Trimebutinum

General Ida® (idarubicin hydrochloride) should be administered only under the supervision of physicians experienced in chemotherapy. Patients should recover from acute toxicities such as stomatitis (inflammation of the oral mucosa), neutropenia (a decrease in a type of defensive blood cell: neutrophils), thrombocytopenia (a decrease in the clotting cells of the blood: platelets) and generalised infections, as well as from prior cytotoxic therapies (treatment for previous neoplasms), before starting treatment with Ida® (idarubicin hydrochloride). Cardiac function Cardiotoxicity (toxicity to the heart) is a risk of anthracycline therapy that may present with early (i.e. acute) or late (i.e. delayed) events. Early (acute) events The early cardiotoxicity of idarubicin consists mainly of sinus tachycardia (acceleration of heart rate) and/or electrocardiographic abnormalities (changes on the electrocardiogram – ECG), such as non-specific ST-T changes (alterations seen on the ECG). Tachyarrhythmias (arrhythmias with an increased heart rate), including premature ventricular contractions (a type of cardiac arrhythmia), ventricular tachycardia (a type of arrhythmia with increased heart rate) and bradycardia (decreased heart rate), as well as atrioventricular and bundle branch blocks (interruption of the cardiac impulse in specific regions of the heart) have also been reported. These effects do not usually predict subsequent development of late cardiotoxicity (cardiac toxicity that appears later), are rarely of clinical importance, and should not generally be a reason for discontinuing treatment with Ida® (idarubicin hydrochloride). Late (delayed) events Late cardiotoxicity usually develops later in the course of idarubicin therapy or within 2 to 3 months after treatment completion, but the occurrence of late events several months or years after the end of treatment has also been reported. Delayed cardiomyopathy (damage to the heart muscle) manifests as a reduction in left ventricular ejection fraction (LVEF – the volume of blood pumped from the heart into the arteries) and/or signs and symptoms of congestive heart failure (CHF – the heart's inability to pump an adequate volume of blood), such as dyspnoea (shortness of breath), pulmonary oedema (fluid accumulation in the lungs), postural oedema (fluid accumulation in various regions of the body, varying with position), cardiomegaly (enlargement of the heart), hepatomegaly (enlargement of the liver), oliguria (decreased urine output), ascites (fluid accumulation in the abdomen), pleural effusion (fluid accumulation in the layer surrounding the lungs) and gallop rhythm (a type of cardiac arrhythmia). Subacute effects such as pericarditis (inflammation of the membrane covering the heart)/myocarditis (inflammation of the heart muscle) have also been reported. Life-threatening CHF is the most severe form of anthracycline-induced cardiomyopathy and represents the cumulative dose-limiting toxicity (the toxicity beyond which the dose of the drug cannot be increased) of the agent. Cumulative dose limits for intravenous idarubicin have not been defined. However, idarubicin-related cardiomyopathy has been reported in 5% of patients who received cumulative intravenous doses of 150 to 290 mg/m². Cardiac function should be assessed before the patient undergoes treatment with Ida® (idarubicin hydrochloride) and should be monitored throughout therapy to minimise the risk of severe heart failure. The risk may be reduced by regular monitoring of LVEF (left ventricular ejection fraction – the volume of blood pumped from the heart into the arteries) during treatment, with immediate discontinuation of Ida® (idarubicin hydrochloride) at the first sign of dysfunction. Suitable quantitative methods for repeated assessment of cardiac function (LVEF evaluation) include nuclear cardiac imaging (MUGA scan) or echocardiography (ECHO). Baseline cardiac assessment with an electrocardiogram combined with nuclear cardiac imaging or echocardiography is recommended, particularly for patients with increased risk factors for cardiotoxicity (toxicity to the heart). Repeated LVEF determinations by nuclear cardiac imaging or echocardiography should be performed, particularly with higher cumulative anthracycline doses. The technique used for cardiac assessment should be consistent throughout follow-up. Risk factors for cardiac toxicity include active or inactive cardiovascular disease, prior or concomitant radiotherapy to the mediastinal/pericardial region (in the mediastinum or near the heart), prior therapy with other anthracyclines or anthracenediones, and concomitant use of other drugs capable of reducing cardiac contractility or of cardiotoxic medicines (e.g. trastuzumab). Anthracyclines, including Ida® (idarubicin hydrochloride), should not be administered in combination with other cardiotoxic agents unless the patient's cardiac function is closely monitored. Patients receiving anthracyclines after the discontinuation of other cardiotoxic agents (toxic to the heart), especially those with long half-lives (the time required for the body to eliminate half of the drug's blood concentration), such as trastuzumab, may be at 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, when possible, physicians should avoid anthracycline-based therapy for up to 7 months after discontinuing trastuzumab. If anthracyclines are used before this time, careful monitoring of cardiac function is recommended. Monitoring of cardiac function should be particularly rigorous in patients receiving high cumulative doses (doses that add up) and in those with risk factors. However, cardiotoxicity with Ida® (idarubicin hydrochloride) can occur at lower cumulative doses regardless of the presence of cardiac risk factors. Long-term and periodic assessment of cardiac function should be performed in children, as they have shown greater susceptibility to anthracycline-induced cardiac toxicity. The toxicity of idarubicin and other anthracyclines or anthracenediones is likely to be additive (the toxicities add up). Haematological toxicity (toxicity to the blood) Ida® (idarubicin hydrochloride) is a potent bone marrow suppressant (reduces bone marrow function). Severe myelosuppression (a marked decrease in bone marrow function) will occur in all patients receiving therapeutic doses of this agent. The haematological profile (blood tests) should be assessed before and during each cycle of Ida® (idarubicin hydrochloride) therapy, including a differential white