Bortebin
UkraineTable of Contents
INSTRUCTIONS for medical use of the medicinal product BORTEBIN (BORTEBIN)
Composition:
Active substance: bortezomib;
1 vial contains 3.5 mg of bortezomib;
after reconstitution: 1 ml of solution for subcutaneous injection contains 2.5 mg of bortezomib;
after reconstitution: 1 ml of solution for intravenous administration contains 1 mg of bortezomib;
Excipients: mannitol (E 421), nitrogen.
Pharmaceutical form. Powder for solution for injection.
Main physicochemical properties: White or almost white lyophilized powder or tablet.
Pharmacotherapeutic group.
Antineoplastic agents. ATC code L01X X32.
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 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 the numerous tested receptors and proteases and is more than 1500-fold more selective for the proteasome than for other enzymes. The inhibition kinetics of the proteasome were determined in vitro; bortezomib dissociated from the proteasome with a half-life (t1/2) of 20 minutes, demonstrating that proteasome inhibition by bortezomib is reversible. By inhibiting the proteasome, bortezomib affects cancer cells through multiple pathways, including but not limited to, altering cell cycle regulatory proteins and inhibiting activation of the nuclear transcription 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.
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 to 11 patients with multiple myeloma and creatinine clearance exceeding 50 mL/min, the mean maximum plasma concentration (Cmax) of the first dose of bortezomib was 57 and 112 ng/mL, respectively. With subsequent doses, mean maximum plasma concentrations of bortezomib ranged from 67 to 106 ng/mL for the 1.0 mg/m² dose and from 89 to 120 ng/mL for the 1.3 mg/m² dose.
After intravenous bolus or subcutaneous administration of 1.3 mg/m² to patients with multiple myeloma (n=14 in the intravenous group and n=17 in the subcutaneous group), the total systemic exposure after repeated dosing (AUClast) was equivalent between subcutaneous and intravenous administration. The maximum drug concentration (Cmax) after subcutaneous administration (20.4 ng/mL) was lower than after intravenous administration (223 ng/mL). The geometric mean ratio of AUClast was 0.99, with a 90% confidence interval of 80.18–122.80%.
Distribution. The mean volume of distribution (Vd) of bortezomib ranges from 1659 to 3294 liters following single or multiple doses of 1.0 mg/m² or 1.3 mg/m² in patients with multiple myeloma. This indicates extensive distribution of bortezomib into peripheral tissues. At bortezomib concentrations of 0.01–1.0 µg/mL, plasma protein binding is 83%. The fraction of bortezomib bound to plasma proteins is independent of its concentration.
Metabolism. In vitro, bortezomib metabolism is primarily mediated by cytochrome P450 enzymes, specifically CYP3A4, CYP2C19, and CYP1A2. The main metabolic pathway involves deboronation, leading to two metabolites, which are subsequently hydroxylated into further metabolites. Bortezomib deboronated metabolites are inactive as inhibitors of the 26S proteasome.
Elimination. The mean half-life (t1/2) of bortezomib after multiple administrations ranges from 40 to 193 hours. Bortezomib is eliminated more rapidly after the first dose than after subsequent doses. Mean total clearance was 102 and 112 L/hour after the first dose of 1.0 mg/m² and 1.3 mg/m², respectively, and ranged from 15–32 L/hour and 18–32 L/hour 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, predominantly 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 the area under the plasma concentration-time curve (AUC) of bortezomib compared to patients with 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) into the following groups: normal (CrCL ≥60 mL/min/1.73 m², n=12), mild impairment (CrCL=40–59 mL/min/1.73 m², n=10), moderate impairment (CrCL=20–39 mL/min/1.73 m², n=9), and severe impairment (CrCL<20 mL/min/1.73 m², n=3). Patients undergoing dialysis who received bortezomib after dialysis were also included in the study (n=8). Patients received intravenous bortezomib at doses of 0.7–1.3 mg/m² twice weekly. The pharmacokinetic parameters of bortezomib (dose-normalized AUC and Cmax) were comparable across all groups.
Age. Pharmacokinetic parameters of bortezomib were evaluated in 104 pediatric patients (aged 2–16 years) with acute lymphoblastic leukemia or acute myeloid leukemia, who received bortezomib 1.3 mg/m² twice weekly via intravenous bolus injection. According to population pharmacokinetic analysis, bortezomib clearance increases with increasing body surface area. The geometric mean (%CV) for clearance was 7.79 (25%) L/h/m², the volume of distribution at steady state was 834 (39%) L/m², and t1/2 was 100 (44%) hours. After adjusting for body surface area, other demographic factors (age, body weight, and sex) did not have a 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 line and who have undergone hematopoietic stem cell transplantation or who are not candidates for transplantation (second-line therapy).
Treatment of multiple myel游戏副本
Special precautions for use.
When using Bortebin in combination with other medicinal products, the instructions for medical use of these products should be consulted prior to initiating treatment. Special attention should be paid to pregnancy testing and contraceptive methods before using thalidomide.
