U.S. patent application number 15/142225 was filed with the patent office on 2016-08-25 for method of treating middle ear infections.
The applicant listed for this patent is Alcon Pharmaceuticals Ltd.. Invention is credited to Peter J. Conroy, G. Michael Wall.
Application Number | 20160243029 15/142225 |
Document ID | / |
Family ID | 23261416 |
Filed Date | 2016-08-25 |
United States Patent
Application |
20160243029 |
Kind Code |
A1 |
Wall; G. Michael ; et
al. |
August 25, 2016 |
METHOD OF TREATING MIDDLE EAR INFECTIONS
Abstract
Aqueous suspension formulations containing dexamethasone and
ciprofloxacin are disclosed for the treatment of middle ear
infections in human patients having an open tympanic membrane.
Inventors: |
Wall; G. Michael; (Fort
Worth, TX) ; Conroy; Peter J.; (Forth Worth,
TX) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Alcon Pharmaceuticals Ltd. |
Fribourg |
|
CH |
|
|
Family ID: |
23261416 |
Appl. No.: |
15/142225 |
Filed: |
April 29, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14838637 |
Aug 28, 2015 |
9345714 |
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15142225 |
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14468257 |
Aug 25, 2014 |
9149486 |
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14838637 |
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12357697 |
Feb 13, 2009 |
8846650 |
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14468257 |
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12119185 |
May 12, 2008 |
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12357697 |
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10946792 |
Sep 22, 2004 |
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12119185 |
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10243341 |
Sep 13, 2002 |
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10946792 |
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60323951 |
Sep 21, 2001 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 31/04 20180101;
A61K 9/0046 20130101; A61P 43/00 20180101; A61K 47/38 20130101;
A61P 27/16 20180101; A61P 31/00 20180101; A61K 31/573 20130101;
A61K 47/32 20130101; A61K 31/545 20130101; A61K 31/56 20130101;
A61K 31/57 20130101; A61K 47/02 20130101; A61K 47/12 20130101; A61K
31/495 20130101; A61K 9/10 20130101; A61K 31/496 20130101; A61K
31/495 20130101; A61K 2300/00 20130101; A61K 31/545 20130101; A61K
2300/00 20130101; A61K 31/56 20130101; A61K 2300/00 20130101; A61K
31/57 20130101; A61K 2300/00 20130101 |
International
Class: |
A61K 9/00 20060101
A61K009/00; A61K 31/496 20060101 A61K031/496; A61K 31/573 20060101
A61K031/573 |
Claims
1. A method of treating a human patient comprising the steps of:
(a) diagnosing the patient as having otitis media and an open
tympanic membrane and/or having acute otitis externa in at least
one ear; and (b) topically applying into the ear canal of the
patients ear an aqueous suspension composition containing a
combination of ciprofloxacin and dexamethasone, wherein the
composition comprises a) 0.01-0.5% (wt.) dexamethasone; b) 0.1-0.4%
(wt.) ciprofloxacin; c) 0.1-0.9% (wt.) tonicity agent; d) 0.01-0.2%
(wt.) of a nonionic surfactant; and e) a buffer; wherein three or
four drops of the aqueous suspension composition are administered
to the patients ear twice a day, and wherein each drop is 30-35
.mu.L.
2. The method of claim 1 wherein the dexamethasone is dexamethasone
alcohol and the ciprofloxacin is ciprofloxacin hydrochloride,
monohydrate.
3. The method of claim 1 wherein the aqueous suspension composition
contains 0.1% (wt.) dexamethasone and 0.3% (wt.) ciprofloxacin.
4. The method of claim 1 wherein the dexamethasone has an average
particle size on a mean volume basis of less than 3 .mu.m.
5. The method of claim 1 wherein said tonicity agent is NaCl.
6. The method of claim 5 wherein said NaCl is present in an amount
sufficient to cause the composition to have an osmolality of
250-350 mOsm.
7. The method of claim 1 wherein said nonionic surfactant is
tyloxapol.
8. The method of claim 7 wherein said tyloxapol is present at a
concentration of 0.05% (wt.).
9. The method of claim 1 wherein said aqueous suspension further
comprises a suspending agent.
10. The method of claim 9 wherein said suspending agent is
hydroxyethylcellulose.
11. The method of claim 10 wherein said hydroxyethylcellulose is
present at a concentration of 0.2% (wt.).
12. The method of claim 1 wherein the aqueous suspension
composition consists essentially of a) 0.1% (wt.) dexamethasone
alcohol; b) 0.35% (wt.) ciprofloxacin hydrochloride, monohydrate;
c) NaCl in an amount sufficient to cause the composition to have an
osmolality of 250-350 mOsm; d) 0.2% (wt.) hydroxyethyl cellulose;
e) 0.05% (wt.) tyloxapol; f) a buffer comprising sodium acetate and
acetic acid; g) 0.01% (wt.) benzalkonium chloride; h) 0.01% (wt.)
edetate disodium; i) 0.6% (wt.) boric acid; and wherein the
composition has a pH of about 4.5.
13. The method of claim 1 wherein the method further comprises the
step of pumping the tragus to force the aqueous suspension
composition through the open tympanic membrane and into the middle
ear.
14. The method of claim 1 wherein the otitis media is acute otitis
media.
15. The method of claim 1 wherein the otitis media is chronic
suppurative otitis media.
16. The method of claim 1 wherein the patient is a pediatric
patient.
17. The method of claim 1 wherein the aqueous suspension
composition containing a combination of ciprofloxacin and
dexamethasone is packaged with directions for use that indicate the
composition may be used to treat otitis media in patients with an
open tympanic membrane.
18. The method of claim 1 wherein the aqueous suspension has a pH
of 3-6.
19. The method of claim 1 wherein said treating comprises treating
otorrhea associated with a middle ear infection.
20. The method of claim 1 wherein said treating comprises treating
acute otitis externa associated with a middle ear infection.
21. The method of claim 1 wherein said treating comprises treating
granulation tissue associated with a middle ear infection.
22. The method of claim 1 wherein four drops of said aqueous
suspension composition are administered to the patients ear twice a
day.
