Elzomy 3.5 Mg Solution

VELZOMY is indicated for:

• 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.

Monotherapy:

Recommended dosage:

The recommended starting dose of VELZOMY 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 VELZOMY. It is recommended that patients with a confirmed complete response receive 2 additional cycles of VELZOMY beyond a confirmation. It is also recommended that responding patients who do not achieve a complete remission receive a total of 8 cycles of VELZOMY therapy. There are limited data concerning re-treatment with VELZOMY.

Recommended dosage adjustments during treatment and re-initiation of treatment:

VELZOMY treatment must be withheld at the onset of any Grade 3 non-haematological or any Grade 4 haematological toxicities, excluding neuropathy (see section 4.4). Once the symptoms of the toxicity have resolved, VELZOMY 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 VELZOMY must be considered.

Neuropathic pain and/or neuropathy:

Patients who experience VELZOMY 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 VELZOMY only after careful risk/benefit assessment.

Table 1: Recommended* dose modifications for VELZOMY related Neuropathic Pain and/or Peripheral Sensory Neuropathy.

SEVERITY OF PERIPHERAL NEUROPATHY: MODIFICATION OF DOSE 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/m2.
• Grade 2 with pain or Grade 3 (interfering with activities of daily living). Withhold VELZOMY treatment until symptoms of toxicity have resolved. When toxicity resolves re-initiate VELZOMY 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). Discontinue VELZOMY.

* Based on dose modifications in phase II and III multiple myeloma studies.

Paediatric population:

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

Elderly population:

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

Renal impairment:

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

Impaired hepatic function:

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

Administration:

The reconstituted solution is administered as a 3 to 5 second bolus intravenous injection through a peripheral or central intravenous catheter followed by a flush with 0,9 % sodium chloride solution for injection.

Combination therapy:

VELZOMY is administered as a 3 to 5 second bolus IV injection in combination with oral melphalan and oral prednisone for nine 6-week treatment cycles as shown in Table 2. In Cycles 1-4, VELZOMY is administered twice weekly (days 1, 4, 8, 11, 22, 25, 29 and 32). In Cycles 5-9, VELZOMY is administered once weekly (days 1, 8, 22 and 29).

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

TWICE WEEKLY VELZOMY (CYCLES 1-4)

Week 1 2 3 4 5 6

VELZOMY (1,3 mg/m2) D - - D 1 4 D - - D 8 11 Rest period D - - D 22 25 D - - D 29 32 Rest period m (9 mg/m2) p (60 mg/m2) D D D D 1 2 3 4 - - Rest period - - - - Rest period

ONCE WEEKLY VELZOMY (CYCLES 5 - 9)

Week 1 2 3 4 5 6

VELZOMY (1,3 mg/m2) D - - - 1 D 8 Rest period D 22 D 29 Rest period m (9 mg/m2) p (60 mg/m2) D D D D 1 2 3 4 - Rest period - - Rest period

* D = Day; 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 109/L and the ANC should be u2265 1,0 x 109/L.
• Non-haematological toxicities should have resolved to Grade 1 or baseline.

Table 3: Dose modifications during subsequent cycles.

TOXICITY: DOSE MODIFICATIONS 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 109/L or ANC u2264 0,75 x 109/L on a VELZOMY dosing day (other than day 1). VELZOMY dose should be withheld.
• If several VELZOMY doses in a cycle are withheld (u2265 3 doses during twice weekly administration or u2265 2 doses during weekly administration). VELZOMY 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 u2265 3 non-haematological toxicities. VELZOMY therapy should be withheld until symptoms of the toxicity have resolved to Grade 1 or baseline. Then, VELZOMY 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 VELZOMY-related neuropathic pain and/or peripheral neuropathy, hold and/or modify VELZOMY as outlined in Table 1. For additional information concerning melphalan and prednisone, see the respective professional information.

Method of administration:

VELZOMY 3,5 mg powder for solution for injection is available for intravenous administration. VELZOMY should not be given by other routes. Intrathecal administration has resulted in death. For instructions on reconstitution of VELZOMY before administration, (see section 6.6).

