Loratadine

Loratadine is indicated for the symptomatic relief of allergies such as hay fever (allergic rhinitis), urticaria (hives), chronic idiopathic urticaria,{{cite journal | vauthors = Pons-Guiraud A, Nekam K, Lahovsky J, Costa A, Piacentini A | title = Emedastine difumarate versus loratadine in chronic idiopathic urticaria: a randomized, double-blind, controlled European multicentre clinical trial | journal = European Journal of Dermatology | volume = 16 | issue = 6 | pages = 649–54 | year = 2006 | pmid = 17229605 }} and other skin allergies.{{cite book|title=Austria-Codex| veditors = Jasek W |publisher=Österreichischer Apothekerverlag|location=Vienna|year=2007|edition=2007/2008|volume=1|pages=1768–71|isbn= 978-3-85200-181-4|language=de}} For allergic rhinitis, loratadine is indicated for both nasal and eye symptoms including sneezing, runny nose, and itchy or burning eyes.{{cite web | title=Claritin- loratadine tablet | website=DailyMed | date=10 February 2020 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=660ac9df-f1b1-4c89-94dd-9fae0a013f3c | access-date=10 April 2020}}

Similarly to cetirizine, loratadine attenuates the itching associated with Kimura's disease.{{cite journal | vauthors = Ueda T, Arai S, Amoh Y, Katsuoka K | title = Kimura's disease treated with suplatast tosilate and loratadine | journal = European Journal of Dermatology | volume = 21 | issue = 6 | pages = 1020–1 | year = 2011 | pmid = 21914581 | doi = 10.1684/ejd.2011.1539 }}

Loratadine/pseudoephedrine is a fixed dose combination of the drug with pseudoephedrine, a nasal decongestant.{{cite book|title=Austria-Codex| veditors = Jasek W |publisher=Österreichischer Apothekerverlag|location=Vienna|year=2007|edition=2007/2008|volume=1|pages=1731–34|isbn=9783852001814|language=de}}

File:Loratadine10mg.png

The medication is available in many different forms, including tablets, oral suspension, and syrups. Also available are quick-dissolving tablets.

Loratadine is usually compatible with breastfeeding (classified category L-2 - probably compatible, by the American Academy of Pediatrics).{{cite journal | author = Committee on Drugs | title = Transfer of drugs and other chemicals into human milk | journal = Pediatrics | volume = 108 | issue = 3 | pages = 776–89 | date = September 2001 | pmid = 11533352 | doi = 10.1542/peds.108.3.776 | doi-access = free }} In the U.S., it is classified as category B in pregnancy, meaning animal reproduction studies have failed to demonstrate a risk to the fetus, but no adequate and well-controlled studies in pregnant women have been conducted.{{cite journal | vauthors = See S | title = Desloratadine for allergic rhinitis | journal = American Family Physician | volume = 68 | issue = 10 | pages = 2015–6 | date = November 2003 | pmid = 14655812 | url = http://www.aafp.org/afp/20031115/steps.html | url-status = live | archive-url = https://web.archive.org/web/20050724082052/http://www.aafp.org/afp/20031115/steps.html | archive-date = 24 July 2005 }}

As a "non-sedating" antihistamine, loratadine causes less (but still significant, in some cases) sedation and psychomotor retardation than the older antihistamines, because it penetrates the blood/brain barrier less.{{cite web | url = http://allergies.emedtv.com/claritin/claritin-and-alcohol.html | title = Claritin and Alcohol | vauthors = Monson K | publisher = emedtv.com | url-status = dead | archive-url = https://web.archive.org/web/20120424203016/http://allergies.emedtv.com/claritin/claritin-and-alcohol.html | archive-date = 24 April 2012 | access-date = 7 May 2012 }} Headache is also a possible side effect.{{cite book| vauthors = Mutschler E, Geisslinger G, Kroemer HK |title=Arzneimittelwirkungen|publisher=Wissenschaftliche Verlagsgesellschaft|location=Stuttgart|year=2001|edition=8|pages=456–461|isbn=978-3-8047-1763-3|language=de}}

