IKERVIS 1mg / ml ophthalmic drops emulsion medication leaflet

IKERVIS 1 mg/mL eye drops, emulsion

One mL of emulsion contains 1 mg of ciclosporin.

One mL of emulsion contains 0.05 mg cetalkonium chloride (see section 4.4).

For the full list of excipients, see section 6.1.

Eye drops, emulsion.

Milky white emulsion.

Treatment of severe keratitis in adult patients with dry eye disease, which has not improved despitetreatment with tear substitutes (see section 5.1).

Treatment must be initiated by an ophthalmologist or a healthcare professional qualified inophthalmology.

The recommended dose is one drop once daily to be applied to the affected eye(s) at bedtime.

Response to treatment should be reassessed at least every 6 months.

If a dose is missed, treatment should be continued on the next day as normal. Patients should beadvised not to instil more than one drop in the affected eye(s).

The elderly population has been studied in clinical studies. No dose adjustment is required.

The effect of ciclosporin has not been studied in patients with hepatic or renal impairment. However,no special considerations are needed in these populations.

There is no relevant use of ciclosporin in children and adolescents aged below 18 in the treatment ofsevere keratitis in patients with dry eye disease, which has not improved despite treatment with tearsubstitutes.

Ocular use.

Precautions to be taken before administering the medicinal product

Patients should be instructed to first wash their hands.

Prior to administration, the single-dose container should be gently shaken.

For single use only. Each single-dose container is sufficient to treat both eyes. Any unused emulsionshould be discarded immediately.

Patients should be instructed to use nasolacrimal occlusion and to close the eyelids for 2 minutes afterinstillation, to reduce the systemic absorption. This may result in a decrease in systemic undesirableeffects and an increase in local activity.

If more than one topical ophthalmic medicinal product is being used, the medicinal products must beadministered at least 15 minutes apart. IKERVIS should be administered last (see section 4.4).

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

Ocular or peri-ocular malignancies or premalignant conditions.

Active or suspected ocular or peri-ocular infection.

IKERVIS has not been studied in patients with a history of ocular herpes and should therefore be usedwith caution in such patients.

Contact lenses

Patients wearing contact lenses have not been studied. Careful monitoring of patients with severekeratitis is recommended. Contact lenses should be removed before instillation of the eye drops atbedtime and may be reinserted at wake-up time.

Concomitant therapy

There is limited experience with ciclosporin in the treatment of patients with glaucoma. Regularclinical monitoring should be exercised when treating these patients concomitantly with IKERVIS,especially with beta-blockers which are known to decrease tear secretion.

Effects on the immune system

Ophthalmic medicinal products, which affect the immune system, including ciclosporin, may affecthost defences against local infections and malignancies. Therefore, regular examination of the eye(s) isrecommended, e.g. at least every 6 months, when IKERVIS is used for years.

Cetalkonium chloride content

IKERVIS contains cetalkonium chloride. Contact lenses should be removed prior to application andmay be reinserted at wake-up time. Cetalkonium chloride may cause eye irritation. Patients should bemonitored in case of prolonged use.

No interaction studies have been performed with IKERVIS.

Combination with other medicinal products that affect the immune system

Co-administration of IKERVIS with eye drops containing corticosteroids could potentiate the effectsof ciclosporin on the immune system (see section 4.4).

IKERVIS is not recommended in women of childbearing potential not using effective contraception.

There is no data from the use of IKERVIS in pregnant women.

Studies in animals have shown reproductive toxicity following systemic administration of ciclosporinat exposure considered sufficiently in excess of the maximum human exposure indicating littlerelevance to the clinical use of IKERVIS.

IKERVIS is not recommended during pregnancy unless the potential benefit to the mother outweighsthe potential risk to the foetus.

Following oral administration, ciclosporin is excreted in breast milk. There is insufficient informationon the effects of ciclosporin in newborns/infants. However, at therapeutic doses of ciclosporin in eyedrops, it is unlikely that sufficient amounts would be present in breast milk. A decision must be madewhether to discontinue breast-feeding or to discontinue/abstain from IKERVIS therapy taking intoaccount the benefit of breast-feeding for the child and the benefit of therapy for the woman.

