Velcade

1.

NAME OF THE MEDICINAL PRODUCT

VELCADE 1 mg powder for solution for injection

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains 1 mg bortezomib (as a mannitol boronic ester).

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

Excipients

For a full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Powder for solution for injection.

White to off-white cake or powder.

4.

CLINICAL PARTICULARS

4.1 Therapeutic indications

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.

4.2 Posology and method of administration

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/m 2 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.

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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/m 2 reduced to 1.0 mg/m 2 ; 1.0 mg/m 2 reduced to 0.7 mg/m 2 ). 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 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.

Severity of neuropathy

Posology modification

Grade 1 (paraesthesia, weakness and/or loss of

reflexes) with no pain or loss of function

None

Grade 1 with pain or Grade 2 (interfering with

function but not with activities of daily living)

Reduce VELCADE to 1.0 mg/m 2

Grade 2 with pain or Grade 3 (interfering with

activities of daily living)

Withhold VELCADE treatment until symptoms

of toxicity have resolved. When toxicity resolves

re-initiate VELCADE treatment and reduce dose

to 0.7 mg/m 2 and change treatment schedule to

once per week.

Grade 4 (sensory neuropathy which is disabling

or motor neuropathy that is life threatening or

leads to paralysis)

and/or severe autonomic neuropathy

Discontinue VELCADE

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

experience.

Special populations

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).

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 m 2 ); 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 m 2 ). Since

dialysis may reduce bortezomib concentrations, VELCADE should be administered after the dialysis

procedure (see section 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).

Paediatric population

The safety and efficacy of VELCADE in children below age 18 have not yet been established (see

sections 5.1 and 5.2).

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

3

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

Twice weekly VELCADE (cycles 1-4)

Week

1

2

3

4

5

6

Vc

(1.3 mg/m 2)

Day

1

--

Day

4

Day

8

Day

11

rest

period

Day

22

Day

25

Day

29

Day

32

rest

period

M (9 mg/m 2 )

P (60 mg/m 2)

Day

1

Day

2

Day

3

Day

4

--

rest

period

--

rest

period

Once weekly VELCADE (cycles 5-9)

Week

1

2

3

4

5

6

Vc

(1.3 mg/m 2)

Day

1

--

Day 8

rest

period

Day 22

Day 29

rest

period

M (9 mg/m 2 )

P (60 mg/m 2)

Day

1

Day

2

Day

3

Day

4

--

rest

period

--

rest

period

Vc = VELCADE; M = melphalan, P = prednisone

Dose adjustments during treatment and re-initiation of treatment for combination therapy

Prior to initiating a new cycle of therapy:

• Platelet counts should be ≥ 70 x 10 9 /l and the absolute neutrophils count should be ≥ 1.0 x 10 9 /l

• Non-haematological toxicities should have resolved to Grade 1 or baseline

Table 3: Posology modifications during subsequent cycles:

Toxicity

Posology modification or delay

Haematological toxicity during a cycle

• If prolonged Grade 4 neutropenia or

thrombocytopenia, or thrombocytopenia

with bleeding is observed in the previous

cycle

Consider reduction of the melphalan dose by 25%

in the next cycle.

• If platelet counts ≤30 × 10 9 /l or ANC

≤0.75 x 10 9 /l on a VELCADE dosing day

(other than Day 1)

VELCADE therapy should be withheld

• If several VELCADE doses in a cycle are

withheld (≥ 3 doses during twice weekly

administration or ≥ 2 doses during weekly

administration)

VELCADE dose should be reduced by 1 dose

level (from 1.3 mg/m 2 to 1 mg/m 2 , or from

1 mg/m 2 to 0.7 mg/m 2 )

Grade ≥ 3 non-haematological toxicities

VELCADE therapy should be withheld until

symptoms of the toxicity have resolved to Grade 1

or baseline. Then, VELCADE may be reinitiated

with one dose level reduction (from 1.3 mg/m 2 to

1 mg/m 2 , or from 1 mg/m 2 to 0.7 mg/m 2 ). For

VELCADE-related neuropathic pain and/or

peripheral neuropathy, hold and/or modify

VELCADE as outlined in Table 1.

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

Product Characteristics.

4

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.

4.3 Contraindications

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

Severe hepatic impairment (see section 4.4).

Acute diffuse infiltrative pulmonary and pericardial disease.

