INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BORTIB® (BORTIB)

Composition:

Active substance: bortezomib;

1 ml contains bortezomib (as boric acid mannitol ester) 2.5 mg;

1 vial (1.4 ml) contains bortezomib (as boric acid mannitol ester) 3.5 mg;

Excipients: mannitol (E 421), water for injections.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: clear, colorless solution filled in a transparent glass vial. The solution should be practically free from visible particles.

Pharmacotherapeutic group. Antineoplastic and immunomodulating agents. Antineoplastic agents. Other antineoplastic agents. 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 crucial role in regulating the turnover of specific proteins, thereby maintaining cellular homeostasis. Inhibition of the 26S proteasome leads to blockade 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 1,500-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 inhibition of the proteasome by bortezomib is reversible. By inhibiting the proteasome, bortezomib affects cancer cells through multiple mechanisms, including altering regulatory proteins that control the cell cycle and inhibiting activation of the nuclear factor NF-kB. Proteasome inhibition leads to cell cycle arrest and apoptosis. NF-kB is a transcription factor whose activation is essential for many aspects of tumor development, including cell growth and survival, angiogenesis, cell–cell interactions, and metastasis. In multiple myeloma, bortezomib affects 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 a reduction in the growth of many experimental human tumors, including multiple myeloma.

Data from in vitro, ex vivo, and animal model studies indicate that bortezomib enhances differentiation and activity of osteoblasts 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 use of bortezomib (1.3 mg/m² administered intravenously) in combination with melphalan (9 mg/m²) and prednisone (60 mg/m²) improved time to progression (TTP) compared to melphalan (9 mg/m²) and prednisone (60 mg/m²) in patients with previously untreated multiple myeloma. Treatment was administered for up to 9 cycles (approximately 54 weeks) and could be 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, a median hemoglobin level of 105 g/L, and a median platelet count of 221.5 x 10⁹/L. Similar proportions of patients had creatinine clearance ≤ 30 mL/min (3% in each group).

At a pre-specified interim analysis, the primary endpoint, time to progression, was reached, and patients in the melphalan + prednisone (M+P) group were offered treatment with bortezomib + melphalan + prednisone. 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 treatment group (hazard ratio = 0.695; p = 0.00043), despite 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.

Efficacy results after final survival update in the VISTA study

Table 1

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 of 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) by 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 is 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 doublet and triplet 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 intravenous 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 transplants were received by 198 (82%) patients and 208 (87%) patients in the VDDx and BzDx groups, respectively; most patients underwent a single transplant procedure. Demographic characteristics and baseline disease characteristics were balanced between treatment groups. The median patient age 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 by both groups was 4 cycles.

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 combination 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.

Efficacy results from the IFM-2005-01 study

Table 2

CI = confidence interval; CR = complete response; nCR = near complete response; ITT = intention-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 rates after second transplantation for subjects who received a second transplantation (42/240 [18%] in the BzDx group and 52/242 [21%] in the VDDx group).

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

In the MMY-3010 study, 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 increased to 200 mg daily).

One autologous stem cell transplantation was received by 105 (81%) patients and 78 (61%) patients in the BzTDx and TDx groups, respectively. Patient demographics and baseline disease characteristics were similar between treatment groups. Patients in the BzTDx and TDx groups had a mean age of 57 versus 56 years, 99% versus 98% were Caucasian, and 58% versus 54% were male. In the BzTDx group, 12% of patients were cytogenetically classified as high risk compared to 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. Secondary efficacy endpoints included progression-free survival and overall survival. The main efficacy results are presented in Table 3.

Efficacy results from the MMY-3010 study

Table 3

CI = confidence interval; CR = complete response; nCR = near complete response; ITT = intention 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 estimate of overall odds ratio for stratified tables; p-value from Cochran-Mantel-Haenszel test.

Note: OR > 1 indicates benefit 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 randomized, controlled Phase III trial (APEX) versus dexamethasone (Dex) in 669 patients with relapsed or resistant multiple myeloma who had received 1–3 prior lines of therapy, and a single-arm Phase II study in 202 patients with relapsed and refractory multiple myeloma who had received at least 2 prior lines of therapy and had progressed during the most recent treatment.

In the Phase III study, treatment with bortezomib resulted in significantly longer time to progression, significantly prolonged survival, and significantly higher response rates compared to dexamethasone treatment (see Table 4) in all patients, as well as in patients who had received 1 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 all patients randomized to dexamethasone were offered bortezomib regardless of disease status. Due to this early crossover, the median follow-up duration for surviving patients was 8.3 months. In both patients who were refractory to their most recent prior therapy and those who were not refractory, overall survival was significantly longer and response rates were significantly higher in the bortezomib group.

