REYATAZ - Drug Information from Guideline Central

REYATAZ (ATAZANAVIR) capsule, gelatin coated
E.R. Squibb & Sons, L.L.C.

1 INDICATIONS AND USAGE

REYATAZ^® is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and in pediatric patients 3 months and older weighing at least 5 kg.

Limitations of Use:

REYATAZ is not recommended for use in pediatric patients below the age of 3 months due to the risk of kernicterus [see Use in Specific Populations (8.4)].
Use of REYATAZ with ritonavir in treatment-experienced patients should be guided by the number of baseline primary protease inhibitor resistance substitutions [see Microbiology (12.4)].

REYATAZ is a protease inhibitor indicated for use in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and in pediatric patients 3 months and older weighing at least 5 kg. (1)

2 DOSAGE AND ADMINISTRATION

Pretreatment testing: Renal laboratory testing should be performed in all patients prior to initiation of REYATAZ and continued during treatment with REYATAZ. Hepatic testing should be performed in patients with underlying liver disease prior to initiation of REYATAZ and continued during treatment with REYATAZ. (2.2)
Treatment-naive adults: REYATAZ 300 mg with ritonavir 100 mg once daily with food or REYATAZ 400 mg once daily with food. (2.3)
Treatment-experienced adults: REYATAZ 300 mg with ritonavir 100 mg once daily with food. (2.3)
Pediatric patients: REYATAZ capsule dosage is based on body weight not to exceed the adult dose and must be taken with food. (2.4)
REYATAZ oral powder: Must be taken with ritonavir and food and should not be used in pediatric patients who weigh less than 5 kg. (2.5)
Pregnancy: REYATAZ 300 mg with ritonavir 100 mg once daily with food, with dosing modifications for some concomitant medications. (2.6)
Dosing modifications: may be required for concomitant therapy ( 2.3, 2.4, 2.5, 2.6), renal impairment (2.7), and hepatic impairment (2.8).

2.1 Overview

REYATAZ capsules and oral powder must be taken with food.
Do not open the capsules.
The recommended oral dosage of REYATAZ depends on the treatment history of the patient and the use of other coadministered drugs. When coadministered with H₂-receptor antagonists or proton-pump inhibitors, dose separation may be required [see Dosage and Administration (2.3, 2.4, 2.5, and 2.6) and Drug Interactions (7)].
REYATAZ capsules without ritonavir are not recommended for treatment-experienced adult or pediatric patients with prior virologic failure [see Clinical Studies (14)].
REYATAZ oral powder must be taken with ritonavir and is not recommended for use in children who weigh less than 5 kg [see Dosage and Administration (2.5) ].
Efficacy and safety of REYATAZ with ritonavir when ritonavir is administered in doses greater than 100 mg once daily have not been established. The use of higher ritonavir doses may alter the safety profile of atazanavir (cardiac effects, hyperbilirubinemia) and, therefore, is not recommended. Prescribers should consult the complete prescribing information for ritonavir when using ritonavir.

2.2 Testing Prior to Initiation and During Treatment with REYATAZ

Renal laboratory testing should be performed in all patients prior to initiation of REYATAZ and continued during treatment with REYATAZ. Renal laboratory testing should include serum creatinine, estimated creatinine clearance, and urinalysis with microscopic examination [see Warnings and Precautions (5.5, 5.6)].

Hepatic laboratory testing should be performed in patients with underlying liver disease prior to initiation of REYATAZ and continued during treatment with REYATAZ [see Warnings and Precautions (5.4)].

2.3 Dosage of REYATAZ in Adult Patients

Table 1 displays the recommended dosage of REYATAZ capsules in treatment-naive and treatment-experienced adults. Table 1 also displays recommended dosage of REYATAZ and ritonavir when given concomitantly with other antiretroviral drugs and H₂-receptor antagonists (H2RA). Ritonavir is required with several REYATAZ dosage regimens (see the ritonavir complete prescribing information about the safe and effective use of ritonavir). The use of REYATAZ in treatment-experienced adult patients without ritonavir is not recommended.

Table 1: Recommended REYATAZ and Ritonavir Dosage in Adults^a,b

^a See Drug Interactions (7) for instructions concerning coadministration of acid-reducing medications (eg, H2RA or proton pump inhibitors [PPIs]), and other antiretroviral drugs (eg, efavirenz, tenofovir DF, and didanosine). ^b For adult patients who cannot swallow the capsules, REYATAZ oral powder is taken once daily with food at the same recommended adult dosage as the capsules along with ritonavir.
	REYATAZ Once Daily Dosage	Ritonavir Once Daily Dosage
Treatment-Naive Adult Patients
recommended regimen	300 mg	100 mg
unable to tolerate ritonavir	400 mg	N/A
in combination with efavirenz	400 mg	100 mg
Treatment-Experienced Adult Patients
recommended regimen	300 mg	100 mg
in combination with both H2RA and tenofovir DF	400 mg	100 mg

2.4 Dosage of REYATAZ Capsules in Pediatric Patients

The recommended daily dosage of REYATAZ capsules and ritonavir in pediatric patients (6 years of age to less than 18 years of age) is based on body weight (see Table 2).

Table 2: Recommended Dosage of REYATAZ Capsules and Ritonavir in Pediatric Patients (6 to less than 18 years of age)^a,b

^a Administer REYATAZ capsules and ritonavir simultaneously with food. ^b The same recommendations regarding the timing and maximum doses of concomitant PPIs and H2RAs in adults also apply to pediatric patients. See Drug Interactions (7) for instructions concerning coadministration of acid-reducing medications (eg, H2RA or PPIs), and other antiretroviral drugs (eg, efavirenz, tenofovir DF, and didanosine). ^c In treatment-experienced patients, REYATAZ capsules must be administered with ritonavir.
Body weight	REYATAZ Daily Dosage	Ritonavir Daily Dosage
Treatment-Naive and Treatment-Experienced^c
Less than 15 kg	Capsules not recommended	N/A
At least 15 kg to less than 35 kg	200 mg	100 mg
At least 35 kg	300 mg	100 mg
Treatment-Naive, at least 13 years old and cannot tolerate ritonavir
At least 40 kg	400 mg	N/A

When transitioning between formulations, a change in dose may be needed. Consult the dosing table for the specific formulation.

2.5 Dosage and Administration of REYATAZ Oral Powder in Pediatric Patients

REYATAZ oral powder is for use in treatment-naive or treatment-experienced pediatric patients who are at least 3 months of age and weighing at least 5 kg. REYATAZ oral powder must be mixed with food or a beverage for administration and ritonavir must be given immediately afterwards. Table 3 displays the recommended dosage of REYATAZ oral powder and ritonavir.

Table 3: Recommended Dosage of REYATAZ Oral Powder and Ritonavir in Pediatric Patients (at least 3 months of age and weighing at least 5 kg)^a,b

^a The same recommendations regarding the timing and maximum doses of concomitant PPIs and H2RAs in adults also apply to pediatric patients. See Drug Interactions (7) for instructions concerning coadministration of acid-reducing medications (eg, H2RA or PPIs), and other antiretroviral drugs (eg, efavirenz, tenofovir DF, and didanosine). ^b For pediatric patients at least 25 kg who cannot swallow REYATAZ capsules, 300 mg (6 packets) REYATAZ oral powder is taken once daily with food along with 100 mg ritonavir. ^c Only patients weighing 5 to less than 10 kg who do not tolerate the 200 mg (4 packets) dose of REYATAZ oral powder and have not previously taken an HIV protease inhibitor, may take 150 mg (3 packets) REYATAZ oral powder with close HIV viral load monitoring. ^d Each packet contains 50 mg of REYATAZ.
Body Weight	Daily Dosage of REYATAZ Oral Powder	Daily Dosage of Ritonavir Oral Solution
5 kg to less than 15 kg	200 mg (4 packets)^c,d	80 mg
15 kg to less than 25 kg	250 mg (5 packets)^d	80 mg

When transitioning between formulations, a change in dose may be needed. Consult the dosing table for the specific formulation.

Instructions for Mixing REYATAZ Oral Powder [see FDA-approved Instructions for Use]

Determine the number of packets (3, 4, 5 or 6 packets) that are needed.
Prior to mixing, tap the packet to settle the powder.
It is preferable to mix REYATAZ oral powder with food such as applesauce or yogurt. Mixing REYATAZ oral powder with a beverage (milk, infant formula, or water) may be used for infants who can drink from a cup. For young infants (less than 6 months) who cannot eat solid food or drink from a cup, REYATAZ oral powder should be mixed with infant formula and given using an oral dosing syringe. Administration of REYATAZ and infant formula using an infant bottle is not recommended because full dose may not be delivered.
Use a clean pair of scissors to cut each packet along the dotted line.
Mixing with food: Using a spoon, mix the recommended number of REYATAZ oral powder packets with a minimum of one tablespoon of food (such as applesauce or yogurt). Feed the mixture to the infant or young child. Add an additional one tablespoon of food to the small container, mix, and feed the child the residual mixture.
Mixing with a beverage such as milk or water in a small drinking cup: Using a spoon, mix the recommended number of REYATAZ oral powder packets with a minimum of 30 mL of the beverage. Have the child drink the mixture. Add an additional 15 mL more of beverage to the drinking cup, mix, and have the child drink the residual mixture. If water is used, food should also be taken at the same time.
Mixing with liquid infant formula using an oral dosing syringe and a small medicine cup: Using a spoon, mix the recommended number of REYATAZ oral powder packets with 10 mL of prepared liquid infant formula. Draw up the full amount of the mixture into an oral syringe and administer into either right or left inner cheek of infant. Pour another 10 mL of formula into the medicine cup to rinse off remaining REYATAZ oral powder in cup. Draw up residual mixture into the syringe and administer into either right or left inner cheek of infant.
Administer ritonavir immediately following REYATAZ powder administration.
Administer the entire dosage of REYATAZ oral powder (mixed in the food or beverage) within one hour of preparation [may leave the mixture at a temperature of 68°F to 86°F (20°C to 30°C) for up to one hour]. Ensure that the patient eats or drinks all the food or beverage that contains the powder. Additional food may be given after consumption of the entire mixture.

2.6 Dosage Adjustments in Pregnant Patients

Table 4 includes the recommended dosage of REYATAZ capsules and ritonavir in treatment-naive and treatment-experienced pregnant patients. In these patients, REYATAZ must be administered with ritonavir. There are no dosage adjustments for postpartum patients (see Table 1 for the recommended REYATAZ dosage in adults) [see Use in Specific Populations (8.1)].

