Rosatop

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

Composition:

Active substance: bimatoprost;

1 ml of solution contains bimatoprost 0.3 mg;

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

Pharmaceutical form. Eye drops, solution.

Main physicochemical characteristics: practically clear solution, practically free from particles.

Pharmacotherapeutic group. Agents used in ophthalmology. Anti-glaucoma preparations and miotics. Prostaglandin analogues. ATC code: S01E E03.

Pharmacological properties.

Pharmacodynamics.

The mechanism 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 of intraocular pressure begins approximately 4 hours after the first administration. Maximum effect is reached within approximately 8–12 hours. The duration of action is at least 24 hours.

Bimatopresent 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 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 in vitro studies, bimatoprost readily penetrated the human iris and sclera. Following ocular instillation in adults, systemic exposure to bimatoprost is very low. No systemic accumulation has been observed. After instillation of bimatoprost solution, one drop in both eyes 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 (AUC_{0–24 h}) values of bimatoprost were similar on day 7 and day 14 of administration, amounting to 0.08 ng/mL and 0.09 ng·h/mL, respectively, indicating that steady-state concentrations of bimatoprost were achieved within the first week of topical administration.

Bimatoprost is moderately distributed into tissues, and the volume of distribution at steady state was 0.67 L/kg. Bimatoprost is predominantly located in plasma. The plasma protein binding of bimatoprost is approximately 88%.

Bimatoprost is the main circulating compound in blood after entering the systemic circulation following instillation. Subsequently, bimatoprost undergoes oxidation, N-deethylation, and glucuronidation, forming various metabolites.

Bimatoprost is primarily eliminated via the kidneys. Approximately 67% of the drug administered intravenously to healthy volunteers was excreted in urine, and 25% via the gastrointestinal tract. The elimination half-life (T_1/2) of bimatoprost, determined after intravenous administration, was approximately 45 minutes, and total body clearance was 1.5 L/h/kg.

Parameters in elderly patients

After instillation of 0.3 mg/mL bimatoprost ophthalmic solution twice daily, the mean area under the concentration-time curve (AUC_{0–24 h}) in elderly patients (aged 65 years and older) was 0.0634 ng·h/mL of bimatoprost, which is significantly higher than in younger healthy adults (0.0218 ng·h/mL). However, these data are not clinically significant, as systemic exposure remained very low in both elderly and younger 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 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 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 due to extremely low systemic concentrations of bimatoprost (less than 0.2 mg/mL) in the body following 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.

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

Concomitant use of Rozatop and other glaucoma treatments, 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 periocular changes associated with prostaglandin analogues (PGAs), such as increased pigmentation of the iris, which may persist during treatment with bimatoprost. Some of these changes may be permanent and may lead to visual field disturbances and differences in appearance between the eyes when only one eye is treated.

The use of Rozatop has not been studied in patients with respiratory disorders. Limited information is available regarding patients with a history of asthma or chronic obstructive pulmonary disease (COPD). Rozatop should be used with caution in patients with COPD, asthma, or other respiratory disorders affecting lung function.

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

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

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

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

Increased growth of eyelashes or eyelid hair may occur in skin areas that are repeatedly exposed to the drug. Rozatop should be used strictly according to the instructions for medical use, and care should be taken to avoid contact of the solution with the skin.

Cases of bacterial keratitis associated with the use of multidose containers for topical ophthalmic products have been reported. These containers were often inadvertently contaminated by patients, most of whom had concomitant ocular disease. Patients with disruption of the ocular epithelial surface are at greater risk of developing bacterial keratitis.

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

Rozatop contains the preservative benzalkonium chloride, 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 should be removed prior to instillation and may be reinserted 15 minutes after administration. Benzalkonium chloride has been reported to cause punctate keratopathy and/or toxic ulcerative keratopathy. Since Rozatop 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. In addition, patients undergoing long-term treatment should be monitored regularly.

The use of Rozatop in patients with moderate to severe renal or hepatic impairment has not been studied. Therefore, caution is advised when treating patients in these groups. In patients with a history of mild to moderate hepatic impairment or elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST), and/or bilirubin within normal limits, the use of bimatoprost ophthalmic solution did not result in hepatic adverse effects over a 24-month period.

Administering 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 Rozatop together with other prostaglandin analogues should be under medical supervision and have their intraocular pressure monitored regularly.

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

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.

Rozatop 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 Rozatop should be made taking into account the benefits of breastfeeding for the child and the benefits of therapy for the woman.

Effect on ability to drive and use machines

Rozatop has a 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: 1 drop instilled into the affected eye (eyes) once daily in the evening|in the morning|.

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

Children.

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

Overdose.

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

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

Adverse reactions.

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 based on available data). Adverse reactions are presented in Table 1 according to system organ classification in order of decreasing clinical significance.

Description of individual adverse reactions

Periocular changes associated with prostaglandin analogues, including RozatoP, may cause periocular lipoatrophy, leading to deepening of the eyelid sulcus, ptosis, enophthalmos, eyelid retraction, dermatochalasis, and inferior scleral show. These changes are usually mild, may appear as early as one month after initiation of RozatoP treatment, and may result in visual field disturbances even in the absence of patient recognition. PGAs are also associated with periocular skin hyperpigmentation or changes in skin color and hypertrichosis. It has been observed that all these changes are partially or completely reversible after discontinuation or switching to alternative therapy.

Iris hyperpigmentation

Increased pigmentation of the iris is likely to be permanent. The change in pigmentation occurs due to increased 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 use of bimatoprost may be subtle and may take several months or years to become apparent. 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. Treatment does not affect iris nevi or freckles. After 12 months of treatment with bimatoprost 0.1 mg/mL eye drops, solution, the incidence of iris hyperpigmentation was 0.5%. After 12 months of treatment with bimatoprost 0.3 mg/mL eye drops, solution, the incidence was 1.5% (see section 4.8), and did not increase further after 3 years of treatment.

Shelf life. 3 years.

Shelf life after first opening of the container: 28 days.

Storage conditions. No special storage conditions are required for this medicinal product.

Packaging. 3 ml of solution in a bottle; 1 or 3 bottles with dropper in a cardboard box.

Prescription status. Prescription only.

Manufacturer: Adamed Pharma S.A., Poland.

Address of the manufacturer and location of its business operations:
ul. marsz. J. Piłsudskiego 5, 95-200 Pabianice, Poland / ul. marsz. J. Pilsudskiego 5, Pabianice, 95-200, Poland.