REYATAZ^®
(atazanavir sulfate) Capsules

REYATAZ^® (atazanavir sulfate) is an azapeptide inhibitor of HIV-1 protease.

The chemical name for atazanavir sulfate is (3S,8S,9S,12S)-3,12-Bis(1,1-dimethylethyl)-8-hydroxy-4,11-dioxo-9-(phenylmethyl)-6-[[4-(2-pyridinyl)phenyl]methyl]-2,5,6,10,13-pentaazatetradecanedioic acid dimethyl ester, sulfate (1:1). Its molecular formula is C₃₈H₅₂N₆O₇•H₂SO₄, which corresponds to a molecular weight of 802.9 (sulfuric acid salt). The free base molecular weight is 704.9. Atazanavir sulfate has the following structural formula:

Atazanavir sulfate is a white to pale yellow crystalline powder. It is slightly soluble in water (4-5 mg/mL, free base equivalent) with the pH of a saturated solution in water being about 1.9 at 24 ± 3° C.

REYATAZ Capsules are available for oral administration in strengths containing the equivalent of 100 mg, 150 mg, 200 mg, or 300 mg of atazanavir as atazanavir sulfate and the following inactive ingredients: crospovidone, lactose monohydrate, and magnesium stearate. The capsule shells contain the following inactive ingredients: gelatin, FD&C Blue #2, titanium dioxide, black iron oxide, red iron oxide, and yellow iron oxide. The capsules are printed with ink containing shellac, titanium dioxide, FD&C Blue #2, isopropyl alcohol, ammonium hydroxide, propylene glycol, n-butyl alcohol, simethicone, and dehydrated alcohol.

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 (see Table 3).

Figure 1 displays the mean plasma concentrations of atazanavir at steady state after REYATAZ 400 mg once daily (as two 200-mg capsules) with a light meal and after REYATAZ 300 mg (as two 150-mg capsules) with ritonavir 100 mg once daily with a light meal in HIV-infected adult patients.

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 predose 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 a pharmacodynamic interaction in humans between atazanavir and other drugs that prolong the PR interval of the electrocardiogram. (See WARNINGS.)

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.

Atazanavir is metabolized in the liver by CYP3A. Atazanavir is a metabolism-dependent CYP3A inhibitor, with a K_inact value of 0.05 to 0.06 min^-1 and K_i value of 0.84 to 1.0 µM. Atazanavir is also a direct inhibitor for UGT1A1 (K_i=1.9 µM) and CYP2C8 (K_i=2.1 µM). REYATAZ should not be administered concurrently with medications with narrow therapeutic windows that are substrates of CYP3A, UGT1A1, or CYP2C8 (see CONTRAINDICATIONS).

Clinically significant interactions are not expected between atazanavir and substrates of CYP2C19, CYP2C9, CYP2D6, CYP2B6, CYP2A6, CYP1A2, or CYP2E1.

Atazanavir has been shown in vivo not to induce its own metabolism, nor to increase the biotransformation of some drugs metabolized by CYP3A. In a multiple-dose study, REYATAZ decreased the urinary ratio of endogenous 6β-OH cortisol to cortisol versus baseline, indicating that CYP3A production was not induced.

Drugs that induce CYP3A activity may increase the clearance of atazanavir, resulting in lowered plasma concentrations. Coadministration of REYATAZ and other drugs that inhibit CYP3A may increase atazanavir plasma concentrations.

Drug interaction studies were performed with REYATAZ and other drugs likely to be coadministered and some drugs commonly used as probes for pharmacokinetic interactions. The effects of coadministration of REYATAZ on the AUC, C_max, and C_min are summarized in Tables 4 and 5. For information regarding clinical recommendations, see PRECAUTIONS: Drug Interactions, Tables 10 and 11.

REYATAZ (atazanavir sulfate) is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection.

This indication is based on analyses of plasma HIV-1 RNA levels and CD4+ cell counts from controlled studies of 48 weeks duration in antiretroviral-naive and antiretroviral-treatment-experienced patients.

