Milatib - 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 / m² patients 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 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 The drug is quickly withdrawn after the first dose compared with subsequent doses.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 / hr for subcutaneous administration and 151 ng * h / ml for intravenous administration). FROM_m_Ohafter subcutaneous administration (20.4 ng / ml) was lower than after intravenous administration (223 ng / ml). The geometric mean AUC_last was 0.99, and 90% confidence intervals were 80.18-122.80%. T_m_Oh was 30 minutes with subcutaneous injection and 2 minutes with intravenous administration.After a single or multiple doses of 1.0 mg / m² and 1.3 mg / m² the 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.

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. The ways of removing bortezomib in humans have not been studied. The influence of age, sex, and race on the pharmacokinetics of bortezomib has not been studied.

Studies of the pharmacokinetics of bortezomib in cancer patients with impaired hepatic function were performed in 61 patients with varying degrees of severity of hepatic impairment (cf.Table 5) with the use of doses of bortezomib 0.5-1.3 mg / m². Light violations of the liver do not affect the pharmacokinetics of bortezomib. In patients with violations of liver function of medium and severe degree, a 60% increase is observed AUC (area under the concentration-time curve) of bortezomib 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.

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

Indications:

Milatib is intended for treatment of:

- multiple myeloma;

- mantle cell lymphoma.

Contraindications:

- Hypersensitivity to bortezomibu, boron and mannitol;

- pregnancy and the period of breastfeeding;

- children's age (lack of experience);

- acute diffuse infiltrative lung diseases;

- defeat of the pericardium;

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

Carefully:

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

- severe renal dysfunction;

- 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 and oral hypoglycemic agents.

Pregnancy and lactation:

The use of bortezomib during pregnancy is contraindicated.

If you need to use the drug during lactation, breastfeeding should be discontinued.

Dosing and Administration:

The drug Milatib 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

Milatib is administered intravenously struino for 3-5 seconds or subcutaneously. The recommended dose of bortezomib is 1.3 mg / m 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 Milatib 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 treatment duration is more than 8 cycles, Milatib can be used according to the standard scheme or under the maintenance therapy scheme - weekly for 4 weeks (days 1,8, 15, 22) followed by a 13-day rest period (days 23-35).

Patients in whom Milatib 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 Milatib can be prescribed. In this case, 40 mg of dexamethasone is administered orally with each dose of Milatib preparation: 20 mg per day of administration of Milatib and 20 mg the day after the administration of Milatib. 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-hematological toxic effect of the third degree, with the exception of neuropathy, treatment with Milatib should be stopped. After the disappearance of symptoms of toxicity, Milatib treatment can be resumed in 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 a milatib-associated neuropathic pain and / or peripheral sensory neuropathy appear, the dose of the drug is changed in accordance with Table 1. There have been cases of severe vegetative neuropathy leading to discontinuation or suspension of therapy. In patients with severe neuropathy in a history of Milatib can only be used after a thorough assessment of the risk / benefit ratio.

Table 1.The recommended dose change for the development of Milatib-induced 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 Milatib until the symptoms of toxicity disappear. After this, resume treatment, lowering the dose of Milatib to 0.7 mg / m² and reducing the frequency of administration to once a week
4th degree (sensory neuropathy leading to disability or motor neuropathy, life threatening or leading to paralysis)	Stop using Milatib

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

The drug is injected intravenously in a jet or subcutaneous route in combination with melphalan and prednisone taken internally. Nine 6-week cycles are performed as shown in Table 2. In cycles 1-4 Milatib is administered 2 times a week (days 1, 4, 8, 11, 22, 25, 29 and 32), and in cycles 5-9 - 1 time per week (days 1, 8, 22 and 29).

