Bortezol - instructions for use, dose, side effects, contraindications

Bortezomib is a reversible inhibitor of chymotrypsin-like activity 26S-proteasomes of mammalian cells. This proteasome is a large protein complex that cleaves proteins conjugated to ubiquitin.The ubiquitin-proteasome pathway plays a key role in regulating the intracellular concentration of certain proteins and, thus, supports intracellular homeostasis. Suppression of proteasome activity prevents this selective proteolysis, which can affect many cascades of signal transduction reactions in the cell. Violation of the mechanism of maintaining homeostasis can lead to cell death.

In vivo bortezomib caused a slowdown in tumor growth in many experimental models, including multiple myeloma.

In experiments in vitro, ex vivo and in animal models bortezomib strengthened the differentiation and activity of osteoblasts and inhibited the function of osteoclasts. These effects were observed in patients with multiple myeloma with multiple foci of osteolysis receiving bortezomib therapy.

Pharmacokinetics:

When intravenously sprayed with bortezomib in doses of 1.0 mg / m² and 1.3 mg / m²patients with multiple myeloma, the maximum plasma concentrations of the drug are 57 and 112 ng / ml, respectively. With the subsequent administration of the drug, the maximum plasma concentrations are in the range of 67-106 ng / ml for a dose of 1.0 mg / m² and about 89-120 for a dose of 1.3 mg / m². The average half-life of the drug with repeated administration is 40-193 hours.

The drug is quickly withdrawn after the first dose compared with subsequent doses. After the first administration in doses of 1.0 mg / m² and 1.3 mg / m² the average total ground clearance is 102 and 112 l / h, respectively, and after subsequent introductions - respectively 15-32 l / h.

When administered at a dose of 1.3 mg / m² subcutaneously or intravenously to a patient with multiple myeloma, the total systemic exposure after repeated administration at the same dose (AUC_last) was equivalent for both administration routes (155 ng * h / ml for subcutaneous administration and 151 ng * h / ml for intravenous administration). FROM_mOh after subcutaneous administration (20.4 ng / ml) was lower than after intravenous administration (223 ng / ml).

The average geometric ratio of AUC_last was 0.99, and 90% confidence intervals were 80.18-122.80%. T_max was 30 minutes with subcutaneous injection and 2 minutes with intravenous administration.

Distribution

After a single or multiple doses of 1.0 mg / m² and 1.3 mg / m²the average volume of bortezomib distribution in patients with multiple myeloma is 1659-3294 l (489-1884 l / m²). This suggests that bortezomib intensively distributed in peripheral tissues. At concentrations of bortezomib 100-1000 ng / ml, the binding of the drug to plasma proteins is on average 83%. The fraction of bortezomib bound to plasma proteins does not depend on concentration.

Metabolism

In conditions in vitro the metabolism of bortezomib is mainly carried out by isoenzymes of cytochrome P450 - CYP3A4, CYP2C19 and CYP1A2.

Participation of isoenzymes CYP2D6 and CYP2C9 in the metabolism of bortezomib is insignificant. The main pathway of metabolism is the elimination of boron atoms with the formation of two metabolites, which are subsequently hydroxylated to form several other metabolites. Bortezomib metabolites do not inhibit proteasome 26S.

Excretion

The ways of removing bortezomib in humans have not been studied.

Pharmacokinetics in special patient groups

Age, gender and race

The pharmacokinetics of bortezomib has been studied in children aged 2 to 16 years with acute lymphoblastic leukemia or acute myeloid leukemia with intravenous bolus administration at a dose of 1.3 mg / m² 2 times per week. According to the population analysis of pharmacokinetics, the removal of bortezomib was accelerated as the body surface area of the patient increased.

The mean (variation coefficient,%) of clearance of bortezomib was 7.79 (25%) l / h / m², the equilibrium volume of distribution was 834 (39%) l / m², and the elimination half-life is 100 (44%) h.

After correcting the effect of body surface area, other demographic variables (such as age, body weight and gender) did not have a clinically significant effect on the clearance of bortezomib.

The clearance of bortezomib in children, normalized for body surface area, was comparable to that of adults.

The effect of sex and race on the pharmacokinetics of bortezomib has not been studied.

Patients with impaired hepatic function

Studies of the pharmacokinetics of bortezomib in cancer patients with impaired liver function were performed in 61 patients with varying degrees of severity of liver function disorders (see Table 5) using bortezomib 0.5-1.3 mg / m².

A mild liver function disorder does not affect the pharmacokinetics of bortezomib.

In patients with impaired liver function of medium and severe degree, a 60% increase in AUC (area under the concentration-time curve) of bortezomib is observed compared to patients with normal liver function. For patients with moderate or severe liver dysfunction, a reduction in the initial dose of bortezomib is recommended.Careful observation of such patients is required.

Patients with impaired renal function

Pharmacokinetics of bortezomib in doses of 0.7-1.3 mg / m² intravenously twice a week in patients with impaired renal function of mild, moderate or severe, including patients on dialysis, is comparable to the pharmacokinetics of the drug in patients with normal renal function.

Indications:

- Multiple myeloma;

- mantle cell leukemia.

Contraindications:

- Hypersensitivity to bortezomibu, boron and mannitol;

- pregnancy and the period of breastfeeding;

- children under 18 years of age (lack of experience);

- acute diffuse infiltrative lung diseases;

- defeat of the pericardium;

- simultaneous application with powerful isoenzyme inducers CYP3A (rifampicin, carbamazepine, phenytoin, phenobarbital, St. John's wort pitted).

