drug-monograph

liposomal DOXOrubicin

A - Drug Name

liposomal DOXOrubicin

SYNONYM(S): Doxorubicin Hydrochloride Liposomes

COMMON TRADE NAME(S): Myocet ® (Sopherion)

B - Mechanism of Action and Pharmacokinetics

Liposomal doxorubicin (Myocet®) is doxorubicin hydrochloride encapsulated in liposomes that are composed of egg phosphatidylcholine and cholesterol, but which are not pegylated. Liposomal encapsulation prolongs exposure to doxorubicin, although pegylation results in longer exposure than non-pegylated liposomal doxorubicin. Doxorubicin molecules encapsulated in liposomes can extravasate into tumours with abnormal vascular endothelium but may not penetrate normal tissues. Both prolonged exposure and differential tissue/tumour penetration may alter the therapeutic index and toxicity. Free doxorubicin damages DNA by intercalation of the anthracycline portion, metal ion chelation, or by generation of free radicals. Doxorubicin has also been shown to inhibit DNA topoisomerase II which is critical to DNA function. Cytotoxic activity is cell cycle phase non-specific.

Absorption

Bioavailability

oral : no

Distribution

Compared to conventional doxorubicin, plasma levels are higher, clearance is less (9 times) and volume of distribution is less (25 times).

Cross blood brain barrier?

not clear

PPB

Approximately 70% (doxorubicin)

Metabolism

Liposomal doxorubicin undergoes metabolism similar to that of doxorubicin. Doxorubicin is metabolized mainly in the liver but doxorubicinol appears later than with non-liposomal doxorubicin.

Active metabolites

Doxorubicinol (major metabolite).

Inactive metabolites

yes

Elimination

The elimination of doxorubicin is primarily via the biliary system.

Half-life

Total doxorubicin: 16.4 hours
Doxorubicinol: 50.7 hours

Urine

6.44% of doxorubicin (after 48 hours)

C - Indications and Status

Health Canada Approvals:

First-line treatment of metastatic breast cancer in combination with cyclophosphamide

D - Adverse Effects

Emetogenic Potential:

Low

Extravasation Potential: Irritant

The following side effects were observed in combination use with cyclophosphamide.

ORGAN SITE	SIDE EFFECT* (%)	ONSET**
Cardiovascular	Arrhythmia (<5%)	E
	Cardiotoxicity (5%)	E D L
	Chest pain (<5%)	E
	Pericardial effusion (<5%)	E
Dermatological	Alopecia (91%)	E
	Nail disorder (<5%)	E
	Radiation recall reaction (low grade: < 1%)	E
	Rash (11%) (cutaneous reaction)	I E
Gastrointestinal	Anorexia, weight loss (<5%)	E
	Constipation (<5%)	E
	Diarrhea (28%) (grade 3 or 4: 3%)	E
	GI ulcer (gastric; <5%)	E
	Mucositis (40%) (grade 3 or 4: 4%)	E
	Nausea, vomiting (80%) (grade 3 or 4: 13%)	I E
General	Fatigue (42%) (grade 3 or 4: 6%)	E
Hematological	Myelosuppression ± infection, bleeding (61%) (may be severe)	E
Hepatobiliary	↑ LFTs (<5%)	E
Hypersensitivity	Infusion related reaction (<10%, hot flushes, dyspnea, fever, headache, facial swelling, back pain, chills, hypotension)	I
Metabolic / Endocrine	Abnormal electrolyte(s) (<5%)	E
	Hyperglycemia (<5%)	E
Musculoskeletal	Musculoskeletal pain (<5%)	E
Nervous System	Agitation (<5%)	E
	Ataxia (<5%)	E
	Dizziness (<5%)	E
	Headache (<5%)	E
	Insomnia (<5%)	E
	Somnolence (<5%)	E
Respiratory	Dysphonia (<5%)	E
	Dyspnea (<5%)	E
	Pneumonitis (<5%)	E
Urinary	Hemorrhagic Cystitis (<5%, likely related to cyclophosphamide)	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.
Dose-limiting side effects are underlined.

** I = immediate (onset in hours to days) E = early (days to weeks)
D = delayed (weeks to months) L = late (months to years)

All common side effects (> 5%) are incidences associated with liposomal doxorubicin (75mg/m²) when given with cyclophosphamide. Toxicity is less frequent with lower doses.

Myelosuppression is the most common and dose-limiting side effect associated with liposomal doxorubicin. Hematologic toxicity may require dose reductions or delays. Therapy with colony-stimulating factors may also be considered. Prolonged and / or severe mucositis or gastrointestinal side effects also warrant dose reduction.

