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:
`
`The mechanism of action of epirubicin appears to be related to its ability to bind to nucleic acids.2 It forms a complex
`with DNA by intercalation between base pairs, resulting in inhibition of DNA and RNA synthesis.4 Intercalation also
`triggers DNA cleavage by topoisomerase II, resulting in cytocidal activity.3,4 Binding to cell membranes and plasma
`proteins may also be involved.2 Epirubicin also generates cytotoxic free radicals.3,4 Epirubicin is the 4’-epimer of
`DOXOrubicin; i.e., there is a different spatial orientation of the hydroxyl group at the 4’ carbon of the sugar moiety.4
`This difference may account for faster elimination and reduced toxicity.2
`
`PHARMACOKINETICS:
`rapidly and widely distributed into tissues3; may concentrate in red blood cells, whole blood
`Distribution
`concentrations are approximately twice those of plasma3
`cross blood brain barrier?
`no
`volume of distribution3
`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)
`
`Metabolism
`
`inactive metabolite(s)
`
`Excretion
`
`epirubicinol (13-OH epirubicin)3; cytotoxic activity one-
`tenth that of epirubicin; plasma levels consistently lower
`than epirubicin
`glucuronides of epirubicin and epirubicinol;
`DOXOrubicin; aglycones of doxorubicinol, 7-
`deoxydoxorubicin, and 7-deoxydoxorubicinol3
`predominantly hepatobiliary; rapid elimination of parent compound from plasma
`9-10% within 48 h2; 20-27% within 4 days3
`urine
`feces
`40% of dose recovered in bile within 72 h
`terminal half life3
`33 h
`clearance3
`65-83 L/h
`no differences observed3
`Gender
`clearance may be decreased in elderly women3
`Elderly
`Adapted from standard reference3 unless specified otherwise.
`
`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
`Pediatric, soft tissue sarcoma7
`Soft tissue sarcoma8-10
`
`
`
`
`
`BC Cancer Agency Cancer Drug Manual©
`Developed: February 2006
`Revised: 01 March 2006, 1 March 2012, 1 August 2013, 1 January 2015
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`Page 1 of 9
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`Epirubicin
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`Ex. 1046-0001
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`Epirubicin
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`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
`spermatozoa.3
`
`Fertility: Dose-related infertility has been observed in mammals of both sexes.3 Epirubicin may cause premature
`menopause in premenopausal women.
`
`Pregnancy: FDA Pregnancy Category D.3 There is positive evidence of human fetal risk, but the benefits from use
`in pregnant women may be acceptable despite the risk. Chemotherapy protocols including epirubicin have been
`administered during pregnancy to treat breast cancer.11-15 For more information, please refer to The BC Cancer
`Agency Cancer Management Guidelines for Breast Cancer in Pregnancy.
`
`Breastfeeding is not recommended due to the potential secretion into breast milk.
`
`
`SIDE EFFECTS:
`
`The table includes adverse events that presented during drug treatment but may not necessarily have a causal
`relationship with the drug. Because clinical trials are conducted under very specific conditions, the adverse event
`rates observed may not reflect the rates observed in clinical practice. Adverse events are generally included if they
`were reported in more than 1% of patients in the product monograph or pivotal trials, and/or determined to be
`clinically important.16
`
`ORGAN SITE
`
`SIDE EFFECT
`
`Clinically important side effects are in bold, italics
`
`allergy/immunology
`
`blood/bone marrow/
`
`anaphylaxis
`chills, fever, shock, urticaria
`anemia (13-72%)
`
`BC Cancer Agency Cancer Drug Manual©
`Developed: February 2006
`Revised: 01 March 2006, 1 March 2012, 1 August 2013, 1 January 2015
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`Page 2 of 9
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`Epirubicin
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`Ex. 1046-0002
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`Epirubicin
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`ORGAN SITE
`
`febrile neutropenia
`
`cardiovascular
`(arrhythmia)
`cardiovascular (general)
`
`constitutional symptoms
`
`dermatology/skin
`
`endocrine
`gastrointestinal
`
`hemorrhage
`hepatic
`infection
`metabolic/laboratory
`ocular/visual
`
`Clinically important side effects are in bold, italics
`
`SIDE EFFECT
`
`leukopenia (50-80%, severe 2-59%), neutropenia (54-80%, severe 10-67%); nadir 10-
`14 days after treatment; recovery by day 21
`neutropenic fever (6%)
`thrombocytopenia (5-49%)
