MYOCET 50mg powder+mixture for concentrate for liposomal dispersion for infusion medication leaflet

Myocet liposomal 50 mg powder, dispersion and solvent for concentrate for dispersion for infusion.

Liposome-encapsulated doxorubicin-citrate complex corresponding to 50 mg doxorubicinhydrochloride (HCl).

Excipient(s) with known effect: The reconstituted medicinal product contains approximately 108 mgsodium for a 50 mg doxorubicin HCl dose.

For the full list of excipients, see section 6.1.

Powder, dispersion and solvent for concentrate for dispersion for infusion

Myocet liposomal is supplied as a three-vial system as follows:

Vial 1 - doxorubicin HCl is a red lyophilised powder.

Vial 2 - liposomes is a white to off-white, opaque and homogeneous dispersion.

Vial 3 - buffer is a clear colourless solution.

Myocet liposomal, in combination with cyclophosphamide, is indicated for the first line treatment ofmetastatic breast cancer in adult women.

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

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

Older people

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

As metabolism and excretion of doxorubicin occurs primarily by the hepatobiliary route, evaluation ofhepatobiliary function should be performed before and during therapy with Myocet liposomal.

Based on limited data in patients with liver metastases, it is recommended that the initial dose of

Myocet liposomal is reduced in accordance with the following table.

Liver function tests Dose

Bilirubin < ULN and normal AST Standard dose of 60 - 75mg/m2

Liver function tests Dose

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 liposomal should be avoided in patients with bilirubin > 50 μmol/l as therecommendation is based mainly on extrapolations.

For dose reductions due to other toxicity, see section 4.4.

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

The safety and efficacy of Myocet liposomal in children aged up to 17 years has not been established.

No data are available.

Myocet liposomal must be reconstituted and further diluted prior to administration. A finalconcentration of between 0.4 mg/ml to 1.2 mg/ml doxorubicin HCl, is required. Myocet liposomal isadministered by intravenous infusion over a period of 1 hour.

Myocet liposomal must not be administered by the intramuscular or subcutaneous route or as a bolusinjection.

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

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

Myocet liposomal.

A meta-analysis showed a statistically significant lower rate of grade 4 neutropenia (RR = 0.82,p=0.005) in patients treated with Myocet liposomal versus conventional doxorubicin. However, nosignificant differences were identified in the occurrence of anaemia, thrombocytopenia and episodesof neutropenic fever.

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

Haematological Toxicity

Grade Nadir ANC Nadir Platelet Count Modification(cells/µl) (cells/µl)1 1500 - 1900 75,000 - 150,000 None2 1000 - Less than 1500 50,000 - Less than 75,000 None

Haematological Toxicity

Grade Nadir ANC Nadir Platelet Count Modification(cells/µl) (cells/µl)3 500 - 999 25,000 - Less than 50,000 Wait until ANC 1500 ormore and/or platelets100,000 or more then redoseat 25% dose reduction4 Less than 500 Less than 25,000 Wait until ANC 1500 and/orplatelets 100,000 or morethen redose at 50% dosereduction

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

Mucositis

Grade Symptoms Modification1 Painless ulcers, erythema, or mild Nonesoreness.

2 Painful erythema, oedema or ulcers but Wait one week and if the symptomscan eat. improve redose at 100% dose3 Painful erythema, oedema or ulcers and Wait one week and if symptoms improvecannot eat redose at 25% dose reduction4 Requires parenteral or enteral support Wait one week and if symptoms improveredose at 50% dose reduction

For dose reduction of Myocet liposomal due to liver function impairment, see section 4.2.

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

Analyses of cardiotoxicity in clinical trials have shown a statistically significant reduction in cardiacevents in patients treated with Myocet liposomal compared to patients treated with conventionaldoxorubicin at the same dose in mg. A meta-analysis showed a statistically significant lower rate ofboth clinical heart failure (RR = 0.20, p=0.02) and clinical and subclinical heart failure combined (RR= 0.38, p<0.0001) in patients treated with Myocet liposomal versus conventional doxorubicin. Thereduced risk of cardiotoxicity has also been shown in a retrospective analysis in patients who hadreceived prior adjuvant doxorubicin (log-rank P=0.001, Hazard Ratio=5.42).

