Tobrex®-dex

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT TOBROSOPT®-DEX (TOBROSOPT-DEX)

Composition:

Active substances: tobramycin, dexamethasone;

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

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

Pharmaceutical form. Eye drops, suspension.

Main physicochemical characteristics: white-colored suspension.

Pharmacotherapeutic group.

Anti-inflammatory and antimicrobial combinations. Corticosteroids and antimicrobial agents in combination.

ATC Code S01CA01.

Pharmacological Properties

Pharmacodynamics

Tobrosopht®-DEX is a combination of a corticosteroid and an antimicrobial agent. Corticosteroids (in this case, dexamethasone) help prevent or reduce ocular inflammation. Antimicrobial agents (in this case, tobramycin) are active against a broad spectrum of microorganisms that can infect the eye(s).

Dexamethasone

The efficacy of corticosteroids in treating inflammatory ocular conditions is well established. The anti-inflammatory action of corticosteroids is based on the inhibition of endothelial adhesion protein expression, cyclooxygenase I and II, and cytokines. This reduces the release of inflammatory mediators and suppresses leukocyte adhesion to the endothelium, thereby preventing leukocyte attack on inflamed ocular tissues. Dexamethasone exerts pronounced anti-inflammatory effects with limited mineralocorticoid activity compared to other steroids.

Tobramycin

Tobramycin is a highly active, rapidly acting bactericidal antibiotic of the aminoglycoside group, exerting strong and rapid bactericidal activity against both gram-positive and gram-negative bacteria. It primarily acts within the bacterial cell by inhibiting polypeptide formation and ribosomal synthesis.

Tobramycin's in vitro activity is primarily determined by the minimal inhibitory concentration (MIC), a measure of the antibiotic's potency against specific bacterial species.

Given the low MIC of tobramycin against most ocular pathogens, it is considered a broad-spectrum antibiotic. MIC thresholds have been established to classify bacterial strains as susceptible or resistant to the antibiotic. The MIC breakpoints for tobramycin take into account the intrinsic susceptibility of the species and pharmacokinetic parameters, including maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC), determined in plasma after oral administration. These breakpoints, used to classify microorganisms as susceptible or resistant, are intended to predict clinical efficacy for systemically administered antibiotics and cannot be directly applied when the antibiotic is administered topically at high concentrations. Most strains classified as resistant according to systemic breakpoints still respond to topical treatment, or such topical use provides effective antibiotic prophylaxis against infection by these strains.

Clinical studies have demonstrated that topically applied tobramycin solution is effective against many existing strains of ocular pathogens in study participants. Some of these ocular pathogens are considered resistant based on systemic breakpoint determinations. Clinical studies have confirmed that tobramycin is effective in treating superficial ocular infections caused by the following microorganisms:

Gram-positive bacteria:

Staphylococcus aureus (methicillin-sensitive or resistant*).

Staphylococcus epidermidis (methicillin-sensitive or resistant*).

Other coagulase-negative Staphylococcus species.

Streptococcus pneumoniae (penicillin-sensitive or resistant*).

Other Streptococcus species.

* The beta-lactam resistance phenotype (i.e., methicillin, penicillin) is unrelated to the aminoglycoside resistance phenotype, and neither is linked to virulence or pathogenic phenotypes. Many methicillin-resistant staphylococci have been found to be resistant to tobramycin (and other aminoglycoside antibiotics). However, these resistant staphylococcal cultures (as defined by MIC breakpoints) usually respond successfully to treatment with topically applied tobramycin.

Gram-negative bacteria:

Acinetobacter spp.

Citrobacter spp.

Enterobacter spp.

Escherichia coli

Haemophilus influenzae

Klebsiella pneumoniae

Moraxella spp.

Morganella morganii

Proteus mirabilis

Pseudomonas aeruginosa

Serratia marcescens

Susceptibility testing has shown that in some cases, microorganisms resistant to gentamicin remain susceptible to tobramycin. Resistance to tobramycin has not yet developed in a significant portion of the microflora; however, bacterial resistance may develop during prolonged use.

Cross-sensitivity with other aminoglycoside antibiotics is possible. If hypersensitivity occurs 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 the 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

After topical administration, systemic exposure is low. Cmax following instillation of one drop into the conjunctival sac of both eyes four times daily for 2 days ranges from 220 to 888 pg/mL (mean 555 ± 217 pg/mL).

