TobraDex

TobraDex

tobramycin + dexamethasone

Manufacturer:

Novartis

Distributor:

Zuellig
/
Firma Chun Cheong
Full Prescribing Info
Contents
Tobramycin, dexamethasone.
Description
Ophthalmic suspension: 1 ml suspension contains 3 mg tobramycin and 1 mg dexamethasone.
Preservative: 1 ml suspension contains 0.1 mg benzalkonium chloride.
Ophthalmic ointment: 1 g ointment contains 3 mg tobramycin and 1 mg dexamethasone.
Excipients/Inactive Ingredients: Ophthalmic suspension: Benzalkonium Chloride, Tyloxapol, Disodium Edetate, Sodium Chloride, Hydroxyethylcellulose, Sodium sulphate anhydrous, Sulphuric Acid and/or Sodium Hydroxide (to adjust pH), Purified water.
Ophthalmic ointment: Chlorobutanol anhydrous, Mineral Oil, White Petrolatum.
Action
Pharmacotherapeutic group: corticosteroids and anti-infectives in combination. ATC code: S 01 CA 01.
Pharmacology: Pharmacodynamics: Mode of Action: The preparation contains tobramycin, a rapidly bactericidal aminoglycoside antibiotic. It exerts its primary effect on bacterial cells by inhibiting polypeptide assembly and synthesis on the ribosome.
Mechanism of resistance: Resistance to tobramycin occurs by several different mechanisms including (1) alterations of the ribosomal subunit within the bacterial cell; (2) interference with the transport of tobramycin into the cell, and (3) inactivation of tobramycin by an array of adenylylating, phosphorylating, and acetylating enzymes. Genetic information for production of inactivating enzymes may be carried on the bacterial chromosome or on plasmids. Cross resistance to other aminoglycosides may occur.
Breakpoints: The breakpoints and the in vitro spectrum as mentioned below are based on systemic use. These breakpoints might not be applicable on topical ocular use of the medicinal product as higher concentrations are obtained locally and the local physical/chemical circumstances can influence the activity of the product on the site of administration. In accordance with EUCAST, the following breakpoints are defined for tobramycin: Enterobacteriaceae S ≤ 2 mg/l, R > 4 mg/l; Pseudomonas spp. S ≤ 4 mg/l, R > 4 mg/l; Staphylococcus spp. S ≤ 1 mg/l, R > 1 mg/l; Not species-related S ≤ 2 mg/l, R > 4 mg/l.
PK/PD relationship: A specific PK/PD relationship has not been established for TOBRADEX. Dexamethasone has demonstrated dose-independent pharmacokinetics in published animal studies.
Published in vitro and in vivo studies have shown that tobramycin features a prolonged postantibiotic effect, which effectively suppresses bacterial growth despite low serum concentrations. Systemic administration studies of tobramycin have reported higher maximum concentrations with once daily compared to multiple daily dosing regimens. However, the weight of current evidence suggests that once daily systemic dosing is equally as efficacious as multiple-daily dosing. Tobramycin exhibits a concentration-dependent antimicrobial kill and greater efficacy with increasing levels of antibiotic above the MIC or minimum bactericidal concentration (MBC).
Clinical efficacy against specific pathogens: The information listed as follow gives only an approximate guidance on probabilities whether microorganisms will be susceptible to tobramycin in this medicine. Bacterial species that have been recovered from external infections of the eye such as observed in conjunctivitis are presented here.
The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of tobramycin in at least some types of infections is questionable.
COMMONLY SUSCEPTIBLE SPECIES: Aerobic Gram-positive microorganisms: Corynebacterium species, Staphylococcus aureus (methicillin susceptible).
Aerobic Gram-negative microorganisms: Enterobacter cloacae, Klebsiella oxytoca, Moraxella catarrhalis, Neisseria meningitidis, Pseudomonas aeruginosa, Serratia marescens.
