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1. Idarubicin Hydrochloride 1mg/Ml Solution For Injection
2. Idarubicin Hydrochloride 1mg/Ml Solution For Injection

SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Idarubicin Hydrochloride 1 mg/ml Solution for Injection

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml of solution contains 1 mg idarubicin hydrochloride.

One vial of 5 ml solution for injection contains 5 mg idarubicin hydrochloride One vial of 10 ml solution for injection contains 10 mg idarubicin hydrochloride

For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Solution for injection

Clear, orange-reddish solution, free from visible particles. pH:    3.0-4.0

osmolarity: 281mOsm/kg

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Idarubicin is indicated:

•    for the treatment of acute myelogenous leukaemia (also known as Acute Myeloid Leukaemia or AML. This type of leukaemia was previously called “acute non-lymphoblastic leukaemia” or ANLL) in adults, for remission induction in untreated patients or for remission induction in relapsed or refractory patients.

•    for the treatment of relapsed acute lymphocytic leukaemia (also known as acute lymphoblastic leukaemia or ALL) as second line treatment in adults and children.

Idarubicin may be used in combination chemotherapy regimens involving other

cytotoxic agents.

•    Idarubicin, in combination with cytarabin, is indicated for the first-line treatment (remission induction) of previously untreated children with acute myeloid leukaemia (AML).

4.2 Posology and method of administration

Warning: For intravenous use only! Not for intrathecal use.

Administration

Idarubicin hydrochloride injection must be administered only by the intravenous route and the reconstituted solution should be given via the tubing of a freely running intravenous infusion of 0.9% sodium chloride injection taking 5 to 10 minutes over the injection. This technique minimises the risk of thrombosis or perivenous extravasation which can lead to severe cellulitis and necrosis. Venous sclerosis may result from injection into small veins or repeated injections into the same vein.

Posology

Dosage is calculated on the basis of body surface area.

Acute myelogenous leukaemia (AML)

Adults:

•    12 mg/m /day i.v. daily for 3 days in combination with cytarabine. or

•    8 mg/m /day i.v. daily for 5 days with/without combination.

Paediatric Population

Acute myeloid leukaemia (AML)

Combination therapy:

In children with AML the recommended dose range of idarubicin, in combination with cytarabin, is 10-12 mg/m body surface daily for 3 days by slow intravenous injection.

Note: These are general guidelines. Refer to individual protocols for exact dosage.

Acute lymphocytic leukaemia (ALL)

Adults

₂

•    The suggested dose in adults is 12 mg/m i.v. daily for 3 days in adequate combination regimens.

Children

₂

•    10 mg/m i.v. daily for 3 days in adequate combination regimens.

All of these dosage schedules should, however take into account the haematological status of the patient, the chemotherapy protocol used and the dosages of other cytotoxic drugs when used in combination.

Administration of the second course should be delayed in patients who develop severe mucositis until recovery from this toxicity has occurred and a dose reduction of 25% is recommended.

Patients with hepatic and/or renal impairment

A dosage adjustment may be required in patients with impaired renal or liver function (see section 4.3 and 4.4).

4.3 Contraindications

•    Hypersensitivity to idarubicin or to any other excipients of the product, other anthracyclines or anthracenediones.

•    Severe hepatic impairment (see    section    4.4)

•    Severe renal impairment ( see    section    4.4)

•    Persistent myelosuppression

•    Uncontrolled infections

•    Severe cardiac failure

•    Severe cardiomyopathy

•    Recent myocardial infarction

•    Severe arrhythmias

•    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)

•    Combination with yellow fever vaccine (see section 4.5)

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.

Haematological 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 cell (WBC) counts.

A dose-dependant reversible leukopenia and/or granulocytopenia (neutropenia) is the predominant manifestation of idarubicin hematologic toxicity and is the most common acute dose-limiting toxicity of this 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. During the phase of severe myelosuppression, deaths due to infections and/or haemorrhages have been reported. Clinical consequences of severe myelosuppression include fever, infections, sepsis/septicemia, septic shock, haemorrhage, tissue hypoxia, or death. If febrile neutropenia occurs, treatment with an IV antibiotic is recommended.

Secondary leukaemia:

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 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 leukaemias 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 dyspnoea, pulmonary oedema, dependent oedema, 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 or cardiotoxic drugs (e.g., trastuzumab). Anthracyclines including idarubicin should not be administered in combination with other cardiotoxic agents unless the patient's cardiac function is closely monitored. 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 half-life of trastuzumab is approximately 28.5 days and may persist in the circulation for up to 24 weeks. Therefore, physicians should avoid anthracycline-based therapy for up to 24 weeks 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 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/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 employed 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 minimize 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.

