NDC 71288-127 Topotecan

Topotecan Hydrochloride

NDC Product Code 71288-127

NDC 71288-127-15

Package Description: 1 VIAL, SINGLE-DOSE in 1 CARTON > 15 mL in 1 VIAL, SINGLE-DOSE

NDC Product Information

Topotecan with NDC 71288-127 is a a human prescription drug product labeled by Meitheal Pharmaceuticals Inc.. The generic name of Topotecan is topotecan hydrochloride. The product's dosage form is injection, powder, lyophilized, for solution and is administered via intravenous form.

Labeler Name: Meitheal Pharmaceuticals Inc.

Dosage Form: Injection, Powder, Lyophilized, For Solution - A dosage form intended for the solution prepared by lyophilization ("freeze drying"), a process which involves the removal of water from products in the frozen state at extremely low pressures; this is intended for subsequent addition of liquid to create a solution that conforms in all respects to the requirements for Injections.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Topotecan Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.

  • TOPOTECAN HYDROCHLORIDE 4 mg/15mL

Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • MANNITOL (UNII: 3OWL53L36A)
  • TARTARIC ACID (UNII: W4888I119H)
  • HYDROCHLORIC ACID (UNII: QTT17582CB)
  • SODIUM HYDROXIDE (UNII: 55X04QC32I)

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Intravenous - Administration within or into a vein or veins.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Topoisomerase Inhibitor - [EPC] (Established Pharmacologic Class)
  • Topoisomerase Inhibitors - [MoA] (Mechanism of Action)

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Meitheal Pharmaceuticals Inc.
Labeler Code: 71288
FDA Application Number: ANDA201166 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: ANDA - A product marketed under an approved Abbreviated New Drug Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 09-02-2019 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2020 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA’s requests for correction to deficient or non-compliant submissions. Values = ‘Y’ or ‘N’.

* Please review the disclaimer below.

Topotecan Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

Warning: Myelosuppression

Topotecan hydrochloride can cause severe myelosuppression. Administer first cycle only to patients with baseline neutrophil counts of greater than or equal to 1,500/mm3 and platelet counts greater than or equal to 100,000/mm3. Monitor blood cell counts [see Warnings and Precautions (5.1)].

1.1 Ovarian Cancer

Topotecan Hydrocholoride 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 Hydrocholoride 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 Hydrocholoride 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.

2.1 Important Safety Information

Verify dosage using body surface area. Do not exceed a single dose of 4 mg intravenously.

The recommended dosage of topotecan hydrochloride for 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 cycle until disease progression or unacceptable toxicity.

The recommended dosage of topotecan hydrochloride for 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 cycle.

The recommended dosage of topotecan hydrochloride for injection 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, of a 21-day cycle.

Other

  • HematologicDo not administer subsequent cycles of topotecan hydrochloride for injection until neutrophils recover to greater than 1,000/mm3, platelets recover to greater than 100,000/mm3, 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/m2/day for:
  • Neutrophil counts of less than 500/mm3 or administer granulocyte-colony stimulating factor (G-CSF) starting no sooner than 24 hours following the last dose
  • Platelet counts less than 25,000/mm3 during previous cycle
  • For topotecan hydrochloride for injection in combination with cisplatin, reduce the dose to 0.6 mg/m2/day (and further to 0.45 mg/m2 if necessary) for:
  • Febrile neutropenia (defined as neutrophil counts less than 1,000/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
  • Platelet counts less than 25,000/mm3 during previous cycle

  • PreparationReconstitute 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.

  • StabilityBecause 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.

Single AgentGrade 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 CisplatinGrade 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/mm3 and a platelet count greater than or equal to 100,000/mm3. 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)].

