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pegylated liposomal DOXOrubicin
pegylated liposomal DOXOrubicin
SYNONYM(S): Doxorubicin Hydrochloride Pegylated Liposomes
COMMON TRADE NAME(S): Caelyx®
“Pegylated liposomal doxorubicin (Caelyx®) is doxorubicin hydrochloride encapsulated in long-circulating liposomes, microscopic vesicles composed of a phospholipid bilayer that are capable of encapsulating active drugs. The Stealth® liposomes are formulated with surface-bound methoxypolyethylene glycol (MPEG), a process often referred to as pegylation, to protect liposomes from detection by the mononuclear phagocyte system and to increase blood circulation time. It is hypothesized that pegylated liposomal doxorubicin molecules are able to penetrate the vasculature of tumours. Incorporation of doxorubicin into a liposomal preparation substantially alters the pharmacokinetic properties of the drug compared with those of the non-liposomal doxorubicin.”
The pharmacokinetics of pegylated liposomal doxorubicin are non-linear. Pegylated liposomal doxorubicin distributes mainly in intravascular fluid.
| Volume of distribution | 1.93 L/m2 |
| Cross blood brain barrier? | yes |
| PPB | Approximately 70 % (doxorubicin) |
Liposomal doxorubicin undergoes metabolism mainly in the liver.
| Active metabolites | Doxorubicinol (major metabolite). |
| Inactive metabolites | Yes |
The elimination of doxorubicin is primarily via the biliary system. Very low or absent plasma concentrations of doxorubicin metabolites suggest that either doxorubicin is not released in great extent from the liposomes as they circulate, or the doxorubicinol elimination rate exceeds the release rate.
| Urine | 5% (in 72 hours) |
| Half-life | (apparent mean): 74 hours |
- Treatment of advanced ovarian carcinoma in women who have failed standard first-line therapy (platinum and paclitaxel based chemotherapy).
- Treatment of patients with AIDS-related Kaposi’s sarcoma with CD4 counts < 200/mm3 and extensive mucocutaneous or visceral disease, who have failed or are intolerant of prior systemic combination chemotherapy (with at least 2 of vinca alkaloid, bleomycin, and doxorubicin or another anthracycline).
- Monotherapy in metastatic breast cancer, for patients with an increased cardiac risk with conventional doxorubicin.
Emetogenic Potential:
Extravasation Potential: Irritant
The following adverse effects were reported mainly in single agent studies in breast cancer.
| ORGAN SITE | SIDE EFFECT* (%) | ONSET** | |||
|---|---|---|---|---|---|
| Cardiovascular | Arrhythmia (<1%) | E D | |||
| Arterial thromboembolism (<1%) | E D | ||||
| Cardiotoxicity (3-9%) | E | ||||
| Venous thromboembolism (<1%) | E D | ||||
| Dermatological | Alopecia (20%) | E | |||
| Hand-foot syndrome (48%) | E | ||||
| Nail disorder (<5%) | E | ||||
| Radiation recall reaction (rare) | E | ||||
| Rash (10%) (may be severe) | I | ||||
| Gastrointestinal | Abdominal pain (8%) | E | |||
| Anorexia (11%) | I | ||||
| Constipation (8%) | E | ||||
| Diarrhea (7%) | E | ||||
| Dyspepsia (<5%) | E | ||||
| Mucositis (23%) | E | ||||
| Nausea, vomiting (37%) | I | ||||
| Weight changes (≤5%) | E | ||||
| General | Fatigue (12%) | E | |||
| Pain (<5%) | E | ||||
| Hematological | Myelosuppression ± infection, bleeding (>10%) (may be severe) | E | |||
| Hepatobiliary | ↑ LFTs (2%) | E | |||
| Hypersensitivity | Infusion related reaction (11-13%) | I | |||
| Injection site | Phlebitis (rare) | E | |||
| Metabolic / Endocrine | Abnormal electrolyte(s) (≤5%) | E | |||
| Neoplastic | Secondary malignancy (rare) | D L | |||
| Nervous System | Dysgeusia (<5%) | I E | |||
| Respiratory | Cough (1-5%) | E | |||
* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare"
may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal
reports.
** I = immediate (onset in hours to days)
E = early (days to weeks)
D = delayed (weeks to months)
L = late (months to years)
The most common side effects reported were infusion reactions, hand-foot syndrome, nausea/vomiting, mucositis, alopecia and fatigue.
