Bortezomib-baxter
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BORTEZOMIB-BAXTER (Bortezomib-Baxter)
Composition:
Active ingredient: bortezomib;
1 vial contains 3.5 mg of bortezomib;
Excipient: mannitol (E 421).
Pharmaceutical form. Powder for solution for injection.
Main physicochemical characteristics: lyophilized solid or powder, white to almost white.
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. It is specifically designed to inhibit the chymotrypsin-like activity of the 26S proteasome in mammalian cells. The 26S proteasome is a large protein complex that degrades ubiquitin-conjugated proteins. The ubiquitin-proteasome pathway plays a major role in regulating the turnover of specific proteins, thereby maintaining cellular homeostasis. Inhibition of the 26S proteasome prevents this targeted proteolysis and affects several intracellular signaling cascades, leading to apoptosis of cancer cells.
Bortezomib is highly selective for the proteasome. At a concentration of 10 µM, bortezomib does not inhibit any of a large number of tested receptors and proteases, and is more than 1500-fold more selective for the proteasome than for other enzymes. The kinetics of proteasome inhibition were determined in vitro; bortezomib dissociated from the proteasome with a t½ of 20 minutes, indicating that bortezomib-induced proteasome inhibition is reversible.
By inhibiting the proteasome, bortezomib affects cancer cells through multiple mechanisms, including, in particular, altering regulatory proteins that control the cell cycle and activation of nuclear factor kappa B (NF-kB). Proteasome inhibition leads to cell cycle arrest and apoptosis. NF-kB is a transcription factor whose activation is essential for many aspects of tumor development, including cell growth and survival, angiogenesis, cell–cell interactions, and metastasis. In myeloma, bortezomib affects the ability of myeloma cells to interact with the bone marrow microenvironment.
Studies have shown that bortezomib is cytotoxic to many types of cancer cells and that cancer cells are more susceptible to apoptosis induced by proteasome inhibition than normal cells. In vivo, bortezomib causes inhibition of growth in multiple experimental human tumors, including multiple myeloma.
Data from in vitro, ex vivo, and animal model studies indicate that bortezomib enhances differentiation and activity of osteoblasts 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 of the first dose of bortezomib was 57 and 112 ng/mL, respectively. With subsequent administrations, the mean maximum plasma concentration of bortezomib ranged from 67 to 106 ng/mL for the 1.0 mg/m² dose and from 89 to 120 ng/mL for the 1.3 mg/m² dose.
After intravenous bolus or subcutaneous administration of 1.3 mg/m² to patients with multiple myeloma (n = 14 in the intravenous group and n = 17 in the subcutaneous group), the total systemic exposure after repeated dosing (AUClast) was equivalent between subcutaneous and intravenous administration. The Cmax after subcutaneous administration (20.4 ng/mL) was lower than after intravenous administration (223 ng/mL). The geometric mean ratio of AUClast was 0.99, and the 90% confidence interval (CI) was 80.18–122.80%.
Distribution
The mean volume of distribution (Vd) of bortezomib ranges from 1659 to 3294 liters following single or multiple intravenous doses of 1.0 mg/m² or 1.3 mg/m² in patients with multiple myeloma. This indicates extensive distribution of bortezomib into peripheral tissues. At bortezomib concentrations of 0.01–1.0 µg/mL, plasma protein binding of the drug is 82.9%. The fraction of bortezomib bound to plasma proteins was independent of concentration.
Metabolism
In vitro studies using human liver microsomes and human cDNA-expressed cytochrome P450 isoenzymes showed that oxidative metabolism of bortezomib is primarily mediated by cytochrome P450 enzymes 3A4, 2C19, and 1A2. The main metabolic pathway involves deboronation to two metabolites, which are subsequently hydroxylated into other metabolites. The deboronated metabolites of bortezomib are inactive as inhibitors of the 26S proteasome.
Elimination
The mean elimination half-life (T½) of bortezomib after multiple dosing ranges from 40 to 193 hours. Bortezomib is eliminated more rapidly after the first dose compared to subsequent doses. Mean total clearance was 102 and 112 L/h after the first doses of 1.0 mg/m² and 1.3 mg/m², respectively, and ranged from 15 to 32 L/h and from 18 to 32 L/h after subsequent doses of 1.0 mg/m² and 1.3 mg/m², respectively.
Special Patient Populations
Hepatic Impairment
The effect of hepatic impairment on the pharmacokinetics of bortezomib was evaluated in a Phase I study during the first treatment cycle involving 61 patients primarily with solid tumors and varying degrees of hepatic dysfunction, with bortezomib doses ranging from 0.5 to 1.3 mg/m².
Mild hepatic impairment did not alter the dose-normalized AUC of bortezomib compared to normal hepatic function. However, dose-normalized mean AUC values of bortezomib increased by approximately 60% in patients with moderate and severe hepatic impairment. A lower starting dose is recommended for patients with moderate or severe hepatic impairment, and these patients require careful monitoring (see section "Dosage and Administration", Table 6).
Renal Impairment
Pharmacokinetic studies were conducted in patients with varying degrees of renal impairment, categorized according to creatinine clearance (CrCL) as follows: normal (CrCL ≥ 60 mL/min/1.73 m², n = 12), mild impairment (CrCL = 40–59 mL/min/1.73 m², n = 10), moderate impairment (CrCL = 20–39 mL/min/1.73 m², n = 9), and severe impairment (CrCL < 20 mL/min/1.73 m², n = 3). Patients on dialysis who received bortezomib after dialysis were also included in the study (n = 8). Patients received intravenous bortezomib doses of 0.7–1.3 mg/m² twice weekly. Bortezomib exposure (dose-normalized AUC and Cmax) was comparable across all groups (see section "Dosage and Administration").
Age
Pharmacokinetic parameters of bortezomib were evaluated in 104 pediatric patients (aged 2–16 years) with acute lymphoblastic leukemia or acute myeloid leukemia, who received bortezomib 1.3 mg/m² twice weekly via intravenous bolus injection. According to population pharmacokinetic analysis, bortezomib clearance increases with increasing body surface area. The geometric mean (% CV) clearance was 7.79 L/h/m² (25%), the volume of distribution at steady state was 834 L/m² (39%), and the elimination half-life was 100 hours (44%). After adjusting for body surface area, other demographic factors such as age, body weight, and sex had no clinically significant effect on bortezomib clearance. Bortezomib clearance values in children, adjusted for body surface area, were comparable to those in adults.