Of the 669 patients, 245 (37%) were aged 65 years or older. Response parameters as well as TTP remained significantly better with bortezomib regardless of age. Regardless of baseline β2-microglobulin levels, all efficacy parameters (time to progression and overall survival, as well as 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 Bone Marrow Transplantation. Median overall survival for all patients was 17 months (range: <1 to 36+ months). This survival was longer than the expected median survival of six to nine months anticipated by clinical investigator consultants for a similar patient group. According to multivariate analysis, response rate did not depend on myeloma type, disease status, chromosome 13 deletion status, or number or type of prior therapies. Patients who had received 2 to 3 prior therapeutic regimens had a response rate of

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

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

Table 4

a Planned number of patients to be treated (ITT);

b p-value from stratified log-rank test; analysis by lines of therapy excludes stratification by prior therapy;

p < 0.0001

c Response-evaluable population includes patients with measurable disease at baseline who 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 lines 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 the 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. Eighteen percent of patients achieved or improved their response [MR (11%) or PR (7%)] with combination therapy.

Clinical efficacy of subcutaneous administration of 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 8 cycles. Patients who did not achieve an optimal response (less than complete response [CR]) to bortezomib monotherapy after 4 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.

In this study, the primary objective of non-inferiority in overall response rate (CR+PR) after 4 cycles of bortezomib monotherapy was met for both subcutaneous and intravenous administration, with a response rate of 42% in both groups. Furthermore, secondary efficacy endpoints related to response and time-to-event outcomes demonstrated consistent results between subcutaneous and intravenous administration (Table 5).

Summary of efficacy analyses comparing subcutaneous and intravenous

bortezomib administration

Table 5

a p-value for the hypothesis of non-inferiority, according to which subcutaneous administration maintains at least 60% of the response rate compared to 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, phase III study with parallel groups 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 who did not progress during anthracycline-based therapy. The primary efficacy endpoint was improvement in progression-free survival, 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, predefined by the protocol (based on 249 progression-free survival events), triggered early termination of the study for efficacy. This interim analysis showed 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 progression-free survival was 6.5 months for patients receiving bortezomib monotherapy compared to 9.3 months for patients receiving combination therapy with bortezomib and pegylated liposomal doxorubicin. These results, although not final, met the protocol-defined stopping criteria for efficacy.

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 patients 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 outcomes 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 matched with patients in the comparator group (e.g., bortezomib monotherapy) on confounding factors through individual pair matching. 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 retreatment with bortezomib upon relapse of multiple myeloma.

The phase II study MMY-2036 (RETRIEVE), an open single-group study, was conducted to determine the efficacy and safety of bortezomib retreatment.

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, treatment 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 every 3 weeks for up to 8 cycles, either as monotherapy or in combination with dexamethasone according to standard of care. Dexamethasone was used in combination with bortezomib in 83 patients during cycle 1, and an additional 11 patients received dexamethasone during subsequent cycles of bortezomib retreatment.

The primary endpoint was best confirmed response to retreatment according to EBMT criteria. The overall best response (CR+PR) to retreatment 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 in combination with 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, 11, rest period days 12–21), rituximab 375 mg/m² intravenously on day 1; cyclophosphamide 750 mg/m² intravenously on day 1; doxorubicin 50 mg/m² intravenously on day 1; and prednisone 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 treatment.

The primary efficacy endpoint was progression-free survival based on assessment by an independent review committee (IRC). Secondary endpoints included time to progression (TTP), time to next anti-lymphoma therapy (TNT), duration of treatment-free interval (TFI), overall response rate (ORR), and 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 positive bone marrow biopsy for mantle cell lymphoma, 54% had an International Prognostic Index (IPI) score ≥ 3, and 76% had stage IV disease. Duration of treatment (median = 17 weeks) and duration of follow-up (median = 40 months) were comparable in both treatment groups. Patients received a median of 6 cycles in both treatment arms; 14% of patients in the BzR-CAP group and 17% in the R-CHOP group received 2 additional cycles. Most patients in both groups completed treatment: 80% in the BzR-CAP group and 82% in the R-CHOP group. Efficacy results are presented in Table 6.

Efficacy results of study LYM-3002

Table 6

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

b Hazard ratio estimation was based on a Cox model stratified by IPI risk and disease stage. A hazard ratio < 1 indicates benefit with 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 Mantel-Haenszel estimate of the overall odds ratio was used for stratified tables with IPI risk and disease stage as stratification factors. An odds ratio (OR) > 1 indicates benefit with 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.

The median PFS assessed by the investigator 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). The median duration of complete response was
42.1 months in the BzR-CAP group compared to 18 months in the R-CHOP group. The 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). The final overall survival analysis was performed after a median follow-up of 82 months. The 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 determine the safety and efficacy of bortezomib in patients with previously treated AL amyloidosis. No new safety concerns were identified during the study, and in particular, bortezomib did not exacerbate organ-target involvement (heart, kidneys, and liver). In the efficacy analysis, an overall response rate of 67.3% (including a CR rate of 28.6%) was reported, measured by hematological 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 the results of bortezomib studies in all paediatric subpopulations 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 reinduction chemotherapy in children and young patients with lymphoid malignancies (pre-B-cell acute lymphoblastic leukaemia [ALL], T-cell lymphoblastic leukaemia, and T-cell lymphoblastic lymphoma [LL]). An effective reinduction multi-agent chemotherapy regimen was administered in 3 blocks. BORTIB® was administered only in blocks 1 and 2 to avoid potential overlapping toxicities with agents administered concurrently in block 3.

