4.1. Therapeutic indications

Ponatinib Incyte is indicated in adult patients with

• chronic phase, accelerated phase, or blast phase chronic myeloid leukaemia (CML) who are resistant to dasatinib or nilotinib; who are intolerant to dasatinib or nilotinib and for whom subsequent treatment with imatinib is not clinically appropriate; or who have the T315I mutation

• Philadelphia chromosome positive acute lymphoblastic leukaemia (Ph+ ALL) who are resistant to dasatinib; who are intolerant to dasatinib and for whom subsequent treatment with imatinib is not clinically appropriate; or who have the T315I mutation.

See sections 4.2 for the assessment of cardiovascular status prior to start of therapy and 4.4 for situations where an alternative treatment may be considered.

4.2. Posology and method of administration

Therapy should be initiated by a physician experienced in the diagnosis and treatment of patients with leukaemia. Haematologic support such as platelet transfusion and haematopoietic growth factors can be used during treatment if clinically indicated.

Before starting treatment with ponatinib, the cardiovascular status of the patient should be assessed, including history and physical examination, and cardiovascular risk factors should be actively managed. Cardiovascular status should continue to be monitored and medical and supportive therapy for conditions that contribute to cardiovascular risk should be optimised during treatment with ponatinib.

Posology

The recommended starting dose is 45 mg of ponatinib once daily. For the standard dose of 45 mg once daily, a 45 mg film-coated tablet is available. Treatment should be continued as long as the patient does not show evidence of disease progression or unacceptable toxicity.

Patients should be monitored for response according to standard clinical guidelines.

Discontinuing ponatinib should be considered if a complete haematologic response has not occurred by 3 months (90 days).

The risk of arterial occlusive events is likely to be dose-related. Reducing the dose of Ponatinib to 15 mg should be considered for CP-CML patients who have achieved molecular response (MR2 i.e. ≤1% BCR-ABL1IS) taking the following factors into account in the individual patient assessment: cardiovascular risk, side effects of ponatinib therapy, time to response, and BCR-ABL transcript levels (see sections 4.4 and 5.1). If dose reduction is undertaken, close monitoring of response is recommended. In patients with loss of response the dose of Ponatinib can be re‑escalated to a previously tolerated dosage of 30 mg or 45 mg orally once daily. Ponatinib should be continued until loss of response at the re‑escalated dose or unacceptable toxicity.

Management of toxicities

Dose modifications or interruption of dosing should be considered for the management of haematological and non-haematological toxicities. In the case of severe adverse reactions, treatment should be withheld.

For patients whose adverse reactions are resolved or attenuated in severity, Ponatinib may be restarted and escalation of the dose back to the daily dose used prior to the adverse reaction may be considered, if clinically appropriate.

For a dose of 30 mg or 15 mg once daily, 15 mg and 30 mg film-coated tablets are available.

Myelosuppression

Dose modifications for neutropenia (ANC* < 1.0 x 109/L) and thrombocytopenia (platelet < 50 x 109/L) that are unrelated to leukaemia are summarized in Table 1.

Table 1 Dose modifications for myelosuppression

ANC* < 1.0 x 109/L

or

platelet < 50 x 109/L

First occurrence:

• Ponatinib should be withheld and resumed at the same dose after recovery to ANC ≥ 1.5 x 109/L and platelet ≥ 75 x 109/L

Recurrence at 45 mg:

• Ponatinib should be withheld and resumed at 30 mg after recovery to ANC ≥ 1.5 x 109/L and platelet ≥ 75 x 109/L

Recurrence at 30 mg:

• Ponatinib should be withheld and resumed at 15 mg after recovery to ANC ≥ 1.5 x 109/L and platelet ≥ 75 x 109/L

*ANC = absolute neutrophil count

Arterial occlusion and venous thromboembolism

In a patient suspected of developing an arterial occlusive event or a venous thromboembolism, Ponatinib should be immediately interrupted. A benefit-risk consideration should guide a decision to restart Ponatinib therapy (see sections 4.4 and 4.8) after the event is resolved.