Carefully:

- Dysfunction of the liver of a severe and moderate degree;

- impaired renal function of a serious degree;

- seizures or epilepsy in the anamnesis;

- fainting;

- diabetic neuropathy in the anamnesis;

- simultaneous reception of antihypertensive drugs;

- Dehydration against diarrhea or vomiting;

- constipation;

- risk of developing chronic heart failure;

- simultaneous administration of inhibitors or isoenzyme substrates CYP3A4, simultaneous reception of isoenzyme substrates CYP2C9, oral hypoglycemic drugs.

Pregnancy and lactation:The use of the drug is contraindicated in pregnancy and during breastfeeding.

For the duration of treatment, stop breastfeeding.

Dosing and Administration:

Bortezomib is administered intravenously struino for 3-5 seconds or subcutaneously. The drug Bortezol is indicated only for intravenous and subcutaneous administration. With intrathecal administration, deaths were documented.

When administered intravenously, the solution concentration should be 1 mg / ml. For subcutaneous administration, the solution concentration should be 2.5 mg / ml. The concentration of the solution should be calculated very carefully due to the difference in the concentrations of the solution for intravenous administration and the solution for subcutaneous administration.

Monotherapy

Recurrent multiple myeloma and recurrent mantle cell lymphoma

The recommended dose of bortezomib is 1.3 mg / m² body surface area twice a week for 2 weeks (days 1, 4, 8 and 11) followed by a 10-day break (days 12-21). Between the introduction of consecutive doses of the drug Bortezol should be at least 72 hours. The degree of clinical response is recommended to be evaluated after 3 and 5 cycles of treatment.

If a complete clinical response is achieved, two additional treatment cycles are recommended.

If the duration of treatment is more than 8 cycles, Bortezol can be used according to the standard scheme or according to the scheme of maintenance therapy of relapsing multiple myeloma - weekly for 4 weeks (days 1, 8, 15, 22) followed by a 13-day rest period (days 23-35). Patients in whom Bortezol therapy did not give a clinical response (progression or stabilization of the disease after 2 or 4 cycles, respectively), a combination of high doses of dexamethasone with Bortezol can be prescribed. In this case, 40 mg of dexamethasone is administered orally with each dose of Bortezol: 20 mg on the day of administration of the drug Bortezol and 20 mg the day after the administration of the drug Bortezol. Thus, dexamethasone is given on days 1, 2, 4, 5, 8, 9, 11 and 12, totaling 160 mg in 3 weeks.

Correction of dose and resumption of therapy

With the development of hematological toxicity of the 4th degree or any non-hematologic toxic effect of the third degree, with the exception of neuropathy, treatment with Bortezol should be stopped. After the disappearance of toxicity symptoms, treatment with Bortezol can be resumed at a dose reduced by 25% (dose 1.3 mg / m² reduce to 1.0 mg / m²; dose of 1.0 mg / m² reduce to 0.7 mg / m²).

When the associated with the use of Bortezol neuropathic pain and / or peripheral sensory neuropathy dose of the drug is changed in accordance with Table 1. There were cases of severe vegetative neuropathy, leading to the cessation or suspension of therapy. In patients with severe neuropathy in an anamnesis, Bortezol can only be used after a thorough assessment of the risk / benefit ratio.

Table 1. Recommended dose changes in the development of drug-induced bortezol neuropathic pain and / or peripheral sensory or motor neuropathy

Severity of peripheral neuropathy	Change in dose and frequency of administration
1st degree (paresthesia, weakness and / or extinction of reflexes) without pain or loss of function.	Dose and mode of administration do not require correction.
1st degree with pain or 2nd degree (impaired function, but not daily activity).	Reduce the dose to 1.0 mg / m² or change the mode of administration by 1.3 mg / m² Once a week
2nd degree with pain or grade 3 (violation of daily activity).	Suspend the use of bortezomib until the symptoms of toxicity disappear. After that, resume treatment, lowering the dose to 0.7 mg / m² and reducing the frequency of administration to once a week.
4th degree (sensory neuropathy, resulting in disability or motor neuropathy, life threatening or leading to paralysis).	Stop using bortezomib.

Combination Therapy

Multiple myeloma in previously untreated patients and who are not candidates for stem cell transplantation

The recommended dose in combination with melphalan and prednisone

Bortezomib administered intravenously struino for 3-5 seconds or subcutaneously in combination with melphalan and prednisone, which are taken orally. Nine six-week cycles are carried out as shown in Table 2. In cycles 1 to 4 bortezomib applied 2 times a week (days 1, 4, 8, 11, 22, 25, 29 and 32), and in cycles 5-9 - 1 weekly (days 1, 8, 22 and 29).

Table 2.The recommended dosage regimen of bortezomib used in combination with melphalan and prednisone in patients with previously untreated multiple myeloma who do not demonstrate stem cell transplantation

Bortezomib 2 times a week (cycles 1-4)

A week

Bortezomib (1.3 mg / m²)

day

- day

day

period

recreation

day

period

recreation

Melphalan (9 mg / m²) + Prednisone (60 mg / m²)

day

period recreation

Bortezomib once a week (cycles 5-9)

A week

Bortezomib (1.3 mg / m²)

day

period

recreation

day

period

recreation

Melphalan (9 mg / m²) + Prednisone (60 mg / m²)

day

rest period

Correction of the dose and the regimen for use with bortezomib in conjunction with melphalan and prednisone

Before the start of a new treatment cycle:

- the platelet content should be ≥ 70000 / μL;

- the absolute content of neutrophils (ASN) ≥ 1000 / μL;

- Non-hematologic toxicity should be reduced to 1 degree or to the baseline level.

