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PRODUCT MONOGRAPH
Pr
ZADITOR*
Ketotifen Fumarate Ophthalmic Solution
(0.025% as ketotifen)
Anti-allergy Agent
Novartis Pharmaceuticals Canada Inc.
385 Bouchard Boulevard
Dorval, Quebec
H9S 1A9
Date of Preparation:
June 5, 2008
Submission Control No: 121056
*ZADITOR is a registered trademark
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Table of Contents
PART I: HEALTH PROFESSIONAL INFORMATION.........................................................3
SUMMARY PRODUCT INFORMATION ........................................................................3
INDICATIONS AND CLINICAL USE..............................................................................3
CONTRAINDICATIONS ...................................................................................................3
WARNINGS AND PRECAUTIONS..................................................................................3
ADVERSE REACTIONS....................................................................................................4
DRUG INTERACTIONS....................................................................................................4
DOSAGE AND ADMINISTRATION................................................................................4
OVERDOSAGE ..................................................................................................................5
ACTION AND CLINICAL PHARMACOLOGY ..............................................................5
STORAGE AND STABILITY............................................................................................5
DOSAGE FORMS, COMPOSITION AND PACKAGING ...............................................5
PART II: SCIENTIFIC INFORMATION.................................................................................7
PHARMACEUTICAL INFORMATION............................................................................7
DETAILED PHARMACOLOGY.......................................................................................8
TOXICOLOGY ...................................................................................................................9
REFERENCES ..................................................................................................................11
PART III: CONSUMER INFORMATION..............................................................................12
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ZADITOR*
Ketotifen Fumarate Ophthalmic Solution
PART I: HEALTH PROFESSIONAL INFORMATION
SUMMARY PRODUCT INFORMATION
Route of
Administration
Dosage Form /
Strength
Clinically Relevant Nonmedicinal
Ingredients
Topical (instillation) Ophthalmic Solution
0.025% as ketotifen
Multi dose container: Preservative
benzalkonium chloride 0.01%
For a complete listing see Dosage Forms,
Composition and Packaging section.
INDICATIONS AND CLINICAL USE
ZADITOR* (ketotifen fumarate ophthalmic solution) is indicated for:
$ treatment of allergic conjunctivitis.
CONTRAINDICATIONS
$ Patients who are hypersensitive to this drug or to any ingredient in the formulation or
component of the container. For a complete listing, see the Dosage Forms, Composition
and Packaging section of the product monograph.
WARNINGS AND PRECAUTIONS
General
For topical use only. Not for injection or oral use.
Multi Dose Container: As with all ophthalmic preparations containing benzalkonium chloride,
patients are advised not to instill ZADITOR* (ketotifen fumarate ophthalmic solution) while
wearing soft (hydrophilic) contact lenses. Wearers of soft contact lenses should be instructed to
remove lenses prior to instillation of drops and to wait at least ten minutes after instilling
ZADITOR™ before they insert their contact lenses.
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To prevent contaminating the dropper tip and solution, care should be taken not to touch the
eyelids or surrounding areas with the dropper tip of the bottle. Keep the bottle tightly closed
when not in use.
Special Populations
Pregnant Women: There are no clinical trials on the use of ZADITOR* (ketotifen fumarate
ophthalmic solution) in pregnant or nursing women, therefore, ZADITOR* should not be used
during pregnancy, except if the benefit justifies the potential risk to the foetus.
Pediatrics (> 3 years of age): ZADITOR* is indicated for use in pediatric patients over the age
of 3 years.
ADVERSE REACTIONS
Adverse Drug Reaction Overview
In controlled clinical studies with ZADITOR* (ketotifen fumarate ophthalmic solution),
conjunctival injection was the most common ocular adverse reaction related to therapy, with a
reported incidence of 7.0%. Headache was the most common non-ocular adverse reaction related
to therapy, with a reported incidence of 1.5%. The occurrence of these side effects were
generally mild and did not result in discontinuation or interruption of trial medication.
The following ocular adverse reactions related to therapy were reported at an incidence of less
than 3%.
