Universal reference book for medicines
Product name: RIBOMUSTINE (RIBOMUSTINE)

Active substance: bendamustine

Type: Antitumor drug.
Alkylating compound
The manufacturer: ASTELLAS PHARMA EUROPE (Netherlands) is produced by Cenexi-Laboratoires THISSEN (Belgium), which issues quality control TEMMLER WERKE (Germany) or manufactures quality control HAUPT PHARMA WOLFRATSHAUSEN (Germany) or produces quality control ORTAT (Russia)
Powder for the preparation of concentrate for the preparation of a solution for white infusions , lyophilized, microcrystalline.
1 f.

bendamustine hydrochloride 25 mg

[PRING] mannitol - 30 mg.

55 mg - bottles made of brown glass with a volume of 26 ml (1) - packs of cardboard.

55 mg - bottles made of brown glass with a volume of 26 ml (5) - packs of cardboard.

55 mg - bottles made of brown glass with a volume of 26 ml (10) - packs of cardboard.

55 mg - bottles made of brown glass with a volume of 26 ml (20) - packs of cardboard.

Powder for the preparation of concentrate for the preparation of a solution for white infusions , lyophilized, microcrystalline.

1 f.

bendamustine hydrochloride 100 mg

[PRING] mannitol - 120 mg.

220 mg - bottles of brown glass with a volume of 60 ml (1) - packs of cardboard.

220 mg - bottles made of brown glass with a volume of 60 ml (5) - packs of cardboard.

INSTRUCTION FOR THE SPECIALIST.

Description of the drug approved by the manufacturer for the printed edition of 2017.

PHARMACHOLOGIC EFFECT

Antitumor drug with bifunctional alkylating activity.
The mechanism of action is predominantly associated with the cross-linking of single-stranded and double-stranded DNA molecules due to alkylation. As a result, the matrix function of DNA and its synthesis are violated. There is also evidence that bendamustine 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 brain) and in vivo - on various experimental models of tumors (melanoma, breast cancer, sarcoma, lymphoma, leukemia and small cell lung cancer). Bendamustine does not demonstrate or demonstrates only a slight degree of cross-resistance in human tumor cell lines with different resistance mechanisms.
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.
PHARMACOKINETICS

Distribution

After a single 30-minute intravenous infusion of bendamustine at a dose of 120 mg / m 2 of the body surface, the beta-phase elimination (T 1/2? ) Is 28.3 min.
V d with a 30-minute IV infusion is 19.3 liters, with subsequent systematic administration and achieving an equilibrium concentration of V d is 15.8 to 20.5 liters. In the systemic circulation, bendamustine actively binds to plasma proteins (> 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.

Metabolism

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

The average total clearance after a 30-minute intravenous infusion of the drug to 12 subjects at a dose of 120 mg / m 2 of the body surface was 639.4 ml / min.
About 20% of the administered dose of the drug was excreted by the kidneys for 24 hours.
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.

Pharmacokinetics in special clinical cases

With 30-70% tumor damage to the liver and a slightly reduced liver function (serum bilirubin <1.2 mg / dl), the pharmacokinetics did not differ significantly from that in patients with normal liver and kidney function with respect to C max , T max , AUC, T 1 / 2?
, V d and deduction.
Pharmacokinetic parameters in patients with CK> 10 ml / min, incl.
of patients on dialysis did not differ significantly from those in patients with normal renal function in relation to C max , T max , AUC, T 1/2? , V d and deduction.
Patients older than 84 years were not included in the study of the pharmacokinetics of bendamustine, in patients older than 18 and under 84 years of age pharmacokinetic parameters did not differ significantly.

There were no differences in pharmacokinetics, depending on the race.

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 against or for 6 months after the end of therapy with rituximab included and in combination therapy as 1st line therapy;

- first-line therapy for multiple myeloma (stage II with progression or III stage for Dury-Salmon) in combination with prednisolone for patients older than 65 years who do not show autologous stem cell transplantation and who have clinical manifestations of neuropathy at the time of diagnosis, preventing use therapy with the inclusion of thalidomide or bortezomib.

