir. (See DRUG INTERACTIONS.)

Dose Adjustments:

Patients With Renal Impairment

For patients with renal impairment, including those with severe renal impairment who are not managed with hemodialysis, no dose adjustment is required for REYATAZ. Treatment-naive patients with end stage renal disease managed with hemodialysis should receive REYATAZ 300 mg with ritonavir 100 mg. REYATAZ, with or without ritonavir, should not be used in antiretroviral-treatment experienced patients with end stage renal disease managed with

hemodialysis

. REYATAZ without ritonavir should not be administered to patients managed with hemodialysis. (see WARNINGS AND PRECAUTIONS and ACTION AND CLINICAL PHARMACOLOGY : Special Populations and Conditions).

Patients With Hepatic Impairment

A dose reduction to 300 mg once daily should be considered for patients with moderate hepatic impairment (Child-Pugh Class B). REYATAZ should not be used in patients with severe hepatic impairment (Child Pugh Class C). REYATAZ in combination with ritonavir has not been studied in subjects with hepatic impairment and should be used with caution in patients with mild hepatic impairment. REYATAZ with ritonavir is not recommended for patients with moderate- severe impairment. (See WARNINGS AND PRECAUTIONS: Hepatic/Biliary; ACTION AND CLINICAL PHARMACOLOGY : Special Populations and Conditions.)

Missed Dose

If a dose of REYATAZ is missed, patients should take the dose as soon as possible and then return to their normal schedule. However, if a dose is skipped, the patient should not double the next dose.

OVERDOSAGE

For management of a suspected drug overdose, please contact your regional Poison Control Centre. Administration of activated charcoal may be used to aid in removal of unabsorbed drug. Treatment of overdosage with atazanavir should consist of general supportive measures, including monitoring of vital signs and ECG, and observations of the patient's clinical status. There is no specific antidote for overdose with atazanavir. Since atazanavir is extensively metabolized by the liver and is highly protein bound, dialysis is unlikely to be beneficial in significant removal of this medicine. Human experience of acute overdose with atazanavir is limited. Single doses up to 1200 mg have been taken by healthy volunteers without symptomatic untoward effects. A single self- administered overdose of 58.4 g of atazanavir in an HIV-infected patient (146 times the 400 mg recommended dose) was associated with asymptomatic bilateral bundle branch block and PR interval prolongation. These events resolved spontaneously. At high doses that lead to high drug exposures, jaundice due to indirect (unconjugated) hyperbilirubinemia (without associated liver function test changes) or cardiac conduction abnormalities, including PR and/or QT interval prolongations, may be observed. (See WARNINGS AND PRECAUTIONS : Cardiovascular, and DETAILED PHARMACOLOGY : Electrocardiogram.)

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

REYATAZ (atazanavir) is an azapeptide HIV-1 protease inhibitor. The compound selectively inhibits the virus-specific processing of viral Gag and Gag-Pol polyproteins in HIV-1 infected cells, thus preventing formation of mature virions.

Pharmacokinetics

The pharmacokinetics of atazanavir were evaluated in healthy adult volunteers and in HIV- infected patients, after administration of REYATAZ 400 mg once daily and after administration of REYATAZ 300 mg with ritonavir 100 mg once daily.

Table 15: Steady-State Pharmacokinetics of Atazanavir in Healthy Adult Subjects or HIV-Infected Patients in the Fed State

1. n = 26

2. n = 12

Absorption

Atazanavir is rapidly absorbed with a Tmax of approximately 2.5 hours. Atazanavir demonstrates nonlinear pharmacokinetics with greater than dose-proportional increases in AUC and Cmax values over the dose range of 200-800 mg once daily. Steady-state is achieved between Days 4 and 8, with an accumulation of approximately 2.3-fold. Figure 1 displays the mean plasma concentrations of atazanavir on Day 29 (steady state) following atazanavir 400 mg once daily (as two 200-mg capsules) with a light meal and after atazanavir 300 mg (as two 150-mg capsules) with ritonavir 100 mg once daily with a light meal in HIV-infected adult patients.