Unlike earlier-generation antihistamines, loratadine is considered largely free of antimuscarinic effects (urinary retention, dry mouth, blurred vision).{{cite book|doi=10.1016/bs.podrm.2021.10.002 |title=Loratadine |date=2022 | vauthors = AlMasoud N, Bakheit AH, Alshammari MF, Abdel-Aziz HA, AlRabiah H |series=Profiles of Drug Substances, Excipients, and Related Methodology |volume=47 |pages=55–90 |pmid=35396016 |isbn=978-0-323-85482-5 }}{{cite book|doi=10.1016/B978-0-444-53717-1.00314-0 |chapter=Antihistamines |title=Meyler's Side Effects of Drugs |date=2016 |pages=606–618 |isbn=978-0-444-53716-4 }}

Substances that act as inhibitors of the CYP3A4 enzyme such as ketoconazole, erythromycin, cimetidine, and furanocoumarin derivatives (found in grapefruit) lead to increased plasma levels of loratadine — that is, more of the drug was present in the bloodstream than typical for a dose. This had clinically significant effects in controlled trials of 10 mg loratadine treatment. {{cite journal | vauthors = Kosoglou T, Salfi M, Lim JM, Batra VK, Cayen MN, Affrime MB | title = Evaluation of the pharmacokinetics and electrocardiographic pharmacodynamics of loratadine with concomitant administration of ketoconazole or cimetidine | journal = British Journal of Clinical Pharmacology | volume = 50 | issue = 6 | pages = 581–9 | date = December 2000 | pmid = 11136297 | pmc = 2015013 | doi = 10.1046/j.1365-2125.2000.00290.x }}

Antihistamines should be discontinued 48 hours before skin allergy tests, since these drugs may prevent or diminish otherwise positive reactions to dermal activity indicators.

Loratadine is a tricyclic antihistamine, which acts as a selective inverse agonist of peripheral histamine H₁ receptors.{{cite journal | vauthors = Devillier P, Roche N, Faisy C | title = Clinical pharmacokinetics and pharmacodynamics of desloratadine, fexofenadine, and levocetirizine: a comparative review | journal = Clinical Pharmacokinetics | volume = 47 | issue = 4 | pages = 217–30 | year = 2008 | pmid = 18336052 | doi = 10.2165/00003088-200847040-00001 | s2cid = 9189476 }} The potency of second generation histamine antagonists is (from strongest to weakest) desloratadine (K_i 0.4 nM) > levocetirizine (K_i 3 nM) > cetirizine (K_i 6 nM) > fexofenadine (K_i 10 nM) > terfenadine > loratadine. However, the onset of action varies significantly and clinical efficacy is not always directly related to only the H₁ receptor potency, as the concentration of free drug at the receptor must also be considered.{{cite journal | vauthors = Church MK, Church DS | title = Pharmacology of antihistamines | journal = Indian Journal of Dermatology | volume = 58 | issue = 3 | pages = 219–24 | date = May 2013 | pmid = 23723474 | pmc = 3667286 | doi = 10.4103/0019-5154.110832 | doi-access = free }} Loratadine also shows anti-inflammatory properties independent of H₁ receptors.{{cite journal | vauthors = Bielory L, Lien KW, Bigelsen S | title = Efficacy and tolerability of newer antihistamines in the treatment of allergic conjunctivitis | journal = Drugs | volume = 65 | issue = 2 | pages = 215–28 | date = 2005 | pmid = 15631542 | doi = 10.2165/00003495-200565020-00004 | s2cid = 46791611 | url = }}{{cite journal | vauthors = Canonica GW, Blaiss M | title = Antihistaminic, anti-inflammatory, and antiallergic properties of the nonsedating second-generation antihistamine desloratadine: a review of the evidence | journal = The World Allergy Organization Journal | volume = 4 | issue = 2 | pages = 47–53 | date = February 2011 | pmid = 23268457 | pmc = 3500039 | doi = 10.1097/WOX.0b013e3182093e19 | url = }} The effect is exhibited through suppression of the NF-κB pathway, and by regulating the release of cytokines and chemokines, thereby regulating the recruitment of inflammatory cells.{{cite journal | vauthors = Hunto ST, Kim HG, Baek KS, Jeong D, Kim E, Kim JH, Cho JY | title = Loratadine, an antihistamine drug, exhibits anti-inflammatory activity through suppression of the NF-kB pathway | journal = Biochemical Pharmacology | volume = 177 | issue = | pages = 113949 | date = July 2020 | pmid = 32251678 | doi = 10.1016/j.bcp.2020.113949| s2cid = 215408324 }}{{cite journal | vauthors = Fumagalli F, Baiardini I, Pasquali M, Compalati E, Guerra L, Massacane P, Canonica GW | title = Antihistamines: do they work? Further well-controlled trials involving larger samples are needed | journal = Allergy | volume = 59 | issue = Suppl 78 | pages = 74–7 | date = August 2004 | pmid = 15245363 | doi = 10.1111/j.1398-9995.2004.00573.x| s2cid = 39936983 }}

