Tobradex

TOBRADEX®

(TOBRADEX

®)

Composition:

Active substances: tobramycin, dexamethasone;

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

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

Pharmaceutical form. Eye drops.

Main physicochemical properties: white or almost white 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 the treatment of inflammatory conditions of the eye is well known. 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 formation of inflammatory mediators is reduced and the adhesion of circulating leukocytes to vascular endothelium is inhibited, thus 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 active, rapidly bactericidal aminoglycoside antibiotic effective against both Gram-positive and Gram-negative microorganisms. Its mechanism of action is related to inhibition of the polypeptide complex and synthesis in bacterial ribosomes.

In general, the activity of tobramycin has been described in vitro by determining the minimum inhibitory concentration (MIC), which defines the antibiotic 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 culture susceptibility or resistance to a specific antibiotic. The existing critical MIC value for tobramycin against relevant bacterial species takes into account inherent susceptibility, as well as maximum concentration and time/concentration pharmacokinetic values measured in serum after oral administration. Determination of these critical values, which classify microorganisms as susceptible or resistant, has been used to determine the clinical efficacy of systemically administered antibiotics. However, when antibiotics are applied locally in high concentrations directly at the site of infection, critical value determination is not applicable. Most microorganisms that might be classified as resistant based on critical value determination during systemic administration actually respond well to local treatment. For prophylaxis, there is a possibility to prevent the development of infection-causing microorganisms.

In clinical studies, topical tobramycin solution 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 determination during systemic administration. Clinical studies have shown 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

* The beta-lactam resistance phenotype (i.e., methicillin; penicillin) is not associated with the aminoglycoside resistance phenotype, and neither is associated with virulence and pathogenic organism 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 critical values) usually respond successfully 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 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 occurs during treatment, the drug should be discontinued and appropriate therapy initiated.

Pharmacokinetics.

Dexamethasone

Systemic exposure to dexamethasone after topical ophthalmic administration of TOBRADEX® eye drops is low. Peak plasma concentration levels range from 220 to 888 pg/ml (mean 555 ± 217 pg/ml) after instilling one drop of TOBRADEX® 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 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/hr/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 TOBRADEX® eye drops is low. Tobramycin plasma concentrations were below quantifiable levels in 9 out of 12 patients who received TOBRADEX® eye drops (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 via glomerular filtration, primarily in unchanged form. The plasma half-life is approximately 2 hours, with a clearance of 0.04 L/hr/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 studied. Systemic effects of tobramycin at toxic doses, which greatly exceed the dose used for local ocular application, may be associated with nephrotoxicity and ototoxicity. Systemic effects of dexamethasone may be related to glucocorticoid imbalance effects. Repeated-dose toxicity studies of TOBRADEX® eye drops in rabbits revealed systemic effects related to corticosteroids, but even at doses significantly exceeding the human dose, this manifestation has minimal clinical relevance. With TOBRADEX® use at recommended doses, occurrence of these effects is unlikely.

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 and ototoxic effects. Other studies conducted in rats and rabbits using tobramycin at doses exceeding 100 mg/kg/day via parenteral administration (>400 times the maximum clinical dose) did not reveal any fertility impairment or harmful effects on the fetus.

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

TOBRADEX® 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 TOBRADEX®.

Clinical characteristics.

Indications.

Inflammatory conditions of the eye in patients sensitive to steroids, where corticosteroid use is indicated and there is a superficial bacterial infection or risk of developing a bacterial eye infection. These inflammatory processes may occur after surgery 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.
• Smallpox, chickenpox, and other viral infections of the cornea and conjunctiva.
• Fungal diseases of ocular structures or untreated parasitic eye infections.
• Mycobacterial eye infections.
• Infections or injuries limited to the corneal surface epithelium.
• TOBRADEX® should not be used after uncomplicated removal of a foreign body from the cornea.

Interaction with other medicinal products and other types of interaction.

Concomitant use of locally applied steroids and NSAIDs (non-steroidal anti-inflammatory drugs) for local use 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 locally applied medicinal products with toxic (harmful) effects on the nervous system, hearing organs, or kidneys may lead to additive toxicity; therefore, such use should be avoided if possible.

In patients receiving ritonavir, dexamethasone plasma concentration may increase (see section "Special precautions").

If more than one ophthalmic agent is applied locally, the interval between applications 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 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 tamper-evident ring.

