Dasatinib

Registered South African indications:

• Philadelphia chromosome-positive (Ph+) chronic myeloid leukaemia (CML) in chronic phase
• Philadelphia chromosome-positive acute lymphoblastic leukaemia (Ph+ ALL) with resistance or intolerance to prior therapy
• Chronic, accelerated, or myeloid or lymphoid blast phase chronic myeloid leukaemia (CML) with resistance or intolerance to prior therapy

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients

Cautions

• Pregnancy
• Breastfeeding
• Males of reproductive potential
• Hepatic impairment
• Elderly
• Porphyria
• Children
• Uncontrolled or significant cardiovascular disease
• Pulmonary disease or risk factors thereof
• Cardiac disease or history/risk factors thereof
• Hypertension
• Hyperlipidaemia
• Diabetes
• Prior percutaneous coronary intervention
• Coronary artery disease
• QT prolongation or risk factors thereof
• Congenital long QT syndrome
• Hypokalaemia
• Hypomagnesaemia
• Chronic carriers of hepatitis B virus
• Pre-existing bleeding disorders
• Grade 3 or 4 thrombocytopaenia
• Galactose intolerance
• Total lactase deficiency
• Glucose-galactose malabsorption
• May impair ability to drive and operate machinery

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

Used for the treatment of

• Newly diagnosed Philadelphia chromosome-positive (Ph+) chronic myeloid leukaemia (CML) in chronic phase
• Philadelphia chromosome-positive acute lymphoblastic leukaemia (Ph+ ALL) and lymphoid blast CML with resistance or intolerance to prior therapy
• Chronic, accelerated, or myeloid or lymphoid blast phase chronic myeloid leukaemia (CML) with resistance or intolerance to prior therapy including imatinib

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Consult specialist for dosages and regimens

Not established for use in children below 18 years in South Africa

Used for the treatment of

• Newly diagnosed Philadelphia chromosome-positive (Ph+) chronic myeloid leukaemia (CML) in chronic phase (Ph+ CML-CP) or Ph+ CML-CP resistant or intolerant to prior therapy including imatinib
• Philadelphia chromosome-positive acute lymphoblastic leukaemia (Ph+ ALL) in combination with chemotherapy

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Consult specialist for dosages and regimens

Pregnancy

• Caution; positive evidence of risk
• Based on human experience, dasatinib is suspected to cause congenital malformations including neural tube defects, and harmful pharmacological effects on the foetus when administered during pregnancy. Studies in animals have shown reproductive toxicity
• Dasatinib should not be used during pregnancy unless the clinical condition of the woman requires treatment with dasatinib. If Dasatinib is used during pregnancy, the patient must be informed of the potential risk to the foetus
• Both sexually active men and women of childbearing potential should use effective methods of contraception during treatment

Breastfeeding

• Caution; not recommended
• There is insufficient/limited information on the excretion of dasatinib in human or animal breast milk. Physico-chemical and available pharmacodynamic/toxicological data on dasatinib point to excretion in breast milk and a risk to the suckling child cannot be excluded
• Breastfeeding should be stopped during treatment with dasatinib
   

Fertility

• In animal studies, the fertility of male and female rats was not affected by treatment with dasatinib. Counsel male patients of appropriate age about possible effects of dasatinib on fertility and this counselling may include consideration of semen deposition

Renal Impairment

• No dose adjustment recommended

Hepatic Impairment

• Caution; no dose adjustment recommended

Elderly

• Caution; no dose adjustment recommended

Porphyria Information

• Possibly porphyrinogenic (PSP)

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Depression
• Insomnia
• Anxiety
• Confusional state
• Affect lability
• Decreased libido
• Headache
• Neuropathy (including peripheral neuropathy)
• Dizziness
• Dysgeusia
• Somnolence
• Central nervous system bleeding
  - Haemorrhage
  - Cerebral hematoma
  - Cerebral haemorrhage
  - Extradural hematoma
  - Haemorrhage intracranial
  - Haemorrhagic stroke
  - Subarachnoid haemorrhage
  - Subdural hematoma
  - Subdural haemorrhage
• Syncope
• Tremor
• Amnesia
• Balance disorder
• Cerebrovascular accident
• Transient ischaemic attack
• Cerebral infarction
• Ischaemic stroke
• Seizures
• Optic neuritis 
• VIIth nerve paralysis
• Dementia
• Ataxia
• Fatigue

