Bortezomib
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BortezoVista (BortezoVista)
Composition:
Active substance: bortezomib;
1 vial contains 2.5 mg of bortezomib;
Excipient: mannite (E 421).
Pharmaceutical form. Powder for solution for injection.
Main physicochemical properties: white or almost white lyophilized tablet or powder in a glass vial with a stopper and a tamper-evident disc.
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 suppresses the chymotrypsin-like activity of the 26S proteasome in mammalian cells. The 26S proteasome is a large protein complex involved in the degradation of key regulatory proteins. This pathway plays a central role in regulating the turnover of specific proteins, thereby maintaining cellular homeostasis. Inhibition of the 26S proteasome leads to suppression of proteolysis and triggers a cascade of reactions resulting in apoptosis.
Bortezomib is highly selective for the proteasome. At a concentration of 10 µM, bortezomib does not inhibit any of 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 determined in vitro; bortezomib dissociated from the proteasome with a half-life of 20 minutes, indicating that proteasome inhibition by bortezomib is reversible. By inhibiting the proteasome, bortezomib affects cancer cells through multiple pathways, including altering regulatory proteins controlling the cell cycle 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.
Experimental studies have shown that bortezomib is toxic to many types of cancer cells and that cancer cells are more susceptible to bortezomib-induced apoptosis than normal cells. In vivo, bortezomib causes 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 bone disease and were treated with bortezomib.
Pharmacokinetics.
Absorption. After intravenous bolus administration of doses of 1.0 and 1.3 mg/m² in 11 patients with multiple myeloma and creatinine clearance (CrCl) above 50 mL/min, the mean maximum plasma concentration (Cmax) of bortezomib after the first dose was 57 and 112 ng/mL, respectively. With subsequent doses, mean maximum 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 of 1.3 mg/m² in 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 maximum plasma concentration (Cmax) after subcutaneous administration (20.4 ng/mL) was lower than after intravenous administration (223 ng/mL). The geometric mean ratio of AUClast was 0.99, with a 90% confidence interval of 80.18–122.80%.
Distribution. The mean volume of distribution (Vd) of bortezomib ranges from 1659 to 3294 liters following single or multiple doses of 1.0 or 1.3 mg/m² in patients with multiple myeloma, indicating extensive distribution into peripheral tissues. At bortezomib concentrations of 0.01–1.0 µg/mL, plasma protein binding is 83%. The fraction of bortezomib bound to plasma proteins is independent of concentration.
Metabolism. In vitro, bortezomib metabolism is primarily mediated by cytochrome P450 enzymes, including CYP3A4, CYP2C19, and CYP1A2. The main metabolic pathway involves deboronation to two metabolites, which are subsequently hydroxylated into other metabolites. The deboronated metabolites 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/hour after the first dose of 1.0 and 1.3 mg/m², respectively, and ranged from 15 to 32 L/hour and 18 to 32 L/hour after subsequent doses of 1.0 and 1.3 mg/m², respectively.
Special patient groups.
Hepatic impairment. The effect of hepatic impairment on the pharmacokinetics of bortezomib was evaluated in a Phase I study during the first treatment cycle involving 60 patients, primarily with solid tumors, and varying degrees of hepatic dysfunction; bortezomib doses ranged from 0.5 to 1.3 mg/m².
Mild hepatic impairment did not alter bortezomib AUC compared to normal hepatic function. Mean AUC values of bortezomib increased by approximately 60% in patients with moderate to severe hepatic impairment. Dose adjustment and careful monitoring during treatment are recommended for these patients.
Renal impairment. Pharmacokinetic studies were conducted in patients with varying degrees of renal function, categorized by creatinine clearance (CrCl) into the following groups: normal (CrCl ≥ 60 mL/min/1.73m², n = 12), mild impairment (CrCl = 40–59 mL/min/1.73m², n = 10), moderate impairment (CrCl = 20–39 mL/min/1.73m², n = 9), and severe impairment (CrCl < 20 mL/min/1.73m², n = 3). Patients on dialysis who received bortezomib post-dialysis were also included in the study (n = 8). Patients received intravenous bortezomib doses of 0.7–1.3 mg/m² twice weekly. Bortezomib exposure (dose-normalized AUC and Cmax) was comparable across all groups.
Age. Pharmacokinetic parameters of bortezomib were evaluated in 104 pediatric patients (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/hour/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, adjusted for body surface area, were comparable between pediatric and adult patients.
Clinical characteristics.
Indications.
- Multiple myeloma, in combination therapy with melphalan and prednisone, for treatment of previously untreated patients who are not eligible for high-dose chemotherapy with hematopoietic stem cell transplantation (first-line therapy).
- Relapsed multiple myeloma, as monotherapy or in combination therapy with pegylated liposomal doxorubicin or dexamethasone, for treatment of patients who have received at least one prior therapy line and who have undergone hematopoietic stem cell transplantation or are not candidates for transplantation (second-line therapy).
- Multiple myeloma, in combination therapy with dexamethasone or dexamethasone and thalidomide, for treatment of previously untreated patients who are candidates for high-dose chemotherapy with hematopoietic stem cell transplantation (induction therapy).
- Mantle cell lymphoma, in combination therapy with rituximab, cyclophosphamide, doxorubicin, and prednisone, for treatment of previously untreated patients who are not candidates for hematopoietic stem cell transplantation.
Contraindications.
Hypersensitivity to bortezomib, boron, or any of the excipients of the medicinal product.
Acute diffuse infiltrative pulmonary and pericardial diseases.
When bortezomib is used in combination with other medicinal products, refer to the respective instructions for medical use of these products for additional contraindications.
Special safety precautions.
General warnings. BortezoVista is a cytotoxic medicinal product. Therefore, caution must be exercised during its reconstitution and administration. Use of gloves and protective clothing is recommended to prevent skin contact. Appropriate aseptic techniques must be strictly followed when handling BortezoVista, as the product contains no preservatives.
Fatal outcomes have been reported following accidental intrathecal administration of BortezoVista. The medicinal product must be administered only intravenously or subcutaneously. DO NOT ADMINISTER INTRATHECALLY.
Instructions for solution preparation. Solution reconstitution must be performed only by qualified healthcare personnel.
For intravenous administration, prior to use, the contents of the vial should be carefully reconstituted with 2.5 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 absence of particles and discoloration prior to administration. Do not use the solution if particles are present or if discoloration occurs.
For subcutaneous administration, prior to use, the contents of one vial should be carefully reconstituted with 1 mL of 0.9% sodium chloride injection solution using a syringe of appropriate size, without removing the rubber stopper from the vial. The reconstitution process takes 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 absence of particles and discoloration prior to administration. Do not use the solution if particles are present or if discoloration occurs.
Disposal of unused or expired medicinal product.
For single use only. Environmental contamination should be minimized. The medicinal product must not be disposed of via wastewater or household waste. A "waste collection system" should be used if available. Any unused medicinal products or waste materials must be disposed of in accordance with local requirements.
Interaction with other medicinal products and other 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 distribution are not expected in poor metabolizers of this enzyme.
