Ofloxacin Mibe

Document: Ofloxacin mibe eye drops, solution ENG SmPC change

Summary of Product characteristics

1. Name of the medicinal product

<product name> 3 mg/ml eye drops, solution.

2. Qualitative and quantitative Composition

1 ml eye drops solution contains 3 mg ofloxacin.

One single dose (1 drop) contains 0.1 mg ofloxacin.

Excipient with known effect:

1 ml eye drops solution contains 0.025 mg benzalkonium chloride.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Eye drops, solution.

Clear yellowish solution (pH 6.2 to 6.7, 280 to 340 mOsmol/kg).

4. Clinical particulars

4.1 Therapeutic indications

<product name> is used for infections of the anterior eye segment in adults and children caused by ofloxacin-susceptible pathogens.

Consideration should be given to official guidance on the appropriate use of antibacterial agents (see section 5.1).

4.2 Posology and method of administration

Posology

Instillation of one drop of <product name> in the conjunctival sac of the affected eye(s) every two to four hours for the first two days, followed by four times daily.

The product should not be used for more than 14 days.

Specific populations

Elderly

No dosage adjustment is necessary for elderly patients (see section 4.4).

Paediatric population

Safety and effectiveness in infants below the age of one year have not been established.

The dosage for children does not differ from the one for adults. However, experience in children is limited. Dose-finding-studies are not available.

Method of administration

Ocular use.

If other eye drops/eye ointments are used concomitantly, an interval of about 15 minutes should be kept between the applications and an eye ointment should always be applied last.

4.3 Contraindications

Hypersensitivity to ofloxacin or to any other quinolones or any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

<product name>is not for injection.

Serious and occasionally fatal hypersensitivity (anaphylactic/anaphylactoid) reactions, some following the first dose, have been reported in patients receiving systemic quinolones, including ofloxacin. Some reactions were accompanied by cardiovascular collapse, loss of consciousness, angioedema (including laryngeal, pharyngeal or facial edema), airway obstruction, dyspnea, urticaria, and itching.

If an allergic reaction to <product name> occurs, discontinue the drug. Use <product name> with caution in patients who have exhibited sensitivities to other quinolone antibacterial agents.

When using <product name> the risk of rhinopharyngeal passage which can contribute to the occurrence and the diffusion of bacterial resistance should be considered. As with other anti-infectives, prolonged use may result in overgrowth of non-susceptible organisms.

If worsening infection occurs, or if clinical improvement is not noted within a reasonable period, discontinue use and institute alternative therapy.

The use of <product name> in neonates with ophthalmia neonatorum caused by Neisseria gonorrhoeaeor Chlamydia trachomatisis not recommended as it has not been evaluated in such patients.

Neonates with ophthalmia neonatorum should receive appropriate treatment for their condition.

Use in elderly: No comparative data are available with topical dosing in elderly versus other age groups, but considering the minimal systemic absorption the same posology can be applied.

Clinical and non-clinical publications have reported the occurrence of corneal perforation in patients with pre-existing corneal epithelial defect or corneal ulcer, when treated with topical fluoroquinolone antibiotics. However, significant confounding factors were involved in many of these reports, including advanced age, presence of large ulcers, concomitant ocular conditions (e.g. severe dry eye), systemic inflammatory diseases (e.g. rheumatoid arthritis), and concomitant use of ocular steroids or non-steroidal anti-inflammatory drugs. Nevertheless, it is necessary to advise caution regarding the risk of corneal perforation when using product to treat patients with corneal epithelial defects or corneal ulcers.

Corneal precipitates have been reported during treatment with topical ophthalmic ofloxacin. However, a causal relationship has not been established.

Sun or UV-exposition should be avoided during use of ofloxacin due to the potential for photosensitivity.

<Product name> contains the preservative benzalkonium chloride which may cause ocular irritation and discolour soft contact lenses.

Use of contact lenses is not recommended in patients receiving treatment for an eye infection.

4.5 Interaction with other medicinal products and other forms of interactions

It has been shown that the systemic administration of some quinolones inhibits the metabolic clearance of caffeine and theophylline. Drug interaction studies conducted with systemic ofloxacin have demonstrated that metabolic clearance of caffeine and theophylline are not significantly affected by ofloxacin.

