Cardioprotectant Agents

Indications: Anthracycline- induced cardiotoxicity The anthracycline cytotoxic drugs are associated with dose- related, cumulative, and potentially life-threatening cardiotoxic side effects.

Dexrazoxane, an iron chelator, is licensed for the prevention of chronic cumulative cardiotoxicity caused by doxorubicin or epirubicin treatment in advanced or metastatic breast cancer patients who have received a prior cumulative dose of 300 mg/m2 of doxorubicin or a prior cumulative dose of 540 mg/m2 of epirubicin when further anthracycline treatment is required. Patients receiving dexrazoxane should still be monitored for cardiac toxicity. The myelosuppressive effects of dexrazoxane may be additive to those of chemotherapy. The use of dexrazoxane is restricted to adults with advanced or metastatic breast cancer.

Cautions:

●May interfere with activity of antineoplastic drugs; do NOT initiate until cumulative doxorubicin dose reaches 300 mg/m² give doxorubicin prior to dexrazoxane.

●Does not eliminate potential for anthracycline-induced cardiactoxicity; monitor cardiac function carefully Secondary malignancies (eg, AML, MDS) reported with combination chemotherapy.

Dexrazoxane is licensed for the treatment of anthracycline extravasation. The first dose should be given as soon as possible and within six hours after the injury.

Extravasation: Extravasation injury follows leakage of drugs or intravenous fluids from the veins or inadvertent administration into the subcutaneous or subdermal tissue. It must be dealt with promptly to prevent tissue necrosis. Acidic or alkaline preparations and those with an osmolarity greater than that of plasma can cause extravasation injury; excipients including alcohol and polyethylene glycol have also been implicated.Cytotoxic drugs commonly cause extravasation injury. In addition, certain patients such as the very young and the elderly are at increased risk. Those receiving anticoagulants are more likely to lose blood into surrounding tissues if extravasation occurs, while those receiving sedatives or analgesics may not notice the early signs or symptoms of extravasation.

Prevention of extravasation:

Precautions should be taken to avoid extravasation; ideally, drugs likely to cause extravasation injury should be given through a central line and patients receiving repeated doses of hazardous drugs peripherally should have the cannula resited at regular intervals. Attention should be paid to the manufacturers' recommendations for administration. Placing a glyceryl trinitrate patch distal to the cannula may improve the patency of the vessel in patients with small veins or in those whose veins are prone to collapse. Patients should be asked to report any pain or burning at the site of injection immediately.

Management of extravasation

If extravasation is suspected the infusion should be stopped immediately but the cannula should not be removed until after an attempt has been made to aspirate the area (through the cannula) in order to remove as much of the drug as possible. Aspiration is sometimes possible if the extravasation presents with a raised bleb or blister at the injection site and is surrounded by hardened tissue, but it is often unsuccessful if the tissue is soft or soggy.

Corticosteroids are usually given to treat inflammation, although there is little evidence to support their use in extravasation.

Hydrocortisone or dexamethasone can be given either locally by subcutaneous injection or intravenously at a site distant from the injury. Antihistamines and analgesics may be required for symptom relief. The management of extravasation beyond these measures is not well standardised and calls for specialist advice. Treatment depends on the nature of the offending substance; one approach is to localise and neutralise the substance whereas another is to spread and dilute it. The first method may be appropriate following extravasation of vesicant drugs and involves administration of an antidote (if available) and the application of cold compresses 3–4 times a day (consult specialist literature for details of specific antidotes). Spreading and diluting the offending substance involves infiltrating the area with physiological saline, applying warm compresses, elevating the affected limb, and administering hyaluronidase A saline flush- out technique (involving flushing the subcutaneous tissue with physiological saline) may be effective but requires specialist advice. Hyaluronidase should not be administered following extravasation of vesicant drugs (unless it is either specifically indicated or used in the saline flush-out technique). Dexrazoxane is licensed for the treatment of anthracycline-induced extravasation.

Hepatic impairment: Monitor liver function

Renal impairment: Use with caution—risk of accumulation; manufacturer of Cardioxane advises reduce dose by 50% if creatinine clearance less than 40 ml/minute.

Pregnancy: Avoid unless essential (toxicity in animal studies); ensure effective contraception during and for at least 3 months after treatment in men and women.

Breast-feeding: Discontinue breast-feeding

Contra-indications: -Hypersensitivity -Use in chemotherapy when an anthracycline is not being administered.

Side Effects: Nausea, vomiting, dyspepsia, abdominal pain, diarrhoea, stomatitis, dry mouth, anorexia; dyspnea; dizziness, syncope, asthenia, paraesthesia, tremor, fatigue, drowsiness; pyrexia; vaginal haemorrhage; myalgia; blood disorders (including anaemia, leucopenia, neutropenia, thrombocytopenia, and increased myelosuppression); alopecia, pruritus; peripheral oedema, injection-site reactions including phlebitis; also reported secondary malignancies.

Dose: Powder for injection •250mg 500mg For adult:

Doxorubicin-Induced Cardiomyopathy, Prophylaxis (Zinecard/Generic):

10: 1 ratio of dexrazoxane to doxorubicin dose (500 mg/m² dexrazoxane : 50 mg/m² doxorubicin) slow IVP or rapid drip IV infusion

Give doxorubicin within 30 minutes of beginning of dexrazoxane infusion.

Monitor cardiac function and discontinue combination therapy in patients who develop a decline in left ventricular ejection fraction or develop clinical congestive failure.

Renal impairment: Moderate-to-severe: 5x doxorubicin dose

Anthracycline Extravasation (Totect):

Give first infusion within 6 hr after extravasation Day 1: 1000 mg/m² IV; not to exceed 2000 mg Day 2: 1000 mg/m² IV; not to exceed 2000 mg Day 3: 500 mg/m² IV; not to exceed 1000 mg

Infuse IV over 1-2 hr; begin treatment within 6 hr of extravasation

Renal Impairment: CrCl <40 ml/min: Reduce dose by 50%. For pediatric: Safety and efficacy not established Cardiomyopathy Prophylaxis (Orphan)

Orphan designation for prevention of anthracycline- induced cardiomyopathy in children and adolescents