Instructions for Tobrinext Combi eye ointment tube 5 g
Composition
Active ingredients: tobramycin, dexamethasone;
1 g of ointment contains tobramycin sulfate, equivalent to tobramycin 3 mg, and dexamethasone 1 mg;
Excipients: methyl parahydroxybenzoate (E 218), propyl parahydroxybenzoate (E 216), liquid paraffin, white soft paraffin.
Dosage form
Eye ointment.
Main physicochemical properties
Ointment with a homogeneous consistency from white to pale yellow.
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 suppression 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 susceptibility or resistance of a bacterial culture to a particular antibiotic. The existing MIC breakpoints for tobramycin against the relevant bacterial species take into account the susceptibility of the species, as well as the maximum concentration and pharmacokinetic time/concentration values measured in serum after oral administration. Determination of these breakpoints, which divide microorganisms into susceptible and resistant, have been used to determine the clinical efficacy of antibiotics that are used systemically.
However, when the antibiotic is applied topically at high concentrations directly to the site of infection, no breakpoints have been established. Most organisms that would be classified as resistant by the breakpoints when applied systemically do indeed respond well to topical treatment. For the purpose of prevention, it is possible to stop the growth of the microorganisms that cause the infection.
In clinical studies, topical tobramycin solution was effective against many existing ocular pathogens in patients enrolled in the studies. Some of these ocular pathogens are considered resistant based on the determination of systemic breakpoints. Tobramycin has been shown to be effective in the treatment of superficial ocular infections caused by the following pathogens in clinical studies.
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 Streptococcus species.
* The beta-lactam (i.e., methicillin, penicillin) resistance phenotype is not associated with the aminoglycoside resistance phenotype and both are unrelated to 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 sensitive to tobramycin. Resistance to tobramycin has not yet developed in a significant part of the microflora, however, bacterial resistance may develop with 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 of tobramycin and dexamethasone eye ointment have not been conducted. However, data from a study conducted with eye drops containing tobramycin and dexamethasone indicate 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 a preparation containing tobramycin and dexamethasone into 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 tobramycin and dexamethasone ophthalmic ointment have not been conducted. However, studies with eye drops containing tobramycin and dexamethasone have shown that systemic exposure to tobramycin after topical ophthalmic administration is low.
Plasma tobramycin concentrations were not quantifiable in 9 of 12 patients who received one drop of the eye drops in each eye 4 times daily for 2 consecutive days. The highest measured level was 0.25 μg/mL, which is 8-fold lower than the concentration of 2 μg/mL, which is known to be below the risk of nephrotoxicity.
Tobramycin is actively and extensively excreted in the urine by glomerular filtration, mainly unchanged. The plasma half-life is about 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 (<10%). Oral bioavailability of tobramycin is low (<1%).
Preclinical safety data
The systemic toxicity of the active substances is well established. Systemic exposure to tobramycin at toxic doses significantly 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 of eye drops containing tobramycin and dexamethasone 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 using Tobrinext Combi in 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 in rats and rabbits using tobramycin at doses above 100 mg/kg/day by parenteral administration (more than 400 times the maximum clinical dose) have not revealed any cases of impaired fertility or harmful effects on the fetus.
Corticosteroids have been shown to be teratogenic in animal studies. Ocular application 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 dexamethasone for prolonged periods.
Tobrinext combi 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 the drug.
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 eye trauma.
Contraindication
Hypersensitivity to the active substances or components of the drug.
Keratitis caused by the herpes simplex virus.
Cowpox, chickenpox and other viral infections of the cornea and conjunctiva.
Fungal diseases of the eye structures or untreated parasitic infections of the eye.
Mycobacterial infections of the eye.
Untreated purulent eye infections.
Interaction with other medicinal products and other types of interactions
Concomitant use of topical steroids and topical 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 with toxic (harmful) effects on the nervous system, hearing, or kidneys may result in additive toxicity and should be avoided if possible.
Dexamethasone is metabolized by cytochrome P 450 3 A 4 (CYP 3 A 4) enzymes. CYP 3 A 4 inhibitors (including ritonavir and cobicistat) may decrease the clearance of dexamethasone, leading to increased drug effects and adrenal suppression/Cushing's syndrome. These combinations should be avoided unless the benefit outweighs the increased risk of systemic corticosteroid adverse reactions. In such cases, patients should be monitored for systemic corticosteroid effects.
If more than one ophthalmic agent is applied topically, the interval between applications should be at least 5 minutes. Eye ointments should be applied last.
Application features
For ophthalmic use only.
Some patients may be hypersensitive to topical aminoglycosides. The severity of hypersensitivity reactions may vary from local effects to generalized reactions such as erythema, pruritus, urticaria, skin rash, anaphylaxis, anaphylactoid reactions, or bullous reactions. If a hypersensitivity reaction occurs, the drug should be discontinued.
Cross-sensitivity to other aminoglycosides is possible. 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.
