EDITORIAL ESPANOL:

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Hola amigos Dermagicos, la FEXOFENADINA, metabolito activo de la terfenadina, aprobado para su mercadeo en 1.996 y recientemente introducido en Venezuela ha demostrado ser uno de los nuevos antihistamínicos no asociados a trastornos cardiacos, principalmente arritmias. The lancet en JUNIO de 1.999 publica efectos de la fexofenadina en el intervalo QT (alargamiento).

De la nueva generación de antihistamínicos el ASTEMIZOL, TERFENADINA Y EBASTINA están asociado a arritmias cardiacas. Estas 33 referencias nos ILUSTRAN sobre la fexofenadina y otros Antihistamínicos y sus efectos. Al final una monografía del producto Allegra. 

Saludos,,,

Dr. José Lapenta R.,,,

 EDITORIAL ENGLISH:

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Hello Dermagic friends, the FEXOFENADINA, active metabolite of the terfenadine approved for their marketing in 1.996 and recently introduced in Venezuela it has demonstrated to be one of those new antihistamines not associated to heart dysfunctions, mainly arrhythmias. 

In The lancet in  JUNE of 1.999 a letter and a correspondence about the effects of the fexofenadina in the interval QT (lengthening), was published. Of the new one antihistamines generation the ASTEMIZOLE, TERFENADINE AND EBASTINE are associated to heart arrhythmias. These 33 references ILLUSTRATE us on the fexofenadina, the Antihistamines and their effects. At the end a monograph of the product Allegra. 

Greetings,,,

Dr. José Lapenta R. 

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REFERENCIAS BIBLIOGRÁFICAS / BIBLIOGRAPHICAL REFERENCES 

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A.- QT lengthening and arrhythmias associated with fexofenadine. 

B.- QT lengthening and life-threatening arrhythmias associated with fexofenadine.

C.- Prolonged QTc time and ventricular arrhythmia with fexofenadine. 

D.- Bradyarrhythmia Cardiac Arrest—A Rare Manifestation of Fexofenadine Cardiotoxicity

E.- Fexofenadine (Allegra) Associated with Ventricular Arrhythmias

1.) The efficacy and safety of fexofenadine HCl and pseudoephedrine, alone 

and in combination, in seasonal allergic rhinitis. 

2.) Cardiovascular safety of second-generation antihistamines. 

3.) Clinical pharmacology of new histamine H1 receptor antagonists. 

4.) QT lengthening and arrhythmias associated with fexofenadine. 

5.) Comparison of the effects of terfenadine with fexofenadine on nasal 

provocation tests with allergen. 

6.) Comparative tolerability of second generation antihistamines. 

7.) Variations among non-sedating antihistamines: are there real differences? 

8.) Cardiovascular safety of fexofenadine HCl. 

9.) Treating allergic rhinitis in pregnancy. Safety considerations. 

10.) Second-generation antihistamines: the risk of ventricular arrhythmias. 

11.) Second-generation antihistamines: a comparative review. 

12.) Terfenadine and fexofenadine reduce in vitro ICAM-1 expression on 

human continuous cell lines. 

13.) Pharmacokinetics, pharmacodynamics, and tolerance of single- and 

multiple-dose fexofenadine hydrochloride in healthy male volunteers. 

14.) Pharmacokinetic overview of oral second-generation H1 antihistamines. 

15.) Fexofenadine. 

16.) Efficacy and safety of fexofenadine hydrochloride for treatment of 

seasonal allergic rhinitis. 

17.) Dose proportionality and comparison of single and multiple dose 

pharmacokinetics of fexofenadine (MDL 16455) and its enantiomers in healthy 

male volunteers. 

18.) Fexofenadine's effects, alone and with alcohol, on actual driving and 

psychomotor performance. 

19.) Onset of action, efficacy, and safety of a single dose of fexofenadine 

hydrochloride for ragweed allergy using an environmental exposure unit. 

20.) Effectiveness and safety of fexofenadine, a new nonsedating 

H1-receptor antagonist, in the treatment of fall allergies. 

