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.

INTELENCE (NDA-022187)

(ETRAVIRINE)

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

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07/10/2019 (SUPPL-25)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Severe Skin and Hypersensitivity Reactions

Additions and/or revisions underlined:

… In clinical trials, these include cases of Stevens-Johnson syndrome, toxic … The incidence of rash was higher in females. Stevens-Johnson syndrome was reported in 1.1% (2/177) of pediatric patients less than 18 years of age receiving INTELENCE in combination with other HIV-1 antiretroviral agents in an observational study.

5.3 Immune Reconstitution Syndrome

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

6 Adverse Reactions

Addition of ‘Immune reconstitution syndrome’ to bulleted line listing.

6.2 Postmarketing Experience

Additions and/or revisions underlined:

Skin and Subcutaneous Tissue Disorders: Fatal cases of toxic epidermal necrolysis and Stevens- Johnson syndrome have been reported.

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined:

… Both studies were open-label, single arm trials of etravirine plus an optimized background regimen. In clinical trials, the safety, pharmacokinetics, and efficacy were comparable to that observed in adults except for rash (greater than or equal to Grade 2) which was observed more frequently in pediatric subjects. Postmarketing reports of Stevens-Johnson syndrome in pediatric patients receiving INTELENCE have been reported.

11/06/2018 (SUPPL-23)

Approved Drug Label (PDF)

5 Warnings and Precautions

Newly added subsection:

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

The concomitant use of INTELENCE and other drugs may result in potentially significant drug interactions, some of which may lead to:

Loss of therapeutic effect of concomitant drug or INTELENCE and possible development of resistance.
Possible clinically significant adverse reactions from greater exposures of INTELENCE or other concomitant drugs.

See Table 4 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 INTELENCE therapy and review concomitant medications during INTELENCE therapy.

6 Adverse Reactions

6.1 Clinical Trials Experience

Common Adverse Reactions

Additions and/or revisions underlined:

Table 2: Adverse Drug Reactions (Grades 2 to 4) in at Least 2% of Adult Subjects (Pooled TMC125- C206 and TMC125-C216 Trials)

Laboratory Abnormalities in Treatment-Experienced Patients

Table 3: Selected Grade 2 to 4 Laboratory Abnormalities Observed in Treatment-Experienced Subjects (Pooled TMC125-C206 and TMC125-C216 Trials)

Clinical Trials Experience in Pediatric Subjects (2 Years to Less Than 18 years of age)

The safety assessment in pediatric subjects is based …

7 Drug Interactions

Additions and/or revisions underlined:

7.1 Potential for Other Drugs to Affect INTELENCE

Etravirine is a substrate of CYP3A, CYP2C9, and CYP2C19 …

7.2 Potential for INTELENCE to Affect Other Drugs

Etravirine is an inducer of CYP3A and inhibitor of CYP2C9, CYP2C19 and P-glycoprotein (P- gp) …

7.3 Significant Drug Interactions

Table 4 shows significant drug interactions based on …

Table 4: Significant Drug Interactions

7.4 Drugs Without Clinically Significant Interactions with INTELENCE

In addition to the drugs included in Table 4, the interaction between INTELENCE and …

8 Use in Specific Populations

8.1 Pregnancy

8.2 Lactation

PLLR conversion. Extensive changes; please refer to label for complete information.

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

PATIENT COUNSELING INFORMATION

Addition of the following:

Pregnancy Registry

Inform patients that there is an antiretroviral pregnancy registry to monitor fetal outcomes of pregnant individuals exposed to INTELENCE.

Lactation

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

07/16/2018 (SUPPL-24)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

(additions underlined)

…

Clinical Trials Experience in Pediatric Subjects (2 Years to Less Than 18 years of age)

The safety assessment in children and adolescents is based on two single-arm trials. TMC125-C213 is a Phase 2 trial in which 101 antiretroviral treatment-experienced HIV-1 infected pediatric subjects 6 years to less than 18 years of age received INTELENCE in combination with other antiretroviral agents (Week 24 analysis). TMC125-C234/IMPAACT P1090 is a Phase 1/2 trial in which 20 antiretroviral treatment-experienced HIV-1 infected pediatric subjects 2 years to less than 6 years of age received INTELENCE in combination with other antiretroviral agents (Week 24 analysis).

