Drug Safety-related Labeling Changes (SrLC)

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EVOTAZ (NDA-206353)

(ATAZANAVIR SULFATE; COBICISTAT)

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

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05/12/2025 (SUPPL-9)

Approved Drug Label (PDF)

4 Contraindications

Extensive changes; please refer to label for complete information

7 Drug Interactions

Extensive changes; please refer to label for complete information

8 Use in Specific Populations

8.2 Lactation

Additions and/or revisions underlined:

Risk Summary

There is no information regarding the effects of EVOTAZ on the breastfed infant or on milk production.

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. Cobicistat is present in rat milk (see Data). There is no information regarding the presence of cobicistat in human milk, the effects on the breastfed infant, or the effects on milk production. 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 and/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:

. . .

Do not take EVOTAZ if you:

• are allergic to any of the ingredients in EVOTAZ. See the end of this leaflet for a complete list of ingredients in EVOTAZ.

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

• . . .

• Apalutamide

• Encorafenib

• Ivosidenib

. . .

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

• have heart problems

• have liver problems, including hepatitis B or C virus

• have kidney problems

• are receiving dialysis treatment

  . . .

  Pregnancy Exposure Registry. There is a pregnancy exposure registry for people who take EVOTAZ during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk to your healthcare provider about how you can take part in this registry.

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

• Talk to your healthcare provider about the following risks to your baby from breastfeeding during treatment with EVOTAZ:

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

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

• Your baby may get side effects from EVOTAZ.

. . .

How should I take EVOTAZ?

• Take EVOTAZ exactly as your healthcare provider tells you.

• Do not change your dose or stop taking EVOTAZ without talking to your healthcare provider.

• Stay under a healthcare provider’s care during treatment with EVOTAZ.

• EVOTAZ must be used with other HIV-1 medicines.

• Take EVOTAZ 1 time a day with food.

• Do not miss a dose of EVOTAZ. If you miss a dose of EVOTAZ, take it as soon as possible. Take your next dose at your normal scheduled time. Do not take 2 doses at the same time to make up for a missed dose.

  . . .

  What are the possible side effects of EVOTAZ? EVOTAZ can cause serious side effects, including:

• A change in the way your heart beats (heart rhythm change). If you have certain heart rhythm problems, your healthcare provider may check your heart rhythm with a test called an electrocardiogram (ECG). Tell your healthcare provider right away if you get dizzy or lightheaded. These could be symptoms of a heart problem.
• 
  

Severe skin reactions.

. . .

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

• Kidney stones have happened in some people who take atazanavir, one of the medicines in EVOTAZ, and sometimes may lead to hospitalization. Tell your healthcare provider right away if you get symptoms of kidney stones, which may include pain in your low back or low stomach area, blood in your urine, or pain when you urinate.

Gallbladder stones have happened in some people who take atazanavir, one of the medicines in EVOTAZ, and sometimes may lead to hospitalization. Tell your healthcare provider right away if you get symptoms of gallbladder problems, which may include:

. . .

• Diabetes and high blood sugar (hyperglycemia). New or worsening diabetes and hyperglycemia have happened in people who take protease inhibitor medicines like EVOTAZ. Some people have had to start taking medicine to treat diabetes or have had to change their diabetes medicine. Tell your healthcare provider if you notice an increase in thirst or if you start urinating more often during treatment with EVOTAZ.

. . .

How should I store EVOTAZ?

• Store EVOTAZ tablets at room temperature between 68°F and 77°F (20°C and 25°C).

• The EVOTAZ bottle contains a desiccant that helps keep your medicine dry.

• The EVOTAZ bottle has a child-resistant closure.

  . . .

05/12/2023 (SUPPL-8)

Approved Drug Label (PDF)

7 Drug Interactions

7.3 Established and Other Potentially Significant Drug Interactions

Additions and revisions to Table 5 regarding potential drug-drug interactions with concomitant drug classes of antiplatelets (i.e., ticagrelor, clopidogrel, prasugrel) and corticosteroids; please refer to label for complete information.

