Bortezomib

Registered South African indications:

• Multiple myeloma
• Mantle cell lymphoma

Contraindications

South African recommendations

• Hypersensitivity to the active ingredient, boron or any of its excipients
• Acute diffuse infiltrative pulmonary and pericardial disease

Recommendations in other jurisdictions

• Hypersensitivity to the active substance, to boron, or to any of the excipients
• Acute diffuse infiltrative pulmonary and pericardial disease
• When bortezomib is given in combination with other medicinal products, refer to their professional information for additional contraindications

Cautions

• Pregnancy
• Breastfeeding
• Male and female patients of childbearing potential (during and for 3 months following treatment)
• Severe renal impairment (CrCl<20ml/min)
• Moderate to severe hepatic impairment
• Elderly
• Platelet count is <25,000/µl or, in the case of combination with melphalan and prednisone when the platelet count is ≤30,000/µl
• Moderate to severe thrombocytopenia
• Risk factors for neutropenia
• Carriers of hepatitis B and patients with a history of hepatitis B
• Risk factors or history of seizures
• Epilepsy
• Diabetic neuropathy
• Amyloidotic neuropathy
• Dehydration
• Risk factors for or existing cardiac disease
• Patients at risk of tumour lysis syndrome
  - High tumour burden
• Patients with a history of syncope
• Existing QT-interval prolongation
• History of serum-sickness-type reaction
• Polyarthritis with rash
• Proliferative glomerulonephritis
• Coadministration  with potent CYP3A4 inhibitors
• Coadministration with CYP3A4 or CYP2C19 substrates
• Coadministration with oral hypoglycaemic agents
• May impair ability to drive and operate machinery

Forms avail. in SA and covered in this monograph: inj, poi

Dosages below include:

• South African registered indications and dosages

South African registered indications and dosages

Used for the treatment of

Multiple myeloma
- Progressive multiple myeloma in patients who have received at least 1 prior therapy and who have already undergone or are unsuitable for haematopoietic stem cell transplantation as monotherapy or in combination with pegylated liposomal doxorubicin or dexamethasone
- Induction treatment of patients with previously untreated multiple myeloma who are eligible for high dose chemotherapy with haematopoietic stem cell transplantation in combination with dexamethasone, or with dexamethasone and thalidomide
- Treatment of patients with previously untreated multiple myeloma who are not eligible for high-dose chemotherapy with haematopoietic stem cell transplantation in combination with melphalan and prednisone
Mantle cell lymphoma
- 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
- Treatment for newly diagnosed mantle cell lymphoma (MCL) in adults, in combination with rituximab, cyclophosphamide, doxorubicin and prednisone who are unsuitable for haematopoietic stem cell transplantation

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Bortezomib is for intravenous and subcutaneous use only and should not be given by other routes (consult product specific information). Intrathecal administration has resulted in death

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Bortezomib retreatment may be considered for multiple myeloma patients who had previously responded to treatment with bortezomib

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Consult specialist for dosages and regimens (including dose modifications during the management of adverse reactions)

Not established for use in children and adolescents

Pregnancy

South African recommendations

• Caution
• Safety in pregnancy has not been established
• If bortezomib is used during pregnancy, alone or in combination with other medicines, or if the patient becomes pregnant while receiving bortezomib, the patient needs to be informed of the potential hazards to the foetus
• Males and females of childbearing capacity must use effective contraceptive measures during treatment and for 3 months following bortezomib therapy

Recommendations in other jurisdictions

• Caution; not recommended
• No clinical data are available for bortezomib with regard to exposure during pregnancy and 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
• Refer to the professional information of thalidomide for additional information
• Male and female patients of childbearing potential must use effective contraceptive measures during and for 3 months following treatment

Breastfeeding

South African recommendations

• Caution; not recommended
• Safety in lactation has not been established
• It is not known whether bortezomib is excreted in human milk
• Because of the potential for serious undesirable effects in breastfed infants from mothers on bortezomib, women should not breastfeed their infants while receiving bortezomib

