Bortezomib for injection
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BORTEZOMIB FOR INJECTION
Composition:
Active ingredient: bortezomib;
1 vial contains 3.5 mg of bortezomib;
Excipient: mannitol (E 421).
Pharmaceutical form. Lyophilized powder for solution for injection.
Main physicochemical properties: white to almost white lyophilized mass or powder in a 10 ml type I USP clear cylindrical glass vial with a 13 mm bromobutyl double split rubber stopper, sealed with a 13 mm aluminum cap fitted with a polypropylene disc.
Pharmacotherapeutic group. Antineoplastic agents. Other antineoplastic agents.
ATC code L01XG01.
Pharmacological Properties
Pharmacodynamics
Mechanism of action. Bortezomib is a proteasome inhibitor that suppresses the chymotrypsin-like activity of the 26S proteasome in mammalian cells. The 26S proteasome is a large protein complex involved in the degradation of key regulatory proteins. This pathway plays a central role in regulating the turnover of specific proteins, thereby maintaining cellular homeostasis. Inhibition of the 26S proteasome leads to suppression of proteolysis and a cascade of reactions resulting in apoptosis. Bortezomib is highly selective for the proteasome. At a concentration of 10 µM, bortezomib does not inhibit any of the numerous tested receptors and proteases and is more than 1500 times more selective for the proteasome than for other enzymes. The kinetics of proteasome inhibition were calculated in vitro; bortezomib dissociated from the proteasome with a t½ of 20 minutes, demonstrating that bortezomib-induced proteasome inhibition is reversible. By inhibiting the proteasome, bortezomib affects cancer cells through multiple mechanisms, including (but not limited to) altering regulatory proteins controlling the cell cycle and 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.
Experiments have demonstrated that bortezomib has cytotoxic effects against many types of cancer cells, and 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 patients with multiple myeloma and creatinine clearance values above 50 ml/min, the mean peak plasma concentration after the first dose of bortezomib was 57 and 112 ng/ml, respectively. Following subsequent doses, mean peak plasma concentrations of bortezomib ranged from 67 to 106 ng/ml at the 1.0 mg/m² dose and from 89 to 120 ng/ml at the 1.3 mg/m² dose.
After intravenous bolus or subcutaneous administration at a dose of 1.3 mg/m² to patients with multiple myeloma, the total systemic exposure following repeated dosing (AUClast) was equivalent for subcutaneous and intravenous administration. Cmax after subcutaneous administration (20.4 ng/ml) was lower than after intravenous administration (223 ng/ml). The geometric mean ratio of AUClast was 0.99, and the 90% confidence interval was 80.18–122.80%.
Distribution. The mean volume of distribution of bortezomib ranges from 1659 liters to 3294 liters following single or multiple doses of 0.1 mg/m² or 1.3 mg/m² to 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 was independent of concentration.
Metabolism. In vitro, bortezomib is primarily metabolized by cytochrome P450 enzymes, specifically CYP3A4, CYP2C19, and CYP1A2. The main metabolic pathway involves deboronation to two deboronated metabolites, which are subsequently hydroxylated into other metabolites. The deboronated metabolites of bortezomib are inactive as inhibitors of the 26S proteasome.
Elimination. The mean elimination half-life (T½) of bortezomib after multiple doses ranges from 40 to 193 hours. Bortezomib is eliminated more rapidly after the first dose compared to subsequent doses. Mean total clearance was 102 and 112 L/h after the first dose of 1.0 mg/m² and 1.3 mg/m², respectively, and ranged from 15 to 32 L/h and from 18 to 32 L/h after subsequent doses of 1.0 mg/m² and 1.3 mg/m², respectively.
Special patient populations
Hepatic impairment
The effect of hepatic impairment on the pharmacokinetics of bortezomib was evaluated in a Phase I study during the first treatment cycle involving 61 patients, primarily with solid tumors and various degrees of hepatic dysfunction, 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 to severe hepatic impairment. Dose adjustment and careful monitoring during treatment are recommended for these patients.
Renal impairment. Pharmacokinetic studies were conducted in patients with varying degrees of renal function, categorized by creatinine clearance (CrCL) as follows: normal (CrCL ≥ 60 ml/min/1.73m², n=12), mild impairment (CrCL = 40–59 ml/min/1.73m², n=10), moderate impairment (CrCL = 20–39 ml/min/1.73m², n=9), and severe impairment (CrCL < 20 ml/min/1.73m², n=3). Patients on dialysis who received bortezomib after dialysis were also included in the study (n=8). Patients received intravenous bortezomib doses of 0.7–1.3 mg/m² twice weekly. The effect of bortezomib (standardized dose 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 (39%) L/m², and the elimination half-life was 100 (44%) hours. After adjusting for body surface area, other demographic factors such as age, body weight, and sex had no clinically significant effect on bortezomib clearance. Bortezomib clearance values in children, adjusted for body surface area, were comparable to those 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 stem cell transplantation or who are not candidates for transplantation (second-line therapy).
Treatment of multiple myeloma, in combination with dexamethasone or dexamethasone and thalidomide, in previously untreated patients who are candidates for high-dose chemotherapy with hematopoietic stem cell transplantation (induction therapy).
