Bimaproste ®

INSTRUCTION for medical use of the medicinal product Bimaproste® (Bimaprost)

Composition:

Active substance: bimatoprost;

1 ml of solution contains 0.3 mg of bimatoprost;

Excipients: benzalkonium chloride, sodium chloride, disodium hydrogen phosphate heptahydrate, citric acid monohydrate, sodium hydroxide and/or hydrochloric acid (for pH adjustment), water for injections.

Pharmaceutical form. Eye drops, solution.

Main physico-chemical properties: clear, colorless solution, practically free from particles.

Pharmacotherapeutic group.

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

ATC code S01E E03.

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 from the eye. Reduction in intraocular pressure begins approximately 4 hours after the first application. Maximum effect is reached 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. Chemically, it is structurally related to prostaglandin F2α (PGF2α), but 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 defined.

Clinical efficacy and safety

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

In a 6-month clinical study comparing bimatoprost 0.3 mg/mL with latanoprost, statistically significant greater mean reduction in IOP (from -7.6 to -8.2 mmHg for bimatoprost compared to -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 discontinuation due to adverse events was low, with no statistically significant difference between the groups.

Compared to treatment with beta-blockers alone, 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 or pigmentary glaucoma, as well as chronic angle-closure glaucoma with patent iridotomy.

Clinically significant effects on heart rate and blood pressure were not observed in clinical studies.

Pediatric population

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

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 similar 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 volume of distribution at steady state of 0.67 L/kg. Bimatoprost is primarily located in plasma. Plasma protein binding of bimatoprost is approximately 88%.

Bimatoprost is the principal circulating compound in blood after ocular instillation and systemic absorption. It undergoes oxidation, N-deethylation, and glucuronidation to form various metabolites.

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

Parameters in elderly patients

After ocular 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 findings are not considered clinically relevant, as systemic exposure remained very low in both elderly and young patients after ocular instillation. No cumulative increase in bimatoprost blood concentrations over time was observed, and the safety profile of the medicinal product was nearly identical between 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 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 interactions.

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.

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

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 of the eye, 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 «Adverse reactions»).

Since cases of cystoid macular edema have been infrequently reported after treatment with bimatoprost ophthalmic solution 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 rupture of the posterior lens capsule).

There have been isolated spontaneous reports of reactivation of previous corneal infiltrates or ocular infections during treatment with 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 ocular diseases, neovascular, inflammatory, or angle-closure glaucoma, congenital glaucoma, or narrow-angle glaucoma.

Skin

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

Respiratory disorders

The use of bimatoprost ophthalmic solution has not been studied in patients with respiratory disorders. Although limited data are available regarding treatment of patients with a history of asthma or chronic obstructive pulmonary disease (COPD), post-marketing reports have described exacerbations of asthma, dyspnea, and COPD, as well as new-onset asthma. The frequency of these events 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 have been limited 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

In clinical trials treating patients with glaucoma or ocular hypertension using bimatoprost ophthalmic solution 0.3 mg/mL, it was shown that administration of more than one dose of bimatoprost per day may reduce the intraocular pressure (IOP)-lowering effect. Patients using bimatoprost concomitantly with other prostaglandin analogs should be monitored for changes in IOP.

Bimaproste® contains the preservative benzalkonium chloride, 0.05 mg per mL, 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 reinserted no sooner than 15 minutes after administration of the drug.

Benzalkonium chloride has been reported to cause punctate keratopathy and/or toxic ulcerative keratopathy. Because Bimaproste® contains benzalkonium chloride, patients with dry eye or corneal epithelial damage should be monitored during frequent or prolonged use. Cases of bacterial keratitis associated with the use of multidose containers of topical ophthalmic products have been reported. These containers were inadvertently contaminated by patients, most of whom had concomitant ocular diseases. Patients with corneal epithelial surface damage have a higher risk of developing bacterial keratitis.

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

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.

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

It is unknown whether bimatoprost is excreted in human breast milk. The decision whether to continue/stop breastfeeding or to continue/stop therapy with the drug should be made taking into account the benefits of breastfeeding for the child and the benefits of therapy for the woman.

There are no data on the effect of bimatoprost on human fertility.

Ability to affect reaction rate when driving or operating machinery.

