Bortezomib Adco 3,5 mg Injection

Bortezomib Adco is indicated in adults 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.

Posology

Bortezomib Adco 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. Bortezomib Adco should not be given by other routes. Intrathecal administration has resulted in death.

Monotherapy

The recommended starting dose of Bortezomib Adco 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 Bortezomib Adco.

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

There is limited data concerning re-treatment with Bortezomib Adco.

Recommended dosage adjustments during treatment and re-initiation of treatment

Bortezomib Adco 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 section 4.4). Once the symptoms of the toxicity have resolved, Bortezomib Adco treatment may be re-initiated at a 25 % reduced dose (1,3 mg/mu00b2 reduced to 1,0 mg/mu00b2; 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 Bortezomib Adco must be considered.

Patients who experience Bortezomib Adco 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 Bortezomib Adco only after careful risk/benefit assessment.

Table 1: Recommended dose modifications for Bortezomib Adco 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 Bortezomib Adco treatment until symptoms of toxicity have resolved. When toxicity resolves re-initiate Bortezomib Adco 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 Bortezomib Adco

Combination Therapy

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

Table 2: Recommended dosage regimen for Bortezomib Adco when used in combination with melphalan and prednisone for patients with previously untreated multiple myeloma

Twice Weekly Bortezomib (Cycles 1 u2013 4)

Week 1 2 3 4 5 6

Bz (1,3 mg/mu00b2) Day Day 1 4 Day Day 8 11 Rest period Day Day 22 25 Day Day 29 32 Rest period M (9 mg/mu00b2) P (60 mg/mu00b2) Day Day Day Day 1 2 3 4 -- -- Rest period -- -- -- -- Rest period

Once Weekly Bortezomib (Cycles 5 u2013 9)

Week 1 2 3 4 5 6

Bz (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 Day Day Day 1 2 3 4 -- Rest period -- -- Rest period

Bz = BORTEZOMIB; M = melphalan; P=prednisone

Dose Management Guidelines for Combination Therapy

Prior to initiating a new cycle of therapy:

• Platelet count should be u2265 70 x 10u2079/L and the ANC should be u2265 1,0 x 10u2079/L
• Non-haematological toxicities should have resolved to Grade 1 or baseline

Table 3: Dose modifications during subsequent cycles:

Toxicity Dose 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 count u2264 30 x 10u2079/L or ANC u2264 0,75 x 10u2079/L on a Bortezomib Adco dosing day (other than day 1) Bortezomib Adco dose should be withheld
• If several Bortezomib Adco doses in a cycle are withheld (u2265 3 doses during twice weekly administration or u2265 2 doses during weekly administration) Bortezomib Adco dose should be reduced by 1 dose level (from 1,3 mg/mu00b2 to 1 mg/mu00b2, or from 1 mg/mu00b2 to 0,7 mg/mu00b2)

Grade u2265 3 non-haematological toxicities Bortezomib Adco therapy should be withheld until symptoms of the toxicity have resolved to Grade 1 or baseline. Then, Bortezomib Adco may be reinitiated with one dose level reduction (from 1,3 mg/mu00b2 to 1 mg/mu00b2, or from 1 mg/mu00b2 to 0,7 mg/mu00b2). For Bortezomib Adco-related neuropathic pain and/or peripheral neuropathy, hold and/or modify Bortezomib Adco as outlined in Table 1. For additional information concerning melphalan and prednisone, refer to their respective professional information.

Special populations

Elderly patients There is no evidence to suggest that dose adjustments are necessary in the elderly (see Section 4.8).

Renal Impairment The pharmacokinetics of Bortezomib Adco are not influenced by the degree of renal impairment. Therefore, dosing adjustments of Bortezomib Adco are not necessary for patients with renal insufficiency. Since dialysis may reduce Bortezomib Adco concentrations, Bortezomib Adco should be administered after dialysis procedure (see Section 5.2).

Hepatic Impairment Patients with mild hepatic impairment do not require a starting dose adjustment and should be treated per the recommended Bortezomib Adco dose. Patients with moderate or severe hepatic impairment should be started on Bortezomib Adco 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 4).

Table 4: Recommended Starting Dose Modification for Bortezomib Adco 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 u2013 1,5 x ULN Any None
• Moderate > 1,5 x u2013 3 x ULN Any Reduce Bortezomib Adco 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

Abbreviations: SGOT = serum glutamic oxaloacetic transaminase; AST = aspartate aminotransferase, ULN = upper limit of the normal range.

