MYOCET 50 MG

Israel - English - Ministry of Health

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Active ingredient:
DOXORUBICIN HYDROCHLORIDE
Available from:
MEDISON PHARMA LTD
ATC code:
L01DB01
Pharmaceutical form:
POWDER,DISPERSION AND SOLVENT FOR CONCENTRATE FOR DISPERSION FOR INFUSION
Composition:
DOXORUBICIN HYDROCHLORIDE 50 MG VIALS
Administration route:
I.V
Prescription type:
Required
Manufactured by:
GP-PHARM POLIGON INDUSTIRAL ELS VINYETS-ELS FOGARS, SPAIN
Therapeutic group:
DOXORUBICIN
Therapeutic area:
DOXORUBICIN
Therapeutic indications:
Myocet, in combination with cyclophosphamide, is indicated for the first line treatment of metastatic breast cancer in women.
Authorization number:
145 22 33081 00
Authorization date:
2016-01-31

– )תוחיטב עדימ ( הרמחה לע העדוה אפורל ןולע

:ךיראת

30.12.2013

:תילגנאב רישכת םש

Myocet

:םושיר רפסמ

145-22-33081-00

מ"עב המראפ ןוסידמ :םושירה לעב םש ןולעב םייונישה בוהצ עקר לע םינמוסמ אפורל ןולעב םי/שקובמה םי/יונישה לע םיטרפ ןולעב קרפ יחכונ טסקט שדח טסקט

4.8

Undesirable

effects

Skin and subcutaneous tissue

disorders

Alopecia

Very

Comm

Comm

Rash

Comm

known

Nail

disorder

Comm

Uncom

Pruritus

Uncom

Uncom

Folliculitis

Uncom

Uncom

Dry skin

Uncom

known

Skin and subcutaneous tissue

disorders

Alopecia

Very

Comm

Comm

Rash

Comm

known

Palmar-

plantar

erythrodysa

esthesia

syndrome

known

known

Nail

disorder

Comm

Uncom

Pruritus

Uncom

Uncom

Folliculitis

Uncom

Uncom

Dry skin

Uncom

known

ב"צמ

ובש ,ןולע

םינמוסמ

תורמחהה

תושקובמה

לע

עקר

בוהצ

.

םייוניש

םניאש

רדגב

תורמחהה

ונמוס

ןולעב

עבצב

הנוש

רבעוה

ראודב

ינורטקלא

ךיראתב

30.12.2013

PHYSICIAN PRESCRIBING INFORMATION

1.

NAME OF THE MEDICINAL PRODUCT

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

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Liposome–encapsulated doxorubicin–citrate complex corresponding to 50 mg doxorubicin

hydrochloride (HCl).

Excipient(s) with known effect: The reconstituted medicinal product contains approximately 108 mg

sodium for a 50 mg doxorubicin HCl dose.

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Powder, dispersion and solvent for concentrate for 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/m

) the initial

recommended dose of Myocet is 60-75 mg/m

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/m

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 or to any of the excipients listed in section 6.1.

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/

l or platelets less than 100,000/

l prior

to the next cycle. Careful haematological monitoring (including white blood cell and platelet count,

and haemoglobin) should be performed during therapy with Myocet.

A meta-analysis showed a statistically significant lower rate of grade 4 neutropenia (RR = 0.82,

p=0.005) in patients treated with Myocet versus conventional doxorubicin. However, no significant

differences were identified in the occurrence of anaemia, thrombocytopenia and episodes of

neutropenic fever.

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/

l)

Nadir Platelet Count

(cells/

l)

Modification

1500 – 1900

75,000 – 150,000

None

1000 – Less than 1500

50,000 – Less than 75,000

None

500 – 999

25,000 – Less than 50,000

Wait until ANC 1500 or

Haematological Toxicity

Grade

Nadir ANC

(cells/

l)

Nadir Platelet Count

(cells/

l)

Modification

more and/or platelets

100,000 or more then redose

at 25% dose reduction

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

Painless ulcers, erythema, or mild

soreness.

