INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BORTEZOMIB EVER PHARMA

Composition:

Active substance: bortezomib;

1 vial containing 1 ml of solution contains 2.5 mg of bortezomib;
1 vial containing 1.4 ml of solution contains 3.5 mg of bortezomib;

Excipients: mannitol (E 421), sodium chloride, sodium hydroxide, hydrochloric acid, water for injections.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: solution ranging from colorless to slightly yellow.

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. It is specifically designed to inhibit the chymotrypsin-like activity of the 26S proteasome in mammalian cells. The 26S proteasome is a large protein complex that degrades ubiquitin-conjugated proteins. The ubiquitin-proteasome pathway plays a crucial role in regulating the turnover of specific proteins, thereby maintaining cellular homeostasis. Inhibition of the 26S proteasome prevents this targeted proteolysis and affects several intracellular signaling cascades, leading to cancer cell death.

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 times more selective for the proteasome than for other enzymes. The kinetics of proteasome inhibition were determined in vitro; bortezomib dissociated from the proteasome with a 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, in particular, altering the regulatory protein controlling cell cycle progression and activation of nuclear factor kappa B (NF-kB). Proteasome inhibition leads to cell cycle arrest and apoptosis. NF-kB is a transcription factor whose activation is essential for many aspects of tumor development, including cell growth and survival, angiogenesis, cell–cell interactions, and metastasis. In myeloma, bortezomib affects the ability of myeloma cells to interact with the bone marrow microenvironment.

Experiments have shown that bortezomib is cytotoxic to many types of cancer cells and that cancer cells are more susceptible to apoptosis induced by proteasome inhibition than normal cells. In vivo, bortezomib causes inhibition of growth in many experimental human tumors, including multiple myeloma.

Data from in vitro, ex vivo, and animal model studies indicate that bortezomib enhances osteoblast differentiation and activity and inhibits osteoclast function. These effects have been observed in patients with multiple myeloma who also had advanced-stage osteolytic disease and were treated with bortezomib.

Clinical efficacy in previously untreated patients with 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 intravenously) to melphalan (9 mg/m²) and prednisone (60 mg/m²) would prolong time to progression (TTP) compared to melphalan and prednisone alone in previously untreated patients with multiple myeloma. Treatment was administered for up to 9 cycles (approximately 54 weeks) and discontinued early due to disease progression or unacceptable toxicity. The median patient age 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 × 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 M + P group were offered treatment with B + M + P. The median follow-up was 16.3 months. At the time of the final survival data update, the median follow-up duration was 60.1 months. A statistically significant survival advantage was observed in favor of the B + M + P treatment group (HR = 0.695; p = 0.00043), despite subsequent therapies, including bortezomib-based regimens. The median overall survival in the B + M + P treatment group was 56.4 months compared to 43.1 months in the M + P treatment group. Efficacy results are presented in Table 1.

Table 1

Efficacy results after final survival data update from the VISTA study

a Kaplan-Meier estimate.

b Hazard ratio based on the Cox proportional hazards model adjusted for stratification factors: β2-microglobulin, albumin, and region. A hazard ratio less than 1 indicates benefit of B + M + P.

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 Response-evaluable population includes patients with measurable disease at baseline.

f CR = complete response; PR = partial response. EBMT criteria.

g All randomized patients with secretory disease.

* Survival data updated based on additional follow-up with a median duration of 60.1 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 evaluate the safety and efficacy of bortezomib in doublet and triplet combinations with other chemotherapeutic agents as induction therapy prior to stem cell transplantation in previously untreated patients with multiple myeloma.

In the IFM-2005-01 study, bortezomib in combination with dexamethasone (BDx, n = 240) was compared to vincristine-doxorubicin-dexamethasone (VDDx, n = 242). Patients in the BDx 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 9–12 of cycles 1 and 2, and on days 1–4 of cycles 3 and 4).

Autologous stem cell transplantation was performed in 198 (82%) patients in the VDDx group and 208 (87%) patients in the BDx group; the majority of patients underwent a single transplantation.

Demographic 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% had high-risk cytogenetics. The median duration of treatment was 13 weeks in the VDDx group and 11 weeks in the BDx group. The median number of cycles received by patients in both groups was 4 cycles.

The primary efficacy endpoint of the study was response rate after induction therapy (CR [complete response] + nCR [near complete response]). A statistically significant difference in favor of the bortezomib-dexamethasone combination group was observed for CR + nCR. Secondary efficacy endpoints included response rates after transplantation (CR + nCR, CR + nCR + VGPR [very good partial response] + PR [partial response]), progression-free survival, and overall survival. Key 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;

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

* Primary endpoint.

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

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

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

In the MMY-3010 study, induction treatment with bortezomib in combination with thalidomide and dexamethasone (BTDx, n = 130) was compared with thalidomide-dexamethasone combination (TDx, n = 127). Patients in the BTDx 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 break from day 12 to day 28), dexamethasone (40 mg orally on days 1–4 and 8–11), and thalidomide (50 mg orally daily on days 1–14, increased to 100 mg daily on days 15–28, then to 200 mg daily).

One autologous stem cell transplant was received by 105 (81%) and 78 (61%) of patients in the BTDx and TDx groups, respectively. Demographic and baseline disease characteristics were similar between treatment groups. Patients in the BTDx 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 BTDx group, 12% of patients were cytogenetically classified as high-risk compared with 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, which was similar across treatment groups.

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 bortezomib in combination with dexamethasone and thalidomide. Secondary efficacy endpoints included progression-free survival and overall survival. Key efficacy results are presented in Table 3.

Table 3

Efficacy results in the MMY-3010 study

CI = confidence interval; CR = complete response; nCR = near complete response; ITT = intention-to-treat; RR = response rate;

B = bortezomib; BTDx = bortezomib, thalidomide, dexamethasone; TDx = thalidomide, dexamethasone;

PR = partial response; OR = odds ratio.

* Primary endpoint.

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

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

Clinical efficacy in relapsed or refractory multiple myeloma

The safety and efficacy of bortezomib (intravenous) were evaluated in two studies at the recommended dose of 1.3 mg/m²: a randomized, controlled phase III trial (APEX), comparing bortezomib with dexamethasone (Dex) in 669 patients with relapsed or refractory multiple myeloma who had received 1–3 prior lines of therapy, and an uncontrolled phase II trial involving 202 patients with relapsed or refractory multiple myeloma who had received at least 2 prior lines of therapy and had disease progression during their most recent treatment.

In the phase III trial, 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. Based on the results of a pre-planned interim analysis, treatment in the dexamethasone arm was discontinued upon recommendation of the data monitoring committee, and all patients randomized to the dexamethasone arm were allowed to receive bortezomib regardless of disease status. Due to this early crossover, the median duration of subsequent patient follow-up was 8.3 months. In both patients refractory to their last prior therapy and those not refractory, overall survival was significantly longer and the response rate was significantly higher in the bortezomib group.

