Bimoptic rompharm

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BIMOPTIC ROMPHARM (BIMOPTICROMPHARM)

Composition:

Active substance: bimatoprost;

1 ml of solution contains 0.3 mg of bimatoprost;

Excipients: benzalkonium chloride; sodium hydrogen phosphate heptahydrate; citric acid monohydrate; sodium chloride; sodium hydroxide 1 M or hydrochloric acid 1 M; purified water.

Pharmaceutical form. Eye drops, solution.

Main physicochemical properties: clear, colorless solution, practically free from visible particles.

Pharmacotherapeutic group.

Medicinal products used in ophthalmology. Anti-glaucoma agents 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 uveoscleral outflow. Reduction in intraocular pressure begins approximately 4 hours after the first administration. Maximum effect is achieved within approximately 8–12 hours. The duration of effect lasts at least 24 hours.

Bimatoprost is a potent intraocular pressure-lowering agent belonging to the synthetic prostamide class, structurally related to prostaglandin F2α (PGF2α). It does not act on any of the known prostaglandin receptors. Bimatoprost selectively mimics the action of recently discovered biologically synthesized substances called prostamides. However, the prostamide receptor has not yet been structurally identified.

Clinical Efficacy and Safety

During a 12-month monotherapy study in adult patients using bimatoprost eye drops at a concentration of 0.3 mg/mL compared to timolol, the mean change in intraocular pressure (IOP) from baseline, measured in the morning at 8 a.m., ranged from -7.9 to -8.8 mmHg. At each study visit during the 12-month period, mean diurnal IOP values varied by no more than 1.3 mmHg and never exceeded 18.0 mmHg.

In a 6-month clinical study comparing bimatoprost 0.3 mg/mL with latanoprost, a statistically significant greater reduction in mean IOP (from -7.6 to -8.2 mmHg for bimatoprost versus -6.0 to -7.2 mmHg for latanoprost) was observed at all visits throughout the study. Conjunctival hyperemia, eyelash growth, and ocular pruritus were statistically significantly higher with bimatoprost than with latanoprost; however, the frequency of treatment discontinuation due to adverse events was low, with no statistically significant difference between groups.

Compared to beta-blocker monotherapy, adjunctive therapy with a beta-blocker and bimatoprost 0.3 mg/mL reduced mean morning (8:00 a.m.) intraocular pressure by -6.5 to -8.1 mmHg.

There is limited experience with use in patients with open-angle glaucoma associated with pseudoexfoliative and pigmentary glaucoma, as well as chronic angle-closure glaucoma with patent iridotomy.

In clinical studies, no clinically significant effect on heart rate or blood pressure was observed.

Pediatric Population

The safety and efficacy of bimatoprost in children aged 0 to 18 years have not been established.

Pharmacokinetics.

Absorption

In in vitro studies, bimatoprost penetrated 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 instillation of bimatoprost solution 0.3 mg/mL, one drop in each eye once daily for 2 weeks, the maximum plasma concentration (Cmax) of bimatoprost was reached within 10 minutes after administration 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 of bimatoprost were similar on day 7 and day 14, averaging 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.

Distribution

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

Biotransformation

Bimatoprost is the main circulating substance in blood after ocular instillation and entry into systemic circulation. Bimatoprost undergoes oxidation, N-deethylation, and glucuronidation, forming various metabolites.

Elimination

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

After instillation of bimatoprost solution 0.3 mg/mL as eye 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 for bimatoprost, which is significantly higher than in young healthy adults (0.0218 ng*h/mL). However, these data are not clinically meaningful because systemic exposure remained very low in both elderly and young individuals after ocular instillation. No cumulative effect of bimatoprost in blood was observed over time, and the safety profile of the medicinal product was nearly identical between elderly and younger patients.

Safety Preclinical Data

Effects observed in preclinical studies occurred only at doses substantially exceeding the recommended human dose, indicating low relevance for clinical use.

Daily ocular instillation of bimatoprost at concentrations ≥0.3 mg/mL in monkeys for 1 year resulted in iris hyperpigmentation and reversible, dose-dependent periorbital effects characterized by a noticeable upper and/or lower sulcus and enlargement of the palpebral fissure. Hyperpigmentation appears to result from increased melanin content stimulation in melanocytes, rather than an increase in the number of melanocytes. No functional or microscopic changes related to periorbital effects were observed, and the mechanism of action of these periorbital changes is unknown.

In in vitro and in vivo studies, bimatoprost was not mutagenic or carcinogenic.

Bimatoprost did not impair fertility in rats at doses up to 0.6 mg/kg/day (at least 103 times the recommended human dose). In experimental studies in rats and mice, no embryotoxic or teratogenic effects or adverse effects on offspring development were observed at doses at least 860 and 1700 times, respectively, the human equivalent dose. These doses resulted in systemic exposure at least 33 and 97 times, respectively, greater than the recommended human dose. In peri-/postnatal studies in rats, maternal toxicity led to shortened gestation, intrauterine fetal death, and reduced pup body weight at doses ≥0.3 mg/kg/day (at least 41 times the recommended human dose). Neurobehavioral functions in offspring were not impaired.

