CYSTADROPS 3.8mg / ml ophthalmic drops solution medication leaflet

Cystadrops 3.8 mg/mL eye drops solution

Each mL contains mercaptamine hydrochloride equivalent to 3.8 mg mercaptamine (cysteamine).

Each mL of eye drops solution contains 0.1 mg of benzalkonium chloride.

For the full list of excipients, see section 6.1.

Eye drops solution.

Viscous, clear solution.

Cystadrops is indicated for the treatment of corneal cystine crystal deposits in adults and children from6 months of age with cystinosis.

Treatment with Cystadrops should be initiated under the supervision of a physician experienced in themanagement of cystinosis.

The recommended dose is one drop in each eye, 4 times a day during waking hours. Therecommended interval between each instillation is 4 hours. The dose could be decreased progressively(to a minimum total daily dose of 1 drop in each eye) depending on the results of ophthalmicexamination (such as, corneal cystine crystal deposits, photophobia).

If the patient misses an instillation, the patient should be told to continue the treatment with the nextinstillation.

The dose should not exceed 4 drops a day in each eye.

The accumulation of corneal cystine crystals increases if Cystadrops is discontinued. The treatmentshould not be stopped.

Cystadrops may be used in paediatric patients from 6 months of age at the same dose as in adults (seesection 5.1).

The safety and efficacy of Cystadrops in children aged less than 6 months has not been established. Nodata are available.

For ocular use.

Before the first admnistration, in order to facilitate the administration, the patient should be told tobring back Cystadrops at room temperature. After first opening, the patient should be told to keep thedropper bottle at room temperature.

To avoid sticky eyes in the morning, the patient should be advised to apply the last drop of the day atleast 30 minutes before going to bed.

To prevent contamination of the dropper tip and solution, care must be taken not to touch the eyelids,surrounding areas, or other surfaces with the dropper tip of the dropper bottle.

The patient should be told to discard the dropper bottle after 7 days of use.

In case of concomitant therapy with other topical ocular medicinal products, an interval of ten minutesshould be allowed between successive applications. Eye ointments should be administered last.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Contact lenses

Benzalkonium chloride is known to discolour soft contact lenses. Contact with soft contact lensesshould be avoided. Patients should be instructed to remove contact lenses prior to the administration ofthe eye drops and wait at least 15 minutes before re-inserting contact lenses.

Excipents with known effect

Cystadrops contains benzalkonium chloride which may cause eye irritation.

Benzalkonium chloride, which is commonly used as a preservative in ophtalmic products, has alsobeen reported to cause punctate keratopathy and/or toxic ulcerative keratopathy. Monitoring isrequired.

No interaction studies have been performed.

Since the recommended total daily dose of cysteamine base is no more than approximately 0.4% of thehighest recommended oral dose of cysteamine base in any age group, no interactions with orallyadministered medicinal products are anticipated.

The recommended total daily ocular dose of cysteamine is no more than approximately 0.4% of thehighest recommended dose of oral cysteamine in any age group. Systemic exposure of cysteaminefollowing ocular administration is therefore lower than following oral administration. Although noeffects during pregnancy and breast-feeding are anticipated, since systemic exposure to cysteamine isnegligible, precautions should be taken with concomitant treatment with oral cysteamine.

There are no adequate data from the use of cysteamine in pregnant women. Studies in animals haveshown reproductive toxicity, including teratogenesis (see section 5.3). The potential risk for humans isunknown. The effect on pregnancy of untreated cystinosis is also unknown.

Therefore, oral cysteamine should not be used during pregnancy, particularly during the first trimester,unless clearly necessary.

If a pregnancy is diagnosed or planned, the treatment should be carefully reconsidered and the patientmust be advised of the possible teratogenic risk of cysteamine.

Cysteamine excretion in human's milk is unknown. However, due to the results of animal studies inbreast-feeding mothers and neonates (see section 5.3), women taking oral cysteamine should notbreast-feed.

No data on the effect of cysteamine on human fertility are available. Studies in animals have shown areduction on fertility (see section 5.3).

Cystadrops may have a minor influence on the ability to drive and use machines.

Temporary (in average less than 1 minute) blurred vision or other visual disturbances may affect theability to drive or use machines.

If blurred vision occurs at instillation, the patient must wait until the vision clears before driving orusing machines.

The most common adverse reactions are eye pain, ocular hyperaemia, eye pruritus, lacrimationincreased, blurred vision or eye irritation. The majority of these adverse reactions are transient andmost are mild or moderate.

The following adverse reactions were reported during clinical trials and the French NPU programmewith Cystadrops. Reported adverse reactions are listed below, by system organ class and by frequency(by patient).

Frequencies are defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10 000 to < 1/1 000), very rare (< 1/10 000), not known (cannot beestimated from the available data).

System organ class Adverse reactions

Eye disorders Very common : eye pain, vision blurred, eye irritation, ocularhyperaemia, eye pruritus, lacrimation increased, deposit eye

Common : abnormal sensation in eye, dry eye, foreign bodysensation in eye, eyelid oedema, eyelid irritation, visualimpairment, hordeolum

General disorders and administration Very common : instillation site discomfort (mainly sticky eyessite conditions and sticky eyelashes)

Common : instillation site pain

Frequency, type and severity of adverse reactions in children are the same as in adults.74 paediatric patients were followed through clinical trials and the French NPU programme. 5 patientswere below 2 years old , the youngest was 13 months old, 19 patients were under 6 years old, 21between 6 and 12 years old and 29 between 12 and 18 years old.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Overdose is unlikely to occur with ocular administration.