Itching, dry eyes, burning or stinging, eyelid disorder and discharge.
DRUG INTERACTIONS
Overview
If ZADITOR* (ketotifen fumarate ophthalmic solution) is used concomitantly with other eye
medications, patients should be advised to wait at least 5 minutes between the medications.
DOSAGE AND ADMINISTRATION
Dosing Considerations
Single dose containers:
$ The contents remain sterile until the original closure is broken.
$ Single dose containers must be discarded after use.
• After opening a blister, any unused single-dose containers should be discarded after 4
weeks unless they have been stored in the outer carton, in which case they should be
discarded after 3 months.
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Recommended Dose and Dosage Adjustment
The recommended dose is one drop in the affected eye(s) every 8 to 12 hours.
OVERDOSAGE
Oral ingestion of the contents of a 5 mL bottle would be equivalent to 1.25 mg of ketotifen
fumarate. Clinical results have shown no serious signs or symptoms after the ingestion of up to
20 mg of ketotifen fumarate.
ACTION AND CLINICAL PHARMACOLOGY
Mechanism of Action
Ketotifen is a fast acting non-competitive histamine antagonist (H1-receptor). In addition,
ketotifen inhibits the release of mediators from mast cells involved in hypersensitivity reactions.
Decreased chemotaxis and activation of eosinophils has also been demonstrated. Additionally,
ketotifen attenuates the effects of PAF and inhibits cAMP phosphodiesterase.
In human conjunctival allergen challenge studies, ZADITOR* (ketotifen fumarate ophthalmic
solution) was significantly more effective than placebo in preventing ocular itching and redness
associated with allergic conjunctivitis. The effect was seen within minutes after administration
and lasted up to 12 hours.
Pharmacodynamics
In human conjunctival allergen challenge studies, ZADITOR* was significantly more effective
than placebo in preventing ocular itching and redness associated with allergic conjunctivitis. The
effect was seen within minutes after administration and lasted up to 12 hours.
In a placebo-controlled clinical study designed to evaluate safety, ZADITOR*, administered four
times a day for 6 weeks, was shown to be safe and well-tolerated in subjects aged 3 years and
older.
STORAGE AND STABILITY
Multi dose containers: Store between 4°C and 25°C.
Single dose containers
: Store between 4°C and 25°C. After opening a blister, unused single
dose containers may be stored for 4 weeks. Single dose containers may be stored outside the
blister in the outer carton for 3 months.
DOSAGE FORMS, COMPOSITION AND PACKAGING
Multi dose containers
: Each mL of ZADITOR* (ketotifen fumarate ophthalmic solution)
contains:
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Active: 0.345 mg ketotifen fumarate equivalent to 0.25 mg ketotifen.
Preservative: benzalkonium chloride 0.01%
Inactives: glycerol, hydrochloric acid/sodium hydroxide and purified water.
Single dose containers
: Each mL of ZADITOR*(ketotifen fumarate ophthalmic solution)
contains:
Active: 0.345 mg ketotifen fumarate equivalent to 0.25 mg ketotifen.
Inactives: glycerol, sodium hydroxide and water for injection.
Packaging :
Multi dose containers
: ZADITOR* is available in multi dose in white plastic bottles with
controlled dropper tips containing 5 mL of clear solution.
Single dose containers: ZADITOR* is available in preservative-free single dose, transparent
containers containing 0.4 mL of clear solution. Blocks of 5 single dose containers are each
packed in a blister. Carton boxes of 30 single dose containers are available.
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PART II: SCIENTIFIC INFORMATION
PHARMACEUTICAL INFORMATION
Drug Substance
Proper name: Ketotifen fumarate
Chemical name: 4,9-Dihydro-4-(1-methyl-4-piperidylidene)-
10Hbenzo[4,5]cyclohepta[1,2-b] thiophen-10-one fumarate
Molecular formula: C19H19NOS + C4H4O4
Molecular Weight: 425.50
Structural formula:
Physicochemical properties:
Description:
Fine crystalline, white to yellowish or brown-tinged yellowish
powder
Solubility: In the form of the hydrogen fumarate, it is soluble in water.
pH:
The pH of a 1.2% solution in water is 3.6
pKa Value Ka I = 8.43 ± 0.11
Estimated with ketotifen base by linear extrapolation with values
from 5 different mixtures in ethanol/water.
