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.

TOPOTECAN HYDROCHLORIDE (NDA-200582)

(TOPOTECAN HYDROCHLORIDE)

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

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12/16/2019 (SUPPL-3)

Approved Drug Label (PDF)

4 Contraindications

(Additions and/or revisions underlined)

Topotecan Injection is contraindicated in patients who have a history of severe hypersensitivity reactions to topotecan. Reactions have included anaphylactoid reactions.

5 Warnings and Precautions

5.1 Myelosuppression

(Additions and/or revisions underlined)

Topotecan can cause severe myelosuppression.

Grade 4 neutropenia occurred in 78% of 879 patients, with a median duration of 7 days and was most common during Cycle 1 (58% of patients). Grade 4 neutropenia associated with infection occurred in 13% and febrile neutropenia occurred in 5%. Sepsis occurred in 4% and was fatal in 1%.

Grade 4 thrombocytopenia occurred in 27%, with a median duration of 5 days.

Grade 3 or 4 anemia occurred in 37% of patients.

Topotecan can cause fatal typhlitis (neutropenic enterocolitis). Consider the possibility of typhlitis in patients presenting with fever, neutropenia, and abdominal pain.

Administer the first cycle of Topotecan Injection only to patients with a baseline neutrophil count of greater than or equal to 1,500/mm3 and a platelet count greater than or equal to 100,000/mm3. Monitor blood counts frequently during treatment. Withhold and reduce dose of Topotecan Injection based on neutrophil counts, platelet counts and hemoglobin levels.

5.4 Embryo-Fetal Toxicity

(Additions and/or revisions underlined)

Based on animal data, topotecan can cause fetal harm when administered to a pregnant woman. Topotecan caused embryolethality, fetotoxicity, and teratogenicity in rats and rabbits when administered during organogenesis. Advise women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for 6 months after the last dose of Topotecan Injection. Advise males with a female partner of reproductive potential to use effective contraception during treatment with Topotecan Injection and for 3 months after the last dose.

6 Adverse Reactions

(Additions and/or revisions underlined)

The following serious adverse reactions are described elsewhere in the labeling:

Myelosuppression
Interstitial Lung Disease
Extravasation and Tissue Injury

6.1 Clinical Trials Experience

(Additions and/or revisions underlined)

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data in Warnings and Precautions reflect exposure to topotecan from 8 trials in which 879 patients with small cell lung cancer (SCLC) and other solid tumors received topotecan 1.5 mg/m2 by intravenous infusion daily for 5 consecutive days, starting on Day 1 of a 21-day cycle.

Small Cell Lung Cancer (SCLC)

The safety of topotecan was evaluated in randomized, comparative trial in patients with recurrent or progressive SCLC (Study 090). Table 1 shows the Grade 3 or 4 hematologic and non-hematologic adverse reactions in patients with SCLC.

Hepatobiliary Disorders

Based on 879 patients with small cell lung cancer or another solid tumor who were treated with topotecan, Grade 3 or 4 elevated aspartate (AST) or alanine transaminase (ALT) occurred in 4% and Grade 3 or 4 elevated bilirubin occurred in less than 2% of patients

6.2 Postmarketing Experience

(Additions and/or revisions underlined)

The following reactions have been identified during postapproval use of topotecan. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and Lymphatic System

Severe bleeding (in association with thrombocytopenia)

Hypersensitivity

Allergic manifestations, anaphylactoid reactions, angioedema

Gastrointestinal

Abdominal pain potentially associated with neutropenic enterocolitis, gastrointestinal perforation

Pulmonary

Interstitial lung disease

Skin and Subcutaneous Tissue

Severe dermatitis, severe pruritus

General and Administration Site Conditions

Extravasation, mucosal inflammation

8 Use in Specific Populations

8.1 Pregnancy

(Pregnancy and Lactation Labeling Rule (PLLR) conversion; Additions and/or revisions underlined)

Risk Summary

Based on animal data and its mechanism of action, Topotecan Injection can cause fetal harm when administered to a pregnant woman. There are no available clinical data on the use of topotecan in pregnancy. Topotecan caused embryolethality, fetotoxicity, and teratogenicity in rats and rabbits when administered during organogenesis at doses similar to the clinical dose. Advise pregnant women of the potential risk to a fetus.

In the U.S. general population, the background risk of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies.

