Ribomustine, 25 mg

Pharmacodynamics

Antitumor drug with bifunctional alkylating activity. Mechanism of action is mainly connected with 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 (purine analogue effect).

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, and colorectal cancer, melanoma, renal cell carcinoma, prostate and brain malignancies) and in vivo – in various experimental tumor models (melanoma, breast cancer, sarcoma, lymphoma, leukemia and small cell lung cancer). Bendamustine shows no or only slight cross-resistance in human tumor cell lines with different resistance mechanisms.

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

Pharmacokinetics

Distribution

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

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

Metabolism

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

Elimation

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

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

The polar metabolites are mainly excreted with the bile.

Pharmacokinetics in special clinical cases

In 30-70% tumorigenic liver damage and mildly reduced liver function (serum bilirubin < 1.2 mg/dL), pharmacokinetics had no significant differences from those in patients with normal hepatic and renal function with respect to Cmax, Tmax, AUC, T1/2β, Vd, and excretion.

Pharmacokinetic parameters in patients with CK > 10 ml/min, including those on dialysis, were not significantly different from those in patients with normal renal function with respect to Cmax, Tmax, AUC, T1/2β, Vd and excretion.

Patients older than 84 years of age were not included in the pharmacokinetic study of bendamustine; pharmacokinetic parameters were not significantly different in those over 18 and under 84 years of age.

There were no differences in pharmacokinetics by race.

Indications

Active ingredient

Composition

1 vial contains:

Active substances:

bendamustine hydrochloride 25 mg.

Auxiliary substances:

Mannitol – 30 mg.

In a vial 25 mg of concentrate. There is 1 vial in the package.

How to take, the dosage

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

Ribomustine is intended for intravenous administration.

Chronic lymphocytic leukemia

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

In case of development of grade 3-4 hematologic toxicity or non-hematologic toxicity ≥ grade 2 severity, administration of Ribomustin should be delayed at least until recovery of absolute neutrophil counts ≥ 1000/μL and platelet counts ≥ 75,000/μL and/or reduction of non-hematologic toxicity severity to grade 1 or less.

Dose modification in hematologic toxicity: In case of development of grade 3-4 toxicity the drug dose in subsequent cycles should be reduced to 50 mg/m2. In cases of recurrent hematologic toxicity of grade 3-4, the drug dose should be reduced to 25 mg/m2.

Dose modification for non-hematologic toxicity: If there are clinically significant signs of grade 3-4 toxicity, the dose of Ribomustin should be reduced to 50 mg/m2 in subsequent cycles.

Non-Hodgkin’s lymphoma

Monotherapy: Ribomustin 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 hematologic toxicity: If grade 4 toxicity develops, the drug dose in subsequent cycles should be reduced to 90 mg/m2. In the case of recurrent grade 4 hematologic toxicity, the drug dose should be reduced to 60 mg/m2.

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

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

The use in patients with impaired liver function

Based on pharmacokinetic data, no dose adjustment is necessary in patients with normal liver function (serum bilirubin concentration 3×BHN) bendamustine should not be used.

Patients with impaired renal function

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

Regulations for preparation of the infusion solution

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 complete dissolution.

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

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

Interaction

No specific drug interaction studies have been performed.

The active metabolites of bendamustine, gamma-hydroxybendamustine (M3) and N-desmethyl-bendamustine (M4) are formed under the action of CYP1A2. CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin) can potentially increase the concentration of bendamustine and decrease the plasma concentration of active metabolites.

CYP1A2 inducers (e.g., omeprazole, smoking) can potentially decrease plasma concentrations of bendamustine and increase the concentration of its active metabolites in plasma. Caution should be exercised when concomitant use of CYP1A2 inhibitors or inducers is observed or alternative treatment should be considered.

Bendamustine in combination with other myelosuppressive drugs increases the effects of bone marrow suppression and toxicity. Like other cytostatics, bendamustine suppresses antibody production, increasing the risk of infection with vaccines.

Special Instructions

Treatment with Ribomustin should be done under the supervision of a physician experienced in antitumor drugs.

Peripheral blood counts and liver enzyme activity should be monitored regularly at least once a week during therapy.

The decrease of leukocytes, neutrophils and thrombocytes is usually observed on days 14-20, recovery – after 3-5 weeks.

When using Ribomustin, changes in renal function have been noted, so close monitoring of renal function should be ensured during treatment.

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

Bendamustine has teratogenic and mutagenic effects.

Patients should use reliable contraception during therapy and for at least 6 months after completion of therapy. For men, cryopreservation of sperm prior to treatment is recommended due to the risk of infertility associated with the use of the drug.

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

Impact on ability to drive vehicles and other mechanisms requiring high concentration

There have been no studies of the effect of the drug Ribomustin on the ability to drive vehicles and mechanisms. However, ataxia, peripheral neuropathy and somnolence have been reported during the drug therapy. If such phenomena are observed, patients should avoid driving motor transport and operating mechanisms.

Contraindications

With caution: the drug should be prescribed in patients with mild hepatic impairment and impaired renal function. Patients with a history of serious cardiac diseases (myocardial infarction, ischemic episodes, arrhythmia) require close monitoring of water-electrolyte balance, especially potassium, and ECG monitoring during Ribomustin therapy.

Side effects

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

Unwanted reactions are listed by their frequency of occurrence according to the following gradation:

Overdose

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

A 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.

Pregnancy use

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