Boramilan lyophilizate 2.5mg

Pharmacodynamics: Bortezomib is a reversible inhibitor of chymotrypsin-like activity of 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 tumor growth inhibition, 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. 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. 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 of 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 binding to plasma proteins is on average 83%. Metabolism Under in vitro metabolism of bortezomib is primarily performed by cytochrome P450 isoenzymes – CYP3A4, CYP2C19 and CYP1A2. Participation of CYP2D6 and CYP2C9 isoenzymes in bortezomib metabolism 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 26S-proteasome. Excretion The average elimination half-life of bortezomib when administered repeatedly is 40-193 hours. The drug is rapidly eliminated after the first dose compared to subsequent administrations. After the first injection of 1.0 mg/m2 and 1.3 mg/m2 doses, mean total clearance is 102 l/h and 112 l/h, respectively, and after subsequent injections – 15-32 l/h, respectively. The excretion routes of bortezomib in humans have not been studied. The effect of sex, age and race on bortezomib pharmacokinetics has not been studied. Pharmacokinetics in patients with hepatic and renal dysfunction Mild hepatic dysfunction has no effect on the pharmacokinetics of bortezomib. In patients with moderate to severe hepatic impairment a 60% increase in AUC (area under the curve “concentration – time”) of bortezomib is observed compared to patients with normal hepatic function. For patients with moderate to severe hepatic dysfunction it is recommended to reduce the initial dose of bortezomib and dynamical monitoring. 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, is comparable to 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

Bortezomib

Composition

Composition per vial: 2.5 mg Active substance Bortezomib in the form of three-dimensional boroxin (in terms of bortezomib in monomer form) 2.5 mg Excipients D-Mannitol 25 mg

How to take, the dosage

Boramilan is indicated only for intravenous and subcutaneous administration. When administered intravenously, the concentration of the solution should be 1 mg/ml. When administered subcutaneously, the solution concentration should be 2.5 mg/ml. The solution concentration must be calculated very carefully due to the different concentrations of the intravenous solution and the solution for subcutaneous injection. Do not administer intrathecally. Death may occur when bortezomib is administered intrathecally. Boramilan® is an antitumor drug. Caution should be exercised when preparing the solution and handling the drug. Appropriate aseptic measures should be observed. It is recommended to use gloves and other protective clothing to prevent skin contact. The drug shall not be mixed with other drugs, except for 0.9 % sodium chloride solution. Chemical and physical stability is preserved for 8 hours at a temperature not exceeding 25 °С when stored in the original vial or syringe in natural light. From the microbiological point of view the prepared solution should be used immediately. If the drug was not used immediately, the consumer is responsible for compliance with the terms and conditions of storage after opening before use. The contents of the vial with 2.5 mg dose is dissolved in 2.5 ml of 0.9% sodium chloride solution, and the contents of the vial with 3.0 mg dose is dissolved in 3.0 ml of 0.9% sodium chloride solution. The concentration of the prepared solution for intravenous injection shall be 1 mg/ml. The prepared solution should be clear and colorless. If mechanical inclusions or color changes are detected, the prepared solution should not be used. The prepared solution is administered by intravenous bolus injection for 3-5 seconds through a peripheral or central venous catheter, which is then flushed with 0.9% sodium chloride solution for injection. The contents of the 2.5 mg vial are dissolved in 1.0 ml of 0.9% sodium chloride solution and the contents of the 3.0 mg vial are dissolved in 1.2 ml of 0.9% sodium chloride solution. The concentration of the prepared solution for subcutaneous injection shall be 2.5 mg/ml. The prepared solution should be clear and colorless. If mechanical inclusions or color changes are detected, the prepared solution should not be used. The prepared solution shall be injected subcutaneously into the thigh area (right and left) or into the abdominal area (right or left). It is necessary to constantly change the place of injection of the drug. 12 Each subsequent injection should be administered at a distance of at least 2.5 cm from the previous injection site. The drug should not be injected into sensitive areas, damaged areas (redness, bruises), as well as in the areas where it is difficult to insert the needle. If there are local reactions at the site of subcutaneous injection of Boramilan® , a less concentrated solution for subcutaneous injection can be used (1 mg/ml instead of 2.5 mg/ml; the 2.5 mg bottle is dissolved in 2.5 ml of 0.9% sodium chloride solution, and the 3.0 mg bottle is dissolved in 3.0 ml of 0.9% sodium chloride solution) or Boramilan® can be injected intravenously.

