Velcade

Velcade

bortezomib

Manufacturer:

Janssen

Distributor:

DCH Auriga - Healthcare
/
Four Star
Full Prescribing Info
Contents
Bortezomib.
Description
Each vial contains 3.5 mg bortezomib (as a mannitol boronic ester).
After reconstitution, 1 mL of solution for subcutaneous injection contains 2.5 mg bortezomib.
After reconstitution, 1 mL of solution for intravenous injection contains 1 mg bortezomib.
Excipients/Inactive Ingredients: Mannitol, nitrogen.
Action
Pharmacotherapeutic Group: Antineoplastic agents, other antineoplastic agents. ATC Code: L01XX32.
Pharmacology: 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 ubiquitinated proteins. The ubiquitin-proteasome pathway plays an essential role in regulating the turnover of specific proteins, thereby maintaining homeostasis within cells. Inhibition of the 26S proteasome prevents this targeted proteolysis and affects multiple signalling cascades within the cell, ultimately resulting in cancer cell death.
Bortezomib is highly selective for the proteasome. At 10 μM concentrations, bortezomib does not inhibit any of a wide variety of receptors and proteases screened and is more than 1,500-fold more selective for the proteasome than for its next preferable enzyme. The kinetics of proteasome inhibition were evaluated in vitro, and bortezomib was shown to dissociate from the proteasome with a t½ of 20 minutes, thus demonstrating that proteasome inhibition by bortezomib is reversible.
Bortezomib mediated proteasome inhibition affects cancer cells in a number of ways, including, but not limited to, altering regulatory proteins, which control cell cycle progression and nuclear factor kappa B (NF-kB) activation. Inhibition of the proteasome results in cell cycle arrest and apoptosis. NF-kB is a transcription factor whose activation is required for many aspects of tumourigenesis, 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 demonstrated that bortezomib is cytotoxic to a variety of cancer cell types and that cancer cells are more sensitive to the pro-apoptotic effects of proteasome inhibition than normal cells. Bortezomib causes reduction of tumour growth in vivo in many preclinical tumour models, including multiple myeloma.
Data from in vitro, ex vivo, and animal models with bortezomib suggest that it increases osteoblast differentiation and activity and inhibits osteoclast function. These effects have been observed in patients with multiple myeloma affected by an advanced osteolytic disease and treated with bortezomib.
Clinical Efficacy in Previously Untreated Multiple Myeloma: A prospective Phase III, international, randomised (1:1), open label clinical study (MMY-3002 VISTA) of 682 patients was conducted to determine whether VELCADE (1.3 mg/m2 injected intravenously) in combination with melphalan (9 mg/m2) and prednisone (60 mg/m2) resulted in improvement in time to progression (TTP) when compared to melphalan (9 mg/m2) and prednisone (60 mg/m2) in patients with previously untreated multiple myeloma. Treatment was administered for a maximum of 9 cycles (approximately 54 weeks) and was discontinued early for disease progression or unacceptable toxicity. The median age of the patients in the study was 71 years, 50% were male, 88% were Caucasian and the median Karnofsky performance status score for the patients was 80. Patients had IgG/IgA/Light chain myeloma in 63%/25%/8% instances, a median hemoglobin 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 arm).
At the time of a pre-specified interim analysis, the primary endpoint, time to progression, was met and patients in the M+P arm were offered Vc+M+P treatment. Median follow up was 16.3 months. The final survival update was performed with a median duration of follow up of 60.1 months. A statistically significant survival benefit in favour of the Vc+M+P treatment group was observed (HR=0.695; p=0.00043) despite subsequent therapies including VELCADE-based regimens. Median survival for the Vc+M+P treatment group was 56.4 months compared to 43.1 for the M+P treatment group. Efficacy results are presented in Table 1. (See Table 1.)

Click on icon to see table/diagram/image

Patients Eligible for Stem Cell Transplantation: Two randomised, open-label, multicenter Phase III trials (IFM-2005-01, MMY-3010) were conducted to demonstrate the safety and efficacy of VELCADE in dual and triple combinations with other chemotherapeutic agents, as induction therapy prior to stem cell transplantation in patients with previously untreated multiple myeloma.
In study IFM-2005-01 VELCADE combined with dexamethasone [VcDx, n=240] was compared to vincristine-doxorubicin-dexamethasone [VDDx, n=242]. Patients in the VcDx group received four 21 day cycles, each consisting of VELCADE (1.3 mg/m2 administered intravenously twice weekly on days 1, 4, 8, and 11), and oral dexamethasone (40 mg/day on days 1 to 4 and days 9 to 12, in Cycles 1 and 2, and on days 1 to 4 in Cycles 3 and 4).
Autologous stem cell transplants were received by 198 (82%) patients and 208 (87%) patients in the VDDx and VcDx groups respectively; the majority of patients underwent one single transplant procedure. Patient demographic and baseline disease charateristics were similar between the treatment groups. Median age of the patients in the study was 57 years, 55% were male and 48% of patients had high-risk cytogenetics. The median duration of treatment was 13 weeks for the VDDx group and 11 weeks for the VcDx group. The median number of cycles received for both groups was 4 cycles.
The primary efficacy endpoint of the study was post induction response rate (CR+nCR). A statistically significant difference in CR+nCR was observed in favour of the VELCADE combined with dexamethasone group. Secondary efficacy endpoints included post transplant response rates (CR+nCR, CR+nCR+VGPR+PR), Progression Free Survival and Overall Survival. Main efficacy results are presented in Table 2.

Click on icon to see table/diagram/image

In study MMY-3010 induction treatment with VELCADE combined with thalidomide and dexamethasone [VcTDx, n=130] was compared to thalidomide dexamethasone [TDx, n=127]. Patients in the VcTDx group received six 4-week cycles, each consisting of VELCADE (1.3 mg/m2 administered twice weekly days 1, 4, 8, and 11, followed by a 17-day rest period from day 12 to day 28), dexamethasone (40 mg administered orally on days 1 to 4 and days 8 to 11), and thalidomide (administered orally at 50 mg daily on days 1-14, increased to 100 mg on days 15-28 and thereafter to 200 mg daily).
One single autologous stem cell transplant was received by 105 (81%) patients and 78 (61%) patients in the VcTDx and TDx groups, respectively. Patient demographic and baseline disease charateristics were similar between the treatment groups. Patients in the VcTDx and TDx groups respectively had a median age of 57 versus 56 years, 99% versus 98% patients were Caucasians, and 58% versus 54% were males. In the VcTDx group 12% of patients were cytogenetically classified as high risk versus 16% of patients in the TDx group. The median duration of treatment was 24 weeks and the median number of treatment cycles received was 6, and was consistent across treatment groups.
The primary efficacy endpoints of the study were post-induction and post-transplant response rates (CR+nCR). A statistically significant difference in CR+nCR was observed in favour of the VELCADE combined with dexamethasone and thalidomide group. Secondary efficacy endpoints included Progression Free Survival and Overall Survival. Main efficacy results are presented in Table 3.

