Brecer
UkraineTable of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BRECER (BRECER)
Composition:
Active substance: bortezomib;
1 vial contains bortezomib 1.0 mg;
Excipient: mannitol (E 421).
Pharmaceutical form. Lyophilisate for solution for injection.
Main physicochemical properties: white or almost white powder or mass.
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 reversibly 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 essential proteins. This pathway plays a key 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 cellular events resulting in apoptosis.
Bortezomib is highly selective for the proteasome. At a concentration of 10 μM, bortezomib does not inhibit a wide range 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 have been determined in vitro; bortezomib dissociates from the proteasome with a half-life (t½) of 20 minutes, demonstrating that proteasome inhibition by bortezomib is reversible. By inhibiting the proteasome, bortezomib affects cancer cells through multiple mechanisms, including but not limited to, altering regulatory proteins controlling the cell cycle and inhibiting activation of the nuclear transcription factor NF-kB. Proteasome inhibition results in 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 multiple myeloma, bortezomib affects the ability of myeloma cells to interact with the bone marrow microenvironment.
Studies have shown that bortezomib is cytotoxic to various types of cancer cells and that cancer cells are more susceptible to bortezomib-induced apoptosis than normal cells. In vivo, bortezomib has been shown to slow the growth of several experimental human tumors, including multiple myeloma.
Data from in vitro, ex vivo, and animal models 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 above 50 mL/min, the mean maximum plasma concentration (Cmax) of the first dose of bortezomib was 57 and 112 ng/mL, respectively. With subsequent doses, mean Cmax values 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. Plasma protein binding of bortezomib at concentrations of 0.01–1.0 μg/mL is 82.9%. The fraction of bortezomib bound to plasma proteins was independent of concentration.
Metabolism. In vitro studies using human liver microsomes and expressed cDNA indicate that bortezomib is primarily metabolized by cytochrome P450 enzymes, including CYP3A4, CYP2C19, and CYP1A2. The main metabolic pathway involves deboronation, leading to two primary metabolites, which are further hydroxylated into additional metabolites. The deboronated metabolites of bortezomib are inactive as inhibitors of the 26S proteasome.
Elimination. The mean elimination half-life (T1/2) 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 61 patients, mostly with solid tumors and varying degrees of hepatic dysfunction. Bortezomib doses ranged from 0.5 to 1.3 mg/m².
Mild hepatic impairment did not alter bortezomib AUC compared to patients with normal liver function. Mean AUC values of bortezomib increased by approximately 60% in patients with moderate and severe hepatic impairment. Dose adjustment and careful monitoring are recommended for such patients during treatment.
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 (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 at 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) for clearance was 7.79 (25%) L/h/m², the volume of distribution at steady state was 834 (39%) L/m², and the elimination half-life was 100 (44%) hours. After adjusting for body surface area, other demographic factors such as age, body weight, and sex had no clinically significant effect on bortezomib clearance. Bortezomib clearance values in children, adjusted for body surface area, were comparable to those observed 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 line and have undergone 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 to any of the excipients of the medicinal product.
Acute diffuse infiltrative pulmonary and pericardial diseases.
When using the medicinal product in combination with other medicinal products, refer to the instructions for medical use of these products for additional contraindications.
Special precautions.
General warnings. Brecer is a cytotoxic medicinal product. Therefore, caution must 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 Brecer, as the product does not contain preservatives.
Fatal cases have occurred due to accidental intrathecal administration of bortezomib. Bortezomib must be administered intravenously only. DO NOT ADMINISTER BORTEZOMIB INTRATHECALLY.
Instructions for solution preparation. Solution preparation must be performed by qualified medical personnel.
Prior to administration, the contents of each vial should be carefully reconstituted with 1 mL of 0.9% sodium chloride injection solution using a 1 mL syringe, without removing the vial stopper. 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 absence of particles and discoloration prior to administration. If particles are present or discoloration occurs, the solution must not be used.
Proper disposal procedure. For single use only. Any 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 isoenzymes 1A2, 2C9, 2C19, 2D6, and 3A4. Since CYP2D6 plays a minor role in bortezomib metabolism, changes in overall drug disposition are 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 by 35% (90% CI [1.032 to 1.772]) based on data from 12 patients. Therefore, careful monitoring of patients is recommended when bortezomib is administered concomitantly with potent CYP3A4 inhibitors (such as ketoconazole, ritonavir).
A study evaluating the effect of omeprazole, a potent CYP2C19 inhibitor, on the pharmacokinetics of bortezomib (after intravenous administration) in 17 patients did not show a significant effect on bortezomib pharmacokinetics.