Of the 669 patients included in the study, 245 (37%) were aged 65 years or older. Response parameters as well as time to progression outcomes 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 better in the bortezomib group.

In the refractory population of the phase II study, responses were assessed by an independent review committee using criteria from the European Group for Bone Marrow Transplantation. The median survival in all patients enrolled in the study was 17 months (range <1 to 36+ months). This survival duration was longer than the median survival of six to nine months anticipated by the study's clinical consultants for a similar patient group. According to multivariate analysis, response rate was independent of myeloma type, performance status, deletion 13 chromosome status, or number and type of prior treatment regimens. 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 trials

a ITT (as per assigned treatment) – population.

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

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

d P-value according to 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.

B = 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 optimal response with bortezomib monotherapy could receive high-dose dexamethasone in combination with bortezomib. The protocol allowed patients to receive dexamethasone if they had less than optimal response to bortezomib monotherapy. Overall, 74 evaluable patients received dexamethasone in combination with bortezomib. 18% of patients achieved either improved 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 non-inferiority 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 subcutaneously or intravenously over 8 cycles. Patients who did not achieve optimal response (less than complete response (CR)) with bortezomib monotherapy after 4 cycles were allowed to receive dexamethasone 20 mg once daily on the day of and after bortezomib administration. Patients with peripheral neuropathy ≥ grade 2 or platelet counts < 50,000/µL at baseline were excluded. Overall, 218 patients were evaluable for response assessment.

The study met its primary objective of non-inferiority in overall response rate (CR + PR) after 4 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 comparable results between subcutaneous and intravenous administration (see Table 5).

Table 5

Summary of efficacy analysis comparing subcutaneous and intravenous administration of bortezomib

a p-value for the hypothesis of non-inferior efficacy, according to which the subcutaneous administration group has at least 60% of the response rate observed in the intravenous administration group.

b 222 patients were included in the study; 221 patients received bortezomib treatment.

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

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

e Median duration of additional 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 to compare 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 whose disease had not progressed during anthracycline-based treatment. The primary efficacy endpoint was time to progression (TTP), while secondary efficacy endpoints included overall survival (OS) and overall response rate (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 TTP events), led to early termination of the study for efficacy reasons. This interim analysis demonstrated a 45% reduction in the risk of TTP (95% CI: 29–57%, p < 0.0001) in patients receiving combination therapy with bortezomib and pegylated liposomal doxorubicin. The median TTP was 6.5 months in patients receiving bortezomib monotherapy compared to 9.3 months in those receiving combination therapy with bortezomib and pegylated liposomal doxorubicin. These results, although not fully mature, were consistent with the final analysis defined by the protocol.

The final OS analysis, performed after a follow-up period with a median of 8.6 years, did not show a significant difference in OS between the two treatment groups. Median OS was 30.8 months (95% CI: 25.2–36.5 months) in patients receiving bortezomib monotherapy and 33.0 months (95% CI: 28.9–37.1 months) in the combination therapy group (bortezomib plus 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 matched-pair analysis was performed to compare outcomes in a non-randomized group receiving bortezomib in combination with dexamethasone (open-label phase II study MMY-2045) with those from bortezomib monotherapy groups in various randomized phase III trials (M34101-039 [APEX] and DOXIL MMY-3001) with the same indications.

Matched-pair analysis is a statistical method whereby patients in the treatment group (e.g., bortezomib plus dexamethasone) and the control group (e.g., bortezomib monotherapy) are matched based on confounding factors by pairing individual patients. This minimizes the impact of observed confounding factors when evaluating treatment effects using non-randomized data.

One hundred and twenty-seven matched pairs of patients were identified. The analysis demonstrated improved outcomes for bortezomib in combination with dexamethasone compared to bortezomib monotherapy in terms of 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 TTP (hazard ratio 0.385; 95% CI: 0.212–0.698; p = 0.001).

Information on retreatment with bortezomib in relapsed multiple myeloma is limited.

An open-label, non-comparative, phase II study MMY-2036 (RETRIEVE) was conducted to evaluate the efficacy and safety of retreatment 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. Bortezomib was restarted at least 6 months after prior bortezomib therapy, 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 practice. Eighty-three patients received dexamethasone in combination with bortezomib during the first cycle, and an additional 11 patients received dexamethasone during subsequent bortezomib cycles.

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

Clinical efficacy in patients with 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 (BR-CAP; n = 243) versus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP; n = 244) in adult patients with previously untreated MCL (stage II, III, or IV). Patients in the BR-CAP treatment group received bortezomib (1.3 mg/m² on days 1, 4, 8, and 11, with a break from day 12 to 21), rituximab 375 mg/m² intravenously on day 1; cyclophosphamide 750 mg/m² IV on day 1; doxorubicin 50 mg/m² IV on day 1; and prednisone 100 mg/m² orally from days 1 to 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 (PFS) based on assessment by an independent review committee (IRC). Secondary endpoints included time to progression (TTP), time to next anti-lymphoma treatment (TNT), treatment-free interval (TFI), overall response rate (ORR), complete response rate (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% had positive bone marrow aspirate and/or positive bone marrow biopsy for MCL, 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. Both treatment groups received a median of 6 cycles, and 14% of patients in the BR-CAP group and 17% in the R-CHOP group received 2 additional cycles.

The majority of patients in both groups completed treatment: 80% in the BR-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 an independent review committee (IRC) (radiological data only).

b Risk ratio assessment based on a Cox model stratified by IPI risk and disease stage. Risk ratios < 1 indicate an advantage for BR-CAP.

c Based on Kaplan-Meier confidence limits.

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

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

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

g P-value from the Cochran-Mantel-Haenszel chi-square test, with IPI and disease stage as stratification factors.

h Includes all radiological CR + CRu + PR as assessed by IRC, regardless of bone marrow and LDH data verification.

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

Median PFS assessed by investigators was 30.7 months in the BR-CAP group and 16.1 months in the R-CHOP group (hazard ratio [HR] = 0.51; p < 0.001). A statistically significant advantage (p < 0.001) in favor of the BR-CAP treatment group compared to the R-CHOP group was observed for TTP (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 BR-CAP group compared to 18 months in the R-CHOP group. Duration of overall response was 21.4 months longer in the BR-CAP group (median 36.5 months vs. 15.1 months in the R-CHOP group). The final OS analysis was performed after a median follow-up duration of 82 months. Median OS was 90.7 months in the BR-CAP group compared to 55.7 months in the R-CHOP group (HR = 0.66; p = 0.001). The observed difference in median OS between the two treatment groups was 35 months.

