Download NEW MEDICINES COMMITTEE BRIEFING - Stoke-on

New Medicines Committee Briefing
May 2013
Levofloxacin 0.5% (Oftaquix®) eye drops
Levofloxacin (Oftaquix®) is to be reviewed for use within:
Primary Care
Secondary Care

Summary:
Oftaquix® is indicated for the topical treatment of bacterial external ocular
infections.
Oftaquix® is a broad spectrum antibacterial agent of the fluoroquinolone class.
Oftaquix® is the L-isomer of the racemic drug substance ofloxacin with the
antibacterial activity residing primarily in the L-isomer.
Oftaquix® is a black triangle drug ( ) and is monitored intensively by the CHM
and MHRA.
Oftaquix® has a high corneal penetration compared to ofloxacin and
ciprofloxacin
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Formulary application
Consultant submitting application:
Ms Anupama Pherwani
(Consultant Ophthalmologist)
Clinical Director supporting application: Gareth Rowland (Clinical Director)
Ms Pherwani has requested that Oftaquix® be considered for inclusion in the North
Staffordshire Joint Formulary for the treatment of infectious keratitis (infective corneal ulcers).
Currently, this is being treated with ofloxacin 0.3% or combination of gentamicin 1.5% and
cefuroxime 5% (unlicensed). Ms Pherwani states that levofloxacin achieves higher concentration
in tear film and anterior chamber and can be used in patients more than 1 year old. She also
noted that it is a broad spectrum antibiotics and more effective against key ocular pathogens –
strep. pneumoniae and P. aeruginosa. Levofloxacin have a low cytotoxicity compared to other
antibiotics, with neutral pH, it is well tolerated compared to ciprofloxacin. Ms Pherwani did
note the cost as a disadvantage to the proposed addition although cheaper to the current
combination of gentamicin and cefuroximine.
Background1,2,3,4,5,6,7
Keratitis or corneal inflammation is a potentially sight threatening condition which may have
infectious or non-infectious aetiology. Bacterial keratitis is a sight-threatening process that can
lead to severe visual loss. A particular feature of bacterial keratitis is its rapid progression;
corneal destruction may be complete in 24-48 hours with some of the more virulent bacteria.
Corneal ulceration, stromal abscess formation, surrounding corneal oedema, and anterior
segment inflammation are characteristic of this disease. Interruption of an intact corneal
epithelium and/or abnormal tear film permits entrance of microorganisms into the corneal
stroma, where they may proliferate and cause ulceration. Virulence factors may initiate
microbial invasion, or secondary effector molecules may assist the infective process.
Risk factors for bacterial corneal infection include contact lens wear, ocular surface disease,
corneal trauma and previous ocular or eyelid surgery. Certain ocular diseases and systemic
conditions which depress the immune system also increase the possibility of bacterial keratitis.
Early diagnosis and treatment are vital to minimizing any visual-threatening progression. In
addition, close follow-up, attention to laboratory data, and changing antimicrobials if no clinical
improvement is evident are important elements for successful outcome.
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Treatment for corneal ulcers and infections depends on the cause. Treatment should be started
as soon as possible to prevent scarring of the cornea. Topical antibiotics constitute the mainstay
of treatment in cases of bacterial keratitis whereas the use of topical corticosteroids remains
controversial. If the exact cause is not known, patients may be given antibiotic drops that work
against many kinds of bacteria.
The most common groups of bacteria responsible for bacterial keratitis are as follows:
Streptococcus, Pseudomonas, Enterobacteriaceae (including Klebsiella, Enterobacter, Serratia,
and Proteus), and Staphylococcus species. Once the exact cause is known, drops that treat
bacteria, herpes, other viruses, or a fungus are prescribed. Severe ulcers sometimes require a
corneal transplant.
Most acute superficial eye infections can be treated topically. Bacterial eye infections are
generally treated topically with eye drops and ointments. The treatment regimen for bacterial
keratitis usually includes the administration of topical broad-spectrum antibiotics at short
intervals to achieve local concentrations greater than the minimum inhibitory concentration for
most bacteria. A common clinical practice associate cephalosporin active against some grampositive organisms frequently associated with bacterial keratitis with an aminoglycoside
(gentamicin) active against large spectrum of gram-negative organisms. These antibiotics are
used in highly concentrated solutions generally referred to as “fortified antibiotics”, to achieve
high concentrations. Fluoroquinolones offer an alternative to fortified antibiotics. Ofloxacin,
ciprofloxacin, levofloxacin, gatifloxacin and moxifloxacin offer the theoretical advantage of a
good ocular penetration and of a broad-spectrum activity against both gram-positive and gramnegative pathogens at non-fortified concentrations.
