Doxil


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doxorubicin hydrochloride, liposomal

Caelyx (CA) (UK), Doxil, Myocet (UK)

Pharmacologic class: Anthracycline

Therapeutic class: Antibiotic antineoplastic

Pregnancy risk category D

FDA Box Warning

• Drug may cause cardiotoxicity. Myocardial damage may lead to heart failure and may occur as total cumulative dose (which includes previous use of other anthracyclines or anthracenediones) approaches 550 mg/m2. Toxicity may occur at lower cumulative doses in patients who have had previous mediastinal irradiation or are receiving concurrent cyclophosphamides.

• Acute infusion-related reactions occur in up to 10% of patients. They usually resolve over several hours to 1 day after infusion ends; in some patients, they resolve with slower infusion rate. Serious and sometimes life-threatening allergic or anaphylactoid-like infusion reactions may occur. Keep emergency equipment and drugs to treat reaction available for immediate use.

• Drug may cause severe myelosuppression.

• Reduce dosage in hepatic impairment.

• Accidental substitution of liposomal form for doxorubicin hydrochloride may cause severe adverse effects. Don't substitute on mg-per-mg basis.

Action

Unclear. Thought to inhibit DNA and RNA synthesis by forming complex with DNA. Also exerts immunosuppressive activity. Liposomal encapsulation increases uptake by tumors, prolongs drug action, and may decrease toxicity. Cell-cycle-S-phase specific.

Availability

Liposomal dispersion for injection: 2 mg/ml in 10-ml vial, 2 mg/ml in 25-ml vials

Indications and dosages

AIDS-related Kaposi's sarcoma

Adults: 20 mg/m2 I.V. once q 3 weeks

Metastatic ovarian carcinoma

Adults: Initially, 50 mg/m2 I.V. at a rate of 1 mg/minute q 4 weeks for at least four courses. If no adverse reactions occur, increase infusion rate to complete the infusion over 1 hour.

Dosage adjustment

• Hepatic impairment

Contraindications

• Hypersensitivity to drug
• Malignant melanoma
• CNS metastases
• Bone marrow depression
• Cardiac disease
• Breastfeeding

Precautions

Use cautiously in:
• hepatic impairment, brain tumor, renal carcinoma, myelosuppression
• elderly patients
• females of childbearing age
• pregnant patients
• children.

Administration

• Follow facility policy for handling and preparing antineoplastics.
• Dilute dose (up to 90 mg) in 250 ml of dextrose 5% in water. Don't use any other diluent.

Don't dilute solution with bacteriostatic diluent. Don't mix with other drugs.
• Don't use in-line filter.
• Administer slowly by I.V. infusion at initial rate of 1 mg/minute. If no infusion reaction occurs, increase rate to complete infusion over 1 hour. Don't give as I.V. bolus.

Avoid rapid infusion, which may increase the risk of infusion-related reactions (back pain, chest tightness, flushing).

If extravasation occurs, stop infusion immediately, apply ice, and notify prescriber.
• Don't give I.M. or subcutaneously.
• Know that drug is a translucent red dispersion, not a clear solution.

Adverse reactions

CNS: drowsiness, dizziness, asthenia, fatigue, malaise, paresthesia, headache, depression, insomnia, anxiety, emotional lability

CV: chest pain, hypotension, tachycardia, peripheral edema, cardiomyopathy, heart failure, arrhythmias, pericardial effusion

GI: nausea, vomiting, diarrhea, constipation, abdominal pain, enlarged abdomen, dyspepsia, moniliasis, stomatitis, glossitis, oral candidiasis, esophagitis, dysphagia

GU: albuminuria, red urine

Hematologic: anemia, leukopenia, thrombocytopenia, neutropenia, bone marrow depression

Hepatic: jaundice

Metabolic: hypocalcemia, hyperglycemia

Musculoskeletal: myalgia, back pain, hand-foot syndrome

Respiratory: dyspnea, increased cough, pneumonia

Skin: rash, dry skin, pruritus, skin discoloration, alopecia, diaphoresis, exfoliative dermatitis, palmar-plantar erythrodysesthesia

