5.1 Cardiac Conduction Abnormalities

REYATAZ has been shown to prolong the PR interval of the electrocardiogram in some patients. In healthy volunteers and in patients, abnormalities in atrioventricular (AV) conduction were asymptomatic and generally limited to first-degree AV block. There have been 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 patients (n=920), 5.2% of lopinavir/ritonavir-treated patients (n=252), 10.4% of nelfinavir-treated patients (n=48), and 3.0% of efavirenz-treated patients (n=329). In Study AI424-045, asymptomatic first-degree AV block was observed in 5% (6/118) of atazanavir/ritonavir-treated patients and 5% (6/116) of lopinavir/ritonavir-treated patients who had on-study electrocardiogram measurements. Because of limited clinical experience in patients 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 patients 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 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).]

5.4 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.

5.5 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 ADVERSE REACTIONS (6.1) and USE IN SPECIFIC POPULATIONS (8.8).]

5.6 Nephrolithiasis and Cholelithiasis

Cases of nephrolithiasis and/or cholelithiasis have been reported during postmarketing surveillance in HIV-infected patients 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 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 REYATAZ/ritonavir therapy; review concomitant medications during REYATAZ/ritonavir therapy; and monitor for the adverse reactions associated with the concomitant medications [see CONTRAINDICATIONS (4) and DRUG INTERACTIONS (7)].

5.8 Diabetes Mellitus/Hyperglycemia

New-onset diabetes mellitus, exacerbation of preexisting diabetes mellitus, and hyperglycemia have been reported during postmarketing surveillance in HIV-infected patients receiving protease inhibitor therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued protease inhibitor therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and a causal relationship between protease inhibitor therapy and these events has not been established. [See ADVERSE REACTIONS (6.2).]

5.9 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 jiroveci pneumonia, or tuberculosis), which may necessitate further evaluation and treatment.

Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) 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.

5.10 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.

5.11 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.

5.12 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).]