INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT BORTEXASUN (BORTEXASUN)

Composition:

Active substance: bortezomib; bortezomib;

1 vial contains bortezomib 3.5 mg;

Excipient: mannitol (E 421).

Pharmaceutical form. Lyophilisate for solution for injection.

Main physicochemical characteristics: white or almost white lyophilized solid or powder.

Pharmacotherapeutic group. Antineoplastic and immunomodulating agents. Antineoplastic agents. Other antineoplastic agents. Proteasome inhibitors. Bortezomib.

ATC code L01XG01.

Pharmacological Properties

Pharmacodynamics

Mechanism of Action

Bortezomib is a proteasome inhibitor that reversibly 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-fold more selective for the proteasome than for other enzymes. The kinetics of proteasome inhibition were determined in vitro; bortezomib dissociated from the proteasome with a half-life (t½) of 20 minutes, thus demonstrating that proteasome inhibition by bortezomib is reversible. By inhibiting the proteasome, bortezomib affects cancer cells through multiple pathways, including altering regulatory proteins controlling the cell cycle and inhibiting activation of the nuclear factor NF-kB. Proteasome inhibition results in 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 interferes with the ability of myeloma cells to interact with the bone marrow microenvironment.

Experiments 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 inhibition of growth in multiple 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.

Clinical Efficacy in Previously Untreated Multiple Myeloma

A prospective, international, randomized (1:1), open-label Phase III clinical trial (MMY-3002 VISTA) involving 682 patients was conducted to determine whether the addition of bortezomib (1.3 mg/m² administered intravenously) to melphalan (9 mg/m²) and prednisone (60 mg/m²) improved time to progression (TTP) compared to melphalan and prednisone alone in patients with previously untreated multiple myeloma. Treatment was administered for up to 9 cycles (approximately 54 weeks) and was discontinued earlier due to disease progression or unacceptable toxicity. The median age of patients in the study was 71 years, 50% were male, 88% were Caucasian, and the median Karnofsky performance status score was 80. Patients had IgG/IgA/light chain myeloma in 63%/25%/8% of cases, the median hemoglobin level was 105 g/L, and the median platelet count was 221.5 x 10⁹/L. Similar proportions of patients had a creatinine clearance ≤30 mL/min (3% in each group).

At a pre-specified interim analysis, the primary endpoint, time to progression, was met, and patients in the melphalan + prednisone (M+P) group were offered crossover to bortezomib + melphalan + prednisone treatment. The median follow-up time was 16.3 months. Final survival update was performed with a median observation time of 60.1 months. A statistically significant improvement in overall survival was observed in favor of the bortezomib + melphalan + prednisone group (hazard ratio = 0.695; p = 0.00043), regardless of subsequent therapies, including bortezomib-based regimens. Median overall survival was 56.4 months in the bortezomib + melphalan + prednisone group compared to 43.1 months in the melphalan + prednisone group. Efficacy results are presented in Table 1.

Table 1

Efficacy results after final survival update in the VISTA study

a Kaplan-Meier estimate.

b Hazard ratio estimation is based on the Cox proportional hazards model, adjusted for stratification factors: β2-microglobulin, albumin, and region. A hazard ratio less than 1 indicates superiority of VMP.

c Nominal p-value based on stratified log-rank test adjusted for stratification factors: β2-microglobulin, albumin, and region.

d p-value for response rate (CR + PR) based on the Cochran-Mantel-Haenszel chi-square test, adjusted for stratification factors.

e The response population includes patients with measurable disease at baseline.

f CR = complete response, PR = partial response.

g All randomized patients with secretory disease.

* Survival update based on a median follow-up duration of 60.1 months.

mo: months.

CI = confidence interval.

Patients eligible for stem cell transplantation

Two randomized, open-label, multicenter Phase III studies (IFM-2005-01, MMY-3010) were conducted to demonstrate the safety and efficacy of bortezomib in double and triple combinations with other chemotherapeutic agents as induction therapy prior to stem cell transplantation in patients with previously untreated multiple myeloma.

In the IFM-2005-01 study, bortezomib in combination with dexamethasone [BzDx, n = 240] was compared to vincristine-doxorubicin-dexamethasone [VDDx, n = 242]. Patients in the BzDx group received four 21-day cycles, each consisting of bortezomib (1.3 mg/m² intravenously twice weekly on days 1, 4, 8, and 11) and oral dexamethasone (40 mg/day on days 1–4 and days 9–12 in cycles 1 and 2, and on days 1–4 in cycles 3 and 4).

Autologous stem cell transplantation was received by 198 (82%) patients in the VDDx group and 208 (87%) patients in the BzDx group; most patients underwent a single transplantation procedure. Demographic characteristics and baseline disease characteristics were similar between treatment groups. The median age of patients in the study was 57 years, 55% were male, and 48% of patients had high-risk cytogenetics. Median duration of treatment was 13 weeks in the VDDx group and 11 weeks in the BzDx group. The median number of cycles received in both groups was four.

The primary efficacy endpoint of the study was response rate after induction (CR + nCR). A statistically significant difference in CR + nCR was observed in favor of the bortezomib plus dexamethasone group. Secondary efficacy endpoints included response rate after transplantation (CR + nCR, CR + nCR + VGPR + PR), progression-free survival, and overall survival. Primary efficacy results are presented in Table 2.

Table 2

Efficacy results from the IFM-2005-01 study

CI = confidence interval; CR = complete response; nCR = near complete response; ITT = intent to treat; RR = response rate.

Bz = bortezomib; BzDx = bortezomib, dexamethasone; VDDx = vincristine, doxorubicin, dexamethasone; VGPR = very good partial response; PR = partial response; OR = odds ratio.

* Primary endpoint.

a OR for response rates based on Mantel–Haenszel estimate of overall odds ratio for stratified tables; p-value from Cochran–Mantel–Haenszel test.

b Refers to response rate after second transplant among patients who received a second transplant (42/240 [18%] in the BzDx group and 52/242 [21%] in the VDDx group).

Note: OR > 1 indicates advantage for Bz-containing induction therapy.

In study MMY-3010, induction treatment with bortezomib in combination with thalidomide and dexamethasone [BzTDx, n = 130] was compared to thalidomide-dexamethasone [TDx, n = 127]. Patients in the BzTDx group received six 4-week cycles, each consisting of bortezomib (1.3 mg/m² twice weekly on days 1, 4, 8, and 11, followed by a 17-day rest period from days 12 to 28), dexamethasone (40 mg orally on days 1–4 and days 8–11), and thalidomide (orally 50 mg daily on days 1–14, increased to 100 mg on days 15–28, then to 200 mg daily).

One autologous stem cell transplant was received by 105 (81%) patients and 78 (61%) patients in the BzTDx and TDx groups, respectively. Demographic characteristics and baseline disease characteristics were similar between treatment groups. Patients in the BzTDx and TDx groups had a median age of 57 versus 56 years, 99% versus 98% of patients were Caucasian, and 58% versus 54% were male. In the BzTDx group, 12% of patients were cytogenetically classified as high risk versus 16% in the TDx group. The median duration of treatment was 24.0 weeks, and the median number of treatment cycles received was 6.0 and was identical across all treatment groups.

The primary efficacy endpoints of the study were response rates after induction and after transplantation (CR + nCR). A statistically significant difference in CR + nCR was observed in favor of the bortezomib combination with dexamethasone and thalidomide group. Secondary efficacy endpoints included progression-free survival and overall survival. The key efficacy results are presented in Table 3.

Table 3

Efficacy results from study MMY-3010

CI = confidence interval; CR = complete response; nCR = near complete response; ITT = intent to treat; RR = response rate.

Bz = bortezomib; BzTDx = bortezomib, thalidomide, dexamethasone; TDx = thalidomide, dexamethasone; PR = partial response; OR = odds ratio.

* Primary endpoint.

a OR for response rates based on Mantel–Haenszel estimation of the overall odds ratio for stratified tables; p-value from the Cochran–Mantel–Haenszel test.

Note: OR > 1 indicates superiority of Bz-containing induction therapy.

Clinical efficacy in relapsed or refractory multiple myeloma

The safety and efficacy of bortezomib (administered intravenously) were evaluated in two studies at the recommended dose of 1.3 mg/m²: a phase III randomized comparative study (APEX) versus dexamethasone (Dex) in 669 patients with relapsed or resistant multiple myeloma who had received 1–3 prior lines of therapy, and a phase II single-arm study in 202 patients with relapsed and refractory multiple myeloma who had received at least two prior lines of treatment and had progressed during the most recent therapy.

In the phase III study, bortezomib treatment resulted in a significantly longer time to progression, significantly prolonged survival, and a significantly higher response rate compared to dexamethasone treatment (see Table 4) in all patients, as well as in patients who had received one prior line of therapy. As a result of a pre-planned interim analysis, the dexamethasone arm was discontinued per recommendation of the data monitoring committee, and bortezomib was offered to all patients randomized to dexamethasone, regardless of disease status. Due to this early crossover, the median duration of follow-up for surviving patients was 8.3 months. Overall survival was significantly longer and the response rate was significantly higher in the bortezomib group compared to the dexamethasone group, both in patients who were refractory to their most recent prior therapy and in those who were not.