Treatment of mantle cell lymphoma, in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone, in previously untreated patients who are not candidates for hematopoietic stem cell transplantation.
Contraindications
Hypersensitivity to bortezomib, boron, or to any of the excipients of the medicinal product.
Acute diffuse infiltrative pulmonary and pericardial diseases.
When bortezomib is used in combination with other medicinal products (see instructions for medical use of these medicinal products for additional contraindications).
Special precautions
General warnings
Bortezomib is a cytotoxic medicinal product. Therefore, caution should be exercised during its preparation and administration. Use of gloves and protective clothing is recommended to prevent skin contact.
Appropriate aseptic techniques should be strictly followed when handling bortezomib, as the product does not contain preservatives.
Fatal outcomes have occurred due to accidental intrathecal administration of bortezomib. Bortezomib must be administered only intravenously or subcutaneously. DO NOT ADMINISTER BORTEZOMIB INTRATHECALLY.
Instructions for solution preparation . Solution preparation must be performed only by qualified healthcare personnel.
For intravenous administration, the content of the vial should be reconstituted carefully with 3.5 mL of 0.9% sodium chloride injection solution using a syringe of appropriate size, without removing the rubber stopper from the vial. The lyophilized powder dissolves in less than 2 minutes. After reconstitution, 1 mL of solution contains 1 mg of bortezomib. The resulting solution should be clear and colorless, with a pH of 4–7. The prepared solution should be visually inspected for particulate matter and discoloration prior to administration. If particulates are present or discoloration has occurred, the solution must not be used.
For subcutaneous administration, the content of each vial should be reconstituted with 1.4 mL of 0.9% sodium chloride injection solution using a syringe of appropriate size, without removing the rubber 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 visually inspected for particulate matter and discoloration prior to administration. If particulates are present or discoloration has occurred, the solution must not be used.
Proper disposal procedure. For single use only. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Interaction with other medicinal products and other forms of interaction
In vitro studies have shown that bortezomib exhibits weak inhibitory properties against cytochrome P450 isoenzymes – 1A2, 2C9, 2C19, 2D6, and 3A4. Given the minor role of CYP2D6 in bortezomib metabolism (7%), changes in overall drug disposition are not expected in individuals with low activity 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: 1.032–1.772). Therefore, careful monitoring of patients is recommended when bortezomib is administered concomitantly with potent CYP3A4 inhibitors (such as ketoconazole, ritonavir).
Studies evaluating the effect of omeprazole, a potent CYP2C19 inhibitor, on the pharmacokinetics of bortezomib (after intravenous administration) did not demonstrate a significant effect on bortezomib pharmacokinetics.
Studies involving 6 patients evaluating the effect of rifampicin, a potent CYP3A4 inducer, revealed an average reduction in bortezomib AUC (after intravenous administration) by 45%. Therefore, concomitant administration of bortezomib with potent CYP3A4 inducers (such as rifampicin, carbamazepine, phenytoin, phenobarbital, and St. John’s wort extract) is not recommended, as the efficacy of bortezomib may be reduced.
In the same study, dexamethasone, a weak CYP3A4 inducer, did not significantly alter bortezomib pharmacokinetics based on data from 7 patients.
A drug interaction study evaluating the effects of melphalan and prednisone on bortezomib pharmacokinetics (after intravenous administration) in 21 patients demonstrated an average increase in bortezomib AUC by 17%. This increase in bortezomib AUC is not considered clinically significant.
In patients with diabetes mellitus receiving oral hypoglycemic agents, cases of hypo- and hyperglycemia have been reported with frequencies ranging from rare to common. Patients taking oral antidiabetic medications should have their blood glucose levels monitored and antidiabetic drug doses adjusted during bortezomib treatment.
Special precautions for use
If bortezomib is used in combination with other medicinal products, the instructions for medical use of these medicinal products should be consulted prior to initiating treatment. If thalidomide is used, special attention should be paid to pregnancy diagnosis and contraceptive measures.
Intrathecal administration. Fatal cases due to accidental intrathecal administration of bortezomib have been reported. Bortezomib must be administered only intravenously or subcutaneously. BORTEZOMIB MUST NOT BE ADMINISTERED INTRATHECALLY.
Gastrointestinal toxicity. Treatment with bortezomib may cause gastrointestinal toxicity, including nausea, diarrhea, vomiting, and constipation, which are very common during treatment. Cases of intestinal obstruction (reported as uncommon) have been reported; therefore, patients with constipation should be under medical supervision.
Hematological toxicity. Hematological toxicity (thrombocytopenia, neutropenia, and anemia) is very common during bortezomib therapy. During 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 were typically lowest on day 11 of each bortezomib treatment cycle and returned to baseline before the start of the next cycle. Cumulative thrombocytopenia was not observed. On average, the lowest measured platelet count was approximately 40% of the baseline level in studies of bortezomib monotherapy in multiple myeloma patients and 50% in studies of bortezomib in mantle cell lymphoma patients. In patients with progressive myeloma, the severity of thrombocytopenia was related to the platelet count before treatment: in 90% of 21 patients with a baseline platelet count < 75,000/µL, platelet counts were ≤ 25,000/µL during the study, including 14% with < 10,000/µL, whereas in patients 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 was observed more frequently in the group receiving bortezomib (VcR-CAP regimen) than in the group 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 transfusion compared to 2.9% in the R-CHOP treatment 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. Bortezomib therapy should be withheld if platelet counts decrease to < 25,000/µL during monotherapy or to ≤ 30,000/µL during combination therapy with melphalan and prednisone. The benefit-risk ratio of bortezomib treatment should be evaluated, especially in cases of moderate or severe thrombocytopenia and risk factors for bleeding.
