Summary of Product Characteristics (SmPC) - Levofloxacin 5 mg/ml eye drops, solution in single dose Container
1 NAME OF THE MEDICINAL PRODUCT
Levofloxacin 5 mg/ml eye drops, solution in single dose container
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each ml (28 drops) of eye drops, solution contains levofloxacin hemihydrate equivalent to 5 mg of levofloxacin (corresponding to 0.18 mg/drop).
For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Eye drops, solution in single dose container.
Clear, light yellow to light greenish-yellow solution.
pH: 6.0-7.0; Osmolality: 260-340 mOsm/kg H2O.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Levofloxacin 5 mg/ml eye drops are indicated for the topical treatment of bacterial external ocular infections in patients ≥1 year of age caused by levofloxacin susceptible microorganisms (see also sections 4.4 and 5.1).
Considerations should be given to official guidance on the appropriate use of antibacterial agents.
Levofloxacin 5 mg/ml eye drops are indicated in adults, children aged ≥1 year to 12 years and adolescents aged 12 to 18 years.
4.2 Posology and method of administration
Posology
All patients should instil one to two drops in the affected eye(s) every two hours up to 8 times per day while awake for the first two days; and then four times daily the third to the fifth day.
If different topical ophthalmic medicinal products are used at the same time, an interval of at least 15 minutes should be observed between the individual applications.
The duration of treatment depends on the severity of the eye disease, as well as on the clinical and bacteriological course of infection. The usual treatment duration is 5 days.
Safety and efficacy in the treatment of corneal ulcers and ophthalmia neonatorum have not been established.
Levofloxacin 5 mg/ml eye drops is not recommended for use in children below age 1 year due to a lack of data on safety and efficacy.
Elderly
No dose adjustment is necessary in elderly patients.
Paediatric population
The posology is the same in adults and children ≥1 year of age.
The safety and efficacy of Levofloxacin eye drops in children aged ≥1 year have been established.
The safety and efficacy of Levofloxacin eye drops in children aged < 1 year have not been established. There are no studies available.
Method of administration
Levofloxacin eye drops is for ocular use only.
For single use only.
A single-dose container contains enough solution to treat both eyes.
The eye drops, solution should be used immediately after first opening the single dose container.
The used single dose container should be discarded.
4.3 Contraindications
Hypersensitivity to the active substance or to other quinolones or to any of the excipients listed in section 6.1.
4.4 Special warnings and precautions for use
Levofloxacin eye drops should not be injected sub-conjunctivally. The solution should not be introduced directly into the anterior chamber of the eye.
As with other anti-infectives, prolonged use may result in overgrowth of non-susceptible organisms including fungi. If worsening of infection occurs or if clinical improvement is not noted within a reasonable period, the medicinal product should be discontinued and alternative therapy instituted. Whenever clinical judgement dictates, the patient should be examined with the aid of magnification, such as slit-lamp biomicroscopy, and, where appropriate, fluorescein staining.
Patients with bacterial infections in the anterior segment of the eye should not wear contact lenses.
Systemic fluoroquinolones have been associated with hypersensitivity reactions, even following a single dose. If an allergic reaction occurs after administration of levofloxacin, treatment should be discontinued.
Tendon inflammation and rupture may occur with systemic fluoroquinolone therapy, including levofloxacin, particularly in elderly patients and those treated concurrently with corticosteroids. Therefore, caution should be exercised and treatment with Levofloxacin eye drops should be discontinued at the first sign of tendon inflammation (see section 4.8).
Paediatric population
The special warnings and precautions for use are the same in adults and children aged ≥1 year.
4.5 Interaction with other medicinal products and other forms of interaction
Specific drug interaction studies have not been conducted with Levofloxacin eye drops.
Since the maximum plasma concentrations of levofloxacin after ocular administration are at least 1000 times lower than those reported after standard oral doses, interactions mentioned for systemic use are unlikely to be clinically relevant when using Levofloxacin eye drops.
Paediatric population
No interaction studies have been performed.
4.6 Fertility, pregnancy and lactation
Pregnancy
There are no adequate data from the use of levofloxacin in pregnant women. Animal studies do not indicate any direct or indirect evidence of harmful effects with respect to reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Levofloxacin eye drops should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.
