Revised Jan 1, 2007
SYNONYM(S): PLD

COMMON TRADE NAME(S): CAELYX®, DOXIL®

CLASSIFICATION: anthracycline antineoplastic antibiotic¹, cytotoxic²

Special pediatric considerations are noted when applicable, otherwise adult provisions apply.

MECHANISM OF ACTION:

Liposomal anthracyclines were developed to decrease the risk of cardiotoxicity experienced with conventional doxorubicin while preserving the anti-tumour efficacy.³ Liposomal anthracyclines achieve lower cardiotoxicity by changing tissue distribution and by decreasing rate of drug release. Liposomes cannot escape from the vascular space in areas that have narrow capillary junctions, such as the heart muscle, but they can reach tissues and organs that do not have narrow capillary junctions such as areas of tumour growth.³ Liposomal doxorubicin formulations include:

• liposomal doxorubicin
• pegylated liposomal doxorubicin

Pegylated liposomal doxorubicin (PLD) is a formulation of doxorubicin in polyethylene glycol (PEG) coated Stealth® liposomes.⁴ “Pegylation” is the process whereby the doxorubicin-containing liposomes are enclosed within a PEG layer.³ Pegylation protects the liposomes from detection by the mononuclear phagocyte system³ and provides a stabilization effect that reduces adhesion to cells, blood vessel walls and other surfaces.⁵ During circulation, at least 90% of PLD remains encapsulated within the liposomes, resulting in an extended half life compared to conventional doxorubicin^5,6 The active ingredient of the formulation is doxorubicin (see doxorubicin monograph).

PHARMACOKINETICS:

Adapted from standard reference⁸ unless specified otherwise.

USES:

*Health Canada approved indication

SPECIAL PRECAUTIONS:

Contraindicated in patients with the following conditions⁸:

• hypersensitivity to conventional formulation of doxorubicin
• hypersensitivity to any components of the PLD preparation

Cardiac toxicity has been seen with PLD at cumulative doses both above and below 550 mg/m², although at a significantly lower frequency than with conventional doxorubicin.⁸ One study comparing the use of PLD with conventional doxorubicin in patients with metastatic breast cancer found a frequency of 3.9% cardiotoxicity in patients treated with PLD compared to a frequency of 18.8% in patients treated with conventional doxorubicin.⁹ Cardiotoxicity was defined as a pre-specified reduction in resting left ventricular ejection fraction.⁹ In this study no patients receiving PLD developed symptomatic congestive heart failure (CHF), while 3.9% of the patients receiving conventional doxorubicin developed CHF.⁹

Retrospective and prospective trials have not identified a maximum “cardiac safe” cumulative dose of PLD above which CHF is expected to occur, despite doses exceeding 2,000 mg/m² in some patients.⁶ Caution should be observed in patients who have received other anthracyclines or anthracenediones and in patients who have a history of cardiovascular disease.⁸ Baseline MUGA scans should be performed on all patients treated with PLD.¹⁰ Repeat MUGA scans should be performed after cumulative dose reaches 400 mg/m², and again at every 100-120 mg/m² cumulative dose increase. In patients who have received prior anthracycline treatment or have other pre-disposing risk factors, MUGA scans should be performed more frequently.

Carcinogenicity: Carcinogenic potential of PLD has not been determined; however, conventional doxorubicin is carcinogenic in animals and is potentially carcinogenic in humans.⁶

Mutagenicity: Conventional doxorubicin is mutagenic and clastogenic (see doxorubicin monograph). The STEALTH® Liposome component of PLD tested negative for the Ames test and mammalian in vitro mutation test.⁸ The liposome component was found to be non-clastogenic in mammalian in vitro and in vivo chromosome tests.⁸

Fertility: Although not specific to PLD, conventional doxorubicin may produce gonadal suppression, resulting in amenorrhea or azoospermia.⁶

Pregnancy: FDA Pregnancy Category D. Women of childbearing age should be advised to avoid pregnancy while they or their male partners are receiving PLD and for six months following discontinuation.⁸ Although there is positive evidence of human fetal risk, the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).

Breastfeeding is not recommended due to the potential secretion into breast milk.⁸

PLD formulations are not interchangeable with conventional doxorubicin or with other liposomal anthracyclines.¹¹ Care must be taken to avoid mistaking PLD for conventional doxorubicin or other liposomal anthracyclines, and PLD should be stored separately from conventional doxorubicin.¹⁰

SIDE EFFECTS:

The table includes adverse events that presented during drug treatment but may not necessarily have a causal relationship with the drug. Because clinical trials are conducted under very specific conditions, the adverse event rates observed may not reflect the rates observed in clinical practice. Adverse events are generally included if they were reported in more than 1% of patients in the product monograph or pivotal trials, and/or determined to be clinically important.¹²

Adapted from standard reference¹¹ unless specified otherwise.