Table 2. Recommended dosing regimen Milatib. used in combination with melphalan and prednisone in patients with previously untreated multiple myeloma who do not show stem cell transplantation

Milbit 2 times a week (cycles 1-4)
A week	1				2		3	4		5		6
Milatib (1.3 mg / m²)	day 1	-	-	day 4	day 8	day 11	rest period	day 22	day 25	day 29	day 32	rest period
Melphalan (9 mg / m²)+ Prednisone (60 mg / m²)	day 1	day 2	day 3	day 4	-	-	rest period	-	-	-	-	rest period
MIlatib once a week (cycles 5-9)
A week	1				2		3	4		5		6
Milatib (1.3 mg / m²)	day 1	-	-	-	Day 8		period recreation	day 22		Day 29		period recreation
Melphalan (9 mg / m²)+ Prednisone (60 mg / m²)	day 1	day 2	day 3	day 4	-		period recreation	-		-		period recreation

Dose adjustment for combination therapy with melphalan and prednisone

Correction of the dose and the regimen for the use of Milatib together with melphalan and prednisone

Before the start of a new treatment cycle:

- Platelet content should be ≥ 750,000 / μL

- Absolute number of neutrophils (AChN) ≥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 ACHN ≤ 750 / μL on the day of Milatib administration (except for day 1)	Delay the introduction of Milatib
- Several delays in the administration of Milatib in one cycle (≥3 times when administered twice a week or ≥2 times when administered once a week)	The dose of Milatib is reduced by 1 step (from 1.3 mg / m² up to 1.0 mg / m² ; with 1.0 mg / m²up to 0,7 mg / m² )
Non-hematological toxicity ≥ 3 degrees	The use of Milatib is delayed until the non-hematologic toxicity is reduced to 1 degree or to the original level. After this, treatment with Milatib can be resumed at a dose reduced by 1 step (s 1, 3 mg / m² before 1, 0 mg / m²; from 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 Milatib, the administration of the next dose is postponed and / or adjusted to the dose as described in the 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 and 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 Milatib 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 the dosage of medications used in combination with Milatib are given in the relevant instructions for medical use.

Recurrent multiple myeloma

The recommended dose when used in combination with pegylated liposomal doxorubicin

Guidance on dose and dose adjustment Milatib is described above in the section "Monotherapy". Pegylated liposomal doxorubicin is used at a dose of 30 mg / m on the 4th day of a 3-week cycle of Milatib preparation 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

Guidance on dose and dose adjustment Milatib is described above in the section "Monotherapy".

Dexamethasone is taken orally at a dose of 20 mg per day on the day of Milatib and the day following it.

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 Milatib therapy (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

Guidance on dose and dose adjustment Milatib is described above in the section "Monotherapy". It is necessary to conduct 6 cycles of therapy with bortezomib. In case the patient responds to therapy for the first time during the 6th cycle, two additional cycles of Milatib therapy are recommended. On the first day of each 3-week cycle of therapy with Milatib, 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 Milatib therapy cycle.

Correction of dose during therapy of previously untreated mantle cell lymphoma

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

- Platelet content should be ≥100000 / μL and absolute neutrophil count (ACH)> 1500 / μL;

- The concentration of hemoglobin should be ≥8 g / dL (≥ 4.96 mmol / d);

- 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-hematologic toxic effect of the third degree, with the exception of neuropathy, treatment with Milatib 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 <10,000 / μL	Therapy with Milatib should be suspended for up to 2 weeks before the moment when the patient will have the following indicators: AHN ≥750 / μL, platelet count ≥ 25,000 / μL - If, after suspension of therapy, toxicity is not permitted until the parameters described above, the therapy must be completely discontinued - If the toxicity is resolved to the following values: ACHN ≥ 750 / μL platelet content ≥ 25,000 / μl, the dose of Milatib should be reduced by one step (from 1.3 mg / m² up to 1.0 mg / m², or from 1.0 mg / m to 0.7 mg / m²)
- Platelet content <25000 / μL or ACHN <750 / μL on the day of Milatib drug administration (except for day 1)	Delay the introduction of Milatib
Non-hematological toxicity ≥ 3 degrees	The use of Milatib is delayed until the non-hematologic toxicity is reduced to grade 2 or lower. After this, treatment with Milatib 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 Milatib, 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 Milatib.Therefore, for patients with renal insufficiency, dose adjustment is not required. Since dialysis can reduce the concentration of Milatib in the blood, the drug should be administered after dialysis.

Patients with impaired liver function

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

Table 5. Recommended changes in the initial dose of Milatib in patients with hepatic impairment

Severity of hepatic impairment	Concentration of bilirubin	ACT activity	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	It is required to prescribe Milatib in a 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

Milatib 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 3.0 ml of 0.9% sodium chloride solution for a dosage of 3.0 mg and in 3.5 ml of 0.9% sodium chloride solution for a dosage of 3.5 mg. Accordingly, the concentration of the prepared solution for intravenous administration should be 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 an intravenous bolus injection of 3-5 seconds duration through a peripheral or central venous catheter, which is then washed with 0.9% sodium chloride solution for injection.

