Gloftrinid
UkraineTable of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT GLOFTRINID GLOFTRINID
Composition:
Active substance: bortezomib;
1 vial contains 3.5 mg of bortezomib (as mannitol boronic ester);
after reconstitution, 1 ml of solution for subcutaneous injection contains 2.5 mg of bortezomib;
after reconstitution, 1 ml of solution for intravenous injection contains 1 mg of bortezomib;
Excipient: mannitol (E 421).
Pharmaceutical form. Powder for solution for injections.
Main physicochemical properties: white or almost white powder or mass.
Pharmacotherapeutic group.
Antineoplastic and immunomodulating 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 resulting in apoptosis. 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 times more selective for the proteasome than for other enzymes. The kinetics of proteasome inhibition were determined in vitro; bortezomib dissociated from the proteasome with a half-life (t1/2) of 20 minutes, demonstrating that proteasome inhibition by bortezomib is reversible. By inhibiting the proteasome, bortezomib affects cancer cells through multiple pathways, including but not limited to, altering regulatory proteins controlling the cell cycle and activation of the nuclear factor NF-kB. Inhibition of the proteasome 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 multiple 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 bortezomib-induced apoptosis than normal cells. In vivo, bortezomib causes a reduction in the growth of 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 11 patients with multiple myeloma and creatinine clearance above 50 ml/min, the mean maximum plasma concentration of bortezomib after the first dose was 57 ng/ml and 112 ng/ml, respectively. With subsequent administrations, the mean maximum plasma concentration of bortezomib ranged from 67 ng/ml to 106 ng/ml for the 1.0 mg/m² dose and from 89 ng/ml to 120 ng/ml for the 1.3 mg/m² dose.
After intravenous bolus or subcutaneous administration of a 1.3 mg/m² dose 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 maximum concentration (Cmax) after subcutaneous administration (20.4 ng/ml) was lower than after intravenous administration (223 ng/ml). The geometric mean ratio of AUClast was 0.99, with a 90% confidence interval of 80.18–122.80%.
Distribution. The mean volume of distribution (Vd) of bortezomib ranges from 1659 to 3294 liters following single or multiple doses of 1.0 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 is 82.9%. The fraction of bortezomib bound to plasma proteins is independent of concentration.
Metabolism. In vitro studies using human liver microsomes and expressed cDNA indicate that bortezomib metabolism is primarily mediated by cytochrome P450 enzymes, including CYP3A4, CYP2C19, and CYP1A2. The main metabolic pathway involves deboronation to two metabolites, which are subsequently hydroxylated into other metabolites. The deboronated metabolites of bortezomib are inactive as inhibitors of the 26S proteasome.
Elimination. The mean t1/2 of bortezomib after multiple administrations ranges from 40 to 193 hours. Bortezomib is eliminated more rapidly after the first dose compared to subsequent doses. The mean total clearance was 102 L/h and 112 L/h after the first dose of 1.0 mg/m² and 1.3 mg/m², respectively, and ranged from 15 L/h to 32 L/h and from 18 L/h to 32 L/h after subsequent doses of 1.0 mg/m² and 1.3 mg/m², respectively.
Special patient populations
Hepatic impairment. The effect of hepatic impairment on the pharmacokinetics of bortezomib was evaluated in a Phase I study during the first treatment cycle involving 61 patients, mostly with solid tumors and varying degrees of hepatic dysfunction; bortezomib doses ranged from 0.5 mg/m² to 1.3 mg/m².
Mild hepatic impairment did not alter bortezomib AUC compared to normal hepatic function. Mean bortezomib AUC values 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 function, categorized by creatinine clearance (CrCL) into the following groups: patients without renal impairment (CrCL ≥60 ml/min/1.73 m², n=12), mild renal impairment (CrCL=40–59 ml/min/1.73 m², n=10), moderate renal impairment (CrCL=20–39 ml/min/1.73 m², n=9), and severe renal impairment (CrCL<20 ml/min/1.73 m², n=3). Patients undergoing dialysis who received the drug dose after dialysis were also included in the study (n=8). Patients received intravenous bortezomib at doses of 0.7–1.3 mg/m² twice weekly. The pharmacokinetic parameters of bortezomib (dose-normalized AUC and Cmax) were comparable across all groups.
Age. Pharmacokinetic parameters of bortezomib were evaluated in 104 pediatric patients (aged 2–16 years) with acute lymphoblastic leukemia or acute myeloid leukemia, who received bortezomib 1.3 mg/m² twice weekly via intravenous bolus injection. According to population pharmacokinetic analysis, bortezomib clearance increases with increasing body surface area. The geometric mean (%CV) for clearance was 7.79 (25%) L/h/m², the volume of distribution at steady state was 834 (39%) L/m², and t1/2 was 100 (44%) hours. After adjusting for body surface area, other demographic factors such as age, body weight, and sex had no clinically significant effect on bortezomib clearance. Bortezomib clearance values in children, adjusted for body surface area, were comparable to those 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 who have undergone hematopoietic stem cell transplantation or who are not candidates for transplantation (second-line therapy).
Treatment of multiple myel游戏副本, in combination with dexamethasone or dexamethasone and thalidomide, in previously untreated patients who are candidates for high-dose chemotherapy with hematopoietic stem cell transplantation (induction therapy).
Treatment of mantle cell lymphoma, in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone, in previously untreated patients who are not candidates for hematopoietic stem cell transplantation.
Contraindications.
Hypersensitivity to bortezomib, to boron, or to any excipient of the medicinal product. Acute diffuse infiltrative lung and pericardial diseases.
When bortezomib is used in combination with other medicinal products, refer to the instructions for medical use of these products for additional contraindications.
Special safety precautions.
General warnings. Gloftrinid is a cytotoxic agent; therefore, caution should be exercised during reconstitution and administration. Use of gloves and protective clothing is recommended to prevent skin contact.
Appropriate aseptic techniques must be strictly followed when handling bortezomib, as the product contains no preservatives.
Fatal outcomes have been reported following accidental intrathecal administration of bortezomib. The medicinal product Gloftrinid must be administered only intravenously or subcutaneously.
DO NOT ADMINISTER GLOFTRINID INTRATHECALLY.
Procedure for proper disposal. 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 types of interactions.
In vitro studies have demonstrated that bortezomib is a weak inhibitor of cytochrome P450 isoenzymes 1A2, 2C9, 2C19, 2D6, and 3A4. Since CYP2D6 plays a minor role in bortezomib metabolism, altered overall exposure to the drug is not expected in poor metabolizers of this enzyme.