`acute transient ECG changes, sinus tachycardia; see discussion following table
`
`congestive heart failure, symptomatic3 (0.9-3.3%, dose-related); risk increases
`steeply after cumulative dose of 900 mg/m2; see paragraph following Side Effects table
`decreased left ventricular ejection fraction, asymptomatic (1-3%); see paragraph
`following Side Effects table
`thromboembolism (including fatal pulmonary embolism), thrombophlebitis, venous
`sclerosis
`fever (1-5%)
`fatigue/lethargy (1-46%)
`malaise/asthenia
`extravasation hazard: vesicant
`alopecia (70-96%), regrowth occurs 2-3 months after discontinuing epirubicin therapy3
`flushing
`injection site reactions (2-20%)
`photosensitivity
`radiation recall reaction
`rash/itch (1-9%)
`skin changes (1-5%)
`skin and nail hyperpigmentation
`hot flashes(5-39%)
`emetogenic potential: dose-related17; high-moderate for > 90 mg/m2, low-moderate for ≤
`90 mg/m2
`anorexia (2-3%)
`dehydration
`diarrhea (7-25%)
`dyspepsia
`hyperpigmentation of the oral mucosa
`mucositis (9-58%)
`nausea/vomiting (83-92%)
`bleeding, GI
`increased transaminases18
`infection (15-22%)
`hyperuricemia
`conjunctivitis (1-15%), keratitis
`
`BC Cancer Agency Cancer Drug Manual©
`Developed: February 2006
`Revised: 01 March 2006, 1 March 2012, 1 August 2013, 1 January 2015
`
`Page 3 of 9
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`Epirubicin
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`Ex. 1046-0003
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`Epirubicin
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`ORGAN SITE
`
`SIDE EFFECT
`
`renal/genitourinary
`secondary malignancy
`sexual/reproductive
`function
`syndromes
`
`Clinically important side effects are in bold, italics
`
`red colouration of urine for 1-2 days after administration
`acute myeloid leukemia, myelodysplastic syndrome (0.3-0.6%)
`amenorrhea (69-72%), premature menopause
`
`tumour lysis syndrome
`
`Adapted from standard reference3 unless specified otherwise.
`
`Cardiotoxicity is thought to be due to free radical damage as myocardial tissue is susceptible to these highly
`reactive species.19 Anthracycline cardiotoxicity may present with early or late effects.20,21 The following information
`applies to all anthracyclines, anthracenediones and mitoXANTRONE.19,21,22
`
`Early cardiotoxic effects are not dose-related and may present from mild ECG changes to life-threatening
`arrhythmias.19,20,22 These events may occur during or immediately after a single dose of anthracycline treatment,19,22
`but do not predict subsequent development of delayed cardiotoxicity and are not considered indications for
`suspension of therapy.19,20,22-25
`
`Late cardiotoxic effects, which are dose-related and clinically the most important type of cardiotoxic effect, present
`as reduced LVEF or symptomatic CHF, and typically occur weeks to years after completion of treatment.19,21-24
`Abnormalities in LVEF are associated with all the anthracyclines and their derivatives.21 LVEF changes are related
`to the total cumulative dose, are irreversible and refractory to medical therapy. 19,26
`
`Prevention and treatment: Cardiac assessment should occur at baseline and throughout therapy. Monitor for
`symptomatic congestive heart failure (CHF) or reduced left ventricular ejection fraction (LVEF). Sensitive, non-
`invasive methods to measure LVEF include radionucleotide angiography (RNA), MUGA, or echocardiogram.21 Late
`cardiotoxic effects may be prevented by stopping treatment with the associated anthracycline once patients have
`reached the suggested maximum cumulative dose.19,26 Management of anthracycline cardiotoxicity includes
`discontinuation of the drug and initiating standard treatment of CHF.21
`
`Cardiotoxicity risk can be reduced but not eliminated with the use of alternative anthracyclines (i.e., epirubicin or
`liposomal DOXOrubicin) or by altering the frequency of administration (once a week vs. once every 3 weeks, or
`continuous infusion).21 Cardioprotectant therapy with dexrazoxane may be considered for patients with cumulative
`DOXOrubicin-equivalent doses greater than 300 mg/m2.22,27,28
`
`Cumulative doses should be calculated using the following table, taking into account all previous anthracyclines or
`anthracenediones received during the patient’s lifetime.
`
`
`AGENT
`
`SUGGESTED CONVERSION
`FACTOR TO DOXORUBICIN
`DOSE29-31*
`
`SUGGESTED MONITORING
`THRESHOLD20,21,32**
`
`
`
`x 0.5-0.83
`DAUNOrubicin
`x 1
`DOXOrubicin
`x 0.5-0.67
`epirubicin
`x 2-5
`IDArubicin
`x 2.2-4
`mitoXANTRONE
`* based on relative hematological toxicities30
`** Treatment may continue beyond these doses in selected patients, if the clinician has considered the potential risks and benefits.
