Source: European Medicines Agency (EU) Revision Year: 2021 Publisher: Recordati Rare Diseases, Immeuble Le Wilson, 70, Avenue du Général de Gaulle, 92800 Puteaux, France
Pharmacotherapeutic group: Ophtalmologicals, other ophtalmologicals
ATC code: S01XA21
Cysteamine reduces corneal cystine crystal accumulation acting as a cystine-depleting agent by converting cystine to cysteine and cysteine-cysteamine mixed disulfides.
Two clinical trials were performed with Cystadrops: a single arm clinical trial on 8 children and adults (OCT-1 study) and a randomised, multi-centre, open label, active controlled phase III clinical trial (CHOC study) conducted on 32 patients.
This study assessed the safety and efficacy of Cystadrops during 5 years. Dose adaptation was performed following ocular examination. None of the patients discontinued treatment over the 5 year follow-up.
The efficacy was assessed with In-Vivo Confocal Microscopy total score (IVCM score) by quantifying the cystine crystals in the 7 layers of the cornea. After 30 days of treatment and at a median frequency of 4 instillations per day, an average 30% decrease in the IVCM total score was observed. A mean decrease in corneal cystine crystal deposits of 30%, in comparison with baseline, was maintained over time with a median dosing regimen of 3 drops/eye/day (range 1-3 drops) for 7 of the 8 patients. Photophobia tended to improve over time.
This study was a randomised, controlled trial to assess the efficacy and the safety profile of Cystadrops following a period of 90 days of treatment at a dose regimen of 4 drops/eye/day. The IVCM total score was the primary efficacy endpoint. 15 patients were exposed to Cystadrops. The mean IVCM total score was calculated for 11 patients. A trend towards a lower IVCM total score in Cystadrops arm was observed at day 30. The mean decrease by 40% in the Cystadrops arm was confirmed at day 90. Superiority of Cystadrops was demonstrated compared to the control arm (cysteamine hydrochloride 0.10%) p<0.001 95% CI (2.11; 5.58). Superiority of Cystadrops was also demonstrated for photophobia rated by the investigator compared to the control arm (cysteamine hydrochloride 0.10%) p<0.048 95% CI (0.23; 1.14).
Clinical data on safety and efficacy were collected during the 2 clinical trials (OCT-1 and CHOC studies). In total 15 paediatric patients were exposed to Cystadrops whereof 3 subjects (including one 2 year and one 3 year old subject) being less than 6 years of age. The efficacy and safety results are similar in both paediatric and adult populations.
The European Medicines Agency has deferred the obligation to submit the results of studies with Cystadrops in one or more subsets of the paediatric population in the treatment of corneal cystine crystal deposits in cystinosis patients (see section 4.2 for information on paediatric use).
Human pharmacokinetic assessment following ocular administration of Cystadrops was not performed.
Similarly to other topically administered ocular products, systemic absorption is likely to occur. However it should be considered that the recommended daily dose of cysteamine applied as eye drops is no more than approximately 0.4% of the highest recommended daily oral dose of cysteamine in any age group.
Systemic exposure following ocular administration is anticipated to be low. When there is concomitant use of ocular and oral treatment with cysteamine the contribution to any systemic risk from ocular administration is considered negligible.
Genotoxicity studies have been performed: induction of chromosome aberrations in cultured eukaryotic cell lines has been reported and specific studies with cysteamine did not show any mutagenic effects in the Ames test or any clastogenic effect in the mouse micronucleus test.
Reproduction studies showed embryofoetotoxic effects (resorptions and post-implantation losses) in rats at the 100 mg/kg/day dose level and in rabbits receiving cysteamine 50 mg/kg/day. Teratogenic effects have been described in rats when cysteamine is administered over the period of organogenesis at a dose of 100 mg/kg/day.
This is equivalent to 0.6 g/m²/day in the rat, which is less than half the recommended clinical maintenance dose of cysteamine, i.e. 1.30 g/m²/day. A reduction of fertility was observed in rats at 375 mg/kg/day, a dose at which body weight gain was retarded. At this dose, weight gain and survival of the offspring during lactation was also reduced. High doses of cysteamine impair the ability of lactating mothers to feed their pups. Single doses of the drug inhibit prolactin secretion in animals.
Administration of cysteamine in neonate rats induced cataracts.
High doses of cysteamine, either by oral or parenteral routes, produce duodenal ulcers in rats and mice but not in monkeys. Experimental administration of the drug causes depletion of somatostatin in several animal species. The consequence of this for the clinical use of the drug is unknown.
No carcinogenic studies have been conducted with cysteamine.
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