VELCADE 3.5 mg powder for solution for injection

Each vial contains 3.5 mg bortezomib (as a mannitol boronic ester).

After reconstitution, 1 ml of solution for injection contains 1 mg bortezomib.

For a full list of excipients, see section 6.1.

Powder for solution for injection.

White to off-white cake or powder.

VELCADE in combination with melphalan and prednisone is indicated for the treatment of patients with previously untreated multiple myeloma who are not eligible for high-dose chemotherapy with bone marrow transplant.

VELCADE is indicated as monotherapy for the treatment of progressive multiple myeloma in patients who have received at least 1 prior therapy and who have already undergone or are unsuitable for bone marrow transplantation.

Treatment must be initiated and administered under the supervision of a physician qualified and experienced in the use of chemotherapeutic agents.

Posology for monotherapy

The recommended starting dose of bortezomib is 1.3 mg/m² body surface area twice weekly for two weeks (days 1, 4, 8, and 11) followed by a 10-day rest period (days 12-21). This 3-week period is considered a treatment cycle. At least 72 hours should elapse between consecutive doses of VELCADE.

It is recommended that patients with a confirmed complete response receive 2 additional cycles of VELCADE beyond a confirmation. It is also recommended that responding patients who do not achieve a complete remission receive a total of 8 cycles of VELCADE therapy.

Currently there are limited data concerning re-treatment with 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 also section 4.4). 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.

Patients who experience bortezomib-related neuropathic pain and/or peripheral neuropathy are to be managed as presented in Table 1 (see section 4.4). Patients with pre-existing severe neuropathy may be treated with VELCADE only after careful risk/benefit assessment.

Table 1: Recommended* posology modifications for bortezomib-related neuropathy.

*Based on posology modifications in Phase II and III multiple myeloma studies and post-marketing experience.

Paediatric patients

VELCADE is not intended for use in children below age 18 due to a lack of data on safety and efficacy (see sections 5.1 and 5.2).

Elderly patients

There is no evidence to suggest that dose adjustments are necessary in patients over 65 years of age (see section 4.8).

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 section 5.2).

Hepatic impairment

VELCADE has not been studied in patients with impaired hepatic function. Significant hepatic impairment may have an impact on the elimination of bortezomib and may increase the likelihood of interactions with other active substances. Patients with impaired liver function should be treated with extreme caution and a dose reduction should be considered (see sections 4.3 and 4.4).

Posology for combination therapy

VELCADE (bortezomib) is administered in combination with oral melphalan and oral prednisone for nine 6-week treatment cycles as shown in Table 2. In Cycles 1-4, VELCADE is administered twice weekly (days 1, 4, 8, 11, 22, 25, 29 and 32). In Cycles 5-9, VELCADE is administered once weekly (days 1, 8, 22 and 29). Melphalan and prednisone should both be given orally on days 1, 2, 3 and 4 of the first week of each cycle.

Table 2: Recommended Posology for VELCADE in combination with melphalan and prednisone for patients with previously untreated multiple myeloma

Vc = VELCADE; M = melphalan, P=prednisone

Dose adjustments for combination therapy

Dose modification and re-initiation of therapy when VELCADE is administered in combination 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

Table3: Posology modifications during subsequent cycles

For additional information concerning melphalan and prednisone, see the corresponding Summary of Product Characteristics.

Method of administration

The 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.

Hypersensitivity to bortezomib, boron or to any of the excipients.

Severe hepatic impairment (see section 4.4).

Acute diffuse infiltrative pulmonary and pericardial disease.

Gastrointestinal toxicity

Gastrointestinal toxicity, including nausea, diarrhoea, vomiting and constipation are very common with VELCADE treatment. Cases of ileus have been uncommonly reported (see section 4.8), therefore patients who experience constipation should be closely monitored.

Haematological toxicity

VELCADE treatment is very commonly associated with haematological toxicities (thrombocytopenia, neutropenia and anaemia). The most common haematologic toxicity is transient thrombocytopenia. Platelets were lowest at Day 11 of each cycle of VELCADE treatment. There was no evidence of cumulative thrombocytopenia, including in the Phase II extension study. The mean platelet count nadir measured was approximately 40% of baseline. 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 25×10⁹/l during the study. Platelet counts should be monitored prior to each dose of VELCADE. Therapy should be held when the platelet count is <25,000/μl and re-initiated at a reduced dose after resolution (see section 4.2). 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.

Therefore, complete blood counts (CBC) including platelet counts should be frequently monitored throughout treatment with VELCADE.

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. Patients experiencing new or worsening peripheral neuropathy should undergo neurological evaluation and may require the dose and schedule of VELCADE to be modified (see section 4.2). Neuropathy has been managed with supportive care and other therapies. Improvement in, or resolution of, peripheral neuropathy was reported in 51% of patients with Grade 2 peripheral neuropathy in the single-agent Phase III multiple myeloma study and 71% of patients with grade 3 or 4 peripheral neuropathy or peripheral neuropathy leading to discontinuation of treatment in Phase II studies, respectively.

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 undesirable effects are mild to moderate in nature and are observed throughout treatment. Patients developing orthostatic hypotension on VELCADE 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.