Intrathecal administration. Fatal cases have been reported due to accidental intrathecal administration of bortezomib. Bortebin should only be administered intravenously or subcutaneously. BORTEBIN MUST NOT BE ADMINISTERED INTRATHECALLY.
Gastrointestinal complications. Treatment with bortezomib very frequently causes gastrointestinal toxicity, including nausea, diarrhea, constipation, and vomiting. Cases of intestinal obstruction (reported as uncommon in frequency) have been observed; therefore, patients with constipation should be under medical supervision.
Hematological complications. Hematological toxicity (thrombocytopenia, neutropenia, and anemia) is very commonly observed during therapy with Bortebin. In clinical trials evaluating the use of the drug in patients with relapsed multiple myeloma and its use in combination therapy with rituximab, cyclophosphamide, doxorubicin, and prednisone (VcR-CAP regimen) in previously untreated mantle cell lymphoma patients, 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. 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 involving mantle cell lymphoma patients. In patients with progressive myeloma, the severity of thrombocytopenia correlated with pre-treatment platelet counts: in 90% of 21 patients with baseline platelet counts < 75,000/µL, platelet counts dropped to ≤ 25,000/µL during the study, including 14% with counts < 10,000/µL, whereas in patients with baseline platelet counts > 75,000/µL, only 14% of 309 patients had platelet counts ≤ 25,000/µL.
In patients with mantle cell lymphoma, grade ≥3 thrombocytopenia occurred more frequently in the group receiving bortezomib (VcR-CAP regimen) compared to those receiving R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). The overall incidence of bleeding events of all grades, as well as bleeding events of at least grade 3, was similar in both groups. In the VcR-CAP treatment group, 22.5% of patients required platelet transfusions compared to 2.9% in the R-CHOP group.
Cases of gastrointestinal and intracranial hemorrhages associated with bortezomib use have been reported. Therefore, platelet counts should be monitored before each dose of Bortebin. Therapy with Bortebin should be withheld if platelet counts fall below 25,000/µL during monotherapy or below ≤ 30,000/µL when used in combination with melphalan and prednisone. The benefit-risk ratio of treatment with Bortebin should be carefully evaluated, especially in cases of moderate or severe thrombocytopenia and in the presence of bleeding risk factors.
Complete blood counts, including leukocyte differential and platelet counts, should be frequently monitored during Bortebin therapy. Platelet transfusion should be considered if clinically indicated.
In patients with mantle cell lymphoma, reversible neutropenia between treatment cycles has been observed, with no cumulative neutropenia reported. White blood cell counts were typically lowest on day 11 of each bortezomib treatment cycle and returned to baseline levels before the start of the next cycle. In a clinical trial of bortezomib in mantle cell lymphoma patients, 78% of patients in the VcR-CAP group and 61% in the R-CHOP group received granulocyte colony-stimulating factor. Since patients with neutropenia are at increased risk of infections, they should be monitored for signs of infection and appropriate therapeutic measures taken. The use of granulocyte colony-stimulating factor should be considered for managing hematological toxicity. If initiation of a new treatment cycle is delayed multiple times, prophylactic use of granulocyte colony-stimulating factor should be considered.
Herpes zoster reactivation. Antiviral prophylaxis should be considered for patients treated with Bortebin. In phase III trials of previously untreated multiple myeloma patients, the overall incidence of herpes zoster reactivation (shingles) was higher in the group receiving bortezomib + melphalan + prednisone (14%) compared to the melphalan + prednisone group (4%).
Among patients with mantle cell lymphoma, the incidence of shingles was 6.7% in the VcR-CAP group and 1.2% in the R-CHOP group.
Reactivation and infection with hepatitis B virus (HBV). Prior to initiating treatment with rituximab in combination with Bortebin, 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 markers during and after combination therapy with rituximab and bortezomib. Antiviral prophylaxis should be considered.
Progressive multifocal leukoencephalopathy (PML). Very rare cases of John Cunningham virus infection leading to fatal PML have been reported in patients treated with bortezomib. Patients diagnosed with PML had a history of or were concurrently receiving immunosuppressive therapy with bortezomib. Most PML cases were diagnosed within the first 12 months after initiating 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 PML management and appropriate diagnostic measures initiated. Upon confirmation of PML, treatment with Bortebin should be discontinued.
Peripheral neuropathy. Treatment with bortezomib is very frequently associated with peripheral neuropathy, predominantly sensory. However, cases of severe motor neuropathy, with or without sensory peripheral neuropathy, have been reported. The incidence of peripheral neuropathy typically peaks during the fifth treatment cycle with Bortebin.
Careful monitoring of patients for neuropathy symptoms such as burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain, or weakness is recommended.
