Brecer
UkraineTable of Contents
INSTRUCTIONS for medical use of the medicinal product BRECER (BRECER)
Composition:
Active substance: bortezomib;
1 vial contains bortezomib 3.5 mg;
Excipients: mannite (E 421).
Pharmaceutical form. Lyophilisate for solution for injection.
Main physicochemical properties: white to almost white mass or powder.
Pharmacotherapeutic group. Antineoplastic and immunomodulating agents. Antineoplastic agents. Other antineoplastic agents. Proteasome inhibitors. Bortezomib. ATC code L01XG01.
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 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 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 the numerous 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 calculated in vitro; dissociation of bortezomib from the proteasome was observed with a t½ of 20 minutes, indicating reversibility of proteasome inhibition by bortezomib.
By inhibiting the proteasome, bortezomib affects cancer cells through multiple mechanisms, including but not limited to, altering regulatory proteins controlling cell cycle progression and activation of the nuclear 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.
Experiments have demonstrated that bortezomib has cytotoxic activity against many types of cancer cells and that cancer cells are more susceptible to bortezomib-induced apoptosis than normal cells. In vivo, bortezomib causes inhibition of growth in 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 at doses of 1.0 mg/m² and 1.3 mg/m² to patients with multiple myeloma and creatinine clearance values exceeding 50 ml/min, the mean peak plasma concentration of the first dose of bortezomib was 57 and 112 ng/ml, respectively. With subsequent doses, mean peak plasma concentrations 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 at a dose 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 concentration 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. This indicates extensive distribution of bortezomib into peripheral tissues. At bortezomib concentrations of 0.01–1.0 µg/ml, plasma protein binding of the drug is 83%. The fraction of bortezomib bound to plasma proteins was independent of concentration.
Metabolism. In vitro studies using human liver microsomes and human cDNA-encoded cytochrome P450 isoenzymes showed that oxidative metabolism of bortezomib is primarily mediated by cytochrome P450 enzymes, specifically 3A4, 2C19, and 1A2. The main metabolic pathway involves deboronation to two metabolites, which are subsequently hydroxylated to form additional metabolites. Bortezomib-deboronated metabolites are inactive as inhibitors of the 26S proteasome.
Elimination. The mean elimination half-life (t1/2) of bortezomib after multiple dosing ranges from 40 to 193 hours. Bortezomib is eliminated 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 from 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 patients primarily with solid tumors and various degrees of hepatic dysfunction who received bortezomib at doses ranging from 0.5 to 1.3 mg/m².
Compared to patients with normal liver function, mild hepatic impairment did not alter the dose-normalized AUC of bortezomib. However, mean values of the dose-normalized AUC of bortezomib increased by approximately 60% in patients with moderate or severe hepatic impairment. Dose adjustment and careful monitoring during treatment are recommended for patients with moderate or severe hepatic impairment (see Table 6).
Renal impairment. Pharmacokinetic studies were conducted in patients with varying degrees of renal impairment, classified by creatinine clearance (CrCL) into the following groups: 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 undergoing dialysis who received the dose after dialysis were also included in the study (n=8). Bortezomib was administered intravenously at doses of 0.7–1.3 mg/m² twice weekly. Bortezomib exposure (dose-normalized AUC and Cmax values) was comparable across all groups.
Age. Pharmacokinetic parameters of bortezomib were evaluated after administration of bortezomib twice weekly via intravenous bolus injection at a dose of 1.3 mg/m² to 104 pediatric patients (ages 2–16 years) with acute lymphoblastic leukemia or acute myeloid leukemia. According to population pharmacokinetic analysis data, 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 gender 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.
Treatment of multiple myeloma in combination with melphalan and prednisone in previously untreated patients who are not eligible for high-dose chemotherapy with hematopoietic stem cell transplantation (first-line therapy).
Treatment of progressive multiple myeloma as monotherapy or in combination with pegylated liposomal doxorubicin or dexamethasone in patients who have received at least one prior therapy and either hematopoietic stem cell transplantation or who are not candidates for transplantation (second-line therapy).
Treatment of multiple myeloma in combination with dexamethasone or dexamethasone and thalidomide in previously untreated patients who are candidates for high-dose chemotherapy with hematopoietic stem cell transplantation (induction therapy).
Treatment of mantle cell lymphoma in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone in 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 Brecere in combination with other medicinal products, refer to the instructions for medical use of these medicinal products for additional contraindications.
Special precautions.
General warnings. Brecere is a cytotoxic medicinal product. Therefore, caution should be exercised during its reconstitution and administration. It is recommended to use gloves and protective clothing to prevent skin contact.
Appropriate aseptic techniques must be strictly observed when handling Brecere, as the product does not contain preservatives.
Fatal cases due to accidental intrathecal administration of the medicinal product have been reported. Bortezomib must be administered only intravenously or subcutaneously.
