Professional Information

Doxorubicin, Conventional

Pronouncation: (DOX-oh-ROO-bi-sin)
Class: Anthracycline

Trade Names:
Adriamycin PFS
- Injection, preservative-free solution 2 mg/mL

Trade Names:
Adriamycin RDF
- Injection, lyophilized powder for solution 10 mg
- Injection, lyophilized powder for solution 20 mg
- Injection, lyophilized powder for solution 50 mg
- Injection, lyophilized powder for solution 150 mg

Trade Names:
Doxorubicin Hydrochloride
- Injection, lyophilized powder for solution 10 mg
- Injection, lyophilized powder for solution 20 mg
- Injection, lyophilized powder for solution 50 mg
- Solution for injection 2 mg/mL

Caelyx (Canada)
Myocet (Canada)

Pharmacology

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Cells treated with doxorubicin have been shown to manifest the characteristic morphologic changes associated with apoptosis or programmed cell death. Doxorubicin-induced apoptosis may be an integral component of the cellular mechanism of action relating to therapeutic effects, toxicities, or both.

Pharmacokinetics

Distribution

Distribution t _½ approximately 5 min. Vd greater than 20 to 30 L/kg (at steady state). 74% to 76% protein bound.

Metabolism

Metabolized to doxorubicinol (active).

Elimination

The t _½ is 20 to 48 h. Cl is 8 to 20 mL/min/kg. Approximately 40% is excreted in the bile and 5% to 12% in the urine in 5 days.

Special Populations

Renal Function Impairment

The influence of renal function on the pharmacokinetics has not been evaluated.

Hepatic Function Impairment

Excretion is slower, resulting in increased retention and accumulation. Reduce dose in those with elevated bilirubin.

Elderly

No dosage adjustment is recommended based on age.

Children

Cl in children older than 2 yr of age was increased compared with adults.

Gender

Cl appears to be higher in men than women; however, the t _½ was longer in men compared with women.

Race

The influence of race on the pharmacokinetics has not been evaluated.

Indications and Usage

Produce regression of disseminated neoplastic conditions, such as acute lymphoblastic leukemia, acute myeloblastic leukemia, breast carcinoma, gastric carcinoma, Hodgkin disease, malignant lymphoma and bronchogenic carcinoma, neuroblastoma, ovarian carcinoma, soft tissue and bone sarcomas, thyroid carcinoma, transitional cell bladder carcinoma, Wilms tumor; component of adjuvant therapy in women with evidence of axillary lymph node involvement following resection of primary breast cancer.

Unlabeled Uses

Refractory multiple myeloma; endometrial, islet cell, and lung carcinomas; AIDS-related Kaposi sarcoma.

Contraindications

Baseline neutrophil count less than 1,500 cells/mm ³ ; marked myelosuppression induced by previous treatment with other antitumor agents or by radiotherapy; history of hypersensitivity reactions to conventional or liposomal doxorubicin or their components; previous treatment with complete cumulative doses of daunorubicin, doxorubicin, idarubicin, or other anthracyclines and anthracenediones; severe hepatic function impairment; recent MI; severe myocardial insufficiency; severe arrhythmias.

Dosage and Administration

Single Agent Therapy
Adults and Children

IV 60 to 75 mg/m ² as a single dose every 21 days. Give the lower dose to patients with inadequate marrow reserves because of old age, prior therapy, or neoplastic marrow infiltration.

Combination Therapy
Adults

IV 40 to 60 mg/m ² as a single dose every 21 to 28 days.

Patients With Elevated Bilirubin
Dosage reduction

If serum bilirubin is 1.2 to 3 mg/dL, give 50% of adjusted dose from prior course. If serum bilirubin is 3.1 to 5 mg/dL, give 25% of adjusted dose from prior course.