Clinical Characteristics
Indications
Treatment of multiple myeloma in combination with melphalan and prednisone in previously untreated patients who are not eligible for high-dose chemotherapy with hematopoietic stem cell transplantation (first-line therapy).
Treatment of progressive multiple myeloma as monotherapy or in combination with pegylated liposomal doxorubicin or dexamethasone in patients who have received at least one prior therapy and either stem cell transplantation or 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 adult patients who have not received prior therapy and are not candidates for hematopoietic stem cell transplantation.
Contraindications
Hypersensitivity to bortezomib, boron, or any excipients of the medicinal product.
Acute diffuse infiltrative pulmonary and pericardial diseases.
When using Bortezomib-Baxter in combination with other medicinal products, refer to the instructions for medical use of these products for additional contraindications.
Special Precautions
General Warnings
Bortezomib is a cytotoxic agent. Appropriate precautions should be taken during reconstitution and administration. Gloves and protective clothing are recommended to prevent skin contact.
Strict aseptic techniques must be followed when handling Bortezomib-Baxter, as the medicinal product does not contain preservatives.
Fatal outcomes have been reported following accidental intrathecal administration of bortezomib. Bortezomib-Baxter must be administered only intravenously or subcutaneously. Intrathecal administration is strictly contraindicated.
Proper Disposal Procedure
The medicinal product is intended for single use only. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Interaction with Other Medicinal Products and Other Forms of Interaction
In vitro studies have shown 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 assessing 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 from 1.032 to 1.772), based on data from 12 patients. Therefore, careful monitoring of patients is recommended when bortezomib is co-administered with potent CYP3A4 inhibitors (e.g., ketoconazole, ritonavir).
A study evaluating the effect of omeprazole, a potent CYP2C19 inhibitor, on the pharmacokinetics of bortezomib (after intravenous administration) showed no significant impact on bortezomib pharmacokinetics in 17 patients included in the study.
Studies evaluating 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 use of bortezomib with potent CYP3A4 inducers (e.g., 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 bortezomib pharmacokinetics based on data from 7 patients.
Drug interaction studies assessing the effects of melphalan and prednisone on bortezomib pharmacokinetics (after intravenous administration) in 21 patients demonstrated an average increase in bortezomib AUC by 17%. This increase in bortezomib AUC is not considered clinically significant.
During clinical trials, cases of hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral antidiabetic agents. Blood glucose levels should be monitored and doses of antidiabetic agents adjusted accordingly in patients receiving bortezomib therapy.
Special precautions for use
If Bortezomib-Baxter is used in combination with other medicinal products, the instructions for medical use of these medicinal products should be consulted prior to initiating treatment. If thalidomide is used, special attention should be paid to pregnancy diagnosis and contraceptive measures.
Intrathecal administration
Fatal cases due to accidental intrathecal administration of bortezomib have been reported. Bortezomib-Baxter should only be administered intravenously or subcutaneously. DO NOT ADMINISTER BORTEZOMIB-BAXTER INTRATHECALLY.
Gastrointestinal complications
Bortezomib treatment may very commonly cause gastrointestinal toxicity, including nausea, diarrhea, constipation, and vomiting. Cases of intestinal obstruction (reported as "uncommon") have been reported; therefore, patients with constipation should be under medical supervision.
Hematological complications
Hematological toxicity (thrombocytopenia, neutropenia, and anemia) is very commonly observed during bortezomib therapy. In clinical trials of bortezomib in patients with relapsed multiple myeloma and in combination therapy with rituximab, cyclophosphamide, doxorubicin, and prednisone (BR-CAP regimen) in patients with previously untreated mantle cell lymphoma, one of the most common hematological toxicities was reversible thrombocytopenia. Platelet counts were typically lowest on day 11 of each bortezomib treatment cycle and returned to baseline levels before the start of the next cycle. Cumulative thrombocytopenia was not observed. On average, the lowest measured platelet count was approximately 40% of the baseline level in trials of bortezomib monotherapy in 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 ≤ 25,000/µL.
In patients with mantle cell lymphoma, grade ≥3 thrombocytopenia occurred more frequently in the group receiving bortezomib (BR-CAP regimen) than in patients 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 3, was similar in both groups. In the BR-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 Bortezomib-Baxter. Therapy with Bortezomib-Baxter should be interrupted if platelet counts decrease to < 25,000/µL during monotherapy or to ≤ 30,000/µL during combination therapy with melphalan and prednisone. The benefit-risk ratio associated with Bortezomib-Baxter therapy should be carefully evaluated, particularly in cases of moderate or severe thrombocytopenia and presence of bleeding risk factors.
Complete blood counts, including white blood cell differential and platelet counts, should be frequently performed during therapy with Bortezomib-Baxter. Platelet transfusion should be considered if clinically indicated.
In patients with mantle cell lymphoma, reversible neutropenia between treatment cycles has been observed, and cumulative neutropenia was not observed. White blood cell counts were typically lowest 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 BR-CAP group and 61% in the R-CHOP group received granulocyte colony-stimulating factor. Since patients with neutropenia are at increased risk of developing infections, their condition 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 the management of 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 treated with Bortezomib-Baxter. In a Phase III trial in patients with untreated multiple myeloma, the overall incidence of Herpes zoster (shingles) reactivation 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 BR-CAP treatment 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 bortezomib, patients with risk factors should be tested for HBV. HBV carriers and patients with a history of hepatitis B should be closely monitored for clinical signs and laboratory parameters during and after combination therapy with rituximab and bortezomib. Antiviral prophylaxis should be considered.
Progressive multifocal leukoencephalopathy (PML)
Very rare cases of infection with the John Cunningham virus causing fatal PML have been reported in patients treated with bortezomib. Patients diagnosed with PML had received immunosuppressive therapy either prior to or concurrently with bortezomib. Most cases of PML were diagnosed within the first 12 months after initiation of bortezomib therapy. 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. Bortezomib-Baxter therapy should be discontinued if PML is confirmed.
