Medetrom

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

Composition:

Active substances: tobramycin, dexamethasone;

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

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

Pharmaceutical form. Eye drops, suspension.

Main physicochemical characteristics: white or almost white suspension; sediment may be present, which disappears upon gentle shaking.

Pharmacotherapeutic group.

Anti-inflammatory and antimicrobial agents in combination. Corticosteroids and antimicrobial agents in combination. ATC code S01CA01.

Pharmacological properties.

Pharmacodynamics.

Dexamethasone

Dexamethasone belongs to the group of glucocorticosteroid agents. The efficacy of corticosteroids in the treatment of inflammatory conditions of the eye is well established. Corticosteroids exert their anti-inflammatory effects by inhibiting adhesion molecules to vascular endothelial cells, cyclooxygenase I or II, and cytokine release. As a result, the production of inflammatory mediators is reduced and the adhesion of circulating leukocytes to vascular endothelium is suppressed, thereby preventing their infiltration into inflamed ocular tissues. Dexamethasone exerts a pronounced anti-inflammatory effect with reduced mineralocorticoid activity compared to some other steroids and is one of the most potent anti-inflammatory agents available.

Tobramycin

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

In general, tobramycin activity has been described in vitro by determining the minimum inhibitory concentration (MIC), which defines the antibiotic's activity against each bacterial species. Since the MIC of tobramycin is very low against most ocular pathogenic organisms, it is considered a broad-spectrum antibiotic. Critical MIC values have been established to define bacterial culture susceptibility or resistance to a specific antibiotic. The current critical MIC values for tobramycin against relevant bacterial species take into account the inherent susceptibility of species, as well as the maximum concentration and time/concentration-dependent pharmacokinetic parameters measured in plasma after oral administration. These critical values, which classify microorganisms as susceptible or resistant, have been used to determine the clinical efficacy of systemically administered antibiotics. However, when antibiotics are applied topically in high concentrations directly at the site of infection, such critical values are not applicable. Most microorganisms that might be classified as resistant based on systemic critical values actually respond well to topical treatment. For prophylactic purposes, there is a possibility to prevent the development of such infection-causing microorganisms.

In clinical studies, topically administered tobramycin solution demonstrated efficacy against many existing strains of ocular pathogens isolated from patients enrolled in the trials. Some of these ocular pathogens are considered resistant based on critical value determinations for systemic administration. However, clinical studies have shown that tobramycin is effective in the treatment of superficial ocular infections caused by the following pathogenic microorganisms.

*The beta-lactam resistance phenotype (i.e., methicillin; penicillin) is not associated with the aminoglycoside resistance phenotype, and neither is associated with the virulence and pathogenic phenotypes of organisms. It has been found that many methicillin-resistant staphylococci are resistant to tobramycin (and other aminoglycoside antibiotics). However, these resistant staphylococcal strains (as defined by MIC critical values) usually respond successfully to treatment with topically applied tobramycin.

Bacterial susceptibility testing has demonstrated that in some cases, microorganisms resistant to gentamicin remain sensitive to tobramycin. A significant portion of the microflora has not yet developed resistance to tobramycin; however, bacterial resistance may develop during prolonged use.

Cross-sensitivity to other aminoglycoside antibiotics may occur. If hypersensitivity reactions occur during treatment, the drug should be discontinued and appropriate therapy initiated.

Children

The safety and efficacy of the tobramycin/dexamethasone combination in children have been established through extensive clinical experience, although 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 between adults and children were observed.

Pharmacokinetics

Dexamethasone

Systemic exposure to dexamethasone following topical ophthalmic administration 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 four times daily for two consecutive days.

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

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

Oral bioavailability is approximately 70%.

Tobramycin

Systemic exposure to tobramycin following topical ophthalmic administration of eye drops is low. Plasma concentrations after two days of dosing were mostly below the quantitation limit (≤ 0.25 µg/mL).

Plasma protein binding is minimal—less than 10%. The plasma half-life is approximately 2 hours, with a clearance of 0.04 L/hr/kg and a volume of distribution of 0.26 L/kg.

Tobramycin is rapidly and actively excreted in urine by glomerular filtration, primarily in unchanged form.

Oral bioavailability of tobramycin is low (<1%).

Preclinical safety data

Safety data

Data on systemic toxicity of the active substances are well established. Systemic exposure to tobramycin at toxic doses, which greatly exceed the dose used for topical ocular application, may be associated with nephrotoxicity and ototoxicity. Systemic exposure to dexamethasone may be associated with effects related to glucocorticoid imbalance. Repeated-dose toxicity studies of tobramycin/dexamethasone eye drops in rabbits revealed systemic effects related to corticosteroids; however, even at doses significantly exceeding the human dose, this manifestation has minimal clinical relevance. The occurrence of these effects is unlikely when tobramycin/dexamethasone combination is used at recommended doses.

