Bortezomib
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BortezoVista (BortezoVista)
Composition:
Active substance: bortezomib;
1 vial contains 1 mg of bortezomib;
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-fold 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 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 controlling 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. Studies have shown 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 suppression of growth in multiple 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 bone disease and were treated with bortezomib.
Pharmacokinetics.
Absorption. After intravenous bolus administration of doses of 1.0 mg/m² and 1.3 mg/m² to 11 patients with multiple myeloma and creatinine clearance exceeding 50 mL/min, the mean peak plasma concentration (Cmax) of bortezomib after the first dose was 57 and 112 ng/mL, respectively. With subsequent doses, mean peak plasma concentrations 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.
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. At bortezomib concentrations of 0.01–1.0 µg/mL, plasma protein binding is 83%. The fraction of bortezomib bound to plasma proteins was independent of concentration.
Metabolism. In vitro, bortezomib metabolism is primarily mediated by cytochrome P450 enzymes, particularly CYP3A4, CYP2C19, and CYP1A2. The primary metabolic pathway involves deboronation, leading to two metabolites, which are subsequently hydroxylated into other metabolites. 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.
Moderate hepatic impairment did not alter bortezomib AUC compared to normal hepatic function. Mean AUC values of bortezomib increased by approximately 60% in patients with moderate to 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 impairment, categorized by creatinine clearance (CrCL) into the following groups: normal (CrCL ≥ 60 mL/min/1.73 m², n = 12), mild (CrCL = 40–59 mL/min/1.73 m², n = 10), moderate (CrCL = 20–39 mL/min/1.73 m², n = 9), and severe (CrCL < 20 mL/min/1.73 m², n = 3). Patients undergoing 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 (standardized AUC and Cmax) was comparable across all groups.
Age. Pharmacokinetic parameters of bortezomib were evaluated in 104 pediatric patients (aged 2–16 years) 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) 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 with melphalan and prednisone, for treatment of previously untreated patients who are not eligible for high-dose chemotherapy with hematopoietic stem cell transplantation (first-line therapy).
Relapsed multiple myeloma, as monotherapy or in combination with pegylated liposomal doxorubicin or dexamethasone, for treatment of patients who have received at least one prior therapy and who have undergone or are not candidates for hematopoietic stem cell transplantation (second-line therapy).
Relapsed multiple myeloma, in combination with dexamethasone or dexamethasone and thalidomide, for treatment of previously untreated patients who are eligible for high-dose chemotherapy with hematopoietic stem cell transplantation (induction therapy).
Mantle cell lymphoma, in combination 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 any of the excipients of the medicinal product.
Acute diffuse infiltrative pulmonary and pericardial diseases.
When using BortezoVista in combination with other medicinal products, refer to the instructions for medical use of these products for additional contraindications.
Special precautions.
General warnings. BortezoVista is a cytotoxic medicinal product. Therefore, caution should be exercised during its preparation and administration. It is recommended to use gloves and protective clothing to prevent skin contact. Appropriate aseptic techniques must be strictly followed when handling BortezoVista, as the product does not contain preservatives.
Fatal cases due to accidental intrathecal administration of bortezomib have been reported. BortezoVista must be administered intravenously only.
DO NOT ADMINISTER BORTEZOVISTA INTRATHECALLY.
Instructions for solution preparation. Solution preparation must be performed by qualified medical personnel.
Prior to administration, reconstitute the contents of each vial with 1 mL of 0.9% sodium chloride injection solution. 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. If particles are present or discoloration occurs, do not use the solution.
Disposal of unused or expired medicinal product.
For single use only. Environmental release of the medicinal product should be minimized. The medicinal product must not be disposed of via wastewater or household waste. A so-called "waste collection system" should be used for disposal, if available. Any unused medicinal products or waste 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, altered overall exposure to the drug is not expected in poor metabolizers of this enzyme.
Drug interaction studies and assessment of 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]). Therefore, careful monitoring of patients receiving bortezomib concomitantly with potent CYP3A4 inhibitors (such as ketoconazole, ritonavir) is recommended.
