Ponatinib

Oral
Accelerated phase chronic myeloid leukaemia, Blast phase chronic myeloid leukaemia, Chronic phase chronic myeloid leukaemia, Philadelphia chromosome-positive acute lymphoblastic leukaemia

Patient taking strong CYP3A inhibitors (e.g. ketoconazole, clarithromycin, indinavir, nefazodone, nelfinavir, saquinavir, boceprevir, telaprevir, grapefruit juice): Initially, 30 mg once daily.

Mild to severe (Child-Pugh class A, B or C): Initially, 30 mg once daily.

May be taken with or without food. Swallow whole. Do not crush/dissolve tab.

Lactation.

Patients with history of cardiac disease, ischaemia, hypertension, diabetes, hyperlipidaemia, hepatitis B infection, history of MI or stroke, pancreatitis, alcohol abuse. Not recommended for treatment of newly diagnosed chronic phase myeloid leukaemia. Renal (CrCl <50 mL/min or ESRD) and hepatic impairment. Elderly. Pregnancy. Patient taking strong CYP3A inhibitors.

Significant: Myelosuppression (e.g. thrombocytopenia, neutropenia, anaemia), fluid retention (e.g. peripheral oedema, pleural and pericardial effusions, peripheral swelling), cardiac arrhythmias (e.g. atrial fibrillation, bradyarrhythmia, tachyarrhythmia), retinal arterial occlusions, renal artery stenosis, venous thromboembolism (e.g. DVT, pulmonary embolism, thrombophlebitis, retinal vein thrombosis), hypertension (e.g. symptomatic hypertension, hypertensive crisis), ocular toxicity (e.g. blindness, blurred vision, corneal erosion, dry eye, conjunctivitis), reversible posterior leucoencephalopathy syndrome (e.g. seizure, headache, neurological disturbances, altered mental status), pancreatitis, hyperuricaemia, neuropathy (e.g. peripheral neuropathy, paraesthesia, hypoesthesia, hyperesthesia, dysgeusia, muscular weakness), wound healing impairment. Rarely, gastrointestinal perforation (fistula), cranial neuropathy and tumour lysis syndrome.
Cardiac disorders: Angina pectoris, decreased ejection fraction, pericardial effusion, peripheral ischaemia, dyspnoea.
Eye disorders: Visual impairment, periorbital oedema, eyelid oedema, eye pain.
Endocrine disorders: Hypothyroidism.
Gastrointestinal disorders: Abdominal pain, diarrhoea, vomiting, constipation, nausea, stomatitis.
General disorders and administration site conditions: Lethargy, fatigue, pyrexia, chills.
Infections and infestations: Sepsis, folliculitis, cellulitis.
Investigations: Decreased weight; increased lipase, AST, ALT, bilirubin, alkaline phosphatase.
Metabolism and nutrition disorders: Decreased appetite, dehydration, hypocalcaemia, hyperglycaemia, hypophosphataemia, hypertriglyceridaemia, hypokalaemia, hyponatraemia.
Musculoskeletal and connective tissue disorders: Bone pain, back pain, arthralgia, myalgia, pain in extremity, muscle spasms, musculoskeletal pain, neck pain.
Nervous system disorders: Headache, dizziness, cerebrovascular accident, cerebral infarction, migraine.
Psychiatric disorders: Insomnia.
Reproductive system and breast disorders: Erectile dysfunction.
Respiratory, thoracic and mediastinal disorders: Cough, pneumonia, upper respiratory tract infection.
Skin and subcutaneous tissue disorders: Rash, dry skin, pruritus, erythema, alopecia.
Vascular disorders: Transient ischaemic attack, epistaxis.
Potentially Fatal: Arterial occlusion (e.g. MI, stroke), brain oedema, heart failure, left ventricular dysfunction, hepatic failure, severe haemorrhage (e.g. gastrointestinal haemorrhage, subdural haematoma), hepatitis B reactivation, peripheral arterial occlusive events (e.g. mesenteric artery occlusion, peripheral arterial disease).

PO: D

This drug may cause dizziness, lethargy or blurred vision, if affected, do not drive or operate machinery.

Assess CV status prior and during therapy. Monitor CBC with differential and platelets every 2 weeks for the 1st 3 months and monthly thereafter or as indicated; LFT at baseline and monthly thereafter or as clinically indicated; serum lipase every 2 weeks for the 1st 2 months then monthly thereafter. Perform ocular exam at baseline and periodically. Monitor cardiac function, blood pressure, serum electrolytes, uric acid. Monitor for signs and symptoms of arterial or venous occlusion or thromboembolism, hepatotoxicity (e.g. jaundice, anorexia, bleeding, bruising), haemorrhage, fluid retention, pancreatitis, gastrointestinal perforation, neuropathy.

Symptoms: Pneumonia, systemic inflammatory response, atrial fibrillation, and asymptomatic, moderate pericardial effusion. Management: Supportive treatment.

Increased ponatinib serum concentration with strong CYP3A4 inhibitors (e.g. ketoconazole, clarithromycin, indinavir, nefazodone, nelfinavir, saquinavir, boceprevir, telaprevir). Decreased ponatinib serum concentration with strong CYP3A4 inducers (e.g. rifampin, carbamazepine, phenobarbital, phenytoin). May increase plasma concentrations of substrates of P-glycoprotein (e.g. digoxin, dabigatran, colchicine, pravastatin) or breast cancer resistance protein (e.g. methotrexate, rosuvastatin, sulfasalazine).

Increased ponatinib serum concentration with grapefruit juice. Decreased ponatinib serum concentration with St. John’s Wort.

Description: Ponatinib is a tyrosine kinase inhibitor that blocks the activity of cells expressing native or mutant BCR-ABL including T315I. It also inhibits the activities of VEGFR, FGFR, PDGFR, EPH, SRC kinases, KIT, RET, TIE2 and FLT3.
Pharmacokinetics:
Absorption: Time to peak plasma concentration: ≤6 hours.
Distribution: Volume of distribution: 1,223 L. Plasma protein binding: >99%.
Metabolism: Undergoes phase I metabolism in the liver mainly by CYP3A4, and to a lesser extent by CYP2C8, CYP2D6 and CYP3A5; phase II metabolism by esterases and or/amidases.
Excretion: Via faeces (approx 87%); urine (approx 5%). Elimination half-life: Approx 24 hours (range: 12-66 hours).

Source: National Center for Biotechnology Information. PubChem Database. Ponatinib, CID=24826799, https://pubchem.ncbi.nlm.nih.gov/compound/Ponatinib (accessed on Mar. 26, 2020)

Store between 20-25°C.

Targeted Cancer Therapy

L01EA05 - ponatinib ; Belongs to the class of BCR-ABL tyrosine kinase inhibitors. Used in the treatment of cancer.

Anon. Ponatinib. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 17/12/2019.

Buckingham R (ed). Ponatinib. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 17/12/2019.

Iclusig Tablets (Millennium Pharmaceuticals, Inc.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 17/12/2019.

Joint Formulary Committee. Ponatinib. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 16/01/2020.