Table 3. Correction of dose in subsequent treatment cycles

Toxicity	Correction or delay of dose
*Hematologic toxicity during the previous cycle:*
Prolonged neutropenia or thrombocytopenia of grade 4, or thrombocytopenia with bleeding	In the next cycle, the dose of melphalan should be reduced by 25%
- Platelet content <30000 / μL or ASN <750 / μL on the day of bortezomib (excluding day 1)	Postpone the introduction of bortezomib
- Several postponement of bortezomib in one cycle (> 3 times with 2 times a week or> 2 times with 1 time per week)	The dose of bortezomib is reduced by 1 step (from 1.3 mg / m² up to 1.0 mg / m²; with 1.0 mg / m² up to 0,7 mg / m²).
Non-hematological toxicity ≥ 3 degrees	The use of bortezomib is delayed until the non-hematologic toxicity is reduced to 1 degree or to the baseline level. After this, treatment with bortezomib can be resumed in a dose reduced by 1 step (from 1.3 mg / m² up to 1.0 mg / m²; with 1.0 mg / m² up to 0,7 mg / m²). With the development of neuropathic pain and / or peripheral neuropathy associated with the use of bortezomib, the administration of the next dose is postponed and / or adjusted to the dose as described in Table 1.

Further information on melphalan and prednisone is given in the instructions for the medical use of these drugs.

Multiple myeloma in previously untreated patients who are candidates for stem cell transplantation

Recommended dose

The recommended initial dose of bortezomib when used in combination with other drugs is 1.3 mg / m² body surface area twice a week for 2 weeks (days 1, 4, 8, 11) followed by a break of 10-18 days, which is 1 cycle of treatment. It is necessary to spend from 3 to 6 such cycles. Between the introduction of consecutive doses of the drug Bortezol should pass at least 72 hours.

Correction of the dose in patients who are shown to perform stem cell transplantation should be done according to the recommendations described in Table 1.

Instructions on dosing of drugs used in combination with the drug Bortezol, are given in the relevant instructions for medical use.

Recurrent multiple myeloma

The recommended dose when used in combination with pegylated liposomal doxorubicin

The dosage and dose adjustment of Bortezol is described above in the section "Monotherapy".

Pegylated liposomal doxorubicin applied at a dose of 30 mg / m²in the 4th day of the 3-week cycle of taking Bortezol in the form of an intravenous infusion of 1 hour duration immediately after the administration of bortezomib.

For more information on pegylated liposomal doxorubicin, see the instructions for the medical use of this drug.

The recommended dose when used in combination with dexamethasone

The dosage and dose adjustment of Bortezol is described above in the section "Monotherapy".

Dexamethasone is taken orally at a dose of 20 mg per day on the day of administration of the drug Bortezol and the next day.

Additional information about dexamethasone is given in the instructions for the medical use of this drug.

Repeated therapy of multiple myeloma

In case of relapse in patients who have previously responded to therapy with Bortezol (monotherapy or combination therapy), it is necessary to start therapy with the highest tolerated dose.

Instructions for dosing are described in the section "Monotherapy".

Previously untreated mantle cell leukemia

The recommended dose when administered in combination with rituximab, cyclophosphamide, doxorubicin and prednisone

The dosage and dose adjustment of Bortezol is described above in the section "Monotherapy". It is necessary to conduct 6 cycles of therapy with bortezomib.If patients respond to therapy for the first time during the 6th cycle, two additional cycles of therapy with Bortezol are recommended. On the 1st day of each 3-week cycle of therapy with Bortezol, the following medications should be administered in the form of intravenous infusions: rituximab in a dose of 375 mg / m², cyclophosphamide in a dose of 750 mg / m² and doxorubicin in a dose of 50 mg / m². Prednisone is taken orally at a dose of 100 mg / m² in days 1, 2, 3, 4 and 5 of each cycle of therapy with Bortezol.

Correction of dose during therapy of previously untreated mantle cell lymphoma

Before starting a new treatment cycle (except cycle 1):

- Platelet content should be ≥ 100,000 / μL and the absolute number of neutrophils (ACH) ≥ 1500 / μL

- Concentration of hemoglobin should be ≥ 8 g / dL (≥ 4.96 mmol / L)

- Non-hematologic toxicity should be reduced to 1 degree or to the baseline level

With the development of hematological toxicity of the third degree or any non-hematological toxic effect of the third degree, with the exception of neuropathy, treatment with Bortezol should be stopped. Guidance on dose adjustment is given in Table 4.

Table 4. Correction of dose during therapy the patients with previously untreated mantle cell lymphoma

Toxicity	Correction or delay of dose
Hematologic Toxicity: Neutropenia ≥ 3 degrees with fever or grade 4 neutropenia lasting more than 7 days, platelet count ≤ 10000 / μL	Bortezol therapy should be suspended for up to 2 weeks before the patient has the following indicators: AHN ≥ 750 / μL, containing platelets ≥ 25,000 / μL.
	If toxicity is not resolved when the therapy is stopped before the parameters described above, then therapy must be completely discontinued.
	If the toxicity is resolved to the following values: LCHN> 750 / μL platelet count> 25000 / μL, then the dose of Bortezol should be reduced by one step (from 1.3 mg / m² up to 1.0 mg / m², or e 1.0 mg / m² up to 0,7 mg / m²)
Platelet content <25000 / μL or LCHN <750 / mcd on the day of administration of Bortezol (excluding day 1)	Postpone the introduction of Bortezol
Non-hematologic toxicity 3 ≥ degree	The use of Bortezol is postponed until the non-hematologic toxicity is reduced to grade 2 or lower.After this, treatment with Bortezol can be resumed in a dose reduced by 1 step (from 1.3 mg / m² up to 1.0 mg / m², or with 1.0 mg / m² up to 0,7 mg / m²). With the development of neuropathic pain and / or peripheral neuropathy associated with the use of Bortezol, the administration of the next dose is postponed and / or adjusted as described in Table 1.

