ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
Myocet 50 mg powder and pre-admixtures for concentrate for liposomal dispersion for infusion
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.
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.
Myocet, in combination with cyclophosphamide, is indicated for the first line treatment of metastatic
breast cancer in adult women.
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
2
) the initial
recommended dose of Myocet is 60-75 mg/m
2
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
2
Bilirubin < ULN and raised AST
Consider a 25% dose reduction
2
Liver function tests
Dose
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.
Hypersensitivity to the active substance, to the pre-admixtures or to any of the excipients.
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/
μ
l)
Nadir Platelet Count
(cells/
μ
l)
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
3
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/m
2
) +
CPA (600 mg/m
2
) versus doxorubicin (60 mg/m
2
) + CPA (600 mg/m
2
), 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
2
) versus single-agent doxorubicin (75 mg/m
2
),
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
2
, compared to 480 mg/m
2
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
2
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.
4
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.
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.
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
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.
5
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
Uncommon
Uncommon
Sepsis
Injection site infection
Uncommon
Not known
Blood and lymphatic system disorders
Neutropenia
Very common
Very common
Thrombocytopenia
Very common
Very common
Very common
Very common
Anaemia
Leucopenia
Very common
Very common
Lymphopenia
Common
Common
Common
Uncommon
Pancytopenia
Neutropenic sepsis
Uncommon
Uncommon
Purpura
Uncommon
Uncommon
Metabolism and nutrition disorders
Anorexia
Very common
Very common
Dehydration
Common
Very common
Common
Uncommon
Hypokalaemia
Hyperglycaemia
Uncommon
Uncommon
Psychiatric disorders
Agitation
Uncommon
Not known
Nervous system disorders
Insomnia
Common
Uncommon
Uncommon
Uncommon
Abnormal gait
Dysphonia
Uncommon
Not known
Somnolence
Uncommon
Not known
Cardiac disorders
Arrhythmia
Common
Uncommon
Cardiomyopathy
Common
Common
Common
Common
Congestive cardiac failure
Pericardial effusion
Uncommon
Uncommon
Vascular disorders
Hot flushes
Common
Uncommon
Hypotension
Uncommon
Uncommon
6
All grades
Grades ≥ 3
Respiratory, thoracic and mediastinal disorders
Chest pain
Common
Uncommon
Dyspnoea
Common
Uncommon
Common
Uncommon
Epistaxis
Haemoptysis
Uncommon
Not known
Pharyngitis
Uncommon
Not known
Uncommon
Uncommon
Pleural effusion
Pneumonitis
Uncommon
Uncommon
Gastrointestinal disorders
Nausea/vomiting
Very common
Very common
Stomatitis/mucositis
Very common
Common
Diarrhoea
Very common
Common
Common
Uncommon
Constipation
Oesophagitis
Common
Uncommon
Gastric ulcer
Uncommon
Uncommon
Hepato-biliary disorders
Increased hepatic transaminases
Common
Uncommon
Increased alkaline phosphatase
Uncommon
Uncommon
Uncommon
Uncommon
Jaundice
Increased serum bilirubin
Uncommon
Not known
Skin and subcutaneous tissue disorders
Alopecia
Very Common
Common
Rash
Common
Not known
Nail disorder
Common
Uncommon
Uncommon
Uncommon
Pruritus
Folliculitis
Uncommon
Uncommon
Uncommon
Not known
Dry skin
Musculoskeletal, connective tissue and bone disorders
Back pain
Common
Uncommon
Common
Uncommon
Myalgia
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
Very Common
Uncommon
Rigors
Dizziness
Common
Uncommon
Headache
Common
Uncommon
Common
Uncommon
Weight loss
Injection site reaction
Uncommon
Uncommon
Malaise
Uncommon
Not known
7
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.
