Universal reference book for medicines
Product name: BARTIZAR (BARTIZAR)

Active substance: bortezomib

Type: Antitumor preparation

Manufacturer: FarmThirm SOTEKS (Russia) manufactured by ONCOMED MANUFACTURING (Czech Republic)
Composition, form of production and packaging
Lyophilizate for the preparation of a solution for intravenous and / or injection
in the form of lyophilized mass or powder white or almost white.

1 f.

bortezomib (in the form of three-dimensional boroksin) 3.336 mg,

which corresponds to the content of bortezomib (in the form of a monomer) 3.5 mg

Excipients: mannitol - 35 mg.

3.5 mg - bottles of colorless glass (1) - packs of cardboard.

INSTRUCTION FOR THE SPECIALIST.

Description of the drug approved by the manufacturer for the printed edition of 2015.

PHARMACHOLOGIC EFFECT

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

With iv injection of bortezomib in doses of 1.0 mg / m 2 and 1.3 mg / m 2, patients with multiple myeloma C max in plasma are respectively 55-60 ng / ml and 110-115 ng / ml, respectively.
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 / m 2 and 85-125 ng / ml for a dose of 1.3 mg / m 2 . The mean T 1/2 bortezomib with repeated administration is 40-193 hours.
Bortezomib is quickly excreted after the first dose compared with subsequent doses.
After the first administration at doses of 1.0 mg / m 2 and 1.3 mg / m 2, theaverage total clearance is 102 l / h and 112 l / h, respectively, and after subsequent administration, 15-32 l / h, respectively.
When administered at a dose of 1.3 mg / m 2 SC or IV in patients with multiple myeloma, the overall systemic exposure after repeated administration at the same dose was equivalent for both routes of administration.
C max after SC administration (20.4 ng / ml) was lower than after IV injection (223 ng / ml).
After a single or multiple injection at doses of 1.0 mg / m 2 and 1.3 mg / m 2, the average V d of bortezomib in patients with multiple myeloma is 1659-3294 L (489-1884 L / m 2 ).
This suggests that bortezomib is 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 vitro, the metabolism of bortezomib is predominantly carried out by cytochrome P450 - CYP3A4, CYP2C19 and CYP1A2 isoenzymes.
The participation of CYP2D6 and CYP2C9 isoenzymes 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 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.

In patients with impaired liver function of medium and severe degree, a 60% increase in AUC of bortezomib is observed 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. Light violations of the liver do not affect the pharmacokinetics of bortezomib.
Pharmacokinetics of bortezomib in doses of 0.7-1.3 mg / m 2 iv / 2 times 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;

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

DOSING MODE

Bartizar in a dosage of 3.5 mg is indicated for IV administration and SC administration.

With intrathecal administration, deaths were documented.

With IV administration, the concentration of the solution should be 1 mg / ml.
When n / k introduction, the concentration of the solution should be 2.5 mg / 1 ml.
The concentration of the solution must be calculated very carefully due to the difference in the concentration of the IV solution and the solution for the SC administration.

Monotherapy

The bartizar is injected intravenously into the jet for 3-5 seconds or s.c.
The recommended dose of Bartizar is 1.3 mg / m 2 body surface area 2 times a week for 2 weeks (days 1, 4, 8 and 11). with a subsequent 10-day break (days 12-21). Between the introduction of consecutive doses of the drug Bartizar 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.
If the treatment duration is more than 8 cycles, Bartizar can be used according to the standard scheme or according to 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 Bartizar's 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 administered orally with each dose of the drug Bartizar: 20 mg and the day of administration and 20 mg the day after the administration of 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-hematological 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 toxicity symptoms, treatment with the drug can be resumed at a dose reduced by 25% (dose 1.3 mg / m 2 reduced to 1.0 mg / m 2 , dose 1.0 mg / m 2 reduced to 0.7 mg / m 2 ). If the symptoms of toxicity do not disappear or appear again at the lowest dose, then the possibility of withdrawal of the drug Bartizar should be considered. if only the benefits of its use clearly do not exceed the risk.
When a Bartizar neuropathic pain associated with the use of the drug and / or peripheral sensory neuropathy appears, 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

The severity of peripheral neuropathy Changes 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 dose to 1.0 mg / m 2

2nd degree with pain or grade 3 (violation of daily activity) Suspend use of Bartizar until symptoms of toxicity disappear.
After that, resume treatment, lowering the dose to 0.7 mg / m 2 and reducing the frequency of administration to once a week
4th degree (sensory neuropathy, resulting in disability or motor neuropathy, life-threatening or leading to paralysis) 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 can 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 violations of moderate and severe liver function should be prescribed Bartizar in a reduced dose (Table 2).
Table 2. Recommended changes in the initial dose of the drug Bartizar in patients with impaired liver function

