Systemic Therapy Program

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Drug Monographs
Treatment Regimens

Scientific Name:
DOXORUBICIN
Brand Name(s):
Adriamycin®

Drug Monograph

Pharmacology

Mechanism of Action

Inhibition of DNA and RNA synthesis by intercalation between DNA base pairs and by steric obstruction. It intercalates at points of local uncoiling of the double helix. The exact mechanism is unclear, it appears that direct binding to DNA (intercalation) and inhibition of DNA repair (topoisomerase 2 inhibition) result in blockade of DNA and RNA synthesis and fragmentation of DNA. Doxorubicin is also a powerful iron chelator; the iron-doxorubicin complex can bind DNA and cell membranes and produce free radicals that immediately cleave the DNA and cell membranes.

Pharmacokinetics

Oral Absorption:
poor (<50%)
Distribution:
highest concentrations in liver, spleen, kidney, heart, small intestines, lung; crosses placenta; found in breast milk
cross blood brain barrier? no
Vd: 25 L/kg 
PPB: 70%
Metabolism:
liver (major site) and other tissues; elimination primarily via liver and biliary system
metabolite(s) active- doxorubicinol (major metabolite) inactive- Yes: aglycones, conjugated sulfates, glucuronides
Excretion:
predominantly in bile (80%; 50% as unchanged drug, 30% as metabolites); 40% of dose is excreted in the bile within 7 days (42% unchanged drug, 22% doxorubicinol, 36% other metabolites)
urine 3-10% is excreted in the urine as metabolites (1% doxorubicinol, <1% adrimycine aglycones) and unchanged drug.
Distribution t½ a 10 minutes; Elimination t½ b 1-3 hours for doxorubicin; 3-3.5 hours for metabolites; Terminal t½ g 29.6 hours (17-30 hours)
Cl: Male: 113 L/hour; Female: 44 L/hour

Side Effects

IMMEDIATE ONSET (hours to days)
* anaphylaxis (rare)
   pain at injection site during injection (vesicant- tissue necrosis upon extravasation, erythematous streaking along the vein proximal to the site of the injection), flare reaction (histamine release), vein irritation (phlebitis)
   facial flushing, nasal congestion
   nausea and vomiting (60%, onset 3-4 hours, duration 6-12 hours)
   urine discolouration (reddish, lasts 1-2 days)
   radiation recall reaction (rare)
* irregular heartbeat (41%, acute transient arrhythmias)
   increased uric acid levels (hyperuricemia)
EARLY ONSET (days to weeks)
* myelosuppression- leukopenia, neutropenia, anemia, thrombocytopenia (nadir 6-13 days, recovery 21-24 days); infection, sepsis/septicemia
* thromboembolism
   mouth sores (stomatitis starts in 5-10 days)
   diarrhea, anorexia, esophagitis, gastrointestinal tract bleeding, colitis
   eye irritation (rare, conjunctivitis)
   hair loss (90%, alopecia)
   dermatologic toxicities: rash/itch, skin and nail hyperpigmentation, photosensitivity, urticaria, acral erythema, palmar plantar erythrodysesthesia
   malaise/asthenia, fever, chills
   conjunctivitis/keratitis, lacrimation
   hepatic toxicity: changes in transaminase levels
DELAYED/LATE ONSET (weeks to years)
* cardiovascular symptoms: sinus tachycardia, ECG abnormalities, atrioventricular and bundle branch block, asymptomatic reductions in left ventricular ejection fraction (LVEF), congestive heart failure- increased risk with maximum cumulative dose (550 mg/m2) lifetime
* cancer (secondary malignancies- eg, myeloproliferative, or lymphoproliferative malignancies)
   darkening of skin (hyperpigmentation)
   infertility (amenorrhea, oligospermia, azoospermia)

Therapeutics

Approved Indications

• Acute lymphocytic leukemia       
• Acute myeloblastic leukemia       
• Acute non-lymphocytic leukemia       
• Bladder cancer
• Breast cancer
• Endometrial cancer       
• Gastric cancer
• Head and neck cancer, squamous cell
• Hodgkin’s disease       
• Lung cancer, small cell
• Lung cancer, non-small cell      
• Neuroblastoma
• Non-Hodgkin’s lymphoma       
• Osteogenic sarcoma       
• Ovarian cancer
• Sarcoma, soft tissue
• Testicular cancer       
• Thyroid cancer
• Wilms’ tumour 