Click on icon to see table/diagram/image

Clinical Efficacy in Relapsed or Refractory Multiple Myeloma: The safety and efficacy of VELCADE (injected intravenously) were evaluated in 2 studies at the recommended dose of 1.3 mg/m2: a Phase III randomised, comparative study (APEX), versus dexamethasone (Dex), of 669 patients with relapsed or refractory multiple myeloma who had received 1-3 prior lines of therapy, and a Phase II single arm study of 202 patients with relapsed and refractory multiple myeloma, who had received at least 2 prior lines of treatment and who were progressing on their most recent treatment.
In the Phase III study, treatment with VELCADE led to a significantly longer time to progression, a significantly prolonged survival and a significantly higher response rate, compared to treatment with dexamethasone (see Table 4), in all patients as well as in patients who have received 1 prior line of therapy. As a result of a pre-planned interim analysis, the dexamethasone arm was halted at the recommendation of the data monitoring committee and all patients randomised to dexamethasone were then offered VELCADE, regardless of disease status. Due to this early crossover, the median duration of follow up for surviving patients is 8.3 months. Both in patients who were refractory to their last prior therapy and those who were not refractory, overall survival was significantly longer and response rate was significantly higher on the VELCADE arm.
Of the 669 patients enrolled, 245 (37%) were 65 years of age or older. Response parameters as well as TTP remained significantly better for VELCADE independently of age. Regardless of β2-microglobulin levels at baseline, all efficacy parameters (time to progression and overall survival, as well as response rate) were significantly improved on the VELCADE arm.
In the refractory population of the Phase II study, responses were determined by an independent review committee and the response criteria were those of the European Bone Marrow Transplant Group. The median survival of all patients enrolled was 17 months (range <1 to 36+ months). This survival was greater than the six-to-nine month median survival anticipated by consultant clinical investigators for a similar patient population. By multivariate analysis, the response rate was independent of myeloma type, performance status, chromosome 13 deletion status, or the number or type of previous therapies. Patients who had received 2 to 3 prior therapeutic regimens had a response rate of 32% (10/32) and patients who received greater than 7 prior therapeutic regimens had a response rate of 31% (21/67).

Click on icon to see table/diagram/image

In the Phase II study, patients who did not obtain an optimal response to therapy with VELCADE alone were able to receive high dose dexamethasone in conjunction with VELCADE. The protocol allowed patients to receive dexamethasone if they had had a less than optimal response to VELCADE alone. A total of 74 evaluable patients were administered dexamethasone in combination with VELCADE. Eighteen percent of patients achieved, or had an improved response [MR (11%) or PR (7%)] with combination treatment.
Clinical Efficacy with Subcutaneous Administration of VELCADE in Patients with Relapsed/Refractory Multiple Myeloma: An open label, randomised, Phase III non-inferiority study compared the efficacy and safety of the subcutaneous administration of VELCADE versus the intravenous administration. This study included 222 patients with relapsed/refractory multiple myeloma, who were randomised in a 2:1 ratio to receive 1.3 mg/m2 of VELCADE by either the subcutaneous or intravenous route for 8 cycles. Patients who did not obtain an optimal response (less than Complete Response [CR]) to therapy with VELCADE alone after 4 cycles were allowed to receive dexamethasone 20 mg daily on the day of and after VELCADE administration. Patients with baseline Grade ≥2 peripheral neuropathy or platelet counts <50,000/µL were excluded. A total of 218 patients were evaluable for response.
This study met its primary objective of non inferiority for response rate (CR+PR) after 4 cycles of single agent VELCADE for both the subcutaneous and intravenous routes, 42% in both groups. In addition, secondary response related and time to event related efficacy endpoints showed consistent results for subcutaneous and intravenous administration (see Table 5).

Click on icon to see table/diagram/image

VELCADE Combination Treatment with Pegylated Liposomal Doxorubicin (study DOXIL-MMY-3001): A Phase III randomised, parallel-group, open-label, multicentre study was conducted in 646 patients comparing the safety and efficacy of VELCADE plus pegylated liposomal doxorubicin versus VELCADE monotherapy in patients with multiple myeloma who had received at least 1 prior therapy and who did not progress while receiving anthracycline-based therapy. The primary efficacy endpoint was TTP while the secondary efficacy endpoints were OS and ORR (CR+PR), using the European Group for Blood and Marrow Transplantation (EBMT) criteria.
A protocol-defined interim analysis (based on 249 TTP events) triggered early study termination for efficacy. This interim analysis showed a TTP risk reduction of 45% (95% CI; 29 57%, p <0.0001) for patients treated with combination therapy of VELCADE and pegylated liposomal doxorubicin. The median TTP was 6.5 months for the VELCADE monotherapy patients compared with 9.3 months for the VELCADE plus pegylated liposomal doxorubicin combination therapy patients. These results, though not mature, constituted the protocol defined final analysis.
VELCADE Combination Treatment with Dexamethasone: In the absence of any direct comparison between VELCADE and VELCADE in combination with dexamethasone in patients with progressive multiple myeloma, a statistical matched-pair analysis was conducted to compare results from the non randomised arm of VELCADE in combination with dexamethasone (Phase II open label study MMY-2045), with results obtained in the VELCADE monotherapy arms from different Phase III randomised studies (M34101-039 [APEX] and DOXIL MMY-3001) in the same indication.
The matched-pair analysis is a statistical method in which patients in the treatment group (e.g. VELCADE in combination with dexamethasone) and patients in the comparison group (e.g. VELCADE) are made comparable with respect to confounding factors by individually pairing study subjects. This minimises the effects of observed confounders when estimating treatment effects using non-randomised data.
One hundred and twenty seven matched pairs of patients 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), TTP (hazard ratio 0.385; 95% CI 0.212 0.698; p=0.001) for VELCADE in combination with dexamethasone over VELCADE monotherapy.
Limited information on VELCADE retreatment in relapsed multiple myeloma is available.
Phase II study MMY 2036 (RETRIEVE), single arm, open-label study was conducted to determine the efficacy and safety of retreatment with VELCADE. One hundred and thirty patients (≥18 years of age) with multiple myeloma who previously had at least partial response on a VELCADE containing regimen were retreated upon progression. At least 6 months after prior therapy, VELCADE was started at the last tolerated dose of 1.3 mg/m2 (n=93) or ≤1.0 mg/m2 (n=37) and given on days 1, 4, 8 and 11 every 3 weeks for maximum of 8 cycles either as single agent or in combination with dexamethasone in accordance with the standard of care. Dexamethasone was administered in combination with VELCADE to 83 patients in Cycle 1 with an additional 11 patients receiving dexamethasone during the course of VELCADE retreatment cycles.
The primary endpoint was best confirmed response to retreatment as assessed by EBMT criteria. The overall best response rate (CR + PR), to retreatment in 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 Phase III, randomised, open label study comparing the efficacy and safety of the combination of VELCADE, rituximab, cyclophosphamide, doxorubicin, and prednisone (VcR CAP; n=243) to that of 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 VcR-CAP treatment arm received VELCADE (1.3 mg/m2; on days 1, 4, 8, 11, rest period days 12 21), rituximab 375 mg/m2 IV on day 1; cyclophosphamide 750 mg/m2 IV on day 1; doxorubicin 50 mg/m2 IV on day 1; and prednisone 100 mg/m2 orally on day 1 through day 5 of the 21 day VELCADE treatment cycle. For patients with a response first documented at cycle 6, two additional treatment cycles were given.
The primary efficacy endpoint was progression free survival based on Independent Review Committee (IRC) assessment. Secondary endpoints included, time to progression (TTP), time to next anti lymphoma treatment (TNT), duration of treatment free interval (TFI), overall response rate (ORR) and complete response (CR/CRu) rate, overall survival (OS) and response duration.
The demographic and baseline disease characteristics were generally well balanced between the two treatment arms: median patient age was 66 years, 74% were male, 66% were Caucasian and 32% Asian, 69% of patients had a positive bone marrow aspirate and/or a positive bone marrow biopsy for MCL, 54% of patients had an International Prognostic Index (IPI) score of ≥3, and 76% had Stage IV disease. Treatment duration (median=17 weeks) and duration of follow up (median=40 months) were comparable in both treatment arms. A median of 6 cycles was received by patients in both treatment arms with 14% of subjects in the VcR-CAP group and 17% of patients in the R-CHOP group receiving 2 additional cycles. The majority of the patients in both groups completed treatment, 80% in the VcR-CAP group and 82% in the R-CHOP group. Efficacy results are presented in Table 6.

