Bortezomib
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BortezoVista (BortezoVista)
Composition:
Active substance: bortezomib;
One vial contains bortezomib 3.5 mg.
Excipients: mannitol (E 421).
Pharmaceutical form. Powder for solution for injection.
Main physicochemical properties: white or almost white lyophilized tablet or powder.
Pharmacotherapeutic group. Antineoplastic and immunomodulating agents. Antineoplastic agents. Other antineoplastic agents. Proteasome inhibitors. Bortezomib. ATC code L01X G01.
Pharmacological Properties
Pharmacodynamics
Mechanism of action. Bortezomib is a proteasome inhibitor that inhibits the chymotrypsin-like activity of the 26S proteasome in mammalian cells. The 26S proteasome is a large protein complex involved in the degradation of key regulatory proteins. This pathway plays a central role in regulating the turnover of specific proteins, thereby maintaining cellular homeostasis. Inhibition of the 26S proteasome leads to suppression of proteolysis and triggers a cascade of reactions resulting in apoptosis.
Bortezomib is highly selective for the proteasome. At a concentration of 10 µM, bortezomib does not inhibit any of a large number of tested receptors and proteases and is more than 1500 times more selective for the proteasome than for other enzymes. The kinetics of proteasome inhibition were determined in vitro; bortezomib dissociated from the proteasome with a half-life (t½) of 20 minutes, indicating that proteasome inhibition by bortezomib is reversible. By inhibiting the proteasome, bortezomib affects cancer cells through multiple mechanisms, including altering regulatory proteins that control the cell cycle and activation of the nuclear transcription factor NF-kB. Proteasome inhibition leads to cell cycle arrest and apoptosis. NF-kB is a transcription factor whose activation is essential for many aspects of tumor development, including cell growth and survival, angiogenesis, cell–cell interactions, and metastasis. In myeloma, bortezomib affects the ability of myeloma cells to interact with the bone marrow microenvironment. Experimental data show that bortezomib is toxic to many types of cancer cells and that cancer cells are more susceptible to bortezomib-induced apoptosis than normal cells. In vivo, bortezomib causes a reduction in the growth of various experimental human tumors, including multiple myeloma.
Data from in vitro, ex vivo, and animal model studies indicate that bortezomib enhances osteoblast differentiation and activity and inhibits osteoclast function. These effects have been observed in patients with multiple myeloma who also had advanced-stage osteolytic disease and were treated with bortezomib.
Pharmacokinetics
Absorption. After intravenous bolus administration of doses of 1.0 mg/m² and 1.3 mg/m² in 11 patients with multiple myeloma and creatinine clearance exceeding 50 mL/min, the mean peak plasma concentration (Cmax) of the first dose of bortezomib was 57 and 112 ng/mL, respectively. With subsequent doses, the mean peak plasma concentration of bortezomib ranged from 67 to 106 ng/mL for the 1.0 mg/m² dose and from 89 to 120 ng/mL for the 1.3 mg/m² dose.
After intravenous bolus or subcutaneous administration of 1.3 mg/m² to patients with multiple myeloma (n=14 in the intravenous group and n=17 in the subcutaneous group), the total systemic exposure after repeated dosing (AUClast) was equivalent between subcutaneous and intravenous administration. The Cmax after subcutaneous administration (20.4 ng/mL) was lower than after intravenous administration (223 ng/mL). The geometric mean ratio of AUClast was 0.99, with a 90% confidence interval of 80.18–122.80%.
Distribution. The mean volume of distribution (Vd) of bortezomib ranges from 1659 to 3294 liters following single or multiple doses of 1.0 mg/m² or 1.3 mg/m² in patients with multiple myeloma, indicating extensive distribution into peripheral tissues. Plasma protein binding of bortezomib ranges from 83% at concentrations of 0.01–1.0 µg/mL. The fraction of bortezomib bound to plasma proteins was independent of concentration.
Metabolism. In vitro, bortezomib is primarily metabolized by cytochrome P450 enzymes, including CYP3A4, CYP2C19, and CYP1A2. The main metabolic pathway involves deboronation to two metabolites, which are subsequently hydroxylated into further metabolites. The deboronated metabolites are inactive as inhibitors of the 26S proteasome.
Elimination. The mean elimination half-life (T½) of bortezomib after multiple doses ranges from 40 to 193 hours. Bortezomib is cleared more rapidly after the first dose compared to subsequent doses. Mean total clearance was 102 and 112 L/h after the first dose of 1.0 mg/m² and 1.3 mg/m², respectively, and ranged from 15 to 32 L/h and 18 to 32 L/h after subsequent doses of 1.0 mg/m² and 1.3 mg/m², respectively.
Special patient populations
Hepatic impairment. The effect of hepatic impairment on the pharmacokinetics of bortezomib was evaluated in a Phase I study during the first treatment cycle involving 60 patients, mostly with solid tumors, and varying degrees of hepatic dysfunction; bortezomib doses ranged from 0.5 to 1.3 mg/m².
Mild hepatic impairment did not alter bortezomib AUC compared to normal hepatic function. Mean bortezomib AUC values increased by approximately 60% in patients with moderate and severe hepatic impairment. Dose adjustment and careful monitoring during treatment are recommended for these patients.
Renal impairment. Pharmacokinetic studies were conducted in patients with varying degrees of renal function, categorized by creatinine clearance (CrCL) as follows: normal (CrCL ≥ 60 mL/min/1.73 m², n = 12), mild impairment (CrCL = 40–59 mL/min/1.73 m², n = 10), moderate impairment (CrCL = 20–39 mL/min/1.73 m², n = 9), and severe impairment (CrCL < 20 mL/min/1.73 m², n = 3). Patients on dialysis who received bortezomib after dialysis were also included in the study (n = 8). Patients received intravenous bortezomib doses of 0.7–1.3 mg/m² twice weekly. Bortezomib exposure (dose-normalized AUC and Cmax) was comparable across all groups.
Age. Pharmacokinetic parameters of bortezomib were evaluated in 104 pediatric patients (2–16 years of age) with acute lymphoblastic leukemia or acute myeloid leukemia, who received bortezomib 1.3 mg/m² twice weekly via intravenous bolus injection. According to population pharmacokinetic analysis, bortezomib clearance increases with increasing body surface area. The geometric mean (% CV) for clearance was 7.79 (25%) L/h/m², the volume of distribution at steady state was 834 (39%) L/m², and the elimination half-life was 100 (44%) hours. After adjusting for body surface area, other demographic factors such as age, body weight, and sex had no clinically significant effect on bortezomib clearance. Bortezomib clearance values in children, adjusted for body surface area, were comparable to those in adults.
Clinical characteristics.
Indications.
Multiple myeloma, in combination therapy with melphalan and prednisone, for treatment of previously untreated patients who are not candidates for high-dose chemotherapy with hematopoietic stem cell transplantation (first-line therapy).
Relapsed multiple myeloma, as monotherapy or in combination therapy with pegylated liposomal doxorubicin or dexamethasone, for treatment of patients who have received at least one prior therapy and who have undergone hematopoietic stem cell transplantation or who are not candidates for transplantation (second-line therapy).
Multiple myeloma, in combination therapy with dexamethasone or dexamethasone and thalidomide, for treatment of previously untreated patients who are candidates for high-dose chemotherapy with hematopoietic stem cell transplantation (induction therapy).
Mantle cell lymphoma, in combination therapy with rituximab, cyclophosphamide, doxorubicin, and prednisone, for treatment of previously untreated patients who are not candidates for hematopoietic stem cell transplantation.
Contraindications.
Hypersensitivity to bortezomib, boron, or to any of the excipients of the medicinal product.
Acute diffuse infiltrative pulmonary and pericardial diseases.
When bortezomib is used in combination with other medicinal products, refer to the instructions for medical use of these products for additional contraindications.
Special safety precautions.
General warnings. Bortezovista is a cytotoxic medicinal product. Therefore, caution should be exercised during its preparation and administration. Gloves and protective clothing are recommended to prevent skin contact. Appropriate aseptic techniques must be strictly followed when handling Bortezovista, as the product does not contain preservatives.
Fatal outcomes have been reported following accidental intrathecal administration of Bortezovista. The medicinal product must be administered only intravenously or subcutaneously. BORTEZOVISTA MUST NOT BE ADMINISTERED INTRATHECALLY.
Instructions for solution preparation. Solution preparation must be performed only by qualified healthcare personnel.