In TMC125-C213, the frequency, type and severity of adverse drug reactions in pediatric subjects 6 years to less than 18 years of age were comparable to those observed in adult subjects, except for rash which was observed more frequently in pediatric subjects. The most common adverse drug reactions in at least 2% of pediatric subjects were rash and diarrhea. Rash was reported more frequently in female subjects than in male subjects (rash greater than or equal to Grade 2 was reported in 13/64 [20.3%] females versus 2/37 [5.4%] males; discontinuations due to rash were reported in 4/64 [6.3%] females versus 0/37 [0%] males). Rash (greater than or equal to Grade 2) occurred in 15% of pediatric subjects from 6 years to less than 18 years of age. In the majority of cases, rash was mild to moderate, of macular/papular type, and occurred in the second week of therapy. Rash was self-limiting and generally resolved within 1 week on continued therapy. The safety profile for subjects who completed 48 weeks of treatment was similar to the safety profile for subjects who completed 24 weeks of treatment.

In TMC125-C234/IMPAACT P1090, the frequency, type and severity of adverse drug reactions in pediatric subjects 2 years to less than 6 years of age through Week 24 were comparable to those observed in adults. The most common adverse drug reactions (any grade) of pediatric subjects were rash (50% [10/20]) and diarrhea (25% [5/20]). In this age group, no subjects had Grade 3 or Grade 4 rash and no subjects discontinued prematurely due to rash. One subject discontinued etravirine due to asymptomatic lipase elevation.

8 Use in Specific Populations

8.4 Pediatric Use

(subsection updated, additions underlined)

The safety and effectiveness of INTELENCE have been established for the treatment of HIV- infected pediatric patients from 2 years of age to less than 18 years.

Use of INTELENCE in pediatric patients 2 years to less than 18 years of age is supported by evidence from adequate and well-controlled studies of INTELENCE in adults with additional data from two Phase 2 trials in treatment-experienced pediatric subjects, TMC125-C213, 6 years to less than 18 years of age (N=101) and TMC125- C234/IMPAACT P1090, 2 years to less than 6 years of age (N=20). Both studies were open- label, single arm trials of etravirine plus an optimized background regimen. The safety, pharmacokinetics, and efficacy were comparable to that observed in adults.

Treatment with INTELENCE is not recommended in pediatric patients less than 2 years of age. Five HIV-infected subjects from 1 year to < 2 years of age were enrolled in TMC125-C234/IMPAACT P1090. Etravirine exposure was lower than reported in HIV-infected adults (AUC12h geometric mean ratio [90% CI] was 0.59 [0.34, 1.01] for pediatric subjects from 1 year to < 2 years of age compared to adults). Virologic failure at Week 24 (confirmed HIV-RNA greater than or equal to 400 copies/mL) occurred in 3 of 4 evaluable subjects who discontinued before or had reached Week 24. Genotypic and phenotypic resistance to etravirine developed in 1 of the 3 subjects who experienced virologic failure.

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

PATIENT COUNSELING INFORMATION

(additions underlined)

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

Administration

Advise patients to take INTELENCE following a meal twice a day on a regular dosing schedule, as missed doses can result in development of resistance. The type of food does not affect the exposure to etravirine. Inform patients not to take more or less than the prescribed dose of INTELENCE or discontinue therapy with INTELENCE without consulting their physician. INTELENCE must always be used in combination with other antiretroviral drugs.

Advise patients to swallow the INTELENCE tablet(s) whole with a liquid such as water. Instruct patients not to chew the tablets. Patients who are unable to swallow the INTELENCE tablet(s) whole may disperse the tablet(s) in a glass of water. The patient should be instructed to do the following:

place the tablet(s) in 5 mL (1 teaspoon) of water, or at least enough liquid to cover the medication,
stir well until the water looks milky,
ifadd approximately 15 mL (1 tablespoon) of liquid. Water may be used, but orange juice or milk may improve taste. Patients should not place the tablets in orange juice or milk without first adding water. The use of warm (temperature greater than 104°F [greater than 40°C]) or carbonated beverages should be avoided.
drink the mixture immediately,
rinse the glass several times with orange juice, milk or water and completely swallow the rinse each time to make sure the patient takes the entire dose.

…

Immune Reconstitution Syndrome

Advise patients to inform their healthcare provider immediately of any symptoms of infection, as in some patients with advanced HIV infection (AIDS), signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started.

PATIENT INFORMATION

(additions and revisions, please refer to label)