Topotecan Hydrochloride

Sagent Pharmaceuticals

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use Topotecan Hydrochloride for Injection safely and effectively. See full prescribing information for Topotecan Hydrochloride for Injection. Topotecan Hydrochloride for Injection Initial U.S. Approval: 1996 BOXED WARNING WARNING: BONE MARROW SUPPRESSION See full prescribing information for complete boxed warning. Do not give topotecan hydrochloride to patients with baseline neutrophil counts less than 1,500 cells/mm 3 . In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection and death, monitor peripheral blood cell counts frequently on all patients receiving topotecan hydrochloride. (5.1) INDICATIONS AND USAGETopotecan hydrochloride is a topoisomerase inhibitor indicated for: small cell lung cancer sensitive disease after failure of first-line chemotherapy. (1) combination therapy with cisplatin for stage IV-B, recurrent, or persistent carcinoma of the cervix which is not amenable to curative treatment with surgery and/or radiation therapy. (1) DOSAGE AND ADMINISTRATION Small cell lung cancer: 1.5 mg/m2 by intravenous infusion over 30 minutes daily for 5 consecutive days, starting on day one of a 21-day course. (2.1) Cervical cancer: 0.75 mg/m2 by intravenous infusion over 30 minutes on days 1, 2, and 3 followed by cisplatin 50 mg/m2 by intravenous infusion on day 1 repeated every 21 days. (2.2) See Dosage Modification Guidelines for patients with neutropenia or reduced platelets. (2.1, 2.2) See Dosage Adjustment in Renal Impairment. (2.3) DOSAGE FORMS AND STRENGTHS4-mg (free base) single-dose vial. (3) CONTRAINDICATIONS History of severe hypersensitivity reactions (e.g., anaphylactoid reactions) to topotecan or any of its ingredients (4) Severe bone marrow depression (4) WARNINGS AND PRECAUTIONS Bone marrow suppression: Administer Topotecan Hydrochloride for Injection only to patients with adequate bone marrow reserves. Monitor peripheral blood counts and adjust the dose if needed. (5.1) Topotecan-induced neutropenia can lead to neutropenic colitis. (5.2) Interstitial lung disease: Topotecan Hydrochloride for Injection has been associated with reports of interstitial lung disease. Monitor patients for symptoms and discontinue Topotecan Hydrochloride for Injection if the diagnosis is confirmed. (5.3) Pregnancy: Can cause fetal harm. Advise women of potential risk to the fetus. (5.4, 8.1) Side EffectsSmall cell lung cancer: The most common hematologic adverse reactions were: neutropenia (97%), leukopenia (97%), anemia (89%), and thrombocytopenia (69%). (6.1) The most common (>25%) non-hematologic adverse reactions (all grades) were: nausea, alopecia, vomiting, sepsis or pyrexia/infection with neutropenia, diarrhea, constipation, fatigue, and pyrexia. (6.1) Cervical cancer (topotecan hydrochloride plus cisplatin): The most common hematologic adverse reactions (all grades) were: anemia (94%), leukopenia (91%), neutropenia (89%), and thrombocytopenia (74%). (6.1) The most common (>25%) non-hematologic adverse reactions (all grades) were: pain, nausea, vomiting, and infection/febrile neutropenia. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Sagent Pharmaceuticals, Inc. at 1-866-625-1618 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS Do not initiate G-CSF until 24 hours after completion of treatment with Topotecan Hydrochloride for Injection. Concomitant administration can prolong duration of neutropenia. (7) Greater myelosuppression is likely to be seen when used in combination with other cytotoxic agents. (7) USE IN SPECIFIC POPULATIONS Nursing Mothers: Discontinue nursing when receiving Topotecan Hydrochloride for Injection. (8.3)

