Spalbort 3,5 Mg Solution

SPALBORT 3,5 mg for injection is indicated as:

• primary treatment of multiple myeloma in combination with melphalan and prednisone.
• monotherapy for the treatment of patients with multiple myeloma who have received at least one prior therapy and who have progressive disease.
• treatment of relapsed or refractory mantle cell lymphoma for patients who have received at least 1 prior line of therapy, one of which should have included an anthracycline (or mitoxantrone) and/or rituximab as part of their chemotherapy regimen.

SPALBORT 3,5 mg powder for solution for injection is available for:

• intravenous administration at a concentration of 1 mg/ml (as a 3-5 second bolus injection) or
• subcutaneous administration at a concentration 2,5 mg/ml.

Because each route of administration has a different reconstituted concentration, caution should be used when calculating the volume to be administered. SPALBORT 3,5 mg should not be given by other routes. Intrathecal administration has resulted in death. See Reconstitution Instructions below.

Posology

Monotherapy

The recommended starting dose of SPALBORT 3,5 mg is 1,3 mg/mu00b2 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 SPALBORT 3,5 mg. It is recommended that patients with a confirmed complete response receive 2 additional cycles of SPALBORT 3,5 mg beyond a confirmation. It is also recommended that responding patients who do not achieve a complete remission receive a total of 8 cycles of SPALBORT 3,5 mg therapy.

There is limited data concerning re-treatment with bortezomib such as in SPALBORT 3,5 mg.

Recommended dosage adjustments during treatment and re-initiation of treatment

SPALBORT 3,5 mg 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, SPALBORT 3,5 mg treatment may be re-initiated at a 25 % reduced dose (1,3 mg/mu00b2 reduced to 1,0 mg/mu00b2 or 1,0 mg/mu00b2 reduced to 0,7 mg/mu00b2). If the toxicity is not resolved or if it recurs at the lowest dose, discontinuation of SPALBORT 3,5 mg must be considered.

Patients who experience SPALBORT 3,5 mg related neuropathic pain and/or peripheral neuropathy are to be managed as presented in Table 1. Patients with pre-existing severe neuropathy may be treated with SPALBORT 3,5 mg only after careful risk/benefit assessment.

Table 1: Recommended dose modifications for SPALBORT 3,5 mg related Neuropathic Pain and/or Peripheral Sensory Neuropathy.

Severity of peripheral neuropathy

Modification of dose and regimen

• Grade 1 (paraesthesia, weakness and/or loss of reflexes) with no pain or loss of function: No action
• Grade 1 with pain or Grade 2 (interfering with function but not activities of daily living): Reduce to 1,0 mg/mu00b2
• Grade 2 with pain or Grade 3 (interfering with activities of daily living): Withhold SPALBORT 3,5 mg treatment until symptoms of toxicity have resolved. When toxicity resolves re-initiate SPALBORT 3,5 mg treatment and reduce dose to 0,7 mg/mu00b2 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): Discontinue SPALBORT 3,5 mg

Special populations

Pediatric patients

SPALBORT 3,5 mg has not been studied in children and adolescents. Therefore, it should not be used in the paediatric age group until further data become available.

Elderly patients

There is no evidence to suggest that dose adjustments are necessary in the elderly.

Patients with Renal Impairment

The pharmacokinetics of SPALBORT 3,5 mg are not influenced by the degree of renal impairment. Therefore, dosing adjustments of SPALBORT 3,5 mg are not necessary for patients with renal insufficiency. Since dialysis may reduce SPALBORT 3,5 mg concentrations, SPALBORT 3,5 mg should be administered after the dialysis procedure (see section 5.2).

Patients with Hepatic Impairment

Patients with mild hepatic impairment do not require a starting dose adjustment and should be treated per the recommended SPALBORT 3,5 mg dose. Patients with moderate to severe hepatic impairment should be started on SPALBORT 3,5 mg at a reduced dose of 0,7 mg/mu00b2 per injection during the first cycle, and a subsequent dose escalation to 1,0 mg/mu00b2 or further dose reduction to 0,5 mg/mu00b2 may be considered based on patient tolerance (see Table 2).