Peripheral neuropathy
Bortezomib therapy 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 sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain, or weakness is recommended.
In a Phase III trial comparing intravenous versus subcutaneous administration of bortezomib, the incidence of grade 2 peripheral neuropathy was 24% in the subcutaneous group and 41% in the intravenous group. Grade 3 peripheral neuropathy occurred in 6% of patients in the subcutaneous group and 16% in the intravenous group.
If peripheral neuropathy develops or worsens, patients should undergo a neurological examination; dose adjustment, schedule modification, or change in route of administration to subcutaneous may be necessary. Neuropathy should be managed with supportive measures.
Regular monitoring for treatment-related neuropathic symptoms and neurological examinations are recommended for patients receiving Bortezomib-Baxter in combination with neurotoxic agents (such as thalidomide); dose reduction or discontinuation of therapy should be considered as necessary.
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. Particular caution is required when treating patients with any predisposing 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 therapy. Most patients required treatment for orthostatic hypotension, and a smaller number experienced syncope. Orthostatic/postural hypotension was not clearly associated with bolus infusion of bortezomib; the mechanism of its development is unknown. It may be related to autonomic neuropathy. Autonomic neuropathy may be associated with bortezomib use or bortezomib may exacerbate underlying conditions, including diabetic or amyloid neuropathy. Caution is advised when treating patients with a history of syncope, those receiving antihypertensive medications, and those with dehydration due to diarrhea or vomiting. In case of orthostatic hypotension, hydration, glucocorticoids, and/or sympathomimetics are recommended; antihypertensive medications may need to be reduced if necessary. Patients should be instructed to seek medical attention 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 bortezomib. PRES is a rare, reversible neurological disorder characterized by seizures, arterial hypertension, headache, lethargy, confusion, visual disturbances, and other neurological symptoms. Diagnosis is confirmed by brain imaging, preferably magnetic resonance imaging (MRI). Bortezomib-Baxter therapy 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 heart disease should be under medical supervision.
ECG investigations
Isolated cases of QT interval prolongation have been observed in clinical trials; the cause has not been established.
Lung function disorders
Rare cases of acute diffuse infiltrative lung diseases of unknown etiology, such as pneumonitis, interstitial pneumonia, pulmonary infiltration, and acute respiratory distress syndrome (ARDS), have been observed in patients receiving bortezomib. Some of these cases were fatal. Radiological examination is recommended prior to treatment initiation to establish baseline lung status and for comparison in case of potential treatment-related pulmonary impairment.
In case 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 Bortezomib-Baxter therapy should be carefully considered.
In clinical trials, two out of two patients with relapsed acute myeloid leukemia who received high-dose cytarabine (2 g/m²/day) as a continuous 24-hour infusion in combination with daunorubicin and bortezomib died from ARDS at the beginning of the treatment course. Therefore, this specific regimen of concomitant high-dose cytarabine (2 g/m²/day) as a continuous 24-hour infusion is not recommended.
Renal function disorders
Renal function disorders are common in patients with multiple myeloma. Close monitoring of such patients is recommended.
Hepatic function disorders
Bortezomib is metabolized by hepatic enzymes. In patients with moderate to severe hepatic impairment, bortezomib concentrations may increase; these patients should be treated with reduced doses and closely monitored for signs of toxicity.
Hepatic reactions
Rare cases of acute liver failure have been reported in patients receiving bortezomib concomitantly with other drugs and in patients with serious underlying medical conditions. Cases of elevated liver enzymes, hyperbilirubinemia, and hepatitis, which resolved after discontinuation of bortezomib, 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 particular risk. Close monitoring of such patients is recommended, and appropriate preventive measures should be taken.
Precautions regarding concomitant use of other medicinal products
Patients should be under close physician supervision when bortezomib is combined with strong CYP3A4 inhibitors. Caution should be exercised when combining bortezomib with CYP3A4 or CYP2C9 substrates.
Liver function should be corrected prior to initiating treatment in case of hepatic impairment, and caution should be exercised when treating patients receiving oral hypoglycemic agents.
Potentially immune complex-mediated reactions
Immune complex-mediated reactions, such as serum sickness, polyarthritis with rash, and proliferative glomerulonephritis, have been reported uncommonly. Bortezomib should be discontinued if serious reactions occur.
Use during pregnancy or breastfeeding
Contraception in women and men
Men and women of reproductive potential must use effective contraception during treatment and for 3 months after completion of treatment.
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 maximum 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 bortezomib therapy. If bortezomib is used during pregnancy or if pregnancy occurs during treatment with this medicinal product, the patient should be informed of the potential harmful effects on the fetus.
Thalidomide is a medicinal product with known teratogenic effects in humans, causing severe, life-threatening congenital malformations. Thalidomide is contraindicated during pregnancy and in women of reproductive potential. Patients receiving bortezomib in combination with thalidomide must comply with pregnancy prevention requirements. For additional information, refer to the thalidomide product information.
< Breastfeeding >
It is unknown whether bortezomib is excreted in human milk, but to prevent serious adverse effects in the infant, breastfeeding is not recommended during bortezomib treatment.
< Fertility >
Studies on the effect of bortezomib on fertility have not been conducted.
Ability to affect reaction speed when driving or operating machinery
Bortezomib has a moderate effect on reaction speed when driving or operating 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 doses
Treatment with Bortezomib-Baxter should be initiated under the supervision of a qualified physician experienced in treating cancer patients; however, treatment may also be administered under the supervision of a healthcare professional experienced in the use of antineoplastic agents. Preparation of the solution must be performed only by qualified medical personnel (see section "Safety precautions").
Relapsed multiple myeloma (patients who have received at least one prior therapy)
Monotherapy
The recommended dose of Bortezomib-Baxter is 1.3 mg/m² body surface area administered intravenously or subcutaneously twice weekly for two 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 with a partial response but not complete remission should continue treatment with Bortezomib-Baxter for up to a maximum of 8 cycles. At least 72 hours must elapse between consecutive doses of Bortezomib-Baxter.
