Bortezomib shilpa
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BORTEZOMIB SHILPA
Composition:
Active substance: bortezomib;
1 vial contains 3.5 mg of bortezomib;
Excipients: mannitol.
Pharmaceutical form. Lyophilisate for solution for injection.
Main physico-chemical properties: white or almost white lyophilized solid or powder.
Pharmacotherapeutic group. Antineoplastic agents. Bortezomib. ATC code L01XG01.
Pharmacological Properties
Pharmacodynamics
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 t½ of 20 minutes, indicating that proteasome inhibition by bortezomib is reversible. By inhibiting the proteasome, bortezomib affects cancer cells through multiple mechanisms, including altering regulatory proteins that control the cell cycle and activating the nuclear transcription factor NF-κB. Inhibition of the proteasome leads to cell cycle arrest and apoptosis. NF-κB is a transcription factor whose activation is essential for many aspects of tumor development, including cell growth and survival, angiogenesis, cell–cell interactions, and metastasis. In myeloma, bortezomib affects the ability of myeloma cells to interact with the bone marrow microenvironment.
Studies have shown that bortezomib is cytotoxic to many types of cancer cells and that cancer cells are more susceptible to 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 bone disease and were treated with bortezomib.
Pharmacokinetics
Absorption. After intravenous bolus administration of doses of 1.0 mg/m² and 1.3 mg/m² in 11 patients with multiple myeloma and creatinine clearance exceeding 50 mL/min, the mean peak plasma concentration (Cmax) of the first dose of bortezomib was 57 and 112 ng/mL, respectively. With subsequent doses, mean Cmax values 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 of 1.3 mg/m² to patients with multiple myeloma (n = 14 in the intravenous group and n = 17 in the subcutaneous group), the total systemic exposure after repeated dosing (AUClast) was equivalent between subcutaneous and intravenous administration. 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 after 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 83%. The fraction of bortezomib bound to plasma proteins was independent of concentration.
Metabolism. In vitro, bortezomib is primarily metabolized by cytochrome P450 enzymes, including CYP3A4, 2C19, and 1A2. The main metabolic pathway involves deboronation to two metabolites, which are subsequently hydroxylated into other metabolites. Deborylated bortezomib metabolites 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 cleared more rapidly after the first dose compared to subsequent doses. Mean total clearance was 102 and 112 L/h after the first dose of 1.0 mg/m² and 1.3 mg/m², respectively, and ranged from 15 to 32 L/h and 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 60 patients, primarily with solid tumors and varying degrees of hepatic dysfunction; bortezomib doses ranged from 0.5 to 1.3 mg/m².
Mild hepatic impairment did not alter bortezomib AUC compared to normal hepatic function. Mean bortezomib AUC values increased by approximately 60% in patients with moderate to severe hepatic impairment. Dose adjustment and close 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/1.73 m², n = 12), mild impairment (CrCL = 40–59 mL/min/1.73 m², n = 10), moderate impairment (CrCL = 20–39 mL/min/1.73 m², n = 9), and severe impairment (CrCL < 20 mL/min/1.73 m², n = 3). Patients undergoing dialysis who received bortezomib after dialysis were also included in the study (n = 8). Patients received intravenous bortezomib doses of 0.7–1.3 mg/m² twice weekly. Bortezomib exposure (standardized AUC and Cmax) was comparable across all groups.
Age. Pharmacokinetic parameters of bortezomib were evaluated after administration of 1.3 mg/m² twice weekly via intravenous bolus injection in 104 pediatric patients (aged 2–16 years) with acute lymphoblastic leukemia or acute myeloid leukemia. According to population pharmacokinetic analysis, bortezomib clearance increases with increasing body surface area. The geometric mean (% CV) 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.
Use in combination with melphalan and prednisone for the treatment of multiple myeloma in previously untreated patients who are not eligible for high-dose chemotherapy with hematopoietic stem cell transplantation (first-line therapy).
Use as monotherapy, or in combination with pegylated liposomal doxorubicin or dexamethasone for the treatment of relapsed multiple myeloma in patients who have received at least one prior therapy and who have undergone hematopoietic stem cell transplantation or are not candidates for transplantation (second-line therapy).
Use in combination with dexamethasone or with dexamethasone and thalidomide for the treatment of multiple myeloma in previously untreated patients who are candidates for high-dose chemotherapy with hematopoietic stem cell transplantation (induction therapy).
Use in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone for the treatment of mantle cell lymphoma in previously untreated patients who are not candidates for hematopoietic stem cell transplantation.
Contraindications.
Hypersensitivity to bortezomib, boron, or any of the excipients of the medicinal product.
Acute diffuse infiltrative pulmonary and pericardial diseases.
When bortezomib is used in combination with other medicinal products, refer to the respective product information leaflets for additional contraindications.
Safety precautions.
General warnings. Bortezomib Shilpa is a cytotoxic medicinal product. Therefore, caution must be exercised during its reconstitution and administration. The use of gloves and protective clothing is recommended to prevent skin contact.
Appropriate aseptic techniques must be strictly observed when handling Bortezomib Shilpa, as the product contains no preservatives.
Fatal cases have been reported following accidental intrathecal administration of bortezomib-based products. Bortezomib Shilpa must be administered only intravenously or subcutaneously. DO NOT ADMINISTER BORTEZOMIB SHILPA INTRATHECALLY.
Reconstitution of the solution. Reconstitution must be performed only by qualified healthcare personnel.
For intravenous administration, 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 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 before administration. Do not use the solution if particulate matter is present or if discoloration occurs.
For subcutaneous administration, the contents of each vial should be carefully 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. The reconstitution process takes less than 2 minutes. After reconstitution, 1 mL of solution contains 2.5 mg of bortezomib. The resulting solution should be clear and colorless, with a pH of 4–7. The prepared solution should be visually inspected for particulate matter and discoloration before administration. Do not use the solution if particulate matter is present or if discoloration occurs.
