Tobrinext combi
Ukraine
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INSTRUCTION for medical use of the medicinal product Tobrinext combi (Tobrinext combi) Composition: Active substances: tobramycin, dexamethasone; 1 g of ointment contains tobramycin sulfate equivalent to 3 mg of tobramycin and 1 mg of dexamethasone; Excipients: methylparahydroxybenzoate (E 218), propylparahydroxybenzoate (E 216), liquid paraffin, white soft paraffin. Pharmaceutical form. Ophthalmic ointment. Main physicochemical properties: ointment of uniform consistency, from white to pale yellow in colour. 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 ocular inflammatory conditions 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 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 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 minimal 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 whether a bacterial culture is sensitive or resistant to a given antibiotic. The current critical MIC values for tobramycin against relevant bacterial species take into account inherent species sensitivity as well as maximum concentration and pharmacokinetic time/concentration dependency measured in serum after oral administration. These critical values, which classify microorganisms as sensitive or resistant, have been used to determine clinical efficacy of systemically administered antibiotics. However, when antibiotics are applied locally at high concentrations directly at the site of infection, critical value determinations have not been performed. Most microorganisms that might be classified as resistant based on systemic application critical values are actually sensitive to local treatment. There is a possibility of preventing the development of such infection-causing microorganisms. In clinical studies, locally applied tobramycin solution proved effective against many existing strains of ocular pathogens in study participants. Some of these ocular pathogens are considered resistant based on critical values for systemic administration. Clinical studies 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. * The beta-lactam resistance phenotype (i.e., methicillin, penicillin) is not related to the 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 (as defined by MIC critical values) 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 . 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, although bacterial resistance may develop during prolonged use. Cross-sensitivity to other aminoglycoside antibiotics is possible. If hypersensitivity occurs during use of the medicinal product, treatment should be discontinued and appropriate therapy initiated. Pharmacokinetics. Dexamethasone Clinical pharmacokinetic studies of the ophthalmic ointment containing tobramycin and dexamethasone have not been conducted. However, data from studies with eye drops containing tobramycin and dexamethasone show that systemic exposure to dexamethasone after local ophthalmic administration is low. Peak plasma concentration levels range from 220 to 888 pg/mL (average 555 ± 217 pg/mL) after instilling one drop of the preparation containing tobramycin and dexamethasone into 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 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 Clinical pharmacokinetic studies of the ophthalmic ointment containing tobramycin and dexamethasone have not been conducted. However, studies with eye drops containing tobramycin and dexamethasone showed that systemic exposure to tobramycin after local ophthalmic administration is low. Plasma concentrations of tobramycin were below quantifiable levels in 9 out of 12 patients who used 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 actively and extensively 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/h/kg and 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 Systemic toxicity data for the active substances are well established. Systemic exposure to tobramycin at toxic doses, much higher than the dose used in local ocular application, may be associated with nephrotoxicity and ototoxicity. Systemic exposure to dexamethasone may be associated with effects related to glucocorticoid imbalance. Repeated-dose toxicity studies in rabbits with eye drops containing tobramycin and dexamethasone revealed systemic corticosteroid-related effects, but even at doses significantly exceeding the human dose, this manifestation has minimal clinical relevance. When Tobrinext combi is used at recommended doses, the occurrence of these effects is unlikely. Mutagenicity Studies in vitro and in vivo did not reveal mutagenic effects of either active substance. 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 (more than 400 times the maximum clinical dose) showed no impairment of fertility or adverse effects on the fetus. In animal studies, corticosteroids showed teratogenic effects. Ocular application of 0.1% dexamethasone to pregnant rabbits led to increased fetal developmental abnormalities and intrauterine growth retardation. Growth retardation and increased mortality were observed in rats with 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 the drug. Clinical characteristics. Indications. Ocular inflammation in patients sensitive to steroids where corticosteroid use is indicated and there is either existing superficial bacterial infection or risk of developing bacterial ocular infection. These inflammatory conditions may occur after surgical intervention (cataract removal) or may be caused by infection, foreign body penetration, or ocular trauma. Contraindications.
