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

Active substance:
Bortezomib in the form of three-dimensional boroksin	3.336 mg
in terms of bortezomib in the form of a monomer	3.5 mg
Excipient: mannitol	35.0 mg

Description:

Lyophilized mass or powder of white or almost white color.

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.This proteasome is a large protein complex that cleaves proteins conjugated to ubiquitin. The ubiquitin-proteasome pathway plays a key role in regulating the intracellular concentration of certain proteins and, thus, supports intracellular homeostasis. Suppression of proteasome activity prevents this selective proteolysis, which can affect many cascades of signal transduction reactions in the cell. Violation of the mechanism of maintaining homeostasis can lead to cell death, in vivo bortezomib caused a slowdown in tumor growth in many experimental models, including multiple myeloma.

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

Pharmacokinetics:

When intravenously sprayed with bortezomib in doses of 1.0 mg / m² and 1.3 mg / m²patients with multiple myeloma maximum concentrations (C_mOh) in the plasma are respectively 55-60 ng / ml and 110-115 ng / ml.With the subsequent administration of bortezomib, the maximum plasma concentrations are in the range of 60-110 ng / ml for a dose of 1.0 mg / m² and 85-125 ng / ml for a dose of 1.3 mg / m². The average half-life of bortezomib with repeated administration is 40-193 hours.

Bortezomib is quickly excreted 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 overall clearance is 102 l / h and 112 l / h, respectively, and after subsequent injections, respectively, 15-32 l / h.

When administered at a dose of 13 mg / m² subcutaneously or intravenously to patients with multiple myeloma, the total systemic exposure after repeated administration at the same dose was equivalent for both routes of administration. FROM_mOh after subcutaneous administration (20.4 ng / ml) was lower than after intravenous administration (223 ng / ml).

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%.

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.

Impact age, sex and race the pharmacokinetics of bortezomib has not been studied.

In patients with impaired liver function of moderate and severe severity there are 60% an increase in LPS (area under the concentration-time curve) of bortezomib compared with 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.

Mild hepatic dysfunction do not affect the pharmacokinetics of bortezomib.

Pharmacokinetics of bortezomib in doses of 0.7-1.3 mg / m² intravenously 2 times a week In patients with mild, moderate or severe impairment of renal function, 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 previously received at least 1 line of therapy.

Contraindications:

- Hypersensitivity to bortezomibu, boron and mannitol;

- 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);

- pregnancy and the period of breastfeeding;

- Children and adolescence under 18 years (no experience of use).

Carefully:

- Hepatic and moderate liver function abnormalities;

- severe renal dysfunction;

- seizures or epilepsy in the anamnesis;

- fainting;

- a history of diabetic neuropathy;

- 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 Bartizar® during pregnancy and during breastfeeding is contraindicated.

For the duration of treatment, stop breastfeeding.

Dosing and Administration:

Bartizar® in a dosage of 3.5 mg is indicated for intravenous administration 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 concentration of the solution for intravenous administration and the solution for subcutaneous administration.

Monotherapy

Bartizar® is administered intravenously (iv) for 3-5 seconds or subcutaneously (sc). The recommended dose of Bartizar® is 1.3 mg / m² body surface area twice a week for 2 weeks (days 1, 4, 8 and 11), followed by a 10-day break (days 12-21). Between the introduction of consecutive doses of the drug Bartizar® should 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.

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

Patients in whom Bartizar® therapy did not show a clinical response (progression or stabilization of the disease after 2 or 4 cycles, respectively), a combination of high doses of dexamethasone with bortezomib can be prescribed. In this case, 40 mg of dexamethasone is given orally with each dose of Bartizar®: 20 mg on the day of administration and 20 mg the day after bortezomib. 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 Bartizar®

With the development of any non-hematologic toxic effect of the 3rd degree or hematological toxicity of the 4th degree, with the exception of neuropathy, treatment with Bartizar® should be stopped. After the disappearance of symptoms of toxicity treatment with the drug 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). If the toxicity symptoms do not disappear or reappear at the lowest dose, then the possibility of discontinuing Bartizar® should be considered, unless the benefits of its use clearly exceed the risk.

When Bartizar® neuropathic pain and / or peripheral sensory neuropathy are associated with the drug, the dose of the drug is changed in accordance with Table 1. In patients with severe neuropathy in history, Bartizar® can only be used after a thorough assessment of the risk / benefit ratio.

