Ketotifen acts by blocking theH1 histamine receptors, which are found on various cells in the body, such assmooth muscle,endothelium, andnerve cells. This blocking prevents the binding of histamine to these receptors and thus reduces the symptoms of histamine-mediated reactions, such as itching, sneezing, wheezing, and swelling. Ketotifen also prevents the release of histamine and other inflammatory substances from immune cells (mast cells); this action helps reduce symptoms of conditions (including allergic conditions) by blocking the activation of these cells. In addition to itsantihistaminic activity, ketotifen also functions as aleukotriene antagonist, which blocks inflammation-causing chemicals known asleukotrienes; it also acts as aphosphodiesterase inhibitor that regulates blood vessel dilation.
Ketotifen can have side effects, including drowsiness, weight gain, dry mouth, irritability, increased nosebleeds when taken orally, and temporary burning or stinging sensations in the eyes when used in the ophthalmic form. Ketotifen has contraindications for individuals with certain medical conditions, such as acuteporphyrias orepilepsy. Controversies surrounding ketotifen include its classification as a first-generation or second-generation antihistamine due to varying criteria of classification.
In 2023, it was the 299th most commonly prescribed medication in the United States, with more than 400,000 prescriptions.[6][7]
Ketotifen, an antihistamine medication and a mast cell stabilizer, is most commonly sold as asalt withfumaric acid, ketotifen fumarate, and is available in two forms:[8]
in itsoral form (tablets or syrup),[8] it is used to preventasthma attacks or anaphylaxis,[12][13] as well as various mast cell and allergy disorders.[14][15][16]
Ketotifen ophthalmic solution (eye drops) relieves and prevents eye itchiness and/or irritation associated with mostseasonal 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,[1][failed verification] whereas drug-eluting contact lenses have not been studied in children under eleven years old.[5]
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 andfarsightedness. These lenses are meant for people who don't have red eyes, can comfortably wear contact lenses, and have less than 1 degree ofastigmatism.[5]
As an antihistamine medication, ketotifen acts by blocking theH1 histamine receptors,[11] which are found on various cells in the body, such assmooth muscle,endothelium, andnerve cells.[18] This blocking prevents the binding of histamine to these receptors and thus reduces the symptoms of histamine-mediated reactions, such as itching, sneezing, wheezing,[19][20] and swelling.[21]
As a mast cell stabilizer to treat MCAS, oral ketotifen prevents the release of histamine and other inflammatory substances frommast cells, which areimmune cells that react to allergens.[17] Therefore, ketotifen, by blocking acalcium channel essential for mast cell activation,[22] helps reduce symptoms of conditions typically associated with mast cell activation.[17] These conditions include asthma, hay fever, and conjunctivitis.[17] 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.[23][24] Ketotifen inhibit calcium influx into cells,[25][26] reducing mast cell degranulation.[22] In Canada, Europe, and Mexico, oral ketotifen is commonly prescribed for these indications (asthma, hay fever, and conjunctivitis caused by mast cell activation).[27][16][12] In patients with MCAS, ketotifen reduces episodes offlushing, 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.[17]
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.[28] 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.[29]
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 theFood and Drug Administration (FDA) for adults and older children with asthma or allergic conditions.[16][12] However, ketotifen eye drops are approved in the US for people who are at least three years of age.[30][31] In the EU, ketotifen oral formulation (syrup, tablets and capsules) are approved by theEuropean Medicines Agency for adult use.[32][failed verification] In the UK, ketotifen is available as tables and elixir (liquid).[33]
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 forbronchodilators, 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.[34]
One small study in men found that the mean elimination half-life of oral ketotifen is 12 hours.[35] Besides its anti-histaminic activity, it is also a functionalleukotriene antagonist[36] (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)[37][38] and aphosphodiesterase inhibitor[39][40] (a medication that blocks the enzymes that regulate the levels ofcAMP andcGMP, which are molecules that controlblood vessel dilation andsmooth muscle relaxation in the body).[41][42]
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,[43][31][44] whereas drug-eluting contact lenses are not recommended for children under eleven years of age.[5]
For oral ketotifen, the contraindication is for known hypersensitivity to any component of the product. Caution should be taken on the following conditions:[11]
acute porphyrias[45] (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.[46]
