SYNONYM(S): Hydroxyl daunorubicin, Dox, Adria

COMMON TRADE NAME(S): Adriamycin®, Adriamycin® PFS, Adriamycin® RDF, Oncoject®

CLASSIFICATION: Antitumour Antibiotic

Special pediatric considerations are noted when applicable, otherwise adult provisions apply.

MECHANISM OF ACTION: [1,2,3,4]

Daunorubicin and its 14-hydroxy derivative, doxorubicin, are anthracycline antibiotics produced by the fungus streptomyces peucetius. Doxorubicin damages DNA by intercalation of the anthracycline portion, metal ion chelation, or by generation of free radicals. Doxorubicin has also been shown to inhibit DNA topoisomerase II which is critical to DNA function. Cytotoxic activity is cell cycle phase-nonspecific.

PHARMACOKINETICS: [3,4,5,6,7,8,9,10,11,12,13,14]

Oral Absorption	no (5%)
Distribution	highest concentrations in liver, spleen, kidney, heart, small intestines, lung; crosses placenta; found in breast milk
	cross blood brain barrier?	no information found
	Vd	25 L/kg
	PPB	79-85%
Metabolism	liver (major site) and other tissues; elimination primarily via liver and biliary system
	active metabolite(s)	doxorubicinol (major metabolite)
	inactive metabolite(s)	yes
Excretion	predominantly in bile, 40-50% in feces within 7 days
	urine	4-5% over 5 days
	t½	12 minutes
	t½	3.3 hours
	t½	29.6 hours
	Cl	173 mL/min/kg 503 mL/min/m² (higher in children)

USES: [15,16]

SPECIAL PRECAUTIONS: [6,7,11,12,17,18,19,20,21,22]

Cardiac toxicity is cumulative across members of the anthracycline (doxorubicin, epirubicin, daunorubicin, idarubicin) and anthracenedione (mitoxantrone) class of drugs. Patients who have received these agents are at increased risk of toxicity, and should be carefully monitored. The cumulative doses are lower in patients who have received radiation to the mediastinal area or concomitant therapy with other cardiotoxic agents such as cyclophosphamide.

Contraindicated in patients with severe cardiovascular disease, unstable conditions including hypertension, angina and arrhythmias; and in patients with hyperbilirubinemia.

Doxorubicin has been shown to have mutagenic and carcinogenic properties in experimental models. Its safe use in pregnancy and its effects on fertility have not been established. Present in breast milk, therefore breast feeding is not recommended.

SIDE EFFECTS: [6,7,15,17,23,24,25]

Dose-limiting side effects are underlined.
I = immediate (onset in hours to days); E = early (days to weeks);
D = delayed (weeks to months); L = late (months to years)

Hyperuricemia during periods of active cell lysis, which is caused by cytotoxic chemotherapy of highly proliferative tumours of massive burden (eg, some leukemias and lymphomas), can be minimized with allopurinol and hydration. In hospitalized patients the urine may be alkalinized, by addition of sodium bicarbonate to the IV fluids, if tumour lysis is expected.

Cardiotoxicity can be divided into an initial acute effect with transient electrocardiographic abnormalities, reported in up to 41% of patients; and a later cumulative, dose-dependent cardiomyopathy. The acute electrocardiographic changes are usually reversible, unrelated to total dose, return to baseline readings within a few days to two months and usually are not an indication to discontinue the doxorubicin. The more serious cardiotoxicity is the dose-dependent cardiomyopathy (0.4-9% of all patients), which has an attendant mortality as high as 61%. Risk factors include total dose, schedule, increased age, pre-existing cardiac disease, prior mediastinal radiotherapy and other antineoplastic drugs. The onset of cardiomyopathy may be delayed, occurring 6 months or more after therapy. Follow-up of doxorubicin-treated patients must include assessment of cardiac function.

The incidence of drug-induced congestive heart failure ranges from 0.1-1.2% with cumulative dose of <550 mg/m² in contrast to 30% incidence with cumulative dose >550 mg/m². There are data to suggest that continuous infusion of doxorubicin is safer than bolus doses, and that cumulative doses could be higher than 550 mg/m². Cardiac monitoring (echocardiogram) should be performed before treatment, and for every increment of 60-70 mg/m². Patients who have reached 450 mg/m² with their tumours responding should have careful cardiac assessment before continuing treatment. Referral to a cardiologist may be useful. In the adjuvant setting, cardiac consultation is recommended at 300 mg/m². For a graphic estimate of the cumulative probability of developing doxorubicin-induced congestive heart failure (CHF) in adults versus total cumulative dose see Von Hoff 1979. It has been observed that children less than 15 years of age are more likely to develop CHF from cumulative doses greater than 550 mg/m² than those patients aged 15 to 40 years. Agents which are currently being investigated for prevention of doxorubicin-induced CHF include chelation of iron with ICRF-187, liposome encapsulation and free radical scavengers.

