Imatinib

Registered South African indications:

• Chronic myeloid leukaemia
• Acute lymphoblastic leukaemia 
• Myelodysplastic/ myeloproliferative diseases
• Hypereosinophilic syndrome/ chronic eosinophilic leukaemia
• Dermatofibrosarcoma protuberans 
• Metastatic malignant gastrointestinal stromal tumours
• Adjuvant treatment of adult patients following resection of Kit-positive GIST
• Systemic mastocytosis

Registered South African contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Pregnancy
• Breastfeeding

• Renal impairment
• Hepatic impairment
• Elderly
• Children
• Thyroidectomy patients undergoing levothyroxine replacement
• Reactivation of hepatitis B
• Cardiac dysfunction
• Severe fluid retention
• Risk factors for cardiac failure
• Dehydration
• Gastrointestinal haemorrhage
• History of tumour lysis syndrome
• Neutropaenia
• History of drug-induced phototoxicity
• High uric acid levels
• Chronic carriers of hepatitis B
• Exposure to direct sunlight
• May affect ability to drive and operate machinery

Forms avail. in SA and covered in this monograph: tab, cap

Used for the treatment of

• Chronic myeloid leukaemia
• Acute lymphoblastic leukaemia
• Myelodysplastic/ myeloproliferative diseases
• Hypereosinophilic syndrome/ chronic eosinophilic leukaemia
• Dermatofibrosarcoma protuberans 
• Metastatic malignant gastrointestinal stromal tumours
• Adjuvant treatment of adult patients following resection of Kit-positive GIST
• Systemic mastocytosis

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Consult specialist for dosages and regimens

Paed. forms avail. in SA and covered in this monograph: cap, tab

Used for the treatment of

• Chronic myeloid leukaemia (CML) 
• Philadelphia chromosome positive acute lymphoblastic leukaemia (Ph+ ALL)

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Consult specialist for dosages and regimens

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There is no experience with the use of imatinib in children with CML below 2 years of age and with Ph+ ALL below 1 year of age. There is very limited experience with the use of imatinib in children in other indications

Pregnancy

South African recommendations

• Contraindicated
• Imatinib is contraindicated in pregnancy
• Imatinib can cause foetal harm when administered to a pregnant woman based on findings from animal reproduction studies
• Reproductive studies in rats have demonstrated that imatinib mesylate induced teratogenicity (increased incidence of congenital abnormalities) following prenatal exposure to imatinib mesylate at doses equal to the highest recommended human dose of 800mg/day based on body surface area
• There have been post-marketing reports of spontaneous abortions and infant congenital anomalies from women who have taken imatinib during pregnancy. Imatinib should therefore not be used during pregnancy

Breastfeeding

South African recommendations

• Contraindicated
• Imatinib is contraindicated in lactation
• Both imatinib and its active metabolite are transferred into human milk
• The effects of low-dose exposure of the infant to imatinib are unknown
• Because of the potential for serious adverse drug reactions in the breastfed child, breastfeeding is not recommended during treatment and for at least 15 days after stopping treatment with imatinib

Fertility

South African recommendations

• Women of childbearing potential must be advised to use highly effective contraception (methods that result in less than 1% pregnancy rates) such as use of oral, injected or implanted hormonal methods of contraception or placement of an intrauterine device (IUD) during treatment with imatinib and for at least 15 days after stopping treatment with imatinib
• Human studies on male patients receiving imatinib and its effect on male fertility and spermatogenesis have not been performed
• Males using imatinib should use barrier contraceptives (condoms) for at least 15 days after stopping treatment with imatinib
• Fertility was not affected in the preclinical fertility and early embryonic development study although lower testes and epididymal weights as well as a reduced number of motile sperm were observed in the high dose males rats
• In pre- and postnatal study in rats, fertility in the first generation offspring was also not affected by imatinib

• Caution; no dose adjustment recommended
  Minimum recommended dose to be used. Reduce if not tolerated

• Caution; dose adjustment recommended 
  Minimum recommended dose to be used. Reduce if not tolerated

• Caution; no dose adjustment recommended

Central Nervous System Disorders

• Insomnia
• Depression
• Decreased libido
• Anxiety
• Confusional state
• Headache
• Dizziness  
• Paraesthesia  
• Hypoaesthesia  
• Migraine
• Somnolence
• Syncope
• Peripheral neuropathy
• Memory impairment
• Sciatica
• Restless leg syndrome
• Tremor
• Cerebrovascular accident
• Transient ischaemic attack
• Ischaemic stroke
• Cerebral infarction
• Cerebral haemorrhage
• Increased intracranial pressure
• Convulsions
• Optic neuritis
• Cerebral oedema
• Malaise