Of the 669 patients, 245 (37%) were aged 65 years or older. Response parameters as well as time to response (TTR) remained significantly better with bortezomib regardless of age. Regardless of baseline β2-microglobulin level, all efficacy parameters (time to progression, overall survival, and response rate) were significantly improved in the bortezomib group.

In the refractory population of the phase II study, responses were assessed by an independent review committee, and response criteria were those of the European Group for Blood and Marrow Transplantation. Median overall survival for all patients was 17 months (range: <1 to 36+ months). This survival was longer than the 6- to 9-month median survival expected by clinical consultant investigators for a similar patient group. According to multivariate analysis, response rate did not depend on myeloma type, performance status, chromosome 13 deletion status, or number or type of prior therapies. Patients who had received 2 to 3 prior treatment regimens had a response rate of

32% (10/32), and patients who had received more than 7 prior treatment regimens had a response rate of 31% (21/67).

Table 4

Summary of disease outcomes from phase III (APEX) and phase II studies

a Planned number of patients for treatment (ITT).

b p-value from stratified log-rank test; analysis by line of therapy excludes stratification by prior therapy; p < 0.0001.

c Response population includes patients who had measurable disease at baseline and received at least one dose of investigational medicinal product.

d p-value from Cochran–Mantel–Haenszel chi-square test, adjusted for stratification factors; analysis by line of therapy excludes stratification by prior therapy.

* CR + PR + MR **CR = CR, (IF-); nCR = CR (IF+).

TTP – time to progression.

CI = confidence interval.

Bz = bortezomib; Dex = dexamethasone.

CR = complete response; nCR = near complete response.

PR = partial response; MR = minimal response.

In a phase II study, patients who did not achieve an optimal response to bortezomib monotherapy could receive high-dose dexamethasone in combination with bortezomib. The protocol allowed patients to receive dexamethasone if they had less than an optimal response to bortezomib alone. Overall, 74 evaluable patients received dexamethasone in combination with bortezomib. 18% of patients achieved or improved their response [MR (11%) or PR (7%)] with combination therapy.

Clinical efficacy of subcutaneous bortezomib in patients with relapsed/refractory multiple myeloma

An open-label, randomized phase III study compared the efficacy and safety of subcutaneous versus intravenous administration of bortezomib. This study included 222 patients with relapsed/refractory multiple myeloma who were randomized in a 2:1 ratio to receive 1.3 mg/m² bortezomib either subcutaneously or intravenously over eight cycles. Patients who did not achieve an optimal response (less than complete response [CR]) to bortezomib monotherapy after four cycles were permitted to add dexamethasone 20 mg daily on the day of and after bortezomib administration. Patients with pre-existing peripheral neuropathy ≥ grade 2 or platelet count < 50,000/μL were excluded. Overall, 218 patients were evaluable for response assessment.

The study met its primary objective of non-inferior efficacy in terms of response rate (CR + PR) after four cycles of bortezomib monotherapy for both subcutaneous and intravenous administration, with 42% in both groups. Furthermore, secondary efficacy endpoints related to response and time-to-event outcomes demonstrated consistent results between subcutaneous and intravenous administration (see Table 5).

Table 5

Summary of efficacy analyses comparing subcutaneous and intravenous administration of bortezomib

a p-value for the non-inferiority hypothesis, according to which subcutaneous administration maintains at least 60% of the response rate of intravenous administration.

b 222 subjects were enrolled in the study; 221 subjects received bortezomib treatment.

c Hazard ratio estimation is based on a Cox model adjusted for stratification factors: ISS stage and number of prior lines.

d Log-rank test adjusted for stratification factors: ISS stage and number of prior lines.

e Median duration of follow-up is 11.8 months.

Combination therapy with bortezomib and pegylated liposomal doxorubicin (study DOXIL-MMY-3001)

A randomized, open-label, multicenter, parallel-group, phase III study was conducted in 646 patients comparing the safety and efficacy of bortezomib in combination with pegylated liposomal doxorubicin versus bortezomib monotherapy in patients with multiple myeloma who had received at least one prior therapy and had not progressed during anthracycline-based therapy. The primary efficacy endpoint was improvement in time to progression, while secondary efficacy endpoints included OS and ORR (CR + PR), using criteria from the European Group for Blood and Marrow Transplantation (EBMT).

An interim analysis, as specified by the protocol (based on 249 events of improved progression-free survival), triggered early study termination for efficacy. This interim analysis demonstrated a 45% reduction in the risk of progression (95% CI 29–57%; p < 0.0001) for patients receiving combination therapy with bortezomib and pegylated liposomal doxorubicin. Median time to progression was 6.5 months for patients receiving bortezomib monotherapy compared to 9.3 months for those receiving combination therapy with bortezomib and pegylated liposomal doxorubicin. These results, although not final, met the protocol-defined criteria for the final analysis.

The final OS analysis, performed after a median follow-up of 8.6 years, showed no significant difference in OS between the two treatment groups. Median OS was 30.8 months (95% CI 25.2–36.5 months) for patients receiving bortezomib monotherapy and 33.0 months (95% CI 28.9–37.1 months) for those receiving combination therapy with bortezomib and pegylated liposomal doxorubicin.

Combination therapy with bortezomib and dexamethasone

In the absence of any direct comparison between bortezomib and bortezomib in combination with dexamethasone in patients with relapsed multiple myeloma, a statistical matched-pair analysis was conducted to compare outcomes from the non-randomized bortezomib plus dexamethasone group (open-label phase II study MMY-2045) with results from the bortezomib monotherapy groups in various phase III randomized trials (M34101-039 [APEX] and DOXIL MMY-3001) for the same indication.

Matched-pair analysis is a statistical method in which patients in the treatment group (e.g., bortezomib plus dexamethasone) are individually matched with patients in the comparator group (e.g., bortezomib) based on confounding factors. This minimizes the impact of observed factors when assessing treatment effects using non-randomized data.

A total of 127 matched patient pairs were identified. The analysis demonstrated improved ORR (CR + PR) (odds ratio 3.769; 95% CI 2.045–6.947; p < 0.001), PFS (hazard ratio 0.511; 95% CI 0.309–0.845; p = 0.008), and time to progression (hazard ratio 0.385; 95% CI 0.212–0.698; p = 0.001) for bortezomib in combination with dexamethasone compared to bortezomib monotherapy.

Limited information is available on re-treatment with bortezomib in relapsed multiple myeloma.

The phase II MMY-2036 (RETRIEVE) study, an open single-group trial, was conducted to evaluate the efficacy and safety of re-treatment with bortezomib.

A total of 130 patients (aged ≥ 18 years) with multiple myeloma who had previously achieved at least a partial response to a bortezomib-containing regimen were re-treated after disease progression. At least 6 months after prior bortezomib therapy, bortezomib was restarted at the last tolerated dose of 1.3 mg/m² (n = 93) or ≤ 1.0 mg/m² (n = 37), administered on days 1, 4, 8, and 11 of every 3-week cycle for up to eight cycles, either as monotherapy or in combination with dexamethasone according to standard of care. Dexamethasone was administered in combination with bortezomib to 83 patients in cycle 1, and an additional 11 patients received dexamethasone during subsequent re-treatment cycles.

The primary endpoint was best confirmed response to re-treatment according to EBMT criteria. The overall best response (CR + PR) to re-treatment in the 130 patients was 38.5% (95% CI 30.1; 47.4).

Clinical efficacy in previously untreated mantle cell lymphoma (MCL)

Study LYM-3002 was a randomized, open-label, phase III trial comparing the efficacy and safety of bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone (BzR-CAP; n = 243) versus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP; n = 244) in adult patients with previously untreated mantle cell lymphoma (stage II, III, or IV). Patients in the BzR-CAP treatment group received bortezomib (1.3 mg/m² on days 1, 4, 8, and 11, rest period days 12–21), rituximab 375 mg/m² IV on day 1; cyclophosphamide 750 mg/m² IV on day 1; doxorubicin 50 mg/m² IV on day 1; and prednisolone 100 mg/m² orally from day 1 to day 5 of the 21-day bortezomib treatment cycle. Patients who responded, with response first documented at cycle 6, received two additional cycles of therapy.

The primary efficacy endpoint was progression-free survival assessed by an independent review committee (IRC). Secondary endpoints included time to progression (TTP), time to next anti-lymphoma therapy (TNT), treatment-free interval (TFI), overall response rate (ORR), complete response (CR/CRu), overall survival (OS), and duration of response.

Demographic and baseline disease characteristics were generally well balanced between the two treatment groups: median patient age was 66 years, 74% were male, 66% were Caucasian, 32% were Asian, 69% of patients had positive bone marrow aspirate and/or biopsy for mantle cell lymphoma, 54% had International Prognostic Index (IPI) ≥ 3, and 76% had stage IV disease. Treatment duration (median = 17 weeks) and duration of follow-up (median = 40 months) were comparable in both treatment groups. Patients received a median of six cycles in both treatment arms; 14% of patients in the BzR-CAP group and 17% in the R-CHOP group received two additional cycles. The majority of patients completed treatment in both groups: 80% in the BzR-CAP group and 82% in the R-CHOP group. Efficacy results are presented in Table 6.

