Glumax

INSTRUCTION for medical use of the medicinal product GLAUMAX® (GLAUMAX®)

Composition:

Active ingredient: latanoprost;

1 ml of eye drops contains 50 mcg of latanoprost;

Excipients: benzalkonium chloride, sodium chloride, sodium dihydrogen phosphate dihydrate, disodium hydrogen phosphate anhydrous, water for injections.

Pharmaceutical form. Eye drops, solution.

Main physicochemical properties: clear, colorless solution.

Pharmacotherapeutic group.

Anti-glaucoma agents and miotics. Prostaglandin analogues. ATC code S01E E01.

Pharmacological Properties

Pharmacodynamics

The active substance, latanoprost, a prostaglandin F2α analog, is a selective prostaglandin FP receptor agonist that reduces intraocular pressure by increasing the outflow of aqueous humor. Reduction in intraocular pressure in humans begins approximately 3–4 hours after administration of the drug, with maximum effect observed at 8–12 hours. The hypotensive effect lasts for 24 hours.

Preclinical studies have shown that latanoprost is effective as monotherapy. In addition, clinical studies on combination therapy have been conducted. These included studies demonstrating that latanoprost is effective in combination with beta-adrenergic blockers (timolol). Short-term (1 or 2 weeks) studies indicate that the effect of latanoprost is additive when used in combination with adrenergic agonists (dipivefrin epinephrine), oral carbonic anhydrase inhibitors (acetazolamide), and at least partially additive when used with cholinergic agonists (pilocarpine).

Clinical trials have shown that latanoprost has no significant effect on aqueous humor production. No effect of latanoprost on the blood-aqueous barrier has been observed.

In short-term treatment courses in patients with pseudophakia, latanoprost did not cause leakage of fluorescein into the posterior segment of the eye.

It has been established that latanoprost, at therapeutic doses, has no pharmacological effect on the cardiovascular and respiratory systems.

Children

The efficacy of latanoprost in pediatric patients aged ≤ 18 years was demonstrated in a 12-week, double-masked, clinical study comparing latanoprost with timolol in 107 patients diagnosed with elevated intraocular pressure and childhood glaucoma. In this study, neonates were required to have a gestational age of at least 36 weeks. Patients received either 0.005% latanoprost once daily or 0.5% timolol (or 0.25% for patients under 3 years of age at investigator’s discretion) twice daily. The primary efficacy endpoint was mean reduction in intraocular pressure (IOP) from baseline at week 12. Mean IOP reductions were similar between the latanoprost and timolol treatment groups. Across all age subgroups studied (birth to 3 years, 3 to 12 years, and 12 to 18 years), mean IOP reductions at week 12 were similar between latanoprost and timolol groups. However, efficacy data for latanoprost in the birth to 3 years age group were based on only 13 patients, and no significant efficacy was demonstrated in the 4 patients representing the birth to 1 year age subgroup in the clinical study. Data on use in preterm neonates (born before 36 weeks of gestation) are lacking.

IOP reduction outcomes in the subgroup of patients with primary congenital glaucoma / infantile glaucoma (PCG) were similar between latanoprost and timolol groups. Results in the non-PCG subgroup (e.g., patients with juvenile open-angle glaucoma, aphakic glaucoma) were consistent with those in PCG patients.

The effect on IOP was evident after the first week of treatment (see table) and was maintained throughout the 12-week study period, similar to observations in adults.

SP — standard error.

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

Pharmacokinetics.

Latanoprost is an isopropyl ester of the active substance, i.e., a prodrug that is inactive per se but becomes biologically active after hydrolysis to form latanoprost acid.

Studies have shown that maximum concentration in the aqueous humor of humans is reached approximately 2 hours after topical administration.

Studies in humans have demonstrated that maximum concentration in the intraocular fluid is achieved approximately 2 hours after topical administration. Practically no metabolism of latanoprost acid occurs in the eye. The primary metabolism of the drug takes place in the liver. In humans, the plasma half-life is 17 minutes. Metabolites are mainly excreted in urine.

