Chemical formula: C₁₉H₂₅BN₄O₄ Molecular mass: 384.237 g/mol PubChem compound: 387447
Bortezomib interacts in the following cases:
Acute development or exacerbation of congestive heart failure, and/or new onset of decreased left ventricular ejection fraction has been reported during bortezomib 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.
A drug-drug interaction study assessing the effect of ketoconazole, a potent CYP3A4 inhibitor, on bortezomib 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 bortezomib in combination with potent CYP3A4 inhibitors (e.g. ketoconazole, ritonavir).
A drug-drug interaction study assessing the effect of rifampicin, a potent CYP3A4 inducer, on the pharmacokinetics of bortezomib (injected intravenously), 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.
Patients with mild hepatic impairment do not require a dose adjustment and should be treated per the recommended dose. Patients with moderate or severe hepatic impairment should be started on bortezomib at a reduced dose of 0.7 mg/m² per injection during the first treatment cycle, and a subsequent dose escalation to 1.0 mg/m² or further dose reduction to 0.5 mg/m² may be considered based on patient tolerability.
Recommended starting dose modification for bortezomib in patients with hepatic impairment:
| Grade of hepatic impairment* | Bilirubin level | SGOT (AST) levels | Modification of starting dose |
|---|---|---|---|
| Mild | ≤1.0 x ULN | >ULN | None |
| >1.0 × 1.5 x ULN | Any | None | Reduce VELCADE to 0.7 mg/m² in the first treatment cycle. Consider dose escalation to 1.0 mg/m² or further dose reduction to 0.5 mg/m² in subsequent cycles based on patient tolerability. |
| Moderate | >1.5 × 3 x ULN | Any |
Abbreviations: SGOT=serum glutamic oxaloacetic transaminase; AST=aspartate aminotransferase; ULN=upper limit of the normal range.
* Based on NCI Organ Dysfunction Working Group classification for categorising hepatic impairment (mild, moderate, severe).
During clinical trials, hypoglycemia and hyperglycemia were uncommonly and commonly reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving bortezomib treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetics.
A drug-drug interaction study assessing the effect of melphalan-prednisone on the pharmacokinetics of bortezomib (injected intravenously), showed a mean bortezomib AUC increase of 17% based on data from 21 patients. This is not considered clinically relevant.
Very rare cases with unknown causality of John Cunningham (JC) virus infection, resulting in PML and death, have been reported in patients treated with bortezomib. Patients diagnosed with PML had prior or concurrent immunosuppressive therapy. Most cases of PML were diagnosed within 12 months of their first dose of bortezomib. Patients should be monitored at regular intervals for any new or worsening neurological symptoms or signs that may be suggestive of PML as part of the differential diagnosis of CNS problems. If a diagnosis of PML is suspected, patients should be referred to a specialist in PML and appropriate diagnostic measures for PML should be initiated. Discontinue bortezomib if PML is diagnosed.
Because bortezomib is a cytotoxic agent 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.
Bortezomib treatment is commonly 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 bortezomib (injected intravenously) did not have evidence of orthostatic hypotension prior to treatment with bortezomib. 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 bortezomib. 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.
Treatment with bortezomib 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 bortezomib 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 bortezomib administered intravenously was lower in the historical studies with bortezomib 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. 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 bortezomib in combination with medicinal products known to be associated with neuropathy (e.g. thalidomide) 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.
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 bortezomib. 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. The benefit/risk ratio should be considered prior to continuing bortezomib 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 bortezomib 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.
There have been reports of posterior reversible encephalopathy syndrome in patients receiving bortezomib. Posterior reversible encephalopathy syndrome 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 Posterior reversible encephalopathy syndrome, bortezomib should be discontinued.
Antiviral prophylaxis is recommended in patients being treated with bortezomib. 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 bortezomib+Melphalan+Prednisone compared with Melphalan+Prednisone (14% versus 4% respectively).
In patients with MCL (study LYM-3002), the incidence of herpes zoster infection was 6.7% in the VcR-CAP arm and 1.2% in the R-CHOP arm.
When rituximab is used in combination with bortezomib, 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. Antiviral prophylaxis should be considered.
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.
No clinical data are available for bortezomib with regard to exposure during pregnancy. The teratogenic potential of bortezomib has not been fully investigated.
In non-clinical studies, bortezomib had no effects on embryonal/foetal development in rats and rabbits at the highest maternally tolerated doses. Animal studies to determine the effects of bortezomib on parturition and post-natal development were not conducted. Bortezomib should not be used during pregnancy unless the clinical condition of the woman requires treatment with bortezomib. If bortezomib 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.
