Bortezomib
Ukraine
Table of Contents
Instructions for medical use of the medicinal product BORTEZOMIB (BORTEZOMIB)
Composition:
Active ingredient: bortezomib;
1 vial contains 3.5 mg of bortezomib;
Excipients: mannitol (E421), nitrogen.
Pharmaceutical form. Lyophilized powder for solution for injection.
Main physicochemical properties: lyophilisate 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 that inhibits the chymotrypsin-like activity of the 26S proteasome in mammalian cells. The 26S proteasome is a large protein complex involved in the degradation of key regulatory proteins. This pathway plays a central role in regulating the turnover of specific proteins, thereby maintaining cellular homeostasis. Inhibition of the 26S proteasome leads to suppression of proteolysis and triggers a cascade of reactions that ultimately result in the death 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 major enzymes. The kinetics of proteasome inhibition were determined in vitro; bortezomib dissociated from the proteasome with a t½ of 20 minutes, demonstrating that inhibition of the proteasome by bortezomib is reversible. By inhibiting the proteasome, bortezomib affects cancer cells through multiple mechanisms, including altering regulatory proteins that control 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.
Bortezomib is cytotoxic to many types of cancer cells, and cancer cells are more susceptible to bortezomib-induced apoptosis than normal cells. In vivo, bortezomib causes inhibition of growth in various experimental human tumors, including multiple myeloma.
Data from in vitro, ex vivo, and animal model studies indicate that bortezomib enhances osteoblast differentiation and activity and inhibits osteoclast function. These effects have been observed in patients with multiple myeloma who also had advanced-stage osteolytic disease and were treated with bortezomib.
Pharmacokinetics
Absorption. After intravenous bolus administration of doses of 1.0 mg/m² and 1.3 mg/m² to patients with multiple myeloma and creatinine clearance values above 50 mL/min, the mean peak plasma concentration (Cmax) of bortezomib after the first dose was 57 and 112 ng/mL, respectively. After subsequent doses, the mean peak plasma concentration of bortezomib ranged from 67 to 106 ng/mL with the 1.0 mg/m² dose and from 89 to 120 ng/mL with the 1.3 mg/m² dose.
Distribution. The mean volume of distribution (Vd) of bortezomib ranges from 1659 to 3294 liters following single or multiple doses of 1.0 mg/m² or 1.3 mg/m² in patients with multiple myeloma, indicating extensive distribution into peripheral tissues. At bortezomib concentrations of 0.01–1.0 µg/mL, plasma protein binding is 83%. The fraction of bortezomib bound to plasma proteins was independent of concentration.
Metabolism. In vitro, bortezomib metabolism is primarily mediated by cytochrome P450 enzymes, including CYP3A4, CYP2C19, and CYP1A2. The main metabolic pathway involves deboronation to two metabolites, which are subsequently hydroxylated. The deboronated metabolites 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 cleared more rapidly after the first dose compared to subsequent doses. Mean total clearance was 102 and 112 L/h after the first dose of 1.0 mg/m² and 1.3 mg/m², respectively, and ranged from 15 to 32 L/h and 18 to 32 L/h after subsequent doses of 1.0 mg/m² and 1.3 mg/m², respectively.
Special patient populations
Hepatic impairment. The effect of hepatic impairment on the pharmacokinetics of bortezomib was evaluated in a Phase I study during the first treatment cycle, including 60 patients predominantly with solid tumors and varying degrees of hepatic impairment, with bortezomib doses ranging 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 and severe hepatic impairment. Dose adjustment and careful monitoring during treatment are recommended for these patients.
Renal impairment. Pharmacokinetic studies were conducted in patients with varying degrees of renal impairment, categorized by creatinine clearance (CrCL) into the following groups: normal (CrCL ≥ 60 mL/min/1.73 m², n = 12), mild impairment (CrCL = 40–59 mL/min/1.73 m², n = 10), moderate impairment (CrCL = 20–39 mL/min/1.73 m², n = 9), and severe impairment (CrCL < 20 mL/min/1.73 m², n = 3). Patients undergoing dialysis who received bortezomib after dialysis were also included in the study (n = 8). Patients received intravenous bortezomib doses of 0.7–1.3 mg/m² twice weekly. Bortezomib exposure (standardized AUC and Cmax) was comparable across all groups.
Age. Pharmacokinetic parameters of bortezomib were evaluated in 104 pediatric patients (aged 2–16 years) with acute lymphoblastic leukemia or acute myeloid leukemia who received bortezomib 1.3 mg/m² twice weekly via intravenous bolus injection. According to population pharmacokinetic analysis, bortezomib clearance increases with increasing body surface area. The geometric mean (% CV) of clearance was 7.79 (25%) L/h/m², 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 previously untreated patients who are not eligible for high-dose chemotherapy with hematopoietic stem cell transplantation, as part of combination therapy with melphalan and prednisone (first-line therapy).
Treatment of relapsed multiple myeloma in patients who have received at least one prior therapy and who have undergone hematopoietic stem cell transplantation or are not candidates for transplantation – as monotherapy or in combination with pegylated liposomal doxorubicin or dexamethasone (second-line therapy).
Treatment of previously untreated multiple myeloma in patients eligible for high-dose chemotherapy with hematopoietic stem cell transplantation – as part of combination therapy with dexamethasone or dexamethas0ne and thalidomide (induction therapy).
Treatment of mantle cell lymphoma in previously untreated patients who are not candidates for hematopoietic stem cell transplantation – as part of combination therapy with rituximab, cyclophosphamide, doxorubicin, and prednisone.
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 also to the instructions for medical use of these products regarding additional contraindications.
Special precautions.
General warnings. Bortezomib is a cytotoxic medicinal product. Therefore, caution should be exercised during its preparation and administration. It is recommended to use gloves and protective clothing to prevent skin contact.
Appropriate aseptic handling procedures should be strictly followed when handling Bortezomib, as it contains no preservatives.
Fatal cases have been reported following accidental intrathecal administration of bortezomib. Bortezomib must be administered intravenously or subcutaneously. DO NOT ADMINISTER BORTEZOMIB INTRATHECALLY!
Disposal. The medicinal product is intended for single use only. Any unused medicinal product should be disposed of according to local requirements.
Interaction with other medicinal products and other forms of interaction.