Dexamethasone undergoes biotransformation via metabolic processes. Approximately 60% of the dose is excreted in urine as 6-β-hydroxydexamethasone. Unchanged dexamethasone is not detectable in urine. The plasma half-life of dexamethasone is relatively short, ranging from 3 to 4 hours. Approximately 77–84% of dexamethasone is bound to plasma albumin. Dexamethasone clearance ranges from 0.111 to 0.225 L/h/kg body weight, and the volume of distribution is 0.576–1.15 L/kg body weight. The oral bioavailability of dexamethasone is 70%.

Tobramycin

After topical administration of eye drops containing tobramycin and dexamethasone, systemic exposure to tobramycin is low. Plasma tobramycin concentrations after 2 days of topical administration four times daily in patients were low or below the quantifiable limit (≤ 25 µg/mL), which is 8 times lower than the 2 µg/mL concentration known to be below the nephrotoxicity risk threshold.

Tobramycin is rapidly eliminated by the kidneys via glomerular filtration, primarily in unchanged form. The plasma half-life is approximately 2 hours, clearance is 0.04 L/h/kg body weight, and the volume of distribution is 0.26 L/kg body weight. Tobramycin binds poorly to plasma proteins (< 10%). The oral bioavailability of tobramycin is low (< 1%).

Preclinical Safety Data

Safety Data

Systemic toxicity data for the active substances are well established. Systemic effects of tobramycin at toxic doses, significantly exceeding the dose used for topical ocular administration, may be associated with nephrotoxicity and ototoxicity. Systemic effects of dexamethasone may be related to glucocorticosteroid imbalance. Repeated-dose toxicity studies of Tobrosopht®-DEX eye drops in rabbits revealed systemic effects related to corticosteroids; however, even at doses substantially exceeding the human dose, the clinical relevance of these effects is minimal. The occurrence of such effects with Tobrosopht®-DEX at recommended doses is unlikely.

Mutagenicity

In vitro and in vivo studies of each active ingredient 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 nephrotoxicity 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. Administration of 0.1% dexamethasone to pregnant rabbits via ocular instillation resulted in increased incidences of fetal developmental abnormalities and intrauterine growth retardation. Fetal growth retardation and increased mortality were observed in rats following prolonged therapy. Tobrosopht®-DEX 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 Tobrosopht®-DEX.

Clinical characteristics.

Indications.

Inflammation of the eye in patients who are steroid-responsive, in whom corticosteroid therapy is indicated and in whom there is a superficial bacterial infection or risk of developing a bacterial eye infection. These inflammatory conditions may occur following surgical intervention or may be caused by infection, foreign body penetration into the eye, or ocular trauma.

Contraindications.

• Hypersensitivity to the active substances or to any component of the medicinal product.
• Hypersensitivity to aminoglycosides.
• Herpes simplex virus-induced keratitis.
• Vaccinia, varicella, and other viral infections of the cornea and conjunctiva.
• Fungal diseases of ocular structures or untreated parasitic eye infections.
• Mycobacterial eye infections caused by acid-fast bacteria such as Mycobacterium tuberculosis, Mycobacterium leprae, Mycobacterium avium, and others.
• Untreated purulent eye infections.
• Infections or injuries limited to the corneal surface epithelium.
• Tobrasopt®-DEX should not be used after uneventful removal of a corneal foreign body.

Interaction with other medicinal products and other forms of interaction.

Concomitant use of locally applied corticosteroids and nonsteroidal anti-inflammatory drugs (NSAIDs) for local application increases the risk of corneal wound healing complications.

Concomitant and/or sequential use of aminoglycoside antibiotics (such as tobramycin) and other systemic oral or locally 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").

If more than one ophthalmic agent is applied locally, the interval between administrations should be at least 5 minutes. Ophthalmic ointments should be applied last.

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 combinations should be avoided, except when the benefit outweighs the risk of increased systemic side effects of corticosteroids; in such cases, careful monitoring of systemic corticosteroid effects is required.

Special precautions for use.

For ophthalmic use only.

In some patients, hypersensitivity to topically applied aminoglycosides may occur. The severity of hypersensitivity reactions may vary from local manifestations to generalized reactions such as erythema, itching, 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 occur. Patients who are hypersensitive 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 this product concomitantly with systemic aminoglycosides.

Prolonged treatment with locally applied ophthalmic corticosteroids 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 long-term ophthalmic corticosteroid therapy should have intraocular pressure monitored regularly and repeatedly. This is particularly important for children aged 6 years and older, as they have a higher risk of corticosteroid-induced elevated intraocular pressure compared to adults.