Drug interaction studies evaluating the effect of ketoconazole, a potent CYP3A4 inhibitor, on the pharmacokinetics of bortezomib (after intravenous administration) demonstrated an average increase in bortezomib AUC by 35% (90% CI [1.032 to 1.772]) based on data from 12 patients. Therefore, careful monitoring of patients is recommended when bortezomib is administered concomitantly 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 effect on bortezomib pharmacokinetics in 17 patients included in the study.
Studies investigating the effect of rifampicin, a potent CYP3A4 inducer, in 6 patients revealed an average reduction in bortezomib AUC (after intravenous administration) by 45%. Therefore, concomitant administration of bortezomib with potent CYP3A4 inducers (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 the pharmacokinetics of bortezomib based on data from 7 patients.
Drug interaction studies evaluating the effect of melphalan and prednisone on the pharmacokinetics of bortezomib (after intravenous administration) in 21 patients demonstrated an average increase in bortezomib AUC by 17%. This increase in bortezomib AUC is not considered clinically significant.
During clinical trials, cases of hypo- and hyperglycemia were reported in diabetic patients receiving oral hypoglycemic agents. Patients receiving oral antidiabetic medications 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, the instructions for medical use of these products should be consulted prior to initiating treatment. If thalidomide is used, special attention must be paid to pregnancy diagnosis and contraceptive measures.
Intrathecal administration. Fatal cases have been reported due to accidental intrathecal administration of bortezomib. Bortezomib should only be administered intravenously or subcutaneously. INTRATHECAL ADMINISTRATION OF BORTEZOMIB IS CONTRAINDICATED.
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 treatment. In clinical trials of bortezomib in patients with relapsed multiple myeloma and in combination therapy with rituximab, cyclophosphamide, doxorubicin, and prednisone (VcR-CAP regimen) in previously untreated mantle cell lymphoma patients, one of the most common hematological toxicities was reversible thrombocytopenia. Platelet counts typically reached their lowest point on day 11 of each bortezomib treatment cycle and returned to baseline before the start of the next cycle. No cumulative thrombocytopenia was observed. On average, the lowest recorded platelet count was approximately 40% of baseline in trials of bortezomib monotherapy in multiple myeloma patients and 50% in trials in mantle cell lymphoma patients. In patients with progressive myeloma, the severity of thrombocytopenia correlated with baseline platelet count: in 90% of 21 patients with baseline platelets < 75,000/µL, platelet counts dropped to ≤ 25,000/µL during treatment, including 14% with counts < 10,000/µL, whereas in 14% of 309 patients with baseline platelets > 75,000/µL, platelet counts were ≤ 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 (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). The overall incidence of bleeding events of all grades and of grade ≥ III bleeding 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 hemorrhage associated with bortezomib use have been reported. Therefore, platelet counts should be monitored before each dose of bortezomib. Bortezomib therapy should be withheld if platelet counts fall below 25,000/µL during monotherapy or below ≤ 30,000/µL when used in combination with melphalan and prednisone. The benefit-risk ratio of bortezomib treatment should be carefully evaluated, especially in cases of moderate or severe thrombocytopenia and risk factors for bleeding.
Complete blood counts, including leukocyte differential and platelet counts, should be frequently monitored during bortezomib therapy. Platelet transfusion should be considered if clinically indicated.
In patients with mantle cell lymphoma, reversible neutropenia between treatment cycles has been observed, with no cumulative neutropenia. White blood cell counts typically reached their lowest point on day 11 of each bortezomib treatment cycle and returned to baseline before the start of the next cycle. In a clinical trial of bortezomib in mantle cell lymphoma patients, 78% of patients in the VcR-CAP group and 61% in the R-CHOP group received granulocyte colony-stimulating factor. Since patients with neutropenia are at increased risk of infections, they should be monitored for signs of infection and appropriate therapeutic measures taken. Granulocyte colony-stimulating factor should be considered for managing hematological toxicity. If initiation of a new treatment cycle is delayed multiple times, prophylactic use of granulocyte colony-stimulating factor should be considered.
Reactivation of Herpes zoster virus. Antiviral prophylaxis should be considered for patients receiving bortezomib. In a phase III trial involving patients with previously untreated multiple myeloma, the overall incidence of Herpes zoster reactivation (shingles) was higher in the bortezomib + melphalan + prednisone group (14%) compared to the melphalan + prednisone group (4%).
Among patients with mantle cell lymphoma, the incidence of shingles was 6.7% in the VcR-CAP group and 1.2% in the R-CHOP group.
Reactivation and infection with hepatitis B virus (HBV). 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 combination therapy with rituximab and bortezomib. Antiviral prophylaxis should be considered.
Progressive multifocal leukoencephalopathy (PML). Very rare cases of John Cunningham (JC) virus infection leading to PML with fatal outcomes have been reported in patients treated with bortezomib. Patients diagnosed with PML had received prior or concomitant immunosuppressive therapy with bortezomib. Most PML cases were diagnosed within the first 12 months of starting bortezomib treatment. Patients should be regularly monitored for new or worsening neurological symptoms that may indicate PML, which should be considered in the differential diagnosis of central nervous system (CNS) disorders. If PML is suspected, the patient should be referred to a physician experienced in PML management and appropriate diagnostic measures initiated. 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 fifth treatment cycle.
Patients should be carefully monitored for neuropathic symptoms such as burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain, or weakness.
In a phase III trial comparing intravenous versus subcutaneous bortezomib administration, 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, schedule modification, or switching to subcutaneous administration may be necessary. Neuropathy should be managed with supportive measures.
Regular monitoring for treatment-induced neuropathy symptoms and neurological examinations are recommended for patients receiving bortezomib in combination with other neurotoxic agents (e.g., thalidomide); dose reduction or discontinuation of bortezomib should be considered.
In addition to peripheral neuropathy, autonomic neuropathy may contribute to certain adverse reactions such as orthostatic hypotension and acute constipation with intestinal obstruction. Information on autonomic neuropathy and its impact on these adverse reactions is limited.
Seizures. Rare cases of seizures have been reported in patients with a history of seizures or epilepsy. 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. Most patients who developed orthostatic hypotension during bortezomib (intravenous) administration did not have symptoms of orthostatic hypotension prior to treatment. 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 is unknown and may be related to autonomic neuropathy. Autonomic neuropathy may be caused by bortezomib 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, or those with dehydration due to diarrhea or vomiting. Management of orthostatic hypotension may include hydration, glucocorticoids, and/or sympathomimetics; antihypertensive medications may need to be reduced if necessary. Patients should be instructed to seek medical attention if they experience dizziness, pre-syncope, or syncope.