In general, acute hypersensitivity infusion reactions occur during the first infusion of pegylated liposomal doxorubicin, usually within the first few minutes after the start of the infusion. Symptoms include flushing, rash, shortness of breath, facial swelling, headache, chills, back pain, tightness in the chest and throat, and hypotension. These acute reactions do not appear to occur during subsequent cycles of chemotherapy in patients who did not react to the first cycle. Hold the infusion if a patient experiences signs or symptoms of an infusion reaction. These symptoms usually resolve without further therapy; however, some patients may require treatment with antihistamines and/or corticosteroids.
Left ventricular failure is less common than with doxorubicin but is reported and is more common in patients who have received high cumulative lifetime doses of doxorubicin (> 550mg/m2), other anthracyclines or anthracenediones, who have had doxorubicin doses > 400mg/m2 plus mediastinal radiation or have other cardiac risk factors. Congestive heart failure and/or myocardiopathy may occur suddenly or may happen several weeks after treatment completion.
A frequent dose-limiting adverse effect of pegylated liposomal doxorubicin is myelosuppression, predominantly leukopenia, with higher incidence and greater severity in patients with Kaposi’s sarcoma who are immuno-compromised at baseline. In patients with ovarian cancer, myelosuppression is generally mild to moderate, reversible and is not associated with neutropenic infection or sepsis. Growth factor support is infrequently required. Pegylated liposomal doxorubicin does not appear to offer any advantage over standard doxorubicin in terms of hematological adverse events.
Palmar-plantar erythrodysesthesia (PPE; hand-foot syndrome) is another common dose and schedule-related adverse effect associated with pegylated liposomal doxorubicin. The syndrome is characterized by painful, macular reddening skin eruptions, swelling, pain, and, for some patients, desquamation of the skin on the hands and feet. PPE is generally seen after 2 or 3 cycles of treatment but may occur earlier. Strategies to prevent and treat PPE, which may be initiated 4-7 days after treatment, include keeping hands and feet cool, avoiding excessive heat/hot water and keeping them unrestricted. Emollients and petroleum-based balms may also provide some relief.
Pegylated liposomal doxorubicin associated stomatitis is dose and schedule-dependent and occurs in up to 39% of patients. Mouth care with regular rinsing should be encouraged as prophylaxis. Mouth sores usually subside with dosage reduction and treatment delay (see Dosing), along with appropriate stomatitis treatment protocol.
Secondary oral cancers, including fatal cases were reported during treatment and up to 6 years following treatment completion. Patients should be monitored regularly for oral ulceration or discomfort.
Dose adjustment is required in patients with history of prior anthracyclines use, prior mediastinal irradiation, concurrent cyclophosphamide therapy, or pre-existing cardiovascular disease.
Ovarian or breast cancer:
- q4 weeks: 50mg/m2 IV
AIDS-Kaposi's Sarcoma:
- q2-3 weeks: 20mg/m2 IV
Dosage modifications for toxicity differ for ovarian cancer and Kaposi’s sarcoma. This is due to differences in the population group, immunity status, and dose of pegylated liposomal doxorubicin indicated for specific use.
Non-HIV Indications:
|
Worst Toxicity & Toxicity on day of planned dosing |
Action*: Week 4-5
|
Action*: Week 6
|
|
Grade 1 skin/stomatitis
|
If was ≥ grade 3, delay for 1-2 weeks; otherwise treat on time
|
If still grade 1, ↓ dose by 25%
|
|
Grade 2 skin/stomatitis
|
Delay for 1-2 weeks;
|
If still grade 1 or 2, ↓ dose by 25%
|
|
Grade 3 or 4 skin/stomatitis
|
Delay for 1-2 weeks;
|
Discontinue if still ≥ grade 3
Consider discontinuing if was grade 4
Otherwise ↓ dose by 25%
|
|
Grade 4 ANC, platelets, febrile neutropenia or thrombocytopenic bleeding |
↓ dose by 25%
|
|
| Worst Toxicity & Toxicity on day of planned dosing | Action*: Week 4-5 | Action*: Week 6 |
