The recommended dose is one drop (corresponding to 0.01 mg active substance) twice daily to be applied to each eye approximately 12 hours apart.

 

If a dose is missed, treatment should be continued with the next dose as normal. Patients should be advised not to instil more than one drop in each eye.

For ocular use only.

 

Patients should be instructed to first wash their hands. Patients should be advised not to allow the dropper tip to touch the eye or any other surface, as this may contaminate the solution.

 

If more than one topical ophthalmic medicinal product is being used, the medicinal products should be administered at least 15 minutes apart (see section 4.4). For patients who wear contact lenses, please refer to section 4.4. 

Regular examinations of the eye are recommended for topical ocular active substance therapy, e.g. within 3 months after treatment initiation and thereafter approximately every 6 months.

There is limited experience with active substance in the treatment of patients with ocular hypertension or glaucoma. Regular clinical monitoring should be exercised when treating patients receiving glaucoma medication and active substance eye drops.

MedicineX should not be administered while wearing contact lenses. If contact lenses are worn, they should be removed prior to the administration of the solution. Lenses may be reinserted 15 minutes following administration of MedicineX.

Ophthalmic medicinal products, which affect the immune system, including active substance, may affect host defence against local infections and malignancies. In case of signs of an eye infection the patient should seek medical advice.

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

 

Animal studies have shown reproductive toxicity following systemic administration of active substance at exposure considered sufficiently in excess of the maximum human exposure indicating little relevance to the clinical use of MedicineX.

 

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

No effects on the breastfed newborn/infant are anticipated since the systemic exposure of the breast-feeding woman to active substance in MedicineX is negligible. As a precautionary measure, it is preferable to avoid the use of MedicineX during breast-feeding.

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

 

No effects on fertility are anticipated since the systemic exposure to active substance is negligible.

The most common adverse reactions are instillation site reactions (8.1%) followed by blurred vision (0.8%). Instillation site reactions were more common in patients ≥ 65 years of age as compared to younger patients.

The following adverse reactions listed below were observed in clinical studies.

 

Adverse reactions are presented below according to MedDRA system organ classification (SOC and preferred term level). They are ranked according to frequency: 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).

 

Table 1:   Adverse reactions

System organ class	Frequency	Adverse reactions
General disorders and administration site conditions	Common	Instillation site pain (burning)
Eye disorders	Uncommon	Vision blurred, Eye irritation, Eye pain, Eye erythema, Visual acuity reduced, Eye pruritus

Instillation site pain (reported as burning) (7.9%) was the most frequently reported adverse reaction associated with the use MedicineX during clinical trials. Other instillation site reactions such as erythema or pruritus occurred at lower frequency (0.1%). All instillation site reactions are typically mild and transient.

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.

Active substance is a calcineurin inhibitor with anti-inflammatory and immunosuppressant properties. Calcineurin inhibition leads to various secondary effects (a) blockage of the opening of the mitochondrial permeability transition pore (MPTP) thereby inhibiting activation of caspases in the mitochondria, which in turn blocks apoptosis of inflamed conjunctival cells and restores goblet cell density (b) in activated T cells on the ocular surface MPTP are opened, resulting in the activation of apoptosis (c) the nuclear factor kappa B (NFκB) translocation and the mitogen-activated protein kinase pathway is blocked, inhibiting the transcription and secretion of inflammatory cytokines and subsequent T cell recruitment.  

 

The spreading properties of the water-free vehicle reduce friction and thereby contribute to the efficacy.

The efficacy of MedicineX for the treatment of dry eye disease was assessed by two randomised, multi-centre, double-masked, vehicle-controlled studies (ESSENCE-1 and ESSENCE-2). Both studies included moderate to severe dry eye disease (DED) patients as defined by total corneal staining (tCFS) score of ≥ 10 on the National Eye Institute (NEI) scale, unanaesthetised Schirmer’s test score between 1 and 10 mm, total lissamine green conjunctival score of ≥ 2 and the presence of symptoms.

 

In the ESSENCE-1 study, 328 patients were randomised in a 1:1 ratio to MedicineX (N=162) or vehicle (N=166) twice daily for 3 months. In the ESSENCE-2 study, 834 patients were randomised in a 1:1 ratio to receive MedicineX (N=423) or vehicle (N=411) twice daily for 1 month.