Proper disposal procedure. The medicinal product is intended for single use only. Any unused 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 demonstrated that bortezomib is a weak inhibitor of the 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 intravenously administered bortezomib showed 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 (such as ketoconazole, ritonavir).
A study evaluating the effect of omeprazole, a potent CYP2C19 inhibitor, on the pharmacokinetics of intravenously administered bortezomib showed no significant effect on bortezomib pharmacokinetics in 17 patients included in the study.
In a study involving 6 patients, rifampicin, a potent CYP3A4 inducer, was found to reduce the AUC of intravenously administered bortezomib by an average of 45%. Therefore, concomitant use of bortezomib with potent CYP3A4 inducers (such as rifampicin, carbamazepine, phenytoin, phenobarbital, and St. John’s wort extract) is not recommended, as it may reduce the efficacy of bortezomib.
In the same study, dexamethasone, a weak CYP3A4 inducer, did not significantly alter the pharmacokinetics of bortezomib based on data from 7 patients.
A drug interaction study evaluating the effect of melphalan and prednisone on the pharmacokinetics of intravenously administered bortezomib in 21 patients showed an average increase in bortezomib AUC by 17%, which is not considered clinically significant.
During clinical trials, cases of hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral antidiabetic agents. If a patient is taking oral antidiabetic medications, blood glucose levels should be monitored and the dose of antidiabetic agents adjusted accordingly during bortezomib treatment.
Special precautions for use.
If Bortezomib Shilpa is used in combination with other medicinal products, refer to the instructions for medical use of these medicinal products before starting treatment. If thalidomide is used, special attention should be paid to pregnancy testing and contraceptive measures.
Intrathecal administration. Fatal outcomes have been reported due to accidental intrathecal administration of bortezomib-based products. Bortezomib Shilpa must be administered only intravenously or subcutaneously. DO NOT ADMINISTER BORTEZOMIB SHILPA INTRATHECALLY.
Gastrointestinal complications. Bortezomib therapy very commonly causes gastrointestinal toxicity, including nausea, diarrhea, constipation, and vomiting. Cases of intestinal obstruction (reported with uncommon frequency) have been reported; therefore, patients with constipation should be under medical supervision.
Hematological complications. Hematological toxicity (thrombocytopenia, neutropenia, and anemia) is very commonly observed during bortezomib therapy. In clinical trials evaluating bortezomib in patients with relapsed multiple myeloma and in combination therapy with rituximab, cyclophosphamide, doxorubicin, and prednisone (VcR-CAP regimen) in patients with previously untreated mantle cell lymphoma, reversible thrombocytopenia was one of the most common hematological toxicities. Platelet counts were typically lowest on day 11 of each bortezomib treatment cycle and returned to baseline levels before the start of the next cycle. No cumulative thrombocytopenia was observed. On average, the lowest measured platelet count was approximately 40% of the baseline level in trials of bortezomib monotherapy in patients with multiple myeloma and 50% in trials of bortezomib in patients with mantle cell lymphoma. In patients with progressive myeloma, the severity of thrombocytopenia was related to pre-treatment platelet counts: in 90% of 21 patients with baseline platelet counts < 75,000/μL, platelet counts were ≤ 25,000/μL during the study, including 14% with counts < 10,000/μL, whereas in patients with baseline platelet counts > 75,000/μL, only 14% of 309 patients had platelet counts ≤ 25,000/μL.
In patients with mantle cell lymphoma, grade ≥ 3 thrombocytopenia was observed more frequently in the group receiving bortezomib (VcR-CAP) than in the group receiving R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). The overall incidence of bleeding events of all grades, as well as bleeding events of at least grade 3, was similar in both groups. In the VcR-CAP treatment group, 22.5% of patients required platelet transfusion compared to 2.9% in the R-CHOP group.
Cases of gastrointestinal and intracranial hemorrhages associated with bortezomib use have been reported. Therefore, platelet counts should be monitored before each dose of Bortezomib Shilpa. Bortezomib therapy should be withheld if platelet counts decrease to < 25,000/μL during monotherapy or to ≤ 30,000/μL when used in combination with melphalan and prednisone. The benefit-risk ratio of bortezomib treatment should be evaluated, especially in cases of moderate or severe thrombocytopenia and presence of bleeding risk factors.
Complete blood counts with differential leukocyte count and platelet count should be frequently performed during treatment with Bortezomib Shilpa. 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. Leukocyte 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 clinical trial of bortezomib in patients with mantle cell lymphoma, 78% of patients in the VcR-CAP group and 61% in the R-CHOP group received colony-stimulating factor. Since patients with neutropenia are at increased risk of infections, they should be monitored for signs of infection and appropriate therapeutic measures taken. The use of granulocyte colony-stimulating factor should be considered for managing hematological toxicity. If initiation of a new treatment cycle is delayed several times, prophylactic use of granulocyte colony-stimulating factor should be considered.
Herpes zoster reactivation. Antiviral prophylaxis should be considered for patients receiving bortezomib therapy. In phase III trials in patients with untreated multiple myeloma, the overall incidence of herpes zoster reactivation (shingles) was higher in the group receiving bortezomib + melphalan + prednisone (14%) compared to the group receiving melphalan + prednisone (4%).
Among patients with mantle cell lymphoma, the incidence of shingles was 6.7% in the VcR-CAP group and 1.2% in the R-CHOP group.
Reactivation and infection with hepatitis B virus (HBV).
HBV testing should be performed before starting treatment with rituximab in combination with bortezomib 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 infection with John Cunningham virus leading to fatal PML have been reported in patients receiving bortezomib therapy. Patients diagnosed with PML had received prior or concomitant immunosuppressive therapy with bortezomib. Most PML cases were diagnosed within the first 12 months after initiation of bortezomib therapy. Patients should be regularly monitored for new or worsening neurological symptoms that may indicate PML, which should be considered in the differential diagnosis of central nervous system (CNS) disorders. If PML is suspected, patients should be referred to a physician experienced in managing PML and appropriate diagnostic measures taken. Bortezomib therapy should be discontinued if PML is confirmed.