A study investigating the effect of rifampicin, a potent CYP3A4 inducer, in 6 patients revealed an average reduction in bortezomib AUC (after intravenous administration) by 45%. Therefore, concomitant administration of bortezomib with potent CYP3A4 inducers (such as rifampicin, carbamazepine, phenytoin, phenobarbital, and St. John's wort extract) is not recommended, as the efficacy of bortezomib may be reduced.
In the same interaction study, assessment of the effect of dexamethasone, a weak CYP3A4 inducer, based on data from 7 patients, did not show clinically significant changes in bortezomib pharmacokinetics.
A drug interaction study evaluating the effect of melphalan and prednisone on the pharmacokinetics of bortezomib (after intravenous administration) in 21 patients 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 antidiabetic agents. Patients taking oral antidiabetic medications should monitor their blood glucose levels closely during bortezomib treatment and adjust the dose of antidiabetic agents as needed.
Special precautions for use.
If Brexar 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, particular attention should be paid to pregnancy testing and contraceptive measures.
Intrathecal administration. Fatal cases have occurred due to accidental intrathecal administration of bortezomib. Bortezomib must be administered intravenously only. BORTEZOMIB MUST NOT BE ADMINISTERED INTRATHECALLY.
Gastrointestinal complications. Bortezomib treatment very commonly causes gastrointestinal toxicity, including nausea, diarrhea, constipation, and vomiting. Cases of intestinal obstruction (reported as uncommon in frequency) 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 evaluating bortezomib in patients with relapsed multiple myeloma and bortezomib in combination therapy with rituximab, cyclophosphamide, doxorubicin, and prednisone (VcR-CAP regimen) in patients with previously untreated mantle cell lymphoma, reversible thrombocytopenia was one of the most common hematological toxicities. The lowest platelet counts typically occurred on day 11 of each bortezomib treatment cycle. Platelet counts returned to baseline levels by the start of the next cycle. Cumulative thrombocytopenia was not observed. On average, the lowest measured platelet count was approximately 40% of the baseline level in trials of bortezomib monotherapy in patients with multiple myeloma and
50% in trials of bortezomib in patients with mantle cell lymphoma. In patients with progressive myeloma, the severity of thrombocytopenia was related to baseline platelet counts: in patients with baseline platelet counts < 75,000/µL, 90% of 21 patients had platelet counts ≤ 25,000/µL during the study, including 14% with counts < 10,000/µL, whereas in patients with baseline platelet counts > 75,000/µL, only 14% of 309 patients had platelet counts ≤ 25×10⁹/L.
In patients with mantle cell lymphoma, thrombocytopenia of grade ≥ III was more frequent 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, 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. Therefore, platelet counts should be monitored before each dose of Brexar. Bortezomib therapy should be withheld if platelet counts decrease to < 25,000/µL during monotherapy or to ≤ 30,000/µL when used in combination with melphalan and prednisone. The benefit-risk ratio of Brexar treatment should be carefully evaluated, especially in cases of moderate or severe thrombocytopenia and risk factors for bleeding.
Complete blood counts with differential and platelet counts should be frequently performed during Brexar 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 counts typically occurred on day 11 of each bortezomib treatment cycle and returned to baseline levels before the start of the next cycle. In a trial of bortezomib in patients with mantle cell lymphoma, 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 should be 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 for patients receiving bortezomib. In phase III trials of previously untreated multiple myeloma patients, the overall incidence of Herpes zoster reactivation (shingles) was higher in the group receiving bortezomib + melphalan + prednisone (14%) compared to the 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.
Reactivation and infection with hepatitis B virus (HBV).
Prior to initiating treatment with rituximab in combination with Brexar, 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 Brexar. Antiviral prophylaxis should be considered.
Progressive multifocal leukoencephalopathy (PML). Very rare cases of John Cunningham (JC) virus infection leading to PML with fatal outcome have been reported in patients treated with Brexar. Patients diagnosed with PML had a history of or were concurrently receiving immunosuppressive therapy with Brexar. Most PML cases were diagnosed within the first 12 months of starting Brexar treatment. Patients should be regularly monitored for new or worsening neurological symptoms that may indicate PML, which should be considered in the differential diagnosis of central nervous system (CNS) disorders. If PML is suspected, patients should be referred to a physician experienced in managing PML and appropriate diagnostic measures should be taken. If PML is confirmed, Brexar treatment should be discontinued.
Peripheral neuropathy. Treatment with Brexar 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 fifth treatment cycle with Brexar.
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 is required for patients receiving Brexar 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 risk factors for seizures.
