Loratadine

Loratadine
Names
Trade namesClaritin, Claratyne, Clarityn, others
IUPAC name
  • Ethyl 4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate
Clinical data
Drug classSecond-generation antihistamine
Main usesMinor allergies[1]
Side effectsSleepiness, dry mouth, headache[2]
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Pregnancy
category
  • AU: B1[3]
  • US: N (Not classified yet)[3]
    Routes of
    use    		By mouth
    Defined daily dose10 mg[4]
    External links
    AHFS/Drugs.comMonograph
    MedlinePlusa697038
    Legal
    License data
    Legal status
    Pharmacokinetics
    BioavailabilityAlmost 100%
    Protein binding97–99%
    MetabolismLiver (CYP2D6- and 3A4-mediated)
    Elimination half-life8 hours, active metabolite desloratadine 27 hours
    Excretion40% as conjugated metabolites into urine
    Similar amount into the feces
    Chemical and physical data
    FormulaC22H23ClN2O2
    Molar mass382.89 g·mol−1
    3D model (JSmol)
    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 checkY
    • Key:JCCNYMKQOSZNPW-UHFFFAOYSA-N checkY

    Loratadine, sold under the brand name Claritin among others, is a medication used to treat allergies.[2] This includes allergic rhinitis (hay fever) and hives.[2] It is also available in combination with pseudoephedrine, a decongestant, known as loratadine/pseudoephedrine.[2] It is taken by mouth.[2]

    Common side effects include sleepiness, dry mouth, and headache.[2] Serious side effects are rare and include allergic reactions, seizures, and liver problems.[6] Use during pregnancy appears to be safe but has not been well studied.[7] It is not recommended in children less than two years old.[6] It is in the second-generation antihistamine family of medication.[2]

    Loratadine was patented in 1980 and came to market in 1988.[8] It is on the World Health Organization's List of Essential Medicines.[9] Loratadine is available as a generic medication.[2] The wholesale cost in the developing world is about US$0.01 to 0.06 per dose as of 2015.[10] In the United States, it is available over the counter.[2] In 2017, it was the 59th most commonly prescribed medication in the United States, with more than twelve million prescriptions.[11][12]

    Medical uses

    Loratadine is indicated for the symptomatic relief of allergy such as hay fever (allergic rhinitis), urticaria (hives), chronic idiopathic urticaria,[13] and other skin allergies.[14] For allergic rhinitis, loratadine is indicated for both nasal and eye symptoms - sneezing, runny nose, and itchy or burning eyes.[15] Similarly to cetirizine, loratadine attenuates the itching associated with Kimura's disease.[16]

    Loratadine is less sedating than cetirizine.[17]

    Dosage

    An example of a loratadine 10-mg tablet (Rx)

    For those who weight more than 30 kg the typical dose is 10 mg taken once per day while in children over the age of two the dose is 5 mg once per day.[1] Doses up to 40 mg per day; however, may be used.[18] The defined daily dose is 10 mg by mouth.[4]

    The drug is available in many different forms, including tablets, oral suspension, and syrup,[14] and in combination with pseudoephedrine.[19]

    Contraindications

    People with severe liver disorders may need to start with a lower dose. No dose adaptation is necessary for elderly or kidney impaired.[14][20]

    Loratadine is usually compatible with breastfeeding (classified category L-2 - probably compatible, by the American Academy of Pediatrics).[21] 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.[22]

    Side 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 to a smaller extent.[23]

    Other possible side effects include headache and antimuscarinic effects such as urinary retention, dry mouth, blurred vision, and gastrointestinal problems.[14][20]

    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 [24]

    Antihistamines should be discontinued 48 hours prior to 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.[20][25] The potency of second generation histamine antagonists is (from strongest to weakest) desloratadine (Ki 0.4 nM) > levocetirizine (Ki 3 nM) > cetirizine (Ki 6 nM) > fexofenadine (Ki 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 concentration of free drug at the receptor must also be considered.[26][25]

    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.[27][28] 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%.[14]

    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.[29] 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.[14]

    In structure, it is closely related to tricyclic antidepressants, such as imipramine, and is distantly related to the atypical antipsychotic quetiapine.[30]

    History

    Schering-Plough developed loratadine as part of a quest for a potential blockbuster drug: a nonsedating antihistamine. However, 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.[31]

    Loratadine was approved by the FDA in 1993.[31] The drug continued to be available only by prescription in the U.S. until it went off patent in 2002.[32] 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

    Cost

    The wholesale cost in the developing world is about US$0.01 to 0.06 per dose as of 2015.[10] In 2017, it was the 59th most commonly prescribed medication in the United States, with more than twelve million prescriptions.[11][12]

    • Loratadine costs (US)
      Loratadine costs (US)
    • Loratadine prescriptions (US)
      Loratadine prescriptions (US)

    Over-the-counter

    In 1998, in an unprecedented action, the American insurance company Anthem petitioned the FDA to allow loratadine and two other antihistamines to be made available over the counter (OTC) while it was still under patent; the FDA granted the request, which was not binding on manufacturers.[33] In the US, Schering-Plough made loratadine available OTC in 2002.[33] As of 2015 loratadine was available in many countries OTC.[34]