Levofloxacin is a later-generation antibacterial agent of the fluoroquinolone class. It was
launched in several European countries in 2002. The main indications for treatment are bacterial
blepharitis and conjunctivitis, bacterial keratitis – especially when associated with contact lenses
– and endophthalmitis, where it is provided as an additional therapeutic agent. It is also used as
prophylaxis to reduce the bacterial conjunctival flora prior to intraocular surgery.
Levofloxacin is the L- isomer of the racemic drug ofloxacin with a broad spectrum antimicrobial
activity. It has similar physicochemical, pharmacological and toxicological properties to other
marketed fluoroquinolones such as ofloxacin, ciprofloxacin and moxifloxacin. Levofloxacin has
been demonstrated in in vivo and in vitro studies to be up to four times more active than
ofloxacin. The bactericidal activity of ofloxacin resides primarily in the L-isomer and this is
thought to be related to the higher binding affinity of the L-isomer to the DNA-DNA gyrase
complex. Therefore, levofloxacin is by its nature, twice as active as ofloxacin per unit of mass.
Like other fluoroquinolones, levofloxacin acts by inhibiting two bacterial enzymes that control
the topological state of DNA: DNA gyrase and topoisomerase IV. The primary target of
levofloxacin in Gram-negative bacteria such as Escherichia coli and Neisseria gonorrhoeae is DNA
gyrase, while topoisomerase IV is the primary target in Gram-positive cocci such as S. aureus and
S. pneumonia. The antimicrobial action is characterised by concentration-dependent bactericidal
activity and the ability to induce a post-antibiotic effect against a range of bacteria.
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In addition, levofloxacin is at least 10 times more soluble than ofloxacin and 400 times more
soluble than ciprofloxacin in water at neutral pH. This characteristic may contribute to its
increased penetration into the aqueous humour compared with the earlier generation
fluoroquinolones norfloxacin, ciprofloxacin, or ofloxacin.8
Current Formulary Status
The North Staffordshire Joint Formulary currently lists the following agents:
11.3
ANTI-INFECTIVE EYE PREPARATIONS

11.3.1 Antibacterials
Gentamicin
Ofloxacin
Therapeutic class and mode of action:3
Levofloxacin is a synthetic antibacterial agent of the fluoroquinolone class with the L-isomer of
the racemic drug substance ofloxacin. The antibacterial activity of ofloxacin resides primarily in
the L-isomer.
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.
Licensed Indications:3
Oftaquix® 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.
Dosage and Administration:3
One ml of eye drops, solution, contains 5.12 mg of levofloxacin hemihydrate equivalent to 5 mg
of levofloxacin
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.
4
If different topical ocular medications are used concomitantly, at least a 15-minute interval is
required between instillations.
To prevent contaminating the dropper tip and solution, the dropper tip should not come into
contact with the eyelids or surrounding areas.
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.
NICE and other guidance
NONE
Efficacy
1. The pharmacokinetics and ocular bioavailability of levofloxacin in an open-label study9
A 2 day, open-label, single centre study of levofloxacin concentrations in human tears following
a single topical administration of 0.5% levofloxacin ophthalmic solution in 30 healthy adult
volunteers with asymptomatic eyes. The objective of the study was to assess the
pharmacokinetics and ocular bioavailability of levofloxacin in human tears, and to determine the
tear concentration of levofloxacin. Each volunteer received 1 drop of 0.5% levofloxacin in each
eye and were assigned 1 of 5 groups with 9 defined time point for tear sampling after
administration from 5 minutes to 24 hours after administration. Six tear samples were collected
at each time point (1 eye each from 6 volunteers), except at 24 hour time point, at which 12
samples were collected (both eyes of 6 volunteers.
All volunteers had a baseline Schirmr tear test of 10 mm or more in each eye, and a best
corrected visual acuity score of +0.3 logMar in each eye. Levofloxacin concentrations were
measured using reverse-phase high-performance liquid chromatography. At 5 minutes after
administration of a single topical dose of levofloxacin, the mean tear concentration was 49.19
+/- 26.73 microgram/mL. The mean peak concentration of levofloxacin in the tear film, 221.06
+/- 256.68 microgram/mL, was reached at 15 minutes after administration. At 4 hours after
administration, the mean tear concentration of levofloxacin was 17.04 +/- 15.13 microgram/mL.