Left ventricular failure is less common than with conventional doxorubicin but is reported and is more common in patients who have received high cumulative lifetime doses of doxorubicin (> 750mg/m²), other anthracyclines or anthracenediones, or who have received mediastinal radiation or have other cardiac risk factors. Caution should be exercised when lifetime cumulative dose is reached. This lifetime cumulative dose could be comprised of both conventional doxorubicin and liposomal doxorubicin, or it could be exclusively liposomal doxorubicin.

Occasional infusion reactions have been reported with liposomal doxorubicin. This may be avoided by moderating or slowing the drug infusion rate. Premedication is usually not required. Hand-foot syndrome has not been commonly described.

E - Dosing

Refer to protocol by which patient is being treated.

Adults:

Intravenous: 60-75 mg/m² every 3 weeks
in combination with cyclophosphamide (600mg/m²)

Dosage with Toxicity:

Dosage in myelosuppression:

Growth factors OR dose modification should be instituted for grade 4 neutropenia ≥ 7 days duration or febrile neutropenia.

Dose Level Reduction:
Liposomal doxorubicin : 75mg/m² → 60 mg/m² → 50 mg/m² → 40 mg/m²
Cyclophosphamide : 600mg/m² → 500mg/m² → 400 mg/m²

(Continued on next page)

Counts and/or Worst Toxicity in the Previous Cycle		Counts and/or Worst Toxicity in the Previous Cycle		Counts and/or Worst Toxicity in the Previous Cycle	Modification for liposomal doxorubicin and cyclophosphamide
ANC < 0.5 ≥ 7 days or febrile neutropenia	And/or	Platelets < 25	And/or	Grade 4 hemoglobin	Hold, ↓ one dose level (or use growth factor support if isolated ↓ANC)
Grade 3 mucositis (lasting 3 or more days)	Or	Grade 4 mucositis	And/or	Grade 3 or 4 or persistent GI toxicity	Hold*, ↓ one dose level
Cardiotoxicity**					Discontinue
Other grade 3 related toxicity					Hold*, ↓ one dose level for related drug(s)
Other Grade 4 related toxicity					Discontinue

*Do not re-treat until ANC ≥ 1.2 x 10⁹/L, platelets ≥ 100 x 10⁹/L, hemoglobin and other toxicities ≤ Grade 2. **including any signs and symptoms of heart failure, greater than 10% decline in LVEF to below the lower limit of normal, a greater than 20% decline in LVEF from any level, or LVEF ≤ 45%.

Dosage with Hepatic Impairment:

Bilirubin	AST/ALT	% usual dose
Normal	↑	75%
1-2.5 x ULN	Any	50%
> 2.5 x ULN	Any	25% or OMIT

Dosage with Renal Impairment:

No adjustment required

Dosage in the elderly:

No dose adjustment required; use with caution.

Children:

Safety and efficacy not established.

F - Administration Guidelines

Follow manufacturer’s instructions for reconstitution.
Dilute liposomal doxorubicin (Myocet®) in NS or D5W to a concentration of ≥ 0.04 mg/mL (e.g. maximum 50 × dilution).
Liposomal doxorubicin (Myocet®) must be given IV through a peripheral or central line, piggyback into a running IV line of NS or D5W. Infuse over 1 hour.
Avoid extravasation. If extravasation occurs, the infusion should be immediately terminated and patient should be managed appropriately. If re-starting the drug, it should be given via a different vein.
Do not administer as a bolus injection or undiluted solution.
Do not mix with other drugs.

G - Special Precautions

Other:

Cardiotoxicity precautions for doxorubicin, anthracyclines or anthracenediones should be observed for liposomal doxorubicin even though the incidence appears lower. Extreme caution should be exercised if dosed above a lifetime cumulative (both conventional and liposomal) doxorubicin dose of 750mg/m². Patients with a history of cardiovascular disease should be administered liposomal doxorubicin only when the potential benefit of treatment outweighs the risk. It should not be given with other anthracyclines or anthracenediones.

Liposomal doxorubicin is contraindicated in patients who have a history of hypersensitivity reactions to a conventional formulation of doxorubicin, other anthracyclines or anthracenediones or components of the liposome, including egg and egg products.

Liposomal doxorubicin is embryotoxic, may be teratogenic, an abortifacient and should not be administered to pregnant women. Adequate contraception should be used by both sexes, during liposomal doxorubicin treatment and for at least 6 months after the last dose. It is not known whether this drug is excreted in human milk; discontinue nursing prior to using this drug.

