Drug Safety-related Labeling Changes (SrLC)

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PREZCOBIX (NDA-205395)

(COBICISTAT; DARUNAVIR ETHANOLATE)

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

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05/29/2019 (SUPPL-14)

Approved Drug Label (PDF)

4 Contraindications

(additions underlined)

PREZCOBIX is contraindicated in patients receiving the following co-administered drugs.

  • Cardiac Disorders: dronedarone, ivabradine, ranolazine

  • Opioid Antagonist: naloxegol

5 Warnings and Precautions

5.10 Immune Reconstitution Syndrome

(additions underlined)

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 antiretroviral treatment.

6 Adverse Reactions

(addition underlined)

  • Immune Reconstitution Syndrome

7 Drug Interactions

7.3 Established and Other Potentially Significant Drug Interactions

(extensive additions and deletions, please refer to label)

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

PATIENT INFORMATION

(additions underlined)

Who should not take PREZCOBIX?

Do not take PREZCOBIX with any medicine that contains:

  • ivabradine

 

  • naloxegol


 

01/28/2019 (SUPPL-12)

Approved Drug Label (PDF)

7 Drug Interactions

7.3 Established and Other Potentially Significant Drug Interactions

Table 1 Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended

Addition of information that coadministration with hepatitis C virus direct acting antivirals, glecaprevir/pibrentasvir is not recommended; please refer to label for complete information.

09/07/2018 (SUPPL-10)

Approved Drug Label (PDF)

4 Contraindications

4 CONTRAINDICATIONS

(Additions and/or revisions are underlined)

  • Hepatitis C direct acting antiviral: elbasvir/grazoprevir

  • HMG-CoA reductase Lipid modifying agents: lomitapide, lovastatin, simvastatin

  • PDE-5 inhibitor: sildenafil when used for treatment of pulmonary arterial hypertension

  • Sedatives/hypnotics: orally administered midazolam, triazolam

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions are underlined)

Pregnancy Exposure Registry

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

Risk Summary

There are insufficient data with PREZCOBIX in pregnant individuals from the APR to inform a drug-associated risk of pregnancy outcomes. Available data from the APR show no difference in rate of overall birth defects for darunavir 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) (see Data). The APR uses the MACDP as the U.S. reference population for birth defects in the general population. The MACDP evaluates pregnant individuals and infants from a limited geographic area and does not include outcomes for births that occurred at less than 20 weeks gestation.

Clinical Considerations

Not Recommended During Pregnancy

PREZCOBIX is not recommended for use during pregnancy because of substantially lower exposures of darunavir and cobicistat during pregnancy.

PREZCOBIX should not be initiated in pregnant individuals. An alternative regimen is recommended for individuals who become pregnant during therapy with PREZCOBIX.

Data

Human Data

Darunavir/Cobicistat: PREZCOBIX in combination with a background regimen was evaluated in a clinical trial of 7 pregnant individuals taking PREZCOBIX prior to enrollment and who were willing to remain on PREZCOBIX throughout the study. The study period included the second and third trimesters, and through 12 weeks postpartum. Six pregnant individuals completed the trial.

Exposure to darunavir and cobicistat as part of an antiretroviral regimen was substantially lower during the second and third trimesters of pregnancy compared with postpartum.

One out of 6 pregnant individuals who completed the study experienced virologic failure with HIV-1 RNA >1,000 copies/mL from the third trimester visit through the postpartum period. Five pregnant individuals had sustained virologic response (HIV RNA <50 copies/mL) throughout the study period. There are no clinical data on the virologic response when PREZCOBIX is initiated during pregnancy.

8.3 Females and Males of Reproductive Potential

(Newly added subsection)

Contraception

Additional or alternative (non-hormonal) forms of contraception should be considered when estrogen-containing   contraceptives   are   co-administered   with   PREZCOBIX.   For   co-administration with drospirenone, clinical monitoring is recommended due to the potential for hyperkalemia. No data are available to make recommendations on co-administration with other hormonal contraceptives.

