Environmental Assessment

PAR-Oftaquix Unit Dose 5mg/ml Eye Drops UK/H/464/002/MR

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Public Assessment Report

Mutual Recognition Procedure

Oftaquix Unit Dose 5 mg/ml Eye Drops

UK/H/0464/002/MR UK licence no: PL 16058/0007

Applicant: Santen Oy


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LAY SUMMARY The MHRA granted Santen Oy a Marketing Authorisation (national licence) for the medicinal product Oftaquix Unit Dose 5 mg/ml Eye Drops on 21st June 2006. This is a prescription-only medicine (POM) indicated for the treatment of eye infections.

Completion of first wave Mutual Recognition Procedure (UK/H/0464/002/MR) was approved on 30th April 2007 in the following countries: Denmark, Finland, Germany, Iceland, Italy and Sweden.

Levofloxacin, the active ingredient in this medicinal product, is an antibiotic that belongs to a group of medicines called fluoroquinolones and works by killing some types of bacteria that cause infections to the front surface of the eye. No new or unexpected safety concerns arose from these applications and it was therefore judged that the benefits of taking Oftaquix Unit Dose 5 mg/ml Eye Drops outweigh the risks; hence a Marketing Authorisation has been granted.


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TABLE OF CONTENTS

Module 1: Information about initial procedure Page 4 Module 2: Summary of Product Characteristics Page 5 Module 3: Product Information Leaflets Page 12 Module 4: Labelling Page 14 Module 5: Scientific Discussion Page 15 1 Introduction Page 20 2 Quality aspects Page 22 3 Non-clinical aspects Page 23 4 Clinical aspects Page 24 5 Overall conclusions Page 30 Module 6: Steps taken after initial procedure Page 31


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Module 1

Product Name

Oftaquix Unit Dose 5 mg/ml Eye Drops

Type of Application

Known active substance, Article 8.3

Active Substance

Levofloxacin

Form

Eye drops, solution

Strength

5 mg/ml

MA Holder

Santen Oy, Nittyhaankatu 20, 33720 Tampere, Finland

Reference Member State (RMS)

UK

CMS

Denmark, Finland, Germany, Iceland, Italy, Sweden

Procedure Number

UK/H/0464/002/MR

Timetable

Day 90 – 30th April 2007


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Module 2

SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT Oftaquix Unit Dose 5 mg/ml eye drops

2 QUALITATIVE AND QUANTITATIVE COMPOSITION One ml of eye drops, solution, contains 5.12 mg of levofloxacin hemihydrate equivalent to 5 mg of levofloxacin.

One single-dose container (0.5 ml) contains 2.5 mg of levofloxacin. For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM Eye drops, solution in a single-dose container. Clear, light yellow to light greenish-yellow solution, practically free of visible particulate matter.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications Oftaquix Unit Dose 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.

4.2 Posology and method of administration Posology For all patients 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 on days 3 through 5. If different topical ocular medications are used concomitantly, at least a 15-minute interval is required between instillations. The duration of treatment depends on the severity of the disorder and on the clinical and bacteriological course of infection. The usual treatment duration is 5 days. Safety and efficacy in the treatment of corneal ulcer and ophthalmia neonatorum has not been established. Oftaquix Unit Dose is not recommended for use in children below age 1 year due to a lack of data on safety and efficacy.

Use in the Elderly No adjustment of dosage is required. Method of administration Ocular use. For single use only. The contents of one single-dose container are sufficient for both eyes.


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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 levofloxacin, to other quinolones or to any of the excipients (see also section 6.1.).

4.4 Special warnings and precautions for use Oftaquix Unit Dose 5 mg/ml eye drops must not be injected sub-conjunctivally. The solution should not be introduced directly into the anterior chamber of the eye. Systemic fluoroquinolones have been associated with hypersensitivity reactions, even following a single dose. If an allergic reaction to levofloxacin occurs, discontinue the medication. As with other anti-infectives, prolonged use may result in overgrowth of non-susceptible organisms, including fungi. If worsening of infection occurs, or if a clinical improvement is not noted within a reasonable period, discontinue use and institute alternative therapy. 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 external bacterial ocular infections should not wear contact lenses.