For intravenous administration, the content of the vial should be carefully reconstituted with 3.5 mL of 0.9% sodium chloride injection solution using a syringe of appropriate size, without removing the rubber stopper from the vial. The lyophilized powder dissolves in less than 2 minutes. After reconstitution, 1 mL of solution contains 1 mg of bortezomib. The resulting solution should be clear and colorless, with a pH of 4–7. The prepared solution should be visually inspected for the presence of particles and discoloration prior to administration. Do not use the solution if particles are present or if discoloration occurs.
For subcutaneous administration, the content of each vial should be carefully reconstituted with 1.4 mL of 0.9% sodium chloride injection solution using a syringe of appropriate size, without removing the rubber stopper from the vial. The reconstitution occurs in less than 2 minutes. After reconstitution, 1 mL of solution contains 2.5 mg of bortezomib. The resulting solution should be clear and colorless, with a pH of 4–7. The prepared solution should be visually inspected for the presence of particles and discoloration prior to administration. Do not use the solution if particles are present or if discoloration occurs.
Disposal of unused or expired medicinal product.
For single use only. Environmental release of the medicinal product should be minimized. The product must not be disposed of via wastewater or household waste. A "waste collection system" should be used if available. Any unused medicinal products or waste materials must be disposed of in accordance with local requirements.
Interaction with other medicinal products and other forms of interaction.
In vitro studies have demonstrated that bortezomib is a weak inhibitor of cytochrome P450 isoenzymes 1A2, 2C9, 2C19, 2D6, and 3A4. Since CYP2D6 plays a minor role in bortezomib metabolism, changes in overall drug distribution are not expected in poor metabolizers of this enzyme.
Drug interaction studies assessing the effect of ketoconazole, a potent CYP3A4 inhibitor, on the pharmacokinetics of bortezomib (after intravenous administration) demonstrated an average increase in bortezomib AUC of 35% (90% CI [1.032 to 1.772]) based on data from 12 patients. Therefore, careful monitoring of patients is recommended when bortezomib is administered concomitantly with potent CYP3A4 inhibitors (such as ketoconazole, ritonavir).
Studies evaluating the effect of omeprazole, a potent CYP2C19 inhibitor, on the pharmacokinetics of bortezomib (after intravenous administration) did not show a significant effect on bortezomib pharmacokinetics in 17 patients enrolled in the study. In studies evaluating the effect of rifampicin, a potent CYP3A4 inducer, involving 6 patients, a mean reduction in bortezomib AUC (after intravenous administration) of 45% was observed. Therefore, concomitant administration of bortezomib with potent CYP3A4 inducers (such as rifampicin, carbamazepine, phenytoin, phenobarbital, and St. John's wort extract) is not recommended, as the efficacy of bortezomib may be reduced.
In the same study, dexamethasone, a weak CYP3A4 inducer, did not significantly alter the pharmacokinetics of bortezomib, as evidenced by data from 7 patients.
Drug interaction studies assessing the effect of melphalan and prednisone on the pharmacokinetics of bortezomib (after intravenous administration) in 21 patients demonstrated a mean increase in bortezomib AUC of 17%, which is not considered clinically significant.
During clinical trials, cases of hypoglycemia and hyperglycemia were reported in patients with diabetes mellitus receiving oral hypoglycemic agents. Patients receiving oral antidiabetic medicinal products should monitor their blood glucose levels and adjust the dose of antidiabetic agents accordingly during treatment with Bortezovista.
Special precautions for use.
If BortezoVist is used in combination with other medicinal products, the instructions for medical use of these medicinal products should be consulted prior to initiating treatment. If thalidomide is used, special attention should be paid to pregnancy diagnosis and contraceptive measures.
Intrathecal administration. Fatal cases have been reported due to accidental intrathecal administration of bortezomib. BortezoVist must be administered only intravenously or subcutaneously. DO NOT ADMINISTER INTRATHECALLY.
Gastrointestinal complications. Bortezomib treatment may very commonly cause gastrointestinal toxicity, including nausea, diarrhea, constipation, and vomiting. Cases of intestinal obstruction (reported as uncommon) have been reported; therefore, patients with constipation should be under medical supervision.
Hematological complications. Hematological toxicity (thrombocytopenia, neutropenia, and anemia) is very commonly observed during bortezomib therapy. In clinical trials of bortezomib for relapsed multiple myeloma and in combination therapy with rituximab, cyclophosphamide, doxorubicin, and prednisone (VcR-CAP regimen) in previously untreated mantle cell lymphoma patients, one of the most common hematological toxicities was reversible thrombocytopenia. Platelet counts were typically lowest on day 11 of each bortezomib treatment cycle and returned to baseline levels before the start of the next cycle. Cumulative thrombocytopenia was not observed. On average, the lowest measured platelet count was approximately 40% of the baseline level in trials of bortezomib monotherapy in multiple myeloma patients and 50% in trials in mantle cell lymphoma patients. In patients with progressive myeloma, the severity of thrombocytopenia was related to pre-treatment platelet counts: in patients with baseline platelet counts < 75,000/µL, 90% of 21 patients had platelet counts ≤ 25,000/µL during the study, including 14% with < 10,000/µL, whereas in patients with baseline platelet counts > 75,000/µL, only 14% of 309 patients had platelet counts ≤ 25,000/µL.
In patients with mantle cell lymphoma, thrombocytopenia of ≥ grade 3 was more frequent in the group receiving bortezomib (VcR-CAP) compared to those receiving R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). The overall incidence of bleeding events of all grades, as well as bleeding events of at least grade 3, was similar in both groups. In the VcR-CAP treatment group, 22.5% of patients required platelet transfusion compared to 2.9% in the R-CHOP group. Cases of gastrointestinal and intracranial hemorrhage associated with bortezomib use have been reported. Therefore, platelet counts should be monitored before each dose of BortezoVist. Bortezomib therapy should be withheld if platelet counts decrease to < 25,000/µL during monotherapy or to ≤ 30,000/µL when used in combination with melphalan and prednisone. The benefit-risk ratio of BortezoVist treatment should be carefully evaluated, especially in cases of moderate or severe thrombocytopenia and presence of bleeding risk factors. Complete blood counts with differential and platelet counts should be frequently performed during treatment with BortezoVist. Platelet transfusion should be considered if clinically indicated.
In patients with mantle cell lymphoma, reversible neutropenia between treatment cycles has been observed, and cumulative neutropenia has not been reported. White blood cell counts were typically lowest on day 11 of each treatment cycle and returned to baseline before the start of the next cycle. In a clinical trial of bortezomib in mantle cell lymphoma patients, 78% of patients in the VcR-CAP group and 61% in the R-CHOP group received colony-stimulating factor. Since patients with neutropenia are at increased risk of infections, they should be monitored for signs of infection and appropriate therapeutic measures taken. The use of granulocyte colony-stimulating factor should be considered for managing hematological toxicity. If initiation of a new treatment cycle is delayed multiple times, prophylactic use of granulocyte colony-stimulating factor should be considered.
Herpes zoster reactivation. Antiviral prophylaxis should be considered for patients receiving bortezomib. In phase III trials in previously untreated multiple myeloma patients, the overall incidence of Herpes zoster reactivation (shingles) was higher in the group receiving bortezomib + melphalan + prednisone (14%) compared to the melphalan + prednisone group (4%).
In patients with mantle cell lymphoma, the incidence of shingles was 6.7% in the VcR-CAP group and 1.2% in the R-CHOP group.
Hepatitis B virus (HBV) reactivation and infection.
Before initiating treatment with rituximab in combination with bortezomib, HBV testing should be performed in patients with risk factors. HBV carriers and patients with a history of hepatitis B should be closely monitored for clinical signs and laboratory parameters during and after combination therapy with rituximab and bortezomib. Antiviral prophylaxis should be considered.
Progressive multifocal leukoencephalopathy (PML). Very rare cases of John Cunningham (JC) virus infection leading to fatal PML have been reported in patients treated with bortezomib. Patients diagnosed with PML had previously or concurrently received immunosuppressive therapy with bortezomib. Most PML cases were diagnosed within the first 12 months of bortezomib treatment. Patients should be regularly monitored for new or worsening neurological symptoms that may indicate PML, which should be considered in the differential diagnosis of central nervous system (CNS) disorders. If PML is suspected, patients should be referred to a physician experienced in managing PML and appropriate diagnostic measures taken. Bortezomib treatment should be discontinued if PML is confirmed.
Peripheral neuropathy. Bortezomib treatment is very commonly associated with peripheral neuropathy, predominantly sensory. However, cases of severe motor neuropathy, with or without sensory peripheral neuropathy, have been reported. The incidence of peripheral neuropathy typically peaks during the 5th treatment cycle.
Careful monitoring of patients for neuropathic symptoms such as burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain, or weakness is recommended.
