Velcade^® (Lyophilisate) Instructions for Use

ATC Code

L01XG01 (Bortezomib)

Active Substance

Bortezomib (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antineoplastic drug

Pharmacotherapeutic Group

Antineoplastic agent

Pharmacological Action

Bortezomib is a reversible inhibitor of the chymotrypsin-like activity of the 26S proteasome in mammalian cells. This proteasome is a large protein complex that degrades ubiquitin-conjugated proteins. The ubiquitin-proteasome pathway plays a key role in regulating the intracellular concentration of specific proteins and thus maintains intracellular homeostasis. Inhibition of proteasome activity prevents this selective proteolysis, which can affect multiple signaling cascades within the cell. Disruption of this homeostatic mechanism can lead to cell death. In vivo, Bortezomib caused delayed tumor growth in many experimental models, including multiple myeloma.

In in vitro, ex vivo, and animal model experiments, Bortezomib enhanced osteoblast differentiation and activity and inhibited osteoclast function. These effects were observed in patients with multiple myeloma with multiple osteolytic lesions receiving bortezomib therapy.

Pharmacokinetics

Following intravenous bolus administration of bortezomib at doses of 1.0 mg/m² and 1.3 mg/m² to patients with multiple myeloma, the maximum plasma concentrations of the drug were 57 and 112 ng/ml, respectively. Upon 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 mean elimination half-life of the drug after multiple administrations is 40-193 hours.

The drug is eliminated faster after the first dose compared to subsequent doses. After the first administration at doses of 1.0 mg/m² and 1.3 mg/m², the mean total clearance is 102 and 112 L/h, respectively, and after subsequent administrations, it is 15-32 L/h, respectively.

When administered subcutaneously or intravenously at a dose of 1.3 mg/m² to patients with multiple myeloma, the total systemic exposure after repeated administration of the same dose (AUC _last) was equivalent for both routes of administration (155 ng·h/ml for subcutaneous and 151 ng·h/ml for intravenous administration). C_max after subcutaneous administration (20.4 ng/ml) was lower than after intravenous administration (223 ng/ml). The geometric mean ratio for AUC _last was 0.99, with 90% confidence intervals of 80.18-122.80%. T_max was 30 minutes for subcutaneous administration and 2 minutes for intravenous administration.

After single or multiple administrations 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 extensively distributed into peripheral tissues. At bortezomib concentrations of 100-1000 ng/ml, the binding of the drug to plasma proteins averages 83%. The fraction of bortezomib bound to plasma proteins is concentration-independent.

In vitro, the metabolism of bortezomib is primarily mediated by cytochrome P450 isoenzymes – CYP3A4, CYP2C19, and CYP1A2.

The involvement of CYP2D6 and CYP2C9 isoenzymes in the metabolism of bortezomib is minor. The main metabolic pathway is deboronation to form two metabolites, which are subsequently hydroxylated to form several other metabolites. Bortezomib metabolites do not inhibit the 26S proteasome. The routes of elimination of bortezomib in humans have not been studied.

The influence of age, gender, and race on the pharmacokinetics of bortezomib has not been studied.

Studies of the pharmacokinetics of bortezomib in cancer patients with impaired hepatic function were conducted in 61 patients with varying degrees of hepatic impairment (see Table 2) using bortezomib doses of 0.5-1.3 mg/m². Mild hepatic impairment does not affect the pharmacokinetics of bortezomib. In patients with moderate and severe hepatic impairment, a 60% increase in the AUC (area under the concentration-time curve) of bortezomib was observed compared to patients with normal hepatic function. For patients with moderate and severe hepatic impairment, a reduction in the initial dose of bortezomib is recommended. Close monitoring of such patients is required.

The pharmacokinetics of bortezomib at doses of 0.7-1.3 mg/m² administered intravenously twice weekly in patients with mild, moderate, or severe renal impairment, including patients on dialysis, are comparable to the pharmacokinetics of the drug in patients with normal renal function.

