Drug interactions with the nonsedating antihistamines

Drug interactions with the nonsedating antihistamines – includes patient information

Paul W. Ament

Following the U.S. Food and Drug Administration’s approval of terfenadine (Seldane) in 1985, serious ventricular arrhythmias, including torsades de pointes that occasionally resulted in death, have been associated with its use. Identified risk factors include concomitant use with macrolide antibiotics such as erythromycin, and antifungal agents, including itraconazole (Sporanox) and ketoconazole (Nizoral). Attempts to alert physicians to these potentially fatal drug-drug interactions have included “Dear Doctor” mailings and a black-box warning added to the prescribing information for both astemizole (Hismanal) and terfenadine.[1] Recently, the manufacturer of terfenadine has encouraged patients taking that drug to switch to fexofenadine (Allege), which it also manufactures.

A review of Medicaid prescription claims showed that, despite educational attempts, physicians are often unaware of these drug-drug interactions; unfortunately, concomitant prescribing of potentially fatal drug combinations continues.[2] Pharmacists also sometimes overlook these serious drug-drug interactions. A recent report[3] showed that pharmacists failed to contact physicians 30 percent of the time when receiving prescriptions from patients taking both terfenadine and erythromycin and did not warn patients about signs or symptoms of the potential adverse effects one third of the time.

Currently, four nonsedating antihistamine agents have FDA approval: astemizole, fexofenadine, loratadine (Claritin) and terfenadine. In Claritin-D and Seldane-D, pseudoephedrine is combined with loratadine or terfenadine. All of these agents are frequently prescribed, accounting for more than 14 million prescriptions in 1996.[4] In addition, loratadine, loratadine plus pseudoephedrine, and terfenadine were the 18th, 41st and 86th most commonly prescribed medications in the United States in 1996.[4]

This article reviews the cytochrome [P.sub.450] pathway implicated in drug-drug interactions with astemizole and terfenadine, the potential risks of combining nonsedating antihistamines with other medications, current drug-drug interaction data on fexofenadine and loratadine, and general concepts for evaluating potential drug-drug interactions with new medications.

Clinical Indications

Table 1 reviews current FDA-approved indications for the nonsedating antihistamines. A complete review of their mechanism of action, side effect profiles and clinical applications has been published previously.[5]


FDA-Approved Indication for the Newer Antihistamines

Adult indications(*)

Seasonal Chronic

Agent allergic rhinitis urticaria

Astemizole (Hismanal) X X

Cetrizine (Zyrtec) X X

Fexofenadine (Allegra) X –

Loratadine (Claritin) X X

Terfenadine (Seldane) X –

Pediatric indications([dagger])


Agent allergic rhinitis

Astemizole (Hismanal) – –

Cetrizine (Zyrtec) X X

Fexofenadine (Allegra) – –

Loratadine (Claritin) X X

Terfenadine (Seldane) – –

([dagger]) –Not a “black-box” warning in the product literature.

([double dagger]) –Not a “black-box” warning in terfenadine product literature.

TABLE 5 Agents Demonstrating Safe Concomitant Administration with Astemizole (Hismanal), Fexofenadine (Allege), Loratadine (Claritin) or Terfenadine (Seldane)

Antifungal agents

Fluconazole (Diflucan)

Terbinafine (Lamisil)


Paroxetine (Paxil)

Sertraline (Zoloft)


Histamine [H.sub.2] antagonists


(Tagamet) Famotidine

(Pepcid) Nizatidine (Axid)

Ranitidine (Zantac)

[17.] Honig PK, Worham DC, Zamani K, Mullin JC, Conner DP, Cantilena LR. The effect of fluconazole on the steady-state pharmacokinetics and electrocardiographic pharmacodynamics of terfenadine in humans. Clin Pharmacol Ther 1993;53:630-6.

[18.] Honig PK, Wortham DC, Zamani K, Conner DP, Mullin JC, Cantilena LR. Effect of concomitant administration of cimetidine and ranitidine on the pharmacokinetics and electrocardiographic effects of terfenadine. Eur J Clin Pharmacol 1993,45:41-6.

[19.] Marchiando RJ, Cook MD, Jue SG. Probable terfenadine-fluoxetine-associated cardiac toxicity [Letter]. Ann Pharmacother 1995;29:937-8.

[20.] Brannan MD, Reidenberg P, Radwanski E, Shneyer L, Lin CC, Cayen MN, et al. Loratadine administered concomitantly with erythromycin: pharmacokinetic and electrocardiographic evaluations. Clin Pharmacol Ther 1995;58:269-78.

[21.] Affrime MB, Lorber R, Danzig M, Cuss F, Brannan MD. Three months evaluation of electrocardiographic effects of loratadine in humans [Abstract]. 50th Anniversary of the American Academy of Allergy and Immunology. 49th Annual Meeting. Chicago, Illinois, March 12-17,1993. J Allergy Clin Immunol 1993,91(1 Pt 2):259.

[22.] Juniper EF, Ponte CD, Shapiro GG. Drug spotlight: the newer antihistamines. Patient Care 1996;30(7):34-48.

[23.] Sale M, Woosley R, Thakker K, Phillips K, Caridi F, Chung M. A randomized, placebo-controlled, multiple-dose study to evaluate the electrocardiographic and pharmacokinetic interactions of azithromycin and cetirizine [Abstract]. Abstracts presented during concurrent sessions and at poster sessions at the annual meeting of the American College of Allergy, Asthma and Immunology, November 11-15,1995, Dallas, Texas. Ann Allergy Asthma Immunol 1996;76:93.

[24.] Simons FE, Sussman GL, Simons KJ. Effect of the [H.sub.2]-antagonist cimetidine on the pharmacokinetics and pharmacodynamics of the [H.sub.1] hydroxyzine and cetirizine in patients with chronic urticaria. J Allergy Clin Immunol 1995;95:685-93.

Richard W. Sloan, M.D., R.PH., coordinator of this series, is chairman and residency program director of the Department of Family Medicine at York (Pa.) Hospital and clinical associate professor in family and community medicine at the Milton S. Hershey Medical Center, Pennsylvania State University, Hershey, Pa.

PAUL W. AMENT, PHARM.D. is assistant director of pharmacy and family medicine residency faculty member at Latrobe Area (Pa.) Hospital, and instructor in family medicine at Jefferson Medical College of Thomas Jefferson University, Philadelphia. A graduate of Duquesne University School of Pharmacy, Pittsburgh, he completed a residency in hospital pharmacy at the Mercy Hospital of Pittsburgh.

ALEX PATERSON, M.D. is a family medicine faculty member at Latrobe Area Hospital and instructor in family medicine at Jefferson Medical College, where he graduated from medical school. Dr. Paterson completed a residency in family medicine at Latrobe Area Hospital.

Address correspondence to Alex Paterson, M.D., Latrobe Area Hospital, 121 W. 2nd Ave., Latrobe, PA 15650.

COPYRIGHT 1997 American Academy of Family Physicians

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