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

Active substance:
Bortezomib in the form of three-dimensional boroksin (in terms of bortezomib in the form of a monomer)	3.5 mg
Excipients:
D-Mannitol	35 mg

Solvent: sodium chloride, solution for injection 0.9%

Composition per ml:

Sodium chloride	9.0 mg
Water for injections	up to 1.0 ml

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

Solvent: colorless transparent 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 / m²patients with multiple myeloma maximum concentrations (C_mOh) of bortezomib in plasma are 57 ng / ml and 112 ng / ml, respectively. With the subsequent administration of the drug, the maximum plasma concentrations are in the range of 67-106 ng / ml for a dose of 1.0 mg / m and 89-120 ng / ml for a dose of 1.3 mg / m². The maximum concentration (C_mOh) bortezomib after subcutaneous administration (20.2 ng / ml) is lower than after intravenous administration (223 ng / ml). When administered at a dose of 1.3 mg / m² subcutaneously and intravenously to patients with multiple myeloma, the total systemic exposure after repeated administration at the same dose (AUC_last) is equivalent for both paths.

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%.

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 administration of 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.

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

Pharmacokinetics in patients with impaired hepatic and renal function

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.

The pharmacokinetics of bortezomib in doses of 0.7-1.3 mg /m² intravenously twice a week in patients with mild, moderate and 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 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.

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 reception of inhibitors or substrates of isoenzymes 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 Boromylan® is 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 should be calculated very carefully due to the difference in the concentrations of the solution for intravenous administration and the solution for subcutaneous administration.

Monotherapy

Boromylan® injected intravenously in a jet for 3-5 seconds or subcutaneously. The recommended initial 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). The treatment cycle is 21 days. 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 in whom the drug monotherapy Boromylan® did not show a clinical response (progression or stabilization of the disease after 2 and 4 cycles, respectively), a combination of the drug Boromylan® with high doses of dexamethasone. In this case, with each dose of the drug Boromylan® 40 mg dexamethasone is administered orally: 20 mg per day of drug administration Boromylan® and 20 mg the day after the administration of the drug Boromylan®. Dexamethasone is administered on days 1, 2, 4, 5, 8, 9, 11 and 12, totaling 160 mg for 3 weeks.

Recommendations for dose adjustment and administration of the drug Boramilan®

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 Boromylan® should be paused. After the disappearance of symptoms of toxicity, drug treatment Boramilan® can be resumed in a dose reduced by 25% (dose 1.3 mg / m² reduce to 1.0 mg / m², a dose of 1.0 mg / m² decreasing to 0.7 mg / m). If the toxicity symptoms do not disappear or appear again at the lowest dose, then the possibility of discontinuing the drug should be considered Boramylan® FS, if only the benefits of its use clearly do not exceed the risk.

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. In 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 in the development of drug-induced Boramylan® neuropathic pain and / or peripheral sensory or motor neuropathy

Severity of peripheral neuropathy	Change in dose and frequency of administration
1 degree (paresthesia and / or extinction of reflexes) without pain or loss of function	Dose and mode of administration do not require correction
1 degree with pain or 2 degree (impaired function, but not daily activity)	Reduce the dose to 1.0 mg / m²
2 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 Boramilan® up to 0,7 mg / m² and reducing the frequency of administration up to 1 time per week
4 degree (sensory neuropathy, resulting in disability or motor neuropathy, life threatening or leading to paralysis)	Stop using Boramylan®

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, since dialysis can reduce the concentration of the drug in the blood.

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 Boromylan® in a reduced dose (Table 2).