Indications

Velcade^® is indicated for the treatment of

• Multiple myeloma;
• Mantle cell lymphoma in patients who have received at least 1 prior line of therapy.

ICD codes

Dosage Regimen

Lyophilisate

Velcade^® is indicated for intravenous and subcutaneous administration only.

Cases of death have been reported following intrathecal administration.

For intravenous administration, the solution concentration should be 1 mg/ml. For subcutaneous administration, the solution concentration should be 2.5 mg/ml.

The solution concentration should be calculated very carefully due to the difference in concentrations for intravenous and subcutaneous administration.

Monotherapy

The drug is administered as an intravenous bolus over 3-5 seconds and subcutaneously.

The recommended initial dose of bortezomib is 1.3 mg/m² of body surface area twice weekly for 2 weeks (days 1, 4, 8, and 11) followed by a 10-day rest period (days 12-21). At least 72 hours should elapse between consecutive doses of Velcade^®.

It is recommended to assess the degree of clinical response after 3 and 5 treatment cycles.

In case of a complete clinical response, it is recommended to conduct 2 additional treatment cycles.

For treatment durations longer than 8 cycles, Velcade^® can be used according to the standard schedule or according to a maintenance therapy schedule – weekly for 4 weeks (days 1, 8, 15, 22) followed by a 13-day rest period (days 23-35).

For patients in whom therapy with Velcade^® has not shown a clinical response (disease progression or stabilization after 2 or 4 cycles, respectively), a combination of high-dose dexamethasone with Velcade^® may be prescribed. In this case, dexamethasone at a dose of 40 mg is administered orally with each dose of Velcade^®: 20 mg on the day of Velcade^® administration and 20 mg on the day following Velcade^® administration. Thus, dexamethasone should be taken on days 1, 2, 4, 5, 8, 9, 11, and 12, totaling 160 mg over 3 weeks.

Recommendations for dose adjustment and administration regimen of Velcade^®

If grade 4 hematological toxicity or any grade 3 non-hematological toxic effect develops, except for neuropathy, treatment with Velcade^® should be withheld. After the toxic symptoms resolve, treatment with Velcade^® can be resumed at a dose reduced by 25% (dose reduced from 1.3 mg/m² to 1 mg/m²; from 1 mg/m² to 700 mcg/m²).

If drug-related neuropathic pain and/or peripheral sensory neuropathy occurs, the dose of the drug should be adjusted according to Table 1. In patients with a history of severe neuropathy, Velcade^® should be used only after careful assessment of the risk/benefit ratio.

Table 1. Recommended dose modification for the development of drug-induced neuropathic pain and/or peripheral sensory or motor neuropathy caused by Velcade^®.

Combination Therapy

Velcade^® is administered as an intravenous bolus over 3-5 seconds or subcutaneously in combination with oral melphalan and prednisone. Nine 6-week cycles are conducted, as shown in Table 3. In cycles 1-4, Velcade^® is used twice weekly (days 1, 4, 8, 11, 22, 25, 29, and 32), and in cycles 5-9 – once weekly (days 1, 8, 22, and 29).

Table 3. Recommended dosing schedule for Velcade^® used in combination with melphalan and prednisone in patients with previously untreated multiple myeloma.

Velcade^® twice weekly (cycles 1-4)

Velcade^® once weekly (cycles 5-9)

Recommendations for dose adjustment in combination therapy

Dose and regimen adjustment when using Velcade^® in combination with melphalan and prednisone

Before starting a new treatment cycle

• Platelet count must be >70,000/µl;
• Absolute neutrophil count (ANC) >1000/µl;
• Non-hematological toxicity must have decreased to grade 1 or to baseline.

Table 4. Dose adjustment for subsequent treatment cycles.

Additional information on melphalan and prednisone is provided in the prescribing information for these drugs.

