Treatment of severe vernal keratoconjunctivitis (VKC)

Treatment of severe vernal keratoconjunctivitis (VKC) in children from 4 years of age and adolescents.

Treatment of severe keratitis in dry eye disease

Treatment of severe keratitis in adult patients with dry eye disease, which has not improved despite treatment with tear substitutes.

Verkazia treatment should only be initiated by an ophthalmologist or a healthcare professional qualified in ophthalmology.

Posology

Treatment of severe VKC

Children from 4 years of age and adolescents

The recommended dose is one drop of Verkazia 4 times a day (morning, noon, afternoon and evening) to be applied to each affected eye during the VKC season. If signs and symptoms of VKC persist after the end of the season, the treatment can be maintained at the recommended dose or decreased to one drop twice daily once adequate control of signs and symptoms is achieved. Treatment should be discontinued after signs and symptoms are resolved, and reinitiated upon their recurrence.

Missed dose

If a dose is missed, treatment should be continued on the next instillation as normal. Patients should be advised not to instill more than one drop for each instillation in the affected eye(s).

Paediatric population

There is no relevant use of Verkazia in children below 4 years in the treatment of severe vernal keratoconjunctivitis.

Treatment of severe keratitis in dry eye disease

Adults

The recommended dose is one drop of Verkazia 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).

Elderly patients

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

Paediatric population

There is no relevant use of Verkazia in children and adolescents aged below 18 in the treatment of severe keratitis in dry eye disease, which has not improved despite treatment with tear substitutes.

Patients with renal or hepatic impairment

The effect of Verkazia has not been studied in patients with renal or hepatic impairment. However, no special dose adjustment is needed in these populations.

Method of administration

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.

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.

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

Treatment of severe VKC

Contact lenses

Patients wearing contact lenses have not been studied. Therefore, the use of Verkazia with contact lenses is not recommended.

Concomitant therapy

Co-administration of Verkazia with eye drops containing corticosteroids may potentiate the effects of Verkazia on the immune system. However, in clinical studies, 18 patients received Verkazia (4 times daily) in co-administration with eye drops containing corticosteroids and no increase in the risk of adverse reactions related to the immune system was identified. Therefore, caution should be exercised when corticosteroids are administered concomitantly with Verkazia.

Effects on the immune system

Ophthalmic medicinal products, which affect the immune system, including ciclosporin, may affect host defences against local infections and malignancies. Therefore, regular examination of the eye(s) is recommended, e.g. every 3 to 6 months, when Verkazia is used for more than 12 months.

Verkazia has not been studied in patients with an active orofacial herpes simplex infection, a history of ocular herpes, varicella-zoster, or vaccinia virus infection and should therefore be used with caution in such patients.

Treatment of severe keratitis in dry eye disease

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

Contact lenses

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.

Concomitant therapy

There is limited experience with Verkazia in the treatment of patients with glaucoma. Caution should be exercised when treating these patients concomitantly with Verkazia, 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 Verkazia with eye drops containing corticosteroids could potentiate the effects of Verkazia on the immune system.

Excipient

Verkazia contains cetalkonium chloride which may cause eye irritation.

No interaction studies have been performed with Verkazia.

Women of childbearing potential/contraception in females

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

Pregnancy

There are no data from the use of  Verkazia in pregnant women.

Studies in animals have shown reproductive toxicity following systemic administration of ciclosporin at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to the clinical use of Verkazia.

Verkazia is not recommended during pregnancy unless the potential benefit to the mother outweighs the potential risk to the foetus.

Breast-feeding

Following systemic absorption, 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 Verkazia therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

There are no data on the effects of Verkazia on human fertility.

Verkazia 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

Treatment of severe VKC

The most common adverse reactions with Verkazia are eye pain (11%) and eye pruritus (9%) which are usually transitory and occurred during instillation.

Treatment of severe keratitis in dry eye disease

In five clinical studies including 532 patients who received ciclosporin 1 mg/ml eye drops emulsion and 398 who received vehicle (control), ciclosporin 1 mg/ml eye drops emulsion 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 ciclosporin 1 mg/ml eye drops emulsion were ocular and mild to moderate in severity.

Tabulated list of adverse reactions

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 the following convention: very common (³1/10), common (³1/100 to <1/10), uncommon (³1/1,000 to <1/100), rare (³1/10,000 to <1/1,000), very rare (<1/10,000), or not known (cannot be estimated from the available data).

Treatment of severe VKC

Treatment of severe keratitis in dry eye disease

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.