4.4 Special warnings and precautions for use

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 ≤25×10 9 /l during the

study. 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 combination with melphalan and

prednisone when the platelet count is ≤ 30,000/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

5

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.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS)

There have been reports of RPLS in patients receiving VELCADE. RPLS is a rare, reversible,

rapidly evolving neurological condition, which can present with seizure, hypertension, headache,

lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging,

preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients

developing RPLS, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients

previously experiencing RPLS is not known.

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/m 2 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/m 2 per day) by continuous

infusion over 24 hours is not recommended.

6

Renal impairment

Renal complications are frequent in patients with multiple myeloma. Patients with renal impairment

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 hepatic 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.

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 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.

4.5 Interaction with other medicinal products and other forms of interaction

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.

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.

7

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.

4.6 Fertility, pregnancy and lactation

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 section 5.3). VELCADE should not be

used during pregnancy unless the clinical condition of the woman requires treatment with VELCADE.

Contraception in males and females

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.

Breastfeeding

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.

Fertility

Fertility studies were not conducted with VELCADE (see section 5.3).

4.7 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,

orthostatic/postural hypotension or blurred vision commonly. Therefore, patients must be cautious

when operating machinery, or when driving (see section 4.8).

4.8 Undesirable effects

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. Serious adverse reactions uncommonly reported during treatment with

VELCADE include cardiac failure, tumour lysis syndrome, pulmonary hypertension, reversible

posterior leukoencephalopathy syndrome (RPLS), acute diffuse infiltrative pulmonary disorders and

rarely autonomic neuropathy.

The following undesirable effects in Table 4 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). In addition, this table contains adverse reactions from post-marketing reports* with frequency

categorization estimated from safety data comprising 2017 patients from clinical trials (including the

patients from the 6 studies described above). These patients were from company-sponsored trials with

VELCADE studied at 1.3 mg/m 2 as single chemotherapeutic agent or in combination with

8

dexamethasone for multiple myeloma (1995 patients), or for B cell chronic lymphocytic leukemia (22

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.

9

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

Infections and infestations

Very common : herpes zoster (including disseminated).

Common : pneumonia, bronchitis, sinusitis, nasopharyngitis, herpes simplex.

Uncommon : septic shock*, sepsis, herpes meningoencephalitis*, bacteraemia, pneumonia

pneumococcal, bronchopneumonia, upper and lower respiratory tract infection, catheter related

infection, pleural infection, haemophilus infection, cytomegalovirus infection, influenza, infectious

mononucleosis, varicella, urinary tract infection, gastroenteritis, candidal infection, fungal infection,

post herpetic neuralgia, oral candidiasis, blepharitis, infection.

Neoplasms benign and malignant (including cysts and polyps)

Uncommon : tumour lysis syndrome (see section 4.4).

Blood and the lymphatic system disorders (see section 4.4)

Very commo n: thrombocytopenia, neutropenia, anaemia .

Common : leukopenia, lymphopenia .

Uncommon : pancytopenia, febrile neutropenia, haemolytic anaemia, thrombocytopenic purpura,

lymphadenopathy.

Immune system disorders

Uncommon : angioedema*, hypersensitivity, immunocomplex mediated hypersensitivity, potentially

immunocomplex-mediated reactions, such as serum-sickness-type reaction, polyarthritis with rash and

proliferative glomerulonephritis (see section 4.4).

Endocrine disorders

Uncommon : inappropriate antidiuretic hormone (ADH) secretion .

Metabolism and nutrition disorders

Very common : appetite decreased .

Common : dehydration, hypokalaemia, hyperglycaemia.

Uncommon : hyperkalaemia, cachexia, hypercalcaemia, hypocalcaemia, hypernatraemia,

hyponatraemia, hypoglycaemia, hyperuricaemia, vitamin B12 deficiency, appetite increased,

hypomagnesaemia, hypophosphataemia.

Psychiatric disorders

Common : confusion, depression, insomnia, anxiety.

Uncommon : agitation, delirium, hallucinations, restlessness, mood swings, mental status changes,

sleep disorder, irritability, abnormal dreams.

Nervous system disorders (see sections 4.4 and 4.7)

Very common : peripheral neuropathy, peripheral sensory neuropathy (see section 4.4),

paraesthesia, headache.

