TOPOTECAN- topotecan hydrochloride injection, solution, concentrate
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use TOPOTECAN INJECTION safely and effectively. See full prescribing information for TOPOTECAN INJECTION.
TOPOTECAN INJECTION, for intravenous use
Initial U.S. Approval: 1996
WARNING: BONE MARROW SUPPRESSION
See full prescribing information for complete boxed warning.
Topotecan injection 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)
RECENT MAJOR CHANGES
Contraindications, Bone Marrow Depression, removed (4)
INDICATIONS AND USAGE
Topotecan Injection is a topoisomerase inhibitor indicated for:
DOSAGE AND ADMINISTRATION
DOSAGE FORMS AND STRENGTHS
WARNINGS AND PRECAUTIONS
Small cell lung cancer:
To report SUSPECTED ADVERSE REACTIONS, contact Hospira, Inc. at 1-800-441-4100 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
USE IN SPECIFIC POPULATIONS
See 17 for PATIENT COUNSELING INFORMATION.
FULL PRESCRIBING INFORMATION: CONTENTS*
Topotecan injection 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)].
Topotecan injection 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.
Verify dose using body surface area prior to dispensing. Recommended dosage should generally not exceed 4 mg intravenously [see Overdosage (10)].
Recommended Dose and Schedule
The recommended dose of Topotecan injection 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.
Dose reduce Topotecan injection to 1.25 mg/m2 for:
For combination use with cisplatin, dose reduce Topotecan injection to 0.60 mg/m2 (and further to 0.45 mg/m2 if necessary) for:
For single-agent use, dose reduce Topotecan injection 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 injection [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].
Topotecan injection is a cytotoxic drug. Follow applicable special handling and disposable procedures.1
Preparation and Administration
The appropriate volume of Topotecan injection is diluted in a minimum of 50 mL of 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP prior to administration. Infuse over 30 minutes.
Topotecan injection diluted for infusion is stable between 20°C and 25°C (68°F and 77°F) in ambient lighting conditions for 24 hours.
Each vial of Topotecan injection is intended for single use only. Any unused drug remaining after injection must be discarded.
Injection: 4 mg/4 mL (1 mg/mL, topotecan free base equivalent) clear, yellow to yellow-green solution in single use vial for intravenous infusion only following dilution.
Bone marrow suppression (primarily neutropenia) is the dose-limiting toxicity of topotecan. Neutropenia is not cumulative over time. Severe myelotoxicity has been reported when topotecan is used in combination with cisplatin [see Drug Interactions (7)].
Administer Topotecan injection only to patients with a baseline neutrophil count of greater than or equal to 1,500 cells/mm3 and a platelet count greater than or equal to 100,000/mm3. Monitor peripheral blood counts frequently during treatment with Topotecan injection. Refer to Section 2.4 for dose modification guidelines for hematological toxicities in subsequent courses. Do not treat patients with subsequent courses of Topotecan injection until neutrophils recover to greater than 1,000 cells/mm3, platelets recover to greater than 100,000 cells/mm3, and hemoglobin levels recover to 9.0 g/dL (with transfusion if necessary).
Topotecan can cause fatal typhlitis (neutropenic enterocolitis). Consider the possibility of typhlitis in patients presenting with fever, neutropenia, and abdominal pain.
Interstitial lung disease (ILD), including fatalities, has occurred with Topotecan. Underlying risk factors include history of ILD, pulmonary fibrosis, lung cancer, thoracic radiation, and use of pneumotoxic drugs and/or colony stimulating factors. Monitor patients for pulmonary symptoms indicative of ILD (e.g., cough, fever, dyspnea, and/or hypoxia), and discontinue Topotecan injection if a new diagnosis of ILD is confirmed.
Based on animal data, Topotecan 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 females of reproductive potential to use effective contraception during treatment and for at least 1 month after the last dose of Topotecan. Advise women of the potential risk to a fetus [see Use in Specific Populations (8.1, 8.3)].
Extravasation with topotecan has been observed; severe cases have been reported. If signs or symptoms of extravasation occur, immediately stop administration of Topotecan and institute recommended management procedures [see Adverse Reactions (6)].
The following serious adverse reactions are described below and elsewhere in the labeling:
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.