Bimatoprost has a minor 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 dosage should not exceed 1 instillation once daily, since more frequent administration of the drug may reduce the effect of lowering elevated intraocular pressure.

If a patient uses 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

The use of bimatoprost in patients with renal impairment or moderate to severe hepatic impairment has not been studied; therefore, the drug 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, treatment with bimatoprost ophthalmic solution 0.3 mg/mL for up to 24 months did not result in adverse effects on liver function.

Children

The efficacy and safety of the drug 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 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.

If bimatoprost is accidentally ingested, the following information may be helpful: in two-week oral studies in rats and mice, doses up to 100 mg/kg/day did not result in toxicity. This dose, expressed in mg/m², is at least 70 times higher than the accidental dose of one vial of bimatoprost 0.3 mg/mL eye drops solution in a child weighing 10 kg.

Adverse reactions

During a 3-month clinical study, adverse reactions were observed in approximately 29% of patients receiving a single dose of bimatoprost 0.3 mg/mL. The most frequently reported adverse reactions were conjunctival hyperemia (mostly mild and non-inflammatory in nature), occurring in 24% of patients, and ocular pruritus, occurring in 4% of patients. Approximately 0.7% of patients in the single-dose bimatoprost 0.3 mg/mL group discontinued treatment due to any adverse event during the 3-month study.

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

Adverse reactions are listed by system organ class 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); not known (cannot be estimated from available data).

Description of individual adverse reactions

Periocular changes associated with prostaglandin analogues (PGAs)

Prostaglandin analogues, including Bimatoprost®, may cause periocular lipodystrophic changes, which can lead to deepening of the superior sulcus, ptosis, enophthalmos, eyelid retraction, involution of dermatochalasis, 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 worsening of the visual field even in the absence of patient symptoms. PGAs are also associated with periocular hyperpigmentation or skin depigmentation and hypertrichosis. It has been observed that all these changes are partially or completely reversible after discontinuation of the drug or switching to alternative therapies.

Iris hyperpigmentation

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. Changes in iris color 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 darker brown. Iris nevi or freckles are not prone to be affected by the treatment. During 12 months of treatment with bimatoprost 0.1 mg/mL ophthalmic solution, the incidence of iris hyperpigmentation was

0.3%. With the use of bimatoprost 0.3 mg/mL ophthalmic solution over 12 months, the incidence of iris hyperpigmentation was 1.5% (see «Adverse reactions») and did not increase after 3 years of treatment.

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

• eyelash growth in up to 45% during the first year, with the rate of new reports decreasing to 7% in year 2 and 2% in year 3
• conjunctival hyperemia (mostly mild and considered non-inflammatory) in 44% during the first year, with the rate of new reports decreasing to 13% in year 2 and 12% in year 3
• eye pruritus in 14% of patients during the first year, with the rate 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 event during the first year, with additional discontinuation rates of 3% in both year 2 and year 3.

Table 2 lists adverse reactions observed during a 12-month clinical study with bimatoprost 0.3 mg/mL (multi-dose formulation) that were reported at a higher frequency compared to bimatoprost 0.3 mg/mL (single-dose formulation). Most of these reactions were ocular, mild or moderate in severity, and none were serious.

Table 2

In addition to the adverse reactions observed with single-dose administration of bimatoprost 0.3 mg/mL, Table 3 lists additional adverse reactions observed with the use of bimatoprost 0.3 mg/mL (multi-dose formulation). Most of these were ocular, mild or moderate in severity, and none were serious.

Table 3

Adverse reactions reported for ophthalmic solutions containing phosphates

In rare cases, corneal calcification has been reported in some patients with significant corneal damage following the use of ophthalmic solutions containing phosphates.

Reporting of suspected adverse reactions after drug registration is of great importance. It enables continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 2 years. After opening the bottle, store no longer than 28 days.

Storage conditions. Store at a temperature not exceeding 25 °C, in a place inaccessible to children.

Packaging.

2.5 ml; 5 ml; 7.5 ml in a dropper bottle; 1 dropper bottle per cardboard box.

Prescription status. Prescription only.

Manufacturer. Micro Labs Limited.

Manufacturer's address and site of operations.

Plot No. 113-116, Phase IV, KIADB, Bommassandra Industrial Area, Jigani Link Road, Anekal Taluk, Bangalore 560 099, India.