In a phase III study in combination with cyclophosphamide (CPA) comparing Myocet liposomal(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 liposomal (75 mg/m2) versus single-agentdoxorubicin (75 mg/m2), 12% versus 27% of patients, respectively developed a significant decrease in

LVEF. The corresponding figures for congestive heart failure, which was less accurately assessed,were 0% for Myocet liposomal + CPA versus 3% for doxorubicin + CPA, and 2% for Myocetliposomal versus 8% for doxorubicin. The median lifetime cumulative dose of Myocet liposomal incombination with CPA to a cardiac event was > 1260 mg/m2, compared to 480 mg/m2 for doxorubicincombination with CPA.

There is no experience with Myocet liposomal in patients with a history of cardiovascular disease, e.g.myocardial infarction within 6 months prior to treatment. Thus, caution should be exercised in patientswith impaired cardiac function. The cardiac function of the patients treated concomitantly with

Myocet liposomal and trastuzumab must be appropriately monitored as described below.

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

Before initiation of Myocet liposomal therapy a measurement of left ventricular ejection fraction(LVEF) is routinely recommended, either by Multiple Gated Arteriography (MUGA) or byechocardiography. These methods should also be applied routinely during Myocet liposomaltreatment. The evaluation of left ventricular function is considered mandatory before each additionaladministration of Myocet liposomal once a patient exceeds a lifetime cumulative anthracycline dose of550 mg/m2 or whenever cardiomyopathy is suspected. If LVEF has decreased substantially frombaseline e.g. by > 20 points to a final value > 50% or by > 10 points to a final value of < 50%, thebenefit of continued therapy must be carefully evaluated against the risk of producing irreversiblecardiac damage. However, the most definitive test for anthracycline myocardial injury, i.e.,endomyocardial biopsy, should be considered.

All patients receiving Myocet liposomal should also routinely undergo ECG monitoring. Transient

ECG changes such as T-wave flattening, S-T segment depression and benign arrhythmias are notconsidered mandatory indications for the cessation of Myocet liposomal therapy. However, reductionof the QRS complex is considered more indicative of cardiac toxicity.

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

Gastroinstestinal disorders

A meta-analysis showed a statistically significant lower rate of nausea/vomiting grade ≥ 3 (RR = 0.65,p=0.04) and diarrhoea grade ≥ 3(RR = 0.33, p=0.03) in patients treated with Myocet liposomal versusconventional doxorubicin.

Myocet liposomal should be considered an irritant and precautions should be taken to avoidextravasation. If extravasation occurs, the infusion should be immediately terminated. Ice may beapplied to the affected area for approximately 30 minutes. Subsequently, the Myocet liposomalinfusion should be restarted in a different vein than that in which the extravasation has occurred. Notethat Myocet liposomal may be administered through a central or peripheral vein. In the clinicalprogram, there were nine cases of accidental extravasation of Myocet liposomal, none of which wereassociated 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 avoidedby using a 1-hour infusion time.

For precautions regarding the use of Myocet liposomal with other medicinal products, see section 4.5.

As for other anthracyclines and doxorubicin products, radiation recall may occur in previouslyirradiated fields.

Efficacy and safety of Myocet liposomal in the adjuvant treatment of breast cancer have not beendetermined. The importance of apparent differences in tissue distribution between Myocet liposomaland conventional doxorubicin has not been elucidated with respect to long-term antitumour efficacy.

This medicinal product contains approximately 108 mg sodium per 50 mg doxorubicin HCL dose,equivalent to 5.4 % of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Specific medicinal product compatibility studies have not been performed with Myocet liposomal.

Myocet liposomal is likely to interact with substances that are known to interact with conventionaldoxorubicin. Plasma levels of doxorubicin and its metabolite, doxorubicinol, may be increased whendoxorubicin 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 liposomal on other substancesare also lacking. However, doxorubicin may potentiate the toxicity of other antineoplastic agents.

