Drug Safety-related Labeling Changes (SrLC)

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REYATAZ (NDA-021567)

(ATAZANAVIR SULFATE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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12/05/2024 (SUPPL-49)

Approved Drug Label (PDF)

4 Contraindications

Additions and/or revisions underlined:

…

• when coadministered with drugs that are strong inducers of CYP3A due to the potential for loss of therapeutic effect and development of resistance.

 Coadministration is contraindicated with, but not limited to, the following drugs listed in Table 6:

Please refer to label to view Table 6.

8 Use in Specific Populations

8.2 Lactation

Additions and/or revisions underlined:

…

Potential risks of breastfeeding include: (1) HIV-1 transmission (in infants without HIV-1), (2) developing viral resistance (in infants with HIV-1), and (3) adverse reactions in a breastfed infant similar to those seen in adults.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Additions ad/or revisions underlined:

…

Lactation

Instruct patients with HIV-1 that the potential risks of breastfeeding include: (1) HIV-1 transmission to infants without HIV-1, (2) developing viral resistance in infants with HIV-1, and

(3) adverse reactions in a breastfed infant similar to those seen in adults [see Use in Specific Populations (8.2)].

PATIENT INFORMATION

Additions and/or revisions underlined:

…

Before taking REYATAZ, tell your healthcare provider about all of your medical conditions, including if you:

…

 

• are breastfeeding or plan to breastfeed. REYATAZ can pass into your breast milk.

  • Talk to your healthcare provider about the following risks of breastfeeding during treatment with REYATAZ:

    • The HIV-1 virus may pass to your baby if your baby does not have the HIV-1 virus.

    • The HIV-1 virus may become harder to treat if your baby has the HIV-1 virus.

    • Your baby may get side effects from REYATAZ.

…

11/07/2023 (SUPPL-48)

Approved Drug Label (PDF)

4 Contraindications

(Additions and/or revisions underlined)

Table 6: Drugs Contraindicated with REYATAZ (Information in the table applies to REYATAZ with or without ritonavir, unless otherwise indicated)

…

Anticonvulsants       Carbamazepine, phenobarbital, phenytoin

Antimycobacterials  Rifampin

Antineoplastics        Apalutamide, encorafenib, irinotecan, ivosidenib

…

5 Warnings and Precautions

5.7 Risk of Serious Adverse Reactions Due to Drug Interactions

(Additions and/or revisions underlined)

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 (virologic response) of REYATAZ with ritonavir and possible development of resistance.

09/24/2020 (SUPPL-44)

Approved Drug Label (PDF)

4 Contraindications

(Extensive changes; please refer to label)

5 Warnings and Precautions

5.1 Cardiac Conduction Abnormalities

(Additions and/or revisions underlined)

REYATAZ has been shown to prolong the PR interval of the electrocardiogram in some subjects. In healthy subjects and in subjects with HIV-1 infection 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 (6.2) and Overdosage (10)]. In clinical trials that included electrocardiograms, asymptomatic first-degree AV block was observed in 5.9% of atazanavir- treated subjects (n=920), 5.2% of lopinavir/ritonavir-treated subjects (n=252), 10.4% of nelfinavir- treated subjects (n=48), and 3.0% of efavirenz-treated subjects (n=329). In Study AI424-045, asymptomatic first-degree AV block was observed in 5% (6/118) of atazanavir with ritonavir- treated subjects and 5% (6/116) of lopinavir/ritonavir-treated subjects 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 (12.2)].

5.10 Immune Reconstitution Syndrome

(Additions and/or revisions underlined)

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, Guillain-Barré syndrome, and autoimmune hepatitis) 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.

5.2 Severe Skin Reactions

(Additions and/or revisions underlined)

In controlled clinical trials, rash (all grades, regardless of causality) occurred in approximately 20% of subjects with HIV-1 infection 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 greater than or equal to 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.

5.5 Chronic Kidney Disease

(Additions and/or revisions underlined)

Chronic kidney disease in patients with HIV-1 infection treated with atazanavir, with or without ritonavir, has been reported during postmarketing surveillance. Reports included biopsy-proven cases of granulomatous interstitial nephritis associated with the deposition of atazanavir drug crystals in the renal parenchyma. Consider alternatives to REYATAZ in patients at high risk for renal disease or with preexisting renal disease. Renal laboratory testing (including serum creatinine, estimated creatinine clearance, and urinalysis with microscopic examination) should be conducted in all patients prior to initiating therapy with REYATAZ and continued during treatment with REYATAZ. Expert consultation is advised for patients who have confirmed renal laboratory abnormalities while taking REYATAZ. In patients with progressive kidney disease, discontinuation of REYATAZ may be considered [see Dosage and Administration (2.2 and 2.7) and Adverse Reactions (6.2)].

