Chemistry:Loratadine

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Short description: Antihistamine medication
Loratadine
Loratadine.svg
Loratadine - 3d, portrait orientation.png
Clinical data
Trade namesClaritin, Claratyne, Clarityn, others
AHFS/Drugs.comMonograph
MedlinePlusa697038
License data
Pregnancy
category
Routes of
administration		By mouth
Drug classSecond-generation antihistamine
ATC code
Legal status
Legal status
Pharmacokinetic data
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
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC22H23ClN2O2
Molar mass382.89 g·mol−1
3D model (JSmol)
 ☒N☑Y (what is this?)  (verify)

Loratadine, sold under the brand name Claritin among others, is a medication used to treat allergies.[4] This includes allergic rhinitis (hay fever) and hives.[4] It is also available in drug combinations such as loratadine/pseudoephedrine, in which it is combined with pseudoephedrine, a nasal decongestant.[4] It is taken orally.[4]

Common side effects include sleepiness, dry mouth, and headache.[4] Serious side effects are rare and include allergic reactions, seizures, and liver problems.[5] Use during pregnancy appears to be safe but has not been well studied.[6] It is not recommended in children less than two years old.[5] It is in the second-generation antihistamine family of medication.[4]

Loratadine was patented in 1980 and came to market in 1988.[7] It is on the World Health Organization's List of Essential Medicines.[8] Loratadine is available as a generic medication.[4][9] In the United States, it is available over the counter.[4] In 2021, it was the 67th most commonly prescribed medication in the United States, with more than 9 million prescriptions.[10][11]

Medical uses

Loratadine is indicated for the symptomatic relief of allergies such as hay fever (allergic rhinitis), urticaria (hives), chronic idiopathic urticaria,[12] and other skin allergies.[13] For allergic rhinitis, loratadine is indicated for both nasal and eye symptoms including sneezing, runny nose, and itchy or burning eyes.[14]

Similarly to cetirizine, loratadine attenuates the itching associated with Kimura's disease.[15]

Combination drugs

Loratadine/pseudoephedrine is a fixed dose combination of the drug with pseudoephedrine, a nasal decongestant.[16]

Dosage forms

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

The medication is available in many different forms, including tablets, oral suspension, and syrups.[13] Also available are quick-dissolving tablets.[13]

Contraindications

Loratadine is usually compatible with breastfeeding (classified category L-2 - probably compatible, by the American Academy of Pediatrics).[17] 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.[18]

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.[19]

Other side effects include headache and antimuscarinic effects, such as urinary retention, dry mouth, blurred vision, and gastrointestinal problems.[13][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. [21]

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.[13]

Pharmacology

Pharmacodynamics

Loratadine is a tricyclic antihistamine, which acts as a selective inverse agonist of peripheral histamine H1 receptors.[20][22] 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.[23][22] Loratadine also shows anti-inflammatory properties independent of H1 receptors.[24][25] 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.[26][27]

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.[28][29] 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%.[13]

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.[30] 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.[13]

In structure, it is closely related to tricyclic antidepressants, such as imipramine, and is distantly related to the atypical antipsychotic quetiapine.[31]

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.[32] 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.[33][34]

Loratadine was approved by the FDA in 1993.[32] The drug continued to be available only by prescription in the U.S. until it went off patent in 2002.[35] 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]

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.[36] In the United States, Schering-Plough made loratadine available over the counter in 2002.[36] In 2015, loratadine was available over the counter in many countries.[37][vague]

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.[38]

List of brands

In 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.[38]

In 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.[38]

In 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.[38]

In 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 was available as Nularef Cort.[38]

In 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.[38]

In 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.[38]

In 2017, in a combination drug with dexamethasone, it was available as Alerfast Forte and Frenaler Forte.[38]

Marketing

The marketing of the Claritin brand is important in the history of direct-to-consumer advertising of drugs.[39][40]

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 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.[39]

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]."[39][40] The first ads made people aware of the brand and increased prescriptions, which led Schering-Plough and others to aggressively pursue the advertising strategy.[40]

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.[41]

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.[39] 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.[39][42]

Schering-Plough invested US$322 million in Claritin direct-to-consumer advertising in 1998 and 1999, far more than any other brand.[32] 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.[39]

