Instructions for use Tobradex eye ointment tube 3.5 g
Composition
active ingredients: tobramycin, dexamethasone;
1 g of ointment contains tobramycin 3 mg and dexamethasone 1 mg;
excipients: anhydrous chlorobutanol, mineral oil, white soft paraffin.
Dosage form
Eye ointment.
Main physicochemical properties: homogeneous ointment from white to almost white color.
Pharmacotherapeutic group
Anti-inflammatory and antimicrobial agents in combination. Corticosteroids and antimicrobial agents in combination. ATX code S01C A01.
Pharmacological properties
Pharmacodynamics
Dexamethasone
The efficacy of corticosteroids in the treatment of inflammatory ocular conditions is well established. Corticosteroids achieve their anti-inflammatory effects by inhibiting adhesion molecules to vascular endothelial cells, cyclooxygenase I or II, and cytokine release. This results in reduced production of inflammatory mediators and inhibition of the adhesion of circulating leukocytes to vascular endothelium, preventing their entry into inflamed ocular tissues. Dexamethasone has a pronounced anti-inflammatory effect with reduced mineralocorticoid activity compared with some other steroids and is one of the most potent anti-inflammatory agents.
Tobramycin
Tobramycin is a highly active, fast-acting bactericidal antibiotic of the aminoglycoside group that counteracts both gram-positive and gram-negative microorganisms. Its mechanism of action is associated with the inhibition of the polypeptide complex and synthesis in the ribosomes of bacterial cells.
In general, the action of tobramycin has been described in vitro by determining the minimum inhibitory concentration (MIC), which determines the activity of the antibiotic against each bacterial species. Since the MIC of tobramycin is very low against most ocular pathogens, it is considered a broad-spectrum antibiotic. MIC breakpoints have been determined, which determine the sensitivity or resistance of a bacterial culture to a particular antibiotic. The existing MIC breakpoints for tobramycin for the respective bacterial species take into account the inherent sensitivity of the species, as well as the maximum concentration and pharmacokinetic time/concentration values measured in serum after oral administration. The determination of these breakpoints, which divide microorganisms into susceptible and resistant, has been used to determine the clinical efficacy of antibiotics administered systemically. However, when the antibiotic is applied topically in high concentrations directly to the site of infection, breakpoints have not been determined. Most microorganisms that would be classified as resistant by determining the breakpoints for systemic use actually respond well to topical treatment. For the purpose of prevention, it is possible to stop the development of such microorganisms that cause infection.
In clinical studies, topical tobramycin solution was effective against many existing strains of ocular pathogens in patients enrolled in the studies. Some of these ocular pathogens are considered resistant based on the determination of systemic breakpoints. In clinical studies, tobramycin has been shown to be effective in the treatment of superficial ocular infections caused by the following pathogens.
Gram-positive bacteria:
Staphylococcus aureus (methicillin-susceptible or resistant*)
Staphylococcus epidermidis (methicillin-susceptible or resistant*)
Other coagulase-negative Staphylococcus species
Streptococcus pneumoniae (penicillin-susceptible or resistant*)
Other species of Streptococcus.
* The beta-lactam (i.e., methicillin, penicillin) resistance phenotype is not associated with the aminoglycoside resistance phenotype, and both are not associated with the virulence and phenotypes of the pathogenic organisms. Many methicillin-resistant staphylococci have been found to be resistant to tobramycin (and other aminoglycoside antibiotics). However, these resistant staphylococcal cultures (as determined by MIC breakpoints) usually respond well to treatment with topical 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.
Bacterial susceptibility studies have shown that in some cases, microorganisms resistant to gentamicin remain susceptible to tobramycin. A significant proportion of the microflora has not yet developed resistance to tobramycin, however, bacterial resistance may develop during prolonged use.
Cross-sensitivity to other aminoglycoside antibiotics is possible; if hypersensitivity occurs during use of the drug, its use should be discontinued and appropriate treatment should be initiated.
Pharmacokinetics
Clinical pharmacokinetic studies with TOBRADEX® eye ointment have not been conducted. However, studies with TOBRADEX® eye drops have shown that systemic exposure to dexamethasone after topical ophthalmic administration is low. Peak plasma concentrations range from 220 to 888 pg/mL (mean 555 ± 217 pg/mL) after instillation of one drop of TOBRADEX® in each eye 4 times daily for two consecutive days.