Ovarian CancerThe safety of topotecan hydrochloride 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.
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 and 0% of patients receiving paclitaxel.
b Pain includes body pain, skeletal pain, and back pain.
Adverse ReactionTopotecan Hydrochloride(n = 112)Paclitaxel (n = 114)Grade 3-4 (%)Grade 3-4 (%)Hematologic     Grade 4 neutropenia (< 500/mm3)     Grade 3 or 4 anemia (Hgb < 8 g/dL)     Grade 4 thrombocytopenia (< 25,000/mm3)     Febrile neutropenia
80412723
21634
Non-HematologicInfections     Sepsisa5
2
Respiratory, thoracic, and mediastinal     Dyspnea
6
5
Gastrointestinal     Vomiting     Nausea     Diarrhea     Abdominal pain     Intestinal obstruction     Constipation
10106555
321440
General and administrative site conditions     Fatigue     Painb     Asthenia
755
673

Small Cell Lung Cancer (SCLC)The safety of topotecan hydrochloride 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 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.
c CAV = cyclophosphamide, doxorubicin and vincristine.
Adverse ReactionsTopotecan Hydrochloride(n = 107)CAVc(n = 104)Grade 3-4 (%)Grade 3-4 (%)Hematologic     Grade 4 neutropenia (< 500/mm3)     Grade 3 or 4 anemia (Hgb < 8 g/dL)     Grade 4 thrombocytopenia (< 25,000/mm3)     Febrile neutropenia
70422928
7220526
Non-HematologicInfections     Sepsisa5
5
Respiratory, thoracic, and mediastinal     Dyspnea     Pneumonia
98
146
Gastrointestinal     Nausea     Abdominal pain
86
64
General and administrative site conditions     Asthenia     Fatigue     Painb965
7107

Hepatobiliary Disorders in Ovarian and Small Cell Lung CancerBased on the combined experience of 453 patients with metastatic ovarian cancer and 426 patients with SCLC treated with topotecan hydrochloride, Grade 3 or 4 increases aspartate transaminase (AST) or alanine transaminase (ALT) occurred in 4% and Grade 3 or 4 elevated bilirubin occurred in less than 2%.

Cervical CancerThe safety of topotecan hydrochloride was evaluated in a comparative trial of topotecan hydrochloride with cisplatin versus cisplatin as a single agent in patients with cervical cancer (Study GOG 0179). Table 3 shows the hematologic and non-hematologic adverse reactions in patients with cervical cancer.
Table 3. Adverse Reactions Occurring in Greater than or Equal to 5% of Patients with Cervical Cancer (Between-Arm Difference ≥ 2%)a in Study GOG 0179
a Includes patients who were eligible and treated.
b Severity based on using National Cancer Institute (NCI) Common Toxicity Criteria (CTC), Version 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%.
Adverse ReactionTopotecan Hydrochloride with Cisplatin(n = 140)%Cisplatin(n = 144)%HematologicNeutropenia     Grade 3 (< 1,000-500/mm3)     Grade 4 (< 500/mm3)
2648
11
Anemia     Grade 3 (Hgb < 8-6.5 g/dL)     Grade 4 (Hgb < 6.5 g/dL)
346
193
Thrombocytopenia     Grade 3 (< 50,000-10,000/mm3)     Grade 4 (< 10,000/mm3)
267
30
Non-Hematologicb,cGeneral and administrative site conditions     Constitutionald     Paine6959
6250
Gastrointestinal     Vomiting     Stomatitis-pharyngitis     Other
40663
37056
Dermatologyf48
20
Infection     Febrile neutropeniaf28
18
Cardiovascularf25
15

Risk SummaryBased on animal data and its mechanism of action, topotecan hydrochloride can cause fetal harm when administered to a pregnant woman. There are no available clinical data on the use of topotecan hydrochloride 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 DataIn rabbits, an intravenous dose of 0.10 mg/kg/day [about equal to the 1.5 mg/m2 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/m2 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/m2 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.

Risk SummaryThere 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 and for 1 week after the last dose.

DataFollowing intravenous administration of topotecan to lactating rats at a dose of 4.72 mg/m2 (about twice the 1.5 mg/m2 clinical dose based on BSA) to lactating rats, topotecan was excreted into milk at concentrations up to 48-fold higher than those in plasma.

Pregnancy TestingVerify pregnancy status of females of reproductive potential prior to initiating topotecan hydrochloride for injection [see Use in Specific Populations (8.1)].

