Ponatinib

Ponatinib is an oral, multi-targeted tyrosine kinase inhibitor developed against BCR-ABL, the fusion protein created by the Philadelphia chromosome that drives chronic myeloid leukaemia and Philadelphia chromosome-positive acute lymphoblastic leukaemia. A carbon–carbon triple bond in its structure allows high-affinity binding to native BCR-ABL and to mutant forms of the ABL kinase, including T315I, the mutation that prevents other BCR-ABL inhibitors from binding.

Mechanism of Action

• BCR-ABL inhibition: ponatinib is a potent pan-BCR-ABL inhibitor. It blocks the tyrosine kinase activity of ABL and of T315I mutant ABL, with IC50 values of 0.4 and 2.0 nM respectively.
• Overcoming resistance: in cell assays it overcame resistance to imatinib, dasatinib and nilotinib caused by BCR-ABL kinase-domain mutations. In preclinical studies, 40 nM was enough to reduce the viability of cells expressing every tested BCR-ABL mutant (including T315I) by more than 50% and to suppress the emergence of mutant clones; no mutation conferring resistance to 40 nM was detected in an accelerated mutagenesis assay.
• Target inhibition in patients: at doses of 30 mg or more, steady-state trough concentrations typically exceed 21 ng/mL (40 nM). At doses of 15 mg or more, 32 of 34 patients (94%) showed at least a 50% fall in phosphorylation of CRKL, a biomarker of BCR-ABL inhibition, in peripheral blood mononuclear cells.
• Other kinases: ponatinib also inhibits other clinically relevant kinases (IC50 below 20 nM) and is active in cells against RET, FLT3, KIT and members of the FGFR, PDGFR and VEGFR families. DrugBank additionally lists TIE2, EPH receptors and SRC-family kinases.
• Animal data: in mice, tumours expressing native or T315I-mutant BCR-ABL shrank and survival was prolonged.
• Cardiac electrophysiology: in 39 patients with leukaemia given 30, 45 or 60 mg once daily, no clinically significant QT prolongation was seen. A thorough QT study has not been performed, so an effect cannot be excluded.

Pharmacokinetics

• Absorption: peak concentrations are reached about 4 hours after an oral dose. Cmax and AUC rise in proportion to dose between 15 and 60 mg. At 45 mg daily at steady state, the geometric mean Cmax is 77 ng/mL and AUC(0–τ) 1,296 ng·h/mL. High-fat and low-fat meals do not change exposure compared with fasting. A potent inhibitor of gastric acid secretion produced only a minor fall in Cmax, without a fall in AUC.
• Distribution: more than 99% bound to plasma proteins in vitro; blood-to-plasma ratio 0.96; not displaced by ibuprofen, nifedipine, propranolol, salicylic acid or warfarin. The apparent steady-state volume of distribution at 45 mg daily is about 1,101 L, indicating extensive distribution outside the blood vessels. In vitro it is not a substrate, or only a weak one, of P-gp and BCRP, and not a substrate of OATP1B1, OATP1B3 or OCT-1.
• Metabolism: esterases and/or amidases convert ponatinib to an inactive carboxylic acid, and CYP3A4 forms an N-desmethyl metabolite that is 4 times less active than ponatinib. These account for about 58% and 2% of circulating ponatinib levels respectively. In vitro, CYP2C8, CYP2D6 and CYP3A5 play a smaller part (DrugBank).
• Elimination: mainly in faeces. After a single radiolabelled oral dose, about 87% of the radioactivity was recovered in faeces and about 5% in urine. The terminal half-life is about a day (range 12 to 66 hours).
• Special populations: no dose adjustment is needed in patients aged 65 years or over; patients with hepatic impairment may start at the usual dose with caution; renal excretion is not a major route of elimination, but the medicine has not been studied in renal impairment (see Administration and Dosage).

Ponatinib is used as monotherapy unless stated otherwise.

• Chronic myeloid leukaemia (CML) in adults: chronic phase, accelerated phase or blast phase CML that is resistant to dasatinib or nilotinib; or intolerant to dasatinib or nilotinib when subsequent treatment with imatinib is not clinically appropriate; or that carries the T315I mutation.
• Philadelphia chromosome-positive acute lymphoblastic leukaemia (Ph+ ALL) in adults: Ph+ ALL that is resistant to dasatinib; or intolerant to dasatinib when subsequent treatment with imatinib is not clinically appropriate; or that carries the T315I mutation.
• Newly diagnosed Ph+ ALL in adults: in combination with reduced-intensity chemotherapy.
• Chronic phase CML in children aged 6 years and over: chronic phase CML (CP-CML) that is resistant to dasatinib or nilotinib; or intolerant to dasatinib or nilotinib when subsequent treatment with imatinib is not clinically appropriate; or that carries the T315I mutation.

