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

	2.5 mg	3.0 mg
Active substance:
Bortezomib in the form of three-dimensional boroksin (in terms of bortezomib in the form of a monomer)	2.5 mg	3.0 mg
Excipients:
D-Mannitol	25 mg	30 mg

Solvent: sodium chloride, solution for injection 0.9%;

Composition per ml:

Sodium chloride	0.009 g
Water for injections	up to 1.0 ml

Description:Lyophilizate: white or almost white, porous mass or powder.

Solvent: colorless, clear liquid.

Pharmacotherapeutic group:Antitumor agent

ATX: & nbsp

L.01.X.X.32 Bortezomib

Pharmacodynamics:

Bortezomib is a reversible inhibitor of chymotrypsin-like activity 26S-proteasomes of mammalian cells. 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.

Suppressing activity 26S-Proteasomes prevent 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 many experimental models in vivo Bortezomib causes a slowdown in tumor growth, including multiple myeloma.

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

Pharmacokinetics:

Suction

When intravenously sprayed with bortezomib in doses of 1.0 mg / m² and 1.3 mg / m² patients with multiple myeloma maximum concentrations (C_mOh) bortezomib in blood plasma are correspondingly 57 ng / ml and 112 ng / ml. With the subsequent introduction of bortezomib, the maximum plasma concentrations are in the range of 67-106 ng / ml for a dose of 1.0 mg / m² and 89-120 ng / ml for a dose of 1.3 mg / m². When administered at a dose of 1.3 mg / m² subcutaneously or intravenously to patients with multiple myeloma, the total systemic exposure after repeated administration at the same dose (AUC_last) was equivalent for both administration routes (155 ng^xh / ml with subcutaneous administration and 151 ng^xh / ml with intravenous administration), C_mOh Bortezomib after subcutaneous administration (20.4 ng / ml) is 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_mOhwas 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 / 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.

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. The metabolites of bortezomib do not inhibit the 26S-proteasome.

Excretion

The average half-life of bortezomib with repeated administration is 40-193 hours. The drug is quickly withdrawn after the first dose compared with subsequent administrations. After the first administration in doses of 1.0 mg / m² and 1.3 mg / m² the average overall clearance is 102 l / h and 112 l / h, respectively, and after subsequent injections, respectively, 15-32 l / h.

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

Pharmacokinetics in selected patient groups

The influence of age, sex, and race on the pharmacokinetics of bortezomib has not been studied.

Patients with hepatic impairment

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 with patients with normal liver function. For patients with impaired liver function of moderate and severe degree, a reduction in the initial dose of bortezomib and dynamic observation is recommended.

Patients with impaired renal function

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:

- Multiple myeloma;

- mantial cell lymphoma in patients who have previously received at least 1 treatment line.

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 CYP3A4 (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, oral hypoglycemic drugs.

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:

A drug Boramilan® is indicated only for intravenous and subcutaneous administration.

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 must be calculated very carefully.

Do not enter intrathecally. With intrathecal administration of bortezomib, deaths are possible.

Monotherapy

Boromylan® injected intravenously in a jet for 3-5 seconds or subcutaneously. 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 administration of consecutive doses of the drug Boromylan® must pass 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.

With a treatment duration of more than 8 cycles Boromylan® can be used according to the standard scheme or according to the scheme of maintenance therapy - weekly for 4 weeks (days 1, 8, 15, 22) followed by a 13-day rest period (days 23-35).

Patients with drug therapy Boromylan® did not give a clinical response (progression or stabilization of the disease after 2 or 4 cycles, respectively), a combination of Boramylan® with high doses of dexamethasone may be prescribed.In this case, 40 mg dexamethasone is administered orally to each dose of Boromylan®: 20 mg per day of administration of Boramylan® and 20 mg the day after the administration of Boramylan®. Thus, dexamethasone is given on days 1, 2, 4, 5, 8, 9, 11 and 12, totaling 160 mg in 3 weeks.

Recommendations for dose adjustment and administration of the drug Boromylan®

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 the drug Boramilan® should be suspended. After the disappearance of symptoms of toxicity, drug treatment Boromylan® 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 there is a drug associated with the use Boromylan® neuropathic pain and / or peripheral sensory neuropathy, the dose of the drug is changed in accordance with Table 1. Patients with a history of severe neuropathy Boromylan® It can only be used after a thorough assessment of the risk / benefit ratio.

