Label: TOPOTECAN HYDROCHLORIDE- topotecan hydrochloride injection, powder, lyophilized, for solution

  • NDC Code(s): 69097-262-67, 69097-262-68
  • Packager: Cipla USA Inc.
  • Category: HUMAN PRESCRIPTION DRUG LABEL
  • DEA Schedule: None
  • Marketing Status: Abbreviated New Drug Application

Drug Label Information

Updated December 10, 2018

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  • BOXED WARNING(What is this?)

    WARNING: BONE MARROW SUPPRESSION 

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

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  • HIGHLIGHTS OF PRESCRIBING INFORMATION
    These 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, for intravenous use
    Initial U.S. Approval:1996

    WARNING: MYELOSUPPRESSION

    See full prescribing information for complete boxed warning.

    Topotecan hydrochloride for injection can cause severe myelosuppression. Administer first cycle only to patients with baseline neutrophil counts greater than or equal to 1,500 /mm3 and platelet counts greater than or equal to 100,000/mm3. Monitor blood cell counts. (2.4, 5.1).

    INDICATIONS AND USAGE

    Topotecan hydrochloride for injection is a topoisomerase inhibitor indicated for treatment of:

    •   Patients with metastatic ovarian cancer after disease progression on or after initial or subsequent chemotherapy, as a single agent. (1.1)
    •   Patients with small cell lung cancer (SLSC) platinum-sensitive disease who progressed at least 60 days after initiation of first-line chemotherapy, as a single agent (1.2)
    •   Patients with Stage IV-B, recurrent, or persistent cervical cancer which is not amenable to curative treatment in combination with cisplatin. (1.3)

    DOSAGE AND ADMINISTRATION

    •   Ovarian Cancer and Small Cell Lung Cancer: 1.5 mg/m2by intravenous infusion over 30 minutes daily for 5 consecutive days, starting on Day 1 of a 21-day cycle. (2.1, 2.2)
    •   Cervical Cancer: 0.75 mg/m2by intravenous infusion over 30 minutes on Days 1, 2, and 3 repeated every 21 days in combination with cisplatin 50 mg/m2on Day 1 of a 21-day cycle. (2.3)
    •   Renal Impairment: Reduce dose if creatinine clearance (20 to 39 mL/min) (2.6)

    DOSAGE FORMS AND STRENGTHS

    For injection: 4-mg (free base) lyophilized powder in single-dose vial. (3)

    CONTRAINDICATIONS

    • History of severe hypersensitivity reactions to topotecan. (4)

    WARNINGS AND PRECAUTIONS

    •   Interstitial lung disease (ILD): Fatal cases have occurred. Permanently discontinue if ILD confirmed. (5.2)
    •   Extravasation and Tissue Injury: Severe cases have been occured. If extravasation occurs, immediately stop administration and institute recommended management procedures. (5.3)
    •   Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of potential risk to the fetus and to use effectives contraception. (5.4, 8.1, 8.3)

    ADVERSE REACTIONS

    Ovarian Cancer:

    •   The most common Grade 3 or 4 hematologic adverse reactions (incidence > 5%) were: neutropenia (Grade 4: 80%), anemia (Grade 3/4: 41%), thrombocytopenia (Grade 4: 27%), and febrile neutropenia (23%). (6.1)
    •   The most common (incidence >5%) non-hematologic adverse reactions (all Grades) were: nausea, vomiting, fatigue, diarrhea, and dyspnea. (6.1)

    SCLC:

    •   The most common Grade 3 or 4 hematologic adverse reactions were (incidence > 5%) neutropenia, anemia, thrombocytopenia (Grade 4: 29%), and febrile neutropenia (6.1).
    •   The most common (incidence>5%) non-hematologic adverse reactions (all Grades) were: asthenia, dyspnea, nausea, pneumonia, abdominal pain, and fatigue.(6.1)

    Cervical Cancer

    • The most common Grade 3 or 4 hematologic adverse reactions were (incidence > 5%) neutropenia, anemia and thrombocytopenia (6.1)
    • The most common (incidence >25% and ≥ 2% higher than cisplatin alone) non-hematologic adverse reactions (all grades) were: pain, vomiting, and infection/febrile neutropenia. (6.1)

    To report SUSPECTED ADVERSE REACTIONS, contact Cipla Ltd, at 1-866-604-3268 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

    USE IN SPECIFIC POPULATIONS

    •   Lactation: Advise not to breastfeed. (8.2)

    See 17 for PATIENT COUNSELING INFORMATION.