Intravenous injection:

VELZOMY 3,5 mg reconstituted solution is administered as a 3 to 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. At least 72 hours should elapse between consecutive doses of VELZOMY.

Hypersensitivity to bortezomib, to boron or to any of the excipients listed in section 6.1.

Severe hepatic impairment.

Acute diffuse infiltrative pulmonary and pericardial disease.

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

When VELZOMY is given in combination with other medicines, the professional information of these other medicines must be consulted prior to initiation of treatment with VELZOMY.

Intrathecal administration: There have been fatal cases of inadvertent intrathecal administration of bortezomib. Bortezomib 1 mg powder for solution for injection is for intravenous use only, while bortezomib 3,5 mg powder for solution for injection is for intravenous use. VELZOMY should not be administered intrathecally.

Gastrointestinal toxicity: Gastrointestinal toxicity, including nausea, diarrhoea, vomiting and constipation are very common with bortezomib treatment. Reactions usually occur early in treatment (Cycle 1 and 2) and may persist for several cycles. Cases of ileus have been reported (see section 4.8). Therefore, patients who experience constipation should be closely monitored.

Haematological toxicity: VELZOMY treatment is frequently associated with haematological toxicities (thrombocytopenia and neutropenia). However febrile neutropenia is a less frequent undesirable effect. The most frequent haematologic toxicity is transient thrombocytopenia, which generally resolves between treatment cycles. Platelets were lowest at Day 11 of each cycle of VELZOMY 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 thrombocytopenia. The mean platelet count nadir measured was approximately 40 % of baseline. Severe bleeding, including CNS and gastrointestinal bleeding, associated with thrombocytopenia, has been reported. 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 VELZOMY. Therapy should be held when the platelet count is <25 000/u03bcl and re-initiated at a reduced dose after resolution (see SIDE EFFECTS). 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.

Herpes zoster virus reactivation: Antiviral prophylaxis is recommended in patients being treated with VELZOMY. In studies in patients with previously untreated multiple myeloma, the overall incidence of herpes zoster reactivation was more frequent in patients treated with bortezomib+melphalan+prednisone compared with melphalan+prednisone (14 % versus 4 % respectively).

Hepatitis B virus (HBV) reactivation and infection: When rituximab is administered in combination with VELZOMY, 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 VELZOMY. 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 VELZOMY. Patients diagnosed with PML had prior or concurrent immunosuppressive therapy. Most cases of PML were diagnosed within 12 months of their first dose of VELZOMY. 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 VELZOMY if PML is diagnosed.

Peripheral neuropathy: Treatment with VELZOMY is frequently 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 VELZOMY 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, neuropathic pain or weakness. Patients experiencing new or worsening peripheral neuropathy should undergo neurological evaluation and may require a change in the dose or schedule. Neuropathy has been managed with supportive care and other therapies. Early and regular monitoring for symptoms of treatment-emergent neuropathy with neurological evaluation should be considered in patients receiving VELZOMY in combination with medicines known to be associated with neuropathy and appropriate dose reduction or treatment discontinuation should be considered. 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 less frequently reported in patients without previous history of seizures or epilepsy. Special care is required when treating patients with any risk factors for seizures.

Hypotension: VELZOMY treatment is frequently associated with orthostatic/postural hypotension. Most adverse reactions are mild to moderate in nature and are observed throughout treatment. Patients who developed orthostatic hypotension on VELZOMY (injected intravenously) did not have evidence of orthostatic hypotension prior to treatment with VELZOMY. 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 VELZOMY. The mechanism of this event is unknown although a component may be due to autonomic neuropathy. Autonomic neuropathy may be related to VELZOMY or VELZOMY may aggravate an underlying condition such as diabetic or amyloidotic neuropathy. Caution is advised in these patients. 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 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.

Posterior Reversible Encephalopathy Syndrome (PRES): There have been reports of PRES in patients receiving bortezomib. PRES is a rare, often reversible, rapidly evolving neurological condition, which can present with seizure, hypertension, headache, lethargy, confusion, blindness and other visual and neurological disturbances. Brain imaging, preferably Magnetic Resonance Imaging (MRI), is used to confirm the diagnosis. In patients developing PRES, VELZOMY should be discontinued.

