Ponatinib oral
- Drugs List
- Therapeutic Indications
- Dosage
- Contraindications
- Precautions and Warnings
- Pregnancy and Lactation
- Side Effects
- Monograph
Presentation
Oral formulations of ponatinib (as hydrochloride).
Drugs List
Therapeutic Indications
Uses
Chronic, accelerated or blast phase chronic myeloid leukaemia
Philadelphia chromosome positive (Ph+) acute lymphoblastic leukaemia
Treatment of chronic, accelerated or blast phase chronic myeloid leukaemia (CML) with resistance or intolerance to dasatinib or nilotinib and for treatment of patients where subsequent treatment with imatinib is not clinically appropriate or who have the T315I mutation.
Treatment of Philadelphia chromosome positive acute lymphoblastic leukaemia (Ph+ ALL) with resistance or intolerance to dasatinib and for treatment of patients where subsequent treatment with imatinib is not clinically appropriate or who have the T315I mutation.
Dosage
Whilst the doses stated below are those recommended by the manufacturer, local cancer network protocols for the relevant indication should be consulted.
Adults
45mg of ponatinib once daily.
Dose adjustment may be necessary for the management of treatment toxicity or to reduce the risk of arterial occlusion. A dose reduction to 15mg should also be considered for chronic phase CML patients who have achieved a major cytogenetic response.
If a dose reduction is considered the following factors should be taken into account: cardiovascular risk, side effects, time to cytogenetic response and BCR-ABL transcript levels.
Additional Dosage Information
Dose adjustments in myelosuppression
Absolute neutrophil count (ANC) less than 1 x 10 to the power of 9/L or Platelets less than 50 x 10 to the power of 9/L
In each case withhold until recovery to ANC equal to or greater than 1.5 x 10 to the power of 9/L and platelets equal to or greater than 75 x 10 to the power of 9/L, then dose as follows.
Occurrence at initial dose: Resume at same dose.
Occurrence at 45mg: Resume at 30mg.
Occurrence at 30mg: Resume at 15mg.
Arterial occlusion and venous thromboembolism
Interrupt treatment. Assess the benefit of treatment against the risk to the patient before resuming treatment following resolution of event.
Dose adjustments in non-haematological toxicity
Grade 2 pancreatitis and/or asymptomatic elevation of lipase/amylase
Continue at the same dose.
Grade 3 or 4 asymptomatic elevation of lipase/amylase (greater than 2 times institution upper limit of normal (IULN)) only
In each case withhold until recovery to less than or equal to Grade 1 (less than 1.5 times IULN)
Occurrence at 45mg: Resume at 30mg.
Occurrence at 30mg: Resume at 15mg.
Occurrence at 15mg: Consider discontinuing.
Grade 3 pancreatitis
In each case withhold until recovery to less than or equal to grade 2 pancreatitis and reduce dose as follows.
Occurrence at 45mg: Resume at 30mg.
Occurrence at 30mg: Resume at 15mg.
Occurrence at 15mg: Consider discontinuing.
Grade 4 pancreatitis
Discontinue.
Dose adjustments for hepatic toxicity
Elevation of liver transaminase greater than 3 times upper limit of normal (ULN), persistent grade 2 (longer than 7 days), Grade 3 or higher
In each case withhold until recovery to less than or equal to Grade 1 (less than 3 times ULN) or pre-treatment grade
Occurrence at 45mg: Resume at 30mg.
Occurrence at 30mg: Resume at 15mg.
Occurrence at 15mg: Discontinue.
Elevation of AST or ALT (equal to or greater than 3 times ULN) with concurrent elevation of bilirubin (greater than 2 times ULN) and alkaline phosphatase less than 2 times ULN
Discontinue.
Concurrent use of potent cytochrome P450 3A4 inhibitors
Consider reducing initial dose to 30mg once daily with concomitant use of potent inhibitors of cytochrome P450 3A4 (e.g. clarithromycin, itraconazole, ketoconazole, ritonavir, saquinavir, telithromycin, or voriconazole).
