Drug Class Description

Generic Name

Drug Description

Presentation

Indications

Adult Dosage

The use of Myocet should be confined to units specialised in the administration of cytotoxic chemotherapy and should only be administered under the supervision of a physician experienced in the use of chemotherapy.

Dosage When Myocet is administered in combination with cyclophosphamide (600 mg/m²) the initial recommended dose of Myocet is 60-75 mg/m² every three weeks.

Administration Myocet must be reconstituted and further diluted prior to administration (see section 6.6). A final concentration of between 0.4 to 1.2 mg/ml doxorubicin HCl, is required. Myocet is administered by intravenous infusion over a period of 1 hour.

Myocet must not be administered by the intramuscular or subcutaneous route or as a bolus injection.

Paediatric patients The safety and efficacy of Myocet has not yet been established in paediatric patients (below 18 years of age).

Use in patients with impaired hepatic function As metabolism and excretion of doxorubicin occurs primarily by the hepatobiliary route, evaluation of hepatobiliary function should be performed before and during therapy with Myocet.

Based on limited data in patients with liver metastases, it is recommended that the initial dose of Myocet is reduced in accordance with the following table

If possible, Myocet should be avoided in patients with bilirubin > 50 μmol/l as the recommendation is based mainly on extrapolations.

Use in patients with impaired renal function Doxorubicin is metabolised largely by the liver and excreted in the bile. Therefore dose modification is not required for patients with renal function impairment.

Child Dosage

Elderly Dosage

Safety and efficacy of Myocet have been assessed in 61 patients with metastatic breast cancer, age 65 and over. Data from randomised controlled clinical trials show that the efficacy and cardiac safety of Myocet in this population was comparable to that observed in patients less than 65 years old.

Contra Indications

Hypersensitivity to the active substance, to the pre-admixtures or to any of the excipients.

Special Precautions

Myelosuppression Therapy with Myocet causes myelosuppression. Myocet should not be administered to individuals with absolute neutrophil counts (ANC) lower than 1,500 cells/μl or platelets less than 100,000/μl prior to the next cycle. Careful haematological monitoring (including white blood cell and platelet count, and haemoglobin) should be performed during therapy with Myocet.

Haematological as well as other toxicity may require dose reductions or delays. The following dosage modifications are recommended during therapy and should be performed in parallel for both Myocet and cyclophosphamide. Dosing subsequent to a dose reduction is left to the discretion of the physician in charge of the patient.

If myelotoxicity delays treatment to greater than 35 days after the first dose of the previous cycle, then consideration should be given to stopping treatment.

Cardiac toxicity Doxorubicin and other anthracyclines can cause cardiotoxicity. The risk of toxicity rises with increasing cumulative doses of those medicinal products and is higher in individuals with a history of cardiomyopathy, or mediastinal irradiation or pre-existing cardiac disease.

Analyses of cardiotoxicity in clinical trials have shown a statistically significant reduction in cardiac events in patients treated with Myocet compared to patients treated with conventional doxorubicin at the same dose in mg. The full clinical relevance of these findings is currently unclear.

In a phase III study in combination with cyclophosphamide (CPA) comparing Myocet (60 mg/m²) + CPA (600 mg/m²) versus doxorubicin (60 mg/m²) + CPA (600 mg/m²), 6% versus 21% of patients, respectively, developed a significant decrease in left ventricular ejection fraction (LVEF). In a phase III study comparing single-agent Myocet (75 mg/m²) versus single-agent doxorubicin (75 mg/m²), 12% versus 27% of patients, respectively developed a significant decrease in LVEF. The corresponding figures for congestive heart failure (CHF), which was less accurately assessed, were 0% for Myocet + CPA versus 3% for doxorubicin + CPA, and 2% for Myocet versus 8% for doxorubicin. The median lifetime cumulative dose of Myocet in combination with CPA to a cardiac event was > 1260 mg/m², compared to 480 mg/m² for doxorubicin combination with CPA.

There is no experience with Myocet in patients with a history of cardiovascular disease, e.g. myocardial infarction within 6 months prior to treatment. Thus, caution should be exercised in patients with impaired cardiac function. The cardiac function of the patients treated concomitantly with Myocet and trastuzumab must be appropriately monitored as described below.

The total dose of Myocet should also take into account any previous, or concomitant, therapy with other cardiotoxic compounds, including anthracyclines and anthraquinones.

Before initiation of Myocet therapy a measurement of left ventricular ejection fraction (LVEF) is routinely recommended, either by Multiple Gated Arteriography (MUGA) or by echocardiography. These methods should also be applied routinely during Myocet treatment. The evaluation of left ventricular function is considered mandatory before each additional administration of Myocet once a patient exceeds a lifetime cumulative anthracycline dose of 550 mg/m² or whenever cardiomyopathy is suspected. If LVEF has decreased substantially from baseline e.g. by > 20 points to a final value > 50% or by > 10 points to a final value of < 50%, the benefit of continued therapy must be carefully evaluated against the risk of producing irreversible cardiac damage. However, the most definitive test for anthracycline myocardial injury, i.e., endomyocardial biopsy, should be considered.

All patients receiving Myocet should also routinely undergo ECG monitoring. Transient ECG changes such as T-wave flattening, S-T segment depression and benign arrhythmias are not considered mandatory indications for the cessation of Myocet therapy. However, reduction of the QRS complex is considered more indicative of cardiac toxicity.

Congestive heart failure due to cardiomyopathy may occur suddenly, and may also be encountered after discontinuation of therapy.

