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.

IXEMPRA KIT (NDA-022065)

(IXABEPILONE)

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

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01/21/2022 (SUPPL-11)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.1 Peripheral Neuropathy

Additions underlined

Peripheral neuropathy (sensory and motor neuropathy) occurred in patients treated with IXEMPRA in combination with capecitabine and in patients treated with single agent IXEMPRA as shown in Table 3.

Please refer to label to view Table 3

…

Monitor patients for symptoms of neuropathy, such as burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, or neuropathic pain. Closely monitor patients with diabetes mellitus or preexisting peripheral neuropathy. Withhold, reduce, or discontinue IXEMPRA depending on the severity and persistence of peripheral neuropathy [see Dosage and Administration (2.3)].

5.2 Myelosuppression

Additions underlined

Severe, life threatening, or fatal myelosuppression can occur in patients treated with IXEMPRA.

…

IXEMPRA is contraindicated for use in patients with a neutrophil count of <1500 cells/mm3 [see Contraindications (4)].

Monitor patients receiving IXEMPRA for myelosuppression with frequent peripheral blood cell counts. Withhold, reduce, or discontinue IXEMPRA depending on the severity and persistence of myelosuppression [see Dosage and Administration (2.3)].

5.6 Embryo-Fetal Toxicity

Additions and/or revisions underlined

Based on findings in animals and its mechanism of action, IXEMPRA can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, intravenous administration of ixabepilone to pregnant rats and rabbits during the period of organogenesis caused maternal toxicity, embryo-fetal lethality, and fetal abnormalities at maternal exposures below the human clinical exposure based on AUC. Advise females of reproductive potential and pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with IXEMPRA and for 7 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with IXEMPRA and for 4 months after the last dose [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.1)].

5.7 Alcohol Content

Additions underlined

The alcohol content in a dose of IXEMPRA may affect the central nervous system and should be taken into account for patients in whom alcohol intake should be avoided or minimized. Consideration should be given to the alcohol content in IXEMPRA on the ability to drive or use machines immediately after the infusion. Each administration of IXEMPRA at the recommended dosage of 40 mg/m2 delivers approximately 8.4 g/m2 of ethanol. For a patient with a BSA of 2.0 m2, this would deliver approximately 16.8 grams of ethanol [see Description (11)].

6 Adverse Reactions

Addition of the following to the bulleted line listing:

Cardiac Adverse Reactions [see Warnings and Precautions (5.5)]

8 Use in Specific Populations

8.4 Pediatric Use

Additions and/or revisions underlined

The alcohol content of IXEMPRA should be taken into account when given to pediatric patients [see Warnings and Precautions (5.6)].

The safety and effectiveness of IXEMPRA in pediatric patients has not been established. Safety and efficacy were assessed, but not established for IXEMPRA across two studies: an open-label, dose-finding trial in 21 patients aged 2 to 18 years with advanced or refractory solid tumors and hematologic malignancies [NCT00030108] and a trial with 28 patients aged 3 to 18 years with advanced or refractory solid tumors [NCT00331643] that was terminated early due to lack of efficacy. No new safety signals were identified. The median BSA normalized clearance of ixabepilone in 16 patients aged 2 to 18 years

(17 L/h/m2) was within range of that of patients greater than 18 years (20 L/h/m2).

8.6 Hepatic Impairment

Additions underlined

Monitor hepatic function before initiation of IXEMPRA and periodically thereafter.

Dose reduction is recommended when administering IXEMPRA as a single agent to patients with hepatic impairment [see Dosage and Administration (2.4)].

IXEMPRA in combination with capecitabine is contraindicated in patients with AST or ALT >2.5 x ULN or bilirubin >1 x ULN [see Contraindications (4)].

The alcohol content of IXEMPRA should be taken into account when given to patients with hepatic impairment [see Warnings and Precautions (5.7)].

8.1 Pregnancy

PLLR conversion

Risk Summary

Based on findings in animals and its mechanism or action, IXEMPRA can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data on the use of IXEMPRA in pregnant women to inform the drug- associated risk. IXEMPRA contains alcohol which can interfere with neurobehavioral development [see Clinical Considerations]. In animal reproduction studies, intravenous administration of ixabepilone to pregnant rats and rabbits during the period of organogenesis caused maternal toxicity, embryo-fetal lethality, and fetal abnormalities at maternal exposures below the human clinical exposure based on AUC (see Data). Advise females of reproductive potential and pregnant women of the potential risk to a fetus.

