Bortezomib

2024 Author: Rachel Wainwright | [email protected]. Last modified: 2023-12-15 07:39

Bortezomib: instructions for use and reviews

1. Release form and composition
2. Pharmacological properties
3. Indications for use
4. Contraindications
5. Method of application and dosage
6. Side effects
7. Overdose
8. Special instructions
9. Application during pregnancy and lactation
10. Use in childhood
11. In case of impaired renal function
12. For violations of liver function
13. Drug interactions
14. Analogs
15. Terms and conditions of storage
16. Terms of dispensing from pharmacies
17. Reviews
18. Price in pharmacies

Latin name: Bortezomib

ATX code: L01XX32

Active ingredient: bortezomib (bortezomib)

Producer: ZAO Biocad (Russia), OOO BratskKhimSintez (Russia), OOO Company Deco (Russia), Synthon sro (Czech Republic)

Description and photo updated: 2019-27-08

Lyophilisate for the preparation of a solution for subcutaneous and intravenous administration Bortezomib

Bortezomib is a drug with an antitumor effect.

Release form and composition

The dosage form is a lyophilisate for the preparation of a solution for subcutaneous and intravenous administration: an almost white or white porous mass (in glass vials of 3.5 mg, in a cardboard box 1 bottle and instructions for use of Bortezomib).

Composition of 1 bottle of lyophilisate for single use:

active substance: bortezomib - 3.5 mg;
auxiliary components: mannitol - 35 mg, nitrogen - in sufficient quantity.

Pharmacological properties

Pharmacodynamics

Bortezomib is a reversible inhibitor of the chymotrypsin-like activity of the 26S proteasome in mammalian cells. The 26S proteasome is a large protein complex that leads to the degradation of ubiquitin-conjugated proteins. The main role in the regulation of the intracellular concentration of some proteins is played by the ubiquitin-proteasome pathway, thanks to this process, intracellular homeostasis is maintained. By suppressing the activity of the proteasome, this selective proteolysis is prevented, which can affect various cascades of signal transduction reactions in the cell. When the mechanism for maintaining homeostasis is disturbed, cell death occurs.

Bortezomib in many experimental models leads to a slowdown in tumor growth, including multiple myeloma. During the research, it was found that the substance enhances the differentiation and activity of osteoblasts and inhibits the function of osteoclasts. Such effects during therapy were recorded in patients with multiple myeloma with multiple foci of osteolysis.

Pharmacokinetics

In multiple myeloma, the maximum plasma concentrations of Bortezomib are 57 and 112 ng / ml with intravenous jet injection at doses of 1 and 1.3 mg / m ^2, respectively. With subsequent injections of the same doses, the maximum plasma concentrations are in the range of 67-106 and 89-120 ng / ml, respectively. With repeated administration, the average half-life of the substance is 40-193 hours.

After the first dose, in comparison with subsequent doses, the drug is excreted faster. The average total clearance after the first application of doses of 1 and 1.3 mg / m ² is 102 and 112 l / h, respectively, after subsequent injections it is in the range from 15 to 32 l / h.

In multiple myeloma, the total systemic exposure after repeated subcutaneous or intravenous administration (AUC _last) of a dose of 1.3 mg / m ² for both routes of administration is equivalent (155 and 151 nghh / ml for subcutaneous and intravenous administration, respectively). After subcutaneous administration, C _max (maximum concentration of the substance) is lower than after intravenous administration (20.4 and 223 ng / ml, respectively). The geometric mean AUC _last is 0.99, and the 90% confidence intervals range from 80.18 to 122.8%. T _max (time to reach the maximum concentration of the substance) is: subcutaneous administration - 30 minutes, intravenous administration - 2 minutes.

The average volume of distribution after a single / multiple administration of Bortezomib at doses of 1 and 1.3 mg / m ² is 1659–3294 l (from 489 to 1884 l / m ²). This suggests that bortezomib undergoes intensive distribution in peripheral tissues. At a substance concentration of 100–1000 ng / ml, binding to blood plasma proteins averages 83%. The fraction of bortezomib bound to plasma proteins does not depend on the concentration.