Injection site reactions Myocet should be considered an irritant and precautions should be taken to avoid extravasation. If extravasation occurs, the infusion should be immediately terminated. Ice may be applied to the affected area for approximately 30 minutes. Subsequently, the Myocet infusion should be restarted in a different vein than that in which the extravasation has occurred. Note that Myocet may be administered through a central or peripheral vein. In the clinical program, there were nine cases of accidental extravasation of Myocet, none of which were associated with severe skin damage, ulceration or necrosis.

Infusion associated reactions

When infused rapidly acute reactions associated with liposomal infusions have been reported.

Reported symptoms have included flushing, dyspnoea, fever, facial swelling, headache, back pain, chills, tightness in the chest and throat, and/or hypotension. These acute phenomena may be avoided by using a 1-hour infusion time.

Other

Efficacy and safety of Myocet in the adjuvant treatment of breast cancer have not been determined.

The importance of apparent differences in tissue distribution between Myocet and conventional doxorubicin has not been elucidated with respect to long-term antitumour efficacy.

Interactions

Specific drug compatibility studies have not been performed with Myocet. Myocet is likely to interact with substances that are known to interact with conventional doxorubicin. Plasma levels of doxorubicin and its metabolite, doxorubicinol, may be increased when doxorubicin is administered with cyclosporin, verapamil, paclitaxel or other agents that inhibit P-glycoprotein (P-Gp).

Interactions with doxorubicin have also been reported for streptozocin, phenobarbital, phenytoin and warfarin. Studies of the effect of Myocet on other substances are also lacking. However, doxorubicin may potentiate the toxicity of other antineoplastic agents. Concomitant treatment with other substances reported to be cardiotoxic or with cardiologically active substances (e.g. calcium antagonists) may increase the risk for cardiotoxicity. Concomitant therapy with other liposomal or lipid-complexed substances or intravenous fat emulsions could change the pharmacokinetic profile of Myocet.

Adverse Reactions

Clinical Program

Adverse drug reactions (ADR) data obtained from 323 patients with metastatic breast cancer in three randomised phase III trials of Myocet as a single agent and in combination with Cyclophosphamide (CPA) have been provided in Table 1 as pooled data. Treatment cycles were every three weeks in each trial and G-CSF was used in 38-56% of the cycles.

Table 1: Adverse reactions from pooled study results of three randomised Phase III clinical trials of Myocet as a single agent and in combination with Cyclophosphamide (CPA). (n=323)

System Organ Class	Frequency (as percentage)	Adverse Reactions 1,2
Infections and Infestations		Infection
	40	All Grades)
	8	(Grade 3)
		Neutropenic Fever 3
	11	ANC < 500 & fever >38 ?C 3,4
	9	ANC > 500 & fever > 38 ?C 3,4
Blood and Lymphatic System Disorders		Neutropenia
	94	<2000/µl
	64	<500/µl
	6	<500/µl for 7 days
		Thrombocytopenia
	62	<100,000/µl
	7	<20,000/µl
		Anaemia
	89	<11 g/dl
	23	<8 g/dl
Gastrointestinal Disorders		Nausea/Vomiting
	85	(All Grades)
	15	(Grade 3)
		Stomatitis/Mucositis
	44	(All Grades)
	6	(Grade 3)
		Diarrhoea
	26	(All Grades)
	2	(Grade 3)
Skin and Subcutaneous Tissue Disorders	86	Alopecia - Pronounced
		Skin Related Toxicities (e.g. rash, dry skin)
	11	(All Grades)
	0	(Grade 3)
General Disorders and Administration Site Conditions		Fatigue/Malaise/Asthenia
	49	(All Grades)
	7	(Grade 3)
		Injection Site Toxicity
	7	(All Grades)
	0	(Grade 3)

¹ Incidence of the adverse reaction considered at least possibly related by the investigator, from pooled clinical trials involving 323 patients taking the medicinal product.

² all adverse reactions have been ranked by frequency within each system organ class.

³ with IV antibiotics and/or hospitalisation

⁴ absolute neutrophil counts (ANC)

The following clinically relevant grade 3/4 adverse reactions with an incidence of < 5% were also observed from clinical trials involving 948 patients with solid tumours. AIDS patients with Kaposi's sarcoma were not included.

Incidence of less than 5% (Grade 3 or 4, possibly, probably, or definitely related):

Infections and Infestations: fever, Herpes Zoster, injection site infection, sepsis Blood and Lymphatic System Disorders: leukopenia, lymphopenia, neutropenic sepsis, purpura Metabolism and Nutrition Disorders: anorexia, dehydration, hypokalaemia, hyperglycaemia Psychiatric Disorders: agitation Nervous System Disorders: abnormal gait, dysphonia, insomnia, somnolence Cardiac Disorders: arrhythmia, cardiomyopathy, congestive cardiac failure, pericardial effusion Vascular Disorders: hot flushes, hypotension Respiratory, Thoracic and Mediastinal Disorders: chest pain, dyspnoea, epistaxis, haemoptysis,

pharyngitis, pleural effusion, pneumonitis Gastrointestinal Disorders: constipation, gastric ulcer, oesophagitis Hepato-Biliary Disorders: increased hepatic transaminases, increased alkaline phosphatase,

increased serum bilirubin, jaundice Musculoskeletal, Connective Tissue and Bone Disorders: back pain, muscle weakness, myalgia Skin and Subcutaneous Tissue Disorders: folliculitis, nail disorder, pruritus, Renal and Urinary Disorders: haemorrhagic cystitis, oliguria General Disorders and Administration Site Conditions: dizziness, headache, injection site reaction,

pain, rigors, weight loss

Post-Marketing

Relevant adverse reactions obtained from post marketing surveillance have been tabulated in Table 2.

Table 2: Adverse reactions obtained from post-marketing surveillance (4.5 years data).

Manufacturer

Drug Availability

Updated