4.5 Interaction with other medicinal products and other forms of interaction Specific drug interaction studies have not been conducted with Oftaquix Unit Dose 5 mg/ml eye drops. Since 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 Oftaquix Unit Dose 5 mg/ml eye drops.

4.6 Pregnancy and lactation Pregnancy: There are no adequate data from the use of levofloxacin in pregnant women. Animal studies are insufficient with respect to effects on pregnancy and embryonal/foetal development and parturition and postnatal development (see section 5.3). The potential risk for humans is unknown. Oftaquix Unit Dose 5 mg/ml eye drops should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus. Lactation: Levofloxacin is excreted in human milk. However, at therapeutic doses of Oftaquix no effects on the suckling child are anticipated. Oftaquix Unit Dose 5 mg/ml eye drops should be used during lactation only if the potential benefit justifies any potential risk to the nursing child.

4.7 Effects on ability to drive and use machines Oftaquix Unit Dose 5 mg/ml 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 Oftaquix 5 mg/ml Eye Drops: Eye disorders


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Common (≥1/100 to <1/10): Ocular burning, decreased vision and mucous strand. Uncommon (≥1/1,000 to < 1/100): 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. Immune system disorders Rare (≥1/10,000 to < 1/1,000): extra-ocular allergic reactions, including skin rash Very rare (<1/10,000), not known (cannot be estimated from the available data): anaphylaxis Nervous system disorders Uncommon (≥1/1,000 to < 1/100): headache Respiratory, thoracic and mediastinal disorders Uncommon (≥1/1,000 to < 1/100): rhinitis Very rare (<1/10,000), not known (cannot be estimated from the available data): Laryngeal oedema

4.9 Overdose The total amount of levofloxacin in the provided amount of single-dose container of eye drops is too small to induce toxic effects after an accidental oral intake. If considered necessary, the patient can be observed clinically and supportive measures can be undertaken. After a local overdose with Oftaquix Unit Dose 5 mg/ml eye drops, the eyes can be flushed with clean (tap) water at room temperature.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties Pharmacotherapeutic group: Ophthalmologicals, other antiinfectives ATC code: S01AX19 Levofloxacin is the L-isomer of the racemic drug substance ofloxacin. The antibacterial activity of ofloxacin resides primarily in the L-isomer. Mode of action As a fluoroquinolone antibacterial agent, levofloxacin inhibits bacterial type II topoisomerases—DNA gyrase and topoisomerase IV. Levofloxacin preferentially targets DNA gyrase in Gramnegative bacteria and topoisomerase IV in Gram-positive bacteria. Mechanisms of resistance Bacterial resistance to levofloxacin can develop primarily due to two main mechanisms, namely a decrease in the intrabacterial concentration of a drug, or alterations in a 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.


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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 ≤ 1mg/L, resistant > 2mg/L Streptococcus pneumoniae: Susceptible ≤ 2mg/L, resistant > 2mg/L Haemophilus influenzae, Moraxella catarrhalis: Susceptible ≤ 1mg/L, resistant > 1mg/L All other pathogens: Susceptible ≤ 1mg/L, resistant > 2mg/L Antibacterial spectrum 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. Therefore the information presented 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


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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.