Studies evaluating the effect of omeprazole, a potent CYP2C19 inhibitor, on the pharmacokinetics of bortezomib (after intravenous administration) did not demonstrate a significant effect on bortezomib pharmacokinetics.
Studies assessing the effect of rifampicin, a potent CYP3A4 inducer, revealed an average reduction in bortezomib AUC (after intravenous administration) of 45%. Therefore, concomitant use 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.
Evaluation of the effect of dexamethasone, a weak CYP3A4 inducer, did not show clinically significant changes in bortezomib pharmacokinetics.
Drug interaction studies and assessment of the effects of melphalan and prednisone on the pharmacokinetics of bortezomib (after intravenous administration) demonstrated an average increase in bortezomib AUC of 17%, which is not considered clinically significant.
During clinical trials, cases of hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemic agents. Patients treated with oral antidiabetic medicinal products should monitor their blood glucose levels and adjust antidiabetic drug doses accordingly during treatment with BortezoVista.
Special precautions.
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 occurred due to inadvertent intrathecal administration of bortezomib. BortezoVist should be administered intravenously only. DO NOT ADMINISTER BORTEZOVIST INTRATHECALLY.
Gastrointestinal complications. Treatment with BortezoVist 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 in patients with 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 toxicity reactions was reversible thrombocytopenia. The lowest platelet count was typically observed on day 11 of each bortezomib treatment cycle. Platelet counts 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 studies of bortezomib monotherapy in multiple myeloma patients and 50% in studies of bortezomib in mantle cell lymphoma patients. In patients with progressive myeloma, the severity of thrombocytopenia was related to the pre-treatment platelet count: in patients with a baseline platelet count < 75,000/µL, 90% of 21 patients had platelet counts ≤ 25,000/µL during the study, including 14% with counts < 10,000/µL, whereas in patients with a baseline platelet count > 75,000/µL, only 14% of 309 patients had platelet counts ≤ 25×10⁹/L. In patients with mantle cell lymphoma, a higher incidence of grade ≥3 thrombocytopenia was observed in the group receiving bortezomib (VcR-CAP regimen) compared to those receiving R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). The overall incidence of bleeding events of all grades and 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. Treatment with BortezoVist 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 leukocyte count and platelet count should be frequently performed during BortezoVist therapy. Platelet transfusion should be considered if clinically indicated. In patients with mantle cell lymphoma, reversible neutropenia between treatment cycles has been observed; cumulative neutropenia was not observed. The lowest leukocyte count was typically observed on day 11 of each bortezomib treatment cycle. Leukocyte counts returned to baseline levels before the start of the next cycle. In a study of bortezomib in mantle cell lymphoma patients, 78% of patients in the VcR-CAP group and 61% in the R-CHOP group received granulocyte colony-stimulating factor. Since patients with neutropenia are at increased risk of developing 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 the management of hematological toxicity. If initiation of a new treatment cycle has been delayed several times, prophylactic use of granulocyte colony-stimulating factor should be considered.
Herpes zoster reactivation. Antiviral prophylaxis should be considered for patients treated with BortezoVist. In phase III trials in patients with previously untreated multiple myeloma, the overall incidence of Herpes zoster reactivation (shingles) was higher in the group receiving BortezoVist + melphalan + prednisone (14%) compared to the group receiving melphalan + prednisone (4%).
Among 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. Prior to initiating treatment with rituximab in combination with BortezoVist, 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 BortezoVist. Antiviral prophylaxis should be considered.
Progressive multifocal leukoencephalopathy (PML). Very rare cases of John Cunningham virus infection leading to PML with fatal outcome 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 after initiation of bortezomib therapy. Patients should be regularly monitored for the development of 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 should be taken. If PML is confirmed, BortezoVist treatment should be discontinued.
Peripheral neuropathy. Treatment with bortezomib 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 bortezomib treatment cycle.
Careful monitoring of patients for neuropathic symptoms such as burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain, or weakness is recommended.
If peripheral neuropathy develops or worsens, patients should undergo a neurological examination; dose adjustment or modification of the administration schedule may be necessary. Neuropathy should be managed with supportive measures.
