Instructions for Visulta eye drops 0.024% 5 ml No. 1
Composition
active ingredient: latanoprostene bunod;
1 ml of solution contains latanoprostene bunod 0.24 mg;
Excipients: benzalkonium chloride, 50% solution; polysorbate 80; disodium edetate dihydrate; sodium citrate dihydrate; citric acid, anhydrous; glycerin; water for injections.
Dosage form
Eye drops, solution.
Main physicochemical properties: transparent solution from colorless to light yellow.
Pharmacotherapeutic group
Drugs used in ophthalmology. Antiglaucoma drugs and miotics. Prostaglandin analogues.
Code AT XS01EE06.
Pharmacological properties
Mechanism of action.
Latanoprostene bunod is thought to reduce intraocular pressure by increasing the outflow of aqueous humor through the trabecular meshwork and uveoscleral pathways. Intraocular pressure is a major modifiable risk factor for glaucoma progression. Lowering intraocular pressure reduces the risk of glaucomatous visual field loss.
Pharmacodynamics.
The reduction in intraocular pressure begins approximately 1-3 hours after the first administration, with the maximum effect achieved after 11-13 hours in eyes with elevated intraocular pressure.
Pharmacokinetics.
Absorption
The systemic exposure to latanoprostene bunode and its metabolites latanoprost acid and butanediol mononitrate was evaluated in a single study in 22 healthy subjects following topical ophthalmic administration of Visult 0.024% once daily (one drop in each eye in the morning) for 28 days. No quantifiable concentrations of latanoprostene bunode (lower limit of quantification (LLOQ), 10.0 pg/mL) or butanediol mononitrate (LLOQ 200 pg/mL) were detected on Day 1 and Day 28. The mean maximum plasma concentrations (Cmax) of latanoprost acid (LLOQ 30 pg/mL) were 59.1 pg/mL and 51.1 pg/mL on Day 1 and Day 28, respectively. The mean time to maximum plasma concentration (Tmax) for latanoprost acid was approximately 5 minutes after administration on both Day 1 and Day 28.
Distribution.
Ophthalmic distribution studies in humans have not been conducted.
Metabolism.
After topical ocular administration of latanoprostene, bunode is rapidly metabolized in the eye to latanoprost acid (the active moiety of the active substance molecule), a prostaglandin F2a analogue, and butanediol mononitrate. After latanoprost acid reaches the systemic circulation, it is primarily metabolized by the liver to 1,2-dinor and 1,2,3,4-tetranor metabolites via β-oxidation of fatty acids.
Butanediol mononitrate is metabolized to 1,4-butanediol and nitric oxide. The metabolite 1,4-butanediol is further oxidized to succinic acid and enters the tricarboxylic acid cycle (TCA).
Breeding.
The elimination of latanoprost acid from human plasma is rapid, as plasma latanoprost acid concentrations fell below the LLOQ (30 pg/mL) in most subjects within 15 min after ocular administration of Visulta 0.024% in humans.
Preclinical safety data.
Carcinogenesis, mutagenesis, impaired fertility.
Latanoprostene bunod was not mutagenic in bacteria and did not induce micronuclei in the rat bone marrow micronucleus assay in vivo. Chromosomal aberrations were observed in vitro with human lymphocytes in the absence of metabolic activation.
Latanoprostene bunode has not been tested for carcinogenic activity in long-term animal studies. Latanoprost acid is the major metabolite of latanoprostene bunode. Latanoprost acid exposure in rats and mice resulting from oral administration of latanoprost in lifetime bioassays in rodents was not carcinogenic.
Fertility studies with latanoprostene bunode have not been conducted. The potential to affect fertility may be partly due to the effects of latanoprost acid, a common metabolite of both latanoprost and latanoprost. There was no effect of latanoprost acid on male or female fertility in animal studies.
Toxicology and/or pharmacology in animals.
In a 9-month toxicology study, topical ocular doses of latanoprostene bunoda were administered to cynomolgus monkeys in one eye: control (vehicle only), one drop of 0.024%, one drop of 0.04%, and two drops of 0.04% per dose, twice daily. Systemic exposures were equivalent to 4.2, 7.9, and 13.5 times the clinical dose, respectively, based on body surface area (assuming 100% absorption). Lung microscopy at 9 months showed pleural/subpleural chronic fibrosis/inflammation in the 0.04% dose group of males, with an increased incidence and severity compared to controls. No pulmonary toxicity was observed at the 0.024% dose.
Clinical studies.