23. A kit for treating otic infections, the kit comprising an
aqueous suspension composition comprising a) 0.01-0.5% (wt.)
dexamethasone; b) 0.1-0.4% (wt.) ciprofloxacin; c) 0.1-0.9% (wt.)
tonicity agent; d) 0.01-0.2% (wt.) of a nonionic surfactant; and e)
a buffer, said composition in a sealed container together with
instructions for use thereof, and wherein said instructions
indicate that four drops of the aqueous suspension composition are
administered to a patients ear twice a day and/or wherein said
instructions indicate that three drops of the aqueous suspension
composition are administered to a patients ear twice a day.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a Continuation (CON) of co-pending U.S.
application Ser. No. 14/838,637 filed Aug. 28, 2015; which is a
Continuation of U.S. application Ser. No. 14/468,257 filed Aug. 25,
2014, now U.S. Pat. No. 9,149,486; which is a continuation of U.S.
application Ser. No. 12/357,697 filed Feb. 13, 2009, now U.S. Pat.
No. 8,846,650; which is a Continuation of Ser. No. 12/119,185 filed
May 12, 2008 now abandoned; which is a Continuation of Ser. No.
10/946,792 filed Sep. 22, 2004 now abandoned; which is a Divisional
of Ser. No. 10/243,341 filed Sep. 13, 2002 now abandoned, priority
of which is claimed under 35 U.S.C. .sctn.120, the contents of
which are incorporated herein by reference. This application also
claims priority under 35 U.S.C. .sctn.119 to U.S. Provisional
Application, Ser. No. 60/323,951, filed Sep. 21, 2001, the contents
of which are incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0002] This invention relates to the use of formulations of
ciprofloxacin and dexamethasone to treat otic infections.
Specifically, the invention relates to the topical use of such a
fixed combination to treat middle ear infections in humans.
[0003] External ear infections, known as acute otitis externa
("AOE"), are currently treated with oral antibiotics, topical
single-entity antibiotics, or topical antibiotic/steroid
combination products. An example of an oral antibiotic product used
to treat AOE is AUGMENTIN.RTM. (amoxicillin and clavulanic acid).
An example of a single-entity antibiotic product approved for
topical use in treating AOE is FLOXIN.RTM. (ofloxacin). Examples of
combination products approved for this use include CORTISPORIN.RTM.
(hydrocortisone, neomycin sulfate, and polymyxin b sulfate) and
CIPRO.RTM. HC (ciprofloxacin and hydrocortisone). A product called
SOFRADEX (gramicidin, framycetin and hydrocortisone) is available
in some European countries and in Australia. External ear
infections typically involve bacteria of the following types:
Pseudomonas aeruginosa, Staphylococcus aureus. Staphylococcus sp.
and Coryneforms.
[0004] In contrast, middle ear infections known as otitis media
("OM") typically involve bacteria of the following types: S.
pneumonia, H. influenzae and M. catarrhalis. Patients with chronic
or severe middle ear infections may have their ear drums (tympanic
membranes) intentionally punctured and drainage tubes, often
referred to as a tympanostomy tubes, implanted. In other cases,
particularly in patients with severe OM, the tympanic membrane may
rupture. Whether surgically punctured or accidentally ruptured,
open tympanic membranes allow the bacteria characteristic of AOE
and OM to mix.
[0005] Patients with OM are currently treated with oral antibiotics
such as AUGMENTIN.RTM.. When drainage through an open tympanic
membrane into the outer ear persists, either an oral antibiotic
(e.g., AUGMENTIN.RTM.) or a topical antibiotic (e.g., FLOXIN.RTM.)
is often prescribed. Additionally, topical antibiotic/steroid
combination products approved for AOE have been used "off-label" in
some cases to treat OM in patients with an open tympanic membrane,
including CORTISPORIN.RTM., CIPRO.RTM. HC, and TOBRADEX.RTM.
(tobramycin and dexamethasone). To date, however, no topical
antibiotic/steroid combination product has been approved by the
Food and Drug Administration in the U.S. for the treatment of OM in
patients with an open tympanic membrane.
[0006] Fixed combination products containing ciprofloxacin and
dexamethasone are known. Although no such product is currently
approved in the U.S., this combination is commercially available
for ophthalmic use in certain countries in South America as
Biomotil-D (Allergan Frumtost) and Cilodex (Alcon Laboratories).
Although the use of ciprofloxacin/dexamethasone combinations for
the treatment of ocular and/or otic infections has been disclosed
in the scientific and patent literature (see, for example, Spanish
Patent Application No. 2,065,846 A1 (Feb. 16, 1995), WO 90/01933
and U.S. Pat. No. 6,284,804), there has been no disclosure of the
use of such a combination specifically for treating OM in patients
with open tympanic membranes.
SUMMARY OF THE INVENTION
[0007] The present invention provides a method of topically
treating OM in human patients who have open tympanic membranes. The
method involves the topical application of a fixed combination of
ciprofloxacin and dexamethasone as an aqueous suspension product.
Although the dosing regimen may vary depending on the age and
weight of the patient, as well as the severity of the infection, in
most cases, the combination product would be applied twice a day.
Each application would involve topically administering three or
four drops into the ear canal, preferably pumping the tragus to
force product through the opening in the tympanic membrane and to
the site of the infection/inflammation in the middle ear.
[0008] Among other factors, the present invention is based on the
finding that an aqueous combination of ciprofloxacin and
dexamethasone was not statistically more effective than
ciprofloxacin alone in the treatment of AOE, but was surprisingly
statistically more effective that ciprofloxacin alone in the
treatment of OM in patients with an open tympanic membrane. The
fact that a contribution of elements for ciprofloxacin and
dexamethasone could be demonstrated for only OM and not AOE was not
predictable, nor was the fact that such a contribution of elements
would be shown in OM.
BRIEF DESCRIPTION OF THE DRAWINGS
[0009] FIG. 1 shows the average number of days to time of cessation
of ear pain in a human clinical study comparing a
ciprofloxacin/dexamethasone combination product to a ciprofloxacin
single-entity product.
[0010] FIG. 2 shows the average number of days to cessation of
otorrhea in a human clinical study comparing a
ciprofloxacin/dexamethasone combination product to a ciprofloxacin
single-entity product.
DETAILED DESCRIPTION OF THE INVENTION
[0011] Unless indicated otherwise, all ingredient amounts presented
as a percentage are in units of weight %.
[0012] The methods of the present invention involve diagnosing a
human patient as having OM and an open tympanic membrane. "Open
tympanic membrane" means that the membrane has been intentionally
punctured, with or without tympanostomy tube implantation, or has
accidentally ruptured. Once diagnosed with OM and an open tympanic
membrane, the method of the present invention involves topically
administering to the ear canal of the patient's affected ear an
aqueous suspension formulation of a fixed combination of
ciprofloxacin and dexamethasone. OM includes, but is not limited
to, acute otitis media and chronic supprative otitis media.