ContraceptionTopotecan hydrochloride can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

FemalesAdvise females of reproductive potential to use effective contraception during treatment with topotecan hydrochloride and for 6 months after the last dose.

MalesTopotecan hydrochloride 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 and for 3 months after the last dose [see Nonclinical Toxicology (13.1)].

Infertility

FemalesTopotecan hydrochloride can have both acute and long-term effects on fertility [see Nonclinical Toxicology (13.1)].

MalesEffects on spermatogenesis occurred in animals administered topotecan [see Nonclinical Toxicology (13.1)].

DistributionProtein binding of topotecan is approximately 35%.

EliminationThe terminal half-life of topotecan is 2 to 3 hours following intravenous administration.

MetabolismTopotecan undergoes a reversible pH-dependent hydrolysis of its pharmacologically active lactone moiety. At pH less than or equal to 4, the lactone is exclusively present, whereas the ring-opened hydroxy-acid form predominates at physiologic pH. Topotecan is metabolized to an N-demethylated metabolite in vitro. The mean metabolite: parent AUC ratio was about 3% for total topotecan and topotecan lactone following intravenous administration.

ExcretionThe overall recovery of total topotecan and its N-desmethyl metabolite in urine and feces over 9 days averaged 73% ± 2% following an intravenous dose. Mean values of 51% ± 3% as total topotecan and 3% ± 1% as N-desmethyl topotecan were excreted in the urine. Fecal elimination of total topotecan accounted for 18% ± 4% 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.

Specific PopulationsNo clinically significant differences in the pharmacokinetics of topotecan were observed based on age, sex, or hepatic impairment following intravenous administration.

Patients with Renal ImpairmentCompared to patients with CLcr (calculated by the Cockcroft-Gault method using ideal body weight) greater than 60 mL/min, plasma clearance of topotecan lactone decreased by 33% in patients with CLcr 40-60 mL/min and decreased 65% in patients with CLcr 20-39 mL/min. The effect on topotecan pharmacokinetics in patients with CLcr less than 20 mL/min is unknown [see Dosage and Administration (2.6)].

Drug Interaction Studies

Clinical StudiesNo clinically significant changes in topotecan pharmacokinetics were observed when coadministered cisplatin.
No clinically significant changes in the pharmacokinetics of free platinum were observed in patients coadministered cisplatin with topotecan.

In Vitro StudiesTopotecan does not inhibit CYP1A2, CYP2A6, CYP2C8/9, CYP2C19, CYP2D6, CYP2E, CYP3A, or CYP4A or dihydropyrimidine dehydrogenase.

Randomized Comparative TrialIn a randomized, comparative trial, 211 patients were randomized 1:1 to receive topotecan hydrochloride (1.5 mg/m2 once daily intravenously for 5 days starting on Day 1 of a 21-day cycle) or CAV (cyclophosphamide 1,000 mg/m2, doxorubicin 45 mg/m2, vincristine 2 mg administered sequentially on Day 1 of a 21-day cycle). 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 hydrochloride and 79% of patients treated with CAV received platinum/etoposide with or without other agents as first-line chemotherapy. The efficacy outcome measures were overall response rate, response duration, time to progression or OS.
The results of the trial did not show statistically significant improvements in response rate, response duration, time to progression, or OS as shown in Table 5.
Table 5. Efficacy Results in Patients with Small Cell Lung Cancer Sensitive to First-Line Chemotherapy in Study 090
Abbreviations: CI, confidence interval.
a The calculation for duration of response was based on the interval between first response and time to progression.
b CAV = cyclophosphamide, doxorubicin and vincristine.
ParameterTopotecan Hydrochloride(n = 107)CAVb(n = 104)Overall response rate (95% CI)     Complete response rate     Partial response rate
24% (16%, 32%)0%24%
18% (11%, 26%)1%17%
Response durationa (months)     Median (95% CI)
3.3 (3, 4.1)
3.5 (3, 5.3)
Time to progression (months)     Median (95% CI)
3.1 (2.6, 4.1)
2.8 (2.5, 3.2)
     Hazard ratio (95% CI)
0.92 (0.69, 1.22)
Overall survival (months)     Median (95% CI)5.8 (4.7, 6.8)
5.7 (5, 7)
     Hazard ratio (95% CI)
1.04 (0.78, 1.39)
The median time to response was similar in both arms: topotecan hydrochloride, 6 weeks (2.4 weeks to 3.6 months) versus CAV, 6 weeks (5.1 weeks to 4.2 months).
Changes on a disease-related symptom scale are presented in Table 6. 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.
Table 6. Symptom Improvementa in Patients with Small Cell Lung Cancer in Study 090
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.
SymptomTopotecan Hydrochloride(n = 107)CAV(n = 104)nb(%)nb(%)Shortness of breathInterference with daily activityFatigueHoarsenessCoughInsomniaAnorexiaChest painHemoptysis
686770406957564415
282723332533322527
616365386153574112
7119131519161733