Heart failure: Acute development or exacerbation of congestive heart failure, and/or new onset of decreased left ventricular ejection fraction has been reported during VELZOMY treatment. 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. Patients using angiotensin inhibitors, beta-blockers, antihypertensives, calcium channel blockers, angiotensin receptor blockers and diuretics may have a higher incidence of cardiac failure during VELZOMY treatment.

Electrocardiogram 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 VELZOMY (see section 4.8). Some of these events have been fatal. A pre-treatment chest radiograph is recommended 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. High-dose cytarabine (2 g/m2 per day) by continuous infusion over 24 hours with daunorubicin and bortezomib has been associated with ARDS and death early in the course of therapy. Therefore, this specific regimen with VELZOMY and high-dose cytarabine (2 g/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 metabolised by liver enzymes. Bortezomib exposure is increased in patients with moderate or severe hepatic impairment; these patients should be treated with VELZOMY 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 VELZOMY and concomitant medicines 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 VELZOMY (see section 4.8).

Tumour lysis syndrome: Because VELZOMY is a cytotoxic medicine and can rapidly kill malignant plasma cells and MCL 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 medicines: Patients should be closely monitored when given VELZOMY in combination with potent CYP3A4-inhibitors. Caution should be exercised when VELZOMY 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 hypoglycaemics (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 less frequently. VELZOMY should be discontinued if serious reactions occur.

In vitro studies indicate that VELZOMY 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 metaboliser phenotype is not expected to affect the overall disposition of VELZOMY.

A medicine interaction study assessing the effect of ketoconazole, a potent CYP3A4 inhibitor, on the pharmacokinetics of VELZOMY (injected intravenously), showed a mean bortezomib AUC increase of 35 % (CI 90 % [1,032 to 1,772]) based on data from 12 patients. Therefore, patients should be closely monitored when given VELZOMY in combination with potent CYP3A4 inhibitors (e.g. ketoconazole, ritonavir).

In a medicine interaction study assessing the effect of omeprazole, a potent CYP2C19 inhibitor, on the pharmacokinetics of VELZOMY (injected intravenously), there was no significant effect on the pharmacokinetics of VELZOMY based on data from 17 patients.

Concomitant exposure to narcotics may increase the incidence of constipation, nausea and vomiting.

A medicine interaction study assessing the effect of rifampicin, a potent CYP3A4 inducer, on the pharmacokinetics of VELZOMY (injected intravenously), showed a mean bortezomib AUC reduction of 45 % based on data from 6 patients. Therefore, the concomitant use of VELZOMY with strong CYP3A4 inducers (e.g., rifampicin, carbamazepine, phenytoin, phenobarbital and St. Johnu2019s Wort) is not recommended, as efficacy may be reduced.

In the same medicine interaction study assessing the effect of dexamethasone, a weaker CYP3A4 inducer, on the pharmacokinetics of bortezomib (injected intravenously), there was no significant effect on the pharmacokinetics of VELZOMY based on data from 7 patients.

A medicine interaction study assessing the effect of melphalan-prednisone on the pharmacokinetics of VELZOMY (injected intravenously), showed a mean bortezomib AUC increase of 17 % 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 VELZOMY treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medicines.

Contraception in males and females:

Male and female patients of childbearing potential must use effective contraceptive measures during and for 3 months following VELZOMY treatment.

Pregnancy:

No clinical data are available for VELZOMY with regard to exposure during pregnancy. The teratogenic potential of VELZOMY has not been fully investigated. VELZOMY should not be used during pregnancy and if the patient becomes pregnant while receiving VELZOMY, the patient should be informed of the potential for hazard to the foetus.

Breastfeeding:

It is not known whether VELZOMY is excreted in human milk. Because of the potential for serious adverse reactions in breastfed infants, breastfeeding should be discontinued during treatment with VELZOMY.

Fertility:

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

VELZOMY may have a moderate influence on the ability to drive and use machines. VELZOMY may be associated with fatigue, dizziness, syncope and orthostatic/postural hypotension or blurred vision. Therefore, patients must be cautious when driving or using machines (see section 4.8).

