1. Name Of The Medicinal Product
Myocet 50 mg powder and pre-admixtures for concentrate for liposomal dispersion for infusion
2. Qualitative And Quantitative Composition
Liposome–encapsulated doxorubicin–citrate complex corresponding to 50 mg doxorubicin hydrochloride (HCl).
Excipient(s): The reconstituted medicinal product contains approximately 108 mg sodium for a 50 mg doxorubicin HCl dose.
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Powder and pre-admixtures for concentrate for liposomal dispersion for infusion
Myocet is supplied as a three-vial system:
Myocet doxorubicin HCl is a red lyophilised powder.
Myocet liposomes is a white to off-white, opaque and homogeneous dispersion.
Myocet buffer is a clear colourless solution.
4. Clinical Particulars
4.1 Therapeutic Indications
Myocet, in combination with cyclophosphamide, is indicated for the first line treatment of metastatic breast cancer in adult women.
4.2 Posology And Method Of Administration
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.
Posology
When Myocet is administered in combination with cyclophosphamide (600 mg/m2) the initial recommended dose of Myocet is 602 every three weeks.
Elderly patients
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.
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
Liver function tests
|
Dose
|
Bilirubin < ULN and normal AST
|
Standard dose of 60 - 75mg/m2
|
Bilirubin < ULN and raised AST
|
Consider a 25% dose reduction
|
Bilirubin> ULN but < 50 μmol/l
|
50% dose reduction
|
Bilirubin> 50 μmol/l
|
75% dose reduction
|
If possible, Myocet should be avoided in patients with bilirubin> 50 μmol/l as the recommendation is based mainly on extrapolations.
For dose reductions due to other toxicity, see section 4.4.
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.
Paediatric population
The safety and efficacy of Myocet in children aged up to 17 years has not been established. No data are available.
Method of administration
Myocet must be reconstituted and further diluted prior to administration (see section 6.6). A final concentration of between 0.4 mg/ml 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.
4.3 Contraindications
Hypersensitivity to the active substance, to the pre-admixtures or to any of the excipients.
4.4 Special Warnings And Precautions For Use
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.
Haematological Toxicity
|
|
|
|
Grade
|
Nadir ANC
(cells/μl)
|
Nadir Platelet Count
(cells/μl)
|
Modification
|
1
|
1500 – 1900
|
75,000 – 150,000
|
None
|
2
|
1000 – Less than 1500
|
50,000 – Less than 75,000
|
None
|
3
|
500 – 999
|
25,000 – Less than 50,000
|
Wait until ANC 1500 or more and/or platelets 100,000 or more then redose at 25% dose reduction
|
4
|
Less than 500
|
Less than 25,000
|
Wait until ANC 1500 and/or platelets 100,000 or more then redose at 50% dose reduction
|
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.
Mucositis
|
|
|
Grade
|
Symptoms
|
Modification
|
1
|
Painless ulcers, erythema, or mild soreness.
|
None
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2
|
Painful erythema, oedema or ulcers but can eat.
|
Wait one week and if the symptoms improve redose at 100% dose
|
3
|
Painful erythema, oedema or ulcers and cannot eat
|
Wait one week and if symptoms improve redose at 25% dose reduction
|
4
|
Requires parenteral or enteral support
|
Wait one week and if symptoms improve redose at 50% dose reduction
|
For dose reduction of Myocet due to liver function impairment, see section 4.2.
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
For precautions regarding the use of Myocet with other medicinal products, see section 4.5.
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.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Specific medicinal product 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
4.6 Pregnancy And Lactation
Women of childbearing potential
Women of childbearing potential should use an effective contraceptive during treatment with Myocet and up to 6 months following discontinuation of therapy.
Pregnancy
Due to the known cytotoxic, mutagenic and embryotoxic properties of doxorubicin, Myocet should not be used during pregnancy unless clearly necessary.
Breastfeeding
Women receiving Myocet should not breastfeed.
4.7 Effects On Ability To Drive And Use Machines
Myocet has been reported to cause dizziness. Patients who suffer from this should avoid driving and operating machinery.
4.8 Undesirable Effects
During clinical trials, the most frequently reported adverse reactions were nausea/vomiting (73%), leucopoenia (70%), alopecia (66%), neutropenia (46%), asthenia/fatigue (46%), stomatitis/mucositis (42%), thrombocytopenia (31%) and anaemia (30%).
