Introduction
Ketotifen is a second-generation antihistamine and mast cell stabilizer with unique dual mechanisms of action. Originally developed in the 1970s, it has established clinical utility in allergic conditions, particularly in ophthalmology and as an adjunct in asthma management. Unlike many antihistamines, ketotifen provides both immediate symptomatic relief and long-term prophylactic benefits through its mast cell stabilizing properties.
Mechanism of Action
Ketotifen exerts its therapeutic effects through two primary mechanisms: 1. Histamine H₁-receptor antagonism: Competitively blocks histamine binding at H₁ receptors, preventing histamine-mediated allergic responses 2. Mast cell stabilization: Inhibits the release of preformed and newly generated mediators (histamine, leukotrienes, prostaglandins, platelet-activating factor) from mast cells and basophils 3. Additional anti-inflammatory effects: Demonstrates eosinophil chemotaxis inhibition and potential leukotriene antagonism
Indications
FDA-approved indications:- Prevention and temporary relief of ocular itching due to allergic conjunctivitis (ophthalmic solution)
- Off-label uses:
- Prophylactic management of allergic asthma (oral formulation) - Chronic urticaria - Atopic dermatitis - Mast cell disorders
Note: Oral ketotifen is not FDA-approved in the United States but is available in many other countries for asthma prophylaxis.Dosage and Administration
Ophthalmic solution:- Adults and children ≥3 years: 1 drop in affected eye(s) every 8-12 hours
- Adults: 1-2 mg twice daily
- Children >3 years: 0.5-1 mg twice daily
- Initiate with lower doses and titrate based on response and tolerability
- Renal impairment: Use with caution; consider dose reduction
- Hepatic impairment: Use with caution; consider dose reduction
- Geriatric patients: Initiate at lower end of dosing range
- Pregnancy: Category C; use only if potential benefit justifies potential risk
Pharmacokinetics
Absorption:- Oral: Well absorbed (~90% bioavailability); peak plasma concentrations in 2-4 hours
- Ophthalmic: Minimal systemic absorption following ocular administration
- Volume of distribution: ~17 L/kg
- Protein binding: ~75%
- Crosses blood-brain barrier (explains sedative effects)
- Extensive hepatic metabolism via cytochrome P450 system
- Forms inactive metabolites
- Half-life: ~21 hours (allows twice-daily dosing)
- Excretion: Primarily renal (60-70% as metabolites); fecal elimination (10-20%)
Contraindications
- Hypersensitivity to ketotifen or any component of the formulation
- Acute asthmatic attack (not for rescue treatment)
- Ophthalmic use: Contact lens wear (remove lenses before administration)
Warnings and Precautions
- Sedation: May cause drowsiness; warn patients about driving or operating machinery
- Weight gain: Monitor weight regularly, particularly in children
- Paradoxical bronchospasm: Discontinue if worsening bronchospasm occurs
- Ocular effects: May cause burning, stinging, or conjunctival injection
- Withdrawal effects: Taper gradually after long-term use to avoid rebound hyperreactivity
- Phenylketonuria: Some formulations contain aspartame
Drug Interactions
- CNS depressants: Enhanced sedation with alcohol, benzodiazepines, opioids
- Anticholinergic agents: Additive anticholinergic effects
- Enzyme inducers/inhibitors: CYP450 modulators may affect ketotifen levels
- MAO inhibitors: Contraindicated due to increased anticholinergic effects
- Theophylline: Ketotifen may increase theophylline levels
Adverse Effects
Common (≥1%):- Sedation/drowsiness (10-30%)
- Dry mouth (5-15%)
- Weight gain (5-10%)
- Dizziness (5-10%)
- Ophthalmic: Transient burning/stinging (10-25%)
- Headache
- Nausea
- Nervousness
- Increased appetite
- Thickened bronchial secretions
- Anaphylaxis
- Severe bronchospasm
- Blood dyscrasias
- Hepatitis
Monitoring Parameters
- Efficacy: Symptom control, reduction in rescue medication use
- Safety: Sedation level, weight changes, liver function tests (with long-term use)
- Ophthalmic: Corneal integrity with prolonged use
- Asthma: Pulmonary function tests, symptom diaries
- Behavioral: Mood changes, particularly in children
Patient Education
- Take as prescribed; do not exceed recommended dosage
- Ophthalmic: Wait at least 10 minutes before reinserting contact lenses
- Be aware of potential sedation; avoid alcohol and CNS depressants
- Report significant weight gain or behavioral changes
- Do not use for acute asthma attacks
- Store at room temperature; protect from light
- Shake ophthalmic suspension well before use
- Allow 2-4 weeks for full prophylactic effect in asthma
References
1. Grant SM, Goa KL, Fitton A, et al. Ketotifen. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in asthma and allergic disorders. Drugs. 1990;40(3):412-448.
2. Bachert C. Ketotifen in the management of allergic rhinitis and asthma: a review. J Investig Allergol Clin Immunol. 1993;3(6):300-307.
3. Novartis Pharmaceuticals. Zaditor (ketotifen fumarate) prescribing information. 2021.
4. Brogden RN, Speight TM, Avery GS. Ketotifen: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in asthma and allergic disorders. Drugs. 1982;24(2):93-110.
5. Walsh GM. The anti-inflammatory effects of ketotifen. Clin Exp Allergy. 1994;24(11):1032-1035.
6. Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention, 2022.
7. Micromedex Solutions. Ketotifen monograph. Truven Health Analytics, 2023.
8. Pharmaceutical Society of Japan. Japanese Pharmacopoeia, 18th Edition. 2021.
This information is intended for educational purposes only and should not replace professional medical advice. Always consult with a healthcare provider for personalized medical guidance.