Loratadine is given orally, is well absorbed from the gastrointestinal tract, and has rapid first-pass hepatic metabolism; it is metabolized by isoenzymes of the cytochrome P450 system, including CYP3A4, CYP2D6, and, to a lesser extent, several others.{{cite book | vauthors = Nelson WL | veditors = Williams DH, Foye WO, Lemke TL |title=Foye's principles of medicinal chemistry |publisher=Lippincott Williams & Wilkins |location=Hagerstown, MD |year=2002 |chapter=Antihistamines and related antiallergic and antiulcer agents |pages=805 |isbn=978-0-683-30737-5}}{{cite journal | vauthors = Ghosal A, Gupta S, Ramanathan R, Yuan Y, Lu X, Su AD, Alvarez N, Zbaida S, Chowdhury SK, Alton KB | title = Metabolism of loratadine and further characterization of its in vitro metabolites | journal = Drug Metabolism Letters | volume = 3 | issue = 3 | pages = 162–70 | date = August 2009 | pmid = 19702548 | doi = 10.2174/187231209789352067 }} Loratadine is almost totally (97–99%) bound to plasma proteins. Its metabolite desloratadine, which is largely responsible for the antihistaminergic effects, binds to plasma proteins by 73–76%.

Loratadine's peak effect occurs after 1–2 hours, and its biological half life is on average eight hours (range 3 to 20 hours) with desloratadine's half-life being 27 hours (range 9 to 92 hours), accounting for its long-lasting effect.{{cite journal | vauthors = Affrime M, Gupta S, Banfield C, Cohen A | title = A pharmacokinetic profile of desloratadine in healthy adults, including elderly | journal = Clinical Pharmacokinetics | volume = 41 | issue = Suppl 1 | pages = 13–9 | year = 2002 | pmid = 12169042 | doi = 10.2165/00003088-200241001-00003 | s2cid = 25555379 }} About 40% is excreted as conjugated metabolites into the urine, and a similar amount is excreted into the feces. Traces of unmetabolised loratadine can be found in the urine.

In structure, it is closely related to tricyclic antidepressants, such as imipramine, and is distantly related to the atypical antipsychotic quetiapine.{{cite journal | vauthors = Kay GG, Harris AG | title = Loratadine: a non-sedating antihistamine. Review of its effects on cognition, psychomotor performance, mood and sedation | journal = Clinical and Experimental Allergy | volume = 29 | issue = Suppl 3 | pages = 147–50 | date = July 1999 | pmid = 10444229 | doi = 10.1046/j.1365-2222.1999.0290s3147.x | s2cid = 26012715 }}