           

07/31/2020 (SUPPL-7)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Cardia Conduction Abnormalities

Additions and/or revisions underlined:

Atazanavir prolongs the PR interval of the electrocardiogram in some patients. 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 (6.1) and Overdosage (10)]. In clinical trials of atazanavir in subjects with HIV-1 infection that included electrocardiograms, asymptomatic first-degree AV block was observed in 6% of subjects treated with atazanavir (n=920) and 5% of subjects (n=118) treated with atazanavir coadministered with ritonavir.

5.11 Immune Reconstitution Syndrome

… 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 …

6 Adverse Reactions

6.1 Clinical Trial Experience

Additions and/or revisions underlined:

Adverse Reactions from Clinical Trial Experience in Adult Subjects

The safety of atazanavir and cobicistat coadministered as single agents is based on Week 144 data from a Phase 3 trial, Study GS-US-216-0114, in which 692 antiretroviral treatment-naive subjects with HIV-1 infection received … Table 2 lists the frequency of adverse reactions (Grades 2-4) occurring in at least 2% of subjects in the atazanavir coadministered with cobicistat group in Study GS-US-216-0114.

Laboratory Abnormalities

The frequency of laboratory abnormalities (Grades 3-4) occurring in at least 2% of subjects in the atazanavir coadministered with cobicistat group in Study GS-US-216-0114 is presented in Table 3. Throughout the remainder of the subsection. Study 114 is referred to as GS-US-216-0114

Newly added information following Table 4:

Adverse Reactions from Clinical Trial Experience in Pediatric Subjects

Although no clinical trial with EVOTAZ as the fixed-dose tablet was conducted in a pediatric population, the safety of atazanavir coadministered with cobicistat plus two nucleoside reverse transcriptase inhibitors was evaluated in treatment-experienced virologically suppressed subjects with HIV-1 infection between the ages of 12 to less than 18 years (N=14) through Week 48 in an open-label clinical trial (Study GS-US-216-0128) [see Clinical Studies (14.2)]. Results from this study showed that the safety profile of atazanavir and cobicistat coadministered with a background regimen was similar to that in adults.

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

The safety and effectiveness of EVOTAZ for the treatment of HIV-1 infection in pediatric subjects weighing at least 35 kg was established through a study with components of EVOTAZ. Use of EVOTAZ for this indication is supported by evidence from adequate and well-controlled studies in adults, and by pharmacokinetic, safety, and virologic data from an open-label trial of components of EVOTAZ (Study GS-US-216-0128) in pediatric subjects with HIV-1 infection aged 12 years and older. The safety in these subjects through 48 weeks was similar to that in antiretroviral treatment-naive adults [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.2)].

Safety and effectiveness of EVOTAZ in the pediatric population weighing less than 35 kg have not been established. Atazanavir, a component of EVOTAZ, is not recommended for use in pediatric patients below the age of 3 months due to the risk of kernicterus.

8.6 Renal Impairment

EVOTAZ 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 (2.3), Warnings and Precautions (5.3), and Clinical Pharmacology (12.3)].

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

PATIENT INFORMATION

Additions and/or revisions underlined:

What is EVOTAZ?

EVOTAZ is a prescription medicine that is used with other HIV-1 medicines to treat HIV-1 infection in adults and children weighing at least 77 pounds (35 kg) …

… It is not known if EVOTAZ is safe and effective in children who weigh less than 77 pounds (35 kg).

04/22/2020 (SUPPL-6)

Approved Drug Label (PDF)

4 Contraindications

Additions and/or revisions underlined:

The concomitant use of EVOTAZ and the following drugs in Table 1, are contraindicated due to the potential for serious and/or life-threatening events or loss of therapeutic effect [see Warnings and Precautions (5.8, 5.9), Drug Interactions (7) and Clinical Pharmacology (12.3)] …

• when coadministered with drugs that strongly induce CYP3A and may lead to lower exposure and loss of efficacy of EVOTAZ (see Table 1).

