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All about: Doxorubicin, Liposomal

Big Image Pronouncation: (DOX-oh-ROO-bih-sin)
Class: Antineoplastic, Anthracycline antibiotic

Trade Names:
Doxil
- Solution for injection equivalent to 2 mg/mL doxorubicin hydrochloride liposomal in single-use 10 or 30 mL vials

Mechanism of Action

Pharmacology

Binds DNA and inhibits nucleic acid synthesis. Cell structure studies have demonstrated rapid cell penetration and perinuclear chromatin binding, rapid inhibition of mitotic activity and nucleic acid synthesis, and induction of mutagenesis and chromosomal aberrations.

Pharmacokinetics

Absorption

C max approximately 4.12 to 8.34 mcg/mL. AUC approximately 277 to 590 mcg/mL•h.

Distribution

Vd approximately 2.72 to 2.83 L/m 2 (at steady-state).

Metabolism

Metabolized to doxorubicinol.

Elimination

The t ½ is approximately 4.7 to 5.2 h (first phase) and approximately 52.3 to 55 h (second phase). Plasma Cl approximately 0.041 to 0.056 L/h/m 2 .

Indications and Usage

Treatment of ovarian cancer in patients whose disease has progressed or recurred after platinum-based chemotherapy; treatment of AIDS-related Kaposi sarcoma in patients whose disease has progressed on prior combination chemotherapy or who are intolerant to such therapy.

Contraindications

Hypersensitivity to doxorubicin or the components of this product; breast-feeding mothers.

Dosage and Administration

Paclitaxel- and Platinum-Refractory Metastatic Ovarian Cancer
Adults

IV 50 mg/m 2 /dose at an initial rate of 1 mg/ min. If no infusion events observed, can increase rate of drug to over 1 h. Repeat every 4 wk. Give minimum of 4 courses, continuing therapy until disease progression occurs. Consider pretreatment with or concomitant use of antiemetics.

Kaposi Sarcoma
Adults

IV 20 mg/m 2 /dose at an initial rate of 1 mg/min. If no infusion adverse reactions observed, can increase rate of drug to over 1 h. Repeat every 3 wk, for as long as patient responds satisfactorily and tolerates treatment.

Alternative Dose Schedules
Adults

IV Alternative dosing schedules are recommended for patients with palmar-plantar erythrodysesthesia, hematologic toxicity, or stomatitis.

Dosage Adjustment for Hepatic Function Impairment

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

Lifetime Cumulative Doses Above Which Frequency of Cardiotoxicity Increases
Adults

IV up to 500 mg/m 2 .

Adults who have received mediastinal radiation or other cardiotoxic drugs

IV up to 400 mg/m 2 .

Adults older than 70 yr of age with or without mediastinal radiation

IV up to 300 mg/m 2 .

General Advice

  • For IV infusion only. Not for intradermal, subcutaneous, IM, IV bolus, or intraarterial administration; do not administer as undiluted solution.
  • Liposomal doxorubicin cannot be substituted for conventional doxorubicin on a mg/mg basis.
  • Follow institutional and National Institutes of Health guidelines for preparing and administering liposomal doxorubicin, and disposing of used supplies and unused doxorubicin.
  • If accidental skin contact occurs, wash immediately and thoroughly with soap and water. If accidental eye or mucus membrane contact occurs, immediately institute copious irrigation with plain water.
  • Injection must be diluted prior to administration. Dilute doses up to 90 mg in 250 mL of dextrose 5% injection; dilute doses exceeding 90 mg in 500 mL dextrose 5% injection.
  • Discard unused portions of vial. Do not save for future use.
  • Do not mix with any IV solution other than dextrose 5% nor mix with any other medication. Do not use any bacteriostatic agent (eg, benzyl alcohol).
  • Solution will have a red translucent appearance. Do not administer if solution is opaque or contains particulate matter.
  • Administer at an initial rate of 1 mg/min to minimize risk of infusion reactions. If no infusion-related reactions occur, rate of infusion can be increased to complete administration of drug over 1 h.
  • Do not use in-line filters; avoid rapid flushing of infusion line.
  • Take precautions to avoid extravasation. If any signs or symptoms of extravasation occur, terminate infusion immediately and restart in another vein. Applying ice over the site of extravasation for approximately 30 min may be helpful in alleviating the local reaction.

Storage/Stability

Refrigerate vials (36° to 46°F). Avoid freezing. Prolonged freezing may adversely affect liposomal doxorubicin; short-term freezing (less than 1 mo) does not appear to have a deleterious effect. If not used immediately, store diluted solution in refrigerator for up to 24 h.

Drug Interactions

Digoxin

Doxorubicin may decrease oral absorption of digoxin tablets.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

Cardiac arrest, chest pain, deep thrombophlebitis, hypotension, pallor, tachycardia, vasodilation (at least 1% to 5%).

CNS

Asthenia (40%); headache (11%); paresthesia (10%); dizziness (4%); agitation, anxiety, confusion, depression, emotional liability, hypertonia, insomnia, neuralgia, neuropathy, peripheral neuritis, somnolence, vertigo (at least 1% to 5%).

Dermatologic

Hand-foot syndrome (51%); rash (28%); alopecia (19%); acne, pruritus, dry skin, exfoliative dermatitis, fungal dermatitis, furunculosis, herpes simplex, herpes zoster, itching, maculopapular rash, rash, skin discoloration, sweating, vesiculobullous rash (at least 1% to 5%).

