Reduction of elevated intraocular pressure (IOP) in patients suffering from open-angle glaucoma and ocular hypertension in adults (including elderly subjects).

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

Posology

Adults (including elderly subjects)

The recommended dose is one drop per day in the affected eye(s). For an optimal effect, administer Xalatan in the evening.

Xalatan may not be administered more than once per day, because it has been shown that more frequent administration decreases the IOP lowering effect.

If a dose is missed, treatment should continue by administering the next dose at the regular time.

Paediatric population:

Xalatan Eye drops, solution may be used in children at the same posology as in adults. No data are available for preterm infants (gestational age less than 36 weeks). Data in the age group < 1 year (4 patients) are very limited (see section 5.1).

Method of administration

As with all eye drops, to avoid possible systemic absorption, pressing on the lacrimal sac for one minute at the internal canthus (lachrymal point occlusion) is recommended immediately after administering each drop.

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

In case of ocular administration of multiple medicinal products, different medicinal products should be administered at an interval of at least 5 minutes.

Xalatan may progressively modify eye colour by increasing the quantity of brown pigment in the iris. Before starting treatment, 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 especially been observed in patients whose irises were multi-coloured, that is, blue-brown, grey-brown, yellow-brown or green-brown. In studies performed with latanoprost, this change generally appeared during the first 8 months of treatment, rarely during the second or third year, and was not observed after the fourth year of treatment. The rate of progression of iris pigmentation decreases over time and is stable after five years. The effect of increased pigmentation beyond five years has not been evaluated. In a 5-year, open-label safety study with latanoprost, 33% of patients developed iris pigmentation (see section 4.8).  In most cases, the change in iris colour is mild; it is often not perceived clinically. Its incidence, in patients whose irises were multi-coloured, ranged from 7 to 85%; it was highest in patients whose irises were yellow-brown.  In patients with uniformly blue eyes, no change was observed; in patients with uniformly grey, green or brown eyes, it was observed very rarely.

The change in colour is due to an increase in 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 of the affected eye, but it is possible that the entire iris or only parts may become browner. After stopping treatment, no subsequent increase in brown pigmentation has been observed. In clinical studies to date, this change has not been associated with any symptoms or pathological changes.

Naevi and freckles of the iris are not affected by the treatment. No accumulation of pigment was observed in the trabecular meshwork or any other point in the anterior chamber during clinical studies. Based on clinical experience gathered over 5 years, the increase in iris pigmentation does not seem to have negative clinical consequences; administration of Xalatan may be continued in case of iris pigmentation. However, patients should be regularly monitored and, if the clinical situation so justifies, Xalatan treatment may be discontinued.

Experience available about the use of Xalatan in chronic closed-angle glaucoma, in open-angle glaucoma in patients with artificial lenses and in pigmentary glaucoma is limited. There is no experience regarding use of Xalatan in inflammatory and neovascular glaucoma or in ocular inflammatory diseases. Xalatan has little effect, if any, on the pupil but there is no experience with acute closed-angle glaucoma attacks. It is therefore recommended that Xalatan should be used with caution in these conditions until more experience is available.

Data regarding use of Xalatan in the perioperative period in cataract surgery are limited. In these patients, Xalatan should be used with caution.

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

Cases of macular oedema have been described (see section 4.8), mainly in aphakic patients, in pseudophakic patients with a torn posterior lens capsule or implanted 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 a torn posterior lens capsule or bearers of anterior chamber lenses, as well as in patients with known risk factors for cystoid macular oedema.

Xalatan should be used with caution in patients with known risk factors for iritis/uveitis.

Experience with Xalatan in asthmatic patients is limited, but some cases of worsening of the asthma and/or dyspnoea have been reported after post-marketing of Xalatan. Asthmatic patients should therefore be treated with necessary caution until there is sufficient experience; see section 4.8.

Periorbital skin discolouration has been observed; the majority of cases were described in Japanese patients. Experience available at present shows that this change is not permanent and, in some cases, disappeared during continued treatment with Xalatan.

