Lumigan

INSTRUCTIONS for medical use of the medicinal product LUMIGAN® (LUMIGAN®)

Composition:

Active substance: bimatoprost;

1 ml of solution contains 0.1 mg of bimatoprost;

Excipients: benzalkonium chloride; sodium hydrogen phosphate heptahydrate; citric acid monohydrate; sodium chloride; hydrochloric acid diluted or sodium hydroxide; purified water.

Pharmaceutical form. Eye drops, solution.

Main physicochemical characteristics: clear, almost colorless solution.

Pharmacotherapeutic group. Medicinal products used in ophthalmology. Anti-glaucoma preparations and miotics. Prostaglandin analogues.

ATC code: S01EE03.

Pharmacological properties.

Pharmacodynamics.

The mechanism of action by which bimatoprost reduces intraocular pressure in humans involves increasing the outflow of aqueous humor through the trabecular meshwork and enhancing outflow via the uveoscleral pathways of the eye. Reduction in intraocular pressure begins approximately 4 hours after the first administration. Maximum effect is reached within approximately 8–12 hours. The duration of effect lasts at least 24 hours.

Bimatoprost is a potent agent that reduces intraocular pressure and belongs to the group of synthetic prostamides. Chemically, it is structurally related to prostaglandin F2α (PGF2α), but does not act on any of the known prostaglandin receptor types. Bimatoprost selectively mimics the action of recently discovered biologically synthesized substances called prostamides. However, the prostamide receptor has not yet been structurally identified.

During a 12-month study of Lumigan® 0.1 mg/mL ophthalmic solution administered once daily to adults, mean diurnal intraocular pressure values measured at each study visit throughout the entire 12-month period varied by no more than 1.1 mmHg throughout the day and never exceeded 17.7 mmHg.

Lumigan® 0.1 mg/mL ophthalmic solution contains benzalkonium chloride at a concentration of 0.02%.

Pharmacokinetics.

In vitro studies have shown that bimatoprost penetrates well into the human iris and sclera. After ocular instillation in adults, systemic exposure to bimatoprost is very low. No systemic accumulation has been observed. Following administration of one drop of bimatoprost solution in both eyes once daily for 2 weeks, maximum plasma concentration (Cmax) of bimatoprost was reached within 10 minutes after dosing and declined to the lower limit of quantification (0.025 ng/mL) within 1.5 hours after administration. Mean Cmax and area under the concentration-time curve (AUC0–24h) values for bimatoprost were comparable on Day 7 and Day 14, at 0.08 ng/mL and 0.09 ng*h/mL, respectively, indicating that steady-state concentrations of bimatoprost are achieved within the first week of topical administration.

Bimatoprost is moderately distributed into tissues, with a steady-state volume of distribution of 0.67 L/kg. Bimatoprost is primarily located in plasma. Plasma protein binding of bimatoprost is approximately 88%.

Bimatoprost is the main circulating substance in blood after entering the systemic circulation following ocular instillation. Bimatoprost is subsequently metabolized via oxidation, N-deethylation, and glucuronidation, forming various metabolites.

Bimatoprost is primarily eliminated via the kidneys. Approximately 67% of the intravenously administered dose was excreted in urine and 25% via the gastrointestinal tract in healthy volunteers. The elimination half-life (T1/2) of bimatoprost, determined after intravenous administration, was approximately 45 minutes, and total clearance was 1.5 L/h/kg.

Parameters in elderly patients.

Following ocular instillation of bimatoprost solution 0.3 mg/mL as ophthalmic drops twice daily, the mean area under the concentration-time curve (AUC0–24h) in elderly patients (aged 65 years and older) was 0.0634 ng*h/mL of bimatoprost, which is significantly higher than in young healthy adults (0.0218 ng*h/mL). However, these findings are not considered clinically significant because systemic exposure remained very low in both elderly and young individuals after ocular instillation. No time-dependent accumulation of bimatoprost in blood was observed, and the safety profile of the medicinal product was nearly identical in elderly and younger patients.

Clinical characteristics.

Indications.