[0013] Dexamethasone can be present in any ophthalmically or
otically acceptable form having poor water solubility such that the
resulting formulation is a suspension formulation. Suitable forms
of dexamethasone include dexamethasone alcohol (alcohol form of
dexamethasone), dexamethasone acetate and dexamethasone phosphate.
Dexamethasone alcohol is the preferred form of dexamethasone. The
average particle size (mean volume basis) of the dexamethasone
ingredient should be less than 10 .mu.m to avoid irritation or
discomfort. The average particle size is preferably less than 6
.mu.m and most preferably less than 3 .mu.m. Dexamethasone
particles can be sized using known techniques, such as
ball-milling, microfluidization and sonication. The ciprofloxacin
ingredient can be any otically acceptable form such that the
ciprofloxacin ingredient is in solution in the final formulation. A
preferred form of ciprofloxacin is ciprofloxacin hydrochloride,
monohydrate.
[0014] The dexamethasone ingredient will comprise about 0.01-0.5%
and the ciprofloxacin ingredient will comprise about 0.1-0.4% of
the aqueous suspension formulations administered according to the
present invention. The preferred amounts of dexamethasone and
ciprofloxacin in the formulations used in the present invention are
0.1% and 0.3%, respectively.
[0015] In addition to the active agents, the suspension
formulations used in the present invention contain a tonicity
agent. The tonicity agent may be ionic (e.g., NaCl) or nonionic
(e.g., mannitol). The tonicity agent is preferably NaCl. The amount
of NaCl will depend on the desired tonicity for the final
formulation, but will generally range from 0.1-0.9%. The suspension
formulations of the present invention preferably contain an amount
of tonicity agent sufficient to cause the formulations to have an
osmolality of about 250-350 mOsm.
[0016] The suspension formulations also contain a nonionic polymer
as a suspending agent. Many otically acceptable nonionic polymers
are known. These polymers include hydroxyethyl cellulose;
hydroxypropylmethyl cellulose; methyl cellulose; carboxymethyl
cellulose; polyvinyl pyrrolidone and polyvinyl alcohol. The
preferred nonionic polymer is hydroxyethyl cellulose. The nonionic
polymer will be present in the formulations of the present
invention in an amount of about 0.1-0.5%. In the case of
hydroxyethyl cellulose, the preferred concentration of nonionic
polymer is 0.2%.
[0017] The formulations of the present invention also contain a
nonionic surfactant in an amount from about 0.01-0.2%. Many
otically acceptable nonionic surfactants are known. Suitable
nonionic surfactants include tyloxapol; polyoxyethylene sorbitan
esters, such as polysorbate 20, polysorbate 60, and polysorbate 80;
polyethoxylated castor oils, such as Cremaphor EL; polyethoxylated
hydrogenated castor oils, such as HCO-40; and poloxamers. The
preferred surfactant is tyloxapol.
[0018] If desired, the formulations may contain a quaternary
ammonium halide as a preservative. Suitable quaternary ammonium
halides include polyquaternium-1 and benzalkonium halides.
Preferred benzalkonium halides are benzalkonium chloride ("BAC")
and benzalkonium bromide. In general, the amount of the
preservative ingredient will range from about 0.005-0.3%. In the
preferred case where the preservative is BAC, it is preferably
present at a concentration of 0.01%.
[0019] If desired, a chelating agent may also be present in the
suspension formulations used in the methods of the present
invention. Suitable chelating agents include edetate disodium
("EDTA"); edetate trisodium; edetate tetrasodium; and
diethyleneamine pentaacetate. Most preferred is EDTA. The chelating
agent, if any, will typically be present in an amount from about
0.001-0.1%. In the case of EDTA, the chelating agent is preferably
present at a concentration of 0.01%.
[0020] In the case of preserved or multi-dose formulations, the
suspension formulations of the present invention may contain boric
acid in an amount from 0.1-1.5%.
[0021] The formulations administered according to the present
invention have a pH from 3-6, preferably 4.5. pH can be adjusted
with NaOH/HCl. The preferred buffering system for these
formulations is a combination of sodium acetate and acetic acid.
The concentration of sodium acetate will generally range from
0.015-0.06%, and will preferably be about 0.03%. The concentration
of acetic acid will generally range from 0.02-0.08, and will
preferably be about 0.04%.
[0022] Though physicians may prescribe other dosing regimens
depending on a number of factors including the severity of the OM,
the age and weight of the patient, etc., the
ciprofloxacin/dexamethasone combination products administered
according to the present invention will generally be administered
twice a day. Each administration will typically involve placing 3-4
drops (with a typical drop volume of 30-35 .mu.L) of the suspension
product in the affected ear. Preferably, the patient will pump the
tragus of the affected ear to force the administered product
through the opening in the tympanic membrane and to the site of the
infection/inflammation in the middle ear.
[0023] In one embodiment, the present invention relates to a
ciprofloxacin/dexamethasone aqueous suspension composition that is
packaged with directions for use that indicate the composition may
be used to treat otitis media in patients with an open tympanic
membrane. As used herein, "directions for use" includes information
contained in product labeling, package inserts and cartons or other
packaging materials that accompany the ciprofloxacin/dexamethasone
aqueous suspension composition of the present invention.
[0024] The following examples are intended to illustrate, but not
limit, the present invention.
Example 1
Representative Formulations
TABLE-US-00001 [0025] A B C D E Ingredients % (w/w) % (w/w) % (w/w)
% (w/w) % (w/w) Ciprofloxacin HCl, 0.35* 0.35 0.35 0.35 0.35
Monohydrate Dexamethasone Alcohol 0.1 0.1 0.1 0.1 0.1 Hydroxyethyl
Cellulose 0.2 0.2 0.2 0.2 0.2 Benzalkonium Chloride 0.01 0.01 0.01
0.01 0.01 Sodium Acetate 0.03 0.03 0.03 0.03 0.03 (Trihydrate)
Acetic Acid 0.04 0.04 0.04 0.04 0.04 Sodium Chloride 0.25 0.25 0.80
0.53 -- Edetate Disodium 0.01 0.01 0.01 0.01 0.01 Tyloxapol 0.05
0.05 0.05 0.05 0.05 Glycerin 1.5 -- -- -- 2.35 Boric Acid -- -- --
0.6 -- NaOH/HCl q.s. pH q.s. pH q.s. pH q.s. pH q.s. pH 4.5 .+-.