Method of Administration

Velcade^® is an antineoplastic agent. Caution should be exercised during preparation and handling. Appropriate aseptic technique should be used. The use of gloves and other protective clothing is recommended to prevent skin contact. The drug should not be mixed with other medicinal products except for 0.9% sodium chloride solution.

Preparation and administration of the solution for intravenous injection. The contents of the vial (10 ml) are reconstituted with 3.5 ml of 0.9% sodium chloride solution. The concentration of the prepared solution for intravenous injection is 1 mg/ml. The prepared solution should be clear and colorless. If particulate matter or discoloration is observed, the prepared solution must not be used. The resulting solution is administered as a 3-5-second intravenous bolus injection through a peripheral or central venous catheter, which is then flushed with 0.9% sodium chloride injection.

Preparation of the solution for subcutaneous injection. The contents of the vial are reconstituted with 1.4 ml of 0.9% sodium chloride solution. The concentration of the prepared solution for subcutaneous injection is 2.5 mg/ml. The prepared solution should be clear and colorless. If particulate matter or discoloration is observed, the prepared solution must not be used. The resulting solution is administered subcutaneously into the thigh (right or left) or abdomen (right or left). The injection site should be rotated consistently. Each subsequent injection should be given at least 2.5 cm away from the previous injection site. The drug should not be injected into areas that are tender, damaged (redness, bruising), or where needle insertion is difficult. If local reactions occur at the subcutaneous injection site of Velcade^®, a less concentrated solution for subcutaneous injection (1 mg/ml instead of 2.5 mg/ml) can be used or a switch to intravenous administration of the drug can be made.

Adverse Reactions

Overall, the safety profile of Velcade^® when used as monotherapy is similar to that when Velcade^® is used in combination with melphalan and prednisone.

The following are undesirable side effects that were considered probably or possibly related to the use of Velcade^®.

Undesirable side effects are grouped by organ system and frequency of occurrence. Frequency was defined as: very common >10%, common – 1-10%, uncommon – 0.1-1%, rare – 0.01-0.1%, very rare <0.01%, including isolated cases.

Blood and lymphatic system disorders very common – thrombocytopenia, neutropenia, anemia; common – leukopenia, lymphopenia; uncommon – pancytopenia, febrile neutropenia, hemolytic anemia, thrombocytopenic purpura, lymphadenopathy, coagulopathy, leukocytosis; rare – disseminated intravascular coagulation (DIC syndrome), thrombocytosis, hyperviscosity syndrome, hemorrhagic diathesis, lymphocytic infiltration.

Cardiac disorders common – cardiac arrest, cardiogenic shock, myocardial infarction, angina pectoris, development and exacerbation of chronic heart failure, ventricular hypokinesia, pulmonary edema (including acute), sinus arrest, complete atrioventricular block, tachycardia (including sinus and supraventricular), arrhythmia, atrial fibrillation, palpitations, decreased blood pressure, orthostatic and postural hypotension, phlebitis, hematoma, increased blood pressure; uncommon – atrial flutter, bradycardia, intracerebral hemorrhage, intracranial hemorrhage, subarachnoid hemorrhage, vasculitis, stroke, pulmonary congestion, pulmonary hypertension, petechiae, ecchymosis, purpura, vein discoloration, vein distension, wound bleeding, flushing, cardiomyopathy, deep vein thrombosis, hemorrhage, thrombophlebitis, hypovolemic shock, decreased peripheral circulation, hyperemia; rare – decreased left ventricular ejection fraction, cardiac tamponade, pericarditis, ventricular arrhythmias, pulmonary embolism, peripheral embolism, cardiogenic shock, torsades de pointes ventricular tachyarrhythmia, unstable angina, heart valve disorders, lymphedema, erythromelalgia, vasodilation, venous insufficiency.