Interaction

In in vitro and in vivo studies, bortezomib showed properties of a weak inhibitor of cytochrome Р450 isoenzymes 1A2, 2C9, 2C19, 2D6 and 3A4. Based on the insignificant contribution of CYP2D6 isoenzyme in metabolism of bortezomib (7%), in people with low activity of this isoenzyme no changes in total drug distribution are expected. A study of drug interaction with the strong CYP3A4 isoenzyme inhibitor ketoconazole showed an average increase in the AUC of bortezomib by 35%. Therefore, patients receiving bortezomib and a strong CYP3A4 isoenzyme inhibitor (ketoconazole, ritonavir) simultaneously should be closely monitored. The study of the effect of drug interaction with the strong CYP2C19 isoenzyme inhibitor omeprazole on bortezomib pharmacokinetics showed no significant changes in bortezomib pharmacokinetics. A study of the effect of drug interaction with rifampicin, a strong inducer of CYP3A4 isoenzyme, on the pharmacokinetics of bortezomib showed an average 45% decrease in the AUC of bortezomib. Therefore, it is not recommended to use Boramilan® together with strong CYP3A4 inducers, because the effectiveness of therapy may be reduced. CYP3A4 inducers include rifampicin, carbamazepine, phenytoin, phenobarbital and St. John’s wort. The same study also evaluated the effect of dexamethasone, a weaker CYP3A4 inducer. Based on the results of the study, no significant changes in the pharmacokinetics of bortezomib were found. The study of drug interaction of bortezomib with melphalan-prednisolone combination showed a 17% increase in the average AUC of bortezomib. This change is considered clinically insignificant. Cases of hypoglycemia and hyperglycemia have been reported in patients with diabetes mellitus who received oral hypoglycemic agents. Caution should be exercised when using bortezomib in combination with drugs that may be associated with peripheral neuropathy (such as amiodarone, antivirals, isoniazid, nitrofurantoin or statins) and drugs that reduce blood pressure.

Contraindications

Pregnancy and lactation; Childhood (no experience of use); Hypersensitivity to bortezomib, boron, and mannitol; Acute diffuse infiltrative lung disease; Pericardial damage; Concurrent use with strong CYP3A isoenzyme inducers (rifampicin, carbamazepine, phenytoin, phenobarbital, St. John’s wort)