The risk of corticosteroid-induced elevated intraocular pressure and/or corticosteroid-induced cataract formation is increased in predisposed patients (e.g., patients with diabetes mellitus).

Visual disturbances may occur following systemic or local administration of corticosteroids. If blurred vision or other visual disturbances occur, patients should consult an ophthalmologist to determine possible causes, which may include cataract, glaucoma, or other rare conditions such as central serous chorioretinopathy, which has been reported after systemic corticosteroid administration.

Due to the potential for systemic absorption of dexamethasone, Cushing's syndrome and/or adrenal suppression may occur, particularly after prolonged continuous use of dexamethasone eye drops in susceptible patients, including children and patients taking CYP3A4 inhibitors (including ritonavir and cobicistat). In such cases, treatment should be tapered gradually.

Corticosteroids may reduce resistance to bacterial, fungal, or viral infections and may mask clinical signs of infection, thereby interfering with their detection.

In cases of persistent corneal ulceration, fungal infection should be considered. If fungal infection occurs, corticosteroid therapy should be discontinued.

Prolonged use of antibiotics such as tobramycin may lead to overgrowth of non-susceptible microorganisms, including fungi. If superinfection occurs, appropriate therapy should be initiated.

Ophthalmic corticosteroids may delay healing of corneal wounds. It is also known that topically applied NSAIDs may slow or delay wound healing. Concomitant use of topical NSAIDs and topical corticosteroids increases the risk of wound healing complications (see section "Interaction with other medicinal products and other forms of interaction").

In patients with diseases causing thinning of the cornea or sclera, topical steroid use may lead to perforation.

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

Tobrosopht®-DEX, eye drops, 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 administering Tobrosopht®-DEX eye drops and to wait at least 15 minutes before reinserting them.

To minimize systemic absorption after instillation of eye drops:

• Keep the eyelid closed for 2 minutes;
• Press a finger against the tear duct for 2 minutes.

The medicinal product may be used in children aged 2 years and older.

Use during pregnancy or breastfeeding.

Reproductive function

Studies evaluating the effect on fertility in humans following topical use of Tobrosopht®-DEX eye drops have not been conducted. Clinical data on the effect 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 with dexamethasone administration.

Pregnancy

Data on the use of tobramycin or dexamethasone in pregnant women are lacking or limited in quantity. After intravenous administration in pregnant women, tobramycin crosses the placenta and affects the fetus. In utero, tobramycin does not cause ototoxicity. 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 carefully monitored for signs of hypoadrenalism. Animal studies have demonstrated reproductive toxicity following systemic administration of corticosteroids and tobramycin.

The use of Tobrosopht®-DEX is not recommended during pregnancy.

Breastfeeding period

After systemic administration, tobramycin is excreted in breast milk. Data on the excretion 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 administration. However, a risk to the breastfed infant cannot be excluded.

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

Since many medicinal products are excreted in breast milk, the possibility of temporarily discontinuing breastfeeding during treatment with Tobrosopht®-DEX should be considered.

Ability to influence reaction rate while driving or operating machinery.

Tobrosopht®-DEX, eye drops, 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, patients should wait until vision clears before driving or operating machinery.

Administration and Dosage.

For topical use in ophthalmology.

Use in children aged 12 to 18 years, adults, and elderly patients.

1–2 drops into the conjunctival sac of the affected eye(s) every 4–6 hours. During the first 24–48 hours, the dose may be increased to 1–2 drops every 2 hours. The frequency of administration should be gradually reduced as symptoms resolve. Care should be taken not to discontinue treatment prematurely.

In severe cases, administer 1–2 drops into the conjunctival sac of the affected eye(s) every hour until improvement occurs. Then gradually reduce the frequency to 1–2 drops every 2 hours for 3 days, followed by 1–2 drops every 4 hours for 5–8 days, and finally 1–2 drops once daily for 5–8 days, if deemed necessary by the physician.

Following cataract surgery, administer 1 drop 4 times daily starting on the first day after surgery and continuing for 24 days. The medicinal product may be used 1 day before surgery, 1 drop 4 times daily, then 1 drop after surgery, followed by 1 drop 4 times daily for 23 days. If necessary, the drug may be administered more frequently: 1 drop every 2 hours during the first 2 days of treatment.

Intraocular pressure should be monitored.

