Medetrom eye drops suspension dropper bottle 5 ml

Instructions for use Medetrom eye drops suspension dropper bottle 5 ml

Composition

active ingredients: tobramycin, dexamethasone;

1 ml of suspension contains tobramycin 3 mg and dexamethasone 1 mg;

excipients: tyloxapol, hypromellose, sodium sulfate anhydrous, sodium chloride, disodium edetate, benzalkonium chloride, sulfuric acid or sodium hydroxide, purified water.

Dosage form

Eye drops, suspension.

Main physicochemical properties: white or almost white suspension, possible presence of a precipitate, which disappears upon gentle shaking.

Pharmacotherapeutic group

Anti-inflammatory and antimicrobial agents in combination. Corticosteroids and antimicrobial agents in combination. ATX code S01C A01.

Pharmacological properties

Pharmacodynamics

Dexamethasone

Dexamethasone belongs to the group of glucocorticoids. The effectiveness of corticosteroids in the treatment of anti-inflammatory conditions of the eye is well known. Corticosteroids achieve their anti-inflammatory action by inhibiting adhesion molecules to vascular endothelial cells, cyclooxygenase I or II, and the release of cytokines. As a result, the formation of inflammatory mediators is reduced and the adhesion of circulating leukocytes to the vascular endothelium is inhibited, which prevents their penetration into inflamed tissues of the eye. Dexamethasone has a pronounced anti-inflammatory effect with reduced mineralocorticoid activity compared with some other steroids and is one of the most potent anti-inflammatory agents.

Tobramycin

Tobramycin is a highly active, fast-acting bactericidal antibiotic of the aminoglycoside group, which counteracts both gram-positive and gram-negative microorganisms. Its mechanism of action is associated with the inhibition of the polypeptide complex and synthesis in the ribosomes of bacterial cells.

In general, the action of tobramycin has been described in vitro by determining the minimum inhibitory concentration (MIC), which determines the activity of the antibiotic against each bacterial species. Since the MIC of tobramycin is very low against most ocular pathogens, it is considered a broad-spectrum antibiotic. MIC breakpoints have been determined that determine the sensitivity or resistance of a bacterial culture to a particular antibiotic. The existing MIC breakpoints for tobramycin against the relevant bacterial species take into account the inherent sensitivity of the species, as well as the maximum concentration and pharmacokinetic time/concentration values measured in blood plasma after oral administration. The determination of these breakpoints, which divide microorganisms into susceptible and resistant, has been used to determine the clinical efficacy of antibiotics administered systemically. However, when the antibiotic is applied topically in high concentrations directly to the site of infection, the determination of breakpoints is not used. Most microorganisms that would be classified as resistant by determining the breakpoints for systemic use actually respond well to topical treatment. For the purpose of prevention, it is possible to stop the development of such microorganisms that cause infection.

In clinical studies, topical tobramycin solution was effective against many existing strains of ocular pathogens in patients enrolled in the studies. Some of these ocular pathogens are considered resistant based on the determination of systemic breakpoints. In clinical studies, tobramycin has been shown to be effective in the treatment of superficial ocular infections caused by the following pathogens.

*The beta-lactam (i.e., methicillin; penicillin) resistance phenotype is not associated with the aminoglycoside resistance phenotype, and both are unrelated to the virulence and phenotypes of the pathogenic organisms. Many methicillin-resistant staphylococci have been found to be resistant to tobramycin (and other aminoglycoside antibiotics). However, these resistant staphylococcal cultures (as determined by MIC breakpoints) usually respond successfully to topical tobramycin.

Bacterial susceptibility studies have shown that in some cases, microorganisms resistant to gentamicin remain susceptible to tobramycin. A significant proportion of the microflora has not yet developed resistance to tobramycin; however, bacterial resistance may develop during prolonged use.

Cross-sensitivity to other aminoglycoside antibiotics is possible. If hypersensitivity occurs during use of the drug, its use should be discontinued and appropriate treatment should be initiated.

The safety and efficacy of tobramycin/dexamethasone in children have been established through extensive clinical experience, but only limited data are available. In a clinical study of tobramycin/dexamethasone suspension for the treatment of bacterial conjunctivitis, 29 children aged 1 to 17 years received 1 or 2 drops of tobramycin/dexamethasone suspension every 4 or 6 hours for 5 or 7 days. In this study, no differences in the safety profile were observed between adults and children.