Table 2. Recommended changes in the initial dose of Boramylan® in patients with hepatic impairment

Severity of hepatic impairment	Concentration of bilirubin	ACT activity *	Change in the initial dose
Lightweight	≤ 1.0 x VGN	> VGN**	Not required
Lightweight	> 1.0 x 1.5 x VGN	Any	Not required
Average	> 1.5 x - 3 x VGN	Any	Required to assign Boramilan® in a reduced dose of 0.7 mg / m² during the first cycle. Consider increasing the dose to 1.0 mg / m² or further decrease to 0.5 mg / m in subsequent cycles, depending on the patient's tolerability.
Heavy	> 3 x VGN	Any

* AST - aspartate aminotransferase;

** VGN - the upper limit of the norm

Combination Therapy

Recommended dose

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

Table 3. Recommended dosage formulation Boramilan® diagram used in combination with melphalan and prednisone in patients with previously untreated multiple myeloma

Boramilan® 2 once a week (cycles 1-4)
1 week	2 ned.			3 weeks		4 weeks		5 weeks.		6 weeks
*Boromylan® (1.3 mg / m²)*
1st day 4 th day	8th day 11th day			Period of rest		The 22nd day 25th day		29th day 32nd day		Period of rest
*Melphalan (9 mg / m² ) + prednisone (60 mg / m²)*
1st day 2 nd day Day 3 4 th day	-			Period of rest		-		-		Period of rest
Boromylan® Once a week (cycles 5-9)
1 week		2 weeks	3 weeks		4 weeks		5 weeks.		6 weeks
Boromylan® (1.3 mg / m²)
1st day		8th day	Period of rest		The 22nd day		29th day		Period of rest
*Melphalan (9 mg / m²) + prednisone (60 mg / m²)*
1 th day 2 nd day Day 3 4 th day		-	Period of rest		-		-		Period of rest

Recommendations for dose adjustment in combination therapy

Dose correction and treatment regimens with Boromalan® together with melphalan and prednisone

Before the start of a new treatment cycle:

- the content of platelets should be> 70 x 10⁹/ l;

- the absolute content of neutrophils (ASN) should be> 1.0 x 10⁹/ l;

- Non-hematologic toxicity should be reduced to 1 degree or to the baseline 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 grade 4, or thrombocytopenia with bleeding	In the next cycle, the dose of melphalan should be reduced by 25%
Platelet content ≤ 30 x 10⁹/ l or ASN ≤ 0.75 x 10⁹/ l on the day of drug administration Boramilan® (except for the 1st day)	Delay the introduction of the drug Boromylan®
Several postponements of drug administration Boramilan® in one cycle (> 3 times when administered 2 times a week or ≥ 2 times when administered once a week)	Dose of the drug Boramilan® 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-hematologic toxicity ≥3 degrees:	Application of the drug Boramilan® postponed until the reduction of non-hematologic toxicity to 1 degree or to the baseline level. After this treatment with the drug Boramilan® can be resumed in a dose reduced by 1 step (from 1.3 mg / m² up to 1.0 mg / m²; with 1.0 mg / m² up to 0,7 mg / m²). With the development of neuropathic pain and / or peripheral neuropathy associated with the use of the drug Boramilan®, the administration of the next dose is postponed and / or adjusted to a dose as described in Table 1 above.

Further information on melphalan and prednisone 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 and handling the drug. Appropriate rules should be followed, aseptic.It is recommended to use gloves and other protective clothing to prevent contact with the skin.

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

Preparation of a solution for intravenous administration

The contents of the vial are dissolved in 3.5 ml of 0.9% solution of sodium chloride.

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 are dissolved in 1.4 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 region (left or right) or into the abdominal region (left or right). 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), in an area where needle insertion is difficult. If local reactions occur in the subcutaneous administration of the drug, a less concentrated solution of the preparation for subcutaneous administration (1 mg / ml instead of 2.5 mg / ml) or switch to intravenous administration of the drug Boramilan®.

Side effects:

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

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

Undesirable side effects are grouped by organs and frequency of occurrence. The frequency was defined as: very often (> 10%), often (1-10%), infrequently (0.1-1%), rarely (0.01-0.1%), very rarely (<0.01% ), including individual cases.

Violations from the blood and lymphatic system:

very often - thrombocytopenia, anemia, neutropenia;

often - leukopenia, lymphopenia;

infrequently - pancytopenia, febrile neutropenia, hemolytic anemia, thrombocytopenic purpura, lymphadenopathy;

rarely - a syndrome of disseminated intravascular coagulation (DVS-syndrome);

frequency unknown - coagulopathy, leukocytosis.