Dose modification and re-initiation recommendations for monotherapy
If any non-hematologic toxicity of grade 3 or hematologic toxicity of grade 4 occurs, except for neuropathies, treatment with Bortezomib-Baxter must be withheld. After resolution of toxic symptoms, treatment with Bortezomib-Baxter 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-Baxter should be considered, unless the benefits of continued treatment outweigh the risks.
Neuropathic pain and/or peripheral neuropathy
The dose of the drug should be adjusted in case of development of neuropathic pain and/or peripheral neuropathy (see Table 1). Bortezomib-Baxter 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 for bortezomib-Baxter-induced neuropathy
| Severity of neuropathy |
Dose and administration frequency modification |
| Grade 1 (asymptomatic; loss of deep tendon reflexes or paresthesia) without pain or functional loss |
Dose and administration schedule do not require adjustment |
| Grade 1 with pain or Grade 2 (moderate severity symptoms; limitation of instrumental activities of daily living)** |
Reduce dose to 1 mg/m² or change administration schedule of Bortezomib-Baxter to 1.3 mg/m² once weekly |
| Grade 2 with pain or Grade 3 (severe symptoms; limitation of self-care activities)*** |
Withhold Bortezomib-Baxter treatment until resolution of toxicity symptoms. After that, resume treatment at a reduced dose of 0.7 mg/m² once weekly |
| Grade 4 (life-threatening consequences; requiring urgent intervention) and/or severe autonomic neuropathy |
Discontinue Bortezomib-Baxter treatment |
*Based on dosage modifications observed in Phase II and III multiple myeloma studies and in the post-marketing period.
**Instrumental activities of daily living include cooking, shopping, using the telephone, etc.
***Self-care activities include bathing, dressing/undressing, eating, using the toilet, taking medication, and being out of bed.
Combination therapy with pegylated liposomal doxorubicin
The recommended dose of bortezomib for adults is 1.3 mg/m² body surface area administered intravenously or subcutaneously twice weekly for 2 weeks (Days 1, 4, 8, and 11), followed by a 10-day rest period (Days 12–21). This 3-week period constitutes one treatment cycle. At least 72 hours should elapse between consecutive doses of Bortezomib-Baxter.
Pegylated liposomal doxorubicin should be administered at a dose of 30 mg/m² on Day 4 of the Bortezomib-Baxter treatment cycle via a 1-hour intravenous infusion, after administration of Bortezomib-Baxter.
Up to 8 cycles of this combination therapy should be administered, provided the disease does not progress and patients tolerate treatment well. Patients who achieve a complete remission may continue treatment for at least 2 additional cycles after achieving complete response, even if this requires more than 8 treatment cycles. Patients whose paraprotein levels continue to decline after 8 cycles may also continue treatment as long as the treatment 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 constitutes one treatment cycle. At least 72 hours should elapse between consecutive doses of Bortezomib-Baxter.
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-Baxter treatment cycle.
Patients who show a response to treatment or stable disease after four cycles may continue treatment with this combination for up to four additional cycles. For further information on dexamethasone, refer to the prescribing information for this medicinal product.
Dose modification recommendations for combination therapy in patients with relapsed multiple myeloma
See the dose modification recommendations for Bortezomib-Baxter monotherapy described above.
Previously untreated multiple myeloma in patients not eligible for hematopoietic stem cell transplantation
Combination therapy with melphalan and prednisone
Bortezomib-Baxter should be administered intravenously or subcutaneously in combination with oral melphalan and oral prednisone over nine 6-week treatment cycles (see Table 2). In cycles 1–4, Bortezomib-Baxter is administered twice weekly (Days 1, 4, 8, 11, 22, 25, 29, and 32). In cycles 5–9, Bortezomib-Baxter is administered once weekly (Days 1, 8, 22, and 29). At least 72 hours should elapse between consecutive doses of Bortezomib-Baxter.
Melphalan and prednisone should be administered orally on Days 1, 2, 3, and 4 of the first week of each cycle.
Nine cycles of this combination therapy should be administered.
Table 2
Recommended dosing regimen of Bortezomib-Baxter in combination with melphalan and prednisone
| Bortezomib-Baxter 2 times per week (cycles 1–4) |
||||||||||||
| Week |
1 |
2 |
3 |
4 |
5 |
6 |
||||||
| Bortezomib-Baxter (1.3 mg/m²) |
1st |
-- |
-- |
4th day |
8th day |
11th day |
Break |
22nd day |
25th day |
29th day |
32nd day |
Break |
| M (9 mg/m²) P (60 mg/m²) |
1st day |
2nd day |
3rd day |
4th day |
-- |
-- |
Break |
-- |
-- |
-- |
-- |
Break |
| Bortezomib-Baxter 1 time per week (cycles 5–9) |
||||||||||||
| Week |
1 |
2 |
3 |
4 |
5 |
6 |
||||||
| Bortezomib-Baxter (1.3 mg/m²) |
1st day |
-- |
-- |
-- |
8th day |
Break |
22nd day |
29th day |
Break |
|||
| M (9 mg/m²) P (60 mg/m²) |
1st day |
2nd day |
3rd day |
4th day |
-- |
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 is ≥ 70 × 109/l and absolute neutrophil count is ≥ 1.0 × 109/l;
- non-hematological toxicity has returned to grade 1 or baseline level.
Table 3
Dose adjustment during subsequent cycles of treatment with Bortezomib-Baxter 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 administration of Bortezomib-Baxter |
|
The dose of Bortezomib-Baxter should be reduced by one level (from 1.3 mg/m2 to 1 mg/m2 or from 1 mg/m2 to 0.7 mg/m2) |
| Non-hematologic toxicity ≥ grade 3 |
Treatment with Bortezomib-Baxter should be discontinued until symptoms improve to baseline or grade 1 severity. Then, Bortezomib-Baxter 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). For bortezomib-induced neuropathic pain and/or peripheral neuropathy, dose holding and/or modification of Bortezomib-Baxter should be performed 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 hematopoietic stem cell transplantation (induction therapy)
Combination therapy with dexamethasone
The recommended dose of bortezomib is 1.3 mg/m² body surface area administered intravenously or subcutaneously twice weekly for 2 weeks (on days 1, 4, 8, and 11), followed by a 10-day rest period (days 12–21). This 3-week period constitutes one treatment cycle. At least 72 hours should elapse between consecutive doses of Bortezomib-Baxter.
