SAVENE 20mg / ml powder for concentrate + solvent infusion solution medication leaflet

Savene 20 mg/ml powder and solvent for concentrate for solution for infusion.

Each vial contains 500 mg dexrazoxane (589 mg dexrazoxane hydrochloride).

Each ml contains 20 mg of dexrazoxane after reconstitution with 25 ml of Savene solvent.

Solvent bottle:

Potassium 98 mg/500 ml or 5.0 mmol/l

Sodium 1.61 g/500 ml or 140 mmol/l

For the full list of excipients, see section 6.1.

Powder and solvent for concentrate for solution for infusion.

Powder vial:

White to off-white lyophilisate.

Solvent bottle:

Clear isotonic solution (295 mOsml/l, pH approx. 7.4).

Savene is indicated in adults for the treatment of anthracycline extravasation.

Savene must be administered under the supervision of a physician experienced in the use of anti-cancer medicinal products.

Treatment should be given once daily for 3 consecutive days. The recommended dose is:

Day 1: 1000 mg/m2

Day 2: 1000 mg/m2

Day 3: 500 mg/m2

The first infusion should be initiated as soon as possible, within the first six hours after the accident.

Treatment Day 2 and Day 3 should start at the same hour (+/- 3 hours) as Day 1.

For patients with a body surface area of more than 2 m2 the single dose should not exceed 2000 mg.

In patients with moderate to severe renal impairment (creatinine clearance <40 mL/min) the Savenedose should be reduced by 50% (see section 4.4 and 5.2).

Dexrazoxane has not been studied in patients with impaired hepatic function and its use in suchpatients is not recommended (see section 4.4).

Safety and efficacy have not been evaluated in the elderly and the use of dexrazoxane in such patientsis not recommended.

The safety and efficacy of Savene in children below the age of 18 years have not been established andno data are available.

For intravenous use after reconstitution and dilution.

For instructions on reconstitution and dilution of the medicinal product before administration, seesection 6.6.

The indicated dose should be administered as an intravenous infusion over 1-2 hours into a large veinof an extremity or area other than the one affected by the extravasation. Cooling procedures such asice packs should have been removed from the area at least 15 minutes before the Saveneadministration in order to allow sufficient blood flow.

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

* Women of childbearing potential not using contraceptive measures (see section 4.6).

* Breast-feeding (see section 4.6).

* Concomitant vaccination with yellow fever vaccine (see section 4.5).

Continuous monitoring

Local examination should be performed on a regular basis after treatment until resolution.

If there is suspicion of extravasation by vesicant compounds other than anthracyclines through thesame IV access, e.g. vincristine, mitomycin, and vinorelbine, Savene would not be effective againstthe effects from these compounds.

Since Savene will be administered to patients undergoing cytotoxic therapy with anthracyclines itscytotoxic potential (especially resulting in reversible haematological toxicity with a nadir occurring ondays 11-12) will therefore add to that of the other chemotherapy administered. Haematologicalmonitoring should therefore be undertaken regularly.

Hepatic and renal-function monitoring

Since liver dysfunction (increases in transaminases and bilirubin) may occur (especially after doses ofabove 1 000 mg/m2 dexrazoxane), it is recommended that routine liver function tests be performedbefore each administration of dexrazoxane in patients with known liver function disorders (seesection 4.2).

Since renal dysfunction may decrease the rate of elimination of dexrazoxane, patients with impairedrenal function should be monitored for signs of haematological toxicity (see section 4.2 for dosingrecommendations in patients with moderate to severe renal impairment (creatinine clearance<40 mL/min)).

Anaphylactic reaction including angioedema, skin reactions, bronchospasm, respiratory distress,hypotension and loss of consciousness have been observed in patients treated with dexrazoxane andanthracyclines (see section 4.8). Previous history of allergy to dexrazoxane should be carefullyconsidered prior to administration (see section 4.3).

Women of child-bearing potential/Contraception in males and females

Since dexrazoxane possesses mutagenic activity and is used with anthracyclines known to havecytotoxic, mutagenic and embryotoxic properties, both sexually active men and women ofchildbearing potential should be advised not to father a child/become pregnant and must use effectivecontraceptive measures during and up to 6 months after treatment. Women must inform their doctorimmediately if they become pregnant (see section 4.3 and 4.6).

Potassium and sodium contents

Savene solvent contains 98 mg potassium per 500 ml bottle. This must be taken into consideration bypatients with reduced kidney function or patients on a controlled potassium diet. Plasma potassiumlevel must be closely monitored in patients at risk of hyperkalaemia.

