Ribomustine

Bendamustine hydrochloride is an alkylating anticancer drug with bifunctional alkylating activity.

Indications Ribomustine

• First-line therapy for chronic lymphocytic leukemia (Binet stage B and C) when combination therapy with fludarabine is inappropriate.
• Monotherapy for indolent non-Hodgkin lymphoma for disease progression during or 6 months after rituximab or rituximab-containing therapy.-First-line therapy in combination with prednisone for multiple myeloma (Dury-Salmon classification stage II with progression or stage III) in patients over 65 years of age for whom stem cell transplantation is inappropriate and who have clinical neuropathy at the time of diagnosis using thalidomide or bortezomib.

Release form

1 vial contains 25 mg or 100 mg of bendamustine hydrochloride;

Excipient : mannitol (E 421).

Powder for preparation of concentrate for preparation of solution for infusion.

Main physicochemical properties: white powder of microcrystalline color.

Pharmacodynamics

The antineoplastic and cytotoxic effect of bendamustine hydrochloride is mainly due to the formation of cross-links of single- and double-stranded DNA molecules due to alkylation. As a result, the matrix function of DNA and its synthesis are impaired.

The antineoplastic effect of bendamustine hydrochloride 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 in vivo on various experimental models of glandular tumors, sarcoma, lymphoma, leukemia and small cell lung cancer).

The activity profile of bendamustine hydrochloride was evident in human tumor cells and differed from that of other alkylating agents.

Bendamustine hydrochloride shows no or only mild cross-resistance in human tumor cell lines with different resistance mechanisms, which is at least partly due to interactions with DNA that last longer compared to other alkylating agents. In addition, clinical studies have found that there is no complete cross-resistance between bendamustine and anthracyclines or alkylating agents or rituximab. However, a small number of pa

Pharmacokinetics

Distribution

The half-life in phase 1 (t 1/2 ) after intravenous 30-minute infusion of bendamustine at a dose of 120 mg/m 2 body surface area was 28.2 min. After intravenous infusion of the drug for 30 min, the central volume of distribution was 19.3 L. After bolus administration of the drug at equilibrium, the volume of distribution was 15.8-20.5 L.

More than 95% of the active substance binds to blood plasma proteins (mainly albumin).

Metabolism

Bendamustine hydrochloride is metabolized mainly in the liver. The main route of excretion of bendamustine hydrochloride from the body is its hydrolysis to form monohydroxy- and dihydroxybendamustine.Cytochrome P450 isoenzyme CYP 1A2 is involved in the formation of N-desmethylbendamustine and the metabolite gamma-hydroxybendamustine in the liver.Other significant pathways of bendamustine metabolism include binding to glutathione. In vitro, bendamustine does not inhibit CYP 1A4, CYP 2C9/10, CYP 2D6, CYP 2E1 and CYP ZA4.

Excretion

The mean total clearance after a 30-minute infusion of the drug to 12 subjects at a dose of 120 mg/m 2 was 639.4 mL/min. About 20% of the administered dose was excreted with urine within 24 hours.

Urinally excreted unchanged bendamustine and its metabolites are distributed in decreasing order as follows: monohydroxybendamustine > bendamustine > dihydroxybendamustine > oxidized metabolite > N-desmethylbendamustine.

Polar metabolites are predominantly excreted with bile.

Pharmacokinetics in hepatic dysfunction

In patients with 30-70% tumor/metastatic organ involvement and a slight decrease in liver function (serum bilirubin < 1.2 mg/dL) compared to patients with normal liver and kidney function, no significant differences in the values were observed: Bendamustine maximum plasma concentration (C mah ), time to reach maximum blood concentration (t mah ), area under the pharmacokinetic curve (AUC), beta-phase half-life (t 1/2β ), volume of distribution, clearance and excretion.

Pharmacokinetics in renal dysfunction

In patients with creatinine clearance > 10 mL/min (including patients on dialysis) compared to patients with normal hepatic and renal function, there were no significant differences in: in beta phase (t 1/2β ), volume of distribution and excretion.

