ketotifen

Ketotifen, an antihistamine medication and a mast cell stabilizer, is most commonly sold as a salt with fumaric acid, ketotifen fumarate, and is available in two forms:

1. in its ophthalmic form (eye drops or drug-eluting contact lenses),{{cite journal |vauthors=Ono J, Toshida H |title=Use of Ketotifen Fumarate-Eluting Daily Disposable Soft Contact Lens in Management of Ocular Allergy: Literature Review and Report of Two Cases |journal=Cureus |volume=14 |issue=7 |pages=e27093 |date=July 2022 |pmid=36000122 |pmc=9391663 |doi=10.7759/cureus.27093 |doi-access=free | title-link=doi }}{{cite web|url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d222d68c-911e-48a9-9bde-a1ca7e992d18|title=Acuvue Theravision with ketotifen |website=DailyMed |date=11 March 2022|archive-url=https://web.archive.org/web/20231203205156/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d222d68c-911e-48a9-9bde-a1ca7e992d18 |archive-date=3 December 2023|url-status=live}}{{cite journal |vauthors=García-Martín E, Canto G, Agúndez JA |title=Metabolic considerations of drugs in the treatment of allergic diseases |journal=Expert Opin Drug Metab Toxicol |volume=9 |issue=11 |pages=1437–52 |date=November 2013 |pmid=23902458 |doi=10.1517/17425255.2013.823400 |s2cid=30634949}} it is used to treat allergic conjunctivitis;{{cite journal |vauthors=Dou XY, Zhang W |title=Topical ketotifen treatment for allergic conjunctivitis: a systematic review and Meta-analysis |journal=Int J Ophthalmol |volume=16 |issue=2 |pages=286–292 |date=2023 |pmid=36816214 |pmc=9922628 |doi=10.18240/ijo.2023.02.17 |doi-access=free | title-link=doi }}{{cite web | title=Zaditor- ketotifen fumarate solution | website=DailyMed | date=13 February 2020 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ac66b1e4-c2b0-a4c3-09e3-ebd44a2f7c9f | access-date=4 September 2020 | archive-date=11 June 2021 | archive-url=https://web.archive.org/web/20210611120517/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ac66b1e4-c2b0-a4c3-09e3-ebd44a2f7c9f | url-status=live }}
2. in its oral form (tablets or syrup), it is used to prevent asthma attacks or anaphylaxis,{{cite journal | vauthors = Zuberbier T, Asero R, Bindslev-Jensen C, Walter Canonica G, Church MK, Giménez-Arnau AM, Grattan CE, Kapp A, Maurer M, Merk HF, Rogala B, Saini S, Sánchez-Borges M, Schmid-Grendelmeier P, Schünemann H, Staubach P, Vena GA, Wedi B | title = EAACI/GA(2)LEN/EDF/WAO guideline: management of urticaria | journal = Allergy | volume = 64 | issue = 10 | pages = 1427–1443 | date = October 2009 | pmid = 19772513 | doi = 10.1111/j.1398-9995.2009.02178.x | s2cid = 14587946 }}{{cite conference | vauthors = Li Z, Celestin J |date=23 February 2015 |title=Ketotifen: A Role in the Treatment of Idiopathic Anaphylaxis |conference=American Academy of Allergy, Asthma & Immunology Annual Meeting |location=Houston }} as well as various mast cell, allergic-type disorders.{{cite journal |doi=10.1016/j.ejmhg.2015.04.003 |title=The relation between antihistamine medication during early pregnancy & birth defects |journal=Egyptian Journal of Medical Human Genetics |volume=16 |issue=4 |pages=287–90 |year=2015 | vauthors = Shawky RM, Seifeldin NS |doi-access=free | title-link=doi }}{{cite journal | vauthors = Zuberbier T | title = A Summary of the New International EAACI/GA(2)LEN/EDF/WAO Guidelines in Urticaria | journal = The World Allergy Organization Journal | volume = 5 | issue = Suppl 1 | pages = S1–S5 | date = January 2012 | pmid = 23282889 | pmc = 3488932 | doi = 10.1186/1939-4551-5-S1-S1 | doi-access = free | title-link = doi }}

Ketotifen ophthalmic solution (eye drops) relieves and prevents eye itchiness and/or irritation associated with most seasonal allergies. It starts working within minutes after administering the drops. Ketotifen in the form of eye drops has not been studied in children under three years old, whereas drug-eluting contact lenses have not been studied in children under eleven years old.

Drug-eluting contact lenses, which release ketotifen medication, are used to help prevent itchy eyes caused by allergies. The lenses can also correct vision problems, namely, nearsightedness and farsightedness. These lenses are meant for people who don't have red eyes, can comfortably wear contact lenses, and have less than 1 degree of astigmatism.

Oral ketotifen is used to treat asthma, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, chronic urticaria (hives), cold-induced urticaria, cholinergic urticaria, exercise-induced urticaria, systemic mast cell diseases such as mastocytosis and mast cell activation syndrome (MCAS), as well as allergic and nonallergic anaphylaxis. Ketotifen has also shown efficacy in managing angioedema and food allergies.

As an antihistamine medication, ketotifen acts by blocking the H₁ histamine receptors, which are found on various cells in the body, such as smooth muscle, endothelium, and nerve cells.{{cite journal |vauthors=Thangam EB, Jemima EA, Singh H, Baig MS, Khan M, Mathias CB, Church MK, Saluja R |title=The Role of Histamine and Histamine Receptors in Mast Cell-Mediated Allergy and Inflammation: The Hunt for New Therapeutic Targets |journal=Front Immunol |volume=9 |issue= |pages=1873 |date=2018 |pmid=30150993 |pmc=6099187 |doi=10.3389/fimmu.2018.01873|doi-access=free }} This blocking prevents the binding of histamine to these receptors and thus reduces the symptoms of histamine-mediated reactions, such as itching, sneezing, wheezing,{{cite journal |vauthors=Simons FE, Simons KJ |title=Histamine and H1-antihistamines: celebrating a century of progress |journal=J Allergy Clin Immunol |volume=128 |issue=6 |pages=1139–1150.e4 |date=December 2011 |pmid=22035879 |doi=10.1016/j.jaci.2011.09.005}}{{cite journal |vauthors=Linton S, Hossenbaccus L, Ellis AK |title=Evidence-based use of antihistamines for treatment of allergic conditions |journal=Ann Allergy Asthma Immunol |volume=131 |issue=4 |pages=412–420 |date=October 2023 |pmid=37517656 |doi=10.1016/j.anai.2023.07.019 |url=}} and swelling.{{cite journal |vauthors=Ormerod AD |title=Urticaria. Recognition, causes and treatment |journal=Drugs |volume=48 |issue=5 |pages=717–30 |date=November 1994 |pmid=7530629 |doi=10.2165/00003495-199448050-00006}}

