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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.
Medication Safety Issues
Sound-alike/look-alike issues:
Hycamtin® may be confused with Hycomine®, Mycamine®
High alert medication: The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drugs which have a heightened risk of causing significant patient harm when used in error.
Pronunciation
(toe poe TEE kan)
U.S. Brand Names
Index Terms
Generic Available
No
Canadian Brand Names
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Treatment of ovarian cancer and small cell lung cancer; cervical cancer (in combination with cisplatin)
Use: Unlabeled/Investigational
Investigational: Treatment of nonsmall cell lung cancer, myelodysplastic syndrome, sarcoma (pediatrics), neuroblastoma (pediatrics), refractory solid tumors (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
Warnings/Precautions
Boxed warnings:
• Bone marrow suppression: See “Concerns related to adverse effects” below.
• Experienced physician: See “Other warnings/precautions” below.
Special handling:
• Hazardous agent - use appropriate precautions for handling and disposal.
Concerns related to adverse effects:
• Bone marrow suppression: The dose-limiting toxicity is bone marrow suppression (primarily neutropenia; may also cause thrombocytopenia and anemia); monitor bone marrow function. Neutropenia is not cumulative overtime. [U.S. Boxed Warning]: Should only administer to patients with adequate bone marrow reserves, baseline neutrophils at least 1500 cells/mm3 and platelet counts at least 100,000/mm3. In a clinical study comparing I.V. to oral topotecan, G-CSF support was administered in a higher percentage of patients receiving oral topotecan.
• Diarrhea: Diarrhea has been reported with oral topotecan; may be severe; educate patients on proper management of diarrhea. The incidence of diarrhea may be higher in the elderly.
• Neutropenic colitis: Topotecan-induced neutropenia may lead to neutropenic colitis; 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.
Special populations:
• Pediatrics: Safety and efficacy have not been established in children.
Other warnings/precautions:
• Experienced physician: [U.S. Boxed Warning]: Should be administered under the supervision of an experienced cancer chemotherapy physician.
Adverse Reactions
>10%:
Central nervous system: Fatigue (11% to 29%), fever (5% to 28%), pain (23%), headache (18%)
Dermatologic: Alopecia (10% to 49%), rash (16%)
Gastrointestinal: Nausea (27% to 64%), vomiting (19% to 45%), diarrhea (14% to 32%; Oral: grade 3: 4%; grade 4: ?1%; onset: 9 days), constipation (29%), abdominal pain (22%), anorexia (7% to 19%), stomatitis (18%)
Hematologic: Neutropenia (83% to 97%; grade 4: 32% to 80%; nadir 8-11 days; duration: 7 days; recovery <21 days), leukopenia (86% to 97%; grade 4: 15% to 32%), anemia (89% to 98%; grade 4: 7% to 10%), thrombocytopenia (69% to 81%; grade 4: 6% to 29%; duration: 3 days), neutropenic fever/sepsis (2% to 28%)
Neuromuscular & skeletal: Weakness (3% to 25%)
Respiratory: Dyspnea (22%), cough (15%)
1% to 10%:
Hepatic: Liver enzymes increased (transient; 8%)
Neuromuscular & skeletal: Paresthesia (7%)
Miscellaneous: Sepsis (grades 3/4: 5%)
<1%, postmarketing, and/or case reports: Abdominal pain, allergic reactions, anaphylactoid reactions, angioedema, bleeding (severe, associated with thrombocytopenia), dermatitis (severe), injection site reactions (mild erythema, bruising), neutropenic colitis, pancytopenia, pruritus (severe)
Drug Interactions
BCRP/ABCG2 Inhibitors: May increase the serum concentration of Topotecan. Risk D: Consider therapy modification
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
Platinum Derivatives: May enhance the adverse/toxic effect of Topotecan. Risk D: Consider therapy modification
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). Risk X: Avoid combination
Ethanol/Nutrition/Herb Interactions
Ethanol: Avoid ethanol (due to GI irritation).
Storage
I.V.: Store intact vials of lyophilized powder for injection 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). When further diluted in 50-100 mL D5W or NS, solution is 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 vials with 4 mL SWFI. May be further diluted 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 (1.5-4 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 (refer to individual protocols): Note: Baseline neutrophil count should be >1500/mm3; retreatment neutrophil count should be >1000/mm3; baseline and retreatment platelet count should be >100,000/mm3; (also, for oral topotecan, retreatment hemoglobin should be ?9 g/dL):
Small cell lung cancer:
IVPB: 1.5 mg/m2/day for 5 days; repeated every 21 days
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
I.V. continuous infusion (unlabeled dose) 0.2-0.7 mg/m2/day for 7-21 days
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 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 neutropenia)
Cervical cancer: Severe febrile neutropenia (ANC <1000/mm3 with temperature of 38°C) or platelet count <10,000/mm3: Reduce topotecan to 0.6 mg/m2/day for subsequent cycles (may consider C-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). Note: Cisplatin may also require dose adjustment.