In clinical studies of up to 12 months duration in patients with open-angle glaucoma or ocular hypertension with a mean baseline intraocular pressure (IOP) of 26.7 mm Hg, the IOP-lowering effect of Visulta (latanoprostene bunod ophthalmic solution), 0.024% was 7-9 mm Hg.
Indication
Reduction of intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension.
Contraindication
Missing.
Interaction with other medicinal products and other types of interactions
Unknown.
Application features
Pigmentation.
Visulta may cause changes in pigmented tissues. The most commonly reported changes with prostaglandin analogues are: increased pigmentation of the iris and periorbital tissue (eyelids).
Pigmentation is expected to increase as long as latanoprostene bunoda ophthalmic solution is administered. The change in pigmentation is due to an increase in melanin content in melanocytes, not an increase in the number of melanocytes. After discontinuation of Visulta, iris pigmentation is likely to be irreversible, while periorbital pigmentation and eyelash changes are likely to be reversible in most patients. Patients receiving prostaglandin analogues, including Visulta, should be informed of the possibility of increased pigmentation, including irreversible changes. The long-term effects of increased pigmentation are unknown.
The change in iris color may be unnoticed for several months to several years. Typically, the brown pigmentation around the pupil spreads concentrically to the periphery of the iris and the entire iris or parts of it may acquire a more intense brown color. Neither nevi nor freckles on the iris are affected by the treatment. Although treatment with Visulta can be continued in patients with markedly increased iris pigmentation, these patients should be regularly examined.
Changes in the eyelashes.
Visulta may gradually change the eyelashes and vellus hair around the eye being treated. These changes include increased length, thickness, and number of eyelashes or hairs. Changes to the eyelashes are usually reversible after treatment is stopped.
Patients should be informed that changes in the eyelashes and vellus hair around the treated eye may occur during the use of Visult. These changes may result in discrepancies between eyes in length, density, pigmentation, number of eyelashes or vellus hair, and/or direction of eyelash growth.
Intraocular inflammation.
Visulta should be used with caution in patients with a history of intraocular inflammation (iritis/uveitis) and should generally not be used in patients with active intraocular inflammation as it may lead to exacerbation of the disease.
Macular edema.
Macular edema, including cystoid macular edema, has been reported with prostaglandin analogues. Caution is advised when using Visulta in patients with aphakia, pseudophakia, and posterior capsule tear, and in patients with known risk factors for macular edema.
Bacterial keratitis.
Bacterial keratitis has been reported to be associated with the use of multidose containers for topical ophthalmic products. These containers were inadvertently contaminated by patients, most of whom had underlying corneal disease or epithelial surface disorders.
Use with other ophthalmic drugs.
If more than one topical ophthalmic drug is used, the drugs should be administered with an interval of at least five (5) minutes between applications.
Handling of the container with the medicine.
When using the medicinal product, avoid touching the tip of the dosing container to the eye, adnexa, fingers or any other surface to avoid contamination of the solution with common bacteria that cause eye infections. Use of contaminated solutions may result in serious eye damage and subsequent loss of vision.
Use with contact lenses.
The drug contains benzalkonium chloride, which discolors soft contact lenses, so contact with lenses should be avoided (remove contact lenses before using the drug and reinsert them 15 minutes after use).
When should you seek medical advice?
If a new visual disorder occurs (e.g., trauma or infection), sudden decrease in visual acuity, ophthalmic surgery, or any visual reactions occur, especially conjunctivitis and eyelid reactions, you should immediately consult a doctor for advice on continuing to use Visult.
Use in the elderly.
Overall, no clinical difference in efficacy and safety of the drug was observed between elderly patients and other adult patients.
Use during pregnancy or breastfeeding
Pregnancy.
Risk summary.
In rabbits, latanoprostene bunode caused abortions, miscarriages, and fetal harm. Latanoprostene bunode has been shown to be abortifacient and teratogenic when administered intravenously (IV) to pregnant rabbits at exposures ≥0.28 times the clinical dose. Doses ≥20 mcg/kg/day (23 times the clinical dose) resulted in 100% embryofetal lethality. Structural abnormalities observed in rabbit fetuses included anomalies of the great vessels and aortic arch, domed head, skeletal anomalies of the sternum and vertebrae, hyperextension and malrotation of the limbs, abdominal distension, and edema. Latanoprostene bunode was not teratogenic in rats at 150 mcg/kg/day IV (87 times the clinical dose).
The background risk of major birth defects and miscarriage in this population is unknown. However, the background risk of major birth defects in the general US population is 2 to 4%, and the risk of miscarriage is 15 to 20% of clinically recognized pregnancies.
