Zavedos lyophilizate 5 mg

Pharmacodynamics

Antitumor drug from the group of anthracycline antibiotics. Idarubicin, being integrated into DNA molecule, interacts with topoisomerase II and inhibits the synthesis of nucleic acids. Idarubicin is highly lipophilic and has a higher rate of cell penetration compared to doxorubicin and daunorubicin.

The main metabolite of idarubicin, idarubicinol, has antitumor activity and is less cardiotoxic than idarubicin.

Pharmacokinetics

Absorption

In oral administration, absorption is high. Time to reach Cmax – 2-4 hours. Bioavailability is 18-39%. When administered intravenously Cmax is reached within a few minutes.

Distribution

The uptake of idarubicin by nucleated blood cells and bone marrow in leukemia patients is very fast and almost coincides with its appearance in blood plasma. The concentrations of idarubicin and idarubicinol in nucleated cells of blood 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 idarubicinol.

It is excreted mainly as idarubicinol in the bile, but also in the urine unchanged (1-2%) and as idarubicinol (4.6%).

The T1/2 of idarubicinol after oral administration is 10-35 h, after intravenous administration – 11-25 h. Idarubicinol is characterized by a longer T1/2 – 33-60 h when administered orally and 41-69 h when administered intravenously. Excretion rate of idarubicin and idarubicinol from blood plasma and cells is almost the same (terminal T1/2 of idarubicin from cells is about 15 hours, and of idarubicinol – about 72 hours).

Indications

Active ingredient

Composition

Active ingredients:

idarubicin hydrochloride 5 mg.

Associates:

lactose.

How to take, the dosage

The drug is administered by IV fluids (very slowly) for 5-10 min. To reduce the risk of extravasation it is recommended to administer Zavedos through a tube system for intravenous injection (during the infusion of 0.9% sodium chloride solution).

The capsules are taken orally with a small amount of water. It can be taken with food. The capsule should be swallowed whole (do not bite, do not chew, do not liquefy).

In acute non-lymphoblastic leukemia (ALL) in adults the drug is administered by IV in a dose of 12 mg/m2 body surface area daily for 3 days (in combination with cytarabine) or by 8 mg/m2 daily for 5 days as monotherapy or in combination with other anticancer drugs. If iv infusion is not possible, idarubicin is administered orally at 30 mg/m2/day for 3 days as monotherapy or at 15-30 mg/m2 daily for 3 days in combination with other antileukemia drugs.

In acute lymphoblastic leukemia, 12 mg/m2 in adults, 10 mg/m2 in children; the drug is administered by IV daily for 3 days as monotherapy.

In advanced breast cancer the drug is administered orally as monotherapy at a rate of 45 mg/m2 for one day, or 15 mg/m2/day for 3 days every 3-4 weeks, depending on the hematological status of the patient. In combined chemotherapy, the drug is used at a dose of 35 mg/m2 for one day.

All regimens given 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.

The data on the use of Zavedos are limited in liver and kidney function disorders. In case of elevated serum bilirubin and/or creatinine it is recommended to use the drug in reduced doses.

In case of bilirubin content in serum within the range of 1.2-2 mg% the dose of anthracycline is usually reduced by 50%; if it exceeds 2 mg% – the preparation is discontinued.

Regulations for preparation and administration of the solution

Only water for injection is used as a solvent for the drug Zavedos. To prepare the solution, 5 mg of the drug is dissolved in 5 ml of water for injection.

Interaction

Combination chemotherapy with Zavedos and other drugs of similar activity can lead to additive toxic effects, especially with respect to the hematopoietic/bone marrow system and the gastrointestinal tract.

Additive myelosuppressive effect may also be seen if radiation therapy has been performed against or 2-3 weeks prior to therapy with Zavedos.

The concomitant use with other cardiotoxic or cardiovascular medications (e.g., calcium channel blockers) requires careful monitoring of cardiac function throughout treatment.

Changes in liver function as a result of concomitant therapy may impair the metabolism of idarubicin as well as its pharmacokinetics, therapeutic efficacy and/or increase its toxicity.

The risk of nephropathy increases when co-administered with uricosuric drugs.

Pharmaceutical interactions.

Zavedos should not be mixed with other drugs. It is not pharmaceutically compatible with any solutions with an alkaline pH value – Idarubicin is destroyed.

The drug should not be mixed with heparin due to possible precipitation.

Special Instructions

Zavedos should only be used under the supervision of a physician experienced in cytotoxic chemotherapy.

Before initiating the use of Zavedos, the patient should be assured that there are no signs of acute toxicity (stomatitis, neutropenia, thrombocytopenia, generalized infections) resulting from prior cytotoxic drug therapy.

Before and during each cycle of therapy, peripheral blood counts and leukocyte counts should be closely monitored.

To reduce the risk of severe toxic cardiac damage, regular monitoring of cardiac function (using the same assessment methodology throughout the duration of therapy), including assessment of left ventricular ejection fraction by echocardiography or multichannel radioisotope angiography, and ECG monitoring is recommended before and during Zavedos therapy. Monitoring of cardiac function 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 detected, treatment with Zavedos should be discontinued immediately. Risk factors for cardiotoxicity include cardiovascular disease in the active or latent phase, prior or concomitant radiotherapy of the mediastinal or pericardial area, prior therapy with other anthracyclines or anthracenedione, concomitant use of other drugs that suppress the cardiac contractility. However, cardiotoxicity due to the use of the drug may also develop at lower cumulative doses and regardless of the presence or absence of risk factors for cardiotoxicity. The toxicity of idarubicin and other anthracyclines and anthracenediols is thought to be additive.