References

  1. ↑ "Loratadine Use During Pregnancy". 10 February 2020. https://www.drugs.com/pregnancy/loratadine.html. 
  2. ↑ "Claritin Allergy Product information". 25 April 2012. https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=10533. 
  3. ↑ "Clarityn Allergy 10mg Tablets (P & GSL) - Patient Information Leaflet (PIL)". 30 August 2019. https://www.medicines.org.uk/emc/product/8999/. 
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 4.6 4.7 "Loratadine". The American Society of Health-System Pharmacists. https://www.drugs.com/monograph/loratadine.html. 
  5. ↑ 5.0 5.1 "Clarityn Allergy 10mg Tablets (P) - Summary of Product Characteristics (SmPC) - (eMC)". 7 October 2015. https://www.medicines.org.uk/emc/medicine/29550. 
  6. ↑ "Loratadine Use During Pregnancy". https://www.drugs.com/pregnancy/loratadine.html. 
  7. ↑ Analogue-based Drug Discovery. John Wiley & Sons. 2006. p. 549. ISBN 9783527607495. https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA549. 
  8. ↑ World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. 2019. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO. 
  9. ↑ "Competitive Generic Therapy Approvals". 3 March 2023. https://www.fda.gov/drugs/generic-drugs/competitive-generic-therapy-approvals. 
  10. ↑ "The Top 300 of 2021". https://clincalc.com/DrugStats/Top300Drugs.aspx. 
  11. ↑ "Loratadine - Drug Usage Statistics". https://clincalc.com/DrugStats/Drugs/Loratadine. 
  12. ↑ "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. 2006. PMID 17229605. 
  13. ↑ 13.0 13.1 13.2 13.3 13.4 13.5 13.6 (in de) Austria-Codex. 1 (2007/2008 ed.). Vienna: Österreichischer Apothekerverlag. 2007. pp. 1768–71. ISBN 978-3-85200-181-4. 
  14. ↑ "Claritin- loratadine tablet". 10 February 2020. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=660ac9df-f1b1-4c89-94dd-9fae0a013f3c. 
  15. ↑ "Kimura's disease treated with suplatast tosilate and loratadine". European Journal of Dermatology 21 (6): 1020–1. 2011. doi:10.1684/ejd.2011.1539. PMID 21914581. 
  16. ↑ (in de) Austria-Codex. 1 (2007/2008 ed.). Vienna: Österreichischer Apothekerverlag. 2007. pp. 1731–34. ISBN 9783852001814. 
  17. ↑ Committee on Drugs (September 2001). "Transfer of drugs and other chemicals into human milk". Pediatrics 108 (3): 776–89. doi:10.1542/peds.108.3.776. PMID 11533352. 
  18. ↑ "Desloratadine for allergic rhinitis". American Family Physician 68 (10): 2015–6. November 2003. PMID 14655812. http://www.aafp.org/afp/20031115/steps.html. 
  19. ↑ "Claritin and Alcohol". emedtv.com. http://allergies.emedtv.com/claritin/claritin-and-alcohol.html. 
  20. ↑ 20.0 20.1 (in de) Arzneimittelwirkungen (8 ed.). Stuttgart: Wissenschaftliche Verlagsgesellschaft. 2001. pp. 456–461. ISBN 978-3-8047-1763-3. 
  21. ↑ "Evaluation of the pharmacokinetics and electrocardiographic pharmacodynamics of loratadine with concomitant administration of ketoconazole or cimetidine". British Journal of Clinical Pharmacology 50 (6): 581–9. December 2000. doi:10.1046/j.1365-2125.2000.00290.x. PMID 11136297. 
  22. ↑ 22.0 22.1 "Clinical pharmacokinetics and pharmacodynamics of desloratadine, fexofenadine and levocetirizine : a comparative review". Clinical Pharmacokinetics 47 (4): 217–30. 2008. doi:10.2165/00003088-200847040-00001. PMID 18336052. 
  23. ↑ "Pharmacology of antihistamines". Indian Journal of Dermatology 58 (3): 219–24. May 2013. doi:10.4103/0019-5154.110832. PMID 23723474. 
  24. ↑ "Efficacy and tolerability of newer antihistamines in the treatment of allergic conjunctivitis". Drugs 65 (2): 215–28. 2005. doi:10.2165/00003495-200565020-00004. PMID 15631542. 