Bortezomib metabolism occurs mainly with the help of cytochrome P ₄₅₀ isoenzymes such as CYP3A4, CYP1A2 and CYP2C19. The isoenzymes CYP2D6 and CYP2C9 take insignificant part in the metabolism of the substance. The main metabolic pathway is the splitting off of boron atoms, resulting in the formation of two metabolites. They are subsequently hydroxylated, resulting in the formation of several other metabolites. Bortezomib metabolites do not inhibit the 26S proteasome.

The ways of removing the substance from the human body have not been studied.

In the presence of moderate and severe hepatic dysfunctions, there is an increase in AUC (area under the concentration-time curve) by 60% in comparison with the values of the indicator in patients without these disorders. Patients with moderate / severe hepatic impairment are advised to start therapy at a reduced initial dose. The condition of such patients should be carefully monitored.

The efficacy / safety of Bortezomib in children with recurrent pre-B-cell acute lymphoblastic leukemia has not been studied. Pharmacokinetic parameters of the substance were studied in children aged 2-16 years with acute lymphoblastic and myeloid leukemia (intravenous bolus injection 2 times a week at a dose of 1.3 mg / m ²). Excretion of bortezomib, according to population pharmacokinetic analysis, increases with increasing body surface area. The clearance of a substance in the pediatric population, normalized by body surface area, has similar values to that in adults.

Indications for use

multiple myeloma;
mantle cell lymphoma in patients who have previously received at least the first line of therapy.

Contraindications

Absolute:

damage to the pericardium;
diffuse infiltrative lung diseases in acute course;
age up to 18 years (the safety profile for this group of patients has not been studied);
pregnancy and lactation;
individual intolerance to the components of the drug.

Relative (the appointment of Bortezomib requires caution in the presence of the following diseases / conditions):

constipation;
severe renal impairment;
moderate / severe hepatic dysfunction;
dehydration with diarrhea or vomiting;
aggravated history of diabetic neuropathy, seizures, or epilepsy;
the risk of chronic heart failure;
fainting;
combined use with antihypertensive drugs, oral hypoglycemic drugs, inhibitors or substrates of the CYP3A4 isoenzyme, substrates of the CYP2C9 isoenzyme.

Bortezomib, instructions for use: method and dosage

The route of administration of Bortezomib is intravenous (IV) jet for 3-5 seconds or subcutaneously (SC). Intrathecal administration is prohibited as deaths have been reported.

Solution concentration:

IV injection: 1 mg / ml;
s / c administration: 2.5 mg / ml.

Monotherapy

The recommended dose - 1.3 mg / m ² body surface area, bortezomib is administered 2 times a week for 2 weeks (1, 4, 8 and 11 days), then make a break of 10 days (12 to 21 day). The interval between the injections of successive doses of Bortezomib should be at least 72 hours.

It is recommended to evaluate the effectiveness of therapy after the end of the 3rd and 5th cycles. With a complete clinical response, 2 additional cycles are recommended.

If the duration of therapy exceeds 8 cycles, Bortezomib can be used according to the standard regimen or according to the maintenance treatment regimen - weekly for 4 weeks (on days 1, 8, 15 and 22), followed by a thirteen-day interval (from 23 to 35 days). In the absence of a clinical response (progression / stabilization of the disease after 2 or 4 cycles, respectively), a combination of Bortezomib with dexamethasone in high doses may be prescribed. In such cases, dexamethasone is administered orally at a dose of 40 mg with each dose of Bortezomib (20 mg on the day of administration and the next day after administration). Thus, dexamethasone is taken on days 1, 2, 4, 5, 8, 9, 11 and 12, the course dose for 3 weeks is 160 mg.

In cases of grade IV hematological toxicity or any non-hematological grade III toxic effect, except for neuropathy, the use of Bortezomib is suspended. Resumption of therapy is possible after the disappearance of symptoms of toxicity, but the drug is prescribed in a dose reduced by 25%. Also, dose adjustment is required in cases of peripheral sensory neuropathy and / or neuropathic pain.

Patients on dialysis must receive Bortezomib after dialysis.

In cases of moderate and severe hepatic dysfunction, treatment begins with reduced doses.

Combination therapy

When carrying out a combined treatment, Bortezomib is administered in the same way as in monotherapy. The drugs used simultaneously are melphalan and prednisolone (oral).