In cases of extravasation dexrazoxane can be used to prevent or reduce tissue injury. Tumour Lysis Syndrome:

Idarubicin may induce hyperuricemia as a consequence of the extensive purine catabolism that accompanies rapid drug-induced lysis of neoplastic cells ('tumour 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 tumour lysis syndrome.

Immunosuppressant Effects/Increased Susceptibility to Infections:

Administration of live or live-attenuated vaccines (like yellow fever) 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 (See section 4.6).

Other:

As with other cytotoxic agents, thrombophlebitis and thromboembolic phenomena, including pulmonary embolism have been coincidentally reported with the use of Idarubicin.

The product may impart a red colouration of the urine for 1 - 2 days after administration and patients should be advised of this fact.

4.5 Interaction 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 myelosuppressive 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.

•    Prolonged contact with any solution of an alkaline pH should be avoided as it will result in degradation of the drug. Idarubicin should not be mixed with heparin as a precipitate may form and it is not recommended to be mixed with other drugs.

Concomitant use of live attenuated vaccines (e.g. yellow fever) is not recommended, due to a risk of possibly fatal systemic disease. The risk is increased in subjects who are already immunosuppressed by their underlying disease. An inactivated vaccine should be used if available.

Phenytoin and fosfophenytoin: Risk of exacerbation of convulsions resulting from the decrease of phenytoin digestive absorption by cytotoxic drug or risk of toxicity enhancement or lose of efficacy of the cytotoxic drug due to increased hepatic metabolism by phenytoin.

Cyclosporin A: The co-adminstration of cyclosporin A as a single chemosensitizer significantly increased idarubicin AUC (1.78-fold) and idarubicinol AUC (2.46-fold) in patients with acute leukaemia. The clinical significance of this interaction is unknown. A dosage adjustment may be necessary in some patients.

At combination of oral anticoagulants and anticancer chemotherapy, increased frequency of the INR (International Normalised Ratio) monitoring is recommended, since the risk for an interaction cannot be excluded.

4.6 Fertility, pregnancy and lactation

Women of child-bearing potential

Women of child-bearing potential should be advised not to become pregnant during treatment and adopt adequate contraceptive measures during therapy as suggested by a physician.

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. Idarubicin 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 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.

Breast-feeding

It is not known whether idarubicin or its metabolites are excreted in human milk. Mothers should not breast-feed during treatment with idarubicin hydrochloride.

Fertility

Idarubicin can induce chromosomal damage in human spermatozoa. For this reason, males undergoing treatment with idarubicin should use effective contraception methods up to 3 months after treatment (See section 4.4).

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 adverse events are ranked according to the following:

> 1/10

>    1/100 to < 1/10

>    1/1000 to < 1/100

>    1/10000 to < 1/1000 < 1/10000

not known (cannot be estimated from the available data)

Infection and Infestation:
Very common -	Infections
Uncommon -	Sepsis, Septicaemia
Neoplasms benign, malignant and unspecified (including cysts and polyps'):
Uncommon -	Secondary leukemias (acute myeloid leukemia and myelodysplastic syndrome)
Blood and lymphatic system disorders:
Very common -	Anaemia Severe leukopenia and neutropenia Thrombocytopenia
Not biown -	Pancytopenia
Immune system disorders:
Very rare -	Anaphylaxis
Endocrine disorders:
Very common -	Anorexia
Uncommon -	Dehydration

Metabolism and nutrition disorders

Uncommon - Hyperuricaemia

Not known - Tumour Lysis Syndrome

-	Hyperphosphatemia
-	Hyperkalemia
-	Hypocalcemia
-	Hypophosphaturia
Nervous system disorders:
Rare -	Cerebral hemorrhages
Cardiac disorders:
Common -	Cardiomyopathies1
-	Bradycardia
-	Sinus tachycardia
-	Tachyarrhythmia
-	Asymptomatic reductions in left ventricular ejection fraction
-	Congestive heart failure
Uncommon -	2 ECG abnormalities
-	Myocardial infarction
Very rare -	Myocarditis
-	Atrio-ventricular and bundle branch block
-	Pericarditis
Vascular disorders
Common -	Local phlebitis
-	Thrombophlebitis
-	Hemorrhages
Uncommon -	Shock
Very rare -	Thromboembolism
-	Flush
Gastrointestinal disorders:
Very common -	Nausea
-	Vomiting
-	Mucositis/Stomatitis
-	Diarrhoea
-	Abdominal pain or burning sensation
Common -	Gastrointestinal tract bleeding, bellyache
Uncommon -	Esophagitis
-	Colitis''
Very rare -	Gastric erosions or ulcerations
Hepatobiliary disorders
Common -	Elevation of liver enzymes and bilirubin

Skin and subcutaneous tissue disorders

Very common -	Alopecia
Common -	Rash Itch Hypersensitivity of irradiated skin4
Uncommon -	Skin and nail hyperpigmentation Urticaria Cellulites5 Tissue necrosis
Very rare -	Acral erythema
Not known -	Local reaction
Renal and urinary tract disorders
Very common -	Red colour to the urine for 1-2 days after the treatment
General disorders and infusion site reactions:
Very common -	Fever Chills Headache

¹    See section 4.4 for associated signs and symptoms

²    Non-specific ST segment changes

³    Including severe enterocolitis/neutropenic enterocolitis with perforation

⁴    "Radiation recall reaction"

⁵    This event can be severe

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)

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).