Melting Point
: Ketotifen hydrogen fumarate melts with decomposition at about
190ºC. Ketotifen hydrogen fumarate with 2.5 H
2
0 melts at
approximately 130ºC.
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DETAILED PHARMACOLOGY
Pharmacodynamics
Ketotifen is a benzocycloheptathiophene derivative. Based upon animal pharmacology studies, it
exerts anti-anaphylactic and antihistaminic activities, mainly through inhibition of the release of
chemical mediators such as histamine and leukotrienes from sensitized mast cells. It also inhibits
platelet activating factor (PAF)-induced acute bronchoconstrictor response, airway
hyperresponsiveness and accumulation of eosinophils in the airways as well as antigen-induced
degranulation of eosinophils in allergic subjects. In addition, ketotifen exhibits a powerful and
sustained non-competitive H1-receptor blocking activity distinctly dissociated from its
antianaphylactic properties.
The efficacy of ophthalmic solutions of ketotifen fumarate was evaluated by a method utilizing
dye leakage in the conjunctiva and/or eyeball following intravenous Evans blue dye. The
procedure was originally described as an indicator of accelerated permeability in IgE-mediated
conjunctivitis in rats. Ketotifen suppressed dye leakage dose dependently in a model system in
which allergic-like effects were induced in the eyes of rats by the single instillation of compound
48/80, which induces the release of histamine and other inflammatory/allergy mediators from
mast cells leading to ocular edema. Topical ketotifen ophthalmic solution also resulted in dose-
dependent inhibition of vascular permeability in passive anaphylactic IgE-mediated
conjunctivitis in rats and guinea pigs. These positive effects on IgE-mediated conjunctivitis in
rats were also supported by an improved histopathological picture.
Pharmacokinetics
After topical single or repeated administrations of 50 mL drops of approximately 10 mg/mL in
albino rabbits, the highest levels of radioactivity were found in the cornea, the conjunctiva, the
sclera and the iris, soon after drug administration. In these structures, the experimental Tmax was
15 minutes, and levels decreased rapidly thereafter. In a whole body autoradiography study in
male albino rats, it was shown that the instilled test substance migrated from around the eyes to
the nasal and oral cavities via the lacrimal ducts, then to the digestive tract. Tissue migration,
other than to the ocular tissues, following ocular instillation, does not differ fundamentally from
the distribution following oral administration. .
The urinary excretion rate was 9.8% after ocular instillation. This rate was found quite similar to
urinary excretion rates after oral (10.5%) or intravenous (13.0%) administrations. In addition, the
fecal excretion rate after ocular instillation (83.3%) was not significantly different than the rate
after oral (94.0%) or intravenous (82.9%) administration.
After a single topical administration, the highest AUCs were found in the cornea, then the
conjunctiva, the iris and the anterior sclera. Levels of ketotifen were 5-14 fold higher in most
tissues 6 hours after multiple topical administrations as compared to the levels after a single
administration (except from the plasma and aqueous humor, where a 2-fold rise was observed).
The kinetics in blood and plasma after ocular instillation were similar. The half-life was
approximately 1.5 hours, while the AUC was 0.3-0.4 mg·hr/mL, and the mean residence time in
the body was approximately 3 hours. The mean level was found as low as 0.1-0.2 mg/mL during
the steady state with administration at 24-hour intervals.
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Clinical Pharmacology
In human conjunctival allergen challenge studies, ZADITOR* (ketotifen fumarate ophthalmic
solution) was significantly more effective than placebo in preventing ocular itching and redness
associated with allergic conjunctivitis. The effect was seen within minutes after administration
and lasted up to 12 hours.
In a placebo-controlled clinical study designed to evaluate safety, ZADITOR*, administered four
times a day for 6 weeks, was shown to be safe and well-tolerated in subjects aged 3 years and
older.
