Бортезомиб

General characteristics. Structure:

Active ingredient: 3,5 mg of a bortezomib.

Excipients: mannitol, nitrogen.

Pharmacological properties:

Pharmacodynamics. Бортезомиб is reversible inhibitor of chymotrypsin-like activity of a 26S-proteasoma of cells of mammals. This proteasoma represents a large proteinaceous complex which splits the proteins conjugated with ubiquitin.
 
Ubikvitin-proteasomny the way plays a key role in regulation of intracellular concentration of some proteins and, thus, supports an intracellular homeostasis. Suppression of activity of a proteasoma prevents this selection proteolysis that can influence many cascades of reactions of signal transmission in a cell. Disturbance of the mechanism of maintenance of a homeostasis can lead of cells to death.
 
In the researches in vivo бортезомиб caused delay of growth of a tumor on many experimental models, including a multiple myeloma.
 
In experiments of in vitro, ex vivo and on animal models бортезомиб strengthened a differentiation and activity of osteoblasts and inhibited function of osteoclasts. These effects were observed at the patients with a multiple myeloma with the multiple centers of ossifluence receiving therapy bortezomiby.

Pharmacokinetics. Distribution. Patients with a multiple myeloma at intravenous jet administration have a bortezomiba in doses of 1,0 mg/sq.m and 1,3 mg/sq.m the maximum concentration of drug in plasma make, respectively, 57 and 112ng/ml. At the subsequent administration of drug the maximum concentration in a blood plasma are in limits of 67-106 ng/ml for a dose of 1,0 mg/sq.m and 89-120 ng/ml for a dose of 1,3 mg/sq.m. The average elimination half-life of a bortezomib at repeated introduction makes 40-193 hours.
 
Drug is quicker removed after the first dose in comparison with the subsequent doses. After the first introduction in doses of 1,0 mg/sq.m and 1,3 mg/sq.m the average general clearance makes, respectively, 102 and 112 l/h, and after the subsequent introductions - 15-32 l/h.
 
At introduction in a dose of 1,3 mg/sq.m subcutaneously or intravenously sick with a multiple myeloma the general system influence after repeated introduction in the same dose (AUClast) was equivalent for both ways of introduction. Cmax after hypodermic introduction (20,4 ng/ml) was lower, than after intravenous administration (223 ng/ml).
 
After single or repeated introduction the average volume of distribution is equal in doses of 1,0 mg/sq.m and 1,3 mg/sq.m to 1659-3294 l (489-1884 l/sq.m). It allows to assume that it бортезомиб is intensively distributed in peripheral fabrics. At concentration of a bortezomib of 100-1000 ng/ml linkng of drug with proteins of a blood plasma averages 83%.
 
Metabolism. In the conditions of in vitro metabolism of a bortezomib is preferential carried out by P450 cytochrome isoenzymes - CYP3A4, CYP2C19 and CYP1A2. Participation of isoenzymes of CYP2D6 and CYP2C9 in metabolism of a bortezomib is insignificant. The main way of metabolism is eliminating of boron atoms with formation of two metabolites which are hydroxylated further with formation of several other metabolites. Metabolites of a bortezomib do not inhibit to 26S-proteasy.
 
Removal. Ways of removal of a bortezomib at the person were not studied.
 
Pharmacokinetics in special groups of patients. Influence of age, sex and race on pharmacokinetics of a bortezomib was not studied. The pharmacokinetics research at oncological patients with abnormal liver functions was conducted with participation of 51 patients with abnormal liver functions of varying severity (see tab. 2) using doses of a bortezomib in the range of 0,5-1,3 mg/sq.m. The abnormal liver function of easy degree does not influence pharmacokinetics of a bortezomib. At patients with abnormal liver functions of average and heavy degree 60% increase in AUC (the area under a curve "concentration time") a bortezomiba in comparison with patients with normal function of a liver are observed. For patients with abnormal liver functions of average and heavy degree reduction of an initial dose of a bortezomib is recommended. Attentive observation of similar patients is required. The pharmacokinetics of a bortezomib at introduction in doses of 0,7-1,3 mg/sq.m intravenously 2 times a week by the patient with renal failures of easy, average or heavy degree, including the patients who are on dialysis is comparable to drug pharmacokinetics at patients with normal function of kidneys.

Indications to use:

- Multiple myeloma;
 
- The Mantiynokletochny lymphoma at the patients who earlier received, at least, 1 line of therapy.

Route of administration and doses:

Бортезомиб it is shown only for intravenous and hypodermic administration. At intrathecal introduction of a bortezomib death cases were registered.
 