5.1
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
2
) + CPA (600 mg/m
2
) was compared with conventional doxorubicin + CPA (at the
same doses) and Myocet (75 mg/m
2
) + CPA (600 mg/m
2
) was compared to epirubicin + CPA (at the
same doses). In a third trial, Myocet (75 mg/m
2
) 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
2
)
(n=142)
Dox 60/CPA
(60/600
mg/m
2
)
(n=155)
Myocet/CPA
(75/600
mg/m
2
)
(n=80)
Epi/CPA
(75/600
mg/m
2
)
(n=80)
Myocet
(75 mg/m
2
)
(n=108)
Dox
(75 mg/m
2
)
(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 (V
d
) was
56.6 ± 61.5 l whereas after conventional doxorubicin, clearance and V
d
were 46.7 ± 9.6 l/h and
8
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.
6.1
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
ο
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 longer than 24 hours at 2
ο
C – 8
ο
C, unless reconstitution and dilution has taken
place in controlled and validated aseptic conditions.
6.4
Special precautions for storage
9
Store in a refrigerator (2ºC – 8ºC).
For storage conditions of the reconstituted medicinal product, see section 6.3.
6.5
Nature and contents of container
Myocet is available in cartons containing 2 sets of the three constituents.
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%), (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.
10
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 product or waste material should be disposed of in accordance with local requirements.
Cephalon Europe
5 Rue Charles Martigny
94700 Maisons Alfort
France
EU/1/00/141/001
Date of first authorisation: 13/07/2000
Date of latest renewal:
Detailed information on this product is available on the website of the European Medicines Agency
http://www.ema.europa.eu.
11
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDER(S) RESPONSIBLE
FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
12
A. MANUFACTURING AUTHORISATION HOLDER(S) RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer(s) responsible for batch release
GP-Pharm
Polígon Industrial Els Vinyets - Els Fogars,
Sector 2, Carretera Comarcal C244, km 22
08777 Sant Quintí de Mediona (Barcelona)
Spain
B. CONDITIONS OF THE MARKETING AUTHORISATION
•
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product
Characteristics, section 4.2)
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable.
•
OTHER CONDITIONS
The holder of this marketing authorisation must inform the European Commission about the marketing
plans for the medicinal product authorised by this decision.
13
ANNEX III
LABELLING AND PACKAGE LEAFLET
14
A. LABELLING
15
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
Outer carton
Myocet 50 mg powder and pre-admixtures for concentrate for liposomal dispersion for infusion
Doxorubicin hydrochloride
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Liposome–encapsulated doxorubicin corresponding to 50 mg doxorubicin hydrochloride
3.
LIST OF EXCIPIENTS
Excipients:
Myocet doxorubicin HCl
lactose
Myocet liposomes
egg phosphatidylcholine, cholesterol, citric acid, sodium hydroxide, water for injections
Myocet buffer
sodium carbonate, water for injections
Powder and pre-admixtures for concentrate for liposomal dispersion for infusion
Carton contents:
2 sets each containing:
1 vial Myocet doxorubicin HCl
1 vial Myocet liposomes
1 vial Myocet buffer
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
For intravenous use after reconstitution and dilution.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
For single use only.
16
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Store in a refrigerator.
10.
SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Cytotoxic. Any unused product or waste material should be disposed of in accordance with local
requirements.
Cephalon Europe
5 Rue Charles Martigny
94700 Maisons Alfort
France
EU/1/00/141/001
13.
BATCH NUMBER
Lot
14.
GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription
15.
INSTRUCTIONS ON USE
16.
INFORMATION IN BRAILLE
Justification for not including Braille accepted
17
PARTICULARS TO APPEAR ON THE INTERMEDIATE PACKAGING
Myocet 50 mg powder and pre-admixtures for concentrate for liposomal dispersion for infusion
Doxorubicin hydrochloride
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Liposome–encapsulated doxorubicin corresponding to 50 mg doxorubicin hydrochloride
3.
LIST OF EXCIPIENTS
Excipients:
Myocet doxorubicin HCl
lactose
Myocet liposomes
egg phosphatidylcholine, cholesterol, citric acid, sodium hydroxide, water for injections
Myocet buffer
sodium carbonate, water for injections
Powder and pre-admixtures for concentrate for liposomal dispersion for infusion
Carton contents:
1 vial Myocet doxorubicin HCl
1 vial Myocet liposomes
1 vial Myocet buffer
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
For intravenous use after reconstitution and dilution.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
For single use only.
