Data from FDA - Curated by Marshall Pearce - Last updated 28 July 2017

Indication(s)

1 INDICATIONS AND USAGE Topotecan hydrochloride for injection is a topoisomerase inhibitor indicated for: • metastatic carcinoma of the ovary after disease progression on or after initial or subsequent chemotherapy. (1.1) • small cell lung cancer platinum-sensitive disease in patients who progressed after first-line chemotherapy. (1.2) • combination therapy with cisplatin for Stage IV-B, recurrent, or persistent carcinoma of the cervix which is not amenable to curative treatment. (1.3) 1.1 Ovarian Cancer Topotecan hydrochloride for injection, as a single agent, is indicated for the treatment of patients with metastatic carcinoma of the ovary 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 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 carcinoma of the cervix not amenable to curative treatment.

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Advisory information

contraindications
4 CONTRAINDICATIONS Topotecan hydrochloride is contraindicated in patients who have a history of severe hypersensitivity reactions to topotecan. History of severe hypersensitivity reactions to topotecan. (4)
Adverse reactions
6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in the labeling: • Bone Marrow Suppression [see Warnings and Precautions (5.1)] • Neutropenic Enterocolitis [see Warnings and Precautions (5.2)] • Interstitial Lung Disease [see Warnings and Precautions (5.3)] • Extravasation and Tissue Injury[see Warnings and Precautions (5.5)] Ovarian cancer: • The most common hematologic adverse reactions were: neutropenia (Grade 4: 80%), anemia (Grade 3/4: 41%), thrombocytopenia (Grade 4: 27%), and febrile neutropenia (23%). (6.1) • The most common (> 5%) non-hematologic adverse reactions (all grades) were: nausea, vomiting, fatigue, diarrhea, and dyspnea. (6.1) Small cell lung cancer: • The most common hematologic adverse reactions were: neutropenia (Grade 4: 70%), anemia (Grade 3/4: 42%), thrombocytopenia (Grade 4: 29%), and febrile neutropenia (28%). • The most common (> 5%) non-hematologic adverse reactions (all grades) were: asthenia, dyspnea, nausea, pneumonia, abdominal pain, and fatigue. Cervical cancer (topotecan hydrochloride plus cisplatin): • The most common hematologic adverse reactions were: neutropenia (Grade 3/4: 74%), anemia (Grade 3/4: 40%), and thrombocytopenia (Grade 3/4: 33%). (6.1) • The most common (> 25% and greater than or equal to 2% more than cisplatin alone) non-hematologic adverse reactions (all grades) were: pain, vomiting, and infection/febrile neutropenia. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176 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. Ovarian Cancer Table 1 shows the Grade 3/4 hematologic and major non-hematologic adverse reactions in the topotecan/paclitaxel comparator trial in ovarian cancer. Table 1. Adverse Reactions Experienced by ≥ 5% of Ovarian Cancer Patients Randomized to Receive Topotecan Hydrochloride or Paclitaxel Adverse Reaction Topotecan Hydrochloride (n = 112) Paclitaxel (n = 114) Hematologic Grade 3/4 % % Grade 4 neutropenia (< 500 cells/mm3) 80 21 Grade 3/4 anemia (Hgb < 8 g/dL) 41 6 Grade 4 thrombocytopenia (< 25,000 plts/mm3) 27 3 Febrile neutropenia 23 4 Non-hematologic Grade 3/4 % % Infections and infestations Sepsisa 5 2 Respiratory, thoracic, and mediastinal disorders Dyspnea 6 5 Gastrointestinal disorders Abdominal pain Constipation Diarrhea Intestinal obstruction Nausea Vomiting 5 5 6 5 10 10 4 0 1 4 2 3 General disorders and administrative site conditions Fatigue Asthenia Painb 7 5 5 6 3 7 a Death related to sepsis occurred in 2% of patients receiving topotecan hydrochloride and 0% of patients receiving paclitaxel. b Pain includes body pain, skeletal pain, and back pain. Small Cell Lung Cancer Table 2 shows the Grade 3/4 hematologic