Table 6

Efficacy results from study LYM-3002

a Based on assessment by the Independent Review Committee (IRC) (radiological data only).

b Risk ratio estimation is based on a Cox model stratified by IPI risk and disease stage. A risk ratio < 1 indicates benefit for BzR-CAP.

c Based on Kaplan-Meier product-limit estimates.

d Based on the log-rank test, stratified by IPI risk and disease stage.

e The Mantel-Haenszel estimate of the overall odds ratio for stratified tables was used, with IPI risk and disease stage as stratification factors. Odds ratio (OR) > 1 indicates benefit for BzR-CAP.

f Includes all CR + CRu by IRC, bone marrow, and LDH.

g P-value from the Cochran-Mantel-Haenszel chi-square test, stratified by IPI risk and disease stage.

h Including all radiological CR + CRu + PR by IRC, regardless of bone marrow and LDH confirmation.

CR = complete response; CRu = complete response unconfirmed; PR = partial response; CI = confidence interval;
HR = hazard ratio; OR = odds ratio; ITT = intention-to-treat population.

Median PFS by investigator assessment was 30.7 months in the BzR-CAP group and 16.1 months in the R-CHOP group (hazard ratio [HR] = 0.51; p < 0.001). A statistically significant benefit (p < 0.001) in favor of the BzR-CAP treatment group compared to the R-CHOP group was observed for time to progression (median 30.5 vs. 16.1 months), TNT (median 44.5 vs. 24.8 months), and TFI (median 40.6 vs. 20.5 months). Median duration of complete response was 42.1 months in the BzR-CAP group compared to 18 months in the R-CHOP group. Duration of overall response was 21.4 months longer in the BzR-CAP group (median 36.5 months vs. 15.1 months in the R-CHOP group). A final overall survival analysis was conducted after a median follow-up of 82 months. Median OS was 90.7 months in the BzR-CAP group compared to 55.7 months in the R-CHOP group (HR = 0.66; p = 0.001). The observed final median difference in OS between the two treatment groups was 35 months.

Patients with previously treated immunoglobulin light chain (AL) amyloidosis

An open-label, non-randomized Phase I/II study was conducted to evaluate the safety and efficacy of bortezomib in patients with previously treated AL amyloidosis. No new safety concerns were identified during the study, including no exacerbation of organ-target involvement (heart, kidneys, and liver). In an efficacy analysis, a response rate of 67.3% (including a CR rate of 28.6%) was reported based on hematologic response (M-protein) in 49 evaluable patients who received the maximum tolerated doses of 1.6 mg/m² weekly and 1.3 mg/m² twice weekly. The overall one-year survival rate in these patients was 88.1%.

Paediatric population

The European Medicines Agency has waived the obligation to submit results of bortezomib studies in all subsets of the paediatric population for multiple myeloma and mantle cell lymphoma (see section "Posology and method of administration" for information on use in children).

A Phase II study of activity, safety, and pharmacokinetics conducted by the Children's Oncology Group evaluated the efficacy of adding bortezomib to re-induction chemotherapy in children and young patients with lymphoid malignancies (pre-B-cell acute lymphoblastic leukemia [ALL], T-cell lymphoblastic leukemia, and T-cell lymphoblastic lymphoma [LL]). An effective re-induction multi-agent chemotherapy regimen was administered in 3 blocks. The medicinal product BORTEXA SAN was administered only in blocks 1 and 2 to avoid potential overlapping toxicity with agents administered concurrently in block 3.

Complete response (CR) was assessed at the end of block 1. In patients with B-ALL relapsing within 18 months of diagnosis (n = 27), the CR rate was 67% (95% CI 46; 84); 4-month event-free survival was 44% (95% CI 26; 62). In patients with B-ALL relapsing 18–36 months after diagnosis (n = 33), the complete remission rate was 79% (95% CI 61; 91), and 4-month event-free survival was 73% (95% CI 54; 85). The CR rate in patients with first relapse of T-cell ALL (n = 22) was 68% (95% CI 45; 86), and 4-month event-free survival was 67% (95% CI 42; 83). The reported efficacy data are considered inconclusive (see section "Posology and method of administration").

A total of 140 patients with ALL or LL were enrolled and assessed for safety; the median age was 10 years (range 1 to 26). No new safety concerns were observed when BORTEXA SAN was added to standard pediatric pre-B-cell ALL chemotherapy. The following adverse reactions (grade ≥ 3) occurred more frequently in the regimen including BORTEXA SAN compared to a historical control study using the backbone regimen alone: in block 1, peripheral sensory neuropathy (3% vs. 0%), intestinal obstruction (2.1% vs. 0%), and hypoxia (8% vs. 2%). In this study, there was no information on the potential outcomes or rate of resolution of peripheral neuropathy. Increases were also observed for infections with neutropenia ≥ grade 3 (24% vs. 19% in block 1 and 22% vs. 11% in block 2), elevated ALT (17% vs. 8% in block 2), hypokalemia (18% vs. 11% in block 2, 6% in block 1 and 21% vs. 12% in block 2), and hyponatremia (12% vs. 5% in block 1 and 4% vs. 0% in block 2).

Pharmacokinetics

Absorption

After intravenous bolus administration of doses of 1.0 and 1.3 mg/m² in 11 patients with multiple myeloma and creatinine clearance above 50 mL/min, the mean peak plasma concentration of the first dose of bortezomib was 57 and 112 ng/mL, respectively. With subsequent doses, mean peak 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 in patients with multiple myeloma, the total systemic exposure following repeated doses (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% CI of 80.18–122.80%.

Distribution

The mean volume of distribution (Vd) of bortezomib ranged from 1659 to 3294 liters following single or multiple doses of 1.0 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 in vitro, plasma protein binding was 83%. The fraction of bortezomib bound to plasma proteins was independent of concentration.

Metabolism

In vitro, bortezomib is primarily metabolized by cytochrome P450 enzymes 3A4, 2C19, and 1A2. The main metabolic pathway involves deboronation to two metabolites, which are subsequently hydroxylated to other metabolites. The deboronated bortezomib metabolites are inactive as 26S proteasome inhibitors.

Elimination

The mean half-life (T1/2) of bortezomib after multiple dosing ranges from 40 to 193 hours. Bortezomib is cleared more rapidly after the first dose compared to subsequent doses. Mean total clearance was 102 and 112 L/h after the first dose of 1.0 and 1.3 mg/m², respectively, and ranged from 15 to 32 L/h and 18 to 32 L/h after subsequent doses of 1.0 and 1.3 mg/m², respectively.

Special patient populations

Hepatic impairment. The effect of hepatic impairment on the pharmacokinetics of bortezomib was evaluated in a Phase I study during the first treatment cycle involving 61 patients, primarily with solid tumors and varying degrees of hepatic impairment; 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 and severe hepatic impairment. Dose adjustment and careful monitoring during treatment are recommended for these patients (see section "Posology and method of administration").

Renal impairment. Pharmacokinetic studies were conducted in patients with varying renal function, categorized by creatinine clearance (CrCL) as follows: normal (CrCL ≥ 60 mL/min/1.73m², n = 12), mild impairment (CrCL = 40–59 mL/min/1.73m², n = 10), moderate impairment (CrCL = 20–39 mL/min/1.73m², n = 9), and severe impairment (CrCL < 20 mL/min/1.73m², n = 3). Patients on dialysis who received bortezomib after dialysis were also included (n = 8). Patients received intravenous bortezomib doses of 0.7–1.3 mg/m² twice weekly. Bortezomib exposure (dose-normalized AUC and Cmax) was comparable across all groups (see section "Posology and method of administration").

Age. Pharmacokinetic parameters of bortezomib were evaluated in 104 pediatric patients (2–16 years) with acute lymphoblastic leukemia or acute myeloid leukemia receiving 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, volume of distribution at steady state was 834 (39%) L/m², and t½ 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.

Non-clinical safety data

Bortezomib showed clastogenic activity (structural chromosomal aberrations) in an in vitro chromosomal aberration assay using Chinese hamster ovary (CHO) cells at low concentrations of 3.125 µg/mL, the lowest concentration tested. Bortezomib did not show genotoxicity in in vitro mutagenicity testing (Ames test) or in an in vivo mouse micronucleus assay.

Developmental toxicity studies in rats and rabbits demonstrated embryofetal lethality at doses toxic to the mother but did not show direct embryofetal toxicity at doses below those causing maternal toxicity. Fertility studies were not conducted, but evaluation of reproductive tissues was performed in general toxicity studies. Degenerative effects in both testes and ovaries were observed in a 6-month rat study. Therefore, bortezomib may potentially affect male or female fertility. Peri- and postnatal developmental studies were not conducted.

In multi-cycle general toxicity studies in rats and monkeys, the main target organs were the gastrointestinal tract, leading to vomiting and/or diarrhea; hematopoietic and lymphatic tissues, resulting in peripheral cytopenia, lymphoid tissue atrophy, and hypocellularity of hematopoietic bone marrow; peripheral neuropathy (observed in monkeys, mice, and dogs) involving sensory nerve axons; and mild kidney changes. All these target organs showed partial or complete recovery after treatment cessation.

Based on animal studies, bortezomib penetration across the blood-brain barrier is limited, if any, and its relevance to human use is unknown.