18
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Store in a refrigerator.
10.
SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR
WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Cytotoxic. Any unused product or waste materials should be disposed of in accordance with local
requirements.
Cephalon Europe
5 Rue Charles Martigny
94700 Maisons Alfort
France
EU/1/00/141/001
13.
BATCH NUMBER
Lot
14.
GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription
15.
INSTRUCTIONS ON USE
16.
INFORMATION IN BRAILLE
Justification for not including Braille accepted
19
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
MYOCET DOXORUBICIN HCL VIAL
Myocet
doxorubicin HCl
IV use
2.
METHOD OF ADMINISTRATION
Read the package leaflet before use
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
50 mg
6.
OTHER
20
STICKER/TEAR OFF SECTION OF LABEL FOR RELABELLING THE MYOCET
DOXORUBICIN HCL VIAL CONTAINING RECONSTITUTED FINISHED
CONCENTRATE FOR DISPERSION FOR INFUSION
1.
Myocet 50 mg concentrate for dispersion for infusion
Doxorubicin hydrochloride
IV
2.
METHOD OF ADMINISTRATION
Read the package leaflet before use
3.
EXPIRY DATE
4.
BATCH NUMBER
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
6.
OTHER
Preparation Date: ______________
Preparation Time: ______________
Prepared By: __________________
21
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
MYOCET LIPOSOMES
Myocet liposomes
2.
METHOD OF ADMINISTRATION
Read the package leaflet before use
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
1.9 ml
6.
OTHER
22
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
MYOCET BUFFER
Myocet buffer
2.
METHOD OF ADMINISTRATION
Read the package leaflet before use
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
3 ml
6.
OTHER
23
B. PACKAGE LEAFLET
24
PACKAGE LEAFLET: INFORMATION FOR THE USER
Myocet 50 mg powder and pre-admixtures for concentrate for liposomal dispersion for infusion
Doxorubicin hydrochloride
Read all of this leaflet carefully, before you start using this medicine.
-
Keep this leaflet. You may need to read it again.
-
If you have any further questions, ask your doctor or your pharmacist.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if
their symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or nurse.
In this leaflet:
1.
What Myocet is and what it is used for
2.
Before you are given Myocet
3.
How Myocet is given
4.
Possible side effects
5.
How Myocet is stored
6.
Further information
1.
WHAT MYOCET IS AND WHAT IT IS USED FOR
Myocet contains a medicine called “doxorubicin”, which damages tumour cells. This type of medicine
is called “chemo-therapy”. The medicine is contained inside very small droplets of fat called
“liposomes”.
Myocet is used in adult women for the first-line treatment of breast cancer that has spread (“metastatic
breast cancer”). It is used with another medicine called “cyclophosphamide”.
2.
BEFORE YOU ARE GIVEN MYOCET
Do not have Myocet if:
•
you are allergic to doxorubicin or any of the other ingredients of Myocet listed in Section 6.
Do not have Myocet if this applies to you. If you are not sure, talk to your doctor or nurse before
having Myocet.
Take special care with Myocet
Check with your doctor or nurse before having your medicine if:
•
you have ever had heart problems such as a heart attack, heart failure or you have had high blood
pressure for a long time
•
you have liver problems.
If any of the above apply to you (or you are not sure), talk to your doctor or nurse before having
Myocet.
Tests
Your doctor will do tests during your treatment to check that the medicine is working properly. They
will also look out for any side effects such as blood problems or heart problems.
Taking other medicines
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines. This
includes medicines obtained without a prescription and herbal medicines. This is because Myocet can
affect the way some other medicines work. Also some other medicines can affect the way Myocet
works.
25
In particular tell your doctor or nurse if you are taking any of the following medicines:
•
phenobarbital or phenytoin – for epilepsy
•
warfarin – for thinning the blood
•
streptozotocin – for cancer of the pancreas
•
cyclosporine – for changing your immune system.
If any of the above apply to you (or you are not sure), please talk to your doctor or nurse before having
Myocet.
Pregnancy and breast-feeding
Talk to your doctor or nurse before having Myocet if you are pregnant, think you may be pregnant or
are breast-feeding.