Degree of severity of liver dysfunction Concentration of bilirubin ACT activity * Change in initial dose

Easy? 1.0? VGN **> UGN Not required

> 1.0-1.5? VGN Any Not required

Medium> 1.5-3? VGN Any It is required to prescribe Bartizar at a reduced dose of 0.7 mg / m 2 during the first cycle.
In subsequent cycles, depending on the patient's tolerance, the dose of Bartizar can be increased to 1.0 mg / m 2 or reduced to 0.5 mg / m 2 .
Heavy> 3? VGN Any

* AST - aspartate aminotransferase

** VGN - the upper limit of the norm

Combination Therapy

Recommended dose

The bartizar is injected intravenously in the course of 3-5 seconds or s / c in combination with melphalan and prednisone taken internally.
Nine 6-week cycles are carried out, in cycles 1-4 Bartizar is used 2 times a week (days 1, 4, 8, 11, 22, 25, 29 and 32). and in 5-9 cycles - once a week (days 1, 8, 22 and 29), Table 3.
Table 3. Recommended dosing regimen of the drug Bartizar, used in combination with melphalan and prednisone in large with previously untreated multiple myeloma

Bartizar 2 times a week (cycles 1-4)

Week 1 2 3 4 5 6

Bartizar 1.3 mg / m 2 day 1 - - day 4 day 8 day 11 rest period day 22 day 23 day 29 day 32 rest period

melphalan 9 mg / m 2 + prednisone 60 mg / m 2 day 1 day 2 day 3 day 4 rest period

Bartizar 1 time per week (cycles 5-9)

Week 1 2 3 4 5 6

Bartizar 1.3 mg / m day 1 - - day 4 day 8 day 11 rest period day 22 day 23 day 29 day 32 rest period

melphalan 9 mg / m 2 + prednisone 60 mg / m 2 day 1 day 2 day 3 day 4 rest period

Recommendations for dose adjustment in combination therapy

Before the start of a new treatment cycle:

- the content of platelets should be> 70? 10 9 / l;

- the absolute content of neutrophils (ASN)> 1 × 10 9 / l;

- non-hematological toxicity should be reduced to 1 degree or to the initial 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 grade 4, or thrombocytopenia with bleeding. In the next cycle, the dose of melphalan should be reduced by 25%

the content of platelets? 30? 10 9 / l or ASN? 0.75? 10 9 / l the day of the drug Bartizar (except for day 1) Postpone the introduction of the drug Bartizar

several delays in the administration of the drug Bartizar in one cycle (> 3 times when administered 2 times per pedel or 2 times when administered once a week). The dose of Bartizar is reduced by 1 step (from 1.3 mg / m 2 to 1.0 mg / m 2 ; from 1.0 mg / m 2 to 0.7 mg / m 2 )

Non-hematologic toxicity? 3 degrees The drug Bartizar is postponed until the reduction of non-hematologic toxicity to 1 degree or to the initial level.
After that, treatment with the drug can be resumed in a dose reduced by 1 step (from 1.3 mg / m 2 to 1.0 mg / m 2 , from 1.0 mg / m 2 to 0.7 mg / m 2 ). With the development of neuropathic pain and or peripheral neuropathy associated with the use of the drug Bartizar, the administration of a regular dose is postponed and / or adjusted to the dose as described in Table 1
Additional information on metalfan and pedidone is set out in the instructions for the medical use of these drugs.

Method of preparation and administration of the drug solution Bartizar

Preparation and administration of the drug Bartizar must be carried out by medical personnel trained in the safe handling of antitoxic 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 must 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 vial (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 IV injection via a peripheral or central venous catheter, which is then washed with 0.9% sodium chloride solution for injection.

For n / to the introduction

The contents of the Bartizar vial (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 the SC administration is 2.5 mg / ml.
The resulting solution is injected s / c into the thigh (right or left) or into the abdominal region (right or left).
It is necessary to constantly change the place of administration of the drug. Each subsequent injection should be administered at a distance of at least 2.5 cm from the site of the previous injection. Do not administer the drug to sensitive areas, damaged areas (redness, bruises), or in areas where needle insertion is difficult.
In case of local reactions in the area of ​​SC administration of Bartizar, a less concentrated solution for SC administration (1 mg / 1 ml instead of 2.5 mg / 1 ml) or switch to IV administration of the drug can be used.

