Denerel

Adults and children 3 years of age and older: Put 1 drop in the affected eye(s) twice daily, every 8-12 hours, no more than twice per day.

Children under 3 years of age: Consult a doctor.

WARNINGS

For topical ophthalmic use only. Not for injection or oral use.

PRECAUTIONS

See PATIENT INFORMATION section.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Ketotifen fumarate was determined to be non-mutagenic in a battery of in vitro and in vivo mutagenicity assays including: Ames test, in vitro chromosomal aberration test with V79 Chinese hamster cells, in vivo micronucleus assay in mouse, and mouse dominant lethal test.

Treatment of male rats with oral doses of ketotifen ³10 mg/kg/day orally [6,667 times the maximum recommended human ocular dose of 0.0015 mg/kg/day on a mg/kg basis (MRHOD)] for 70 days prior to mating resulted in mortality and a decrease in fertility. Treatment with ketotifen did not impair fertility in female rats receiving up to 50 mg/kg/day of ketotifen orally (33,333 times the MRHOD) for 15 days prior to mating.

Pregnancy

Pregnancy Category C

Oral treatment of pregnant rabbits during organogenesis with 45 mg/kg/day of ketotifen (30,000 times the MRHOD) resulted in an increased incidence of retarded ossification of the sternebrae. However, no effects were observed in rabbits treated with up to 15 mg/kg/day (10,000 times the MRHOD). Similar treatment of rats during organogenesis with 100 mg/kg/day of ketotifen (66,667 times the MRHOD) did not reveal any biologically relevant effects.

Oral treatment of pregnant rats (up to 100 mg/kg/day or 66,667 times the MRHOD) and rabbits (up to 45 mg/kg/day or 30,000 times the MRHOD) during organogenesis did not result in any biologically relevant embryofetal toxicity. In the offspring of the rats that received ketotifen orally from day 15 of pregnancy to day 21 post partum at 50 mg/kg/day (33,333 times the MRHOD), a maternally toxic treatment protocol, the incidence of postnatal mortality was slightly increased, and body weight gain during the first four days post partum was slightly decreased.

Nursing Mothers

Ketotifen fumarate has been identified in breast milk in rats following oral administration. It is not known whether topical ocular administration could result in sufficient systemic absorption to produce detectable quantities in breast milk. Nevertheless, caution should be exercised when ketotifen fumarate is administered to a nursing mother.

Pediatric Use

Safety and effectiveness in pediatric patients below the age of 3 years have not been established.

Any patient who experiences blurred vision or somnolence should not drive or operate machines.

In controlled clinical studies, conjunctival injection, headaches, and rhinitis were reported at an incidence of 10 to 25%. The occurrence of these side effects was generally mild. Some of these events were similar to the underlying ocular disease being studied.

The following ocular and non-ocular adverse reactions were reported at an incidence of less than 5%:

Ocular: Allergic reactions, burning or stinging, conjunctivitis, discharge, dry eyes, eye pain, eyelid disorder, itching, keratitis, lacrimation disorder, mydriasis, photophobia, and rash.

Non-Ocular: Flu syndrome, pharyngitis.

Oral ingestion of the contents of a 5 mL bottle would be equivalent to 1.725 mg of ketotifen fumarate. Clinical results have shown no serious signs or symptoms after the ingestion of up to 20 mg of ketotifen fumarate.

Pharmacotherapeutic group: Ophthalmologicals, other antiallergics

ATC code: S01GX08

Ketotifen is a histamine H1-receptor antagonist. In vivo animal studies and in vitro studies suggest the additional activities of mast cell stabilisation and inhibition of infiltration, activation and degranulation of eosinophils.

In a pharmacokinetic study conducted in 18 healthy volunteers with Zaditen eye drops, plasma levels of ketotifen after repeated ocular administration for 14 days were in most cases below the limit of quantitation (20pg/ml).

After oral administration, ketotifen is eliminated biphasically with an initial half-life of 3 to 5 hours and a terminal half-life of 21 hours. About 1% of the substance is excreted unchanged in the urine within 48 hours and 60 to 70% as metabolites. The main metabolite is the practically inactive ketotifen-Nglucuronide.

Preclinical data reveal no special hazard which is considered relevant in connection with use of Zaditen eye drops in humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction.

Not applicable.

No special requirements.