Thalidomide is a known human teratogenic active substance that causes severe life-threatening birth defects. Thalidomide is contraindicated during pregnancy and in women of childbearing potential unless all the conditions of the thalidomide pregnancy prevention programme are met. Patients receiving bortezomib in combination with thalidomide should adhere to the pregnancy prevention programme of thalidomide.
It is not known whether bortezomib is excreted in human milk. Because of the potential for serious adverse reactions in breast-fed infants, breast-feeding should be discontinued during treatment with bortezomib.
Male and female patients of childbearing potential must use effective contraceptive measures during and for 3 months following treatment.
Fertility studies were not conducted with bortezomib.
Bortezomib may have a moderate influence on the ability to drive and use machines. Bortezomib 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 and should be advised not to drive or operate machinery if they experience these symptoms.
Serious adverse reactions uncommonly reported during treatment with bortezomib 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 are nausea, diarrhoea, constipation, vomiting, fatigue, pyrexia, thrombocytopenia, anaemia, neutropenia, peripheral neuropathy (including sensory), headache, paraesthesia, decreased appetite, dyspnoea, rash, herpes zoster and myalgia.
Undesirable effects in the following list were considered by the investigators to have at least a possible or probable causal relationship to bortezomib. These adverse reactions are based on an integrated data set of 5,476 patients of whom 3,996 were treated with bortezomib at 1.3 mg/m 2 and included in the list below. Overall, bortezomib was administered for the treatment of multiple myeloma in 3,974 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. The following list has been generated using Version 14.1 of the MedDRA. Post-marketing adverse reactions not seen in clinical trials are also included.
Adverse reactions in patients with Multiple Myeloma treated with bortezomib in clinical trials, and all post-marketing adverse reactions regardless of indication#:
Common: Herpes zoster (inc disseminated & ophthalmic), Pneumonia*, Herpes simplex*, Fungal infection*
Uncommon: Infection*, Bacterial infections*, Viral infections*, Sepsis (inc septic shock), Bronchopneumonia, Herpes virus infection, Meningoencephalitis herpetic# , Bacteraemia (inc staphylococcal), Hordeolum, Influenza, Cellulitis, Device related infection, Skin infection*, Ear infection*, Staphylococcal infection, Tooth infection*
Rare: Meningitis (inc bacterial), Epstein-Barr virus infection, Genital herpes, Tonsillitis, Mastoiditis, Post viral fatigue syndrome
Rare: Neoplasm malignant, Leukaemia plasmacytic, Renal cell carcinoma, Mass, Mycosis fungoides, Neoplasm benign*
Very Common: Thrombocytopenia*, Neutropenia*, Anaemia*
Common: Leukopenia*, Lymphopenia*
Uncommon: Pancytopenia*, Febrile neutropenia, Coagulopathy*, Leukocytosis*, Lymphadenopathy, Haemolytic anaemia#
Rare: Disseminated intravascular coagulation, Thrombocytosis*, Hyperviscosity syndrome, Platelet disorder NOS, Thrombotic microangiopathy (inc thrombocytopenic purpura) # , Blood disorder NOS, Haemorrhagic diathesis, Lymphocytic infiltration
Uncommon: Angioedema# , Hypersensitivity*
Rare: Anaphylactic shock, Amyloidosis, Type III immune complex mediated reaction
Uncommon: Cushing’s syndrome*, Hyperthyroidism*, Inappropriate antidiuretic hormone secretion
Rare: Hypothyroidism
Very Common: Decreased appetite
Common: Dehydration, Hypokalaemia*, Hyponatraemia*, Blood glucose abnormal*, Hypocalcaemia*, Enzyme abnormality*
Uncommon: Tumour lysis syndrome, Failure to thrive*, Hypomagnesaemia*, Hypophosphataemia*, Hyperkalaemia*, Hypercalcaemia*, Hypernatraemia*, Uric acid abnormal*, Diabetes mellitus*, Fluid retention
Rare: Hypermagnesaemia*, Acidosis, Electrolyte imbalance*, Fluid overload, Hypochloraemia*, Hypovolaemia, Hyperchloraemia*, Hyperphosphataemia*, Metabolic disorder, Vitamin B complex deficiency, Vitamin B12 deficiency, Gout, Increased appetite, Alcohol intolerance
Common: Mood disorders and disturbances*, Anxiety disorder*, Sleep disorders and disturbances*
Uncommon: Mental disorder*, Hallucination*, Psychotic disorder*, Confusion*, Restlessness
Rare: Suicidal ideation*, Adjustment disorder, Delirium, Libido decreased
Very Common: Neuropathies*, Peripheral sensory neuropathy, Dysaesthesia*, Neuralgia*
Common: Motor neuropathy*, Loss of consciousness (inc syncope), Dizziness*, Dysgeusia*, Lethargy, Headache*
Uncommon: Tremor, Peripheral sensorimotor neuropathy, Dyskinesia*, Cerebellar coordination and balance disturbances*, Memory loss (exc 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