Respiratory, thoracic and mediastinal disorders very common – dyspnea; common – upper and lower respiratory tract infections, exertional dyspnea, epistaxis, cough, rhinorrhea; uncommon – respiratory arrest, hypoxia, pleural effusion, bronchospasm, respiratory alkalosis, tachypnea, wheezing, nasal congestion, hoarseness, rhinitis, pulmonary hyperventilation, orthopnea, chest pain, sinus pain, throat tightness, hemoptysis, chronic obstructive pulmonary disease, hypoxemia, pleurisy, dysphonia; rare – pneumonitis, pneumonia (including interstitial), acute respiratory distress syndrome, acute diffuse infiltrative pulmonary disease, pulmonary hypertension, respiratory failure, pulmonary alveolar hemorrhage, acute respiratory distress syndrome, pneumothorax, atelectasis, hemoptysis, hyperventilation, pulmonary fibrosis, hypocapnia, increased upper airway secretion, throat irritation.

Gastrointestinal disorders very common – nausea, vomiting, diarrhea, constipation, decreased appetite; common – abdominal pain, stomatitis, dyspepsia, loose stools, flatulence, hiccups, oropharyngeal pain, dry mouth, abdominal distension; uncommon – hematemesis, lip swelling, abdominal discomfort, gingival bleeding, pseudomembranous colitis, irritable bowel syndrome, acute pancreatitis, paralytic ileus, colitis, melena, gastrointestinal hemorrhage, enteritis, dysphagia, eructation, splenic pain, esophagitis, gastritis, gastroesophageal reflux, oral mucosa petechiae, salivary hypersecretion, tongue coating, tongue discoloration, tongue ulceration, increased appetite; rare – ischemic colitis, peritonitis, tongue edema, ascites, cheilitis, fecal incontinence, anal sphincter atony, gastrointestinal ulceration and perforation, gingival hypertrophy, megacolon, periodontitis, anal fissure, proctalgia.

From the hepatobiliary system infrequently – hepatitis, hepatic hemorrhage, hypoproteinemia, hyperbilirubinemia, increased ALT and AST activity, hepatotoxicity, cholestasis; rarely – hepatic failure, hepatomegaly, Budd-Chiari syndrome, cytomegalovirus hepatitis, cholelithiasis.

From the nervous system very common – peripheral sensory neuropathy, peripheral neuropathy, paresthesia, headache; common – polyneuropathy, dizziness (excluding vertigo), taste disturbance, dysesthesia, hypesthesia, tremor; infrequently – dyskinesia, balance disorder, postherpetic neuralgia, migraine, sciatica, parosmia, paraplegia, seizures, peripheral motor neuropathy, syncope, paresis, impaired concentration, loss of taste, somnolence, cognitive disorders, jerky movements, postural dizziness, mononeuropathy, speech disorders, restless legs syndrome; rarely – brain edema, transient ischemic attack, coma, brainstem syndrome, cerebrovascular accident, radicular syndrome, spinal cord compression, radiculitis, salivation, encephalopathy, autonomic neuropathy, posterior reversible leukoencephalopathy syndrome.

Psychiatric disorders common – confusion, depression, insomnia, anxiety; infrequently – psychotic disorder, agitation, delirium, hallucinations, excited state, mood swings, mental status changes, sleep disorders, irritability, unusual dreams; rarely – suicidal thoughts, decreased libido, adjustment disorder.

From the urinary system common – renal function impairment, dysuria; infrequently – renal failure (including acute), oliguria, renal colic, hematuria, proteinuria, urinary retention, frequent urination, difficult urination, low back pain, urinary incontinence.

From the hearing organ common – vertigo; infrequently – tinnitus, hearing impairment, ear discomfort; rarely – bleeding, vestibular neuronitis, bilateral deafness.

From the organ of vision common – blurred vision, eye pain; infrequently – eyelid infections, eye inflammation, diplopia, eye hemorrhage, visual disturbances, dry eyes, conjunctivitis, photophobia, eye irritation, increased lacrimation, conjunctival hyperemia, eye discharge; rarely – corneal lesion, exophthalmos, retinitis, scotoma, dacryoadenitis, photopsia, ocular herpes, optic neuropathy, blindness.