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

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Pregnancy

Advise patients that PREZCOBIX is not recommended during pregnancy and to alert their healthcare provider if they get pregnant while taking PREZCOBIX [see Use in Specific Populations (8.1)]. Inform patients that there is an antiretroviral pregnancy registry to monitor fetal outcomes of pregnant individuals exposed to PREZCOBIX [see Use in Specific Populations (8.1)].

Lactation

Instruct individuals 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)

 ...

Who should not take PREZCOBIX?

Do not take PREZCOBIX with any medicine that contains:

  • alfuzosin

  • carbamazepine

  • cisapride

  • colchicine, if you have liver or kidney problems

  • dronedarone

  • elbasvir and grazoprevir

  • ergot-containing medicines:

  • dihydroergotamine

  • ergotamine tartrate

  • methylergonovine

  • lomitapide

  • lovastatin


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

  • have liver problems, including hepatitis B or hepatitis C

  • have kidney problems

  • are allergic to sulfa (sulfonamide)

  • have diabetes

  • have hemophilia

  • have any other medical condition

  • are pregnant or plan to become pregnant.

    • It is not known if PREZCOBIX will harm your unborn baby.

    • PREZCOBIX should not be used in pregnant individuals because you may not have enough PREZCOBIX in your body during pregnancy.

  • Tell your healthcare provider if you become pregnant while taking PREZCOBIX. Your healthcare provider will prescribe different medicines if you become pregnant while taking PREZCOBIX.

    • Pregnancy Registry: There is a pregnancy registry for individuals who take antiretroviral medicines during pregnancy. The purpose of the 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.

06/04/2018 (SUPPL-9)

Approved Drug Label (PDF)

4 Contraindications

Additions and/or revisions underlined:

PREZCOBIX is contraindicated in patients receiving the following co-administered drugs:

Table 1: Drugs That Are Contraindicated with Prezcobix reformatted to a bulleted line listing; please refer to label for complete information.

6 Adverse Reactions

6.2 Postmarketing Experience

Newly added information:

The following events have been identified during post-approval use of darunavir. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Metabolism and Nutrition Disorders:

Redistribution of body fat

Musculoskeletal and Connective Tissue Disorders:

Rhabdomyolysis (associated with co-administration with HMG-CoA reductase inhibitors)

Skin and Subcutaneous Tissue Disorders

Toxic epidermal necrolysis, acute generalized exanthematous pustulosis, drug rash with eosinophilia and systemic symptoms

7 Drug Interactions

7.3 Established and Other Potentially Significant Drug Interactions

Table 2 is now Table 1: Established and Other Potentially Significant* Drug Interactions: Alterations in Dose or Regimen May Be Recommended

Addition of the phrase (this table is not all inclusive) in the text leading up to the table.

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

Clinical Considerations

Not Recommended During Pregnancy

PREZCOBIX is not recommended for use in pregnant women because of substantially lower exposures of darunavir and cobicistat during pregnancy.

PREZCOBIX should not be initiated in pregnant women. An alternative regimen is recommended for women who become pregnant during therapy with PREZCOBIX.

Data

Human Data

Darunavir/Cobicistat: PREZCOBIX in combination with a background regimen was evaluated in a clinical trial of 7 pregnant women taking PREZCOBIX prior to enrollment and who were willing to remain on PREZCOBIX throughout the study. The study period included the second and third trimesters, and through 12 weeks postpartum. Six women completed the trial.

Exposure to darunavir and cobicistat as part of an antiretroviral regimen was substantially lower during the second and third trimesters of pregnancy compared with postpartum.

One out of 6 women who completed the study experienced virologic failure with HIV-1 RNA

Greater than 1,000 copies/mL from the third trimester visit through the postpartum period. Five women had sustained virologic response (HIV RNA less than 50 copies/mL) throughout the study period. There are no clinical data on the virologic response when PREZCOBIX is initiated during pregnancy.

There were no new clinically relevant safety findings compared with the known safety profile of PREZCOBIX in HIV-1-infected adults.

