Instructions for use Yellox eye drops 0.9 mg/ml 5 ml
Composition
active ingredient: bromfenac;
1 ml of solution contains bromfenac sodium sesquihydrate 1 ml, which is equivalent to 0.9 mg of bromfenac;
excipients: boric acid, sodium tetraborate, sodium sulfite anhydrous (E 221), tyloxanol, povidone (K 30), disodium edetate, benzalkonium chloride, sodium hydroxide, water for injections.
Dosage form
Eye drops, solution.
Main physicochemical properties: almost transparent yellow solution.
Pharmacotherapeutic group
Drugs used in ophthalmology. Nonsteroidal anti-inflammatory drugs. Code S01BC11.
Pharmacological properties
Mechanism of action
Bromfenac is a nonsteroidal anti-inflammatory drug (NSAID) that has anti-inflammatory activity thought to be due to its ability to block prostaglandin synthesis by inhibiting primarily cyclooxygenase 2 (COX-2). Cyclooxygenase 1 (COX-1) is inhibited only to a minor extent.
In vitro, bromfenac inhibited prostaglandin synthesis in the rabbit iris ciliary body. IC50 values were lower for bromfenac (1.1 μM) than for indomethacin (4.2 μM) and pranoprofen (11.9 μM).
Bromfenac at concentrations of 0.02%, 0.05%, 0.1%, and 0.2% suppressed almost all signs of ocular inflammation in a rabbit model of experimental uveitis.
Clinical efficacy
Two multicenter, randomized, double-blind, parallel-group Phase II studies were conducted in Japan and two multicenter, randomized (2:1), double-blind, placebo-controlled, parallel-group Phase III studies were conducted in the United States to evaluate the clinical efficacy and safety of Yellox administered twice daily for the treatment of postoperative inflammation in patients undergoing cataract surgery. In these studies, the study agent was instilled approximately 24 hours after cataract surgery and administered for up to 14 days. The treatment effect was evaluated for up to 29 days.
A significantly higher proportion of patients in the Yellowox group (64.0% vs. 43.3% in the placebo group) reported complete resolution of ocular inflammation by study day 15 (p < 0.0001). During the first 2 weeks after surgery, there was significantly less cellular elements and anterior chamber opalescence (85.1% of patients with opalescence score ≤1) vs. placebo (52%). The difference in the rate of resolution of inflammation was evident as early as day 3.
In a large, well-controlled study conducted in Japan, Yellowox was shown to be as effective as pranoprofen ophthalmic solution.
Children
The European Medicines Agency has waived the requirement to submit the results of studies on the use of Yellox in all subgroups of pediatric patients with postoperative eye inflammation (information on the use of the drug in children is provided in the “Method of administration and dosage” section).
Pharmacokinetics.
Absorption
Bromfenac penetrates the cornea of patients with cataracts effectively. A single dose resulted in a mean maximum aqueous humor concentration of 79 ± 68 ng/mL 150-180 minutes after drug administration. Concentrations were maintained for 12 hours in the aqueous humor with measurable levels for up to 24 hours in major ocular tissues, including the retina. Plasma concentrations could not be quantified with twice-daily administration of bromfenac eye drops.
Distribution
Bromfenac is highly bound to plasma proteins. In vitro, 99.8% of bromfenac was bound to human plasma proteins.
No biologically significant melanin binding was observed in vitro.
Studies in rabbits using radiolabeled bromfenac showed that the highest concentrations after topical administration were observed in the cornea, followed by the conjunctiva and aqueous humor. Low concentrations were observed only in the lens and vitreous.
Metabolism
In vitro studies show that bromfenac is primarily metabolized by the CYP2C9 protein, which is absent in both the iris-ciliary body and the retina/choroid, and the level of this enzyme in the cornea is less than 1% of the corresponding level in the liver.
In humans, the unchanged parent compound is the major component in plasma after oral administration. Several conjugated and unconjugated metabolites have been identified, with the cyclic amide being the major metabolite excreted in the urine.
Breeding
After instillation into the eye, the half-life of bromfenac from the aqueous humor is 1.4 hours, indicating rapid elimination.
Following oral administration of 14C-bromfenac to healthy volunteers, urinary excretion was found to be the major route of excretion of the radioactive components, accounting for approximately 82%, while faecal excretion accounted for approximately 13% of the dose.
Nonclinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, and carcinogenic potential. However, oral doses of 0.9 mg/kg/day in rats (900 times the recommended ophthalmic dose) caused embryo-fetal lethality, increased neonatal mortality, and reduced postnatal growth. In pregnant rabbits, oral doses of 7.5 mg/kg/day (7500 times the recommended ophthalmic dose) caused increased postimplantation fetal loss (see section 4.6).