epilepsy (a disorder causing recurrent seizures) -[47] ketotifen may increase the risk of seizures,[48]
pyloroduodenal obstruction[49][50][43] (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),[51][52]
susceptibility toangle-closure glaucoma[53] (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),[54] and
The use of ketotifen eye drops during pregnancy and lactation is considered safe, asabsorption 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, theNational Institute of Child Health and Human Development advises to apply pressure on thetear duct near the corner of the eye for at least one minute and remove any excess solution with a tissue.[55] 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.[55]
Common side effects of ophthalmic use are eye redness andswelling. Less common areeye discharge, eye discomfort, eye pain,hives, increaseditching 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.[31]
Side effects of systemic (oral) use includedrowsiness,weight gain (5.0–5.4 kilograms (11.0–11.9 lb)),dry mouth, irritability, and increasednosebleeds.[56] 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 asanaphylaxis, liver dysfunction, blood disorders, or seizures. Systemic use of ketotifen may interact with other drugs that cause sedation, such asalcohol, antihistamines,opioids,benzodiazepines, orantidepressants. Systemic use of ketotifen may affect the results of some laboratory tests, such as skin tests for allergies or blood glucose levels.[8]
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.[57][58][59]
The most common symptom of ketotifen overdose is significantsedation. 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), andslurred speech.[57][58][59]
Other symptoms of ketotifen overdose may includetachycardia (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.[58][59]
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, andcardiac arrest. The respiratory effects may include respiratory depression,sleep apnea, andpulmonary edema. The gastrointestinal effects may include nausea, vomiting, abdominal pain, diarrhea, andpancreatitis. The renal effects may includeacute renal failure andurinary retention. The hepatic effects may includehepatitis andjaundice. The hematologic effects may includeanemia,leukopenia,thrombocytopenia, andcoagulopathy. The neurologic effects of ketotifen overdose may includeconvulsions, hyperexcitability,coma, and death. The risk of seizures is higher in children, especially those with a history of epilepsy orfebrile 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.[57][58]
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.[60][61][59]
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 oralhypoglycemic agents, antihistamines, and medications with sedative properties.[62][63]
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 monitorthrombocyte counts in patients who are concurrently taking oral antidiabetic agents.[62][63]
Systemic use of ketotifen may decrease the effectiveness ofbenzylpenicilloyl polylysine as a diagnostic agent.[64] 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.[64]
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.[67]
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.[77]
In addition, ketotifen has weakanticholinergic andantiserotonergic activity.[72][80] 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.[81]
Ketotifen is alipophilic compound that can cross theblood–brain barrier and exert central nervous system effects, such as sedation,[82] weight gain, and anticonvulsant activity. Theoccupancy of the H1 receptor in the human brain by ketotifen has been found to be around 75% with a single 1mg dose.[83] Sedating antihistamines showed occupancies of 50 to 100%, with ketotifen having one of the highest occupancies.[83] Ketotifen also has peripheral effects, such as inhibition of platelet aggregation, modulation of cytokine production, and enhancement ofmucociliary clearance.[8][84][85]
Ketotifen has a dual mode of action as an antihistamine and amast cell stabilizer, which makes it effective in the prophylaxis and treatment of various allergic and respiratory conditions, such as asthma, allergic rhinitis, conjunctivitis,[11] dermatitis, urticaria, and anaphylaxis. Ketotifen can also reduce thebronchial hyperreactivity and airway inflammation that are characteristic ofchronic asthma.[88][14][87]
Ketotifen is anoncompetitive H1-antihistamine andmast cell stabilizer.[89] There is no academic consensus[8] on whether ketotifen should be classified as a medication belonging to the first[90][91][14] or the second generations of antihistamine drugs;[92][93] the classification can vary depending on the criteria used and the context of the study,[94] and is primarily based on chemical structure, pharmacological properties, and side effect profiles of an antihistamine drug.[95][94][8][96] First-generation H1 antihistamines, such asdiphenhydramine, reduceskin 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.[97] Ketotifen is atricyclic,benzocycloheptene-based compound with chemical structures similar to first-generation antihistamines such asazatadine,cyproheptadine,chlorpheniramine, anddiphenhydramine, and other compounds with antihistamine properties such aspizotifen. 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 theblood–brain barrier.[95] While ketotifen has some sedative properties, it is generally considered to have a milder sedative effect compared to traditional first-generation antihistamines,[94][8] so this reduced sedation is one of the reasons why ketotifen is sometimes classified as a second-generation antihistamine.[96]
