Axitinib

Registered South African indications:

• Advanced renal cell carcinoma with a clear cell component or advanced papillary cell renal carcinoma
  - After failure of previous systemic therapy and total nephrectomy of the involved kidney

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients

Cautions

• Pregnancy
• Breastfeeding
• Men and women of childbearing potential
• Severe renal impairment (CrCl <15ml/ml)
• Moderate to severe hepatic impairment (Child-Pugh Classes B&C)
• Hypertension
• Thyroid dysfunction
• Risk of or history of arterial embolic and thrombotic events
  - Transient ischemic attack
  - Myocardial infarction
  - Cerebrovascular accident
  - Retinal artery occlusion
  - Patients who had an arterial embolic or thrombotic event within the previous 12 months
• Risk of or history of venous embolic and thrombotic events
  - Pulmonary embolism
  - Deep vein thrombosis
  - Retinal vein occlusion/thrombosis
  - Patients who had a venous embolic or thrombotic event within the previous 6 months
• Untreated brain metastasis
• Recent active gastrointestinal bleeding
• Risk factors for aneurysms or artery dissections
  - Hypertension
  - History of aneurysms
• Surgery within 24 hours of treatment (see additional prescribing points)
• Proteinuria
• 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

• Advanced renal cell carcinoma
  - After failure of prior treatment with sunitinib or a cytokine
  - With a clear cell component or advanced papillary cell renal carcinoma, after failure of previous systemic therapy and total nephrectomy of the involved kidney

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Consult specialist for dosages and regimens

Not established for use in children below 18 years

Pregnancy

• Caution
• There are no data regarding the use of axitinib in pregnant women. Based on the pharmacological properties of axitinib, it may cause foetal harm when administered to a pregnant woman. Studies in animals have shown reproductive toxicity including malformations
• Axitinib should not be used during pregnancy unless the clinical condition of the woman requires treatment with this medicinal product
• Women of childbearing potential must use effective contraception during and up to 1 week after treatment

Breastfeeding

• Caution; not recommended
• It is unknown whether axitinib is excreted in human milk. A risk to the breastfeeding child cannot be excluded. Axitinib should not be used during breastfeeding

Fertility

• Based on non-clinical findings, axitinib has the potential to impair reproductive function and fertility in humans

Renal Impairment

• CrCl ≥15ml/min: No dose adjustment is recommended
• CrCl <15ml/min: Caution; no information available

Hepatic Impairment

• Mild (Child-Pugh Class A): No dose adjustment recommended
• Moderate (Child-Pugh Class B): Caution; dose adjustment recommended
• Severe (Child-Pugh Class C): Caution; no information available
  Axitinib has not been studied in these patients and should not be used in this population

Elderly

• No dose adjustment is recommended

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Headache
• Dizziness
• Posterior reversible encephalopathy syndrome
  - Headache
  - Seizure
  - Lethargy
  - Confusion
  - Blindness
  - Other visual and neurologic disturbances
  - Mild to severe hypertension
• Leukoencephalopathy
• Fatigue

Cardiovascular Disorders

• Cardiac failure events
  - Cardiac failure
  - Congestive cardiac failure
  - Cardiopulmonary failure
  - Decreased ejection fraction
  - Left ventricular dysfunction
  - Right ventricular failure
• Hypertension (including severe or persistent hypertension)
• Accelerated hypertension
• Increased blood pressure
• Hypertensive crisis
• Haemorrhage
  - Prolonged activated partial thromboplastin time
  - Anal haemorrhage
  - Arterial haemorrhage
  - Blood urine
  - Central nervous system haemorrhage
  - Cerebral haemorrhage
  - Prolonged coagulation time
  - Conjunctival haemorrhage
  - Contusion
  - Haemorrhagic diarrhoea
  - Dysfunctional uterine bleeding
  - Epistaxis
  - Gastric haemorrhage
  - Gastrointestinal haemorrhage
  - Gingival bleeding
  - Haematemesis
  - Haematochezia
  - Decreased haematocrit
  - Haematoma
  - Haematuria
  - Decreased haemoglobin
  - Haemoptysis
  - Coronary artery haemorrhage
  - Urinary tract haemorrhage
  - Haemorrhoidal haemorrhage
  - Haemostasis
  - Increased tendency to bruise
  - Increased International Normalized Ratio
  - Lower gastrointestinal haemorrhage
  - Melaena
  - Petechiae
  - Pharyngeal haemorrhage
  - Prolonged prothrombin time
  - Pulmonary haemorrhage
  - Purpura
  - Rectal haemorrhage
  - Decreased red blood cell count
  - Renal haemorrhage
  - Scleral haemorrhage
  - Scrotal haematocoele
  - Splenic hematoma
  - Splinter haemorrhage
  - Subarachnoid haemorrhage
  - Tongue haemorrhage
  - Upper gastrointestinal haemorrhage
  - Vaginal haemorrhage
• Venous embolic and thrombotic events
  - Budd-Chiari syndrome
  - Deep vein thrombosis
  - Jugular vein thrombosis
  - Pelvic venous thrombosis
  - Pulmonary embolism
  - Retinal vein occlusion
  - Retinal vein thrombosis
  - Subclavian vein thrombosis
  - Venous thrombosis
  - Venous thrombosis limb
• Arterial embolic and thrombotic events
  - Acute myocardial infarction
  - Embolism
  - Myocardial infarction
  - Retinal artery occlusion
  - Transient ischaemic attack
• Aneurysms and artery dissections