Recommendations in other jurisdictions

• Caution; not recommended
• It is not known whether bortezomib is excreted in human milk
• Because of the potential for serious adverse reactions in breastfed infants, breastfeeding should be discontinued during treatment with bortezomib

Fertility

• Fertility studies were not conducted with bortezomib
• Fertility studies were not performed but evaluation of reproductive tissues has been performed in the general toxicity studies. In the 6-month rat study, degenerative effects in both the testes and the ovary have been observed
• It is, therefore, likely that bortezomib could have a potential effect on either male or female fertility. Peri- and postnatal development studies were not conducted

Renal Impairment

• Mild to moderate (CrCl>20ml/min): No dose adjustment recommended
• Severe (CrCl<20ml/min): Caution; no information available
  It is unknown if the pharmacokinetics of bortezomib are influenced in patients with severe renal impairment not undergoing dialysis
  Since dialysis may reduce bortezomib concentrations, bortezomib should be administered after the dialysis procedure

Hepatic Impairment

• Mild: No dose adjustment recommended
• Moderate to severe: Caution; dose adjustment recommended
  A lower starting dose is recommended in patients with moderate or severe hepatic impairment, and those patients should be closely monitored

Grade of hepatic impairment	Bilirubin level	Modification of starting dose
Mild	≤1.0 x ULN SGOT (AST) level: >ULN	No adjustment recommended
	>1.0 x-1.5x ULN SGOT (AST) level: Any	No adjustment recommended
Moderate	>1.5 x-3x ULN SGOT (AST) level: Any	Reduce bortezomib to 0.7mg/m2 in the first treatment cycle Consider dose escalation to 1.0mg/m2 or further dose reduction to 0.5mg/m2 in subsequent cycles based on patient tolerability
Severe	>3 x ULN SGOT (AST) level: Any

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

Elderly

• Caution; no dose adjustment recommended

Porphyria Information 

• Possibly porphyrinogenic (PSP)

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Mood disorders
• Anxiety disorder
• Sleep disorders
• Mental disorder
• Hallucination
• Psychotic disorder
• Confusion
• Restlessness
• Suicidal ideation
• Adjustment disorder
• Delirium
• Decreased libido
• Neuropathies
• Peripheral sensory neuropathy
• Dysaesthesia
• Neuralgia
• Motor neuropathy
• Loss of consciousness
  - Syncope
• Dizziness
• Dysgeusia
• Lethargy
• Headache
• Tremor
• Peripheral sensorimotor neuropathy
• Dyskinesia
• Cerebellar coordination and balance disturbances
• Memory loss (excluding dementia)
• Encephalopathy
• Posterior reversible encephalopathy syndrome
• Neurotoxicity
• Seizure disorders
• Post herpetic neuralgia
• Speech disorder
• Restless legs syndrome
• Migraine
• Sciatica
• Disturbance in attention
• Abnormal reflexes
• Parosmia
• Cerebral haemorrhage
• Intracranial haemorrhage
  - Including subarachnoid 
• Brain oedema
• Transient ischaemic attack
• Coma
• Autonomic nervous system imbalance
• Autonomic neuropathy
• Cranial palsy
• Paralysis
• Paresis
• Presyncope
• Brain stem syndrome
• Cerebrovascular disorder
• Nerve root lesion
• Psychomotor hyperactivity
• Spinal cord compression
• Cognitive disorder NOS
• Motor dysfunctionx
• Nervous system disorder NOS
• Radiculitis
• Drooling
• Hypotonia
• Guillian Barré syndrome
• Demyelinating polyneuropathy
• Fatigue
• Irritability
• Meningitis
  - Including bacterial
• Meningoencephalitis herpetic