Table 1. Recommended dose change in the development of drug-induced Bartizar® 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
2nd degree with pain or grade 3 (violation of daily activity)	Suspend the use of the drug Bartizar® until the disappearance of symptoms of toxicity. After this, resume treatment, lowering the dose to 0.7 mg / m² and reducing the frequency of administration to once a week
4th degree (sensory neuropathy, resulting in disability or motor neuropathy, threatening life or resulting in paralysis)	Discontinue use of the drug Bartizar®

Patients with impaired renal function

The degree of impaired renal function does not affect the pharmacokinetics of the drug Bartizar®. For patients with renal insufficiency, dose adjustment is not required. Dialysis may reduce the concentration of bortezomib in the blood, so Bartizar® should be administered after dialysis.

Patients with hepatic impairment

In patients with mild liver function disorders, no change in the initial dose is required. The recommended dose should be given. Patients with impaired liver function of moderate and severe degree should be assigned Bartizar® in a reduced dose (Table 2).

Table 2. Recommended changes in the initial dose of the drug Bartizar® 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	> 1.5x - 3x VGN	Any	Required to appoint Bartizar® in 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

Bartizar® 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 Bartizar® 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 Bartizar®, used in combination with melphalan and prednisolone in patients with previously untreated multiple myeloma

Bartizar® 2 times a week (cycles 1-4)

A week

Bartizar®

1.3 mg / m²

day

period

recreation

day

period

recreation

Melphalan

9 mg / m²

Prednisolone

60 mg / m²

day

period

recreation

Bartizar® once a week (cycles 5-9)

A week

Bartizar®

1.3 mg / m²

day

Day 8

period

recreation

day 22

Day 29

period

recreation

Melphalan

9 mg / m²

Prednisolone

60 mg / m²

day

period

recreation

Recommendations for dose adjustment in combination therapy

Before the start of a new treatment cycle:

- the platelet count should be> 70x10⁹/ l,

- absolute neutrophil count (ASN)> 1.0x10⁹/ l,

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

Table 4. Dose adjustments for 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 ≤30x10⁹/ l, or ASN ≤ 0.75x10⁹/ l, on the day of drug administration Bartizar® (except for day 1)	Delay the introduction of the drug Bartizar®
Several postponements of drug administration Bartizar® in one cycle (> 3 times when administered 2 times a week or ≥2 times when administered once a week)	Dose of the drug Bartizar® 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 Bartizar® postpone to reduce non-hematologic toxicity to 1 degree or to the original level. After this treatment with the drug 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 Bartizar®, the administration of the next dose is postponed and / or dose adjusted, as described in Table 1.

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

Method of preparation and introduction of the plantinRand nBartizar®

The preparation and administration of Bartizar® should be carried out by medical personnel trained in the safe handling of cytotoxic drugs. To prevent direct contact with the drug, personal protective equipment (gown, gloves, mask, etc.) should be used.

The drug should not be mixed with other medicines, with the exception of 0.9% sodium chloride solution. The drug solution Bartizar® should be clear and colorless.If a mechanical inclusion or color change is detected, the prepared solution can not be used.

For intravenous administration

The contents of the Bartizar® bottle (3.5 mg of bortezomib in the vial) are dissolved in 3.5 ml of 0.9% sodium chloride solution.

The concentration of the prepared solution for intravenous administration is 1.0 mg / ml. The resulting solution is administered by a 3-5 second intravenous injection through peripheral or central venous catheter, which is then washed with 0.9% sodium chloride solution for injection.

For subcutaneous administration

The contents of the Bartizar® bottle (3.5 mg of bortezomib in the vial) are dissolved in 1.4 ml of 0.9% sodium chloride solution. The concentration of the prepared solution for subcutaneous administration is 2.5 mg / ml.

The 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 my administration of the drug. Each subsequent injection should be administered at a distance of at least 2.5 cm from the site of the previous injection. Do not administer the drug to sensitive areas, damaged areas (redness, bruises), or in areas where needle insertion is difficult.

In case of local reactions in the subcutaneous administration of Bartizar®, a less concentrated solution for subcutaneous administration (1 mg / ml instead of 2.5 mg / ml) or switch to intravenous administration of the drug can be used.

Side effects:

The safety indices of bortezomib when used in monotherapy are similar to those for bortezomib in combination with melphalan and prednisone.