Concomitant treatment with other substances reported to be cardiotoxic or with cardiologically activesubstances (e.g. calcium antagonists) may increase the risk for cardiotoxicity. Concomitant therapywith other liposomal or lipid-complexed substances or intravenous fat emulsions could change thepharmacokinetic profile of Myocet liposomal.

Women of childbearing potential should use an effective contraceptive during treatment with Myocetliposomal and for 6.5 months following discontinuation of therapy.

Women desiring to have children following completion of therapy should be recommended to obtaingenetic counselling and advice on fertility preservation before treatment.

Due to the known cytotoxic, mutagenic and embryotoxic properties of doxorubicin, Myocet liposomalshould not be used during pregnancy unless clearly necessary.

Women receiving Myocet liposomal should not breastfeed.

Myocet liposomal has been reported to cause dizziness. Patients who suffer from this should avoiddriving and operating machinery.

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 liposomal during clinical studies andpost marketing experience. Adverse reactions are listed below as MedDRA preferred term by systemorgan class and frequency (frequencies are defined as: very common ≥1/10, common ≥1/100 to <1/10,uncommon ≥ 1/1,000 to <1/100, not known (cannot be estimated from the available data)).

All grades Grades ≥ 3

Neutropenic fever Very common Very common

Infections Very common Common

Herpes zoster Uncommon Uncommon

Sepsis Uncommon Uncommon

Injection site infection Uncommon Not known

Neutropenia Very common Very common

Thrombocytopenia Very common Very common

Anaemia Very common Very common

All grades Grades ≥ 3

Leucopenia Very common Very common

Lymphopenia Common Common

Pancytopenia Common Uncommon

Neutropenic sepsis Uncommon Uncommon

Purpura Uncommon Uncommon

Anorexia Very common Very common

Dehydration Common Very common

Hypokalaemia Common Uncommon

Hyperglycaemia Uncommon Uncommon

Agitation Uncommon Not known

Insomnia Common Uncommon

Abnormal gait Uncommon Uncommon

Dysphonia Uncommon Not known

Somnolence Uncommon Not known

Arrhythmia Common Uncommon

Cardiomyopathy Common Common

Congestive cardiac failure Common Common

Pericardial effusion Uncommon Uncommon

Hot flushes Common Uncommon

Hypotension Uncommon Uncommon

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

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

Increased hepatic transaminases Common Uncommon

Increased alkaline phosphatase Uncommon Uncommon

Jaundice Uncommon Uncommon

Increased serum bilirubin Uncommon Not known

All grades Grades ≥ 3

Alopecia Very Common Common

Rash Common Not known

Palmar-plantar Not known Not knownerythrodysaesthesia syndrome

Nail disorder Common Uncommon

Pruritus Uncommon Uncommon

Folliculitis Uncommon Uncommon

Dry skin Uncommon Not known

Back pain Common Uncommon

Myalgia Common Uncommon

Muscle weakness Uncommon Uncommon

Haemorrhagic cystitis Uncommon Uncommon

Oliguria Uncommon Uncommon

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

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Acute overdose with Myocet liposomal will worsen toxic side effects. Treatment of acute overdoseshould focus on supportive care for expected toxicity and may include hospitalisation, antibiotics,platelet and granulocyte transfusions and symptomatic treatment of mucositis.

Pharmacotherapeutic group: Antineoplastic agents, anthracyclines and related substances, ATC code:

L01DB01

The active substance in Myocet liposomal is doxorubicin HCl. Doxorubicin may exert its antitumourand toxic effects by a number of mechanisms including inhibition of topoisomerase II, intercalationwith DNA and RNA polymerases, free radical formation and membrane binding. Liposomal-encapsulated doxorubicin compared with conventional doxorubicin was not found more active indoxorubicin resistant cell lines in vitro. In animals, liposome-encapsulated doxorubicin reduced thedistribution to heart and gastrointestinal mucosa compared with conventional doxorubicin, whileantitumoural efficacy in experimental tumours was maintained.

Myocet liposomal (60 mg/m2) + CPA (600 mg/m2) was compared with conventional doxorubicin +

CPA (at the same doses) and Myocet liposomal (75 mg/m2) + CPA (600 mg/m2) was compared toepirubicin + CPA (at the same doses). In a third trial, Myocet liposomal (75 mg/m2) monotherapy wascompared with conventional doxorubicin monotherapy (at the same dose). Findings regardingresponse rate and progression-free survival are provided in Table 3.