Drug interaction studies assessing the effect of ketoconazole, a strong 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 receiving bortezomib concomitantly with strong CYP3A4 inhibitors (such as ketoconazole, ritonavir) is recommended.
A study evaluating the effect of omeprazole, a strong CYP2C19 inhibitor, on the pharmacokinetics of bortezomib (after intravenous administration) in 17 patients showed no significant impact on bortezomib pharmacokinetics. In a study involving 6 patients, rifampicin, a strong CYP3A4 inducer, was shown to reduce the AUC of bortezomib (after intravenous administration) by an average of 45%. Therefore, concomitant use of bortezomib with strong CYP3A4 inducers (such as rifampicin, carbamazepine, phenytoin, phenobarbital, and St. John’s wort extract) is not recommended, as the efficacy of bortezomib may be reduced.
In the same study, dexamethasone, a weak CYP3A4 inducer, did not significantly alter the pharmacokinetics of bortezomib, as evidenced by data from 7 patients.
Drug interaction studies assessing the effects 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 hypoglycemic agents. Patients receiving oral antidiabetic medicinal products should monitor their blood glucose levels during treatment with BortezoVista and adjust the dose of antidiabetic agents accordingly.
Special precautions for use.
If BortezoVist is used in combination with other medicinal products, the instructions for medical use of these products should be consulted prior to initiating treatment. If thalidomide is used, special attention should be paid to pregnancy diagnosis and contraceptive measures.
Intrathecal administration. Fatal cases due to accidental intrathecal administration of bortezomib have been reported. BortezoVist must be administered only intravenously or subcutaneously. DO NOT ADMINISTER INTRATHECALLY.
Gastrointestinal complications. Treatment with bortezomib very commonly causes gastrointestinal toxicity, including nausea, diarrhea, constipation, and vomiting. Cases of intestinal obstruction (reported as uncommon) have been observed; 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 with rituximab, cyclophosphamide, doxorubicin, and prednisone (VcR-CAP regimen) in previously untreated mantle cell lymphoma patients, reversible thrombocytopenia was one of the most common hematological toxicities. Platelet counts typically reached their lowest level on day 11 of each bortezomib treatment cycle and returned to baseline before the start of the next cycle. Cumulative thrombocytopenia was not observed. On average, the lowest measured platelet count was approximately 40% of the baseline level in trials of bortezomib monotherapy in multiple myeloma patients and 50% in trials of bortezomib in mantle cell lymphoma patients. In patients with progressive myeloma, the severity of thrombocytopenia was related to baseline platelet counts: in 90% of 21 patients with baseline platelet counts < 75,000/µL, platelet counts were ≤ 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 ≤ 25,000/µL.
In patients with mantle cell lymphoma, grade ≥3 thrombocytopenia occurred more frequently in the group receiving bortezomib (VcR-CAP) than in those receiving R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). The overall incidence of bleeding events of all grades, as well as bleeding events of at least grade 3, was similar in both groups. In the VcR-CAP treatment group, 22.5% of patients required platelet transfusion compared to 2.9% in the R-CHOP group. Cases of gastrointestinal and intracranial hemorrhage associated with bortezomib use have been reported. Therefore, platelet counts should be monitored before each dose of BortezoVist. Bortezomib therapy should be withheld if platelet counts decrease to < 25,000/µL during monotherapy or to ≤ 30,000/µL when used in combination with melphalan and prednisone. The benefit-risk ratio of BortezoVist treatment should be carefully evaluated, especially in cases of moderate or severe thrombocytopenia and in the presence of bleeding risk factors. Complete blood counts, including leukocyte differential and platelet counts, should be frequently performed during BortezoVist therapy. Platelet transfusion should be considered if clinically indicated.
In patients with mantle cell lymphoma, reversible neutropenia between treatment cycles has been observed; cumulative neutropenia was not observed. Leukocyte counts typically reached their lowest level on day 11 of each cycle and returned to baseline before the start of the next cycle. In a clinical trial of bortezomib in mantle cell lymphoma patients, 78% of patients in the VcR-CAP group and 61% in the R-CHOP group received granulocyte colony-stimulating factor. Since patients with neutropenia have an 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. Antiviral prophylaxis should be considered for patients receiving bortezomib. In a phase III trial in previously untreated multiple myeloma patients, the overall incidence of Herpes zoster reactivation (shingles) was higher in the group receiving bortezomib + melphalan + prednisone (14%) compared to the melphalan + prednisone group (4%).
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).
Before initiating treatment with rituximab in combination with bortezomib, HBV testing should be performed in patients with risk factors. HBV carriers and patients with a history of hepatitis B should be closely monitored for clinical signs and laboratory parameters during and after combination therapy with rituximab and bortezomib. Antiviral prophylaxis should also be considered.
Progressive multifocal leukoencephalopathy (PML). Very rare cases of infection with John Cunningham virus leading to PML with fatal outcome have been reported in patients treated with bortezomib. Patients diagnosed with PML had previously or concurrently received immunosuppressive therapy with bortezomib. Most PML cases were diagnosed within the first 12 months of starting bortezomib treatment. Patients should be regularly monitored for new or worsening neurological symptoms that may indicate PML, which should be considered in the differential diagnosis of central nervous system (CNS) disorders. If PML is suspected, patients should be referred to a physician experienced in PML management and appropriate diagnostic evaluation initiated. Bortezomib treatment should be discontinued if PML is confirmed.
Peripheral neuropathy (PN). Treatment with bortezomib is very commonly associated with peripheral neuropathy, predominantly sensory. However, cases of severe motor neuropathy, with or without sensory peripheral neuropathy, have been reported. The incidence of peripheral neuropathy typically peaks during the fifth treatment cycle.
Careful monitoring of patients for neuropathic symptoms such as burning sensations, 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. If peripheral neuropathy develops or worsens, patients should undergo neurological evaluation; dose adjustment, schedule modification, or switching to subcutaneous administration may be necessary. Neuropathy should be managed with supportive measures. Regular monitoring for treatment-induced neuropathy symptoms and neurological assessment are required, especially in patients receiving bortezomib in combination with neurotoxic agents (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 orthostatic 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. Extreme caution is required when treating patients with risk factors for seizures.
Hypotension. Bortezomib therapy is frequently associated with postural/orthostatic 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, and a smaller number experienced syncope. Orthostatic/postural hypotension was not clearly linked to bolus infusion of bortezomib; the mechanism is unknown but may be related to autonomic neuropathy. Autonomic neuropathy may be caused by bortezomib or may be exacerbated by underlying conditions such as diabetic or amyloid neuropathy. Caution is advised when treating patients with a history of syncope, those taking antihypertensive drugs, and those with dehydration due to diarrhea or vomiting. Management of orthostatic hypotension may include hydration, glucocorticoids, and/or sympathomimetics; antihypertensive drug doses should be reduced if necessary. Patients should be instructed to seek medical attention if they experience dizziness, presyncope, or loss of consciousness.