The following points should be considered when initiating therapy with REYATAZ:

• In antiretroviral-experienced patients with prior virologic failure, coadministration of REYATAZ/ritonavir is recommended.
• In Study AI424-045 REYATAZ/ritonavir and lopinavir/ritonavir were similar for the primary efficacy outcome measure of time-averaged difference in change from baseline in HIV RNA level. This study was not large enough to reach a definitive conclusion that REYATAZ/ritonavir and lopinavir/ritonavir are equivalent on the secondary efficacy outcome measure of proportions below the HIV RNA lower limit of detection (see Description of Clinical Studies).
• The number of baseline primary protease inhibitor mutations affects the virologic response to REYATAZ/ritonavir (see CLINICAL PHARMACOLOGY: Microbiology).
• There are no data regarding the use of REYATAZ/ritonavir in therapy-naive patients.

REYATAZ (atazanavir sulfate) is contraindicated in patients with known hypersensitivity to any of its ingredients, including atazanavir.

Coadministration of REYATAZ is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events. These drugs are uled in Table 9.

ALERT: Find out about medicines that should NOT be taken with REYATAZ. This statement is included on the product’s bottle label. (See CONTRAINDICATIONS, WARNINGS: Drug Interactions, and PRECAUTIONS: Drug Interactions.)

Atazanavir is an inhibitor of CYP3A, CYP2C8, and UGT1A1. Coadministration of REYATAZ and drugs primarily metabolized by CYP3A [eg, calcium channel blockers, HMG-CoA reductase inhibitors, immunosuppressants, and phosphodiesterase (PDE5) inhibitors], CYP2C8, or UGT1A1 (eg, irinotecan) may result in increased plasma concentrations of the other drug that could increase or prolong its therapeutic and adverse effects. (Also see PRECAUTIONS: Drug Interactions, Tables 10 and 11.)

Particular caution should be used when prescribing PDE5 inhibitors for erectile dysfunction (eg, sildenafil, tadalafil, or vardenafil) for patients receiving protease inhibitors, including REYATAZ. Coadministration of a protease inhibitor with a PDE5 inhibitor is expected to substantially increase the PDE5 inhibitor concentration and may result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, visual changes, and priapism. (See PRECAUTIONS: Drug Interactions and Information for Patients, and the complete prescribing information for the PDE5 inhibitor.)

Concomitant use of REYATAZ with lovastatin or simvastatin is not recommended. 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 (eg, atorvastatin). The risk of myopathy, including rhabdomyolysis, may be increased when HIV protease inhibitors, including REYATAZ, are used in combination with these drugs.

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 postmarketing 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 (see PRECAUTIONS: Drug Interactions).

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.

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 generally limited to first-degree AV block. There have been rare reports of second-degree AV block and other conduction abnormalities and no reports of third-degree AV block (see OVERDOSAGE). In clinical trials, asymptomatic first-degree AV block was observed in 5.9% of atazanavir-treated patients (n=920), 5.2% of lopinavir/ritonavir-treated patients (n=252), 10.4% of nelfinavir-treated patients (n=48), and 3.0% of efavirenz-treated patients (n=329). In Study AI424-045, asymptomatic first-degree AV block was observed in 5% (6/118) of atazanavir/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 (eg, marked first-degree AV block or second- or third-degree AV block). (See CLINICAL PHARMACOLOGY: Effects on Electrocardiogram.)

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 PRECAUTIONS: 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 CYP3A (eg, verapamil). (See PRECAUTIONS: Drug Interactions.)

New-onset diabetes mellitus, exacerbation of preexisting 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 a causal relationship between protease inhibitor therapy and these events has not been established.

A statement to patients and healthcare providers is included on the product’s bottle label: ALERT: Find out about medicines that should NOT be taken with REYATAZ. A Patient Package Insert (PPI) for REYATAZ is available for patient information.

Patients should be told that sustained decreases in plasma HIV RNA have been associated with a reduced risk of progression to AIDS and death. Patients should remain under the care of a physician while using REYATAZ. Patients should be advised to take REYATAZ with food every day and take other concomitant antiretroviral therapy as prescribed. REYATAZ must always be used in combination with other antiretroviral drugs. Patients should not alter the dose or discontinue therapy without consulting with their doctor. 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.

Patients should be informed that REYATAZ is not a cure for HIV infection and that they may continue to develop opportunistic infections and other complications associated with HIV disease. Patients should be told that there are currently no data demonstrating that therapy with REYATAZ can reduce the risk of transmitting HIV to others through sexual contact.

REYATAZ may interact with some drugs; therefore, patients should be advised to report to their doctor the use of any other prescription, nonprescription medication, or herbal products, particularly St. John’s wort.

Patients receiving a PDE5 inhibitor and atazanavir should be advised that they may be at an increased risk of PDE5 inhibitor-associated adverse events including hypotension, visual changes, and prolonged penile erection, and should promptly report any symptoms to their doctor.