In a phase III trial comparing intravenous and subcutaneous administration of bortezomib, the incidence of grade 2 peripheral neuropathy was 24% in the subcutaneous group and 41% in the intravenous group. Grade 3 peripheral neuropathy occurred in 6% of patients in the subcutaneous group and 16% in the intravenous group. If peripheral neuropathy develops or worsens, patients should undergo a neurological examination; dose adjustment, schedule modification, or switching to subcutaneous administration may be necessary. Neuropathy should be managed with supportive measures. Regular monitoring for treatment-related neuropathy symptoms and neurological examination are required, especially in patients receiving bortezomib in combination with neurotoxic agents (such as thalidomide); dose reduction or discontinuation of treatment should be considered.
In addition to peripheral neuropathy, autonomic neuropathy may contribute to certain adverse reactions such as postural hypotension and acute constipation with intestinal obstruction. Information on autonomic neuropathy and its impact on these adverse reactions is limited.
Seizures. Rare cases of seizures have been reported in patients with a history of seizures or epilepsy. Particular caution is required when treating patients with risk factors for seizures.
Hypotension. Bortezomib therapy is often associated with postural/orthostatic hypotension. In most cases, it is mild or moderate in severity and occurs throughout treatment. Patients who developed orthostatic hypotension during bortezomib (intravenous) administration did not have symptoms of orthostatic hypotension prior to bortezomib treatment. Most patients required treatment for orthostatic hypotension, and a smaller number experienced syncope. Orthostatic/postural hypotension was not clearly associated with bolus infusion of bortezomib; the mechanism of its development is unknown. It may be related to autonomic neuropathy. Autonomic neuropathy may be associated with bortezomib use or bortezomib may exacerbate underlying conditions, including diabetic or amyloid neuropathy. Caution is advised when treating patients with a history of syncope, those taking antihypertensive medications, and those with dehydration due to diarrhea or vomiting. In case of orthostatic hypotension, hydration, glucocorticoids, and/or sympathomimetics are recommended; antihypertensive medications should be reduced if necessary. Patients should be instructed to consult a physician if they experience dizziness, presyncope, or syncope.
Posterior reversible encephalopathy syndrome (PRES). Cases of PRES have been reported in patients treated with bortezomib. PRES is a rare reversible neurological disorder characterized by seizures, arterial hypertension, headache, lethargy, confusion, visual disturbances, and other neurological impairments. Brain imaging, preferably magnetic resonance imaging (MRI), is required to confirm the diagnosis. BortezoVist treatment should be discontinued if PRES occurs.
Heart failure. Cases of development or worsening of pre-existing congestive heart failure and/or reduced left ventricular ejection fraction have been reported with bortezomib use. Fluid retention may contribute to the development of signs and symptoms of heart failure. Patients with risk factors or pre-existing cardiac disease should be closely monitored.
ECG parameters. Isolated cases of QT interval prolongation have been observed in clinical trials; the cause has not been established.
Lung function disorders. Rare cases of acute diffuse infiltrative lung diseases of unknown etiology, such as pneumonitis, interstitial pneumonia, pulmonary infiltration, and acute respiratory distress syndrome (ARDS), have been observed in patients receiving bortezomib. Some of these cases were fatal. Chest X-ray before treatment initiation is recommended to establish baseline lung status for comparison in case of potential treatment-related lung dysfunction.
In case of new or worsening pulmonary symptoms (e.g., cough, dyspnea), prompt diagnosis and appropriate therapeutic measures should be taken. The benefit-risk ratio of continued drug use should be carefully considered. In clinical trials, two out of two patients with relapsed acute myeloid leukemia who received high-dose cytarabine (2 g/m²/day) as a continuous 24-hour infusion in combination with daunorubicin and bortezomib died from ARDS at the beginning of treatment. Therefore, this specific regimen combining high-dose cytarabine (2 g/m²/day) as a continuous 24-hour infusion is not recommended.
Renal function disorders. Renal impairment is common in patients with multiple myeloma. Close monitoring of such patients is recommended.
Hepatic function disorders. Bortezomib is metabolized by hepatic enzymes. In patients with moderate to severe hepatic impairment, bortezomib concentrations may increase; these patients should be treated with reduced doses and closely monitored for signs of toxicity.
Hepatic reactions. Rare cases of acute liver failure have been reported in patients treated with bortezomib in combination with other medicinal products and in patients with serious comorbid conditions. Cases of elevated liver enzymes, hyperbilirubinemia, and hepatitis, which resolved after bortezomib discontinuation, have also been reported.
Tumor lysis syndrome. Since bortezomib is a cytotoxic agent capable of rapidly killing tumor plasma cells, there is a risk of complications associated with tumor lysis syndrome. Patients with high tumor burden prior to treatment initiation are primarily at risk. Close monitoring of such patients and appropriate preventive measures are recommended.
Warnings regarding concomitant use of other medicinal products. Patients should be closely monitored when bortezomib is used with strong CYP3A4 inhibitors. Caution should be exercised when combining bortezomib with CYP3A4 or CYP2C9 substrates.
Hepatic function should be corrected if impaired prior to initiating bortezomib treatment, and caution should be exercised when administering drugs to patients taking oral hypoglycemic agents.
Potentially immune complex-mediated reactions. Immune complex-mediated reactions, such as serum sickness, polyarthritis with rash, and proliferative glomerulonephritis, have been reported uncommonly. Bortezomib should be discontinued if serious reactions occur.
Use during pregnancy or breastfeeding.
Contraception in women and men.
Men and women of reproductive potential must use effective contraception during treatment and for 3 months after completion of treatment.
Pregnancy.
There are no clinical data on the use of bortezomib in pregnant women. The teratogenic properties of bortezomib have not been fully studied.
In preclinical studies, bortezomib at maximally tolerated doses did not affect embryonic development in rats and rabbits during organogenesis. Pre- and postnatal developmental studies in animals have not been conducted. BortezoVist is not recommended during pregnancy except when the woman's clinical condition requires bortezomib treatment. If bortezomib is used during pregnancy or if pregnancy occurs during BortezoVist treatment, the patient should be informed of the potential harmful effects on the fetus.
Thalidomide is a medicinal product with known teratogenic effects in humans, causing severe, life-threatening congenital malformations. Thalidomide is contraindicated during pregnancy and in women of reproductive potential. Patients receiving bortezomib in combination with thalidomide must comply with pregnancy prevention requirements. For additional information, refer to the thalidomide product information.
Breastfeeding.
It is unknown whether bortezomib is excreted in human milk, but to prevent the development of serious adverse effects in the infant, breastfeeding is not recommended during bortezomib treatment.
Fertility.
Studies on the effect of bortezomib on fertility have not been conducted.
Ability to affect reaction speed when driving or operating machinery.
Bortezomib has a moderate influence on the ability to drive or operate machinery. The use of the medicinal product is very commonly associated with fatigue, frequently with dizziness, orthostatic/postural hypotension, or visual disturbances, and uncommonly with syncope. Therefore, patients should be cautious when driving or operating machinery and should avoid such activities if these symptoms occur.
Administration and Dosage
Treatment should be initiated under the supervision of a qualified physician experienced in the use of anticancer agents. Preparation of the solution must be performed by qualified medical personnel.
Relapsed multiple myeloma (patients who have received at least one prior therapy).
Monotherapy
The recommended dose of bortezomib in adults is 1.3 mg/m² of body surface area administered intravenously or subcutaneously twice weekly for 2 weeks (on days 1, 4, 8, and 11), followed by a 10-day rest period (days 12–21). This 3-week period constitutes one treatment cycle. After achieving a complete clinical response, administration of two additional cycles is recommended. Patients with partial response but not complete remission should continue bortezomib therapy for up to 8 cycles. At least 72 hours should elapse between consecutive bortezomib doses.
Dosage adjustment and re-initiation recommendations for BortezoVist as monotherapy
In the event of any grade III non-hematologic toxicity or grade IV hematologic toxicity, except for neuropathies, bortezomib treatment should be withheld. After resolution of toxic symptoms, treatment may be resumed at a dose reduced by 25% (reduce dose from 1.3 mg/m² to 1.0 mg/m²; reduce dose from 1.0 mg/m² to 0.7 mg/m²). If toxic symptoms do not resolve or recur during treatment with the reduced dose, discontinuation of bortezomib should be considered, unless the benefits of continued treatment outweigh the risks.
Neuropathic pain and/or peripheral neuropathy
The dose of the medicinal product should be adjusted in the event of neuropathic pain and/or peripheral neuropathy (see Table 1). Bortezomib should be used with caution in patients with a history of severe neuropathy only after careful benefit-risk assessment.