Latanoprost may gradually change eyelashes and hair on the eyelid of the treated eye and surrounding areas; these changes include increased length, thickness, pigmentation, number of eyelashes or hairs and poorly directed growth of the eyelashes. Changes in the eyelashes are reversible when treatment stops.

Preservative

Xalatan contains benzalkonium chloride, which is generally used as a preservative agent 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.. Xalatan should be used with caution in patients with ocular dryness or in patients in whom the cornea may be compromised. Patients should be monitored in case of prolonged use.

Contact lenses

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

Paediatric population

Safety and efficacy data in the age group < 1 year (4 patients) are very limited (see section 5.1). No data are available for preterm infants (gestational age less than 36 weeks).

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

Safety of long-term use in children has not yet been established.

No definitive drug-induced interaction data are available.

Cases of paradoxical increases in IOP have been reported after concomitant ophthalmic administration of two prostaglandin analogues. The use of two or more prostaglandins, prostaglandin analogues or prostaglandin derivatives is not recommended.

Paediatric population:

Interaction studies have only been conducted in adults.

Pregnancy

The safety of this medicinal product for use during pregnancy in humans has not been established. It may have toxic pharmacological effects on the course of pregnancy, on the unborn child or the newborn. Therefore, Xalatan should not be used during pregnancy.

Breast-feeding

Latanoprost and its metabolites can pass into breast milk. Therefore, Xalatan should not be used in breast-feeding women or breast-feeding should be stopped, if applicable.

Fertility

No effect of latanoprost on male or female fertility has been observed in studies in animals (see section 5.3).

Xalatan has minor influence on the ability to drive and use machines. In common with other preparations for ophthalmic use, administration of eye drops may temporarily blur vision. Patients should not drive or use machines until their vision returns to normal.

a. Summary of the safety profile

The majority of adverse reactions relate to the ocular system. In a 5-year, open-label safety study with latanoprost, 33% of patients developed iris pigmentation (see 4.4). Other ocular adverse reactions are generally transient and occur when the dose is administered.

b. Tabulated list of adverse reactions

Adverse reactions are classified according to their frequency, as follows: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1,000, < 1/100), rare (≥ 1/10,000, < 1/1,000), and very rare (< 1/10,000), not known (cannot be estimated from the available data).

*Undesirable effects identified post‑marketing

§Frequency of undesirable 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 2 short-term clinical trials (≤ 12 weeks), including 93 (25 and 68) paediatric patients, the safety profile was comparable to that of adults and no new adverse events were identified. The short-term safety profiles in the different paediatric subsets were also comparable (see section 5.1). The undesirable effects seen more frequently in the paediatric population than in adults are: rhinopharyngitis and fever.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after marketing 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 according to their local requirements

To report side effects

·        Saudi Arabia

·        Other GCC States

Symptoms

Apart from ocular irritation and conjunctival hyperaemia, no other ocular effects have been described in case of Xalatan overdose.

Treatment

In case of accidental ingestion of Xalatan, the following information may be of use:

One bottle contains 125 micrograms of latanoprost. Over 90% of the dose is metabolised after the first hepatic passage. Intravenous infusion of 3 micrograms/kg in healthy volunteers caused no symptoms, but a dose of 5.5–10 micrograms/kg caused nausea, abdominal pain, vertigo, fatigue, hot flashes and excessive perspiration. In monkeys, administration of latanoprost in intravenous infusion at doses of up to 500 micrograms/kg had no major effect on the cardiovascular system.

In monkeys, intravenous administration of latanoprost was associated with transient bronchoconstriction. However, in patients with moderate bronchial asthma, administration of latanoprost in the eyes at a dose 7 times greater than the clinical dose of Xalatan did not induce bronchoconstriction.

In case of overdose with Xalatan, treatment should be symptomatic.

5.1.       Pharmacodynamic properties

Pharmacotherapeutic group Ophthalmologicals; Antiglaucoma preparations and miotics, prostaglandin analogues. ATC code: S01EE01

The active substance latanoprost, a prostaglandin F_2a analogue, is a selective prostanoid FP receptor agonist which reduces IOP by increasing the outflow of aqueous humour. In humans, IOP starts to lower about 3 to 4 hours after administration; maximum effect is reached after 8 to 12 hours. The reduction in IOP continues for at least 24 hours.