The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

IXEMPRA contains alcohol [see Warnings and Precautions (5.7)]. Published studies have demonstrated that alcohol is associated with fetal harm including central nervous system abnormalities, behavioral disorders, and impaired intellectual development.

Data

Animal data

In embryo-fetal development studies, pregnant rats and rabbits received intravenous doses of 0.02, 0.08, and 0.3 mg/kg/day and 0.01, 0.03, 0.11, and 0.3 mg/kg/day, respectively during the period of organogenesis. In rats, an increase in resorptions and post-implantation loss and a decrease in the number of live fetuses and fetal weight was observed at the maternally toxic dose of 0.3 mg/kg/day (approximately 0.1 times the human clinical exposure based on AUC). Abnormalities included a reduced ossification of caudal vertebrae, sternebrae, and metacarpals. In rabbits, ixabepilone caused maternal toxicity (death) and embryo-fetal toxicity (resorptions) at 0.3 mg/kg/day (approximately

0.1 times the human clinical dose based on body surface area).

8.2 Lactation

PLLR conversion

Risk Summary

There is no data on the presence of IXEMPRA in human milk, the effects on the breastfed child, or the effects on milk production. Ixabepilone and/or its metabolites were present in milk of lactating rats (see Data). Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with IXEMPRA and for 2 weeks after the last dose.

Data

Animal data

Following intravenous administration of radiolabeled ixabepilone to rats on days 7 to 9 postpartum, concentrations of radioactivity in milk were comparable with those in plasma and declined in parallel with the plasma concentrations.

8.3 Females and Males of Reproductive Potential

PLLR conversion

Based on findings in animals and its mechanism of action, IXEMPRA can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to initiating treatment with IXEMPRA.

Contraception

Females

Advise females of reproductive potential to use effective contraception during treatment with IXEMPRA and for 7 months after the last dose.

Males

Based on genotoxicity and animal studies, advise male patients with female partners of reproductive potential to use effective contraception during treatment with IXEMPRA and for 4 months after the last dose [see Nonclinical Toxicology (13.1)].

Infertility

Based on findings in animals, IXEMPRA may impair male and female fertility [see Nonclinical Toxicology (13.1)].

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

PATIENT COUNSELING INFORMATION

Additions underlined

…

Embryo-Fetal Toxicity

Advise females of reproductive potential and pregnant women of the potential risk to a fetus. Advise patients to inform their healthcare provider of a known or suspected pregnancy.

Advise females of reproductive potential to use effective contraception during treatment with IXEMPRA and for 7 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with IXEMPRA and for 4 months after the last dose [see Warnings and Precautions (5.6) and Use in Specific Populations (8.1, 8.3)].

Lactation

Advise women not to breastfeed during treatment with IXEMPRA and for 2 weeks after the last dose [see Use in Specific Populations (8.2)].

Infertility

Advise males and females of reproductive potential that IXEMPRA may impair fertility

[see Use in Specific Populations (8.3)].

Alcohol Content in IXEMPRA

Explain to patients the possible effects of the alcohol content in IXEMPRA, including possible effects on the central nervous system [see Warnings and Precautions (5.7)].

PATIENT INFORMATION

Additions underlined

…

Before you receive IXEMPRA, tell your healthcare provider about all of your medical conditions, including if you:

…

are pregnant or plan to become pregnant. IXEMPRA can harm your unborn baby. Tell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with IXEMPRA.
- If you are able to become pregnant, your healthcare provider should do a pregnancy test before you start treatment with IXEMPRA.
- Females who are able to become pregnant should use effective birth control during treatment with IXEMPRA and for 7 months after the last dose.
- Males with female partners who are able to become pregnant should use effective birth control during treatment with IXEMPRA and for 4 months after the last dose.
are breastfeeding or plan to breastfeed. It is not known if IXEMPRA passes into breast milk. Do not breastfeed during treatment with IXEMPRA and for 2 weeks after the last dose.
…