Patients should be informed that atazanavir may produce changes in the electrocardiogram (PR prolongation). Patients should consult their physician if they are experiencing symptoms such as dizziness or lightheadedness.

REYATAZ (atazanavir sulfate) should be taken with food to enhance absorption.

Patients should be informed that asymptomatic elevations in indirect bilirubin have occurred in patients receiving REYATAZ. This may be accompanied by yellowing of the skin or whites of the eyes and alternative antiretroviral therapy may be considered if the patient has cosmetic concerns.

Patients should be informed that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy including protease inhibitors and that the cause and long-term health effects of these conditions are not known at this time. It is unknown whether long-term use of REYATAZ will result in a lower incidence of lipodystrophy than with other protease inhibitors.

Atazanavir is an inhibitor of CYP3A, CYP2C8, and UGT1A1. Coadministration of REYATAZ and drugs primarily metabolized by CYP3A (eg, calcium channel blockers, HMG-CoA reductase inhibitors, immunosuppressants, and PDE5 inhibitors), CYP2C8, or UGT1A1 (eg, irinotecan) may result in increased plasma concentrations of the other drug that could increase or prolong both its therapeutic and adverse effects (see Tables 10 and 11). Atazanavir is metabolized in the liver by the cytochrome P450 enzyme system. Coadministration of REYATAZ and drugs that induce CYP3A, such as rifampin, may decrease atazanavir plasma concentrations and reduce its therapeutic effect. Coadministration of REYATAZ (atazanavir sulfate) and drugs that inhibit CYP3A may increase atazanavir plasma concentrations.

The potential for drug interactions with REYATAZ changes when REYATAZ is coadministered with the potent CYP3A inhibitor ritonavir. The magnitude of CYP3A-mediated drug interactions (effect on atazanavir or effect on coadministered drug) may change when REYATAZ is coadministered with ritonavir. See the complete prescribing information for Norvir^® (ritonavir) for information on drug interactions with ritonavir.

Atazanavir solubility decreases as pH increases. Reduced plasma concentrations of atazanavir are expected if proton-pump inhibitors (see Table 10), antacids, buffered medications, or H₂-receptor antagonists (see Table 11) are administered with atazanavir.

Atazanavir has the potential to prolong the PR interval of the electrocardiogram in some patients. Caution should be used when coadministering REYATAZ with medicinal products known to induce PR interval prolongation (eg, atenolol, diltiazem [see Table 11]).

Drugs that are contraindicated or not recommended for coadministration with REYATAZ are included in Table 10. 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.

Based on known metabolic profiles, clinically significant drug interactions are not expected between REYATAZ (atazanavir sulfate) and fluvastatin, pravastatin, dapsone, trimethoprim/sulfamethoxazole, azithromycin, erythromycin, or fluconazole. 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.

Two-year carcinogenicity studies in mice and rats were conducted with atazanavir. At the high dose in female mice, the incidence of benign hepatocellular adenomas was increased at systemic exposures 7.2-fold higher than those in humans at the recommended 400-mg clinical dose. There were no increases in the incidence of tumors in male mice at any dose in the study. In rats, no significant positive trends in the incidence of neoplasms occurred at systemic exposures up to 5.7-fold higher than those in humans at the recommended 400-mg clinical dose. The clinical relevance of the carcinogenic findings in female mice is unknown.

Atazanavir tested positive in an in vitro clastogenicity test using primary human lymphocytes, in the absence and presence of metabolic activation. Atazanavir tested negative in the in vitro Ames reverse-mutation assay, in vivo micronucleus and DNA repair tests in rats, and in vivo DNA damage test in rat duodenum (comet assay).

At the systemic drug exposure levels (AUC) equal to (in male rats) or two times (in female rats) those at the human clinical dose (400 mg once daily), atazanavir did not produce significant effects on mating, fertility, or early embryonic development.

The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV. It is not known whether atazanavir is secreted in human milk. A study in lactating rats has demonstrated that atazanavir is secreted in milk. 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.

The optimal dosing regimen for use of REYATAZ in pediatric patients has not been established. REYATAZ (atazanavir sulfate) should not be administered to pediatric patients below the age of 3 months due to the risk of kernicterus.