Heart Disease:

often cardiac arrest, cardiogenic shock, myocardial infarction, angina pectoris, development and exacerbation of chronic heart failure, ventricular hypokinesia, pulmonary edema (including acute), stop of sinus node, complete atrioventricular blockade, tachycardia (including sinus and supraventricular), arrhythmia, atrial fibrillation, palpitation; infrequent - atrial flutter, bradycardia, stagnation of blood in a small circle of blood circulation, pulmonary hypertension;

rarely - reduction of the fraction of the ejection of the left ventricle, cardiac tamponade, pericarditis, ventricular arrhythmias.

Vascular disorders:

often phlebitis, hematoma, lowering blood pressure (BP), orthostatic and postural hypotension, increasing blood pressure;

infrequently - intracerebral haemorrhage, intracranial hemorrhage, subarachnoid hemorrhage, vasculitis, stroke, petechiae, ecchymosis, purpura, change in color of veins, swelling of veins, bleeding of wounds, blood flushes;

rarely - pulmonary embolism, peripheral vascular embolism;

frequency unknown - deep vein thrombosis, thrombophlebitis.

Disturbances from the respiratory system, chest and mediastinal organs:

very often - shortness of breath;

often - dyspnoea with physical exertion, epistaxis, cough, rhinorrhea;

infrequent breathing, hypoxia, pleural effusions, bronchospasm, respiratory alkalosis, tachypnea, wheezing, nasal congestion, hoarseness, rhinitis, lung hyperventilation, orthopnea, pain in the chest, pain in the paranasal sinuses, a feeling of tightness in the throat, coughing up blood ;

rarely - pneumonitis, pneumonia (including interstitial), acute respiratory failure syndrome, acute diffuse infiltrative lung injury, pulmonary hypertension, respiratory failure, alveolar hemorrhage into the lung.

Disorders from the gastrointestinal tract:

very often - nausea, vomiting, diarrhea, constipation, decreased appetite;

often - pain in the abdomen, stomatitis, dyspepsia, loose stools, flatulence, hiccough, pain in the throat and pharynx, dry mouth;

infrequently - acute pancreatitis, 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 in the tongue, change coloring of the tongue, ulceration in the tongue, increased appetite;

rarely - ischemic colitis, peritonitis, ascites, cheilitis.

Disorders from the liver and bile ducts:

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

rarely - hepatic insufficiency, hepatomegaly, cytomegalovirus hepatitis, cholelithiasis.

Impaired nervous system:

very often - peripheral neuropathy, paresthesia, headache;

often - polyneuropathy, dizziness (with the exception of vertigo), taste distortion, dysesthesia, hypesthesia, tremor;

infrequently - paraplegia, convulsions, peripheral motor neuropathy, fainting, paresis, impaired concentration, loss of taste, drowsiness, cognitive disorders, postural dizziness, mononeuropathy, speech disorders, restless legs syndrome; rarely - encephalopathy, autonomic neuropathy, reverse reversible leukoencephalopathy syndrome.

Disorders of the psyche:

often confusion, depression, insomnia, anxiety;

infrequent - agitation, delirium, hallucinations, nervous state, mood swings, changes in mental status, sleep disturbances, irritability, unusual dreams;

rarely - suicidal mood, orientation disorder, delirium, decreased libido.

Disorders from the kidneys and urinary tract:

often - renal dysuria, dysuria;

infrequent - renal failure (including acute), oliguria, renal colic, hematuria, proteinuria, urinary retention, frequent urination, difficulty urinating, back pain, urinary incontinence.

Hearing disorders and labyrinthine disturbances:

often - vertigo;

infrequent - ringing in the ears, hearing loss;

rarely - bilateral deafness.

Disorders from the side of the organ of vision:

often - reduced vision clarity, pain in the eyes;

infrequent - hemorrhage in the eye, visual impairment, dry eyes, conjunctivitis, photophobia, eye irritation, increased lacrimation, conjunctival hyperemia;

rarely - ophthalmoherpes, optic neuropathy, blindness;

frequency is unknown - diplopia.