Information on the dosage regimen of rituximab, cyclophosphamide, doxorubicin and prednisone is given in the instructions for the medical use of these drugs.

Special patient groups

Patients with impaired renal function

The degree of impaired renal function does not affect the pharmacokinetics of bortezomib. Therefore, for patients with renal insufficiency, dose adjustment is not required. Since dialysis can reduce the concentration of bortezomib in the blood, the drug should be injected after dialysis.

Patients with hepatic impairment

In patients with mild liver function disorders, no change in the initial dose is required. The recommended dose should be given. Patients with violations of liver function of moderate and severe degree should be prescribed bortezomib in a reduced dose (see Table 5).

Table 5. Recommended changes in the initial dose of bortezomib the patients with impaired hepatic function

Power the severity of liver function disorders	Concentration bilirubin	Activity ACT	Change in the initial dose
Lightweight	≤ 1.0 x VGN	> VGN	Not required
Lightweight	> 1.0 x -1.5 x VGN	any	Not required
Average	> 1.5 x - 3 x VGN	any	Required to appoint bortezomib at reduced dose of 0.7 mg / m² during the first cycle. Consider increasing the dose to 1.0 mg / m² or further reduction of the dose to 0.5 mg / m² in subsequent cycles, depending on the patient's tolerability.
Heavy	> 3 x VGN	any

ACT = aspartate aminotransferase

VGN = upper limit of normal

Mode of application

Bortezol is an antitumor drug. Care should be taken when preparing the solution and handling the drug. Appropriate aseptic measures should be observed. It is recommended to use gloves and other protective clothing to prevent contact with the skin.

The drug should not be mixed with other medicines, with the exception of 0.9% sodium chloride solution.

Preparation of a solution for intravenous administration

The contents of the vial are dissolved in 3.5 ml of 0.9% sodium chloride solution.The concentration of the prepared solution for intravenous administration is 1.0 mg / ml. The prepared solution must be clear and colorless. If a mechanical inclusion or color change is detected, the prepared solution can not be used.

The resulting solution is administered by intravenous bolus injection for 3-5 seconds through a peripheral or central venous catheter, which is then washed with 0.9% solution of sodium chloride for injection.

Preparation of a solution for subcutaneous administration

The contents of the vial are dissolved in 1.4 ml of 0.9% sodium chloride solution. The concentration of the prepared solution for subcutaneous administration is 2.5 mg / ml.

The prepared solution must be clear and colorless. If a mechanical inclusion or color change is detected, the prepared solution can not be used.

The resulting solution is injected subcutaneously into the thigh region (right or left) or into the abdominal region (right or left). It is necessary to constantly change the place of administration of the drug. Each subsequent injection should be administered at a distance of at least 2.5 cm from the site of the previous injection. Do not administer the drug to sensitive areas, damaged areas (redness, bruises), or in areas where needle insertion is difficult.

In case of local reactions in the area of subcutaneous administration of bortezomib, a less concentrated solution for subcutaneous administration (1 mg / ml instead of 2.5 mg / ml, for this purpose the contents of the vial is dissolved in 3.5 ml of 0.9% sodium chloride solution) or switch to intravenous administration of the drug.

Side effects:

In general, the safety parameters of bortezomib when used in monotherapy are similar to those when used in combination with melphalan and prednisone. Serious adverse reactions were rarely observed during bortezomib therapy and included heart failure, tumor lysis syndrome, pulmonary hypertension, reversible rear encephalopathy syndrome, acute diffuse infiltrative pulmonary diseases. In addition, in rare cases, vegetative neuropathy was observed.

The most frequently observed adverse events during therapy with bortezomib were nausea, diarrhea, constipation, vomiting, fatigue, pyrexia, thrombocytopenia, anemia, neutropenia, peripheral neuropathy (including sensory), headache, paresthesia, decreased appetite, dyspnea, rash, surrounding herpes and myalgia.

The following are undesirable reactions that were regarded as likely or possibly related to the use of bortezomib. Undesired reactions are grouped according to system-organ classes and frequency of occurrence. The frequency of unwanted reactions was classified as follows: very often (> 1/10), often (≥1 / 100, <1/10), infrequently (≥1 / 1000 and <1/100), rarely (≥1 / 10000 and < 1/1000) and the frequency is unknown.

Infectious and parasitic diseases:

often - herpes simplex surrounding herpes (including disseminated and ophthalmoherpes), pneumonia, fungal infections;

infectious, bacterial, viral infections, sepsis (including septic shock), bronchopneumonia, herpesvirus infection, herpetic meningoencephalitis, bacteremia (including staphylococcal), barley, influenza, inflammation of subcutaneous fat, infections, associated with the use of medical devices, skin infections, ear infections, staphylococcal infections, dental infections;

rarely - meningitis (including bacterial), Epstein-Barr virus infection, genital herpes, tonsillitis, mastoiditis, chronic fatigue syndrome.

Neoplasms benign, Malignant and vague (including cysts and polyps):

rarely - malignant neoplasm, plasmacytic leukemia, kidney carcinoma, neoplasms, mushroom mycosis, benign neoplasms.