Children

An open-label pharmacokinetic study of latanoprost acid plasma concentrations was conducted in adult patients and pediatric patients (from newborns to children up to 18 years of age) with ocular hypertension and glaucoma. Patients in all age groups received treatment with 0.005% latanoprost, one drop in each eye, for at least 2 weeks. Systemic exposure to latanoprost acid was approximately twice as high in patients aged 3 to <12 years and six times higher in children under 3 years of age compared to adult patients; however, a wide safety margin for systemic adverse effects was maintained. The median time to reach peak plasma concentration of the drug was 5 minutes after dosing across all age groups. The median plasma elimination half-life of the drug was short (less than 20 minutes) and similar in both pediatric and adult patients, indicating no accumulation of latanoprost acid in the systemic circulation at steady state.

Clinical characteristics.

Indications.

Reduction of elevated intraocular pressure in patients with open-angle glaucoma and ocular hypertension.

Reduction of elevated intraocular pressure in pediatric patients with elevated intraocular pressure and childhood glaucoma.

Contraindications.

Hypersensitivity to any component of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

Comprehensive data on interactions with other medicinal products are lacking.

Paradoxical increase in intraocular pressure (IOP) has been reported after concomitant ophthalmic administration of two prostaglandin analogs. Therefore, concomitant use of two or more prostaglandins, prostaglandin analogs, or prostaglandin derivatives is not recommended.

Drug interaction studies have been conducted only in adult patients.

Special precautions for use.

Latanoprost may cause a gradual change in eye colour due to increased brown pigment in the iris. Patients should be informed about the possibility of a permanent change in eye colour before initiating treatment. Treatment of only one eye may lead to permanent heterochromia.

Colour changes in the eye are observed predominantly in patients with mixed iris colour, for example: blue-brown, grey-brown, yellow-brown or green-brown. In clinical studies, onset of colour change usually occurred within the first 8 months of treatment, rarely during the second or third year, and was not observed after the fourth year of treatment. Progression of iris pigmentation decreases over time and stabilizes after 5 years. The effect of enhanced pigmentation after 5 years of treatment with the drug has not been evaluated. In an open-label 5-year safety study of latanoprost, increased iris pigmentation was recorded in 33% of patients (see section "Adverse reactions"). Iris colour changes are mostly minor and often clinically unnoticeable. The incidence of cases in patients with mixed iris colour ranged from 7% to 85%, with the highest frequency observed in patients with yellow-brown iris colour. Changes in eye colour were not observed in patients with uniformly blue iris colour and were rare in patients with uniformly grey, green or brown iris colour.

The change in eye colour occurs due to increased melanin concentration in the iris stromal melanocytes, not due to an increase in the number of melanocytes. Typically, brown pigmentation around the pupil spreads concentrically towards the periphery of the iris, resulting in the entire iris or parts of it becoming more distinctly brown. After discontinuation of treatment, further progression of brown iris pigmentation does not occur. To date, clinical studies have not provided evidence that this phenomenon is associated with any symptoms or pathological changes.

No changes in iris nevi or freckles were observed under the influence of therapy. During clinical studies, no pigment accumulation was detected in the trabecular meshwork or any other part of the anterior chamber of the eye. In clinical studies evaluating iris pigmentation over five years, there was no evidence of adverse consequences due to increased pigmentation, even with prolonged administration of latanoprost. In addition, intraocular pressure (IOP) reduction was similar in patients regardless of whether enhanced iris pigmentation developed. Therefore, treatment with latanoprost may continue in patients who develop increased iris pigmentation. These patients should be examined regularly, and—depending on the clinical situation—treatment may be discontinued.

Experience with the use of the medicinal product Glumax® in chronic angle-closure glaucoma, open-angle glaucoma in pseudophakic patients, and pigmentary glaucoma is limited. Currently, there are no data on the use of Glumax® in inflammatory or neovascular glaucoma or in inflammatory eye diseases. Glumax® has no effect or only a minimal effect on the pupil, but data on the use of the drug during acute attacks of angle-closure glaucoma are lacking. Therefore, Glumax® should be used with caution in such conditions until more data become available.