In a phase III trial comparing intravenous versus subcutaneous administration of bortezomib, the incidence of grade 2 peripheral neuropathy was 24% in the subcutaneous group and 41% in the intravenous group. Grade 3 peripheral neuropathy occurred in 6% of patients in the subcutaneous group and 16% in the intravenous group.
If peripheral neuropathy develops or worsens, patients should undergo neurological evaluation; dose adjustments, changes in administration schedule, or switching to subcutaneous administration may be necessary. Neuropathy should be managed with supportive measures.
Regular monitoring for treatment-related neuropathy symptoms and neurological examinations are required for patients receiving Bortebin in combination with neuropathy-associated drugs (e.g., thalidomide); dose reduction or discontinuation of treatment should be considered if necessary.
In addition to peripheral neuropathy, autonomic neuropathy may contribute to certain adverse reactions such as orthostatic hypotension and acute constipation with intestinal obstruction. Information on autonomic neuropathy and its impact on these adverse reactions is limited.
Seizures. Rare cases of seizures have been reported in patients with a history of seizures or epilepsy. Particular caution is required when treating patients with any risk factors for seizures.
Hypotension. Treatment with Bortebin frequently causes postural/orthostatic hypotension. In most cases, it is mild to moderate in severity and occurs throughout treatment. Patients who developed orthostatic hypotension during bortezomib (intravenous) administration did not have symptoms of orthostatic hypotension prior to bortezomib 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 the drug; 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, pre-syncope, or syncope.
Reversible posterior leukoencephalopathy syndrome (PRES). Cases of PRES have been reported in patients treated with bortezomib. PRES is a rare reversible neurological disorder characterized by seizures, arterial hypertension, headache, lethargy, confusion, visual disturbances, and other neurological impairments. Brain imaging, preferably magnetic resonance imaging (MRI), is required to confirm diagnosis. Bortebin treatment should be discontinued if PRES is diagnosed.
Heart failure. Cases of new-onset or worsening pre-existing congestive heart failure and/or reduced left ventricular ejection fraction have been reported with bortezomib use. Development of signs and symptoms of heart failure may be associated with fluid retention. Patients with risk factors or pre-existing cardiac conditions should be closely monitored.
ECG monitoring. Isolated cases of QT interval prolongation have been observed in clinical trials; the cause has not been established.
Lung function disorders. Rare cases of acute diffuse infiltrative lung diseases of unknown etiology, such as pneumonitis, interstitial pneumonia, pulmonary infiltration, and acute respiratory distress syndrome (ARDS), have been observed in patients receiving bortezomib. Some of these cases were fatal. Chest X-ray before treatment initiation 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 Bortebin treatment should be carefully evaluated.
In clinical trials, two out of two patients receiving high-dose cytarabine (2 g/m²/day) as continuous 24-hour infusion combined with daunorubicin and bortezomib for relapsed acute myeloid leukemia died from ARDS at the beginning of treatment. Therefore, this specific regimen combining high-dose cytarabine (2 g/m²/day) as continuous 24-hour infusion is not recommended.
Renal function disorders. Renal dysfunction 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 receive reduced doses and be closely monitored for signs of toxicity.
Hepatic reactions. Rare cases of acute liver failure have been reported in patients treated with bortezomib in combination with other drugs and in patients with serious 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 prior to treatment initiation are at particular risk. Close monitoring of such patients and appropriate preventive measures are recommended.
Warnings regarding concomitant use of other medicinal products. Patients should be closely monitored when bortezomib is combined with strong CYP3A4 inhibitors. Caution should be exercised when combining bortezomib with CYP3A4 or CYP2C9 substrates.
Liver function should be corrected prior to treatment initiation in case of hepatic impairment, and caution should be exercised when administering the drug to patients taking oral hypoglycemic agents.
Potentially immune complex-mediated reactions. Immune complex-mediated reactions such as serum sickness, polyarthritis with rash, and proliferative glomerulonephritis have been reported uncommonly. Bortezomib should be discontinued if serious reactions occur.
Use during pregnancy or breastfeeding.
Contraception in women and men
Men and women of reproductive potential must use effective contraceptive methods during treatment and for 3 months after completion of treatment.
Pregnancy
There are no clinical data on the use of bortezomib during pregnancy. The teratogenic potential of bortezomib has 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 were not conducted. Bortebin is not recommended during pregnancy except in cases where the patient's clinical condition necessitates treatment with this drug. If Bortebin is used during pregnancy or if pregnancy occurs during treatment, the patient should be informed of the potential risk to the fetus.
Thalidomide is a medicinal product with known teratogenic effects in humans, causing severe, life-threatening congenital malformations. Thalidomide is contraindicated in pregnant women and women of reproductive potential. Patients receiving Bortebin in combination with thalidomide must comply with pregnancy prevention requirements. For additional information, refer to the thalidomide product information.
Breastfeeding period
It is unknown whether Bortebin is excreted in human milk, but to prevent the occurrence of severe adverse effects in the infant, breastfeeding is not recommended during treatment with Bortebin.