Cardiovascular Disorders

• Hypotension
• Orthostatic hypotension
• Hypertension
• Cerebrovascular accident
• Deep vein thrombosis
• Haemorrhage
• Thrombophlebitis
  - Including superficial
• Circulatory collapse
  - Including hypovolaemic shock
• Phlebitis
• Flushing
• Haematoma
  - Including perirenal
• Poor peripheral circulation
• Vasculitis
• Hyperaemia
  - Including ocular
• Peripheral embolism
• Lymphoedema
• Pallor
• Erythromelalgia
• Vasodilatation
• Vein discolouration
• Venous insufficiency
• Cardiac tamponade
• Cardio-pulmonary arrest
• Cardiac fibrillation
  - Including atrial
• Cardiac failure
  - Left ventricular
  - Right ventricular
• Arrhythmia
• Tachycardia
• Palpitations
• Angina pectoris
• Pericarditis
  - Including pericardial
• Cardiomyopathy
• Ventricular dysfunction
• Bradycardia
• Atrial flutter
• Myocardial infarction
• Atrioventricular block
• Cardiogenic shock
• Torsade de pointes
• Unstable angin
• Cardiac valve disorders
• Coronary artery insufficiency
• Sinus arrest
• Contusion
• Abnormal electrocardiogram
  - QA prolongation
• Increased troponin I
• Chest pain
• Chest discomfort

Respiratory Disorders

• Dyspnoea
• Epistaxis
• Respiratory tract infection
• Cough
• Pulmonary embolism
• Pleural effusion
• Pulmonary oedema
  - Including acute
• Pulmonary alveolar haemorrhage
• Bronchospasm
• Chronic obstructive pulmonary disease
• Hypoxaemia
• Respiratory tract congestion
• Hypoxia
• Pleurisy
• Hiccups
• Rhinorrhoea
• Dysphonia
• Wheezing
• Respiratory failure
• Acute respiratory distress syndrome
• Apnoea
• Pneumothorax
• Atelectasis
• Pulmonary hypertension
• Haemoptysis
• Hyperventilation
• Orthopnoea
• Pneumonitis
• Respiratory alkalosis
• Tachypnoea
• Pulmonary fibrosis
• Bronchial disorder
• Hypocapnia
• Interstitial lung disease
• Lung infiltration
• Throat tightness
• Dry throat
• Increased upper airway secretion
• Throat irritation
• Upper-airway cough syndrome
• Pneumonia
• Bronchopneumonia
• Tonsillitis
• Mastoiditis

Gastrointestinal Disorders

• Nausea and vomiting
• Diarrhoea
• Constipation
• Gastrointestinal haemorrhage
  - Including mucosal
• Dyspepsia
• Stomatitis
• Abdominal distension
• Oropharyngeal pain
• Abdominal pain
  - Including gastrointestinal and splenic pain
• Oral disorder
• Flatulence
• Pancreatitis
  - Including chronic
• Haematemesis
• Lip swelling
• Gastrointestinal obstruction
  - Small intestinal  obstruction
  - Ileus
• Abdominal discomfort
• Oral ulceration
• Enteritis
• Gastritis
• Gingival bleeding
• Gastrooesophageal reflux disease
• Colitis
  - Including clostridium difficile
• Ischaemic colitis
• Gastrointestinal inflammation
• Dysphagia
• Irritable bowel syndrome
• Gastrointestinal disorder NOS
• Gastrointestinal motility disorder
• Coated tongue
• Salivary gland disorder
• Acute pancreatitis
• 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
• Decreased gastric pH
• Hernia
  - Hiatus
• Gastrointestinal malformation
• Tooth infection

Hepatobiliary Disorders

• Hepatic enzyme abnormality
• Hepatotoxicity
  - Hepatic disorder
• Hepatitis
• Cholestasis
• Hepatic failure
• Hepatomegaly
• Budd-Chiari syndrome
• Cytomegalovirus hepatitis
• Hepatic haemorrhage
• Cholelithiasis
• Hyperbilirubinaemia