Table 1
Recommended* dose modifications for bortezomib-induced neuropathy
| Severity of neuropathy |
Change in dose and frequency of administration |
| Grade 1 (asymptomatic; loss of deep tendon reflexes or paresthesia) without pain or functional loss |
Dose and administration schedule do not require adjustment |
| Grade 1 with pain or Grade 2 (moderate severity symptoms; limitation of instrumental activities of daily living)** |
Reduce dose to 1 mg/m² or change bortezomib administration schedule to 1.3 mg/m² once weekly |
| Grade 2 with pain or Grade 3 (severe symptoms; limitation of self-care activities)*** |
Withhold bortezomib until resolution of toxicity symptoms. Then resume treatment at a reduced dose of 0.7 mg/m² once weekly. |
| Grade 4 (life-threatening consequences; requiring urgent intervention) and/or severe autonomic neuropathy |
Discontinue bortezomib |
* Based on dose modifications observed in Phase II and III multiple myeloma studies and in the post-marketing period.
** Instrumental activities of daily living include cooking, shopping, using the telephone, etc.
*** Self-care activities include bathing, dressing/undressing, eating, using the toilet, taking medications, being out of bed, etc.
Combination therapy with pegylated liposomal doxorubicin.
The recommended dose of bortezomib for adults is 1.3 mg/m² body surface area administered intravenously or subcutaneously twice weekly for 2 weeks (Days 1, 4, 8, and 11), followed by a 10-day rest period (Days 12–21). This 3-week period constitutes one treatment cycle. At least 72 hours should elapse between consecutive doses of bortezomib.
Pegylated liposomal doxorubicin should be administered at a dose of 30 mg/m² on Day 4 of the bortezomib treatment cycle by 1-hour intravenous infusion after bortezomib injection.
Up to 8 cycles of this combination therapy should be administered provided the disease does not progress and patients tolerate treatment well. Patients who achieve a complete remission may continue treatment for at least 2 additional cycles after achieving complete response, even if this requires administration of more than 8 cycles. Patients whose paraprotein levels continue to decrease after 8 cycles may also continue treatment as long as treatment remains well tolerated and a response is observed.
Combination therapy with dexamethasone.
The recommended dose of bortezomib is 1.3 mg/m² body surface area administered intravenously or subcutaneously twice weekly for 2 weeks (Days 1, 4, 8, and 11), followed by a 10-day rest period (Days 12–21). This 3-week period constitutes one treatment cycle. At least 72 hours should elapse between consecutive doses of Bortezomib.
Dexamethasone should be administered orally at a dose of 20 mg on Days 1, 2, 4, 5, 8, 9, 11, and 12 of the Bortezomib treatment cycle.
Patients who show a response to treatment or stable disease after four cycles may continue this combination for up to four additional cycles. For further information on dexamethasone, refer to the prescribing information for that medicinal product.
Dose modification recommendations for combination therapy in patients with relapsed multiple myeloma.
See dose modification recommendations for bortezomib monotherapy described above.
Untreated multiple myeloma in patients not eligible for hematopoietic stem cell transplantation.
Combination therapy with melphalan and prednisone.
Bortezomib must be administered intravenously or subcutaneously in combination with oral melphalan and oral prednisone over nine 6-week treatment cycles (see Table 2). In cycles 1–4, Bortezomib is administered twice weekly (Days 1, 4, 8, 11, 22, 25, 29, and 32). In cycles 5–9, Bortezomib is administered once weekly (Days 1, 8, 22, and 29). At least 72 hours should elapse between consecutive doses of Bortezomib.
Melphalan and prednisone are administered orally on Days 1, 2, 3, and 4 of the first week of each cycle.
Table 2
Recommended dosing regimen of Bortezomib in combination with melphalan and prednisone
| Bortezomib twice weekly (cycles 1–4) |
||||||||||||||||||||
| Week |
1 |
2 |
3 |
4 |
5 |
6 |
||||||||||||||
| Bortezomib (1.3 mg/m²) |
Day 1 |
-- |
-- |
Day 4 |
Day 8 |
Day 11 |
Break |
Day 22 |
Day 25 |
Day 29 |
Day 32 |
Break |
||||||||
| M (9 mg/m²) P (60 mg/m²) |
Day 1 |
Day 2 |
Day 3 |
Day 4 |
-- |
-- |
Break |
-- |
-- |
-- |
-- |
Break |
||||||||
| Bortezomib once weekly (cycles 5–9) |
||||||||||||||||||||
| Week |
1 |
2 |
3 |
4 |
5 |
6 |
||||||||||||||
| Bortezomib (1.3 mg/m²) |
Day 1 |
-- |
-- |
-- |
Day 8 |
Break |
Day 22 |
Day 29 |
Break |
|||||||||||
| M (9 mg/m²) P (60 mg/m²) |
Day 1 |
Day 2 |
Day 3 |
Day 4 |
-- |
Break |
-- |
-- |
Break |
|||||||||||
M — melphalan, P — prednisone.
Recommendations for dose adjustment and resumption of combination therapy with melphalan and prednisone.
Prior to starting a new treatment cycle:
- platelet count must be ≥ 70×10⁹/L and absolute neutrophil count must be ≥ 1.0×10⁹/L,
- non-hematological toxicity must have recovered to Grade 1 or baseline levels.
Table 3
Dose adjustment during subsequent cycles of therapy with BortezoVist in combination with melphalan and prednisone.
| Toxicity |
Dose modification or treatment discontinuation |
| Hematologic toxicity during cycle:
|
Consider reducing melphalan dose by 25% in the next cycle |
|
Delay administration of BortezoVista dose |
|
BortezoVista dose should be reduced by one level (from 1.3 mg/m2 to 1 mg/m2 or from 1 mg/m2 to 0.7 mg/m2) |
| Non-hematologic toxicity ≥ grade III |
Treatment with BortezoVista should be withheld until symptoms improve to baseline or grade I severity. Then BortezoVista may be restarted at a dose reduced by one level (from 1.3 mg/m2 to 1 mg/m2 or from 1 mg/m2 to 0.7 mg/m2). In case of BortezoVista-dependent neuropathic pain and/or peripheral neuropathy, dose should be held or modified as specified in Table 1. |
For additional information on melphalan and prednisone, please refer to the package leaflets of these medicinal products.
Untreated multiple myeloma in patients eligible for hematopoietic stem cell transplantation (induction therapy). Combination therapy with dexamethasone.
The recommended dose of BortezoVist is 1.3 mg/m² body surface area administered intravenously or subcutaneously twice weekly for 2 weeks (on days 1, 4, 8, and 11), followed by a 10-day treatment-free period (days 12–21). This 3-week period is considered one treatment cycle. At least 72 hours should elapse between consecutive doses of BortezoVist.
Dexamethasone is administered orally at a dose of 40 mg on days 1, 2, 3, 4, 8, 9, 10, and 11 of the BortezoVist treatment cycle.
Administer 4 treatment cycles of this combination.
Combination therapy with dexamethasone and thalidomide.
The recommended dose of BortezoVist is 1.3 mg/m² body surface area administered intravenously or subcutaneously twice weekly for 2 weeks (on days 1, 4, 8, and 11), followed by a 17-day treatment-free period (days 12–28). This 4-week period is considered one treatment cycle. At least 72 hours should elapse between consecutive doses of BortezoVist.
Dexamethasone is administered orally at a dose of 40 mg on days 1, 2, 3, 4, 8, 9, 10, and 11 of the BortezoVist treatment cycle.
Thalidomide is administered orally at a dose of 50 mg daily on days 1–14 of the cycle. If the drug is well tolerated, the dose should be increased to 100 mg daily on days 15–28. Starting from the second cycle, the dose may be further increased to 200 mg daily (see Table 4).
Administer 4 treatment cycles. Patients achieving at least a partial response to treatment are recommended to receive 2 additional cycles of therapy.