Posterior reversible encephalopathy syndrome (PRES). Cases of PRES have been reported in patients receiving bortezomib. PRES is a rare, reversible neurological disorder characterized by seizures, arterial hypertension, headache, lethargy, confusion, visual disturbances, and other neurological impairments. Brain imaging, preferably MRI, is required for diagnosis. Bortezomib treatment should be discontinued if PRES occurs.
Heart failure. Cases of new onset or worsening of pre-existing congestive heart failure and/or reduced left ventricular ejection fraction have been reported with bortezomib use. Fluid retention may lead to signs and symptoms of heart failure. Patients with risk factors or pre-existing cardiac disease should be under medical supervision.
ECG monitoring. Isolated cases of QT interval prolongation have been observed in clinical trials, although the cause has not been established.
Pulmonary disorders. Rare cases of acute diffuse infiltrative lung diseases of unknown etiology, such as pneumonitis, interstitial pneumonia, pulmonary infiltration, and acute respiratory distress syndrome (ARDS), have been reported in patients receiving bortezomib. Some of these cases were fatal. Chest radiography is recommended before treatment initiation to establish baseline pulmonary status for comparison in case of treatment-related pulmonary dysfunction.
In the event of new or worsening pulmonary symptoms (e.g., cough, dyspnea), prompt diagnosis and appropriate therapeutic measures should be initiated. The benefit-risk ratio of continuing bortezomib treatment should be carefully evaluated.
In clinical trials, two out of two patients receiving high-dose cytarabine (2 g/m²/day) as continuous 24-hour infusion in combination with daunorubicin and bortezomib for relapsed acute myeloid leukemia died from ARDS early in the treatment course. Therefore, this specific regimen combining high-dose cytarabine (2 g/m²/day) as continuous 24-hour infusion is not recommended.
Renal function impairment. Renal dysfunction is common in patients with multiple myeloma. Close monitoring of such patients is recommended.
Hepatic function impairment. Bortezomib is metabolized by hepatic enzymes. In patients with moderate to severe hepatic impairment, bortezomib concentrations may increase; therefore, reduced doses should be used and patients closely monitored for signs of toxicity.
Hepatic reactions. Rare cases of acute liver failure have been reported in patients treated with bortezomib in combination with other drugs and in patients with serious comorbidities. Cases of elevated liver enzymes, hyperbilirubinemia, and hepatitis, which resolved after bortezomib discontinuation, have also been reported.
Tumor lysis syndrome. Since bortezomib is a cytotoxic agent capable of rapidly killing tumor plasma cells, complications associated with tumor lysis syndrome may occur. Patients with high tumor burden prior to treatment initiation are at particular risk. Close monitoring and appropriate preventive measures are recommended.
Concomitant use of other medicinal products. Patients should be closely monitored when bortezomib is combined with strong CYP3A4 inhibitors. Caution should be exercised when combining bortezomib with CYP3A4 or CYP2C9 substrates.
Prior to initiating treatment with glofitamab, hepatic function should be corrected if impaired, and caution should be exercised in 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 in case of severe reactions.
Use during pregnancy or breastfeeding.
Contraception in women and men
Due to the genotoxic potential of bortezomib, women of reproductive potential must use effective contraception and avoid pregnancy during treatment with bortezomib and for 8 months after treatment completion. Male patients should use effective contraception and be advised against fathering a child during bortezomib treatment and for 5 months after treatment completion.
Pregnancy
There are no clinical data on the use of bortezomib in pregnant women. The teratogenic potential of bortezomib has not been fully investigated.
In preclinical studies, bortezomib at the 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 treatment with bortezomib. If bortezomib is used during pregnancy or if pregnancy occurs during treatment, the patient should be informed of the potential risk to the fetus.
Thalidomide is a medicinal product with known teratogenic effects in humans, causing severe, life-threatening congenital malformations. Thalidomide is contraindicated in pregnant women and women of reproductive potential. Patients receiving bortezomib in combination with thalidomide must comply with pregnancy prevention requirements (for further information, see the thalidomide product information).
Breastfeeding period
It is unknown whether bortezomib is excreted in human milk; however, 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 influence the speed of reactions when driving or operating machinery.
Bortezomib has a moderate effect on the ability to drive or operate machinery. Bortezomib treatment is very commonly associated with fatigue, commonly with dizziness, orthostatic/postural hypotension, or visual disturbances, and uncommonly with syncope. Therefore, patients should be cautious when driving or operating machinery and avoid such activities if these symptoms occur (see section "Adverse reactions").
Method of Administration and Dosage
Treatment with bortezomib should be initiated under the supervision of a qualified physician experienced in treating cancer patients. However, bortezomib therapy 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 "Special Precautions").
Instructions for Solution Preparation. Solution preparation must be performed only by qualified medical personnel.
For intravenous administration: Prior to use, the contents of the vial should be carefully reconstituted with 3.5 mL of 0.9% sodium chloride injection solution using a syringe of appropriate size, without removing the stopper from the vial. The lyophilized powder dissolves in less than 2 minutes. After reconstitution, 1 mL of solution contains 1 mg of bortezomib. The resulting solution should be clear and colorless, with a pH of 4–7. The prepared solution should be inspected visually for particulate matter and discoloration prior to administration. If particulate matter is present or discoloration occurs, the solution must not be used.
For subcutaneous administration: Prior to use, the contents of the vial should be carefully reconstituted with 1.0 mL of 0.9% sodium chloride injection solution using a syringe of appropriate size, without removing the stopper from the vial. Reconstitution occurs in less than 2 minutes. After reconstitution, 1 mL of solution contains 2.5 mg of bortezomib. The resulting solution should be clear and colorless, with a pH of 4–7. The prepared solution should be inspected visually for particulate matter and discoloration prior to administration. If particulate matter is 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 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. After achieving a complete clinical response, administration of two additional treatment cycles is recommended. Patients achieving a partial response but not complete remission should continue bortezomib therapy, but for no more than 8 cycles. At least 72 hours should elapse between consecutive doses of bortezomib.
In the event of any grade III non-hematological toxicity or grade IV hematological toxicity (excluding neuropathies), bortezomib treatment must be withheld. After resolution of toxicity symptoms, treatment may be resumed at a dose reduced by 25% (reduce 1.3 mg/m² dose to 1.0 mg/m²; reduce 1.0 mg/m² dose to 0.7 mg/m²). If toxicity symptoms do not resolve or recur upon administration of 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 the event of neuropathic pain and/or peripheral neuropathy, the drug dose should be adjusted (see Table 1). Bortezomib should be administered to patients with a history of severe neuropathy only after careful assessment of the benefit-risk ratio.