Prolonged treatment with topical ophthalmic corticosteroids may lead to ocular hypertension and/or glaucoma with optic nerve damage, decreased visual acuity and visual fields, and the formation of subcapsular cataracts in the posterior chamber of the eye. Patients receiving prolonged corticosteroid therapy should have their intraocular pressure monitored regularly and repeatedly. This is especially important in children, 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., diabetic patients).
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 ritonavir. In these cases, treatment should be discontinued gradually.
Corticosteroids may reduce resistance to bacterial, viral, fungal, or parasitic infections and may prevent the detection of such infections by masking the clinical signs of infection.
In cases of persistent corneal ulceration, the possibility of fungal infection should be considered. If fungal infection occurs, corticosteroid therapy should be discontinued.
Prolonged use of antibiotics such as tobramycin may result in overgrowth of non-susceptible organisms, including fungi. If superinfection occurs, appropriate therapy should be initiated.
Ophthalmic corticosteroids may slow the healing of corneal wounds. Topical nonsteroidal anti-inflammatory drugs are also known to slow or delay wound healing.
The simultaneous use of topical non-steroidal anti-inflammatory drugs and topical steroids may increase the risk of wound healing complications (see section "Interaction with other medicinal products and other types of interactions").
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 when treating eye inflammation or infection.
The medicine contains methyl parahydroxybenzoate (E 218) and propyl parahydroxybenzoate (E 216), which may cause allergic reactions (possibly delayed).
Use during pregnancy or breastfeeding
Studies to evaluate the effects of tobramycin and dexamethasone on human or animal reproductive function have not been conducted. Clinical data evaluating 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 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 application of dexamethasone and systemic application of dexamethasone and tobramycin.
The use of Tobrinext combi during pregnancy is not recommended.
Breastfeeding period
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 excreted 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 Combi.
Ability to influence reaction speed when driving vehicles or other mechanisms
Tobrinext Combi, eye 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 vision problems occur during use, the patient should wait until vision clears before driving or using machines.
Method of administration and doses
For ophthalmic use.
A small amount of ointment (a strip approximately 1.5 cm long) should be applied to 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 the use of eye drops containing tobramycin and dexamethasone 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 eyes, which reduces the likelihood of systemic side effects.
It is recommended to constantly monitor intraocular pressure.
Application for children
The data obtained confirm the safety and effectiveness of the drug in children aged 2 years and older.
It can be used in children who need cataract surgery.
Use in liver and kidney dysfunction
Tobramycin Combi 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.
Overdose
Given the characteristics of this drug, intended for topical use, no toxic effect is expected either when used in ophthalmology at recommended doses or when the contents of the tube are accidentally swallowed. In case of overdose with Tobrin EXT Combi for topical use, wash the excess drug from the eye with warm water.
Possible clinical signs and symptoms of drug overdose (capsular keratitis, erythema, increased lacrimation, eyelid edema and itching) may be similar to the side effects observed in some patients.
Adverse reactions
In clinical studies with tobramycin and dexamethasone eye ointment, the following adverse reactions were reported and are ranked according to the following frequency: very common (≥ 1/10); common (≥ 1/100 - < 1/10); uncommon (≥ 1/1000 - < 1/100); rare (≥ 10,000 - < 1/1000); rare (< 1/10,000). Within each grouping, adverse reactions are presented in order of decreasing seriousness.
System Organ Classes / Adverse Reactions (MedDRA (v.15.1) corresponding term):
On the part of the organs of vision / 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 experience.
It is impossible to calculate the frequency of their occurrence from the data presented.
System Organ Classes/Adverse Reactions (MedDRA (v.15.1) corresponding term):
Immune system disorders/Hypersensitivity, anaphylactic reaction
Nervous system / Dizziness, headache
Eye disorders/ Eyelid swelling, eyelid erythema, mydriasis, lacrimation increased, ulcerative keratitis
Gastrointestinal / Nausea, stomach discomfort
Skin and subcutaneous tissue disorders / Rash, facial edema, pruritus, erythema multiforme
Description of some adverse reactions
Prolonged use of topical corticosteroids in the eyes may lead to increased intraocular pressure with subsequent damage to the optic nerve, deterioration of visual acuity and visual impairment, as well as the formation of posterior subcapsular cataracts and delayed wound healing (see section "Special instructions").
Since the drug contains a corticosteroid, the risk of perforation is increased in the presence of diseases that lead to thinning of the cornea or sclera, especially after prolonged use (see section "Special instructions").
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, eyelid pruritus, urticaria, dermatitis, madarosis, leukoderma, 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
3 years.
After first opening, store for 28 days at a temperature not exceeding 25°C.
Storage conditions
Store in the original packaging in a place protected from light at a temperature not exceeding 25 ° C. Keep out of the reach of children.
Packaging
5 g of ointment in an aluminum foil tube with a cannula and a plastic screw cap; 1 tube in a cardboard box.
Vacation category
According to the recipe.
