Zavedos Special Precautions

General: Idarubicin hydrochloride should be administered only under the supervision of physicians experienced in the use of cytotoxic chemotherapy.
Patients should recover from acute toxicities of prior cytotoxic treatment (such as stomatitis, neutropenia, thrombocytopenia, and generalized infections) before beginning treatment with idarubicin hydrochloride.
Facilities with laboratory and supportive resources adequate to monitor drug tolerability and protect and maintain a patient compromised by drug toxicity should be available. It must be possible to treat a severe hemorrhagic condition and/or a severe infection rapidly and effectively.
Cardiac Function: Cardiotoxicity is a risk of anthracycline treatment that may be manifested by early (i.e., acute) or late (i.e., delayed) events.
Early (i.e., Acute) Events. Early cardiotoxicity of idarubicin hydrochloride consists mainly of sinus tachycardia and/or electrocardiogram (ECG) abnormalities, such as non-specific ST-T wave changes. Tachyarrhythmias, including premature ventricular contractions and ventricular tachycardia, bradycardia, as well as atrioventricular and bundle-branch block have also been reported. These effects do not usually predict subsequent development of delayed cardiotoxicity, are rarely of clinical importance, and are generally not a reason for the discontinuation of idarubicin hydrochloride treatment.
Late (i.e., Delayed) Events. Delayed cardiotoxicity usually develops late in the course of therapy or within 2 to 3 months after treatment termination, but later events, several months to years after completion of treatment have also been reported. Delayed cardiomyopathy is manifested by reduced left ventricular ejection fraction (LVEF) and/or signs and symptoms of congestive heart failure (CHF) such as dyspnea, pulmonary edema, dependent edema, cardiomegaly, hepatomegaly, oliguria, ascites, pleural effusion, and gallop rhythm. Subacute effects, such as pericarditis/myocarditis have also been reported. Life-threatening CHF is the most severe form of anthracycline-induced cardiomyopathy and represents the cumulative dose-limiting toxicity of the drug.
Cumulative dose limits for IV idarubicin hydrochloride have not been defined. However, idarubicin hydrochloride-related cardiomyopathy was reported in 5% of patients who received cumulative IV doses of 150 to 290 mg/m².
Cardiac function should be assessed before patients undergo treatment with idarubicin hydrochloride and must be monitored throughout therapy to minimize the risk of incurring severe cardiac impairment.
The risk may be decreased through regular monitoring of LVEF during the course of treatment with prompt discontinuation of idarubicin hydrochloride at the first sign of impaired function. The appropriate quantitative method for repeated assessment of cardiac function (evaluation of LVEF) includes Multiple Gated Acquisition (MUGA) scan or echocardiography (ECHO). A baseline cardiac evaluation with an ECG and either a MUGA scan or an ECHO is recommended, especially in patients with risk factors for increased cardiotoxicity. Repeated MUGA or ECHO determinations of LVEF should be performed, particularly with higher, cumulative anthracycline doses. The technique used for assessment should be consistent throughout follow-up.
Risk factors for cardiac toxicity include active or dormant cardiovascular disease, prior or concomitant radiotherapy to the mediastinal/pericardial area, previous therapy with other anthracyclines or anthracenediones, and concomitant use of drugs with the ability to suppress cardiac contractility or cardiotoxic drugs (e.g., trastuzumab). Anthracyclines including idarubicin hydrochloride should not be administered in combination with other cardiotoxic agents unless the patient's cardiac function is closely monitored (see Interactions). Patients receiving anthracyclines after stopping treatment with other cardiotoxic agents, especially those with long half-lives, such as trastuzumab, may also be at an increased risk of developing cardiotoxicity. The reported half-life of trastuzumab is variable. Trastuzumab may persist in the circulation for up to 7 months. Therefore, physicians should avoid anthracycline-based therapy for up to 7 months after stopping trastuzumab when possible. If anthracyclines are used before this time, careful monitoring of cardiac function is recommended.
Cardiac function monitoring must be particularly strict in patients receiving high cumulative doses and in those with risk factors. However, cardiotoxicity with idarubicin hydrochloride may occur at lower cumulative doses whether or not cardiac risk factors are present.
In infants and children there appears to be a greater susceptibility to anthracycline-induced cardiac toxicity, and a long-term periodic evaluation of cardiac function has to be performed.