Elderly patients

The pharmacokinetic studies included patients up to 84 years of age. Bic factor has no significant effect on the pharmacokinetics of bendamustine hydrochloride.

Dosing and administration

Designed to be administered over 30-60 min.

Ribomustine is used only under the supervision of a doctor experienced in antitumor therapy. During treatment with the drug, the instructions for its use should be strictly followed.

Suppression of bone marrow function is associated with increased hematologic toxicity of chemotherapy. Treatment with the drug should not be initiated if peripheral blood leukocyte count <3×109 / L and/or platelet count <75×109 / L (see section "Contraindications").

Monotherapy for chronic lymphocytic leukemia

Ribomustine is administered at a dose of 100 mg/m 2 on days 1 and 2 of the course; the course is repeated every 4 weeks.

Monotherapy of indolent non-Hodgkin's lymphoma refractory to rituximab.

Ribomustine is administered at a dose of 120 mg/m 2 on days 1 and 2 of the course; the course is repeated every 3 weeks.

Multiple myeloma

Ribomustin is used at a dose of 120-150 mg/m 2 on the 1st and 2nd day of the course, at a dose of 60 mg/m 2 daily from the 1st to the 4th day of the course with prednisolone intravenously or orally; the course is repeated every 4 weeks.

Treatment with the drug should be discontinued if the peripheral blood leukocyte count <3×109 / L and/or platelet count <75×109 / L. Treatment can be continued if the leukocyte count rises to >4×109 / L and platelet count >100×109 / L.

Reduction of leukocytes, neutrophils and platelets, as a rule, is observed on 14-20 days, recovery - after 3-5 weeks. During therapy it is recommended to monitor blood counts (see section "Peculiarities of use").

For non-hematologic toxicity, dose reduction should be based on the worsening of the general toxicity criteria during the preliminary course of treatment. It is recommended to reduce the dose by 50% at level 3 of the general toxicity criteria, to discontinue the drug - at level 4 of the general toxicity criteria.

If necessary, dose reduction should be carried out individually on the 1st and 2nd day of the course of treatment.

Use in patients with impaired liver function

Based on pharmacokinetic data, no dose adjustment is necessary for patients with moderately reduced liver function (serum bilirubin level < 1.2 mg/dL).

A 30% dose reduction is recommended for patients with moderate hepatic impairment (serum bilirubin level 1.2-3 mg/dL). No data are available for use in patients with severe hepatic impairment (serum bilirubin level > 3 mg/dL) (see Contraindications).

Use in patients with impaired renal function

Based on pharmacokinetic data, no dose adjustment is necessary for patients with creatinine clearance > 10 mL/min. Limited experience with use in patients with severe renal impairment.

Recommendations for the preparation of solution for infusion.

When preparing the solution, respiratory organs, skin and mucous membranes of medical personnel should be protected (wear gloves and protective clothing). In case of contact with skin and mucous membranes it is necessary to wash them with soap and water, in case of contact with eyes - rinse with physiological saline solution. If possible, it is recommended to use disposable special protective equipment with waterproof absorbent surface. Pregnant women should not dilute cytostatics.

To prepare the solution, the contents of a vial of Ribomustine are dissolved in water for injection as indicated below:

• in a vial containing 25 mg of bendamustine hydrochloride, add 10 ml of water for injection, after which the vial is shaken;
• to a vial containing 100 mg of bendamustine hydrochloride, add 40 ml of water for injection, after which the vial is shaken.

Immediately after obtaining a clear solution (usually after 5-10 min), the total dose of Ribomustine is diluted with 0.9% sodium chloride solution, and the final volume of the solution should be about 500 ml.

Ribomustine can be diluted only with 0.9% sodium chloride solution; other solutions for injection should not be used.

The rules of asepsis must be observed.

Children

Ribomustin is not used in children due to the lack of data on the efficacy and safety of the drug.