Animal studies have shown excretion of bromfenac in breast milk following oral administration of 2.35 mg/kg, which is 2350 times the recommended ophthalmic dose. However, plasma levels were undetectable following ocular instillation (see Pharmacokinetics).
Indication
Treatment of postoperative eye inflammation after cataract removal in adults.
Contraindication
Hypersensitivity to bromfenac or any of the excipients of this medicinal product, or to other non-steroidal anti-inflammatory drugs (NSAIDs). Yellox is contraindicated in patients whose asthma, urticaria or acute rhinitis attacks are provoked by acetylsalicylic acid or other medicinal products capable of inhibiting the activity of prostaglandin synthetase.
Interaction with other medicinal products and other types of interactions
Clinical studies of interactions with other drugs have not been conducted. No interactions have been reported with antibiotic eye drops used in conjunction with surgery.
Application features
All topical NSAIDs may slow or delay healing, as may topical corticosteroids. Concomitant use of NSAIDs and topical steroids may impair healing.
Cross-sensitivity: There is potential for cross-sensitivity to acetylsalicylic acid, phenylacetic acid derivatives and other NSAIDs. Therefore, treatment of individuals with a history of hypersensitivity to these drugs should be avoided (see section 4.3).
Susceptible patients. In susceptible patients, prolonged use of topical NSAIDs, including bromfenac, may cause epithelial breakdown, corneal thinning, corneal erosion, corneal ulceration, or corneal perforation. This may result in loss of vision. NSAIDs should be discontinued immediately in patients with evidence of corneal breakdown and monitored until the cornea has resolved. Therefore, in patients at risk, concomitant use of ophthalmic corticosteroids with NSAIDs may be associated with an increased risk of corneal adverse events.
Post-marketing experience: Post-marketing experience with topical NSAIDs suggests that patients with complex ophthalmic surgery, corneal denervation, corneal epithelial defects, diabetes mellitus, and ocular surface tissue diseases such as dry eye syndrome, rheumatoid arthritis, or repeated ophthalmic surgeries within a short period of time may be at increased risk of corneal adverse events that pose a risk of vision loss. NSAIDs should be used with caution in such patients.
Ophthalmic NSAIDs have been reported to cause increased bleeding from ocular tissues (including hyphema) in association with ophthalmic surgery. Yellowox should be used with caution in patients with a tendency to bleed or in those taking other medications that may prolong bleeding time.
In rare cases, it has been observed that after discontinuation of the drug Yellox, a sudden exacerbation of the inflammatory reaction may occur, for example, in the form of macular edema caused by cataract surgery.
Ophthalmic infections: Acute ophthalmic infection may be masked by topical anti-inflammatory medications.
Contact lens use: In general, contact lens wear is not recommended in the postoperative period following cataract surgery. Therefore, patients should be advised not to wear contact lenses during treatment with Yellox.
Yellox contains benzalkonium chloride (1 ml of solution contains 50 mcg of benzalkonium chloride), frequent or prolonged use of the drug should be accompanied by careful monitoring. Benzalkonium chloride is known to discolor soft contact lenses. Contact with soft contact lenses should be avoided. Cases of eye irritation, punctate keratopathy and/or toxic ulcerative keratopathy have been reported in association with the use of benzalkonium chloride. Yellox contains sodium sulfite, which may cause allergic reactions, including symptoms of anaphylaxis and life-threatening or less severe asthma attacks in susceptible patients.
Use during pregnancy or breastfeeding
There are no adequate data from the use of bromfenac in pregnant women. Animal studies have shown reproductive toxicity (see section 5.3). The potential risk to humans is unknown. Since systemic exposure in non-pregnant women is negligible after treatment with Yellox, the risk during pregnancy can be considered low.
However, due to the known effects of drugs that inhibit prostaglandin biosynthesis on the fetal cardiovascular system (closure of the ductus arteriosus), the use of Yellox should be avoided during the third trimester of pregnancy. The use of Yellox is generally not recommended during pregnancy unless the benefit outweighs the potential risk.
Breastfeeding period
It is not known whether bromfenac or its metabolites are excreted in human milk. Animal studies have shown excretion of bromfenac in the milk of rats after very high oral doses (see section 5.3). No effects on the newborn/infant are expected, as the systemic exposure of bromfenac to the breast-feeding woman is negligible. Yellowox can be used during breast-feeding.