Although there have been reports of an increased prevalence of CNS toxicity with systemic dosing of fluoroquinolones when used concomitantly with systemic nonsteroidal anti-inflammatory drugs (NSAIDs), this has not been reported with the concomitant systemic use of NSAIDs and ofloxacin.

Since the systemic exposure of oflaxacin is anticipated to be very low after use of <product name>, no relevant interactions are however expected.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no adequate data on the use of ofloxacin eye drops in pregnant women. Animal studies have not shown teratogenic effects (section 5.3). Serum concentrations after ophthalmic doses are at least 1000x lower that after standard oral doses.

Ofloxacin eye drops 0.3% should only be used during pregnancy if clearly needed.

Lactation

It is not known if ofloxacin is excreted in human milk after ophthalmic administration. Maximum serum concentrations after ophthalmic doses are x1000 lower than after standard oral doses. Caution should be applied when administered during breast-feeding.

Fertility

Ofloxacin had no influence on fertility in rats (see section 5.3).

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed.

Transient blurring of vision may occur on instillation of eye drops. Do not drive or operate hazardous machinery unless vision is clear.

4.8 Undesirable effects

General

Since a small amount of ofloxacin is systemically absorbed after topical administration, side-effects reported with systemic use could possibly occur.

Frequency categories: 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) and not known (cannot be estimated from the available data).

Immune system disorders

Very rare: Hypersensitivity (including angioedema, dyspnea, anaphylactic reaction/shock, oropharyngeal swelling and tongue swollen).

Nervous system disorders

Not known: Dizziness.

Eye disorders

Common: Eye irritation; Ocular discomfort.

Not known: Keratitis; Conjunctivitis; Vision blurred; Photophobia; Eye oedema; Periorbital oedema (including eyelid oedema); Foreign body sensation in eyes; Lacrimation increased; Dry eye; Eye pain; Ocular hyperaemia; Hypersensitivity (including eye pruritus and eyelid pruritus).

Gastrointestinal disorders

Not known: Nausea.

Skin and subcutaneous tissue disorders

Not known: Facial oedema; Stevens-Johnson syndrome, Toxic epidermal necrolysis

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system:

4.9 Overdose

No case of overdose has been reported.

In the event of a topical overdosage, flush the eye with water.

5. Pharmacological properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: ophthalmologicals, antiinfectives, fluoroquinolones.

ATC code: S01AE01

Mode of action

The derivative of chinolonic acid, ofloxacin, is a gyrase inhibitor of the fluoroquinolone sub-group with bactericidal effect.

Mechanism of resistance

Development of resistance to fluoroquinolones by the sensitive bacteria generally happens by mutation of the gyrA gene that codes for the A subunit of DNA gyrase. In addition, active efflux is responsible for low-level resistance that might act as a first step in resistance selection. Resistance can occur through a multistep process with subsequent mutations producing a progressively higher level of resistance in a stepwise fashion. Species of borderline susceptibility can become resistant in a single mutational step.

Plasmid-mediated resistance has been found in E. coli and Klebsiella organisms.

Bacteria resistant to one fluoroquinolone show cross-resistance to other members of the quinolone-group.

Breakpoints

Note that the breakpoints and in vitro activity spectra detailed below refers to systemically administered ofloxacin. These breakpoints may not be applicable for ofloxacin for local ocular administration since the local concentration achieved as well as local physicochemical properties may affect the overall activity of the product at the site of application.

In the resistance study mentioned below bacterial isolates were classified as susceptible or resistant in accordance with the recommendations of the European Committee of Antimicrobial Susceptibility Testing (EUCAST). Where established by EUCAST epidemiological cut-off values (ECOFF) were used, otherwise EUCAST clinical breakpoints for systemically administered antibacterial agents were applied:

	susceptible	resistent	ECOFF
Staphylococcus spp.	≤ 1 mg/l	> 1 mg/l	≤ 1 mg/l
Streptococcus pneumoniae	≤ 0.125 mg/l	> 4 mg/l	≤ 4 mg/l
Haemophilus influenzae	≤ 0.5 mg/l	> 0.5 mg/l	≤ 0.064 mg/l
Moraxella catarrhalis	≤ 0.5 mg/l	> 0.5 mg/l	≤ 0.25 mg/l
Enterobacteriaceae	≤ 0.5 mg/l	> 1 mg/l	≤ 0.25 mg/l
Acinetobacter spp	ND	ND	≤ 1 mg/l
Pseudomonas aeruginosa	ND	ND	≤ 2 mg/l
Enterococcus faecalis	ND	ND	≤ 4 mg/l