Serious adverse reactions were rarely observed during bortezomib therapy and included heart failure, tumor lysis syndrome, pulmonary hypertension, reversible rear encephalopathy syndrome, acute diffuse infiltrative pulmonary diseases.

In addition, in rare cases, vegetative neuropathy was observed.

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

The following are side effects that were regarded as likely or possibly related to the use of bortezomib.

Side effects are grouped according to the frequency of occurrence: very often (> 1/10), often (≥ 1/100 to <1/10), infrequently (≥ 1/1000 to <1/100), rarely (≥ 1/10000 to < 1/1000), very rarely (<1/10000), the frequency is unknown.

Infectious and parasitic diseases:

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

rarely bacterial, viral infections, sepsis (including septic shock), bronchopneumonia, herpesvirus infection, herpetic meningoencephalitis, bacteremia (including staphylococcal), barley, influenza, inflammation of subcutaneous fat, skin infections, ear infections, staphylococcal infections , dental infections;

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

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

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

On the part of the blood and lymphatic system:

very often - thrombocytopenia, neutropenia, anemia;

often - leukopenia, lymphopenia;

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

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

From the immune system:

infrequently - Quincke's edema, hypersensitivity;

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

From the endocrine system:

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

rarely - hypothyroidism.

From the side of metabolism and nutrition:

very often - a decrease in appetite;

often - dehydration, hypokalemia, hyponatremia, hyperglycemia, changes in enzyme activity;

infrequently - tumor lysis syndrome, lack of weight gain, hypomagnesemia, hypophosphatemia, hyperkalemia, hypercalcemia, hypernatremia, hyperuricemia, diabetes mellitus, fluid retention, cachexia, hypocalcemia, hypoglycemia, weight loss;

rarely - hypermagnesia, acidosis, water-electrolyte balance disturbance, excessive fluid accumulation, hypochloraemia, hypovolemia, hyperchloremia, hyperphosphatemia, metabolic disorders, deficiency of B vitamins, vitamin B deficiency12, gout, alcohol intolerance, weight gain.

Disorders of the psyche:

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

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

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

From the nervous system:

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

often - motor neuropathy, loss of consciousness (including syncope..), dizziness, dysgeusia, fatigue, 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 - cerebral hemorrhage, intracranial hemorrhage (including subarachnoidal), cerebral edema, transient ischemic attack, coma, imbalance of the autonomic nervous system, autonomic neuropathy, cranial nerve paralysis, paralysis, paresis, presyncope, lesions of the brainstem syndrome, cerebral circulation, radicular syndrome, psychomotor hyperactivity, spinal cord compression, cognitive disorders, movement disorders, nervous system disorders, radiculitis, salivation, hypotension we шц.

From the side of the organ of vision:

often - periglacial edema, visual impairment, conjunctivitis, decreased vision;

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

rarely - corneal lesions, exophthalmos, retinitis, scotoma, eye lesions (including age), dacryoadenitis, photophobia, photopsy. optic neuropathy, blindness.

From the side of the hearing organ and labyrinthine disorders:

often - vertigo;

infrequent - ringing in the ears, hearing impairment (to deafness), discomfort in the ear;

rarely bleeding, vestibular neuronitis, impaired ear.

From the heart:

often cardiac arrest, cardiovascular disorders (including cardiogenic shock), myocardial infarction, angina pectoris, development and exacerbation of chronic heart failure, ventricular hypokinesia, sinus node arrest, atrioventricular blockade, tachycardia (including sinus and supraventricular), arrhythmia, atrial fibrillation, palpitation;

infrequent atrial flutter, bradycardia, cardiopulmonary shock, cardiac fibrillation (including atrial fibrillation), pericarditis (including exudative pericarditis), cardiomyopathy, ventricular dysfunction;

rarely - reduction of the fraction of the left ventricular ejection, cardiac tamponade, arrhythmia, ventricular tachysystolic type "pirouette", unstable angina, heart valve disease, coronary insufficiency.

From the side of the vessels:

often - lowering blood pressure, orthostatic and postural hypotension, phlebitis, hematoma (including perirenal), increasing blood pressure;

infrequently - vasculitis, stroke, petechiae, ecchymosis, purpura, change in the color of veins,swelling of the veins, bleeding of wounds, blood flushes, deep vein thrombosis, thrombophlebitis, bleeding, circulatory collapse (including hypovolemic shock), decreased peripheral circulation, hyperemia (including ocular);

rarely - pulmonary embolism, peripheral vascular embolism, lymphedema, pallor, erythromelalgia, vasodilation, venous insufficiency.

