Nilotinib (Specialist drug)

SOURCE: UK SPC (Nilotinib 150 mg Hard Capsules, https://www.medicines.org.uk/emc/product/101249/smpc), section 4.2. Therapy should be initiated by a physician experienced in the diagnosis and treatment of patients with CML. Treatment should be continued as long as clinical benefit is observed or until unacceptable toxicity occurs. MISSED DOSE: the patient should not take an additional dose, but take the usual prescribed next dose. HAEMATOLOGICAL DOSE ADJUSTMENT (section 4.2, Table 2) — adults with newly diagnosed chronic phase CML at 300 mg twice daily and imatinib-resistant or intolerant chronic phase CML at 400 mg twice daily: for ANC below 1.0 x 10^9/L and/or platelets below 50 x 10^9/L, interrupt nilotinib and monitor blood counts; resume within 2 weeks at the prior dose if ANC is above 1.0 x 10^9/L and/or platelets above 50 x 10^9/L; if blood counts remain low, a dose reduction to 400 mg ONCE daily may be required. Adults with imatinib-resistant or intolerant accelerated phase CML at 400 mg twice daily: for ANC below 0.5 x 10^9/L and/or platelets below 10 x 10^9/L, interrupt and monitor; resume within 2 weeks at the prior dose if ANC is above 1.0 x 10^9/L and/or platelets above 20 x 10^9/L; if counts remain low, a dose reduction to 400 mg once daily may be required. NON-HAEMATOLOGICAL TOXICITY: if clinically significant moderate or severe non-haematological toxicity develops, interrupt dosing, monitor and treat; if the prior dose was 300 mg twice daily (adult newly diagnosed chronic phase) or 400 mg twice daily (adult resistant or intolerant chronic or accelerated phase), dosing may be resumed at 400 mg ONCE daily once the toxicity has resolved; if the prior dose was already 400 mg once daily, treatment should be discontinued. Where clinically appropriate, re-escalation to the starting dose should be considered. ELEVATED SERUM LIPASE: for Grade 3 to 4 elevations, reduce the adult dose to 400 mg once daily or interrupt; test serum lipase monthly or as clinically indicated. ELEVATED BILIRUBIN AND HEPATIC TRANSAMINASES: for Grade 3 to 4 elevations in adults, reduce to 400 mg once daily or interrupt; test monthly or as clinically indicated. TREATMENT DISCONTINUATION (treatment-free remission) is described in section 4.2 for two adult chronic-phase populations — those treated with nilotinib as first-line therapy at 300 mg twice daily for a minimum of 3 years with a sustained deep molecular response (MR4.5) for at least one year immediately prior, and those who achieved sustained MR4.5 on nilotinib following prior imatinib therapy after a minimum of 3 years. Discontinuation must be initiated by a physician experienced in treating CML; BCR-ABL transcript levels and full blood count with differential must be monitored monthly for one year, then every 6 weeks for the second year, then every 12 weeks, using a quantitative diagnostic test validated to at least MR4.5 sensitivity (BCR-ABL/ABL 0.0032% IS or less). First-line group: for loss of MR4 but not MMR, monitor BCR-ABL every 2 weeks until levels return to between MR4 and MR4.5; patients maintaining levels between MMR and MR4 for at least 4 consecutive measurements can return to the original monitoring schedule; patients who lose MMR must re-initiate treatment within 4 weeks, at 300 mg twice daily or at a reduced dose of 400 mg once daily if the patient had a dose reduction prior to discontinuation. Post-imatinib group: confirmed loss of MR4 (two consecutive measures at least 4 weeks apart) or loss of MMR requires re-initiation within 4 weeks, at either 300 mg or 400 mg twice daily. HEPATIC IMPAIRMENT: hepatic impairment has a modest effect on pharmacokinetics and dose adjustment is not considered necessary, but such patients should be treated with caution. CARDIAC: patients with uncontrolled or significant cardiac disease were excluded from clinical studies; caution should be exercised in patients with relevant cardiac disorders. MONITORING: lipid profiles should be determined prior to initiating therapy, at months 3 and 6, and at least yearly during chronic therapy; blood glucose should be assessed prior to initiation and monitored during treatment; complete blood counts every two weeks for the first 2 months and then monthly, or as clinically indicated; a baseline ECG is recommended prior to initiating therapy and as clinically indicated, and hypokalaemia or hypomagnesaemia must be corrected before starting. PAEDIATRIC — NOT structured in paedDose because the SPC dose is body-surface-area based (mg/m2), not per kg: 'Dosing in paediatric patients is individualised and is based on body surface area (mg/m2). The recommended dose of nilotinib is 230 mg/m2 twice daily, rounded to the nearest 50 mg dose (to a maximum single dose of 400 mg).' SPC Table 1 dosing scheme (dose twice daily by BSA): up to 0.32 m2 — 50 mg; 0.33 to 0.54 m2 — 100 mg; 0.55 to 0.76 m2 — 150 mg; 0.77 to 0.97 m2 — 200 mg; 0.98 to 1.19 m2 — 250 mg; 1.20 to 1.41 m2 — 300 mg; 1.42 to 1.63 m2 — 350 mg; 1.64 m2 and above — 400 mg. Different capsule strengths can be combined to attain the desired dose. Safety and efficacy have been established from 2 to under 18 years of age in Philadelphia chromosome positive chronic phase CML; there is no experience below 2 years of age or in accelerated phase or blast crisis, no data in newly diagnosed patients below 10 years, and limited data in imatinib-resistant or intolerant patients below 6 years. Paediatric dose modification: for ANC below 1.0 x 10^9/L and/or platelets below 50 x 10^9/L, interrupt and monitor, resume within 2 weeks at the prior dose if ANC is above 1.5 x 10^9/L and/or platelets above 75 x 10^9/L, and if counts remain low reduce to 230 mg/m2 ONCE daily; if the event recurs after dose reduction, consider discontinuing. For non-haematological toxicity, elevated lipase (Grade 3 to 4) or elevated bilirubin (Grade 2 or higher) or hepatic transaminases (Grade 3 or higher), interrupt until Grade 1 or lower, then resume at 230 mg/m2 once daily if the prior dose was 230 mg/m2 twice daily; if the prior dose was already 230 mg/m2 once daily, discontinue (for bilirubin/transaminases, discontinue if recovery to Grade 1 or lower takes longer than 28 days). Verify any under-18 use against a children's formulary. SPC sections 4.4 and 4.8 were truncated at the source-fetch limit.