For additional information, including clinical comments and potential impact on exposure levels associated with drugs that are contraindicated with EVOTAZ, refer to Table 5 [see Drug Interactions (7.3)].

Table 1: Drugs Contraindicated with EVOTAZ

Table formatting has changed; please refer to the label.

In the Antigout drug class, the following language is added after colchicine: ‘(when used in patients with hepatic and/or renal impairment)’

In Lipid-modifying Agents, ‘lomitapide’ added to lovastatin and simvastatin

5 Warnings and Precautions

5.4 New Onset or Worsening Renal Impairment When Used with Tenofovir DF

Additions and/or revisions underlined:

In a clinical trial over 144 weeks (N=692), 10 (2.9%) subjects … One subject in the cobicistat group had renal impairment at baseline (e.g., estimated creatinine clearance less than 70 mL/min). The laboratory findings in these 7 subjects treated with cobicistat, with evidence of proximal tubulopathy …

7 Drug Interactions

Additions and/or revisions underlined:

7.2 Potential for Other Drugs to Affect EVOTAZ

… Atazanavir solubility decreases as pH increases. Reduced plasma concentrations of atazanavir are

expected if proton-pump inhibitors, antacids, buffered medications, or H2-receptor antagonists are

administered with EVOTAZ (see Table 5) …

7.3 Established and Other Potentially Significant Drug Interactions

Table 5: Established and Other Potentially Significant Drug Interactions with EVOTAZ: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studiesa or Predicted Interactions

Numerous additions and/or revisions to table data; please refer to label for complete information.

8 Use in Specific Populations

8.1 Pregnancy

Throughout subsection, the words ‘woman’ and ‘women’ are replaced by ‘individual’ or ‘individuals’

Risk Summary

Newly added information:

EVOTAZ is not recommended for use during pregnancy and should not be initiated in pregnant individuals [see Dosage and Administration (2.5)]; use of an alternative regimen is recommended for individuals who become pregnant during therapy with EVOTAZ. Pharmacokinetic data from studies conducted in pregnant individuals receiving cobicistat showed substantially lower exposure during the second and third trimesters, and consequently also for the coadministered antiretroviral agent. Consult the full prescribing information for cobicistat for additional information. Pharmacokinetic data from the evaluation of atazanavir and cobicistat in a limited number of pregnant individuals showed a similar trend in lower exposures of the antiretroviral component atazanavir.

Clinical Considerations

EVOTAZ is not recommended for use during pregnancy and should not be initiated in pregnant individuals. An alternative regimen is recommended for individuals who become pregnant during therapy with EVOTAZ (see Risk Summary).

Data

Human Data

Atazanavir

Additions and/or revisions underlined:

The APR has received prospective reports of live births following exposure to atazanavir containing regimens during pregnancy, including 1361 exposures in the first trimester and 737 exposures in second/third trimester. Birth defects occurred in live births in 30 of 1361 (2.2%, 95% CI: 1.5% to 3.1%) with first trimester exposure to atazanavir-containing regimens and 17 of 737 (2.3%, 95% CI: 1.3% to 3.7%) with second/third trimester exposure to atazanavir-containing regimens. There was no increase in the overall rate of birth defects for atazanavir compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP.

Cobicistat

The APR has received prospective reports of live births following exposure to cobicistat containing regimens during pregnancy, including 347 exposures in the first trimester and 79 exposures in the second/third trimester. Birth defects occurred in 13 of 347 (3.7%, 95% CI: 2.0% to 6.3%) live births with first trimester exposure and 1 of 79 (1.3%, 95% CI: 0.0% to 6.9%) with second/third trimester exposure to cobicistat-containing regimens. Among pregnant individuals in the U.S. reference population, the background rate of birth defects is 2.7%. There was no increase in the overall rate of birth defects for cobicistat compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. Methodological limitations of the APR include the use of MACDP as the external comparator group. Limitations of using an external comparator include differences in methodology and populations, as well as confounding due to the underlying disease.

