Medexol
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MEDEXOL (MEDEXOL)
Composition:
Active substance: dexamethasone;
1 ml of solution contains dexamethasone sodium phosphate 1 mg;
Excipients: polysorbate 80; hypromellose; sodium chloride; disodium phosphate, dodecahydrate; citric acid, monohydrate; benzalkonium chloride; edetate disodium; water for injections.
Pharmaceutical form. Eye drops, solution.
Main physicochemical properties: clear, colorless solution.
Pharmacotherapeutic group.
Anti-inflammatory agents used in ophthalmology. Corticosteroids. Dexamethasone. ATC code S01B A01.
Pharmacological Properties.
Pharmacodynamics.
The efficacy of corticosteroids in treating ocular inflammatory conditions is well established. Corticosteroids exert their anti-inflammatory action by inhibiting adhesion molecules on vascular endothelial cells, cyclooxygenase I or II, and cytokine release. As a result, the production of inflammatory mediators is reduced and leukocyte adhesion to vascular endothelium is suppressed, thereby preventing their migration into inflamed ocular tissues.
Dexamethasone has potent anti-inflammatory activity with reduced mineralocorticoid effects compared to some other steroids and is one of the most potent corticosteroids available.
The high level of activity results from the addition of a methyl group and fluorine to the prednisolone molecule. This synthetic glucocorticoid suppresses inflammatory responses to mechanical, chemical, or immunological stimuli.
The precise mechanism underlying this property has not yet been elucidated.
The exact mechanism of dexamethasone’s anti-inflammatory action is not fully understood. It suppresses numerous inflammatory cytokines and exerts multiple glucocorticoid and mineralocorticoid effects.
Dexamethasone is one of the most potent corticosteroids; it is 5–10 times more potent than prednisolone and 25 times more potent than cortisone and hydrocortisone.
The systemic toxicity of the active substance is well characterized. Systemic effects of dexamethasone may be associated with glucocorticosteroid imbalance.
Pharmacokinetics.
Absorption.
Ophthalmic bioavailability of dexamethasone after topical ocular administration has been studied in patients undergoing cataract surgery. Maximum dexamethasone levels in intraocular fluid, approximately 30 ng/mL, were reached within 90–120 minutes. Subsequently, concentration declined with a half-life of 3 hours. Systemic absorption following topical application is low.
Distribution.
Following intravenous administration, the observed volume of distribution was 0.58 L/kg. In vitro, no changes in plasma protein binding were observed at dexamethasone concentrations ranging from 0.04 to 4 µg/mL, with an average plasma protein binding of 77.4%.
Metabolism.
Dexamethasone is primarily metabolized in the liver, mainly by CYP3A4. After topical administration, low concentrations were detected in intraocular fluid up to 12 hours, indicating that dexamethasone is stable against metabolism after penetrating into the intraocular fluid.
Excretion.
After intravenous administration, 2.6% of the unchanged parent compound was found in urine. Following oral administration (≤ 4 mg/day) over several weeks, 60% of the dose was recovered as 6β-hydroxydexamethasone and 5–10% as another metabolite, 6β-hydroxy-20-dihydrodexamethasone. Unchanged dexamethasone was not detected in urine. The systemic plasma half-life is relatively short—3–4 hours—but may be slightly longer in males. This difference was not related to changes in systemic clearance but rather to differences in volume of distribution and body mass. Dexamethasone is approximately 77–84% bound to plasma albumin. Clearance ranges from 0.10 to 0.25 L/h/kg, and volume of distribution ranges from 0.576 to 1.15 L/kg. Oral bioavailability of dexamethasone is approximately 70%.
Linearity/Non-linearity.
The area under the concentration–time curve after oral administration of dexamethasone increased linearly within the dose range of 0.5 mg to 1.5 mg.
Special patient populations.
The pharmacokinetics of systemic dexamethasone do not differ significantly in patients with impaired renal function compared to healthy subjects.
Preclinical safety data.
Repeated-dose toxicity studies of dexamethasone ophthalmic drops in rabbits revealed systemic corticosteroid-related effects; however, even at doses substantially exceeding the human dose, these findings are not considered clinically relevant. The occurrence of such effects following the recommended doses of dexamethasone eye drops is unlikely.
Dexamethasone demonstrated clastogenic properties in an in vitro chromosomal aberration assay in human lymphocytes and in an in vivo micronucleus test in mice.
Standard carcinogenicity studies with dexamethasone have not been conducted.
Standard fertility studies with dexamethasone have not been conducted.
It has been established that dexamethasone is teratogenic in animals following oral administration: dexamethasone induced fetal developmental abnormalities, including cleft palate, intrauterine growth retardation, retrognathia, umbilical hernia, thymic hypoplasia, skeletal deformities (including impaired development of long bones), and effects on brain growth and development.
Clinical characteristics.