There is no data on the effects of IKERVIS on human fertility.

No impairment of fertility has been reported in animals receiving intravenous ciclosporin (seesection 5.3).

IKERVIS has moderate influence on the ability to drive and use machines.

This medicinal product may induce temporary blurred vision or other visual disturbances which mayaffect the ability to drive or use machines (see section 4.8). Patients should be advised not to drive oruse machines until their vision has cleared.

The most common adverse reactions are eye pain (19.0%), eye irritation (17.5%), ocular hyperaemia(5.5%), lacrimation increased (4.9%) and eyelid erythema (1.7%) which are usually transitory andoccurred during instillation.These adverse reactions are consistent with those that have been reportedduring post-marketing experience.

The following adverse reactions listed below were observed in clinical studies or during post-marketing experience. They are ranked according to system organ class and classified according to thefollowing convention: very common (1/10), common (1/100 to <1/10), uncommon (1/1,000 to<1/100), rare (1/10,000 to <1/1,000), very rare (<1/10,000), or not known (cannot be estimated fromthe available data).

System Organ Class Frequency Adverse reactions

Infections and Uncommon Keratitis bacterial,infestations Herpes zoster ophthalmic.

Eye disorders Very Eye pain,common Eye irritation

Common Erythema of eyelid,

Lacrimation increased,

Ocular hyperaemia,

Vision blurred,

Eyelid oedema,

Conjunctival hyperaemia,

Eye pruritus

Uncommon Conjunctival oedema,

Lacrimal disorder,

Eye discharge,

Conjunctival irritation,

Conjunctivitis,

Foreign body sensation in eyes,

Deposit eye,

Keratitis,

Blepharitis,

Chalazion,

Corneal infiltrates,

Corneal scar,

Eyelid pruritus,

Iridocyclitis.

Ocular discomfort

General disorders and Uncommon Instillation site reactionadministration siteconditions

Nervous system Uncommon Headachedisorders

Eye pain

A frequently reported local adverse reaction associated with the use of IKERVIS during clinical trials.

It is likely to be attributable to ciclosporin.

Generalised and localised infections

Patients receiving immunosuppressive therapies, including ciclosporin, are at increased risk ofinfections. Both generalised and localised infections can occur. Pre-existing infections may also beaggravated (see section 4.3). Cases of infections have been reported uncommonly in association withthe use of IKERVIS.

As precautionary measure, action should be taken to reduce the systemic absorption (see section 4.2).

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.

A topical overdose is not likely to occur after ocular administration. If overdose with IKERVIS occurs,treatment should be symptomatic and supportive.

Pharmacotherapeutic group: Ophthalmologicals, other ophthalmologicals, ATC code: S01XA18.

Mechanism of action and pharmacodynamic effects

Ciclosporin (also known as ciclosporin A) is a cyclic polypeptide immunomodulator withimmunosuppressant properties. It has been shown to prolong survival of allogeneic transplants inanimals and significantly improved graft survival in all types of solid organ transplantation in man.

Ciclosporin has also been shown to have an anti-inflammatory effect. Studies in animals suggest thatciclosporin inhibits the development of cell-mediated reactions. Ciclosporin has been shown to inhibitthe production and/or release of pro-inflammatory cytokines, including interleukin 2 (IL-2) or T-cellgrowth factor (TCGF). It is also known to up-regulate the release of anti-inflammatory cytokines.

Ciclosporin appears to block the resting lymphocytes in the G0 or G1 phase of the cell cycle. Allavailable evidence suggests that ciclosporin acts specifically and reversibly on lymphocytes and doesnot depress haematopoiesis or has any effect on the function of phagocytic cells.

In patients with dry eye disease, a condition that may be considered to have an inflammatoryimmunological mechanism, following ocular administration, ciclosporin is passively absorbed into T-lymphocyte infiltrates in the cornea and conjunctiva and inactivates calcineurin phosphatase.