Click on icon to see table/diagram/image

Median PFS by investigator assessment was 30.7 months in the VcR-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 favour of the VcR-CAP treatment group over the R-CHOP group was observed for TTP (median 30.5 versus 16.1 months), TNT (median 44.5 versus 24.8 months) and TFI (median 40.6 versus 20.5 months). The median duration of complete response was 42.1 months in the VcR-CAP group compared with 18 months in the R-CHOP group. The duration of overall response was 21.4 months longer in the VcR-CAP group (median 36.5 months versus 15.1 months in the R-CHOP group). With a median duration of follow up of 40 months, median OS (56.3 months in the R-CHOP group, and not reached in the VcR-CAP group) favoured the VcR-CAP group, (estimated HR=0.80; p=0.173). There was a trend towards prolonged overall survival favouring the VcR-CAP group; the estimated 4 year survival rate was 53.9% in the R-CHOP group and 64.4% in the VcR-CAP group.
Patients with Previously Treated Light Chain (AL) Amyloidosis: An open label non randomised Phase I/II study was conducted to determine the safety and efficacy of VELCADE in patients with previously treated light chain (AL) Amyloidosis. No new safety concerns were observed during the study, and in particular VELCADE did not exacerbate target organ damage (heart, kidney and liver). In an exploratory efficacy analysis, a 67.3% response rate (including a 28.6% CR rate) as measured by hematologic response (M-protein) was reported in 49 evaluable patients treated with the maximum allowed doses of 1.6 mg/m2 weekly and 1.3 mg/m2 twice weekly. For these dose cohorts, the combined 1 year survival rate was 88.1%.
Paediatric Population: The European Medicines Agency has waived the obligation to submit the results of studies with VELCADE in all subsets of the paediatric population in multiple myeloma and in mantle cell lymphoma (see Dosage & Administration).
Pharmacokinetics: Absorption: Following intravenous bolus administration of a 1.0 mg/m2 and 1.3 mg/m2 dose to 11 patients with multiple myeloma and creatinine clearance values greater than 50 mL/min, the mean first-dose maximum plasma concentrations of bortezomib were 57 and 112 ng/mL, respectively. In subsequent doses, mean maximum observed plasma concentrations ranged from 67 to 106 ng/mL for the 1.0 mg/m2 dose and 89 to 120 ng/mL for the 1.3 mg/m2 dose.
Following an intravenous bolus or subcutaneous injection of a 1.3 mg/m2 dose to patients with multiple myeloma (n=14 in the intravenous group, n=17 in the subcutaneous group), the total systemic exposure after repeat dose administration (AUClast) was equivalent for subcutaneous and intravenous administrations. The Cmax after subcutaneous administration (20.4 ng/mL) was lower than intravenous (223 ng/mL). The AUClast geometric mean ratio was 0.99 and 90% confidence intervals were 80.18% 122.80%.
Distribution: The mean distribution volume (Vd) of bortezomib ranged from 1,659 l to 3,294 l following single- or repeated dose intravenous administration of 1.0 mg/m2 or 1.3 mg/m2 to patients with multiple myeloma. This suggests that bortezomib distributes widely to peripheral tissues. Over a bortezomib concentration range of 0.01 to 1.0 μg/mL, the in vitro protein binding averaged 82.9% in human plasma. The fraction of bortezomib bound to plasma proteins was not concentration-dependent.
Biotransformation: In vitro studies with human liver microsomes and human cDNA-expressed cytochrome P450 isozymes indicate that bortezomib is primarily oxidatively metabolised via cytochrome P450 enzymes, 3A4, 2C19, and 1A2. The major metabolic pathway is deboronation to form two deboronated metabolites that subsequently undergo hydroxylation to several metabolites. Deboronated-bortezomib metabolites are inactive as 26S proteasome inhibitors.
Elimination: The mean elimination half life (t1/2) of bortezomib upon multiple dosing ranged from 40-193 hours. Bortezomib is eliminated more rapidly following the first dose compared to subsequent doses. Mean total body clearances were 102 and 112 L/h following the first dose for 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 following subsequent doses for doses of 1.0 mg/m2 and 1.3 mg/m2, respectively.
Special Populations: Hepatic Impairment: The effect of hepatic impairment on the pharmacokinetics of bortezomib was assessed in a Phase I study during the first treatment cycle, including 61 patients primarily with solid tumors and varying degrees of hepatic impairment at bortezomib doses ranging from 0.5 to 1.3 mg/m2.
When compared to patients with normal hepatic function, mild hepatic impairment did not alter dose-normalised bortezomib AUC. However, the dose normalised mean AUC values were increased by approximately 60% in patients with moderate or severe hepatic impairment. A lower starting dose is recommended in patients with moderate or severe hepatic impairment, and those patients should be closely monitored (see Table 12).
Renal Impairment: A pharmacokinetic study was conducted in patients with various degrees of renal impairment who were classified according to their creatinine clearance values (CrCL) into the following groups: Normal (CrCL ≥60 mL/min/1.73 m2, n=12), Mild (CrCL=40-59 mL/min/1.73 m2, n=10), Moderate (CrCL=20 39 mL/min/1.73 m2, n=9), and Severe (CrCL <20 mL/min/1.73 m2, n=3). A group of dialysis patients who were dosed after dialysis was also included in the study (n=8). Patients were administered intravenous doses of 0.7 to 1.3 mg/m2 of VELCADE twice weekly. Exposure of VELCADE (dose-normalised AUC and Cmax) was comparable among all the groups (see Dosage & Administration).
Toxicology: Preclinical Safety Data: Bortezomib was positive for clastogenic activity (structural chromosomal aberrations) in the in vitro chromosomal aberration assay using Chinese hamster ovary (CHO) cells at concentrations as low as 3.125 μg/mL, which was the lowest concentration evaluated. Bortezomib was not genotoxic when tested in the in vitro mutagenicity assay (Ames assay) and in vivo micronucleus assay in mice.
Developmental toxicity studies in the rat and rabbit have shown embryo-fetal lethality at maternally toxic doses, but no direct embryo-fetal toxicity below maternally toxic doses. Fertility studies were not performed but evaluation of reproductive tissues has been performed in the general toxicity studies. In the 6-month rat study, degenerative effects in both the testes and the ovary have been observed. It is, therefore, likely that bortezomib could have a potential effect on either male or female fertility. Peri- and postnatal development studies were not conducted.
In multi-cycle general toxicity studies conducted in the rat and monkey, the principal target organs included the gastrointestinal tract, resulting in vomiting and/or diarrhoea; haematopoietic and lymphatic tissues, resulting in peripheral blood cytopenias, lymphoid tissue atrophy and haematopoietic bone marrow hypocellularity; peripheral neuropathy (observed in monkeys, mice and dogs) involving sensory nerve axons; and mild changes in the kidneys. All these target organs have shown partial to full recovery following discontinuation of treatment.
Based on animal studies, the penetration of bortezomib through the blood-brain barrier appears to be limited, if any and the relevance to humans is unknown.
Cardiovascular safety pharmacology studies in monkeys and dogs show that intravenous doses approximately two to three times the recommended clinical dose on a mg/m2 basis are associated with increases in heart rate, decreases in contractility, hypotension and death. In dogs, the decreased cardiac contractility and hypotension responded to acute intervention with positive inotropic or pressor agents. Moreover, in dog studies, a slight increase in the corrected QT interval was observed.
Indications/Uses
VELCADE as monotherapy or in combination with pegylated liposomal doxorubicin or dexamethasone is indicated for the treatment of adult patients with progressive multiple myeloma who have received at least 1 prior therapy and who have already undergone or are unsuitable for haematopoietic stem cell transplantation.
VELCADE in combination with melphalan and prednisone is indicated for the treatment of adult patients with previously untreated multiple myeloma who are not eligible for high dose chemotherapy with haematopoietic stem cell transplantation.
VELCADE in combination with dexamethasone, or with dexamethasone and thalidomide, is indicated for the induction treatment of adult patients with previously untreated multiple myeloma who are eligible for high dose chemotherapy with haematopoietic stem cell transplantation.
VELCADE in combination with rituximab, cyclophosphamide, doxorubicin and prednisone is indicated for the treatment of adult patients with previously untreated mantle cell lymphoma who are unsuitable for haematopoietic stem cell transplantation.
Dosage/Direction for Use
Treatment must be initiated and administered under the supervision of a physician qualified and experienced in the use of chemotherapeutic agents. VELCADE must be reconstituted by a healthcare professional.
Posology for Treatment of Progressive Multiple Myeloma (Patients who have Received at Least One Prior Therapy): Monotherapy: VELCADE 3.5 mg powder for solution for injection is administered via 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 in a 21-day treatment cycle. This 3-week period is considered a treatment cycle. It is recommended that patients receive 2 cycles of VELCADE following a confirmation of a complete response. It is also recommended that responding patients who do not achieve a complete remission receive a total of 8 cycles of VELCADE therapy. At least 72 hours should elapse between consecutive doses of VELCADE.
Dose Adjustments During Treatment and Re-initiation of Treatment for Monotherapy: VELCADE treatment must be withheld at the onset of any Grade 3 non-haematological or any Grade 4 haematological toxicities, excluding neuropathy as discussed below (see Precautions). Once the symptoms of the toxicity have resolved, VELCADE treatment may be re initiated at a 25% reduced dose (1.3 mg/m2 reduced to 1.0 mg/m2; 1.0 mg/m2 reduced to 0.7 mg/m2). If the toxicity is not resolved or if it recurs at the lowest dose, discontinuation of VELCADE must be considered unless the benefit of treatment clearly outweighs the risk.
Neuropathic Pain and/or Peripheral Neuropathy: Patients who experience bortezomib related neuropathic pain and/or peripheral neuropathy are to be managed as presented in Table 7 (see Precautions). Patients with pre existing severe neuropathy may be treated with VELCADE only after careful risk/benefit assessment.