None

Painful erythema, oedema or ulcers but

can eat.

Wait one week and if the symptoms

improve redose at 100% dose

Painful erythema, oedema or ulcers and

cannot eat

Wait one week and if symptoms improve

redose at 25% dose reduction

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. A meta-analysis showed a statistically significant lower rate of both 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 versus conventional doxorubicin. The reduced risk of

cardiotoxicity has also been shown in a retrospective analysis in patients who had received prior

adjuvant doxorubicin (log-rank P=0.001, Hazard Ratio=5.42).

In a phase III study in combination with cyclophosphamide (CPA) comparing Myocet (60 mg/m

CPA (600 mg/m

) versus doxorubicin (60 mg/m

) + CPA (600 mg/m

), 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/m

) versus single-agent doxorubicin (75 mg/m

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/m

, compared to 480 mg/m

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/m

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.

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 versus

conventional doxorubicin.

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.

As for other anthracyclines and doxorubicin products, radiation recall may occur in previously

irradiated fields.

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

Interactions with other medicinal products and other forms of interactions

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-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.

4.6

Fertility, 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.

Breast-feeding

Women receiving Myocet should not breastfeed.

4.7

Effect 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 ≥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

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

All grades

Grades ≥ 3

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

Palmar-plantar

erythrodysaesthesia syndrome

Not known

Not known

Nail disorder

Common

Uncommon

Pruritus

Uncommon

Uncommon

Folliculitis

Uncommon

Uncommon

All grades

Grades ≥ 3

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/m

) + CPA (600 mg/m

) was compared with conventional doxorubicin + CPA (at the

same doses) and Myocet (75 mg/m

) + CPA (600 mg/m

) was compared to epirubicin + CPA (at the

same doses). In a third trial, Myocet (75 mg/m

) 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/m

(n=142)

Dox 60/CPA

(60/600

mg/m

(n=155)

Myocet/CPA

(75/600

mg/m

(n=80)

Epi/CPA

(75/600

mg/m

(n=80)

Myocet

(75 mg/m

(n=108)

(75 mg/m

(n=116)

Tumour response rate

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)

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

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 (V

) was

56.6 ± 61.5 l whereas after conventional doxorubicin, clearance and V

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

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 longer than 24 hours at 2

C – 8

C, unless reconstitution and dilution has taken

place in controlled and validated aseptic conditions.

6.4

Special precautions for storage

Store in a refrigerator (2ºC – 8ºC).

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

6.5

Nature and contents of container

Myocet is available in cartons containing 1 set or 2 sets of the three constituents. Not all pack-sizes

may be marketed.

Myocet 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.

Myocet 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.

Myocet buffer

Glass vials sealed with siliconised grey stopper and blue aluminium flip-off seals, containing not less

than 3 ml of buffer.

6.6

Special precautions for disposal and other handling

Preparation of Myocet

Aseptic technique must be strictly observed throughout handling of Myocet since no preservative is

present.

Caution should be exercised in the handling and preparation of Myocet. The use of gloves is required

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 the

temperature 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 levels

the temperature of the vial contents are in the same range (55°C-60°C)).

Remove the carton of Myocet constituents from the refrigerator.

Step 2. Reconstitute doxorubicin HCl

Withdraw 20 ml sodium chloride solution for injection (0.9%), preservative free (not provided in

the package), and inject into each Myocet 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 Myocet doxorubicin HCl vial in the Techne DB-3 Dri Block heater with the

thermometer in the block reading (75°C-76°C) for 10 minutes (not to exceed 15 minutes). If using

the water bath heat the Myocet doxorubicin HCl vial with the thermometer temperature reading

55°C-60°C for 10 minutes (not to exceed 15 minutes).

While heating proceed to step 4

Step 4. Adjust Ph of liposomes

Withdraw 1.9 ml of Myocet liposomes. Inject into Myocet buffer vial to adjust the Ph of

liposomes. Pressure build-up may require venting.

Shake well.

Step 5. Add Ph-adjusted liposomes to doxorubicin

Using syringe, withdraw the entire vial contents of Ph-adjusted liposomes from the Myocet buffer

vial.