Side effects

Serious adverse reactions are infrequently observed during therapy with bortezomib and include heart failure, tumor lysis syndrome, pulmonary hypertension, reversible posterior encephalopathy syndrome, and acute diffuse infiltrative pulmonary disease. In addition, autonomic neuropathy has been observed in rare cases. The most common adverse reactions reported during therapy with bortezomib are: nausea, diarrhea, constipation, vomiting, fatigue, pyrexia, thrombocytopenia, anemia, neutropenia, peripheral neuropathy (including sensory), headache, paresthesia, decreased appetite, dyspnea, rash, shingles herpes and myalgia. Listed below are the adverse reactions that have been considered likely or probably related to the use of bortezomib. The frequency of adverse reactions that may occur during therapy is given as the following gradation: Very common (> 1/10), common (> 1/100, < 1/10), infrequent (> 1/1000, < 1/100), rare (> 1/10000, < 1/1000), very rare (< 1/10000, including individual reports) and unspecified frequency (frequency cannot be calculated from available data). Infectious and parasitic diseases: often – herpes simplex, herpes zoster (including disseminated and ophthalmoherpes), pneumonia, fungal infections; infrequent – infection, bacterial, viral infections, sepsis (including septic shock), bronchopneumonia, herpesvirus infection, herpes meningoencephalitis, bacteremia (including 13 Rarely – meningitis (including bacterial), barley, influenza, subcutaneous fatty tissue inflammation, infections associated with the use of medical devices, skin infections, ear infections, staphylococcal infections, dental infections; rarely – meningitis (including bacterial), Epstein-Barr virus infection, genital herpes, tonsillitis, mastoiditis, chronic fatigue syndrome. 13 Benign, malignant and unspecified neoplasms (including cysts and polyps): rarely – malignant neoplasms, plasmacytic leukemia, renal carcinoma, neoplasms, fungal mycosis, benign neoplasms. Blood and lymphatic system disorders: very common – thrombocytopenia, neutropenia, anemia; common – leukopenia, lymphopenia; infrequent – pancytopenia, febrile neutropenia, coagulopathy, leukocytosis, lymphadenopathy. hemolytic anemia, rarely – disseminated intravascular coagulation (DIC-syndrome), thrombocytosis, high blood viscosity syndrome, platelet disorders, thrombocytopenic purpura, blood disorders, hemorrhagic diathesis, lymphocytic infiltration. Immune system disorders: infrequent – Quincke’s edema, hypersensitivity, rarely – anaphylactic shock, amyloidosis, reactions with formation of immune complexes (type III). Endocrine system disorders: infrequent – Icenko-Cushing’s syndrome, hyperthyroidism, disorders of antidiuretic hormone secretion, rarely – hypothyroidism. Metabolic and nutritional disorders: very common – decreased appetite; common – dehydration, hypokalemia, hyponatremia, hyponatremia, changes in blood glucose concentration, hypocalcemia, changes in enzyme activity; infrequent – tumor lysis syndrome, no weight gain, hypomagnesemia, hypophosphatemia, hyperkalemia, hypercalcemia, hypernatremia, changes in uric acid concentration, diabetes, fluid retention; rarely – hypermagnesemia, acidosis, disorder of water-electrolyte balance, excessive fluid accumulation, hypochloremia, hypovolemia, hyperchloremia, hyperphosphatemia, metabolic disorders, vitamin B group deficiency, vitamin B12 deficiency, gout, increased appetite, alcohol intolerance. Mental disorders: often – mood and mood disorders, anxiety, disorders and sleep disorders; infrequent – mental status changes, hallucinations, psychotic disorder, confusion, agitation; rarely – suicidal thoughts, adjustment disorder, delirium, decreased libido. Nervous system disorders: very common – neuropathy, peripheral sensory neuropathy, dysesthesia, neuralgia; common – motor neuropathy, loss of consciousness (including fainting), dizziness, perversion of taste, drowsiness, headache; infrequent – tremor, peripheral sensorimotor neuropathy, dyskinesia, balance disorders, memory loss (excl. dementia), encephalopathy, posterior reversible encephalopathy syndrome, neurotoxicity, seizures, postherpetic neuralgia, speech disorder, restless legs syndrome, migraine, sciatica, concentration disorder, pathological reflexes, parosmia; rarely – intracerebral hemorrhage, intracranial hemorrhage (incl.ч. subarachnoid hemorrhage), cerebral edema, transient ischemic attack, coma, autonomic nervous system imbalance, autonomic neuropathy, cranial nerve palsy, paralysis, paresis, preconsciousness, brain stem damage syndrome, cerebral circulation disorder, radicular syndrome, psychomotor hyperactivity, spinal cord compression, cognitive disorders, movement disorders, nervous system disorders, sciatica, salivation, muscle hypotonia. Visual disorders: often – ocular edema, visual disturbances, conjunctivitis; infrequent – ocular hemorrhage, eyelid infections, eye inflammation, diplopia, dry eyes, eye irritation, eye pain, increased lacrimation, eye discharge; rare – corneal damage, exophthalmus, retinitis, scotoma, eye lesions (including eyelids), dacryrioctomy.eyelids), dacryoadenitis, photophobia, photopsia, optical neuropathy, various degrees of visual impairment (up to blindness). Hearing and labyrinth disorders: frequently – vertigo; infrequently – tinnitus, hearing loss (up to deafness), discomfort in the ear; rarely – bleeding, vestibular neuronitis, ear damage. Cardiac disorders: infrequent – cardiac tamponade, cardiopulmonary shock, cardiac fibrillation (including atrial fibrillation), heart failure (including left and right ventricular), arrhythmia, tachycardia, palpitations, angina pectoris, pericarditis (including exudative pericarditis), cardiomyopathy, ventricular dysfunction, bradycardia; rarely – atrial flutter, myocardial infarction, atrioventricular block, cardiovascular disorders (including cardiogenic shock), pirouette-type ventricular tachycardia, unstable angina, heart valve disease, coronary failure, sinus node arrest. Vascular disorders: frequently – decreased blood pressure, orthostatic hypotension, increased blood pressure; infrequently – stroke, deep vein thrombosis, bleeding, thrombophlebitis (including superficial), circulatory collapse (including hypovolemic shock), phlebitis, tides, hematoma (including perirenal), decreased peripheral circulation, vasculitis, hyperemia (including ocular); rarely – peripheral vascular embolism, lymphedema, pallor, erythromelalgia, vasodilation, color changes in veins, venous insufficiency. 