21.) Effect of fexofenadine on eosinophil-induced changes in epithelial 

permeability and cytokine release from nasal epithelial cells of patients 

with seasonal allergic rhinitis. 

22.) Peripheral H1-blockade effect of fexofenadine. 

23.) Is my antihistamine safe? 

24.) Drug interactions with the nonsedating antihistamines. 

25.) The Lancet, Correspondence : QT lengthening and arrhythmias associated with fexofenadine 

26.) FDA, DEPARTMENT OF HEALTH AND HUMAN SERVICES, FEXOFENADINE AND TERBINAFINE 

27.) Non-sedating antihistamines and cardiac arrhythmia 

28.) FEXOFENADINE (Systemic)¾Introductory Version, The product 

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1.) The efficacy and safety of fexofenadine HCl and pseudoephedrine, alone 

and in combination, in seasonal allergic rhinitis. 

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J Allergy Clin Immunol 1999 Jul;104(1):100-106 

Sussman G, Mason J, Compton D, Stewart J, Ricard N 

St Michael's Hospital, Toronto; Hoechst Marion Roussel, Kansas City; and 

Hoechst Marion Roussel, Laval. 

BACKGROUND: Antihistamines effectively treat seasonal allergic rhinitis 

(SAR), although the ability of this drug class to reduce nasal congestion 

is limited. Nasal decongestants effectively treat nasal congestion but not 

the histamine-related components of SAR. Therefore antihistamine/nasal 

decongestant combinations are commonly used to maximize the treatment of 

SAR. Fexofenadine HCl is a nonsedating, long-acting H1 receptor antagonist 

that provides fast and effective relief from SAR. It is well tolerated, 

with no sedative or cardiotoxic effects. OBJECTIVE: We sought to compare 

the efficacy and safety of a fexofenadine HCl/pseudoephedrine HCl 

combination with that of each individual component in the treatment of 

ragweed allergy. METHODS: In this Canadian multicenter, double-blind, 

parallel-group study, 651 patients allergic to ragweed were randomized to 

receive 60 mg of fexofenadine HCl twice daily, 120 mg of sustained-release 

pseudoephedrine HCl twice daily, or a combination of the 2 drugs (60 mg of 

fexofenadine HCl/120 mg of sustained-release pseudoephedrine HCl) twice 

daily for 2 weeks. Efficacy analyses were based on symptom severity. In 

addition, a health economic assessment was performed. RESULTS: Combination 

therapy was significantly more effective than pseudoephedrine alone in 

improving primarily histamine-mediated symptoms (sneezing; rhinorrhea; 

itchy nose, palate, and/or throat; and itchy, watery, red eyes) and 

significantly more effective than fexofenadine alone in reducing nasal 

congestion. Combination therapy also produced greater improvements in daily 

activities and work productivity compared with the individual components. 

No serious adverse events were reported in any of the treatment groups. In 

addition, no clinically significant changes in 12-lead electrocardiogram 

parameters, vital signs, or clinical laboratory values were observed. 

CONCLUSION: Combination therapy is more effective than fexofenadine alone 

or pseudoephedrine alone in relieving the full spectrum of SAR symptoms 

(ie, both the primarily histamine-related symptoms and nasal congestion). 

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2.) Cardiovascular safety of second-generation antihistamines. 

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Am J Rhinol 1999 May-Jun;13(3):235-43 

Barbey JT, Anderson M, Ciprandi G, Frew AJ, Morad M, Priori SG, Ongini E, 

Affrime MB 

Department of Cardiology and Clinical Pharmacology, Georgetown University 

Medical Center, Washington, DC 20007, USA. 