Reduction of elevated intraocular pressure (IOP) in adult patients with chronic open-angle glaucoma and ocular hypertension (as monotherapy or as adjunctive therapy to beta-adrenergic blocking agents).

Contraindications.

Hypersensitivity to the active substance or to any of the excipients contained in the medicinal product, including benzalkonium chloride.

Interaction with other medicinal products and other forms of interaction.

Interaction studies have not been conducted.

No interaction is expected in humans because systemic concentrations of bimatoprost are extremely low (less than 0.2 ng/mL) in the body after administration of bimatoprost solution at a dose of 0.3 mg/mL as ophthalmic drops.

Preclinical studies have shown that bimatoprost is biotransformed in the body via multiple enzymes and metabolic pathways and does not affect liver enzymes involved in drug metabolism.

In clinical trials, bimatoprost solution as ophthalmic drops was administered concomitantly with several different ophthalmic beta-adrenergic blocking agents (timolol 0.5%) without evidence of interaction.

Concomitant use of Lumigan® and other glaucoma medications, apart from topical beta-adrenergic blocking agents, has not been studied during adjunctive glaucoma therapy.

Special precautions for use.

Prior to initiating treatment, patients should be informed about the possible increase in eyelash growth, increased pigmentation of the eyelid skin, and increased pigmentation of the iris, as these effects have been observed during clinical studies with Lumigan®. Some of these changes may be permanent and may result in differences between the eyes if the medication has been instilled in only one eye. Increased pigmentation of the iris may be permanent. The change in pigmentation is likely due to an increased melanin content in melanocytes rather than an increase in the number of melanocytes. Long-term adverse reactions in the form of progressive iris pigmentation are not known. Changes in iris color following ocular administration of bimatoprost may be subtle and may not become noticeable for several months or even years. Typically, brown pigmentation around the pupil spreads concentrically toward the outer part of the iris, resulting in the iris becoming partially or completely darker brown. The use of Lumigan® does not affect the development of iris nevi or lentigo. In a 12-month clinical trial using bimatoprost 0.1 mg/mL as eye drops, only one case of iris hyperpigmentation was reported (incidence 0.5%). Changes in pigmentation of the periorbital tissues have been reported to be reversible and resolve after discontinuation of the medication.

The use of Lumigan® in patients with respiratory disorders has not been studied. Limited information is available for patients with a history of asthma or chronic obstructive pulmonary disease (COPD). Exacerbations of asthma, dyspnea, and COPD have been reported, as well as cases of asthma in the post-marketing period. The frequency of these symptoms is not known. Lumigan® should be used with caution in patients with COPD, asthma, or impaired respiratory function due to other conditions.

The use of Lumigan® has not been studied in patients with heart block or uncontrolled congestive heart failure. Lumigan® should be used with caution in patients predisposed to low heart rate or low blood pressure.

The use of Lumigan® has not been studied in patients with ocular inflammatory diseases, neovascular, inflammatory, congenital glaucoma, or angle-closure glaucoma.

Lumigan® should be used with caution in patients at risk of macular edema (e.g., aphakia, pseudophakia with damaged posterior lens capsule).

Lumigan® should be used with caution in patients with a history of viral ocular infections (e.g., herpes simplex) or uveitis/iris inflammation.

Increased hair growth may occur on skin areas that are repeatedly exposed to the medication. Lumigan® should be used strictly according to the instructions for medical use, and care should be taken to avoid contact of the medication with the skin.

Cases of bacterial keratitis associated with the use of multi-dose containers for topical ophthalmic products have been reported. These containers were accidentally contaminated by patients, most of whom had concomitant ocular disease. Patients with disruption of the corneal epithelial surface are at higher risk of developing bacterial keratitis.

The dropper tip of the bottle must not come into contact with the eye, surrounding surfaces, fingers, or other surfaces to avoid microbial contamination of the solution.

Lumigan® 0.1 mg/mL contains the preservative benzalkonium chloride (0.02%), which may be absorbed by soft contact lenses. Irritation of the ocular mucosa and discoloration of soft contact lenses may also occur due to the presence of benzalkonium chloride. Contact lenses must be removed prior to instillation of the medication and may be reinserted 15 minutes after instillation.

