Dexrazoxane

Dexrazoxane is a cyclic derivative of EDTA that readily enters cells. It belongs to the group of detoxifying agents for antineoplastic treatments. In the EU it is authorised for two different uses: Savene treats anthracycline extravasation, and Cardioxane prevents the cumulative cardiotoxicity of anthracyclines. The Savene SmPC notes that two pharmacodynamic properties of dexrazoxane are described in the literature, prevention of anthracycline cardiotoxicity and an antineoplastic action.

Mechanism of Action

• Metal chelation: dexrazoxane is a prodrug that is hydrolysed inside cells. According to the Savene SmPC it passes through two one-ring-open intermediates to a two-ring-opened form (ADR-925), a strong chelator of iron and of divalent cations such as calcium. The Cardioxane SmPC describes hydrolysis in cardiac cells to the ring-opened product ICRF-198 and states that both dexrazoxane (ICRF-187) and ICRF-198 can chelate metal ions.
• Cardioprotection (Cardioxane): the exact mechanism is not fully elucidated. The dose-dependent cardiotoxicity of anthracyclines is attributed to oxidative stress from free radicals generated by iron-dependent, anthracycline-induced reactions in relatively unprotected heart muscle. By capturing metal ions, dexrazoxane and its ring-opened product are thought to prevent redox cycling of the iron(III)–anthracycline complex and the formation of reactive radicals.
• Topoisomerase II inhibition: the second major mechanism named in the Savene SmPC; the Cardioxane SmPC likewise describes dexrazoxane as a cytotoxic agent with topoisomerase II inhibitory activity.
• Extravasation (Savene): it is not known to what extent iron chelation and topoisomerase II inhibition each contribute to preventing tissue destruction after anthracycline extravasation. The chelating property probably also explains the increased urinary excretion of iron and zinc and the lower serum calcium seen in a few studies. Two open, single-arm, multicentre studies (TT01 and TT02) tested whether Savene, started within 6 hours and repeated after 24 and 48 hours, could prevent tissue damage and so avoid surgical excision; only historical comparison data were available, with surgical rates of 35–50%.
• Clinical evidence for cardioprotection (Cardioxane): the benefit appears to grow with the cumulative anthracycline dose, and dexrazoxane does not protect against the non-cardiac toxicities of anthracyclines. In two studies that used a dexrazoxane to doxorubicin ratio of 20:1, mortality was higher with dexrazoxane plus chemotherapy than with chemotherapy alone or placebo; the ratio was then reduced to 10:1, with no significant survival difference reported.

Pharmacokinetics

• Administration: both products are given only by the intravenous route.
• Distribution: for Savene, kinetics follow an open two-compartment model independent of schedule and dose, with an apparent volume of distribution of 0.13–1.3 L/kg (median 0.49 L/kg), rapid tissue distribution (highest levels in liver and kidneys) and about 2% protein binding. For Cardioxane, a 12–15 minute infusion of 1,000 mg/m² gives a peak concentration of about 80 µg/mL (AUC 130 ± 27 mg·h/L); the apparent volume of distribution is 44.0 ± 3.9 L, suggesting distribution mainly in total body water; protein binding is about 2%; and no clinically significant amount enters the cerebrospinal fluid.
• Metabolism: hydrolysis to the ring-opened forms described above. The Cardioxane SmPC names dihydropyrimidine amidohydrolase in the liver and kidney as the enzyme involved. The Savene SmPC reports high stability in human microsomes, so major metabolism through cytochrome P450 is unlikely.
• Elimination: Savene shows biphasic elimination with a terminal half-life of 1.9–9.1 hours (median 2.8 hours) and urinary recovery of unchanged drug of 34–60%; clearance is independent of dose. For Cardioxane the half-life is 2.2 ± 0.42 hours, total body clearance in adults is about 14.4 ± 2.8 L/h, and about 40% of the dose is excreted unchanged in urine.
• Special populations: in moderate to severe renal impairment (creatinine clearance below 50 mL/min), exposure is twice that of subjects with clearance above 80 mL/min, and modelling in the Cardioxane SmPC suggests that halving the dose when clearance is below 40 mL/min gives equivalent exposure. The Savene SmPC has insufficient data on age, gender, race and weight, with between-patient variability of about 30%. The Cardioxane SmPC reports very limited paediatric data (clearance normalised to body surface area not significantly different from adults), no studies in people over 65 (clearance may be reduced in older patients and in those with low creatinine clearance) and no studies in hepatic impairment.