The SmPC asks prescribers to assess cardiovascular status before treatment and to consider alternative treatment in some situations (see Special Instructions).

• Hypersensitivity to ponatinib or to any of the excipients (see Composition).

The reactions below come from the monotherapy trials in previously treated CML and Ph+ ALL (PACE, 449 patients, and OPTIC, 94 patients with chronic phase CML) unless stated otherwise. The most common serious reactions in PACE were pneumonia (7.3%), pancreatitis (5.8%), abdominal pain (4.7%), atrial fibrillation (4.5%), pyrexia (4.5%) and myocardial infarction (4.0%). After at least 64 months of follow-up, adverse reactions led to discontinuation in 20% of patients with chronic phase CML, 11% with accelerated phase CML, 15% with blast phase CML and 9% with Ph+ ALL.

Very common (≥1/10): upper respiratory tract infection, anaemia, decreased platelet count, decreased neutrophil count, decreased appetite, hypertriglyceridaemia, hypercholesterolaemia, insomnia, headache, dizziness, hypertension, dyspnoea, cough, abdominal pain, diarrhoea, vomiting, constipation, nausea, raised lipase, raised ALT and AST, raised transaminases, hepatotoxicity, rash, dry skin, pruritus, bone pain, joint pain, muscle pain, pain in the limbs, back pain, muscle spasms, fatigue, asthenia, peripheral oedema, pyrexia, pain.

Common (≥1/100 to <1/10): pneumonia, sepsis, folliculitis, cellulitis, herpes zoster; pancytopenia, febrile neutropenia, reduced white cell count, eosinophilia, raised neutrophil count, myelosuppression; hypothyroidism; dehydration, fluid retention, low calcium, potassium, sodium or phosphate, hyperglycaemia, hyperuricaemia, dyslipidaemia, raised LDL cholesterol, weight loss or gain, impaired glucose tolerance, tumour lysis syndrome; anxiety; cerebrovascular accident, cerebral infarction, transient ischaemic attack, carotid artery stenosis, peripheral neuropathy, lethargy, migraine, hyperaesthesia, hypoaesthesia, paraesthesia, facial nerve disorder; blurred vision, dry eye, eyelid and periorbital oedema, conjunctivitis, visual impairment, blepharitis, eye pain, ocular hyperaemia, retinal vein occlusion; heart failure (including congestive and chronic), myocardial infarction, coronary artery disease, angina pectoris (including unstable angina), acute coronary syndrome, myocardial ischaemia, pericardial effusion, atrial fibrillation, atrial flutter, reduced ejection fraction, left ventricular dysfunction or hypertrophy, bradycardia, tachycardia, palpitations, extrasystoles, QT prolongation, raised natriuretic peptides; peripheral arterial occlusive disease, peripheral ischaemia, peripheral arterial stenosis, intermittent claudication, deep vein thrombosis, flushing, hot flushes, hypertensive crisis; pulmonary embolism, pleural effusion, epistaxis, dysphonia, pulmonary hypertension, oropharyngeal pain, productive cough; pancreatitis, raised amylase, reflux disease, stomatitis, dyspepsia, abdominal distension or discomfort, dry mouth, gastric haemorrhage, gastritis, gastric ulcer, gingival bleeding; raised bilirubin, alkaline phosphatase and gamma-glutamyltransferase, hypertransaminasaemia; itchy, exfoliative, macular, maculo-papular, erythematous, pustular and papular rashes, erythema, alopecia, skin exfoliation, night sweats, hyperhidrosis, petechiae, ecchymosis, skin pain, dermatitis (exfoliative, acneiform, allergic, psoriasiform), hyperkeratosis, skin hyperpigmentation, acne, eczema, keratosis pilaris, contusion, pityriasis rubra pilaris, panniculitis (including erythema nodosum), erythema multiforme, skin papilloma; musculoskeletal pain, neck pain, musculoskeletal and non-cardiac chest pain, muscular weakness, musculoskeletal stiffness, spinal pain, tendinitis; proteinuria; erectile dysfunction, amenorrhoea; chills, influenza-like illness, palpable nodule, face oedema; raised C-reactive protein, hypoalbuminaemia.