Ketotifen has anelimination half-life of about 12hours. 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.[98]
Ketotifen, like other antihistamines,[82][99] is mainly metabolized by thecytochrome P450 (CYP) enzymes, especiallyCYP3A4[100][101] in the liver. The CYP enzymes are responsible for the oxidation and demethylation of ketotifen, producing the major metabolitesnorketotifen and10-hydroxyketotifen. Norketotifen is pharmacologically active and has a similar potency as ketotifen, while10-hydroxyketotifen is inactive. The metabolites are then conjugated withglucuronic acid or sulfate and excreted in the urine and feces.[102][103]
A closeanalogue of ketotifen ispizotifen, which is atricyclic (having three rings of atoms),benzocycloheptene-based compound with antihistamine properties: the only difference between the structures of the compounds 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.[104]
Ketotifen was approved for medical use in Canada in December 1990.[2] Ketotifen was approved for medical use in the United States in July 1999.[109] TA contact lens with ketotifen was approved for medical use in the United States in 2022.[110][111]
Ketotifen is sold under various brand names worldwide, depending on country and formulation, with over 200 different names used.[112][113][114] In the United States, ketotifen fumarate ophthalmic solution is marketed under brand name Zaditor, which is owned byAlcon Inc., a Swiss-American pharmaceutical company.[115][116]
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 nordisodium 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—a topic of ongoing research.[117][118]
Research directions for ketotifen include the investigation ofnorketotifen (NK), a metabolite of ketotifen.In vitro studies using humanlivermicrosomes andhepatocytes suggest that NK may be the majordemethylated 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 thepro-inflammatory cytokineTNF-α, suggesting potentialanti-inflammatory activity. thus, ketotifen can probably be considered a sedatingprodrug that converts to NK, a nonsedatingmetabolite with anti-inflammatory properties, when used as an anti-inflammatory medication.[119] The potential future applications of norketotifen are researched by Emergo Therapeutics, a US company.[120][121][122][123][124]
The underlying mechanisms of why ketotifen (similarly to other antihistamine drugs such asastemizole,azelastine)[94] may increase appetite and lead to weight gain in some people, are not fully understood.[94]
Different studies have shown conflicting results about the amount of weight gain caused by ketotifen. In one study (postmarketing surveillance),[94] it was found that around 1 to 2 out of every 100 people who took the drug experienced weight gain, with adults gaining about 1 kilogram (2.2 lb) and children over the age of one gaining 2.8–3.3 kilograms (6.2–7.3 lb). However, in another study,[56] adults gained a higher amount of weight: 5.0–5.4 kilograms (11.0–11.9 lb).[56]
Ketotifen exhibits a chemical resemblance topizotifen, a substance known for itsappetite-stimulating properties.[94] One proposed mechanism of the increase in appetite involves the inhibitory effect of ketotifen on the production ofTNF-α, which is acytokine that plays a role in regulating energy metabolism. TNF-α can act directly onadipocytes (fat cells) to regulate the release ofleptin. Leptin is a hormone produced byadipose tissue and acts as a satiety signal by binding to receptors in thehypothalamus, where it inhibits appetite. By reducing TNF-α production, ketotifen may lead to decreased leptin levels, reducing appetite control inhibition. Furthermore, ketotifen's influence onserotonin regulation could be involved in central serotonindisinhibition. 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.[125] Studies on mice suggest thatcaffeine[125] orcitrus aurantifolia oil[126] may prevent weight-gain induced by ketotifen, but, this has not been confirmed on human subjects.[126]
Ketotifen is being studied in context of a possible link between abnormalities in intestinal mast cells andirritable bowel syndrome, but there are no solid results yet.[118][127]
^abcdefgGrant SM, Goa KL, Fitton A, Sorkin EM (September 1990). "Ketotifen. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in asthma and allergic disorders".Drugs.40 (3):412–448.doi:10.2165/00003495-199040030-00006.PMID2226222.S2CID242916740.
^García-Martín E, Canto G, Agúndez JA (November 2013). "Metabolic considerations of drugs in the treatment of allergic diseases".Expert Opin Drug Metab Toxicol.9 (11):1437–52.doi:10.1517/17425255.2013.823400.PMID23902458.S2CID30634949.