Schering-Plough developed loratadine as part of a quest for a potential blockbuster drug: a nonsedating antihistamine. By the time Schering submitted the drug to the U.S. Food and Drug Administration (FDA) for approval, the agency had already approved a competitor's nonsedating antihistamine, terfenadine (trade name Seldane), and, therefore, put loratadine on a lower priority.{{cite news | url=https://www.nytimes.com/2001/03/11/magazine/the-claritin-effect-prescription-for-profit.html?pagewanted=all | work=The New York Times | title=The Claritin Effect; Prescription for Profit | vauthors = Hall SS | date=11 March 2001 | access-date=28 June 2010 | url-status=live | archive-url=https://web.archive.org/web/20150527160442/http://www.nytimes.com/2001/03/11/magazine/the-claritin-effect-prescription-for-profit.html?pagewanted=all | archive-date=27 May 2015 }} However, terfenadine had to be removed from the U.S. market by the manufacturer in late 1997 after reports of serious ventricular arrhythmias among those taking the drug.{{cite web| title= FDA Approves Allegra-D, Manufacturer To Withdraw Seldane From Marketplace | publisher= Food and Drug Administration | url= https://www.fda.gov/bbs/topics/ANSWERS/ANS00843.html | archive-url= https://web.archive.org/web/20080223144824/https://www.fda.gov/bbs/topics/ANSWERS/ANS00843.html | archive-date= 23 February 2008 | access-date=11 November 2010}}{{cite journal | vauthors = Thompson D, Oster G | title = Use of terfenadine and contraindicated drugs | journal = JAMA | volume = 275 | issue = 17 | pages = 1339–41 | date = May 1996 | pmid = 8614120 | doi = 10.1001/jama.1996.03530410053033 | publisher = American Medical Association }}

Loratadine was approved by the FDA in 1993. The drug continued to be available only by prescription in the U.S. until it went off patent in 2002.{{Cite web|url=http://www.prnewswire.com/news-releases/schering-plough-loses-patent-lawsuit-over-claritin-opening-door-for-cheaper-generic-versions-70880857.html|title=Schering-Plough Loses Patent Lawsuit Over Claritin, Opening Door For Cheaper Generic Versions|date=5 August 2003|website=PRNewswire|publisher=Leiner Health Products|access-date=26 June 2016|url-status=live|archive-url=https://web.archive.org/web/20160812201604/http://www.prnewswire.com/news-releases/schering-plough-loses-patent-lawsuit-over-claritin-opening-door-for-cheaper-generic-versions-70880857.html|archive-date=12 August 2016}} It was then subsequently approved for over-the-counter sales. Once it became an unpatented over-the-counter drug, the price dropped significantly.{{citation needed|date=April 2020}}

Schering also developed desloratadine (Clarinex/Aerius), which is an active metabolite of loratadine.

In 1998, in an unprecedented action in the United States, an American insurance company, Anthem Inc., petitioned the federal Food and Drug Administration to allow loratadine and two other antihistamines to be made available over the counter (OTC) while they were still protected by patents; the administration granted the request, which was not binding on manufacturers.{{cite journal | vauthors = Cohen JP, Paquette C, Cairns CP | title = Switching prescription drugs to over the counter | journal = BMJ | volume = 330 | issue = 7481 | pages = 39–41 | date = January 2005 | pmid = 15626806 | pmc = 539854 | doi = 10.1136/bmj.330.7481.39 }} In the United States, Schering-Plough made loratadine available over the counter in 2002. By 2015, loratadine was available over the counter in many countries.Association of the European Self-Medication Industry Database. [http://www.aesgp.eu/facts-figures/otc-ingredients/?result=name&multiselect=all&country=28&country=29&country=4&country=1&country=18&country=31&country=32&country=33&country=19&country=20&country=6&country=42&country=7&country=9&country=3&country=10&country=21&country=11&country=12&country=34&country=22&country=36&country=37&country=23&country=38&country=24&country=14&country=39&country=25&country=26&country=35&country=15&country=16&country=27&country=13&country=17&country=40&country=41&otc=230 Loratadine OTC regulation] {{webarchive|url=https://web.archive.org/web/20151208062901/http://www.aesgp.eu/facts-figures/otc-ingredients/?result=name&multiselect=all&country=28&country=29&country=4&country=1&country=18&country=31&country=32&country=33&country=19&country=20&country=6&country=42&country=7&country=9&country=3&country=10&country=21&country=11&country=12&country=34&country=22&country=36&country=37&country=23&country=38&country=24&country=14&country=39&country=25&country=26&country=35&country=15&country=16&country=27&country=13&country=17&country=40&country=41&otc=230 |date=8 December 2015 }} Page accessed 11 April 2015

