Epirubicin

Topics: Chemotherapy, Oncology, Cancer Pages: 16 (4207 words) Published: April 19, 2013
Epirubicin

DRUG NAME: Epirubicin
SYNONYM(S): 4’-epidoxorubicin,1 IMI-28,1 NSC-2569421 COMMON TRADE NAME(S): PHARMORUBICIN®,2 ELLENCE®3 CLASSIFICATION: anthracycline antineoplastic antibiotic4 MECHANISM OF ACTION: 2 The mechanism of action of epirubicin appears to be related to its ability to bind to nucleic acids. It forms a complex 4 with DNA by intercalation between base pairs, resulting in inhibition of DNA and RNA synthesis. Intercalation also 3,4 triggers DNA cleavage by topoisomerase II, resulting in cytocidal activity. Binding to cell membranes and plasma 2 proteins may also be involved. Epirubicin also generates cytotoxic free radicals.3,4 Epirubicin is the 4’-epimer of 4 DOXOrubicin; i.e., there is a different spatial orientation of the hydroxyl group at the 4’ carbon of the sugar moiety. This difference may account for faster elimination and reduced toxicity.2

PHARMACOKINETICS:
Distribution rapidly and widely distributed into tissues3; may concentrate in red blood cells, whole blood 3 concentrations are approximately twice those of plasma cross blood brain barrier? no 3 volume of distribution 21-27 L/kg plasma protein binding3 77% extensive hepatic metabolism; also metabolized by other organs and cells, including red blood cells3 active metabolite(s) epirubicinol (13-OH epirubicin)3; cytotoxic activity onetenth that of epirubicin; plasma levels consistently lower than epirubicin inactive metabolite(s) glucuronides of epirubicin and epirubicinol; DOXOrubicin; aglycones of doxorubicinol, 73 deoxydoxorubicin, and 7-deoxydoxorubicinol predominantly hepatobiliary; rapid elimination of parent compound from plasma urine 9-10% within 48 h2; 20-27% within 4 days3 feces 40% of dose recovered in bile within 72 h terminal half life3 33 h 3 65-83 L/h clearance 3 no differences observed clearance may be decreased in elderly women3 3

Metabolism

Excretion

Gender Elderly

Adapted from standard reference unless specified otherwise.

BC Cancer Agency Cancer Drug Manual© Developed: February 2006 Revised: 01 March 2006, 1 March 2012

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Epirubicin

Epirubicin

USES:
Primary uses: * Breast cancer * Gastric cancer * Lung cancer, non-small cell * Lung cancer, small cell * Lymphoma, Hodgkin’s * Lymphoma, non-Hodgkin’s * Ovarian cancer *Health Canada approved indication

Other uses: Bladder cancer5,6 7 Pediatric, soft tissue sarcoma Soft tissue sarcoma8-10

SPECIAL PRECAUTIONS:
Contraindicated in patients with the following conditions3: • • • • • • • • • • hypersensitivity to epirubicin or any component of the product hypersensitivity to other anthracyclines (e.g., DAUNOrubicin, DOXOrubicin) hypersensitivity to anthracenediones (e.g., mitoXANTRONE, mitomycin) severe hepatic impairment severe myocardial insufficiency recent myocardial infarction severe arrhythmias history of severe cardiac disease previous therapy with high cumulative doses of anthracyclines (e.g., DOXOrubicin, DAUNOrubicin, epirubicin, IDArubicin) previous therapy with high cumulative doses of some anthracenediones (e.g., mitoXANTRONE)

Cardiac toxicity is a risk of epirubicin therapy that may be manifested by early (acute) or late (delayed) effects.4 Cardiac function should be assessed at baseline and continue during treatment; refer to Side Effects section for more information. Risk factors for developing epirubicin-induced cardiotoxicity include3: • • • • high cumulative dose, previous therapy with other anthracyclines or anthracenediones prior or concomitant radiotherapy to the mediastinal/pericardial area pre-existing heart disease concomitant use of drugs that can suppress cardiac contraction

Carcinogenicity: Epirubicin has been associated with an increased risk of secondary leukemia in human trials.3 Mutagenicity: Epirubicin is mutagenic and clastogenic in animals, and may induce chromosomal damage in human 3 spermatozoa. 3 Fertility: Dose-related infertility has been observed in mammals of both sexes. Epirubicin...