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 were typically lowest on day 11 of each bortezomib treatment cycle and returned to baseline 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 treatment group and 61% in the R-CHOP treatment group received colony-stimulating factor. Since patients with neutropenia are at increased risk of infection, they should be monitored for signs of infection and appropriate therapeutic measures taken. The use of granulocyte colony-stimulating factor should be considered for managing hematological toxicity. If initiation of a new treatment cycle is delayed several times, prophylactic use of granulocyte colony-stimulating factor should be considered.
Reactivation of Herpes zoster virus. Antiviral prophylaxis should be considered for patients treated with bortezomib. During phase III studies in patients with previously untreated multiple myeloma, the overall frequency of reactivation of Herpes zoster (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 treatment group and 1.2% in the R-CHOP treatment group.
Reactivation and infection with hepatitis B virus (HBV).
Before starting 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. For additional information, refer to the medical instructions for the medicinal product rituximab.
Progressive multifocal leukoencephalopathy (PML). Very rare cases of infection with John Cunningham virus leading to fatal PML have been reported in patients treated with bortezomib. Patients diagnosed with PML had received prior or concomitant immunosuppressive therapy with bortezomib. Most cases of PML were diagnosed within the first 12 months after initiation of 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. Typically, the incidence of peripheral neuropathy peaks during the fifth bortezomib treatment cycle.
Careful monitoring of patients for symptoms of neuropathy such as burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain, or weakness is recommended.
In a phase III study 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, 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 examination is recommended 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 frequently associated with postural/orthostatic hypotension. In most cases, it is mild or moderate in severity and occurs throughout treatment. Patients who developed orthostatic hypotension during bortezomib administration (intravenous) did not have symptoms of orthostatic hypotension before 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 of orthostatic hypotension is unknown. It may be related to autonomic neuropathy. Autonomic neuropathy may be associated with bortezomib, and bortezomib may worsen underlying conditions, particularly diabetic or amyloid neuropathy. Therapy should be used cautiously in patients with a history of syncope, diabetic neuropathy, those taking antihypertensive medicinal products, and in cases of dehydration due to diarrhea or vomiting. In case of orthostatic hypotension, hydration, glucocorticoids and/or sympathomimetics are recommended; if necessary, the dose of antihypertensive medicinal products should be reduced. Patients should consult a physician if dizziness, lightheadedness, or loss of consciousness occurs.
Reversible posterior leukoencephalopathy syndrome (PRES). Cases of PRES have been reported in patients treated with the medicinal product. PRES is a rare reversible neurological disorder characterized by seizures, arterial hypertension, headache, lethargy, confusion, visual disturbances, and other neurological impairments. Brain imaging, preferably magnetic resonance imaging (MRI), is required to confirm the diagnosis. Bortezomib treatment should be discontinued if PRES occurs.
Heart failure. Development or worsening of pre-existing acute congestive heart failure and/or reduced left ventricular ejection fraction has been observed with bortezomib use. Fluid retention may contribute to the development of signs and symptoms of heart failure. Patients with risk factors or pre-existing heart disease should be under medical supervision.
ECG monitoring. Isolated cases of QT interval prolongation have been observed in clinical trials; the cause has not been established.
Lung function disorders. Isolated cases of acute diffuse infiltrative lung diseases of unknown etiology, such as pneumonitis, pulmonary infiltration, and acute respiratory distress syndrome (ARDS), have been observed. Some of these cases were fatal. Radiological examination is recommended before starting treatment to establish baseline lung status and for comparison in case of potential treatment-induced lung function impairment. Rapid diagnostic evaluation and appropriate treatment are required if new or worsening pulmonary symptoms (e.g., cough, dyspnea) occur. The benefits and risks of continuing bortezomib treatment should be carefully considered.
Concomitant use with high-dose cytarabine (2 g/m²/day) administered as continuous infusion over 24 hours is not recommended.
In clinical trials, two out of two patients who received high-dose cytarabine (2 g/m²/day) as continuous 24-hour infusion 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 use with high-dose cytarabine (2 g/m²/day) as continuous 24-hour infusion is not recommended.
Renal function impairment. Renal function impairment is frequently observed 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; these patients should be treated with reduced doses and closely monitored for signs of toxicity.
Hepatic reactions. Rare cases of acute liver failure have been reported in patients receiving bortezomib concomitantly with several other medicinal products 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 destroying 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 highest risk. Close monitoring and appropriate preventive measures are required for such patients.
Warnings regarding concomitant use of other medicinal products. Patients should be closely monitored by a physician when bortezomib is combined with strong CYP3A4 inhibitors. Caution should be exercised when combining bortezomib with CYP3A4 or CYP2C9 substrates.