Disturbances from the hematopoiesis and lymphatic system:

very often - thrombocytopenia, neutropenia, anemia; often - leukopenia, lymphopenia;

infrequently - pancytopenia, febrile neutropenia, coagulopathy, leukocytosis, lymphadenopathy, hemolytic anemia;

rarely - disseminated intravascular coagulation (DVS-syndrome), thrombocytosis, high blood viscosity syndrome, platelet abnormalities, thrombocytopenic purpura, blood disorders, hemorrhagic diathesis, lymphocytic infiltration.

Immune system disorders:

infrequently - Quincke's edema, hypersensitivity;

rarely - anaphylactic shock, amyloidosis, reactions with the formation of immune complexes (type III).

Disorders from the endocrine system:

infrequently - the Itenko-Cushing syndrome, hyperthyroidism, a violation of the secretion of antidiuretic hormone;

rarely - hypothyroidism.

Metabolic disorders and eating disorders:

very often - a decrease in appetite;

often - dehydration, hypokalemia, hyponatremia, changes in blood glucose concentration, hypocalcemia, changes in enzyme activity;

infrequently - tumor lysis syndrome, lack of weight gain, hypomagnesemia, hypophosphatemia, hyperkalemia, hypercalcemia, hypernatremia, changes in uric acid concentration, diabetes mellitus, fluid retention;

rarely hypermagnesemia, acidosis, water-electrolyte balance disturbance, excessive fluid accumulation, hypochloremia, hypovolemia, hyperchloremia, hyperphosphataemia, metabolic disorders, vitamin B deficiency, vitamin B12 deficiency, gout, increased appetite, alcohol intolerance.

Disorders of the psyche:

often - disorders and mood disorders, anxiety, frustration and sleep disorders;

infrequently - changes in mental status, hallucinations, psychotic disorder, confusion, excited state;

rarely - suicidal thoughts, adaptation disorder, delirium, decreased libido.

Disturbances from the nervous system:

very often - neuropathy, peripheral sensory neuropathy, dysesthesia, neuralgia;

often - motor neuropathy, loss of consciousness (including fainting), dizziness, taste distortion, lethargy, headache;

infrequent - tremor, peripheral sensorimotor neuropathy, dyskinesia, impaired balance, memory loss (excluding dementia.), encephalopathy, posterior reversible encephalopathy syndrome, neurotoxicity, seizures, post-herpetic neuralgia, speech disorder, a syndrome of "restless legs", migraine, sciatica, impaired concentration attention, pathological reflexes, parosmia;

rarely - intracerebral haemorrhage, intracranial hemorrhage (including subarachnoid), cerebral edema, transient ischemic attack, coma, autonomic nervous system imbalance, autonomic neuropathy, cranial nerve paralysis, paralysis, paresis, pre-occlusive condition, brainstem disease syndrome, violation cerebral circulation, radicular syndrome, psychomotor hyperactivity, spinal cord compression, cognitive disorders, movement disorders, nervous system disorders, radiculitis, salivation, hypotension we шц.

Disturbances on the part of the organ of sight:

often - swelling of the eyes, visual impairment, conjunctivitis;

infrequent - eye hemorrhage, eyelid infections, eye inflammation, diplopia, dry eyes, eye irritation, eye pain, increased lacrimation, discharge from the eyes;

rarely - corneal damage, exophthalmos, retinitis, scotoma, eye damage (including age), dacryoadenitis, photophobia, photopsy, optic neuropathy, various degrees of visual impairment (before blindness).

Hearing and balance disorders:

often - vertigo;

infrequent - ringing in the ears, hearing impairment (to deafness), discomfort in the ear; rarely bleeding, vestibular neuronitis, ear damage.

Heart Disease:

infrequently - cardiac tamponade, cardiopulmonary shock, cardiac fibrillation (including atrial fibrillation), heart failure (including left and right ventricles), arrhythmia, tachycardia, palpitations, angina, pericarditis (incl. exudative pericarditis), cardiomyopathy, ventricular dysfunction, bradycardia;

rarely - atrial flutter, myocardial infarction, atrioventricular blockade, cardiovascular disorders (including cardiogenic shock), pirouette ventricular tachysystolic type arrhythmia, unstable angina, heart valve diseases, coronary insufficiency, sinus node stop.

Disorders from the vascular system:

often - lowering blood pressure, orthostatic hypotension, increasing blood pressure;

infrequently, stroke, deep vein thrombosis, bleeding, thrombophlebitis (including superficial), circulatory collapse (including hypovolemic shock), phlebitis, hot flashes, hematoma (including perirenal), decreased peripheral circulation, vasculitis, hyperemia (including ocular);

rarely - embolism of peripheral vessels, lymphedema, pallor, erythromelalgia, vasodilation, change in color of veins, venous insufficiency.

Disturbances from the respiratory system, thorax and mediastinum:

often shortness of breath, nosebleeds, upper and lower respiratory tract infections, cough;

infrequent - pulmonary embolism, pleural effusion, pulmonary edema (including acute), pulmonary alveolar hemorrhage, bronchospasm, chronic obstructive pulmonary disease, hypoxemia, airway obstruction, hypoxia, pleurisy, hiccough, rhinorrhea, dysphonia, wheezing;

rarely - respiratory failure, acute respiratory distress syndrome, apnea, pneumothorax, atelectasis, pulmonary hypertension, hemoptysis, hyperventilation, orthopnea, pneumonitis,respiratory alkalosis, tachypnea, pulmonary fibrosis, bronchial dysfunction, hypocapnia, interstitial lung disease, pulmonary infiltration, throat tightness, dryness in the throat, increased secretion in the upper respiratory tract, throat irritation, upper respiratory tract cough syndrome.