Table 1
Recommended* dose adjustment in the event of bortezomib-induced neuropathy
| Severity of neuropathy |
Change in dose and frequency of administration |
| Grade I (asymptomatic; loss of deep tendon reflexes or paresthesia) without pain or loss of function |
Dose and schedule do not require adjustment |
| Grade I with pain or Grade II (moderately severe symptoms; limitation of instrumental activities of daily living)** |
Reduce dose to 1 mg/m² or change bortezomib administration schedule to 1.3 mg/m² once weekly |
| Grade II with pain or Grade III (severe symptoms; limitation of self-care activities)*** |
Withhold bortezomib until resolution of toxicity symptoms. After that, 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, and using the telephone.
*** Basic self-care activities include bathing, dressing/undressing, eating, using the toilet, taking medications, 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 (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 must elapse between consecutive doses of bortezomib.
Pegylated liposomal doxorubicin is administered at a dose of 0.3 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 the patient tolerates treatment well. Patients who achieve a complete remission may continue treatment for at least 2 additional cycles after achieving complete response, even if this requires administration of more than 8 cycles. Patients in whom paraprotein levels continue to decline after 8 cycles may also continue treatment as long as treatment remains 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 (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 must elapse between consecutive doses of bortezomib.
Dexamethasone is administered orally at a dose of 20 mg on Days 1, 2, 4, 5, 8, 9, 11, and 12 of the bortezomib treatment cycle.
Patients who show a response to treatment or stable disease after four cycles may continue treatment with this combination for up to four additional cycles. For further information on dexamethasone, refer to the prescribing information for this medicinal product.
Dose modification recommendations for combination therapy in patients with relapsed multiple myeloma
See dose modification recommendations for bortezomib monotherapy described above.
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 is administered twice weekly (on Days 1, 4, 8, 11, 22, 25, 29, and 32). In Cycles 5–9, bortezomib is administered once weekly (on Days 1, 8, 22, and 29). At least 72 hours must elapse between consecutive doses of bortezomib.
Melphalan and prednisone are administered orally on Days 1, 2, 3, and 4 of the first week of each cycle.
Table 2
Recommended dosing regimen of bortezomib in combination with melphalan and prednisone
| Bortezomib 2 times a 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 a 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.
Dosing modification and re-initiation recommendations for 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 modifications during subsequent cycles of bortezomib in combination with melphalan and prednisone therapy
| Toxicity |
Dose modification or discontinuation of treatment |
| Hematologic toxicity during cycle: if prolonged grade IV neutropenia or thrombocytopenia, or thrombocytopenia with bleeding occurred in the previous cycle |
Consider reducing melphalan dose by 25% in the next cycle |
| if platelet count ≤ 30×109/L or absolute neutrophil count ≤ 0.75×109/L on the day of bortezomib administration (except day 1) |
Delay bortezomib dose administration |
| if multiple bortezomib doses in a cycle are missed (≥ 3 doses during twice-weekly administration or ≥ 2 doses during once-weekly administration) |
Bortezomib dose should be reduced by one level (from 1.3 mg/m2 to 1 mg/m2 or from 1 mg/m2 to 0.7 mg/m2) |
| Non-hematologic toxicity ≥ grade III |
Bortezomib treatment should be discontinued until symptoms improve to baseline level or grade I severity. Bortezomib may then be restarted at a dose reduced by one level (from 1.3 mg/m2 to 1 mg/m2 or from 1 mg/m2 to 0.7 mg/m2). In case of bortezomib-dependent neuropathic pain and/or peripheral neuropathy, hold and/or modify bortezomib dose as specified in Table 1. |
For additional information on 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 treatment-free period (days 12–21). This 3-week period constitutes one treatment cycle. At least 72 hours should elapse between consecutive doses of bortezomib.
Dexamethasone is administered orally at a dose of 40 mg on days 1, 2, 3, 4, 8, 9, 10, and 11 of the bortezomib treatment cycle.
Administer 4 treatment cycles of this combination.
Combination therapy with dexamethasone and thalidomide
The recommended dose of bortezomib is 1.3 mg/m² body surface area administered intravenously or subcutaneously twice weekly for 2 weeks (on days 1, 4, 8, and 11), followed by a 17-day treatment-free period (days 12–28). This 4-week period constitutes one treatment cycle. At least 72 hours should elapse between consecutive doses of bortezomib.
Dexamethasone is 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 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 be further increased to 200 mg daily starting from the second cycle (see Table 4).
A total of 4 treatment cycles are recommended. Patients achieving at least a partial response to treatment should receive 2 additional cycles.
Table 4
Recommended dosing regimen of bortezomib in combination with dexamethasone and thalidomide for patients with untreated multiple myeloma eligible for hematopoietic stem cell transplantation
| B+Dx |
Cycles 1-4 |
||||||
| Week |
1 |
2 |
3 |
||||
| B (1.3 mg/m²) |
Day 1, 4 |
Day 8, 11 |
Break |
||||
| Dx (40 mg) |
Day 1, 2, 3, 4 |
Day 8, 9, 10, 11 |
- |
||||
| B+Dx+T |
Cycle 1 |
||||||
| Week |
1 |
2 |
3 |
4 |
|||
| B (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 |
|||||||
| B (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 |
- |
- |
|||
B = bortezomib, Dx = dexamethasone, T = thalidomide.
a – Increase the dose of thalidomide to 100 mg starting from week 3 of cycle 1 if the 50 mg dose is tolerated, and to 200 mg if the 100 mg dose is tolerated.
b – Patients who achieve a partial response after 4 cycles of treatment may receive up to 6 cycles of treatment.
Dosing recommendations for patients eligible for transplantation
For dose adjustments in case of neuropathy, refer to the dose modification recommendations for bortezomib used as monotherapy.
If bortezomib is used in combination with other chemotherapeutic agents, refer to the prescribing information for those agents for dose adjustment recommendations in the event of toxicity.
Untreated mantle cell lymphoma
Combination therapy with rituximab, cyclophosphamide, doxorubicin, and prednisone (VcR-CAP regimen).
The recommended dose of bortezomib is 1.3 mg/m² body surface area administered intravenously or subcutaneously twice weekly for 2 weeks (on days 1, 4, 8, and 11), followed by a 10-day rest period (days 12–21). This 3-week period constitutes one treatment cycle. At least 72 hours should elapse between consecutive bortezomib doses. A total of 6 treatment cycles is recommended. Patients who first demonstrate a response to treatment during the 6th cycle should receive 2 additional cycles of therapy.