Reversible posterior leukoencephalopathy syndrome (PRES). Cases of PRES have been reported in patients treated with bortezomib. PRES is a rare reversible neurological disorder characterized by seizures, hypertension, headache, lethargy, confusion, visual disturbances, and other neurological symptoms. Brain imaging, preferably MRI, is required for diagnosis. BortezoVist treatment should be discontinued if PRES occurs.
Heart failure. Cases of development or worsening of pre-existing congestive heart failure and/or reduced left ventricular ejection fraction have been reported with bortezomib use. Fluid retention may contribute to the development of signs and symptoms of heart failure. Patients with risk factors or pre-existing cardiac conditions should be closely monitored.
ECG parameters. Isolated cases of QT interval prolongation have been observed in clinical trials. The cause has not been established.
Lung function disorders. Rare cases of acute diffuse infiltrative lung diseases of unknown etiology, such as pneumonitis, interstitial pneumonia, pulmonary infiltration, and acute respiratory distress syndrome (ARDS), have been reported in patients receiving bortezomib. Some of these cases were fatal. Chest X-ray before treatment initiation is recommended to establish baseline lung status for comparison in case of potential treatment-related lung dysfunction.
In the event of new or worsening pulmonary symptoms (e.g., cough, dyspnea), prompt diagnosis and appropriate therapeutic measures should be initiated. The benefit-risk ratio of continuing the drug should be carefully evaluated. In clinical trials, two out of two patients receiving high-dose cytarabine (2 g/m²/day) as continuous 24-hour infusion with daunorubicin and bortezomib for relapsed acute myeloid leukemia died from ARDS early in the treatment course. 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 common in patients with multiple myeloma. Close monitoring of such patients is recommended.
Hepatic function disorders. Bortezomib is metabolized by hepatic enzymes. In patients with moderate to severe hepatic impairment, bortezomib concentrations may increase. These patients should receive reduced doses and be closely monitored for signs of toxicity.
Hepatic reactions. Rare cases of acute liver failure have been reported in patients receiving bortezomib concomitantly with other medicinal products and in patients with serious underlying medical conditions. Cases of elevated liver enzymes, hyperbilirubinemia, and hepatitis, which resolved after bortezomib discontinuation, have also been reported.
Tumor lysis syndrome. Because bortezomib is a cytotoxic agent capable of rapidly killing tumor plasma cells, there is a risk of complications associated with tumor lysis syndrome. Patients with high tumor burden prior to treatment initiation are at particular risk. Close monitoring of such patients and implementation of necessary preventive measures are recommended.
Precautions regarding concomitant use of other medicinal products. Patients should be under close medical supervision when bortezomib is used with strong CYP3A4 inhibitors. Caution is advised when combining bortezomib with CYP3A4 or CYP2C9 substrates.
Hepatic function should be corrected if impaired prior to starting bortezomib therapy, and caution is advised when administering drugs to patients taking oral hypoglycemic agents.
Potentially immune complex-mediated reactions. Immune complex-mediated reactions such as serum sickness, polyarthritis with rash, and proliferative glomerulonephritis have been reported uncommonly. Bortezomib should be discontinued if serious reactions occur.
Use during pregnancy or breastfeeding.
Contraception in men and women.
Men and women of reproductive potential must use effective contraception during treatment and for 3 months after treatment completion.
Pregnancy.
There are no clinical data on the use of bortezomib in pregnant women. The teratogenic potential of bortezomib has not been fully investigated.
In preclinical studies, bortezomib at maximally tolerated doses did not affect embryonic development in animals during organogenesis. Pre- and postnatal developmental studies in animals have not been conducted. BortezoVist is not recommended during pregnancy except when the patient's clinical condition requires its use. 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 period.
It is unknown whether bortezomib is excreted in human milk, but to prevent the development of severe adverse effects in the infant, breastfeeding is not recommended during bortezomib treatment.
Fertility.
Studies on the effect of bortezomib on fertility have not been conducted.
Ability to affect reaction speed when driving or operating machinery.
Bortezomib has a moderate effect on reaction speed when driving or operating machinery. The use of the medicinal product is very commonly associated with fatigue, frequently with dizziness, orthostatic/postural hypotension, or visual disturbances, and uncommonly with syncope. Therefore, patients should be cautious when driving or operating machinery and should avoid such activities if these symptoms occur.
Method of 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 by qualified medical personnel only.
Relapsed multiple myeloma (patients who have received at least one prior therapy line).
Monotherapy
The recommended dose of bortezomib for adults is 1.3 mg/m² body surface area administered either intravenously or subcutaneously twice weekly for 2 weeks (on days 1, 4, 8, and 11), followed by a 10-day rest period (days 12–21). This 3-week period constitutes one treatment cycle. Upon achieving a complete clinical response, administration of two additional treatment cycles is recommended. Patients achieving a partial response but not a complete remission should continue bortezomib therapy for up to a maximum of eight cycles. At least 72 hours should elapse between consecutive bortezomib doses.
Recommendations for dose adjustment and resumption of Bortezovista administration as monotherapy
In the event of any grade 3 non-hematological toxicity or grade 4 hematological toxicity (excluding neuropathy), bortezomib treatment must be interrupted. After resolution of toxic symptoms, treatment may be resumed at a dose reduced by 25% (reduce dose from 1.3 mg/m² to 1.0 mg/m²; reduce dose from 1.0 mg/m² to 0.7 mg/m²). If toxic symptoms do not resolve or recur during treatment with the reduced dose, discontinuation of bortezomib should be considered, unless the benefits of continued therapy outweigh the risks.
Neuropathic pain and/or peripheral neuropathy
The drug dosage should be adjusted in case of development of neuropathic pain and/or peripheral neuropathy (see Table 1). Bortezomib should be administered to patients with a history of severe neuropathy only after careful benefit-risk assessment.
Table 1
Recommended* dose modification for bortezomib-induced neuropathy.
| Severity of neuropathy |
Dose and administration frequency adjustment |
| Grade I (asymptomatic; loss of deep tendon reflexes or paresthesia) without pain or functional loss |
Dose and administration schedule do not require modification |
| Grade I with pain or Grade II (moderately severe symptoms; limitation of instrumental activities of daily living)** |
Reduce dose to 1 mg/m² or change bortezomib administration schedule to 1.3 mg/m² once weekly |
| Grade II with pain or Grade III (severe symptoms; limitation of self-care activities)*** |
Withhold bortezomib until resolution of toxic symptoms. After recovery, 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 treatment |
* 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.
*** Self-care activities include bathing, dressing/undressing, eating, using the toilet, taking medication, being out of bed, etc.
Combination therapy with pegylated liposomal doxorubicin.
The recommended dose of bortezomib for adults is 1.3 mg/m² body surface area administered intravenously or subcutaneously twice weekly for 2 weeks (Days 1, 4, 8, and 11), followed by a 10-day rest period (Days 12–21). This 3-week period is considered 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 bortezomib injection.
