doxorubicin, liposomal

dox-oh-ROO-bi-sin LYE-poe-sohm-al

Therapeutic Classification: antineoplastics

Pharmacologic Classification: anthracyclines

High Alert

AIDS-related Kaposi’s sarcoma in patients who cannot tolerate or fail conventional therapy.
Ovarian cancer that has progressed or recurred after platinum-based chemotherapy.
Multiple myeloma with bortezomib in patients who have not previously received bortezomib and have received ≥1 prior therapy.

Inhibits DNA and RNA synthesis by forming a complex with DNA; action is cell-cycle S-phase–specific.
Also has immunosuppressive properties.
Encapsulation in a liposome increases uptake by tumors, prolongs action, and may decrease some toxicity.

Therapeutic effects:

Death of rapidly replicating cells, particularly malignant ones.

Absorption: IV administration results in complete bioavailability.

Distribution: Widely distributed to tissues; does not cross the blood-brain barrier (↑concentrations delivered to Kaposi's sarcoma lesions due to liposomal carrier).

Metabolism/Excretion: Mostly metabolized by the liver with conversion to an active compound. Excreted mostly in bile, 50% as unchanged drug. <5% eliminated unchanged in the urine.

Half-Life: 55 hr.

(effect on blood counts)

ROUTE	ONSET	PEAK	DURATION
IV	10 days	14 days	21–24 days

Contraindicated in:

Hypersensitivity;
OB: Pregnancy;
Lactation: Lactation.

Use Cautiously in:

Pre-existing cardiac disease or ↑ cumulative doses of anthracyclines;
Depressed bone marrow reserve;
Hepatic impairment (dose ↓ required if serum bilirubin >1.2 mg/dL);
Rep: Women of reproductive potential;
Geri: Children, older adults, prior mediastinal radiation, concurrent cyclophosphamide ( risk of cardiotoxicity).

CV: CARDIOMYOPATHY

Derm: hand-foot syndrome (HFS), alopecia

GI: nausea, diarrhea, ↑alkaline phosphatase, moniliasis, ORAL MALIGNANCY, stomatitis, vomiting

Hemat: anemia, leukopenia, thrombocytopenia

Local: injection site reactions

Neuro: weakness

Misc: acute infusion-related reactions, ANAPHYLACTOID ALLERGIC REACTIONS, fever

Drug-drug:

↑bone marrow depression with other antineoplastics or radiation therapy.
Pediatric patients who have received concurrent doxorubicin and dactinomycin have ↑ risk of recall pneumonitis following local radiation therapy.
May ↑ skin reactions at previous radiation therapy sites.
If paclitaxel is administered first, clearance of doxorubicin is ↓ and incidence and severity of neutropenia and stomatitis are ↑ (problem is less if doxorubicin is administered first).
Hematologic toxicity is ↑ by concurrent use of cyclosporine; risk of coma and seizures is also ↑.
Incidence and severity of neutropenia and thrombocytopenia are ↑ by concurrent progesterone.
Phenobarbital may ↑ clearance and ↓ effects of doxorubicin.
Doxorubicin may ↓ metabolism and ↑ effects of phenytoin.
May ↑ risk of hemorrhagic cystitis from cyclophosphamide or hepatitis from mercaptopurine.
Cardiac toxicity may be ↑ by radiation therapy or cyclophosphamide.
May ↓ antibody response to live-virus vaccines and ↑ risk of adverse reactions.

AIDS-Related Kaposi's Sarcoma

IV (Adults ): 20 mg/m² every 3 wk until disease progression or unacceptable toxicity.

Ovarian Cancer

IV (Adults ): 50 mg/m² every 4 wk until disease progression or unacceptable toxicity.

Multiple Myeloma

IV (Adults ): 30 mg/m² on day 4 (after bortezomib) of each 21-day cycle for 8 cycles or until disease progression or unacceptable toxicity.

