Product Monograph - Zaditor (Laboratoires Thea)
RECENT MAJOR LABEL CHANGES
| 4 DOSAGE AND ADMINISTRATION- 4.1 Dosing Considerations | 07/2024 |
|---|---|
| 4 DOSAGE AND ADMINISTRATION- 4.4 Administration | 07/2024 |
| 7 WARNINGS AND PRECAUTIONS – General | 07/2024 |
| 7 WARNINGS AND PRECAUTIONS – 7.1 Special Populations | 07/2024 |
TABLE OF CONTENTS
Sections or subsections that are not applicable at the time of authorization are not listed.
RECENT MAJOR LABEL CHANGES ............................................................................................ 2
TABLE OF CONTENTS .............................................................................................................. 2
PART I: HEALTH PROFESSIONAL INFORMATION ...................................................................... 4
1 INDICATIONS ............................................................................................................... 4
1.1 Pediatrics .............................................................................................................. 4
1.2 Geriatrics .............................................................................................................. 4
2 CONTRAINDICATIONS ................................................................................................. 4
4 DOSAGE AND ADMINISTRATION ................................................................................. 4
4.1 Dosing Considerations .......................................................................................... 4
4.2 Recommended Dose and Dosage Adjustment ..................................................... 4
4.4 Administration ...................................................................................................... 4
4.5 Missed Dose ......................................................................................................... 4
5 OVERDOSAGE .............................................................................................................. 5
6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ................................. 5
7 WARNINGS AND PRECAUTIONS .................................................................................. 5
7.1 Special Populations ............................................................................................... 5
7.1.1 Pregnant Women ............................................................................................. 5
7.1.2 Breast-feeding: ................................................................................................. 6
7.1.3 Pediatrics .......................................................................................................... 6
8 ADVERSE REACTIONS .................................................................................................. 6
8.1 Adverse Reaction Overview .................................................................................. 6
8.2 Clinical Trial Adverse Reactions ............................................................................ 6
8.3 Less Common Clinical Trial Adverse Reactions .................................................... 6
8.5 Post-Market Adverse Reactions ........................................................................... 7
9 DRUG INTERACTIONS .................................................................................................. 7
9.2 Drug Interactions Overview .................................................................................. 7
10 CLINICAL PHARMACOLOGY ......................................................................................... 7
10.1 Mechanism of Action ............................................................................................ 7
10.2 Pharmacodynamics .............................................................................................. 8
10.3 Pharmacokinetics ................................................................................................. 8
11 STORAGE, STABILITY AND DISPOSAL ........................................................................... 9
12 SPECIAL HANDLING INSTRUCTIONS ............................................................................. 9
PART II: SCIENTIFIC INFORMATION ....................................................................................... 10
13 PHARMACEUTICAL INFORMATION ............................................................................ 10
14 CLINICAL TRIALS ........................................................................................................ 11
16 NON-CLINICAL TOXICOLOGY ..................................................................................... 11
PATIENT MEDICATION INFORMATION .................................................................................. 12
PART I: HEALTH PROFESSIONAL INFORMATION
1 INDICATIONS
ZADITOR* (ketotifen fumarate ophthalmic solution) is indicated for:
- treatment of allergic conjunctivitis.
1.1 Pediatrics
- Pediatrics (> 3 years of age): ZADITOR* is indicated for use in pediatric patients over the age of 3 years.
1.2 Geriatrics
- Geriatrics: No data are available to Health Canada; therefore, Health Canada has not authorized an indication for geriatric use
2 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 6 DOSAGE FORMS, COMPOSITION AND PACKAGING section of the product monograph.
4 DOSAGE AND ADMINISTRATION
4.1 Dosing Considerations
- Wearer of soft contact lenses should be instructed to remove lenses prior to instillation of drops and to wait at least 15 minutes after instilling ZADITOR* before inserting their contact lenses.
- To avoid contamination, do not touch any surface with the tip of the container.
4.2 Recommended Dose and Dosage Adjustment
- The recommended dose is one drop in the affected eye(s) every 8 to 12 hours.
4.4 Administration
Wash hands carefully prior to instillation.
To avoid contamination do not touch eye, eyelids or any surface with the dropper tip.
To administer close the effected eye and use nasolacrimal occlusion for 1-2 minutes after administration. This will help to reduce systemic absorption.
Close the bottle after every use.
4.5 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 apply double doses.
5 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.
| For management of a suspected drug overdose, contact your regional poison control centre. |
|---|
6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING
Table 1 – Dosage Forms, Strengths, Composition and Packaging
ZADITOR* is available in multi dose in white plastic bottles with controlled dropper tips containing 5 mL of clear solution.
Each mL of ZADITOR* (ketotifen fumarate ophthalmic solution) contains:
Medicinal ingredient: 0.345 mg ketotifen fumarate equivalent to 0.25 mg ketotifen.
Preservative: benzalkonium chloride 0.01%
Non-medicinal ingredients: see Table 1 for complete list.
7 WARNINGS AND PRECAUTIONS
General
For topical use only. Not for injection or oral use.