At intravenous administration concentration of solution has to make 1 mg/ml. At hypodermic introduction concentration of solution has to make 2,5 mg/ml.
 
Concentration of solution has to be calculated very carefully in connection with distinction of concentration of solution for intravenous administration and solution for hypodermic introduction.
 
Monotherapy. Бортезомиб it is entered intravenously struyno within 3-5 seconds or subcutaneously. The recommended dose of a bortezomib makes 1,3 mg/sq.m of surface area of a body two times a week within 2 weeks (days 1, 4, 8 and 11) with the subsequent 10-day break (days 12-21). Between introduction of consecutive doses of a bortezomib there have to pass not less than 72 h.
 
Degree of the clinical answer is recommended to be estimated after carrying out 3 and 5 cycles of treatment. In case of achievement of the full clinical answer carrying out 2 additional cycles of treatment is recommended.
 
Lasting treatment more than 8 cycles drug бортезомиб can be used according to the standard scheme or according to the scheme of a maintenance therapy - weekly within 4 weeks (days 1,8, 15, 22) with the subsequent 13-day period of rest (days 23-35). Did not show to patients who have a therapy bortezomiby the clinical answer (progressing or stabilization of a disease after the 2nd or 4th cycles, respectively), the combination of high doses of dexamethasone with bortezomiby can be appointed. In this case 40 mg of dexamethasone are appointed orally with each dose of a bortezomib: 20 mg in day of introduction of a bortezomib and 20 mg in the next day after introduction of a bortezomib. Thus, reception of dexamethasone is made in the 1, 2, 4, 5, 8, 9, 11 and 12 day, totally by 160 mg in 3 weeks.
 
Correction of the mode of dosing. At development of hematologic toxicity of the 4th degree or any not hematologic toxic effect of the 3rd degree, except for neuropathy, treatment bortezomiby should be suspended. After disappearance of symptoms of toxicity treatment bortezomiby can be resumed in the dose lowered by 25%:
 
- the dose of 1,3 mg/sq.m is reduced to 1,0 mg/sq.m,
 
- the dose of 1,0 mg/sq.m is reduced to 0,7 mg/sq.m.
 
At emergence of the neyropatichesky pain connected using a bortezomib and/or peripheral touch neuropathy the dose of drug is changed according to table 1. At patients with heavy neuropathy in the anamnesis бортезомиб it is possible to apply only after careful assessment of a ratio risk/advantage.
 
Table 1. The recommended change of a dose at development by Bortezomib of neyropatichesky pain and/or peripheral touch or motive neuropathy caused by drug.

Patients with abnormal liver functions. Change of an initial dose is not required from patients with abnormal liver functions of easy degree. It is necessary to appoint the recommended dose. Patients with abnormal liver functions of average and heavy degree should appoint бортезомиб in the reduced dose (see table 2).
 
Table 2. The recommended changes of an initial dose of a bortezomib at patients with abnormal liver functions.

ACT - aspartate aminotransferase;
 
VGN - the upper bound of norm.
 
Combination therapy. Бортезомиб it is entered intravenously struyno within 3-5 seconds or subcutaneously into combinations with Melphalanum and Prednisolonum which accept inside. Carry out nine 6 weeks cycles, as shown in table 3. In cycles 1-4 бортезомиб 2 times a week (days 1, 4, 8, 11, 22, 25, 29 and 32), and in cycles 5-9 - once a week are entered (days 1, 8, 22 and 29).
 
Table 3. The recommended scheme of dosing of the bortezomib applied in a combination with Melphalanum and Prednisolonum at patients with earlier not a treated multiple myeloma.

B - Bortezomib, M - Melphalanum, P - Prednisolonum.
 
Correction of the mode of dosing
 
 Before a new cycle of treatment:
 
- the maintenance of thrombocytes has to be> 70 x 109/l;
 
- absolute number of neutrophils (ANN)> 1 x 109/l;
 
- not hematologic toxicity has to decrease to 1 degree or to initial level.
 
Table 4. Dose adjustment at the subsequent cycles of treatment.

Additional information on Melphalanum and Prednisolonum is provided in instructions on a medical use of these drugs.
 
Preparation and administration of solution. Бортезомиб is antineoplastic drug. At preparation of solution and the treatment of drug it is necessary to show care. It is necessary to observe the appropriate measures of an asepsis. It is recommended to use gloves and other protective clothes for prevention of contact with skin. Drug cannot be mixed with other medicines, except for 0,9% of solution of sodium of chloride.
 