Single-Arm TrialsTopotecan hydrochloride was also studied in three open-label, non-comparative trials (Studies 014, 092 and 053) in a total of 319 patients with recurrent or progressive SCLC after treatment with first-line chemotherapy. In all three 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 three trials and the comparative trial.

MyelosuppressionInform patients that topotecan hydrochloride decreases blood cell counts such as white blood cells, platelets, and red blood cells. Advise patients to notify their healthcare provider promptly for fever, other signs of infection, or bleeding [see Warnings and Precautions (5.1)].

Interstitial Lung Disease (ILD)Inform patients of the risks of severe ILD. Advise patients to contact their healthcare provider immediately to report new or worsening respiratory symptoms [see Warnings and Precautions (5.2)].

Embryo-Fetal ToxicityAdvise females of reproductive potential and males with female partners of reproductive potential of the potential risk to a fetus. Advise women to contact their healthcare provider if they become pregnant, or if pregnancy is suspected during treatment with topotecan hydrochloride [see Warnings and Precautions (5.4), Use in Specific Populations (8.1, 8.3)].
Advise females of reproductive potential to use effective contraception during treatment and for 6 months after the last dose of topotecan hydrochloride for injection [see Use in Specific Populations (8.1, 8.3)].
Advise males with a female partner of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of topotecan hydrochloride for injection [see Use in Specific Populations (8.1, 8.3), Nonclinical Toxicology (13.1)].

LactationAdvise women to discontinue breastfeeding during treatment and for 1 week after the last dose of topotecan hydrochloride for injection [see Use in Specific Populations (8.2)].

InfertilityAdvise male and female patients of the potential risk for impaired fertility [see Use in Specific Populations (8.3), Nonclinical Toxicology (13.1)].

Asthenia and FatigueAdvise patients that topotecan hydrochloride may cause asthenia or fatigue. These symptoms may impair the ability to safely drive or operate machinery.
meitheal®Mfd. for Meitheal PharmaceuticalsChicago, IL 60631 (USA)©2019 Meitheal Pharmaceuticals Inc.
June 2019

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.

3 Dosage Forms And Strengths

Topotecan Hydrochloride for Injection: 4 mg (free base) of topotecan as a yellow to greenish lyophilized powder in single-dose vial for reconstitution.

4 Contraindications

Topotecan hydrochloride is contraindicated in patients who have a history of severe hypersensitivity reactions to topotecan. Reactions have included anaphylactoid reactions [see Adverse Reactions (6.2)].

5.1 Myelosuppression

Topotecan hydrochloride can cause severe myelosuppression.

5.2 Interstitial Lung Disease

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

5.3 Extravasation And Tissue Injury

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

5.4 Embryo-Fetal Toxicity

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. 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 and for 3 months after the last dose [see Use in Specific Populations (8.1, 8.3), Nonclinical Toxicology (13.1)].