and major non-hematologic adverse reactions in the topotecan/CAV (cyclophosphamide-doxorubicin-vincristine) comparator trial in small cell lung cancer. Table 2. Adverse Reactions Experienced by ≥ 5% of Small Cell Lung Cancer Patients Randomized to Receive Topotecan Hydrochloride or CAV Adverse Reaction Topotecan Hydrochloride (n = 107) CAV (n = 104) Hematologic Grade 3/4 % % Grade 4 neutropenia (< 500 cells/mm3) 70 72 Grade 3/4 anemia (Hgb < 8 g/dL) 42 20 Grade 4 thrombocytopenia (< 25,000 plts/mm3) 29 5 Febrile neutropenia 28 26 Non-hematologic Grade 3/4 % % Infections and infestations Sepsisa 5 5 Respiratory, thoracic, and mediastinal disorders Dyspnea Pneumonia 9 8 14 6 Gastrointestinal disorders Abdominal pain Nausea 6 8 4 6 General disorders and administrative site conditions Fatigue Asthenia Painb 6 9 5 10 7 7 a Death related to sepsis occurred in 3% of patients receiving topotecan hydrochloride and 1% of patients receiving CAV. b Pain includes body pain, skeletal pain, and back pain. Hepatobiliary Disorders in Ovarian and Small Cell Lung Cancer Patients Receiving topotecan hydrochloride: Based on the combined experience of 453 patients with metastatic ovarian carcinoma, and 426 patients with small cell lung cancer treated with topotecan hydrochloride, Grade 1 transient elevations in hepatic enzymes occurred in 8% of patients. Grade 3/4 elevations occurred in 4%. Grade 3/4 elevated bilirubin occurred in less than 2% of patients. 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 3 shows the hematologic and non-hematologic adverse reactions in patients with cervical cancer. Table 3. Adverse Reactions Experienced by ≥ 5% of Patients with Cervical Cancer Randomized to Receive Topotecan Hydrochloride plus Cisplatin or Cisplatin Monotherapy (Between-Arm Difference ≥ 2%)a Adverse Reaction Topotecan Hydrochloride plus Cisplatin (n = 140) % Cisplatin (n = 144) % Hematologic Neutropenia Grade 3 (< 1,000 to 500 cells/mm3) Grade 4 (< 500 cells/mm3) 26 48 1 1 Anemia Grade 3 (Hgb < 8 to 6.5 g/dL) Grade 4 (Hgb < 6.5 g/dL) 34 6 19 3 Thrombocytopenia Grade 3 (< 50,000 to 10,000 cells/mm3) Grade 4 (< 10,000 cells/mm3) 26 7 3 0 Non-hematologicb,c General disorders and administrative site conditions Constitutionald Paine 69 59 62 50 Gastrointestinal disorders Vomiting Stomatitis-pharyngitis Other 40 6 63 37 0 56 Dermatology f 48 20 Infection-febrile neutropenia f 28 18 Cardiovascular f 25 15 a Includes patients who were eligible and treated. b Data were collected using NCI Common Toxicity Criteria, v. 2.0. c Grades 1 through 4 only. There were 3 patients who experienced deaths with investigator-designated attribution. The first patient experienced a Grade 5 hemorrhage in which the drug-related thrombocytopenia aggravated the event. A second patient experienced bowel obstruction, cardiac arrest, pleural effusion, and respiratory failure which were not treatment-related but probably aggravated by treatment. A third patient experienced a pulmonary embolism and adult respiratory distress syndrome; the latter was indirectly treatment-related. d Constitutional includes fatigue (lethargy, malaise, asthenia), fever (in the absence of neutropenia), rigors, chills, sweating, and weight gain or loss. e Pain includes abdominal pain or cramping, arthralgia, bone pain, chest pain (non-cardiac and non-pleuritic), dysmenorrhea, dyspareunia, earache, headache, hepatic pain, myalgia, neuropathic pain, pain due to radiation, pelvic pain, pleuritic pain, rectal or perirectal pain, and tumor pain. f High-level terms were included if the between-arm difference was ≥ 10%. 6.2 Postmarketing Experience The following reactions have been identified during postmarketing 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 enterocolitis [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 Extravasation [see Warnings and Precautions (5.5)].

