Drug Safety-related Labeling Changes (SrLC) Database
ANDA | Abbreviated New Drug Application |
BLA | Biologics License Application |
CDER | Center for Drug Evaluation and Research |
MG | Medication Guide |
NDA | New Drug Application |
PCI | Patient Counseling Information |
PI | Patient Information |
PLR | Physician Labeling Rule |
PLLR | Pregnancy and Lactation Labeling Rule |
Italics | For the most part, italics indicate an FDA comment such as:
Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section. |
Underlines | Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text. |
Sections
BW | Box Warning |
WP | Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format) |
AR | Adverse Reactions (in pre-PLR format, this may be a subheading under precautions). |
DI | Drug Interactions (in pre-PLR format, this may be a subheading under precautions). |
USP | Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format. |
PCI/PI/MG | Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events. |
Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.
Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.
PREZCOBIX (NDA-205395)
(COBICISTAT; DARUNAVIR ETHANOLATE)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
03/31/2023 (SUPPL-25)
6 Adverse Reactions
6.2 Postmarketing Experience
(Additions and/or revisions underlined)
The following adverse reactions have been identified during post-approval use of darunavir. Because these reactions 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.
…
Renal and Urinary Disorders
Crystal nephropathy, crystalluria
10/20/2022 (SUPPL-24)
7 Drug Interactions
7.3 Established and Other Potentially Significant Drug InteractionsUpdated dosing recommendations; please refer to label
04/14/2022 (SUPPL-22)
4 Contraindications
Newly added information:
Darunavir and cobicistat are both inhibitors of the cytochrome P450 3A (CYP3A) isoform. PREZCOBIX should not be co-administered with medicinal products that are highly dependent on CYP3A for clearance and for which increased plasma concentrations are associated with serious and/or life threatening events (narrow therapeutic index). Darunavir and cobicistat are both substrates of the cytochrome P450 3A (CYP3A) isoform. Co- administration of PREZCOBIX with CYP3A inducers may lead to lower exposures of darunavir and cobicistat and potential loss of efficacy of darunavir and possible resistance. Examples of drugs that are contraindicated for co- administration with PREZCOBIX [see Drug Interactions (7.3) and Clinical Pharmacology (12.3)] are listed below.
7 Drug Interactions
7.3 Established and Other Potentially Significant Drug InteractionsAdditions and/or revisions underlined:
The table includes examples of potentially significant interactions but is not all inclusive, and therefore the label of each drug that is co-administered with PREZCOBIX should be consulted for information related to the route of metabolism, interaction pathways, potential risks, and specific actions to be taken with regard to co-administration. For the list of examples of contraindicated drugs, [see Contraindications (4)].
8 Use in Specific Populations
8.1 PregnancyAdditions and/or revisions underlined:
Risk Summary
PREZCOBIX is not recommended during pregnancy because of substantially lower exposures of darunavir and cobicistat during the second and third trimesters [see Dosage and Administration (2.5)]. A study evaluating the pharmacokinetics of antiretrovirals during pregnancy demonstrated substantially lower exposures of darunavir and cobicistat in the second and third trimesters compared to the post-partum period (see Data) and [see Clinical Pharmacology (12.3)].
Prospective pregnancy data from the APR are not sufficient to adequately assess the risk of birth defects or miscarriage. However, available data from the APR show no statistically significant difference in the overall risk of major birth defects for darunavir and cobicistat 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).
Data
Human Data
Additions and/or revisions underlined:
Prospective reports from the APR of overall major birth defects in pregnancies exposed to the components of PREZCOBIX are compared with a U.S. background major birth defect rate. 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.
Darunavir: Based on prospective reports to the APR of over 980 exposures to darunavir- containing regimens during pregnancy resulting in live births (including over 660 exposed in the first trimester and over 320 exposed in the second/third trimester), the prevalence of birth defects in live births was 3.6% (95% CI: 2.3% to 5.3%) with first trimester exposure to darunavir- containing regimens and 2.5% (95% CI: 1.1% to 4.8%) with second/third trimester exposure to darunavir-containing regimens.
Cobicistat: Based on
prospective reports to the APR of over 570 exposures to cobicistat- containing
regimens during pregnancy resulting in live births (including over 480 exposed
in the first trimester and over 80 exposed in the second/third trimester), the
prevalence of birth defects in live births was 3.7% (95% CI: 2.2% to 5.7%) and
1.1% (95% CI: 0.0% to 6.2%) with first and second/third trimester,
respectively, to cobicistat-containing regimens.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT INFORMATIONAdditions and/or revisions underlined:
Do not take PREZCOBIX with any medication that contains:..
Serious problems can happen if you take any of these medicines with PREZCOBIX. This is not a complete list of medicines. Therefore, tell your healthcare provider about all medicines you take.
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, topical creams, vitamins, and herbal supplements. Some medicines interact with PREZCOBIX. Keep a list of your medicines to show your healthcare provider and pharmacist.