Contraindications
Children under 18 years
Breastfeeding
Galactosaemia
Pregnancy
Uncontrolled hypertension
Precautions and Warnings
Neutrophil count below 1.0 x 10 to the power of 9 / L
Patients over 65 years
Platelet count below 50 x 10 to the power of 9 / L
Tobacco smoking
Alcoholism
Behcet's disease
Cerebrovascular disorder
Diabetes mellitus
End stage renal disease
Giant cell arteritis
Glucose-galactose malabsorption syndrome
Hepatic impairment
History of alcohol abuse
History of aneurysm
History of cerebrovascular accident
History of hepatitis B
History of ischaemic heart disease
History of myocardial infarction
History of pancreatitis
Hyperlipidaemia
Hypertension
Ischaemic heart disease
Lactose intolerance
Marfan syndrome
Occlusive peripheral arterial disease
Pancreatitis
Renal impairment - creatinine clearance below 50ml/minute
Takayasu arteritis
Vascular Ehlers-Danlos syndrome
Advise ability to drive/operate machinery may be affected by side effects
Before initiating screen all patients for hepatitis B infection
Ensure hypertension is controlled prior to treatment
Evaluate patients for cardiovascular disease prior to treatment
Hepatitis B: Refer prior to initiation to liver disease specialist
Treatment to be initiated and supervised by a specialist
Contains lactose
Consult local policy on the safe use of oral anti-cancer drugs
Staff: Not to be handled by pregnant staff
Monitor cardiac function before and regularly during treatment
Monitor hepatic function before treatment and regularly during treatment
Discontinue if AST/ALT > 3x ULN & bilirubin > 2x ULN & ALKP < 2x ULN
If visual disturbances occur, perform ophthalmic evaluation
Monitor blood counts every 2 weeks for first 3 months then monthly
Monitor blood pressure
Monitor patients at risk for signs & symptoms of venous thromboembolism
Monitor serum lipase every 2 weeks for first 2 months then periodically
Advise patient to report headaches, seizures, confusion, visual disturbance
Advise patient to report mucosal/skin reactions (blistering or peeling)
Advise patients to report symptoms of acute pancreatitis immediately
Consider discontinuing therapy if significant cardiac failure develops
Consider pancreatitis in patients with unexplained abdominal pain
Reactivation of hepatitis B may occur in chronic carriers
Suspend treatment and/or reduce dose for persistent grade 2 hepatotoxicity
Suspend treatment if transaminases >3 times upper limit of normal
Consider reducing or interrupting treatment if lipase levels are elevated
Discontinue if an adequate response not achieved within 3 months
Discontinue if posterior reversible encephalopathy syndrome (PRES) develops
Discontinue treatment if grade 4 pancreatitis occurs
Suspend if venous thromboembolism develops
Suspend therapy &/or reduce dose if neutrophil count <1 x 10 to power 9/L
Suspend therapy &/or reduce dose if platelets below 50 x 10 to power 9/L
Suspend treatment and/or reduce dose if grade 3 or higher hepatotoxicity
Suspend treatment and/or reduce dose if grade 3 pancreatitis occurs
Suspend treatment if arterial or venous occlusion suspected
Suspend treatment if elevated serum lipase plus abdominal pain
Suspend treatment if grade 3 or greater elevations in lipase or amylase
Suspend treatment if hypertension cannot be controlled
Suspend treatment if bleeding requiring medical treatment occurs
Advise patient not to take St John's wort concurrently
Advise patient grapefruit products may increase plasma level
Female: Barrier or non-hormonal contraception required during treatment
Male & female: Ensure adequate contraception during treatment
Advise patient on giving up smoking
Posterior Reversible Encephalopathy Syndrome (PRES) also known as Reversible Posterior Leucoencephalopathy Syndrome (RPLS) has been reported in some patients treated with this agent. If patients present with symptoms indicating PRES such as headache, altered mental state, seizures and visual disturbances, an MRI should be performed. Interrupt treatment if PRES is diagnosed and only resume once it has resolved and the benefit of treatment outweigh the risks.
Cardiovascular status of the patient should be assessed, and cardiovascular risk factors should be actively managed before starting treatment. Cardiovascular status should continue to be monitored and optimised during treatment.
Serious haemorrhage events have been reported in patients taking ponatinib, the most common being cerebral and gastrointestinal haemorrhage. The majority of bleeding events occurred in patients with grade 3/4 thrombocytopenia. Suspend treatment in patients with severe haemorrhage and evaluate.
Haematologic support such as platelet transfusion and haematopoietic growth factors can be used during treatment when clinically indicated.
Risk factors for aneurysm and artery dissection
Use of systemic VEGF inhibitors may promote the formation of aneurysms or artery dissections, mainly in relation to aortic aneurysm rupture and aortic dissection. It is therefore important to consider the risk of aneurysm and artery dissection in patients with risk factors such as hypertension, history of aneurysm, smoking, diabetes, coronary, cerebrovascular or peripheral arterial disease, and hyperlipidaemia. Other risk factors include Marfan syndrome, vascular Ehlers-Danlos syndrome, Takayasu arteritis, and the use of fluoroquinolones. In patients receiving VEGF inhibitors, any modifiable risk factors such as smoking and hypertension should be reduced as far as possible.