Respiratory Disorders

• Dyspnoea
• Cough
• Dysphonia
• Oropharyngeal pain

Gastrointestinal Disorders

• Diarrhoea
• Nausea and vomiting
• Abdominal pain
• Constipation
• Stomatitis
• Dyspepsia
• Upper abdominal pain
• Flatulence
• Haemorrhoids
• Glossodynia
• Gastrointestinal perforation and fistula
  - Abdominal abscess
  - Anal abscess
  - Anal fistula
  - Fistula
  - Gastrointestinal anastomotic leak
  - Gastrointestinal perforation
  - Large intestine perforation
  - Oesophagobronchial fistula
  - Peritonitis

Hepatobiliary Disorders

• Hyperbilirubinaemia
• Cholecystitis
  - Acute cholecystitis
  - Infective cholecystitis
• Increased alanine aminotransferase
• Increased aspartate aminotransferase
• Increased alkaline phosphatase

Genitourinary Disorders

• Proteinuria
• Renal failure
  - Acute renal failure
• Increased creatinine

Endocrine and Metabolic Disorders

• Hypothyroidism
• Hyperthyroidism
• Decreased appetite
• Dehydration
• Hyperkalaemia
• Hypercalcaemia
• Decreased weight
• Increased lipase
• Increased amylase
• Increased thyroid-stimulating hormone

Musculoskeletal Disorders

• Arthralgia
• Pain in extremity
• Myalgia

Skin and Subcutaneous Tissue Disorders

• Palmar-plantar erythrodysaesthesia (hand-foot syndrome)
• Rash
• Dry skin
• Pruritus
• Erythema
• Alopecia
• Mucosal inflammation

Immune, Blood and Lymphatic System Disorders

• Anaemia
• Thrombocytopenia
• Polycythaemia
• Neutropaenia
• Leukopaenia

Sensory Disorders

• Dysgeusia
• Tinnitus

• CYP3A4/5 inhibitors
• Ketoconazole
• Itraconazole
• Clarithromycin
• Erythromycin
• Atazanavir
• Indinavir
• Nefazodone
• Nelfinavir
• Ritonavir
• Saquinavir
• Telithromycin
• CYP3A4/5 inducers
• Rifampicin
• Dexamethasone
• Phenytoin
• Carbamazepine
• Rifabutin
• Rifapentine
• Phenobarbital
• CYP1A2 substrates
• Theophylline
• CYP1A2 inhibitors (see additional prescribing points)
• CYP2C19 inhibitors (see additional prescribing points)

Other interactions 

• Grapefruit
• Hypericum perforatum (St. John's wort)

• Hepatic function
• Thyroid function
• Urinalysis
• Haemoglobin
• Haemotocrit

Specific cases may require

• Left ventricular ejection fraction
• Blood pressure
• Pregnancy status
• Brain magnetic resonance image

Additional observations

• Signs/symptoms of
  - Reversible posterior leukoencephalopathy syndrome 
  - Gastrointestinal bleeding/perforation/fistula
  - Major adverse cardiovascular events (MACE)
• Adherence

Wound healing complications

• No formal studies of the effect of axitinib on wound healing have been conducted
• Treatment with axitinib should be stopped at least 24 hours prior to scheduled surgery. The decision to resume axitinib therapy after surgery should be based on clinical judgment of adequate wound healing

CYP1A2 and CYP2C19 inhibitors

• CYP1A2 and CYP2C19 constitute minor (< 10%) pathways in axitinib metabolism
• The effect of strong inhibitors of these isozymes on axitinib pharmacokinetics has not been studied
• Caution should be exercised due to the risk of increased axitinib plasma concentrations in patients taking strong inhibitors of these isozymes

Axitinib is a potent and selective tyrosine kinase inhibitor of vascular endothelial growth factor receptors (VEGFR)-1, VEGFR-2 and VEGFR-3. These receptors are implicated in pathologic angiogenesis, tumour growth, and metastatic progression of cancer. Axitinib has been shown to potently inhibit VEGF-mediated endothelial cell proliferation and survival. Axitinib inhibited the phosphorylation of VEGFR-2 in xenograft tumour vasculature that expressed the target in vivo and produced tumour growth delay, regression, and inhibition of metastases in many experimental models of cancer.

Tablet 1mg

• Inlyta (Pfizer Laboratories) originator

Tablet 3mg

• Inlyta (Pfizer Laboratories) originator

Tablet 5mg

• Inlyta (Pfizer Laboratories) originator

Tablet 7mg

• Inlyta (Pfizer Laboratories) originator