0.2 4.5 .+-. 0.2 4.5 .+-. 0.2 4.5 .+-. 0.2 4.5 .+-. 0.2 Purified
Water q.s. 100 q.s. 100 q.s. 100 q.s. 100 q.s. 100 Osmolality
(mOsm) 272 99 274 286 290 *equivalent to 0.3% ciprofloxacin
base
Formulations A-E were made using the following method: [0026] (1)
For a formulation batch size of 500 ml, form a slurry by combining
75 g of 3 mm zirconium beads, 12 g of tyloxapol 1.0% stock solution
and 0.5 g dexamethasone alcohol in a 30 ml polypropylene milling
bottle (approx. 48% of the final batch requirement of tyloxapol is
used); [0027] (2) steam sterilize (autoclave) the slurry, including
beads; [0028] (3) aseptically ball mill the sterilized slurry for
18 hrs at 50 to 55 rpm; [0029] (4) prepare an aqueous solution
containing the remaining requirement of tyloxapol and the required
amounts of all remaining ingredients (e.g., in the case of
Formulation D, the remaining ingredients are ciprofloxacin
hydrochloride monohydrate, benzalkonium chloride, sodium acetate,
acetic acid, sodium chloride, hydroxyethylcellulose, boric acid,
edetate disodium, and purified water; [0030] (5) steam sterilize
(autoclave) the aqueous solution prepared in step (4); [0031] (6)
combine the sterile slurry obtained in step 3 to the sterile
solution obtained in step 5 by aseptically pouring the slurry
through a sterile sieve (to remove the beads) into the solution
obtained in step 5; [0032] (7) adjust the formulation weight to
80-90% of batch weight using sterile-filtered purified water;
[0033] (8) check the final pH and adjust to pH 4.5.+-.0.2 by
sterile-filtered sodium hydroxide or hydrochloric acid, if needed;
and [0034] (9) bring the formulation to 100% of batch weight using
sterile-filtered purified water. An alternative method of preparing
Formulations A-E, especially when the dexamethasone raw material is
supplied or available already meeting the desired particle size
specifications, is as follows: [0035] (1) dry heat sterilize the
dexamethasone raw material (recommended specification: between 7-11
hrs. at 130-140.degree. C. (internal powder temperature); [0036]
(2) prepare a tyloxapol solution containing the batch requirement
of tyloxapol in purified water; [0037] (3) sterilize the tyloxapol
solution by passing it through a 0.2 .mu.m filter; [0038] (4)
aseptically combine the sterilized dexamethasone with the
sterilized tyloxapol solution to form a sterile slurry and stir
until homogenous; [0039] (5) prepare an aqueous solution containing
the required amounts of the remaining ingredients (e.g., in the
case of Formulation D, the remaining ingredients are ciprofloxacin
hydrochloride, monohydrate benzalkonium chloride, sodium acetate,
acetic acid, sodium chloride, hydroxyethylcellulose, boric acid,
edetate disodium and purified water; [0040] (6) steam sterilize
(autoclave) the aqueous solution prepared in step (5); [0041] (7)
aseptically combine the sterile slurry prepared in step (4) with
the sterilized solution prepared in step (6); [0042] (8) adjust the
formulation weight to 80-90% of batch weight using
sterile-filtered, purified water. [0043] (9) check the final pH and
adjust to pH 4.5.+-.0.2 by sterile-filtered sodium hydroxide or
hydrochloric acid, if needed; and [0044] (10) bring the formulation
to 100% of batch weight using sterile-filtered purified water.
Example 2
AOE Clinical Study in Human Patients
[0045] A clinical study with a primary objective of demonstrating
superiority of a ciprofloxacin/dexamethasone combination product
(ciprofloxacin 0.3%, dexamethasone 0.1%; Formulation D above)
("CIPRODEX") relative to the marketed CILOXAN.RTM. single-agent
(ciprofloxacin 0.3%; Alcon Laboratories, Inc.) product for time to
cessation of ear pain in patients with moderate to severe acute
otitis externa (AOE) was conducted. A summary of the study details
for this AOE study is provided below.
TABLE-US-00002 Summary of AOE Study CIPRODEX (Ciprofloxacin 0.3%)
Suspension vs. CILOXAN (Ciprofloxacin 0.3%) Solution vs.
CORTISPORIN Suspension (Neomycin 0.35%, Polymyxin B 10,000 IU/mL,
Hydrocortisone 1.0%) for Topical Treatment of patients with
moderate to severe Acute Otitis Externa (AOE). Study Design: Phase
III multicenter, randomized, single-blind, active controlled,
parallel group study. Study Primary objectives of the study were to
demonstrate: Objectives: Superiority of CIPRODEX combination
relative to CILOXAN single agent for time to cessation of ear pain.
Therapeutic non-inferiority of CIPRODEX combination relative to
CILOXAN single agent based on clinical response at the test of cure
(TOC) visit (Day 18). Therapeutic non-inferiority of CIPRODEX
combination relative to CORTISPORIN combination for clinical
response at the TOC visit. Therapeutic non-inferiority of CILOXAN
single agent relative to CORTISPORIN combination for clinical
response at the TOC visit. Patient A total of 909 patients enrolled
into the study at 48 investigative sites in Population: the United
States between April 1998 and May 2000. Inclusion Clinical
diagnosis of moderate or severe AOE, at least one year of age,
Criteria: gave informed consent, and agreed to follow study
procedures. Posology: Eligible patients were treated for 7 days
with three drops BID CIPRODEX (n = 305), three drops BID CILOXAN (n
= 305), or four drops TID CORTISPORIN (n = 299). Study Visits: Day
1, Day 3, Day 8 (End of Therapy, EOT), and Day 18 (TOC). Clinical
Patient assessment of pain and tenderness using a daily diary.
Evaluation: Physician evaluation of signs and symptoms of AOE,
including inflammation, tenderness, edema, and otic discharge by
visit. Microbiology: Microbiology outcomes were based on presumed
or confirmed bacterial eradication. Efficacy Cessation of ear pain
was defined as the first day where the patient dairy Criteria: pain
score was zero, with no analgesics used in the prior 24 hours, and
the ear pain score remained zero for all subsequent entries.
