Topotecan Hydrochloride

TOPOTECAN HYDROCHLORIDE- topotecan hydrochloride injection, powder, lyophilized, for solution
Accord Healthcare, Inc.

WARNING: MYELOSUPPRESSION

Topotecan hydrochloride for injection can cause severe myelosuppression. Administer first cycle only to patients with baseline neutrophil counts of greater than or equal to 1,500/mm 3 and platelet counts greater than or equal to 100,000/mm 3. Monitor blood cell counts [see Warnings and Precautions ( 5.1)] .

1 INDICATIONS AND USAGE

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

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/m2/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 (free base) of topotecan as a light yellow to greenish lyophilized powder in single-dose vial for reconstitution.

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)] .

5 WARNINGS AND PRECAUTIONS

5.1 Myelosuppression

Topotecan hydrochloride for injection 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. 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 topotecan hydrochloride for injection only to patients with a baseline neutrophil count of greater than or equal to 1,500/mm 3 and a platelet count greater than or equal to 100,000/mm 3. Monitor blood counts frequently during treatment. Withhold and reduce dose of topotecan hydrochloride for injection based on neutrophil counts, platelet counts and hemoglobin levels [see Dosage and Administration ( 2.5)] .

5.2 Interstitial Lung Disease

Interstitial lung disease (ILD), including fatalities, can occur with topotecan hydrochloride for injection. 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 topotecan hydrochloride for injection if ILD is confirmed.

5.3 Extravasation and Tissue Injury

Extravasation, including severe cases, can occur with topotecan hydrochloride for injection. If signs or symptoms of extravasation occur, immediately stop administration of topotecan hydrochloride for injection and institute recommended management procedures [see Adverse Reactions ( 6.1)] .

5.4 Embryo-Fetal Toxicity

Based on animal data, topotecan hydrochloride for injection 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 hydrochloride for injection. 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 Use in Specific Populations ( 8.1, 8.3), Nonclinical Toxicology ( 13.1)] .

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