Drug Safety-related Labeling Changes (SrLC)

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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.

PREZISTA (NDA-202895)

(DARUNAVIR ETHANOLATE)

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

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03/31/2023 (SUPPL-36)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

(Additions and/or revisions underlined)

The following adverse reactions have been identified during post-approval use of PREZISTA. 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.

Metabolism and Nutrition Disorders: Redistribution of body fat

Musculoskeletal and Connective Tissue Disorders: Rhabdomyolysis (associated with co-administration with HMG-CoA reductase inhibitors and PREZISTA/ritonavir)

Skin and Subcutaneous Tissue Disorders: Toxic epidermal necrolysis, acute generalized exanthematous pustulosis, drug rash with eosinophilia and systemic symptoms [see Warnings and Precautions (5.3)]

Renal and Urinary Disorders: Crystal nephropathy, crystalluria

10/20/2022 (SUPPL-35)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

Redistribution of body fat has been reported.

Rarely, rhabdomyolysis (associated with co-administration with HMG-CoA reductase inhibitors and PREZISTA/ritonavir) has been reported.

In addition, toxic epidermal necrolysis, acute generalized exanthematous pustulosis and drug rash with eosinophilia and systemic symptoms have been reported rarely [see Warnings and Precautions (5.3)].

7 Drug Interactions

7.3 Established and Other Potentially Significant Drug Interactions

Updated dosing recommendations; please refer to label

07/23/2021 (SUPPL-31)

Approved Drug Label (PDF)

7 Drug Interactions

7.3 Established and Other Potentially Significant Drug Interactions

Table 10: Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May be Recommended Based on Drug Interaction Studies or Predicted Interaction

Under the Corticosteroids heading, information has changed; please refer to the label for complete information.

12/22/2020 (SUPPL-29)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.5 Risk of Serious Adverse Reactions due to Drug Interactions

(Additions and/or revisions underlined)

Initiation of PREZISTA/ritonavir, a CYP3A inhibitor, in patients receiving medications metabolized by CYP3A or initiation of medications metabolized by CYP3A in patients already receiving PREZISTA/ritonavir, 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 increase or decrease concentrations of PREZISTA/ritonavir, respectively.

These interactions may lead to:

Clinically significant adverse reactions, potentially leading to severe, life threatening, or fatal events from greater exposures of concomitant medications.
Clinically significant adverse reactions from greater exposures of PREZISTA/ritonavir.
Loss of therapeutic effect of the concomitant medications from lower exposures of active metabolite(s).
Loss of therapeutic effect of PREZISTA/ritonavir and possible development of resistance from lower exposures of PREZISTA/ritonavir.

7 Drug Interactions

7.1 Potential for PREZISTA/ritonavir to Affect Other Drugs

(Newly added information)

PREZISTA co-administered with ritonavir with drugs that have active metabolite(s) formed by CYP3A may result in reduced plasma concentrations of these active metabolite(s), potentia lly leading to loss of their therapeutic effect. . .

7.3 Established and Other Potentially Significant Drug Interactions

(Table 10 updated with the addition of information regarding clopidogrel and prasugrel)

05/28/2019 (SUPPL-27)

Approved Drug Label (PDF)

4 Contraindications

Consolidation of information regarding antianginal and antiarrhythmic drugs into a new category, titled “Cardiac Disorders” and addition of the drug ivabradine. In addition, a new drug class, “Opioid Antagonists” is added with information on naloxegol.

5 Warnings and Precautions

5.8 Immune Reconstitution Syndrome

Additions and/or revisions underlined:

Autoimmune disorders (such as Graves’ disease, polymyositis, Guillain-Barré syndrome, and autoimmune hepatitis) …

7 Drug Interactions

7.3 Established and Other Potentially Significant Drug Interactions

Additions and/or revisions underlined:

… and potential for serious adverse events or loss of efficacy. The table includes potentially significant interactions but is not all inclusive.

Table 10: Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May be Recommended Based on Drug Interaction Studies or Predicted Interaction

Antifungals: newly added information on use of isavuconazole.
Cardiac Disorders: new category added with drugs previously listed under “Other Agents, Antiarrhythmics and Antianginal” moved to this category. Added information on use of ivabradine.
Systemic/Inhaled/ Nasal/Ophthalmic Corticosteroids: addition of prednisone as a corticosteroid less affected by strong CYP3A inhibitor relative to other corticosteroids.
Hormonal Contraceptives: recategorization of heading, previously read “Oral contraceptives/estrogen”
Immunosuppressant/neoplastic: newly added information on use of irinotecan.
Opioid Antagonist: newly added information on use of naloxegol
Urinary Antispasmodics: newly added information on use of fesoterodine and solifenacin

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

PATIENT INFORMATION

Who should not take PREZISTA?

