Ribomustin

General characteristics. Structure:

Active agent of a bendamustin hydrochloride of 25 mg, 100 mg
excipients: Mannitolum.

Description
The lyophilized powder of white color, microcrystallic.

Pharmacological properties:

Pharmacodynamics. Action mechanism
Bendamustin is antineoplastic drug with the bifunctional alkylating activity. The mechanism of action is preferential connected with formation of cross stitchings of molecules one-chained and two chained DNA owing to alkylation. As a result of it the DNA matrix function and its synthesis is broken. There are also data on  what бендамустин has additional anti-metabolic properties (effect of a purine analog).

The anti-neoplastic effect of a bendamustin  was confirmed in the numerous researches in vitro on various tumoral cellular lines (a breast cancer, not small-celled and small-celled cancer of a lung, ovarian cancer and different types of a leukosis, and also a colon cancer, a melanoma, a pochechnokletochny carcinoma, malignant new growths of a prostate and brain) and in vivo - on various experimental models of tumors (a melanoma, a breast cancer, sarcoma, a lymphoma, a leukosis and small-celled cancer of a lung). Bendamustin does not show or shows only in insignificant degree cross resistance in human tumoral cellular lines with various mechanisms of stability.

It partially has a talk interaction with DNA which, in comparison with other alkylating means, lasts longer (for example, only partial cross resistance with other alkylating means, such as cyclophosphamide, кармустин or Cisplatinum was found). Besides, in clinical trials it was revealed that there is no full cross resistance between bendamustiny and anthracyclines or alkylates.

Pharmacokinetics. Distribution
After single 30-minute intravenous infusion of a bendamustin in a dose of 120 mg/sq.m of a body surface the beta phase of elimination (Т1/2β) makes 28,3 min. Distribution volume at 30-minute intravenous infusion makes 19,3 l, at the subsequent systematic introduction and achievement of equilibrium concentration the volume of distribution makes from 15,8 to 20,5 l. In a system blood-groove бендамустин actively contacts proteins of plasma (> 95%), mainly, with albumine.

Ability of a bendamustin to linkng with proteins of a blood plasma is not broken at low concentration of albumine in a blood plasma, at patients 70 years are aged more senior and at late stages of tumors.

Metabolism
Bendamustina a hydrochloride is metabolized preferential in a liver. The main way of removal of a bendamustin of a hydrochloride from an organism is its hydrolysis with education monogidroksi-and a digidroksibendamustina. Gamma гидроксибендамустина (MZ) and N-desmetilbendamustina (M4) in a liver is involved in education an isoenzyme of CYP 1A2 of cytochrome P450, In vitro бендамустин does not inhibit CYP 1A4, CYP 2C9/10, CYP 2D6, CYP 2E1 and CYP 3A4.

Elimination and excretion
Average value of the general clearance after 30-minute intravenous infusion of drug to 12 subjects in a dose of 120 mg/sq.m of a body surface made 639,4 ml/min. About 20% of the entered dose of drug were excreted by kidneys for 24 hours.
Quantities of not changed bendamustin excreted with kidneys and its metabolites is located   in decreasing order   as follows:  моногидроксибендамустин > бендамустин> дигидроксибендамустин> the oxidized metabolite> N-desmetilbendamustin.
With bile preferential polar metabolites are removed.

Pharmacokinetics at various groups of patients

Patients with the broken function of a liver:
at 30-70% tumoral damage of a liver and slightly reduced function of a liver  (serumal bilirubin <1,2 mg/dl), pharmacokinetics      concentration - time" (AUC), an elimination half-life (Т1/2β) had no significant distinctions from that at patients with normal function of a liver and kidneys concerning the maximum concentration (Cmax), time of achievement of the maximum concentration (tmax), the area under a curve ", the volume of distribution and removal.

Patients with a renal failure:
pharmacokinetic parameters at patients with clearance of creatinine> 10 ml/min. including which are on dialysis did not differ significantly from those at patients with normal function of kidneys in the relation Stakh, ttakh, AUC, T1/2β, the volume of distribution and removal.

Elderly patients, patients are more senior than 84 years did not join in a research of pharmacokinetics of a bendamustin, at persons is more senior 18 and 84 years pharmacokinetic are younger
parameters significantly did not differ.

Distinctions in pharmacokinetics depending on race are not revealed.

Indications to use:

• A chronic lymphocytic leukosis (efficiency of use in therapy of the first
the line in comparison with other himiopreparata except a hlorambutsil was not
it is established).
• Indo-flight nekhodzhkinsky lymphoma in monotherapy at patients, at which
progressing against the background of or within 6 months after the termination was observed
therapies with inclusion of a rituksimab and in a combination therapy as therapy
1st line.

Route of administration and doses:

At individual selection of a dose it is necessary to be guided by data of special literature.
Ribomustin is intended for intravenous (in/in) introductions.

Chronic lymphocytic leukosis
Ribomustin of 100 mg/m of a body surface intravenously in the form of the 30th minute infusion in 1 and 2
days of every 28th day cycle (to 6 cycles).