Uncommon (≥1/1,000 to <1/100): cerebral artery stenosis, cerebral haemorrhage, intracranial haemorrhage, posterior reversible encephalopathy syndrome (from post-marketing reports); retinal vein thrombosis, retinal artery occlusion; cardiac discomfort, ischaemic cardiomyopathy, coronary artery vasospasm; poor peripheral circulation, splenic infarction, venous embolism, venous thrombosis, renal artery stenosis; hepatic failure, jaundice.

Not known: aneurysms and artery dissections.

Arterial and venous occlusion. In PACE (minimum follow-up 64 months), arterial occlusive reactions affected the heart, the brain and the peripheral vessels in 13%, 9% and 11% of patients respectively (serious reactions in 10%, 7% and 9%). Overall, 25% had an arterial occlusive reaction and 20% had a serious one, and some patients had more than one type. The median time to the first cardiovascular, cerebrovascular and peripheral vascular event was 351, 611 and 605 days. Venous thromboembolic reactions occurred in 6%, and were more frequent in Ph+ ALL and blast phase CML than in chronic or accelerated phase CML; none was fatal. In OPTIC (45 mg cohort), arterial occlusive reactions occurred in 13.8% of patients (serious in 8.5%, two fatal), and one of 94 patients had a venous reaction (grade 1 retinal vein occlusion). These events occurred in patients with and without cardiovascular risk factors, including patients aged 50 years or younger.

Blood and liver changes. Myelosuppression events were reported in 60% of patients in PACE and 63% in OPTIC (45 mg cohort), and hepatotoxicity events in 30% and 28%. In PACE, grade 3 or 4 laboratory abnormalities included thrombocytopenia (40%), neutropenia (34%), leucopenia (25%), anaemia (20%), lymphopenia (17%) and raised lipase (14%); they were more frequent in accelerated phase CML, blast phase CML and Ph+ ALL than in chronic phase CML. Hepatitis B reactivation has been reported with BCR-ABL kinase inhibitors, in some cases with acute liver failure, fulminant hepatitis, liver transplantation or a fatal outcome. Severe skin reactions such as Stevens–Johnson syndrome have been reported with some BCR-ABL kinase inhibitors; patients should report suspicious skin reactions at once, especially with blistering, peeling, mucosal involvement or general symptoms.

With chemotherapy in newly diagnosed Ph+ ALL (PhALLCON, 163 patients). Myelosuppression was reported in 83% of patients and hepatotoxicity in 64%. The most frequent reactions were thrombocytopenia (47%), neutropenia (44%) and anaemia (44%). Chemotherapy-related myelosuppression (febrile neutropenia, pyrexia, pneumonia, sepsis), peripheral sensory neuropathy and stomatitis were more frequent than with ponatinib alone. Very common reactions in this setting also included febrile neutropenia, leucopenia, leucocytosis, hypokalaemia, hyperglycaemia, hypocalcaemia, hypophosphataemia, hyperuricaemia, peripheral and peripheral sensory neuropathy, paraesthesia, stomatitis, and raised lipase, amylase, gamma-glutamyltransferase and lactate dehydrogenase. Arterial occlusive reactions were less frequent (cardiovascular 1.2%, cerebrovascular 0.6%, peripheral vascular 0.6%), but venous thromboembolic events occurred in 12%.

Children. In 61 paediatric patients (aged 1 year to under 18 years) with relapsed or refractory leukaemias, lymphomas or solid tumours in a phase 1/2 study, the safety profile of ponatinib alone was generally consistent with that in adults.

Ponatinib is metabolised by CYP3A4, so strong inhibitors and inducers of this enzyme change its exposure.