Studies in animals and humans indicate that the primary mechanism of action is increased uveoscleral outflow, although a slight increase in outflow capacity (decrease in outflow resistance) has been reported in  humans.

Pivotal studies have shown that Xalatan was effective as monotherapy. In addition, clinical studies have evaluated its use in combination therapy. These are, among others, studies showing the efficacy of latanoprost in association with beta-adrenergic antagonists (timolol). Short-term studies (1 or 2 weeks) suggest that the effect of latanoprost is additive to that of adrenergic agonists (dipivalyl epinephrine), oral carbonic anhydrase inhibitors (acetazolamide) and, at least partly, to that of cholinergic agonists (pilocarpine).

Clinical studies have shown that latanoprost has no significant effect on the production of aqueous humour. Latanoprost does not seem to have any effect on the blood-aqueous barrier.

In monkeys and at clinical doses, latanoprost has only a negligible effect, if any, on intraocular blood circulation. However, mild to moderate conjunctival or episcleral hyperaemia may occur during local treatment.

Chronic treatment using latanoprost in monkey eyes, which had undergone extracapsular lens extraction did not affect the retinal blood vessels at all in fluorescein angiography.

During short-term treatment, latanoprost has not induced fluorescein leakage in the posterior segment of pseudophakic human eyes.

No significant pharmacological effect on the cardiovascular or respiratory system has been observed with latanoprost at clinical doses.

Paediatric population:

The efficacy of Xalatan in paediatric patients ≤ 18 years of age was demonstrated in a 12-week, double-blind clinical study comparing latanoprost to timolol in 107 patients diagnosed with ocular hypertension and paediatric glaucoma. Newborn infants were required to have a gestational age of at least 36 weeks. Patients were randomised with either latanoprost 50 µg/ml once per day or timolol 0.5% (or optionally timolol 0.25% for subjects less than 3 years old) twice per day. The primary efficacy endpoint was the mean reduction from baseline IOP after 12 weeks of treatment. The mean IOP reduction was similar in the 2 groups treated (latanoprost and timolol). In all age groups studied (0 to < 3 years, 3 to < 12 years and 12 to 18 years) the mean reduction in IOP after 12 weeks of treatment in the latanoprost group was similar to that of the timolol group. However, efficacy data in the latanoprost group for the 0 to < 3 years age group were based on only 13 patients and no relevant efficacy was shown in the 4 patients age 0 to < 1 year old in the clinical paediatric study. No data are available for preterm infants (gestational age less than 36 weeks).

Similarly, reduction of IOP among subjects in the PCG subgroup were similar between in the 2 groups treated (latanoprost and timolol). Similar results were observed in the other sub-group (Non-PCG, e.g.: juvenile open-angle glaucoma, aphakic glaucoma).

The effect on IOP was seen after the first week of treatment (see table) and was maintained during the 12 weeks of the study, as in adults.

SD: standard deviation,

^†Adjusted mean based on analysis of covariance (ANCOVA) model

Absorption

Latanoprost (molecular weight 432.58) is an isopropyl ester prodrug which per se is inactive but which, after hydrolysis to acid of latanoprost, becomes biologically active.

The prodrug is well-absorbed through the cornea and all of the medicinal product that penetrates the aqueous humour is hydrolysed during passage through the cornea.

Distribution

Studies in human beings indicate that the peak concentration in the aqueous humour is reached about 2 hours after topical administration. After topical application in monkeys, latanoprost is primarily distributed in the anterior segment, the conjunctivae and the eyelids. Only minute quantities of the medicine reach the posterior segment.

Biotransformation and elimination

There is practically no metabolism of the acid of latanoprost in the eye. Metabolism is mainly hepatic. The plasma half-life in humans is about 17 minutes. In animal studies, the primary metabolites, the 1,2-dinor and 1,2,3,4-tetranor metabolites, had only a weak biological activity, if any, and were primarily excreted in the urine.

