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.

APRETUDE (NDA-215499)

(CABOTEGRAVIR)

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

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04/11/2025 (SUPPL-9)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.4 Hypersensitivity Reactions

Additions and/or revisions underlined:

Serious or severe hypersensitivity reactions have been reported with cabotegravir and include Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) [see Adverse Reactions (6.2)]. Administration of cabotegravir oral lead-in dosing was used in clinical studies to help identify participants who may be at risk of a hypersensitivity reaction. Remain vigilant and discontinue APRETUDE if a hypersensitivity reaction is suspected [see Dosage and Administration (2.4), Contraindications (4), Adverse Reactions (6)].

…

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

…

Skin and Subcutaneous Tissue Disorders

Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) [see Warnings and Precautions (5.4)].

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

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

…

Hypersensitivity Reactions

Advise individuals to immediately contact their healthcare provider if they develop a rash. Instruct individuals to immediately stop taking APRETUDE and seek medical attention if they develop a rash associated with any of the following symptoms as it may be a sign of a more serious reaction such as Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN): fever; generally ill feeling; extreme tiredness; muscle or joint aches; blisters; oral blisters or lesions; eye inflammation; facial swelling; swelling of the eyes, lips, tongue, or mouth; difficulty breathing; and/or signs and symptoms of liver problems (e.g., yellowing of the skin or whites of the eyes; dark or tea-colored urine; pale-colored stools or bowel movements; nausea; vomiting; loss of appetite; or pain, aching, or sensitivity on the right side below the ribs). Advise individuals that if hypersensitivity occurs, they will be closely monitored, laboratory tests will be ordered, and appropriate therapy will be initiated [see Warnings and Precautions (5.4)].

…

09/20/2024 (SUPPL-8)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

…

APRETUDE for HIV-1 PrEP was evaluated in 2 open-label multicenter clinical trials, HPTN 083-01 and HPTN 084-01, in adolescent individuals 12 to less than 18 years of age weighing at least 35 kg who are at risk for HIV-1 acquisition. Sixty-four adolescents were enrolled. Of these, 62 adolescent participants received one or more injections. In adolescents receiving APRETUDE for HIV-1 PrEP, the safety data were comparable to the safety data reported in adults receiving APRETUDE for HIV-1 PrEP.

…

8.6 Renal Impairment

Additions and/or revisions underlined:

Based on studies with oral cabotegravir, no dosage adjustment of APRETUDE is necessary for individuals with mild (creatinine clearance greater than or equal to 60 to <90 mL/min), moderate (creatinine clearance

Greater than or equal to 30 to <60 mL/min) or severe renal impairment (creatinine clearance greater than or equal to 15 to <30 mL/min) [see Clinical Pharmacology (12.3)]. In individuals with end-stage renal disease not on dialysis, effects on the pharmacokinetics of cabotegravir are unknown. As cabotegravir is >99% protein bound, dialysis is not expected to alter exposures of cabotegravir.

12/13/2023 (SUPPL-4)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.4 Hypersensitivity Reactions

(Additions and/or revisions underlined)

Serious or severe hypersensitivity reactions have been reported in association with other integrase inhibitors and could occur with APRETUDE [see Adverse Reactions (6.1

, 6.2)].

5.6 Depressive Disorders

(Additions and/or revisions underlined)

Depressive disorders (including depression, depressed mood, major depression, persistent depressive disorder, suicidal ideation, suicide attempt) have been reported with APRETUDE [see Adverse Reactions (6.1]. Promptly evaluate individuals with depressive symptoms to assess whether the symptoms are related to APRETUDE and to determine whether the risks of continued therapy outweigh the benefits.

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions and/or revisions underlined)

Less Common Adverse Reactions: The following select adverse reactions (regardless of severity) occurred in <1% of participants receiving APRETUDE in HPTN 083 or HPTN 084.

…

Psychiatric Disorders: Depression; suicidal ideation, and suicide attempt (these events were observed primarily in subjects with a pre-existing history of depression or other psychiatric illness).