Pharmacokinetics

Dexamethasone

Systemic exposure to dexamethasone after topical ophthalmic application of eye drops is low. Peak plasma concentrations range from 220 to 888 pg/mL (mean 555 ± 217 pg/mL) after instillation of one drop in each eye 4 times daily for two consecutive days.

Dexamethasone is approximately 77-84% bound to plasma albumin. The plasma half-life is relatively short, 3-4 hours. Clearance ranges from 0.111 to 0.225 l/h/kg and volume of distribution ranges from 0.576 to 1.15 l/kg.

Dexamethasone is eliminated from the body by metabolism. Approximately 60% of the dose is excreted in the urine as 6-β-hydroxydexamethasone. Unchanged dexamethasone was not detected in the urine.

Oral bioavailability is approximately 70%.

Tobramycin

Systemic exposure to tobramycin after topical ophthalmic application of eye drops is low. Its plasma concentration after two days of application was in most cases below the limit of quantification (≤ 0.25 μg/ml).

Plasma protein binding is negligible, less than 10%. The plasma elimination half-life is approximately 2 hours with a clearance of 0.04 l/h/kg and a volume of distribution of 0.26 l/kg.

Tobramycin is rapidly and extensively excreted into the urine by glomerular filtration, mainly unchanged.

The oral bioavailability of tobramycin is low (<1%).

Preclinical safety data.

Safety data

The systemic toxicity of the active substances is well established. Systemic exposure to tobramycin at toxic doses that are much higher than the dose for topical ocular administration may be associated with nephrotoxicity and ototoxicity. Systemic exposure to dexamethasone may be associated with effects related to glucocorticosteroid imbalance. Repeated dose toxicity studies of tobramycin/dexamethasone eye drops in rabbits have shown systemic corticosteroid-related effects, but even at doses that are significantly higher than the human dose, this manifestation is of little clinical relevance. When using the combination of tobramycin/dexamethasone at recommended doses, these effects are unlikely to occur.

Mutagenicity

In vitro and in vivo studies of each of the active substances did not reveal any mutagenic effects.

Teratogenicity

Tobramycin crosses the placenta into the fetal circulation and amniotic fluid. Animal studies with systemic administration of high doses of tobramycin to pregnant animals during organogenesis have shown renal toxicity and ototoxicity in the fetus. Other studies conducted in rats and rabbits with tobramycin at doses greater than 100 mg/kg/day parenterally (>400 times the maximum clinical dose) have revealed no evidence of impaired fertility or harm to the fetus.

Corticosteroids have been shown to be teratogenic in animal studies. Ocular administration of 0.1% dexamethasone to pregnant rabbits resulted in increased incidence of fetal malformations and intrauterine growth retardation. Fetal growth retardation and increased mortality were observed in rats treated with dexamethasone for prolonged periods.

The drug should be used during pregnancy only if the potential benefit of using the drug outweighs the potential risk to the fetus.

No studies have been conducted to evaluate the carcinogenic potential of tobramycin/dexamethasone eye drops.

Indication

Ocular inflammation in steroid-sensitive patients in whom corticosteroids are indicated and there is a superficial bacterial infection or risk of developing a bacterial infection of the eye. These inflammatory processes may occur after surgery or may be caused by infection, foreign body in the eye or ocular trauma.

Contraindication

Hypersensitivity to the active substances or to other components of the drug.

Hypersensitivity to aminoglycosides.

Keratitis caused by the herpes simplex virus.

Cowpox, chickenpox and other viral infections of the cornea and conjunctiva.

Fungal diseases or untreated parasitic infections of the eye.

Mycobacterial infection of the eye.

Untreated purulent eye infection.

Infections or injuries limited to the superficial corneal epithelium.

Use of the drug after the removal of a foreign body from the cornea without complications.

Interaction with other medicinal products and other types of interactions

The simultaneous and/or sequential use of aminoglycoside antibiotics (including tobramycin) and other systemic oral or topical drugs that have toxic (harmful) effects on the nervous system, hearing organs or kidneys may lead to additive toxicity and should be avoided if possible.

In patients receiving ritonavir, plasma concentrations of dexamethasone may increase (see section "Special warnings and precautions for use").

