Ketotifen
Ketotifen
Generic Name
Ketotifen
Mechanism
- Histamine H1‑receptor antagonism – competitively blocks H1 receptors on mast cells, epithelial, and smooth‑muscle cells, reducing vasodilation, pruritus, and bronchospasm.
- Mast‑cell stabilizer – inhibits Ca²⁺ influx into mast cells, preventing degranulation and release of histamine, leukotrienes, prostaglandins, and cytokines.
- Neurokinin‑1 (NK1) receptor antagonism – may contribute to anti‑emetic and anti‑seizure properties.
The combination of receptor blockade and degranulation inhibition yields a broad anti‑allergic effect.
Pharmacokinetics
| Parameter | Typical Value |
| Absorption | Oral bioavailability ~20–25 % (limited by first‑pass). Intranasal application bypasses systemic metabolism. |
| Distribution | Extensive tissue distribution; high volume of distribution (~6–10 L/kg). Crosses the blood‑brain barrier, explaining CNS side effects. |
| Metabolism | Predominantly by CYP1A2 and CYP2D6 to inactive metabolites. Hepatic metabolism is linear. |
| Elimination | Renally excreted (~35 %) and via feces (~55 %). Half‑life ~12 h for oral; ~15–20 h for intranasal, allowing twice‑daily dosing. |
| Protein Binding | ~77 % to plasma proteins, mainly albumin. |
Indications
| Indication | Formulation | Typical Use |
| Allergic conjunctivitis | Ophthalmic drops 1 mg/mL | 1–2 drops q12h |
| Allergic rhinitis | Intranasal spray 0.1 mg/actuation | 1 actuation q12h per nostril |
| Asthma/bronchial hyperreactivity | Oral 1 mg BID (historical, limited evidence) | Add‑on for persistent symptoms |
| Migraine prophylaxis | Oral 1 mg BID (off‑label) | Early onset of prophylaxis |
| Pruritus or urticaria | Oral or topical (rare) | Adjunct after H1‑antagonists |
> Note: While ketotifen is FDA‑approved only for ocular and nasal use, its systemic antihistamine and mast‑cell stabilizing properties have led to off‑label use in asthma and migraine prophylaxis.
Contraindications
- Contraindications
- Hypersensitivity to ketotifen or any excipient.
- Severe hepatic impairment (due to first‑pass metabolism).
- Warnings
- CNS effects – drowsiness, sedation, dizziness; caution with driving or operating machinery.
- Pregnancy – Category C; use only if benefits outweigh risks.
- Breastfeeding – minimal data; generally avoided.
- Liver disease – dose adjustment may be needed.
- Pediatrics – data limited; use primarily ophthalmic formulation.
- Precautions
- Monitor for anaphylactic reactions in patients with known severe allergies.
- May mask early signs of infection due to anti‑inflammatory effects; keep under review.
Dosing
| Formulation | Adult Dose | Pediatric Dose | Frequency |
| Ophthalmic drops | 1–2 drops in affected eye(s) | 1–2 drops (age >2 yr) | Q12h |
| Intranasal spray | 1 actuation (0.1 mg) per nostril | 1 actuation (age >2 yr) | Q12h |
| Oral tablets (1 mg) | 1 mg BID | 0.5–1 mg BID | BID |
| Formulation adjustment | Juvenile (<2 yr) | Apneal; avoid systemic | — |
• Administration cautions
• Use preservative‑free preparations in contact lens wearers.
• Ensure correct measuring device – intranasal spray delivered via puff, not spray bottle.
Adverse Effects
| Adverse Effect | Frequency | Comments |
| CNS – drowsiness, fatigue, headache | ~10–20 % | May preclude daytime use; avoid alcohol. |
| Local irritation – burning, stinging (drops) | <5 % | Mild; often transient. |
| Palpitations, tachycardia | <2 % | Rare; monitor in patients with cardiac disease. |
| Weight gain/edema | <1 % | Occurs mainly with chronic oral use. |
| Allergic reactions – rash, pruritus | <1 % | Severe reactions graded as anaphylaxis. |
| Gastrointestinal upset | <1 % | Nausea, constipation. |
| Glaucoma/sight changes | Rare | Ocular formulation may elevate intraocular pressure in predisposed patients. |
| Serious systemic toxicity (rare) | <0.01 % | Hypersensitivity, severe CNS depression. |
Monitoring
| Parameter | Frequency | Rationale |
| Symptom assessment – itching, congestion, ocular discharge | Baseline, 1 wk, 1 mo | Determine efficacy. |
| Intraocular pressure (IOP) | Baseline, 1 mo, if unstable | Detect steroid‑like pressure rise. |
| Pulse & BP | Baseline, 1 wk, 1 mo (oral use) | Identify tachycardia or hypotension. |
| Weight | Baseline ± 1 mo | Detect chronic weight gain. |
| Liver function | Baseline, 1 mo (oral use) | Detect hepatotoxicity with high-dose uses. |
| Pregnancy test | Baseline (female) | Safety concern in pregnancy. |
Clinical Pearls
- Dual‑action profile – unlike other antihistamines, ketotifen both blocks H1 receptors and prevents mast‑cell degranulation; this is why it remains a mainstay in ophthalmic allergic conjunctivitis.
- Intranasal spray pre‑treatment – give twice daily for 2–3 days before a high‑allergen season; patients often see a 30–50 % reduction in symptoms compared with antihistamine spray alone.
- Topical ocular uses – do not give eye drops together with artificial tears or contact lens solutions; ketotifen’s preservatives can interact with those products, causing irritation.
- Neurokinin‑1 blockade – useful for migraine prophylaxis; consider ketotifen when valproate or propranolol are contraindicated or not tolerated.
- Pediatric dosing – avoid systemic (oral) ketotifen in children under 5 years; use the ophthalmic drops only.
- Heat‑induced respiratory reactions – ketotifen’s mast‑cell stabilizing effect can blunt exercise‑induced bronchospasm in susceptible individuals; a low dose (0.5 mg BID) can be trialed in controlled settings.
- Drug‑interaction check – patients on cimetidine (a CYP1A2 inhibitor) may experience higher serum ketotifen leading to increased sedation; dose adjustment may be necessary.
- Preservative‑free formulations – consider for tear‑film disorders where pheromone irritation may exacerbate symptoms.
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• Key Takeaway: Ketotifen uniquely combines antihistamine activity with mast‑cell stabilization, making it the drug of choice for allergic eye disease and a useful adjunct in conditions with mast‑cell involvement such as asthma, migraines, and certain skin disorders. Use dosing guidelines, be watchful for CNS effects, and monitor for ocular and systemic side effects for optimal patient care.