Patients with previously treated 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 light-chain (AL) amyloidosis. No new safety concerns were observed during the study, including no exacerbation of organ-target involvement (heart, kidneys, and liver) by bortezomib. In an efficacy subset analysis, a response rate of 67.3% (including a CR rate of 28.6%), assessed by hematological response (M-protein), was reported in 49 evaluable patients receiving maximum tolerated doses of 1.6 mg/m² once weekly and 1.3 mg/m² twice weekly. For these dose cohorts, the combined one-year survival rate was 88.1%.

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of bortezomib studies in all paediatric subgroups with multiple myeloma and MCL (see section "Posology and method of administration" for information on paediatric use).

An uncontrolled Phase II study evaluating activity, safety, and pharmacokinetics, conducted by the Children's Oncology Group, assessed the addition of bortezomib to reinduction multi-agent chemotherapy in children and young adult patients with malignant lymphoid tumours (pre-B-cell acute lymphoblastic leukaemia (ALL), T-cell ALL, and T-cell lymphoblastic lymphoma (LL)). A standard reinduction multi-agent chemotherapy regimen was administered in 3 blocks. Bortezomib was administered only in blocks 1 and 2 to avoid potential overlapping toxicities with agents used in block 3.

Complete response (CR) was assessed at the end of block 1. In relapsed B-ALL patients 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 B-ALL patients with relapse occurring 18–36 months after diagnosis (n = 33), the CR 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 evaluated for safety; median age was 10 years (range 1 to 26). No new safety concerns were observed when bortezomib was added to standard backbone chemotherapy for paediatric pre-B-cell ALL. The following adverse reactions (grade ≥ 3) occurred more frequently in the bortezomib-containing regimen compared to a historical control study where the backbone regimen was used alone: in block 1, peripheral sensory neuropathy (3% vs. 0%), intestinal obstruction (2.1% vs. 0%), hypoxia (8% vs. 2%). Higher frequencies were also observed for infections with neutropenia ≥ grade 3 (24% vs. 19% in block 1 and 22% vs. 11% in block 2), increased ALT (17% vs. 8% in block 2), hypokalaemia (18% vs. 6% 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

Following intravenous bolus administration of doses of 1.0 mg/m² 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 administrations, 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 intravenous bolus or subcutaneous administration of 1.3 mg/m² in patients with multiple myeloma (n = 14 in the intravenous group and n = 17 in the subcutaneous group), the total systemic exposure after repeated dosing (AUClast) was equivalent between subcutaneous and intravenous administration. The maximum concentration (Cmax) after subcutaneous administration (20.4 ng/ml) was lower than after intravenous administration (223 ng/ml). The geometric mean ratio of AUClast was 0.99, with a 90% 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 intravenous administrations of 1.0 mg/m² or 1.3 mg/m² in patients with multiple myeloma. This indicates extensive distribution of bortezomib into peripheral tissues. At bortezomib concentrations of 0.01–1.0 µg/ml, the in vitro binding to human plasma proteins was 82.9%. The fraction of bortezomib bound to plasma proteins was independent of concentration.

Metabolism

In vitro studies using human liver microsomes and human cDNA-expressed cytochrome P450 isoenzymes showed that oxidative metabolism of bortezomib is primarily mediated 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 metabolites of bortezomib are inactive as inhibitors of the 26S proteasome.

Elimination

The mean elimination 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 doses 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 61 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 the dose-normalized AUC of bortezomib compared to normal hepatic function. However, dose-normalized mean AUC values of bortezomib increased by approximately 60% in patients with moderate and severe hepatic impairment. A lower starting dose is recommended for patients with moderate or severe hepatic impairment, and these patients require close monitoring (see section "Posology and method of administration", Table 12).

Renal impairment

Pharmacokinetic studies were conducted in patients with varying degrees of renal impairment, categorized according to 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 a dose post-dialysis were also included in the study (n = 8). Patients received intravenous bortezomib at doses of 0.7–1.3 mg/m² twice weekly. The effect of bortezomib (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 via intravenous bolus injection 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 L/h/m² (25%), volume of distribution at steady state was 834 L/m² (39%), and elimination half-life was 100 hours (44%). 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 was positive for clastogenic activity (structural chromosomal aberrations) in an in vitro chromosomal aberration assay using Chinese hamster ovary (CHO) cells at a concentration as low as 3.125 µg/ml, the lowest concentration tested. Bortezomib was not genotoxic in the in vitro mutagenicity test (Ames test) or in the in vivo micronucleus test in mice.

Developmental toxicity studies in rats and rabbits demonstrated embryonal-foetal lethality at doses toxic to the dam, but did not show direct embryonal-foetal toxicity at doses below those toxic to the dam. Fertility studies were not conducted, but reproductive tissues were evaluated in general toxicity studies. In a 6-month rat study, degenerative effects were observed in both testes and ovaries. Therefore, bortezomib may potentially affect fertility in men or women. 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, causing vomiting and/or diarrhoea; haematopoietic and lymphatic tissues, leading to peripheral cytopenia, lymphoid atrophy, and hypocellularity of haematopoietic bone marrow; peripheral neuropathy (observed in monkeys, mice, and dogs) involving sensory nerve axons; and minor changes in the kidneys. Partial or complete recovery in all these target organs was demonstrated after treatment discontinuation.

According to animal studies, penetration of bortezomib across the blood-brain barrier is likely limited, and its significance in humans is unknown.

Pharmacological cardiovascular safety studies in monkeys and dogs demonstrated that intravenous doses approximately two to three times higher than the recommended clinical dose (on a mg/m² basis) were associated with increased heart rate, reduced contractility, hypotension, and death. In dogs, reduced cardiac contractility and hypotension responded to acute administration of agents with positive inotropic or pressor effects. Additionally, minor QTc interval prolongation was observed in dog studies.

Clinical characteristics.

Indications.

The medicinal product Bortezomib Ever Pharma as monotherapy or in combination with pegylated liposomal doxorubicin or dexamethasone is indicated for the treatment of relapsed multiple myeloma in adult patients who have received at least one prior therapy and who have undergone or are not candidates for hematopoietic stem cell transplantation.

Bortezomib Ever Pharma in combination with melphalan and prednisone is indicated for the treatment of multiple myeloma in adult patients who have not received prior therapy and who are not eligible for high-dose chemotherapy with hematopoietic stem cell transplantation.

Bortezomib Ever Pharma in combination with dexamethasone or dexamethasone and thalidomide is indicated for induction treatment of multiple myeloma in adult patients who have not received prior therapy and who are eligible for high-dose chemotherapy with hematopoietic stem cell transplantation.

Bortezomib Ever Pharma in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone is indicated for the treatment of mantle cell lymphoma in adult patients who have not received prior therapy and who are not eligible for hematopoietic stem cell transplantation.