Newly added subsection:

8.3 Females and Males of Reproductive Potential

Contraception

Atazanavir and cobicistat, components of EVOTAZ, interact with certain oral contraceptives [see Contraindications (4) and Drug Interactions (7.3)]. Nonhormonal forms of contraceptive should be considered.

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

PATIENT COUNSELING INFORMATION

Following ‘Fat Redistribution’, newly added information:

Not Recommended During Pregnancy

Advise patients that EVOTAZ is not recommended during pregnancy and to alert their healthcare provider if they get pregnant while taking EVOTAZ [see Use in Specific Populations (8.1)].

Additions and/or revisions underlined:

Pregnancy Registry

Inform patients that there is a pregnancy exposure registry to monitor fetal outcomes of pregnant individuals exposed to EVOTAZ during pregnancy [see Use in Specific Populations (8.1)].

Lactation

Advise individuals with HIV-1 infection …

PATIENT INFORMATION

Additions and/or revisions underlined:

Who should not take EVOTAZ?

Do not take EVOTAZ if you:

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

  • lomitapide

Before taking EVOTAZ, tell your healthcare provider about all of your medical conditions,

including if you:

• are pregnant or plan to become pregnant. It is not known if EVOTAZ will harm your unborn baby.

  • EVOTAZ should not be used during pregnancy, because the EVOTAZ levels in your blood may be lower during pregnancy and may not control your HIV-1.

  • Tell your healthcare provider right away if you become pregnant during treatment with EVOTAZ.

  • Your healthcare provider may prescribe different medicines if you become pregnant during treatment with EVOTAZ.

  • People who are pregnant have developed a serious condition called lactic acidosis …

How should I take EVOTAZ?

• Do not miss a dose of EVOTAZ.

• When your EVOTAZ supply starts to run low, get more from your healthcare provider or pharmacy. This is very important because the amount of virus in your blood may increase if the medicine is stopped for even a short time. The virus may develop resistance to EVOTAZ and become harder to treat.

04/18/2018 (SUPPL-5)

Approved Drug Label (PDF)

4 Contraindications

(additions to Table 1, please refer to label)

5 Warnings and Precautions

5.5 Chronic Kidney Disease

(new subsection added)

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 EVOTAZ 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 EVOTAZ and continued during treatment with EVOTAZ. Expert consultation is advised for patients who have confirmed renal laboratory abnormalities while taking EVOTAZ. In patients with progressive kidney disease, discontinuation of EVOTAZ may be considered.

6 Adverse Reactions

(additions underlined)

 

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

• cardiac conduction abnormalities

• rash

• effects on serum creatinine

• new onset or worsening renal impairment when used with tenofovir DF

• chronic kidney disease

• nephrolithiasis and cholelithiasis

• hepatotoxicity

• hyperbilirubinemia

7 Drug Interactions

7.3 Established and Other Potentially Significant Drug Interactions

(additions to Table 5, please refer to label)

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

PATIENT COUNSELING INFORMATION

(additions underlined)

…

Chronic Kidney Disease

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

…

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 breast milk. Atazanavir, a component of EVOTAZ, can also be passed to the baby in breast milk, and it is not known whether it could harm the baby.

PATIENT INFORMATION

(additions underlined)

…

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

• are allergic to any of the ingredients in EVOTAZ. See the end of this leaflet for a complete list of ingredients in EVOTAZ.

