Tobrinext combi

Tobrinext Combi

(

Tobrinext combi)

Composition:

Active substances: tobramycin, dexamethasone;

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

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

Pharmaceutical form. Eye drops, suspension.

Main physicochemical properties: white, homogeneous suspension.

Pharmacotherapeutic group. Anti-inflammatory and anti-infective agents in combination. Corticosteroids and anti-infective agents in combination.

ATC Code S01C A01.

Pharmacological properties.

Pharmacodynamics.

Dexamethasone

The efficacy of corticosteroids in treating inflammatory conditions of the eye is well established. Corticosteroids exert their anti-inflammatory effect 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 penetration 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.

Tobramycin

Tobramycin is a highly effective, rapidly acting bactericidal antibiotic of the aminoglycoside group, active 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 pathogens, it is considered a broad-spectrum antibiotic. Critical MIC values have been established to determine bacterial susceptibility or resistance to a given antibiotic. The current critical MIC values for tobramycin against relevant bacterial species take into account inherent species susceptibility, as well as maximum concentration and pharmacokinetic time/concentration dependency measured in serum after oral administration. Determination of these critical values, which classify microorganisms as susceptible or resistant, has been used to predict clinical efficacy of systemically administered antibiotics. However, when an antibiotic is applied topically in high concentrations directly at the site of infection, critical values are not applicable. Most microorganisms that might be classified as resistant based on systemic critical values actually respond well to topical treatment. There is a possibility to prevent the development of such microorganisms causing infection.

In clinical studies, the tobramycin solution applied topically demonstrated efficacy against many existing strains of ocular pathogens in patients enrolled in the studies. Some of these ocular pathogens are considered resistant based on critical value determinations during systemic administration. Clinical studies have shown 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 not associated with the aminoglycoside resistance phenotype, and neither is linked to the virulence or pathogenic phenotypes of the organisms. 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 critical values) usually respond successfully to topical 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

Susceptibility testing has shown that in some cases, microorganisms resistant to gentamicin remain sensitive 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 may occur. If increased sensitivity occurs during treatment, the drug should be discontinued and appropriate therapy initiated.

Pharmacokinetics.

Dexamethasone

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

Dexamethasone is eliminated from the body via metabolism. Approximately 60% of the dose is excreted in urine as 6-β-hydroxydexamethasone. Unchanged dexamethasone was not detected in urine. The plasma elimination 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 Tobrinext Combi eye drops is low. Tobramycin plasma concentrations could not be quantified in 9 out of 12 patients who received Tobrinext Combi eye drops (1 drop in each eye four times daily for 2 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 via glomerular filtration, primarily in unchanged form. The plasma elimination half-life is approximately 2 hours, with a clearance of 0.04 L/h/kg and 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

Safety data

Systemic toxicity data for the active substances are well established. Systemic exposure to tobramycin at toxic doses, much higher than those used in topical ocular administration, 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 Tobrinext Combi eye drops in rabbits revealed systemic effects related to corticosteroids, but even at doses significantly exceeding the human dose, these findings have minimal clinical relevance. The occurrence of these effects is unlikely when Tobrinext Combi 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 with systemic administration of high doses of tobramycin to pregnant animals during organogenesis revealed fetal renal toxicity and ototoxicity. Other studies in rats and rabbits using tobramycin doses exceeding 100 mg/kg/day via parenteral administration (> 400 times the maximum clinical dose) did not show 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 animals resulted in increased incidence of fetal developmental abnormalities and intrauterine growth retardation. Growth retardation and increased fetal mortality were observed in rats during prolonged dexamethasone therapy.

Tobrinext Combi should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus.

No studies have been conducted to evaluate the carcinogenic potential of Tobrinext Combi.

Clinical characteristics.

Indications.

Ocular inflammation in patients sensitive to steroids, where corticosteroid therapy is indicated and there is a superficial bacterial infection or risk of bacterial ocular infection. These inflammatory conditions may occur after surgical intervention or may be caused by infection, foreign body entry into the eye, or ocular trauma.

Contraindications.

• Hypersensitivity to the active substances or to any component of the medicinal product.
• Hypersensitivity to aminoglycosides.
• Keratitis caused by the virus herpes simplex.
• Cowpox, varicella, and other viral infections of the cornea and conjunctiva.
• Fungal diseases of ocular structures or untreated parasitic ocular infections.
• Mycobacterial ocular infections.
• Infections or injuries limited to the superficial corneal epithelium.
• Tobrinext Combi should not be used after uncomplicated removal of a foreign body from the cornea.

Interaction with other medicinal products and other types of interaction.

No clinically significant interactions have been reported after topical administration of the drug. Concomitant use of topical corticosteroids and topical nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk of corneal wound healing complications.

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

If more than one ophthalmic agent is used topically, at least a 5-minute interval should be maintained between applications. Ophthalmic ointments should be applied last.

Dexamethasone is metabolized by cytochrome P450 3A4 (CYP3A4) enzymes. CYP3A4 inhibitors (including ritonavir and cobicistat) may reduce dexamethasone clearance, leading to more severe adverse effects and adrenal suppression/Cushing's syndrome. Such combinations should be avoided unless 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 ophthalmic use only.

After first opening the bottle, remove the protective ring designed for first opening control.