Regular monitoring for treatment-induced neuropathy symptoms and neurological examination are required in patients receiving BortezoVist in combination with medicinal products associated with neuropathy (e.g., 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 any seizure risk factors.
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 therapy. Most patients required treatment for orthostatic hypotension, and a smaller number experienced syncope. Orthostatic/postural hypotension was not clearly linked to bolus infusion of bortezomib; its mechanism 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 medicinal products, and those with dehydration due to diarrhea or vomiting. In case of orthostatic hypotension, hydration, glucocorticoids, and/or sympathomimetics are recommended; antihypertensive medicinal product doses should be reduced if necessary. Patients should be instructed to consult a physician if they experience dizziness, presyncope, or loss of consciousness.
Reversible posterior 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, blindness, other neurological impairments, and visual disturbances. Brain imaging, preferably magnetic resonance imaging (MRI), should be performed to confirm the diagnosis. If PRES occurs, BortezoVist treatment should be discontinued.
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 heart disease should be 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. Radiological examination is recommended before treatment initiation to establish baseline lung status and for comparison in case of potential treatment-induced lung function impairment.
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 BortezoVist use should be carefully considered. In clinical trials, two patients (out of two) receiving high-dose cytarabine (2 g/m²/day) as continuous 24-hour infusion with daunorubicin and bortezomib for relapsed acute myeloid leukemia died from ARDS at the beginning of treatment. Therefore, this specific regimen combining high-dose cytarabine (2 g/m²/day) as continuous 24-hour infusion is not recommended.
Renal function disorders. Renal function impairment is commonly observed in patients with multiple myeloma. Careful 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 concomitantly 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 at highest risk. Careful monitoring of such patients and implementation of necessary measures are recommended.
Precautions 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 prior to bortezomib initiation in case of impairment, and caution should be exercised when administering medicinal products 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 in case of serious reactions.
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 treatment completion.
Pregnancy.
There are no clinical data on the use of bortezomib in pregnant women. The teratogenic properties of bortezomib have not been fully investigated.
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 in cases where the woman's clinical condition requires treatment with BortezoVist. If BortezoVist is used during pregnancy or if pregnancy occurs during treatment with BortezoVist, 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 BortezoVist 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 risk of serious adverse effects in the infant, breastfeeding is not recommended during BortezoVist treatment.
Fertility.
Studies on the effect of bortezomib on fertility have not been conducted.
Ability to affect reaction speed when driving or operating machinery.
BortezoVist has a moderate effect on the ability to drive or operate machinery. The use of BortezoVist 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 only by qualified medical personnel.
Relapsed multiple myeloma (patients who have received at least one prior therapy).
Monotherapy.
The recommended dose of bortezomib for adults is 1.3 mg/m² body surface area administered intravenously twice weekly for 2 weeks (on days 1, 4, 8, and 11), followed by a 10-day treatment break (days 12–21). This 3-week period constitutes one treatment cycle. Upon achieving a complete clinical response, administration of 2 additional treatment cycles is recommended. Patients achieving a partial response but not complete remission should continue therapy with BortezoVista, but for no more than 8 cycles in total. At least 72 hours must elapse between consecutive doses of BortezoVista.
Dose modification and re-initiation recommendations for BortezoVista monotherapy.
In the event of any grade III non-hematologic toxicity or grade IV hematologic toxicity, except for neuropathies, treatment with BortezoVista must be discontinued. After resolution of toxic symptoms, treatment with BortezoVista 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 BortezoVista 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 according to Table 1 in case of development of neuropathic pain and/or peripheral neuropathy. BortezoVista should be administered to patients with a history of severe neuropathy only after careful assessment of the benefit-risk ratio.
Table 1
Recommended* dose adjustment in the event of bortezomib-induced neuropathy.
| Severity of neuropathy |
Dose and administration frequency adjustment |
| Grade I (asymptomatic; loss of deep tendon reflexes or paresthesia) without pain or functional loss |
Dose and administration schedule do not require adjustment |
| Grade I with pain or Grade II (moderate severity symptoms; limitation in instrumental activities of daily living)** |
Reduce dose to 1 mg/m² or change BortezoVist administration schedule to 1.3 mg/m² once weekly |
| Grade II with pain or Grade III (severe symptoms; limitation in self-care activities of daily living)*** |
Withhold BortezoVist until toxic symptoms resolve. Then resume treatment at a reduced dose of 0.7 mg/m² once weekly. |
| Grade IV (life-threatening consequences; requiring urgent intervention) and/or severe autonomic neuropathy |
Discontinue BortezoVist administration |
*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 medication, and not being bedridden.