Rare: Cerebral haemorrhage*, Haemorrhage intracranial (inc 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
Common: Eye swelling*, Vision abnormal*, Conjunctivitis*
Uncommon: Eye haemorrhage*, Eyelid infection*, Chalazion# , Blepharitis# , Eye inflammation*, Diplopia, Dry eye*, 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: Dysacusis (inc tinnitus),Hearing impaired (up to and inc deafness), Ear discomfort
Rare: Ear haemorrhage, Vestibular neuronitis, Ear disorder NOS
Uncommon: Cardiac tamponade# , Cardio-pulmonary arrest*, Cardiac fibrillation (inc atrial), Cardiac failure (inc left and right ventricular), Arrhythmia, Tachycardia*, Palpitations, Angina pectoris, Pericarditis (inc pericardial effusion), Cardiomyopathy, Ventricular dysfunction*, Bradycardia
Rare: Atrial flutter, Myocardial infarction*, Atrioventricular block*, Cardiovascular disorder (inc cardiogenic shock), Torsade de pointes, Angina unstable, Cardiac valve disorders*, Coronary artery insufficiency, Sinus arrest
Common: Hypotension*, Orthostatic hypotension, Hypertension*
Uncommon: Cerebrovascular accident# , Deep vein thrombosis*, Haemorrhage*, Thrombophlebitis (inc superficial), Circulatory collapse (inc hypovolaemic shock), Phlebitis, Flushing*, Haematoma (inc perirenal), Poor peripheral circulation, Vasculitis, Hyperaemia (inc ocular)*
Rare: Peripheral embolism, Lymphoedema, Pallor, Erythromelalgia, Vasodilatation, Vein discolouration, Venous insufficiency
Common: Dyspnoea*, Epistaxis, Upper/lower respiratory tract infection*, Cough*
Uncommon: Pulmonary embolism, Pleural effusion, Pulmonary oedema (inc acute), Pulmonary alveolar haemorrhage# , Bronchospasm, Chronic obstructive pulmonary disease*, Hypoxaemia*, Respiratory tract congestion*, Hypoxia, Pleurisy*, Hiccups, Rhinorrhoea, Dysphonia, Wheezing
Rare: 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
Very Common: Nausea and vomiting symptoms*, Diarrhoea*, Constipation
Common: Gastrointestinal haemorrhage (inc mucosal), Dyspepsia, Stomatitis, Abdominal distension, Oropharyngeal pain*, Abdominal pain (inc gastrointestinal and splenic pain), Oral disorder, Flatulence
Uncommon: Pancreatitis (inc chronic), Haematemesis, Lip swelling, Gastrointestinal obstruction (inc small intestinal obstruction, ileus), Abdominal discomfort, Oral ulceration, Enteritis*, Gastritis*, Gingival bleeding, Gastrooesophageal reflux disease*, Colitis (inc clostridium difficile), Colitis ischaemic# , Gastrointestinal inflammation, Dysphagia, Irritable bowel syndrome, Gastrointestinal disorder NOS, Tongue coated, Gastrointestinal motility disorder*, Salivary gland disorder*
Rare: 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
Common: Hepatic enzyme abnormality*
Uncommon: Hepatotoxicity (inc liver disorder), Hepatitis*, Cholestasis
Rare: Hepatic failure, Hepatomegaly, Budd-Chiari syndrome, Cytomegalovirus hepatitis, Hepatic haemorrhage, Cholelithiasis
Common: Rash*, Pruritus*, Erythema, Dry skin
Uncommon: 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*
Rare: 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
Very Common: Musculoskeletal pain*
Common: Muscle spasms*, Pain in extremity, Muscular weakness
Uncommon: Muscle twitching, Joint swelling, Arthritis*, Joint stiffness, Myopathies*,Sensation of heaviness
Rare: Rhabdomyolysis, Temporomandibular joint syndrome, Fistula, Joint effusion, Pain in jaw, Bone disorder, Musculoskeletal and connective tissue infections and inflammations*, Synovial cyst
Common: Renal impairment*
Uncommon: Renal failure acute, Renal failure chronic*, Urinary tract infection*, Urinary tract signs and symptoms*, Haematuria*, Urinary retention, Micturition disorder*, Proteinuria, Azotaemia, Oliguria*, Pollakiuria
Rare: Bladder irritation
Uncommon: Vaginal haemorrhage, Genital pain*, Erectile dysfunction,
Rare: Testicular disorder*, 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*, Malaise*
Uncommon: 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*
Rare: Death (inc sudden), Multi-organ failure, Injection site haemorrhage*, Hernia(inc hiatus), Impaired healing, Inflammation, Injection site phlebitis*, Tenderness, Ulcer, Irritability, Non-cardiac chest pain, Catheter site pain, Sensation of foreign body
Common: Weight decreased
Uncommon: Hyperbilirubinaemia*, Protein analyses abnormal*, Weight increased, Blood test abnormal*,C-reactive protein increased
Rare: Blood gases abnormal*, Electrocardiogram abnormalities (inc QT prolongation), International normalised ratio abnormal, Gastric pH decreased, Platelet aggregation increased, Troponin I increased, Virus identification and serology*, Urine analysis abnormal*
Uncommon: Fall, Contusion
Rare: Transfusion reaction, Fractures*, Rigors*, Face injury, Joint injury*, Burns, Laceration, Procedural pain, Radiation injuries*
Rare: Macrophage activation
NOS=not otherwise specified
* Grouping of more than one MedDRA preferred term.