Benzalkonium chloride may be absorbed by soft contact lenses and may change the colour of the contact lenses. Remove contact lenses prior to application and wait at least 15 minutes before reinsertion.
Benzalkonium chloride may also cause eye irritation, especially in dry eyes or disorders of the cornea.
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.
Driving and using machines
Any patient who experiences blurred vision or somnolence should not drive or operate machines.
7.1 Special Populations
7.1.1 Pregnant Women
There are no clinical trials on the use of ZADITOR* (ketotifen fumarate ophthalmic solution) in pregnant or nursing women. Animal studies using maternally toxic oral doses showed increased pre- and
| Route of Administration | Dosage Form / Strength/Composition | Non-medicinal Ingredients |
| Ophthalmic | Ophthalmic Solution 0.025% as ketotifen | Benzalkonium chloride, glycerol, hydrochloric acid/sodium hydroxide and water for injections |
postnatal mortality, but no teratogenicity. Therefore, ZADITOR* should not be used during pregnancy, except if the benefit justifies the potential risk to the foetus.
7.1.2 Breast-feeding:
Animal data following oral administration show excretion into breast milk. It is unknown whether topical ocular administration of ZADITOR is excreted in human breast milk. Caution should be exercised when ZADITOR is administered to a nursing mother.
7.1.3 Pediatrics
Pediatrics (> 3 years of age): ZADITOR* is indicated for use in pediatric patients over the age of 3 years.
8 ADVERSE REACTIONS
8.1 Adverse Reaction Overview
In controlled clinical studies with ZADITOR* (ketotifen fumarate ophthalmic solution), conjunctival hyperemia 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.
8.2 Clinical Trial Adverse Reactions
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The most frequently reported ocular adverse reaction was conjunctival hyperemia and the most common non-ocular adverse reaction was headache (Table 2).
Table 2: Adverse Reactions Reported by ≥ 1% of Subjects Receiving ZADITOR
| Adverse reaction | Number of subjects (Incidence (%)) |
|---|---|
| Conjunctival hyperaemia | 29 (7.0%) |
| Eye irritation / Eye pain | 19 (4.6%) |
| Eye pruritus | 12 (2.9%) |
| Dry eye | 10 (2.4%) |
| Eye discharge | 9 (2.2%) |
| Eyelid disorder | 7 (1.7%) |
| Headache | 6 (1.5%) |
8.3 Less Common Clinical Trial Adverse Reactions
The less common adverse reactions (<1%) are presented below.
Cardiac disorders: tachycardia
Eye disorders: visual impairment, conjunctivitis, foreign body sensation in eye, keratitis, corneal lesion, photophobia, mydriasis
General disorders and administration site conditions: asthenia
Infection and infestations: rhinitis
Nervous system disorders: somnolence
Skin and subcutaneous tissue disorders: rash
8.5 Post-Market Adverse Reactions
The following post marketing events have also been observed (frequency not known):
Eye disorders: punctate keratitis, punctate corneal epithelial erosion, vision blurred (during installation) and conjunctival haemorrhage
Gastrointestinal disorders: dry mouth
Immune system disorders: hypersensitivity
Hypersensitivity reactions including local allergic reaction (mostly contact dermatitis, eye swelling, eyelid pruritis and oedema), systemic allergic reactions including facial swelling/oedema (in some cases associated with contact dermatitis) and exacerbation of pre-existing allergic conditions such as asthma and eczema.
Nervous system disorders: dizziness
Skin and subcutaneous tissue disorders: eczema, urticaria
9 DRUG INTERACTIONS
9.2 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. If an eye ointment is applied, it should be applied last.
The use of oral dosage forms of ketotifen may potentiate the effects of Central Nervous System depressants, antihistamines and alcohol. Although this has not been observed with ketotifen eye drops, the possibility of such effects cannot be excluded.
10 CLINICAL PHARMACOLOGY
10.1 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.
10.2 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.
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.
10.3 Pharmacokinetics
Absorption
In a pharmacokinetic study conducted in 18 healthy human volunteers with ketotifen fumarate (0.025% w/v) eye drops, plasma levels of ketotifen after twice daily ocular administration for 14 days were, in most cases, below the limit of quantitation (20 pg/ml).
In animial studies, 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.
Distribution
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.
After a single topical ocular administration of 50µL of 0.025% ketotifen solution in rabbit, 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.
11 STORAGE, STABILITY AND DISPOSAL
Store between 4°C and 25°C. After opening the bottle, the eye drops can only be stored for 4 weeks.
12 SPECIAL HANDLING INSTRUCTIONS
No special requirements.
PART II: SCIENTIFIC INFORMATION
13 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 and molecular mass: C19H19NOS + C4H4O4, 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 H2O melts at approximately 130oC.
14 CLINICAL TRIALS
Detailed data on which indications were initially approved is not available in the product monograph.
16 NON-CLINICAL TOXICOLOGY
General 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 non-irritating, 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 non-irritating, 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.
Genotoxicity: No mutagenic potential was observed when ketotifen fumarate was tested in a battery of in vitro tests including: bacterial mutation (Ames) tests, 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.
Carcinogenicity: 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.
Reproductive and Developmental Toxicology: 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.