Борамилан® FS

General characteristics. Structure:

Active ingredient: 3,5 mg of a bortezomib in the form of a three-dimensional boroksin (in terms of бортезомиб in the form of monomer).

Vspomgatelny substances: D-Mannitolum.

Solvent: sodium chloride, solution for injections of 0,9%.

Pharmacological properties:

Pharmacodynamics. Бортезомиб is a reversible inhibitor of chymotrypsin-like activity of a 26S-proteasoma of cells of mammals. 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 26S-proteasoma prevents the 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 many experimental in vivo models бортезомиб causes delay of growth of a tumor, including a multiple myeloma.

In experiments of in vitro, ex vivo and on animal models бортезомиб strengthens a differentiation and activity of osteoblasts and inhibits function of osteoclasts. These effects were observed at the patients with a multiple myeloma with the multiple centers of ossifluence receiving therapy bortezomiby.

Pharmacokinetics. Absorption. At intravenous jet administration of a bortezomib in doses of 1,0 mg/sq.m and 1,3 mg/sq.m to patients with a multiple myeloma the maximum concentration (Cmax) of a bortezomib in plasma make respectively 57 ng/ml and 112 ng/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 maximum concentration (Cmax) of a bortezomib after hypodermic introduction (20,2 ng/ml) is lower, than after intravenous administration (223 ng/ml). At introduction in a dose of 1,3 mg/sq.m subcutaneously and intravenously the general system influence after repeated introduction in the same dose (AUClast) is equivalent to patients with a multiple myeloma for both ways.

Distribution. After single or repeated introduction in doses of 1,0 mg/sq.m and 1,3 mg/sq.m the average volume of distribution of a bortezomib at patients with a multiple myeloma makes 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 CYP2S9 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. The average elimination half-life of a bortezomib at repeated introduction makes    40-193 hours. Drug is quicker removed after introduction of the first dose in comparison with the subsequent introductions. 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 l/h and 112 l/h, and after the subsequent introductions - respectively 15-32 l/h. Ways of removal of a bortezomib at the person were not studied. Influence of a sex, age and race on pharmacokinetics of a bortezomib were not studied.
 
Pharmacokinetics at patients with disturbances of functions of a liver and kidneys. Easy abnormal liver functions do 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 and dynamic observation is recommended.

The pharmacokinetics of a bortezomib in doses of 0,7-1,3 mg/sq.m intravenously two times a week at patients with easy, average and heavy renal failures, including the patients who are on dialysis is comparable to drug pharmacokinetics at patients with normal function of kidneys.

Indications to use:

• Multiple myeloma.
• Mantiynokletochny lymphoma at the patients who earlier received at least 1 line of therapy.

Route of administration and doses:

The drug Boramilan® FS is shown only for intravenous and hypodermic administration. 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. Борамилан® FS enter intravenously struyno within 3-5 seconds or subcutaneously. The recommended initial 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). The cycle of treatment makes 21 days. Between introduction of consecutive doses of the drug Boramilan® FS there have to pass not less than 72 hours.

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 Boramilan® FS it is possible to apply 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). To patients at whom monotherapy by the drug Boramilan® FS did not show the clinical answer (progressing or stabilization of a disease after 2 and 4 cycles respectively) the combination of the drug Boramilan® FS with high doses of dexamethasone can be appointed. In this case with each dose of the drug Boramilan® FS 40 mg of dexamethasone are appointed orally: 20 mg in day of administration of the drug Boramilan® FS and 20 mg in the next day after administration of the drug Boramilan® FS. Reception of dexamethasone is made in the 1, 2, 4, 5, 8, 9, 11 and 12 day, totally by 160 mg in 3 weeks.

Recommendations about dose adjustment and mode of administration of the drug Boramilan® FS. At development of hematologic toxicity of the 4th degree or any not hematologic toxic effect of the 3rd degree, except for neuropathy, treatment by the drug Boramilan® FS should be suspended. After disappearance of symptoms of toxicity treatment by the drug Boramilan® FS 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). If symptoms of toxicity do not disappear or appear again at the minimum dose, then it is necessary to consider the possibility of drug withdrawal of Boramilan® of FS if only the advantage of its use obviously does not exceed risk.

At emergence of the neyropatichesky pain connected using the drug Boramilan® FS and/or peripheral touch neuropathy the dose of drug is changed according to table 1. At patients with heavy neuropathy in the anamnesis Boramilan® of FS it is possible to apply only after careful assessment of a ratio risk/advantage.