The cumulative dose limits of Zavedos when administered by injection and ingestion have not yet been established. Cases of cardiomyopathy have been reported in approximately 5% of patients when an IV cumulative dose of 150-290 mg/m2 is administered. The available data on patients who have taken Zavedos orally at a total cumulative dose of up to 400 mg/m2 suggest a low probability of developing cardiotoxicity.

Because impaired hepatic and/or renal function may affect the distribution of idarubicin, hepatic and renal function (with determination of serum bilirubin and creatinine levels) should be monitored before and during treatment.

Before prescribing Zavedos capsules to patients at increased risk of bleeding and/or gastrointestinal perforation, the ratio of the expected benefit of the drug to the risk of developing complications should be assessed.

Patients taking Zavedos orally should be closely monitored because gastrointestinal bleeding and severe gastrointestinal mucosal damage are possible.

Due to the possible development of hyperuricemia during therapy it is recommended to determine serum levels of uric acid, potassium, calcium, phosphate and creatinine. Prophylactic measures (hydration, alkalinization of urine, allopurinol administration) minimize the risk of complications associated with tumor lysis syndrome.

Phlebosclerosis may develop after injection into small-diameter veins or after repeated injections into the same vein. The risk of phlebitis/thrombophlebitis at the injection site may be reduced if the recommendations for drug administration are strictly followed.

In case of the first signs of extravasation (burning or soreness at the injection site), the infusion should be stopped immediately, and then the infusion should be resumed in another vein until the full dose is administered.

The rules for handling cytotoxic agents must be followed when working with Zavedos.

In case of accidental contact of the drug on the skin, rinse immediately with plenty of soap and water or sodium bicarbonate solution; in case of accidental contact of the drug in the eyes – rinse the eyes with plenty of water for at least 15 minutes.

The surface contaminated with the drug is recommended to be treated with diluted solution of sodium hypochlorite (containing 1% chlorine).

Contraindications

With caution: the drug should be prescribed in myocarditis, varicella, shingles, gout or urate nephrolithiasis (history), infections, leukopenia, thrombocytopenia, elderly patients (over 60 years).

Side effects

Cardiovascular system: phlebitis, thrombophlebitis and thromboembolism, including pulmonary embolism. Manifestation of early (acute) cardiotoxicity is sinus tachycardia and/or ECG changes (nonspecific changes in ST-segment or T-wave). Tachyarrhythmias, including ventricular extrasystole and ventricular tachycardia, bradycardia, AV-blockade and Gis bundle branch block may also be noted. The occurrence of these phenomena is not always a prognostic factor for later delayed cardiotoxicity, they are rarely clinically significant and do not require withdrawal of therapy with Zavedos. Late (delayed) cardiotoxicity usually occurs during the last courses of therapy or several months or years after completion of therapy. Late cardiomyopathy is manifested by decreased left ventricular ejection fraction and/or symptoms of congestive heart failure (dyspnea, pulmonary edema, hypostatic edema, cardiomegaly and hepatomegaly, oliguria, ascites, exudative pleurisy, galloping rhythm). Subacute phenomena (pericarditis/myocarditis) may also be noted. The most severe form of anthracycline-induced cardiomyopathy is life-threatening congestive heart failure, which limits the total dose of the drug.

Hematopoietic system: leukopenia, neutropenia, thrombocytopenia, anemia. Number of neutrophils and platelets usually reaches the lowest values by 10-14 days after drug administration; recovery of blood picture is observed during the third week. Dose-dependent reversible leukopenia and neutropenia are manifestations of toxicity, which limits the dose of the drug. Clinical manifestations of severe myelosuppression may include chills, infections, sepsis/septicemia, septic shock, hemorrhages and tissue hypoxia.

Digestive system disorders: nausea, vomiting, anorexia, dehydration, mucositis, stomatitis, esophagitis, abdominal pain, heartburn, gastrointestinal mucosa erosions/ ulcers, diarrhea, colitis (including neutropenic enterocolitis with perforation), increased liver enzyme activity and increased bilirubin levels. Rarely against the background of oral administration of the drug the development of severe complications of the gastrointestinal tract (perforation, bleeding) has been observed.

Urinary system disorders: red staining of urine for 1-2 days after taking the drug.

Dermatological reactions: alopecia, rash, itching, skin and nail hyperpigmentation, hypersensitivity of irradiated skin (“radiation response”), urticaria and peripheral erythema.

Allergic reactions: hot flashes to the face, anaphylaxis.

Local reactions: if the drug gets under the skin – blistering, severe cellulitis, necrosis of the surrounding soft tissues.

Others: hyperuricemia due to rapid lysis of tumor cells (“tumor lysis syndrome”), secondary leukemia with or without preleukemic phase (most often seen with anthracyclines in combination with DNA-disrupting anticancer agents) with a latency period of 1 to 3 years.

Overdose

Symptoms: acute cardiotoxicity in the first 24 h (late cardiotoxicity may be observed several months after an anthracycline overdose) and severe myelosuppression (within 1-2 weeks).

Treatment: symptomatic therapy is carried out.