ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
Savene 20 mg/ml powder for concentrate and diluent for solution for infusion.
Each ml contains 20 mg of dexrazoxane after reconstitution with 25 ml of water for injections.
Each vial contains 500 mg dexrazoxane (as hydrochloride).
Excipients in the diluent:
Potassium 98 mg/500 ml
Sodium 1.61 g/500 ml
For a full list of excipients, see section 6.1.
Powder for concentrate and diluent for solution for infusion.
Savene powder:
White to off-white powder.
Savene diluent:
Clear isotonic diluent (295 mOsml/l, pH approx. 7.4).
Savene is indicated for the treatment of anthracycline extravasation.
Savene must be administered under the supervision of a physician experienced in the use of cancer
chemotherapeutic agents.
Savene should be given once daily for 3 consecutive days.
The recommended dose is:
Day one:
1000 mg/m
2
Day two:
1000 mg/m
2
Day three:
500 mg/m
2
There is no experience with dose reduction/increase or modification of the schedule in the treatment of
extravasation. For patients with a body surface area of more than 2 m
2
the single dose should not
exceed 2000 mg
.
The indicated dose should be administered as an intravenous infusion over 1-2 hours into a large vein
in extremity/area other than the one affected by the extravasation. The first infusion should be initiated
as soon as possible and within the first six hours after the accident. Cooling procedures such as ice
packs should have been removed from the area at least 15 min before the Savene administration in
order to allow sufficient blood flow. Treatment Day 2 and Day 3 should start at the same hour (+/- 3
hours) as on the first day.
2
Before infusion, Savene powder must be reconstituted with 25 ml sterile water to give a concentration
of 20 mg dexrazoxane per ml sterile water.
After reconstitution the solution should be further diluted in the bag with the Savene diluent. (See
section 6.6).
Special populations:
Paediatric patients
Savene is not recommended for use in children due to a lack of data on safety and efficacy.
Patients with renal impairment
Savene has not been studied in patients with impaired renal function and its use in such patients is not
recommended (see section 4.4). Decreased renal function may lead to decreased rate of elimination
and prolonged systemic exposure.
Patients with hepatic impairment
Savene has not been studied in patients with impaired hepatic function and its use in such patients is
not recommended (see section 4.4).
Elderly patients
Safety and efficacy have not been evaluated in the elderly.
Hypersensitivity to the active substance or to any of the excipients.
Women of childbearing potential not using contraceptive measures (see section 4.4 and 4.6).
Lactation (see section 4.6).
Concomitant vaccination with yellow fever vaccine (see section 4.5).
Local examination should be performed on regular basis after treatment until resolution.
If there is suspicion of extravasation by vesicant compounds other than anthracyclines through the
same IV access, e.g. vincristine, mitomycin, and vinorelbine, Savene would not be effective against
the reaction from these compounds.
Savene will be administered to patients undergoing cytotoxic therapy with anthracycline containing
chemotherapy and its cytotoxic potential (especially resulting in reversible haematological toxicity
with a nadir occurring on days 11-12) will therefore be added to that of the other chemotherapy
administered.
Haematological monitoring should therefore be undertaken regularly.
Patients with neutropenia and thrombocytopenia > Common Toxicity Criteria (CTC) grade 1 have not
been included in the clinical studies.
Since liver dysfunction (increases in transaminases and bilirubin) may occur (especially after doses of
above 1 000 mg/m
2
dexrazoxane), it is recommended that routine liver function tests are performed
before each administration of dexrazoxane in patients with known liver function disorders.
Since renal dysfunction may decrease the rate of elimination of dexrazoxane, patients with initial
impaired renal function should be monitored for signs of haematological toxicity.
As dexrazoxane possesses mutagenic activity, men being treated with dexrazoxane are advised not to
father a child during and up to three months after treatment. Women of childbearing potential must use
contraceptive measures during treatment.
This product is generally not recommended in combination with live attenuated vaccines, or with
phenytoin (see section 4.5).
3
Dimethylsulfoxide (DMSO) should not be used in patients who are administered dexrazoxane to treat
anthracycline-induced extravasation.
As the Savene diluent contains potassium (98 mg/500 ml) the plasma potassium level of the patient
must be closely monitored in patients at risk of hyperkalaemia. It also contains sodium (1.61 g/500 ml)
which may be harmful to patients on a low sodium diet.
Interactions common to all cytotoxics:
Due to increase of thrombotic risk in patients with malignant diseases, the use of anticoagulants
treatment is frequent. Cytotoxic agents may interact with oral anticoagulants. Patients treated with
anticoagulant should be monitored more frequently.