Dexamethasone is metabolized by the cytochrome P450 3A4 (CYP3A4) system. CYP3A4 inhibitors (including ritonavir and cobicistat) may decrease the clearance of dexamethasone, leading to increased effects and adrenal suppression/Cushing's syndrome. Such interactions should be avoided unless the benefit outweighs the increased risk of systemic corticosteroid-related side effects. In such cases, systemic corticosteroid effects should be monitored.

If more than one ophthalmic agent is applied topically, the interval between their applications should be at least 5 minutes. Eye ointments should be applied last.

Application features

During the use of the drug, some patients may develop hypersensitivity to topical aminoglycosides. The severity of hypersensitivity reactions can vary from local effects to generalized reactions such as erythema, pruritus, urticaria, skin rashes, anaphylaxis, anaphylactoid reactions or bullous reactions. In the event of a hypersensitivity reaction, the drug should be discontinued.

Cross-sensitivity to other aminoglycosides is also possible. It should be considered that patients with hypersensitivity to topical tobramycin may also be sensitive to other aminoglycosides administered topically or systemically.

Serious adverse reactions, including neurotoxicity, ototoxicity, and nephrotoxicity, have been reported in patients receiving systemic aminoglycoside therapy. Caution should be exercised when using the drug concomitantly with systemic aminoglycosides.

The drug should be used with caution in patients with known suspected neuromuscular disorders such as myasthenia gravis or Parkinson's disease. Aminoglycosides may exacerbate muscle weakness due to potential effects on neuromuscular function.

Cases of visual disturbances may occur with systemic or topical corticosteroids. If a patient experiences symptoms such as blurred vision or other visual disturbances, they should consult an ophthalmologist to determine possible causes, which may include cataracts, glaucoma, or rare conditions such as central serous chorioretinopathy (CSR), which has been reported with systemic or topical corticosteroids.

Prolonged treatment (more than 24 days) with topical ophthalmic corticosteroids (including dexamethasone) may lead to ocular hypertension and/or glaucoma with optic nerve damage, visual acuity and field of view deterioration, and the formation of subcapsular cataracts in the posterior chamber of the eye. In patients receiving prolonged ocular corticosteroid therapy, regular and repeated monitoring of intraocular pressure is necessary. This is especially important in children, since the risk of corticosteroid-induced intraocular pressure may be greater in children and may occur earlier than in adults. The risk of corticosteroid-induced intraocular pressure elevation and/or the risk of corticosteroid-induced cataract formation is increased in predisposed patients (e.g., diabetic patients).

Cushing's syndrome and/or adrenal suppression associated with systemic absorption of ophthalmic dexamethasone may occur after intensive or prolonged continuous therapy in susceptible patients, including children and patients taking CYP3A4 inhibitors (including ritonavir and cobicistat). In such cases, treatment should be discontinued gradually.

Long-term use may contribute to the development of secondary eye infections due to suppression of the body's response.

Corticosteroids (including dexamethasone) may reduce resistance to bacterial, viral, fungal or parasitic infections and may prevent the detection of such infections and mask the clinical signs of infection.

In case of persistent corneal ulceration, the possibility of fungal infection should be considered. In case of fungal infection, the drug should be discontinued.

Ophthalmic corticosteroids (including dexamethasone) may slow the healing of corneal wounds. Topical NSAIDs are also known to slow or delay wound healing. Concomitant use of topical NSAIDs and topical steroids may increase the risk of wound healing complications (see section 4.5).

In the presence of diseases that lead to thinning of the cornea or sclera, the use of topical steroids (including dexamethasone) may cause perforation.

It is not recommended to wear contact lenses while treating eye inflammation or infection.

The product contains benzalkonium chloride, which may cause eye irritation and is known to discolour soft contact lenses. Contact with soft contact lenses should be avoided. If the patient is permitted to wear contact lenses, they should be advised to remove contact lenses before using the eye drops and to wait at least 15 minutes before reinserting them.

After using eye drops, to reduce systemic absorption, keep the eyelid closed and close the tear duct with a finger for 2 minutes.

Use during pregnancy or breastfeeding

Pregnancy

There are no or limited data from the use of tobramycin or dexamethasone in pregnant women. After intravenous administration to pregnant women, tobramycin crosses the placenta and affects the fetus. Tobramycin does not cause ototoxicity in utero. Prolonged or repeated use of corticosteroids during pregnancy is associated with an increased risk of intrauterine growth retardation. Infants whose mothers received high doses of corticosteroids during pregnancy should be closely observed for signs of hypoadrenalism. Animal studies have shown reproductive toxicity after topical application of dexamethasone and systemic administration of dexamethasone and tobramycin. The drug is not recommended for use during pregnancy.