Disorders from the gastrointestinal tract:

very often - nausea, vomiting, diarrhea, constipation;

often bleeding from the gastrointestinal tract (including bleeding of the mucous membrane), dyspepsia, stomatitis, a violation of the tone of the gastrointestinal tract, pain in the throat and pharynx, pain in the abdomen (including gastrointestinal pain and pain in the spleen) , disorders of the oral cavity, flatulence;

infrequently - pancreatitis (including chronic), vomiting of blood, puffiness of the lips, obstruction of the gastrointestinal tract (including intestinal obstruction), discomfort in the abdomen, ulceration of the oral mucosa, enteritis, gastritis, bleeding from the gums, gastroesophageal reflux disease, colitis (including pseudomembranous colitis), ischemic colitis, inflammation of the mucous membrane of the gastrointestinal tract, dysphagia, irritable bowel syndrome, gastrointestinal disturbances, plaque in the tongue, motor motility disorder, disorders of the salivary glands;

rarely acute pancreatitis, peritonitis, edema of the tongue, ascites, esophagitis, cheilitis, fecal incontinence, anal sphincter atony, fecaloma, ulceration and perforation of the gastrointestinal tract, gingival hypertrophy, megacolon, rectal discharge, blistering in the throat, pain in the throat lips, periodontitis, anal fissure, change in the rhythm of defecation, procalgia, stool disorders.

Disorders from the hepatobiliary system:

often - changes in the activity of "liver" enzymes;

infrequently - hepatotoxicity (including liver disorders), hepatitis, cholestasis;

rarely - hepatic insufficiency, hepatomegaly, Badd-Chiari syndrome, cytomegalovirus hepatitis, hepatic bleeding, cholelithiasis.

Disturbances from the skin and subcutaneous tissue:

often - a rash, itching, erythema, dry skin;

infrequent erythema multiforme, urticaria, acute febrile neutrophilic dermatosis, toxic skin rash, toxic epidermal necrolysis, Stevens-Johnson syndrome, dermatitis, changes in hair structure, petechia, ecchymosis, skin lesions, purpura, skin tumors, psoriasis, hyperhidrosis, night sweats, pressure ulcers, acne, blisters, skin pigmentation disorder;

rarely - reactions from the skin, Jessner's lymphocytic infiltration, palmar-plantar erythrodysesthesia, subcutaneous bleeding, reticular ledo, skin induration, papule, photosensitivity reactions, seborrhea, cold sweats, skin lesions, erythrosis, skin ulcers, nail lesions.

Disorders from the musculoskeletal system and connective tissue:

very often - musculoskeletal pain;

often - muscle spasms, pain in the limbs, muscle weakness;

infrequently - muscle twitching, swelling of the joints, arthritis, joint stiffness, myopathy, a feeling of heaviness;

rarely - rhabdomyolysis, temporomandibular joint syndrome, fistula, joint effusion, pain in the jaw, bone disorders, infections and inflammation of the musculoskeletal and connective tissue, synovial cysts.

Disorders from the kidneys and urinary tract:

often - renal dysfunction;

infrequent - acute renal failure, chronic renal failure, urinary tract infections, urinary tract complaints, hematuria, urinary retention, urination disorder, proteinuria, azotemia, oliguria, pollakiuria;

rarely - irritation of the bladder.

Violations of the genitals and mammary gland:

infrequently - vaginal bleeding, pain in the genitals, erectile dysfunction;

rarely - dysfunction of the testicles, prostatitis, malfunction of the breast, soreness of the epididymis, epididymitis, pain in the pelvic region, ulceration of the vulva.

Congenital, family and hereditary disorders:

rarely - aplasia, malformation of the gastrointestinal tract, ichthyosis.

General disorders and disorders due to the method of application:

very often - pyrexia, increased fatigue, asthenia; often - swelling (including peripheral), chills, pain, discomfort;

infrequent general physical health, facial swelling, reactions at the injection site, mucosal disorders, chest pain, gait disturbance, cold feeling, extravasation, complications from the use of a catheter, a change in thirst, discomfort in the chest, a sense of change body temperature, pain at the injection site;

rarely - death (including sudden), multiple organ failure, bleeding at the injection site, hernia, violation of healing processes, inflammation, phlebitis at the injection site,soreness, ulceration, irritability, non-cardiac pain in the chest, pain at the site of insertion of the catheter, sensation of a foreign body.

Changes in laboratory indicators:

often - a decrease in body weight;

infrequently - hyperbilirubinemia, changes in protein indexes, weight gain, changes in blood counts, increased concentration of C-reactive protein;

rarely - changes in the content of gases in the blood, changes in the cardiogram (including an increase in the tooth QT), a change in prothrombin time, a decrease in the pH of gastric juice, an increase in platelet aggregation, an increase in troponin concentration, 1 detection of viruses and a change in serology, changes in urine analysis.

Injuries, poisoning and complications of procedures:

infrequently - falls, concussion;

rarely - transfusion reactions, fractures, rigidity, facial trauma, joint trauma, burns, ruptures, pain during the procedure, radiation damage.

Surgical and therapeutic procedures:

rarely - activation of macrophages.

Patients with mantle cell lymphoma

The safety indices of bortezomib in these patients were similar to those in patients with multiple myeloma.