Reports of serious cardiac arrhythmia associated with some 

second-generation antihistamines have prompted concern for their 

prescription. This article reviews the nature of the adverse events 

reported and concludes that the blockade of potassium channels, 

particularly the subtype responsible for the rapid component of the delayed 

rectifier current (IKr), is largely responsible for such adverse cardiac 

events. Consequently, antihistamines with little or no interaction with 

these channels are expected to have the greatest safety margin. The main 

cardiac arrhythmia of concern is that of torsades de pointes, a potentially 

fatal phenomenon characterized by prolonged ventricular depolarization that 

manifests as a prolonged QT interval and polymorphic ventricular 

tachycardia, with twisting of the QRS complexes. Based on pre-clinical and 

clinical evidence, it appears that loratadine, cetirizine, and fexofenadine 

are safe from cardiac arrhythmia via the IKr channel, whereas astemizole 

and terfenadine have a propensity to cause ventricular tachyarrhythmias. 

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3.) Clinical pharmacology of new histamine H1 receptor antagonists. 

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Clin Pharmacokinet 1999 May;36(5):329-52 

Simons FE, Simons KJ 

Faculty of Medicine, University of Manitoba, Winnipeg, Canada. 

lmcniven@hsc.mb.ca 

The recently introduced H1 receptor antagonists ebastine, fexofenadine and 

mizolastine, and the relatively new H1 antagonists acrivastine, astemizole, 

azelastine, cetirizine, levocabastine and loratadine, are diverse in terms 

of chemical structure and clinical pharmacology, although they have similar 

efficacy in the treatment of patients with allergic disorders. Acrivastine 

is characterised by a short terminal elimination half-life (t1/2 beta) [1.7 

hours] and an 8-hour duration of action. Astemizole and its metabolites, in 

contrast, have relatively long terminal t1/2 beta values; astemizole has a 

duration of action of at least 24 hours and is characterised by a 

long-lasting residual action after a short course of treatment. Azelastine, 

which has a half-life of approximately 22 hours, is primarily administered 

intranasally although an oral dosage formulation is used in some countries. 

Cetirizine is eliminated largely unchanged in the urine, has a terminal 

t1/2 beta of approximately 7 hours and a duration of action of at least 24 

hours. Ebastine is extensively and rapidly metabolised to its active 

metabolite; carebastine, has a half-life of approximately 15 hours and 

duration of action of at least 24 hours. Fexofenadine, eliminated largely 

unchanged in the faeces and urine, has a terminal t1/2 beta of 

approximately 14 hours and duration of action of 24 hours, making it 

suitable for once or twice daily administration. Levocabastine has a 

terminal t1/2 beta of 35 to 40 hours regardless of the route of 

administration, but is only available as a topical application administered 

intranasally or ophthalmically in patients with allergic 

rhinoconjunctivitis. Loratadine is rapidly metabolised to an active 

metabolite descarboethoxyloratadine and has a 24-hour duration of action. 

Mizolastine has a terminal t1/2 beta of approximately 13 hours and duration 

of action of at least 24 hours. Most orally administered new H1 receptor 

antagonists are well absorbed and appear to be extensively distributed into 

body tissues; many are highly protein-bound. Most of the new H1 antagonists 

do not accumulate in tissues during repeated administration and have a 

residual action of less than 3 days after a short course has been 

completed. Tachyphylaxis, or loss of peripheral H1 receptor blocking 

activity during regular daily use, has not been found for any new H1 

antagonist. Understanding the pharmacokinetics and pharmacodynamics of 

these new H1 antagonists provides the objective basis for selection of an 

appropriate dose and dosage interval and the rationale for modification in 

the dosage regimen that may be needed in special populations, including 

elderly patients, and those with hepatic dysfunction or renal dysfunction. 

The studies cited in this review provide the scientific foundation for 

using the new H1 antagonists with optimal effectiveness and safety. 

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4.) QT lengthening and arrhythmias associated with fexofenadine. 

Lancet 1999 Jun 12;353(9169):2072-3 Giraud T 

Letter 

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5.) Comparison of the effects of terfenadine with fexofenadine on nasal 

provocation tests with allergen. 

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J Allergy Clin Immunol 1999 Jun;103(6):1025-30 

Terrien MH, Rahm F, Fellrath JM, Spertini F 

Division of Immunology and Allergy and ENT Service, Centre Hospitalier 

Universitaire Vaudois, Lausanne, Switzerland. 

