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Ketotifen

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Not to be confused withKetoprofen,a nonsteroidal anti-inflammatory drug with analgesic and antipyretic effects.

Ketotifen
Clinical data
Trade namesZaditor,[1]Alaway, others
Other namesketotifen fumarate (USANUS)
AHFS/DrugsMonograph
MedlinePlusa604033
License data
Pregnancy
category
  • AU:B1
Routes of
administration		By mouth,eye drops,drug-eluting contact lenses
ATC code
Legal status
Legal status
Pharmacokineticdata
Bioavailability60%
Protein binding75%
MetabolismLiver
Eliminationhalf-life12 hours
Identifiers
  • 4-(1-Methylpiperidin-4-ylidene)-4,9-dihydro-10H-benzo[4,5]cyclohepta[1,2-b]thiophen-10-one
CAS Number
PubChemCID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard(EPA)
ECHA InfoCard100.047.348Edit this at Wikidata
Chemical and physical data
FormulaC19H19NOS
Molar mass309.43g·mol−1
3D model (JSmol)
  • O=C3c1sccc1C(\c2c(cccc2)C3)=C4/CCN(C)CC4
  • InChI=1S/C19H19NOS/c1-20-9-6-13(7-10-20)18-15-5-3-2-4-14(15)12-17(21)19-16(18)8-11-22-19/h2-5,8,11H,6-7,9-10,12H2,1H3checkY
  • Key:ZCVMWBYGMWKGHF-UHFFFAOYSA-NcheckY
  • Key:YNQQEYBLVYAWNX-WLHGVMLRSA-N
(verify)

Ketotifenis anantihistaminemedication and amast cell stabilizerused to treat allergic conditions such asconjunctivitis,asthma,and urticaria (hives). Ketotifen is available in ophthalmic (eye drops or drug-eluting contact lenses) and oral (tablets or syrup) forms: the ophthalmic form relieves eyeitchinessand irritation associated withseasonal allergies,while the oral form helps preventsystemic conditionssuch as asthma attacks and allergic reactions. In addition to treating allergies, ketotifen has shown efficacy in managing systemicmast cell diseasessuch asmastocytosisandmast cell activation syndrome(MCAS), which involve abnormal accumulation or activation ofmast cellsthroughout the body. Ketotifen is also used for other allergic-type conditions likeatopic dermatitis(eczema) andfood allergies.

Ketotifen acts by blocking theH1histamine receptors,which are found on various cells in the body, such assmooth muscle,endothelium,andnerve cells,so that ketotifen 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 called mast cells; this action helps reduce symptoms of conditions (including allergic conditions) by blocking the activation of these cells. In addition to itsantihistaminicactivity, ketotifen also functions as aleukotriene antagonist,which blocks inflammation-causing chemicals known asleukotrienes;it also acts as aphosphodiesterase inhibitorthat regulates blood vessel dilation.

While well-tolerated, 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 ophtalmic form. Ketotifen has contraindications for individuals with certain medical conditions, such as acuteporphyriasorepilepsy.Controversies surrounding ketotifen include its classification as a first-generation or second-generation antihistamine due to varying criteria of classification.

Medical uses

[edit]

Ketotifen, an antihistamine medication and a mast cell stabilizer, is most commonly sold as asaltwithfumaric acid,ketotifen fumarate, and is available in two forms:[6]

  1. in itsophthalmicform (eye drops or drug-eluting contact lenses),[7][5][8]it is used to treatallergic conjunctivitis;[9][1]
  2. in itsoralform (tablets or syrup),[6]it is used to preventasthmaattacks or anaphylaxis,[10][11]as well as various mast cell, allergic-type disorders.[12][13][14]

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]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 like 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.[5]

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 asmastocytosisandmast cell activation syndrome(MCAS), as well as allergic and nonallergicanaphylaxis.Ketotifen has also shown efficacy in managingangioedemaand food allergies. As a mast cell stabilizer to treat MCAS, oral ketotifen prevents the release of histamine and other inflammatory substances frommast cells,which areimmune cellsthat react to allergens, therefore, ketotifen, by blocking acalcium channelessential for mast cell activation, helps reduce symptoms of allergic conditions such as asthma, hay fever, and conjunctivitis caused by mast cell activation. In Canada, Europe, and Mexico, oral ketotifen is commonly prescribed for these indications.[15][14][10]In patients with MCAS, ketotifen reduce 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.[16]

The maximum antihistamine and mast cell stabilizing effect of oral ketotifen is achieved on long-term administration, and least 6-12 weeks is necessary for a maximum therapeutic effect to start.[17]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.[18]

