Multiple Myeloma: Herpes Zoster Virus Reactivation:
The administration of bortezomib has been associated with herpes zoster reactivation. In the randomized Phase III study in relapsed multiple myeloma, the incidence of herpes zoster occurring on treatment with bortezomib was 13% (42/331) versus 5% (15/332) in the high-dose dexamethasone group. In the randomized study in patients with previously untreated multiple myeloma, the overall incidence of herpes zoster reactivation was more common in subjects treated with intravenous bortezomib, melphalan and prednisone (VMP) than in the control group treated with melphalan and prednisone (14% vs 4%, respectively). In this study, antiviral prophylaxis was administered to 26% (90/340) of patients in the VMP treatment group. In this treatment group, herpes zoster virus reactivation was less common in subjects receiving prophylactic antiviral therapy (3% [3/90]) than in subjects who did not receive prophylactic antiviral therapy (17% [43/250]). In the post-market setting, cases of herpes meningoencephalitis and ophthalmic herpes have been reported.
Blood and lymphatic system disorders:
Disseminated intravascular coagulation.
Angina pectoris, atrial fibrillation aggravated, atrial flutter, bradycardia, sinus arrest, cardiac amyloidosis, cardiac arrest, congestive heart failure, myocardial ischemia, myocardial infarction, pericarditis, pericardial effusion, pulmonary edema, ventricular tachycardia.
One case of torsades de pointes (not described previously) has been reported in a patient receiving bortezomib; causality has not been established.
Ear and labyrinth disorders:
Ascites, dysphagia, fecal impaction, gastroenteritis, gastritis hemorrhagic, gastrointestinal hemorrhage, hematemesis, hemorrhagic duodenitis, ileus paralytic, large intestinal obstruction, paralytic intestinal obstruction, small intestinal obstruction, large intestinal perforation, stomatitis, melena, acute pancreatitis.
General disorders and administration site conditions:
Injection site erythema.
Cholestasis, hepatic hemorrhage, hyperbilirubinemia, portal vein thrombosis, hepatitis and liver failure.
Immune system disorders:
Anaphylactic reaction, drug hypersensitivity, immune complex mediated hypersensitivity, acute renal failure (proliferative glomerulonephropathy), diffuse polyarthritis and rash.
Infections and infestations:
Aspergillosis, bacteremia, urinary tract infection, herpes viral infection, listeriosis, septic shock, toxoplasmosis, oral candidiasis.
Injury, poisoning and procedural complications:
Skeletal fracture, subdural hematoma.
Metabolism and nutrition disorders:
Hypocalcemia, hyperuricemia, hypokalemia, hyperkalemia, hypernatremia, hyponatreamia, tumour lysis syndrome.
Ataxia, coma, dizziness, dysarthria, dysautonomia, encephalopathy, cranial palsy, grand mal convulsion, hemorrhagic stroke, motor dysfunction, spinal cord compression, paraplegia, transient ischemic attack.
Agitation, confusion, mental status changes, psychotic disorder, suicidal ideation.
Renal and urinary:
Calculus renal, bilateral hydronephrosis, bladder spasm, hematuria, hemorrhagic cystitis, urinary incontinence, urinary retention, renal failure - acute and chronic, glomerular nephritis proliferative.
Respiratory, thoracic and mediastinal:
Acute respiratory distress syndrome, aspiration, pneumonia, atelectasis, chronic obstructive airways disease exacerbated, dysphagia, epistaxis, hemoptysis, hypoxia, lung infiltration, pleural effusion, pneumonitis, respiratory distress, respiratory failure.
Skin and subcutaneous tissue disorders:
Urticaria, face edema.
Cerebrovascular accident, deep venous thrombosis, peripheral embolism, pulmonary embolism, pulmonary hypertension.
Abnormal Hematologic and Clinical Chemistry Findings:
Hematological abnormalities are expected in patients with advanced multiple myeloma. With bortezomib, cyclical thrombocytopenia was seen, with a general progressive decrease in platelet count during the bortezomib dosing period (Days 1 to 11) and a return to baseline in platelet count during the rest period (Days 12 to 21) in each treatment cycle. A trend towards an increase in hemoglobin and absolute neutrophil count across treatment cycles was noted especially with an improvement in the underlying disease. A trend towards a decrease in the absolute lymphocyte count was noted across the 8 treatment cycles; however, no trend was noted by cycle. Effects on electrolytes and calcium (hyper- and hypokalemia, hyper- and hyponatremia, hyper- and hypocalcemia) and hyphosphatemia, hypochloremia and hypomagnesmia were noted.
Post-Market Adverse Drug Reactions:
The following adverse events have been reported from post-marketing experience: Central neurotoxicity/psychiatric events including seizures, mental status changes, encephalopathy, acute psychosis, bilateral hearing loss, dysautonomia, posterior reversible encephalopathy syndrome.
Cardiovascular and pulmonary events including tachycardia, heart failure, cardiac tamponade, pericarditis, pulmonary hypertension, cardiac and cardiopulmonary arrest, complete heart block, pneumonitis, respiratory failure, pulmonary alveolar hemorrhage, pleural effusion, acute pulmonary edema, cardiogenic shock.
Serious bleeding events including subarachnoid hemorrhage, intracerebral hemorrhage, disseminated intravascular coagulation, ischemic stroke, ischemic colitis, spinal cord ischemia.
Hypersensitivity events including immune complex type diseases, angioedema, anaphylactic reaction.
Tumour lysis syndrome.
Hepatic abnormalities including increased transaminases, alkaline phosphatase, gamma-glutamyl transferase, hepatocellular damage, hepatitis, pancreatitis.
Renal abnormalities including acute renal failure, nephrotic syndrome, renal tubular acidosis, renal necrosis, graft loss and renal graft loss.
Sepsis and septic shock.
Gastrointestinal events including ischemic colitis and paralytic ileus.
Hyper- and hypocalcemia, hyper- and hypokalemia, severe hyponatremia, inappropriate ADH secretion.
Acute diffuse infiltrative pulmonary disease.
Stevens-Johnson syndrome, and toxic epidermal necrolysis.
Herpes meningoencephalitis and ophthalmic herpes.
Optic neuropathy and blindness.
Progressive multifocal leukoencephalopathy (John Cunningham [JC]) virus infection.