# Post-marketing adverse reaction regardless of indication
The safety profile of bortezomib in 240 MCL patients treated with bortezomib at 1.3 mg/m 2 in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (VcR-CAP) versus 242 patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP] was relatively consistent to that observed in patients with multiple myeloma with main differences described below. Additional adverse drug reactions identified associated with the use of the combination therapy (VcR-CAP) were hepatitis B infection (<1%) and myocardial ischaemia (1.3%). The similar incidences of these events in both treatment arms, indicated that these adverse drug reactions are not attributable to bortezomib alone. Notable differences in the MCL patient population as compared to patients in the multiple myeloma studies were a ≥5% higher incidence of the haematological adverse reactions (neutropenia, thrombocytopenia, leukopenia, anemia, lymphopenia), peripheral sensory neuropathy, hypertension, pyrexia, pneumonia, stomatitis, and hair disorders.
Adverse drug reactions identified as those with a ≥1% incidence, similar or higher incidence in the VcR-CAP arm and with at least a possible or probable causal relationship to the components of the VcR-CAP arm, are listed in the list below. Also included are adverse drug reactions identified in the VcR-CAP arm that were considered by investigators to have at least a possible or probable causal relationship to bortezomib based on historical data in the multiple myeloma studies.
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. The following list has been generated using Version 16 of the MedDRA.
Adverse reactions in patients with Mantle Cell Lymphoma treated with VcR-CAP in a clinical trial:
Very Common: Pneumonia*
Common: Sepsis (inc septic shock), Herpes zoster (inc disseminated & ophthalmic), Herpes virus infection, Bacterial infections*, Upper/lower respiratory tract infection*, Fungal infection*, Herpes simplex*
Uncommon: Hepatitis B, Infection*, Bronchopneumonia
Very Common: Thrombocytopenia*, Febrile neutropenia, Neutropenia*, Leukopenia*, Anaemia*, Lymphopenia*
Uncommon: Pancytopenia*
Common: Hypersensitivity*
Uncommon: Anaphylactic reaction
Very Common: Decreased appetite
Common: Hypokalaemia*, Blood glucose abnormal*, Hyponatraemia*, Diabetes mellitus*, Fluid retention
Uncommon: Tumour lysis syndrome
Common: Sleep disorders and disturbances*
Very Common: Peripheral sensory neuropathy, Dysaesthesia*, Neuralgia*
Common: Neuropathies*, Motor neuropathy*, Loss of consciousness (inc syncope), Encephalopathy*, Peripheral sensorimotor neuropathy, Dizziness*, Dysgeusia*, Autonomic neuropathy
__Uncommon :__Autonomic nervous system imbalance
Common: Vision abnormal*
Common: Dysacusis (inc tinnitus)*
Uncommon: Vertigo*, Hearing impaired (up to and inc deafness)
Common: Cardiac fibrillation (inc atrial), Arrhythmia*, Cardiac failure (inc left and right ventricular), Myocardial ischaemia, Ventricular dysfunction
Uncommon: Cardiovascular disorder (inc cardiogenic shock)
Common: Hypertension*, Hypotension*, Orthostatic hypotension
Common: Dyspnoea*, Cough*, Hiccups
Uncommon: Acute respiratory distress syndrome, Pulmonary embolism, Pneumonitis, Pulmonary hypertension, Pulmonary oedema (inc acute)
Very Common: Nausea and vomiting symptoms*, Diarrhoea*, Stomatitis*, Constipation
Common: Gastrointestinal haemorrhage (inc mucosal), Abdominal distension, Dyspepsia, Oropharyngeal pain, Gastritis*, Oral ulceration*, Abdominal discomfort, Dysphagia, Gastrointestinal inflammation*, Abdominal pain (inc gastrointestinal and splenic pain), Oral disorder
Uncommon: Colitis (inc clostridium difficile)*
Common: Hepatotoxicity (inc liver disorder)
Uncommon: Hepatic failure
Very Common: Hair disorder*
Common: Pruritus*, Dermatitis*, Rash*
Common: Muscle spasms*, Musculoskeletal pain*, Pain in extremity
Common: Urinary tract infection*
Very Common: Pyrexia*, Fatigue, Asthenia
Common: Oedema (inc peripheral), Chills, Injection site reaction*, Malaise*
Common: Hyperbilirubinaemia*, Protein analyses abnormal*, Weight decreased, Weight increased
* Grouping of more than one MedDRA preferred term.