EENT

Pharyngitis (16%); conjunctivitis, dry eyes, ear pain, retinitis, rhinitis, taste perversion (at least 1% to 5%).

GI

Nausea (46%); stomatitis (41%); abdominal pain (34%); vomiting (33%); constipation (30%); diarrhea (21%); anorexia (20%); dyspepsia (12%); intestinal obstruction (11%); oral moniliasis (6%); ascites, dry mouth, dysphagia, enlarged abdomen, esophagitis, flatulence, gingivitis, ileus, mouth ulceration, rectal bleeding, anorexia, aphthous stomatitis, glossitis (at least 1% to 5%).

Genitourinary

Albuminuria, cystitis, dysuria, hematuria, leucorrhea, pelvic pain, urinary frequency, urinary incontinence, UTI, urinary urgency, vaginal bleeding, vaginal moniliasis (at least 1% to 5%).

Hematologic-Lymphatic

Thrombocytopenia (61%); anemia (58%); neutropenia (46%); hypochromic anemia (10%); hemolysis, ecchymosis, increased PT (at least 1% to 5%).

Hepatic

Hyperbilirubinemia (1% to 5%).

Lab Tests

Increased alkaline phosphatase (8%).

Metabolic-Nutritional

Peripheral edema (11%); cachexia, dehydration, edema, hyperbilirubinemia, hypercalcemia, hypokalemia, hyponatremia, hyperglycemia, hypocalcemia, increased ALT, weight loss (at least 1% to 5%).

Musculoskeletal

Back pain (12%); arthralgia, myalgia, pathological fracture (1% to 10%); back pain (1% to 5%).

Respiratory

Dyspnea (15%); increased cough (10%); apnea, epistaxis, pleural effusion, pneumonia, sinusitis (at least 1% to 5%).

Miscellaneous

Fever, pain (21%); mucous membrane disorder (14%); infection (12%); allergic reactions, chills (1% to 5%).

Precautions

Warnings

Doxorubicin may lead to cardiac toxicity. Myocardial damage leading to heart failure may be encountered as the total cumulative dose approaches 550 mg/m 2 . Include prior use of other anthracyclines or anthracenediones in calculations of total cumulative dose. Cardiac toxicity also may occur at lower cumulative doses (eg, 400 mg/m 2 ) in patients with prior mediastinal irradiation or who are receiving concurrent cyclophosphamide therapy.

Acute infusion-related reactions including serious and sometimes life-threatening or fatal allergic/anaphylactoid-like infusion reactions have been reported in up to 10% of patients. Flushing, shortness of breath, facial swelling, headache, chills, back pain, tightness in the chest or throat, and hypotension have occurred. In most cases, these reactions resolve over several hours to a day once the infusion is terminated. Slowing the infusion rate has resolved the reaction in some patients. Have medications and emergency equipment available for immediate use. Administer doxorubicin at an initial rate of 1 mg/min to minimize the risk of infusion reactions.

Severe myelosuppression may occur.

Liposomal doxorubicin cannot be substituted for doxorubicin hydrochloride on a mg/mg basis. Accidental substitution has resulted in severe adverse reactions.


Monitor

Monitor cardiac function carefully (endomyocardial biopsy, echocardiography, or multigated radionuclide scans). Assess renal function before initiating therapy. Monitor WBC, CBC, differential, platelet counts, and Hgb/Hct frequently and at a minimum prior to each dose. Assess hepatic function before starting therapy.


Pregnancy

Category D .

Lactation

Undetermined. Discontinue breast-feeding prior to starting therapy.

Children

Safety and efficacy not established.

Hepatic Function

Reduce dose in patient with hepatic function impairment.

Carcinogenesis

Secondary acute myelogenous leukemia has been reported in patients treated with topoisomerase II inhibitors, including anthracyclines.

CV disease

Use only when potential benefit outweighs risk.

Extravasation risk

Local irritation or phlebitis may occur. Refer to your institution-specific protocol.

Hand-foot syndrome

Palmar-plantar skin eruptions can occur. Usually seen after 2 or 3 cycles of therapy but may occur earlier.

Radiation therapy

Recall of skin reaction because of prior radiotherapy has occurred.

Overdosage

Symptoms

Mucositis, leukopenia, and thrombocytopenia.

Patient Information

  • Review the treatment regimen, including dosing schedule, duration of treatment, and monitoring that will be required.
  • Advise patient or caregiver that medication will be prepared and administered by health care providers in a health care setting.
  • Advise patient or caregiver that medication may cause a red coloration of the urine. Advise that this is expected because the medication is being eliminated in the urine.
  • Advise patient or caregiver to immediately report any of the following to health care provider: rash; hives; difficulty breathing; chest pain; fever, chills, or other signs of infection; mouth or lip sores; bleeding or unusual bruising; tingling or burning, redness, flaking, bothersome swelling, small blisters or sores on the palms of hands or soles of feet; pain, redness, or swelling at injection site.
  • Advise patient or caregiver to report any of the following to health care provider: persistent nausea, vomiting, or appetite loss; persistent or worsening general body weakness.
  • Advise patient or caregiver that hair loss is a common adverse reaction of therapy, which usually is reversible after therapy has been completed.
  • Caution women of childbearing potential to avoid becoming pregnant during therapy.

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