Common : polyneuropathy, peripheral neuropathy aggravated, dizziness (excluding vertigo),

dysgeusia, dysaesthesia, hypoaesthesia, tremor.

Uncommon: encephalopathy*, reversible posterior leukoencephalopathy syndrome* (see section 4.4),

paraplegia, intracranial haemorrhage, subarachnoid haemorrhage convulsions (see section 4.4),

peripheral motor neuropathy, syncope, paresis, disturbance in attention, increased activity, ageusia,

somnolence, migraine, cognitive disorder, jerky movements, dizziness postural, sciatica,

mononeuropathy, speech disorder, restless leg syndrome.

Rare : autonomic neuropathy*

10

Eye disorders

Common : vision blurred (see section 4.7), eye pain.

Uncommon : eye haemorrhage, vision abnormal, dry eye, conjunctivitis, eye discharge, photophobia,

eye irritation, lacrimation increased, conjunctival hyperaemia, eye swelling.

Rare : herpes zoster ophthalmic*

Ear and labyrinth disorders

Common : vertigo.

Uncommon : deafness, tinnitus, hypoacusis, hearing impaired .

Cardiac disorders

Uncommon : cardiac tamponade*, cardiopulmonary arrest*, cardiac arrest, cardiogenic shock,

myocardial infarction, angina pectoris, angina unstable, development or exacerbation of congestive

heart failure (see section 4.4), cardiac failure, ventricular hypokinesia, pulmonary oedema and acute

pulmonary oedema, sinus arrest, atrioventricular block complete, tachycardia, sinus tachycardia,

supraventricular tachycardia, arrhythmia, atrial fibrillation, palpitations.

Rare : new onset of decreased left ventricular ejection fraction, pericarditis*, ventricular

arrhythmia*, ventricular tachycardia*

Vascular disorders

Common : hypotension, orthostatic and postural hypotension (see sections 4.4 and 4.7), phlebitis,

haematoma, hypertension.

Uncommon : cerebral hemorrhage, vasculitis, cerebrovascular accident, pulmonary hypertension,

petechiae, ecchymosis, purpura, vein discolouration, vein distended, wound hemorrhage, flushing, hot

flushes .

Respiratory, thoracic and mediastinal disorders

Very commo n: dyspnoea.

Common : dyspnoea exertional, epistaxis, cough, rhinorrhoea.

Uncommon : respiratory failure*, pneumonitis*, pulmonary embolism*, pulmonary hypertension*,

interstitial pneumonia*, acute diffuse infiltrative pulmonary disease*, pulmonary alveolar

haemorrhage*, respiratory arrest, hypoxia, pulmonary congestion, pleural effusion, asthma,

respiratory alkalosis, tachypnoea, wheezing, nasal congestion,hoarseness, rhinitis, hyperventilation,

orthopnoea, chest wall pain, sinus pain, throat tightness, productive cough.

Rare : acute respiratory distress syndrome (ARDS)*, peripheral embolism*,

Gastrointestinal disorders (see section 4.4)

Very common : vomiting, diarrhoea, nausea, constipation.

Common : abdominal pain, stomatitis, dyspepsia, loose stools, abdominal pain upper, flatulence,

abdominal distension, hiccups, mouth ulceration, pharyngolaryngeal pain, dry mouth.

Uncommon : colitis ischaemic*, acute pancreatitis, ileus paralytic, antibiotic associated colitis, colitis,

haematemesis, diarrhoea haemorrhagic, gastrointestinal haemorrhage, rectal haemorrhage, enteritis,

dysphagia, abdominal discomfort, eructation, gastrointestinal motility disorder, oral pain, retching,

change in bowel habit, spleen pain, oesophagitis, gastritis, gastro-oesophageal reflux disease,

gastrointestinal pain, gingival bleeding, gingival pain, hiatus hernia, irritable bowel syndrome, oral

mucosal petechiae, salivary hypersecretion, tongue coated, tongue discolouration, faecal impaction.

Hepato-biliary disorders (see section 4.4)

Uncommon : hepatitis, hepatic haemorrhage, hypoproteinaemia, hyperbilirubinaemia .

Rare : hepatic failure*

11

Skin and subcutaneous tissue disorders

Very common : rash.

Common : periorbital oedema, urticaria, rash pruritic, pruritus, erythema, sweating increased, dry

skin, eczema.

