Update of sections 4.3, 4.4, 4.5, 4.6, 4.7, 4.8 and 4.9 of the SPC in line with core safety updates as approved by the Austrian Agency.
4.3 Contra-indications
• Hypersensitivity to idarubicin or to any other component of the product, other anthracyclines or anthracenediones
• Severe hepatic impairment
• Severe renal impairment
• Uncontrolled infections
• Severe myocardial insufficiency
• Recent myocardial infarction
• Severe arrhythmias
• Persistent myelosuppression
• Previous treatment with maximum cumulative doses of idarubicin and/ or other anthracyclines and anthracenediones (See section 4.4)
• Breast-feeding should be stopped during drug therapy (See section 4.6)
4.4 Special warnings and precautions for use
General. Idarubicin should be administered only under the of physicians
experienced in the use of cytotoxic chemotherapy.
This ensures that immediate and effective treatment of severe complications of the disease and/or its treatment (e.g. hemorrhage, overwhelming infections) may be carried out.
Patients should recover from acute toxicities of prior cytotoxic treatment (such as stomatitis, neutropenia, thrombocytopenia, and generalized infections) before beginning
treatment with idarubicin.
Haemotological Toxicity:
Idarubicin is a potent bone marrow suppressant. Severe myelosuppression, will occur in all patients given a therapeutic dose of this agent.
Haematological profiles should be assessed before and during each cycle of therapy with idarubicin, including differential white blood cells (WBC) counts.
A dose-dependant, reversible luekopenia and/or granulocytopenia (neutropenia) is the predominant manifestation of idarubicin hematologic toxicity and is the most common acute doselimiting toxicity of the drug. Leukopenia and neutropenia are usually severe, thrombocytopenia and anaemia 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/septicaemia, septic shock, hemorrhage, tissue hypoxia or death.
Secondary Leukemia. Secondary leukemia, with or without a preleukemic phase, has been reported in patients treated with anthracyclines, including idarubicin. Secondary leukemia is more common when such drugs are given in combination with DNA damaging antineoplastic agents, when patients have been heavily pretreated with cytotoxic drugs, or when doses of the anthracyclines have been escalated. These leukemias can have a 1- to 3-year latency period.
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 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 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, oliguira, ascitres, 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 or oral idarubicin have not been defined. However, idarubicin-related cardiomyopathy was reported in 5% of patients who received cumulative IV doses of 150 to 290mg/m2. Available data on patients treated with oral idarubicin total cumulative doses up to 400 mg/m2 suggest a low probability of cardiotoxicity.
Cardiac function should be assessed before patients undergo treatment with idarubicin 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 at the first sign of impaired function.The appropriate quantitative method for repeated assessment of cardiac function (evaluation of LVEF) includes multi-gated radionuclide angiography (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. Cardiac function monitoring must be particularly strict in
patients receiving high cumulative doses and in those with risk factors However, cardiotoxicity with idarubicin 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 and other anthracyclines or anthracenediones is additive.
Hepatic and renal function:
Since hepatic and/or renal function impairment can affect the disposition of idarubicin, 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 - 2.0-mg%.
Gastrointestinal:
Idarubicin is emetigenic. 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.
Occasionally, episodes of serious gastrointestinal events (such as perforation or bleeding) have been observed in patients receiving oral idarubicin who had acute leukemia or a history of other pathologies or had received medications known to lead to gastrointestinal
complications. In patients with active gastrointestinal disease with increased risk of bleeding and/or perforation, the physician must balance the benefit of oral idarubicin therapy against the risk.
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 minimise the risk of phlebitis/thrombophlebitis at the injection site.
Extravasation. Extravasation of idarubicin 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, the drug infusion should be immediately stopped.
Tumor Lysis Syndrome. Idarubicin 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, may result in serious or fatal infections. Vaccination with a live vaccine should be avoided in patients receiving idarubicin. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.
Reproductive system: Men treated with idarubicin hydrochloride are advised to adopt contraceptive measures during therapy and, if appropriate and available, to seek advice on sperm preservation due to the possibility of irreversible infertility caused by the therapy.
Other:
As with other cytotoxic agents, thrombophlebitis and thromboembolic phenomena, including pulmonary embolism have been coincidentally reported with the use of idarubicin.
4.5 Interactions with other medicinal products and other forms of interaction
Idarubicin is a potent myelosuppressant and combination chemotherapy regimens including other agents with similar action may be expected to induce additive myelosuppressant effects (See section 4.4).