Hypotension. Treatment with Brexar is frequently associated with postural/orthostatic hypotension. In most cases, it is mild to moderate in severity and occurs throughout treatment. Most patients who developed orthostatic hypotension during Brexar (intravenous) administration did not have symptoms of orthostatic hypotension prior to treatment. The majority of patients required treatment for orthostatic hypotension, and a smaller number experienced syncope. Orthostatic/postural hypotension was not clearly associated with bolus infusion of Brexar; the mechanism of its development is unknown. It may be related to autonomic neuropathy. Autonomic neuropathy may be associated with bortezomib use or bortezomib may exacerbate underlying conditions, including diabetic or amyloid neuropathy. Caution should be exercised when treating patients with a history of syncope, those taking antihypertensive medications, and those with dehydration due to diarrhea or vomiting. In case of orthostatic hypotension, hydration, glucocorticoids, and/or sympathomimetics are recommended; antihypertensive drug doses should be reduced if necessary. Patients should be instructed to consult a physician if they experience dizziness, pre-syncope, or loss of consciousness.
Reversible posterior leukoencephalopathy syndrome (PRES). Cases of PRES have been reported in patients treated with Brexar. PRES is a rare reversible neurological disorder characterized by symptoms such as seizures, arterial hypertension, headache, lethargy, confusion, visual disturbances, and other neurological impairments. Brain imaging, preferably magnetic resonance imaging (MRI), should be performed to confirm the diagnosis. Brexar treatment should be discontinued if PRES is diagnosed.
Heart failure. Cases of development or worsening of pre-existing congestive heart failure and/or decreased left ventricular ejection fraction have been reported with bortezomib use. Fluid retention may contribute to the development of signs and symptoms of heart failure. Patients with risk factors or pre-existing cardiac disease should be monitored.
ECG monitoring. 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 Brexar. Some of these cases were fatal. Chest X-ray before treatment initiation is recommended to establish baseline lung status for comparison in case of potential treatment-related lung dysfunction.
Prompt diagnostic evaluation and appropriate therapeutic measures should be taken if new or worsening pulmonary symptoms (e.g., cough, dyspnea) occur. The benefit-risk ratio of continuing Brexar treatment 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 Brexar 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 impairment is commonly observed in patients with multiple myeloma. Close monitoring of such patients is recommended.
Hepatic function disorders. Bortezomib is metabolized by hepatic enzymes. Bortezomib concentrations may increase in patients with moderate to severe hepatic impairment; 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 Brexar concomitantly with other drugs 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, complications related to tumor lysis syndrome may occur. Patients with high tumor burden prior to treatment initiation are at highest risk. Close monitoring of such patients and appropriate preventive measures are recommended.
Precautions regarding concomitant use of other medicinal products. Patients should be closely monitored when bortezomib is combined with strong CYP3A4 inhibitors. Caution should be exercised when combining bortezomib with CYP3A4 or CYP2C9 substrates.
Hepatic function should be corrected prior to initiating treatment if impaired, and caution should be exercised when prescribing the drug to patients taking oral hypoglycemic agents.
Potentially immune complex-mediated reactions. Immune complex-mediated reactions such as serum sickness, polyarthritis with rash, and proliferative glomerulonephritis have been reported uncommonly. Bortezomib should be discontinued if serious reactions occur.
Use during pregnancy or breastfeeding.
Contraception in women and men
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 bortezomib treatment and for 5 months after completion of treatment.
Pregnancy
There are no clinical data on the use of bortezomib during pregnancy. The teratogenic potential of bortezomib has 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. Bortezomib is not recommended during pregnancy except when the woman's clinical condition requires treatment with bortezomib. If bortezomib is used during pregnancy or if pregnancy occurs during treatment, the patient should be informed of the potential risk 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 bortezomib in combination with thalidomide must comply with pregnancy prevention requirements. For additional information, refer to the thalidomide product information.
Breastfeeding
It is unknown whether bortezomib is excreted in human milk, but to prevent the occurrence of serious adverse effects in the infant, breastfeeding is not recommended during bortezomib treatment.
Fertility
Studies on the effect of bortezomib on fertility have not been conducted. Due to the genotoxic potential of bortezomib, male patients should seek advice on sperm preservation prior to treatment initiation, and women of reproductive age should consult on oocyte cryopreservation.
Ability to affect reaction speed when driving or operating machinery.
Bortezomib has a moderate effect on the ability to drive or operate machinery. Bortezomib use 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 (see section "Adverse reactions").
Method of Administration and Dosage
Treatment with Brecer should be initiated under the supervision of a qualified physician experienced in the treatment of cancer patients. However, treatment with Brecer may also be administered under the supervision of a healthcare professional experienced in the use of anticancer agents. Preparation of the solution must be performed only by qualified medical personnel (see section "Special Safety Precautions").