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 (Oftaquix 5 mg/ml eye drops in multi dose container preserved with 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 Oftaquix 5 mg/ml in multi dose container and ofloxacin 3 mg/ml eye drops into the aqueous humor 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 min, 30 min and 15 min before the operation). The mean concentration of levofloxacin of Oftaquix 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 Oftaquix 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 Oftaquix 5 mg/ml eye drops, indicating little relevance to clinical use. Gyrase inibitors 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 certainity 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 between single and multiple oral doses. Systemic exposure in rats dosed at 810 mg/kg/day is approximately 50,000 times greater than that achieved in humans after doses of 2 drops of Oftaquix 5 mg/ml eye drops to both eyes. No teratogenic effect was observed when rabbits were dosed orally with up to 50 mg/kg/day or when dosed intravenously as high as 25 mg/kg/day.


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Levofloxacin caused no impairment of fertility or reproduction 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 humans. 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 or above 100 µg/mL 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 cutaneous photosensitising potential nor 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 in rats, levofloxacin exhibited no carcinogenic or tumorigenic potential following daily dietary administration of up to 100 mg/kg/day for 2 years.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients Sodium chloride Diluted sodium hydroxide solution or diluted hydrochloric acid Water for injections

6.2 Incompatibilities In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3 Shelf life 2 years. After first opening the pouch: 3 months Discard any unused single-dose container after that time. After first use: Discard the opened single-dose container with any remaining solution immediately.

6.4 Special precautions for storage Store in the original pouch in order to protect from light.

6.5 Nature and contents of container Low-density polyethylene (LDPE) single-dose containers. Single-dose containers of strip of ten are packed in paper-coated, aluminium-polyethylene foil pouch. Pack sizes: 10 x 0.5 ml, 20 x 0.5 ml, 30 x 0.5 ml and 60 x 0.5 ml. Not all pack sizes may be marketed.

6.6 Special precautions for disposal No special requirements.

7 MARKETING AUTHORISATION HOLDER Santen Oy Niittyhaankatu 20 33720 Tampere


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Finland

8 MARKETING AUTHORISATION NUMBER(S) PL 16058/0007

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 21/06/2006

10 DATE OF REVISION OF THE TEXT 22/10/2007


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Module 3

Patient Information Leaflet


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Module 4

Labelling

Outer carton: 10 x 0,5 ml


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20 x 0.5 ml


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30 x 0.5 ml


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60 x 0.5 ml


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Pouch (0.5 ml x 10)


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Label of single-dose container:


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Module 5

Scientific discussion during initial procedure I INTRODUCTION Based on the review of the data on quality, safety and efficacy, the RMS considered that the application for Oftaquix Unit Dose 5 mg/ml Eye Drops in the topical treatment of bacterial external ocular infections caused by levofloxacin susceptible microorganisms, could be approved. A national marketing authorisation was granted on 21st June 2006. This application was submitted under Article 8.3 of Directive 2001/83 (as amended), for a known active substance. The product is a line extension, with a change or addition of a new pharmaceutical form. The original product is the preserved product Oftaquix 5 mg/ml eye drops (PL 16058/0006) which was approved in the UK on 31st July 2001. Levofloxacin is the S-(-) optical isomer of ofloxacin and is a broad spectrum anti-infective compound, with similar physicochemical, pharmacological and toxicological properties compared to other marketed fluoroquinolones. It has been demonstrated in in vivo and in vitro studies to be up to four times more active than ofloxacin. No new preclinical studies were conducted, which is acceptable given that the application was based on a well-known active substance that has been used in other licences granted previously. Clinical studies concerning pharmacokinetic properties on Oftaquix Unit Dose 5 mg/ml Eye Drops were carried out in accordance with Good Clinical Practice (GCP). The clinical programme showed that Oftaquix Unit Dose 5 mg/ml Eye Drops provides satisfactory clinical benefits. The RMS has been assured that acceptable standards of GMP are in place for these product types at all sites responsible for the manufacture and assembly of this product prior to granting its national authorisation. For manufacturing sites within the community, the RMS has accepted copies of current manufacturer authorisations issued by inspection services of the competent authorities as certification that acceptable standards of GMP are in place at those sites. A package leaflet has been submitted to the MHRA along with results of consultations with target patient groups ("user testing"), in accordance with Article 59 of Council Directive 2001/83/EC. The results indicate that the package leaflet is well-structured and organised, easy to understand and written in a comprehensive manner. The test shows that the patients/users are able to act upon the information that it contains.