DO NOT ADMINISTER BORTEZOMIB INTRATHECALLY
Instructions for preparation of solution for intravenous administration
Preparation of the solution must be performed by qualified healthcare personnel.
Appropriate aseptic technique should be used.
For intravenous administration, the contents of the vial should be reconstituted carefully 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. If particles are present or discoloration occurs, the solution must not be used.
For subcutaneous administration, the contents of each vial should be reconstituted carefully 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. Dissolution 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. If particles are present or discoloration occurs, the solution must not be used.
Stability. Unopened vials of bortezomib for injection are stable until the expiry date stated on the packaging, provided they are stored in the original packaging in a place protected from light.
Bortezomib for injection does not contain antimicrobial preservatives. The reconstituted solution of bortezomib for injection should be administered within 8 hours after preparation. If reconstituted according to instructions, bortezomib for injection may be stored at 20–25 °C. The reconstituted solution may be stored in the original vial and/or syringe prior to administration. The solution may be stored in a syringe for up to 8 hours; however, the total storage time of the reconstituted solution must not exceed 8 hours under normal indoor lighting conditions.
Proper disposal procedure. For single use only. Unused medicinal product or waste material must be disposed of in accordance with local requirements.
Interaction with other medicinal products and other types of interactions.
In vitro studies have demonstrated that bortezomib is a weak inhibitor of cytochrome P450 (CYP) isoenzymes 1A2, 2C9, 2C19, 2D6, and 3A4. Given the minor role of CYP2D6 in bortezomib metabolism (7%), changes in the low-activity CYP2D6 phenotype are not expected to affect the overall disposition of the drug.
Drug interaction studies evaluating the effect of ketoconazole, a potent CYP3A4 inhibitor, on the pharmacokinetics of bortezomib (after intravenous administration) demonstrated an average increase in bortezomib AUC by 35% (90% CI [1.032 to 1.772]). Therefore, careful monitoring of patients is recommended when treating with bortezomib in combination with potent CYP3A4 inhibitors (e.g., ketoconazole, ritonavir).
A study 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.
Limited data are available on the effect of rifampicin, a potent inducer of CYP3A4, on the pharmacokinetics of bortezomib: a mean reduction in bortezomib AUC (after intravenous administration) by 45% was observed. Therefore, concomitant use of bortezomib with potent CYP3A4 inducers (e.g., rifampicin, carbamazepine, phenytoin, phenobarbital, and St. John’s wort preparations) is not recommended, as the efficacy of bortezomib may be reduced.
A drug interaction study evaluating the effect of dexamethasone, a weaker inducer of CYP3A4, did not show a clinically significant effect on bortezomib pharmacokinetics.
Drug interaction studies evaluating the effects of melphalan and prednisone on the pharmacokinetics of bortezomib (after intravenous administration) demonstrated an average increase in bortezomib AUC by 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 taking oral antidiabetic medications should have their blood glucose levels monitored and antidiabetic drug doses adjusted during bortezomib treatment.
Special precautions for use.
If Brecer is used in combination with other medicinal products, the instructions for medical use of these medicinal products should be consulted prior to initiating treatment. When thalidomide is used, special attention must be paid to pregnancy diagnosis and contraceptive measures.
Intrathecal administration. Fatal cases have been reported due to accidental intrathecal administration of bortezomib. Bortezomib must be administered only intravenously or subcutaneously.
DO NOT ADMINISTER BORTEZOMIB INTRATHECALLY
Gastrointestinal toxicity. Treatment with bortezomib is very commonly associated with gastrointestinal toxicity, including nausea, diarrhea, vomiting, and constipation. Rare cases of intestinal obstruction (reported as uncommon) have been observed. Therefore, patients with constipation should be under medical supervision.
Hematological toxicity. Treatment with bortezomib is very frequently associated with hematological toxicity (thrombocytopenia, neutropenia, and anemia). 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 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. The nadir mean platelet count was approximately 40% of the baseline level.
On average, the lowest measured platelet count was about 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 the pre-treatment platelet count: when baseline platelet count was <75,000/µL, 90% of patients had platelet counts ≤25,000/µL during the trials, including 14% with platelet counts <10,000/µL; in contrast, when baseline platelet count was >75,000/µL, only 14% of patients had platelet counts ≤25,000/µL during the trials.
In patients with mantle cell lymphoma, grade ≥3 thrombocytopenia occurred more frequently in the group receiving bortezomib (VcR-CAP regimen) 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 III, was similar in both groups. In the VcR-CAP treatment group, 22.5% of patients required platelet transfusions compared to 2.9% in the R-CHOP group.
Cases of gastrointestinal and intracranial hemorrhages associated with bortezomib use have been reported.
Platelet counts should be monitored before each dose of bortezomib. Treatment with bortezomib should be withheld if platelet counts fall below 25,000/µL, and if used in combination with melphalan and prednisone, treatment should be withheld if platelet counts are ≤30,000/µL; after recovery, treatment should be resumed at reduced doses. The potential benefit of treatment should be carefully weighed against the risks, especially in cases of moderate or severe thrombocytopenia and risk factors for bleeding.