Disorders from the endocrine system:

infrequently - a violation of the secretion of antidiuretic hormone (ADH);

rarely - hypothyroidism;

frequency unknown - hypercortisy, hyperthyroidism.

Disturbances from 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, pain in the jaws.

Metabolic disorders:

often - dehydration, hypokalemia, hyperglycemia;

infrequently - hyperkalemia, cachexia, hypercalcemia, hypocalcemia, hypernatremia, hyponatremia, hypoglycemia, hyperuricemia, vitamin B12 deficiency, hypomagnesemia, hypophosphatemia.

Disorders from the reproductive system:

infrequently - pain in the testicle, erectile dysfunction;

rarely - prostatitis.

Immune system disorders:

infrequently - hypersensitivity;

rarely - Quincke's edema, anaphylactic shock, amyloidosis.

Disturbances from the skin and subcutaneous tissues:

very often - skin rash;

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

infrequent erythematous rash, photosensitivity, bruising, generalized itching, macular rash, papular rash, psoriasis, generalized rash, edema of the eyelids, face swelling, dermatitis, alopecia, nail damage, skin pigmentation change, atopic dermatitis, hair structure change, night sweats, ichthyosis, nodules on the skin;

rarely acute febrile neutrophilic dermatosis (Sweet syndrome);

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

Violations of laboratory-instrumental indicators:

often - increased lactate dehydrogenase activity in the blood;

infrequently - increased activity of alkaline phosphatase, increased urea concentration 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 - deviations from the norm of the ECG (including the lengthening of the interval QT), the deviation from the norm of the indicator of the international normalized ratio, a decrease in the pH of the gastric juice, an increase in the content of troponin I, an increase in the aggregation of platelets.

Local reactions:

infrequently - pain, burning sensation and hyperemia at the injection site, phlebitis. When extravasation - inflammation of subcutaneous fat.

Other:

very often - increased fatigue, fever, herpes zoster (including disseminated), herpes simplex, fungal infections;

often - asthenia, weakness, a feeling of malaise, flu-like symptoms, peripheral edema, swelling, weight loss, attachment of secondary infections;

infrequently - neuralgia, chills, chest tightness, chest discomfort, pain in the groin, complications associated with the catheter, tumor lysis syndrome, weight gain;

rarely - herpetic meningoencephalitis, septic shock;

very rarely - progressive multifocal leukoencephalopathy.

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 are that thrombocytopenia, neutropenia, anemia, nausea, vomiting and fever are 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 overdose, monitor the patient's vital functions and body temperature, conduct appropriate therapy to maintain blood pressure (infusion therapy, vasoconstrictor and / or inotropic drugs).

Interaction:

In studies in vitro and in vivo bortezomib showed the properties of a weak inhibitor of cytochrome isoenzymes P450 - 1A2, 2C9, 2C19, 2D6 and 3A4. Proceeding from the insignificant contribution CYP2D6 in the metabolism of bortezomib (7%), in people with a low activity of this enzyme, 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 (area under the concentration-time curve) of bortezomib on average by 35%. Therefore, it is necessary to carefully monitor patients receiving simultaneously bortezomib and a strong inhibitor of isoenzyme CYP3A4 (ketoconazole, ritonavir).

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

Study of drug interaction with a combination melphalan - prednisone showed an increase in the mean values AUC bortezomib by 17%. This change is considered clinically insignificant.

Investigation of the effect of drug interaction with rifampicin - a strong inhibitor CYP3A4 - the pharmacokinetics of bortezomib showed a decrease AUC Bortezomib on average by 45%. Therefore, do not use the drug Boromylan® together with a strong inductor CYP3A4, since the effectiveness of therapy can be reduced. To inducers CYP3A4 are rifampicin, carbamazepine, phenytoin, phenobarbital and St. John's wort. There was no significant change in the pharmacokinetics of bortezomib in the study of the effect of drug interaction with dexamethasone, a weaker inhibitor CYP3A4.

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 drug Boramilan® should be carried out only under the supervision of a doctor who has experience in the use of antitumor chemotherapy.