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II. ABOUT THE PRODUCT Name of the product in the Reference Member State

Oftaquix Unit Dose 5mg/ml Eye Drops

Name(s) of the active substance(s) (INN) Levofloxacin Pharmacotherapeutic classification (ATC code)

Levofloxacin (S01AX19)

Pharmaceutical form and strength(s) 5 mg/ml eye drops, solution Reference numbers for the Mutual Recognition Procedure

UK/H/0464/002/MR

Reference Member State United Kingdom Member States concerned Denmark, Germany, Finland, Iceland, Italy,

Sweden Marketing Authorisation Number(s) PL 16058/0007 Name and address of the authorisation holder

Santen Oy, Nittyhaankatu 20, 33720 Tampere, Finland


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III SCIENTIFIC OVERVIEW AND DISCUSSION III.1 QUALITY ASPECTS S. Active substance INN/Ph.Eur name: Levofloxacin Chemical name: (-)-(S)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-

piperazinyl)-7-oxo-7H-pyrido[1, 2,3-de]-[1,4]-benzoxazine-6-carboxylic acid hemihydrate

Structural formula

Molecular formula: C18H20FN3O4

.1/2H2O Molecular weight: 370.38 Characteristics: Light yellowish white to yellowish white crystals or crystalline

powder. The active substance has a DMF and letters of access have been provided for use with Oftaquix Unit Dose 5 mg/ml eye drops. The relevant applicant part has been included in module 3. The DMF has been assessed and is satisfactory. The finished product manufacturer evaluates microbial purity of the active substance in addition to the specifications set out by the active substance manufacturer. The finished product manufacturer fully tests one batch of active substance per year with all other batches partly analysed with an accompanying certificate of analysis from the active substance manufacturer. Appropriate stability data have been generated showing the active substance to be a physically and chemically stable drug. The active substance manufacturer is stated as being an approved supplier. P. Medicinal Product Other Ingredients Other ingredients consist of pharmaceutical excipients namely sodium chloride, hydrochloric acid, sodium hydroxide and water for injections. All excipients have a respective European Pharmacopoeia monograph. Satisfactory certificates of analysis have been provided for all ingredients showing compliance with their respective monograph/specifications. None of the excipients used contain material derived from animal or human origin.


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Pharmaceutical development The aim of the development programme was to produce an eye drop solution containing levofloxacin 5 mg/ml, but without the preservative benzalkonium chloride. The product is a simple aqueous solution with pH adjustment. The formulation is entirely based on the multi-dose product except for the presence of preservative which is removed, with the difference in quantity being made up with water for injections. Consequently there is no formulation development. The rationale and function of each excipient added is discussed. Levels of each ingredient are typical for a product of this nature and have been optimised on the basis of results from development studies. Manufacturing Process Satisfactory batch formulae have been provided for the manufacture of the product, along with an appropriate account of the manufacturing process. The manufacturing process has been validated on three production-scale batches with satisfactory results. Finished Product Specification The finished product specifications proposed are acceptable. Test methods have been described and have been adequately validated, as appropriate. Batch data have been provided and comply with the release specification. Certificates of analysis have been provided for any working standards used. Container-Closure System The product is packaged in low-density polyethylene (LDPE) single-dose containers. The single dose containers in strips of 10 are packed into paper coated, aluminium-polyethylene foil pouches to prevent water loss of the solution. There are overall pack sizes of 10, 20, 30 and 60 single-dose containers per pack. Satisfactory specifications and certificates of analysis have been provided for all packaging components. Stability of the product Stability studies were performed on three batches of the finished product and in the packaging proposed for marketing, in accordance with current guidelines. All results from stability studies were within specified limits. This data supports a shelf-life of 2 years. The single-dose containers have to be stored in the original pouch to protect from light. SPC, PIL, Labels The SPC, PIL and Labels are pharmaceutically acceptable. Conclusion The grant of marketing authorisations is recommended. III.2 PRE-CLINICAL ASPECTS No new preclinical data have been supplied with this application and none are required for applications of this type.