Table 2: Recommended Starting Dose Modification for SPALBORT 3,5 mg in Patients with Hepatic Impairment.

Grade of hepatic impairment *

Bilirubin Level

SGOT (AST) Levels

Modification of Starting Dose

• Mild u2264 1,0 x ULN > ULN: None
• > 1,0 x - 1,5 x ULN: Any: None
• Moderate > 1,5 x u2212 3 x ULN: Any: Reduce SPALBORT 3,5 mg to 0,7 mg/mu00b2 in the first cycle. Consider dose escalation to 1,0 mg/mu00b2 or further dose reduction to 0,5 mg/mu00b2 in subsequent cycles based on patient tolerability.
• Severe > 3 x ULN: Any

Administration Precautions

There have been fatal cases of inadvertent intrathecal administration of bortezomib. DO NOT ADMINISTER SPALBORT 3,5 mg INTRATHECALLY.

SPALBORT 3,5 mg Intravenous injection: 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 0,9 % sodium chloride solution for injection. At least 72 hours should elapse between consecutive doses of SPALBORT 3,5 mg.

Subcutaneous injection: The reconstituted solution is injected into the thighs (right or left) or abdomen (right or left). Injection sites should be rotated for successive injections. If local injection site reactions occur following SPALBORT 3,5 mg injection subcutaneously, a less concentrated SPALBORT 3,5 mg solution (1 mg/ml instead of 2,5 mg/ml) may be administered subcutaneously, or changed to IV injection.

Combination Therapy

Recommended Dosage

SPALBORT 3,5 mg (bortezomib) for injection 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, SPALBORT 3,5 mg is administered twice weekly (days 1, 4, 8, 11, 22, 25, 29 and 32). In Cycles 5-9, SPALBORT 3,5 mg is administered once weekly (days 1, 8, 22 and 29).

Table 3: Recommended Dosage Regimen for SPALBORT 3,5 mg when used in combination with melphalan and prednisone for Patients with Previously Untreated Multiple Myeloma

Twice Weekly SPALBORT 3,5 mg (Cycles 1 - 4)

Week

1 2 3 4 5 6

Vc (1,3 mg/mu00b2)

Day 1 Day 4 Day 8 Day 11 rest period Day 22 Day 25 Day 29 Day 32 rest period

m (9 mg/mu00b2)

p (60 mg/mu00b2)

Day 1 Day 2 Day 3 Day 4 -- -- rest period -- -- -- -- rest period

Once Weekly SPALBORT 3,5 mg (Cycles 5 - 9)

Week

1 2 3 4 5 6

Vc (1,3 mg/mu00b2)

Day 1 -- -- -- Day 8 rest period Day 22 Day 29 rest period

m (9 mg/mu00b2)

p (60 mg/mu00b2)

Day 1 Day 2 Day 3 Day 4 -- rest period -- -- rest period

Vc = SPALBORT 3,5 mg; m = melphalan, p=prednisone

Hypersensitivity to bortezomib, or to any of the excipients of SPALBORT 3,5 mg (see section 6.1 for list of excipients).

Severe hepatic impairment.

Acute diffuse infiltrative pulmonary and pericardial disease.

When SPALBORT 3.5 mg is given in combination with other medicines, refer to their professional information for additional contraindications.

Treatment must be initiated and administered under the supervision of a medical practitioner experienced in the use of chemotherapeutic medicines.

There have been fatal cases of inadvertent intrathecal administration of SPALBORT 3,5 mg. SPALBORT 3,5 mg is for IV or SC use. DO NOT ADMINISTER SPALBORT 3,5 mg INTRATHECALLY.

Herpes Zoster Virus Reactivation

Medical practitioners should reconsider using antiviral prophylaxis in patients being treated with SPALBORT 3,5 mg. In studies in patients with previously untreated multiple myeloma, the overall incidence of herpes zoster reactivation was very common in patients treated with Bortezomib, Melphalan and Prednisone (VcMP) compared with Melphalan + Prednisone.