Combination therapy with pegylated liposomal doxorubicin.
The recommended dose of bortezomib for adults is 1.3 mg/m² body surface area administered intravenously 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. At least 72 hours should elapse between consecutive doses of BortezoVist.
Pegylated liposomal doxorubicin is administered at a dose of 30 mg/m² on Day 4 of the BortezoVist treatment cycle via 1-hour intravenous infusion, after BortezoVist 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 response may continue treatment for at least 2 additional cycles after achieving complete response, even if this requires more than 8 cycles. Patients whose paraprotein levels continue to decline after 8 cycles may also continue treatment as long as treatment is 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 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. At least 72 hours should elapse between consecutive doses of BortezoVist.
Dexamethasone is administered orally at a dose of 20 mg on Days 1, 2, 4, 5, 8, 9, 11, and 12 of the BortezoVist 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 this medicinal product.
Dose modification recommendations for combination therapy in patients with relapsed multiple myeloma.
See dose modification recommendations for BortezoVist monotherapy provided above.
Previously untreated multiple myeloma in patients not eligible for hematopoietic stem cell transplantation.
Combination therapy with melphalan and prednisone.
BortezoVist (bortezomib) must be administered intravenously in combination with oral melphalan and oral prednisone over nine 6-week treatment cycles (Table 2). In Cycles 1–4, BortezoVist is administered twice weekly (on Days 1, 4, 8, 11, 22, 25, 29, and 32). In Cycles 5–9, BortezoVist is administered once weekly (on Days 1, 8, 22, and 29). At least 72 hours should elapse between consecutive doses of BortezoVist.
Melphalan and prednisone are administered orally on Days 1, 2, 3, and 4 of the first week of each cycle.
Table 2
Recommended dosing schedule of BortezoVist in combination with melphalan and prednisone.
| Bortezomib twice weekly (cycles 1–4) |
||||||||||||||||||
| Week |
1 |
2 |
3 |
4 |
5 |
6 |
||||||||||||
| Bortezomib (1.3 mg/m²) |
1 day |
-- |
-- |
4 day |
8th day |
11th day |
Break |
22nd day |
25th day |
29th day |
32nd day |
Break |
||||||
| M (9 mg/m²) P (60 mg/m²) |
1st day |
2nd day |
3rd day |
4th day |
-- |
-- |
Break |
-- |
-- |
-- |
-- |
Break |
||||||
| Bortezomib once weekly (cycles 5–9) |
||||||||||||||||||
| Week |
1 |
2 |
3 |
4 |
5 |
6 |
||||||||||||
| Bortezomib (1.3 mg/m²) |
1 day |
-- |
-- |
-- |
8th day |
Break |
22nd day |
29th day |
Break |
|||||||||
| M (9 mg/m²) P (60 mg/m²) |
1 day |
2 day |
3rd day |
4th day |
-- |
Break |
-- |
-- |
Break |
|||||||||
M = melphalan, P = prednisone.
Dosing adjustment and re-escalation recommendations for 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 resolved to Grade 1 or baseline levels.
Table 3
Dose adjustments during subsequent cycles of therapy with Bortezomib in combination with melphalan and prednisone.
| Toxicity |
Dose modification or treatment discontinuation |
| Hematological toxicity during cycle:
|
Consider reducing melphalan dose by 25% in the next cycle |
≤ 30×109/L or absolute neutrophil count ≤ 0.75×109/L on the day of Velcade administration (except day 1) |
Delay Velcade administration |
|
Velcade 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-hematological toxicities ≥ grade III |
Velcade treatment should be withheld until symptoms improve to baseline or grade I severity. Then, Velcade 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 neuropathic pain or peripheral neuropathy occurring after Velcade administration, hold or modify the Velcade dose as specified in Table 1. |
For additional information on melphalan and prednisone, please refer to the instructions for medical use 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 bortezomib is 1.3 mg/m² body surface area administered intravenously 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. 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 with this combination.