The following drugs are administered via intravenous infusion on day 1 of each 3-week bortezomib treatment cycle: rituximab at 375 mg/m², cyclophosphamide at 750 mg/m², doxorubicin at 50 mg/m².
Prednisone is administered orally at a dose of 100 mg/m² on days 1, 2, 3, 4, and 5 of each bortezomib treatment cycle.
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 (ANC) ≥ 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.
Bortezomib treatment should be withheld in the event of any non-hematologic toxicity ≥ grade III (except neuropathy) related to bortezomib administration, or hematologic toxicity ≥ grade III. Refer to Table 5 for dose modification recommendations.
Granulocyte colony-stimulating factors (G-CSF) may be used to manage hematologic toxicity. If initiation of a new treatment cycle is delayed multiple times, consider prophylactic use of G-CSF. Platelet transfusion should be considered as necessary for the management of thrombocytopenia.
Table 5
Dose modification during therapy for patients with untreated mantle cell lymphoma
| Toxicity |
Dose adjustment or treatment interruption |
| Hematologic toxicity |
|
| Grade ≥ III neutropenia accompanied by fever, grade IV neutropenia lasting more than 7 days, platelet count ˂ 10,000 cells/µL. |
Bortezomib treatment 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 return to the levels stated above), bortezomib should be discontinued. If toxicity resolves (absolute neutrophil count recovers to ≥ 750 cells/µL and platelet count to ≥ 25,000 cells/µL), bortezomib treatment may be resumed at a reduced dose level (from 1.3 mg/m² to 1.0 mg/m² or from 1.0 mg/m² to 0.7 mg/m²). |
| If platelet count is ˂ 25,000 cells/µL or absolute neutrophil count is ˂ 750 cells/µL on the day of bortezomib administration (except on day 1 of each treatment cycle). |
Delay bortezomib dosing. |
| Grade ≥ III non-hematologic toxicity related to bortezomib administration. |
Bortezomib treatment should be withheld until symptoms improve to at least grade II severity. Bortezomib may then be restarted at a reduced dose level (from 1.3 mg/m² to 1.0 mg/m² or from 1.0 mg/m² to 0.7 mg/m²). For bortezomib-dependent neuropathic pain and/or peripheral neuropathy, dose holding and/or modification should be performed as specified in Table 1. |
If bortezomib 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 populations
Elderly patients
To date, there are no data indicating the need for dose adjustment in patients aged 65 years and older.
There have been 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 given for this patient group.
In a study of bortezomib use in patients with previously untreated mantle cell lymphoma, 42.9% of patients were aged 65–74 years and 10.4% were aged ≥75 years. Patients aged 75 years and older tolerated treatment less well in both treatment groups (VcR-CAP and R-CHOP regimens).
Patients with hepatic impairment
Dose adjustment is not required for patients with mild hepatic impairment. For patients with moderate to severe hepatic impairment, treatment with bortezomib should be initiated at a dose of 0.7 mg/m² during the first treatment cycle, with subsequent gradual dose escalation to 1.0 mg/m² or dose reduction to 0.5 mg/m², depending on patient tolerability.
Table 6
Recommendations for adjustment of initial bortezomib doses in patients with hepatic impairment
| Severity of hepatic impairment* |
Bilirubin level |
AST level |
Initial dose adjustment |
| Mild |
≤ 1.0x ULN |
> ULN |
Not required |
| > 1.0x-1.5x ULN |
any |
Not required |
|
| Moderate |
> 1.5x-3x ULN |
any |
Reduce bortezomib dose to 0.7 mg/m² in the first treatment cycle. Subsequent dose escalation to 1.0 mg/m² or reduction to 0.5 mg/m² depending on drug tolerability. |
| Severe |
> 3x ULN |
any |
AST – aspartate aminotransferase; ULN – upper limit of normal.
*Based on the classification of organ dysfunction by the National Cancer Institute Working Group for severity of liver function impairment (mild, moderate, and severe).
Patients with renal impairment
Mild to moderate renal impairment (creatinine clearance > 20 ml/min/1.73 m²) does not affect the pharmacokinetics of bortezomib; therefore, dose adjustment is not required in this patient group. It is unknown whether severe renal impairment (creatinine clearance < 20 ml/min/1.73 m²) affects the pharmacokinetics of bortezomib. Since dialysis may reduce bortezomib concentrations, the drug should be administered after the dialysis procedure.
Method of administration
Gloftrinid 3.5 mg, powder for solution for injection, is intended for intravenous or subcutaneous administration.
Gloftrinid 1 mg, powder for solution for injection, is intended for intravenous administration only.
Gloftrinid must not be administered by any other route. Accidental intrathecal administration of the drug has resulted in fatal outcomes.
Intravenous injection
Gloftrinid 3.5 mg, powder for solution for injection, is intended for intravenous or subcutaneous administration only. The reconstituted solution should be administered as a 3- to 5-second intravenous bolus injection through a peripheral or central venous catheter, which should be flushed with 0.9% sodium chloride solution for injection after administration. At least 72 hours must elapse between consecutive doses of Gloftrinid.
Subcutaneous injection
Gloftrinid 3.5 mg ready-to-use solution is administered subcutaneously into the thigh area (right or left) or abdomen (right or left) at a 45- to 90-degree angle. Injection sites should be rotated.
If local reactions occur at the injection site after subcutaneous administration of Gloftrinid, a less concentrated solution of Gloftrinid 3.5 mg (diluted to 1 mg/ml instead of 2.5 mg/ml) may be administered subcutaneously, or administration may be switched to the intravenous route.
Children
The safety and efficacy of bortezomib in children (under 18 years of age) have not been established. Available data are insufficient to establish dosing recommendations for pediatric use.
Overdose
In patients, overdose exceeding the recommended dose by more than two-fold has been associated with acute hypotension and thrombocytopenia resulting in death.
There is no specific antidote for bortezomib. In case of overdose, careful monitoring of hemodynamic parameters (infusion therapy, vasopressors and/or inotropic agents) and body temperature is recommended.
Adverse Reactions
Severe adverse reactions reported during bortezomib treatment include rare cases of cardiac arrest, 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, asthenia, pyrexia, thrombocytopenia, anemia, neutropenia, peripheral neuropathy (including sensory neuropathy), headache, paresthesia, decreased appetite, dyspnea, rash, herpes zoster, and myalgia.
Multiple Myeloma
The adverse reactions listed in Table 7 are considered possibly related to bortezomib use. These adverse reactions are based on pooled data from 5,476 patients, of whom 3,996 received bortezomib at a dose of 1.3 mg/m². Overall, bortezomib was administered to 3,974 patients for the treatment of multiple myeloma.
