Ribomustine - instructions for use, reviews, analogues and forms of release (injections in ampoules for injections of 25 mg and 100 mg in powder for the preparation of a solution) of a drug for the treatment of lymphocytic leukemia and non-Hodgkin's lymphoma in adults, children and in pregnancy

In this article, you can read the instructions for using the drug Ribomustine. There are reviews of visitors to the site - consumers of this medication, as well as opinions of doctors specialists on the use of ribomustine in their practice. A big request is to actively add their feedback on the drug: the medicine helped or did not help get rid of the disease, which were observed complications and side effects, possibly not declared by the manufacturer in the annotation. Ribomustine analogues in the presence of existing structural analogues.Use for the treatment of lymphocytic leukemia and non-Hodgkin's lymphoma in adults, children, as well as in pregnancy and lactation.

Ribomustine antitumor agent with bifunctional alkylating activity. The mechanism of action is mainly associated with the formation of cross-linking of single-stranded and double-stranded deoxyribonucleic acid (DNA) molecules due to alkylation. As a result, the matrix function of DNA and its synthesis are violated. There is also evidence that bendamustine (the active substance of the drug Ribomustine) has additional antimetabolic properties (the effect of a 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 neoplasms of the prostate and head brain) and in vivo - on various experimental models of tumors (melanoma, breast cancer, sarcoma, lymphoma, leukemia and small cell lung cancer).The absence or presence of only a slight degree of cross-resistance in human tumor cell lines with different resistance mechanisms is shown.

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

Composition

Bendamustine + excipients.

Pharmacokinetics

In the systemic circulation, bendamustine actively binds to plasma proteins (more than 95%), mainly with albumin. The ability of bendamustine to bind to blood plasma proteins is not impaired at low concentrations of albumin in the blood plasma, in patients over the age of 70 years and in the late stages of tumors. Ribomustine is metabolized predominantly in the liver mainly by hydrolysis with the formation of monohydroxy- and dihydroxybendamustine.The amount of unchanged bendamustine and its metabolites excreted with the kidneys is arranged in descending order as follows: monohydroxybenzamustine, bendamustine, dihydroxybendamustine, oxidized metabolite, N-desmethylbendamustine. With bile, mainly polar metabolites are excreted. In individuals over 18 and under 84 years of age, pharmacokinetic parameters did not differ significantly.

Indications

• chronic lymphocytic leukemia (efficacy in first-line therapy compared with other chemotherapy drugs other than chlorambucil has not been established);
• indolent non-Hodgkin's lymphomas in monotherapy in patients who have progressed on the background or for 6 months after the end of therapy with rituximab included and in combination therapy as first-line therapy.

Forms of release

Powder for the preparation of concentrate for the preparation of a solution for infusions of 25 mg and 100 mg (injections in ampoules for injections).

Instructions for use and dosing regimen

Ribomustine is administered intravenously. For individual dose selection, reference should be made to the literature.

Chronic lymphocytic leukemia

Ribomustine 100 mg per 1 m2 of body surface intravenously as a 30-minute infusion on the 1st and 2nd days of each 28-day cycle (up to 6 cycles).

In the case of hematological toxicity of grade 3-4 or non-hematologic toxicity of more than 2 degrees, the administration of ribomustine should be postponed at least until the recovery of absolute neutrophil counts of more than 1000 in 1 μl, and platelets more than 75,000 in 1 μl and / the severity of non-hematologic toxicity to 1 st degree or less.

Modification of doses for hematologic toxicity: with the development of toxicity of the 3-4th degree, the dose of the drug for subsequent cycles should be reduced to 50 mg per 1 m2 of the body surface. In the case of repeated occurrence of hematological toxicity of the 3-4th degree, the dose of the drug should be reduced to 25 mg per 1 m2.

Modification of doses for non-hematologic toxicity: with clinically expressed signs of the 3rd-4th degree of toxicity, the dose of Ribomustine in subsequent cycles should be reduced to 50 mg per 1 m2.

Non-Hodgkin's Lymphoma

Monotherapy. Ribomustine 120 mg per 1 m2 as a 60-minute infusion on the 1 st and 2 nd days of each 21-day cycle (up to 8 cycles).

Modification of doses for hematological toxicity: with the development of toxicity of the 4th degree, the dose of the drug for subsequent cycles should be reduced to 90 mg per 1 m2. In case of repeated occurrence of hematological toxicity of the 4th degree, the dose of the drug should be reduced to 60 mg per 1 m2.