Up to eight cycles of this combination therapy should be administered, provided the disease does not progress and patients tolerate the treatment well. Patients who achieve a complete remission may continue treatment for at least two additional cycles after achieving complete response, even if this requires more than eight cycles. Patients whose paraprotein levels continue to decrease after eight cycles may also continue treatment as long as the therapy is well tolerated and a response is observed.
Combination therapy with dexamethasone.
The recommended dose of bortezomib is 1.3 mg/m² body surface area administered intravenously or subcutaneously twice weekly for 2 weeks (Days 1, 4, 8, and 11), followed by a 10-day rest period (Days 12–21). This 3-week period is considered one treatment cycle. At least 72 hours should elapse between consecutive doses of Bortezomib Vist.
Dexamethasone is administered orally at a dose of 20 mg on Days 1, 2, 4, 5, 8, 9, 11, and 12 of the Bortezomib Vist treatment cycle.
Patients who show a response to treatment or stable disease after four cycles may continue this combination for up to four additional cycles. For further information on dexamethasone, refer to the medical instructions for use of this medicinal product. Dose modification recommendations for combination therapy in patients with relapsed multiple myeloma.
See the dose modification recommendations for bortezomib monotherapy provided above. Newly diagnosed multiple myeloma in patients not eligible for hematopoietic stem cell transplantation.
Combination therapy with melphalan and prednisone.
Bortezomib Vist must be administered intravenously or subcutaneously in combination with oral melphalan and oral prednisone over nine 6-week treatment cycles (see Table 2). In Cycles 1–4, the drug is administered twice weekly (Days 1, 4, 8, 11, 22, 25, 29, and 32). In Cycles 5–9, the medicinal product is administered once weekly (Days 1, 8, 22, and 29). At least 72 hours should elapse between consecutive doses of the drug.
Melphalan and prednisone are administered orally on Days 1–4 of the first week of each cycle.
Table 2
Recommended dosing regimen of bortezomib in combination with melphalan and prednisone.
| Bortezomib twice weekly (cycles 1–4) |
||||||||||||||||||||
| Week |
1 |
2 |
3 |
4 |
5 |
6 |
||||||||||||||
| Bortezomib (1.3 mg/m²) |
Day 1 |
-- |
-- |
Day 4 |
Day 8 |
Day 11 |
Break |
Day 22 |
Day 25 |
Day 29 |
Day 32 |
Break |
||||||||
| M (9 mg/m²) P (60 mg/m²) |
Day 1 |
Day 2 |
Day 3 |
Day 4 |
-- |
-- |
Break |
-- |
-- |
-- |
-- |
Break |
||||||||
| Bortezomib once weekly (cycles 5–9) |
||||||||||||||||||||
| Week |
1 |
2 |
3 |
4 |
5 |
6 |
||||||||||||||
| Bortezomib (1.3 mg/m²) |
Day 1 |
-- |
-- |
-- |
Day 8 |
Break |
Day 22 |
Day 29 |
Break |
|||||||||||
| M (9 mg/m²) P (60 mg/m²) |
Day 1 |
Day 2 |
Day 3 |
Day 4 |
-- |
Break |
-- |
-- |
Break |
|||||||||||
M — melphalan, P — prednisone.
Recommendations for dose adjustment and resumption of combination therapy with melphalan and prednisone.
Prior to starting a new treatment cycle:
- platelet count must be ≥ 70×109/l, absolute neutrophil count must be ≥ 1.0×109/l,
- non-hematological toxicity must have resolved to Grade 1 or baseline level.
Table 3
Dose adjustment during subsequent cycles of bortezomib therapy in combination with melphalan and prednisone.
| Toxicity |
Dose modification or treatment discontinuation |
| Hematologic toxicity during cycle:
|
Consider reducing melphalan dose by 25% in the next cycle |
≤ 30 × 109/L or absolute neutrophil count ≤ 0.75 × 109/L on the day of bortezomib administration (except day 1) |
Delay bortezomib dose administration |
|
Bortezomib dose should be reduced by one level (from 1.3 to 1 mg/m2 or from 1 to 0.7 mg/m2) |
| Non-hematologic toxicity ≥ grade III. |
Treatment with BortezoVista should be withheld until symptoms improve to baseline or grade I severity. BortezoVista may then be restarted at a reduced dose by one level (from 1.3 mg/m2 to 1 mg/m2 or from 1 mg/m2 to 0.7 mg/m2). For neuropathic pain and/or peripheral neuropathy occurring after bortezomib administration, bortezomib should be withheld or dose modified as specified in Table 1. |
For additional information on melphalan and prednisone, please refer to the package leaflets of these medicinal products.
Untreated multiple myeloma in patients eligible for hematopoietic stem cell transplantation (induction therapy).
Combination therapy with dexamethasone.
The recommended dose of BortezoVist is 1.3 mg/m² body surface area administered intravenously or subcutaneously twice weekly for 2 weeks (on days 1, 4, 8, and 11), followed by a 10-day treatment break (days 12–21). This 3-week period constitutes one treatment cycle. At least 72 hours should elapse between consecutive doses of BortezoVist.
Dexamethasone is administered orally at a dose of 40 mg on days 1, 2, 3, 4, 8, 9, 10, and 11 of the BortezoVist treatment cycle.
Administer 4 treatment cycles of this combination.
Combination therapy with dexamethasone and thalidomide.
The recommended dose of BortezoVist is 1.3 mg/m² body surface area administered intravenously or subcutaneously twice weekly for 2 weeks (on days 1, 4, 8, and 11), followed by a 17-day treatment break (days 12–28). This 4-week period constitutes one treatment cycle. At least 72 hours should elapse between consecutive doses of BortezoVist.
Dexamethasone is administered orally at a dose of 40 mg on days 1, 2, 3, 4, 8, 9, 10, and 11 of the BortezoVist treatment cycle.
Thalidomide is administered orally at a dose of 50 mg daily on days 1–14 of the cycle. If the medicinal product is well tolerated, the dose should be increased to 100 mg daily on days 15–28. 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.
Table 4
Recommended dosing regimen of bortezomib in combination with dexamethasone and thalidomide for patients with untreated multiple myeloma eligible for hematopoietic stem cell transplantation.
| Bortezomib + Dx |
Cycles 1–4 |
||||||
| Week |
1 |
2 |
3 |
||||
| Bortezomib (1.3 mg/m²) |
day 1, 4 |
day 8, 11 |
break |
||||
| Dx (40 mg) |
day 1, 2, 3, 4 |
day 8, 9, 10, 11 |
- |
||||
| Bortezomib + Dx + T |
Cycle 1 |
||||||
| Week |
1 |
2 |
3 |
4 |
|||
| Bortezomib (1.3 mg/m²) |
day 1, 4 |
day 8, 11 |
break |
break |
|||
| T (50 mg) |
daily |
daily |
- |
- |
|||
| T (100 mg)ᵃ |
- |
- |
daily |
daily |
|||
| Dx (40 mg) |
day 1, 2, 3, 4 |
day 8, 9, 10, 11 |
- |
- |
|||
| Cycles 2–4ᵇ |
|||||||
| Bortezomib (1.3 mg/m²) |
day 1, 4 |
day 8, 11 |
break |
break |
|||
| T (200 mg)ᵃ |
daily |
daily |
daily |
daily |
|||
| Dx (40 mg) |
day 1, 2, 3, 4 |
day 8, 9, 10, 11 |
- |
- |
|||
Dx — dexamethasone; Th — thalidomide.
a Increase thalidomide dose to 100 mg from week 3 of cycle 1 if the 50 mg dose is tolerated, and to 200 mg if the 100 mg dose is tolerated.
b Patients who achieve a partial response after four cycles of treatment may receive up to six cycles of treatment.