Paediatric population Bortezomib Adco has not been studied in children and adolescents. Therefore, it should not be used in the paediatric age group until further data becomes available.

Method of administration

Precaution to be taken before manipulating or administering the product Refer to section 6.6 Special precautions for disposal and other handling. Inadvertent intrathecal administration of Bortezomib Adco may be fatal. DO NOT ADMINISTER Bortezomib Adco INTRATHECALLY.

Bortezomib Adco 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 Bortezomib Adco.

Subcutaneous injection: The reconstituted solution is injected into the thighs (right or left) or abdomen (right or left). Injections sites should be rotated for successive injections. If local injection site reactions occur following Bortezomib Adco injection subcutaneously, a less concentrated Bortezomib Adco solution (1 mg/ml instead of 2,5 mg/ml) may be administered subcutaneously, or changed to IV injection. For instructions on reconstitution of the medicine before administration, see section 6.6.

Hypersensitivity to the active substance, to boron, or to any of the excipients of Bortezomib Adco listed in section 6.1.

Acute diffuse infiltrative pulmonary and pericardial disease.

Bortezomib Adco should be initiated and administered under the supervision of a medical practitioner experienced in the use of chemotherapeutic medicines.

Inadvertent intrathecal administration of Bortezomib Adco may be fatal. Bortezomib Adco 3,5 mg is for IV or SC use. DO NOT ADMINISTER Bortezomib Adco INTRATHECALLY.

Women should not become pregnant during treatment. Women of childbearing potential must use effective contraception to avoid pregnancy while they are receiving Bortezomib Adco. The recommended duration of contraception in female patients of childbearing potential is until the end of the relevant systemic exposure to Bortezomib Adco including potential metabolites (i.e.: five half-lifeu2019s after the last dose) plus 6 months. On this basis, female patients of childbearing potential should be advised to use effective contraception during treatment with Bortezomib Adco and for at least 8 months after the final dose.

Male patients should be advised not to father a child during treatment and should be advised on the use of effective contraception to avoid conception. The recommended duration of contraception in male patients is until the end of the relevant systemic exposure to Bortezomib Adco including potential metabolites (i.e.: five half-lifeu2019s after the last dose) plus 3 months. On this basis male patients should be advised on the use of effective contraception during treatment with Bortezomib Adco and for at least 5 months after the final dose (see section 4.6). Male patients should also be counselled to seek advice on conservation of sperm prior to treatment because of the possibility of irreversible infertility due to therapy with Bortezomib Adco.

Herpes Zoster Virus Reactivation Medical practitioners should reconsider using antiviral prophylaxis in patients being treated with Bortezomib Adco.

Patients with mantle cell lymphoma: Safety profile of Bortezomib Adco between patients with multiple myeloma and mantle cell lymphoma is similar. Patients with mantle cell lymphoma may experience peripheral neuropathy, rash and puritis whereas patients with multiple myeloma may experience thrombocytopenia, neutropenia, anaemia, nausea, vomiting and pyrexia.

Safety profile is similar between treatment with Bortezomib Adco in monotherapy and Bortezomib Adco in combination with melphalan and prednisolone.

Laboratory Tests Full blood counts (FBC) including platelet counts should be frequently monitored throughout treatment with Bortezomib Adco.

Gastrointestinal toxicity Gastrointestinal toxicity, including diarrhoea, constipation, nausea and vomiting are very common with Bortezomib Adco 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 Bortezomib Adco treatment is very commonly associated with haematological toxicities (thrombocytopenia and neutropenia). However, febrile neutropenia is an uncommon undesirable effect. The most common haematologic toxicity is transient thrombocytopenia, which generally resolves between treatment cycles. The cyclical pattern of platelet decrease and recovery remains consistent with no evidence of cumulative thrombocytopenia. Severe bleeding, including central nervous system (CNS) and gastrointestinal bleeding, associated with thrombocytopenia may occur. In patients with advanced myeloma, the severity of thrombocytopenia was related to pre-treatment platelet count. Platelet counts should be monitored prior to each dose of Bortezomib Adco. 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 thrombocytopenic patients at high risk of bleeding.

