Doxorubicin (Adriamycin)

Today's med: Doxorubicin (doks oh ROO bi sin)

(brand name: Adriamycin; Index terms: ADR, Adria, Doxorubicin Hydrochloride, Hydroxydaunomycin Hydrochloride)

Drug Class: Anthracycline Topoisomerase Inhibitor

Other Drugs in this class: Epirubicin,Daunorubicin, Idarubicin, Doxorubicin Hydrochloride, Epirubicin Hydrochloride,Daunorubicin Hydrochloride, Idarubicin Hydrochloride, Daunorubicin citrate

Indications:  Labeled Indications

Treatment of acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), Hodgkin’s disease, malignant lymphoma, soft tissue and bone sarcomas, thyroid cancer, small cell lung cancer, breast cancer, gastric cancer, ovarian cancer, bladder cancer, neuroblastoma, and Wilms' tumor

Use: Unlabeled

Treatment of multiple myeloma, endometrial carcinoma, uterine sarcoma, head and neck cancer, liver cancer, kidney cancer

Action:  Inhibition of DNA and RNA synthesis by intercalation between DNA base pairs by inhibition of topoisomerase II and by steric obstruction. Doxorubicin intercalates at points of local uncoiling of the double helix. Although the exact mechanism is unclear, it appears that direct binding to DNA (intercalation) and inhibition of DNA repair (topoisomerase II 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.

Absorption

Oral: Poor (<50%)

Distribution

V_d: 809-1214 L/m²; to many body tissues, particularly liver, spleen, kidney, lung, heart; does not distribute into the CNS; crosses placenta

Metabolism

Primarily hepatic to doxorubicinol (active), then to inactive aglycones, conjugated sulfates, and glucuronides

Contraindications: Hypersensitivity to doxorubicin, any component of the formulation, or to other anthracyclines or anthracenediones; recent MI, severe myocardial insufficiency, severe arrhythmia; previous therapy with high cumulative doses of doxorubicin, daunorubicin, idarubicin, or other anthracycline and anthracenediones; baseline neutrophil count <1500/mm³; severe hepatic impairment

Adverse Effects: Frequency not defined.

Cardiovascular:

Acute cardiotoxicity: Atrioventricular block, bradycardia, bundle branch block, ECG abnormalities, extrasystoles (atrial or ventricular), sinus tachycardia, ST-T wave changes, supraventricular tachycardia, tachyarrhythmia, ventricular tachycardia

Delayed cardiotoxicity: LVEF decreased, CHF (manifestations include ascites, cardiomegaly, dyspnea, edema, gallop rhythm, hepatomegaly, oliguria, pleural effusion, pulmonary edema, tachycardia); myocarditis, pericarditis

Central nervous system: Malaise

Dermatologic: Alopecia, itching, photosensitivity, radiation recall, rash; discoloration of saliva, sweat, or tears

Endocrine & metabolic: Amenorrhea, dehydration, infertility (may be temporary), hyperuricemia

Gastrointestinal: Abdominal pain, anorexia, colon necrosis, diarrhea, GI ulceration, mucositis, nausea, vomiting

Genitourinary: Discoloration of urine

Hematologic: Leukopenia/neutropenia (75%; nadir: 10-14 days; recovery: by day 21); thrombocytopenia and anemia

Local: Skin “flare” at injection site, urticaria

Neuromuscular & skeletal: Weakness

Postmarketing and/or case reports: Anaphylaxis, azoospermia, bilirubin increased, coma (when in combination with cisplatin or vincristine), conjunctivitis, fever, gonadal impairment (children), growth failure (prepubertal), hepatitis, hyperpigmentation (nail, skin & oral mucosa), infection, keratitis, lacrimation, myelodysplastic syndrome, neutropenic fever, neutropenic typhlitis, oligospermia, peripheral neurotoxicity (with intra-arterial doxorubicin), phlebosclerosis, radiation recall pneumonitis (children), secondary acute myelogenous leukemia, seizure (when in combination with cisplatin or vincristine), sepsis, shock, Stevens-Johnson syndrome, systemic hypersensitivity (including urticaria, pruritus, angioedema, dysphagia, and dyspnea), toxic epidermal necrolysis, transaminases increased, urticaria

Standard Dosing: (see 5 minute clinical consult for dosing adjustments d/t toxicity and disease conditions)

I.V.: Refer to individual protocols. Note: Lower dosage should be considered for patients with inadequate marrow reserve (due to old age, prior treatment or neoplastic marrow infiltration)

Children:

35-75 mg/m²/dose every 21 days or

20-30 mg/m²/dose once weekly or

60-90 mg/m²/dose given as a continuous infusion over 96 hours every 3-4 weeks

Adults: Usual or typical dose: 60-75 mg/m²/dose every 21 days or

60 mg/m²/dose every 2 weeks (dose dense) or

40-60 mg/m²/dose every 3-4 weeks or

20-30 mg/m²/day for 2-3 days every 4 weeks or

20 mg/m²/dose once weekly

Administration

Vesicant. Administer I.V. push over at least 3-5 minutes or by continuous infusion (infusion via central venous line recommended). Avoid extravasation associated with severe ulceration and soft tissue necrosis. Flush with 5-10 mL of I.V. solution before and after drug administration. Incompatible with heparin. Monitor for local erythematous streaking along vein and/or facial flushing (may indicate rapid infusion rate).

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH, 2012).

Drug interactions: http://www.drugs.com/drug-interactions/doxorubicin.html

A total of 410 drugs (1349 brand and generic names) are known to interact with doxorubicin.

• 73 major drug interactions (184 brand and generic names)
• 273 moderate drug interactions (851 brand and generic names)
• 64 minor drug interactions (314 brand and generic names)

Show all medications in the database that may interact with doxorubicin.

CYP3A4, CYP2D6 Inhibitors

DoxoRubicin...DNA and RNA synthesis inhibition.