Dexamethasone is administered orally at a dose of 40 mg on days 1, 2, 3, 4, 8, 9, 10, and 11 of each Bortezomib-Baxter treatment cycle.
Administer 4 treatment cycles with this combination.
Combination therapy with dexamethasone and thalidomide
The recommended dose of bortezomib is 1.3 mg/m² body surface area administered intravenously or subcutaneously twice weekly for 2 weeks (on days 1, 4, 8, and 11), followed by a 17-day rest period (days 12–28). This 4-week period constitutes one treatment cycle. At least 72 hours should elapse between consecutive doses of Bortezomib-Baxter.
Dexamethasone is administered orally at a dose of 40 mg on days 1, 2, 3, 4, 8, 9, 10, and 11 of each Bortezomib-Baxter treatment cycle.
Thalidomide is administered orally at a dose of 50 mg daily on days 1–14 of the cycle; if tolerated, the dose should be increased to 100 mg daily on days 15–28 of the cycle. The dose may subsequently be 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-Baxter 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.
aIncrease 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.
bPatients who achieve at least a partial response after 4 treatment cycles may continue up to 6 treatment cycles.
Dosing recommendations for patients eligible for transplantation
For dose adjustments, refer to the dose modification guidelines for Bortezomib-Baxter when used as monotherapy.
If Bortezomib-Baxter is used in combination with other chemotherapeutic agents, refer to the respective product information for dose reductions of these agents in the event of toxicity.
Untreated mantle cell lymphoma
Combination therapy with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHOP-like regimen)
The recommended dose of bortezomib is 1.3 mg/m² body surface area administered intravenously or subcutaneously twice weekly for 2 weeks (on days 1, 4, 8, and 11), followed by a 10-day rest period (days 12–21). This 3-week period constitutes one treatment cycle. At least 72 hours should elapse between consecutive doses of Bortezomib-Baxter. Administer 6 treatment cycles. Patients who first demonstrate response during cycle 6 are recommended to receive 2 additional treatment cycles.
Drugs administered by intravenous infusion on day 1 of each 3-week treatment cycle with Bortezomib-Baxter: 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 treatment cycle with Bortezomib-Baxter.
Dose modification recommendations for patients with untreated mantle cell lymphoma
Prior to initiating a new treatment cycle:
- Platelet count ≥ 100,000 cells/µL and absolute neutrophil count ≥ 1,500 cells/µL,
- Platelet count ≥ 75,000 cells/µL in patients with bone marrow infiltration or splenic sequestration,
- Hemoglobin level ≥ 8 g/dL,
- Non-hematologic toxicity has resolved to grade 1 or baseline levels.
Treatment with Bortezomib-Baxter should be withheld in the event of any non-hematologic toxicity ≥ grade 3 (except neuropathy) related to Bortezomib-Baxter, or hematologic toxicity ≥ grade 3. Refer to Table 5 for dose modification recommendations.
Granulocyte colony-stimulating factors may be used to manage hematologic toxicity. If initiation of a new treatment cycle has been delayed multiple times, consider prophylactic use of granulocyte colony-stimulating factor. Platelet transfusion should be considered for management of thrombocytopenia.
Table 5
Dose modification during therapy for patients with untreated mantle cell lymphoma
| Toxicity |
Dose modification or treatment interruption |
| Hematological toxicity |
|
|
Treatment with Bortezomib-Baxter should be interrupted for up to 2 weeks until the absolute neutrophil count recovers to ≥ 750 cells/μL and platelet count recovers to ≥ 25,000 cells/μL. If toxicity does not resolve (blood counts do not recover to the levels stated above), Bortezomib-Baxter should be discontinued. If toxicity resolves (absolute neutrophil count recovers to ≥ 750 cells/μL and platelet count to ≥ 25,000 cells/μL), treatment with Bortezomib-Baxter may be resumed at a reduced dose by one level (from 1.3 mg/m² to 1 mg/m² or from 1 mg/m² to 0.7 mg/m²). |
|
Delay administration of Bortezomib-Baxter dose |
| Non-hematological toxicity ≥ grade 3 related to Bortezomib-Baxter |
Treatment with Bortezomib-Baxter should be interrupted until symptoms improve to at least grade 2 severity. Bortezomib-Baxter 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 drug-related neuropathic pain and/or peripheral neuropathy, dose holding and/or modification of Bortezomib-Baxter should be performed as specified in Table 1. |
If bortezomib-Baxter is used in combination with other chemotherapeutic agents, refer to the instructions for use of those medicinal products for information on dose adjustments in the event of toxicity.
Special patient groups
Elderly patients
There are currently no data indicating the need for dose adjustment in patients aged 65 years and older.
Studies on the use of bortezomib in elderly patients with previously untreated multiple myeloma who are candidates for high-dose chemotherapy with hematopoietic stem cell transplantation have not been conducted. Therefore, no recommendations on dose adjustment can be given for this patient group.
In a study evaluating bortezomib use in patients with previously untreated mantle cell lymphoma, 42.9% of patients were aged 65–74 years and 10.4% were aged ≥75 years. Patients aged 75 years and older tolerated treatment less well in both treatment groups (BR-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 should be initiated at a dose of 0.7 mg/m² during the first treatment cycle, followed by gradual dose escalation to 1.0 mg/m² or dose reduction to 0.5 mg/m², depending on patient tolerability.
Table 6
Recommended adjustments of initial bortezomib doses for 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. Subsequent dose increases to 1.0 mg/m² or reductions to 0.5 mg/m² should be based on drug tolerability. |
| Severe |
> 3 × ULN |
Any |
AST — aspartate aminotransferase; ULN — upper limit of normal.
*Based on the National Cancer Institute Organ Dysfunction Working Group classification of severity of liver function impairment (mild, moderate, and severe).
Patients with renal impairment
Mild to moderate renal impairment (creatinine clearance > 20 ml/min/1.73 m²) does not affect the pharmacokinetics of bortezomib; therefore, dose adjustment is not required in this patient group. It is unknown whether severe renal impairment (creatinine clearance < 20 ml/min/1.73 m²) affects the pharmacokinetics of bortezomib. Since dialysis may reduce bortezomib concentrations, the drug should be administered after the dialysis procedure.