6 Adverse Reactions

  • The following serious adverse reactions are described elsewhere in the labeling:
  • Myelosuppression [see Warnings and Precautions (5.1)]Interstitial Lung Disease [see Warnings and Precautions (5.2)]Extravasation and Tissue Injury [see Warnings and Precautions (5.3)]

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 from eight trials in which 879 patients with ovarian cancer or small cell lung cancer (SCLC) received topotecan hydrochloride 1.5 mg/m2 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 0.75 mg/m2 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.

6.2 Postmarketing Experience

The following reactions have been identified during post approval use of topotecan hydrochloride. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Blood and Lymphatic System: severe bleeding (in association with thrombocytopenia)
Hypersensitivity: allergic manifestations, anaphylactoid reactions, angioedema
Gastrointestinal: abdominal pain potentially associated with neutropenic enterocolitis, gastrointestinal perforation
Pulmonary: interstitial lung disease
Skin and Subcutaneous Tissue: severe dermatitis, severe pruritus
General and Administration Site Conditions: extravasation, mucosal inflammation

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% were aged 65 years and older, while 3.8% 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 for injection who received topotecan hydrochloride with cisplatin in the randomized clinical trial, 6% were aged 65 years and older, while 3% were aged 75 years and older. No overall differences in effectiveness or safety were observed between these patients and younger patients and other reported clinical experience has not identified differences in responses between the elderly and younger patients.

8.6 Renal Impairment

Reduce the dose of topotecan hydrochloride for injection in patients with a CLcr of 20 to 39 mL/min [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)]. No dosage adjustment is recommended for patients with CLcr greater than or equal to 40 mL/min. Insufficient data are available in patients with CLcr less than 20 mL/min to provide a dosage recommendation for topotecan hydrochloride for injection.

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.

11 Description

Topotecan is a topoisomerase inhibitor. 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. The molecular formula is C23H23N3O5•HCl and the molecular weight is 457.9 g/mol. 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, for intravenous use is supplied as a sterile, lyophilized, buffered, yellow to greenish powder available in single-dose vials. Each vial contains 4 mg topotecan hydrochloride as free base. The reconstituted solution ranges in color from yellow to yellow-green.
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.

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.

12.3 Pharmacokinetics

Following administration of topotecan hydrochloride for injection at doses of 0.5 to 1.5 mg/m2 (0.1 to 0.3 times the recommended single agent dose) administered as a 30-minute infusion, area under the curve (AUC) increases proportionally with dose.

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

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 an intravenous dose of 1.4 mg/m2 [about equal to the clinical dose based on body surface area (BSA)] 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 at an intravenous dose of 0.4 mg/m2 (about 0.25 times the clinical dose based on BSA) of topotecan daily for a month suggest that treatment may cause an increase in the incidence of multinucleated spermatogonial giant cells in the testes.

