Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2012 Publisher: JANSSEN-CILAG INTERNATIONAL NV Turnhoutseweg 30 B-2340 Beerse Belgium
Hypersensitivity to bortezomib, boron or to any of the excipients.
Acute diffuse infiltrative pulmonary and pericardial disease.
There have been fatal cases of inadvertent intrathecal administration of VELCADE. VELCADE 1 mg is for intravenous use only, while VELCADE 3.5 mg is for intravenous or subcutaneous use. VELCADE should not be administered intrathecally.
Gastrointestinal toxicity, including nausea, diarrhoea, vomiting and constipation are very common with VELCADE treatment. Cases of ileus have been uncommonly reported (see section 4.8). Therefore, patients who experience constipation should be closely monitored.
VELCADE treatment is very commonly associated with haematological toxicities (thrombocytopenia, neutropenia and anaemia). In the Phase III study evaluating VELCADE (injected intravenously) versus dexamethasone, the most common haematologic toxicity was transient thrombocytopenia. In a Phase II study, platelets were lowest at Day 11 of each cycle of VELCADE treatment. There was no evidence of cumulative thrombocytopenia, including in the Phase II extension study. The mean platelet count nadir measured was approximately 40% of baseline. In patients with advanced myeloma the severity of thrombocytopenia was related to pre-treatment platelet count: for baseline platelet counts <75,000/μl, 90% of 21 patients had a count ≤25,000/μl during the study, including 14% <10,000/μl; in contrast, with a baseline platelet count >75,000/μl, only 14% of 309 patients had a count ≤25×109/l during the study. Platelet counts should be monitored prior to each dose of VELCADE. VELCADE therapy should be withheld when the platelet count is <25,000/μl or in combination with melphalan and prednisone when the platelet count is ≤ 30,000/μl and re-initiated at a reduced dose after resolution (see section 4.2). Potential benefit of the treatment should be carefully weighed against the risks, particularly in case of moderate to severe thrombocytopenia and risk factors for bleeding.
Therefore, complete blood counts (CBC) with differential and including platelet counts should be frequently monitored throughout treatment with VELCADE.
Antiviral prophylaxis should be considered in patients being treated with VELCADE. In the Phase III study in patients with previously untreated multiple myeloma, the overall incidence of herpes zoster reactivation was more common in patients treated with VELCADE+Melphalan+Prednisone compared with Melphalan+Prednisone (14% versus 4% respectively).
Treatment with VELCADE is very commonly associated with peripheral neuropathy, which is predominantly sensory. However, cases of severe motor neuropathy with or without sensory peripheral neuropathy have been reported. The incidence of peripheral neuropathy increases early in the treatment and has been observed to peak during cycle 5.
It is recommended that patients be carefully monitored for symptoms of neuropathy such as a burning sensation, hyperesthesia, hypoesthesia, paraesthesia, discomfort, neuropathic pain or weakness.
In the Phase III study comparing VELCADE administered intravenously versus subcutaneously, the incidence of Grade ≥2 peripheral neuropathy events was 24% for the subcutaneous injection group and 41% for the intravenous injection group (p=0.0124). Grade ≥3 peripheral neuropathy occurred in 6% of patients in the subcutaneous treatment group, compared with 16% in the intravenous treatment group (p=0.0264). The incidence of all grade peripheral neuropathy with VELCADE administered intravenously was lower in the historical studies with VELCADE administered intravenously than in study MMY-3021.
Patients experiencing new or worsening peripheral neuropathy should undergo neurological evaluation and may require a change in the dose, schedule or route of administration to subcutaneous (see section 4.2). In the Phase III study comparing VELCADE (injected intravenously) versus dexamethasone neuropathy has been managed with supportive care and other therapies and improvement was reported in 51% of patients with ≥ Grade 2 peripheral neuropathy. Resolution occurred in 71% of patients with grade 3 or 4 peripheral neuropathy or peripheral neuropathy leading to discontinuation of treatment in VELCADE (injected intravenously) Phase II studies.
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 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.
