Akistan

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT AKISTAN (AKISTAN)

Composition:

Active substance: latanoprost;

1 ml of ophthalmic solution contains 50 mcg of latanoprost;

Excipients: sodium dihydrogen phosphate dihydrate; sodium hydrogen phosphate dodecahydrate; sodium chloride; benzalkonium chloride 10% m/m solution; sodium hydroxide 10% m/v solution and/or phosphoric acid 10% m/m solution; purified water.

Pharmaceutical form. Eye drops, solution.

Main physical and chemical properties: clear, transparent solution, free from visible particles.

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

Pharmacological properties.

Pharmacodynamics.

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

Preclinical studies have demonstrated that Akistan is effective as monotherapy. In addition, clinical studies on combination therapy have been conducted. These included studies showing 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), oral carbonic anhydrase inhibitors (acetazolamide), and at least partially additive when used with cholinergic agonists (pilocarpine).

Clinical studies have shown that latanoprost does not significantly affect aqueous humor production. No effect of latanoprost on the blood-aqueous barrier has been observed.

Latanoprost did not cause fluorescein leakage into the posterior segment of pseudophakic human eyes during short-term treatment.

No significant pharmacological effect of latanoprost on the cardiovascular and respiratory systems has been observed at clinical doses.

Children

The efficacy of Akistan 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 ocular hypertension and childhood glaucoma. In this study, gestational age of neonates had to be 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 in the latanoprost and timolol treatment groups were similar. 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 comparable between latanoprost and timolol groups. However, efficacy data for latanoprost in the age group under 3 years were derived from only 13 patients, and no significant efficacy was demonstrated in the 4 patients representing the birth to 1 year age group in the clinical trial. 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 treatment groups. Results in the non-PCG subgroup (i.e., patients with, for example, 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 and was maintained throughout the 12-week study period, similar to that observed in adults.

SP – standard error.

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

Pharmacokinetics.

Absorption

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

Prodrugs penetrate well through the cornea, and all the drug that reaches the intraocular fluid is hydrolyzed during passage through the cornea.

Distribution

Studies in humans have shown that maximum concentration in the intraocular fluid is reached approximately 2 hours after topical administration.

Biotransformation and elimination

There is virtually no metabolism of latanoprost acid in the eye. The main metabolism of the drug occurs in the liver. In humans, the elimination half-life of the drug in plasma is 17 minutes.

Paediatric population

An open-label pharmacokinetic study of plasma concentrations of latanoprost acid was conducted in adult patients and paediatric patients (from newborns to children under 18 years of age) with intraocular 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, but 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 elimination half-life of the drug in plasma was short (less than 20 minutes) and similar in paediatric 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 adult patients, including elderly patients, with open-angle glaucoma and elevated intraocular pressure.

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

Contraindications.

Known hypersensitivity to any component of the Akistan 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 has been reported following concomitant ocular administration of two prostaglandin analogs. Therefore, concomitant use of two or more prostaglandins, prostaglandin analogs, or their derivatives is not recommended.

Interaction studies with latanoprost have been conducted only in adult patients.

Special precautions for use.

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

Color changes are predominantly observed in patients with mixed iris pigmentation, such as blue-brown, gray-brown, yellow-brown, or green-brown. In clinical studies with latanoprost, color changes typically occurred within the first 8 months of treatment, less frequently during the second or third year, and were not observed after the fourth year of treatment. Progression of iris pigmentation decreases over time and stabilizes after 5 years. The effect of increased pigmentation after 5 years of latanoprost treatment has not been evaluated. In an open-label 5-year safety study, increased iris pigmentation was recorded in 33% of patients (see section "Adverse reactions"). Iris color changes are mostly mild and often clinically insignificant. The incidence of cases in patients with mixed iris color ranged from 7% to 85%, with the highest frequency observed in patients with yellow-brown iris color. Eye color changes were not observed in patients with uniformly blue eyes and were rare in patients with uniformly gray, green, or brown eyes.

The color change occurs due to increased melanin content in the iris stromal melanocytes, not due to an increase in the number of melanocytes. Typically, brown pigmentation around the pupil spreads concentrically toward the periphery of the affected eye, although the entire iris or parts of it may become more brown. No further increase in brown iris pigmentation was observed after discontinuation of treatment. 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 have been observed under the influence of therapy. In clinical studies, no pigment accumulation in the trabecular meshwork or any other part of the anterior chamber of the eye has been observed.

Results from 5 years of clinical use of latanoprost indicate that increased iris pigmentation does not lead to clinical complications. Latanoprost treatment may be continued if iris pigmentation changes occur. However, patients should undergo regular examinations, and treatment with latanoprost should be discontinued if the clinical situation so requires.

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

Data on the use of latanoprost in the perioperative period of cataract surgery are limited. The medicinal product Akistan should be used with caution in such patients.

This medicinal product should be used with caution in patients with a history of herpetic keratitis. The use of the drug should be avoided in cases of active herpetic keratitis caused by herpes simplex virus and in patients with a history of recurrent herpetic keratitis, especially if associated with prostaglandin analogues.

Cases of macular edema have been reported (see section "Adverse reactions"), primarily in aphakic patients, pseudophakic patients with posterior capsule rupture or anterior chamber lenses, and in patients with known risk factors for cystoid macular edema (diabetic retinopathy and retinal vein occlusion). The medicinal product Akistan should be used with caution in aphakic patients, pseudophakic patients with posterior capsule rupture or anterior chamber lenses, and in patients with known risk factors for cystoid macular edema.

