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.

KORLYM (NDA-202107)

(MIFEPRISTONE)

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

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11/05/2019 (SUPPL-8)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.6 Use of Strong CYP3A Inhibitors

Additions and/or revisions underlined:

… KORLYM should be used in combination with strong CYP3A inhibitors only when necessary, and in such cases the dose should be limited to 900 mg per day.

7 Drug Interactions

7.2 CYP3A Inhibitors

Additions and/or revisions underlined:

.. The dose of KORLYM should be limited to 900 mg, and strong inhibitors of CYP3A should be used only when necessary.

8 Use in Specific Populations

8.1 Pregnancy

PLLR conversion; additions and/or revisions underlined:

Risk Summary

KORLYM is contraindicated in pregnancy because the use of KORLYM results in pregnancy loss. There are no data that assess the risk of birth defects in women exposed to KORLYM during pregnancy.

Available data limited to exposure following a single dose of mifepristone during pregnancy showed a higher rate of major birth defects compared to the general population comparator.

Mifepristone administered to pregnant mice, rats, and rabbits during organogenesis caused pregnancy loss in all species at clinically relevant doses based on body surface area comparisons. The inhibition of both endogenous and exogenous progesterone by mifepristone at the progesterone receptor results in pregnancy loss. If KORLYM is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

The estimated risk of fetal loss is elevated in patients with active Cushing’s syndrome (24-30%), and the risk of major birth defects is unknown. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2-4% and 15-20%, respectively.

Data

Human Data

There are no data on long term exposure to mifepristone in pregnancy. Available data are limited to exposure to a single dose of mifepristone for pregnancy termination. In a prospective study in France of 46 pregnancies exposed to a single dose of mifepristone alone and 59 pregnancies exposed to a single dose of mifepristone and misoprostol, the overall major birth defect rate (4%) was greater than the general population background rate of 2 to 3% (2 birth defects in each group). There was no pattern of birth defects identified.

Animal Data

Reproductive studies were performed in mice, rats and rabbits at doses of 0.25 to 4.0 mg/kg (less than human exposure at the maximum clinical dose, based on body surface area). Because of the anti- presentational activity of mifepristone, fetal losses were much higher than in control animals. Skull deformities were detected in rabbit studies at less than human exposure, although mifepristone did not cause any adverse developmental effects in rats or mice during organogenesis. These deformities were most likely due to the mechanical effects of uterine contractions resulting from antagonism of the progesterone receptor.

8.2 Lactation

PLLR conversion; additions and/or revisions underlined:

Risk Summary

Mifepristone is present in human milk, however, there are no data on the amount of mifepristone in human milk, the effects on the breastfed infant, or the effects on milk production during long term use of mifepristone (see Data). The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Korlym and any potential adverse effects on the breastfed child from Korlym or from the underlying maternal condition.

Clinical Considerations

To minimize exposure to a breastfed infant, women who discontinue or interrupt KORLYM treatment may consider pumping and discarding milk during treatment and for 18-21 days (5-6 half-lives) after the last dose, before breastfeeding.

Data

Available published data based on intake of a single dose of 600 mg of mifepristone in 10 breastfeeding women who were 6-12 months postpartum showed a small amount in breast milk (the estimated relative infant dose was 0.5%). The half-life of mifepristone is longer with repeat dosing compared to a single dose; therefore, there may be greater exposure with long term use.

8.3 Females and Males of Reproductive Potential

PLLR conversion; newly added information:

Pregnancy Testing

Due to its anti-presentational activity, KORLYM causes pregnancy loss. Perform pregnancy testing before the initiation of treatment with KORLYM or if treatment is interrupted for more than 14 days in females of reproductive potential.

Contraception

Recommend non-hormonal contraception for the duration of treatment and for one month after stopping treatment. KORLYM interferes with the effectiveness of hormonal contraceptives.

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

MEDICATION GUIDE

Additions and/or revisions underlined:

What are the possible side effects of KORLYM? KORLYM can cause serious side effects including:

Loss of pregnancy
Disruption of menstrual cycle

PATIENT COUNSELING INFORMATION

Additions and/or revisions underlined:

17.1 Importance of Preventing Pregnancy

KORLYM reduces the effectiveness of hormonal contraceptives. Counsel females of reproductive potential regarding pregnancy prevention and planning with a non-hormonal contraceptive prior to use of KORLYM and up to one month after the end of treatment.

05/16/2017 (SUPPL-7)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.6 Use of Strong CYP3A Inhibitors

(Additions and/or revisions are underlined)

KORLYM should be used with caution in patients taking ketoconazole and other strong inhibitors of CYP3A, such as itraconazole, nefazodone, ritonavir, nelfinavir, indinavir, atazanavir, amprenavir, fosamprenavir, clarithromycin, conivaptan, lopinavir/ritonavir, posaconazole, saquinavir, telithromycin, or voriconazole, as these could increase the concentration of mifepristone in the blood. The benefit of concomitant use of these agents should be carefully weighed against the potential risks. KORLYM should be used in combination with strong CYP3A inhibitors only when necessary, and in such cases the dose should be limited to 600 mg per day.

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions and/or revisions are underlined)

The adverse reactions that occurred in greater than or equal to 10% of the Cushing’s syndrome patients receiving KORLYM, regardless of relationship to KORLYM, are shown in Table 2.

Table 2. Treatment Emergent Adverse Events Occurring in greater than or equal to 10% of Cushing’s Syndrome Patients Receiving KORLYM

7 Drug Interactions

7.2 CYP3A Inhibitors

(Additions and/or revisions are underlined)

Ketoconazole and other strong inhibitors of CYP3A, such as itraconazole, nefazodone, ritonavir, nelfinavir, indinavir, atazanavir, amprenavir and fosamprenavir, clarithromycin, conivaptan, lopinavir/ritonavir, posaconazole, saquinavir, telithromycin, or voriconazole may increase exposure to mifepristone. Caution should be used when strong CYP3A inhibitors are prescribed in combination with KORLYM. The benefit of concomitant use of these agents should be carefully weighed against the potential risks. The dose of KORLYM should be limited to 600 mg, and strong inhibitors of CYP3A should be used only when necessary.

10/25/2016 (SUPPL-6)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience (subsection added)

The following adverse reaction has been identified during post-approval use of KORLYM. 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.

- Angioedema