In vitro studies have demonstrated that bortezomib is a weak inhibitor of cytochrome P450 isoenzymes: 1A2, 2C9, 2C19, 2D6, and 3A4. Since CYP2D6 plays a minor role in bortezomib metabolism, changes in overall exposure are not expected in poor metabolizers of this enzyme.
Studies investigating the effect of ketoconazole, a potent CYP3A4 inhibitor, on the pharmacokinetics of bortezomib (after intravenous administration) showed an average increase of 35% in bortezomib AUC. Therefore, careful monitoring of patients receiving bortezomib concomitantly with potent CYP3A4 inhibitors (such as ketoconazole, ritonavir) is recommended.
Studies investigating the effect of omeprazole, a potent CYP2C19 inhibitor, on the pharmacokinetics of bortezomib (after intravenous administration) did not reveal a significant impact on bortezomib pharmacokinetics.
Studies investigating the effect of rifampicin, a potent CYP3A4 inducer, showed an average reduction of 45% in bortezomib AUC (after intravenous administration). Therefore, concomitant use of bortezomib with potent CYP3A4 inducers (such as rifampicin, carbamazepine, phenytoin, phenobarbital, and St. John's wort extract) is not recommended, as the efficacy of bortezomib may be reduced.
In the same interaction study, evaluation of the effect of dexamethasone, a weak CYP3A4 inducer, did not show a clinically significant impact on bortezomib pharmacokinetics.
Drug interaction studies and the effect of melphalan and prednisone on bortezomib pharmacokinetics (after intravenous administration) demonstrated an increase in bortezomib AUC, which is not considered clinically relevant.
In patients with diabetes mellitus receiving oral hypoglycemic agents, cases of hypoglycemia and hyperglycemia have been reported. Patients taking oral antidiabetic drugs should monitor their blood glucose levels closely during bortezomib treatment and adjust the dose of antidiabetic agents accordingly.
Special precautions for use.
If bortezomib is used in combination with other medicinal products, refer to the instructions for medical use of these medicinal products prior to initiating treatment. Particular attention should be paid to pregnancy testing and contraceptive measures when thalidomide is used.
Intrathecal administration. Fatal cases have been reported due to accidental intrathecal administration of bortezomib. Bortezomib should only be administered intravenously or subcutaneously. DO NOT ADMINISTER BORTEZOMIB INTRATHECALLY!
Gastrointestinal complications. Treatment with bortezomib very commonly causes gastrointestinal toxicity, including nausea, diarrhea, constipation, and vomiting. Cases of intestinal obstruction (reported as uncommon in frequency) have been reported; therefore, patients with constipation should be under medical supervision.
Hematological complications. Hematological toxicity (thrombocytopenia, neutropenia, and anemia) is very commonly observed during bortezomib therapy. In studies of bortezomib use in patients with relapsed multiple myeloma and in combination therapy with rituximab, cyclophosphamide, doxorubicin, and prednisone (VcR-CAP regimen) in previously untreated mantle cell lymphoma patients, one of the most common hematological toxicities was reversible thrombocytopenia. Platelet counts typically reached their lowest level 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 studies of bortezomib monotherapy in multiple myeloma patients and 50% in studies in mantle cell lymphoma patients. In patients with progressive myeloma, the severity of thrombocytopenia was related to the pre-treatment platelet count: with a baseline platelet count < 75,000/µL, 90% of 21 patients had platelet counts ≤ 25,000/µL during the study, including 14% with < 10,000/µL, whereas with a baseline platelet count > 75,000/µL, only 14% of 309 patients had platelet counts ≤ 25,000/µL.
In patients with mantle cell lymphoma, grade ≥ III thrombocytopenia occurred more frequently in the group receiving bortezomib (VcR-CAP regimen) compared to those receiving R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). The overall frequency of bleeding events of all grades, as well as bleeding events of at least grade III, was similar in both groups. In the VcR-CAP treatment group, 22.5% of patients required platelet transfusions compared to 2.9% in the R-CHOP group.
Cases of gastrointestinal and intracranial hemorrhages associated with bortezomib use have been reported. Therefore, platelet counts should be monitored before each dose of bortezomib. Therapy with bortezomib 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 bortezomib treatment should be evaluated, especially 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 bortezomib therapy. Platelet transfusion should be considered if clinically indicated.
Reversible neutropenia between treatment cycles has been observed in patients with mantle cell lymphoma; cumulative neutropenia was not observed. White blood cell counts typically reached their lowest level on day 11 of each bortezomib treatment cycle and returned to baseline levels before the start of the next cycle. In a study of bortezomib use in mantle cell lymphoma patients, 78% of patients in the VcR-CAP group and 61% in the R-CHOP group received colony-stimulating factor. Since patients with neutropenia are at increased risk of developing infections, they should be monitored for signs of infection and appropriate therapeutic measures taken. The use of granulocyte colony-stimulating factor should be considered for the management of hematological toxicity. If initiation of a new treatment cycle is delayed several times, prophylactic use of granulocyte colony-stimulating factor should be considered.
Herpes zoster reactivation. Antiviral prophylaxis should be considered for patients treated with bortezomib. In phase III trials involving previously untreated multiple myeloma patients, the overall frequency of herpes zoster reactivation (shingles) was higher in the group receiving bortezomib + melphalan + prednisone (14%) compared to the group receiving melphalan + prednisone (4%).
Among patients with mantle cell lymphoma, the incidence of shingles was 6.7% in the VcR-CAP group and 1.2% in the R-CHOP group.
Hepatitis B virus (HBV) reactivation and infection.
Prior to 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 combined treatment with rituximab and bortezomib. Antiviral prophylaxis should be considered.
Progressive multifocal leukoencephalopathy (PML). Very rare cases of John Cunningham virus infection causing PML with fatal outcome have been reported in patients treated with bortezomib. Patients diagnosed with PML had received immunosuppressive therapy in their history or concurrently with bortezomib. Most PML cases were diagnosed within the first 12 months after 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 managing PML and appropriate diagnostic measures taken. Bortezomib treatment should be discontinued if PML is confirmed.
Peripheral neuropathy. Treatment with bortezomib is very commonly associated with peripheral neuropathy, predominantly sensory. However, cases of severe motor neuropathy with or without sensory peripheral neuropathy have been reported. The incidence of peripheral neuropathy typically peaks during the 5th treatment cycle with bortezomib.