Small Cell Lung Cancer
Table 1 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.
|a Death related to sepsis occurred in 3% of patients receiving Topotecan and 1% of patients receiving CAV.|
b Pain includes body pain, skeletal pain, and back pain.
(n = 107)
(n = 104)
Hematologic Grade 3/4
Grade 4 neutropenia
Grade 3/4 anemia
(Hgb <8 g/dL)
Grade 4 thrombocytopenia
Non-hematologic Grade 3/4
Infections and infestations
Respiratory, thoracic, and mediastinal
General disorders and administrative site
Hepatobiliary Disorders in Small Cell Lung Cancer Patients Receiving Topotecan: Based on 426 patients with small cell lung cancer treated with topotecan, 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.
The following reactions have been identified during postmarketing use of topotecan. 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.
Blood and Lymphatic System Disorders
Severe bleeding (in association with thrombocytopenia) [see Warnings and Precautions (5.1)].
Immune System Disorders
Allergic manifestations, anaphylactoid reactions.
Abdominal pain potentially associated with neutropenic enterocolitis [see Warnings and Precautions (5.2)].
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)].
Based on animal data, topotecan 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.
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.
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, advise nursing mothers to discontinue breastfeeding during treatment with topotecan.
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.
Females: Advise female patients of reproductive potential to use effective contraception during treatment with topotecan 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 [see Use in Specific Populations (8.1)].
Males: Topotecan 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 [see Nonclinical Toxicology (13.1)].
Females: Topotecan 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. 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)].
Of the 879 patients in a combined experience of topotecan which included patients with small cell lung cancer in clinical trials of topotecan, 32% (n = 281) were aged 65 years and older, while 3.8% (n = 33) 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.
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 in patients with moderate renal impairment (Clcr = 20 to 39 mL/min). No dosage adjustment of Topotecan is recommended for patients with mild renal impairment (Clcr = 40 to 60 mL/min) [see Dosage and Administration (2.2), 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.
Overdoses (up to 10-fold of the prescribed dose) occurred in patients treated with intravenous topotecan. The primary complication of overdosage is bone marrow suppression. The observed signs and symptoms of overdose are consistent with the known adverse reactions associated with Topotecan Injection [see Adverse Reactions (6.1, 6.2)]. In addition, elevated hepatic enzymes and mucositis have been reported following overdose.
One patient received a single dose of 40 mg/m2 of intravenous topotecan and developed gastrointestinal toxicity, skin toxicity, and myelosuppression leading to septic shock. Another patient received a single dose of 35 mg/m2 and experienced severe, reversible neutropenia.
There is no known antidote for overdosage with Topotecan injection. If an overdose is suspected, monitor the patient closely for bone marrow suppression and institute supportive-care measures (such as the prophylactic use of G-CSF and antibiotic therapy) as appropriate.
Topotecan 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-1H-pyrano[3’,4’:6,7]indolizino[1,2-b]quinoline-3,14-(4H,12H)-dione 1.25 hydrochloride. It has the molecular formula C23H23N3O5 nHCl (n=1.25) and a molecular weight of 467.02. Topotecan hydrochloride is soluble in water and melts with decomposition at 213°C to 218°C. As formulated in Topotecan injection, topotecan hydrochloride has the following structural formula:
Topotecan injection is supplied as a sterile, non-pyrogenic, clear, yellow to yellow-green solution at a topotecan free base concentration of 4 mg/4 mL (1 mg/mL) available in single use vials. Each mL of Topotecan injection contains topotecan hydrochloride equivalent to 1 mg of topotecan as free base, 5 mg tartaric acid, NF and water for injection, USP. Hydrochloric acid and/or sodium hydroxide may be used for pH adjustment to pH 2.6 – 3.2.
The solution must be diluted before administration by intravenous infusion.
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.
Following administration of Topotecan injection at doses of 0.5 to 1.5 mg/m2 administered as a 30-minute infusion to cancer patients, topotecan exhibited multiexponential pharmacokinetics with a terminal half-life of 2 to 3 hours. Total exposure (AUC) is approximately dose-proportional.
Binding of topotecan to plasma proteins is approximately 35%.
