4.1. Therapeutic indications

Reduction of elevated intraocular pressure (IOP) in patients with open angle glaucoma and ocular hypertension in adults (including the elderly).

Reduction of elevated IOP in paediatric patients with elevated IOP and paediatric glaucoma.

4.2. Posology and method of administration

Posology

Adults (including the elderly)

Recommended therapy is one eye drop in the affected eye(s) once daily. Optimal effect is obtained if Xalatan is administered in the evening.

The dosage of Xalatan should not exceed once daily since it has been shown that more frequent administration decreases the IOP lowering effect.

If one dose is missed, treatment should continue with the next dose as normal.

Paediatric population

Xalatan Eye drops, solution may be used in paediatric patients at the same posology as in adults. No data are available for preterm infants (less than 36 weeks gestational age). Data in the age group < 1 year are limited (see section 5.1).

Method of administration

As with any eye drops, to reduce possible systemic absorption, it is recommended that the lachrymal sac be compressed at the medial canthus (punctal occlusion) for one minute. This should be performed immediately following the instillation of each drop.

Contact lenses should be removed before instillation of the eye drops and may be reinserted after 15 minutes.

If more than one topical ophthalmic medicinal product is being used, the medicinal products should be administered at least five minutes apart.

4.3. Contraindications

Hypersensitivity to latanoprost or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

Iris pigmentation changes

Xalatan may gradually change eye colour by increasing the amount of brown pigment in the iris. Before treatment is instituted, patients should be informed of the possibility of a permanent change in eye colour. Unilateral treatment can result in permanent heterochromia.

This change in eye colour has predominantly been seen in patients with mixed coloured irides, i.e. blue-brown, grey-brown, yellow-brown and green-brown. In studies with latanoprost, the onset of the change is usually within the first 8 months of treatment, rarely during the second or third year, and has not been seen after the fourth year of treatment. The rate of progression of iris pigmentation decreases with time and is stable for five years. The effect of increased pigmentation beyond five years has not been evaluated. In an open 5-year latanoprost safety study, 33% of patients developed iris pigmentation (see section 4.8). The iris colour change is slight in the majority of cases and often not observed clinically. The incidence in patients with mixed colour irides ranged from 7 to 85%, with yellow-brown irides having the highest incidence. In patients with homogeneously blue eyes, no change has been observed and in patients with homogeneously grey, green or brown eyes, the change has only rarely been seen.

In a long-term observational paediatric study evaluating hyperpigmentation changes in the eye among patients with paediatric glaucoma, iris colour darkening and localised iris pigmentation were observed to a slightly greater extent in patients exposed to latanoprost group compared with the unexposed group (see section 5.1).

The colour change is due to increased melanin content in the stromal melanocytes of the iris and not to an increase in number of melanocytes. Typically, the brown pigmentation around the pupil spreads concentrically towards the periphery in affected eyes, but the entire iris or parts of it may become more brownish. No further increase in brown iris pigment has been observed after discontinuation of treatment. It has not been associated with any symptom or pathological changes in clinical trials to date.

Neither naevi nor freckles of the iris have been affected by treatment. Accumulation of pigment in the trabecular meshwork or elsewhere in the anterior chamber has not been observed in clinical trials. Based on 5 years clinical experience, increased iris pigmentation has not been shown to have any negative clinical sequelae and Xalatan can be continued if iris pigmentation ensues. However, patients should be monitored regularly and if the clinical situation warrants, Xalatan treatment may be discontinued.

There is limited experience of Xalatan in chronic angle closure glaucoma, open angle glaucoma of pseudophakic patients and in pigmentary glaucoma. There is no experience of Xalatan in inflammatory and neovascular glaucoma or inflammatory ocular conditions. Xalatan has no or little effect on the pupil, but there is no experience in acute attacks of closed angle glaucoma. Therefore, it is recommended that Xalatan should be used with caution in these conditions until more experience is obtained.

There are limited study data on the use of Xalatan during the peri-operative period of cataract surgery. Xalatan should be used with caution in these patients.

Xalatan should be used with caution in patients with a history of herpetic keratitis, and should be avoided in cases of active herpes simplex keratitis and in patients with a history of recurrent herpetic keratitis specifically associated with prostaglandin analogues.

Reports of macular oedema have occurred (see section 4.8) mainly in aphakic patients, in pseudophakic patients with torn posterior lens capsule or anterior chamber lenses, or in patients with known risk factors for cystoid macular oedema (such as diabetic retinopathy and retinal vein occlusion). Xalatan should be used with caution in aphakic patients, in pseudophakic patients with torn posterior lens capsule or anterior chamber lenses, or in patients with known risk factors for cystoid macular oedema.

In patients with known predisposing risk factors for iritis/uveitis, Xalatan can be used with caution.

There is limited experience from patients with asthma, but some cases of exacerbation of asthma and/or dyspnoea were reported in post marketing experience. Asthmatic patients should therefore be treated with caution until there is sufficient experience, see also section 4.8.

Periorbital skin discolouration has been observed, the majority of reports being in Japanese patients. Experience to date shows that periorbital skin discolouration is not permanent and in some cases has reversed while continuing treatment with Xalatan.

Latanoprost may gradually change eyelashes and vellus hair in the treated eye and surrounding areas; these changes include increased length, thickness, pigmentation, number of lashes or hairs and misdirected growth of eyelashes. Eyelash changes are reversible upon discontinuation of treatment.