Other: altered taste, fever, chills, infection, herpes zoster, injection site reactions, allergic reactions including anaphylaxis, acute infusion reaction

Interactions

Drug-drug.Antineoplastics: additive bone marrow depression

Cyclophosphamide: increased risk of hemorrhagic cystitis

Cyclosporine: profound and prolonged hematologic toxicity, increased risk of coma and seizures, increased cardiotoxicity

Dactinomycin (in children): increased risk of pneumonitis

Live-virus vaccines: decreased antibody response to vaccine, increased risk of adverse reactions

Mercaptopurine: hepatitis

Paclitaxel (if administered first): reduced doxorubicin clearance, increased incidence and severity of neutropenia and stomatitis

Phenobarbital: increased clearance and decreased effects of doxorubicin

Phenytoin: decreased phenytoin blood level

Progesterone: increased risk and severity of neutropenia and thrombocytopenia

Streptozocin: prolonged doxorubicin half-life

Verapamil: increased doxorubicin blood level

Drug-diagnostic tests.Alkaline phosphatase, bilirubin, glucose, prothrombin time, serum and urine uric acid: increased levels

Calcium, hemoglobin, neutrophils, platelets, white blood cells: decreased levels

Patient monitoring

Observe patient closely for anaphylaxis and bleeding problems.

Stay alert for acute life-threatening arrhythmias, which may occur during or within a few hours after administration.

Assess for cardiomyopathy and subsequent heart failure with chronic overdose (more common in children).

Monitor closely for acute infusion reaction.
• Assess for and report liver engorgement and yellowing of skin or eyes.
• Check CBC, coagulation tests, hepatic profile, and bilirubin, glucose, calcium and uric acid levels.
• Watch for nausea and vomiting. Give antiemetics, as needed and prescribed.
• Assess for constipation and give fluids and stool softeners, as needed and prescribed.

Patient teaching

Instruct patient to immediately report shortness of breath; tingling or burning, redness, flaking, bothersome swelling, small blisters, or small sores on palms of hands or soles of feet; rash, chest pain, or palpitations.
• Advise patient to avoid people with colds, flu, or other contagious illnesses.
• As appropriate, review all other significant and life-threatening adverse reactions and interactions, especially those related to the drugs and tests mentioned above.

DOXOrubicin, liposomal

(dox-oh-roo-bi-sin lye-poe-sohm-al) ,

Doxil

(trade name)

Classification

Therapeutic: antineoplastics
Pharmacologic: anthracyclines
Pregnancy Category: D

Indications

AIDS-related Kaposi’s sarcoma (KS) in patients who cannot tolerate or fail conventional therapy.Ovarian carcinoma.Multiple myeloma with bortezomib in patients who have not previously received bortezomib and have received at least one prior therapy.

Action

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.

Pharmacokinetics

Absorption: Administered IV only, resulting in complete bioavailability.
Distribution: Widely distributed; does not cross the blood-brain barrier; extensively bound to tissues (↑concentrations delivered to KS lesions due to liposomal carrier).
Metabolism and 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.

Time/action profile (effect on blood counts)

ROUTEONSETPEAKDURATION
IV10 days14 days21–24 days

Contraindications/Precautions

Contraindicated in: Hypersensitivity; Obstetric / Lactation: Pregnancy or lactation.
Use Cautiously in: Pre-existing cardiac disease or ↑ cumulative doses of anthracyclines;Depressed bone marrow reserve;Liver impairment (dose ↓ required if serum bilirubin >1.2 m g/dL); Geriatric / Pediatric: Children, geriatric patients, prior mediastinal radiation, concurrent cyclophosphamide (↑ risk of cardiotoxicity); Obstetric: Patients with child-bearing potential.

