- 1. NAME OF THE MEDICINAL PRODUCT
- 2. QUALITATIVE AND QUANTITATIVE COMPOSITION
- 3. PHARMACEUTICAL FORM
- 4. CLINICAL PARTICULARS
- 4.1 Therapeutic indication
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. PHARMACOLOGICAL PROPERTIES
- 6. PHARMACEUTICAL PARTICULARS
- 7. MARKETING AUTHORISATION HOLDER
- 8. MARKETING AUTHORISATION NUMBERS
- 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
- 10. DATE OF REVISION OF THE TEXT
1.NAME OF THE MEDICINAL PRODUCT
IKERVIS 1 mg/mL eye drops, emulsion
2.QUALITATIVE AND QUANTITATIVE COMPOSITION
One mL of emulsion contains 1 mg of ciclosporin.
Excipient with known effect:
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 despite treatment with tear substitutes (see section 5.1).
4.2Posology and method of administration
IKERVIS treatment must be initiated by an ophthalmologist or a healthcare professional qualified in ophthalmology.
The recommended dose is one drop of IKERVIS 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 be advised 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.
Patients with renal or hepatic impairment
The effect of IKERVIS 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 IKERVIS in children and adolescents aged below 18 in the treatment of severe keratitis in patients with dry eye disease, which has not improved despite treatment with tear substitutes.
Method of administration
Precautions to be taken before administering the medicinal product
Patients should be instructed to first wash their hands.
Prior to administration, the
For single use only. Each
Patients should be instructed to use nasolacrimal occlusion and to close the eyelids for 2 minutes after instillation, to reduce the systemic absorption. This may result in a decrease in systemic undesirable effects and an increase in local activity (see section 4.4).
If more than one topical ophthalmic medicinal product is being used, the medicinal products must be administered 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. Active or suspected ocular or
4.4Special warnings and precautions for use
IKERVIS has not been studied in patients with a history of ocular herpes and should therefore be used with caution in such patients.
Patients wearing contact lenses have not been studied. Careful monitoring of patients with severe keratitis is recommended. Contact lenses should be removed before instillation of the eye drops at bedtime and may be reinserted at
There is limited experience with IKERVIS in the treatment of patients with glaucoma. Caution should be exercised when treating these patients concomitantly with IKERVIS, especially with
Effects on the immune system
Medicinal products, which affect the immune system, including ciclosporin, may affect host defences against infections and malignancies.
IKERVIS contains cetalkonium chloride which may cause eye irritation.
4.5Interaction with other medicinal products and other forms of interaction
No interaction studies have been performed with IKERVIS.
Combination with other medicinal products that affect the immune system
4.6Fertility, pregnancy and lactation
Women of childbearing potential/contraception in females
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 ciclosporin at exposure considered sufficiently in excess of the maximum human exposure indicating little relevance to the clinical use of IKERVIS.
IKERVIS is not recommended during pregnancy unless the potential benefit to the mother outweighs the potential risk to the foetus.
Following oral administration, ciclosporin is excreted in breast milk. There is insufficient information on the effects of ciclosporin in newborns/infants. However, at therapeutic doses of ciclosporin in eye drops, it is unlikely that sufficient amounts would be present in breast milk. A decision must be made whether to discontinue
There is no data on the effects of IKERVIS on human fertility.
No impairment of fertility has been reported in animals receiving intravenous ciclosporin (see section 5.3).
4.7Effects on ability to drive and use machines
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 may affect the ability to drive or use machines (see section 4.8). Patients should be advised not to drive or use machines until their vision has cleared.
Summary of the safety profile
In five clinical studies including 532 patients who received IKERVIS and 398 who received IKERVIS vehicle (control), IKERVIS was administered at least once a day in both eyes, for up to one year. The most common adverse reactions were eye pain (19.2%), eye irritation (17.8%), lacrimation (6.4%), ocular hyperaemia (5.5%) and eyelid erythema (1.7%) which were usually transitory and occurred during instillation.
The majority of adverse reactions reported in clinical studies with the use of IKERVIS were ocular and mild to moderate in severity.
Tabulated list of adverse reactions
The following adverse reactions listed below were observed in clinical studies. They are ranked according to system organ class and classified according to the following 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 from the available data).