Clinical studies of REYATAZ did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Based on a comparison of mean single-dose pharmacokinetic values for C_max and AUC, a dose adjustment based upon age is not recommended. In general, appropriate caution should be exercised in the administration and monitoring of REYATAZ in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

The following events have been identified during postapproval use of REYATAZ. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Body as a Whole: edema

Cardiovascular System: second-degree AV block (see WARNINGS: PR Interval Prolongation)

Gastrointestinal System: pancreatitis

Hepatic System: hepatic function abnormalities

Metabolic System and Nutrition Disorders: hyperglycemia, diabetes mellitus (see WARNINGS: Diabetes Mellitus/Hyperglycemia)

Musculoskeletal System: arthralgia

Renal System: nephrolithiasis

Skin and Appendages: pruritus, alopecia, maculopapular rash (see PRECAUTIONS: General, Rash)

The percentages of adult treatment-naive patients treated with combination therapy including REYATAZ (atazanavir sulfate) with Grade 3-4 laboratory abnormalities are presented in Table 14.

The percentages of adult treatment-experienced patients treated with combination therapy including REYATAZ/ritonavir with Grade 3-4 laboratory abnormalities are presented in Table 16.

Human experience of acute overdose with REYATAZ is limited. Single doses up to 1200 mg have been taken by healthy volunteers without symptomatic untoward effects. A single self-administered overdose of 29.2 g of REYATAZ in an HIV-infected patient (73 times the 400-mg recommended dose) was associated with asymptomatic bifascicular 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 PR interval prolongation may be observed. (See WARNINGS, PRECAUTIONS, and CLINICAL PHARMACOLOGY: Effects on Electrocardiogram.)

Treatment of overdosage with REYATAZ should consist of general supportive measures, including monitoring of vital signs and ECG, and observations of the patient’s clinical status. If indicated, elimination of unabsorbed atazanavir should be achieved by emesis or gastric lavage. Administration of activated charcoal may also be used to aid removal of unabsorbed drug. There is no specific antidote for overdose with REYATAZ. 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.

REYATAZ Capsules must be taken with food.

   The recommended oral dose of REYATAZ is as follows:

There are insufficient data to recommend a dosage adjustment for patients with renal impairment (see CLINICAL PHARMACOLOGY: Special Populations, Impaired Renal Function).

REYATAZ should be used with caution in patients with mild to moderate hepatic impairment. For patients with moderate hepatic impairment (Child-Pugh Class B) who have not experienced prior virologic failure, a dose reduction to 300 mg once daily should be considered. REYATAZ should not be used in patients with severe hepatic impairment (Child-Pugh Class C). REYATAZ/ritonavir has not been studied in subjects with hepatic impairment and is not recommended. (See PRECAUTIONS and CLINICAL PHARMACOLOGY: Special Populations, Impaired Hepatic Function.)

REYATAZ^® (atazanavir sulfate) Capsules are available in the following strengths and configurations of plastic bottles with child-resistant closures.

REYATAZ (atazanavir sulfate) Capsules should be stored at 25° C (77° F); excursions permitted to 15–30° C (59–86° F) [see USP Controlled Room Temperature].

US Patent Nos: 5,849,911 and 6,087,383.

REYATAZ^® (RAY-ah-taz)

(generic name = atazanavir sulfate)

Capsules

ALERT: Find out about medicines that should NOT be taken with REYATAZ. Read the section "What important information should I know about taking REYATAZ with other medicines?"

Read the Patient Information that comes with REYATAZ (atazanavir sulfate) before you start using it and each time you get a refill. There may be new information. This leaflet provides a summary about REYATAZ and does not include everything there is to know about your medicine. This information does not take the place of talking with your healthcare provider about your medical condition or treatment.

What is REYATAZ?

REYATAZ is a prescription medicine used with other anti-HIV medicines to treat people who are infected with the human immunodeficiency virus (HIV). HIV is the virus that causes acquired immune deficiency syndrome (AIDS). REYATAZ is a type of anti-HIV medicine called a protease inhibitor. HIV infection destroys CD4+ (T) cells, which are important to the immune system. The immune system helps fight infection. After a large number of (T) cells are destroyed, AIDS develops. REYATAZ helps to block HIV protease, an enzyme that is needed for the HIV virus to multiply. REYATAZ may lower the amount of HIV in your blood, help your body keep its supply of CD4+ (T) cells, and reduce the risk of death and illness associated with HIV.

Does REYATAZ cure HIV or AIDS?