Preparation and administration of solution for intravenous administration. Contents of one bottle dissolve 0,9% of solution of sodium of chloride in 3,5 ml. Concentration of the prepared solution for intravenous administration makes 1,0 mg/ml.
 
The prepared solution of a bortezomib has to be transparent and colourless. At detection of mechanical inclusions or discolorations the prepared solution cannot be used.
 
The received solution is entered by 3-5 second intravenous bolyusny injections through a peripheral or central venous catheter which then is washed out by 0,9% chloride sodium solution for injections.
 
Preparation and administration of solution for hypodermic introduction. Contents of one bottle dissolve 0,9% of solution of sodium of chloride in 1,4 ml. Concentration of the prepared solution for hypodermic introduction makes 2,5 mg/ml. The prepared solution of a bortezomib has to be transparent and colourless. At detection of mechanical inclusions or discoloration the prepared solution cannot be used.
 
The received solution is entered subcutaneously into the area of a hip (right or left) or into the area of a stomach (on the right or at the left). It is necessary to change a drug injection site constantly. Each subsequent injection has to be made in the zone which is at distance of at least 2,5 cm from the place of the previous injection. It is impossible to administer the drug to sensitive areas, the damaged areas (reddenings, bruises), and also in the area where introduction of a needle is complicated.
 
In case of local reactions in the field of hypodermic introduction of a bortezomib it is possible to use less strong solution for hypodermic introduction (1 mg/ml instead of 2,5 mg/ml) or to pass to intravenous administration of drug.

Features of use:

Pregnancy and lactation. Use of drug is contraindicated at pregnancy and during breastfeeding.

Treatment bortezomiby should be carried out only under observation of the doctor having experience of use of antineoplastic chemotherapy.
 
At unintentional introduction of a bortezomib death cases are intratekalno recorded. Medicine of Bortezomib is shown only for intravenous and hypodermic administration. Not to enter intratekalno.
 
Prior to the beginning of and during each cycle of therapy it is necessary to make clinical blood test with calculation of a leukocytic formula and the maintenance of thrombocytes.
 
Thrombocytopenia. Most often at therapy bortezomiby passing thrombocytopenia is observed, at the same time the smallest number of thrombocytes usually fall on the 11th day of a cycle. Cyclic frequency of reduction and increase in quantity of thrombocytes was observed throughout all 8 cycles at drug use 2 times a week, thus, are not present the data confirming the accruing thrombocytopenia. At decrease in quantity of thrombocytes <25Õ109/l therapy bortezomiby should be suspended. At recovery of quantity of thrombocytes treatment should be continued in the reduced doses by careful comparison of possible advantage and risk of treatment.
 
It is possible to apply colony stimulating factors, transfusion to treatment of hematologic toxicity platelet and a packed red cells.
 
Gastrointestinal disturbances. For the purpose of prevention of nausea and vomiting use of antiemetic drugs is recommended. When developing diarrhea appoint antidiarrheal medicines. For prevention or treatment of dehydration by the patient it is necessary to carry out rehydration therapy and to support water and electrolytic balance.

Peripheral neuropathy. When developing neuropathy carry out a maintenance therapy. Usually the frequency of development of peripheral neuropathy reaches a maximum on the 5th cycle of treatment bortezomiby. At emergence new or strengthening of the available symptoms of peripheral neuropathy the dose decline and change of the mode of administration of drug of Bortezomib can be required. Patients have to be under constant observation in connection with possibility of symptoms of neuropathy (a burning sensation, a hyperesthesia, a hypesthesia, paresthesia, a sensation of discomfort, neyropatichesky pain or weakness). Frequency of developing of neuropathy at hypodermic introduction of a bortezomib is lower, than that at intravenous administration.
 
At patients with spasms or epilepsy in the anamnesis infrequent cases of development of spasms are described. At treatment of the patients having any risk factors of development of spasms extra care is required.
 
Orthostatic hypotension. Therapy bortezomiby often is followed by orthostatic hypotension. In most cases she is weak or moderately severe and can be observed during all treatment. It was seldom noted short-term losses of consciousness. It is necessary to be careful at treatment of the patients having faints, diabetic neuropathy in the anamnesis, receiving hypotensive drugs and also at patients with dehydration against the background of diarrhea or vomiting. Patients should be instructed about need of the address to the doctor in case of dizziness, feelings of "ease in the head" or a faint. At development of orthostatic hypotension hydration, introduction of glucocorticoids and/or sympathomimetics is recommended; if necessary it is necessary to lower a dose of hypotensive drugs.
 