Hepatitis B virus (HBV) reactivation and infection:

When rituximab is administered in combination with SPALBORT 3,5 mg, HBV screening must always be performed in patients at risk of infection with HBV before initiation of treatment. Carriers of hepatitis B and patients with a history of hepatitis B must be closely monitored for clinical and laboratory signs of active HBV infection during and following rituximab combination treatment with SPALBORT 3,5 mg. Antiviral prophylaxis should be considered.

Progressive multifocal leukoencephalopathy (PML):

Very rare cases with unknown causality of John Cunningham (JC) virus infection, resulting in PML and death, have been reported in patients treated with bortezomib. Patients diagnosed with PML had prior or concurrent immunosuppressive therapy. Most cases of PML were diagnosed within 12 months of their first dose of bortezomib. Patients should be monitored at regular intervals for any new or worsening neurological symptoms or signs that may be suggestive of PML as part of the differential diagnosis of CNS problems. If a diagnosis of PML is suspected, patients should be referred to a specialist in PML and appropriate diagnostic measures for PML should be initiated. Discontinue SPALBORT 3,5 mg if PML is diagnosed.

Patients with mantle cell lymphoma: Safety data for patients with mantle cell lymphoma was similar to that observed in patients with multiple myeloma. Notable differences between the two patient populations were that thrombocytopaenia, neutropaenia, anaemia, nausea, vomiting and pyrexia were reported more often in the patients with multiple myeloma than in those with mantle cell lymphoma; whereas peripheral neuropathy, rash and pruritus were higher among patients with mantle cell lymphoma compared to patients with multiple myeloma.

Based on the integrated safety database from 256 patients with relapsed and/or refractory multiple myeloma, the following special precautions are suggested: Overall, the safety profile of patients treated with bortezomib in monotherapy was similar to that observed in patients treated with bortezomib in combination with melphalan and prednisone.

Laboratory Tests

Complete blood counts (CBC) including platelet counts should be frequently monitored throughout treatment with SPALBORT 3,5 mg.

Gastrointestinal toxicity

Gastrointestinal toxicity, including diarrhoea, constipation, nausea and vomiting are very common with SPALBORT 3,5 mg treatment (see section 4.8). Reactions usually occur early in treatment (Cycles 1 and 2) and may persist for several cycles. Patients experiencing treatment emergent gastrointestinal toxicity may benefit from administration of anti-emetics and anti-diarrhoeals. Fluid and electrolyte replacement should be administered to prevent or treat dehydration. Cases of ileus have been reported therefore patients who experience constipation should be closely monitored.

Haematological toxicity

SPALBORT 3,5 mg treatment is very commonly associated with haematological toxicities (thrombocytopaenia and neutropaenia). However, febrile neutropaenia is an uncommon undesirable effect. The most common haematologic toxicity is transient thrombocytopaenia, which generally resolves between treatment cycles. Platelets were lowest at Day 11 of each cycle of SPALBORT 3,5 mg treatment and typically recovered to baseline by the next cycle. The cyclical pattern of platelet decrease and recovery remained consistent over the 8 cycles of twice weekly dosing and there was no evidence of cumulative thrombocytopaenia. The mean platelet count nadir measured was approximately 40 % of baseline. Severe bleeding, including central nervous system (CNS) and gastrointestinal bleeding, associated with thrombocytopaenia, has been reported. In patients with advanced myeloma, the severity of thrombocytopaenia was related to pre-treatment platelet count. Platelet counts should be monitored prior to each dose of SPALBORT 3,5 mg. Therapy should be held when the platelet count is < 25,000/u03bcL and re-initiated at a reduced dose after resolution (see section 4.8). Potential benefit of the treatment should be carefully weighed against the risks. Platelet transfusions, red blood cell (RBC) transfusions and administration of growth factors may be utilised in the management of haematologic toxicities. Prophylactic platelet transfusions should be considered in thrombocytopaenic patients at high risk of bleeding.

Peripheral Neuropathy

SPALBORT 3,5 mg treatment causes a peripheral neuropathy that is predominantly sensory. However, cases of severe motor neuropathy with or without sensory peripheral neuropathy have been reported. Patients with pre-existing symptoms (numbness, pain or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy are likely to experience worsening peripheral neuropathy (including u2265 Grade 3) during treatment with SPALBORT 3,5 mg. 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, hyperaesthesia, hypoaesthesia, paraesthesia, discomfort or neuropathic pain. Patients experiencing new or worsening peripheral neuropathy may require the dose and schedule of SPALBORT 3,5 mg to be modified (see section 4.2).