Dexamethasone is eliminated from the body by metabolism. Approximately 60% of the dose is excreted in the urine as 6-β-hydroxydexamethasone. Unchanged dexamethasone was not detected in the 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 the volume of distribution ranges from 0.576 to 1.15 l/kg. Oral bioavailability is approximately 70%.
Tobramycin
Clinical pharmacokinetic studies with TOBRADEX® eye ointment have not been conducted. However, studies with TOBRADEX® eye drops have shown that systemic exposure to tobramycin following topical ophthalmic administration is low. Plasma tobramycin concentrations were not quantifiable in 9 of 12 patients receiving 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-fold lower than the concentration of 2 μg/mL known to be below the threshold for nephrotoxicity.
Tobramycin is actively and extensively excreted in the urine by glomerular filtration, mainly unchanged. 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
Safety data
Systemic toxicity data for the active substances are well established. Systemic exposure to tobramycin at toxic doses far exceeding the dose for topical ocular administration may be associated with nephrotoxicity and ototoxicity. Systemic exposure to dexamethasone may be associated with effects related to glucocorticosteroid imbalance. Repeated dose toxicity studies with TOBRADEX® eye drops in rabbits have shown systemic corticosteroid-related effects, but even at doses significantly exceeding the human dose, this manifestation is of little clinical relevance. When TOBRADEX® is used at recommended doses, these effects are unlikely to occur.
Mutagenicity
In vitro and in vivo studies of each of the active substances did not reveal any mutagenic effects.
Teratogenicity
Tobramycin crosses the placenta into the fetal circulation and amniotic fluid. Animal studies with systemic administration of high doses of tobramycin to pregnant animals during organogenesis have shown renal toxicity and ototoxicity in the fetus. Other studies conducted in rats and rabbits with tobramycin at doses greater than 100 mg/kg/day parenterally (>400 times the maximum clinical dose) have revealed no evidence of impaired fertility or harm to the fetus.
Corticosteroids have been shown to be teratogenic in animal studies. Ocular administration of 0.1% dexamethasone to pregnant rabbits resulted in increased incidence of fetal malformations and intrauterine growth retardation. Fetal growth retardation and increased mortality were observed in rats treated with long-term dexamethasone.
TOBRADEX® should be used during pregnancy only if the potential benefit of using the drug outweighs the potential risk to the fetus.
No studies have been conducted to evaluate the carcinogenic effects of TOBRADEX®.
Indication
Ocular inflammation in steroid-sensitive patients in whom corticosteroids are indicated and there is a superficial bacterial infection or risk of developing a bacterial infection of the eye. These inflammatory processes may occur after surgery (cataract removal) or may be caused by infection, foreign body in the eye or ocular trauma.
Contraindication
Hypersensitivity to the active substances or to any component of the medicinal product. Hypersensitivity to aminoglycosides. Keratitis caused by the herpes simplex virus. Cowpox, chickenpox and other viral infections of the cornea and conjunctiva. Fungal diseases of the structures of the eye or untreated parasitic infections of the eye. Mycobacterial infections of the eye. Infections or injuries limited to the superficial epithelium of the cornea. TOBRADEX® should not be used after uncomplicated removal of a foreign body from the cornea.
Interaction with other medicinal products and other types of interactions
Concomitant use of topical steroids and topical NSAIDs (nonsteroidal anti-inflammatory drugs) 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 drugs that have toxic (harmful) effects on the nervous system, hearing, or kidneys may result in additive toxicity and should be avoided if possible.
In patients receiving ritonavir, plasma concentrations of dexamethasone may increase (see section "Special warnings and precautions for use").
If more than one ophthalmic agent is applied topically, the interval between their applications should be at least 5 minutes. Eye ointments should be applied last.
CYP3A4 inhibitors (including ritonavir and cobicistat) may decrease dexamethasone clearance, leading to more severe adverse events and adrenocortical suppression of Cushing's syndrome. This combination should be avoided unless the benefit outweighs the increased risk of systemic corticosteroid side effects, in which case patients should be monitored for systemic corticosteroid side effects.
Application features
For ophthalmic use only.