From the immune system infrequently – hypersensitivity; rarely – anaphylactic shock, amyloidosis, immune complex reactions (type III), angioedema.

From the endocrine system infrequently – Cushing’s syndrome, hyperthyroidism, impaired antidiuretic hormone secretion; rarely – hypothyroidism.

From the skin and subcutaneous tissues very common – skin rash; common – periorbital edema, urticaria, pruritic rash, pruritus, redness, increased sweating, dry skin, eczema; infrequently – erythematous rash, photosensitivity, bruising, generalized pruritus, maculopapular rash, papular rash, psoriasis, generalized rash, eyelid edema, facial edema, dermatitis, alopecia, nail disorders, skin pigmentation changes, atopic dermatitis, hair texture changes, night sweats, ichthyosis, skin nodules, skin lesion, hyperhidrosis, acne; rarely – acute febrile neutrophilic dermatosis (Sweet’s syndrome), lymphocytic infiltration, palmar-plantar erythrodysesthesia, subcutaneous bleeding, skin induration, seborrhea, cold sweat, erythroderma, skin ulcers; very rarely – Stevens-Johnson syndrome and toxic epidermal necrolysis.

From the musculoskeletal system very common – myalgia; common – muscle weakness, musculoskeletal pain, limb pain, muscle cramps, arthralgia, bone pain, back pain; infrequently – muscle spasms, muscle twitching, muscle rigidity, joint swelling, joint stiffness, jaw pain; rarely – rhabdomyolysis, temporomandibular joint syndrome, jaw pain, infections and inflammations of the musculoskeletal and connective tissue, synovial cyst.

From the kidneys and urinary tract infrequently – urinary tract infections, azotemia, pollakiuria; rarely – bladder irritation.

From the reproductive system infrequently – vaginal bleeding, genital pain, testicular pain, erectile dysfunction; rarely – prostatitis, epididymitis.

Local reactions infrequently – pain, burning sensation and redness at the injection site, phlebitis.

Metabolic disorders common – dehydration, hypokalemia, hyperglycemia; infrequently – diabetes mellitus, fluid retention, hyperkalemia, cachexia, hypercalcemia, hypocalcemia, hypernatremia, hyponatremia, hypoglycemia, hyperuricemia, vitamin B₁₂ deficiency, hypomagnesemia, hypophosphatemia; rarely – acidosis, fluid and electrolyte imbalance, hypochloremia, hypovolemia, hyperchloremia, hyperphosphatemia, B vitamin deficiency, gout, increased appetite, alcohol intolerance.

Changes in laboratory parameters common – increased blood LDH activity; infrequently – increased blood alkaline phosphatase activity, increased blood urea concentration, increased gamma-glutamyltransferase activity, increased blood amylase activity, decreased blood bicarbonate concentration, increased C-reactive protein concentration.

Infections and infestations common – herpes simplex, herpes zoster (including disseminated), fungal infections; infrequently: bacterial, viral infections, bronchopneumonia, bacteremia (including staphylococcal), stye, cellulitis, skin infections, ear infections, staphylococcal infections, tooth infections; rarely – meningitis (including bacterial), Epstein-Barr virus infection, genital herpes, tonsillitis, mastoiditis, chronic fatigue syndrome.

Neoplasms rarely – malignant neoplasms, plasmacytic leukemia, renal carcinoma, mycosis fungoides, benign neoplasms.

Other very common – increased fatigue, increased body temperature; common – asthenia, weakness, malaise, flu-like symptoms, peripheral edema, edema, weight loss, secondary infections; infrequently – neuralgia, chills, chest tightness, chest discomfort, groin pain, infections associated with the use of medical devices, including catheter, tumor lysis syndrome, weight gain; rarely – herpes meningoencephalitis, septic shock; very rarely – progressive multifocal leukoencephalopathy.