Cardiovascular Disorders 

• Palpitations
• Tachycardia
• Cardiac failure congestive
• Pulmonary oedema
• Arrhythmia
• Atrial fibrillation
• Cardiac arrest
• Myocardial infarction
• Angina pectoris
• Pericardial effusion
• Pericarditis
• Cardiac tamponade
• Vascular disorders
• Flushing
• Haemorrhage
• Hypertension
• Haematoma
• Subdural haematoma
• Peripheral coldness
• Hypotension
• Raynaud's phenomenon
• Thrombosis
• Embolism

Respiratory Disorders

• Dyspnoea
• Epistaxis
• Cough
• Pleural effusion
• Pharyngolaryngeal pain
• Pharyngitis
• Pleuritic pain
• Pulmonary fibrosis
• Pulmonary hypertension
• Pulmonary haemorrhage
• Acute respiratory failure  
• Interstitial lung disease
• Nasopharyngitis
• Pneumonia
• Sinusitis
• Upper respiratory tract infection
• Influenza

Gastrointestinal Disorders

• Nausea and vomiting
• Diarrhoea
• Dyspepsia
• Abdominal pain
• Flatulence
• Abdominal distension
• Gastro-oesophageal reflux
• Constipation
• Dry mouth  
• Gastritis
• Stomatitis
• Mouth ulceration
• Gastrointestinal haemorrhage
• Eructation
• Melaena
• Oesophagitis
• Ascites
• Gastric ulcer
• Haematemesis
• Cheilitis
• Dysphagia
• Pancreatitis
• Colitis
• Ileus
• Inflammatory bowel disease
• Ileus
• Intestinal obstruction
• Gastrointestinal perforation
• Diverticulitis
• Gastric antral vascular ectasia
• Gastroenteritis

Hepatobiliary Disorders

• Increased hepatic enzymes
• Hyperbilirubinaemia
• Hepatitis
• Jaundice
• Hepatic failure
• Hepatic necrosis
• Hepatitis B reactivation

Genitourinary Disorders

• Renal pain
• Haematuria
• Renal failure
• Increased urinary frequency
• Renal failure chronic
• Increased blood creatinine
• Gynaecomastia
• Erectile dysfunction
• Menorrhagia
• Menstruation irregular
• Sexual dysfunction
• Nipple pain
• Breast enlargement
• Scrotal oedema
• Haemorrhagic corpus luteum/ ovarian cyst
• Urinary tract infection

Endocrine and Metabolic Disorders

• Anorexia
• Hypokalaemia
• Increased appetite
• Decreased appetite
• Dehydration
• Gout
• Hypophosphataemia
• Hyperuricaemia
• Hypercalcaemia
• Hyperglycaemia
• Hyponatraemia
• Hyperkalaemia
• Hypomagnesaemia

Musculoskeletal Disorders

• Muscle spasm and cramps
• Musculoskeletal pain, including myalgia
• Arthralgia
• Bone pain
• Joint swelling
• Joint and muscle stiffness
• Muscular weakness
• Arthritis
• Rhabdomyolysis/myopathy
• Avascular necrosis

Skin and Subcutaneous Tissue Disorders

• Periorbital oedema
• Dermatitis
• Pruritus
• Eczema
• Rash
• Face oedema
• Dry skin
• Erythema
• Alopecia
• Night sweats
• Photosensitivity reaction
• Contusion
• Sweating increased
• Urticaria
• Ecchymosis
• Increased tendency to bruise
• Hypotrichosis
• Skin hypopigmentation
• Dermatitis exfoliative
• Onychoclasis
• Folliculitis
• Petechiae
• Psoriasis
• Purpura
• Skin hyperpigmentation
• Bullous eruptions
• Acute febrile neutrophilic dermatosis
• Nail discolouration
• Angioneurotic oedema
• Erythema multiforme
• Leucocytoclastic vasculitis
• Stevens-Johnson syndrome
• Acute generalised exanthematous pustulosis (AGEP)
• Palmoplantar erythrodysesthesia syndrome
• Lichenoid keratosis
• Lichen planus
• Toxic epidermal necrolysis
• Drug rash with eosinophilia and systemic symptoms (DRESS)

Immune, Blood and Lymphatic System Disorders

• Anaphylactic shock
• Neutropenia
• Thrombocytopenia
• Anaemia
• Pancytopenia
• Febrile neutropenia
• Thrombocythaemia
• Lymphopenia
• Bone marrow depression
• Eosinophilia
• Lymphadenopathy
• Haemolytic anaemia
• Thrombotic microangiopathy
• Herpes zoster
• Herpes simplex
• Cellulitis
• Sepsis
• Fungal infection
• Tumour lysis syndrome
• Tumour haemorrhage
• Tumour necrosis
• Pyrexia
• Chills