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III.3 CLINICAL ASPECTS BACKGROUND Levofloxacin is the S-(-) optical isomer of ofloxacin and is a broad spectrum anti-infective compound, with similar physicochemical, pharmacological and toxicological properties compared to other marketed fluoroquinolones. It has been demonstrated in in vivo and in vitro studies to be up to four times more active than ofloxacin.

Santen Oy has developed this non-preserved formulation of levofloxacin Oftaquix 5 mg/ml Eye Drops in unit dose containers in addition to the original preserved formulation. The main rationale for this is because there are several facts which support the using preservative-free solution, mainly: 1. Topical antibiotics containing benzalkonium chloride may delay the healing

process in compromised eyes with epithelial defects. 2. Although benzalkonium chloride is known to be a weak allergen, patients with

allergy do exist. 3. Preservative-free unit dose formulation is more convenient and hygienic. It may

enhance patient compliance.

INDICATIONS Therapeutic Indications Oftaquix Unit Dose 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 micro-organisms (see also sections 4.4 and 5.1). Considerations should be given official guidance on the appropriate use of antibacterial agents. These are identical to the indications for the innovator product.

DOSE & DOSE SCHEDULE For all patients 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 on days 3 through 5. If different topical ocular medications are used concomitantly, at least a 15-minute interval is required between instillations. The duration of treatment depends on the severity of the disorder and on the clinical and bacteriological course of infection. The usual treatment duration is 5 days. Safety and efficacy in the treatment of corneal ulcer and ophthalmia neonatorum has not been established. Use in the elderly No adjustment of dosage is required.


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Method of administration Ocular use. For single use only. The contents of one single-dose container are sufficient for both eyes. The eye drops, solution should be used immediately after first opening the single-dose container. This is consistent with the SPC for the innovator product. TOXICOLOGY The toxicological profile of levofoxacin has been well described. No new toxicological concerns are described and no new toxicological data are required. CLINICAL PHARMACOLOGY Pharmacokinetics No dissolution, bioavailability, or bioequivalence studies have been performed. The applicant states in the dossier (see Module 2.7.1) that it is assumed that similar concentrations of levofloxacin is achieved on the ocular surface by using 5 mg/ml Oftaquix multidose and unit dose formulation based on pharmacokinetic studies (see Module 2.7.2). Supportive Pharmacokinetics As supportive evidence the company included pharmacokinetic studies performed with preserved Oftaquix 5 mg/ml Eye Drops and unpreserved formulation in this application dossier. In Summary: Two pharmacokinetic studies were submitted which measured the concentrations of levofloxacin achieved in the aqueous humor after application prior to cataract surgery of either preserved (Oftaquix 5 mg/ml Eye Drops) conducted by Koch et al (J. Cataract Refract Surg 2005;31:1377-85) or unpreserved (Cravit ophthalmic solution, marketed by Santen in Japan) conducted by Yamada et al (Current Eye Research; 24:403-6). Results The concentration of levofloxacin in the aqueous humor was similar with both the preserved and non-preserved formulations. In addition, three studies, 03-005, 03-006, measuring concentrations of levofloxacin eye drops with preservative in plasma and tears respectively and 95034, without preservative in plasma in 95034 were described in the dossier. The two studies (03-005 and 03-006) using the preserved formulation demonstrated low measurable levels of levofloxacin in serum and levels above MIC90 in the tear fluid for at least 6 hours, respectively. In the third study, 95034, using the unpreserved formulation, levofloxacin was not detected in the serum. This latter result was at variance to study 03-005, but this was explained by the fact that the