VELCADE treatment is commonly associated with orthostatic/postural hypotension. Most undesirable effects are mild to moderate in nature and are observed throughout treatment. Patients who developed orthostatic hypotension on VELCADE (injected intravenously) did not have evidence of orthostatic hypotension prior to treatment with VELCADE. Most patients required treatment for their orthostatic hypotension. A minority of patients with orthostatic hypotension experienced syncopal events. Orthostatic/postural hypotension was not acutely related to bolus infusion of VELCADE. The mechanism of this event is unknown although a component may be due to autonomic neuropathy. Autonomic neuropathy may be related to bortezomib or bortezomib may aggravate an underlying condition such as diabetic or amyloidotic neuropathy. Caution is advised when treating patients with a history of syncope receiving medicinal products known to be associated with hypotension; or who are dehydrated due to recurrent diarrhoea or vomiting. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medicinal products, rehydration or administration of mineralocorticosteroids and/or sympathomimetics. Patients should be instructed to seek medical advice if they experience symptoms of dizziness, light-headedness or fainting spells.
There have been reports of PRES in patients receiving VELCADE. 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, VELCADE should be discontinued.
Acute development or exacerbation of congestive heart failure, and/or new onset of decreased left ventricular ejection fraction has been reported during bortezomib treatment. In the Phase III randomised, comparative study the incidence of heart failure in the VELCADE (injected intravenously) group was similar to that in the dexamethasone group. Fluid retention may be a predisposing factor for signs and symptoms of heart failure. Patients with risk factors for or existing heart disease should be closely monitored.
There have been isolated cases of QT-interval prolongation in clinical studies, causality has not been established.
There have been rare reports of acute diffuse infiltrative pulmonary disease of unknown aetiology such as pneumonitis, interstitial pneumonia, lung infiltration, and acute respiratory distress syndrome (ARDS) in patients receiving VELCADE (see section 4.8). Some of these events have been fatal. A pre-treatment chest radiograph is recommended to determine if any additional diagnostic measures are necessary and to serve as a baseline for potential post-treatment pulmonary changes.
In the event of new or worsening pulmonary symptoms (e.g. cough, dyspnoea), a prompt diagnostic evaluation should be performed and patients treated appropriately. The benefit/risk ratio should be considered prior to continuing VELCADE therapy.
In a clinical trial, two patients (out of 2) given high-dose cytarabine (2 g/m² per day) by continuous infusion over 24 hours with daunorubicin and VELCADE for relapsed acute myelogenous leukaemia died of ARDS early in the course of therapy, and the study was terminated. Therefore, this specific regimen with concomitant administration with high-dose cytarabine (2 g/m² per day) by continuous infusion over 24 hours is not recommended.
Renal complications are frequent in patients with multiple myeloma. Patients with renal impairment should be monitored closely (see sections 4.2 and 5.2).
Bortezomib is metabolized by liver enzymes. Bortezomib exposure is increased in patients with moderate or severe hepatic impairment; these patients should be treated with VELCADE at reduced doses and closely monitored for toxicities (see sections 4.2 and 5.2).
Rare cases of hepatic failure have been reported in patients receiving VELCADE and multiple concomitant medicinal products and with serious underlying medical conditions. Other reported hepatic reactions include increases in liver enzymes, hyperbilirubinaemia, and hepatitis. Such changes may be reversible upon discontinuation of bortezomib (see section 4.8).
Because bortezomib is a cytotoxic agent and can rapidly kill malignant plasma cells, the complications of tumour lysis syndrome may occur. The patients at risk of tumour lysis syndrome are those with high tumour burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.
Patients should be closely monitored when given bortezomib in combination with potent CYP3A4-inhibitors. Caution should be exercised when bortezomib is combined with CYP3A4- or CYP2C19 substrates (see section 4.5).
Normal liver function should be confirmed and caution should be exercised in patients receiving oral hypoglycemics (see section 4.5).
Potentially immunocomplex-mediated reactions, such as serum-sickness-type reaction, polyarthritis with rash and proliferative glomerulonephritis have been reported uncommonly. Bortezomib should be discontinued if serious reactions occur.