    Revised: 12/2018

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  • FULL PRESCRIBING INFORMATION: CONTENTS*
  • 1 INDICATIONS AND USAGE

    1.1 Ovarian Cancer

    Topotecan hydrochloride for injection, as a single agent, is indicated for the treatment of patients with metastatic ovarian cancer after disease progression on or after initial or subsequent chemotherapy.

    1.2 Small Cell Lung Cancer

    Topotecan hydrochloride for injection, as a single agent, is indicated for the treatment of patients with small cell lung cancer (SCLC) with platinum-sensitive disease who progressed at least 60 days after initiation of first-line chemotherapy.

    1.3 Cervical Cancer

    Topotecan hydrochloride for injection in combination with cisplatin is indicated for the treatment of patients with Stage IV-B, recurrent, or persistent cervical cancer of the cervix not amenable to curative treatment.

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  • 2 DOSAGE AND ADMINISTRATION

    2.1 Important Safety Information

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

    2.2 Recommended Dosage for Ovarian Cancer

    The recommended dosage of topotecan hydrochloride for injection is 1.5 mg/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.

    2.3 Recommended Dosage Small Cell Lung Cancer SCLC

    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. 

    2.4 Recommended Dosage for Cervical Cancer

    Recommended Dose and Schedule

    The recommended dose 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, repeated every 21 days.

    2.5 Dose Modifications for Adverse Reactions

    Hematologic

    Do 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 /mm3during 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/m2if necessary) for:

    • febrile neutropenia (defined as neutrophil counts less than 1,000 /mm3with 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 /mm3during previous cycle.

    2.6 Dosage Modification for Renal Impairment

    For topotecan hydrochloride for injection as a single agent, reduce the dose to 0.75 mg/m2/day for patients with creatinine clearance (CLcr) of 20 to 39 mL/min. (calculated with the Cockcroft-Gault method using ideal body weight) [see Clinical Pharmacology (12.3)].

    2.7 Preparation and Intravenous Administration

    Visually inspect for particulate matter and discoloration prior to administration, whenever solution and container permit.

    Preparation

    Reconstitute each 4-mg vial of topotecan hydrochloride for injection with 4 mL Sterile Water for Injection, USP.

    Dilute the appropriate volume of the reconstituted solution in either 0.9% Sodium Chloride Intravenous Infusion, USP or 5% Dextrose in Water Injection, USP.

    Stability

    Because the vials contain no preservative, use contents immediately after reconstitution. Discard any unused portion.

    Store reconstituted product diluted for infusion at approximately 20°C to 25°C (68°F to 77°F) protected from light for no more than 24 hours. Discard after 24 hours.

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  • 3 DOSAGE FORMS AND STRENGTHS

    For injection: 4 mg (free base) of topotecan as light yellow to greenish lyophilized powder in single-dose vial for reconstitution.

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  • 4 CONTRAINDICATIONS

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

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  • 5 WARNINGS AND PRECAUTIONS

    5.1 Myelosuppression

    Topotecan hydrochloride for injection can cause severe myelosuppression.

    Single Agent

    Grade 4 neutropenia occurred in 78% of 879 patients, with a median duration of 7 days and was most common during Cycle 1 (58% of patients). Grade 4 neutropenia associated with infection occurred in 13% and febrile neutropenia occurred in 5%. Sepsis occurred in 4% of patients and was fatal in 1%. Grade 4 thrombocytopenia occurred in 27%, with a median duration of 5 days. Grade 3 or 4 anemia occurred in 37% of patients.

    Combination with Cisplatin

    Grade 4 neutropenia occurred in 48% and Grade 4 thrombocytopenia occurred in 7% of 147 patients. Grade 3 or 4 anemia occurred in 40% of patients.

    Topotecan can cause fatal typhlitis (neutropenic enterocolitis). Consider the possibility of typhlitis in patients presenting with fever, neutropenia, and abdominal pain.

    Administer the first cycle of topotecan hydrochloride for injection only to patients with a baseline neutrophil count of greater than or equal to 1,500/mm3and 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)].

    5.3 Interstitial Lung Disease

    Interstitial lung disease (ILD), including fatalities, can occur with topotecan hydrochloride for injection. Underlying risk factors include history of ILD, pulmonary fibrosis, lung cancer, thoracic radiation, and use of pneumotoxic drugs or colony stimulating factors. Monitor for pulmonary symptoms indicative of ILD. Permanently discontinue topotecan hydrochloride for injection if ILD is confirmed.