Some patients may be hypersensitive to topical aminoglycosides. The severity of hypersensitivity reactions may range from local effects to generalized reactions such as erythema, pruritus, urticaria, rash, anaphylaxis, anaphylactoid reactions, or bullous reactions. If a hypersensitivity reaction occurs, the drug should be discontinued. Cross-sensitivity to other aminoglycosides may occur. It should be considered 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 used concomitantly with systemic aminoglycosides. Caution should be exercised when prescribing Tobradex to patients with known 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 topical ophthalmic corticosteroids may result in ocular hypertension and/or glaucoma with optic nerve damage, deterioration of visual acuity and visual fields, and the formation of subcapsular cataracts in the posterior chamber of the eye. In patients receiving prolonged ocular corticosteroid therapy, intraocular pressure should be monitored regularly and repeatedly. This is especially important for children aged 6 years and older, as the risk of corticosteroid-induced increased intraocular pressure may be greater in children and may occur earlier than in adults. The risk of corticosteroid-induced increased intraocular pressure and/or the risk of corticosteroid-induced cataract formation is increased in predisposed patients (e.g. diabetics). Visual disturbances may occur with systemic and topical corticosteroids. If the patient presents with symptoms such as blurred vision or other visual disturbances, he or she should be referred to an ophthalmologist for evaluation of possible causes, which include cataracts, glaucoma or rare diseases such as central serous chorioretinopathy, which have been observed with systemic and topical corticosteroids. 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 these cases, treatment should be discontinued gradually. Corticosteroids may reduce resistance to bacterial, viral, fungal or parasitic infections and may obscure the detection of such infections by masking clinical signs of infection. If persistent corneal ulceration occurs, the possibility of fungal infection should be considered. If a fungal infection occurs, corticosteroid therapy should be discontinued. Prolonged use of antibiotics such as tobramycin may result in overgrowth of nonsusceptible organisms, including fungi. If superinfection occurs, appropriate therapy should be initiated.
In the presence of diseases that lead to thinning of the cornea or sclera, topical steroid use may cause perforation. It is not recommended to wear contact lenses during treatment of inflammation or infection of the eye. The drug can be used in children from 2 years of age.
Ability to influence reaction speed when driving vehicles or other mechanisms
TOBRADEX®, ophthalmic ointment, has no or negligible influence on the ability to drive or use machines. Temporary blurred vision or other visual disturbances may affect the ability to drive or use machines. If blurred vision occurs during use, the patient should wait until the vision clears before driving or using machines.
Use during pregnancy or breastfeeding
Reproductive function
Studies to evaluate the effects of tobramycin and dexamethasone on human or animal reproductive function have not been conducted. Clinical data to evaluate the effects of dexamethasone on male or female reproductive function are limited. No adverse reproductive effects were observed when dexamethasone was administered to rats sensitized to chorionic gonadotropin.
Pregnancy
There are no or limited data from the use of tobramycin or dexamethasone in pregnant women. Tobramycin crosses the placenta after intravenous administration to pregnant women. Tobramycin does not cause ototoxicity when exposed in utero. Prolonged or repeated use of corticosteroids during pregnancy is associated with an increased risk of intrauterine growth retardation. Infants whose mothers received high doses of corticosteroids during pregnancy should be closely monitored for signs of hypoadrenalism. Animal studies have shown reproductive toxicity following topical administration of dexamethasone and systemic administration of dexamethasone and tobramycin.
The use of TOBRADEX® during pregnancy is not recommended.
Breast-feeding
Tobramycin is excreted in breast milk after systemic administration. There are no data on the excretion of dexamethasone in breast milk. It is not known whether tobramycin and dexamethasone are excreted in breast milk after topical ophthalmic administration. It is unlikely that tobramycin and dexamethasone will be detected in breast milk after topical administration of the medicinal product or that they will cause clinical effects in the newborn. A risk to the breastfed child cannot be excluded.
A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
Because many drugs are excreted in human milk, consideration should be given to temporarily discontinuing breast-feeding while using TOBRADEX®.
Method of administration and doses
For ophthalmic use.
Use in adults, including elderly patients, and children aged 12 to 18 years.
A small amount of ointment (a strip approximately 1.5 cm long) should be instilled into the conjunctival sac(s) of the affected eye(s) up to 3 or 4 times daily. The frequency of application should be gradually reduced as clinical signs improve. Care should be taken not to discontinue therapy prematurely.
The eye ointment can be used at night in combination with TOBRADEX® eye drops during the day.
After applying the ointment, it is recommended to carefully close the eyelids. This reduces the systemic absorption of the drug administered into the eye, which reduces the likelihood of systemic side effects.
It is recommended to constantly monitor intraocular pressure.
Application to children.
The data obtained confirm the safety and efficacy of the drug in children aged 2 years and older who were treated with the drug for 7 days for the treatment of superficial bacterial eye inflammation.