From the respiratory system, chest and mediastinum:

very often - shortness of breath;

often shortness of breath during physical exertion, epistaxis, cough, rhinorrhea, upper and lower respiratory infections;

infrequent - stopping breathing, hypoxia, pleural effusion, pulmonary edema (including acute), bronchospasm, respiratory alkalosis, tachypnea, wheezing, nasal congestion, hoarseness, rhinitis, hyperventilation of the lungs, orthopnea, pain in the chest, pain in the paranasal sinuses, a feeling of tightness in the throat, hemoptysis, chronic obstructive pulmonary disease, hypoxemia, pleurisy, dysphonia;

rarely - pneumonitis, pneumonia (including interstitial), acute respiratory failure syndrome, acute diffuse infiltrative lung injury,pulmonary hypertension, respiratory failure, alveolar hemorrhage in the lung, acute respiratory distress syndrome, pneumothorax, atelectasis, pulmonary fibrosis, bronchial dysfunction, interstitial lung disease, hypocapnia, dryness in the throat, increased secretion in the upper respiratory tract, throat irritation, cough upper respiratory tract syndrome.

From the gastrointestinal tract:

very often - nausea, vomiting, diarrhea, constipation;

often - pain in the abdomen, stomatitis, dyspepsia, loose stools, flatulence, hiccough, pain in the throat and pharynx, disorders of the oral cavity;

infrequently - pancreatitis (including chronic), paralytic intestinal obstruction, colitis, melena, bleeding from the gastrointestinal tract, enteritis, dysphagia, belching, pain in the spleen, esophagitis, gastritis, gastroesophageal reflux, petechia of the oral mucosa, hypersecretion of the salivary glands , plaque on the tongue, discoloration of the tongue, ulceration in the tongue, increased appetite, vomiting of blood, puffiness of the lips, discomfort in the abdomen, ulceration of the oral mucosa, bleeding from the gums, pseudomembranous colitis, inflammation of the gastrointestinal mucosa, shenie GI motility, irritable bowel syndrome;

rarely ischemic colitis, peritonitis, edema of the tongue, ascites, 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 crack, change in the rhythm of defecation, procalgia, stool disorders.

From the side of the liver and bile ducts:

infrequently - hepatitis, hemorrhage in the liver, hypoproteinemia, hyperbilirubinemia, increased activity of alanine aminotransferase and aspartate aminotransferase, hepatotoxicity, cholestasis;

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

From the skin and subcutaneous fabrics:

very often - skin rash;

often - hives, itching rash, itching, redness, increased sweating, dry skin, eczema;

infrequent erythema multiforme, erythema rash, photosensitivity, bruise, general itching, macular rash, papular rash, psoriasis, generalized rash, eyelid swelling, face swelling, dermatitis, alopecia, nail damage, skin pigmentation change, atopic dermatitis,changes in hair structure, night sweats, ichthyosis, nodules on the skin, toxic skin rash, skin lesions, skin lesions, pressure sores, acne, blisters;

rarely - acute febrile neutrophilic dermatosis (Sweet syndrome), skin reactions, Jessner's lymphocytic infiltration, palmar-plantar erythrodysesthesia, subcutaneous bleeding, reticuloedvedo, skin tightening, seborrhea, cold sweat, erythrosis, skin ulcers;

very rarely - Stevens-Johnson syndrome and toxic epidermal necrolysis.

From the side of the musculoskeletal and connective tissue:

very often - myalgia;

often - muscle weakness, musculoskeletal pain, pain in the limbs, muscle cramps, arthralgia, bone pain, back pain;

infrequently - muscle spasms, muscle twitchings, muscle stiffness, joint swelling, joint stiffness, jaw pain, arthritis, myopathy, sensations of heaviness;

rarely - rhabdomyolysis, temporomandibular joint syndrome, fistula, joint effusion, bone disorders, infection and inflammation of the musculoskeletal and connective tissue, synovial cyst.

From the side of the kidneys and urinary tract:

often - renal dysuria, dysuria;

infrequently, renal failure (including acute), oliguria, renal colic, hematuria, proteinuria, urinary retention, frequent urination, difficulty urinating, back pain, urinary incontinence, urinary tract infection, urinary tract complaints, azotemia, pollakiuria;

rarely - irritation of the bladder.