Mutagenicity

In vitro and in vivo studies of each active substance did not reveal mutagenic effects.

Teratogenicity

Tobramycin crosses the placenta into fetal circulation and amniotic fluid. Animal studies involving systemic administration of high doses of tobramycin to pregnant animals during organogenesis revealed fetal kidney toxicity and ototoxicity. Other studies conducted in rats and rabbits using tobramycin doses exceeding 100 mg/kg/day via parenteral administration (>400 times the maximum clinical dose) did not reveal any impairment of fertility or adverse effects on the fetus.

It has been established that corticosteroids have teratogenic effects in animal studies. Ocular administration of 0.1% dexamethasone to pregnant rabbits resulted in increased incidence of fetal developmental abnormalities and intrauterine growth retardation. Fetal growth retardation and increased fetal mortality were observed in rats during prolonged dexamethasone therapy.

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

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

Clinical characteristics.

Indications.

Inflammation of the eye in patients sensitive to steroids, in whom corticosteroid therapy is indicated and where there is a superficial bacterial infection or a risk of developing a bacterial eye infection. These inflammatory conditions may occur following surgical procedures or may be caused by infection, foreign body penetration into the eye, or ocular trauma.

Contraindications.

• Hypersensitivity to the active substances or to any of the excipients of the medicinal product.

• Hypersensitivity to aminoglycosides.

• Herpes simplex virus-induced keratitis.

• Vaccinia, varicella (chickenpox), and other viral infections of the cornea and conjunctiva.

• Fungal infections of the eye or untreated parasitic infections of the eye.

• Mycobacterial infection of the eye.

• Untreated purulent ocular infection.

• Infections or injuries limited to the corneal surface epithelium.

• Use of the medicinal product after uncomplicated removal of a foreign body from the cornea.

Interaction with other medicinal products and other forms of interaction.

Concomitant use of topically applied corticosteroids and nonsteroidal anti-inflammatory drugs (NSAIDs) for topical use may increase the risk of corneal wound healing complications.

Concomitant and/or sequential use of aminoglycoside antibiotics (including tobramycin) and other systemic, oral, or topically applied medicinal products with neurotoxic, ototoxic, or nephrotoxic effects may result in additive toxicity; therefore, such use should be avoided if possible.

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

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

If more than one ophthalmic product is being used, the interval between applications should be at least 5 minutes. Ophthalmic ointments should be administered last.

Special precautions for use.

During the use of the drug, some patients may develop increased sensitivity to topically applied aminoglycosides. The severity of hypersensitivity reactions may vary from local effects to generalized reactions such as erythema, pruritus, urticaria, skin rashes, anaphylaxis, anaphylactoid reactions, or bullous reactions. If a hypersensitivity reaction occurs, the drug should be discontinued.

Cross-sensitivity to other aminoglycosides may also occur. It should be considered that patients with hypersensitivity to topical tobramycin may also be sensitive to other aminoglycosides administered either 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 or suspected neuromuscular disorders such as myasthenia gravis or Parkinson's disease. Aminoglycosides may exacerbate muscle weakness due to their potential effect on neuromuscular function.

Visual disorders may occur during treatment with systemic or topical corticosteroid preparations. If a patient experiences symptoms such as blurred vision or other visual disturbances, they should consult an ophthalmologist to determine possible causes, including cataract, glaucoma, or rare conditions such as central serous chorioretinopathy (CSC), which has been reported following the use of systemic or topical corticosteroids.

Prolonged treatment (longer than 24 days) with topical ophthalmic corticosteroids (including dexamethasone) may lead to ocular hypertension and/or glaucoma with optic nerve damage, decreased visual acuity and visual field, and posterior subcapsular cataract formation. Patients receiving prolonged ocular corticosteroid therapy require regular and repeated monitoring of intraocular pressure. This is particularly important in children, as the risk of corticosteroid-induced elevated intraocular pressure may be higher in children and may occur earlier than in adults. The risk of corticosteroid-induced elevated intraocular pressure and/or corticosteroid-induced cataract formation increases in predisposed patients (e.g., patients with diabetes mellitus).

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 tapered gradually.

Prolonged use may promote the development of secondary ocular infections due to suppression of the body's immune response.

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

In cases of persistent corneal ulceration, fungal infection should be considered. If a fungal infection occurs, the drug should be discontinued.