In vitro studies indicate that bortezomib is a weak inhibitor of the cytochrome P450 (CYP) isozymes 1A2, 2C9, 2C19, 2D6 and 3A4. Based on the limited contribution (7%) of CYP2D6 to the metabolism of bortezomib, the CYP2D6 poor metabolizer phenotype is not expected to affect the overall disposition of bortezomib.
A drug-drug interaction study assessing the effect of ketoconazole, a potent CYP3A4 inhibitor, on bortezomib showed a mean bortezomib AUC increase of 35% (CI90% [1.032 to 1.772]) based on data from 12 patients. Therefore, patients should be closely monitored when given bortezomib in combination with potent CYP3A4 inhibitors (e.g. ketoconazole, ritonavir).
In a drug-drug interaction study assessing the effect of omeprazole, a potent CYP2C19 inhibitor, on bortezomib, there was no significant effect on the pharmacokinetics of bortezomib based on data from 17 patients.
A drug-drug interaction study assessing the effect of rifampicin, a potent CYP3A4 inducer, on bortezomib, showed a mean bortezomib AUC reduction of 45% based on data from 6 patients. Therefore, the concomitant use of bortezomib with strong CYP3A4 inducers (e.g., rifampicin, carbamazepine, phenytoin, phenobarbital and St. John’s Wort) is not recommended, as efficacy may be reduced.
In the same drug-drug interaction study assessing the effect of dexamethasone, a weaker CYP3A4 inducer, on bortezomib, (injected intravenously), there was no significant effect on the pharmacokinetics of bortezomib based on data from 7 patients.
A drug-drug interaction study assessing the effect of melphalan-prednisone on bortezomib (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, hypoglycemia and hyperglycemia were uncommonly and commonly reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving VELCADE treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetics.
No clinical data are available for bortezomib with regard to exposure during pregnancy. Male and female patients of childbearing potential must use effective contraceptive measures during and for 3 months following treatment.
The teratogenic potential of bortezomib has not been fully investigated.
In non-clinical studies, bortezomib had no effects on embryonal/foetal development in rats and rabbits at the highest maternally tolerated doses. Animal studies to determine the effects of bortezomib on parturition and post-natal development were not conducted (see section 5.3). VELCADE should not be used during pregnancy unless the clinical condition of the woman requires treatment with VELCADE.
If VELCADE is used during pregnancy, or if the patient becomes pregnant while receiving this medicinal product, the patient should be informed of potential for hazard to the foetus.
It is not known whether bortezomib is excreted in human milk. Because of the potential for serious undesirable effects in breast-fed infants, lactation should be discontinued during treatment with VELCADE.
Fertility studies were not conducted with VELCADE (see section 5.3).
VELCADE may have a moderate influence on the ability to drive and use machines. VELCADE may be associated with fatigue very commonly, dizziness commonly, syncope uncommonly and orthostatic/postural hypotension or blurred vision commonly. Therefore, patients must be cautious when driving or using machines (see section 4.8).
The most commonly reported adverse reactions during treatment with VELCADE are nausea, diarrhoea, constipation, vomiting, fatigue, pyrexia, thrombocytopenia, anaemia, neutropenia, peripheral neuropathy (including sensory), headache, paraesthesia, decreased appetite, dyspnoea, rash, herpes zoster and myalgia. Serious adverse reactions uncommonly reported during treatment with VELCADE include cardiac failure, tumour lysis syndrome, pulmonary hypertension, PRES, acute diffuse infiltrative pulmonary disorders and rarely autonomic neuropathy.
Undesirable effects in Table 5 were considered by the investigators to have at least a possible or probable causal relationship to VELCADE. These adverse reactions are based on an integrated data set of 3,628 patients of whom 2,606 were treated with VELCADE at 1.3 mg/m². These 2,606 patients include:
Overall, VELCADE was administered for the treatment of multiple myeloma in 2,584 patients.
Adverse reactions are listed below by system organ class and frequency grouping. Frequencies are defined as: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Table 5 has been generated using Version 13.1 of the MedDRA.
Postmarketing adverse reactions not seen in clinical trials are also included.