Remove the reconstituted Myocet 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 heated

reconstituted Myocet 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 Myocet. Three

inserts, each with two 43.7mm openings per insert must be used. To ensure correct temperature

control the use of a 35mm immersion thermometer is recommended.

The resulting reconstituted preparation of Myocet contains 50 mg of doxorubicin HCl/25 ml of

liposomal dispersion (2 mg/ml).

After reconstitution the finished product must be further diluted in 0.9% (w/v) sodium chloride for

injection, or 5% (w/v) glucose solution for injection to a final volume of 40 ml to 120 ml per 50 mg

reconstituted Myocet so that a final concentration of 0.4 mg/ml to 1.2 mg/ml doxorubicin is obtained.

Once constituted, the liposomal dispersion for infusion containing liposome-encapsulated doxorubicin

should be a red orange opaque homogeneous dispersion. All parenteral solutions should be inspected

visually for particulate matter and discoloration prior to administration. Do not use the preparation if

foreign particulate matter is present.

Procedure for proper disposal

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

requirements.

7.

MANUFACTURER

GP-Pharm Poligon Industrial Els Vinyets-Els Fogars, Spain for Teva B.V., The Netherland.

8.

MARKETING AUTHORIZATION HOLDER

Medison Pharma Ltd.

POB 7090, Petach Tikva

Israel

רשואו קדבנ ונכותו תואירבה דרשמ י"ע עבקנ הז ןולע טמרופ

01.14

העדוה העדוה

לע לע

הרמחה הרמחה

(

(

עדימ עדימ

)תוחיטב )תוחיטב :ךיראת

07.2012

םש

רישכת

:תילגנאב

Myocet 50 mg

רפסמ

:םושיר

145-22-33081-00

םש

לעב

:םושירה

Medison

םייונישה

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םינמוסמ

לע

עקר

בוהצ ןולעב ןולעב

אפורל אפורל םיטרפ

לע

םייונישה

םישקובמה קרפ

ןולעב טסקט

יחכונ טסקט

שדח

Name of

medicinal

product

Myocet 50 mg powder and pre-

admixtures for concentrate for

liposomal dispersion for infusion

Myocet 50 mg powder

dispersion and solvent for

concentrate for dispersion for

infusion

2

.

Qualitative and

quantitative

composition

Liposome–encapsulated

doxorubicin–citrate complex

corresponding to 50 mg

doxorubicin hydrochloride (HCl).

For a full list of excipients, see

section 6.1.

Liposome–encapsulated

doxorubicin–citrate complex

corresponding to 50 mg

doxorubicin hydrochloride (HCl).

Excipient(s) with known effect: The

reconstituted medicinal product

contains approximately 108 mg

sodium for a 50 mg doxorubicin

HCl dose.

For the full list of excipients, see

section 6.1.

3

.

Pharmaceutical

form

Powder and pre-admixtures for

concentrate for liposomal

dispersion for infusion

Powder, dispersion and solvent for

concentrate for dispersion for

infusion

4.2

Posology and

method of

administration

Pediatric patients

The safety and efficacy of Myocet

has not been established in

peadiatric patients (below 18 years

of age)

Paediatric population

The safety and efficacy of Myocet

in children aged up to 17 years has

not been established. No data are

available.

Special warnings and 4.4

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/

l or

platelets less than 100,000/

l 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.

Myelosuppression

Therapy with Myocet causes

myelosuppression. Myocet should

not be administered to individuals

with absolute neutrophil counts

(ANC) lower than 1,500 cells/

l or

platelets less than 100,000/

l prior

to the next cycle. Careful

haematological monitoring

(including white blood cell and

platelet count, and haemoglobin)

should be performed during therapy

with Myocet.

A meta-analysis showed a

statistically significant lower rate of

grade 4 neutropenia (RR = 0.82,

p=0.005) in patients treated with

Myocet versus conventional

doxorubicin. However, no

significant differences were

identified in the occurrence of

anaemia, thrombocytopenia and

episodes of neutropenic fever.