Neuropathy has been managed with supportive care and other therapies. Peripheral neuropathy may not be reversible. Improvement in, or resolution of, peripheral neuropathy was reported in 51 % of patients with u2265 Grade 2 peripheral neuropathy in a single medicine 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 reported in patients without previous history of seizures or epilepsy. Special care is required when treating patients with any risk factors for seizures.

Hypotension

SPALBORT 3,5 mg treatment is commonly associated with orthostatic/postural hypotension. Most patients require treatment for their orthostatic hypotension. Patients with orthostatic hypotension may experience syncopal events. The mechanism of this event is unknown although a component may be due to autonomic neuropathy. Autonomic neuropathy may be related to SPALBORT 3,5 mg or SPALBORT 3,5 mg may aggravate an underlying condition such as diabetic 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 is symptomatic and 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.

Cardiac Disorders

Development or exacerbation of congestive heart failure, and/or new onset of decreased left ventricular ejection fraction has been reported. Patients with risk factors for, or existing heart disease should be closely monitored. Fluid retention may be a predisposing factor for signs and symptoms of heart failure. There have been isolated cases of QT-interval prolongation in clinical trials; causality has not been established.

Pulmonary Disorders

There have been 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 bortezomib (SPALBORT 3,5 mg). Some of these events have been fatal. A higher proportion of these events have been reported in Japan. In the event of new or worsening pulmonary symptoms, a prompt diagnostic evaluation should be performed and patients treated appropriately. In a clinical trial, the first two patients given high-dose cytarabine (2 g/mu00b2 per day) by continuous infusion in combination with daunorubicin and bortezomib (SPALBORT 3,5 mg) for relapsed acute myelogenous leukaemia died of ARDS early in the course of therapy. The trial was discontinued subsequently.

Renal Events

Renal complications are frequent in patients with multiple myeloma. Such patients should be monitored closely.

Hepatic Events

Cases of acute liver failure have been reported. Other reported hepatic events include asymptomatic increases in liver enzymes, hyperbilirubinaemia, and hepatitis. Such changes may be reversible upon discontinuation of SPALBORT 3,5 mg. There is limited re-challenge information in these patients.

Hepatic Impairment

SPALBORT 3,5 mg is metabolised by liver enzymes (see section 5.2). SPALBORT 3,5 mg exposure is increased in patients with moderate or severe hepatic impairment. These patients should be treated with SPALBORT 3,5 mg at reduced starting doses and closely monitored for toxicities (see section 4.2).

Tumour lysis syndrome

Because SPALBORT 3,5 mg is a cytotoxic medicine 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. Symptoms of tumour lysis syndrome are weakness, vomiting, cramps, seizure, oedema and fluid overload, congestive heart failure, dysrrhythmias and syncope. These patients should be monitored closely and appropriate precautions taken.

Amyloidosis

The impact of proteasome inhibition by SPALBORT 3,5 mg on disorders associated with protein accumulation such as amyloidosis is unknown. Caution is advised in these patients.

Potentially immunocomplex-mediated reactions

Potentially immunocomplex-mediated reactions, such as serum-sicknessu2013type reaction, polyarthritis with rash and proliferative glomerulonephritis have been reported uncommonly. SPALBORT 3,5 mg should be discontinued if severe reactions occur. SPALBORT 3,5 mg contains mannitol and may have a laxative effect.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS)

There have been reports of RPLS in patients receiving SPALBORT 3,5 mg. RPLS is a rare, reversible, neurological disorder 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 SPALBORT 3,5 mg.

In vitro studies indicate that SPALBORT 3,5 mg 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 (SPALBORT 3,5 mg) the CYP2D6, poor metaboliser phenotype is not expected to affect the overall disposition of SPALBORT 3,5 mg.