Heart failure. At use of a bortezomib development or strengthening of the available chronic heart failure is described. The liquid delay can contribute to development of signs and symptoms of heart failure. It is necessary to watch carefully patients with risk factors or with heart diseases in the anamnesis. Liver failure
 
Cases of developing of an acute liver failure at patients who against the background of therapy bortezomiby at the same time accepted other drugs as the accompanying treatment are described. Such signs of an abnormal liver function as increase in activity of liver enzymes, a hyperbilirubinemia or hepatitis, usually passed at cancellation of a bortezomib. Data on a condition of these patients after resuming of therapy by them bortezomiby are limited.
 
To patients with symptoms of an abnormal liver function, it is necessary to appoint бортезомиб in lower initial doses and to carry out monitoring regarding toxicity emergence as бортезомиб it is metabolized by liver enzymes and its concentration can increase at an abnormal liver function of average - heavy degree (see the section "Route of Administration and Doses").
 
Syndrome of back reversible encephalopathy. At the patients accepting бортезомиб the syndrome of back reversible encephalopathy - rare, reversible neurologic disturbance which can be followed by spasms, increase in arterial pressure, a headache, a lethargy, confusion of consciousness, a blindness and other visual and neurologic disturbances was noted. For confirmation of the diagnosis the magnetic and resonant tomography of a brain is carried out. At development of a syndrome of back reversible encephalopathy it is necessary to stop administration of drug бортезомиб. Safety of resuming of therapy by drug бортезомиб after earlier revealed syndrome of back reversible encephalopathy is unknown.
 
Reactivation of the Herpes zoster virus. Attending physicians should consider the possibility of performing antiviral prevention at the patients receiving therapy by drug бортезомиб. The patients receiving therapy by drug бортезомиб, Melphalanum and Prednisonum, had a bigger frequency of reactivation of the Herpes zoster virus in comparison with the patients receiving therapy by Melphalanum and Prednisonum (14% and 4%, respectively). Performing antiviral prevention authentically reduces the frequency of reactivation of the Herpes zoster virus.
 
Dysfunctions of lungs. In rare instances at use of a bortezomib acute diffusion infiltrative pulmonary diseases of an unknown etiology, such as pneumonitis, intersticial pneumonia, pulmonary infiltration and syndrome of acute respiratory insufficiency were observed. Some of these states led to a lethal outcome. In case of symptoms of respiratory insufficiency or deterioration in already available symptoms it is necessary to carry out at once diagnosis and to appoint the corresponding treatment.
 
Syndrome of a lysis of a tumor. Due to the possible development of the hyperuricemia connected with a syndrome of a lysis of a tumor, patients during therapy are recommended to determine the level of uric acid and creatinine in blood serum. For prevention of a hyperuricemia plentiful drink, if necessary - Allopyrinolum and alkalization of urine is recommended.
 
At use of a bortezomib for the patients who are at the same time accepting peroral hypoglycemic drugs it is necessary to control carefully glucose level in blood and if necessary to adjust a dose of hypoglycemic drugs.
 
During treatment drug of Bortezomib of any of sexual partners recommends to use reliable methods of contraception.
 
Precautionary measures at use. During the work with bortezomiby it is necessary to follow the standard rules of the treatment of cytotoxic drugs.

Influence on ability to manage vehicles and mechanisms. Patients need to be warned about a possibility of emergence during treatment by drug of Bortezomib of dizziness, faint, visual frustration and other undesirable phenomena which can affect ability to manage vehicles. At emergence of these symptoms patients are recommended to refrain from driving and occupations other potentially dangerous types of activity demanding the increased concentration of attention and speed of psychomotor reactions.

Side effects:

In general indicators of safety of a bortezomib in the mode of monotherapy are similar to those at its use in a combination with Melphalanum and Prednisolonum.
 
Serious undesirable reactions were infrequently observed during therapy bortezomiby and included heart failure, a syndrome of a lysis of a tumor, pulmonary hypertensia, a syndrome of reversible back encephalopathy, acute diffusion infiltrative pulmonary diseases. Besides, vegetative neuropathy was in rare instances observed. Most often during therapy bortezomiby the following undesirable reactions were noted: nausea, diarrhea, a lock, vomiting, increased fatigue, fever, thrombocytopenia, anemia, a neutropenia, peripheral neuropathy (including touch), a headache, paresthesia, a loss of appetite, short wind, rash, the surrounding herpes and a mialgiya.
 
Side effects which were regarded as possibly or perhaps connected using a bortezomib are listed below.
 