Uncommon : Stevens-Johnson Syndrome*, toxic epidermal necrolysis*, rash erythematous,

photosensitivity reaction, contusion, pruritus generalised, rash macular, rash papular, psoriasis, rash

generalized, eyelid oedema, face oedema, dermatitis, alopecia, nail disorder, skin discolouration,

dermatitis atopic, hair texture abnormal, heat rash, night sweats, pressure sore, ichthyosis, skin nodule.

Rare : acute febrile neutrophilic dermatosis (Sweet’s syndrome)*, vasculitic rash (including

leukocytoclastic vasculitis)*

Musculoskeletal, connective tissue and bone disorders

Very common : myalgia.

Common : muscle weakness, musculoskeletal pain, pain in limb, muscle cramps, arthralgia, bone

pain, back pain, peripheral swelling.

Uncommon : muscle spasms, muscle twitching or sensation of heaviness, muscle stiffness, joint

swelling, joint stiffness, buttock pain, swelling, pain in jaw.

Renal and urinary disorders

Common : renal impairment, dysuria.

Uncommon : renal failure acute, renal failure, oliguria, renal colic, haematuria, proteinuria, urinary

retention, urinary frequency, difficulty in micturition, loin pain, urinary incontinence, micturition

urgency.

Reproductive system and breast disorders

Uncommon : testicular pain, erectile dysfunction.

General disorders and administration site conditions

Very common : fatigue (see section 4.7), pyrexia.

Common : asthenia, weakness, lethargy, rigors, malaise, influenza like illness, oedema peripheral,

chest pain, pain, oedema.

Uncommon : fall, mucosal haemorrhage, mucosal inflammation, neuralgia, injection site phlebitis,

extravasation inflammation tenderness, injection site erythema, feeling cold, chest pressure sensation,

chest discomfort, groin pain, chest tightness.

Investigations

Common : weight decreased, blood lactate dehydrogenase increased.

Uncommon : alanine aminotransferase increased, aspartate aminotransferase increased, blood bilirubin

increased, blood alkaline phosphatase increased, blood creatinine increased, blood urea increased,

gamma-glutamyltransferase increased, blood amylase increased, liver function tests abnormal, red

blood cell count decreased, white blood cell count decreased, blood bicarbonate decreased, heart rate

irregular, C-reactive protein increased, blood phosphate decreased, weight increased.

Injury and poisoning

Uncommon : catheter related complications, post procedural pain, post procedural haemorrhage, burns.

*from post-marketing sources

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/m 2 ) in combination with melphalan (9 mg/m 2 ) and

prednisone (60 mg/m 2 ) 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.

12

Table 5: Treatment emergent drug-related adverse reactions reported in ≥ 10% of patients treated

with VELCADE in combination with melphalan and prednisone

-------------- Vc+M+P ------------ ---------------- M+P ---------------

(n=340)

(n=337)

MedDRA System Organ Class

Total Toxicity Grade, n (%) Total Toxicity Grade, n (%)

Preferred Term

n (%)

3 ≥ 4

n (%)

3 ≥ 4

Infections and Infestations

Herpes Zoster

39 ( 11)

11 ( 3)

0

9 ( 3)

4 ( 1)

0

Blood and lymphatic system

disorders

Thrombocytopenia

164 ( 48) 60 ( 18) 57 ( 17) 140 ( 42) 48 ( 14) 39 ( 12)

Neutropenia

160 ( 47) 101 ( 30) 33 ( 10) 143 ( 42) 77 ( 23) 42 ( 12)

Anaemia

109 ( 32) 41 ( 12)

4 ( 1) 156 ( 46) 61 ( 18)

18 ( 5)

Leukopenia

108 ( 32) 64 ( 19)

8 ( 2)

93 ( 28) 53 ( 16)

11 ( 3)

Lymphopenia

78 ( 23) 46 ( 14)

17 ( 5) 51 ( 15)

26 ( 8)

7 ( 2)

Metabolism and nutrition disorders

Anorexia

64 ( 19)

6 ( 2)

0

19 ( 6)

0

Psychiatric disorders

Insomnia

35 ( 10)

1 ( <1)

0

21 ( 6)

0

Nervous system disorders

Peripheral Neuropathy

156 ( 46) 42 ( 12)

2 ( 1)

4 ( 1)