Table 1. Recommended dose change for drug-induced development Boromylan® 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 does not require correction
1st degree with pain or 2nd degree (impaired function, but not daily activity)	Reduce the dose to 1.0 mg / m²
2nd degree with pain or grade 3 (violation of daily activity)	Suspend the use of the drug Boromylan® until the disappearance of symptoms of toxicity. After that, resume treatment, lowering the dose of the drug Boromylan® up 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)	Discontinue use of the drug Boromylan®

Patients with impaired renal function

The degree of renal dysfunction does not affect the pharmacokinetics of the drug Boromylan®. Therefore, for patients with renal insufficiency, dose adjustment is not required, Boromylan® should be administered after dialysis, because Dialysis can reduce the concentration of the drug in the blood plasma.

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 Boramilan® in a reduced dose (see Table 2).

Table 2. Recommended changes in the initial dose of the drug Boramilan® in patients with impaired hepatic function

Severity of hepatic impairment	Concentration bilirubin	Activity ACT *	Change in the initial dose
Lightweight	≤1,0x VGN	> VGN **	Not required
Lightweight	> 1.0x - 1.5x VGN	Any	Not required
Average	> 1,5х - 3хВГН	Any	It is required to prescribe Boromalan® at a reduced dose of 0.7 mg / m²during 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	> 3x VGN	Any

* AST - aspartate aminotransferase

** VGN - the upper limit of the norm

Combination Therapy

Recommended dose

Boromylan® injected intravenously in a jet for 3-5 seconds or subcutaneously in combination with melphalan and prednisolone taken internally.Nine six-week cycles are carried out, as shown in Table 3. In cycles 1 to 4 Boromylan® apply 2 times a week (days 1, 4, 8, 11, 22, 25, 29 and 32), and in cycles 5-9 - once a week (days 1, 8, 22 and 29).

Table 3. Recommended dosage regimen Boromylan®, used in combination with melphalan and prednisolone in patients with previously untreated multiple myeloma

Boromylan® 2 times a week (cycles 1-4)
A week	1					2		3	4		5		6
Boromylan® (1.3 mg / m²)	day 1		--	--	day 4	day 8	day 11	period recreation	day 22	day 25	day 29	day 32	period recreation
Melphalan (9 mg / m²) + Prednisolone (60 mg / m²)	day 1		day 2	day 3	day 4	--	--	period recreation	--	--	--	--	period recreation
Boromylan® Once a week (cycles 5-9)
A week	1					2		3	4		5		6
Boromylan® 1.3 mg / m²	day 1	--		--	--	Day 8		period recreation	day 22		Day 29		period recreation
Melphalan (9 mg / m²) + Prednisolone (60 mg / m²)	day 1	day 2		day 3	day 4	--		period recreation	--		--		period recreation

Recommendations for dose adjustment in combination therapy

Correction of the dose and the regimen of application when the drug is used Boromylan® together with melphalan and prednisolone

Before the start of a new treatment cycle:

- the platelet count should be> 70,000 / μL;

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

- non-hematological toxicity should be reduced to 1 degree or to the initial level.

Table 4. Correction of dose in subsequent treatment cycles

Toxicity	Correction or delay of dose
Hematologic toxicity during the previous cycle:
Prolonged neutropenia or thrombocytopenia of the 4th degree, 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 drug administration Boromylan® (except for day 1)	Delay the introduction of the drug Boromylan®
Several postponements of drug administration Boromylan® in one cycle (> 3 times when administered 2 times a week or ≥2 times when administered once a week)	Dose of the drug Boromylan® 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 ≥ 3rd degree	Application of the drug Boromylan® postpone to reduce non-hematologic toxicity to 1 degree or to the original level. After this treatment with the drug Boromylan® can be resumed in a dose reduced by 1 step (from 1.3 mg / m² up to 1.0 mg / m²; from 1.0 mg / m to 0.7 mg / m²). With the development of neuropathic pain and / or peripheral neuropathy associated with the use of the drug Boramilan®, the administration of the next dose is postponed and / or dose adjusted, as described in Table 1.

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

Mode of application

Boramilan® 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. Chemical and physical stability is maintained for 8 hours at a temperature of no higher than 25 ° C when stored in an original vial or syringe under natural light. From the microbiological point of view, the prepared solution should be used immediately. In the event that the preparation has not been used immediately, the consumer is responsible for observing the terms and conditions of storage after dissection prior to use.

Preparation of a solution for intravenous administration

Contents of the vial with a dosage of 2.5 mg are dissolved in 2.5 ml of 0.9% sodium chloride solution, and the contents of the vial with a dosage of 3.0 mg are dissolved in 3.0 ml of 0.9% sodium chloride solution.The concentration of the prepared solution for intravenous administration should be 1 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% sodium chloride solution for injection.