Peripheral neuropathy. Bortezomib use is very commonly associated with peripheral neuropathy, predominantly sensory. However, cases of severe motor neuropathy, with or without sensory peripheral neuropathy, have been reported. The incidence of peripheral neuropathy typically peaks during the 5th cycle of bortezomib administration.
Careful monitoring of patients for neuropathic symptoms such as burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain, or weakness is recommended.
In a phase III trial comparing intravenous and subcutaneous administration of bortezomib, the incidence of grade 2 peripheral neuropathy was 24% in the subcutaneous group and 41% in the intravenous group. Grade 3 peripheral neuropathy occurred in 6% of patients in the subcutaneous group and 16% in the intravenous group.
If peripheral neuropathy develops or worsens, patients should undergo a neurological examination; dose adjustment, schedule modification, or change in route of administration to subcutaneous may be necessary. Neuropathy should be managed with supportive measures.
Regular monitoring for treatment-induced neuropathy symptoms and neurological examination are required in patients receiving bortezomib in combination with neurotoxic agents (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 orthostatic hypotension and acute constipation with intestinal obstruction. Information on autonomic neuropathy and its impact on these adverse reactions is limited.
Seizures. Uncommon cases of seizures have been observed in patients with a history of seizures or epilepsy. Extreme caution is required when treating patients with any risk factors for seizures.
Hypotension. Bortezomib therapy is often associated with postural/orthostatic hypotension. In most cases, it is mild to moderate in severity and occurs throughout treatment. Patients who developed orthostatic hypotension during bortezomib (intravenous) administration did not have symptoms of orthostatic hypotension before starting bortezomib therapy. Most patients required treatment for orthostatic hypotension, and a smaller number experienced syncope. Orthostatic/postural hypotension was not clearly associated with bolus infusion of bortezomib; the mechanism of its development is unknown. It may be related to autonomic neuropathy. Autonomic neuropathy may be associated with bortezomib use or bortezomib may exacerbate underlying conditions, including diabetic or amyloid neuropathy. Caution is advised when treating patients with a history of syncope, those taking antihypertensive drugs, and those with dehydration due to diarrhea or vomiting. In case of orthostatic hypotension, hydration, glucocorticoids, and/or sympathomimetics are recommended; antihypertensive drug doses should be reduced if necessary. Patients should be instructed to seek medical attention if they experience dizziness, presyncope, or syncope.
Reversible posterior leukoencephalopathy syndrome (PRES). Cases of PRES have been reported in patients receiving bortezomib therapy. 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 should be discontinued if PRES occurs.
Heart failure. Cases of development or worsening of pre-existing congestive heart failure and/or reduced left ventricular ejection fraction have been reported with bortezomib use. Fluid retention may contribute to the development of signs and symptoms of heart failure. Patients with risk factors or pre-existing heart disease should be closely monitored.
ECG findings. Isolated cases of QT interval prolongation were observed in clinical trials. The cause was not established.
Lung function disorders. Rare cases of acute diffuse infiltrative lung diseases of unknown etiology, such as pneumonitis, interstitial pneumonia, pulmonary infiltration, and acute respiratory distress syndrome (ARDS), have been observed in patients receiving bortezomib. Some of these cases were fatal. Chest X-ray before starting treatment is recommended to establish baseline lung status for comparison in case of potential treatment-related lung dysfunction.
In case of new or worsening pulmonary symptoms (e.g., cough, dyspnea), prompt diagnosis and appropriate therapeutic measures should be initiated. The benefit-risk ratio of continuing bortezomib therapy should be carefully considered.
In clinical trials, two out of two patients with relapsed acute myeloid leukemia who received high-dose cytarabine (2 g/m²/day) as continuous 24-hour infusion in combination with daunorubicin and bortezomib died from ARDS at the beginning of treatment. Therefore, this specific regimen of concomitant high-dose cytarabine (2 g/m²/day) as continuous 24-hour infusion is not recommended.
Renal function disorders. Renal impairment is commonly observed in patients with multiple myeloma. Close monitoring of such patients is recommended.
Hepatic function disorders. Bortezomib is metabolized by hepatic enzymes. 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 in combination with other drugs and in patients with serious concomitant medical conditions. Cases of elevated liver enzymes, hyperbilirubinemia, and hepatitis, which resolved after discontinuation of bortezomib, have also been reported.
Tumor lysis syndrome. Since bortezomib is a cytotoxic agent capable of rapidly killing tumor plasma cells, complications associated with tumor lysis syndrome may occur. Patients with high tumor burden before treatment initiation are primarily at risk. Close monitoring of such patients and implementation of necessary measures are recommended.
Precautions regarding concomitant use of other medicinal products. Patients should be under close medical supervision when bortezomib is combined with strong CYP3A4 inhibitors. Caution is advised when combining bortezomib with CYP3A4 or CYP2C9 substrates.
Hepatic function should be corrected prior to starting treatment if impaired, and caution is advised when administering the drug to patients taking oral hypoglycemic agents.
Potentially immune-mediated reactions. Immune-mediated reactions such as serum sickness, polyarthritis with rash, and proliferative glomerulonephritis have been reported uncommonly. Bortezomib should be discontinued if serious reactions occur.
Use during pregnancy or breastfeeding.
Contraception in women and men
Men and women of reproductive potential must use effective contraception during treatment and for 3 months after completion of treatment.
Pregnancy
There are no clinical data on the use of bortezomib in pregnant women. The teratogenic properties of bortezomib have not been fully investigated.
In preclinical studies, bortezomib at maximally 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 Shilpa is not recommended during pregnancy except in cases where the woman's clinical condition requires bortezomib therapy. If bortezomib is used during pregnancy or if pregnancy occurs during bortezomib treatment, the patient should be informed of the potential risk to the fetus.
Thalidomide is a medicinal product with known teratogenic effects in humans, causing severe life-threatening congenital malformations. Thalidomide is contraindicated during pregnancy and in women of reproductive potential. Patients receiving bortezomib in combination with thalidomide must comply with pregnancy prevention requirements. See also the prescribing information for thalidomide.