`The addition of dexrazoxane may be considered, and monitoring should be increased. Maximum tolerated doses are variable;
`
`450 mg/m2
`300 mg/m2
`600 mg/m2
`150 mg/m2
`not defined
`
`BC Cancer Agency Cancer Drug Manual©
`Developed: February 2006
`Revised: 01 March 2006, 1 March 2012, 1 August 2013, 1 January 2015
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`Page 4 of 9
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`Ex. 1046-0004
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`Epirubicin
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`some patients may tolerate DOXOrubicin equivalent doses exceeding 1000 mg/m2 while other patients exhibit symptomatic CHF at
`DOXOrubicin equivalent doses doses less than 300 mg/m2.
`
`Local effects: Extravasation of epirubicin can occur with or without accompanying stinging or burning sensation,
`and even if blood returns well on aspiration of the infusion needle.3 Severe local tissue necrosis may occur. To
`minimize the risk of thrombosis or perivenous extravasation, the usual administration time should be 15 to 20
`minutes, and never less than 3 minutes.3 For more information on prevention and treatment of extravasation with
`DOXOrubicin refer to BC Cancer Agency Provincial Systemic Therapy Program: Prevention and Management of
`Extravasation of Chemotherapy. Also, monitor for local erythematous streaking along vein and/or facial flushing
`which may indicate a too rapid infusion rate.33 This has traditionally been called the “epirubicin flare.”34,35
`
`Hyperuricemia may result from cell lysis by cytotoxic chemotherapy and may lead to electrolyte disturbances or
`acute renal failure.36 It is most likely with highly proliferative tumours of massive burden, such as leukemias, high-
`grade lymphomas, and myeloproliferative diseases. The risk may be increased in patients with preexisting renal
`dysfunction, especially ureteral obstruction. Suggested prophylactic treatment for high-risk patients37:
`•
`aggressive hydration: 3 L/m²/24 hr with target urine output >100 ml/h
`•
`if possible, discontinue drugs that cause hyperuricemia (e.g., thiazide diuretics) or acidic urine (e.g., salicylates)
`• monitor electrolytes, calcium, phosphate, renal function, LDH, and uric acid q6h x 24-48 hours
`•
`replace electrolytes as required
`•
`allopurinol 600 mg po initially, then 300 mg po q6h x6 doses, then 300 mg po daily x 5-7 days
`
`Urine should be alkalinized only if the uric acid level is elevated, using sodium bicarbonate IV or PO titrated to
`maintain urine pH>7. Rasburicase (FASTURTEC®) is a novel uricolytic agent that catalyzes the oxidation of uric
`acid to a water-soluble metabolite, removing the need for alkalinization of the urine.38 It may be used for treatment or
`prophylaxis of hyperuricemia; however, its place in therapy has not yet been established. Aluminium hydroxide
`(AMPHOGEL®) may be added orally if phosphate becomes elevated. If aluminium hydroxide has been added,
`discontinue sodium bicarbonate.39
`
`
`EFFECT
`anthracycline-induced cardiotoxicity
`may be increased
`anthracycline-induced cardiotoxicity
`may be increased
`
`MECHANISM
`unknown
`
`additive toxicity
`
`MANAGEMENT
`monitor cardiac function
`throughout treatment
`monitor cardiac function
`throughout treatment
`
`increases AUC of epirubicin by
`50% and decreases clearance of
`epirubicin by 30%
`no influence on epirubicin
`pharmacokinetics
`toxicity of both agents may be
`increased when given concurrently,
`regardless of which drug is given
`first; lower neutrophil and platelet
`nadirs, and slower neutrophil
`recovery have been observed
`anthracycline-induced cardiotoxicity
`may be increased
`
`unknown; does not
`seem to be related to
`cytochrome P450
`
`
`discontinue cimetidine
`and choose alternate
`therapy; e.g., ranitidine
`
`
`increased levels of
`epirubicin metabolites,
`decreased taxane
`clearance
`
`separate administration
`by 24 hours if possible
`
`unknown
`
`monitor cardiac function
`throughout treatment
`
`INTERACTIONS:
`
`AGENT
`bevacizumab40
`
`calcium channel
`blockers (e.g.,
`verapamil)2,4
`cimetidine2,3,41
`
`gemcitabine42
`
`taxanes42-48 (e.g.,
`DOCEtaxel, PACLitaxel)
`
`trastuzumab49
`
`
`
`BC Cancer Agency Cancer Drug Manual©
`Developed: February 2006
`Revised: 01 March 2006, 1 March 2012, 1 August 2013, 1 January 2015
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`Page 5 of 9
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`Ex. 1046-0005
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`Epirubicin
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`SUPPLY AND STORAGE:
`
`Injection: Sterile solution for injection, 2 mg/mL, in 5 mL, 25 mL, and 100 mL glass vials and polypropylene vials.3
`Store vials between 2-8ºC and protect from light (keep intact vials in their carton until use). Discard unused portion
`within 8 hours after puncture.