References: 1. Dorr RT, Von-Hoff DD. Drug monographs. Cancer Chemotherapy Handbook. 2nd ed. Norwalk, Conneticut: Appleton and Lange; 1994. p. 434-439. 2. Pfizer Canada Inc. PHARMORUBICIN® product monograph. Kirkland, Quebec; 5 May 2005. 3. Pfizer Inc. ELLENCE® product monograph. New York, NY; May 2005. 4. McEvoy G, editor. AHFS 2005 Drug Information. Bethesda, MD: American Society of Health-System Pharmacists, Inc.; 2005. 5. de Reijke TM, Kurth KH, Sylvester RJ, et al. Bacillus Calmette-Guerin versus epirubicin for primary, secondary or concurrent carcinoma in situ of the bladder: results of a European Organization for the Research and Treatment of Cancer--Genito-Urinary Group Phase III Trial (30906). Journal of Urology 2005;173(2):405-9. 6. Rajala P, Kaasinen E, Raitanen M, et al. Perioperative single dose instillation of epirubicin or interferon-alpha after transurethral resection for the prophylaxis of primary superficial bladder cancer recurrence: a prospective randomized multicenter study-FinnBladder III long-term results. Journal of Urology 2002;168(3):981-5. 7. Orbach D, Rey A, Oberlin O, et al. Soft tissue sarcoma or malignant mesenchymal tumors in the first year of life: experience of the International Society of Pediatric Oncology (SIOP) Malignant Mesenchymal Tumor Committee. Journal of Clinical Oncology 2005;23(19):4363-71. 8. Ottaiano A, De Chiara A, Fazioli F, et al. Neoadjuvant chemotherapy for intermediate/high-grade soft tissue sarcomas: five-year results with epirubicin and ifosfamide. Anticancer Research 2002;22(6B):3555-9. 9. Petrioli R, Coratti A, Correale P, et al. Adjuvant epirubicin with or without Ifosfamide for adult soft-tissue sarcoma. American Journal of Clinical Oncology 2002;25(5):468-73. 10. Lopez M, Vici P, Di Lauro L, et al. Increasing single epirubicin doses in advanced soft tissue sarcomas. Journal of Clinical Oncology 2002;20(5):1329-34. 11. Andreadis C, Charalampidou M, Diamantopoulos N, et al. Combined chemotherapy and radiotherapy during conception and first two trimesters of gestation in a woman with metastatic breast cancer. Gynecologic Oncology 2004;95(1):252-255. 12. Cardonick E, Iacobucci A. Use of chemotherapy during human pregnancy. The Lancet Oncology 2004;5(5):283-291. 13. Gadducci A, Cosio S, Fanucchi A, et al. Chemotherapy with epirubicin and paclitaxel for breast cancer during pregnancy: case report and review of the literature. Anticancer Research 2003;23(6D):5225-9. 14. Goldwasser F, Pico JL, Cerrina J, et al. Successful chemotherapy including epirubicin in a pregnant non-Hodgkin 's lymphoma patient. Leukemia & Lymphoma 1995;20(1-2):173-6. 15. Muller T, Hofmann J, Steck T. Eclampsia after polychemotherapy for nodal-positive breast cancer during pregnancy. European Journal of Obstetrics & Gynecology and Reproductive Biology 1996;67(2):197-198. 16. Susan Ellard MD. Personal Communication. Medical Oncologist, BC Cancer Agency; 27 January 2006. 17. BC Cancer Agency. (SCNAUSEA) Guidelines for Prevention and Treatment of Chemotherapy-induced Nausea and Vomiting in Adults. Vancouver, British Columbia: BC Cancer Agency; 1 November 2005. 18. Rose BD editor. Epirubicin: Drug Information. Waltham, Massachusetts: UpToDate®; accessed 30 November 2005. 19. Seiter K. Toxicity of the topoisomerase II inhibitors. Expert Opin Drug Saf 2005;4(2):219-234. 20. Pfizer Canada Inc. IDAMYCIN® product monograph. Kirkland, Quebec; 19 February 2009. 21. Carver JR, Shapiro CL, Ng A, et al. American Society of Clinical Oncology clinical evidence review on the ongoing care of adult cancer survivors: cardiac and pulmonary late effects. J Clin Oncol 2007;25(25):3991-4008. 