Concomitant use contraindicated:
Yellow fever vaccine: Risk of fatal generalised vaccinial disease (see section 4.3).
Concomitant use not recommended:
Live attenuated vaccines: risk of systemic, possible fatal disease. This risk is increased in subjects who
are already immunosuppressed by their underlying disease
Phenytoin: concomitant use of cytotoxic medicinal products may reduce the absorption of phenytoin
leading to an exacerbation of convulsions.
Use an inactivated vaccine where this exists (poliomyelitis).
Concomitant use to take into consideration:
Ciclosporine, Tacrolimus: Excessive immunosuppression with risk of lymphoproliferative disease.
Interaction specific to dexrazoxane:
When tested in five major cytochrome P450 isoenzymes: CYP1A, CYP2C9, CYP2C19, CYP2D6 and
CYP3A4, none of these were inhibited by dexrazoxane.
Savene may add to the toxicity induced by the chemotherapy cycle during which the accident took
place, requiring careful monitoring of haematological parameters.
There are no data from the use of dexrazoxane in pregnant women. Savene may cause foetal harm
when administered to pregnant women. Few pre-clinical data are available with respect to
reproductive toxicity (see section 5.3). Savene should not be administered to pregnant women unless
clearly necessary. Women of childbearing potential should use contraceptive measures during
treatment and should inform their doctor immediately if they become pregnant. (See section 4.3)
As dexrazoxane possesses mutagenic activity, male patients should use contraceptives during
treatment and for 3 months after treatment with dexrazoxane has been concluded (see section 4.4).
It is not known whether dexrazoxane is excreted in human milk. Because of the potential for serious
adverse reactions in nursing infants exposed to dexrazoxane, mothers should discontinue nursing
during Savene therapy. (See section 4.3)
No studies on the effects on the ability to drive and use machines have been performed but it is
unlikely that Savene will affect this function, as it has rarely been associated with any impairment of
the central nervous system such as confusion.
4
A number of published reports comprising more than 1000 patients have demonstrated a uniform
pattern of dose dependant adverse reactions such as nausea/vomiting, diarrhoea, stomatitis, bone
marrow suppression (neutropenia, thrombocytopenia) and affected liver function (increased
ALT/AST). All adverse reactions have been rapidly reversible.
The following information is based on two clinical studies, TT01 and TT02, of Savene administered to
extravasation patients already receiving cycles of chemotherapeutic agents.
The adverse reactions are those typically seen with standard chemotherapy and also with dexrazoxane:
Nausea/vomiting in about one third of the patients, neutropenia and thrombocytopenia in about half of
the patients, more rarely increased concentration of liver enzymes (ALT/AST).
The treatment related adverse events observed in the clinical studies are listed below.
Incidence of adverse reactions (MedDRA) in studies TT01 and TT02 that are related or possible
related to treatment.
(Note that numbers for Blood and Lymphatic System Disorders are described in
a separate table of laboratory examinations)
Adverse reactions described as very common were experienced in more than 1 in 10 patients (≥ 1/10).
Adverse reactions described as common were experienced by up to 1 in 10 patients (> 1/100 to <
1/10).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
(Number of patients = 80)
System Organ
Classes (SOC)
Frequency
Preferred
Terms (PT)
All grades
Grade 3+4
Gastrointestinal
disorders
Very common
Nausea
15 (18.8%)
0 (0%)
Common
Vomiting
6 (7.5%)
0 (0%)
Diarrhoea
3 (3.8%)
1 (1.3%)
Stomatitis
2 (2.5%)
2 (2.5%)
Dry mouth
1 (1.3%)
0 (0%)
General
disorders and
administration
site conditions
Very common
Injection site
pain
13 (16.3%)
1 (1.3%)
Pyrexia
6 (7.5%)
2 (2.5%)
Injection site
phlebitis
5 (6.3%)
0 (0%)
Injection site
erythema
3 (3.8%)
0 (0%)
Fatigue
2 (2.5%)
0 (0%)
Common
Injection site
induration
2 (2.5%)
0 (0%)
Injection site
swelling
2 (2.5%)
0 (0%)
Oedema
peripheral
1 (1.3%)
0 (0%)
Somnolence
1 (1.3%)
0 (0%)
Infections and
infestations
Very common
Postoperative
infection
8 (10.0%)
3 (3.8%)
Common
Infection