Keratitis bacterial, herpes zoster ophthalmic.
Erythema of eyelid, lacrimation increased, ocular
hyperaemia, vision blurred, eyelid oedema, conjunctival
hyperaemia, eye irritation, eye pain.
Conjunctival oedema, lacrimal disorder, eye discharge,
eye pruritus, conjunctival irritation, conjunctivitis, foreign
body sensation in eyes, deposit eye, keratitis, blepharitis,
corneal decompensation, chalazion, corneal infiltrates,
corneal scar, eyelid pruritus, iridocyclitis.
General disorders and
Instillation site pain.
Instillation site irritation, instillation site erythema,
instillation site lacrimation.
Instillation site reaction, instillation site discomfort,
instillation site pruritus, instillation site foreign body
Description of selected adverse reactions
Instillation site pain was a frequently reported local adverse reaction associated with the use of IKERVIS during clinical trials. It is likely to be attributable to ciclosporin.
One case of severe epithelial erosion of the cornea identified as corneal decompensation by the investigator resolved without sequeleae was reported.
Patients receiving immunosuppressive therapies, including ciclosporin, are at increased risk of infections. Both generalised and localised infections can occur.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed 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 with immunosuppressant properties. It has been shown to prolong survival of allogeneic transplants in animals and significantly improved graft survival in all types of solid organ transplantation in man. Ciclosporin has also been shown to have an
In patients with dry eye disease, a condition that may be considered to have an inflammatory immunological mechanism, following ocular administration, ciclosporin is passively absorbed into T- lymphocyte infiltrates in the cornea and conjunctiva and inactivates calcineurin phosphatase.
Clinical efficacy and safety
The efficacy and safety of IKERVIS were evaluated in two randomised,
In the 12 month,
The severity of keratitis, assessed using CFS, improved significantly from baseline at Month 6 with IKERVIS compared to vehicle (mean change from baseline was
The mean change from baseline in the
A reduction in the ocular surface inflammation assessed with Human Leukocyte
In the 6 month,
The mean change from baseline in ocular discomfort score (assessed using a Visual Analogic Scale) was
In both studies, no significant improvement of symptoms was observed for IKERVIS compared to vehicle 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 overall population, a statistically significant improvement in CFS in favour of IKERVIS was observed in this subgroup of patients.
At completion of the SANSIKA study (12 month study), patients were asked to enter the Post SANSIKA study. This study was an
This study was designed to monitor the
The primary objective of the study was to assess the duration of the improvement following IKERVIS treatment discontinuation once the patient was improved with respect to the baseline of the SANSIKA study (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
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 treated 12 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 2.4 weeks/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 time treatment was first stopped to the time it was restarted except pain which remained relatively low and stable. The median global VAS score increased from the time treatment was first stopped (23.3%) to the time treatment was restarted (45.1%).
No significant changes have been observed in the other secondary endpoints (TBUT, lissamine green staining and Schirmer test,
The European Medicines Agency has waived the obligation to submit the results of studies with IKERVIS in all subsets of the paediatric population for dry eye disease (see section 4.2 for information on paediatric use).
Formal pharmacokinetic studies have not been conducted in humans with IKERVIS.
Blood concentrations of IKERVIS were measured using a specific
be negligible. Three patients had values above the upper limit of quantification (5 ng/mL) however they 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 below the low limit of quantification in 19 patients. Seven patients had measurable values (from 0.105 to 1.27 ng/mL), all considered to be negligible values. Two patients had values above the upper limit of quantification, however they were also on oral ciclosporin at a stable dose since their inclusion in the study.
5.3Preclinical safety data
6.1List of excipients
Sodium hydroxide (to adjust pH)
Water for injections
6.4Special precautions for storage
Do not freeze.
After opening of the aluminium pouches, the
6.5Nature and contents of container
IKERVIS is supplied in 0.3 mL
One pouch contains five
Pack sizes: 30 and 90
Not all pack sizes may be marketed.
6.6Special precautions for disposal
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7.MARKETING AUTHORISATION HOLDER
8.MARKETING AUTHORISATION NUMBERS
9.DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 19 March 2015
10.DATE OF REVISION OF THE TEXT
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.