22. McEvoy GK, editor. AHFS 2005 Drug Information. Bethesda, Maryland: American Society of Health-System Pharmacists, Inc.; 2005. 23. Mayne Pharma (Canada) Inc. Doxorubicin Product Monograph. Montreal, Quebec; 2002. 24. Novopharm Limited. Doxorubicin Product Monograph. Scarborough, Ontario; 1996. 25. Repchinsky C, BSP. Compendium of Pharmaceuticals and Specialties. Ottawa, Ontario: Canadian Pharmacists association; 2005. p. 676. 26. Rose BD editor. Cardiotoxicity in patients receiving chemotherapy. Waltham, Massachusetts: UpToDate®; accessed 22 September 2005. 27. Schuchter LM, Hensley ML, Meropol NJ, et al. 2002 Update of Recommendations for the Use of Chemotherapy and Radiotherapy Protectants: Clinical Practice Guidelines of the American Society of Clinical Oncology. J Clin Oncol 2002;20(12):2895-2903. 28. Hensley M, Hagerty K, Kewalramani T, et al. American society of clinical oncology 2008 clinical practice guideline update: use of chemotherapy and radiation therapy protectants. J Clin Oncol 2009;27(1):127-145. 29. Keefe DL. Anthracycline-induced cardiomyopathy. Semin Oncol 2001;28(4 Suppl 12):2-7. 30. Le Deley M, Leblanc T, Shamsaldin A, et al. Risk of secondary leukemia after a solid tumor in childhood according to the dose of epipodophyllotoxins and anthracyclines: a case-control study by the Société Française d’Oncologie Pédiatrique. J Clin Oncol 2003;21(6):1074-1081. 31. Children 's Oncology Group. Long-term follow-up guidelines for survivors of childhood, adolescent, and young adult cancers. Children 's Oncology Group, March 2008. Available at: www.survivorshipguidelines.org. Accessed 4 March 2011. 32. Novopharm Limited. Daunorubicin Product Monograph. Scarborough, Ontario; 1997. 33. Rose BD editor. Doxorubicin: Drug Information. Waltham, Massachusetts: UpToDate®; accessed 31 August 2005. 34. Harwood KV, Aisner J. Treatment of chemotherapy extravasation: current status. Cancer Treatment Reports 1984;68(7-8):93945. 35. Boyle DM, Engelking C. Vesicant extravasation: myths and realities. Oncology Nursing Forum 1995;22(1):57-67. 36. DeVita VT, Hellman S, Rosenberg SA. Cancer Principles & Practice of Oncology. 6th ed. Philadelphia: Lippincott Williams & Wilkins; 2001.
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37. Leukemia/Bone Marrow Transplant Program of British Columbia. Leukemia/BMT Manual. 4th ed. Vancouver, British Columbia: Vancouver Hospital and Health Sciences Centre / BC Cancer Agency; 2003. p. 27. 38. Sanofi-Synthelabo. FASTURTEC® product information. Markham, Ontario; 2004. 39. Arnold TM, Reuter JP, Delman BS, et al. Use of single-dose rasburicase in an obese female. Ann Pharmacother 2004;38(9):1428-1431. 40. Rose BD editor. Antineoplastic agents (Anthracyclines)/Bevacizumab. www.uptodate.com ed. Waltham, Massachusetts: UpToDate®; accessed 15 December 2005. 41. Murray LS, Jodrell DI, Morrison JG, et al. The effect of cimetidine on the pharmacokinetics of epirubicin in patients with advanced breast cancer: Preliminary evidence of a potentially common drug interaction. Clinical Oncology (Royal College of Radiologists) 1998;10(1):35-38. 42. Fogli S, Danesi R, Gennari A, et al. Gemcitabine, epirubicin and paclitaxel: Pharmacokinetic and pharmacodynamic interactions in advanced breast cancer. Annals of Oncology 2002;13(6):919-927. 43. Baker AF, Dorr RT. Drug interactions with the taxanes: clinical implications. Cancer Treatment Reviews 2001;27(4):221-33. 