REYATAZ does not cure HIV infection or AIDS. At present there is no cure for HIV infection. People taking REYATAZ may still get opportunistic infections or other conditions that happen with HIV infection. Opportunistic infections are infections that develop because the immune system is weak. Some of these conditions are pneumonia, herpes virus infections, and Mycobacterium avium complex (MAC) infections. It is very important that you see your healthcare provider regularly while taking REYATAZ.

REYATAZ does not lower your chance of passing HIV to other people 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 using a latex or polyurethane condom or other barrier to lower the chance of sexual contact with semen, vaginal secretions, or blood. Never use or share dirty needles.

Who should not take REYATAZ?

Do not take REYATAZ if you:

• are taking certain medicines. (See “What important information should I know about taking REYATAZ with other medicines?") Serious life-threatening side effects or death may happen. Before you take REYATAZ, tell your healthcare provider about all medicines you are taking or planning to take. These include other prescription and nonprescription medicines, vitamins, and herbal supplements.
• are allergic to REYATAZ or to any of its ingredients. The active ingredient is atazanavir sulfate. See the end of this leaflet for a complete ul of ingredients in REYATAZ. Tell your healthcare provider if you think you have had an allergic reaction to any of these ingredients.

What should I tell my healthcare provider before I take REYATAZ?

Tell your healthcare provider:

• If you are pregnant or planning to become pregnant. It is not known if REYATAZ can harm your unborn baby. Pregnant women have experienced serious side effects when taking REYATAZ with other HIV medicines called nucleoside analogues. You and your healthcare provider will need to decide if REYATAZ is right for you. If you use REYATAZ while you are pregnant, talk to your healthcare provider about the Antiretroviral Pregnancy Registry.
• If you are breast-feeding. You should not breast-feed if you are HIV-positive because of the chance of passing HIV to your baby. Also, it is not known if REYATAZ can pass into your breast milk and if it can harm your baby. If you are a woman who has or will have a baby, talk with your healthcare provider about the best way to feed your baby.
• If you have liver problems or are infected with the hepatitis B or C virus. See “What are the possible side effects of REYATAZ?"
• If you have diabetes. See "What are the possible side effects of REYATAZ?"
• If you have hemophilia. See "What are the possible side effects of REYATAZ?"
• About all the medicines you take including prescription and nonprescription medicines, vitamins, and herbal supplements. Keep a ul of your medicines with you to show your healthcare provider. For more information, see "What important information should I know about taking REYATAZ with other medicines?" and "Who should not take REYATAZ?" Some medicines can cause serious side effects if taken with REYATAZ.

How should I take REYATAZ?

• Take REYATAZ once every day exactly as instructed by your healthcare provider. Your healthcare provider will prescribe the amount of REYATAZ that is right for you.
  • For adults who have never taken anti-HIV medicines before, the usual dose is 400 mg (two 200-mg capsules) once daily taken with food.
  • For adults who have taken anti-HIV medicines in the past, the usual dose is 300 mg (one 300-mg capsule or two 150-mg capsules) plus 100 mg of NORVIR^® (ritonavir) once daily taken with food.

Your dose will depend on your liver function and on the other anti-HIV medicines that you are taking. REYATAZ is always used with other anti-HIV medicines. If you are taking REYATAZ with SUSTIVA^® (efavirenz) or with VIREAD^® (tenofovir disoproxil fumarate), you should also be taking NORVIR^® (ritonavir).

• Always take REYATAZ with food (a meal or snack) to help it work better. Swallow the capsules whole. Do not open the capsules. Take REYATAZ at the same time each day.
• If you are taking antacids or didanosine (VIDEX^® or VIDEX^® EC), take REYATAZ 2 hours before or 1 hour after these medicines.
• If you are taking medicines for indigestion, heartburn, or ulcers such as AXID^® (nizatidine), PEPCID AC^® (famotidine), TAGAMET^® (cimetidine), or ZANTAC^® (ranitidine), talk to your healthcare provider.
• Do not change your dose or stop taking REYATAZ without first talking with your healthcare provider. It is important to stay under a healthcare provider's care while taking REYATAZ.
• When your supply of REYATAZ starts to run low, get more from your healthcare provider or pharmacy. It is important not to run out of REYATAZ. The amount of HIV in your blood may increase if the medicine is stopped for even a short time.
• If you miss a dose of REYATAZ, take it as soon as possible and then take your next scheduled dose at its regular time. If, however, it is within 6 hours of your next dose, do not take the missed dose. Wait and take the next dose at the regular time. Do not double the next dose. It is important that you do not miss any doses of REYATAZ or your other anti-HIV medicines.
• If you take more than the prescribed dose of REYATAZ, call your healthcare provider or poison control center right away.