Table 4
Recommended dosing regimen of BortezoVist when used in combination with dexamethasone and thalidomide in patients with untreated multiple myeloma eligible for hematopoietic stem cell transplantation.
| Bortezomib + Dx |
Cycles 1–4 |
||||||
| Week |
1 |
2 |
3 |
||||
| Bortezomib (1.3 mg/m²) |
Day 1, 4 |
Day 8, 11 |
Break |
||||
| Dx (40 mg) |
Day 1, 2, 3, 4 |
Day 8, 9, 10, 11 |
- |
||||
| Bortezomib + Dx + T |
Cycle 1 |
||||||
| Week |
1 |
2 |
3 |
4 |
|||
| Bortezomib (1.3 mg/m²) |
Day 1, 4 |
Day 8, 11 |
Break |
Break |
|||
| T (50 mg) |
Daily |
Daily |
- |
- |
|||
| T (100 mg)ᵃ |
- |
- |
Daily |
Daily |
|||
| Dx (40 mg) |
Day 1, 2, 3, 4 |
Day 8, 9, 10, 11 |
- |
- |
|||
| Cycles 2–4ᵇ |
|||||||
| Bortezomib (1.3 mg/m²) |
Day 1, 4 |
Day 8, 11 |
Break |
Break |
|||
| T (200 mg)ᵃ |
Daily |
Daily |
Daily |
Daily |
|||
| Dx (40 mg) |
Day 1, 2, 3, 4 |
Day 8, 9, 10, 11 |
- |
- |
|||
Dx — dexamethasone; Th — thalidomide.
a Increase thalidomide dose to 100 mg from week 3 of cycle 1 if 50 mg is tolerated, and to 200 mg if 100 mg is tolerated.
b Patients who achieve a partial response after 4 cycles of treatment may continue up to a maximum of 6 cycles.
Dosing recommendations for patients eligible for transplantation.
For dose adjustments in the event of neuropathy, see Table 1.
If BortezoVist must be used in combination with other chemotherapeutic agents, refer to the respective product information for guidance on dose adjustments in the event of toxicity.
Untreated mantle cell lymphoma.
Combination therapy with rituximab, cyclophosphamide, doxorubicin, and prednisone (VcR-CAP regimen).
The recommended dose of BortezoVist is 1.3 mg/m² body surface area administered intravenously or subcutaneously twice weekly for 2 weeks (on days 1, 4, 8, and 11), followed by a 10-day treatment-free period (days 12–21). This 3-week period constitutes one treatment cycle. At least 72 hours should elapse between consecutive doses of BortezoVist. Administer 6 treatment cycles. Patients who first demonstrate response during the 6th treatment cycle are recommended to receive 2 additional cycles of therapy.
Medications administered by intravenous infusion on day 1 of each 3-week treatment cycle with BortezoVist: rituximab 375 mg/m², cyclophosphamide 750 mg/m², doxorubicin 50 mg/m².
Prednisone is administered orally at a dose of 100 mg/m² on days 1, 2, 3, 4, and 5 of each BortezoVist treatment cycle.
Dose modification recommendations for patients with untreated mantle cell lymphoma.
Prior to initiation of a new treatment cycle:
- Platelet count must be ≥ 100,000 cells/µL and absolute neutrophil count must be ≥ 1,500 cells/µL;
- Platelet count must be ≥ 75,000 cells/µL in patients with bone marrow infiltration or splenic sequestration;
- Hemoglobin level must be ≥ 8 g/dL;
- Non-hematologic toxicity must have resolved to grade 1 or baseline levels.
Treatment with BortezoVist should be withheld in the event of any non-hematologic toxicity ≥ grade III (except neuropathy) related to BortezoVist, or hematologic toxicity ≥ grade III. Refer to Table 5 for dose modification recommendations.
Granulocyte colony-stimulating factors may be used to manage hematologic toxicity. If initiation of a new treatment cycle is delayed multiple times, consider prophylactic use of granulocyte colony-stimulating factor. Platelet transfusion should be considered for the management of thrombocytopenia.
Table 5
Dose modification during therapy for patients with untreated mantle cell lymphoma
| Toxicity |
Dose modification or treatment interruption |
| Hematological toxicity |
|
| Grade ≥ III neutropenia accompanied by fever, grade IV neutropenia lasting more than 7 days, platelet count ˂ 10,000 cells/μL. |
Treatment with BortezoVista should be interrupted for up to 2 weeks until the absolute neutrophil count recovers to ≥ 750 cells/μL and platelet count to ≥ 25,000 cells/μL. If toxicity does not improve (blood counts do not recover to the above-mentioned levels), BortezoVista should be discontinued. If toxicity improves (absolute neutrophil count recovers to ≥ 750 cells/μL and platelet count to ≥ 25,000 cells/μL), treatment with BortezoVista can be resumed at a reduced dose by one level (from 1.3 mg/m² to 1 mg/m² or from 1 mg/m² to 0.7 mg/m²). |
| If platelet count is ˂ 25,000 cells/μL or absolute neutrophil count is ˂ 750 cells/μL on the day of BortezoVista administration (except day 1 of each treatment cycle). |
Delay administration of the BortezoVista dose. |
| Non-hematological toxicity ≥ grade III related to BortezoVista administration. |
Treatment with BortezoVista should be interrupted until symptoms improve to grade II severity or better. Then, BortezoVista may be reinitiated at a dose reduced by one level (from 1.3 mg/m² to 1 mg/m² or from 1 mg/m² to 0.7 mg/m²). In case of BortezoVista-induced neuropathic pain and/or peripheral neuropathy, dose holding or modification should be performed as specified in Table 1. |
If BortezoVist is used in combination with other chemotherapeutic agents, also refer to the instructions for use of these medicinal products regarding dose adjustments in the event of toxicity.
Special patient groups.
Elderly patients.
Currently, there are no data indicating the need for dose adjustment in patients aged 65 years and older.
There have been no studies on the use of bortezomib in elderly patients with previously untreated multiple myeloma who are candidates for high-dose chemotherapy with hematopoietic stem cell transplantation. Therefore, no recommendations on dose adjustment can be provided for this patient group.
In a study evaluating the use of bortezomib in patients with previously untreated mantle cell lymphoma, 42.9% of patients were aged 65–74 years and 10.4% were aged ≥75 years. Patients aged 75 years and older tolerated treatment less well in both treatment groups (VcR-CAP and R-CHOP regimens).
Patients with hepatic impairment.
Dose adjustment is not required for patients with mild hepatic impairment. For patients with moderate and severe hepatic impairment, treatment with BortezoVist should be initiated at a dose of 0.7 mg/m² during the first treatment cycle, with subsequent gradual dose escalation to 1.0 mg/m² or dose reduction to 0.5 mg/m², depending on patient tolerability.
Table 6
Recommended adjustments of initial doses of BortezoVist in patients with hepatic impairment.
| Severity of hepatic impairment* |
Level of bilirubin |
Levels of AST |
Initial dose adjustment |
| Mild |
≤ 1.0 × ULN |
> ULN |
Not required |
| > 1.0–1.5× ULN |
Any |
Not required |
|
| Moderate |
> 1.5–3× ULN |
Any |
Reduce the dose of BortezoVist to 0.7 mg/m² in the first treatment cycle. Subsequent dose escalation to 1.0 mg/m² or dose reduction to 0.5 mg/m² depending on drug tolerability. |
| Severe |
> 3 × ULN |
Any |
AST — aspartate aminotransferase; ULN — upper limit of normal.
* Based on the classification of severity of hepatic impairment (mild, moderate, and severe) by the Organ Dysfunction Working Group of the National Cancer Institute [USA].
Patients with renal impairment.
Mild to moderate renal impairment (creatinine clearance > 20 ml/min/1.73 m²) does not affect the pharmacokinetics of bortezomib; therefore, dose adjustment is not required in this patient group. It is unknown whether severe renal impairment (creatinine clearance < 20 ml/min/1.73 m²) affects the pharmacokinetics of bortezomib. Since dialysis may reduce bortezomib concentrations, the drug should be administered after the dialysis procedure.
Method of administration.
BortezoVista is administered by intravenous or subcutaneous injection. Accidental intrathecal administration of the drug has resulted in fatal outcomes. Intravenous.
The reconstituted solution should be administered immediately as a 3–5 second intravenous bolus injection through a peripheral or central venous catheter, which should then be flushed with 0.9% sodium chloride injection solution. At least 72 hours must elapse between consecutive doses of BortezoVista.
Subcutaneous.
The reconstituted solution should be administered immediately by subcutaneous injection at a 45–90° angle, selecting injection sites on the thighs (left or right) or abdomen (left or right). Injection sites should be rotated.
If adverse reactions occur at the injection site following subcutaneous injections, the BortezoVista solution may be administered subcutaneously at a lower concentration (1 mg/ml instead of 2.5 mg/ml) or BortezoVista may be administered intravenously.
Children.
The safety and efficacy of BortezoVista in pediatric patients (under 18 years of age) have not been established. Current data are insufficient to provide dosing recommendations for pediatric patients.
Overdose.
Symptoms. Doses exceeding the recommended dose by more than two times have been associated with acute hypotension and thrombocytopenia resulting in death.
Treatment. There is no known specific antidote for bortezomib. In case of overdose, careful monitoring of hemodynamic parameters (infusion therapy, vasopressors and/or inotropic agents) and body temperature is recommended.