Gastrointestinal

Stomatitis and in severe cases ulceration of mucosa, dehydration caused by severe vomiting and diarrhoea; risk of perforation of colon etc.

Administration site

Phlebitis/thrombophlebitis and prevention measures discussed in section 4.2 of SPC; unintended paravenous infiltrates may cause pain, severe cellulites and tissue necrosis.

Other adverse reactions: hyperuricaemia

Prevention of symptoms by hydration, urine alkalinisation, and prophylaxis with allopurinol may minimise potential complications of tumor lysis syndrome.

Paediatric population

Undesirable effects are similar in adults and children except a greater susceptibility to anthracycline-induced cardiac toxicity of children.

4.9 Overdose

Very high doses of Idarubicin may be expected to cause acute myocardial toxicity within 24 hours and severe myelosuppression within one or two weeks. Delayed cardiac failure has been seen with the anthracyclines up to several months after the overdose. Patients treated with oral idarubicin should be observed for possible gastrointestinal haemorrhage and severe mucosal damage.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Cytotoxic antibiotics; Anthracyclines aand related substances ATCcode: L01D B06

Idarubicin is a DNA intercalating anthracycline which interacts with the enzyme topoisomerase II and has an inhibitory effect on nucleic acid synthesis.

Idarubicin exhibits antitumour activity against murine leukaemia and lymphomas both by I.V. and oral routes. In in-vitro studies on human and murine anthracycline-resistant cells idarubicin shows a low degree of crossresistance.

The modification of position 4 of the anthracycline structure gives the compound a high lipophilicity which results in an increased rate of cellular uptake compared with doxorubicin and daunorubicin.

Idarubicin has been shown to have a higher potency with respect to daunorubicin and to be an effective agent against murine leukaemia and lymphomas both by i.v. and oral routes. Studies in-vitro on human and murine anthracycline-resistant cells have shown a lower degree of cross-resistance for idarubicin compared with doxorubicin and daunorubicin. Cardiotoxicity studies in animals have indicated that idarubicin has a better therapeutic index than daunorubicin and doxorubicin. The main metabolite, idarubicinol, has shown, in-vitro and in-vivo, antitumoural activity in experimental models. In

the rat, idarubicinol administered at the same doses as the parent drug, is clearly less cardiotoxic than idarubicin.

5.2 Pharmacokinetic properties

After IV administration to patients with normal renal and hepatic function, idarubicin is eliminated from systemic circulation with a terminal plasma t_1/2 ranging between 11-25 hours and is extensively metabolised by CYP2C9 and CYP2D6 to an active metabolite, idarubinicol, which is more slowly eliminated with a plasma t_1/2 ranging between 41 and 69 hours. The drug is eliminated by biliary and renal excretion, mostly in the form of idarubicinol.

Studies of cellular (nucleated blood and bone marrow cells) drug concentrations in leukaemic patients have shown that peak cellular idarubicin concentrations are reached a few minutes after injection. Idarubicin and idarubicinol concentrations in nucleated blood and bone marrow cells are more than a hundred times the plasma concentrations. Idarubicin disappearance rates in plasma and cells were almost comparable with a terminal half life of about 15 hours. The terminal half-life of idarubicinol in cells was about 72 hours.

In vitro studies have shown plasma protein binding of at least 95% for this product. This fact should be borne in mind when considering its use in combination with other drugs.

Paediatric Population:

Pharmacokinetic measurements in 7 paediatric patients receiving intravenous idarubicin in doses ranging from 15 to 40 mg/m²/3 days of treatment, showed a median idarubicin half-life of 8.5 hrs (range: 3.6 - 26.4 hrs). The active metabolite, idarubicinol, accumulated during the 3 days of treatment, exhibiting a median half-life of 43.7 hrs (range: 27.8 - 131 hrs). In a separate study, pharmacokinetic measurements in 15 paediatric patients receiving oral idarubicin in doses ranging from 30 to 50 mg/m / during the 3 days of treatment, the maximum plasma concentration of idarubicin was 10.6 ng/mL (range 2.7 - 16.7 ng/mL at the 40 mg/m² dose). The median terminal half-life of idarubicin was 9.2 hrs (range: 6.4 - 25.5 hrs). Significant accumulation of idarubicinol was seen over the 3 day treatment period. The observed terminal half-life value of idarubicin after IV was comparable to that following oral administration in paediatric patients.