• Strong CYP3A inhibitors (clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin, voriconazole, grapefruit juice): ketoconazole 400 mg daily raised ponatinib AUC(0–∞) by 78% and Cmax by 47% after a single 15 mg dose. Use with caution; a reduction of the adult starting dose to 30 mg should be considered. For children, a reduction of the starting dose should also be considered (the SmPC gives a table). Moderate CYP3A inhibitors also call for caution.
• Strong CYP3A inducers (carbamazepine, phenobarbital, phenytoin, rifabutin, rifampicin, St John’s wort): rifampicin 600 mg daily lowered ponatinib AUC(0–∞) by 62% and Cmax by 42% in 19 healthy volunteers. Avoid the combination and look for alternatives, unless the benefit outweighs the risk of underexposure. Moderate CYP3A inducers also call for caution.
• P-gp and BCRP substrates: in vitro, ponatinib inhibits P-gp and BCRP, so close clinical surveillance is recommended when it is given with substrates of these transporters.
• Anti-clotting medicines (anticoagulants, antiplatelet agents): use with caution in patients at risk of bleeding; formal studies have not been done.
• Chemotherapy: in Ph+ ALL, combining ponatinib with chemotherapy may increase adverse events such as hepatotoxicity and myelosuppression, and requires special precaution.
• Gastric acid suppression: a potent inhibitor of gastric acid secretion only slightly lowered Cmax and did not change AUC.
• Hormonal contraceptives: it is unknown whether ponatinib affects the effectiveness of systemic hormonal contraceptives, so an alternative or additional method of contraception should be used.
• Food and herbal products: ponatinib may be taken with or without food. Avoid St John’s wort, which induces CYP3A4 and may lower ponatinib levels. Grapefruit juice inhibits CYP3A4 and is treated like a strong CYP3A inhibitor.

Treatment must be started by a physician experienced in the diagnosis and treatment of leukaemia. Haematological support, such as platelet transfusion and haematopoietic growth factors, can be used during treatment when clinically indicated. Ponatinib is taken by mouth once daily, with or without food.

Before treatment starts, the cardiovascular status of the patient must be assessed (history and physical examination) and cardiovascular risk factors actively managed. Cardiovascular status continues to be monitored during treatment (see Special Instructions).

Tablets are swallowed whole and must not be crushed or dissolved. The 5 mg hard capsules are for doses that cannot be made up with the tablets and for children who cannot swallow tablets; they can be swallowed whole, or opened and the contents mixed into soft food (apple sauce or yoghurt) and taken immediately.

Doses in Adults

• CML and Ph+ ALL previously treated with other tyrosine kinase inhibitors, or with the T315I mutation: starting dose 45 mg once daily, continued as long as there is no disease progression or unacceptable toxicity. Response is monitored according to standard clinical guidelines, and stopping should be considered if a complete haematological response has not occurred by 3 months (90 days).
• Dose reduction in chronic phase CML: the risk of arterial occlusive events is likely to be dose-related. A reduction to 15 mg should be considered once a molecular response is achieved (MR2, BCR-ABL1 IS of 1% or less), weighing cardiovascular risk, side effects, time to response and BCR-ABL transcript levels. Response is monitored closely after any reduction. If response is lost, the dose can be raised again to a previously tolerated 30 mg or 45 mg once daily, and treatment continued until response is lost again at that dose or toxicity becomes unacceptable.
• Newly diagnosed Ph+ ALL with chemotherapy: 30 mg once daily together with chemotherapy, reduced to 15 mg once daily when a minimal residual disease (MRD)-negative complete response (BCR-ABL1 of 0.01% or less) is reached at the end of induction. If MRD negativity is lost, the dose can be raised again to a previously tolerated dose of up to 30 mg once daily.

Children Aged 6 Years and Over with Chronic Phase CML

• Ponatinib is given once daily as tablets or capsules, and the starting dose depends on body weight: 45 mg above 45 kg, 30 mg above 30 kg up to 45 kg, and 15 mg for 15 to 30 kg.
• A reduced dose may be considered after a molecular response, on the same considerations as in adults: 15 mg, 10 mg and 5 mg for the three weight bands respectively. If response is lost, the dose can be raised again to a previously tolerated daily dose.
• With strong CYP3A inhibitors, a reduction of the starting dose should be considered (the SmPC gives a table for children).
• Safety and efficacy below 6 years of age, and in combination with chemotherapy in children, have not been established. Growth is monitored closely (see Special Instructions).

Interrupting Treatment for Side Effects

Detailed dose-modification steps are in section 4.2 of the SmPC. In summary, the SmPC advises:

• Arterial occlusion or venous thromboembolism: interrupt immediately; a benefit-risk assessment guides any restart.
• Hypertension that is not medically controlled: interrupt temporarily.
• Raised lipase with abdominal symptoms: withhold and evaluate for pancreatitis.
• Myelosuppression: usually managed by withholding ponatinib temporarily or reducing the dose.
• Serious or severe haemorrhage: interrupt and evaluate.
• Serious heart failure: interrupt, and consider discontinuation.
• Posterior reversible encephalopathy syndrome: interrupt, and resume only once it has resolved and if the benefit outweighs the risk.

