Summary of medicine characteristics - ZAVEDOS CAPSULES 5 MG
1 NAME OF THE MEDICINAL PRODUCT
Zavedos 5 mg Capsules
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Idarubicin Hydrochloride 5.0 mg HSE
3 PHARMACEUTICAL FORM
3 PHARMACEUTICAL FORMOpaque red cap and body, self-locking, hard gelatin capsule, size no. 4, containing an orange powder.
4.1 Therapeutic indications
Whenever intravenous idarubicin hydrochloride cannot be employed e.g. for medical, psychological or social reasons, oral idarubicin can be used for remission induction in patients with previously untreated, relapsed or refractory acute non-lymphocytic leukaemia.
Zavedos may be used in combination chemotherapy regimens involving other cytotoxic agents.
As a single agent in the treatment of advanced breast cancer after failure of front line chemotherapy not including anthracyclines.
4.2 Posology and method of administration
Route of Administration: Oral
Dosage is usually calculated on the basis of body surface area.
In adult acute non-lymphocytic leukaemia (ANLL) also referred to as acute myelogenous leukaemia (AML), the recommended dose schedule suggested is 30mg/m2 orally given daily for 3 days as a single agent, or between 15 and 30mg/m2 orally daily for 3 days in combination with other anti-leukemic agents.
In advanced breast cancer the recommended dose schedule as single agent is 45mg/m2 orally given either on a single day or divided over 3 consecutive days, to be repeated every 3 or 4 weeks based on the haematological recovery.
A maximum cumulative dose of 400mg/m2 is recommended.
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.
In patients with hepatic impairment a dose reduction of Zavedos should be considered. (See section 4.4).
The capsules should be swallowed whole with some water and should not be sucked, bitten or chewed. Zavedos Capsules may also be taken with a light meal.
4.3 Contraindications
– sypersensitivity to idarubicin or to any of the excipients listed in section 6.1, other anthracyclines or anthracenediones
– severe hepatic impairment
– severe renal impairment
– severe cardiomyopathy
– uncontrolled infections
– 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 dose-limiting 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.
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 (tumourlysis 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 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.
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 coadminstration 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 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 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 (cannot be estimated from the available data)
Very common
Uncommon
Uncommon
Very common
Not known
Very rare
Very common
Uncommon
Uncommon
Not Known
Rare
Common
Infections
Sepsis, septicaemia
Uncommon
Very rare
Secondary leukaemia (acute myeloid leukaemia and myelodysplastic syndrome)
Anaemia, severe leukopenia and neutropenia, thrombocytopenia
Pancytopenia
Anaphylaxis
Anorexia
Dehydration
Hyperuricaemia
Tumour Lysis Syndrome
Cerebral haemorrhages
Bradycardia, sinus tachycardia, tachyarrhythmia, asymptomatic reduction of left ventricular ejection fraction, congestive heart failure, cardiomyopathies (see section 4.4 for associated signs and symptoms)
ECG abnormalities (e.g. nonspecific ST segment changes), myocardial infarction Pericarditis, myocarditis, atrioventricular and bundle branch block
Common Local phlebitis, thrombophlebitis,
Uncommon
Very rare
Very common
Common
Uncommon
Very rare
Common
Very common
Common
Uncommon
Very rare
Very common
Very common
Description of selected adverse reactions
Haematopoietic system
haemorrhages
Shock
Thromboembolism, flush
Nausea, vomiting, mucositis/stomatitis, diarrhoea, abdominal pain or burning sensation
Gastrointestinal tract bleeding, bellyache
Oesophagitis, colitis (including severe enterocolitis / neutropenic enterocolitis with perforation)
Gastric erosions or ulcerations
Elevation of the liver enzymes and bilirubin
Alopecia
Rash, itch, hypersensitivity of irradiated skin (‘radiation recall reaction’)
Skin and nail hyperpigmentation, urticaria, cellulitis (this event can be severe), tissue necrosis
Acral erythema
Red colouration of the urine for 1 – 2 days after the treatment.
Fever, headache, chills
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.
Other adverse reactions: hyperuricaemia
Prevention of symptoms by hydration, urine alkalinisation, and prophylaxis with allopurinol may minimise potential complications of tumour lysis syndrome.
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
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 haemorrhage and severe mucosal damage.
5 PHARMACOLOGICAL PROPERTIES
6.1. List of excipients
7 MARKETING AUTHORISATION HOLDER
Pfizer Limited
Ramsgate Road
Sandwich
Kent CT13 9NJ
United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL 00057/1064
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION
10/05/2002