Hepatic function should be corrected prior to starting treatment if impaired, and caution should be exercised when treating patients taking oral hypoglycemic agents.
Potential immune complex-mediated reactions. Immune complex-mediated reactions, such as serum sickness, polyarthritis with rash, and proliferative glomerulonephritis, have been reported infrequently. Bortezomib should be discontinued if serious reactions occur.
This medicinal product contains mannitol and may therefore have a mild laxative effect.
Use during pregnancy or breastfeeding
Contraception in men and women
Men and women of reproductive potential must use effective contraception during treatment and for 3 months after the end of treatment.
Pregnancy
There are no clinical data on the use of bortezomib in pregnant women. The teratogenic properties of bortezomib have not been fully investigated. Bortezomib is not recommended during pregnancy except in cases where the woman's clinical condition requires treatment with bortezomib. If bortezomib is 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 should comply with requirements for pregnancy prevention. For additional information, see the thalidomide medical instructions.
Breastfeeding
It is unknown whether bortezomib is excreted in breast milk, but to prevent the development of serious adverse effects in the infant, breastfeeding should be discontinued during bortezomib treatment.
Fertility
Fertility studies with bortezomib have not been conducted.
Ability to affect reaction rate when driving or operating machinery
Bortezomib has a moderate effect on reaction rate when driving or operating machinery. Bortezomib use is very commonly associated with fatigue, commonly with dizziness, orthostatic/postural hypotension, or visual disturbances, and infrequently with loss of consciousness. Therefore, patients should be cautious when driving or operating machinery and should avoid driving or operating machinery if these symptoms occur.
Method of Administration and Dosage
Treatment should be initiated under the supervision of a qualified physician experienced in the treatment of patients with oncological diseases, although bortezomib may be administered by a healthcare professional experienced in the use of antineoplastic agents. Preparation of the solution must be performed only by qualified medical personnel.
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) of a 21-day treatment cycle. This three-week period constitutes one treatment cycle. Upon achieving a complete clinical response, two additional treatment cycles are recommended. Patients with a partial response but not complete remission should continue bortezomib therapy, but for no more than 8 cycles. At least 72 hours must elapse between consecutive doses of bortezomib.
Dosage adjustment and re-initiation recommendations for bortezomib monotherapy
In the event of any grade III non-hematological toxicity or grade IV hematological toxicity, except for neuropathies, bortezomib treatment must be interrupted. 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
The drug dosage should be adjusted in case of development of neuropathic pain and/or peripheral neuropathy (see Table 1). Bortezomib should be administered to patients with a history of severe neuropathy only after careful benefit-risk assessment.
Table 1
Recommended* dose modification for bortezomib-induced neuropathy
| Severity of neuropathy |
Dose and administration frequency adjustment |
| Grade I (asymptomatic; loss of deep tendon reflexes or paresthesia) without pain or functional impairment |
Dose and administration schedule do not require modification |
| Grade I with pain or Grade II (moderate severity symptoms; limitation in 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 resolution of toxic symptoms. 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. Classification according to NCI CTCAE v 4.0 general toxicity criteria.
** Instrumental activities of daily living include cooking, shopping, using the telephone, managing money, etc.
*** Basic self-care activities include bathing, dressing/undressing, eating, using the toilet, taking medications, being out of bed, etc.
Combination therapy with pegylated liposomal doxorubicin
The recommended dose of bortezomib for adults is 1.3 mg/m² body surface area administered intravenously or subcutaneously twice weekly for 2 weeks (Days 1, 4, 8, and 11), followed by a 10-day rest period (Days 12–21). This three-week period constitutes one treatment cycle. At least 72 hours should elapse between consecutive bortezomib doses.
Pegylated liposomal doxorubicin should be administered at a dose of 30 mg/m² on Day 4 of the bortezomib treatment cycle via a one-hour intravenous infusion, administered after bortezomib injection.
Up to 8 cycles of this combination therapy should be administered provided the disease does not progress and patients tolerate treatment well. Patients who achieve a complete response may continue treatment for at least 2 additional cycles after achieving complete response, even if this requires administration of more than 8 cycles. Patients whose paraprotein levels continue to decline after 8 cycles may also continue treatment as long as the treatment is well tolerated and a response is observed.
Combination therapy with dexamethasone
The recommended dose of bortezomib is 1.3 mg/m² body surface area administered intravenously or subcutaneously twice weekly for 2 weeks (Days 1, 4, 8, and 11), followed by a 10-day rest period (Days 12–21). This three-week period constitutes one treatment cycle. At least 72 hours should elapse between consecutive bortezomib doses.
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 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.
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 is administered twice weekly (Days 1, 4, 8, 11, 22, 25, 29, and 32). In cycles 5–9, bortezomib is administered once weekly (Days 1, 8, 22, and 29). At least 72 hours should elapse between consecutive bortezomib doses.
Melphalan and prednisone should be administered orally on Days 1, 2, 3, and 4 of the first week of each cycle.