To report any side effect(s):

·       Saudi Arabia:

·       Other GCC States:

For United Arab Emirates, you can report any side effects through the Ministry of health and prevention:

Pharmacovigilance and Medical Device Section

P.O.Box : 1853

Tel: 800011111

Email: pv@mohap.gov.ae

Drug Department

Ministry of Health and Prevention

Dubai, U.A.E

Systemic exposure to Verkazia following topical ocular administration has been shown to be negligible. If overdose with Verkazia occurs, it may be flushed from the eye(s) with water and treatment should be symptomatic and supportive.

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

Mechanism of action and pharmacodynamic effects

Following ocular administration, ciclosporin is passively absorbed by T-lymphocytes where its binding to cyclophilin A inactivates calcineurin, and prevents nuclear factor of activated T cells (NF-AT) translocation into the nucleus, thus blocking the release of pro-inflammatory cytokines such as IL-2 and hence T-lymphocyte activation. Blocking NF-AT also interferes in the allergy process. Ciclosporin inhibits histamine release from mast cells and basophils through a reduction in IL-5 production, and may reduce eosinophil recruitment and effects on the conjunctiva and cornea. Ciclosporin is also known to up-regulate the release of anti-inflammatory cytokines. All available evidence suggests that ciclosporin acts specifically and reversibly on lymphocytes and does not depress haematopoiesis or have any effect on the function of phagocytic cells.

Clinical efficacy

Treatment of severe vernal keratoconjunctivitis (VKC)

In a 12 month double-masked, vehicle controlled, pivotal clinical trial (VEKTIS study), 169 patients with severe VKC and severe keratitis (grade 4 or 5 on the modified Oxford scale) were randomised to 4 drops of ciclosporin 1 mg/ml eye drops emulsion (high dose) or 2 drops of ciclosporin 1 mg/ml eye drops emulsion (low dose) and 2 drops of vehicle or 4 drops of vehicle for the first 4 months (Period 1). Patients randomised to the vehicle group were switched to ciclosporin 1 mg/ml eye drops emulsion (four times or twice daily) from Month 4 to Month 12 (Period 2).

168 patients [127 children (75.6%) and 41 adolescents (24.4%)] were included in the efficacy analyses. Mean age was 9.2 years (SD: 3.3, age range: 4-17 years). There were more male [n=132 (78.6%)] than female patients [n=36 (21.4%)].

The primary efficacy endpoint which was the average penalties adjusted change of the Corneal Fluorescein Staining (CFS) score from baseline and over Period 1, considered all patients (n=168). Efficacy was assessed every month during the 4 month treatment period and compared with baseline using a composite criterion based on keratitis assessed by the modified Oxford scale, the need for rescue medicinal product (use of topical steroids) and the occurrence of corneal ulceration.

The difference in the Least Square (LS) mean vs. vehicle was 0.76 (95% CI: 0.26, 1.27) for the high dose group and 0.67 (95% CI: 0.16, 1.18) for the low dose group. Both differences were statistically significant with p=0.007 for the high dose and p=0.010 for the low dose group.

Clinical relevance of the primary efficacy endpoint was however difficult to address. In that context, responder rate’s results were considered as more reliable endpoint. A responder was defined as a patient 1) with a mean CFS score over the 4 months of treatment ≤ 50% of baseline, 2) who did not withdraw from the study for a reason possibly due to treatment, 3) with no experience of corneal ulceration and 4) no use of rescue medicinal product in the last 4 months of treatment. There was a significantly higher number of CFS responders in both active groups as compared to vehicle (p=0.005 for the high dose group, and p=0.010 for the low dose group) with 55.4%, 50.0% and 27.6% of responders in the high dose, low dose and vehicle groups respectively. The excess rate with respect to vehicle was 27.8% for the high dose regimen and 22.4% for the low dose one.

Rescue medicinal product (topical steroids) was used more often in the vehicle than in the high dose regimen: 32.1% in the high dose group and 31.5% in the low dose group received at least one course of rescue medicinal product while they were 53.4% in the vehicle group.

All four symptoms (photophobia, tearing, itching and mucous discharge) improved over time and the difference from baseline at Month 4 for each symptom largely exceeded 10 mm.

For the average of VKC symptoms, the difference in the LS mean vs. vehicle in the high dose group was statistically significant at all time points compared to vehicle: -19.4 mm (p<0.05).

Patient quality of life (Quick questionnaire) improved significantly better in the high dose group compared to vehicle. The improvement was clinically relevant as illustrated by the effect size over 4 months (symptoms domain: 0.67 and daily activities domain: 0.44).

In Period 2, analyses demonstrated stability of improvements achieved during Period 1 for both doses regimen.