1 (1.3%)
0 (0%)
Neutropenic
infection
1 (1.3%)
1 (1.3%)
Injury,
poisoning and
procedural
complications
Common
Wound
complication
3 (3.8%)
0 (0%)
Investigations
Common
Weight
decreased
1 (1.3%)
0 (0%)
Metabolism and
nutrition
disorders
Common
Decreased
appetite
1 (1.3%)
0 (0%)
5
System Organ
Classes (SOC)
Frequency
Preferred
Terms (PT)
All grades
Grade 3+4
Musculoskeletal
and connective
tissue disorders
Common
Myalgia
1 (1.3%)
0 (0%)
Nervous system
disorders
Common
Dizziness
2 (2.5%)
1 (1.3%)
Sensory loss
1 (1.3%)
0 (0%)
Syncope
1 (1.3%)
1 (1.3%)
Tremor
1 (1.3%)
0 (0%)
Reproductive
system and
breast disorders
Common
Vaginal
haemorrhage
1 (1.3%)
0 (0%)
Respiratory,
thoracic and
mediastinal
disorders
Common
Dyspnoea
1 (1.3%)
0 (0%)
Pneumonia
1 (1.3%)
0 (0%)
Skin and
subcutaneous
tissue disorders
Common
Alopecia
5 (6.3%)
0 (0%)
Pruritus
1 (1.3%)
0 (0%)
Vascular
disorders
Common
Phlebitis
2 (2.5%)
0 (0%)
Thrombophlebit
is superficial
1 (1.3%)
0 (0%)
Venous
thrombosis limb
1 (1.3%)
0 (0%)
Incidence of laboratory abnormalities (all patients) in TT01 and TT02
CTC grade 3-4
No of pts with post
baseline value
Lab test
N
%
Haemoglobin
80
2
2.5%
WBC
80
36
45.0%
Neutrophils
78
36
46.2%
Platelets
80
17
21.3%
Sodium (Hypo)
79
5
6.3%
Potassium (Hypo)
79
2
2.5%
Potassium (Hyper)
79
0
0.0%
Alkaline Phosphatase
77
0
0.0%
Bilirubin
77
1
1.3%
AST
57
2
3.5%
ALT
71
3
3.9%
Creatinine
76
2
2.6%
LDH
78
0
0.0%
Calcium Total (Hypo)
28
2
7.1%
Signs and symptoms of overdosage are likely to consist of leucopenia, thrombocytopenia, nausea,
vomiting, diarrhoea, skin reactions and alopecia. Treatment should be symptomatic.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Detoxifying agents for antineoplastic agents, ATC code: V03AF02
6
Two pharmacodynamic properties of dexrazoxane, its antineoplastic effect and its use in the
prevention of anthracycline cardiotoxicity, are described in the literature.
Mechanism of action
Dexrazoxane has two major mechanisms of action:
1. Prevention of anthracycline cardiotoxicity: chelation of iron especially through its ring-opened
metabolite reduces the iron-dependant free radical oxidative stress associated with anthracycline-
induced cardiotoxicity.
2. Antineoplastic effect: inhibition of topoisomerase II.
It is not known to which extent each of these mechanisms contributes to the protective effect of tissue
destruction following anthracycline extravasation.
The chelating property is probably also responsible for an increased urinary excretion of iron and zinc
and a decreased serum concentration of calcium as described in a few studies.
The following efficacy data relate to Savene used as treatment of anthracycline extravasation.
The clinical programme for Savene (dexrazoxane) included two open, single arm, multicentre studies.
The overall purpose of each trial was to investigate the efficacy of intravenous Savene in preventing
tissue damage from accidentally extravasated anthracycline, and thus preventing the patients from
undergoing the routinely used surgical excision of the affected tissue.
Due to the rarity of the condition only historical data could be used for comparison (demonstrating
surgical rates of 35-50%, in one country 100% in biopsy proven cases)
In both studies, the dosage regimen was the same. Treatment with Savene had to be started within 6
hours from the incident and was repeated after 24 and 48 hours. The first and second doses were at
1000 mg/m
2
and the third was 500 mg/m
2
.
A requirement for inclusion in the efficacy part of the study was that the anthracycline extravasation
was proven by fluorescence microscopy of one or more biopsies.
Patients with neutropenia and thrombocytopenia > CTC grade 1 have not been included in the clinical
studies.
In study
TT01
23 patients were entered and received treatment with Savene. Eighteen were evaluable
for efficacy and safety and a further five patients were evaluable for toxicity only. None of the patients
required surgical intervention.
In study
TT02
, 57 patients entered the study and received the first dose of Savene. 36 patients were
evaluable for efficacy. Only one of the 36 patients required surgery.
In both studies all patients had received anthracycline. Overall, the most commonly received
anthracycline was epirubicin (56% of the patients).