Therefore, complete blood counts with differential and platelet counts should be frequently monitored during bortezomib therapy. Platelet transfusion should be considered if clinically indicated.
In patients with mantle cell lymphoma, cases of reversible neutropenia between treatment cycles have been observed; cumulative neutropenia was not observed. White blood cell counts were typically lowest on day 11 of each bortezomib treatment cycle and returned to baseline before the start of the next cycle. In a trial 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 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.
Reactivation of Herpes zoster virus. Antiviral prophylaxis should be considered in patients receiving bortezomib treatment. In phase III trials in patients with previously untreated multiple myeloma, the overall incidence of Herpes zoster reactivation was higher in patients receiving bortezomib plus melphalan plus prednisone compared to melphalan plus prednisone (14% vs. 4%, respectively).
Among patients with mantle cell lymphoma, the incidence of herpes zoster was 6.7% in the VcR-CAP group and 1.2% in the R-CHOP group.
Reactivation and infection with hepatitis B virus (HBV). Prior to initiating treatment with rituximab in combination with Brecer, 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 Brecer. Antiviral prophylaxis should be considered.
Progressive multifocal leukoencephalopathy (PML). Very rare cases of infection with JC virus (John Cunningham virus) of unknown etiology, leading to PML and fatal outcomes, have been reported in patients receiving bortezomib treatment. Patients diagnosed with PML were concurrently or previously receiving immunosuppressive therapy. In most cases, PML was diagnosed within 12 months of the first bortezomib dose. 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 PML specialist and appropriate diagnostic procedures for PML should be performed. Bortezomib should be discontinued if PML is confirmed.
Peripheral neuropathy. Treatment with bortezomib is very commonly associated with peripheral neuropathy, predominantly sensory. However, cases of acute motor neuropathy with or without sensory peripheral neuropathy have been reported. The incidence of peripheral neuropathy increases early in treatment and peaks at cycle 5.
Close 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 II peripheral neuropathy was 24% in the subcutaneous group and 41% in the intravenous group. Grade III peripheral neuropathy occurred in 6% of patients in the subcutaneous group and 16% in the intravenous group.
Patients developing or experiencing worsening of existing peripheral neuropathy should undergo neurological evaluation and may require dose and schedule adjustments of bortezomib or a change in route of administration to subcutaneous. Neuropathy should be managed with supportive measures.
Regular monitoring for treatment-induced neuropathy symptoms and neurological examination are required in patients receiving bortezomib 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 effects is limited.
Seizures. Uncommon cases of seizure development 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 orthostatic/postural hypotension. In most cases, it is mild to 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. A smaller number of patients with orthostatic hypotension experienced episodes of syncope. Orthostatic/postural hypotension was not clearly linked to bolus infusion of bortezomib. The mechanism of this phenomenon is unknown, although a possible association with autonomic neuropathy exists. Autonomic neuropathy may be related to bortezomib use or bortezomib may exacerbate underlying conditions, including diabetic or amyloid neuropathy. Patients with a history of syncope during treatment with hypotensive agents, as well as patients with dehydration due to recurrent diarrhea or vomiting, should be treated with caution. Management of orthostatic/postural hypotension may include dose adjustment of antihypertensive medications, rehydration, or administration of glucocorticoids and/or sympathomimetics; antihypertensive medications may need to be reduced if necessary. Patients should be instructed to consult a physician if they experience dizziness, pre-syncope, or episodes of syncope.
Reversible posterior leukoencephalopathy syndrome (RPLS). Cases of RPLS have been reported in patients receiving bortezomib. RPLS is a rare, reversible, rapidly progressive neurological disorder characterized by seizures, arterial hypertension, headache, lethargy, confusion, visual disturbances including blindness, and other neurological impairments. Diagnosis is confirmed by brain imaging techniques, primarily MRI (magnetic resonance imaging). Bortezomib treatment must be discontinued if RPLS occurs. The safety of re-administering bortezomib in patients with a history of RPLS is unknown.
Heart failure. Cases of acute onset or worsening of pre-existing congestive heart failure and/or reduced left ventricular ejection fraction have been reported during bortezomib treatment. Fluid retention may contribute to the development of signs and symptoms of heart failure. Patients with cardiac disease or risk factors for such conditions require careful monitoring.
ECG monitoring. Isolated cases of QT interval prolongation have been observed in clinical trials; causality has not been established.
Lung 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 reported in patients receiving bortezomib. Some of these cases were fatal. Radiological examination is recommended before treatment initiation to establish baseline lung status for comparison in case of potential treatment-related lung function impairment.
In case of new or worsening pulmonary symptoms (e.g., cough, dyspnea), rapid diagnostic evaluation should be performed and appropriate treatment initiated. The benefit-risk ratio should be considered before continuing bortezomib treatment.