Physician's assessment of clinical response of the patient at TOC
on a 4-point scale (0 = cured, 1 = improved, 2 = no change, 3 =
worse). Safety Based on the frequency and incidence of adverse
events reported. Evaluation: Overall Time to cessation of pain is
not different between CIPRODEX and Conclusions: CILOXAN treatments
(i.e., no contribution of elements). CIPRODEX is non-inferior to
CILOXAN for clinical cures and microbiological eradication.
CIPRODEX produces more clinical cures than CORTISPORIN and is
non-inferior for microbiological eradication. CILOXAN is superior
to CORTISPORIN for clinical response in culture positive patients,
and non-inferior for microbial eradication. CIPRODEX and CILOXAN
are safe and well tolerated in pediatric and adult patients with
AOE.
[0046] Time to no pain was evaluated for CIPRODEX and CILOXAN, with
the results shown in Table 1 and FIG. 1. These results show the
average number of days to cessation of ear pain for the "modified
intent-to-treat" ("MITT") population of the study. MITT is a term
of art in the clinical sciences. For this study, the MITT
population is defined as the population that received study drug,
met inclusion criteria and was culture positive for bacteria on Day
1. The MITT population for this study comprised 267 patients for
CIPRODEX and 261 patients for CILOXAN.
TABLE-US-00003 TABLE 1 MITT: Time to No Pain (in days) Treatment
Mean Median CIPRODEX 6.8* 5.0 CILOXAN 6.3 5.0 *p-value = 0.29
(Log-Rank Test; Kaplan-Meier Life Table Survival Estimates)
[0047] Data obtained in this AOE study demonstrate that time to
cessation of ear pain was not different between CIPRODEX and
CILOXAN, and therefore, no contribution of elements was shown for
CIPRODEX. These results show a slight advantage for CILOXAN (6.8
days) over CIPRODEX (6.3 days) in average time to no otorrhea, but
the differences were not statistically significant
(p-value=0.29).
Example 3
OM with Open Tympanic Membrane Clinical Study in Human Patients
[0048] A clinical study with a primary objective of showing
therapeutic superiority of CIPRODEX (Formulation D above) relative
to CILOXAN for cessation of otorrhea (ear discharge) in
tympanostomy tube patients with Acute Otitis Media (AOM) was
conducted. A summary of the study details for this OM study is
provided below.
TABLE-US-00004 Summary of AOM Study Safety and Efficacy of Topical
CIPRODEX (Ciprofloxacin 0.3%, Dexamethasone 0.1%) Suspension
Compared to CILOXAN (Ciprofloxacin 0.3%) Solution in the Treatment
of Acute Otitis Media with Tympanostomy Tubes (AOMT) Study Design:
Phase II multicenter, randomized, evaluator-blind, active
controlled, parallel group study. Study The study objectives were
to: Objectives: Demonstrate therapeutic superiority of CIPRODEX
combination relative to CILOXAN single agent for cessation of
otorrhea, and to Evaluate the efficacy and safety of topical
CIPRODEX Suspension in AOMT patients Patient A total of 201
patients enrolled into the study at 21 investigative sites in
Population: the United States between March 2000 and January 2001.
Inclusion Pediatric patients (6 months to 12 years) with a patent
tympanostomy Criteria: tube and clinically diagnosed with acute
otitis media with otorrhea that is visible by the parent/guardian
of 3 weeks or less duration. Posology: Eligible patients were
treated for 7 days with BID CIPRODEX (n = 103) or 7 days with BID
CILOXAN (n = 98). Study Visits: Day 1, Day 3, Day 8 (End of
Therapy, EOT), and Day 14 (Test of Cure, TOC). Clinical Twice daily
patient assessment of cessation of otorrhea using a daily
Evaluation: diary. Physician evaluation of signs and symptoms of
AOMT, including presence of otorrhea, characteristics of otorrhea,
presence of granulation tissue, tube patency, and overall clinical
response by visit. Microbiology: Microbiology outcomes were based
on presumed or confirmed bacterial eradication. Efficacy Cessation
of otorrhea was defined as ending on the first day on which
Criteria: the otorrhea is absent and remains absent for all
subsequent diary entries. Physician's assessment of clinical
response of the patient at TOC on a 4-point scale (0 = resolved, 1
= improved, 2 = no change, 3 = worse). Safety Based on the
frequency and incidence of adverse events reported. Evaluation:
Overall CIPRODEX has a statistically significantly shorter Time to
Conclusions: Cessation of Otorrhea when compared to CILOXAN (using
Log- Rank test of equality over strata). CIPRODEX is statistically
significantly more effective than CILOXAN for Physician's Clinical
Impression at the Day 3 Visit, but not at the Day 8 or Day 14
Visits (using Cochran-Mantel-Haenszel Rank Scores Test). No
statistically significant differences were detected between
CIPRODEX and CILOXAN for Microbiological Eradication Rates at the
Test of Cure Visit (using Fisher's Exact Test). CIPRODEX and
CILOXAN are safe and well tolerated in pediatric with AOMT.
[0049] The results of this study for the MITT population are
presented in Table 2 and FIG. 2. For this study, the MITT
population is defined as the population that received study drug,
met inclusion criteria, participated in at least one on-therapy
visit, and was culture positive for bacteria on Day 1. The MITT
population for this study comprised 87 patients for CIPRODEX and 80
patients for CILOXAN.
TABLE-US-00005 TABLE 2 MITT: Time to No Otorrhea (in days)
Treatment Mean Median Std. N Min. Max. CIPRODEX 4.22* 4 2.04 87 2
10 CILOXAN 5.31 5 1.94 80 2 10 *p-value = 0.0040 (Log-Rank test of
equality over strata)
[0050] The results of this OM demonstrate a clinically and
statistically significant difference in the time to cessation of
otorrhea for CIPRODEX-treated patients (4.03 days) compared to
CILOXAN-treated patients (5.06 days), approximately a 20% reduction
in time to no otorrhea. In this study, contribution of elements for
CIPRODEX was shown.
Example 4
CIPRODEX vs. FLOXIN Study
[0051] A clinical study comparing CIPRODEX (Formulation D above) to
FLOXIN in the treatment of tympanostomy tube patients with Acute
Otitis Media (AOM) was conducted. A summary of the study details
for this OM study is provided below.
Summary of CIPRODEX vs. FLOXIN Study
[0052] Safety and Efficacy of Topical CIPRODEX Otic (Ciprofloxacin
0.3%/Dexamethason 0.1%) Suspension Compared to FLOXIN Otic
(Ofloxacin 0.3%) Solution in the Treatment of Acute Otitis Media
with Tympanostomy Tubes (AOMT)
[0053] Study Design:
[0054] Phase III, randomized, evaluator-masked, active-controlled,
parallel-group study.