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 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 a neurological examination; dose adjustment, change in administration schedule, or switching to subcutaneous administration may be necessary. Neuropathy should be managed with supportive measures.
Regular monitoring for treatment-induced neuropathic symptoms and neurological examination are required for patients receiving bortezomib in combination with medicinal products associated with neuropathy (such as thalidomide); dose reduction or discontinuation of treatment should be considered.
In addition to peripheral neuropathy, autonomic neuropathy may contribute to certain adverse reactions such as postural hypotension and acute constipation with intestinal obstruction. Information on autonomic neuropathy and its impact on these adverse reactions is limited.
Seizures. Rare cases of seizure development have been observed in patients with a history of seizures or epilepsy. Particular caution is required when treating patients with any risk factors for seizures.
Hypotension. Bortezomib therapy is often 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 administration (intravenous) did not have symptoms of orthostatic hypotension prior to bortezomib treatment. Most patients required treatment for orthostatic hypotension, and a smaller number experienced episodes of syncope. Orthostatic/postural hypotension was not clearly associated with bolus infusion of bortezomib, and its mechanism is unknown. It may be related to autonomic neuropathy. Autonomic neuropathy may be associated with bortezomib use or bortezomib may exacerbate underlying conditions, including diabetic or amyloid neuropathy. Caution is advised when treating patients with a history of syncope, those taking antihypertensive medications, and those with dehydration due to diarrhea or vomiting. In case of orthostatic hypotension, hydration, glucocorticoids, and/or sympathomimetics are recommended; antihypertensive medications should be reduced if necessary. Patients should be instructed to consult a physician if they experience dizziness, presyncope, or syncope.
Reversible posterior leukoencephalopathy syndrome (RPLS). Cases of RPLS have been reported in patients treated with bortezomib. RPLS is a rare, reversible neurological disorder characterized by seizures, arterial hypertension, headache, lethargy, confusion, visual disturbances, and other neurological impairments. Brain imaging, preferably with magnetic resonance imaging (MRI), should be performed to confirm the diagnosis. Bortezomib treatment should be discontinued if RPLS occurs.
Heart failure. Cases of development or worsening of 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 heart failure symptoms. Patients with risk factors or pre-existing heart disease should be monitored.
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. Chest X-ray is recommended before starting treatment to establish baseline lung status and for comparison in case of potential treatment-induced lung dysfunction.
In case of new or worsening pulmonary symptoms (e.g., cough, dyspnea), prompt diagnosis and appropriate therapeutic measures should be taken. The benefit-risk ratio of continuing bortezomib treatment should be carefully considered.
In clinical trials, two out of two patients treated with high-dose cytarabine (2 g/m²/day) as continuous 24-hour infusion in combination with daunorubicin and bortezomib for relapsed acute myeloid leukemia died from ARDS at the beginning of the treatment course. Therefore, this specific regimen of concomitant high-dose cytarabine (2 g/m²/day) as continuous 24-hour infusion is not recommended.
Renal function disorders. Renal function impairment is commonly observed in patients with multiple myeloma. Close monitoring of such patients is recommended.
Hepatic function disorders. Bortezomib is metabolized by hepatic enzymes. Bortezomib concentrations may increase in patients with moderate to severe hepatic impairment; these patients should be treated with reduced doses and closely monitored for signs of toxicity.
Hepatic reactions. Rare cases of acute liver failure have been reported in patients treated with 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, 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 appropriate preventive measures are recommended.
Precautions regarding concomitant use of other medicinal products. Patients should be under close physician supervision when bortezomib is used in combination with strong CYP3A4 inhibitors. Caution should be exercised when combining bortezomib with CYP3A4 or CYP2C9 substrates.
Liver function should be corrected prior to initiating treatment if impaired, and caution should be exercised when administering the drug to patients taking oral hypoglycemic agents.
Potentially immune complex-mediated reactions. Immune complex-mediated reactions such as serum sickness, polyarthritis with rash, and proliferative glomerulonephritis have been reported uncommonly. Bortezomib should be discontinued in case of serious reactions.
Use during pregnancy or breastfeeding.
Contraception in men and women
Men and women of reproductive potential must use effective contraceptive measures during treatment and for 3 months after completion of treatment.
Pregnancy
There are no clinical data on the use of bortezomib during pregnancy. The teratogenic properties of bortezomib have not been fully investigated.
Bortezomib has been reported not to affect embryonic development in rats and rabbits during organogenesis at the maximum tolerated doses. Pre- and postnatal developmental studies in animals have not been conducted. Bortezomib is not recommended during pregnancy except in cases where the woman's clinical condition requires treatment with bortezomib. If bortezomib must be used during pregnancy or if pregnancy occurs during bortezomib treatment, 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 avoid pregnancy. See also the thalidomide product information.
Breastfeeding
It is unknown whether bortezomib passes into breast 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. Bortezomib use is very commonly associated with fatigue, frequently with dizziness, uncommonly with syncope, orthostatic/postural hypotension, and frequently with visual disturbances. Therefore, patients should be cautious when driving or operating machinery.
Method of Administration and Dosage
Treatment should be initiated under the supervision of a qualified physician experienced in the use of anticancer agents. Preparation of the solution must be performed only by qualified medical personnel.
Preparation of the Solution. The preparation of the solution must be performed only by qualified medical personnel.
For intravenous administration, the contents of the vial should be reconstituted with 3.5 mL of 0.9% sodium chloride injection solution. The lyophilized powder dissolves in less than 2 minutes. After reconstitution, 1 mL of solution contains 1 mg of bortezomib. The resulting solution should be clear and colorless, with a pH of 4–7. Before administration, the prepared solution should be inspected visually for particulate matter and discoloration. If particles are present or discoloration occurs, the solution must not be used.
For subcutaneous administration, the contents of each vial should be reconstituted with 1.4 mL of 0.9% sodium chloride injection solution. The dissolution 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. Before administration, the prepared solution should be inspected visually for particulate matter and discoloration. If particles are present or discoloration occurs, the solution must not be used.
Relapsed Multiple Myeloma (patients who have received at least one prior therapy)
Monotherapy
The recommended dose of bortezomib for adults is 1.3 mg/m² body surface area administered as intravenous or subcutaneous injections 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. If a complete clinical response is achieved, two additional cycles of treatment are recommended. For patients with a partial response but not complete remission, continuation of bortezomib therapy is recommended, but not for more than 8 cycles in total. At least 72 hours must elapse between consecutive doses of bortezomib.