BACKGROUND: Fexofenadine, the hydrochloride salt of terfenadine active 

metabolite, is a nonsedative, noncardiotoxic antihistamine derivative for 

the treatment of allergic rhinitis. OBJECTIVE: We sought to compare the 

effects of terfenadine and fexofenadine on nasal provocation tests with 

allergen. METHODS: A preliminary provocation test (screening phase) was 

performed in 25 patients with a history of seasonal allergic rhinitis to 

grass pollen to determine the combined nasal reaction threshold, which was 

defined as 2 of the 3 following criteria: (1) at least a 40% decrease in 

peak nasal inspiratory flow and/or a 30% decrease in minimal 

cross-sectional area as measured by acoustic rhinometry, nasal secretions 

of 0.5 g, and 5 to 10 sneezes per minute. Patients were then included into 

a double-blind, randomized, 2-way crossover study to receive terfenadine or 

fexofenadine 120 mg 2 hours before provocation. Rhinorrhea, sneezing, peak 

nasal flow, and minimal nasal cross-sectional area, as well as symptom 

scores for nasal congestion and itchiness, were recorded at each allergen 

concentration up to the reaction threshold. The whole study was performed 

out of allergy season. RESULTS: Fexofenadine was as potent as terfenadine 

in limiting pruritus and nasal congestion. Rhinorrhea and sneezing were 

better controlled by fexofenadine than by terfenadine. Overall, the 

allergen concentration necessary to reach the combined reaction threshold 

was increased after treatment with both drugs. Comparison between screening 

and each treatment phase indicated that the shift in allergen concentration 

to reach the reaction threshold was significantly greater after 

fexofenadine than after terfenadine (P =. 033). CONCLUSION: After oral 

administration, fexofenadine provided better protection than terfenadine 

against the immediate allergic reaction. 

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6.) Comparative tolerability of second generation antihistamines. 

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Drug Saf 1999 May;20(5):385-401 

Horak F, Stubner UP 

ENT-Clinic, University of Vienna, Austria. friedrich.horak@akh-wien.at.ac 

Second generation histamine H1 receptor antagonists, the so-called 

'nonsedating' antihistamines, have high potency and additional antiallergic 

properties as well as H1 antagonism and are associated with fewer adverse 

effects compared with the first generation antihistamines. A number of 

drugs in this class are approved for use: acrivastine, astemizole, 

azelastine, cetirizine, ebastine, fexofenadine, loratadine, mizolastine and 

terfenadine. All of them have a more favourable risk-benefit ratio with 

regard to the CNS adverse effects. Even those second generation 

antihistamines that are not actually 'nonsedating' are less impairing than 

their predecessors, but not one of them is entirely devoid of CNS activity. 

Under certain circumstances some antihistamines may affect cardiac 

repolarisation resulting in cardiovascular adverse effects. Serious 

cardiovascular effects have been reported with terfenadine and astemizole 

when they are used in high dosages or when they are given to 'at risk' 

patients. Animal models indicate that there might be a potential risk of 

cardiovascular adverse effects with other antihistamines as well. However, 

up to now there is no clinical evidence for this assumption, despite some 

confusing reports. Likewise there has been much discussion about a link 

between these agents and carcinogenicity. However, there is no evidence 

that any of the second generation antihistamines increase the risk of 

tumour growth in humans. Small children, elderly patients and persons with 

chronic renal or liver impairment are special groups in which the 

individual adverse effects of the second generation antihistamines must be 

kept in mind. The dosage for an individual has to be modified with respect 

to their metabolic situation. Despite the fact that some of the second 

generation antihistamines are listed in the US Food and Drug Administration 

pregnancy risk classification as class B, the use of second generation 

antihistamines should be avoided during pregnancy and they should never be 

administered to nursing mothers. Taking into account their negligible CNS 

activity, the low incidence of cardiovascular adverse effects, their lack 

of anticholinergic effects and other benefits, this class of antiallergic 

drugs represents a definite advance in therapy. 