    5.5 Extravasation and Tissue Injury

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

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

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  • 6 ADVERSE REACTIONS

    The following serious adverse reactions are described elsewhere in the labelling:

    •   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 for injection from eight trials in which 879 patients with ovarian cancer or small cell lung cancer (SCLC) received topotecan hydrochloride for injection 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 for injection 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.

    Ovarian Cancer

    The safety of topotecan hydrochloride for injection 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 for injection.

    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 for injection and 0% of patients receiving paclitaxel.

    b Pain includes body pain, skeletal pain, and back pain.

    Adverse Reaction
    Topotecan Hydrochloride for Injection
    (n = 112)
    Paclitaxel
    (n = 114)
    Grade 3-4 (%)
    Grade 3-4 (%)
    Hematologic
    Grade 4 neutropenia (<500/mm3)
    80
    21
    Grade 3 or 4 anemia (Hgb <8 g/dL)
    41
    6
    Grade 4 thrombocytopenia (<25,000/mm3)
    27
    3
    Febrile neutropenia
    23
    4
    Non-hematologic
    %
    %
    Infections
    Sepsisa
    5
    2
    Respiratory, thoracic, and mediastinal
    Dyspnea
    6
    5
    Gastrointestinal
    Vomiting
    Nausea
    Diarrhea
    Abdominal pain
    Intestinal obstruction
    Constipation
    10
    10
    6
    5
    5
    5
    3
    2
    1
    4
    4
    0
    General and administrative site conditions
    Fatigue
    Painb
    Asthenia
    7
    5
    5
    6
    7
    3

    Small Cell Lung Cancer (SCLC)

    The safety of topotecan hydrochloride for injection 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 for injection and 1% of patients receiving CAV.

    b Pain includes body pain, skeletal pain, and back pain.

    cCAV = cyclophosphamide, doxorubicin and vincristine.




    Adverse Reactions
    Topotecan Hydrochloride for Injection
    (n = 107)
    CAVc

    (n = 104)
    Grade 3-4 (%)
    Grade 3-4 (%)
    Hematologic
    Grade 4 neutropenia (<500/mm3)
    70
    72
    Grade 3or 4 anemia (Hgb <8 g/dL)
    42
    20
    Grade 4 thrombocytopenia (<25,000/mm3)
    29
    5
    Febrile neutropenia
    28
    26
    Non-Hematologic
    Infections
      Sepsisa
    5
    5
    Respiratory, thoracic, and mediastinal
      Dyspnea
      Pneumonia
    9
    8
    14
    6
    Gastrointestinal
      Nausea
      Abdominal pain
    8
    6
    6
    4
    General and administrative site conditions
      Asthenia
      Fatigue
      Painb
    9
    6
    5
    7
    10
    7

    Hepatobiliary Disorders in Ovarian and Small Cell Lung Cancer

    Based on the combined experience of 453 patients with metastatic ovarian cancer and 426 patients with SCLC treated with topotecan hydrochloride for injection, 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 Cancer

    The safety of topotecan hydrochloride for injection 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%)ain 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 Reaction
    Topotecan Hydrochloride for Injection with Cisplatin (n = 140)
    %


    Cisplatin
     (n = 144)
    %
    Hematologic
    Neutropenia
    Grade 3 (<1,000-500/mm3)
    Grade 4 (<500/mm3)
    26
    48
    1
    1
    Anemia
    Grade 3 (Hgb <8-6.5 g/dL)
    Grade 4 (Hgb <6.5 g/dL)
    34
    6
    19
    3
    Thrombocytopenia
    Grade 3 (<50,000-10,000/mm3)
    Grade 4 (<10,000/mm3)
    26
    7
    3
    0
    Non-Hematologicb,c
    General and administrative site conditions
    Constitutionald
    Paine
    69
    59
    62
    50
    Gastrointestinal
    Vomiting
    Stomatitis-pharyngitis
    Other
    40
    6
    63
    37
    0
    56
    Dermatologyf
    48
    20
    Infection
       Febrile neutropeniaf
    28
    18
    Cardiovascularf
    25
    15

    6.2 Postmarketing Experience

    The following reactions have been identified during post approval use of topotecan hydrochloride for injection. 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

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  • 8 USE IN SPECIFIC POPULATIONS

    8.1 Pregnancy

    Risk Summary

    Based on animal data and its mechanism of action, topotecan hydrochloride for injection can cause fetal harm when administered to a pregnant woman.There are no available clinical data on the use of topotecan hydrochloride for injection 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 Data:

    In 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.

