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EPIRUBICIN Powered By Docstoc
					                                      CANCER DRUG MONOGRAPHS

                                  (Antineoplastic Agent; Anthracycline: Antibiotic)          Revision Date:Feb 03
                                   COMMERCIAL PRODUCT DESCRIPTION
Brand Name:          Pharmorubicin®     Vials with 10mg/5mL, 50mg/25mL, 200mg/100mL
Vials with 10mg, 50mg for reconstitution
 Epirubicin is an anthracycline cytotoxic agent. The precise mechanism of its cytotoxic and antiproliferative
 effect has not been elucidated. Epirubicin is known to inhibit DNA and RNA synthesis by steric obstruction
 after intercalating between DNA base pairs: active throughout entire cell cycle. Intercalation triggers DNA
 cleavage by topoisomerase 2, resulting in cytocidal activity. It also inhibits DNA helicase, and generates
 cytotoxic free radicals.

                 PHARMACOKINETICS                                           IV COMPATIBILITY
Oral Absorption                                             normal saline, dextrose 5%
Distribution                                                                       ROUTES
highest concentrations in liver, spleen, kidney, small      direct IV     (preferred)
intestines; excretion in breast-milk unknown                intermittent IV (in 100 mL over 1 h, VAD preferred)
cross blood brain barrier? no information
Vd      1430 L/m2; 31.8-46.1 L/kg                                            ADMINISTRATION
PPB 77% (albumin)                                          • Slow push through sidearm of free flowing IV (5%
Metabolism                                                   Dextrose, Normal Saline) over 3-5 minutes
rapidly and extensively metabolized in liver and other       (administering nurse should be certified to
tissues (including RBC’s routes)                             administer IV push chemotherapy agents)
metabolite(s):        active- epirubicinol (major          • Slow down injection rate if erythematous streaking
metabolite) inactive- Yes                                    occurs
Excretion                                                  • Protect from light
biliary excretion is major route of elimination (40%       • May administer dose in 50 mL NS or D5W and
within 72 hours), renal                                      infuse over 15 minutes.
urine 9-11% within 48 hours
t½ α 3-5 minutes t½ $ 1.1-2.6 hours                                  INDICATIONS AND OTHER USES
t½ ( 30-40 hours             mean terminal: 33 hours        • Breast cancer
Cl      0.8-1.5 L/minute                                    • Gastric cancer
                                                            • Hodgkin’s disease
                                                            • Lung cancer
                                                            • Non-Hodgkin’s lymphoma
• q1w: 12.5-25 mg/m² IV
                                                            • Ovarian cancer
• q2w: 35 mg/m² IV
• q3-4w: 50-120 mg/m² IV                                    OTHER ONCOLOGY USES (Not Approved)
Maximum lifetime dose:                                      Acute leukemia
• 1000 mg/m² (normal cardiac function, less in              Pancreatic cancer
    children)                                               Sarcoma, soft tissue
• 650 mg/m² (in combination with thoracic radiation
    or previous anthracycline, anthracenedione or
    cyclophosphamide treatment)                             known hypersensitivity to epirubicin
• Careful cardiac monitoring is important, as               pregnancy and breast feeding
    cardiotoxicity may occasionally occur at lower          low WBC, RBC, platelets (myelosuppression)
    cumulative doses. If tumour responding when             > maximum lifetime dose of an anthracycline or
    lifetime dose reached, obtain cardiac consultation      anthracenedione (daunorubicin, doxorubicin,
    before continuing treatment.                            epirubicin, mitoxantrone, idarubicin)
Pediatric: Safety & effectiveness not established           liver problems (hepatic failure)
                                                            heart (cardiac) disease including unstable
  Other dosing may be indicated in specific regimens
                                                            hypertension, angina or arrhythmias

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                                     CANCER DRUG MONOGRAPHS

                                                 EPIRUBICIN (continued)
                                                SIDE EFFECTS
 * may be life-threatening                     side effects in bold, italic type are common
IMMEDIATE ONSET                (hours to days)
   flare reaction (histamine release- Symptoms: erythematous streaking and/or urticaria along the vein
   proximal to the site of administration)
   vein irritation (phlebitis)
   nausea and vomiting (53%, 7% severe)
   urine discolouration (reddish, lasts 1-2 days)
   irregular heartbeat (transient arrhythmias)
   radiation recall reaction (rare)
EARLY ONSET                (days to weeks)
* low WBC, platelets (myelosuppression, nadir 10-14 days, recovery 21 days)
  mouth sores (11%, stomatitis)
  hair loss (54%, alopecia)
  irregular heartbeat (transient ECG changes and arrhythmias)
DELAYED/LATE ONSET (weeks to years)
* heart problems (congestive heart failure and/or cardiomyopathy, dose-related)