DOSING MODE

For individual dose selection, reference should be made to the literature.

Ribomustine is intended for intravenous administration.

Chronic lymphocytic leukemia

Monotherapy: Ribomustine is given IV at a dose of 100 mg / m 2 of the body surface as a 30-minute infusion on days 1 and 2 of each 28-day cycle (up to 6 cycles).

In the case of hematological toxicity of 3-4 degrees or non-hematologic toxicity? 2 degrees of severity, the administration of ribomustine should be postponed until at least the recovery of absolute neutrophil counts of ≤ 1000 / μL and platelet count ≥75,000 / μL and / or a decrease in the degree of non-hematologic toxicity to ? 1 degree or less.

Modification of doses for hematological toxicity: with the development of toxicity of 3-4 degrees, the dose of the drug in subsequent cycles should be reduced to 50 mg / m 2 .
In case of recurrence of hematological toxicity of 3-4 degrees, the dose of the drug should be reduced to 25 mg / m 2 .
Modification of doses for non-hematologic toxicity: with clinically expressed signs of 3-4 degrees of toxicity, the dose of Ribomustine in subsequent cycles should be reduced to 50 mg / m 2 .

Non-Hodgkin's Lymphoma

Monotherapy: Ribomustine is administered at a dose of 120 mg / m 2 as a 60-minute infusion on days 1 and 2 of each 21-day cycle (up to 8 cycles).

Modification of doses for hematological toxicity: with the development of toxicity level 4, the dose of the drug in subsequent cycles should be reduced to 90 mg / m 2.
In the case of repeated occurrence of hematological toxicity of 4 degrees, the dose of the drug should be reduced to 60 mg / m 2 .
Modification of doses for non-hematologic toxicity: with the development of toxicity of 3-4 degrees, the dose of Ribomustine in subsequent cycles should be reduced to 90 mg / m 2 .
In case of recurrence of non-hematological toxicity of 3-4 degrees, the dose of the drug should be reduced to 60 mg / m 2 .
Combination therapy: Ribomustine is administered at a dose of 60 mg / m 2 of the body surface of the IV in the form of a 30-minute infusion every day from the 1st to the 5th day, vincristine - IV on the 1st day, prednisolone - in a dose of 100 mg / m 2 IV daily from the 1st to the 5th day of each 21-day cycle.

Multiple myeloma

Ribomustine is administered at a dose of 120-150 mg / m 2 body surface IV on days 1 and 2 in combination with prednisolone at a dose of 60 mg / m 2 IV orally from 1 to 4 days every 4 weeks.

Use in patients with impaired liver function

Based on pharmacokinetic data, there is no need for dose adjustment in patients with normal liver function (serum bilirubin concentration <1.2 mg / dL).
For mild hepatic insufficiency, the drug should be used with caution. At moderate (ALT and / or AST activity 2.5-10 times higher than IGN or serum bilirubin concentration higher than IGN 1.5-3 times) or severe hepatic insufficiency (bilirubin concentration in serum> 3? VGN), 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 CK> 10 ml / min.

Rules 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 / ml bendamustine.
After a 5-10 minute 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 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 ready-to-use medication is not administered immediately after preparation, the person who prepared it is responsible for the time and storage conditions of the finished solution.

SIDE EFFECT

In the analysis of safety data, no clinically significant differences were found depending on sex or race.

Undesirable reactions are listed according to the frequency of their registration in accordance with the following gradation: often (from? 1/100 to <1/10), infrequently (from? 1/1000 to <1/100), rarely (from? 1/10 000 to <1/1000), the frequency is unknown (the available data do not allow to determine the frequency).

