Composition, form of production and packaging
Capsules hard gelatinous, size 4, with opaque case and lid of red-orange color, with a radially placed inscription "IDARUBICIN 5" on the lid, made in black ink; the contents of the capsules are orange powder.
1 caps.
idarubicin hydrochloride 5 mg
Excipients: microcrystalline cellulose, glyceryl palmitostearate.
The composition of the capsule shell: gelatin, iron oxide red, titanium dioxide.
1 PC. - bottles of dark glass (1) - packs of cardboard.
Hard gelatin capsules, size 4, with an opaque lid of a red-orange color and an opaque white body, with a radially placed inscription "IDARUBICIN 10" on the lid, made in black ink; the contents of the capsules are orange powder.
1 caps.
idarubicin hydrochloride 10 mg
Excipients: microcrystalline cellulose, glyceryl palmitostearate.
The composition of the capsule shell: gelatin, iron oxide red, titanium dioxide.
1 PC. - bottles of dark glass (1) - packs of cardboard.
Hard gelatin capsules, size 2, with an opaque case and a lid of white color, with a radially placed inscription "IDARUBICIN 25" on the lid, made in black ink; the contents of the capsules are orange powder.
1 caps.
idarubicin hydrochloride 25 mg
Excipients: microcrystalline cellulose, glyceryl palmitostearate.
The composition of the capsule shell: gelatin, iron oxide red, titanium dioxide.
1 PC. - bottles of dark glass (1) - packs of cardboard.
Lyophilizate for the preparation of a solution for intravenous administration in the form of a porous mass (powder) or tablets of red-orange color.
1 f.
idarubicin hydrochloride 5 mg
Excipients: lactose.
Vials (1) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2008.
PHARMACHOLOGIC EFFECT
Antitumor drug from the group of anthracycline antibiotics. Idarubicin, embedded in the DNA molecule, interacts with topoisomerase II and inhibits the synthesis of nucleic acids. Idarubicin has a high lipophilicity and is characterized by a higher penetration rate in cells compared to doxorubicin and daunorubicin.
The main metabolite of idarubicin - idarubicinol has antitumor activity and has less pronounced cardiotoxicity than idarubicin.
PHARMACOKINETICS
Suction
When ingested absorption is high. Time to reach C max is 2-4 hours. Bioavailability is 18-39%. With the / in the introduction of C max is achieved within a few minutes.
Distribution
Capture of idarubicin by nucleated cells of blood and bone marrow in patients with leukemia is very fast and practically coincides with its appearance in blood plasma. Concentrations of idarubicin and idarubicinol in nucleated blood cells and bone marrow are more than 100-200 times higher than the corresponding concentrations in blood plasma.
Metabolism and excretion
Idarubicin is rapidly metabolized to the active metabolite of idarubicinol.
It is excreted mainly in the form of idarubicinol with bile, as well as in urine in unchanged form (1-2%) and in the form of idarubicinol (4.6%).
T1 / 2 idarubicin after oral administration is 10-35 hours, after intravenous administration - 11-25 hours Idarubicinol is characterized by a longer T 1/2 - 33-60 hours with ingestion and 41-69 hours - with / in the introduction. The rate of excretion of idarubicin and idarubicinol from blood plasma and cells is practically the same (terminal T1 / 2 of idarubicin from cells is about 15 hours, and idarubicinol is about 72 hours).
INDICATIONS
- Acute non-lymphoblastic or myeloblastic leukemia in adults (first-line therapy for induction of remission, as well as in relapses or resistant cases);
- Acute lymphoblastic leukemia in adults and children (second-line therapy);
- widespread breast cancer (with ineffective chemotherapy of the first line, not including anthracyclines).
DOSING MODE
The drug is injected / injected (very slowly) into the for 5-10 minutes. To reduce the risk of extravasation, it is recommended to inject Zavedos through the tube of the IV system (during the infusion of 0.9% sodium chloride solution).
Capsules are taken orally, with a small amount of water. Can be taken with food. Capsules should be swallowed whole (do not bite, do not dissolve, do not chew).
In case of acute non-lymphoblastic leukemia (ONLL), the drug is administered iv to a dose of 12 mg / m 2 body surface area daily for 3 days (in combination with cytarabine) or 8 mg / m 2 daily for 5 days as monotherapy or in combination with other antitumor drugs. If iv administration is not possible, idarubicin is administered orally at 30 mg / m 2 / day for 3 days as monotherapy or 15-30 mg / m 2 daily for 3 days in combination with other antileukemic drugs.
In acute lymphoblastic leukemia, adults are prescribed 12 mg / m 2 , children - 10 mg / m 2 ; The drug is given intravenously daily for 3 days in the form of monotherapy.
In the case of advanced breast cancer, the drug is administered orally in the form of monotherapy at a rate of 45 mg / m 2 for one day, or 15 mg / m 2 / day for 3 days every 3-4 weeks, depending on the hematologic status of the patient. With combined chemotherapy, the drug is administered at a dose of 35 mg / m 2 for one day.