Savene solvent also contains 1.61 g sodium per 500 ml bottle, equivalent to 81% of the WHOrecommended maximum daily intake of 2 g sodium for an adult.

Yellow fever vaccine: Risk of fatal generalised vaccinial disease (see section 4.3).

* Other live attenuated vaccines: risk of systemic, possible fatal disease. This risk is increased insubjects who are already immunosuppressed by their underlying disease or by concomitantchemotherapy. Use an inactivated vaccine where this exists (poliomyelitis).

* Dimethylsulfoxide (DMSO) should not be used in patients who are administered dexrazoxane totreat anthracycline extravasation (see section 5.3)

* Phenytoin: cytotoxic agents may reduce the absorption of phenytoin leading to an exacerbationof convulsions. Dexrazoxane is not recommended in combination with phenytoin.

Concomitant use to assess carefully:

Ciclosporin, tacrolimus: Excessive immunosuppression with risk of lymphoproliferative disease.

Interactions common to all cytotoxics:

* Due to an increased thrombotic risk in patients with malignant diseases, the use ofanticoagulants treatment is frequent. Patients treated with anticoagulants should be monitoredmore frequently as cytotoxic agents may interact with oral anticoagulants.

* Dexrazoxane may add to the toxicity induced by the chemotherapy cycle during which theaccident took place, requiring careful monitoring of haematological parameters (seesection 4.4).

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.

Co-administration of doxorubicin (50 to 60 mg/m2) or epirubicin (60 to 100 mg/m2) did not affectdexrazoxane pharmacokinetics significantly. In studies, dexrazoxane did not affect thepharmacokinetics of doxorubicin. There is limited evidence from studies that suggests epirubicinclearance may be increased when dexrazoxane is pre-administered, this occurred at high doses ofepirubicin (120-135 mg/m2). Note that in these studies dexrazoxane was administered prior toanthracyline administration.

Since dexrazoxane possesses mutagenic activity and is used with anthracyclines known to havecytotoxic, mutagenic and embryotoxic properties, both sexually active men and women ofchildbearing potential should be advised not to father a child/become pregnant and must use effectivecontraceptive measures during and up to 6 months after treatment. Women must inform their doctorimmediately if they become pregnant (see section 4.3).

There are no data from the use of dexrazoxane in pregnant women. Dexrazoxane may cause foetalharm when administered to pregnant women. Studies in animals have shown reproductive toxicity (seesection 5.3). Dexrazoxane should not be administered to pregnant women unless clearly necessary.

It is not known whether dexrazoxane is excreted in human milk. Because of the potential for seriousadverse reactions in breast-fed infants exposed to dexrazoxane, breast-feeding is contraindicatedduring Savene therapy (see section 4.3).

There are limited fertility data from animal studies available, but testicular changes were observed inrats and rabbits following repeat dosing (see section 5.3).

Dizziness, somnolence and syncope have been reported in a few patients included in Savene studies

TT01 and TT02 (see section 4.8). Dexrazoxane has minor influence on the ability to drive and usemachines.

A number of published reports comprising more than 1000 patients have demonstrated a uniformpattern of dose dependent adverse reactions. Most common adverse reactions are nausea/vomiting,bone marrow suppression (neutropenia, thrombocytopenia), injection site reactions, diarrhoea,stomatitis and increase in hepatic transaminases (ALT/AST). All adverse reactions have been rapidlyreversible.

The following information is based on two clinical studies, TT01 and TT02, of Savene administered toextravasation patients already receiving cycles of chemotherapeutic agents.

The adverse reactions were those typically seen with standard chemotherapy and also withdexrazoxane: Nausea/vomiting in about one third of the patients, neutropenia and thrombocytopenia inabout half of the patients, more rarely increased concentration of liver enzymes (ALT/AST).

Adverse reactions observed in the two studies are listed below.

Incidence of adverse reactions (MedDRA) in studies TT01 and TT02 (n=80 patients)(Note that numbers for Blood and Lymphatic System Disorders are described in a separate table oflaboratory examinations)

Adverse reactions reported are listed according to the following frequency:

Very common (≥1/10)

Common (≥1/100 to <1/10)

Uncommon (≥1/1,000 to <1/100)

Rare (≥1/10,000 to <1/1,000)

Very rare (<1/10,000)