Table 4: Recommended Dosage of REYATAZ and Ritonavir in Pregnant Patients^a

^a See Drug Interactions (7) for instructions concerning coadministration of acid-reducing medications (eg, H2RA or PPIs), and other antiretroviral drugs (eg, efavirenz, tenofovir DF, and didanosine). ^b REYATAZ is not recommended for treatment-experienced pregnant patients during the second and third trimester taking REYATAZ with BOTH tenofovir DF and H2RA.
	REYATAZ Once Daily Dosage	Ritonavir Once Daily Dosage
Treatment-Naive and Treatment-Experienced
Recommended Regimen	300 mg	100 mg
Treatment-Experienced During the Second or Third Trimester When Coadministered with either H2RA or Tenofovir DF^b
In combination with EITHER H2RA OR tenofovir DF	400 mg	100 mg

2.7 Dosage in 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 is not recommended in treatment-experienced patients with HIV-1 infection who have end-stage renal disease managed with hemodialysis [see Use in Specific Populations (8.7)].

2.8 Dosage Adjustments in Patients with Hepatic Impairment

Table 5 displays the recommended REYATAZ dosage in treatment-naive patients with hepatic impairment. The use of REYATAZ in patients with severe hepatic impairment (Child-Pugh Class C) is not recommended. The coadministration of REYATAZ with ritonavir in patients with any degree of hepatic impairment is not recommended.

Table 5: Recommended Dosage of REYATAZ Capsules in Treatment-Naive Adults with Hepatic Impairment

	REYATAZ Once Daily Dosage
Mild hepatic impairment (Child-Pugh Class A)	400 mg
Moderate hepatic impairment (Child-Pugh Class B)	300 mg
Severe hepatic impairment (Child-Pugh Class C)	REYATAZ with or without ritonavir is not recommended

3 DOSAGE FORMS AND STRENGTHS

REYATAZ Capsules:

150 mg capsule with blue cap and powder blue body, printed with white ink “BMS 150 mg” on the cap and with blue ink “3624” on the body.
200 mg capsule with blue cap and blue body, printed with white ink “BMS 200 mg” on the cap and with white ink “3631” on the body.
300 mg capsule with red cap and blue body, printed with white ink “BMS 300 mg” on the cap and with white ink “3622” on the body.

REYATAZ Oral Powder:

50 mg of atazanavir as an oral powder in a packet.

Capsules: 150 mg, 200 mg, 300 mg. (3, 16)
Oral powder: 50 mg packet. (3, 16)

4 CONTRAINDICATIONS

REYATAZ is contraindicated:

in patients with previously demonstrated clinically significant hypersensitivity (eg, Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to any of the components of REYATAZ capsules or REYATAZ oral powder [see Warnings and Precautions (5.2)].
when coadministered with drugs that are highly dependent on CYP3A or UGT1A1 for clearance, and for which elevated plasma concentrations of the interacting drugs are associated with serious and/or life-threatening events (see Table 6).
when coadministered with drugs that strongly induce CYP3A and may lead to lower exposure and loss of efficacy of REYATAZ (see Table 6).

Table 6 displays drugs that are contraindicated with REYATAZ.

Table 6: Drugs Contraindicated with REYATAZ (Information in the table applies to REYATAZ with or without ritonavir, unless otherwise indicated)

^a See Drug Interactions, Table 16 (7) for parenterally administered midazolam. ^b See Drug Interactions, Table 16 (7) for sildenafil when dosed as VIAGRA^® for erectile dysfunction.
Drug Class	Drugs within class that are contraindicated with REYATAZ
Alpha 1-adrenoreceptor antagonist	Alfuzosin
Anticonvulsants	Carbamazepine, phenobarbital, phenytoin
Antiarrhythmics	Amiodarone (with ritonavir), quinidine (with ritonavir)
Antimycobacterials	Rifampin
Antineoplastics	Apalutamide, encorafenib, irinotecan, ivosidenib
Antipsychotics	Lurasidone (with ritonavir), pimozide
Benzodiazepines	Orally administered midazolam^a, triazolam
Ergot Derivatives	Dihydroergotamine, ergonovine, ergotamine, methylergonovine
GI Motility Agent	Cisapride
Hepatitis C Direct-Acting Antivirals	Elbasvir/grazoprevir; glecaprevir/pibrentasvir
Herbal Products	St. John’s wort (Hypericum perforatum)
Lipid-Modifying Agents:	Lomitapide, lovastatin, simvastatin
Phosphodiesterase-5 (PDE-5) Inhibitor	Sildenafil^b when dosed as REVATIO® for the treatment of pulmonary arterial hypertension
Protease Inhibitors	Indinavir
Non-nucleoside Reverse Transcriptase Inhibitors	Nevirapine

REYATAZ is contraindicated in patients with previously demonstrated hypersensitivity (eg, Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to any of the components of this product. (4)
Coadministration with alfuzosin, amiodarone (if REYATAZ is coadministered with ritonavir), carbamazepine, quinidine (if REYATAZ is coadministered with ritonavir), triazolam, orally administered midazolam, ergot derivatives, rifampin, apalutamide, encorafenib, irinotecan, ivosidenib, lurasidone (if REYATAZ is coadministered with ritonavir), lovastatin, simvastatin, lomitapide, indinavir, cisapride, phenobarbital, phenytoin, pimozide, St. John’s wort, nevirapine, elbasvir/grazoprevir, glecaprevir/pibrentasvir, and sildenafil when dosed as REVATIO^®. (4)

5 WARNINGS AND PRECAUTIONS

Cardiac conduction abnormalities: PR interval prolongation may occur in some patients. ECG monitoring should be considered in patients with preexisting conduction system disease or when administered with other drugs that may prolong the PR interval. (5.1, 7.3, 12.2, 17)
Severe Skin Reactions: Discontinue if severe rash develops. (5.2, 17)
Hyperbilirubinemia: Most patients experience asymptomatic increases in indirect bilirubin, which is reversible upon discontinuation. Do not dose reduce. If a concomitant transaminase increase occurs, evaluate for alternative etiologies. (5.8)
Phenylketonuria: REYATAZ oral powder contains phenylalanine which can be harmful to patients with phenylketonuria. (5.3)
Hepatotoxicity: Patients with hepatitis B or C infection are at risk of increased transaminases or hepatic decompensation. Monitor hepatic laboratory tests prior to therapy and during treatment. (2.8, 5.4, 8.8)
Chronic kidney disease has been reported during postmarketing surveillance in patients with HIV-1 infection treated with atazanavir, with or without ritonavir. Consider alternatives in patients at high risk for renal disease or with preexisting renal disease. Monitor renal laboratory tests prior to therapy and during treatment. Consider discontinuation of REYATAZ in patients with progressive renal disease. (5.5)
Nephrolithiasis and cholelithiasis have been reported. Consider temporary interruption or discontinuation. (5.6)
The concomitant use of REYATAZ with ritonavir and certain other medications may result in known or potentially significant drug interactions. Consult the full prescribing information prior to and during treatment for potential drug interactions. (5.7, 7.3)
Patients receiving REYATAZ may develop new onset or exacerbations of diabetes mellitus/hyperglycemia (5.9), immune reconstitution syndrome (5.10), and redistribution/accumulation of body fat (5.11).
Hemophilia: Spontaneous bleeding may occur, and additional factor VIII may be required. (5.12)

5.1 Cardiac Conduction Abnormalities

REYATAZ has been shown to prolong the PR interval of the electrocardiogram in some subjects. In healthy subjects and in subjects with HIV-1 infection treated with atazanavir, abnormalities in atrioventricular (AV) conduction were asymptomatic and generally limited to first-degree AV block. There have been reports of second-degree AV block and other conduction abnormalities [see Adverse Reactions (6.2) and Overdosage (10)]. In clinical trials that included electrocardiograms, asymptomatic first-degree AV block was observed in 5.9% of atazanavir-treated subjects (n=920), 5.2% of lopinavir/ritonavir-treated subjects (n=252), 10.4% of nelfinavir-treated subjects (n=48), and 3.0% of efavirenz-treated subjects (n=329). In Study AI424-045, asymptomatic first-degree AV block was observed in 5% (6/118) of atazanavir with ritonavir-treated subjects and 5% (6/116) of lopinavir/ritonavir-treated subjects who had on-study electrocardiogram measurements. Because of limited clinical experience in those with preexisting conduction system disease (eg, marked first-degree AV block or second- or third-degree AV block), ECG monitoring should be considered in these patients [see Clinical Pharmacology (12.2)].

5.2 Severe Skin Reactions

In controlled clinical trials, rash (all grades, regardless of causality) occurred in approximately 20% of subjects with HIV-1 infection treated with REYATAZ. The median time to onset of rash in clinical studies was 7.3 weeks and the median duration of rash was 1.4 weeks. Rashes were generally mild-to-moderate maculopapular skin eruptions. Treatment-emergent adverse reactions of moderate or severe rash (occurring at a rate of ≥2%) are presented for the individual clinical studies [see Adverse Reactions (6.1)]. Dosing with REYATAZ was often continued without interruption in patients who developed rash. The discontinuation rate for rash in clinical trials was <1%. Cases of Stevens-Johnson syndrome, erythema multiforme, and toxic skin eruptions, including drug rash, eosinophilia, and systemic symptoms (DRESS) syndrome, have been reported in patients receiving REYATAZ [see Contraindications (4) and Adverse Reactions (6.1)]. REYATAZ should be discontinued if severe rash develops.

5.3 Patients with Phenylketonuria

Phenylalanine can be harmful to patients with phenylketonuria (PKU). REYATAZ oral powder contains phenylalanine (a component of aspartame). Each packet of REYATAZ oral powder contains 35 mg of phenylalanine. REYATAZ capsules do not contain phenylalanine.

5.4 Hepatotoxicity

Patients with underlying hepatitis B or C viral infections or marked elevations in transaminases before treatment may be at increased risk for developing further transaminase elevations or hepatic decompensation. In these patients, hepatic laboratory testing should be conducted prior to initiating therapy with REYATAZ and during treatment [see Dosage and Administration (2.2), Adverse Reactions (6.1), and Use in Specific Populations (8.8)].

5.5 Chronic Kidney Disease

Chronic kidney disease in patients with HIV-1 infection treated with atazanavir, with or without ritonavir, has been reported during postmarketing surveillance. Reports included biopsy-proven cases of granulomatous interstitial nephritis associated with the deposition of atazanavir drug crystals in the renal parenchyma. Consider alternatives to REYATAZ in patients at high risk for renal disease or with preexisting renal disease. Renal laboratory testing (including serum creatinine, estimated creatinine clearance, and urinalysis with microscopic examination) should be conducted in all patients prior to initiating therapy with REYATAZ and continued during treatment with REYATAZ. Expert consultation is advised for patients who have confirmed renal laboratory abnormalities while taking REYATAZ. In patients with progressive kidney disease, discontinuation of REYATAZ may be considered [see Dosage and Administration (2.2 and 2.7) and Adverse Reactions (6.2)].