Preparation of a solution for subcutaneous administration

The contents of the vial are dissolved in 1.2 ml of a 0.9% solution of sodium chloride for a dosage of 3.0 mg and 1.4 ml of a 0.9% solution of sodium chloride for a dosage of 3.5 mg. Accordingly, the concentration of the prepared solution for subcutaneous administration should be 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), as well as areas where needle insertion is difficult.

In case of local reactions in the subcutaneous administration of Milatib, 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 3.0 ml of 0.9% sodium chloride solution for dosages of 3.0 mg and in 3.5 ml of 0.9% sodium chloride solution for a dosage of 3.5 mg).

Side effects:

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 (the frequency can not be estimated from the available data). In each frequency group, unwanted reactions are presented in order of decreasing severity.

Infections and invasions:

often - herpes simplex, surrounding herpes (incl.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 are 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 - hypermagnesia, acidosis, disturbance of water-electrolyte balance, excessive accumulation of fluid,hypochloremia, hypovolemia, hyperchloremia, hyperphosphatemia, metabolic disorders, vitamin B deficiency, vitamin B12 deficiency, gout, increased appetite, alcohol intolerance.

Mental disorders:

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.

Violation of the heart:

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, a feeling of tightness in the throat, dryness in the throat, increased secretion in the upper respiratory tract, irritation of the throat, cough syndrome of the upper respiratory tract.

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 (incl.gastrointestinal pain and pain in the spleen), disorders of the mouth, 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, tongue edema, ascites, oesophagitis, cheilitis, fecal incontinence, anal sphincter atony, fekaloma, ulceration, and perforation of the gastrointestinal tract, gingival hypertrophy, megacolon, discharge from the rectum, blisters in the throat, pain in the 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 (incl.hepatic 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;

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

rarely - skin reactions, lymphocytic infiltration of Jessner, palmar-plantar eritrodizesteziya, subcutaneous bleeding, livedo reticularis, skin induration, a papule, photosensitivity reactions, seborrhea, cold sweat, skin lesions, unspecified, erythrose, skin ulcer, nail infections.

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 to the injection site;

rarely - death (including sudden), multiple organ failure, bleeding at the injection site, hernia, disruption of healing processes, inflammation, phlebitis at the site of injection, tenderness, ulceration, irritability, non-cardial chest pain, pain at the site of the catheter, foreign body sensation.

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 (incl.augmentation QT), a change in prothrombin time, a decrease in the pH of gastric juice, an increase in platelet aggregation, an increase in troponin I concentration, a detection of viruses and a change in serology, a change in urine analysis.

Injury, 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:

Overdose exceeding the recommended dose more than 2 times, was accompanied in patients with acute lowering of arterial pressure and thrombocytopenia with fatal outcome.The specific antidote to Milatib is not known. In case of overdose, monitor the vital signs of the patient and conduct appropriate therapy to maintain blood pressure (infusion therapy, vasoconstrictor and / or inotropic drugs) and body temperature.

Interaction:

In studies in vitro and research in vivo bortezomib showed the properties of a weak inhibitor of cytochrome isoenzymes P450 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 strong inhibitor of isoenzyme CYP3A4 ketoconazole on the pharmacokinetics of Milatib, 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 strong inhibitor of isoenzyme CYP3A4 (ketoconazole, ritonavir).

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

Investigation of the effect of drug interaction with rifampicin - a strong isoenzyme inducer CYP3A4 - the pharmacokinetics of Milatib showed a decrease in the mean values AUC (area under the concentration-time curve) for bortezomib on average 45%. Therefore, it is not recommended to use Milatib preparation together with strong inducers 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 drug interaction with a combination of melphalan-prednisone 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 Milatib should be done only under the supervision of a doctor who has experience in the use of antitumor chemotherapy.

With the unintentional administration of Milatib, intrathecally, deaths were recorded.

The drug Milatib is indicated 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 Milatib 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 / mm3, therapy with Milatib 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 simultaneously with melphalan and prednisone, when the number of platelets ≤ 30000 / μl, therapy with Milatib 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 to death have been reported in patients taking Milatib. Patients diagnosed with PML received immunosuppressive therapy before or at the same time as Milatib. In most cases, PML was diagnosed within 12 months of the administration of the first dose of Milatib. 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 Milatib in case of diagnosis of PML.