Breastfeeding
It is unknown whether bortezomib is excreted in breast milk, but to prevent the development of serious adverse effects in the infant, breastfeeding is not recommended during treatment with Bortezomib Shilpa.
Fertility
Studies on the effect of bortezomib on fertility have not been conducted.
Ability to affect reaction speed when driving or operating machinery.
Bortezomib has a moderate effect on reaction speed when driving or operating machinery. The use of Bortezomib Shilpa is very commonly associated with fatigue, frequently with dizziness, orthostatic/postural hypotension, or visual disturbances, and uncommonly with syncope. Therefore, patients should be cautious when driving or operating machinery and should avoid such activities if these symptoms occur.
Administration and Dosage
Treatment should be initiated under the supervision of a qualified physician experienced in the treatment of oncology patients, although Bortezomib Shilpa 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 of 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 2 additional cycles is recommended. Patients with a partial response but not complete remission should continue bortezomib therapy for up to a maximum of 8 cycles. At least 72 hours should elapse between consecutive bortezomib doses.
Dosage modification and re-initiation recommendations for bortezomib monotherapy.
If any grade 3 non-hematologic toxicity or grade 4 hematologic toxicity (excluding neuropathies) occurs, bortezomib therapy should be withheld. After resolution of toxicity symptoms, treatment may be resumed at a dose reduced by 25% (reduce dose from 1.3 mg/m² to 1.0 mg/m²; reduce dose from 1.0 mg/m² to 0.7 mg/m²). If toxicity symptoms do not resolve or recur during treatment with the reduced dose, discontinuation of bortezomib should be considered, unless the benefits of continued treatment outweigh the risks.
Neuropathic pain and/or peripheral neuropathy
The dose 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 assessment of the benefit-risk ratio.
Table 1
Recommended* dose adjustments for bortezomib-induced neuropathy
| Severity of neuropathy |
Dose and administration frequency modification |
| Grade 1 (asymptomatic; loss of deep tendon reflexes or paresthesia) without pain or functional impairment |
Dose and administration schedule do not require adjustment |
| Grade 1 with pain or Grade 2 (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 2 with pain or Grade 3 (severe symptoms; limitation of self-care activities)*** |
Withhold bortezomib until resolution of toxic symptoms. After that, resume treatment at a reduced dose of 0.7 mg/m² once weekly. |
| Grade 4 (life-threatening consequences requiring urgent intervention) and/or severe autonomic neuropathy |
Discontinue bortezomib administration |
* Based on dose modifications observed in Phase II and III multiple myeloma studies and during the post-marketing period.
** Instrumental activities of daily living include cooking, shopping, using the telephone, etc.
*** Activities of daily living 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 3-week period is considered one treatment cycle. At least 72 hours should elapse between consecutive doses of bortezomib.
Pegylated liposomal doxorubicin should be administered at a dose of 30 mg/m² on Day 4 of the bortezomib treatment cycle via 1-hour intravenous infusion, after bortezomib injection.
Up to 8 cycles of this combination therapy should be administered provided the disease does not progress and patients tolerate treatment well. Patients who achieve complete remission may continue treatment for at least 2 additional cycles after achieving complete response, even if this requires more than 8 treatment cycles. Patients whose paraprotein levels continue to decline after 8 cycles may also continue treatment as long as treatment remains tolerable and a response is observed.
Combination therapy with dexamethasone.
The recommended dose of bortezomib is 1.3 mg/m² body surface area administered intravenously or subcutaneously twice weekly for 2 weeks (Days 1, 4, 8, and 11), followed by a 10-day rest period (Days 12–21). This 3-week period constitutes one treatment cycle. At least 72 hours should elapse between consecutive doses of bortezomib.
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 this combination for up to four additional cycles. See also the dexamethasone prescribing information.
Dose modification recommendations for combination therapy in patients with relapsed multiple myeloma.
Refer to the 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 Shilpa (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 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 Shilpa twice weekly (cycles 1–4) |
|||||||||||||||||||
| Week |
1 |
2 |
3 |
4 |
5 |
6 |
|||||||||||||
| Bortezomib (1.3 mg/m²) |
1 |
-- |
-- |
4 day |
8 day |
11 day |
Break |
22 day |
25 day |
29 day |
32 day |
Break |
|||||||
| M (9 mg/m²) P (60 mg/m²) |
1 day |
2 day |
3 day |
4 day |
-- |
-- |
Break |
-- |
-- |
-- |
-- |
Break |
|||||||
| Bortezomib Shilpa once weekly (cycles 5–9) |
|||||||||||||||||||
| Week |
1 |
2 |
3 |
4 |
5 |
6 |
|||||||||||||
| Bortezomib (1.3 mg/m²) |
1 day |
-- |
-- |
-- |
8 day |
Break |
22 day |
29 day |
Break |
||||||||||
| M P |
1 day |
2 day |
3 day |
4 day |
-- |
Break |
-- |
-- |
Break |
||||||||||
M − melphalan, P − prednisone.
Recommendations for dose adjustment and resumption of combination therapy with melphalan and prednisone.
Prior to starting a new treatment cycle:
- platelet count must be ≥ 70 × 10⁹/L and absolute neutrophil count must be ≥ 1.0 × 10⁹/L,
- non-hematologic toxicity must have resolved to Grade 1 or baseline levels.
Table 3
Dose adjustment during subsequent cycles of bortezomib therapy in combination with melphalan and prednisone
| Toxicity |
Dose modification or treatment discontinuation |
| Hematologic toxicity during cycle:
|
Consider reducing melphalan dose by 25% in the next cycle |
≤ 30 × 109/L or absolute neutrophil count ≤ 0.75 × 109/L on the day of bortezomib administration (except Day 1) |
Delay administration of Bortezomib Shilpa dose |
|
Bortezomib dose should be reduced by one level |
| Non-hematologic toxicity ≥ Grade III |
Bortezomib therapy should be withheld until symptoms improve to baseline or Grade I severity. Bortezomib may then be restarted at a dose reduced by one level |
See also the instructions for medical use of melphalan and prednisone.