General Advice

Do not mix doxorubicin with other drugs.
Administer IV infusion slowly into a freely running IV infusion of sodium chloride injection or dextrose 5% injection. Attach tubing to a butterfly needle inserted into a large vein. Avoid veins over joints or in extremities with compromised venous or lymphatic drainage. Administer over at least 3 to 5 min. Local erythematous streaking along the vein, as well as facial flushing, may indicate too rapid administration.

Storage/Stability

Store lyophilized powder at room temperature (59° to 86°F) and protect from sunlight. Refrigerate preservative-free solution and protect from light. Store doxorubicin hydrochloride injection lyophilized powder for solution 10, 20, and 50 mg, and doxorubicin hydrochloride injection solution 2 mg/mL in the refrigerator. Reconstituted solution is stable for 7 days at room temperature (59° to 86°F) and under normal room light (100 foot-candles), and 15 days under refrigeration (36° to 46°F). Protect from sunlight. Discard any of the unused solution from the 10, 20, and 50 mg single-dose vials. Discard unused solutions of the multiple-dose vials remaining beyond the recommended storage times. Store sterile, isotonic preparation in refrigerator (36° to 46°F). Protect from light.

Drug Interactions

Ciprofloxacin

Ciprofloxacin absorption may be decreased, reducing the efficacy.

Cyclophosphamide

Cyclophosphamide-induced hemorrhagic cysts may be exacerbated; risk of occurrence of acute myeloid leukemia may be increased.

Cyclosporine

Doxorubicin and doxorubinol concentrations may be increased. Profound and prolonged hematologic toxicity, as well as coma and seizures, have been reported.

Cytarabine

Bloody stools, life-threatening reactions, and necrotizing colitis have been reported.

Dexrazoxane

Data are conflicting. Tumor response rate may be decreased.

Digoxin

Doxorubicin may decrease oral absorption of digoxin tablets.

Paclitaxel

Risk of cardiotoxicity may be increased.

Phenobarbital

Elimination of doxorubicin may be increased.

Phenytoin

Concentrations may be reduced by doxorubicin.

Progesterone

Risk of neutropenia and thrombocytopenia may be increased.

Streptozocin

Doxorubicin concentrations may be elevated.

Vaccines

Administration of live vaccines may be hazardous.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

Acute arrhythmias, cardiomyopathy.

CNS

Malaise/asthenia, peripheral neurotoxicity.

Dermatologic

Alopecia, facial flushing, hyperpigmentation of nail beds and dermal creases, onycholysis, palmar-plantar erythrodysesthesia, radiation recall, urticaria, vein itching or streaking.

EENT

Conjunctivitis, keratitis, lacrimation.

GI

Mucositis, nausea, necrotizing colitis, vomiting.

Hematologic

Bone marrow suppression.

Hematologic-Lymphatic

Secondary acute myeloid leukemia.

Hypersensitivity

Anaphylaxis, cross-sensitivity to lincomycin.

Miscellaneous

Fever, chills.

Precautions

Warnings

Acute myelogenous leukemia (AML) or myelodysplastic syndrome

AML or myelodysplastic syndrome has been reported in patients receiving anthracyclines, including doxorubicin. Refractory AML or myelodysplastic syndrome is more common when anthracycline is coadministered with DNA-damaging anti neoplastic agents or radiotherapy, when patients have been heavily pretreated with cytotoxic drugs, or when the anthracycline dose has been escalated.

Cardiac toxicity

Potentially fatal CHF may occur during therapy or months to years after termination of therapy. The risk of developing CHF increases rapidly with increasing total cumulative doses of doxorubicin in excess of 400 mg/m ² . Factors increasing the risk of cardiac toxicity include active or dormant CV disease, prior or concurrent radiotherapy to the mediastinal/pericardial area, prior therapy with other anthracyclines or anthracenediones, and concurrent use of other cardiotoxic drugs. However, cardiac toxicity may occur at low cumulative doses whether or not cardiac risk factors are present. Children are at increased risk for developing delayed cardiotoxicity.

Accidental substitution

Accidental substitution of liposomal doxorubicin for conventional doxorubicin has resulted in severe side effects. Do not substitute liposomal doxorubicin for conventional doxorubicin on a mg per mg basis.