5.6 Nephrolithiasis and Cholelithiasis

(Additions and/or revisions underlined)

Cases of nephrolithiasis and/or cholelithiasis have been reported during postmarketing surveillance in patients with HIV-1 infection 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

(Additions and/or revisions underlined)

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 therapy containing REYATAZ with ritonavir; and monitor for the adverse reactions associated with concomitant medications [see Contraindications (4) and Drug Interactions (7)].

5.9 Diabetes Mellitus/Hyperglycemia

(Additions and/or revisions underlined)

New-onset diabetes mellitus, exacerbation of preexisting diabetes mellitus, and hyperglycemia have been reported during postmarketing surveillance in patients with HIV-1 infection 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)].

6 Adverse Reactions

6.1 Clinical Trial Experience

(Extensive changes; please refer to label)

7 Drug Interactions

7.3 Established and Other Potentially Significant Drug Interactions

(Extensive changes; please refer to label)

8 Use in Specific Populations

8.1 Pregnancy

(Extensive changes; please refer to label)

8.2 Lactation

(Additions and/or revisions underlined)

Risk Summary

The Centers for Disease Control and Prevention recommend that patients with HIV-1 infection, not breastfeed their infants to avoid risking postnatal transmission of HIV-1. Atazanavir has been detected in human milk. No data are available regarding atazanavir effects on milk production. Atazanavir was present in the milk of lactating rats and was associated with neonatal growth retardation that reversed after weaning.

Because of both the potential for HIV-1 transmission and the potential for serious adverse reactions in breastfed infants, advise women not to breastfeed.

8.4 Pediatric Use

(Additions and/or revisions underlined)

REYATAZ is indicated in combination with other antiretroviral agents for the treatment of pediatric patients with HIV-1 infection, 3 months of age and older weighing at least 5 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 (1)]. All REYATAZ contraindications, warnings, and precautions apply to pediatric patients [see Contraindications (4) and Warnings and Precautions (5)].

The safety, pharmacokinetic profile, and virologic response of REYATAZ in pediatric patients at least 3 months of age and older weighing at least 5 kg were established in three open-label, multicenter clinical trials: PACTG 1020A, AI424-451, and AI424-397 [see Clinical Pharmacology (12.3) and Clinical Studies (14.3)]. The safety profile in pediatric patients was generally similar to that observed in adults [see Adverse Reactions (6.1)]. See Dosage and Administration (2.4, 2.5) for dosing recommendations for the use of REYATAZ capsules and REYATAZ oral powder in pediatric patients.

8.7 Impaired Renal Function

(Additions and/or revisions underlined)

REYATAZ is not recommended for use in treatment-experienced patients with HIV-1 infection, who have end-stage renal disease managed with hemodialysis [see Dosage and Administration (2.7) and Clinical Pharmacology (12.3)].

8.8 Impaired Hepatic Function

(Additions and/or revisions underlined)

REYATAZ is not recommended for use in patients with severe hepatic impairment. REYATAZ with ritonavir is not recommended in patients with any degree of hepatic impairment [see Dosage and Administration (2.8) and Clinical Pharmacology (12.3)].

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

REYATAZ is not a cure for HIV-1 infection. Advise patients to remain under the care of a healthcare provider while using REYATAZ.

…

Pregnancy

Inform pregnant patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in pregnant patients exposed to REYATAZ during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry [see Use in Specific Populations (8.1)].

PATIENT INFORMATION

(Extensive changes; please refer to label)

04/18/2018 (SUPPL-42)

Approved Drug Label (PDF)

4 Contraindications

(additions to Table 6, please refer to label)

7 Drug Interactions

7.3 Established and Other Potentially Significant Drug Interactions

(additions to Table 16, please refer to label)

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT INFORMATION

(additions underlined)

…

Who should not take REYATAZ? Do not take REYATAZ if you:

• are allergic to atazanavir or any of the ingredients in REYATAZ. See the end of this

leaflet for a complete list of ingredients in REYATAZ.