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION Verify dose using body surface area prior to dispensing. Recommended dosage should generally not exceed 4 mg intravenously [see Overdosage (10)]. • Ovarian cancer and small cell lung cancer: 1.5 mg/m2 by intravenous infusion over 30 minutes daily for 5 consecutive days, starting on Day 1 of a 21-day course. (2.1, 2.2) • Cervical cancer: 0.75 mg/m2 by intravenous infusion over 30 minutes on Days 1, 2, and 3 repeated every 21 days in combination with cisplatin 50 mg/m2 on Day 1. (2.3) • Renal impairment: Dose reduce topotecan hydrochloride for injection in patients with moderate renal impairment (20 to 39 mL/min). (2.4) 2.1 Ovarian Cancer Recommended Dose and Schedule 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. 2.2 Small Cell Lung Cancer Recommended Dose and Schedule 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. 2.3 Cervical Cancer Recommended Dose and Schedule The recommended dose of topotecan hydrochloride is 0.75 mg/m2 by intravenous infusion over 30 minutes daily on Days 1, 2, and 3 in combination with cisplatin 50 mg/m2 on Day 1, repeated every 21 days. 2.4 Dose Modifications Hematologic Toxicities For single-agent use, dose reduce topotecan hydrochloride to 1.25 mg/m2 for: • neutrophil counts of less than 500 cells/mm3, or administer granulocyte-colony stimulating factor (G-CSF) starting no sooner than 24 hours following the last dose of topotecan hydrochloride. • platelet counts less than 25,000 cells/mm3 during previous cycle. For combination use with cisplatin, dose reduce topotecan hydrochloride to 0.60 mg/m2 (and further to 0.45 mg/m2 if necessary) for: • febrile neutropenia (defined as neutrophil counts less than 1,000 cells/mm3 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 of topotecan hydrochloride. • platelet counts less than 25,000 cells/mm3 during previous cycle. Renal Impairment For single-agent use, dose reduce topotecan hydrochloride to 0.75 mg/m2 in patients with moderate renal impairment (creatinine clearance [Clcr] = 20 to 39 mL/min). Insufficient data are available in patients with severe renal impairment (Clcr less than 20 mL/min) to provide a dosage recommendation for topotecan hydrochloride [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)]. 2.5 Preparation and Intravenous Administration Topotecan hydrochloride is a cytotoxic drug. Follow applicable special handling and disposable procedures.1 Preparation and Administration Reconstitute each 4 mg vial of topotecan hydrochloride 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 prior to administration. Stability Unopened vials of topotecan hydrochloride 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 carton. Because the vials contain no preservative, contents should be used immediately after reconstitution. Reconstituted vials of topotecan hydrochloride diluted for infusion are stable at approximately 20° to 25°C (68° to 77°F) and ambient lighting conditions for 24 hours.
Use in special populations
8 USE IN SPECIFIC POPULATIONS Lactation: Discontinue breastfeeding. (8.2) 8.1 Pregnancy Risk Summary Based on animal data, 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 at doses similar to the clinical dose [see Data]. There are no available human data informing the drug-associated risk. Advise pregnant women of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated populations are unknown; however, the background risk in the US general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies. Data Animal Data: 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. Administration of an intravenous 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. 8.2 Lactation Risk Summary It is not known whether this drug is present in human milk; however, topotecan is excreted in rat milk at high concentrations [see Data]. Because many drugs are present in human milk and because of the potential for serious adverse reactions in nursing infants with topotecan hydrochloride, advise nursing mothers to discontinue breastfeeding during treatment with topotecan hydrochloride. Data Animal Data: Following intravenous administration of topotecan to lactating rats at a dose of 4.72 mg/m2 (about twice the clinical dose on a mg/m2 basis), topotecan was excreted into milk at concentrations up to 48-fold higher than those in plasma. 8.3 Females and Males of Reproductive Potential Contraception Females: Advise female patients of reproductive potential to use effective contraception during treatment with topotecan hydrochloride and for one month after the last dose. Advise females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking topotecan hydrochloride [see Use in Specific Populations (8.1)]. Males: Topotecan hydrochloride may damage spermatozoa, resulting in possible genetic and fetal abnormalities. Advise males with a female sexual partner of reproductive potential to use effective contraception during and for three months after treatment with topotecan hydrochloride [see Nonclinical Toxicology (13.1)]. Infertility Females: Topotecan hydrochloride may have both acute and long-term effects on fertility [see Nonclinical Toxicology (13.1)]. Males: Effects on spermatogenesis have been observed in animals administered topotecan hydrochloride. Advise males of the potential risk for impaired fertility and to seek counseling on fertility and family planning options prior to starting treatment [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, 32% (n = 281) were aged 65 years and older, while 3.8% (n = 33) were aged 75 years and older. Of the 140 patients with Stage IV-B, relapsed, or refractory cervical cancer in clinical trials of topotecan hydrochloride who received topotecan hydrochloride plus cisplatin in the randomized clinical trial, 6% (n = 9) were aged 65 years and older, while 3% (n = 4) were aged 75 years 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. 8.6 Renal Impairment The systemic exposure to both topotecan lactone and total topotecan increased in patients with moderate renal impairment (Clcr = 20 to 39 mL/min) compared with patients with normal renal function (Clcr greater than 60 mL/min). Reduce the dose of topotecan hydrochloride in patients with moderate renal impairment (Clcr = 20 to 39 mL/min). No dosage adjustment of topotecan hydrochloride is recommended for patients with mild renal impairment (Clcr = 40 to 60 mL/min) [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)]. Insufficient data are available in patients with severe renal impairment (Clcr less than 20 mL/min) to provide a dosage recommendation for topotecan hydrochloride.
Pregnancy and lactation
8.3 Females and Males of Reproductive Potential Contraception Females: Advise female patients of reproductive potential to use effective contraception during treatment with topotecan hydrochloride and for one month after the last dose. Advise females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking topotecan hydrochloride [see Use in Specific Populations (8.1)]. Males: Topotecan hydrochloride may damage spermatozoa, resulting in possible genetic and fetal abnormalities. Advise males with a female sexual partner of reproductive potential to use effective contraception during and for three months after treatment with topotecan hydrochloride [see Nonclinical Toxicology (13.1)]. Infertility Females: Topotecan hydrochloride may have both acute and long-term effects on fertility [see Nonclinical Toxicology (13.1)]. Males: Effects on spermatogenesis have been observed in animals administered topotecan hydrochloride. Advise males of the potential risk for impaired fertility and to seek counseling on fertility and family planning options prior to starting treatment [see Nonclinical Toxicology (13.1)].