Genitourinary Disorders

• Renal impairment
• Acute renal failure
• Chronic renal failure
• Urinary tract infection
• Haematuria
• Urinary retention
• Micturition disorder
• Proteinuria
• Azotaemia
• Oliguria
• Pollakiuria
• Bladder irritation
• Vaginal haemorrhage
• Genital pain
• Erectile dysfunction
• Testicular disorder
• Prostatitis
• Femal breast disorder
• Epididymal tenderness
• Epididymitis
• Pelvic pain
• Vulval ulceration
• Abnormal urine analysis
• Catheter site pain
• Genital herpes
• Catheter-related complication

Endocrine and Metabolic Disorders

• Cushing's syndrome
• Hyperthyroidism
• Inappropriate antidiuretic hormone secretion
• Hypothyroidism
• Decreased appetite
• Dehydration
• Hypokalaemia
• Hyponatraemia
• Abnormal blood glucose
• Hypocalcaemia
• Enzyme abnormality
• Tumour lysis syndrome
• Failure to thrive
• Hypomagnesaemia
• Hypophosphataemia
• Hyperkalaemia
• Hypercalcaemia
• Hypernatraemia
• Abnormal uric acid
• 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
• Decreased weight
• Abnormal protein analyse
• Increased weight
• Abnormal blood test
• Increased C-reactive protein
• Abnormal blood gases
• Change in thirst
• Feeling of body temperature change

Musculoskeletal Disorders

• Musculoskeletal pain
• Muscle spasms
• Pain in extremity
• Muscular weakness
• 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
• Fall
• Fractures
• Joint injury
• Gait disturbance

Skin and Subcutaneous Tissue Disorders

• Rash
• Pruritus
• Erythema
• Dry skin
• 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
• Subcutaneous haemorrhage
• Livedo reticularis
• Skin induration
• Papule
• Photosensitivity reaction
• Seborrhoea
• Cold sweat
• Skin disorder
• Erythrosis
• Skin ulcer
• Nail disorder
• Burns
• Laceration
• Procedural pain
• Radiation injuries
• Cellulitis
• Device related infection
• Skin infection
• Injection site reaction
• Mucosal disorder
• Injection site pain
• Injection site haemorrhage
• Injection site phlebitis
• Face oedema
• Ichthyosis
• Face injury

Immune, Blood and Lymphatic System Disorders

• Malignant neoplasm
• Plasmacytic leukaemia
• Renal cell carcinoma
• Mass
• Mycosis fungoides
• Benign neoplasm
• Thrombocytopenia
• Neutropenia
• Anaemia
• Leukopenia
• Lymphopenia
• Pancytopenia
• Febrile neutropenia
• Coagulopathy
• Leukocytosis
• Lymphadenopathy
• Haemolytic anaemia
• Disseminated intravascular coagulation
• Thrombocytosis
• Hyperviscosity syndrome
• Platelet disorder
• Thrombocytopenic purpura
  - Thrombocytopenia purpura
• Blood disorder
• Haemorrhagic diathesis
• Lymphocytic infiltration
• Angioedema
• Hypersensitivity
• Anaphylactic shock
• Amyloidosis
• Type III immune complex mediated reaction
• Macrophage activation
• Herpes zoster
  - Disseminated
  - Ophthalmic
• Herpes simplex
• Fungal infection
• Infection
• Bacterial infections
• Viral infections
• Sepsis
  - Septic shock
• Transfusion reaction
• Rigors
• Pyrexia
• Herpes virus infection
• Bacteraemia
  - Including staphylococcal
• Hordeolum
• Influenza
• Epstein-Barr virus infection
• Post viral fatigue syndrome
• Staphylococcal infection
• Impaired healing
• Inflammation
• Oedema
  - Including peripheral
• Extravasation
• Abnormal international normalised ratio
• Increased platelet aggregation