At 6 hours after administration, the mean concentration of levofloxacin was 6.57 +/- 5.26
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microgram/mL. At 24 hours after administration, levofloxacin concentrations > 2 microgram/mL
were measured in 2 of 6 (33%) subjects.
Only 2 of 30 volunteers reported adverse event which were both mild (stinging and decreased
vision) as they resolved without treatment. There were no notable changes from baseline in
mean visual acuity during the study and no subject experienced a change from baseline of >0.2
logMar units. One subject experienced a transient decrease in visual acuity in 1 eye secondary to
chemosis.
The authors concluded that levofloxacin concentrations in the tear fluid after a single topical
dose (1 drop) reached high levels quickly and remained above the minimum inhibitory
concentration (MIC) for most suspected ophthalmic pathogens (< 2 microg/mL) for at least 6
hours in most healthy volunteers, and for up to 24 hours in some volunteers.
2. Aqueous humour levels of levofloxacin compared to ciprofloxacin10
A total of 59 patients (16 males, 43 females; mean age 67.2 ± 15.4 years) undergoing elective
cataract surgery were randomly assigned to topical treatment with either levofloxacin 0.5% or
ciprofloxacin 0.3% eye drops, at one drop every 15 min for four doses immediately prior to
surgery. The purpose of the study was to compare aqueous humour levels of levofloxacin and
ciprofloxacin following topical application to patients scheduled for cataract surgery.
Patients were not eligible for participation in the study if they failed to meet standard provisions
regarding antibiotic treatment in the previous week or required the use of any topical or
systemic medication that could interfere with study measurements. Patients with pre-existing
corneal disorders, uveitis or glaucoma were excluded.
At the beginning of the cataract operation, 50 µl of aqueous humour were withdrawn from the
anterior chamber via a cannula attached to a tuberculin syringe after paracentesis. The
concentrations of levofloxacin and ciprofloxacin in the aqueous humour were analysed using
high performance liquid chromatography. Only 55 patients (30 were levofloxacin group and 25
were in ciprofloxacin group) had adequate aqueous humour samples.
29 right eyes (19 in the levofloxacin group and 10 in the ciprofloxacin group) and 30 left eyes (12
in the levofloxacin group and 18 in the ciprofloxacin group) were operated on. About 80% of the
patients in both groups had visual acuity of 0.5 or less in the eye to be operated on. The mean
axial length of eyes to be operated on was 25.1 ± 3.2 mm in the levofloxacin group and 24.2 ±
2.8 mm in the ciprofloxacin group. No clinically significant changes were seen in the group
means of intraocular pressure (IOP) during the course of the study.
The results showed that the mean and median concentrations (µg/ml), and the minimum,
maximum and lower quartile (Q1, 25%) and upper quartile (Q3, 75%) values of levofloxacin were
significantly higher than ciprofloxacin in the aqueous humour samples. Although the
concentration of levofloxacin (0.5%) in the ophthalmic drops tested was only 1.67 times that of
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ciprofloxacin in the control drops (0.3%), the (geometric) mean concentration of levofloxacin in
aqueous humour (0.728 µg/ml) was 9.1 times that of ciprofloxacin (0.080 µg/ml). The difference
was statistically highly significant (95% CI: 5.9–14.1; p < 0.0001).
The authors concluded that levofloxacin achieves 9.1 times the aqueous humour concentration
of ciprofloxacin. It could be considered a better choice than ofloxacin or ciprofloxacin for topical
ophthalmic use.
3. Aqueous humour levels of levofloxacin compared to ofloxacin11
This was a randomised investigator-masked study of 69 patients who received 4 drops of either
levofloxacin 0.5% or ofloxacin 0.3% eye drops within 1 hour (60 min, 45 min, 30 min, and 15
min) of elective cataract surgery. The eye drops were administered in the absence of the
surgeon. Aqueous humour samples of at least 50 µL were drawn from the anterior chamber at
the beginning of the cataract operation. The concentrations of the fluoroquinolones in the
anterior chambers were measured using high-performance liquid chromatography. To exclude a
dilution effect of the anterior chamber (AC), they were related to the AC volumes and AC depths
(measured by ultrasound). An early postoperative examination (1-2 hours after surgery)
consisted of biomicroscopy and measurement of the intraocular pressure as well as an inquiry
into possible adverse events.
The aim of the study was to investigate the penetration of topically applied levofloxacin 0.5%
and ofloxacin 0.3% eye drops into the aqueous humour of patients having cataract surgery. The
mean concentration of levofloxacin (1139.9 ng/mL +/- 717.1 [SD]) in the aqueous humour was
significantly higher (P = 0.0008) than that of ofloxacin (621.7 +/- 368.7 ng/mL). The aqueous
humour concentrations correlated negatively with the measured volumes and depths of the
ACs.