Untreated multiple myeloma in patients eligible for hematopoietic stem cell transplantation (induction therapy)
Combination therapy with dexamethasone
The recommended dose of bortezomib is 1.3 mg/m² body surface area administered intravenously or subcutaneously twice weekly for 2 weeks (days 1, 4, 8, and 11), followed by
a 10-day rest period (days 12–21). This 3-week period is considered one treatment cycle. At least 72 hours should elapse between consecutive doses of bortezomib.
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 cycles of treatment with this combination.
Combination therapy with dexamethasone and thalidomide
The recommended dose of bortezomib is 1.3 mg/m² body surface area administered intravenously or subcutaneously twice weekly for 2 weeks (days 1, 4, 8, and 11), followed by
a 17-day rest period (days 12–28). This 4-week period is considered one treatment cycle. At least 72 hours should elapse between consecutive doses of bortezomib.
Dexamethasone should be administered orally at a dose of 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; the dose may be further increased to 200 mg daily starting from the second cycle (see Table 4).
Administer 4 cycles of treatment. Patients achieving at least a partial response to treatment are recommended to receive 2 additional cycles of therapy.
Table 4
Recommended dosing regimen of Bortezomib Shilpa in combination with dexamethasone and thalidomide for patients with untreated multiple myeloma eligible for hematopoietic stem cell transplantation
| Bortezomib + Dx |
Cycles 1–4 |
||||||
| Week |
1 |
2 |
3 |
||||
| Bortezomib (1.3 mg/m²) |
Day 1, 4 |
Day 8, 11 |
Break |
||||
| Dx (40 mg) |
Day 1, 2, 3, 4 |
Day 8, 9, 10, 11 |
- |
||||
| Bortezomib + Dx + T |
Cycle 1 |
||||||
| Week |
1 |
2 |
3 |
4 |
|||
| Bortezomib (1.3 mg/m²) |
Day 1, 4 |
Day 8, 11 |
Break |
Break |
|||
| T (50 mg) |
Daily |
Daily |
- |
- |
|||
| T (100 mg)ᵃ |
- |
- |
Daily |
Daily |
|||
| Dx (40 mg) |
Day 1, 2, 3, 4 |
Day 8, 9, 10, 11 |
- |
- |
|||
| Cycles 2–4ᵇ |
|||||||
| Bortezomib (1.3 mg/m²) |
Day 1, 4 |
Day 8, 11 |
Break |
Break |
|||
| T (200 mg)ᵃ |
Daily |
Daily |
Daily |
Daily |
|||
| Dx (40 mg) |
Day 1, 2, 3, 4 |
Day 8, 9, 10, 11 |
- |
- |
|||
Dx – dexamethasone; T – thalidomide.
a Increase the dose of thalidomide to 100 mg from the 3rd week of the 1st cycle 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 adjustment recommendations for patients eligible for transplantation
For dose adjustments in the event of neuropathy, refer to the dose adjustment recommendations for Bortezomib Shilpa when used as monotherapy.
If Bortezomib Shilpa is used in combination with other chemotherapeutic agents, refer to the respective product information for dose adjustment recommendations of these agents 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. Administer
6 treatment cycles. Patients who first demonstrate a response during the 6th treatment cycle are recommended to receive 2 additional treatment cycles.
Medicinal products administered by intravenous infusion on day 1 of each
3-week bortezomib treatment cycle: rituximab at a dose of 375 mg/m², cyclophosphamide –
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 adjustment recommendations for patients with untreated mantle cell lymphoma
Prior to initiation of a new treatment cycle:
- platelet count must be ≥ 100,000 cells/µL and absolute neutrophil count must be ≥ 1,500 cells/µL;
- platelet count must be ≥ 75,000 cells/µL in patients with bone marrow infiltration or splenic sequestration;
- hemoglobin level must be ≥ 8 g/dL;
- non-hematological toxicity must have resolved to grade 1 or baseline levels.
Bortezomib therapy should be withheld upon occurrence of any non-hematological toxicity
≥ grade III severity (except neuropathy) related to bortezomib administration, or hematological toxicity ≥ grade III severity. Refer to Table 5 for dose adjustment recommendations.
Granulocyte colony-stimulating factors may be used to manage hematological toxicity. If initiation of a new treatment cycle has been delayed multiple times, consider prophylactic use of granulocyte colony-stimulating factor. Platelet transfusion should be considered for management of thrombocytopenia.
Table 5
Dose adjustment during therapy for patients with untreated mantle cell lymphoma
| Toxicity |
Dose modification or treatment interruption |
| Hematological toxicity |
|
|
Bortezomib administration should be withheld for up to 2 weeks until the absolute neutrophil count recovers to ≥ 750 cells/µL and platelet count to ≥ 25,000 cells/µL.
|
|
Delay bortezomib dose administration. |
| Non-hematological toxicity ≥ Grade III related to bortezomib administration. |
Treatment with Bortezomib Shilpa should be interrupted until symptoms improve to at least Grade II severity. Bortezomib may then be restarted at a reduced dose by one level (from 1.3 mg/m² to 1 mg/m² or from 1 mg/m² to 0.7 mg/m²). For bortezomib-induced neuropathic pain and/or peripheral neuropathy, bortezomib dose adjustments should be made as specified in Table 1. |
If Bortezomib Shilpa is used in combination with other chemotherapeutic agents, also refer to the instructions for use of these medicinal products regarding dose adjustments of these agents in the event of toxicity.
Special patient groups
Elderly patients
Currently, there are no data indicating the need for dose adjustment in patients aged 65 years and older.
There are no studies evaluating the use of bortezomib in elderly patients with previously untreated multiple myeloma who are candidates for high-dose chemotherapy with hematopoietic stem cell transplantation. Therefore, no dose adjustment recommendations can be provided for this patient group.
In a study evaluating bortezomib 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 arms (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 and severe hepatic impairment, bortezomib therapy 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 based on patient tolerability.