Sensory Disorders

• Eye swelling
• Abnormal vision
• Conjunctivitis
• Eye haemorrhage
• Eyelid infection
• Chalazion
• Blepharitis
• Eye inflammation
• Diplopia
• Dry eye
• Eye irritation
• Eye pain
• Increased lacrimation
• Eye discharge
• Corneal lesion
• Exophthalmos
• Retinitis
• Scotoma
• Eye disorder
• Acquired dacryoadenitis
• Photophobia
• Photopsia
• Optic neuropathy
• Different degrees of visual impairment
• Vertigo
• Dysacusis
• Impaired hearing
  - Including deafness
• Ear discomfort
• Ear haemorrhage
• Vestibular neuronitis
• Ear disorder
• Ear infection
• Sensation of a foreign body

Others

• Non-cardiac chest pain
• Death
  - Including sudden
• Multi-organ failure
• General physical health deterioration
• Aplasia
• Chills/ Feeling cold
• Pain
• Tenderness
• Ulcer

• Potent CYP3A4 inhibitors
• Ketoconazole
• Ritonavir
• Oral hypoglycaemics
• Strong CYP3A4 inducer
• Rifampicin
• Carbamazepine
• Phenytoin
• Phenobarbital

Other interactions

• St. John's wort

• Full blood count with differential and platelets
• Renal function
• Chest x-ray

Specific cases may require

• Pulmonary function
• Hepatic function
• Pregnancy status
• Blood glucose
• Hepatitis B virus (HBV) screening
  - Hepatitis B surface antigen
  - Hepatitis B core antibody
  - Total Ig or IgG
  - Antibody to hepatitis B surface antigen

Additional observations

• Signs and symptoms of
  - Peripheral neuropathy
  - Dehydration
  - Hypotension
  - Posterior reversible encephalopathy syndrome
  - Progressive multifocal leukoencephalopathy
  - Constipation
  - Infection

Bortezomib is a proteasome inhibitor. It is specifically designed to inhibit the chymotrypsin-like activity of the 26S proteasome in mammalian cells. The 26S proteasome is a large protein complex that degrades ubiquitinated proteins. The ubiquitin-proteasome pathway plays an essential role in regulating the turnover of specific proteins, thereby maintaining homeostasis within cells. Inhibition of the 26S proteasome prevents this targeted proteolysis and affects multiple signalling cascades within the cell, ultimately resulting in cancer cell death. Bortezomib is highly selective for the proteasome. 

Bortezomib mediated proteasome inhibition affects cancer cells in a number of ways, including, but not limited to, altering regulatory proteins, which control cell cycle progression and nuclear factor kappa B (NF-kB) activation. Inhibition of the proteasome results in cell cycle arrest and apoptosis. NF-kB is a transcription factor whose activation is required for many aspects of tumourigenesis, including cell growth and survival, angiogenesis, cell-cell interactions, and metastasis. In myeloma, bortezomib affects the ability of myeloma cells to interact with the bone marrow microenvironment.

Experiments have demonstrated that bortezomib is cytotoxic to a variety of cancer cell types and that cancer cells are more sensitive to the pro-apoptotic effects of proteasome inhibition than normal cells. Bortezomib causes reduction of tumour growth in vivo in many preclinical tumour models, including multiple myeloma. Data from in vitro, ex-vivo, and animal models with bortezomib suggest that it increases osteoblast differentiation and activity and inhibits osteoclast function. These effects have been observed in patients with multiple myeloma affected by an advanced osteolytic disease and treated with bortezomib.

Injection (per ml) 1mg

• Velcade (Janssen) originator
• Valtib (Accord)

Injection (per ml) 3.5mg

• Bortiv (Hetero Drugs SA)
• Bertred (Dr Reddy)
• Bortrac (Glenmark)
• Botigen 3.5 (Ranbaxy Pharmaceuticals)
• Miblex (Eurolab)
• Onbort (Hetero Drugs SA)
• Valoma 3.5 (Curanto Pharma)
• Velcade (Janssen) originator
• Velzomy (Teva Pharmaceuticals)