Prolonged use of antibiotics (including tobramycin) may lead to overgrowth of resistant microorganisms, including fungi. If superinfection occurs, appropriate therapy should be initiated.

Ophthalmic corticosteroids (including dexamethasone) may delay healing of corneal wounds. Topically applied NSAIDs are also known to slow or delay 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").

In patients with conditions leading to thinning of the cornea or sclera, use of topical steroids (including dexamethasone) may result in perforation.

Wearing contact lenses is not recommended during treatment of ocular inflammation or infection.

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

After instillation of eye drops, to minimize systemic absorption, the eyelid should be kept closed and the nasolacrimal duct pressed with a finger for 2 minutes.

Use during pregnancy or breastfeeding.

Pregnancy

Data on the use of tobramycin or dexamethasone in pregnant women are lacking or limited. Tobramycin administered intravenously to pregnant women crosses the placenta and affects the fetus. Ototoxicity of tobramycin in utero has not been observed. Prolonged or repeated use of corticosteroids during pregnancy is associated with an increased risk of intrauterine growth retardation. Infants born to mothers who received high doses of corticosteroids during pregnancy should be closely monitored for signs of adrenal insufficiency. Animal studies have demonstrated reproductive toxicity following topical dexamethasone and systemic dexamethasone and tobramycin. The drug is not recommended for use during pregnancy.

Breastfeeding

Tobramycin administered systemically passes into breast milk. Data on the passage of dexamethasone into breast milk are lacking. It is unknown whether tobramycin and dexamethasone pass into breast milk following topical ophthalmic administration. It is unlikely that tobramycin and dexamethasone will be present in breast milk or cause clinical effects in newborns after topical use. However, a risk to the breastfed infant cannot be excluded.

A decision should be made whether to discontinue breastfeeding or to discontinue/abstain from treatment, taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

Since many medicinal products pass into breast milk, temporary discontinuation of breastfeeding during treatment with the drug should be considered.

Fertility

Studies specifically designed to evaluate the effects of tobramycin and dexamethasone on human or animal fertility have not been conducted. Clinical data on the effects of dexamethasone on male or female reproductive function are limited. In rats sensitized to chorionic gonadotropin, no adverse effects on the reproductive system were observed following dexamethasone administration.

Ability to influence reaction speed when driving or operating machinery.

The combination of dexamethasone/tobramycin has no or negligible influence on the ability to drive or operate machinery.

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.

Dosage and Administration

The product is intended for ophthalmic use.

Intraocular pressure should be monitored regularly during treatment with this product.

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

Dosage

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

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

In severe conditions, administer 1 or 2 drops every hour until inflammation is under control, then gradually reduce the frequency to 1 or 2 drops every 2 hours for 3 days; thereafter, instill 1 to 2 drops every 4 hours for 5 to 8 days, and finally 1 to 2 drops once daily for the last 5 to 8 days, if necessary.

After cataract surgery, the dose is 1 drop 4 times daily, starting on the day of surgery and continuing for 24 days. Treatment may begin one day before surgery with 1 drop 4 times daily, continuing after surgery with 1 drop 4 times daily for 23 days. If necessary, the frequency of administration may be increased to 1 drop every 2 hours during the first two days of treatment.

Children

Data support the safety and efficacy of dexamethasone/tobramycin ophthalmic solution in children aged 2 years and older, who were treated for 7 days for bacterial superficial ocular inflammation.

Use in children undergoing cataract surgery may be considered.

Patients with hepatic or renal impairment

The combination of dexamethasone/tobramycin has not been studied in these patient populations. However, due to the low systemic absorption of both tobramycin and dexamethasone following topical ophthalmic administration, dose adjustment is not required.

Administration Instructions

1. Wash your hands before using the medication.
2. Shake the bottle well and unscrew the cap.
3. Hold the bottle vertically between the index and middle fingers.
4. Tilt your head backward.
5. Pull down the lower eyelid with a clean finger to form a small pocket between the eyelid and the eye (the drop should go into this pocket).
6. Bring the dropper tip close to the eye. A mirror may be used.
7. Do not touch the dropper tip to the eye, eyelids, surrounding areas, or any other surface. This may contaminate the drops.
8. Gently press the bottle to release one drop at a time.
9. Do not squeeze the bottle; only apply slight pressure to the bottom.
10. After instillation, release the lower eyelid, close the eye, and gently press with a finger on the inner corner of the eye near the nose for 2 minutes.
11. This helps prevent the medication from affecting other parts of the body.
12. If needed, repeat the same procedure for the other eye. Immediately after administration, tightly replace the cap on the bottle.
13. If the drop did not enter the eye, repeat the procedure.
14. If you forget to instill the medication, instill the missed dose as soon as you remember. However, if it is almost time for the next dose, skip the missed dose and return to your regular schedule. Do not use a double dose.
15. If too much medication has been instilled, rinse the eye with warm water.