Fertility
Studies on the effect of bortezomib on fertility have not been conducted.
Ability to affect reaction rate when driving or operating machinery.
Bortebin has a moderate effect on the ability to drive or operate machinery. The use of Bortebin is very frequently 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 patients with oncological diseases, although Bortebin 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, it is recommended to administer 2 additional treatment cycles. Patients achieving a partial response but not complete remission should continue treatment with Bortebin, but for no more than 8 cycles. At least 72 hours must elapse between consecutive doses of Bortebin.
Dose modification and re-initiation recommendations for Bortebin monotherapy
If any grade 3 non-hematological toxicity or grade 4 hematological toxicity occurs, except for neuropathies, treatment with Bortebin 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 symptoms of toxicity do not resolve or recur during treatment with the reduced dose, discontinuation of Bortebin should be considered, unless the benefits of continued treatment outweigh the risks.
Neuropathic pain and/or peripheral neuropathy
The dose of the drug should be adjusted in case of development of neuropathic pain and/or peripheral neuropathy (see Table 1). Bortebin should be used in 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 adjustment |
| Grade I (asymptomatic; loss of deep tendon reflexes or paresthesia) without pain or functional loss |
Dose and administration schedule do not require adjustment |
| Grade I with pain or Grade II (moderate severity symptoms; limitation of instrumental activities of daily living)** |
Reduce dose to 1 mg/m² or change bortezomib administration schedule to 1.3 mg/m² once weekly |
| Grade II with pain or Grade III (severe symptoms; limitation of self-care activities)*** |
Withhold Bortebine treatment until resolution of toxicity 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 Bortebine treatment |
* Based on dose modifications observed in Phase II and III multiple myeloma studies and in the post-marketing period.
** Instrumental activities of daily living include cooking, shopping, and using the telephone.
*** Basic activities of daily living include bathing, dressing/undressing, eating, using the toilet, taking medications, and being out of bed.
Combination therapy with pegylated liposomal doxorubicin
The recommended dose of bortezomib in 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 must elapse between consecutive doses of Bortebin.
Pegylated liposomal doxorubicin should be administered at a dose of 0.3 mg/m² on Day 4 of the Bortebin treatment cycle via a 1-hour intravenous infusion after bortezomib injection.
Up to 8 cycles of this combination therapy should be administered, provided the disease does not progress and patients tolerate treatment well. Patients who achieve a complete remission may continue treatment for at least 2 additional cycles after achieving complete response, even if this requires more than 8 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 must elapse between consecutive doses of Bortebin.
Dexamethasone should be administered orally at a dose of 20 mg on Days 1, 2, 4, 5, 8, 9, 11, and 12 of the Bortebin 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 administration, refer to the prescribing information for that medicinal product.
Dose modification recommendations for combination therapy in patients with relapsed multiple myeloma
See dose modification recommendations for Bortebin monotherapy described above.
Previously untreated multiple myeloma in patients not eligible for hematopoietic stem cell transplantation
Combination therapy with melphalan and prednisone
Bortebin must 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, Bortebin is administered twice weekly (Days 1, 4, 8, 11, 22, 25, 29, and 32). In cycles 5–9, Bortebin is administered once weekly (Days 1, 8, 22, and 29). At least 72 hours must elapse between consecutive doses of Bortebin.
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 Bortebin in combination with melphalan and prednisone
| Bortezomib 2 times per week (cycles 1-4) |
|||||||||||||||||||
| Week |
1 |
2 |
3 |
4 |
5 |
6 |
|||||||||||||
| Bortezomib (1.3 mg/m²) |
Day 1 |
-- |
-- |
Day 4 |
Day 8 |
Day 11 |
Break |
Day 22 |
Day 25 |
Day 29 |
Day 32 |
Break |
|||||||
| M (9 mg/m²) P (60 mg/m²) |
Day 1 |
Day 2 |
Day 3 |
Day 4 |
-- |
-- |
Break |
-- |
-- |
-- |
-- |
Break |
|||||||
| Bortezomib 1 time per week (cycles 5-9) |
|||||||||||||||||||
| Week |
1 |
2 |
3 |
4 |
5 |
6 |
|||||||||||||
| Bortezomib (1.3 mg/m²) |
Day 1 |
-- |
-- |
-- |
Day 8 |
Break |
Day 22 |
Day 29 |
Break |
||||||||||
| M (9 mg/m²) P (60 mg/m²) |
Day 1 |
Day 2 |
Day 3 |
Day 4 |
-- |
Break |
-- |
-- |
Break |
||||||||||
M − melphalan, P − prednisone.
Recommendations for dose adjustment and resumption of combination therapy with melphalan and prednisone
Before 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 has returned to Grade 1 or baseline level.