Dosing recommendations for patients eligible for transplantation.
For dose adjustment in case of neuropathy, see Table 1.
If VELCADE is to be used in combination with other chemotherapeutic agents, refer to the prescribing information for those medicinal products 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 VELCADE is 1.3 mg/m² body surface area administered intravenously or subcutaneously twice weekly for two weeks (days 1, 4, 8, and 11), followed by a 10-day rest period (days 12–21). This 3-week period constitutes one treatment cycle. At least 72 hours must elapse between consecutive doses of VELCADE. Administer six treatment cycles. Patients who first demonstrate response to treatment during the sixth treatment cycle are recommended to receive two additional cycles of therapy.
Medicinal products administered by intravenous infusion on day 1 of each 3-week VELCADE treatment cycle: rituximab at 375 mg/m², cyclophosphamide at 750 mg/m², doxorubicin at 50 mg/m².
Prednisone is administered orally at 100 mg/m² on days 1, 2, 3, 4, and 5 of each VELCADE 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; 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 VELCADE should be withheld in the event of any non-hematologic toxicity ≥ grade III (except neuropathy) related to VELCADE 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 for the management of thrombocytopenia.
Table 5
Dose adjustment during therapy for patients with untreated mantle cell lymphoma.
| Toxicity |
Dose modification or treatment interruption |
| Haematological toxicity |
|
| Grade ≥ III neutropenia associated with fever, grade IV neutropenia lasting more than 7 days, platelet count ˂ 10,000/µL. |
Treatment with BortezoVista should be withheld for up to 2 weeks until the absolute neutrophil count recovers to ≥ 750/µL and platelet count to ≥ 25,000/µL. If toxicity does not improve (blood counts do not recover to the values indicated above), BortezoVista should be discontinued. If toxicity improves (absolute neutrophil count recovers to ≥ 750/µL and platelet count to ≥ 25,000/µL), treatment with BortezoVista may be resumed at a reduced dose level (from 1.3 to 1 mg/m² or from 1 to 0.7 mg/m²). |
| If platelet count is ˂ 25,000/µL or absolute neutrophil count is ˂ 750/µL on the day of BortezoVista administration (except on day 1 of each treatment cycle). |
Delay administration of the BortezoVista dose. |
| Non-haematological toxicity ≥ grade III related to BortezoVista. |
Treatment with BortezoVista should be withheld until symptoms improve to grade II severity or better. BortezoVista may then be restarted at a reduced dose level (from 1.3 to 1 mg/m² or from 1 to 0.7 mg/m²). For BortezoVista-induced neuropathic pain and/or peripheral neuropathy, dose interruption or modification should be performed as specified in Table 1. |
If BortezoVist is used in combination with other chemotherapeutic agents, also refer to the instructions for use of these medicinal products regarding dose adjustments in the event of toxicity.
Special patient groups.
Elderly patients.
Currently, there are no data indicating the need for dose adjustment in patients aged 65 years and older.
There are no studies on the use of bortezomib in elderly patients with untreated multiple myeloma who are planned to receive 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 ≥75 years. Patients aged 75 years and older tolerated treatment less well in both treatment groups (VcR-CAP and R-CHOP regimens).
Patients with hepatic impairment.
Dose adjustment is not required for patients with mild hepatic impairment. For patients with moderate to severe hepatic impairment, treatment with BortezoVist should be initiated at a dose of 0.7 mg/m² during the first treatment cycle, with subsequent gradual dose escalation to 1.0 mg/m² or dose reduction to 0.5 mg/m², depending on the patient's tolerance to the medicinal product.
Table 6
Recommendations for initial dose adjustments of BortezoVist in patients with hepatic impairment.
| 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 dose of BortezoVist to 0.7 mg/m² in the first treatment cycle. Further dose escalation to 1.0 mg/m² or dose reduction to 0.5 mg/m² depending on drug tolerability. |
| Severe |
> 3 × ULN |
any |
AST — aspartate aminotransferase; ULN — upper limit of normal.
* Based on the classification of severity of liver dysfunction (mild, moderate, and severe) by the National Cancer Institute Organ Dysfunction Working Group [USA].
Patients with renal impairment.
Mild to moderate renal impairment (CrCL > 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 (CrCL < 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.
BortezoVist is administered by intravenous or subcutaneous injection. Accidental intrathecal administration of the drug has resulted in fatal outcomes.
Intravenous.
The reconstituted solution should be administered immediately after preparation as a 3–5 second intravenous bolus injection through a peripheral or central venous catheter, which should be flushed with 0.9% sodium chloride injection solution after administration. At least 72 hours must elapse between consecutive doses of BortezoVist.
Subcutaneous.
The reconstituted solution should be administered immediately after preparation by subcutaneous injection at a 45–90° angle, selecting injection sites on the thighs (left or right) or abdomen (left or right). Injection sites should be rotated.
If adverse reactions at the injection site occur following subcutaneous injections, the BortezoVist solution may be administered subcutaneously at a lower concentration (1 mg/mL instead of 2.5 mg/mL) or administered intravenously.
Children.
The safety and efficacy of BortezoVist in children (under 18 years of age) have not been established. Current data are insufficient to provide dosing recommendations for pediatric patients.
Overdose.
Symptoms. In patients, exceeding the recommended dose by more than twice has been associated with acute hypotension and thrombocytopenia resulting in fatal outcomes.
Treatment. There is no specific antidote for bortezomib. In case of overdose, careful monitoring of hemodynamic parameters (infusion therapy, vasopressors and/or inotropic agents) and body temperature is recommended.
Adverse Reactions
Serious adverse reactions rarely reported during bortezomib treatment include heart failure, tumor lysis syndrome, pulmonary hypertension, reversible posterior leukoencephalopathy syndrome (PRES), acute diffuse infiltrative pulmonary disorders, and, rarely, autonomic neuropathy. The most commonly reported adverse reactions during bortezomib therapy are nausea, diarrhea, constipation, vomiting, asthenia, pyrexia, thrombocytopenia, anemia, neutropenia, peripheral neuropathy (including sensory neuropathy), headache, paresthesia, decreased appetite, dyspnea, rash, herpes zoster, and myalgia.
