CITIGEN

Ketotifen is a benzocycloheptathiophene derivative with potent antihistaminic and mast cell stabilizing properties.

It has a similar structure to some other first-generation antihistamines such as cyproheptadine and azatadine.

Ketotifen was first developed in Switzerland in by Sandoz Pharmaceuticals and was initially marketed for the treatment of anaphylaxis.

In the

US, it is now used in an over-the-counter ophthalmic formulation for the treatment of itchy eyes associated with allergies, 6 and in Canada a prescription-only oral formulation is available and indicated as an add-on therapy for children with atopic asthma.

In addition, oral ketotifen is used in Mexico and across Europe for the treatment of various allergic symptoms and disorders, 3 including urticaria, mastocytosis, and food allergy.

Oral, ketotifen is indicated as an add-on medication in the chronic treatment of mild atopic asthma in children.

It is also available as an over-the-counter ophthalmic solution which is indicated for the temporary prevention of itching of the eye due to allergic conjunctivitis.

Ketotifen is a non-competitive histamine antagonist and mast cell stabilizer.

Oral, it functions as a non-bronchodilator antiasthmatic drug by inhibiting the effects of endogenous substances known to be inflammatory mediators.

While effects can take 6-12 weeks to become apparent, 5 the use of ketotifen has been demonstrated to reduce the frequency, severity, and duration of asthma symptoms, and may allow for a reduction in the use of other asthma therapies.

Following oral administration, absorption is relatively quick (with a T max of ~3 hours) and nearly complete as judged by plasma concentrations and urinary excretion levels.

• despite this, oral bioavailability is only ~50% due to a significant first-pass effect in the liver.

Ketotifen is extensively metabolized in humans and three distinct metabolites have been detected in human urine.

The main metabolite is the

N-glucuronide, comprising roughly 50% of urinary drug product, 5 with the N-demethylated nor-ketotifen and the 10-hydroxyl derivative comprising 2% and <1%, respectively.

Nor-ketotifen appears to be equally as active as its parent drug, 7 though the clinical relevance of this is unclear given the relatively small proportion in which nor-ketotifen is found in the plasma.

Formation of the N-glucuronide metabolite is carried out by several UGT enzymes, including UGT1A3, UGT1A4, and UGT2B10.

Hover over products below to view reaction partners Ketotifen Ketotifen-N-glucuronide 10-alpha-hydroxyl Ketotifen Nor-ketotifen.

More than 60% of an administered dose is excreted in the urine, primarily as metabolites 7.

• of this material, <1% is found as unchanged drug, while the glucuronide and pharmacologically active nor-ketotifen metabolites account for 50% and 10%, respectively.

Ketotifen clearance is biphasic.

• the half-life of the distribution phase is approximately 3-5 hours and the half-life of the elimination phase is 22 hours.

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Oral ingestion of up to 60x the recommended dose has been reported, although no fatal overdoses of ketotifen have been described.

Symptoms of ketotifen overdosage may include significant sedation, confusion, disorientation, tachycardia, hypotension, convulsions, hyperexcitability (particularly in children), and/or reversible coma.

If ingestion is recent, consider the use of gastric lavage or activated charcoal.

Other treatments should be supportive and administered as necessary based on symptoms.

Physostigmine may be useful to mitigate anticholinergic effects, and short-acting barbiturates or benzodiazepines may be used if the patient presents with excitation or convulsions.