Indications.
Treatment of steroid-responsive non-infectious inflammatory and allergic conditions of the conjunctiva, cornea, and anterior segment of the eye, including inflammatory reactions in the postoperative period.
Contraindications.
- Hypersensitivity to the active substance and/or to any of the excipients.
- Acute untreated bacterial infections.
- Cattlepox and smallpox, and other viral infections of the cornea and conjunctiva (except keratitis caused by Herpes zoster).
- Fungal diseases of ocular structures.
- Untreated parasitic infections of the eye.
- Mycobacterial infections of the eye.
- Acute epithelial keratitis caused by Herpes zoster (dendritic keratitis).
- Acute untreated purulent bacterial infections of the eye.
- Infections or injuries limited to the corneal surface epithelium.
- Use after removal of a foreign body from the cornea without complications.
Interaction with other medicinal products and other types of interactions.
Interaction studies with other medicinal products have not been conducted.
Concomitant use of topically applied ophthalmic steroids and local non-steroidal anti-inflammatory drugs (NSAIDs) may increase the risk of corneal wound healing complications.
In patients receiving ritonavir or other potent CYP3A4 inhibitors, plasma concentration of dexamethasone may be increased (see section "Special precautions for use").
CYP3A4 inhibitors (including ritonavir and cobicistat) may reduce dexamethasone clearance, leading to more severe adverse effects and suppression of adrenal cortex function / Cushing's syndrome. Such interactions should be avoided unless the benefit outweighs the increased risk of systemic side effects associated with corticosteroid use. In such cases, patients should be monitored for the development of systemic corticosteroid-related adverse effects.
Topical ophthalmic administration of dexamethasone may additionally increase intraocular pressure when used concomitantly with mydriatic eye drops (e.g., atropine or other anticholinergic agents), which themselves may cause elevated intraocular pressure.
When using multiple topical ophthalmic medicinal products, the interval between administrations should be at least 5 minutes. Ophthalmic ointments should be applied last.
Special precautions for use.
The medicinal product is intended for ophthalmic use only. It is not intended for injection or oral administration.
The medicinal product should not be used without prior medical examination. It should be prescribed only after biomicroscopic examination using a slit lamp and fluorescein staining test.
This medicinal product is not effective in the treatment of keratoconjunctivitis sicca (Sjögren's syndrome).
Excessive and/or prolonged use of ophthalmic corticosteroids increases the risk of ocular complications and may lead to systemic adverse effects. If inflammation does not subside during treatment, alternative therapies should be considered to reduce these risks.
Prolonged treatment with locally applied ophthalmic corticosteroids may lead to ocular hypertension and/or glaucoma, resulting in optic nerve damage, decreased visual acuity, visual field defects, and posterior subcapsular cataract formation. Patients receiving prolonged topical ophthalmic corticosteroid therapy should have regular and frequent monitoring of intraocular pressure. This is particularly important in children, as the risk of corticosteroid-induced ocular hypertension is higher in children than in adults. The medicinal product is not recommended for use in children. Patients with a personal or family history of glaucoma have an increased risk of developing corticosteroid-induced intraocular pressure elevation. In patients with glaimcoma, ocular monitoring should be performed weekly.
In acute purulent ocular infections, corticosteroids may mask or exacerbate existing infections. If treatment lasts longer than 10 days, intraocular pressure should be monitored.
The risk of increased intraocular pressure and/or cataract formation associated with corticosteroid use is increased in predisposed patients (e.g., patients with diabetes mellitus).
Visual disturbances may occur with both systemic and topical corticosteroid use.
If a patient experiences symptoms such as blurred vision or other visual disturbances, they should be referred to an ophthalmologist for evaluation of possible causes, including cataract, glaucoma, or rare conditions such as central serous chorioretinopathy (CSCR), which have been reported following systemic and topical corticosteroid use.
Cushing's syndrome and/or adrenal suppression associated with systemic absorption of ophthalmic dexamethasone formulations may occur after intensive or long-term continuous therapy in susceptible patients, including children and patients receiving CYP3A4 inhibitors (e.g., ritonavir and cobicistat). In such cases, treatment should be tapered gradually.
Corticosteroids may reduce resistance to bacterial, viral, fungal, or parasitic infections and may mask clinical signs of infection, thereby interfering with the detection of antibiotic inefficacy.
Fungal infection should be considered in patients with persistent corneal ulceration who are receiving or have received these medications. If a fungal infection develops, corticosteroid therapy should be discontinued.
Ophthalmic corticosteroids may delay corneal wound healing. Nonsteroidal anti-inflammatory drugs (NSAIDs) for topical use are also known to slow or delay corneal wound healing. Concomitant use of topical NSAIDs and topical corticosteroids may increase the risk of wound healing complications (see section "Interaction with other medicinal products and other forms of interaction").