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 two weeks (on days 1, 4, 8, and 11), followed by a 10-day treatment-free period (days 12–21). This three-week period is considered one treatment cycle. After achieving a complete clinical response, administration of two additional treatment cycles is recommended. Patients achieving a partial response but not complete remission should continue Brecer therapy, but not for more than 8 cycles in total. At least 72 hours should elapse between consecutive doses of Brecer.
Recommendations for Dose Adjustment and Resumption of Brecer as Monotherapy
If any grade III non-hematologic toxicity or grade IV hematologic toxicity occurs, except for neuropathies, treatment with Brecer should be withheld.
After resolution of toxic symptoms, bortezomib treatment may be resumed at a dose reduced by 25% (reduce the 1.3 mg/m² dose to 1.0 mg/m²; reduce the 1.0 mg/m² dose to 0.7 mg/m²). If toxic symptoms do not resolve or recur during treatment with the reduced dose, discontinuation of Brecer should be considered, unless the benefits of continued treatment outweigh the risks.
Neuropathic Pain and/or Peripheral Neuropathy
In the event of neuropathic pain associated with bortezomib administration and/or peripheral neuropathy, the dose should be adjusted according to Table 1. Bortezomib 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 Brecer-induced neuropathy.
| Severity of neuropathy |
Dose and frequency adjustment |
| Grade I (asymptomatic; diminished deep tendon reflexes or paresthesia) without pain or functional impairment |
No adjustment required |
| Grade I with pain or Grade II (moderate severity symptoms; limitation of instrumental activities of daily living (instrumental ADLs)** |
Reduce dose to 1.0 mg/m² |
| Grade II with pain or Grade III (severe symptoms; limitation of self-care activities of daily living (self-care ADLs)*** |
Withhold bortezomib until resolution of toxic symptoms. After symptom resolution, resume bortezomib therapy at a reduced dose of 0.7 mg/m² once weekly |
| Grade IV (life-threatening consequences; requires urgent intervention) and/or severe autonomic neuropathy |
Discontinue bortezomib |
* Based on dose modifications observed in Phase II and III multiple myeloma studies and in the post-marketing period. Severity grades are defined according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.0.
** Instrumental Activities of Daily Living Scale (ADL-instrumental activities): includes assessment of the patient's ability to perform instrumental activities such as meal preparation, shopping, telephone use, managing finances, etc.
*** Patient's Self-care Ability Assessment Scale (ADL-self-care) includes assessment of the patient's ability to independently bathe, dress/undress, eat, use the toilet, and take medications; the patient is not 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 (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 bortezomib.
Pegylated liposomal doxorubicin is administered at a dose of 30 mg/m² on day 4 of the bortezomib treatment cycle via a 1-hour intravenous infusion after Brexucarb injection.
Up to 8 cycles of this combination therapy should be administered provided the disease does not progress and the patient tolerates treatment well. Patients who achieve a complete remission may continue treatment for at least 2 additional cycles after achieving complete response, even if this requires more than 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.
See also the medical instructions for use of pegylated liposomal doxorubicin.
Combination therapy with dexamethasone.
The recommended dose of bortezomib is 1.3 mg/m² body surface area administered intravenously 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 constitutes one treatment cycle. At least 72 hours should elapse between consecutive doses of bortezomib.
Dexamethasone should be administered orally at a dose of 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 of the bortezomib treatment cycle.
Patients who show a response to treatment or disease stabilization after four cycles may continue this combination therapy for up to four additional cycles. For further information on dexamethasone, refer to the medical instructions for use of this medicinal product.
Dose modification recommendations for combination therapy components in patients with relapsed multiple myeloma
See dose modification recommendations for bortezomib monotherapy provided above.
Untreated multiple myeloma in patients not eligible for hematopoietic stem cell transplantation
Combination therapy with melphalan and prednisone.
Bortezomib should be administered intravenously in combination with oral melphalan and oral prednisone over nine 6-week treatment cycles (Table 2). During cycles 1–4, bortezomib is administered twice weekly (days 1, 4, 8, 11, 22, 25, 29, and 32). During 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 should be administered orally on days 1, 2, 3, and 4 of the first week of each cycle.
Table 2
Recommended dosing regimen of bortezomib in combination with melphalan and prednisone
| Bortezomib, twice weekly (1 ˗ 4 cycles) |
||||||||||||
| Week |
1 |
2 |
3 |
4 |
5 |
6 |
||||||
| B (1.3 mg/m²) |
Day 1 |
- |
- |
Day 4 |
Day 8 |
Day 11 |
Break |
Day 22 |
Day 25 |
Day 29 |
Day 32 |
Break |
| M (9 mg/m²) P (60 mg/m²) |
Day 1 |
Day 2 |
Day 3 |
Day 4 |
- |
- |
Break |
- |
- |
- |
- |
Break |
| Bortezomib, once weekly (5 ˗ 9 cycles) |
||||||||||||
| Week |
1 |
2 |
3 |
4 |
5 |
6 |
||||||
| B (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 |
|||
B – bortezomib; M – melphalan; P – prednisone.