Method of administration
Bortezomib-Baxter is administered by intravenous or subcutaneous injection. Accidental intrathecal administration of the drug has resulted in fatal outcomes.
Intravenous administration
The reconstituted solution should be administered immediately after preparation as a 3–5 second intravenous bolus injection through a peripheral or central venous catheter, followed by flushing the catheter with 0.9% (9 mg/ml) sodium chloride injection solution. At least 72 hours should elapse between consecutive doses of Bortezomib-Baxter.
Subcutaneous administration
The reconstituted solution should be administered immediately after preparation by subcutaneous injection at a 45–90° angle, selecting sites on the thighs (left or right) or abdomen (left or right). Injection sites should be rotated.
If adverse reactions occur at the injection site during subcutaneous administration, the solution of Bortezomib-Baxter may be administered subcutaneously at a lower concentration (1 mg/ml instead of 2.5 mg/ml) or bortezomib may be administered intravenously.
Instructions for solution preparation
Reconstitution instructions
The medicinal product Bortezomib Baxter must be reconstituted by a healthcare professional.
After reconstitution, do not cool the solution.
Chemical and physical in-use stability has been demonstrated for 8 hours at 25°C. From a microbiological standpoint, the reconstituted medicinal product should be used immediately, unless the reconstitution procedure excludes the risk of microbial contamination. If the medicinal product is not used immediately, the responsibility for storage conditions and duration lies with the user.
Intravenous administration
Carefully add 3.5 ml of 9 mg/ml (0.9%) sodium chloride injection solution to the 10 ml vial of Bortezomib Baxter using a syringe of appropriate size, without removing the stopper. The lyophilized powder dissolves in less than 2 minutes.
After reconstitution, 1 ml of solution contains 1 mg of bortezomib. The reconstituted solution is clear and colorless, with a final pH between 4 and 7.
Before administration, the reconstituted solution should be inspected visually for particles and discoloration. If discoloration or particulate matter is observed, the reconstituted solution should be discarded.
Subcutaneous injection
Carefully add 1.4 ml of 9 mg/ml (0.9%) sodium chloride injection solution to the 10 ml vial of Bortezomib Baxter using a syringe of appropriate size, without removing the stopper. The lyophilized powder dissolves in less than 2 minutes.
After reconstitution, 1 ml of solution contains 2.5 mg of bortezomib. The reconstituted solution is clear and colorless, with a final pH between 4 and 7. Before administration, the reconstituted solution should be inspected visually for particles and discoloration. If discoloration or particulate matter is observed, the reconstituted solution should be discarded.
Children
The safety and efficacy of Bortezomib Baxter in children (under 18 years of age) have not been established. Currently available data are insufficient to provide dosing recommendations for children.
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 specific antidote for bortezomib. In case of overdose, close monitoring of vital signs is recommended, along with appropriate supportive measures to maintain blood pressure (such as fluid balance support, use of vasopressor and/or inotropic agents) and body temperature (see sections "Special precautions" and "Method of administration and dosage").
Adverse Reactions
Serious adverse reactions reported during treatment with bortezomib have included heart failure, tumor lysis syndrome, pulmonary hypertension, reversible posterior leukoencephalopathy syndrome (PRES), acute diffuse infiltrative pulmonary disorders, and, rarely, autonomic neuropathy. The most commonly observed adverse reactions during bortezomib therapy are nausea, diarrhea, constipation, vomiting, fatigue, pyrexia, thrombocytopenia, anemia, neutropenia, peripheral neuropathy (including sensory neuropathy), headache, paresthesia, decreased appetite, dyspnea, rash, herpes zoster, and myalgia.
Multiple Myeloma
The adverse reactions listed in Table 7 are considered possibly related to the use of bortezomib. These adverse reactions were identified based on pooled data from 5476 patients, of whom 3996 received bortezomib at a dose of 1.3 mg/m². Overall, bortezomib was used to treat 3974 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. Also included are adverse reactions not observed during clinical studies but reported in the post-marketing period.
Table 7
| Organ systems |
Frequency |
Adverse reactions |
| Infections and infestations |
Common |
Herpes zoster (including disseminated and with ocular complications), pneumonia*, herpes simplex*, fungal infection* |
| Uncommon |
Infections*, bacterial infections*, viral infections*, sepsis (including septic shock)*, bronchopneumonia, herpesvirus infection*, herpetic meningoencephalitis#, bacteremia (including staphylococcal), hordeolum, influenza, cellulitis, device-related infections, skin infections*, ear infections*, staphylococcal infection, dental infection* |
|
| Rare |
Meningitis (including bacterial), Epstein-Barr virus infection, genital herpes, tonsillitis, mastoiditis, post-viral fatigue syndrome |
|
| Benign, malignant and unspecified neoplasms (including cysts and polyps) |
Rare |
Malignant tumor, plasma cell leukemia, renal cell carcinoma, tumor 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*, disturbance in 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, worsening of patient condition*, hypomagnesemia*, hypophosphatemia*, hyperkalemia*, hypercalcemia*, hypernatremia*, uric acid level disturbances*, diabetes mellitus*, fluid retention |
|
| Rare |
Hypermagnesemia*, acidosis, electrolyte imbalance*, hypervolemia, hypochloremia*, hypovolemia, hyperchloremia*, hyperphosphatemia*, metabolic disorders, vitamin B complex deficiency, vitamin B12 deficiency, gout, increased appetite, alcohol intolerance |
|
| Psychiatric disorders |
Common |
Mood and sensation disturbances*, anxiety disorder*, sleep disorders* |
| Uncommon |
Psychiatric disorder*, hallucinations*, psychotic disorder*, confusion*, excitement |
|
| 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, convulsion 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 syndrome, cerebrovascular disorder, nerve root damage, psychomotor hyperactivity, spinal cord compression, other cognitive disorders, motor dysfunctions, other nervous system disorders, radiculitis, hypersalivation, hypotonia, Guillain-Barré syndrome#, demyelinating polyneuropathy# |
|
| Eye disorders |