FULL PRESCRIBING INFORMATION: CONTENTS*

• WARNING: BONE MARROW SUPPRESSION
• 1 TOPOTECAN HYDROCHLORIDE INDICATIONS AND USAGE
• 2 TOPOTECAN HYDROCHLORIDE DOSAGE AND ADMINISTRATION
  • 2.1 Small Cell Lung Cancer
  • 2.2 Cervical Cancer
  • 2.3 Dosage Adjustment in Specific Populations
  • 2.4 Instructions for Handling, Preparation and Intravenous Administration
• 3 DOSAGE FORMS AND STRENGTHS
• 4 TOPOTECAN HYDROCHLORIDE CONTRAINDICATIONS
• 5 WARNINGS AND PRECAUTIONS
  • 5.1 Bone Marrow Suppression
  • 5.2 Neutropenic Colitis
  • 5.3 Interstitial Lung Disease
  • 5.4 Pregnancy
  • 5.5 Inadvertent Extravasation
• 6 TOPOTECAN HYDROCHLORIDE ADVERSE REACTIONS
  • 6.1 Clinical Trials Experience
  • 6.2 Postmarketing Experience
• 7 DRUG INTERACTIONS
• 8 USE IN SPECIFIC POPULATIONS
  • 8.1 Pregnancy
  • 8.3 Nursing Mothers
  • 8.4 Pediatric Use
  • 8.5 Geriatric Use
  • 8.6 Renal Impairment
• 10 OVERDOSAGE
• 11 TOPOTECAN HYDROCHLORIDE DESCRIPTION
• 12 CLINICAL PHARMACOLOGY
  • 12.1 Mechanism of Action
  • 12.2 Pharmacodynamics
  • 12.3 Pharmacokinetics
• 13 NONCLINICAL TOXICOLOGY
  • 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
• 14 CLINICAL STUDIES
  • 14.2 Small Cell Lung Cancer
  • 14.3 Cervical Cancer
• 15 REFERENCES
• 16 HOW SUPPLIED/STORAGE AND HANDLING
• 17 PATIENT COUNSELING INFORMATION
  • 17.1 Bone Marrow Suppression
  • 17.2 Pregnancy and Breastfeeding
  • 17.3 Asthenia and Fatigue

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

Topotecan hydrochloride is indicated for the treatment of:

• small cell lung cancer sensitive disease after failure of first-line chemotherapy. In clinical studies submitted to support approval, sensitive disease was defined as disease responding to chemotherapy but subsequently progressing at least 60 days (in the Phase 3 study) or at least 90 days (in the Phase 2 studies) after chemotherapy [see Clinical Studies (14)].

Topotecan hydrochloride in combination with cisplatin is indicated for the treatment of:

• stage IV-B, recurrent, or persistent carcinoma of the cervix which is not amenable to curative treatment with surgery and/or radiation therapy.

2 DOSAGE AND ADMINISTRATION

Prior to administration of the first course of topotecan hydrochloride, patients must have a baseline neutrophil count of >1,500 cells/mm³ and a platelet count of >100,000 cells/mm³.

2.1 Small Cell Lung Cancer

Recommended Dosage:

• The recommended dose of topotecan hydrochloride is 1.5 mg/m² by intravenous infusion over 30 minutes daily for 5 consecutive days, starting on day 1 of a 21-day course.
• In the absence of tumor progression, a minimum of 4 courses is recommended because tumor response may be delayed. The median time to response in 4 small cell lung cancer trials was 5 to 7 weeks.

Dosage Modification Guidelines:

• In the event of severe neutropenia (defined as <500 cells/mm³) during any course, reduce the dose by 0.25 mg/m² (to 1.25 mg/m²) for subsequent courses.
• Alternatively, in the event of severe neutropenia, administer G-CSF (granulocyte-colony stimulating factor) following the subsequent course (before resorting to dose reduction) starting from day 6 of the course (24 hours after completion of topotecan administration).
• In the event the platelet count falls below 25,000 cells/mm³, reduce doses by 0.25 mg/m² (to 1.25 mg/m²) for subsequent courses.

2.2 Cervical Cancer

Recommended Dosage: The recommended dose of topotecan hydrochloride is 0.75 mg/m² by intravenous infusion over 30 minutes daily on days 1, 2, and 3; followed by cisplatin 50 mg/m² by intravenous infusion on day 1 repeated every 21 days (a 21-day course).

Dosage Modification Guidelines: Dosage adjustments for subsequent courses of topotecan hydrochloride in combination with cisplatin are specific for each drug. See manufacturer's prescribing information for cisplatin administration and hydration guidelines and for cisplatin dosage adjustment in the event of hematologic toxicity.

• In the event of severe febrile neutropenia (defined as <1000 cells/mm³ with temperature of 38.0°C or 100.4°F), reduce the dose of topotecan hydrochloride to 0.60 mg/m² for subsequent courses.
• Alternatively, in the event of severe febrile neutropenia, administer G-CSF following the subsequent course (before resorting to dose reduction) starting from day 4 of the course (24 hours after completion of administration of topotecan hydrochloride).
• If febrile neutropenia occurs despite the use of G-CSF, reduce the dose of topotecan hydrochloride to 0.45 mg/m² for subsequent courses.
• In the event the platelet count falls below 25,000 cells/mm³, reduce doses to 0.60 mg/m² for subsequent courses.