15 Respiratory, thoracic and mediastinal disorders: frequently – dyspnea, nasal bleeding, upper and lower respiratory tract infections, cough; infrequently – pulmonary embolism, pleural effusion, pulmonary edema (including acute), pulmonary alveolar hemorrhage, bronchospasm, chronic obstructive pulmonary disease, hypoxemia, airway obstruction, hypoxia, pleurisy, hiccups, rhinorrhea, dysphonia, wheezing; rare – respiratory failure, acute respiratory distress syndrome, apnea, pneumothorax, atelectasis, pulmonary hypertension, hemoptysis, hyperventilation, orthopnea, pneumonitis, respiratory alkalosis, tachypnea, pulmonary fibrosis, bronchial disorders, hypocapnia, interstitial lung disease, lung infiltration, feeling of tightness in the throat, dry throat, increased secretion in the upper respiratory tract, throat irritation, upper respiratory cough syndrome. Gastrointestinal tract disorders: very common – nausea, vomiting, diarrhea, constipation; common – bleeding from the GI tract (including mucosal bleeding), dyspepsia, stomatitis, GI tone disorder, pain in the throat and pharynx, abdominal pain (including. gastrointestinal pain and spleen pain), oral disorders, flatulence; infrequent – pancreatitis (including chronic), vomiting blood, lip swelling, GI obstruction (including intestinal obstruction), abdominal discomfort, oral mucosal ulcers, enteritis, gastritis, gingival bleeding, gastroesophageal reflux disease, colitis (incl.ч. pseudomembranous colitis), ischemic colitis, inflammation of the mucous membrane of the gastrointestinal tract, dysphagia, irritable bowel syndrome, GI disorders, plaque on the tongue, GI motility disorders, salivary gland disorders; rarely – acute pancreatitis, peritonitis, tongue swelling, ascites, esophagitis, cheilitis, fecal incontinence, anal sphincter atony, fecaloma, GI ulceration and perforation, gum hypertrophy, megacolon, discharge from the rectum, the appearance of blisters in the throat, lip pain, periodontitis, anal fissure, changes in defecation rate, proctalgia, stool disorders. Liver and biliary tract disorders: frequently – changes in the activity of “liver” enzymes; infrequently – hepatotoxicity (including liver disorders), hepatitis, cholestasis; rarely – liver failure, hepatomegaly, Budd-Chiari syndrome, cytomegalovirus hepatitis, liver bleeding, gallstone disease. Skin and subcutaneous tissue disorders: common – rash, itching, erythema, dry skin; infrequent – erythema multiforme, urticaria, acute febrile neutrophilic dermatosis, toxic skin rash, toxic epidermal necrolysis, Stevens-Johnson syndrome, dermatitis, altered hair structure, petechiae, ecchymosis, skin lesions, purpura, skin growths, psoriasis, hyperhidrosis, night sweats, bedsores, acne, blisters, skin pigmentation disorders; rare – skin reactions, lymphocytic infiltration of Jessner, palm and plantar erythrodysesthesia, subcutaneous bleeding, reticular lividity, skin induration, papule, photosensitivity reactions, seborrhea, cold sweats, unspecified skin lesions, erythrosis, skin ulcers, nail lesions. Musculoskeletal and connective tissue disorders: very common – musculoskeletal pain; common – muscle cramps, limb pain, muscle weakness; infrequent – muscle twitching, joint swelling, arthritis, joint stiffness, myopathy, feeling of heaviness; rare – rhabdomyolysis, temporomandibular joint syndrome, fistula, joint effusion, pain in jaw, bone disorders, infections and inflammation of musculoskeletal and connective tissue, synovial cysts. Renal and urinary tract disorders: often – impaired renal function, infrequently – acute renal failure, chronic renal failure, urinary tract infections, urinary tract complaints, hematuria, urinary retention, urinary disorders, proteinuria, azotemia, oliguria, pollakiuria; rarely – irritation of the bladder. Genital and breast disorders: infrequent – vaginal bleeding, pain in the genitals, erectile dysfunction; rarely – testicular dysfunction, prostatitis, breast dysfunction, pain in testicular appendages, epididymitis, pain in the pelvis, vulvar ulceration. Congenital, hereditary and genetic disorders: rarely – aplasia, GI malformation, ichthyosis. General disorders and disorders at the place of administration: very often – pyrexia, fatigue, asthenia; often – edema (including peripheral), chills, pain, discomfort; infrequently – deterioration of general physical health, facial edema, reactions at the injection site, mucous membrane disorders, pain in the chest, gait disturbance, feeling of cold, extravasation, complications from catheter use, change of thirst, discomfort in the chest, feeling of body temperature changes, pain in the injection site; rarely – death (including sudden), death of the injected drug.death (including sudden), multiple organ failure, bleeding at the insertion site, hernia, impaired healing processes, inflammation, phlebitis at the insertion site, pain, ulceration, irritability, noncardiac pain in the chest, pain at the insertion site, feeling of a foreign body. 17 Laboratory and instrumental data: often – weight loss; infrequently – hyperbilirubinemia, changes in protein parameters, weight gain, changes in blood parameters, increased concentration of C-reactive protein; rarely – changes in blood gases, changes in cardiogram (including QT wave), changes in prothrombin time, decreased pH of gastric juice, increased platelet aggregation, increased concentration of troponin I, virus detection and changes in serology, changes in urinalysis. Injuries, intoxications and complications of manipulations: infrequent – falls, contusions; rare – transfusion reactions, fractures, stiffness, facial injuries, joint injuries, burns, lacerations, pain during the procedure, radiation exposure. Surgical and therapeutic manipulations: rarely – activation of macrophages.

Overdose

Overdose exceeding the recommended dose by more than 2 times 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, vital signs of the patient should be monitored and appropriate therapy to maintain blood pressure (infusion therapy, vasoconstrictors and/or inotropic drugs) and body temperature should be carried out.