Ciclosporin-induced inactivation of calcineurin inhibits the dephosphorylation of the transcriptionfactor NF-AT and prevents NF-AT translocation into the nucleus, thus blocking the release of pro-inflammatory cytokines such as IL-2.

The efficacy and safety of IKERVIS were evaluated in two randomised, double-masked, vehicle-controlled clinical studies in adult patients with dry eye disease (keratoconjunctivitis sicca) who metthe International Dry Eye Workshop (DEWS) criteria.

In the 12 month, double-masked, vehicle controlled, pivotal clinical trial (SANSIKA study), 246 Dry

Eye Disease (DED) patients with severe keratitis (defined as a corneal fluorescein staining (CFS)score of 4 on the modified Oxford scale) were randomised to one drop of IKERVIS or vehicle daily atbedtime for 6 months. Patients randomised to the vehicle group were switched to IKERVIS after6 months. The primary endpoint was the proportion of patients achieving by month 6 at least a two-grade improvement in keratitis (CFS) and a 30% improvement in symptoms, measured with the

Ocular Surface Disease Index (OSDI). The proportion of responders in the IKERVIS group was28.6%, compared to 23.1% in the vehicle group. The difference was not statistically significant(p=0.326).

The severity of keratitis, assessed using CFS, improved significantly from baseline at month 6 with

IKERVIS compared to vehicle (mean change from baseline was -1.764 with IKERVIS vs. -1.418 withvehicle, p=0.037). The proportion of IKERVIS-treated patients with a 3-grade improvement in CFSscore at month 6 (from 4 to 1) was 28.8%, compared to 9.6% of vehicle-treated subjects, but this was apost-hoc analysis, which limits the robustness of this outcome. The beneficial effect on keratitis wasmaintained in the open phase of the study, from month 6 and up to month 12.

The mean change from baseline in the 100-point OSDI score was -13.6 with IKERVIS and -14.1 withvehicle at month 6 (p=0.858). In addition, no improvement was observed for IKERVIS compared tovehicle at month 6 for other secondary endpoints, including ocular discomfort score, Schirmer test, useof concomitant artificial tears, investigator’s global evaluation of efficacy, tear break-up time,lissamine green staining, quality of life score, and tear osmolarity.

A reduction in the ocular surface inflammation assessed with Human Leukocyte Antigen-DR (HLA-

DR) expression (an exploratory endpoint), was observed at month 6 in favour of IKERVIS (p=0.021).

In the 6 month, double-masked, vehicle controlled, supportive clinical trial (SICCANOVE study),492 DED patients with moderate to severe keratitis (defined as a CFS score of 2 to 4) were alsorandomised to IKERVIS or vehicle daily at bedtime for 6 months. The co-primary endpoints were thechange in CFS score, and the change in global score of ocular discomfort unrelated to studymedication instillation, both measured at month 6. A small but statistically significant difference in

CFS improvement was observed between the treatment groups at month 6 in favour of IKERVIS(mean change from baseline in CFS -1.05 with IKERVIS and -0.82 with vehicle, p=0.009).

The mean change from baseline in ocular discomfort score (assessed using a Visual Analogic Scale)was -12.82 with IKERVIS and -11.21 with vehicle (p=0.808).

In both studies, no significant improvement of symptoms was observed for IKERVIS compared tovehicle after 6 months of treatment, whether using a visual analogue scale or the OSDI.

In both studies one third of the patients in average had Sjögren’s syndrome; as for the overallpopulation, a statistically significant improvement in CFS in favour of IKERVIS was observed in thissubgroup of patients.

At completion of the SANSIKA study (12 month study), patients were asked to enter the Post

SANSIKA study. This study was an open-label, non-randomised, one-arm, 24-month study extensionof the Sansika Study. In Post SANSIKA study patients alternatively received IKERVIS treatment orno treatment depending on CFS score (patients received IKERVIS when there was a worsening ofkeratitis).

This study was designed to monitor the long-term efficacy and relapse rates in patients who havepreviously received IKERVIS.