Interactions

7 DRUG INTERACTIONS Do not initiate G-CSF until 24 hours after completion of treatment with topotecan hydrochloride. Concomitant administration can prolong duration of neutropenia. (7) 7.1 G-CSF Concomitant administration with G-CSF can prolong the duration of neutropenia. If G-CSF is used, it should be started no sooner than 24 hours following the last dose of topotecan hydrochloride.

More information

Category Value
Authorisation number ANDA091089
Agency product number 956S425ZCY
Orphan designation No
Product NDC 63323-762
Date Last Revised 26-06-2017
Type HUMAN PRESCRIPTION DRUG
RXCUI 1799416
Marketing authorisation holder Fresenius Kabi USA, LLC
Warnings WARNING: BONE MARROW SUPPRESSION Topotecan hydrochloride can cause severe myelosuppression. Administer only to patients with baseline neutrophil counts of greater than or equal to 1,500 cells/mm3 and platelet counts greater than or equal to 100,000 cells/mm3. Monitor blood cell counts [see Warnings and Precautions ( 5.1 )]. WARNING: BONE MARROW SUPPRESSION See full prescribing information for complete boxed warning. Topotecan hydrochloride can cause severe myelosuppression. Administer only to patients with baseline neutrophil counts greater than or equal to 1,500 cells/mm3 and platelet count greater than or equal to 100,000/mm3. Monitor blood cell counts. (5.1)