System Organ Classes (SOC) Frequency Adverse reactions

Infections and infestations Very common Postoperative infection

Common Infection

Neutropenic infection

Immune system disorders Not known Anaphylactic reactions

Not known Hypersensitivity

Metabolism and nutrition disorders Common Decreased appetite

Nervous system disorders Common Dizziness

Sensory loss

Tremor

Vascular disorders Common Phlebitis

Superficial thrombophlebitis

Venous thrombosis limb

Respiratory, thoracic and mediastinal Common Dyspnoeadisorders

Gastrointestinal disorders Very common Nausea

Common Vomiting

Stomatitis

Dry mouth

Skin and subcutaneous tissue Common Alopeciadisorders

Pruritus

Musculoskeletal and connective Common Myalgiatissue disorders

Reproductive system and breast Common Vaginal haemorrhagedisorders

General disorders and administration Very common Injection site painsite conditions

Common Pyrexia

Injection site phlebitis

Injection site erythema

Injection site induration

Peripheral oedema

Somnolence

Investigations Common Weight decreased

Injury, poisoning and procedural Common Wound complicationcomplications

Incidence of laboratory abnormalities in TT01 and TT02 (n=80 patients)

No of patients with CTC grade 3-4

Lab test post baseline value 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%

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

Signs and symptoms of overdosage are likely to consist of leucopenia, thrombocytopenia, nausea,vomiting, diarrhoea, skin reactions and alopecia. Treatment should be symptomatic.

Pharmacotherapeutic group: Detoxifying agents for antineoplastic agents, ATC code: V03AF02

Two pharmacodynamic properties of dexrazoxane are described in the literature:1. Prevention of anthracycline cardiotoxicity, and2. Antineoplastic action

Dexrazoxane has two major mechanisms of action:1. Chelation of iron, especially through its ring-opened metabolite thus reducing the iron-dependent oxidative stress causing anthracycline-induced cardiotoxicity.2. Inhibition of topoisomerase II.

It is not known to what extent each of these mechanisms contributes to the preventive effect on tissuedestruction following anthracycline extravasation.

The chelating property is probably also responsible for an increased urinary excretion of iron and zincand a decreased serum concentration of calcium as described in a few studies.

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 preventingtissue damage from accidentally extravasated anthracycline, and thus preventing the patients fromundergoing the routinely used surgical excision of the affected tissue.

Due to the rarity of the condition only historical data could be used for comparison (demonstratingsurgical 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 within6 hours from the incident and was repeated after 24 and 48 hours. The first and second doses were1000 mg/m2 and the third was 500 mg/m2.

A requirement for inclusion in the efficacy part of the study was that the anthracycline extravasationwas proven by fluorescence microscopy of one or more biopsies.

For study purposes, patients with extravasations from a central venous access device (CVAD) werenot included in the efficacy evaluation.

Patients with neutropenia and thrombocytopenia > CTC grade 1 (Common Toxicity Criteria) have notbeen included in the clinical studies.

In study TT01, 23 patients were entered and received treatment with Savene. Eighteen were evaluablefor efficacy and safety and a further five patients were evaluable for toxicity only. None of the patientsrequired surgical intervention.

In study TT02, 57 patients entered the study and received the first dose of Savene. 36 patients wereevaluable for efficacy. Only one of the 36 patients required surgery.

In both studies all patients had received anthracycline. Overall, the most commonly receivedanthracycline was epirubicin (56 % of the patients).

In both studies dexrazoxane treatment prevented the development of necrosis, allowed cancertreatment to continue as scheduled in the majority of patients (70.4 %), and reduced the occurrence ofsequelae (only few and mild long-term sequelae were observed).

Savene must only be administered intravenously.

Bibliographical data demonstrate that serum kinetics of dexrazoxane after intravenous administrationfollow an open two-compartment model independent of schedule and dose. The apparent volumes ofdistribution are 0.13-1.3 l/kg (median 0.49 l/kg). Volume of distribution is independent of dose. AUCswere dose-proportional. Tissue distribution is rapid, with the highest levels of unchanged parentcompound and hydrolysed product appearing in liver and kidneys. About 2% of dexrazoxane isprotein-bound.

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 astrong chelator of iron and divalent cations as calcium ions.

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 ofunchanged dexrazoxane is 34-60 %. Systemic clearance is independent of dose. The pharmacokineticsof the metabolites is derived from a single study with five patients. The mean elimination half-lives ofthe 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 inliterature. ADR-925 is reported to increase three-fold within 15 min after infusion of 1500 mg/m2 andremain relatively constant on a plateau for 4 hours and then decreased to about half at 24 hours.

In-vitro studies on dexrazoxane in human microsomes have shown high stability of dexrazoxaneindicating that major metabolism via cytochrome P450 is unlikely.

There is insufficient data available to draw any definite conclusions regarding intrinsic pharmaco-kinetic factors such as age, gender, race and weight. Inter- and intra-individual pharmacokineticvariabilities have not been studied systematically. Based on a limited number of patients, inter-individual variability calculated as the coefficient of variation (CV %) was estimated to beapproximately 30 % for the main pharmacokinetic parameters.