Pharmacological safety studies for the cardiovascular system in monkeys and dogs showed that intravenous doses approximately two to three times higher than the recommended clinical dose (based on mg/m²) were associated with tachycardia, reduced contractility, arterial hypotension, and fatal outcomes. In dogs, reduced cardiac contractility and arterial hypotension responded to acute intervention with positive inotropic or pressor agents. Additionally, a slight increase in the corrected QT interval was observed in dog studies.

Clinical Characteristics

Indications

Treatment of relapsed multiple myeloma as monotherapy or in combination with pegylated liposomal doxorubicin or dexamethasone in adult patients who have received at least one prior therapy and stem cell transplantation, or who are not candidates for stem cell transplantation.

Treatment of multiple myeloma in combination with melphalan and prednisone in adult patients who have not received prior therapy and who are not candidates for high-dose chemotherapy with stem cell transplantation.

Treatment of multiple myeloma in combination with dexamethasone or dexamethasone and thalidomide in adult patients who have not received prior therapy and who are candidates for high-dose chemotherapy with stem cell transplantation (induction therapy).

Treatment of mantle cell lymphoma in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone in adult patients who have not received prior therapy and who are not candidates for 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 using the medicinal product BORTEXA SAN in combination with other medicinal products, refer to the instructions for medical use of these medicinal products for additional contraindications.

Special precautions

General precautions

BORTEXA SAN is a cytotoxic agent; therefore, caution should be exercised during its reconstitution and administration. It is recommended to wear gloves and protective clothing to prevent skin contact.

Aseptic techniques must be strictly observed when handling BORTEXA SAN, as the product contains no preservatives.

Fatal cases have been reported following accidental intrathecal administration of bortezomib. BORTEXA SAN is intended for subcutaneous administration and, after reconstitution, for intravenous administration. BORTEZOMIB MUST NOT BE ADMINISTERED INTRATHECALLY.

Instructions for preparation and administration

Preparation of BORTEXA SAN solution must be performed only by qualified healthcare personnel.

Intravenous administration

Each vial of BORTEXA SAN should be carefully reconstituted with 0.9% sodium chloride injection solution for intravenous injection using a syringe of appropriate size without removing the vial stopper. After reconstitution, each milliliter of solution contains 1 mg of bortezomib.

Each vial contains an additional 0.1 mL overfill. Thus, each 1.4 mL vial contains 3.75 mg of bortezomib.

Each 1.4 mL vial should be reconstituted with 2.2 mL of 0.9% sodium chloride injection solution.

The reconstituted solution is a clear, colorless liquid. The solution should be visually inspected for particulate matter and discoloration prior to administration. If discoloration or particulate matter is observed, the reconstituted solution must be discarded.

Subcutaneous injection

Each vial of BORTEXA SAN is ready for use for subcutaneous injection. Each milliliter of solution contains 2.5 mg of bortezomib. The solution is a clear, colorless liquid. It should be visually inspected for solid particles and discoloration before administration. If discoloration or solid particles are observed, the solution must be discarded.

Disposal

BORTEXA SAN is intended for single use only. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Interaction with other medicinal products and other forms of interaction

In vitro studies have demonstrated that bortezomib is a weak inhibitor of cytochrome P450 isoenzymes 1A2, 2C9, 2C19, 2D6, and 3A4. Since CYP2D6 contributes minimally (7%) to bortezomib metabolism, changes in overall drug disposition are not expected in poor metabolizers of this enzyme.

Drug interaction studies assessing the effect of ketoconazole, a potent CYP3A4 inhibitor, on the pharmacokinetics of bortezomib (after intravenous administration) demonstrated an average increase in bortezomib AUC by 35% (90% CI 1.032–1.772) 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 and ritonavir.

A study evaluating the effect of omeprazole, a potent CYP2C19 inhibitor, on the pharmacokinetics of bortezomib (after intravenous administration) in 17 patients did not demonstrate a significant effect on bortezomib pharmacokinetics.

A study investigating the effect of rifampicin, a potent CYP3A4 inducer, on the pharmacokinetics of bortezomib (after intravenous administration) in 6 patients showed an average reduction in bortezomib AUC by 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 the efficacy of bortezomib may be reduced.

A drug interaction study assessing the effect of dexamethasone, a weak CYP3A4 inducer, on the pharmacokinetics of bortezomib (intravenous administration) in 7 patients did not reveal a clinically significant effect on bortezomib pharmacokinetics.

A drug interaction study involving 21 patients evaluating the effect of melphalan and prednisone on the pharmacokinetics of bortezomib (after intravenous administration) demonstrated 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 during treatment with BORTEXA SAN.

Special Warnings and Precautions for Use

If BORTEXA SAN is used in combination with other medicinal products, the instructions for medical use of these medicinal products should be consulted before initiating treatment. When thalidomide is used, particular attention should be paid to pregnancy diagnosis and contraceptive measures (see section "Use during pregnancy or breastfeeding").

Intrathecal administration

Fatal cases have been reported due to accidental intrathecal administration of bortezomib. BORTEXA SAN must be administered only intravenously or subcutaneously. BORTEZOMIB MUST NOT BE ADMINISTERED INTRATHECALLY.

Gastrointestinal toxicity

Treatment with bortezomib may very commonly cause gastrointestinal toxicity, including nausea, diarrhea, constipation, and vomiting. Cases of intestinal obstruction (reported with an incidence classified as uncommon, see section "Adverse reactions") have been reported; therefore, patients with constipation should be under medical supervision.

Hematological toxicity

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, one of the most common hematological toxicities was reversible thrombocytopenia. Platelet counts were typically at their lowest on day 11 of each bortezomib treatment cycle and returned to baseline levels by 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 trials of bortezomib monotherapy in multiple myeloma patients and 50% in trials in mantle cell lymphoma patients. In patients with progressive myeloma, the severity of thrombocytopenia was related to pre-treatment platelet count: in patients with baseline platelet counts < 75,000/µL, 90% of 21 patients had platelet counts ≤ 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 (study LYM-3002), a higher incidence (56.7% vs. 5.8%) of grade ≥ III thrombocytopenia was observed in the group receiving bortezomib (BzR-CAP) compared to the group receiving R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). The two treatment groups were similar regarding the overall incidence of bleeding of all grades (6.3% in the BzR-CAP group and 5.0% in the R-CHOP group), as well as cases of grade III or higher bleeding (BzR-CAP: 4 patients [1.7%]; R-CHOP: 3 patients [1.2%]). In the BzR-CAP group, 22.5% of patients received platelet transfusions compared to 2.9% in the R-CHOP group.

Cases of gastrointestinal and intracranial hemorrhage associated with bortezomib use have been reported. Therefore, platelet counts should be monitored before each dose of BORTEXA SAN.

Treatment with BORTEXA SAN 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 (see section "Special warnings and precautions for use"). The benefit-risk ratio of continuing BORTEXA SAN should be carefully evaluated, especially in cases of moderate or severe thrombocytopenia and in the presence of bleeding risk factors.

Complete blood counts, including white blood cell differential and platelet counts, should be frequently monitored during treatment with BORTEXA SAN. Platelet transfusion should be considered if clinically indicated (see section "Dosage and administration").

In patients with mantle cell lymphoma, episodes of reversible neutropenia between treatment cycles have been observed; cumulative neutropenia was not observed. Neutrophil counts were typically at their lowest on day 11 of each bortezomib treatment cycle and returned to baseline levels by the start of the next cycle. In the clinical trial of bortezomib in mantle cell lymphoma (LYM-3002), 78% of patients in the BzR-CAP treatment group and 61% in the R-CHOP group received granulocyte colony-stimulating factor. Since patients with neutropenia are at increased risk of developing infections, they should be monitored for signs of infection and appropriate therapeutic measures taken. The use of granulocyte colony-stimulating factor should be considered for managing hematological toxicity according to standard local treatment protocols. If initiation of a new treatment cycle is delayed multiple times, prophylactic use of granulocyte colony-stimulating factor should be considered (see section "Dosage and administration").

Reactivation of Herpes zoster virus

Antiviral prophylaxis should be considered for patients receiving bortezomib. In phase III trials in patients with previously 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 (study LYM-3002), the incidence of shingles was 6.7% in the BzR-CAP treatment group and 1.2% in the R-CHOP treatment group (see section "Adverse reactions").

Reactivation and infection with hepatitis B virus (HBV)

Before initiating treatment with rituximab in combination with bortezomib, HBV testing should be performed in patients with risk factors. HBV carriers and patients with a history of hepatitis B should be closely monitored for clinical and laboratory signs during and after combination therapy with rituximab and bortezomib. Antiviral prophylaxis should be considered. For more detailed information on rituximab use, refer to the product information for this medicinal product.

Progressive multifocal leukoencephalopathy (PML)

Very rare cases of John Cunningham virus infection causing PML with fatal outcome have been reported in patients treated with bortezomib. Patients diagnosed with PML had received immunosuppressive therapy either prior to or concurrently with bortezomib. Most cases of PML 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, the patient should be referred to a physician experienced in managing PML and appropriate diagnostic measures taken. If PML is confirmed, bortezomib treatment should be discontinued.