Table 3

Antitumour efficacy summary for combination and single-agent studies

Myocet Dox 60/CPA Myocet Epi/CPA Myocet Doxliposomal/CP (60/600 liposomal/CP (75/600 liposomal (75 mg/m2)

A mg/m2) A mg/m2) (75 mg/m2) (n=116)(60/600 (n=155) (75/600 (n=80) (n=108)mg/m2) mg/m2)(n=142) (n=80)

Tumour response rate 43% 43% 46% 39% 26% 26%

Relative Risk 1.01 1.19 1.00(95% C.I.) (0.78-1.31) (0.83-1.72) (0.64-1.56)

Median PFS (months)a 5.1 5.5 7.7 5.6 2.9 3.2

Risk Ratio 1.03 1.52 0.87(95% C.I.) (0.80-1.34) (1.06-2.20) (0.66-1.16)

Abbreviations: PFS, progression-free survival; Dox, doxorubicin; Epi, epirubicin; Relative Risk,comparator taken as reference; Risk Ratio, Myocet liposomal taken as referencea Secondary endpoint

The plasma pharmacokinetics for total doxorubicin in patients receiving Myocet liposomal shows ahigh degree of inter-patient variability. In general however, the plasma levels of total doxorubicin aresubstantially higher with Myocet liposomal than with conventional doxorubicin, while the dataindicate that peak plasma levels of free (not liposome-encapsulated) doxorubicin are lower with

Myocet liposomal than with conventional doxorubicin. Available pharmacokinetic data precludeconclusions regarding the relationship between plasma levels of total/free doxorubicin and itsinfluence on the efficacy/safety of Myocet liposomal. The clearance of total doxorubicin was5.1 ± 4.8 l/h and the volume of distribution at steady state (Vd) was 56.6 ± 61.5 l whereas afterconventional doxorubicin, clearance and Vd were 46.7 ± 9.6 l/h and 1,451 ± 258 l, respectively. Themajor circulating metabolite of doxorubicin, doxorubicinol, is formed via aldo-keto-reductase. Thepeak levels of doxorubicinol occur in the plasma later with Myocet liposomal than with conventionaldoxorubicin.

The pharmacokinetics of Myocet liposomal have not been specifically studied in patients with renalinsufficiency. Doxorubicin is known to be eliminated in large part by the liver. A dose reduction of

Myocet liposomal has been shown to be appropriate in patients with impaired hepatic function (seesection 4.2 for dosage recommendations).

Substances that inhibit P-glycoprotein (P-Gp) have been shown to alter the disposition of doxorubicinand doxorubicinol (see also section 4.5).

Studies of genotoxicity, carcinogenicity and reproductive toxicity of Myocet liposomal have not beenperformed but doxorubicin is known to be both mutagenic and carcinogenic and may cause toxicity toreproduction.

Vial 1 - doxorubicin HCl

* lactose

Vial 2 - liposomes

* phosphatidylcholine

* cholesterol

* citric acid

* sodium hydroxide

* water for injections

Vial 3 - buffer

* sodium carbonate

* water for injections

This medicinal product must not be mixed with other medicinal products except those mentioned insection 6.6.

18 months

Chemical and physical in-use stability after reconstitution has been demonstrated for up to 8 hours at25°C, and for up to 5 days at 2°C - 8οC.

From a microbiological point of view, the medicinal product should be used immediately. If not usedimmediately, in-use storage times and conditions prior to use are the responsibility of the user andwould normally not be longer than 24 hours at 2οC - 8οC, unless reconstitution and dilution has takenplace in controlled and validated aseptic conditions.

Store in a refrigerator (2ºC - 8ºC).

For storage conditions after reconstitution of the medicinal product, see section 6.3.

Myocet liposomal is available in cartons containing 1 set or 2 sets of the three constituent vials. Not allpack-sizes may be marketed.