Preservative

Xalatan contains benzalkonium chloride, which is commonly used as a preservative in ophthalmic products. From the limited data available, there is no difference in the adverse event profile in children compared to adults. Generally, however, eyes in children show a stronger reaction for a given stimulus than the adult eye. Irritation may have an effect on treatment adherence in children. Benzalkonium chloride has been reported to cause eye irritation, symptoms of dry eyes and may affect the tear film and corneal surface. Should be used with caution in dry eye patients and in patients where the cornea may be compromised. Patients should be monitored in case of prolonged use.

Contact lenses

Contact lenses may absorb benzalkonium chloride and these should be removed before applying Xalatan but may be reinserted after 15 minutes (see section 4.2).

Paediatric population

Efficacy and safety data in the age group < 1 year are very limited (see section 5.1). No data are available for preterm infants (less than 36 weeks gestational age).

In children from 0 to < 3 years old that mainly suffer from primary congenital glaucoma (PCG), surgery (e.g. trabeculotomy/goniotomy) remains the first line treatment.

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

Definitive drug interaction data are not available.

There have been reports of paradoxical elevations in IOP following the concomitant ophthalmic administration of two prostaglandin analogues. Therefore, the use of two or more prostaglandins, prostaglandin analogues or prostaglandin derivatives is not recommended.

Paediatric population

Interaction studies have only been performed in adults.

4.6. Fertility, pregnancy and lactation

Pregnancy

The safety of this medicinal product for use in human pregnancy has not been established. It has potential hazardous pharmacological effects with respect to the course of pregnancy, to the unborn or the neonate. Therefore, Xalatan should not be used during pregnancy.

Breast-feeding

Latanoprost and its metabolites may pass into breast milk and Xalatan should therefore not be used in breast-feeding women or breast feeding should be stopped.

Fertility

Latanoprost has not been found to have any effect on male or female fertility in animal studies (see section 5.3).

4.7. Effects on ability to drive and use machines

Xalatan has minor influence on the ability to drive and use machines.In common with other eye preparations, instillation of eye drops may cause transient blurring of vision. Until this has resolved, patients should not drive or use machines.

4.8. Undesirable effects

a. ​Summary of the safety profile

The majority of adverse reactions relate to the ocular system. In an open 5-year latanoprost safety study, 33% of patients developed iris pigmentation (see section 4.4). Other ocular adverse reactions are generally transient and occur on dose administration.

b. ​Tabulated list of adverse reactions

Adverse reactions are categorized by frequency as follows: 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) and very rare (<1/10,000), not known (frequency cannot be estimated from the available data).

System Organ Class

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

Infections and infestations

Herpetic keratitis*§

Nervous system disorders

Headache*; dizziness*

Eye disorders

Iris hyperpigmentation; mild to moderate conjunctival hyperaemia; eye irritation (burning grittiness, itching, stinging and foreign body sensation); eyelash and vellus hair changes of the eyelid (increased length, thickness, pigmentation and number of eyelashes)

Punctate keratitis, mostly without symptoms; blepharitis; eye pain; photophobia; conjunctivitis*

Eyelid oedema; dry eye; keratitis*; vision blurred; macular oedema including cystoid macular oedema*; uveitis*

Iritis*; corneal oedema*; corneal erosion; periorbital oedema; trichiasis*; distichiasis; iris cyst*§; localised skin reaction on the eyelids; darkening of the palpebral skin of the eyelids; pseudopemphigoid of ocular conjunctiva*§

Periorbital and lid changes resulting in deepening of the eyelid sulcus

Cardiac disorders

Angina; palpitations*

Angina unstable

Respiratory, thoracic and mediastinal disorders

Asthma*; dyspnoea*

Asthma exacerbation

Gastrointestinal disorders

Nausea*; Vomiting*

Skin and subcutaneous tissue disorders

Rash

Pruritus

Musculoskeletal and connective tissue disorders

Myalgia*; arthralgia*

General disorders and administration site conditions

Chest pain*

*ADR identified post-marketing

§ADR frequency estimated using “The Rule of 3”

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.

c. ​Description of selected adverse reactions

No information is provided.

d. ​Paediatric population

In two short-term clinical trials (≤ 12 weeks), involving 93 (25 and 68) paediatric patients the safety profile was similar to that in adults and no new adverse events were identified. The short-term safety profiles in the different paediatric subsets were also similar (see section 5.1). Adverse events seen more frequently in the paediatric population as compared to adults are: nasopharyngitis and pyrexia.

In a long-term observational paediatric study involving 115 patients, the safety profile was consistent with that reported in previous paediatric studies and no new adverse events were identified (see section 5.1).

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

4.9. Overdose

Symptoms

Apart from ocular irritation and conjunctival hyperaemia, no other ocular side effects are known if Xalatan is overdosed.

Treatment

If Xalatan is accidentally ingested the following information may be useful: One bottle contains 125 micrograms latanoprost. More than 90% is metabolised during the first pass through the liver.

Intravenous infusion of 3 micrograms/kg in healthy volunteers induced no symptoms, but a dose of 5.5-10 micrograms/kg caused nausea, abdominal pain, dizziness, fatigue, hot flushes and sweating. In monkeys, latanoprost has been infused intravenously in doses of up to 500 micrograms/kg without major effects on the cardiovascular system.

Intravenous administration of latanoprost in monkeys has been associated with transient bronchoconstriction. However, in patients with moderate bronchial asthma, bronchoconstriction was not induced by latanoprost when applied topically on the eyes in a dose of seven times the clinical dose of Xalatan.

If overdosage with Xalatan occurs, treatment should be symptomatic.