Drug Safety-related Labeling Changes (SrLC)

Get Email Alerts | Guide

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.

HYCAMTIN (NDA-020671)

(TOPOTECAN HYDROCHLORIDE)

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

Download Data

Expand all

09/05/2018 (SUPPL-23)

Approved Drug Label (PDF)

Boxed Warning

Boxed Warning

WARNING: MYELOSUPPRESSION

HYCAMTIN can cause severe myelosuppression. Administer first cycle only to patients with baseline neutrophil counts of greater than or equal to 1,500/mm3 and platelet counts greater than or equal to 100,000/mm3. Monitor blood cell counts.

4 Contraindications

4 CONTRAINDICATIONS

HYCAMTIN 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 are underlined)

HYCAMTIN can cause severe myelosuppression.

Single Agent:

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% of patients and was fatal in 1%. Grade 4 thrombocytopenia occurred in 27%, with a median duration of 5 days. Monotherapy: Grade 3 or 4 anemia occurred in 37% of patients.

Combination with Cisplatin

Grade 4 neutropenia occurred in 48% and Grade 4 thrombocytopenia occurred in 7% of 147 patients. Grade 3 or 4 anemia occurred in 40% 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 HYCAMTIN for 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 HYCAMTIN for injection based on neutrophil counts, platelet counts and hemoglobin levels.

5.2 Interstitial Lung Disease

(Additions and/or revisions are underlined)

Interstitial lung disease (ILD), including fatalities, can occur with HYCAMTIN. Underlying risk factors include history of ILD, pulmonary fibrosis, lung cancer, thoracic radiation, and use of pneumotoxic drugs or colony stimulating factors. Monitor for pulmonary symptoms indicative of ILD. Permanently discontinue HYCAMTIN for injection if ILD is confirmed.

5.3 Embryo-Fetal Toxicity

(Additions and/or revisions are underlined)

Based on animal data, HYCAMTIN 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 HYCAMTIN for injection.

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

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions and/or revisions are 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 HYCAMTIN for injection from eight trials in which 879 patients with ovarian cancer or small cell lung cancer (SCLC) received HYCAMTIN for injection 1.5 mg/m2 by intravenous infusion daily for 5 consecutive days, starting on Day 1 of a 21 day cycle and from one trial (Study GOG 0179) in which 147 patients with cervical cancer received HYCAMTIN for injection 0.75 mg/m2 by intravenous infusion daily on Days 1, 2, and 3, with cisplatin 50 mg/m2 by intravenous infusion on Day 1, of a 21-day cycle.

Ovarian Cancer

The safety of HYCAMTIN for injection was evaluated in a randomized trial conducted in 226 patients with metastatic ovarian cancer (Study 039). Table 1 shows the incidence of Grade 3 and 4 hematologic and non-hematologic adverse reactions that occurred in patients receiving HYCAMTIN for injection.

Table 1. Adverse Reactions Occurring in Greater than or Equal to 5% of Patients with Ovarian Cancer in Study 039

(Table has been revised; please refer to label)

…

Small Cell Lung Cancer (SCLC)

The safety of HYCAMTIN for injection was evaluated in randomized, comparative trial in patients with recurrent or progressive SCLC (Study 090). Table 2 shows the Grade 3 or 4 hematologic and non-hematologic adverse reactions in patients with SCLC.

Table 2. Adverse Reactions Occurring in Greater than or Equal to 5% of Patients with Small Cell Lung Cancer in Study 090

(Table has been revised; please refer to label)

Hepatobiliary Disorders in Ovarian and Small Cell Lung Cancer

Based on the combined experience of 453 patients with metastatic ovarian cancer and 426 patients with SCLC treated with HYCAMTIN for injection, Grade 3 or 4 increases aspartate transaminase (AST) or alanine transaminase (ALT) occurred in 4% and Grade 3 or 4 elevated bilirubin occurred in less than 2%.

Cervical Cancer

The safety of HYCAMTIN for injection was evaluated in a comparative trial of HYCAMTIN with cisplatin versus cisplatin as a single agent in patients with cervical cancer (Study GOG 0179). Table 3 shows the hematologic and non-hematologic adverse reactions in patients with cervical cancer.

Table 3. Adverse Reactions Occurring in Greater than or Equal to 5% of Patients with Cervical Cancer (Between-Arm Difference ? 2%)a in Study GOG 0179

(Table has been revised; please refer to label)

6.2 Postmarketing Experience

(Additions and/or revisions are underlined)

The following reactions have been identified during post approval use of HYCAMTIN. 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: 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.

ADVERSE REACTIONS

(Additions and/or revisions are underlined)

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

Myelosuppression
Interstitial Lung Disease
Extravasation and Tissue Injury

8 Use in Specific Populations

8.1 Pregnancy

(Additions and/or revisions are underlined)

Risk Summary

Based on animal data and its mechanism of action, HYCAMTIN can cause fetal harm when administered to a pregnant woman. There are no available clinical data on the use of HYCAMTIN 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

(Additions and/or revisions are 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 HYCAMTIN for 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) to lactating rats, 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 are underlined)

Pregnancy Testing

Verify pregnancy status of females of reproductive potential prior to initiating HYCAMTIN for injection.

Contraception

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

Females

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

Males

HYCAMTIN 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 HYCAMTIN for injection and for 3 months after the last dose.

Infertility

Females can have both acute and long-term effects on fertility.

Males

Effects on spermatogenesis occurred in animals administered topotecan.

8.5 Geriatric Use

(Additions and/or revisions are underlined)

Of the 879 patients with metastatic ovarian cancer or small cell lung cancer in clinical trials of HYCAMTIN for injection, 32% were aged 65 years and older, while 3.8% were aged 75 years and older. Of the 140 patients with Stage IV-B, relapsed, or refractory cervical cancer in clinical trials of HYCAMTIN for injection who received HYCAMTIN with cisplatin in the randomized clinical trial, 6% were aged 65 years and older, while 3% were aged 75 years and older.

…

8.6 Renal Impairment

(Additions and/or revisions are underlined)

Reduce the dose of HYCAMTIN for injection in 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 HYCAMTIN for injection.

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

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Myelosuppression

Inform patients that HYCAMTIN 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 HYCAMTIN for injection.

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

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

Lactation

Advise women to discontinue breastfeeding during treatment and for 1 week after the last dose of HYCAMTIN for injection.

Infertility

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

Asthenia and Fatigue

Advise patients that HYCAMTIN for injection may cause asthenia or fatigue. These symptoms may impair the ability to safely drive or operate machinery.