Benzalkonium chloride has been reported to cause punctate keratopathy and/or toxic ulcerative keratopathy. Because Lumigan® 0.1 mg/mL contains benzalkonium chloride, it should be used with caution in patients with dry eye syndrome, corneal damage, or those using multiple ophthalmic medications containing benzalkonium chloride. Additionally, patients undergoing long-term treatment should be monitored regularly.

Administration of more than one dose of bimatoprost per day leads to reduced efficacy in lowering elevated intraocular pressure in patients with glaucoma or ocular hypertension. Patients using Lumigan® together with other prostaglandin analogs should be under medical supervision and have their intraocular pressure monitored.

Use during pregnancy or breastfeeding.

There are no adequate data on the use of bimatoprost in pregnant women.

Animal studies have demonstrated reproductive toxicity with toxic effects on the female at high doses.

Lumigan® should be used during pregnancy only if clearly needed, when the expected benefit to the woman outweighs the potential risk to the fetus.

It is not known whether bimatoprost is excreted in human breast milk. The decision to continue or discontinue breastfeeding or to continue or discontinue treatment with Lumigan® should be made by taking into account the benefits of breastfeeding for the child and the benefits of treatment for the woman.

Ability to influence reaction speed when driving or operating machinery.

Lumigan® has a negligible influence on reaction speed when driving or operating machinery. As with other ophthalmic solutions, if transient blurred vision occurs after instillation, patients should wait until vision clears before driving or operating machinery.

Dosage and Administration.

For adults: instill 1 drop into the affected eye(s) once daily in the evening.

The dose should not exceed 1 administration once daily, as more frequent use of the drug may reduce its effect in lowering elevated intraocular pressure.

The use of Lumigan® in patients with moderate to severe renal or hepatic impairment has not been studied. Therefore, caution should be exercised when treating patients in these groups. In patients with a history of moderate hepatic impairment or with abnormal alanine aminotransferase (ALT), aspartate aminotransferase (AST), and/or normal bilirubin levels, the use of bimatoprost solution as ophthalmic drops did not lead to hepatic adverse effects over a period of 24 months.

If more than one topical ophthalmic medication is used, a 5-minute interval between each instillation is required.

Children.

The efficacy and safety of Lumigan® in children have not been studied; therefore, the drug is not recommended for use in children under 18 years of age.

Overdose.

Cases of overdose with Lumigan® have not been reported. Overdose is unlikely with topical administration as ophthalmic drops.

In case of overdose, supportive and symptomatic therapy is required.

Adverse reactions

During clinical studies, adverse reactions occurred in approximately 38% of patients undergoing treatment with 0.1 mg/mL Bimatoprost ophthalmic solution (Lumigan®). The most frequent adverse reaction (in 29% of patients) was conjunctival hyperemia (mostly mild and non-inflammatory). Approximately 4% of patients discontinued the use of the medication due to adverse effects that occurred during the study.

The following adverse reactions were identified during clinical trials with 0.1 mg/mL Bimatoprost ophthalmic solution (Lumigan®). Most of these reactions were ocular in nature, mild in severity, and none were severe.

The frequency of adverse reactions is defined 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); very rare (<1/10,000); not known (cannot be estimated from available data). Adverse reactions are listed in the table below by organ system classification in descending order of clinical significance.

During clinical studies, the possibility of hair growth in areas of skin that are continuously in contact with the medication has been observed.

Shelf life.

2 years.

The shelf life of the medication after first opening the dropper bottle is 28 days.

Do not use after the expiry date stated on the packaging.

Storage conditions.

No special storage conditions required.

Keep out of reach of children.

Packaging.

3 mL of the medication in an opaque dropper bottle made of low-density white polyethylene with a screw cap made of polystyrene.

1 dropper bottle in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Allergan Pharmaceuticals Ireland.

Allergan Pharmaceuticals Ireland.

Manufacturer's address and place of business.

Castlebar Road, Westport, Co. Mayo, F28 AW83, Ireland.