5.6 Nephrolithiasis and Cholelithiasis

Cases of nephrolithiasis and/or cholelithiasis have been reported during postmarketing surveillance in patients with HIV-1 infection receiving REYATAZ therapy. Some patients required hospitalization for additional management, and some had complications. Because these events were reported voluntarily during clinical practice, estimates of frequency cannot be made. If signs or symptoms of nephrolithiasis and/or cholelithiasis occur, temporary interruption or discontinuation of therapy may be considered [see Adverse Reactions (6.2)].

5.7 Risk of Serious Adverse Reactions Due to Drug Interactions

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

clinically significant adverse reactions potentially leading to severe, life-threatening, or fatal events from greater exposures of concomitant medications.
clinically significant adverse reactions from greater exposures of REYATAZ with ritonavir.
loss of therapeutic effect (virologic response) of REYATAZ with ritonavir and possible development of resistance.

See Table 16 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations [see Drug Interactions (7)]. Consider the potential for drug interactions prior to and during therapy containing REYATAZ with ritonavir; and monitor for the adverse reactions associated with concomitant medications [see Contraindications (4) and Drug Interactions (7)].

5.8 Hyperbilirubinemia

Most patients taking REYATAZ experience asymptomatic elevations in indirect (unconjugated) bilirubin related to inhibition of UDP-glucuronosyl transferase (UGT). This hyperbilirubinemia is reversible upon discontinuation of REYATAZ. Hepatic transaminase elevations that occur with hyperbilirubinemia should be evaluated for alternative etiologies. No long-term safety data are available for patients experiencing persistent elevations in total bilirubin >5 times the upper limit of normal (ULN). Alternative antiretroviral therapy to REYATAZ may be considered if jaundice or scleral icterus associated with bilirubin elevations presents 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 (6.1)].

5.9 Diabetes Mellitus/Hyperglycemia

New-onset diabetes mellitus, exacerbation of preexisting diabetes mellitus, and hyperglycemia have been reported during postmarketing surveillance in patients with HIV-1 infection 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 [see Adverse Reactions (6.2)].

5.10 Immune Reconstitution Syndrome

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

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

5.11 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.

5.12 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.

5.13 Resistance/Cross-Resistance

Various degrees of cross-resistance among protease inhibitors have been observed. Resistance to atazanavir may not preclude the subsequent use of other protease inhibitors [see Microbiology (12.4)].

6 ADVERSE REACTIONS

The following adverse reactions are discussed in greater detail in other sections of the labeling:

cardiac conduction abnormalities [see Warnings and Precautions (5.1)]
rash [see Warnings and Precautions (5.2)]
hyperbilirubinemia [see Warnings and Precautions (5.8) ]
chronic kidney disease [see Warnings and Precautions (5.5)]
nephrolithiasis and cholelithiasis [see Warnings and Precautions (5.6)]

Most common adverse reactions (≥2%) are nausea, jaundice/scleral icterus, rash, headache, abdominal pain, vomiting, insomnia, peripheral neurologic symptoms, dizziness, myalgia, diarrhea, depression, and fever. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adverse Reactions in Treatment-Naive Adult Subjects

The safety profile of REYATAZ in treatment-naive adults is based on 1625 subjects with HIV-1 infection in clinical trials. 536 subjects received REYATAZ 300 mg with ritonavir 100 mg and 1089 subjects received REYATAZ 400 mg or higher (without ritonavir).

The most common adverse reactions were nausea, jaundice/scleral icterus, and rash.

Selected clinical adverse reactions of moderate or severe intensity reported in ≥ 2% of treatment-naive subjects receiving combination therapy including REYATAZ 300 mg with ritonavir 100 mg and REYATAZ 400 mg (without ritonavir) are presented in Tables 7 and 8, respectively.

Table 7: Selected Adverse Reactions^a of Moderate or Severe Intensity Reported in ≥2% of Adult Treatment-Naive Subjects with HIV-1 Infection,^b Study AI424-138

* None reported in this treatment arm. ^a Includes events of possible, probable, certain, or unknown relationship to treatment regimen. ^b Based on the regimen containing REYATAZ. ^c Median time on therapy. ^d Administered as a fixed-dose. ^e As a fixed-dose product: 300 mg tenofovir DF, 200 mg emtricitabine once daily.
	96 weeks^c REYATAZ 300 mg with ritonavir 100 mg (once daily) and tenofovir DF/emtricitabine^d (n=441)	96 weeks^c lopinavir/ritonavir^d 400 mg/100 mg (twice daily) and tenofovir DF/emtricitabine^e (n=437)
Digestive System
Nausea	4%	8%
Jaundice/scleral icterus	5%	*
Diarrhea	2%	12%
Skin and Appendages
Rash	3%	2%

Table 8: Selected Adverse Reactions^a of Moderate or Severe Intensity Reported in ≥2% of Adult Treatment-Naive Subjects with HIV-1 Infection,^b Studies AI424-034, AI424-007, and AI424-008

* None reported in this treatment arm. ^a Includes events of possible, probable, certain, or unknown relationship to treatment regimen. ^b Based on regimens containing REYATAZ. ^c Median time on therapy. ^d Includes long-term follow-up. ^e As a fixed-dose product: 150 mg lamivudine/300 mg zidovudine twice daily.
	Study AI424-034		Studies AI424-007, -008
	64 weeks^c REYATAZ 400 mg (once daily) with lamivudine/ zidovudine^e (n=404)	64 weeks^c efavirenz 600 mg (once daily) with lamivudine/ zidovudine^e (n=401)	120 weeks^c,d REYATAZ 400 mg (once daily) with stavudine and lamivudine or didanosine (n=279)	73 weeks^c,d nelfinavir 750 mg TID or 1250 mg BID with stavudine and lamivudine or didanosine (n=191)
Body as a Whole
Headache	6%	6%	1%	2%
Digestive System
Nausea	14%	12%	6%	4%
Jaundice/scleral icterus	7%	*	7%	*
Vomiting	4%	7%	3%	3%
Abdominal pain	4%	4%	4%	2%
Diarrhea	1%	2%	3%	16%
Nervous System
Insomnia	3%	3%	<1%	*
Dizziness	2%	7%	<1%	*
Peripheral neurologic symptoms	<1%	1%	4%	3%
Skin and Appendages
Rash	7%	10%	5%	1%

Adverse Reactions in Treatment-Experienced Adult Subjects

The safety profile of REYATAZ in treatment-experienced adults with HIV-1 infection is based on 119 subjects with HIV-1 infection in clinical trials.

The most common adverse reactions are jaundice/scleral icterus and myalgia.

Selected clinical adverse reactions of moderate or severe intensity reported in ≥2% of treatment-experienced subjects receiving REYATAZ with ritonavir are presented in Table 9.

Table 9: Selected Adverse Reactions^a of Moderate or Severe Intensity Reported in ≥2% of Adult Treatment-Experienced Subjects with HIV-1 Infection,^b Study AI424-045

* None reported in this treatment arm. ^a Includes events of possible, probable, certain, or unknown relationship to treatment regimen. ^b Based on the regimen containing REYATAZ. ^c Median time on therapy. ^d As a fixed-dose product.
	48 weeks^c REYATAZ with ritonavir 300/100 mg (once daily) and tenofovir DF and NRTI (n=119)	48 weeks^c lopinavir/ritonavir 400/100 mg (twice daily^d) and tenofovir DF and NRTI (n=118)
Body as a Whole
Fever	2%	*
Digestive System
Jaundice/scleral icterus	9%	*
Diarrhea	3%	11%
Nausea	3%	2%
Nervous System
Depression	2%	<1%
Musculoskeletal System
Myalgia	4%	*

Laboratory Abnormalities in Treatment-Naive Subjects

The percentages of adult treatment-naive subjects with HIV-1 infection treated with combination therapy, including REYATAZ 300 mg with ritonavir 100 mg or REYATAZ 400 mg (without ritonavir) with Grade 3–4 laboratory abnormalities, are presented in Tables 10 and 11, respectively.

Table 10: Grade 3–4 Laboratory Abnormalities Reported in ≥2% of Adult Treatment-Naive Subjects with HIV-1 Infection,^a Study AI424-138

^a Based on the regimen containing REYATAZ. ^b Median time on therapy. ^c Administered as a fixed-dose product. ^d As a fixed-dose product: 300 mg tenofovir DF, 200 mg emtricitabine once daily. ^e ULN=upper limit of normal.
		96 weeks^b REYATAZ 300 mg with ritonavir 100 mg (once daily) and tenofovir DF/emtricitabine^c	96 weeks^b lopinavir/ritonavir 400 mg/100 mg^c (twice daily) and tenofovir DF/emtricitabine^d
Variable	Limit^e	(n=441)	(n=437)
Chemistry	High
SGOT/AST	≥5.1 × ULN	3%	1%
SGPT/ALT	≥5.1 × ULN	3%	2%
Total Bilirubin	≥2.6 × ULN	44%	<1%
Lipase	≥2.1 × ULN	2%	2%
Creatine Kinase	≥5.1 × ULN	8%	7%
Total Cholesterol	≥240 mg/dL	11%	25%
Hematology	Low
Neutrophils	<750 cells/mm³	5%	2%

Table 11: Grade 3–4 Laboratory Abnormalities Reported in ≥2% of Adult Treatment-Naive Subjects with HIV-1 Infection,^a Studies AI424-034, AI424-007, and AI424-008

* None reported in this treatment arm. ^a Based on regimen(s) containing REYATAZ. ^b Median time on therapy. ^c Includes long-term follow-up. ^d ULN = upper limit of normal. ^e As a fixed-dose product: 150 mg lamivudine, 300 mg zidovudine twice daily.
		Study AI424-034		Studies AI424-007, -008
		64 weeks^b REYATAZ 400 mg once daily and lamivudine/zidovudine^e	64 weeks^b efavirenz 600 mg once daily and lamivudine/zidovudine^e	120 weeks^b,c REYATAZ 400 mg once daily with stavudine and lamivudine or with stavudine and didanosine	73 weeks^b,c nelfinavir 750 mg TID or 1250 mg BID with stavudine and lamivudine or with stavudine and didanosine
Variable	Limit^d	(n=404)	(n=401)	(n=279)	(n=191)
Chemistry	High
SGOT/AST	≥5.1 × ULN	2%	2%	7%	5%
SGPT/ALT	≥5.1 × ULN	4%	3%	9%	7%
Total Bilirubin	≥2.6 × ULN	35%	<1%	47%	3%
Amylase	≥2.1 × ULN	*	*	14%	10%
Lipase	≥2.1 × ULN	<1%	1%	4%	5%
Creatine Kinase	≥5.1 × ULN	6%	6%	11%	9%
Total Cholesterol	≥240 mg/dL	6%	24%	19%	48%
Triglycerides	≥751 mg/dL	<1%	3%	4%	2%
Hematology	Low
Hemoglobin	<8.0 g/dL	5%	3%	<1%	4%
Neutrophils	<750 cells/mm³	7%	9%	3%	7%

Change in Lipids from Baseline in Treatment-Naive Subjects with HIV-1 Infection

For Study AI424-138 and Study AI424-034, changes from baseline in LDL-cholesterol, HDL-cholesterol, total cholesterol, and triglycerides are shown in Tables 12 and 13, respectively.