Table 1. The recommended change of a dose at development of the neyropatichesky pain caused by the drug Boramilan® FS and/or peripheral touch or motive neuropathy.

Weight of peripheral neuropathy	Change of a dose and frequency of introduction
1 degree (paresthesia and/or fading reflexes) without pain or defunctionalization	The dose and the mode of introduction do not demand corrections
1 degree with pain or the 2nd degree (dysfunction, but not daily activity)	To lower a dose to 1,0 mg/sq.m
2 degree with pain or the 3rd degree (disturbance of daily activity)	To suspend drug use Борамилан® FS before disappearance toxicity symptoms. After that to resume treatment, having lowered a dose the drug Boramilan® FS to 0,7 mg/sq.m and having reduced introduction frequency to 1 time a week
4 degree (touch neuropathy, resulting in disability or the motive neuropathy menacing lives or leading to paralysis)	To stop drug use Борамилан® FS

Patients with renal failures. Degree of a renal failure does not influence drug Boramilan®FS pharmacokinetics. Therefore for patients with a renal failure dose adjustment is not required. Борамилан® FS should be entered after carrying out dialysis as dialysis can reduce concentration of drug in blood.

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 Boramilan® of FS in the reduced dose (table 2). 

Table 2. The recommended changes of an initial dose of the drug Boramilan® FS at patients with abnormal liver functions.

Severity of abnormal liver functions	Concentration of bilirubin	Activity of nuclear heating plant *	Change of an initial dose
Easy	≤ 1,0 x VGN	> VGN **	It is not required
	> 1,0 x - 1,5 x VGN	Any	It is not required
Average	> 1,5 x – 3 x VGN	Any	It is required to appoint Борамилан® FS in the reduced dose of 0,7 mg/sq.m during the first cycle. It is necessary to consider the possibility of increase in a dose up to 1,0 mg/sq.m or further reduction to 0,5 mg/sq.m in the subsequent cycles depending on portability patient.
Heavy	> 3 x VGN	Any

* Nuclear heating plant – aspartate aminotransferase; ** VGN – the upper bound of norm.

Combination therapy. The recommended dose. Борамилан® FS enter intravenously struyno within 3-5 seconds or subcutaneously into combinations with Melphalanum and Prednisonum accepted inside. Carry out nine 6 weeks cycles, as shown in table 3. In the cycles 1-4 Boramilan® FS apply 2 times a week (days 1, 4, 8, 11, 22, 25, 29 and 32), and in cycles 5-9 - once a week (days 1, 8, 22 and 29).

Table 3. The recommended scheme of a drug dosing Boramilan® of FS applied in a combination with Melphalanum and Prednisonum at patients with earlier not a treated multiple myeloma.

Борамилан® FS 2 times in a week (cycles 1-4)

1 week.	2 weeks.	3 weeks.	4 weeks.	5 weeks.	6 weeks.
Борамилан® FS (1,3 mg/sq.m)
1st day 4th day	8th day 11 day	Rest period	22nd day 25th day	29th day 32nd day	Rest period
Melphalanum (9 mg/sq.m) + Prednisonum (60 mg/sq.m)
1st day 2nd day 3rd day 4th day	-	Rest period	-	-	Rest period
Борамилан® FS once a week (cycles 5-9)
1 week.	2 weeks.	3 weeks.	4 weeks.	5 weeks.	6 weeks.
Борамилан® FS (1,3 mg/sq.m)
1st day	8th day	Rest period	22nd day	29th day	Rest period
Melphalanum (9 mg/sq.m) + Prednisonum (60 mg/sq.m)
1st day 2nd day 3rd day 4th day	-	Rest period	-	-	Rest period

Recommendations about dose adjustment at a combination therapy. Dose adjustment and schemes of treatment at use of the drug Boramilan® FS together with Melphalanum and Prednisonum

Before a new cycle of treatment:
- the maintenance of thrombocytes has to be> 70 * 109/l;
- the absolute maintenance of neutrophils (AMN) has to be> 1,0 * 109/l;
- negematologicheskaya toxicity has to decrease to 1 degree or to initial level.