Side effects are grouped in systems of bodies and frequency of emergence. Frequency was determined as: very often (≥ 10%), it is frequent (≥ 1% and <10%), infrequently (≥ 0,1% and <1%), is rare (≥ 0,01% and <0,1%), is very rare (<0,01%, including separate cases).
 
Infectious and parasitic diseases: often - the herpes simplex surrounding herpes (including disseminated and офтальмогерпес), fungal infections; infrequently - sepsis (including septic shock), bronchial pneumonia, a herpesviridae infection, a herpetic encephalomeningitis, bacteremia (including staphylococcal), barley, flu, an inflammation of a hypodermic fatty tissue, a skin infection, ear infections, staphylococcal infections, tooth infections; seldom - meningitis (including bacterial), Epstein-Barre a viral infection, genital herpes, tonsillitis, a mastoiditis, a syndrome of chronic fatigue.

The high-quality, malignant and not specified new growths (including cysts and polyps): seldom - malignant new growths, a plazmotsitarny leukosis, a carcinoma of a kidney, a new growth, fungoid mycosis, high-quality new growths.
 
Disturbances from blood and lymphatic system: very often - thrombocytopenia, a neutropenia, anemia; often - a leukopenia, a lymphopenia; infrequently - a pancytopenia, a febrile neutropenia, hemolitic anemia, a Werlhof's disease, a lymphadenopathy, a coagulopathy, a leukocytosis; seldom - a syndrome of the disseminated intravascular coagulation (IDCS), a thrombocytosis, a syndrome of the increased viscosity of blood, disturbance from thrombocytes, disturbances from blood, hemorrhagic diathesis, lymphocytic infiltration.

Disturbances from immune system: infrequently - hypersensitivity; seldom - a Quincke's edema, an acute anaphylaxis, an amyloidosis, reactions with formation of cell-bound immune complexes (type III).
 
Disturbances from endocrine system: infrequently - disturbance of secretion of antidiuretic hormone, an Icenco-Cushing syndrome, a hyperthyroidism; seldom - a hypothyroidism.
 
Disturbances from a metabolism and food: very often - a loss of appetite; often - dehydration, a hypopotassemia, a hyperglycemia, change of activity of enzymes; infrequently - a syndrome of a lysis of a tumor, a hyperpotassemia, a cachexia, a hypercalcemia, a hypocalcemia, a hypernatremia, a hyponatremia, a hypoglycemia, a hyperuricemia, deficit of B12 vitamin, a hypomagnesiemia, a hypophosphatemia, lack of an increase of body weight, a diabetes mellitus, a liquid delay, a body degrowth; seldom - a gipermagniyemiya, acidosis, disturbance of water and electrolytic balance, excess accumulation of liquid, a hypochloraemia, a hypovolemia, a hyperchloremia, a hyperphosphatemia, disbolism, a group B vitamin deficiency, gout, intolerance of alcohol, increase in body weight.
 
Disturbances of mentality: often - frustration and disturbances of mood, uneasiness, frustration and sleep disorders; infrequently - changes of the mental status, a hallucination, psychotic disorder, confusion of consciousness, the excited state; seldom - suicide thoughts, disorder of adaptation, a delirium, decrease in a libido.

Disturbances from a nervous system: very often - neuropathy, peripheral touch neuropathy, a dizesteziya, neuralgia; often - motive neuropathy, a loss of consciousness (including a syncope), dizziness, a food faddism, slackness, a headache; infrequently - a tremor, peripheral sensomotor neuropathy, dyskinesia, balance disturbance, memory loss (искл. dementia), encephalopathy, syndrome of back reversible encephalopathy, neurotoxicity, spasms, post-herpetic neuralgia, alalia, syndrome of "uneasy legs", migraine, sciatica, disturbance of concentration of attention, pathological reflexes, parosmiya; seldom - intracerebral bleeding, intracraneal hemorrhage (including subarachnoidal), wet brain, the tranzitorny ischemic attack, a coma, an imbalance of the autonomic nervous system, vegetative neuropathy, paralysis of cranial nerves, paralysis, paresis, a preunconscious condition, a syndrome of defeat of a brainstem, disturbance of cerebral circulation, a radicular syndrome, a psychomotor hyperactivity, a compression of a spinal cord, cognitive disorders, disorders of the movements, frustration of a nervous system, radiculitis, hypersalivation, hypotonia of muscles.
 
Disturbances from an organ of sight: often - okologlaznichny hypostasis, decrease in clearness of sight, eye pain; infrequently - a hematopsia, vision disorders, a xerophthalmus, conjunctivitis, a photophobia, irritation of eyes, the strengthened dacryagogue, a hyperemia of a conjunctiva, an infection a century, an inflammation of eyes, a diplopia, allocation from eyes; seldom - optical neuropathy, a blindness, defeat of a cornea, an exophthalmos, a retinitis, scotoma, damages of eyes (including a century), a dacryadenitis, a photopsia.
 