Table 3
Dose adjustment during subsequent cycles of bortezomib in combination with melphalan and prednisone therapy
| Toxicity |
Dose adjustment or discontinuation of treatment |
| Haematological toxicity during cycle:
|
Consider reducing melphalan dose by 25% in the next cycle |
≤ 0.75×109/l on the day of Bortezomib administration (except day 1) |
Delay Bortezomib administration |
|
Bortezomib dose should be reduced by 1 level |
| Non-haematological toxicity ≥ Grade III |
Bortezomib treatment should be withheld until symptoms improve to baseline or Grade I severity. Bortezomib may then be restarted at a dose reduced by 1 level |
For additional information on melphalan and prednisone, see the instructions for medical use of these medicinal products.
Untreated multiple myeloma in patients eligible for hematopoietic stem cell transplantation (induction therapy)
Combination therapy with dexamethasone
The recommended dose of bortezomib is 1.3 mg/m² body surface area administered intravenously or subcutaneously twice weekly for 2 weeks (days 1, 4, 8, and 11), followed by
a 10-day treatment break (days 12–21). This 3-week period is considered one treatment cycle. At least 72 hours should elapse between consecutive doses of Bortebiv.
Dexamethasone should be administered orally at a dose of 40 mg on days 1, 2, 3, 4, 8, 9, 10, and 11 of the Bortebiv treatment cycle.
Administer 4 treatment cycles with this combination.
Combination therapy with dexamethasone and thalidomide
The recommended dose of bortezomib is 1.3 mg/m² body surface area administered intravenously or subcutaneously twice weekly for 2 weeks (days 1, 4, 8, and 11), followed by
a 17-day treatment break (days 12–28). This 4-week period is considered one treatment cycle. At least 72 hours should elapse between consecutive doses of Bortebiv.
Dexamethasone should be administered orally at a dose of 40 mg on days 1, 2, 3, 4, 8, 9, 10, and 11 of the Bortebiv 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 treatment cycles. Patients achieving at least a partial response to treatment are recommended to receive 2 additional cycles of therapy.
Table 4
Recommended dosing regimen of Bortebiv in combination with dexamethasone and thalidomide for untreated multiple myeloma patients 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 starting from week 3 of cycle 1 if the 50-mg dose is tolerated, and to 200 mg if the 100-mg dose is tolerated.
b Patients who achieve a partial response after 4 cycles of treatment may receive up to 6 cycles of treatment.
Dosing recommendations for patients eligible for transplantation
For dose adjustment in case of neuropathy, see dose adjustment recommendations for bortezomib used as monotherapy.
If bortezomib 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 response during cycle 6 are recommended to receive 2 additional treatment cycles.
Medications administered by intravenous infusion on day 1 of each 3-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 adjustment 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 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.
Bortezomib treatment should be withheld in the event of any bortezomib-related non-hematologic toxicity ≥ grade III (except neuropathy) or hematologic toxicity ≥ grade III. Refer to Table 5 for dose adjustment recommendations.
Granulocyte colony-stimulating factors 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 management of thrombocytopenia.
Table 5
Dose adjustment during therapy for patients with untreated mantle cell lymphoma
| Toxicity |
Dose modification or treatment interruption |
| Hematologic toxicity |
|
˂ 10,000 cells/μL. |
Treatment with Bortezomib should be interrupted for up to 2 weeks until the absolute neutrophil count recovers to
|
|
Delay administration of the Bortezomib dose. |
| Non-hematologic toxicity ≥ Grade III related to Bortezomib administration. |
Treatment with Bortezomib should be interrupted until symptoms improve to Grade II or better. Afterward, Bortezomib may be restarted at a reduced dose level (from 1.3 to 1 mg/m² or from 1 to 0.7 mg/m²). For bortezomib-induced neuropathic pain and/or peripheral neuropathy, dose holding and/or dose modification of Bortezomib should be performed as specified in Table 1. |
If Bortebib 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
There are currently no data indicating the need for dose adjustment in patients aged 65 years and older.
There have been no studies on the use of Bortebib in elderly patients with untreated multiple myeloma who are candidates for high-dose chemotherapy with hematopoietic stem cell transplantation. Therefore, no recommendations on dose adjustment can be provided for this patient group.
In a study of bortezomib use in patients with 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, treatment with Bortebib should be initiated at a dose of 0.7 mg/m² during the first treatment cycle, followed by gradual dose escalation to 1.0 mg/m² or dose reduction to 0.5 mg/m², depending on patient tolerability.
Table 6
Recommendations for initial dose modifications of Bortebib in patients with hepatic impairment
| Severity of hepatic dysfunction* |
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 |
| 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 function impairment (mild, moderate, and severe).
Patients with renal impairment
Mild to moderate renal impairment (creatinine clearance > 20 ml/min/1.73 m²) does not affect the pharmacokinetics of bortezomib; therefore, dose adjustment is not required in this patient group. It is unknown whether severe renal impairment (creatinine clearance < 20 ml/min/1.73 m²) affects the pharmacokinetics of bortezomib. Since dialysis may reduce bortezomib concentrations, the drug should be administered after the dialysis procedure.