Antibacterial activity against other relevant pathogens: SPECIES FOR WHICH ACQUIRED RESISTANCE MIGHT BE A PROBLEM: Aerobic Gram-positive microorganisms: Corynebacterium diphtheriae, Staphylococcus aureus (methicillin resistant), Staphylococcus, other coagulase-negative spp. (methicillin resistant).
Aerobic Gram-negative microorganisms: Neisseria gonorrhoeae.
INHERENTLY RESISTANT ORGANISMS: Aerobic Gram-positive microorganisms: Streptococcus pneumoniae, Streptococcus pyogenes.
Aerobic Gram-negative microorganisms: Haemophilus influenzae.
Anaerobic Bacteria: Propionibacterium acnes.
Other: Chlamydia trachomatis.
Dexamethasone is a moderately powerful corticosteroid, which has a good penetration in the ocular tissue. Corticosteroids have an anti-inflammatory as well as a vasoconstrictive effect. They suppress the inflammatory response and symptoms in various disorders without basically curing these disorders.
Data from clinical studies: Cumulative safety data from clinical studies are presented in Adverse Reactions.
Paediatric population: The safety and efficacy of TOBRADEX eye drops and eye ointment in children have been established by broad clinical experience, but only limited data are available. In a clinical study of TOBRADEX suspension for the treatment of bacterial conjunctivitis, 29 paediatric patients, ranging in age from 1 to 17 years, were treated with 1 or 2 drops of TOBRADEX every 4 or 6 hours for 5 or 7 days. In this study, differences in the safety profile between adult and paediatric patients were not observed. See Dosage & Administration and Precautions for more information on paediatric use.
Pharmacokinetics: Dexamethasone: The studies conducted with TOBRADEX eye drops, suspension have demonstrated that the systemic exposure to dexamethasone is low after topical eye use. The maximum plasma concentrations ranged between 220-888 pg/ml (medium values 555 ± 217 pg/ml) after the instillation of one drop of TOBRADEX in each eye, 4 times a day, for two consecutive days.
Dexamethasone is eliminated through the metabolism. Approximate 60% of the dose is recovered in urine as 6-β-hydroxydexamethasone. Unmodified dexamethasone is not recovered in urine. The plasma half-life through elimination is relatively short, 3-4 hours. Dexamethasone binds to the serum albumin approximately 77-84%. The clearance varies from 0.111 to 0.225 l/hour and kg, and the distribution volume varies from 0.576 to 1.15 l/kg. The oral bioavailability of dexamethasone is approximately 70%.
Tobramycin: The studies conducted on TOBRADEX eye drops, suspension have shown that the systemic exposure to tobramycin is low after topical ocular use. The plasma concentrations of tobramycin could not be determined in 9 of 12 patients to whom one drop of TOBRADEX has been administered, 4 times a day, for two consecutive days. The highest plasma concentration that could be measured was 0.25 μg/ml, a value that is 8 times smaller than the 2 μg/ml concentration known to be under the threshold associated with the risk of nephrotoxicity.
Tobramycin is rapidly excreted in large quantities in the urine through glomerular filtration, mainly unmodified. The plasma half-life is approx. 2 hours, with a 0.04 l/hour and kg clearance and a distribution volume of 0.26 l/kg. Binding of tobramycin to plasma albumin is low, less than 10%. The oral bioavailability is low (<1%).
Toxicology: Preclinical safety data: Effects in conventional non-clinical studies of repeated dose toxicity were observed only at exposures considered sufficiently in excess of the maximum human exposure after topical application, indicating little relevance to clinical use.
Non-clinical data reveal no special hazard for humans based on conventional studies of genotoxicity. No studies have been conducted to evaluate the carcinogenic potential of dexamethasone.
Tobramycin crosses the placenta into the foetal circulation and amniotic fluid. Animal studies with maternal systemic administration of high doses of tobramycin during organogenesis have been reported to result in renal toxicity in foetuses. Other studies performed in rats and rabbits with tobramycin at doses up to 100 mg/kg/day parenterally (> 400-times the maximum clinical dose) revealed no evidence of harm to the foetus.
