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One mL of emulsion contains 1 mg of ciclosporin.
Excipient with known effect:
One mL of emulsion contains 0.05 mg cetalkonium chloride.
Treatment of severe keratitis in adult patients with dry eye disease, which has not improved despite treatment with tear substitutes.
Hypersensitivity to the active substance or to any of the excipients.
Active or suspected ocular or peri-ocular infection.
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 anti-inflammatory effect. Studies in animals suggest that ciclosporin inhibits the development of cell-mediated reactions. Ciclosporin has been shown to inhibit the production and/or release of pro-inflammatory cytokines, including interleukin 2 (IL-2) or T-cell growth 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. All available evidence suggests that ciclosporin acts specifically and reversibly on lymphocytes and does not 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 inflammatory immunological 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 transcription factor NF-AT and prevents NF-AT translocation into the nucleus, thus blocking the release of pro-inflammatory cytokines such as IL-2.
1. Adverse effect
Summary of the safety profile
In four 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%), eye irritation (17.8%), lacrimation (6.2%), 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 5
(≧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).
|Infections and infestations||Uncommon||Keratitis bacterial, herpes zoster ophthalmic.|
|Eye disorders||Common||Erythema of eyelid, lacrimation increased, ocular hyperaemia, vision blurred, eyelid oedema, conjunctival hyperaemia, eye irritation, eye pain.|
|Uncommon||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 administration site conditions||Very common||Instillation site pain.|
|Common||Instillation site irritation, instillation site erythema, instillation site lacrimation.|
|Uncommon||Instillation site reaction, instillation site discomfort, instillation site pruritus, Instillation site reaction, instillation site discomfort, instillation site pruritus, instillation site foreign body sensation.|
2. Precautions concerning 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 wake-up time.
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 beta-blockers which are known to decrease tear secretion.
Effects on the immune system
Medicinal products, which affect the immune system, including ciclosporin, may affect host defences against infections and malignancies.
Co-administration of IKERVIS with eye drops containing corticosteroids could potentiate the effects of IKERVIS on the immune system.
Effects on 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. Patients should be advised not to drive or use machines until their vision has cleared.
3. Fertility, 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 breast-feeding or to discontinue/abstain from IKERVIS therapy taking into account 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.
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 met the 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 at bedtime for 6 months. Patients randomised to the vehicle group were switched to IKERVIS after 6 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 was 28.6%, 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 -1.81 with IKERVIS vs. -1.48 with vehicle, p=0.037). The proportion of IKERVIS-treated patients with a 3-grade improvement in CFS score at Month 6 (from 4 to 1) was 28.8%, compared to 9.6% of vehicle-treated subjects, but this was a post-hoc analysis, which limits the robustness of this outcome. The beneficial effect on keratitis was maintained 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 with vehicle at Month 6 (p=0.858). In addition, no improvement was observed for IKERVIS compared to vehicle at Month 6 for other secondary endpoints, including ocular discomfort score, Schirmer test, use of 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 also randomised to IKERVIS or vehicle daily at bedtime for 6 months. The co-primary endpoints were the change in CFS score, and the change in global score of ocular discomfort unrelated to study medication 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 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 Sjoögren's syndrome; as for the overall population, a statistically significant improvement in CFS in favour of IKERVIS was observed in this subgroup of patients.
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 Dosage section for information on paediatric use).
Dosage and 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 instill 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 adult patients with dry eye disease, which has not improved despite treatment with tear substitutes.
milky white ophthalmic emulsion.
Store at temperatures not exceeding 30℃. Do not freeze.
After opening of the aluminium pouches, the single-dose containers should be kept in the pouches in order to protect from light and avoid evaporation. Any opened individual single-dose container with any remaining emulsion should be discarded immediately after use.
30 x 0.3 mL single-dose container.