Complete response (CR) was assessed at the end of block 1. In patients with relapsed B-ALL within 18 months of diagnosis (n = 27), the CR rate was 67% (95% CI: 46, 84); the 4-month event-free survival rate was 44% (95% CI: 26, 62). In patients with B-ALL relapsing 18–36 months after diagnosis (n = 33), the CR rate was 79% (95% CI: 61, 91), and the 4-month event-free survival rate 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 the 4-month event-free survival rate was 67% (95% CI: 42, 83). The efficacy data reported 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 BORTIB® was added to standard paediatric pre-B-cell ALL chemotherapy. The following adverse reactions (grade ≥ 3) occurred at higher frequencies with the regimen including BORTIB® 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%), hypoxia (8% vs. 2%). In this study, there was no information on the potential outcomes or resolution rate of peripheral neuropathy. First occurrences were also noted 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), hypokalaemia (18% vs. 11% in block 2, 6% vs. 0% in block 1 and 21% vs. 12% in block 2), and hyponatraemia (12% vs. 5% in block 1 and 4% vs. 0% in block 2).

Pharmacokinetics

Absorption

After intravenous bolus administration of doses of 1.0 mg/m² and 1.3 mg/m² to 11 patients with multiple myeloma and creatinine clearance above 50 mL/min, the mean peak plasma concentration (Cmax) 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.

Following repeated intravenous bolus or subcutaneous administration of 1.3 mg/m² in patients with multiple myeloma, the total systemic exposure (AUClast) was equivalent between subcutaneous and intravenous administration. The Cmax after subcutaneous administration (20.4 ng/mL) was lower than after intravenous administration (223 ng/mL). The geometric mean ratio of AUClast was 0.99, with a 90% confidence interval (CI) of 80.18–122.80%.

Distribution

The mean volume of distribution (Vd) of bortezomib ranged from 1659 to 3294 litres following single or multiple doses of 1.0 mg/m² or 1.3 mg/m² in patients with multiple myeloma. This indicates extensive distribution of bortezomib into peripheral tissues. In vitro, at bortezomib concentrations of 0.01–1.0 µg/mL, 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, specifically CYP3A4, CYP2C19, and CYP1A2. The primary metabolic pathway involves deboronation to two metabolites, which are subsequently hydroxylated into further metabolites. The deboronated bortezomib metabolites are inactive as inhibitors of the 26S proteasome.

Elimination

The mean elimination half-life (T½) of bortezomib after multiple doses ranges from 40 to 193 hours. Bortezomib is cleared more rapidly after the first dose compared to subsequent doses. Mean total clearance was 102 and 112 L/h after the first dose of 1.0 mg/m² and 1.3 mg/m², respectively, and ranged from 15 to 32 L/h and 18 to 32 L/h after subsequent doses of 1.0 mg/m² and 1.3 mg/m², respectively.

Special patient populations

Hepatic impairment. The effect of hepatic impairment on the pharmacokinetics of bortezomib was evaluated in a Phase I study during the first treatment cycle involving 60 patients primarily with solid tumours and varying degrees of hepatic dysfunction; bortezomib doses ranged from 0.5 to 1.3 mg/m².

Mild hepatic impairment did not alter bortezomib AUC compared to normal hepatic function. Mean bortezomib AUC values increased by approximately 60% in patients with moderate 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) into the following groups: normal (CrCL ≥ 60 mL/min/1.73 m², n = 12), mild impairment (CrCL = 40–59 mL/min/1.73 m², n = 10), moderate impairment (CrCL = 20–39 mL/min/1.73 m², n = 9), and severe impairment (CrCL < 20 mL/min/1.73 m², n = 3). Patients on dialysis who received bortezomib post-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 determined following administration of bortezomib twice weekly as intravenous bolus injections at a dose of 1.3 mg/m² in 104 paediatric patients (aged 2–16 years) with acute lymphoblastic leukaemia or acute myeloid leukaemia. 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.

Preclinical 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.

Toxicity studies of development in rats and rabbits demonstrated embryo-fetal lethality at doses toxic to the mother, but did not show direct embryo-fetal toxicity at doses below those toxic to the mother. Fertility studies were not conducted, but evaluation of reproductive tissues was performed in general toxicity studies. In a 6-month rat study, degenerative effects were observed in both testes and ovaries. Therefore, bortezomib is likely to have potential effects on male or female fertility. Peri- and postnatal development studies were not conducted.