Contraindications.

Hypersensitivity to bortezomib, boron, or to any excipient of the medicinal product.

Acute diffuse infiltrative pulmonary and pericardial diseases.

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

Special precautions.

Pregnant personnel should not handle this medicinal product.

General warnings

Bortezomib is a cytotoxic agent; therefore, caution should be exercised when handling it. The use of gloves and protective clothing is recommended to prevent skin contact.

Appropriate aseptic techniques should be strictly followed when handling Bortezomib Ever Pharma, as this medicinal product does not contain preservatives.

Fatal outcomes have been reported following accidental intrathecal administration of bortezomib. Bortezomib Ever Pharma, solution for injection, 2.5 mg/mL is intended for subcutaneous and, after dilution, also for intravenous administration. Bortezomib Ever Pharma must not be administered intrathecally.

Proper disposal procedure

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

Interaction with other medicinal products and other forms of interactions.

In vitro studies have demonstrated that bortezomib is a weak inhibitor of cytochrome P450 (CYP) 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.

A drug interaction study evaluating the effect of ketoconazole, a potent CYP3A4 inhibitor, on the pharmacokinetics of bortezomib (after intravenous administration) demonstrated an average increase in bortezomib AUC by 35% (90% CI from 1.032 to 1.772) based on data from 12 patients. Therefore, careful monitoring of patients receiving bortezomib concomitantly with potent CYP3A4 inhibitors (such as ketoconazole, ritonavir) is recommended.

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

A drug interaction study evaluating the effect of rifampicin, a potent CYP3A4 inducer, on the pharmacokinetics of bortezomib (after intravenous administration) in 6 patients revealed a mean decrease in bortezomib AUC by 45%. Therefore, concomitant administration of bortezomib with potent CYP3A4 inducers (such as rifampicin, carbamazepine, phenytoin, phenobarbital, and St. John's wort extract) is not recommended, as the efficacy of bortezomib may be reduced.

In the same drug interaction study evaluating the effect of dexamethasone, a weak inducer of CYP3A4, on the pharmacokinetics of bortezomib (after intravenous administration), dexamethasone did not significantly alter the pharmacokinetics of bortezomib based on data from 7 patients.

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

During clinical trials, cases of hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemic agents. Blood glucose levels should be monitored and doses of antidiabetic agents adjusted accordingly in patients receiving bortezomib.

Special precautions for use.

If the medicinal product Bortezomib Ever Pharma is used in combination with other medicinal products, refer to the instructions for medical use of these medicinal products before initiating treatment. If thalidomide is used, special attention should be paid to pregnancy diagnosis and contraceptive measures (see section "Use during pregnancy or breastfeeding").

Intrathecal administration

Fatal cases due to accidental intrathecal administration of bortezomib have been reported. The medicinal product Bortezomib Ever Pharma must be administered only intravenously or subcutaneously and must not be administered intrathecally.

Gastrointestinal toxicity

Treatment with bortezomib may very commonly cause gastrointestinal toxicity, including nausea, diarrhea, constipation, and vomiting. Rare cases of intestinal obstruction have been reported (see section "Undesirable effects"), therefore patients with constipation should be under medical supervision.

Hematological toxicity

Hematological toxicity (thrombocytopenia, neutropenia, and anemia) is very commonly observed during bortezomib therapy. During studies of bortezomib in patients with relapsed multiple myeloma and in combination therapy with rituximab, cyclophosphamide, doxorubicin, and prednisone (BR-CAP regimen) in previously untreated MCL patients, one of the most common hematological toxicities was reversible thrombocytopenia. Platelet counts were typically lowest on day 11 of each bortezomib treatment cycle and usually returned to baseline levels before the start of the next cycle. Cumulative thrombocytopenia was not observed. On average, the lowest measured platelet count was approximately 40% of the baseline level in studies of bortezomib monotherapy in multiple myeloma patients and 50% in studies of bortezomib in MCL patients. In patients with progressive myeloma, the severity of thrombocytopenia was related to the platelet count before treatment: in 90% of 21 patients with baseline platelet counts < 75,000/µL, platelet counts were ≤ 25,000/µL during the study, including 14% with counts < 10,000/µL, whereas in 14% of 309 patients with baseline platelet counts > 75,000/µL, platelet counts were ≤ 25,000/µL.

In MCL patients (study LYM-3002), thrombocytopenia of grade ≥ 3 was observed more frequently (56.7% compared to 5.8%) in the group receiving bortezomib (BR-CAP) than in patients receiving R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). The two treatment groups were similar regarding the overall frequency of bleeding of any severity (6.3% in the BR-CAP group vs. 5.0% in the R-CHOP group), as well as grade 3 or higher bleeding (BR-CAP: 4 patients (1.7%); R-CHOP: 3 patients (1.2%)). In the BR-CAP group, 22.5% of patients received platelet transfusions compared to 2.9% in the R-CHOP group.

Cases of gastrointestinal and intracranial hemorrhages associated with bortezomib use have been reported. Therefore, platelet counts should be monitored before each dose of Bortezomib Ever Pharma. Therapy with Bortezomib Ever Pharma 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 "Dosage and administration"). The benefit-risk ratio associated with Bortezomib Ever Pharma therapy should be evaluated, especially in cases of moderate or severe thrombocytopenia and presence of bleeding risk factors.

Complete blood counts with differential white blood cell count and platelet count should be frequently performed during treatment with Bortezomib Ever Pharma. Platelet transfusion should be considered if clinically indicated (see section "Dosage and administration").

Reversible neutropenia between treatment cycles has been observed in MCL patients; cumulative neutropenia was not observed. Neutrophil counts were typically lowest on day 11 of each bortezomib treatment cycle and returned to baseline levels before the start of the next cycle. In study LYM-3002, 78% of patients in the BR-CAP treatment group and 61% in the R-CHOP group received colony-stimulating factor. Since patients with neutropenia have an increased risk of developing infections, their condition 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 practice. If initiation of a new treatment cycle is delayed several 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 treated with Bortezomib Ever Pharma. In phase III trials involving patients with untreated multiple myeloma, the overall frequency of Herpes zoster (shingles) reactivation was higher in the group receiving bortezomib + melphalan + prednisone (14%) compared to the group receiving melphalan + prednisone (4%).

Among patients with mantle cell lymphoma, the incidence of shingles was 6.7% in the BR-CAP treatment group and 1.2% in the R-CHOP treatment group (see section "Undesirable effects").

Reactivation and infection with hepatitis B virus (HBV)

Testing for HBV should always be performed before initiating treatment with rituximab in combination with bortezomib in patients with risk factors. HBV carriers and patients with a history of hepatitis B should be carefully monitored for clinical signs and laboratory indicators of active HBV during and after combination therapy with rituximab and bortezomib. Antiviral prophylaxis should be considered (for detailed information, see the prescribing information for rituximab).