Table 12: Lipid Values, Mean Change from Baseline, Study AI424-138

^a REYATAZ 300 mg with ritonavir 100 mg once daily with the fixed-dose product: 300 mg tenofovir DF/200 mg emtricitabine once daily. ^b Values obtained after initiation of serum lipid-reducing agents were not included in these analyses. At baseline, serum lipid-reducing agents were used in 1% in the lopinavir/ritonavir treatment arm and 1% in the REYATAZ with ritonavir arm. Through Week 48, serum lipid-reducing agents were used in 8% in the lopinavir/ritonavir treatment arm and 2% in the REYATAZ with ritonavir arm. Through Week 96, serum lipid-reducing agents were used in 10% in the lopinavir/ritonavir treatment arm and 3% in the REYATAZ with ritonavir arm. ^c Lopinavir/ritonavir (400 mg/100 mg) twice daily with the fixed-dose product 300 mg tenofovir DF/200 mg emtricitabine once daily. ^d The change from baseline is the mean of within-subject changes from baseline for subjects with both baseline and Week 48 or Week 96 values and is not a simple difference of the baseline and Week 48 or Week 96 mean values, respectively. ^e Number of subjects with LDL-cholesterol measured. ^f Fasting.
	REYATAZ with ritonavir^a,b					lopinavir/ritonavir^b,c
	Baseline	Week 48		Week 96		Baseline	Week 48		Week 96
	mg/dL	mg/dL	Change^d	mg/dL	Change^d	mg/dL	mg/dL	Change^d	mg/dL	Change^d
	(n=428^e)	(n=372^e)	(n=372^e)	(n=342^e)	(n=342^e)	(n=424^e)	(n=335^e)	(n=335^e)	(n=291^e)	(n=291^e)
LDL-Cholesterol^f	92	105	+14%	105	+14%	93	111	+19%	110	+17%
HDL-Cholesterol^f	37	46	+29%	44	+21%	36	48	+37%	46	+29%
Total Cholesterol^f	149	169	+13%	169	+13%	150	187	+25%	186	+25%
Triglycerides^f	126	145	+15%	140	+13%	129	194	+52%	184	+50%

Table 13: Lipid Values, Mean Change from Baseline, Study AI424-034

^a REYATAZ 400 mg once daily with the fixed-dose product: 150 mg lamivudine, 300 mg zidovudine twice daily. ^b Values obtained after initiation of serum lipid-reducing agents were not included in these analyses. At baseline, serum lipid-reducing agents were used in 0% in the efavirenz treatment arm and <1% in the REYATAZ arm. Through Week 48, serum lipid-reducing agents were used in 3% in the efavirenz treatment arm and 1% in the REYATAZ arm. ^c Efavirenz 600 mg once daily with the fixed-dose product: 150 mg lamivudine/300 mg zidovudine twice daily. ^d The change from baseline is the mean of within-subject changes from baseline for patients with both baseline and Week 48 values and is not a simple difference of the baseline and Week 48 mean values. ^e Number of subjects with LDL-cholesterol measured. ^f Fasting.
	REYATAZ^a,b			efavirenz^b,c
	Baseline mg/dL (n=383^e)	Week 48 mg/dL (n=283^e)	Week 48 Change^d (n=272^e)	Baseline mg/dL (n=378^e)	Week 48 mg/dL (n=264^e)	Week 48 Change^d (n=253^e)
LDL-Cholesterol^f	98	98	+1%	98	114	+18%
HDL-Cholesterol	39	43	+13%	38	46	+24%
Total Cholesterol	164	168	+2%	162	195	+21%
Triglycerides^f	138	124	−9%	129	168	+23%

Laboratory Abnormalities in Treatment-Experienced Subjects with HIV-1 Infection

The percentages of adult treatment-experienced subjects with HIV-1 infection treated with combination therapy, including REYATAZ with ritonavir having Grade 3–4 laboratory abnormalities, are presented in Table 14.

Table 14: Grade 3–4 Laboratory Abnormalities Reported in ≥2% of Adult Treatment-Experienced Subjects with HIV-1 Infection, Study AI424-045^a

^a Based on regimen(s) containing REYATAZ. ^b Median time on therapy. ^c ULN = upper limit of normal. ^d As a fixed-dose product.
		48 weeks^b	48 weeks^b
		REYATAZ with ritonavir 300/100 mg (once daily) and tenofovir DF and NRTI	lopinavir/ritonavir 400/100 mg (twice daily^d) and tenofovir DF and NRTI
Variable	Limit^c	(n=119)	(n=118)
Chemistry	High
SGOT/AST	≥5.1 × ULN	3%	3%
SGPT/ALT	≥5.1 × ULN	4%	3%
Total Bilirubin	≥2.6 × ULN	49%	<1%
Lipase	≥2.1 × ULN	5%	6%
Creatine Kinase	≥5.1 × ULN	8%	8%
Total Cholesterol	≥240 mg/dL	25%	26%
Triglycerides	≥751 mg/dL	8%	12%
Glucose	≥251 mg/dL	5%	<1%
Hematology	Low
Platelets	<50,000 cells/mm³	2%	3%
Neutrophils	<750 cells/mm³	7%	8%

Change in Lipids from Baseline in Treatment-Experienced Subjects with HIV-1 Infection

For Study AI424-045, changes from baseline in LDL-cholesterol, HDL-cholesterol, total cholesterol, and triglycerides are shown in Table 15. The observed magnitude of dyslipidemia was less with REYATAZ with ritonavir than with lopinavir/ritonavir. However, the clinical impact of such findings has not been demonstrated.

Table 15: Lipid Values, Mean Change from Baseline, Study AI424-045

^a REYATAZ 300 mg once daily with ritonavir and tenofovir DF, and 1 NRTI. ^b Values obtained after initiation of serum lipid-reducing agents were not included in these analyses. At baseline, serum lipid-reducing agents were used in 4% in the lopinavir/ritonavir treatment arm and 4% in the REYATAZ with ritonavir arm. Through Week 48, serum lipid-reducing agents were used in 19% in the lopinavir/ritonavir treatment arm and 8% in the REYATAZ with ritonavir arm. ^c Lopinavir/ritonavir (400/100 mg), as a fixed dose regimen, BID with tenofovir DF and 1 NRTI. ^d The change from baseline is the mean of within-subject changes from baseline for subjects with both baseline and Week 48 values and is not a simple difference of the baseline and Week 48 mean values. ^e Number of subjects with LDL-cholesterol measured. ^f Fasting.
	REYATAZ with ritonavir^a,b			Lopinavir/ritonavir^b,c
	Baseline mg/dL (n=111^e)	Week 48 mg/dL (n=75^e)	Week 48 Change^d (n=74^e)	Baseline mg/dL (n=108^e)	Week 48 mg/dL (n=76^e)	Week 48 Change^d (n=73^e)
LDL-Cholesterol^f	108	98	−10%	104	103	+1%
HDL-Cholesterol	40	39	−7%	39	41	+2%
Total Cholesterol	188	170	−8%	181	187	+6%
Triglycerides^f	215	161	−4%	196	224	+30%

Adverse Reactions in Pediatric Subjects with HIV-1 Infection: REYATAZ Capsules

The safety and tolerability of REYATAZ Capsules with and without ritonavir have been established in pediatric subjects with HIV-1 infection, at least 6 years of age from the open-label, multicenter clinical trial PACTG 1020A.

The safety profile of REYATAZ in pediatric subjects with HIV-1 infection (6 to less than 18 years of age) taking the capsule formulation was generally similar to that observed in clinical studies of REYATAZ in adults. The most common Grade 2–4 adverse events (≥5%, regardless of causality) reported in pediatric subjects were cough (21%), fever (18%), jaundice/scleral icterus (15%), rash (14%), vomiting (12%), diarrhea (9%), headache (8%), peripheral edema (7%), extremity pain (6%), nasal congestion (6%), oropharyngeal pain (6%), wheezing (6%), and rhinorrhea (6%). Asymptomatic second-degree atrioventricular block was reported in <2% of subjects. The most common Grade 3–4 laboratory abnormalities occurring in pediatric subjects taking the capsule formulation were elevation of total bilirubin (≥3.2 mg/dL, 58%), neutropenia (9%), and hypoglycemia (4%). All other Grade 3–4 laboratory abnormalities occurred with a frequency of less than 3%.

Adverse Reactions in Pediatric Subjects with HIV-1 Infection: REYATAZ Oral Powder

The data described below reflect exposure to REYATAZ oral powder in 155 subjects weighing at least 5 kg to less than 35 kg, including 134 subjects exposed for 48 weeks. These data are from two pooled, open-label, multi-center clinical trials in treatment-naive and treatment-experienced pediatric subjects with HIV-1 infection (AI424-397 [PRINCE I] and AI424-451 [PRINCE II]). Age ranged from 3 months to 10 years of age. In these studies, 51% were female and 49% were male. All subjects received ritonavir and 2 nucleoside reverse transcriptase inhibitors (NRTIs).

The safety profile of REYATAZ in pediatric subjects taking REYATAZ oral powder was generally similar to that observed in clinical studies of REYATAZ in pediatric subjects taking REYATAZ capsules. The most common Grade 3–4 laboratory abnormalities occurring in pediatric subjects weighing 5 kg to less than 35 kg taking REYATAZ oral powder were increased amylase (33%), neutropenia (9%), increased SGPT/ALT (9%), elevation of total bilirubin (≥2.6 times ULN, 16%), and increased lipase (8%). All other Grade 3–4 laboratory abnormalities occurred with a frequency of less than 3%.