Adverse reactions are categorized by system organ class and frequency of occurrence. Frequencies are defined as: very common (>1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), and frequency not known (cannot be estimated from available data). Within each 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
Adverse reactions in patients with multiple myeloma treated with bortezomib in clinical trials, and all adverse reactions reported in the post-marketing period regardless of indication
| System Organ Class |
Frequency |
Adverse Reaction |
| Infections and infestations |
Common |
Herpes zoster (including disseminated and with ocular complications), pneumonia*, herpes simplex*, fungal infection* |
| Uncommon |
Infection*, bacterial infection*, viral infections*, sepsis (including septic shock)*, bronchopneumonia, herpes viral infection*, herpetic meningoencephalitis#, bacteremia (including staphylococcal), hordeolum, influenza, cellulitis, device-related infections, skin infection*, ear infections*, staphylococcal infection, dental infection* |
|
| Rare |
Meningitis (including bacterial), Epstein-Barr viral infection, genital herpes, tonsillitis, mastoiditis, post-viral fatigue syndrome |
|
| Benign, malignant and unspecified neoplasms (including cysts and polyps) |
Rare |
Malignant neoplasm, plasma cell leukemia, renal cell carcinoma, tumor growth, mycosis fungoides, benign neoplasm* |
| Blood and lymphatic system disorders |
Very common |
Thrombocytopenia*, neutropenia*, anemia* |
| Common |
Leukopenia*, lymphopenia* |
|
| Uncommon |
Pancytopenia*, febrile neutropenia, coagulopathy*, leukocytosis*, lymphadenopathy, hemolytic anemia# |
|
| Rare |
Disseminated intravascular coagulation, thrombocytosis*, hyperviscosity syndrome, thrombopathy, thrombotic microangiopathy (including thrombotic thrombocytopenic purpura), other blood and hematopoietic disorders, hemorrhagic diathesis, lymphocytic infiltration |
|
| Immune system disorders |
Uncommon |
Angioedema#, hypersensitivity* |
| Rare |
Anaphylactic shock, amyloidosis, type III immune complex-mediated reactions |
|
| Endocrine disorders |
Uncommon |
Cushing's syndrome*, hyperthyroidism*, syndrome of inappropriate antidiuretic hormone secretion |
| Rare |
Hypothyroidism |
|
| Metabolism and nutrition disorders |
Very common |
Decreased appetite |
| Common |
Dehydration, hypokalemia*, hyponatremia*, blood glucose disturbances*, hypocalcemia*, enzyme level disturbances* |
|
| Uncommon |
Tumor lysis syndrome, patient condition aggravated ª*, hypomagnesemia*, hypophosphatemia*, hyperkalemia*, hypercalcemia*, hypernatremia*, uric acid abnormalities*, diabetes mellitus*, fluid retention |
|
| Rare |
Hypermagnesemia*, acidosis, electrolyte imbalance*, hypervolemia, hypochloremia*, hypovolemia, hyperchloremia*, hyperphosphatemia*, metabolic disorders, vitamin B group deficiency, vitamin B12 deficiency, gout, increased appetite, alcohol intolerance |
|
| Psychiatric disorders |
Common |
Mood and sensation disorders*, anxiety disorder*, sleep disorders* |
| Uncommon |
Psychiatric disorder*, hallucinations*, psychotic disorder*, confusion*, agitation |
|
| Rare |
Suicidal ideation*, adjustment disorder, delirium, decreased libido |
|
| Nervous system disorders |
Very common |
Neuropathy*, peripheral sensory neuropathy, dysesthesia*, neuralgia* |
| Common |
Motor neuropathy*, loss of consciousness (including syncope), dizziness*, dysgeusia*, lethargy, headache* |
|
| Uncommon |
Tremor, sensorimotor peripheral neuropathy, dyskinesia*, coordination and balance disorders*, memory loss (without dementia)*, encephalopathy*, reversible posterior encephalopathy syndrome#, neurotoxicity, seizure disorders*, postherpetic neuralgia, speech disorders*, restless legs syndrome, migraine, sciatica, attention disorders, reflex abnormalities*, parosmia |
|
| Rare |
Intracranial hemorrhage*, intracerebral hemorrhage (including subarachnoid)*, brain edema, transient ischemic attack, coma, autonomic nervous system disorders, autonomic neuropathy, cranial nerve paralysis*, paralysis*, paresis*, presyncope, brainstem syndrome, cerebrovascular disorder, nerve root damage, psychomotor hyperactivity, spinal cord compression, other cognitive disorders, motor dysfunction, other nervous system disorders, radiculitis, salivation, hypotonia, Guillain-Barré syndrome#, demyelinating polyneuropathy# |
|
| Eye disorders |
Common |
Eye swelling*, visual disturbances*, conjunctivitis* |
| Uncommon |
Ocular hemorrhage*, eyelid infections*, chalazion#, blepharitis#, eye inflammation*, diplopia, dry eyes*, eye irritation*, eye pain, increased lacrimation, eye discharge |
|
| Rare |
Corneal damage*, exophthalmos, retinitis, scotoma, other eye (and eyelid) diseases, acquired dacryoadenitis, photophobia, photopsia, optic neuropathy#, various degrees of visual disturbance (up to blindness)* |
|
| Ear and labyrinth disorders |
Common |
Vertigo* |
| Uncommon |
Dysacusis (including tinnitus)*, hearing impairment (up to deafness), ear discomfort* |
|
| Rare |
Otic hemorrhage, vestibular neuronitis, other ear disorders |
|
| Cardiac disorders |
Uncommon |
Cardiac tamponade#, cardiopulmonary shock*, cardiac fibrillation (including atrial), heart failure (including left and right ventricular)*, arrhythmia*, tachycardia*, palpitations, angina pectoris, pericarditis (including pericardial effusion)*, cardiomyopathy*, ventricular dysfunction*, bradycardia |
| Rare |
Atrial flutter, myocardial infarction*, atrioventricular block*, cardiovascular disorders (including cardiogenic shock), 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 perinephric)*, peripheral circulation disorders*, vasculitis, hyperemia (including ocular)* |
|
| Rare |
Peripheral embolism, lymphedema, pallor, erythromelalgia, vasodilation, vascular discoloration, venous insufficiency |
|
| Respiratory, thoracic and mediastinal disorders |
Common |
Dyspnea*, epistaxis, lower/upper respiratory tract infection*, cough* |
| Uncommon |
Pulmonary embolism, pleural effusion, pulmonary edema (including acute), pulmonary alveolar hemorrhage#, bronchospasm, chronic obstructive pulmonary disease*, hypoxemia*, impaired airway patency*, hypoxia, pleuritis*, hiccups, rhinorrhea, dysphonia, wheezing |
|
| Rare |
Pulmonary insufficiency, 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, 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 pain)*, oral cavity disorders*, meteorism |
|
| Uncommon |
Pancreatitis (including chronic)*, vomiting with blood, lip swelling*, gastrointestinal obstruction (including small intestine obstruction, ileus)*, abdominal discomfort, oral ulcer*, enteritis*, gastritis*, gingival 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 disorder*, 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, defecation rhythm changes, proctalgia, abnormal defecation |
|
| Hepatobiliary disorders |
Common |
Liver enzyme level disturbances* |
| Uncommon |
Hepatotoxicity (including liver disorders), hepatitis*, cholestasis |
|
| Rare |
Liver failure, hepatomegaly, Budd-Chiari syndrome, cytomegalovirus hepatitis, hepatic hemorrhage, cholelithiasis |