Method of administration
Bortebin should be administered by intravenous or subcutaneous injection. Accidental intrathecal administration of the drug has resulted in fatal outcomes.
Intravenous
The reconstituted solution should be administered as a 3- to 5-second intravenous bolus injection through a peripheral or central venous catheter immediately after preparation. The catheter should be flushed with 0.9% sodium chloride injection solution after injection. At least 72 hours should elapse between consecutive doses of Bortebin.
Subcutaneous
The reconstituted solution should be administered subcutaneously immediately after preparation at a 45-90° angle, injecting into areas of the thigh (left or right) or abdomen (left or right). Injection sites should be rotated.
If adverse local reactions occur with subcutaneous injections, the Bortebin solution may be administered subcutaneously at a lower concentration (1 mg/ml instead of 2.5 mg/ml) or Bortebin may be administered intravenously.
Children
The safety and efficacy of Bortebin in children (under 18 years of age) have not been established. Current available data are insufficient to establish dosing recommendations for children.
Overdose
In patients, overdose exceeding the recommended dose by more than two-fold has been associated with acute hypotension and thrombocytopenia resulting in death.
There is no known 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 treatment with bortezomib 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 reported 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 pooled data from 5,476 patients, of whom 3,996 received bortezomib at a dose of 1.3 mg/m². Overall, bortezomib was administered to 3,974 patients for the treatment of multiple myeloma.
Adverse reactions are categorized by system organ class and frequency of occurrence. Frequency is defined as: very common (>1/10), common (≥1/100, <1/10), uncommon (≥1/1,000, <1/100), rare (≥1/10,000, <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. 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, postviral fatigue syndrome |
|
| Benign, malignant and unspecified neoplasms (including cysts and polyps) |
Rare |
Malignant neoplasm, plasma cell leukemia, renal cell carcinoma, tumor proliferation, mycosis fungoides, benign neoplasm* |
| Blood and lymphatic system disorders |
Very common |
Thrombocytopenia*, neutropenia*, anemia* |
| Common |
Leukopenia*, lymphopenia* |
|
| Uncommon |
Pancytopenia*, febrile neutropenia, coagulopathy*, leukocytosis*, lymphadenopathy, hemolytic anemia# |
|
| Rare |
Disseminated intravascular coagulation syndrome, thrombocytosis*, hyperviscosity syndrome, 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 complex-mediated reactions |
|
| Endocrine system disorders |
Uncommon |
Cushing's syndrome*, hyperthyroidism*, disturbance in antidiuretic hormone secretion |
| Rare |
Hypothyroidism |
|
| Metabolism and nutrition disorders |
Very common |
Decreased appetite |
| Common |
Dehydration, hypokalemia*, hyponatremia*, blood glucose disturbances*, hypocalcemia*, enzyme level disturbances* |
|
| Uncommon |
Tumor lysis syndrome, 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 disorders*, memory loss (without dementia)*, encephalopathy*, reversible posterior encephalopathy syndrome#, neurotoxicity, seizure disorders*, postherpetic neuralgia, speech disorders*, restless legs syndrome, migraine, sciatica, attention disorders, reflex abnormalities*, parosmia |
|
| Rare |
Intracranial hemorrhage*, intracranial 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, Guillain-Barré syndrome#, demyelinating polyneuropathy#, radiculitis, salivation, hypotonia |
|
| Eye disorders |
Common |
Eye swelling*, visual disturbance*, conjunctivitis* |
| Uncommon |
Ocular 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 vision deterioration (up to blindness)* |
|
| Frequency unknown |
Chalazion, blepharitis |
|
| Ear and labyrinth disorders |
Common |
Vertigo* |
| Uncommon |
Dysacusis (including tinnitus)*, hearing impairment (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, vasodilation, vessel discoloration, venous insufficiency |
|
| Frequency unknown |
Thrombotic microangiopathy |
|
| 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*, airway patency deterioration*, hypoxia, pleuritis*, hiccups, rhinorrhea, dysphonia, wheezing |
|
| Rare |
Lung failure, acute respiratory distress syndrome, apnea, pneumothorax, lung collapse, pulmonary hypertension, hemoptysis, pulmonary hyperventilation, orthopnea, pneumonitis, respiratory alkalosis, tachypnea, pulmonary fibrosis, bronchial disorders*, hypocapnia*, interstitial lung disease, lung infiltration, throat tightness, dry throat, increased upper respiratory tract secretion, throat irritation, upper respiratory tract cough syndrome |
|
| Gastrointestinal disorders |
Very common |
Nausea and vomiting*, diarrhea*, constipation |
| Common |
Gastrointestinal hemorrhage (including mucosal)*, dyspepsia, stomatitis*, abdominal distension, oropharyngeal pain*, abdominal pain (including gastrointestinal and splenic region)*, oral cavity disorders*, flatulence |
|
| Uncommon |