Table 6
Recommendations for modifying initial doses of bortezomib in patients with hepatic impairment
| Severity of hepatic impairment* |
Level of bilirubin |
Levels of AST |
Initial dose adjustment |
| Mild |
≤ 1.0 × ULN |
> ULN |
Not required |
| > 1.0× ‒1.5× ULN |
Any |
Not required |
|
| Moderate |
> 1.5×‒3× ULN |
Any |
Reduce bortezomib dose to |
| Severe |
> 3× ULN |
Any |
AST – aspartate aminotransferase; ULN – upper limit of normal.
* Based on the classification of severity of liver dysfunction (mild, moderate, and severe) by the Organ Dysfunction Working Group of the National Cancer Institute, USA.
Patients with renal impairment
Mild to moderate renal impairment (creatinine clearance > 20 ml/min/1.73 m²) does not affect the pharmacokinetics of bortezomib; therefore, dose adjustment is not required in this patient group. It is unknown whether severe renal impairment (creatinine clearance < 20 ml/min/1.73 m²) affects the pharmacokinetics of bortezomib. Since dialysis may reduce bortezomib concentrations, the drug should be administered after the dialysis procedure.
Method of administration.
Bortezomib Shilpa must be administered by intravenous or subcutaneous injection. Accidental intrathecal administration has resulted in fatal outcomes.
Intravenous administration.
The reconstituted solution should be administered immediately after preparation as a 3–5 second intravenous bolus injection through a peripheral or central venous catheter. After injection, the catheter should be flushed with 0.9% sodium chloride injection solution. At least 72 hours should elapse between consecutive doses of bortezomib.
Subcutaneous administration.
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 at the injection site occur during subcutaneous injections, the diluted solution of Bortezomib Shilpa may be administered subcutaneously at a lower concentration (1 mg/ml instead of 2.5 mg/ml), or the solution may be administered intravenously.
Children.
The safety and efficacy of bortezomib in children (under 18 years of age) have not been established. Current data are insufficient to establish dosing 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 known specific antidote for bortezomib. In case of overdose, careful monitoring of hemodynamic parameters (infusion therapy, vasopressors and/or inotropic agents) and body temperature is recommended.
Adverse reactions
Serious adverse reactions reported during bortezomib therapy 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 treatment 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 the use of bortezomib. These adverse reactions are based on 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 classes 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 decreasing 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*, herpetic meningoencephalitis#, bacteremia (including staphylococcal), hordeolum, influenza, cellulitis, device-related infections, skin infections*, ear infections*, staphylococcal infection, dental infection* |
|
| Rare |
Meningitis (including bacterial), Epstein-Barr virus infection, genital herpes, tonsillitis, mastoiditis, post-viral fatigue syndrome |
|
| Benign, malignant and unspecified neoplasms (including cysts and polyps) |
Rare |
Malignant neoplasm, plasma cell leukemia, renal cell carcinoma, tumor proliferation, mycosis fungoides, benign neoplasm* |
| Blood and lymphatic system disorders |
Very common |
Thrombocytopenia*, neutropenia*, anemia* |
| Common |
Leukopenia*, lymphopenia* |
|
| Uncommon |
Pancytopenia*, febrile neutropenia, coagulopathy*, leukocytosis*, lymphadenopathy, hemolytic anemia# |
|
| Rare |
Disseminated intravascular coagulation syndrome, thrombocytosis*, hyperviscosity syndrome, thrombocytopathy, 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-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 level changes*, hypocalcemia*, enzyme level changes* |
|
| 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 disorders*, sleep disorders* |
| Uncommon |
Psychiatric disorders*, hallucinations*, psychotic disorders*, confusion*, agitation |
|
| Rare |
Suicidal ideation*, adjustment disorder, delirium, decreased libido |
|
| Nervous system disorders |
Very common |
Neuropathies*, peripheral sensory neuropathy, dysesthesia*, neuralgia* |
| Common |
Motor neuropathy*, loss of consciousness (including syncope), dizziness*, dysgeusia*, lethargy, headache* |
|
| Uncommon |
Tremor, sensorimotor peripheral neuropathy, dyskinesia*, coordination and balance 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 disorders*, 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 disorders, psychomotor hyperactivity, spinal cord compression, other cognitive disorders, motor dysfunctions, other nervous system disorders, radiculitis, hypersalivation, hypotonia |
|
| Eye disorders |
Common |
Eye swelling*, visual disturbance*, conjunctivitis* |
| Uncommon |
Eye hemorrhage*, eyelid infections*, eye inflammation*, diplopia, dry eye*, eye irritation*, eye pain, increased lacrimation, eye discharge |
|
| Rare |
Corneal damage*, exophthalmos, retinitis, scotoma, other eye (and eyelid) diseases, acquired dacryoadenitis, photophobia, photopsia, optic nerve neuropathy#, various degrees of visual impairment (up to blindness)* |
|
| Ear and labyrinth disorders |
Common |
Vertigo* |
| Uncommon |
Dysacusis (including tinnitus)*, hearing loss (up to deafness), ear discomfort* |