 

The change from baseline in tCFS score at Day 29 was the primary endpoint in both trials. tCFS score was the sum score (range 0-15) of the 5 cornea subregions (inferior, superior, central, nasal, and temporal), each region was rated by the investigator using the National Eye Institute (NEI) scale from grade 0 (no staining) to grade 3 (heavy staining).  Primary symptom endpoints were ocular surface disease index (OSDI, range 0-100) in ESSENCE-1 and dryness score (visual analogue scale, range 0-100) in ESSENCE-2. Key secondary endpoints included tCFS score at Day 15, tCFS responders defined as ≥ 3 grades improvement, conjunctival lissamine green staining score (Oxford sum of temporal and nasal; range 0-10) at Day 29, central corneal fluorescein staining score (cCFS [National Eye Institute scale; range 0-3]), and blurred vision score (visual analogue scale, range 0-100) and Schirmer responder at Day 85 in ESSENCE-1 and Day 29 in ESSENCE-2.

 

The majority of patients in this clinical program were female (73%), the mean (standard deviation [SD]) age was 58 (15.2) years and 38% were 65 years and older. The mean (SD) baseline tCFS score was 11.5 (1.35), the mean (SD) baseline cCFS score was 2.1 (0.60), the mean (SD) baseline conjunctival lissamine green staining score was 3.9 (1.71), the mean (SD) baseline unanaesthetised Schirmer’s tear test score was 5.0 mm (2.83), the mean (SD) baseline OSDI was 47.1 (19.23), and the mean (SD) baseline dryness score was 69.9 (15.43).

 

At Day 29, a statistically significant reduction in tCFS favouring MedicineX was observed in both studies (see Figure 1).

 

Figure 1: Mean change (SD) from baseline in tCFS at Day 29

CFS = corneal fluorescein staining; CfB= change from baseline

 

Responder analyses showed that the proportion of patients with a clinically meaningful tCFS improvement of ≥ 3 grades at Day 29 was statistically significantly different and favouring MedicineX in both studies at Day 29 (see Table 2).

 

Table 2: Percent of patients achieving ≥ 3 Grades improvement in total corneal fluorescein staining score (tCFS) at Day 29 in studies in patients with dry eye disease

	ESSENCE-1		ESSENCE-2
	MedicineX	Vehicle	MedicineX	Vehicle
Number of subjects at Day 29	157	165	409	395
≥ 3 grades improvement in tCFS at Day 29 (% of subjects)	52.9%	40.6%	71.6%	59.7%
Difference (95% CI)	12.3% (1.3%, 23.0%)		12.6% (6.0%, 19.3%)
p-value	0.0337		0.0002

 

In ESSENCE-1, the second hierarchically tested primary symptom endpoint change from baseline in OSDI at Day 29 showed numerical improvement in the MedicineX group (least squares [LS] mean -8.8) but did not reach statistical significance when compared to vehicle (LS mean -6.8) (p=0.2634).

In ESSENCE-2, the second hierarchically tested primary symptom endpoint, dryness score, improved statistically significantly compared to baseline in both groups: MedicineX LS mean -12.2 and vehicle LS mean -13.6 the between group difference was not significant (p=0.3842).

 

All other key secondary ocular surface sign endpoints (tCFS at Day 15, conjunctival staining at Day 29 and central corneal staining at Day 29) showed statistically significant effects favouring MedicineX in both studies (see Figure 2).

In addition, patients with significant central staining scores at baseline treated with MedicineX showed statistically significantly larger reductions in the blurred vision score at Day 29 compared to this group of patients treated with vehicle in both studies (see Figure 2).

 

Figure 2: Mean change (SD) from baseline in key secondary endpoints in both pivotal studies

* Subgroup with high central staining; CFS = corneal fluorescein staining; CfB= change from baseline

 

Statistically significantly higher proportions of responders to Schirmer`s tear test in the active arm compared to vehicle were demonstrated in ESSENCE-1 at Day 85 (Δ 6.74% [95% CI 0.50-12.98%] p=0.0344) and in ESSENCE-2 at Day 29 (Δ 3.92% [95% CI 0.02%-7.82%] p=0.0487).

 

A total of 202 patients who completed ESSENCE 2 entered an open label extension study for 12 months (ESSENCE-2-OLE). Eligible patients receive MedicineX bilaterally twice-daily for 1 additional year. More than 80% of the patients where responder (≥ 3 grades in tCFS) after 4 weeks and this response was maintained throughout observation period.

The European Medicines Agency has waived the obligation to submit the results of studies with MedicineX in all subsets of the paediatric population in dry eye disease (see section 4.2 for information on paediatric use).