Do not take PREZISTA with any medicine that contains:

Addition of the following:

Ivabradine
Naloxegol

03/21/2019 (SUPPL-24)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

DATA

Human Data

Additions and/or revisions underlined:

… Eighteen subjects were enrolled in each BID and QD treatment arms. Twenty-nine subjects completed the trial …

… Virologic response was preserved. In the BID arm, the proportion of subjects with HIV-1 RNA

<50 copies/mL were 39% (7/18) at baseline, 61% (11/18) through the third trimester visit, and 61% (11/18) through the 6-12-week postpartum visit. Virologic outcomes during the third trimester visit showed HIV-1 RNA ?50 copies/mL for 11% (2/18) of subjects and were missing for 5 subjects (1 subject discontinued prematurely due to virologic failure). In the QD arm, the proportion of subjects with HIV-1 RNA <50 copies/mL were 61% (11/18) at baseline, 83% (15/18) through the third trimester visit, and 78% (14/18) through the 6-12-week postpartum visit … Among the 31 infants with HIV test results available data, born to the 31 HIV-infected pregnant women who completed trial through delivery or postpartum period, all 31 infants had test results that were negative for HIV-1 at the time of delivery and/or through 16 weeks postpartum. All 31 infants received antiretroviral prophylactic treatment containing zidovudine …

01/31/2019 (SUPPL-25)

Approved Drug Label (PDF)

7 Drug Interactions

7.3 Established and Other Potentially Significant Drug Interactions

Table 10: Established and Other Potentially Significant Drug Interactions: Alterations in Dose or

Regimen May be Recommended Based on Drug Interaction Studies or Predicted Interaction

Update Table 10, with information that coadministration of PREZISTA/ritonavir with hepatitis C virus direct-acting antivirals, glecaprevir and pibrentasvir is not recommended. Please refer to label with complete information.

09/07/2018 (SUPPL-22)

4 Contraindications

4 CONTRAINDICATIONS

(Additions and/or revisions are underlined)

Co-administration of PREZISTA/ritonavir is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events (narrow therapeutic index). These drugs and other contraindicated drugs (which may lead to reduced efficacy of darunavir) are listed below. Due to the need for co-administration of PREZISTA with ritonavir, please refer to ritonavir prescribing information for a description of ritonavir contraindications.

Alpha 1-adrenoreceptor antagonist: alfuzosin

Antianginal: ranolazine
Antiarrhythmic: dronedarone
Anti-gout: colchicine, in patients with renal/and or hepatic impairment
Antimycobacterial: rifampin
Antipsychotics: lurasidone, pimozide
Ergot derivatives, e.g. dihydroergotamine, ergotamine, methylergonovine
GI motility agent: cisapride
Herbal product: St. John’s wort (Hypericum perforatum)
Hepatitis C direct acting antiviral: elbasvir/grazoprevir
Lipid modifying agents: lomitapide, lovastatin, simvastatin
PDE-5 inhibitor: sildenafil when used for treatment of pulmonary arterial hypertension
Sedatives/hypnotics: orally administered midazolam, triazolam

7 Drug Interactions

7.3 Established and Other Potentially Significant Drug Interactions

(Table has been revised; please refer to label)

8 Use in Specific Populations

8.3 Females and Males of Reproductive Potential

(Additions and/or revisions are underlined)

Contraception

Use of PREZISTA may reduce the efficacy of combined hormonal contraceptives and the progestin only pill. Advise patients to use an effective alternative (non-hormonal) contraceptive method or add a barrier method of contraception. For co-administration with drospirenone, clinical monitoring is recommended due to the potential for hyperkalemia.

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

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

…

Contraception

Instruct patients receiving combined hormonal contraception or the progestin only pill to use an effective alternative (non-hormonal) contraceptive method or add a barrier method during therapy with PREZISTA/ritonavir because hormonal levels may decrease.