Peripheral Neuropathy

Whenever neuropathy occurs, maintenance therapy is provided. Usually, the frequency of development of peripheral neuropathy reaches a maximum at the 5 cycle of treatment with Milatib. When new or worsening of the existing symptoms of peripheral neuropathy, a dose reduction and a change in the mode of administration of Milatib 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 injection of Milatib is lower than that of intravenous administration.

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 a neurological evaluation should be performed in patients taking Milatib in combination with drugs that can cause neuropathy (for example, thalidomide). Consideration should be given to 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

Therapy with Milatib 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 liver dysfunction, such as an increase in hepatic enzyme activity, hyperbilirubinemia or hepatitis, usually occurred when the drug Milatib was withdrawn. Data on the status of these patients after the resumption of therapy with Milatib is limited.

Patients with symptoms of liver dysfunction should be prescribed Milatib at 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 posterior reversible encephalopathy

Patients taking Milatib had reverse reversible encephalopathy syndrome - a rare, reversible neurologic disorder that may be accompanied by seizures, increased blood pressure, headache, lethargy, confusion, blindness and other visual and neurological impairments. To confirm the diagnosis, a magnetic resonance imaging of the brain is performed.When developing a syndrome of reverse reversible encephalopathy, stop taking Milatib. The safety of the resumption of therapy with Milatib after the previously identified reverse reversible encephalopathy syndrome is unknown.

Reactivation of the Herpes zoster virus

The treating physicians should consider the possibility of antiviral prophylaxis in patients receiving therapy with Milatib. In patients receiving therapy with Milatib, 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, using the Milatib preparation, acute diffuse infiltrative lung 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.

In clinical studies, 2 patients (out of 2) who received high doses of cytarabine (2 g / m² per day) by continuous infusion over 24 hours with daunorubicin and Milatib preparation for recurrent acute myeloid leukemia, died of acute respiratory distress syndrome at the beginning of the course of therapy, and the study was completed. Thus, this treatment regimen with simultaneous administration of high doses of cytarabine (2 g / m² per day) by continuous infusion within 24 hours is not recommended.

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 Milatib in patients who simultaneously take oral hypoglycemic drugs, you should carefully monitor the concentration of glucose in the blood 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.

When working with the drug Milatib should comply with the generally accepted rules for the treatment of cytotoxic drugs.

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.

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

Patients should be warned about the possibility of dizziness, fainting, visual disturbances and other undesirable effects that may affect the ability to drive vehicles during treatment with Milatib. When these symptoms occur to patients it is recommended to refrain from driving and practicing other potentially dangerous activities that require an increased concentration of attention and speed of psychomotor reactions.

Form release / dosage:

Lyophilizate for the preparation of solution for intravenous and subcutaneous administration, 3.0 and 3.5 mg.

Packaging:

The lyophilisate containing 3.0 or 3.5 mg of bortezomib is placed in vials of dark neutral glass.The vials are sealed with rubber stoppers and aluminum-plastic caps.

For 5.0 ml of the solvent (Sodium chloride, 0.9% injection) is placed in neutral glass ampoules with a ring or break point for dissection.

1 bottle with the drug, 1 ampoule with the solvent is placed in a contour cell packaging from a polyvinyl chloride film.

1 circuit cell pack and instructions for medical use are placed in a cardboard box.

The kit is designed for one injection.

Storage conditions:

Store in a dry, dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

The finished product should be stored at a temperature of no higher than 25 ° C, with normal illumination in the original vial or in a syringe no more than 8 hours.

Shelf life:

Lyophilizate: 3 years.

Solvent: 5 years.

Do not use after the expiration date indicated on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-004023

Date of registration:22.12.2016 / 19.01.2018

Expiration Date:22.12.2021

The owner of the registration certificate:FARM-SYNTHESIS, CJSC FARM-SYNTHESIS, CJSC Russia

Manufacturer: & nbsp

RAFARMA, JSC Russia

Company DEKO, LLC Russia

Representation: & nbspFARM-SYNTHESIS CJSC FARM-SYNTHESIS CJSC Russia

Information update date: & nbsp09.06.2018

Illustrated instructions

Instructions

Milatib (Milatib)