TOPOTECAN HYDROCHLORIDE

Boxed Warning 05/2020 Contraindications ( 4 ) 05/2020 Warnings and Precautions ( 5.1 , 5.2 , 5.3 ) 05/2020

1 INDICATIONS AND USAGE Topotecan hydrochloride for injection is a topoisomerase inhibitor indicated for treatment of: • Patients with metastatic ovarian cancer after disease progression on or after initial or subsequent chemotherapy, as a single agent. ( 1.1 ) • Patients with small cell lung cancer (SCLC) platinum-sensitive disease who progressed at least 60 days after initiation of first-line chemotherapy, as a single agent. ( 1.2 ) • Patients with Stage IV-B, recurrent, or persistent cervical cancer which is not amenable to curative treatment, in combination with cisplatin. ( 1.3 ) 1.1 Ovarian Cancer Topotecan hydrochloride for injection, as a single agent, is indicated for the treatment of patients with metastatic ovarian cancer after disease progression on or after initial or subsequent chemotherapy. 1.2 Small Cell Lung Cancer Topotecan hydrochloride for injection, as a single agent, is indicated for the treatment of patients with small cell lung cancer (SCLC) with platinum-sensitive disease who progressed at least 60 days after initiation of first-line chemotherapy. 1.3 Cervical Cancer Topotecan hydrochloride for injection in combination with cisplatin is indicated for the treatment of patients with Stage IV-B, recurrent, or persistent cervical cancer not amenable to curative treatment.

2 DOSAGE AND ADMINISTRATION Ovarian Cancer and Small Cell Lung Cancer: 1.5 mg/m 2 by intravenous infusion over 30 minutes daily for 5 consecutive days, starting on Day 1 of a 21-day cycle ( 2.1 , 2.2 ) Cervical Cancer: 0.75 mg/m 2 by intravenous infusion over 30 minuteson Days 1, 2, and 3, with cisplatin 50 mg/m 2 on Day 1, of a 21-day cycle ( 2.3 ) Renal Impairment: Reduce dose if creatinine clearance (CLcr) 20 to 39 mL/min ( 2.6 ) 2.1 Important Safety Information Verify dosage using body surface area. Do not exceed a single dose of 4 mg intravenously. 2.2 Recommended Dosage for Ovarian Cancer The recommended dosage of topotecan hydrochloride for injection is 1.5 mg/m 2 by intravenous infusion over 30 minutes daily for 5 consecutive days, starting on Day 1 of a 21-day cycle until disease progression or unacceptable toxicity. 2.3 Recommended Dosage for Small Cell Lung Cancer (SCLC) The recommended dosage of topotecan hydrochloride for injection is 1.5 mg/m 2 by intravenous infusion over 30 minutes daily for 5 consecutive days, starting on Day 1 of a 21-day cycle. 2.4 Recommended Dosage for Cervical Cancer The recommended dosage of topotecan hydrochloride for injection is 0.75 mg/m 2 by intravenous infusion over 30 minutes daily on Days 1, 2, and 3, in combination with cisplatin 50 mg/m 2 on Day 1, of a 21-day cycle. 2.5 Dosage Modifications for Adverse Reactions Hematologic Do not administer subsequent cycles of topotecan hydrochloride for injection until neutrophils recover to greater than 1,000/mm 3 , platelets recover to greater than 100,000/mm 3 , and hemoglobin levels recover to greater than or equal to 9 g/dL (with transfusion if necessary). For topotecan hydrochloride for injection as a single agent, reduce the dose to 1.25 mg/m 2 /day for: •neutrophil counts of less than 500/mm 3 or administer granulocyte-colony stimulating factor (G-CSF) starting no sooner than 24 hours following the last dose platelet counts less than 25,000/mm 3 during previous cycle For topotecan hydrochloride for injection in combination with cisplatin, reduce the dose to 0.6 mg/m 2 /day (and further to 0.45 mg/m 2 if necessary) for: febrile neutropenia (defined as neutrophil counts less than 1,000/mm 3 with temperature of greater than or equal to 38.0°C (100.4°F) or administer G-CSF starting no sooner than 24 hours following the last dose platelet counts less than 25,000/mm 3 during previous cycle 2.6 Dosage Modification for Renal Impairment For topotecan hydrochloride for injection as a single agent, reduce the dose to 0.75 mg/m 2 /day for patients with creatinine clearance (CLcr) of 20 to 39 mL/min (calculated with the Cockcroft-Gault method using ideal body weight) [see Clinical Pharmacology ( 12.3 )] . 2.7 Preparation and Intravenous Administration Visually inspect for particulate matter and discoloration prior to administration, whenever solution and container permit. Preparation Reconstitute each 4 mg vial of topotecan hydrochloride for injection with 4 mL sterile water for injection, USP. Dilute the appropriate volume of the reconstituted solution in either 0.9% sodium chloride intravenous infusion, USP or 5% dextrose in water injection, USP. Stability Because the vials contain no preservative, use contents immediately after reconstitution. Discard any unused portion. Store reconstituted product diluted for infusion at approximately 20°C to 25°C (68°F to 77°F) protected from light for no more than 24 hours. Discard after 24 hours. Topotecan hydrochloride for injection is a cytotoxic drug. Follow applicable handling and disposal procedures. 1