From the genitals and the breast:

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

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

General disorders and disorders at the site of administration:

very often - increased fatigue, asthenia, fever;

often - deterioration in overall physical health, mucosal disorders, gait disturbance, cold feeling, weakness, feeling of malaise, flu-like symptoms, peripheral edema, edema;

infrequent - chills, a feeling of chest tightness, chest discomfort, a change in thirst, a feeling of change in body temperature, pain at the injection site, complications associated with the use of medical devices (incl.with a catheter);

rarely - death (including sudden), multiple organ failure, bleeding at the injection site, hernia, violation of healing processes, non-cardial pain in the chest, irritability, foreign body sensation, inflammation, phlebitis at the injection site. When extravasation - inflammation of subcutaneous fat.

Laboratory and instrumental data:

often - increased activity lactate dehydrogenase;

infrequently, an increase in the activity of alkaline phosphatase of the blood, an increase in the concentration of urea in the blood, an increase in the activity of gamma-glutamyltransferase, an increase in the activity of blood amylase, a decrease in the concentration of hydrocarbonates in the blood, an increase in the concentration of the C-reactive protein;

rarely changes in the content of gases in the blood, changes in the electrocardiogram (including an increase in the QT tooth), changes in prothrombin time, a decrease in gastric juice pH, increased platelet aggregation, increased troponin I concentration, virus detection and changes in serology, changes in urine analysis.

Injuries, 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.

Congenital, hereditary and genetic disorders:

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

Patients with mantle cell lymphoma

The safety parameters of bortezomib in these patients are similar to those in patients with multiple myeloma. Significant differences between the two groups of patients concluded that thrombocytopenia, neutropenia, anemia, nausea, vomiting and fever were more common in patients with multiple myeloma as compared to patients with mantle cell lymphoma and peripheral neuropathy, rash and itching - in patients with mantle cell lymphoma.

Overdose:

Symptoms: overdose, exceeding the recommended dose is more than 2 times, accompanied by acute decline in patients with arterial pressure and fatal thrombocytopenia.

Treatment: monitor the indicators of the patient's vital functions and body temperature, to carry out the appropriate therapy for maintaining blood pressure (infusion therapy, vasoconstrictors and / or inotropic agents).The specific antidote is unknown.

Interaction:

Bortezomib shows 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 low activity, the total isoenzyme is not expected to change the overall distribution of the drug.

Investigation of the effect of drug interaction with a strong inhibitor of isoenzyme CYP3A4 ketoconazole on the pharmacokinetics of bortezomib showed an increase in the mean values AUC (area under the concentration-time curve) of bortezomib on average by 35%. Therefore, it is necessary to carefully monitor patients who apply 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 omeprazole on the pharmacokinetics of bortezomib ns revealed a 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 for bortezomib on average 45%.Therefore, it is not recommended to use Bartizar® together with strong inducers CYP3A4. Because 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 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 Bartizar® should only be carried out under the supervision of a physician with experience in the use of antitumor chemotherapy.

Bartizar® is indicated only for intravenous and subcutaneous administration. Do not enter intrathecally.

Before and during each cycle of therapy, a complete a blood test with a count of the leukocyte formula and platelet count.

Thrombocytopenia

Most often, with therapy with bortezomib, transient thrombocytopenia is observed, with the smallest number of platelets usually observed on day 11 of the cycle. The cycle periodicity of the decrease and increase in the number of platelets was observed during all 8 cycles with the use of the drug 2 times a week, thus, there is no evidence of increasing thrombocytopenia. With a decrease in the number of platelets <25x10⁹/ l or when used concomitantly with melphalan and prednisolone, when the platelet count ≤ 30x10⁹/ l, therapy with Bartizar® 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.

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 undergo, rehydration therapy and maintain a water-electrolyte balance.

In connection with the possible development of intestinal obstruction, it is necessary to conduct dynamic monitoring of patients with constipation.

Progressive multifocal leukoencephalopathy

Very rare cases occurred with an unidentified cause of progressive multifocal leukoencephalopathy (PML) with a fatal outcome with the use of bortezomib. Patients diagnosed with PML were treated with immunosuppressants before or simultaneously with bortezomib. Most PML cases were diagnosed within 12 months of the onset of treatment with bortezomib. Special attention is required regarding suspicious PML symptoms, which the patient himself can not notice (for example, cognitive, neurological or psychiatric).If PML is suspected, further treatment with bortezomib should be discontinued until the diagnosis of PML is excluded.