Fertility
In animal studies, no effect of bromfenac on fertility was observed. In addition, the systemic exposure to bromfenac is negligible, for this reason, pregnancy tests or the use of contraceptives are not required.
Ability to influence reaction speed when driving vehicles or other mechanisms
Yellowox has minor influence on the ability to drive and use machines. Instillation may be accompanied by temporary blurred vision. If instillation is accompanied by blurred vision, patients should be advised to refrain from driving or operating machinery until vision clears.
Method of administration and doses
One drop of the drug contains approximately 33 mcg of bromfenac.
Method of administration. The drug is intended for use in ophthalmology in adults, including elderly patients.
If more than one topical ophthalmic drug is used, an interval of at least 5 minutes should be observed between applications.
To prevent contamination of the dropper tip and solution, care should be taken not to touch the eyelids, surrounding areas, or other surfaces with the dropper tip of the bottle.
Dosage: One drop of Yellox is instilled into the affected eye(s) twice daily, starting the day after cataract surgery and continuing for the first 2 weeks of the postoperative period.
The duration of treatment should not exceed 2 weeks, as there is no data on the safety of use for a longer period.
The use of Yellox has not been studied in patients with impaired liver or kidney function.
Children
The safety and efficacy of bromfenac in children and adolescents have not been studied. Data are not available.
Overdose
No abnormal findings or adverse reactions have been observed in clinical practice when two drops of the 2 mg/ml solution were applied four times daily for 28 days. Accidental application of more than one drop should not result in increased exposure at the injection site, as the excess amount will be washed out of the eye due to the limited volume of the conjunctival sac.
In case of accidental oral administration, there is practically no risk of side effects. The intake of the contents of a 5 ml vial corresponds to an oral dose of less than 5 mg of bromfenac, which is 30 times lower than the daily oral dose of bromfenac used previously.
If you accidentally swallow the medicine Yellowks, you must drink liquids to dilute the medicine.
Side effects
Summary of the safety profile. Based on the available clinical data, a total of 3.4% of patients experienced one or more adverse reactions. The most common or most important reactions in the pooled studies were abnormal eye sensation (0.5%), corneal erosion (mild or moderate) (0.4%), eye pruritus (0.4%), eye pain (0.3%), and eye redness (0.3%). Corneal adverse reactions were observed only in Japanese subjects. Adverse reactions rarely led to discontinuation of the drug, with a total of 8 (0.8%) patients discontinuing treatment in the study due to an adverse reaction. This included 3 (0.3%) patients with mild corneal erosion, 2 (0.2%) patients with eyelid edema, and 1 (0.1%) patient each with abnormal eye sensation, corneal edema, or eye pruritus.
List of adverse reactions in tabular form
Adverse reactions are classified as follows: 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). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
The table below describes adverse reactions by system organ class and frequency.
| MedDRA system organ classes | Frequency | Adverse reactions |
| From the organ of vision | Infrequently | Decreased visual acuity Hemorrhagic retinopathy Corneal epithelial defect** Corneal erosion (mild or moderate) Corneal epithelium disorders Corneal edema Retinal exudates Bleeding from the eyelids Blurred vision Photophobia Eyelid swelling Discharge and eyes Itchy eyes Eye irritation Redness of the eyes Conjunctival hyperemia Abnormal sensations in the eyes Feeling of discomfort in the eyes |
| Rarely | Corneal perforation* Corneal ulceration* Corneal erosion, serious* Scleromalia* Corneal infiltrates* Corneal disorders * Corneal scar* | |
| 3 sides of the respiratory system, chest and mediastinum | Infrequently | Nosebleed Cough Discharge from the paranasal sinuses |
| Rarely | Bronchial asthma* |
| General disorders and administration site conditions | Infrequently | Facial swelling |
* Serious reports during post-marketing use in more than 20 million patients.
** Observed when used four times a day. Patients with signs of corneal epithelial breakdown should be informed to immediately discontinue use of Yellox and should be under medical supervision until the cornea normalizes (see section "Special instructions").
Expiration date
2 years. After first opening, store for no more than 4 weeks.
Storage conditions
Store at a temperature not exceeding 25 ° C. Keep out of the reach of children.
Packaging
5 ml in a bottle with a dropper, 1 bottle with a dropper in a cardboard box.
Vacation category
According to the recipe.
Producer
Dr. Gerhard Mann Chem.-Pharm. Factory LLC.
Location of the manufacturer and its business address
Brunsbütteler Damm 165/173, 13581 Berlin, Germany.