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

Based on animal studies, penetration of bortezomib 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 increased heart rate, reduced contractility, hypotension, and fatal outcomes. In dogs, reduced cardiac contractility and hypotension responded to acute intervention with positive inotropic or pressor agents.

Additionally, minor QT interval prolongation 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 eligible 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 lung and pericardial diseases.

When using BORTIB® in combination with other medicinal products, refer to the instructions for medical use of these products for additional contraindications.

Special precautions.

General precautions

BORTIB® is a cytotoxic agent. Therefore, caution must be exercised when reconstituting and administering BORTIB®. Use of gloves and protective clothing is recommended to prevent skin contact.

Appropriate aseptic techniques must be strictly followed when handling BORTIB® because it contains no preservatives.

Fatal cases have been reported following accidental intrathecal administration of bortezomib. BORTIB® is intended for subcutaneous or, after dilution, for intravenous administration. Bortezomib must not be administered intrathecally.

Instructions for preparation and administration

Preparation of BORTIB® solution must be performed only by qualified healthcare personnel.

Intravenous administration

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

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

The 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 solution. The reconstituted 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 BORTIB® is ready for use for subcutaneous injection. Each mL of solution contains 2.5 mg of bortezomib. The solution is clear and colorless, and should be visually inspected for solid particles and discoloration before administration. If discoloration or solid particles are observed, the solution must be discarded.

Disposal

BORTIB® is intended for single use only. Any unused medicinal product or waste material must 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 plays only a minor role (7%) in bortezomib metabolism, no change in overall drug disposition is expected in poor metabolizers of this enzyme.

Drug interaction studies evaluating the effect of ketoconazole, a strong 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 strong CYP3A4 inhibitors (such as ketoconazole, ritonavir).

A study evaluating the effect of omeprazole, a strong CYP2C19 inhibitor, on the pharmacokinetics of bortezomib (after intravenous administration) showed no significant effect on bortezomib pharmacokinetics in 17 patients included in the study.

In a study evaluating the effect of rifampicin, a strong CYP3A4 inducer, on the pharmacokinetics of bortezomib (after intravenous administration) involving 6 patients, a 45% reduction in bortezomib AUC was observed on average. Therefore, concomitant use of bortezomib with strong CYP3A4 inducers (such as rifampicin, carbamazepine, phenytoin, phenobarbital, and St. John's wort extract) is not recommended, as the efficacy of bortezomib may be reduced.

In the same drug interaction study evaluating the effect of dexamethasone, a weak CYP3A4 inducer, on the pharmacokinetics of bortezomib (intravenously administered), no significant effect on bortezomib pharmacokinetics was observed based on data from 7 patients.

A drug interaction study evaluating the effect of melphalan and prednisone on the pharmacokinetics of bortezomib (after intravenous administration) in 21 patients demonstrated an average increase in bortezomib AUC by 17%, which is not considered clinically significant.

During clinical trials, cases of hypoglycemia and hyperglycemia were reported in patients with diabetes mellitus 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 BORTIB®.

Special precautions for use.

If BORTYB® is used in combination with other medicinal products, the instructions for medical use of these medicinal products should be consulted prior to initiating treatment with BORTYB®. If thalidomide is used, special attention should be paid to pregnancy testing and contraception methods (see section "Use during pregnancy or breastfeeding").

Intrathecal administration

Fatal cases have been reported due to accidental intrathecal administration of bortezomib. BORTYB® must be administered only intravenously or subcutaneously. Intrathecal administration of BORTYB® is contraindicated.

Gastrointestinal toxicity

Bortezomib treatment may very commonly cause gastrointestinal toxicity, including nausea, diarrhea, constipation, and vomiting. Cases of intestinal obstruction (reported frequency: uncommon, see section "Side effects") 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 previously untreated patients with mantle cell lymphoma receiving bortezomib in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (VcR-CAP regimen), one of the most common hematological toxicities was reversible thrombocytopenia. Platelet counts were typically lowest on day 11 of each treatment cycle and returned to baseline levels before the start of the next cycle. Cumulative thrombocytopenia was not observed. On average, the lowest measured platelet count was approximately 40% of the baseline value in studies of bortezomib monotherapy in patients with multiple myeloma and 50% in studies in patients with mantle cell lymphoma. In patients with progressive myeloma, the severity of thrombocytopenia was related to the baseline platelet count: in 90% of 21 patients with baseline platelet counts < 75,000/μL, platelet counts decreased to ≤ 25,000/μL during the study, including 14% with counts < 10,000/μL, whereas in patients with baseline platelet counts > 75,000/μL, only 14% of 309 patients had platelet counts ≤ 25,000/μL.

In patients with mantle cell lymphoma (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 (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 vs. 5.0% in the R-CHOP group) and grade III or higher bleeding events (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 administration of each dose of BORTYB®.