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7.) Variations among non-sedating antihistamines: are there real differences? 

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Eur J Clin Pharmacol 1999 Apr;55(2):85-93 

Mattila MJ, Paakkari I 

Institute of Biomedicine, Department of Pharmacology and Toxicology, 

University of Helsinki, Finland. 

Most of the modern non-sedating H1 receptor antagonists (antihistamines) 

penetrate the brain poorly, allowing the use of doses large enough to 

counteract allergic processes in peripheral tissues without important 

central effects. The antihistamines reviewed here are acrivastine, 

astemizole, cetirizine, ebastine, fexofenadine, loratadine, mizolastine, 

and terfenadine. However, these drugs are not entirely free from central 

effects, and there are at least quantitative differences between them. 

Although psychomotor and sleep studies in healthy subjects in the 

laboratory may predict that an antihistamine does not cause drowsiness, the 

safety margin can be narrow enough to cause a central sedating effect 

during actual treatment. This might result from a patient's individual 

sensitivity, disease-induced sedation, or drug dosages that are for various 

reasons relatively or absolutely larger (patient's weight, poor response, 

reduced drug clearance, interactions). Mild to even moderate sedation is 

not necessarily a major nuisance, particularly if stimulants need be added 

to the regimen (e.g. in perennial rhinitis). Furthermore, patients can 

adjust doses themselves if needed. Sedating antihistamines are not needed 

for long-term itching, because glucocorticoids are indicated and more 

effective. It is wise to restrict or avoid using antihistamines 

(astemizole, terfenadine) that can cause cardiac dysrhythmias, because even 

severe cardiotoxicity can occur in certain pharmacokinetic drug-drug 

interactions. Histamine H1 receptor antagonists (antihistamines) are used 

in the treatment of allergic disorders. The therapeutic effects of most of 

the older antihistamines were associated with sedating effects on the 

central nervous system (CNS) and antimuscarinic effects causing dry mouth 

and blurred vision. Non-specific "quinidine-like" or local anaesthetic 

actions often led to cardiotoxicity in animals and man. Although such 

adverse effects varied from drug to drug, there was some degree of sedation 

with all old antihistamines. Non-sedating antihistamines have become 

available during the past 15 years. Some of them also have antiserotonin or 

other actions that oppose allergic inflammation, and they are not entirely 

free from sedative effects either. In small to moderate "clinical" 

concentrations they are competitive H1 receptor antagonists, although large 

concentrations of some of them exert non-competitive blockade. Daytime 

drowsiness and weakness are seldom really important, and they restrict 

patients' activities less than the old antihistamines. Some new 

antihistamines share with old antihistamines quinidine-like effects on the 

cardiac conducting tissues, and clinically significant interactions have 

raised the question of drug safety. This prodysrhythmic effect has also 

been briefly mentioned in comparisons of non-sedative H1 antihistamines. 

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8.) Cardiovascular safety of fexofenadine HCl. 

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Am J Cardiol 1999 May 15;83(10):1451-4 

Pratt CM, Mason J, Russell T, Reynolds R, Ahlbrandt R 

Department of Internal Medicine, Baylor College of Medicine, Houston, 

Texas, USA. 

Fexofenadine HCl is the acid metabolite of terfenadine (Seldane). The 

effect of this recently approved nonsedating antihistamine on the corrected 

QT interval (QTc) was evaluated in dose-tolerance, safety, and 

drug-interaction studies with healthy volunteers, and in clinical studies 

in patients with seasonal allergic rhinitis (SAR). Twelve-lead 

electrocardiographic data were collected once before and after dosing or 

serially throughout these studies. Outliers were defined as QTc > 440 ms 

with a > or = 10 ms increase from baseline. The recommended fexofenadine 

HCl dose is 60 mg twice daily. Fexofenadine HCl doses up to 800 mg once 

daily or 690 mg twice daily for 28 days resulted in no dose-related 

increases in QTc. Longer term studies indicated no statistically 

significant QTc increases compared with placebo in patients receiving 

fexofenadine HCl 80 mg twice daily for 3 months, 60 mg twice daily for 6 

months, or 240 mg once daily for 12 months. Interaction studies showed no 

significant increases in QTc when fexofenadine HCl 120 mg twice daily was 

administered in combination with erythromycin (500 mg 3 times daily) or 

ketoconazole (400 mg once daily) after dosing to steady state (6.5 days). 