Hypertension may contribute to risk of arterial occlusive events. Ponatinib treatment should be temporarily interrupted if hypertension is not medically controlled.

Pancreatitis

Recommended modifications for pancreatic adverse reactions are summarized in Table 2.

Table 2 Dose modifications for pancreatitis and elevation of lipase

Grade 2 pancreatitis and/or Grade 2 elevation of lipase (>1.5 - 2.0 x IULN or >2.0 - 5.0 x IULN and asymptomatic)

Ponatinib should be continued at the same dose

Grade 3 asymptomatic elevation of lipase (> 5.0 x IULN*)

Occurrence at 45 mg:

• Ponatinib should be withheld and resumed at 30 mg after recovery to ≤ Grade 1 (< 1.5 x IULN)

Occurrence at 30 mg:

• Ponatinib should be withheld and resumed at 15 mg after recovery to ≤ Grade 1 (< 1.5 x IULN)

Occurrence at 15 mg:

• Ponatinib discontinuation should be considered

Grade 3 pancreatitis or Grade 3 symptomatic elevation of lipase (> 2.0 - 5.0 x IULN)

Occurrence at 45 mg:

• Ponatinib should be withheld until complete resolution of symptoms and after recovery of lipase elevation to < Grade 2 and resumed at 30 mg

Occurrence at 30 mg:

• Ponatinib should be withheld until complete resolution of symptoms and after recovery of lipase elevation to < Grade 2 and resumed at 15 mg

Occurrence at 15 mg:

• Ponatinib discontinuation should be considered

Grade 4 pancreatitis or Grade 4 elevation of lipase (>5.0 x IULN and symptomatic)

Ponatinib should be discontinued

*IULN = institution upper limit of normal

Hepatic toxicity

Dose interruption or discontinuation may be required as described in Table 3.

Table 3 Recommended dose modifications for hepatic toxicity

Elevation of liver transaminase > 3 × ULN*

Persistent grade 2 (longer than 7 days)

Grade 3 or higher

Occurrence at 45 mg:

• Ponatinib should be interrupted and hepatic function should be monitored

• Ponatinib should be resumed at 30 mg after recovery to ≤ Grade 1 (< 3 × ULN), or recovery to pre-treatment grade

Occurrence at 30 mg:

• Ponatinib should be interrupted and resumed at 15 mg after recovery to ≤ Grade 1, or recovery to pre-treatment grade

Occurrence at 15 mg:

• Ponatinib should be discontinued

Elevation of AST or ALT ≥ 3 × ULN concurrent with an elevation of bilirubin > 2 × ULN and alkaline phosphatase < 2 × ULN

Ponatinib should be discontinued

*ULN = Upper Limit of Normal for the lab

Elderly patients

Of the 732 patients in the PACE and OPTIC clinical studies of Ponatinib, 191 (26%) were ≥ 65 years of age. Compared to patients < 65 years, older patients are more likely to experience adverse reactions.

Hepatic impairment

Patients with hepatic impairment may receive the recommended starting dose. Caution is recommended when administering Ponatinib to patients with hepatic impairment (see sections 4.4 and 5.2).

Renal impairment

Renal excretion is not a major route of ponatinib elimination. Ponatinib has not been studied in patients with renal impairment. Patients with estimated creatinine clearance of ≥ 50 mL/min should be able to safely receive Ponatinib with no dosage adjustment. Caution is recommended when administering Ponatinib to patients with estimated creatinine clearance of < 50 mL/min, or end-stage renal disease.

Paediatric population

The safety and efficacy of Ponatinib in patients less than 18 years of age have not been established. No data are available.

Method of administration

Ponatinib is for oral use. The tablets should be swallowed whole. Patients should not crush or dissolve the tablets. Ponatinib may be taken with or without food.