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, a dose reduction and a change in the mode of administration of the drug may be required.

Patients should be under constant observation in connection with the possibility of the appearance of symptoms of neuropathy (burning sensation, hyperesthesia, kinesisia, paresthesia, discomfort, neuropathic pain or weakness). It is necessary to constantly monitor the condition of patients receiving bortezomib therapy together with other drugs that contribute to the onset of neuropathy (including simultaneous thalidumIda). Frequency of occurrence Neuropathy with subcutaneous administration of the drug Bartizar® is lower than that of intravenous administration.

In patients with seizures or epilepsy, the history of seizures is described in an anamnesis.Special care is required in the treatment of patients who have any risk factors for seizures.

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.

Caution should be exercised when using bortezomib in patients who have a history of syncope, diabetic neuropathy, receiving antihypertensive drugs, as well as in patients who are dehydrated against diarrhea or vomiting. 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 liver dysfunction, as an increase in the activity of "hepatic" enzymes, hyperbilirubinemia or hepatitis, usually passed with the abolition of bortezomib.

Patients with symptoms of liver dysfunction should be prescribed at a lower initial dose and monitored for toxicity, since bortezomib is metabolized by "hepatic" enzymes and its concentration may increase if the liver function is moderate and severe (see section "Method of administration and dose").

Syndromem of posterior reversible leukoencephalopathy

In patients receiving bortezomib, a syndrome of posterior reversible leukoencephalopathy was noted - a rare, reversible neurologic disorder, which can be accompanied by convulsions, 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 reversible leukoencephalopathy, bortezomib should be discontinued. The safety of resumption of treatment with bortezomib after the previously identified reverse reversible leukoencephalopathy syndrome is unknown.

Reactivation of the virus Herpes zoster

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

Dysfunction of the lungs

In rare cases, when using bortezomib, sharp diffuse infiltrative lung diseases of unknown etiology, such as pneumonia, 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.

It is not recommended to use bortezomib with simultaneous application of high doses of cytarabine (2 g / m² per day) by continuous infusion within 24 hours (may lead to death).

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, an abundant drink is recommended, if necessary allopurinol and alkalinization of urine.

When using Bartizar® in patients who simultaneously take oral hypoglycemic drugs, the concentration of glucose in the blood should be carefully monitored and, if necessary, corrected for the dose of hypoglycemic drugs.

Immunocomplex type reactions

The cases of occurrence of immunocomplex type reactions (serum sickness, polyarthritis with rash and proliferative glomerulonephritis) are described.In these cases, treatment with bortezomib should be discontinued.

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

When working with Bartizar®, the generally accepted rules for handling centnerstoxic preparations.

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

During treatment with bortezomib, dizziness, fainting, visual disturbances and other undesirable phenomena that could adversely affect the ability to drive vehicles and work with mechanisms are possible. When these undesirable phenomena appear, one should refrain from performing these activities.

Form release / dosage:Lyophilizate for the preparation of solution for intravenous and subcutaneous administration, 3.5 mg.

Packaging:

At 38,336 mg (corresponding to 3.5 mg bortezomib) of the drug in vials of colorless glass, corked with rubber stoppers and crimped with aluminum caps with a printed number of the series or without drawing the series number, equipped with plastic caps with the inscription "FLIP OFF".

1 bottle with instructions for use in a pack of cardboard.

Storage conditions:

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

After dilution with 0.9% solution of sodium chloride, storage in a vial or syringe is allowed not more than 8 hours at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

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

Terms of leave from pharmacies:On prescription

Registration number:LP-002939

Date of registration:01.04.2015 / 01.11.2016

Expiration Date:01.04.2020

The owner of the registration certificate:FarmSirma Soteks, ZAO FarmSirma Soteks, ZAO Russia

Manufacturer: & nbsp

RNTS named after N.N. Blokhin RAMS Russia

FarmSirma Soteks, ZAO Russia

SYNTHON HISPANIA, S.L. Spain

RAFARMA, JSC Russia

Information update date: & nbsp21.01.2017

Illustrated instructions

Instructions

Bartizar® (BARTIZAR®)