Common |
Eye edema*, vision disturbances*, conjunctivitis* |
| Uncommon |
Ocular hemorrhage*, eyelid infections*, chalazion#, blepharitis#, eye inflammation*, diplopia, dry eyes*, eye irritation*, eye pain, increased lacrimation, eye discharge |
|
| Rare |
Corneal damage*, exophthalmos, retinitis, scotoma, other eye (and eyelid) diseases, acquired dacryoadenitis, photophobia, photopsia, optic neuropathy#, various degrees of vision deterioration (up to blindness)* |
|
| Ear and labyrinth disorders |
Common |
Vertigo* |
| Uncommon |
Dysacusis (including tinnitus)*, hearing loss (up to deafness), ear discomfort* |
|
| Rare |
Ear hemorrhage, vestibular neuronitis, other ear disorders |
|
| Cardiac disorders |
Uncommon |
Cardiac tamponade#, cardiopulmonary shock*, cardiac fibrillation (including atrial), heart failure (including left and right ventricular)*, arrhythmia*, tachycardia*, palpitations, angina, 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 disorders#, deep vein thrombosis*, hemorrhage*, thrombophlebitis (including superficial), vascular collapse (including hypovolemic shock), phlebitis, flushing*, hematoma (including perinephric)*, peripheral circulation disorders*, vasculitis, hyperemia (including ocular)* |
|
| Rare |
Peripheral vascular embolism, lymphedema, pallor, erythromelalgia, vasodilation, vascular discoloration, venous insufficiency |
|
| Respiratory, thoracic and mediastinal disorders |
Common |
Dyspnea*, epistaxis, lower/upper respiratory tract infections*, cough* |
| Uncommon |
Pulmonary embolism, pleural effusion, pulmonary edema (including acute), pulmonary alveolar hemorrhage#, bronchospasm, chronic obstructive pulmonary disease*, hypoxemia*, worsening of airway patency*, hypoxia, pleurisy*, 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, pulmonary fibrosis, bronchial disorders*, hypocapnia*, interstitial pneumonia, lung infiltration, throat tightness sensation, throat dryness, increased upper respiratory tract secretion, throat irritation, upper respiratory tract cough syndrome |
|
| Gastrointestinal disorders |
Very common |
Nausea and vomiting*, diarrhea*, constipation |
| Common |
Gastrointestinal hemorrhage (including mucosal)*, dyspepsia, stomatitis*, abdominal distension, oropharyngeal pain*, abdominal pain (including gastrointestinal and splenic region)*, oral cavity disorders*, flatulence |
|
| Uncommon |
Pancreatitis (including chronic)*, vomiting 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 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, oral pharyngeal blistering*, lip pain, periodontitis, anal fissure, altered defecation rhythm, proctalgia, abnormal defecation |
|
| Hepatobiliary disorders |
Common |
Liver enzyme level disturbances* |
| Uncommon |
Hepatotoxicity (including liver disorders), hepatitis*, cholestasis |
|
| Rare |
Liver failure, hepatomegaly, Budd-Chiari syndrome, cytomegalovirus hepatitis, liver 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*, bullae*, 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 system and connective tissue*, synovial cyst |
|
| Renal and urinary system disorders |
Common |
Renal failure* |
| Uncommon |
Acute renal failure, chronic renal failure*, urinary tract infections*, signs and symptoms of urinary tract disorders*, hematuria*, urinary retention, micturition disorders*, proteinuria, azotemia, oliguria*, polyuria |
|
| Rare |
Bladder irritation |
|
| Reproductive system and breast disorders |
Uncommon |
Vaginal bleeding, genital pain*, erectile dysfunction |
| Rare |
Testicular disorders*, prostatitis, breast disorders in women, epididymis tenderness, epididymitis, pelvic pain, vulvar ulcers |
|
| Congenital, familial and genetic disorders |
Rare |
Aplasia, gastrointestinal tract malformations, ichthyosis |
| General disorders and administration site conditions |
Very common |
Pyrexia*, fatigue, asthenia |
| Common |
Edema (including peripheral), chills, pain*, fever* |
|
| Uncommon |
General physical health disturbances*, facial edema*, injection site reactions*, mucosal disorders*, chest pain, gait disturbance, feeling cold, extravasation*, complications related to catheter*, thirst sensation*, chest discomfort, sensation of body temperature change*, pain related to injection* |
|
| Rare |
Lethal outcome (including sudden), multiorgan failure, bleeding 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 |
|
| Investigation parameter changes |
Common |
Weight loss |
| Uncommon |
Hyperbilirubinemia*, deviation of protein levels from normal*, weight gain, blood analysis abnormalities*, increased C-reactive protein level |
|
| Rare |
Blood gas abnormalities*, ECG abnormalities (including QT interval prolongation)*, international normalized ratio (INR) abnormalities*, increased gastric acidity, increased platelet aggregation, elevated troponin I level, virus identification in serological tests*, urine analysis abnormalities* |
|
| Injury, poisoning and 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 |
*Aggregate of more than one MedDRA term [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 the drug at a dose of 1.3 mg/m² in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP), and in 242 patients who received rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), was generally similar to the safety profile observed in patients with multiple myeloma; the main differences are outlined below. Additional adverse reactions observed with bortezomib when used as part of combination therapy (VR-CAP) included hepatitis B virus infection (˂1%) and myocardial ischemia (1.3%). The similar incidence of these events in both treatment groups suggests that these adverse reactions may not be solely attributable to bortezomib. Treatment with bortezomib in patients with mantle cell lymphoma was associated with ≥5% higher frequencies of hematologic adverse reactions (neutropenia, thrombocytopenia, leukopenia, anemia, lymphopenia), peripheral sensory neuropathy, arterial hypertension, pyrexia, pneumonia, stomatitis, and hair disorders compared to patients with multiple myeloma.
Adverse reactions observed at a frequency ≥1% in the VR-CAP treatment group and considered possibly or probably related to the medicinal products included in the VR-CAP combination regimen are listed in Table 8. Also included are adverse reactions observed in the VR-CAP treatment group that, in the opinion of investigators, were at least 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 (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), and not known (cannot be estimated from available data). Within each category, adverse reactions are listed in order of decreasing severity.