Patients should be advised not to swallow the desiccant canister found in the bottle.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

Important adverse reactions

Myelosuppression

Ponatinib is associated with severe (National Cancer Institute Common Terminology Criteria for Adverse Events grade 3 or 4) thrombocytopenia, neutropenia, and anaemia. Most of the patients with grade 3 or 4 platelet count decreased, anaemia or neutropenia, developed it within the first 3 months of treatment. The frequency of these events is greater in patients with accelerated phase CML (AP-CML), blast phase CML (BP-CML), or Ph+ ALL than in chronic phase CML (CP-CML). A complete blood count should be performed every 2 weeks for the first 3 months and then monthly or as clinically indicated. Myelosuppression was generally reversible and usually managed by withholding Ponatinib temporarily or reducing the dose (see section 4.2).

Arterial occlusion

Arterial occlusions, including fatal myocardial infarction, stroke, retinal arterial occlusions associated in some cases with permanent visual impairment or vision loss, stenosis of large arterial vessels of the brain, severe peripheral vascular disease, renal artery stenosis (associated with worsening, labile or treatment-resistant hypertension), and the need for urgent revascularization procedures have occurred in Ponatinib-treated patients. Patients with and without cardiovascular risk factors, including patients age 50 years or younger, experienced these events. Arterial occlusion adverse events were more frequent with increasing age and in patients with history of ischaemia, hypertension, diabetes, or hyperlipidaemia.

The risk of arterial occlusive events is likely to be dose-related (see sections 4.8 and 5.1).

Arterial occlusive adverse reactions including serious reactions, have occurred in the clinical development (see section 4.8). Some patients experienced more than 1 type of event.

Ponatinib should not be used in patients with a history of myocardial infarction, prior revascularization or stroke, unless the potential benefit of treatment outweighs the potential risk (see sections 4.2 and 4.8). In these patients, alternative treatment options should also be considered before starting treatment with ponatinib.

Before starting treatment with ponatinib, the cardiovascular status of the patient should be assessed, including history and physical examination, and cardiovascular risk factors should be actively managed. Cardiovascular status should continue to be monitored and medical and supportive therapy for conditions that contribute to cardiovascular risk should be optimised during treatment with ponatinib.

Monitoring for evidence of arterial occlusion should be performed and if decreased vision or blurred vision occurs, an ophthalmic examination (including fundoscopy) should be performed. Ponatinib should be interrupted immediately in case of arterial occlusion. A benefit -risk consideration should guide a decision to restart Ponatinib therapy (see sections 4.2 and 4.8).

Venous thromboembolism

Venous thromboembolic adverse reactions including serious reactions have occurred in the clinical development (see section 4.8).

Monitoring for evidence of thromboembolism should be performed. Ponatinib should be interrupted immediately in case of thromboembolism. A benefit -risk consideration should guide a decision to restart Ponatinib therapy (see sections 4.2 and 4.8).

Retinal venous occlusions associated in some cases with permanent visual impairment or vision loss have occurred in Ponatinib-treated patients. If decreased vision or blurred vision occurs, an ophthalmic examination (including fundoscopy) should be performed.

Hypertension

Hypertension may contribute to risk of arterial thrombotic events, including renal artery stenosis. During Ponatinib treatment, blood pressure should be monitored and managed at each clinic visit and hypertension should be treated to normal. Ponatinib treatment should be temporarily interrupted if hypertension is not medically controlled (see section 4.2).

In the event of significant worsening, labile or treatment-resistant hypertension, treatment should be interrupted and evaluation for renal artery stenosis should be considered.

Treatment-emergent hypertension (including hypertensive crisis) occurred in Ponatinib-treated patients. Patients may require urgent clinical intervention for hypertension associated with confusion, headache, chest pain, or shortness of breath.

Aneurysms and artery dissections

The use of VEGF pathway inhibitors in patients with or without hypertension may promote the formation of aneurysms and/or artery dissections. Before initiating Ponatinib, this risk should be carefully considered in patients with risk factors such as hypertension or history of aneurysm.

Congestive heart failure

Fatal and serious heart failure or left ventricular dysfunction occurred in Ponatinib-treated patients, including events related to prior vascular occlusive events. Patients should be monitored for signs or symptoms consistent with heart failure and they should be treated as clinically indicated, including interruption of Ponatinib. Discontinuation of ponatinib should be considered in patients who develop serious heart failure (see sections 4.2 and 4.8).