• are taking any of the following medicines. Taking REYATAZ with these medicines may affect how REYATAZ works. REYATAZ may cause serious life-threatening side effects or death when used with these medicines:

   

  …

• dihydroergotamine mesylate (D.H.E. 45, MIGRANAL)

• methylergonovine (METHERGINE)

• oglecaprevir/pibrentasvir (MAVYRET)

• oindinavir (CRIXIVAN)

• oirinotecan (CAMPTOSAR)

• olurasidone (LATUDA) if REYATAZ is used with ritonavir (NORVIR)

  
  

…

10/20/2017 (SUPPL-41)

Approved Drug Label (PDF)

4 Contraindications

Table 6: Drugs that are Contraindicated with REYATAZ (Information in the table applies to REYATAZ with or without ritonavir, unless otherwise indicated)

(Table has been revised; please refer to label)

5 Warnings and Precautions

5.5 Chronic Kidney Disease

(Newly added subsection)

Chronic kidney disease in HIV-infected patients treated with atazanavir, with or without ritonavir, has been reported during postmarketing surveillance. Reports included biopsy-proven cases of granulomatous interstitial nephritis associated with the deposition of atazanavir drug crystals in the renal parenchyma. Consider alternatives to REYATAZ in patients at high risk for renal disease or with preexisting renal disease. Renal laboratory testing (including serum creatinine, estimated creatinine clearance, and urinalysis with microscopic examination) should be conducted in all patients prior to initiating therapy with REYATAZ and continued during treatment with REYATAZ. Expert consultation is advised for patients who have confirmed renal laboratory abnormalities while taking REYATAZ. In patients with progressive kidney disease, discontinuation of REYATAZ may be considered.

6 Adverse Reactions

(Additions and/or revisions are underlined)

The following adverse reactions are discussed in greater detail in other sections of the labeling:

• chronic kidney disease

6.2 Postmarketing Experience

(Additions and/or revisions are underlined)

Renal System: nephrolithiasis, interstitial nephritis, granulomatous interstitial nephritis, chronic kidney disease

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Chronic Kidney Disease

Inform patients that treatment with REYATAZ may lead to the development of chronic kidney disease, and to maintain adequate hydration while taking REYATAZ.

PATIENT INFORMATION

(Additions and/or revisions are underlined)

Who should not take REYATAZ?

Do not take REYATAZ if you:

• elbasvir/grazoprevir (ZEPATIER®)

What are the possible side effects of REYATAZ?

REYATAZ can cause serious side effects, including:

• Chronic kidney disease. REYATAZ may affect how well your kidneys work. Your healthcare provider will do blood and urine tests to check your kidneys before you start REYATAZ and during treatment.

05/23/2017 (SUPPL-40)

Approved Drug Label (PDF)

4 Contraindications

Table 6 Drugs that are Contraindicated with REYATAZ (Information in the table applies to REYATAZ with or without ritonavir, unless otherwise indicated) This table has undergone changes; please refer to label.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Addition of the following:

Immune Reconstitution Syndrome

Advise patients to inform their healthcare provider immediately of any symptoms of infection, as in some patients with advanced HIV infection (AIDS), signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started.

Lactation

Instruct women with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in the breast milk. REYATAZ can also be passed to the baby in breast milk and it is not known whether it could harm the baby.

09/15/2016 (SUPPL-39)

Approved Drug Label (PDF)

4 Contraindications

Table 6- Drugs that are Contraindicated with REYATAZ (Information in the table applies to       REYATAZ with or without ritonavir, unless otherwise indicated)

Drug Class : Antipsychotics (added)

                  Lurasidone

                    Clinical Comment : Potential for serious and/or life-threatening reactions if REYATAZ is coadministered with ritonavir.

                  Pimozide

                  Clinical Comment : Potential for serious and/or life-threatening reactions such as cardiac arrhythmias.

7 Drug Interactions

7.3 Established and Other Potentially Significant Drug Interactions

Table 16: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studiesa or Predicted Interactions (Information in the table applies to REYATAZ with or without ritonavir, unless otherwise indicated)

 

Concomitant Drug Class:

Specific Drugs:

            Antipsychotics- Lurasidone (added)

Effect on Concentration of Atazanavir or Concomitant Drug::

                  REYATAZ: Lurasidone concentration will increase

Clinical Comment: If coadministration is necessary, reduce the lurasidone dose. Refer to the lurasidone prescribing informationfor concomitant use with moderate CYP3A4 inhibitors.

 

                  REYATAZ/ritonavir: Lurasidone concentration will increase

Clinical Comment: Use of lurasidone is contraindicated.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

Do not take REYATAZ if you:

 are taking any of the following medicines. Taking REYATAZ with these medicines may affect how REYATAZ works. REYATAZ may cause serious life-threatening side effects or death when used with these medicines:

o   lurasidone (LATUDA) if REYATAZ is used with ritonavir (NORVIR)- (added)