Dosage Adjustment and Reintroduction Recommendations for Bortezomib as Monotherapy.
If any non-hematological toxicity of grade III or hematological toxicity of grade IV occurs, except for neuropathies, bortezomib treatment must be withheld. After resolution of toxicity 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 toxicity symptoms do not resolve or recur during treatment with the reduced dose, discontinuation of bortezomib should be considered, unless the benefits of continued treatment outweigh the risks.
Neuropathic Pain and/or Peripheral Neuropathy.
In case of development of neuropathic pain and/or peripheral neuropathy, the dose should be adjusted according to Table 1. Bortezomib should be administered to patients with a history of severe neuropathy only after careful assessment of the benefit-risk ratio.
Recommended* dose modification in the event of bortezomib-induced neuropathy.
Table 1
| Severity of neuropathy |
Dose and administration frequency adjustment |
| Grade I (asymptomatic; loss of deep tendon reflexes or paresthesia) without pain or functional impairment |
No dose or administration adjustment required |
| 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 in self-care activities)*** |
Withhold bortezomib until toxic symptoms resolve. Then resume treatment at a reduced dose of 0.7 mg/m² once weekly. |
| Grade IV (life-threatening consequences; requiring urgent intervention) and/or severe autonomic neuropathy |
Discontinue bortezomib |
* Based on dose modifications observed in Phase II and III multiple myeloma studies and in the post-marketing period.
** Instrumental activities of daily living include: cooking, shopping, using the telephone, etc.
*** Self-care activities of daily living include: bathing, dressing/undressing, eating, using the toilet, taking medications, non-bedridden status.
Combination therapy with pegylated liposomal doxorubicin.
The recommended dose of bortezomib for adults is 1.3 mg/m² body surface area administered as intravenous or subcutaneous injections twice weekly for 2 weeks (Days 1, 4, 8, and 11), followed by a 10-day treatment-free 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 should be 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 8 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 2 additional cycles after achieving complete response, even if this requires treatment beyond 8 cycles. Patients whose paraprotein levels continue to decrease after 8 cycles may also continue treatment as long as the therapy is well tolerated and a response to treatment 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 treatment-free period (Days 12–21). This 3-week period is considered one treatment cycle. At least 72 hours should elapse between consecutive doses of bortezomib.
Dexamethasone should be administered orally at a dose of 20 mg on Days 1, 2, 4, 5, 8, 9, 11, and 12 of the bortezomib treatment cycle.
Patients who show a response to treatment or stable disease after four cycles may continue treatment with this combination for up to 4 additional cycles. See also the dexamethasone prescribing information.
Dose modification recommendations for combination therapy in patients with relapsed multiple myeloma.
See dose modification recommendations for bortezomib monotherapy provided above.
Previously untreated multiple myeloma in patients not eligible for hematopoietic stem cell transplantation
Combination therapy with melphalan and prednisone.
Bortezomib should be administered intravenously or subcutaneously in combination with oral melphalan and oral prednisone over nine 6-week treatment cycles (see Table 2). In cycles 1−4, bortezomib should be administered twice weekly
(on Days 1, 4, 8, 11, 22, 25, 29, and 32). In cycles 5−9, bortezomib should be administered once weekly (on Days 1, 8, 22, and 29). At least 72 hours should elapse between consecutive doses of bortezomib.
Melphalan and prednisone should be administered orally on Days 1, 2, 3, and 4 of the first week of each cycle.
Recommended dosing regimen of bortezomib in combination with melphalan and prednisone
Table 2
| Bortezomib 2 times per week (cycles 1–4) |
|||||||||||||||||||
| Week |
1 |
2 |
3 |
4 |
5 |
6 |
|||||||||||||
| Bortezomib (1.3 mg/m²) |
Day 1 |
˗ |
˗ |
Day 4 |
Day 8 |
Day 11 |
Break |
Day 22 |
Day 25 |
Day 29 |
Day 32 |
Break |
|||||||
| M (9 mg/m²) P (60 mg/m²) |
Day 1 |
Day 2 |
Day 3 |
Day 4 |
˗ |
˗ |
Break |
˗ |
˗ |
˗ |
˗ |
Break |
|||||||
| Bortezomib 1 time per week (cycles 5–9) |
|||||||||||||||||||
| Week |
1 |
2 |
3 |
4 |
5 |
6 |
|||||||||||||
| Bortezomib (1.3 mg/m²) |
Day 1 |
˗ |
˗ |
Day 8 |
Break |
Day 22 |
Day 29 |
Break |
|||||||||||
| M (9 mg/m²) P (60 mg/m²) |
Day 1 |
Day 2 |
Day 3 |
Day 4 |
˗ |
Break |
˗ |
˗ |
Break |
||||||||||
M = melphalan, P = prednisone.
Recommendations for dose adjustment and resumption of combination therapy with melphalan and prednisone.
Prior to starting a new treatment cycle:
- platelet count must be ≥ 70×10⁹/L and absolute neutrophil count must be ≥ 1.0×10⁹/L;
- non-hematological toxicity must have resolved to Grade 1 or baseline levels.
Dose adjustment during subsequent cycles of bortezomib combination therapy
with melphalan and prednisone
Table 3
| Toxicity |
Dose modification or treatment discontinuation |
| Hematological toxicity during cycle:
|
Consider reducing melphalan dose by 25% in the next cycle |
≤ 30×109/L or absolute neutrophil count ≤ 0.75×109/L on the day of bortezomib administration (except day 1) |
Dose administration should be delayed |
|
Bortezomib dose should be reduced by 1 level (from 1.3 mg/m2 to 1 mg/m2 or from 1 mg/m2 to 0.7 mg/m2) |
| Non-hematological toxicity ≥ grade III |
Bortezomib treatment should be withheld until symptoms improve to baseline level or grade I severity. Then bortezomib may be restarted at a dose reduced by 1 level (from 1.3 mg/m2 to 1 mg/m2 or from 1 mg/m2 to 0.7 mg/m2). In case of bortezomib-dependent neuropathic pain and/or peripheral neuropathy, hold and/or modify bortezomib dosing as specified in Table 1. |
See also the instructions for medical use of melphalan and prednisone.