Pancreatitis and serum lipase

Ponatinib is associated with pancreatitis. The frequency of pancreatitis is greater in the first 2 months of use. Check serum lipase every 2 weeks for the first 2 months and then periodically thereafter. Dose interruption or reduction may be required. If lipase elevations are accompanied by abdominal symptoms, Ponatinib should be withheld and patients evaluated for evidence of pancreatitis (see section 4.2). Caution is recommended in patients with a history of pancreatitis or alcohol abuse. Patients with severe or very severe hypertriglyceridemia should be appropriately managed to reduce the risk of pancreatitis.

Hepatotoxicity

Ponatinib may result in elevation in ALT, AST, bilirubin, and alkaline phosphatase. Most patients who had an event of hepatotoxicity had their first event during the first year of treatment. Hepatic failure (including fatal outcome) has been observed. Liver function tests should be performed prior to treatment initiation and monitored periodically, as clinically indicated.

Haemorrhage

Severe haemorrhage, including fatalities, occurred in Ponatinib-treated patients. The incidence of severe bleeding events was higher in patients with AP-CML, BP-CML and Ph+ ALL. Gastrointestinal haemorrhage and subdural hematoma were the most commonly reported grade 3/4 bleeding events. Most haemorrhagic events, but not all, occurred in patients with grade 3/4 thrombocytopenia. Ponatinib should be interrupted and patients evaluated for serious or severe haemorrhage.

Hepatitis B reactivation

Reactivation of hepatitis B in patients who are chronic carriers of this virus has occurred after these patients received BCR-ABL tyrosine kinase inhibitors. Some cases resulted in acute hepatic failure or fulminant hepatitis leading to liver transplantation or a fatal outcome.

Patients should be tested for HBV infection before initiating treatment with Ponatinib. Experts in liver disease and in the treatment of hepatitis B should be consulted before treatment is initiated in patients with positive hepatitis B serology (including those with active disease) and for patients who test positive for HBV infection during treatment. Carriers of HBV who require treatment with Ponatinib should be closely monitored for signs and symptoms of active HBV infection throughout therapy and for several months following termination of therapy (see section 4.8).

Posterior Reversible Encephalopathy Syndrome

Post-marketing cases of Posterior Reversible Encephalopathy Syndrome (PRES) have been reported in Ponatinib-treated patients.

PRES is a neurological disorder that can present with signs and symptoms such as seizure, headache, decreased alertness, altered mental functioning, vision loss, and other visual and neurological disturbances.

If diagnosed, interrupt Ponatinib treatment and resume treatment only once the event is resolved and if the benefit of continued treatment outweighs the risk of PRES.

Medicinal product interactions

Caution should be exercised with concurrent use of Ponatinib and moderate and strong CYP3A inhibitors and moderate and strong CYP3A inducers (see section 4.5).

Concomitant use of ponatinib with anti-clotting agents should be approached with caution in patients who may be at risk of bleeding events (see “Myelosuppression” and “Haemorrhage”). Formal studies of ponatinib with anti-clotting medicinal products have not been conducted.

QT prolongation

The QT interval prolongation potential of Ponatinib was assessed in 39 leukaemia patients and no clinically significant QT prolongation was observed (see section 5.1). However, a thorough QT study has not been performed; therefore a clinically significant effect on QT cannot be excluded.

Special populations

Hepatic impairment

Patients with hepatic impairment may receive the recommended starting dose. Caution is recommended when administering Ponatinib to patients with hepatic impairment (see sections 4.2 and 5.2).

Renal impairment

Caution is recommended in when administering Ponatinib to patients with estimated creatinine clearance of < 50 mL/min or end-stage renal disease (see section 4.2).

Lactose

This medicinal product contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

4.5. Interaction with other medicinal products and other forms of interaction

Substances that may increase ponatinib serum concentrations

CYP3A inhibitors

Ponatinib is metabolized by CYP3A4.

Co-administration of a single 15 mg oral dose of Ponatinib in the presence of ketoconazole (400 mg daily), a strong CYP3A inhibitor, resulted in modest increases in ponatinib systemic exposure, with ponatinib AUC0-∞ and Cmax values that were 78% and 47% higher, respectively, than those seen when ponatinib was administered alone.