OTHER ONCOLOGY USES (Not Approved)
• Ewing’s sarcoma
• Kaposi’s sarcoma
• Rhabdomyosarcoma       
• Adrenocortical cancer
• Carcinoid syndrome (small bowel)
• Gynecological sarcoma       
• Hepatic cancer
• Islet cell cancer
• Multiple myeloma       
• Pancreatic cancer
• Prostate cancer
• Retinoblastoma

Routes

• Direct IV (preferred)
• Intermittent IV  (in 100 mL over 1 h, venous access device preferred)
• Continuous IV (via venous access device)
• Intravesical (2 mg/mL in Normal Saline)

Administration

• Slow push through sidearm of free flowing IV (5% Dextrose, Normal Saline) over no less than 3-5 minutes (administering nurse should be certified to administer IV push chemotherapy agents and other vesicant agents)
• Slow down injection rate if erythematous streaking occurs
• May be administered by continuous infusion using ambulatory infusion pump; Infuse through central venous access device; do not filter
Protect from light

IV Compatibility

normal saline, dextrose 5%, lactated Ringer’s

Dosing

Intravenous:
• q1-2w: 10-30 mg/m² bolus
• q3-4w: 60-90 mg/m² bolus
• q3-4w: 20-30 mg/m²/day bolus for 3 consecutive days
• q3w: 60-75 mg/m² 10 hour infusion
• q3-4w: 60-90 mg/m² 24-96 hour infusion

Intra-arterial:
• q3-4w: 25 mg/m²/day for 3 consecutive days
Intravesical:
• q1w: 50-80 mg via bladder instillation, retained 1-2 hours, weekly x 4 then monthly

Maximum lifetime dose:
• 450 mg/m² (normal cardiac function)
• 300 mg/m² (in combination with thoracic radiation or cyclophosphamide)
• Careful cardiac monitoring is important, as cardiotoxicity may occasionally occur at lower cumulative doses. If tumour responding when lifetime dose reached, obtain cardiac consultation before continuing treatment.

Pediatric
Intravenous:
• 45-75 mg/m² q3-8w IV
• 20-30 mg/m²/day IV x 3 days

Dose Adjustment Criteria

Hepatic dysfunction
Reduce to 50% dose if Bili=26-51µmol/L or AST=60-180IU/L; 
Reduce to 25% dose if Bili= 52-85µmol/L or AST>180IU/L; 
Omit if Bili >85µmol/L

Renal failure
Reduce to 50% dose if Serum Creatinine >265µmol/L
 (Suggested action)

Antiemetic Risk

HIGH RISK (30-90% of patients) 
• Use a serotonin receptor antagonist PLUS dexamethasone pre-chemotherapy and post-chemotherapy
When combined with cyclophosphamide for breast cancer treatment, consider:
• A serotonin receptor antagonist pre-chemotherapy PLUS a neurokinin-1 receptor antagonist pre-chemotherapy and post-chemotherapy PLUS dexamethasone pre-chemotherapy and post-chemotherapy

Contraindications

• Pregnancy and breast feeding • Low WBC, RBC, platelets (myelosuppression) • > Maximum lifetime dose of an anthracycline (daunorubicin, doxorubicin, epirubicin, Idarubicin, mitoxantrone) • Liver (hepatic) failure • Heart (cardiac) failure

Monitoring

Clinical Monitoring

RECOMMENDED CRITERIA
• Complete blood count including differential, platelets and hemoglobin (CBC) before each cycle of treatment
• Clinical exam for symptoms of Congestive Heart Failure
• Periodic cardiac tests for all patients with cardiac risk factors or patients at or above the threshold dose levels
• Baseline liver function tests [serum alkaline phosphatase, GGT, ALT, AST & Bilirubin levels (serum proteins may be added if indicated)]
 
Cardiac 
0. None 
1. —-
2. Asymptomatic, resting ejection fraction decline by >10% baseline; or abnormal cardiac function tests (LVEF >50) with no baseline for comparison
3. Mild Congestive Heart Failure, responds to therapy
4. Severe/refractory Congestive Heart Failure
At cumulative dose threshold and subsequent intervals

SUGGESTED CRITERIA
• Baseline cardiac function tests (Echo RNA and/or MUGA scans) for all patients with cardiac risk factors
• Baseline renal function tests (if failure suspected) [serum creatinine, electrolytes & BUN]
For Cardiac Toxicity Ratings:
First rating at the Doxorubicin cumulative dose threshold of 300mg/m², & repeat ratings at each cumulative dose increment of 100mg/m² above threshold (Cumulative dose sooner for high risk patients, eg. pre-existing cardiac disease, prior chest irradiation)
Note: Threshold Cumulative dose reduced proportionately if other anthracycline or anthracenedione drugs have been given; cardiotoxicity is additive.