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 treatment break (days 12–21). This 3-week period constitutes one treatment cycle. At least 72 hours should elapse between consecutive doses of bortezomib.
Dexamethasone should be administered orally at a dose of 40 mg on days 1, 2, 3, 4, 8, 9, 10, and 11 of the bortezomib treatment cycle.
Administer 4 treatment cycles of this combination.
Combination therapy with dexamethasone and thalidomide.
The recommended dose of bortezomib is 1.3 mg/m² body surface area administered as intravenous or subcutaneous injections 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 bortezomib.
Dexamethasone should be administered orally at a dose of 40 mg on days 1, 2, 3, 4, 8, 9, 10, and 11 of the bortezomib treatment cycle.
Thalidomide should be administered orally at a dose of 50 mg daily on days 1–14 of the cycle; if tolerated, the dose should be increased to 100 mg daily on days 15–28 of the cycle. Starting from the second cycle, the dose may be further increased to 200 mg daily (see Table 4).
Administer 4 treatment cycles. Patients achieving at least a partial response to treatment are recommended to receive 2 additional cycles of therapy.
Recommended dosing regimen of bortezomib in combination with dexamethasone and thalidomide for patients with untreated multiple myeloma who are eligible for hematopoietic stem cell transplantation.
Table 4
| Bortezomib + Dx |
Cycles 1−4 |
||||||
| Week |
1 |
2 |
3 |
||||
| Bortezomib (1.3 mg/m²) |
Day 1, 4 |
Day 8, 11 |
Rest |
||||
| 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 |
Rest |
Rest |
|||
| 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 |
Rest |
Rest |
|||
| T (200 mg)ᵃ |
Daily |
Daily |
Daily |
Daily |
|||
| Dx (40 mg) |
Day 1, 2, 3, 4 |
Day 8, 9, 10, 11 |
- |
- |
|||
Dx = dexamethasone; Thal = thalidomide.
a Increase the dose of thalidomide to 100 mg starting from the 3rd week of the first cycle if the patient tolerates the 50 mg dose, and to 200 mg if the patient tolerates the 100 mg dose.
b Patients who achieve a partial response after 4 cycles of treatment may continue up to a maximum of 6 cycles of treatment.
Dosage modification recommendations for patients who are candidates for transplantation.
For dose adjustments in the event of neuropathy, see Table 1.
If bortezomib is used in combination with other chemotherapeutic agents, refer also to the prescribing information for those medicinal products regarding dose adjustments in the event of toxicity.
Untreated mantle cell lymphoma
Combination therapy with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHOP-like regimen VcR-CAP)
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. A total of 6 cycles should be administered. Patients who first demonstrate response during the 6th cycle of treatment are recommended to receive 2 additional cycles of therapy.
Medicinal products administered by intravenous infusion on Day 1 of each 3-week bortezomib treatment cycle: rituximab at a dose of 375 mg/m², cyclophosphamide at 750 mg/m², doxorubicin at 50 mg/m².
Prednisone should be administered orally at a dose of 100 mg/m² on Days 1, 2, 3, 4, and 5 of each bortezomib treatment cycle.
Dosage modification recommendations for patients with untreated mantle cell lymphoma
Prior to initiation of a new treatment cycle:
- Platelet count must be ≥ 100,000 cells/µL, and absolute neutrophil count must be ≥ 1,500 cells/µL;
- For patients with bone marrow infiltration or splenic sequestration, platelet count must be ≥ 75,000 cells/µL;
- Hemoglobin level ≥ 8 g/dL;
- Non-hematological toxicity must have resolved to Grade 1 or baseline levels.
Bortezomib treatment should be withheld in the event of any non-hematological toxicity ≥ Grade III (except neuropathy) related to bortezomib administration, or in the event of hematological toxicity ≥ Grade III. Refer to Table 5 for dosage modification recommendations.
Granulocyte colony-stimulating factors may be used to manage hematological 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 as necessary for the management of thrombocytopenia.
Dose modification during therapy for patients with untreated mantle cell lymphoma
Table 5
| Toxicity |
Dose adjustment or treatment interruption |
| Hematologic toxicity |
|
|
Treatment with bortezomib should be interrupted for up to 2 weeks until the absolute neutrophil count recovers to ≥ 750 cells/μL and platelet count to ≥ 25,000 cells/μL.
|
|
Delay bortezomib dose administration |
| Non-hematologic toxicity ≥ Grade III related to bortezomib administration |
Bortezomib treatment should be interrupted until symptoms improve to at least Grade II severity. Bortezomib may then be reinitiated with a dose reduction by one level (from 1.3 mg/m² to 1 mg/m² or from 1 mg/m² to 0.7 mg/m²). In cases of bortezomib-induced neuropathic pain and/or peripheral neuropathy, bortezomib should be withheld and/or dose adjusted as specified in Table 1. |
If bortezomib is used in combination with other chemotherapeutic agents, also refer to the instructions for use of these medicinal products regarding dose adjustments of these agents in the event of toxicity.
Special patient groups
Elderly patients
Currently, there are no data indicating the need for dose adjustment in patients aged 65 years and older.
There are no studies on the use of bortezomib in elderly patients with untreated multiple myeloma who are candidates for high-dose chemotherapy with hematopoietic stem cell transplantation. Therefore, no recommendations on dose adjustment can be provided for this patient group.
In a study of bortezomib use in patients with untreated mantle cell lymphoma, patient ages were 65–74 years and ≥ 75 years. Patients aged ≥ 75 years 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 or severe hepatic impairment, treatment with bortezomib should be initiated at a dose of 0.7 mg/m² during the first treatment cycle, with subsequent gradual dose escalation to 1.0 mg/m² or dose reduction to 0.5 mg/m² depending on patient tolerability.
Recommendations for modification of initial bortezomib doses in patients with hepatic impairment
Table 6
| Severity of hepatic impairment* |
Bilirubin level |
AST level |
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 bortezomib pharmacokinetics. Since dialysis may reduce bortezomib concentrations, the drug should be administered after the dialysis procedure.
Method of administration.
Bortezomib should be administered as intravenous or subcutaneous injections. Accidental intrathecal administration 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. After injection, the catheter should be flushed with 0.9% sodium chloride injection solution. At least 72 hours should elapse between consecutive doses of bortezomib.
Subcutaneous.