• 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, pruritus, urticaria, skin rashes, anaphylaxis, anaphylactoid reactions, or bullous reactions. If a hypersensitivity reaction occurs, discontinue the drug.
• Cross-hypersensitivity to other aminoglycosides may occur. Consider the possibility that patients hypersensitive to tobramycin when applied topically 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 is advised when used concomitantly with systemic aminoglycosides.
• Caution is required when prescribing Tobrinext Combi to 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.
• Long-term treatment with topically administered 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 ocular corticosteroid therapy should have intraocular pressure monitored regularly and repeatedly. 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., diabetic patients).
• Visual disturbances may occur with systemic and topical corticosteroid use. If a patient experiences symptoms such as blurred vision or other visual disturbances, they should be referred to an ophthalmologist to evaluate possible causes, including cataract, glaucoma, or rare conditions such as central serous chorioretinopathy, which have been observed after systemic and topical corticosteroid use.
• 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 receiving CYP3A4 inhibitors (including ritonavir and cobicistat). In such cases, treatment should be tapered off gradually.
• Corticosteroids may reduce resistance to bacterial, fungal, viral, or parasitic infections and may mask the clinical signs of such infections.
• In persistent corneal ulceration, fungal infection should be considered. If fungal infection occurs, corticosteroid therapy should be discontinued.
• Long-term 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 corneal wound healing. Topically applied NSAIDs are also known to delay or impair 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 types of interaction").
• Topical steroid use in patients with diseases leading to thinning of the cornea or sclera may result in perforation.
• Wearing contact lenses during treatment of ocular inflammation or infection is not recommended.
• Tobrinext Combi eye drops contain 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 allowed to wear contact lenses, they should be advised to remove contact lenses before instilling Tobrinext Combi eye drops and wait at least 15 minutes before reinserting contact lenses.
• After instillation of eye drops to minimize systemic absorption:
  • keep the eyelid closed for 2 minutes;
  • press the lacrimal sac with a finger for 2 minutes.
• The drug can be used in children aged 2 years and older.

Use during pregnancy or breastfeeding.

Fertility

Studies 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 fertility are limited. No adverse effects on the reproductive system were observed in dexamethasone-treated rats sensitized to chorionic gonadotropin.

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 demonstrated reproductive toxicity after topical dexamethasone administration and systemic administration of dexamethasone and tobramycin.

Tobrinext Combi is not recommended during pregnancy.

Breastfeeding

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 penetrate into breast milk after 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.

Risk to the breastfed infant cannot be excluded.

A decision must 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 are excreted in breast milk, temporary discontinuation of breastfeeding during Tobrinext Combi use should be considered.

Effects on ability to drive and use machines.

Tobrinext Combi eye drops have no or negligible effect on the ability to drive or use machinery. Transient blurred vision or other visual disturbances may affect the ability to drive or use 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, instill 1 or 2 drops every hour until inflammation is controlled, then gradually reduce the frequency to 1 or 2 drops every 2 hours for 3 days; thereafter, instill 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 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 may be increased to 1 drop every 2 hours during the first two days of therapy.

Regular monitoring of intraocular pressure is recommended.

It is recommended to press the lacrimal sac area and gently close the eyelids for at least 1 minute 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 medicinal product in children aged 2 years and older treated for 7 days for superficial bacterial ocular inflammation.

May be used in children undergoing cataract surgery.

Use in hepatic and renal impairment

Tobrinext Combi has not been studied in this patient population. However, due to the low systemic absorption of tobramycin and dexamethasone after topical administration, dose adjustment is not necessary.

Method of administration

Shake the bottle well before use.

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

Store the bottle in an upright position.

Children.

Data confirm the safety and efficacy of the medicinal product in children aged 2 years and older.

Safety and efficacy in children under 2 years of age have not been established. Tobrinext Combi may be used in children from 2 years of age.

Overdose.

Given the characteristics of this medicinal product 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 signs and symptoms of overdose (punctate keratitis, erythema, increased lacrimation, eyelid swelling, and pruritus) may resemble adverse effects observed in some patients.

In case of overdose with Tobrinext Combi during topical use, flush the eye(s) with warm water to remove excess drug.

Adverse reactions.

Based on clinical trial data, the most frequently reported adverse reactions were: eye pain, increased intraocular pressure, eye irritation, and eye pruritus, occurring in less than 1% of patients.

Based on clinical trial data for tobramycin and dexamethasone eye drops, the following adverse reactions have been reported, categorized by frequency: 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). Within each group, adverse effects are listed in order of decreasing severity.

Table 1

Based on post-marketing studies, the adverse reactions listed below have been identified.

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

Table 2

Description of some adverse reactions

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

Since the product contains a corticosteroid, in patients with diseases causing thinning of the cornea or sclera, the risk of perforation is increased, 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").

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

Some adverse reactions such as eye pain, 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, scaling of eyelid margins, decreased visual acuity, corneal erosion, eyelid ptosis, headache, and nasopharyngeal catarrh have been observed during dexamethasone therapy.

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

Reporting suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is important. It allows ongoing monitoring of the benefit-risk balance of the medicine. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life.

24 months.

After first opening, use within 4 weeks.

Storage conditions.

The medicinal product does not require special storage conditions.

Keep out of reach of children.

Packaging.

5 mL of suspension in a dropper bottle.

1 dropper bottle per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

RAFARM SA/RAFARM SA.

Manufacturer's address and location of its business activity.

Thesi Pousi-Xatzi Agiou Louka, Paiania (Attica), ZIP 19002, P.O. Box 37, Greece/

Thesi Pousi-Xatzi Agiou Louka, Paiania Attiki, TK 19002, TO 37, Greece.