|
Significant cardiotoxicity
|
Discontinue
|
|
|
Grade 3 other
|
↓ dose by 25%
|
|
|
Grade 4 other
|
Discontinue
|
|
|
*Do not retreat until ANC > 1.5 x 109/L, platelets > 75-100 x 109/L and other toxicity ≤ grade 2 / or as indicated above |
||
HIV/AIDS indication:
|
Worst Toxicity & Toxicity on day of planned dosing |
Action*: Week 3
|
Action*: Week 4
|
|
Grade 1 skin
|
If was ≥grade 3, delay for 1 week; otherwise treat on time
|
If still grade 1, ↓ dose by 25%
|
|
Grade 1 stomatitis
|
Treat on time with no dose modification
|
Not applicable
|
|
Grade 2 skin
|
Delay for 1 week
|
If still grade 2, ↓ dose by 50%
If grade 1, ↓ dose by 25%
|
|
Grade 2 stomatitis
|
Delay for 1 week
|
If still grade 2, ↓ dose by 25%
|
|
Grade 3 skin
|
Delay for 1 week
|
If still grade 3, discontinue
If grade 2, then ↓ dose by 50%
If grade 1, ↓ dose by 25%
|
|
Grade 3 stomatitis
|
Delay for 1 week
|
If improved, ↓ dose by 25%
|
|
Grade 4 skin
|
Delay for 1 week
|
If still ≥ grade 3, discontinue
If ≤ grade 2, ↓ dose by 50%
|
|
Grade 4 stomatitis
|
Delay for 1 week
|
If still grade 4, discontinue
If improved, ↓ dose by 50%
|
|
Grade 3 myelosuppression
|
↓ dose by 25%
|
|
|
Grade 4 ANC, platelets, febrile neutropenia or thrombocytopenic bleeding |
↓ dose by 50%
|
|
| Worst Toxicity & Toxicity on day of planned dosing | Action*: Week 3 | Action*: Week 4 |
|
Significant cardiotoxicity
|
Discontinue
|
|
|
Grade 3 other
|
↓ dose by 25%
|
|
|
Grade 4 other
|
Discontinue or ↓ dose by 50%
|
|
|
*Do not retreat until ANC > 1 x 109/L, platelets > 50-100 x 109/L and other toxicity ≤ grade 2 / or as indicated above
|
||
Management of Infusion-related reactions with Anthracyclines:
| Grade | Management | Re-challenge |
| 1 or 2 |
|
|
| 3 or 4 |
|
|
|
Bilirubin (µmol/L) |
Ovarian, Breast cancer |
HIV/AIDS |
|
|
% of Standard Dose
|
|||
|
Cycle 1 (% normal dose) |
Cycle 2 onwards if cycle 1 tolerated with no changes in liver function tests (% normal dose) |
Each cycle (% normal dose) |
|
|
21-51 |
75% |
100% |
50% |
|
>51 |
50% |
75%* |
25% |
No modifications are necessary for mild to moderate renal impairment (creatinine clearance > 30 mL/min). No studies have been done in patients with severe renal impairment.
Limited information in patients ≥ 60 years. Use with caution.
Safety and efficacy not established.
Pegylated liposomal doxorubicin must not be given by the intramuscular or subcutaneous route.
- For dose < 90mg, dilute drug in 250mL D5W.
- For dose ≥ 90mg, dilute drug in 500mL D5W.
- Only use 5% Dextrose solution for further dilution. Use of other diluents or ones containing bacteriostatic agents (i.e. benzyl alcohol) may cause drug precipitation.
- Do not administer as a bolus injection or undiluted solution. The Caelyx® infusion line can be connected through the side port of a 5% Dextrose infusion for further diluent, or to minimize risk of thrombosis or extravasation.
- Do not use in-line filters. Do not admix Caelyx® with other drugs.
- To minimize the risk of infusion reactions, the initial dose is administered at a rate no greater than 1 mg/minute. If no infusion reaction is observed, subsequent infusions may be administered over 60-minutes (in ovarian or breast cancer) and 30 minutes (for Kaposi’s sarcoma patients).
- The following graduated rate was used for patients who experienced an infusion reaction in the breast clinical trial: 5% of the total dose infused IV over 15 minutes. If tolerated, double the infusion rate for the next 15 minutes. If tolerated, complete the infusion over the next hour for a total infusion time of 90 minutes.
- Avoid extravasation. It may occur with or without an accompanying stinging or burning sensation, and even if blood returns well on aspiration of the infusion needle. If any signs or symptoms of extravasation occur, the injection or infusion should be immediately terminated and restarted in another vein. Any known or suspected extravasation should be managed promptly.
Also refer to the CCO guideline for detailed description of Management of Cancer Medication-Related Infusion Reactions.