The following adverse reactions have been reported with Myocet during clinical studies and post marketing experience. Adverse reactions are listed below as MedDRA preferred term by system organ class and frequency (frequencies are defined as: very common
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All grades
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Grades
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Infections and infestations
|
|
|
Neutropenic fever
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Very common
|
Very common
|
Infections
|
Very common
|
Common
|
Herpes zoster
|
Uncommon
|
Uncommon
|
Sepsis
|
Uncommon
|
Uncommon
|
Injection site infection
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Uncommon
|
Not known
|
Blood and lymphatic system disorders
|
|
|
Neutropenia
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Very common
|
Very common
|
Thrombocytopenia
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Very common
|
Very common
|
Anaemia
|
Very common
|
Very common
|
Leucopenia
|
Very common
|
Very common
|
Lymphopenia
|
Common
|
Common
|
Pancytopenia
|
Common
|
Uncommon
|
Neutropenic sepsis
|
Uncommon
|
Uncommon
|
Purpura
|
Uncommon
|
Uncommon
|
Metabolism and nutrition disorders
|
|
|
Anorexia
|
Very common
|
Very common
|
Dehydration
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Common
|
Very common
|
Hypokalaemia
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Common
|
Uncommon
|
Hyperglycaemia
|
Uncommon
|
Uncommon
|
Psychiatric disorders
|
|
|
Agitation
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Uncommon
|
Not known
|
Nervous system disorders
|
|
|
Insomnia
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Common
|
Uncommon
|
Abnormal gait
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Uncommon
|
Uncommon
|
Dysphonia
|
Uncommon
|
Not known
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Somnolence
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Uncommon
|
Not known
|
Cardiac disorders
|
|
|
Arrhythmia
|
Common
|
Uncommon
|
Cardiomyopathy
|
Common
|
Common
|
Congestive cardiac failure
|
Common
|
Common
|
Pericardial effusion
|
Uncommon
|
Uncommon
|
Vascular disorders
|
|
|
Hot flushes
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Common
|
Uncommon
|
Hypotension
|
Uncommon
|
Uncommon
|
Respiratory, thoracic and mediastinal disorders
|
|
|
Chest pain
|
Common
|
Uncommon
|
Dyspnoea
|
Common
|
Uncommon
|
Epistaxis
|
Common
|
Uncommon
|
Haemoptysis
|
Uncommon
|
Not known
|
Pharyngitis
|
Uncommon
|
Not known
|
Pleural effusion
|
Uncommon
|
Uncommon
|
Pneumonitis
|
Uncommon
|
Uncommon
|
Gastrointestinal disorders
|
|
|
Nausea/vomiting
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Very common
|
Very common
|
Stomatitis/mucositis
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Very common
|
Common
|
Diarrhoea
|
Very common
|
Common
|
Constipation
|
Common
|
Uncommon
|
Oesophagitis
|
Common
|
Uncommon
|
Gastric ulcer
|
Uncommon
|
Uncommon
|
Hepato-biliary disorders
|
|
|
Increased hepatic transaminases
|
Common
|
Uncommon
|
Increased alkaline phosphatase
|
Uncommon
|
Uncommon
|
Jaundice
|
Uncommon
|
Uncommon
|
Increased serum bilirubin
|
Uncommon
|
Not known
|
Skin and subcutaneous tissue disorders
|
|
|
Alopecia
|
Very Common
|
Common
|
Rash
|
Common
|
Not known
|
Nail disorder
|
Common
|
Uncommon
|
Pruritus
|
Uncommon
|
Uncommon
|
Folliculitis
|
Uncommon
|
Uncommon
|
Dry skin
|
Uncommon
|
Not known
|
Musculoskeletal, connective tissue and bone disorders
|
|
|
Back pain
|
Common
|
Uncommon
|
Myalgia
|
Common
|
Uncommon
|
Muscle weakness
|
Uncommon
|
Uncommon
|
Renal and urinary disorders
|
|
|
Haemorrhagic cystitis
|
Uncommon
|
Uncommon
|
Oliguria
|
Uncommon
|
Uncommon
|
General disorders and administration site conditions
|
|
|
Asthenia/Fatigue
|
Very Common
|
Common
|
Fever
|
Very common
|
Common
|
Pain
|
Very Common
|
Common
|
Rigors
|
Very Common
|
Uncommon
|
Dizziness
|
Common
|
Uncommon
|
Headache
|
Common
|
Uncommon
|
Weight loss
|
Common
|
Uncommon
|
Injection site reaction
|
Uncommon
|
Uncommon
|
Malaise
|
Uncommon
|
Not known
|
4.9 Overdose
Acute overdose with Myocet will worsen toxic side effects. Treatment of acute overdose should focus on supportive care for expected toxicity and may include hospitalisation, antibiotics, platelet and granulocyte transfusions and symptomatic treatment of mucositis.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmaco-therapeutic group: Antineoplastic agents, anthracyclines and related substances, ATC code: L01DB01
The active substance in Myocet is doxorubicin HCl. Doxorubicin may exert its antitumour and toxic effects by a number of mechanisms including inhibition of topoisomerase II, intercalation with DNA and RNA polymerases, free radical formation and membrane binding. Liposomal-encapsulated compared with conventional doxorubicin was not found more active in doxorubicin resistant cell lines in vitro. In animals, liposome-encapsulated doxorubicin reduced the distribution to heart and gastrointestinal mucosa compared with conventional doxorubicin, while antitumoural efficacy in experimental tumours was maintained.
