SAVENE Powder and solvent for solution for infusion Ref.[9514] Active ingredients: Dexrazoxane

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 the same IV access, e.g. vincristine, mitomycin, and vinorelbine, Savene would not be effective against the effects from these compounds.

Since Savene will be administered to patients undergoing cytotoxic therapy with anthracyclines its cytotoxic potential (especially resulting in reversible haematological toxicity with a nadir occurring on days 11-12) will therefore add to that of the other chemotherapy administered.

Haematological monitoring should therefore be undertaken regularly.

Hepatic and renal-function monitoring

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 be performed before each administration of dexrazoxane in patients with known liver function disorders (see section 4.2). Since renal dysfunction may decrease the rate of elimination of dexrazoxane, patients with impaired renal function should be monitored for signs of haematological toxicity (see section 4.2 for dosing recommendations in patients with moderate to severe renal impairment (creatinine clearance <40 mL/min)).

Anaphylactic reaction

Anaphylactic reaction including angioedema, skin reactions, bronchospasm, respiratory distress, hypotension and loss of consciousness have been observed in patients treated with dexrazoxane and anthracyclines (see section 4.8). Previous history of allergy to dexrazoxane should be carefully considered 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 have cytotoxic, mutagenic and embryotoxic properties, both sexually active men and women of childbearing potential should be advised not to father a child/become pregnant and must use effective contraceptive measures during and up to 6 months after treatment. Women must inform their doctor immediately 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 by patients with reduced kidney function or patients on a controlled potassium diet. Plasma potassium level 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 WHO recommended maximum daily intake of 2 g sodium for an adult.

Concomitant use contraindicated:

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

Concomitant use not recommended:

• Other live attenuated vaccines: risk of systemic, possible fatal disease. This risk is increased in subjects who are already immunosuppressed by their underlying disease or by concomitant chemotherapy. Use an inactivated vaccine where this exists (poliomyelitis).
• Dimethylsulfoxide (DMSO) should not be used in patients who are administered dexrazoxane to treat anthracycline extravasation (see section 5.3).
• Phenytoin: cytotoxic agents may reduce the absorption of phenytoin leading to an exacerbation of 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 of anticoagulants treatment is frequent. Patients treated with anticoagulants should be monitored more frequently as cytotoxic agents may interact with oral anticoagulants.
• Dexrazoxane may add to the toxicity induced by the chemotherapy cycle during which the accident took place, requiring careful monitoring of haematological parameters (see section 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 affect dexrazoxane pharmacokinetics significantly. In studies, dexrazoxane did not affect the pharmacokinetics of doxorubicin. There is limited evidence from studies that suggests epirubicin clearance may be increased when dexrazoxane is pre-administered, this occurred at high doses of epirubicin (120-135 mg/m²). Note that in these studies dexrazoxane was administered prior to anthracyline administration.

Women of childbearing potential/Contraception in males and females

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

Pregnancy

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

Breast-feeding

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

Fertility

There are limited fertility data from animal studies available, but testicular changes were observed in rats 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 use machines.

A number of published reports comprising more than 1000 patients have demonstrated a uniform pattern 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 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 were 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). 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 of laboratory 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)

Infections and infestations

Very common: Postoperative infection

Common: Infection, Neutropenic infection

Immune system disorders

Not known: Anaphylactic reactions, Hypersensitivity

Metabolism and nutrition disorders

Common: Decreased appetite

Nervous system disorders

Common: Dizziness, Sensory loss, Syncope, Tremor

Vascular disorders

Common: Phlebitis, Superficial thrombophlebitis, Venous thrombosis limb

Respiratory, thoracic and mediastinal disorders

Common: Dyspnoea, Pneumonia

Gastrointestinal disorders

Very common: Nausea

Common: Vomiting, Diarrhoea, Stomatitis, Dry mouth

Skin and subcutaneous tissue disorders

Common: Alopecia, Pruritus

Musculoskeletal and connective tissue disorders

Common: Myalgia

Reproductive system and breast disorders

Common: Vaginal haemorrhage

General disorders and administration site conditions

Very common: Injection site pain

Common: Pyrexia, Injection site phlebitis, Injection site erythema, Fatigue, Injection site induration, Injection site swelling, Peripheral oedema, Somnolence

Investigations

Common: Weight decreased

Injury, poisoning and procedural complications

Common: Wound complication

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reaction via the national reporting system listed in Appendix V.

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