Velcade 3.5mg powder for solution for injection

1. Name Of The Medicinal Product

VELCADE

2. Qualitative And Quantitative Composition

Each vial contains 3.5 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/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.

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/m2
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/m2 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

Patients with mild hepatic impairment do not require a dose adjustment and should be treated per the recommended dose. Patients with moderate or severe hepatic impairment should be started on VELCADE at a reduced dose of 0.7 mg/m² per injection during the first treatment cycle, and a subsequent dose escalation to 1.0 mg/m² or further dose reduction to 0.5 mg/m² may be considered based on patient tolerability. (see Table 2, sections 4.4 and 5.2).

Table 2: Recommended Starting Dose Modification for VELCADE in Patients with Hepatic Impairment

Grade of hepatic impairment*	Bilirubin Level	SGOT (AST) Levels	Modification of Starting Dose
Mild		> ULN	None
> 1.0x−1.5x ULN	Any	None
Moderate	> 1.5x−3x ULN	Any	Reduce VELCADE to 0.7 mg/m2 in the first treatment cycle. Consider dose escalation to 1.0 mg/m2 or further dose reduction to 0.5 mg/m2 in subsequent cycles based on patient tolerability.
Severe	> 3x ULN	Any

Abbreviations: SGOT = serum glutamic oxaloacetic transaminase;

AST = aspartate aminotransferase; ULN = upper limit of the normal range.

*Based on NCI Organ Dysfunction Working Group classification for categorising hepatic impairment (mild, moderate, severe).

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).

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 3. 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.

Table3: 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/m2)	Day 1	--	--	Day 4	Day 8	Day 11	rest period	Day 22	Day 25	Day 29	Day 32	rest period
M (9 mg/m2) P (60 mg/m2)	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/m2)	Day 1	--	--	--	Day 8	rest period	Day 22	Day 29	rest period
M (9 mg/m2) P (60 mg/m2)	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 ⁹/l and the absolute neutrophils count should be ⁹/l

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

Table 4: 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 9/l or ANC 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 (	VELCADE dose should be reduced by 1 dose level (from 1.3 mg/m2 to 1 mg/m2, or from 1 mg/m2 to 0.7 mg/m2)
Grade	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/m2 to 1 mg/m2, or from 1 mg/m2 to 0.7 mg/m2). 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.

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.

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 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

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.

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/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. Patients with renal impairment should be monitored closely (see sections 4.2 and 5.2).

Hepatic impairment

Bortezomib is metabolized by liver enzymes. Bortezomib exposure is increased in patients with moderate or severe hepatic impairment; these patients should be treated with VELCADE at reduced doses and closely monitored for toxicities (see sections 4.2 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.

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 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 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 5 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 postmarketing 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/m² as single chemotherapeutic agent or in combination with 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.

Table 5: 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 lymphatic system disorders (see section 4.4) Very common: 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*

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 Common: 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*

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 postmarketing sources

Summary of safety data