Figure 1 : Mean (SD) Steady-state Plasma Concentrations of Atazanavir 400-mg (n = 13) and 300 mg with Ritonavir (n = 10) for HIV-infected Adult Patients

Food Effect

Administration of a single 400-mg dose of atazanavir with a light meal (357 kcal, 8.2 g fat, 10.6 g protein) resulted in a 70% increase in AUC and 57% increase in Cmax relative to the fasting state. Administration of a single 400-mg dose of atazanavir with a high fat meal (721 kcal, 37.3 g fat, 29.4 g protein) resulted in a mean increase in AUC of 35% with no change in Cmax relative to the fasting state. Administration of REYATAZ with either a light meal or high-fat meal decreased the coefficient of variation of AUC and Cmax by approximately one half compared to the fasting state. Thus, REYATAZ is taken with food in order to enhance its bioavailability and reduce the pharmacokinetic variability. Coadministration of REYATAZ and ritonavir with food optimizes the bioavailability of atazanavir. Coadministration of a single 300-mg dose of REYATAZ and a 100-mg dose of ritonavir with a light meal (336 total kcal, 5.1 g fat, 9.3 g protein and 63.3 g carbohydrates) resulted in a 33% increase in the AUC and a 40% increase in both the Cmax and the 24-hour concentration of atazanavir relative to the fasting state. Coadministration with a high-fat meal (951 total kcal, 54.7 g fat, 35.9 g protein and 77.9 g carbohydrates) did not affect the AUC of atazanavir relative to fasting conditions and the Cmax was within 11% of fasting values. The 24- hour concentration following a high-fat meal was increased by approximately 33% due to delayed absorption; the median Tmax increased from 2.0 to 5.0 hours. Coadministration of REYATAZ with ritonavir with either a light or a high-fat meal decreased the coefficient of variation of AUC and Cmax by approximately 25% compared to the fasting state.

Distribution

Atazanavir is 86% bound to human serum proteins and protein binding is independent of concentration. Atazanavir binds to both alpha-1-acid glycoprotein (AAG) and albumin to a similar extent (89% and 86%, respectively). In a multiple-dose study in HIV-infected patients dosed with atazanavir 400 mg once daily with a light meal for 12 weeks, atazanavir was detected in the cerebrospinal fluid and semen. The cerebrospinal fluid/plasma ratio for atazanavir (n = 4) ranged between 0.0021 and 0.0226 and seminal fluid/plasma ratio (n = 5) ranged between 0.11 and 4.42.

Metabolism

Studies in humans and in vitro studies using human liver microsomes have demonstrated that atazanavir is principally metabolized by CYP3A4 isozyme to oxygenated metabolites, which are then excreted in the bile as either free or glucuronidated metabolites. Additional minor metabolic pathways consist of N-dealkylation, hydrolysis and oxygenation with dehydrogenation. Two minor metabolites of atazanavir in plasma have been characterized. Neither metabolite demonstrated in vitro antiviral activity.

Elimination

Following a single 400-mg dose of 14C-atazanavir, 79% and 13% of the total radioactivity was recovered in the feces and urine, respectively. Unchanged drug accounted for approximately 20% and 7% of the administered dose in the feces and urine, respectively. The mean elimination half- life of atazanavir in healthy volunteers (n=214) and HIV-infected adult patients (n=13) was approximately 7 hours at steady state following a dose of 400 mg daily with a light meal.

Electrocardiogram : Effect on PR and QT intervals

Concentration - and dose - dependent prolongation of the PR interval in the electrocardiogram has been observed in healthy volunteers receiving atazanavir. In a placebo-controlled study (AI424-076), the mean (+ / -SD) maximum change in PR interval from the pre-dose value was 24 (+ / -15 msec) following oral dosing with 400 mg of atazanavir (n = 65) compared to 13 (+ 11 msec) following dosing with placebo (n = 67). The PR interval prolongations in this study were asymptomatic. There is limited information on the potential for pharmacodynamic interaction in humans between atazanavir and other drugs that prolong the PR interval of the electrocardiogram (see WARNINGS AND PRECAUTIONS). Electrocardiographic effects of atazanavir were determined in a clinical pharmacology study of 72 healthy subjects. Oral doses of 400 mg and 800 mg were compared with placebo; there was no concentration - dependent effect of atazanavir on the QTc interval (using Fridericia's correction). In 1793 HIV - infected patients receiving antiretroviral regimens, QTc prolongation was comparable in the atazanavir and comparator regimens. No atazanavir-treated healthy subject or HIV-infected patient had a QTc interval > 500 msec.