After instillation, it is recommended to gently close the eyelid and apply light pressure to the inner corner of the eye. This may reduce systemic absorption of the locally administered drug and help minimize systemic adverse effects.

When using other topical ophthalmic medications concurrently, an interval of at least 5 minutes between administrations should be maintained.

Use in children

Available data confirm the safety and efficacy of the drug in children aged 2 years and older, who were treated for 7 days for superficial bacterial eye infections (see section "Pharmacodynamics").

The drug may be used in children requiring cataract surgery.

Use in patients with renal or hepatic impairment

The effect of the medicinal product containing tobramycin and dexamethasone has not been studied in these patient populations. Given the low degree of systemic absorption of these substances after topical administration, dosage adjustment is considered unnecessary.

Administration method

The bottle should be shaken well before use.

To prevent contamination of the dropper tip and the suspension in the bottle, contact between the tip and skin, eyelids, ocular mucous membranes, or any other surface should be avoided.

Children

Available data confirm the safety and efficacy of the drug in children aged 2 years and older.

Safety and efficacy of the drug in children under 2 years of age have not been established.

Tobrosopht®-DEX may be used in children aged 2 years and older.

Overdose.

Due to the characteristics of this drug intended for topical use, no toxic effects are expected either with ophthalmic use at recommended doses or with accidental ingestion of the bottle contents. Possible clinical symptoms of overdose such as punctate keratitis, erythema, increased lacrimation, eyelid edema, and itching may resemble the adverse effects observed in some patients.

In case of overdose with Tobrosopht®-DEX during topical administration, rinse the eye(s) with warm water.

Adverse reactions.

The most commonly reported adverse effects associated with treatment were those related to local ocular tolerance, including hypersensitivity reactions occurring in less than 4% of patients and comprising ocular discomfort, eye irritation, eye pain, ocular hyperemia, eye pruritus, eyelid pruritus, eyelid edema, and foreign body sensation in the eye.

Adverse reactions were classified as follows: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10,000, <1/1000), very rare (<1/10,000), frequency not known (cannot be estimated from available data). Within each group, adverse effects are listed in order of decreasing severity.

Immune system disorders:

Frequency not known: anaphylactic reactions, hypersensitivity.

Nervous system disorders:

Uncommon: headache.

Frequency not known: dizziness.

Eye disorders:

Common: ocular discomfort, eye pain, eye irritation.

Uncommon: ocular allergic manifestations (hypersensitivity), increased intraocular pressure, keratitis, punctate keratitis, ocular hyperemia, eye pruritus, eyelid pruritus, eyelid erythema, blurred vision, foreign body sensation in the eye, conjunctival edema, dry eye, eyelid edema, increased lacrimation, ulcerative keratitis.

Frequency not known: glaucoma, cataract, decreased visual acuity, mydriasis, photophobia.

Respiratory, thoracic and mediastinal disorders:

Uncommon: laryngospasm, rhinorrhea.

Gastrointestinal disorders:

Uncommon: dysgeusia (bitter or unusual taste in mouth).

Frequency not known: vomiting, nausea, stomach discomfort.

Skin and subcutaneous tissue disorders:

Frequency not known: rash, facial edema, pruritus, erythema multiforme.

Endocrine system disorders:

Frequency not known: Cushing's syndrome, adrenal suppression.

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").

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

Secondary infections may develop following use of combinations containing corticosteroids and antimicrobial agents. Fungal infections of the cornea may particularly develop during prolonged steroid use (see section "Special precautions").

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

Some adverse reactions such as corneal abrasion, decreased vision, conjunctival edema, eyelid disorders, eye discharge, eyelid pruritus, urticaria, dermatitis, madarosis, leukoderma, and dry skin have been observed during tobramycin therapy.

Adverse reactions such as keratoconjunctivitis, corneal pigmentation, photophobia, scaling of eyelid margins, decreased visual acuity, corneal erosion, and eyelid ptosis have been observed during dexamethasone therapy.

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

Shelf life.

2 years.

The shelf life of the medicinal product after first opening is 4 weeks.

Storage conditions.

Store in the original packaging at a temperature not exceeding 30°C.

Keep out of reach of children.

Packaging.

5 ml in a dropper bottle with cap and tamper-evident seal.

1 bottle per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Warsaw Pharmaceutical Works Polfa SA.

Manufacturer's address and place of business.

22/24 Karolkowa Str., 01-207 Warsaw, Poland.