Breastfeeding
Levofloxacin is excreted in human milk. However, at therapeutic doses of Levofloxacin eye drops no effects on the suckling child are anticipated. Levofloxacin eye drops should be used during lactation only if the potential benefit justifies the potential risk to the breast-fed child.
Fertility
Levofloxacin caused no impairment of fertility in rats at exposures considerably in excess of the maximum human exposure after ocular administration (see section 5.3).
4.7 Effects on ability to drive and use machines
Levofloxacin eye drops have minor influence on the ability to drive and use machines.
If there are any transient effects on vision, the patient should be advised to wait until this clears before driving or operating machinery.
4.8 Undesirable effects
Approximately 10% of patients can be expected to experience adverse reactions. The reactions are usually graded as mild or moderate, are transient, and are generally restricted to the eye.
The following undesirable effects assessed as definitely, probably or possibly related to treatment were reported during clinical trials and post-marketing experience with levofloxacin containing eye drops.
Adverse reactions are listed below, sorted by MedDRA system organ class and frequency.
Frequencies are defined as follows:
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).
| System organ class | Common | Uncommon | Rare | Very rare |
| Immune system disorders | Extra-ocular allergic reactions including skin rash | Anaphylaxis | ||
| Nervous system disorders | Headache | |||
| Eye disorders | Ocular burning, decreased vision and mucous strand | Lid matting, chemosis, conjunctival papillary reaction, lid oedema, ocular discomfort, ocular itching, ocular pain, conjunctival injection, conjunctival follicles, ocular dryness, lid erythema and photophobia. No corneal precipitates were observed in clinical studies. | ||
| Respiratory, thoracic and mediastinal disorders | Rhinitis | Laryngeal oedema |
Additional adverse reactions observed with the systemic use of the active substance (levofloxacin) and which may potentially occur also with Levofloxacin eye drops:
Rupture of tendons in the shoulder, hand, Achilles heel or other tendons that required surgical repair or resulted in prolonged disability have been reported in patients receiving systemic fluoroquinolones. Studies and post-marketing experience with systemic quinolones indicate that a risk of these ruptures may be increased in patients receiving corticosteroids, especially geriatric patients and in tendons under high stress, including Achilles tendon (see section 4.4).
Paediatric population
Frequency, type and severity of adverse reactions in children are expected to be the same as in adults.
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 Yellow Card Scheme website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
4.9 Overdose
The total amount of levofloxacin in the provided amount of single-dose containers is too small to induce toxic effects after an accidental oral intake. If considered necessary, the patient can be observed clinically and other supportive measures can be undertaken. After a local overdose with Levofloxacin eye drops, the eyes can be flushed with clean (tap) water at room temperature.
Paediatric population
Actions to be taken in case of overdose are the same in adults and in children aged ≥1 year.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Ophthalmologicals, Antiinfectives, Fluoroquinolones, ATC code: S01AE05
Levofloxacin is the L-isomer of the racemic drug substance ofloxacin. The antibacterial activity of ofloxacin resides primarily in the L-isomer.
Mechanism of action
As a fluoroquinolone antibacterial agent, levofloxacin inhibits bacterial type II topoisomerases—DNA gyrase and topoisomerase IV. Levofloxacin preferentially targets DNA gyrase in Gram-negative bacteria and topoisomerase IV in Gram-positive bacteria.
Mechanisms of resistance
Bacterial resistance to levofloxacin can develop primarily due to two mechanisms, namely a decrease in the intrabacterial concentration of the drug, or alterations in the drug's target enzymes. Target site alteration results from mutations in the chromosomal genes encoding the DNA gyrase (gyrA and gyrB) and topoisomerase IV (parC and parE; grlA and grlB in Staphylococcus aureus). Resistance due to low intrabacterial drug concentration follows either from altered outer-membrane porins (OmpF) leading to reduced entry of fluoroquinolones in Gram-negative bacteria or from efflux pumps. Efflux-mediated resistance has been described in pneumococci (PmrA), staphylococci (NorA), anaerobes, and Gram-negative bacteria. Finally, plasmid-mediated resistance to quinolones (determined by the qnr gene) has been reported in Klebsiella pneumoniae and in E.coli.
Cross-resistance
Cross-resistance between fluoroquinolones may occur. Single mutations may not result in clinical resistance, but multiple mutations generally do result in clinical resistance to all drugs within the fluoroquinolone class. Altered outer-membrane porins and efflux systems may have a broad substrate specificity, targeting several classes of antibacterial agents and leading to multiresistance.