Table 4. Dose adjustment at the subsequent cycles of treatment

Toxicity	Correction or delay of a dose
Hematologic toxicity in the course previous cycle:
Long neutropenia or thrombocytopenia 4 degrees, or thrombocytopenia with bleeding	In the following cycle Melphalanum dose it is necessary to reduce by 25%
The maintenance of thrombocytes ≤ 30 * 109/l or ASN ≤ 0,75 * 109/l in day of administration of the drug Boramilan® FS (except the 1st day)	To postpone administration of drug Борамилан® FS
Several delays of administration of the drug Boramilan® FS in one cycle (> 3 times at introduction 2 times a week or ≥ 2 times at introduction once a week)	The dose of the drug Boramilan® FS is reduced on 1 step (from 1,3 mg/sq.m to 1,0 mg/sq.m; from 1,0 mg/sq.m to 0,7 mg/sq.m)
Negematologicheskaya toxicity> 3 degrees:	Use of the drug Boramilan® FS postpone until decrease not hematologic toxicity to 1 degrees or to initial level. After that treatment by drug Борамилан® FS can be renewed in the dose lowered on 1 step (from 1,3 mg/sq.m to 1,0 mg/sq.m; from 1,0 mg/sq.m to 0,7 mg/sq.m). At development of the neyropatichesky pain and/or peripheral neuropathy connected using the drug Boramilan® FS, introduction of the next dose is postponed and/or adjust a dose as above in table 1 is described.

Additional information on Melphalanum and Prednisonum is provided in instructions on a medical use of these drugs.

Route of administration. Борамилан® FS is antineoplastic drug. At preparation and the treatment of drug it is necessary to show care. It is necessary to carry out the corresponding rules 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 of solution for intravenous administration. Contents of a bottle dissolve 0,9% of solution of sodium of chloride in 3,5 ml. Concentration of the prepared solution for intravenous administration has to make 1mg/ml. The prepared solution 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 an intravenous bolyusny injection within 3-5 seconds through a peripheral or central venous catheter which then is washed out by 0,9% chloride sodium solution for injections.

Preparation of solution for hypodermic introduction. Contents of a bottle dissolve 0,9% of solution of sodium of chloride in 1,4 ml. Concentration of the prepared solution for hypodermic introduction has to make 2,5 mg/ml.

The prepared solution has to be transparent and colourless. At detection of mechanical inclusions or discolorations the prepared solution cannot be used. The received solution is entered subcutaneously into the area of a hip (left or right) or into the area of a stomach (at the left or on the right). It is necessary to change a drug injection site constantly.

Each subsequent injection has to be entered at distance not less than 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), in the area where introduction of a needle is complicated.

At emergence of local reactions in the field of hypodermic administration of drug it is possible to use less strong solution of drug for hypodermic introduction – (1 mg/ml instead of 2,5 mg/ml) or to pass to intravenous administration of the drug Boramilan® FS.

Features of use:

Use at pregnancy and during breastfeeding. Use of a bortezomib during pregnancy is contraindicated. In need of use of drug in the period of a lactation breastfeeding should be stopped.

Treatment by the drug Boramilan® FS should be carried out only under observation of the doctor having experience of use of antineoplastic chemotherapy.

FS Boramilan® medicine is intended only for intravenous and hypodermic administration. At unintentional introduction of a bortezomib death cases were intratekalno recorded. The drug Boramilan® FS cannot be administered intratektalno. Prior to the beginning of and during each cycle of therapy it is necessary to carry out an integrated analysis of blood 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 is usually observed for 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 <25 * 109/l therapy by the drug Boramilan® FS 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. At emergence at the patient of 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. 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, neuropathic pain, weakness). Frequency of developing of neuropathy at hypodermic administration of drug of a bortezomib is lower, than at intravenous administration. 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 the drug Boramilan® FS can be required.

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 is observed during all treatment. The short-term loss of consciousness was seldom noted. At 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, it is necessary to be careful. 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 hypotonia 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 heart failure. Patients with risk factors or with heart diseases in the anamnesis have to be exposed to careful observation.

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 abnormal liver functions as increase in activity of "hepatic" enzymes, a hyperbilirubinemia or hepatitis, usually pass at drug withdrawal. Data on a condition of these patients after therapy resuming bortezomiby are limited.

To patients with symptoms of an abnormal liver function, it is necessary to appoint Boramilan® of FS in lower initial doses and to carry out monitoring regarding toxicity emergence since бортезомиб it is metabolized by "hepatic" enzymes, and its concentration can increase at an abnormal liver function of average and heavy degree (see the section "Route of Administration and Doses").