Disturbances from an acoustic organ and labyrinth disturbances: often - вертиго; infrequently - a ring in ears, a hearing disorder (to deafness), discomfort in an ear; seldom - bleeding, vestibular neyronit, disturbances from an ear.
 
Disturbances from heart: often - a cardiac standstill, cardiovascular disturbances (including cardiogenic shock), a myocardial infarction, stenocardia, development and an exacerbation of chronic heart failure, a hypokinesia of ventricles, a stop of a sinus node, an atrioventricular block, tachycardia (including sinus and supraventricular), arrhythmia, fibrillation of auricles, a heart consciousness; infrequently - an atrial flutter, bradycardia, cardiopulmonary shock, fibrillation of heart (including fibrillation of auricles), a pericardis (including an exudative pericardis), a cardiomyopathy, ventricular dysfunction; seldom - decrease in fraction of emission of a left ventricle, a cardiac tamponade, arrhythmia ventricular takhisistolichesky the pirouette type, stenocardia unstable, diseases of valves of heart, coronary insufficiency.
 
Disturbances from vessels: often - a lowering of arterial pressure, orthostatic and postural hypotension, phlebitis, a hematoma, increase in arterial pressure; infrequently - a vasculitis, stagnation of blood in a small circle of blood circulation, pulmonary hypertensia, petechias, an ecchymoma, a purpura, change of coloring of veins, swelling of veins, bleeding of wounds, blood "inflows", a deep vein thrombosis, bleeding, thrombophlebitis (including superficial), a circulator collapse (including hypovolemic shock), decrease in peripheric circulation, a hyperemia (including ocular); seldom - an embolism of a pulmonary artery, an embolism of peripheral vessels, a limfedema, pallor, an eritromelalgiya, a vazodilatation, venous insufficiency.
 
Disturbances from respiratory system, bodies of a thorax and a mediastinum: very often - an asthma; often - an asthma at exercise stresses, nasal bleeding, cough, a rhinorrhea, infections of upper and lower respiratory tracts; infrequently - an apnoea, a hypoxia, a pleural exudate, a fluid lungs (including acute), a bronchospasm, a respiratory alkalosis, a tachypnea, goose breathing, a nose congestion, a hoarseness, rhinitis, a hyperventilation of lungs, an orthopnea, pain in a thorax, paranasal sinuses pain, feeling of constraint in a throat, a blood spitting, a chronic obstructive pulmonary disease, an anoxemia, pleurisy, a dysphonia; seldom - a pneumonitis, pneumonia (including intersticial), a syndrome of acute respiratory insufficiency, acute diffusion infiltrative damage of lungs, respiratory insufficiency, alveolar hemorrhage in a lung, an acute respiratory distress - a syndrome, pheumothorax, an atelectasis, a pneumosclerosis, disturbance from bronchial tubes, an intersticial disease of lungs, a hypocapny, hypersecretion in upper respiratory tracts, irritation of a throat, a tussive syndrome of upper respiratory tracts.

Disturbances from digestive tract: very often - nausea, vomiting, diarrhea, a lock; often - pains in a stomach, stomatitis, dyspepsia, a liquid chair, a meteorism, a hiccups, pain in a throat and drinks, dryness in a mouth, disturbances from an oral cavity, vomiting blood, puffiness of lips; infrequently - acute pancreatitis, paralytic intestinal impassability, colitis, a melena, bleeding from digestive tract, enteritis, a dysphagy, an eructation, pains in a spleen, an esophagitis, gastritis, a gastroesophageal reflux, petechias of a mucous membrane of a mouth, hypersecretion of sialadens, a fur, change of coloring of language, an ulceration in language, increase in appetite, discomfort in a stomach, an ulceration of a mucous membrane of an oral cavity, an odontorrhagia, pseudomembranous colitis, an inflammation of a mucous membrane of a GIT, disturbance of motility of a GIT; seldom - ischemic colitis, a syndrome of the angry intestines, peritonitis, a paraglossa, ascites, a cheilitis, an incontience a calla, an atony of a proctal sphincter, a fekalom, a gastro intestinal path of an ulceration and perforation of digestive tract, a hypertrophy of gums, megacolon, allocations from a rectum, emergence of blisters in a drink, lip pain, periodontitis, a proctal crack, change of a rhythm of defecation, a proctalgia, disturbances of a chair.
 
