4.1. Therapeutic indications

Treatment of moderate-to-severe Dry Eye Disease (keratoconjunctivitis sicca) in adult patients who have not responded adequately to artificial tears (see Section 5.1).

4.2. Posology and method of administration

Treatment must be initiated by an ophthalmologist or a healthcare professional qualified in ophthalmology. The response to treatment should be reassessed at least every 3 months.

Posology

The recommended dose is one drop of this medicine twice daily (approximately 12 hours apart) into the affected eye(s).

Special populations

Elderly population

No overall differences in safety or effectiveness have been observed between elderly and younger adult patients. No dose adjustment is required.

Patients with renal or hepatic impairment

The safety and efficacy of this medicine has not been studied in patients with hepatic or renal impairment. However, the systemic exposure to ciclosporin associated with the use of this medicine is very low (see section 5.2), and no special considerations are needed in these populations.

Paediatric population

The effect of this medicine has not been studied in children. There is no relevant use of this medicine in the treatment of signs of moderate to severe dry eye disease in the paediatric and adolescent population aged below 18 years.

Method of administration

For ocular use.

Precautions to be taken before administering the medicinal product

Patients should be instructed to first wash their hands.

Each Cequa single-dose container is for single use for both eyes in one patient only.

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 an increase in local activity and decrease in systemic undesirable effects.

Cequa can be used concomitantly with artificial tears, allowing a 15-minute interval between products. Discard the single-dose container immediately after using in both eyes.

To avoid the potential for eye injury and contamination, advise patients not to touch the single-dose container tip to the eye or other surfaces.

4.3. Contraindications

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

Ocular or peri-ocular malignancies or premalignant conditions.

Active or suspected ocular or peri-ocular infection (see section 4.4).

4.4. Special warnings and precautions for use

Use with Contact Lenses

Cequa has not been studied in patients wearing contact lenses. If contact lenses are worn, they should be removed prior to administration of the solution. Lenses may be reinserted 15 minutes following administration of this medicine ophthalmic solution.

Concomitant therapy

Ciclosporin treatment experience in patients with glaucoma is limited. When treating these patients concomitantly with this medicine it is recommended to have a regular clinical monitoring, especially with beta-blockers which are known to decrease tear secretion.

Infections

Resolve existing or suspected ocular or peri-ocular infections before initiating Cequa treatment. If an infection occurs during treatment, this medicine should be temporarily withheld until the infection has been resolved.

Effects on the immune system

Ophthalmic medicinal products, which affect the immune system, including ciclosporin, may affect host defences against local infections and malignancies. A regular examination of the eye(s) is recommended.

Phosphates content

Cequa contains phosphates. Phosphates may cause in very rare cases cloudy patches on the cornea due to calcium build-up during treatment.

4.5. Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed with this medicine.

Combination with other medicinal products that affect the immune system

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

4.6. Fertility, pregnancy and lactation

Women of childbearing potential/contraception in females.

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

Pregnancy

There are no adequate and well-controlled studies of Cequa administration 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 this medicine.

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

Breastfeeding

Information on the effects of ciclosporin in newborns/infants is very limited; considering the therapeutic doses of ciclosporin in eye drops, it is unlikely that sufficient amounts would be present in breast milk. Therefore, adverse effects in breast-fed infants are not expected given the low level of potential exposure but cannot be excluded. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for ciclosporin and any potential adverse effects on the breast-fed child from ciclosporin.

Fertility

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

No impairment of fertility has been reported in animals receiving intravenous ciclosporin or oral ciclosporin up to high doses (see section 5.3).

4.7. Effects on ability to drive and use machines

Eye drops may induce temporary blurred vision and influence the ability to drive or operate machines. Patients should be advised not to drive or operate machines until their vision is cleared.

4.8. Undesirable effects

a. Summary of the safety profile

The primary assessment of safety for this medicine is based on vehicle-controlled studies. Supportive safety data are provided by the uncontrolled safety extension of one study for long term usage, and a Phase 1 study in healthy volunteers. In the vehicle controlled clinical studies over 520 patients were treated with this medicine. The most common adverse reactions are instillation site pain (21.6% vs 3.8% of subjects in the vehicle group), observed immediately after administration of this medicine, conjunctival hyperaemia (5.7% vs 3.6% in the vehicle group), and eye irritation (1.1% vs 0.2% in the vehicle group).

The majority of adverse reactions reported in clinical studies with the use of this medicine were ocular and predominantly mild in intensity (approximately 70% of the AEs in both treatment groups were mild), and in most cases resolved without treatment or sequelae. Adverse events of severe intensity were uncommon.

AEs leading to discontinuation of study drug (4.2% versus 1.7%) were low across the OTX-101 and Vehicle groups.

Long term (9 to ≥12months exposure) safety data was available from 220 patients. No new adverse reactions were identified in these patients.

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).

b. Tabulated list of adverse reactions

System Organ Class

Frequency

Adverse reactions

Eye disorders

Common

Conjunctival hyperaemia, eye irritation

Uncommon

Increased lacrimation, punctate keratitis, photophobia, eye pain, conjunctival oedema, blepharitis, ocular and periocular infections

Very rare

Cases of corneal calcification have been reported very rarely in association with the use of phosphate containing eye drops in some patients with significantly damaged corneas.

General disorders and administration site conditions

Very common

Instillation site pain*

Common

Instillation site reaction Instillation site lacrimation

Uncommon

Instillation site dryness, instillation site pruritus, headache, and throat irritation

* See section 4.8c

c. Description of selected adverse reactions

Instillation site pain

Instillation site pain was very common observed in users of Cequa. Typically, it occurs immediately after instillation but is of a short duration (seconds to a few minutes), and resolves without further action being required.

Instillation pain was predominantly mild: of the 21.6% patients with instillation site pain, 17.8% experienced mild instillation site pain.

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 Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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