^abcZuberbier T, Asero R, Bindslev-Jensen C, Walter Canonica G, Church MK, Giménez-Arnau AM, et al. (October 2009). "EAACI/GA(2)LEN/EDF/WAO guideline: management of urticaria".Allergy.64 (10):1427–1443.doi:10.1111/j.1398-9995.2009.02178.x.PMID19772513.S2CID14587946.
^Li Z, Celestin J (23 February 2015).Ketotifen: A Role in the Treatment of Idiopathic Anaphylaxis. American Academy of Allergy, Asthma & Immunology Annual Meeting. Houston.
^Simons FE, Simons KJ (December 2011). "Histamine and H1-antihistamines: celebrating a century of progress".J Allergy Clin Immunol.128 (6): 1139–1150.e4.doi:10.1016/j.jaci.2011.09.005.PMID22035879.
^Linton S, Hossenbaccus L, Ellis AK (October 2023). "Evidence-based use of antihistamines for treatment of allergic conditions".Ann Allergy Asthma Immunol.131 (4):412–420.doi:10.1016/j.anai.2023.07.019.PMID37517656.
^Suzuki Y, Inoue T, Ra C (14 February 2012). "Calcium Signaling in Mast Cells: Focusing on L-Type Calcium Channels".Calcium Signaling. Advances in Experimental Medicine and Biology. Vol. 740. pp. 955–977.doi:10.1007/978-94-007-2888-2_44.ISBN978-94-007-2888-2.PMID22453979.
^Markham A, Goa KL (1996)."Ketotifen".Clinical Immunotherapeutics.5 (5):400–411.doi:10.1007/BF03259336.Archived from the original on 6 August 2024. Retrieved17 July 2024.
^Grahnén A, Lönnebo A, Beck O, Eckernäs SA, Dahlström B, Lindström B (May 1992). "Pharmacokinetics of ketotifen after oral administration to healthy male subjects".Biopharmaceutics & Drug Disposition.13 (4):255–262.doi:10.1002/bdd.2510130404.PMID1600111.S2CID72293850.
^Sasaki F, Yokomizo T (August 2019). "The leukotriene receptors as therapeutic targets of inflammatory diseases".Int Immunol.31 (9):607–615.doi:10.1093/intimm/dxz044.PMID31135881.
^abCastillo JG, Gamboa PM, García BE, Oehling A (1990). "Effect of ketotifen on phosphodiesterase activity from asthmatic individuals".Allergologia et Immunopathologia.18 (4):197–201.PMID1702263.
^Chaplin S, Scadding G (2011). "Antihistamines: Their properties and use in hay fever".Prescriber.22 (10):29–31.doi:10.1002/psb.758.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)
^Waterfield J (29 September 2013). "Antihistamines: Mode of action, prescribing rationale and uses".Nurse Prescribing.7 (4):166–170.doi:10.12968/npre.2009.7.4.41711.
^Chaplin S, Scadding G (13 June 2011). "Antihistamines: Their properties and use in hay fever".Prescriber.22 (10):29–31.doi:10.1002/psb.758.
^Jue TL, Storm AC, Naveed M, Fishman DS, Qumseya BJ, McRee AJ, et al. (2021). "ASGE guideline on the role of endoscopy in the management of benign and malignant gastroduodenal obstruction".Gastrointestinal Endoscopy.93 (2): 309–322.e4.doi:10.1016/j.gie.2020.07.063.PMID33168194.
^Shim K (2019). "Endoscopic Management for Pyloric Stricture and Gastric Outlet Obstruction: Dilation and Stenting".Therapeutic Gastrointestinal Endoscopy. pp. 277–289.doi:10.1007/978-981-13-1184-0_16.ISBN978-981-13-1184-0.
^ab"Ketotifen".Drugs and Lactation Database (LactMed) [Internet]. Bethesda (MD): National Institute of Child Health and Human Development. 2006.PMID30000587.NCBINBK501527.Archived from the original on 3 October 2023. Retrieved22 November 2023.
^Nonaka H, Otaki S, Ohshima E, Kono M, Kase H, Ohta K, et al. (March 1998). "Unique binding pocket for KW-4679 in the histamine H1 receptor".Eur J Pharmacol.345 (1):111–117.doi:10.1016/s0014-2999(97)01620-8.PMID9593602.
^Appl H, Holzammer T, Dove S, Haen E, Strasser A, Seifert R (February 2012). "Interactions of recombinant human histamine H₁R, H₂R, H₃R, and H₄R receptors with 34 antidepressants and antipsychotics".Naunyn Schmiedebergs Arch Pharmacol.385 (2):145–170.doi:10.1007/s00210-011-0704-0.PMID22033803.