Peripheral Neuropathy Bortezomib Adco 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 Bortezomib Adco. 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, hypaesthesia, paraesthesia, discomfort or neuropathic pain. Patients experiencing new or worsening peripheral neuropathy may require the dose and schedule of Bortezomib Adco 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 has been reported in patients with u2265 Grade 2 peripheral neuropathy and patients with grade 3 or 4 peripheral neuropathy or peripheral neuropathy leading to discontinuation of treatment. 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. The long-term outcome of peripheral neuropathy has not been studied in Mantle Cell Lymphoma.

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 Bortezomib Adco treatment is commonly associated with orthostatic/postural hypotension. Most patients required treatment for their orthostatic hypotension. Patients with orthostatic hypotension experienced syncopal events. The mechanism of this event is unknown although a component may be due to autonomic neuropathy. Autonomic neuropathy may be related to Bortezomib Adco or Bortezomib Adco may aggravate an underlying condition such as diabetic neuropathy. Caution is advised when treating patients with a history of syncope receiving medicines 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 medicines, 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 cases of QT-interval prolongation; causality has not been established. Patients using angiotensin converting enzyme inhibitors, beta-blockers, antihypertensives, calcium channel blockers, angiotensin receptor blockers and diuretics may have a higher incidence of cardiac failure during Bortezomib Adco treatment.

Pulmonary Disorders There have been reports of acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration and Acute Respiratory Distress Syndrome (ARDS) in patients receiving Bortezomib Adco. 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.

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 Bortezomib Adco. There is limited re-challenge information in these patients.

Hepatic Impairment Bortezomib Adco is metabolised by liver enzymes. Bortezomib Adco exposure is increased in patients with moderate or severe hepatic impairment. These patients should be treated with Bortezomib Adco at reduced starting doses and closely monitored for toxicities (See sections 4.2 and 5.2).

Tumour lysis syndrome Because Bortezomib Adco 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, dysrhythmias and syncope. These patients should be monitored closely and appropriate precautions taken.

Amyloidosis The impact of proteasome inhibition by Bortezomib Adco 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. Bortezomib Adco should be discontinued if severe reactions occur.

Posterior Reversible Encephalopathy Syndrome (PRES) There have been reports of PRES in patients receiving Bortezomib Adco. PRES 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 PRES, discontinue Bortezomib Adco. The safety of reinitiating Bortezomib Adco therapy in patients previously experiencing PRES is not known.

Hepatitis B Virus (HBV) reactivation and infection When rituximab is used in combination with Bortezomib Adco, 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 Bortezomib Adco. Antiviral prophylaxis should be considered.

Progressive multifocal leukoencephalopathy (PML) Cases with unknown causality of John Cunningham (JC) virus infection, resulting in PML and death, have been reported in patients treated with Bortezomib Adco. 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 Adco. 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 Bortezomib Adco if PML is diagnosed.

Concomitant medicines Patients should be closely monitored when given Bortezomib Adco in combination with potent CYP3A4-inhibitors. Caution should be exercised when Bortezomib Adco is combined with CYP3A4- or CYP2C19 substrates (see section 4.5).

Bortezomib Adco 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 Adco the CYP2D6, poor metaboliser phenotype is not expected to affect the overall disposition of Bortezomib Adco.

Ketoconazole, a potent CYP3A4 inhibitor, showed 35 % increase in mean bortezomib AUC. Therefore, patients should be monitored closely when given Bortezomib Adco in combination with potent CYP3A4-inhibitors (e.g. ketoconazole, ritonavir).

Omeprazole, a potent inhibitor of CYP2C19, has no significant effect on bortezomib efficacy. The concomitant use of Bortezomib Adco with strong CYP3A4 inducers is not recommended, as efficacy of Bortezomib Adco may be reduced. Examples of CYP3A4 inducers are rifampicin, carbamazepine, phenytoin, phenobarbitone and St. Johnu2019s Wort. Dexamethasone, a weak CYP3A4 inducer has no significant effect on Bortezomib Adco efficacy.

Concomitant exposure to narcotics may increase the incidence of constipation, nausea and vomiting. Melphalan-prednisone showed a 17 % increase in mean bortezomib AUC and is not considered clinically relevant. Hypoglycaemia and hyperglycaemia may be experienced in diabetic patients receiving oral hypoglycaemics. Patients on oral antidiabetic medicines receiving Bortezomib Adco 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.