As a mast cell stabilizer to treat MCAS, oral ketotifen prevents the release of histamine and other inflammatory substances from mast cells, which are immune cells that react to allergens. Therefore, ketotifen, by blocking a calcium channel essential for mast cell activation,{{cite journal |vauthors=Sastre E, Caracuel L, Xavier FE, Balfagón G, Blanco-Rivero J |title=Opposite effect of mast cell stabilizers ketotifen and tranilast on the vasoconstrictor response to electrical field stimulation in rat mesenteric artery |journal=PLOS ONE |volume=8 |issue=8 |pages=e73232 |date=2013 |pmid=23977380 |pmc=3748149 |doi=10.1371/journal.pone.0073232 |doi-access=free |bibcode=2013PLoSO...873232S |url=}} helps reduce symptoms of allergic conditions. These allergic conditions include asthma, hay fever, and conjunctivitis caused by mast cell activation. Calcium channels are proteins in mast cell membranes that allow calcium ions to enter the cell, triggering the release of histamine and other inflammatory substances. When these channels open, calcium floods into the cells, causing them to degranulate.{{cite book|isbn=978-94-007-2888-2|date=14 February 2012|doi=10.1007/978-94-007-2888-2_44 |chapter=Calcium Signaling in Mast Cells: Focusing on L-Type Calcium Channels |title=Calcium Signaling |series=Advances in Experimental Medicine and Biology |volume=740 |pages=955–977 |pmid=22453979 | vauthors = Suzuki Y, Inoue T, Ra C }}{{cite journal |vauthors=Holowka D, Wilkes M, Stefan C, Baird B |title=Roles for Ca2+ mobilization and its regulation in mast cell functions: recent progress |journal=Biochem Soc Trans |volume=44 |issue=2 |pages=505–9 |date=April 2016 |pmid=27068962 |pmc=5293407 |doi=10.1042/BST20150273}} By blocking these channels, ketotifen prevents this process, reducing allergic reactions. In Canada, Europe, and Mexico, oral ketotifen is commonly prescribed for these indications (asthma, hay fever, and conjunctivitis caused by mast cell activation).{{cite journal | vauthors = El-Alali EA, Abukhiran IM, Alhmoud TZ | title = Successful use of montelukast in eosinophilic gastroenteritis: a case report and a literature review | journal = BMC Gastroenterology | volume = 21 | issue = 1 | pages = 279 | date = July 2021 | pmid = 34238222 | pmc = 8265096 | doi = 10.1186/s12876-021-01854-x | doi-access = free | title-link = doi }} In patients with MCAS, ketotifen reduces episodes of flushing, gastrointestinal symptoms (such as abdominal pain, diarrhea), respiratory symptoms (such as wheezing), and other systemic manifestations. Still, treatment plans for MCAS typically involve a combination of medications targeting different aspects of mast cell activation along with lifestyle modifications to minimize triggers.{{cite journal |vauthors=Frieri M |title=Mast Cell Activation Syndrome |journal=Clin Rev Allergy Immunol |volume=54 |issue=3 |pages=353–365 |date=June 2018 |pmid=25944644 |doi=10.1007/s12016-015-8487-6 |s2cid=5723622 }}

The maximum antihistamine and mast cell stabilizing effect of oral ketotifen is achieved on long-term administration, and a period of at least 6-12 weeks is necessary for a maximum therapeutic effect to start.{{cite journal | url=https://doi.org/10.1378/chest.82.1.30S | doi=10.1378/chest.82.1.30S | title=An Overview of Ketotifen | date=1982 | journal=Chest | volume=82 | issue=1 Suppl | pages=30s–32s | pmid=6806019 | vauthors=MacDonald G | url-access=subscription | access-date=17 July 2024 | archive-date=17 July 2024 | archive-url=https://web.archive.org/web/20240717165310/https://doi.org/10.1378/chest.82.1.30S | url-status=live }} The sedation side effect decreases over time during such long-term administration, but the antihistamine and mast cell stabilizing properties persist even if administered for 12 months or longer.{{cite journal | url=https://link.springer.com/article/10.1007/BF03259336 | doi=10.1007/BF03259336 | title=Ketotifen | date=1996 | journal=Clinical Immunotherapeutics | volume=5 | issue=5 | pages=400–411 | vauthors=Markham A, Goa KL | access-date=17 July 2024 | archive-date=6 August 2024 | archive-url=https://web.archive.org/web/20240806000924/https://link.springer.com/article/10.1007/BF03259336 | url-status=live | url-access=subscription }}

Oral ketotifen is available at compounding pharmacies in the United States with a prescription requirement, still, the use of oral ketotifen is only approved by the Food and Drug Administration (FDA) for adults and older children with asthma or allergic conditions. However, ketotifen eye drops are approved in the US for people who are at least three years of age.{{cite web|url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/022388s000lbl.pdf|year=2022|title=Acuvue Theravision with ketotifen (etafilcon A drug-eluting contact lens with ketotifen), for ophthalmic use|access-date=13 April 2024|archive-date=8 March 2024|archive-url=https://web.archive.org/web/20240308064948/https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/022388s000lbl.pdf|url-status=live}} In the EU, ketotifen oral formulatios (syrup, tables and capsules) are approved by the European Medicines Agency for adult use.{{Cite web |url=https://www.ema.europa.eu/en/documents/psusa/ketotifen-oral-formulations-list-nationally-authorised-medicinal-products-psusa00001813201710_en.pdf |title=List of nationally authorised medicinal products|publisher=European Medicines Agency|date=14 June 2018 |access-date=13 April 2024 |archive-date=13 April 2024 |archive-url=https://web.archive.org/web/20240413010133/https://www.ema.europa.eu/en/documents/psusa/ketotifen-oral-formulations-list-nationally-authorised-medicinal-products-psusa00001813201710_en.pdf |url-status=live }} In the UK, ketotifen is available as tables and elixir (liquid).{{cite web | url=https://ukmasto.org/ketotifen-update-4th-december-2019/#gsc.tab=0 | title=Ketotifen Update (4th December 2019) | date=4 December 2019 | access-date=13 April 2024 | archive-date=29 November 2023 | archive-url=https://web.archive.org/web/20231129085408/https://ukmasto.org/ketotifen-update-4th-december-2019/#gsc.tab=0 | url-status=live }}

Oral ketotifen can be used as a long-term control medication for asthma and wheeze in children, and it has been shown to improve the control of asthma by reducing the need for bronchodilators, decreasing symptoms, preventing exacerbations, and reducing the use of rescue oral steroids, ketotifen has also been found to be effective when used alone or in combination with other medications. Oral ketotifen is an alternative to inhaled therapy for asthma in children, especially for younger children who may have difficulty using inhalers.{{cite journal |vauthors=Schwarzer G, Bassler D, Mitra A, Ducharme FM, Forster J |title=Ketotifen alone or as additional medication for long-term control of asthma and wheeze in children |journal=Cochrane Database Syst Rev |volume=2004 |issue=1 |pages=CD001384 |date=2004 |pmid=14973969 |pmc=8406918 |doi=10.1002/14651858.CD001384.pub2 }}

The mean elimination half-life of oral ketotifen is 12 hours.{{cite journal | vauthors = Grahnén A, Lönnebo A, Beck O, Eckernäs SA, Dahlström B, Lindström B | title = Pharmacokinetics of ketotifen after oral administration to healthy male subjects | journal = Biopharmaceutics & Drug Disposition | volume = 13 | issue = 4 | pages = 255–262 | date = May 1992 | pmid = 1600111 | doi = 10.1002/bdd.2510130404 | s2cid = 72293850 }} Besides its anti-histaminic activity, it is also a functional leukotriene antagonist{{cite journal |vauthors=Zhu TH, Zou G, Ding SJ, Li TT, Zhu LB, Wang JZ, Yao YX, Zhang XM |title=Mast cell stabilizer ketotifen reduces hyperalgesia in a rodent model of surgically induced endometriosis |journal=J Pain Res |volume=12 |pages=1359–1369 |date=2019 |pmid=31118754 |pmc=6500880 |doi=10.2147/JPR.S195909 |doi-access=free | title-link=doi |quote=Ketotifen has a stronger effect on stabilizing MCs than sodium cromoglycate. This drug has antihistamine activity and is also a functional leukotriene antagonist}} (a medication that blocks the action of leukotrienes, which are chemicals that cause inflammation and narrowing of the airways in some allergic and respiratory conditions){{cite book|chapter=Leukotrienes|doi=10.1007/978-3-7643-8550-7_105 |title=Compendium of Inflammatory Diseases |date=2016 |pages=849–857 |isbn=978-3-7643-8530-9 | vauthors = Bäck M }}{{cite journal |vauthors=Sasaki F, Yokomizo T |title=The leukotriene receptors as therapeutic targets of inflammatory diseases |journal=Int Immunol |volume=31 |issue=9 |pages=607–615 |date=August 2019 |pmid=31135881 |doi=10.1093/intimm/dxz044}} and a phosphodiesterase inhibitor{{cite journal |vauthors=Mostafa GA, Bakheit A, AlMasoud N, AlRabiah H |title=Charge Transfer Complexes of Ketotifen with 2,3-Dichloro-5,6-dicyano-p-benzoquinone and 7,7,8,8-Tetracyanoquodimethane: Spectroscopic Characterization Studies |journal=Molecules |volume=26 |issue=7 |date=April 2021 |page=2039 |pmid=33918481 |pmc=8038309 |doi=10.3390/molecules26072039 |doi-access=free | title-link=doi }}{{cite journal | vauthors = Castillo JG, Gamboa PM, García BE, Oehling A | title = Effect of ketotifen on phosphodiesterase activity from asthmatic individuals | journal = Allergologia et Immunopathologia | volume = 18 | issue = 4 | pages = 197–201 | date = 1990 | pmid = 1702263 }} (a medication that blocks the enzymes that regulate the levels of cAMP and cGMP, which are molecules that control blood vessel dilation and smooth muscle relaxation in the body).{{cite journal |vauthors=Omori K, Kotera J |title=Overview of PDEs and their regulation |journal=Circ Res |volume=100 |issue=3 |pages=309–27 |date=February 2007 |pmid=17307970 |doi=10.1161/01.RES.0000256354.95791.f1 |doi-access= | title-link=doi }}{{cite journal|doi=10.1093/bjaceaccp/mkm039 |title=Phosphodiesterase inhibitors and the cardiovascular system |date=1 December 2007|journal=Continuing Education in Anaesthesia Critical Care & Pain |volume=7 |issue=6 |pages=203–207 | vauthors = Feneck R |doi-access=free | title-link=doi }}