Caution should be exercised and a reduction of the starting dose of Ponatinib to 30 mg should be considered with concurrent use of strong CYP3A inhibitors such as clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin, voriconazole, and grapefruit juice.

Substances that may decrease ponatinib serum concentrations

CYP3A inducers

Co-administration of a single 45 mg dose of Ponatinib in the presence of rifampin (600 mg daily), a strong CYP3A inducer, to 19 healthy volunteers, decreased the AUC0-∞ and Cmax of ponatinib by 62% and 42%, respectively, when compared to administration of ponatinib alone.

Co‑administration of strong CYP3A4 inducers such as carbamazepine, phenobarbital, phenytoin, rifabutin, rifampicin, and St. John's Wort with ponatinib should be avoided, and alternatives to the CYP3A4 inducer should be sought, unless the benefit outweighs the possible risk of ponatinib underexposure.

Substances that may have their serum concentrations altered by ponatinib

Transporter substrates

In vitro, ponatinib is an inhibitor of P-gp and BCRP. Therefore, ponatinib may have the potential to increase plasma concentrations of co-administered substrates of P-gp (e.g., digoxin, dabigatran, colchicine, pravastatin) or BCRP (e.g., methotrexate, rosuvastatin, sulfasalazine) and may increase their therapeutic effect and adverse reactions. Close clinical surveillance is recommended when ponatinib is administered with these medicinal products.

Paediatric population

Interaction studies have only been performed in adults.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential/Contraception in males and females

Women of childbearing age being treated with Ponatinib should be advised not to become pregnant and men being treated with Ponatinib should be advised not to father a child during treatment. An effective method of contraception should be used during treatment. It is unknown whether ponatinib affects the effectiveness of systemic hormonal contraceptives. An alternative or additional method of contraception should be used.

Pregnancy

There are no adequate data from the use of Ponatinib in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Ponatinib should be used during pregnancy only when clearly necessary. If it is used during pregnancy, the patient must be informed of the potential risk to the foetus.

Breast-feeding

It is unknown whether Ponatinib is excreted in human milk. Available pharmacodynamic and toxicological data cannot exclude potential excretion in human milk. Breast-feeding should be stopped during treatment with Ponatinib.

Fertility

No human data on the effect of ponatinib on fertility are available. In rats, treatment with ponatinib has shown effects on female fertility and male fertility was not affected (see section 5.3). The clinical relevance of these findings to human fertility is unknown.

4.7. Effects on ability to drive and use machines

Ponatinib has minor influence on the ability to drive and use machines. Adverse reactions such as lethargy, dizziness, and vision blurred have been associated with Ponatinib. Therefore, caution should be recommended when driving or operating machines.

4.8. Undesirable effects

Summary of the safety profile

Previously Treated CML or Ph+ALL (PACE Study)

In the PACE phase 2 trial (see section 5.1) the most common serious adverse reactions >2% (treatment-emergent frequencies) were pneumonia (7.3%), pancreatitis (5.8%), abdominal pain (4.7%), atrial fibrillation (4.5%), pyrexia (4.5%), myocardial infarction (4.0%), peripheral arterial occlusive disease (3.8%), anaemia (3.8%), angina pectoris (3.3%), platelet count decreased (3.1%), febrile neutropenia (2.9%), hypertension (2.9%), coronary artery disease (2.7%), cardiac failure congestive (2.4%), cerebrovascular accident (2.4%), sepsis (2.4%), cellulitis (2.2%), acute kidney injury (2.0%), urinary tract infection (2.0%) and lipase increased (2.0%).

Serious arterial cardiovascular, cerebrovascular, and peripheral vascular occlusive adverse reactions (treatment-emergent frequencies) occurred in 10%, 7%, and 9% of Ponatinib treated patients, respectively. Serious venous occlusive reactions (treatment-emergent frequencies) occurred in 5% of patients.