07/23/2021 (SUPPL-20)
7 Drug Interactions
7.3 Established and Other Potentially Significant Drug InteractionsTable 1: Established and Other Potentially Significant* Drug Interactions: Alterations in Dose or Regimen May Be Recommended
Under the Corticosteroids heading, information has changed; please refer to the label for complete information.12/22/2020 (SUPPL-18)
5 Warnings and Precautions
5.5 Risk of Serious Adverse Reactions or Loss of Virologic Response Due to Drug Interactions(Additions and/or revisions underlined)
Initiation of PREZCOBIX, which inhibits CYP3A, in patients receiving medications metabolize d by CYP3A, or initiation of medications metabolized by CYP3A in patients already receiving PREZCOBIX may increase plasma concentrations of medications metabolized by CYP3A and reduce plasma concentrations of active metabolite(s) formed by CYP3A. Initiation of medications that inhibit or induce CYP3A may respectively increase or decrease concentrations of PREZCOBIX.
These interactions 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.
loss of therapeutic effect of the concomitant medications from lower exposures of active metabolite(s).
loss of therapeutic effect of PREZCOBIX and possible development of resistance from lower exposures of PREZCOBIX.
7 Drug Interactions
7.1 Potential for PREZCOBIX to Affect Other Drugs(Newly added information)
Co-administration of PREZCOBIX with drugs that have active metabolite(s) formed by CYP3A may result in reduced plasma concentrations of these active metabolite(s), potentially leading to loss of their therapeutic effect. . .
(Table 1 updated with the addition of information about platelet aggregation inhibitors clopidogrel and prasugrel)
07/31/2020 (SUPPL-16)
6 Adverse Reactions
6.1 Clinical Trials ExperienceAdditions and/or revisions underlined:
Clinical Trials in Adults
During the darunavir clinical development program, where darunavir was co-administered with ritonavir 100 mg once or twice daily, the most common clinical adverse reactions …
Newly added information:
Clinical Trials in Pediatric Patients
No clinical trials with PREZCOBIX were performed in pediatric patients. However, the safety of the components of PREZCOBIX, darunavir and cobicistat, co-administered with two nucleoside reverse transcriptase inhibitors was evaluated in pediatric subjects of 12 to less than 18 years of age with HIV-1 infection through clinical trial GS-US-216-0128 (virologically-suppressed, N=7 with weight greater than or equal to40 kg) through Week 48. Safety analyses of this trial in these pediatric subjects did not identify new safety concerns compared to the known safety profile of PREZCOBIX in adult subjects [see Clinical Studies (14.2)].
8 Use in Specific Populations
8.4 Pediatric UseAdditions and/or revisions underlined:
The safety and effectiveness of PREZCOBIX for the treatment of HIV-1 infection in pediatric patients weighing at least 40 kg was established through a trial with components of PREZCOBIX. Use of PREZCOBIX in this group is supported by evidence from adequate and well-controlled studies in adults with additional pharmacokinetic, safety, and virologic data from a study of components of PREZCOBIX (Trial GS-US-216-0128) in pediatric subjects with HIV-1 infection aged 12 to less than 18 years [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.2)].
The safety and effectiveness of PREZCOBIX have not been established in pediatric patients weighing less than 40 kg. 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.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT INFORMATIONWhat is PREZCOBIX?
Additions and/or revisions underlined:
PREZCOBIX is a prescription medicine that is used with other HIV-1 medicines to treat HIV-1 infection in adults and in children who weigh at least 88 pounds (40 kg).
HIV-1 is the virus that causes Acquired Immune Deficiency Syndrome (AIDS).
PREZCOBIX contains the prescription medicines darunavir and cobicistat.
It is not known if PREZCOBIX is safe and effective in children weighing less than 88 pounds (40 kg).
Before taking PREZCOBIX, tell your healthcare provider about all your medical conditions, including if you:
are pregnant or plan to become pregnant.
PREZCOBIX should not be used during pregnancy because the PREZCOBIX levels in your blood may be lower during pregnancy and may not control your HIV-1.
Hormonal forms of birth control, such as injections, vaginal rings or implants, contraceptive patches, and some birth control pills may not work during treatment with PREZCOBIX. Talk to your healthcare provider about forms of birth control that may be used during treatment with PREZCOBIX.
05/29/2019 (SUPPL-14)
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)
7 Drug Interactions
7.3 Established and Other Potentially Significant Drug InteractionsTable 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)
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 PregnancyAdditions 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
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.
…
(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)].
Instruct individuals with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in breast milk.
…
(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)
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 ExperienceNewly 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 InteractionsTable 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 PregnancyAdditions 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
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 INFORMATIONAdditions 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)
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)
(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)
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)
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).
(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…
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)
(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.
(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.
(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)
4 Contraindications
Table 1: Drugs That Are Contraindicated With PREZCOBIXAnticonvulsants 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 InteractionsInitiation 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 InteractionsThese 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 InformationImmune 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.
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)
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.