Treatment with BORTYB® 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 precautions for use"). The benefit-risk ratio of treatment with BORTYB® should be carefully evaluated, particularly in cases of moderate or severe thrombocytopenia and presence of bleeding risk factors.

Complete blood counts with differential and platelet counts should be frequently monitored during treatment with BORTYB®. Platelet transfusion should be considered if clinically indicated (see section "Dosage and administration").

Reversible neutropenia between treatment cycles has been observed in patients with mantle cell lymphoma; cumulative neutropenia was not observed. Neutrophil counts were typically lowest on day 11 of each bortezomib treatment cycle and returned to baseline before the start of the next cycle. In the study of bortezomib in patients with mantle cell lymphoma (LYM-3002), 78% of patients in the BzR-CAP group and 61% in the R-CHOP group received colony-stimulating factors. Since patients with neutropenia are at increased risk of infections, they should be monitored for signs of infection and appropriate therapeutic measures taken. The use of granulocyte colony-stimulating factor should be considered for managing hematological toxicity 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").

Herpes zoster reactivation

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 group and 1.2% in the R-CHOP group (see section "Side effects").

Hepatitis B virus (HBV) reactivation and infection

Prior to initiating treatment with rituximab in combination with bortezomib, HBV testing should be performed in patients with risk factors. HBV carriers and patients with a history of hepatitis B should be closely monitored for clinical signs and laboratory markers 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 leading to fatal PML have been reported in patients treated with bortezomib. Patients diagnosed with PML had a history of or were concurrently receiving immunosuppressive therapy with bortezomib. Most PML cases were diagnosed within the first 12 months of initiating bortezomib treatment. Patients should be regularly monitored for new or worsening neurological symptoms that may indicate PML, which should be considered in the differential diagnosis of central nervous system (CNS) disorders. If PML is suspected, patients should be referred to a physician experienced in PML management, and appropriate diagnostic measures should be taken. Bortezomib treatment should be discontinued if PML is confirmed.

Peripheral neuropathy

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

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

In a phase III trial comparing intravenous versus subcutaneous bortezomib administration, the incidence of grade II peripheral neuropathy was 24% in the subcutaneous group and 41% in the intravenous group (p = 0.0124). Grade III peripheral neuropathy occurred in 6% of patients in the subcutaneous group and 16% in the intravenous group (p = 0.0264). The incidence of all-grade peripheral neuropathy with intravenous bortezomib was lower in historical intravenous bortezomib trials than in study MMY-3021.

Neurological evaluation is recommended upon onset of new symptoms or worsening of peripheral neuropathy; dose adjustment, schedule modification, or switching to subcutaneous administration may be necessary (see section "Dosage and administration"). Neuropathy was managed with supportive measures and other treatments.

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

In addition to peripheral neuropathy, autonomic neuropathy may contribute to certain adverse reactions such as orthostatic hypotension and acute constipation with intestinal obstruction. Information on autonomic neuropathy and its impact on these adverse reactions is limited.

Seizures

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 risk factors for seizures.

Hypotension

Bortezomib therapy is frequently associated with postural/orthostatic hypotension. In most cases, it is mild to moderate in severity and occurs throughout treatment. Patients who developed orthostatic hypotension during bortezomib (intravenous) administration did not have symptoms of orthostatic hypotension prior to bortezomib treatment. Most patients required treatment for orthostatic hypotension, and a smaller number experienced syncope. Orthostatic/postural hypotension was not clearly associated with bolus infusion of bortezomib; the mechanism is unknown and may be related to autonomic neuropathy. Autonomic neuropathy may be caused by bortezomib or bortezomib may exacerbate underlying conditions, including diabetic or amyloid neuropathy. Caution is advised in patients with a history of syncope, those taking antihypertensive medications, and those with dehydration due to diarrhea or vomiting. Management of orthostatic hypotension may require adjustment of antihypertensive drug doses, rehydration, mineralocorticoid and/or sympathomimetic agents; antihypertensive drugs may need to be reduced if necessary. Patients should be instructed to seek medical attention if they experience dizziness, presyncope, or syncope.

Reversible posterior leukoencephalopathy syndrome (PRES)

Cases of PRES have been reported in patients receiving bortezomib. PRES is a rare, often reversible neurological disorder that may 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 "Side effects"). Some of these cases were fatal. Chest X-ray is recommended prior to treatment initiation to establish baseline lung status and for comparison in case of potential treatment-related lung dysfunction.

Prompt diagnosis and appropriate therapeutic measures should be initiated if new or worsening pulmonary symptoms (e.g., cough, dyspnea) occur. The benefit-risk ratio of continuing bortezomib treatment should be carefully considered.

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 treatment, leading to termination of the study. Therefore, this specific regimen combining high-dose cytarabine (2 g/m²/day) as continuous 24-hour infusion is not recommended.

Kidney function disorders

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

Liver function disorders

Bortezomib is metabolized by hepatic enzymes. Bortezomib concentrations may increase in patients with moderate to severe hepatic impairment; these 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 upon discontinuation of bortezomib, have also been reported (see section "Side effects").