TOXICOLOGY
The acute toxicity of ketotifen fumarate has been investigated in mice, rats and rabbits. Oral
LD50 values were 165, mg/kg, 360 mg/kg and 790 mg/kg in mice, rats and rabbits, respectively.
Subchronic and chronic oral toxicity studies in rats and dogs demonstrated that the liver was a
target organ for ketotifen fumarate toxicity. In general, toxicity was observed only after
long-term administration of ketotifen fumarate at doses up to 700 times those required to obtain
antiallergic and anti-histaminic effects.
In a 4-week ocular toxicity study in rabbits, ketotifen fumarate concentrations of up to 0.267%
were classified as practically nonirritating, while 1.104% was considered minimally irritating. In
a 13-week ocular study in rabbits, ketotifen fumarate at a concentration of 0.069% was classified
as practically nonirritating, while concentrations of 0.276% to 1.104% were classified as
minimally irritating. In both studies, histopathological and ultrastructural evaluations revealed no
abnormalities in ocular tissue.
A chronic toxicity study was conducted with ketotifen fumarate in albino and pigmented rabbits.
Administration of ketotifen fumarate ophthalmic solution 0.025% BID or QID had no effects on
mortality, clinical signs, body weight, food consumption, ophthalmoscopic examinations,
hematology, clinical chemistry, and urinalysis. No treatment-related findings were observed in
gross and histopathological examinations of the tissues and organs particularly on the eye and
adnexa.
Carcinogenesis: Ketotifen fumarate demonstrated no carcinogenic effects in lifetime studies in
mice and rats at dietary doses more than 70,000 times and 59,000 times the maximum
recommended ocular human use level of 0.0012 mg/kg/day for a 50 kg adult respectively.
Mutagenesis: No mutagenic potential was observed when ketotifen fumarate was tested in a
battery of in vitro tests including: a bacterial mutation (Ames) test, a bacterial reverse mutation
(Ames) test, a mammalian chromosome aberration test and a mutagenicity test in V79 Chinese
hamster cells or in the following in vivo tests: a mouse dominant lethal test, a mouse
micronucleus test and a Chinese hamster chromosome aberration test on bone marrow cells.
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Reproduction and Teratology: There was no evidence of impaired fertility or reproductive
capability in studies with ketotifen fumarate in male rats at 8,330 times and in female rats at
41,000 times the maximum recommended ocular human use level. Teratology and peri- and
post-natal studies have been conducted with ketotifen fumarate in rats and rabbits. At 80,000
times and 37,000 times the maximum recommended ocular human use level, ketotifen fumarate
was shown not to be teratogenic in rats and rabbits respectively and no effects on peri/post-natal
development were observed in rats at 37,000 times the maximum recommended ocular human
use level.
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REFERENCES
1. Abelson MB, Chambers WA and Smith LM. Conjunctival Allergen Challenge – A
Clinical approach to Studying Allergic Conjunctivitis. Arch Opthamol 1990; 108:84-88.
2. Abelson MB, McGarr PJ and Richard KP. Antiallergic Therapies in Textbook of Ocular
Pharmacology. Ed. TJ Zimmerman et al. Lippincott-Raven Publishers, Philadelphia;
1997:609-633.
3. Ishizaki M et al. Long-Term Use of Ketotifen Ophthalmic Solution in the Treatment of
Allergic Conjunctivitis and Vernal Conjunctivitis. Progress in Medicine 1989; 9(5):1625-
1634.
4. Mikuni I et al. Evaluation of Ketotifen Ophthalmic Solution in Efficacy and Safety on
Allergic Conjunctivitis and Vernal Conjunctivitis - Result on Multiclinic Open Trial.
Rinsho Iyaku (J Clin Ther Med) 1988; 4(12):2371-2383.
5. Mikuni I et al. Clinical Effect of Ketotifen Ophthalmic Solution on Allergic
Conjunctivitis and Vernal Conjunctivitis - Multicenter Double Blind Study in
Comparison with Sodium Cromoglycate Ophthalmic Solution. Clin Eval 1989;
17(2):275-297.
