Loratadine

More commonly known under the brand name formulation Claritin, loratadine is a second-generation anti-histamine indicated for the treatment of seasonal allergic rhinitis and chronic idiopathic urticaria (1). The development of loratadine was spurred in by the marked drowsiness users experienced when taking first-generation antihistamines such as diphenhydramine (Benadryl) (1). One recommended dose of diphenhydramine evokes an impairment degree analogous to a blood-alcohol level of 0.10, perceptibly greater than the legal BAC of 0.08 (2). Drowsiness is an adverse effect seen in a lot of first-generation drugs and is a notable driving force behind development of subsequent generations. Especially for over-the-counter drugs where patients are using them for less serious ailments, being able to continue with their day is almost expected.

Both generations of antihistamines mentioned elicit their effects as inverse agonists of H₁ receptors (3). Loratadine mitigates any sedative effects by acting preferentially on peripheral H₁ and is unable to cross the blood-brain-barrier (exact mechanism of action is not elucidated) (1). Modification to the parent compound, azatadine, includes the addition of a carboxymethyl ester group (4). Advantages to this are a less basic and more polar compound that is unable to breach the blood-brain-barrier (4). Azatadine was another first-generation anti-histamine developed by Schering-Plough but was withdrawn from the market by the company in 2005 (5). This was most likely due to significant favoring of loratadine, over azatadine, after its approval in 1993 (5). Synthetic synthesis of loratadine has been reported as a six-step process starting with 2-cyano-3-methylpyridine (6). 

Once rapidly absorbed into the body (40% bioavailability for oral formulations), Tmax of loratadine is reached in 1.3 hours and 2.5 hours for its active metabolite, descarboethoxyloratadine (7). In vitro human liver microsome studies indicate extensive first pass metabolism is done by hepatic CYP3A4 enzymes (8). In the presence of CYP3A4 inhibitors the CYP2D6 class is the predominant metabolizer (8). Most patients reach steady-state dosing in five days. Average elimination half-life of the active metabolite is 28 hours (n = 54, range = 8.8 to 92 hours in clinical trials) (8). This contrasts with 8.4 hours for unmetabolized loratadine (n = 54, range = 3 to 20 hours) (8). About 80% of the total dose is found equally distributed between urine and fecal excretion. (7)

In two-year rat carcinogenicity studies, male rats given 10 mg/kg dosing had significantly higher rates of hepatocellular tumors versus controls (8). For reference, exposure levels of the rats given 10 mg/kg were 10 times the exposure in human adults given the maximum recommended daily oral dose (8). It is acknowledged that the clinical significance of this is not known for long-term use of loratadine. While the drug is an FDA pregnancy category B and is recommended to only be taken if needed, both loratadine and its active metabolite readily pass into breast milk (7). About 0.03% of a 40 mg dose was found in breast milk over 48 hours (8). Common adverse events in clinical trials (placebo n = 2545/loratadine n = 1926) were reported at comparable rates including headache (11%/12%), somnolence (6%/8%), fatigue (3%/4%), and dry mouth (2%/3%) (8).

Unlike first-generation antihistamines like diphenhydramine, loratadine does not have the adverse effect of extreme drowsiness. Derived from another proprietary first-generation antihistamine, azatadine, loratadine is more polar and less basic rendering it unable to cross the blood-brain barrier. This allows preferential binding to peripheral H₁ receptors mitigating sedative effects. Once in the body, loratadine undergoes extensive first-pass metabolism by hepatic CYP3A4 enzymes. Both generations are readily available over-the-counter and are applicable to treatment of chronic allergies. Night-time relief of symptoms may lend diphenhydramine (Benadryl) more advantageous while daily use favors loratadine (Claritin).