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.[14][10]However, ketotifen eye drops are approved in the US for people who are at least three years of age.[19][20]In the EU, ketotifen oral formulatios (syrup, tables and capsules) are approved by theEuropean Medicines Agencyfor adult use.[21]In the UK, ketotifen is available as tables and elixir (liquid).[22]

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.[23]

The mean elimination half-life of oral ketotifen is 12 hours.[24]Besides its anti-histaminic activity, it is also a functionalleukotrieneantagonist[25](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)[26][27]and aphosphodiesterase inhibitor[28][29](a medication that blocks the enzymes that regulate the levels ofcAMPandcGMP,which are molecules that controlblood vessel dilationandsmooth muscle relaxationin the body).[30][31]

Contraindications

[edit]

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,[32][20][33]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:acute porphyrias(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),epilepsy(a disorder causing recurrent seizures),prostatic hypertrophy(in adults),pyloroduodenal obstruction[34][35][32](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), susceptibility toangle-closure glaucoma(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, a nerve that connects the eye to the brain), andurinary retention(inability to urinate).[32]

The use of ketotifen eye drops during pregnancy and lactation is considered safe, asabsorptionthrough 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 Developmentadvises to apply pressure on thetear ductnear the corner of the eye for at least one minute and remove any excess solution with a tissue.[36]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.[36]

Side effects

[edit]

Common side effects of ophthalmic use are eye redness andswelling.Less common areeye discharge,eye discomfort, eye pain,hives,increaseditchingof eyes, and rash. Ophthalmic use of ketotifen may also cause burning, stinging, or itching of the eyes, blurred vision, or increased sensitivity to light.[20]

Side effects of systemic (oral) use includedrowsiness,weight gain(5.0–5.4 kilograms (11.0–11.9 lb)),dry mouth,irritability, and increasednosebleeds.[37]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.[6]

Overdose

[edit]

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.[38][39][40]

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.[38][39][40]

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.[39][40]

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 failureandurinary retention.The hepatic effects may includehepatitisandjaundice.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.[38][39]

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.[41][42][40]

Interactions

[edit]

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.[43][44]

Oral ketotifen may interact withamphetamineandbenzphetamine,which may decrease the activities of ketotifen.[45][46]

The concomitant use of oral ketotifen withamifampridine,bupropion,donepezil,andpitolisant,is not recommended.[47]

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 monitorthrombocytecounts in patients who are concurrently taking oral antidiabetic agents.[43][44]

Systemic use of ketotifen may decrease the effectiveness ofbenzylpenicilloyl polylysineas a diagnostic agent.[45]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.[45]

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.[48]

Pharmacology

[edit]

Ketotifen is aselectiveantihistamine– that is, aninverse agonistof thehistamineH1receptor(Ki= 0.166 nM)[49]– andmast cell stabilizer.[50][51][52]By preventing the degranulation of mast cells, ketotifen inhibits the release of inflammatory mediators such as histamine andleukotrienes,which are implicated in allergic reactions.[50]Ketotifen action is also based on its inhibition of serotonin release.[50]

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.[50]

In addition, ketotifen has weakanticholinergic(Ki= 204 nM formAChTooltip muscarinic acetylcholine receptor) andantiserotonergic(Ki= 38.9 nM for5-HT2A) activity.[49][53]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.[54]

Ketotifen is alipophilic compoundthat can cross theblood–brain barrierand exert central nervous system effects, such as sedation,[55]weight gain, and anticonvulsant activity. Ketotifen also has peripheral effects, such as inhibition of platelet aggregation, modulation of cytokine production, and enhancement ofmucociliary clearance.[6][56][57]

Ketotifen acts as a mast cell stabilizer by preventing thedegranulationand release of histamine and other inflammatory mediators, such asleukotrienes,[25]prostaglandins,andcytokines,frommast cells.Ketotifen also inhibits the activation and migration ofeosinophils,basophils,andneutrophils,which are involved in the inflammatory response and tissue damage in allergic and respiratory diseases.[58][29][59]

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,[9]dermatitis, urticaria, and anaphylaxis. Ketotifen can also reduce thebronchial hyperreactivityand airway inflammation that are characteristic ofchronic asthma.[60][12][59]

Ketotifen hasplasma half-lifeof 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.[61]

Ketotifen, like other antihistamines,[55][62]is mainly metabolized by thecytochrome P450 (CYP) enzymes,especiallyCYP3A4[63][64]in the liver. The CYP enzymes are responsible for the oxidation and demethylation of ketotifen, producing the major metabolitesnorketotifenand10-hydroxyketotifen.Norketotifen is pharmacologically active and has a similar potency as ketotifen, while10-hydroxyketotifenis inactive. The metabolites are then conjugated withglucuronic acidor sulfate and excreted in the urine and feces.[65][66]