Corticosteroids have been found to be teratogenic in animal studies. Ocular administration of a 0.1% dexamethasone preparation to pregnant rabbits resulted in increased incidences of foetal anomalies. Foetal growth retardation and increased mortality rates have been observed in rats with chronic dexamethasone therapy.
Indications/Uses
For ocular steroid-responsive inflammatory conditions for which a corticosteroid is indicated and where bacterial ocular infection, or a risk of bacterial ocular infection, exists, due to tobramycin-responsive microorganisms resistant to most of the other antibiotics, especially Pseudomonas aeruginosa, in adults and children aged 2 years and older. See Pharmacology: Pharmacodynamics under Actions.
Ocular steroids are indicated in inflammatory conditions of the palpebral and bulbar conjunctiva, cornea and anterior segment of the eye where the inherent risk of steroid use in certain infective conjunctivitis is accepted to obtain a decrease in oedema and inflammation. They are also indicated in chronic anterior uveitis and corneal injury from chemical agents, radiation, thermal burns, or penetration of foreign bodies (considering the contraindications).
Corticosteroids in eye drops or eye ointment should be prescribed only after ocular examination.
Please consider the official recommendations regarding the adequate use of antibiotics.
Dosage/Direction for Use
Ophthalmic suspension: Posology: Instil 1 to 2 drops into the conjunctival sac every 4 hours. During the initial 24 to 48 hours the dosage may be increased to 1 or 2 drops every 2 hours. In severe disease, instil 1 or 2 drops every hour until inflammation is controlled, and gradually decrease frequency to 1 to 2 drops every 2 hours during 3 days, and thereafter 1 to 2 drops every 4 hours during 5 to 8 days, and finally 1 to 2 drops every day during the last 5 to 8 days, if necessary.
Care should be taken not to discontinue therapy prematurely.
Gently closing the eyelid and nasolacrimal occlusion after instillation is recommended. This may reduce the systemic absorption of medicinal products administered via the ocular route and result in a decrease in systemic side effects.
In case of concomitant therapy with other topical ocular medicinal products, an interval of 5 minutes should be allowed between successive applications. Eye ointments should be administered last (see Interactions).
Paediatric population: TOBRADEX eye drops, suspension may be used in children 2 years of age and older at the same dose as in adults. Currently available data is described in Pharmacology: Pharmacodynamics under Actions. The safety and efficacy in children younger than 2 years of age have not been established, and no data are available.
Method of administration: To prevent contamination of the dropper tip and suspension, care must be taken not to touch the eyelids, surrounding areas, or other surfaces with the dropper tip. Keep the bottle tightly closed when not in use.
After cap is removed, if tamper evident snap collar is loose, remove before using product.
Ophthalmic ointment: Posology: Apply a small amount (1 to 1.5 cm) into the conjunctival sac up to 3 or 4 times daily, or use adjunctively with the eye drops during the day and the eye ointment at bedtime.
Gently closing the eyelid and nasolacrimal occlusion after instillation is recommended. This may reduce the systemic absorption of medicinal products administered via the ocular route and result in a decrease in systemic side effects.
In case of concomitant therapy with other topical ocular medicinal products, an interval of 5 minutes should be allowed between successive applications. Eye ointments should be administered last (see Interactions).
Paediatric population: TOBRADEX eye ointment may be used in children 2 years of age and older at the same dose as in adults. Currently available data is described in Pharmacology: Pharmacodynamics under Actions. The safety and efficacy in children younger than 2 years of age have not been established, and no data are available.
Method of administration: For ocular use.
To prevent contamination of the tube tip and ointment, care must be taken not to touch the eyelids, surrounding areas, or other surfaces with the tube tip. Keep the tube tightly closed when not in use.
1. Tilt the head back.
2. Place a finger on the cheek just below the eye and gently pull down until a "V" pocket is formed between the eye and the lower eyelid.