Can children take REYATAZ?

REYATAZ has not been fully studied in children under 16 years of age. REYATAZ should not be used in babies under the age of 3 months.

What are the possible side effects of REYATAZ?

The following ul of side effects is not complete. Report any new or continuing symptoms to your healthcare provider. If you have questions about side effects, ask your healthcare provider. Your healthcare provider may be able to help you manage these side effects.

The following side effects have been reported with REYATAZ:
• rash (redness and itching) sometimes occurs in patients taking REYATAZ, most often in the first few weeks after the medicine is started. Rashes usually go away within 2 weeks with no change in treatment. Tell your healthcare provider if rash occurs.
• yellowing of the skin or eyes. These effects may be due to increases in bilirubin levels in the blood (bilirubin is made by the liver). Call your healthcare provider if your skin or the white part of your eyes turn yellow. Although these effects may not be damaging to your liver, skin, or eyes, it is important to tell your healthcare provider promptly if they occur.
• a change in the way your heart beats (heart rhythm change). Call your healthcare provider right away if you get dizzy or lightheaded. These could be symptoms of a heart problem.
• diabetes and high blood sugar (hyperglycemia) sometimes happen in patients taking protease inhibitor medicines like REYATAZ. Some patients had diabetes before taking protease inhibitors while others did not. Some patients may need changes in their diabetes medicine.
• if you have liver disease including hepatitis B or C, your liver disease may get worse when you take anti-HIV medicines like REYATAZ (atazanavir sulfate).
• some patients with hemophilia have increased bleeding problems with protease inhibitors like REYATAZ.
• changes in body fat. These changes may include an increased amount of fat in the upper back and neck ("buffalo hump"), breast, and around the trunk. Loss of fat from the legs, arms, and face may also happen. The cause and long-term health effects of these conditions are not known at this time.

Other common side effects of REYATAZ taken with other anti-HIV medicines include nausea; headache; stomach pain; vomiting; diarrhea; depression; fever; dizziness; trouble sleeping; numbness, tingling, or burning of hands or feet; and muscle pain.

What important information should I know about taking REYATAZ with other medicines?

Do not take REYATAZ if you take the following medicines (not all brands may be uled; tell your healthcare provider about all the medicines you take). REYATAZ may cause serious, life-threatening side effects or death when used with these medicines.

• Ergot medicines: dihydroergotamine, ergonovine, ergotamine, and methylergonovine such as CAFERGOT^®, MIGRANAL^®, D.H.E. 45^®, ergotrate maleate, METHERGINE®, and others (used for migraine headaches).
• HALCION^® (triazolam, used for insomnia).
• VERSED^® (midazolam, used for sedation).
• ORAP^® (pimozide, used for Tourette’s disorder).
• PROPULSID^® (cisapride, used for certain stomach problems).

Do not take the following medicines with REYATAZ (atazanavir sulfate) because of possible serious side effects:

• CAMPTOSAR^® (irinotecan, used for cancer).
• CRIXIVAN^® (indinavir, used for HIV infection). Both REYATAZ and CRIXIVAN sometimes cause increased levels of bilirubin in the blood.
• Cholesterol-lowering medicines MEVACOR^® (lovastatin) or ZOCOR^® (simvastatin).

Do not take the following medicines with REYATAZ because they may lower the amount of REYATAZ in your blood. This may lead to an increased HIV viral load. Resistance to REYATAZ or cross-resistance to other HIV medicines may develop:

• Rifampin (also known as RIMACTANE^®, RIFADIN^®, RIFATER^®, or RIFAMATE^®, used for tuberculosis).
• St. John’s wort (Hypericum perforatum), an herbal product sold as a dietary supplement, or products containing St. John’s wort.
• "Proton-pump inhibitors” used for indigestion, heartburn, or ulcers such as AcipHex^® (rabeprazole), NEXIUM^® (esomeprazole), PREVACID^® (lansoprazole), PRILOSEC^® (omeprazole), or PROTONIX^® (pantoprazole).

Do not take the following medicine if you are taking REYATAZ and NORVIR^® together.

• VFEND® (voriconazole).