2.3 Dosage Adjustment in Specific Populations

Renal Impairment: No dosage adjustment of topotecan hydrochloride appears to be required for patients with mild renal impairment (Cl_cr 40 to 60 mL/min.). Dosage adjustment of topotecan hydrochloride to 0.75 mg/m² is recommended for patients with moderate renal impairment (20 to 39 mL/min.). Insufficient data are available in patients with severe renal impairment to provide a dosage recommendation for topotecan hydrochloride [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

Topotecan hydrochloride in combination with cisplatin for the treatment of cervical cancer should only be initiated in patients with serum creatinine ≤1.5 mg/dL. In the clinical trial, cisplatin was discontinued for a serum creatinine >1.5 mg/dL. Insufficient data are available regarding continuing monotherapy with topotecan hydrochloride after cisplatin discontinuation in patients with cervical cancer.

2.4 Instructions for Handling, Preparation and Intravenous Administration

Handling: Topotecan Hydrochloride for Injection is a cytotoxic anticancer drug. Prepare Topotecan Hydrochloride for Injection under a vertical laminar flow hood while wearing gloves and protective clothing. If Topotecan Hydrochloride for Injection solution contacts the skin, wash the skin immediately and thoroughly with soap and water. If Topotecan Hydrochloride for Injection contacts mucous membranes, flush thoroughly with water.

Use procedures for proper handling and disposal of anticancer drugs. Several guidelines on this subject have been published.^1-4

Preparation and Administration: Each 4-mg vial of Topotecan Hydrochloride for Injection is reconstituted with 4 mL Sterile Water for Injection. Then the appropriate volume of the reconstituted solution is diluted in either 0.9% Sodium Chloride Intravenous Infusion or 5% Dextrose Intravenous Infusion prior to administration.

Stability: Unopened vials of Topotecan Hydrochloride for Injection are stable until the date indicated on the package when stored between 20° and 25°C (68° and 77°F) [see USP] and protected from light in the original package. Because the vials contain no preservative, contents should be used immediately after reconstitution.

Reconstituted vials of Topotecan Hydrochloride for Injection diluted for infusion are stable at approximately 20° to 25°C (68° to 77°F) and ambient lighting conditions for 24 hours.

3 DOSAGE FORMS AND STRENGTHS

4-mg (free base) single-dose vial, light yellow lyophilisate.

4 CONTRAINDICATIONS

Topotecan hydrochloride is contraindicated in patients who have a history of severe hypersensitivity reactions (e.g., anaphylactoid reactions) to topotecan or to any of its ingredients. Topotecan hydrochloride should not be used in patients with severe bone marrow depression.

5 WARNINGS AND PRECAUTIONS

5.1 Bone Marrow Suppression

Bone marrow suppression (primarily neutropenia) is the dose-limiting toxicity of topotecan hydrochloride. Neutropenia is not cumulative over time. In the comparative study in small cell lung cancer, however, the treatment-related death rates were 5% for topotecan hydrochloride and 4% for CAV (cyclophosphamide-doxorubicin-vincristine).

Neutropenia:

• Small cell lung cancer experience: Grade 4 neutropenia (<500 cells/mm³) was most common during course 1 of treatment (60% of patients) and occurred in 39% of all courses, with a median duration of 7 days. The nadir neutrophil count occurred at a median of 12 days. Therapy-related sepsis or febrile neutropenia occurred in 23% of patients, and sepsis was fatal in 1%. Pancytopenia has been reported.
• Cervical cancer experience: Grade 3 and grade 4 neutropenia affected 26% and 48% of patients, respectively.

Thrombocytopenia:

• Small cell lung cancer experience: Grade 4 thrombocytopenia (<25,000/mm³) occurred in 27% of patients and in 9% of courses, with a median duration of 5 days and platelet nadir at a median of 15 days. Platelet transfusions were given to 15% of patients in 4% of courses.
• Cervical cancer experience: Grade 3 and grade 4 thrombocytopenia affected 26% and 7% of patients, respectively.

Anemia:

• Small cell lung cancer experience: Grade 3/4 anemia (<8 g/dL) occurred in 37% of patients and in 14% of courses. Median nadir was at day 15. Transfusions were needed in 52% of patients in 22% of courses.
• Cervical cancer experience: Grade 3 and grade 4 anemia affected 34% and 6% of patients, respectively.