Modification of doses for non-hematologic toxicity: with the development of toxicity of the 3rd-4th degree, the dose of Ribomustine in subsequent cycles should be reduced to 90 mg per 1 m2. In case of recurrence of non-hematological toxicity of the 3rd and 4th degree, the dose of the drug should be reduced to 60 mg per 1 m2.

Combined therapy. Ribomustine at a dose of 60 mg per 1 m2 of the body surface intravenously as a 30-minute infusion daily from day 1 to day 5, vincristine intravenously on day 1, Prednisolone 100 mg per m2 intravenously daily from day 1 to day 5 th days of each 21-day cycle.

Use in patients with impaired liver function

Based on the pharmacokinetic data, there is no need to adjust the dose at a serum bilirubin concentration of less than 1.2 mg / dL. For mild hepatic insufficiency, the drug should be used with caution. At moderate (enzyme activityAlanine aminotransferase (ALT) and / or aspartate aminotransferase (ACT) 2.5-10 times higher than the upper limit of normal (UGN) or serum bilirubin concentration higher than UGN 1.5-3 times) or severe hepatic insufficiency (serum bilirubin concentration higher VGN more than 3 times) bendamustine can not be used.

Use in patients with impaired renal function

Based on pharmacokinetic data, there is no need for dose adjustment in patients with creatinine clearance greater than 10 ml / min.

Recommendations for the preparation of a 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 the 100 mg bottle are diluted in 40 ml of water for injection and shaken until completely dissolved.

The resulting colorless transparent concentrate contains 2.5 mg of bendamustine in 1 ml. After 5-10 minutes exposure, the required dose of Ribomustine is dissolved in 500 ml of a 0.9% solution of sodium chloride for infusion. The chemical and physical stability of this solution is maintained for 5 hours at room temperature and 5 days when stored in a refrigerator.

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

Side effect

• leukopenia, neutropenia, lymphocytopenia, anemia, thrombocytopenia;
• bleeding;
• hemolysis;
• nausea, vomiting;
• anorexia (a disorder manifested by an obsessive desire to lose weight, fear of obesity);
• inflammation of the mucous membranes of the gastrointestinal tract (GIT);
• abdominal pain;
• dyspepsia (abnormal gastric activity);
• diarrhea, constipation;
• gastroesophageal reflux (throwing of gastric contents into the lumen of the esophagus);
• dry mouth;
• increased activity of ALT, AST, alkaline phosphatase (AF), bilirubin concentration;
• hemorrhagic esophagitis (inflammation of the esophagus mucosa with hemorrhages in its wall);
• gastrointestinal bleeding;
• arrhythmia, tachycardia (rapid heartbeat);
• lowering blood pressure;
• effusion in the pericardial cavity;
• acute vascular insufficiency;
• myocardial infarction;
• cardiopulmonary insufficiency;
• phlebitis (inflammation of the walls of veins);
• violation of the function of breathing;
• cough;
• shortness of breath, wheezing;
• nasopharyngitis (inflammation of the mucous membrane of the nasal cavity and pharynx);
• fibrosis of the lungs;
• primary atypical pneumonia;
• headache, dizziness;
• insomnia;
• violation of taste;
• anxiety, depression;
• increased drowsiness;
• aphonia (loss of sonority of voice with whispered speech);
• paresthesia (a sensitivity disorder characterized by spontaneous sensations of burning, tingling, crawling);
• peripheral sensory neuropathy (diffuse changes in peripheral nerves that cause muscle weakness, sensitivity disorders and reflex disorders);
• anticholinergic syndrome (disorders of the central nervous system);
• ataxia (partial or complete loss of coordination of voluntary muscle movements);
• encephalitis (inflammation of the brain);
• alopecia (baldness);
• skin rash;
• itching;
• dry skin, increased night sweats;
• erythema, dermatitis;
• backache;
• arthralgia (joint pain);
• pain in the extremities, pain in the bones;
• hypersensitivity reactions (allergic dermatitis, urticaria);
• anaphylactic / anaphylactoid reactions, anaphylactic shock (allergic reaction of immediate type);
• amenorrhea (absence of menstruation during several menstrual cycles);
• infertility;
• pain at the injection site, erythema (redness);
• necrosis surrounding the injection site of tissues;
• fever, chills;
• increased pain;
• weakness, increased fatigue;
• decreased body weight;
• dehydration (dehydration);
• joining of secondary infections;
• Hyperuricemia (high uric acid in the blood);
• peripheral edema;
• hypokalemia (decrease in the concentration of potassium in the blood);
• sepsis;
• syndrome of tumor lysis.