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analytical technique used in this study had a level of detection of 10 ng/mL, a value that exceeded the actual levels found in study 03-005. Assessor’s comments Oftaquix/ levofloxacin pharmacokinetics The indication for Oftaquix Unit Dose 5 mg/ml is for the topical treatment of extra-ocular infections. The product is an aqueous topical ophthalmic solution containing the same active substance, levofloxacin in the same concentration as the original cross-referral product, PL 16058/0006) Oftaquix 5 mg/ml Eye Drops with preservative. The concentration of levofloxacin achieved on the ocular surface is unlikely to be affected by the absence of the relatively small amount of benzalkonium chloride preservative. The pharmacology of levofloxacin eye drops has been adequately demonstrated in the previous MRP application MRP UK/H/464/01. Therefore the pharmacokinetic studies submitted in the dossier and described above are superfluous to requirements in this application and are not directly relevant. EFFICACY The preservation of levofloxacin’s anti-infective activity may be affected by the lack of preservative in the eye drops solution filled in multi-dose container especially once the dropper bottle is opened. The packaging of the unpreserved solution in single-dose containers is required to bypass this occurrence and this has been done. It is also noted that, since benzalkonium chloride is a preservative, it may theoretically contribute to the antimicrobial efficacy of levofloxacin in Oftaquix 5 mg/ml Eye Drops. To address this, the marketing authorisation holder has also provided in vitro efficacy data for the non-preserved formulation of Oftaquix Unit Dose 5 mg/ml Eye Drops, in which levofloxacin and benzalkonium chloride are tested alone as well as in combination against clinical isolates of three bacterial species known to cause bacterial conjunctivitis. The three species used were Haemophilus influenzae, Staphylococcus aureus, and Streptococcus pneumoniae. Each substance was evaluated alone as well as in combination at a ratio of 100:1 (as found in the preserved formulation). Based on MIC50 and MIC90 values measured, levofloxacin combined with benzalkonium chloride was no more or less active than levofloxacin alone for the three bacterial species tested. Based on these data, it can be concluded that the antimicrobial activity of the preservative and non-preservative formulations of the finished product are the same. The efficacy of the (preserved) Oftaquix 5 mg/ml Eye Drops has already been established in the UK. Non-preserved formulations The applicant submits the two pharmacokinetic studies by Yamada et al, and Koch et al, discussed in Section Clinical Pharmacology (above), and the in vitro efficacy data of levofloxacin and benzalkonium chloride (tested alone as well as in combination). In the Yamada et al and Koch et al studies, the applicant suggests that both the non-preserved unit dose formulation and preserved multi-dose Oftaquix formulation achieve similar concentrations of levofloxacin on the ocular surface as well as the aqueous humor. Therefore, this suggests that the Oftaquix (unit dose) non-preserved