    Brands

    As of 2017, loratadine was available under many brand names and forms worldwide, including several combination drug formulations with pseudoephedrine, paracetamol, betamethasone, ambroxol, salbutamol, phenylephrine, and dexamethasone.[35]

    List of brands

    As of 2017 brands included: Actalor, Actidin, Aerotina, Alaspan, Alavert, Albatrina, Alerdina, Alerfast, Alergan, Alergiano, Alergiatadina, Alergin Ariston, Alergipan, Alergit, Alergitrat L, Aleric Lora, Alermuc, Alernitis, Alerpriv, Alertadin, Alertine, Aleze, Algac, Algecare, Algistop, Alledryl, Aller-Tab, Allerfre, Allerget, Allergex Non Drowsy, Allergyx, Allerhis, Allernon, Allerta, Allertyn, Allohex, Allor, Allorat, Alloris, Alor, Analor, Anhissen, Anti-Sneeze, Antial, Antil, Antimin, Ao Hui Feng, Ao Mi Xin, Ao Shu, Ardin, Atinac, Avotyne, Axcel Loratadine, Bai Wei Le, Bang Nuo, Bedix, Belodin, Benadryl, Besumin, Bi Sai Ning, Bi Yan Tong, Biliranin, Biloina, Biolorat, Bollinol, Boots Hayfever Relief, Boots Hooikoortstabletten, Boots Once-a-Day Allergy Relief, Carin, Carinose, Chang Ke, Civeran, Clara, Claratyne, Clarid, Clarihis, Clarihist, Clarilerg, Clarinese, Claritin, Claritine, Clarityne, Clarityne SP, Clarotadine, Clatatin, Clatine, Clear-Atadine, Clear-Atadine Children's, Clistin, Contral, Cronitin, Da Sheng Rui Li, Dao Min Qi, Dayhist, Debimin, Desa, Devedryl, Dexitis, Dimegan, Dimens, Dimetapp Children's ND Non-Drowsy Allergy, Doliallérgie Loratadine, Effectine, Eladin, Elo, Emilora, Encilor, Eradex, Erolin, Ezede, Fei Ge Man, Finska, Flonidan, Flonidan Control, Florgan, Folerin, Frenaler, Fristamin, Fu Lai Xi, Fucole Minlife, Genadine, Glodin, Gradine, Halodin, Helporigin, Hisplex, Histaclar, Histafax, Histalor, Horestyl, Hua Chang, Hysticlar, Igir, Immunix, Immunex, Inclarin, Inversyn, Jin Su Rui, Jing Wei, Ke Mi, Klarihist, Klinset, Klodin, Kui Yin, Lallergy, Larotin, Latoren, Laura, LD, Lei Ning, Lesidas, Liberec, Lisaler, Logadine, Logista, Lohist, Lolergi, Lolergy, Lomidine, Lomilan, Loptame, Lora, Lora-Lich, Lora-Mepha Allergie, Loracare, Loracil, Loraclear, Loradad, Loraderm, Loradin, Loradine, Lorado Pollen, Loradon, Lorafix, Lorahexal, Lorahist, Lorakids, Loralab-D, Loralerg, Loralivio, Loramax, Loramin, Loramine, Loran, Lorange, Loranil, Lorano, Loranox, Lorantis, LoraPaed, Lorastad, Lorastamin, Lorastine, Lorastyne, Lorat, Loratab, Loratadim, Loratadin, Loratadina, Loratadine, Loratadinum, Loratadyna, Loratan, Loratin, Loraton, Loratrim, Loratyne, Lorchimin, Lordamin, Lordinex, Loremex, Loremix, Lorfast, Lorid, Loridin, Lorihis, Lorimox, Lorin, Lorine, Loristal, Lorita, Loritex, Loritin, Lorly, Lormeg, Lorsedin, Lortadine, Losta, Lostop, Lotadin, Lotadine, Lotarin, Lotin, Megalorat, Mildin, Min Li Ke, Minlife, Mintapp, Mosedin, Mudantil L, Nasaler, Neoday, Niltro, Non-Drowsy Allergy Relief, Nosedin, Noseling, Novacloxab, NT-Alergi, Nufalora, Nularef, Numark Allergy, Omega, Oradin, Oradine, Oramine, Orin, Orinil, Pollentyme, Pressing, Pretin, Primorix, Profadine, Pulmosan Aller, Pylor, Rahistin, Ralinet, Ramitin, Refenax, Restamine, Rhinigine, Rihest, Rinalor, Rinconad, Rinityn, Rinolan, Riprazo, Rityne, Roletra, Rotadin, Rui Fu, Run Lai, Rupton, Sensibit, She Tai, Shi Nuo Min, Shi Tai Shu, Shu Rui, Shun Ta Xin, Silora, Sinaler, Sohotin, Soneryl, Sunadine, Symphoral, Tabcin, Tai Ming Ke, Ticevis, Tidilor, Tinnic, Tirlor, Toral, Triaminic, Tricel, Tuulix, Urtilar, Utel, Vagran, Winatin, Xanidine, Xepalodin, Xian Ning, Xin Da Yue, Xing Yuan Jia, XSM, Xue Fei, Yi Fei, Yi Shu Chang, Yibang, Zhengshu, Zhi Min, Zifar, Zoratadine, and Zylohist.[35]