Arterial cardiovascular, cerebrovascular, and peripheral vascular occlusive adverse reactions (treatment-emergent frequencies) occurred in 13%, 9%, and 11% of Ponatinib-treated patients, respectively. Overall arterial occlusive adverse reactions have occurred in 25% of Ponatinib-treated patients from the PACE phase 2 trial with a minimum 64 months follow-up, with serious adverse reactions occurring in 20% of patients. Some patients experienced more than one type of event.

Venous thromboembolic reactions (treatment-emergent frequencies) occurred in 6% of patients. The incidence of thromboembolic events is higher in patients with Ph+ ALL or BP-CML than those with AP-CML or CP-CML. No venous occlusive events were fatal.

After a minimum follow-up of 64 months, the rates of adverse reactions resulting in discontinuation were 20% in CP-CML, 11% in AP-CML, 15% in BP-CML and 9% in Ph+ ALL.

Previously Treated CP-CML (OPTIC Study)

In the OPTIC phase 2 trial (see section 5.1) with a median duration of follow‑up of 77.93 months, overall arterial occlusive adverse reactions have occurred in 13.8% of Ponatinib‑treated patients (45 mg cohort) including 2 of which were fatal, and serious adverse reactions occurred in 8.5% of patients (45 mg cohort). Arterial cardiovascular, cerebrovascular, and peripheral vascular occlusive adverse reactions (treatment‑emergent frequencies) occurred in 5.3%, 4.3%, and 4.3% of Ponatinib‑treated patients (45 mg cohort), respectively. Of the 94 patients in the 45 mg cohort, 1 patient experienced a venous thromboembolic reaction (Grade 1 retinal vein occlusion).

Tabulated list of adverse reactions

The frequencies of adverse reactions are based on 449 CML and Ph+ALL patients exposed to ponatinib in the PACE phase 2 trial and the 94 CML patients exposed to ponatinib (45 mg starting dose) in the OPTIC phase 2 trial. See section 5.1 for information on the main characteristics of participants in the trials. Adverse reactions reported in all CML and Ph+ ALL patients are listed by system organ class and by frequency in Table 4. Frequency categories are very common (≥ 1/10), common (≥ 1/100 to < 1/10) and uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), and not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 4 Adverse reactions observed in previously treated CML and Ph+ ALL patients – frequency reported by incidence of treatment emergent events

System organ class

Frequency

Adverse reactions

Infections and infestations

Very common

upper respiratory tract infection

Common

pneumonia, sepsis, folliculitis, cellulitis, herpes zoster

Blood and lymphatic system disorders

Very common

anaemia, platelet count decreased, neutrophil count decreased

Common

pancytopenia, febrile neutropenia, white blood cell count decreased, lymphocyte count decreased, myelosuppression

Endocrine disorders

Common

hypothyroidisma

Metabolism and nutrition disorders

Very common

decreased appetite, hypertriglyceridaemia, hypercholesterolaemia

Common

dehydration, fluid retention, hypocalcaemia, hyperglycaemia, hyperuricaemia, hypophosphataemia, hypokalaemia, weight decreased, hyponatraemia, dyslipidaemia, glucose tolerance impaired, low density lipoprotein increased, weight increase, tumour lysis syndrome

Psychiatric disorders

Very common

insomnia

Common

anxiety

Nervous system disorders

Very common

headache, dizziness

Common

cerebrovascular accident, cerebral infarction, neuropathy peripheral, lethargy, migraine, hyperaesthesia, hypoaesthesia, paraesthesia, transient ischaemic attack, facial nerve disorder, carotid artery stenosis

Uncommon

cerebral artery stenosis, cerebral haemorrhage, haemorrhage intracranial, posterior reversible encephalopathy syndrome *

Eye disorders

Common

vision blurred, dry eye, periorbital oedema, eyelid oedema, conjunctivitis, visual impairment, eye pain, retinal vein occlusion

