Sunday 23 September 2012

Myocet





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




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



















































































































































































































































 


All grades




Grades




Infections and infestations


  


Neutropenic fever




Very common




Very common




Infections




Very common




Common




Herpes zoster




Uncommon




Uncommon




Sepsis




Uncommon




Uncommon




Injection site infection




Uncommon




Not known




Blood and lymphatic system disorders


  


Neutropenia




Very common




Very common




Thrombocytopenia




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




Common




Very common




Hypokalaemia




Common




Uncommon




Hyperglycaemia




Uncommon




Uncommon




Psychiatric disorders


  


Agitation




Uncommon




Not known




Nervous system disorders


  


Insomnia




Common




Uncommon




Abnormal gait




Uncommon




Uncommon




Dysphonia




Uncommon




Not known




Somnolence




Uncommon




Not known




Cardiac disorders


  


Arrhythmia




Common




Uncommon




Cardiomyopathy




Common




Common




Congestive cardiac failure




Common




Common




Pericardial effusion




Uncommon




Uncommon




Vascular disorders


  


Hot flushes




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




Very common




Very common




Stomatitis/mucositis




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

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