0

Neuralgia

117 ( 34) 27 ( 8)

2 ( 1)

1 ( <1)

0

Paraesthesia

42 ( 12)

6 ( 2)

0

4 ( 1)

0

Gastrointestinal disorders

Nausea

134 ( 39) 10 ( 3)

0

70 ( 21)

1 ( <1)

0

Diarrhoea

119 ( 35) 19 ( 6)

2 ( 1)

20 ( 6)

1 ( <1)

0

Vomiting

87 ( 26)

13 ( 4)

0

41 ( 12)

2 ( 1)

0

Constipation

77 ( 23)

2 ( 1)

0

14 ( 4)

0

Abdominal Pain Upper

34 ( 10)

1 ( <1)

0

20 ( 6)

0

Skin and subcutaneous tissue

disorders

Rash

38 ( 11)

2 ( 1)

0

7 ( 2)

0

General disorders and

administration site conditions

Fatigue

85 ( 25)

19 ( 6)

2 ( 1)

48 ( 14)

4 ( 1)

0

Asthenia

54 ( 16)

18 ( 5)

0

23 ( 7)

3 ( 1)

0

Pyrexia

53 ( 16)

4 ( 1)

0

19 ( 6)

1 ( <1)

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 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.

13

4.9 Overdose

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).

5.

PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Other antineoplastic agents,

ATC code: L01XX32

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 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 (VISTA) of 682

patients was conducted to determine whether VELCADE (1.3 mg/m 2 ) in combination with melphalan

(9 mg/m 2 ) and prednisone (60 mg/m 2 ) resulted in improvement in time to progression (TTP) when

compared to melphalan (9 mg/m 2 ) and prednisone (60 mg/m 2 ) in patients with previously untreated

multiple myeloma. Treatment was administered for a maximum of 9 cycles (approximately 54 weeks)

14

and was discontinued early for disease progression or unacceptable toxicity. Baseline demographics

and patient characteristics are summarized in Table 6.

Table 6: Summary of baseline patient and disease characteristics in the VISTA study

Patient characteristics

Vc+M+P

n=344

M+P

n=338

Median age in years (range)

71.0 (57, 90)

71.0 (48, 91)

Gender: male/female

51% / 49%

49% / 51%

Race: caucasian/asian/black/other

88% / 10% / 1% / 1% 87% / 11% / 2% / 0%

Karnofsky performance status score ≤70

35%

33%

Hemoglobin <100 g/l

37%

36%

Platelet count <75 x 10 9 /l

<1%

1%

Disease Characteristics

Type of myeloma (%): IgG/IgA/Light chain

64% / 24% / 8%

62% / 26% / 8%

Median β 2 -microglobulin (mg/l)

4.2

4.3

Median albumin (g/l)

33.0

Creatinine clearance ≤30 ml/min [n (%)]

20 (6%)

16 (5%)

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. A

survival update was performed with a median duration of follow-up of 36.7 months. A statistically

significant survival benefit in favour of the Vc+M+P treatment group was observed (HR=0.65;

p=0.00084) despite subsequent therapies including VELCADE-based regimens. While the median

survival in M+P treatment group has now been estimated at 43.1 months, the median survival on the

Vc+M+P treatment group has not been reached. Efficacy results are presented in Table 7:

15

Table 7: Updated efficacy results following pre-plan ned interim analysis in the VISTA study

Efficacy endpoint

Vc+M+P

n=344

M+P

n=338

Time to progression

Events n (%)

101 (29)

152 (45)

Median a (95% CI)

20.7 mo

(17.6, 24,7)

15.0 mo

(14.1, 17.9)

Hazard ratio b

(95% CI)

0.54

(0.42, 0.70)

p-value c

0.000002

Progression-free survival

Events n (%)

135 (39)

190 (56)

Median a (95% CI)

18.3 mo

(16.6, 21.7)

14.0 mo

(11.1, 15.0)

Hazard ratio b

(95% CI)

0.61

(0.49, 0.76)

p-value c

0.00001

Overall survival*

Events (deaths) n (%)

109 (32)

148 (44)

Median a

(95% CI)

NR

(46.2, NR )

43.1 mo

(34.8, NR)

Hazard ratio b

(95% CI)

0.65

(0.51, 0.84)

p-value c

0.00084

Response rate

population e n = 668

n=337

n=331

CR f n (%)