The reconstituted solution should be administered immediately after preparation by subcutaneous injection, inserting the needle at an angle of 45–90° into the thigh (left or right) or abdominal area (left or right side). Injection sites should be rotated.
If adverse reactions at the injection site occur with subcutaneous administration, the bortezomib solution may be administered subcutaneously at a lower concentration (1 mg/mL instead of 2.5 mg/mL) or bortezomib may be administered intravenously.
Children.
The safety and efficacy of bortezomib in children (under 18 years of age) have not been established. Current available information is insufficient to provide dosage recommendations for pediatric patients.
Overdose.
Administration of doses more than twice the recommended dose has been associated with acute hypotension and thrombocytopenia resulting in fatal outcomes.
There is no known specific antidote for bortezomib. In case of overdose, careful monitoring of hemodynamic parameters (infusion therapy, vasopressors and/or inotropic agents) and body temperature is recommended.
Adverse reactions
Among the serious adverse reactions reported during bortezomib treatment, heart failure, tumor lysis syndrome, pulmonary hypertension, reversible posterior leukoencephalopathy syndrome (PRES), acute diffuse infiltrative pulmonary disorders have been reported infrequently, and autonomic neuropathy has been reported rarely. The most common adverse reactions during bortezomib treatment include nausea, diarrhea, constipation, vomiting, asthenia, pyrexia, thrombocytopenia, anemia, neutropenia, peripheral neuropathy (including sensory), headache, paresthesia, decreased appetite, dyspnea, rash, herpes zoster, and myalgia.
Multiple myeloma
The adverse reactions listed in Table 7 may be related to the use of bortezomib. Adverse reactions are grouped by organ systems and frequency of occurrence. Frequencies are defined as: very common (> 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), very rare (< 1/10000), and not known (cannot be estimated from available data). Within each group, adverse reactions are listed in decreasing order of severity. Also included are adverse reactions not observed during clinical trials but reported during 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, postviral fatigue syndrome |
|
| Benign, malignant and unspecified neoplasms (including cysts and polyps) |
Rare |
Malignant neoplasm, plasma cell leukemia, renal cell carcinoma, tumor proliferation, mycosis fungoides, benign neoplasm* |
| Blood and lymphatic system disorders |
Very common |
Thrombocytopenia*, neutropenia*, anemia* |
| Common |
Leukopenia*, lymphopenia* |
|
| Uncommon |
Pancytopenia*, febrile neutropenia, coagulopathy*, leukocytosis*, lymphadenopathy, hemolytic anemia# |
|
| Rare |
Disseminated intravascular coagulation syndrome, thrombocytosis*, hyperviscosity syndrome, thrombopathy, thrombotic microangiopathy (including thrombotic thrombocytopenic purpura), other blood and hematopoietic organ disorders, hemorrhagic diathesis, lymphocytic infiltration |
|
| Immune system disorders |
Uncommon |
Angioedema#, hypersensitivity* |
| Rare |
Anaphylactic shock, amyloidosis, type III immune complex-mediated reactions |
|
| Endocrine disorders |
Uncommon |
Cushing's syndrome*, hyperthyroidism*, syndrome of inappropriate antidiuretic hormone secretion |
| Rare |
Hypothyroidism |
|
| Metabolism and nutrition disorders |
Very common |
Decreased appetite |
| Common |
Dehydration, hypokalemia*, hyponatremia*, blood glucose disturbances*, hypocalcemia*, enzyme level disturbances* |
|
| Uncommon |
Tumor lysis syndrome, worsening of patient conditionª*, hypomagnesemia*, hypophosphatemia*, hyperkalemia*, hypercalcemia*, hypernatremia*, uric acid level disturbances*, diabetes mellitus*, fluid retention |
|
| Rare |
Hypermagnesemia*, acidosis, electrolyte imbalance*, hypervolemia, hypochloremia*, hypovolemia, hyperchloremia*, hyperphosphatemia*, metabolic disorders, vitamin B complex deficiency, vitamin B12 deficiency, gout, increased appetite, alcohol intolerance |
|
| Psychiatric disorders |
Common |
Mood and sensation disorders*, anxiety disorder*, sleep disorders* |
| Uncommon |
Psychiatric disorder*, hallucinations*, psychotic disorder*, confusion*, agitation |
|
| Rare |
Suicidal ideation*, adjustment disorder, delirium, decreased libido |
|
| Nervous system disorders |
Very common |
Neuropathies*, peripheral sensory neuropathy, dysesthesia*, neuralgia* |
| Common |
Motor neuropathy*, loss of consciousness (including syncope), dizziness*, dysgeusia*, lethargy, headache* |
|
| Uncommon |
Tremor, sensorimotor peripheral neuropathy, dyskinesia*, coordination and balance disturbances*, memory loss (without dementia)*, encephalopathy*, reversible posterior encephalopathy syndrome#, neurotoxicity, seizure disorders*, postherpetic neuralgia, speech disorders*, restless legs syndrome, migraine, sciatica, attention disorders, reflex disturbances*, parosmia |
|
| Rare |
Intracranial hemorrhage*, cerebral 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 disorders, psychomotor hyperactivity, spinal cord compression, other cognitive disorders, motor dysfunctions, other nervous system disorders, radiculitis, salivation, hypotonia, Guillain-Barré syndrome#, demyelinating polyneuropathy# |
|
| Eye disorders |
Common |
Eye edema*, visual disturbances*, conjunctivitis* |
| Uncommon |
Eye hemorrhages*, eyelid infections*, chalazion#, blepharitis#, eye inflammation*, diplopia, dry eyes*, eye irritation*, eye pain, increased lacrimation, eye discharge |
|
| Rare |