Uncommon

retinal vein thrombosis, retinal artery occlusion

Cardiac disorders

Common

cardiac failure, myocardial infarction, cardiac failure congestive, coronary artery disease, angina pectoris, pericardial effusion, atrial fibrillation, ejection fraction decreased, acute coronary syndrome, atrial flutter, left ventricular dysfunction, left ventricular hypertrophy, sinus bradycardia, tachycardia, n-terminal prohormone brain natriuretic peptide increased, angina unstable, myocardial ischaemia, supraventricular extrasystoles, ventricular extrasystoles, electrocardiogram qt prolonged, cardiac failure chronic, brain natriuretic peptide increased

Uncommon

cardiac discomfort, ischemic cardiomyopathy, arteriospasm coronary

Vascular disorders

Very common

hypertension

Common

peripheral arterial occlusive disease, peripheral ischaemia, peripheral artery stenosis, intermittent claudication, deep vein thrombosis, hot flush, flushing, hypertensive crisis

Uncommon

poor peripheral circulation, splenic infarction, embolism venous, venous thrombosis, renal artery stenosis

Not known

aneurysms and artery dissections

Respiratory, thoracic and mediastinal disorders

Very common

dyspnoea, cough

Common

pulmonary embolism, pleural effusion, epistaxis, dysphonia, pulmonary hypertension, oropharyngeal pain, productive cough

Gastrointestinal disorders

Very common

abdominal pain, diarrhoea, vomiting, constipation, nausea, lipase increased

Common

pancreatitis, blood amylase increased, gastrooesophageal reflux disease, stomatitis, dyspepsia, abdominal distension, abdominal discomfort, dry mouth, gastric haemorrhage, gastritis, gastric ulcer, gingival bleeding

Hepatobiliary disorders

Very common

alanine aminotransferase increased, aspartate aminotransferase increased

Common

blood bilirubin increased, blood alkaline phosphatase increased, gamma‑glutamyltransferase increased, transaminases increased, hepatotoxicity

Uncommon

hepatic failure, jaundice

Skin and subcutaneous tissue disorders

Very common

rash, dry skin, pruritus

Common

rash pruritic, exfoliative rash, erythema, alopecia, skin exfoliation, night sweats, hyperhidrosis, petechia, ecchymosis, pain of skin, dermatitis exfoliative, hyperkeratosis, skin hyperpigmentation, panniculitis (including erythema nodosum), dermatitis, rash maculo-papular, dermatitis acneiform, rash erythematous, eczema, rash macular, rash papular, erythema multiforme, dermatitis allergic, skin papilloma, dermatitis psoriasiform

Musculoskeletal and connective tissue disorders

Very common

bone pain, arthralgia, myalgia, pain in extremity, back pain, muscle spasms

Common

musculoskeletal pain, neck pain, musculoskeletal chest pain, muscular weakness, musculoskeletal stiffness, spinal pain, tendonitis

Reproductive system and breast disorders

Common

erectile dysfunction

General disorders and administrative site conditions

Very common

fatigue, asthenia, oedema peripheral, pyrexia, pain

Common

chills, influenza like illness, non-cardiac chest pain, mass, face oedema, c-reactive protein increased, chest pain

* Spontaneous reports from post-marketing experience

a hypothyroidism includes hypothyroidism, and primary hypothyroidism

Description of selected adverse reactions

Vascular occlusion (see section 4.2 and 4.4).

Serious vascular occlusion has occurred in patients treated with Ponatinib, including cardiovascular, cerebrovascular and peripheral vascular events, and venous thrombotic events. Patients with and without cardiovascular risk factors, including patients age 50 years or younger, experienced these events. Arterial occlusive adverse events were more frequent with increasing age and in patients with history of ischaemia, hypertension, diabetes, or hyperlipidaemia.

In the PACE phase 2 trial (see section 5.1) with a minimum 64‑month follow‑up, arterial cardiovascular, cerebrovascular, and peripheral vascular occlusive adverse reactions (treatment‑emergent frequencies) occurred in 13%, 9%, and 11% of Ponatinib‑treated patients, respectively. Overall, arterial occlusive adverse reactions have occurred in 25% of Ponatinib‑treated patients from the PACE phase 2 trial, with serious adverse reactions occurring in 20% of patients. Some patients experienced more than one type of event. The median time to onset of the first cardiovascular, cerebrovascular, and peripheral vascular arterial occlusive events was 351, 611, and 605 days, respectively in the PACE trial. Venous thromboembolic reactions (treatment‑emergent frequencies) occurred in 6% of patients.