Peripheral neuropathy

Treatment with bortezomib is very commonly associated with peripheral neuropathy, predominantly sensory. However, cases of severe motor neuropathy, with or without sensory peripheral neuropathy, have been reported. Typically, the incidence of peripheral neuropathy peaks during the fifth treatment cycle with bortezomib.

Careful monitoring of patients for neuropathic symptoms such as burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain, or weakness is recommended.

If new symptoms occur or peripheral neuropathy worsens, patients should undergo a neurological examination; dose adjustment, change in administration schedule, or switching to subcutaneous administration may be necessary (see section "Dosage and administration"). Neuropathy should be managed with supportive measures and other treatments.

Early and regular monitoring for treatment-induced neuropathy and neurological examination are required in patients receiving bortezomib in combination with medicinal products associated with neuropathy (such as thalidomide); dose reduction or discontinuation of treatment should be considered.

In addition to peripheral neuropathy, autonomic neuropathy may contribute to certain adverse reactions such as 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 no prior history of seizures or epilepsy. Particular caution is required when treating patients with any risk factors for seizures.

Arterial hypotension

Bortezomib therapy is frequently associated with postural/orthostatic hypotension. In most cases, it is mild to moderate in severity and occurs throughout the treatment period. Patients who developed orthostatic hypotension during bortezomib (intravenous) administration did not have symptoms of orthostatic hypotension prior to treatment. Most patients required treatment for orthostatic hypotension, and a smaller number experienced episodes of 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 caused by bortezomib or bortezomib may exacerbate underlying conditions, including diabetic or amyloid neuropathy. Caution is advised when treating patients with a history of syncope, those taking antihypertensive medications, and those with dehydration due to diarrhea or vomiting. In case of orthostatic hypotension, adjustment of antihypertensive drug doses may be required; rehydration, mineralocorticosteroids, and/or sympathomimetics are recommended. If necessary, antihypertensive drug doses should be reduced. Patients should be instructed to consult a physician if they experience dizziness, pre-syncope, or syncope.

Reversible posterior leukoencephalopathy syndrome (PRES)

Cases of PRES have been reported in patients receiving bortezomib. PRES is a rare, often reversible neurological disorder that can develop rapidly. Symptoms may include seizures, arterial hypertension, headache, lethargy, confusion, blindness, visual disturbances, and other neurological impairments. Brain imaging, preferably magnetic resonance imaging (MRI), is required to confirm the diagnosis. Bortezomib treatment should be discontinued if PRES occurs.

Heart failure

Cases of development or worsening of pre-existing congestive heart failure (CHF) 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 for cardiac disease or pre-existing cardiac conditions should be closely monitored.

ECG monitoring

Isolated cases of QT interval prolongation have been observed in clinical trials; a causal relationship has not been established.

Lung function disorders

Rare cases of acute diffuse infiltrative lung disorders of unknown etiology, such as pneumonitis, interstitial pneumonia, pulmonary infiltration, and acute respiratory distress syndrome (ARDS), have been observed in patients receiving bortezomib (see section "Adverse reactions"). Some of these cases were fatal. Radiological examination is recommended before initiating treatment to establish baseline lung status and for comparison in case of potential treatment-related lung function impairment.

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 treatment should be carefully evaluated.

In a clinical trial, two out of two patients receiving high-dose cytarabine (2 g/m²/day) as continuous 24-hour infusion with daunorubicin and bortezomib for relapsed acute myeloid leukemia died from ARDS at the beginning of the treatment course, leading to termination of the study. Therefore, this specific regimen of concomitant use with high-dose cytarabine (2 g/m²/day) as continuous 24-hour infusion is not recommended.

Kidney function disorders

Renal function impairment is common in patients with multiple myeloma. Close monitoring of such patients is recommended (see sections "Pharmacological properties" and "Dosage and administration").

Liver function disorders

Bortezomib is metabolized by hepatic enzymes. Bortezomib concentrations may increase in patients with moderate to severe hepatic impairment; such patients should be treated with reduced doses and closely monitored for signs of toxicity (see sections "Pharmacological properties" and "Dosage and administration").

Hepatic reactions

Rare cases of hepatic failure have been reported in patients receiving bortezomib in combination with other drugs and in patients with serious comorbid conditions. Cases of elevated liver enzymes, hyperbilirubinemia, and hepatitis, which may be reversible after discontinuation of bortezomib, have also been reported (see section "Adverse reactions").

Tumor lysis syndrome

Since bortezomib is a cytotoxic agent capable of rapidly killing tumor plasma cells and mantle cell lymphoma 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 implementation of necessary preventive measures are recommended.

Warnings regarding concomitant use of other medicinal products

Patients should be closely monitored by a physician when bortezomib is combined with strong CYP3A4 inhibitors. Caution should be exercised when combining bortezomib with CYP3A4 or CYP2C19 substrates (see section "Interaction with other medicinal products and other forms of interaction").

Liver function should be corrected prior to initiating treatment in case of hepatic impairment, and caution should be exercised in patients receiving oral hypoglycemic agents (see section "Interaction with other medicinal products and other forms of interaction").

Potentially immune complex-mediated reactions

Immune complex-mediated reactions, such as serum sickness, polyarthritis with rash, and proliferative glomerulonephritis, have been reported uncommonly. Bortezomib should be discontinued in case of serious reactions.

Use during pregnancy or breastfeeding

Contraception in women and men

Due to the genotoxic potential of bortezomib, women of reproductive potential must use effective contraception and avoid pregnancy during treatment with BORTEXA SAN and for 8 months after completion of treatment. Male patients should use effective contraception, and physicians should advise them not to plan fatherhood during treatment with BORTEXA SAN and for 5 months after completion of treatment.

Pregnancy

There are no clinical data on the use of bortezomib in pregnant women. The teratogenic potential of bortezomib has not been fully investigated.

In preclinical studies, bortezomib at the maximum tolerated doses did not affect embryonic development in rats and rabbits during organogenesis. Pre- and postnatal developmental studies in animals have not been conducted (see section "Pharmacological properties"). Bortezomib is not recommended during pregnancy except in cases where the woman's clinical condition requires treatment with bortezomib. If bortezomib is used during pregnancy or if pregnancy occurs during treatment with this medicinal product, the patient should be informed of the potential harmful effects on the fetus.

Thalidomide is a medicinal product with known teratogenic effects in humans, causing severe, life-threatening congenital malformations. Thalidomide is contraindicated during pregnancy and in women of reproductive potential. Patients receiving bortezomib in combination with thalidomide must comply with pregnancy prevention requirements. For additional information, refer to the thalidomide product information.

Breastfeeding period

It is unknown whether bortezomib is excreted in human milk, but to prevent the occurrence of severe adverse effects in the infant, women are advised not to breastfeed during treatment with BORTEXA SAN.

Fertility

Studies on the effect of bortezomib on fertility have not been conducted (see section "Pharmacological properties").

Effects on ability to drive and use machines

Bortezomib has a moderate influence on the ability to drive and use machines. Treatment with bortezomib 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 (see section "Adverse reactions").

Dosage and Administration

Treatment with bortezomib should be initiated under the supervision of a qualified physician experienced in the treatment of oncology patients, although the medicinal product BORTEKSA SAN 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 (see section "Special Instructions").

Relapsed multiple myeloma (patients who have received at least one prior therapy)

Monotherapy

The recommended dose of BORTEKSA SAN for adults is 1.3 mg/m² body surface area administered intravenously or subcutaneously twice weekly for 2 weeks (on days 1, 4, 8, and 11) within a 21-day treatment cycle. This three-week period constitutes one treatment cycle. After achieving a complete clinical response, administration of two additional treatment cycles is recommended. Patients achieving a partial response but not a complete remission should continue treatment with BORTEKSA SAN for up to eight cycles. At least 72 hours must elapse between consecutive doses.

Dosage adjustment and re-initiation recommendations for bortezomib as monotherapy

If any non-hematological toxicity of grade III or hematological toxicity of grade IV develops, except for neuropathies as described below (see also section "Special Instructions"), administration of BORTEKSA SAN must be withheld. After resolution of toxic symptoms, treatment with BORTEKSA SAN 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 toxic symptoms do not resolve or recur during treatment with the reduced dose, discontinuation of BORTEKSA SAN should be considered, unless the benefit outweighs the risk.

Neuropathic pain and/or peripheral neuropathy

The dose should be adjusted according to Table 7 in case of development of neuropathic pain and/or peripheral neuropathy (see also section "Special Instructions"). BORTEKSA SAN should be administered to patients with a history of severe neuropathy only after careful assessment of benefit-risk ratio.

Table 7

Recommended* dose modification for bortezomib-induced neuropathy

* Based on dose modifications observed in Phase II and Phase III multiple myeloma studies and in the post-marketing period. Classification according to NCI CTCAE v 4.0 general toxicity criteria.

** Usual productive activities include cooking, shopping, and using the telephone.

*** Usual self-care activities include bathing, dressing/undressing, eating, using the toilet, taking medication, and being out of bed.

Combination therapy with pegylated liposomal doxorubicin

BORTEZOMIB SAN must be administered by intravenous or subcutaneous injection at the recommended dose of 1.3 mg/m² body surface area twice weekly for two weeks on days 1, 4, 8, and 11 of a 21-day treatment cycle. This three-week period constitutes one treatment cycle. At least 72 hours must elapse between consecutive doses of BORTEZOMIB SAN.

