Ketotifen

Ketotifen belongs to the pharmacological class of Second generation non competitive antihistamines and mast cell stabilizer.

Ketotifen is an H1 receptor antagonist. Ketotifen appears to have Antihistamine effects.

Ketotifen has been approved for relieving symptoms as well as for the treatment and maintenance of episodes of atopic asthma and allergic conjunctivitis.

After the oral administration, absorption is relatively quick, and the oral; bioavailability is 50% due to the presence of the first-pass effects in the liver. Ketotifen is found to be extensively metabolized in humans, and 3 distinct metabolites have been detected in human urine; the main metabolite is the N-glucuronide, comprising roughly about 50% of urinary drug products, with the N-demethylated nor-ketotifen as well as the 10-hydroxyl derivative comprising 2% and <1%, respectively.

The common side effects associated with Ketotifen are Headache, dizziness, flu symptoms, cold, eye itching, drowsiness, blurred vision, watery eyes, and dry eyes.

Ketotifen is found to be available in the form of ophthalmic solutions, syrups, and oral tablets.

Ketotifen is available in the U.S., Canada, E.U., India, Australia, and Japan.

Ketotifen belongs to the pharmacological class of Second generation non competitive antihistamines and mast cell stabilizer.

Ketotifen is an H1 receptor antagonist. Ketotifen appears to have Antihistamine effects.

Ketotifen is found to be a potent and non-competitive antagonist of H1 histamine receptors, which is likely to be a significant contributor to the anti-allergic activity. In addition, Ketotifen stabilizes mast cells and has demonstrated in vitro the ability to inhibit the release of allergic and inflammatory mediators such as histamine, leukotrienes C4 and D4 (i.e. SRS-A), and platelet-activating factor (PAF).

Ketotifen had been approved for relieving symptoms as well as for the treatment and maintenance of episodes of atopic asthma and allergic conjunctivitis.

Ketotifen of 1mg oral drug had achieved Cmax of 0.53+/-0.12ng/ml and Tmax of about 3.7+/-1.3hr.

The onset of action of Ketotifen is very slow, about 4 to 6 weeks, and the duration of action is 8-12 hours.

Ketotifen is available in ophthalmic solutions, syrups, and oral tablets.

Ketotifen can be used in the treatment of the following conditions:

• Atopic asthma
• Allergic conjunctivitis

Ketotifen can help to relieve symptoms and also for the treatment and maintenance of atopic asthma and allergic conjunctivitis.

Ketotifen is approved for use in the following clinical indications/conditions:

• Atopic asthma
• Allergic conjunctivitis

Atopic asthma

Infants and Children 6 months to 3 years: Initial: 0.05 mg/kg once daily or in 2 divided doses for five days; Maintenance: 0.05 mg/kg/dose twice daily (maximum dose: 1 mg twice daily)

Children >3 years and Adolescents: Initial: 1 mg once daily or in 2 divided doses for five days; Maintenance: 1 mg twice daily

Allergic conjunctivitis:

Children ≥3 years and Adolescents: Ophthalmic: Instill one drop into the lower conjunctival sac of affected eye(s) twice daily (spaced 8 to 12 hours apart). Note: Do not exceed two applications per day.

OTC labeling: Ophthalmic solution: Instill one drop into the affected eyes two times a day

Ophthalmic

Allergic conjunctivitis

0.1 % Ketotifen ophthalmic drops

Systemic

Atopic asthma

Syrup:0.2mg/ml

Tablet: 1mg

Ophthalmic solution and systemic solution.

• Dosage Adjustments in Pediatric Patients:

Infants and Children aged 6 months to 3 years: Initial dose of 0.05 mg/kg once daily or in two divided doses for five days; Maintenance: 0.05 mg/kg/dose two times a day maximum dose up to 1 mg twice daily.

Children aged >3 years and Adolescents: Initial: 1 mg once a day or in 2 divided doses for five days; Maintenance: 1 mg twice daily.

Smoking cessation and maintaining health are a must.

Caffeine should be avoided or limited to use as it might lead to the risk of nausea, palpitations, nervousness, rapid heartbeat, etc.

Alcohol intake should be avoided in patients, especially those with an underlying liver disorder or liver dysfunction.

A diet containing food with high sugar content and carbohydrates should be restricted. This includes pies, cakes, honey, cookies, jams, candies, chips, and bread. It is also advised to reduce or limit the intake of cholesterol and saturated fat and instead chooses poultry, lean meat, or fish.