All these regimens should be used taking into account the hematologic status of the patient, as well as the doses of other cytotoxic drugs used in combination therapy.
With violations of the liver and kidneys data on the use of Zavedos are limited. With an elevated bilirubin and / or creatinine content in the blood serum, it is recommended to use the drug in reduced doses.
With a serum level of bilirubin in the blood serum of 1.2-2 mg%, the dose of anthracyclines is usually reduced by 50%, above 2 mg% - the drug is canceled.
Rules for the preparation and administration of a solution
As a solvent for the drug Zavedos only water for injection is used. To prepare the solution, 5 mg of the drug is dissolved in 5 ml of water for injection.
SIDE EFFECT
From the cardiovascular system: phlebitis, thrombophlebitis and thromboembolism, incl. embolism of the pulmonary artery. The manifestation of early (acute) cardiotoxicity is sinus tachycardia and / or changes in the ECG (nonspecific changes in the ST segment or T wave). There may also be tachyarrhythmias, including ventricular extrasystole and ventricular tachycardia, bradycardia, AV blockade and bundle bundle bundle blockade. The emergence of these phenomena is not always a prognostic factor in the development of subsequently delayed cardiotoxicity, they are rarely clinically significant and do not require the abolition of therapy with Zavedos. Late (delayed) cardiotoxicity is usually observed during the last course of therapy or several months or years after completion of therapy. Late cardiomyopathy is manifested by a decrease in the left ventricular ejection fraction and / or symptoms of congestive heart failure (dyspnea, pulmonary edema, hypostatic edema, cardiomegaly and hepatomegaly, oliguria, ascites, exudative pleurisy, gallop rhythm). There may also be subacute phenomena (pericarditis / myocarditis). The most severe form of anthracycline-induced cardiomyopathy is life-threatening congestive heart failure, which limits the total dose of the drug.
On the part of the hematopoiesis system: leukopenia, neutropenia, thrombocytopenia, anemia. The number of neutrophils and platelets usually reaches the lowest values ​​by 10-14 days after the administration of the drug, the restoration of the blood picture is observed during the third week. Dose-dependent reversible leukopenia and neutropenia are a manifestation of toxicity, which limits the dose of the drug. Clinical manifestations of severe myelosuppression may include chills, infections, sepsis / septicemia, septic shock, hemorrhage and tissue hypoxia.
On the part of the digestive system: nausea, vomiting, anorexia, dehydration, mucositis, stomatitis, esophagitis, abdominal pain, heartburn, erosion / ulcers of the gastrointestinal tract, diarrhea, colitis (including neutropenic enterocolitis with perforation), increased hepatic activity enzymes and an increase in the level of bilirubin. Rarely on the background of taking the drug inside, there was a development of severe complications from the gastrointestinal tract (perforation, bleeding).
From the urinary system: red staining of urine within 1-2 days after taking the drug.
Dermatological reactions: alopecia, rash, itching, hyperpigmentation of skin and nails, hypersensitivity of irradiated skin ("response to radiation"), hives and peripheral erythema.
Allergic reactions: hot flushes to the face, anaphylaxis.
Local reactions: when the drug gets under the skin - blistering, heavy cellulite, necrosis of surrounding soft tissues.
Other: hyperuricemia due to rapid lysis of tumor cells ("tumor lysis syndrome"), secondary leukemia with or without preleukemic phase (most often observed with anthracyclines in combination with DNA-breaking antitumor agents) with a latent period of 1 to 3 years.
CONTRAINDICATIONS
- marked hepatic or renal insufficiency;
- severe heart failure;
- recently transferred myocardial infarction;
clinically significant arrhythmias;
- persistent myelosuppression;
- Prior therapy with maximum cumulative doses of idarubicin and / or other anthracyclines or anthracendones;
- Pregnancy;
- lactation (breastfeeding);
- hypersensitivity to idarubicin and / or other components of the drug, as well as to other anthracyclines and anthracenedions.
Caution should be given to the drug in case of myocarditis, chicken pox, shingles, gout or urate nephrolithiasis (in the anamnesis), infections, leukopenia, thrombocytopenia, elderly patients (over 60 years).
PREGNANCY AND LACTATION
Zavedos contraindicated in pregnancy and lactation (breastfeeding).
Patients of childbearing age receiving therapy with Zavedos should use reliable methods of contraception.
APPLICATION FOR FUNCTIONS OF THE LIVER
For violations of renal function in patients with elevated serum creatinine levels, the dose of Zavedos should be reduced or canceled therapy with the drug.
Contraindication: severe liver dysfunction
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
When violations of liver function in patients with elevated serum creatinine levels, the dose of Zavedos should be reduced or canceled therapy with the drug. If the serum bilirubin level exceeds 2 mg%, Zavedos should be canceled; if the level of bilirubin is in the range 1.2-2 mg%, the dose of Zavedos should be reduced by 50%.