(Generic available)

Liposomal dispersion for injection: 2 mg/mL

Monitor BP, pulse, respiratory rate, and temperature frequently during administration. Report significant changes.
Monitor for acute infusion-related reactions consisting of flushing, shortness of breath, facial swelling, headache, chills, chest pain, back pain, chest or throat tightness, fever, tachycardia, pruritus, rash, cyanosis, syncope, bronchospasm, asthma, apnea, and hypotension. Reactions usually resolve over 1 day and are usually limited to first dose. Slowing infusion rate may minimize this reaction. Reaction is thought to be due to liposome.
Observe for signs and symptoms of anaphylaxis (rash, pruritus, laryngeal edema, wheezing). Discontinue doxorubicin liposomal and notify health care professional immediately if these problems occur. Keep epinephrine, an antihistamine, and resuscitation equipment close by in case of an anaphylactic reaction.
Monitor for bone marrow depression. Assess for bleeding (bleeding gums, bruising, petechiae, guaiac stools, urine, and emesis) and avoid IM injections and taking rectal temperatures if platelet count is low. Apply pressure to venipuncture sites for 10 min. Assess for signs of infection during neutropenia. Anemia may occur. Monitor for increased fatigue, dyspnea, and orthostatic hypotension.
Monitor intake and output ratios, and report occurrence of significant discrepancies. Encourage fluid intake of 2000–3000 mL/day. Allopurinol and alkalinization of the urine may be used to decrease serum uric acid levels and to help prevent urate stone formation.
Severe and protracted nausea and vomiting may occur as early as 1 hr after therapy and may last 24 hr. Administer parenteral antiemetics 30–45 min prior to therapy and routinely around the clock for the next 24 hr as indicated. Monitor amount of emesis and notify health care professional if emesis exceeds guidelines to prevent dehydration.
Assess left ventricular cardiac function (echocardiogram) prior to initiation of therapy, during treatment to detect acute changes, and after treatment to detect delayed cardiotoxicity. Monitor for development of signs of cardiac toxicity, which may be either acute and transient (ST segment depression, flattened T wave, sinus tachycardia, and extrasystoles) or late onset (usually occurs 1–6 mo after initiation of therapy) and characterized by intractable HF (peripheral edema, dyspnea, rales/crackles, weight gain); occurs more frequently in patients receiving a cumulative dose of ≥550 mg/m². Cardiotoxicity is more prevalent in children younger than 2 yr and geriatric patients. Dexrazoxane may be used to prevent cardiotoxicity in patients receiving cumulative doses of >300 m g/m².
Assess injection site frequently for redness, irritation, or inflammation. Doxorubicin liposomal is an irritant but may infiltrate painlessly even if blood returns on aspiration of infusion needle. Severe tissue damage may occur if doxorubicin liposomal extravasates. If extravasation occurs, stop infusion immediately, restart, and complete dose in another vein. If possible, withdraw 3–5 mL of blood to remove doxorubicin liposomal. Apply ice to site for 15 min 4 times daily for 3 days. Local infiltration of antidote is not recommended. Delineate the infiltrated area on patient's skin with a felt-tip marker. Elevate for 48 hr above heart level using a sling or stockinette dressing with an observation window cut in the dressing. Avoid pressure or friction. Do not rub the area. Observe for signs of increased erythema, pain, or skin necrosis. If increased symptoms occur, consult a plastic surgeon. After 48 hr, encourage patient to use extremity normally to promote full range of motion.
Assess oral mucosa frequently for development of stomatitis. Increased dosing interval and/or decreased dose is recommended if lesions are painful or interfere with nutrition. For Grade 1: Painless ulcers, erythema, or mild soreness, If no previous Grade 3 or 4 toxicity: no dose adjustment. If previous Grade 3 or 4 toxicity: delay up to 2 wk then ↓ dose by 25%. For Grade 2: Painful erythema, edema, or ulcers, but can eat, Delay dosing up to 2 wk or until resolved to Grade 0–1. Discontinue therapy if no resolution after 2 wk. If resolved to Grade 0–1 within 2 wk: if no previous Grade 3 or 4 stomatitis: resume therapy at previous dose. If previous Grade 3 or 4 toxicity: ↓ dose by 25%. For Grade 3: Painful erythema, edema, or ulcers, and cannot eat, Delay dosing up to 2 wk or until resolved to Grade 0–1. ↓ dose by 25% and return to original dose interval. If no resolution after 2 wk, discontinue therapy. For Grade 4: Requires parenteral or enteral support, Delay dosing up to 2 wk or until resolved to Grade 0–1. ↓ dose by 25% and return to original dose interval. If no resolution after 2 wk, discontinue therapy.
Continue to assess oral mucosa regularly during and for at least 6 yr for ulceration or any discomfort; may indicate secondary oral cancer.
Monitor for skin toxicity with prolonged use; HFS usually occurs after 6 wk of treatment and consists of swelling, pain, and erythema of the hands and feet. This may progress to desquamation but usually regresses after 2 wk. In severe cases, modification and delay of future doses of doxorubicin liposomal may be necessary. For Grade 1: Mild erythema, swelling, or desquamation not interfering with daily activities, if no previous Grade 3 or 4 HFS: no dose adjustment. If previous Grade 3 or 4 HFS: delay dose up to 2 wk, then ↓ dose by 25%. For Grade 2: Erythema, desquamation, or swelling interfering with, but not precluding normal physical activities; small blisters or ulcerations less than 2 cm in diameter, delay dosing up to 2 wk or until resolved to Grade 0–1. Discontinue therapy if no resolution after 2 wk. If resolved to Grade 0–1 within 2 wk: if no previous Grade 3 or 4 HFS: continue treatment at previous dose. If previous Grade 3 or 4 toxicity: ↓ dose by 25%. For Grade 3: Blistering, ulceration, or swelling interfering with walking or normal daily activities; cannot wear regular clothing, Delay dosing up to 2 wk or until resolved to Grade 0–1, then ↓ dose by 25%. Discontinue therapy if no resolution after 2 wk. For Grade 4: Diffuse or local process causing infectious complications, or a bedridden state or hospitalization, Delay dosing up to 2 wk or until resolved to Grade 0–1, then ↓ dose by 25%. Discontinue therapy if no resolution after 2 wk.