An interaction study assessing the effect of ketoconazole, a potent CYP3A4 inhibitor, on the pharmacokinetics of SPALBORT 3,5 mg, showed a bortezomib AUC mean increase of 35 %, based on data from 12 patients. Therefore, patients should be monitored closely when given SPALBORT 3,5 mg in combination with potent CYP3A4-inhibitors (e.g. ketoconazole, ritonavir, chloramphenicol, clarithromycin).

In an interaction study assessing the effect of omeprazole, a potent inhibitor of CYP2C19, on the pharmacokinetics of SPALBORT 3,5 mg, there was no significant effect on the pharmacokinetics of bortezomib, based on data from 17 patients.

An interaction study assessing the effect of rifampicin a potent CYP3A4 inducer, on the pharmacokinetics of SPALBORT 3,5 mg showed a mean bortezomib AUC reduction of 45 % based on data from 6 patients. The concomitant use of SPALBORT 3,5 mg with strong CYP3A4 inducers is therefore not recommended, as efficacy may be reduced. Examples of CYP3A4 inducers are rifampicin, carbamazepine, phenytoin, phenobarbital and St. Johnu2019s Wort. In the same interaction study, the effect of dexamethasone, a weaker CYP3A4 inducer was assessed. There was no significant effect on bortezomib pharmacokinetics based on data from 7 patients.

Concomitant exposure to narcotics may increase the incidence of constipation, nausea and vomiting. An interaction study assessing the effect of melphalan-prednisone on SPALBORT 3,5 mg showed a 17 % increase in mean bortezomib AUC based on data from 21 patients. This is not considered clinically relevant. During clinical trials, hypoglycaemia and hyperglycaemia were reported in diabetic patients receiving oral hypoglycaemics. Patients on oral antidiabetic medicines receiving SPALBORT 3,5 mg treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication. Normal liver function should be confirmed and caution should be exercised in patients receiving oral hypoglycaemics.

Safety in pregnancy and lactation has not been established. Males and females of childbearing capacity should use effective contraceptive measures during treatment and for 3 months following SPALBORT 3,5 mg therapy. If SPALBORT 3,5 mg is used during pregnancy, or if the patient becomes pregnant while receiving SPALBORT 3,5 mg, the patient needs to be informed of potential for hazards to the foetus. It is not known whether SPALBORT 3,5 mg is excreted in human milk. Because of the potential for serious undesirable effects in breastfed infants from mothers on SPALBORT 3,5 mg, women should not breastfeed their infants while receiving SPALBORT 3,5 mg.

SPALBORT 3,5 mg may have a moderate influence on the ability to drive and use machines. SPALBORT 3,5 mg may be associated with fatigue, dizziness, syncope, orthostatic/postural hypotension or blurred vision. Therefore, patients must be cautious when operating machinery, or when driving.

The following undesirable effects included are considered to have at least a possible or probable causal relationship to SPALBORT 3,5 mg:

Infections and infestations

Frequent: Herpes zoster (including disseminated). Pneumonia, herpes simplex, fungal infection.

Less Frequent: Sepsis, bacteraemia, bronchopneumonia, cytomegalovirus infection, influenza, herpes virus infection, meningoencephalitis herpetic, hordeolum, influenza, cellulitis, device related infection, skin infection, ear infection, staphylococcal infection, tooth infection, meningitis (incl bacterial), Epstein-Barr virus infection, genital herpes, tonsillitis, mastoiditis, post viral fatigue syndrome.

Blood and lymphatic system disorders

Frequent: Thrombocytopaenia, neutropaenia, anaemia. Leukopaenia, lymphopaenia.

Less Frequent: Pancytopenia, febrile neutropenia, coagulopathy, leukocytosis, lymphadenopathy, haemolytic anaemia, disseminated intravascular coagulation, thrombocytosis, hyperviscosity syndrome, platelet disorder, thrombocytopenic purpura, blood disorder, haemorrhagic diathesis, lymphocytic infiltration, thrombotic microangiopathy (including thrombocytopenic purpura).

Immune system disorders

Frequency unknown: Immunocomplex mediated hypersensitivity, such as serum-sickness- type reaction, polyarthritis with rash and proliferative glomerulonephritis.