Special Populations

• Elderly: no dose adjustment for patients aged 65 years or over. Of the 732 patients in PACE and OPTIC, 191 (26%) were 65 or older, and older patients were more likely to have adverse reactions.
• Hepatic impairment: the usual starting dose may be used; caution is advised.
• Renal impairment: renal excretion is not a major route and ponatinib has not been studied in renal impairment. No adjustment is needed with an estimated creatinine clearance of 50 mL/min or more; caution is advised below 50 mL/min or in end-stage renal disease.
• Children: see above.

Arterial Occlusive Events and Cardiovascular Assessment

Arterial occlusion is the most important safety issue with ponatinib. Reported events include fatal myocardial infarction, stroke, retinal artery occlusion (in some cases with permanent visual impairment or vision loss), stenosis of large cerebral arteries, severe peripheral vascular disease, renal artery stenosis (with worsening, labile or treatment-resistant hypertension) and the need for urgent revascularisation. They occurred in patients with and without cardiovascular risk factors, including patients aged 50 years or younger, and were more frequent with increasing age and in patients with a history of ischaemia, hypertension, diabetes or hyperlipidaemia. The risk is likely to be dose-related.

• Before treatment: the cardiovascular status of the patient must be assessed, including history and physical examination, and cardiovascular risk factors must be actively managed.
• During treatment: cardiovascular status continues to be monitored, and medical and supportive therapy for conditions that add to cardiovascular risk is optimised.
• Previous heart attack, revascularisation or stroke: ponatinib should not be used unless the potential benefit outweighs the risk, and alternative treatment options should be considered before starting.
• Atrial fibrillation: the safety of ponatinib has not been studied in patients with atrial fibrillation.
• Watching for occlusion: patients are monitored for evidence of arterial occlusion. Decreased or blurred vision calls for an ophthalmic examination, including fundoscopy.
• If occlusion occurs: ponatinib is interrupted immediately, and a benefit-risk assessment guides any decision to restart.
• Dose: because the risk is likely to be dose-related, a reduction to 15 mg should be considered in chronic phase CML once a molecular response is reached (see Administration and Dosage).

Hypertension

Hypertension may contribute to arterial thrombotic events, including renal artery stenosis. Blood pressure is monitored and managed at each clinic visit, and hypertension is treated to normal. Ponatinib is interrupted temporarily if hypertension is not medically controlled; in the event of significant worsening, labile or treatment-resistant hypertension, treatment is interrupted and evaluation for renal artery stenosis considered. Hypertensive crisis has occurred, and hypertension with confusion, headache, chest pain or shortness of breath may need urgent clinical intervention.

Aneurysms and Artery Dissections

Inhibitors of the VEGF pathway, in patients with or without hypertension, may promote the formation of aneurysms and artery dissections. This risk should be weighed carefully before starting, particularly in patients with risk factors such as hypertension or a history of aneurysm.

Venous Thromboembolism and Retinal Vein Occlusion

Venous thromboembolic reactions, some serious, have occurred. Patients are monitored for thromboembolism; ponatinib is interrupted immediately if it occurs, and a benefit-risk assessment guides any restart. Retinal vein occlusion, in some cases with permanent visual impairment or vision loss, has also occurred, and decreased or blurred vision calls for an ophthalmic examination including fundoscopy.

Heart Failure and QT Interval

Fatal and serious heart failure or left ventricular dysfunction has occurred, including in patients with earlier vascular occlusive events. Patients are monitored for signs and symptoms of heart failure and treated as clinically indicated, including by interrupting ponatinib; discontinuation should be considered in serious heart failure. No clinically significant QT prolongation was seen in 39 patients, but a thorough QT study has not been performed.

Myelosuppression

Ponatinib can cause severe (grade 3 or 4) thrombocytopenia, neutropenia and anaemia, mostly within the first 3 months and more often in accelerated phase CML, blast phase CML and Ph+ ALL than in chronic phase CML. A complete blood count is performed every 2 weeks for the first 3 months and then monthly or as clinically indicated. Myelosuppression is generally reversible and is usually managed by withholding ponatinib temporarily or reducing the dose.