The authors concluded that levofloxacin, is more soluble in water enabling the use of higher
drug concentrations (0.5%) compared with other currently available fluoroquinolone eye drops
(0.3%). The concentration AC with levofloxacin eye drops was about 2-fold that reached with
ofloxacin eye drops. The concentration of the antibacterial isomer was approximately 3.5 to 4
times higher when levofloxacin was administered.
4. Levofloxacin versus fortified antibiotics (amikacin and cefazolin) for treating bacterial
keratitis12
A prospective, double-blinded, randomized controlled clinical trial was conducted in 71 eyes
from 69 patients suspected of having infectious bacterial keratitis. The patients were
randomized into two arms, 0.5% levofloxacin eye drops (34 eyes) or fortified cefazolin 5% and
amikacin 5% (37 eyes). 68 eyes were included in the efficacy analysis. During treatment, on days
2, 7, 14, and 21, the patient’s symptoms and signs were scored from grade 0-3 (absent to
severe).
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Both groups would apply their assigned medications every 10 minutes during the first 30
minutes of treatment and later decreased it to one hour every three days. On days 4-7, one drop
was used every two to four hours depending on the patients’ clinical responses. After day 7,
topical antibiotics were tapered to every six hours and discontinued when there was evidence
that the ulcer had completely healed. During treatment, the patients were followed on days 2,
7, 14, and 21. During each visit, the patient’s symptoms and signs were assessed using scores
from grade 0-3 (absent to severe). Symptoms accessed were for discomfort, pain, tearing,
photophobia, and itching. Changes in clinical signs, such as swollen eyelids, chemosis, and
conjunctival hyperaemia were evaluated using biomicroscopy examination. Those patients
whose symptoms worsened or did not respond to the assigned drugs were considered as
failures, and subsequently withdrew from the study.
The primary outcome of this study was to assess the resolution of keratitis (healed or not
healed). Cured or healed ulcer was defined as no corneal infiltration, no sign of inflammation
and complete epithelial healing. Treatment failure was defined as those who were unresponsive
to their treatment and showed no clinical improvement or worsening of clinical signs within 72
hours. At the end of the treatment, 61 out of 71 eyes completely healed.
There were no statistical differences for the resolution of keratitis (p=0.81) and mean time to
heal between the two groups (p=0.92). Further analysis of the mean time-duration to heal by
the severity of the ulcer also showed no statistically significant differences between groups
(Mild ulcers had a p-value of 0.50. Severe ulcers had a p-value of 0.75). Concerning the timeduration for the clinical signs (p=0.37) and symptoms (p=0.38) to disappear, they did not
observe any statistical differences between groups. The patients compliance was 80% based on
the self-reported diaries.
The authors concluded that the efficacy and safety of 0.5% topical levofloxacin was comparable
to fortified cefazolin 5% and amikacin 5% for the treatment of mild-to-moderate bacterial
keratitis.
Safety and adverse effects:3
Contraindication:
Hypersensitivity to the active substance levofloxacin, to other
quinolones or to any of the excipients, e.g. benzalkonium chloride.
Adverse effect:
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.
As the product contains benzalkonium chloride, contact eczema and/or
irritation may be due to the active component or to this preservative.
8
Common (1/100 to <1/10): ocular burning, visual disturbances and
mucous strand.
Drug Interactions:3
Uncommon (>1/1,000, <1/100): headache, rhinitis, conjunctival follicles.
Specific drug interaction studies have not been conducted with Oftaquix 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 5 mg/ml eye drops.
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. The potential risk for humans is unknown. Oftaquix 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 5 mg/ml eye drops should be used during lactation
only if the potential benefit justifies any potential risk to the nursing child.
Presentation:3
Eye drops, solution, clear, light yellow to light greenish-yellow solution, practically free of visible
particulate matter.
9
Costing:
Dr Pherwani estimated that 15-20 patients will be treated per year. The estimated expenditure
per year per treatment course (190 drops) will be £1,795.50 - £2,394.00 when the single dose
units are used.