- Patients who have a history of hypersensitivity reactions to a conventional formulation of doxorubicin, other anthracyclines, anthracenediones, or components of the pegylated liposome
- Patients with Kaposi's Sarcoma and HIV who have had splenectomy (no experience)
- Use with caution in patients with a history of cardiovascular disease and/or prior anthracycline use
- care should be exercised in patients with diabetes as the infusate is dextrose water
- pegylated liposomal doxorubicin (Caelyx) is a unique formulation of doxorubicin and should never be used interchangeably with other formulations of doxorubicin
Other Drug Properties:
-
Carcinogenicity:
Probable
-
Embryotoxicity:
Yes
-
Teratogenicity:
Probable
Pegylated liposomal doxorubicin is not recommended for use in pregnancy. Adequate contraception should be used by both sexes during treatment, and for at least 6 months after the last dose. -
Breastfeeding:
Pegylated liposomal doxorubicin is contraindicated in breastfeeding.
| AGENT | EFFECT | MECHANISM | MANAGEMENT |
|---|---|---|---|
| barbiturates | ↓ efficacy of doxorubicin | ↑ clearance of doxorubicin | monitor |
| cyclophosphamide | exacerbation of hemorrhagic cystitis | uncertain | Caution |
| cyclophosphamide | ↑ cardiotoxicity | uncertain | monitor, adjust as needed |
| digoxin | ↓ digoxin levels | ↓ digoxin absorption | monitor digoxin levels and patient |
| mercaptopurine | ↑ hepatotoxicity | uncertain | monitor |
| quinolones | ↓ efficacy of quinolones | ↓ absorption of quinolones | monitor, may need to modify dose of quinolones |
| High dose progesterone | ↑ hematologic toxicity | unknown | caution |
| Calcium channel blockers | ↑ cardiotoxicity | additive | avoid |
| Sorafenib | possibly ↑ doxorubicin toxicity | ↑ doxorubicin exposure | caution |
| cyclosporine | ↑ hematologic toxicity | ↓ doxorubicin clearance or metabolism | caution |
| cytarabine | typhlitis | uncertain | caution; treat appropriately |
| Streptozocin | ↑ toxicity of doxorubicin | liver damage due to streptozocin decreasing metabolism of doxorubicin | caution |
| zidovudine | ↓ effect of zidovudine | doxorubicin decreases intracellular activation | avoid |
| stavudine | ↓ effect of stavudine | inhibits stavudine phosphorylation/metabolism | avoid |
| radiation | ↑ toxicity | radiation sensitizer | caution; consider dose modification, especially in patients with prior mediastinal radiation |
| Paclitaxel followed by doxorubicin | ↑ neutropenia and stomatitis | ↓ doxorubicin clearance | use paclitaxel after doxorubicin |
| Dactinomycin | ↑ radiation recall pneumonitis | additive effects | caution |
| phenytoin | ↓ phenytoin levels | ↑ phenytoin metabolism | caution, check levels |
| Trastuzumab | ↑ cardiotoxicity | additive | avoid anthracycline-based therapy for up to 24 weeks after stopping Trastuzumab |
| Vincristine | seizures | unknown | caution |
| Monitor Type | Monitor Frequency |
|---|---|
Cardiac function tests (Echo, RNA and/or MUGA scans) for all patients with cardiac risk factors. Regular cardiac function tests before each additional dose over the cumulative dose threshold of 450 mg/m2. (Cumulative dose lower for high risk patients) |
Baseline and as clinically indicated |
CBC |
Baseline and at each visit |
Liver function tests |
Baseline and at each visit |
Clinical toxicity assessment for stomatitis, rash, hand-foot syndrome, hypersensitivity, infection, bleeding and cardiac symptoms |
At each visit |
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
New Drug Funding Program (NDFP Website )
- Liposomal Doxorubicin - Platinum-Resistant Ovarian Fallopian Tube or Primary Peritoneal Cancer
- Liposomal DOXOrubicin - Single Agent Treatment of Platinum Sensitive Ovarian Fallopian Tube or Primary Peritoneal Cancer
- Liposomal Doxorubicin with Carboplatin - Platinum-Sensitive Recurrent Ovarian Fallopian Tube and Primary Peritoneal Cancer
- Liposomal Doxorubicin - HIV-positive Kaposi's Sarcoma
McEvoy GK, editor. AHFS Drug Information 2009. Bethesda: American Society of Health-System Pharmacists, p. 1046-55.
Doxorubicin drug monograph, Cancer Care Ontario, 2011.
Product Monograph: Caelyx® (pegylated liposomal doxorubicin). Janssen Inc., October 10, 2013.
December 2019 Updated NDFP form titles
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
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