Pegylated liposomal doxorubicin should be administered at a dose of 30 mg/m² on day 4 of the BORTEZOMIB SAN treatment cycle via one-hour intravenous infusion after administration of BORTEZOMIB SAN.

This combination therapy may be continued for up to eight cycles, provided the disease does not progress and patients tolerate treatment well. Patients who achieve a complete clinical response may continue treatment for at least two additional cycles after achieving complete response, even if this requires more than eight treatment cycles. Patients whose paraprotein levels continue to decline after eight cycles may also continue treatment as long as treatment is well tolerated and a response is observed. For use of pegylated liposomal doxorubicin, refer also to the instructions for medical use of this medicinal product.

Combination therapy with dexamethasone

BORTEZOMIB SAN must be administered by intravenous or subcutaneous injection at the recommended dose of 1.3 mg/m² body surface area twice weekly for two weeks on days 1, 4, 8, and 11 of a 21-day treatment cycle. This three-week period constitutes one treatment cycle. At least 72 hours must elapse between consecutive doses of BORTEZOMIB SAN.

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 SAN 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. See also the instructions for medical use of dexamethasone.

Refer to the dose modification recommendations for BORTEZOMIB SAN monotherapy provided above.

Untreated multiple myeloma in patients not eligible for hematopoietic stem cell transplantation

Combination therapy with melphalan and prednisone

BORTEZOMIB SAN should be administered intravenously or subcutaneously in combination with oral melphalan and oral prednisone as shown in Table 8. A six-week period is considered one treatment cycle.

In cycles 1–4, BORTEZOMIB SAN is administered twice weekly (on days 1, 4, 8, 11, 22, 25, 29, and 32).

In cycles 5–9, BORTEZOMIB SAN is administered once weekly (on days 1, 8, 22, and 29). At least 72 hours must elapse between consecutive doses of BORTEZOMIB SAN.

Melphalan and prednisone should be administered orally on days 1, 2, 3, and 4 of the first week of each cycle. A total of nine treatment cycles of this combination therapy are administered.

Table 8

Recommended dosing regimen of BORTEZOMIB SAN in combination with melphalan and prednisone

BORTEKSA SAN 2 times a week (1–4 cycles)
Week	1					2		3	4		5		6
BORTEKSA SAN (1.3 mg/m²)	1 day		--	--	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
BORTEKSA SAN 1 time a week (5–9 cycles)
Week	1					2		3	4		5		6
BORTEKSA SAN (1.3 mg/m²)	1 day	--		--	--	8 day		Break	22 day		29 day		Break
M (9 mg/m²) P (60 mg/m²)	1 day	2 day		3 day	4 day	--		Break	--		--		Break

M — melphalan, P — prednisone.

Dosing adjustment and reinitiation recommendations for combination therapy with melphalan and prednisone

Prior to starting a new treatment cycle:

• platelet count must be ≥ 70×10⁹/L and absolute neutrophil count must be ≥ 1.0×10⁹/L;
• non-hematological toxicity must have resolved to Grade 1 or baseline levels.

Table 9

Dose adjustment during subsequent treatment cycles with BORTEKSA SAN

in combination with melphalan and prednisone

Toxicity	Dose modification or treatment interruption
Hematologic toxicity during cycle: if prolonged grade IV neutropenia or thrombocytopenia, or thrombocytopenia with bleeding occurred in the previous cycle	Consider reducing melphalan dose by 25% in the next cycle
if platelet count ≤ 30×109/L or absolute neutrophil count ≤ 0.75×109/L on the day of BORTEXA SAN administration (except Day 1)	Delay administration of BORTEXA SAN dose
if multiple doses of BORTEXA SAN are missed during a cycle (≥ 3 doses during twice-weekly administration or ≥ 2 doses during once-weekly administration)	The dose of BORTEXA SAN should be reduced by one level (from 1.3 mg/m2 to 1 mg/m2 or from 1 mg/m2 to 0.7 mg/m2)
Non-hematologic toxicity ≥ Grade III	Administration of BORTEXA SAN should be delayed until symptoms improve to baseline or Grade I severity. Then, BORTEXA SAN may be restarted at a reduced dose by one level (from 1.3 to 1 mg/m2 or from 1 to 0.7 mg/m2). In case of bortezomib-induced neuropathic pain and/or peripheral neuropathy, hold and/or modify the dose of BORTEXA SAN as specified in Table 7.

For melphalan and prednisone, see also 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 medicinal product BORTEZOMIB SAN is administered by intravenous or subcutaneous injection at the recommended dose of 1.3 mg/m² body surface area twice weekly for two weeks on days 1, 4, 8, and 11 of a 21-day treatment cycle. This three-week period constitutes one treatment cycle. At least 72 hours must elapse between consecutive administrations of BORTEZOMIB SAN.

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 SAN treatment cycle.

Administer four treatment cycles of this combination.

Combination therapy with dexamethasone and thalidomide

The medicinal product BORTEZOMIB SAN is administered by intravenous or subcutaneous injection at the recommended dose of 1.3 mg/m² body surface area twice weekly for two weeks on days 1, 4, 8, and 11 of a 28-day treatment cycle. This four-week period constitutes one treatment cycle. At least 72 hours must elapse between consecutive administrations of BORTEZOMIB SAN.

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 SAN 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, and may be further increased to 200 mg daily starting from the second cycle (see Table 10).

Administer four treatment cycles. Patients achieving at least a partial response to treatment are recommended to receive two additional cycles of therapy.

Table 10

Recommended dosing regimen of the medicinal product BORTEZOMIB SAN in combination with dexamethasone and thalidomide for patients with untreated multiple myeloma eligible for hematopoietic stem cell transplantation

BORTEKSA SAN + Dx	Cycles 1–4
	Week	1		2		3
	BORTEKSA SAN (1.3 mg/m²)	Day 1, 4		Day 8, 11		Rest
	Dx (40 mg)	Day 1, 2, 3, 4		Day 8, 9, 10, 11		-
BORTEKSA SAN + Dx + T	Cycle 1
	Week	1	2		3		4
	BORTEKSA SAN (1.3 mg/m²)	Day 1, 4	Day 8, 11		Rest		Rest
	T (50 mg)	Daily	Daily		-		-
	T (100 mg)ᵃ	-	-		Daily		Daily
	Dx (40 mg)	Day 1, 2, 3, 4	Day 8, 9, 10, 11		-		-
	Cycles 2–4ᵇ
	BORTEKSA SAN (1.3 mg/m²)	Day 1, 4	Day 8, 11		Rest		Rest
	T (200 mg)ᵃ	Daily	Daily		Daily		Daily
	Dx (40 mg)	Day 1, 2, 3, 4	Day 8, 9, 10, 11		-		-

Dx – dexamethasone; Th – thalidomide.

a Increase the dose of thalidomide to 100 mg starting from the 3rd week of the first 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 four cycles of treatment may receive up to six cycles of treatment.

Dosing recommendations for patients eligible for transplantation

See dosing adjustment recommendations for BORTEZA SAN used as monotherapy.

If BORTEZA SAN is used in combination with other chemotherapeutic agents, refer to the prescribing information for those agents for dose adjustment recommendations in the event of toxicity.

Untreated mantle cell lymphoma

Combination therapy with rituximab, cyclophosphamide, doxorubicin, and prednisone (VcR-CAP regimen)

The recommended dose of BORTEZA SAN is 1.3 mg/m² body surface area administered intravenously or subcutaneously twice weekly for 2 weeks (Days 1, 4, 8, and 11), followed by a 10-day rest period (Days 12–21). This three-week period constitutes one treatment cycle. Six treatment cycles are recommended. Patients who first demonstrate a response during the 6th treatment cycle are recommended to receive two additional cycles of therapy. At least 72 hours should elapse between consecutive doses of BORTEZA SAN.

Medications administered by intravenous infusion on Day 1 of each three-week treatment cycle with BORTEZA SAN: 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 treatment cycle with BORTEZA SAN.

Dosing 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 (ANC) must be ≥ 1,500 cells/µL;
• Platelet count must be ≥ 75,000 cells/µL in patients with bone marrow infiltration or splenic sequestration;
• Hemoglobin level ≥ 8 g/dL;
• Non-hematological toxicity must have resolved to Grade 1 or baseline levels.

Treatment with bortezomib should be withheld in the event of any non-hematological toxicity ≥ Grade III severity (except neuropathy) related to bortezomib administration, or hematological toxicity ≥ Grade III severity (see also section "Special precautions"). Dose adjustment recommendations are provided in Table 11.

Granulocyte colony-stimulating factors may be used to manage hematological toxicity according to local standard protocols. 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 the management of thrombocytopenia.