Patients with extravasations from a central venous access device (CVAD) were not included in the
efficacy evaluation.
In both studies dexrazoxane treatment prevented the development of necrosis, allowed cancer
treatment to continue as scheduled in the majority of patients, and reduced the occurrence of sequelae
(only few and mild long-term sequelae were observed).
5.2 Pharmacokinetic properties
Savene is only administered intravenously.
Bibliographical data demonstrate that serum kinetics of dexrazoxane after intravenous administration,
follow an open two-compartment model independent of schedule and dose. The apparent volumes of
distribution
are 0.13-1.3 l/kg (median 0.49 l/kg). Volume of distribution is independent of dose. AUCs
were dose-proportional. Tissue distribution is rapid, with the highest levels of unchanged parent
compound and hydrolysed product appearing in liver and kidneys. About 2% of dexrazoxane is
protein-bound.
7
Biotransformation
:
Dexrazoxane undergoes intracellular hydrolysis first to its two one-ring open
intermediates (B and C) and then to the two-ring opened form (ADR-925) which has a structure
similar to EDTA and is a strong chelator of iron and divalent cations as calcium ions.
Elimination
:
Dexrazoxane displays biphasic elimination kinetics. Initial elimination half lives (alpha)
are 0.18-1 h (median 0.34 h) and terminal elimination half lives 1.9-9.1 h (median 2.8 h). Total urinary
recovery of unchanged dexrazoxane is 34%-60%. Systemic clearance is independent of dose. The
pharmacokinetics of the metabolites is derived from a single study with five patients. The mean
elimination half-lives of the one-ring opened metabolite B and metabolite C are 0.9-3.9 h (n=5) and
0.5-0.8 h (n=3), respectively. The elimination half-life of the two-ring opened metabolite ADR-925 is
not given in literature. ADR-925 is reported to increase three-fold within 15 min after infusion of 1500
mg/m
2
and remain relatively constant on a plateau for 4 hours and then decreased to about half at 24 h.
Clearance may be reduced in patients with low creatinine clearance.
In vitro studies on dexrazoxane when tested in human microsomes have shown high stability of
dexrazoxane indicating that major metabolism via cytochrome P450 is unlikely
There is insufficient data available to draw any definite conclusions regarding intrinsic
pharmacokinetic factors such as age, gender, race and weight. Inter- and intraindividual
pharmacokinetic variabilities have not been studied systematically. Based on a limited number of
patients, interindividual variability calculated as the coefficient of variation (CV %), was estimated to
be approximately 30% for the main pharmacokinetic parameters.
5.3 Preclinical safety data
Dexrazoxane has been shown to possess mutagenic activity. The carcinogenic potential of
dexrazoxane has not been investigated, however, razoxane, (the racemic mixture of dexrazoxane and
levrazoxane), has been reported to be associated with the development of secondary malignancies in
mice (lymphoid neoplasms) and rats (uterine carcinomas) after administration for a prolonged period
of time. Both of these effects are expected for this class of compound.
Repeat-dose toxicity studies have shown that primary target organs were tissues that undergo rapid
cell division: bone marrow, lymphoid tissue, testes and digestive tract. Myelosuppression is thus
common. The apparent effects were greater during chronic administration than acute. The toxicity in
combination with doxorubicin was additive and not synergistic.
The related razoxane has been demonstrated to be embryotoxic in mice, rats and rabbits and
teratogenic in rats and mice.
When mice with experimental daunorubicin extravasation were treated with dexrazoxane systemically
combined with topical treatment with DMSO on the daunorubicin-affected skin area, 67% of the mice
developed small skin wounds, whereas dexrazoxane treatment alone completely prevented the
daunorubicin induced skin necrosis in another group of mice, Thus, DMSO should not be used in
patients treated with dexrazoxane to prevent anthracycline extravasation.
6.1 List of excipients
Savene powder
Hydrochloric acid
Savene diluent
Sodium chloride
Potassium chloride
Magnesium chloride hexahydrate
Sodium acetate trihydrate
Sodium gluconate
8
Sodium hydroxide
Water for injections
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal
products.
6.3 Shelf life
Vials and bags:
3 years.
After reconstitution and dilution:
Chemical and physical in-use stability has been demonstrated for 4 hours when stored at 2 to 8°C.
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 4 hours at 2 to 8°C.
6.4 Special precautions for storage
Store below 25°C.
Keep the vials and bags in the outer carton in order to protect from light.
6.5 Nature and contents of container
Savene powder: Amber coloured glass type I vial with rubber stopper made of chlorobutyl and a flip-
off or tear off cap.