In case of accidental ingestion, monitoring and symptomatic management of the patient should beimplemented.

Pharmacotherapeutic group: Ophtalmologicals, other ophtalmologicals, ATC code: S01XA21.

Cysteamine reduces corneal cystine crystal accumulation acting as a cystine-depleting agent byconverting cystine to cysteine and cysteine-cysteamine mixed disulfides.

Three clinical trials were performed with Cystadrops:

* a single arm clinical trial on 8 children and adults (OCT-1 study)

* a randomised, multi-centre, open label, active controlled phase III clinical trial (CHOC study)conducted on 32 patients.

* an open-label, single arm, multicenter Study (CYT-C2-001) conducted on 5 patients under 2years of age.

OCT-1 study

This study assessed the safety and efficacy of Cystadrops during 5 years. Dose adaptation wasperformed following ocular examination. None of the patients discontinued treatment over the 5 yearfollow-up.

The efficacy was assessed with In-Vivo Confocal Microscopy total score (IVCM score) byquantifying the cystine crystals in the 7 layers of the cornea. After 30 days of treatment and at amedian frequency of 4 instillations per day, an average 30% decrease in the IVCM total score wasobserved. 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 ofthe 8 patients. Photophobia tended to improve over time.

CHOC study

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. Themean 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 wasconfirmed at day 90. Superiority of Cystadrops was demonstrated compared to the control arm(cysteamine hydrochloride 0.10%) p<0.0001 95% CI (2.11; 5.58). Superiority of Cystadrops was alsodemonstrated for photophobia rated by the investigator compared to the control arm (cysteaminehydrochloride 0.10%) p=0.0048 95% CI (0.23; 1.14).

Clinical data on safety and efficacy were collected during the 3 clinical trials (OCT-1, CHOC and

CYT-C2-001 studies). In total 20 paediatric patients were exposed to Cystadrops whereof 5 subjectswere younger than 2 years of age. The youngest enrolled patient was 13 months old. The efficacy andsafety results are similar in both paediatric and adult populations.

Human pharmacokinetic assessment following ocular administration of Cystadrops was notperformed.

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 dropsis no more than approximately 0.4% of the highest recommended daily oral dose of cysteamine in anyage group.

Systemic exposure following ocular administration is anticipated to be low. When there is concomitantuse of ocular and oral treatment with cysteamine the contribution to any systemic risk from ocularadministration is considered negligible.

Preclinical data on oral cysteamine:

Genotoxicity studies have been performed: induction of chromosome aberrations in culturedeukaryotic cell lines has been reported and specific studies with cysteamine did not show anymutagenic effects in the Ames test or any clastogenic effect in the mouse micronucleus test.

Reproduction studies showed embryofoetotoxic effects (resorptions and post-implantation losses) inrats at the 100 mg/kg/day dose level and in rabbits receiving cysteamine 50 mg/kg/day. Teratogeniceffects have been described in rats when cysteamine is administered over the period of organogenesisat 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 clinicalmaintenance dose of cysteamine, i.e. 1.30 g/m2/day. A reduction of fertility was observed in rats at375 mg/kg/day, a dose at which body weight gain was retarded. At this dose, weight gain and survivalof the offspring during lactation was also reduced. High doses of cysteamine impair the ability oflactating mothers to feed their pups. Single doses of the medicinal product inhibit prolactin secretionin 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 micebut not in monkeys. Experimental administration of the medicinal product causes depletion ofsomatostatin in several animal species. The consequence of this for the clinical use of the medicinalproduct is unknown.

No carcinogenic studies have been conducted with cysteamine.

Disodium edetate

Carmellose sodium

Citric acid monohydrate

Sodium hydroxide (for pH adjustment)

Hydrochloric acid (for pH adjustment)

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.

6 months

After first opening: 7 days. Store below 25°C. Do not refrigerate. Keep the dropper bottle tightlyclosed in the outer carton in order to protect from light.

Before first opening:

Store in a refrigerator (2°C - 8°C).

Keep the vial in the outer carton in order to protect from light.

For storage conditions after first opening of the medicinal product, see section 6.3.

5 mL solution in a 10 mL amber glass vial closed by a bromobutyl stopper and sealed with analuminium tear-off cap. A PVC dropper applicator with HDPE closure is packed separately andincluded in each carton box.

Each carton box contains 1 vial and 1 dropper applicator.

Pack of 1 carton box or multipack containing 4 carton boxes.

Not all pack sizes may be marketed.

The patient should be advised to follow the instructions below for opening of the vial and attachementof the dropper applicator:

* Wash your hands carefully in order to avoid microbiological contamination of the content in thevial.

* Remove the green protective cap (picture 1).

* Remove the metal seal (picture 2).

* Remove the grey stopper (picture 3) from the vial.

* Do not touch the opening of the vial after removing the grey stopper.

removeremove removegreen protective cap metal seal greystoppervial

* Take the dropper out of its sachet, without touching the end intended to be attached to the vial,attach it (picture 4) to the vial and do not remove it.

small white capturn and push small white capto attach dropperdropper vialvial

* Make sure that you do not lose the small white cap (picture 5) that comes on the top of thedropper.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Recordati Rare Diseases

Tour Hekla52, Avenue du Général de Gaulle92800 Puteaux

France

EU/1/15/1049/001

EU/1/15/1049/002

Date of first authorisation: 19 January 2017

Date of latest renewal: 15 September 2021

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.