Breakpoints
MIC breakpoints separating susceptible from intermediately susceptible organisms and intermediately susceptible from resistant organisms according to breakpoint of EUCAST (European Committee on Antimicrobial Susceptibility Testing) are as follows:
Pseudomonas spp., Staphylococcus spp., Streptococcus A,B,C,G:
Susceptible ≤ 1 mg/l, resistant > 2 mg/l
Streptococcus pneumoniae: Susceptible ≤ 2 mg/l, resistant > 2 mg/l
Haemophilus influenzae, Moraxella catarrhalis: Susceptible ≤ 1 mg/l, resistant >
1 mg/l
All other pathogens: Susceptible ≤ 1 mg/l, resistant > 2 mg/l
Antibacterial spectrum
The prevalence of acquired resistance may vary geographically and with time for selected species. Local information on resistance is desirable, particularly when treating severe infections. Therefore, the information presented here provides only an approximate guidance on probabilities as to whether microorganisms will be susceptible to levofloxacin or not.
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.
Only those bacterial species that are commonly responsible for external ocular infections, such as conjunctivitis, are presented here in the following table.
Antibacterial spectrum – susceptibility category and resistance characteristics according to EUCAST
Category I: Commonly susceptible species Aerobic Gram-positive micro-organisms
Staphylococcus aureus (MSSA)*
Streptococcus pneumoniae
| Streptococcus pyogenes | |
| Viridans group streptococci | |
| Aerobic Gram-negative micro-organisms | |
| Escherichia coli | |
| Haemophilus influenzae | |
| Moraxella catarrhalis | |
| Pseudomonas aeruginosa | (Community isolates) |
| Other micro-organisms | |
| Chlamydia trachomatis | (Treatment of patients with chlamydial conjunctivitis requires concomitant systemic antimicrobial treatment) |
| Category II: Species for which acquired resistance may be a problem | |
| Aerobic Gram-positive micro-organisms | |
| Staphylococcus aureus (MRSA)** | |
| Staphylococcus epidermidis | |
| Aerobic Gram-negative micro-organisms | |
| Pseudomonas aeruginosa | (Hospital isolates) |
* MSSA = methicillin-susceptible strains of Staphylococcus aureus
** MRSA = methicillin-resistant strains of Staphylococcus aureus
Resistance data presented in the table are based on the results of a multicentre surveillance study (Ophthalmic Study) on the prevalence of resistance among bacterial isolates obtained from patients with eye infections in Germany, June – November 2004.
Organisms have been classified as levofloxacin-susceptible based on in-vitro susceptibility and plasma concentrations reached after systemic therapy. Topical therapy achieves higher peak concentrations than found in plasma. However, it is not known if or how the kinetics of the drug after topical application to the eye may modify the antibacterial activity of levofloxacin.
Paediatric population
Pharmacodynamic properties are the same in adults and children aged ≥1 year.
5.2 Pharmacokinetic properties
After ocular instillation, levofloxacin is well maintained in the tear film.
In a healthy-volunteer study, mean tear-film concentrations of levofloxacin (levofloxacin 5 mg/ml eye drops, drops in multidose container with the preservative benzalkonium chloride) measured four and six hours after topical dosing were 17.0 and 6.6 µg/ml, respectively. Five of six subjects studied had concentrations of 2 μg/ml or above at 4 hours post dose. Four of six subjects maintained this concentration at 6 hours post dose.
The penetration of topically applied levofloxacin 5 mg/ml eye drops in multidose container and ofloxacin 3 mg/ml eye drops into the aqueous humour of 35 patients undergoing cataract surgery was investigated. One drop of either drug was administered four times into the eye to be operated (1 hour, 45, 30 and 15 minutes before surgery). The mean concentration of levofloxacin from levofloxacin 5 mg/ml eye drops in the aqueous humour was statistically significantly higher than that of ofloxacin (p=0.0008). In fact, it was approximately twice as high as that of ofloxacin (1139.9 ± 717.1 ng/ml vs. 621.7 ± 368.7 ng/ml).