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

  …

  • drospirenone/ethinyl estradiol (BEYAZ, SAFYRAL, YASMIN, YAZ)

  • elbasvir/grazoprevir (ZEPATIER)

    …

               

    What are the possible side effects of EVOTAZ? EVOTAZ can cause serious side effects, including:

    …

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

…

01/27/2017 (SUPPL-3)

Approved Drug Label (PDF)

4 Contraindications

Table 1 displays drugs that are contraindicated with EVOTAZ. (Table has been revised; please refer to label)

5 Warnings and Precautions

5.4 New Onset or Worsening Renal Impairment When Used with Tenofovir DF

(Additions and/or revisions are underlined)

In a clinical trial over 144 weeks (N=692), 10 (2.9%) subjects treated with atazanavir coadministered with cobicistat and tenofovir DF and 11 (3.2%) subjects treated with atazanavir coadministered with ritonavir and tenofovir DF discontinued study drug due to a renal adverse event. Seven of the 10 subjects (2.0% overall) in the cobicistat group had laboratory findings consistent with proximal renal tubulopathy leading to study drug discontinuation, compared to 7 of 11 subjects (2.0% overall) in the ritonavir group. One subject in the cobicistat group had renal impairment at baseline (e.g., estimated creatinine clearance less than 70 mL/min). The laboratory findings in these 7 subjects with evidence of proximal tubulopathy improved but did not completely resolve in all subjects upon discontinuation of cobicistat coadministered with atazanavir and tenofovir DF.

5.7 Risk of Serious Adverse Reactions or Loss of Virologic Response Due to Drug Interactions

(Additions and/or revisions are underlined)

Increased concentrations of EVOTAZ may lead to: …

 

Decreased concentrations of EVOTAZ may lead to:…

6 Adverse Reactions

6.1 Clinical Trial Experience in Adults

(Additions and/or revisions are underlined)

The safety of atazanavir and cobicistat coadministered as single agents is based on Week 144 data from a Phase 3 trial, Study 114, in which 692 HIV-1 infected, antiretroviral treatment-naive subjects received:

• atazanavir coadministered with cobicistat and emtricitabine/tenofovir DF (N=344) or

• atazanavir coadministered with ritonavir and emtricitabine/tenofovir DF (N=348).

The most common adverse reactions (Grades 2-4) and reported in greater than or equal to 5% of subjects in the atazanavir coadministered with cobicistat group were jaundice (6%) and rash (5%).

The proportion of subjects who discontinued study treatment due to adverse events regardless of severity was 11% in both the atazanavir coadministered with cobicistat and atazanavir coadministered with ritonavir groups.

Table 2: Selected Adverse Reactionsa (Grades 2-4) Reported in =2% of HIV-1 Infected Treatment-Naive Adults in the Atazanavir Coadministered with Cobicistat Group in Study 114 (Week 144 analysis) (Table has been revised; please refer to label)

 

Less Common Adverse Reactions

Renal and Urinary Disorders: nephropathy, Fanconi syndrome acquired, nephrolithiasis

Table 3: Laboratory Abnormalities (Grades 3-4) Reported in =2% of HIV-1 Infected Treatment-Naive Adults in the Atazanavir Coadministered with Cobicistat Group in Study 114 (Week 144 analysis) (Table has been revised; please refer to label)

Increase in Serum Creatinine: … The mean (plus or minus SD) change in estimated glomerular filtration rate (eGFR) by Cockcroft-Gault method after 144 weeks of treatment was 15.1 plus or minus 16.5 mL/min in the atazanavir coadministered with cobicistat group and 8.0 plus or minus 16.8 mL/min in the atazanavir coadministered with ritonavir group.

Table 4: Lipid Values, Mean Change from Baseline, Reported in HIV-1 Infected Treatment-Naive Adults Receiving Atazanavir Coadministered with Cobicistat and Emtricitabine/Tenofovir DF or Atazanavir Coadministered with Ritonavir and Emtricitabine/Tenofovir DF in Study 114 (Week 144 analysis) (Table has been revised; please refer to label)

8 Use in Specific Populations

8.1 Pregnancy

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; Additions and/or revisions are underlined)

Pregnancy xposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to EVOTAZ during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.