Data on the use of the medicinal product Glumax® during the perioperative period of cataract surgery are limited. These patients should be treated with Glumax® with caution.

Glumax® should be used with caution in patients with a history of herpetic keratitis, and the use of the medicinal product should be avoided in cases of active herpetic keratitis caused by herpes simplex virus and in patients with a history of recurrent herpetic keratitis, particularly associated with prostaglandin analogues.

Cases of macular edema have been reported (see section "Adverse reactions"), primarily in aphakic patients, pseudophakic patients with a ruptured posterior lens capsule or anterior chamber lenses, and patients with risk factors for cystoid macular edema (such as diabetic retinopathy and retinal vein occlusion). Glumax® should be used with caution in aphakic patients, pseudophakic patients with a ruptured posterior lens capsule or anterior chamber lenses, and patients with risk factors for cystoid macular edema.

Glumax® may be used with caution in patients with risk factors for development of iritis/uveitis.

Experience with the use of the drug in patients with bronchial asthma is limited, although some cases of asthma exacerbation and/or dyspnea have been reported during the post-marketing period. Until sufficient clinical experience is accumulated, the drug should be prescribed with caution to patients with bronchial asthma (see also section "Adverse reactions").

Skin colour changes in the periorbital area have been observed, with most cases reported in patients of Japanese nationality. Available data indicate that periorbital skin pigmentation is not permanent and in some cases resolves during continued treatment with Glumax®.

Latanoprost may gradually change the eyelashes and vellus hair of the treated eye; these changes include increased length, thickness, pigmentation, number of eyelashes or hair, and misdirected eyelash growth. Eyelash changes are reversible and resolve after discontinuation of treatment.

Glumax® contains benzalkonium chloride, which is commonly used as a preservative in ophthalmic preparations. Reports have indicated that benzalkonium chloride may cause punctate keratopathy and/or toxic ulcerative keratopathy. It may also cause ocular irritation and discolouration of soft contact lenses. Patients with dry eye or conditions involving corneal damage require careful monitoring when using Glumax® frequently or over a prolonged period. Contact lenses may absorb benzalkonium chloride; therefore, they should be removed before applying Glumax®, but may be reinserted 15 minutes after instillation (see section "Dosage and administration").

Use during pregnancy or breastfeeding

Pregnancy

The safety of this medicinal product in pregnant women has not been established. Its pharmacological action poses a potential risk to the course of pregnancy, the fetus or the newborn. Therefore, Glumax® should not be used during pregnancy.

Breastfeeding

Latanoprost and its metabolites may pass into breast milk; therefore, women who are breastfeeding should either discontinue treatment with Glumax® or stop breastfeeding.

Ability to affect reaction speed when driving or operating machinery

Like other eye drops, Glumax® may cause blurred vision. Patients should not drive or operate complex machinery until these effects have subsided.

Method of Administration and Dosage

Recommended dosage for adults (including elderly patients)

Recommended therapy: 1 drop in the affected eye once daily. The optimal effect is achieved when the medication is administered in the evening.

Latanoprost should not be used more frequently than once daily, as this may reduce the intraocular pressure-lowering effect.

If a dose is missed, treatment should be continued as usual with the next dose.

As with any ophthalmic drops, to minimize potential systemic absorption, it is recommended to press on the lacrimal sac in the medial canthus of the eye (nasolacrimal occlusion) for one minute immediately after instillation of each drop.

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

When using multiple topical ophthalmic agents, the medications should be administered at least 5 minutes apart.

Children

Glaumaks® eye drops may be used in pediatric patients at the same dosage as in adults.

Data on efficacy and safety of Glaumaks® in patients under 1 year of age are very limited (4 patients). Data on use in preterm infants (born before 36 weeks of gestation) are lacking. For children from birth to 3 years of age, who mainly suffer from primary congenital glaucoma, surgical intervention (e.g., trabeculotomy/goniotomy) remains the first-line treatment. The long-term safety of Glaumaks® in pediatric patients has not been established.

Overdose

Apart from eye irritation and conjunctival hyperemia, no other ocular adverse effects have been observed with overdose of Glaumaks®.