Usually 9 cycles of 6 weeks are prescribed. In 1-4 cycles, Bortezomib is administered 2 times a week (on days 1, 4, 8, 11, 22, 25, 29 and 32), in 5-9 - once a week (on days 1, 8, 22 and 29).

Single doses: Bortezomib - 1.3 mg / m ²; melphalan - 9 mg / m ²; prednisolone - 60 mg / m ².

Before starting a new treatment cycle, the following indicators should be checked:

ANC (absolute neutrophil count): should be> 1 x 10 ⁹ / l;
platelet count: should be> 70 x 10 ⁹ / l;
non-hematological toxicity: should be reduced to baseline or grade I.

When preparing the solution, appropriate aseptic measures must be observed. Bortezomib cannot be mixed with other drugs, except for 0.9% sodium chloride solution.

Features of preparation and administration of solutions:

i / v: the contents of 1 bottle must be dissolved in a 0.9% sodium chloride solution of 3.5 ml. The solution is given by intravenous bolus injection over 3–5 seconds through a central or peripheral venous catheter;
s / c: the contents of 1 bottle must be dissolved in 0.9% sodium chloride solution of 1.4 ml. The solution is injected into the thigh or abdomen. The injection site should be constantly changed. The distance between the sites of successive injections is at least 2.5 cm. In sensitive / damaged areas, the introduction of Bortezomib is contraindicated. With the development of local reactions, it is allowed to use a less concentrated solution (1 mg / ml) or switch to intravenous administration of the drug.

Side effects

The safety profile of using Bortezomib as monotherapy and in combination with other drugs is identical.

Serious disorders, including tumor lysis syndrome, heart failure, pulmonary hypertension, acute diffuse infiltrative pulmonary disease, and reversible posterior encephalopathy syndrome, are uncommon. In rare cases, the development of autonomic neuropathy has been noted. Most often, the following adverse reactions developed: neutropenia, nausea, herpes zoster, fatigue, diarrhea, rash, vomiting, constipation, fever, shortness of breath, thrombocytopenia, anemia, myalgia, peripheral neuropathy, pain, loss of appetite, paresthesia.

Possible side effects of Bortezomib (very often - ≥ 10%; often - ≥ 1% and <10%; infrequently - ≥ 0.1% and <1%; rarely - ≥ 0.01% and <0.1%; very rarely - <0.01%, taking into account individual cases):