Recommended bortezomib dosing regimen when used in combination with melphalan and prednisone
Table 2
| 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 adjustment and re-initiation recommendations for combination therapy with melphalan and prednisone
Prior to starting a new treatment cycle:
- platelet count must be ≥ 70×10⁹/L and absolute neutrophil count must be ≥ 1.0×10⁹/L,
- non-hematological toxicity must have resolved to Grade 1 or baseline levels.
Dose adjustment during subsequent cycles of bortezomib therapy in combination with melphalan and prednisone
Table 3
| Toxicity |
Dose modification or discontinuation of treatment |
| 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) |
Delay bortezomib administration |
|
Bortezomib dose should be reduced by one level |
| Non-hematological toxicity ≥ Grade III |
Treatment with the medicinal product should be delayed until symptoms improve to baseline level or Grade I severity. Then, bortezomib may be re-administered with a dose reduction by one level |
For additional information regarding melphalan and prednisone, see the package leaflets for these medicinal products.
Untreated multiple myeloma in patients eligible for hematopoietic stem cell transplantation (induction therapy)
Combination therapy with dexamethasone
The recommended dose of bortezomib is 1.3 mg/m² body surface area administered intravenously or subcutaneously twice weekly for two weeks (days 1, 4, 8, and 11), followed by
a 10-day rest period (days 12–21). This three-week period constitutes one treatment cycle. At least 72 hours should elapse between consecutive bortezomib doses.
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 with this combination.
Combination therapy with dexamethasone and thalidomide
The recommended dose of bortezomib is 1.3 mg/m² body surface area administered intravenously or subcutaneously twice weekly for two weeks (days 1, 4, 8, and 11), followed by
a 17-day rest period (days 12–28). This four-week period constitutes one treatment cycle. At least 72 hours should elapse between consecutive bortezomib doses.
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 candidates 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 |
Break |
||||
| Dx (40 mg) |
Day 1, 2, 3, 4 |
Day 8, 9, 10, 11 |
- |
||||
| Bortezomib + Dx + T |
Cycle 1 |
||||||
| Week |
1 |
2 |
3 |
4 |
|||
| Bortezomib (1.3 mg/m²) |
Day 1, 4 |
Day 8, 11 |
Break |
Break |
|||
| T (50 mg) |
Daily |
Daily |
- |
- |
|||
| T (100 mg)ᵃ |
- |
- |
Daily |
Daily |
|||
| Dx (40 mg) |
Day 1, 2, 3, 4 |
Day 8, 9, 10, 11 |
- |
- |
|||
| Cycles 2-4ᵇ |
|||||||
| Bortezomib (1.3 mg/m²) |
Day 1, 4 |
Day 8, 11 |
Break |
Break |
|||
| T (200 mg)ᵃ |
Daily |
Daily |
Daily |
Daily |
|||
| Dx (40 mg) |
Day 1, 2, 3, 4 |
Day 8, 9, 10, 11 |
- |
- |
|||
Dx – dexamethasone; T – thalidomide.
a Increase the dose of thalidomide to 100 mg from week 3 of cycle 1 if the 50 mg dose is tolerated, and to 200 mg if the 100 mg dose is tolerated.
b Patients who achieve a partial response after 4 cycles of treatment may receive up to 6 cycles of treatment.
Dosing recommendations for patients eligible for transplantation
For dose adjustments in the event of neuropathy, refer to the dose modification recommendations for bortezomib when used as monotherapy.
If bortezomib is used in combination with other chemotherapeutic agents, refer to the respective product information 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 three-week period constitutes one treatment cycle. At least 72 hours should elapse between consecutive doses of bortezomib. Administer 6 treatment cycles. Patients who first demonstrate a response during cycle 6 are recommended to receive 2 additional treatment cycles.
Medications administered by intravenous infusion on day 1 of each three-week bortezomib treatment cycle: rituximab 375 mg/m², cyclophosphamide 750 mg/m², doxorubicin 50 mg/m².
Prednisone should be administered orally at a dose of 100 mg/m² on days 1, 2, 3, 4, and 5 of each bortezomib treatment cycle.
Dose modification recommendations for patients with untreated mantle cell lymphoma
Prior to initiating a new treatment cycle:
- Platelet count must be ≥ 100,000 cells/µL and absolute neutrophil count (ANC) must be ≥ 1,500 cells/µL,
- Platelet count must be ≥ 75,000 cells/µL in patients with bone marrow infiltration or splenic sequestration,
- Hemoglobin level must be ≥ 8 g/dL,
- Non-hematologic toxicity must have resolved to grade 1 or baseline levels.
Treatment with bortezomib should be withheld in the event of any non-hematologic toxicity ≥ grade III (except neuropathy) related to drug 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 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 modification or treatment interruption |
| Hematological toxicity |
|
|
Treatment with bortezomib should be interrupted for up to 2 weeks until the absolute neutrophil count recovers to
|
|
Delay bortezomib dose administration |
| Non-hematological toxicity ≥ Grade III related to bortezomib administration |
Bortezomib treatment should be interrupted until symptoms improve to Grade II severity or better. Bortezomib may then be restarted at a reduced dose level by one level (from 1.3 mg/m² to 1 mg/m² or from 1 mg/m² to 0.7 mg/m²). For bortezomib-related neuropathic pain and/or peripheral neuropathy, hold and/or modify bortezomib dosing as outlined in Table 1. |
If bortezomib is used in combination with other chemotherapeutic agents, refer to the instructions for use of these medicinal products for information on dose adjustments of these agents in the event of toxicity.