Adverse Reactions in Subjects with HIV-1 Infection, Co-Infected with Hepatitis B and/or Hepatitis C Virus

In Study AI424-138, 60 subjects administered REYATAZ 300 mg with ritonavir 100 mg once daily, and 51 subjects treated with lopinavir/ritonavir 400 mg/100 mg (as fixed-dose product) twice daily, each with fixed-dose tenofovir DF/emtricitabine, were seropositive for hepatitis B and/or C at study entry. ALT levels >5 times ULN developed in 10% (6/60) of the subjects administered REYATAZ with ritonavir and 8% (4/50) of the subjects treated with lopinavir/ritonavir. AST levels >5 times ULN developed in 10% (6/60) of the subjects administered REYATAZ with ritonavir and none (0/50) of the subjects treated with lopinavir/ritonavir.

In Study AI424-045, 20 subjects administered REYATAZ 300 mg with ritonavir 100 mg once daily, and 18 subjects treated with lopinavir/ritonavir 400 mg/100 mg twice daily (as fixed-dose product), were seropositive for hepatitis B and/or C at study entry. ALT levels >5 times ULN developed in 25% (5/20) of the subjects administered REYATAZ with ritonavir and 6% (1/18) of the subjects treated with lopinavir/ritonavir treated. AST levels >5 times ULN developed in 10% (2/20) of the subjects administered REYATAZ with ritonavir and 6% (1/18) of the subjects treated with lopinavir/ritonavir.

In Studies AI424-008 and AI424-034, 74 subjects treated with REYATAZ 400 mg once daily, 58 who received efavirenz, and 12 who received nelfinavir were seropositive for hepatitis B and/or C at study entry. ALT levels >5 times ULN developed in 15% of the subjects treated with REYATAZ, 14% of the subjects treated with efavirenz, and 17% of the subjects treated with nelfinavir. AST levels >5 times ULN developed in 9% of the subjects treated with REYATAZ, 5% of the subjects treated with efavirenz, and 17% of the subjects treated with nelfinavir. Within REYATAZ and control regimens, no difference in frequency of bilirubin elevations was noted between seropositive and seronegative subjects [see Warnings and Precautions (5.8) ].

6.2 Postmarketing Experience

The following events have been identified during postmarketing 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, third-degree AV block, left bundle branch block, QTc prolongation [see Warnings and Precautions (5.1)]

Gastrointestinal System: pancreatitis

Hepatic System: hepatic function abnormalities

Hepatobiliary Disorders: cholelithiasis [see Warnings and Precautions (5.6) ], cholecystitis, cholestasis

Metabolic System and Nutrition Disorders: diabetes mellitus, hyperglycemia [see Warnings and Precautions (5.9) ]

Musculoskeletal System: arthralgia

Renal System: nephrolithiasis [see Warnings and Precautions (5.6)], interstitial nephritis, granulomatous interstitial nephritis, chronic kidney disease [see Warnings and Precautions (5.5)]

Skin and Appendages: alopecia, maculopapular rash [see Contraindications (4) and Warnings and Precautions (5.2)], pruritus, angioedema

7 DRUG INTERACTIONS

Coadministration of REYATAZ can alter the concentration of other drugs and other drugs may alter the concentration of atazanavir. The potential drug-drug interactions must be considered prior to and during therapy. (4, 7, 12.3)

7.1 Potential for REYATAZ to Affect Other Drugs

Atazanavir is an inhibitor of CYP3A and UGT1A1. Coadministration of REYATAZ and drugs primarily metabolized by CYP3A or UGT1A1 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. Use of REYATAZ without ritonavir is not recommended when coadministered with drugs highly dependent on CYP2C8 with narrow therapeutic indices (eg, paclitaxel, repaglinide). When REYATAZ with ritonavir is coadministered with substrates of CYP2C8, clinically significant interactions are not expected [see Clinical Pharmacology, Table 22 (12.3)].

The magnitude of CYP3A-mediated drug interactions on coadministered drug may change when REYATAZ is coadministered with ritonavir. See the complete prescribing information for ritonavir for information on drug interactions with ritonavir.

7.2 Potential for Other Drugs to Affect REYATAZ

Atazanavir is a CYP3A4 substrate; therefore, drugs that induce CYP3A4 may decrease atazanavir plasma concentrations and reduce REYATAZ’s therapeutic effect.

Atazanavir solubility decreases as pH increases. Reduced plasma concentrations of atazanavir are expected if proton-pump inhibitors, antacids, buffered medications, or H₂-receptor antagonists are administered with REYATAZ [see Dosage and Administration ( 2.3, 2.4, 2.5 and 2.6)].

7.3 Established and Other Potentially Significant Drug Interactions

Table 16 provides dosing recommendations in adults as a result of drug interactions with REYATAZ. 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 16: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies^a or Predicted Interactions (Information in the table applies to REYATAZ with or without ritonavir, unless otherwise indicated)