It is probable that the toxicity of idarubicin hydrochloride and other anthracyclines or anthracenediones is additive.
Hematologic Toxicity: Idarubicin hydrochloride is a potent bone marrow suppressant. Severe myelosuppression will occur in all patients given a therapeutic dose of this agent. Hematologic profiles should be assessed before and during each cycle of therapy with idarubicin hydrochloride, including differential white blood cell (WBC) counts. A dose-dependent, reversible leukopenia and/or granulocytopenia (neutropenia) is the predominant manifestation of idarubicin hydrochloride hematologic toxicity and is the most common acute dose-limiting toxicity of this drug. Leukopenia and neutropenia are usually severe; thrombocytopenia and anemia may also occur. Neutrophil and platelet counts usually reach their nadir 10 to 14 days after drug administration; however, cell counts generally return to normal levels during the third week. Clinical consequences of severe myelosuppression include fever, infections, sepsis/septicemia, septic shock, hemorrhage, tissue hypoxia, or death.
Secondary Leukemia: Secondary leukemia, with or without a pre-leukemic phase, has been reported in patients treated with anthracyclines, including idarubicin hydrochloride. Secondary leukemia is more common when such drugs are given in combination with DNA-damaging antineoplastic agents, when patients have been heavily pre-treated with cytotoxic drugs, or when doses of the anthracyclines have been escalated. These leukemias can have a 1- to 3-year latency period.
Gastrointestinal: Idarubicin hydrochloride is emetogenic. Mucositis (mainly stomatitis, less often esophagitis) generally appears, early after drug administration and, if severe, may progress over a few days to mucosal ulcerations. Most patients recover from this adverse event by the third week of therapy.
Hepatic and/or Renal Function: Since hepatic and/or renal function impairment can affect the disposition of idarubicin hydrochloride, liver and kidney function should be evaluated with conventional clinical laboratory tests (using serum bilirubin and serum creatinine as indicators) prior to, and during, treatment. In a number of Phase III clinical trials, treatment was contraindicated if bilirubin and/or creatinine serum levels exceeded 2.0 mg%. With other anthracyclines, a 50% dose reduction is generally used if bilirubin levels are in the range 1.2 to 2.0 mg% (see Dosage & Administration).
Effects at Site of Injection: Phlebosclerosis may result from an injection into a small vessel or from previous injections into the same vein. Following the recommended administration procedures may minimize the risk of phlebitis/thrombophlebitis at the injection site (see Dosage & Administration).
Extravasation: Extravasation of idarubicin hydrochloride during intravenous injection may cause local pain, severe tissue lesions (vesication, severe cellulitis), and necrosis. Should signs or symptoms of extravasation occur during intravenous administration of idarubicin hydrochloride, the drug infusion should be immediately stopped.
Tumor Lysis Syndrome: Idarubicin hydrochloride may induce hyperuricemia as a consequence of the extensive purine catabolism that accompanies rapid drug-induced lysis of neoplastic cells ('tumor lysis syndrome'). Blood uric acid levels, potassium, calcium phosphate, and creatinine should be evaluated after initial treatment. Hydration, urine alkalinization, and prophylaxis with allopurinol to prevent hyperuricemia may minimize potential complications of tumor lysis syndrome.
Immunosuppressant Effects/Increased Susceptibility to Infections: Administration of live or live-attenuated vaccines in patients immunocompromised by chemotherapeutic agents including idarubicin hydrochloride, may result in serious or fatal infections. Vaccination with a live vaccine should be avoided in patients receiving idarubicin hydrochloride. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.
Embryo-fetal Toxicity: Idarubicin can cause genotoxicity. An effective method of contraception is required for both male and female patients during and for a period after treatment with idarubicin. Patients desiring to have children after completion of therapy should be advised to obtain genetic counselling if appropriate and available (see Use in Pregnancy & Lactation and Pharmacology: Toxicology: Preclinical safety data under Actions).
Other: As with other cytotoxic agents, thrombophlebitis and thromboembolic phenomena, including pulmonary embolism have been coincidentally reported with the use of idarubicin hydrochloride.
Effects on ability to drive and use machines: The effect of idarubicin on the ability to drive or use machinery has not been systematically evaluated.