Myocet (60 mg/m2) + CPA (600 mg/m2) was compared with conventional doxorubicin + CPA (at the same doses) and Myocet (75 mg/m2) + CPA (600 mg/m2) was compared to epirubicin + CPA (at the same doses). In a third trial, Myocet (75 mg/m2) monotherapy was compared with conventional doxorubicin monotherapy (at the same dose). Findings regarding response rate and progression-free survival are provided in Table 3.
Table 3
Antitumour efficacy summary for combination and single-agent studies
|
Myocet/CPA
(60/600 mg/m2)
(n=142)
|
Dox 60/CPA
(60/600 mg/m2)
(n=155)
|
Myocet/CPA
(75/600 mg/m2)
(n=80)
|
Epi/CPA
(75/600 mg/m2)
(n=80)
|
Myocet
(75 mg/m2)
(n=108)
|
Dox
(75 mg/m2)
(n=116)
|
Tumour response rate
|
43%
|
43%
|
46%
|
39%
|
26%
|
26%
|
Relative Risk
(95% C.I.)
|
1.01
(0.78-1.31)
|
1.19
(0.83-1.72)
|
1.00
(0.64-1.56)
|
|
|
|
Median PFS (months)a
|
5.1
|
5.5
|
7.7
|
5.6
|
2.9
|
3.2
|
Risk Ratio
(95% C.I.)
|
1.03
(0.80-1.34)
|
1.52
(1.06-2.20)
|
0.87
(0.66-1.16)
|
|
|
|
Abbreviations: PFS, progression-free survival; Dox, doxorubicin; Epi, epirubicin; Relative Risk, comparator taken as reference; Risk Ratio, Myocet taken as reference
a Secondary endpoint
5.2 Pharmacokinetic Properties
The plasma pharmacokinetics for total doxorubicin in patients receiving Myocet shows a high degree of inter-patient variability. In general however, the plasma levels of total doxorubicin are substantially higher with Myocet than with conventional doxorubicin, while the data indicate that peak plasma levels of free (not liposome-encapsulated) doxorubicin are lower with Myocet than with conventional doxorubicin. Available pharmacokinetic data preclude conclusions regarding the relationship between plasma levels of total/free doxorubicin and its influence on the efficacy/safety of Myocet. The clearance of total doxorubicin was 5.1 ± 4.8 l/h and the volume of distribution at steady state (Vd) was 56.6 ± 61.5 l whereas after conventional doxorubicin, clearance and Vd were 46.7 ± 9.6 l/h and 1,451 ± 258 l, respectively. The major circulating metabolite of doxorubicin, doxorubicinol, is formed via aldo-keto-reductase. The peak levels of doxorubicinol occur in the plasma later with Myocet than with conventional doxorubicin.
The pharmacokinetics of Myocet have not been specifically studied in patients with renal insufficiency. Doxorubicin is known to be eliminated in large part by the liver. A dose reduction of Myocet has been shown to be appropriate in patients with impaired hepatic function (see section 4.2 for dosage recommendations).
Substances that inhibit P-glycoprotein (P-Gp) have been shown to alter the disposition of doxorubicin and doxorubicinol (see also section 4.5).
5.3 Preclinical Safety Data
Studies of genotoxicity, carcinogenicity and reproductive toxicity of Myocet have not been performed but doxorubicin is known to be both mutagenic and carcinogenic and may cause toxicity to reproduction.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Myocet doxorubicin HCl
• lactose
Myocet liposomes
• egg phosphatidylcholine
• cholesterol
• citric acid
• sodium hydroxide
• water for injections
Myocet buffer
• sodium carbonate
• water for injections
6.2 Incompatibilities
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
6.3 Shelf Life
18 months
Chemical and physical in-use stability after reconstitution has been demonstrated for up to 8 hours at 25°C, and for up to 5 days at 2°C – 8°C.
From a microbiological point of view, the medicinal product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be long