Clinical trials in patients with SAR (n = 1,160) treated with 40, 60, 120, 

or 240 mg twice-daily fexofenadine HCl or placebo indicated no dose-related 

increases in QTc and no statistically significant increases in mean QTc 

compared with placebo. In controlled trials with approximately 6,000 

persons, no case of fexofenadine-associated torsades de pointes was 

observed. The frequency and magnitude of QTc outliers were similar between 

fexofenadine HCl and placebo in all studies. Based on a large clinical 

database, we conclude that fexofenadine HCl has no significant effect on 

QTc, even at doses > 10-fold higher than that is efficacious for SAR. 

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9.) Treating allergic rhinitis in pregnancy. Safety considerations. 

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Drug Saf 1999 Apr;20(4):361-75 

Mazzotta P, Loebstein R, Koren G 

Motherisk Program, Division of Clinical Pharmacology and Toxicology, 

Hospital for Sick Children, University of Toronto, Ontario, Canada. 

Allergic rhinitis affects approximately one-third of women of childbearing 

age. As a result, symptoms ranging from sneezing and itching to severe 

nasal obstruction may require pharmacotherapy. However, product labels 

state that medications for allergic rhinitis should be avoided during 

pregnancy due to lack of fetal safety data, even though the majority of the 

agents have human data which refute these notions. We present a systematic 

and critical review of the medical literature on the use of pharmacotherapy 

for the management of allergic rhinitis during pregnancy. Electronic 

databases and other literature sources were searched to identify 

observational controlled studies focusing on the rate of fetal 

malformations in pregnant women exposed to agents used to treat allergic 

rhinitis and related diseases compared with controls. Immunotherapy and 

intranasal sodium cromoglycate (cromolyn) and beclo-methasone would be 

considered as first-line therapy, both because of their lack of association 

with congenital abnormalities and their superior efficacy to other agents. 

First-generation (e.g. chlorpheniramine) and second-generation (e.g. 

cetirizine) antihistamines have not been incriminated as human teratogens. 

However, first-generation antihistamines are favoured over their second 

generation counterparts based on their longevity, leading to more 

conclusive evidence of safety. There are no controlled trials with 

loratadine and fexofenadine in human pregnancy. Oral, intranasal and 

ophthalmic decongestants (e.g. pseudoephedrine, phenylephrine and 

oxymetazoline, respectively) should be considered as second-line therapy, 

although further studies are needed to clarify their fetal safety. No human 

reproductive studies have been reported with the ophthalmic antihistamines 

ketorolac and levocabastine, although preliminary data reported suggest no 

association between pheniramine and congenital malformations. There are no 

documented epidemiological studies with intranasal corticosteroids (e.g. 

budesonide, fluticasone propionate, mometasone) during pregnancy; however, 

inhaled corticosteroids (e.g. beclomethasone) have not been incriminated as 

teratogens and are commonly used by pregnant women who have asthma. In 

summary, women with allergic rhinitis during pregnancy can be treated with 

a number of pharmacological agents without concern of untoward effects on 

their unborn child. Although the choice of agents in part should be based 

on evidence of fetal safety, issue of efficacy needs to be addressed in 

order to optimally manage this condition. 

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10.) Second-generation antihistamines: the risk of ventricular arrhythmias. 

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Clin Ther 1999 Feb;21(2):281-95 

DuBuske LM 

Brigham and Women's Hospital, Boston, Massachusetts, USA. 