 

Risk Summary

Prospective pregnancy data from the Antiretroviral Pregnancy Registry (APR) are not sufficient to adequately assess the risk of birth defects or miscarriage. Cobicistat use in women during pregnancy has not been evaluated; however, atazanavir use during pregnancy has been evaluated in a limited number of women. The pharmacokinetics of EVOTAZ have not been evaluated in pregnant patients. Available data from the APR show no difference in the risk of overall major birth defects for atazanavir compared with the background rate for major birth defects of 2.7% in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP).

In animal reproduction studies, no evidence of adverse developmental outcomes was observed following oral administration of the components of EVOTAZ (atazanavir or cobicistat) to pregnant rats and rabbits. During organogenesis in the rat and rabbit, atazanavir exposures (AUC) were similar to those observed at the human clinical dose (300 mg/day atazanavir boosted with 100 mg/day ritonavir), while exposures were up to 1.4 (rats) and 3.3 (rabbits) times human exposures at the maximal recommended human dose (MRHD) of 150 mg.

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

 

Clinical Considerations

 

Dose Adjustment During Pregnancy and the Postpartum Period

Dosing recommendations cannot be made because the pharmacokinetics, safety, and efficacy of EVOTAZ cannot be predicted from studies of other atazanavir-containing products in pregnant women.

 

Maternal Adverse Reactions

Atazanavir

…Refer to the atazanavir prescribing information for use of atazanavir in pregnancy.

Advise pregnant women of the potential risks of lactic acidosis syndrome and hyperbilirubinemia.

 

Fetal/Neonatal Adverse Reactions

Atazanavir

Advise pregnant women of the potential risk to newborn infants. Refer to the atazanavir prescribing information for use of atazanavir in pregnancy.

 

Data

Human Data

Atazanavir

Based on prospective reports from the interim APR of approximately 1600 live births following exposure to atazanavir-containing regimens (including 1037 live births in infants exposed in the first trimester and 569 exposed in second/third trimesters), there was no difference in the overall rate for birth defects for atazanavir (2.3%) compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. Based on prospective reports to the APR, the prevalence of birth defects in live births was 2.1% following first trimester exposure to atazanavir-containing regimens.

 

CobicistatInsufficient numbers of pregnancies with exposure to cobicistat have been reported to the APR to estimate the rate of birth defects.

 

Animal Data

Atazanavir was administered orally to pregnant rats (at 0, 200, 600, and 1920 mg/kg/day) and rabbits (at 0, 4, 15, and 60 mg/kg/day) during organogenesis (on gestation Days 6 through 15 and through 19, respectively). No significant toxicological effects were observed in embryo-fetal toxicity studies performed with atazanavir 100 mat exposures (AUC) approximately 1.2 times higher (rats) and 0.7 times (rabbits) human exposures at the MRHD. In a rat pre- and postnatal developmental study, atazanavir was administered orally at doses of 0, 50, 220, and 1000 mg/kg/day from gestation Day 6 to postnatal Day 20. At a maternal toxic dose (1000 mg/kg/day), atazanavir caused body weight loss or weight gain suppression in the animal offspring at atazanavir exposures  (AUC) of approximately 1.3 times higher than human exposures at the MRHD.

 

Cobicistat

Cobicistat was administered orally to pregnant rats at doses of 0, 25, 50, 125 mg/kg/day on gestation Day 6 to 17. Maternal toxicity was noted at 125 mg/kg/day and was associated with increases in post-implantation loss and decreased fetal weights. No malformations were noted at doses up to 125 mg/kg/day. Systemic exposures (AUC) at 50 mg/kg/day in pregnant females were 1.4 times higher than the human exposures at the MRHD. In pregnant rabbits, cobicistat was administered orally at doses of 0, 20, 50, and 100 mg/kg/day during the gestation Days 7 to 20. No maternal or embryo/fetal effects were noted at the highest dose of 100 mg/kg/day. Systemic exposures (AUC) at 100 mg/kg/day were 3.3 times higher than exposures at the MRHD.