SIDE EFFECT

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.
syndrome of reversible posterior encephalopathy, acute diffuse infiltrative pulmonary diseases. In addition, in rare cases, vegetative neuropathy was observed. Most frequently during the therapy with bortezomib, the following adverse 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 simple herpes, surrounding herpes (including disseminated and ophthalmoherpes), fungal infections: infrequently - 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: rarely - meningitis (including bacterial), Epstein-Barr virus infection, genitosis
herpes simplex, 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.

From 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 - angioedema, hypersensitivity;
rarely - anaphylactic shock, amyloidosis, reactions with the formation of immune complexes (type III).
On the part of the endocrine system: infrequently - Itzenko-Cushing syndrome, hyperthyroidism, 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 - gipermagniemiya, acidosis, disruption of water-electrolyte balance, excessive accumulation of fluid, hypochloremia, hypovolemia, hyperchloremia, hyperphosphatemia, metabolic disease, deficiency of vitamin B, vitamin B deficiency 12 , gout, alcohol intolerance, an increase in body weight.
Mental disorders: often - disorders and mood disorders, anxiety disorders, and sleep disorders; infrequently - mental status changes, hallucinations, psychotic disorder, confusion, restlessness; rarely - suicidal thoughts, adjustment 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, parosmiya; 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,lightheadedness, lesions of the brain stem syndrome, stroke, radicular syndrome, psychomotor hyperactivity, spinal cord compression, cognitive disorders, movement disorders, nervous system disorders, sciatica, drooling, muscle hypotonia.
From a sight organ: often - periorbital edema, blurred vision, conjunctivitis, decrease in visual acuity; rarely - bleeding in the eye, infection eyelids, inflammation of the eye, double vision, dry eye, eye irritation, sore gases, increased lacrimation, eye discharge, redness of the conjunctiva; rarely - corneal lesions, exophthalmos, retinitis, scotoma, eye damage (including age), dacryoadenitis, photophobia, photopsia, optic neuropathy, blindness.
On the part of the organ of hearing and labyrinth disorders: often - vertigo; infrequently - tinnitus, hearing impairment (deafness), discomfort in the ear; rarely - bleeding, vestibular neurons disorders of the ear.
Of the heart:often - heart failure, cardiovascular disorders (including cardiogenic shock), myocardial infarction, angina pectoris, the development and exacerbation of congestive heart failure, ventricular hypokinesia, sinus arrest, AV-block, tachycardia (including sinus and supraventricular) arrhythmia, atrial fibrillation, palpitations; infrequently - atrial flutter, bradycardia, cardiopulmonary shock, cardiac fibrillation (including atrial fibrillation), pericarditis (including pericardial effusion), cardiomyopathy, ventricular dysfunction; rare - decrease in left ventricular ejection fraction, cardiac tamponade, ventricular arrhythmia tachysystolic type "pirouette", unstable angina, valvular heart disease, coronary insufficiency.
On the part of the vessels:often - lowering blood pressure, and orthostatic postural hypotension, phlebitis, hematoma (including perirenal), increased blood pressure; infrequently - vasculitis, stroke, petechiae, ecchymosis, purpura, vein discoloration, swelling of veins, bleeding wounds, "tides" of blood, deep vein thrombosis, thrombophlebitis, bleeding, circulatory collapse (including hypovolemic shock), decreased peripheral circulation , congestion (including ocular): rarely - pulmonary embolism, peripheral vascular embolism, lymphedema, pallor, rodonalgia, vasodilatation, venous insufficiency.
The respiratory system, organs, thoracic and mediastinal disorders:very often - shortness of breath; often - exertional dyspnea, epistaxis, cough, runny nose, infections of the upper and lower respiratory tract; infrequently - apnea, hypoxia, pleural effusion, pulmonary edema (including acute) bronchoconstriction, respiratory alkalosis, tachypnea, wheezing, nasal congestion, hoarseness, rhinitis, hyperventilation, orthopnea, in the chest pain, pain in the paranasal sinuses, feeling of tightness in the throat, coughing up blood, chronic obstructive pulmonary disease, hypoxemia, pleural effusion, hoarseness; rarely - pneumonitis, pneumonia (including interstitial), acute respiratory distress syndrome, acute, diffuse infiltrative lung disease, pulmonary hypertension, respiratory distress, alveolar hemorrhage in the lung, acute respiratory distress syndrome, pneumothorax, atelectasis,pulmonary fibrosis, disorders of the bronchi, interesttsialnoe pulmonary disease, hypocapnia, dry throat, increased secretion of the upper respiratory tract, throat irritation, cough upper respiratory tract syndrome.