Concomitant Drug Class: Specific Drugs	Effect on Concentration of Atazanavir or Concomitant Drug	Clinical Comment
^a For magnitude of interactions see Clinical Pharmacology, Tables 21 and 22 (12.3) . ^b See Contraindications (4), Table 6 for orally administered midazolam. ^c In combination with atazanavir 300 mg with ritonavir 100 mg once daily. ^d In combination with atazanavir 400 mg once daily.
HIV Antiviral Agents
Nucleoside Reverse Transcriptase Inhibitors (NRTIs): didanosine buffered formulations enteric coated (EC) capsules	↓ atazanavir ↓ didanosine	It is recommended that REYATAZ be given (with food) 2 h before or 1 h after didanosine buffered formulations. Simultaneous administration of didanosine EC and REYATAZ with food results in a decrease in didanosine exposure. Thus, REYATAZ and didanosine EC should be administered at different times.
Nucleotide Reverse Transcriptase Inhibitors: tenofovir disoproxil fumarate (DF)	↓ atazanavir ↑ tenofovir	When coadministered with tenofovir DF in adults, it is recommended that REYATAZ 300 mg be given with ritonavir 100 mg and tenofovir DF 300 mg (all as a single daily dose with food). The mechanism of this interaction is unknown. Higher tenofovir concentrations could potentiate tenofovir-associated adverse reactions, including renal disorders. Patients receiving REYATAZ and tenofovir DF should be monitored for tenofovir-associated adverse reactions. For pregnant patients taking REYATAZ with ritonavir and tenofovir DF, [see Dosage and Administration (2.6) ] .
Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs): efavirenz	↓ atazanavir	In HIV-treatment-naive adult patients: If REYATAZ is combined with efavirenz, REYATAZ 400 mg (two 200-mg capsules) should be administered with ritonavir 100 mg simultaneously once daily with food, and efavirenz 600 mg should be administered once daily on an empty stomach, preferably at bedtime. In HIV-treatment-experienced adult patients: Coadministration of REYATAZ with efavirenz is not recommended.
nevirapine	↓ atazanavir ↑ nevirapine	Coadministration of REYATAZ with nevirapine is contraindicated due to the potential loss of virologic response and development of resistance, as well as the potential risk for nevirapine-associated adverse reactions [see Contraindications (4)].
Protease Inhibitors: saquinavir (soft gelatin capsules)	↑ saquinavir	Appropriate dosing recommendations for this combination, with or without ritonavir, with respect to efficacy and safety have not been established. In a clinical study, saquinavir 1200 mg coadministered with REYATAZ 400 mg and tenofovir DF 300 mg (all given once daily), and nucleoside analogue reverse transcriptase inhibitors did not provide adequate efficacy [see Clinical Studies (14.2)].
indinavir		Coadministration of REYATAZ with indinavir is contraindicated. Both REYATAZ and indinavir are associated with indirect (unconjugated) hyperbilirubinemia [see Contraindications (4)].
ritonavir	↑ atazanavir	If REYATAZ is coadministered with ritonavir, it is recommended that REYATAZ 300 mg once daily be given with ritonavir 100 mg once daily with food in adults. See the complete prescribing information for ritonavir for information on drug interactions with ritonavir.
Others	↑ other protease inhibitor	Coadministration with other protease inhibitors is not recommended.
Hepatitis C Antiviral Agents
elbasvir/grazoprevir	↑ grazoprevir	Coadministration of REYATAZ with grazoprevir is contraindicated due to the potential for increased risk of ALT elevations [see Contraindications (4)].
glecaprevir/pibrentasvir	↑ glecaprevir ↑ pibrentasvir	Coadministration of REYATAZ with glecaprevir/pibrentasvir is contraindicated due to the potential for increased risk of ALT elevations [see Contraindications (4)].
voxilaprevir/sofosbuvir/velpatasvir	↑ voxilaprevir	Coadministration with REYATAZ is not recommended.
Other Agents
Alpha 1-Adrenoreceptor Antagonist: alfuzosin	↑ alfuzosin	Coadministration of REYATAZ with alfuzosin is contraindicated due to risk for hypotension [see Contraindications (4)].
Antacids and buffered medications:	↓ atazanavir	REYATAZ should be administered 2 hours before or 1 hour after antacids and buffered medications.
Antiarrhythmics: amiodarone, quinidine amiodarone, bepridil, lidocaine (systemic), quinidine	↑ amiodarone, bepridil, lidocaine (systemic), quinidine	Concomitant use of REYATAZ with ritonavir and either quinidine or amiodarone is contraindicated due to the potential for serious or life-threatening reactions such as cardiac arrhythmias [see Contraindications (4)]. Coadministration with REYATAZ without ritonavir has the potential to produce serious and/or life-threatening adverse events but has not been studied. Caution is warranted and therapeutic concentration monitoring of these drugs is recommended if they are used concomitantly with REYATAZ without ritonavir.
Anticoagulants: warfarin	↑ warfarin	Coadministration with REYATAZ has the potential to produce serious and/or life-threatening bleeding and has not been studied. It is recommended that International Normalized Ratio (INR) be monitored.
Direct-Acting Oral Anticoagulants: betrixaban, dabigatran, edoxaban	↑ betrixaban ↑ dabigatran ↑ edoxaban	Concomitant use of REYATAZ with ritonavir, a strong CYP3A4/P-gp inhibitor, may result in an increased risk of bleeding. Refer to the respective DOAC prescribing information regarding dosing instructions for coadministration with P-gp inhibitors.
rivaroxaban	REYATAZ with ritonavir ↑ rivaroxaban	Coadministration of REYATAZ with ritonavir, a strong CYP3A4/P-gp inhibitor, and rivaroxaban is not recommended, as it may result in an increased risk of bleeding.
	REYATAZ ↑ rivaroxaban	Coadministration of REYATAZ, a CYP3A4 inhibitor, and rivaroxaban may result in an increased risk of bleeding. Close monitoring is recommended when REYATAZ is coadministered with rivaroxaban.
apixaban	REYATAZ with ritonavir ↑ apixaban	Concomitant use of REYATAZ with ritonavir, a strong CYP3A4/P-gp inhibitor, may result in an increased risk of bleeding. Refer to apixaban dosing instructions for coadministration with strong CYP3A4 and P-gp inhibitors in the apixaban prescribing information.
	REYATAZ ↑ apixaban	Concomitant use of REYATAZ, a CYP3A4 inhibitor, and apixaban may result in an increased risk of bleeding. Close monitoring is recommended when apixaban is coadministered with REYATAZ.
Antidepressants: tricyclic antidepressants	↑ tricyclic antidepressants	Coadministration with REYATAZ has the potential to produce serious and/or life-threatening adverse events and has not been studied. Concentration monitoring of these drugs is recommended if they are used concomitantly with REYATAZ.
trazodone	↑ trazodone	Nausea, dizziness, hypotension, and syncope have been observed following coadministration of trazodone with ritonavir. If trazodone is used with a CYP3A4 inhibitor such as REYATAZ, the combination should be used with caution and a lower dose of trazodone should be considered.
Antiepileptics: carbamazepine	↓ atazanavir ↑ carbamazepine	Coadministration of REYATAZ (with or without ritonavir) with carbamazepine is contraindicated due to the risk for loss of virologic response and development of resistance [see Contraindications (4)].
phenytoin, phenobarbital	↓ atazanavir ↓ phenytoin ↓ phenobarbital	Coadministration of REYATAZ (with or without ritonavir) with phenytoin or phenobarbital is contraindicated due to the risk for loss of virologic response and development of resistance [see Contraindications (4)].
lamotrigine	↓ lamotrigine	Coadministration of lamotrigine and REYATAZ with ritonavir may require dosage adjustment of lamotrigine. No dose adjustment of lamotrigine is required when coadministered with REYATAZ without ritonavir.
Antifungals: ketoconazole, itraconazole	REYATAZ with ritonavir: ↑ ketoconazole ↑ itraconazole	Coadministration of ketoconazole has only been studied with REYATAZ without ritonavir (negligible increase in atazanavir AUC and C_max). Due to the effect of ritonavir on ketoconazole, high doses of ketoconazole and itraconazole (>200 mg/day) should be used cautiously when administering REYATAZ with ritonavir.
voriconazole	REYATAZ with ritonavir in subjects with a functional CYP2C19 allele: ↓ voriconazole ↓ atazanavir REYATAZ with ritonavir in subjects without a functional CYP2C19 allele: ↑ voriconazole ↓ atazanavir	The use of voriconazole in patients receiving REYATAZ with ritonavir is not recommended unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Patients should be carefully monitored for voriconazole-associated adverse reactions and loss of either voriconazole or atazanavir efficacy during the coadministration of voriconazole and REYATAZ with ritonavir. Coadministration of voriconazole with REYATAZ (without ritonavir) may affect atazanavir concentrations; however, no data are available.
Antigout: colchicine	↑ colchicine	The coadministration of REYATAZ with colchicine in patients with renal or hepatic impairment is not recommended. Recommended adult dosage of colchicine when administered with REYATAZ: Treatment of gout flares: 0.6 mg (1 tablet) for 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Not to be repeated before 3 days. Prophylaxis of gout flares: If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever (FMF): Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Antimycobacterials: rifampin	↓ atazanavir	Coadministration of REYATAZ with rifampin is contraindicated due to the risk for loss of virologic response and development of resistance [see Contraindications (4)].
rifabutin	↑ rifabutin	A rifabutin dose reduction of up to 75% (eg, 150 mg every other day or 3 times per week) is recommended. Increased monitoring for rifabutin-associated adverse reactions including neutropenia is warranted.
Antineoplastics: irinotecan	↑ irinotecan	Coadministration of REYATAZ with irinotecan is contraindicated. Atazanavir inhibits UGT1A1 and may interfere with the metabolism of irinotecan, resulting in increased irinotecan toxicities [see Contraindications (4)].
apalutamide	↓ atazanavir	Coadministration of REYATAZ (with or without ritonavir) and apalutamide is contraindicated due to the potential for subsequent loss of virologic response and possible resistance to the class of protease inhibitors [see Contraindications (4)].
ivosidenib	↓ atazanavir ↑ ivosidenib	Coadministration of ivosidenib with REYATAZ (with or without ritonavir) is contraindicated due to the potential for loss of virologic response and risk of serious adverse events such as QT interval prolongation.
encorafenib	↓ atazanavir ↑ encorafenib	Coadministration of encorafenib with REYATAZ (with or without ritonavir) is contraindicated due to the potential for the loss of virologic response and risk of serious adverse events such as QT interval prolongation.
Antiplatelets:
ticagrelor	↑ ticagrelor	Coadministration with ticagrelor is not recommended due to potential increase in the risk of dyspnea, bleeding and other adverse events associated with ticagrelor.
clopidogrel	↓ clopidogrel active metabolite	Coadministration of REYATAZ (with or without ritonavir) and clopidogrel is not recommended. This is due to the potential reduction of the antiplatelet activity of clopidogrel.
Antipsychotics: pimozide	↑ pimozide	Coadministration of REYATAZ with pimozide is contraindicated. This is due to the potential for serious and/or life-threatening reactions such as cardiac arrhythmias [see Contraindications (4)].
lurasidone	REYATAZ with ritonavir ↑ lurasidone	REYATAZ with ritonavir Coadministration of lurasidone with REYATAZ with ritonavir is contraindicated. This is due to the potential for serious and/or life-threatening reactions [see Contraindications (4)].
	REYATAZ ↑ lurasidone	REYATAZ without ritonavir If coadministration is necessary, reduce the lurasidone dose. Refer to the lurasidone prescribing information for concomitant use with moderate CYP3A4 inhibitors.
quetiapine	↑ quetiapine	Initiation of REYATAZ with ritonavir in patients taking quetiapine: Consider alternative antiretroviral therapy to avoid increases in quetiapine exposures. If coadministration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring. Initiation of quetiapine in patients taking REYATAZ with ritonavir: Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine.
Benzodiazepines: midazolam (oral) triazolam	↑ midazolam ↑ triazolam	Coadministration of REYATAZ with either orally administered midazolam or triazolam is contraindicated. Triazolam and orally administered midazolam are extensively metabolized by CYP3A4, and coadministration with REYATAZ can lead to the potential for serious and/or life-threatening events such as prolonged or increased sedation or respiratory depression [see Contraindications (4)].
parenterally administered midazolam^b	↑ midazolam	Coadministration with parenteral midazolam should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered.
Calcium channel blockers: diltiazem	↑ diltiazem and desacetyl-diltiazem	Caution is warranted. A dose reduction of diltiazem by 50% should be considered. ECG monitoring is recommended. Coadministration of diltiazem and REYATAZ with ritonavir has not been studied.
felodipine, nifedipine, nicardipine, and verapamil	↑ calcium channel blocker	Caution is warranted. Dose titration of the calcium channel blocker should be considered. ECG monitoring is recommended.
Corticosteroids: dexamethasone and other corticosteroids (all routes of administration)	↓ atazanavir ↑ corticosteroids	Coadministration with dexamethasone or other corticosteroids that induce CYP3A may result in loss of therapeutic effect of REYATAZ and development of resistance to atazanavir and/or ritonavir. Alternative corticosteroids should be considered. Coadministration with corticosteroids (all routes of administration) that are metabolized by CYP3A, particularly for long-term use, may increase the risk for development of systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression. Consider the potential benefit of treatment versus the risk of systemic corticosteroid effects. For coadministration of cutaneously administered corticosteroids sensitive to CYP3A inhibition, refer to the prescribing information of the corticosteroid for additional information.
Endothelin receptor antagonists: bosentan	REYATAZ ↓ atazanavir REYATAZ with ritonavir ↑ bosentan	Coadministration of bosentan and REYATAZ without ritonavir is not recommended. For adult patients who have been receiving REYATAZ with ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based on individual tolerability. For adult patients who have been receiving bosentan, discontinue bosentan at least 36 hours before starting REYATAZ with ritonavir. At least 10 days after starting REYATAZ with ritonavir, resume bosentan at 62.5 mg once daily or every other day based on individual tolerability.
Ergot derivatives: dihydroergotamine, ergotamine, ergonovine, methylergonovine	↑ ergot derivatives	Coadministration of REYATAZ with ergot derivatives is contraindicated. This is due to the potential for serious and/or life-threatening events such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues [see Contraindications (4)].
GI Motility Agents: cisapride	↑ cisapride	Coadministration of REYATAZ with cisapride is contraindicated. This is due to the potential for serious and/or life-threatening reactions such as cardiac arrhythmias [see Contraindications (4)].
Gonadotropin-releasing hormone Receptor (GnRH) Antagonists: elagolix	↓ atazanavir ↑ elagolix	Coadministration of elagolix and REYATAZ with or without ritonavir is not recommended due to the potential of loss of virologic response and the potential risk of adverse events such as bone loss and hepatic transaminase elevations associated with elagolix. In the event coadministration is necessary, limit concomitant use of elagolix 200mg twice daily with REYATAZ with or without ritonavir for up to 1 month or limit concomitant use of elagolix 150 mg once daily with REYATAZ (with or without ritonavir) for up to 6 months and monitor virologic response.
Herbal Products: St. John’s wort (Hypericum perforatum)	↓ atazanavir	Coadministration of products containing St. John’s wort with REYATAZ is contraindicated. This may result in loss of therapeutic effect of REYATAZ and the development of resistance [see Contraindications (4)].
Kinase inhibitors: fostamatinib	↑ R406 (active metabolite of fostamatinib)	When coadministering fostamatinib with REYATAZ (with or without ritonavir), monitor for toxicities of R406 exposure resulting in dose-related adverse events such as hepatotoxicity and neutropenia. Fostamatinib dose reduction may be required.
Lipid-modifying agents HMG-CoA reductase inhibitors: lovastatin, simvastatin	↑ lovastatin ↑ simvastatin	Coadministration of REYATAZ with lovastatin or simvastatin is contraindicated. This is due to the potential for serious reactions such as myopathy, including rhabdomyolysis [see Contraindications (4)].
atorvastatin, rosuvastatin	↑ atorvastatin ↑ rosuvastatin	Titrate atorvastatin dose carefully and use the lowest necessary dose. Rosuvastatin dose should not exceed 10 mg/day. The risk of myopathy, including rhabdomyolysis, may be increased when HIV protease inhibitors, including REYATAZ, are used in combination with these drugs.
Other Lipid Modifying Agents: lomitapide	↑ lomitapide	Coadministration of REYATAZ with lomitapide is contraindicated. This is due to the potential for risk of markedly increased transaminase levels and hepatotoxicity associated with increased plasma concentrations of lomitapide. The mechanism of interaction is CYP3A4 inhibition by atazanavir and/or ritonavir [see Contraindications (4)].
H₂ -Receptor antagonists	↓ atazanavir	Coadministration may result in loss of virologic response and development of resistance. In HIV-treatment-naive adult patients: REYATAZ 300 mg with ritonavir 100 mg once daily with food should be administered simultaneously with, and/or at least 10 hours after, a dose of the H₂-receptor antagonist (H2RA). An H2RA dose comparable to famotidine 20 mg once daily up to a dose comparable to famotidine 40 mg twice daily can be used with REYATAZ 300 mg with ritonavir 100 mg in treatment-naive patients. OR For patients unable to tolerate ritonavir, REYATAZ 400 mg once daily with food should be administered at least 2 hours before and at least 10 hours after a dose of the H2RA. No single dose of the H2RA should exceed a dose comparable to famotidine 20 mg, and the total daily dose should not exceed a dose comparable to famotidine 40 mg. The use of REYATAZ without ritonavir in pregnant patients is not recommended. In treatment-experienced adult patients: Whenever an H2RA is given to a patient receiving REYATAZ with ritonavir, the H2RA dose should not exceed a dose comparable to famotidine 20 mg twice daily, and the REYATAZ with ritonavir doses should be administered simultaneously with, and/or at least 10 hours after, the dose of the H2RA. REYATAZ 300 mg with ritonavir 100 mg once daily (all as a single dose with food) if taken with an H2RA. REYATAZ 400 mg with ritonavir 100 mg once daily (all as a single dose with food) if taken with both tenofovir DF and an H2RA. REYATAZ 400 mg with ritonavir 100 mg once daily (all as a single dose with food) if taken with either tenofovir DF or an H2RA for pregnant patients during the second and third trimester. REYATAZ is not recommended for pregnant patients during the second and third trimester taking REYATAZ with both tenofovir DF and an H2RA.
Hormonal contraceptives: ethinyl estradiol and norgestimate or norethindrone	↓ ethinyl estradiol ↑ norgestimate^c ↑ ethinyl estradiol ↑ norethindrone^d	Use caution if considering coadministration of oral contraceptives with REYATAZ or REYATAZ with ritonavir. If REYATAZ with ritonavir is coadministered with an oral contraceptive, it is recommended that the oral contraceptive contain at least 35 mcg of ethinyl estradiol. If REYATAZ is administered without ritonavir, the oral contraceptive should contain no more than 30 mcg of ethinyl estradiol. Potential safety risks include substantial increases in progesterone exposure. The long-term effects of increases in concentration of the progestational agent are unknown and could increase the risk of insulin resistance, dyslipidemia, and acne. Coadministration of REYATAZ or REYATAZ with ritonavir and other hormonal contraceptives (eg, contraceptive patch, contraceptive vaginal ring, or injectable contraceptives) or oral contraceptives containing progestogens other than norethindrone or norgestimate, or less than 25 mcg of ethinyl estradiol, has not been studied; therefore, alternative methods of contraception are recommended.
Immunosuppressants: cyclosporine, sirolimus, tacrolimus	↑ immunosuppressants	Therapeutic concentration monitoring is recommended for these immunosuppressants when coadministered with REYATAZ.
Inhaled beta agonist: salmeterol	↑ salmeterol	Coadministration of salmeterol with REYATAZ is not recommended. Concomitant use of salmeterol and REYATAZ may result in increased risk of cardiovascular adverse reactions associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia.
Inhaled/nasal steroid: fluticasone	REYATAZ ↑ fluticasone	Concomitant use of fluticasone propionate and REYATAZ without ritonavir should be used with caution. Consider alternatives to fluticasone propionate, particularly for long-term use.
	REYATAZ with ritonavir ↑ fluticasone	With concomitant use of fluticasone propionate and REYATAZ with ritonavir, 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. Coadministration of fluticasone propionate and REYATAZ with ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects [see Warnings and Precautions (5.1)].
Macrolide antibiotics: clarithromycin	↑ clarithromycin ↓ 14-OH clarithromycin ↑ atazanavir	Increased concentrations of clarithromycin may cause QTc prolongations; therefore, a dose reduction of clarithromycin by 50% should be considered when it is coadministered with REYATAZ. In addition, concentrations of the active metabolite 14-OH clarithromycin are significantly reduced; consider alternative therapy for indications other than infections due to Mycobacterium avium complex. Coadministration of REYATAZ with ritonavir and clarithromycin has not been studied.
Opioids: buprenorphine	REYATAZ or REYATAZ with ritonavir ↑ buprenorphine ↑ norbuprenorphine	Coadministration of REYATAZ with ritonavir and buprenorphine warrants clinical monitoring for sedation and cognitive effects. A dose reduction of buprenorphine may be considered.
	REYATAZ ↓ atazanavir	The coadministration of REYATAZ and buprenorphine without ritonavir is not recommended.
PDE5 inhibitors: sildenafil, tadalafil, vardenafil	↑ sildenafil ↑ tadalafil ↑ vardenafil	Coadministration with REYATAZ has not been studied but may result in an increase in PDE5 inhibitor-associated adverse reactions, including hypotension, syncope, visual disturbances, and priapism. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): Coadministration of REYATAZ with REVATIO® (sildenafil) for the treatment of pulmonary hypertension (PAH) is contraindicated [see Contraindications (4)]. The following dose adjustments are recommended for the use of ADCIRCA^®(tadalafil) with REYATAZ: Coadministration of ADCIRCA^® in patients on REYATAZ (with or without ritonavir): For patients receiving REYATAZ (with or without ritonavir) for at least one week, start ADCIRCA^® at 20 mg once daily. Increase to 40 mg once daily based on individual tolerability. Coadministration of REYATAZ (with or without ritonavir) in patients on ADCIRCA^®: Avoid the use of ADCIRCA^® when starting REYATAZ (with or without ritonavir). Stop ADCIRCA^® at least 24 hours before starting REYATAZ (with or without ritonavir). At least one week after starting REYATAZ (with or without ritonavir), resume ADCIRCA^® at 20 mg once daily. Increase to 40 mg once daily based on individual tolerability. Use of PDE5 inhibitors for erectile dysfunction: Use VIAGRA^® (sildenafil) with caution at reduced doses of 25 mg every 48 hours with increased monitoring for adverse events. Use CIALIS^® (tadalafil) with caution at reduced doses of 10 mg every 72 hours with increased monitoring for adverse events. REYATAZ with ritonavir: Use vardenafil with caution at reduced doses of no more than 2.5 mg every 72 hours with increased monitoring for adverse reactions. REYATAZ : Use vardenafil with caution at reduced doses of no more than 2.5 mg every 24 hours with increased monitoring for adverse reactions.
Proton-pump inhibitors: omeprazole	↓ atazanavir	Coadministration of REYATAZ with or without ritonavir and omeprazole may result in loss of virologic response and development of resistance. In HIV-treatment-naive adult patients: The proton-pump inhibitor (PPI) dose should not exceed a dose comparable to omeprazole 20 mg and must be taken approximately 12 hours prior to the REYATAZ 300 mg with ritonavir 100 mg dose. In HIV-treatment-experienced adult patients: Coadministration of REYATAZ with PPIs is not recommended.