Monitoring of Bone Marrow Function: Administer topotecan hydrochloride only in patients with adequate bone marrow reserves, including baseline neutrophil count of at least 1,500 cells/mm³ and platelet count at least 100,000/mm³. Monitor peripheral blood counts frequently during treatment with topotecan hydrochloride. Do not treat patients with subsequent courses of topotecan hydrochloride until neutrophils recover to >1,000 cells/mm³, platelets recover to >100,000 cells/mm³, and hemoglobin levels recover to 9.0 g/dL (with transfusion if necessary). Severe myelotoxicity has been reported when topotecan hydrochloride is used in combination with cisplatin [see Drug Interactions (7)].

5.2 Neutropenic Colitis

Topotecan-induced neutropenia can lead to neutropenic colitis. Fatalities due to neutropenic colitis have been reported in clinical trials with topotecan hydrochloride. In patients presenting with fever, neutropenia, and a compatible pattern of abdominal pain, consider the possibility of neutropenic colitis.

5.3 Interstitial Lung Disease

Topotecan hydrochloride has been associated with reports of interstitial lung disease (ILD), some of which have been fatal [see Adverse Reactions (6.2)]. Underlying risk factors include history of ILD, pulmonary fibrosis, lung cancer, thoracic exposure to radiation, and use of pneumotoxic drugs and/or colony stimulating factors. Monitor patients for pulmonary symptoms indicative of interstitial lung disease (e.g., cough, fever, dyspnea, and/or hypoxia), and discontinue topotecan hydrochloride if a new diagnosis of ILD is confirmed.

5.4 Pregnancy

Pregnancy Category D

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

Topotecan caused embryolethality, fetotoxicity, and teratogenicity in rats and rabbits when administered during organogenesis. There are no adequate and well controlled studies of topotecan hydrochloride in pregnant women. If this drug is used during pregnancy, or if a patient becomes pregnant while receiving topotecan hydrochloride, the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations, Pregnancy (8.1)].

5.5 Inadvertent Extravasation

Inadvertent extravasation with topotecan hydrochloride has been observed, most reactions have been mild but severe cases have been reported.

6 ADVERSE REACTIONS

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 to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Small Cell Lung Cancer: Data in the following section are based on the combined experience of 879 patients, including 426 patients with small cell lung cancer, treated with topotecan hydrochloride. Table 1 lists the principal hematologic adverse reactions and Table 2 lists non-hematologic adverse reactions occurring in at least 15% of patients.

Nervous System Disorders: Paresthesia occurred in 7% of patients but was generally grade 1.

Hepatobiliary Disorders: Grade 1 transient elevations in hepatic enzymes occurred in 8% of patients. Greater elevations, grade 3/4, occurred in 4%. Grade 3/4 elevated bilirubin occurred in <2% of patients.

Table 4 shows the grade 3/4 hematologic and major non-hematologic adverse reactions in the topotecan/CAV comparator trial in small cell lung cancer.

Cervical Cancer: In the comparative trial with topotecan hydrochloride plus cisplatin versus cisplatin in patients with cervical cancer, the most common dose-limiting adverse reaction was myelosuppression. Table 5 shows the hematologic adverse reactions and Table 6 shows the non-hematologic adverse reactions in patients with cervical cancer.

6.2 Postmarketing Experience

In addition to adverse reactions reported from clinical trials or listed in other sections of the prescribing information, the following reactions have been identified during post-marketing use of topotecan hydrochloride. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These reactions have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to topotecan hydrochloride.

Blood and Lymphatic System Disorders: Severe bleeding (in association with thrombocytopenia) [see Warnings and Precautions (5.1)].

Immune System Disorders: Allergic manifestations; Anaphylactoid reactions.

Gastrointestinal Disorders: Abdominal pain potentially associated with neutropenic colitis [see Warnings and Precautions (5.2)].

Pulmonary Disorders: Interstitial lung disease [see Warnings and Precautions (5.3)].

Skin and Subcutaneous Tissue Disorders: Angioedema, severe dermatitis, severe pruritus.

General Disorders and Administration Site Conditions: Inadvertent extravasation [see Warnings and Precautions (5.5)].

7 DRUG INTERACTIONS

G-CSF: Concomitant administration of G-CSF can prolong the duration of neutropenia, so if G-CSF is to be used, do not initiate it until day 6 of the course of therapy, 24 hours after completion of treatment with topotecan hydrochloride.

Platinum and Other Cytotoxic Agents: Myelosuppression was more severe when topotecan hydrochloride, at a dose of 1.25 mg/m²/day for 5 days, was given in combination with cisplatin at a dose of 50 mg/m² in Phase 1 studies. In one study, 1 of 3 patients had severe neutropenia for 12 days and a second patient died with neutropenic sepsis.

