Tobiflamin

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

Composition:

Active substances: tobramycin, dexamethasone;

1 ml of suspension contains tobramycin 3.0 mg and dexamethasone 1.0 mg;

Excipients: benzalkonium chloride, edetate disodium, sodium chloride, anhydrous sodium sulfate, tyloxapol, hydroxyethylcellulose, sulfuric acid and/or sodium hydroxide, water for injections.

Pharmaceutical form. Eye drops, suspension.

Main physicochemical properties: white homogeneous suspension.

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

Pharmacological Properties

Pharmacodynamics

Dexamethasone

The efficacy of corticosteroids in the treatment of inflammatory ocular conditions is well established. Corticosteroids exert their anti-inflammatory effects 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 the adhesion of circulating leukocytes to vascular endothelium is suppressed, thereby preventing their migration 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 involves inhibition of the polypeptide complex and protein synthesis in bacterial ribosomes.

Overall, 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. Threshold MIC values have been established to define bacterial culture susceptibility or resistance to a specific antibiotic. The MIC breakpoint for tobramycin against relevant bacterial species takes into account intrinsic susceptibility, maximum concentration, and pharmacokinetic time/concentration dependency measured in serum after oral administration. These breakpoints, used to classify microorganisms as susceptible or resistant, were established 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 breakpoints are not applicable. Most microorganisms that might be classified as resistant according to systemic breakpoints often respond well to topical treatment. There is potential for prophylaxis to prevent the development of infection-causing microorganisms.

Clinical studies have shown that topically applied tobramycin solution is effective against many existing strains of ocular pathogens in patients enrolled in the studies. Some of these ocular pathogens are considered resistant based on systemic breakpoints. Clinical trials have demonstrated that tobramycin is effective in treating superficial ocular infections caused by the following pathogens.

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

* Beta-lactam resistance phenotype (i.e., methicillin, penicillin) is not associated with aminoglycoside resistance phenotype, and neither is related 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 (according to MIC breakpoints) usually respond well to locally applied tobramycin treatment.

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

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

Cross-resistance to other aminoglycoside antibiotics is possible. If hypersensitivity occurs during treatment, the drug should be discontinued and appropriate therapy initiated.

Pharmacokinetics

Dexamethasone

Systemic exposure to dexamethasone after 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 eliminated via metabolism. Approximately 60% of the dose is excreted in urine as 6-β-hydroxydexamethasone. Unchanged dexamethasone has not been detected in urine. The plasma half-life is relatively short—3–4 hours.

Dexamethasone is approximately 77–84% bound to serum albumin. Clearance ranges from 0.111 to 0.225 L/h/kg, and volume of distribution ranges from 0.576 to 1.15 L/kg. Oral bioavailability is approximately 70%.

Tobramycin

Systemic exposure to tobramycin after topical ophthalmic administration of eye drops is low. Tobramycin plasma concentrations were below quantifiable limits in 9 out of 12 patients who received one drop in each eye four times daily for two consecutive days. The highest measured level was 0.25 µg/mL, which is 8 times lower than the 2 µg/mL concentration known to be below the nephrotoxicity risk threshold.

Tobramycin is rapidly and actively excreted in urine by glomerular filtration, primarily in unchanged form. The plasma 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. Plasma protein binding of tobramycin is negligible—less than 10%. Oral bioavailability of tobramycin is low (<1%).

Preclinical Safety Data

Data on systemic toxicity of the active substances are well established. Systemic exposure to tobramycin at toxic doses, significantly exceeding the dose for topical ocular use, may be associated with nephrotoxicity and ototoxicity. Systemic exposure to dexamethasone may cause effects related to glucocorticoid imbalance. Repeated-dose toxicity studies of eye drops in rabbits revealed systemic effects related to corticosteroids; however, even at doses substantially exceeding the human dose, the clinical relevance of these findings is minimal. When used at recommended doses, the occurrence of such effects 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 renal toxicity and ototoxicity in the fetus. Other studies conducted in rats and rabbits using tobramycin at doses exceeding 100 mg/kg/day administered parenterally (>400 times the maximum clinical dose) did not reveal any impairment of fertility or adverse effects on the fetus.

Corticosteroids have shown teratogenic effects in animal studies. Ocular administration of 0.1% dexamethasone to pregnant rabbits resulted in an increased incidence of fetal developmental abnormalities and intrauterine growth retardation. Prolonged dexamethasone therapy in rats was associated with delayed fetal development and increased mortality.