Syndrome of a back reversible leukoencephalopathy. At the patients receiving бортезомиб the syndrome of a back reversible leukoencephalopathy - 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 a back reversible leukoencephalopathy it is necessary to stop use of the drug Boramilan® FS.

Safety of resuming of therapy by the drug Boramilan® FS after earlier revealed syndrome of a back reversible leukoencephalopathy is unknown.

Reactivation of the Herpes zoster virus. It is necessary to consider the possibility of performing antiviral prevention at the patients receiving therapy by the drug Boramilan® FS. The patients receiving therapy bortezomiby, 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 (a pneumonitis, intersticial pneumonia, pulmonary infiltration, a syndrome of acute respiratory insufficiency) are observed. Some of these states led to a lethal outcome. In case of symptoms of disorder of function of lungs 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 define concentration of uric acid and creatinine in blood serum. For prevention of a hyperuricemia plentiful drink, if necessary - Allopyrinolum and alkalinization of urine is recommended.

Other. At use of the drug Boramilan® FS 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 carry out dose adjustment of hypoglycemic drugs.

During treatment bortezomiby any of sexual partners it is recommended to use reliable methods of contraception.

During the work with the drug Boramilan® FS it is necessary to follow the standard rules of the treatment of cytotoxic drugs.

Possible influence of medicine on ability to manage vehicles, mechanisms. Some side effects of drug, such as dizzinesses, a syncope, visual frustration and other undesirable phenomena can negatively influence ability to driving and performance of potentially dangerous types of activity demanding the increased concentration of attention and speed of psychomotor reactions.

Patients need to be warned about a possibility of emergence of the specified symptoms during treatment by the drug Boramilan® FS. At emergence of these symptoms patients are recommended to refrain from driving and performance of potentially dangerous types of activity demanding the increased concentration of attention and speed of psychomotor reactions.

Side effects:

Indicators of safety of a bortezomib at use in monotherapy are similar to the corresponding indicators at use of a bortezomib in a combination with Melphalanum and Prednisonum.

Undesirable side effects which were regarded as possibly or perhaps connected using a bortezomib are listed below. Undesirable side effects are grouped in bodies and frequency of emergence. Frequency was determined as: very often (> 10%), it is frequent (1-10%), infrequently (0,1-1%), is rare (0,01-0,1%), is very rare (<0,01%), including separate cases.

Disturbances from blood and lymphatic system: very often - thrombocytopenia, anemia, a neutropenia; often - a leukopenia, a lymphopenia; infrequently - a pancytopenia, a febrile neutropenia, hemolitic anemia, a Werlhof's disease, a lymphadenopathy; seldom - a syndrome of the disseminated intravascular coagulation (IDCS); frequency is unknown - a coagulopathy, a leukocytosis.

Disturbances from heart: often - a cardiac standstill, cardiogenic shock, a myocardial infarction, stenocardia, development and an exacerbation of chronic heart failure, a hypokinesia of ventricles, a fluid lungs (including acute), a stop of a sinus node, a total atrioventricular block, tachycardia (including sinus and supraventricular), arrhythmia, fibrillation of auricles, a heart consciousness; infrequently - an atrial flutter, bradycardia, stagnation of blood in a small circle of blood circulation, pulmonary hypertensia; seldom - decrease in fraction of emission of a left ventricle, a cardiac tamponade, a pericardis, ventricular arrhythmias.

Disturbances from vessels: often - phlebitis, a hematoma, a lowering of arterial pressure (ABP), orthostatic and postural hypotension, increase in the ABP; infrequently - intracerebral bleeding, intracraneal hemorrhage, subarachnoidal hemorrhage, a vasculitis, a stroke, petechias, an ecchymoma, a purpura, change of coloring of veins, swelling of veins, bleeding of wounds, blood "inflows"; seldom - an embolism of a pulmonary artery, an embolism of peripheral vessels; frequency is unknown – a deep vein thrombosis, thrombophlebitis.

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; infrequently - an apnoea, a hypoxia, a pleural exudate, 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; seldom - a pneumonitis, pneumonia (including intersticial), a syndrome of acute respiratory insufficiency, acute diffusion infiltrative damage of lungs, pulmonary hypertensia, respiratory insufficiency, alveolar hemorrhage in a lung.