The medicinal product should not be used after uncomplicated removal of a foreign body from the cornea. Interaction with other medicinal products and other forms of interaction. Concurrent use of locally applied steroids and non-steroidal anti-inflammatory drugs (NSAIDs) for local application increases the risk of corneal wound healing complications. Concomitant and/or sequential use of aminoglycoside antibiotics (such as tobramycin) and other systemic oral medicinal products 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, plasma concentrations of dexamethasone may increase (see section "Special precautions"). CYP3A4 inhibitors (including ritonavir and cobicistat) may reduce dexamethasone clearance, leading to increased drug effects and adrenal suppression / Cushing's syndrome. This combination should be avoided unless the benefit outweighs the increased risk of systemic corticosteroid side effects. In such cases, monitoring for systemic corticosteroid effects is recommended. 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. Special precautions. 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 medicinal product should be discontinued. Cross-hypersensitivity to other aminoglycosides is possible. Consideration should be given to 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. 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 posterior subcapsular cataract formation. Patients receiving long-term ocular corticosteroid therapy require regular and repeated monitoring of intraocular pressure. This is particularly important for 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). 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 such cases, treatment should be tapered off gradually. Corticosteroids may reduce resistance to bacterial, viral, fungal, or parasitic infections and may mask clinical signs of such infections. In 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. Appropriate therapy should be initiated if superinfection occurs. Ophthalmic corticosteroids may delay corneal wound healing. NSAIDs for topical use are also known to slow or delay wound healing. Concurrent use of topical NSAIDs and topical steroids increases the risk of wound healing complications (see section "Interaction with other medicinal products and other forms of interaction"). In conditions leading to thinning of the cornea or sclera, local steroid application may cause perforation. Wearing contact lenses is not recommended during treatment of ocular inflammation or infection. The medicinal product contains methylparahydroxybenzoate (E 218) and propylparahydroxybenzoate (E 216), which may cause allergic reactions (possibly delayed). Use during pregnancy or breastfeeding. Reproductive function Studies evaluating 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 treated with dexamethasone. 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 placental barrier. In utero exposure to tobramycin does not cause ototoxicity. Prolonged or repeated use of corticosteroids during pregnancy is associated with an increased risk of intrauterine growth retardation. Signs of hypoadrenalism should be carefully monitored in infants whose mothers received high doses of corticosteroids during pregnancy. Animal studies demonstrated reproductive toxicity after topical dexamethasone and systemic dexamethasone and tobramycin administration. Use of Tobrinext combi during pregnancy is not recommended. Breastfeeding period After systemic administration, tobramycin passes into breast milk. Data on dexamethasone passage into breast milk are lacking. It is unknown whether tobramycin and dexamethasone pass into breast milk after local ophthalmic administration. It is unlikely that tobramycin and dexamethasone will be present in breast milk or cause clinical effects in newborns after local application of the medicinal product. 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 pass into breast milk, consider the possibility of temporarily discontinuing breastfeeding during treatment with Tobrinext combi. Ability to affect reaction speed when driving or operating machinery. Tobrinext combi, ophthalmic ointment, has no effect or has a 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 during use, the patient should wait until vision clears before driving or operating machinery. Method and dosage. For ophthalmic use. A small amount of ointment (a strip approximately 1.5 cm long) should be instilled into the conjunctival sac (sacs) of the affected eye(s) up to 3 or 4 times daily. The frequency of administration should be gradually reduced as clinical signs improve. Care should be taken not to discontinue therapy prematurely. The ophthalmic ointment may be used at night in combination with eye drops containing tobramycin and dexamethasone during the day. After ointment application, gently closing the eyelids is recommended. This reduces systemic absorption of the drug administered into the eye, thereby decreasing the likelihood of systemic adverse effects. Regular monitoring of intraocular pressure is recommended. Use in children Available data confirm the safety and efficacy of the medicinal product in children aged 2 years and older. May be used in children requiring surgical cataract removal. 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 local application, dose adjustment is not necessary. Method of application To prevent contamination of the tube tip and contents, care should be taken not to touch eyelids, adjacent areas, or other surfaces with the tube tip. Keep the tube tightly closed. How to apply the ointment
Children. Safety and efficacy in children under 2 years of age have not been established. Available data confirm the safety and efficacy of the medicinal product in children aged 2 years and older. 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 tube contents. In case of overdose of Tobrinext combi with topical application, wash out excess ointment from the eye(s) with warm water. Probable clinical signs and symptoms of overdose (punctate keratitis, erythema, increased lacrimation, eyelid swelling and itching) may resemble adverse effects observed in some patients. Adverse reactions. In clinical studies, the most common adverse reactions were eye pain, increased intraocular pressure, eye irritation, and eye itching, occurring in less than 1% of patients. Listed below are adverse reactions from clinical studies with ophthalmic ointment containing tobramycin and dexamethasone. Frequency is categorized as follows: very common (≥ 1/10); common (≥ 1/100 — < 1/10); uncommon (≥ 1/1,000 — < 1/100); rare (≥ 1/10,000 — < 1/1,000); very rare (< 1/10,000). Within each frequency 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 local ocular use of corticosteroids may lead to increased 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 "Special precautions for use"). Since the medicinal product contains a corticosteroid, there is an increased risk of perforation in patients with diseases causing thinning of the cornea or sclera, especially after prolonged use (see section "Special precautions for use"). Secondary infections may develop following the use of corticosteroid-antimicrobial combinations. Fungal infections of the cornea may particularly develop during prolonged steroid use (see section "Special precautions for use"). Serious adverse reactions including neurotoxicity, ototoxicity, and nephrotoxicity have occurred in patients receiving systemic therapy with tobramycin. 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, scaling of the eyelid margins, decreased visual acuity, corneal erosion, and eyelid ptosis have been observed during dexamethasone therapy. Hypersensitivity reactions to aminoglycosides may occur with topical application in some patients (see section "Special precautions for use"). Reporting suspected adverse reactions Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua. Shelf life. 3 years. After first opening, store for up to 28 days at a temperature not exceeding 25 °C. Storage conditions. Store in the original packaging, protected from light, at a temperature not exceeding 25 °C. Keep out of reach of children. Packaging. 5 g of ointment in an aluminum foil tube with a nozzle and a screw plastic cap; 1 tube per cardboard box. Prescription status. Prescription only. Manufacturer. BALKANPHARMA-RAZGRAD AD / BALKANPHARMA-RAZGRAD AD. Manufacturer's address and place of business. 68 Aprilsko vastanie Blvd., Razgrad 7200, Bulgaria / 68 Aprilsko vastanie Blvd., Razgrad 7200, Bulgaria. |