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.

BIMOPTIC ROMPHARM 0.3 mg/ml is contraindicated in patients who have previously experienced an adverse reaction to benzalkonium chloride that led to discontinuation of the drug.

Interaction with other medicinal products and other forms of interaction.

Interaction studies have not been conducted.

No interaction is expected because systemic concentrations of bimatoprost are extremely low (less than 0.2 mg/ml) in the body, even 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 hepatic enzymes involved in drug metabolism.

During clinical trials, bimatoprost solution in the form of eye drops was administered concomitantly with several different topical ophthalmic beta-adrenergic blocking agents without evidence of interaction.

Concomitant use of bimatoprost products and other glaucoma treatments, apart from topical beta-adrenergic blockers, has not been studied during adjunctive glaucoma therapy.

There is a potential for reduced intraocular pressure-lowering effect of prostaglandin analogs (e.g., bimatoprost) in patients with glaucoma or ocular hypertension when used concomitantly with other prostaglandin analogs (see section "Special precautions for use").

Special precautions for use.

Ophthalmology

Prior to initiating treatment, patients should be informed about the possibility of developing prostaglandin-associated periorbitopathy (PAP) and increased pigmentation of the iris, as these have been observed during treatment with bimatoprost. Some of these changes may be permanent and may lead to visual field disturbances and differences in the external appearance between the eyes if only one eye is treated (see section "Adverse reactions").

Since cystoid macular edema has been reported infrequently (≥1/1000 to <1/100) following treatment with bimatoprost ophthalmic solution at a concentration of 0.3 mg/mL, the drug should be used with caution in patients with known risk factors for macular edema (e.g., aphakia and pseudophakia with posterior capsule rupture of the lens).

There have been isolated spontaneous reports of reactivation of previous corneal infiltrates or ocular infections with the use of bimatoprost ophthalmic solution 0.3 mg/mL. The drug should be used with caution in patients with a history of significant ocular viral infections (e.g., herpes simplex) or uveitis/iritis.

The use of bimatoprost has not been studied in patients with inflammatory eye diseases, neovascular, inflammatory, or angle-closure glaucoma, congenital glaucoma, or narrow-angle glaucoma.

Skin

Hair growth may occur in areas where the bimatoprost solution is in constant contact with the skin surface. Therefore, it is important to use the drug according to instructions and avoid contact with the cheek or other areas of the skin.

Respiratory disorders

The use of bimatoprost ophthalmic solution 0.3 mg/mL has not been studied in patients with respiratory disorders. Although limited information exists regarding treatment of patients with asthma or chronic obstructive pulmonary disease (COPD) in their medical history, post-marketing reports include exacerbations of asthma, dyspnea, and COPD, as well as new-onset asthma. The frequency of these symptoms is not known. The drug should be used with caution in patients with COPD, asthma, or respiratory disorders due to other causes.

Cardiovascular disorders

The use of bimatoprost has not been studied in patients with heart block more severe than first-degree or uncontrolled congestive heart failure. There is a limited number of spontaneous reports of bradycardia or arterial hypotension associated with the use of bimatoprost ophthalmic solution 0.3 mg/mL. Therefore, the drug should be used with caution in patients predisposed to low heart rate or low blood pressure.

Other information

Clinical trials in patients with glaucoma or ocular hypertension treated with bimatoprost ophthalmic solution 0.3 mg/mL have shown that administration of more than one dose of bimatoprost per day may reduce the intraocular pressure (IOP)-lowering effect (see section "Interaction with other medicinal products and other forms of interaction"). Patients using bimatoprost concomitantly with other prostaglandin analogues should be monitored for changes in IOP.

BIMOPTIK ROMPHARM contains the preservative benzalkonium chloride, which may be absorbed by soft contact lenses. Due to the presence of benzalkonium chloride, eye irritation and discoloration of soft contact lenses may also occur. Contact lenses should be removed prior to instillation and may be reinserted no sooner than 15 minutes after administration of the drug.

Benzalkonium chloride, commonly used as a preservative in ophthalmic preparations, has been reported to cause punctate keratopathy and/or toxic ulcerative keratopathy. Since BIMOPTIK ROMPHARM contains benzalkonium chloride, patients with dry eye or corneal damage should be monitored during frequent or prolonged use of the drug. There have been reports of bacterial keratitis associated with the use of multidose containers of topical ophthalmic preparations. These containers were inadvertently contaminated by patients, most of whom had concomitant ocular diseases. Patients with damaged ocular epithelial surface have an increased risk of developing bacterial keratitis.

Patients should be instructed that the dropper tip of the bottle must not touch the eye or surrounding surfaces to avoid eye injury and microbial contamination of the solution.

Use during pregnancy or breastfeeding.

Pregnancy

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

Animal studies have demonstrated reproductive toxicity with a toxic effect on the female at high doses of the drug (see section "Preclinical safety data").

Bimatoprost should not be used during pregnancy unless clearly necessary, when the expected benefit to the mother outweighs the potential risk to the fetus.