Less frequent: Angioedema, hypersensitivity, anaphylactic shock, amyloidosis, Type III- immune complex mediated reactions.

Endocrine disorders

Less Frequent: Cushing's syndrome, hyperthyroidism, inappropriate antidiuretic hormone secretion, hypothyroidism.

Metabolism and nutrition disorders

Frequent: Decreased appetite, dehydration, hypokalaemia, hyponatraemia, blood glucose abnormal, hypocalcaemia, enzyme abnormality.

Less Frequent: Tumour lysis syndrome, failure to thrive, hypomagnesaemia, hypophosphataemia, hyperkalaemia, hypercalcaemia, hypernatraemia, uric acid abnormal, diabetes mellitus, fluid retention, hypermagnesaemia, acidosis, electrolyte imbalance, fluid overload, hypochloraemia, hypovolaemia, hyperchloraemia, hyperphosphataemia, metabolic disorder, vitamin B complex deficiency, vitamin B12 deficiency, gout, increased appetite, alcohol intolerance.

Psychiatric disorders

Frequent: Confusion, depression, insomnia, anxiety, mood disorders and disturbances, sleep disorders and disturbances.

Less Frequent: Mental disorder, hallucination, psychotic disorder, confusion, restlessness, suicidal ideation, adjustment disorder, delirium, libido decreased.

Nervous system disorders

Frequent: Neuropathies, peripheral sensory neuropathy, dysaesthesia, neuralgia, motor neuropathy, loss of consciousness (incl syncope), dizziness, dysgeusia, lethargy, headache.

Less Frequent: Tremor, peripheral sensorimotor neuropathy, dyskinesia, cerebellar coordination and balance disturbances, memory loss (excl dementia), encephalopathy, posterior reversible encephalopathy syndrome, neurotoxicity, seizure disorders, post herpetic neuralgia, speech disorder, restless legs syndrome, migraine, sciatica, disturbance in attention, reflexes abnormal, parosmia, cerebral haemorrhage, haemorrhage intracranial (incl subarachnoid), brain oedema, transient ischaemic attack, coma, autonomic nervous system imbalance, autonomic neuropathy, cranial palsy, paralysis, paresis, presyncope, brain stem syndrome, cerebrovascular disorder, nerve root lesion, psychomotor hyperactivity, spinal cord compression, cognitive disorder, motor dysfunction, nervous system disorder, radiculitis, drooling, hypotonia, Guillain-Barru00e9 syndrome, demyelinating polyneuropathy.

Eye disorders

Frequent: Vision blurred, conjunctivitis, eye swelling.

Less Frequent: Eye haemorrhage, abnormal vision, keratitis sicca, eye discharge, eye pain, photophobia, photopsia, optic neuropathy, different degrees of visual impairment (up to blindness), eye irritation, lacrimation increased, conjunctival hyperaemia, retinitis, scotoma, exophthalmos, corneal lesion, eyelid infection, eye inflammation, diplopia.

Ear and labyrinth disorders

Frequent: Vertigo.

Less Frequent: Deafness, tinnitus, hypoacusis, hearing impaired, ear discomfort, vestibular neuritis, ear disorder.

Cardiac disorders

Less Frequent: Cardiac arrest, cardiogenic shock, myocardial infarction, unstable angina pectoris, development or exacerbation of congestive heart failure (see section 4.4), cardiac failure, ventricular hypokinesia, pulmonary oedema and acute pulmonary oedema, sinus arrest, complete atrioventricular block, tachycardia, sinus tachycardia, supraventricular tachycardia, dysrhythmia, atrial fibrillation, palpitations.

Frequency unknown: New onset of decreased left ventricular ejection fraction (see section 4.4).

Vascular disorders

Frequent: Hypotension, orthostatic and postural hypotension (see section 4.4), phlebitis, haematoma, hypertension.

Less Frequent: Cerebral haemorrhage, vasculitis, cerebrovascular accident, pulmonary hypertension, petechiae, ecchymosis, purpura, vein discolouration, distended vein, wound hemorrhage, flushing, hot flushes.

Respiratory, thoracic and mediastinal disorders

Frequent: Dyspnoea. Exertional dyspnea, epistaxis, cough, rhinorrhoea.

