Bortezol (Lyophilisate) Instructions for Use

Marketing Authorization Holder

Pharmasintez-Nord, JSC (Russia)

ATC Code

L01XG01 (Bortezomib)

Active Substance

Bortezomib (Rec.INN registered by WHO)

Dosage Form

Bortezol

Lyophilisate for preparation of solution for intravenous and subcutaneous administration 3.5 mg: 1 or 5 vials

Dosage Form, Packaging, and Composition

Lyophilisate for preparation of solution for intravenous and subcutaneous administration in the form of a lyophilized mass or powder from white to almost white in color.

Excipients: mannitol.

3.5 mg – vials of colorless glass (type I) with a capacity of 10 ml (1) – cardboard packs.
3.5 mg – vials of colorless glass (type I) with a capacity of 10 ml (5) – cardboard boxes (for hospitals).

Clinical-Pharmacological Group

Antineoplastic drug

Pharmacotherapeutic Group

Antineoplastic agent

Pharmacological Action

A highly selective reversible inhibitor of the 26S proteasome activity, it is a modified boric acid.

The 26S proteasome is present in the nucleus and cytosol of all eukaryotic cells and is a key component that catalyzes the breakdown of major proteins involved in controlling the cell life cycle. Bortezomib inhibits the chymotrypsin-like action of the proteasome, causes inhibition of proteolysis and leads to apoptosis.

Myeloma cells are almost 1000 times more susceptible to apoptosis induced by bortezomib than normal plasma cells.

The main factor explaining the ability of the proteasome inhibitor bortezomib to destroy myeloma cells is its ability to block the activation of NF-kB. In normal cells, NF-kB (which exists as a p50-p65 dimer) is bound to the inhibitory protein IkB, which keeps it in an inactive form in the cytosol. Some tumors contain activated forms of NF-kB, and the proteasome plays an important role in this activation, as it catalyzes the proteolytic generation of the NF-kB p50 subgroup from the inactive precursor p150 and the destruction of the inhibitory protein IkB. Activated NF-kB, penetrating into the nucleus, helps the cell to survive and proliferate. By inhibiting the proteasome and, consequently, inhibiting the activation of NF-kB, Bortezomib helps to reduce the number of anti-apoptotic factors, inflammatory molecules, cell adhesion molecules (which allow connecting cells to attach to bone marrow cells) and cytokines (which stimulate the growth of myeloma cells).

Bortezomib causes a slowdown in the growth of human tumors in many experimental models, including multiple myeloma.

Pharmacokinetics

After a single intravenous administration, the concentration of bortezomib in blood plasma decreases in a biphasic manner, the AUC is characterized by a rapid initial distribution phase and a longer terminal elimination phase.

The T_1/2 of bortezomib in the initial distribution phase ranges from 5 to 15 hours.

The bioavailability of bortezomib is dose-dependent in the dose range from 1.45 to 2 mg/m², and in the dose range of 1-1.3 mg/m² it increases proportionally to the dose.

With repeated administration of bortezomib, a decrease in its clearance is observed, which leads to a corresponding increase in T_1/2 in the elimination phase and AUC_0-24. Repeated administrations do not affect the kinetics of the initial distribution of bortezomib, and the values of C_max and T_1/2 in this phase do not change. After the third dose in the first treatment cycle, the average elimination time of bortezomib in the terminal phase increases from 5.45 to 19.7 hours, and AUC_0-24 – from 30.1 to 54 hours/ng/ml.

At bortezomib concentrations of 0.01-1 μg/ml, binding to blood plasma proteins is 82.9%. The proportion of bortezomib bound to blood plasma proteins does not depend on its concentration.

The metabolism of bortezomib is carried out mainly with the participation of the isoenzymes CYP3A4 and CYP2C19. Only a small amount of the intact substance is excreted in the urine; unchanged Bortezomib is not detected in bile and feces.

Indications

Multiple myeloma.

Mantle cell lymphoma in patients who have previously received at least 1 line of therapy.

ICD codes

Dosage Regimen

Administer the recommended initial dose of 1.3 mg/m² as an intravenous or subcutaneous injection.

Follow a twice-weekly schedule for two weeks, specifically on Days 1, 4, 8, and 11.

Observe a 10-day treatment-free rest period from Days 12 to 21 to complete one 21-day cycle.

Ensure a minimum interval of 72 hours is maintained between consecutive doses to mitigate toxicity.

Subsequent treatment cycles are contingent upon clinical response and tolerability.

For patients experiencing specific toxicities, implement dose modifications or schedule interruptions as clinically indicated.

Adjust the regimen based on the severity of hematological toxicity, gastrointestinal events, or peripheral neuropathy.

Perform complete blood counts prior to each dose and throughout the treatment cycle to monitor for cytopenias.

For subcutaneous administration, rotate injection sites to manage local reactions.

Reconstitute the lyophilisate strictly according to the manufacturer’s instructions using sterile 0.9% Sodium Chloride.