Page 12 of 14
PART III: CONSUMER INFORMATION
ZADITOR*
Ketotifen Fumarate Ophthalmic Solution
Single dose container
This leaflet is part III of a three-part "Product Monograph"
published when ZADITOR* was approved for sale in Canada
and is designed specifically for Consumers. This leaflet is a
summary and will not tell you everything about ZADITOR*.
Contact your doctor or pharmacist if you have any questions
about the drug.
ABOUT THIS MEDICATION
What the medication is used for:
$ Treatment of seasonal allergic conjunctivitis (itchy, watery, red
or swollen eyes and/or eyelids) for adults and children over 3
years old.
What it does:
ZADITOR* is an anti-allergy agent.
When it should not be used:
Do not use ZADITOR* if you are allergic to ketotifen or any of the
nonmedicinal ingredients or any component of the container.
What the medicinal ingredient is:
Ketotifen fumarate
What the important nonmedicinal ingredients are:
Glycerol, water for injection, sodium hydroxide.
What dosage forms it comes in:
Transparent plastic containers containing 0.4mL of clear 0.025%
ketotifen solution. Blocks of 5 single dose containers are each
packed in a blister. The blisters are packed in carton boxes of 30
containers.
WARNINGS AND PRECAUTIONS
Before using ZADITOR*, tell your doctor if:
you are pregnant or breastfeeding
you wear contact lenses
INTERACTIONS WITH THIS MEDICATION
If you are using ZADITOR* with any other eye medications, you
must wait at least 5 minutes between the use of each medication
PROPER USE OF THIS MEDICATION
For topical use only.
Usual dose:
The usual dose is one drop of ZADITOR* in the affected eye
every 8 to 12 hours.
• The contents of the container remain sterile until the original
closure is broken. You must use the contents immediately
after the container has been opened.
• Discard the container after use. This is to avoid the risk of
microbial contamination of the product.
• After opening a blister, any unused single-dose containers
should be discarded after 4 weeks unless they have been
stored in the outer carton, in which case they should be
discarded after 3 months.
How to use your medication
:
• In order to receive the optimum benefits from ZADITOR*, it
is essential to use the eye drops regularly (usually 2 to 3 times
a day) as directed by your physician.
• Cut pouch along dotted line and remove the strip of single use
units. Tear off one single dose unit from the strip (figure 1).
• Hold it by the tab with the nozzle pointing downwards and tap
the unit gently until all the air bubbles are above the solution.
• Twist the tab off the single dose unit (figure 2). Make sure that
the tip of the unit does not touch anything.
• Hold the single dose unit in one hand between the thumb and
forefinger. With your head tilted back (figure 3), use the fore-
finger of your other hand to pull down the lower lid of your
eye.
• Place the single dose unit tip close to your eye, but without
touching your eye or lid, and gently squeeze the unit to allow
one drop to be applied (figure 4).
• Close your eyelid and gently press the inner corner of your
eye with your forefinger for one minute (figure 5).
• Discard the single dose unit and the remaining solution.
Missed Dose:
If a dose of this medication has been missed, it should be taken as
soon as possible. However, if it is almost time for the next dose,
skip the missed dose and go back to the regular schedule. Do not
double doses.
SIDE EFFECTS AND WHAT TO DO ABOUT THEM
The most common side effects are red eyes and headache.
Other side effects are itching, dry eyes, burning or stinging in the
eyes, sore eyelids and discharge from the eyes.
This is not a complete list of side effects. For any unexpected
effects while taking ZADITOR*, contact your doctor or
pharmacist.
IMPORTANT: PLEASE READ
Page 13 of 14
HOW TO STORE IT
Store between 4ºC and 25ºC.
After opening a blister pack, unused containers may be stored for 4
weeks. Single dose containers may be stored outside the blister in
the carton box for 3 months.