Data obtained from animal studies.
Embryofetal studies were performed in pregnant rabbits administered latanoprostene bunode daily by intravenous injection from gestation day 7 to 19, targeting the period of organogenesis. The dose range administered was 0.24 to 80 mcg/kg/day. Abortion occurred at doses ≥0.24 mcg/kg/day of latanoprostene bunode (0.28 times the clinical dose, based on body surface area, assuming 100% absorption). Embryofetal lethality (resorption) was increased in the latanoprostene bunode treatment groups, as evidenced by an increase in early resorption at doses ≥0.24 mcg/kg/day and late resorption at doses ≥6 mcg/kg/day (approximately 7 times the clinical dose). No fetuses survived in pregnant rabbits at doses of 20 mcg/kg/day (23 times the clinical dose) or higher. At doses ≥ 0.24 mcg/kg/day, latanoprostene bunoda resulted in structural abnormalities (0.28 times the clinical dose). Abnormalities included sternal anomalies, coarctation of the aorta with pulmonary trunk dilation, retroesophageal subclavian artery with absent brachiocephalic artery, domed head, hyperextension of the forelimb and malrotation of the hindlimb, abdominal distension/edema, and absent/fused tail vertebrae.
An embryofetal study was conducted in pregnant rats, which were administered latanoprostene bunod daily by intravenous injection from 7 to 17 days of gestation, targeting the period of organogenesis. The dose range was 150 to 1500 μg/kg/day. Maternal toxicity occurred at 1500 μg/kg/day (870 times the clinical dose, based on body surface area, assuming 100% absorption), as evidenced by reduced maternal body weight gain. Embryofetal lethality (resorption and fetal death) and structural abnormalities occurred at doses ≥300 μg/kg/day (174 times the clinical dose). Developmental malformations included sternal anomalies, domed head, forelimb hyperextension and hindlimb malrotation, vertebral anomalies, and delayed ossification of distal limb bones. This study established a NOAEL of 150 μg/kg/day (87 times the clinical dose).
Breastfeeding period
Risk summary.
There are no data on the presence of Vizult in breast milk, the effects on breastfed infants, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Vizult and any potential adverse effects of Vizult on the breastfed infant.
Ability to influence reaction speed when driving vehicles or other mechanisms
Unknown. As with other medicines, instillation of eye drops may cause temporary blurred vision. Until this effect has passed, patients should not drive or operate machinery.
Method of administration and doses
The recommended dose is one drop in the conjunctival sac of the affected eye(s) once daily in the evening. Do not use Visulta more than once daily, as it has been shown that more frequent administration of prostaglandin analogues may reduce the intraocular pressure-lowering effect.
If Visulta is to be used concomitantly with other topical ophthalmic drugs to reduce intraocular pressure, administer each drug at least five (5) minutes apart.
Children.
Use in children 16 years of age and younger is not recommended due to potential safety concerns related to increased pigmentation after long-term chronic use.
Overdose
Unknown.
Side effects
On the part of the organs of vision: pigmentation, changes in the eyelashes, intraocular inflammation, macular edema, bacterial keratitis (See section "Special instructions").
Visulta was evaluated in 811 patients in 2 controlled clinical trials of up to 12 months duration. The most common visual adverse reactions observed in patients treated with latanoprostene bunod were: conjunctival hyperemia (6%), eye irritation (4%), eye pain (3%), and instillation site pain (2%). Approximately 0.6% of patients discontinued therapy due to visual adverse reactions, including ocular hyperemia, conjunctival irritation, eye irritation, eye pain, conjunctival edema, blurred vision, punctate keratitis, and foreign body sensation.
Contains benzalkonium chloride, which may cause irritation.
Expiration date
36 months for packaging of 5 ml in a bottle with a dropper, 1 bottle with a dropper in a cardboard box;
24 months for packaging of 2.5 ml in a dropper bottle, 1 dropper bottle in a cardboard box.
After first opening - store no more than 8 weeks.
Storage conditions
Store at a temperature of 2°C to 8°C.
After first opening - store at a temperature of 2°C to 25°C for no more than 8 weeks.
Protect from light.
Do not freeze.
Keep out of reach of children.
Packaging
5 ml in a bottle with a dropper, 1 bottle with a dropper in a cardboard box;
2.5 ml in a bottle with a dropper, 1 bottle with a dropper in a cardboard box.
Vacation category
According to the recipe.
Producer
Bausch & Lomb Incorporated.
Location of the manufacturer and its business address.
8500 Hidden River Parkway Tampa, FL 33637, United States of America.