  25. ↑ "Antihistaminic, anti-inflammatory, and antiallergic properties of the nonsedating second-generation antihistamine desloratadine: a review of the evidence". The World Allergy Organization Journal 4 (2): 47–53. February 2011. doi:10.1097/WOX.0b013e3182093e19. PMID 23268457. 
  26. ↑ "Loratadine, an antihistamine drug, exhibits anti-inflammatory activity through suppression of the NF-kB pathway". Biochemical Pharmacology 177: 113949. July 2020. doi:10.1016/j.bcp.2020.113949. PMID 32251678. 
  27. ↑ "Antihistamines: do they work? Further well-controlled trials involving larger samples are needed". Allergy 59 (Suppl 78): 74–7. August 2004. doi:10.1111/j.1398-9995.2004.00573.x. PMID 15245363. 
  28. ↑ "Antihistamines and related antiallergic and antiulcer agents". Foye's principles of medicinal chemistry. Hagerstown, MD: Lippincott Williams & Wilkins. 2002. pp. 805. ISBN 978-0-683-30737-5. 
  29. ↑ "Metabolism of loratadine and further characterization of its in vitro metabolites". Drug Metabolism Letters 3 (3): 162–70. August 2009. doi:10.2174/187231209789352067. PMID 19702548. 
  30. ↑ "A pharmacokinetic profile of desloratadine in healthy adults, including elderly". Clinical Pharmacokinetics 41 (Suppl 1): 13–9. 2002. doi:10.2165/00003088-200241001-00003. PMID 12169042. 
  31. ↑ "Loratadine: a non-sedating antihistamine. Review of its effects on cognition, psychomotor performance, mood and sedation". Clinical and Experimental Allergy 29 (Suppl 3): 147–50. July 1999. doi:10.1046/j.1365-2222.1999.0290s3147.x. PMID 10444229. 
  32. ↑ 32.0 32.1 32.2 "The Claritin Effect; Prescription for Profit". The New York Times. 11 March 2001. https://www.nytimes.com/2001/03/11/magazine/the-claritin-effect-prescription-for-profit.html?pagewanted=all. 
  33. ↑ "FDA Approves Allegra-D, Manufacturer To Withdraw Seldane From Marketplace". Food and Drug Administration. https://www.fda.gov/bbs/topics/ANSWERS/ANS00843.html. 
  34. ↑ "Use of terfenadine and contraindicated drugs". JAMA (American Medical Association) 275 (17): 1339–41. May 1996. doi:10.1001/jama.275.17.1339. PMID 8614120. 
  35. ↑ "Schering-Plough Loses Patent Lawsuit Over Claritin, Opening Door For Cheaper Generic Versions". Leiner Health Products. 5 August 2003. http://www.prnewswire.com/news-releases/schering-plough-loses-patent-lawsuit-over-claritin-opening-door-for-cheaper-generic-versions-70880857.html. 
  36. ↑ 36.0 36.1 "Switching prescription drugs to over the counter". BMJ 330 (7481): 39–41. January 2005. doi:10.1136/bmj.330.7481.39. PMID 15626806. 
  37. ↑ Association of the European Self-Medication Industry Database. Loratadine OTC regulation Page accessed 11 April 2015
  38. ↑ 38.0 38.1 38.2 38.3 38.4 38.5 38.6 38.7 "Loratadine International Brands". Drugs.com. https://www.drugs.com/international/loratadine.html. 
  39. ↑ 39.0 39.1 39.2 39.3 39.4 39.5 "The untold story of TV's first prescription drug ad". STAT. 11 December 2015. https://www.statnews.com/2015/12/11/untold-story-tvs-first-prescription-drug-ad/. 
  40. ↑ 40.0 40.1 40.2 "DTC: The first 10 years". MM&M. 1 April 2007. http://www.mmm-online.com/features/dtc-the-first-10-years/article/24443/. 
  41. ↑ Batman: Claritin Allergy Special, https://comicbookrealm.com/series/49106/417043/dc-comics-batman-claritin-allergy-special-one-shot-issue-1, retrieved 6 December 2020 
  42. ↑ "Ten Years Later: Direct to Consumer Drug Advertising". http://adage.com/article/news/ten-years-direct-consumer-drug-advertising/112215/. 



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