|
| Rare |
Ear hemorrhage, vestibular neuronitis, other ear disorders |
|
| Cardiac disorders |
Uncommon |
Cardiac tamponade#, cardiopulmonary shock*, atrial fibrillation (including atrial), heart failure (including left and right ventricular)*, arrhythmia*, tachycardia*, palpitations, angina 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 perirenal)*, peripheral circulation disorders*, vasculitis, hyperemia (including ocular)* |
|
| Rare |
Peripheral vascular embolism, lymphedema, pallor, erythromelalgia, vasodilation, vessel discoloration, venous insufficiency |
|
| Respiratory, thoracic and mediastinal disorders |
Common |
Dyspnea*, epistaxis, lower/upper respiratory tract infections*, cough* |
| Uncommon |
Pulmonary embolism, pleural effusion, pulmonary edema (including acute), pulmonary alveolar hemorrhage#, bronchospasm, chronic obstructive pulmonary disease*, hypoxemia*, worsening airway patency*, hypoxia, pleuritis*, hiccup, rhinorrhea, dysphonia, wheezing |
|
| Rare |
Pulmonary failure, acute respiratory distress syndrome, apnea, pneumothorax, lung collapse, pulmonary hypertension, hemoptysis, pulmonary hyperventilation, orthopnea, pneumonitis, respiratory alkalosis, tachypnea, pulmonary fibrosis, bronchial disorders*, hypocapnia*, interstitial lung disease, lung infiltration, throat tightness, dry throat, increased upper respiratory tract secretion, throat irritation, upper respiratory tract cough syndrome |
|
| Gastrointestinal disorders |
Very common |
Nausea and vomiting*, diarrhea*, constipation |
| Common |
Gastrointestinal hemorrhage (including mucosal)*, dyspepsia, stomatitis*, abdominal distension, oropharyngeal pain*, abdominal pain (including gastrointestinal and splenic region)*, oral cavity disorders*, flatulence |
|
| Uncommon |
Pancreatitis (including chronic)*, vomiting blood, lip swelling*, gastrointestinal obstruction (including small bowel obstruction, ileus)*, abdominal discomfort, oral ulcers*, enteritis*, gastritis*, 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 disorders*, salivary gland disorders* |
|
| Rare |
Acute pancreatitis, peritonitis*, tongue swelling*, ascites, esophagitis, cheilitis, fecal incontinence, anal sphincter atony, fecaloma*, gastrointestinal ulcers and perforations*, gingival hyperplasia, megacolon, rectal discharge, blister formation in oropharynx*, lip pain, periodontitis, anal fissure, altered defecation rhythm, proctalgia, abnormal defecation |
|
| Hepatobiliary disorders |
Common |
Liver enzyme level changes* |
| 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 pigmentation disorders* |
|
| Rare |
Skin reactions, Jessner's lymphocytic infiltration, hand-foot erythrodysesthesia syndrome, subcutaneous hemorrhage, livedo reticularis, skin induration, papules, photosensitivity reactions, seborrhea, cold sweat, other skin disorders, erythrosis, skin ulcers, nail disorders |
|
| Musculoskeletal and connective tissue disorders |
Very common |
Musculoskeletal pain* |
| Common |
Muscle spasms*, limb pain, muscle weakness |
|
| Uncommon |
Muscle twitching, joint swelling, arthritis*, joint stiffness, myopathies*, heaviness sensation |
|
| Rare |
Rhabdomyolysis, temporomandibular joint dysfunction, fistula, joint effusion, jaw pain, bone disorders, infections and inflammations of musculoskeletal system and connective tissue*, synovial cyst |
|
| Renal and urinary disorders |
Common |
Renal failure* |
| Uncommon |
Acute renal failure, chronic renal failure*, urinary tract infections*, signs and symptoms of urinary tract disorders*, hematuria*, urinary retention, micturition disorders*, proteinuria, azotemia, oliguria*, polyuria |
|
| Rare |
Bladder irritation |
|
| Reproductive system and breast disorders |
Uncommon |
Vaginal bleeding, genital pain*, erectile dysfunction |
| Rare |
Testicular disorders*, prostatitis, breast disorders in women, epididymis tenderness, epididymitis, pelvic pain, vulvar ulcers |
|
| Congenital, familial and genetic disorders |
Rare |
Aplasia, gastrointestinal tract malformations, ichthyosis |
| General disorders and administration site conditions |
Very common |
Pyrexia*, fatigue, asthenia |
| Common |
Edema (including peripheral), chills, pain*, fever* |
|
| Uncommon |
General physical health aggravated*, facial edema*, injection site reactions*, mucous membrane disorders*, chest pain, gait disturbance, cold sensation, extravasation*, catheter-related complications*, thirst sensation*, chest discomfort, sensation of body temperature change*, pain related to injection* |
|
| Rare |
Fatal outcome (including sudden), multiple organ failure, injection site hemorrhage*, 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*, blood protein level deviations*, weight increased, blood test abnormalities*, C-reactive protein level increased |
|
| 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 analysis abnormalities* |
|
| Procedural complications |
Uncommon |
Fall, confusion |
| Rare |
Transfusion reactions, fractures*, tremor*, facial injury, joint injury*, burns, skin laceration, procedural pain, radiation injuries* |
|
| Surgical and medical procedures |
Rare |
Macrophage activation |
* The term encompasses more than one MedDRA term (MedDRA – Medical Dictionary for Regulatory Activities).
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, cognitive, or psychosocial condition.
Mantle cell lymphoma.