In the OPTIC phase 2 trial (see section 5.1) with a median 77.9 months follow‑up, arterial cardiovascular, cerebrovascular, and peripheral vascular occlusive adverse reactions (treatment‑emergent frequencies) occurred in 5.3%, 4.3%, and 4.3% of Ponatinib‑treated patients (45 mg cohort), respectively. Overall, arterial occlusive adverse reactions have occurred in 13.8% of Ponatinib‑treated patients (45 mg cohort) with serious adverse reactions occurring in 8.5% of patients (45 mg cohort). The median time to onset of the first cardiovascular, cerebrovascular, and peripheral vascular arterial occlusive events was 473, 356, and 108 days, respectively, in the OPTIC trial. Of the 94 patients in OPTIC (45 mg cohort), 1 patient experienced a venous thromboembolic reaction.

Myelosuppression

Myelosuppression was commonly reported in all patient populations. The frequency of Grade 3 or 4 thrombocytopenia, neutropenia, and anaemia was higher in patients with AP-CML and BP‑CML/Ph+ ALL than in patients with CP-CML (see Table 5). Myelosuppression was reported in patients with normal baseline laboratory values as well as in patients with pre-existing laboratory abnormalities.

Discontinuation due to myelosuppression was infrequent (thrombocytopenia 4%, neutropenia and anaemia < 1% each).

Hepatitis B reactivation

Hepatitis B reactivation has been reported in association with BCR-ABL TKIs. Some cases resulted in acute hepatic failure or fulminant hepatitis leading to liver transplantation or a fatal outcome (see section 4.4).

Severe Cutaneous Adverse Reactions (SCARs)

Severe skin reactions (such as Stevens-Johnson Syndrome) have been reported with some BCR-ABL Tyrosine Kinase Inhibitors. Patients should be warned to immediately report suspected skin reactions, especially if associated with blistering, peeling, mucosal involvement or systemic symptoms.

Table 5 Incidence of clinically relevant grade 3/4* laboratory abnormalities in ≥ 2% of patients in any disease group from the PACE Phase 2 Trial (N=449): minimum follow-up of 64 month for all ongoing patients

Laboratory test

All patients

(N=449)

(%)

CP-CML

(N=270)

(%)

AP-CML

(N=85)

(%)

BP-CML/Ph+ ALL (N=94)

(%)

Haematology

Thrombocytopenia (platelet count decreased)

40

35

49

46

Neutropenia (ANC decreased)

34

23

52

52

Leukopenia (WBC decreased)

25

12

37

53

Anaemia (Hgb decreased)

20

8

31

46

Lymphopenia

17

10

25

28

Biochemistry

Lipase increased

14

14

13

14

Phosphorus decreased

10

10

13

9

Glucose increased

7

8

13

1

ALT increased

6

4

8

7

Sodium decreased

5

6

6

2

AST increased

4

3

5

3

Amylase increased

4

4

4

3

Potassium decreased

2

< 1

6

2

Potassium increased

2

2

1

3

Alkaline phosphatase increased

2

2

4

2

Bilirubin

1

< 1

2

1

Calcium decreased

1

< 1

2

1

ALT=alanine aminotransferase, ANC=absolute neutrophil count, AST=aspartate aminotransferase, Hgb=haemoglobin, WBC=white blood cell count.

*Reported using National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Isolated reports of unintentional overdose with Ponatinib were reported in clinical trials. Single doses of 165 mg and an estimated 540 mg in two patients did not result in any clinically significant adverse reactions. Multiple doses of 90 mg per day for 12 days in a patient resulted in pneumonia, systemic inflammatory response, atrial fibrillation, and asymptomatic, moderate pericardial effusion. Treatment was interrupted, the events resolved, and Ponatinib was restarted at 45 mg, once daily. In the event of an overdose of Ponatinib, the patient should be observed and appropriate supportive treatment given.