• Savene, anthracycline extravasation: indicated in adults for the treatment of anthracycline extravasation.
• Cardioxane, prevention of anthracycline cardiotoxicity: indicated in adults for the prevention of chronic cumulative cardiotoxicity caused by anthracycline use in patients with advanced and/or metastatic breast cancer who have received a prior cumulative dose of 300 mg/m² of doxorubicin or of 540 mg/m² of epirubicin, when further anthracycline treatment is required.

Savene

• Hypersensitivity to the active substance or to any of the excipients.
• Women of childbearing potential not using contraceptive measures.
• Breast-feeding.
• Concomitant vaccination with yellow fever vaccine.

Cardioxane

• Hypersensitivity to dexrazoxane.
• Children and adolescents aged 0 to 18 years who are expected to receive a cumulative dose below 300 mg/m² of doxorubicin, or the equivalent cumulative dose of another anthracycline.
• Breast-feeding.
• Concomitant vaccination with yellow fever vaccine.

Savene

The SmPC draws on published reports covering more than 1,000 patients, which show a uniform pattern of dose-dependent reactions, and on two clinical studies (TT01 and TT02, 80 patients) in which Savene was given to patients with extravasation who were already receiving cycles of chemotherapy. The most common reactions are nausea and vomiting, bone marrow suppression (neutropenia, thrombocytopenia), injection site reactions, diarrhoea, stomatitis and increased liver transaminases (ALT/AST); all have been rapidly reversible. In TT01 and TT02, nausea and vomiting occurred in about one third of patients, neutropenia and thrombocytopenia in about half, and raised liver enzymes more rarely.

Very common (≥1/10): postoperative infection, nausea, injection site pain.

Common (≥1/100 to <1/10): infection, neutropenic infection, decreased appetite, dizziness, sensory loss, syncope, tremor, phlebitis, superficial thrombophlebitis, venous thrombosis of the limb, dyspnoea, pneumonia, vomiting, diarrhoea, stomatitis, dry mouth, alopecia, pruritus, myalgia, vaginal haemorrhage, pyrexia, fatigue, peripheral oedema, somnolence, injection site reactions (phlebitis, erythema, induration, swelling), decreased weight, wound complication.

Not known: anaphylactic reactions, hypersensitivity.

In TT01 and TT02, grade 3–4 laboratory abnormalities included neutrophils (46.2%), white blood cells (45.0%), platelets (21.3%) and haemoglobin (2.5%). The haematological toxicity is reversible, with a nadir around days 11 and 12, and adds to that of the chemotherapy.

Cardioxane

Cardioxane is given together with anthracycline chemotherapy, so the relative contribution of each to the reactions may not be clear. The most common reactions are haematological and gastrointestinal, mainly anaemia, leukopenia, nausea, vomiting and stomatitis, together with asthenia and alopecia. The myelosuppressive effects can add to those of the chemotherapy. The table in the SmPC combines clinical trial and post-marketing reactions; spontaneous post-marketing reports not previously identified in trials are listed as ‘not known’. The trial data come from 375 patients given chemotherapy plus Cardioxane (76% treated for breast cancer, 24% for various advanced cancers) and 157 patients given chemotherapy alone.

Very common (≥1/10): anaemia, leukopenia, nausea, vomiting, stomatitis, alopecia, asthenia.

Common (≥1/100 to <1/10): neutropenia, thrombocytopenia, febrile neutropenia, granulocytopenia, febrile bone marrow aplasia, decreased white blood cell count, anorexia, paraesthesia, dizziness, headache, peripheral neuropathy, decreased ejection fraction, tachycardia, phlebitis, dyspnoea, cough, pharyngitis, respiratory tract infections, diarrhoea, constipation, abdominal pain, dyspepsia, increased transaminases, nail disorder, erythema, mucosal inflammation, pyrexia, fatigue, malaise, injection site reactions (including pain, swelling, burning sensation, erythema, pruritus, thrombosis), oedema.