Special patient groups
Elderly patients
Currently, there are no data indicating the need for dose adjustment in patients aged 65 years and older.
There have been no studies on the use of bortezomib in elderly patients with previously untreated multiple myeloma who are candidates for high-dose chemotherapy followed by hematopoietic stem cell transplantation. Therefore, no recommendations on dose adjustment can be provided for this patient group.
In a study of bortezomib use in patients with previously untreated mantle cell lymphoma, 42.9% of patients were aged 65–74 years and 10.4% were aged ≥75 years. Patients aged 75 years and older tolerated treatment 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, followed by gradual dose escalation to 1.0 mg/m² or dose reduction to 0.5 mg/m², depending on patient tolerance.
Recommendations for initial dose modification of bortezomib in patients with hepatic impairment
Table 6
| Severity of hepatic impairment* |
Bilirubin level |
AST levels |
Initial dose adjustment |
| Mild |
≤ 1.0 x 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 National Cancer Institute Organ Dysfunction Working Group classification of severity of liver dysfunction (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 adjustments are not required in these patients. It is unknown whether severe renal impairment (creatinine clearance < 20 ml/min/1.73 m²) affects the pharmacokinetics of bortezomib. Since dialysis may reduce bortezomib concentrations, the drug should be administered after the dialysis procedure.
Method of administration
Bortezomib is administered by intravenous or subcutaneous injection. Accidental intrathecal administration of the drug has resulted in fatal outcomes.
Intravenous
The reconstituted solution should be administered immediately after preparation as a 3- to 5-second intravenous bolus injection through a peripheral or central venous catheter, which should then be flushed with 0.9% sodium chloride injection solution. At least 72 hours should elapse between consecutive doses of bortezomib.
Subcutaneous
The reconstituted solution should be administered immediately after preparation by subcutaneous injection at a 45–90° angle, selecting injection sites on the thighs (left or right) or abdomen (left or right side). Injection sites should be rotated.
If adverse reactions occur at the injection site during subcutaneous administration, bortezomib solution may be administered subcutaneously at a lower concentration (1 mg/ml instead of 2.5 mg/ml) or via intravenous route.
Children
The safety and efficacy of bortezomib in children (under 18 years of age) have not been established. Current data are insufficient to provide dosage recommendations for pediatric patients.
Overdose
In patients, overdose exceeding the recommended dose by more than two-fold has been associated with acute hypotension and thrombocytopenia resulting in death.
There is no specific antidote for bortezomib. In case of overdose, careful monitoring of hemodynamic parameters (infusion therapy, vasopressor and/or inotropic agents) and body temperature is recommended.
Adverse Reactions
Serious adverse reactions reported during bortezomib treatment included rare reports 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 reported adverse reactions during bortezomib therapy include nausea, diarrhea, constipation, vomiting, fatigue, pyrexia, thrombocytopenia, anemia, neutropenia, peripheral neuropathy (including sensory neuropathy), headache, paresthesia, decreased appetite, dyspnea, rash, herpes zoster, and myalgia.
Multiple Myeloma
The adverse reactions listed in Table 7 are considered related to the use of bortezomib. These adverse reactions are based on pooled data from 5476 patients, of whom
3996 received bortezomib at a dose of 1.3 mg/m². Overall, bortezomib was used to treat multiple myeloma in 3974 patients.
Adverse reactions are categorized by system organ class and frequency of occurrence. Frequencies are defined as: very common (>1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000), and not known (cannot be estimated from available data). Within each group, adverse reactions are listed in descending order of severity. Also included are adverse reactions not observed during clinical trials but reported in the post-marketing period.