Disturbances from digestive tract: very often - nausea, vomiting, diarrhea, a lock, a loss of appetite; often - pains in a stomach, stomatitis, dyspepsia, a liquid chair, a meteorism, a hiccups, pain in a throat and drinks, dryness in a mouth; infrequently - acute pancreatitis, paralytic intestinal impassability, colitis, a melena, bleeding from a GIT, enteritis, a dysphagy, an eructation, pains in a spleen, an esophagitis, gastritis, a gastroesophageal reflux, petechias of a mucous membrane of an oral cavity, hypersecretion of sialadens, a fur, change of coloring of language, an ulceration in language, increase in appetite; seldom - ischemic colitis, peritonitis, ascites, a cheilitis.

Disturbances from a liver and biliary tract: infrequently - hepatitis, hemorrhage in a liver, a hypoproteinemia, a hyperbilirubinemia, increase in activity of alaninaminotranspherase and aspartate aminotransferase; seldom - a liver failure, a hepatomegalia, Cytomegaloviral hepatitis, cholelithiasis.

Disturbances from a nervous system: very often - peripheral neuropathy, paresthesia, a headache; often - polyneuropathy, dizziness (behind an exception вертиго), a food faddism, a dizesteziya, a hypesthesia, a tremor; infrequently - a paraplegia, spasms, peripheral motive neuropathy, a syncope, paresis, disturbance of concentration of attention, taste loss, drowsiness, cognitive frustration, postural dizziness, mononeuropathy, disturbances of the speech, a syndrome of "uneasy legs"; seldom - encephalopathy, vegetative neuropathy, a syndrome of a back reversible leukoencephalopathy.

Disturbances of mentality: often - confusion of consciousness, a depression, sleeplessness, uneasiness; infrequently - excitement, nonsense, hallucinations, the excited state, differences of mood, change of the mental status, a sleep disorder, irritability, unusual dreams; seldom - a suicide spirit, disorder of orientation, a delirium, decrease in a libido.

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 urine incontience.

Disturbances from an acoustic organ and labyrinth disturbances: often - вертиго; infrequently - a ring in ears, a hearing disorder; seldom - bilateral deafness.

Disturbances from an organ of sight: often - decrease in clearness of sight, eye pain; infrequently - a hematopsia, vision disorders, a xerophthalmus, conjunctivitis, a photophobia, irritation of eyes, the strengthened dacryagogue, a conjunctiva hyperemia; seldom - офтальмогерпес, optical neuropathy, a blindness; frequency is unknown – a diplopia.

Disturbances from endocrine system: infrequently - disturbance of secretion of antidiuretic hormone (ADG); seldom – a hypothyroidism; frequency is unknown - a hypercorticoidism, a hyperthyroidism.

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, muscular twitchings, muscle tension, hypostases of joints, rigidity of joints, jaw pain.

Metabolism disturbances: often - dehydration, a hypopotassemia, a hyperglycemia; infrequently - a hyperpotassemia, a cachexia, a hypercalcemia, a hypocalcemia, a hypernatremia, a hyponatremia, a hypoglycemia, a hyperuricemia, deficit of B12 vitamin, a hypomagnesiemia, a hypophosphatemia.

Disturbances from reproductive system: infrequently - pain in a small egg, erectile dysfunction; seldom - prostatitis.

Disturbances from immune system: infrequently - hypersensitivity; seldom - a Quincke's edema, an acute anaphylaxis, an amyloidosis.

Disturbances from skin and hypodermic fabrics: very often - skin rash; often - okologlaznichny hypostasis, a small tortoiseshell, 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 swelled; seldom - an acute febrile neutrophylic dermatosis (a syndrome It is twisted); very seldom - Stephens's syndrome - Johnson and a toxic epidermal necrolysis.

Disturbances of laboratory and tool indicators: often - increase in activity of a lactate dehydrogenase in blood; infrequently - increase in activity of an alkaline phosphatase, increase in concentration of urea in blood, increase in activity gamma глютамилтрансферазы, increase in activity of amylase of blood, decrease in concentration of hydrocarbonates in blood, increase in concentration of S-reactive protein; seldom – ECG aberrations (including lengthening of an interval of QT), an aberration of an indicator of the international normalized relation, decrease in pH of a gastric juice, increase in maintenance of a troponin of I, increase in aggregation of thrombocytes.