immune system: infrequently - hypersensitivity; rarely - amyloidosis, Quincke's edema, anaphylactic shock, reactions with the formation of type III immune complexes;
lymphatic system and blood: very often - neutropenia, thrombocytopenia, anemia; often - lymphopenia, leukopenia; infrequently - coagulopathy, lymphadenopathy, febrile neutropenia, pancytopenia, thrombocytopenic purpura, hemolytic anemia, leukocytosis; rarely - disseminated intravascular coagulation syndrome (disseminated intravascular coagulation syndrome), thrombocytosis, high blood viscosity syndrome, platelet disorders, lymphocytic infiltration, hemorrhagic diathesis;
neoplasms (including polyps / cysts): rarely - fungal mycosis, malignant neoplasms, renal carcinoma, benign neoplasms, plasmacytic leukemia, unspecified neoplasms;
infections and parasitic diseases: often - fungal infections, herpes zoster / herpes simplex; infrequently - herpetic meningoencephalitis, sepsis, herpesvirus infection, bronchopneumonia, bacteremia, influenza, barley, inflammation of the subcutaneous fat, skin, ear, dental and staphylococcal infections; rarely - mastoiditis, meningitis, chronic fatigue syndrome, Epstein-Barr viral infection, tonsillitis, genital herpes;
endocrine system: infrequently - Itsenko-Cushing's syndrome, impaired secretion of antidiuretic hormone, hyperthyroidism; rarely - hypothyroidism;
psyche: often - disturbances / disorders of mood and sleep, anxiety; infrequently - confusion, changes in mental status, psychotic disorder, hallucinations, agitated state; rarely - suicidal thoughts, decreased libido, delirium, adjustment disorder;
nutrition and metabolism: very often - decreased appetite; often - changes in enzyme activity, hypokalemia, dehydration, hyperglycemia; infrequently - hyponatremia, tumor lysis syndrome, cachexia, hyperkalemia, vitamin B ₁₂ deficiency, hypocalcemia, hypercalcemia, hypernatremia, hyperuricemia, hypoglycemia, hypophosphatemia, hypomagnesemia, diabetes mellitus, no weight gain, weight loss, fluid retention; rarely - excessive fluid accumulation, acidosis, hypermagnesemia, deficiency of B vitamins, weight gain, alcohol intolerance, imbalance in water and electrolyte balance, hypochloremia, hypovolemia, hyperchloremia, metabolic disorders, hyperphosphatemia, gout;
nervous system: very often - peripheral sensory neuropathy, neuropathy, neuralgia, dysesthesia; often - dizziness, motor neuropathy, headache, loss of consciousness, lethargy, taste perversion; infrequently - dyskinesia, tremor, peripheral sensorimotor neuropathy, posterior reversible encephalopathy syndrome, imbalance, migraine, impaired concentration, sciatica, memory loss (excluding dementia), speech disorder, encephalopathy, neurotoxicity, postherpetic neuralgia, seizures, restless legs syndrome, paroxysmal, pathological reflexes; rarely - light-headedness, impaired cerebral circulation, radicular syndrome, cognitive disorders, disorders of the nervous system and movements, muscle hypotension, salivation, sciatica, psychomotor hyperactivity, spinal cord compression, autonomic neuropathy,intracerebral hemorrhage, intracranial hemorrhage, cerebral edema, coma, transient ischemic attack, imbalance of the autonomic nervous system, cranial nerve palsy, paralysis, paresis, brain stem lesion syndrome;
organ of hearing and labyrinthine disorders: often - vertigo; infrequently - ringing in the ears, discomfort in the ear, hearing impairment; rarely - vestibular neuronitis, bleeding from the ear;
organ of vision: often - decreased vision clarity, periorbital edema, pain in the eyes; infrequently - conjunctivitis, dry eyes, photophobia, eyelid infections, diplopia, eye inflammation, eye irritation, conjunctival hyperemia, increased lacrimation, bleeding in the eye, visual impairment, discharge from the eyes; rarely - retinitis, photopsia, dacryoadenitis, optic neuropathy, exophthalmos, blindness, corneal lesions, scotoma, eye lesions;
respiratory system: very often - shortness of breath; often - infections of the upper / lower respiratory tract, nosebleeds, shortness of breath on exertion, rhinorrhea, cough; infrequently - tachypnea, respiratory arrest, pleural effusion, nasal congestion, hypoxia, pulmonary edema, hemoptysis, feeling of tightness in the throat, bronchospasm, respiratory alkalosis, wheezing, hoarseness, rhinitis, pulmonary hyperventilation, chronic obstructive pulmonary disease, pleurisy, hypoxemia, dysphonia, pain in the paranasal sinuses and chest area; rarely - pneumonitis, pneumonia, acute respiratory failure syndrome, respiratory failure, acute diffuse infiltrative lung damage, cough syndrome of the upper respiratory tract, alveolar hemorrhage in the lung, atelectasis, pneumothorax, pulmonary fibrosis, hypocapnia, bronchial disturbance,interstitial lung disease, throat irritation, increased secretion in the upper respiratory tract;
cardiovascular system: often - postural / orthostatic hypotension, cardiac arrest, cardiovascular disorders, myocardial infarction, sinus node arrest, angina pectoris, atrioventricular block, lowering / increasing blood pressure, chronic heart failure, ventricular hypokinesia, tachycardia, atrial fibrillation, arrhythmia, palpitations, phlebitis, hematoma; infrequently - hyperemia, pulmonary hypertension, bradycardia, atrial flutter, cardiopulmonary shock, cardiac fibrillation, cardiomyopathy, pericarditis, ventricular dysfunction, vasculitis, thrombophlebitis, circulatory collapse, blood congestion in the pulmonary circulation, circulatory system, petechiae, petechiae discoloration of veins, decreased peripheral circulation, deep vein thrombosis, vein swelling, bleeding wounds;rarely - cardiac tamponade, lower left ventricular ejection fraction, unstable angina pectoris, lymphedema, vasodilation, erythromelalgia, venous insufficiency, ventricular tachysystolic arrhythmia, pirouette type, heart valve disease, coronary insufficiency, pallor, pulmonary artery / peripheral embolism;