Contraindications

• moderate and severe hepatic impairment;
• jaundice;
• the number of neutrophils is less than 1500 in 1 μl and / or platelets less than 75,000 in 1 μl;
• surgical interventions less than 30 days before therapy;
• infection, especially accompanied by leukocytopenia;
• childhood;
• pregnancy, lactation (breastfeeding);
• increased sensitivity to bendamustine.

Application in pregnancy and lactation

Contraindicated in the use of Ribomustine during pregnancy and lactation (breastfeeding).

Bendamustine has a teratogenic and mutagenic effect.Patients on the background of therapy and at least 6 months after the end should use reliable methods of contraception. Men are encouraged to resort to cryopreservation of sperm before treatment because of the risk of infertility due to the use of bendamustine.

Use in children

Contraindicated in childhood.

special instructions

With caution should be used in patients with mild hepatic insufficiency, with violations of kidney function.

Patients with a history of serious cardiac diseases (myocardial infarction, episodes of ischemia, arrhythmia) need careful monitoring of water-electrolyte balance, especially potassium, and electrocardiography (ECG) monitoring during bendamustine therapy.

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

On the background of therapy should be regularly, at least once a week to monitor the performance of peripheral blood and liver enzymes activity. Reduction of leukocytes, neutrophils and platelets, usually observed on days 14-20, recovery - after 3-5 weeks.

With the use of bendamustine, there has been a change in the function of the kidneys, so during the treatment it is necessary to ensure a careful monitoring of the kidney function.

In case of contact with skin and mucous membranes, rinse with water and soap.

Drug Interactions

Active metabolites of bendamustine, gamma-hydroxybendamustine (M3) and N-desmethyl-bendamustine (M4) are formed by the action of CYP1A2. CYP1A2 inhibitors (eg, fluvoxamine, ciprofloxacin) can potentially increase the concentration of bendamustine and reduce the concentration of active metabolites in the blood plasma. CYP1A2 inducers (eg, omeprazole, smoking) can potentially reduce plasma concentrations of bendamustine and increase the concentration of its active metabolites in blood plasma. Caution is required when concurrent use of inhibitors or inducers of CYP1A2 or the possibility of considering alternative treatments.

Ribomustine 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.

Analogues of the drug Ribomustine

Ribomustine has no structural analogs for the active substance.

Analogues of Ribomustine by pharmacological group (alkylating agents):

• Alkeran;
• Aranosa;
• Astroglyph;
• BikNU;
• Blastocarb;
• Blastol;
• Vero-Ifosfamide;
• Dacarbazine;
• Displanor;
• Ifosfamide;
• Carboplatin;
• Carbothers;
• Kemokarb;
• Кемоплат;
• Ledoxine;
• Leukeran;
• Lysomustine;
• Lomustine;
• Myelosan;
• Mileran;
• Moustophoran;
• Natulan;
• Nidran;
• Oxaliplatin;
• Oxter;
• Oxiplates;
• Oxitane;
• Oncoplatinum;
• Paract;
• Paraplatin;
• Plaksat;
• Platidiam;
• Platycad;
• Platimit;
• Platinum;
• Prospidin;
• Sarcolysin;
• CINU;
• Spirobromin;
• Thesal;
• Temodal;
• Temozolomide;
• Temomide;
• Temtical;
• Tepadine;
• Thiotepa-Thioplex;
• Thiophosphamide;
• Chlorobutin;
• Holoksan;
• Cycloplatin;
• Cyclophosphamide;
• Cyclophosphane;
• Cisanplat;
• Cisoter;
• Cisplatin;
• Cytoxan;
• Cytoplatin;
• The Exorcise;
• Eloxatin;
• Endoxane.

Review of the oncologist's doctor

Ribomustine therapy patients with chronic lymphatic leukemia suffer extremely difficult. Side effects are noted almost from the very beginning of treatment. This is a serious change in indicators in clinical and biochemical blood tests, and gastrointestinal disorders, and alopecia.Many patients are concerned about pain in the bones and joints, anxiety, fever.

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