Topotecan undergoes a reversible pH-dependent hydrolysis of its lactone moiety; it is the lactone form that is pharmacologically active. At pH ≤4, the lactone is exclusively present, whereas the ring-opened hydroxy-acid form predominates at physiologic pH. In vitro studies in human liver microsomes indicate topotecan is metabolized to an N-demethylated metabolite. The mean metabolite:parent AUC ratio was about 3% for total topotecan and topotecan lactone following IV administration.
Renal clearance is the primary route of topotecan elimination.
In a mass balance/excretion trial in 4 patients with solid tumors, the overall recovery of total topotecan and its N-desmethyl metabolite in urine and feces over 9 days averaged 73.4% ± 2.3% of the administered IV dose. Mean values of 50.8% ± 2.9% as total topotecan and 3.1% ± 1.0% as N-desmethyl topotecan were excreted in the urine following IV administration. Fecal elimination of total topotecan accounted for 17.9% ± 3.6% while fecal elimination of N-desmethyl topotecan was 1.7% ± 0.6%. An O-glucuronidation metabolite of topotecan and N-desmethyl topotecan has been identified in the urine.
Gender: Plasma clearance of topotecan lactone in male patients was approximately 24% higher than that in female patients, largely reflecting difference in body size.
Age: Population pharmacokinetic analysis in female patients did not identify age as a significant factor. Decreased renal clearance, which is common in the elderly, is a more important determinant of topotecan clearance [see Dosage and Administration (2.2), Use in Specific Populations (8.5)].
Renal Impairment: In patients with mild renal impairment (Clcr = 40 to 60 mL/min), plasma clearance of topotecan lactone was decreased by 33% compared with patients with normal renal function (Clcr greater than 60 mL/min). In patients with moderate renal impairment (Clcr = 20 to 39 mL/min), plasma clearance of topotecan lactone was reduced by 65% compared with patients with normal renal function. Dosage adjustment is recommended for patients with moderate renal impairment. No dosage adjustment is required in patients with mild renal impairment [see Dosage and Administration (2.2), Use in Specific Populations (8.6)].
Hepatic Impairment: Plasma clearance of topotecan lactone in patients with hepatic impairment serum bilirubin levels between 1.7 and 15.0 mg/dL was decreased by 33% compared with patients with normal hepatic function (serum bilirubin levels less than 1.7 mg/dL).
Effects of Topotecan on Drug-Metabolizing Enzymes: In vitro inhibition studies using marker substrates for human P450 CYP1A2, CYP2A6, CYP2C8/9, CYP2C19, CYP2D6, CYP2E, CYP3A, or CYP4A or dihydropyrimidine dehydrogenase indicate that the activities of these enzymes were not altered by topotecan.
Cisplatin: Administration of cisplatin (60 or 75 mg/m2 on Day 1) before topotecan (0.75 mg/m2/day on Days 1 to 5) in 9 patients with ovarian cancer had no significant effect on the Cmax and AUC of total topotecan.
Topotecan (0.3 mg/m2 IV daily on Days 2 to 6) had no effect on the pharmacokinetics of free platinum in 15 patients with ovarian cancer who were administered cisplatin 50 mg/m2 (n = 9) or 75 mg/m2 (n = 6) on Day 2 after paclitaxel 110 mg/m2 on Day 1. Topotecan (0.75 mg/m2 IV daily on Days 1 to 5) had no effect on dose-normalized (60 mg/m2) Cmax values of free platinum in 13 patients with ovarian cancer who were administered 60 mg/m2 (n = 10) or 75 mg/m2 (n = 3) cisplatin on Day 1.
Carcinogenicity testing of topotecan has not been performed. Topotecan is known to be genotoxic to mammalian cells and is a probable carcinogen. Topotecan was mutagenic to L5178Y mouse lymphoma cells and clastogenic to cultured human lymphocytes with and without metabolic activation. It was also clastogenic to mouse bone marrow. Topotecan did not cause mutations in bacterial cells.