Adverse reactions
Serious adverse reactions reported during bortezomib treatment include heart failure, tumor lysis syndrome, pulmonary hypertension, reversible posterior leukoencephalopathy syndrome (PRES), acute diffuse infiltrative pulmonary disorders, and, rarely, autonomic neuropathy. The most commonly observed adverse reactions during bortezomib therapy are nausea, diarrhea, constipation, vomiting, fatigue, pyrexia, thrombocytopenia, anemia, neutropenia, peripheral neuropathy (including sensory neuropathy), headache, paresthesia, decreased appetite, dyspnea, rash, herpes zoster, and myalgia.
Multiple myeloma
The adverse reactions listed in Table 7 are considered possibly related to bortezomib use. Data on these adverse reactions were obtained from 5,476 patients, of whom 3,996 received bortezomib at a dose of 1.3 mg/m². Overall, bortezomib was administered to 3,974 patients for the treatment of multiple myeloma. Adverse reactions are categorized by system organ class and frequency of occurrence. Frequency is defined as: very common (> 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), and not known (cannot be estimated from available data). Within each category, adverse reactions are listed in order of decreasing severity. Also included are adverse reactions not observed during clinical trials but reported in the post-marketing period.
Table 7
| Organ Systems |
Frequency |
Adverse Reaction |
| Infections and infestations |
Common |
Herpes zoster (including disseminated and with ocular complications), pneumonia*, herpes simplex*, fungal infection* |
| Uncommon |
Infections*, bacterial infections*, viral infections*, sepsis (including septic shock)*, bronchopneumonia, herpesvirus infection*, herpetic meningoencephalitis#, bacteremia (including staphylococcal), hordeolum, influenza, cellulitis, device-related infections, skin infections*, ear infections*, staphylococcal infection, dental infection* |
|
| Rare |
Meningitis (including bacterial), Epstein-Barr virus infection, genital herpes, tonsillitis, mastoiditis, post-viral fatigue syndrome |
|
| Benign, malignant and unspecified neoplasms (including cysts and polyps) |
Rare |
Malignant tumor, plasma cell leukemia, renal cell carcinoma, tumor growth, mycosis fungoides, benign neoplasm* |
| Blood and lymphatic system disorders |
Very common |
Thrombocytopenia*, neutropenia*, anemia* |
| Common |
Leukopenia*, lymphopenia* |
|
| Uncommon |
Pancytopenia*, febrile neutropenia, coagulopathy*, leukocytosis*, lymphadenopathy, hemolytic anemia# |
|
| Rare |
Disseminated intravascular coagulation syndrome, thrombocytosis*, hyperviscosity syndrome, thrombopathy, thrombotic microangiopathy (including thrombotic purpura), other blood and hematopoietic disorders, hemorrhagic diathesis, lymphocytic infiltration |
|
| Immune system disorders |
Uncommon |
Angioedema#, hypersensitivity* |
| Rare |
Anaphylactic shock, amyloidosis, type III immune complex-mediated reactions |
|
| Endocrine disorders |
Uncommon |
Cushing's syndrome*, hyperthyroidism*, disturbance in antidiuretic hormone secretion |
| Rare |
Hypothyroidism |
|
| Metabolism and nutrition disorders |
Very common |
Decreased appetite |
| Common |
Dehydration, hypokalemia*, hyponatremia*, blood glucose level disturbance*, hypocalcemia*, enzyme level disturbance* |
|
| Uncommon |
Tumor lysis syndrome, patient condition aggravatedª*, hypomagnesemia*, hypophosphatemia*, hyperkalemia*, hypercalcemia*, hypernatremia*, uric acid level disturbance*, diabetes mellitus*, fluid retention |
|
| Rare |
Hypermagnesemia*, acidosis, electrolyte imbalance*, hypervolemia, hypochloremia*, hypovolemia, hyperchloremia*, hyperphosphatemia*, metabolic disorders, vitamin B group deficiency, vitamin B12 deficiency, gout, increased appetite, alcohol intolerance |
|
| Psychiatric disorders |
Common |
Mood and sensation disorders*, anxiety disorder*, sleep disorders* |
| Uncommon |
Psychiatric disorder*, hallucinations*, psychotic disorder*, confusion*, agitation |
|
| Rare |
Suicidal ideation*, adjustment disorder, delirium, decreased libido |
|
| Nervous system disorders |
Very common |
Neuropathies*, peripheral sensory neuropathy, dysesthesia*, neuralgia* |
| Common |
Motor neuropathy*, loss of consciousness (including syncope), dizziness*, dysgeusia*, lethargy, headache* |
|
| Uncommon |
Tremor, sensorimotor peripheral neuropathy, dyskinesia*, coordination and balance disorders*, memory loss (without dementia)*, encephalopathy*, reversible posterior encephalopathy syndrome#, neurotoxicity, seizure disorders*, postherpetic neuralgia, speech disorders*, restless legs syndrome, migraine, sciatica, attention disorders, reflex disturbances*, parosmia |
|
| Rare |
Intracranial hemorrhage*, intracerebral hemorrhage (including subarachnoid)*, brain edema, transient ischemic attack, coma, autonomic nervous system disorders, autonomic neuropathy, cranial nerve paralysis*, paralysis*, paresis*, presyncope, brainstem lesion syndrome, cerebrovascular disorder, nerve root damage, psychomotor hyperactivity, spinal cord compression, other cognitive disorders, motor dysfunctions, other nervous system disorders, radiculitis, salivation, hypotension, Guillain-Barré syndrome#, demyelinating polyneuropathy# |
|
| Eye disorders |
Common |
Eye edema*, vision disturbances*, conjunctivitis* |
| Uncommon |
Ocular hemorrhage*, eyelid infections*, chalazion#, blepharitis#, eye inflammation*, diplopia, dry eyes*, eye irritation*, eye pain, increased lacrimation, eye discharge |
|
| Rare |
Corneal damage*, exophthalmos, retinitis, scotoma, other eye (and eyelid) diseases, acquired dacryoadenitis, photophobia, photopsia, optic neuropathy#, various degrees of vision deterioration (up to blindness)* |
|
| Ear and labyrinth disorders |
Common |
Vertigo* |
| Uncommon |
Dysacusis (including tinnitus)*, hearing loss (up to deafness), ear discomfort* |
|
| Rare |
Ear hemorrhage, vestibular neuronitis, other ear disorders |
|
| Cardiac disorders |
Uncommon |
Cardiac tamponade#, cardiopulmonary shock*, cardiac fibrillation (including atrial), heart failure (including left and right ventricular)*, arrhythmia*, tachycardia*, palpitations, angina pectoris, pericarditis (including pericardial effusion), cardiomyopathy*, ventricular dysfunction*, bradycardia |
| Rare |
Atrial flutter, myocardial infarction*, atrioventricular block*, cardiovascular disorders (including cardiogenic shock), flutter/fibrillation, unstable angina, heart valve disorders*, coronary artery insufficiency, sinus node arrest |
|
| Vascular disorders |
Common |
Hypotension*, orthostatic hypotension, hypertension* |
| Uncommon |
Cerebrovascular disorder#, deep vein thrombosis*, hemorrhage*, thrombophlebitis (including superficial), vascular collapse (including hypovolemic shock), phlebitis, flushing*, hematoma (including retroperitoneal)*, peripheral circulation disorders*, vasculitis, hyperemia (including ocular)* |
|
| Rare |
Peripheral vascular embolism, lymphedema, pallor, erythromelalgia, vasodilation, vessel decolorization, venous insufficiency |
|
| Respiratory, thoracic and mediastinal disorders |
Common |
Dyspnea*, epistaxis, lower/upper respiratory tract infections*, cough* |
| Uncommon |
Pulmonary embolism, pleural effusion, pulmonary edema (including acute), pulmonary alveolar hemorrhage#, bronchospasm, chronic obstructive pulmonary disease*, hypoxemia*, worsening airway patency*, hypoxia, pleurisy*, hiccups, rhinorrhea, dysphonia, wheezing |
|
| Rare |