On the part of the digestive tract:very often - nausea, vomiting, diarrhea, constipation; often - abdominal pain, stomatitis, dyspepsia, loose stools, flatulence, hiccups, pain in the throat and pharynx, disorders of the oral cavity; infrequently - pancreatitis (including chronic), paralytic ileus, colitis, melena, bleeding from the gastrointestinal tract, enteritis, dysphagia, belching, in spleen pain, esophagitis, gastritis, gastroesophageal reflux, petechiae oral mucosa, salivary gland hypersecretion , tongue coating, changing the language of color, ulcers on the tongue, increased appetite, vomiting blood, swelling of the mouth, abdominal discomfort, ulceration of the oral mucosa, bleeding from the gums, pseudomembranous colitis, an inflammation of the gastrointestinal mucosa, naru shenie GI motility, irritable bowel syndrome; rarely - ischemic colitis, peritonitis, tongue edema, ascites,cheilitis, fecal incontinence, the agony of the anal sphincter, 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, a change in bowel movement rhythm iroktalgiya, violations of the chair.
Of the liver and biliary tract: infrequently - hepatitis, liver hemorrhaging, hypoproteinemia, hyperbilirubinemia, increased activity of alanine aminotransferase and aspartate aminotransferase, hepatotoxicity, cholestasis; rare - hepatic failure, hepatomegaly, Budd-Chiari syndrome, cytomegalovirus hepatitis, cholelithiasis.
Skin and subcutaneous tissue disorders:very often - skin rash; often - rash, itchy rash, itching, redness, increased sweating, dry skin, eczema; rarely erythema multiforme, erythematous rash, photosensitivity, bruising, generalized itching, makuleznaya rash, maculopapular rash, psoriasis, generalized rash, swelling of the eyelids, face edema, dermatitis, alopecia, nail infections, skin discoloration, atopic dermatitis, changes in the structure of hair, night sweating, ichthyosis, skin nodules, toxic skin rash, skin lesions, skin growths, sores, acne, blisters; rarely - acute febrile neutrophilic dermatosis (Sweet's syndrome), of the skin reaction, Jessner lymphocytic infiltration, palmar-plantar eritrodizesteziya, subcutaneous bleeding, livedo reticularis, skin tightening, seborrhea, cold sweat, erythrose, skin ulcers;very rarely - Stevens-Johnson syndrome and toxic epidermal necrolysis.
On the part of the musculoskeletal and connective tissue disorders: very often - myalgia; often - muscle weakness, musculoskeletal pain, pain in extremities, muscle cramps, arthralgia, bone pain, back pain; infrequently - muscle spasms, muscle twitching, muscle stiffness, joint swelling, joint stiffness, pain in the jaw, arthritis, myopathy, heaviness; rarely - rhabdomyolysis, temporomandibular joint syndrome, fistula, joint effusion, bone disorders, infection and inflammation of the musculoskeletal and connective tissue, synovial cyst.
On the part of the kidney and urinary tract:often - renal dysfunction, dysuria; infrequently - renal failure (including acute), oliguria, renal colic, hematuria, proteinuria, urinary retention, frequent urination, urination difficulty, pain, urinary incontinence, urinary tract infections, complaints of the urinary tract, azotemia, pollakiuria; rare - irritation of the bladder.
Popov on the part of authorities and breast: infrequently - erectile dysfunction, vaginal bleeding, pain in the genitals; rarely - a violation of testicular function, prostate, breast violation of the functions of the epididymis pain, pain in the pelvic area, epididymitis, ulceration of the vulva.
General disorders and the site of injection:very often - fatigue, asthenia, increase in body temperature; often - the deterioration of overall physical health, disorders of the mucous membranes, gait disturbance, feeling cold, fatigue, malaise, flu-like symptoms, peripheral edema, swelling; infrequently - chills, feeling of constriction in the chest, chest discomfort, changes in thirst, the sensation changes in body temperature, pain at the injection site, complications associated with the use of medical devices (including catheter); rarely - death (including flash), multiple organ failure, bleeding at the injection site, hernia, impaired healing processes, non-cardiac chest pain, irritation, foreign body sensation, inflammation, phlebitis at the injection site. If extravasation - inflammation of subcutaneous fat.
Laboratory and instrumental data: often - increase in blood lactate dehydrogenase activity; infrequently - increase of blood AP activity, increasing concentrations of urea in the blood, the increase in gamma glutamiltranferazy, elevated blood amylase, reducing the concentration of hydrocarbons in the blood, increasing concentrations of C-reactive protein; rarely - changing the gas content in the blood, ECG changes (including tooth increase QT), the change prothrombin time, lowering pH of gastric juice, increase of platelet aggregation, increasing the concentration of troponin I, virus detection and serology change, changes in urine analysis.
Injury, poisoning and complications of manipulation:infrequently - falling, concussion; rarely - transfusion reactions, fractures, stiffness, facial injuries, joint injuries, burns, fractures, pain during the procedure, radiation damage.
Surgical and therapeutic manipulation: rarely - activation of macrophages.
Congenital, hereditary and genetic disorders: rarely - aplasia, malformation of the gastrointestinal tract, ichthyosis.
Patients with mantle cell lymphoma
Bortezomib safety performance in these patients are similar with those of 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.
CONTRAINDICATIONS