Savene diluent: Bags made of polyolefin/polyamide co-extruded plastic and over wrapped with a
protective plastic bag composed of polyamide/polypropylene.
Pack sizes:
Savene is available in a box consisting of 10 vials of Savene powder containing 500 mg dexrazoxane
and 3 bags of 500 ml Savene diluent.
6.6 Special precautions for disposal
and other handling
Before infusion, Savene powder must be reconstituted with 25 ml sterile water to give a concentration
of 20 mg dexrazoxane per ml sterile water.
The reconstituted solution is slightly yellow.
The reconstituted solution should then be diluted in 500 ml Savene diluent.
Caution must be exercised when handling and preparing the reconstituted solution and the normal
procedures for proper handling of cytotoxic medicinal products should be adopted.
If the powder or solution contacts the skin or mucous membranes, wash immediately and thoroughly
with water.
Any unused product or waste material should be disposed of in accordance with local requirements.
SpePharm Holding B.V.
Kingsfordweg 151
NL – 1043 GR Amsterdam
Netherlands
9
EU/1/06/350/001
28/07/2006
Detailed information on this product is available on the website of the European Medicines Agency
(EMA) http://www.ema.europa.eu
10
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDER
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING
AUTHORISATION
11
A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer responsible for batch release
SpePharm Holding B.V.
Kingsfordweg 151
NL – 1043 GR Amsterdam
Netherlands
B. CONDITIONS OF THE MARKETING AUTHORISATION
Medicinal product subject to restricted medical prescription.
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable.
OTHER CONDITIONS
The MAH must ensure that the system of pharmacovigilance is in place and functioning before the
product is placed on the market and for as long as the marketed product remains in use.
12
ANNEX III
LABELLING AND PACKAGE LEAFLET
13
A. LABELLING
14
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
Box ( Pack of 10 vials and 3 bags of diluent)
1.
Savene 20 mg/ml powder for concentrate and diluent for solution for infusion
Dexrazoxane
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each vial contains 500 mg dexrazoxane (as hydrochloride)
Each ml contains 20 mg of dexrazoxane after reconstitution with 25 ml of water for injections
3.
LIST OF EXCIPIENTS
Savene powder:
Hydrochloric acid
Savene diluent:
Sodium chloride
Potassium chloride
Magnesium chloride hexahydrate
Sodium acetate trihydrate
Sodium gluconate
Sodium hydroxide
Water for injections
4.
Powder for concentrate and diluent for solution for infusion
10 vials of 500 mg dexrazoxane
3 bags of 500 ml diluent
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
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
To be administered under the supervision of a physician experienced in the use of cytotoxic agents
8.
EXPIRY DATE
EXP {MM/YYYY}
9.
SPECIAL STORAGE CONDITIONS
15
Store below 25°C
Reconstituted and diluted solution may be stored at 2 to 8°C for 4 hours
Keep vials and bags in the outer carton in order to protect from light
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Contains cytostatics.
Any unused product or waste material should be disposed of in accordance with local requirements.
SpePharm Holding B.V.
Kingsfordweg 151
NL – 1043 GR Amsterdam
Netherlands
EU/1/06/350/001
13. BATCH NUMBER
Batch:
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription
15. INSTRUCTIONS ON USE
Emergency kit for Anthracycline Extravasation
16. INFORMATION IN BRAILLE
No information in Braille is available.
16
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
Vial
1.
Savene powder
Dexrazoxane
Powder for concentrate
Intravenous use after reconstitution and dilution
2.
METHOD OF ADMINISTRATION
Intravenous use after reconstitution and dilution
Read the package leaflet before use
3.
EXPIRY DATE
EXP {MM/YYYY}
4.
BATCH NUMBER
Batch:
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
500 mg
6. OTHER
17
PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING
Infusion bag
1.
Savene diluent
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Not applicable
3.
LIST OF EXCIPIENTS
Sodium chloride
Potassium chloride
Magnesium chloride hexahydrate
Sodium acetate trihydrate
Sodium gluconate
Sodium hydroxide
Water for injections
4.
Diluent for solution for infusion 500 ml
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
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
8.
EXPIRY DATE
EXP {MM/YYYY}
9.
SPECIAL STORAGE CONDITIONS
Store below 25°C. Keep in the outer carton in order to protect from light
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Contains after reconstitution and dilution cytostatics
Any unused product or waste material should be disposed of in accordance with local requirements
18
SpePharm Holding B.V.