Administer the reconstituted solution intravenously as a 3-5 second bolus or subcutaneously.

Do not administer the drug via intrathecal injection under any circumstances.

Adverse Reactions

From the hematopoietic and lymphatic systems: very often – thrombocytopenia, anemia, neutropenia; often – leukopenia, lymphopenia; infrequently – pancytopenia, febrile neutropenia, hemolytic anemia, thrombocytopenic purpura, lymphadenopathy; rarely – DIC syndrome.

From the cardiovascular system: often – cardiac arrest, cardiogenic shock, myocardial infarction, angina pectoris, development and exacerbation of chronic heart failure, ventricular hypokinesia, pulmonary edema (including acute), sinus node arrest, complete AV block, tachycardia (including sinus and supraventricular), arrhythmia, atrial fibrillation, palpitations, decreased blood pressure, orthostatic and postural hypotension, phlebitis, hematoma, increased blood pressure; infrequently – atrial flutter, bradycardia, intracerebral hemorrhage, intracranial hemorrhage, subarachnoid hemorrhage, vasculitis, stroke, pulmonary congestion, pulmonary hypertension, petechiae, ecchymosis, purpura, vein discoloration, vein swelling, wound bleeding, hot flashes; rarely – decreased left ventricular ejection fraction, cardiac tamponade, pericarditis, ventricular arrhythmias, pulmonary embolism, peripheral vascular embolism.

From the respiratory system: very often – shortness of breath; often – shortness of breath on exertion, nosebleeds, cough, rhinorrhea; infrequently – respiratory arrest, hypoxia, pleural effusion, bronchospasm, respiratory alkalosis, tachypnea, wheezing, nasal congestion, hoarseness, rhinitis, pulmonary hyperventilation, orthopnea, chest pain, sinus pain, feeling of tightness in the throat, hemoptysis; rarely – pneumonitis, pneumonia (including interstitial), acute respiratory distress syndrome, acute diffuse infiltrative lung disease, pulmonary hypertension, respiratory failure, alveolar pulmonary hemorrhage.

From the digestive system: very often – nausea, vomiting, diarrhea, constipation, decreased appetite; often – abdominal pain, stomatitis, dyspepsia, loose stools, flatulence, hiccups, throat and pharynx pain, dry mouth; infrequently – acute pancreatitis, paralytic intestinal obstruction, colitis, melena, gastrointestinal bleeding, enteritis, dysphagia, belching, spleen pain, esophagitis, gastritis, gastroesophageal reflux, petechiae of the oral mucosa, salivary gland hypersecretion, tongue coating, tongue discoloration, tongue ulceration, increased appetite; rarely – ischemic colitis.

From the hepatobiliary system: infrequently – hepatitis, liver hemorrhage, hypoproteinemia, hyperbilirubinemia, increased ALT and AST activity; rarely – liver failure.

From the nervous system: very often – peripheral neuropathy, paresthesia, headache; often – polyneuropathy, dizziness (excluding vertigo), taste perversion, dysesthesia, hypesthesia, tremor; infrequently – paraplegia, seizures, peripheral motor neuropathy, fainting, paresis, impaired concentration, loss of taste, drowsiness, cognitive disorders, jerky movements, postural dizziness, mononeuropathy, speech disorders, restless legs syndrome; rarely – encephalopathy, autonomic neuropathy, reversible leukoencephalopathy syndrome; very rarely – symmetrical muscle weakness, tingling and decreased sensitivity first in the legs, then in the arms, face; in severe cases, complete loss of sensation and immobilization (paralysis) with respiratory distress may occur – signs of autoimmune damage to peripheral nerves (Guillain-Barré syndrome; demyelinating polyneuropathy).

Mental disorders: often – confusion, depression, insomnia, anxiety; infrequently – agitation, delirium, hallucinations, agitation, mood swings, changes in mental status, sleep disorders, irritability, unusual dreams.

From the urinary system: often – renal dysfunction, dysuria; infrequently – renal failure (including acute), oliguria, renal colic, hematuria, proteinuria, urinary retention, frequent urination, difficulty urinating, lower back pain, urinary incontinence.

From the hearing organ: often – vertigo; infrequently – tinnitus, hearing impairment; rarely – bilateral deafness.

From the organ of vision: often – blurred vision, eye pain; infrequently – eye hemorrhage, visual disturbances, dry eyes, conjunctivitis, photophobia, eye irritation, increased lacrimation, conjunctival hyperemia; rarely – ophthalmic herpes, optic neuropathy, blindness.

From the immune system: infrequently – hypersensitivity; rarely – angioedema.

From the endocrine system: infrequently – impaired ADH secretion.

From the metabolism: often – dehydration, hypokalemia, hyperglycemia; infrequently – hyperkalemia, cachexia, hypercalcemia, hypocalcemia; hypernatremia, hyponatremia, hypoglycemia, hyperuricemia, vitamin B₁₂ deficiency, hypomagnesemia, hypophosphatemia.

