Tobrex

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TOBREX® (TOBREX®)

Composition:

Active ingredient: 1 ml of solution contains 3 mg of tobramycin;

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

Pharmaceutical form. Eye drops.

Main physicochemical properties: clear solution ranging from colorless to pale yellow or brown.

Pharmacotherapeutic group.
Ophthalmological agents. Antimicrobial agents. Antibiotics.
ATC code S01A A12.

Pharmacological properties.

Pharmacodynamics.

Tobramycin is a rapidly-acting bactericidal antibiotic of the aminoglycoside group. Its primary action targets bacterial cells and consists in the inhibition of polypeptide complex formation and protein synthesis in ribosomes.

Resistance to tobramycin arises through several different mechanisms, including alterations in ribosomal subunits within the bacterial cell, impaired transport of tobramycin into the cell, and inactivation of tobramycin by a group of adenylating, phosphorylating, and acetylating enzymes. Genetic information responsible for the production of inactivating enzymes can be transferred via bacterial chromosomes or plasmids. Cross-resistance to other aminoglycosides may occur.

The in vitro breakpoints and spectrum of activity listed below are based on systemic administration. These values may not be applicable when the medicinal product is applied topically to the eye, as higher concentrations are achieved with local application and local physical/chemical conditions may influence the drug's activity at the site of administration. According to the European Committee on Antimicrobial Susceptibility Testing (EUCAST), the following breakpoints have been established for tobramycin:

Enterobacteriaceae S ≤ 2 mg/L, R > 4 mg/L,
Pseudomonas spp. S ≤ 4 mg/L, R > 4 mg/L,
Acinetobacter spp. S ≤ 4 mg/L, R > 4 mg/L,
Staphylococcus spp. S ≤ 1 mg/L, R > 1 mg/L,
Non-species-related S ≤ 2 mg/L, R > 4 mg/L.

The information provided below offers approximate data on whether microorganisms will be susceptible to tobramycin in the TOBREX® formulation. The instruction includes only those bacterial species typically causing external eye infections, such as conjunctivitis.

The prevalence of acquired resistance may vary geographically and over time for relevant microbial species; therefore, local information on microbial resistance patterns is desirable, especially when treating severe infections. If necessary, advice from a specialist should be sought when local resistance prevalence renders the activity of tobramycin at least questionable against certain types of infections.

*Resistance rate is over 50%.

Preclinical safety data

Data on systemic toxicity are well established. Systemic effects of tobramycin at toxic doses, which greatly exceed the dose used for local ocular application, may be associated with nephrotoxicity and ototoxicity.

In vitro and in vivo studies of tobramycin did not reveal mutagenic effects.

Tobramycin crosses the placenta into the fetal circulation and amniotic fluid. Animal studies involving systemic administration of high doses of tobramycin to pregnant animals during organogenesis revealed fetal nephrotoxicity and ototoxicity. Other studies conducted in rats and rabbits using parenteral administration of tobramycin at doses exceeding 100 mg/kg/day (> 400 times the maximum clinical dose) showed no evidence of impaired fertility or adverse effects on the fetus.

No studies have been conducted to evaluate the carcinogenic potential of tobramycin.

Pediatric population

Over 600 pediatric patients were included in 10 clinical trials evaluating the use of tobramycin ophthalmic drops or ointment for the treatment of bacterial conjunctivitis, blepharitis, or blepharoconjunctivitis. Patient ages ranged from 1 to 18 years. Overall, the safety profile in pediatric patients was comparable to that in adults. No dosage recommendations can be made for infants under 1 year of age due to insufficient data.

Pharmacokinetics

Systemic exposure to tobramycin following topical ophthalmic administration of TOBREX® eye drops is low. Tobramycin plasma concentrations were below the quantifiable limit in 9 out of 12 patients who received the ophthalmic suspension containing 0.3% tobramycin and 0.1% dexamethasone, instilled into each eye four times daily for two consecutive days. The highest measured plasma concentration was 0.25 µg/mL, which is 8 times lower than the 2 µg/mL concentration known to be below the threshold associated with risk of nephrotoxicity.