Paediatric population Not for paediatric use, see section 4.2

Women of childbearing potential must use effective contraception to avoid pregnancy while they are receiving Bortezomib Adco, and for at least 8 months following completion of treatment (i.e.: after the final dose).

Pregnancy Bortezomib Adco is contraindicated in pregnancy. If Bortezomib Adco is used during pregnancy, or if the patient becomes pregnant while receiving Bortezomib Adco, the patient needs to be informed of potential for hazards to the foetus.

Breastfeeding Safety in lactation has not been established. It is not known whether Bortezomib Adco is excreted in human milk. Because of the potential for serious undesirable effects in breastfed infants from mothers on Bortezomib Adco, women should not breastfeed their infants while receiving Bortezomib Adco.

Fertility Male fertility Bortezomib Adco can have genotoxic effects. Therefore, male patients should not father a child during and up to 5 months following completion of treatment (i.e.: after the final dose). Advice on conservation of sperm should be sought prior to treatment because of the possibility of irreversible infertility due to therapy with Bortezomib Adco.

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

a. Summary of the safety profile Serious adverse reactions uncommonly reported during treatment with Bortezomib Adco include cardiac failure, tumour lysis syndrome, pulmonary hypertension, posterior reversible encephalopathy syndrome, acute diffuse infiltrative pulmonary disorders and rarely autonomic neuropathy. The most commonly reported adverse reactions during treatment with Bortezomib Adco are nausea, diarrhoea, constipation, vomiting, fatigue, pyrexia, thrombocytopenia, anaemia, neutropenia, peripheral neuropathy (including sensory), headache, paraesthesia, decreased appetite, dyspnoea, rash, herpes zoster and myalgia.