Patients with mantle cell lymphoma

The safety profile of Velcade^® in these patients was similar to that in patients with multiple myeloma. Significant differences between the two patient groups were that thrombocytopenia, neutropenia, anemia, nausea, vomiting, and increased body temperature were more frequently observed in patients with multiple myeloma compared to patients with mantle cell lymphoma; while peripheral neuropathy, rash, and pruritus were more frequent in patients with mantle cell lymphoma.

Contraindications

• Hypersensitivity to bortezomib, boron or mannitol;
• Pregnancy and breastfeeding;
• Childhood (lack of experience in use);
• Acute diffuse infiltrative lung diseases;
• Pericardial involvement;
• Concomitant use with strong inducers of the CYP3A isoenzyme (rifampicin, carbamazepine, phenytoin, phenobarbital, St. John’s wort).

With caution

• Moderate and severe hepatic impairment;
• Severe renal impairment;
• History of seizures or epilepsy;
• Syncope;
• History of diabetic neuropathy;
• Concomitant use of antihypertensive drugs;
• Dehydration due to diarrhea or vomiting;
• Constipation;
• Risk of developing chronic heart failure;
• Concomitant use of inhibitors or substrates of the CYP3A4 isoenzyme, concomitant use of substrates of the CYP2C9 isoenzyme, oral hypoglycemic drugs.

Use in Hepatic Impairment

With caution : moderate and severe hepatic impairment

Use in Renal Impairment

With caution : severe renal impairment.

Pediatric Use

Contraindicated: childhood (lack of experience in use).

Special Precautions

Treatment with Velcade^® should be carried out only under the supervision of a physician experienced in anticancer chemotherapy.

Cases of death have been reported following unintentional intrathecal administration of Velcade^®.

For subcutaneous administration. Do not administer intrathecally.

A complete blood count with differential white blood cell count and platelet count should be performed before starting and during each cycle of therapy.

Thrombocytopenia

Transient thrombocytopenia is most commonly observed during therapy with Velcade^®, with the lowest platelet count usually occurring on day 11 of the cycle. A cyclical pattern of decrease and increase in platelet count was observed throughout all 8 cycles when the drug was administered twice a week, thus there is no data confirming cumulative thrombocytopenia. If the platelet count decreases to <25000/µL, therapy with Velcade^® should be suspended. Upon platelet count recovery, treatment may be resumed at reduced doses with careful assessment of the potential benefit and risk of treatment. Colony-stimulating factors, platelet and red blood cell transfusions may be used to treat hematologic toxicity. When used concomitantly with melphalan and prednisone, therapy should be suspended when the platelet count is < 30000/µL.

Gastrointestinal disorders

Antiemetics are recommended to prevent nausea and vomiting. Antidiarrheal medications should be prescribed if diarrhea occurs. To prevent or treat dehydration, patients should receive rehydration therapy and maintain fluid and electrolyte balance. Cases of intestinal obstruction have been reported (infrequently).

Progressive multifocal leukoencephalopathy (PML)

Very rare cases of JC virus infection of unknown etiology leading to progressive multifocal leukoencephalopathy and death have been reported in patients taking Velcade^®. Patients diagnosed with PML had received immunosuppressive therapy prior to or concurrently with Velcade^®. In most cases, PML was diagnosed within 12 months of the first dose of Velcade^®. Patients should be monitored regularly for the onset or worsening of neurological symptoms or signs that may suggest PML. If PML is suspected, the patient should be referred to a PML specialist and appropriate diagnostic measures should be taken. Administration of Velcade^® should be discontinued if PML is diagnosed.

Peripheral neuropathy

Supportive care is provided if neuropathy occurs. The incidence of peripheral neuropathy usually peaks at cycle 5 of treatment with Velcade^®. If new symptoms of peripheral neuropathy appear or existing symptoms worsen, a dose reduction and change in the administration schedule of Velcade^® may be required. Patients should be continuously monitored for the possible occurrence of neuropathy symptoms (burning sensation, hyperesthesia, hypesthesia, paresthesia, discomfort, neuropathic pain, or weakness). The incidence of neuropathy with subcutaneous administration of Velcade^® is lower than with intravenous administration. Early and regular monitoring for neuropathy symptoms with neurological assessment should be performed in patients taking Velcade^® in combination with drugs that can cause neuropathy (e.g., thalidomide). Consideration should be given to appropriate dose reduction or discontinuation of treatment.