                                           CLINICAL MONITORING
RECOMMENDED CRITERIA                                   SUGGESTED CRITERIA
C Complete blood count including differential, C Baseline cardiac function tests (Echo, RNA and/
   platelets and hemoglobin (CBC) before each or MUGA scans) for all patients with cardiac risk
   cycle of treatment                                  factors
C Clinical exam for symptoms of Congestive Heart C Local Site Toxicity ratings, if incident of phlebitis
   Failure                                                 LOCAL SITE TOXICITY
C Periodic cardiac tests for all patients with cardiac 0. None
   risk factors or patients at or above the threshold 1. Pain
   dose levels (especially if poor Performance Status) 2. Pain & inflammation; phlebitis
C Baseline liver function tests [serum alkaline 3. Ulceration
   phosphatase, GGT, ALT, AST & Bilirubin levels 4. Plastic surgery
   (serum proteins may be added if indicated)]         Upon Patient Complaint Or Clinical Event
0. None                                                               For Cardiac Toxicity Ratings:
1. —-                                                  First rating at the Epirubicin cumulative dose
2. Asymptomatic, resting ejection fraction decline by threshold of 450m², & repeat ratings at each
   >10% baseline; or abnormal cardiac function tests cumulative dose increment of 150mg/m² above
   (LVEF >50) with no baseline for comparison          threshold (Cumulative dose sooner for high risk
3. Mild Congestive Heart Failure, responds to therapy patients, eg. pre-existing cardiac disease, prior chest
4. Severe/refractory Congestive Heart Failure          irradiation)
At cumulative dose threshold and subsequent Note: Threshold Cumulative dose reduced
   intervals                                           proportionately if other anthracycline or
                                                       anthracenedione drugs have been given; cardiotoxicity
                                                       is additive.

                ANTIEMETIC RISK                                       EXTRAVASATION HAZARD
HIGH RISK (30-90% of patients)                           VESICANT (tissue damage on extravasation)
• Use a serotonin receptor antagonist PLUS               Management:         stop IV, aspirate, elevate limb,
  dexamethasone pre-chemotherapy and post-               cold intermittent compresses
  chemotherapy                                           Follow Extravasation Guidelines
   See Nausea & Vomiting Guidelines for more detail                         See Appendix 4D
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Drugs 108                                             Systemic Therapy Manual for Cancer Treatment
                                       CANCER DRUG MONOGRAPHS

                              EPIRUBICIN (continued)
                                      PHARMACEUTICAL CONSIDERATIONS
Pharmorubicin RDF: Vials of. Store at room temperature (15-30°C) protected from sunlight. Also contains 0.2
mg methylparaben (to enhance dissolution) and 5 mg lactose per mg epirubicin.
Pharmorubicin PFS: 2 mg/mL clear, red, preservative-free solution. Also contains hydrochloric acid to adjust
pH. Store in refrigerator. Protect from sunlight (eg, store in carton until use). The manufacturer recommends
discarding the unused portion of vials.
Reconstitute powder with NS or SWI to a final concentration of 2 mg/mL; a slight suspension may form which
will completely dissolve on further shaking. Do not use bacteriostatic diluents; early experience with
doxorubicin suggested that the use of diluents containing benzyl alcohol results in hypersensitivity reactions.
Vials are under negative pressure.
Reconstituted solution for injection
Clear, red solution. Physically stable for 24 hours at room temperature and 48 hours when refrigerated (2-
10°C). Protect solutions from direct light. Walker et al reported stability of 150 days of 1 mg/mL and 2 mg/mL
solution, when stored at 4 and 23°C in their original vials. Like doxorubicin, epirubicin should not be stored in
contact with aluminum but may be safely injected through an aluminum-hubbed needle.
Diluted solution for infusion
Compatible with D5W and NS. Physically stable for at least 7 days refrigerated and stored in the dark. No
protection from light is necessary during IV administration of solutions 0.5 mg/mL or greater. After 8 days
storage in PVC containers, variable drug loss occurs due to adsorption to the container.
Stability in syringes
A 0.5 mg/mL solution in NS is stable in plastic syringes for at least 28 days if stored below 20°C. A 2 mg/mL
solution in sterile water is stable in Plastipak (Becton-Dickinson) plastic syringes for at least 43 days at 4°C.
It is recommended that epirubicin not be mixed with other drugs. Incompatible with heparin.

  cimetidine, other antineoplastic agents, quinine,       CCNS Provincial Formulary Status- Intermediate Level
 trastuzumab, verapamil                                   CDHA Formulary Status          Formulary
                                                          Pharmacare Formulary Status Formulary (red)
Hepatic dysfunction
50% if Bili=35-51µmol/L or AST=60-180IU/L;
25-50% if Bili= 52-85µmol/L or AST>180IU/L;
 Omit if Bili >85µmol/L
Renal failure
50% if Serum Creatinine >265µmol/L
   (Suggested action)

Systemic Therapy Manual for Cancer Treatment                                                            Drugs 109