Significant differences between the two groups of patients were that thrombocytopenia, neutropenia, anemia, nausea, vomiting and pyrexia were more common in patients with multiple myeloma compared with patients with mantle cell lymphoma; and peripheral neuropathy, rash and itching - in patients with mantle cell lymphoma.

Overdose:

The introduction of bortezomib in a dose exceeding the recommended dose by more than 2 times was accompanied by an acute decrease in arterial pressure and thrombocytopenia with a fatal outcome.

The specific antidote to bortezomib is not known. In case of overdose, monitor the patient's vital functions and body temperature, conduct appropriate therapy to maintain blood pressure (infusion therapy, vasoconstrictor and / or inotropic drugs).

Interaction:

Bortezomib shows the properties of a weak inhibitor of cytochrome P450 isoenzymes 1A2, 2C9, 2C19, 2D6 and 3A4.

Based on the insignificant contribution of the isoenzyme CYP2D6 in the metabolism of bortezomib (7%), in people with a low activity of this isoenzyme, the overall distribution of the drug is not expected to change.

Investigation of the effect of drug interaction with a potent inhibitor of isoenzyme CYP3A4 ketoconazole on the pharmacokinetics of bortezomib showed an increase in the mean values AUC (area under the concentration-time curve) of bortezomib on average by 35%. Therefore, it is necessary to carefully monitor patients receiving simultaneously bortezomib and a potent inhibitor of isoenzyme CYP3A4 (ketoconazole, ritonavir).

In the study of the effect of drug interaction with a potent inhibitor of isoenzyme CYP2C19 with omeprazole on the pharmacokinetics of bortezomib, there was no significant change in the pharmacokinetics of bortezomib.

Investigation of the effect of drug interaction with rifampicin - a powerful isoenzyme inducer CYP3A4 - the pharmacokinetics of bortezomib showed a decrease in mean values AUC (area under the concentration-time curve) of bortezomib on average by 45%. Therefore, it is not recommended to apply bortezomib together with powerful inductors CYP3A4, since the effectiveness of therapy can be reduced. To inducers CYP3A4 are rifampicin, carbamazepine, phenytoin, phenobarbital and St. John's wort.

In the same study, the effect of dexamethasone, a weaker inductor CYP3A4. Based on the results of the study, there was no significant change in the pharmacokinetics of bortezomib.

The study of the effect of drug interaction with the melphalan-prednisone combination showed an increase in the mean values AUC (area under the concentration-time curve) of bortezomib by 17%. This change is considered clinically insignificant.

In patients with diabetes mellitus who received oral hypoglycemic drugs, cases of hypoglycemia and hyperglycemia have been reported.

When using bortezomib in combination with drugs that can be associated with peripheral neuropathy (such as amiodarone, antiviral agents, isoniazid, nitrofurantoin or statins) and drugs that reduce blood pressure, you should be careful.

Special instructions:

Treatment with bortezomib should be done only under the supervision of a doctor who has experience in the use of antitumor chemotherapy.

Inadvertently administered bortezomib intrathecally recorded deaths. Bortezomib is only for intravenous and subcutaneous administration. Do not enter intrathecally.

Before and during each cycle of therapy, a complete blood count should be performed to count the leukocyte count and platelet count.

Thrombocytopenia / neutropenia

Therapy with Bortezol may lead to thrombocytopenia and neutropenia. The smallest number of platelets is usually observed on the 11th day of the cycle and is restored to the beginning of the next cycle.

The cycle periodicity of the decrease and increase in the number of platelets was observed in clinical studies in patients with multiple myeloma or mantle cell lymphoma.

There are no data confirming increasing thrombocytopenia or neutropenia in any of the dosing regimens. With a decrease in the number of platelets <25,000 / μl, therapy with bortezomib should be stopped. When restoring the number of platelets, treatment should be continued in reduced doses, with careful comparison of the possible benefits and risks of treatment.

To treat hematological toxicity, colony-stimulating factors, transfusion of platelet and erythrocyte mass can be used.

When used concomitantly with melphalan and prednisolone, when the platelet count is <30000 / μl, therapy with the drug should be stopped.

Gastrointestinal disorders

To prevent nausea and vomiting, antiemetics are recommended. When diarrhea occurs, antidiarrhoeal drugs are prescribed. To prevent or treat dehydration patients need to conduct rehydration therapy and maintain a water-electrolyte balance. There have been reports of cases of development of intestinal obstruction (infrequently).

Progressive multifocal leukoencephalopathy (PML)

Very rare cases of the development of John Cunningham's viral infection of unknown etiology leading to progressive multifocal leukoencephalopathy and death were reported in patients taking the drug Bortezol. Patients diagnosed with PML received immunosuppressive therapy before or simultaneously with the use of Bortezol. In most cases, PML was diagnosed within 12 months of the first dose of Bortezol. Patients should be monitored on a regular basis for the appearance or deterioration of neurological symptoms or signs that may indicate PML.If a patient is suspected of having PML, the patient should be referred to a PML specialist and appropriate diagnostic measures taken. It should stop using Bortezol in case of PML diagnosis.

Peripheral Neuropathy

Whenever neuropathy occurs, maintenance therapy is provided. Usually, the incidence of peripheral neuropathy reaches a maximum on the 5 cycle of bortezomib treatment. When new or worsening symptoms of peripheral neuropathy appear, a dose reduction and a change in the mode of bortezomib administration may be required.

Patients should be constantly monitored for possible symptoms of neuropathy (burning sensation, hyperesthesia, hypesthesia, paresthesia, discomfort, neuropathic pain or weakness).

The incidence of neuropathy with subcutaneous administration of bortezomib is lower than that of intravenous injection.