In adults, following oral administration of 10 to 60 mg/m idarubicin, idarubicin was rapidly absorbed with the maximum plasma concentrations of 4 - 12.65 ng/mL achieved in 1 to 4 hours after dosing. The terminal half-life was 12.7±6.0 hrs (mean±SD). Following intravenous administration of idarubicin in adults, the terminal half-life was 13.9±5.9 hrs, similar to that observed after the oral administration.

Since C_max of idarubicin is similar in children and adults following oral administrations, absorption kinetics seem not to differ between adults and children.

Following both oral and IV administrations, the elimination half-life values of idarubicin in children and adults differ:

Total body clearance values of 30 - 107.9 L/h/m for idarubicin reported for adults are higher than the values of 18 - 33 L/h/m² reported for paediatric populations. Although idarubicin has a very large volume of distribution in both adults and children, suggesting that much of the drug is bound to tissues, the shorter elimination half-life and lower total body clearance are not entirely explained by a smaller apparent volume of distribution in children compared to adults.

5.3 Preclinical safety data

Following single iv administration to the mouse, rat and dog, the major target organ was the haematological system and in the case of dogs also the gastrointestinal system.

During a time period of 13 weeks rats and dogs were administered single intravenous doses at 0.4 mg/kg and 0.3 mg/kg on 3 consecutive days, the target organs were: haemolymphopoetic system (decrease of leukocytes, erythrocytes and related parameters and platelets; atrophy and involution of the spleen and thymus), gastro-intestinal tract (inflammation of the intestine and/or erosions), liver (necrosis, steatosis), kidney (tubular degeneration or atrophy), testis (inhibition of spermatogenesis).

Idarubicin is mutagenic. The substance induces gene and chromosome mutations in a series of test systems.

Idarubicin was teratogenic and embryo toxic in rats, but not in rabbits.

Idarubicin was carcinogenic in rats, even following a single iv dose.

In a local tolerance study on dogs, tissue necrosis was observed in case of paravasal application.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Glycerol,

Hydrochloric acid (for pH adjustment)

Water for injections

6.2    Incompatibilities

Prolonged contact with any solution of an alkaline pH should be avoided as it will result in degradation of the drug. Idarubicin injection should not be mixed with heparin as a precipitate may form and it is not recommended that it be mixed with other drugs

This medicinal product ,must not be mixed with other medicinal products except those mentioned in section 6.6.

6.3 Shelf life

3 years

6.4 Special precautions for storage

Store in a refrigerator (2°C - 8°C). Keep container in the outer carton in order to protect from light.

After first opening the content of the vial should be used immediately

6.5 Nature and contents of container

Idarubicin Hydrochloride 5 mg/5ml Solution for Injection

One 5 ml clear glass vial, with bromobutyl rubber stoppers and blue flip-off

aluminium seals.

Idarubicin Hydrochloride 10 mg/10 ml Solution forIinjection

One 14 ml clear glass vial, with bromobutyl rubber stoppers and blue flip-off

aluminium seals.

6.6 Special precautions for disposal

The following protective recommendations are given due to the toxic nature of this substance:

•    This product should be handled only by personnel who have been trained in the safe handling of such preparations.

•    Pregnant staff should be excluded from working with this drug

•    Personnel handling Idarubicin injection should wear protective clothing: goggles, gowns and disposable gloves and masks

•    All items used for administration or cleaning, including gloves, should be placed in high risk, waste-disposal bags for high temperature incineration.

•    The solution is hypotonic and the recommended administration procedure described below must be followed.

Intravenous administration:

Idarubicin injection must be administered only by the intravenous route. A slow administration over 5 to 10 minutes via the tubing of a freely running intravenous infusion of sodium chloride 9 mg/ml (0.9%) solution for infusion, must be followed. A direct push injection is not recommended due to the risk of extravasation, which may occur even in the presence of adequate blood return upon needle aspiration, see section 4.4.

Spillage or leakage should be treated with dilute sodium hypochlorite (1% available chlorine) solution, preferably by soaking, and then with water.

All cleaning materials should be disposed of as indicated previously. Accidental contact with the skin and eyes should be treated immediately by

copious lavage with water, or sodium bicarbonate solution, medical attention should be sought.

Discard any unused solution.

7    MARKETING AUTHORISATION HOLDER

TEVA UK Limited Brampton Road,

Hampden Park,

Eastbourne,

East Sussex BN22 9AG UNITED KINGDOM

8    MARKETING AUTHORISATION NUMBER(S)

PL 00289/1080

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

09/06/2010

10 DATE OF REVISION OF THE TEXT

04/07/2014