Boramilan lyophilizate 3.5mg

Pharmacotherapeutic group:

Antitocancer drug

ATX:

L.01.X.X.32 Bortezomib

Pharmacodynamics:

Bortezomib is a reversible inhibitor of the chymotrypsin-like activity of the 26S proteasome of mammalian cells. The 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 maintains intracellular homeostasis. Suppression of 26S-proteasome activity prevents selective proteolysis, which can affect many cascades of signal transduction reactions in the cell. Disruption of the homeostasis maintenance mechanism can lead to cell death. In many in vivo experimental models bortezomib causes inhibition of tumor growth, including multiple myeloma.

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

Pharmacokinetics:

Intravenous absorption

When bortezomib is administered intravenously by jet injection at doses of 1.0 mg/m2 and 1.3 mg/m2 to patients with multiple myeloma, the maximum plasma concentrations (Cmax) of bortezomib are 57 ng/mL and 112 ng/mL, respectively. On subsequent administration of the drug, maximum plasma concentrations range from 67-106 ng/mL for the 1.0 mg/m2 dose and 89-120 ng/mL for the 1.3 mg/m2 dose. The maximum concentration (Cmax) of 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 in patients with multiple myeloma, total systemic exposure after repeated administration at the same dose (AUClast ) is equivalent for both routes.

Distribution

After single or repeated administration at doses of 1.0 mg/m2 and 1.3 mg/m2, the mean volume distribution of bortezomib in patients with multiple myeloma is 1659-3294 L (489-1884 L/m2). This suggests that bortezomib is intensively distributed in peripheral tissues. At bortezomib concentrations of 100-1000 ng/ml, the drug’s binding to plasma proteins averages 83%.

Metabolism

In vitro metabolism of bortezomib is primarily performed by cytochrome P450 isoenzymes – CYP3A4, CYP2C19 and CYP1A2. Participation of CYP2D6 and CYP2C9 isoenzymes in metabolism of bortezomib is insignificant.

The main pathway of metabolism is the detachment of boron atoms to form two metabolites, which are further hydroxylated to form several other metabolites. Bortezomib metabolites do not inhibit the 26S proteasome.

Elimation

The average elimination half-life of bortezomib when administered multiple times is 40-193 hours. The drug is rapidly eliminated after the first dose compared to subsequent doses. After the first administration in doses of 1.0 mg/m2 and 1.3 mg/m2 the mean total clearance is 102 l/h and 112 l/h, respectively, and after subsequent administrations it is 15-32 l/h, respectively.

The excretion routes of bortezomib in humans have not been studied.

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

Pharmacokinetics in patients with hepatic and renal impairment

Mild hepatic impairment does not affect the pharmacokinetics of bortezomib. In patients with moderate to severe hepatic dysfunction there is a 60% increase in AUC (area under the curve “concentration – time”) of bortezomib compared to patients with normal liver function. For patients with moderate to severe hepatic dysfunction, a reduction in the initial dose of bortezomib and dynamic monitoring is recommended.

The pharmacokinetics of bortezomib at doses of 0.7-1.3 mg/m2 intravenously twice weekly in patients with mild, moderate and severe renal impairment, including patients on dialysis, are 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 line of therapy.

Active ingredient

Composition

Composition per 1 vial:

Active substance:

Bortezomib in the form of three-dimensional boroxin (in terms of bortezomib in monomer form) 3.5 mg

Auxiliary substances:

D-Mannitol 35 mg

Solvent: sodium chloride, 0.9% solution for injection

Composition per 1 ml:

Sodium chloride 9.0 mg

Water for injection up to 1.0 ml

How to take, the dosage

Interaction

Special Instructions

Contraindications

– Hypersensitivity to bortezomib, boron and mannitol;

– pregnancy and lactation;

– childhood (no experience with use);

– acute diffuse infiltrative lung disease;

– pericardial involvement.

– Severe to moderate liver function disorders;

– Severe renal function disorders;

– history of seizures or epilepsy;

– fainting;

– history of diabetic neuropathy;

– concurrent use of hypotensive drugs;

p> – dehydration from diarrhea or vomiting;

– constipation;

– risk of chronic heart failure;

– concomitant use of inhibitors or substrates of CYP3A4 isoenzymes, concomitant use of CYP2C9 isoenzyme substrates, oral hypoglycemic agents.