Corneal disorders*, exophthalmos, retinitis, scotoma, other eye (and eyelid) diseases, acquired dacryoadenitis, photophobia, photopsia, optic neuritis#, various 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*, atrial 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), flutter-fibrillation, unstable angina, heart valve disorders*, coronary artery insufficiency, sinus node arrest |
|
| Vascular disorders |
Common |
Hypotension*, orthostatic hypotension, hypertension* |
| Uncommon |
Cerebrovascular disorder#, deep vein thrombosis*, hemorrhage*, thrombophlebitis (including superficial), vascular collapse (including hypovolemic shock), phlebitis, flushing*, hematoma (including retroperitoneal)*, 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, 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, pulmonary fibrosis, bronchial disorders*, hypocapnia*, interstitial lung disease, lung infiltration, throat tightness, dry throat, increased upper respiratory tract secretion, throat irritation, upper respiratory tract cough syndrome |
|
| Gastrointestinal disorders |
Very common |
Nausea and vomiting*, diarrhea*, constipation |
| Common |
Gastrointestinal hemorrhage (including mucosal)*, dyspepsia, stomatitis*, abdominal distension, oropharyngeal pain*, abdominal pain (including gastrointestinal and splenic region)*, oral cavity disorders*, flatulence |
|
| Uncommon |
Pancreatitis (including chronic)*, vomiting blood, lip swelling*, gastrointestinal obstruction (including small bowel obstruction, ileus)*, abdominal discomfort, oral ulcers*, enteritis*, gastritis*, gum bleeding, gastroesophageal reflux disease*, colitis (including Clostridium difficile-induced)*, ischemic colitis#, gastrointestinal tract inflammation*, dysphagia, irritable bowel syndrome, other gastrointestinal disorders, coated tongue, gastrointestinal motility disorders*, salivary gland disorders* |
|
| Rare |
Acute pancreatitis, peritonitis*, tongue edema*, ascites, esophagitis, cheilitis, fecal incontinence, anal sphincter atony, fecaloma*, gastrointestinal ulcers and perforations*, gingival hyperplasia, megacolon, rectal discharge, blister formation in oropharynx*, lip pain, periodontitis, anal fissure, altered defecation rhythm, proctalgia, abnormal defecation |
|
| Hepatobiliary disorders |
Common |
Liver enzyme level disturbances* |
| Uncommon |
Hepatotoxicity (including liver disorders), hepatitis*, cholestasis |
|
| Rare |
Liver failure, hepatomegaly, Budd-Chiari syndrome, cytomegalovirus hepatitis, liver hemorrhage, cholelithiasis |
|
| Skin and subcutaneous tissue disorders |
Common |
Rash*, pruritus*, erythema, dry skin |
| Uncommon |
Multiform erythema, urticaria, acute febrile neutrophilic dermatosis, toxic skin eruptions, toxic epidermal necrolysis#, Stevens-Johnson syndrome#, dermatitis*, hair disorders*, petechiae, ecchymosis, skin irritation, purpura, skin induration*, psoriasis, hyperhidrosis, night sweats, pressure ulcers#, acne*, bullae*, skin pigmentation disturbances* |
|
| Rare |
Skin reactions, Jessner's lymphocytic infiltration, 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*, urinary tract disorder symptoms*, 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, cold sensation, extravasation*, catheter-related complications*, thirst sensation*, chest discomfort, sensation of body temperature change*, pain related to injection* |
|
| Rare |
Fatal outcome (including sudden), multiple organ failure, injection site hemorrhages*, 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*, electrocardiogram 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 test abnormalities* |
|
| Procedural complications |
Uncommon |
Fall, confusion |
| Rare |
Transfusion reactions, fractures*, tremor*, facial injury, joint injury*, burns, skin laceration, procedural pain, radiation injuries* |
|
| Surgical and medical procedures |
Rare |
Macrophage activation |
* More than one MedDRA term has been grouped.
From post-marketing sources.
ª Patient 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, mental, or psychosocial condition.
Mantle cell lymphoma.
The safety profile of bortezomib in patients with mantle cell lymphoma who received bortezomib at a dose of 1.3 mg/m² in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (VcR-CAP), and in patients who received rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), was generally similar to the safety profile observed in patients with multiple myeloma; the main differences are described below. Additional adverse reactions observed with bortezomib in combination therapy (VcR-CAP) included hepatitis B virus infection and myocardial ischemia. The similar incidence of these events in both treatment groups suggests that these adverse reactions may not be solely related to bortezomib. Treatment with bortezomib in patients with mantle cell lymphoma was associated with higher frequencies of hematologic adverse reactions (neutropenia, thrombocytopenia, leukopenia, anemia, lymphopenia), peripheral sensory neuropathy, arterial hypertension, pyrexia, pneumonia, stomatitis, and hair disorders compared to treatment in patients with multiple myeloma.
Adverse reactions with an incidence ≥ 1%, occurring at a similar or higher frequency in the VcR-CAP treatment group, which may be related to the medicinal products included in the VcR-CAP combination regimen, are listed in Table 8. Also listed are adverse reactions observed in the VcR-CAP treatment group during studies in patients with multiple myeloma, which may be related to bortezomib.
Adverse reactions are categorized by system organ class and frequency of occurrence. Frequencies are defined as: very common (> 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), very rare (< 1/10000), and not known (cannot be estimated from available data). Within each group, adverse reactions are listed in order of decreasing severity.
