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Reyataz

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Reyataz

Warnings
Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

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 and OVERDOSAGE]. 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]

Rash

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-tomoderate 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.

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]

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.

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 and Use In Specific Populations]

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]

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]

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.

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.

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.

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]

Patient Counseling Information

See FDA-approved patient labeling (PATIENT INFORMATION and Instructions for Use).

A statement to patients and healthcare providers is included on the product's label: ALERT: Find out about medicines that should NOT be taken with REYATAZ® .

REYATAZ is not a cure for HIV infection and patients may continue to experience illnesses associated with HIV infection, including opportunistic infections. Patients should remain under the care of a healthcare provider when using REYATAZ.

Patients should be advised to avoid doing things that can spread HIV infection to others.

  • Do not share or re-use needles or other injection equipment.
  • Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.
  • Do not have any kind of sex without protection. Always practice safer sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood.
  • Do not breastfeed. It is not known if REYATAZ can be passed to your baby in your breast milk and whether it could harm your baby. Also, mothers with HIV should not breastfeed because HIV can be passed to the baby in breast milk.
Dosing Instructions

Patients should be told that sustained decreases in plasma HIV RNA have been associated with a reduced risk of progression to AIDS and death. Patients should remain under the care of a healthcare provider while using REYATAZ. Patients should be advised to take REYATAZ with food every day and take other concomitant antiretroviral therapy as prescribed. REYATAZ must always be used in combination with other antiretroviral drugs. Patients should not alter the dose or discontinue therapy without consulting with their healthcare provider. If a dose of REYATAZ is missed, patients should take the dose as soon as possible and then return to their normal schedule. However, if a dose is skipped the patient should not double the next dose.

REYATAZ oral powder is available for pediatric patients who are 3 months and older weighing 10 kg to less than 25 kg. Caregivers should be advised on how to mix the REYATAZ oral powder with a food or beverage such as milk or water for infants and young children who can take solid foods or drink liquids from a cup. For infants who cannot take solid food or drink from a cup, the powder formulation mixed in liquid infant formula should be given with an oral dosing syringe. Caregivers should carefully follow the Instructions for Use and storage of the powder [see DOSAGE AND ADMINISTRATION and FDA-approved patient labeling (PATIENT INFORMATION and Instructions for Use)].

Caregivers of patients with phenylketonuria should be advised that REYATAZ oral powder contains phenylalanine.

Patients or caregivers should call their healthcare provider or pharmacist if they have any questions.

Drug Interactions

REYATAZ may interact with some drugs; therefore, patients should be advised to report to their heathcare provider the use of any other prescription, nonprescription medication, or herbal products, particularly St. John's wort.

Patients receiving a PDE5 inhibitor and atazanavir should be advised that they may be at an increased risk of PDE5 inhibitor-associated adverse events including hypotension, syncope, visual disturbances, and priapism, and should promptly report any symptoms to their doctor.

Patients should be informed that REVATIO® (used to treat pulmonary arterial hypertension) is contraindicated with REYATAZ and that dose adjustments are necessary when REYATAZ is used with CIALIS®, LEVITRA®, or VIAGRA® (used to treat erectile dysfunction), or ADCIRCA® (used to treat pulmonary arterial hypertension).

Cardiac Conduction Abnormalities

Patients should be informed that atazanavir may produce changes in the electrocardiogram (eg, PR prolongation). Patients should consult their healthcare provider if they are experiencing symptoms such as dizziness or lightheadedness.

Rash

Patients should be informed that mild rashes without other symptoms have been reported with REYATAZ use. These rashes go away within two weeks with no change in treatment. However, there have been reports of severe skin reactions (eg, Stevens-Johnson syndrome, erythema multiforme, and toxic skin eruptions) with REYATAZ use. Patients developing signs or symptoms of severe skin reactions or hypersensitivity reactions (including, but not limited to, severe rash or rash accompanied by one or more of the following: fever, general malaise, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, granulocytopenia, lymphadenopathy, and renal dysfunction) must discontinue REYATAZ and seek medical evaluation immediately.

Hyperbilirubinemia

Patients should be informed that asymptomatic elevations in indirect bilirubin have occurred in patients receiving REYATAZ. This may be accompanied by yellowing of the skin or whites of the eyes and alternative antiretroviral therapy may be considered if the patient has cosmetic concerns.

Nephrolithiasis and Cholelithiasis

Patients should be informed that kidney stones and/or gallstones have been reported with REYATAZ use. Some patients with kidney stones and/or gallstones required hospitalization for additional management and some had complications. Discontinuation of REYATAZ may be necessary as part of the medical management of these adverse events.