In case of development of hematologic toxicity 3-4 degrees or not hematologic toxicity> 2 degrees of manifestation Ribomustin's introduction has to be postponed as
at least before recovery of indicators of absolute quantity of neutrophils> 1000/mkl and
quantities of thrombocytes > 75000/mkl and/or decrease in degree of manifestation of not hematologic toxicity to 1 degree less.

Modification of doses at hematologic toxicity: at toxicity development 3-4 degrees the drug dose at the subsequent cycles has to be lowered to 50 mg/m. In case of repeated emergence of hematologic toxicity 3-4 degrees the dose of drug has to be lowered to 25 mg/sq.m.

Modification of doses at not hematologic toxicity; at clinically expressed signs 3-4 degrees of toxicity Ribomustin's dose at the subsequent cycles should be lowered to 50 mg/m.

Nekhodzhkinsky lymphoma
Monotherapy: Ribomustin of 120 mg/sq.m in the form of the 60th minute infusion in the 1 and 2 days of everyone 21
day cycle (to 8 cycles).

Modification of doses at hematologic toxicity: at toxicity development 4 degrees
the drug dose at the subsequent cycles has to be lowered to 90 mg/sq.m. In a case
repeated emergence of hematologic toxicity 4 degrees the dose of drug has to
to be lowered to 60 mg/m.

Modification of doses at not hematologic toxicity: at development of toxicity 3-4
degree should lower Ribomustin's dose at the subsequent cycles to 90 mg/m. In a case
repeated emergence of not hematologic toxicity 3-4 degrees drug dose
it has to be lowered to 60 mg/m.

Combination therapy: Ribomustin of 60 mg/m of a body surface intravenously in the form of 30-minute infusion daily from 1 to 5 days, Vincristinum intravenously in 1 day, Prednisolonum
100 mg/m  intravenously daily from 1 to 5 days of each 21 day cycle.

Use for patients with an abnormal liver function
On the basis of pharmacokinetic data, there is no need for dose adjustment at
patients with normal function of a liver (concentration of bilirubin in blood serum <1,2 mg/dl). At easy degree of a liver failure drug should be used with care. At moderated (activity of alaninaminotranspherase (ALT) and/or aspartate aminotransferase (ACT) is 2,5-10 times higher than the upper bound of norm (UBN) or concentration of serumal bilirubin is higher than VGN by 1.5-3 times) or a heavy liver failure (concentration of bilirubin in blood serum> 3 X VGN) бендамустин it is impossible to apply.

Use for patients with a renal failure
On the basis of pharmacokinetic data patients have no need for dose adjustment with clearance of creatinine> 10 ml/min.

Recommendations about preparation of solution for infusions
Contents of a bottle of 25 mg are parted in 10 ml of water for injections and stirred up to full
dissolution.
Contents of a bottle of 100 mg are parted in 40 ml of water for injections and stirred up to full
dissolution.
The received colourless transparent concentrate contains 2,5 mg/ml of a bendamustin. After 5-10 minute exposures  the necessary dose of Ribomustin is dissolved  in 500 ml of 0,9%
chloride sodium solution for infusions. Chemical and physical stability of this solution remains for 5 hours at the room temperature and 5 days at
storage in the refrigerator.
From the microbiological point of view the drug should be administered at once after preparation
solution if the dilution method does not exclude a possibility of its microbic planting.
If  the drug, ready to use, is not administered at once after preparation,
responsibility for time and storage conditions of ready solution bears the prepared his face.

Features of use:

Treatment by Ribomustin should be carried out under observation of the doctor having experience with antineoplastic drugs. Against the background of therapy follows regularly, at least once a week to control indicators of peripheral blood and indicators of activity of "hepatic" enzymes.
Decrease in leukocytes, neutrophils and thrombocytes is, as a rule, observed for 14-20 day, recovery - in 3-5 weeks.
When using Ribomustin's change of function of kidneys therefore during an echeniye it is necessary to provide careful monitoring of function of kidneys is noted. In case of an ekstravazation infusion should be stopped immediately with the subsequent cooling of an injection site and a raising of a hand where there was an ekstravazation. The remained drug has to be administered in other vein.

Bendamustin possesses teratogenic and mutagen action. Patients against the background of therapy and at least within 6 months after its termination should use reliable methods of contraception. Men are recommended to resort sperm cryopreservations prior to treatment in connection with the risk of infertility caused by use of this drug. At hit on skin and mucous membranes it is necessary to wash out them water with soap.

Side effects:

In the analysis of data on safety depending on a floor or race clinically significant distinctions were not revealed.
Undesirable reactions are listed on the frequency of their registration according to the following gradation: often: from> 1/100 to <1/10, infrequently: from> 1/1000 to <1/100, it is rare: from
> 1/10 000 to <1/1000, frequency is unknown (the available data do not allow to determine frequency).

 From bodies of a hemopoiesis: very often - a leukopenia, a neutropenia, an openiye lymphocyte, anemia, thrombocytopenia; often - bleedings; very seldom - hemolysis.