In a clinical trial, two out of two patients receiving high-dose cytarabine (2 g/m²/day) by continuous infusion over 24 hours in combination with daunorubicin and bortezomib for relapsed acute myeloid leukemia died from ARDS at the beginning of treatment, leading to trial termination. Therefore, this specific regimen of concomitant administration with high-dose cytarabine (2 g/m²/day) by continuous infusion over 24 hours is not recommended.
Renal function impairment. Renal complications are commonly observed in patients with multiple myeloma. Patients with impaired renal function require careful monitoring.
Hepatic function impairment. Bortezomib is metabolized by hepatic enzymes. Exposure to bortezomib is increased in patients with moderate or severe hepatic impairment; therefore, bortezomib doses should be reduced and careful monitoring for signs of toxicity is required in such patients.
Hepatic reactions. Rare cases of acute liver failure have been reported in patients treated with bortezomib in combination with other agents and in patients with serious concomitant medical conditions. Other hepatic reactions have also been reported, including elevated liver enzymes, hyperbilirubinemia, and hepatitis. These changes were reversible upon discontinuation of bortezomib.
Tumor lysis syndrome. Since bortezomib is a cytotoxic agent capable of rapidly killing tumor plasma cells, complications associated with tumor lysis syndrome may occur. Patients with high tumor burden prior to treatment initiation are primarily at risk. Such patients require careful monitoring and appropriate preventive measures.
Concomitant use of medicinal products. Patients require careful monitoring when bortezomib is used in combination with strong CYP3A4 inhibitors. Caution should be exercised when combining bortezomib with CYP3A4 or CYP2C9 substrates.
Liver function should be corrected prior to initiating treatment if impaired, and caution should be exercised when administering the drug to patients taking oral hypoglycemic agents.
Immune complex-mediated reactions. Immune complex-mediated reactions, such as serum sickness-like reactions, 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
Due to the genotoxic potential of bortezomib, women of reproductive potential must use effective contraception and avoid pregnancy during treatment and for 8 months after completion of treatment.
Men must use effective contraception during treatment with bortezomib and for 5 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. Bortezomib is not recommended during pregnancy except in cases where the woman's clinical condition necessitates bortezomib treatment. If bortezomib is used during pregnancy or if pregnancy occurs during treatment, the patient should be informed of the potential harm to 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 Brecer 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 occurrence of severe adverse effects in the infant, breastfeeding is not recommended during treatment with bortezomib.
Fertility
Studies on the effect of bortezomib on fertility have not been conducted. Due to the genotoxic potential of bortezomib, male patients should be advised to seek counseling on sperm preservation prior to treatment initiation, and women of reproductive age should consult regarding oocyte cryopreservation.
Ability to drive and use machines.
Bortezomib has a moderate effect on the ability to drive and use machines. Bortezomib treatment may be associated with fatigue, dizziness, syncope, orthostatic/postural hypotension, and visual disturbances. 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 antineoplastic 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 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 three-week period constitutes one treatment cycle. After achieving a complete clinical response, two additional cycles of treatment are recommended. Patients achieving a partial response but not complete remission should continue bortezomib therapy for up to 8 cycles. At least 72 hours must elapse between consecutive bortezomib doses.
Dosage Adjustment and Reinitiation Recommendations for Bortezomib Monotherapy
If any non-hematologic toxicity of grade III or hematologic toxicity of grade IV (excluding neuropathies) occurs, bortezomib treatment must be discontinued. After resolution of toxic symptoms, treatment may be reinitiated 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 should be adjusted according to Table 1 in the event of neuropathic pain and/or peripheral neuropathy. Bortezomib should be used with caution in patients with a history of severe neuropathy only after careful assessment of benefit-risk ratio.
Recommended* dose modification for bortezomib-induced neuropathy
Table 1
| Severity of neuropathy |
Change in dose and frequency of administration |
| Grade I (asymptomatic; loss of deep tendon reflexes or paresthesia) without pain or functional impairment |
Dose and schedule do not require modification |
| Grade I with pain or Grade II (moderate symptoms; limitation of instrumental activities of daily living)** |
Reduce dose to 1 mg/m² |
| Grade II with pain or Grade III (severe symptoms; limitation of self-care activities)*** |
Withhold bortezomib until toxicity 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 bortezomib |
*Based on dose modifications 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.
*** Basic activities of daily living 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 three-week period is considered 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 via a one-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 response may continue treatment for at least 2 additional cycles after achieving complete response, even if this requires treatment beyond 8 cycles. Patients whose paraprotein levels continue to decline after 8 cycles may also continue treatment as long as treatment remains tolerable 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 three-week period is considered 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 treatment with 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 when used as monotherapy, described above.
Previously untreated multiple myeloma in patients not eligible for hematopoietic stem cell transplantation
Combination therapy with melphalan and prednisone
Bortezomib should be administered intravenously or subcutaneously in combination with oral melphalan and oral prednisone over nine 6-week treatment cycles (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.