Tobramycin is rapidly and extensively excreted in urine by glomerular filtration, primarily in unchanged form. The elimination half-life from plasma 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 is negligible, less than 10%. Oral bioavailability of tobramycin is low (<1%).

Pediatric population

TOBREX® can be used in children aged 1 year and older at the same dosage as in adults. Information regarding use in children under 1 year of age is limited.

Clinical characteristics.

Indications.

Treatment of external eye infections and adjacent tissues caused by pathogenic microorganisms sensitive to tobramycin.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients.

Interaction with other medicinal products and other forms of interaction.

When topical corticosteroids and tobramycin at a concentration of 3 mg/mL are used concomitantly, clinical signs of bacterial, fungal, or viral infection may be masked, and hypersensitivity reactions may be suppressed.

Interactions with other medicinal products have been reported following systemic administration of tobramycin. However, systemic absorption of tobramycin after topical application is so low that the risk of any interaction is minimal.

If several topical ophthalmic medicinal products are used simultaneously, an interval of at least 10–15 minutes between applications is required. Ophthalmic ointments should be administered last.

Special precautions for use.

• For topical ophthalmic use only. Not intended for injection or oral administration.
• After the first opening of the bottle, the tamper-evident ring should be removed.
• Hypersensitivity to topically applied aminoglycosides may occur in some patients. 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 hypersensitivity occurs during treatment with this medicinal product, its use should be discontinued, as well as the use of any other concurrently administered drugs (see section "Adverse reactions").
• Cross-sensitivity to other aminoglycosides may occur; it should also be noted that patients who become sensitive to topically applied tobramycin may also become sensitive to other aminoglycosides administered topically and/or systemically.
• Serious adverse reactions, including neurotoxicity, ototoxicity, and nephrotoxicity, have occurred in patients receiving systemic tobramycin therapy. Caution is advised when tobramycin is used concomitantly with topical and systemic aminoglycosides; monitoring of total serum aminoglycoside concentrations is recommended (see section "Adverse reactions").
• TOBREX® should be used with caution in patients with known or suspected neuromuscular disorders such as myasthenia gravis or Parkinson's disease. Aminoglycosides may exacerbate muscle weakness due to their potential effects on neuromuscular function.
• As with other antibiotics, prolonged use of TOBREX® may result in overgrowth of nonsusceptible microorganisms, including fungi. If superinfection occurs, appropriate therapy should be initiated.
• Wearing contact lenses is not recommended during treatment of ocular infections. Therefore, patients should not wear contact lenses during treatment with this medicinal product.
• TOBREX® ophthalmic solution contains benzalkonium chloride, which may cause irritation and is known to discolor soft contact lenses. Contact with soft contact lenses should be avoided. If patients are permitted to wear contact lenses, they should be advised to remove the lenses before administering TOBREX® and to wait 15 minutes after instillation before reinserting the lenses.
• To prevent contamination of the dropper tip and solution, care should be taken not to touch the eyelids, adjacent areas, or other surfaces with the tip of the dropper bottle.

Use during pregnancy or breastfeeding.

Reproductive function

Studies on the effects of tobramycin on human or animal reproductive function following topical application have not been conducted (see section "Pharmacological properties").

Pregnancy

Data on the use of tobramycin administered topically to the eye in pregnant women are lacking or very limited. Studies in volunteers have not shown an association between tobramycin use and developmental abnormalities. After intravenous administration to pregnant women, tobramycin crosses the placenta and reaches the fetus. In utero exposure to tobramycin does not cause ototoxicity.

Animal studies have shown toxic effects on reproductive function at doses exceeding the maximum recommended human dose; therefore, these data have limited clinical relevance (see section "Pharmacological properties").

Despite the expected minimal systemic effect of tobramycin following topical administration, as a precautionary measure, the use of tobramycin should be avoided during pregnancy. TOBREX® can be used in women who are planning pregnancy. TOBREX® is not recommended during pregnancy.