The primary objective of the study was to assess the duration of the improvement following IKERVIStreatment discontinuation once the patient was improved with respect to the baseline of the SANSIKAstudy (i.e. at least 2 grade improvement on the modified Oxford scale).67 patients were enrolled (37.9% of the 177 patients having ended Sansika). After the 24-monthperiod, 61.3% of 62 patients included in the primary efficacy population did not experience a relapsebased on CFS scores. Percentage of patients who experienced a severe keratitis recurrence was 35%and 48% in patients treated 12 months and 6 months with IKERVIS respectively in the SANSIKAstudy.

Based on the first quartile (the median could not be estimated due to the small number of relapses),time to relapse (back to CFS grade 4) was ≤224 days and ≤175 days in patients previously treated12 months and 6 months with IKERVIS, respectively. Patients spent more time on CFS grade 2(Median 12.7 weeks/year) and grade 1 (Median 6.6 weeks/year) than CFS grade 3 (Median 2.4weeks/year), CFS grades 4 and 5 (Median time 0 week/year).

Assessment of DED symptoms by VAS showed a worsening of patient’s discomfort from the timetreatment was first stopped to the time it was restarted except pain which remained relatively low andstable. The median global VAS score increased from the time treatment was first stopped (23.3%) tothe time treatment was restarted (45.1%).

No significant changes have been observed in the other secondary endpoints (TBUT, lissamine greenstaining and Schirmer test, NEI-VFQ and EQ-5D) over the course of the extension study.

The European Medicines Agency has waived the obligation to submit the results of studies with

IKERVIS in all subsets of the paediatric population in dry eye disease (see section 4.2 for informationon paediatric use).

Formal pharmacokinetic studies have not been conducted in humans with IKERVIS.

Blood concentrations of IKERVIS were measured using a specific high-pressure liquidchromatography-mass spectrometry assay. In 374 patients from the two efficacy studies, plasmaconcentrations of ciclosporin were measured before administration and after 6 months (SICCANOVEstudy and SANSIKA study) and 12 months of treatment (SANSIKA study). After 6 months of ocularinstillation of IKERVIS once per day, 327 patients had values below the lower limit of detection(0.050 ng/mL) and 35 patients were below the lower limit of quantification (0.100 ng/mL).

Measurable values not exceeding 0.206 ng/mL were measured in eight patients, values considered tobe negligible. Three patients had values above the upper limit of quantification (5 ng/mL) howeverthey were already taking oral ciclosporin at a stable dose, which was allowed by the studies’ protocol.

After 12 months of treatment, values were below the low limit of detection for 56 patients and belowthe low limit of quantification in 19 patients. Seven patients had measurable values (from 0.105 to1.27 ng/mL), all considered to be negligible values. Two patients had values above the upper limit ofquantification, however they were also on oral ciclosporin at a stable dose since their inclusion in thestudy.

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity, phototoxicity and photoallergy, genotoxicity, carcinogenicpotential, toxicity to reproduction and development.

Effects in non-clinical studies were observed only with systemic administration or at exposuresconsidered sufficiently in excess of the maximum human exposure indicating little relevance toclinical use.

Medium-chain triglycerides

Cetalkonium chloride

Glycerol

Tyloxapol

Poloxamer 188

Sodium hydroxide (for pH adjustment)

Water for injections

Not applicable.

3 years.

Do not freeze.

Store below 25°C.

After opening of the aluminium pouches, the single-dose containers should be kept in the pouches inorder to protect from light and avoid evaporation.

Any opened individual single-dose container with any remaining emulsion should be discardedimmediately after use.

IKERVIS is supplied in 0.3 mL single-dose, low-density polyethylene (LDPE) containers presented ina sealed laminate aluminium pouch.

One pouch contains five single-dose containers.

Pack sizes: 30 and 90 single-dose containers.

Not all pack sizes may be marketed.

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

SANTEN Oy

Niittyhaankatu 2033720 Tampere

Finland

EU/1/15/990/001

EU/1/15/990/002

Date of first authorisation: 19 March 2015

Date of latest renewal: 09 March 2020

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

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