Less Frequent: 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.

Gastrointestinal disorders

Frequent: Vomiting, diarrhoea, nausea, constipation. Abdominal pain, stomatitis, dyspepsia, loose stools, abdominal pain upper, flatulence, abdominal distension, hiccups, mouth ulceration, pharyngolaryngeal pain, dry mouth.

Less Frequent: Acute pancreatitis, paralytic ileus, antibiotic associated colitis, colitis, haematemesis, haemorrhagic diarrhoea, 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, coated tongue, tongue discolouration, faecal impaction.

Hepatobiliary disorders

Frequent: Hepatic enzyme abnormality.

Less Frequent: Hepatitis, hepatic haemorrhage, hypoproteinaemia, hyperbilirubinaemia.

Skin and subcutaneous tissue disorders

Frequent: Rash. Periorbital oedema, urticaria, pruritic rash, pruritus, erythema, increased sweating, dry skin, eczema.

Less Frequent: Vasculitic rash (including leukocytoclastic vasculitis), erythematous rash, photosensitivity reaction, contusion, generalised pruritus, macular rash, papular rash, psoriasis, generalised rash, eyelid oedema, face oedema, dermatitis, alopecia, nail disorder, skin discolouration, atopic dermatitis, abnormal hair texture, heat rash, night sweats, pressure sore, ichthyosis, skin nodule.

Musculoskeletal and connective tissue disorders

Frequent: Myalgia. Muscle weakness, musculoskeletal pain, pain in limb, muscle cramps, arthralgia, bone pain, back pain, peripheral swelling.

Less Frequent: Muscle spasms, muscle twitching or sensation of heaviness, muscle stiffness, joint swelling, joint stiffness, buttock pain, swelling, pain in jaw.

Renal and urinary disorders

Frequent: Renal impairment, dysuria.

Frequency unknown: Acute renal failure, 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

Less frequent: Vaginal haemorrhage, genital pain, erectile dysfunction, testicular disorder, prostatitis, breast disorder female, epididymal tenderness, epididymitis, pelvic pain, vulval ulceration.

General disorders and administration site conditions

Frequent: Fatigue, pyrexia. Asthenia, weakness, lethargy, rigors, malaise, influenza like illness, peripheral oedema, chest pain, pain, oedema.

Less frequent: 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

Frequent: Decreased weight, increased blood lactate dehydrogenase.

Less frequent: Increased alanine aminotransferase, increased aspartate aminotransferase, increased blood bilirubin, increased blood alkaline phosphatase, increased blood creatinine, increased blood urea, increased gamma-glutamyltransferase, increased blood amylase, abnormal liver function tests, decreased red blood cell count, decreased white blood cell count, decreased blood bicarbonate, irregular heart rate, increased C-reactive protein, decreased blood phosphate, increased weight.

Injury, poisoning and procedural complications

Less frequent: Catheter related complications, post procedural pain, post procedural haemorrhage, burns.

Clinically significant adverse reactions are listed here if they have not been reported above.

Blood and lymphatic system disorders

Disseminated intravascular coagulation.

Cardiac Disorders

Atrioventricular block complete, cardiac tamponade.

Ear and labyrinth disorders

Deafness bilateral.

Eye disorders

Ophthalmic herpes, optic neuropathy, blindness.

Gastrointestinal Disorders

Ischaemic colitis, acute pancreatitis, intestinal obstruction.

Infections and infestations

Herpes meningoencephalitis, septic shock, progressive multifocal leukoencephalopathy.

Immune System Disorders

Angioedema.

Nervous System Disorders

Encephalopathy, autonomic neuropathy, reversible posterior leukoencephalopathy syndrome.

Respiratory, thoracic and mediastinal disorders

Acute diffuse infiltrative pulmonary disease (see section 4.4), pulmonary hypertension.

Skin and subcutaneous tissue disorders

Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN).

Overdosage was associated with acute onset of symptomatic hypotension and thrombocytopenia and the patient subsequently died. It is recommended that in the event of overdosage, patients should undergo careful haemodynamic monitoring, and hypotension should be treated aggressively with intravenous hydration and other clinically appropriate measures.