Topical corticosteroid use is known to potentially cause perforations in patients with diseases leading to thinning of the cornea or sclera.
Treatment should not be discontinued prematurely due to the risk of inflammatory relapse following abrupt withdrawal of high-dose corticosteroids.
The medicinal product should be used with particular caution and only in combination with antiviral therapy when treating stromal keratitis or uveitis caused by Herpes simplex; periodic slit-lamp microscopy is required.
Wearing contact lenses during treatment of ocular inflammation is not recommended.
The medicinal product contains benzalkonium chloride, which may cause eye irritation and is known to discolor soft contact lenses. Contact with soft contact lenses should be avoided. However, if the physician considers contact lens use acceptable, patients should be advised to remove contact lenses before instilling eye drops and to wait 15 minutes after instillation before reinserting contact lenses. Benzalkonium chloride may cause eye irritation, particularly in patients with dry eye symptoms or corneal diseases (the transparent front layer of the eye).
After instillation of eye drops, the following measures are recommended to reduce systemic absorption:
- keep eyelids closed for 2 minutes;
- press the lacrimal sac with a finger for 2 minutes.
The medicinal product contains disodium phosphate dodecahydrate, which may rarely cause adverse reactions (see section "Adverse reactions").
Use during pregnancy or breastfeeding.
Pregnancy.
There are no adequate or well-controlled studies evaluating the effects of topical ophthalmic dexamethasone use in pregnant women. Prolonged or repeated corticosteroid use during pregnancy has been associated with an increased risk of intrauterine growth retardation. Infants born to mothers who received significant doses of corticosteroids during pregnancy should be carefully monitored for signs of adrenal insufficiency (see section "Special precautions for use"). Reproductive toxicity has been demonstrated in animal studies following systemic administration. Ophthalmic use of 0.1% dexamethasone solution caused fetal abnormalities in rabbits. The medicinal product is not recommended during pregnancy.
Breastfeeding.
Systemic corticosteroid use results in their presence in human breast milk in amounts that may affect the breastfed infant. However, systemic exposure following topical ophthalmic dexamethasone is minimal. It is unknown whether dexamethasone is excreted into breast milk. Data on the mechanism of dexamethasone transfer into breast milk are lacking. It is unlikely that dexamethasone will be present in breast milk or cause clinical effects in infants after maternal use of the medicinal product. However, a risk to the breastfed infant cannot be excluded. Consideration should be given to temporarily discontinuing breastfeeding during treatment with the medicinal product or to discontinuing or withholding treatment, taking into account the potential benefit of the medicinal product for the mother and the benefits of breastfeeding for the infant.
Fertility.
No studies have been conducted to evaluate the effect of dexamethasone on reproductive function following topical ophthalmic administration. There are limited clinical data on the effect of dexamethasone on reproductive function in men and women.
In rat models treated with chorionic gonadotropin, no adverse effects of dexamethasone on reproductive function were observed.
Ability to influence reaction rate when driving or operating machinery.
Topically applied ophthalmic dexamethasone has no or negligible effect on the ability to drive or operate machinery. As with other ophthalmic agents, transient blurred vision or other visual disturbances may affect the ability to drive or operate machinery.
If blurred vision occurs after instillation, the patient should wait until vision clears before driving or operating machinery.
Method of Administration and Dosage
The medicinal product is intended for topical use only (in the conjunctival sac).
Dosage.
Adults (including elderly patients).
In severe or acute inflammation, instill 1–2 drops of the medicinal product into the conjunctival sac(s) of the affected eye(s) every 30–60 minutes (initial therapy).
When a positive effect is observed, reduce the dose to 1–2 drops into the conjunctival sac(s) of the affected eye(s) every 2–4 hours.
Subsequently, the dose may be further reduced to 1 drop 3–4 times daily, if this dosage is sufficient to control inflammation.
If the desired effect is not achieved within 3–4 days, additional systemic or subconjunctival therapy may be prescribed.
For chronic inflammation, the dosage is 1–2 drops into the conjunctival sac(s) of the affected eye(s) every 3–6 hours, or more frequently if necessary.
For allergy or mild inflammation, the dosage is 1–2 drops into the conjunctival sac(s) of the affected eye(s) every 3–4 hours until the desired effect is achieved.
Do not discontinue treatment prematurely (see section "Special Warnings and Precautions for Use").
During treatment with this medicinal product, regular monitoring of intraocular pressure is recommended.
Patients with hepatic and/or renal impairment.
Safety and efficacy in these patients have not been established. However, due to the low systemic absorption of dexamethasone following topical ophthalmic administration of this medicinal product, dosage adjustment is not required.
Method of Administration.
- Wash hands before instillation.
- Shake the bottle well.
- Sit comfortably in front of a mirror.
- Remove the cap. Be careful not to touch the dropper tip. Contact with any surface may contaminate the bottle contents.