Children

Safety and efficacy in children under 2 years of age have not been established; available data are lacking. The product can be used in children aged 2 years and older.

Overdose

Given the characteristics of this product intended for topical use, no toxic effects are expected following ophthalmic administration at recommended doses or even after accidental ingestion of the bottle contents. Possible clinical signs and symptoms of overdose (punctate keratitis, erythema, increased lacrimation, eyelid edema, and itching) may resemble the adverse effects observed in some patients. In case of overdose during topical administration, wash out the excess medication from the eye(s) with warm water.

Side effects

During clinical trials of the tobramycin/dexamethasone combination, the most commonly reported adverse reactions were eye pain, increased intraocular pressure, eye irritation, and eye pruritus, occurring in less than 1% of patients.

The following adverse reactions have been reported during clinical trials and in the post-marketing period, categorized by frequency 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); not known (frequency cannot be estimated from the available data). Within each frequency category, adverse reactions are listed in decreasing order of severity.

Immune system disorders:

Not known – hypersensitivity reactions, anaphylactic reactions.

Endocrine disorders:

Not known – Cushing's syndrome, adrenal suppression (see section "Special precautions for use").

Nervous system disorders:

Uncommon – headache; not known – dizziness.

Eye disorders:

Uncommon – eye pain, eye pruritus, eye discomfort, ocular hypertension, conjunctival edema, increased intraocular pressure, eye irritation; rare – keratitis, eye allergy, blurred vision (see section "Special precautions for use"), dry eyes, eye hyperemia; not known – eyelid edema, eyelid erythema, eyelid pruritus, mydriasis, increased lacrimation, ulcerative keratitis.

Respiratory, thoracic and mediastinal disorders:

Uncommon – rhinorrhea, laryngospasm.

Gastrointestinal disorders:

Rare – dysgeusia; not known – nausea, vomiting, stomach discomfort.

Skin and subcutaneous tissue disorders:

Not known – erythema multiforme, rash, facial swelling, pruritus.

Adverse reactions observed with individual components

Dexamethasone

Nervous system disorders:

Common – headache.

Eye disorders:

Common – eye irritation, eye hyperemia, eyelid edema, abnormal eye sensitivity; not known – keratoconjunctivitis, corneal pigmentation, photophobia, scaling of eyelid margins, decreased visual acuity, corneal erosion, ptosis.

Respiratory, thoracic and mediastinal disorders:

Common – nasopharyngeal discharge.

Tobramycin

Eye disorders:

Common – eye hyperemia, eye pain; uncommon – eye pruritus, eye discomfort, eye allergy, eyelid edema, conjunctivitis, photophobia, increased lacrimation, keratitis; not known – corneal abrasion, visual disturbance, conjunctival edema, eyelid disorders, eye discharge, eyelid pruritus, urticaria, dermatitis, madarosis, leukoderma, dry skin.

Description of selected adverse reactions

Prolonged topical ocular use of corticosteroids may lead to increased intraocular pressure, resulting in optic nerve damage, decreased visual acuity, and visual field defects, as well as posterior subcapsular cataract formation and delayed wound healing (see section "Special precautions for use").

Since the product contains a corticosteroid, there is an increased risk of corneal or scleral perforation in patients with diseases that cause thinning of the cornea or sclera, particularly after prolonged use (see section "Special precautions for use").

Secondary infections may develop following the use of corticosteroid-antimicrobial combinations. Fungal corneal infections are particularly prone to develop during prolonged steroid use (see section "Special precautions for use").

Serious adverse reactions, including neurotoxicity, ototoxicity, and nephrotoxicity, have been observed in patients receiving systemic tobramycin therapy (see section "Special precautions for use").

Hypersensitivity reactions to aminoglycosides may occur with topical application in some patients (see section "Special precautions for use").

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is extremely important. It allows continuous monitoring of the benefit-risk balance of the medicine. Healthcare professionals are encouraged to report any suspected adverse reactions via the national reporting system.

Shelf life.

3 years.

After opening the bottle, the product can be used for up to 4 weeks.

Storage conditions.

Store at temperatures not exceeding 25 °C, in a place inaccessible to children.

Packaging.

5 mL of solution in plastic dropper bottles, 1 dropper bottle per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

C.O. Rompharm Company S.R.L. /
S.C. Rompharm Company S.R.L.

Manufacturer's address.

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

Marketing Authorization Holder.

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