Lab Test Considerations:

Obtain negative pregnancy test before starting therapy.Monitor CBC and differential prior to and periodically during therapy. The WBC nadir occurs 10–14 days after administration, and recovery usually occurs by the 21st day. Thrombocytopenia and anemia may also occur. ↑ dosing interval and/or ↓ dose is recommended if ANC is <1000 cells/mm³ and/or platelet count is <50,000 cells/mm³. If ANC 1500–1900 cells/mm³ and platelets 75,000–150,000 cells/mm³ (Grade 1), resume treatment with no dose reduction. If ANC 1000–<1500 cells/mm³ and platelets 50,000–<75,000 cells/mm³ (Grade 2), wait until ANC >1500 and platelets >75,000; then redose with no dose reduction. If ANC 500–999 cells/mm³ and platelets 25,000–<50,000 cells/mm³ (Grade 3), wait until ANC >1500 and platelets >75,000; then redose with no dose reduction. If ANC <500 and platelets <25,000 cells/mm³ (Grade 4), wait until ANC >1500 and platelets >75,000, then redose at 25% dose reduction or continue full dose with prophylactic granulocyte growth factor.
- Recommended modifications of doxorubicin liposomal when administered with bortezomib.If fever ≥38°C and ANC <1,000/mm³, withhold dose for this cycle if before Day 4; ↓ dose by 25%, if after Day 4 of previous cycle. If on any day of drug administration after Day 1 of each cycle: Platelet count <25,000/mm³ or Hemoglobin <8 g/dL or ANC <500/mm³, withhold dose for this cycle if before Day 4; ↓ dose by 25%, if after Day 4 of previous cycle AND if bortezomib is reduced for hematologic toxicity. If Grade 3 or 4 nonhematologic drug related toxicity, do not dose until recovered to Grade <2, then ↓ dose by 25%.
- Monitor renal (BUN and serum creatinine) and hepatic (AST, ALT, LDH, and serum bilirubin) function prior to and periodically during therapy. Dose reduction is required for bilirubin >1.2 m g/dL or serum creatinine >3 m g/dL.
- May cause ↑ serum and urine uric acid concentrations.