Lactation

Minimal exposure of tobramycin in human breast milk has been observed after intravenous or intramuscular administration of up to 150 mg of tobramycin three times daily. Despite the lack of specific data on systemic exposure to tobramycin following ophthalmic administration, considering the much lower doses administered topically to the eye compared to the systemic doses mentioned above, and minimal transfer into breast milk, no adverse effects are expected in breastfed newborns/infants. Local ophthalmic use of tobramycin may be considered during breastfeeding if the benefit to the mother outweighs the potential risk to the breastfed newborn/infant.

Effect on ability to drive and use machines.

There is no effect or a negligible effect of TOBREX® on the ability to drive or operate machinery. Transient blurred vision or other visual disturbances may affect the ability to drive or operate machinery. If blurred vision occurs after instillation, patients should wait until vision clears before driving or operating machinery.

Dosage and Administration

As with other antibiotics, appropriate monitoring of bacterial sensitivity to the drug should be carried out.

Administration to adults, including elderly patients

For mild to moderate severity of the disease, instill 1–2 drops into the conjunctival sac of the affected eye(s) every 4 hours.

For severe disease, instill 1–2 drops into the conjunctival sac of the affected eye(s) every hour until improvement occurs; the frequency of administration should then be gradually reduced until treatment is completely discontinued.

Treatment usually lasts 7–10 days.

After instillation, it is recommended to gently close the eyelids or apply pressure at the lacrimal punctum area. This reduces systemic absorption of drugs administered into the eye, thereby decreasing the likelihood of systemic adverse effects.

If concomitant therapy with other topical ophthalmic agents is required, an interval of 10–15 minutes should be maintained between administrations.

Patients with hepatic or/and renal impairment.

There are no study data on the use of TOBREX® in these patient populations. However, due to the low systemic absorption of tobramycin following topical administration, no dose adjustment is necessary.

Children

TOBREX® ophthalmic solution may be used in children aged 1 year and older at the same dosage as in adults. Current data are described in the section "Pharmacological Properties". The safety and efficacy of TOBREX® ophthalmic solution in children under 1 year of age have not been established.

Overdose

No toxic effects are expected in case of overdose during topical administration or accidental ingestion of the contents of one vial, considering the characteristics of this drug.

Possible clinical signs and symptoms of TOBREX® overdose (punctate keratitis, erythema, increased lacrimation, eyelid swelling, and itching) may resemble adverse reactions observed in some patients.

In case of overdose during topical administration, excess TOBREX® should be washed out from the eye(s) with warm water.

Adverse reactions.

During clinical studies, the most commonly reported adverse reactions were ocular hyperemia and eye discomfort, occurring in approximately 1.4% and 2% of patients, respectively. The adverse reactions listed below were observed during clinical studies of TOBREX® and classified according to frequency as follows: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10,000, <1/1000), and very rare (<1/10,000). Within each frequency group, adverse reactions are listed in order of decreasing severity.

The following additional adverse reactions have been identified during the post-marketing surveillance period, the frequency of which cannot be estimated based on the available data.

Description of some adverse reactions

• Hypersensitivity to topically applied aminoglycosides may occur in some patients (see section "Special precautions").
• Serious adverse reactions, including neurotoxicity, ototoxicity, and nephrotoxicity, have been reported in patients receiving systemic tobramycin therapy. However, such reactions have not been reported following topical ocular administration of tobramycin (see section "Special precautions").
• TOBREX® eye drops can be administered to children aged 1 year and older at the same dose as in adults. Currently available data are described in the section "Pharmacological properties". The safety and efficacy of TOBREX® eye drops in children under 1 year of age have not been established (see section "Dosage and administration").

Shelf life. 3 years.

Storage period after first opening of the container – 4 weeks.

Storage conditions.

Store at a temperature not exceeding 25 °C, in a place inaccessible to children. Keep the bottle tightly closed.

Packaging.

5 ml in a dropper bottle; 1 dropper bottle per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Alcon Couvreur/Alcon Couvreur.

Manufacturer's address.

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