In a pre- and postnatal developmental study in rats, cobicistat was administered orally at doses of 0, 10, 30, and 75 mg/kg from gestation Day 6 to postnatal Day 20, 21, or 22. At doses of 75 mg/kg/day of cobicistat, neither maternal nor developmental toxicity was noted. Systemic exposures (AUC) at this dose were 0.9 times lower than exposures at the MRHD.

8.2 Lactation

(Pregnancy and Lactation Labeling Rule (PLLR) Conversion; Additions and/or revisions are underlined)

Risk Summary

There is no information regarding the effects of EVOTAZ on the breastfed infant or on milk production.

Atazanavir has been detected in human milk. No data are available regarding atazanavir effects on milk production. Cobicistat is present in rat milk. There is no information regarding the presence of cobicistat in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for (1) HIV transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants), and (3) adverse reactions in a breastfed infant, instruct women not to breastfeed.

 

Data

Animal Data

Cobicistat: During the prenatal and postnatal development toxicology study at doses up 75 mg/kg/day, mean cobicistat milk to plasma ratio of up to 1.9 was measured 2 hours after administration to rats on lactation Day 10.

8.7 Hepatic Impairment

(Additions and/or revisions are underlined)

EVOTAZ is not recommended for use in patients with any degree of hepatic impairment.

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

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Instructions for Use

…Inform patients to avoid missing doses as it can result in development of resistance, and not to discontinue therapy without consulting with their healthcare provider. Advise patients if a dose of EVOTAZ is missed, they 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.

Drug Interactions

EVOTAZ may interact with many drugs; therefore, inform patients of the potential for serious drug interactions with EVOTAZ, and that some drugs are contraindicated with EVOTAZ and other drugs require dosage adjustment.

Pregnancy Registry

Inform patients that there is a pregnancy exposure registry to monitor fetal outcomes of pregnant women exposed to EVOTAZ.

Lactation

Instruct women with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in breast milk.

PATIENT INFORMATION

(Additions and/or revisions are underlined)

How should I take EVOTAZ?

• If you miss a dose of EVOTAZ, take the dose as soon as possible and then return to your normal schedule.

What are the possible side effects of EVOTAZ? EVOTAZ can cause serious side effects, including:

…The most common side effects of EVOTAZ were yellowing of the skin and rash.

07/01/2016 (SUPPL-2)

Approved Drug Label (PDF)

4 Contraindications

Table 1: Drugs that are Contraindicated with EVOTAZ

• Anticonvulsants Drug Class added to table containing the following drugs: carbamazepine, phenobarbital and phenytoin with the following clinical comment: Potential for decreased atazanavir plasma concentrations, which may result in loss of therapeutic effect and development of resistance.

5 Warnings and Precautions

Severe Skin Reactions replaces Rash

 

7 Drug Interactions

Table 5: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studiesa or Predicted Interactions

• Addition of Anticonvulsants concomitant Drug Class to table, including:
  • Anticonvulsants with CYP3A induction effects that are NOT contraindicated (eslicarbazepine, and oxcarbazepine).
  • Anticonvulsants that are metabolized by CYP3A (clonazepam)
  • Other anticonvulsants (lamotrigine)

• Please refer to table 5 for effects on concentration and clinical comments.

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

PCI - Severe Skin Reactions replaces Rash

 

PI - Who should not take EVOTAZ?

• Do not take EVOTAZ if you:
• are taking any of the following medicines…: (additions)
• carbamazepine (CARBATROL®, EPITOL®, EQUETRO®, TEGRETOL®)
• phenobarbital (LUMINAL®)
• phenytoin (DILANTIN®, PHENYTEX®)