Kingsfordweg 151
NL – 1043 GR Amsterdam
Netherlands
EU/1/06/350/001
13. BATCH NUMBER
Batch:
14. GENERAL CLASSIFICATION FOR SUPPLY
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
No information in Braille is available
19
B. PACKAGE LEAFLET
20
PACKAGE LEAFLET: INFORMATION FOR THE USER
Savene 20 mg/ml powder for concentrate and diluent for solution for infusion
Dexrazoxane
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.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor.
In this leaflet
:
1.
What Savene is and what it is used for
2.
Before you are given Savene
3.
Possible side effects
5
How to store Savene
6.
Further information
1.
WHAT SAVENE IS AND WHAT IT IS USED FOR
Savene is a detoxifying agent for anti-cancer treatment.
Most anti-cancer medicines are administered intravenously. Occasionally an accident occurs and the
medicine is infused outside the vein and into the surrounding tissue. This event is called extravasation.
It is a serious complication as it can cause severe tissue damage. Savene is used as an antidote to treat
extravasations caused by the group of anti-cancer medicines called anthracyclines.
2.
BEFORE YOU ARE GIVEN SAVENE
Savene will not be used:
-
If you are allergic (hypersensitive) to dexrazoxane or any of the other ingredients of Savene
-
If you are planning to become pregnant and do not use adequate contraceptive measures
-
If you are given yellow fever vaccine
Special care with Savene should be taken
-
Savene should only be given to you if you have had an extravasation in connection with
anthracycline-containing chemotherapy.
-
During treatment with Savene you will have blood tests taken regularly to check your blood
cells.
-
If you have kidney dysfunction your doctor will monitor for signs of changes to your blood
cells.
-
Men being treated with dexrazoxane are advised not to father a child during and up to three
months after treatment.
-
Women of childbearing potential must use contraceptive measures during treatment.
-
If you receive live attenuated vaccines or phenytoin (anti-epileptic medicines).
Taking other medicines
Savene should not be mixed with any other medicines during the infusion.
It is not advisable to use any medical treatment without telling your doctor as there may be
interactions between Savene and other medicines.
21
4.
How to use Savene
-
If you are breast-feeding
-
If you have liver dysfunction your doctor will monitor your liver function during treatment
-
Savene should not be administered to children.
Please tell your doctor if you are taking or have recently taken any other medicines, including
medicines obtained without a prescription.
Pregnancy and breast-feeding
Savene should not be administered if you are pregnant. If you are a man, you must take adequate
contraceptive precautions during therapy and for at least three months after treatment.
You must not breast-feed while you are treated with Savene.
Ask your doctor or pharmacist for advice before taking any medicine.
Driving and using machines
No studies on the effects on the ability to drive and use machines have been performed but it is
unlikely that Savene will affect this function.
Important information about some of the ingredients of Savene
The Savene diluent contains potassium (98 mg/500 ml) which may be harmful to people on a low
potassium diet.
It also contains sodium (1.61 g/500 ml) which may be harmful to people on a low sodium diet.
3.
HOW TO USE SAVENE
Usual dose
The dose will depend on your height and weight. Your doctor will calculate your body surface area in
square meter (m
2
) and will determine the dose you should receive.
The usual adult dose is
Day 1 and Day 2: 1000 mg/m
2
Day 3: 500 mg/m
2
Savene will be given by infusion into one of your veins. The infusion will last 1-2 hours.
Before infusion, Savene powder is reconstituted with 25 ml sterile water to give a concentration of 20
mg dexrazoxane per ml sterile water.
After reconstitution the solution should be further diluted in the bag with the Savene diluent.
Frequency of administration
You will receive your infusion once daily for 3 consecutive days. The first infusion will be given as
soon as possible, and within the first six hours, after extravasation with an anthracycline medicine.
If you have any further questions on the use of this product, ask your doctor.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Savene can cause side effects, although not everybody gets them.
Side effects described as very common were experienced by more than 1 in 10 patients.
Side effects described as common were experienced by up to 1 in 10 patients.
The very common (more than 1 in 10 patients) side effects are:
Nausea. Pain in the blood vessel where the treatment is given. Very common side effects are
furthermore a temporary lowering of the white blood cells, neutrophils and the platelets, side effects
which also are caused by the chemotherapy you receive for your disease. Control blood tests will be
performed regularly.
The common (up to 1 in 10 patients) side-effects are:
A general feeling of being unwell including feeling tired, sleepy or dizzy. Furthermore there can be
inflammation of the blood vessel where the treatment is given (phlebitis), diarrhoea, dry mouth, hair
22
loss. At the site of injection you may get a reaction, where the skin may be red, swollen or hurt when
touched.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor
.
5.
HOW TO STORE SAVENE
Keep out of the reach and sight of children.