digestive system: very often - constipation, nausea, diarrhea, vomiting; often - dry mouth, stomatitis, dyspepsia, hiccups, swelling of the lips, vomiting of blood, flatulence, loose stools, pain in the abdomen, mouth, throat and pharynx; infrequently - melena, colitis, acute pancreatitis, paralytic intestinal obstruction, bleeding from the gastrointestinal tract, enteritis, belching, dysphagia, pain in the spleen area, esophagitis, gastritis, gastroesophageal reflux, pseudomembranous colitis, petechiae of the mucous membrane of the mouth ulceration of the oral mucosa, abdominal discomfort, hypersecretion of the salivary glands, plaque on the tongue, discoloration of the tongue, increased appetite, bleeding from the gums, inflammation of the mucous membrane and impaired motility of the gastrointestinal tract; rarely - peritonitis, fecal incontinence, tongue edema, cheilitis, ascites,ischemic colitis, irritable bowel syndrome, atony of the anal sphincter, fecaloma, periodontitis, ulceration of the gastrointestinal tract and perforation of the gastrointestinal tract, megacolon, stool disorders, gingival hypertrophy, rectal discharge, blistering in the pharynx, pain in the lips, anal crack, change in the rhythm of defecation, proctalgia;
subcutaneous tissue and skin: very often - skin rash; often - eczema, redness, dry skin, increased sweating, itchy rash, hives, itching; infrequently - erythematous rash, photosensitivity, psoriasis, bruising, atopic dermatitis, generalized pruritus, macular rash, skin nodules, ichthyosis, erythema multiforme, toxic skin rash, ecchymosis, petechiae, purpura, papular rash and face, swelling changes in hair structure, dermatitis, alopecia, nail damage, changes in skin pigmentation, night sweats, skin lesions, acne, pressure sores, blisters, skin neoplasms, hyperhidrosis; rarely - cold sweat, subcutaneous bleeding, livedo mesh, skin induration, skin ulcers, acute febrile neutrophilic dermatosis, Jessner's lymphocytic infiltration - Kanof, seborrhea, erythrosis,palmar-plantar erythrodysesthesia, skin reactions; very rarely - toxic epidermal necrolysis, Stevens-Johnson syndrome;
biliary tract and liver: infrequently - hepatotoxicity, hemorrhage in the liver, hepatitis, hyperbilirubinemia, hypoproteinemia, cholestasis; rarely - hepatomegaly, liver failure, cytomegalovirus hepatitis, Budd-Chiari syndrome, cholelithiasis;
genitals and mammary gland: infrequently - erectile dysfunction, pain in the genitals, vaginal bleeding; rarely - ulceration of the vulva, soreness of the epididymis, prostatitis, epididymitis, dysfunction of the testicles and mammary gland, pain in the pelvic area;
kidneys and urinary tract: often - dysuria, impaired renal function; infrequently - pollakiuria, renal failure, oliguria, renal colic, proteinuria, hematuria, urinary retention, urinary tract infections, back pain, azotemia, frequent urination, difficulty urinating, urinary incontinence; rarely - irritation of the bladder;
musculoskeletal system: very often - myalgia; often - musculoskeletal pain, muscle weakness / cramps, arthralgia, pain in the back, bones, limbs; infrequently - muscle twitching, myopathy, arthritis, muscle stiffness, feeling of heaviness, muscle spasms, joint stiffness / swelling, pain in the jaws; rarely - temporomandibular joint syndrome, rhabdomyolysis, joint effusion, fistula, jaw pain, bone disorders, synovial cyst, inflammation / infection of connective and musculoskeletal tissues;
genetic, hereditary and congenital disorders: rarely - malformation of the gastrointestinal tract, ichthyosis, aplasia;
instrumental and laboratory data: often - weight loss, increased activity of blood lactate dehydrogenase; infrequently - a decrease in the concentration of bicarbonates in the blood, an increase in the concentration of urea in the blood, an increase in the activity of blood alkaline phosphatase, gamma-glutamyltransferase and blood amylase, an increase in the concentration of C-reactive protein, weight gain; rarely - changes in urine analysis, an increase in troponin I concentration, a change in the content of gases in the blood, a decrease in the pH of gastric juice, ECG changes, a change in prothrombin time, an increase in platelet aggregation;
therapeutic and surgical manipulations: rarely - activation of macrophages;
intoxication, injury and complications of manipulation: infrequently - contusions, falls; rarely - burns, transfusion reactions, rigidity, pain during the procedure, fractures, injuries to the joints and face, ruptures, radiation damage;
violations at the injection site and general disorders: very often - fever, fatigue; often - flu-like symptoms, asthenia, weakness, peripheral edema, a feeling of malaise, edema; infrequently - discomfort in the chest, deterioration in general physical health, swelling of the mucous membranes / face, chills, feeling of pressure in the chest, pain in the chest, feeling cold, disturbed gait, change in feeling of thirst, phlebitis, sensation of changes in body temperature, complications, associated with the catheter, pain, flushing and burning sensation at the injection site; with extravasation - inflammation of the subcutaneous fat; rarely - hernia, death, impaired healing processes, multiple organ failure, foreign body sensation, bleeding at the injection site, non-cardial chest pain.