The medicinal product Akistan may be used with caution in patients with known risk factors for development of iritis/uveitis.

Experience with latanoprost use 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, latanoprost should be prescribed with caution to patients with bronchial asthma (see also section "Adverse reactions").

Skin pigmentation changes in the periorbital area have been observed, with most cases reported in Japanese patients. Current data indicate that periorbital skin pigmentation changes are not permanent and may resolve during continued latanoprost treatment.

Latanoprost may gradually alter the eyelashes and vellus hair around the treated eye and adjacent areas, including increased length, thickness, pigmentation, and number of eyelashes or vellus hairs, as well as misdirected eyelash growth. Changes in eyelashes are reversible and disappear after discontinuation of the drug.

Preservative

The medicinal product Akistan contains benzalkonium chloride, commonly used as a preservative in ophthalmic preparations. According to limited available data, there are no differences in the adverse effect profile between children and adults. However, overall, children's eyes are more sensitive to irritants than those of adults. Irritation may lead to non-compliance with the treatment regimen in children. Reports indicate that benzalkonium chloride may cause eye irritation, dry eye symptoms, and may affect the tear film and corneal surface. The drug should be used with caution in patients with dry eye and in patients with potentially damaged corneas. Careful monitoring of patients is required during prolonged use.

Contact lenses

Contact lenses may absorb benzalkonium chloride; therefore, they should be removed before applying Akistan and may be reinserted 15 minutes after instillation (see section "Dosage and administration").

Use during pregnancy or breastfeeding.

Pregnancy

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

Breastfeeding period

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

Ability to influence reaction speed when driving or operating machinery.

Latanoprost has a minor influence on reaction speed when driving or operating machinery. As with other ophthalmic preparations, instillation of eye drops may cause temporary blurred vision. Patients should not drive or operate machinery until this effect has resolved.

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 Akistan is administered in the evening.

The medicinal product Akistan should not be used more frequently than once daily, as increased frequency reduces the effectiveness of intraocular pressure reduction.

If a dose is missed, treatment should be continued by administering the next dose at the usual time.

As with any ophthalmic drops, to minimize potential systemic absorption, it is recommended to press on the tear duct (punctal occlusion) at the inner corner of the eye for one minute immediately after instillation of each drop.

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

When using multiple ophthalmic medicinal products, they should be administered at intervals of at least 5 minutes.

Children

Akistan eye drops may be used in children at the same dosage as in adults.

Data on the efficacy and safety of latanoprost in children under 1 year of age are very limited. There are no available data on the use of the drug in preterm infants (born before 36 weeks of gestation).

In children from birth to 3 years of age, primarily suffering from primary congenital glaucoma, surgical intervention (e.g., trabeculotomy/goniotomy) remains the first-line treatment.

The long-term safety of the drug in children has not been established.

Overdose

Apart from eye irritation and conjunctival hyperemia, no other ocular adverse effects have been reported with latanoprost overdose.

The following information may be helpful in case of accidental ingestion of Akistan. One vial contains 125 mcg of latanoprost. More than 90% is metabolized during the first pass through the liver. Intravenous infusion of the drug at a dose of 3 mcg/kg in healthy volunteers did not cause any symptoms, whereas doses of 5.5–10 mcg/kg caused nausea, abdominal pain, dizziness, increased fatigue, flushing, and increased sweating.

However, when latanoprost doses 7 times higher than the clinical dose of Akistan were administered locally into the eyes of patients with moderate bronchial asthma, bronchoconstriction was not observed.

In case of Akistan overdose, symptomatic treatment should be administered.

Adverse Reactions

Most adverse reactions are related to the eye. Changes in iris pigmentation have been reported (see section "Special Warnings and Precautions for Use"). Other ocular adverse reactions are usually temporary and occur after administration of the medicinal product.

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

Infections and infestations

Rare: Herpetic keratitis*§.

Nervous system disorders

Uncommon: Headache*, dizziness*.

Eye disorders

Very common: Increased pigmentation of the iris; mild or moderate conjunctival hyperemia; ocular irritation (burning sensation with feeling of "sand in the eye", itching, burning, and foreign body sensation in the eye); 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 the 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".

There have been very rare reports of corneal calcification associated with the use of phosphate-containing eye drops in some patients with significantly damaged corneas.

Children

The safety profile was similar to that in adults, and no new adverse reactions were identified in short-term clinical studies.

In pediatric patients, nasopharyngitis and increased body temperature were observed more frequently than in adults.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization 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 automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua.

Shelf life.

36 months.

After first opening of the bottle, the shelf life is 4 weeks.

Storage conditions.

Store in a refrigerator at 2–8°C in the original packaging to protect from light. Keep out of reach and sight of children.

After first opening, store the bottle at a temperature not exceeding 25°C and use within 4 weeks.

Packaging.

2.5 ml in a polyethylene bottle with a polyethylene dropper and a polypropylene cap; 1 bottle in a cardboard box or 3 bottles in a cardboard box, or 6 bottles in a cardboard box together with the instructions for medical use.

Prescription status.

Prescription only.

Manufacturer.

Pharmaselect International Beteiligungs GmbH.

Manufacturer's address and location of operations.

Ernst-Melchior-Gasse 20, 1020 Vienna, Austria / Ernst-Melchior-Gasse 20, 1020 Vienna, Austria.