Preparation of a solution for subcutaneous administration

The contents of the vial with a dosage of 2.5 mg are dissolved in 1.0 ml of 0.9% sodium chloride solution, and the contents of the vial with a dosage of 3.0 mg are dissolved in 1.2 ml of 0.9% sodium chloride solution. 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 (right and 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 the case of local reactions in the subcutaneous administration of the drug Boromylan® a less concentrated solution for subcutaneous administration may be used (1 mg / ml instead of 2.5 mg / ml, for this purpose, the contents of the 2.5 mg dose vial are dissolved in 2.5 ml of 0.9% sodium chloride solution, and the contents of the dosage vial 3.0 mg is dissolved in 3.0 ml of 0.9% sodium chloride solution) or switch to intravenous administration of the drug Boramilan®.

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.

Most often during the therapy with bortezomib, the following undesirable reactions were noted: nausea, diarrhea, constipation, vomiting, fatigue, pyrexia, thrombocytopenia, anemia, neutropenia, peripheral neuropathy (incl.sensory), headache, paresthesia, decreased appetite, dyspnea, rash, herpes zoster and myalgia.

The following are undesirable side effects that were regarded as likely or possibly related to the use of bortezomib. The frequency of adverse reactions that may occur during therapy is given in the following gradation: very often (> 1/10), often (> 1/100, <1/10), infrequently (> 1/1000, <1/100), rarely (> 1/10000, <1/1000), very rarely (<1/10000, included separate messages) and an unknown frequency (the frequency can not be calculated from the available data).

Infectious and parasitic diseases:

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

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

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

Benign, malignant and unspecified neoplasms (including cysts and polyps):

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

Violations of the blood and lymphatic system:

very often - thrombocytopenia, neutropenia, anemia;

often - Lakopenia, 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 - syndrome of Itenko-Cushing, hyperthyroidism, violation of the secretion of antidiuretic hormone;

rarely hypothyroidism.

Disorders from the metabolism and nutrition:

Often - decreased appetite;

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

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

rarely - hypermagnesia, acidosis, disturbance of water-electrolyte balance, excessive accumulation of fluid, hypochloraemia, hypovolemia, hyperchloremia, hyperphosphatemia, metabolic disorders, deficiency of B vitamins, vitamin deficiency AT₁₂, gout, increased appetite, alcohol intolerance.

Disorders of the psyche:

often - disorders and mood disorders, anxiety, disorders 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:

Often - Neuropathy, peripheral sensory neuropathy, dysesthesia, neuralgia;

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

infrequently - tremor, peripheral sensorimotor neuropathy, dyskinesia, imbalance, memory loss (excluding dementia), encephalopathy, reverse reversible encephalopathy syndrome, neurotoxicity, seizures, postherpetic neuralgia, speech disorder, restless legs syndrome, migraine, sciatica, attention deficit disorder , pathological reflexes, parosmia;

rarely - intracerebral hemorrhage, intracranial hemorrhage (including subarachnoid), cerebral edema, transient ischemic attack, coma, autonomic nervous system imbalance, autonomic neuropathy, cranial nerve paralysis, paralysis, paresis, presyncope, brainstroke syndrome, cerebrovascular accident , radicular syndrome, psychomotor hyperactivity, spinal cord compression, cognitive disorders, movement disorders, nervous system disorders, radiculitis, salivation, muscle hypotension.

Disorders from the side of the organ of vision:

often - edema of the eye, visual impairment, conjunctivitis;

infrequently - eye hemorrhage, pectitis, eye inflammation, diplopia, dry eyes, eye irritation, eye pain, increased lacrimation, discharge from the eyes;

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

Hearing disorders and labyrinthine disturbances:

often - vertigo;

infrequently - 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 (including exudative pericarditis), cardiomyopathy, ventricular dysfunction, bradycardia;

rarely - atrial flutter, myocardial infarction, atrioventricular blockade, cardiovascular disorders (incl.cardiogenic shock), arrhythmia ventricular tachysystolic type "pirouette," unstable angina, heart valve disease, coronary insufficiency, stopping the sinus node.