Recommended dosing regimen of bortezomib in combination with melphalan and prednisone
Table 2
| Bortezomib 2 times per week (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 1 time per week (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 resolved to Grade 1 or baseline level.
Dose adjustment during subsequent cycles of bortezomib combination therapy
with melphalan and prednisone
Table 3
| Toxicity |
Dose modification or discontinuation of treatment |
| Hematologic toxicity during cycle:
|
Consider reducing melphalan dose by 25% in the next cycle |
|
Bortezomib dose should be omitted |
|
Bortezomib dose should be reduced by 1 level (from 1.3 mg/m2 to 1 mg/m2 or from 1 mg/m2 to 0.7 mg/m2) |
| Non-hematologic toxicities ≥ Grade III |
Bortezomib treatment should be discontinued until symptoms improve to baseline level or Grade I severity. Bortezomib may then be restarted at a reduced dose by 1 level (from 1.3 mg/m2 to 1 mg/m2 or from 1 mg/m2 to 0.7 mg/m2). For bortezomib-induced neuropathic pain and/or peripheral neuropathy, withhold and/or modify bortezomib dose as specified in Table 1. |
For additional information regarding melphalan and prednisone, see 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 or subcutaneously twice weekly for 2 weeks (days 1, 4, 8, and 11), followed by a 10-day treatment break (days 12–21). This three-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 40 mg on days 1, 2, 3, 4, 8, 9, 10, and 11 of the bortezomib treatment cycle.
Administer 4 treatment cycles of this combination.
Combination therapy with dexamethasone and thalidomide
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 17-day treatment break (days 12–28). This four-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 40 mg on days 1, 2, 3, 4, 8, 9, 10, and 11 of the bortezomib treatment cycle.
Thalidomide should be administered orally at a dose of 50 mg daily on days 1–14 of the cycle; if tolerated, the dose should be increased to 100 mg daily on days 15–28 of the cycle. The dose may be further increased to 200 mg daily starting from the second cycle (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.
Recommended dosing regimen of bortezomib in combination with dexamethasone and thalidomide in untreated multiple myeloma patients eligible for hematopoietic stem cell transplantation
Table 4
| 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; Thal = thalidomide
a Increase the dose of thalidomide to 100 mg starting from the 3rd week of the first cycle 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 cycles of treatment may receive up to 6 cycles of therapy.
Dosing recommendations for patients undergoing transplantation
For dose adjustments in case of neuropathy, see Table 1.
When bortezomib 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 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 three-week period constitutes one treatment cycle. At least 72 hours should elapse between consecutive doses of Brecere. Administer 6 treatment cycles. Patients who first demonstrate response during the sixth treatment cycle are recommended to receive two additional cycles of therapy.
Medications administered by intravenous infusion on day 1 of each three-week Brecere treatment cycle: rituximab 375 mg/m², cyclophosphamide 750 mg/m², doxorubicin 50 mg/m².
Prednisone should be administered orally at a dose of 100 mg/m² on days 1, 2, 3, 4, and 5 of each Brecere treatment cycle.
Dose adjustment 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 ≥ 8 g/dL;
- Non-hematologic toxicity must have resolved to grade 1 or baseline levels.
Treatment with Brecere should be withheld in the event of any non-hematologic toxicity ≥ grade III (except neuropathy) related to Brecere administration, or hematologic toxicity ≥ grade III. Refer to Table 5 for dose adjustment 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 as necessary for management of thrombocytopenia.
Dose adjustments during therapy for patients with untreated mantle cell lymphoma
Table 5
| Toxicity |
Dose modification or treatment interruption |
| Hematological toxicity |
|
|
Treatment with Brecere should be withheld for up to 2 weeks until the absolute neutrophil count recovers to ≥ 750 cells/μL and platelet count to ≥ 25,000 cells/μL.
≥ 25,000 cells/μL), Brecere treatment may be resumed with a dose reduction by one level (from 1.3 mg/m² to 1 mg/m² or from 1 mg/m² to 0.7 mg/m²). |
|
Delay administration of the Brecere dose. |
| Non-hematological toxicity ≥ Grade III related to Brecere administration. |
Brecere treatment should be withheld until symptoms improve to Grade II severity or better. Brecere may then be restarted with a dose reduction by one level (from 1.3 mg/m² to 1 mg/m² or from 1 mg/m² to 0.7 mg/m²). For Brecere-related neuropathic pain and/or peripheral neuropathy, withholding and/or dose modification of Brecere should be performed as specified in Table 1. |
If Brecer is used in combination with other chemotherapeutic agents, refer to the instructions for use of these medicinal products for information on dose adjustments of these agents 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.