Special Populations and Conditions

Age/Gender/Race

A study of the pharmacokinetics of atazanavir was performed in young (n=29; 18-40 years) and elderly (n=30; >=65 years) healthy subjects. There were no clinically important pharmacokinetic differences observed due to age or gender. There are insufficient data to determine whether there are any effects of race on the pharmacokinetics of atazanavir.

Pediatrics (from 6 to 18 years of age)

The pharmacokinetic data from pediatric patients receiving REYATAZ Capsules with ritonavir based on body surface area are presented in Table 16.

Table 16: Steady-State Pharmacokinetics of Atazanavir with ritonavir in HIV Infected Pediatric Patients (6 to 18 years of age) in the Fed State

Renal impairment

In healthy subjects, approximately 7% of the dose of atazanavir is eliminated unchanged in the urine. REYATAZ has been studied in adult subjects with severe renal impairment (n=20), including those on hemodialysis, at multiple doses of 400 mg once daily. The mean atazanavir Cmax was 9% lower, AUC was 19% higher, and Cmin was 96% higher in subjects with severe renal impairment not undergoing hemodialysis (n=10), than in age, weight, and gender matched subjects with normal renal function. Atazanavir was not appreciably cleared during hemodialysis. In a 4-hour dialysis session, 2.1% of the administered dose was removed. Subjects on hemodialysis appeared to display lower exposures as compared to healthy subjects and renally-impaired subjects without hemodialysis. The geometric means for ATV AUC, Cmax and Cmin, for REYATAZ administered immediately following dialysis in subjects on hemodialysis (n=10) were 42%, 37% and 54% lower, respectively, relative to subjects with normal renal function. When REYATAZ was administered 2 hours before a 4-hour hemodialysis session, the geometric means for ATV AUC, Cmax and Cmin in hemodialysis subjects were 28%, 25% and 43% lower, respectively, than subjects with normal renal function. The mechanism of this decrease is unknown. (See DOSAGE AND ADMINISTRATION.)

Impaired hepatic function

Atazanavir is metabolized and eliminated primarily by the liver. Atazanavir has been studied in adult patients with moderate to severe hepatic impairment (14 Child-Pugh B and 2 Child-Pugh C) after a single 400-mg dose. The mean AUC(0-[?]) was 42% greater in patients with impaired hepatic function than in healthy volunteers. The mean half-life of atazanavir in hepatically impaired patients was 12.1 hours compared to 6.4 hours in healthy volunteers. Increased concentrations of atazanavir are expected in patients with moderately or severely impaired hepatic function (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).

STORAGE AND STABILITY

REYATAZ capsules should be stored at 25degC (77degF); excursions permitted to 15-30degC (59- 86degF). Protect from moisture.

DOSAGE FORMS, COMPOSITION AND PACKAGING

REYATAZ (atazanavir sulfate) Capsules are available for oral administration in strengths containing atazanavir sulfate equivalent to 100 mg, 150 mg, 200 mg or 300 mg of atazanavir and the following inactive ingredients : crospovidone, lactose monohydrate, and magnesium stearate. The capsule shells contain the following inactive ingredients: gelatin, FD&C Blue #2, and titanium dioxide (for all strengths), black iron oxide, red iron oxide and yellow iron oxide (300 mg only). REYATAZ capsules are supplied in HDPE bottles containing 60 capsules (100 mg, 150 mg and 200 mg) and 30 capsules (300 mg).

100 mg capsule

Blue opaque cap and white opaque body hard gelatin capsule printed in white with "BMS", "100 mg" and in blue with "3623".

150 mg capsule

Blue opaque cap and powder-blue opaque body, hard gelatin capsule printed in white with "BMS", "150 mg", and in blue "3624".

200 mg capsule

Blue opaque cap and body, hard gelatin capsule printed in white with "BMS", "200 mg", and "3631".

300 mg capsule

Red opaque cap and blue opaque body, hard gelatin capsule printed in white with "BMS", "300 mg", and "3622".