Vascular disorders:

often - lowering of blood pressure, orthostatic hypotension, increased 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, chest and mediastinal organs:

often - shortness of breath, nosebleeds, upper and lower respiratory infections, cough; infrequently - pulmonary embolism, pleural effusion, pulmonary edema (including acute), pulmonary alveolar hemorrhage, bronchospasm, chronic obstructive pulmonary disease, hypoxemia, respiratory obstruction, hypoxia, pleurisy, hiccough, rhinorrhea, dysphonia, wheezing;

rarely Atherosclerosis, 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, lung infiltration, feeling 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:

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), abdominal discomfort, ulceration of the oral mucosa, enteritis, gastritis, gum bleeding, gastroesophageal reflux disease , colitis (including,pseudomembranous colitis), ischemic colitis, inflammation of the mucous membrane of the gastrointestinal tract, dysphagia, irritable bowel syndrome, gastrointestinal disorders, plaque in the tongue, motility disorder of the digestive tract, 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 lips, periodontitis, anal fissure, change in the rhythm of defecation, procalgia, stool disorders.

Disorders from the liver and bile ducts:

often - change 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 tissues:

often - rash, itching, erythema, dry skin;

infrequently - 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, bedsores, acne, blisters, skin pigmentation disorder;

rarely - skin reactions, 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 damage.

Disturbances from the musculoskeletal and connective tissue:

Often - musculoskeletal pain;

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

infrequently - Muscular twitching, swelling of the joints, arthritis, joint stiffness, myopathy, sensation of heaviness;

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

Disorders from the kidneys and urinary tract:

often - impaired renal function;

infrequently - acute renal failure, chronic renal failure, urinary tract infections, complaints of the urinary tract, hematuria, urinary retention, impaired micturition, proteinuria, azotemia, oliguria, pollakiuria;

rarely irritation of the bladder.

Violations from the part of the genitals and the breast:

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

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

Congenital, hereditary and genetic disorders:

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

General disorders and disorders at the site of administration:

Often - Pyrexia, increased fatigue, asthenia;

often - edema (including peripheral), chills, pain, discomfort;

infrequently - deterioration in overall physical health, facial swelling, reactions at the injection site, mucosal disorders, chest pain, gait disturbance, cold feeling, extravasation, complications from the use of the catheter, a change in thirst, discomfort in the chest, sensation of body temperature changes , pain at 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-cardiac pain in the chest, pain at the site of catheter injection, sensation foreign body.

Laboratory and instrumental data:

often - lowering of body weight;

infrequently - hyperbilirubinemia, changes in protein indexes, increase in body weight, changes in blood levels, increased concentration of C-reactive protein;

rarely - change 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 I concentration, a detection of viruses and a change in serology, a change in urine analysis.

Trauma, intoxication and complications of manipulation:

infrequently - falls, concussion;

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

Surgical and therapeutic manipulations:

rarely - activation of macrophages.

Patients with mantle cell lymphoma

Safety indices of bortezomib the these patients are 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 to patients with mantle cell lymphoma; and peripheral neuropathy, rash and itching - in patients with mantle cell lymphoma.

Overdose:

Overdose exceeding the recommended dose of more than 2 times, accompanied by an acute decrease in blood pressure and thrombocytopenia with a fatal outcome.

The specific antidote to bortezomib is not known. In case of an 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.

Study of drug interaction with a strong inhibitor of isoenzyme CYP3A4 ketoconazole showed an increase in mean values AUC Bortezomib on average by 35%. Therefore, 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 bortezomib, there was 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 bortezomib showed a decrease in mean values AUC Bortezomib on average by 45%. Therefore, do not use the drug Boramilan® together with strong 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 drug interaction of bortezomib with a combination of melphalan-prednisolone showed an increase in the mean values AUC 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 documented.

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 drug Boramilan® should only be carried out under observation a doctor with experience in the use of antitumor chemotherapy.

Medicinal preparation Boramilan® is intended for intravenous and subcutaneous administration only. Do not enter intrathecally.When unintentional administration of bortezomib was intrathecally recorded, deaths occurred.

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

Thrombocytopenia

Most often in the treatment with bortezomib, transient thrombocytopenia is observed, with the smallest number of platelets usually observed on the 11th day of the cycle. The cycle periodicity of the decrease and increase in the number of platelets is observed during all 8 cycles with the application of the drug 2 times a week, thus, there is no evidence of increasing thrombocytopenia. With a decrease in the number of platelets <25000 / μL therapy with the drug Boramilan® should be paused. 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 prednisolone, when the amount of platelets is <30000 / μl, drug therapy Boramilan® should be paused.

Gastrointestinal disorders

To prevent nausea and vomiting, antiemetics are recommended. When diarrhea occurs, antidiarrhoeic medicines are prescribed. To prevent or treat dehydration, patients need to undergo 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 receiving bortezomib therapy. Patients diagnosed with PML received immunosuppressive therapy before or simultaneously with the use of bortezomib. In most cases, PML was diagnosed within 12 months of the first dose of bortezomib.

