Zavedos Powder for Solution for Injection 5mg and 10mg
1. What Zavedos is and what it is used for
• Zavedos contains an active ingredient called idarubicin, which belongs to a group of medicines called anthracyclines. Zavedos interferes with ways in which the cells of your body grow and increase in number and is used in the treatment of cancers (chemotherapy).
• Zavedos is used for the treatment of leukaemia.
2. Before you are given Zavedos
Do not take Zavedos if:
You have ever had an allergic (hypersensitivity) reaction to idarubicin or any of the other ingredients of Zavedos other anthracyclines You have an infection which is not under control. Your liver or kidneys are not working properly.
You have an intolerance to sugars? If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.
Take special care with Zavedos
Tell your doctor if you:
Suffer from bone marrow depression caused by previous therapy. – Have suffered from heart trouble in the past or are presently receiving treatment for this. Zavedos might not be a suitable treatment for you, or a reduced dose might have to be used.
Taking other medicines
Please tell your doctor or pharmacist if you:
Are given medicines that have a similar action to Zavedos. They can make the effects of Zavedos stronger.
Are receiving radiotherapy.
Avoid becoming pregnant while you or your partner is being treated with Zavedos. If you are sexually active, you are advised to use effective birth control to prevent pregnancy during treatment, whether you are male or female. Zavedos may harm an unborn child, so it is important to tell your doctor if you think you are pregnant.
You should not breast-feed whilst receiving Zavedos, as some of the drug may get into your milk and possibly harm your child.
Ask your doctor or pharmacist for advice before taking any medicine.
Driving and using machinery
Special care should be taken if it is essential that you drive or operate machinery while undergoing treatment especially if you are lacking strength or are in a debilitated condition.
3. How Zavedos will be given to you.
Zavedos will be given to you by injection.
• Your doctor will prescribe the required amount (the dose). The dose is decided by taking into account your condition being treated, your height and weight.
• From your height and weight the doctor will work out your body surface area; this is necessary because the dose is usually calculated as “… milligrams per square metre” (mg/m2), given by injection, on 3 days running.
• However, your doctor may alter the dose and number of days treatment depending on your condition and any other treatment you may receive.
Regular checks by your doctor during Zavedos treatment
During treatment you will need regular checks including blood tests. Your doctor will be making regular checks of:
• Your blood, to check for low blood cell counts that may need treatment.
• Your heart function, as Zavedos can have effects upon this.
• Your liver and kidneys – again using blood tests – to check that Zavedos is not affecting the way they functions in a harmful way.
• Blood uric acid levels – Zavedos may increase uric acid levels in the blood, which might cause gout. Another medicine may be given if your uric acid levels are too high.
You will find more information on some of these effects in Section 4 ‘Possible Side Effects’.
If you receive high doses of Zavedos:
High doses can worsen side effects like sores in the mouth or may decrease the number of white blood cells and platelets (these help the blood to clot) in the blood. Should this happen, you may need antibiotics or blood transfusions. Mouth ulcers can be treated to make them less uncomfortable as they heal.
Heart damage can occur when high doses of Zavedos are given. This may not be detected for several weeks, so regular tests may be required during this period.
4. Possible side effects
Like all medicines Zavedos can have side effects.
Allergic reactions can occur- you may feel dizzy, feverish, short of breath with a tight chest or throat or have an itchy rash. If this happens, tell your doctor or nurse immediately as this type of reaction can be very serious.
Low numbers of the following blood cells
• Red cells causing anaemia that can leave you feeling tired and lethargic.
• White cells(which fight infection) increasing the chance of infections, a raised temperature or fever and chills (like flu). Severe infections can occur after treatment with idarubicin alone or in combination, and may be fatal.
• Platelets (these help the blood to clot) making you bruise more easily, or bleed more than usual if you hurt yourself.
It is important to seek medical advice if this happens.
You may also notice the following side effects:
Effects on your heart
• Symptoms of damage to the heart muscles, which include tiredness, shortness of breath, weight gain and swollen ankles.
Effects on your kidneys and bladder
• A red colour in your urine may appear when you pass water for a few days after treatment. This is quite normal and should not be cause for concern.
Effects on your skin and hair:
• You may lose all or part of your hair, which usually grows back after treatment has finished.
• You may get skin rashes.
Effects on your mouth, stomach and intestines:
•Soreness or ulcers in the mouth, which may not appear until 3-10 days after treatment, heartburn, feeling sick (nausea) being sick (vomiting) or diarrhoea.
If any of the side effects get serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.
5. How to store Zavedos
• Keep out of the reach and sight of children.
• Do not use Zavedos after the expiry date, which is stated on the vial. The expiry date refers to the last date of that month.
• Zavedos should be given to you by injection within 24 hours of being made up from the dry powder in the vial. It should be kept in the fridge during this time.
6. Further information
What Zavedos contains
Zavedos is supplied as an orange-red powder in a vial containing either 5mg or lOmg of the active ingredient, idarubicin hydrochloride. Your medicine also contains lactose monohydrate. The vials are packed singly in cartons. Your doctor or nurse will make up the Zavedos with water into an injection.
Idarubicin hydrochloride Powder for Solution for Injection
Idarubicin, an original anthracycline, is a DNA inter-calating agent which interacts with topoisomerase II and has an inhibitory effect on nucleic acid synthesis.
The modification in 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 leukemia 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, darubicinol, administered at the same doses as the parent drug, is clearly less cardiotoxic than idarubicin.