Contraindications

Hypersensitivity to bendamustine hydrochloride and/or mannitol; breastfeeding period; severe hepatic insufficiency (bilirubin level > 3.0 mg/dL); jaundice; severe bone marrow suppression and marked changes in the number of form elements in the blood (decrease in the number of leukocytes up to <3×109 /L and/or platelets <75×109 /L); surgical intervention less than 30 days before treatment; infections, especially those accompanied by leukopenia; period of vaccination against yellow fever

Side effects Ribomustine

The most common adverse reactions with bendamustine hydrochloride are hematologic adverse reactions (leukopenia, thrombocytopenia), skin toxicity (allergic reactions), constitutional symptoms (fever), and gastrointestinal symptoms (nausea, vomiting).

Clas /syste-ma /organization by MedDRA	Very often. ≥ 1/10	Often ≥ 1/100 to < 1/10	Infrequently ≥ 1/1000 to < 1/100	Rarely ≥ 1/10,000 to < 1/1000	Very rare < 1/10000	Frequency unknown (cannot be estimated from available data)
Infections and infestations	NOS infection. including opportunistic infections (e.g., herpes zoster, cytomegalovirus, hepatitis B)		Pneumo-cystic pneumonia	Sepsis	Primary atypical pneumonia
A new formation of dobro- qualitative, malignant		Tumor lysis syndrome	Myelodysplastic syndrome, acute myeloid leukemia
Blood and lymphatic system	Leukopenia NOS*, thrombocytopenia, lymphopenia	Bleeding, anemia, neutropenia	Pancytopenia	Defeat bone marrow	Hemolysis
Immune system		NOS hypersensitivity reactions *		Anaphylactic reaction, anaphylactoid reaction	Anaphylactic shock
Nervous system	Headache	Insomnia, dizziness		Drowsiness, aphonia	Taste disorders, paresthesia, peripheral sensory neuropathy, anticholinergic syndrome, neurologic disorders, ataxia, encephalitis
On the heart side		Cardiac functional disorders such as palpitations, angina pectoris, arrhythmias	Pericardial effusion, myocardial infarction, heart failure		Tachycardia	Atrial fibrillation
Vascular		Hypotension, hypertension.		Acute circul- vascular insufficiency	Phlebitis
Respiratory system, chest and mediastinal organs.		Pulmonary dysfunction			Pulmonary fibrosis
Gastrointestinal tract disorders	Nausea, blu- shafting	Diarrhea, constipation, stomatitis			Hemorrhagic esophagitis, gastrointestinal bleeding.
Skin and subcutaneous tissue		Alopecia, skin disorders NAS.		Erythema, dermatitis, pruritus, maculopapu-lesional rash, hyperhidrosis		Stevens-Johnson syndrome, toxic epidermal necrolysis, Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome)*
Disorders of the reproductive system and mammary glands		Amenorrhea			Infertility
Hepatobiliary disorders						Liver failure
General disorders, disorders at the site of administration	Inflammation of the mucous membranes, weakness, pyrexia.	Pain, fever, dehydration, anorexia.			Polyorgan failure
Laboratory tests	Decrease in hemoglobin, increase in creatinine and urea	Elevation of alanine amino-trans-ferase/ aspartate-amino-transferase, alkaline phosphatase, bilirubin level, hypokalemia
Renal and genitourinary disorders						Renal failure

NOS - Not Otherwise Specified.

* combination therapy with rituximab.

There have been isolated reports of urticaria; local irritation and thrombophlebitis; soft tissue necrosis following accidental off-vessel administration; pancytopenia; hepatitis B virus reactivation; tumor lysis syndrome and anaphylaxis.

The risk of myelodysplastic syndrome and acute myeloid leukemia is increased in patients receiving alkylating agents (including bendamustine). The occurrence of secondary tumors may develop several years after chemotherapy has been discontinued.

Overdose

The maximum tolerated dose was 280 mg/m 2 30-minute infusion of Ribomustine once every 3 weeks.

Cardiac events of general criteria for grade 2 toxicity were manifested by ischemic ECG changes and were assessed as borderline dose-related.

In a further study with a 30-minute infusion of Ribomustine on days 1 and 2 of the course every three weeks, the maximum tolerated dose was 180 mg/m 2. The dose-limiting toxicity was grade 4 thrombocytopenia. Cardiac toxicity was not a dose-limiting toxicity in this treatment regimen.

