Bendamustyn | Ribomustin powder d / prig. concentrate d / pr. solution for infusion 25 mg vials 1 pc.

Latin name

RIBOMUSTINE

Release form for solution for preparation srdlk.

Packing

In a bottle of 25 mg of concentrate.

In the package 1 bottle.

Pharmacological action

Pharmacodynamics

Antitumor drug with bifunctional alkylating activity. The mechanism of action is mainly associated with the formation of cross-linking of single-stranded and double-stranded DNA molecules due to alkylation. As a result, the matrix function of DNA and its synthesis are disrupted. There is also evidence that that bendamustine has additional antimetabolic properties (effect of purine analogue).

The antineoplastic effect of bendamustine has been confirmed in numerous in vitro studies on various tumor cell lines (breast cancer, non-small cell and small cell lung cancer, ovarian cancer and various types of leukemia, as well as colon cancer, melanoma, renal cell carcinoma, malignant and malignant neoplasms brain) and in vivo - on various experimental models of tumors (melanoma, breast cancer, sarcoma, lymphoma, leukemia and small cell lung cancer). Bendamustine does not, or only slightly, shows cross-resistance in human tumor cell lines with different resistance mechanisms.

This is partially explained by the interaction with DNA, which, compared with other alkylating agents, lasts longer (for example, only partial cross-resistance was detected with other alkylating agents, such as cyclophosphamide, carmustine or cisplatin). In addition, in clinical studies, it was found that there is no complete cross-resistance between bendamustine and anthracyclines or alkylates.

Pharmacokinetics

Distribution of

After a single 30-minute iv infusion of bendamustine at a dose of 120 mg / m2 of the body surface, the beta elimination phase (T1 / 2 ) is 28.3 min. Vd with a 30-minute iv infusion is 19.3 liters, with subsequent systematic administration and reaching an equilibrium concentration, Vd is from 15.8 to 20.5 liters. In the systemic circulation, bendamustine actively binds to plasma proteins (> 95%), mainly albumin.

The ability of bendamustine to bind to plasma proteins is not impaired at low concentrations of albumin in blood plasma, in patients over the age of 70 years and in advanced stages of tumors.

Metabolism

Bendamustine hydrochloride is metabolized primarily in the liver. The main way to remove bendamustine hydrochloride from the body is to hydrolyze it with the formation of monohydroxy and dihydroxybendamustine. In the formation of gamma-hydroxybendamustine (M3) and N-desmethylbendamustine (M4) in the liver, the isoenzyme CYP1A2 of cytochrome P450 is involved. In vitro, bendamustine does not inhibit CYP1A4, CYP2C9 / 10, CYP2D6, CYP2E1 and CYP3A4.

Excretion of

The average total clearance after a 30-minute iv infusion of the drug to 12 subjects at a dose of 120 mg / m2 of body surface was 639.4 ml / min. About 20% of the administered dose of the drug was excreted by the kidneys for 24 hours.

The amount of unchanged bendamustine and its metabolites excreted with the kidneys is arranged in decreasing order as follows: monohydroxybendamustine> bendamustine> dihydroxybendamustine> oxidized metabolite> N-desmethylbendamustine.

Mostly polar metabolites are excreted with bile.

Pharmacokinetics in special clinical cases

With 30-70% tumor of the liver and slightly reduced liver function (serum bilirubin <1.2 mg / dL), pharmacokinetics did not have significant differences from that in patients with normal liver and kidney function with respect to Cmax, Tmax, AUC, T1 / 2 , Vd and excretion.

Pharmacokinetic parameters in patients with CC> 10 ml / min, incl. those on dialysis did not differ significantly from those in patients with normal renal function with respect to Cmax, Tmax, AUC, T1 / 2 , Vd and excretion.

Patients older than 84 years were not included in the study of the pharmacokinetics of bendamustine, in patients older than 18 and younger than 84 years the pharmacokinetic parameters did not significantly differ.

There were no differences in pharmacokinetics by race.

Indications

Chronic lymphocytic leukemia (the efficacy of first-line therapy compared to other chemotherapy drugs other than chlorambucil has not been established)

indolent non-Hodgkin's lymphomas in monotherapy in patients who showed progression on the background or within 6 months after completion of therapy with rituximab and in combination therapy as a first-line therapy.