From the skin and subcutaneous tissues: very often – skin rash; often – periorbital edema, urticaria, itchy rash, itching, redness, increased sweating, dry skin, eczema; infrequently – erythematous rash, photosensitivity, bruising, generalized itching, macular rash, papular rash, psoriasis, generalized rash, eyelid edema, facial edema, dermatitis, alopecia, nail lesions, skin pigmentation changes, atopic dermatitis, hair texture changes, night sweats, ichthyosis, skin nodules; rarely – acute febrile neutrophilic dermatosis (Sweet’s syndrome); very rarely – Stevens-Johnson syndrome and toxic epidermal necrolysis.

From the musculoskeletal system: very often – myalgia; often – muscle weakness, musculoskeletal pain, limb pain, muscle cramps, arthralgia, bone pain, back pain; infrequently – muscle spasms, muscle twitching, muscle stiffness, joint swelling, joint stiffness, jaw pain.

From the reproductive system: infrequently – testicular pain, erectile dysfunction.

From laboratory parameters: often – increased LDH activity in the blood; infrequently – increased ALP activity, increased blood urea concentration, increased GGT activity, increased blood amylase activity, decreased blood bicarbonate concentration, increased C-reactive protein concentration.

Local reactions: infrequently – pain, burning sensation and hyperemia at the injection site, phlebitis; with extravasation – inflammation of the subcutaneous fat.

Other: very often – increased fatigue, increased body temperature, herpes zoster (including disseminated); often – asthenia, weakness, malaise, flu-like symptoms, peripheral edema, edema, secondary infection; infrequently – neuralgia, chills, feeling of pressure in the chest, chest discomfort, groin pain, complications associated with the catheter, tumor lysis syndrome, weight gain; rarely – herpetic meningoencephalitis, septic shock; very rarely – progressive multifocal leukoencephalopathy.

Contraindications

Pregnancy, lactation (breastfeeding), childhood, hypersensitivity to bortezomib, boron.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and during lactation (breastfeeding).

Use in Hepatic Impairment

Use with caution in severe liver dysfunction.

Use in Renal Impairment

Use with caution in severe renal dysfunction.

Pediatric Use

Contraindicated in childhood.

Special Precautions

Use with caution in severe liver and kidney dysfunction, with a history of fainting, diabetic neuropathy, in patients receiving antihypertensive drugs, as well as in dehydration due to diarrhea or vomiting.

If orthostatic hypotension develops, hydration, administration of corticosteroids and/or sympathomimetics is recommended; if necessary, the dose of antihypertensive drugs should be reduced.

Special caution is required when prescribing the drug to patients with risk factors for seizures.

Before starting and during each cycle of therapy, a complete blood count with leukocyte count and platelet count should be performed.

If the platelet count decreases <25,000/μl, therapy should be suspended. When the platelet count recovers, treatment should be continued at reduced doses with careful consideration of the potential benefits and risks of treatment. Colony-stimulating factors, platelet and red blood cell transfusions can be used to treat hematologic toxicity.

To prevent nausea and vomiting, the use of antiemetic drugs is recommended. If diarrhea occurs, antidiarrheal drugs are prescribed. To prevent or treat dehydration, patients should undergo rehydration therapy and maintain water and electrolyte balance.

Due to the possible development of intestinal obstruction, patients with constipation should be monitored dynamically.

If neuropathy occurs, supportive therapy is carried out. Usually, the frequency of peripheral neuropathy reaches a maximum by the 5th cycle of treatment. If new or worsening symptoms of peripheral neuropathy appear, it may be necessary to reduce the dose and change the regimen of bortezomib administration.

Fluid retention may predispose to the development of symptoms of heart failure.

Due to the possible development of hyperuricemia associated with tumor lysis syndrome, patients are recommended to determine the level of uric acid and creatinine in the blood serum during therapy. To prevent hyperuricemia, plenty of fluids are recommended, if necessary – allopurinol and urine alkalinization.

When treating patients with amyloidosis with bortezomib, caution should be exercised, since the effect of proteasome activity inhibition in diseases accompanied by an increase in protein content is unknown.

When used in patients receiving oral hypoglycemic drugs, blood glucose levels should be carefully monitored and, if necessary, the dose of hypoglycemic drugs should be adjusted.

When working with bortezomib, generally accepted rules for handling cytotoxic drugs should be observed.

Drug Interactions

Cases of hypoglycemia and hyperglycemia have been reported in diabetic patients taking oral hypoglycemic drugs.

Although there are no data on the interaction of bortezomib with drugs, patients require careful monitoring when used concomitantly with active inhibitors of CYP3A4 (ketoconazole, ritonavir) and CYP2C19 (fluoxetine) or inducers of CYP3A4 (rifampicin). Use with caution concomitantly with substrates of the CYP3A4 and CYP2C19 isoenzymes.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.