Local reactions: infrequently - pain, burning sensation and a hyperemia in the place of an injection, phlebitis. At an ekstravazation - an inflammation of a hypodermic fatty tissue.

Others: very often - increased fatigue, fervescence, the surrounding herpes (including disseminated), a herpes simplex, fungal infections; often - an adynamy, weakness, feeling of an indisposition, grippopodobny symptoms, peripheral hypostases, hypostases, a body degrowth, accession of consecutive infections; infrequently - neuralgia, a fever, feeling of a prelum in a thorax, discomfort in a thorax, the groin pain, complications associated with a catheter, a syndrome of a lysis of a tumor, increase in body weight; seldom - a herpetic encephalomeningitis, septic shock; very seldom – the progressing multifocal leukoencephalopathy.

Patients with a mantiynokletochny lymphoma. Indicators of safety of a bortezomib at these patients are similar to the corresponding indicators at patients with a multiple myeloma. Significant differences between two groups of patients are that thrombocytopenia, the neutropenia, anemia, nausea, vomiting and fervescence are 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 showed properties of weak inhibitor of isoenzymes of P450 1A2, 2C9, 2C19, 2D6 and 3A4 cytochrome. Proceeding from an insignificant contribution of CYP2D6 to metabolism of a bortezomib (7%), at people with low activity of this enzyme change of the general distribution of drug is not expected.

The research of medicinal interaction with strong inhibitor of an isoenzyme CYP3A4 ketokonazoly showed increase in average AUC values (the area under a curve "concentration time") a bortezomiba on average for 35%. Therefore it is necessary to watch carefully the patients receiving at the same time бортезомиб and strong inhibitor of an isoenzyme CYP3A4 (кетоконазол, ритонавир).

In a research of influence of medicinal interaction with strong CYP2C19 inhibitor omeprazoly on pharmacokinetics of a bortezomib, essential change of pharmacokinetics of a bortezomib is not revealed.

The research 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.

The research of influence of medicinal interaction with rifampicin – strong CYP3A4 inhibitor – on pharmacokinetics of a bortezomib showed decrease in AUC of a bortezomib on average by 45%. Therefore it is not recommended to use the drug Boramilan® FS together with the strong inductor 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. Essential change of pharmacokinetics of a bortezomib in a research of influence of medicinal interaction with dexamethasone – weaker CYP3A4 inhibitor is not revealed.

At the patients with a diabetes mellitus receiving peroral hypoglycemic drugs cases of a hypoglycemia and a hyperglycemia are registered.

At use of a bortezomib in combination with 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:

Pregnancy and period of feeding by a breast.

Children's age (lack of an otpyt of use).

Hypersensitivity to a bortezomib, boron and Mannitolum.

Acute diffusion infiltrative diseases of lungs.

Defeat of a pericardium.

With care:
- abnormal liver functions of heavy and average degree;
- heavy renal failures;
- 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 isoenzymes CYP3A4, concomitant use of substrates of an isoenzyme of CYP2C9, peroral hypoglycemic drugs.

Overdose:

The overdose 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 not known. At overdose it is necessary to control indicators of vital signs of the patient and body temperature, to carry out the corresponding therapy for maintenance of arterial pressure (infusional therapy, vasoconstrictive and/or inotropic drugs).

Storage conditions:

Period of validity - 3 years. Not to use after a period of validity. In the dry, protected from light place at a temperature not above 25 °C. After recovery solution to store at a temperature not above 25 °C at natural lighting in an original bottle or in the syringe no more than 8 h. To store in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Lyophilisate for preparation of solution for intravenous and hypodermic administration of 3,5 mg. On 3,5 mg of a bortezomib in the bottles of dark glass with a capacity of 10 ml which are hermetically corked by traffic jams from rubber and caps aluminum-plastic. On bottles paste the self-adhesive label. On 5 ml of solvent in ampoules of neutral glass of the NS-1 brand. On ampoules paste the self-adhesive label. 1 bottle with drug complete with 1 ampoule of solvent or without solvent is packed into a blister strip packaging from a film polyvinyl chloride. 1 blister strip packaging and the application instruction are placed in a cardboard pack. At a drug complete set the solvent packed into the ampoules which do not have a tension ring for opening or without break point in a pack put a knife for opening of ampoules in ampoules or the scarificator ampoule.