nt of life-threatening bradycardia Zykadia should be permanently discontinued if no contributing concomitant medicinal product is identified; however, if associated with a concomitant medicinal product known to cause bradycardia or hypotension, Zykadia should be withheld until recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above. If the concomitant medicinal product can be adjusted or discontinued, Zykadia should be reinitiated with dose reduced by 150 mg on recovery to asymptomatic bradycardia or to a heart rate of 60 bpm or above, with frequent monitoring (see sections 4.2 and 4.8).
Gastrointestinal adverse reactions
Diarrhoea, nausea, or vomiting occurred in 74.2% of 89 patients treated with Zykadia at the recommended dose of 450 mg taken with food in a dose optimisation study and were mainly grade 1 events (49.4%). One patient (1.1%) experienced grade 3 diarrhoea. Seven patients (7.9%) required study drug interruption due to diarrhoea or nausea. The incidence and severity of gastrointestinal adverse drug reactions were higher for patients treated with Zykadia 750 mg fasted (diarrhoea 76%, nausea 50%, vomiting 56%; 12% reported a grade 3/4 event) compared to 450 mg with food (diarrhoea 56%, nausea 45%, vomiting 35%; 1.1% reported a grade 3/4 event).
No patients required dose reduction or discontinuation of Zykadia due to diarrhoea, nausea or vomiting (see section 4.8).
Patients should be monitored and managed using standards of care, including anti-diarrhoeals, anti-emetics or fluid replacement, as clinically indicated. Dose interruption and dose reduction should be employed as necessary (see sections 4.2 and 4.8). If vomiting occurs during the course of treatment, the patient should not take an additional dose, but should continue with the next scheduled dose.
Hyperglycaemia
Cases of hyperglycaemia (all grades) have been reported in less than 10% of patients treated with ceritinib in clinical studies; grade 3-4 hyperglycaemia was reported in 5.4% of patients. The risk of hyperglycaemia was higher in patients with diabetes mellitus and/or concurrent steroid use.
Patients should be monitored for fasting plasma glucose prior to the start of Zykadia treatment and periodically thereafter as clinically indicated. Anti-hyperglycaemic medicinal products should be initiated or optimised as indicated (see sections 4.2 and 4.8).
Lipase and/or amylase elevations
Elevations of lipase and/or amylase have occurred in patients treated with ceritinib in clinical studies. Patients should be monitored for lipase and amylase elevations prior to the start of Zykadia treatment and periodically thereafter as clinically indicated (see sections 4.2 and 4.8). Cases of pancreatitis have been reported in patients treated with ceritinib (see section 4.8).
4.5 Interaction with other medicinal products and other forms of interaction
Agents that may increase ceritinib plasma concentrations
Strong CYP3A inhibitors
In healthy subjects, co-administration of a single 450 mg fasted ceritinib dose with ketoconazole (200 mg twice daily for 14 days), a strong CYP3A/P-gp inhibitor, resulted in 2.9-fold and 1.2-fold increase in ceritinib AUCinf and Cmax, respectively, compared to when ceritinib was given alone. The steady-state AUC of ceritinib at reduced doses after co-administration with ketoconazole 200 mg twice daily for 14 days was predicted by simulations to be similar to the steady-state AUC of ceritinib alone. Avoid conc |