Table 8
| Organ systems |
Frequency |
Adverse reactions |
| 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*, fluid retention |
|
| Uncommon |
Tumor lysis syndrome |
|
| Psychiatric disorders |
Common |
Sleep disorders* |
| Nervous system disorders |
Very common |
Peripheral sensory neuropathy, dysesthesia*, neuralgia* |
| Common |
Neuropathies*, motor neuropathy*, loss of consciousness (including syncope), encephalopathy*, sensory-motor peripheral neuropathy, dizziness*, dysgeusia*, autonomic neuropathy |
|
| Uncommon |
Autonomic nervous system disorders |
|
| Eye disorders |
Common |
Visual disturbances* |
| Ear and labyrinth disorders |
Common |
Dysacusis (including tinnitus)* |
| Uncommon |
Vertigo*, hearing impairment (up to deafness) |
|
| Cardiac disorders |
Common |
Atrial fibrillation (including atrial), arrhythmia*, heart failure (including left and right ventricular)*, myocardial ischemia, ventricular dysfunction* |
| Uncommon |
Cardiovascular disorders (including cardiogenic shock) |
|
| Vascular disorders |
Common |
Hypertension*, hypotension*, orthostatic hypotension |
| Respiratory, thoracic and mediastinal disorders |
Common |
Dyspnea*, cough*, hiccups |
| Uncommon |
Acute respiratory distress syndrome, pulmonary embolism, pneumonitis, pulmonary hypertension, pulmonary edema (including acute) |
|
| Gastrointestinal disorders |
Very common |
Nausea and vomiting*, diarrhea*, stomatitis*, constipation |
| Common |
Gastrointestinal hemorrhage (including mucosal)*, abdominal distension, dyspepsia, oropharyngeal pain*, gastritis*, oral ulcers*, abdominal discomfort, dysphagia, gastrointestinal inflammation*, abdominal pain (including gastrointestinal and splenic region pain)*, oral cavity disorders* |
|
| Uncommon |
Colitis (including Clostridium difficile-induced)* |
|
| Hepatobiliary disorders |
Common |
Hepatotoxicity (including 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 reactions |
Very common |
Pyrexia*, fatigue, asthenia |
| Common |
Edema (including peripheral), chills, injection site reactions*, fever* |
|
| Investigations |
Common |
Hyperbilirubinemia*, abnormal protein levels*, decreased body weight, increased body weight |
* MedDRA terms aggregated.
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. 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 in combination therapy with the BR-CAP regimen. Herpes zoster occurred in 10.7% of patients who did not receive antiviral agents, compared to 3.6% of patients who received antiviral prophylaxis.
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 BR-CAP regimen (rituximab, cyclophosphamide, doxorubicin, and prednisone). The overall incidence of hepatitis B was similar in both treatment groups (0.8% in the BR-CAP group versus 1.2% in the R-CHOP group).
Peripheral neuropathy during combination therapy
Multiple myeloma
Peripheral neuropathy was observed in clinical trials where bortezomib was used as induction therapy in combination with dexamethasone (study IFM-2005-01) and with dexamethasone and thalidomide (study MMY-3010) (see Table 9).
Table 9
Incidence of peripheral neuropathy (PN) during induction therapy by toxicity grade and need for treatment interruption due to PN
| Peripheral neuropathy indicators |
IFM-2005-01 |
MMY-3010 |
||
| VDDx (N = 239) |
BDx (N = 239) |
TDx (N = 126) |
BTDx (N = 130) |
|
| Frequency of PN (%) |
||||
| All grades of PN |
3 |
15 |
12 |
45 |
| PN ≥ Grade 2 |
1 |
10 |
2 |
31 |
| PN ≥ Grade 3 |
< 1 |
5 |
0 |
5 |
| Discontinuation due to PN (%) |
< 1 |
2 |
1 |
5 |
VDDx — vincristine, doxorubicin, dexamethasone; BDx — bortezomib, dexamethasone; TDx — thalidomide, dexamethasone; BTDx — bortezomib, thalidomide, dexamethasone.
Peripheral neuropathy includes: peripheral neuropathy, peripheral motor neuropathy, peripheral sensory neuropathy, and polyneuropathy.
Mantle cell lymphoma
In the LYM-3002 study, in which bortezomib was administered in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHOP), cases of peripheral neuropathy were observed (see 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
| Peripheral neuropathy parameters |
BR-CAP (N = 240) |
R-CHOP (N = 242) |
| Incidence of PN (%) |
||
| All-grade PN |
30 |
29 |
| PN ≥ Grade 2 |
18 |
9 |
| PN ≥ Grade 3 |
8 |
4 |
| Discontinuation due to PN (%) |
2 |
< 1 |
BR-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 sensory-motor neuropathy.
Elderly patients with mantle cell lymphoma
In the BR-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 incidence of serious adverse reactions was 68% in the BR-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 3 toxicity or higher was 13% lower compared to patients receiving intravenous bortezomib, and the incidence of treatment interruption due to bortezomib was 5% lower. The overall incidence of diarrhea, lower abdominal pain and abdominal pain, asthenic conditions, upper respiratory tract infections, and peripheral neuropathies was 12–15% lower in the subcutaneous group compared to the intravenous group. Additionally, the incidence of Grade 3 or higher peripheral neuropathies was 10% lower, and the incidence 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.
Severe 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. Mortality due to disease progression was 18% in the subcutaneous group and 9% in the intravenous group.
Re-treatment of patients with relapsed multiple myeloma
In a study of bortezomib re-treatment involving 130 patients with relapsed multiple myeloma who had previously achieved at least a partial response to bortezomib-containing therapy, treatment-emergent adverse reactions of all severity 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 3 were observed in 40% and 8.5% of patients, respectively.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, or their legal representatives should report all cases of suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.
Shelf life. 3 years.
Storage conditions. Store at temperatures not exceeding 30 °C in the original packaging to protect from light. Keep out of reach of children.
Incompatibilities. No data available.
Packaging. Powder for solution for injection in a vial, 1 vial per cardboard box.
Prescription status. Prescription only.
Manufacturer. Baxter Oncology GmbH.
Manufacturer's address and location of its operations.
Kantstraße 2, 33790 Halle/Westfalen, Germany.