Tobiflam 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 the drug.

Clinical characteristics.

Indications.

Inflammation of the eye in patients who are steroid-responsive, in whom corticosteroid treatment is indicated and where there is either superficial bacterial infection or a risk of developing bacterial ocular 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 ocular infections.
• Mycobacterial infections of the eye.
• Infections or injuries limited to the corneal surface epithelium.

Tobiflamin should not be used after uncomplicated removal of a foreign body from the cornea.

Interaction with other medicinal products and other forms of interaction.

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

Concomitant or sequential administration of aminoglycoside antibiotics (such as tobramycin) and other systemic oral medications or locally applied medicinal products with neurotoxic, ototoxic, or nephrotoxic effects may result in additive toxicity; therefore, such combination should be avoided whenever possible.

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

When more than one ophthalmic agent is used locally, the interval between applications should be at least 5 minutes. Ophthalmic ointments should be administered last.

CYP3A4 inhibitors (particularly 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 used only if the benefit outweighs the increased risk of systemic corticosteroid side effects, and in such cases, systemic corticosteroid adverse effects should be monitored in patients.

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 effects 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 is possible. Consider the likelihood 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 this product concomitantly with systemic aminoglycosides.

Tobiflamin should be prescribed with caution in patients with suspected neuromuscular disorders such as myasthenia gravis or Parkinson’s disease. Aminoglycosides may exacerbate muscle weakness due to their potential effects on neuromuscular function.

Prolonged treatment with locally applied ophthalmic corticosteroids may lead to elevated intraocular pressure and/or glaucoma with optic nerve damage, decreased visual acuity and visual field, and posterior subcapsular cataract formation. Patients receiving long-term ocular corticosteroid therapy should have intraocular pressure monitored regularly and repeatedly. This is particularly important for children aged 6 years and older, as the risk of corticosteroid-induced intraocular pressure elevation is higher and occurs earlier in children than in adults.

The risk of corticosteroid-induced intraocular pressure elevation and corticosteroid-induced cataract formation increases in predisposed patients (e.g., patients with diabetes mellitus).

Visual disturbances may occur with both systemic and topical corticosteroid use. If a patient develops symptoms such as blurred vision or other visual disturbances, they should be referred to an ophthalmologist to evaluate possible causes, including cataract, glaucoma, or rare conditions such as central serous chorioretinopathy, which have been reported following systemic and topical corticosteroid use.

Cushing’s syndrome and/or adrenal suppression, related to systemic absorption of ophthalmic dexamethasone, may occur after intensive or prolonged continuous therapy in susceptible patients, including children and patients receiving CYP3A4 inhibitors (particularly cobicistat and ritonavir). In such cases, treatment should be tapered off gradually.

Corticosteroids may reduce resistance to bacterial, viral, fungal, or parasitic infections and may mask the clinical signs of infection.

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. Topically applied NSAIDs are also known to 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.

The medicinal product contains benzalkonium chloride, which may cause eye irritation and may discolor soft contact lenses. Contact with soft contact lenses should be avoided. If patients are permitted to wear contact lenses, they should be advised to remove the lenses before applying the product and wait at least 15 minutes before reinserting the lenses.

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 can be used in children aged 2 years and older.

Use during pregnancy or breastfeeding.

Fertility. Studies evaluating 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 fertility are limited. In rats sensitized to chorionic gonadotropin, no adverse effects on the reproductive system were observed with dexamethasone use.

Pregnancy. Data on the use of tobramycin or dexamethasone in pregnant women are lacking or limited. After intravenous administration to 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 closely monitored for signs of hypoadrenalism. Animal studies have shown reproductive toxicity following topical and systemic administration of dexamethasone and systemic administration of tobramycin.

The use of Tobiflamin during pregnancy is not recommended.

Breastfeeding. After systemic administration, tobramycin is excreted in breast milk. Data on the excretion of dexamethasone in breast milk are lacking. It is unknown whether tobramycin and dexamethasone pass into breast milk following topical ophthalmic use. It is unlikely that tobramycin and dexamethasone will be present in breast milk or cause clinical effects in neonates 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, temporary discontinuation of breastfeeding during treatment should be considered.

Ability to influence reaction speed when driving or operating machinery.

Tobiflamin, 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, the patient should wait until vision clears before driving or operating machinery.

Method of Administration and Dosage

For ophthalmic use.