Table 7
| 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*, herpes meningoencephalitis#, bacteremia (including staphylococcal), hordeolum, influenza, cellulitis, device-related infections, skin infections*, ear infections*, staphylococcal infection, dental infection* |
|
| Rare |
Meningitis (including bacterial), Epstein-Barr virus infection, genital herpes, tonsillitis, mastoiditis, post-viral fatigue syndrome |
|
| Benign, malignant and unspecified neoplasms (including cysts and polyps) |
Rare |
Malignant tumor, plasma cell leukemia, renal cell carcinoma, tumor 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 syndrome, thrombocytosis*, hyperviscosity syndrome, thrombocytopathy, 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*, impaired antidiuretic hormone secretion |
| Rare |
Hypothyroidism |
|
| Metabolic and nutritional disorders |
Very common |
Decreased appetite |
| Common |
Dehydration, hypokalemia*, hyponatremia*, blood glucose disturbances*, hypocalcemia*, enzyme level disturbances* |
|
| Uncommon |
Tumor lysis syndrome, patient condition aggravatedª*, hypomagnesemia*, hypophosphatemia*, hyperkalemia*, hypercalcemia*, hypernatremia*, uric acid level disturbances*, diabetes mellitus*, fluid retention |
|
| Rare |
Hypermagnesemia*, acidosis, electrolyte imbalance*, hypervolemia, hypochloremia*, hypovolemia, hyperchloremia*, hyperphosphatemia*, metabolic disorders, vitamin B group deficiency, vitamin B12 deficiency, gout, increased appetite, alcohol intolerance |
|
| Psychiatric disorders |
Common |
Mood disorders*, anxiety disorder*, sleep disorders* |
| Uncommon |
Psychiatric disorder*, hallucinations*, psychotic disorder*, confusion*, agitation |
|
| Rare |
Suicidal thoughts*, adjustment disorder, delirium, decreased libido |
|
| Nervous system disorders |
Very common |
Neuropathies*, peripheral sensory neuropathy, dysesthesia*, neuralgia* |
| Common |
Motor neuropathy*, loss of consciousness (including syncope), dizziness*, dysgeusia*, lethargy, headache* |
|
| Uncommon |
Tremor, sensorimotor peripheral neuropathy, dyskinesia*, coordination and balance disturbances*, memory loss (without dementia)*, encephalopathy*, reversible posterior encephalopathy syndrome#, neurotoxicity, seizure disorders*, postherpetic neuralgia, speech disorders*, restless legs syndrome, migraine, sciatica, attention disorders, reflex disturbances*, parosmia |
|
| Rare |
Intracranial hemorrhage*, intracerebral hemorrhage (including subarachnoid)*, brain edema, transient ischemic attack, coma, autonomic nervous system disturbances, autonomic neuropathy, cranial nerve paralysis*, paralysis*, paresis*, presyncope, brainstem lesion syndrome, cerebrovascular disorder, nerve root damage, psychomotor hyperactivity, spinal cord compression, other cognitive disorders, motor dysfunctions, other nervous system disorders, radiculitis, drooling, hypotonia, Guillain-Barré syndrome, demyelinating polyneuropathy |
|
| Eye disorders |
Common |
Eye swelling*, vision disturbances*, conjunctivitis* |
| Uncommon |
Ocular hemorrhage*, eyelid infections*, eye inflammation*, chalazion, blepharitis, diplopia, dry eye*, eye irritation*, eye pain, increased lacrimation, eye discharge |
|
| Rare |
Corneal damage*, exophthalmos, retinitis, scotoma, other eye (and eyelid) disorders, acquired dacryoadenitis, photophobia, photopsia, optic neuropathy#, 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*, 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 vascular embolism, lymphedema, pallor, erythromelalgia, vascular dilation, 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*, impaired airway patency*, hypoxia, pleurisy*, hiccups, rhinorrhea, dysphonia, wheezing |
|
| Rare |
Respiratory 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 intestine obstruction, ileus)*, abdominal discomfort, oral ulcers*, enteritis*, gastritis*, gum bleeding, gastroesophageal reflux disease*, colitis (including Clostridium difficile-induced)*, ischemic colitis#, gastrointestinal tract inflammation*, dysphagia, irritable bowel syndrome, other gastrointestinal disorders, coated tongue, gastrointestinal motility 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, blistering in oropharynx*, lip pain, periodontitis, anal fissure, altered bowel 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*, blisters*, skin pigmentation disturbances* |
|
| Rare |
Skin reactions, Jessner's lymphocytic infiltration, palmoplantar erythrodysesthesia syndrome, subcutaneous hemorrhage, livedo reticularis, skin induration, papules, photosensitivity reactions, seborrhea, cold sweat, other skin disorders, erythrosis, skin ulcers, nail disorders |
|
| Musculoskeletal and connective tissue disorders |
Very common |
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 disorders |
Common |
Renal failure* |
| Uncommon |
Acute renal failure, chronic renal failure*, urinary tract infections*, signs and symptoms of urinary tract disorders*, hematuria*, urinary retention, micturition disorders*, proteinuria, azotemia, oliguria*, pollakiuria |
|
| 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 reactions*, mucous membrane disorders*, chest pain, gait disturbance, cold sensation, extravasation*, complications related to catheter placement*, thirst sensation*, chest discomfort, sensation of body temperature change*, pain associated with injection* |
|
| Rare |
Lethal outcome (including sudden), multi-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*, protein level deviations*, weight increased, blood test abnormalities*, increased C-reactive protein level |
|
| Rare |
Blood gas abnormalities*, ECG abnormalities (including QT interval prolongation)*, international normalized ratio (INR) deviations*, increased gastric acidity, increased platelet aggregation, elevated troponin I level, virus identification in serological tests*, urine test abnormalities* |
|
| Procedural complications |
Uncommon |
Falls, confusion |
| Rare |
Transfusion reactions, fractures*, tremor*, facial injury, joint injury*, burns, skin laceration, procedural pain, radiation injuries* |
|
| Surgical and medical procedures |
Rare |
Macrophage activation |
* Grouping of 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 at a dose of 1.3 mg/m² in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (VcR-CAP), and in 242 patients who received rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHOP). 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 in the combination regimen (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 may not be solely related to bortezomib. Treatment with bortezomib in patients with mantle cell lymphoma was associated with ≥5% higher frequencies of hematologic adverse reactions (neutropenia, thrombocytopenia, leukopenia, anemia, lymphopenia), peripheral sensory neuropathy, arterial hypertension, pyrexia, pneumonia, stomatitis, and hair disorders compared to treatment in patients with multiple myeloma.