b. Tabulated summary of adverse reactions Infection and Infestations Frequent Herpes zoster (includes disseminated and ophthalmic), pneumonia, bronchitis, sinusitis, nasopharyngitis, herpes simplex, fungal infection Less frequent Infection, bacterial infections, viral infections, sepsis (including septic shock), pneumonia (especially pneumococcal), bronchopneumonia, herpes virus infection, meningoencephalitis herpetic, bacteraemia (including staphylococcal), hordeolum, influenza, cellulitis, device related infection, skin infection, ear infection, staphylococcal infection, tooth infection, upper and lower respiratory tract infection, catheter related infection, pleural infection, haemophilus infection, cytomegalovirus infection, infectious mononucleosis, varicella, urinary tract infection, gastroenteritis, candida infection, fungal infection, post herpetic neuralgia, oral candidiasis, blepharitis Neoplasms benign, malignant and unspecified (incl cysts and polyps) Less frequent Neoplasm malignant, leukaemia plasmacytic, renal cell carcinoma, mass, mycosis fungoides, neoplasm benign Blood and lymphatic system disorders Frequent Thrombocytopenia, neutropenia, anaemia, leukopenia, lymphopenia Less frequent Pancytopenia, febrile neutropenia, coagulopathy, leukocytosis, lymphadenopathy, haemolytic anaemia, disseminated intravascular coagulation, thrombocytosis, hyperviscosity syndrome, platelet disorder NOS, thrombotic microangiopathy (including thrombocytopenic purpura), blood disorder NOS, haemorrhagic diathesis, lymphocytic infiltration Immune system disorders Less frequent Angioedema, hypersensitivity, polyarthritis with rash and proliferative glomerulonephritis, anaphylactic shock, amyloidosis, type III immune complex mediated reaction, potentially immunocomplex-mediated reactions, such as serum-sickness-type reaction Endocrine disorders Less frequent Cushing's syndrome, hyperthyroidism, inappropriate antidiuretic hormone secretion, hypothyroidism Metabolism and nutritional disorders Frequent Decreased appetite, dehydration, hypokalaemia, hyponatraemia, blood glucose abnormal, hypocalcaemia, enzyme abnormality Less frequent Tumour lysis syndrome (see section 4.4), 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 Mood disorders and disturbances, anxiety disorder, sleep disorders and disturbances Less frequent Mental disorder, hallucination, psychotic disorder, confusion, restlessness, suicidal ideation, adjustment disorder, delirium, libido decreased, agitation, irritability, abnormal dreams Nervous system disorders Frequent Neuropathies, peripheral sensory neuropathy, dysaesthesia, neuralgia, motor neuropathy, loss of consciousness (including syncope), dizziness, dysgeusia, lethargy, headache, tremor Less frequent Peripheral sensorimotor neuropathy, dyskinesia, cerebellar coordination and balance disturbances, memory loss (excluding dementia), encephalopathy, posterior reversible leukoencephalopathy syndrome, neurotoxicity, seizure disorders, post herpetic neuralgia, speech disorder, restless legs syndrome, migraine, sciatica, disturbance in attention, reflexes abnormal, parosmia, cerebral haemorrhage, haemorrhage intracranial (including 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 nos, motor dysfunction, nervous system disorder nos, radiculitis, drooling, hypotonia Eye disorders Frequent Eye swelling, vision abnormal, conjunctivitis Less frequent Eye haemorrhage, eyelid infection, chalazion, blepharitis, eye inflammation, diplopia, dry eye, eye irritation, eye pain, lacrimation increased, eye discharge, corneal lesion, exophthalmos, retinitis, scotoma, eye disorder (including eyelid) nos, dacryoadenitis acquired, photophobia, photopsia, optic neuropathy, different degrees of visual impairment (up to blindness) Ear and labyrinth disorders Frequent Vertigo Less frequent Dysacusis (including tinnitus), hearing impaired (up to and including deafness), ear discomfort, ear haemorrhage, vestibular neuronitis, ear disorder NOS, hypoacusis Cardiac disorders Less frequent Cardiac tamponade, cardio - pulmonary arrest, cardiac fibrillation (including atrial), cardiac failure (including left and right ventricular), arrhythmia, tachycardia, palpitations, angina pectoris, pericarditis (including pericardial effusion), cardiomyopathy, ventricular dysfunction, bradycardia atrial flutter, myocardial infarction, atrioventricular block, cardiovascular disorder (including cardiogenic shock), torsade de pointes, angina unstable, cardiac valve disorders, coronary artery insufficiency, sinus arrest, new onset of decreased left ventricular ejection fraction Vascular disorders Frequent Hypotension, orthostatic hypotension, hypertension, haematoma, phlebitis Less frequent Cerebral haemorrhage, vasculitis, cerebrovascular accident, deep vein thrombosis, pulmonary hypertension, petechiae, ecchymosis, pupura, haemorrhage, thrombophlebitis (including superficial), circulatory collapse (including hypovolaemic shock), flushing, poor peripheral circulation, vasculitis, hyperaemia (including ocular), peripheral embolism, lymphoedema, pallor, erythromelalgia, vasodilatation, vein discolouration, venous insufficiency Respiratory, thoracic and mediastinal disorders Frequent Dyspnoea and exertional dyspnoea, epistaxis, upper/lower respiratory tract infection, cough Less frequent Pulmonary embolism, pleural effusion, pulmonary oedema (including acute), pulmonary alveolar haemorrhage, bronchospasm, chronic obstructive pulmonary disease, hypoxaemia, respiratory tract congestion, hypoxia, pleurisy, hiccups, rhinorrhoea, dysphonia, wheezing, respiratory failure, acute respiratory distress