…

01/25/2018 (SUPPL-21)

Approved Drug Label (PDF)

7 Drug Interactions

7.3 Established and Other Potentially Significant Drug Interactions

Table 11: Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May be Recommended Based on Drug Interaction Studies or Predicted Interaction

(Table has been revised; please refer to label)

7.4 Drugs without Clinically Significant Interactions with PREZISTA

(Additions and/or revisions are underlined)

No dosage adjustments are recommended when PREZISTA/ritonavir is co-administered with the following medications: atazanavir, dolutegravir, efavirenz, etravirine, nevirapine, nucleoside reverse transcriptase inhibitors (abacavir, emtricitabine, emtricitabine/tenofovir alafenamide fumarate, lamivudine, stavudine, tenofovir disoproxil fumarate, zidovudine), pitavastatin, raltegravir, ranitidine, or rilpivirine.

8 Use in Specific Populations

8.1 Pregnancy

(Additions and/or revisions are underlined)

Data

Human Data

…Seventeen subjects were enrolled in each BID and QD treatment arms. Twenty-seven subjects completed the trial through the postpartum period (6-12 weeks after delivery) and 7 subjects discontinued before trial completion, 5 subjects in the BID arm and 2 subjects in the QD arm.

…Exposure reductions during pregnancy were greater for the once daily regimen as compared to the twice daily regimen.

Virologic response was preserved. In the BID arm, the proportion of subjects with HIV-1 RNA <50 copies/mL were 35% (6/17) at baseline, 59% (10/17) through the third trimester visit, and 59% (10/17) through the 6-12 week postpartum visit. Virologic outcomes during the third trimester visit showed HIV-1 RNA greater than or equal to 50 copies/mL for 12% (2/17) of subjects and were missing for 5 subjects (1 subject discontinued prematurely due to virologic failure). In the QD arm, the proportion of subjects with HIV-1 RNA <50 copies/mL were 59% (10/17) at baseline, 82% (14/17) through the third trimester visit, and 82% (14/17) through the 6-12 week postpartum visit. Virologic outcomes during the third trimester visit showed HIV-1 RNA greater than or equal to 50 copies/mL for none of the subjects and were missing for 3 subjects (1 subject discontinued prematurely due to virologic failure).

…

Among the 29 infants with HIV test results available data, born to the 29 HIV-infected pregnant women who completed trial through delivery or postpartum period, all 29 infants had test results that were negative for HIV-1 at the time of delivery and/or through 16 weeks postpartum. All 29 infants received antiretroviral prophylactic treatment containing zidovudine.

…

09/15/2016 (SUPPL-19)

Approved Drug Label (PDF)

4 Contraindications

Table 6: Drugs That Are Contraindicated With PREZISTA/ritonavir (updated)

Drug class :

Antipsychotic: Lurasidone (added)

Clinical comment : Potential for serious and/or life-threatening reactions.

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

Do not take PREZISTA with any of the following medicines:

· lurasidone (Latuda®) (added)

06/17/2016 (SUPPL-17)

Approved Drug Label (PDF)

5 Warnings and Precautions

Importance of Co-administration with Ritonavir (updated subheading – replaces General subheading)

Not Recommended in Pediatric Patients Below 3 Years of Age (updated subheading - replaces Pediatric Patients subheading)

6 Adverse Reactions

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

Hepatotoxicity
Severe Skin Reactions
Diabetes Mellitus/Hyperglycemia
Fat Redistribution
Immune Reconstitution Syndrome
Hemophilia

7 Drug Interactions

Drugs without Clinically Significant Interactions with PREZISTA (added subheading)

No dosage adjustments are recommended when PREZISTA/ritonavir is co-administered with the following medications: atazanavir, dolutegravir, efavirenz, etravirine, nevirapine, nucleoside reverse transcriptase inhibitors (abacavir, emtricitabine, lamivudine, stavudine, tenofovir disoproxil fumarate, zidovudine), pitavastatin, raltegravir, ranitidine, and rilpivirine.

TABLE 11

HIV-1-Antiviral Agents: HIV-Protease Inhibitors (PIs)

Other HIV protease inhibitors, except atazanavir (added under Drug name column)
As coadministration with PREZISTA/ritonavir has not been studied, coadministration is not recommended.(added in same row, under clinical comment)
Oral contraceptives/estrogen - Update the clinical comment for this group of drugs: Effective alternative contraceptive method or barrier method of contraception is recommended.

8 Use in Specific Populations

Juvenile Animal Data (addition)

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.

Pediatric Use

PREZISTA/ritonavir is not recommended in pediatric patients… replaces Do not administer Prezista/ritonavir in pediatric patients …

PLLR Conversion; please refer to label.

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

PCI - Extensive changes; please refer to label.

PI - Extensive changes; please refer to label.