^Gianotti M, Botta M, Brough S, Carletti R, Castiglioni E, Corti C, et al. (November 2010). "Novel spirotetracyclic zwitterionic dual H(1)/5-HT(2A) receptor antagonists for the treatment of sleep disorders".J Med Chem.53 (21):7778–7795.doi:10.1021/jm100856p.PMID20942472.
^Lim HD, van Rijn RM, Ling P, Bakker RA, Thurmond RL, Leurs R (September 2005). "Evaluation of histamine H1-, H2-, and H3-receptor ligands at the human histamine H4 receptor: identification of 4-methylhistamine as the first potent and selective H4 receptor agonist".J Pharmacol Exp Ther.314 (3):1310–1321.doi:10.1124/jpet.105.087965.PMID15947036.
^abLi L, Liu R, Peng C, Chen X, Li J (July 2022). "Pharmacogenomics for the efficacy and side effects of antihistamines".Exp Dermatol.31 (7):993–1004.doi:10.1111/exd.14602.PMID35538735.
^Bittner L, Teixidó E, Keddi I, Escher BI, Klüver N (May 2019). "pH-Dependent Uptake and Sublethal Effects of Antihistamines in Zebrafish (Danio rerio) Embryos".Environmental Toxicology and Chemistry.38 (5):1012–1022.Bibcode:2019EnvTC..38.1012B.doi:10.1002/etc.4395.PMID30779379.S2CID73482611.
^Janeczko P, Norris MR, Bielory L (October 2021). "Assessment of receptor affinities of ophthalmic and systemic agents in dry eye disease".Current Opinion in Allergy and Clinical Immunology.21 (5):480–485.doi:10.1097/ACI.0000000000000773.PMID34387278.S2CID236998913.
^Triantafillou V, Maina IW, Patel NN, Tong CC, Papagiannopoulos P, Kohanski MA, et al. (February 2020). "In vitro safety of ketotifen as a topical nasal rinse".International Forum of Allergy & Rhinology.10 (2):265–270.doi:10.1002/alr.22461.PMID32086998.S2CID211246051.
^abSagara A, Nagahama A, Aki H, Yoshimura H, Hiraide M, Shimizu T, et al. (October 2023). "Potential risk of driving performance under combined conditions of taking second-generation antihistamines and attending calls using a hands-free function".Traffic Injury Prevention.25 (1):36–40.doi:10.1080/15389588.2023.2265002.PMID37815801.S2CID263801715.
^abAelony Y (September 1998). "First-generation vs second-generation antihistamines".Archives of Internal Medicine.158 (17):1949–1950.doi:10.1001/archinte.158.17.1949 (inactive 12 July 2025).PMID9759694.{{cite journal}}: CS1 maint: DOI inactive as of July 2025 (link)
^Fahmy RH, Badr-Eldin SM (August 2014). "Novel delivery approach for ketotifen fumarate: dissofilms formulation using 3² experimental design: in vitro/in vivo evaluation".Pharm Dev Technol.19 (5):521–30.doi:10.3109/10837450.2013.800108.PMID23713715.S2CID45012360.
^Jáuregui I, Mullol J, Bartra J, del Cuvillo A, Dávila I, Montoro J, et al. (2006). "H1 antihistamines: psychomotor performance and driving".J Investig Allergol Clin Immunol.16 (Suppl 1):37–44.PMID17357376.
^Eltze M, Mutschler E, Lambrecht G (1992). "Affinity profiles of pizotifen, ketotifen and other tricyclic antimuscarinics at muscarinic receptor subtypes M1, M2 and M3".European Journal of Pharmacology.211 (3):283–293.doi:10.1016/0014-2999(92)90383-F.PMID1377628.
^"Ketotifen Fumarate".Inxight Drugs. Bethesda MD, US: National Center for Advancing Translational Sciences (NCATS). 12 April 2024.Archived from the original on 13 April 2024. Retrieved13 April 2024.
^Aberg AK, Arulnesan N, Bolger GT, Ciofalo VB, Pucaj K, Walle K, et al. (April 2022). "Ketotifen is a Prodrug. Norketotifen is the active metabolite".Drug Development Research.83 (2):362–367.doi:10.1002/ddr.21865.PMID34410005.S2CID237216445.