The safety profile of bortezomib in 240 patients with mantle cell lymphoma who received bortezomib 1.3 mg/m² in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (VcR-CAP), and 242 patients who received rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHOP), was generally similar to the safety profile observed in patients with multiple myeloma; the main differences are described below. Additional adverse reactions observed with bortezomib use as part of the combination therapy (VcR-CAP) included hepatitis B virus infection (˂ 1%) and myocardial ischemia (1.3%). The similar incidence rates in both treatment groups suggest that these adverse reactions are not solely related to bortezomib. Bortezomib use in patients with mantle cell lymphoma was associated with ≥ 5% higher frequencies of hematologic adverse reactions (neutropenia, thrombocytopenia, leukopenia, anemia, lymphopenia), peripheral sensory neuropathy, arterial hypertension, pyrexia, pneumonia, stomatitis, and hair disorders compared to use 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 listed are adverse reactions observed in the VcR-CAP treatment group that, in the investigators' assessment, were 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*, infections of upper/lower respiratory tract*, fungal infection*, herpes simplex* |
|
| Uncommon |
Hepatitis B, infections*, bronchopneumonia |
|
| Blood and lymphatic system disorders |
Very common |
Thrombocytopenia*, febrile neutropenia, neutropenia*, leukopenia*, anemia*, lymphopenia* |
| Uncommon |
Pancytopenia* |
|
| Immune system disorders |
Common |
Hypersensitivity* |
| Uncommon |
Anaphylactic reaction |
|
| Metabolism and nutrition disorders |
Very common |
Decreased appetite |
| Common |
Hypokalemia*, blood glucose abnormalities*, hyponatremia*, diabetes*, fluid retention |
|
| Uncommon |
Tumor lysis syndrome |
|
| Psychiatric disorders |
Common |
Sleep disorders* |
| Nervous system disorders |
Very common |
Peripheral sensory neuropathy, dysesthesia*, neuralgia* |
| Common |
Neuropathies*, motor neuropathy*, loss of consciousness (including syncope), encephalopathy*, dizziness*, dysgeusia*, autonomic neuropathy |
|
| Uncommon |
Autonomic nervous system disorders |
|
| Eye disorders |
Common |
Visual disturbances* |
| Ear and labyrinth disorders |
Common |
Dysesthesia (including tinnitus)* |
| Uncommon |
Vertigo*, hearing impairment (up to deafness) |
|
| Cardiac disorders |
Common |
Atrial fibrillation (including atrial), arrhythmia*, heart failure (including left and right ventricular)*, myocardial ischemia, ventricular dysfunction* |
| Uncommon |
Cardiovascular disorders (including cardiogenic shock) |
|
| Vascular disorders |
Common |
Hypertension*, hypotension*, orthostatic hypotension |
| Respiratory, thoracic and mediastinal disorders |
Common |
Dyspnea*, cough*, hiccups |
| Uncommon |
Acute respiratory distress syndrome, pulmonary embolism, pneumonitis, pulmonary hypertension, pulmonary edema (including acute) |
|
| Gastrointestinal disorders |
Very common |
Nausea and vomiting*, diarrhea*, stomatitis*, constipation |
| Common |
Gastrointestinal hemorrhage (including mucosal)*, abdominal distension, dyspepsia, oropharyngeal pain*, gastritis*, oral ulcers*, abdominal discomfort, dysphagia, gastrointestinal inflammation*, abdominal pain (including gastrointestinal and splenic region pain)*, oral cavity disorders* |
|
| Uncommon |
Colitis (including Clostridium difficile-induced)* |
|
| Hepatobiliary disorders |
Common |
Hepatotoxicity (including hepatic disorders) |
| Uncommon |
Liver failure |
|
| Skin and subcutaneous tissue disorders |
Very common |
Hair disorders* |
| Common |
Pruritus*, dermatitis*, rash* |
|
| Musculoskeletal and connective tissue disorders |
Common |
Muscle spasms*, musculoskeletal pain*, limb pain |
| Renal and urinary disorders |
Common |
Urinary tract infections* |
| General disorders and administration site conditions |
Very common |
Pyrexia*, fatigue, asthenia |
| Common |
Edema (including peripheral), chills, injection site reactions*, fever* |
|
| Investigations |
Common |
Hyperbilirubinemia*, abnormal protein levels*, weight decreased, weight increased |
* The term encompasses more than one MedDRA term.
Description of individual adverse reactions.
Herpes zoster virus reactivation
Multiple myeloma.
Antiviral prophylaxis was administered in 26% of patients receiving the combination of bortezomib with melphalan and prednisone. Herpes zoster was observed in 17% of patients who did not receive antiviral agents, compared to 3% of patients who received antiviral agents.
Mantle cell lymphoma.
Antiviral prophylaxis was administered in 57% of patients receiving bortezomib as part of combination therapy with the VcR-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.
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 cases 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.
During studies in which bortezomib was used as induction therapy in combination with dexamethasone (study IFM-2005-01) and with dexamethasone/thalidomide (study MMY-3010), peripheral neuropathy was observed (see Table 9).
Table 9
Frequency of peripheral neuropathy (PN) during induction therapy by severity grade and number of cases with treatment discontinuation due to PN
| 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 of treatment 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.
Table 10
Frequency of peripheral neuropathy (PN) in the bortezomib study in patients with mantle cell lymphoma by toxicity grade and number of treatment discontinuations due to PN.
| Signs of peripheral neuropathy |
VcR-CAP (N = 240) |
R-CHOP (N = 242) |
| Frequency of PN (%) |
||
| All grades of PN |
30 |
29 |
| ≥ Grade II PN |
18 |
9 |
| ≥ Grade III PN |
8 |
4 |
| Discontinuation 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 5% lower. The overall incidence of diarrhea, lower abdominal pain, abdominal pain, asthenic conditions, upper respiratory tract infections, and peripheral neuropathies was 12–15% lower in the subcutaneous group compared to the intravenous group. Additionally, the incidence of peripheral neuropathies of Grade III or higher was 10% lower, and the rate of treatment discontinuation due to peripheral neuropathy was 8% lower.
Injection site reactions occurred in 6% of patients, predominantly erythema. Symptoms resolved on average within 6 days, and dose modification was required in 2 patients. Two patients (1%) experienced serious reactions: 1 case of pruritus and 1 case of erythema.
The frequency 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 shown at least a partial response to bortezomib-containing therapy, adverse reactions of all grades occurring in at least 25% of patients were 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.
Shelf life. 2 years.
Storage conditions.
Store in the original packaging at a temperature not exceeding 30 °C.
Keep out of the reach of children.
After reconstitution, the medicinal product can be stored at a temperature not exceeding 25 °C, in normal lighting conditions, in the original vial or syringe for up to 8 hours.
Incompatibilities. This medicinal product must not be mixed with other medicinal products except those specified in the section “Instructions for use and dosage.”
Packaging.
3.5 mg of lyophilisate for solution for injection in glass vials stoppered with a rubber plug and sealed with an aluminum cap with a “flip-off” component. One vial per cardboard box.
Prescription status.
Prescription only.
Manufacturer. Shilpa Medicare Limited, India.
Manufacturer’s address and location of operations. Unit 4, Pharmaceutical Formulations SEZ, Plots S-20 to S-26, Pharma SEZ, TSIIC, Green Industrial Park, Polepally, Jadcherla, Mahbubnagar, Telangana, 509301, India