Fatalities have occurred with incorrect administration of chemotherapeutic agents. Before administering, clarify all ambiguous orders; double-check single, daily, and course-of-therapy dose limits; have second practitioner independently double-check original order, calculations, and infusion pump settings.
Do not confuse doxorubicin liposomal with doxorubicin hydrochloride. Do not confuse Doxil with Paxil. Clarify orders that do not include both generic and brand names.
Prepare solution in a biologic cabinet. Wear gloves, gown, and mask while handling medication. Discard IV equipment in specially designated containers.
- Aluminum needles may be used to administer doxorubicin but should not be used during storage, because prolonged contact results in discoloration of solution and formation of a dark precipitate. Solution is red.
- Do not increase dose if reduction is made due to toxicity.

IV Administration:

Intermittent Infusion: Diluent: Dilute dose, up to 90 mg, in 250 mL and doses >90 mg in 500 mL of D5W. Do not dilute with other diluents or diluents containing a bacteriostatic agent. Solution is not clear, but a translucent red liposomal dispersion. Do not use in-line filters. Refrigerate diluted solutions and administer within 24 hr of dilution.
Rate: Initial rate of infusion should be 1 mg/min to minimize risk of infusion reactions. If no reactions occur, increase rate to complete administration within 1 hr. Do not administer as a bolus or undiluted solution. Rapid infusion may increase infusion-related reactions.

Instruct patient to notify health care professional promptly if fever; sore throat; signs of infection; bleeding gums; bruising; petechiae; blood in stools, urine, or emesis; increased fatigue; dyspnea; or orthostatic hypotension occurs. Caution patient to avoid crowds and persons with known infections. Instruct patient to use soft toothbrush and electric razor and to avoid falls. Caution patient not to drink alcoholic beverages or take medication containing aspirin or NSAIDs; may precipitate gastric bleeding.
Instruct patient to report pain at injection site immediately.
Instruct patient to inspect oral mucosa for erythema and ulceration. If ulceration occurs, advise patient to use sponge brush, rinse mouth with water after eating and drinking, and confer with health care professional if mouth pain interferes with eating. Pain may require treatment with opioid analgesics. The risk of developing stomatitis is greatest 5–10 days after a dose; the usual duration is 3–7 days.
Instruct patient to notify health care professional immediately if irregular heartbeat, shortness of breath, swelling of lower extremities, or skin irritation (swelling, pain, or redness of feet or hands) occurs.
Discuss the possibility of hair loss with patient. Explore methods of coping. Regrowth usually occurs 2–3 mo after discontinuation of therapy.
Instruct patient not to receive any vaccinations without advice of health care professional.
Inform patient that medication may cause urine to appear red for 1–2 days.
Instruct patient to notify health care professional if skin irritation occurs at site of previous radiation therapy.
Advise family and/or caregivers to take precautions (i.e., latex gloves) in handling body fluids for at least 5 days post-treatment.
Rep: May cause fetal harm. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during and for at least 6 mo after last dose of therapy. Inform patient before initiating therapy that this medication may cause irreversible gonadal suppression. In females, may cause infertility, amenorrhea, and premature menopause. In men, may result in oligospermia, azoospermia, and permanent loss of fertility. Some sperm counts have returned to normal several years after therapy ended. Advise female patient to avoid breastfeeding during therapy.
Emphasize the need for periodic lab tests to monitor for side effects.

Decrease in size or spread of malignancies.
Arrested progression of KS in patients with HIV infection.

Doxil

Caelyx

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