Contraindications

Moderate and severe hepatic insufficiency

jaundice

neutrophils count less than 1500 / μl and / or platelets less than 75 000 / μl

surgical interventions less than 30 days before the start of treatment for

infection, especially in children efficacy and safety)

pregnancy

lactation (breastfeeding)

hypersensitivity to the active substance or any of the auxiliary components or their neperen osimost.

Caution:

should be prescribed in patients with mild liver failure, with impaired renal function. Patients with a history of serious cardiological diseases (myocardial infarction, episodes of ischemia, arrhythmia) need careful monitoring of the water-electrolyte balance, especially potassium, and ECG monitoring during treatment with Ribomustine.

Use during pregnancy and lactation

The drug is contraindicated in pregnancy and lactation (breastfeeding).

Composition

1 vial contains:

Active substances:

bendamustine hydrochloride 25 mg.

Excipients:

mannitol - 30 mg.

Dosage and administration of

For individual dose selection, be guided by the literature.

Ribomustine is for intravenous administration.

Chronic lymphocytic leukemia

Ribomustine is administered at a dose of 100 mg / m2 body surface iv in the form of a 30-minute infusion on days 1 and 2 of each 28-day cycle (up to 6 cycles).

In case of development of hematological toxicity of 3-4 degrees or non-hematological toxicity? 2 severity of administration of Ribomustin should be delayed at least until restoration of the absolute number of neutrophils? 1000 / µl and platelet counts? 75,000 / μl and / or decrease in the severity of non-hematological toxicity to 1 degree or less.

Dose modification for hematologic toxicity: if toxicity develops in grade 3-4, the dose should be reduced to 50 mg / m2 in subsequent cycles. In case of repeated occurrence of hematological toxicity of the 3-4 degree, the dose of the drug should be reduced to 25 mg / m2.

Dose modification for non-hematologic toxicity: for clinically evident signs of a 3-4 degree of toxicity, the dose of Ribomustine in subsequent cycles should be reduced to 50 mg / m2.

Non-Hodgkin's lymphoma

Monotherapy: Ribomustine is administered at a dose of 120 mg / m2 as a 60-minute infusion on days 1 and 2 of each 21-day cycle (up to 8 cycles).

Dose modification for hematological toxicity: if grade 4 toxicity develops, the dose should be reduced to 90 mg / m2 in subsequent cycles. In case of repeated occurrence of hematological toxicity of the 4th degree, the dose of the drug should be reduced to 60 mg / m2.

Dose modification for non-hematologic toxicity: if grade 3-4 toxicity develops, the dose of Ribomustine in subsequent cycles should be reduced to 90 mg / m2. In the case of repeated occurrence of hematologic toxicity of 3-4 degrees, the dose of the drug should be reduced to 60 mg / m2.

Combination therapy: Ribomustine is administered at a dose of 60 mg / m2 body surface iv in the form of a 30-minute infusion daily from the 1st to the 5th day, vincristine - iv in the 1st day, prednisolone - at a dose of 100 mg / m2 iv daily from the 1st to the 5th day of each 21-day cycle.

Use in patients with impaired liver function

Based on pharmacokinetic data, there is no need for dose adjustment in patients with normal liver function (serum bilirubin concentration 3? VGN) bendamustine cannot be used.

Use in patients with impaired renal function

Based on pharmacokinetic data, there is no need for dose adjustment in patients with CC> 10 ml / min.

Rules for preparing an infusion solution

The contents of a 25 mg vial are diluted in 10 ml of water for injection and shaken until completely dissolved.

The contents of a 100 mg vial are diluted in 40 ml of water for injection and shaken until completely dissolved.

The resulting colorless transparent concentrate contains 2.5 mg / ml bendamustine. After a 5-10 minute exposure, the required dose of Ribomustine is dissolved in 500 ml of 0.9% sodium chloride solution for infusion. The chemical and physical stability of this solution is maintained for 5 hours at room temperature and 5 days when stored in the refrigerator.

