1. Name Of The Medicinal Product
Savene
2. Qualitative And Quantitative Composition
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.
3. Pharmaceutical Form
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).
4. Clinical Particulars
4.1 Therapeutic Indications
Savene is indicated for the treatment of anthracycline extravasation.
4.2 Posology And Method Of Administration
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/m2 |
Day two: | 1000 mg/m2 |
Day three: | 500 mg/m2 |
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 m2 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.
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.
4.3 Contraindications
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).
4.4 Special Warnings And Precautions For Use
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/m2 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).
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.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
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.
4.6 Pregnancy And Lactation
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)
4.7 Effects On Ability To Drive And Use 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, as it has rarely been associated with any impairment of the central nervous system such as confusion.
4.8 Undesirable Effects
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 (
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)
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Incidence of laboratory abnormalities (all patients) in TT01 and TT02
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4.9 Overdose
Signs and symptoms of overdosage are likely to consist of leucopenia, thrombocytopenia, nausea, vomiting, diarrhoea, skin reactions and alopecia. Treatment should be symptomatic.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: Detoxifying agents for antineoplastic agents, ATC code: V03AF02
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/m2 and the third was 500 mg/m2.
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.
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/m2 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. Pharmaceutical Particulars
6.1 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
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.
7. Marketing Authorisation Holder
SpePharm Holding B.V.
Kingsfordweg 151
NL – 1043 GR Amsterdam
Netherlands
8. Marketing Authorisation Number(S)
EU/1/06/350/001
9. Date Of First Authorisation/Renewal Of The Authorisation
28/07/2006
10. Date Of Revision Of The Text
05/2010
Detailed information on this product is available on the website of the European Medicines Agency (EMA) http://www.ema.europa.eu
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