In children, clinical cardiotoxicity increases rapidly at a cumulative dose of about 450 mg/m², but individual patients may have a lower threshold and develop toxicity at a significantly lower dose. For children receiving anthracyclines, the Cardiology Committee of the Children's Cancer Group recommends the following monitoring of cardiac function: 

1. Echocardiogrm [echo] (or radionucleotide angiocardiography [RNA]) as baseline.       
2. Echo before every other subsequent course of anthracycline when the cumulative dose is <300 mg/m².       
3. Echo (or RNA) before each course of anthracycline when the total cumulative dose >300 mg/m² plus mediastinal radiation >1000 rads.       
4. Echo and RNA before each course of anthracycline when the total course is 400 mg/m².

Cardiac dysfunction may appear several months to years after anthracycline therapy, therefore monitoring should continue after therapy is complete. An echocardiogram should be done at 3, 6 and 12 months following therapy, with RNA as a confirmatory test, if possible at 12 months.

Erythematous streaking (a histamine release phenomena) along the vein proximal to the site of injection has been reported, and must be differentiated from an extravasation event. This 'doxorubicin flare' reaction usually subsides within 30 minutes. The injection may be continued, more slowly in the same site or may be changed to another site. Diphenhydramine 25 mg (1 mg/kg/dose in children), or hydrocortisone 100 mg (1 mg/kg/dose in children), by slow IV push over 5 minutes into the IV line may hasten clearing of the reaction.

The tissue necrosis that occurs with extravasation may happen days to weeks after the treatment. Patients must be observed for delayed reactions and prior injection sites carefully inspected.

Doxorubicin has the potential to enhance radiation injury to tissues. While often called 'radiation recall reactions', the timing of the radiation may be before, concurrent with or even after the administration of the doxorubicin. The skin is the site most commonly affected, resulting in erythema followed by dry desquamation. Skin reactions generally occur only if the drug is given within 7 days of the radiation. Rarely, reactions after 30 days have been noted. Skin involvement, while unpleasant, is not as debilitating as is the case for internal organs. Patients who have received prior radiotherapy to the mediastinum (and specifically to the heart), should not receive greater than a total cumulative dose of 300 mg/m². Enhancement of radiation injury to the esophagus and gastrointestinal tract is most severe when the drug and the radiation are given concomitantly. Recurrent injury to a previously irradiated site may occur weeks to months following radiation.

INTERACTIONS: [6,7,26,27,28]

SOLUTION PREPARATION AND COMPATIBILITY: [15,29,30,31,32,33,34]

Injection
Adriamycin RDF: 10 mg, 50 mg, 150 mg vials powder. Also 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 in 5 mL, 25 mL and 100 mL vials and in 15 mL, 17.5 mL, 20 mL and 25 mL pre-filled syringes (Oncoject). 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.

PARENTERAL ADMINISTRATION: [4,5,6,7,35,36,37,38]

DOSAGE GUIDELINES: [4,5,6,7,35,36,39,40,41,42,43]

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 white blood cell count. Dosage may be reduced and/or delayed in patients with bone marrow depression due to cytotoxic/radiation therapy.

Adults:

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 high dose 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.

Dosage in myelosuppression:
modify according to protocol by which patient is being treated; if no guidelines available, refer to Appendix 6 "Dosage Modification for Myelosuppression"

Dosage in renal failure:
no adjustment required

Dosage in hepatic failure:	Bilirubin (mol/L)	% usual dose
	25-50	50%
	51-85	25%
	>85	0%

Children:

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

DOXORUBICIN FACT SHEET
FOR THE HEALTH CARE PROFESSIONAL

Notes:

• Do not use solutions which have changed colour to purple.       
• Streaking along the vein (doxorubicin flare reaction) proximal to the injection site may mimic an extravasation. If in doubt, treat as an extravasation.       
• The maximum lifetime dose is decreased for patients treated with another cardiotoxic drug (cyclophosphamide, other anthracyclines) or thoracic radiation.       
• Increased serum uric acid levels (hyperuricemia) may be minimized with hydration and allopurinol. In hospitalized patients the urine may be alkalinized, by addition of sodium bicarbonate to the IV fluids, if tumour lysis is expected.

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Cancer Drug Manual^© 1994