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. In a single-agent Phase III randomised, comparative study the incidence of heart failure in the VELCADE group was similar to that in the dexamethasone group. 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.

ECG 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 section 4.8). Some of these events have been fatal. A pre-treatment chest radiograph is recommended to determine if any additional diagnostic measures are necessary and 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 (2g/m² per day) by continuous infusion over 24 hours is not recommended.

Renal impairment

Renal complications are frequent in patients with multiple myeloma. Such patients should be monitored closely (see sections 4.2 and 5.2).

Hepatic impairment

Patients with hepatic impairment should be treated with extreme caution and a dose reduction should be considered (see sections 4.2, 4.3 and 5.2).

Hepatic reactions

Rare cases of acute liver failure have been reported in patients receiving multiple concomitant medications 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 section 4.8).

Tumour lysis syndrome

Because bortezomib is a cytotoxic agent and can rapidly kill malignant plasma 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.

Amyloidosis

The impact of proteasome inhibition by bortezomib on disorders associated with protein accumulation such as amyloidosis is unknown. Caution is advised in these patients.

Concomitant medicinal products

Patients should be closely monitored when given bortezomib in combination with potent CYP3A4inhibitors. Caution should be exercised when bortezomib is combined with CYP3A4- or CYP2C19 substrates (see section 4.5).

Normal liver function should be confirmed and caution should be exercised in patients receiving oral hypoglycemics (see section 4.5).

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.

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 metabolizer phenotype is not expected to affect the overall disposition of bortezomib.

An interaction study based on data from 12 patients, assessing the effect of ketoconazole, a potent CYP3A4 inhibitor, showed a bortezomib AUC mean increase of 35% (CI_90% [1.032 to 1.772]). Therefore patients should be closely monitored when given bortezomib in combination with potent CYP3A4 inhibitors (e.g. ketoconazole, ritonavir).

In an interaction study based on data from 17 patients, assessing the effect of omeprazole, a potent CYP2C19 inhibitor, there was no significant effect on the pharmacokinetics of bortezomib.

Patients should be closely monitored when given bortezomib in combination with CYP2C19-inhibitors (e.g. fluoxetine).

In the absence of interaction studies investigating the effect of CYP3A4 inducers on the pharmacokinetics of bortezomib, patients should be closely monitored when given bortezomib in combination with potent CYP3A4 inducers (e.g. rifampicin).

An interaction study assessing the effect of melphalan-prednisone on bortezomib showed a 17% increase in mean bortezomib AUC 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.

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 parturition and post-natal development were not conducted (see section 5.3). VELCADE should not be used during pregnancy unless clearly necessary.

For VELCADE no clinical data with regard to exposure during pregnancy are available. Male and female patients of childbearing potential must use effective contraceptive measures during and for 3 months following treatment. 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.

It is not known whether bortezomib is excreted in human milk. Because of the potential for serious undesirable effects in breast-fed infants,lactation should be discontinued during treatment with VELCADE.

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, orthostatic/postural hypotension or blurred vision commonly. Therefore, patients must be cautious when operating machinery, or when driving (see section 4.8).

The following undesirable effects were considered by the investigators to have at least a possible or probable causal relationship to VELCADE during the conduct of 5 non-comparative Phase II studies and 1 comparative Phase III trial VELCADE vs dexamethasone in 663 patients with relapsed or refractory multiple myeloma, of whom 331 received VELCADE as single agent. The safety database comprises data from patients with multiple myeloma or B-cell lymphocytic leukemia (CLL). Patients were treated with VELCADE as a single agent, or in combination with dexamethasone.

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 4: Adverse reactions in patients with relapsed/refractory multiple myeloma

Summary of safety data in patients with previously untreated multiple myeloma:

The following table 5 describes safety data from 340 patients with previously untreated multiple myeloma who received VELCADE (1.3 mg/m²) in combination with melphalan (9 mg/m²) and prednisone (60 mg/m²) in a prospective Phase III study.

Overall, the safety profile of patients treated with VELCADE in monotherapy was similar to that observed in patients treated with VELCADE in combination with melphalan and prednisone.

Table 5: Treatment emergent drug-related adverse reactions reported in 10% of patients treated with VELCADE in combination with melphalan and prednisone

Herpes zoster virus reactivation

Antiviral prophylaxis should be considered 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 Vc+M+P compared with M+P (14% vs 4% respectively). Antiviral prophylaxis was administered to 26% of the patients in the VcMP arm. The incidence of herpes zoster among patients in the VcMP treatment group was 17% for patients not administered antiviral prophylaxis compared to 3% for patients administered antiviral prophylaxis.

Post Marketing Experience

Clinically significant adverse reactions are listed in Table 6, if they have been reported during post approval use of VELCADE and may or may not have been reported in clinical trials. Their frequency is not known.

Table 6: Adverse reactions from post-marketing reports

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 section 5.3.

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 sections 4.2 and 4.4).

Pharmacotherapeutic group: Other antineoplastic agent, ATC code: L01XX32

This medicinal product has been authorised under “Exceptional Circumstances”. This means that for scientific reasons it has not been possible to obtain complete information on this medicinal product.