- hypersensitivity to bortezomib, boron, and mannitol;
- acute diffuse infiltrative pulmonary disease: the defeat of the pericardium;
- simultaneous application of strong inducers isoenzyme CYP3A4 (rifampicin, carbamazepine, phenytoin, phenobarbital, St. John's wort);
- Pregnancy and lactation;
- child and adolescence to 18 years (lack of application experience).
Be wary
- severe liver dysfunction and moderate;
- severe renal dysfunction;
- seizures or epilepsy in history;
- fainting;
- a history of diabetic neuropathy;
- concomitant use of antihypertensive drugs;
- dehydration during diarrhea or vomiting;
- constipation;
- the risk of developing congestive heart failure;
- simultaneous reception of inhibitors or substrates isozyme CYP3A4;
- simultaneous reception of substrates isoenzyme CYP2C9, oral hypoglycemic drugs.
PREGNANCY AND LACTATION

Application Bartizar drug during pregnancy and lactation is contraindicated.
At the time of treatment should stop breastfeeding.
APPLICATION FOR FUNCTIONS OF THE LIVER

Precautions apply to patients with severe renal impairment.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS

Precautions apply to patients with impaired liver function severe and moderate degree, it is recommended starting dose of bortezomib decrease.
APPLICATION FOR CHILDREN

Use of the drug for children and adolescents under the age of 18 years is contraindicated.
SPECIAL INSTRUCTIONS

Treatment with Bartizar should be performed only under the supervision of a physician who is experienced in the use of anticancer chemotherapy.
Bartizar shown only in / and s / c administration. Do not administer intrathecally.
Prior to and during each cycle of therapy is necessary to conduct a complete blood count with leukocyte and platelet count.
Thrombocytopenia
most commonly in the treatment of bortezomib observed transient thrombocytopenia, while the smallest number of platelets is usually observed on the 11th day of the cycle. The cycle frequency decrease and increase in platelet count was observed for all 8 cycles when using the drug two times a week, so there is no data to support the increasing thrombocytopenia. By reducing platelet counts <25 x 109 / L or while the use of melphalan and prednisone when the platelet count? 30 × 10 9/ L, drug therapy Bartizar should be suspended. When recovering the platelet count should continue treatment in small doses with careful comparison of the potential benefits and risks of treatment. For the treatment of hematological toxicity may be used colony stimulating factors, platelet transfusions and zritrotsitarnoy mass.
Gastrointestinal disturbances
In order to prevent nausea and vomiting it is recommended to use antiemetics. In the event of diarrhea is assigned antidiarrheal drugs. To prevent or treat dehydration patients need to spend rehydration therapy and maintain water and electrolyte balance. In connection with the possible development of intestinal obstruction should be carried out dynamic monitoring of patients with constipation.
Progressive multifocal leukoencephalopathy
Cases with unknown cause progressive multifocal leukoencephalopathy (PML) fatal when applying bortezomib very rare. Patients diagnosed with PML were treated with immunosuppressants prior to or concurrently with bortezomib. Most cases of PML was diagnosed within 12 months of starting treatment with bortezomib. It requires special attention on suspicious symptoms of PML that the patient himself can not notice (eg cognitive, neurological or psychiatric). If PML is suspected, should suspend further treatment with bortezomib to exclude PML diagnosis.
peripheral neuropathy
When neuropathy occurs a supportive therapy. Typically, the frequency of peripheral neuropathy reaches a maximum at 5 bortezomib treatment cycle. When new or worsening of existing symptoms of peripheral neuropathy may require dose reduction and change the mode of administration.
Patients should be under constant supervision in connection with the possibility of sympto
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