Pancreatitis and Serum Lipase

Ponatinib is associated with pancreatitis, which is more frequent in the first 2 months. Serum lipase is checked every 2 weeks for the first 2 months and periodically thereafter. Dose interruption or reduction may be needed; if raised lipase comes with abdominal symptoms, ponatinib is withheld and the patient evaluated for pancreatitis. Caution is advised in patients with a history of pancreatitis or alcohol abuse, and severe or very severe hypertriglyceridaemia should be managed to reduce the risk.

Liver Function and Hepatitis B

Ponatinib can raise ALT, AST, bilirubin and alkaline phosphatase. Most first events occurred during the first year, and hepatic failure, including fatal cases, has been observed. Liver function tests are performed before treatment and monitored periodically as clinically indicated, with particular care when ponatinib is combined with chemotherapy that can also affect the liver. Patients must be tested for hepatitis B virus (HBV) infection before treatment. Liver and hepatitis B specialists should be consulted for patients with positive HBV serology and for those who test positive during treatment, and HBV carriers who need ponatinib are monitored closely for signs of active infection throughout treatment and for several months afterwards.

Haemorrhage

Severe haemorrhage, including fatal cases, has occurred, more often in accelerated phase CML, blast phase CML and Ph+ ALL. Gastrointestinal haemorrhage and subdural haematoma were the grade 3 or 4 bleeding events reported most often. Most bleeding events, but not all, occurred in patients with grade 3 or 4 thrombocytopenia. Ponatinib is interrupted and the patient evaluated for serious or severe haemorrhage.

Posterior Reversible Encephalopathy Syndrome

Post-marketing cases have been reported. It is a neurological disorder that can cause seizure, headache, decreased alertness, altered mental function, vision loss and other visual or neurological disturbances. If it is diagnosed, ponatinib is interrupted and resumed only once the event has resolved and if the benefit outweighs the risk.

Use with Chemotherapy

In Ph+ ALL, adverse events such as hepatotoxicity and myelosuppression may increase when ponatinib is given with chemotherapy, which requires special precaution.

Growth in Children

Growth retardation has been seen in children treated with BCR-ABL tyrosine kinase inhibitors. Growth is monitored closely in paediatric patients taking ponatinib.

Pregnancy, Breastfeeding and Fertility

• Contraception: women of childbearing age should be advised not to become pregnant, and men not to father a child, during treatment. An effective method of contraception should be used. Because it is unknown whether ponatinib affects systemic hormonal contraceptives, an alternative or additional method should be used.
• Pregnancy: in limited human data (fewer than 50 known pregnancy outcomes), congenital megacolon (Hirschsprung’s disease) was reported in children born to women exposed in the first trimester, and animal studies showed reproductive toxicity. Ponatinib should not be used in pregnancy unless the woman’s clinical condition requires it; if it is used, the patient must be told of the potential risk to the foetus.
• Breastfeeding: it is unknown whether ponatinib passes into human milk and an excretion cannot be excluded. Breastfeeding should be stopped during treatment.
• Fertility: there are no human data. In rats, ponatinib affected female fertility, while male fertility was not affected. The relevance to people is unknown.

Lactose and Sodium

Ponatinib tablets contain 40 mg, 80 mg or 120 mg of lactose monohydrate, and the capsules 35 mg. Patients with rare hereditary galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take it. Each tablet or capsule contains less than 1 mmol (23 mg) of sodium, that is essentially “sodium-free”.

Effect on Driving

Ponatinib has a minor influence on the ability to drive and use machines. Lethargy, dizziness and blurred vision have been associated with it, so caution is advised when driving or operating machines.

Store Iclusig in the original container to protect it from moisture. Each bottle contains a sealed canister with a molecular sieve desiccant; keep the canister in the bottle. The SmPC sets no special temperature requirement. The tablets are supplied in high-density polyethylene bottles with screw-top closures (15 mg: 30, 60 or 180 tablets; 30 mg: 30 tablets; 45 mg: 30 or 90 tablets); not all pack sizes may be marketed. Keep out of the sight and reach of children.

Tablets: 4 years. Hard capsules: 1 year. Do not use after the expiry date on the pack.

Prescription only (Rx), subject to restricted medical prescription (Annex II B); treatment is started by a physician experienced in the diagnosis and treatment of leukaemia. The prescriber must assess the cardiovascular status of the patient before treatment starts and keep monitoring it (see Special Instructions). Ponatinib is taken at home as tablets or capsules, so it is supplied to the patient or to the treating clinic on prescription.