The eye drops are contraindicated for individuals who have a known hypersensitivity to ketotifen or any other ingredient in the formulation, whereas drug-eluting contact lenses are contraindicated for those who experience irritation from wearing contact lenses. Eye drops are not recommended for use in children under three years of age,{{cite web | url=https://www.drugs.com/monograph/ketotifen.html | title=Ketotifen Monograph for Professionals | access-date=16 November 2023 | archive-date=11 June 2021 | archive-url=https://web.archive.org/web/20210611120538/https://www.drugs.com/monograph/ketotifen.html | url-status=live }}{{cite web | url=https://www.drugs.com/mtm/ketotifen-ophthalmic.html | title=Ketotifen ophthalmic Uses, Side Effects & Warnings | access-date=16 November 2023 | archive-date=16 November 2023 | archive-url=https://web.archive.org/web/20231116205539/https://www.drugs.com/mtm/ketotifen-ophthalmic.html | url-status=live }}{{cite web | url=https://www.pediatriconcall.com/drugs/ketotifen/689 | publisher=Pediatric Oncall | title=Ketotifen - Mechanism, Indication, Contraindications, Dosing, Adverse Effect, Interaction, Hepatic Dose; Drug Index; Pediatric Oncall | access-date=16 November 2023 | archive-date=16 November 2023 | archive-url=https://web.archive.org/web/20231116205541/https://www.pediatriconcall.com/drugs/ketotifen/689 | url-status=live }} whereas drug-eluting contact lenses are not recommended for children under eleven years of age.

For oral ketotifen, the contraindication is for known hypersensitivity to any component of the product. Caution should be taken on the following conditions:

• acute porphyrias{{cite book|doi=10.1016/B978-1-4160-3432-2.50022-4 |chapter=Inflammatory and Purpuric Eruptions |title=Neonatal Dermatology |date=2008 |pages=311–342 |isbn=978-1-4160-3432-2 | vauthors = Baselga E, Torrelo A }} (a group of rare disorders that occur when the body cannot make enough of a substance called heme, which is needed for red blood cells to carry oxygen, this causes a build-up of chemicals called porphyrins, which can damage the nerves and the skin) - unlike other histamines, ketotifen appears to be relatively safe in acute porphyria, still, caution should be taken{{cite journal|doi=10.1002/psb.758 | quote=Some antihistamines should not be used in people with acute porphyria. Those believed to be safe are chlorphenamine, desloratadine, fexofenadine, ketotifen (Zaditen), loratadine and promethazine (Phenergan)| title=Antihistamines: Their properties and use in hay fever| date=2011| journal=Prescriber| volume=22| issue=10| pages=29–31| vauthors = Chaplin S, Scadding G }}
• epilepsy (a disorder causing recurrent seizures) - {{cite journal|doi=10.2165/00023210-199605050-00002|date=18 November 2012|volume=5|pages=321–330 |orig-date=May 1996 |title=Histamine and Seizures |journal=CNS Drugs |issue=5 |pmid=26071045 | vauthors = Yokoyama H, Iinuma K }} ketotifen may increase the risk of seizures,{{cite web | url=https://www.drugs.com/cons/ketotifen-oral.html | title=Ketotifen (Oral) Advanced Patient Information | access-date=11 March 2024 | archive-date=2 December 2023 | archive-url=https://web.archive.org/web/20231202143424/https://www.drugs.com/cons/ketotifen-oral.html | url-status=live }}
• pyloroduodenal obstruction{{cite journal|date=29 September 2013|doi=10.12968/npre.2009.7.4.41711 |title=Antihistamines: Mode of action, prescribing rationale and uses |journal=Nurse Prescribing |volume=7 |issue=4 |pages=166–170 | vauthors = Waterfield J }}{{cite journal|date=13 June 2011|doi=10.1002/psb.758 |title=Antihistamines: Their properties and use in hay fever |journal=Prescriber |volume=22 |issue=10 |pages=29–31 | vauthors = Chaplin S, Scadding G }} (a condition where the passage of food from the stomach to the small intestine is blocked by something, such as a muscle, an ulcer, a tumor, or a gallstone),{{cite journal | url=https://doi.org/10.1016/j.gie.2020.07.063 | doi=10.1016/j.gie.2020.07.063 | title=ASGE guideline on the role of endoscopy in the management of benign and malignant gastroduodenal obstruction | date=2021 | journal=Gastrointestinal Endoscopy | volume=93 | issue=2 | pages=309–322.e4 | pmid=33168194 | vauthors = Jue TL, Storm AC, Naveed M, Fishman DS, Qumseya BJ, McRee AJ, Truty MJ, Khashab MA, Agrawal D, Al-Haddad M, Amateau SK, Buxbaum JL, Calderwood AH, Dewitt J, Dimaio CJ, Fujii-Lau LL, Gurudu SR, Jamil LH, Kwon RS, Law JK, Lee JK, Pawa S, Sawhney MS, Thosani NC, Yang J, Wani SB | url-access=subscription }}{{cite book|doi=10.1007/978-981-13-1184-0_16|isbn=978-981-13-1184-0 |chapter=Endoscopic Management for Pyloric Stricture and Gastric Outlet Obstruction: Dilation and Stenting |title=Therapeutic Gastrointestinal Endoscopy |date=2019 |pages=277–289 | vauthors = Shim K }}
• susceptibility to angle-closure glaucoma{{cite journal|doi=10.1517/14656566.3.5.541 |title=Update on ocular allergy treatment |date=2002 |journal=Expert Opinion on Pharmacotherapy |volume=3 |issue=5 |pages=541–553 |pmid=11996633 | vauthors = Bielory L }} (a condition where the iris, the colored part of the eye, bulges and blocks the drainage of fluid from the eye, causing high pressure and damage to the optic nerve, which connects the eye to the brain),{{cite web | url=https://www.merckmanuals.com/professional/eye-disorders/glaucoma/angle-closure-glaucoma | title=Angle-Closure Glaucoma - Angle-Closure Glaucoma | access-date=15 October 2024 | archive-date=17 May 2024 | archive-url=https://web.archive.org/web/20240517073905/https://www.merckmanuals.com/professional/eye-disorders/glaucoma/angle-closure-glaucoma | url-status=live }} and
• urinary retention (inability to urinate).

The use of ketotifen eye drops during pregnancy and lactation is considered safe, as absorption through the eye is limited. It is unlikely to cause any adverse effects in breastfeeding infants after maternal use. To minimize the amount of medication transferred to breast milk when using eye drops, the National Institute of Child Health and Human Development advises to apply pressure on the tear duct near the corner of the eye for at least one minute and remove any excess solution with a tissue.{{cite book|id={{NCBIBook|NBK501527}}|pmid=30000587|title=Ketotifen|date=2006|url=https://www.ncbi.nlm.nih.gov/books/NBK501527|publisher=National Institute of Child Health and Human Development|access-date=22 November 2023|archive-date=3 October 2023|archive-url=https://web.archive.org/web/20231003214505/https://www.ncbi.nlm.nih.gov/books/NBK501527/|url-status=live}} Ketotifen safety when taken via the oral route (tablets or syrup) during pregnancy and lactation remains unknown; therefore, it is not recommended to use ketotifen orally during these periods until sufficient safety data becomes available.

Common side effects of ophthalmic use are eye redness and swelling. Less common are eye discharge, eye discomfort, eye pain, hives, increased itching of eyes, and rash. Ophthalmic use of ketotifen may also cause burning, stinging, or itching of the eyes, blurred vision, or increased sensitivity to light.