Acute infusion reactions can be serious and sometimes life-threatening.⁸ These occur within minutes of starting the PLD infusion.⁸ The earliest and most common symptoms of this reaction are shortness of breath, light-headedness, perspiration, and hypotension.¹⁰ Other symptoms include facial edema, vasodilatation, urticaria, back pain, chest pain, chills, fever, tachycardia, nausea, pharyngitis, rash and pruritus.⁸ At the first sign of an acute infusion reaction, the infusion rate should be reduced or temporarily interrupted.¹⁰ Slowing the rate or interrupting the infusion will usually resolve the symptoms,⁸ although antihistamines, IV H₂-blockers,¹⁰ or steroids are required for some patients.⁵ In most patients, treatment can be resumed after all symptoms have resolved. To minimize the risk of infusion reactions the initial dose should be administered at a rate no greater than 1 mg/minute.^5,8 Infusion reactions rarely recur after the first infusion and subsequent infusions may be administered over a 60 minute period.⁸ Unlike an IgE-mediated (type I) allergic reaction, this reaction occurs with first exposure to the drug without prior sensitization.¹⁴ The lipid component rather than the doxorubicin is likely responsible for these acute infusion reactions.^10,14

Palmar-Plantar Erythrodysesthesia (PPE), also called hand-foot skin reaction, is characterized by painful, macular reddening skin eruptions which include swelling, pain and sometimes desquamation of the skin on the hands and feet.⁸ PPE can affect other parts of the body, including axilla and groin area or wherever the skin surface is warm. PPE is generally seen after 2 or 3 cycles of treatment but can occur earlier.⁸ Patients usually experience slight numbness and tingling days or even weeks before erythema.¹⁰ In most patients the reaction is mild and will resolve in one to two weeks with or without treatment using corticosteroids.⁸ Some patients will require a dose reduction to manage PPE, while patients with severe and debilitating PPE require discontinuation of therapy.⁸ At every visit patients should be asked whether they experienced numbness or tingling anywhere on their bodies since the last dose.^5,10 If numbness or tingling has occurred the dosing interval should be prolonged.^5,10 Pyridoxine at a dose of 50-150 mg per day has been used for the prophylaxis and treatment of PPE without interfering with the anti-tumour efficacy of PLD.^5,8 Corticosteroids may also reduce the incidence of PPE during PLD treatment.⁵ Early measures to prevent or minimize PPE include avoiding all of the following for 3 days after PLD therapy¹⁰:

• Tape on skin
• Tight clothing (especially around waist, groin, wrists and fingers)
• Tight jewelry¹⁵
• Pressure or friction on skin
• Hot water (including showers or dishwashing), beginning 24 hours before treatment
• Sun exposure, sun block recommended¹⁵
• Vigorous activities such as aerobics, heavy cleaning and gardening
• Leaning on bony prominences such as elbows

See dosing guidelines for suggested dose modifications related to PPE.

Stomatitis can occur at any dose of PLD, but higher doses are associated with increased risk of stomatitis.¹⁰ Other risk factors include: prior alcohol and tobacco use, nutritional status, poor dental hygiene and concomitant use of drugs such as antihistamines, anticholinergics, phenytoin and steroids.¹⁰ See dosing guidelines for suggested dose modifications related to stomatitis.

INTERACTIONS⁸:

No drug interaction studies have been conducted with PLD. PLD may interact with drugs known to interact with conventional doxorubicin; e.g., digoxin and cyclosporine. See doxorubicin monograph for more details. In patients who received cyclophosphamide or taxanes, no new toxicities were noted.

SUPPLY AND STORAGE:

Injection⁸: Supplied as a preservative-free, sterile, translucent, red liposomal dispersion of 10 and 25 mL single-use vials. The doxorubicin is encapsulated in STEALTH® liposomes in a pegylated liposomal formulation at a concentration of 2 mg/mL in water for injection and a pH of 6-7. Unopened vials should be stored at 2-8ºC. Avoid freezing. Discard unused portion after puncture.⁸

SOLUTION PREPARATION AND COMPATIBILITY:

For basic information on the current brand used at the BC Cancer Agency, see Chemotherapy Preparation and Stability Chart in Appendix.

Diluted solution for infusion⁸: For doses less than 90 mg, dilute in preservative-free 250 mL D5W (only), for doses > 90 mg dilute in preservative-free 500 mL D5W (only). Do not use with diluent other than Dextrose Injection as stated by the manufacturer. Diluted solutions should be used immediately or refrigerated at 2-8ºC and administered within 24 hours. Do not use in-line filters.