Overdose

The main symptoms (if the dose is exceeded by more than 2 times): acute decrease in blood pressure, fatal thrombocytopenia.

Therapy: control of vital functions, measures aimed at maintaining blood pressure (infusion therapy, inotropic and / or vasoconstrictor drugs) and body temperature. The specific antidote is unknown.

special instructions

It is possible to carry out therapy with Bortezomib only under the supervision of an experienced doctor.

The drug cannot be administered intrathecally.

Before the start, as well as during each cycle of using Bortezomib, a clinical blood test should be performed, calculating the leukocyte formula and platelet count.

When working with the solution, it is necessary to follow the generally accepted rules for handling cytotoxic drugs.

Influence on the ability to drive vehicles and complex mechanisms

Patients are advised to refrain from driving in cases of side effects such as fainting, dizziness, and visual disturbances.

Application during pregnancy and lactation

Bortezomib is not prescribed during pregnancy / lactation.

Adequate safety studies of the substance when used in pregnant women have not been conducted. Bortezomib can adversely affect the fetus.

If bortezomib was used during pregnancy, or pregnancy occurred during therapy, the woman should be informed about the potential risk to the fetus. When conducting studies on rabbits, it was found that the use of bortezomib at a dose lower than the therapeutic dose leads to embryofetal death.

When using Bortezomib, women with preserved reproductive potential should avoid pregnancy.

Whether the substance passes into breast milk is unknown. It should be borne in mind that, like most drugs, bortezomib can be excreted in breast milk. If the substance enters the body of a newborn, serious adverse events are possible.

Pediatric use

Bortezomib therapy is contraindicated in patients under 18 years of age.

With impaired renal function

Bortezomib should be used with caution in severe renal impairment.

For violations of liver function

Bortezomib should be used with caution in moderate / severe hepatic impairment.

Drug interactions

With the combined use of Bortezomib with certain drugs / substances, the following effects may develop:

oral hypoglycemic drugs: development of hyperglycemia and hypoglycemia;
strong inhibitors of the isoenzyme CYP3A4, including ritonavir, ketoconazole: an increase in the mean AUC (area under the concentration-time curve) bortezomib (the combination requires caution);
neurotoxic drugs that may be associated with peripheral neuropathy, including amiodarone, isoniazid, antiviral agents, statins, nitrofurantoin, and blood pressure lowering drugs: development of interactions (caution required).

Analogs

Bortezomib's analogs are: Bartizar, Verozomib, Velcade, Milatib, Bortezol, Mayborte, Boramilan.

Terms and conditions of storage

Store at temperatures up to 30 ° C in a dark place. Keep out of the reach of children.

The shelf life is 3 years.

After dissolution, Bortezomib can be stored for no longer than 8 hours in its original packaging at temperatures up to 25 ° C.

Terms of dispensing from pharmacies

Dispensed by prescription.

Reviews about Bortezomib

Reviews about Bortezomib are few. Since the drug is difficult to purchase in the pharmacy network, its analogues are most often used for therapy.

Price for Bortezomib in pharmacies

The approximate price for Bortezomib (1 bottle of 3.5 mg) is 5950 rubles.

Maria Kulkes Medical journalist About the author

Education: First Moscow State Medical University named after I. M. Sechenov, specialty "General Medicine".

Information about the drug is generalized, provided for informational purposes only and does not replace the official instructions. Self-medication is hazardous to health!