`
`For basic information on the current brand used at the BC Cancer Agency, see Chemotherapy Preparation
`and Stability Chart in Appendix.
`
`
`SOLUTION PREPARATION AND COMPATIBILITY:
`
`For basic information on the current brand used at the BC Cancer Agency, see Chemotherapy Preparation
`and Stability Chart in Appendix.
`
`Additional information:
`
`Compatibility: consult detailed reference
`
`
`PARENTERAL ADMINISTRATION:
`
`Subcutaneous2
`Intramuscular2
`Direct intravenous
`
`Intermittent infusion50-55
`Continuous infusion
`Intraperitoneal
`Intrapleural
`Intrathecal
`Intra-arterial
`Intravesical6,56-60
`
`
`
`BCCA administration guideline noted in bold, italics
`must not be used due to corrosive nature
`must not be used due to corrosive nature
`over at least 3 minutes (usual 3- 20 minutes)
`Preferred method due to need for frequent
`monitoring for signs of extravasation. Via small (21
`or 23) gauge needle into tubing of running IV. Push
`slowly, so that drip of IV solution does not stop or
`reverse. Check for blood return before
`administration and after every 2-3 mL of drug. If no
`blood return, stop the injection and assess the IV
`site. Flush with 20 mL NS or D5W after
`administration to clear any remaining drug from
`tubing.
`has been used
`no information found
`no information found
`no information found
`no information found
`no information found
`has been used as a single dose postoperatively or as
`induction doses of 50-100 mg in 25-100 mL NS weekly
`for 6 to 8 weeks, followed by monthly maintenance
`doses to 1 year; solutions are retained for 1-2 h after
`instillation
`
`DOSAGE GUIDELINES:
`Refer to protocol by which patient is being treated. Numerous dosing schedules exist and depend on disease,
`response and concomitant therapy. Guidelines for dosing also include consideration of absolute neutrophil count
`(ANC). Dosage may be reduced, delayed or discontinued in patients with bone marrow depression due to
`cytotoxic/radiation therapy or with other toxicities.
`
`BC Cancer Agency Cancer Drug Manual©
`Developed: February 2006
`Revised: 01 March 2006, 1 March 2012, 1 August 2013, 1 January 2015
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`Page 6 of 9
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`Epirubicin
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`Cycle Length:
`2 weeks2:
`
`BCCA usual dose noted in bold, italics
`
`
`3 weeks61:
`
`
`3-4 weeks2:
`
`
`4 weeks62-64:
`
`
`4 weeks65-67:
`
`
`Suggested maximum cumulative doses3,61:
`
`Concurrent radiation:
`
`Dosage in myelosuppression:
`
`Adults:
`
`
`Intravenous:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Dosage in renal failure2:
`
`Dosage in hepatic failure2:
`
`
`
`
`Dosage in dialysis:
`
`
`Children:
`
`Oral:
`
`
`
`
`35 mg/m2 IV for one dose on day 1
`(total dose per cycle 35 mg/m2)
`
`100 mg/m2 IV for one dose on day 1
`(total dose per cycle 100 mg/m2)
`
`50-150 mg/m2 IV for one dose on day 1
`(total dose per cycle 50-150 mg/m2)
`
`60 mg/m2 IV for one dose on days 1 and 8
`(total dose per cycle 120 mg/m2)
`
`when given as a dose-dense regimen with filgrastim (G-
`CSF) support:
`60 mg/m2 IV for one dose on days 1 and 15
`(total dose per cycle 120 mg/m2)
`
`720-1000 mg/m2
`
`generally not administered concurrently due to additive toxicity4
`
`
`modify according to protocol by which patient is being treated; if no guidelines
`available, refer to Appendix 6 “Dosage Modification for Myelosuppression”
`
`
`lower starting doses are necessary if serum creatinine > 442 µmol/L
`
`
`
`Bilirubin
`
`AST
`21-51 µmol/L
`or
`2-4 X ULN
`> 51 µmol/L
`or
`> 4 x ULN
`contraindicated in severe hepatic impairment
`
`no information found
`
`
`
`Dose
`50%
`25%
`
`
`safety and effectiveness in children has not been studied3
`
`
`
`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. J Urol 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.
`
`BC Cancer Agency Cancer Drug Manual©
`Developed: February 2006
`Revised: 01 March 2006, 1 March 2012, 1 August 2013, 1 January 2015
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`Epirubicin
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`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.
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`Revised: 01 March 2006, 1 March 2012, 1 August 2013, 1 January 2015
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