The following medicines may require your healthcare provider to monitor your therapy more closely:

• CIALIS^® (tadalafil), LEVITRA^® (vardenafil), or VIAGRA^® (sildenafil). REYATAZ may increase the chances of serious side effects that can happen with CIALIS, LEVITRA, or VIAGRA. Do not use CIALIS, LEVITRA, or VIAGRA while you are taking REYATAZ unless your healthcare provider tells you it is okay.
• LIPITOR^® (atorvastatin). There is an increased chance of serious side effects if you take REYATAZ with this cholesterol-lowering medicine.
• Medicines for abnormal heart rhythm: CORDARONE^® (amiodarone), lidocaine, quinidine (also known as CARDIOQUIN^®, QUINIDEX^®, and others).
• VASCOR^® (bepridil, used for chest pain).
• COUMADIN^® (warfarin).
• Tricyclic antidepressants such as ELAVIL^® (amitriptyline), NORPRAMIN^® (desipramine), SINEQUAN^® (doxepin), SURMONTIL^® (trimipramine), TOFRANIL^®(imipramine), or VIVACTIL^® (protriptyline).
• Medicines to prevent organ transplant rejection: SANDIMMUNE^® or NEORAL^® (cyclosporin), RAPAMUNE^® (sirolimus), or PROGRAF^® (tacrolimus).
• The antidepressant trazodone (DESYREL^® and others).
• Fluticasone propionate (ADVAIR^®, FLONASE^®, FLOVENT^®), given by nose or inhaled to treat allergic symptoms or asthma. Your doctor may choose not to keep you on fluticasone, especially if you are also taking NORVIR^®.

The following medicines may require a change in the dose or dose schedule of either REYATAZ or the other medicine:

• FORTOVASE^®, INVIRASE^® (saquinavir).
• NORVIR^® (ritonavir).
• SUSTIVA^® (efavirenz).
• Antacids or buffered medicines.
• VIDEX^® (didanosine).
• VIREAD^® (tenofovir disoproxil fumarate).
• MYCOBUTIN^® (rifabutin).
• Calcium channel blockers such as CARDIZEM^® or TIAZAC^® (diltiazem), COVERA HS^® or ISOPTIN SR^® (verapamil), and others.
• BIAXIN^® (clarithromycin).
• Medicines for indigestion, heartburn, or ulcers such as AXID^® (nizatidine), PEPCID AC^® (famotidine), TAGAMET^® (cimetidine), or ZANTAC^® (ranitidine).

Women who use birth control pills or “the patch” should choose a different kind of contraception. REYATAZ may affect the safety and effectiveness of birth control pills or the patch. Talk to your healthcare provider about choosing an effective contraceptive.

Remember:
• Know all the medicines you take.
• Tell your healthcare provider about all the medicines you take.
• Do not start a new medicine without talking to your healthcare provider.

How should I store REYATAZ?

• Store REYATAZ Capsules at room temperature, 59° to 86° F (15° to 30° C). Do not store this medicine in a damp place such as a bathroom medicine cabinet or near the kitchen sink.
• Keep your medicine in a tightly closed container.
• Throw away REYATAZ when it is outdated or no longer needed by flushing it down the toilet or pouring it down the sink.

General information about REYATAZ

This medicine was prescribed for your particular condition. Do not use REYATAZ for another condition. Do not give REYATAZ to other people, even if they have the same symptoms you have. It may harm them. Keep REYATAZ and all medicines out of the reach of children and pets.

This summary does not include everything there is to know about REYATAZ. Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Remember no written summary can replace careful discussion with your healthcare provider. If you would like more information, talk with your healthcare provider or you can call 1-800-321-1335.

What are the ingredients in REYATAZ?

Active Ingredient: atazanavir sulfate

Inactive Ingredients: Crospovidone, lactose monohydrate (milk sugar), magnesium stearate, gelatin, FD&C Blue #2, titanium dioxide, black iron oxide, red iron oxide, and yellow iron oxide.

VIDEX^® and REYATAZ^® are registered trademarks of Bristol-Myers Squibb Company. COUMADIN^® and SUSTIVA^® are registered trademarks of Bristol-Myers Squibb Pharma Company. DESYREL^® is a registered trademark of Mead Johnson and Company. Other brands uled are the trademarks of their respective owners and are not trademarks of Bristol-Myers Squibb Company.

Bristol-Myers Squibb Company

Princeton, NJ 08543 USA

This Patient Information Leaflet has been approved by the U.S. Food and Drug Administration.

1193697A5/102006