Use in adults, including elderly patients, and children aged 12 to 18 years. Instill 1 or 2 drops into the conjunctival sac(s) every 4–6 hours. During the first 24–48 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, administer 1–2 drops every 4 hours for 5–8 days, and finally 1–2 drops daily for the last 5–8 days, if necessary.

After cataract surgery, the dosage 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 with 1 drop after surgery, followed by 4 times daily for the next 23 days. If necessary, the frequency of administration may be increased to 1 drop every 2 hours during the first two days of therapy.

Intraocular pressure should be monitored regularly.

It is recommended to press gently on the lacrimal sac area and close the eyelids carefully after instillation. This reduces systemic absorption of the drug administered into the eye, thereby decreasing the likelihood of systemic adverse effects.

Use in children. 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.

The drug may be used in children requiring cataract surgery.

Use in patients with hepatic or renal impairment. The use of Tobiflamin in these patient groups has not been studied. However, due to the low systemic absorption of tobramycin and dexamethasone following topical administration, dosage adjustment is not required.

Method of administration. The suspension should be shaken well before use.

To prevent contamination of the dropper tip and the contents of the bottle, care must be taken not to touch the eyelids, surrounding areas, or other surfaces with the tip of the dropper bottle.

Store the bottle in an upright position.

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

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

Tobiflamin 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 when used in ophthalmology at recommended doses or in case of accidental ingestion of the bottle contents. Possible clinical signs and symptoms of overdose (punctate keratitis, erythema, increased lacrimation, eyelid edema, and itching) may resemble adverse effects observed in some patients.

In case of overdose with Tobiflamin during topical use, wash out the excess drug from the eye(s) with warm water.

Adverse reactions.

It is known that during clinical studies the most common adverse reactions to the medicinal product, occurring in less than 1% of patients, were eye pain, increased intraocular pressure, eye irritation, and eye itching.

The adverse reactions listed below, identified during clinical studies of eye drops, were classified according to frequency as follows: very common (≥ 1/10); common (≥ 1/100 — < 1/10); uncommon (≥ 1/1000 — < 1/100); rare (≥ 1/10,000 — < 1/1,000); very rare (< 1/10,000). Within each group, adverse reactions are listed in order of decreasing severity.

Table 1

Eye disorders	Uncommon: increased intraocular pressure, eye pain, eye pruritus, eye discomfort, eye irritation. Single occurrences: keratitis, eye allergy, blurred vision, dry eyes, eye hyperemia.
Gastrointestinal disorders	Single occurrences: dysgeusia.

The following adverse reactions have been identified from post-marketing experience.

Based on the available data, it is not possible to calculate their frequency of occurrence.

Table 2

Body systems	Adverse reactions [appropriate MedDRA term]
Immune system disorders	Hypersensitivity, anaphylactic reaction
Nervous system disorders	Dizziness, headache
Eye disorders	Periorbital edema, eyelid erythema, mydriasis, increased lacrimation, ulcerative keratitis, blurred vision
Gastrointestinal disorders	Nausea, gastric discomfort
Skin and subcutaneous tissue disorders	Rash, facial swelling, pruritus, erythema multiforme
Endocrine disorders	Cushing's syndrome, adrenal suppression

Description of some adverse reactions

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

Since the medicinal product contains a corticosteroid, in patients with conditions causing thinning of the cornea or sclera, the risk of perforation is increased, especially after prolonged use (see section "Dosage and Administration").

Secondary infections may develop following treatment with combinations containing corticosteroids and antimicrobial agents. Fungal infections of the cornea may particularly intensify during prolonged steroid use (see section "Dosage and Administration").

Serious adverse reactions, including neurotoxicity, ototoxicity, and nephrotoxicity, have been observed in patients receiving systemic therapy with tobramycin (see section "Dosage and Administration").

Some adverse reactions such as corneal abrasion, visual disturbance, 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, eyelid scaling, 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 "Dosage and Administration").

Reporting suspected adverse reactions

Reporting of adverse reactions after medicinal product registration is of great importance. It enables continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 2 years.

After opening the bottle, the product should not be stored for more than 4 weeks.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging.

5 ml in a polyethylene bottle with dropper and first-opening control.

1 bottle per carton.

Prescription status.

Prescription only.

Manufacturer.

JSC "KYIV VITAMIN PLANT" (production from inbulk products of "Rafarm S.A.", Greece).

Manufacturer's address and place of business.

38 Kopilivska Street, Kyiv, 04073, Ukraine.

Web-site: www.vitamin.com.ua.