Ribomustine 100 mg

Pharmacodynamics

Antitumor drug with bifunctional alkylating activity. Mechanism of action is mainly related to 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/msup>2 body surface beta phase elimination (T_1/2β) is 28.3 min. V_d for a 30-minute IV infusion is 19.3 liters, with subsequent systemic administration and reaching equilibrium concentration V_d is 15.8 to 20.5 liters. In the systemic bloodstream, bendamustine is actively bound 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.

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 lesions 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 C_max, T_max, AUC, T_1/2β, V_d and excretion.

Pharmacokinetic parameters in patients with CK > 10 mL/min, incl. on dialysis, were not significantly different from those in patients with normal renal function with respect to C_max, T_max, AUC, T_1/2β, V_d and excretion.

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

No differences in pharmacokinetics were found by race.

Indications

• Cronic lymphocytic leukemia (effectiveness of use in first-line therapy compared to chemotherapies other than chlorambucil has not been established)
• .Indolent non-Hodgkin’s lymphoma in monotherapy in patients who had progression on or within 6 months of completion of therapy with rituximab and in combination therapy as first-line therapy.

Active ingredient

Bendamustine

Composition

1 vial contains:

Active substances: bendamustine hydrochloride 100 mg.

Excipients: mannitol – 120 mg.

The bottle contains 100 mg of concentrate. The package contains 1 vial.

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 body surface by 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 grade 3-4 hematologic toxicity or non-hematologic toxicity ≥2 severity, Ribomustin administration 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 the event of recurrence of grade 3-4 hematologic toxicity, 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 event of recurrence of 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. If non-hematologic grade 3-4 toxicity reoccurs, the drug dose should be reduced to 60 mg/m².

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

The use in patients with impaired hepatic function

Based on pharmacokinetic data, no dose adjustment is necessary in patients with normal hepatic function (serum bilirubin concentration 3×VHN) 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 plasma metabolites. 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 vehicles and operating mechanisms.

Contraindications

• Moderate and severe hepatic failure;
• jaundice;
• number of neutrophils less than 1500/μL and/or platelets less than 75 000/μL;
• surgical interventions less than 30 days before starting therapy;
• infections, especially those accompanied by leukocytopenia;
• childhood (lack of efficacy and safety data);
• pregnancy;
• lactation (breastfeeding) period;
• high sensitivity to or intolerance of the active ingredient or any of the excipients.

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:

• frequent (≥ 1/100 to < 1/10);
• infrequent (≥ 1/1000 to < 1/100);

Blood disorders: very common – leukopenia, neutropenia, lymphocytopenia, anemia, thrombocytopenia; common – bleeding; very rare – hemolysis.

Digestive system disorders: very often – nausea, vomiting, anorexia, inflammation of gastrointestinal mucous membranes, abdominal pain, dyspepsia; often – diarrhea, constipation, gastroesophageal reflux, dry mouth, increased ALT, AST, ALP activity, bilirubin concentration; very rarely – hemorrhagic esophagitis, gastrointestinal bleeding.

The cardiovascular system: frequently – arrhythmia, tachycardia, decreased blood pressure; infrequently – pericardial effusion; rarely – acute vascular failure; very rarely – myocardial infarction, cardiopulmonary failure, phlebitis.

Respiratory system disorders: often – respiratory disorders, cough, shortness of breath, wheezing, nasopharyngitis; very rarely – pulmonary fibrosis, primary atypical pneumonia.

Nervous system disorders: very common – headache, dizziness, insomnia; common – taste disorders, anxiety, depression; rare – increased somnolence, aphonia; very rare – paresthesia, peripheral sensory neuropathy, anticholinergic syndrome, ataxia, encephalitis.

Dermatological reactions: very common – alopecia; common – skin rash, skin itching, dry skin, increased night sweating, hyperhidrosis; very rare – erythema, dermatitis, itching, maculopapular rash.

Muscular system disorders: very common – back pain; common – arthralgia, pain in extremities, bone pain.

Allergic reactions: frequent – hypersensitivity reactions (allergic dermatitis, urticaria); rare – anaphylactic/anaphylactoid reactions; very rare – anaphylactic shock.

With the sexual system: often – amenorrhea; very rare – infertility.

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

Others: very often – body temperature increase, chills, increased pain, weakness, increased fatigue, weight loss, dehydration, accession of secondary infections, hyperuricemia; often – peripheral edema, hypokalemia; rarely – sepsis; very rare – tumor lysis syndrome.

Overdose

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

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).