Do not use Savene after the expiry date stated on the label.
Savene should be stored below 25
o
C. Keep Savene in the outer carton in order to protect from light.
Chemical and physical in-use stability has been demonstrated for 4 hours when stored at 2 to 8
o
C after
reconstitution and subsequent dilution in the diluent.
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 at the responsibility of the
user and would normally not be longer than 4 hours at 2 to 8°C.
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.
Do not use Savene if you notice that the vial is damaged or show signs of tampering.
6.
FURTHER INFORMATION
What Savene contains
The active substance is dexrazoxane. Each vial contains 500 mg dexrazoxane as 589 mg dexrazoxane
hydrochloride.
The other ingredients are hydrochloric acid.
The diluent contains sodium chloride, potassium chloride, magnesium chloride hexahydrate, sodium
acetate trihydrate, sodium gluconate, sodium hydroxide and water for injections.
What Savene looks like and contents of the pack
Savene consists of Savene powder and Savene diluent. Savene powder is presented as a single glass
vial containing a white to off-white powder called dexrazoxane (the active substance). Savene is also
supplied with an infusion bag containing the Savene diluent.
The concentration of the active ingredient following reconstitution with sterile water is 20 mg
dexrazoxane per ml. The reconstituted solution is slightly yellow.
Savene is supplied in a box containing 10 vials of Savene powder and 3 infusion bags of Savene
diluent.
Marketing Authorisation Holder and Manufacturer:
SpePharm Holding B.V.
Kingsfordweg 151
NL – 1043 GR Amsterdam
Netherlands
Tel: +31 (0)88 0074 501
Fax: +31 (0)20 4919 090
23
For any information about this medicinal product, please contact the local representative of
the Marketing Authorisation Holder:
België/Belgique/Belgien
SpePharm Holding B.V.
Kingsfordweg 151
NL – 1043 GR Amsterdam
Tél/Tel: + 31 (0)88 0074 501
Luxembourg/Luxemburg
SpePharm Holding B.V.
Kingsfordweg 151
NL – 1043 GR Amsterdam
Tél/Tel: + 31 (0)88 0074 501
България
SpePharm Holding B.V.
Kingsfordweg 151
NL – 1043 GR Amsterdam
Teл.: + 31 (0)88 0074 501
Magyarország
Medis d.o.o.
Brnciceva 1
SI-1001 Ljubljana
Tel.: + 386 1 589 69 00
Česká republika
SpePharm Holding B.V.
Kingsfordweg 151
NL – 1043 GR Amsterdam
Tel: + 31 (0)88 0074 501
Malta
SpePharm Holding B.V.
Kingsfordweg 151
NL – 1043 GR Amsterdam
Tel: + 31 (0)88 0074 501
Danmark
SpePharm Holding B.V.
Kingsfordweg 151
NL – 1043 GR Amsterdam
Tlf: + 31 (0)88 0074 501
Nederland
SpePharm Holding B.V.
Kingsfordweg 151
NL – 1043 GR Amsterdam
Tel: + 31 (0)88 0074 501
Deutschland
SpePharm Holding B.V.
Kingsfordweg 151
NL – 1043 GR Amsterdam
Tel: + 31 (0)88 0074 501
Norge
SpePharm Holding B.V.
Kingsfordweg 151
NL – 1043 GR Amsterdam n
Tlf: + 31 (0)88 0074 501
Eesti
SpePharm Holding B.V.
Kingsfordweg 151
NL – 1043 GR Amsterdam
Tel: + 31 (0)88 0074 501
Österreich
SpePharm Holding B.V.
Kingsfordweg 151
NL – 1043 GR Amsterdam
Tel: + 31 (0)88 0074 501
Ελλάδα
a VIPharma International A.E.
Μεσογειων 43
GR – 151 26 Μαρούσι
Τηλ: + 30 210-6194170
Polska
SpePharm Holding B.V.
Kingsfordweg 151
NL – 1043 GR Amsterdam
Tel.: + 31 (0)88 0074 501
España
Ferrer Farma, S.A.
Gran Vía Carlos III, 94
E - 08028 Barcelona
Tel: +34 93 600 37 00
Portugal
Ferrer Azevedos, S.A.
Edificio Azevedos, Estrada Nacional 117-2
P-2614-503 Amadora
Tel: +351 21 4725900
France
SpePharm Holding B.V.
Kingsfordweg 151
NL – 1043 GR Amsterdam
România
SpePharm Holding B.V.
Kingsfordweg 151
NL – 1043 GR Amsterdam
24
Tél: + 31 (0)88 0074 501
Tel: + 31 (0)88 0074 501
Ireland
SpePharm Holding B.V.