Darunavir: Based on prospective reports to the APR of 679 live births following exposure to darunavir-containing regimens during pregnancy (including 425 exposed in the first trimester and 254 exposed in the second/third trimester) …

The prevalence of birth defects in live births was 2.1% (95% CI: 1.0% to 4.0%) with first trimester exposure to darunavir-containing regimens and 2.4% (95% CI: 0.9% to 5.1%) with second/third trimester exposure to darunavir-containing regimens.

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

Pregnancy

Advise patients that PREZCOBIX is not recommended in pregnant women and to alert their healthcare provider if they get pregnant while taking PREZCOBIX.  Inform patients that there is an antiretroviral pregnancy registry …

01/25/2018 (SUPPL-6)

Approved Drug Label (PDF)

7 Drug Interactions

7.3 Established and Other Potentially Significant Drug Interactions

(Subsection title has been revised; additions and/or revisions are underlined)

…These recommendations are based on either drug interaction trials or predicted interactions due to the expected magnitude of interaction and potential for serious adverse events or loss of therapeutic effect.

Table 2: Established and Other Potentially Significant* Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Trials or Predicted Interaction

(Table has been revised; please refer to label)

7.4 Drugs without Clinically Significant Interactions with PREZCOBIX

(Additions and/or revisions are underlined)

Clinically relevant drug-drug interactions have not been observed or are not anticipated with concomitant use of darunavir and cobicistat with rilpivirine, dolutegravir, raltegravir, abacavir, emtricitabine, emtricitabine/tenofovir alafenamide, tenofovir DF, lamivudine, stavudine, zidovudine, or acid modifying medications (antacids, H2-receptor antagonists, proton pump inhibitors).

01/25/2018 (SUPPL-7)

Approved Drug Label (PDF)

7 Drug Interactions

7.3 Established and Other Potentially Significant Drug Interactions

(Subsection title has been revised; additions and/or revisions are underlined)

…These recommendations are based on either drug interaction trials or predicted interactions due to the expected magnitude of interaction and potential for serious adverse events or loss of therapeutic effect.

Table 2: Established and Other Potentially Significant* Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Trials or Predicted Interaction

(Table has been revised; please refer to label)

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

PATIENT INFORMATION

(Additions and/or revisions are underlined)

Who should not take PREZCOBIX?

Do not take PREZCOBIX with any of the following medicines:

  • ergot-containing medicines:

    • ergotamine tartrate (CAFERGOT, ERGOMAR, MEDIHALER ERGOTAMINE, MIGERGOT)

06/14/2017 (SUPPL-4)

Approved Drug Label (PDF)

7 Drug Interactions

7.1 Potential for PREZCOBIX to Affect Other Drugs

(Additions and/or revisions are underlined)

Darunavir co-administered with cobicistat is an inhibitor of CYP3A and CYP2D6. Cobicistat inhibits the following transporters: P-glycoprotein (P-gp), BCRP, MATE1, OATP1B1 and OATP1B3. Therefore, co-administration of PREZCOBIX with drugs that are primarily metabolized by CYP3A and/or CYP2D6 or are substrates of P-gp, BCRP, MATE1, OATP1B1 or OATP1B3 may result in increased plasma concentrations of such drugs, which could increase or prolong their therapeutic effect and can be associated with adverse events (see Table 2).

7.2 Potential for Other Drugs to Affect PREZCOBIX

(Additions and/or revisions are underlined)

Co-administration of PREZCOBIX and drugs that induce CYP3A activity are expected to increase the clearance of darunavir and cobicistat, resulting in lowered plasma concentrations of darunavir and cobicistat which may lead to loss of therapeutic effect and development of resistance…

7.3 Potentially Significant Drug Interactions

Table 2: Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Trials or Predicted Interaction (see Contraindications (4) for a complete list of contraindicated drugs) (Table has been revised; please refer to label)

7.4 Drugs without Clinically Significant Interactions with PREZCOBIX

(Newly added subsection title)

8 Use in Specific Populations

8.1 Pregnancy

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

Pregnancy Exposure Registry

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


Risk Summary

There are insufficient data with PREZCOBIX in pregnant women from the APR to inform a drug-associated risk of pregnancy outcomes. Available data from the APR show no difference in rate of overall birth defects for darunavir 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). The APR uses the MACDP as the U.S. reference population for birth defects in the general population. The MACDP evaluates women and infants from a limited geographic area and does not include outcomes for births that occurred at less than 20 weeks gestation.