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formulations are at least as effective as Oftaquix multidose preserved formulation in treating bacterial external ocular infections in patients ≥1 year of age caused by levofloxacin susceptible organisms. In the in vitro efficacy data (also discussed above), it was shown that levofloxacin combined with benzalkonium chloride was no more or less active than levofloxacin alone for treating Haemophilus influenzae, Staphylococcus aureus, and Streptococcus pneumoniae (all known to cause bacterial conjunctivitis). Based on these data, it can be concluded that the antimicrobial activity of the preservative and non-preservative formulations of the finished product are the same. In addition, the applicant submits that the packaging of the eye drops in unit doses is more convenient and is likely to result in better compliance. The efficacy of the preserved formulation has already been established in a previous application. The additional data from Yamada and Koch studies show that both the preservative and non-preservative formulations achieve similar concentrations on the ocular surface and the aqueous humor. The additional in vitro data show that the lack of benzalkonium chloride does not diminish the antimicrobial activity of finished product in treating bacterial conjunctivitis. SAFETY Absence of benzalkonium chloride The original formulation of Oftaquix 5 mg/ml Eye Drops contained 0.005% of benzalkonium chloride as a preservative. This low concentration is regarded as safe. Benzalkonium chloride is a surfactant used as a preservative in many eye drops. It is preferred by many manufacturers because of its stability, excellent antimicrobial properties and long shelf-life. However, it also exhibits toxic effects on both the tear film and corneal epithelium. It has been shown that repeated use of preserved medications negatively affects the ocular surface, especially in patients whose ocular surface is compromised (Baudouin 1996). The usual dosage duration of the treatment with Oftaquix Eye Drops is 5 days. Adverse Effects About 17 million patients have used preserved Oftaquix or Quixin or Cravit in the USA and Japan, respectively) during the period from August 1, 2001 to January 31, 2004. It has been generally well tolerated. Eleven serious adverse effects were reported in this time period. None of theses led to a change in the reference safety information. Several allergic reactions have been reported and the reference safety information has been changed accordingly. Since Oftaquix Unit Dose formulation does not contain benzalkonium chloride, its absence may increase the safety of this formulation compared to Oftaquix multidose with preservative. Assessor’s Comments on Safety The safety of Oftaquix Eye drops with the preservative benzalkonium chloride has been previously demonstrated in the MRP application MRP UK/H/0464/001.


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Non-preserved formulations Adverse reactions. Non-preserved levofloxacin would appear not to be any less safe than preserved, especially when administered in single unit doses because one less chemical in the formulation should be conducive to a lower occurrence of adverse effects. In addition, allergic reactions have been reported with benzalkonium chloride and its removal can only predispose to a reduction in these. Anti-infective properties. In vitro data supplied have shown that benzalkonium chloride has no additional effect against Haemophilus influenzae, Staphylococcus aureus, and Streptococcus pneumoniae, which are three commonly occurring ocular pathogens. Thus, the antibacterial activity of the non-preserved and preserved formulations, and their benefits, can be considered the same. PSUR A Periodic Safety Update Report for Oftaquix (levofloxacin hemihydrate) Eye Drops for the period from August 1, 2001 to January 31, 2004 is included in the submission dossier. This is the period from granting of the first marketing authorisation by the UK MCA on 31 July 2001. Approximately 10 % of patients can be expected to experience adverse reactions after topical treatment with Oftaquix. These reactions are usually mild to moderate, transient and generally restricted to the eye. The most frequently reported adverse reactions are ocular burning, decreased vision and mucous strand. As with other fluoroquinones, allergic reactions may occur in less that 1 % of patients. Several allergic reactions have been reported during levofloxacin treatment. The calculations of patient exposure are based on the sales data. A total of 199,000 units of Oftaquix were sold during the review period. The average patient exposure is estimated to be 5 days per bottle, the most commonly prescribed duration of treatment. An estimate of the patient exposure is therefore 199,000 patients. During the review period a total of 661,000 units of Oftaquix (Quixin in USA) were sold with the same duration of therapy therefore the corresponding number of patients. In Japan, 47 million units of Cravit (unpreserved Oftaquix solution in multi-dose container) were sold and the average treatment duration was 20.4 days using 2.9 bottles per patient, therefore the estimated patient exposure is approximately 16.2 million. In total, about 17 million patients have used Oftaquix (Quixin, USA and Cravit, Japan) during the review period. The PSUR reviews a number of spontaneous reports mostly from physicians directly. In general Oftaquix 5 mg/ml Eye Drops has been well tolerated. Eleven serious adverse drug reactions were reported. It is known that 10 of these recovered and the outcome of the eleventh is unknown. None of them led to a change in the reference safety information. Several allergic reactions have been reported and the reference safety information has been changed accordingly.