3 DOSAGE FORMS AND STRENGTHS For injection: 4 mg (topotecan free base) lyophilized powder in a single-dose vial for reconstitution; light yellow to greenish powder. For injection: 4 mg (free base) lyophilized powder in a single-dose vial. ( 3 )

4 CONTRAINDICATIONS Topotecan Hydrochloride for Injection is contraindicated in patients who have a history of severe hypersensitivity reactions to topotecan. Reactions have included anaphylactoid reactions [see Adverse Reactions ( 6.2 )] . History of severe hypersensitivity reactions to topotecan ( 4 )

6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: Myelosuppression [see Warnings and Precautions ( 5.1 )] Interstitial Lung Disease (ILD) [see Warnings and Precautions ( 5.2 )] Extravasation and Tissue Injury [see Warnings and Precautions ( 5.3 )] Ovarian Cancer The most common Grade 3 or 4 hematologic adverse reactions (incidence > 5%) were neutropenia, anemia, thrombocytopenia, and febrile neutropenia. ( 6.1 ) The most common (incidence > 5%) non-hematologic adverse reactions (all Grades) were nausea, vomiting, fatigue, diarrhea, and dyspnea. ( 6.1 ) SCLC The most common Grade 3 or 4 hematologic adverse reactions were (incidence > 5%) neutropenia, anemia, thrombocytopenia, and febrile neutropenia. ( 6.1 ) The most common (incidence > 5%) non-hematologic adverse reactions (all Grades) were asthenia, dyspnea, nausea, pneumonia, abdominal pain, and fatigue. ( 6.1 ) Cervical Cancer The most common Grade 3 or 4 hematologic adverse reactions were (incidence > 5%) neutropenia, anemia, and thrombocytopenia. ( 6.1 ) The most common (incidence > 25% and ≥ 2% higher than cisplatin alone) non-hematologic adverse reactions were pain, vomiting, and infection/febrile neutropenia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Accord Healthcare Inc. at 1-866-941-7875 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience 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 hydrochloride for injection from eight trials in which 879 patients with ovarian cancer or small cell lung cancer (SCLC) received topotecan hydrochloride for injection 1.5 mg/m 2 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 topotecan hydrochloride for injection 0.75 mg/m 2 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 topotecan hydrochloride for injection was evaluated in a randomized trial conducted in 226 patients with metastatic ovarian cancer (Study 039) [see Clinical Studies ( 14.1 )] . Table 1 shows the incidence of Grade 3 and 4 hematologic and non-hematologic adverse reactions that occurred in patients receiving topotecan hydrochloride for injection. Table 1. Adverse Reactions Occurring in Greater than or Equal to 5% of Patients With Ovarian Cancer in Study 039 a Death related to sepsis occurred in 2% of patients receiving topotecan hydrochloride for injection and 0% of patients receiving paclitaxel. b Pain includes body pain, skeletal pain, and back pain. Adverse Reactions Topotecan Hydrochloride for Injection (n = 112) Paclitaxel (n = 114) Grade 3-4 (%) Grade 3-4 (%) Hematologic Grade 4 neutropenia (< 500/mm 3 ) Grade 3 or 4 anemia (Hgb < 8 g/dL) Grade 4 thrombocytopenia (< 25,000/mm 3 ) Febrile neutropenia 80 41 27 23 21 6 3 4 Non-Hematologic Infections Sepsis a 5 2 Respiratory, thoracic, and mediastinal Dyspnea 6 5 Gastrointestinal Vomiting 10 3 Nausea 10 2 Diarrhea 6 1 Abdominal pain 5 4 Intestinal obstruction 5 4 Constipation 5 0 General and administrative site conditions Fatigue 7 6 Pain b 5 7 Asthenia 5 3 Small Cell Lung Cancer (SCLC) The safety of topotecan hydrochloride for injection was evaluated in randomized, comparative trial in patients with recurrent or progressive SCLC (Study 090) [see Clinical Studies ( 14.2 )] . 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 a Death relate …