The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15-20%. The background risk of major birth defects and miscarriage for the indicated population is unknown.

In animal reproduction studies, no adverse developmental effects were observed when the components of PREZCOBIX were administered separately at darunavir exposures less than 1 (mice and rabbits) and 3-times (rats), and at cobicistat exposures 1.6 (rats) and 3.8 (rabbits) times human exposures at the recommended daily dose of these components in PREZCOBIX. No adverse developmental effects were seen when cobicistat was administered to rats through lactation at cobicistat exposures up to 1.2 times the human exposure at the recommended therapeutic dose.


Clinical Considerations

Dose Adjustment During Pregnancy and the Postpartum Period

Dosing recommendations cannot be made because the pharmacokinetics, safety, and efficacy of PREZCOBIX cannot be predicted from studies of other darunavir-containing regimens in pregnant women.

 

Data

Human Data

Darunavir: Based on prospective reports to the APR of 615 live births following exposure to darunavir-containing regimens during pregnancy (including 385 exposed in the first trimester and 230 exposed in the second/third trimester), there was no difference in rate of overall birth defects for darunavir compared with the background rate for major birth defects in a U.S. reference population of the MACDP.

The prevalence of birth defects in live births was 2.6% (95% CI: 1.2% to 4.7%) with first trimester exposure to darunavir-containing regimens and 1.7% (95% CI: 0.5% to 4.4%) with second/third trimester exposure to darunavir-containing regimens.

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

 

Animal Data

Darunavir: Reproduction studies conducted with darunavir showed no embryotoxicity or teratogenicity in mice (doses up to 1000 mg/kg from gestation day (GD) 6-15 with darunavir alone) and rats (doses up to 1000 mg/kg from GD 7-19 in the presence or absence of ritonavir) as well as in rabbits (doses up to 1000 mg/kg/day from GD 8-20 with darunavir alone)…

Cobicistat: Cobicistat was administered orally to pregnant rats at doses up to 125 mg/kg/day on GD 6-17. Increases in post-implantation loss and decreased fetal weights were observed at a maternal toxic dose of 125 mg/kg/day. No malformations were noted at doses up to 125 mg/kg/day. Systemic exposures (AUC) at 50 mg/kg/day in pregnant females were 1.6 times higher than human exposures at the recommended daily dose of cobicistat.

In pregnant rabbits, cobicistat was administered orally at doses up to 100 mg/kg/day during GD 7-20. 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 3.8 times higher than human exposures at the recommended daily dose of cobicistat.

In a pre/postnatal developmental study in rats, cobicistat was administered orally at doses up to 75 mg/kg from GD 6 to postnatal day 20, 21, or 22. At doses of 75 mg/kg/day, neither maternal nor developmental toxicity was noted. Systemic exposures (AUC) at this dose were 1.2 times the human exposures at the recommended daily dose of cobicistat.

8.2 Lactation

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

Risk Summary

There are no data on the presence of darunavir or cobicistat in human milk, the effects on the breastfed infant, or the effects on milk production. Darunavir and cobicistat are secreted into the milk of lactating rats. Because of the potential for (1) HIV transmission (in HIV- negative infants), (2) developing viral resistance (in HIV-positive infants), and (3)  serious adverse reactions in breastfed infants, instruct mothers not to breastfeed if they are receiving PREZCOBIX.


Data

Animal Data

Darunavir: Studies in rats (with darunavir alone or with ritonavir) have demonstrated that darunavir is secreted in the milk. In the rat pre- and postnatal development study, a reduction in pup body weight gain was observed due to exposure of pups to drug substances via milk. The maximal maternal plasma exposures achieved with darunavir (up to 1000 mg/kg with ritonavir) were approximately 50% of those obtained in humans at the recommended clinical dose of darunavir with ritonavir.

Cobicistat: During the pre/postnatal developmental toxicology study at doses up to 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.