Pancreatitis (including chronic)*, vomiting blood, lip swelling*, gastrointestinal obstruction (including small intestine obstruction, ileus)*, abdominal discomfort, oral ulcers*, enteritis*, gastritis*, gum bleeding, gastroesophageal reflux disease*, colitis (including Clostridium difficile-induced)*, ischemic colitis#, gastrointestinal tract inflammation*, dysphagia, irritable bowel syndrome, other gastrointestinal disorders, coated tongue, gastrointestinal motility disorders*, salivary gland disorders* |
|
| Rare |
Acute pancreatitis, peritonitis*, tongue swelling*, ascites, esophagitis, cheilitis, fecal incontinence, anal sphincter atony, fecaloma*, gastrointestinal ulcers and perforations*, gingival hyperplasia, megacolon, rectal discharge, blistering in oropharynx*, lip pain, periodontitis, anal fissure, altered defecation rhythm, proctalgia, abnormal defecation |
|
| Hepatobiliary disorders |
Common |
Liver enzyme level disturbances* |
| Uncommon |
Hepatotoxicity (including liver disorders), hepatitis*, cholestasis |
|
| Rare |
Liver failure, hepatomegaly, Budd-Chiari syndrome, cytomegalovirus hepatitis, liver hemorrhage, cholelithiasis |
|
| Skin and subcutaneous tissue disorders |
Common |
Rash*, pruritus*, erythema, dry skin |
| Uncommon |
Multiform erythema, urticaria, acute febrile neutrophilic dermatosis, toxic skin rashes, 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 disorders* |
|
| Rare |
Skin reactions, Jessner's lymphocytic infiltration, palmar-plantar 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, myopathy*, feeling of heaviness |
|
| Rare |
Rhabdomyolysis, temporomandibular joint dysfunction, fistula, joint effusion, jaw pain, bone disorders, infections and inflammations of musculoskeletal system and connective tissue*, synovial cyst |
|
| Renal and urinary system disorders |
Common |
Renal failure* |
| Uncommon |
Acute renal failure, chronic renal failure*, urinary tract infections*, signs and symptoms of urinary tract disorders*, hematuria*, urinary retention, micturition disorders*, proteinuria, azotemia, oliguria*, polyuria |
|
| Rare |
Bladder irritation |
|
| Reproductive system and breast disorders |
Uncommon |
Vaginal bleeding, genital pain*, erectile dysfunction |
| Rare |
Testicular disorders*, prostatitis, breast disorders in women, epididymal 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, feeling of cold, extravasation*, complications related to catheter placement*, thirst sensation*, chest discomfort, sensation of body temperature change*, pain associated with injection* |
|
| Rare |
Lethal outcome (including sudden), multiorgan failure, hemorrhage at injection site*, hernia (including hiatal)*, impaired healing*, inflammation, phlebitis at injection site*, pain, ulceration, irritation, non-cardiac retrosternal pain, catheter insertion site pain, foreign body sensation |
|
| Investigations |
Common |
Weight decreased |
| Uncommon |
Hyperbilirubinemia*, deviation of protein levels from normal*, weight increased, blood test abnormalities*, increased C-reactive protein level |
|
| Rare |
Blood gas abnormalities*, ECG abnormalities (including QT interval prolongation)*, international normalized ratio abnormalities*, increased gastric acidity, increased platelet aggregation, increased troponin I level, virus identification in serological tests*, urine test abnormalities* |
|
| Procedural complications |
Uncommon |
Fall, confusion |
| Rare |
Transfusion reactions, fractures*, tremor*, facial injury, joint injury*, burns, skin laceration, procedural pain, radiation injuries* |
|
| Surgical and medical procedures |
Rare |
Macrophage activation |
* Grouping of more than one MedDRA term.
# Adverse reaction reported in the post-marketing period, regardless of indication.
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 administered to 240 patients with mantle cell lymphoma who received the drug at a dose of 1.3 mg/m² in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (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 when used as part of combination therapy (VcR-CAP) were hepatitis B virus infection (<1%) and myocardial ischemia (1.3%). The similar incidence of these events in both treatment groups suggests that these adverse reactions are not solely related to bortezomib. Administration of bortezomib to patients with mantle cell lymphoma was associated with ≥5% higher frequency of hematologic adverse reactions (neutropenia, thrombocytopenia, leukopenia, anemia, lymphopenia), peripheral sensory neuropathy, arterial hypertension, pyrexia, pneumonia, stomatitis, and hair disorders compared to administration in patients with multiple myeloma.
Adverse reactions with a frequency ≥1%, occurring at a similar or higher rate 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 and, according to investigator assessment, possibly or probably related to bortezomib, considering experience from studies in patients with multiple myeloma.
Adverse reactions are grouped by system organ class and frequency of occurrence. Frequency is defined as: very common (>1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10000, <1/1000), very rare (<1/10000), frequency not known (cannot be estimated from available data). Within each group, adverse reactions are listed in order of decreasing severity.