Sensory Disorders

• Eyelid oedema
• Lacrimation increased
• Conjunctival haemorrhage
• Conjunctivitis
• Dry eye
• Blurred vision
• Eye irritation
• Eye pain
• Orbital oedema
• Scleral haemorrhage
• Retinal haemorrhage
• Blepharitis
• Macular oedema
• Cataract
• Glaucoma
• Papilloedema
• Vitreous haemorrhage
• Vertigo
• Tinnitus
• Hearing loss
• Taste disturbance

Others

• Fluid retention and oedema
• Anasarca
• Chest pain
• Pseudoporphyria
• Growth retardation in children
• Blood creatine phosphokinase increased
• Blood lactate dehydrogenase increased
• Blood alkaline phosphatase increased
• Blood amylase increased

• CYP3A4 inhibitors
• Protease inhibitors
• Indinavir
• Lopinavir
• Ritonavir
• Saquinavir
• Telaprevir
• Nelfinavir
• Boceprevir
• Azole antifungals
• Ketoconazole
• Itraconazole
• Posaconazole
• Voriconazole
• Macrolides
• Erythromycin
• Clarithromycin
• Telithromycin
• CYP3A4 inducers 
• Dexamethasone
• Phenytoin
• Carbamazepine
• Rifampicin
• Phenobarbital
• Fosphenytoin
• Primidone
• St. John's Wort (Hypericum perforatum)
• CYP3A4 substrates
• Cyclosporine
• Pimozide
• Tacrolimus
• Sirolimus
• Ergotamine
• Diergotamine
• Fentanyl
• Alfentanil
• Terfenadine
• Bortezomib
• Docetaxel
• Quinidine
• Triazolo-benzodiazepines
• Dihydropyridine
• Calcium channel blockers
• HMG-CoA reductase inhibitors
• Coumarin derivatives
• Warfarin
• CYP2D6 substrates
• Metoprolol
• Paracetamol 
• Levothyroxine
• Chemotherapy   
• L-asparaginase

• Full blood count

Specific cases may require

• Hepatic function
• Renal function
• Cardiac function
• Weight
• Growth (children)

Tablet 100mg - EML (Tertiary)

Tyrosine kinase inhibitors (TKI) and cerebrovascular adverse events safety concern

• TKI containing medicines may have different kinase inhibition profiles and/or off target binding profiles, with some TKIs approved for very similar indications and others approved for different indications
• Although many adverse events/side effects/toxicities could not be explained by a class related adverse event or a related off-target kinase inhibition effect, there is some evidence that the TKIs share to a variable degree, class related cerebrovascular adverse events
• The abovementioned cerebrovascular adverse events may occur in patients on treatment with TKI containing medicines with or without risk factors for these events and may occur at any time during treatment with TKIs
• Patients on treatment with TKI containing medicine should be carefully monitored, and relevant risk factors managed to reduce the risk for these class related cerebrovascular adverse events
• Treatment with TKI containing medicines should be discontinued, and alternative treatment options be considered in patients who develop these class related cerebrovascular adverse events

Imatinib is a protein-tyrosine kinase inhibitor that potently inhibits the activity of the Bcr-Abl tyrosine kinase, as well as several receptor tyrosine kinases; including Kit, the receptor for stem cell factor (SCF) coded for by the c-Kit protooncogene, the discoidin domain receptors (DDR1 and DDR2), the colony stimulating factor receptor (CSF-1R) and the platelet-derived growth factor receptors alpha and beta (PDGFR-alpha and PDGFR-beta). Imatinib can also inhibit cellular events mediated by activation of these receptor kinases.

Tablet 100mg 

• Gleevec (Novartis) originator
• Imatinib Accord 100mg (Accord Healthcare)
• Mivesta 100mg (Eurolab)
• Nuvitab 100 (Hetero Drug South Africa)
• Sunmatin 100 (Ranbaxy Pharmaceuticals)

Tablet 400mg 

• Gleevec (Novartis) originator
• Imatinib Accord 400mg (Accord)
• Mivesta 400mg (Eurolab)
• Nuvitab (Hetero Drug South Africa)
• Sunmatin 400 (Ranbaxy Pharmaceuticals)
• Vativio (Novartis)

Capsule 100mg

• Gleetib 100 (RX Medicals)
• Imavec (Cipla)
• Vativio (Novartis)

Capsule 400mg

• Gleetib 400 (RX Medicals)
• Imavec (Cipla)