Disturbances from a liver and biliary tract: infrequently - hepatitis, hemorrhage in a liver, a hypoproteinemia, a hyperbilirubinemia, a hepatotoxic, a cholestasia; seldom - a liver failure, a hepatomegalia, Badda-Kiari's syndrome, Cytomegaloviral hepatitis, cholelithiasis.
 
Disturbances from skin and hypodermic fabrics: very often - skin rash; often - urticaria, pruritic rash, an itch, reddenings, sweating strengthening, a xeroderma, eczema; infrequently - erythematic rash, a photosensitization, bruise, a generalized itch, makulezny rash, papular rash, psoriasis, generalized rash, the century, a face edema, dermatitis, an alopecia, damage of nails, change of a xanthopathy, atopic dermatitis, change of structure of hair, night perspiration, an ichthyosis, small knots on skin, a multiformny erythema, toxic skin rash, petechias, an ecchymoma, damage of skin, purple, skin new growth, a hyperhidrosis, decubituses, acne rash, blisters swelled; seldom - an acute febrile neutrophylic dermatosis (a syndrome It is twisted), reactions from skin, lymphocytic infiltration of Dzhessner, a palmar and bottom eritrodizesteziya, hypodermic bleedings, mesh a livedo, consolidation of skin, seborrhea, cold sweat, erythroses, a skin ulcer; very seldom - Stephens-Johnson's syndrome and a toxic epidermal necrolysis.

Disturbances from skeletal and muscular and connecting fabric: very often - a mialgiya; often - weakness of muscles, musculoskeletal pains, extremity pains, muscular spasms, an arthralgia, ostealgias, dorsodynias; infrequently - muscular spasms, muscle tension, hypostases of joints, rigidity of joints, jaw pain, muscular twitchings, arthritis, a myopathy, heavy feeling; seldom - рабдомиолиз, a syndrome of a temporal and mandibular joint, a fistula, a joint exudate, a gnathalgia, bone disturbances, infections and inflammations of musculoskeletal and connecting fabric, a synovial cyst.
 
Disturbances from kidneys and urinary tract: often - a renal failure, a dysuria; infrequently - a renal failure (including acute), an oliguria, renal colic, a hamaturia, a proteinuria, an urination delay, frequent urinations, difficulty of an urination, a back pain, an incontience of urine, an infection of urinary tract, an azotemia, a pollakiuria; seldom - irritation of a bladder.
 
Disturbances from generative organs and a mammary gland: infrequently - erectile dysfunction, vaginal bleedings, genitals pain; seldom - dysfunction of testicles, prostatitis, dysfunction of a mammary gland, morbidity of appendages of testicles, pain in a small pelvis, an epididymite, a vulva ulceration.
 
Inborn, inherited and genetic disorders: seldom - an aplasia, a GIT malformation, an ichthyosis.
 
The general frustration and disturbances in an injection site: very often - increased fatigue, fervescence; often - an adynamy, weakness, feeling of an indisposition, grippopodobny symptoms, peripheral hypostases, hypostases; infrequently - a fever, feeling of a prelum in a thorax, discomfort in a thorax, deterioration in the general physical health, a face edema, disturbances from mucous membranes, pain in a breast, the gait disturbance, a cryesthesia, change of feeling of thirst, feeling of change of body temperature, complications associated with a catheter, pain, burning sensation and a hyperemia in the place of an injection, phlebitis. At an ekstravazation - an inflammation of a hypodermic fatty tissue; seldom - death (including sudden), multiorgan insufficiency, bleeding in an injection site, hernia, disturbance of processes of healing, not cardial stethalgia, feeling of a foreign body.
 
Laboratory and tool data: often - increase in activity of a lactate dehydrogenase of blood, a body degrowth; infrequently - increase in activity of an alkaline phosphatase of blood, increase in concentration of urea in blood, increase in activity of a gammaglutamiltransferaza, increase in activity of amylase of blood, decrease in concentration of hydrocarbonates in blood, increase in concentration of S-reactive protein, increase in body weight; seldom - change of content of gases in blood, changes of the electrocardiogram (including increase in a tooth of QT), change of a prothrombin time, decrease in pH of a gastric juice, increase in aggregation of thrombocytes, increase in concentration of a troponin of I, changes in the analysis of urine.
 
Injuries, intoxications and complications of manipulations: infrequently - falling, contusions; seldom - transfusion reactions, changes, rigidity, injuries of the person, an injury of joints, burns, gaps, pain during the procedure, radiation defeat.
 