Side effects of systemic (oral) use include drowsiness, weight gain ({{convert|5.0|-|5.4|kg}}), dry mouth, irritability, and increased nosebleeds.{{cite web|url=http://www.mims.co.uk/drugs/allergic-disorders/allergic-rhinitis-urticaria-other-allergies/zaditen|title=Zaditen - MIMS online|website=www.mims.co.uk|access-date=2 August 2017|archive-date=25 October 2020|archive-url=https://web.archive.org/web/20201025215920/https://www.mims.co.uk/drugs/allergic-disorders/allergic-rhinitis-urticaria-other-allergies/zaditen|url-status=live}} Systemic use of ketotifen may also cause abdominal pain, nausea, vomiting, constipation, diarrhea, headache, dizziness, or fatigue. In rare cases, systemic use of ketotifen may cause serious side effects such as anaphylaxis, liver dysfunction, blood disorders, or seizures. Systemic use of ketotifen may interact with other drugs that cause sedation, such as alcohol, antihistamines, opioids, benzodiazepines, or antidepressants. Systemic use of ketotifen may affect the results of some laboratory tests, such as skin tests for allergies or blood glucose levels.{{cite journal | vauthors = Grant SM, Goa KL, Fitton A, Sorkin EM | title = Ketotifen. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in asthma and allergic disorders | journal = Drugs | volume = 40 | issue = 3 | pages = 412–448 | date = September 1990 | pmid = 2226222 | doi = 10.2165/00003495-199040030-00006 | s2cid = 242916740 }}

The symptoms of ketotifen overdose are dose-dependent and may vary from mild to severe. The onset of symptoms may be delayed for several hours after ingestion, and the duration of symptoms may last for more than 24 hours.{{cite journal | vauthors = Le Blaye I, Donatini B, Hall M, Krupp P | title = Acute ketotifen overdosage. A review of present clinical experience | journal = Drug Safety | volume = 7 | issue = 5 | pages = 387–392 | date = 1992 | pmid = 1418695 | doi = 10.2165/00002018-199207050-00007 | s2cid = 25839342 }}{{cite journal | vauthors = Jeffreys DB, Volans GN | title = Ketotifen overdose: surveillance of the toxicity of a new drug | journal = British Medical Journal | volume = 282 | issue = 6278 | pages = 1755–1756 | date = May 1981 | pmid = 6113023 | pmc = 1505736 | doi = 10.1136/bmj.282.6278.1755 }}{{cite journal|doi=10.2165/00128415-199204220-00009 |title=ACE inhibitors |journal=Reactions Weekly |date=1992 |issue=422 |page=5 }}

The most common symptom of ketotifen overdose is significant sedation. Other symptoms may include confusion, disorientation, agitation, hallucinations, ataxia (impairment of voluntary muscle movement), tremor (involuntary regular muscle contraction), myoclonus (involuntary, irregular muscle twitch), nystagmus (dysfunction of eye movement), dysarthria (poor speech), and slurred speech.

Other symptoms of ketotifen overdose may include tachycardia (fast, pounding, or irregular heartbeat or pulse), hypotension (low blood pressure), convulsions, hyperexcitability (particularly in children), reversible coma, unusual tiredness or weakness, blurred vision, dizziness or fainting, loss of consciousness.

The symptoms of ketotifen overdose may be described according to the affected system of the body. The cardiovascular effects of ketotifen overdose may include tachycardia, hypotension, arrhythmias, and cardiac arrest. The respiratory effects may include respiratory depression, sleep apnea, and pulmonary edema. The gastrointestinal effects may include nausea, vomiting, abdominal pain, diarrhea, and pancreatitis. The renal effects may include acute renal failure and urinary retention. The hepatic effects may include hepatitis and jaundice. The hematologic effects may include anemia, leukopenia, thrombocytopenia, and coagulopathy. The neurologic effects of ketotifen overdose may include convulsions, hyperexcitability, coma, and death. The risk of seizures is higher in children, especially those with a history of epilepsy or febrile seizures. The risk of coma and death is higher in adults, especially those with pre-existing medical conditions or concomitant use of other drugs that cause sedation or lower the seizure threshold.

In children, ketotifen overdose may lead to toxic encephalopathy with lifelong health consequences. There was a reported case of an overdose in a 4-month-old boy that led to growth retardation and mental deterioration.{{cite journal |doi=10.1111/j.1442-200X.2012.03718.x |url=https://www.proquest.com/openview/95fc56e245cc55e5f0fcb6a7f075f1fe |title=Ketotifen overdose. Toxic encephalopathy, epilepsy and mental retardation in an infant: case report |date=2012 |pmid=23279031 |quote=In the present case, a 4-month-old boy was administered ketotifen at 5 times the recommended dose, and he showed mental deterioration and growth retardation. The presence of developmental deterioration strongly suggests that overdose of ketotifen induces toxic encephalopathy. |journal=Pediatrics International |volume=54 |issue=6 |page=963 |vauthors=Yokoyama H, Hirose M, Uematsu M, Haginoya K, Iinuma K, Kimura S |access-date=3 April 2024 |archive-date=13 April 2024 |archive-url=https://web.archive.org/web/20240413010243/https://www.proquest.com/openview/95fc56e245cc55e5f0fcb6a7f075f1fe |url-status=live }}{{cite journal|doi=10.1007/s40278-013-2459-5 |title=Ketotifen overdose |journal=Reactions Weekly |date=2013 |volume=1447 |page=25 }}

In systemic (oral) administration, ketotifen has the potential to enhance the effects of sedatives, hypnotics, antihistamines, and alcohol. Interactions have been observed between oral ketotifen and oral hypoglycemic agents, antihistamines, and medications with sedative properties.{{cite web |url=https://www.hsa.gov.sg/docs/default-source/announcements/reclassified-medicines/patient-information-leaflets/ketotifen-oral-tablets-and-solution-pil-20-05-2017.pdf |title=Ketotifen 2mg Tablets, 1mg/5mL Oral Solution (product monograph) |access-date=11 March 2024 |archive-date=18 July 2022 |archive-url=https://web.archive.org/web/20220718184521/https://www.hsa.gov.sg/docs/default-source/announcements/reclassified-medicines/patient-information-leaflets/ketotifen-oral-tablets-and-solution-pil-20-05-2017.pdf |url-status=live }}{{cite web |url=https://pdf.hres.ca/dpd_pm/00067932.PDF |title=Tablets, 1 mg ketotifen (as ketotifen hydrogen fumarate), Oral (product monograph) |access-date=11 March 2024 |archive-date=21 February 2024 |archive-url=https://web.archive.org/web/20240221141530/https://pdf.hres.ca/dpd_pm/00067932.PDF |url-status=live }}

Oral ketotifen may interact with amphetamine and benzphetamine, which may decrease the activities of ketotifen.{{cite journal | vauthors = Greenwood C | title = The pharmacology of ketotifen | journal = Chest | volume = 82 | issue = 1 Suppl | pages = 45S–48S | date = July 1982 | pmid = 6123414 | doi = 10.1378/chest.82.1_supplement.45s | doi-broken-date = 3 December 2024 }}{{cite journal | vauthors = Rogóz Z, Skuza G, Sowińska H | title = Central action of ketotifen | journal = Polish Journal of Pharmacology and Pharmacy | volume = 33 | issue = 5 | pages = 503–515 | date = 1981 | pmid = 7335554 | doi = }}

The concomitant use of oral ketotifen with amifampridine, bupropion, donepezil, and pitolisant is not recommended.{{cite web |url=https://www.drugs.com/cons/ketotifen-oral.html |title=Ketotifen (Oral) Advanced Patient Information |access-date=11 March 2024 |archive-date=2 December 2023 |archive-url=https://web.archive.org/web/20231202143424/https://www.drugs.com/cons/ketotifen-oral.html |url-status=live }}

In rare instances, patients who have been administered oral ketotifen with oral antidiabetic agents have exhibited a reversible decrease in thrombocyte count. As such, it is recommended to monitor thrombocyte counts in patients who are concurrently taking oral antidiabetic agents.

Systemic use of ketotifen may decrease the effectiveness of benzylpenicilloyl polylysine as a diagnostic agent. Ketotifen may affect the results of some laboratory tests, such as skin tests for allergies or blood glucose levels. Ketotifen may interfere with the skin test reactions by suppressing the histamine response, leading to false-negative results.