Levofloxacin concentration in plasma was measured in 15 healthy adult volunteers at various time points during a 15-day course of treatment with levofloxacin 5 mg/ml eye drops, solution. The mean levofloxacin concentration in plasma 1 hour post-dose ranged from 0.86 ng/ml on Day 1 to 2.05 ng/ml on Day 15. The highest maximum levofloxacin concentration of 2.25 ng/mL was measured on Day 4 following 2 days of dosing every 2 hours for a total of 8 doses per day. Maximum levofloxacin concentrations increased from 0.94 ng/ml on Day 1 to 2.15 ng/ml on Day 15, which is more than 1000 times lower than those reported after standard oral doses of levofloxacin.
As yet, the plasma concentrations of levofloxacin reached after application to infected eyes are not known.
5.3 Preclinical safety data
Preclinical effects were observed only at exposures considerably in excess of the maximum human exposure, after instillation of levofloxacin 5 mg/ml eye drops, solution, indicating little relevance to clinical use.
Gyrase inhibitors have been shown to cause growth disorders of weight bearing joints in animal studies.
In common with other fluoroquinolones, levofloxacin showed effects on cartilage (blistering and cavities) in rats and dogs after high oral doses.
A cataractogenic potential cannot be ruled out due to the lack of specific investigations.
Visual disorders in animals cannot be ruled out with certainty on the basis of the present data.
Reproductive toxicity
Levofloxacin was not teratogenic in rats at oral doses as high as 810 mg/kg/day. Since levofloxacin has been shown to be completely absorbed, the kinetics are linear. No differences were noted in the pharmacokinetic parameters were observed between single and multiple oral doses. The systemic exposure in rats administered 810 mg/kg/day is approximately 50,000 times greater than that achieved in humans after administration of 2 drops of levofloxacin 5 mg/ml eye drops, solution to both eyes. In rats, the highest dose caused increased foetal mortality and delayed maturation, coincident with maternal toxicity.
No teratogenic effects were observed in rabbits administered orally up to 50 mg/kg/day or intravenously as high as 25 mg/kg/day.
Levofloxacin caused no impairment of fertility in rats at oral doses as high as 360 mg/kg/day, resulting in approximately 16,000 times higher plasma concentrations than reached after 8 ocular doses in human.
Genotoxicity
Levofloxacin did not induce gene mutations in bacterial or mammalian cells, but did induce chromosome aberrations in Chinese hamster lung (CHL) cells in vitro at doses of 100 μg/ml or above in the absence of metabolic activation. In vivo tests did not show any genotoxic potential.
Phototoxic potential
Studies in the mouse after both oral and intravenous dosing showed levofloxacin to have phototoxic activity only at very high doses. Neither a cutaneous photosensitizing potential nor a skin phototoxic potential were observed after application of a 3% ophthalmic solution of levofloxacin to the shaven skin of guinea pigs. Levofloxacin did not show any genotoxic potential in a photomutagenic assay and it reduced tumour development in a photocarcinogenicity assay.
Carcinogenic potential
In a long-term carcinogenicity study conducted in rats, levofloxacin exhibited no carcinogenic or tumorigenic potential following daily dietary administration of up to 100 mg/kg/day for 2 year.
Environmental risk assessment (ERA)
The calculated predicted environmental concentration (PECSurfacewater) for levofloxacin 5 mg/ml eye drops, solution is below the action limit of 0.01μg/l and the LogKow of levofloxacin is below the action limit of 4.5.
It is highly unlikely that this medicinal product would represent a risk to the environment because no other environmental concerns are apparent for this product and its active substance levofloxacin.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Sodium chloride
Sodium hydroxide (E524)/ Hydrochloric acid (E507) (for pH-adjustment)
Water for injections
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 years.
After first opening of the sachet: Keep the single-dose containers in the sachet and use them within 10 days.
After opening of the single-dose container: use immediately and discard the single-dose container after use.
6.4 Special precautions for storage
This medicinal product does not require any special temperature storage conditions.
Keep the container in the sachet in order to protect from light.
6.5 Nature and contents of container
Single-dose containers (LDPE) filled with 0.3 ml solution. The containers are presented in polyethylene terephthalate/aluminium/polyethylene sachets of 5 or 10 single-dose containers.
Packages of 10, 20, 30 or 60 single-dose containers.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7 MARKETING AUTHORISATION HOLDER
Aspire Pharma Limited
Unit 4, Rotherbrook Court
Bedford Road, Petersfield
Hampshire, GU32 3QG
United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL 35533/0293
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
31/01/2025
10 DATE OF REVISION OF THE TEXT
31/01/2025