8.4 Pediatric Use

(Additions and/or revisions are underlined)

Safety, effectiveness, and pharmacokinetics of PREZCOBIX in pediatric patients less than 18 years of age have not been established. Darunavir, a component of PREZCOBIX is not recommended in pediatric patients below 3 years of age because of toxicity and mortality observed in juvenile rats dosed with darunavir.


Juvenile Animal Toxicity Data

Darunavir: In a juvenile toxicity study where rats were directly dosed with darunavir (up to 1000 mg/kg), deaths occurred from post-natal day 5 at plasma exposure levels ranging from 0.1 to 1.0 of the human exposure levels. In a 4-week rat toxicology study, when dosing was initiated on post-natal day 23 (the human equivalent of 2 to 3 years of age), no deaths were observed with a plasma exposure (in combination with ritonavir) 2 times the human plasma exposure levels.

09/22/2016 (SUPPL-2)

Approved Drug Label (PDF)

4 Contraindications

Table 1: Drugs That Are Contraindicated With PREZCOBIX

  • Anticonvulsants and Hepatitis C direct-acting antiviral drug classes added to the table with associated clinical comments; please refer to label.

5 Warnings and Precautions

5.5 Risk of Serious Adverse Reactions or Loss of Virologic response due to Drug Interactions

  • Initiation of PREZCOBIX, which inhibits CYP3A, in patients receiving medications metabolized by CYP3A, or initiation of medications metabolized by CYP3A in patients already receiving PREZCOBIX may increase plasma concentrations of medications metabolized by CYP3A.

  • Initiation of medications that inhibit or induce CYP3A may respectively increase or decrease concentrations of PREZCOBIX.

  • Increased concentrations may lead to:

    • clinically significant adverse reactions, potentially leading to severe, life threatening, or fatal events from higher exposures of concomitant medications.

    • clinically significant adverse reactions from higher exposures of PREZCOBIX.

  • Decreased antiretroviral concentrations may lead to:

    • loss of therapeutic effect of PREZCOBIX and possible development of resistance.

  • See Table 2 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during PREZCOBIX therapy; review concomitant medications during PREZCOBIX therapy; and monitor for the adverse reactions associated with concomitant medications.

  • When used with concomitant medications, PREZCOBIX may result in different drug interactions …

7 Drug Interactions

7.3 Potentially significant Drug Interactions

  • These recommendations are based on either drug interaction trials or predicted interactions due to the expected magnitude of interaction and potential for serious adverse events or loss of efficacy… No drug interaction trials have been performed with PREZCOBIX or with darunavir co-administered with cobicistat as single entities. Drug interaction trials have been conducted with darunavir co-administered with ritonavir or with cobicistat alone. (addition underlined)

  • Table 2: Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Trials or Predicted Interaction

    • Updates to the Anticonvulants and Hepatitis C Virus (HCV) Concomitant Drug Classes; please refer to label.

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

Patient Counseling Information

Immune Reconstitution Syndrome (addition)

  • 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.

Pregnancy Registry (addition)

  • Inform patients that there is an antiretroviral pregnancy registry to monitor fetal outcomes of pregnant women exposed to PREZCOBIX.

Lactation (addition)

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

Patient Information

Who should not take PREZCOBIX?

  • Do not take PREZCOBIX with any of the following medicines:

    • carbamazepine (CARBATROL®, EPITOL®, EQUETRO®, TEGRETOL®, TEGRETOL-XR®, TERIL®)

    • elbasvir and grazoprevier (ZEPATIER®)

    • phenobarbital (LUMINAL®)

    • phenytoin (DILANTIN®, DILANTIN-125®, PHENYTEK®)

03/31/2016 (SUPPL-1)

Approved Drug Label (PDF)

7 Drug Interactions

  • Potentially significant (Drug Interactions Table 2): Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Trials or Predicted Interaction
  • quetiapine
    • Initiation of PREZCOBIX in patients taking quetiapine: Consider alternative antiretroviral therapy to avoid increases in quetiapine exposure. If co-administration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring
    • Initiation of quetiapine in patients taking PREZCOBIX: Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine.

Questions related to the drug data in these files should be directed to the Center for Drug Evaluation and Research, Division of Drug Information
druginfo@fda.hhs.gov.

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