From the hemopoietic 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 mucous membranes of the gastrointestinal tract, abdominal pain, indigestion;often - diarrhea, constipation, gastroesophageal reflux, dry mouth, increased activity of ALT, AST, AF, bilirubin concentrations;
very rarely - hemorrhagic esophagitis, gastrointestinal bleeding.
From the cardiovascular system: often - arrhythmia, tachycardia, lowering blood pressure;
infrequent - effusion in the pericardial cavity; rarely acute vascular insufficiency; very rarely - myocardial infarction, cardiopulmonary insufficiency, phlebitis.
On the part of the respiratory system: often - violation of 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 - a violation of taste, anxiety, depression; rarely - increased drowsiness, aphonia; very rarely - paresthesia, peripheral sensory neuropathy, anticholinergic syndrome, ataxia, encephalitis.
Dermatological reactions: very often - alopecia;
often - skin rash, itchy skin, dry skin, increased night sweats, hyperhidrosis; very rarely - erythema, dermatitis, itching, maculopapular rash.
From the musculoskeletal system: very often - back pain;
often - arthralgia, pain in the limbs, pain in the bones.
Allergic reactions: often - hypersensitivity reactions (allergic dermatitis, urticaria);
rarely anaphylactic / anaphylactoid reactions; very rarely - anaphylactic shock.
On the part 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, pain, weakness, fatigue, weight loss, dehydration, secondary infections, hyperuricemia;
often - peripheral edema, hypokalemia; rarely - sepsis; very rarely - tumor lysis syndrome.
CONTRAINDICATIONS

- moderate and severe hepatic impairment;

- jaundice;

- the number of neutrophils is less than 1500 / ОјL and / or platelets less than 75,000 / ОјL;

- surgical intervention less than 30 days before the start of therapy;

- infections, especially those accompanied by leukocytopenia;

- Children's age (lack of data on effectiveness and safety);

- Pregnancy;

- the period of lactation (breastfeeding);

- Hypersensitivity to the active substance or any of the auxiliary components or their intolerance.

With caution should prescribe the drug with mild liver failure, impaired renal 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 ECG monitoring during Ribomustine therapy.

PREGNANCY AND LACTATION

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

APPLICATION FOR FUNCTIONS OF THE LIVER

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

APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS

Based on pharmacokinetic data, there is no need for dose adjustment in patients with normal liver function (serum bilirubin concentration <1.2 mg / dL).
For mild hepatic insufficiency, the drug should be used with caution. At moderate (ALT and / or AST activity 2.5-10 times higher than IGN or serum bilirubin concentration higher than IGN 1.5-3 times) or severe hepatic insufficiency (bilirubin concentration in serum> 3? VGN), bendamustine can not be used.
APPLICATION FOR CHILDREN

Contraindicated in childhood.

SPECIAL INSTRUCTIONS

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 is usually observed on days 14-20, recovery in 3-5 weeks.

When Ribomustine is used, there is a change in kidney function, so during the treatment it is necessary to monitor the kidney function carefully.

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

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 recommended to resort to cryopreservation of sperm before the start of treatment due to the risk of infertility caused by the use of this drug.
In case of contact with skin and mucous membranes, wash with soap and water.

Impact on the ability to drive vehicles and manage mechanisms

Studies of the effects of Ribomustine on the ability to drive vehicles and mechanisms have not been carried out.
However, during therapy with the drug there were ataxia, peripheral neuropathy, drowsiness. If such events are noted, patients should avoid the management of vehicles and work with mechanisms.
OVERDOSE

Symptoms: when a maximum single dose of 280 mg / m 2 was applied in patients on days 7-21, ECG abnormalities including prolongation of the QT interval, sinus tachycardia, changes in the ST segment and the T wave, and blockade of the anterior branch of the left bundle branch were observed.

Treatment: a specific antidote is unknown.
In the event of a possible overdose, the patient should be carefully monitored, including monitoring of hematological and ECG parameters. Treatment is symptomatic. Dialysis is ineffective.
DRUG INTERACTION

No special studies of drug interactions were conducted.

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 should be exercised while using inhibitors or inducers of CYP1A2 or considering the possibility of alternative treatment.
Bendamustine 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.
TERMS OF RELEASE FROM PHARMACY

The drug is released by prescription.

TERMS AND CONDITIONS OF STORAGE

The drug should be stored out of reach of children, protected from light at a temperature of no higher than 25 В° C.
Shelf life - 3 years.
The information is provided for your information, do not self-medicate, it is dangerous for your health.

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