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.

ABRAXANE (NDA-021660)

(PACLITAXEL)

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

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08/25/2020 (SUPPL-47)

Approved Drug Label (PDF)

4 Contraindications

ABRAXANE is contraindicated in patients with:

Baseline neutrophil counts of < 1,500 cells/mm3[see Warnings and Precautions (5.1)]
A history of severe hypersensitivity reactions to ABRAXANE [see Warnings and Precautions (5.5)]

5 Warnings and Precautions

(Additions and/or revisions underlined)

Severe myelosuppression (primarily neutropenia) is dose-dependent and a dose-limiting toxicity of ABRAXANE. In clinical studies, Grade 3-4 neutropenia occurred in 34% of patients with metastatic breast cancer (MBC), 47% of patients with non-small cell lung cancer (NSCLC), and 38% of patients with pancreatic cancer.

Monitor for severe neutropenia and thrombocytopenia by performing complete blood cell counts frequently, including prior to dosing on Day 1 (for MBC) and Days 1, 8, and 15 (for NSCLC and for pancreatic cancer). Do not administer ABRAXANE to patients with baseline absolute neutrophil counts (ANC) of less than 1,500 cells/mm3 [see Contraindications (4)].

5.2 Severe Neuropathy

(Section title revised)

5.5 Severe Hypersensitivity

(Section title revised)

(Additions and/or revisions underlined)

Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have been reported. Do not rechallenge patients who experience a severe hypersensitivity reaction to ABRAXANE with this drug [see Contraindications (4)].

Cross-hypersensitivity between ABRAXANE and other taxane products has been reported and may include severe reactions such as anaphylaxis. Closely monitor patients with a previous history of hypersensitivity to other taxanes during initiation of ABRAXANE therapy.

5.6 Use in Patients with Hepatic Impairment

(Section title revised)

(Additions and/or revisions underlined)

The exposure and toxicity of paclitaxel can be increased in patients with hepatic impairment. Closely monito patients with hepatic impairment for severe myelosuppression.

ABRAXANE is not recommended in patients who have total bilirubin >5 x ULN or AST >10 x ULN. In addition, ABRAXANE is not recommended in patients with metastatic adenocarcinoma of the pancreas who have moderate to severe hepatic impairment (total bilirubin >1.5 x ULN and AST ?10 x ULN). Reduce the starting dose for patients with moderate or severe hepatic impairment [see Dosage and Administration (2.5), Use in Specific Populations (8.7), Clinical Pharmacology (12.3)].

6.2 Postmarketing Experience

(Extensive changes; please refer to label)

8 Use in Specific Populations

8.3 Females and Males of Reproductive Potential

(Additions and/or revisions underlined)

Based on animal studies and mechanism of action, ABRAXANE 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 starting treatment with ABRAXANE.

8.5 Geriatric Use

(Additions and/or revisions underlined)

Of the 229 patients in the randomized study who received ABRAXANE for the treatment of metastatic breast cancer, 13% were at least 65 years of age and < 2% were 75 years or older. This study of ABRAXANE did not include a sufficient number of patients with metastatic breast cancer who were 65 years and older to determine whether they respond differently from younger patients.

8.7 Hepatic Impairment

(Additions and/or revisions underlined)

No adjustment of the starting ABRAXANE dose is required for patients with mild hepatic impairment (total bilirubin > ULN and less than or equal to 1.5 x ULN and aspartate aminotransferase [AST] ? 10 x ULN). Reduce ABRAXANE starting dose in patients with moderate to severe hepatic impairment [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)]. ABRAXANE is not recommended for use in patients with total bilirubin > 5 x ULN or AST > 10 x ULN [see Dosage and Administration (2.5), Warnings and Precautions (5.6), and Clinical Pharmacology (12.3)]. ABRAXANE is not recommended for use in patients with metastatic adenocarcinoma of the pancreas who have moderate to severe hepatic impairment [see Dosage and Administration (2.5)].

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

Patient Counseling Information

(Extensive changes; please refer to label)

Patient Information

(Additions and/or revisions underlined)

ABRAXANE may cause serious side effects, including:

• severe decreased blood cell counts.

severe nerve problems (neuropathy).
severe allergic reactions.

12/06/2019 (SUPPL-46)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.4 Pediatric Use

(additions underlined)

Safety and effectiveness in pediatric patients have not been established. Pharmacokinetics, safety, and antitumor activity of ABRAXANE were assessed in an open-label, dose escalation, dose expansion study (NCT01962103) in 96 pediatric patients aged

1.4 to < 17 years with recurrent or refractory pediatric solid tumors. The maximum tolerated dose (MTD) normalized for body surface area (BSA) was lower in pediatric patients compared to adults. No new safety signals were observed in pediatric patients across these studies.

Paclitaxel protein-bound exposures normalized by dose were higher in 96 pediatric patients (aged 1.4 to < 17 years) as compared to those in adults.

8.7 Hepatic Impairment

(additions underlined)

08/16/2018 (SUPPL-45)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.5 Hypersensitivity

(additions underlined)

Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have been reported. Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with this drug. Cross-hypersensitivity between ABRAXANE and other taxane products has been reported and may include severe reactions such as anaphylaxis.