Seizures

Infrequent cases of seizures have been described in patients with no history of seizures or epilepsy. Particular caution is required when treating patients with any risk factors for seizures.

Orthostatic hypotension

Therapy with Velcade^® is often accompanied by orthostatic hypotension. In most cases, it is mild to moderate and can be observed throughout the treatment. Brief loss of consciousness has been rarely reported. Caution should be exercised in patients with a history of syncope, diabetic neuropathy, those taking antihypertensive drugs, as well as in patients with dehydration due to diarrhea or vomiting. Patients should be instructed to consult a doctor if they experience dizziness, lightheadedness, or fainting. In case of orthostatic hypotension, hydration, administration of glucocorticosteroids and/or sympathomimetics is recommended; if necessary, the dose of antihypertensive drugs should be reduced.

Heart failure

The development or worsening of pre-existing chronic heart failure has been described with the use of bortezomib. Fluid retention may predispose to the development of signs and symptoms of heart failure. Patients with risk factors or a history of heart disease should be closely monitored.

Hepatic failure

Cases of acute hepatic failure have been described in patients who, while on bortezomib therapy, were concomitantly receiving other drugs as part of their treatment. Signs of liver dysfunction such as increased liver enzymes, hyperbilirubinemia, or hepatitis usually resolved upon discontinuation of Velcade^®. Data on the condition of these patients after resuming therapy with Velcade^® are limited.

Patients with symptoms of liver dysfunction should be started on Velcade^® at lower initial doses and monitored for toxicity, as Bortezomib is metabolized by hepatic enzymes and its concentration may increase in moderate to severe hepatic impairment (see section “Dosage and Administration”).

Posterior reversible leukoencephalopathy syndrome

Posterior reversible leukoencephalopathy syndrome, a rare, reversible neurological disorder that may be accompanied by seizures, high blood pressure, headache, lethargy, confusion, blindness, and other visual and neurological disturbances, has been observed in patients taking Velcade^®. Magnetic resonance imaging of the brain is performed to confirm the diagnosis. If posterior reversible leukoencephalopathy syndrome develops, administration of Velcade^® should be discontinued. The safety of resuming therapy with Velcade^® after a previously identified posterior reversible leukoencephalopathy syndrome is unknown.

Herpes zoster virus reactivation

Treating physicians should consider antiviral prophylaxis in patients receiving therapy with Velcade^®. In patients receiving therapy with Velcade^®, melphalan, and prednisone, the incidence of Herpes zoster virus reactivation was higher compared to patients receiving therapy with melphalan and prednisone (14% and 4%, respectively). Antiviral prophylaxis significantly reduces the incidence of Herpes zoster virus reactivation.

Lung function disorders

In rare cases, acute diffuse infiltrative lung diseases of unknown etiology, such as pneumonitis, interstitial pneumonia, pulmonary infiltration, and acute respiratory distress syndrome, have been observed with the use of Velcade^®. Some of these conditions were fatal. If symptoms of lung function disorder appear or existing symptoms worsen, diagnosis should be performed immediately and patients should receive appropriate treatment. In clinical studies, 2 patients (out of 2) receiving high-dose cytarabine (2 g/m² per day) by continuous infusion over 24 hours with daunorubicin and Velcade^® for relapsed acute myeloid leukemia died from acute respiratory distress syndrome at the beginning of the therapy course, and the study was terminated. Thus, this treatment regimen with concomitant administration of high-dose cytarabine (2 g/m² per day) by continuous infusion over 24 hours is not recommended.

