Drug Class-Specific Warnings and Precautions: Diabetes Mellitus/Hyperglycemia: New-onset diabetes mellitus, exacerbation of preexisting diabetes mellitus and hyperglycemia have been reported during post-marketing surveillance in HIV-infected patients receiving protease inhibitor therapy. In some cases, diabetic ketoacidosis has occurred.
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 most reported cases, treatment with protease inhibitors was continued or reintroduced.
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.
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 respond may develop an inflammatory response to indolent or residual opportunistic infections [eg, Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia (PCP) or tuberculosis], which may necessitate further evaluation and treatment.
Product-Specific Warnings and Precautions: PR Interval Prolongation: Atazanavir has the potential to prolong the PR interval of the electrocardiogram in some patients. Reyataz should be used with caution in patients with preexisting conduction system disease. Caution should be used when co-administering Reyataz with medicinal products known to induce PR interval prolongation.
Hyperbilirubinemia: Reversible elevations in indirect (unconjugated) bilirubin related to inhibition of UDP-glucuronosyl transferase (UGT) have occurred in patients receiving Reyataz. Hepatic transaminase elevations that occur with elevated bilirubin in patients receiving Reyataz should be evaluated for alternative etiologies. No long-term safety data are available for patients experiencing persistent elevations in 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 Reyataz is not recommended since long-term efficacy of reduced doses has not been established.
Rash: Rashes are usually mild to moderate maculopapular skin eruptions that occur within the first 3 weeks of initiating therapy with Reyataz. In most patients, rash resolves within 2 weeks while continuing Reyataz therapy. Reyataz should be discontinued if severe rash develops. Cases of Stevens-Johnson syndrome, erythema multiforme and toxic skin eruptions have been reported in patients receiving Reyataz.
Hepatic Impairment and Toxicity: Atazanavir is principally metabolized by the liver; caution should be exercised when administering Reyataz to patients with hepatic impairment because atazanavir concentrations may be increased (see Dosage & Administration: Hepatic Impairment). Patients with underlying hepatitis B or C viral infections or marked elevations in transaminases prior to treatment may be at increased risk for developing further transaminase elevations.
Nephrolithiasis: Cases of nephrolithiasis have been reported during post-marketing surveillance in HIV-infected patients receiving Reyataz therapy. If signs and symptoms of nephrolithiasis occur, temporary interruption or discontinuation of therapy may be considered.
Use in pregnancy & lactation: No teratogenic effects were observed in rats or rabbits at maternally toxic doses producing maternal exposures (AUC) 2 times (rats) and comparable to (rabbits) exposure in humans given 400 mg once daily. In the pre- and postnatal development assessment in rats, atazanavir produced transient body weight loss or gain suppression in the offspring at a maternally toxic dose. Offspring were unaffected at a lower dose which produced maternal exposure equivalent to that observed in humans given 400 mg once daily.
In clinical trial AI424-182, Reyataz/ritonavir (300/100 mg or 400/100 mg) in combination with zidovudine/lamivudine was administered to 41 pregnant women during the 2nd or 3rd trimester. Among the 39 women who completed the study, 38 women achieved an HIV RNA <50 copies/mL at time of delivery. Six (6) of 20 (30%) women on Reyataz/ritonavir 300/100 mg and 13 of 21 (62%) women on Reyataz/ritonavir 400/100 mg experienced grades 3-4 hyperbilirubinemia. There were no cases of lactic acidosis observed in the clinical trial AI424-182.
Forty (40) infants had test result 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. Three (3) of 20 infants (15%) born to women treated with Reyataz/ritonavir 300/100 mg and 4 of 20 infants (20%) born to women treated with Reyataz/ritonavir 400/100 mg experienced grade 3-4 bilirubin. There was no evidence of pathologic jaundice and 6 of 40 infants in this study received phototherapy for a maximum of 4 days. There were no reported cases of kernicterus in neonates.
No dosage adjustment is required if used during pregnancy.
Reyataz should be used during pregnancy only if the potential benefit justifies the potential risk.
It is not known whether atazanavir is secreted in human milk. A study in lactating rats demonstrated that atazanavir is secreted in milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving Reyataz.
Post-Marketing Data: As of December 2009, there were 315 identified cases with prospective 1st trimester exposure to atazanavir and known outcome in the post-marketing database. There was no association between atazanavir and specific birth defects observed in the post-marketing data.
Antiretroviral Pregnancy Registry Data: As of January 2010, the Antiretroviral Pregnancy Registry (APR) has received prospective reports of 635 exposures to atazanavir-containing regimens (425 exposed in the 1st trimester and 160 and 50 exposed in 2nd and 3rd trimester, respectively). Birth defects occurred in 9 of 393 (2.3%) live births (1st trimester exposure) and 5 of 212 (2.4%) live births (2nd/3rd trimester exposure). There was no association between atazanavir and specific birth defects observed in the APR.
Labor and Delivery: Hyperbilirubinemia occurred frequently during treatment with Reyataz. It is not known whether Reyataz administered to the mother during pregnancy will exacerbate physiological hyperbilirubinemia and lead to kernicterus in neonates and young infants. In the prepartum period, additional monitoring should be considered.