Changes in hepatic or renal function induced by concomitant therapies may affect idarubicin metabolism, pharmacokinetics and therapeutic efficacy and/ or toxicity (See section 4.4).
The use of idarubicin in combination chemotherapy with other potentially cardiotoxic drugs, as well as the concomitant use of other cardioactive compounds (e.g. calcium channel blockers), requires monitoring of cardiac function throughout treatment.
An additive myelosuppressant effect may occur when radiotherapy is given concomitantly or within 2-3 weeks prior to treatment with idarubicin.
4.6 Pregnancy and lactation
Impairment of Fertility. Idarubicin can induce chromosomal damage in human spermatozoa. For this reason, males undergoing treatment with idarubicin should use effective contraceptive methods (See section 4.4).
Pregnancy: The embryotoxic potential of idarubicin has been demonstrated in both in vitro and in vivo studies. However, there are no adequate and well-controlled studies in pregnant women. Women of childbearing potential should be advised not to become pregnant during treatment and adopt adequate contraceptive measures during therapy as suggested by a physician.. . Idarubicin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. The patient should be informed of the potential hazard to the foetus. Patients desiring to have children after completion of therapy should be advised to obtain genetic counselling first if appropriate and available.
Lactation: It is not known whether idarubicin or its metabolites are excreted in human milk. Mothers should not breast-feed during treatment with idarubicin hydrochloride.
4.7 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.
4.8 Undesirable effects
The frequencies of undesirable effects are based on the following categories:
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)
Not known (cannot be estimated from the available data)
Infections and infestations
Very common Infections
Uncommon Sepsis, septicemia
Neoplasms benign, malignant and unspecified (including cysts and polyps)
Uncommon Secondary leukemia (acute myeloid leukemia and myelodysplastic syndrome)
Blood and lymphatic system disorders
Very common Anemia, severe leukopenia and neutropenia, thrombocytopenia
Immune system disorders
Very rare Anaphylaxis
Endocrine disorders
Very common Anorexia
Uncommon Hyperuricemia
Nervous system disorders
Rare Cerebral hemorrhages
Cardiac disorders
Common Bradycardia, sinus tachycardia, tachyarrhythmia, asymptomatic reduction of left ventricular ejection fraction, congestive heart failure
Uncommon ECG abnormalities (e.g. nonspecific ST segment changes), myocardial infarction
Very rare Pericarditis, myocarditis, atrioventricular and bundle branch block
Vascular disorders
Common Local phlebitis, thrombophlebitis
Uncommon Shock
Very rare Thromboembolism, flush
Gastrointestinal disorders
Very common Nausea, vomiting, mucositis/stomatitis, diarrhea, abdominal pain or burning sensation
Common Gastrointestinal tract bleeding, bellyache
Uncommon Esophagitis, colitis (including severe enterocolitis / neutropenic enterocolitis with perforation)
Very rare Gastric erosions or ulcerations
Hepatobiliary disorders
Common Elevation of the liver enzymes and bilirubin
Skin and subcutaneous tissue disorders
Very common Alopecia
Common Rash, Itch, hypersensitivity of irradiated skin (‘radiation recall reaction’)
Uncommon Skin and nail hyperpigmentation, urticaria
Very rare Acral erythema
Renal and urinary disorders
Very common Red coloration of the urine for 1 – 2 days after the treatment.
General disorders and administration site conditions
Very common Fever
Common Hemorrhages
Uncommon Dehydration
Hematopoietic system
Pronounced myelosuppression is the most severe adverse effect of idarubicin treatment. However, this is necessary for the eradication of leukemic cells ( See section 4.4)
Leukocyte and thrombocyte counts usually reach their nadir 10 - 14 days after the administration of idarubicin hydrochloride. Cell counts generally return to normal levels during the third week. During the phase of severe myelosuppression, deaths due to infections and/or hemorrhages have been reported.
Clinical consequences of myelosuppression may be fever, infections, sepsis, septic shock, hemorrhages, and tissue hypoxia, which can lead to death. If febrile neutropenia occurs, treatment with an IV antibiotic is recommended.
Cardiotoxicity
Life-threatening CHF is the most severe form of anthracycline-induced cardiomyopathy and represents the cumulative dose-limiting toxicity of the drug (See section 4.4).