IMPORTANT SAFETY INFORMATION for EVOTAZ^® (atazanavir and cobicistat) and REYATAZ^® (atazanavir) 200 mg/300 mg capsules

CONTRAINDICATIONS

• In patients with previously demonstrated clinically significant hypersensitivity (e.g., Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to any of the product components
• When coadministered with drugs 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 Drugs contraindicated with EVOTAZ and REYATAZ below).
• When coadministered with drugs that strongly induce CYP3A and may lead to lower exposure and loss of efficacy of EVOTAZ and REYATAZ (see Drugs contraindicated with EVOTAZ and REYATAZ below).
• Drugs contraindicated with EVOTAZ and REYATAZ: alfuzosin, rifampin, irinotecan, lurasidone (contraindicated with REYATAZ when REYATAZ is coadministered with ritonavir), pimozide, triazolam, orally administered midazolam, dihydroergotamine, ergotamine, methylergonovine, cisapride, elbasvir/grazoprevir, glecaprevir/pibrentasvir, St. John's wort (Hypericum perforatum), lovastatin, simvastatin, nevirapine, sildenafil when used for pulmonary arterial hypertension, indinavir. EVOTAZ is also contraindicated with: ranolazine, dronedarone, carbamazepine, phenobarbital, phenytoin, colchicine in patients with renal and/or hepatic impairment, drospirenone/ethinyl estradiol, lomitapide. REYATAZ is also contraindicated with: ergonovine.

WARNINGS AND PRECAUTIONS

• Cardiac Conduction Abnormalities: PR interval prolongation may occur in some patients. Atrioventricular (AV) conduction abnormalities were asymptomatic and generally limited to first-degree AV block; second-degree AV block and other conduction abnormalities have been reported. Due to limited clinical experience in patients with preexisting conduction system disease, consider ECG monitoring in these patients
• Severe Skin Reactions: 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 atazanavir. Discontinue if severe rash develops. Mild-to-moderate maculopapular skin eruptions have also been reported, and generally did not result in treatment discontinuation
• Chronic Kidney Disease has been reported during postmarketing surveillance with atazanavir, with or without ritonavir. Consider alternatives in patients at high risk for renal disease or with preexisting renal disease. Renal laboratory testing should be performed before and during therapy in all patients. Expert consultation is advised for patients with confirmed renal laboratory abnormalities. Consider discontinuation of atazanavir in patients with progressive kidney disease
• Nephrolithiasis and Cholelithiasis have been reported during postmarketing surveillance with atazanavir. Some patients required hospitalization and some had complications. If signs or symptoms of nephrolithiasis and/or cholelithiasis occur, consider temporary interruption or discontinuation of therapy
• Hepatotoxicity: Patients with hepatitis B or C viral infections or marked elevations in transaminases may be at risk of further transaminase elevations or hepatic decompensation. Hepatic laboratory testing should be performed before and during therapy in patients with underlying liver disease
• Risk of Serious Adverse Reactions or Loss of Virologic Response Due to Drug Interactions: Concomitant administration of EVOTAZ or REYATAZ/ritonavir, both CYP3A inhibitors, and medications metabolized by CYP3A may increase plasma concentrations of these medications. Initiation of medications that inhibit or induce CYP3A may increase or decrease concentrations of EVOTAZ or REYATAZ/ritonavir, respectively. Increased concentrations of EVOTAZ or REYATAZ/ritonavir may lead to clinically significant adverse reactions, potentially leading to severe, life-threatening, or fatal events from higher exposures of concomitant medications, or clinically significant adverse reactions from higher exposures of EVOTAZ or REYATAZ/ritonavir. Decreased concentrations of EVOTAZ or REYATAZ/ritonavir may lead to loss of therapeutic effects and possible development of resistance
• Hyperbilirubinemia: Reversible (upon discontinuation of atazanavir), asymptomatic elevations in indirect (unconjugated) bilirubin occurred in most patients treated with atazanavir. There are no long-term safety data for patients with persistent elevations in total bilirubin >5 times the upper limit of normal. Alternative antiretroviral therapy may be considered if jaundice or scleral icterus present cosmetic concerns
• Immune Reconstitution Syndrome has been reported in patients treated with combination antiretroviral therapy, including atazanavir. Autoimmune disorders (such as Graves’ disease, polymyositis, Guillain-Barré syndrome, and autoimmune hepatitis) have also been reported in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment
• Diabetes Mellitus/Hyperglycemia: New onset diabetes, exacerbation of preexisting diabetes, and hyperglycemia have been reported in postmarketing surveillance with protease inhibitors. A causal relationship has not been established
• Fat Redistribution or accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, breast enlargement, and “cushingoid appearance” have been seen in patients receiving antiretroviral therapy. A causal relationship has not been established
• Hemophilia: Increased bleeding has been reported in patients with hemophilia type A and B treated with protease inhibitors. A causal relationship has not been established