•
Myocet should not be used during pregnancy unless clearly necessary.
•
Women having Myocet should not breast-feed.
•
Women who could get pregnant should use effective contraception during treatment with Myocet
and for 6 months after treatment.
Driving and using machines
You may feel dizzy after having Myocet. If you feel dizzy or are not sure how you feel, do not drive or
use any tools or machines.
Important information about some of the ingredients of Myocet
Myocet is available in cartons containing 2 sets of 3 vials. When the 3 vials have been mixed together,
your medicine contains about 108 mg sodium. This should be taken into consideration by patients on a
controlled sodium diet.
3.
HOW MYOCET IS GIVEN
Myocet is normally given by a doctor or nurse. It is given as a drip (infusion) into a vein.
How much you will be given
Your doctor will work out exactly how much you need. This is based on the size of your body
(measured in “square metres” or “m2”).
The usual dose is between 60 and 75 mg of the medicine for each square meter of your body:
•
this is given once every 3 weeks
•
the medicine “cyclophosphamide” is given on the same day.
The doctor may give you a lower dose if they think you need it.
The number of times you have the drip depends on:
•
the stage of your breast cancer
•
how well your body responds to the medicine.
Treatment usually lasts for about 3 to 6 months.
If you get Myocet on your skin
Myocet can damage your skin and so care needs to be taken. If there are any leaks from the drip
(infusion) onto your skin, the drip will be stopped straight away. Ice will be put on the affected area
for 30 minutes. Then the drip will be started in another vein.
If you have any further questions on the use of this product, ask your doctor or nurse.
26
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Myocet can cause side effects, although not everybody gets them. The following
side effects may happen with this medicine.
Tell your doctor or nurse straight away if you notice any of the following side effects. These are
signs of an allergic reaction and your drip (infusion) may have to be stopped:
•
feeling breathless or a tight chest or throat
•
headache or back pain
•
fever or chills
•
swollen or flushed face
•
feeling tired, dizzy or light-headed.
If you notice any of the side effects listed above, tell your doctor or nurse straight away.
Other side effects
Very common
(affect more than 1 in 10 people)
•
hair loss
•
fever, chills, pain
•
loss of appetite, diarrhoea, feeling or being sick (nausea or vomiting)
•
reduced levels of certain blood cells – your doctor will regularly check your blood for this and
decide if any treatment is required. Signs may include:
-
increased bruising
-
sore mouth, throat or mouth ulcers
-
reduced resistance to infection or fever
-
feeling tired or dizzy, having a lack of energy.
Common
(affect 1 to 10 people in 100):
•
muscle aches, back pain
•
fever and chills, headache
•
difficulty breathing, chest pains
•
feeling thirsty, pain or swelling of your food pipe
•
shortness of breath, swollen ankles, muscle weakness or cramps. These may be signs of heart
failure, uneven heart beat or a low potassium level in your blood
•
difficulty sleeping
•
nose bleeds, hot flushes
•
constipation, weight loss
•
skin rash and nail problems.
Uncommon
(affect 1 to 10 people in 1000):
•
coughing up blood
•
feeling agitated, feeling sleepy
•
low blood pressure, feeling unwell
•
a change in how you walk, speech problems
•
stomach pains which may be a sign of a stomach ulcer forming
•
muscle weakness
•
itchy, dry skin or swollen areas around hair roots
•
swollen, red and blistering skin around where the drip was given
•
high blood glucose level (your doctor will see this in a blood test)
•
yellow skin or eyes. These may be signs of a liver problem called jaundice.
•
change in how often you pass water (urine), pain on passing water or blood in your urine
Myocet may cause some side effects that are related to how fast the drip is given. These include
flushing, fever, chills, headaches and back pain. These side effects may stop if the drip is given more
slowly over a longer period of time.
27
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or nurse.
5.
HOW MYOCET IS STORED
- Keep out of the reach and sight of children.
- Do not use after the expiry date stated on the label and carton.
- Store in a refrigerator (2ºC to 8ºC).
- From a microbiological point of view, the 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
ο
C – 8
ο
C, unless reconstitution and dilution has taken
place in controlled and validated aseptic conditions.