8 USE IN SPECIFIC POPULATIONS Lactation: Advise not to breastfeed. ( 8.2 ) 8.1 Pregnancy Risk Summary Based on animal data and its mechanism of action, topotecan hydrochloride for injection can cause fetal harm when administered to a pregnant woman. There are no available clinical data on the use of topotecan hydrochloride for injection in pregnancy. Topotecan caused embryolethality, fetotoxicity, and teratogenicity in rats and rabbits when administered during organogenesis at doses similar to the clinical dose (see Data ). 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/m 2 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/m 2 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/m 2 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 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 (see Data ) . Because of the potential for serious adverse reactions in breastfed infants, advise women not to breastfeed during treatment with topotecan hydrochloride 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/m 2 (about twice the 1.5 mg/m 2 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 Pregnancy Testing Verify pregnancy status of females of reproductive potential prior to initiating topotecan hydrochloride for injection [see Use in Specific Populations ( 8.1 )] . Contraception topotecan hydrochloride for injection can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations ( 8.1 )] . Females Advise females of reproductive potential to use effective contraception during treatment with topotecan hydrochloride for injection and for 6 months after the last dose. Males Topotecan Hydrochloride for Injection 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 hydrochloride for injection and for 3 months after the last dose [see Nonclinical Toxicology ( 13.1 )] . Infertility Females Topotecan Hydrochloride for Injection can have both acute and long-term effects on fertility [see Nonclinical Toxicology ( 13.1 )] . Males Effects on spermatogenesis occurred in animals administered topotecan [see Nonclinical Toxicology ( 13.1 )] . 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use Of the 879 patients with metastatic ovarian cancer or small cell lung cancer in clinical trials of topotecan hydrochloride for injection, 32% were aged 65 years and older, while 3.8% were aged 75 years and older. Of the 140 patients with …

12.1 Mechanism of Action Topoisomerase I relieves torsional strain in DNA by inducing reversible single-strand breaks. Topotecan binds to the topoisomerase I-DNA complex and prevents re-ligation of these single-strand breaks. The cytotoxicity of topotecan is thought to be due to double-strand DNA damage produced during DNA synthesis, when replication enzymes interact with the ternary complex formed by topotecan, topoisomerase I, and DNA. Mammalian cells cannot efficiently repair these double-strand breaks.

11 DESCRIPTION Topotecan hydrochloride is a semi-synthetic derivative of camptothecin and is an anti-tumor drug with topoisomerase I-inhibitory activity. The chemical name for topotecan hydrochloride is (S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1 H -pyrano[3’,4’:6,7] indolizino [1,2- b ]quinoline-3,14-(4 H ,12 H )-dione monohydrochloride. It has the molecular formula C 23 H 23 N 3 O 5 •HCl and a molecular weight of 457.9. It is soluble in water and melts with decomposition at 213°C to 218°C. Topotecan hydrochloride has the following structural formula: Topotecan Hydrochloride for Injection is supplied as a sterile, lyophilized, buffered, light yellow to greenish powder available in single-dose vials. Each vial contains topotecan hydrochloride equivalent to 4 mg of topotecan as free base. The reconstituted solution ranges in color from yellow to yellow-green and is intended for administration by intravenous infusion. Inactive ingredients are mannitol, 48 mg, and tartaric acid, 20 mg. Hydrochloric acid and sodium hydroxide may be used to adjust the pH. The solution pH ranges from 2.8 to 3.2. 1

10 OVERDOSAGE Overdoses (up to 10-fold of the recommended dose) have occurred in patients receiving intravenous topotecan. The primary complication of overdosage is myelosuppression. Elevated hepatic enzymes, mucositis, gastrointestinal toxicity, and skin toxicity have occurred with overdosages. If an overdose is suspected, monitor the patient closely for myelosuppression and institute supportive-care measures as appropriate.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Topotecan hydrochloride for injection, USP is supplied as a sterile, lyophilized, buffered, light yellow to greenish powder. Topotecan hydrochloride for injection, USP is supplied as follows: Product No. Unit of Sale Strength Each 760210 NDC 63323-762-10 Individually packaged 4 mg (base) per vial NDC 63323-762-10 Single Dose Vial The container closure is not made with natural rubber latex 16.2 Storage and Handling Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Protect from light; product is light-sensitive. Retain in carton. Handle and dispose of topotecan hydrochloride for injection, USP consistent with recommendations for the handling and disposal of hazardous drugs 1 .