There have been cases of the emergence of autonomic neuropathy of severe degree, leading to the cessation or suspension of therapy.

Early and regular monitoring for symptoms of neuropathy with neurological evaluation should be performed in patients,host bortezomib in combination with drugs that can cause neuropathy (for example, thalidomide). In doing so, consider the possibility of an appropriate dose reduction or discontinuation of treatment.

Convulsions

In patients with no seizures or epilepsy, the anamnesis describes infrequent cases of seizures. In treating patients who have any risk factors for seizures, special care is required.

Orthostatic hypotension

Bortezomib therapy is often accompanied by orthostatic hypotension. In most cases, it is mild or moderate and may occur throughout the treatment. Short-term loss of consciousness was rarely noted. In patients who have a history of syncope, diabetic neuropathy, receiving antihypertensive drugs, as well as patients with dehydration in the presence of diarrhea or vomiting, care should be taken. Patients should be instructed about the need to consult a doctor in case of dizziness, a feeling of "lightness in the head" or fainting. When developing orthostatic hypotension, hydration, administration of glucocorticoids and / or sympathomimetics is recommended; if necessary, reduce the dose of antihypertensive drugs.

Heart failure

When using bortezomib, the development or enhancement of existing chronic heart failure is described. The development of signs and symptoms of heart failure may predispose fluid retention. Patients with risk factors or with a history of heart disease should be carefully monitored.

Liver failure

There are cases of acute liver failure in patients who, while taking bortezomib, simultaneously took other drugs as concomitant medication. Such signs of impaired liver function, such as an increase in hepatic enzyme activity, hyperbilirubinemia or hepatitis, usually occurred with the abolition of bortezomib. Data on the status of these patients after resumption of bortezomib therapy are limited.

Patients with symptoms of liver dysfunction should be prescribed bortezomib in lower initial doses and monitor for toxicity, since bortezomib is metabolized by hepatic enzymes and its concentration may increase if the liver function is of medium to severe severity (see section "Method of administration and dose").

Syndrome of reversible leukoencephalopathy

In patients receiving bortezomib, a reversible leukoencephalopathic syndrome was noted - a rare, reversible neurologic disorder that may be accompanied by seizures, increased blood pressure, headache, lethargy, confusion, blindness and other visual and neurological disorders. To confirm the diagnosis, a magnetic resonance imaging of the brain is performed. When developing a syndrome of reverse reversible encephalopathy, bortezomib should be discontinued. The safety of the resumption of bortezomib therapy after the previously identified reverse reversible encephalopathy syndrome is unknown.

Reactivation of the virus Herpes zoster

The treating physicians should consider the possibility of antiviral prophylaxis in patients receiving bortezomib therapy. In patients receiving therapy with bortezomib, melphalan and prednisone, the frequency of reactivation of the virus Herpes zoster was greater in comparison with patients receiving melphalan and prednisone therapy (14% and 4%, respectively). Conducting antiviral prophylaxis significantly reduces the frequency of reactivation of the virus Herpes zoster.

Dysfunction of the lungs

In rare cases, when using bortezomib acute diffuse infiltrative pulmonary diseases of unknown etiology, such as pneumonitis, interstitial pneumonia, pulmonary infiltration and acute respiratory failure syndrome were observed. Some of these conditions led to death. In case of symptoms of pulmonary function disorder or worsening of already existing symptoms, it is necessary to immediately diagnose and prescribe the appropriate treatment for patients.

Tumor lysis syndrome

In connection with the possible development of hyperuricemia related to tumor lysis syndrome, it is recommended that patients during the therapy determine the concentration of uric acid and creatinine in serum. To prevent hyperuricemia, a generous drink is recommended, if necessary - allopurinol and alkalinization of urine.

When using bortezomib in patients who simultaneously take oral hypoglycemic drugs, you should carefully monitor blood glucose and, if necessary, adjust the dose of hypoglycemic drugs.

It is recommended to use reliable methods of contraception during the treatment of any of the sexual partners.

Immunocomplex type reactions

Immunocomplex type reactions such as serum sickness, polyarthritis with rash, proliferative glomerulonephritis have been reported infrequently. You should stop using bortezomib in case of serious reactions.

Precautions for use

When working with bortezomib, the generally accepted rules for handling cytotoxic drugs should be observed.

Effect on the ability to drive transp. cf. and fur:

Patients should be warned about the possible appearance of dizziness, fainting, visual disturbances and other undesirable effects during treatment with bortezomib, which may affect the ability to drive vehicles. If these symptoms occur, patients are advised to refrain from driving and practicing other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Form release / dosage:

Lyophilizate for the preparation of solution for intravenous and subcutaneous administration, 3.5 mg.

Packaging:

For 3.5 mg of bortezomib in a vial of colorless glass (type I) with a capacity of 10 ml, sealed with a bromobutyl stopper and covered with an aluminum cap of the "flip-off".

1 bottle with instructions for use in a cardboard box.

5 bottles with an equal number of instructions for use in a cardboard box (for hospitals).

Storage conditions:

In the dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

The drug should not be used after the expiry date indicated on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-004178

Date of registration:15.03.2017

Expiration Date:15.03.2022

The owner of the registration certificate:Pharmaceuticals Nord, JSCPharmaceuticals Nord, JSC Russia

Manufacturer: & nbsp

FARMASINTEZ, JSC (Irkutsk) Russia

Representation: & nbspPharmasynthesis, JSCPharmasynthesis, JSC

Information update date: & nbsp04.04.2017

Illustrated instructions

Instructions

Bortezol (Bortesol)