The dietary restrictions need to be individualized as per the patient's requirements.

Ketotifen may be contraindicated under the following conditions:

• Hypersensitivity to the ingredients of the medication.

The physician should closely monitor the patients and keep pharmacovigilance as follows:

• Hypersensitivity: Hypersensitivity reactions have occurred.

• Sedation: Might cause drowsiness in the early therapy;It is recommended to initiate therapy at one-half the recommended daily dose and gradually increase over five days to maintenance dose; patients must be cautioned about performing tasks that require mental alertness.

• Thrombocytopenia: Rare cases of thrombocytopenia had been reported in patients who are concurrently using oral Ketotifen and oral antidiabetic agents; The manufacturer labeling does not specify associated agents but recommends monitoring platelet counts in patients receiving concomitant therapy.

Disease-related concerns:

• Epilepsy: Use with caution in epileptic patients; it might lower the seizure threshold. Seizures had been reported rarely during therapy.

Special populations:

• Diabetics: Due to the presence of carbohydrate content of the syrup preparation, diabetic patients may need to use a tablet.

Dosage form-specific issues:

• Benzoate allergy: Syrup products may contain benzoate compounds.

Other warnings/precautions:

• Appropriate use: Indicated for prophylactic treatment; not effective for the prevention or treatment of acute bronchospasm. Therapy with agents used for prophylaxis or relief of asthma-related symptoms (e.g., corticosteroids, beta2-agonists, xanthine derivatives) should be maintained for at least 6 to 12 weeks and then gradually reduced as clinically indicated. An immediate increase in corticosteroid dosage may be necessary for patients with severe relapse of symptoms during corticosteroid dose reduction; assess adrenal and pituitary function prior to initiating corticosteroid dose reduction in patients who have received long-term therapy Steroid-dependent patients with adrenocortical insufficiency can take up to one year to recover a normal stress related pituitary-adrenal response.

• Delayed clinical response: Therapeutic effects may not be clinically evident until several weeks after the initiation of therapy; maximum effectiveness usually requires duration of therapy ≥10 weeks. Therapy should be maintained for at least 2 to 3 months to determine effectiveness. If therapy requires discontinuation, gradually reduce over 2 to 4 weeks.

Avoid alcohol usage while on Ketotifen medication, as alcohol can worsen the effects of any underlying disease condition, including conditions such as dizziness, blurred vision, etc.

Ketotifen fumarate has identified in the human breast milk in rats followed by oral administration. It is not known whether the topical ocular administration can result in sufficient systemic absorption to produce the detectable quantities of breast milk. Nevertheless, caution should be exercised when ketotifen fumarate is being administered to a nursing mother.

Pregnancy Category C

The oral treatment of pregnant rabbits during organogenesis with forty five mg/kg/day of Ketotifen i.e.30,000 the Maximum Recommended Human Oral Dose had resulted in an increased incidence of retarded ossification of the sternebrae. However, there were found to be no effects observed in rabbits which were treated with up to 15 mg/kg/day i.e.10,000 times the MRHOD. Similar treatment of rats during organogenesis with 100 mg/kg/day of Ketotifen i.e.66,667 times the MRHOD didn't reveal any biologically relevant effects.

Oral treatment of pregnant rats i.e.up to 100 mg/kg/day or 66,667 times the Maximum Recommended Human Oral Dose and rabbits i.e.up to 45 mg/kg/day or 30,000 times the MRHOD during organogenesis didn't result in any biologically relevant embryofetal toxicity. In the offspring of the rats which received Ketotifen orally from day fifteen of pregnancy to day twenty one post partum at 50 mg/kg/day i.e.33,333 times the Maximum Recommended Human Oral Dose, a maternally toxic treatment protocol, the incidence of postnatal mortality was found to be slightly increased, and the body weight gain during the first four days postpartum was slightly decreased.

No sufficient scientific evidence is traceable regarding the use and safety of Ketotifen in concurrent use with any particular food.

