Ponatinib (Specialist drug)

PRESCRIBING AND BASELINE ASSESSMENT: therapy should be initiated by a physician experienced in the diagnosis and treatment of patients with leukaemia. Before starting, the cardiovascular status of the patient should be assessed (history and physical examination) and cardiovascular risk factors actively managed; cardiovascular status should continue to be monitored and supportive therapy optimised during treatment. RESPONSE AND DISCONTINUATION: 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). DOSE REDUCTION IN CP-CML: the risk of arterial occlusive events is likely to be dose-related — reducing the dose to 15 mg should be considered for chronic phase CML patients who have achieved molecular response (MR2, i.e. 1% or less BCR-ABL1 IS), taking into account cardiovascular risk, side effects, time to response and BCR-ABL transcript levels; close monitoring of response is recommended after reduction. In patients with loss of response the dose can be re-escalated to a previously tolerated dose of 30 mg or 45 mg once daily, and continued until loss of response at the re-escalated dose or unacceptable toxicity. MYELOSUPPRESSION (ANC below 1.0 x 10^9/L or platelets below 50 x 10^9/L unrelated to leukaemia): first occurrence — withhold and resume at the same dose after recovery to ANC at least 1.5 x 10^9/L and platelets at least 75 x 10^9/L; recurrence at 45 mg — withhold and resume at 30 mg after recovery; recurrence at 30 mg — withhold and resume at 15 mg after recovery. ARTERIAL OCCLUSION AND VENOUS THROMBOEMBOLISM: interrupt immediately if suspected; a benefit-risk consideration should guide restarting after the event resolves. Treatment should be temporarily interrupted if hypertension is not medically controlled. PANCREATITIS AND LIPASE ELEVATION: Grade 2 pancreatitis and/or Grade 2 lipase elevation — continue at the same dose; Grade 3 asymptomatic lipase elevation (above 5.0 x IULN) — withhold and resume at the next lower dose (45 mg to 30 mg, 30 mg to 15 mg) after recovery to Grade 1 or less, and consider discontinuation if it occurs at 15 mg; Grade 3 pancreatitis or Grade 3 symptomatic lipase elevation — withhold until complete resolution of symptoms and recovery of lipase to below Grade 2, then resume at the next lower dose, considering discontinuation if it occurs at 15 mg; Grade 4 pancreatitis or Grade 4 lipase elevation — discontinue. HEPATIC TOXICITY: transaminase elevation above 3 x ULN that is persistent Grade 2 (longer than 7 days) or Grade 3 or higher — interrupt and monitor hepatic function, resuming at 30 mg (if it occurred at 45 mg) or 15 mg (if it occurred at 30 mg) after recovery to Grade 1 or less or to pre-treatment grade, and discontinue if it occurs at 15 mg; discontinue for AST or ALT at least 3 x ULN concurrent with bilirubin above 2 x ULN and alkaline phosphatase below 2 x ULN. TABLET STRENGTHS: 15 mg, 30 mg and 45 mg film-coated tablets are available. ELDERLY: of 732 patients in the PACE and OPTIC studies, 191 (26%) were 65 years or older and older patients are more likely to experience adverse reactions. HEPATIC IMPAIRMENT: patients may receive the recommended starting dose, but caution is recommended. PAEDIATRIC: safety and efficacy in patients under 18 years have not been established and no data are available. US LABELLING DIFFERENCE (from the openFDA provider in the same bundle, for cross-check only): the US label gives a starting dose of 30 mg once daily in combination with chemotherapy for newly diagnosed Ph+ ALL, reduced to 15 mg once daily on achieving MRD-negative complete remission at the end of induction, and continued for up to 20 cycles — this indication and dose are not in the fetched UK SPC. SOURCE LIMITS: eMC §4.5 was not fetched and §4.4/§4.8 were truncated — the interactions listed in this draft come from section 7 of the US prescribing information contained in the same bundle.