Click on icon to see table/diagram/image

Combination therapy with pegylated liposomal doxorubicin: VELCADE 3.5 mg powder for solution for injection is administered via 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 in a 21 day treatment cycle. This 3-week period is considered a treatment cycle. At least 72 hours should elapse between consecutive doses of VELCADE.
Pegylated liposomal doxorubicin is administered at 30 mg/m2 on day 4 of the VELCADE treatment cycle as a 1 hour intravenous infusion administered after the VELCADE injection.
Up to 8 cycles of this combination therapy can be administered as long as patients have not progressed and tolerate treatment. Patients achieving a complete response can continue treatment for at least 2 cycles after the first evidence of complete response, even if this requires treatment for more than 8 cycles. Patients whose levels of paraprotein continue to decrease after 8 cycles can also continue for as long as treatment is tolerated and they continue to respond.
For additional information concerning pegylated liposomal doxorubicin, see the corresponding Summary of Product Characteristics.
Combination with Dexamethasone: VELCADE 3.5 mg powder for solution for injection is administered via 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 in a 21 day treatment cycle. This 3-week period is considered a treatment cycle. At least 72 hours should elapse between consecutive doses of VELCADE.
Dexamethasone is administered orally at 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 of the VELCADE treatment cycle.
Patients achieving a response or a stable disease after 4 cycles of this combination therapy can continue to receive the same combination for a maximum of 4 additional cycles.
For additional information concerning dexamethasone, see the corresponding Summary of Product Characteristics.
Dose Adjustments for Combination Therapy for Patients with Progressive Multiple Myeloma: For VELCADE dosage adjustments for combination therapy follow dose modification guidelines described under monotherapy above.
Posology for Previously Untreated Multiple Myeloma Patients Not Eligible for Haematopoietic Stem Cell Transplantation: Combination Therapy with Melphalan and Prednisone: VELCADE 3.5 mg powder for solution for injection is administered via intravenous or subcutaneous injection in combination with oral melphalan and oral prednisone as shown in Table 8. A 6-week period is considered a treatment cycle. In Cycles 1-4, VELCADE is administered twice weekly on days 1, 4, 8, 11, 22, 25, 29 and 32. In Cycles 5-9, VELCADE is administered once weekly on days 1, 8, 22 and 29. At least 72 hours should elapse between consecutive doses of VELCADE.
Melphalan and prednisone should both be given orally on days 1, 2, 3 and 4 of the first week of each VELCADE treatment cycle.
Nine treatment cycles of this combination therapy are administered.

Click on icon to see table/diagram/image

Dose Adjustments During Treatment and Re-initiation of Treatment for Combination Therapy with Melphalan and Prednisone: Prior to initiating a new cycle of therapy: Platelet counts should be ≥70 x 109/L and the absolute neutrophils count should be ≥1.0 x 109/L; Non haematological toxicities should have resolved to Grade 1 or baseline.

Click on icon to see table/diagram/image

For additional information concerning melphalan and prednisone, see the corresponding Summary of Product Characteristics.
Posology for Previously Untreated Multiple Myeloma Patients Eligible for Haematopoietic Stem Cell Transplantation (Induction Therapy): Combination Therapy with Dexamethasone: VELCADE 3.5 mg powder for solution for injection is administered via 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 in a 21-day treatment cycle. This 3-week period is considered a treatment cycle. At least 72 hours should elapse between consecutive doses of VELCADE.
Dexamethasone is administered orally at 40 mg on days 1, 2, 3, 4, 8, 9, 10 and 11 of the VELCADE treatment cycle.
Four treatment cycles of this combination therapy are administered.
Combination Therapy with Dexamethasone and Thalidomide: VELCADE 3.5 mg powder for solution for injection is administered via 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 in a 28 day treatment cycle. This 4-week period is considered a treatment cycle. At least 72 hours should elapse between consecutive doses of VELCADE.
Dexamethasone is administered orally at 40 mg on days 1, 2, 3, 4, 8, 9, 10 and 11 of the VELCADE treatment cycle.
Thalidomide is administered orally at 50 mg daily on days 1-14 and if tolerated the dose is increased to 100 mg on days 15-28, and thereafter may be further increased to 200 mg daily from cycle 2 (see Table 10).
Four treatment cycles of this combination are administered. It is recommended that patients with at least partial response receive 2 additional cycles.