Breastfeeding

It is unknown whether bimatoprost passes into human breast milk. Animal studies have shown that bimatoprost is excreted in breast milk. The decision whether to discontinue breastfeeding or discontinue therapy with the drug should take into account the importance of breastfeeding for the child and the benefit of therapy for the woman.

Data on the effect of bimatoprost on human fertility are lacking.

Ability to affect reaction speed when driving or operating machinery.

Bimatoprost has negligible influence on the ability to drive or operate machinery. As with other ophthalmic solutions, if transient blurred vision occurs after instillation, patients should wait until vision clears before driving or operating machinery.

Method of administration and dosage.

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

The dose should not exceed 1 administration once daily, since more frequent use of the medication may reduce the effect of lowering elevated intraocular pressure.

If a patient is using more than one topical ophthalmic medication, a 5-minute interval should be maintained between each instillation.

Special patient groups

Patients with hepatic or renal impairment

Treatment with bimatoprost in patients with renal impairment or moderate to severe hepatic impairment has not been studied; therefore, the medication should be used with caution in such patients. In patients with a history of mild liver disease or with baseline abnormalities in alanine aminotransferase (ALT), aspartate aminotransferase (AST), and/or bilirubin, the use of bimatoprost ophthalmic solution 0.3 mg/mL for 24 months did not result in adverse effects on liver function.

Children

The efficacy and safety of the medication in children (under 18 years of age) have not been studied.

Overdose

Cases of overdose have not been reported. Overdose is unlikely with topical administration in the form of eye drops.

In the event of overdose, supportive and symptomatic therapy should be administered.

Adverse Reactions

In clinical studies, over 1800 patients received treatment with bimatoprost 0.3 mg/mL ophthalmic solution. In pooled Phase III monotherapy and adjunctive therapy data for bimatoprost 0.3 mg/mL ophthalmic solution, the most frequently reported treatment-related adverse events were:

• eyelash growth in 45% during the first year, with the incidence of new reports decreasing to 7% in year 2 and 2% in year 3;
• conjunctival hyperemia (mostly mild and considered non-inflammatory in nature) in 44% during the first year, with the incidence of new reports decreasing to 13% in year 2 and 12% in year 3;
• ocular pruritus in 14% of patients during the first year, with the incidence of new reports decreasing to 3% in year 2 and 0% in year 3.

Less than 9% of patients discontinued treatment due to any adverse reaction during the first year, with the rate of additional discontinuations being 3% in both year 2 and year 3.

During clinical trials of bimatoprost 0.3 mg/mL ophthalmic solution, or in the post-marketing period, the following adverse reactions have been reported. Most of these reactions were ocular, mild to moderate in severity, and none were serious.

Adverse reactions are presented by system organ class and in decreasing order of clinical significance: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10,000 to <1/1000); very rare (<1/10,000); unknown (cannot be estimated based on available data).

Description of individual adverse reactions

Prostaglandin-associated periorbitopathy

Prostaglandin analogues, including bimatoprost, may cause periorbital lipodystrophic changes, which can lead to deepening of the inferior orbital sulcus, ptosis, enophthalmos, eyelid retraction, dermatochalasis involution, and lower scleral show. These changes are usually mild, may occur as early as one month after initiation of bimatoprost treatment, and may result in visual field deterioration even in the absence of patient symptoms. Prostaglandin analogues are also associated with periorbital hyperpigmentation or skin depigmentation and hypertrichosis. All such changes have been reported to be partially or completely reversible after discontinuation of the drug or switching to alternative therapies.

Increased iris pigmentation

Increased iris pigmentation is likely to be permanent. The change in pigmentation occurs due to an increase in melanin content within melanocytes, rather than an increase in the number of melanocytes. The long-term consequences of increased iris pigmentation are unknown. Iris color changes observed with ophthalmic administration of bimatoprost may not be noticeable for several months or years. Typically, brown pigmentation around the pupil spreads concentrically toward the periphery of the iris, resulting in the entire iris or parts of it becoming more brown. Iris nevi or freckles are not likely to be affected by treatment. With the use of bimatoprost 0.3 mg/mL ophthalmic solution, the incidence of iris hyperpigmentation was 1.5% after 12 months (see section "Adverse reactions") and did not increase after 3 years of treatment.

Adverse reactions reported with phosphate-containing ophthalmic solutions

Very rarely, corneal calcification has been reported in some patients with significant corneal damage associated with the use of phosphate-containing ophthalmic solutions.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after a medicinal product is authorized is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are encouraged to report any suspected adverse reactions via the national reporting system.

Shelf life

3 years.

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

The shelf life of the medicinal product after first opening of the container is 28 days.

Storage conditions

No special storage conditions are required.

Keep out of the reach and sight of children.

Packaging

3 mL in a bottle with an integrated dropper and a screw cap with a tamper-evident seal.

1 or 3 bottles per cardboard box.

Prescription status

Prescription-only medicine.

Manufacturer

K.T. ROMPHARM COMPANY S.R.L.

(S.C. ROMPHARM COMPANY S.R.L.)

Manufacturer's address and place of business

Eroilor str., No 1A, Otopeni city, 075100, county Ilfov, Romania