Breast-feeding

Tobramycin is excreted in breast milk after systemic administration. There are no data on the excretion of dexamethasone in breast milk. It is not known whether tobramycin and dexamethasone are excreted in breast milk after topical ophthalmic administration. It is unlikely that tobramycin and dexamethasone will be excreted in breast milk after topical administration or that they will cause clinical effects in the newborn. However, a risk to the breastfed child cannot be excluded.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Because many drugs are excreted in human milk, consideration should be given to temporarily discontinuing breastfeeding while using the drug.

Fertility

Studies to evaluate the effects of tobramycin and dexamethasone on human or animal reproductive function have not been conducted. Clinical data to evaluate the effects of dexamethasone on male or female reproductive function are limited. No adverse reproductive effects were observed when dexamethasone was administered to rats sensitized to chorionic gonadotropin.

Ability to influence reaction speed when driving vehicles or other mechanisms

The combination of dexamethasone/tobramycin has no or negligible influence on the ability to drive and use machines.

Temporary blurred vision or other visual disturbances may affect the ability to drive or use machines. If blurred vision occurs during instillation, the patient should wait until vision clears before driving or using machines.

Method of administration and doses

The drug is intended for ophthalmic use.

During use of the drug, it is recommended to constantly monitor intraocular pressure.

It is recommended to press on the nasolacrimal opening and gently close the eyelids after instillation. This reduces the systemic absorption of the drug administered into the eye, which reduces the likelihood of systemic adverse reactions.

Dosage

Adults, including elderly patients, and children aged 2 to 18 years

The drug should be applied 1 or 2 drops into the conjunctival sac(s) every 4-6 hours. During the first 24-48 hours, the dose can be increased to 1 or 2 drops every 2 hours. The frequency of application of the drug should be gradually reduced as clinical signs improve. Care should be taken not to discontinue therapy prematurely.

After cataract surgery, the dose is 1 drop 4 times a day, starting on the day of surgery and continuing for 24 days. Treatment can be started the day before surgery with 1 drop 4 times a day, continuing with 1 drop after surgery, and then 4 times a day for 23 days. If necessary, the frequency of use of the drug can be increased to 1 drop every 2 hours during the first two days of therapy.

Children

The data obtained confirm the safety and efficacy of dexamethasone/tobramycin eye drops in children aged 2 years and older who were treated with the drug for 7 days for the treatment of superficial bacterial eye inflammation.

It can be used in children who need cataract surgery.

Patients with impaired liver and kidney function

The combination of dexamethasone/tobramycin has not been studied in this patient population. However, due to the low systemic absorption of tobramycin and dexamethasone after topical administration, no dose adjustment is necessary.

Method of application

1. Wash your hands before using the product.

2. Shake the bottle well and unscrew the cap.

3. Hold the bottle vertically between your thumb and other fingers.

4. Tilt your head back.

5. Pull back the lower eyelid with a clean finger to form a pouch between the eyelid and the eye (the drop should fall right there).

6. Bring the edge of the bottle to your eye. You can use a mirror.

7. Do not touch the dropper to your eye or eyelids, surrounding areas, or other surfaces. This may contaminate the drops.

8. Gently press the bottle to release 1 drop at a time.

9. Do not squeeze the bottle, just press lightly on its bottom.

10. After applying the drops, release the lower eyelid, close the eye and gently press your finger on the inner corner of the eye near the nose for 2 minutes.

11. This will prevent the drug from affecting other parts of the body.

12. If necessary, repeat the same procedure for the other eye. Immediately after use, tightly screw the cap on the bottle.

13. If the drop does not get into the eye, the procedure should be repeated.

14. If you forget to use the medicine, you should use the single dose as soon as you remember. However, if it is almost time for your next dose, skip the missed dose and go back to your regular schedule. Do not take a double dose.

15. If a larger dose of the drug than required is instilled, the eye should be rinsed with warm water.

Children

Safety and efficacy in children under 2 years of age have not been established, no data are available. The drug can be used in children over 2 years of age.

Overdose

Given the characteristics of this drug, intended for topical use, no toxic effect is expected either when used in ophthalmology at the recommended doses or in the event of accidental ingestion of the contents of the bottle. Possible clinical signs and symptoms of drug overdose (punctate keratitis, erythema, increased lacrimation, eyelid edema and itching) may be similar to the side effects observed in some patients. In case of overdose with the drug for topical use, wash the excess drug from the eye(s) with warm water.