14.1 Ovarian Cancer

The efficacy of topotecan hydrochloride was evaluated in two clinical trials of 223 patients with metastatic ovarian cancer. All patients had disease that had recurred on, or was unresponsive to, a platinum-containing regimen. Patients in these trials received an initial dose of 1.5 mg/m2 as an intravenous infusion for 5 consecutive days, starting on Day 1 of a 21-day cycle.
One trial (Study 039) was a randomized trial of 112 patients who received topotecan hydrochloride and of 114 patients who received paclitaxel (175 mg/m2 intravenously over 3 hours on Day 1 of a 21-day cycle). All patients had recurrent ovarian cancer after a platinum-containing regimen or had not responded to at least 1 prior platinum-containing regimen. Patients who did not respond to the trial therapy, or who progressed, could be given the alternative treatment. The efficacy outcome measures were overall response rate, response duration, time to progression, and overall survival (OS).
The results of the trial did not show statistically significant improvements in response rates, response duration, time to progression, and OS as shown in Table 4.
Table 4. Efficacy Results in Ovarian Cancer in Study 039
Abbreviation: CI, confidence interval.
a The calculation for response duration was based on the interval between first response and time to progression.
ParameterTopotecan Hydrochloride(n = 112)Paclitaxel (n = 114)Overall response rate (95% CI)     Complete response rate     Partial response rate
21% (13%, 28%)5%16%
14% (8%, 20%)3%11%
Response durationa (months)     Median (95% CI)
6 (5.1, 7.6)
5 (3.7, 7.8)
Time to progression (months)
     Median (95% CI)
4.4 (2.8, 5.4)
3.4 (2.7, 4.2)
     Hazard ratio (95% CI)
0.76 (0.57, 1.02)
Overall survival (months)     Median (95% CI)14.5 (10.7, 16.5)
12.2 (9.7, 15.8)
     Hazard ratio (95% CI)
0.97 (0.71, 1.34)
The median time to response was 7.6 weeks (3.1 weeks to 5 months) with topotecan hydrochloride compared with 6 weeks (2.4 weeks to 4.1 months) with paclitaxel. In the cross-over phase, 13% of 61 patients who received topotecan hydrochloride after paclitaxel had a partial response and 10% of 49 patients who received paclitaxel after topotecan hydrochloride had a response (2 complete responses).
Topotecan hydrochloride was active in ovarian cancer patients who had developed resistance to platinum-containing therapy, defined as tumor progression while on, or tumor relapse within 6 months after completion of, a platinum-containing regimen. One complete and 6 partial responses were seen in 60 patients, for a response rate of 12%. In the same trial, there were no complete responders and 4 partial responders on the paclitaxel arm, for a response rate of 7%.
Topotecan hydrochloride was also studied in an open-label, non-comparative trial in 111 patients with recurrent ovarian cancer after treatment with a platinum-containing regimen, or who had not responded to 1 prior platinum-containing regimen. The response rate was 14% (95% CI: 7%, 20%). The median duration of response was 5 months (4.6 weeks to 9.6 months). The time to progression was 2.6 months (5 days to 1.4 years). The median survival was 1.3 years (1.4 weeks, to 2.2 years).

14.2 Small Cell Lung Cancer

The efficacy of topotecan hydrochloride was evaluated in 426 patients with recurrent or progressive small cell lung cancer (SCLC) in a randomized, comparative trial and in 3 single-arm trials.

14.3 Cervical Cancer

The efficacy of topotecan hydrochloride was evaluated in a multi-center, randomized (1:1), open-label study (Study GOG 0179) conducted in 147 patients with histologically confirmed Stage IV-B, recurrent, or persistent cervical cancer considered not amenable to curative treatment with surgery and/or radiation. Patients were randomized to topotecan hydrochloride (0.75 mg/m2 once daily intravenously for 3 consecutive days starting on Day 1 of a 21-day cycle) with cisplatin (50 mg/m2 intravenously on Day 1) or cisplatin as a single agent. Fifty-six percent of patients treated with topotecan hydrochloride with cisplatin and 56% of patients treated with cisplatin had received prior cisplatin with or without other agents as first-line chemotherapy. The efficacy outcome measure was OS.
Median OS of eligible patients receiving topotecan hydrochloride with cisplatin was 9.4 months (95% CI: 7.9, 11.9) compared with 6.5 months (95% CI: 5.8, 8.8) among patients randomized to cisplatin alone with a log rank P-value of 0.033 (significance level was 0.044 after adjusting for the interim analysis). The unadjusted hazard ratio for OS was 0.76 (95% CI: 0.59, 0.98).Figure 1. Kaplan-Meier Curves for Overall Survival in Cervical Cancer in Study GOG 0179

15 References

  • “OSHA Hazardous Drugs.” OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html.

16 How Supplied/Storage And Handling

Topotecan Hydrochloride for Injection is supplied as a sterile, lyophilized, buffered, yellow to greenish powder for reconstitution as follows:
NDCProduct NamePackage Factor71288-127-15
4 mg (free-base) Single-Dose Vial
1 vial per carton

Storage And Handling

Storage ConditionsStore at controlled room temperature between 20° and 25°C (68° and 77°F) [see USP Controlled Room Temperature] in original carton.
Protect from light.
Topotecan Hydrochloride for Injection is a cytotoxic drug. Follow applicable handling and disposal procedures.
Sterile, Nonpyrogenic, Preservative-free.The container closure is not made with natural rubber latex.

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