In 2017, loratadine was available under many brand names and in many forms worldwide, including several combination drug formulations with pseudoephedrine, paracetamol, betamethasone, ambroxol, salbutamol, phenylephrine, and dexamethasone.{{cite web|title=Loratadine International Brands|url=https://www.drugs.com/international/loratadine.html|publisher=Drugs.com|access-date=19 February 2017|url-status=live|archive-url=https://web.archive.org/web/20160304002803/http://www.drugs.com/international/loratadine.html|archive-date=4 March 2016}}

The marketing of the Claritin brand is important in the history of direct-to-consumer advertising of drugs.

The first television commercial for a prescription drug was broadcast in the United States in 1983, by Boots. It caused controversy. The federal Food and Drug Administration responded with strong regulations requiring disclosure of side effects and other information. These rules made pharmaceutical manufacturers balk at spending money on ads that had to highlight negative aspects.{{Cite news|url=https://www.statnews.com/2015/12/11/untold-story-tvs-first-prescription-drug-ad/|title=The untold story of TV's first prescription drug ad|date=11 December 2015|work=STAT|access-date=26 October 2017}}

In the mid-1990s, the marketing team for Claritin at Schering-Plough found a way around these rules. They created brand awareness commercials that never actually said what the drug was for, but instead showed sunny images, and the voiceover said such things as "At last, a clear day is here" and "It's time for Claritin" and repeatedly told viewers "Ask your doctor [about Claritin]." The first ads made people aware of the brand and increased prescriptions, which led Schering-Plough and others to aggressively pursue the advertising strategy.{{Cite news|url=http://www.mmm-online.com/features/dtc-the-first-10-years/article/24443/|title=DTC: The first 10 years|date=1 April 2007|work=MM&M|access-date=26 October 2017}}

In 1998, a 12-page one-shot comic based on the Batman: The Animated Series was given away to advertise Claritin. The book, written by PRIEST, penciled by Joe Staton, and inked by Mike DeCarlo, sees Tim Drake unable to perform his crime-fighting duties because hay fever and antihistamines make him drowsy. After being given a prescription for Claritin, he saved Batman from Poison Ivy.{{Citation |title=Batman: Claritin Allergy Special |url=https://comicbookrealm.com/series/49106/417043/dc-comics-batman-claritin-allergy-special-one-shot-issue-1 |access-date=6 December 2020}}

This trend, along with advice from the Food and Drug Administration's attorneys that it could not win a First Amendment case on the issue, prompted the administration to issue new rules for television commercials in 1997. Instead of including the "brief summary" that took up a full page in magazine ads and would take too long to explain in a short television advertisement, drug makers were allowed to refer viewers to print ads, informative telephone lines, and websites, and to urge people to talk to their doctors if they wanted additional information.{{Cite news|url=http://adage.com/article/news/ten-years-direct-consumer-drug-advertising/112215/|title=Ten Years Later: Direct to Consumer Drug Advertising|access-date=26 October 2017}}

Schering-Plough invested {{US$|322}}{{nbsp}}million in Claritin direct-to-consumer advertising in 1998 and 1999, far more than any other brand. Spending on direct-to-consumer advertising by the pharmaceutical industry rose from {{US$|360}}{{nbsp}}million in 1995 to {{US$|1.3}}{{nbsp}}billion in 1998, and by 2006, was {{US$|5}}{{nbsp}}billion.

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