Respiratory failure, acute respiratory distress syndrome, apnea, pneumothorax, lung collapse, pulmonary hypertension, hemoptysis, pulmonary hyperventilation, orthopnea, pneumonitis, respiratory alkalosis, tachypnea, pulmonary fibrosis, bronchial disorders*, hypocapnia*, interstitial pneumonia, lung infiltration, throat tightness sensation, dry throat, increased upper respiratory tract secretion, throat irritation, upper respiratory tract cough syndrome |
|
| Gastrointestinal disorders |
Very common |
Nausea and vomiting*, diarrhea*, constipation |
| Common |
Gastrointestinal hemorrhage (including mucosal)*, dyspepsia, stomatitis*, abdominal distension, oropharyngeal pain*, abdominal pain (including gastrointestinal and splenic region)*, oral cavity disorders*, meteorism |
|
| Uncommon |
Pancreatitis (including chronic)*, vomiting with blood, lip swelling*, gastrointestinal obstruction (including small intestine obstruction, ileus)*, abdominal discomfort, oral ulcers*, enteritis*, gastritis*, gum bleeding, gastroesophageal reflux disease*, colitis (including Clostridium difficile-induced)*, ischemic colitis#, gastrointestinal inflammation*, dysphagia, irritable bowel syndrome, other gastrointestinal disorders, coated tongue, gastrointestinal motility disorder*, salivary gland disorders* |
|
| Rare |
Acute pancreatitis, peritonitis*, tongue edema*, ascites, esophagitis, cheilitis, fecal incontinence, anal sphincter atony, fecaloma*, gastrointestinal ulcers and perforations*, gingival hyperplasia, megacolon, rectal discharge, blister formation in oropharynx*, lip pain, periodontitis, anal fissure, defecation rhythm changes, proctalgia, abnormal defecation |
|
| Hepatobiliary disorders |
Common |
Changes in liver enzyme levels* |
| Uncommon |
Hepatotoxicity (including liver disorders), hepatitis*, cholestasis |
|
| Rare |
Liver failure, hepatomegaly, Budd-Chiari syndrome, cytomegalovirus hepatitis, hepatic hemorrhage, cholelithiasis |
|
| Skin and subcutaneous tissue disorders |
Common |
Rash*, pruritus*, erythema, dry skin |
| Uncommon |
Multiform erythema, urticaria, acute febrile neutrophilic dermatosis, toxic skin eruptions, toxic epidermal necrolysis#, Stevens-Johnson syndrome#, dermatitis*, hair disorders*, petechiae, ecchymosis, skin irritation, purpura, skin induration*, psoriasis, hyperhidrosis, night sweats, pressure ulcers#, acne*, bullae*, skin pigmentation disorders*. |
|
| Rare |
Skin reactions, Jessner's lymphocytic infiltration, hand-foot erythrodysesthesia syndrome, subcutaneous hemorrhage, livedo reticularis, skin induration, papules, photosensitivity reactions, seborrhea, cold sweat, other skin disorders, erythrosis, skin ulcers, nail disorders. |
|
| Musculoskeletal and connective tissue disorders |
Very common |
Musculoskeletal pain*. |
| Common |
Muscle spasms*, limb pain, muscle weakness. |
|
| Uncommon |
Muscle twitching, joint swelling, arthritis*, joint stiffness, myopathies*, heaviness sensation. |
|
| Rare |
Rhabdomyolysis, temporomandibular joint dysfunction, fistula, joint effusion, jaw pain, bone disorders, infections and inflammation of musculoskeletal system and connective tissue*, synovial cyst. |
|
| Renal and urinary disorders |
Common |
Renal failure*. |
| Uncommon |
Acute renal failure, chronic renal failure*, urinary tract infections*, signs and symptoms of urinary tract disorders*, hematuria*, urinary retention, micturition disorders*, proteinuria, azotemia, oliguria*, polyuria. |
|
| Rare |
Bladder irritation. |
|
| Reproductive system and breast disorders |
Uncommon |
Vaginal bleeding, genital pain*, erectile dysfunction. |
| Rare |
Testicular disorders*, prostatitis, breast disorders in women, epididymis tenderness, epididymitis, pelvic pain, vulvar ulcers. |
|
| Congenital, familial and genetic disorders |
Rare |
Aplasia, gastrointestinal tract malformations, ichthyosis. |
| General disorders and administration site conditions |
Very common |
Pyrexia*, fatigue, asthenia. |
| Common |
Edema (including peripheral), chills, pain*, fever*. |
|
| Uncommon |
General physical health deterioration*, facial edema*, injection site reactions*, mucous membrane disorders*, chest pain, gait disturbance, feeling of cold, extravasation*, catheter-related complications*, thirst sensation*, chest discomfort, sensation of body temperature change*, injection-related pain*. |
|
| Rare |
Lethal outcome (including sudden), multi-organ failure, hemorrhage at infusion site*, hernia (including hiatal)*, impaired healing*, inflammation, phlebitis at injection site*, pain, ulceration, irritation, non-cardiac substernal pain, catheter insertion site pain, foreign body sensation. |
|
| Investigations |
Common |
Weight decreased. |
| Uncommon |
Hyperbilirubinemia*, deviation of protein levels from normal*, weight increased, blood test abnormality*, increased C-reactive protein level. |
|
| Rare |
Blood gas abnormalities*, ECG abnormalities (including QT interval prolongation)*, international normalized ratio deviation*, increased gastric acidity, increased platelet aggregation, increased troponin I level, virus identification in serological tests*, urine test abnormalities*. |
|
| Procedural complications |
Uncommon |
Falls, confusion. |
| Rare |
Transfusion reactions, fractures*, tremor*, facial injury, joint injury*, burns, skin laceration, procedural pain, radiation injuries*. |
|
| Surgical and medical procedures |
Rare |
Macrophage activation. |
* Grouping of two or more MedDRA terms [Medical Dictionary for Regulatory Activities].
#From post-marketing sources.
ªPatient deterioration — a general term defined as weight loss of more than 5%, decreased appetite, poor nutrition, and lack of physical activity, often associated with dehydration, depression, immune dysfunction, and low cholesterol levels. Patient deterioration is not a distinct disease or syndrome; rather, it represents nonspecific manifestations of an underlying physical, cognitive, or psychosocial condition.
Mantle cell lymphoma.
The safety profile of bortezomib in 240 patients with mantle cell lymphoma who received bortezomib at a dose of 1.3 mg/m² in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (VcR-CAP), and 242 patients who received rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), was generally similar to the safety profile observed in patients with multiple myeloma; the main differences are described below. Additional adverse reactions observed with bortezomib in combination therapy (VcR-CAP) were hepatitis B virus infection (< 1%) and myocardial ischemia (1.3%). The similar incidence of these events in both treatment groups suggests that these adverse reactions may not be solely related to bortezomib. Treatment with bortezomib in patients with mantle cell lymphoma was associated with ≥ 5% higher frequencies of hematologic adverse reactions (neutropenia, thrombocytopenia, leukopenia, anemia, lymphopenia), peripheral sensory neuropathy, arterial hypertension, pyrexia, pneumonia, stomatitis, and hair disorders compared to patients with multiple myeloma.
Adverse reactions occurring at a frequency ≥ 1%, with similar or higher frequency in the VcR-CAP treatment group, that were possibly or probably related to the medicinal products included in the VcR-CAP combination regimen, are listed in Table 8. Also included are adverse reactions observed in the VcR-CAP treatment group that, based on investigator assessment, were possibly or probably related to bortezomib, considering experience from studies in patients with multiple myeloma. Adverse reactions are categorized by system organ class and frequency of occurrence. Frequency was defined as: very common (> 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from available data). Within each category, adverse reactions are listed in order of decreasing severity.