Extravasation risk

Local irritation and necrosis may occur. Refer to institution-specific protocol.

Hepatic function impairment

Reduce dose.

Monitor

During initial treatment, closely observe patient and perform extensive laboratory monitoring, including periodic monitoring of CBCs, hepatic function tests, and radionuclide left ventricular ejection fraction. Monitor ECG and systolic ejection fraction as the maximum cumulative lifetime dose approaches. Hospitalize patients during at least the first phase of treatment.

Evaluate blood uric acid levels, potassium, calcium, phosphate, and creatinine after initial treatment. Because children are at increased risk for developing delayed cardiotoxicity, follow-up cardiac evaluations are recommended periodically to monitor for delayed cardiotoxicity.

Pregnancy

Category D .

Lactation

Discontinue breast-feeding.

Children

Children are at increased risk for developing delayed cardiotoxicity and for developing AML and other neoplasms. Doxorubicin may contribute to prepubertal growth failure. It may also contribute to gonadal impairment, which is usually temporary.

Elevated bilirubin

Some clinicians recommend not giving doxorubicin to patients with a bilirubin above 5 mg/dL.

Hematologic toxicity

May produce myelosuppression, which requires careful monitoring. Clinical consequences of severe myelosuppression include death, fever, hemorrhage, infections, sepsis/septicemia, septic shock, or tissue hypoxia.

Hyperuricemia

Monitor serum uric acid. Minimize effects of hyperuricemia with hydration, urinary alkalinization, and allopurinol.

Immunosuppressed patients

Administration of live vaccines to immunosuppressed patients may be hazardous.

Infusion reactions

Appear to occur with the first infusion and do not appear to occur with later infusions if not present initially. In most patients, these reactions resolve over the course of several hours to a day once the infusion is terminated. In some patients, slowing the rate of infusion resolves the reaction.

Mucositis

May occur 5 to 10 days after administration, leading to ulceration, and represent a site or origin for severe infections. Incidence and severity of mucositis is greater with the 3 successive daily dosage regimen. Ulceration and necrosis of the colon, especially the cecum, may occur, leading to bleeding or severe infections that can be fatal.

Necrotizing colitis

Manifested by typhlitis (eg, bloody stools, cecal inflammation, severe and sometimes fatal infections).

Phlebosclerosis

May occur when small veins or a single vein is used for repeated administration; facial flushing may occur if injection is too rapid.

Radiation

Radiation-induced toxicity to the liver, mucosa, myocardium, and skin has been increased.

Overdosage

Symptoms

Acute overdosage enhances the toxic effects of mucositis, leukopenia, pancytopenia, and thrombocytopenia. Chronic overdosage increases the risk of cardiomyopathy and resultant CHF.

Patient Information

Advise patient, family, or caregiver that medication will be prepared and administered by health care provider in a health care setting.
Advise patient, family, or caregiver that medication may be used in combination with other agents to achieve maximum benefit possible.
Review dosing schedule with patient, family, or caregiver.
Advise patient, family, or caregiver that medication will usually cause a red coloration of the urine for 1 to 2 days after administration. Advise that this is not a problem and is expected because the medication is being eliminated in the urine.
Advise patient, family, or caregiver that medication may cause hair loss but that this is reversible when therapy is stopped.
Advise patient, family, or caregiver to immediately report any of the following to health care provider: chest pain; chills or other signs of infection; difficulty breathing; fever; hives; pain, redness, or swelling at injection site; rash; sores in mouth; unusual bleeding or bruising.
Advise patient, family, or caregiver to report any of the following to health care provider: persistent appetite loss, diarrhea, nausea, or vomiting; persistent or worsening general body weakness.
Caution women of childbearing potential to avoid becoming pregnant while being treated.
Advise patient that following discharge from the hospital, frequent follow-up visits, ECGs or heart function tests, and laboratory tests will be required to monitor therapy, and to keep appointments.