8 Use in Specific Populations

8.2 Lactation

Risk Summary

(Additions and/or revisions underlined)

There are no data on the presence of cabotegravir in human milk. Cabotegravir is present in animal milk (see Data). When a drug is present in animal milk, it is likely that the drug will be present in human milk. It is not known if cabotegravir affects human milk production, or has effects on the breastfed infant. If cabotegravir is present in human milk, residual exposures may remain for 12 months or longer after the last injections have been administered [see Warnings and Precautions (5.3)].

Because of detectable cabotegravir concentrations in systemic circulation for up to 12 months or longer after discontinuing injections of APRETUDE, it is recommended that mothers breastfeed only if the expected benefit justifies the potential risk to the infant. The developmental and health benefits of breastfeeding and the mother’s clinical need for APRETUDE for HIV-1 PrEP should be considered along with any potential adverse reactions on the breastfed child from APRETUDE and the risk of HIV-1 acquisition due to nonadherence and subsequent mother to child transmission. Mothers should not breastfeed if acute HIV-1 infection is suspected because of the risk of HIV-1 transmission to the infant.

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

17 PATIENT COUNSELING INFORMATION

Advise the individual to read the FDA-approved patient labeling (Patient Information).

…

(Additions and/or revisions underlined)

Depressive Disorders

Inform individuals that depressive disorders (including depression, depressed mood, major depression, persistent depressive disorder, suicidal ideation, suicide attempt) have been reported with APRETUDE [see Adverse Reactions (6.1)]. Advise individuals to seek prompt medical evaluation if they experience depressive symptoms [see Warnings and Precautions (5.6)].

…

Lactation

Inform individuals that due to the potential for adverse reactions and residual concentrations in the systemic circulation for up to 12 months or longer after discontinuing injections of APRETUDE, it is recommended that mothers breastfeed only if the expected benefit justifies the potential risk to the infant. The benefits and risks of APRETUDE while breastfeeding should be evaluated, including the risk of HIV-1 acquisition due to medication nonadherence and subsequent mother to child transmission. Instruct mothers not to breastfeed if acute HIV-1 infection is suspected because of the risk of passing the HIV-1 virus to the baby [see Use in Specific Populations (8.2)].

02/27/2023 (SUPPL-2)

Approved Drug Label (PDF)

4 Contraindications

Additions and revisions underlined:

APRETUDE is contraindicated in individuals:

with unknown or positive HIV-1 status [see Warnings and Precautions (5.1, 5.2)].
with previous hypersensitivity reaction to cabotegravir [see Warnings and Precautions (5.4)].
receiving the following coadministered drugs for which significant decreases in cabotegravir plasma concentrations may occur due to uridine diphosphate glucuronosyltransferase (UGT)1A1 enzyme induction, which may result in reduced effectiveness [see Drug Interactions (7.2, 7.3), Clinical Pharmacology (12.3)]:
- Anticonvulsants: Carbamazepine, oxcarbazepine, phenobarbital, phenytoin
- Antimycobacterials: Rifampin, rifapentine

6 Adverse Reactions

6.2 Postmarketing Experience

Newly added subsection:

The following adverse reactions have been identified during postmarketing use of cabotegravir- containing regimens. 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.

Immune System Disorders

Hypersensitivity reactions (including angioedema and urticaria) [see Warnings and Precautions (5.4)].

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

Patient Information

Additions and revisions underlined:

Do not receive APRETUDE if you:

• already have HIV-1 infection. If you are HIV-1 positive, you will need to take other medicines to treat

HIV-1. APRETUDE is not approved for treatment of HIV-1.

• do not know your HIV-1 infection status. You may already be HIV-1 positive. You need to take other

medicines to treat HIV-1. APRETUDE can only help reduce your risk of getting HIV-1 infection before

you are infected.

• have ever had an allergic reaction to cabotegravir