Medicinal preparation Boramilan® is intended only for intravenous and subcutaneous administration. When unintentional administration of bortezomib was intrathecally recorded, deaths occurred. A drug Boromylan® can not be entered intrathecally. 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 was observed during all 8 cycles with the drug 2 times a week, thus, there is no evidence of increasing thrombocytopenia. With a decrease in the number of platelets <25 x 10⁹/ L Drug Therapy 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.

Gastrointestinal disorders

To prevent nausea and vomiting, antiemetics are recommended. When a patient develops diarrhea, prescribe antidiarrheal drugs. To prevent or treat dehydration patients need to conduct rehydration therapy and maintain a water-electrolyte balance.

Peripheral Neuropathy

Patients should be under constant observation in connection with the possibility of the appearance of symptoms of neuropathy (burning sensation, hyperesthesia, hypesthesia, paresthesia, a feeling of discomfort, neuropathic pain, weakness). The incidence of neuropathy with subcutaneous administration of bortezomib is lower than with intravenous administration. 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®.

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

Orthostatic hypotension

Bortezomib therapy is often accompanied by orthostatic hypotension. In most cases, it is mild or moderate and is observed throughout the treatment. Rarely was there a brief loss of consciousness.

In patients who have a history of syncope, diabetic neuropathy, receiving antihypertensive drugs, as well as in patients with dehydration with diarrhea or vomiting, care should be taken. Patients should be instructed about the need to consult a doctor in case of dizziness, a feeling of "lightness in the head" or fainting. With the development of orthostatic hypotension, hydration, administration of glucocorticoids and / or sympathomimetics is recommended; if necessary, reduce the dose of antihypertensive drugs.

Heart failure

When using bortezomib, the development or enhancement of existing chronic heart failure is described. To the development of heart failure may predispose a 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 function abnormalities, like an increase in the activity of "liver" enzymes, hyperbilirubinemia or hepatitis, usually occur when the drug is withdrawn. Data on the status of these patients after resumption of bortezomib therapy are limited.

Patients with symptoms of impaired liver function should be prescribed Boromylan® in lower initial doses and monitor for toxicity, because 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").

Syndrome of posterior reversible leukoencephalopathy

In patients receiving bortezomib, there was a syndrome of posterior reversible leukoencephalopathy - a rare, reversible neurologic disorder,which can be accompanied by cramps, 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®. Safety of resumption of drug therapy Boramilan® 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 drug therapy Boramilan^®. In patients receiving therapy with bortezomib, melphalan and prednisone, the frequency of reactivation of the virus Herpes zoster was greater in comparison with patients receiving melphalan and prednisone therapy (14% and 4%, respectively). Conducting antiviral prophylaxis significantly reduces the frequency of reactivation of the virus Herpes zoster.

Dysfunction of the lungs

In rare cases, when using bortezomib, acute diffuse infiltrative pulmonary diseases of unknown etiology (pneumonitis, interstitial pneumonia, pulmonary infiltration,acute respiratory failure syndrome). 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 appropriate treatment.

Tumor lysis syndrome

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

Other

When using the drug Boramilan® in patients who simultaneously take oral hypoglycemic drugs, blood glucose levels should be carefully monitored and, if necessary, corrected for a 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 Boromylan® should comply with the generally accepted rules for the treatment of cytotoxic drugs.

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

Some of the side effects of the drug, such as dizziness, fainting, visual disturbances and other undesirable effects can adversely affect the ability to drive and perform potentially dangerous activities requiring increased concentration 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 solution for intravenous and subcutaneous administration, 3.5 mg.

Packaging:

For 3.5 mg of bortezomib in bottles of dark glass with a capacity of 10 ml, hermetically sealed with stoppers made of rubber and caps of aluminum-plastic. On the vials stick a self-adhesive label.

5 ml of solvent into neutral glass ampoules of grade НС-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 contoured cell pack of a polyvinyl chloride 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 a dry, 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 an 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-002428

Date of registration:09.04.2014 / 04.08.2016

Expiration Date:09.04.2019

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®)