Ophthalmic use of ketotifen may interact with contact lenses, as the eye drops may contain preservatives that can be absorbed by soft contact lenses and cause eye irritation.{{cite web | url=https://www.rxlist.com/ketotifen_ophthalmic/generic-drug.htm | title=Ketotifen Ophthalmic: Generic, Uses, Side Effects, Dosages, Interactions, Warnings | access-date=1 December 2023 | archive-date=24 February 2024 | archive-url=https://web.archive.org/web/20240224233556/https://www.rxlist.com/ketotifen_ophthalmic/generic-drug.htm | url-status=live }}

Ketotifen is a selective antihistamine – that is, an inverse agonist of the histamine H₁ receptor (K_i = 0.166 nM){{cite journal | vauthors = Kakiuchi M, Ohashi T, Musoh K, Kawamura K, Morikawa K, Kato H | title = Studies on the novel antiallergic agent HSR-609: its penetration into the central nervous system in mice and guinea pigs and its selectivity for the histamine H1-receptor | journal = Japanese Journal of Pharmacology | volume = 73 | issue = 4 | pages = 291–298 | date = April 1997 | pmid = 9165365 | doi = 10.1254/jjp.73.291 | doi-access = free | title-link = doi }} – and mast cell stabilizer.{{cite journal |vauthors=Ma C, Li H, Lu S, Li X, Wang S, Wang W |title=Tryptase and Exogenous Trypsin: Mechanisms and Ophthalmic Applications |journal=J Inflamm Res |volume=16 |issue= |pages=927–939 |date=2023 |pmid=36891173 |pmc=9987324 |doi=10.2147/JIR.S402900 |doi-access=free | title-link=doi }}{{cite book| vauthors = Nelson WL | chapter = Antihistamines and Related Antiallergic and Antiulcer Agents | veditors = Lemke TL, Williams DA |title=Foye's Principles of Medicinal Chemistry| chapter-url=https://books.google.com/books?id=R0W1ErpsQpkC&pg=PA1019|year=2008|publisher=Lippincott Williams & Wilkins|isbn=978-0-7817-6879-5|pages=1019–}}{{cite journal | vauthors = Ang DC, Hilligoss J, Stump T | title = Mast Cell Stabilizer (Ketotifen) in Fibromyalgia: Phase 1 Randomized Controlled Clinical Trial | journal = The Clinical Journal of Pain | volume = 31 | issue = 9 | pages = 836–842 | date = September 2015 | pmid = 25370135 | pmc = 4417653 | doi = 10.1097/AJP.0000000000000169 }} By preventing the degranulation of mast cells, ketotifen inhibits the release of inflammatory mediators such as histamine and leukotrienes, which are implicated in allergic reactions. Ketotifen action is also based on its inhibition of serotonin release.

Ketotifen also plays a role in the prevention of accumulation of eosinophils, which are white blood cells that become active during allergic reactions and infections; as such, ketotifen helps in reducing inflammation this way.

In addition, ketotifen has weak anticholinergic (K_i = 204 nM for {{abbrlink|mACh|muscarinic acetylcholine receptor}}) and antiserotonergic (K_i = 38.9 nM for 5-HT_2A) activity.{{cite book| vauthors = Alagarsamy V | chapter = Antihistamines | title=Textbook of Medicinal Chemistry Vol II - E-Book| chapter-url = https://books.google.com/books?id=0FPCuckMacAC&pg=PA38|date=16 June 2012|publisher=Elsevier Health Sciences|isbn=978-81-312-3259-0|pages=38–}} However, at the dosages in which it is typically used clinically, both the anticholinergic and antiserotonergic activity of ketotifen are said not to be appreciable.{{cite book| vauthors = Drews J | chapter = Substances with an Antialergic Effect |title=Immunopharmacology: Principles and Perspectives| chapter-url = https://books.google.com/books?id=mIN9CAAAQBAJ&pg=PT282|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-3-642-75561-3|pages=282–}}

Ketotifen is a lipophilic compound that can cross the blood–brain barrier and exert central nervous system effects, such as sedation, weight gain, and anticonvulsant activity. Ketotifen also has peripheral effects, such as inhibition of platelet aggregation, modulation of cytokine production, and enhancement of mucociliary clearance.{{cite journal |vauthors=Muñoz-Cano RM, Casas-Saucedo R, Valero Santiago A, Bobolea I, Ribó P, Mullol J |title=Platelet-Activating Factor (PAF) in Allergic Rhinitis: Clinical and Therapeutic Implications |journal=J Clin Med |volume=8 |issue=9 |date=August 2019 |page=1338 |pmid=31470575 |pmc=6780525 |doi=10.3390/jcm8091338 |doi-access=free | title-link=doi }}{{cite journal |vauthors=Kahhak L, Roche A, Dubray C, Arnoux C, Benveniste J |title=Decrease of ciliary beat frequency by platelet activating factor: protective effect of ketotifen |journal=Inflamm Res |volume=45 |issue=5 |pages=234–8 |date=May 1996 |pmid=8737746 |doi=10.1007/BF02259609 }}

Ketotifen acts as a mast cell stabilizer by preventing the degranulation and release of histamine and other inflammatory mediators, such as leukotrienes, prostaglandins, and cytokines, from mast cells. Ketotifen also inhibits the activation and migration of eosinophils, basophils, and neutrophils, which are involved in the inflammatory response and tissue damage in allergic and respiratory diseases.{{cite journal |vauthors=Luna-Gomes T, Bozza PT, Bandeira-Melo C |title=Eosinophil recruitment and activation: the role of lipid mediators |journal=Front Pharmacol |volume=4 |issue= |pages=27 |date=2013 |pmid=23525348 |pmc=3605515 |doi=10.3389/fphar.2013.00027 |doi-access=free | title-link=doi }}{{cite journal |vauthors=Martín AP, Urrets-Zavalia J, Berra A, Mariani AL, Gallino N, Gomez Demel E, Gagliardi J, Baena-Cagnani CE, Urrets-Zavalia E, Serra HM |title=The effect of ketotifen on inflammatory markers in allergic conjunctivitis: an open, uncontrolled study |journal=BMC Ophthalmol |volume=3 |issue= |pages=2 |date=January 2003 |pmid=12515585 |pmc=140320 |doi=10.1186/1471-2415-3-2 |doi-access=free | title-link=doi }}

Ketotifen has a dual mode of action as an antihistamine and a mast cell stabilizer, which makes it effective in the prophylaxis and treatment of various allergic and respiratory conditions, such as asthma, allergic rhinitis, conjunctivitis, dermatitis, urticaria, and anaphylaxis. Ketotifen can also reduce the bronchial hyperreactivity and airway inflammation that are characteristic of chronic asthma.{{cite book|doi=10.1007/978-1-4614-9194-1_242|chapter=Oral Mast Cell Stabilizers|date=1 January 2014 |title=Encyclopedia of Medical Immunology |pages=551–555 |isbn=978-1-4614-9193-4 | vauthors = Stone M, Francisco JC, Kumar NN, Barboza J }}

Ketotifen has a plasma half-life of about 12 hours. Ketotifen is extensively metabolized in the liver by oxidation and conjugation, and the metabolites are excreted in the urine and feces. The bioavailability of oral ketotifen is about 50% due to hepatic first-pass metabolism. Peak plasma concentration is reached in about 2 to 4 hours. The pharmacokinetics of ketotifen are not significantly affected by age, gender, or renal impairment, but may be altered by hepatic impairment or concomitant use of other drugs.{{cite journal |vauthors=Fahmy RH, Badr-Eldin SM |title=Novel delivery approach for ketotifen fumarate: dissofilms formulation using 3² experimental design: in vitro/in vivo evaluation |journal=Pharm Dev Technol |volume=19 |issue=5 |pages=521–30 |date=August 2014 |pmid=23713715 |doi=10.3109/10837450.2013.800108 |s2cid=45012360 }}