In case of overdose it is possible to increase manifestations of adverse reactions.

Therapeutic measures

There is no specific antidote. To correct hematological side effects, bone marrow transplantation and transfusion therapy (platelets, red blood cell mass) or the use of hematological growth factors may be necessary. Bendamustine hydrochloride or its metabolites are removed insignificantly during dialysis.

Interactions with other drugs

No in vivo studies have been performed.

In concomitant use of Ribomustine with myelosuppressive agents, the effect of Ribomustine and/or drugs affecting bone marrow may be potentiated. Administration of any treatment that weakens the general condition of the patient or suppresses bone marrow function may increase the toxic effects of Ribomustine.

Concomitant use of Ribomustine with cyclosporine or tacrolimus may result in significant immunosuppression with risk of lymphoproliferation.

Cytostatics may decrease antibody production after vaccination with live vaccines and increase the risk of infection, which can be fatal. The risk is increased in patients with weakened immune systems as a result of underlying disease.

Bendamustine is metabolized by the CYP 1A2 isoenzyme of cytochrome P450 (see Pharmacokinetics section). Thus, there is a potential interaction with CYP 1A2 inhibitors such as fluvoxamine, ciprofloxacin, acyclovir, and cimetidine.

Storage conditions

Store in a place protected from light at a temperature not exceeding 25 °С. Keep out of reach of children.

Special instructions

Myelosuppression

Patients using bendamustine may develop myelosuppression, so it is necessary to monitor the level of leukocytes, platelets, hemoglobin and neutrophils at least once a week. The course of treatment with Ribomustin can be continued if the following indicators: leukocytes >4×109 / L and platelets >100× 109 / L.

Infections

Infections with serious or fatal outcomes have been reported with bendamustine, including bacterial infections (pneumonia and sepsis) and infections caused by opportunistic microorganisms (opportunistic infections), such as pneumocystis pneumonia, varicella zoster and cytomegalovirus.After the use of bendamustine, mainly in combination with rituximab or obinutuzumab, cases of progressive multifocal leukoencephalopathy (PML), including fatal cases, have been reported.

Treatment with bendamustine hydrochloride may result in prolonged lymphocytopenia (< 600/μL) and reduced CD4-positive T cells (T-helper cells) (< 200/μL) for at least 7-9 months after completion of treatment.Lymphocytopenia and a decrease in the number of CD4-positive T cells appear to be more pronounced when bendamustine is used in combination with rituximab. Patients with leukopenia and low CD4-positive T-cell counts induced by bendamustine use are more susceptible to developing (opportunistic) infections.Thus, patients should be monitored for symptoms of respiratory distress during treatment. Patients should be advised to report immediately any new signs of infections, including fever or respiratory symptoms. If there are signs of (opportunistic) infections, discontinuation of bendamustine hydrochloride therapy should be considered.

When making a differential diagnosis in patients with new or worsening neurological, cognitive, or behavioral signs or symptoms, the presence of progressive multifocal leukoencephalopathy should be evaluated. If PML is suspected, appropriate diagnostic tests should be performed and bendamustine should be discontinued until the presence of PML is excluded.

Hepatitis B reactivation

Reactivation of hepatitis B in patients with chronic course of the disease occurs after treatment with bendamustine hydrochloride. In some cases, acute liver failure has been observed, including fatal outcome. Before starting treatment with bendamustine hydrochloride, patients should be tested for HBV infection.Before starting treatment, patients with positive test results for hepatitis B (including those with active disease) and patients with positive results for HBV infection during treatment should consult a physician (hepatologist). HBV carriers requiring treatment with bendamustine hydrochloride should be closely monitored for symptoms of active manifestations of HBV infection during the entire course of therapy and several months after the end of therapy.

Skin reactions

Skin reactions including rash, toxic skin reactions and bullous exanthema have been reported. Stevens-Johnson syndrome, toxic epidermal necrolysis and systemic symptoms (DRESS syndrome) have been reported in association with the use of bendamustine hydrochloride, sometimes with fatal outcome.