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.

Special warnings and 4.4

precautions for use

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.

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.

A meta-analysis showed a

statistically significant lower rate of

both 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 versus

conventional doxorubicin. The

reduced risk of cardiotoxicity has

also been shown in a retrospective

analysis in patients who had

received prior adjuvant doxorubicin

(log-rank P=0.001, Hazard

Ratio=5.42).

Special warnings and 4.4

precautions for use

Section does not exist

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 versus

conventional doxorubicin.

Special warnings and 4.4

precautions for use

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.

Other

For precautions regarding the use of

Myocet with other medicinal

products, see section 4.5.

As for other anthracyclines and

doxorubicin products, radiation

recall may occur in previously

irradiated fields.

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.

Undesirable effects 4.8

ףרוצמ

דומעב

אבה ףרוצמ

דומעב

אבה טסקט

יחכונ

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 Reactions1,2

Infections and Infestations

Infection

(All Grades)

(Grade ≥3

)

Neutropenic Fever3

ANC <500 & fever >38°C

ANC >500 & fever >38°C

Blood and Lymphatic

System

Disorders

Neutropenia

<2000/μl

<500/μl

<500/μl for ≥ 7 days

Thrombocytopenia

<100,000/μl

<20,000/μl

Anaemia

<11 g/dl

<8 g/dl

Gastrointestinal Disorders

Nausea/Vomiting

(All Grades)

(Grade ≥3)

Stomatitis/Mucositis

(All Grades)

(Grade ≥3)

Diarrhoea

(All Grades)

(Grade ≥3)

Skin and Subcutaneous

Tissue Disorders

Alopecia -

Pronounced

Skin Related Toxicities

(e.g. rash, dry skin)

(All Grades)

(Grade ≥3)

General Disorders and

Fatigue/Malaise/Asthenia

Administration Site

Conditions

(All Grades)

(Grade ≥3)

Injection Site Toxicity

(All Grades)

(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).

System Organ Class

Adverse Reactions

Blood and Lymphatic System Disorders

Pancytopenia

טסקט

שדח

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 ≥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

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

All grades

Grades ≥ 3

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

All grades

Grades ≥ 3

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

םיטרפ

לע

םייונישה

םישקובמה

ךשמה - קרפ

ןולעב טסקט

יחכונ טסקט

שדח

5.1

Pharmacodynamic

properties

Pharmaco-therapeutic group:

Cytotoxic agents, anthracyclines

and related substances, ATC code:

L01DB01

Pharmaco-therapeutic group:

Antineoplastic agents,

anthracyclines and related

substances, ATC code: L01DB01

List of excipients 6.1

Myocet liposomes

Egg phosphatidylcholine

cholesterol

citric acid

sodium hydroxide

water for injections

Myocet liposomes

egg phosphatidylcholine

cholesterol

citric acid

sodium hydroxide

water for injections

6.4

Special

precautions for

storage

Store in a refrigerator (2ºC – 8ºC).

Store in a refrigerator (2ºC – 8ºC).

For storage conditions after

reconstitution of the medicinal

product, see section 6.3.

6.5Nature and

contents of

container

Myocet is available in cartons

containing 2 sets of the three

constituents. Sodium chloride for

injection 0.9% needed to dissolve

doxorubicin HCl, is not provided in

the package.

Myocet is available in cartons

containing 1 set or 2 sets of the

three constituents.

Sodium chloride for injection 0.9%

needed to dissolve doxorubicin

HCl, is not provided in the package.

Not all pack sizes may be marketed.

6.6

Special

precautions for

disposal and other

handling

Preparation of Myocet

Step 2. Reconstitute doxorubicin

Withdraw 20 ml sodium

chloride solution for injection

(0.9%), preservative free, (not

provided in the package), and

inject into each Myocet

doxorubicin HCl, intended for

preparation.

Step 2. Reconstitute doxorubicin

Withdraw 20 ml sodium

chloride solution for injection

(0.9%) preservative free, (not

provided in the package), and

inject into each Myocet

doxorubicin HCl, intended for

preparation.

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