3. Place a small amount (1 to 1.5 cm) of TOBRADEX eye ointment in the "V" pocket. Do not let the tip of the tube touch the eye.
4. Look downward for a few moments before closing the eye.
Overdosage
A topical overdose is not likely to occur or to be associated with toxicity.
A topical overdose of TOBRADEX can be flushed from the eye(s) with lukewarm water.
Due to the characteristics of this preparation, no toxic effects are to be expected with an ocular overdose of this product, or in the event of accidental ingestion of the contents of one bottle or tube. Treatment of an accidental ingestion is symptomatic and supportive.
Contraindications
Hypersensitivity to the active substances or to any of the excipients.
Hypersensitivity to aminoglycosides.
Herpes simplex keratitis.
Vaccinia, varicella, and other viral infection of cornea or conjunctiva (except herpes zoster keratitis).
Fungal diseases of ocular structures or untreated parasitic eye infections.
Mycobacterial ocular infections.
Infections or injuries limited to the superficial corneal epithelium.
TOBRADEX should not be used following an uncomplicated removal of a foreign body from the cornea.
Special Precautions
For ocular use only. Not for injection or ingestion.
For TOBRADEX 3 mg/ml + 1 mg/ml eye drops, suspension, after cap is removed, if tamper evident snap collar is loose, remove before using product.
The initial prescription and renewal thereof should be made only after examination of the patient with the aid of magnification such as slit-lamp biomicroscopy and, if necessary, fluorescein staining.
Sensitivity to topically administered aminoglycosides may occur in some patients. Severity of hypersensitivity reactions may vary from local effects to generalized reactions such as erythema, itching, urticarial, skin rash, anaphylaxis, anaphylactoid reactions, or bullous reactions. If hypersensitivity develops during use of this medicine, treatment should be discontinued.
Cross-hypersensitivity to other aminoglycosides can occur, and the possibility that patients who became sensitized to topical tobramycin may also be sensitive to other topical and/or systemic aminoglycosides should be considered.
Serious adverse reactions including neurotoxicity, ototoxicity and nephrotoxicity have occurred in patients receiving systemic aminoglycoside therapy. Caution is advised when TOBRADEX is used concomitantly with systemic aminoglycosides (see Adverse Reactions).
Caution should be exercised when prescribing TOBRADEX to patients with known or suspected neuromuscular disorders such as myasthenia gravis or Parkinson's disease. Aminoglycosides may aggravate muscle weakness because of their potential effect on neuromuscular function.
Excessive and/or prolonged use of topical ophthalmic corticosteroids increases the risk of ocular complications and could cause systemic side effects. If the inflammatory condition does not improve within a reasonable period during the course of the therapy, other forms of therapy should be instituted to reduce these risks.
Topical application of corticosteroids may be accompanied by a decrease in the urinary secretion of cortisol as well as a decrease in plasma cortisol concentration. Corticosteroids have been associated with hypothalamic-pituitary-adrenal (HPA) axis suppression, Cushing's Syndrome, and a decreased rate of growth in children, especially with high-dose or long-term treatment.
Prolonged use of ophthalmic corticosteroids may result in ocular hypertension and/or glaucoma, with damage to the optic nerve, reduced visual acuity and visual field defects, and posterior subcapsular cataract formation. In patients receiving ophthalmic corticosteroid therapy for 10 days or longer, intraocular pressure should be checked routinely and frequently, even though it may be difficult in children and uncooperative patients. This is especially important in paediatric patients, as the risk of corticosteroid-induced ocular hypertension may be greater in children and may occur earlier than in adults. Patients with a family or personal history of glaucoma have a higher risk of a corticosteroid-induced rise in intraocular pressure. Patients with glaucoma should be monitored weekly.
Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical corticosteroids.
Cushing's syndrome and/or adrenal suppression associated with systemic absorption of ocular dexamethasone may occur after intensive or long-term continuous therapy in predisposed patients, including children and patients treated with CYP3A4 inhibitors (including ritonavir and cobicistat). In these cases, treatment should be progressively discontinued.