Extravasation Hazard

VESICANT (tissue damage on extravasation) • Management- stop IV, aspirate, elevate limb, cold intermittent compresses • Follow Extravasation Guidelines

Significant Interactions

Anticonvulsant drugs, barbiturates, cyclophosphamide, digoxin, quinolones (ciprofloxacin, norfloxacin, ofloxacin), mercaptopurine, paclitaxel, radiotherapy, streptozocin, trastuzumab, verapamil, other antineoplastic agents. Cytochrome P450 Substrate.

Product Information

Commercial Product Description

• Vials with 10mg/5mL, 50mg/25mL, 200mg/100mL. • Generic products available Vials with 10mg, 50mg, 150mg for reconstitution.

Pharmaceutical Considerations

Injection:
Adriamycin RDF: Doxorubicin powder (generic) may contain methyl paraben (to enhance dissolution) 1 mg/10 mg doxorubicin and lactose 5 mg/10 mg doxorubicin. Store at room temperature, protected from sunlight (eg, store in carton until use).
Adriamycin 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). Remains stable at room temperature for 7 days, however the manufacturer recommends discarding the unused portion of vials.
Reconstitute powder with NS to a final concentration of 2 mg/mL. Do not use bacteriostatic diluents; early experience with doxorubicin suggested that the use of diluents containing benzyl alcohol resulted in hypersensitivity reactions. Vials are under negative pressure.

Reconstituted solution for injection:
Clear, red solution. A colour change from red to purple indicates decomposition and such discoloured solutions should be discarded. The reconstituted solution is stable for at least 24 hours at room temperature and 48 hours under refrigeration. Walker et al reported physical stability of 124 days at 4 and 23°C when a 2 mg/mL solution was stored in its original vial. They also reported physical stability for 124 days when 1 and 2 mg/mL solutions were stored in Terumo or Monoject syringes at 4 and 23°C. Solutions should be protected from direct light. Doxorubicin should not be stored in contact with aluminum but my be safely injected through an aluminum-hubbed needle.

Diluted solution for infusion:
Stable and compatible for at least 24 hours at room temperature in D5W, NS or lactated Ringer’s injection. Admixture of doxorubicin (1.4 mg/mL) plus vincristine (0.033 mg/mL) in NS or sodium chloride 0.45% and dextrose 2.5% injection are stable at least 4 days in PVC containers and Pharmacia cassettes at temperatures 37°C.
Compatible with ondansetron. Some mixtures with dacarbazine, vinblastine and vincristine are reported stable for at least 24 hours. It is recommended that doxorubicin not be mixed with other drugs. Incompatible with aminophylline, cephalothin, dexamethasone, diazepam, fluorouracil, furosemide, heparin and hydrocortisone.

Handling Risk Level

Pregnancy D/Carcinogen 2AKNOWN HAZARDOUS DRUG
FDA Pregnancy Risk Factor D
IARC Carcinogen Risk Group 2A (Probable Carcinogen)

  • This drug must be handled using precautions outlined in CCNS Policies for Occupational Safety, Preparing Cancer Chemotherapy and Administering Cancer Chemotherapy

Note

HANDLING RISK LEVEL:
HAZARD RISK LEVEL 1
FDA Pregnancy Risk Factor D
IARC Carcinogen Risk Group 2A (Probable Carcinogen)
• This drug must be handled using precautions outlined in CCNS Policies for Preparing Cancer Chemotherapy and Administering Cancer Chemotherapy
• Go to "Additional Information" tab (above) for links to CCNS Policies

Availability & Funding

Administrative Information (Nova Scotia)

• CCNS Provincial Formulary Status- Intermediate Level • Go to "Additional Information" tab (above) for links to Provincial Formulary of Cancer Drugs • Pharmacare Formulary Status- Formulary (red) NOTE: It is recommended to limit ordering of this medication to standard preprinted order forms, for patient safety.



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