h ceritinib.
Reproductive toxicology studies (i.e. embryo-foetal development studies) in pregnant rats and rabbits indicated no foetotoxicity or teratogenicity after dosing with ceritinib during organogenesis; however, maternal plasma exposure was less than that observed at the recommended human dose. Formal non-clinical studies on the potential effects of ceritinib on fertility have not been conducted.
The principal toxicity related to ceritinib administration in rats and monkeys was inflammation of the extra-hepatic bile ducts accompanied by increased neutrophil counts in the peripheral blood. Mixed cell/neutrophilic inflammation of the extra-hepatic ducts extended to the pancreas and/or duodenum at higher doses. Gastrointestinal toxicity was observed in both species characterised by body weight loss, decreased food consumption, emesis (monkey), diarrhoea and, at high doses, by histopathological lesions including erosion, mucosal inflammation and foamy macrophages in the duodenal crypts and submucosa. The liver was also affected in both species, at exposures that approximate clinical exposures at the recommended human dose, and included minimal increases in liver transaminases in a few animals and vacuolation of the intra-hepatic bile duct epithelium. Alveolar foamy macrophages (confirmed phospholipidosis) were seen in the lungs of rats, but not in monkeys, and the lymph nodes of rats and monkeys had macrophage aggregates. Target organ effects showed partial to complete recovery.
Effects on the thyroid were observed in both rat (mild increases in thyroid stimulating hormone and triiodothyronine/thyroxine T3/T4 concentrations with no microscopic correlate) and monkey (depletion of colloid in males in 4-week study, and one monkey at high dose with diffuse follicular cell hyperplasia and increased thyroid stimulating hormone in 13-week study). As these non-clinical effects were mild, variable and inconsistent, the relationship between ceritinib and thyroid gland changes in animals is unclear.
6. Pharmaceutical particulars
6.1 List of excipients
Capsule content
Microcrystalline cellulose
Low substituted-hydroxypropylcellulose
Sodium starch glycolate (type A)
Magnesium stearate
Silica, colloidal anhydrous
Capsule shell
Gelatin
Indigotine (E132)
Titanium dioxide (E171)
Printing ink
Shellac (bleached, de-waxed) glaze 45%
Iron oxide black (E172)
Propylene glycol
Ammonium hydroxide 28%
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 years
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
PVC/polychlorotrifluoroethylene (PCTFE) – Alu blisters containing 10 hard capsules.
Packs containing 40, 90 or 150 (3 packs of 50) hard capsules.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7. Marketing authorisation holder
Novartis Europharm Limited
Vista Building
Elm Park, Merrion Road
Dublin 4
Ireland
8. Marketing authorisation number(s)
EU/1/15/999/001-003
9. Date of first authorisation/renewal of the authorisation
Date of first authorisation: 06 May 2015
Date of latest renewal: 22 March 2017
10. Date of revision of the text
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