• 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, discontinue use of the drug.
• Cross-hypersensitivity to other aminoglycosides may occur. Consider the possibility that patients with hypersensitivity to topically applied 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 is advised when using concomitantly with systemic aminoglycosides.
• Exercise caution when prescribing TOBRADEX to patients with known or suspected neuromuscular disorders such as myasthenia gravis or Parkinson's disease. Aminoglycosides may exacerbate muscle weakness due to potential effects on neuromuscular function.
• 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 formation of posterior subcapsular cataract. Patients receiving long-term ophthalmic corticosteroid therapy should have intraocular pressure monitored regularly and repeatedly. This is especially important for children aged 6 years and older, 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).
• Visual disturbances may occur with systemic and local 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 local 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, viral, fungal, or parasitic infections and may interfere with detection of such infections and mask clinical signs of infection.
• In persistent corneal ulceration, consider the possibility of fungal infection. 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. Appropriate therapy should be initiated if superinfection occurs.
• Ophthalmic corticosteroids may delay corneal wound healing. It is also known that locally applied NSAIDs delay or impair wound healing. Concomitant use of locally applied NSAIDs and locally applied steroids may increase the risk of wound healing complications (see section "Interaction with other medicinal products and other types of interaction").
• In conditions leading to thinning of the cornea or sclera, local steroid use may cause perforation.
• Wearing contact lenses is not recommended during treatment of ocular inflammation or infection.
• TOBRADEX® eye drops contain benzalkonium chloride, which may cause eye irritation and 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 applying TOBRADEX® eye drops and wait at least 15 minutes before reinserting contact lenses.
• After instillation of eye drops to reduce systemic absorption:
  • keep eyelid closed for 2 minutes;
  • press finger over nasolacrimal duct for 2 minutes.
• The drug can be used in children aged 2 years and older.

Use during pregnancy or breastfeeding.

Reproductive function

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

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 carefully monitored for signs of hypoadrenalism. Animal studies demonstrated reproductive toxicity after topical dexamethasone and systemic dexamethasone and tobramycin use.

Use of TOBRADEX® during pregnancy is not recommended.

Breastfeeding

After systemic administration, tobramycin is excreted in breast milk. Data on dexamethasone excretion in breast milk are lacking. It is unknown whether tobramycin and dexamethasone enter 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 should be made whether to discontinue breastfeeding or 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, consider the possibility of temporarily discontinuing breastfeeding during TOBRADEX® use.

Ability to affect reaction speed when driving or operating machinery.

TOBRADEX®, eye drops, has no or negligible effect 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, instill 1 or 2 drops every hour until inflammation is controlled, then gradually reduce frequency to 1 or 2 drops every 2 hours for 3 days; thereafter, 1–2 drops every 4 hours for 5–8 days, and finally 1–2 drops daily for the last 5–8 days, as needed.

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 instillation after surgery, then 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 therapy.

Regular monitoring of intraocular pressure is recommended.

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

Use in children

Available data confirm the safety and efficacy of the medicinal product in children aged 2 years and older treated for 7 days for superficial bacterial eye inflammation.

May be used in children requiring surgical cataract removal.

Use in hepatic and renal impairment

TOBRADEX® has not been studied in this patient population. However, due to low systemic absorption of tobramycin and dexamethasone after local administration, no dose adjustment is necessary.

Method of administration

Shake the bottle well before use.

To prevent contamination of the dropper tip and bottle contents, exercise caution and avoid touching eyelids, adjacent areas, or other surfaces with the dropper tip.

Store the bottle in an upright position.

Children

Available 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.

TOBRADEX® can be used in children aged 2 years and older.

Overdose.

Given the characteristics of this product intended for local 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 itching) may be similar to adverse effects observed in some patients.

In case of overdose with TOBRADEX® during local administration, wash out excess drug from the eye(s) with warm water.

Adverse reactions.

In clinical trials, the most common adverse reactions were eye pain, increased intraocular pressure, eye irritation, and eye itching, occurring in less than 1% of patients.

In clinical trials of TOBRADEX® eye drops, the following adverse reactions were reported, categorized by frequency: 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 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 their frequency of occurrence.

Table 2

Description of some adverse reactions

Prolonged local 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 medicinal product contains corticosteroids, in patients with diseases causing thinning of the cornea or sclera, the risk of perforation increases, especially after prolonged use (see section "Special precautions").

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

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

Some adverse reactions such as corneal abrasion, visual disturbance, conjunctival edema, eyelid disorders, eye discharge, eyelid pruritus, urticaria, dermatitis, madarosis, leukoderma, and dry skin were observed during tobramycin therapy.

Adverse reactions such as keratoconjunctivitis, corneal pigmentation, photophobia, scaling at the eyelid margins, decreased visual acuity, corneal erosion, and eyelid ptosis were observed during dexamethasone therapy.

In some patients, hypersensitivity reactions to aminoglycosides may occur with topical application (see section "Special precautions").

Shelf life.

2 years. The shelf life after first opening the bottle is 1 month.

Storage conditions.

Store at a temperature not exceeding 25 °C.

Do not freeze. Store the bottle in an upright position in places inaccessible to children. Keep the bottle tightly closed.

Packaging.

5 mL in a dropper bottle; 1 dropper bottle in a cardboard box.

Prescription status.

By prescription only.

Manufacturer.

Manufacturer's address and place of business.

Rijksweg 14, Puurs-Sint-Amands, 2870, Belgium / Rijksweg 14, Puurs-Sint-Amands, 2870, Belgium.