Fat Redistribution

Patients should be informed that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy including protease inhibitors and that the cause and long-term health effects of these conditions are not known at this time.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

Long-term carcinogenicity studies in mice and rats were carried out with atazanavir for two years. In the mouse study, drug-related increases in hepatocellular adenomas were found in females at 360 mg/kg/day. The systemic drug exposure (AUC) at the NOAEL (no observable adverse effect level) in females, (120 mg/kg/day) was 2.8 times and in males (80 mg/kg/day) was 2.9 times higher than those in humans at the clinical dose (300 mg/day atazanavir boosted with 100 mg/day ritonavir, non-pregnant patients). In the rat study, no drug-related increases in tumor incidence were observed at doses up to 1200 mg/kg/day, for which AUCs were 1.1 (males) or 3.9 (females) times those measured in humans at the clinical dose.

Mutagenesis

Atazanavir tested positive in an in vitro clastogenicity test using primary human lymphocytes, in the absence and presence of metabolic activation. Atazanavir tested negative in the in vitro Ames reverse-mutation assay, in vivo micronucleus and DNA repair tests in rats, and in vivo DNA damage test in rat duodenum (comet assay).

Impairment of Fertility

At the systemic drug exposure levels (AUC) 0.9 (in male rats) or 2.3 (in female rats) times that of the human clinical dose, (300 mg/day atazanavir boosted with 100 mg/day ritonavir) significant effects on mating, fertility, or early embryonic development were not observed.

Use In Specific Populations

Pregnancy

Pregnancy Category B

Antiretroviral Pregnancy Registry:To monitor maternal-fetal outcomes of pregnant women exposed to REYATAZ, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.

Risk Summary

Atazanavir has been evaluated in a limited number of women during pregnancy and postpartum. Available human and animal data suggest that atazanavir does not increase the risk of major birth defects overall compared to the background rate. However, because the studies in humans cannot rule out the possibility of harm, REYATAZ should be used during pregnancy only if clearly needed.

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

Hyperbilirubinemia occurs frequently in patients who take REYATAZ, including pregnant women. 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.

Clinical Considerations

Dosing During Pregnancy and the Postpartum Period:

  • REYATAZ should not be administered without ritonavir.
  • REYATAZ should only be administered to pregnant women with HIV-1 strains susceptible to atazanavir.
  • For pregnant patients, no dose 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, 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 in treatment-experienced pregnant women.
  • No dose 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 and CLINICAL PHARMACOLOGY]
Human Data

Clinical Trials: In clinical trial AI424-182, REYATAZ/ritonavir (300/100 mg or 400/100 mg) in combination with zidovudine/lamivudine was administered to 41 HIV-infected pregnant women during the second or third trimester. Among the 39 women who completed the study, 38 women achieved an HIV RNA < 50 copies/mL at time of delivery. Six of 20 (30%) women on REYATAZ/ritonavir 300/100 mg and 13 of 21 (62%) women on REYATAZ/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 HIV-infected pregnant women, 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 < 40 mg/dL that could not be attributed to maternal glucose intolerance, difficult delivery, or sepsis.

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 first trimester and 160 and 50 exposed in second and third trimester, respectively). Birth defects occurred in 9 of 393 (2.3%) live births (first trimester exposure) and 5 of 212 (2.4%) live births (second/third trimester exposure). Among pregnant women in the U.S. reference population, the background rate of birth defects is 2.7%. There was no association between atazanavir and overall birth defects observed in the APR.

Pharmacokinetics of Atazanavir in Pregnancy

[See CLINICAL PHARMACOLOGY]

Animal Data

In animal reproduction studies, there was no evidence of 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 body weight loss or weight gain suppression in the animal offspring with maternal drug exposure (AUC) 1.3 times the human exposure at this clinical dose. However, maternal toxicity also occurred at this exposure level.

Nursing Mothers

The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV. It is not known whether atazanavir is present in human 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 taking REYATAZ.

Pediatric Use

REYATAZ is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in pediatric patients 3 months of age and older weighing at least 10 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]. All REYATAZ contraindications, warnings, and precautions apply to pediatric patients [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS].

The safety, pharmacokinetic profile, and virologic response of REYATAZ in pediatric patients at least 3 months of age and older weighing at least 10 kg were established in three open-label, multicenter clinical trials: PACTG 1020A, AI424-451, and AI424-397 [see CLINICAL PHARMACOLOGY and Clinical Studies]. The safety profile in pediatric patients was generally similar to that observed in adults [see ADVERSE REACTIONS]. See DOSAGE AND ADMINISTRATION for dosing recommendations for the use of REYATAZ capsules and REYATAZ oral powder in pediatric patients.

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 Cmax 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.

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.

Impaired Renal Function

REYATAZ is not recommended for use in HIV-treatment-experienced patients with end stage renal disease managed with hemodialysis. [See DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY]

Impaired Hepatic Function

REYATAZ is not recommended for use in patients with severe hepatic impairment. REYATAZ/ritonavir is not recommended in patients with any degree of hepatic impairment. [See DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY]

Last reviewed on RxList: 6/16/2014
This monograph has been modified to include the generic and brand name in many instances.

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