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 at highest risk are those with high tumor burden prior to treatment initiation. Close monitoring of such patients and implementation of appropriate preventive measures are recommended.

Warnings regarding concomitant use of other medicinal products

Patients should be under close physician supervision when bortezomib is combined with strong CYP3A4 inhibitors. Caution is advised 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 if impaired prior to initiating treatment, and caution is advised 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 if serious reactions occur.

Use during pregnancy or breastfeeding.

Contraception in men and women

Men and women of reproductive potential must use effective contraception during treatment and for 3 months after treatment completion.

Pregnancy

There are no clinical data on bortezomib use 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 were not conducted (see section "Pharmacological properties"). Bortezomib is not recommended during pregnancy except when the woman's clinical condition requires bortezomib treatment. If bortezomib is used during pregnancy or if pregnancy occurs during treatment, the patient should be informed of the potential risk to the fetus.

Thalidomide is a medicinal product with known human teratogenic effects 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 avoid the risk of severe adverse effects in the infant, women are advised not to breastfeed during treatment with BORTYB®.

Fertility

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

Ability to affect reaction speed when driving or operating machinery.

Bortezomib has a moderate effect on the ability to drive or operate machinery. Bortezomib use 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 "Side effects").

Method of administration and doses.

Treatment with bortezomib should be initiated under the supervision of a qualified physician experienced in the treatment of patients with oncological diseases, although the medicinal product BORTIB® 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 "Instructions for Use").

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

Monotherapy

The recommended dose of BORTIB® for adults is 1.3 mg/m² body surface area administered intravenously or subcutaneously twice weekly for two weeks (on days 1, 4, 8, and 11) within a 21-day treatment cycle. This three-week period constitutes one treatment cycle. Upon achieving a complete clinical response, administration of two additional treatment cycles is recommended. Patients with a partial response but not complete remission should continue treatment with BORTIB®, but for no more than 8 cycles. At least 72 hours should elapse between consecutive doses of the drug.

Dose modification and re-initiation recommendations for bortezomib as monotherapy

If any non-hematologic toxicity of grade III or hematologic toxicity of grade IV occurs, except for neuropathies as described below (see also section "Instructions for Use"), treatment with BORTIB® must be interrupted. After resolution of toxicity symptoms, treatment with BORTIB® may be resumed at a dose reduced by 25% (reduce dose from 1.3 mg/m² to 1.0 mg/m²; reduce dose from 1.0 mg/m² to 0.7 mg/m²). If toxicity symptoms do not resolve or reappear upon administration of the reduced dose, discontinuation of BORTIB® should be considered, unless the benefit of continued treatment outweighs the risk.

Neuropathic pain and/or peripheral neuropathy

In the event of neuropathic pain and/or peripheral neuropathy, the dose should be adjusted according to Table 7 (see also section "Instructions for Use"). BORTIB® should be administered to patients with a history of severe neuropathy only after careful assessment of the benefit-risk ratio.

Recommended* dose modification in case of bortezomib-induced neuropathy

Table 7

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

** Usual productive activity includes cooking, shopping, using the telephone, etc.

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

Combination therapy with pegylated liposomal doxorubicin

BORTEP® should 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 is considered one treatment cycle. At least 72 hours should elapse between consecutive doses of BORTEP®.

Pegylated liposomal doxorubicin should be administered at a dose of 30 mg/m² on day 4 of the BORTEP® treatment cycle by one-hour intravenous infusion after BORTEP® injection.

This combination therapy may be continued for up to 8 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 2 additional cycles after achieving complete response, even if this requires more than 8 treatment cycles. Patients whose paraprotein levels continue to decrease after 8 cycles may also continue treatment as long as treatment is tolerated and a response is observed. For administration of pegylated liposomal doxorubicin, see also the prescribing information for this medicinal product.

Combination therapy with dexamethasone

BORTEP® should 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 is considered one treatment cycle. At least 72 hours should elapse between consecutive doses of BORTEP®.

Dexamethasone should be administered orally at a dose of 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 of the BORTEP® treatment cycle.

Patients who show a response to treatment or disease stabilization after four cycles may continue treatment with this combination for up to 4 additional cycles. See also the prescribing information for dexamethasone.

Dose modification recommendations for combination therapy in patients with relapsed multiple myeloma

See dose modification recommendations for BORTEP® monotherapy described above.

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

Combination therapy with melphalan and prednisone

BORTEP® 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, BORTEP® is administered twice weekly (on days 1, 4, 8, 11, 22, 25, 29, and 32).

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

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

Recommended dosing regimen for BORTEP® in combination with melphalan and prednisone

Table 8

M — melphalan, P — prednisone.