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:
The FDA-approved labeling recommends the following dosage adjustment:
I.V.:
Clcr 20-39 mL/minute: Reduce to 0.75 mg/m2/dose
Clcr <20 mL/minute: Insufficient data available for dosing recommendation
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 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:
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: The FDA-approved labeling recommends the following:
I.V.: Bilirubin 1.5-10 mg/dL: No adjustment necessary
Oral: Bilirubin >1.5 mg/dL: No adjustment necessary
Dosage: Combination Regimens
Cervical cancer: Topotecan-Cisplatin
Leukemia, acute lymphocytic: TVTG
Leukemia, acute myeloid: TVTG
Lung cancer, nonsmall cell: Topotecan (Oral Regimen)
Lung cancer, small cell:
Topotecan (Oral Regimen)
Topotecan (Oral)-Cisplatin
Topotecan (Weekly)
Ovarian cancer:
Topotecan (Oral Regimen)
Topotecan (Weekly)
Administration: Oral
Administer with or without food. 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 or by 24-hour continuous infusion. For combination chemotherapy with cisplatin, administer pretreatment hydration.
Administration: I.V. Detail
pH: 2.5-3.5
Monitoring Parameters
CBC with differential and platelet count, renal function tests, bilirubin
Test Interactions
None known
Dietary Considerations
May be taken with or without food.
Patient Education
Do not take any new prescription or OTC medications or herbal products during therapy without consulting prescriber. 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 (use soft toothbrush or cotton applicators several times a day and rinse mouth frequently). You will be more susceptible to infection (avoid crowds and exposure to infection and do not have any vaccinations without consulting prescriber). May cause nausea or vomiting (small, frequent meals, frequent mouth care, sucking lozenges, or chewing gum may help); 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; unexplained weakness or fatigue; or other persistent effects. Pregnancy/breast-feeding precautions: Inform prescriber if you are pregnant. Do not get pregnant or cause a pregnancy (males) while taking this medication. Consult prescriber for appropriate contraceptive measures (may cause severe fetal defects). Do not breast-feed.
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
Assess potential for interactions with other pharmacological agents patient may be taking. I.V.: See administration specifics. Evaluate results of laboratory tests, therapeutic effectiveness, and adverse reactions prior to each infusion and on a regular basis with oral formulation (eg, signs of myelosuppression, renal function [I & O, edema], gastrointestinal disturbance [nausea, vomiting, diarrhea, pain], dyspnea). Teach patient appropriate use (oral), possible side effects/appropriate interventions, and adverse symptoms to report.
Oncology: Emetic Potential
Low (10% to 30%)
Oncology: Vesicant
I.V.: No; inadvertent extravasation may result in mild erythema and bruising
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule:
Hycamtin®: 0.25 mg, 1 mg
Injection, powder for reconstitution:
Hycamtin®: 4 mg
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.
Arun B and Frenkel EP, “Topoisomerase I Inhibition With Topotecan: Pharmacologic and Clinical Issues,” Expert Opin Pharmacother, 2001, 2(3):491-505.
Cersosimo RJ, “Topotecan: A New Topoisomerase I Inhibiting Antineoplastic Agent,” Ann Pharmacother, 1998, 32(12):1334-43.
Craig SB, Bhatt UH, and Patel K, “Stability and Compatibility of Topotecan Hydrochloride for Injection With Common Infusion Solutions and Containers,” J Pharm Biomed Anal, 1997, 16(2):199-205.
Dennis MJ, Beijnen JH, Grochow LB, et al, “An Overview of the Clinical Pharmacology of Topotecan,” Semin Oncol, 1997, 24(1 Suppl 5):5-12, 5-18.
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.
Herben VM, ten Bokkel Huinink WW, and Beijnen JH, “Clinical Pharmacokinetics of Topotecan,” Clin Pharmacokinet, 1996, 31(2):85-102.
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.
Kollmannsberger C, Mross K, Jakob A, et al, “Topotecan - A Novel Topoisomerase I Inhibitor: Pharmacology and Clinical Experience,” Oncology, 1999, 56(1):1-12.
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.
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.
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.
Patel K, Craig SB, McBride MG, et al, “Microbial Inhibitory Properties and Stability of Topotecan Hydrochloride Injection,” Am J Health Syst Pharm, 1998, 55(15):1584-7.
International Brand Names
Lexi-Comp.com
Last full review/revision July 2009
Content last modified July 2009
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