Ketotifen, like other antihistamines,{{cite journal |vauthors=Li L, Liu R, Peng C, Chen X, Li J |title=Pharmacogenomics for the efficacy and side effects of antihistamines |journal=Exp Dermatol |volume=31 |issue=7 |pages=993–1004 |date=July 2022 |pmid=35538735 |doi=10.1111/exd.14602}}{{cite journal |vauthors=Merk HF |title=Standard treatment: the role of antihistamines |journal=J Investig Dermatol Symp Proc |volume=6 |issue=2 |pages=153–6 |date=November 2001 |pmid=11764306 |doi=10.1046/j.0022-202x.2001.00032.x|doi-access=free | title-link=doi }} is mainly metabolized by the cytochrome P450 (CYP) enzymes, especially CYP3A4{{cite journal | doi=10.1016/j.ancr.2014.11.003 | title=Analysis for commonly prescribed non-sedating antihistamines | date=2015 | journal=Analytical Chemistry Research | volume=3 | pages=1–12 | vauthors = El-Kommos ME, El-Gizawy SM, Atia NN, Hosny NM | doi-access=free }}{{cite journal |vauthors=Jáuregui I, Mullol J, Bartra J, del Cuvillo A, Dávila I, Montoro J, Sastre J, Valero AL |title=H1 antihistamines: psychomotor performance and driving |journal=J Investig Allergol Clin Immunol |volume=16 |issue= Suppl 1|pages=37–44 |date=2006 |pmid=17357376}} in the liver. The CYP enzymes are responsible for the oxidation and demethylation of ketotifen, producing the major metabolites norketotifen and 10-hydroxyketotifen. Norketotifen is pharmacologically active and has a similar potency as ketotifen, while 10-hydroxyketotifen is inactive. The metabolites are then conjugated with glucuronic acid or sulfate and excreted in the urine and feces.{{cite book | chapter-url=https://doi.org/10.1016/B978-0-323-04404-2.10089-2 | doi=10.1016/B978-0-323-04404-2.10089-2 | chapter=Antihistamines | title=Clinical Immunology | date=2008 | pages=1317–1329 | isbn=978-0-323-04404-2 | vauthors=Lieberman P, Hernandez-Trujillo V, Lieberman J, Frew AJ | access-date=14 February 2024 | archive-date=24 February 2024 | archive-url=https://web.archive.org/web/20240224233628/https://www.sciencedirect.com/science/article/abs/pii/B9780323044042100892?via%3Dihub | url-status=live }}{{cite web |url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/99/21-066_ZADITOR%200.025%25_pharmr_P1.pdf |title=Center for drug evaluation and research. Application no. 21-066|access-date=14 February 2024 |archive-date=14 February 2024 |archive-url=https://web.archive.org/web/20240214190040/https://www.accessdata.fda.gov/drugsatfda_docs/nda/99/21-066_ZADITOR%200.025%25_pharmr_P1.pdf |url-status=live }}

Image:Pizotifen_structure.svg, a tricyclic (having three rings of atoms), benzocycloheptene-based compound with antihistamine properties and a structure similar to that of ketotifen: the only difference is that the ketotifen molecule has an oxygen atom that pizotifen molecule lacks—ketotifen contains a carbonyl group (C=O) in the central (7-membered) ring while pizotifen contains a methylene group (-CH₂-) in that position. In both ketotifen and pizotifen, the spatial restriction and reduced degrees of freedom caused by the rings enable optimal binding to H₁ receptors by providing shape complementarity and facilitating specific interactions with amino acid residues within the receptor's binding site, which plays a role in the ability of both drugs to effectively bind and modulate H₁ receptors, thereby exerting its antihistamine effects.{{cite journal|doi=10.1016/0014-2999(92)90383-F |title=Affinity profiles of pizotifen, ketotifen and other tricyclic antimuscarinics at muscarinic receptor subtypes M1, M2 and M3 |date=1992 |journal=European Journal of Pharmacology |volume=211 |issue=3 |pages=283–293 |pmid=1377628 |vauthors=Eltze M, Mutschler E, Lambrecht G }}]]

Ketotifen is a noncompetitive H₁-antihistamine and mast cell stabilizer.{{cite journal |vauthors=Sarcina D, Giovannini M, Oranges T, Barni S, Pedaci FA, Liccioli G, Canessa C, Sarti L, Lodi L, Filippeschi C, Azzari C, Ricci S, Mori F |title=Case Report and Review of the Literature: Bullous Skin Eruption After the Booster-Dose of Influenza Vaccine in a Pediatric Patient With Polymorphic Maculopapular Cutaneous Mastocytosis |journal=Front Immunol |volume=12 |year=2021 |pmid=34335590 |pmc=8322976 |doi=10.3389/fimmu.2021.688364|doi-access=free | title-link=doi }}

There is no academic consensus on whether ketotifen should be classified as a medication belonging to the first{{cite journal | vauthors = Bittner L, Teixidó E, Keddi I, Escher BI, Klüver N | title = pH-Dependent Uptake and Sublethal Effects of Antihistamines in Zebrafish (Danio rerio) Embryos | journal = Environmental Toxicology and Chemistry | volume = 38 | issue = 5 | pages = 1012–1022 | date = May 2019 | pmid = 30779379 | doi = 10.1002/etc.4395 | bibcode = 2019EnvTC..38.1012B | s2cid = 73482611 }}{{cite journal | vauthors = Pinke KH, Zorzella-Pezavento SF, de Campos Fraga-Silva TF, Mimura LA, de Oliveira LR, Ishikawa LL, Fernandes AA, Lara VS, Sartori A | title = Calming Down Mast Cells with Ketotifen: A Potential Strategy for Multiple Sclerosis Therapy? | journal = Neurotherapeutics | volume = 17 | issue = 1 | pages = 218–234 | date = January 2020 | pmid = 31463682 | pmc = 7007452 | doi = 10.1007/s13311-019-00775-8 }}{{cite journal | vauthors = Sokol KC, Amar NK, Starkey J, Grant JA | title = Ketotifen in the management of chronic urticaria: resurrection of an old drug | journal = Annals of Allergy, Asthma & Immunology | volume = 111 | issue = 6 | pages = 433–436 | date = December 2013 | pmid = 24267353 | pmc = 4309375 | doi = 10.1016/j.anai.2013.10.003 }} or the second generations of antihistamine drugs;{{cite journal | vauthors = Janeczko P, Norris MR, Bielory L | title = Assessment of receptor affinities of ophthalmic and systemic agents in dry eye disease | journal = Current Opinion in Allergy and Clinical Immunology | volume = 21 | issue = 5 | pages = 480–485 | date = October 2021 | pmid = 34387278 | doi = 10.1097/ACI.0000000000000773 | s2cid = 236998913 }}{{cite journal | vauthors = Triantafillou V, Maina IW, Patel NN, Tong CC, Papagiannopoulos P, Kohanski MA, Kennedy DW, Palmer JN, Adappa ND, Cohen NA, Bosso JV | title = In vitro safety of ketotifen as a topical nasal rinse | journal = International Forum of Allergy & Rhinology | volume = 10 | issue = 2 | pages = 265–270 | date = February 2020 | pmid = 32086998 | doi = 10.1002/alr.22461 | s2cid = 211246051 }} the classification can vary depending on the criteria used and the context of the study, and is primarily based on chemical structure, pharmacological properties, and side effect profiles of an antihistamine drug. First-generation H₁ antihistamines, such as diphenhydramine, reduce skin reactivity for up to 24 hours, whereas ketotifen suppresses skin reactivity for over five days, a typical duration for the second generation of the class.{{cite book | chapter-url=https://doi.org/10.1016/B978-0-323-37579-5.00005-2 | doi=10.1016/B978-0-323-37579-5.00005-2 | chapter=Principles of Allergy Diagnosis | title=Middleton's Allergy Essentials | date=2017 | pages=117–131 | isbn=978-0-323-37579-5 | vauthors=Chiriac AM, Bousquet J, Demoly P | access-date=14 February 2024 | archive-date=24 February 2024 | archive-url=https://web.archive.org/web/20240224233608/https://www.sciencedirect.com/science/article/abs/pii/B9780323375795000052?via%3Dihub | url-status=live }} Ketotifen is a tricyclic, benzocycloheptene-based compound with chemical structures similar to first-generation antihistamines such as azatadine, cyproheptadine, chlorpheniramine, and diphenhydramine, and other compounds with antihistamine properties such as pizotifen. The sedative effects of ketotifen are also a reason for differences in classification. First-generation antihistamines are well known for their sedating side effects due to their ability to penetrate the blood–brain barrier.{{cite journal | vauthors = Sagara A, Nagahama A, Aki H, Yoshimura H, Hiraide M, Shimizu T, Sano M, Yumoto T, Hosoe T, Tanaka K | title = Potential risk of driving performance under combined conditions of taking second-generation antihistamines and attending calls using a hands-free function | journal = Traffic Injury Prevention | volume = 25 | issue = 1 | pages = 36–40 | date = October 2023 | pmid = 37815801 | doi = 10.1080/15389588.2023.2265002 | s2cid = 263801715 }} While ketotifen has some sedative properties, it is generally considered to have a milder sedative effect compared to traditional first-generation antihistamines,{{cite journal | vauthors = Slater JW, Zechnich AD, Haxby DG | title = Second-generation antihistamines: a comparative review | journal = Drugs | volume = 57 | issue = 1 | pages = 31–47 | date = January 1999 | pmid = 9951950 | doi = 10.2165/00003495-199957010-00004 | s2cid = 24659435 }} so this reduced sedation is one of the reasons why ketotifen is sometimes classified as a second-generation antihistamine.{{cite journal | vauthors = Aelony Y | title = First-generation vs second-generation antihistamines | journal = Archives of Internal Medicine | volume = 158 | issue = 17 | pages = 1949–1950 | date = September 1998 | pmid = 9759694 | doi = 10.1001/archinte.158.17.1949 | doi-broken-date = 24 November 2024 }}