Side effects

The safety performance of bortezomib in monotherapy is similar to that of bortezomib in combination with melphalan and prednisone.

The following are the undesirable side effects that have been considered likely or probably related to the use of bortezomib.

The unwanted side effects are grouped by organ and frequency of occurrence. Frequency was defined as: very common (>10%), common (1-10%), infrequent (0.1-1%), rare (0.01-0.1%), very rare (<0.01%), including individual cases.

Disorders of the blood and lymphatic system:

very common – thrombocytopenia, anemia, neutropenia;

often – leukopenia, lymphopenia;

infrequent – pancytopenia, febrile neutropenia, hemolytic anemia, thrombocytopenic purpura, lymphadenopathy;

rarely – disseminated intravascular coagulation syndrome (DIC syndrome);

frequency unknown – coagulopathy, leukocytosis.

Chronic disorders:

often – cardiac arrest, cardiogenic shock, myocardial infarction, angina pectoris, development and exacerbation of chronic heart failure, ventricular hypokinesia, pulmonary edema (including acute.Acute), sinus node arrest, complete atrioventricular block, tachycardia (incl.sinus and supraventricular), arrhythmia, atrial fibrillation, palpitations; infrequent – atrial flutter, bradycardia, congestion in the small circle of circulation, pulmonary hypertension;

rarely – decrease of left ventricular ejection fraction, cardiac tamponade, pericarditis, ventricular arrhythmias.

Vascular disorders:

often – phlebitis, hematoma, decreased blood pressure (BP), orthostatic and postural hypotension, increased BP;

infrequent – intracerebral hemorrhage, intracranial hemorrhage, subarachnoid hemorrhage, vasculitis, stroke, petechiae, ecchymosis, purpura, discoloration of veins, swollen veins, bleeding wounds, blood flushes;

Rarely, pulmonary embolism, peripheral vascular embolism;

incidence unknown – deep vein thrombosis, thrombophlebitis.

Disorders of the respiratory system, thoracic and mediastinal organs:

very often – shortness of breath;

often – shortness of breath on exercise, nasal bleeding, cough, rhinorrhea;

infrequent – respiratory arrest, hypoxia, pleural effusion, bronchospasm, respiratory alkalosis, tachypnoea, wheezing, nasal congestion, hoarseness, rhinitis, pulmonary hyperventilation, orthopnea, chest pain, pain in sinus cavities, tightness in throat, hemoptysis;

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

Disorders of the gastrointestinal tract:

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

often – abdominal pain, stomatitis, dyspepsia, loose stools, flatulence, hiccups, pain in the throat and pharynx, dry mouth;

infrequent – acute pancreatitis, paralytic bowel obstruction, colitis, melena, GI bleeding, enteritis, dysphagia, belching, spleen pain, esophagitis, gastritis, gastroesophageal reflux, oral mucosa petechiae, salivary gland hypersecretion, tongue plaque, discolored tongue, tongue ulceration, increased appetite;

Rarely – ischemic colitis, peritonitis, ascites, cheilitis.

Liver and biliary tract disorders:

infrequent – hepatitis, hepatic hemorrhage, hypoproteinemia, hyperbilirubinemia, increased alanine aminotransferase and aspartate aminotransferase activity;

rare – liver failure, hepatomegaly, cytomegalovirus hepatitis, gallstone disease.

Nervous system disorders:

very common – peripheral neuropathy, paresthesia, headache;

often – polyneuropathy, dizziness (except vertigo), perversion of taste, dysesthesia, hypoesthesia, tremor;

infrequent – paraplegia, seizures, peripheral motor neuropathy, syncope, paresis, concentration disorders, loss of taste, somnolence, cognitive disorders, postural vertigo, mononeuropathy, speech disorders, restless legs syndrome; rarely – encephalopathy, autonomic neuropathy, posterior reversible leukoencephalopathy syndrome.