Dosing modification and re-initiation 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 level.
Table 3
Dose modifications during subsequent cycles of bortezomib therapy in combination with melphalan and prednisone
| Toxic effects |
Dose adjustment or treatment interruption |
| Hematologic toxicity during cycle:
|
Consider reducing melphalan dose by 25% in the next cycle |
≤ 30 × 109/L or absolute neutrophil count ≤ 0.75 × 109/L |
Bortezomib therapy should be delayed |
|
Bortezomib dose should be reduced by one level (from 1.3 mg/m2 to 1 mg/m2 or from 1 mg/m2 to 0.7 mg/m2) |
| Non-hematologic toxicities ≥ grade III |
Bortezomib treatment should be withheld until symptoms improve to baseline level or grade I severity. Then bortezomib 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 and/or peripheral neuropathy related to bortezomib administration, bortezomib therapy should be interrupted and/or bortezomib dose adjusted as specified in Table 1 |
For additional information regarding melphalan and prednisone, see the package leaflets for these medicinal products.
Untreated multiple myeloma in patients eligible for haematopoietic 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 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 40 mg on days 1, 2, 3, 4, 8, 9, 10, and 11 of the bortezomib treatment cycle.
Four treatment cycles with this combination should be administered.
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 rest period (days 12–28). This four-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 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 the drug is well 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).
Four treatment cycles should be administered. Patients achieving at least a partial response to treatment are recommended to receive 2 additional cycles of therapy.
Table 4
Recommended dosing regimen of bortezomib in combination with dexamethasone and thalidomide for untreated multiple myeloma patients eligible for haematopoietic stem cell transplantation
| B + Dks |
Cycles 1–4 |
||||||
| Week |
1 |
2 |
3 |
||||
| bortezomib (1.3 mg/m²) |
Day 1, 4 |
Day 8, 11 |
Break |
||||
| Dks 40 mg |
Day 1, 2, 3, 4 |
Day 8, 9, 10, 11 |
|
||||
| B + Dks + 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 mga |
|
|
Daily |
Daily |
|||
| Dks 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 |
Daily |
Daily |
Daily |
Daily |
|||
| Dks 40 mg |
Day 1, 2, 3, 4 |
Day 8, 9, 10, 11 |
|
|
|||
B – bortezomib; Dks – dexamethasone; T – thalidomide.
a Starting from week 3 of cycle 1, the thalidomide dose should be increased to 100 mg, but only if the patient tolerates the 50 mg dose well; from cycle 2 onwards, the dose may be increased to 200 mg if the patient tolerates the 100 mg dose well.
b Patients who achieve at least a partial response after 4 treatment cycles may receive up to 6 treatment cycles.
Dose adjustment recommendations for patients undergoing transplantation.
For dose adjustments in the event of neuropathy, see Table 1.
When Brezera is used in combination with other chemotherapeutic agents, for information on dose adjustments of these medicinal products in the event of toxicity, refer to the prescribing information for those medicinal products.
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 three-week period constitutes one treatment cycle. At least 72 hours should elapse between consecutive bortezomib doses. Administer 6 treatment cycles. Patients who first demonstrate a response during cycle 6 are recommended to receive 2 additional treatment cycles.
Medicinal products administered by intravenous infusion on day 1 of each three-week bortezomib 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 bortezomib 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-hematological toxicity must have resolved to grade 1 or baseline levels.
Treatment with Brezera should be withheld in the event of any non-hematological toxicity ≥ grade III severity (except neuropathy) related to Brezera administration, or hematological toxicity ≥ grade III severity. Dose adjustment recommendations are provided in Table 5.
Granulocyte colony-stimulating factors may be used to manage hematological 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 the management of thrombocytopenia.
Table 5
Dose adjustment recommendations for treatment of patients with untreated mantle cell lymphoma
| Toxicity |
Dose adjustment or treatment interruption |
| Haematological toxicity |
|
|
Bortezomib treatment should be interrupted for up to 2 weeks until the patient achieves an absolute neutrophil count ≥ 750 cells/µL and platelet count ≥ 25,000 cells/µL.
|
|
Bortezomib therapy should be postponed |
| Non-haematological toxicity ≥ Grade III related to bortezomib administration |
Bortezomib treatment should be interrupted until symptoms of toxicity improve to Grade II or lower. Bortezomib may then be restarted at a reduced dose level (from 1.3 mg/m² to 1 mg/m² or from 1 mg/m² to 0.7 mg/m²). In case of bortezomib-related neuropathic pain and/or peripheral neuropathy, bortezomib administration should be interrupted and/or the dose adjusted 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 regarding 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.