From system of digestion: very often - nausea, vomiting, anorexia, an inflammation of mucous membranes of digestive tract, an abdominal pain, dyspepsia; often - diarrhea, a lock,    a gastroesophageal reflux, dryness in a mouth, increase in activity of alaninaminotranspherase, aspartate aminotransferase, an alkaline phosphatase, concentration of bilirubin; very seldom - a hemorrhagic esophagitis, gastrointestinal bleeding.

From cardiovascular system: often - arrhythmia, tachycardia, a lowering of arterial pressure; infrequently - an exudate in a pericardium cavity; seldom - acute vascular insufficiency; very seldom - a myocardial infarction, cardiopulmonary insufficiency, phlebitis.

From respiratory system: often - breath dysfunction, cough, an asthma, goose breathing, a nasopharyngitis; very seldom - a pneumosclerosis, primary atypical pneumonia.

Co of the party of a nervous system: very often - a headache, dizziness, sleeplessness; often - taste disturbances, uneasiness, a depression;  seldom - the increased drowsiness, an aphonia; very seldom - paresthesia, peripheral touch neuropathy, anticholinergic
syndrome, ataxy, encephalitis.

From skin and skin appendages: very often - an alopecia; often - skin rash, a skin itch, a xeroderma, the increased night perspiration, a hyperhidrosis; very seldom - an erythema, dermatitis, an itch, makulopapulezny rash.

From a musculoskeletal system: very often - a dorsodynia; often - an arthralgia, extremity pain, an ostealgia.

From immune system: often - hypersensitivity reactions (allergic dermatitis, a small tortoiseshell); seldom - anaphylactic/anaphylactoid reactions; very seldom - an acute anaphylaxis.

From reproductive system: often - an amenorrhea; very seldom - infertility.

Local reactions: often - pain in the place of an injection, an erythema; seldom - a necrosis of surrounding fabrics.

Others: very often - fervescence, a fever, strengthening of pains, weakness, the increased fatigue, decrease in body weight, dehydration, accession of consecutive infections, a hyperuricemia; often - peripheral hypostases, a hypopotassemia; seldom - sepsis; very seldom - a syndrome of a lysis of a tumor.

Interaction with other medicines:

No special researches of medicinal interactions were conducted. Active metabolites of a bendamustin, gamma гидроксибендамустин  and N-desmetil-bendamustin (M4) are formed (MZ) under the influence of P450 CYP1A2. CYP1A2 inhibitors (for example, флувоксамин, ciprofloxacin) can potentially increase concentration of a bendamustin and reduce concentration of active metabolites in a blood plasma.
The inductors CYP1A2 (for example омепразол, smoking) can potentially reduce plasma concentration of a bendamustin and increase concentration of its active metabolites in a blood plasma.

It is necessary to be careful at simultaneous use of inhibitors or the inductors CYP1A2 or to consider the possibility of alternative treatment, Bendamustin in a combination with other myelosuppressive drugs strengthens effect of suppression of marrow and toxic properties. As well as other cytostatics бендамустин suppresses development of antibodies, strengthening risk of an infection at vaccination.

Contraindications:

• Hypersensitivity to active agent or any of auxiliary
components or their intolerance;
• Pregnancy and lactation;
• The moderated and expressed liver failure;
• Jaundice;
• Quantity of neutrophils less 1500/mkl and/or thrombocytes less 75000/mkl;
• Surgical interventions less than in 30 days prior to therapy;
• The infections which are especially followed by a leykotsitopeniya;
• Children's age (lack of data on efficiency and safety).

With care
At a slight liver failure, at renal failures. Patients with existence in the anamnesis of serious cardiological diseases (a myocardial infarction, ischemia episodes, arrhythmia) need  careful monitoring of water and electrolytic balance,  in particular potassium, and control of an ECG in the course of therapy by Ribomustin.

Overdose:

At use of the maximum single dose of 280 mg / м-at patients for 7-21 days disturbances on an ECG, including lengthening of an interval of Q-T, sinus tachycardia, changes of a segment of ST and a tooth of T and blockade of a front branch of the left leg of a ventriculonector were observed.
The specific antidote is unknown. In case of possible overdose it is necessary to watch carefully the patient, including monitoring of hematologic indicators and indicators of an ECG. Symptomatic treatment. Dialysis is ineffective.

Storage conditions:

In the place protected from light at a temperature not above 25 °C. To store in the place, unavailable to children. Period of validity 3 years. Not to use after a period of validity.

Issue conditions:

According to the recipe

Packaging:

Powder for preparation of a concentrate for preparation of solution for infusions of 25 mg and 100 mg.
Dosage of 25 mg: on 55 mg of the lyophilized powder in a bottle from brown glass of 1 type of 26 ml with a rubber bung and the razvaltsovanny removable aluminum cap intended only for disposable. On 1, 5, 10 or 20 bottles together with the application instruction in a cardboard pack.
Dosage of 100 mg: on 220 mg of the lyophilized powder in a bottle from brown glass  of 1    type of 60 ml with a rubber bung and a razvaltsovanny removable aluminum cap, rednaznachenny only for disposable. On 1 or 5 bottles together with the application instruction in a cardboard pack.