Contraindications: severe renal dysfunction
SPECIAL INSTRUCTIONS
Zavedoz should be used only under the supervision of a doctor who has experience in carrying out cytotoxic chemotherapy.
Before starting to use the drug Zavedos should make sure that the patient does not have signs of acute toxicity (stomatitis, neutropenia, thrombocytopenia, generalized infections) that resulted from previous therapy with cytotoxic drugs.
Before and during each cycle of therapy, careful monitoring of the peripheral blood pattern should be carried out with a count of the leukocyte formula.
To reduce the risk of severe cardiac toxicity, it is recommended that, prior to and during therapy with Zavedos, regular monitoring of its function is performed (using the same evaluation technique throughout the follow-up period), including an evaluation of the left ventricular ejection fraction from echocardiography or multichannel radioisotope angiography , as well as ECG monitoring. Heart function monitoring should be particularly careful in patients with risk factors, as well as in patients receiving high cumulative doses of anthracyclines. If signs of cardiotoxicity are found, treatment with Zavedos should be stopped immediately. Risk factors for cardiotoxicity include cardiovascular diseases in the active or latent phase, previous or concomitant radiotherapy of the mediastinum or pericardial region, previous therapy with other anthracyclines or anthracenedions, simultaneous use of other drugs that suppress the contractile ability of the heart. However, cardiotoxicity due to the use of the drug can develop at lower cumulative doses and regardless of the presence or absence of risk factors for the development of cardiotoxicity. It is assumed that the toxicity of idarubicin and other anthracyclines and anthracendones is additive.
Limit cumulative doses of zavedoza with iv administration and ingestion has not yet been established. There have been reports of cases of cardiomyopathy in about 5% of patients with IV cumulative dose of 150-290 mg / m 2 . The available data on patients taking Zavedos inwards in a total cumulative dose of up to 400 mg / m 2suggest a low probability of cardiotoxicity.
Since impaired liver and / or kidney function can affect the distribution of idarubicin, before and during treatment, it is necessary to monitor liver and kidney function (with determination of bilirubin and serum creatinine levels).
Before prescribing capsules of Zavedos to patients with an increased risk of bleeding and / or perforation of the gastrointestinal tract, it is necessary to evaluate the ratio of the prospective benefit from the use of the drug and the risk of complications.
Patients taking Zavedos inside should be under close supervision, as it is possible the development of gastrointestinal bleeding and severe damage to the gastrointestinal mucosa.
In connection with the possible development of hyperuricemia during therapy, it is recommended to determine the level of uric acid, potassium, calcium, phosphate and creatinine in the blood serum. Conducting preventive measures (hydration, alkalinization of urine, reception of allopurinol) allows to minimize the risk of complications associated with tumor lysis syndrome.
After insertion into veins of small diameter or after repeated injection into the same vein, phlebosclerosis may develop. The risk of phlebitis / thrombophlebitis at the injection site can be reduced by strictly following the recommendations for the administration of the drug.
When the first signs of extravasation appear (burning or pain at the injection site), the infusion should be stopped immediately and then resumed infusion into another vein until the full dose is given.
When working with Zavedos, the rules for handling cytotoxic substances must be observed.
If you accidentally get the drug on the skin, immediately wash it off with plenty of water with soap or a solution of sodium bicarbonate; In case of accidental contact with the eye, wash eyes with plenty of water for at least 15 minutes.
The surface contaminated with the drug is recommended to be treated with dilute sodium hypochlorite solution (containing 1% chlorine).
OVERDOSE
Symptoms: acute cardiotoxicity in the first 24 hours (late cardiotoxicity may occur several months after anthracycline overdose) and severe myelosuppression (within 1-2 weeks).
Treatment: conduct symptomatic therapy.
DRUG INTERACTION
Combined chemotherapy with Zavedos and other drugs of similar effect can lead to an additive toxic effect, especially with regard to the hemopoietic / bone marrow and gastrointestinal system.
Additive myelosuppressive effect can also be observed if radiation therapy was performed against the background or 2-3 weeks before Zavedos therapy.
Joint use with other cardiotoxic or cardiovascular drugs (eg, calcium channel blockers) requires careful monitoring of heart function throughout the treatment period.
A change in liver function as a result of concomitant therapy can disrupt the metabolism of idarubicin, as well as its pharmacokinetics, therapeutic efficacy and / or increase its toxicity.
When combined with uricosuric drugs is increased risk of developing nephropathy.
Pharmaceutical interaction .
Zavedos should not be confused with other drugs. Pharmaceutically incompatible with any solutions with an alkaline pH value - destruction of idarubicin occurs.
The drug should not be mixed with heparin because of the possible formation of a precipitate.
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
List B. The drug should be stored out of reach of children at a temperature of no higher than 25 В° C. The lyophilizate is recommended to be used immediately after the first opening and then reconstituted with a solvent. Shelf life - 3 years.