Click on icon to see table/diagram/image

Dosage Adjustments for Transplant Eligible Patients: For VELCADE dosage adjustments for neuropathy refer to Table 7.
In addition, when VELCADE is given in combination with other chemotherapeutic medicinal products, appropriate dose reductions for these products should be considered in the event of toxicities according to the recommendations in the Summary of Product Characteristics.
Posology for Patients with Previously Untreated Mantle Cell Lymphoma (MCL): Combination therapy with rituximab, cyclophosphamide, doxorubicin and prednisone (VcR-CAP)
VELCADE 3.5 mg powder for solution for injection is administered via 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, followed by a 10 day rest period on days 12-21. This 3-week period is considered a treatment cycle. Six VELCADE cycles are recommended, although for patients with a response first documented at cycle 6, two additional VELCADE cycles may be given. At least 72 hours should elapse between consecutive doses of VELCADE.
The following medicinal products are administered on day 1 of each VELCADE 3 week treatment cycle as intravenous infusions: rituximab at 375 mg/m2, cyclophosphamide at 750 mg/m2 and doxorubicin at 50 mg/m2.
Prednisone is administered orally at 100 mg/m2 on days 1, 2, 3, 4 and 5 of each VELCADE treatment cycle.
Dose Adjustments During Treatment for Patients with Previously Untreated Mantle Cell Lymphoma: Prior to initiating a new cycle of therapy: Platelet counts should be ≥100,000 cells/μL and the absolute neutrophils count (ANC) should be ≥1,500 cells/μL; Platelet counts should be ≥75,000 cells/μL in patients with bone marrow infiltration or splenic sequestration; Haemoglobin ≥8 g/dL; Non haematological toxicities should have resolved to Grade 1 or baseline.
VELCADE treatment must be withheld at the onset of any ≥Grade 3 VELCADE-related non haematological toxicities (excluding neuropathy) or ≥Grade 3 haematological toxicities (see Precautions). For dose adjustments, see Table 11.
Granulocyte colony stimulating factors may be administered for haematologic toxicity according to local standard practice. Prophylactic use of granulocyte colony stimulating factors should be considered in case of repeated delays in cycle administration. Platelet transfusion for the treatment of thrombocytopenia should be considered when clinically appropriate.

Click on icon to see table/diagram/image

In addition, when VELCADE is given in combination with other chemotherapeutic medicinal products, appropriate dose reductions for these medicinal products should be considered in the event of toxicities, according to the recommendations in the respective Summary of Product Characteristics.
Special populations: Elderly: There is no evidence to suggest that dose adjustments are necessary in patients over 65 years of age with multiple myeloma or with mantle cell lymphoma.
There are no studies on the use of VELCADE in elderly patients with previously untreated multiple myeloma who are eligible for high dose chemotherapy with haematopoietic stem cell transplantation. Therefore no dose recommendations can be made in this population.
In a study in previously untreated mantle cell lymphoma patients, 42.9% and 10.4% of patients exposed to VELCADE were in the range 65-74 years and ≥75 years of age, respectively. In patients aged ≥75 years, both regimens, VcR-CAP as well as R-CHOP, were less tolerated (see Adverse Reactions).
Hepatic Impairment: Patients with mild hepatic impairment do not require a dose adjustment and should be treated per the recommended dose. Patients with moderate or severe hepatic impairment should be started on VELCADE at a reduced dose of 0.7 mg/m2 per injection during the first treatment cycle, and a subsequent dose escalation to 1.0 mg/m2 or further dose reduction to 0.5 mg/m2 may be considered based on patient tolerability (see Table 12, Precautions, Pharmacology: Pharmacokinetics under Actions).

Click on icon to see table/diagram/image

Renal Impairment: The pharmacokinetics of bortezomib are not influenced in patients with mild to moderate renal impairment (Creatinine Clearance [CrCL] >20 mL/min/1.73 m2); therefore, dose adjustments are not necessary for these patients. It is unknown if the pharmacokinetics of bortezomib are influenced in patients with severe renal impairment not undergoing dialysis (CrCL <20 mL/min/1.73 m2). Since dialysis may reduce bortezomib concentrations, VELCADE should be administered after the dialysis procedure (see Pharmacology: Pharmacokinetics under Actions).
Paediatric Population: The safety and efficacy of VELCADE in children below 18 years of age have not been established (see Pharmacology under Actions). No data are available.
Administration: VELCADE 3.5 mg powder for solution for injection is available for intravenous or subcutaneous administration.
VELCADE should not be given by other routes. Intrathecal administration has resulted in death.
Intravenous Injection: VELCADE 3.5 mg reconstituted solution is administered as a 3-5 second bolus intravenous injection through a peripheral or central intravenous catheter followed by a flush with sodium chloride 9 mg/mL (0.9%) solution for injection. At least 72 hours should elapse between consecutive doses of VELCADE.
Subcutaneous Injection: VELCADE 3.5 mg reconstituted solution is administered subcutaneously through the thighs (right or left) or abdomen (right or left). The solution should be injected subcutaneously, at a 45-90° angle. Injection sites should be rotated for successive injections.
If local injection site reactions occur following VELCADE subcutaneous injection, either a less concentrated VELCADE solution (VELCADE 3.5 mg to be reconstituted to 1 mg/mL instead of 2.5 mg/mL) may be administered subcutaneously or a switch to intravenous injection is recommended.
When VELCADE is given in combination with other medicinal products, refer to the Summary of Product Characteristics of these products for instructions for administration.
Overdosage
In patients, overdose more than twice the recommended dose has been associated with the acute onset of symptomatic hypotension and thrombocytopenia with fatal outcomes. For preclinical cardiovascular safety pharmacology studies, see Pharmacology: Toxicology: Preclinical Safety Data under Actions.
There is no known specific antidote for bortezomib overdose. In the event of an overdose, the patient’s vital signs should be monitored and appropriate supportive care given to maintain blood pressure (such as fluids, pressors, and/or inotropic agents) and body temperature (See Dosage & Administration, Precautions).