Table 8
| System Organ Classes |
Frequency |
Adverse Reaction |
| Infections and infestations |
Very common |
Pneumonia* |
| Common |
Sepsis (including septic shock)*, herpes zoster (including disseminated and with ocular complications), herpesvirus infection*, bacterial infections*, upper/lower respiratory tract infections*, fungal infection*, herpes simplex* |
|
| Uncommon |
Hepatitis B, infections*, bronchopneumonia |
|
| Blood and lymphatic system disorders |
Very common |
Thrombocytopenia*, febrile neutropenia, neutropenia*, leukopenia*, anemia*, lymphopenia* |
| Uncommon |
Pancytopenia* |
|
| Immune system disorders |
Common |
Hypersensitivity* |
| Uncommon |
Anaphylactic reaction |
|
| Metabolism and nutrition disorders |
Very common |
Decreased appetite |
| Common |
Hypokalemia*, blood glucose abnormalities*, hyponatremia*, diabetes mellitus*, fluid retention |
|
| Uncommon |
Tumor lysis syndrome |
|
| Psychiatric disorders |
Common |
Sleep disorders* |
| Nervous system disorders |
Very common |
Peripheral sensory neuropathy, dysesthesia*, neuralgia* |
| Common |
Neuropathy*, motor neuropathy*, loss of consciousness (including syncope), encephalopathy*, sensorimotor peripheral neuropathy, 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 |
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, inflammation of gastrointestinal tract*, abdominal pain (including gastrointestinal and splenic region pain)*, oral cavity disorders* |
|
| Uncommon |
Colitis (including Clostridiumdifficile-induced)* |
|
| Hepatobiliary disorders |
Common |
Hepatotoxicity (including liver disorders) |
| Uncommon |
Hepatic 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*, protein level abnormalities*, weight decreased, weight increased |
* Grouping of more than one MedDRA term.
Description of selected adverse reactions
Herpes zoster virus reactivation
Multiple myeloma.
Antiviral prophylaxis was administered in 26% of patients receiving bortezomib in combination with melphalan and prednisone. Herpes zoster was observed 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 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 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 (IFM-2005-01 study) and with dexamethasone-thalidomide (MMY-3010 study) (see Table 9).
Table 9
Incidence of peripheral neuropathy (PN) during induction therapy by toxicity grade and need for treatment interruption due to PN
| Indicators 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 need for treatment interruption due to PN.
| Signs of peripheral neuropathy |
VcR-CAP (N=240) |
R-CHOP (N=242) |
| Frequency of PN (%) |
||
| All grades PN |
30 |
29 |
| ≥ Grade II PN |
18 |
9 |
| ≥ Grade III PN |
8 |
4 |
| Discontinuation due to PN (%) |
2 |
˂1 |
VcR-CAP – bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone; R-CHOP – rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone.
Peripheral neuropathy includes peripheral sensory neuropathy, peripheral neuropathy, peripheral motor neuropathy, and peripheral sensorimotor neuropathy.
Elderly patients with mantle cell lymphoma
In the VcR-CAP treatment group, 42.9% of patients were aged 65–74 years and 10.4% were ≥75 years. Although patients aged 75 years and older tolerated both treatment regimens less well, the rate of serious adverse reactions was 68% in the VcR-CAP group compared to 48% in the R-CHOP group.
Known differences in the safety profile of bortezomib when administered intravenously versus subcutaneously
In a Phase III study, in patients receiving subcutaneous bortezomib, the incidence of treatment-emergent adverse reactions of Grade III toxicity or higher was 13% lower compared to patients receiving intravenous bortezomib, and the rate of treatment discontinuation was also 5% lower. The overall incidence of diarrhea, lower abdominal pain, abdominal pain, asthenic conditions, upper respiratory tract infections, and peripheral neuropathy was 12–15% lower in the subcutaneous group compared to the intravenous group. Additionally, the incidence of Grade III or higher peripheral neuropathy was 10% lower, and the rate of treatment discontinuation due to peripheral neuropathy was 8% lower.
Local reactions at the subcutaneous injection site 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%): one case of pruritus and one case of erythema.
The rate of fatal events during treatment was 5% in the subcutaneous group and 7% in the intravenous group. The rate of death 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 were predominantly 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 in a light-protected place at a temperature not exceeding 25°C. Keep out of reach of children.
Incompatibilities.
This medicinal product should not be mixed with other medicinal products except those mentioned in the section “Instructions for use, handling and disposal”.
Packaging. 3.5 mg in a vial. 1 vial with powder in a cardboard box.
Prescription status.
Prescription only.
Manufacturer.
Yugia Pharma Specialities Limited.
Manufacturer's address and location of operations.
Survey No. 550, 551 and 552, Koltur Village, Shamirpet Mandal, Medchal-Malkajgiri, Medchal District, Telangana, 500101, India.