After i.v. 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 metabolized to an active metabolite, idarubicinol, 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 leukemic 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.
Sterile, pyrogen-free, orange-red, freeze-dried powder in vials containing 5 mg and 10 mg of idarubicin hydrochloride with 50 mg and 100 mg of lactose respectively.
Antimitotic and cytotoxic agent. Acute non-lymphocytic leukemia (ANLL) in adults for remission induction in untreated patients or for remission induction in relapsed or refractory patients.
Acute lymphocytic leukemia (ALL) as second line treatment in adults and children.
Zavedos may be used in combination chemotherapy regimens involving other cytotoxic agents.
Dosage and Administration
For reconstitution, the contents of the 5 mg vial should be dissolved in 5 ml of Water for Injections, the 10 mg vial in 10 ml of Water for Injections. Zavedos 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.
Dosage is usually calculated on the basis of body surface area.
Acute non-lymphocytic leukemia (ANLL)
In adult ANLL the dose schedule suggested is 12 mg/m2 i.v. daily for 3 days in combination with cytarabine.
Another dose-schedule which has been used in ANLL as a single agent and in combination is 8 mg/m2 i.v. daily for 5 days.
Acute lymphocytic leukemia (ALL)
As a single agent in ALL the suggested dose in adults is 12 mg/m2 i.v. daily for 3 days and in children is 10 mg/m2 i.v. daily for 3 days.
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.
Warning: this product is not for intrathecal use.
Contra-indications, warnings, etc.:
– hypersensitivity to idarubicin or any other component of the product, other anthracyclines or anthracenediones
– severe hepatic impairment
– severe renal impairment
– severe myocardial insufficiency
– recent myocardial infarction
– severe arrhythmias
– persistent myelosuppression
– previous treatment with maximum cumulative doses of idarubicin and/or other anthracyclines and anthracenediones .
-Breast-feeding should be stopped during drug therapy .
Uncontrolled infections Warnings and Precautions 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 toxi city 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.
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 %
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.
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
Patients with rare hereditary problems of galactose intolerance, the Lapp la deficiency or glucose-galactose malabsorption should not take this medicii
The frequencies of undesirable effects are based on the following categoric
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
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|
Immune system disorders
Nervous system 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|
|Common||Local phlebitis, thrombophlebitis|
|Very rare||Thromboembolism, flush|
|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|
|Common||Elevation of the liver enzymes and bilirubin|
Skin and subcutaneous tissue disorders
|Common||Rash, Itch, hypersensitivity of irradiated skin (‘radiation recall reaction’)|
|Uncommon||Skin and nail hyperpigmentation, urticaria|
|Very rare||Acral erythema|
Renal and urinarv disorders
|Very common||Red coloration of the urine for 1-2 days after the treatment.|
General disorders and administration site conditions
Pronounced myelosuppression is the most severe adverse effect of idarubicin treatment.
However, this is necessary for the eradication of leukemic cells.
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.
Life-threatening CHF is the most severe form of anthracycline-induced cardiomyopathy and
represents the cumulative dose-limiting toxicity of the drug .
Use During 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
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.
Idarubicin is a potent myelosuppressant and combination chemotherapy regimens including other agents with similar action may be expected to induce additive myelosuppressant effects .. 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.
An additive myelosuppressant effect may occur when radiotherapy is given concomitantly or within 2-3 weeks prior to treatment with idarubicin.
Although the single-dose packaging is designed to minimise the risk of overdosage and no data on overdosage exists, should this occur gastric lavage should be carried out as soon as possible.
Patients treated with oral idarubicin should be observed for possible gastro-intestinal hemorrhage and severe mucosal damage. Very high doses of idarubicin may be expected to cause acute myocardial toxicity within 24 hours and severe myelosuppression within one or two weeks. Treatment should further aim to support the patient during this period and should utilise such measures as blood transfusions and reverse-barrier nursing. Delayed cardiac failure has been seen with the anthracyclines up to several months after the overdose. Patients should be observed carefully and if signs of cardiac failure arise, should be treated along conventional lines.
The vial contents are under a negative pressure to minimise aerosol formation during reconstitution; particular care should be taken when the needle is inserted. Inhalation of any aerosol produced during reconstitution must be avoided.
The following protective recommendations which are valid for all cytotoxic agents are given:
– Personnel should be trained in good technique for reconstitution and handling.
– Pregnant staff should be excluded from working with this drug.
– Personnel handling the drug should wear protective clothing; goggles, gowns and disposable gloves and masks.
– A designated area should be defined for reconstitution (preferably under a vertical laminar flow system). The work surface should be protected by disposable, plasticbacked, absorbent paper.
All items used for reconstitution, administration or cleaning, including gloves, should be placed in high-risk, waste disposal bags for high temperature incineration.
Accidental contact with the skin or eyes should be treated immediately by copious lavage with water or sodium bicarbonate solution.
Spillage or leakage should be treated with dilute sodium hypochlorite (1% available chlorine) solution, preferably by soaking, and then water. All cleaning materials should subsequently be disposed of as indicated previously.
When aseptically prepared, the product may be stored for up to 24 hours at 2°C to 8°C.
The product does not contain an antimicrobial preservative. Therefore if aseptic preparation cannot be ensured, the product must be prepared immediately before use and any unused portion discarded.
Prolonged contact 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 and it is not recommended that it be mixed with other drugs.
5 mg and 10 mg vials for injection.
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