Contraindications
Hypersensitivity to the active substance, to boron or to any of the excipients.
Acute diffuse infiltrative pulmonary and pericardial disease.
When VELCADE is given in combination with other medicinal products, refer to their Summaries of Product Characteristics for additional contraindications.
Special Precautions
When VELCADE is given in combination with other medicinal products, the Summary of Product Characteristics of these other medicinal products must be consulted prior to initiation of treatment with VELCADE. When thalidomide is used, particular attention to pregnancy testing and prevention requirements is needed (see Use in Pregnancy & Lactation).
Intrathecal Administration: There have been fatal cases of inadvertent intrathecal administration of VELCADE. VELCADE 3.5 mg powder for solution for injection is for intravenous or subcutaneous use. VELCADE should not be administered intrathecally.
Gastrointestinal Toxicity: Gastrointestinal toxicity, including nausea, diarrhoea, vomiting and constipation are very common with VELCADE treatment. Cases of ileus have been uncommonly reported (see Adverse Reactions). Therefore, patients who experience constipation should be closely monitored.
Haematological Toxicity: VELCADE treatment is very commonly associated with haematological toxicities (thrombocytopenia, neutropenia and anaemia). In studies in patients with relapsed multiple myeloma treated with VELCADE and in patients with previously untreated MCL treated with VELCADE in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (VcR-CAP), one of the most common haematologic toxicity was transient thrombocytopenia. Platelets were lowest at Day 11 of each cycle of VELCADE treatment and typically recovered to baseline by the next cycle. There was no evidence of cumulative thrombocytopenia. The mean platelet count nadir measured was approximately 40% of baseline in the single agent multiple myeloma studies and 50% in the MCL study. In patients with advanced myeloma the severity of thrombocytopenia was related to pre treatment platelet count: for baseline platelet counts <75,000/μL, 90% of 21 patients had a count ≤25,000/μL during the study, including 14% <10,000/μL; in contrast, with a baseline platelet count >75,000/μL, only 14% of 309 patients had a count ≤25,000/μL during the study.
In patients with MCL (study LYM-3002), there was a higher incidence (56.7% versus 5.8%) of Grade ≥3 thrombocytopenia in the VELCADE treatment group (VcR-CAP) as compared to the non-VELCADE treatment group (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP]). The two treatment groups were similar with regard to the overall incidence of all grade bleeding events (6.3% in the VcR-CAP group and 5.0% in the R-CHOP group) as well as Grade 3 and higher bleeding events (VcR-CAP: 4 patients [1.7%]; R-CHOP: 3 patients [1.2%]). In the VcR-CAP group, 22.5% of patients received platelet transfusions compared to 2.9% of patients in the R-CHOP group.
Gastrointestinal and intracerebral haemorrhage, have been reported in association with VELCADE treatment. Therefore, platelet counts should be monitored prior to each dose of VELCADE. VELCADE therapy should be withheld when the platelet count is <25,000/μL or, in the case of combination with melphalan and prednisone, when the platelet count is ≤30,000/μL (see Dosage & Administration). Potential benefit of the treatment should be carefully weighed against the risks, particularly in case of moderate to severe thrombocytopenia and risk factors for bleeding.
Complete blood counts (CBC) with differential and including platelet counts should be frequently monitored throughout treatment with VELCADE. Platelet transfusion should be considered when clinically appropriate (see Dosage & Administration).
In patients with MCL, transient neutropenia that was reversible between cycles was observed, with no evidence of cumulative neutropenia. Neutrophils were lowest at Day 11 of each cycle of VELCADE treatment and typically recovered to baseline by the next cycle. In study LYM-3002, colony stimulating factor support was given to 78% of patients in the VcR-CAP arm and 61% of patients in the R-CHOP arm. Since patients with neutropenia are at increased risk of infections, they should be monitored for signs and symptoms of infection and treated promptly. Granulocyte colony stimulating factors may be administered for haematologic toxicity according to local standard practice. Prophylactic use of granulocyte colony stimulating factors should be considered in case of repeated delays in cycle administration (see Dosage & Administration).
Herpes Zoster Virus Reactivation: Antiviral prophylaxis is recommended in patients being treated with VELCADE.
In the Phase III study in patients with previously untreated multiple myeloma, the overall incidence of herpes zoster reactivation was more common in patients treated with VELCADE+Melphalan+Prednisone compared with Melphalan+Prednisone (14% versus 4% respectively).
In patients with MCL (study LYM-3002), the incidence of herpes zoster infection was 6.7% in the VcR-CAP arm and 1.2% in the R-CHOP arm (see Adverse Reactions).
Hepatitis B Virus (HBV) Reactivation and Infection: When rituximab is used in combination with VELCADE, HBV screening must always be performed in patients at risk of infection with HBV before initiation of treatment. Carriers of hepatitis B and patients with a history of hepatitis B must be closely monitored for clinical and laboratory signs of active HBV infection during and following rituximab combination treatment with VELCADE. Antiviral prophylaxis should be considered. Refer to the Summary of Product Characteristics of rituximab for more information.
Progressive Multifocal Leukoencephalopathy (PML): Very rare cases with unknown causality of John Cunningham (JC) virus infection, resulting in PML and death, have been reported in patients treated with VELCADE. Patients diagnosed with PML had prior or concurrent immunosuppressive therapy. Most cases of PML were diagnosed within 12 months of their first dose of VELCADE. Patients should be monitored at regular intervals for any new or worsening neurological symptoms or signs that may be suggestive of PML as part of the differential diagnosis of CNS problems. If a diagnosis of PML is suspected, patients should be referred to a specialist in PML and appropriate diagnostic measures for PML should be initiated. Discontinue VELCADE if PML is diagnosed.
Peripheral Neuropathy: Treatment with VELCADE is very commonly associated with peripheral neuropathy, which is predominantly sensory. However, cases of severe motor neuropathy with or without sensory peripheral neuropathy have been reported. The incidence of peripheral neuropathy increases early in the treatment and has been observed to peak during cycle 5.
It is recommended that patients be carefully monitored for symptoms of neuropathy such as a burning sensation, hyperesthesia, hypoesthesia, paraesthesia, discomfort, neuropathic pain or weakness.
In the Phase III study comparing VELCADE administered intravenously versus subcutaneously, the incidence of Grade ≥2 peripheral neuropathy events was 24% for the subcutaneous injection group and 41% for the intravenous injection group (p=0.0124). Grade ≥3 peripheral neuropathy occurred in 6% of patients in the subcutaneous treatment group, compared with 16% in the intravenous treatment group (p=0.0264). The incidence of all grade peripheral neuropathy with VELCADE administered intravenously was lower in the historical studies with VELCADE administered intravenously than in study MMY-3021.
Patients experiencing new or worsening peripheral neuropathy should undergo neurological evaluation and may require a change in the dose, schedule or route of administration to subcutaneous (see Dosage & Administration). Neuropathy has been managed with supportive care and other therapies.
Early and regular monitoring for symptoms of treatment emergent neuropathy with neurological evaluation should be considered in patients receiving VELCADE in combination with medicinal products known to be associated with neuropathy (e.g. thalidomide) and appropriate dose reduction or treatment discontinuation should be considered.
In addition to peripheral neuropathy, there may be a contribution of autonomic neuropathy to some adverse reactions such as postural hypotension and severe constipation with ileus. Information on autonomic neuropathy and its contribution to these undesirable effects is limited.
Seizures: Seizures have been uncommonly reported in patients without previous history of seizures or epilepsy. Special care is required when treating patients with any risk factors for seizures.
Hypotension: VELCADE treatment is commonly associated with orthostatic/postural hypotension. Most adverse reactions are mild to moderate in nature and are observed throughout treatment. Patients who developed orthostatic hypotension on VELCADE (injected intravenously) did not have evidence of orthostatic hypotension prior to treatment with VELCADE. Most patients required treatment for their orthostatic hypotension. A minority of patients with orthostatic hypotension experienced syncopal events. Orthostatic/postural hypotension was not acutely related to bolus infusion of VELCADE. The mechanism of this event is unknown although a component may be due to autonomic neuropathy. Autonomic neuropathy may be related to bortezomib or bortezomib may aggravate an underlying condition such as diabetic or amyloidotic neuropathy. Caution is advised when treating patients with a history of syncope receiving medicinal products known to be associated with hypotension; or who are dehydrated due to recurrent diarrhoea or vomiting. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medicinal products, rehydration or administration of mineralocorticosteroids and/or sympathomimetics. Patients should be instructed to seek medical advice if they experience symptoms of dizziness, light headedness or fainting spells.
Posterior Reversible Encephalopathy Syndrome (PRES): There have been reports of PRES in patients receiving VELCADE. PRES is a rare, often reversible, rapidly evolving neurological condition, which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably Magnetic Resonance Imaging (MRI), is used to confirm the diagnosis. In patients developing PRES, VELCADE should be discontinued.
Heart Failure: Acute development or exacerbation of congestive heart failure, and/or new onset of decreased left ventricular ejection fraction has been reported during bortezomib treatment. Fluid retention may be a predisposing factor for signs and symptoms of heart failure. Patients with risk factors for or existing heart disease should be closely monitored.
Electrocardiogram Investigations: There have been isolated cases of QT-interval prolongation in clinical studies, causality has not been established.
Pulmonary Disorders: There have been rare reports of acute diffuse infiltrative pulmonary disease of unknown aetiology such as pneumonitis, interstitial pneumonia, lung infiltration, and acute respiratory distress syndrome (ARDS) in patients receiving VELCADE (see Adverse Reactions). Some of these events have been fatal. A pre-treatment chest radiograph is recommended to serve as a baseline for potential post treatment pulmonary changes.
In the event of new or worsening pulmonary symptoms (e.g., cough, dyspnoea), a prompt diagnostic evaluation should be performed and patients treated appropriately. The benefit/risk ratio should be considered prior to continuing VELCADE therapy.
In a clinical trial, two patients (out of 2) given high dose cytarabine (2 g/m2 per day) by continuous infusion over 24 hours with daunorubicin and VELCADE for relapsed acute myelogenous leukaemia died of ARDS early in the course of therapy, and the study was terminated. Therefore, this specific regimen with concomitant administration with high dose cytarabine (2 g/m2 per day) by continuous infusion over 24 hours is not recommended.
Renal Impairment: Renal complications are frequent in patients with multiple myeloma. Patients with renal impairment should be monitored closely (see Dosage & Administration, Pharmacology: Pharmacokinetics under Actions).
Hepatic Impairment: Bortezomib is metabolised by liver enzymes. Bortezomib exposure is increased in patients with moderate or severe hepatic impairment; these patients should be treated with VELCADE at reduced doses and closely monitored for toxicities (see Dosage & Administration, Pharmacology: Pharmacokinetics under Actions).
Hepatic Reactions: Rare cases of hepatic failure have been reported in patients receiving VELCADE and concomitant medicinal products and with serious underlying medical conditions. Other reported hepatic reactions include increases in liver enzymes, hyperbilirubinaemia, and hepatitis. Such changes may be reversible upon discontinuation of bortezomib (see Adverse Reactions).
Tumour Lysis Syndrome: Because bortezomib is a cytotoxic agent and can rapidly kill malignant plasma cells and MCL cells, the complications of tumour lysis syndrome may occur. The patients at risk of tumour lysis syndrome are those with high tumour burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.
Concomitant Medicinal Products: Patients should be closely monitored when given bortezomib in combination with potent CYP3A4 inhibitors. Caution should be exercised when bortezomib is combined with CYP3A4  or CYP2C19 substrates (see Interactions).
Normal liver function should be confirmed and caution should be exercised in patients receiving oral hypoglycemics (see Interactions).
Potentially Immunocomplex Mediated Reactions: Potentially immunocomplex mediated reactions, such as serum sickness type reaction, polyarthritis with rash and proliferative glomerulonephritis have been reported uncommonly. Bortezomib should be discontinued if serious reactions occur.
Effects on Ability to Drive and Use Machines: VELCADE may have a moderate influence on the ability to drive and use machines. VELCADE may be associated with fatigue very commonly, dizziness commonly, syncope uncommonly and orthostatic/postural hypotension or blurred vision commonly. Therefore, patients must be cautious when driving or using machines (see Adverse Reactions).
Use In Pregnancy & Lactation
Contraception in Males and Females: Male and female patients of childbearing potential must use effective contraceptive measures during and for 3 months following treatment.
Use in Pregnancy: No clinical data are available for bortezomib with regard to exposure during pregnancy. The teratogenic potential of bortezomib has not been fully investigated.
In non clinical studies, bortezomib had no effects on embryonal/foetal development in rats and rabbits at the highest maternally tolerated doses. Animal studies to determine the effects of bortezomib on parturition and post natal development were not conducted (see Pharmacology: Toxicology: Preclinical Safety Data under Actions). VELCADE should not be used during pregnancy unless the clinical condition of the woman requires treatment with VELCADE.
If VELCADE is used during pregnancy, or if the patient becomes pregnant while receiving this medicinal product, the patient should be informed of potential for hazard to the foetus.
Thalidomide is a known human teratogenic active substance that causes severe life threatening birth defects. Thalidomide is contraindicated during pregnancy and in women of childbearing potential unless all the conditions of the thalidomide pregnancy prevention programme are met. Patients receiving VELCADE in combination with thalidomide should adhere to the pregnancy prevention programme of thalidomide. Refer to the Summary of Product Characteristics of thalidomide for additional information.
Use in Lactation: It is not known whether bortezomib is excreted in human milk. Because of the potential for serious adverse reactions in breast fed infants, breast feeding should be discontinued during treatment with VELCADE.
Fertility: Fertility studies were not conducted with VELCADE (see Pharmacology: Toxicology: Preclinical Safety Data under Actions).
Adverse Reactions
Summary of the Safety Profile: Serious adverse reactions uncommonly reported during treatment with VELCADE include cardiac failure, tumour lysis syndrome, pulmonary hypertension, posterior reversible encephalopathy syndrome, acute diffuse infiltrative pulmonary disorders and rarely autonomic neuropathy.
The most commonly reported adverse reactions during treatment with VELCADE are nausea, diarrhoea, constipation, vomiting, fatigue, pyrexia, thrombocytopenia, anaemia, neutropenia, peripheral neuropathy (including sensory), headache, paraesthesia, decreased appetite, dyspnoea, rash, herpes zoster and myalgia.
Tabulated summary of adverse reactions: Multiple Myeloma: Undesirable effects in Table 13 were considered by the investigators to have at least a possible or probable causal relationship to VELCADE. These adverse reactions are based on an integrated data set of 5,476 patients of whom 3,996 were treated with VELCADE at 1.3 mg/m2 and included in Table 13.
Overall, VELCADE was administered for the treatment of multiple myeloma in 3,974 patients.
Adverse reactions are listed below by system organ class and frequency grouping. 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), not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Table 13 has been generated using Version 14.1 of the MedDRA.
Post marketing adverse reactions not seen in clinical trials are also included.