Progressive multifocal leukoencephalopathy (PML)

Very rare cases of infection with John Cunningham virus causing fatal PML have been reported in patients treated with bortezomib. Patients diagnosed with PML had received immunosuppressive therapy either in their history or concurrently with bortezomib. Most cases of PML were diagnosed within the first 12 months after initiation of bortezomib treatment. Patients should be regularly examined for the emergence of 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 progressive multifocal leukoencephalopathy, and appropriate diagnostic measures should be taken. Upon confirmation of PML diagnosis, treatment with Bortezomib Ever Pharma should be discontinued.

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 frequency of peripheral neuropathy increases at the beginning of treatment and reaches a maximum at cycle 5.

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 administration of bortezomib, the incidence of peripheral neuropathy of grade ≥ 2 was 24% in the subcutaneous group and 41% in the intravenous group (p = 0.0124). Peripheral neuropathy of grade ≥ 3 occurred in 6% of patients in the subcutaneous group and 16% in the intravenous group (p = 0.0264). The incidence of peripheral neuropathy of any grade with intravenous bortezomib was lower in previous studies with intravenous bortezomib than in study MMY-3021.

If peripheral neuropathy develops or 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 was managed with supportive measures and other therapies.

Early and regular monitoring for treatment-induced neuropathy symptoms and neurological examination should be initiated in patients receiving Bortezomib Ever Pharma in combination with agents associated with neuropathy (such as thalidomide); dose reduction or discontinuation of treatment should be considered.

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

Seizures

Rare cases of seizure development have been reported in patients without prior history of seizures or epilepsy. Particular caution is required when treating patients with any risk factors for seizures.

Hypotension

Bortezomib therapy is frequently associated with postural/orthostatic hypotension. In most cases, it is mild or moderate in severity and occurs throughout treatment. Patients who developed orthostatic hypotension during bortezomib (intravenous) administration did not have symptoms of orthostatic hypotension before 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 of its development is unknown. It may be related to autonomic neuropathy. Autonomic neuropathy may be associated with bortezomib use or bortezomib may exacerbate underlying conditions, including diabetic or amyloid neuropathy. Caution should be exercised when treating patients with a history of syncope, those taking antihypertensive medications, and those with dehydration due to diarrhea or vomiting. Management of orthostatic/postural hypotension may include dose adjustment of antihypertensive drugs, rehydration, or administration of mineralocorticoids and/or sympathomimetics. Patients should be instructed to consult a physician if they experience dizziness, pre-syncope, or loss of consciousness.

Reversible posterior encephalopathy syndrome (PRES)

Cases of PRES have been reported in patients treated with bortezomib. PRES is a rare, often reversible neurological disorder characterized by seizures, arterial hypertension, headache, lethargy, confusion, visual disturbances, and other neurological impairments. Brain imaging, preferably magnetic resonance imaging (MRI), should be performed to confirm diagnosis. Treatment with Bortezomib Ever Pharma should be discontinued if PRES occurs.

Heart failure

Cases of acute onset or worsening of pre-existing congestive heart failure and/or reduced left ventricular ejection fraction have been reported with bortezomib use. Fluid retention may contribute to the development of signs and symptoms of heart failure. Patients with risk factors or pre-existing cardiac disease should be under medical supervision.

ECG investigations

Isolated cases of QT interval prolongation have been observed in clinical trials; the cause has not been established.

Lung function disorders

Rare cases of acute diffuse infiltrative lung diseases of unknown etiology, such as pneumonitis, interstitial pneumonia, pulmonary infiltration, and acute respiratory distress syndrome (ARDS), have been observed in patients receiving bortezomib (see section "Undesirable effects"). Some of these cases were fatal. Radiological examination is recommended before treatment initiation to establish baseline lung status 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 taken. The benefit-risk balance of continuing treatment with Bortezomib Ever Pharma should be carefully considered.

In clinical trials, 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. Therefore, this specific regimen combining high-dose cytarabine (2 g/m²/day) as continuous 24-hour infusion is not recommended.

Renal function impairment

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

Hepatic function impairment

Bortezomib is metabolized by hepatic enzymes. In patients with moderate to severe hepatic impairment, bortezomib concentrations may increase; 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 acute liver failure have been reported in patients treated with bortezomib concomitantly with other drugs and in patients with serious comorbid conditions. Cases of elevated liver enzymes, hyperbilirubinemia, and hepatitis that resolved after bortezomib discontinuation have also been reported (see section "Undesirable effects").

Tumor lysis syndrome

Since bortezomib is a cytotoxic agent capable of rapidly killing tumor plasma cells, complications associated with tumor lysis syndrome may occur. Patients with high tumor burden prior to treatment initiation are at particular risk. Careful monitoring of such patients and appropriate preventive measures are recommended.

Precautions 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 optimized before initiating treatment, and caution should be exercised when treating patients taking 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 observed rarely. Bortezomib should be discontinued in case of serious reactions.

Excipients

This medicinal product contains less than 1 mmol (23 mg) sodium/vial, i.e., essentially sodium-free.

Use during pregnancy or breastfeeding.

Contraception in women and men

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

Pregnancy

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

In non-clinical studies, bortezomib at the maximum tolerated maternal doses did not affect embryonic/fetal development in rats and rabbits. Studies on the effect of bortezomib on pre- and postnatal development in animals were not conducted (see section "Non-clinical safety data"). Bortezomib is not recommended during pregnancy except when the woman's clinical condition necessitates bortezomib treatment. 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 except when all requirements of the thalidomide pregnancy prevention program are met. Patients receiving bortezomib in combination with thalidomide must comply with the thalidomide pregnancy prevention program. See the thalidomide prescribing information for additional information.

Breastfeeding

It is unknown whether bortezomib is excreted in human breast milk, but to prevent the occurrence of severe adverse reactions in the infant, breastfeeding is not recommended during bortezomib treatment.

Fertility

Studies on the effect of bortezomib on fertility have not been conducted (see section "Non-clinical safety data").

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 rarely with syncope. Therefore, patients should be cautious when driving or operating machinery and should avoid such activities if these symptoms occur (see section "Undesirable effects").

Method of administration and dosage.

Treatment with Bortezomib Ever Pharma should be initiated under the supervision of a qualified physician experienced in the treatment of cancer patients, although treatment may also be administered under the supervision of a healthcare professional experienced in the use of chemotherapeutic agents. Preparation of the solution must be performed only by qualified medical personnel (see section "Special precautions for safety").