    As of 2017, in a combination drug with pseudoephedrine, it was available under the brands: Airet, Alavert D-12, Aldisa SR, Alerfast D, Alergical LP, Alergin Plus Ariston, Alerpriv D, Alledryl-D, Allerpid, Aseptobron Descongestivo, Bai Wei Qing, Benadryl 24 D, Ciprocort D, Claridex, Claridon, Clarinase, Clarinase Repetab, Claritine Active, Claritin Allergy + Sinus, Clarityne, Clarityne D, Clarityne-D, Clear-Atadine, Coderin, Cronase, De-Cold, Decidex Plus, Decongess I, Defonase, Demazin NS, Dimegan-D, Effectine D, Ephedrol, Fedyclar, Finska-LP, Frenaler-D, Hui Fei Shun, Ke Shuai, Claritin-D, Larotin D, Lertamine, Lohist-Extra, Lora Plus, Loralerg D, Loranil-D, Loratin D, Loratin Plus, Lordinex D, Loremix D, Lorexin-D, Lorfast-D, Loridin-D, Lorinase, Minlife -P, Mosedin plus sr, Narine Repetabs, Nasaler Plus, Nularef-D, Oradin Plus, Pretin-D, Primorix-D, Rhinos SR, QiKe, Rinomex, Sinaler D, Sudamin, Sudolor, Tricel-D, Zhuang Qi, Zoman-D, and Zoratadine-P.[35]

    As of 2017, in a combination drug with paracetamol, it was available as Sensibit D and in combination with paracetamol and pseudoephedrine, it was available as: Atshi, Clariflu, and Trimed Flu.[35]

    As of 2017, in a combination drug with betamethasone, it was available as Celestamincort, Celestamine NF, Celestamine NS, Celestamine* L, Ciprocort L, Claricort, Clarityne cort, Corticas L, Cortistamin-L, Histafax Compuesto, Histamino Corteroid L, Labsalerg-B, Lisaler Beta, and Sinaler B, and in combination with betamethadol with available as Nularef Cort.[35]

    As of 2017, in a combination drug with ambroxol, it was available as Aliviatos, Ambroclar, Antitusivo L Labsa, Bronar, Broncovital, Broquixol, Clarixol, Ideobron, Lorabrox, Lorfast-AM, Sensibit XP, and Toraxan, and in a combination drug with ambroxol and salbutamol as Sibilex.[35]

    As of 2017, in a combination drug with phenylephrine, it was available as Bramin-Flu, Clarityne D, Clarityne Plus, Clarityne-D, Histafax D, Brafelix, Loramine R, Loraped, Maxiclear Cold & Nasal, Maxiclear Hayfever & Sinus Relief, and Rinavent, and in combination with phenylephrine and paracetamol it was available as Sensibit D NF.[35]

    As of 2017, in a combination drug with dexamethasone it was available as Alerfast Forte and Frenaler Forte.[35]

    Marketing

    A bottle of loratadine (Claritin)

    The marketing of the Claritin brand is important in the history of direct-to-consumer advertising of drugs.[36][37]

    The first television commercial for a drug was aired in the US in 1983, by Boots, and sparked controversy. The FDA responded with strong regulation 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.[36]

    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 things like "At last, a clear day is here" and "It's time for Claritin" and repeatedly told viewers to "ask your doctor" about Claritin.[36][37] The first ads succeeded in making people aware of the brand and increased prescriptions, which led Schering-Plough and others to aggressively pursue the advertising strategy.[37]

    This trend, along with advice from its attorneys that it could not win a First Amendment case on the issue, led the FDA to issue new rules for TV commercials in 1997.[36] Instead of including the "brief summary" that took up a full page in magazine ads and would take too long to explain in a TV commercial, drug makers were allowed to refer viewers to print ads, 1-800 numbers, or websites, and urge people to talk to their doctor if they wanted additional information.[36][38]

    Schering-Plough invested US$322 million in Claritin direct-to-consumer advertising in 1998 and 1999, far more than any other brand.[31] Overall, 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.[36]

    See also

    • Benzocycloheptenes
    • Azatadine (loratidine minus chlorine atom and ester)

    References

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    4. 1 2 "WHOCC - ATC/DDD Index". www.whocc.no. Archived from the original on 27 July 2020. Retrieved 31 August 2020.
    5. ↑ "Clarityn Allergy 10mg Tablets (P & GSL) - Patient Information Leaflet (PIL)". (emc). 30 August 2019. Archived from the original on 10 April 2020. Retrieved 10 April 2020.
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    13. ↑ Pons-Guiraud A, Nekam K, Lahovsky J, Costa A, Piacentini A (2006). "Emedastine difumarate versus loratadine in chronic idiopathic urticaria: a randomized, double-blind, controlled European multicentre clinical trial". European Journal of Dermatology. 16 (6): 649–54. PMID 17229605.
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