Table 8
| Organ systems |
Frequency |
Adverse reaction |
| Infections and infestations |
Very common |
Pneumonia*. |
| Common |
Sepsis (including septic shock)*, herpes zoster (including disseminated and with ocular complications), herpesvirus infection*, bacterial infections*, infections of upper/lower respiratory tract*, fungal infection*, herpes simplex*. |
|
| Uncommon |
Hepatitis B, infections*, bronchopneumonia. |
|
| Blood and lymphatic system disorders |
Very common |
Thrombocytopenia*, febrile neutropenia, neutropenia*, leukopenia*, anemia*, lymphopenia*. |
| Uncommon |
Pancytopenia*. |
|
| Immune system disorders |
Common |
Hypersensitivity*. |
| Uncommon |
Anaphylactic reaction. |
|
| Metabolism and nutrition disorders |
Very common |
Decreased appetite. |
| Common |
Hypokalemia*, blood glucose alterations*, hyponatremia*, diabetes mellitus*, fluid retention. |
|
| Uncommon |
Tumor lysis syndrome. |
|
| Psychiatric disorders |
Common |
Sleep disorders*. |
| Nervous system disorders |
Very common |
Peripheral sensory neuropathy, dysesthesia*, neuralgia*. |
| Common |
Neuropathies*, motor neuropathy*, loss of consciousness (including syncope), encephalopathy*, sensory-motor peripheral neuropathy, dizziness*, dysgeusia*, autonomic neuropathy. |
|
| Uncommon |
Autonomic nervous system disorders. |
|
| Eye disorders |
Common |
Visual disturbances*. |
| Ear and labyrinth disorders |
Common |
Dysacusis (including tinnitus)*. |
| Uncommon |
Vertigo*, hearing impairment (up to deafness). |
|
| Cardiac disorders |
Common |
Cardiac fibrillation (including atrial), arrhythmia*, heart failure (including left and right ventricular)*, myocardial ischemia, ventricular dysfunction*. |
| Uncommon |
Cardiovascular disorders (including cardiogenic shock). |
|
| Vascular disorders |
Common |
Hypertension*, hypotension*, orthostatic hypotension. |
| Respiratory, thoracic and mediastinal disorders |
Common |
Dyspnea*, cough*, hiccups. |
| Uncommon |
Acute respiratory distress syndrome, pulmonary embolism, pneumonitis, pulmonary hypertension, pulmonary edema (including acute). |
|
| Gastrointestinal disorders |
Very common |
Nausea and vomiting*, diarrhea*, stomatitis*, constipation. |
| Common |
Gastrointestinal hemorrhage (including mucosal)*, abdominal distension, dyspepsia, oropharyngeal pain*, gastritis*, oral ulcers*, abdominal discomfort, dysphagia, gastrointestinal inflammation*, abdominal pain (including gastrointestinal and splenic region pain)*, oral cavity disorders*. |
|
| Uncommon |
Colitis (including Clostridium difficile-induced)*. |
|
| Hepatobiliary disorders |
Common |
Hepatotoxicity (including hepatic disorders). |
| Uncommon |
Hepatic failure. |
|
| Skin and subcutaneous tissue disorders |
Very common |
Hair disorders*. |
| Common |
Pruritus*, dermatitis*, rash*. |
|
| Musculoskeletal and connective tissue disorders |
Common |
Muscle spasms*, musculoskeletal pain*, limb pain. |
| Renal and urinary disorders |
Common |
Urinary tract infections*. |
| General disorders and administration site reactions |
Very common |
Pyrexia*, fatigue, asthenia. |
| Common |
Edema (including peripheral), chills, injection site reactions*, fever*. |
|
| Investigations |
Common |
Hyperbilirubinemia*, protein level abnormalities*, weight loss, weight gain. |
*Grouping of two or more MedDRA terms.
Description of selected adverse reactions.
Reactivation of Herpes zoster virus.
Multiple myeloma. Antiviral prophylaxis was administered in 26% of patients receiving bortezomib in combination with melphalan and prednisone. The incidence of herpes zoster was 17% in patients who did not receive antiviral agents, compared to 3% in those who received antiviral prophylaxis. Mantle cell lymphoma. Antiviral prophylaxis was administered in 137 out of 240 patients (57%) receiving bortezomib as part of combination therapy with the VcR-CAP regimen. Herpes zoster occurred in 10.7% of patients who did not receive antiviral agents, compared to 3.6% of patients who received antiviral prophylaxis.
Reactivation and infection with hepatitis B virus (HBV).
Mantle cell lymphoma. Cases of hepatitis B infection resulting in fatal outcomes were reported in 0.8% of patients (n = 2) in the group receiving R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) and in 0.4% of patients (n = 1) receiving bortezomib as part of combination therapy with the VcR-CAP regimen (rituximab, cyclophosphamide, doxorubicin, and prednisone). The overall incidence of hepatitis B was similar in both treatment groups (0.8% in the VcR-CAP group versus 1.2% in the R-CHOP group).
Peripheral neuropathy during combination therapy.
Multiple myeloma. Peripheral neuropathy was observed in studies where bortezomib was used as induction therapy in combination with dexamethasone (study IFM-2005-01) and with dexamethasone and thalidomide (study MMY-3010) (see Table 9).
Table 9.
Incidence of peripheral neuropathy (PN) during induction therapy by toxicity grade and need for treatment interruption due to PN.
| Signs of peripheral neuropathy |
IFM-2005-01 |
MMY-3010 |
||
| VDDx (N = 239) |
VcDx (N = 239) |
TDx (N = 126) |
VcTDx (N = 130) |
|
| Frequency of PN (%) |
||||
| All grades of PN |
3 |
15 |
12 |
45 |
| ≥ Grade II PN |
1 |
10 |
2 |
31 |
| ≥ Grade III PN |
˂ 1 |
5 |
0 |
5 |
| Discontinuation of treatment due to PN (%) |
˂ 1 |
2 |
1 |
5 |
VDDx — vincristine, doxorubicin, dexamethasone; VcDx — bortezomib, dexamethasone; TDx — thalidomide, dexamethasone; VcTDx — bortezomib, thalidomide, dexamethasone.
Peripheral neuropathy includes: peripheral neuropathy, peripheral motor neuropathy, peripheral sensory neuropathy, and polyneuropathy.
Mantle cell lymphoma. Table 10 shows the frequency of peripheral neuropathy observed in the LYM-3002 study with bortezomib in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CAP).
Table 10.
Frequency of peripheral neuropathy (PN) in the bortezomib study in patients with mantle cell lymphoma, by toxicity grade and need for treatment discontinuation due to PN.
| Peripheral neuropathy parameters |
VcR-CAP (N = 240) |
R-CHOP (N = 242) |
| Incidence of PN (%) |
||
| All grades PN |
30 |
29 |
| ≥ Grade II PN |
18 |
9 |
| ≥ Grade III PN |
8 |
4 |
| Discontinuation of treatment due to PN (%) |
2 |
˂1 |
VcR-CAP — bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone; R-CHOP — rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone.
Peripheral neuropathy includes: peripheral sensory neuropathy, peripheral neuropathy, peripheral motor neuropathy, and peripheral sensorimotor neuropathy.
Elderly patients with mantle cell lymphoma
In the VcR-CAP treatment group, 42.9% of patients were aged 65–74 years and 10.4% were ≥75 years. Although patients aged 75 years and older tolerated both treatment regimens less well, the rate of serious adverse reactions was 68% in the VcR-CAP group compared to 42% in the R-CHOP group.
Known differences in the safety profile of bortezomib when administered intravenously versus subcutaneously.
In a Phase III study, in patients receiving subcutaneous bortezomib, the incidence of treatment-related adverse reactions of Grade III toxicity or higher was 13% lower compared to patients receiving intravenous bortezomib, and the rate of bortezomib treatment interruption was 5% lower. The overall incidence of diarrhea, lower abdominal pain, abdominal pain, asthenic conditions, upper respiratory tract infections, and peripheral neuropathies was 12–15% lower in the subcutaneous group compared to the intravenous group. Additionally, the incidence of peripheral neuropathies of Grade III or higher was 10% lower, and the rate of treatment discontinuation due to peripheral neuropathy was 8% lower. Injection site reactions occurred in 6% of patients, predominantly erythema. Symptoms resolved on average within 6 days, and dose modification was required in 2 patients.
Serious reactions occurred in 2 patients (1%): 1 case of pruritus and 1 case of erythema. The rate of fatal events during treatment was 5% in the subcutaneous group and 7% in the intravenous group. The rate of fatal events due to disease progression was 18% in the subcutaneous group and 9% in the intravenous group.
Re-treatment of patients with relapsed multiple myeloma.
In a study evaluating bortezomib as re-treatment involving 130 patients with relapsed multiple myeloma who had previously achieved at least a partial response to bortezomib-containing therapy, adverse reactions of all grades occurring in at least 25% of patients primarily included thrombocytopenia (55%), neuropathy (40%), anemia (37%), diarrhea (35%), and constipation (28%). Peripheral neuropathy of all grades and peripheral neuropathy ≥ Grade III were observed in 40% and 8.5% of patients, respectively.
Reporting suspected adverse reactions.
Reporting adverse reactions after drug registration is of great importance. It enables ongoing monitoring of the benefit-risk balance of this medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of efficacy to the State Expert Center of the Ministry of Health of Ukraine via the following link: https://aisf.dec.gov.ua
Shelf life. 3 years.
After reconstitution, the medicinal product can be stored at a temperature not exceeding 25 °C in a normally lit room, in the original vial or syringe, for no more than 8 hours.
Storage conditions.
Store in the original packaging, protected from light, at a temperature not exceeding 25 °C. Keep out of reach of children.
Incompatibilities. This medicinal product should not be mixed with other medicinal products except those specified in the section "Dosage and administration."
Packaging.
3.5 mg in a vial. 1 vial in a cardboard pack.
Prescription category.
Prescription only.
Manufacturers.
Sandoz España, S.L.
Sandoz s.r.o.
Manufacturer's address and place of business.
Calle C/Castello, no1, Sant Boi de Llobregat, Barcelona, 08830, Spain.
Brnenska 32/sr. 597, Blansko, 67801, Czech Republic.