There are no studies on the use of bortezomib in elderly patients with untreated multiple myeloma who are candidates for high-dose chemotherapy with hematopoietic stem cell transplantation. Therefore, no recommendations on dose adjustment can be provided for this patient group.
In a study 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 worse in both treatment groups (VcR-CAP and R-CHOP regimens).
Patients with hepatic impairment
Dose adjustment is not required for patients with mild hepatic impairment. For patients with moderate and severe hepatic impairment, treatment with bortezomib should be initiated at a dose of 0.7 mg/m² during the first treatment cycle, with subsequent gradual dose escalation to 1.0 mg/m² or dose reduction to 0.5 mg/m², depending on patient tolerability.
Table 6
Recommendations for initial dose adjustments of bortezomib 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 bortezomib dose to 0.7 mg/m² in the first treatment cycle. Consider increasing the dose to 1.0 mg/m² or reducing it to 0.5 mg/m² in subsequent cycles, depending on patient tolerance |
| Severe |
> 3 × ULN |
Any |
AST – aspartate aminotransferase; ULN – upper limit of normal.
* According to the classification of the National Cancer Institute (NCI) Organ Dysfunction Working Group for categorizing the severity of liver function abnormalities (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 this patient group. It is unknown whether severe renal impairment (creatinine clearance < 20 ml/min/1.73 m²) affects the pharmacokinetics of bortezomib. Since dialysis may reduce bortezomib concentrations, the drug should be administered after the dialysis procedure.
Method of administration.
Brecer must be 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- to 5-second intravenous bolus injection through a peripheral or central venous catheter, which should then be flushed with 0.9% sodium chloride injection solution after the injection. At least 72 hours must elapse between consecutive doses of Brecer.
After reconstitution, the medicinal product may be stored at a temperature not exceeding 25 °C for up to 8 hours, provided it is stored in the original vial and/or syringe. However, the solution should be used immediately after reconstitution. If the drug is not used immediately, responsibility for the storage time and conditions lies with the user.
Children.
The safety and efficacy of bortezomib in pediatric patients (under 18 years of age) have not been established. Current data are insufficient to establish dosing recommendations for pediatric patients.
Overdose.
In patients, overdose exceeding the recommended dose by more than two-fold has been associated with acute hypotension and thrombocytopenia resulting in fatal outcomes.
There is no known 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
Summary of Safety Profile
Among serious adverse reactions during bortezomib treatment, cardiac arrest, tumor lysis syndrome, pulmonary hypertension, reversible posterior leukoencephalopathy syndrome (PRES), acute diffuse infiltrative pulmonary disorders, and autonomic neuropathy have been reported infrequently or 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, paresthesia, 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 the use of bortezomib.
These adverse reactions are based on pooled data from 5,476 patients, of whom 3,996 received bortezomib at a dose of 1.3 mg/m². Overall, the medicinal product was used to treat multiple myeloma in 3,974 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 (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), and frequency not known (cannot be estimated from available data). Within each category, adverse reactions are listed in descending order of 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*, 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, post-viral fatigue syndrome |
|
| Benign, malignant and unspecified neoplasms (including cysts and polyps) |
Rare |
Malignant tumor, 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, thrombopathy, 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*, syndrome of inappropriate 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 worsening (weight loss and growth retardation)ª*, 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 disorders*, sleep disorders* |
| Uncommon |
Psychiatric disorder*, hallucinations*, psychotic disorder*, confusion*, agitation |
|
| Rare |
Suicidal thoughts*, adjustment disorder, delirium, decreased libido |
|
| Nervous system disorders |
Very common |
Neuropathies*, peripheral sensory neuropathy, dysesthesia*, neuralgia* |
| Common |
Motor neuropathy*, loss of consciousness (including syncope), dizziness*, dysgeusia*, lethargy, headache* |
|
| Uncommon |