Table 5 – Adverse reactions in patients treated with VELCADE as single agent or in combination:
Common: Herpes zoster (inc disseminated & ophthalmic), Pneumonia*, Infection*, Herpes simplex*, Fungal infection*
Uncommon: Sepsis*, Bronchopneumonia, Herpes virus infection*, Bacteraemia (inc staphylococcal), Hordeolum, Influenza, Cellulitis, Device related infection, Skin infection*, Ear infection*, Tooth infection*
Rare: Meningitis (inc bacterial), Epstein-Barr virus infection, Erysipelas, Genital herpes, Staphylococcal infection, Tonsillitis, Varicella, Mastoiditis, Post viral fatigue syndrome
Uncommon: Neoplasm malignant
Rare: Leukaemia plasmacytic, Renal cell carcinoma, Mass, Mycosis fungoides, Neoplasm benign
Very Common: Thrombocytopenia*, Neutropenia*, Anaemia*, Leukopenia*
Common: Lymphopenia*
Uncommon: Pancytopenia*, Febrile neutropenia, Coagulopathy*, Leukocytosis*, Lymphadenopathy
Rare: Hyperviscosity syndrome, Thrombocytopenic purpura*, Blood disorder NOS, Haemorrhagic diathesis, Lymphocytic infiltration
Uncommon: Hypersensitivity*
Rare: Anaphylactic shock, Type III immune complex mediated reaction
Uncommon: Hyperthyroidism*, Inappropriate antidiuretic hormone secretion
Rare: Cushing’s syndrome*, Hypothyroidism
Very Common: Decreased appetite
Common: Electrolyte imbalance*, Dehydration, Enzyme abnormality*, Hyperuricaemia*
Uncommon: Tumour lysis syndrome, Failure to thrive*, Hypoglycaemia*, Hyperglycaemia, Hypoproteinaemia*, Fluid retention, Hypovolaemia
Rare: Acidosis, Fluid overload, Hypochloraemia*, Diabetes mellitus*, Hyperproteinaemia*, Hypouricaemia*, Metabolic disorder, Vitamin B complex deficiency, Vitamin B12 deficiency, Gout, Hyperammonaemia*, Increased appetite, Alcohol intolerance
Common: Mood altered*, Anxiety disorder*, Sleep disorder*
Uncommon: Mental disorder*, Hallucination*, Confusion*, Restlessness
Rare: Suicidal ideation*, Psychotic disorder*, Abnormal dreams, Adjustment disorder, Delirium, Libido decreased
Very Common: Neuropathy peripheral*, Peripheral sensory neuropathy, Dysaesthesia*, Neuralgia*, Headache*
Common: Peripheral motor neuropathy, Loss of consciousness (inc syncope), Dizziness*, Dysgeusia*, Lethargy
Uncommon: Haemorrhage intracranial*, Tremor, Peripheral sensorimotor neuropathy, Ataxia*, Dyskinesia*, Memory impairment*, Encephalopathy*, Balance disorder, Neurotoxicity, Presyncope, Post herpetic neuralgia, Speech disorder*, Restless legs syndrome, Migraine, Sciatica, Disturbance in attention, Reflexes abnormal*, Parosmia
Rare: Brain oedema, Cerebral haemorrhage, Transient ischaemic attack, Autonomic nervous system imbalance, Autonomic neuropathy, Convulsion, Cranial palsy*, Paralysis*, Paresis*, 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
Common: Eye swelling*, Vision abnormal*, Conjunctivitis*, Dry eye*
Uncommon: Eye haemorrhage*, Eyelid infection*, Eye inflammation*, Ocular hyperaemia, Diplopia, Eye irritation*, Eye pain, Lacrimation increased, Eye discharge
Rare: Corneal lesion*, Exophthalmos, Retinitis, Scotoma, Eye disorder (inc. eyelid) NOS, Dacryoadenitis acquired, Photophobia, Photopsia, Optic neuropathy#, Different degrees of visual impairment (up to blindness)*,
Common: Vertigo*
Uncommon: Hearing impaired (up to and inc. deafness), Dysacusis*, Tinnitus*, Ear discomfort*
Rare: Ear haemorrhage, Ear disorder NOS
Common: Cardiac failure*, Tachycardia*
Uncommon: Cardio-pulmonary arrest*, Cardiac fibrillation (inc atrial), Arrhythmia*, Palpitations, Angina pectoris, Pericarditis*, Cardiomyopathy*, Ventricular dysfunction*, Bradycardia