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.
Antiviral prophylaxis was administered to 137 of 240 patients (57%) in the VcR-CAP arm. The incidence of herpes zoster among patients in the VcR-CAP arm was 10.7% for patients not administered antiviral prophylaxis compared to 3.6% for patients administered antiviral prophylaxis.
HBV infection with fatal outcomes occurred in 0.8% (n=2) of patients in the non-bortezomib treatment group (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; R-CHOP) and 0.4% (n=1) of patients receiving bortezomib in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (VcR-CAP). The overall incidence of hepatitis B infections was similar in patients treated with VcR-CAP or with R-CHOP (0.8% vs 1.2% respectively).
In trials in which bortezomib was administered as induction treatment in combination with dexamethasone (study IFM-2005-01), and dexamethasone-thalidomide (study MMY-3010), the incidence of peripheral neuropathy in the combination regimens is presented in the table below.
Incidence of peripheral neuropathy during induction treatment by toxicity and treatment discontinuation due to peripheral neuropathy:
| IFM-2005-01 | MMY-3010 | |||
|---|---|---|---|---|
| VDDx (N=239) | VcDx (N=239) | TDx (N=126) | VcTDx (N=130) | |
| Incidence of PN (%) | ||||
| All Grade PN | 3 | 15 | 12 | 45 |
| ≥ Grade 2 PN | 1 | 10 | 2 | 31 |
| ≥ Grade 3 PN | <1 | 5 | 0 | 5 |
| Discontinuation due to PN (%) | <1 | 2 | 1 | 5 |
VDDx = vincristine, doxorubicin, dexamethasone; VcDx = bortezomib, dexamethasone; TDx = thalidomide, dexamethasone; VcTDx = bortezomib, thalidomide, dexamethasone; PN = peripheral neuropathy
Note: Peripheral neuropathy included the preferred terms: neuropathy peripheral, peripheral motor neuropathy, peripheral sensory neuropathy, and polyneuropathy.
In study LYM-3002 in which bortezomib was administered with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CAP), the incidence of peripheral neuropathy in the combination regimens is presented in the table below.
Incidence of peripheral neuropathy in study LYM-3002 by toxicity and treatment discontinuation due to peripheral neuropathy:
| VcR-CAP (N=240) | R-CHOP (N=242) | |
| Incidence of PN (%) | ||
| All Grade PN | 30 | 29 |
| ≥ Grade 2 PN | 18 | 9 |
| ≥ Grade 3 PN | 8 | 4 |
| Discontinuation due to PN (%) | 2 | <1 |
VcR-CAP = bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone; R-CHOP = rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; PN = peripheral neuropathy
Peripheral neuropathy included the preferred terms: peripheral sensory neuropathy, neuropathy peripheral, peripheral motor neuropathy, and peripheral sensorimotor neuropathy
42.9% and 10.4% of patients in the VcR-CAP arm were in the range 65-74 years and ≥75 years of age, respectively. Although in patients aged ≥75 years, both VcR-CAP and R-CHOP were less tolerated, the serious adverse event rate in the VcR-CAP groups was 68%, compared to 42% in the RCHOP group.
In the Phase III study patients who received bortezomib 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 bortezomib. 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.
In a study in which bortezomib retreatment was administered in 130 patients with relapsed multiple myeloma, who previously had at least partial response on a bortezomib-containing regimen, the most common all-grade adverse events occurring in at least 25% of patients were thrombocytopenia (55%), neuropathy (40%), anaemia (37%), diarrhoea (35%), and constipation (28%). All grade peripheral neuropathy and grade ≥3 peripheral neuropathy were observed in 40% and 8.5% of patients, respectively.
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