Ribomustin concentrate powder for infusion solution, 25mg vials 1pc

Composition

1 bottle contains:

Active ingredients:

bendamustine hydrochloride 25 mg.

Auxiliary substances:

mannitol – 30 mg.

The bottle contains 25 mg of concentrate. The package contains 1 bottle.

Pharmacological action

Pharmacodynamics

Antitumor drug with bifunctional alkylating activity. The mechanism of action is mainly associated with the formation of cross-links 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 bendamustine has additional antimetabolic properties (the effect of a purine analog).

The antineoplastic effect of bendamustine has been confirmed in numerous studies in vitro 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, prostate and brain malignancies) and in vivo-on various experimental tumor models (melanoma, breast cancer, sarcoma, lymphoma, leukemia and small cell lung cancer). Bendamustine does not show or only slightly demonstrates cross-resistance in human tumor cell lines with different resistance mechanisms.

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

Pharmacokinetics

Distribution

After a single 30-minute intravenous infusion of bendamustine at a dose of 120 mg/m2 of body surface area, the beta phase of elimination (T1/2b) is 28.3 minutes. Vd with a 30-minute intravenous infusion is 19.3 liters, with subsequent systematic use 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 plasma albumin concentrations, in patients over the age of 70 years, and in late-stage tumors.

Metabolism

Bendamustine hydrochloride is primarily metabolized in the liver. The main route of elimination of bendamustine hydrochloride from the body is its hydrolysis to form monohydroxy – and dihydroxybendamustine. Cytochrome P 450 SUR1 A 2 isoenzyme is involved in the formation of gamma-hydroxybendamustine (M3) and N-desmethylbendamustine (M4) in the liver. In vitro bendamustine does not inhibit SUR 1 A 4, SUR 2 C 9/10, SUR 2 D6, SUR 2 E 1 and SUR 3 A 4.

Deduction

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

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

Mainly polar metabolites are excreted in the bile.

Pharmacokinetics in special clinical cases

With 30-70% liver cancer and slightly reduced liver function (serum bilirubin

Pharmacokinetic parameters in patients with creatinine clearance > 10 ml / min, including those on dialysis, did not differ significantly from those in patients with normal renal function in terms of Cmax, Tmax, AUC, T1/2β, Vd and excretion.

Patients over 84 years of age were not included in the bendamustine pharmacokinetic study; the pharmacokinetic parameters did not significantly differ in individuals over 18 and under 84 years of age.

There were no differences in pharmacokinetics by race.

Indications

• Chronic lymphocytic leukemia (the effectiveness of first-line therapy in comparison with other chemotherapy drugs other than chlorambucil has not been established);
• indolent non-Hodgkin’s lymphoma in monotherapy in patients who have experienced progression during or within 6 months after the end of therapy with rituximab and in combination therapy as first-line therapy.

Use during pregnancy and lactation

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

Contraindications

• Moderate and severe hepatic impairment;
• jaundice;
• the neutrophil count less than 1500/µl and/or platelets less than 75 000/µl;
• surgical intervention in less than 30 days before the start of therapy;
• infection, especially accompanied by leukocytopenia;
• children’s age (the lack of data on efficacy and safety);
• pregnancy;
• lactation (breastfeeding);
• hypersensitivity to the Active ingredient or to any of the ancillary components or intolerance.

With caution: the drug should be prescribed for mild hepatic insufficiency, with impaired renal function. Patients with a history of serious cardiac diseases (myocardial infarction, ischemic episodes, arrhythmia) need careful monitoring of the water-electrolyte balance, especially potassium, and ECG monitoring during Ribomustine therapy.

Side effects

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

Adverse reactions are listed by the frequency of their registration in accordance with the following gradation:

• frequently (≥ 1/100 to < 1/10);
• infrequently (≥ 1/1000 to < 1/100);
• rarely (≥ 1/10,000 to

From the hematopoietic 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 ALT, AST, alkaline phosphatase, bilirubin concentration; very rarely-hemorrhagic esophagitis, gastrointestinal bleeding.

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

From the respiratory system: often-impaired respiratory function, cough, shortness of breath, wheezing, nasopharyngitis; very rarely – pulmonary fibrosis, primary atypical pneumonia.

From the nervous system: very often – headache, dizziness, insomnia; often-taste disorders, anxiety, depression; rarely-increased drowsiness, aphonia; very rarely-paresthesia, peripheral sensory neuropathy, anticholinergic syndrome, ataxia, encephalitis.