Combination therapy with dexamethasone and thalidomide.
The recommended dose of bortezomib is 1.3 mg/m² body surface area administered intravenously 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 constitutes 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 medicinal product is well tolerated, the dose should be increased to 100 mg daily on days 15–28 of the cycle. 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 in combination with dexamethasone and thalidomide for 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 starting from week 3 of cycle 1 if the 50 mg dose is tolerated, and to 200 mg if the 100 mg dose is tolerated.
b Patients who achieve a partial response after 4 treatment cycles may continue up to a maximum of 6 treatment cycles.
Dosing recommendations for patients eligible for transplantation.
For dose adjustments in case of neuropathy, see Table 1.
When BortezoVist is used in combination with other chemotherapeutic agents, refer to the respective product information for dose adjustment recommendations in the event of toxicity. Untreated mantle cell lymphoma.
Combination therapy with rituximab, cyclophosphamide, doxorubicin, and prednisone (VcR-CAP regimen).
The recommended dose of bortezomib is 1.3 mg/m² body surface area administered intravenously 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. At least 72 hours must elapse between consecutive doses of BortezoVist. Administer 6 treatment cycles. Patients who first demonstrate a 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 at 375 mg/m², cyclophosphamide at 750 mg/m², doxorubicin at 50 mg/m².
Prednisone is administered orally at 100 mg/m² on days 1, 2, 3, 4, and 5 of each BortezoVist treatment cycle.
Dose adjustment recommendations for patients with untreated mantle cell lymphoma.
Prior to initiating a new treatment cycle:
- Platelet count must be ≥ 100,000 cells/µL and absolute neutrophil count (ANC) 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 administration, or hematologic toxicity ≥ grade III. Refer to Table 5 for dose adjustment recommendations.
Granulocyte colony-stimulating factors (G-CSF) 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 as necessary for management of thrombocytopenia.
Table 5
Dose adjustment during therapy in patients with untreated mantle cell lymphoma.
| Toxicity |
Dose modification or treatment interruption |
| Hematologic 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 recovers to ≥ 25,000 cells/µL. If toxicity does not resolve (blood counts do not return to the above-mentioned levels) after this period, BortezoVista should be discontinued. If toxicity resolves (absolute neutrophil count recovers to ≥ 750 cells/µL and platelet count to ≥ 25,000 cells/µL), treatment with BortezoVista may 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 on day 1 of each treatment cycle). |
Delay administration of the BortezoVista dose. |
| Non-hematologic toxicity ≥ grade III related to BortezoVista administration. |
Treatment with BortezoVista should be interrupted until symptoms improve to grade II severity or better. BortezoVista may then be restarted 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). For BortezoVista-induced neuropathic pain and/or peripheral neuropathy, dose withholding and/or modification should be performed as outlined in Table 1. |
If BortezoVista is used in combination with other chemotherapeutic agents, also refer to the package leaflets of these medicinal products for 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 are no studies on the use of bortezomib in elderly patients with untreated multiple myeloma eligible 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 of bortezomib use 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 arms (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 or severe hepatic impairment, treatment with BortezoVista should be initiated at a dose of 0.7 mg/m² during the first treatment cycle, followed by gradual dose escalation to 1.0 mg/m² or dose reduction to 0.5 mg/m², depending on patient tolerability.
Table 6
Recommendations for initial dose adjustments of BortezoVista in patients with hepatic impairment.
| Severity of hepatic impairment* |
Bilirubin level |
AST levels |
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 increases to 1.0 mg/m² or reductions to 0.5 mg/m² should be based on patient tolerability. |
| Severe |
> 3 × ULN |
Any |
AST — aspartate aminotransferase; ULN — upper limit of normal.
* Based on the National Cancer Institute (USA) Organ Dysfunction Working Group classification of severity of liver dysfunction (mild, moderate, and severe).
Patients with renal impairment.
