Atazanavir - Warnings and Precautions

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.

If a concomitant transaminase increase occurs, evaluate for alternative etiologies. • Phenylketonuria: REYATAZ oral powder contains phenylalanine which can be harmful to patients with phenylketonuria. • Hepatotoxicity: Patients with hepatitis B or C virus 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 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. • Nephrolithiasis and cholelithiasis have been reported.

Consider temporary interruption or discontinuation. • 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 , immune reconstitution syndrome , and redistribution/accumulation of body fat. • Hemophilia: Spontaneous bleeding may occur, and additional factor VIII may be required.

5.1 Cardiac Conduction Abnormalities REYATAZ has been shown to prolong the PR interval of the electrocardiogram in some study participants.

In healthy participants and in participants with HIV-1 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 and Overdosage ] .

In clinical trials that included electrocardiograms, asymptomatic first-degree AV block was observed in 5.9% of atazanavir-treated participants (n=920), 5.2% of lopinavir/ritonavir-treated participants (n=252), 10.4% of nelfinavir-treated participants (n=48), and 3.0% of efavirenz-treated participants (n=329).

In Study AI424-045, asymptomatic first-degree AV block was observed in 5% (6/118) of atazanavir with ritonavir-treated participants and 5% (6/116) of lopinavir/ritonavir-treated participants 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 ] .

5.2 Severe Skin Reactions In controlled clinical trials, rash (all grades, regardless of causality) occurred in approximately 20% of participants with HIV-1 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 ] .

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 and Adverse Reactions ] .

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).