[0055] Objectives: [0056] To demonstrate the non-inferiority of
CIPRODEX Otic Suspension relative to FLOXIN Otic Solution in
clinical and microbiological response at the test of cure (TOC)
visit; and [0057] To evaluate the efficacy and safety of CIPRODEX
Otic Suspension for the treatment of patients with acute otitis
media and otorrhea with tympanostomy tubes (AOMT).
[0058] Patient Population:
[0059] Approximately 500 pediatric patients with AOMT and
post-tympanostomy tube otorrhea (250/arm) were planned. A total of
599 patients were enrolled.
[0060] Diagnosis and Main Criteria for Inclusion:
[0061] Pediatric patients, from 6 months to 12 years of age, with a
patent tympanostomy tube, clinically diagnosed with acute otitis
media and otorrhea of 3 weeks or less duration, visible by the
parent/guardian, were enrolled.
[0062] Test Product, Dose and Mode of Administration, Batch
Number(s):
[0063] CIPRODEX Otic (ciprofloxacin 0.3%/dexamethasone 0.1%)
Suspension; topical otic administration of 4 drops into the
infected ear(s) twice daily (BID) for 7 days.
[0064] Duration of Treatment:
[0065] Patients were required to undergo treatment for either seven
(7) days if randomized to receive CIPRODEX or ten (10) days if
randomized to receive FLOXIN.
[0066] Reference Therapy, Dose and Mode of Administration, Batch
Number(s):
[0067] FLOXIN Otic (ofloxacin 0.3%) Solution; topical otic
administration of 5 drops into the infected ear(s) twice daily
(BID) for 10 days.
[0068] Criteria for Evaluation:
[0069] Subsequent to the demonstration of non-inferiority,
superiority analyses were conducted. Analyses for the determination
of superiority were based on the data set of patients who received
treatment, had a positive pre-therapy culture and met the
inclusion/exclusion criteria for enrollment (modified
intent-to-treat, MITT). Analyses were also conducted for the
intent-to-treat (ITT), per protocol (PP) and modified per protocol
(MPP) data sets.
[0070] Efficacy:
[0071] The two primary variables were (1) the clinical response at
the TOC visit; those patients rated as resolved/cured by the
physicians based on a 4-point scale (0=resolved/cured, 1=improved,
2=not changed, 3=worsened); and (2) the microbiological response,
success or failure, at the TOC visit for patients with positive
pre-therapy cultures. Secondary efficacy variables were (1) the
time to cessation of otorrhea as recorded in the patient diary; and
as assessed by the physician's at each visit (2) the clinical
response based on a 4-point scale (0=resolved/cured, 1=improved,
2=not changed, 3=worsened); (3) the granulation tissue based on a
4-point scale (0=none, 1=mild, 2=moderate and 3=severe); (4) the
presence or absence of otorrhea; (5) the otorrhea volume based on a
4-point scale (0=absent, 1=scant, 2=moderate and 3=severe); and the
color/type of otorrhea based on a 5-point scale (0=absent,
1=serous, 2=mucoid, 3=purulent, 4=sanguineous).
[0072] Safety:
[0073] The safety evaluation was conducted on all patients who were
randomized into the study and received at least one dose of study
drug. The safety analysis was based on the following; extent of
exposure to study drug; adverse events; and audiometry
examination.
[0074] Statistical Methods:
[0075] The statistical objective was to demonstrate the
non-inferiority of CIPRODEX relative to FLOXIN in clinical and
microbiological response at the TOC visit. Two-sided 95% confidence
intervals for the difference between proportions between the two
treatment groups were constructed. However, due to the lack of zero
within the confidence limits, non-inferiority was demonstrated, and
analyses allowed for a claim of superiority. Therefore, differences
between the two treatments for clinical and microbiological
response were evaluated using the Chi-square test of independence.
For analyses of the secondary variables, the number and proportion
of patients per response in each treatment group was presented and
differences were assessed using LSMEANS (Mixed Model Analysis of
Variance) or the Chi-square test of independence as appropriate.
The log-rank test (Kaplan-Meier survival analysis was conducted to
compare median time to cessation of otorrhea between the two
treatments.
[0076] Summary--Conclusions: [0077] CIPRODEX Otic Suspension is
superior to FLOXIN Otic Solution in clinical and microbiological
response at the test of cure (TOC) visit; and [0078] CIPRODEX Otic
Suspension is effective and safe for the treatment of pediatric
patients with acute otitis media and otorrhea with tympanosotomy
tubes (AOMT).
[0079] These data demonstrate the superior effectiveness of
CIPRODEX, an antibiotic-steroid combination drug, for the treatment
of AOMT as shown in comparative analyses to a marketed product
approved for the same indication.
[0080] This study evaluated the efficacy and safety of CIPRODEX, an
antibiotic-steroid combination product (ciprofloxacin
0.3%/dexamethasone 0.1%) compared to FLOXIN, which contains
antibiotic alone (ofloxacin 0.3%). The study duration was
approximately three weeks long with four scheduled visits.
Conditions between the treatment groups were identical except for
the study drugs and the respective dosing regimens. Both drugs were
topically administered BID, however, the FLOXIN group received 5
drops per dose for 10 days (per the package insert) and the
CIPRODEX group, 4 drops per dose for 7 days. Outcome differences
between the two groups are therefore attributed to the differences
in treatment.
[0081] Efficacy Results:
[0082] A total of 599 patients were evaluable for the ITT analyses,
424 for the MITT, 460 for the PP and 357 for the MPP analyses. Of
the ITT data set, 62% were male, 81% were Caucasian, 41% enrolled
the right ear, 36% enrolled the left ear, and 23% enrolled both
ears. The mean age was 2.45 years and the mean duration of the
current episode of AOMT was 4.49 days in the right ear and 4.71
days in the left ear. In primary analyses, at the TOC visit,
CIPRODEX was superior to FLOXIN for clinical cures for all data
sets (p.ltoreq.0.0027) and for microbiological eradication for MITT
and MPP data sets (p.ltoreq.0.0061). Additionally, for all data
sets, CIPRODEX was superior to FLOXIN for treatment failure rate
(p.ltoreq.0.0189). In analyses of the secondary efficacy variables,
CIPRODEX was superior to FLOXIN for time to cessation of otorrhea
for all data sets (p.ltoreq.0.018). Clinically, this translates to
the cessation of otorrhea in 20 to 33% less time for the CIPRODEX
treated patients in comparison to the FLOXIN treated patients
(median time of 4 days for CIPRODEX versus 5-6 days for FLOXIN).