Classification

[edit]
Chemical structure of apizotifen,atricyclic(having three rings of atoms),benzocycloheptene-based compound with antihistamine properties and the structure similar to that of ketotifen: the only difference is that 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 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 H1receptors 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 H1receptors, thereby exerting its antihistamine effects.[67]

Ketotifen is anoncompetitive H1-antihistamineandmast cell stabilizer.[68]

There is no academic consensus on whether ketotifen should be classified as a medication belonging to the first[69][70][12]or the second generations of antihistamine drugs;[71][72]the classification can vary depending on the criteria used and the context of the study,[73]and is primarily based on chemical structure, pharmacological properties, and side effect profiles of an antihistamine drug.[74][73][6][75]First-generation H1antihistamines, 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.[76]Ketotifen is atricyclic,benzocycloheptene-based compound with chemical structures similar to first-generation antihistamines such asazatadine,cyproheptadine,chlorpheniramineanddiphenhydramine,and other compounds with antihistamine properties such aspizotifen.The sedative effects of ketotifen is also a reason in differences in classification. First-generation antihistamines are well known for their sedating side effects due to their ability to penetrate theblood–brain barrier.[74]While ketotifen has some sedative properties, it is generally considered to have a milder sedative effect compared to traditional first-generation antihistamines,[73][6]so this reduced sedation is one of the reasons why ketotifen is sometimes classified as a second-generation antihistamine.[75]

History

[edit]

Ketotifen was patented in 1970 and came into medical use in 1976.[77]Ketotifen was developed and patented bySandoz Pharmaceuticals(currently a part ofNovartis), a Swiss company.[78][79][80]

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.[81]The contact lens with ketotifen was approved for medical use in the United States in 2022.[82][83]

Society and culture

[edit]
A generic formulation of ketotifen marketed under the Ketotifen Sopharma brand name

Economics

[edit]

In 2021, it was the 301st most commonly prescribed medication in the United States, with more than400000prescriptions.[84]

Brand names

[edit]

Ketotifen is sold under various brand names worldwide, depending on country and formulation, with over 200 different names used.[85][86][87]In the United States, ketotifen fumarate ophtalmic solution is marketed under brand name Zaditor, which is owned byAlcon Inc.,a Swiss-American pharmaceutical company.[88][89]

Litigation

[edit]

There was a litigation related to ketotifen. In 2021, the plaintiff, Edward C. Hanks, brought an action in theUnited States District Court for the Central District of Illinois,against the defendants, Ned Hubbard and others, alleging that they violated his rights under theEighth Amendment to the United States Constitutionby 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 theUnited States Court of Appeals for the Seventh Circuit,which affirmed the district court's judgment on 7 February 2022.[90]

Research

[edit]

Norketotifen

[edit]

Research directions for ketotifen include the investigation ofnorketotifen(NK), a metabolite of ketotifen.In vitrostudies using humanlivermicrosomesandhepatocytessuggest that NK may be the majordemethylatedhepatic 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-inflammatoryactivity. Thus, ketotifen can probably be considered a sedatingprodrugthat is converted to NK, a nonsedatingmetabolitewith anti-inflammatory properties, when used as an anti-inflammatory medication.[91]The potential future applications of norketotifen are researched by Emergo Therapeutics, a US company.[92][93][94][95][96]

Conditions

[edit]

Increased appetite and weight gain

[edit]

The underlying mechanisms of why ketotifen (similarly to other antihistamine drugs such asastemizole,azelastine)[73]may increase appetite and lead to weight gain in some people, are not fully understood.[73]

Different studies have shown conflicting results about the amount of weight gain caused by ketotifen. In one study (postmarketing surveillance),[73]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,[37]adults gained a higher amount of weight: 5.0–5.4 kilograms (11.0–11.9 lb).[37]

Ketotifen exhibits a chemical resemblance topizotifen,a substance known for itsappetite-stimulatingproperties.[73]One proposed mechanism of the increase in appetite involves the inhibitory effect of ketotifen on the production ofTNF-α,which is acytokinethat 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 tissueand 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 onserotoninregulation 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 tendency and heightened appetite. Still, these potential mechanisms have been hypothesized based on limited evidence.[97]Studies on mice suggest thatcaffeine[97]orcitrus aurantifoliaoil[98]may prevent weight-gain induced by ketotifen, but, this has not been confirmed on human subjects.[98]

Irritable bowel syndrome

[edit]

Ketotifen is currently researched in context of a possible link between abnormalities in intestinal mast cells andirritable bowel syndrome,but there are no solid results yet.[99][100]

COVID-19

[edit]

It was hypothesized that ketotifen may be effective againstSARS-CoV-2,a virus behind theCOVID-19 pandemic,but there were no studies to confirm the hypothesis; the research did not proceed behindin-vitroexperiments.[101]

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[edit]
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