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

Mantle Cell Lymphoma (MCL): The safety profile of VELCADE in 240 MCL patients treated with VELCADE at 1.3 mg/m2 in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (VcR-CAP) versus 242 patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP] was relatively consistent to that observed in patients with multiple myeloma with main differences described below. Additional adverse drug reactions identified associated with the use of the combination therapy (VcR-CAP) were hepatitis B infection (<1%) and myocardial ischaemia (1.3%). The similar incidences of these events in both treatment arms, indicated that these adverse drug reactions are not attributable to VELCADE alone. Notable differences in the MCL patient population as compared to patients in the multiple myeloma studies were a ≥5% higher incidence of the haematological adverse reactions (neutropenia, thrombocytopenia, leukopenia, anemia, lymphopenia), peripheral sensory neuropathy, hypertension, pyrexia, pneumonia, stomatitis, and hair disorders.
Adverse drug reactions identified as those with a ≥1% incidence, similar or higher incidence in the VcR-CAP arm and with at least a possible or probable causal relationship to the components of the VcR-CAP arm, are listed in Table 14. Also included are adverse drug reactions identified in the VcR-CAP arm that were considered by investigators to have at least a possible or probable causal relationship to VELCADE based on historical data in the multiple myeloma studies.
Adverse reactions are listed as follows by system organ class and frequency grouping. 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), not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Table 14 has been generated using Version 16 of the MedDRA.

Click on icon to see table/diagram/image

Description of Selected Adverse Reactions: Herpes Zoster Virus Reactivation: Multiple Myeloma: Antiviral prophylaxis was administered to 26% of the patients in the Vc+M+P arm. The incidence of herpes zoster among patients in the Vc+M+P treatment group was 17% for patients not administered antiviral prophylaxis compared to 3% for patients administered antiviral prophylaxis.
Mantle Cell Lymphoma: Antiviral prophylaxis was administered to 137 of 240 patients (57%) in the VcR-CAP arm. The incidence of herpes zoster among patients in the VcR-CAP arm was 10.7% for patients not administered antiviral prophylaxis compared to 3.6% for patients administered antiviral prophylaxis (see Precautions).
Hepatitis B Virus (HBV) Reactivation and Infection: Mantle Cell Lymphoma: HBV infection with fatal outcomes occurred in 0.8% (n=2) of patients in the non VELCADE treatment group (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; R-CHOP ) and 0.4% (n=1) of patients receiving VELCADE in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (VcR-CAP). The overall incidence of hepatitis B infections was similar in patients treated with VcR-CAP or with R-CHOP (0.8% vs 1.2% respectively).
Peripheral Neuropathy in Combination Regimens: Multiple Myeloma: In trials in which VELCADE was administered as induction treatment in combination with dexamethasone (study IFM-2005-01), and dexamethasone thalidomide (study MMY-3010), the incidence of peripheral neuropathy in the combination regimens is presented in Table 15.