Prolonged use of corticosteroids may also reduce resistance to and aid in the establishment of bacterial, viral, fungal or parasitic infections and mask the clinical signs of infection, preventing recognition of ineffectiveness of the antibiotic. TOBRADEX should therefore only be used in acute purulent infections of the eye when treatment with a steroid/anti-infective combination product is medically necessary. Fungal infection should be suspected in patients with persistent corneal ulceration. If fungal infection occurs, corticosteroids therapy should be discontinued.
The use of antibiotics such as tobramycin may also result in overgrowth of non-susceptible organisms, including fungi. If superinfection occurs, appropriate therapy should be initiated.
Ocular herpes simplex has occurred in patients under systemic or local corticosteroid therapy for other conditions. Using corticosteroid medication in the treatment of herpes simplex other than epithelial herpes simplex keratitis, in which it is contraindicated, requires great caution; periodic slit-lamp microscopy is essential.
In those diseases causing thinning of the cornea or sclera, perforations have been known to occur with the use of topical corticosteroids.
Topical ophthalmic corticosteroids may slow corneal wound healing. Topical NSAIDs are also known to slow or delay healing. Concomitant use of topical NSAIDs and topical steroids may increase the potential for healing problems. (See Interactions.)
Treatment should not be discontinued prematurely as a flare-up of the infectious or inflammatory condition may occur with the sudden interruption of a treatment with antibiotics or high doses of corticosteroids, respectively.
The risk of corticosteroid-induced raised intraocular pressure and/or cataract formation is increased in predisposed patients (e.g. diabetes).
Contact lens wear is not recommended during treatment of an ocular infection or inflammation.
TOBRADEX eye drops: This medicine contains 0.1 mg benzalkonium chloride in each ml, which is equivalent to 0.5 mg per 5 ml. Benzalkonium chloride may be absorbed by soft contact lenses and may change the colour of the contact lenses. Patients should be advised to remove contact lenses before using this medicine and to put them back 15 minutes afterwards. Benzalkonium chloride may also cause eye irritation, especially if the patient has dry eyes or disorders of the cornea.
After application of the eye drops following measures are useful to reduce systemic resorption: Keep the eyelid closed for 2 minutes; Close the lachrymal duct with the finger for 2 minutes.
Effects on ability to drive and use machines: TOBRADEX has no or negligible influence on the ability to drive and use machines. However, temporary blurred vision or other visual disturbances may affect the ability to drive or use machines. If blurred vision occurs at application, the patient must wait until the vision clears before driving or using machines.
Use in Children: It is advisable that the intraocular pressure be checked frequently. This is especially important in paediatric patients receiving dexamethasone-containing products, as the risk of steroid-induced ocular hypertension may be greater in children below 6 years of age and may occur earlier than a steroid response in adults. The frequency and duration of treatment should be carefully considered, and the IOP should be monitored from the outset of treatment, recognizing the risk for earlier and greater steroid-induced IOP increases in the paediatric patients.
Use In Pregnancy & Lactation
Fertility: Studies have not been conducted to evaluate the effect of tobramycin on human or animal fertility. There is limited clinical data to evaluate the effect of dexamethasone on male or female fertility. Dexamethasone was free of adverse effects on fertility in a chorionic gonadotropin primed rat model.
Pregnancy: There are no or limited amount of data from the topical ocular use of tobramycin and dexamethasone in pregnant women. Tobramycin does cross the placenta into the fetus after intravenous dosing in pregnant women. Tobramycin is not expected to cause ototoxicity from in utero exposure. Prolonged or repeated corticoid use during pregnancy has been associated with an increased risk of intra-uterine growth retardation. Infants born of mothers who have received substantial doses of corticosteroids during pregnancy should be observed carefully for signs of hypoadrenalism. Studies in animals have shown reproductive toxicity after topical administration of dexamethasone and after systemic administration of dexamethasone and tobramycin (see Pharmacology: Toxicology: Preclinical safety data under Actions).