Ketotifen was patented in 1970 and came into medical use in 1976.{{cite book |vauthors=Alapi EM, Fischer J |chapter=Table of Selected Analogue Classes |veditors=Fischer J, Ganellin CR |title=Analogue-based Drug Discovery |date=2006 |publisher=John Wiley & Sons |isbn=978-3-527-60749-5 |page=548 |chapter-url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA548 |access-date=1 August 2020 |archive-date=10 January 2023 |archive-url=https://web.archive.org/web/20230110031314/https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA548 |url-status=live }} Ketotifen was developed and patented by Sandoz Pharmaceuticals (a part of Novartis), a Swiss company.{{cite web|url=https://go.drugbank.com/drugs/DB00920|title=Ketotifen|date=12 April 2024|publisher=Drugbank|access-date=16 November 2023|archive-date=6 August 2019|archive-url=https://web.archive.org/web/20190806095438/https://www.drugbank.ca/drugs/DB00920|url-status=live}}{{cite web|url=https://drugs.ncats.io/drug/HBD503WORO|title=Ketotifen Fumarate|date=12 April 2024|website=Inxight Drugs|publisher=National Center for Advancing Translational Sciences (NCATS)|location=Bethesda MD, US|access-date=13 April 2024|archive-date=13 April 2024|archive-url=https://web.archive.org/web/20240413010346/https://drugs.ncats.io/drug/HBD503WORO|url-status=live}}{{cite journal |url=https://journal.chestnet.org/article/S0012-3692(15)33591-1/abstract |doi=10.1378/chest.82.1.30S |title=An Overview of Ketotifen |date=1982 |journal=Chest |volume=82 |issue=1 Suppl |pages=30s–32s |pmid=6806019 |vauthors=MacDonald G |access-date=13 April 2024 |archive-date=13 April 2024 |archive-url=https://web.archive.org/web/20240413010421/https://journal.chestnet.org/article/S0012-3692(15)33591-1/abstract |url-status=live |url-access=subscription }}

Ketotifen was approved for medical use in Canada in December 1990. Ketotifen was approved for medical use in the United States in July 1999.{{cite web | title=Drug Approval Package: Zaditor (Ketotifen Fumarate) NDA# 21-066 | website=accessdata.fda.gov | date=20 November 2001 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/99/21-066_Zaditor.cfm | access-date=10 March 2024 | archive-date=8 March 2024 | archive-url=https://web.archive.org/web/20240308064947/https://www.accessdata.fda.gov/drugsatfda_docs/nda/99/21-066_Zaditor.cfm | url-status=live }} TA contact lens with ketotifen was approved for medical use in the United States in 2022.{{cite web | title=Drug Approval Package: Acuvue Theravision with ketotifen | website=accessdata.fda.gov | date=19 September 2022 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/022388Orig1s000TOC.cfm | access-date=10 March 2024 | archive-date=10 March 2024 | archive-url=https://web.archive.org/web/20240310191328/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/022388Orig1s000TOC.cfm | url-status=live }}{{cite press release | title=Johnson & Johnson Vision Care Receives FDA Approval for Acuvue Theravision with Ketotifen – World's First and Only Drug-Eluting Contact Lens | website=Johnson and Johnson Vision | date=2 March 2022 | url=https://www.jjvision.com/press-release/johnson-johnson-vision-care-receives-fda-approval-acuvuer-theravisiontm-ketotifen | access-date=10 March 2024 | archive-date=11 March 2024 | archive-url=https://web.archive.org/web/20240311114818/https://www.jjvision.com/press-release/johnson-johnson-vision-care-receives-fda-approval-acuvuer-theravisiontm-ketotifen | url-status=live }}

File:Ketotifen-generic-sopharma.jpg

Ketotifen is sold under various brand names worldwide, depending on country and formulation, with over 200 different names used.{{cite web | title=Ketotifen International | website=Drugs.com | url=https://www.drugs.com/international/ketotifen.html | access-date=4 September 2020 | archive-date=11 April 2021 | archive-url=https://web.archive.org/web/20210411134835/https://www.drugs.com/international/ketotifen.html | url-status=live }}{{cite web | url=https://www.msn.com/en-in/health/wellness/what-to-know-about-ketotifen-popular-brands-ketasma-and-asthafen/ar-BB1kFqmx | website=MSN | title=What To Know About Ketotifen (popular Brands: Ketasma And Asthafen) | author=Tata | date=28 March 2024 | access-date=2 April 2024 | archive-date=13 April 2024 | archive-url=https://web.archive.org/web/20240413010153/https://www.msn.com/en-in/health/wellness/what-to-know-about-ketotifen-popular-brands-ketasma-and-asthafen/ar-BB1kFqmx | url-status=live }}{{cite web |url=https://www.drugs.com/ingredient/ketotifen.html |title=Ketotifen (Ingredient) |access-date=2 April 2024 |archive-date=2 April 2024 |archive-url=https://web.archive.org/web/20240402191446/https://www.drugs.com/ingredient/ketotifen.html |url-status=live }} In the United States, ketotifen fumarate ophthalmic solution is marketed under brand name Zaditor, which is owned by Alcon Inc., a Swiss-American pharmaceutical company.{{cite web | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ac66b1e4-c2b0-a4c3-09e3-ebd44a2f7c9f | title=DailyMed - ZADITOR- ketotifen fumarate solution | access-date=5 September 2020 | archive-date=11 June 2021 | archive-url=https://web.archive.org/web/20210611120517/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ac66b1e4-c2b0-a4c3-09e3-ebd44a2f7c9f |publisher=National Institutes of Health| url-status=live | date=15 December 2023}}{{Cite web |title=Trademark search - ZADITOR|publisher=USPTO|date=8 April 2024|url=https://tsdr.uspto.gov/#caseNumber=75680062&caseSearchType=US_APPLICATION&caseType=DEFAULT&searchType=statusSearch |access-date=8 April 2024 |archive-date=13 July 2021 |archive-url=https://web.archive.org/web/20210713022850/https://tsdr.uspto.gov/#caseNumber=75680062&caseSearchType=US_APPLICATION&caseType=DEFAULT&searchType=statusSearch |url-status=live }}

There was a litigation related to ketotifen. In 2021, the plaintiff, Edward C. Hanks, brought an action in the United States District Court for the Central District of Illinois against the defendants, Ned Hubbard and others, alleging that they violated his rights under the Eighth Amendment to the United States Constitution by acting with deliberate indifference to his serious medical needs. The plaintiff claimed that he suffered from a chronic eye condition that required medical attention and that the defendant, Dr. Hubbard, prescribed him ketotifen. The plaintiff further claimed that the ketotifen eye drops caused him adverse reactions, such as severe pain, burning, and blurred vision, and that the defendant, Dr. Hubbard, failed to offer him an alternative medication or refer him to an ophthalmologist. The plaintiff also claimed that he sustained permanent eye damage as a result of the ketotifen. The district court granted the defendant's motion to dismiss, finding that the plaintiff failed to state a claim upon which relief could be granted. The plaintiff appealed to the United States Court of Appeals for the Seventh Circuit, which affirmed the district court's judgment on 7 February 2022.{{cite court|litigants=Hanks v. Hubbard|court=C.D. Ill|date=8 March 2021}}