UHNS expenditure for a 12-month period (January-December 2012):
UHNS
Lloyds
Approximate Epact
(Discount & Fees not
included)
Total
Gentamicin 1.5%
£1,666.24
£42.84
£0
£1,709.08
Cefuroxime 5%
£4,576.02
£213.91
£193.43
£4,983.36
Ciprofloxacin 0.3%
£65.34
£75.84
£202.10
£343.28
Levofloxacin 0.5%
£1,461.59
£596.21
£632.67
£2,690.47
Moxifloxacin 0.5%
£0.00
£0.00
£0.00
£0.00
£7,250.76
£277.43
£522.97
£8,051.16
Ofloxacin 0.3%
10
Cost Analysis
Cost comparison to other antibacterial eye drops with broad spectrum activity:
Product
Gentamicin 1.5%
plus
Cefuroxime 5%
Ofloxacin 0.3%
Levofloxacin 0.5%
Formulary status
Dosing freq.
Pack size
Price per
pack
5ml
£24.42
Non Formulary
1 drop every hour Day and Night for 2/7, then
every hour by Day for 2/7, then every 2 hourly
for 4/7, then 6 times per day for 7/7, then QDS
for 7/7.
5ml
£55.44
Formulary
Non Formulary
Ciprofloxacin 0.3%
Non Formulary
Moxifloxacin 0.5%
Non Formulary
1 drop every hour Day and Night for 2/7, then
every hour by Day for 2/7, then every 2 hourly
for 4/7, then 6 times per day for 7/7, then QDS
for 7/7.
1 drop every hour Day and Night for 2/7, then
every hour by Day for 2/7, then every 2 hourly
for 4/7, then 6 times per day for 7/7, then QDS
for 7/7.
1 drop every hour Day and Night for 2/7, then
every hour by Day for 2/7, then every 2 hourly
for 4/7, then 6 times per day for 7/7, then QDS
for 7/7.
1 drop every hour Day and Night for 2/7, then
every hour by Day for 2/7, then every 2 hourly
for 4/7, then 6 times per day for 7/7, then QDS
for 7/7.
Price per
Course
£73.26
£166.32
£239.64
5ml
£1.98
£5.94
5ml
£7.32
£21.96
30 x 0.5ml
18.90
£109.62
5ml
£1.98
£5.94
5ml
£11.76
£35.28
11
References
1
British National Formulary (BNF) 64 September 2012. Accessed via www.bnf.org
Kresken M. et al. Effectiveness of levofloxacin Eye Drops – A Microbiological Perspective.
European Ophthalmic Review, 2009, 2(1):12-5.
3
Summary of Product Characteristics Oftaquix® (levofloxacin) 5 mg/ml eye drops
4
Van Bambeke F, et al. Quinolones in 2005: an update. Clin Microbiol Infect, 2005; 11: 256-80.
5
Hooper DC. Quinolone mode of action. Drugs, 1995;49 (Suppl. 2):10-15.
6
Ross DL, Riley CM. Aqueous solubility of some variously substituted quinolone antimicrobials.
Int J Pharm 1990;63: 237–50.
7
Mitsui Y, Ooishi M, Sasaki K, Ohashi Y. AQCmax as a pharmacokinetic parameter of ophthalmic
solution. J Eye 1995;12:783–6.
8
Sasaki K, Mitsui Y, Fukuda M, et al. Intraocular penetration mode of five fluoroquinolone
ophthalmic solutions evaluated by the newly proposed parameter of AQCmax. J Eye 1995;12:
787–90.
9
Raizman MB, Rubin JM, Graves AL, Rinehart M. Tear concentrations of levofloxacin following
topical administration of a single dose of 0.5% levofloxacin ophthalmic solution in healthy
volunteers. Clin Ther. 2002; 24(9):1439-50.
10
Colin J., Simonpoli S. et al. Corneal penetration of levofloxacin into the human aqueous
humour: a comparison with ciprofloxacin. Acta Ophthalmol. Scand. 2003; 81:611-613.
11
Koch HR, Kulus SC et al. Corneal penetration of fluoroquinolones: aqueous humor
concentrations after topical application of levofloxacin 0.5% and ofloxacin 0.3% eyedrops. J
Cataract Refract Surg. 2005; 31(7):1377-85.
12
Kasetsuwana N, Tanthuvanit P. et al. The efficacy and safety of 0.5% Levofloxacin versus
fortified Cefazolin and Amikacin ophthalmic solution for the treatment of suspected and
culture-proven cases of infectious bacterial keratitis: a comparative study. Asian Biomedicine.
2011; 5: 77-83.
2
Produced by Sr. Maria Chidiamara Njoku
Primary Care/Secondary Care Interface Pharmacist
University Hospital of North Staffordshire
Telephone: 01782 674541
e-mail: [email protected]
Produced for use within the NHS. Not to be reproduced for commercial purposes.
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