Adverse reactions occurring at a frequency of ≥1%, with similar or higher incidence in the VcR-CAP treatment group, considered 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 not known (cannot be estimated from available data). Within each category, adverse reactions are listed in order of decreasing severity.
Table 8
| Organ systems |
Frequency |
Adverse 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*, fluid retention |
|
| Uncommon |
Tumor lysis syndrome |
|
| Psychiatric disorders |
Common |
Sleep disorders* |
| Nervous system disorders |
Very common |
Peripheral sensory neuropathy, dysesthesia*, neuralgia* |
| Common |
Neuropathies*, motor neuropathy*, loss of consciousness (including syncope), encephalopathy*, dizziness*, dysgeusia*, autonomic neuropathy |
|
| Uncommon |
Autonomic nervous system disorders |
|
| Eye disorders |
Common |
Vision disorders* |
| 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 system disorders |
Common |
Dyspnea*, cough*, hiccups |
| Uncommon |
Acute respiratory distress syndrome, pulmonary embolism, pneumonitis, pulmonary hypertension, pulmonary edema (including acute) |
|
| Gastrointestinal disorders |
Very common |
Nausea and vomiting*, diarrhea*, stomatitis*, constipation |
| Common |
Gastrointestinal hemorrhage (including mucosal)*, abdominal distension, dyspepsia, oropharyngeal pain*, gastritis*, oral ulcers*, abdominal discomfort, dysphagia, gastrointestinal inflammation*, abdominal pain (including gastrointestinal and splenic region pain)*, oral cavity disorders* |
|
| Uncommon |
Colitis (including Clostridium difficile-induced)* |
|
| Hepatobiliary disorders |
Common |
Hepatotoxicity (including liver 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 system disorders |
Common |
Urinary tract infections* |
| General disorders and administration site conditions |
Very common |
Pyrexia*, fatigue, asthenia |
| Common |
Edema (including peripheral), chills, injection site reactions*, fever* |
|
| Investigations |
Common |
Hyperbilirubinemia*, abnormal protein levels*, weight loss, weight gain |
* Grouping of more than one MedDRA term.
Description of selected adverse reactions
Herpes zoster virus reactivation
Multiple myeloma
Antiviral prophylaxis was administered to 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 prophylaxis.
Mantle cell lymphoma
Antiviral prophylaxis was administered to 57% of patients 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 prophylaxis.
Hepatitis B virus (HBV) reactivation and infection
Mantle cell lymphoma
Cases of hepatitis B infection with fatal outcome were reported in 0.8% of patients (n=2) in the group receiving R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) and in 0.4% of patients (n=1) receiving bortezomib as part of combination therapy with the VcR-CAP regimen (rituximab, cyclophosphamide, doxorubicin, and prednisone). The overall incidence of hepatitis B was similar in both treatment groups (0.8% in the VcR-CAP group versus 1.2% in the R-CHOP group).
Peripheral neuropathy during combination therapy
Multiple myeloma
Peripheral neuropathy was observed in studies where bortezomib was used as induction therapy in combination with dexamethasone (study IFM-2005-01) and with dexamethasone-thalidomide (study MMY-3010) (see Table 9).
Incidence of peripheral neuropathy (PN) during induction therapy
by toxicity grade and need for treatment interruption due to PN
Table 9
| Signs of peripheral neuropathy |
IFM-2005-01 |
MMY-3010 |
||
| VDDx (N=239) |
VcDx (N=239) |
TDx (N=126) |
VcTDx (N=130) |
|
| Frequency 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
| Peripheral neuropathy parameters |
VcR-CAP (N=240) |
R-CHOP (N=242) |
| Incidence of PN (%) |
||
| All grades of PN |
30 |
29 |
| ≥ Grade II PN |
18 |
9 |
| ≥ Grade III PN |
8 |
4 |
| Treatment 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 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 bortezomib treatment discontinuation was also 5% lower. The overall incidence of diarrhea, lower abdominal pain, abdominal pain, asthenic conditions, upper respiratory tract infections, and peripheral neuropathies was 12–15% lower in the subcutaneous group compared to the intravenous group. Additionally, the incidence of Grade III or higher peripheral neuropathies was 10% lower, and the rate of treatment discontinuation due to peripheral neuropathy was 8% lower.
Injection site reactions occurred in 6% of patients, predominantly erythema. Symptoms resolved on average within 6 days, and dose modification was required in 2 patients. Serious reactions occurred in two patients (1%): 1 case of pruritus and 1 case of erythema.
The rate of on-treatment mortality 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 bortezomib-containing therapy, 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 ≥ Grade III were observed in 40% and 8.5% of patients, respectively.
Reporting suspected adverse reactions
Reporting of suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, or their legal representatives should report all cases of suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.
Shelf life. 2 years.
Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.
Packaging. 1 vial per cardboard box.
Prescription status. Prescription only.
Manufacturer. MSN Laboratories Private Limited, India.
Manufacturer's address and location of its business operations
Formulations Division, Unit-II, Survey Nos. 1277 and 1319 to 1324, Nandigama (Village), Nandigama (Mandal), Rangareddy District, Telangana, 509228, India.