Treatment of severe kertaitis in dry eye disease

The efficacy and safety 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 ciclosporin 1 mg/ml eye drops emulsion or vehicle daily at bedtime for 6 months. Patients randomised to the vehicle group were switched to ciclosporin 1 mg/ml eye drops emulsion 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 ciclosporin 1 mg/ml eye drops emulsion 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 ciclosporin 1 mg/ml eye drops emulsion compared to vehicle (mean change from baseline was -1.764 with ciclosporin 1 mg/ml eye drops emulsion vs. -1.418 with vehicle, p=0.037) . The proportion of ciclosporin 1 mg/ml eye drops emulsion -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 ciclosporin 1 mg/ml eye drops emulsion and ‑14.1 with vehicle at Month 6 (p=0.858). In addition, no improvement was observed for ciclosporin 1 mg/ml eye drops emulsion 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 ciclosporin 1 mg/ml eye drops emulsion(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 ciclosporin 1 mg/ml eye drops emulsion 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 ciclosporin 1 mg/ml eye drops emulsion (mean change from baseline in CFS -1.05 with ciclosporin 1 mg/ml eye drops emulsion 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 ciclosporin 1 mg/ml eye drops emulsion  and -11.21 with vehicle (p=0.808).

In both studies, no significant improvement of symptoms was observed for ciclosporin 1 mg/ml eye drops emulsion 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 ciclosporin 1 mg/ml eye drops emulsion 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 open-label, non-randomized, one-arm, 24-month study extension of the Sansika Study. In Post SANSIKA study patients alternatively received ciclosporin 1 mg/ml eye drops emulsion treatment or no treatment depending on CFS score (patients received ciclosporin 1 mg/ml eye drops emulsion when there was a worsening of keratitis).

This study was designed to monitor the long-term efficacy and relapse rates in patients who have previously received ciclosporin 1 mg/ml eye drops emulsion.

The primary objective of the study was to assess the duration of the improvement following ciclosporin 1 mg/ml eye drops emulsion 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 24-month period, 61.3% of 62 patients included in the primary efficacy population did not experience a relapse based 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 ciclosporin 1 mg/ml eye drops emulsion respectively in the SANSIKA study.

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 ciclosporin 1 mg/ml eye drops emulsion, 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, NEI-VFQ and EQ-5D) over the course of the extension study.

Paediatric population

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

Treatment of severe vernal keratoconjunctivitis (VKC)

Blood concentrations of ciclosporin 1 mg/ml eye drops emulsion were measured using a specific high-pressure liquid chromatography-mass spectrometry assay. In 166 patients with VKC at baseline from one efficacy study (55 patients in the high dose group, 53 in the low dose group and 58 in the vehicle group), plasma concentrations of ciclosporin were measured before administration and after 2, 4 and 12 months of treatment.

In the high dose group after 4 months of ocular instillation of ciclosporin 1 mg/ml eye drops emulsion 4 times daily, the maximum quantifiable value detected in the 14 patients who had quantifiable levels of cyclosporine was 0.670 ng/ml which is considered to be a negligible value. At Month 12, the maximum quantifiable value detected in the 12 patients who had quantifiable levels of cyclosporine was 0.291 ng/ml which is considered to be a negligible value.

In the low dose group, after 4 months of ocular instillation of ciclosporin 1 mg/ml eye drops emulsion 2 times daily, the maximum quantifiable value detected in the 5 patients who had quantifiable levels of cyclosporine was 0.336 ng/ml which is considered to be a negligible value. At Month 12, the maximum quantifiable value detected in the 5 patients who had quantifiable levels of cyclosporine was 0.300 ng/ml which is considered to be a negligible value.

Treatment of severe kertaitis in dry eye disease

In 374 dry eye disease patients from the two efficacy studies, plasma concentrations of ciclosporin were measured before administration and after 6 months (SICCANOVE study and SANSIKA study) and 12 months of treatment (SANSIKA study). After 6 months of ocular instillation of ciclosporin 1 mg/ml eye drops emulsion 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 to 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.

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

Medium-chain triglycerides

Cetalkonium chloride

Glycerol

Tyloxapol

Poloxamer 188

Sodium hydroxide (for pH adjustment)

Water for injections

Not applicable.

Do not freeze.

Store below 30 °C.

Keep single-dose containers in the pouch in order to protect from light and avoid evaporation.

Discard the opened single-dose container immediately after use.

0.3 ml single-dose, low-density polyethylene (LDPE) containers in a sealed laminate aluminium pouch.

One pouch contains 5 single-dose containers.

Pack sizes of 30 or 120 single-dose containers.

Not all pack sizes may be marketed.

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