Patients with a previous history of hypersensitivity to other taxanes should be closely monitored during initiation of ABRAXANE therapy.

5.8 Embryo-Fetal Toxicity

Based on mechanism of action and findings in animals, ABRAXANE can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of paclitaxel formulated as albumin-bound particles to rats during pregnancy at doses lower than the maximum recommended human dose, based on body surface area, caused embryo-fetal toxicities, including intrauterine mortality, increased resorptions, reduced numbers of live fetuses, and malformations.

Advise females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception and avoid becoming pregnant during treatment with ABRAXANE and for at least six months after the last dose of ABRAXANE.

Based on findings from genetic toxicity and animal reproduction studies, advise male patients with female partners of reproductive potential to use effective contraception and avoid fathering a child during treatment with ABRAXANE and for at least three months after the last dose of ABRAXANE.

6 Adverse Reactions

6.4 Postmarketing Experience with ABRAXANE and other Paclitaxel Formulations

(additions underlined)

…

Hypersensitivity Reactions

Severe and sometimes fatal hypersensitivity reactions have been reported with ABRAXANE. The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied. In postmarketing experience, cross-hypersensitivity between ABRAXANE and other taxanes has been reported.

…

Metabolic and Nutritional Disorders

Tumor lysis syndrome has been reported with ABRAXANE.

…

7 Drug Interactions

The metabolism of paclitaxel is catalyzed by CYP2C8 and CYP3A4. Caution should be exercised when administering ABRAXANE concomitantly with medicines known to inhibit or induce either CYP2C8 or CYP3A4.

8 Use in Specific Populations

8.1 Pregnancy

(PLLR conversion)

Risk Summary

Based on its mechanism of action and findings in animals, ABRAXANE can cause fetal harm when administered to a pregnant woman.There are no available human data to inform the drug-associated risk.

In animal reproduction studies, administration of paclitaxel formulated as albumin-bound particles to pregnant rats during the period of organogenesis resulted in embryo-fetal toxicity at doses approximately 2% of the daily maximum recommended human dose on a mg/m2 basis. [see Data]. Advise females of reproductive potential of the potential risk to a fetus.

The background rate of major birth defects and miscarriage is unknown for the indicated population. 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.

Data

Animal Data

In embryo-fetal development studies, intravenous administration of paclitaxel formulated as albumin-bound particles to rats during pregnancy, on gestation days 7 to 17 at doses of 6 mg/m2 (approximately 2% of the daily maximum recommended human dose on a mg/m2 basis) caused embryo-fetal toxicities, as indicated by intrauterine mortality, increased resorptions (up to 5-fold), reduced numbers of litters and live fetuses, reduction in fetal body weight and increase in fetal anomalies. Fetal anomalies included soft tissue and skeletal malformations, such as eye bulge, folded retina, microphthalmia, and dilation of brain ventricles.

8.2 Lactation

(PLLR conversion)

Risk Summary

There are no data on the presence of paclitaxel in human milk, or its effect on the breastfed child or on milk production. In animal studies, paclitaxel and/or its metabolites were excreted into the milk of lactating rats [see Data]. Because of the potential for serious adverse reactions in a breastfed child from ABRAXANE, advise lactating women not to breastfeed during treatment with ABRAXANE and for two weeks after the last dose.

Data

Animal Data

Following intravenous administration of radiolabeled paclitaxel to rats on days 9 to 10 postpartum, concentrations of radioactivity in milk were higher than in plasma and declined in parallel with the plasma concentrations.

8.3 Females and Males of Reproductive Potential

(PLLR conversion)

Pregnancy Testing

Based on animal studies, ABRAXANE can cause fetal harm when administered to a pregnant woman.Females of reproductive potential should have a pregnancy test prior to starting treatment with ABRAXANE.

Contraception

Females

ABRAXANE can cause fetal harm when administered to a pregnant woman.Advise females of reproductive potential to use effective contraception and avoid becoming pregnant during treatment with ABRAXANE and for at least six months after the last dose of ABRAXANE.

Males

Based on findings in genetic toxicity and animal reproduction studies, advise males with female partners of reproductive potential to use effective contraception and avoid fathering a child during treatment with ABRAXANE and for at least three months after the last dose of ABRAXANE.

Infertility

Females and Males

Based on findings in animals, ABRAXANE may impair fertility in females and males of reproductive potential.

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

PATIENT COUNSELING INFORMATION

(additions underlined)

...

Embryo-Fetal Toxicity

ABRAXANE injection can cause fetal harm. Advise patients to avoid becoming pregnant while receiving this drug. Females of reproductive potential should use effective contraception during treatment with ABRAXANE and for at least six months after the last dose of ABRAXANE.
Advise male patients with female partners of reproductive potential to use effective contraception and avoid fathering a child during treatment with ABRAXANE and for at least three months after the last dose of ABRAXANE.
Advise patients not to breastfeed while taking ABRAXANE and for two weeks after receiving the last dose.

Patient Information

(additions, please refer to label)