Multiple Myeloma
The adverse reactions listed in Table 7 are considered possibly related to bortezomib administration. Data on these adverse reactions were obtained from 5,476 patients, of whom 3,996 received bortezomib at a dose of 1.3 mg/m². Overall, bortezomib was administered to 3,974 patients for the treatment of multiple myeloma. Adverse reactions are categorized by system organ class and frequency of occurrence. Frequencies were defined as: very common (> 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), and not known (cannot be estimated from available data). Within each category, adverse reactions are listed in decreasing order of severity. Also included are adverse reactions not observed during clinical studies but reported in the post-marketing period.
Table 7
| Organ systems |
Frequency |
Adverse reaction |
| Infections and infestations |
Common |
Herpes zoster (including disseminated and with ocular complications), pneumonia*, herpes simplex*, fungal infection* |
| Uncommon |
Infections*, bacterial infections*, viral infections*, sepsis (including septic shock)*, bronchopneumonia, herpesvirus infection*, herpetic meningoencephalitis#, bacteremia (including staphylococcal), hordeolum, influenza, cellulitis, device-related infections, skin infections*, ear infections*, staphylococcal infection, dental infection* |
|
| Rare |
Meningitis (including bacterial), Epstein-Barr virus infection, genital herpes, tonsillitis, mastoiditis, post-viral fatigue syndrome |
|
| Benign, malignant and unspecified neoplasms (including cysts and polyps) |
Rare |
Malignant neoplasm, plasma cell leukemia, renal cell carcinoma, tumor proliferation, mycosis fungoides, benign neoplasm* |
| Blood and lymphatic system disorders |
Very common |
Thrombocytopenia*, neutropenia*, anemia* |
| Common |
Leukopenia*, lymphopenia* |
|
| Uncommon |
Pancytopenia*, febrile neutropenia, coagulopathy*, leukocytosis*, lymphadenopathy, hemolytic anemia# |
|
| Rare |
Disseminated intravascular coagulation syndrome, thrombocytosis*, hyperviscosity syndrome, thrombopathy, thrombotic microangiopathy (including thrombotic purpura), other blood and hematopoietic disorders, hemorrhagic diathesis, lymphocytic infiltration |
|
| Immune system disorders |
Uncommon |
Angioedema#, hypersensitivity* |
| Rare |
Anaphylactic shock, amyloidosis, type III immune complex-mediated reactions |
|
| Endocrine system 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 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 and sensation disorders*, anxiety disorder*, sleep disorders* |
| Uncommon |
Psychiatric disorder*, hallucinations*, psychotic disorder*, confusion*, agitation |
|
| Rare |
Suicidal ideation*, adjustment disorder, delirium, decreased libido |
|
| Nervous system disorders |
Very common |
Neuropathies*, peripheral sensory neuropathy, dysesthesia*, neuralgia* |
| Common |
Motor neuropathy*, loss of consciousness (including syncope), dizziness*, dysgeusia*, lethargy, headache* |
|
| Uncommon |
Tremor, sensorimotor peripheral neuropathy, dyskinesia*, coordination and balance disturbances*, memory loss (without dementia)*, encephalopathy*, reversible posterior encephalopathy syndrome#, neurotoxicity, seizure disorders*, postherpetic neuralgia, speech disorders*, restless legs syndrome, migraine, sciatica, attention disorders, reflex disturbances*, parosmia |
|
| Rare |
Intracranial hemorrhage*, intracerebral hemorrhage (including subarachnoid)*, brain edema, transient ischemic attack, coma, autonomic nervous system disturbances, autonomic neuropathy, cranial nerve paralysis*, paralysis*, paresis*, presyncope, brainstem lesion syndrome, cerebrovascular disorder, nerve root damage, psychomotor hyperactivity, spinal cord compression, other cognitive disorders, motor dysfunctions, other nervous system disorders, radiculitis, salivation, hypotension, Guillain-Barré syndrome#, demyelinating polyneuropathy# |
|
| Eye disorders |
Common |
Eye 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) diseases, acquired dacryoadenitis, photophobia, photopsia, optic neuropathy#, varying degrees of visual deterioration (up to blindness)* |
|
| Ear and labyrinth disorders |
Common |
Vertigo* |
| Uncommon |
Dysacusis (including tinnitus)*, hearing loss (up to deafness), ear discomfort* |
|
| Rare |
Ear hemorrhage, vestibular neuronitis, other ear disorders |
|
| Cardiac disorders |
Uncommon |
Cardiac tamponade#, cardiopulmonary shock*, cardiac fibrillation (including atrial), heart failure (including left and right ventricular)*, arrhythmia*, tachycardia*, palpitations, angina pectoris, pericarditis (including pericardial effusion), cardiomyopathy*, ventricular dysfunction*, bradycardia |
| Rare |
Atrial flutter, myocardial infarction*, atrioventricular block*, cardiovascular disorders (including cardiogenic shock), fluttering/palpitations, unstable angina, heart valve disorders*, coronary artery insufficiency, sinus node arrest |
|
| Vascular disorders |
Common |
Hypotension*, orthostatic hypotension, hypertension* |
| Uncommon |
Cerebrovascular disorder#, deep vein thrombosis*, hemorrhage*, thrombophlebitis (including superficial), vascular collapse (including hypovolemic shock), phlebitis, flushing*, hematoma (including paranephric)*, peripheral circulation disturbances*, vasculitis, hyperemia (including ocular)* |
|
| Rare |
Peripheral vascular embolism, lymphedema, pallor, erythromelalgia, vessel dilation, vessel discoloration, venous insufficiency |
|
| Respiratory, thoracic and mediastinal disorders |
Common |
Dyspnea*, epistaxis, lower/upper respiratory tract infections*, cough* |
| Uncommon |
Pulmonary embolism, pleural effusion, pulmonary edema (including acute), pulmonary intra-alveolar hemorrhage#, bronchospasm, chronic obstructive pulmonary disease*, hypoxemia*, worsening of airway patency*, hypoxia, pleuritis*, hiccups, rhinorrhea, dysphonia, wheezing |
|
| Rare |
Lung failure, acute respiratory distress syndrome, apnea, pneumothorax, lung collapse, pulmonary hypertension, hemoptysis, pulmonary hyperventilation, orthopnea, pneumonitis, respiratory alkalosis, tachypnea, lung fibrosis, bronchial disorders*, hypocapnia*, interstitial pneumonia, lung infiltration, throat tightness, dry throat, increased upper respiratory tract secretion, throat irritation, upper respiratory tract cough syndrome |
|
| Gastrointestinal disorders |
Very common |
Nausea and vomiting*, diarrhea*, constipation |