It can be used in children who need cataract surgery.
Use in liver and kidney dysfunction
TOBRADEX® has not been studied in this patient population. However, due to the low systemic absorption of tobramycin and dexamethasone after topical application, no dose adjustment is necessary.
Method of application
To prevent contamination of the tip and contents of the tube, care should be taken not to touch the eyelids, surrounding areas, or other surfaces with the tip of the tube.
Keep the tube tightly closed.
Children
Safety and effectiveness in children under 2 years of age have not been established.
The data obtained confirm the safety and effectiveness of the drug in children aged 2 years and older.
TOBRADEX® can be used in children aged 2 years and over.
Overdose
Possible clinical signs and symptoms of drug overdose (punctate keratitis, erythema, increased lacrimation, eyelid edema and itching) may be similar to the side effects observed in some patients.
Adverse reactions
During clinical trials, the most common adverse reactions were eye pain, increased intraocular pressure, eye irritation, and eye itching, which occurred in less than 1% of patients.
During clinical trials with TOBRADEX® eye ointment, the following adverse reactions were reported, which were assessed according to the following frequency: very common (≥ 1/10); common (≥ 1/100 - < 1/10); uncommon (≥ 1/1000 - < 1/100); rare (≥ 10,000 - < 1/1,000); rare (< 1/10,000). Within each group, adverse reactions are presented in order of decreasing seriousness.
Table 1
| Organ system classes | Adverse reactions [corresponding MedDRA term (v.15.1)] |
| Visual impairment | Uncommon: increased intraocular pressure, eye pain, eye itching, eye discomfort, eye irritation. Rare: keratitis, eye allergy, blurred vision, dry eyes, eye hyperemia. |
| Gastrointestinal disorders | Uncommon: dysgeusia. |
The following adverse reactions have been identified from post-marketing studies.
Based on the data presented, it is impossible to calculate the frequency of their occurrence.
Table 2
| Organ system classes | Adverse reactions [corresponding MedDRA term (v.15.1)] |
| Immune system disorders | Hypersensitivity, anaphylactic reaction |
| Nervous system disorders | Dizziness, headache |
| Visual impairment | Eyelid edema, eyelid erythema, mydriasis, lacrimation increased, ulcerative keratitis, blurred vision |
| Gastrointestinal disorders | Nausea, stomach discomfort |
| Skin and subcutaneous tissue disorders | Rash, facial edema, pruritus, erythema multiforme |
| Endocrine system disorders | Cushing's syndrome, adrenal suppression |
Description of some adverse reactions
Prolonged use of topical corticosteroids in the eye may lead to increased intraocular pressure with subsequent damage to the optic nerve, deterioration of visual acuity and visual field disturbances, as well as the formation of posterior subcapsular cataracts and delayed wound healing (see section "Special instructions").
Since the drug contains a corticosteroid, in the presence of diseases that lead to thinning of the cornea or sclera, the risk of perforation increases, especially after long-term use (see section "Special instructions for use").
Secondary infections may develop after the use of combinations containing corticosteroids and antimicrobials. Fungal infections of the cornea are particularly active with prolonged use of steroids (see section "Special instructions").
Patients receiving systemic therapy with tobramycin have experienced serious adverse reactions, including neurotoxicity, ototoxicity, and nephrotoxicity.
Some adverse reactions such as corneal abrasion, visual impairment, conjunctival edema, eyelid disorders, eye discharge, eyelid pruritus, urticaria, dermatitis, madarosis, leucoderma, and dry skin have been observed during tobramycin therapy.
Adverse reactions such as keratoconjunctivitis, corneal staining, photophobia, eyelid margin scaling, decreased visual acuity, corneal erosion, and eyelid ptosis have been observed during dexamethasone therapy.
Some patients may experience a hypersensitivity reaction to aminoglycosides when used topically (see section "Special warnings and precautions for use").
Expiration date
2 years. Shelf life after first opening the tube is 1 month.
Storage conditions
Store at a temperature not exceeding 25 °C.
Do not freeze.
Keep out of reach of children. Keep the tube tightly closed.
Packaging
3.5 g in a tube; 1 tube in a cardboard box.
Vacation category
According to the recipe.
Producer
Alcon-Couvreur/Alcon-Couvreur.
Location of the manufacturer and its business address
Rijksweg 14, B-2870 Puurs, Belgium/Rijksweg 14, B-2870 Puurs, Belgium.