Surgical and therapeutic manipulations: seldom - activation of macrophages.
 
Patients with a mantiynokletochny lymphoma. Indicators of safety of a bortezomib at these patients were similar to the corresponding indicators at patients with a multiple myeloma. Significant differences between two groups of patients were that thrombocytopenia, the neutropenia, anemia, nausea, vomiting and fervescence were more often observed at patients with a multiple myeloma in comparison with patients with a mantiynokletochny lymphoma; and peripheral neuropathy, rash and an itch - at patients with a mantiynokletochny lymphoma.

Interaction with other medicines:

In the researches in vitro and in vivo бортезомиб shows properties of weak inhibitor of isoenzymes of P450 cytochrome - 1A2, 2C9, 2C19, 2D6 and 3A4.
 
Proceeding from an insignificant contribution of CYP 2D6 to metabolism of a bortezomib (7%), at people with low activity of this enzyme of change of the general distribution of drug it is not expected.
 
The research of influence of medicinal interaction with strong inhibitor of an isoenzyme CYP3A4 ketokonazoly on pharmacokinetics of a bortezomib showed increase in average AUC values (the area under a curve "concentration time") a bortezomiba on average for 35%. Therefore it is necessary to make careful observation of the patients receiving at the same time бортезомиб and strong inhibitors of an isoenzyme CYP3A4 (кетоконазол, ритонавир).
 
In a research of influence of medicinal interaction with strong inhibitor of an isoenzyme CYP2C19 omeprazoly on pharmacokinetics of a bortezomib essential change of pharmacokinetics of a bortezomib is not revealed.
 
The research of influence of medicinal interaction with rifampicin - the strong inductor of an isoenzyme CYP3A4 - on pharmacokinetics of a bortezomib showed decrease in average AUC values (the area under a curve "concentration time") a bortezomiba on average for 45%. Therefore it is not recommended to apply бортезомиб with the strong inductors CYP3A4 as efficiency of therapy can be reduced. The rifampicin, carbamazepine, Phenytoinum, phenobarbital and a St. John's Wort which is made a hole belong to the inductors CYP3A4. In the same research estimated effect of dexamethasone - weaker inductor CYP3A4. Proceeding from results of a research essential change of pharmacokinetics of a bortezomib is not revealed.
 
The research of influence of medicinal interaction with a combination Melphalanum Prednisonum showed increase in average AUC values of a bortezomib by 17%. This change is considered clinically not significant.
 
At the patients with a diabetes mellitus receiving peroral hypoglycemic drugs along with bortezomiby cases of a hypoglycemia and a hyperglycemia are registered. At use of a bortezomib in combination with neurotoxic drugs which can be associated with peripheral neuropathy (such as Amiodaronum, antiviral means, an isoniazid, nitrofurantoin or statines) and the drugs reducing arterial pressure it is necessary to be careful.

Contraindications:

- hypersensitivity to a bortezomib, boron, and also to any of the components which are a part of drug;
- pregnancy and period of feeding by a breast;
- children's age (lack of experience of use);
- acute diffusion infiltrative diseases of lungs;
- defeat of a pericardium.

With care:
- abnormal liver functions of heavy and average degree;
- renal failures of heavy degree;
- spasms or epilepsy in the anamnesis;
- faints;
- diabetic neuropathy in the anamnesis;
- concomitant use of hypotensive drugs;
- dehydration against the background of diarrhea or vomiting;
- lock;
- risk of development of chronic heart failure;
- concomitant use of inhibitors or substrates of an isoenzyme CYP3A4, concomitant use of substrates of an isoenzyme of CYP2C9, peroral hypoglycemic drugs.

Overdose:

Introduction of a bortezomib in the dose exceeding the recommended dose more than twice was followed by an acute lowering of arterial pressure and thrombocytopenia from the death.
 
The specific antidote to a bortezomib is unknown. At overdose it is necessary to control indicators of vital functions of the patient and to carry out the corresponding therapy for maintenance of arterial pressure (infusional therapy, vasoconstrictive and/or inotropic drugs).

Storage conditions:

To store in the place protected from light, at a temperature not above 30 °C. After dissolution to store at a temperature not above 25 °C in an original bottle no more than 8 h. To store in the place, unavailable to children. A period of validity - 3 years. Not to apply after the period of validity specified on packaging.

Issue conditions:

According to the recipe

Packaging:

On 3,5 mg of a bortezomib in the bottles from colourless neutral glass I of a hydrolytic class corked by rubber bungs, which are pressed out by aluminum caps. On 1 bottle together with the application instruction in a pack from a cardboard