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For a summary of the Overall Clinical Safety, see above. EXPERT REPORTS A satisfactory Clinical Overview has been submitted by a relevant qualified person. The review of the data for the finished product, both with and without benzalkonium chloride is satisfactory. SUMMARY OF PRODUCT CHARACTERISTICS

This is identical to the SPC for Oftaquix 5 mg/ml Eye Drops, albeit with any statements referring to benzalkonium chloride removed. This is satisfactory. PATIENT INFORMATION LEAFLET This is identical to the UK approved PIL for Oftaquix 5 mg/ml Eye Drops with preservative, albeit with any statements referring to benzalkonium chloride removed. This is satisfactory. LABELLING This is identical to the approved labelling for Oftaquix 5 mg/ml Eye Drops with preservative , albeit with any statements referring to benzalkonium chloride removed. This is satisfactory. MAA This is clinically satisfactory DISCUSSION This dossier for a standard abridged application of Oftaquix Unit Dose 5 mg/ml Eye Drops without preservative demonstrated that the formulation is otherwise the same as the preserved Oftaquix 5 mg/ml Eye Drops, albeit with the preservative benzalkonium chloride removed. The removal of the preservative is compensated for by the single-dose container packaging of the solution. In addition, the packaging in single-dose container may increase compliance. However, compliance data on the unpreserved unit dose formulation has not been submitted so this claim can not be substantiated. Proof of improved compliance in clinical studies should be presented before any claims of improvement with the unit dose are made. It has been shown that the antibacterial properties of the finished product without the preservative are the same as the formulation with the preservative for treating the three most commonly occurring ocular pathogens (Haemophilus influenzae, Staphylococcus aureus, and Streptococcus pneumoniae). No clinical efficacy studies have been provided. This is satisfactory as the applicant has already shown through the in vitro and pharmacokinetic studies performed that Oftaquix Unit Dose 5 mg/ml Eye Drops has the same antibacterial activity as Oftaquix 5 mg/ml Eye Drops, which has already been granted a UK licence and undergone a first-wave recognition.


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The preservative benzalkonium chloride can be a source of allergic reactions so its absence from the applicant formulation would result in improved safety and decreased incidence of adverse reactions. Balanced with the fact that there is no loss of antibacterial efficacy against ocular pathogens in the preservative-free formulation, the benefit:risk ratio for the formulation without preservative is at least the same as that with preservative (and probably increased, particularly in relation to allergic reactions). The SPC, PIL and labelling are in line with those approved for Oftaquix 5 mg/ml Eye Drops with preservative, with any statements related to the benzalkonium chloride removed. RECOMMENDATION The grant of a marketing authorisation is recommended. IV OVERALL CONCLUSION AND BENEFIT-RISK ASSESSMENT QUALITY The important quality characteristics of unpreserved Oftaquix Unit Dose 5 mg/ml Eye Drops are well-defined and controlled. The specifications and batch analytical results indicate consistency from batch to batch. There are no outstanding quality issues that would have a negative impact on the benefit/risk balance. PRECLINICAL No new preclinical data were submitted and none are required for applications of this type. EFFICACY The applicant has already shown through the in vitro and pharmacokinetic studies performed that unpreserved Oftaquix Unit Dose 5 mg/ml Eye Drops has the same antibacterial activity as the preserved Oftaquix 5 mg/ml Eye Drops, which has already been granted a UK licence. No new or unexpected safety concerns arise from this application. The SPC, PIL and labelling are satisfactory. RISK BENEFIT ASSESSMENT The quality of the product is acceptable and no new preclinical or clinical safety concerns have been identified. Extensive clinical experience with levofloxacin is considered to have demonstrated the therapeutic value of the compound. The risk benefit is, therefore, considered to be positive.


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Module 6

STEPS TAKEN AFTER INITIAL PROCEDURE - SUMMARY

Date submitted

Application type

Scope Outcome

17th September 2007

Type II National Variation

To bring the national licence in-line with the changes made during the MR Procedure.

22nd October 2007

Documents

Environmental Assessment