Recommendations for dose adjustment and resumption of combination therapy with melphalan and prednisone

Prior to starting a new treatment cycle:

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

Dose adjustment during subsequent treatment cycles with BORTY® in combination with melphalan and prednisone

Table 9

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

BORTEP® 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 doses of BORTEP®.

Dexamethasone should be administered orally at a dose of 40 mg on days 1, 2, 3, 4, 8, 9, 10, and 11 of the BORTEP® treatment cycle.

Administer 4 treatment cycles with this combination.

Combination therapy with dexamethasone and thalidomide

BORTEP® 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 doses of BORTEP®.

Dexamethasone should be administered orally at a dose of 40 mg on days 1, 2, 3, 4, 8, 9, 10, and 11 of the BORTEP® treatment cycle.

Thalidomide should be administered orally at a dose of 50 mg daily on days 1–14 of the cycle; if tolerated, the dose should be increased to 100 mg daily on days 15–28 of the cycle. The dose may be further increased to 200 mg daily starting from the second cycle (see Table 10).

Administer 4 treatment cycles. Patients achieving at least a partial response to treatment are recommended to receive 2 additional cycles of therapy.

Recommended dosing regimen of BORTEP® in combination with dexamethasone and thalidomide for patients with untreated multiple myeloma eligible for hematopoietic stem cell transplantation

Table 10

Dx — dexamethasone; Th — thalidomide.

a Increase thalidomide dose to 100 mg from week 3 of cycle 1 if the 50 mg dose is tolerated, and to 200 mg if the 100 mg dose is tolerated.

b Patients who achieve a partial response after 4 treatment cycles may receive up to 6 treatment cycles.

Dosing adjustment recommendations for patients eligible for transplantation

See dosing adjustment recommendations for BORTYZ® used as monotherapy.

If BORTYZ® 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 BORTYZ® is 1.3 mg/m² body surface area administered intravenously or subcutaneously twice weekly for 2 weeks (on days 1, 4, 8, and 11), followed by a 10-day rest period (days 12–21). This three-week period constitutes one treatment cycle. A total of 6 treatment cycles is recommended. Patients who achieve their first documented response during cycle 6 should receive 2 additional cycles of therapy. At least 72 hours should elapse between consecutive doses of BORTYZ®.

Medications administered as intravenous infusions on day 1 of each three-week BORTYZ® treatment cycle: rituximab 375 mg/m², cyclophosphamide 750 mg/m², doxorubicin 50 mg/m².

Prednisone should be administered orally at a dose of 100 mg/m² on days 1, 2, 3, 4, and 5 of each BORTYZ® treatment cycle.

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-hematologic toxicity must have resolved to Grade 1 or baseline levels.

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

Granulocyte colony-stimulating factors may be used to manage hematologic toxicity according to local standard protocols. If initiation of a new treatment cycle is delayed multiple times, consider prophylactic use of granulocyte colony-stimulating factor. Platelet transfusion should be considered as necessary for the management of thrombocytopenia.

Dose adjustments during therapy for patients with untreated mantle cell lymphoma

Table 11

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

Special patient groups

Elderly patients

Currently, there are no data indicating the need for dose adjustment in patients aged 65 years and older.

There have been no studies 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 BORTIB® should be initiated at a dose of 0.7 mg/m² during the first treatment cycle, with subsequent gradual dose escalation to 1.0 mg/m² or dose reduction to 0.5 mg/m² depending on patient tolerability (see sections "Pharmacological properties. Pharmacokinetics" and "Special precautions for use").

Dose modification recommendations for initial doses of BORTIB®

patients with hepatic impairment

Table 12

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

* Based on the National Cancer Institute (USA) classification of severity of liver function impairment (mild, moderate, and severe).

Patients with renal impairment

Mild to moderate renal impairment (creatinine clearance > 20 ml/min/1.73 m²) does not affect the pharmacokinetics of bortezomib; therefore, dose adjustment is not required in this patient group. It is unknown whether severe renal impairment (creatinine clearance < 20 ml/min/1.73 m²) affects the pharmacokinetics of bortezomib. Since dialysis may reduce bortezomib concentrations, the drug should be administered after the dialysis procedure (see section "Pharmacological Properties. Pharmacokinetics").

Children

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

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

BORTIB® must not be administered by other routes. Intrathecal administration has resulted in fatal outcomes.

Intravenous

BORTIB®, solution for injection, 2.5 mg/ml, should first be diluted to 1 mg/ml (see sections "Special precautions for safety" and "Particular methods of administration"), 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 BORTIB®.

Subcutaneous

BORTIB®, 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 administrations.

If adverse reactions occur at the injection site following subcutaneous injections, the BORTIB® solution may be administered subcutaneously at a lower concentration (1 mg/ml instead of 2.5 mg/ml) or administered intravenously.

When BORTIB® is used concomitantly with other medicinal products, refer to the respective product information for those medicinal products.

Children

The safety and efficacy of bortezomib in children (under 18 years of age) have not been established. There is insufficient data to establish dosing recommendations for children.