Uncommon (≥1/1,000 to <1/100): infection, sepsis, acute myeloid leukaemia, increased eosinophil, neutrophil, platelet and white blood cell counts, decreased lymphocyte and monocyte counts, syncope, vertigo, ear infection, venous thrombosis, lymphoedema, gingivitis, oral candidiasis, cellulitis, thirst.

Not known: anaphylactic reaction, hypersensitivity, embolism, pulmonary embolism.

Acute myeloid leukaemia has been reported uncommonly in adults with breast cancer after marketing. In children, second primary malignancies (including acute myeloid leukaemia and myelodysplastic syndrome) were reported in both dexrazoxane and control groups, numerically more often with dexrazoxane but without a statistical difference. At doses near the maximum tolerated dose, studied when dexrazoxane was used as a cytotoxic agent, reactions included neutropenia, thrombocytopenia, nausea, vomiting and raised liver parameters.

Both SmPCs give the same vaccine, phenytoin and immunosuppressant warnings; the other points come from one SmPC each.

• Yellow fever vaccine: contraindicated with either product, because of the risk of fatal generalised vaccinal disease.
• Other live attenuated vaccines: not recommended, because of the risk of systemic, possibly fatal disease, which is higher in patients already immunosuppressed by their underlying disease (and, in the Savene SmPC, by concomitant chemotherapy). An inactivated vaccine should be used where one exists (poliomyelitis).
• Phenytoin: cytotoxic agents may reduce the absorption of phenytoin and worsen convulsions, so dexrazoxane is not recommended with phenytoin.
• Ciclosporin and tacrolimus: to be assessed carefully, because of excessive immunosuppression with a risk of lymphoproliferative disease.
• Anthracyclines: doxorubicin (50–60 mg/m²) and epirubicin (60–100 mg/m²) did not significantly change dexrazoxane pharmacokinetics, and dexrazoxane did not change doxorubicin pharmacokinetics. There is limited evidence that epirubicin clearance may increase when dexrazoxane is given first, at high epirubicin doses (120–135 mg/m²).
• Haematological toxicity: dexrazoxane may add to the toxicity of the chemotherapy cycle during which the accident occurred (Savene) or of chemotherapy or radiation (Cardioxane), so haematological parameters need careful monitoring, and thorough monitoring during the first two cycles with Cardioxane.
• Savene only: dimethylsulfoxide (DMSO) should not be used in patients given dexrazoxane for extravasation. Patients on anticoagulants, which are often used because of the raised thrombotic risk in malignancy, should be monitored more often, as cytotoxic agents may interact with oral anticoagulants. Dexrazoxane did not inhibit CYP1A, CYP2C9, CYP2C19, CYP2D6 or CYP3A4.
• Cardioxane only: it is excreted unchanged by the kidneys and metabolised by dihydropyrimidine amidohydrolase. It must not be mixed with any other medicine during the infusion. Interaction studies have been done only in adults.

Savene must be given under the supervision of a physician experienced in the use of anti-cancer medicinal products. Both products are given as intravenous infusions after reconstitution and dilution (see section 6.6 of each SmPC).

Savene: Recommended Dose

Treatment is given once daily for 3 consecutive days:

• Day 1: 1,000 mg/m²
• Day 2: 1,000 mg/m²
• Day 3: 500 mg/m²

The first infusion should start as soon as possible, within the first 6 hours after the accident. The Day 2 and Day 3 infusions start at the same hour (±3 hours) as Day 1. For a body surface area above 2 m², a single dose should not exceed 2,000 mg.

Savene: Method of Administration

• The powder is reconstituted with the 25 mL of Savene solvent supplied, giving 20 mg/mL, and then diluted.
• Each dose is infused over 1–2 hours into a large vein of an extremity or area other than the one affected by the extravasation.
• Cooling procedures such as ice packs should be removed from the affected area at least 15 minutes before the infusion, so that blood flow is sufficient.