Click on icon to see table/diagram/image

Mantle Cell Lymphoma: In study LYM-3002 in which VELCADE was administered with  cyclophosphamide, doxorubicin, and prednisone (R-CAP), the incidence of peripheral neuropathy in the combination regimens is presented in Table 16.

Click on icon to see table/diagram/image

Elderly MCL Patients: 42.9% and 10.4% of patients in the VcR-CAP arm were in the range 65-74 years and ≥75 years of age, respectively. Although in patients aged ≥75 years, both VcR-CAP and R-CHOP were less tolerated, the serious adverse event rate in the VcR-CAP groups was 68%, compared to 42% in the R-CHOP group.
Notable Differences in the Safety Profile of VELCADE Administered Subcutaneously Versus Intravenously as Single Agent: In the Phase III study patients who received VELCADE subcutaneously compared to intravenous administration had 13% lower overall incidence of treatment emergent adverse reactions that were Grade 3 or higher in toxicity, and a 5% lower incidence of discontinuation of VELCADE. The overall incidence of diarrhoea, gastrointestinal and abdominal pain, asthenic conditions, upper respiratory tract infections and peripheral neuropathies were 12% 15% lower in the subcutaneous group than in the intravenous group. In addition, the incidence of Grade 3 or higher peripheral neuropathies was 10% lower, and the discontinuation rate due to peripheral neuropathies 8% lower for the subcutaneous group as compared to the intravenous group.
Six percent of patients had an adverse local reaction to subcutaneous administration, mostly redness. Cases resolved in a median of 6 days, dose modification was required in two patients. Two (1%) of the patients had severe reactions; 1 case of pruritus and 1 case of redness.
The incidence of death on treatment was 5% in the subcutaneous treatment group and 7% in the intravenous treatment group. Incidence of death from “Progressive disease” was 18% in the subcutaneous group and 9% in the intravenous group.
Retreatment of Patients with Relapsed Multiple Myeloma: In a study in which VELCADE retreatment was administered in 130 patients with relapsed multiple myeloma, who previously had at least partial response on a VELCADE containing regimen, the most common all grade adverse events occurring in at least 25% of patients were thrombocytopenia (55%), neuropathy (40%), anaemia (37%), diarrhoea (35%), and constipation (28%). All grade peripheral neuropathy and grade ≥3 peripheral neuropathy were observed in 40% and 8.5% of patients, respectively.
Reporting of Suspected Adverse Reactions: Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions.
Drug Interactions
In vitro studies indicate that bortezomib is a weak inhibitor of the cytochrome P450 (CYP) isozymes 1A2, 2C9, 2C19, 2D6 and 3A4. Based on the limited contribution (7%) of CYP2D6 to the metabolism of bortezomib, the CYP2D6 poor metaboliser phenotype is not expected to affect the overall disposition of bortezomib.
A drug-drug interaction study assessing the effect of ketoconazole, a potent CYP3A4 inhibitor, on the pharmacokinetics of bortezomib (injected intravenously), showed a mean bortezomib AUC increase of 35% (CI90% [1.032 to 1.772]) based on data from 12 patients. Therefore, patients should be closely monitored when given bortezomib in combination with potent CYP3A4 inhibitors (e.g. ketoconazole, ritonavir).
In a drug-drug interaction study assessing the effect of omeprazole, a potent CYP2C19 inhibitor, on the pharmacokinetics of bortezomib (injected intravenously), there was no significant effect on the pharmacokinetics of bortezomib based on data from 17 patients.
A drug-drug interaction study assessing the effect of rifampicin, a potent CYP3A4 inducer, on the pharmacokinetics of bortezomib (injected intravenously), showed a mean bortezomib AUC reduction of 45% based on data from 6 patients. Therefore, the concomitant use of bortezomib with strong CYP3A4 inducers (e.g., rifampicin, carbamazepine, phenytoin, phenobarbital and St. John’s Wort) is not recommended, as efficacy may be reduced.
In the same drug drug interaction study assessing the effect of dexamethasone, a weaker CYP3A4 inducer, on the pharmacokinetics of bortezomib (injected intravenously), there was no significant effect on the pharmacokinetics of bortezomib based on data from 7 patients.
A drug-drug interaction study assessing the effect of melphalan prednisone on the pharmacokinetics of bortezomib (injected intravenously), showed a mean bortezomib AUC increase of 17% based on data from 21 patients. This is not considered clinically relevant.
During clinical trials, hypoglycemia and hyperglycemia were uncommonly and commonly reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving VELCADE treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetics.
Incompatibilities: VELCADE must not be mixed with other medicinal products except those mentioned in Instructions for Use, Handling and Disposal under Cautions for Usage. (See Cautions for Usage.)
Caution For Usage
Special Precautions for Disposal and Other Handling: General Precautions: Bortezomib is a cytotoxic agent. Therefore, caution should be used during handling and preparation of VELCADE. Use of gloves and other protective clothing to prevent skin contact is recommended.
Aseptic technique must be strictly observed throughout the handling of VELCADE, since it contains no preservative.
There have been fatal cases of inadvertent intrathecal administration of VELCADE. VELCADE 3.5 mg powder for solution for injection is for intravenous or subcutaneous use. VELCADE should not be administered intrathecally.
Instructions for Reconstitution: VELCADE must be reconstituted by a healthcare professional.
Intravenous Injection: Each 10 mL vial of VELCADE must be reconstituted with 3.5 ml of sodium chloride 9 mg/mL (0.9%) solution for injection. Dissolution of the lyophilised powder is completed in less than 2 minutes.
After reconstitution, each mL solution contains 1 mg bortezomib. The reconstituted solution is clear and colourless, with a final pH of 4 to 7.
The reconstituted solution must be inspected visually for particulate matter and discolouration prior to administration. If any discolouration or particulate matter is observed, the reconstituted solution must be discarded.
Subcutaneous Injection: Each 10 mL vial of VELCADE should be reconstituted with 1.4 mL of sodium chloride 9 mg/mL (0.9%) solution for injection. Dissolution of the lyophilised powder is completed in less than 2 minutes.
After reconstitution, each mL solution contains 2.5 mg bortezomib. The reconstituted solution is clear and colourless, with a final pH of 4 to 7. The reconstituted solution must be inspected visually for particulate matter and discolouration prior to administration. If any discolouration or particulate matter is observed, the reconstituted solution must be discarded.
Disposal: VELCADE is for single use only. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Storage
Do not store above 30°C.
Keep the vial in the outer carton in order to protect from light.
Reconstituted Solution: The reconstituted solution should be used immediately after preparation. If not used immediately, in use storage times and conditions prior to use are the responsibility of the user. However, the chemical and physical in use stability of the reconstituted solution has been demonstrated for 8 hours at 25°C stored in the original vial and/or a syringe. The total storage time for the reconstituted medicinal product should not exceed 8 hours prior to administration.
ATC Classification
L01XG01 - bortezomib ; Belongs to the class of proteasome inhibitors. Used in the treatment of cancer.
Presentation/Packing
Single-use vial (white to off-white cake or powder) 3.5 mg x 1's.
Exclusive offer for doctors
Register for a MIMS account and receive free medical publications worth $768 a year.
Sign up for free
Already a member? Sign in