Table 11

Dose adjustment during therapy for patients with untreated mantle cell lymphoma

Toxicity	Dose modification or treatment interruption
Hematological toxicity
Grade ≥ III neutropenia with fever, grade IV neutropenia lasting more than 7 days, platelet count ˂ 10,000 cells/μL.	Administration of BORTECSA SAN should be withheld for up to 2 weeks until ANC recovers to ≥ 750 cells/μL and platelet count recovers to ≥ 25,000 cells/μL. If toxicity does not resolve (blood counts do not recover to the values indicated above), BORTECSA SAN should be discontinued. If toxicity resolves (ANC recovers to ≥ 750 cells/μL and platelet count to ≥ 25,000 cells/μL), treatment with BORTECSA SAN may be resumed at a reduced dose level (from 1.3 to 1 mg/m² or from 1 to 0.7 mg/m²).
If platelet count is ˂ 25,000 cells/μL or ANC is ˂ 750 cells/μL on the day of BORTECSA SAN administration (except Day 1 of each treatment cycle).	Delay administration of the BORTECSA SAN dose.
Non-hematological toxicity ≥ Grade III related to BORTECSA SAN administration.	Administration of BORTECSA SAN should be withheld until symptoms improve to Grade II severity or better. Then, treatment 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, hold and/or modify the dose of BORTECSA SAN as specified in Table 7.

If bortezomib is used in combination with other chemotherapeutic agents, also refer to the instructions for use of these medicinal products regarding dose adjustments in the event of toxicity.

Special patient populations

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 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) (see section "Adverse reactions").

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 BORTEXA SAN 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 (see sections "Pharmacological properties. Pharmacokinetics" and "Special precautions for use").

Table 12

Dose modification recommendations for initial doses of BORTEXA SAN in patients with hepatic impairment

Severity of hepatic impairment*	Bilirubin level	AST level	Initial dose adjustment
Mild	≤ 1.0 × ULN	> ULN	Not required
	> 1.0–1.5 × ULN	Any	Not required
Moderate	> 1.5–3 × ULN	Any	Reduce the dose of BORTEC SAN to 0.7 mg/m² in the first treatment cycle. Subsequent dose escalation to 1.0 mg/m² or reduction to 0.5 mg/m² should be based on drug tolerability.
Severe	> 3 × ULN	Any

AST – aspartate aminotransferase; ULN – upper limit of normal.

* Based on the National Cancer Institute (USA) classification of severity grades for hepatic 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 (see section "Pharmacological properties. Pharmacokinetics").

Paediatric population

The safety and efficacy of bortezomib in children under 18 years of age have not been established (see section "Pharmacological properties"). Available data are described in the section "Pharmacological properties", but dosing recommendations cannot be provided.

Method of administration

BORTEZA SAN, solution for injection, 2.5 mg/ml is available for subcutaneous administration and, after dilution, also for intravenous administration.

BORTEZA SAN must not be administered by other routes. Intrathecal administration has resulted in fatal outcomes.

Intravenous

BORTEZA SAN, solution for injection, 2.5 mg/ml, should first be diluted to 1 mg/ml (see section "Special instructions for use"), and after dilution administered as a 3–5 second intravenous bolus injection via a peripheral or central venous catheter. The catheter should then be flushed with 0.9% sodium chloride solution for injection. At least 72 hours should elapse between consecutive doses of BORTEZA SAN.

Subcutaneous

BORTEZA SAN, solution for injection, 2.5 mg/ml, should be administered subcutaneously into the thigh (right or left) or abdomen (right or left side). The solution should be injected subcutaneously at an angle of 45–90°. Injection sites should be rotated for consecutive injections.

If adverse reactions occur at the injection site during subcutaneous administration, the solution of BORTEZA SAN may be administered subcutaneously at a lower concentration (1 mg/ml instead of 2.5 mg/ml) or administered intravenously.

When BORTEZA SAN is used concomitantly with other medicinal products, refer to the instructions for medical use of these products.

Paediatric population

The safety and efficacy of bortezomib in children (under 18 years of age) have not been established.

Overdose

In patients, overdose exceeding the recommended dose by more than two-fold has been associated with acute hypotension and thrombocytopenia resulting in fatal outcome. Preclinical studies on cardiovascular safety are described in the section "Pharmacological properties".

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 (see sections "Special instructions for use" and "Method and dose of administration").

Adverse Reactions

Summary of the safety profile

Serious adverse reactions observed during bortezomib treatment included heart failure, 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 were nausea, diarrhea, constipation, vomiting, asthenia, pyrexia, thrombocytopenia, anemia, neutropenia, peripheral neuropathy (including sensory neuropathy), headache, paraesthesia, decreased appetite, dyspnoea, rash, herpes zoster, and myalgia.

Tabulated list of adverse reactions

Multiple myeloma

The adverse reactions listed in Table 13 were considered by investigators to have at least a possible or probable causal relationship to bortezomib. Data on adverse reactions were obtained from 5476 patients, of whom 3996 received bortezomib at a dose of 1.3 mg/m²; these data are included in Table 13. Overall, bortezomib was administered to 3974 patients for the treatment of multiple myeloma.

Adverse reactions are grouped by system organ class and frequency of occurrence. Frequencies were defined as: very common (>1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), and frequency not known (cannot be estimated from available data). Within each group, adverse reactions are listed in order of decreasing severity. Adverse reactions not observed during clinical trials but reported during the post-marketing period are also included. Table 13 was compiled using MedDRA version 14.1.

Table 13

Adverse reactions in patients with multiple myeloma treated with bortezomib in clinical trials and adverse reactions from post-marketing sources, regardless of indication

Organ systems	Frequency	Adverse reactions
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 meningioencephalitis#, 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	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, unspecified thrombopathy, thrombotic microangiopathy (including thrombotic thrombocytopenic purpura)#, other blood and hematopoietic organ disorders, hemorrhagic diathesis, lymphocytic infiltration
Immune system	Uncommon	Angioedema#, hypersensitivity*
	Rare	Anaphylactic shock, amyloidosis, type III immune complex-mediated reactions
Endocrine system	Uncommon	Cushing's syndrome*, hyperthyroidism*, inappropriate antidiuretic hormone secretion
	Rare	Hypothyroidism
Metabolism and nutrition disorders	Very common	Decreased appetite
	Common	Dehydration, hypokalemia*, hyponatremia*, blood glucose disturbances*, hypocalcemia*, enzyme level disturbances*
	Uncommon	Tumor lysis syndrome, physical development delay*, 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	Very common	Neuropathy*, peripheral sensory neuropathy, dysesthesia*, neuralgia*
	Common	Motor neuropathy*, loss of consciousness (including syncope), dizziness*, dysgeusia*, lethargy, headache*
	Uncommon	Tremor, sensorimotor peripheral neuropathy, dyskinesia*, coordination and balance disturbances*, memory loss (without dementia)*, encephalopathy*, reversible posterior encephalopathy syndrome#, neurotoxicity, seizure disorders*, postherpetic neuralgia, speech disorders*, restless legs syndrome, migraine, sciatica, attention disorders, reflex disturbances*, parosmia
	Rare	Intracranial hemorrhage*, intracerebral hemorrhage (including subarachnoid)*, brain edema, transient ischemic attack, coma, autonomic nervous system 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, salivation, hypotonia, Guillain-Barré syndrome#, demyelinating polyneuropathy #
Eye disorders	Common	Eye edema*, visual disturbances*, conjunctivitis*
	Uncommon	Eye hemorrhages*, eyelid infections*, chalazion#, blepharitis#, eye inflammation*, diplopia, dry eye*, eye irritation*, eye pain, increased lacrimation, eye discharge
	Rare	Corneal disorders*, exophthalmos, retinitis, scotoma, other eye disorders (including eyelid disorders), 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 impairment (up to deafness), ear discomfort*
	Rare	Ear bleeding, 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), ventricular tachycardia of torsades de pointes type (torsades de pointes), unstable angina, heart valve dysfunction*, coronary artery insufficiency, sinus node arrest
Vascular disorders	Common	Arterial hypotension*, orthostatic hypotension, arterial hypertension*
	Uncommon	Cerebrovascular disorder#, deep vein thrombosis*, hemorrhage*, thrombophlebitis (including superficial), vascular collapse (including hypovolemic shock), phlebitis, flushing*, hematoma (including paranephric)*, peripheral circulation disorders*, vasculitis, hyperemia (including ocular)*
	Rare	Peripheral vascular embolism, lymphedema, pallor, erythromelalgia, vascular dilation, vascular discoloration, venous insufficiency
Respiratory, thoracic and mediastinal disorders	Common	Dyspnea*, epistaxis, lower/upper respiratory tract infections*, cough*
	Uncommon	Pulmonary embolism, pleural effusion, pulmonary edema (including acute), pulmonary alveolar hemorrhage#, bronchospasm, chronic obstructive pulmonary disease*, hypoxemia*, airway obstruction worsening*, hypoxia, pleurisy*, hiccups, rhinorrhea, dysphonia, wheezing
	Rare	Respiratory failure, acute respiratory distress syndrome, apnea, pneumothorax, lung atelectasis, pulmonary hypertension, hemoptysis, pulmonary hyperventilation, orthopnea, pneumonitis, respiratory alkalosis, tachypnea, pulmonary fibrosis, bronchial disorders*, hypocapnia*, interstitial lung disease, lung infiltration, throat tightness, throat dryness, 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 pain)*, 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*, gingival bleeding, gastroesophageal reflux disease*, colitis (including Clostridium difficile-induced)*, ischemic colitis#, gastrointestinal inflammation*, dysphagia, irritable bowel syndrome, other gastrointestinal disorders, coated tongue, gastrointestinal motility disorder*, salivary gland disorders*
	Rare	Acute pancreatitis, peritonitis*, tongue swelling*, ascites, esophagitis, cheilitis, fecal incontinence, anal sphincter atony, fecaloma*, gastrointestinal ulcers and perforations*, gingival hyperplasia, megacolon, rectal discharge, blister formation in oropharynx*, lip pain, periodontitis, anal fissure, altered defecation rhythm, proctalgia, abnormal defecation
Hepatobiliary system	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, skin dryness
	Uncommon	Multiform erythema, urticaria, acute febrile neutrophilic dermatosis, toxic skin eruptions, toxic epidermal necrolysis#, Stevens-Johnson syndrome#, dermatitis*, hair disorders*, petechiae, ecchymosis, skin irritation, purpura, skin induration*, psoriasis, hyperhidrosis, night sweats, pressure ulcers#, acne*, blisters*, skin pigmentation disturbances*
	Rare	Skin reactions, Jessner's lymphocytic infiltration, 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, myopathy*, heaviness sensation
	Rare	Rhabdomyolysis, temporomandibular joint dysfunction, fistula, joint effusion, jaw pain, bone disorders, infections and inflammations of musculoskeletal system and connective tissue*, synovial cyst
Renal and urinary system	Common	Renal function abnormalities*
	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*, malaise*
	Uncommon	General physical health disturbances*, 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*, injection site pain*
	Rare	Fatal outcome (including sudden), multiple organ failure, bleeding at administration site*, hernia (including hiatal)*, impaired healing*, inflammation, phlebitis at injection site*, tenderness, ulceration, irritation, non-cardiac substernal pain, catheter insertion site pain, foreign body sensation
Laboratory investigations	Common	Weight loss
	Uncommon	Hyperbilirubinemia*, deviation of protein levels from normal*, weight gain, blood test abnormalities*, increased C-reactive protein level
	Rare	Blood gas abnormalities*, 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	Falls, confusion
	Rare	Transfusion reactions, fractures*, tremor*, facial injury, joint injury*, burns, skin laceration, procedural pain, radiation injuries*
Surgical and medical procedures	Rare	Macrophage activation