Studies on the use of bortezomib in elderly patients with previously untreated multiple myeloma eligible for high-dose chemotherapy with hematopoietic stem cell transplantation have not been conducted. 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 ≥75 years. Patients aged 75 years and older tolerated treatment less well in both treatment arms (BzR-CAP and R-CHOP regimens).
Patients with hepatic impairment
Dose adjustment is not required for patients with mild hepatic impairment. For patients with moderate to severe hepatic impairment, treatment with bortezomib 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.
Recommendations for modification of initial bortezomib doses in patients with hepatic impairment
Table 6
| 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 bortezomib dose to 0.7 mg/m² in the first treatment cycle. Subsequent dose escalation to 1.0 mg/m² or reduction to 0.5 mg/m² depending on patient tolerability. |
| Severe |
> 3× ULN |
Any |
Abbreviations: AST – aspartate aminotransferase; ULN – upper limit of normal.
* Based on the classification of organ dysfunction by the National Cancer Institute Working Group for severity of liver function impairment (mild, moderate, and severe).
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 dialysis.
Method of administration
Brecer must be administered by intravenous or subcutaneous injection. Accidental intrathecal administration of the drug has resulted in fatal outcomes.
Intravenous injection
The reconstituted solution should be administered immediately after preparation as a 3–5 second intravenous bolus injection through a peripheral or central venous catheter, which should be flushed after injection with 0.9% (9 mg/mL) sodium chloride injection solution. At least 72 hours should elapse between consecutive doses of Brecer.
Subcutaneous injection
The reconstituted solution should be administered immediately after preparation subcutaneously into the thigh (left or right) or abdomen (left or right quadrant). The solution should be injected subcutaneously at an angle of 45–90°. Injection sites should be rotated with subsequent injections.
In case of local reactions at the site of subcutaneous bortezomib injection, it is recommended to administer a less concentrated bortezomib solution subcutaneously (1 mg/mL instead of 2.5 mg/mL) or switch to intravenous injections.
Children
The safety and efficacy of bortezomib in children (under 18 years of age) have not been established. Current available data are insufficient to establish dosing recommendations for children.
Overdose
In patients, overdose exceeding the recommended dose by more than two-fold has been associated with acute development of symptomatic arterial hypotension and thrombocytopenia resulting in death.
There is no specific antidote for bortezomib overdose. In case of overdose, close monitoring of vital signs is recommended, along with appropriate symptomatic measures to support blood pressure (such as infusion therapy to maintain fluid balance, vasopressor and/or inotropic agents) and body temperature.
Adverse Reactions
Summary of safety profile
Among the serious adverse reactions during bortezomib treatment, cardiac arrest, tumor lysis syndrome, pulmonary hypertension, reversible posterior leukoencephalopathy syndrome (PRES), acute diffuse infiltrative pulmonary disorders have been reported infrequently, and autonomic neuropathy has been reported rarely. The most commonly observed adverse reactions during bortezomib therapy include nausea, diarrhea, constipation, vomiting, asthenia, pyrexia, thrombocytopenia, anemia, neutropenia, peripheral neuropathy (including sensory neuropathy), headache, paraesthesia, decreased appetite, dyspnea, rash, herpes zoster, and myalgia.
Summary table of adverse reactions
Multiple Myeloma
The adverse reactions listed in Table 7 are considered possibly related to bortezomib administration. These adverse reactions are based on pooled data from 5476 patients, of whom 3996 received bortezomib at a dose of 1.3 mg/m². Overall, the medicinal product was used for the treatment of multiple myeloma in 3974 patients.
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 (≥1/10000 to <1/1000), very rare (<1/10000), and not known (cannot be estimated from the 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
Adverse reactions in patients with multiple myeloma treated with bortezomib during clinical trials and post-marketing adverse reactions regardless of indication
| Organ systems |
Frequency of occurrence |
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, phlegmon; 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 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, platelet disorder, 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 |
|
| Metabolic and nutritional disorders |
Very common |
Decreased appetite |
| Common |
Dehydration, hypokalemia*, hyponatremia*, blood glucose disturbances*, hypocalcemia*, enzyme level disturbances* |
|
| Uncommon |
Tumor lysis syndrome, patient's condition worseningª*, 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 group deficiency, vitamin B12 deficiency, gout, increased appetite, alcohol intolerance |
|
| Psychiatric disorders |
Common |
Mood 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)*, cerebral edema, transient ischemic attack, coma, autonomic nervous system disorders, autonomic neuropathy, cranial nerve paralysis*, paralysis*, paresis*, presyncope, brainstem lesion syndrome, cerebrovascular disorder, nerve root disorders, psychomotor hyperactivity, spinal cord compression, other cognitive disorders, motor dysfunctions, other nervous system disorders, radiculitis, salivation, hypotonia, Guillain-Barré syndrome#, demyelinating polyneuropathy# |
|
| Eye disorders |
Common |
Eye swelling*, visual 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) disorders, acquired dacryoadenitis, photophobia, photopsia, optic nerve neuropathy#, visual impairment of varying degree (up to blindness)* |