Greater myelosuppression is also likely to be seen when topotecan hydrochloride is used in combination with other cytotoxic agents, thereby necessitating a dose reduction. However, when combining topotecan hydrochloride with platinum agents (e.g., cisplatin or carboplatin), a distinct sequence-dependent interaction on myelosuppression has been reported. Coadministration of a platinum agent on day 1 of dosing with topotecan hydrochloride required lower doses of each agent compared to co-administration on day 5 of the dosing schedule for topotecan hydrochloride.

For information on the pharmacokinetics, efficacy, safety, and dosing of topotecan hydrochloride at a dose of 0.75 mg/m²/day on days 1, 2, and 3 in combination with cisplatin 50 mg/m² on day 1 for cervical cancer, see Dosage and Administration (2), Adverse Reactions (6), Clinical Pharmacology (12.3), and Clinical Studies (14).

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category D [see Warnings and Precautions (5.4)].

Topotecan hydrochloride can cause fetal harm when administered to a pregnant woman. In rabbits, a dose of 0.10 mg/kg/day (about equal to the clinical dose on a mg/m² basis) given on days 6 through 20 of gestation caused maternal toxicity, embryolethality, and reduced fetal body weight. In the rat, a dose of 0.23 mg/kg/day (about equal to the clinical dose on a mg/m² basis) given for 14 days before mating through gestation day 6 caused fetal resorption, microphthalmia, pre-implant loss, and mild maternal toxicity. A dose of 0.10 mg/kg/day (about half the clinical dose on a mg/m² basis) 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.

There are no adequate and well controlled studies of topotecan hydrochloride in pregnant women. If this drug is used during pregnancy, or if a patient becomes pregnant while receiving topotecan hydrochloride, the patient should be apprised of the potential hazard to the fetus [see Warnings and Precautions (5.4)]

8.3 Nursing Mothers

Rats excrete high concentrations of topotecan into milk. Lactating female rats given 4.72 mg/m² IV (about twice the clinical dose on a mg/m² basis) excreted topotecan into milk at concentrations up to 48-fold higher than those in plasma. It is not known whether the drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from topotecan hydrochloride, discontinue breastfeeding when women are receiving topotecan hydrochloride.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Of the 879 patients, with cancer in clinical studies of topotecan hydrochloride, 32% (n = 281) were 65 years of age and older, while 3.8% (n = 33) were 75 years of age and older. Of the 140 patients with stage IV-B, relapsed, or refractory cervical cancer in clinical studies of topotecan hydrochloride who received topotecan hydrochloride plus cisplatin in the randomized clinical trial, 6% (n = 9) were 65 years of age and older, while 3% (n = 4) were 75 years of age and older. No overall differences in effectiveness or safety were observed between these patients and younger adult patients, and other reported clinical experience has not identified differences in responses between the elderly and younger adult patients, but greater sensitivity of some older individuals cannot be ruled out.

There were no apparent differences in the pharmacokinetics of topotecan in elderly patients, once the age-related decrease in renal function was considered [see Clinical Pharmacology (12.3)].

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function [see Dosage and Administration (2.3)].

8.6 Renal Impairment

No dosage adjustment of topotecan hydrochloride appears to be required for patients with mild renal impairment (Cl_cr 40 to 60 mL/min.). Dosage reduction is recommended for patients with moderate renal impairment (Cl_cr 20 to 39 mL/min.). Insufficient data are available in patients with severe renal impairment to provide a dosage recommendation for topotecan hydrochloride [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].

10 OVERDOSAGE

There is no known antidote for overdosage with topotecan hydrochloride. The primary anticipated complication of overdosage would consist of bone marrow suppression.

One patient on a single-dose regimen of 17.5 mg/m² given on day 1 of a 21-day cycle had received a single dose of 35 mg/m². This patient experienced severe neutropenia (nadir of 320/mm³) 14 days later but recovered without incident.

Observe patients closely for bone marrow suppression, and consider supportive measures (such as the prophylactic use of G-CSF and/or antibiotic therapy).

11 DESCRIPTION

Topotecan hydrochloride is a semi-synthetic derivative of camptothecin and is an anti-tumor drug with topoisomerase I-inhibitory activity.

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 2.5 to 3.5.

The chemical name for topotecan hydrochloride is (S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1H-pyrano[3',4':6,7] indolizino [1,2-b]quinoline-3,14-(4H,12H)-dione monohydrochloride. It has the molecular formula C₂₃H₂₃N₃O₅•HCl and a molecular weight of 457.9.

Topotecan hydrochloride has the following structural formula: