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ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.
Pronunciation
(toe poe TEE kan)
Generic Available (U.S.)
Yes: Injection
Index Terms
U.S. Brand Names
Canadian Brand Names
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Treatment of metastatic ovarian cancer, relapsed or refractory small cell lung cancer, recurrent or resistant cervical cancer (in combination with cisplatin)
Use: Unlabeled/Investigational
Treatment of central nervous system lesions (metastatic from lung cancer), central nervous system lymphoma (primary), Ewing's sarcoma, rhabdomyosarcoma (pediatrics), neuroblastoma (pediatrics)
Pregnancy Risk Factor
D
Pregnancy Considerations
Animal studies found reduced fetal body weight, eye, brain, skull, and vertebrae malformations. May cause fetal harm in pregnant women. Use during pregnancy is contraindicated.
Lactation
Excretion in breast milk unknown/contraindicated
Breast-Feeding Considerations
Breast-feeding should be discontinued in women who are receiving topotecan.
Contraindications
Hypersensitivity to topotecan or any component of the formulation; severe bone marrow depression; pregnancy; breast-feeding
Canadian labeling: Additional contraindications (not in U.S. labeling): Severe renal impairment (Clcr <20 mL/minute)
Warnings/Precautions
Boxed warnings:
• Bone marrow suppression: See “Concerns related to adverse effects” below.
Special handling:
• Hazardous agent - use appropriate precautions for handling and disposal.
Concerns related to adverse effects:
• Bone marrow suppression: [U.S. Boxed Warning]: May cause neutropenia, which may be severe or lead to infection or fatalities. Monitor blood counts frequently. Do NOT administer to patients with baseline neutrophils <1500/mm3 and platelets <100,000/mm3. The dose-limiting toxicity is bone marrow suppression (primarily neutropenia); may also cause thrombocytopenia and anemia. Neutropenia is not cumulative over time. In a clinical study comparing I.V. to oral topotecan, G-CSF support was administered in a higher percentage of patients receiving oral topotecan (Eckardt, 2007).
• Diarrhea: Diarrhea has been reported with oral topotecan; may be severe (requiring hospitalization); educate patients on early recognition and proper management, including diet changes, increase in fluid intake, antidiarrheals, and antibiotics. The incidence of diarrhea may be higher in the elderly.
• Interstitial lung disease (ILD): ILD (with fatalities) has been reported; monitor for signs/symptoms (eg, dyspnea, fever, cough, hypoxia) and discontinue use in patients with confirmed ILD. Risk factors for ILD include a history of ILD, pulmonary fibrosis, lung cancer, thoracic radiation, and the use of colony-stimulating factors or medication with pulmonary toxicity. Monitor pulmonary symptoms (cough, fever, dyspnea, and/or hypoxia) and discontinue if ILD is diagnosed.
• Neutropenic colitis: Topotecan-induced neutropenia may lead to neutropenic colitis, including fatalities; should be considered in patients presenting with neutropenia, fever, and abdominal pain.
Disease-related concerns:
• Renal impairment: Use with caution in patients with renal impairment; may require dose adjustment. Use in severe renal impairment is contraindicated in the Canadian labeling.
Adverse Reactions
>10%:
Central nervous system: Fatigue (6% to 29%), fever (5% to 28%), pain (5% to 23%), headache (18%)
Dermatologic: Alopecia (10% to 49%), rash (16%)
Gastrointestinal: Nausea (8% to 64%), vomiting (10% to 45%), diarrhea (6% to 32%; Oral: grade 3: 4%; grade 4: ≤1%; onset: 9 days), constipation (5% to 29%), abdominal pain (5% to 22%), anorexia (7% to 19%), stomatitis (18%)
Hematologic: Anemia (89% to 98%; grade 4: 7% to 37%; nadir: 15 days), neutropenia (83% to 97%; grade 4: 32% to 80%; nadir 12-15 days; duration: 7 days), leukopenia (86% to 97%; grade 4: 15% to 32%), thrombocytopenia (69% to 81%; grade 4: 6% to 27%; nadir: 15 days; duration: 3-5 days), neutropenic fever/sepsis (2% to 43%)
Neuromuscular & skeletal: Weakness (3% to 25%)
Respiratory: Dyspnea (6% to 22%), cough (15%)
1% to 10%:
Gastrointestinal: Obstruction (5%)
Hepatic: Liver enzymes increased (transient; 8%; grades 3/4: 4%), bilirubin increased (grades 3/4: <2%)
Neuromuscular & skeletal: Paresthesia (7%)
Respiratory: Pneumonia (8%)
Miscellaneous: Sepsis (grades 3/4: 5%)
<1%, postmarketing, and/or case reports: Allergic reactions, anaphylactoid reactions, angioedema, bleeding (severe, associated with thrombocytopenia), dermatitis (severe), extravasation (inadvertent), interstitial lung disease (ILD), neutropenic colitis, pancytopenia, pruritus (severe)
Drug Interactions
BCG: Immunosuppressants may diminish the therapeutic effect of BCG. Risk X: Avoid combination
BCRP/ABCG2 Inhibitors: May increase the serum concentration of Topotecan. Risk D: Consider therapy modification
Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Risk C: Monitor therapy
Echinacea: May diminish the therapeutic effect of Immunosuppressants. Risk D: Consider therapy modification
Filgrastim: May enhance the adverse/toxic effect of Topotecan. Risk D: Consider therapy modification
Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Risk D: Consider therapy modification
Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Risk X: Avoid combination
P-Glycoprotein Inhibitors: May increase the serum concentration of Topotecan. Risk X: Avoid combination
Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Risk X: Avoid combination
Platinum Derivatives: May enhance the adverse/toxic effect of Topotecan. Risk D: Consider therapy modification
Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Risk X: Avoid combination
Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Risk C: Monitor therapy
Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Risk X: Avoid combination
Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Risk C: Monitor therapy
Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Risk C: Monitor therapy
Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Vaccinial infections may develop. Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Risk X: Avoid combination
Ethanol/Nutrition/Herb Interactions
Ethanol: Avoid ethanol (due to GI irritation).
Storage
I.V.:
Solution for injection: Store intact vials at 2°C to 8°C (36°F to 45°F). Protect from light. Single-use vials should be discarded after initial vial entry; solutions for infusion are stable for 24 hours at room temperature after diluted.
Lyophilized powder: Store intact vials at room temperature of 20°C to 25°C (68°F to 77°F). Protect from light. Reconstituted solution is stable for up to 28 days at room temperature of 20°C to 25°C (68°F to 77°F). Solutions further diluted for infusion are stable for 24 hours at room temperature or up to 7 days under refrigeration.
Oral: Store at 2°C to 8°C (36°F to 46°F). Protect from light.
Reconstitution
Reconstitute lyophilized powder with 4 mL SWFI. Further dilute in 50-100 mL D5W or NS for infusion.
Compatibility
Stable in D5W, NS.
Y-site administration: Compatible: Carboplatin, cimetidine, cisplatin, cyclophosphamide, doxorubicin, etoposide, gemcitabine, granisetron, ifosfamide, methylprednisolone sodium succinate, metoclopramide, ondansetron, paclitaxel, prochlorperazine edisylate, vincristine. Incompatible: Dexamethasone sodium phosphate, fluorouracil, mitomycin. Variable (consult detailed reference): Ticarcillin/clavulanate.
Mechanism of Action
Binds to topoisomerase I and stabilizes the cleavable complex so that religation of the cleaved DNA strand cannot occur. This results in the accumulation of cleavable complexes and single-strand DNA breaks. Topotecan acts in S phase of the cell cycle.
Pharmacodynamics/Kinetics
Absorption: Oral: Rapid
Distribution: Vdss of the lactone is high (mean: 87.3 L/mm2; range: 25.6-186 L/mm2), suggesting wide distribution and/or tissue sequestering
Protein binding: ~35%
Metabolism: Undergoes a rapid, pH-dependent hydrolysis of the lactone ring to yield a relatively inactive hydroxy acid in plasma; metabolized in the liver to N-demethylated metabolite
Bioavailability: Oral: ~40%
Half-life elimination: I.V.: 2-3 hours; renal impairment: 5 hours; Oral: 3-6 hours
Time to peak, plasma: Oral: 1-2 hours; delayed with high-fat meal (3-4 hours)
Excretion:
I.V.: Urine (51%; 3% as N-desmethyl topotecan); feces (18%; 2% as N-desmethyl topotecan)
Oral: Urine (20%; 2% as N-desmethyl topotecan); feces (33%; <2% as N-desmethyl topotecan)
Dosage
Adults (details concerning dosing in combination regimens should also be consulted): Note: Baseline neutrophil count should be ≥1500/mm3 and platelets should be ≥100,000/mm3 prior to treatment; for retreatment, neutrophil count should be >1000/mm3; platelets >100,000/mm3 and hemoglobin ≥9 g/dL:
Small cell lung cancer:
IVPB: 1.5 mg/m2/day for 5 days; repeated every 21 days, minimum of 4 cycles recommended in the absence of tumor progression
Oral: 2.3 mg/m2/day for 5 days; repeated every 21 days (round dose to the nearest 0.25 mg); if patient vomits after dose is administered, do not give a replacement dose.
Metastatic ovarian cancer: IVPB: 1.5 mg/m2/day for 5 days; repeated every 21 days, minimum of 4 cycles recommended in the absence of tumor progression
Cervical cancer: IVPB: 0.75 mg/m2/day for 3 days (followed by cisplatin 50 mg/m2 on day 1 only, [with hydration]); repeated every 21 days
Dosage adjustment for toxicity:
I.V.:
Ovarian and small cell lung cancer: Dosage adjustment for hematological effects: Severe neutropenia (<500/mm3) or platelet count <25,000/mm3: Reduce dose to 1.25 mg/m2/day for subsequent cycles (may consider G-CSF support [beginning on day 6] prior to instituting dose reduction for severe neutropenia). Note: The Canadian labeling states that the dose may be further reduced to 1 mg/m2/day if necessary.
Cervical cancer (cisplatin may also require dosage adjustment): Severe febrile neutropenia (<1000/mm3 with temperature of 38°C) or platelet count <25,000/mm3: Reduce topotecan to 0.6 mg/m2/day for subsequent cycles (may consider G-CSF support [beginning on day 4] prior to instituting dose reduction for neutropenic fever.
For neutropenic fever despite G-CSF use, reduce dose to 0.45 mg/m2/day for subsequent cycles.
Oral:
Small cell lung cancer: Severe neutropenia (neutrophils <500/mm3 associated with fever or infection or lasting >7 days) or prolonged neutropenia (neutrophils ≥500/mm3 to ≤1000/mm3 lasting beyond day 21) or platelets <25,000/mm3 or grades 3/4 diarrhea: Reduce dose to 1.9 mg/m2/day for subsequent cycles (may consider same dosage reduction for grade 2 diarrhea if clinically indicated).
Dosing adjustment in renal impairment:
Manufacturer's labeling recommends the following dosage adjustment:
I.V.:
Clcr ≥40 mL/minute: No dosage adjustment required
Clcr 20-39 mL/minute: Reduce to 0.75 mg/m2/dose
Clcr <20 mL/minute: Insufficient data available for dosing recommendation (contraindicated in the Canadian labeling)
Note: For topotecan in combination with cisplatin for cervical cancer, do not initiate treatment in patients with serum creatinine >1.5 mg/dL; consider discontinuing treatment in patients with serum creatinine >1.5 mg/dL in subsequent cycles.
Oral:
Clcr ≥50 mL/minute: No dosage adjustment required
Clcr 30-49 mL/minute: Reduce dose to 1.8 mg/m2/day
Clcr <30 mL/minute: Insufficient data available for dosing recommendation
The following guidelines have been used by some clinicians:
Aronoff, 2007: I.V.:
Children:
Clcr 30-50 mL/minute: Administer 75% of dose
Clcr 10-29 mL/minute: Administer 50% of dose or reduce by 0.75 mg/m2/dose
Clcr <10 mL/minute: Administer 25% of dose
Hemodialysis: 0.75 mg/m2
Continuous renal replacement therapy (CRRT): Administer 50% of dose or reduce by 0.75 mg/m2/dose
Adults:
Clcr >50 mL/minute: Administer 75% of dose
Clcr 10-50 mL/minute: Administer 50% of dose
Clcr <10 mL/minute: Administer 25% of dose
Hemodialysis: Avoid use
Continuous ambulatory peritoneal dialysis (CAPD): Avoid use
Continuous renal replacement therapy (CRRT): 0.75 mg/m2
Kintzel, 1995: I.V.:
Clcr 46-60 mL/minute: Administer 80% of dose
Clcr 31-45 mL/minute: Administer 75% of dose
Clcr <30 mL/minute: Administer 70% of dose
Dosing adjustment in hepatic impairment: Manufacturer's labeling recommends the following:
I.V.: Bilirubin 1.7-15 mg/dL: No adjustment necessary (the half-life is increased slightly; usual doses are generally tolerated)
Oral: Bilirubin >1.5 mg/dL: No adjustment necessary
Dosage: Combination Regimens
Cervical cancer: Cisplatin-Topotecan (Cervical Cancer)
Lung cancer, small cell:
Topotecan (Oral)-Cisplatin
Topotecan Oral Regimen (SCLC)
Topotecan (Weekly)
Ovarian cancer:
Topotecan Oral Regimen (Ovarian Cancer)
Topotecan (Weekly)
Sarcoma: Topotecan-Cyclophosphamide (Ewing's Sarcoma)
Administration: Oral
Administer without regard to meals. Swallow whole; do not crush, chew, or divide capsule. If vomiting occurs after dose, do not take replacement dose.
Administration: I.V.
Administer IVPB over 30 minutes. For combination chemotherapy with cisplatin, administer pretreatment hydration.
Monitoring Parameters
CBC with differential and platelet count, renal function tests, bilirubin; monitor for symptoms of interstitial lung disease
Test Interactions
None known
Dietary Considerations
May be taken without regard to meals.
Patient Education
If this drug is administered by intravenous infusion, report immediately any burning, pain, redness, or swelling at infusion site; sudden chest pain; difficulty breathing or swallowing; or chills. Oral form may be taken with or without food. Swallow whole; do not crush, chew, or divide capsule. If vomiting occurs after dose, do not take replacement dose; take next dose at scheduled time. Maintain adequate hydration (3-4 L/day of fluids) unless instructed to restrict fluid intake during therapy. Maintain good oral hygiene. You will be more susceptible to infection. May cause nausea, vomiting, diarrhea, or hair loss (will regrow after treatment is completed). Report unresolved diarrhea, nausea, vomiting, or unusual abdominal pain; alterations in urinary pattern (increased or decreased); opportunistic infection (fever, chills, unusual bruising or bleeding, fatigue, purulent vaginal discharge, unhealed mouth sores); chest pain; respiratory difficulty; or unexplained weakness or fatigue.
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Stomatitis.
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
None reported
Mental Health: Effects on Psychiatric Treatment
May cause myelosuppression; use caution with clozapine and carbamazepine
Nursing: Physical Assessment/Monitoring
Evaluate renal function (I & O, edema) and monitor for signs of myelosuppression, gastrointestinal disturbance (nausea, vomiting, diarrhea, pain), and dyspnea prior to each infusion and on a regular basis with oral formulation.
Oncology: Emetic Potential
Moderate (30% to 90%)
Oncology: Vesicant
Inadvertent extravasation, generally mild (although severe cases have been reported).
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, oral:
Hycamtin®: 0.25 mg, 1 mg
Injection, powder for reconstitution: 4 mg
Hycamtin®: 4 mg
Injection, solution [concentrate]: 1 mg/mL (4 mL)
References
Aronoff GR, Bennett WM, Berns JS, et al, Drug Prescribing in Renal Failure: Dosing Guidelines for Adults and Children, 5th ed. Philadelphia, PA: American College of Physicians; 2007, p 102, 174.
Eckardt JR, von Pawel J, Pujol JL, et al, “Phase III Study of Oral Compared With Intravenous Topotecan as Second-Line Therapy in Small-Cell Lung Cancer,” J Clin Oncol, 2007, 25(15):2086-92.
Hunold A, Weddeling N, Paulussen M, et al, "Topotecan and Cyclophosphamide in Patients With Refractory or Relapsed Ewing Tumors," Pediatr Blood Cancer, 2006, 47(6):795-800.
Kintzel PE and Dorr RT, "Anticancer Drug Renal Toxicity and Elimination: Dosing Guidelines for Altered Renal Function," Cancer Treat Rev, 1995, 21(1):33-64.
Korfel A, Oehm C, von Pawel J, et al, “Response to Topotecan of Symptomatic Brain Metastases of Small-Cell Lung Cancer Also After Whole-Brain Irradiation. a Multicentre Phase II Study,” Eur J Cancer, 2002, 38(13):1724-9.
Kruijtzer CMF, Beijnen JH, Rosing H, et al, “Increased Oral Bioavailability of Topotecan in Combination With the Breast Cancer Resistance Protein and P-Glycoprotein Inhibitor GF120918,” J Clin Oncol, 2002, 20(13):2943-50.
Levy T, Inbar M, Menczer J, et al, "Phase II Study of Weekly Topotecan in Patients With Recurrent or Persistent Epithelial Ovarian Cancer," Gynecol Oncol, 2004, 95(3):686-90.
Long HJ 3rd, Bundy BN, Grendys EC Jr, et al, “Randomized Phase III Trial of Cisplatin With or Without Topotecan in Carcinoma of the Uterine Cervix: A Gynecologic Oncology Group Study,” J Clin Oncol, 2005, 23(21):4626-33.
Mathijssen RH, Loos WJ, Verweij J, et al, “Pharmacology of Topoisomerase I Inhibitors Irinotecan (CPT-11) and Topotecan,” Curr Cancer Drug Targets, 2002, 2(2):103-23.
Monk BJ, Sill MW, McMeekin DS, et al, "Phase III Trial of Four Cisplatin-Containing Doublet Combinations in Stage IVB, Recurrent, or Persistent Cervical Carcinoma: A Gynecologic Oncology Group Study," J Clin Oncol, 2009, 27(28):4649-55.
O'Brien ME, Ciuleanu TE, Tsekov H, et al, “Phase III Trial Comparing Supportive Care Alone With Supportive Care With Oral Topotecan in Patients With Relapsed Small-Cell Lung Cancer,” J Clin Oncol, 2006, 24(34):5441-7.
O'Reilly S, Rowinsky EK, Slichenmyer W, et al, “Phase I and Pharmacologic Study of Topotecan in Patients With Impaired Hepatic Function,” J Natl Cancer Inst, 1996, 88(12):817-24.
O'Reilly S, Rowinsky EK, Slichenmyer W, et al, “Phase I and Pharmacologic Study of Topotecan in Patients With Impaired Renal Function,” J Clin Oncol, 1996, 14(12):3062-73.
Saylors RL 3rd, Stine KC, Sullivan J, et al, “Cyclophosphamide Plus Topotecan in Children With Recurrent or Refractory Solid Tumors: A Pediatric Oncology Group Phase II Study,” J Clin Oncol, 2001, 19(15):3463-9.
Voloschin AD, Betensky R, Wen PY, et al, “Topotecan as Salvage Therapy for Relapsed or Refractory Primary Central Nervous System Lymphoma,” J Neurooncol, 2008, 86(2):211-5.
International Brand Names
Lexi-Comp.com
Last full review/revision May 2011
Content last modified May 2011
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