102 (30)

12 (4)

PR f n (%)

136 (40)

103 (31)

nCR n (%)

5 (1)

0

CR + PR f n (%)

238 (71)

115 (35)

p-value d

<10 -10

Reduction in serum M-protein

population g n=667

n=336

n=331

>=90% n (%)

151 (45)

34 (10)

Time to first response in CR + PR

Median

1.4 mo

4.2 mo

Median a response duration

CR f

24.0 mo

12.8 mo

CR + PR f

19.9 mo

13.1 mo

Time to next therapy

Events n (%)

73 (21)

127 (38)

Median a

(95% CI)

NE

(26.1, NE)

20.8 mo

(18.3, 28.5)

Hazard ratio b

(95% CI)

0.52

(0.39, 0.70)

p-value c

0.000009

a Kaplan-Meier estimate.

b Hazard ratio estimate is based on a Cox proportional-hazard model adjusted for stratification factors:

β 2 -microglobulin, albumin, and region. A hazard ratio less than 1 indicates an advantage for VMP

c Nominal p-value based on the stratified log-rank test adjusted for stratification factors:

β 2 -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

16

e Response population includes patients who had measurable disease at baseline

f EBMT criteria

g All randomized patients with secretory disease

* Survival update based on a median duration of follow-up at 36.7 months

NE: not estimable

NR: not reached

mo: months

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/m 2 : 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 8, 9 and 10).

Table 8: Dosing regimens in Phase II and Phase III studies

Phase

Treatment schedule

Dose

Regimen

II

Vc: Day 1,4,8,11, (rest Day 12-21) 1.3 mg/m 2

(intravenous bolus)

Q3 weeks x 8cycles

(extension**)

III

Vc*

a) Days 1,4,8,11, (Rest Day 12-21)

b) Days 1,8,15,22

1.3 mg/m 2

(intravenous bolus)

a) Q3weeks x 8, then

b) Q5 weeks x 3

III

Dex

a) Days 1–4, 9–12, 17–20

b) Days 1–4

40 mg (oral)

a) Q5 week x 4

b) Q4 week x 5

II

Add Dex***

20 mg (oral)

(Days

1,2,4,5,8,9,11,12)

Q3 weeks

*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

Table9: Patient characteristics in Phase II and Phase III studies

Phase II

Vc

Phase III

Vc

Phase III

Dex

Patient number, ITT analysis

202

333

336

Male %

60

56

60

Median age, yrs (range)

59 (34-84)

61 (33-84)

61 (27-86)

Caucasian

81 %

90 %

88 %

Karnofsky PS >80%

80 %

87 %

84 %

Platelets < 75,000/μl

21 %

6 %

4 %

Hemoglobin < 100g/l

44 %

32 %

28 %

Median Creatinine Clearance, ml/min (range)

74

(14-221)

73.3

(15.6-170.7)

73.3

(15.3-261.1)

Myeloma IgG

60 %

59 %

Myeloma IgA

24 %

23 %

24 %

Myeloma light chain

14 %

12 %

13 %

Median duration since diagnosis (yrs)

4.0

3.5

3.1

Chromosome 13 abnormalities

15 %

25.7 %

25.0 %

Median β 2 -microglobulin (mg/l)

3.5

3.7

3.6

Median number prior treatment lines*

(range)

6 (2-15)

2 (1-7)

2 (1-8)

1 prior line

0

n =132 (40 %) n = 119 (35 %)

17

Phase III

Dex

> 1 prior line n = 186 (60 %) n = 194 (65 %)

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

Phase II

Vc

Phase III

Vc

Table 10: Patient exposure to treatment with VELCADE during Phase II and III studies

Phase II

Vc

Phase III

Vc

Phase III

Dex

Received at least 1 dose

n = 202

n = 331

n = 332

Completed 4 cycles

a) all initial cycles (number)

b) full course (number)

c) extension *

62 %

27 % (8 cycles)

NA

n= 63 pts (median 7

cycles) or total

median 14 cycles

(range 7-32)

69 %

29 % (8 cycles)

9 % (11 cycles)

NA

36 % (4 cycles)

5 % (9 cycles)

NA

*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 11), 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

β 2 -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).