In case of accidental oral ingestion of Glaumaks®, note that a single bottle (2.5 mL of the product) contains 125 mcg of latanoprost. More than 90% is metabolized during first-pass through the liver. Intravenous infusion of 3 mcg/kg in healthy volunteers did not cause any symptoms; however, doses of 5.5–10 mcg/kg caused nausea, abdominal pain, dizziness, headache, weakness, hot flashes, and sweating.

When doses of latanoprost up to 7 times higher than the therapeutic dose of Glaumaks® were administered, no bronchoconstriction was observed in patients with mild to moderate bronchial asthma.

In case of overdose with Glaumaks®, symptomatic treatment should be administered.

Side effects

Most adverse reactions are related to the eye. In an open-label 5-year study of latanoprost, iris pigmentation changes were observed in 33% of patients (see section "Special precautions"). Other ocular adverse reactions are usually transient and occur immediately after instillation of the medication.

Adverse reactions are categorized according to their frequency as follows: very common (≥ 1/10), common (≥ 1/100, <1/10), uncommon (≥ 1/1000, <1/100), rare (≥ 1/10000, <1/1000), very rare (<1/10000), and not known (frequency cannot be estimated from available data).

Infections and infestations

Rare: Herpetic keratitis*§.

Nervous system disorders

Uncommon: Headache*; dizziness*.

Eye disorders

Very common: Increased iris pigmentation; mild or moderate conjunctival hyperemia; eye irritation (burning sensation, foreign body sensation, gritty feeling, itching); changes in eyelashes and vellus hair of the eyelids (increased length, thickness, pigmentation, and number of eyelashes).

Common: Punctate keratitis, mostly asymptomatic; blepharitis; eye pain; photophobia; conjunctivitis*.

Uncommon: Eyelid edema; dry eye; keratitis*; blurred vision; macular edema, including cystoid macular edema*; uveitis*.

Rare: Iritis*; corneal edema*; corneal erosion; periorbital edema; trichiasis*; distichiasis; iris cyst*§; local skin reaction on the eyelids; darkening of the palpebral skin of the eyelids; ocular conjunctival pseudopemphigoid*§.

Very rare: Periorbital changes and eyelid changes leading to deepening of eyelid folds.

Cardiac disorders

Uncommon: Angina pectoris; tachycardia*.

Very rare: Unstable angina.

Respiratory, thoracic and mediastinal disorders

Uncommon: Bronchial asthma*; dyspnea*.

Rare: Exacerbation of bronchial asthma.

Gastrointestinal disorders

Uncommon: Nausea*; vomiting*.

Skin and subcutaneous tissue disorders

Uncommon: Skin rash.

Rare: Itching.

Musculoskeletal and connective tissue disorders

Uncommon: Myalgia*, arthralgia*.

General disorders and administration site conditions

Uncommon: Chest pain*.

* Adverse reaction identified during the post-marketing period.

§ Frequency of the adverse reaction was estimated using the "rule of three."

Very rare cases of corneal calcification have been reported with ophthalmic solutions containing phosphate in some patients with significantly damaged corneas.

Children. In two short-term clinical studies (12 weeks) involving 93 pediatric patients (25 and 68), the safety profile was similar to that in adults, and no new adverse reactions were identified. Short-term safety profiles were also similar across different pediatric subgroups (see section "Pharmacological properties"). In pediatric patients, the following adverse reactions occurred more frequently than in adults: nasopharyngitis and increased body temperature.

Reporting suspected adverse reactions Reporting of suspected adverse reactions after marketing authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life.

2 years.

Storage conditions.

Store in a refrigerator, protected from light, at a temperature between 2 °C and 8 °C. After opening, the bottle should be stored at a temperature not exceeding 25 °C.

After opening, the product should be used within 4 weeks. Keep out of reach of children.

Packaging.

2.5 ml in a 5 ml polyethylene dropper bottle with a dropper cap and screw cap. 1 or 3 dropper bottles per carton.

Prescription status.

Prescription only.

Manufacturer.

JSC "Kevelt".

Manufacturer's address and location of business activity.

Teadupargi 3/1, 12618 Tallinn, Estonia.