EVOTAZ: Additional WARNINGS AND PRECAUTIONS

• Effects on Serum Creatinine: Cobicistat decreases estimated creatinine clearance (CrCl) by inhibiting tubular secretion of creatinine without affecting actual renal glomerular function. Consider this effect when interpreting changes in estimated CrCl in patients initiating EVOTAZ, particularly in patients with medical conditions or receiving drugs needing monitoring with estimated CrCl. Assess estimated CrCl prior to initiating EVOTAZ. Dosage recommendations are not available for drugs that require dosage adjustment in cobicistat-treated patients with renal impairment; consider alternative medications that do not require dosage adjustment in these patients. Patients who experience a confirmed increase in serum creatinine >0.4 mg/dL from baseline should be closely monitored for renal safety
• New Onset or Worsening Renal Impairment when used with tenofovir disoproxil fumarate: Renal impairment, including cases of acute renal failure and Fanconi syndrome, has been reported when cobicistat was used with tenofovir disoproxil fumarate (tenofovir DF)
  • Coadministration of EVOTAZ and tenofovir DF is not recommended in patients who have an estimated CrCl <70 mL/min or in combination with concomitant or recent use of a nephrotoxic agent
  • When EVOTAZ is used with tenofovir DF, document baseline urine glucose and urine protein, and perform routine monitoring of estimated CrCl, urine glucose, and urine protein. Measure serum phosphorus in patients at risk for renal impairment
• Antiretrovirals that are Not Recommended: EVOTAZ is not recommended in combination with other antiretroviral drugs that require CYP3A inhibition to achieve adequate exposures (e.g., other HIV protease inhibitors or elvitegravir) because dosing for such combinations has not been established; coadministration may lead to loss of therapeutic effect and development of resistance due to decreased plasma concentrations of the antiretroviral agents. EVOTAZ is not recommended in combination with ritonavir containing products

REYATAZ: Additional WARNINGS AND PRECAUTIONS

• Patients with Phenylketonuria: Phenylalanine can be harmful to patients with phenylketonuria (PKU). REYATAZ oral powder contains phenylalanine (a component of aspartame). REYATAZ capsules do not contain phenylalanine
• Resistance/Cross-Resistance in various degrees have been observed among protease inhibitors

MOST COMMON MODERATE OR SEVERE ADVERSE REACTIONS

EVOTAZ:

• In treatment-naive adults (≥2%): jaundice (6%), rash (5%), ocular icterus (4%), nausea (2%), diarrhea (2%), and headache (2%)
• Results from an open-label study in patients between the ages of 12 to less than 18 years (N=14) showed that the safety profile of atazanavir and cobicistat coadministered with a background regimen was similar to that in adults.

REYATAZ, regardless of causality:

• In treatment-naive adults (≥2%): nausea (4‑14%), jaundice/scleral icterus (5-7%), rash (3-7%), headache (1-6%), abdominal pain (4%), vomiting (3-4%), peripheral neurologic symptoms (<1-4%), diarrhea (1-3%), insomnia (<1-3%), and dizziness (<1-2%)
• In treatment-experienced adults (≥2%): jaundice/scleral icterus (9%), myalgia (4%), diarrhea (3%), nausea (3%), depression (2%), and fever (2%)
• In pediatric patients taking the capsule formulation (≥5%): 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%)
• In pediatric patients taking the oral powder formulation: The adverse reactions were generally similar to those observed in clinical studies of REYATAZ in pediatric patients taking the capsule formulation

DRUG INTERACTIONS

Coadministration of EVOTAZ and the following drugs is not recommended

• efavirenz, etravirine, ritonavir, sofosbuvir/velpatasvir/voxilaprevir, rivaroxaban, voriconazole, ticagrelor, clopidogrel, salmeterol, atorvastatin, avanafil
• when EVOTAZ is coadministered with tenofovir DF and an H₂-receptor antagonist in treatment-experienced patients
• proton pump inhibitors in treatment-experienced patients

Coadministration of REYATAZ and the following drugs is not recommended

• salmeterol, sofosbuvir/velpatasvir/voxilaprevir
• when REYATAZ is coadministered with ritonavir: boceprevir, other HIV protease inhibitors, voriconazole, fluticasone propionate
• when REYATAZ is coadministered without ritonavir: carbamazepine, phenytoin, phenobarbital, bosentan, buprenorphine
• in treatment-experienced patients: proton pump inhibitors or efavirenz
• in patients with renal or hepatic impairment: colchicine

See Table 5 of the EVOTAZ Full Prescribing Information, and Table 16 of the REYATAZ Full Prescribing Information for additional established and potentially significant Drug Interactions in adults, and related dose modification recommendations.

PREGNANCY/LACTATION:

• EVOTAZ is not recommended for use during pregnancy and should not be initiated in pregnant individuals; use of an alternative regimen is recommended for individuals who become pregnant during EVOTAZ therapy
• Cases of lactic acidosis syndrome and hyperlactatemia when used in combination with nucleoside analogues, and hyperbilirubinemia have occurred in pregnant women taking atazanavir
• Atazanavir has been detected in human milk. Because of the potential for HIV transmission, developing viral resistance, and adverse reactions, instruct individuals with HIV-1 infection not to breastfeed
• Atazanavir and cobicistat interact with certain oral contraceptives. Nonhormonal forms of contraceptive should be considered.

PEDIATRIC USE:

• Use of EVOTAZ for the treatment of HIV-1 infection in pediatric subjects weighing at least 35 kg is supported by evidence from adequate and well-controlled studies in adults, and by pharmacokinetic, safety, and virologic data from an open-label trial of components of EVOTAZ in pediatric subjects with HIV-1 infection aged 12 years and older. The safety in these subjects was similar to that in antiretroviral treatment-naive adults.
• Safety and effectiveness of EVOTAZ in the pediatric population weighing less than 35 kg have not been established. Atazanavir, a component of EVOTAZ, is not recommended for use in pediatric patients below the age of 
  3 months due to the risk of kernicterus.

USE IN RENAL AND HEPATIC IMPAIRMENT:

• EVOTAZ and REYATAZ are not recommended for use in treatment-experienced patients with end-stage renal disease managed with hemodialysis
• EVOTAZ and REYATAZ/ritonavir are not recommended in patients with any degree of hepatic impairment
• REYATAZ is not recommended for patients with severe hepatic impairment

Please see US Full Prescribing Information for EVOTAZ and REYATAZ.