18

Table 11: Summary of disease outcomes from the Phase III and Phase II studies

Phase III

Phase II

All patients

1 Prior line of therapy

>1 Prior line of

therapy

≥ 2 prior

lines

Time related

events

Vc

n=333 a

Dex

n=336 a

Vc

n=132 a

Dex

n=119 a

Vc

n=200 a

Dex

n=217 a

Vc

n=202 a

TTP, days

[95% CI]

189 b

[148, 211]

106 b

[86, 128]

212 d

[188, 267]

169 d

[105, 191]

148 b

[129, 192]

87 b

[84, 107]

210

[154, 281]

1 year survival, %

[95% CI]

80 d

[74,85]

66 d

[59,72]

89 d

[82,95]

72 d

[62,83]

73

[64,82]

62

[53,71]

60

Best response

(%)

Vc

n=315 c

Dex

n=312 c

Vc

n=128

Dex

n=110

Vc

n=187

Dex

n=202

Vc

n=193

CR

20 (6) b

2 (<1) b

8 (6)

2 (2)

12 (6)

0 (0)

(4)**

CR + nCR

41 (13) b

5 (2) b

16 (13)

4 (4)

25 (13)

1 (<1)

(10)**

CR+ nCR + PR

121 (38) b

56 (18) b

57 (45) d

29 (26) d

64 (34) b

27 (13) b

(27)**

CR + nCR+

PR+MR

146 (46)

108 (35)

66 (52)

45 (41)

80 (43)

63 (31)

(35)**

Median duration

Days (months)

242 (8.0)

169 (5.6)

246 (8.1)

189 (6.2)

238 (7.8)

126 (4.1)

385*

Time to response

CR + PR (days)

43

44

46

41

27

38*

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 8).

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.

Patients with previously treated light-chain (AL) Amyloidosis

An open label non randomised phase 1/2 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/m 2 weekly and 1.3 mg/m 2 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. (see section 4.2 for

information on paediatric use).

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 (EMA) will review any new information which may become

available every year and this SmPC will be updated as necessary.

19

5.2 Pharmacokinetic properties

Following intravenous bolus administration of a 1.0 mg/m 2 and 1.3 mg/m 2 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/m 2 dose and 89 to 120 ng/ml for the 1.3 mg/m 2 dose.

Distribution

The mean distribution volume (V d ) of bortezomib ranged from 1659 l to 3294 l following single- or

repeated-dose administration of 1.0 mg/m 2 or 1.3 mg/m 2 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.

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 (t 1/2 ) 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/m 2 and

1.3 mg/m 2 , respectively, and ranged from 15 to 32 l/h and 18 to 32 l/h following subsequent doses for

doses of 1.0 mg/m 2 and 1.3 mg/m 2 , 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 m 2 , n=12), Mild (CrCL = 40-59 ml/min/1.73 m 2 , n = 10), Moderate

(CrCL = 20-39 ml/min/1.73 m 2 , n = 9), and Severe (CrCL < 20 ml/min/1.73 m 2 , 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/m 2 of VELCADE twice weekly. Exposure of

VELCADE (dose-normalized AUC and Cmax) was comparable among all the groups (see section

4.2).

5.3 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 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 6-month rat study, degenerative effects in both the testes and the ovary have been

20

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/m 2 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.

6.

PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Mannitol (E 421) Nitrogen.

6.2 Incompatibilities

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

section 6.6.

6.3 Shelf life

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.

6.4 Special precautions for storage

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.

6.5 Nature and contents of container

Type 1 glass 5 ml-vial with a grey bromobutyl stopper and an aluminium seal, with a green cap.

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

Pack containing 1 single-use vial.

Not all pack sizes may be marketed.

21

6.6 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 handling of VELCADE, since it contains no

preservative.

Instructions for reconstitution

Each vial must be reconstituted with 1 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.

7.

MARKETING AUTHORISATION HOLDER

JANSSEN-CILAG INTERNATIONAL NV

Turnhoutseweg 30

B-2340 Beerse

Belgium

8.

MARKETING AUTHORISATION NUMBER

EU/1/04/274/002

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorization: 26/04/2004

Date of latest renewal: 26/04/2009

10. DATE OF REVISION OF THE TEXT

Detailed information on this product is available on the website of the European Medicines Agency

(EMA) http://www.ema.europa.eu

22

1.

NAME OF THE MEDICINAL PRODUCT

VELCADE 3.5 mg powder for solution for injection

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

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