Rare: Atrial flutter, Myocardial infarction*, Atrioventricular block*, Cardiovascular disorder (inc cardiogenic shock), Torsade de pointes, Angina unstable, Coronary artery insufficiency, Left ventricular failure, Mitral valve incompetence, Sinus arrest
Common: Hypotension*, Orthostatic hypotension, Hypertension*
Uncommon: Deep vein thrombosis*, Haemorrhage*, Thrombophlebitis (inc superficial), Circulatory collapse (inc hypovolaemic shock), Phlebitis, Flushing, Haematoma*, Poor peripheral circulation*, Hot flush, Vasculitis, Pallor
Rare: Peripheral embolism, Lymphoedema, Erythromelalgia, Vasodilatation, Vein discolouration, Venous insufficiency
Common: Dyspnoea*, Epistaxis, Upper/lower respiratory tract infection*, Cough*
Uncommon: Pulmonary embolism, Pleural effusion, Pulmonary oedema (inc acute), Bronchospasm, Chronic obstructive pulmonary disease*, Hypoxaemia*, Pulmonary hypertension, Respiratory tract congestion*, Hypoxia, Pleurisy*, Pulmonary fibrosis, Hiccups, Rhinorrhoea, Dysphonia, Wheezing
Rare: Respiratory failure, Acute respiratory distress syndrome, Apnoea, Pneumothorax, Atelectasis, Haemoptysis, Hyperventilation, Orthopnoea, Pneumonitis, Respiratory alkalosis, Tachypnoea, Hypocapnia*, Interstitial lung disease, Lung infiltration, Throat tightness, Dry throat, Bronchial hyperreactivity, Increased upper airway secretion, Throat irritation
Very Common: Vomiting, Diarrhoea*, Nausea, Constipation, Abdominal pain (inc gastrointestinal pain)*
Common: Gastrointestinal haemorrhage (inc mucosal), Dyspepsia, Stomatitis, Abdominal distension, Oropharyngeal pain*, Abdominal discomfort, Oral disorder*, Flatulence
Uncommon: Pancreatitis (inc chronic), Haematemesis, Lip swelling*, Oral ulceration*, Ileus*, Enteritis*, Gastritis*, Gingival bleeding, Gastrooesophageal reflux disease*, Gastrointestinal inflammation*, Dysphagia, Irritable bowel syndrome, Oesophagitis, Gastrointestinal disorder NOS, Retching, Gastrointestinal motility disorder*, Salivary gland disorder*, Oropharyngeal blistering*
Rare: Pancreatitis acute, Peritonitis*, Tongue oedema*, Ascites, Cheilitis, Faecal incontinence, Anal sphincter atony, Faecaloma, Rectal discharge, Lip pain, Periodontitis, Anal fissure, Change of bowel habit, Proctalgia, Abnormal faeces
Common: Hepatic enzyme abnormality*
Uncommon: Hepatotoxicity (inc liver disorder), Hepatitis*, Cholestasis
Rare: Hepatic failure, Hepatomegaly, Budd-Chiari syndrome, Hepatic haemorrhage, Cholelithiasis
Very Common: Rash*
Common: Urticaria, Pruritus*, Erythema, Dermatitis*, Dry skin
Uncommon: Acute febrile neutrophilic dermatosis, Toxic skin eruption, Hair disorder*, Petechiae, Ecchymosis, Skin lesion, Purpura, Skin nodule*, Psoriasis, Palmar-plantar erythrodysaesthesia syndrome, Hyperhidrosis, Night sweats, Acne*, Blood blister, Pigmentation disorder*, Nail disorder
Rare: Erythema multiforme, Skin reaction, Jessner’s lymphocytic infiltration, Haemorrhage subcutaneous, Livedo reticularis, Skin induration, Blister, Cold sweat, Papule, Photosensitivity reaction, Seborrhoea, Skin disorder NOS
Very Common: Musculoskeletal pain*
Common: Muscle spasms*, Pain in extremity, Muscular weakness
Uncommon: Muscle twitching, Joint swelling, Arthritis*, Joint stiffness, Myopathy*, Sensation of heaviness
Rare: Rhabdomyolysis, Temporomandibular joint syndrome, Fistula, Joint effusion, Pain in jaw, Bone disorder, Dactylitis, Synovial cyst
Common: Renal impairment*, Renal failure chronic*
Uncommon: Renal failure acute, Urinary tract infection*, Haematuria*, Urinary retention, Dysuria*, Micturition disorder*, Proteinuria, Azotaemia, Oliguria*, Pollakiuria