For the remaining secondary efficacy variables, improvement in
clinical response, absence of otorrhea, reduction in otorrhea
volume and absence of otorrhea color, CIPRODEX was superior to
FLOXIN at every study visit after baseline (p.ltoreq.0.0023,
p.ltoreq.0.0012, p.ltoreq.0.0003, and p.ltoreq.0.0003,
respectively). Moreover, at study visits Day 11 and Day 18,
CIPRODEX was superior to FLOXIN for reduction in granulation tissue
(p=0.0086 and p=0.0383, respectively). These outcomes demonstrate
that CIPRODEX is not only a more effective treatment for AOMT in
comparison to FLOXIN, but also results in a more rapid response to
treatment and resolution of the clinical signs and symptoms of AOMT
relative to FLOXIN. CIPRODEX is effective in treating acute otitis
media with otorrhea in tympanostomy (AOMT) patients and results in
90% patients with clinical cure, 92% patients with microbiological
success and a 4-day median time to cessation of otorrhea.
[0083] Efficacy Conclusions:
[0084] 1. CIPRODEX is superior to FLOXIN for clinical cures at the
TOC visit.
TABLE-US-00006 Clinical Cure Rates and 95% Confidence Intervals by
Treatment Group (All Data Sets) Treatment CIPRODEX FLOXIN Clinical
Cure Clinical Cure No Yes No Yes Data Set N % N % N % N % Delta
Lower Upper P-value.sup.a ITT 75 25.25 222 74.75 117 38.74 185
61.26 13.49 6.10 20.88 0.0004 MITT 43 20.67 165 79.33 78 36.11 138
63.89 15.44 6.99 23.88 0.0004 PP 28 12.07 204 87.93 50 22.73 170
77.27 10.66 3.71 17.60 0.0027 MPP 18 10.00 162 90.00 37 21.76 133
78.24 11.76 4.17 19.36 0.0025 .sup.aChi-square test of independence
(Fisher's exact test when N < 5).
[0085] 2. CIPRODEX is superior to FLOXIN for microbiological
eradication at the TOC visit.
TABLE-US-00007 Microbiological Eradication Rates and 95% Confidence
Intervals by Treatment Group (All Data Sets) Treatment CIPRODEX
FLOXIN Microbiological Microbiological Eradication Eradication
Failure Success Failure Success Data Set N % N % N % N % Delta
Lower Upper P-value.sup.a ITT 128 43.10 169 56.90 154 50.99 148
49.01 7.90 -0.07 15.87 0.0529 MITT 41 19.71 167 80.29 72 33.33 144
66.67 13.62 5.33 21.91 0.0015 PP 67 28.88 165 71.12 81 36.82 139
63.18 7.94 -0.70 16.58 0.0722 MPP 15 8.33 165 91.67 31 18.24 139
81.76 9.90 2.83 16.97 0.0061 .sup.aChi-square test of independence
(Fisher's exact test when N < 5).
[0086] 3. CIPRODEX is superior to FLOXIN for treatment failure
rate.
TABLE-US-00008 Discontinuations Due to Treatment Failure by
Treatment Group Treatment CIPRODEX FLOXIN Treatment Failure
Treatment Failure Data No Yes No Yes Set N % N % N % N %
P-value.sup.a ITT 281 94.61 16 5.39 270 89.40 32 10.60 0.0189 MITT
199 95.67 9 4.33 192 88.89 24 11.11 0.0091 PP 220 94.83 12 5.17 188
85.45 32 14.55 0.0008 MPP 172 95.56 8 4.44 146 85.88 24 14.12
0.0017 .sup.aChi-square test of independence (Fisher's exact test
when N < 5).
[0087] 4. CIPRODEX is superior to FLOXIN for improvement in
clinical response at Days 3, 11 and 18.
TABLE-US-00009 Clinical Response by Treatment Group (MITT)
Treatment CIPRODEX FLOXIN Visit Clinical Response N % N %
P-value.sup.a Day 3 Missing 1 0 0 0 <.0001 Cured 64 30.92 38
17.59 Improved 130 62.80 134 62.04 Unchanged 9 4.35 35 16.20 Worse
4 1.93 9 4.17 Day 11 Missing 1 0 0 0 <.0001 Cured 174 84.06 136
62.96 Improved 25 12.08 58 26.85 Unchanged 4 1.93 12 5.56 Worse 4
1.93 10 4.63 Day 18 Missing 1 0 0 0 0.0023 Cured 174 84.06 153
70.83 Improved 20 9.66 38 17.59 Unchanged 6 2.90 12 5.56 Worse 7
3.38 13 6.02 .sup.aTreatment difference from LSMEANS (Mixed Model
Analysis of Variance).
[0088] 5. CIPRODEX is superior to FLOXIN for time to cessation of
otorrhea.
TABLE-US-00010 Time to Cessation of Otorrhea by Treatment Group
(MITT) Treatment CIPRODEX FLOXIN P-value.sup.a Mean 6.02 7.10
0.0204 Median 4.00 5.00 Std 4.87 4.68 N 208 216 Min 2 2 Max 21 21
.sup.aLog-rank test (Kaplan-Meier survival analysis).
[0089] 6. CIPRODEX is superior to FLOXIN for absence of otorrhea at
Days 3, 11 and 18.
TABLE-US-00011 Presence/Absence of Otorrhea by Treatment Group
(MITT) Treatment CIPRODEX FLOXIN Visit Otorrhea N % N %
P-value.sup.a Day 1 Present 208 100.00 216 100.00 Day 3 Absent 67
32.21 40 18.52 0.0012 Present 141 67.79 176 81.48 Day 11 Absent 176
84.62 137 63.43 <.0001 Present 32 15.38 79 36.57 Day 18 Missing
1 0 0 0 0.0004 Absent 176 85.02 153 70.83 Present 31 14.98 63 29.17
.sup.aChi-square test of independence (Fisher's exact test when N
< 5).
[0090] 7. CIPRODEX is superior to FLOXIN for reduction in
granulation tissue at Days 11 and 18.
