ZAVEDOS 1 MG / ML SOLUTION FOR INJECTION - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Zavedos 1mg/mL Solution for Injection

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each mL of solution contains 1 mg of idarubicin hydrochloride.

Each vial of 5 mL of solution contains 5 mg of idarubicin hydrochloride.

Each vial of 10 mL of solution contains 10 mg of idarubicin hydrochloride.

Each vial of 20 mL of solution contains 20 mg of idarubicin hydrochloride.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Solution for Injection Orange-red, clear solution.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Adults

For the treatment of acute myeloid leukaemia (AML), for remission induction in untreated patients or for remission induction in relapsed or refractory patients.

For second line treatment of relapsed acute lymphoblastic leukaemia (ALL).

Paediatric population

For first line treatment of acute myeloid-leukaemia (AML), in combination with cytarabine, for remission induction.

For second line treatment of relapsed acute lymphoblastic leukaemia (ALL).

Zavedos may be used in combination chemotherapy regimens involving other cytotoxic agents (see section 4.2).

4.2 Posology and method of administration

Posology

Dosage is calculated on the basis of body surface area.

Acute myeloid leukaemia (AML)

Adults

12 mg/m2/day i.v. daily for 3 days in combination with cytarabine.

or

8 mg/m2/day i.v. daily for 5 days with/without combination.

Paediatric population

10–12 mg/m2/day i.v. daily for 3 days in combination with cytarabine.

Acute lymphoblastic leukaemia (ALL)

Adults

As single agent in ALL the suggested dose in adults is 12 mg/m2/day i.v. daily for 3 days.

Paediatric population

10 mg/m2/day i.v. daily for 3 days, as a single agent.

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

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

Administration of a 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.

Method of administration

For intravenous use only.

Not for intrathecal use.

4.3 Contraindications

Hypersensitivity to idarubicin or to any of the excipients listed in section 6.1, other anthracyclines or anthracenediones

Severe hepatic impairment

Severe renal impairment

Uncontrolled infections

Severe cardiomyopathy

Recent myocardial infarction

Severe arrhythmias

Persistent myelosuppression

Previous treatment with maximum cumulative doses of idarubicin hydrochloride 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

Doxorubicin should be administered only under the supervision of physicians experienced in the use of cytotoxic therapy.

Patients should recover from the acute toxicities of prior cytotoxic treatment (such as stomatitis, neutropenia, thrombocytopenia, and generalized infections) before beginning treatment with doxorubicin.

The systemic clearance of doxorubicin is reduced in obese patients (i.e. >130% ideal body weight) (see section 4.2).

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 doxorubicin consists mainly of sinus tachycardia and/or 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, and are generally not a consideration for discontinuation of doxorubicin treatment.

Late (i.e. Delayed) Events: Delayed cardiotoxicity usually develops late in the course of therapy with doxorubicin 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 and 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 doselimiting toxicity of the drug.

Cardiac function should be assessed before patients undergo treatment with doxorubicin 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 doxorubicin 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) 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.

The probability of developing CHF, estimated around 1% to 2% at a cumulative dose of 300 mg/m2 slowly increases up to the total cumulative dose of 450–550 mg/m2. Thereafter, the risk of developing CHF increases steeply and it is recommended not to exceed a maximum cumulative dose of 550 mg/m2.

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 of cardiotoxic substances (e.g. trastuzumab) and age over 70 years. 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 this is not possible, the patient’s cardiac function should be monitored carefully.

Cardiac function must be carefully monitored in patients receiving high cumulative doses and in those with risk factors. However, cardiotoxicity with doxorubicin may occur at lower cumulative doses whether or not cardiac risk factors are present.

Children and adolescents are at an increased risk for developing delayed cardiotoxicity following doxorubicin administration. Females may be at greater risk than males. Follow-up cardiac evaluations are recommended periodically to monitor for this effect.

It is probable that the toxicity of doxorubicin and other anthracyclines or anthracenediones is additive.

Haematologic Toxicity

Doxorubicin may produce myelosuppression. Haematologic profiles should be assessed before and during each cycle of therapy with doxorubicin, including differential white blood cell (WBC) counts. A dose-dependent, reversible leucopenia and/or granulocytopenia (neutropenia) is the predominant manifestation of doxorubicin haematologic toxicity and is the most common acute dose-limiting toxicity of this drug. Leucopenia and neutropenia generally reach the nadir between days 10 and 14 after drug administration; the WBC/neutrophil counts return to normal values in most cases by day 21. Thrombocy­topenia and anaemia may also occur.

Clinical consequences of severe myelosuppression include fever, infections, sepsis/septicaemia, septic shock, haemorrhage, tissue hypoxia or death.

Secondary Leukaemia

Secondary leukaemia, with or without a preleukaemic phase, has been reported in patients treated with anthracyclines. 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.

Carcinogenesis, Mutagenesis and Impairment of Fertility

Doxorubicin was genotoxic and mutagenic in vitro and in vivo tests.

In women, doxorubicin may cause infertility during the time of drug administration. Doxorubicin may cause amenorrhoea. Ovulation and menstruation appear to return after termination of therapy, although premature menopause can occur.

Doxorubicin is mutagenic and can induce chromosomal damage in human spermatozoa. Oligospermia or azoospermia may be permanent; however, sperm counts have been reported to return to normospermic levels in some instances. This may occur several years after the end of therapy. Men undergoing doxorubicin treatment should use effective contraceptive methods.