Adverse Reactions/Side Effects

Central nervous system

  • weakness

Cardiovascular

  • cardiomyopathy (life-threatening)

Gastrointestinal

  • nausea (most frequent)
  • diarrhea
  • ↑ alkaline phosphatase
  • moniliasis
  • oral malignancy (life-threatening)
  • stomatitis
  • vomiting

Dermatologic

  • alopecia
  • palmar-plantar erythrodysesthesia

Hematologic

  • anemia (most frequent)
  • leukopenia (most frequent)
  • thrombocytopenia (most frequent)

Local

  • injection site reactions

Miscellaneous

  • anaphylactoid allergic reactions (life-threatening)
  • acute infusion-related reactions (most frequent)
  • fever

Interactions

Drug-Drug interaction

↑ 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.Streptozocin may ↑ the half-life of doxorubicin (dose reduction of doxorubicin recommended).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.

Route/Dosage

Other regimens are used
Intravenous (Adults) AIDS-related KS—20 mg/m2 every 3 wk; Metastatic ovarian cancer—40–50 mg/m2 every 4 wk; Multiple myeloma—30 mg/m2on day 4 after following borezomib for up to 8 cycles.

Availability (generic available)

Liposomal dispersion for injection: 20 mg/10 mL, 50 mg/25 mL

Nursing implications

Nursing assessment

  • 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, which may be accompanied by 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 liposome 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.
  • 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. Chest x ray, echocardiography, ECGs, and radionuclide angiography may be ordered prior to and periodically during therapy. 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 mg/m2.
  • Assess injection site frequently for redness, irritation, or inflammation. Doxorubicin liposome is an irritant but may infiltrate painlessly even if blood returns on aspiration of infusion needle. Severe tissue damage may occur if doxorubicin liposome 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 liposome. 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.
  • 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; palmar-plantar erythrodysesthesia 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 liposome may be necessary.
  • Lab Test Considerations: 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/mm3and 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/mm3and 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 cytokine support.
    • Monitor renal (BUN and 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.

Potential Nursing Diagnoses

Risk for infection (Adverse Reactions)
Decreased cardiac output (Adverse Reactions)

Implementation

  • high alert: 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.
  • high alert: Do not confuse doxorubicin hydrochloride liposome (Doxil) with doxorubicin hydrochloride (Adriamycin, Rubex) or with daunorubicin hydrochloride (Cerubidine). Do not confuse Doxil with Paxil. Clarify orders that do not include 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.
  • Intravenous 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.
  • Y-Site Compatibility: acyclovir, alfentanil, allopurinol, amifostine, amikacin, aminophylline, amphotericin B lipid complex, amphotericin B liposomal, ampicillin, ampicillin/sulbactam, anidulafungin, argatroban, atracurium, azithromycin, aztreonam, bivalirudin, bleomycin, bumetanide, butorphanol, calcium gluconate, carboplatin, caspofungin, cefazolin, cefepime, cefotaxime, cefotetan, cefoxitin, ceftriaxone, cefuroxime, chloramphenicol, chlorpromazine, ciprofloxacin, cisatracurium, cisplatin, clindamycin, cyclophosphamide, cyclosporine, cytarabine, dacarbazine, daptomycin, dexamethasone sodium phosphate, dexmedetomidine, dexrazoxane, digoxin, diphenhydramine, dobutamine, dopamine, droperidol, enalaprilat, ephedrine, epinephrine, eptifibatide, ertapenem, erythromycin, esmolol, etoposide, etoposide phosphate, famotidine, fenoldopam, fentanyl, fluconazole, fluorouracil, foscarnet, furosemide, ganciclovir, gentamicin, glycopyrrolate, granisetron, haloperidol, heparin, hydrocortisone sodium succinate, hydromorphone, ifosfamide, imipenem/cilastatin, insulin, irinotecan, isoproterenol, ketorolac, labetalol, leucovorin, levofloxacin, lidocaine, linezolid, lorazepam, magnesium sulfate, meropenem, mesna, metaraminol, methotrexate, methyldopate, methylprednisolone sodium succinate, metoprolol, metronidazole, midazolam, milrinone, moxifloxacin, mycophenolate, nafcillin, nalbuphine, naloxone, nesiritide, nicardipine, nitroglycerin, nitroprusside, norepinephrine, octreotide, ondansetron, oxaliplatin, palonosetron, pamidronate, pancuronium, pantoprazole, pemetrexed, pentamidine, pentazocine, pentobarbital, phenobarbital, phentolamine, phenylephrine, potassium acetate, potassium chloride, potassium phosphates, procainamide, prochlorperazine, propranolol, quinupristin/dalfopristin, ranitidine, remifentanyl, rituximab, rocuronium, sodium acetate, sodium phosphates, succinylcholine, sufentanil, tacrolimus, thiopental, ticarcillin/clavulanate, tigecycline, tirofiban, tobramycin, topotecan, trastuzumab, trimethoprim/sulfamethoxazole, vancomycin, vasopressin, vecuronium, verapamil, vinblastine, vincristine, vinorelbine, voriconazole, zidovudine, zolendronic acid
  • Y-Site Incompatibility: amiodarone, amphotericin B cholesteryl, amphotericin B colloidal, buprenorphine, calcium chloride, cefoperazone, ceftazidime, dantrolene, diazepam, diltiazem, docetaxel, dolasetron, gemcitabine, hydralazine, hydroxyzine, mannitol, metoclopramide, mitoxantrone, morphine, paclitaxel, phenytoin, piperacillin/tazobactam, promethazine, sodium bicarbonate, theophylline