| Common |
Gastrointestinal hemorrhage (including mucosal)*, dyspepsia, stomatitis*, abdominal distension, oropharyngeal pain*, abdominal pain (including gastrointestinal and splenic region)*, oral cavity disorders*, meteorism |
|
| Uncommon |
Pancreatitis (including chronic)*, vomiting with blood, lip swelling*, gastrointestinal obstruction (including small intestine obstruction, ileus)*, abdominal discomfort, oral ulcers*, enteritis*, gastritis*, gum bleeding, gastroesophageal reflux disease*, colitis (including Clostridium difficile-induced)*, ischemic colitis#, gastrointestinal inflammation*, dysphagia, irritable bowel syndrome, other gastrointestinal disorders, coated tongue, gastrointestinal motility 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 |
Changes in liver enzyme levels* |
| Uncommon |
Hepatotoxicity (including liver disorders), hepatitis*, cholestasis |
|
| Rare |
Liver failure, hepatomegaly, Budd-Chiari syndrome, cytomegalovirus hepatitis, hepatic hemorrhage, cholelithiasis |
|
| Skin and subcutaneous tissue disorders |
Common |
Rash*, pruritus*, erythema, dry skin |
| Uncommon |
Multiform erythema, urticaria, acute febrile neutrophilic dermatosis, toxic skin rashes, 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 disturbances*. |
|
| Rare |
Skin reactions, Jessner's lymphocytic infiltration, hand-foot erythrodysesthesia syndrome, subcutaneous hemorrhage, livedo reticularis, skin induration, papules, photosensitivity reactions, seborrhea, cold sweat, other skin disorders, erythrosis, skin ulcers, nail disorders. |
|
| Musculoskeletal and connective tissue disorders |
Very common |
Musculoskeletal pain*. |
| Common |
Muscle spasms*, limb pain, muscle weakness. |
|
| Uncommon |
Muscle twitching, joint swelling, arthritis*, joint stiffness, myopathies*, heaviness sensation. |
|
| Rare |
Rhabdomyolysis, temporomandibular joint dysfunction, fistula, joint effusion, jaw pain, bone disorders, infections and inflammations of musculoskeletal and connective tissue*, synovial cyst. |
|
| Renal and urinary disorders |
Common |
Renal failure*. |
| Uncommon |
Acute renal failure, chronic renal failure*, urinary tract infections*, signs and symptoms of urinary tract disorders*, hematuria*, urinary retention, micturition disorders*, proteinuria, azotemia, oliguria*, polyuria. |
|
| Rare |
Bladder irritation. |
|
| Reproductive system and breast disorders |
Uncommon |
Vaginal bleeding, genital pain*, erectile dysfunction. |
| Rare |
Testicular disorders*, prostatitis, breast disorders in women, epididymal tenderness, epididymitis, pelvic pain, vulvar ulcers. |
|
| Congenital, familial and genetic disorders |
Rare |
Aplasia, gastrointestinal tract malformations, ichthyosis. |
| General disorders and administration site reactions |
Very common |
Pyrexia*, fatigue, asthenia. |
| Common |
Edema (including peripheral), chills, pain*, fever*. |
|
| Uncommon |
General physical health disturbances*, 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*, injection-related pain*. |
|
| Rare |
Lethal outcome (including sudden), multiorgan failure, hemorrhage at injection site*, hernia (including hiatal)*, impaired healing*, inflammation, phlebitis at injection site*, pain, ulceration, irritation, non-cardiac substernal pain, catheter insertion site pain, foreign body sensation. |
|
| Investigations |
Common |
Weight loss. |
| Uncommon |
Hyperbilirubinemia*, deviation of protein levels from normal*, weight gain, blood test abnormalities*, increased C-reactive protein level. |
|
| Rare |
Blood gas abnormalities*, ECG abnormalities (including QT interval prolongation)*, international normalized ratio deviation*, increased gastric acidity, increased platelet aggregation, elevated troponin I level, virus identification in serological tests*, urine test abnormalities*. |
|
| Procedural complications |
Uncommon |
Falls, confusion. |
| Rare |
Transfusion reactions, fractures*, tremor*, facial injury, joint injury*, burns, skin laceration, procedural pain, radiation injuries*. |
|
| Surgical and medical procedures |
Rare |
Macrophage activation. |
*Grouping of two or more MedDRA terms [Medical Dictionary for Regulatory Activities].
#From post-marketing sources.
ªPatient deterioration — a general term defined as weight loss of more than 5%, decreased appetite, poor nutrition, and lack of physical activity, often associated with dehydration, depression, immune dysfunction, and low cholesterol levels. Patient deterioration is not a distinct disease or syndrome; rather, it represents nonspecific manifestations of an underlying physical, cognitive, or psychosocial condition.
Mantle cell lymphoma.
The safety profile of bortezomib in 240 patients with mantle cell lymphoma who received bortezomib at a dose of 1.3 mg/m² in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (VcR-CAP), and 242 patients who received rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), was generally similar to the safety profile observed in patients with multiple myeloma; the main differences are outlined below. Additional adverse reactions observed with bortezomib use as part of combination therapy (VcR-CAP) included hepatitis B virus infection (< 1%) and myocardial ischemia (1.3%). The similar incidence rates in both treatment groups suggest that these adverse reactions may not be solely related to bortezomib. Bortezomib use in patients with mantle cell lymphoma was associated with ≥ 5% higher frequencies of hematologic adverse reactions (neutropenia, thrombocytopenia, leukopenia, anemia, lymphopenia), peripheral sensory neuropathy, arterial hypertension, pyrexia, pneumonia, stomatitis, and hair disorders compared to its use in patients with multiple myeloma.
Adverse reactions occurring at a frequency ≥ 1%, with similar or higher frequency in the VcR-CAP treatment group, that were possibly or probably related to the medicinal products included in the VcR-CAP combination regimen, are listed in Table 8. Also included are adverse reactions observed in the VcR-CAP treatment group and considered by investigators as possibly or probably related to bortezomib, based on experience from studies in patients with multiple myeloma. Adverse reactions are grouped by system organ class and frequency of occurrence. Frequencies were 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 available data). Within each group, adverse reactions are listed in order of decreasing severity.