|
| Ear and labyrinth disorders |
Common |
Vertigo* |
| Uncommon |
Dysacusis (including tinnitus)*, hearing deterioration (up to deafness), ear discomfort* |
|
| Rare |
Ear bleeding, 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), polymorphic ventricular tachycardia (torsade de pointes), unstable angina, heart valve disorders*, coronary artery insufficiency, sinus node arrest |
|
| Vascular disorders |
Common |
Arterial hypotension*, orthostatic arterial hypotension, arterial hypertension* |
| Uncommon |
Cerebral circulation disorders#, deep vein thrombosis*, hemorrhage*, thrombophlebitis (including superficial veins), 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, venous pigmentation, venous insufficiency |
|
| Respiratory, thoracic and mediastinal disorders |
Common |
Dyspnea*, epistaxis, upper/lower 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, pleuritis*, hiccups, rhinorrhea, dysphonia, wheezing |
|
| Rare |
Respiratory failure, acute respiratory distress syndrome, apnea, pneumothorax, atelectasis, pulmonary hypertension, hemoptysis, pulmonary hyperventilation, orthopnea, pneumonitis, respiratory alkalosis, tachypnea, pulmonary fibrosis, bronchial disorders*, hypocapnia*, interstitial lung disease, lung infiltration, throat tightness, throat dryness, 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 blood, lip swelling*, gastrointestinal obstruction (including small bowel obstruction, ileus)*, abdominal discomfort, oral ulcers*, enteritis*, gastritis*, gum bleeding, gastroesophageal reflux disease*, colitis (including Clostridium difficile-induced)*, ischemic colitis#, inflammatory gastrointestinal disorders*, dysphagia, irritable bowel syndrome, gastrointestinal disorder NOS, gastrointestinal motility disorders*, salivary gland disorders* |
|
| Rare |
Acute pancreatitis, peritonitis*, tongue swelling*, ascites, esophagitis, cheilitis, fecal incontinence, anal sphincter atony, fecaloma*, gastrointestinal ulcers and perforations*, gingival hyperplasia, megacolon, rectal discharge, oral pharyngeal blistering*, lip pain, periodontitis, anal fissure, altered defecation rhythm, proctalgia, abnormal defecation |
|
| Hepatobiliary disorders |
Common |
Liver enzyme level disturbances* |
| 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 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 developmental defects, ichthyosis |
| General disorders and administration site reactions |
Very common |
Pyrexia*, fatigue, asthenia |
| Common |
Edema (including peripheral), chills, pain*, fever* |
|
| Uncommon |
General physical health deterioration*, facial swelling*, injection site reactions*, mucosal disorders*, chest pain, gait disturbance, feeling cold, extravasation*; complications related to catheter placement*; thirst sensation*, chest discomfort, sensation of body temperature change*, injection site pain* |
|
| Rare |
Lethal outcome (including sudden), multiorgan failure, injection site hemorrhages*, hernia (including hiatal)*, impaired healing*, inflammation, phlebitis at injection site*, tenderness on palpation, ulcer, irritation, non-cardiac retrosternal pain, catheter insertion site pain, foreign body sensation |
|
| Investigations |
Common |
Weight loss |
| Uncommon |
Hyperbilirubinemia*, protein level deviations from normal*, weight gain, blood test result deviations from normal*, increased C-reactive protein level |
|
| Rare |
Blood gas parameter deviations from normal*, ECG abnormalities (including QT interval prolongation)*, international normalized ratio deviations from normal*, decreased gastric pH, increased platelet aggregation, increased troponin I level, virus identification in serological tests*, urine test deviations from normal* |
|
| Injury, poisoning and procedural complications |
Uncommon |
Falls, confusion |
| Rare |
Transfusion reactions, fractures*, tremor*, facial injuries, joint injuries*, burns, cuts, procedural pain, radiation injuries* |
|
| Surgical and medical procedures |
Rare |
Macrophage activation |
* – Several MedDRA terms (Medical Dictionary for Regulatory Activities) have been grouped together.
– Adverse reactions reported during the post-marketing period.
ª Deterioration in patient's condition – a general term defined as weight loss of more than 5%, reduced appetite, poor nutrition, and lack of physical activity, often associated with dehydration, depression, immune dysfunction, and low cholesterol levels. Deterioration in patient's condition is not a distinct disease or syndrome; rather, it represents nonspecific manifestations of an underlying physical, mental, or psychosocial state.
Mantle Cell Lymphoma (MCL)
The safety profile of bortezomib in 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), compared to patients who received rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHOP), was generally similar to the safety profile observed in patients with multiple myeloma; however, key differences are outlined below. Additional adverse reactions observed with bortezomib in combination therapy (VcR-CAP) included 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 attributed to bortezomib. Treatment with bortezomib in patients with mantle cell lymphoma was associated with higher frequencies of hematologic adverse reactions (neutropenia, thrombocytopenia, leukopenia, anemia, lymphopenia), peripheral sensory neuropathy, arterial hypertension, pyrexia, pneumonia, stomatitis, and hair disorders compared to treatment 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 that, in the opinion of investigators, were possibly or probably related to bortezomib, based on 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), and not known (cannot be estimated from available data). Within each group, adverse reactions are listed in decreasing order of severity.