Patient/Family Teaching

  • 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.
  • Advise patient that this medication may have teratogenic effects. Contraception should be used during and for at least 4 mo after therapy is concluded. Inform patient before initiating therapy that this medication may cause irreversible gonadal suppression. Advise female patient to avoid breast feeding during therapy.
  • Emphasize the need for periodic lab tests to monitor for side effects.

Evaluation/Desired Outcomes

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

Doxil®

Oncology A liposome formulation of doxorubicin, used for KS, ovarian and other CAs. See AIDS, Doxorubicin, Kaposi sarcoma.
References in periodicals archive ?
In October 2015, Celsion announced results from a large, comprehensive, preclinical program of the Company's GEN-1 IL-12 immunotherapy in combination with Avastin and Doxil for the treatment of platinum resistant ovarian cancer.
Doxil and Caelyx are PEGylated liposomes encapsulating the drug doxorubicin.
The immune stimulating nature of GEN-1 in combination with Avastin and Doxil makes for an ideal therapy, bolstering the anti-cancer effect beyond what has been observed when used alone," said Nicholas Borys, M.
The Company also expects to commence a second ovarian cancer development program with initiation of a Phase I/II dose escalating trial evaluating GEN-1 in combination with Avastin and Doxil in platinum-resistant ovarian cancer patients later this year.
ICRF scientists were also involved in the research that led to the development of Doxil, a drug used in the treatment of breast and ovarian cancer, and Gleevec, a life-saving drug for treatment of chronic myelogenous leukemia.
Combined, CAELYX and DOXIL are marketed in more than 80 countries.
A Phase III pivotal study in ovarian cancer comparing the combination of YONDELIS plus DOXIL to DOXIL alone is ongoing to demonstrate that YONDELIS plus DOXIL is superior to DOXIL as a single agent, in second line in the treatment of patients with ovarian cancer.
Schnipper served as Senior Vice President and Medical Director at SEQUUS Pharmaceuticals, where he was responsible for clinical and regulatory functions and a member of the Executive Committee and was instrumental in leading the successful FDA approval of the leading nanoparticle-based oncology drug, Doxil (liposomal doxorubicin).
Since the maximum tolerated dose was not reached in this study, Celsion plans to expand its ovarian cancer development program to include two Phase 1 dose escalating trials evaluating GEN-1 in first line neoadjuvant ovarian cancer and in combination with Avastin and Doxil in platinum-resistant ovarian cancer.
x) DOXIL is marketed in the United States by Tibotec Therapeutics, a Division of Ortho Biotech Products, L.
The results of the interim analysis indicate that the investigational agent EC145 plus Doxil[R]1 doubled the median progression-free survival compared to Doxil alone, increasing from approximately 3 months to 6 months (hazard ratio of 0.