Data

Animal Data

In rabbits, an intravenous dose of 0.10 mg/kg/day [(about equal to the 1.5 mg/m2 clinical dose based on body surface area (BSA)] given on Days 6 through 20 of gestation caused maternal toxicity, embryolethality, and reduced fetal body weight. In the rat, an intravenous dose of 0.23 mg/kg/day (about equal to the 1.5 mg/m2 clinical dose based on BSA) given for 14 days before mating through gestation Day 6 caused fetal resorption, microphthalmia, pre-implant loss, and mild maternal toxicity.

Administration of an intravenous dose of 0.10 mg/kg/day (about half the 1.5 mg/m2 clinical dose based on BSA) given to rats on Days 6 through 17 of gestation caused an increase in post-implantation mortality.

This dose also caused an increase in total fetal malformations. The most frequent malformations were of the eye (microphthalmia, anophthalmia, rosette formation of the retina, coloboma of the retina, ectopic orbit), brain (dilated lateral and third ventricles), skull, and vertebrae.

8.2 Lactation

(Pregnancy and Lactation Labeling Rule (PLLR) conversion; Additions and/or revisions underlined)

Risk Summary

There are no data on the presence of topotecan or its metabolites in human milk or their effects on the breastfed infant or on milk production. Lactating rats excrete high concentrations of topotecan in milk. Because of the potential for serious adverse reactions in breastfed infants, advise women not to breastfeed during treatment with Topotecan Injection and for 1 week after the last dose.

Data

Following intravenous administration of topotecan to lactating rats at a dose of 4.72 mg/m2 (about twice the 1.5 mg/m2 clinical dose based on BSA), topotecan was excreted into milk at concentrations up to 48-fold higher than those in plasma.

8.3 Females and Males of Reproductive Potential

(Additions and/or revisions underlined)

Pregnancy Testing

Verify pregnancy status of females of reproductive potential prior to initiating Topotecan Injection.

Contraception

Topotecan can cause fetal harm when administered to a pregnant woman.

Females

Advise female patients of reproductive potential to use effective contraception during treatment with Topotecan Injection and for 6 months after the last dose.

Males

Topotecan may damage spermatozoa, resulting in possible genetic and fetal abnormalities. Advise males with a female partner of reproductive potential to use effective contraception during treatment with Topotecan Injection and for 3 months after the last dose.

Infertility

Females

Topotecan may have both acute and long-term effects on fertility.

Males

Effects on spermatogenesis occurred in animals administered topotecan.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

(Additions and/or revisions underlined)

Of the 879 patients with SCLC or another solid tumor who received topotecan in clinical trials, 32% were aged 65 years and older, while 3.8% were aged 75 years and older. No overall differences in effectiveness or safety were observed between these patients and younger patients and other reported clinical experience has not identified differences in responses between the elderly and younger patients.

8.6 Renal Impairment

(Additions and/or revisions underlined)

Reduce the dose of Topotecan Injection for patients with a CLcr of 20 to 39 mL/min. No dosage adjustment is recommended for patients with CLcr greater than or equal to 40 mL/min. Insufficient data are available in patients with CLcr less than 20 mL/min to provide a dosage recommendation for Topotecan Injection.

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

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

Myelosuppression

Inform patients that topotecan decreases blood cell counts such as white blood cells, platelets, and red blood cells. Advise patients to notify their healthcare provider promptly for fever, other signs of infection, or bleeding.

Interstitial Lung Disease (ILD)

Inform patients of the risks of severe ILD. Advise patients to contact their healthcare provider immediately to report new or worsening respiratory symptoms.

Embryo-Fetal Toxicity

Advise females of reproductive potential and males with female partners of reproductive potential of the potential risk to a fetus. Advise women to contact their healthcare provider if they become pregnant, or if pregnancy is suspected during treatment with Topotecan Injection.

Advise females of reproductive potential to use effective contraception during treatment with Topotecan Injection and for 6 months after the last dose.

Advise males with a female sexual partner of reproductive potential to use effective contraception during treatment with Topotecan Injection and for 3 months after the last dose.

Lactation

Advise women to discontinue breastfeeding during treatment with Topotecan Injection and for at least 1 week after the last dose.

Infertility

Advise male and female patients of the potential risk for impaired fertility.

01/29/2016 (SUPPL-2)

Approved Drug Label (PDF)

Boxed Warning

WARNING: BONE MARROW SUPPRESSION

Topotecan injection can cause severe myelosuppression. Administer only to patients with baseline neutrophil counts of greater than or equal to 1,500 cells/mm3and platelet counts greater than or equal to 100,000 cells/mm3. Monitor blood cell counts.