Table 8
| System Organ Classes |
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, infection*, 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 abnormalities*, hyponatremia*, diabetes*, 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 sensation of noise/ringing in ears)* |
| 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 |
Arterial hypertension*, arterial hypotension*, orthostatic arterial hypotension |
| Respiratory, thoracic and mediastinal disorders |
Common |
Dyspnea*, cough*, hiccups |
| Uncommon |
Acute respiratory distress syndrome, pulmonary artery thromboembolism, 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 |
Myalgia*, musculoskeletal pain*, limb pain |
| Renal and urinary disorders |
Common |
Urinary tract infection* |
| General disorders and administration site conditions |
Very common |
Pyrexia*, fatigue, asthenia |
| Common |
Edema (including peripheral), chills, injection site reaction*, fever* |
|
| Investigations |
Common |
Hyperbilirubinemia*, protein abnormalities*, weight decreased, weight increased |
* – Several MedDRA terms have been grouped together.
Description of selected adverse reactions
Herpes zoster virus reactivation
Multiple myeloma
Antiviral prophylaxis was administered in 26% of patients receiving the combination of bortezomib with melphalan and prednisone. Herpes zoster was observed in 17% of patients who did not receive antiviral agents, compared to 3% of patients who received antiviral agents.
Mantle cell lymphoma
Antiviral prophylaxis was administered in 137 out of 240 (57%) patients receiving bortezomib as part of combination therapy with the VcR-CAP regimen. Herpes zoster was observed in 10.7% of patients who did not receive antiviral agents, compared to 3.6% of patients who received antiviral agents.
Hepatitis B virus (HBV) reactivation and infection
Mantle cell lymphoma
Cases of hepatitis B infection resulting in death 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 cases 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
Table 9 presents the incidence of peripheral neuropathy (PN) during studies in which bortezomib was used as induction therapy in combination with dexamethasone (study IFM-2005-01) and with dexamethasone-thalidomide (study MMY-3010).
Incidence of peripheral neuropathy (PN) during induction therapy
by severity of toxicity and need for treatment interruption due to PN
Table 9
| Signs of peripheral neuropathy |
IFM-2005-01 |
MMY-3010 |
||
| VDDx (N = 239) |
VcDx (N = 239) |
TDx (N = 126) |
VcTDx (N = 130) |
|
| Incidence 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; PN – peripheral neuropathy. Peripheral neuropathy includes: peripheral neuropathy, peripheral motor neuropathy, peripheral sensory neuropathy, and polyneuropathy.
Mantle cell lymphoma
The frequency of peripheral neuropathy events observed during the study (LYM-3002) of bortezomib in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone is presented in Table 10.
Frequency of peripheral neuropathy (PN) events in the bortezomib study in patients with mantle cell lymphoma by toxicity grade and need for treatment interruption due to PN
Table 10
| Signs of peripheral neuropathy |
VcR-CAP (N = 240) |
R-CHOP (N = 242) |
| Frequency of PN (%) |
||
| All grades of 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; PN – peripheral neuropathy. Peripheral neuropathy includes: peripheral sensory neuropathy, peripheral neuropathy, peripheral motor neuropathy, and peripheral sensorimotor neuropathy.
Older 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 48% 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 who received subcutaneous bortezomib, the incidence of treatment-emergent adverse reactions of Grade III toxicity or higher was 13% lower compared to patients who received intravenous bortezomib, and the rate of bortezomib treatment discontinuation 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 Grade III or higher peripheral neuropathies 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. Two patients (1%) experienced serious reactions: 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 mortality 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 of bortezomib re-treatment involving 130 patients with relapsed multiple myeloma who previously had at least a partial response to combination therapy including bortezomib, the majority of adverse reactions of all grades occurring in at least 25% of patients 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 of suspected adverse reactions
Reporting of adverse reactions after drug registration 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 cases of suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at the following link: http://aisf.dec.gov.ua.
Shelf life.
2 years.
Storage conditions. Store at temperatures not exceeding 25 °C in the original packaging to protect from light, in a place inaccessible to children.
Incompatibilities.
This medicinal product must not be mixed with other medicinal products except those mentioned in the section “Method of administration and dosage.”
Packaging.
1 vial per cardboard box.
Prescription category.
Prescription only.
Manufacturer.
Dr. Reddy’s Laboratories Ltd, FTO-7
Manufacturer’s address and location of operations.
Plot No. R1-R9, Phase - III, VSE3, Duvvada, Visakhapatnam District, Andhra Pradesh, 530046, India