Table 8
| Organ systems |
Frequency |
Adverse reaction |
|
| Infections and infestations |
Very common |
Pneumonia* |
|
| Common |
Sepsis (including septic shock)*, herpes zoster (including disseminated and with ocular complications), herpesvirus infection*, bacterial infections*, upper/lower respiratory tract infections*, fungal infection*, herpes simplex* |
||
| Uncommon |
Hepatitis B, infections*, bronchopneumonia |
||
| Very common |
Thrombocytopenia*, febrile neutropenia, neutropenia*, leukopenia*, anemia*, lymphopenia* |
||
| Blood and lymphatic system disorders |
Uncommon |
Pancytopenia* |
|
| Common |
Hypersensitivity* |
||
| Immune system disorders |
Uncommon |
Anaphylactic reaction |
|
| Very common |
Decreased appetite |
||
| Metabolism and nutrition disorders |
Common |
Hypokalemia*, blood glucose abnormalities*, hyponatremia*, diabetes mellitus*, fluid retention |
|
| Uncommon |
Tumor lysis syndrome |
||
| Common |
Sleep disorders* |
||
| Psychiatric disorders |
Very common |
Peripheral sensory neuropathy, dysesthesia*, neuralgia* |
|
| Nervous system disorders |
Common |
Neuropathies*, motor neuropathy*, loss of consciousness (including syncope), encephalopathy*, sensory-motor peripheral neuropathy, dizziness*, dysgeusia*, autonomic neuropathy |
|
| Uncommon |
Autonomic nervous system disorders |
||
| Common |
Visual disturbances* |
||
| Eye disorders |
Common |
Dysacusis (including tinnitus)* |
|
| Ear and labyrinth disorders |
Uncommon |
Vertigo*, hearing impairment (up to deafness) |
|
| Common |
Atrial fibrillation (including atrial), arrhythmia*, heart failure (including left and right ventricular)*, myocardial ischemia, ventricular dysfunction* |
||
| Cardiac disorders |
Uncommon |
Cardiovascular disorders (including cardiogenic shock) |
|
| Common |
Hypertension*, hypotension*, orthostatic hypotension |
||
| Vascular disorders |
Common |
Dyspnea*, cough*, hiccups |
|
| Respiratory system disorders |
Uncommon |
Acute respiratory distress syndrome, pulmonary embolism, pneumonitis, pulmonary hypertension, pulmonary edema (including acute) |
|
| Very common |
Nausea and vomiting*, diarrhea*, stomatitis*, constipation |
||
| Gastrointestinal disorders |
Common |
Gastrointestinal hemorrhage (including mucosal)*, abdominal distension, dyspepsia, oropharyngeal pain*, gastritis*, oral ulcers*, abdominal discomfort, dysphagia, inflammation of gastrointestinal tract*, abdominal pain (including gastrointestinal and splenic area pain)*, oral cavity disorders* |
|
| Uncommon |
Colitis (including Clostridium difficile-induced)* |
||
| Common |
Hepatotoxicity (including hepatic disorders) |
||
| Hepatobiliary disorders |
Uncommon |
Hepatic failure |
|
| Very common |
Hair disorders* |
||
| Skin and subcutaneous tissue disorders |
Common |
Pruritus*, dermatitis*, rash* |
|
| Common |
Muscle spasms*, musculoskeletal pain*, limb pain |
||
| Musculoskeletal and connective tissue disorders |
Common |
Urinary tract infections* |
|
| Renal and urinary disorders |
Very common |
Pyrexia*, fatigue, asthenia |
|
| General disorders and administration site conditions |
Common |
Edema (including peripheral), chills, injection site reactions*, fever* |
|
| Common |
Hyperbilirubinemia*, protein abnormalities*, weight loss, weight gain |
* Several MedDRA terms have been grouped.
Description of individual adverse reactions.
Herpes zoster virus reactivation
Multiple myeloma.
Antiviral prophylaxis was administered in 26% of patients receiving the combination of bortezomib with melphalan and prednisone. Herpes zoster occurred in 17% of patients who did not receive antiviral agents, compared to 3% of patients who received antiviral agents.
Mantle cell lymphoma.
Antiviral prophylaxis was administered in 137 out of 240 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 resulting in death were reported in 0.8% of patients (n = 2) in the group receiving treatment with the R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) and in 0.4% of patients (n = 1) receiving bortezomib as part of combination therapy with the VcR-CAP regimen (rituximab, cyclophosphamide, doxorubicin, and prednisone). The overall incidence of hepatitis B cases was similar in both treatment groups (0.8% in the VcR-CAP group vs. 1.2% in the R-CHOP group).
Peripheral neuropathy during combination therapy
Multiple myeloma.
During studies in which bortezomib was used as induction therapy in combination with dexamethasone (IFM-2005-01 study) and with dexamethasone-thalidomide (MMY-3010 study), the frequency of peripheral neuropathy is shown in Table 9.
Frequency of peripheral neuropathy (PN) during induction therapy by toxicity grade and need for treatment interruption due to PN.
Table 9
| 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.
The frequency of peripheral neuropathy events observed during the study of bortezomib in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone is presented in 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.
Table 10
| Signs of peripheral neuropathy |
VcR-CAP (N = 240) |
R-CHOP (N = 242) |
| Frequency of PN (%) |
||
| All grades PN |
30 |
29 |
| ≥ Grade II PN |
18 |
9 |
| ≥ Grade III PN |
8 |
4 |
| Discontinuation due to PN (%) |
2 |
<1 |
VcR-CAP – bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone; R-CHOP – rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone.
Peripheral neuropathy includes: peripheral sensory neuropathy, peripheral neuropathy, peripheral motor neuropathy, and peripheral sensorimotor neuropathy.
Elderly patients with mantle cell lymphoma
In the VcR-CAP treatment group, 42.9% of patients were aged 65–74 years and 10.4% were ≥75 years. Although patients aged 75 years and older tolerated both treatment regimens less well, the rate of serious adverse reactions was 68% in the VcR-CAP group compared to 42% in the R-CHOP group.
Known differences in the safety profile of bortezomib when administered intravenously versus subcutaneously.
In a Phase III study, in patients receiving subcutaneous bortezomib, the incidence of treatment-emergent adverse reactions of Grade III toxicity or higher was 13% lower compared to patients receiving intravenous bortezomib, and the rate of bortezomib treatment discontinuation was 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.
Local reactions at the subcutaneous injection site occurred in 6% of patients, mostly 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 treatment-emergent fatal events was 5% in the subcutaneous group and 7% in the intravenous group. The rate of mortality due to disease progression was 18% in the subcutaneous group and 9% in the intravenous group.
Re-treatment of patients with relapsed multiple myeloma
In a study of bortezomib re-treatment involving 130 patients with relapsed multiple myeloma who had previously achieved at least a partial response to combination therapy including bortezomib, the most common adverse reactions of all grades occurring in at least 25% of patients included thrombocytopenia (55%), neuropathy (40%), anemia (37%), diarrhea (35%), and constipation (28%). Peripheral neuropathy of all grades and peripheral neuropathy of Grade ≥III were observed in 40% and 8.5% of patients, respectively.
Shelf life. 36 months.
Storage conditions.
Store the vial in its outer packaging in a light-protected place at a temperature not exceeding 25°C.
Keep out of reach of children.
Incompatibilities. Data not available.
Use only the solvents specified in the section "Administration and dosage."
Packaging. 1 vial of powder in a cardboard box.
Prescription status. Prescription only.
Manufacturer. PHARMIDEA, Ltd., Latvia / Limited Liability Company «PHARMIDEA», Latvia.
Manufacturer's address and place of business.
4 Rupnicu Str., Olaine, Olaine district, LV-2114, Latvia
Marketing authorization holder. ROCKET-PHARM, LLC, Ukraine.
Address of the marketing authorization holder.
6 Mykhaila Boichuka St., Office 103, Kyiv, 01103, Ukraine