Paediatric population:

An open-label pharmacokinetic study of plasma concentrations of latanoprost acid was undertaken in 22 adults and 25 paediatric patients (from birth to < 18 years of age) with ocular hypertension and glaucoma. All age groups were treated with latanoprost 50 µg/mL, one drop per day in each eye for a minimum of 2 weeks. Systemic exposure to latanoprost acid was approximately 2-fold higher in children ages 3 to < 12 and 6-fold higher in children less than 3 years old compared to adults, but a wide safety margin for systemic undesirable effects was maintained (see section 4.9). Mean time to reach peak plasma concentration was 5 minutes after dose administration across all age groups. The mean plasma elimination half-life was short (< 20 minutes) and similar for paediatric and adult patients, resulting in no accumulation of latanoprost acid in the systemic circulation at steady state.

The ocular and systemic toxicity of latanoprost has been studied in various animal species. Generally, latanoprost is well-tolerated with a high safety margin, systemic toxicity being at least 1,000 times greater than the clinical ocular dose. Intravenous administration of high doses of latanoprost, approximately 100 times the clinical dose/kg of body weight, in non-anaesthetised monkeys, caused an increase in respiratory rate. This probably reflects a short-term bronchoconstriction.  No sensitising properties of latanoprost have been observed in animal studies.

No toxic effects have been observed in rabbits and monkeys receiving doses of a maximum of 100 micrograms/eye/day (the clinical dose is around 1.5 micrograms/eye/day). In monkeys, however, latanoprost has shown that it induces an increase in iris pigmentation.

The mechanism of increased pigmentation seems to be a stimulation of the production of melanin in the melanocytes of the iris, without proliferative change. This change in colour of the iris can be permanent.

In studies on chronic ocular toxicity, administration of latanoprost at a dose of 6 micrograms/eye/day has also induced increased palpebral fissure. This effect is reversible and appears at doses higher than the clinical dose. This effect has not been observed in humans.

Reverse mutation tests on bacteria, genetic mutation tests on mouse lymphoma, and the mouse micronucleus test have all given negative results for latanoprost. Chromosomal aberrations have been observed in vitro on human lymphocytes. Similar effects have been observed with prostaglandin F_2a, a natural prostaglandin, which suggests that this is a class effect.

Other mutagenicity studies on in vitro/in vivo unscheduled DNA synthesis in rats have been negative and indicate that latanoprost has no mutagenic toxicity. Carcinogenicity studies conducted in mice and rats were negative.

In animal studies, no effect of latanoprost has been demonstrated on male or female fertility. In an embryotoxicity study conducted in rats, no embryotoxicity was observed at intravenous doses of 5, 50 and 250 micrograms/kg/day of latanoprost. However, in rabbits, latanoprost induced embryolethal effects at doses of 5 micrograms/kg/day or greater.

The dose of 5 micrograms/kg/day (about 100 times the clinical dose) induced significant embryo-foetal toxicity, characterised by increased incidence of late resorptions and abortions, as well as a reduction in foetal birth weight.

There is no evidence of teratogenic potential.

Sodium chloride

Benzalkonium chloride

Sodium dihydrogen phosphate monohydrate

Disodium phosphate anhydrous

Water for injections

In vitro studies have shown that there is precipitation when eye drops containing thiomersal are mixed with Xalatan. If such medicinal products are used, the eye drops should be administered at an interval of at least 5 minutes.

Store in a refrigerator (2°C – 8°C).

After first opening the bottle: Do not store above 25°C and use within 4 weeks (see section 6.3).

Keep the bottle in the outer carton in order to protect from light.

Dropper container (5 mL) of polyethylene with a screw cap and tamper evident overcap of polyethylene.

Each dropper bottle contains 2.5 mL Eye drops corresponding to approximately 80 drops of solution.

Pack sizes: 1 x 2.5 mL, 3 x 2.5 mL, 6 x 2.5 mL.

Not all pack sizes may be marketed.

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