- Hold the bottle upside down between the index and thumb of one hand.
- Tilt the head backward.
- Gently pull down the lower eyelid with the finger of the other hand.
- Bring the dropper tip close to the eye without touching it, and gently press the base of the bottle with the index finger to release 1–2 drops into the space between the eye and the eyelid.
- Close the eye and gently press with a finger on the inner corner of the eye near the nose for 2 minutes. This reduces the amount of medicinal product entering the bloodstream.
- If necessary, repeat the same procedure for the other eye. Immediately after instillation, tightly replace the cap on the bottle.
If more than the recommended dose is instilled, rinse the eye with warm water and do not administer further doses until the next scheduled dose.
If a dose is missed, instill a single dose as soon as remembered. However, if it is nearly time for the next dose, skip the missed dose and resume the regular dosing schedule. Do not administer a double dose.
To prevent contamination of the dropper tip and bottle contents, avoid touching the eyelids, surrounding areas, or any other surfaces with the dropper tip. The bottle must be kept tightly closed during storage.
After instillation of eye drops, nasolacrimal occlusion or gentle eye closure is recommended. This reduces systemic absorption of the medicinal product administered into the eye, thereby decreasing the likelihood of systemic adverse reactions.
When using more than one topical ophthalmic product, an interval of at least 5 minutes between applications should be maintained. Ophthalmic ointments should be administered last.
Children.
The safety and efficacy of this medicinal product in children (under 18 years of age) have not been established.
Overdose.
No cases of overdose have been reported. In case of acute overdose via ophthalmic administration or accidental ingestion of the bottle contents, considering the properties/characteristics of this medicinal product, additional toxic effects are not expected.
In case of local overdose, flush the excess product from the eye(s) with warm water. In case of accidental ingestion, symptomatic and supportive therapy is indicated.
Side effects.
The most frequently observed side effect during clinical studies was eye discomfort.
Side effects are classified by frequency: very common (≥ 1/10), common (≥ 1/100 and <1/10), uncommon (≥ 1/1000 and <1/100), rare (≥ 1/10000 and <1/1000), very rare (<1/10000), not known (frequency cannot be estimated from available data). Within each group, side effects are listed in order of decreasing severity. Data on side effects were obtained from clinical trials and post-marketing experience with dexamethasone eye drops and/or ophthalmic ointment.
Infections and infestations:
rare – eye infection (exacerbation or secondary).
Immune system disorders:
not known – hypersensitivity reactions.
Endocrine system disorders:
not known – Cushing's syndrome, adrenal suppression (see section "Special precautions for use").
Nervous system disorders:
uncommon – dysgeusia; not known – dizziness, headache.
Eye disorders:
common – eye discomfort; uncommon – keratitis, conjunctivitis, dry eyes, corneal staining, photophobia, blurred vision (see section "Special precautions for use"), eye itching, foreign body sensation in the eye, increased lacrimation, unusual sensation in the eyes, scaling at the eyelid margins, eye irritation, eye hyperemia; rare – subcapsular cataract, glaucoma, visual field defects; not known – ulcerative keratitis, increased intraocular pressure, decreased visual acuity, corneal erosion, ptosis, eye pain, mydriasis.
Very rare cases of corneal calcification have been reported with ophthalmic solutions containing phosphate in some patients with significantly damaged corneas.
Injury, poisoning and procedural complications:
very rare – corneal perforation.
Description of selected side effects.
Prolonged treatment with locally applied ophthalmic corticosteroids may lead to ocular hypertension and/or glaucoma with subsequent optic nerve damage, decreased visual acuity and visual field, and formation of posterior subcapsular cataract (see section "Special precautions for use").
Since the medicinal product contains a corticosteroid, the risk of perforation is increased in patients with diseases causing thinning of the cornea or sclera, especially after prolonged use (see section "Special precautions for use").
Corticosteroids may reduce resistance to infections and increase the risk of developing infections (see section "Special precautions for use").
Reporting of suspected adverse reactions.
Reporting suspected adverse reactions after marketing authorization of the medicinal product is important. This allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions through the national pharmacovigilance system.
Shelf life.
3 years.
Storage conditions.
Store at temperatures not exceeding 25 °C, in a place inaccessible to children.
After opening the bottle, the medicinal product can be used for up to 28 days.
Packaging.
5 ml in a bottle, 1 dropper bottle in a cardboard box.
Prescription status.
Prescription only.
Manufacturer.
UORLД MEDICINE ILAC SAN. VE TIC. A.S./
WORLD MEDICINE ILAC SAN. VE TIC. A.S.
Manufacturer's address.
15 Temmuz Mahallesi Cami Yolu Caddesi No:50 Gunesli Bagcilar/Istanbul, Turkey.
Marketing authorization holder.
WORLD MEDICINE, LLC, Ukraine.