Renal impairment of mild to moderate degree (creatinine clearance > 20 mL/min/1.73 m²) does not affect the pharmacokinetics of bortezomib; therefore, dose adjustment is not required in these patients. 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.
Administration method.
BortezoVist is administered by intravenous injection. Accidental intrathecal administration of the drug has resulted in fatal outcomes. The solution should be administered immediately after preparation 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 should elapse between consecutive doses of BortezoVist.
Children.
The safety and efficacy of bortezomib in children (under 18 years of age) have not been established. Available data are insufficient to provide dosage recommendations for pediatric use.
Overdose.
Symptoms. Doses exceeding the recommended dose by more than two-fold have been associated with acute arterial hypotension and thrombocytopenia resulting in fatal outcomes.
Treatment. There is no specific antidote for bortezomib. In case of overdose, careful monitoring of hemodynamic parameters (infusion therapy, vasopressor and/or inotropic agents) and body temperature is recommended.
Adverse Reactions
Serious adverse reactions rarely 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, asthenia, 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 the use of bortezomib. Data on these adverse reactions were obtained from 5476 patients, of whom 3996 received bortezomib at a dose of 1.3 mg/m². Overall, bortezomib was administered to 3974 patients for the treatment of multiple myeloma. Adverse reactions are categorized by system organ class and frequency of occurrence. Frequencies are defined as: very common (> 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), 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*, herpes 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, postviral fatigue syndrome |
|
| Benign, malignant and unspecified neoplasms (including cysts and polyps) |
Rare |
Malignant neoplasm, plasma cell leukemia, renal cell carcinoma, tumor proliferation, 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, thrombocytopathy, thrombotic microangiopathy (including thrombotic thrombocytopenic purpura), other blood and hematopoietic organ 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*, impaired antidiuretic hormone secretion |
| Rare |
Hypothyroidism |
|
| Metabolism and nutrition disorders |
Very common |
Decreased appetite |
| Common |
Dehydration, hypokalemia*, hyponatremia*, blood glucose disturbances*, hypocalcemia*, enzyme level disturbances* |
|
| Uncommon |
Tumor lysis syndrome, patient condition aggravatedª*, hypomagnesemia*, hypophosphatemia*, hyperkalemia*, hypercalcemia*, hypernatremia*, uric acid level disturbances*, diabetes mellitus*, fluid retention |
|
| Rare |
Hypermagnesemia*, acidosis, electrolyte imbalance*, hypervolemia, hypochloremia*, hypovolemia, hyperchloremia*, hyperphosphatemia*, metabolic disorders, vitamin B complex 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 disturbances*, 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 syndrome, cerebrovascular disorder, nerve root disorders, psychomotor hyperactivity, spinal cord compression, other cognitive disorders, motor dysfunction, other nervous system disorders, radiculitis, hypersalivation, hypotonia, Guillain-Barré syndrome#, demyelinating polyneuropathy# |
|
| Eye disorders |
Common |
Eye edema*, vision disturbances*, conjunctivitis* |
| Uncommon |
Eye hemorrhages*, eyelid infections*, chalazion#, blepharitis#, eye inflammation*, diplopia, dry eyes*, eye irritation*, eye pain, increased lacrimation, eye discharge |
|
| Rare |
Corneal disorders*, exophthalmos, retinitis, scotoma, other eye (and eyelid) disorders, acquired dacryoadenitis, photophobia, photopsia, optic nerve neuropathy#, various degrees of vision deterioration (up to blindness)* |
|
| Ear and labyrinth disorders |
Common |
Vertigo* |
| Uncommon |
Dysacusis (including tinnitus)*, hearing impairment (up to deafness), ear discomfort* |
|
| Rare |
Ear hemorrhage, vestibular neuronitis, other ear disorders |
|
| Cardiac disorders |
Uncommon |
Cardiac tamponade#, cardiopulmonary shock*, atrial 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 perirenal)*, peripheral circulation disorders*, vasculitis, hyperemia (including ocular)* |
|
| Rare |
Peripheral vascular embolism, lymphedema, pallor, erythromelalgia, vasodilation, vascular discoloration, 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*, airway patency deterioration*, hypoxia, pleuritis*, 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, 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*, flatulence |
|
| Uncommon |
Pancreatitis (including chronic)*, vomiting with blood, lip swelling*, gastrointestinal obstruction (including small intestine obstruction, ileus)*, abdominal discomfort, oral ulcers*, enteritis*, gastritis*, gingival bleeding, gastroesophageal reflux disease*, colitis (including Clostridium difficile-induced)*, ischemic colitis#, inflammatory gastrointestinal disorders*, dysphagia, irritable bowel syndrome, other gastrointestinal disorders, coated tongue, gastrointestinal motility disorders*, 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, oral pharyngeal blister formation*, lip pain, periodontitis, anal fissure, altered defecation rhythm, proctalgia, abnormal defecation |