    8.2 Lactation

    Risk Summary

    There 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 for injection and for 1 week after the last dose.

    Data

    Following intravenous administration of topotecan to lactating rats at a dose of 4.72 mg/m2 (about twice the 1.5 mg/m2clinical dose based on BSA) to lactating rats, topotecan was excreted into milk at concentrations up to 48-fold higher than those in plasma.

    8.3 Females and Males of Reproductive Potential

    Pregnancy Testing

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

    Contraception

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

    Females

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

    Males

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

    Infertility

    Females

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

    Males

    Effects on spermatogenesis occurred in animals administered topotecan [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 for injection, 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 for injection 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.

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  • 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.

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  • 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:

    image 1

    Topotecan hydrochloride for injection, for intravenous use is supplied as a sterile, lyophilized, buffered, light yellow to greenish powder available in single-dose vials. Each 4 mg 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.

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  • 12 CLINICAL PHARMACOLOGY

    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.

    Distribution

    Protein binding of topotecan is approximately 35%.

    Elimination

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

    Metabolism

    Topotecan 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.

    Excretion

    The 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 Populations

    No clinically significant differences in the pharmacokinetics of topotecan were observed based on age, sex, or hepatic impairment following intravenous administration.

    Patients with Renal Impairment

    Compared 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 to 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 Interactions Studies

    Clinical Studies

    No 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 Studies

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

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  • 13 NONCLINICAL TOXICOLOGY

    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.

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  • 14 CLINICAL STUDIES

    14.1 Ovarian Cancer

    The efficacy of topotecan hydrochloride for injection 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/m2as 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 for injection and of 114 patients who received paclitaxel (175 mg/m2intravenously 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

    Parameter
    Topotecan hydrochloride for injection
    (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)
    5.0 (3.7, 7.8)
    Time to progression (months)
    Median (95% CI)
    Hazard ratio (95% CI)
    4.4 (2.8, 5.4)                         3.4 (2.7, 4.2)
    0.76 (0.57, 1.02)
    Overall survival (months)
    Median (95% CI)
    Hazard ratio (95% CI)
    14.5 (10.7 to 16.5)               12.2 (9.7, 15.8)
    0.97 (0.71, 1.34)

    The median time to response was 7.6 weeks (3.1 weeks to 5 months) with topotecan hydrochloride for injection 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 for injection after paclitaxel had a partial response and 10% of 49 patients who received paclitaxel after topotecan hydrochloride for injection had a response (2 complete responses).

    Topotecan hydrochloride for injection 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 for injection 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 for injection 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.

    Randomized Comparative Trial

    In a randomized, comparative trial, 211 patients were randomized 1:1 to receive topotecan hydrochloride for injection (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 for injection 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.

    The calculation for duration of response was based on the interval between first response and time to progression.

    b CAV = cyclophosphamide, doxorubicin and vincristine

    Parameter
    Topotecan hydrochloride for injection
    (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)
    Hazard ratio (95% CI)
    3.1 (2.6, 4.1)                         2.8 (2.5, 3.2)
    0.92 (0.69, 1.22)
    Overall survival (months)
    Median (95% CI)
    Hazard ratio (95% CI)
    5.8 (4.7, 6.8)                         5.7 (5, 7)
    1.04 (0.78, 1.39)

    The median time to response was similar in both arms: Topotecan hydrochloride for injection, 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

    aDefined as improvement sustained over at least 2 courses compared with baseline.

    b Number of patients with baseline and at least 1 post-baseline assessment.





    Symptom
    Topotecan Hydrochloride for Injection
    (n = 107)
    CAV
    (n = 104)
    nb
    (%)
    nb
    (%)
    Shortness of breath
    Interference with daily activity
    Fatigue
    Hoarseness
    Cough
    Insomnia
    Anorexia
    Chest pain
    Hemoptysis
    68
    67
    70
    40
    69
    57
    56
    44
    15
    (28)
    (27)
    (23)
    (33)
    (25)
    (33)
    (32)
    (25)
    (27)
    61
    63
    65
    38
    61
    53
    57
    41
    12
    (7)
    (11)
    (9)
    (13)
    (15)
    (19)
    (16)
    (17)
    (33)

    Single-Arm Trials

    Topotecan hydrochloride for injection 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.