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

Monotherapy

Bortezomib Ever Pharma is administered by subcutaneous and, after dilution, intravenous injection at the recommended dose of 1.3 mg/m² body surface area twice weekly for 2 weeks on days 1, 4, 8, and 11 of a 21-day cycle. This 3-week period is considered one treatment cycle. After achieving a complete clinical response, it is recommended to administer two additional cycles of bortezomib treatment. It is also recommended that patients who respond to treatment but do not achieve a complete remission receive a total of 8 treatment cycles with Bortezomib Ever Pharma. At least 72 hours should elapse between consecutive doses of Bortezomib Ever Pharma.

Dose modification and re-initiation recommendations for monotherapy

In the event of any grade 3 non-hematological toxicity or grade 4 hematological toxicity (excluding neuropathies), treatment with Bortezomib Ever Pharma must be interrupted as specified below (see also section "Special instructions"). After resolution of toxicity symptoms, treatment with Bortezomib Ever Pharma may be resumed at a dose reduced by 25% (reduce dose from 1.3 mg/m² to 1.0 mg/m²; reduce dose from 1.0 mg/m² to 0.7 mg/m²). If toxicity symptoms do not resolve or recur upon administration of the reduced dose, discontinuation of Bortezomib Ever Pharma should be considered, unless the benefits of continued treatment outweigh the risks.

Neuropathic pain and/or peripheral neuropathy

The drug dose should be adjusted in case of development of neuropathic pain and/or peripheral neuropathy (see Table 7) (see also section "Special instructions"). Bortezomib Ever Pharma should be used in patients with a history of severe neuropathy only after careful assessment of the benefit-risk ratio.

Table 7

Recommended* dose adjustment for bortezomib-induced neuropathy

* The backslash before the asterisk is preserved as per the original Markdown escape sequence.

*Based on dose modifications in Phase II and III multiple myeloma studies and in the post-marketing period. Grading based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0.

**Instrumental activities of daily living include cooking, shopping for groceries or clothing, using the telephone, managing money, etc.

***Personal care activities of daily living include bathing, dressing/undressing, eating, using the toilet, taking medications, and being out of bed.

Combination therapy with pegylated liposomal doxorubicin

Bortezomib Ever Pharma is administered by subcutaneous injection and, after dilution, by intravenous injection at the recommended dose of 1.3 mg/m² body surface area twice weekly for 2 weeks on days 1, 4, 8, and 11 of a 21-day treatment cycle. This 3-week period is considered one treatment cycle. At least 72 hours should elapse between consecutive doses of Bortezomib Ever Pharma.

Pegylated liposomal doxorubicin is administered at a dose of 30 mg/m² on day 4 of the treatment cycle with Bortezomib Ever Pharma by 1-hour intravenous infusion after administration of Bortezomib Ever Pharma.

Up to 8 cycles of this combination therapy should be administered if the disease does not progress and patients tolerate treatment well. Patients who achieve a complete remission may continue treatment for at least 2 additional cycles after achieving complete response, even if this requires more than 8 treatment cycles. Patients whose paraprotein levels continue to decline after 8 cycles may also continue treatment as long as treatment remains tolerable and a response is observed. For additional information on pegylated liposomal doxorubicin, see the respective summary of product characteristics.

Combination therapy with dexamethasone

Bortezomib Ever Pharma is administered by subcutaneous injection and, after dilution, by intravenous injection at the recommended dose of 1.3 mg/m² body surface area twice weekly for 2 weeks on days 1, 4, 8, and 11 of a 21-day treatment cycle. This 3-week period is considered one treatment cycle. At least 72 hours should elapse between consecutive doses of bortezomib.

Dexamethasone is administered orally at a dose of 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 of the treatment cycle with Bortezomib Ever Pharma.

Patients who show a response to treatment or stable disease after four cycles of combination therapy may continue treatment with this combination for up to four additional cycles. For further information on dexamethasone, refer to the summary of product characteristics for this medicinal product.

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

See dose modification recommendations for Bortezomib Ever Pharma during monotherapy as listed above.

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

Combination therapy with melphalan and prednisone

Bortezomib Ever Pharma is administered by subcutaneous injection and, after dilution, by intravenous injection in combination with oral melphalan and oral prednisone, as shown in Table 8. A 6-week period is considered one treatment cycle. In cycles 1–4, Bortezomib Ever Pharma is administered twice weekly on days 1, 4, 8, 11, 22, 25, 29, and 32. In cycles 5–9, Bortezomib Ever Pharma is administered once weekly on days 1, 8, 22, and 29. At least 72 hours should elapse between consecutive doses of Bortezomib Ever Pharma.

Melphalan and prednisone are administered orally on days 1, 2, 3, and 4 of the first week of each Bortezomib Ever Pharma treatment cycle.

A total of nine cycles of this combination therapy are administered.

Table 8

Recommended dosing regimen of Bortezomib Ever Pharma in combination with melphalan and prednisone

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 is ≥ 70 × 109/l and absolute neutrophil count is ≥ 1.0 × 109/l;
• non-hematological toxicity has recovered to grade 1 or baseline level.

Table 9

Dose adjustment during subsequent cycles of treatment with Bortezomib Ever Pharma in combination with melphalan and prednisone

For additional information on melphalan and prednisone, see the prescribing information for these medicinal products.

Untreated multiple myeloma in patients eligible for hematopoietic stem cell transplantation (induction therapy)

Combination therapy with dexamethasone

The medicinal product Bortezomib Ever Pharma is administered subcutaneously and, after dilution, intravenously at the recommended dose of 1.3 mg/m² body surface area twice weekly for 2 weeks on days 1, 4, 8, and 11 of a 21-day treatment cycle. This 3-week period constitutes one treatment cycle. At least 72 hours must elapse between consecutive doses of Bortezomib Ever Pharma.

Dexamethasone is administered orally at a dose of 40 mg on days 1, 2, 3, 4, 8, 9, 10, and 11 of the treatment cycle with Bortezomib Ever Pharma.

Administer 4 treatment cycles using this combination.

Combination therapy with dexamethasone and thalidomide

The medicinal product Bortezomib Ever Pharma is administered subcutaneously and, after dilution, intravenously at the recommended dose of 1.3 mg/m² body surface area twice weekly for 2 weeks on days 1, 4, 8, and 11 of a 28-day treatment cycle. This 4-week period constitutes one treatment cycle. At least 72 hours must elapse between consecutive doses of Bortezomib Ever Pharma.

Dexamethasone is administered orally at a dose of 40 mg on days 1, 2, 3, 4, 8, 9, 10, and 11 of the treatment cycle with Bortezomib Ever Pharma.

Thalidomide is 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.

Table 10

Recommended dosing regimen of the medicinal product Bortezomib Ever Pharma in combination therapy for patients with untreated multiple myeloma eligible for hematopoietic stem cell transplantation

Dx — dexamethasone; Th — thalidomide.