Tumor lysis syndrome

Due to the possible development of hyperuricemia associated with tumor lysis syndrome, it is recommended to monitor serum uric acid and creatinine concentrations in patients during therapy. To prevent hyperuricemia, adequate fluid intake is recommended, and if necessary, allopurinol and urine alkalinization.

When using Velcade^® in patients concomitantly taking oral hypoglycemic drugs, blood glucose concentration should be carefully monitored and the dose of hypoglycemic drugs should be adjusted if necessary.

During treatment of either sexual partner, reliable methods of contraception are recommended.

When handling Velcade^®, standard precautions for handling cytotoxic drugs should be observed.

Immune complex type reactions

Immune complex type reactions, such as serum sickness, polyarthritis with rash, proliferative glomerulonephritis have been reported infrequently. Bortezomib should be discontinued if serious reactions occur.

Effect on ability to drive and operate machinery

Patients should be warned about the possibility of dizziness, fainting, visual disturbances, and other adverse reactions during treatment with Velcade^® that may affect the ability to drive vehicles. If these symptoms occur, patients are advised to refrain from driving and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Overdose

Overdose exceeding the recommended dose by more than 2 times was accompanied by acute hypotension and fatal thrombocytopenia in patients.

No specific antidote for Velcade^® is known. In case of overdose, the patient’s vital signs should be monitored and appropriate therapy should be administered to maintain blood pressure (infusion therapy, vasoconstrictors and/or inotropic drugs) and body temperature.

Drug Interactions

In in vitro and in vivo studies, Bortezomib exhibited properties of a weak inhibitor of cytochrome P450 isoenzymes 1A2, 2C9, 2C19, 2D6 and 3A4.

Based on the minor contribution of the CYP2D6 isoenzyme to the metabolism of bortezomib (7%), no change in the overall distribution of the drug is expected in people with low activity of this isoenzyme.

A drug interaction study with the strong CYP3A4 isoenzyme inhibitor ketoconazole on the pharmacokinetics of Velcade^® showed an average increase in the mean AUC (area under the concentration-time curve) of bortezomib by 35%. Therefore, patients receiving Bortezomib concomitantly with a strong CYP3A4 isoenzyme inhibitor (ketoconazole, ritonavir) should be closely monitored.

In the study of the effect of drug interaction with the strong CYP2C19 isoenzyme inhibitor omeprazole on the pharmacokinetics of Velcade^®, no significant change in the pharmacokinetics of bortezomib was revealed.

The study of the effect of drug interaction with rifampicin, a strong inducer of the CYP3A4 isoenzyme, on the pharmacokinetics of Velcade^® showed a decrease in the mean AUC (area under the concentration-time curve) values for bortezomib by an average of 45%.

Therefore, it is not recommended to use Velcade^® concomitantly with strong CYP3A4 inducers, as the efficacy of therapy may be reduced. CYP3A4 inducers include rifampicin, carbamazepine, phenytoin, phenobarbital, and St. John’s wort. The same study evaluated the effect of dexamethasone, a weaker CYP3A4 inducer. Based on the study results, no significant change in the pharmacokinetics of bortezomib was revealed. A drug interaction study with the melphalan-prednisone combination showed an increase in the mean AUC (area under the concentration-time curve) of bortezomib by 17%. This change is considered clinically insignificant.

In diabetic patients receiving oral hypoglycemic drugs, cases of hypoglycemia and hyperglycemia have been reported.

Caution should be exercised when using bortezomib in combination with drugs that may be associated with peripheral neuropathy (such as amiodarone, antiviral agents, isoniazid, nitrofurantoin, or statins) and with drugs that lower blood pressure.

Storage Conditions

At a temperature not exceeding 30°C (86°F) in the original packaging to protect from light, in a place inaccessible to children.

After reconstitution, store at a temperature not exceeding 25°C (77°F) in normal lighting conditions in the original vial or in a syringe for no more than 8 hours.

Shelf Life

The shelf life is 3 years. Do not use after the expiration date printed on the packaging.

Dispensing Status

By prescription.

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.