|
| Skin and subcutaneous tissue disorders |
Common |
Rash*, pruritus*, erythema, dry skin |
| Uncommon |
Multiform erythema, urticaria, acute febrile neutrophilic dermatosis, toxic skin eruptions, toxic epidermal necrolysis#, Stevens-Johnson syndrome#, dermatitis*, hair disorders*, petechiae, ecchymosis, skin irritation, purpura, skin induration*, psoriasis, hyperhidrosis, night sweats, pressure ulcers#, acne*, bullae*, skin disorders* |
|
| Rare |
Skin reactions, Jessner's lymphocytic infiltration, hand-foot erythrodysesthesia syndrome, subcutaneous hemorrhage, livedo reticularis, skin induration, papule, photosensitivity reactions, seborrhea, cold sweat, 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, myopathy*, heaviness sensation |
|
| Rare |
Rhabdomyolysis, temporomandibular joint syndrome, fistula, joint effusion, jaw pain, bone disorders, infections and inflammations of musculoskeletal system and connective tissue*, synovial cyst |
|
| Renal and urinary disorders |
Common |
Renal failure* |
| Uncommon |
Acute renal failure, chronic renal failure*, urinary tract infection*, 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 deterioration*, facial swelling*, injection site reaction*, mucosal disorders*, chest pain, gait disturbance, cold sensation, extravasation*, catheter-related complication*, thirst sensation*, chest discomfort, sensation of body temperature change*, injection-related pain* |
|
| Rare |
Fatal outcome (including sudden), multiple organ failure, hemorrhage at injection site*, hernia (including hiatal)*, impaired healing*, inflammation, phlebitis at injection site*, pain, ulceration, irritation, non-cardiac substernal pain, catheter insertion site pain, foreign body sensation |
|
| Investigations |
Common |
Weight decreased |
| Uncommon |
Hyperbilirubinemia*, abnormal protein levels*, weight increased, blood test abnormalities*, increased C-reactive protein |
|
| Rare |
Blood gas abnormalities*, ECG abnormalities (including QT interval prolongation)*, international normalized ratio abnormalities*, increased gastric acidity, increased platelet aggregation, increased 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 lacerations, procedural pain, radiation injury* |
|
| Surgical and medical procedures |
Rare |
Macrophage activation |
* Grouping of more than one MedDRA term.
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 was evaluated in 240 patients with mantle cell lymphoma who received bortezomib 1.3 mg/m² in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (BR-CAP), and in 242 patients who received rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHOP). The overall safety profile was similar to that observed in patients with multiple myeloma; the main differences are described below. Additional adverse reactions observed with bortezomib when used as part of combination therapy (VcR-CAP) included hepatitis B virus infection (<1%) and myocardial ischemia (1.3%). The similar incidence of these events in both treatment groups suggests that these adverse reactions are not solely related to bortezomib. Administration of bortezomib to 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 administration 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 were possibly or probably related to the medicinal products included in the VcR-CAP combination regimen, are listed in Table 8. Also included are adverse reactions observed in the VcR-CAP treatment group and considered by investigators as possibly or probably related to bortezomib, based on experience from studies in patients with multiple myeloma.
Adverse reactions are categorized by system organ class and frequency of occurrence. Frequencies are defined as: very common (>1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), and frequency not known (cannot be estimated from available data). Within each group, adverse reactions are listed in order of decreasing severity.
Table 8
| System Organ Class |
Frequency |
Adverse Reaction |
| Infections and infestations |
Very common |
Pneumonia* |
| Common |
Sepsis (including septic shock)*, herpes zoster (including disseminated and with ocular complications), herpesvirus infection*, bacterial infections*, upper/lower respiratory tract infections*, fungal infection*, herpes simplex* |
|
| Uncommon |
Hepatitis B, infections*, bronchopneumonia |
|
| Blood and lymphatic system disorders |
Very common |
Thrombocytopenia*, febrile neutropenia, neutropenia*, leukopenia*, anemia*, lymphopenia* |
| Uncommon |
Pancytopenia* |
|
| Immune system disorders |
Common |
Hypersensitivity* |
| Uncommon |
Anaphylactic reaction |
|
| Metabolism and nutrition disorders |
Very common |
Decreased appetite |
| Common |
Hypokalemia*, blood glucose abnormalities*, hyponatremia*, diabetes mellitus*, fluid retention |
|
| Uncommon |
Tumor lysis syndrome |
|
| Psychiatric disorders |
Common |
Sleep disorders* |
| Nervous system disorders |
Very common |
Peripheral sensory neuropathy, dysesthesia*, neuralgia* |
| Common |
Neuropathy*, 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 impairment* |
| Ear and labyrinth disorders |
Common |
Dysesthesia (including tinnitus)* |
| Uncommon |
Vertigo*, hearing impairment (up to deafness) |
|
| Cardiac disorders |
Common |
Cardiac fibrillation (including atrial), arrhythmia*, heart failure (including left and right ventricular)*, myocardial ischemia, ventricular dysfunction* |
| Uncommon |
Cardiovascular disorders (including cardiogenic shock) |
|
| Vascular disorders |
Common |
Hypertension*, hypotension*, orthostatic hypotension |
| Respiratory, thoracic and mediastinal disorders |
Common |
Dyspnea*, cough*, hiccups |
| Uncommon |
Acute respiratory distress syndrome, pulmonary embolism, pneumonitis, pulmonary hypertension, pulmonary edema (including acute) |
|
| Gastrointestinal disorders |
Very common |
Nausea and vomiting*, diarrhea*, stomatitis*, constipation |
| Common |
Gastrointestinal hemorrhage (including mucosal)*, abdominal distension, dyspepsia, oropharyngeal pain*, gastritis*, oral ulcers*, abdominal discomfort, dysphagia, gastrointestinal inflammation*, abdominal pain (including gastrointestinal pain and splenic region pain)*, oral cavity disorders* |
|
| Uncommon |
Colitis (including Clostridium difficile-induced)* |
|
| Hepatobiliary disorders |
Common |
Hepatotoxicity (including hepatic disorders) |
| Uncommon |
Liver failure |
|
| Skin and subcutaneous tissue disorders |
Very common |
Hair disorders* |
| Common |
Pruritus*, dermatitis*, rash* |
|
| Musculoskeletal and connective tissue disorders |
Common |
Muscle spasms*, musculoskeletal pain*, limb pain |
| Renal and urinary disorders |
Common |
Urinary tract infections* |
| General disorders and administration site conditions |
Very common |
Pyrexia*, fatigue, asthenia |
| Common |
Edema (including peripheral), chills, injection site reaction*, fever* |
|
| Investigations |
Common |
Hyperbilirubinemia*, abnormal protein levels*, weight loss, weight gain |
* Grouping of more than one MedDRA term.