Side effects

During clinical trials with the tobramycin/dexamethasone combination, the most common adverse reactions were eye pain, increased intraocular pressure, eye irritation, and eye itching, which occurred in less than 1% of patients.

The following adverse reactions have been reported in clinical trials and during post-marketing experience and are classified according to the following frequency: very common (≥ 1/10); common (≥ 1/100 - < 1/10); uncommon (≥ 1/1000 - < 1/100); rare (≥ 10,000 - < 1/1000); very rare (< 1/10,000); not known (frequency cannot be estimated from the available data). Within each grouping, adverse reactions are presented in order of decreasing seriousness.

On the part of the immune system:

unknown - hypersensitivity reactions, anaphylactic reactions.

From the endocrine system:

unknown - Cushing's syndrome, adrenal suppression (see section "Special warnings and precautions for use").

From the nervous system:

uncommon – headache; unknown – dizziness.

On the part of the organs of vision:

infrequently - eye pain, eye itching, eye discomfort, ocular hypertension, conjunctival edema, increased intraocular pressure, eye irritation; rarely - keratitis, eye allergy, blurred vision (see section "Special instructions"), dry eyes, eye hyperemia; unknown - eyelid edema, eyelid erythema, eyelid itching, mydriasis, increased lacrimation, ulcerative keratitis.

From the respiratory system, chest organs and mediastinum:

infrequently - rhinorrhea, laryngospasm.

From the digestive tract:

Rare: dysgeusia; unknown: nausea, vomiting, stomach discomfort.

Skin and subcutaneous tissue disorders:

unknown - erythema multiforme, rash, facial edema, itching.

Adverse reactions observed with the use of individual components

Dexamethasone

From the nervous system:

often - headache.

On the part of the organs of vision:

common - eye irritation, eye hyperemia, eyelid edema, abnormal eye sensitivity; unknown - keratoconjunctivitis, corneal discoloration, photophobia, eyelid margin scaling, decreased visual acuity, corneal erosion, ptosis.

often – nasopharyngeal drip.

Tobramycin

On the part of the organs of vision:

often - eye hyperemia, eye pain; infrequently - eye itching, feeling of discomfort in the eyes, eye allergy, eyelid swelling, conjunctivitis, increased sensitivity to bright light, increased lacrimation, keratitis; unknown - corneal abrasion, visual impairment, conjunctival swelling, eyelid disorders, eye discharge, eyelid itching, urticaria, dermatitis, madarosis, leukoderma, dry skin.

Description of some adverse reactions

Prolonged use of topical corticosteroids in the eye may lead to increased intraocular pressure with subsequent damage to the optic nerve, deterioration of visual acuity and visual field disturbances, as well as the formation of posterior subcapsular cataracts and delayed wound healing (see section "Special instructions").

Since the drug contains a corticosteroid, in the presence of diseases that lead to thinning of the cornea or sclera, the risk of perforation increases, especially after long-term use (see section "Special instructions for use").

Secondary infections may develop after the use of combinations containing corticosteroids and antimicrobials. Fungal infections of the cornea are particularly active with prolonged use of steroids (see section "Special instructions").

Patients receiving systemic therapy with tobramycin have experienced serious adverse reactions, including neurotoxicity, ototoxicity, and nephrotoxicity (see section 4.4).

Some patients may experience a hypersensitivity reaction to aminoglycosides when used topically (see section "Special warnings and precautions for use").

Reporting of suspected adverse reactions

Reporting suspected adverse reactions that occur after the marketing authorisation of a medicinal product is of utmost importance. This allows for continuous monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system.

Expiration date

3 years.

After opening the bottle, the drug can be used for 4 weeks.

Storage conditions

Store at a temperature not exceeding 25 °C out of the reach of children.

Packaging

5 ml of the drug in plastic dropper bottles, 1 dropper bottle in a cardboard box.

Vacation category

According to the recipe.

Producer

K.O. Rompharm Company SRL/SC Rompharm Company SRL

Location of the manufacturer and address of its place of business

Otopeni city, Eroilor str. №1A, 075100, jud. Ilfov, Romania.

Applicant

WORLD MEDICINE LLC, Ukraine/WORLD MEDICINE LLC, Ukraine.