Cardiovascular Disorders

• Congestive cardiac failure
• Cardiac dysfunction
  - Increased brain natriuretic peptide ventricular dysfunction
  - Left ventricular dysfunction
  - Right ventricular dysfunction
  - Cardiac failure (acute, congestive, chronic)
  - Cardiomyopathy
  - Congestive cardiomyopathy
  - Diastolic dysfunction
  - Decreased ejection fraction
  - Ventricular failure (including left and right)
  - Ventricular hypokinesia
• Pericardial effusion
• Arrhythmia (including tachycardia)
• Palpitations
• Myocardial infarction (including fatal outcome)
• QT prolongation
• Pericarditis
• Ventricular arrhythmia 
• Angina pectoris
• Cardiomegaly
• Abnormal ECG T-wave 
• Increased troponin 
• Cor pulmonale 
• Myocarditis 
• Acute coronary syndrome 
• Cardiac arrest 
• PR prolongation 
• Coronary artery disease 
• Pleuropericarditis 
• Atrial fibrillation 
• Atrial flutter 
• Haemorrhage 
• Hypertension 
• Hypotension 
• Thrombophlebitis 
• Deep vein thrombosis 
• Embolism 
• Thrombotic microangiopathy 
• Peripheral oedema
  - Gravitational oedema
  - Localised oedema
• Superficial oedema
• Chest pain
• Generalised oedema
  - Fluid overload
  - Fluid retention
  - Gastrointestinal oedema
  - Peripheral swelling oedema
  - Oedema due to cardiac disease
  - Perinephric effusion
  - Post procedural oedema
  - Visceral oedema

Respiratory Disorders

• Pleural effusion 
• Dyspnoea 
• Pulmonary oedema 
• Pulmonary hypertension 
• Lung infiltration 
• Pneumonitis 
• Cough 
• Pulmonary arterial hypertension 
• Bronchospasm 
• Asthma 
• Pulmonary embolism 
• Acute respiratory distress syndrome 
• Interstitial lung disease 

Gastrointestinal Disorders

• Diarrhoea 
• Nausea and vomiting 
• Abdominal pain 
• Gastrointestinal bleeding 
• Colitis (including neutropenic colitis) 
• Gastritis 
• Mucosal inflammation 
  - Mucositis 
  - Stomatitis 
• Dyspepsia 
• Abdominal distension 
• Constipation 
• Oral soft tissue disorder 
• Pancreatitis (including acute pancreatitis) 
• Upper gastrointestinal ulcer 
• Oesophagitis 
• Ascites 
• Anal fissure 
• Dysphagia 
• Gastroesophageal reflux disease 
• Protein-losing gastroenteropathy 
• Ileus 
• Anal fistula 
• Fatal gastrointestinal haemorrhage 

Hepatobiliary Disorders

• Hepatitis 
• Hepatitis B reactivation 
• Cholecystitis 
• Cholestasis
• Increased gamma-glutamyltransferase

Genitourinary Disorders

• Renal impairment (including renal failure)
• Urinary frequency 
• Proteinuria 
• Nephrotic syndrome 
• Abortion 
• Gynecomastia 
• Menstrual disorder
• Increased blood creatine phosphokinase
• Superficial oedema
  - Genital swelling
  - Genital oedema
  - Penile oedema
  - Penile swelling
  - Scrotal oedema
  - Skin swelling
  - Testicular swelling
  - Vulvovaginal swelling

Endocrine and Metabolic Disorders

• Hypothyroidism
• Hyperthyroidism
• Thyroiditis
• Appetite disturbances
  - Decreased  appetite
  - Early satiety
  - Increased appetite
• Hyperuricaemia
• Tumour lysis syndrome
• Dehydration
• Hypoalbuminemia
• Hypercholesterolemia
• Diabetes mellitus
• Decreased weight
• Increased weight

Musculoskeletal Disorders

• Musculoskeletal pain 
• Arthralgia 
• Myalgia 
• Muscular weakness 
• Musculoskeletal stiffness 
• Muscle spasm 
• Rhabdomyolysis 
• Osteonecrosis 
• Muscle inflammation 
• Tendonitis 
• Arthritis
• Epiphyses delayed fusion (paediatrics)
• Growth retardation (paediatrics)
• Gait disturbance