    14.3 Cervical Cancer

    The efficacy of topotecan hydrochloride for injection 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 for injection (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 for injection 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 for injection 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

    Image 2
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  • 15 REFERENCES

    1. "OSHA Hazardous Drugs." OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html.

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  • 16 HOW SUPPLIED/STORAGE AND HANDLING

    Topotecan hydrochloride for injection is supplied as a sterile, lyophilized, buffered, light yellow to greenish powder for reconstitution in 4-mg (free base) single-dose vials.

    NDC 69097-262-67 (package of 1)

    NDC 69097-262-68 (package of 5)

    Store between 20°C and 25°C (68°F 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.

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  • 17 PATIENT COUNSELING INFORMATION

    Myelosuppression 

    Inform patients that topotecan hydrochloride for injection 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 Toxicity

    Advise 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 for injection [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)].

    Lactation

    Advise 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)].

    Infertility 

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

    Asthenia and Fatigue

    Advise patients that topotecan hydrochloride for injection may cause asthenia or fatigue. These symptoms may impair the ability to safely drive or operate machinery.

    Manufactured by:

    Cipla Limited

    Verna Goa, India

    Manufactured for:

    Cipla USA, Inc.

    1560 Sawgrass Corporate Parkway,

    Suite 130, Sunrise, FL 33323

    Revised: 9/2018

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  • PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

    NDC 69097-262-67

              Topotecan

           Hydrochloride

           For Injection

            4 mg*/vial

    For Intravenous Use Only

         Must be diluted.

    CYTOTOXIC AGENT

    Cipla              Rx Only

    image

    NDC 69097-262-67

              Topotecan

           Hydrochloride

           For Injection

            4 mg*/vial

    For Intravenous Use Only

         Must be diluted.

    CYTOTOXIC AGENT

    This package is sealed for

     the patient's protection.

    Please do not use if safety

         seals are broken.

    One Single Dose-Vial

    Cipla              Rx Only

    cipla-carton-single vial-pack

    cipla-carton-single vial-pack

    NDC 69097-262-68

      Topotecan Hydrochloride

            For Injection

            4 mg*/vial

    For Intravenous Use Only

         Must be diluted.

    CYTOTOXIC AGENT

    Five-Single Dose-Vials

    Cipla              Rx Only

    cipla-carton-5s-pack

    cipla-carton-5s-pack

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  • INGREDIENTS AND APPEARANCE
    TOPOTECAN HYDROCHLORIDE 
    topotecan hydrochloride injection, powder, lyophilized, for solution
    Product Information
    Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:69097-262
    Route of Administration INTRAVENOUS
    Active Ingredient/Active Moiety
    Ingredient Name Basis of Strength Strength
    TOPOTECAN HYDROCHLORIDE (UNII: 956S425ZCY) (TOPOTECAN - UNII:7M7YKX2N15) TOPOTECAN 4 mg  in 4 mL
    Inactive Ingredients
    Ingredient Name Strength
    MANNITOL (UNII: 3OWL53L36A)  
    TARTARIC ACID (UNII: W4888I119H)  
    HYDROCHLORIC ACID (UNII: QTT17582CB)  
    SODIUM HYDROXIDE (UNII: 55X04QC32I)  
    Product Characteristics
    Color YELLOW (light yellow to greenish powder) Score     
    Shape Size
    Flavor Imprint Code
    Contains     
    Packaging
    # Item Code Package Description Marketing Start Date Marketing End Date
    1 NDC:69097-262-68 5 in 1 CARTON 12/01/2010
    1 4 mL in 1 VIAL, SINGLE-DOSE; Type 0: Not a Combination Product
    2 NDC:69097-262-67 1 in 1 CARTON 12/01/2010
    2 4 mL in 1 VIAL, SINGLE-DOSE; Type 0: Not a Combination Product
    Marketing Information
    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    ANDA ANDA091199 12/01/2010
    Labeler - Cipla USA Inc. (078719707)
    Registrant - Cipla USA Inc. (078719707)
    Establishment
    Name Address ID/FEI Business Operations
    Cipla Ltd.- Goa 650072015 MANUFACTURE(69097-262)
    Establishment
    Name Address ID/FEI Business Operations
    Cipla Limited, Bangalore 915154892 API MANUFACTURE(69097-262) , ANALYSIS(69097-262)
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