Kingsfordweg 151
NL – 1043 GR Amsterdam
Tel: + 31 (0)88 0074 501
Slovenija
Medis d.o.o.
Brnciceva 1
SI-1001 Ljubljana
Tel: + 386 1 589 69 00
Ísland
SpePharm Holding B.V.
Kingsfordweg 151
NL – 1043 GR Amsterdam
Sími: + 31 (0)88 0074 501
Slovenská republika
SpePharm Holding B.V.
Kingsfordweg 151
NL – 1043 GR Amsterdam
Tel: + 31 (0)88 0074 501
Italia
SpePharm Italia s.r.l.
Via F. Baracca, 11
IT- 21047 Saronno (VA)
Tel: +39 029 670 4068
Suomi/Finland
SpePharm Holding B.V.
Kingsfordweg 151
NL – 1043 GR Amsterdam
Puh/Tel: + 31 (0)88 0074 501
Κύπρος
SpePharm Holding B.V.
Kingsfordweg 151
NL – 1043 GR Amsterdam
Τηλ: + 31 (0)88 0074 501
Sverige
SpePharm Holding B.V.
Kingsfordweg 151
NL – 1043 GR Amsterdam
Tel: + 31 (0)88 0074 501
Latvija
SpePharm Holding B.V.
Kingsfordweg 151
NL – 1043 GR Amsterdam
Tel: + 31 (0)88 0074 501
United Kingdom
SpePharm Holding B.V.
Kingsfordweg 151
NL – 1043 GR Amsterdam
Tel: + 31 (0)88 0074 501
Lietuva
SpePharm Holding B.V.
Kingsfordweg 151
NL – 1043 GR Amsterdam
Tel: + 31 (0)88 0074 501
This leaflet was last approved in
Detailed information on this medicine is available on the website of the European Medicines Agency
(EMA)
http://www.ema.europa.eu
25
The following information is intended for medical or healthcare professionals only.
Preparation guide for use with Savene powder for concentrate and diluent for solution for
infusion
It is important that you read the entire content of this procedure prior to the preparation of Savene.
1. FORMULATION
Savene is supplied as:
1.
Savene powder
2.
Savene diluent
Savene powder must be reconstituted in 25 ml sterile water and diluted in 500 ml diluent prior to
administration.
2. RECOMMENDATION FOR THE SAFE HANDLING
Savene is an anti-cancer agent and the normal procedures for proper handling and disposal of
anticancer medicines should be adopted, namely:
-
Personnel should be trained to reconstitute the medicine
-
Pregnant staff should be excluded from working with this medicine
-
Personnel handling this medicine during reconstitution should wear protective clothing including
mask, goggles and gloves
-
Accidental contact with the skin or eyes should be treated immediately and thoroughly with
copious amounts of water
3. PREPARATION FOR THE INTRAVENOUS ADMINISTRATION
3.1 Reconstitution of Savene powder
3.1.1 Using a syringe fitted with a needle, aseptically withdraw 25 ml of sterile water.
3.1.2 Inject the entire contents of the syringe into the vial containing the Savene powder.
3.1.3 Remove the syringe and needle and mix manually by repeated inversions until the powder is
fully dissolved. Do not shake.
3.1.4 Allow the vial with the reconstituted solution to stand for 5 minutes at room temperature and
check if the solution is homogenous and clear. The reconstituted solution is slightly yellow.
The reconstituted solution contains 20 mg dexrazoxane per ml and should be used immediately
after preparation. It contains no antibacterial preservative.
3.2 Dilution of the infusion concentrate
3.2.1 More than one vial containing reconstituted solution may be necessary to obtain the required
dose for the patient. Based on the required dose for the patient expressed in mg, aseptically
withdraw the corresponding reconstituted volume containing 20 mg dexrazoxane per ml from
the appropriate number of vials containing reconstituted solution. Use a graduated syringe filled
with a needle.
3.2.2 Inject the required reconstituted volume into the infusion bag with 500 ml diluent. The solution
must not be mixed with any other medicines.
3.2.3 Mix the infusion bag manually using a rocking motion
3.2.4 Savene should be aseptically administered as a 1-2 hours infusion under room temperature and
normal light conditions.
3.2.5 As with all parenteral products, Savene reconstituted solution and infusion solution should be
inspected visually for particulate matter and discoloration prior to administration. Solutions
containing a precipitate should be discarded.
4. DISPOSAL
26
All items for preparation, administration or cleaning, including gloves, as well as liquid waste should
be disposed of in accordance with local requirements.
27
Source: European Medicines Agency
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