Description of individual adverse reactions
Reactivation of herpes zoster virus
Multiple myeloma
Antiviral prophylaxis was administered in 26% of patients receiving the combination of bortezomib with melphalan and prednisone. The incidence of herpes zoster in this group was 17% among patients who did not receive antiviral agents, compared to 3% among those who received antiviral agents.
Mantle cell lymphoma
Antiviral prophylaxis was administered in 57% of patients receiving bortezomib as part of combination therapy with the BcR-CAP regimen. Herpes zoster was observed in 10.7% of patients who did not receive antiviral agents, compared to 3.6% of patients who received antiviral agents.
Reactivation and infection with hepatitis B virus (HBV)
Mantle cell lymphoma
Cases of hepatitis B infection with fatal outcome were reported in 0.8% of patients (n=2) in the group receiving treatment 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 BcR-CAP regimen (rituximab, cyclophosphamide, doxorubicin, and prednisone). The overall incidence of hepatitis B was similar in both treatment groups (0.8% in the BcR-CAP group versus 1.2% in the R-CHOP group).
Peripheral neuropathy during combination therapy
Multiple myeloma
Peripheral neuropathy was observed in studies where bortezomib was used as induction therapy in combination with dexamethasone (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
| Signs of peripheral neuropathy |
IFM-2005-01 |
MMY-3010 |
||
| VDDx (N=239) |
BDx (N=239) |
TDx (N=126) |
BTDx (N=130) |
|
| Frequency of PN (%) |
||||
| All grades PN |
3 |
15 |
12 |
45 |
| ≥ Grade II PN |
1 |
10 |
2 |
31 |
| ≥ Grade III PN |
˂1 |
5 |
0 |
5 |
| Discontinuation of treatment due to PN (%) |
˂1 |
2 |
1 |
5 |
VDDx = vincristine, doxorubicin, dexamethasone; BDx = bortezomib, dexamethasone; TDx = thalidomide, dexamethasone;
BTDx = bortezomib, thalidomide, dexamethasone.
Peripheral neuropathy includes peripheral neuropathy, peripheral motor neuropathy, peripheral sensory neuropathy, and polyneuropathy.
Table 10
Frequency of peripheral neuropathy (PN) events in the bortezomib study in patients with mantle cell lymphoma, by toxicity grade and need for treatment interruption due to PN
| Signs of peripheral neuropathy |
BR-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 |
BR-CAP = bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisolone; R-CHOP = rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone; PN = peripheral neuropathy.
Peripheral neuropathy includes peripheral sensory neuropathy, peripheral neuropathy, peripheral motor neuropathy, and peripheral sensorimotor neuropathy.
Elderly patients with mantle cell lymphoma
In the 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 rate of serious adverse reactions was 68% in the BR-CAP group compared to 48% in the R-CHOP group.
Known differences in the safety profile of bortezomib when administered intravenously versus subcutaneously
In a Phase III study, in patients 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 treatment interruption due to bortezomib was 5% lower. The overall incidence of diarrhea, lower abdominal pain, abdominal pain, asthenic conditions, upper respiratory tract infections, and peripheral neuropathy was 12–15% lower in the subcutaneous group compared to the intravenous group. Additionally, the incidence of Grade III or higher peripheral neuropathy was 10% lower, and the rate of treatment discontinuation due to peripheral neuropathy was 8% lower.
Injection site reactions occurred in 6% of patients, predominantly erythema. On average, symptoms resolved within 6 days, and dose modification was required in 2 patients.
Serious reactions occurred in 2 patients (1%): 1 case of pruritus and 1 case of erythema.
The rate of fatal events during treatment was 5% in the subcutaneous group and 7% in the intravenous group. The rate of 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 a bortezomib-containing regimen, adverse reactions of all grades occurring in at least 25% of patients included primarily thrombocytopenia (55%), neuropathy (40%), anemia (37%), diarrhea (35%), and constipation (28%). Peripheral neuropathy of all grades and peripheral neuropathy ≥ Grade III were observed in 40% and 8.5% of patients, respectively.
Reporting suspected adverse reactions after marketing authorization is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Information System for Pharmacovigilance at the following link: http://aisf.dec.gov.ua/.
Shelf life.
Unopened vial
3 years.
Reconstituted solution
Chemical and physical in-use stability has been demonstrated for up to 8 hours at 25°C/60% humidity in the dark, both in the vial and in a polypropylene syringe.
From a microbiological standpoint, if the reconstitution/dilution method does not exclude the risk of microbial contamination, the medicinal product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user.
Storage conditions.
The vial should be stored in the outer cardboard package to protect from light. This medicinal product does not require special temperature conditions for storage.
For information on storage conditions after dilution of the medicinal product, see the section "Shelf life."
Keep out of the reach of children.
Incompatibilities.
This medicinal product must not be mixed with other medicinal products except those specified in the section "Dosage and administration" ("Instructions for solution preparation").
Packaging.
Each vial contains 3.5 mg of powder for solution for injection in a glass vial with a rubber stopper and flip-off cap.
Each cardboard box contains one single-use vial.
Prescription status.
Prescription only.
Manufacturer.
ALKALOID AD Skopje.
ALKALOID AD Skopje.
Manufacturer's address and location of operations.
Boulevard Aleksandar Makedonski 12, Skopje, 1000, Republic of North Macedonia.
Boulevard Aleksandar Makedonski 12, Skopje, 1000, Republic of North Macedonia.