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

From the musculoskeletal system: very often – back pain; often-arthralgia, pain in the extremities, pain in the bones.

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

From the side of the reproductive system: often-amenorrhea; very rarely-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; very rarely-tumor lysis syndrome.

Interaction

No specific drug interaction studies have been conducted.

The active metabolites of bendamustine, gamma-hydroxybendamustine (M3) and N-desmethyl-bendamustine (M4) are formed by CYP1A2. CYP1A2 inhibitors (for example, fluvoxamine, ciprofloxacin) can potentially increase the concentration of bendamustine and reduce the concentration of active metabolites in blood plasma.

Inducers of CYP1A2 (for example, omeprazole, smoking) can potentially reduce the plasma concentrations of bendamustine and increase the concentration of its active metabolites in the blood plasma. Caution should be exercised when concomitantly using CYP1A2 inhibitors or inducers, or alternative treatment should be considered.

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

How to take it, course of use and dosage

Individual dose selection should be guided by the data of the specialized literature.

Ribomustine is intended for intravenous use.

Chronic lymphocytic leukemia

Ribomustine is administered at a dose of 100 mg/m2 of body surface area IV as 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 of ≥ 2 degrees of severity, Ribomustine use should be postponed at least until the absolute neutrophil count ≥ 1000/µl and platelet count ≥ 75,000/µl are restored and/or the degree of non-hematological toxicity is reduced to 1 degree or less.

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

Dose modification for non-hematological toxicity: in case of clinically expressed signs of 3-4 degrees of toxicity, the dose of Ribomustine should be reduced to 50 mg/m2 in subsequent cycles.

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: with the development of grade 4 toxicity, the dose of the drug in subsequent cycles should be reduced to 90 mg/m2. In case of repeated occurrence of grade 4 hematological toxicity, the dose of the drug should be reduced to 60 mg/m2.

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

Combination therapy: Ribomustine is administered at a dose of 60 mg/m2 of body surface area IV as a 30-minute infusion daily from days 1 to 5, vincristine-iv on day 1, prednisone-at a dose of 100 mg/m2 iv daily from days 1 to 5 of each 21-day cycle.

Use in patients with impaired liver function

Based on pharmacokinetic data, there is no need to adjust the dose in patients with normal liver function (serum bilirubin concentration 3×ULN) bendamustine should not be used.

Use in patients with impaired renal function

Based on pharmacokinetic data, no dose adjustment is necessary in patients with creatinine clearance >10 ml / min. >

Rules for preparing the solution for infusions

The contents of the 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 of bendamustine. After 5-10 minutes of 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 the preparation of the solution, if the dilution method does not exclude the possibility of microbial contamination. If the 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.

Overdose

When patients received a maximum single dose of 280 mg/m2 on days 7-21, ECG abnormalities were observed, including prolongation of the QT interval, sinus tachycardia, changes in the ST segment and T wave, and blockage of the anterior branch of the left bundle branch.

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

Special instructions

Treatment with Ribomustine should be carried out under the supervision of a doctor who has experience with antitumor drugs.

Against the background of therapy, peripheral blood and liver enzyme activity indicators should be monitored regularly, at least once a week.

A decrease in white blood cells, neutrophils and platelets, as a rule, is observed on day 14-20, recovery – after 3-5 weeks.

When using Ribomustine, changes in renal function have been noted, so careful monitoring of renal function should be provided during treatment.

In case of extravasation, the infusion should be stopped immediately, followed by cooling the injection site and raising the hand where the extravasation occurred. The remaining drug must be injected into another vein.

Bendamustine has teratogenic and mutagenic effects.

Patients should use reliable methods of contraception during therapy and for at least 6 months after it ends. Men are advised to resort to cryopreservation of sperm before starting treatment due to the risk of infertility due to the use of this drug.

In case of contact with the skin and mucous membranes, wash them with soap and water.

Influence on the ability to drive vehicles and other mechanisms that require increased concentration of attention

Studies of the effect of Ribomustine on the ability to drive vehicles and mechanisms have not been conducted. However, ataxia, peripheral neuropathy, and drowsiness were reported during drug therapy. If such phenomena occur, patients should avoid driving vehicles and working with mechanisms.

Form of production

Concentrate Preparation Powder for Infusion Solution preparation

Storage conditions

In a dark place, at a temperature not exceeding 25 °C

Shelf life

3 years

Active ingredient

Bendamustin

Conditions of release from pharmacies

By prescription

Dosage form

solution for infusions

Purpose

For adults as directed by your doctor

Indications

Cancer