REPORTING SUSPECTED SIDE EFFECTS
To monitor drug safety, Health Canada collects
information on serious and unexpected effects of drugs . If
you suspect you have had a serious or unexpected reaction
to this drug you may notify Health Canada by:
toll-free telephone: 866-234-2345
toll-free fax 866-678-6789
By email: [email protected]
By regular mail:
National AR Centre
Marketed Health Products Safety and Effectiveness
Information Division
Marketed Health Products Directorate
Tunney’s Pasture, AL 0701C
Ottawa ON K1A 0K9
NOTE: Before contacting Health Canada, you should
contact your physician or pharmacist.
MORE INFORMATION
This document plus the full product monograph, prepared for
health professionals can be obtained by contacting the sponsor,
Novartis Pharmaceuticals Canada Inc., at:
1-866-393-6337
This leaflet was prepared by
Novartis Pharmaceuticals Canada Inc.
Dorval, QC
H9S 1A9
Last revised: June 5, 2008
* ZADITOR is a registered trademark
Page 14 of 14
PART III: CONSUMER INFORMATION
ZADITOR*
Ketotifen Fumarate Ophthalmic Solution
Multi dose container
This leaflet is part III of a three-part "Product Monograph"
published when ZADITOR* was approved for sale in Canada
and is designed specifically for Consumers. This leaflet is a
summary and will not tell you everything about ZADITOR*.
Contact your doctor or pharmacist if you have any questions
about the drug.
ABOUT THIS MEDICATION
What the medication is used for:
Treatment of seasonal allergic conjunctivitis (itchy, watery, red or
swollen eyes and/or eyelids).
What it does:
ZADITOR* is an anti-allergy agent.
When it should not be used:
Do not use ZADITOR* if you are allergic to ketotifen or any of the
nonmedicinal ingredients or any component of the container.
What the medicinal ingredient is:
Ketotifen fumarate
What the important nonmedicinal ingredients are:
Benzalkonium chloride, glycerol, hydrochloric acid/sodium
hydroxide, purified water.
What dosage forms it comes in:
White plastic bottles with controlled dropper tips, containing 5 mL
of clear 0.025% ketotifen solution.
INTERACTIONS WITH THIS MEDICATION
If you are using ZADITOR* with any other eye medications, you
must wait at least 5 minutes between the use of each medication
PROPER USE OF THIS MEDICATION
Usual dose:
The usual dose is one drop of ZADITOR* in the affected eye
every 8 to 12 hours.
• If you wear contact lenses, you should remove your lenses
before using ZADITOR*. Before you put your contact lenses
back in, you should wait at least 10 minutes after using
ZADITOR*.
• To avoid contamination, do not touch any surface with the tip
of the container.
Missed Dose:
If a dose of this medication has been missed, it should be taken as
soon as possible. However, if it is almost time for the next dose,
skip the missed dose and go back to the regular schedule. Do not
double doses.
SIDE EFFECTS AND WHAT TO DO ABOUT THEM
The most common side effects are red eyes and headache.
Other side effects are itching, dry eyes, burning or stinging in the
eyes, sore eyelids and discharge from the eyes.
This is not a complete list of side effects. For any unexpected
effects while taking ZADITOR*, contact your doctor or
pharmacist.
HOW TO STORE IT
Store between 4ºC and 25ºC.
REPORTING SUSPECTED SIDE EFFECTS
To monitor drug safety, Health Canada collects
information on serious and unexpected effects of drugs . If
you suspect you have had a serious or unexpected reaction
to this drug you may notify Health Canada by:
toll-free telephone: 866-234-2345
toll-free fax 866-678-6789
By email: [email protected]
By regular mail:
National AR Centre
Marketed Health Products Safety and Effectiveness
Information Division
Marketed Health Products Directorate
Tunney’s Pasture, AL 0701C
Ottawa ON K1A 0K9
NOTE: Before contacting Health Canada, you should
contact your physician or pharmacist.
MORE INFORMATION
This document plus the full product monograph, prepared for
health professionals can be obtained by contacting the sponsor,
Novartis Pharmaceuticals Canada Inc., at:
1-866-393-6337
This leaflet was prepared by
Novartis Pharmaceuticals Canada Inc.
Dorval, QC
H9S 1A9
Last revised: June 5, 2008
* ZADITOR is a registered trademark