Vial 1 - doxorubicin HCl

Type I glass vials sealed with grey butyl rubber stoppers and orange flip-off aluminium seals,containing 50 mg of doxorubicin HCl lyophilised powder.

Vial 2 - liposomes

Type I flint glass tubing vials sealed with siliconised grey stopper and green flip-off aluminium seals,containing not less than 1.9 ml of liposomes.

Vial 3 - buffer

Glass vials sealed with siliconised grey stopper and blue aluminium flip-off seals, containing not lessthan 3 ml of buffer.

Preparation of Myocet liposomal

Aseptic technique must be strictly observed throughout handling of Myocet liposomal, since nopreservative is present.

Caution should be exercised in the handling and preparation of Myocet liposomal. The use of gloves isrequired

Step 1. Set up

Two alternative heating methods can be used : a Techne DB-3 Dri Block heater or a water bath:

* Turn on the Techne DB-3 Dri Block heater and set the controller to 75°C-76°C. Verify thetemperature set point by checking the thermometer(s) on each heat block insert.

* If using a water bath, turn on the water bath and allow it to equilibrate at 58°C (55°C-60°C).

Verify the temperature set point by checking the thermometer.

(Please note that whilst the control settings on the water bath and heat block are set to different levelsthe temperature of the vial contents are in the same range (55°C-60°C)).

Remove the carton of constituents from the refrigerator.

Step 2. Reconstitute doxorubicin HCl

* Withdraw 20 ml sodium chloride solution for injection (0.9%), (not provided in the package), andinject into each vial of doxorubicin HCl, intended for preparation.

* Shake well in the inverted position to ensure doxorubicin is fully dissolved.

Step 3. Heat in water bath or dry heat block

* Heat the reconstituted doxorubicin HCl vial in the Techne DB-3 Dri Block heater with thethermometer in the block reading (75°C-76°C) for 10 minutes (not to exceed 15 minutes). If usinga water bath, heat the doxorubicin HCl vial with the thermometer temperature reading 55°C-60°Cfor 10 minutes (not to exceed 15 minutes).

* While heating proceed to step 4

Step 4. Adjust pH of liposomes

* Withdraw 1.9 ml of liposomes. Inject into the buffer vial to adjust the pH of liposomes. Pressurebuild-up may require venting.

* Shake well.

Step 5. Add pH-adjusted liposomes to doxorubicin

* Using a syringe, withdraw the entire vial contents of pH-adjusted liposomes from the buffer vial.

* Remove the reconstituted doxorubicin HCl vial from the water bath or dry heat block. SHAKE

VIGOROUSLY. Carefully insert a pressure-venting device equipped with a hydrophobic filter.

Then IMMEDIATELY (within 2 minutes) inject pH-adjusted liposomes into vial of heatedreconstituted doxorubicin HCl. Remove venting device.

* SHAKE VIGOROUSLY.

* WAIT for a minimum of 10 MINUTES before using, keeping the medicine at room temperature.

* The Techne DB-3 Dri Block Heater is fully validated for use in the constitution of Myocetliposomal. Three inserts, each with two 43.7mm openings per insert must be used. To ensurecorrect temperature control the use of a 35mm immersion thermometer is recommended.

The resulting reconstituted preparation of Myocet liposomal contains 50 mg of doxorubicin HCl/25 mlof liposomal dispersion (2 mg/ml).

After reconstitution the finished product must be further diluted in 0.9% (w/v) sodium chloride forinjection, or 5% (w/v) glucose solution for injection to a final volume of 40 ml to 120 ml so that a finalconcentration of 0.4 mg/ml to 1.2 mg/ml doxorubicin is obtained.

Once constituted, the liposomal dispersion for infusion containing liposome-encapsulated doxorubicinshould be a red orange opaque homogeneous dispersion. All parenteral solutions should be inspectedvisually for particulate matter and discoloration prior to administration. Do not use the preparation ifforeign particulate matter is present.

Procedure for proper disposal

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

CHEPLAPHARM Arzneimittel GmbH

Ziegelhof 2417489 Greifswald

Germany

EU/1/00/141/001-002

Date of first authorisation: 13 July 2000

Date of latest renewal: 02 July 2010

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.