Savene: Special Populations

• Renal impairment: in moderate to severe impairment (creatinine clearance below 40 mL/min), the Savene dose is reduced by 50%.
• Hepatic impairment: not studied, and use is not recommended.
• Elderly: safety and efficacy have not been evaluated, and use is not recommended.
• Children and adolescents: safety and efficacy below 18 years have not been established, and no data are available.

Cardioxane: Recommended Dose

• Cardioxane is given as a short intravenous infusion over 15 minutes, starting about 30 minutes before the anthracycline.
• The dose is 10 times the equivalent doxorubicin dose or 10 times the equivalent epirubicin dose: 500 mg/m² with the usual doxorubicin regimen of 50 mg/m², or 600 mg/m² with the usual epirubicin regimen of 60 mg/m².
• Preparation: each vial is dissolved in 25 mL of water for injections, and the solution is diluted before the infusion, to avoid the risk of thrombophlebitis at the injection site, with Ringer lactate or 0.16 M sodium lactate solution (25 to 100 mL per vial; larger volumes raise the pH). Cardioxane is single-use.

Cardioxane: Special Populations

• Renal impairment: in moderate to severe impairment (creatinine clearance below 40 mL/min), the dexrazoxane dose is reduced by 50%.
• Hepatic impairment: the dose ratio is maintained, so if the anthracycline dose is reduced, the dexrazoxane dose is reduced accordingly.
• Elderly: the SmPC gives no specific dose adjustment; caution is advised (see Special Instructions).
• Children and adolescents: safety and efficacy at 0 to 18 years have not been established, and Cardioxane is contraindicated in children expected to receive a cumulative doxorubicin dose below 300 mg/m² (or the equivalent of another anthracycline).

Savene: Local Follow-up and Other Vesicants

A local examination should be done regularly after treatment until the extravasation has resolved. If another vesicant, such as vincristine, mitomycin or vinorelbine, may have leaked through the same intravenous access, Savene would not be effective against its effects.

Savene: Haematological Toxicity, Liver and Kidney Function

Savene has cytotoxic potential of its own, with reversible haematological toxicity and a nadir on days 11 and 12, which adds to that of the anthracycline chemotherapy, so blood counts should be monitored regularly. Liver dysfunction (rises in transaminases and bilirubin) may occur, especially after doses above 1,000 mg/m², and routine liver function tests are recommended before each administration in patients with known liver function disorders. Because renal dysfunction slows elimination of dexrazoxane, patients with impaired kidney function should be monitored for signs of haematological toxicity.

Cardioxane: Myelosuppression

Myelosuppressive effects of Cardioxane may add to those of chemotherapy, and cell counts at the nadir may be lower in treated patients, so haematological monitoring is needed. Leukopenia and thrombocytopenia usually resolve quickly after treatment stops. With higher chemotherapy doses (above 1,000 mg/m²), myelosuppression can increase significantly.

Cardioxane: Second Primary Malignancies and Chemotherapy Efficacy

Dexrazoxane is a cytotoxic agent with topoisomerase II inhibitory activity, and combining it with chemotherapy may increase the risk of second primary malignancies, although cancer patients are at higher risk whatever their treatment. Because dexrazoxane and doxorubicin are both topoisomerase inhibitors, it has been suggested that dexrazoxane could interfere with the antitumour efficacy of anthracyclines. Most adult studies found no significant difference in response rate or overall survival. One study in advanced breast cancer reported a significantly lower tumour response rate with doxorubicin plus dexrazoxane than with doxorubicin plus placebo (the placebo response rate was high, at 60.5%), without a significant difference in time to progression or overall survival. No paediatric study has reported a difference in oncological outcomes (event-free survival).

Cardioxane: Heart, Liver, Kidney and Thromboembolism

Standard cardiac monitoring for doxorubicin or epirubicin treatment must be maintained. There are no data to support the use of dexrazoxane in patients who have had a myocardial infarction in the past 12 months, or who have pre-existing heart failure (including clinical heart failure secondary to anthracycline treatment), uncontrolled angina pectoris or symptomatic valvular heart disease. Because liver dysfunction has occasionally been observed, liver function tests are recommended before and during treatment in patients with known liver function disorders. Clearance of dexrazoxane and its active metabolites may fall in patients with reduced creatinine clearance. Combining dexrazoxane with chemotherapy may increase the risk of thromboembolism.