Overdose

In patients, overdose exceeding the recommended dose by more than two times has been associated with acute hypotension and thrombocytopenia resulting in fatal outcomes. Preclinical pharmacological safety studies on the cardiovascular system 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, vasopressors and/or inotropic agents) and body temperature is recommended (see sections "Method of administration and dosage" and "Particular methods of administration").

Adverse reactions.

Summary of safety profile

Among serious adverse reactions observed during treatment with bortezomib, cardiac failure, tumor lysis syndrome, pulmonary hypertension, reversible posterior encephalopathy syndrome (PRES), acute diffuse infiltrative pulmonary disorders, and autonomic neuropathy have been reported infrequently. The most commonly observed adverse reactions during bortezomib treatment are nausea, diarrhea, constipation, vomiting, weakness, pyrexia, thrombocytopenia, anemia, neutropenia, peripheral neuropathy (including sensory neuropathy), headache, paresthesia, decreased appetite, dyspnea, 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 collected from 5,476 patients, of whom 3,996 received bortezomib at a dose of 1.3 mg/m² and are included in Table 13. Overall, bortezomib was administered for the treatment of multiple myeloma to 3,974 patients.

Adverse reactions are categorized by organ systems and frequency of occurrence. Frequencies are defined as: very common (>1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), and frequency not known (cannot be estimated from available data). Within each category, 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.

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

Table 13

* Terms MedDRA are grouped.

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 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 in combination therapy (BzR-CAP) were hepatitis B virus infection (< 1%) and myocardial ischemia (1.3%). The similar incidence 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%, with 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, according to investigator assessment, were possibly or probably related to bortezomib, based on experience from studies in patients with multiple myeloma.

Adverse reactions are categorized by system organ class and frequency of occurrence. Frequencies are defined as: very common (>1/10), common (≥ 1/100 to <1/10), uncommon (≥ 1/1000 to <1/100), rare (≥ 1/10,000 to <1/1000), very rare (<1/10,000), frequency 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.

Adverse reactions observed in patients with mantle cell lymphoma who received VcR-CAP treatment in clinical trials

Table 14

* MedDRA term abbreviations.

Description of selected 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 (IFM-2005-01 study) and with dexamethasone-thalidomide (MMY-3010 study) (see Table 15).

Incidence of peripheral neuropathy (PN) during induction therapy

by toxicity grade and need for treatment interruption due to PN

Table 15

VDDx — vincristine, doxorubicin, dexamethasone; BzDx — bortezomib, dexamethasone; TDx — thalidomide, dexamethasone; VcTDx — bortezomib, cyclophosphamide, 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 the table below.

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

Table 16

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 neuropathies was 12–15% lower in the subcutaneous group compared to the intravenous group. Additionally, the incidence of Grade III or higher peripheral neuropathies was 10% lower, and the rate of treatment discontinuation due to peripheral neuropathy was 8% lower.

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

The frequency of 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 shown at least a partial response to bortezomib-containing therapy, adverse reactions of all grades occurring in at least 25% of patients included primarily thrombocytopenia (55%), neuropathy (40%), anemia (37%), diarrhea (35%), and constipation (28%). Peripheral neuropathy of all grades and peripheral neuropathy ≥ Grade III were observed in 40% and 8.5% of patients, respectively.

Reporting of suspected adverse reactions

Reporting of adverse reactions after drug registration is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life.

Unopened vial

2 years.

After reconstitution

Chemical and physical stability of the reconstituted solution at a concentration of 1 mg/mL was observed for 24 hours at 20–25 °C when stored in the original packaging and/or syringe.

From a microbiological standpoint, unless the method of opening/reconstitution excludes the risk of microbial contamination, the reconstituted solution should be used immediately. If not used immediately, the duration and conditions of storage prior to use are the responsibility of the user.

Storage conditions.

Store in a refrigerator at 2 °C to 8 °C.

Keep the vial in the outer carton to protect from light.

Keep out of the reach of children.

Incompatibilities. The medicinal product BORTIB® should not be mixed with other medicinal products except those listed in the section "Instructions for use and dosage."

Packaging.

1.4 mL (3.5 mg) in a vial, 1 vial per pack.

Prescription status.

Prescription only.

Manufacturer.

Accord Healthcare Polska Sp. z o.o. Importer's Warehouse/Accord Healthcare Polska Sp. z o.o. Magazyn Importera.

Manufacturer's address and place of business.

ul. Lutomierska 50, Pabianice, 95-200, Poland.

Marketing Authorization Holder. Accord Healthcare S.L.U.

Inquiries regarding substandard quality of the medicinal product; questions related to safety of use, improper use, or complaints are accepted 24/7 via phone: +380993100335 or by email at: [email protected].

Address of the Marketing Authorization Holder.

World Trade Center, Moll de Barcelona, s/n, Edifici Est 6a planta, 08039 Barcelona, Spain.