Liver function

The major route of elimination of doxorubicin is the hepatobiliary system. Serum total bilirubin should be evaluated before and during treatment with doxorubicin. Patients with elevated bilirubin may experience slower clearance of the drug with an increase in overall toxicity. Lower doses are recommended in these patients (see section 4.2). Patients with severe hepatic impairment should not receive doxorubicin (see section 4.3).

Other

Doxorubicin may potentiate the toxicity of other anticancer therapies. Exacerbation of cyclophosphamide-induced haemorrhagic cystitis and enhanced hepatotoxicity of 6-mercaptopurine have been reported. Radiation-induced toxicities (myocardium, mucosae, skin and liver) have also been reported.

As with other cytotoxic agents, thrombophlebitis and thromboembolic phenomena including pulmonary embolism (in some cases fatal) have been coincidentally reported with the use of doxorubicin.

Tumour-Lysis Syndrome

Doxorubicin may induce hyperuricaemia as a consequence of the extensive purine catabolism that accompanies drug-induced rapid 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 hyperuricaemia may minimize potential complications of tumour lysis syndrome.

Vaccinations

Administration of live or live-attenuated vaccines in patients immunocompromised by chemotherapeutic agents including doxorubicin, may result in serious or fatal infections. Vaccination with a live vaccine should be avoided in patients receiving doxorubicin. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.

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).

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.

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.

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.

Cyclosporin A: The co-administration 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.

4.6 Fertility, pregnancy and lactation

Fertility

Idarubicin can induce chromosomal damage in human spermatozoa. For this reason, males undergoing treatment with idarubicin should use effective contraceptive methods up to 3 months after treatment (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 child bearing 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 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.

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 (frequency cannot be estimated from the available data)

Description of selected adverse reactions

Haematopoietic system

Pronounced myelosuppression is the most severe adverse effect of idarubicin treatment. However, this is necessary for the eradication of leukaemic 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; 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 tumour lysis syndrome.

Paediatric population

Undesirable effects are similar in adults and children except a greater susceptibility to anthracycline-induced cardiac toxicity of children (see section 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard.

4.9 Overdose

5   PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Anthracyclines and related substances

ATC Code: L01DB06

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

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 crossresistance 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.

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.

5.2 Pharmacokinetic properties

In adults, following oral administration of 10 to 60 mg/m2 idarubicin, idarubicin was rapidly absorbed with the maximum plasma concentrations of 412.65 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.

After i.v. administration, idarubicin is extensively metabolised to an active metabolite, idarubicinol, which is slowly eliminated with a plasma T% ranging between 41–69 hours). The drug is eliminated by biliary and renal excretion, mostly in the form or idarubicinol.

Studies of cellular (nucleated blood and bone marrow cells) 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 comparable, with a terminal halflife of about 15 hours. The terminal half-life of idarubicinol in cells was about 72 hours.

Paediatric population

Pharmacokinetic measurements in 7 paediatric patients receiving intravenous idarubicin hydrochloride in doses ranging from 15 to 40 mg/m2 over the 3 days of treatment, showed a median idarubicin half-life of 8.5 hrs (range: 3.626.4 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 hydrochloride in doses ranging from 30 to 50 mg/m2 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 of 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 i.v. was comparable to that following oral administration in paediatric patients.

Since Cmax 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 i.v. administrations, the elimination half-life values of idarubicin in children and adults differ.

Total body clearance values of 30–107.9 L/h/m2 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

Idarubicin has mutagenic properties and it is carcinogenic in rats.

Reproduction studies in animals have shown that idarubicin is embryotoxic and teratogenic in rats but not rabbits.

6.1 List of excipients

Glycerol

Water for injection

Hydrochloric acid, used for pH adjustment

6.2 Incompatibilities

Prolonged contact of Zavedos with any solution of an alkaline pH should be avoided as it will result in degradation of the drug.

Zavedos should not be mixed with heparin as a precipitate may form. This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

6.3 Shelf life

Unopened vial

3 years

Opened vial

Each vial is for single use only and should be used immediately after opening. If not used immediately, in use storage times and conditions are the responsibility of the user.

6.4 Special precautions for storage

Unopened vial: Store and transport refrigerated (2°C – 8°C).

Opened vial: From a microbiological point of view, unless the method of opening/dilution precludes the risk of microbial contamination, this medicinal product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user.

Keep the vial in the outer carton in order to protect from light.

6.5 Nature and contents of container

Polypropylene vials which are closed with a siliconised, halobutyl rubber stopper and sealed with an aluminium cap with a plastic flip off top.

Zavedos is available in 5 mL, 10 mL and 20 mL vials packed singly in cartons. Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Preparation and precautions:

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 Zavedos should wear protective clothing: goggles, gowns and disposable gloves and masks.

Any work surfaces used should be protected by disposable, plastic-backed, absorbent paper.

The solution should not be allowed to contact mucous membranes, eyes or skin. 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.

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

Intravenous administration:

Zavedos 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 0.9% sodium chloride, 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.

Disposal:

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

For single use only. Any unused solution should be discarded.

7 MARKETING AUTHORISATION HOLDER

Pfizer Limited

Ramsgate Road

Sandwich

Kent CT13 9NJ, UK

8 MARKETING AUTHORISATION NUMBER(S)

PL 00057/1520

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION

27/03/2017