7.4 Drugs with No Observed Interactions with REYATAZ

No clinically significant drug interactions were observed when REYATAZ was coadministered with methadone, fluconazole, acetaminophen, atenolol, or the nucleoside reverse transcriptase inhibitors lamivudine or zidovudine [see Clinical Pharmacology, Tables 21 and 22 (12.3)].

8 USE IN SPECIFIC POPULATIONS

Pregnancy: Available human and animal data suggest that atazanavir does not increase the risk of major birth defects overall compared to the background rate. (8.1)
Lactation: Breastfeeding is not recommended. (8.2)
Hepatitis B or C co-infection: Monitor liver enzymes. (5.4, 6.1)
Renal impairment: REYATAZ is not recommended for use in treatment-experienced patients with end-stage renal disease managed with hemodialysis. (2.7, 8.7)
Hepatic impairment: REYATAZ is not recommended in patients with severe hepatic impairment. REYATAZ with ritonavir is not recommended in patients with any degree of hepatic impairment. (2.8, 8.8)

8.1 Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in patients exposed to REYATAZ during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.

Risk Summary

Atazanavir has been evaluated in a limited number of women during pregnancy. Available human and animal data suggest that atazanavir does not increase the risk of major birth defects overall compared to the background rate [see Data]. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. No treatment-related malformations were observed in rats and rabbits, for which the atazanavir exposures were 0.7-1.2 times of those at the human clinical dose (300 mg/day atazanavir boosted with 100 mg/day ritonavir). When atazanavir was administered to rats during pregnancy and throughout lactation, reversible neonatal growth retardation was observed [see Data].

Clinical Considerations

Dose Adjustments during Pregnancy and the Postpartum Period

REYATAZ must be administered with ritonavir in pregnant patients.
For pregnant patients, no dosage adjustment is required for REYATAZ with the following exceptions:
- For treatment-experienced pregnant women during the second or third trimester, when REYATAZ is coadministered with either an H₂-receptor antagonist or tenofovir DF, REYATAZ 400 mg with ritonavir 100 mg once daily is recommended. There are insufficient data to recommend a REYATAZ dose for use with both an H₂-receptor antagonist and tenofovir DF in treatment-experienced pregnant patients.
No dosage adjustment is required for postpartum patients. However, patients should be closely monitored for adverse events because atazanavir exposures could be higher during the first 2 months after delivery [see Dosage and Administration (2.6) and Clinical Pharmacology (12.3)].

Maternal Adverse Reactions

Cases of lactic acidosis syndrome, sometimes fatal, and symptomatic hyperlactatemia have occurred in pregnant women using REYATAZ in combination with nucleoside analogues, which are associated with an increased risk of lactic acidosis syndrome.

Hyperbilirubinemia occurs frequently in patients who take REYATAZ [see Warnings and Precautions (5.8) ], including those who are pregnant [see Data].

Advise pregnant women of the potential risks of lactic acidosis syndrome and hyperbilirubinemia.

Fetal/Neonatal Adverse Reactions

All infants, including neonates exposed to REYATAZ in utero, should be monitored for the development of severe hyperbilirubinemia during the first few days of life [see Data].

Data

Human Data

In Study AI424-182, REYATAZ with ritonavir (300/100 mg or 400/100 mg) coadministered with lamivudine/zidovudine (150 mg/ 300 mg, as fixed-dose product) was administered to 41 pregnant women with HIV-1 infection, during the second or third trimester. Among the 39 women who completed the study, 38 women achieved an HIV-1 RNA less than 50 copies/mL at time of delivery. Six of 20 (30%) women on REYATAZ with ritonavir 300/100 mg and 13 of 21 (62%) women on REYATAZ with ritonavir 400/100 mg experienced hyperbilirubinemia (total bilirubin greater than or equal to 2.6 times ULN). There were no cases of lactic acidosis observed in clinical trial AI424-182.