===Anatomy===

Human mast cell heterogeneity (diversity) significantly impacts the efficacy of ketotifen in preventing mediator release (mast cell activation). In experiments, ketotifen inhibits mast cells from lung and tonsillar tissues when stimulated via an IgE-dependent histamine release mechanism. However, neither ketotifen nor disodium cromoglycate, another mast cell stabilizer, failed to inhibit mediator release from skin mast cells, that were unresponsive to these stabilizers. Such patterns of mast cell activation suggests the existence of different types of mast cells across various tissues{{emdash}}a topic of ongoing research.{{cite journal |vauthors=Finn DF, Walsh JJ |title=Twenty-first century mast cell stabilizers |journal=Br J Pharmacol |volume=170 |issue=1 |pages=23–37 |date=September 2013 |pmid=23441583 |pmc=3764846 |doi=10.1111/bph.12138}}

Research directions for ketotifen include the investigation of norketotifen (NK), a metabolite of ketotifen. In vitro studies using human liver microsomes and hepatocytes suggest that NK may be the major demethylated hepatic metabolite of ketotifen. Unlike ketotifen, NK does not seem to induce severe sedative effects, potentially allowing for higher doses to be administered without sedation as a limiting factor. Furthermore, NK may probably have potent and dose-dependent inhibition of the release of the pro-inflammatory cytokine TNF-α, suggesting potential anti-inflammatory activity. thus, ketotifen can probably be considered a sedating prodrug that converts to NK, a nonsedating metabolite with anti-inflammatory properties, when used as an anti-inflammatory medication.{{cite journal | vauthors = Aberg AK, Arulnesan N, Bolger GT, Ciofalo VB, Pucaj K, Walle K, Walle T | title = Ketotifen is a Prodrug. Norketotifen is the active metabolite | journal = Drug Development Research | volume = 83 | issue = 2 | pages = 362–367 | date = April 2022 | pmid = 34410005 | doi = 10.1002/ddr.21865 | s2cid = 237216445 }} The potential future applications of norketotifen are researched by Emergo Therapeutics, a US company.{{cite web | url=https://classic.clinicaltrials.gov/ct2/show/NCT04610047 | title=A Phase 2b Double-blind, Randomized, Placebo-controlled, Parallel-group Study of the Efficacy and Safety of Norketotifen (NKT) in the Treatment of Acute Uncomplicated Influenza-like Illness (ILI) | date=25 January 2023 | access-date=13 April 2024 | archive-date=13 April 2024 | archive-url=https://web.archive.org/web/20240413010149/https://classic.clinicaltrials.gov/ct2/show/NCT04610047 | url-status=live }}{{cite web | url=https://trialbulletin.com/lib/entry/ct-04610047 | title=Efficacy and Safety of Norketotifen in Uncomplicated Influenza-like Illness: Influenza Clinical | date=30 January 2023 | access-date=13 April 2024 | archive-date=13 April 2024 | archive-url=https://web.archive.org/web/20240413010157/https://trialbulletin.com/lib/entry/ct-04610047 | url-status=live }}{{cite web|url=https://ichgcp.net/clinical-trials-registry/NCT04610047|title=Efficacy and Safety of Norketotifen in Uncomplicated Influenza-like Illness|date=25 January 2023|access-date=13 April 2024|archive-date=20 April 2024|archive-url=https://web.archive.org/web/20240420185814/https://ichgcp.net/clinical-trials-registry/NCT04610047|url-status=live}}{{cite web | url=https://www.bioworld.com/articles/392013-emergo-finds-midstage-success-in-developing-flu-fighter-norketotifen | title=Emergo finds midstage success in developing flu-fighter norketotifen + | Bioworld | BioWorld | access-date=13 April 2024 | archive-date=13 April 2024 | archive-url=https://web.archive.org/web/20240413010908/https://www.bioworld.com/articles/392013-emergo-finds-midstage-success-in-developing-flu-fighter-norketotifen | url-status=live }}{{Cite web |url=https://ichgcp.net/clinical-trials-registry/NCT04043923 |title=Norketotifen in Influenza -Like Illness - Clinical Trials Registry - ICH GCP |access-date=13 April 2024 |archive-date=13 April 2024 |archive-url=https://web.archive.org/web/20240413010904/https://ichgcp.net/clinical-trials-registry/NCT04043923 |url-status=live }}

The underlying mechanisms of why ketotifen (similarly to other antihistamine drugs such as astemizole, azelastine) may increase appetite and lead to weight gain in some people, are not fully understood.

Different studies have shown conflicting results about the amount of weight gain caused by ketotifen. In one study (postmarketing surveillance), it was found that around 1 to 2 out of every 100 people who took the drug experienced weight gain, with adults gaining about {{convert|1|kg}} and children over the age of one gaining {{convert|2.8|-|3.3|kg}}. However, in another study, adults gained a higher amount of weight: {{convert|5.0|-|5.4|kg}}.

Ketotifen exhibits a chemical resemblance to pizotifen, a substance known for its appetite-stimulating properties. One proposed mechanism of the increase in appetite involves the inhibitory effect of ketotifen on the production of TNF-α, which is a cytokine that plays a role in regulating energy metabolism. TNF-α can act directly on adipocytes (fat cells) to regulate the release of leptin. Leptin is a hormone produced by adipose tissue and acts as a satiety signal by binding to receptors in the hypothalamus, where it inhibits appetite. By reducing TNF-α production, ketotifen may lead to decreased leptin levels, reducing appetite control inhibition. Furthermore, ketotifen's influence on serotonin regulation could be involved in central serotonin disinhibition. Serotonin is known to have suppressant effects on appetite. It is suggested that ketotifen might cause a decrease in serotonin levels due to this regulatory influence. As a result, the decrease in serotonin function may lead to increased food intake tendencies and heightened appetite. Still, these potential mechanisms have been hypothesized based on limited evidence.{{cite journal | vauthors = Habibi Asl B, Vaez H, Imankhah T, Hamidi S | title = Impact of caffeine on weight changes due to ketotifen administration | journal = Advanced Pharmaceutical Bulletin | volume = 4 | issue = 1 | pages = 83–89 | date = 2014 | pmid = 24409414 | pmc = 3885374 | doi = 10.5681/apb.2014.013 }} Studies on mice suggest that caffeine or citrus aurantifolia oil{{cite journal | vauthors = Asnaashari S, Delazar A, Habibi B, Vasfi R, Nahar L, Hamedeyazdan S, Sarker SD | title = Essential oil from Citrus aurantifolia prevents ketotifen-induced weight-gain in mice | journal = Phytotherapy Research | volume = 24 | issue = 12 | pages = 1893–1897 | date = December 2010 | pmid = 20623616 | doi = 10.1002/ptr.3227 | s2cid = 8888404 | url = https://hal.science/hal-00553269 | access-date = 10 January 2024 | archive-date = 28 January 2024 | archive-url = https://web.archive.org/web/20240128210538/https://hal.science/hal-00553269 | url-status = live }} may prevent weight-gain induced by ketotifen, but, this has not been confirmed on human subjects.

Ketotifen is being studied in context of a possible link between abnormalities in intestinal mast cells and irritable bowel syndrome, but there are no solid results yet.{{cite journal | vauthors = Zhang L, Song J, Hou X | title = Mast Cells and Irritable Bowel Syndrome: From the Bench to the Bedside | journal = Journal of Neurogastroenterology and Motility | volume = 22 | issue = 2 | pages = 181–192 | date = April 2016 | pmid = 26755686 | pmc = 4819856 | doi = 10.5056/jnm15137 }}{{cite journal | vauthors = Klooker TK, Braak B, Koopman KE, Welting O, Wouters MM, van der Heide S, Schemann M, Bischoff SC, van den Wijngaard RM, Boeckxstaens GE | title = The mast cell stabiliser ketotifen decreases visceral hypersensitivity and improves intestinal symptoms in patients with irritable bowel syndrome | journal = Gut | volume = 59 | issue = 9 | pages = 1213–1221 | date = September 2010 | pmid = 20650926 | doi = 10.1136/gut.2010.213108 | s2cid = 18889707 | url = https://pure.uva.nl/ws/files/1485582/95328_340461.pdf | access-date = 24 September 2019 | archive-date = 11 June 2021 | archive-url = https://web.archive.org/web/20210611120523/https://pure.uva.nl/ws/files/1485582/95328_340461.pdf | url-status = live }}

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