Patients should be monitored on a regular basis for occurrence or deterioration neurologic 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 the drug Boromylan® in the case of diagnosing PML.

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 of the existing symptoms of peripheral neuropathy may occur, a dose reduction and a change in the mode of administration of the drug may be required Boromylan®. 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.

Early and regular monitoring for symptoms of neuropathy with a neurological evaluation should be performed in patients receiving drug therapy Boramilan® 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, an anamnesis describes infrequent cases of seizures. In the treatment of 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. Patients who have a history of syncope, diabetic neuropathy, those receiving antihypertensive drugs, as well as patients with dehydration with diarrhea or vomiting should be careful. Patients should be instructed about the need to consult a doctor in case of dizziness, a feeling of "lightness in the head" or fainting. With the development of orthostatic hypotension, hydration, the administration of glucocorticosteroids 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 Boramilan® at lower initial doses and monitor for toxicity, since bortezomib is metabolized by hepatic enzymes and its concentration may increase if the liver function of moderate and severe severity (see section "Method of administration and dose").

Cindra of the posterior reversible leukoencephalopathy

Patients receiving bortezomib therapy had a syndrome of a posterior reversible leukoencephalopathy - 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. With the development of the syndrome of posterior reversible leukoencephalopathy, the drug should be discontinued Boramilan®. The safety of the resumption of bortezomib therapy after the previously identified syndrome of posterior reversible leukoencephalopathy is unknown.

Reactivation of the virus Herpes zoster

Consider the possibility of antiviral prophylaxis in patients receiving bortezomib therapy. In patients receiving therapy with bortezomib, melphalan and prednisolone, the frequency of reactivation of the virus Herpes zoster was greater in comparison with patients receiving melphalan and prednisolone (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 lung diseases of unknown etiology, such as pneumonitis, interstitial pneumonia, pulmonary infiltration and acute respiratory failure syndrome are 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 appoint patients appropriate treatment.

Treatment regimen with simultaneous administration of high doses of cytarabine (2 g / m² per day) by continuous infusion within 24 hours is not recommended, t. cases of death from an acute respiratory distress syndrome at the beginning of a course of therapy with the administration of high doses of cytarabine (2 g / m² per day) by continuous infusion over 24 hours with daunorubicin and bortezomib to treat relapsing acute myeloid leukemia.

Tumor lysis syndrome

In connection with the possible development of hyperuricemia associated with tumor lysis syndrome, patients during therapy are recommended to determine the concentration of uric acid and creatinine in the blood plasma.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 the concentration of glucose in the blood and, if necessary, adjust the dose of hypoglycemic drugs.

During the treatment with bortezomib of any of the sexual partners, it is recommended to use reliable methods of contraception.

When working with the drug Boramilan® should follow 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:

Some side effects of the drug, such as dizziness, fainting, visual disturbances and other unwanted reactions can adversely affect the ability to drive and perform potentially hazardous activities,requiring increased concentration of attention and speed of psychomotor reactions.

Patients should be warned about the possible occurrence of these symptoms during drug treatment Boramilan®. If these symptoms occur, patients are advised to refrain from driving and performing potentially dangerous activities requiring increased concentration and speed of psychomotor reactions.

Form release / dosage:

Lyophilizate for the preparation of a solution for intravenous and subcutaneous administration, 2.5 mg and 3.0 mg.

Packaging:

2.5 mg and 3.0 mg bortezomib in dark glass bottles with a capacity of 10 ml, hermetically sealed with rubber stoppers and aluminum-plastic caps. On the vials stick a self-adhesive label.

For 5 ml of solvent in ampoules of neutral glass grade HC-1. On the ampoules paste a self-adhesive label.

1 bottle with a preparation complete with 1 ampoule of solvent or without solvent is packaged in a contiguous cell pack of a polyvinyl chloride film or a polyethylene terephthalate film.

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

When the preparation is equipped with a solvent packed into ampoules, which do not have a tension ring for opening, or in ampoules without a break point, a knife is inserted into the pack for opening ampoules or an ampoule scarifier.

Storage conditions:

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

After reconstitution, the solution should be stored at a temperature of no higher than 25 ° C, under natural light, in the original vial or in a syringe, no more than 8 hours.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:LP-003210

Date of registration:22.09.2015 / 04.08.2016

Expiration Date:22.09.2020

The owner of the registration certificate:NATIVA, LLC NATIVA, LLC Russia

Manufacturer: & nbsp

NATIVA, LLC Russia

Information update date: & nbsp19.02.2017

Illustrated instructions

Instructions

Boromylan® (Boramilan®)