Tremor, sensorimotor peripheral neuropathy, dyskinesia*, coordination and balance disorders*, memory loss (without dementia)*, encephalopathy*, reversible posterior encephalopathy syndrome#, neurotoxicity, seizure disorders*, postherpetic neuralgia, speech disorders*, restless legs syndrome, migraine, sciatica, attention disorders, reflex disturbances*, parosmia |
|
| Rare |
Intracranial hemorrhage*, intracerebral hemorrhage (including subarachnoid)*, brain edema, transient ischemic attack, coma, autonomic nervous system disorders, autonomic neuropathy, cranial nerve paralysis*, paralysis*, paresis*, presyncope, brainstem lesion syndrome, cerebrovascular disorder, nerve root damage, psychomotor hyperactivity, spinal cord compression, other cognitive disorders, motor dysfunction, nervous system disorder, radiculitis, drooling, hypotonia, Guillain-Barré syndrome#, demyelinating polyneuropathy# |
|
| Eye disorders |
Common |
Eye swelling*, vision disturbances*, conjunctivitis* |
| Uncommon |
Ocular hemorrhage*, eyelid infections*, eye inflammation*, diplopia, dry eyes*, eye irritation*, eye pain, increased lacrimation, eye discharge, chalazion#, blepharitis# |
|
| Rare |
Corneal damage*, exophthalmos, retinitis, scotoma, eye (and eyelid) disorders, acquired dacryoadenitis, photophobia, photopsia, optic nerve neuropathy#, vision deterioration of varying degrees (up to blindness)* |
|
| Ear and labyrinth disorders |
Common |
Vertigo* |
| Uncommon |
Dysacusis (including tinnitus)*, hearing deterioration (up to deafness), ear discomfort* |
|
| Rare |
Ear hemorrhage, vestibular neuronitis, other ear disorders |
|
| Cardiac disorders |
Uncommon |
Cardiac tamponade#, cardiopulmonary shock*, cardiac fibrillation (including atrial), heart failure (including left and right ventricular)*, arrhythmia*, tachycardia*, palpitations, angina pectoris, pericarditis (including pericardial effusion), cardiomyopathy*, ventricular dysfunction*, bradycardia |
| Rare |
Atrial flutter, myocardial infarction*, atrioventricular block*, cardiovascular disorders (including cardiogenic shock), polymorphic ventricular tachycardia (torsade de pointes), unstable angina, heart valve disorders*, coronary artery insufficiency, sinus node arrest |
|
| Vascular disorders |
Common |
Arterial hypotension*, orthostatic hypotension, arterial hypertension* |
| Uncommon |
Cerebral circulation disorders#, deep vein thrombosis*, hemorrhage*, thrombophlebitis (including superficial veins), circulatory collapse (including hypovolemic shock), phlebitis, flushing*, hematoma (including perirenal)*, 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* (COPD), hypoxemia*, worsening of airway patency*, hypoxia, pleurisy*, hiccups, rhinorrhea, dysphonia, wheezing |
|
| Rare |
Pulmonary insufficiency, 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, 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 bleeding (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#, gastrointestinal tract inflammation*, dysphagia, irritable bowel syndrome, other gastrointestinal disorders, coated tongue, 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, blister formation in oropharynx*, 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*, blisters*, skin pigmentation disorders* |
|
| Rare |
Skin reactions, Jessner's lymphocytic infiltration, palmoplantar 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 |
Bone-muscle 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, musculoskeletal and connective tissue infections and inflammations*, synovial cyst |
|
| Renal and urinary disorders |
Common |
Renal failure* |
| Uncommon |
Acute renal failure, chronic renal failure*, urinary tract infections*, signs and symptoms of urinary 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, general weakness |
| Common |
Edema (including peripheral), chills, pain*, fever* |
|
| Uncommon |
Worsening of general physical health*, facial swelling*, injection site reactions*, mucous membrane disorders*, chest pain, gait disturbance, cold sensation, extravasation*, catheter-related complications*, thirst sensation*, chest discomfort, sensation of body temperature change*, pain related to injection* |
|
| Rare |
Fatal outcome (including sudden), multi-organ failure, injection site hemorrhages*, hernia (including hiatal)*, impaired healing*, inflammation, phlebitis at injection site*, tenderness on palpation, ulceration, irritation, non-cardiac substernal pain, catheter insertion site pain, foreign body sensation |
|
| Investigations |
Common |
Weight loss |
| Uncommon |
Hyperbilirubinemia*, protein level deviations 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 abnormalities*, decreased gastric pH, increased platelet aggregation, elevated troponin I level, identification of viruses in serological tests*, urine test abnormalities* |
|
| 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 |
* grouping of more than one MedDRA (Medical Dictionary for Regulatory Activities) term.
Adverse reactions reported in the post-marketing period.