Summary of the safety profile:

Serious adverse reactions less frequently reported during treatment with VELZOMY include cardiac failure, tumour lysis syndrome, pulmonary hypertension, posterior reversible encephalopathy syndrome, acute diffuse infiltrative pulmonary disorders and autonomic neuropathy. The most frequently reported adverse reactions during treatment with VELZOMY are nausea, diarrhoea, constipation, vomiting, fatigue, pyrexia, thrombocytopenia, anaemia, neutropenia, peripheral neuropathy (including sensory), headache, paraesthesia, decreased appetite, dyspnoea, rash, herpes zoster and myalgia.

Table 4: Adverse reactions in patients with multiple myeloma treated with bortezomib in clinical trials, and all post-marketing adverse reactions regardless of indication # :

SYSTEM ORGAN CLASS: INCIDENCE: ADVERSE REACTION:

Infections and infestations:

• Frequent: Herpes zoster (incl disseminated & ophthalmic), pneumonia*, herpes simplex*, fungal infection*
• Less frequent: Infection*, bacterial infections*, viral infections*, sepsis (incl septic shock)*, bronchopneumonia, herpes virus infection*, meningoencephalitis herpetic # , bacteraemia (incl staphylococcal), 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

Neoplasms benign, malignant and unspecified (incl cysts and polyps):

• Less frequent: Neoplasm malignant, leukaemia plasmacytic, renal cell carcinoma, mass, mycosis fungoides, neoplasm benign*, cutaneous T-cell lymphoma

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**, thrombocytopenic purpura, blood disorder**, haemorrhagic diathesis, lymphocytic infiltration, thrombotic microangiopathy (including thrombocytopenic purpura) #

Immune system disorders:

• Less frequent: Angioedema # , hypersensitivity*, anaphylactic shock, amyloidosis, type III immune complex mediated reaction

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: 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

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: Eye swelling*, vision abnormal*, conjunctivitis*
• Less frequent: Eye haemorrhage*, eyelid infection*, eye inflammation*, diplopia, dry eye*, eye irritation*, eye pain, lacrimation increased, eye discharge, corneal lesion*, exophthalmos, retinitis, scotoma, eye disorder (incl eyelid)**, dacryoadenitis acquired, photophobia, photopsia, optic neuropathy # , different degrees of visual impairment (up to blindness)*, chalazion # , blepharitis #

Ear and labyrinth disorders:

• Frequent: Vertigo*
• Less frequent: Dysacusis (incl tinnitus)*, hearing impaired (up to and incl deafness), ear discomfort*, ear haemorrhage, vestibular neuronitis, ear disorder**

Cardiac disorders:

• Less frequent: Cardiac tamponade # , cardio-pulmonary arrest*, cardiac fibrillation (incl atrial), cardiac failure (incl left and right ventricular)*, dysrhythmia*, tachycardia*, palpitations, angina pectoris, pericarditis (incl pericardial effusion)*, cardiomyopathy*, ventricular dysfunction*, bradycardia, atrial flutter, myocardial infarction*, atrioventricular block*, cardiovascular disorder (incl cardiogenic shock), torsade de pointes, angina unstable, cardiac valve disorders*, coronary artery insufficiency, sinus arrest

Vascular disorders:

• Frequent: Hypotension*, orthostatic hypotension, hypertension*
• Less frequent: Cerebrovascular accident # , deep vein thrombosis*, haemorrhage*, thrombophlebitis (incl superficial), circulatory collapse (incl hypovolaemic shock), phlebitis, flushing*, haematoma (incl peri-renal)*, poor peripheral circulation*, vasculitis, hyperaemia (incl ocular)*, peripheral embolism, lymphoedema, pallor, erythromelalgia, vasodilatation, vein discolouration, venous insufficiency

Respiratory, thoracic and mediastinal disorders:

• Frequent: Dyspnoea*, epistaxis, upper/lower respiratory tract infection*, cough*
• Less frequent: Pulmonary embolism, pleural effusion, pulmonary oedema (incl 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

Gastrointestinal disorders:

• Frequent: Nausea and vomiting symptoms*, diarrhoea*, constipation, gastrointestinal haemorrhage (incl mucosal)*, dyspepsia, stomatitis*, abdominal distension, oropharyngeal pain*, abdominal pain (incl gastrointestinal and splenic pain)*, oral disorder*, flatulence
• Less frequent: Pancreatitis (incl chronic)*, haematemesis, lip swelling*, gastrointestinal obstruction (incl small intestinal obstruction, ileus)*, abdominal discomfort, oral ulceration*, enteritis*, gastritis*, gingival bleeding, gastro-oesophageal reflux disease*, colitis (incl clostridium difficile)*, colitis ischaemic # , gastrointestinal inflammation*, dysphagia, irritable bowel syndrome, gastrointestinal disorder**, 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

Hepatobiliary disorders:

• Frequent: Hepatic enzyme abnormality*
• Less frequent: Hepatotoxicity (incl liver disorder), hepatitis*, cholestasis, hepatic failure, hepatomegaly, Budd-Chiari syndrome, cytomegalovirus hepatitis, hepatic haemorrhage, cholelithiasis

Skin and subcutaneous tissue disorders:

• Frequent: Rash*, pruritus*, erythema, dry skin
• Less frequent: Erythema multiforme, urticaria, acute febrile neutrophilic dermatosis, toxic skin eruption, toxic epidermal necrolysis # , Stevens-Johnson syndrome # , dermatitis*, hair disorder*, petechiae, ecchymosis, skin lesion, purpura, skin mass*, psoriasis, hyperhidrosis, night sweats, decubitus ulcer # , acne*, blister*, pigmentation disorder*, skin reaction, jessner's lymphocytic infiltration, palmar-plantar erythrodysaesthesia syndrome, haemorrhage subcutaneous, livedo reticularis, skin induration, papule, photosensitivity reaction, seborrhoea, cold sweat, skin disorder**, erythrosis, skin ulcer, nail disorder

Musculoskeletal and connective tissue disorders:

• Frequent: Musculoskeletal pain*, muscle spasms*, pain in extremity, muscular weakness
• 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

Renal and urinary disorders:

• Frequent: Renal impairment*
• Less frequent: Renal failure acute, renal failure chronic*, urinary tract infection*, urinary tract signs and symptoms*, haematuria*, urinary retention, micturition disorder*, proteinuria, uraemia, oliguria*, pollakiuria, bladder irritation

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

Congenital, familial and genetic disorders:

• Less frequent: Aplasia, gastrointestinal malformation, ichthyosis

General disorders and administration site conditions:

• Frequent: Pyrexia*, fatigue, asthenia, oedema (incl peripheral), chills, pain*, malaise*
• 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 (incl sudden), multi-organ failure, injection site haemorrhage*, hernia (incl hiatus)*, impaired healing*, inflammation, injection site phlebitis*, tenderness, ulcer, irritability, non-cardiac chest pain, catheter site pain, sensation of foreign body

Investigations:

• Frequent: Weight decreased
• Less frequent: Hyperbilirubinaemia*, protein analyses abnormal*, weight increased, blood test abnormal*, C-reactive protein increased, blood gases abnormal*, electrocardiogram abnormalities (incl QT prolongation)*, international normalised ratio abnormal*, gastric pH decreased, platelet aggregation increased, troponin I increased, virus identification and serology*, urine analysis abnormal*

Injury, poisoning and procedural complications:

• Less frequent: Fall, contusion, transfusion reaction, fractures*, rigors*, face injury, joint injury*, burns, laceration, procedural pain, radiation injuries*

Surgical and medical procedures:

• Less frequent: Macrophage activation **

Not otherwise specified

* Grouping of more than one MedDRA preferred term

# Postmarketing adverse reaction regardless of indication

Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare providers are asked to report any suspected adverse reactions to SAHPRA via the u20186.04 Adverse Drug Reactions Reporting Formu2019, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8.

In patients, overdose more than twice the recommended dose has been associated with the acute onset of symptomatic hypotension and thrombocytopenia with fatal outcomes. There is no known specific antidote for VELZOMY overdose. In the event of an overdose, the patientu2019s vital signs should be monitored and appropriate supportive care given to maintain blood pressure.