Topotecan given to female rats prior to mating at a dose of 1.4 mg/m2 IV (about equal to the clinical dose on a mg/m2 basis) caused superovulation possibly related to inhibition of follicular atresia. This dose given to pregnant female rats also caused increased pre-implantation loss. Studies in dogs given 0.4 mg/m2 IV (about 0.25 times the clinical dose on a mg/m2 basis) of topotecan daily for a month suggest that treatment may cause an increase in the incidence of multinucleated spermatogonial giant cells in the testes. Topotecan may impair fertility in women and men.
Another formulation of Topotecan was studied in 426 patients with recurrent or progressive small cell lung cancer in 1 randomized, comparative trial and in 3 single-arm trials.
Randomized Comparative Trial
In a randomized, comparative, Phase 3 trial, 107 patients were treated with topotecan (1.5 mg/m2/day × 5 days starting on Day 1 of a 21-day course) and 104 patients were treated with CAV (1,000 mg/m2 cyclophosphamide, 45 mg/m2 doxorubicin, 2 mg vincristine administered sequentially on Day 1 of a 21-day course). All patients were considered sensitive to first-line chemotherapy (responders who then subsequently progressed greater than or equal to 60 days after completion of first-line therapy). A total of 77% of patients treated with topotecan and 79% of patients treated with CAV received platinum/etoposide with or without other agents as first-line chemotherapy. The efficacy outcome measures were response rate and duration of response.
The results of the trial did not show statistically significant improvements in response rates, response duration, time to progression, and overall survival as shown in Table 2.
|HR = hazard-ratio; CI = confidence interval.|
a The calculation for duration of response was based on the interval between first response and time to progression.
(n = 107)
(n = 104)
Overall response rate (95% CI)
Complete response rate
Partial response rate
Response durationa (months)
Median (95% CI)
24% (16% to 32%)
3.3 (3.0 to 4.1)
18% (11% to 26%)
3.5 (3.0 to 5.3)
Time to progression (months)
Median (95% CI)
HR (Topotecan:CAV) (95% CI)
3.1 (2.6 to 4.1)
2.8 (2.5 to 3.2)
0.92 (0.69 to 1.22)
Median (95% CI)
HR (Topotecan:CAV) (95% CI)
5.8 (4.7 to 6.8)
5.7 (5.0 to 7.0)
1.04 (0.78 to 1.39)
The time to response was similar in both arms: topotecan median of 6 weeks (range: 2.4 to 15.7) versus CAV median 6 weeks (range: 5.1 to 18.1).
Changes on a disease-related symptom scale in patients who received topotecan or who received CAV are presented in Table 3. It should be noted that not all patients had all symptoms, nor did all patients respond to all questions. Each symptom was rated on a 4-category scale with an improvement defined as a change in 1 category from baseline sustained over 2 courses. Limitations in interpretation of the rating scale and responses preclude formal statistical analysis.
|a Defined as improvement sustained over at least 2 courses compared with baseline.|
b Number of patients with baseline and at least 1 post-baseline assessment.
(n = 107)
(n = 104)
Shortness of breath
Interference with daily activity
Topotecan was also studied in 3 open-label, non-comparative trials in a total of 319 patients with recurrent or progressive small cell lung cancer after treatment with first-line chemotherapy. In all 3 trials, patients were stratified as either sensitive (responders who then subsequently progressed greater than or equal to 90 days after completion of first-line therapy) or refractory (no response to first-line chemotherapy or who responded to first-line therapy and then progressed within 90 days of completing first-line therapy). Response rates ranged from 11% to 31% for sensitive patients and 2% to 7% for refractory patients. Median time to progression and median survival were similar in all 3 trials and the comparative trial.
Topotecan injection is supplied in 4 mg/4 mL (1 mg/mL, topotecan free base equivalent) single-use vials. Each vial contains 4 mL of the sterile, clear, yellow to yellow-green solution.
NDC 0409-0302-01 (Package of 1 Single-Use Vial)
Store the vials protected from light in the original cartons, refrigerated between 2°C and 8°C (36°F and 46°F). Topotecan injection diluted for infusion is stable between 20°C and 25°C (68°F and 77°F) in ambient lighting conditions for 24 hours.
Handle and dispose of Topotecan injection consistent with recommendations for the handling and disposal of hazardous drugs1.
Manufactured by: Zydus Hospira Oncology Private Ltd., Gujarat, India