ª Clinical deterioration – 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. 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 1.3 mg/m² in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (VcR-CAP), and in 242 patients who received rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHOP), was generally similar to the safety profile observed in patients with multiple myeloma; the main differences are described below. Additional adverse reactions observed with bortezomib in combination therapy (VcR-CAP) were hepatitis B virus infection (˂1%) and myocardial ischemia (1.3%). The similar incidence of these events in both treatment groups suggests that these adverse reactions are not solely related to bortezomib. Administration of bortezomib to patients with mantle cell lymphoma was associated with a ≥5% higher frequency 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 with a frequency of ≥1%, occurring at a similar or higher rate in the VcR-CAP treatment group and considered 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 considered by investigators as 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. 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 frequency not known (cannot be estimated from available data). Within each group, adverse reactions are listed in order of decreasing 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, 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 abnormalities*, hyponatremia*, diabetes mellitus*, fluid retention |
|
| Uncommon |
Tumor lysis syndrome |
|
| Psychiatric disorders |
Common |
Sleep disorders* |
| Nervous system disorders |
Very common |
Peripheral sensory neuropathy, dysesthesia*, neuralgia* |
| Common |
Neuropathies*, motor neuropathy*, loss of consciousness (including syncope), encephalopathy*, sensory-motor peripheral neuropathy, dizziness*, dysgeusia*, autonomic neuropathy |
|
| Uncommon |
Autonomic nervous system disorders |
|
| Eye disorders |
Common |
Visual disturbances* |
| Ear and labyrinth disorders |
Common |
Dysacusis (including tinnitus)* |
| Uncommon |
Vertigo*, hearing impairment (up to deafness) |
|
| Cardiac disorders |
Common |
Cardiac fibrillation (including atrial), arrhythmia*, heart failure (including left and right ventricular)*, myocardial ischemia, ventricular dysfunction* |
| Uncommon |
Cardiovascular disorders (including cardiogenic shock) |
|
| Vascular disorders |
Common |
Arterial hypertension*, hypotension*, orthostatic hypotension |
| Respiratory, thoracic and mediastinal disorders |
Common |
Dyspnea*, cough*, hiccough |
| Uncommon |
Acute respiratory distress syndrome, pulmonary embolism, pneumonitis, pulmonary hypertension, pulmonary edema (including acute) |
|
| Gastrointestinal disorders |
Very common |
Nausea and vomiting*, diarrhea*, stomatitis*, constipation |
| Common |
Gastrointestinal hemorrhage (including mucosal)*, abdominal distension, dyspepsia, oropharyngeal pain*, gastritis*, oral ulcers*, abdominal discomfort, dysphagia, gastrointestinal inflammation*, abdominal pain (including gastrointestinal and splenic region pain)*, oral cavity disorders* |
|
| Uncommon |
Colitis (including Clostridium difficile-induced)* |
|
| Hepatobiliary disorders |
Common |
Hepatotoxicity (including hepatic disorders) |
| Uncommon |
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*, protein abnormalities*, weight decreased, weight increased |
* Several MedDRA terms have been grouped.
Description of selected adverse reactions.
Herpes zoster virus reactivation
Multiple myeloma
Antiviral prophylaxis was administered in 26% of patients receiving bortezomib in combination with melphalan and prednisone. Herpes zoster occurred 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 according to 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.
Hepatitis B virus (HBV) reactivation and infection
Mantle cell lymphoma
Cases of hepatitis B infection with fatal outcome were reported in 0.8% of patients (n=2) in the group receiving treatment according to the R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) and in 0.4% of patients (n=1) receiving bortezomib as part of combination therapy according to 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
In studies where bortezomib was used as induction therapy in combination with dexamethasone (study IFM-2005-01) and dexamethasone-thalidomide (study MMY-3010), the incidence of peripheral neuropathy is presented in 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) |
|
| 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 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 (PN) events observed during the study (LYM-3002) of bortezomib in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone is presented in Table 10.
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
| Signs of peripheral neuropathy |
VcR-CAP (N = 240) |
R-CHOP (N = 242) |
| Incidence 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.
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.
Retreatment of patients with relapsed multiple myeloma
In a study of bortezomib used as retreatment involving 130 patients with relapsed multiple myeloma who previously achieved at least a partial response to a bortezomib-containing regimen, the most common adverse reactions of any severity 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 suspected adverse reactions after drug authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all 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 in the original packaging in a protected from light place at a temperature not exceeding 25 °C. Keep out of reach and sight of children.
Incompatibilities.
This medicinal product should not be mixed with other medicinal products except those listed in the section "Instructions for use and dosage."
Packaging.
1 vial of lyophilisate in a cardboard box.
Prescription category.
Prescription only.
Manufacturer.
Dr. Reddy’s Laboratories Ltd, FTO-7
Manufacturer's address and location of its business activity.
Plot No. R1-R9, Phase - III, VSEZ, Duvvada, Visakhapatnam District, Andhra Pradesh, 530046, India