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

b Patients who achieve at least a partial response after 4 cycles of treatment may continue up to 6 cycles of treatment.

Dosing recommendations for patients eligible for transplantation

For dose adjustments, refer to the dose modification recommendations for monotherapy with the medicinal product Bortezomib Ever Pharma.

If Bortezomib Ever Pharma is used in combination with other chemotherapeutic agents, refer to the package leaflets of these medicinal products for information on dose reductions in case of toxicity.

Untreated mantle cell lymphoma

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

The medicinal product Bortezomib Ever Pharma is administered by subcutaneous and, after dilution, intravenous injection at the recommended dose of 1.3 mg/m² body surface area twice weekly on days 1, 4, 8, and 11, followed by a 10-day treatment break on days 12–21. This 3-week period constitutes one treatment cycle. Six treatment cycles with Bortezomib Ever Pharma are recommended, although two additional cycles of Bortezomib Ever Pharma may be administered in patients who achieve a response for the first time in cycle 6. At least 72 hours should elapse between consecutive doses of Bortezomib Ever Pharma.

Medicinal products administered by intravenous infusion on day 1 of each 3-week treatment cycle with Bortezomib Ever Pharma: rituximab at a dose of 375 mg/m², cyclophosphamide at 750 mg/m², doxorubicin at 50 mg/m².

Prednisone is administered orally at a dose of 100 mg/m² on days 1, 2, 3, 4, and 5 of each treatment cycle with Bortezomib Ever Pharma.

Dose adjustment recommendations for patients with untreated mantle cell lymphoma

Before starting a new treatment cycle:

• Platelet count ≥ 100,000 cells/µL and absolute neutrophil count ≥ 1,500 cells/µL;
• Platelet count ≥ 75,000 cells/µL in patients with bone marrow infiltration or splenic sequestration;
• Hemoglobin level ≥ 8 g/dL;
• Non-hematological toxicity has resolved to grade 1 or baseline levels.

Treatment with Bortezomib Ever Pharma should be withheld in the event of any non-hematological toxicity ≥ grade 3 severity (except neuropathy) related to bortezomib administration, or hematological toxicity ≥ grade 3 severity (see also section "Special precautions"). Dose adjustment recommendations are provided in Table 11 below.

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

Table 11

Dose adjustments during therapy for patients with untreated mantle cell lymphoma

If the medicinal product Bortezomib Ever Pharma is used in combination with other chemotherapeutic agents, refer to the instructions for use of those medicinal products for information on dose reduction in the event of toxicity.

Special patient groups

Elderly patients

There are currently no data indicating the need for dose adjustment in patients aged 65 years and older with multiple myeloma or mantle cell lymphoma.

There are no studies on 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 given for this patient group.

In a study of bortezomib use in patients with previously untreated mantle cell lymphoma, 42.9% of patients were aged 65–74 years and 10.4% were aged ≥75 years. Patients aged 75 years and older tolerated treatment less well in both treatment groups (BR-CAP and R-CHOP regimens) (see section "Adverse reactions").

Patients with hepatic impairment

Dose adjustment is not required in patients with mild hepatic impairment; the recommended dose should be used. Patients with moderate and severe hepatic impairment should start treatment 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 tolerance to the drug (see Table 12 and sections "Pharmacological properties" and "Dosage and administration").

Table 12

Recommended adjustments of initial bortezomib doses for patients with hepatic impairment

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

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

Patients with renal impairment

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

Method of administration

Bortezomib Ever Pharma is administered subcutaneously and, after dilution, intravenously.

Bortezomib Ever Pharma must not be administered by other routes. Intrathecal administration has resulted in fatal outcomes.

Intravenous injection

Bortezomib Ever Pharma, injection solution, 2.5 mg/ml, is initially diluted to 1 mg/ml (see below Instructions for preparation and administration) and, after dilution, administered as a 3–5 second intravenous bolus injection via a peripheral or central venous catheter, followed by flushing the catheter with 9 mg/ml (0.9 %) sodium chloride injection solution. At least 72 hours must elapse between consecutive doses of Bortezomib Ever Pharma.

Subcutaneous injection

Bortezomib Ever Pharma, injection solution, 2.5 mg/ml, is administered subcutaneously into the thigh (left or right) or abdomen (left or right quadrant). The solution should be injected subcutaneously at an angle of 45–90°. Injection sites should be rotated with subsequent injections.

In case of local reactions at the subcutaneous injection site, it is recommended to administer a less concentrated solution of Bortezomib Ever Pharma (1 mg/ml instead of 2.5 mg/ml) subcutaneously or switch to intravenous injections.

If Bortezomib Ever Pharma is used in combination with other medicinal products, refer to the respective product information leaflets for administration instructions.

Instructions for preparation and administration

Bortezomib Ever Pharma must be prepared by a healthcare professional.

One vial contains an overfill of 0.2 ml.

Chemical and physical stability after first opening and/or dilution has been demonstrated for 35 days at 2–8 °C in the dark, for 35 days at 25 °C in the dark, or for 24 hours at 25 °C under normal room lighting, when stored in the original vial and/or polypropylene syringe.

Intravenous administration

2.5 mg/1.0 ml:

Each vial of Bortezomib Ever Pharma is carefully diluted with 1.8 ml of sodium chloride 9 mg/ml (0.9 %), solution for injection for intravenous administration, using a syringe of appropriate size without removing the stopper from the vial.

OR

3.5 mg/1.4 ml:

Each vial of Bortezomib Ever Pharma is carefully diluted with 2.4 ml of sodium chloride 9 mg/ml (0.9 %), solution for injection for intravenous administration, using a syringe of appropriate size without removing the stopper from the vial.

After dilution, 1 ml of solution contains 1 mg of bortezomib. The diluted solution is clear, colorless to pale yellow, with a final pH of 4 to 7. The diluted solution should be visually inspected for particulate matter and discoloration prior to administration. If discoloration or particulate matter is observed, the solution must be discarded (disposed of).

Subcutaneous administration

Bortezomib Ever Pharma is ready for subcutaneous administration. 1 ml of solution contains 2.5 mg of bortezomib. The solution is clear, colorless to pale yellow, with a pH of 4 to 5.5. The solution should be visually inspected for particulate matter and discoloration prior to administration. If discoloration or particulate matter is observed, the solution must be discarded (disposed of).

Children

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

Overdose

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

There is no specific antidote for bortezomib. In case of overdose, careful monitoring of vital signs is recommended, and appropriate supportive measures should be taken to maintain blood pressure (such as fluid balance support, use of vasopressor and/or inotropic agents) and body temperature (see sections "Special warnings and precautions for use" and "Dosage and administration").