From a microbiological point of view, the drug should be administered immediately after preparation of the solution, if the dilution method does not exclude the possibility of microbial contamination. If a ready-to-use preparation is not administered immediately after preparation, the person who prepared it is responsible for the time and storage conditions of the finished solution.

Side effects

No clinically significant differences were found in the analysis of safety data by sex or race.

Adverse reactions are listed by the frequency of their recording according to the following gradation:

often (from 1/100 to <1/10)

infrequently (from 1/1000 to <1/100)

rarely (from 1/10 000 to <1/1000), the frequency is unknown (the available data do not allow determining the frequency).

From the hemopoietic system: very often - leukopenia, neutropenia, lymphocytopenia, anemia, thrombocytopenia often - bleeding very rarely - hemolysis.

From the digestive system: very often - nausea, vomiting, anorexia, inflammation of the gastrointestinal mucosa, abdominal pain, dyspepsia often - diarrhea, constipation, gastroesophageal reflux, dry mouth, increased activity of ALT, AST, alkaline phosphatase, very rarely bilirubin - hemorrhagic esophagitis, gastrointestinal bleeding.

From the cardiovascular system: often - arrhythmia, tachycardia, decreased blood pressure infrequently - effusion in the pericardial cavity is rare - acute vascular insufficiency is very rare - myocardial infarction, cardiopulmonary failure, phlebitis.

From the respiratory system: often - respiratory failure, cough, shortness of breath, wheezing, nasopharyngitis very rarely - pulmonary fibrosis, primary SARS.

On the part of the nervous system: very often - headache, dizziness, insomnia often - taste disturbances, anxiety, depression rarely - increased drowsiness, aphonia very rarely - paresthesia, peripheral sensory neuropathy, anticholinergic syndrome, ataxia, encephalitis.

Dermatological reactions: very often - alopecia often - skin rash, itching, dry skin, increased night sweats, hyperhidrosis very rarely - erythema, dermatitis, itching, maculopapular rash.

From the musculoskeletal system: very often - back pain often - arthralgia, pain in the limbs, bone pain.

Allergic reactions: often - hypersensitivity reactions (allergic dermatitis, urticaria) rarely - anaphylactic / anaphylactoid reactions very rarely - anaphylactic shock.

From the reproductive system: often - amenorrhea is very rare - infertility.

Local reactions: often - pain at the injection site, erythema rarely - necrosis of surrounding tissues.

Other: very often - fever, chills, increased pain, weakness, increased fatigue, weight loss, dehydration, secondary infections, hyperuricemia often - peripheral edema, hypokalemia rarely - sepsis is very rare - tumor lysis syndrome.

Drug Interaction

No specific drug interaction studies have been performed.

The active metabolites of bendamustine, gamma-hydroxybendamustine (M3) and N-desmethyl-bendamustine (M4) are formed by CYP1A2. CYP1A2 inhibitors (eg, fluvoxamine, ciprofloxacin) can potentially increase the concentration of bendamustine and decrease the concentration of active metabolites in blood plasma. CYP1A2 inducers (e.g. omeprazole, smoking) can potentially decrease plasma concentrations of bendamustine and increase the concentration of its active metabolites in blood plasma. Caution should be exercised when concomitantly administered with CYP1A2 inhibitors or inducers or alternative treatment considered.

Bendamustine in combination with other myelosuppressive drugs enhances the effect of bone marrow suppression and toxic properties. Like other cytostatics, bendamustine inhibits the production of antibodies, increasing the risk of infection during vaccination.

Overdose

When using a maximum single dose of 280 mg / m2 in patients for 7-21 days, ECG abnormalities were observed, including QT lengthening, sinus tachycardia, changes in the ST and T segment, and blockade of the anterior branch of the left bundle branch.

The specific antidote is unknown. In case of possible overdose, the patient should be closely monitored, including monitoring of hematological and ECG parameters. Treatment is symptomatic. Dialysis is ineffective.

Storage conditions

Keep out of the reach of children, protected from light, at a temperature not exceeding 25 РC.

Expiration

3 years.

terms of sale from

pharmacies Prescription

dosage form

dosage form

infusion solution

Astellas Pharm Europe BV, Netherlands