Compatibility¹⁶: The following are compatible via Y-site injection: acyclovir, allopurinol, aminophylline, ampicillin, aztreonam, bleomycin, butorphanol, calcium, carboplatin, cefazolin, cefepime, cefoxitin, ceftizoxime, ceftriaxone, chlorpromazine, cimetidine, ciprofloxacin, cisplatin, clindamycin, cyclophosphamide, cytarabine, dacarbazine, dexamethasone, diphenhydramine, dobutamine, dopamine, droperidol, enalaprilat, etoposide, famotidine, fluconazole, fluorouracil, furosemide, ganciclovir, gentamicin, granisetron, haloperidol, heparin, hydrocortisone, hydromorphone, ifosfamide, leucovorin, leucovorin, lorazepam, magnesium, mesna, methotrexate, methylprednisolone, metronidazole, netilmicin, ondansetron, piperacillin, potassium chloride, prochlorperazine, ranitidine, ticarcillin, ticarcillin-clavulanate, tobramycin, trimethoprim-sulfamethoxazole, vancomycin, vinblastine, vincristine, vinorelbine, zidovudine.

Incompatibility¹⁶: The following are incompatible via Y-site injection: amphotericin B, amphotericin B complex, buprenorphine, cefoperazone, ceftazidime, docetaxel, hydroxyzine, mannitol, meperidine, metoclopramide, mitoxantrone, ofloxacin, paclitaxel, piperacillin, promethazine, sodium bicarbonate.

PARENTERAL ADMINISTRATION:

DOSAGE GUIDELINES:

Refer to protocol by which patient is being treated. Numerous dosing schedules exist and depend on disease, response and concomitant therapy. Guidelines for dosing also include consideration of absolute neutrophil count (ANC). Dosage may be reduced, delayed or discontinued in patients with bone marrow depression due to cytotoxic/radiation therapy or with other toxicities.

Adults:

Children:

PLD is being studied in children, but dosing guidelines have not yet been established.

References:

1. McEvoy GK, editor. AHFS 2005 Drug Information. Bethesda, Maryland: American Society of Health-System Pharmacists, Inc.; 2005. p. 972-82.

2. National Institute for Occupational Safety and Health (NIOSH). Preventing Occupational Exposures to Antineoplastic and Other Hazardous Drugs in Healthcare Settings. Cincinnati, OH; 25 March 2004.

3. Theodoulou M, Hudis C. Cardiac Profiles of Liposomal Anthracyclines. American Cancer Society 2004.

4. Gabizon AA. Pegylated liposomal doxorubicin: metamorphosis of an old drug into a new form of chemotherapy. Cancer Investigation 2001;19(4):424-36.

5. Alberts DS, Franco M, Carmichael J, et al. Efficacy and Safety of Liposomal Anthracycline in Phase I/II Clinical Trials. Seminars in Oncology 2004;32(Suppl 13):53-90:53-90.

6. USPDI. Volume 1. Drug Information for the Health Care Professional. 20th ed. Englewood, Colorado: Micromedex, INC.; 2000. p. 1355-66.

7. Doxorubicin Liposomal. MICROMEDEX: Healthcare series Vol. 123; 2000.

8. Schering Canada Inc. Pegylated Liposomal Doxorubicin. 2003.

9. O'Brien ME, Wigler N, Inbar M, et al. Reduced cardiotoxicity and comparable efficacy in a phase III trial of pegylated liposomal doxorubicin HCl (CAELYX/Doxil) versus conventional doxorubicin for first-line treatment of metastatic breast cancer. Annals of oncology 2004;15(3):440-9.

10. Wood LS. Liposomal anthracycline administration and toxicity management: a nursing perspective. Seminars in Oncology 2004;31(6 Suppl 13):182-90.

11. Liposomal Doxorubicin: Drug Information. In: Rose BD, editor. UpToDate. Wellesley, MA,: UpToDate; 2005.

12. Karen Gelmon. Personal communication. Medical Oncologist, BC Cancer Agency Vancouver Centre 2005.

13. B.C. Cancer Agency, Supportive Care Group. Guidelines for Prevention and Treatment of Chemotherapy-Induced Nausea and Vomiting in Adults (SCNAUSEA) Protocol Summary. Vancouver, British Columbia: BC Cancer Agency; 2005.

14. Chanan-Khan A, Szebeni J, Savay S, et al. Complement activation following first exposure to pegylated liposomal doxorubicin (Doxil): possible role in hypersensitivity reactions. Annals of Oncology 2003;14:1430-7.

15. Schering Canada Inc. Helpful Hints On How To Reduce The Risk And Manage Hand-Foot Syndrome. 2005.

16. Trissel L. Handbook on Injectable Drugs. 13th ed. Houston: American Society of Health-System Pharmacists; 2005. p. 535-42.

17. BC Cancer Agency Kaposi's Sarcoma Tumour Group. BCCA Protocol summary for Therapy of Kaposi's Sarcoma using Liposomal Doxorubicin (Caelyx). Vancouver: BC Cancer Agency; 2001.

18. Schering Canada Inc. CAELYX® Product Monograph. Pointe-Claire, Quebec; 2005.