H - Interactions

AGENT	EFFECT	MECHANISM	MANAGEMENT
Barbiturates	↓ efficacy of doxorubicin	↑ clearance of doxorubicin	Monitor if barbituates initiated or discontinued
Cyclophosphamide	Exacerbation of hemorrhagic cystitis	Unknown	Caution
Cyclophosphamide	↑ cardiotoxicity risk	Uncertain	Monitor; may need to modify doxorubicin dose
Digoxin	↓ digoxin levels, interaction may occur several days after treatment	↓ digoxin absorption	Caution; monitor digoxin levels and patient
Mercaptopurine	↑ hepatotoxicity	Uncertain	Monitor
Quinolones	↓ quinolone antimicrobial effects	↓ quinolone absorption	Caution; monitor, may need to modify quinolone dose
Cytarabine	Typhlitis	Uncertain	Caution, treat appropriately
Streptozocin	↑ doxorubicin toxicity	Liver damage by streptozocin, ↓ metabolism of doxorubicin	Caution
Zidovudine	↓ zidovudine effect	Doxorubicin ↓ intracellular activation	Avoid
Radiation	↑ toxicity	Radiation sensitizer	Monitor
Paclitaxel followed by doxorubicin	↑ neutropenia and stomatitis	↓ doxorubicin clearance	Use paclitaxel after doxorubicin
Dactinomycin	↑ radiation recall pneumonitis		Caution
Phenytoin	↓ phenytoin levels	Unknown	Caution; check levels
Cyclosporin	↑ hematologic toxicity	↓ doxorubicin clearance/metabolism	Caution
High dose progesterone	↑ hematologic toxicity	Unknown	Caution
Curcumin	May ↓ doxorubicin effect	Inhibits doxorubicin induced apoptosis	Avoid concomitant use
Vincristine	Seizure	Unknown	Caution
Liposomal or lipid complexed drugs; IV fat emulsions	Changes in effects of liposomal doxorubicin	May change pharmacokinetics profile of liposomal doxorubicin	Caution
Stavudine	↓ stavudine effect	Inhibits stavudine phosphorylation/metabolism	Avoid
Trastuzumab	↑ cardiotoxicity	Additive	Avoid anthracycline-based therapy for up to 24 weeks after stopping trastuzumab
Calcium channel blockers; other cardioactive agents	↑ cardiotoxicity	Additive effects, and may interact with p-glycoprotein	Avoid
Sorafenib	↑ doxorubicin toxicity	↑ doxorubicin exposure	Caution

I - Recommended Clinical Monitoring

Recommended Clinical Monitoring

Monitor Type	Monitor Frequency
Cardiac function tests for all patients with cardiac risk factors or patients at or above the lifetime cumulative doxorubicin dose of 300mg/m²	periodic
Cardiac function tests (Echo, RNA and/or MUGA scans) for all patients	Baseline
CBC	Baseline and regular
Liver function tests	Baseline and regular
Clinical assessment and grading of stomatitis and CHF	regular

Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version

Suggested Clinical Monitoring

Monitor Type	Monitor Frequency
Cardiac function tests after completion of therapy in patients with clinical cardiac symptoms	monthly for the first 3 months, q3 months thereafter until 12 months post-therapy.

J - Supplementary Public Funding

New Drug Funding Program (

NDFP Website

)

Liposomal Doxorubicin - HIV-positive Kaposi's Sarcoma

K - References

Batist G, Harris L, Azarnia N, et al. Improved anti-tumor response rate with decreased cardiotoxicity of non-pegylated liposomal doxorubicin compared with conventional doxorubicin in first-line treatment of metastatic breast cancer in patients who had received prior adjuvant doxorubicin: results of a retrospective analysis. Anticancer Drugs. 2006 Jun;17(5):587-95.

Doxorubicin drug monograph. Cancer Care Ontario Drug Formulary, October 2010.

Mross K, Niemann B, Massing U, et al. Pharmacokinetics of liposomal doxorubicin (TLC-D99; Myocet) in patients with solid tumors: an open-label, single-dose study. Cancer Chemother Pharmacol 2004; 54: 514–524.

Product monograph: Myocet® (liposomal doxorubicin). Sopherion Thereapeutics, Inc., June 7, 2006.

Swensona CE, Bolcsaka LE, Batist G et al. Pharmacokinetics of doxorubicin administered i.v. as Myocet (TLC D-99; liposome-encapsulated doxorubicin citrate) compared with conventional doxorubicin when given in combination with cyclophosphamide in patients with metastatic breast cancer. Anti-Cancer Drugs 2003; 14: 239–246.

^{_{June 2012: Entire document revision}}

L - Disclaimer

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Last Updated: July 27, 2026

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