TOBRADEX is not recommended during pregnancy.
Breastfeeding: Tobramycin is excreted in human milk after systemic administration. No data is available on the passage of dexamethasone into human breast milk. It is unknown whether tobramycin and dexamethasone are excreted in human milk following topical ocular administration. It is not likely that the amount of Tobramycin and Dexamethasone would be detectable in human milk or be capable of producing clinical effects in the infant following topical use of the product.
A risk to the suckling 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.
Adverse Reactions
Summary of the safety profile: No serious ophthalmic adverse events related to TOBRADEX were reported in clinical studies. The most frequently reported treatment-related adverse reactions were eye pain, intraocular pressure increased, eye irritation, and eye pruritus occurring in less than 1% of patients.
Tabulated summary of adverse reactions: The following adverse reactions are classified according to the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), or not known (cannot be estimated from the available data). Within each frequency-grouping, adverse reactions are presented in order of decreasing seriousness. The adverse reactions have been observed during clinical trials and post-marketing experience with TOBRADEX. (See Table 1.)

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Description of selected adverse reactions: Topical ophthalmic corticosteroid use may result in increased intraocular pressure with damage to the optic nerve, reduced visual acuity and visual field defect, and posterior subcapsular cataract formation (see Precautions).
Due to the steroid component, in diseases causing thinning of the cornea or sclera there is a higher risk for perforation especially after longer treatment (see Precautions).
The development of secondary infection has occurred after use of combinations containing steroids and antimicrobials. Fungal infections of the cornea are particularly prone to develop coincidentally with long term applications of steroids. The possibility of fungal invasion must be considered in any persistent corneal ulceration where steroid treatment has been used. Secondary ocular infection following suppression of host responses also occurs. (See Precautions.)
When administered systemically, tobramycin may induce renal, vestibular and auditory nerve toxicity, especially in patients receiving high doses or prolonged treatment. Doses recommended for ocular administration are significantly lower than those used systemically, and these systemic effects are extremely unlikely with TOBRADEX (see Precautions).
Sensitivity to topically administered aminoglycosides may occur in some patients (see Precautions).
Undesirable effects have occurred with steroid/antibiotic combination drugs which can usually be attributed to either the steroid component or the antibiotic component. The following adverse effects have been reported following use of topical ophthalmic dexamethasone or tobramycin. (See Table 2.)

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Reporting of suspected adverse reactions: Reporting of suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.
Drug Interactions
No interaction studies have been performed.
Interactions have been reported with systemic administration of the individual components. Concomitant use of topical steroids and topical NSAIDs may increase the potential for corneal healing Nevertheless, systemic absorption of ophthalmic tobramycin and dexamethasone is low and the chance of any interaction is minimal.
When using pupil-dilating eye drops (atropine and other anticholinergic substances), which may cause elevation of intraocular pressure, concomitant use of TOBRADEX may lead to an additional elevation of intraocular pressure.
In patients treated with ritonavir or other strong CYP3A4 inhibitors, plasma concentrations of dexamethasone may be increased (see Precautions).
CYP3A4 inhibitors (including ritonavir and cobicistat): may decrease dexamethasone clearance resulting in increased effects and adrenal suppression/Cushing's syndrome. The 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 effects.
If more than one eye preparation is being used, the products must be administered at least 5 minutes apart. Eye ointments should be administered last.
Caution For Usage
Special precautions for disposal and other handling: No special requirements.
Incompatibilities: No specific incompatibility studies with TOBRADEX have been undertaken.
ATC Classification
S01CA01 - dexamethasone and antiinfectives ; Belongs to the class of corticosteroids in combination with antiinfectives. Used in the treatment of eye diseases.
Presentation/Packing
Ophth susp (white to off-white suspension) 5 mL. Ophth oint (white to off-white, homogeneous ointment) 3.5 g.
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