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Loratadine

Clinical data
Trade names	Claritin, Claratyne, Clarityn, others
AHFS/Drugs.com	Monograph
MedlinePlus	a697038
License data	US DailyMed: Loratadine
Pregnancy category	AU: B1
Routes of administration	By mouth
Drug class	Second-generation antihistamine
ATC code	R06AX13 (WHO)
Legal status
Legal status	AU: OTC CA: OTC UK: General sales list (GSL, OTC) / Pharmacy US: WARNINGOTC / Rx-only
Pharmacokinetic data
Bioavailability	almost 100%
Protein binding	97–99%
Metabolism	Liver (CYP2D6- and 3A4-mediated)
Elimination half-life	8 hours, active metabolite desloratadine 27 hours
Excretion	40% as conjugated metabolites into urine Similar amount into the feces
Identifiers
IUPAC name Ethyl 4-(8-chloro-5,6-dihydro-11H-benzocycloheptapyridin-11-ylidene)-1-piperidinecarboxylate
CAS Number	79794-75-5
PubChem CID	3957
IUPHAR/BPS	7216
DrugBank	DB00455
ChemSpider	3820
UNII	7AJO3BO7QN
KEGG	D00364
ChEBI	CHEBI:6538
ChEMBL	ChEMBL998
CompTox Dashboard (EPA)	DTXSID2023224
ECHA InfoCard	100.120.122
Chemical and physical data
Formula	C22H23ClN2O2
Molar mass	382.89 g·mol
3D model (JSmol)	Interactive image
SMILES O=C(OCC)N4CC/C(=C2/c1ccc(Cl)cc1CCc3cccnc23)CC4
InChI InChI=1S/C22H23ClN2O2/c1-2-27-22(26)25-12-9-15(10-13-25)20-19-8-7-18(23)14-17(19)6-5-16-4-3-11-24-21(16)20/h3-4,7-8,11,14H,2,5-6,9-10,12-13H2,1H3 Key:JCCNYMKQOSZNPW-UHFFFAOYSA-N
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Loratadine, sold under the brand name Claritin among others, is a medication used to treat allergies. This includes allergic rhinitis (hay fever) and hives. It is also available in drug combinations such as loratadine/pseudoephedrine, in which it is combined with pseudoephedrine, a nasal decongestant. It is taken orally.

Common side effects include sleepiness, dry mouth, and headache. Serious side effects are rare and include allergic reactions, seizures, and liver problems. Use during pregnancy appears to be safe but has not been well studied. It is not recommended in children less than two years old. It is in the second-generation antihistamine family of medication.

Loratadine was patented in 1980 and came to market in 1988. It is on the World Health Organization's List of Essential Medicines. Loratadine is available as a generic medication. In the United States, it is available over the counter. In 2022, it was the 72nd most commonly prescribed medication in the United States, with more than 9 million prescriptions. In 2022, the combination with pseudoephedrine was the 289th most commonly prescribed medication in the United States, with more than 500,000 prescriptions.

Medical uses

Loratadine is indicated for the symptomatic relief of allergies such as hay fever (allergic rhinitis), urticaria (hives), chronic idiopathic urticaria, and other skin allergies. For allergic rhinitis, loratadine is indicated for both nasal and eye symptoms including sneezing, runny nose, and itchy or burning eyes.

Similarly to cetirizine, loratadine attenuates the itching associated with Kimura's disease.

Combination drugs

Loratadine/pseudoephedrine is a fixed dose combination of the drug with pseudoephedrine, a nasal decongestant.

Dosage forms

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

Contraindications

Loratadine is usually compatible with breastfeeding (classified category L-2 - probably compatible, by the American Academy of Pediatrics). 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.

Adverse effects

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. Headache is also a possible side effect.

Unlike earlier-generation antihistamines, loratadine is considered largely free of antimuscarinic effects (urinary retention, dry mouth, blurred vision).

Interactions

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.

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

Pharmacology

Pharmacodynamics

Loratadine is a tricyclic antihistamine, which acts as a selective inverse agonist of peripheral histamine H₁ receptors. 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. Loratadine also shows anti-inflammatory properties independent of H₁ receptors. 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.

Pharmacokinetics

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. 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. 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.

History

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. 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.

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. It was then subsequently approved for over-the-counter sales. Once it became an unpatented over-the-counter drug, the price dropped significantly.

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

Society and culture

Over the counter

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. 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.

Brands

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.

Marketing

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.

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 ." The first ads made people aware of the brand and increased prescriptions, which led Schering-Plough and others to aggressively pursue the advertising strategy.

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.

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.

Schering-Plough invested US$322 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 million in 1995 to US$1.3 billion in 1998, and by 2006, was US$5 billion.

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