Some reactions have occurred when bendamustine hydrochloride was used in combination with other anticancer agents, so the causal relationship cannot be clearly established. Skin reactions that have occurred may progress with continued treatment, and their manifestations may worsen. If skin reactions progress, ribomostin should be withheld. In case of severe skin reactions, when a causal relationship with bendamustine is suspected, the use of the drug should be discontinued.

Cardiac disorders

During treatment with bendamustine hydrochloride, patients with cardiac disease should have their blood potassium levels monitored and use potassium preparations if potassium levels < 3.5 mmol/L, and electrocardiographic monitoring should be performed.

Fatal myocardial infarction and heart failure have been reported during treatment with bendamustine. Patients with heart disease or a history of heart disease should be closely monitored.

Nausea, vomiting

Antiemetic medications should be used for symptomatic treatment of nausea and vomiting.

Tumor lysis syndrome

Tumor lysis syndrome (TLS) has been reported in clinical trials. It usually occurs within 48 h after the first dose of the drug and, without treatment, may lead to OPN and death. Prophylactic measures such as adequate hydration, careful monitoring of blood chemistry (especially potassium and uric acid levels), and the use of hypouricemic agents (allopurinol and razburicase) are used before therapy.

Several cases of Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported with concomitant use of bendamustine and allopurinol.

Anaphylaxis

Infusion reactions to bendamustine have occurred frequently in clinical trials. Symptoms were usually mild and included fever, chills, pruritus and rash. Rarely, severe anaphylactic and anaphylactoid reactions have occurred. After the first cycle of therapy, patients should be questioned about their history of symptoms characteristic of infusion reactions.For patients with a history of infusion reactions, measures to prevent such reactions should be considered, including the use of antihistamines, antipyretics and corticosteroids.

Patients who have experienced grade III or higher allergic reactions should not be re-prescribed the drug.

Non-melanoma skin cancer

In clinical trials, an increased risk of non-melanoma skin cancer (basaloma and squamous cell cancer) was noted in patients receiving therapy containing bendamustine. Periodic skin examinations are recommended for all patients, especially those with risk factors for skin cancer.

Contraception

Bendamustine hydrochloride has teratogenic and mutagenic effects. Women should use effective contraceptive methods to prevent pregnancy during treatment. Male patients are advised to use effective contraceptive methods during therapy and for 6 months after use of the drug. Prior to treatment with bendamustine hydrochloride, it is recommended to consider sperm preservation due to the possibility of irreversible infertility.

Extravasation

If extravasation occurs, the infusion should be stopped immediately. After brief aspiration, the needle should be withdrawn. The area of extravasation should be cooled; raise the arm where extravasation has occurred. The use of corticosteroids, as well as adjuvant treatment, does not produce significant improvement.

Use during pregnancy or lactation.

Pregnancy

There are insufficient data on the use of Ribomustine during pregnancy. In preclinical studies, bendamustine has embryo/fetotoxic, teratogenic and genotoxic effects. Pregnant women should not be prescribed the drug except for use for vital indications. The woman should be informed of the potential risk to the unborn child. Genetic counseling is required if pregnancy occurs during treatment.

Contraception

It is recommended to use effective contraceptive methods before and during treatment.

Male patients are advised to avoid fatherhood during therapy and for 6 months after use of the drug. Due to the possibility of irreversible infertility, sperm preservation is recommended prior to treatment with bendamustine hydrochloride.

Breastfeeding

It is not known whether bendamustine passes into breast milk, therefore administration of bendamustine hydrochloride during lactation is contraindicated (see section "Contraindications"). If it becomes necessary to use bendamustine hydrochloride during lactation, breastfeeding should be discontinued.

Ability to influence reaction speed when driving motor transport or other mechanisms

Ribomustine has a significant effect on the ability to drive a car and other mechanisms.

Ataxia, peripheral neuropathy and somnolence have been reported during treatment with Rybomustine (see section "Adverse reactions"). Patients should be warned that if such reactions occur, driving motor transport and working with other mechanisms should be avoided.

Shelf life

3 years.