Rare: Renal colic, Bladder irritation, Urine odour abnormal
Uncommon: Vaginal haemorrhage, Genital pain*, Erectile dysfunction, Testicular disorder*
Rare: Prostatitis, Breast disorder female, Epididymal tenderness, Epididymitis, Pelvic pain, Vulval ulceration
Rare: Aplasia, Gastrointestinal malformation, Ichthyosis
Very Common: Pyrexia*, Fatigue, Asthenia
Common: Oedema (inc peripheral), Chills, Pain*, Injection site reaction*, Malaise*
Uncommon: Death (inc sudden), General physical health deterioration*, Face oedema*, Chest pain, Mucosal disorder*, Gait disturbance, Feeling cold, Extravasation*, Catheter related complication*, Thirst, Chest discomfort, Feeling of body temperature change*, Injection site pain*
Rare: Injection site haemorrhage*, Hernia*, Injection site phlebitis*, Impaired healing, Inflammation, Tenderness, Ulcer, Irritability, Non-cardiac chest pain, Catheter site pain, Sensation of foreign body
Common: Weight decreased
Uncommon: Hyperbilirubinaemia*, Weight increased, C-reactive protein increased
Rare: Megakaryocytes decreased, PO2 increased, Blood bicarbonate decreased, Blood creatinine increased*, Electrocardiogram abnormality*, International normalised ratio abnormal*, Beta 2 microglobulin increased, Blood creatinine decreased, Cytomegalovirus test, Gastric pH decreased, Platelet aggregation increased, Troponin I increased, Blood testosterone decreased, Protein urine present, Serum ferritin increased, pH urine increased
Uncommon: Fall, Contusion
Rare: Skull fracture, Transfusion reaction, Rigors*, Face injury, Joint injury, Laceration, Procedural pain, Radiation injuries*
Rare: Macrophage activation
NOS = not otherwise specified
* Grouping of more than one MedDRA preferred term.
# Postmarketing adverse reaction
Herpes zoster virus reactivation: Antiviral prophylaxis was administered to 26% of the patients in the Vc+M+P arm. The incidence of herpes zoster among patients in the Vc+M+P treatment group was 17% for patients not administered antiviral prophylaxis compared to 3% for patients administered antiviral prophylaxis.
Notable differences in the safety profile of VELCADE administered subcutaneously versus intravenously as single agent: In the Phase III study patients who received VELCADE subcutaneously compared to intravenous administration had 13% lower overall incidence of treatment emergent adverse reactions that were grade 3 or higher in toxicity, and a 5% lower incidence of discontinuation of VELCADE. The overall incidence of diarrhoea, gastrointestinal and abdominal pain, asthenic conditions, upper respiratory tract infections and peripheral neuropathies were 12%-15% lower in the subcutaneous group than in the intravenous group. In addition, the incidence of grade 3 or higher peripheral neuropathies was 10 % lower, and the discontinuation rate due to peripheral neuropathies 8% lower for the subcutaneous group as compared to the intravenous group.
Six percent of patients had an adverse local reaction to subcutaneous administration, mostly redness. Cases resolved in a median of 6 days, dose modification was required in two patients. Two (1%) of the patients had severe reactions; 1 case of pruritus and 1 case of redness.
The incidence of death on treatment was 5% in the subcutaneous treatment group and 7% in the intravenous treatment group. Incidence of death from “Progressive disease” was 18% in the subcutaneous group and 9% in the intravenous group.
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
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