Table 8
| Body systems |
Frequency |
Adverse reaction |
| Infections and infestations |
Very common |
Pneumonia*. |
| Common |
Sepsis (including septic shock)*, herpes zoster (including disseminated and with ocular complications), herpesvirus infection*, bacterial infections*, infections of upper/lower respiratory tract*, fungal infection*, herpes simplex*. |
|
| Uncommon |
Hepatitis B, infections*, bronchopneumonia. |
|
| Blood and lymphatic system disorders |
Very common |
Thrombocytopenia*, febrile neutropenia, neutropenia*, leukopenia*, anemia*, lymphopenia*. |
| Uncommon |
Pancytopenia*. |
|
| Immune system disorders |
Common |
Hypersensitivity*. |
| Uncommon |
Anaphylactic reaction. |
|
| Metabolism and nutrition disorders |
Very common |
Decreased appetite. |
| Common |
Hypokalemia*, blood glucose 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*, dizziness*, dysgeusia*, autonomic neuropathy. |
|
| Uncommon |
Autonomic nervous system disorders. |
|
| Eye disorders |
Common |
Visual disturbances*. |
| Ear and labyrinth disorders |
Common |
Dysesthesia (including tinnitus)*. |
| Uncommon |
Vertigo*, hearing impairment (up to deafness). |
|
| Cardiac disorders |
Common |
Cardiac fibrillation (including atrial), arrhythmia*, heart failure (including left and right ventricular)*, myocardial ischemia, ventricular dysfunction*. |
| Uncommon |
Cardiovascular disorders (including cardiogenic shock). |
|
| Vascular disorders |
Common |
Hypertension*, hypotension*, orthostatic hypotension. |
| Respiratory, thoracic and mediastinal disorders |
Common |
Dyspnea*, cough*, hiccups. |
| Uncommon |
Acute respiratory distress syndrome, pulmonary embolism, pneumonitis, pulmonary hypertension, pulmonary edema (including acute). |
|
| Gastrointestinal disorders |
Very common |
Nausea and vomiting*, diarrhea*, stomatitis*, constipation. |
| Common |
Gastrointestinal hemorrhage (including mucosal)*, abdominal distension, dyspepsia, oropharyngeal pain*, gastritis*, oral ulcers*, abdominal discomfort, dysphagia, gastrointestinal inflammation*, abdominal pain (including gastrointestinal and splenic region)*, oral cavity disorders*. |
|
| Uncommon |
Colitis (including Clostridium difficile-induced)*. |
|
| Hepatobiliary disorders |
Common |
Hepatotoxicity (including hepatic disorders). |
| Uncommon |
Hepatic failure. |
|
| Skin and subcutaneous tissue disorders |
Very common |
Hair disorders*. |
| Common |
Pruritus*, dermatitis*, rash*. |
|
| Musculoskeletal and connective tissue disorders |
Common |
Muscle spasms*, musculoskeletal pain*, limb pain. |
| Renal and urinary disorders |
Common |
Urinary tract infections*. |
| General disorders and administration site conditions |
Very common |
Pyrexia*, fatigue, asthenia. |
| Common |
Edema (including peripheral), chills, injection site reactions*, fever*. |
|
| Laboratory investigations |
Common |
Hyperbilirubinemia*, abnormal protein levels*, decreased body weight, increased body weight. |
*Grouping of two or more MedDRA terms.
Description of selected adverse reactions.
Reactivation of Herpes zoster virus.
Multiple myeloma. Antiviral prophylaxis was administered in 26% of patients receiving bortezomib in combination with melphalan and prednisone. The incidence of herpes zoster was 17% in patients who did not receive antiviral agents, compared to 3% in those who received antiviral prophylaxis. Mantle cell lymphoma. Antiviral prophylaxis was administered in 137 out of 240 patients (57%) receiving bortezomib as part of combination therapy with the VcR-CAP regimen. Herpes zoster occurred in 10.7% of patients who did not receive antiviral agents, compared to 3.6% of patients who received antiviral 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 R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) and in 0.4% of patients (n = 1) receiving bortezomib as part of combination therapy with the VcR-CAP regimen (rituximab, cyclophosphamide, doxorubicin, and prednisone). The overall incidence of hepatitis B was similar in both treatment groups (0.8% in the VcR-CAP group versus 1.2% in the R-CHOP group).
Peripheral neuropathy during combination therapy.
Multiple myeloma. Peripheral neuropathy was observed in studies where bortezomib was used as induction therapy in combination with dexamethasone (IFM-2005-01 study) and with dexamethasone and thalidomide (MMY-3010 study) (see Table 9).
Table 9.
Incidence of peripheral neuropathy (PN) during induction therapy by toxicity grade and need for treatment interruption due to PN.
| Peripheral neuropathy indicators |
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.
Peripheral neuropathy includes: peripheral neuropathy, peripheral motor neuropathy, peripheral sensory neuropathy, and polyneuropathy.
Mantle cell lymphoma. Table 10 shows the frequency of peripheral neuropathy observed in the LYM-3002 study with bortezomib in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CAP).
Table 10.
Frequency of peripheral neuropathy (PN) in the bortezomib study in patients with mantle cell lymphoma, by toxicity grade and need for treatment interruption due to PN.
| 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.
Peripheral neuropathy includes: peripheral sensory neuropathy, peripheral neuropathy, peripheral motor neuropathy, and peripheral sensorimotor neuropathy.
Elderly patients with mantle cell lymphoma
In the VcR-CAP treatment group, 42.9% of patients were aged 65–74 years and 10.4% were ≥75 years. Although patients aged 75 years and older tolerated both treatment regimens less well, the rate of serious adverse reactions was 68% in the VcR-CAP group compared to 42% in the R-CHOP group.
Known differences in the safety profile of bortezomib when administered intravenously versus subcutaneously.
In a Phase III study, in patients receiving subcutaneous bortezomib, the incidence of treatment-emergent adverse reactions of Grade III toxicity or higher was 13% lower compared to patients receiving intravenous bortezomib, and the rate of bortezomib treatment interruption was also 5% lower. The overall incidence of diarrhea, lower abdominal pain, abdominal pain, asthenic conditions, upper respiratory tract infections, and peripheral neuropathies was 12–15% lower in the subcutaneous group compared to the intravenous group. Additionally, the incidence of peripheral neuropathies of Grade III or higher was 10% lower, and the rate of treatment discontinuation due to peripheral neuropathy was 8% lower. Injection site reactions occurred in 6% of patients, predominantly erythema. Symptoms resolved on average within 6 days, and dose modification was required in 2 patients.
Serious reactions occurred in 2 patients (1%): 1 case of pruritus and 1 case of erythema. The rate of fatal events during treatment was 5% in the subcutaneous group and 7% in the intravenous group. The rate of fatal events due to disease progression was 18% in the subcutaneous group and 9% in the intravenous group.
Re-treatment of patients with relapsed multiple myeloma.
In a study evaluating bortezomib as re-treatment involving 130 patients with relapsed multiple myeloma who previously achieved at least a partial response to bortezomib-containing therapy, adverse reactions of all grades occurring in at least 25% of patients primarily included thrombocytopenia (55%), neuropathy (40%), anemia (37%), diarrhea (35%), and constipation (28%). Peripheral neuropathy of all grades and peripheral neuropathy ≥ Grade III were observed in 40% and 8.5% of patients, respectively.
Reporting suspected adverse reactions.
Reporting of adverse reactions following drug registration is of great importance. It enables ongoing 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 cases of suspected adverse reactions and lack of efficacy to the State Expert Center of the Ministry of Health of Ukraine via the following link: https://aisf.dec.gov.ua
Shelf life. 3 years.
After reconstitution, the medicinal product can be stored at a temperature not exceeding 25 °C in a normally lit room, in the original vial or syringe, for no more than 8 hours.
Storage conditions.
Store in the original packaging, protected from light, at a temperature not exceeding 25 °C. Keep out of reach of children.
Incompatibilities. This medicinal product should not be mixed with other medicinal products except those specified in the section “Dosage and administration.”
Packaging.
2.5 mg in a vial. 1 vial in a cardboard box.
Prescription status.
Prescription only.
Manufacturers.
Sandoz España, S.L.
Sandoz s.r.o.
Manufacturer's address and location of operations.
Calle Castel·lo, no1, Sant Boi de Llobregat, Barcelona, 08830, Spain.
Brnenska 32/sr. 597, Blansko, 67801, Czech Republic.