Psychiatric disorders:

often – confusion, depression, insomnia, anxiety;

infrequently – agitation, delirium, hallucinations, agitated state, mood swings, changes in mental status, sleep disturbances, irritability, unusual dreams;

Rarely, suicidal ideation, disorientation, delirium, decreased libido.

Renal and urinary tract disorders:

often – renal dysfunction, dysuria;

infrequently – renal failure (including acute acute), oliguria, renal colic, hematuria, proteinuria, urinary retention, frequent urination, difficulty in urination, low back pain, urinary incontinence.

Hearing and labyrinth disorders:

often, vertigo;

infrequently, tinnitus, hearing impairment;

rarely, bilateral deafness.

Visual organ disorders:

often – decreased clarity of vision, eye pain;

infrequent – ocular hemorrhage, visual disturbances, dry eyes, conjunctivitis, photophobia, eye irritation, increased lacrimation, conjunctival hyperemia;

Rarely, ophthalmoherpes, optical neuropathy, blindness;

frequency unknown – diplopia.

Endocrine system disorders:

infrequent – impaired secretion of antidiuretic hormone (ADH);

rare – hypothyroidism;

frequency unknown – hypercorticism, hyperthyroidism.

Muscular and connective tissue disorders:

very common – myalgia;

often – muscle weakness, musculoskeletal pain, pain in the extremities, muscle cramps, arthralgia, bone pain, back pain;

infrequent – muscle cramps, muscle twitching, muscle stiffness, joint swelling, joint stiffness, jaw pain.

Metabolic disorders:

often – dehydration, hypokalemia, hyperglycemia;

infrequent – hyperkalemia, cachexia, hypercalcemia, hypocalcemia, hypernatremia, hyponatremia, hypoglycemia, hyperuricemia, vitamin B12 deficiency, hypomagnesemia, hypophosphatemia.

Reproductive system disorders:

infrequent – testicular pain, erectile dysfunction;

rarely – prostatitis.

Disorders of the immune system:

infrequent – hypersensitivity;

rare – Quincke’s edema, anaphylactic shock, amyloidosis.

Dermal and subcutaneous tissue disorders:

very common – skin rash;

often – periorbital edema, urticaria, pruritus, itching, redness, increased sweating, dry skin, eczema;

infrequent – erythematous rash, photosensitization, bruising, generalized itching, macular rash, papular rash, psoriasis, generalized rash, eyelid edema, facial edema, dermatitis, alopecia, nail lesions, changes in skin pigmentation, atopic dermatitis, changes in hair structure, night sweats, ichthyosis, skin nodules;

Rarely, acute febrile neutrophilic dermatosis (Sweet’s syndrome);

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

Disorders of laboratory and instrumental parameters:

frequently – increased blood lactate dehydrogenase activity;

infrequently – increased alkaline phosphatase activity, increased blood urea concentration, increased gamma-glutamyltransferase activity, increased blood amylase activity, decreased blood hydrocarbonate concentration, increased C-reactive protein concentration;

Rarely, abnormal ECG (including prolongation of the QT interval), abnormal international normalized ratio, decreased pH of gastric juice, increased troponin I, and increased platelet aggregation.

Local reactions:

Infrequent – pain, burning sensation and hyperemia at the injection site, phlebitis. In extravasation – inflammation of subcutaneous fatty tissue.

Others:

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

frequent – asthenia, weakness, malaise, flu-like symptoms, peripheral edema, swelling, weight loss, accession of secondary infections;

infrequent – neuralgia, chills, feeling of tightness in the chest, chest discomfort, groin pain, complications associated with catheter, tumor lysis syndrome, weight gain;

Rarely, herpetic meningoencephalitis, septic shock;

very rarely, progressive multifocal leukoencephalopathy.

Overdose

Overdose of more than twice the recommended dose was accompanied by an acute decrease in blood pressure and thrombocytopenia with fatal outcome.

A specific antidote to bortezomib is not known. In case of overdose, the patient’s vital signs and body temperature should be monitored and appropriate therapy to maintain blood pressure (infusion therapy, vasoconstrictors and/or inotropic drugs) should be administered.