syndrome, apnoea, pneumothorax, atelectasis, pulmonary hypertension, haemoptysis, hyperventilation, orthopnoea, pneumonitis, respiratory alkalosis, tachypnoea, pulmonary fibrosis, bronchial disorder, hypocapnia, interstitial lung disease, lung infiltration, throat tightness, dry throat, increased upper airway secretion, throat irritation, upper airway cough syndrome, chest wall pain, hiccups Gastrointestinal disorders (See section 4.4) Frequent Nausea and vomiting symptoms, diarrhoea, constipation, gastrointestinal haemorrhage (including mucosal), dyspepsia, stomatitis, abdominal distension, oropharyngeal pain, abdominal pain (including gastrointestinal and splenic pain), oral disorder, flatulence, oral ulceration, loose stools Less frequent Pancreatitis (including chronic), haematemesis, lip swelling, gastrointestinal obstruction (including small intestinal obstruction, ileus), abdominal discomfort, enteritis, gastritis, gingival bleeding, gastro-oesophageal reflux disease, colitis (including clostridium difficile), colitis ischaemic, gastrointestinal inflammation, dysphagia, irritable bowel syndrome, gastrointestinal disorder NOS, tongue coated, gastrointestinal motility disorder, salivary gland disorder, pancreatitis acute, peritonitis, tongue oedema, ascites, oesophagitis, cheilitis, faecal incontinence, anal sphincter atony, faecaloma, gastrointestinal ulceration and perforation, gingival hypertrophy, megacolon, rectal discharge, oropharyngeal blistering, lip pain, periodontitis, anal fissure, change of bowel habit, proctalgia, abnormal faeces, retching, spleen pain, oral mucosal petechiae, salivary hypersecretion Hepatobiliary disorders (See section 4.4) Frequent Hepatic enzyme abnormality Less frequent Hepatotoxicity (including liver disorder), hepatitis, cholestasis, hepatic failure, hepatomegaly, budd-chiari syndrome, cytomegalovirus hepatitis, hepatic haemorrhage, cholelithiasis, hypoproteinaemia, hyperibilirubinaemia Skin and subcutaneous tissue disorders Frequent Rash, pruritus, erythema, dry skin, periorbial oedema, eczema, urticaria hyperhydrosis Less frequent Erythema multiforme, acute febrile neutrophilic, dermatosis, toxic skin eruption, toxic epidermal necrolysis, stevens-johnson syndrome, dermatitis, hair disorder, petechiae, ecchymosis, skin lesion, purpura, skin mass, psoriasis, night sweats, decubitus ulcer, acne, blister, pigmentation disorder, skin reaction, jessner's lymphocytic infiltration, palmarplantar erythrodysaesthesia syndrome, haemorrhage subcutaneous, livedo reticularis, skin induration, papule, photosensitivity reaction, seborrhoea, cold sweat, skin disorder nos, erythrosis, skin ulcer, nail disorder Musculoskeletal and connective tissue disorders Frequent Musculoskeletal pain, muscle spasms, pain in extremity, muscular weakness, arthralgia, bone pain, peripheral swelling, muscle cramps, myalgia, back pain Less frequent Muscle twitching, joint swelling, arthritis, joint stiffness, myopathies, sensation of heaviness, rhabdomyolysis, temporomandibular joint syndrome, fistula, joint effusion, pain in jaw, bone disorder, musculoskeletal and connective tissue infections and inflammations, synovial cyst, muscle stiffness, buttock pain Renal and urinary disorders Frequent Renal impairment, dysuria Less frequent Renal failure acute, renal failure chronic, urinary tract infection, urinary tract signs and symptoms, haematuria, urinary retention, micturition disorder, proteinuria, azotaemia, oliguria, pollakiuria, bladder irritation, renal cholic, urinary frequency, loin pain, urinary incontinence Reproductive system and breast disorders Less frequent Vaginal haemorrhage, genital pain, erectile dysfunction, testicular disorder, prostatitis, female breast disorder, epididymal tenderness, epididymitis, pelvic pain, vulval ulceration Congenital, familial and genetic disorders Less frequent Aplasia, gastrointestinal malformation, ichthyosis General disorders and administration site conditions Frequent Pyrexia, fatigue, asthenia, oedema (including peripheral), chills, pain, malaise, weakness, lethargy, rigors, peripheral oedema Less frequent General physical health deterioration, face oedema, injection site reaction, mucosal disorder, chest pain, gait disturbance, feeling cold, extravasation, catheter related complication, change in thirst, chest discomfort, feeling of body temperature change, injection site pain, death (including sudden), multi-organ failure, injection site haemorrhage, hernia (including hiatus), impaired healing, inflammation, injection site phlebitis, tenderness, ulcer, irritability, non-cardiac chest pain, catheter site pain, sensation of foreign body, mucosal inflammation, neuralgia Investigations Frequent Weight decreased; blood lactate dehydrogenase increased Less frequent Hyperbilirubinaemia, protein analyses abnormal, weight increased, blood test abnormal, c - reactive protein increased, blood gases abnormal, electrocardiogram abnormalities (including QT prolongation), international normalised ratio abnormal, gastric pH decreased, platelet aggregation increased, troponin I increased, virus identification and serology, urine analysis abnormal, increased blood alkaline phosphatase, increased blood creatinine, increased blood urea, increased gamma glutamyl transferase, increased blood amylase, abnormal liver function tests, decreased red blood cell count, decreased white blood cell count, decreased blood bicarbonate, irregular heart rate, decreased blood phosphate

Overdosage is associated with acute onset of symptomatic hypotension and thrombocytopenia with fatal outcomes. 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.