Pharmacia Limited

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 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 supervision 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.

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, 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 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 290 mg/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 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. 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.

Hematologic Toxicity. Idarubicin 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, including differential white blood cell (WBC) counts. A dose-dependent,

reversible leukopenia and/or granulocytopenia (neutropenia) is the predominant

manifestation of idarubicin hematologic toxicity and is the most common acute doselimiting

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 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.

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.

Hepatic and/or 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 to 2.0-mg %

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 Medicaments 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). 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. 

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).

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 fetus. 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)

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).

4.9.      Overdose

Very high doses of idarubicin may be expected to cause acute myocardial toxicity within 24 hours and severe myelosuppression within one to two weeks.

Delayed cardiac failure has been seen with anthracyclines for up to several months after the overdose.

Patients treated with oral idarubicin should be observed for possible gastrointestinal hemorrhage and severe mucosal damage.