Pregnancy and Lactation
Pregnancy
Ponatinib is contraindicated during pregnancy.
The manufacturer suggests ponatinib must only be used during pregnancy when deemed essential and if used the patient must be informed of the potential risk to the foetus. At the time of writing, there are no adequate data from the use of ponatinib in pregnant women. Studies in animals have shown reproductive toxicity, including soft tissue and skeletal alterations at non-toxic maternal doses, and post-implantation loss at toxic levels.
The effect of concurrent therapies must also be considered.
Lactation
Ponatinib is contraindicated during breastfeeding.
The manufacturer advises stopping breastfeeding during treatment.
It is not known if ponatinib is excreted in human breast milk. A risk to neonates cannot be excluded.
Side Effects
Abdominal discomfort
Abdominal distension
Alopecia
Anaemia
Angina pectoris
Arterial occlusion
Arthralgia
Asthenia
Atrial fibrillation
Atrial flutter
Blurred vision
Cardiac disorders
Cardiac failure
Cerebral artery stenosis
Cerebral infarct
Cerebrovascular occlusion
Chills
Conjunctivitis
Coronary artery disorder
Cough
Decreased appetite
Decreased ejection fraction
Deep vein thrombosis (DVT)
Dehydration
Dizziness
Dry eyes
Dry mouth
Dyspepsia
Dysphonia
Dyspnoea
Ecchymosis
Electrolyte disturbances
Elevated amylase levels
Elevated serum lipase
Embolism
Epistaxis
Erectile dysfunction
Exfoliative dermatitis
Eyelid oedema
Facial oedema
Fatigue
Febrile neutropenia
Fluid retention
Flushing
Gastro-intestinal disturbances
Gastro-intestinal haemorrhage
Gastroesophageal reflux disease
Headache
Hepatotoxicity
Hyperaesthesia
Hyperglycaemia
Hyperhidrosis
Hypertension
Hypertriglyceridaemia
Hyperuricaemia
Hypoaesthesia
Hypothyroidism
Increases in hepatic enzymes
Infections
Influenza-like symptoms
Insomnia
Jaundice
Left ventricular failure
Lethargy
Migraine
Muscle spasm
Musculoskeletal pain
Myalgia
Myelosuppression
Myocardial infarction
Pain
Pancreatitis
Pancytopenia
Paraesthesia
Pericardial effusion
Periorbital oedema
Peripheral neuropathy
Peripheral oedema
Peripheral vascular disorders
Petechiae
Pleural effusion
Posterior reversible encephalopathy syndrome (PRES)
Pulmonary embolism
Pyrexia
Rash
Reactivation of hepatitis B
Reduced neutrophil count
Reduced platelet count
Retinal vein occlusion
Retinal vein thrombosis
Serum bilirubin increased
Skin disorder
Stevens-Johnson syndrome
Stomatitis
Thromboembolism
Tumour lysis syndrome
Vascular disorders
Weight loss
White blood cell count decreased
Overdosage
It is strongly recommended that the UK National Poisons Information Service be consulted on cases of suspected or actual overdose where there is doubt over the degree of risk or about appropriate management.
The following number will direct the caller to the relevant local centre (0844) 892 0111
Information may be obtained if you have access to ToxBase the primary clinical toxicology database of the National Poisons Information Service. This is available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).
Further Information
Last Full Review Date: March 2020
Reference Sources
Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 10th edition (2015) ed. Briggs, G., Freeman, R. Wolters Kluwer Health, Philadelphia.
Summary of Product Characteristics: Iclusig 15mg, 30mg and 45mg tablets. Incyte Biosciences UK Ltd. Revised August 2019.
MHRA Drug Safety Update October 2018
Available at: https://www.mhra.gov.uk
Last accessed: 11 January 2019
MHRA Drug Safety Update July 2020
Available at: https://www.gov.uk/drug-safety-update/systemically-administered-vegf-pathway-inhibitors-risk-of-aneurysm-and-artery-dissection
Last accessed: 10 November 2020
NICE Evidence Services Available at: www.nice.org.uk Last accessed: 11 January 2019
Medscape UK | Univadis prescription drug monographs & interactions are based on FDB Multilex Content
FDB Disclaimer : FDB Multilex is intended for the use of healthcare professionals and is provided on the basis that the healthcare professionals will retain FULL and SOLE responsibility for deciding what treatment to prescribe or dispense for any particular patient or circumstance.