- Do not use Myocet if you notice that it shows evidence of discoloration, precipitation or any other
particulate matter.
- Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how
to dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER INFORMATION
What Myocet contains:
-
The active substance is liposome–encapsulated doxorubicin. This corresponds to 50 mg
doxorubicin hydrochloride.
-
The other ingredients are lactose (in the doxorubicin HCl vial), egg phosphatidylcholine,
cholesterol, citric acid, sodium hydroxide and water for injections (in the liposomes vial), and
sodium carbonate and water for injections (in the buffer vial).
What Myocet looks like and contents of the pack
Myocet consists of a powder and pre-admixtures for concentrate for liposomal dispersion for infusion.
It is supplied as a three-vial system: Myocet doxorubicin HCl, Myocet liposomes and Myocet buffer.
Once the content of the vials has been mixed together the resulting liposomal dispersion is orange-red
and opaque.
Myocet is available in cartons containing 2 sets of the three constituents.
Marketing Authorisation Holder
Cephalon Europe
5 Rue Charles Martigny
94700 Maisons Alfort
France
Manufacturer
GP-Pharm
Polígon Industrial Els Vinyets - Els Fogars,
Sector 2, Carretera Comarcal C244, km 22
08777 Sant Quintí de Mediona (Barcelona)
Spain
This leaflet was last approved in:
{MM/YYYY}
Detailed information on this medicine is available on the European Medicines Agency website:
28
The following information is intended for healthcare professionals only:
PREPARATION GUIDE
Myocet 50 mg powder and pre-admixtures for concentrate for liposomal dispersion for infusion
Doxorubicin hydrochloride
It is important you read the entire contents of this guide prior to the preparation of this
medicinal product.
1.
PRESENTATION
Myocet is supplied as a three-vial system: (1) Myocet doxorubicin HCl, (2) Myocet liposomes, and
(3) Myocet buffer. In addition to these three components, 0.9% (w/v) sodium chloride solution for
injection will also be required for the reconstitution of the doxorubicin HCl. Myocet must be
reconstituted prior to administration.
2.
RECOMMENDATIONS FOR SAFE HANDLING
The normal procedures for proper handling and disposal of anti-tumour medicinal products should be
adopted, namely:
•
Personnel should be trained to reconstitute the medicinal product.
•
Pregnant staff should be excluded from handling the medicinal product.
•
Personnel handling this medicinal product during reconstitution should wear protective
clothing including masks, goggles and gloves.
•
All items for administration or cleaning, including gloves, should be placed in a high-risk,
waste disposal bag for high-temperature incineration. Liquid waste may be flushed with large
amounts of water.
•
Accidental contact with the skin or eyes should be treated immediately with copious amounts
of water.
3.
PREPARATION FOR THE INTRAVENOUS ADMINISTRATION
Aseptic technique must be strictly observed throughout handling of Myocet since no preservative is
present.
3.1
Preparation of Myocet
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.
29
Step 2. Reconstitute doxorubicin HCl
•
Withdraw 20 ml sodium chloride solution for injection (0.9%), (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 a 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 the pH-adjusted
liposomes into the 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
concentrate for liposomal dispersion for infusion (2 mg/ml).
After reconstitution the finished product must be further diluted in 0.9% (w/v) sodium chloride
solution 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 medicinal products should be
inspected visually for particulate matter and discoloration prior to administration. Do not use the
preparation if foreign particulate matter is present.
It has been demonstrated that once reconstituted Myocet has a chemical and physical in-use stability at
room temperature for up to 8 hours or in a refrigerator (2
ο
C-8
ο
C) for up to 5 days.
From a microbiological point of view, the 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
ο
C-8
ο
C, unless reconstitution and dilution has taken
place in controlled and validated aseptic conditions.
Myocet should be administered by intravenous infusion over a period of 1 hour.
30
Warning: Myocet must not be administered by the intramuscular or subcutaneous route or as a bolus
injection.
4.
DISPOSAL
Any unused product or waste material should be disposed of in accordance with local requirements.
31
Source: European Medicines Agency
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