* Summary of several MedDRA terms.

Data from post-marketing sources regardless of indication.

Mantle Cell Lymphoma

The safety profile of bortezomib in 240 patients with mantle cell lymphoma who received bortezomib at a dose of 1.3 mg/m² in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (BzR-CAP), and in 242 patients who received vincristine, rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHOP), was generally similar to the safety profile in patients with multiple myeloma; the main differences are described below. Additional adverse reactions observed with bortezomib as part of combination therapy (BzR-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. Treatment with bortezomib in patients with mantle cell lymphoma was associated with a higher (≥5%) incidence of hematologic adverse reactions (neutropenia, thrombocytopenia, leukopenia, anemia, lymphopenia), peripheral sensory neuropathy, arterial hypertension, pyrexia, pneumonia, stomatitis, and hair disorders compared to treatment in patients with multiple myeloma.

Adverse reactions with an incidence ≥1%, occurring at a similar or higher frequency in the BzR-CAP treatment group, which were possibly or probably related to the medicinal products included in the BzR-CAP combination regimen, are listed in Table 14. Also listed are adverse reactions observed in the BzR-CAP treatment group that, in the opinion of investigators, were possibly or probably related to bortezomib, based on experience from studies in patients with multiple myeloma.

Adverse reactions are grouped by system organ class and frequency of occurrence. Frequency was 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 group, adverse reactions are listed in order of decreasing severity.

Table 14 was compiled using MedDRA version 16.

Table 14

Adverse reactions occurring in patients with mantle cell lymphoma who received VcR-CAP regimen in clinical studies

Organ systems	Frequency	Adverse reactions
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	Very common	Thrombocytopenia*, febrile neutropenia, neutropenia*, leukopenia*, anemia*, lymphopenia*
	Uncommon	Pancytopenia*
Immune system	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	Very common	Peripheral sensory neuropathy, dysesthesia*, neuralgia*
	Common	Neuropathy*, motor neuropathy*, loss of consciousness (including syncope), encephalopathy*, sensory-motor peripheral neuropathy, dizziness*, dysgeusia*, autonomic neuropathy
	Uncommon	Autonomic nervous system disorders
Eye disorders	Common	Visual disturbances*
Ear and labyrinth disorders	Common	Dysacusis (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	Arterial hypertension*, arterial hypotension*, orthostatic hypotension
Respiratory system	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 Clostridium difficile-induced)*
Hepatobiliary disorders	Common	Hepatotoxicity (including liver disorders)
	Uncommon	Liver failure
Skin and subcutaneous tissue	Very common	Hair disorders*
	Common	Pruritus*, dermatitis*, rash*
Musculoskeletal system	Common	Muscle spasms*, musculoskeletal pain*, limb pain
Renal and urinary system	Common	Urinary tract infections*
General and administration site conditions	Very common	Pyrexia*, fatigue, asthenia
	Common	Edema (including peripheral), chills, injection site reactions*, general malaise*
Laboratory findings	Common	Hyperbilirubinemia*, abnormal protein levels*, weight loss, weight gain

* Terms MedDRA summarized.

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 137 out of 240 patients (57%) receiving bortezomib as part of combination therapy according to the BzR-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 treatment according to the R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) and in 0.4% of patients (n = 1) receiving bortezomib as part of combination therapy according to the BzR-CAP regimen (rituximab, cyclophosphamide, doxorubicin, and prednisone). The overall incidence of hepatitis B cases was similar in both treatment groups (0.8% in the BzR-CAP group versus 1.2% in the R-CHOP group).

Peripheral neuropathy during combination therapy

Multiple myeloma

Peripheral neuropathy was observed in studies where bortezomib was used as induction therapy in combination with dexamethasone (study IFM-2005-01) and with dexamethasone-thalidomide (study MMY-3010) (see Table 15).

Table 15

Incidence of peripheral neuropathy (PN) during induction therapy

by toxicity grade and need for treatment interruption due to PN

Peripheral neuropathy parameters	IFM-2005-01		MMY-3010
	VDDx (N = 239)	BzDx (N = 239)	TDx (N = 126)	BzTDx (N = 130)
Incidence of PN (%)
All grades of PN ≥ Grade II PN ≥ Grade III PN	3 1 ˂1	15 10 5	12 2 0	45 31 5
Discontinuation due to PN (%)	˂1	2	1	5

VDDx – vincristine, doxorubicin, dexamethasone; BzDx – bortezomib, dexamethasone; TDx – thalidomide, dexamethasone; VcTDx – bortezomib, thalidomide, dexamethasone.

Note. Peripheral neuropathy includes peripheral neuropathy, peripheral motor neuropathy, peripheral sensory neuropathy, and polyneuropathy.

Mantle cell lymphoma

In the LYM-3002 study, in which bortezomib was administered in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CAP), the incidence of peripheral neuropathy in the combination regimen is presented in Table 16.

Table 16

Incidence of peripheral neuropathy (PN) in the bortezomib study in patients with mantle cell lymphoma by toxicity grade and need for treatment discontinuation due to PN

Peripheral neuropathy indicators	BzR-CAP (N = 240)	R-CHOP (N = 242)
Incidence of PN (%)
All grades of PN	30	29
≥ Grade II PN	18	9
≥ Grade III PN	8	4
Discontinuation due to PN (%)	2	˂1

BzR-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 BzR-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 incidence of serious adverse reactions was 68% in the BzR-CAP group compared to 48% in the R-CHOP group.

Known differences in the safety profile of bortezomib as monotherapy when administered intravenously versus subcutaneously

In a Phase III study, patients receiving subcutaneous bortezomib had a 13% lower incidence of treatment-related adverse reactions of Grade III toxicity or higher, and a 5% lower incidence of treatment interruption with bortezomib, compared to patients receiving intravenous bortezomib. The overall incidence of diarrhea, gastrointestinal and abdominal pain, asthenic conditions, upper respiratory tract infections, and peripheral neuropathy was 12–15% lower in the subcutaneous group compared to the intravenous group. Additionally, the incidence of Grade III or higher peripheral neuropathy was 10% lower, and the rate of treatment discontinuation due to peripheral neuropathy was 8% lower.

Injection site reactions occurred in 6% of patients, primarily erythema. Symptoms resolved on average within 6 days, and dose modification was required in 2 patients. Two patients (1%) experienced serious reactions: one case of pruritus and one case of erythema.

The frequency of fatal events during treatment was 5% in the subcutaneous group and 7% in the intravenous group. The mortality rate 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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicinal product authorization is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report all cases of suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life

2 years.

Storage conditions

Store at a temperature not exceeding 25 °C in the original packaging to protect from light. Keep out of reach of children.

Incompatibilities

This medicinal product must not be mixed with other medicinal products except those specified in the section “Instructions for use, handling and disposal”.

Packaging

1 vial of powder in a cardboard box.

Prescription status

Prescription only.

Manufacturer

San Pharmaceuticals Industries Ltd.

Manufacturer's address and location of operations

Baroda Highway, Halol, Gujarat, 389350, India