44. Ceruti M, Tagini V, Recalenda V, et al. Docetaxel in combination with epirubicin in metastatic breast cancer: pharmacokinetic interactions. Farmaco 1999;54(11-12):733-9. 45. Danesi R, Conte PF, Del Tacca M. Pharmacokinetic optimisation of treatment schedules for anthracyclines and paclitaxel in patients with cancer. Clinical Pharmacokinetics 1999;37(3):195-211. 46. Esposito M, Venturini M, Vannozzi MO, et al. Comparative effects of paclitaxel and docetaxel on the metabolism and pharmacokinetics of epirubicin in breast cancer patients. J Clin Oncol 1999;17(4):1132. 47. Grasselli G, Vigano L, Capri G, et al. Clinical and pharmacologic study of the epirubicin and paclitaxel combination in women with metastatic breast cancer. Journal of Clinical Oncology 2001;19(8):2222-31. 48. Venturini M, Lunardi G, Del Mastro L, et al. Sequence effect of epirubicin and paclitaxel treatment on pharmacokinetics and toxicity. Journal of Clinical Oncology 2000;18(10):2116-25. 49. Rose BD editor. Antineoplastic Agents (Anthracycline)/Trastuzumab. Waltham, Massachusetts: UpToDate®; accessed 15 December 2005. 50. Hospira Healthcare Corporation. Doxorubicin hydrochloride for injection® product monograph. Saint-Laurent, Quebec; 18 February 2008. 51. Pharmacia Limited. Pharmorubicin Solution for Injection® product monograph. Sandwich, Kent (United Kingdom); 15 September 2010. 52. Actavis UK Ltd. Epirubicin hydrochloride 50 mg powder for injection or infusion® product monograph. Barnstaple, Devon (United Kingdom); 12 April 2011. 53. Hospira UK Ltd. Epirubicin hydrochloride injection® product monograph. Royal Leamington Spa, Warwickshire; 23 August 2010. 54. medac GmbH. Epirubicin hydrochloride for injection® product monograph. Hamburg, Germany; 18 August 2010. 55. Josephine Holmes. Personal communication. Manager Regulatory Affairs, Pharmaceutical Partners of Canada Inc.; 12 June 2009. 56. BC Cancer Agency Breast Tumour Group. (BRAJFEC) BCCA Protocol Summary for Adjuvant Therapy for Breast Cancer Using Fluorouracil, Epirubicin and Cyclophosphamide. Vancouver, British Columbia: BC Cancer Agency; 2005. 57. BC Cancer Agency Breast Tumour Group. (BRAJCEF) BCCA Protocol summary for Adjuvant Therapy for Breast Cancer Using Cyclophosphamide, Epirubicin and Fluorouracil . Vancouver, British Columbia: BC Cancer Agency; 2005. 58. BC Cancer Agency Breast Tumour Group. (BRINFCEF) BCCA Protocol Summary of Therapy for Inflammatory Breast Cancer Using Cyclophosphamide, Epirubicin and Fluorouracil. Vancouver, British Columbia: BC Cancer Agency; 2005. 59. BC Cancer Agency Breast Tumour Group. (BRLACEF) BCCA Protocol Summary of Therapy for Locally Advanced Breast Cancer Using Cyclophosphamide, Epirubicin and Fluorouracil. Vancouver, British Columbia: BC Cancer Agency; 2005. 60. BC Cancer Agency Breast Tumour Group. (BRAJCEFG) BCCA Protocol Summary for Adjuvant Therapy for Breast Cancer Using Cyclophosphamide, Epirubicin, Fluorouracil and Filgrastim (G-CSF). Vancouver, British Columbia: BC Cancer Agency; 2005. 61. BC Cancer Agency Breast Tumour Group. (BRINFCEFG) BCCA Protocol Summary of Therapy for Inflammatory Breast Cancer Using Cyclophosphamide, Epirubicin, Fluorouracil and Filgrastim (G-CSF). Vancouver, British Columbia: BC Cancer Agency; 2005. 62. BC Cancer Agency Breast Tumour Group. (BRLACEFG) BCCA Protocol Summary of Therapy for Locally Advanced Breast Cancer Using Cyclophosphamide, Epirubicin, Fluorouracil and Filgrastim (G-CSF). Vancouver, British Columbia: BC Cancer Agency; 2005.
BC Cancer Agency Cancer Drug Manual© Developed: February 2006 Revised: 01 March 2006, 1 March 2012
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