The European Medicines Agency (EMEA) will review any new information which may become available every year and this SPC will be updated as necessary.

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 1500-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 t_½ 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 proapoptotic effects of proteasome inhibition than normal cells. Bortezomib causes reduction of tumour growth in vivo in many preclinical tumour models, including multiple myeloma.

Clinical efficacy in previously untreated multiple myeloma

A prospective Phase III, international, randomized (1:1), open-label clinical study (VISTA) of 682 patients was conducted to determine whether VELCADE (1.3 mg/m²) 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. Baseline demographics and patient characteristics are summarized in Table 7.

Table 7: Summary of baseline patient and disease characteristics in the VISTA study

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. Survival continued to be followed after the interim analysis. Median follow-up was 16.3 months. Efficacy results are presented in Table 8:

Table 8: Summary of Efficacy Analyses in the VISTA study

^a Kaplan-Meier estimate.

^b Hazard ratio estimate is based on a Cox proportional-hazard model adjusted for stratification factors: β₂-microglobulin, albumin, and region. A hazard ratio less than 1 indicates an advantage for VMP

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

^d p-value for Response Rate (CR + PR) from the Cochran-Mantel-Haenszel chi-square test adjusted for the stratification factors

^e Response population includes patients who had measurable disease at baseline

^f EBMT criteria

^g All randomized patients with secretory disease

NE: Not estimable

Clinical efficacy in relapsed or refractory multiple myeloma

The safety and efficacy of VELCADE were evaluated in 2 studies at the recommended dose of 1.3 mg/m²: a Phase III randomized, comparative study, 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. (see Tables 9, 10 and 11).

Table 9: Dosing regimens in Phase II and Phase III studies

*a) is the initial treatment, a) and b) represent a full course of treatment

**An extension study authorised patients benefiting from treatment to continue receiving VELCADE

***If after 2 or 4 cycles of VELCADE, the patients had progressive disease or stable disease, respectively, they could receive dexamethasone

Table 10: Patient characteristics in Phase II and Phase III studies

*Including steroids, alkylating agents, anthracyclines, thalidomide and stem cell transplants

Table 11: Patient exposure to treatment with VELCADE during Phase II and III studies

*Patients could continue on treatment after completing 8 cycles, in case of benefit

NA = not applicable

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 12), in all patients as well as in patients who have received 1 prior line of therapy. As a result of a preplanned 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).

Table 12: Summary of Disease Outcomes from the Phase III and Phase II studies

^a Intent to Treat (ITT) population

^b p-value from the stratified log-rank test; analysis by line of therapy excludes stratification for therapeutic history; p<0.0001

^c Response population includes patients who had measurable disease at baseline and received at least 1 dose of study drug.

^d p-value from the Cochran-Mantel-Haenszel chi-square test adjusted for the stratification factors; analysis by line of therapy excludes stratification for therapeutic history

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

NA = not applicable, NE = not estimated

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 (see Table 9).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.

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.

Distribution

The mean distribution volume (V_d) of bortezomib ranged from 1659 l to 3294 l following single- or repeateddose 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 concentrationdependent.

Metabolism

In vitro studies with human liver microsomes and human cDNA-expressed cytochrome P450 isozymes indicate that bortezomib is primarily oxidatively metabolized 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 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

Formal studies in patients with severely impaired hepatic function have not been conducted to date (see section 4.4). In the absence of data VELCADE is contraindicated in patients with severe liver impairment (see section 4.3).

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-normalized AUC and Cmax) was comparable among all the groups (see section 4.2).

Bortezomib was positive for clastogenic activity (structural chromosomal aberrations) in the in vitro chromosomal aberration assay using Chinese hamster ovary cells (CHO) 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 dosages, but no direct embryo-foetal toxicity below maternally toxic dosages. Fertility studies were not performed but evaluation of reproductive tissues has been performed in the general toxicity studies. In the 6month 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 hematopoietic 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.

Mannitol (E 421)

Nitrogen.

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

3 years

Reconstituted solution:

The reconstituted solution should be used immediately after preparation. If the reconstituted solution is 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 prior to administration, with a maximum of 8 hours in the syringe.

Do not store above 30°C. Keep the vial in the outer carton in order to protect from light.

For storage conditions of the reconstituted medicinal product, see section 6.3.

Type 1 glass 10 mlvial with a grey bromobutyl stopper and an aluminium seal, with a royal blue cap.

The vial is contained in a transparent blister pack consisting of a tray with a lid.

Pack containing 1 single-use vial.

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 handling of VELCADE, since it contains no preservative.

Instructions for reconstitution

Each 10 ml vial must be reconstituted with 3.5 ml of sodium chloride 9 mg/ml (0.9%) 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.

Disposal

For single use only.

Any unused product or waste material should be disposed of in accordance with local requirements.

JANSSEN-CILAG INTERNATIONAL NV

Turnhoutseweg, 30

B-2340 Beerse

Belgium

EU/1/04/274/001

Date of first authorization: 26/04/2004

Date of latest renewal: 26/04/2009

29^th May 2009