Cardioxane: Elderly Patients

There are no clinical trials comparing efficacy or safety in older and younger patients. Caution is generally needed because of greater use of other medicines, more concomitant diseases and possibly reduced liver, kidney or cardiac function.

Anaphylactic Reactions

With both products, anaphylactic reactions, including angioedema, skin reactions, bronchospasm, respiratory problems, hypotension and loss of consciousness, have been observed in patients treated with dexrazoxane and anthracyclines. Any previous allergy to dexrazoxane must be carefully considered before it is given.

Contraception, Pregnancy, Breastfeeding and Fertility

• Contraception: because dexrazoxane is mutagenic and is used with anthracyclines that are cytotoxic, mutagenic and embryotoxic, the Savene SmPC advises sexually active men and women of childbearing potential not to father a child or become pregnant, and to use effective contraception during treatment and for up to 6 months after it; women must tell their doctor at once if they become pregnant. The Cardioxane SmPC likewise requires effective contraception in sexually active men and women during treatment and for at least 6 months after it ends.
• Pregnancy: there are no adequate data. Savene may cause foetal harm and has shown reproductive toxicity in animals, so it should not be given to pregnant women unless clearly necessary. Cardioxane has shown embryotoxic and teratogenic effects in animals, the risk to humans is unknown, and it should not be used during pregnancy unless clearly necessary.
• Breastfeeding: it is not known whether dexrazoxane or its metabolites pass into breast milk. Breast-feeding is contraindicated during treatment with either product, because of the potential for serious reactions in the infant.
• Fertility: limited animal data show testicular changes after repeated dosing (in rats and rabbits for Savene; in rats and dogs for Cardioxane). The effect of Cardioxane on human fertility has not been studied.

Potassium and Sodium in the Savene Solvent

The Savene solvent contains 98 mg potassium per 500 mL bottle. Patients with reduced kidney function or on a controlled potassium diet should take this into account, and plasma potassium must be monitored closely in patients at risk of hyperkalaemia. The 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. The Cardioxane powder contains no excipients.

Effect on Driving

Savene has a minor influence on the ability to drive and use machines; dizziness, somnolence and syncope were reported in a few patients in the Savene studies. Cardioxane has a moderate influence, and patients should take care when driving or using machines if they feel fatigued during treatment.

Savene: store below 25 °C and keep the vials and bottles in the outer carton to protect them from light. It is supplied as an emergency kit of 10 vials of powder (amber 36 mL glass vials) and 3 bottles of 500 mL solvent, with 3 bottle hangers.

Cardioxane: do not store above 25 °C, and keep it in the original package to protect it from light. It is supplied as amber Type I glass vials of 500 mg powder in a carton, in packs of 1 and 4 vials (not all pack sizes may be marketed).

Neither product needs refrigeration before use. For storage after reconstitution and dilution, see Shelf Life.

Savene (powder and solvent): 3 years. After reconstitution and dilution, chemical and physical in-use stability has been shown for 4 hours at 2–8 °C. From a microbiological point of view the product should be used immediately; otherwise, in-use storage is the responsibility of the user and should not exceed 4 hours at 2–8 °C.

Cardioxane: 3 years before opening. After reconstitution and further dilution, chemical and physical in-use stability is 4 hours at 25 °C. From a microbiological point of view it should be used immediately; otherwise, the user is responsible for storage times, which should not exceed 4 hours at 2–8 °C (refrigerator), protected from light.

Prescription only (Rx).

Savene is subject to restricted medical prescription and must be given under the supervision of a physician experienced in the use of anti-cancer medicinal products. It is supplied as an emergency kit to the hospital or clinic that administers it, and the first infusion must start within 6 hours of the accident.

Cardioxane is a nationally authorised product that is given with anthracycline chemotherapy, as a short (15-minute) intravenous infusion about 30 minutes before each anthracycline dose, so it is supplied to the hospital or clinic that gives the chemotherapy. Its SmPC tells prescribers to follow national or recognised guidelines on handling cytotoxic agents, and states that reconstitution must be carried out only by trained personnel in a designated cytotoxic area and that pregnant women must not handle the preparation.