The adverse reactions related to Ketotifen can be categorized as follows:

More common

• Headache

• Muscle aches and pains
• Nausea
• Loss of appetite
• Unusual tiredness or weakness
• VomitinG
• Runny nose
• Diarrhea
• Fever
• A general feeling of discomfort or illness
• Headache
• Shivering
• Sore throat
• Sweating
• Trouble sleeping
• Chills
• Cough
• Joint pain

Rare

• Unpleasant breath odor
• Vomiting of blood
• Yellow eyes or skin
• Dizziness
• Frequent urge to urinate
• Muscle spasms or jerking of all extremities
• Rash
• Abdominal or stomach pain
• Blistering, itching, peeling, or redness of the skin
• Bloody or cloudy urine
• Clay-colored stools
• Convulsions
• Dark urine
• Difficult, burning, or painful urination
• Sudden loss of consciousness

The clinically relevant drug interactions of Ketotifen are briefly summarized here:

A reversible fall in the thrombocyte count in patients receiving Ketotifen concomitantly with oral antidiabetic agents has been observed in rare cases. Thrombocyte counts should therefore be carried out in patients taking oral antidiabetic agents concomitantly. Ketotifen may potentiate the effects of sedatives, hypnotics, antihistamines, and alcohol.

The common side effects of Ketotifen include the following:

Pregnancy

Pregnancy Category C

The oral treatment of pregnant rabbits during organogenesis with forty five mg/kg/day of Ketotifen i.e.30,000 the MRHOD had resulted in an increased incidence of retarded ossification of the sternebrae. However, there were found to be no effects observed in rabbits which were treated with up to 15 mg/kg/day i.e.10,000 times the Maximum Recommended Human Oral Dose. Similar treatment of rats during organogenesis with 100 mg/kg/day of Ketotifen i.e.66,667 times the Maximum Recommended Human Oral Dose didn't reveal any biologically relevant effects.

Oral treatment of pregnant rats i.e.up to 100 mg/kg/day or 66,667 times the Maximum Recommended Human Oral Dose and rabbits i.e.up to 45 mg/kg/day or 30,000 times the Maximum Recommended Human Oral Doseduring organogenesis didn't result in any biologically relevant embryofetal toxicity. In the offspring of the rats which received Ketotifen orally from day fifteen of pregnancy to day twenty one post partum at 50 mg/kg/day i.e.33,333 times the Maximum Recommended Human Oral Dose, a maternally toxic treatment protocol, the incidence of postnatal mortality was found to be slightly increased, and the body weight gain during the first four days postpartum was slightly decreased.

Nursing Mothers

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

Pediatric Use

Safety and efficacy in children below the age of 3 years of age has not been established.

Geriatric Use

There is no overall difference in the efficacy and safety that has been observed between the older and the younger patients.

Physicians should be knowledgeable and vigilant about the treatment pertaining to the treatment and identification of overdosage of Ketotifen.

Overdosages with up to 120 mg Ketotifen fumarate had been reported. The main symptoms of acute overdose include drowsiness to severe sedation; confusion and disorientation; tachycardia and hypotension; convulsions, especially in children; hyperexcitability in children; reversible coma.

Treatment should be symptomatic. If ingestion is very recent, emptying of the stomach may be considered. The administration of activated charcoal may be beneficial. If necessary, specific or symptomatic treatment and monitoring of the cardiovascular system and physostigmine for anticholinergic effects are recommended; if excitation or convulsions are present, short-acting barbiturates or benzodiazepines may be given.

Pharmacodynamics

Ketotifen is found to be a non-competitive histamine antagonist and mast cell stabilizer.When administered orally, it functions as a non-bronchodilator antiasthmatic drug by inhibiting the effects of the endogenous substances known to be inflammatory mediators. While effects can take six to 12 weeks to become apparent, 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.

Pharmacokinetics

• Absorption

Following oral administration of ketotifen fumarate in both men and animals, the absorption is almost complete, as judged by both plasma and urinary excretion levels. The rate of absorption is fast, with a half-life of absorption of less than 1 hour. Bioavailability amounts to about 50% due to a first-pass effect of 50% in the liver.

• Volume of distribution

Distribution studies after oral or intravenous administration in the rat showed a rapid decline in tissue levels of total radioactivity in parallel with blood concentrations. The liver, kidney, and lungs had the highest drug levels. No retention was observed in any of the organs, as confirmed by the macro autoradiographic studies.

• Metabolism

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 products, 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, seven 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.

• Route of elimination

It has been found that more than 60% of an administered dose is excreted in the urine, which is primarily as metabolites - of this material, <1% is found as an unchanged drug, while the glucuronide and pharmacologically active nor-ketotifen metabolites account for 50% and 10%, respectively.

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