Skin and Subcutaneous Tissue Disorders

• Skin rash
  - Drug eruption
  - Erythema
  - Erythema multiforme
  - Erythrosis
  - Exfoliative rash
  - Generalised erythema
  - Genital rash
  - Heat rash
  - Milia
  - Miliaria
  - Pustular psoriasis
  - Rash
  - Erythematous rash
  - Follicular rash
  - Generalised rash
  - Macular rash
  - Maculopapular rash 
  - Papular rash
  - Pruritic rash
  - Pustular rash 
  - Vesicular rash
  - Skin exfoliation
  - Skin irritation
  - Toxic skin eruption
  - Urticaria vesiculosa
  - Vasculitic rash
• Alopecia
• Dermatitis (including eczema)
• Pruritus
• Acne
• Dry skin
• Urticaria
• Hyperhidrosis
• Neutrophilic dermatosis
• Photosensitivity
• Pigmentation disorder
• Panniculitis
• Skin ulcer
• Bullous conditions
• Nail disorder
• Palmar-plantar erythrodysesthesia syndrome
• Hair disorder
• Leukocytoclastic vasculitis
• Skin fibrosis
• Stevens-Johnson syndrome
• Face oedema
  - Conjunctival oedema
  - Eye oedema
  - Eye swelling
  - Eyelid oedema
  - Lip oedema
  - Macular oedema
  - Mouth oedema
  - Orbital oedema
  - Periorbital oedema
  - Swelling face
• Contusion
• Livedo reticularis
• Flushing 

Immune, Blood and Lymphatic System Disorders

• Infection (bacterial, viral, fungal, non-specified)
• Pneumonia (including bacterial, viral, and fungal)
• Upper respiratory tract infection/inflammation
• Herpes virus infection (including cytomegalovirus - CMV)
• Enterocolitis infection
• Sepsis (including uncommon cases with fatal outcomes)
• Myelosuppression
• Anaemia
• Neutropaenia
• Thrombocytopaenia
• Febrile neutropaenia
• Lymphadenopathy
• Lymphopaenia
• Aplasia pure red cell
• Hypersensitivity (including erythema nodosum)
• Anaphylactic shock
• Fever
• Chills

Sensory Disorders

• Visual disorder
  - Visual disturbance
  - Blurred vision
  - Reduced visual acuity
• Dry eye
• Visual impairment
• Conjunctivitis
• Photophobia
• Increased lacrimation 
• Tinnitus
• Hearing loss
• Vertigo

Others

• Incision site oedema

• Potent CYP3A4 inhibitors
• Ketoconazole
• Itraconazole
• Erythromycin
• Clarithromycin
• Ritonavir
• Telithromycin
• Grapefruit juice
• CYP3A4 inducers
• Dexamethasone
• Phenytoin
• Carbamazepine
• Rifampicin
• Phenobarbital
• St. John's Wort (Hypericum perforatum)
• CYP3A4 substrates
• Astemizole
• Terfenadine
• Cisapride
• Pimozide
• Quinidine
• Bepridil
• Ergot alkaloids (ergotamine, dihydroergotamine)
• CYP2C8 substrates
• Glitazones
• H2-receptor antagonists
• Famotidine
• Proton pump inhibitors
• Omeprazole
• Antacids
• Aluminium hydroxide/magnesium hydroxide
• Antiplatelets
• Anticoagulants
• Anti-arrhythmics
• Agents that lead to QT prolongation
• Anthracyclines (high dose)

• Full blood count with differential
• Electrolytes
• Hepatic function
• Blood pressure
• Thyroid function

Specific cases may require

• ECG
• Bone marrow biopsy
• Chest X-ray

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

Dasatinib inhibits the activity of the BCR-ABL kinase and SRC family kinases along with a number of other selected oncogenic kinases including c-KIT, ephrin (EPH) receptor kinases, and PDGFβ receptor. Dasatinib is a potent, subnanomolar inhibitor of the BCR-ABL kinase with potency at a concentration of 0.6-0.8 nM. It binds to both the inactive and active conformations of the BCR-ABL enzyme. In vitro, dasatinib is active in leukaemic cell lines representing variants of imatinib-sensitive and resistant disease. These non-clinical studies show that dasatinib can overcome imatinib resistance resulting from BCR-ABL overexpression, BCR-ABL kinase domain mutations, activation of alternate signalling pathways involving the SRC family kinases (LYN, HCK), and multidrug resistance gene overexpression. In vivo, dasatinib prevented the progression of chronic CML to blast phase and prolonged the survival of mice bearing patient-derived CML cell lines grown at various sites, including the central nervous system.

Tablet 20mg

• Sprycel (Bristol Myers Squibb) originator

Tablet 50mg

• Sprycel (Bristol Myers Squibb) originator

Tablet 70mg

• Sprycel (Bristol Myers Squibb) originator

Tablet 100mg

• Sprycel (Bristol Myers Squibb) originator