Antibacterial spectrum

The spectrum of action of ofloxacin covers fastidious anaerobes, facultative anaerobes, aerobes and other germs, such as, for example, chlamydia. An absorption of ofloxacin after local application has to be presumed, but does not lead to any clinical or pathological changes.

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 the agent in at least some types of infections is questionable.

Especially in the case of severe infections or therapy failure, a microbiological diagnosis with the proof of the pathogen and the pathogen's sensitivity to ofloxacin should be aimed for.

The information given below originates from a current resistance-testing-study with 1231 isolates of ocular origin (predominantly external smears) from 31 German centres. Hence, the aerobic bacteria mentioned constitute a representative image of the germs to be considered in eye infections in Germany. It is to be assumed that the frequency distribution of ophthalmologically relevent bacteria is not identical in other countries, but will be similar, so that the germs listed below will be the predominant cause of bacterial infections of the outer eye there as well.

Commonly susceptible species

Gram-positive aerobes

Staphylococcus aureus (MSSA)

Gram-negative aerobes

Haemophilus influenzae

Enterobacteriaceae (Escherichia coli, Serratia marcescens^$, Enterobacter cloacae, Klebsiella pneumoniae, Klebsiella oxytoca, Proteus mirabilis)

Acinetobacter baumannii

Acinetobacter lwoffi

Moraxella catarrhalis

Species for which aquired resistance may be a problem

Gram-positive aerobes

Staphylococcus aureus (MRSA)

coagulase-negative staphylococci

Streptococcus pneumonia

Enterococcus spp.

Gram-negative aerobes

Pseudomonas aeruginosa

^$Intermediate susceptibility to ofloxacin

5.2 Pharmacokinetic properties

In a healthy volunteer study, mean tear film concentrations of ofloxacin measured four hours after topical dosing (9.2 μg/g) were higher than the 2 μg/ml minimum concentration of ofloxacin necessary to inhibit 90% of most ocular bacterial strains (MIC90) in-vitro.

Maximum serum ofloxacin concentrations after ten days of topical dosing were about 1000 times lower than those reported after standard oral doses of ofloxacin, and no systemic side-effects attributable to topical ofloxacin were observed.

5.3 Preclinical safety data

No toxicologic effects were observed following local application of ofloxacin at clinically relevant doses.

Several in-vitro- and in-vivo-tests for induction of gene- and chromosome mutations were negative.

Long-term animal studies for carcinogenicity have not been performed. There are no signs for a cataractogenic or co-cataractogenic effect. Ofloxacin has no influence on fertility, peri- and post-natal development and is non-teratogenic. Following systemic administration of ofloxacin to test animals, degenerative changes to the articular cartilage have been observed. The articular cartilage damages that occurred were dose-dependent and age-related. (The younger the animal, the more pronounced the damages were.)

6. Pharmaceutical particulars

6.1 List of excipients

Sodium chloride

Benzalkonium chloride

Hydrochloric acid and sodium hydroxide solution (for pH adjustment)

Water for injections.

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years

After opening, use within 4 weeks.

6.4 Special precautions for storage

Do not store above 25 °C.

Keep bottle in the outer carton in order to protect from light.

For storage conditions after first opening of the medicinal product, see section 6.3.

6.5 Nature and contents of container

LDPE bottle with LDPE dropper applicator and HDPE tamper-proof screw cap.

Each bottle contains 5 ml eye drops solution.

Pack sizes:

1 x 5 ml

2 x 5 ml

3 x 5 ml and

6 x 5 ml

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements.

7. Marketing authorisation holder

8. Marketing authorisation Number(s)

9. Date of first authorisation/Renewal of authorisation

2014-04-23

10. date of revision of the text

2016-04-15

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