Loratadine was originally developed by Schering-Plough Corporation in the early 90’s. On December 12, 2008 an 8-K form was filed with the United States Securities and Exchanges Commission for the acquisition of Schering-Plough Corp. (SGP) by Merck & Co. Inc. for $41 billion (9). This reverse merger came with convertible preferred stock giving SGP shareholders $10.50 cash and 0.5767 Merck & Co. shares per SGP share owned (10). As a result, Schering-Plough was renamed Merck Sharp & Dohme Corp. while “old Merck” became a subsidiary, Merck & Co. Inc.. Merck’s late-stage pipeline products doubled (about 18) from the acquisition leading many to conclude that the deal was in the interest of intellectual property retention (10). In the prior years Merck’s blockbuster drug Fosamax had been released to generic and multiple other high-profile drugs were about to do the same; Schering-Plough had patents on several of it’s drugs that were years from expiring (10). In 2005 SGP held 1.4% of the US pharmaceutical market creating the second-largest global pharmaceutical company under the Merck-SGP merger (10).

Both loratadine and desloratadine are currently sold by Merck under the brand names Claritin and Clarinex. In 1998, Anthem Inc. (previously WellPoint Inc.) historically petitioned to the FDA to allow three antihistamines loratadine, cetirizine, and fexofenadine to be sold over the counter (OTC) despite still being under patent. While the FDA approved the action, it was nonbinding leaving it up to the discretion of the manufacturer to make the switch. Schering-Plough made Claritin available in generic form over the counter in 2002 when the patent expired on loratadine. To retain viability, Claritin was changed to a 10 mg prescription dose in November 2002. (11)

Merck currently holds multiple patents for prescription Clarinex, Clarinex-D 12 Hour, and Clarinex-D 24 Hour. These differ slightly from Claritin as Clarinex and its subsequent formulations are desloratadine, the active form of loratadine (Claritin). Previously, Schering-Plough held patents for both OTC and prescription Claritin which have since expired. Both compounds are currently available in generic formulations over the counter. Prescription loratadine (Clarityn) was withdrawn from the market in December 2001. The company made a point to state that this was not because the loratadine patent expired the following year but that “desloratadine is a better product than loratadine and that it does not make commercial sense for Schering Plough to market both products” (13). Between the three forms of Clarinex, Merck retains three individual U.S. patents for “oral compositions” and formulation procedures of desloratadine: U.S. Patent No. 6,100,274; U.S. Patent No. 6,709,676; U.S. Patent No. 7,618,649.  (11, 12)

References

1.      Waller, D. G., and Sampson, A. P. (2018) 39 - Antihistamines and allergic disease. in Medical Pharmacology and Therapeutics, 5th Ed., pp. 451–456, Elsevier

2.      Banerji, A., Long, A. A., and Camargo, C. A. (2007) Diphenhydramine versus nonsedating antihistamines for acute allergic reactions: A literature review. Allergy and Asthma Proceedings. 28, 418–426

3.      Khilnani, G., and Khilnani, A. K. (2011) Inverse agonism and its therapeutic significance. Indian J. Pharmacology. 43, 492–501

4.      Phil, L., Hernandez-Trujillo, V., Lieberman, J., and Frew, A. J. (2008) 89 - Antihistamines. in Clinical Immunology, Principles and Practice, 3rd Ed., pp. 1317–1329

5.      U.S. Food and Drug Administration, HHS (2005) Hospira, Inc. et al.; Withdrawal of Approval of 76 New Drug Applications and 60 Abbreviated New Drug Applications. Federal Register National Archives, 70 FR 10651

6.      Clissold, S. (1989) Loratadine. Drugs. 37, 42-57

7.      (2005) Loratadine. DrugBank, DB00455

8.      CLARITIN brand of loratadine Product Information. Schering Corporation, NDC 0085-1223-01

9.      United States Securities and Exchanges Commission (2008) Securities and Exchanges Archives, Form 8-K y73249e8vk.htm.

10.  PBS NewsHour (2009) Merck/Schering-Plough Merger Would Create Second-Largest Drug Company. Public Broadcasting Service.

11.  Cohen, J. P., Paquette, C., and Cairns, C. P. (2005) Switching prescription drugs to over the counter. British Medical Journal.

12.  Merck U.S. Patent Rights for Products (2018) Merck.com.

13.  News: Loratadine prescription packs to be withdrawn (2001) The Pharmaceutical Journal. 267, 337–341