|
| Hepatobiliary disorders |
Common |
Liver enzyme level changes* |
| 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 disturbances*. |
|
| Rare |
Skin reactions, Jessner's lymphocytic infiltration, palmar-plantar 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 inflammations of musculoskeletal 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*, pain related to injection*. |
|
| Rare |
Lethal outcome (including sudden), multiple organ failure, hemorrhages at administration site*, hernia (including hiatal)*, impaired healing*, inflammation, phlebitis at injection site*, pain, ulcer, irritation, non-cardiac substernal pain, catheter insertion site pain, foreign body sensation. |
|
| Investigations |
Common |
Weight loss. |
| Uncommon |
Hyperbilirubinemia*, deviation of protein levels from normal*, weight gain, blood test abnormalities*, 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, elevated troponin I level, viral 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.
ªClinical 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. Clinical deterioration is not a distinct disease or syndrome; rather, it represents nonspecific manifestations of an underlying physical, mental, 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 in 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 as part of combination therapy (VcR-CAP) included hepatitis B virus infection (˂1%) and myocardial ischemia (1.3%). The similar incidence rates in both treatment groups suggest that these adverse reactions are not solely related to bortezomib. Administration of bortezomib to 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 administration in patients with multiple myeloma.
Adverse reactions occurring at a frequency ≥1%, with similar or higher incidence in the VcR-CAP treatment group, which were possibly or probably related to the medicinal products included in the VcR-CAP combination regimen, are listed in Table 8. Also listed are adverse reactions observed in the VcR-CAP treatment group and, according to investigator assessment, possibly or probably related to bortezomib, based on experience from studies in patients with multiple myeloma. Adverse reactions are grouped by system organ class and frequency of occurrence. Frequency was defined as: very common (>1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000), and not known (cannot be estimated from available data). Within each group, 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*, upper/lower respiratory tract infections*, 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 disturbances*, 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 |
Atrial 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 liver disorders). |
| Uncommon |
Liver 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 conditions |
Very common |
Pyrexia*, fatigue, asthenia. |
| Common |
Edema (including peripheral), chills, injection site reactions*, fever*. |
|
| Investigations |
Common |
Hyperbilirubinemia*, abnormal protein levels*, weight loss, weight gain. |
*Grouping of two or more MedDRA terms.
Description of individual adverse reactions.
Reactivation of Herpes zoster virus.
Multiple myeloma. Antiviral prophylaxis was administered in 26% of patients receiving the combination of bortezomib 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 agents. Mantle cell lymphoma. Antiviral prophylaxis was administered in 137 out of 240 patients (57%) treated with 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 agents.
Reactivation and infection with hepatitis B virus (HBV).
Mantle cell lymphoma. Cases of hepatitis B infection with fatal outcome 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 interruption 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 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-emergent 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 also 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, on average, resolved 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 treatment-emergent fatal events 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 severity grades occurring in at least 25% of patients predominantly 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 following marketing authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all 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 may 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 the reach of children.
Incompatibilities.
This medicinal product should not be mixed with other medicinal products except those specified in the section “Administration and dosage.”
Packaging.
1 mg per vial. 1 vial per carton.
Prescription category.
Prescription only.
Manufacturers.
Sintex España, S.L.
Sintex s.r.o.
Manufacturer's location and address of place of business.
C/Castello, no1, Sant Boi de Llobregat, Barcelona, 08830, Spain.
Brnenska 32/sr. 597, Blansko, 67801, Czech Republic.