TABLE-US-00012 Granulation Tissue by Treatment Group (MITT)
Treatment CIPRODEX FLOXIN Visit Granulation Tissue N % N %
P-value.sup.a Day 1 Absent 159 76.44 175 81.02 0.3449 Mild 30 14.42
21 9.72 Moderate 15 7.21 16 7.41 Severe 4 1.92 4 1.85 Day 3 Missing
1 0 0 0 0.3285 Absent 177 85.51 182 84.26 Mild 24 11.59 22 10.19
Moderate 6 2.90 10 4.63 Severe 0 0.00 2 0.93 Day 11 Missing 1 0 0 0
0.0086 Absent 198 95.65 186 86.11 Mild 8 3.86 22 10.19 Moderate 1
0.48 8 3.70 Day 18 Missing 1 0 0 0 0.0383 Absent 203 98.07 192
88.89 Mild 3 1.45 21 9.72 Moderate 1 0.48 3 1.39 .sup.aTreatment
difference from LSMEANS (Mixed Model Analysis of Variance).
[0091] 8. CIPRODEX is superior to FLOXIN for reduction in otorrhea
volume at Days 3, 11 and 18.
TABLE-US-00013 Volume by Treatment Group (MITT) Treatment CIPRODEX
FLOXIN Visit Volume N % N % P-value.sup.a 0.3195 Day 1 Scant 17
8.17 14 6.48 Moderate 104 50.00 99 45.83 Copious 87 41.83 103 47.69
Day 3 Missing 1 0 0 0 <.0001 Absent 66 31.88 39 18.06 Scant 98
47.34 84 38.89 Moderate 34 16.43 77 35.65 Copious 9 4.35 16 7.41
Day 11 Missing 1 0 0 0 <.0001 Absent 175 84.54 136 62.96 Scant
19 9.18 42 19.44 Moderate 7 3.38 26 12.04 Copious 6 2.90 12 5.56
Day 18 Missing 2 0 0 0 0.0003 Absent 175 84.95 153 70.83 Scant 14
6.80 21 9.72 Moderate 8 3.88 27 12.50 Copious 9 4.37 15 6.94
.sup.aTreatment difference from LSMEANS (Mixed Model Analysis of
Variance).
[0092] 9. CIPRODEX is superior to FLOXIN for absence of otorrhea
color and less purulent otorrhea at Day 3, and absence of otorrhea
color and less mucoid otorrhea at Days 11 and 18.
TABLE-US-00014 Color/Type by Treatment Group (MITT) Treatment
CIPRODEX FLOXIN Visit Color/Type N % N % P-value.sup.a Day 1 Absent
0 0 0 0 .sup.b Serous 21 60.00 14 40.00 0.2301 Mucoid 100 54.64 83
45.36 0.1417 Purulent 149 46.71 170 53.29 0.0607 Sanguineous 14
48.28 15 51.72 0.8335 Day 3 Absent 67 63.21 39 36.79 0.0003 Serous
55 48.67 58 51.33 0.8593 Mucoid 63 43.75 81 56.25 0.2244 Purulent
36 38.71 57 61.29 0.0461 Sanguineous 1 14.29 6 85.71 0.1244 Day 11
Absent 176 56.23 137 43.77 0.0000 Serous 12 34.29 23 65.71 0.0770
Mucoid 7 15.91 37 84.09 0.0000 Purulent 14 40.00 21 60.00 0.2879
Sanguineous 0 0.00 3 100.00 0.2488 Day 18 Absent 176 53.50 153
46.50 0.0002 Serous 8 44.44 10 55.56 0.7183 Mucoid 7 18.42 31 81.58
0.0001 Purulent 18 41.86 25 58.14 0.3510 Sanguineous 0 0.00 2
100.00 0.4992 .sup.aChi-square test of independence (Fisher's exact
test when N < 5). .sup.b Could not be calculated.
[0093] Safety Results:
[0094] The safety of CIPRODEX and FLOXIN was evaluated in 599
pediatric patients with acute otitis media with tympanostomy tubes.
No serious adverse events related to therapy were reported during
this study. Seventy-eight patients (CIPRODEX: 32; FLOXIN: 46) were
discontinued from the study due to adverse events, of which 76 were
due to treatment-unrelated events. Adverse events in the overall
safety population were all nonserious with the exception of three
reports (abdominal pain, pneumonia, cellulitis), were generally
mild to moderate, usually resolved with or without treatment, and
generally did not interrupt patient continuation in the study.
Similar types of otic and nonotic adverse events were noted in the
infant and toddler population and the children population for
CIPRODEX and FLOXIN. There were no trends observed in the analysis
of adverse events according to age category either within or
between CIPRODEX and FLOXIN treatment groups. Only three patients
in the adolescent population were enrolled, and none of the
adolescents reported adverse events.
[0095] Audiometry testing was performed to further assess the
safety of CIPRODEX in the pediatric population. No clinically
relevant or statistically significant (p=0.3863) difference in mean
change of speech reception threshold (SRT) from baseline was
observed between CIPRODEX and FLOXIN, and no clinically relevant
decrease in hearing from baseline was observed with CIPRODEX or
FLOXIN, based upon an assessment of bone and air conduction
audiometry parameters.
[0096] CIPRODEX administered twice daily in the affected ear(s) is
safe and well tolerated in pediatric patients with acute otitis
media with tympanostomy tubes, based upon a review of adverse
events and an assessment of audiometry parameters.
[0097] Safety Conclusions:
[0098] 1. CIPRODEX administered twice daily in the affected ear(s)
is safe and well tolerated in pediatric patients with acute otitis
media with tympanostomy tubes, based upon a review of adverse
events and an assessment of audiometry parameters.
[0099] 2. Adverse events in the overall safety population were all
nonserious with the exception of three reports (abdominal pain,
pneumonia, cellulitis), were generally mild to moderate, usually
resolved with or without treatment, and generally did not interrupt
patient continuation in the study.
[0100] 3. No clinically relevant or statistically significant
difference in mean change of speech recognition threshold (SRT)
from baseline was observed between CIPRODEX and FLOXIN.
[0101] 4. No clinically relevant decrease in hearing from baseline
was observed with CIPRODEX or FLOXIN, based upon an assessment of
bone and air conduction audiometry parameters.
[0102] The invention has been described by reference to certain
preferred embodiments; however, it should be understood that it may
be embodied in other specific forms or variations thereof without
departing from its spirit or essential characteristics. The
embodiments described above are therefore considered to be
illustrative in all respects and not restrictive, the scope of the
invention being indicated by the appended claims rather than by the
foregoing description.
* * * * *