Atazanavir drug concentrations in fetal umbilical cord blood were approximately 12% to 19% of maternal concentrations. Among the 40 infants born to 40 pregnant women with HIV-1 infection, all had test results that were negative for HIV-1 DNA at the time of delivery and/or during the first 6 months postpartum. All 40 infants received antiretroviral prophylactic treatment containing zidovudine. No evidence of severe hyperbilirubinemia (total bilirubin levels greater than 20 mg/dL) or acute or chronic bilirubin encephalopathy was observed among neonates in this study. However, 10/36 (28%) infants (6 greater than or equal to 38 weeks gestation and 4 less than 38 weeks gestation) had bilirubin levels of 4 mg/dL or greater within the first day of life.

Lack of ethnic diversity was a study limitation. In the study population, 33/40 (83%) infants were Black/African American, who have a lower incidence of neonatal hyperbilirubinemia than Caucasians and Asians. In addition, women with Rh incompatibility were excluded, as well as women who had a previous infant who developed hemolytic disease and/or had neonatal pathologic jaundice (requiring phototherapy).

Additionally, of the 38 infants who had glucose samples collected in the first day of life, 3 had adequately collected serum glucose samples with values of less than 40 mg/dL that could not be attributed to maternal glucose intolerance, difficult delivery, or sepsis.

Based on prospective reports from the APR of approximately 1600 live births following exposure to atazanavir-containing regimens (including 1037 live births in infants exposed in the first trimester and 569 exposed in second/third trimesters), there was no difference between atazanavir, and overall birth defects compared with the background birth defect rate. In the U.S. general population, the estimated background risk of major birth defects in clinically recognized pregnancies is 2-4%.

Animal Data

In animal reproduction studies, there was no evidence of mortality or teratogenicity in offspring born to animals at systemic drug exposure levels (AUC) 0.7 (in rabbits) to 1.2 (in rats) times those observed at the human clinical dose (300 mg/day atazanavir boosted with 100 mg/day ritonavir). In pre- and postnatal development studies in the rat, atazanavir caused neonatal growth retardation during lactation that reversed after weaning. Maternal drug exposure at this dose was 1.3 times the human exposure at the recommended clinical exposure. Minimal maternal toxicity occurred at this exposure level.

8.2 Lactation

Risk Summary

The Centers for Disease Control and Prevention recommend that patients with HIV-1 infection, not breastfeed their infants to avoid risking postnatal transmission of HIV-1. Atazanavir has been detected in human milk. No data are available regarding atazanavir effects on milk production. Atazanavir was present in the milk of lactating rats and was associated with neonatal growth retardation that reversed after weaning.

Because of both the potential for HIV-1 transmission and the potential for serious adverse reactions in breastfed infants, advise women not to breastfeed.

8.4 Pediatric Use

REYATAZ is indicated in combination with other antiretroviral agents for the treatment of pediatric patients with HIV-1 infection, 3 months of age and older weighing at least 5 kg. REYATAZ is not recommended for use in pediatric patients below the age of 3 months due to the risk of kernicterus [see Indications and Usage (1)]. All REYATAZ contraindications, warnings, and precautions apply to pediatric patients [see Contraindications (4) and Warnings and Precautions (5)].

The safety, pharmacokinetic profile, and virologic response of REYATAZ in pediatric patients at least 3 months of age and older weighing at least 5 kg were established in three open-label, multicenter clinical trials: PACTG 1020A, AI424-451, and AI424-397 [see Clinical Pharmacology (12.3) and Clinical Studies (14.3)]. The safety profile in pediatric patients was generally similar to that observed in adults [see Adverse Reactions (6.1)]. See Dosage and Administration (2.4 , 2.5) for dosing recommendations for the use of REYATAZ capsules and REYATAZ oral powder in pediatric patients.

8.5 Geriatric Use

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.

8.6 Age/Gender

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 significant pharmacokinetic differences observed due to age or gender.

8.7 Impaired Renal Function

REYATAZ is not recommended for use in treatment-experienced patients with HIV-1 infection, who have end-stage renal disease managed with hemodialysis [see Dosage and Administration (2.7) and Clinical Pharmacology (12.3)].

8.8 Impaired Hepatic Function

REYATAZ is not recommended for use in patients with severe hepatic impairment. REYATAZ with ritonavir is not recommended in patients with any degree of hepatic impairment [see Dosage and Administration (2.8) and Clinical Pharmacology (12.3)].

10 OVERDOSAGE

Human experience of acute overdose with REYATAZ is limited. Single doses up to 1200 mg (three times the 400 mg maximum recommended dose) have been taken by healthy subjects without symptomatic untoward effects. A single self-administered overdose of 29.2 g of REYATAZ in a patient with HIV-1 infection (73 times the 400-mg recommended dose) was associated with asymptomatic bifascicular block and PR interval prolongation. These events resolved spontaneously. At REYATAZ doses resulting in high atazanavir exposures, jaundice due to indirect (unconjugated) hyperbilirubinemia (without associated liver function test changes) or PR interval prolongation may be observed [see Warnings and Precautions (5.1, 5.8) and Clinical Pharmacology (12.2)].

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.

11 DESCRIPTION

The active ingredient in REYATAZ capsules and oral powder is atazanavir sulfate, which is an HIV-1 protease inhibitor.

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 C₃₈H₅₂N₆O₇H₂SO₄, 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:

Reyataz Chemic Structure

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 of 150 mg, 200 mg, or 300 mg of atazanavir, which are equivalent to 170.8 mg, 227.8 mg, or 341.69 mg of atazanavir sulfate, respectively. The capsules also contain the following inactive ingredients: crospovidone, lactose monohydrate, and magnesium stearate. The capsule shells contain the following inactive ingredients: gelatin, FD&C Blue No. 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 No. 2, isopropyl alcohol, ammonium hydroxide, propylene glycol, n-butyl alcohol, simethicone, and dehydrated alcohol.

REYATAZ oral powder comes in a packet containing 50 mg of atazanavir equivalent to 56.9 mg of atazanavir sulfate in 1.5 g of powder. The powder is off-white to pale yellow and contains the following inactive ingredients: aspartame, sucrose, and orange-vanilla flavor.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Atazanavir is an HIV-1 antiretroviral drug [see Microbiology (12.4)].

12.2 Pharmacodynamics

Cardiac Electrophysiology

Concentration- and dose-dependent prolongation of the PR interval in the electrocardiogram has been observed in healthy subjects receiving atazanavir. In 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 and Precautions (5.1)].

Electrocardiographic effects of atazanavir were determined in a clinical pharmacology study of 72 healthy subjects. Oral doses of 400 mg (maximum recommended dosage) and 800 mg (twice the maximum recommended dosage) were compared with placebo; there was no concentration-dependent effect of atazanavir on the QTc interval (using Fridericia’s correction). In 1793 subjects with HIV-1 infection, receiving antiretroviral regimens, QTc prolongation was comparable in the atazanavir and comparator regimens. No atazanavir-treated healthy subject or subject with HIV-1 infection in clinical trials had a QTc interval >500 msec [see Warnings and Precautions (5.1)].

12.3 Pharmacokinetics

The pharmacokinetics of atazanavir were evaluated in adult subjects who either were healthy, or with HIV infection, after administration of REYATAZ 400 mg once daily and after administration of REYATAZ 300 mg with ritonavir 100 mg once daily (see Table 17).

Table 17: Steady-State Pharmacokinetics of Atazanavir in Healthy Subjects or Subjects with HIV-1 Infection in the Fed State

^a n=26.

REYATAZ (ATAZANAVIR) capsule, gelatin coatedE.R. Squibb & Sons, L.L.C.

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 Overview

2.2 Testing Prior to Initiation and During Treatment with REYATAZ

2.3 Dosage of REYATAZ in Adult Patients

2.4 Dosage of REYATAZ Capsules in Pediatric Patients

2.5 Dosage and Administration of REYATAZ Oral Powder in Pediatric Patients

Instructions for Mixing REYATAZ Oral Powder [see FDA-approved Instructions for Use]

2.6 Dosage Adjustments in Pregnant Patients

2.7 Dosage in Patients with Renal Impairment

2.8 Dosage Adjustments in Patients with Hepatic Impairment

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Cardiac Conduction Abnormalities

5.2 Severe Skin Reactions

5.3 Patients with Phenylketonuria

5.4 Hepatotoxicity

5.5 Chronic Kidney Disease

5.6 Nephrolithiasis and Cholelithiasis

5.7 Risk of Serious Adverse Reactions Due to Drug Interactions

5.8 Hyperbilirubinemia

5.9 Diabetes Mellitus/Hyperglycemia

5.10 Immune Reconstitution Syndrome

5.11 Fat Redistribution

5.12 Hemophilia

5.13 Resistance/Cross-Resistance

6 ADVERSE REACTIONS

6.1 Clinical Trial Experience

Adverse Reactions in Treatment-Naive Adult Subjects

Adverse Reactions in Treatment-Experienced Adult Subjects

Laboratory Abnormalities in Treatment-Naive Subjects

Change in Lipids from Baseline in Treatment-Naive Subjects with HIV-1 Infection

Laboratory Abnormalities in Treatment-Experienced Subjects with HIV-1 Infection

Change in Lipids from Baseline in Treatment-Experienced Subjects with HIV-1 Infection

Adverse Reactions in Pediatric Subjects with HIV-1 Infection: REYATAZ Capsules

Adverse Reactions in Pediatric Subjects with HIV-1 Infection: REYATAZ Oral Powder

Adverse Reactions in Subjects with HIV-1 Infection, Co-Infected with Hepatitis B and/or Hepatitis C Virus

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

7.1 Potential for REYATAZ to Affect Other Drugs

7.2 Potential for Other Drugs to Affect REYATAZ

7.3 Established and Other Potentially Significant Drug Interactions

7.4 Drugs with No Observed Interactions with REYATAZ

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Exposure Registry

Risk Summary

Clinical Considerations

Maternal Adverse Reactions

Fetal/Neonatal Adverse Reactions

Data

Human Data

Animal Data

8.2 Lactation

Risk Summary

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Age/Gender

8.7 Impaired Renal Function

8.8 Impaired Hepatic Function

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

Cardiac Electrophysiology

12.3 Pharmacokinetics

REYATAZ (ATAZANAVIR) capsule, gelatin coated
E.R. Squibb & Sons, L.L.C.