blood cell count (a count of the blood cells responsible for defending the body). Reversible, dose-dependent leukopenia (reduction in defensive blood cells) and/or granulocytopenia (neutropenia: a decrease in a type of defensive blood cell: neutrophils) are the predominant manifestations of idarubicin's haematological toxicity and constitute the most common acute dose-limiting toxicity of this agent. Leukopenia and neutropenia are usually severe; thrombocytopenia (a decrease in the clotting cells of the blood: platelets) and anaemia (a decrease in red blood cells: erythrocytes) may also occur. Leukocyte and neutrophil counts generally reach the nadir (the lowest point of the defensive cell count, from which the number begins to rise) between days 10 and 14 after drug administration; however, cell counts usually return to normal levels during the third week. The clinical consequences of severe myelosuppression include fever, infections, sepsis/septicaemia (generalised infection), septic shock (severe sepsis), haemorrhage, tissue hypoxia (decreased tissue oxygen) or death. Secondary leukaemia (leukaemia arising as a consequence of idarubicin treatment) Secondary leukaemia, with or without a preleukaemic phase, has been reported in patients treated with anthracyclines including idarubicin. Secondary leukaemia is more common when such drugs are administered in combination with DNA-damaging antineoplastic agents (which fight cancer and cause damage to the cell's DNA), when patients have been heavily pretreated with cytotoxic drugs (medicines that cause cellular destruction), or when anthracycline doses have been escalated. These leukaemias have a latency period (a period without clinical manifestations) of 1 to 3 years. Gastrointestinal Idarubicin is emetogenic (causes vomiting). Mucositis (ulcers in the mucosa of the digestive organs, mainly stomatitis of the mouth and tongue), and less frequently oesophagitis (of the oesophagus), generally appears early in treatment and, if severe, may progress within a few days to mucosal ulcers. Most patients recover from this adverse event by the third week of therapy. Hepatic (liver) and/or renal (kidney) function Since impaired hepatic and/or renal function may affect the distribution of idarubicin, liver and kidney function should be assessed by routine laboratory and clinical tests using serum bilirubin (a blood test that evaluates liver function) and serum creatinine (a blood test that evaluates kidney function) before and during treatment. In several Phase III clinical trials (studies of drug efficacy and safety), treatment was contraindicated if serum bilirubin and/or creatinine levels exceeded 2 mg%. With other anthracyclines, a 50% dose reduction is generally used if bilirubin and creatinine levels are around 1.2–2.0 mg%. Effects at the infusion site Phlebosclerosis (fibrosis of the vein used for drug infusion) may result from infusion of the drug into a small vessel or from repeated infusions (multiple administrations) into the same vein. Following the recommended administration procedures may minimise the risk of phlebitis (inflammation of the vein)/thrombophlebitis (inflammation and thrombosis of the vein) at the infusion site. Extravasation (accidental injection or leakage of the medicine from the vein into the surrounding tissues) Extravasation of idarubicin during intravenous administration (presence of the drug outside the vein) may produce local pain, severe tissue injury (vesication – the formation of blisters), severe cellulitis (inflammation of the fatty tissue beneath the skin) and necrosis (tissue death). If signs or symptoms of extravasation occur during intravenous administration of Ida® (idarubicin hydrochloride), the infusion should be discontinued immediately. Tumour lysis syndrome (symptoms caused by the destruction of cancer cells) Idarubicin may induce hyperuricaemia (an increase in blood uric acid) due to extensive catabolism (breakdown) of purines accompanying the rapid lysis (destruction) of neoplastic cells induced by the drug (tumour lysis syndrome). Serum levels of uric acid, potassium, calcium, phosphate and creatinine should be assessed after initial treatment. Hydration, urinary alkalinisation (the use of substances to facilitate elimination of the medicine in the urine) and prophylaxis with allopurinol to prevent hyperuricaemia may minimise the potential complications of tumour lysis syndrome. Immunosuppressive effects (which reduce immune system function)/Increased susceptibility to infections Administration of vaccines containing live (made from active pathogens) or attenuated (inactivated) antigens to patients immunocompromised by chemotherapeutic agents, including idarubicin, may result in serious or fatal infections. Vaccination with live antigens should be avoided in patients receiving idarubicin. Vaccines with killed or inactivated antigens may be administered, although the response to the vaccine may be diminished. Other As with other cytotoxic agents, thrombophlebitis and thromboembolic events, including pulmonary embolism (the presence of a clot in the lungs), have been reported coincidentally with the use of idarubicin. Fertility, pregnancy and lactation (breastfeeding) Pregnancy The embryotoxic potential (capacity to cause damage to the embryo) of idarubicin has been demonstrated in in vitro (laboratory) and in vivo (animal) studies. However, there are no adequate and well-controlled studies in pregnant women. Women of childbearing potential should be advised to avoid pregnancy during treatment. Ida® (idarubicin hydrochloride) should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus. The patient should be informed of the potential harm to the foetus (risk of harm to the foetus). This medicine should not be used by pregnant women without medical advice. Inform your physician immediately if pregnancy is suspected. Lactation (breastfeeding) It is not known whether Ida® (idarubicin hydrochloride) is excreted (eliminated) in human milk. Mothers should not breastfeed while receiving chemotherapy with Ida® (idarubicin hydrochloride). Alteration in fertility Ida® (idarubicin hydrochloride) may cause changes in human spermatozoa. For this reason, men undergoing treatment with Ida® (idarubicin hydrochloride) should use effective contraceptive methods (to avoid impregnating their partner). Effects on the ability to drive and operate machinery The effect of Ida® (idarubicin hydrochloride) on the ability to drive or operate machinery has not been evaluated.