Compared with normal subjects (creatinine clearance (CLCR) >80 mL/min), exposure was 2- foldgreater in subjects with moderate (CLCR of 30 to 50 mL/min) to severe (CLCR <30 mL/min) renalimpairment. Modelling suggested that equivalent exposure (AUC0-inf) could be achieved if dosing werereduced by 50% in subjects with CLCR less than 40 mL/min compared with control subjects (CLCR>80 mL/min) (see section 4.2).

Pharmacokinetics in patients with extravasations

Clinical trial TT04 was conducted on 6 female patients undergoing treatment for anthracyclineextravasations. The aim was to examine the pharmacokinetics of a 3-day dosing regimen ofdexrazoxane and its efficacy in patients for anthracycline extravasation. The systemic clearances weresimilar between day 1 (9.9 L/h ± 3.1) and day 2 (11.1 L/h ± 4.5), and did not differ from thosereported in the literature. The steady-state volume of distribution of dexrazoxane was 30.5 L ± 11.1 forday 1 and 35.8 L ± 19.7 for day 2. The terminal elimination half-life was consistent throughout days1 - 3 (2.1 - 2.2 h). The mean AUC0-24 values for day 1 and day 2 were comparable with each other, andthe AUC0-last at day 3 was approximately half that of the first two days, suggesting that thepharmacokinetics of dexrazoxane are dose-dependent. The overall ranges and mean of AUC0-24between days were very similar; it does not appear that there is any significant accumulation ofdexrazoxane.

Repeat-dose toxicity studies with dexrazoxane have shown that primary target organs were tissues thatundergo rapid cell division: bone marrow, lymphoid tissue, testes and digestive tract.

Myelosuppression is thus common. The apparent effects were greater during chronic than acuteadministration. The toxicity in combination with doxorubicin was additive and not synergistic.

Dexrazoxane has been shown to possess mutagenic activity. The carcinogenic potential ofdexrazoxane has not been investigated, however, razoxane (the racemic mixture of dexrazoxane andlevrazoxane) has been reported to be associated with the development of malignancies in mice(lymphoid neoplasms) and rats (uterine carcinomas) after administration for a prolonged period oftime. Both of these effects are expected for this class of compound.

There are limited fertility data from animal studies available, but testicular changes were observed inrats and rabbits following repeat dosing.

The related razoxane has been demonstrated to be embryotoxic in mice, rats and rabbits andteratogenic in rats and mice.

When mice with experimental daunorubicin extravasation were treated with dexrazoxane systemicallycombined with topical treatment with DMSO on the daunorubicin-affected skin area, 67 % of the micedeveloped small skin wounds, whereas dexrazoxane treatment alone completely prevented thedaunorubicin-induced skin necrosis in another group of mice. Thus, dimethylsulfoxide (DMSO)should not be used in patients who are administered dexrazoxane to treat anthracycline extravasation.

Powder vialnone

Solvent bottle

Sodium chloride

Potassium chloride

Magnesium chloride hexahydrate

Sodium acetate trihydrate

Sodium gluconate

Sodium hydroxide

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.

Powder and solvent:3 years.

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 theuser and should not be longer than 4 hours at 2 to 8 °C.

Store below 25 °C.

Keep the vials and bottles in the outer carton in order to protect from light.

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

Savene powder:

Amber-coloured, 36-ml, glass type I vial with stopper made of chlorobutyl rubber and a flip-off cap.

Savene solvent:500 ml solution in bottles made of Type-I (Ph.Eur.) glass.

Savene is available as an emergency kit consisting of 10 vials of Savene powder and 3 bottles of

Savene solvent supplied with 3 bottle hangers.

Before infusion, Savene powder must be reconstituted with 25 ml Savene solvent to give aconcentration of 20 mg dexrazoxane per ml. The concentrate is slightly yellow. The concentrateshould then be diluted further in the remaining Savene solvent.

Caution must be exercised during reconstitution and dilution and the normal procedures for properhandling of cytotoxic medicinal products should be adopted. The preparation should not be handled bypregnant staff. Use of gloves and other protective clothing to prevent skin contact is recommended.

Skin reactions have been reported following contact with dexrazoxane. If the powder or solutioncontacts the skin or mucous membranes, wash immediately and thoroughly with water.

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

Clinigen Healthcare B.V.

Schiphol Boulevard 359

WTC Schiphol Airport, D Tower 11th floor1118BJ Schiphol

The Netherlands

EU/1/06/350/001

Date of first authorisation: 28 July 2006

Date of latest renewal: 18 July 2011

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

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