Adverse Reactions

Summary of Safety Profile

Severe adverse reactions reported during bortezomib treatment have 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 therapy are nausea, diarrhea, constipation, vomiting, asthenia, pyrexia, thrombocytopenia, anemia, neutropenia, peripheral neuropathy (including sensory neuropathy), headache, paraesthesia, decreased appetite, dyspnea, rash, herpes zoster, and myalgia.

Multiple Myeloma

The adverse reactions listed in Table 13 were considered by investigators to be possibly related to bortezomib administration. These adverse reactions were identified based on pooled data from 5,476 patients, of whom 3,996 received bortezomib at a dose of 1.3 mg/m². Overall, bortezomib was used to treat multiple myeloma in 3,974 patients.

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

Table 13

*Aggregated from more than one MedDRA term.

Post-marketing adverse reaction regardless of indication.

Mantle cell lymphoma

The safety profile of bortezomib was evaluated in 240 patients with mantle cell lymphoma who received bortezomib 1.3 mg/m² in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (BR-CAP), and in 242 patients who received rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). The overall safety profile was similar to that observed in patients with multiple myeloma; the main differences are described below. Additional adverse reactions observed with combination therapy (BR-CAP) included hepatitis B virus infection (< 1%) and myocardial ischemia (1.3%). The similar incidence of these events in both treatment groups suggests that these adverse reactions may not be solely related to bortezomib. Administration of bortezomib to patients with MCL was associated with ≥ 5% higher frequencies of hematologic adverse reactions (neutropenia, thrombocytopenia, leukopenia, anemia, lymphopenia), peripheral sensory neuropathy, arterial hypertension, pyrexia, pneumonia, stomatitis, and hair disorders compared to administration in patients with multiple myeloma.

Adverse reactions observed with a frequency of ≥ 1%, with similar or higher incidence in the BR-CAP group and at least a possible or probable causal relationship to components of the BR-CAP treatment regimen are listed in Table 14 below. Also included are adverse reactions observed in the BR-CAP treatment group that, in the opinion of investigators, were at least 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. Frequencies are defined as: very common (> 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000), and not known (cannot be estimated from available data). Within each group, adverse reactions are listed in order of decreasing severity. Table 14 was created using MedDRA version 16.

Table 14

Adverse reactions in patients with mantle cell lymphoma receiving BR-CAP in a clinical trial

* Aggregated from more than one MedDRA term.

Description of selected adverse reactions

Herpes zoster virus reactivation

Multiple myeloma

Antiviral prophylaxis was administered in 26% of patients receiving the combination of bortezomib with melphalan and prednisone. The incidence of herpes zoster was 17% in patients who did not receive antiviral prophylaxis compared to 3% in those who did.

Mantle cell lymphoma

Antiviral prophylaxis was administered in 137 out of 240 patients (57%) receiving combination therapy with the BR-CAP regimen. Herpes zoster occurred in 10.7% of patients who did not receive antiviral prophylaxis compared to 3.6% of patients who did (see section "Special precautions").

Hepatitis B virus (HBV) reactivation and infection

Mantle cell lymphoma

Cases of hepatitis B infection with fatal outcome were reported in 0.8% of patients (n = 2) in the group receiving R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) and in 0.4% of patients (n = 1) receiving bortezomib as part of combination therapy with the BR-CAP regimen (rituximab, cyclophosphamide, doxorubicin, and prednisone). The overall incidence of hepatitis B was similar in both treatment groups (0.8% in the BR-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 and thalidomide (MMY-3010 study) (see Table 15).

Table 15

Incidence of peripheral neuropathy (PN) during induction therapy by toxicity grade and discontinuation due to PN

VDDx — vincristine, doxorubicin, dexamethasone; BDx — bortezomib, dexamethasone; TDx — thalidomide, dexamethasone; BTDx — bortezomib, thalidomide, dexamethasone.

Peripheral neuropathy includes the following preferred terms: 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-CHP), cases of peripheral neuropathy were observed (see Table 16).

Table 16

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

BR-CAP — bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone; R-CHOP — rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone.

Peripheral neuropathy includes the following preferred terms: peripheral sensory neuropathy, peripheral neuropathy, peripheral motor neuropathy, and peripheral sensorimotor neuropathy.

Elderly patients with mantle cell lymphoma

In the BR-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 BR-CAP group compared to 42% in the R-CHOP group.

Main differences in the safety profile of bortezomib monotherapy administered intravenously versus subcutaneously

In a Phase III study, patients receiving subcutaneous bortezomib had a 13% lower incidence of treatment-emergent adverse reactions of Grade 3 toxicity or higher, and a 5% lower incidence of treatment interruption with bortezomib, compared to those 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 3 or higher peripheral neuropathy was 10% lower, and the incidence of treatment discontinuation due to peripheral neuropathy was 8% lower.

Injection site reactions occurred in 6% of patients, predominantly erythema. Symptoms resolved on average within 6 days, and dose modification was required in 2 patients.

Two patients (1%) experienced severe reactions: one case of pruritus and one case of erythema.

The rate of fatal events during treatment was 5% in the subcutaneous group and 7% in the intravenous group. Mortality due to disease progression was 18% in the subcutaneous group and 9% in the intravenous group.

Re-treatment of patients with relapsed multiple myeloma

In a study of bortezomib re-treatment involving 130 patients with relapsed multiple myeloma who had previously achieved at least a partial response to bortezomib-containing therapy, adverse reactions of all grades occurring in at least 25% of patients primarily included thrombocytopenia (55%), neuropathy (40%), anemia (37%), diarrhea (35%), and constipation (28%). Peripheral neuropathy of all grades and peripheral neuropathy ≥ Grade 3 were observed in 40% and 8.5% of patients, respectively.

Reporting of suspected adverse reactions

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

Shelf life. 2 years.

Storage conditions.

Store at 2 °C to 8 °C in the original packaging to protect from light. Keep out of the reach of children.

Incompatibilities.

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

Packaging.

1. 1 ml in a vial stoppered with a rubber stopper and sealed with an aluminum cap with a plastic flip-off disc, 1 vial in a cardboard box.
2. 1.4 ml in a vial stoppered with a rubber stopper and sealed with an aluminum cap with a plastic flip-off disc, 1 vial in a cardboard box.

Prescription status. Prescription only.

Manufacturer. EVER Pharma Jena GmbH.

Manufacturer’s address and locations of operations.

1. Otto-Schott-Strasse 15, Sued, Jena, Thuringia, 07745, Germany / Otto-Schott-Strasse 15, Sued, Jena, Thuringia, 07745, Germany.
2. Bruesseler Strasse 18, Lobeda, Jena, 07747, Germany / Bruesseler Strasse 18, Lobeda, Jena, 07747, Germany.