Some second-generation antihistamines, notably terfenadine and astemizole, 

have been associated with prolongation of the QT interval and the 

development of torsades de pointes, a potentially fatal ventricular 

arrhythmia. This rare adverse event has been associated with greatly 

elevated blood levels of these agents, resulting from drug overdose, 

hepatic insufficiency (dysfunction), or interactions with other drugs that 

inhibit their metabolism. This paper reviews the data concerning the 

effects of selected second-generation antihistamines on cardiac conduction, 

particularly the QT interval, to evaluate whether ventricular arrhythmias 

are a class effect of these agents. Electrocardiographic studies indicate 

that terfenadine and astemizole, but not loratadine or cetirizine, prolong 

the QT interval in laboratory animals. In vitro studies demonstrate that 

terfenadine and astemizole block the cardiac K+ channels, leading to 

delayed ventricular repolarization and QT-interval prolongation; in 

contrast, neither loratadine nor its metabolite, desloratadine, 

significantly inhibits cardiac K+ channels at clinically achievable blood 

levels. Studies in human volunteers confirm the absence of 

electrocardiographic effects of azelastine, cetirizine, fexofenadine, and 

loratadine administered at several times the recommended dose or 

concomitantly with agents that inhibit their metabolism and elimination. In 

conclusion, the data indicate that the potential to cause ventricular 

arrhythmias is not a class effect of second-generation antihistamines and 

that loratadine, cetirizine, azelastine, and fexofenadine are not 

associated with torsades de pointes or other ventricular arrhythmias. 

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11.) Second-generation antihistamines: a comparative review. 

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Drugs 1999 Jan;57(1):31-47 

Slater JW, Zechnich AD, Haxby DG 

College of Pharmacy, Oregon State University, Portland, USA. 

Second-generation histamine H1 receptor antagonists (antihistamines) have 

been developed to reduce or eliminate the sedation and anticholinergic 

adverse effects that occur with older H1 receptor antagonists. This article 

evaluates second-generation antihistamines, including acrivastine, 

astemizole, azelastine, cetirizine, ebastine, fexofenadine, ketotifen, 

loratadine, mizolastine and terfenadine, for significant features that 

affect choice. In addition to their primary mechanism of antagonising 

histamine at the H1 receptor, these agents may act on other mediators of 

the allergic reaction. However, the clinical significance of activity 

beyond that mediated by histamine H1 receptor antagonism has yet to be 

demonstrated. Most of the agents reviewed are metabolised by the liver to 

active metabolites that play a significant role in their effect. Conditions 

that result in accumulation of astemizole, ebastine and terfenadine may 

prolong the QT interval and result in torsade de pointes. The remaining 

agents reviewed do not appear to have this risk. For allergic rhinitis, all 

agents are effective and the choice should be based on other factors. For 

urticaria, cetirizine and mizolastine demonstrate superior suppression of 

wheal and flare at the dosages recommended by the manufacturer. For atopic 

dermatitis, as adjunctive therapy to reduce pruritus, cetirizine, ketotifen 

and loratadine demonstrate efficacy. Although current evidence does not 

suggest a primary role for these agents in the management of asthma, it 

does support their use for asthmatic patients when there is coexisting 

allergic rhinitis, dermatitis or urticaria. 

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12.) Terfenadine and fexofenadine reduce in vitro ICAM-1 expression on 

human continuous cell lines. 

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Ann Allergy Asthma Immunol 1998 Dec;81(6):601-7 

Paolieri F, Battifora M, Riccio AM, Bertolini C, Cutolo M, Bloom M, 

Ciprandi G, Canonica GW, Bagnasco M 

Department of Internal Medicine, University of Genoa, Italy. 

BACKGROUND: Epithelial cells and fibroblasts play an important role in 

allergic inflammation. Modulation of surface expression of adhesion 

molecules on epithelial cells by antiallergic drugs has been shown by both 

in vivo and in vitro studies. OBJECTIVE: The aim of the study was to 

evaluate the effect exerted by terfenadine and fexofenadine on adhesion 

molecules expression (CD54/ICAM-1 and CD29) of a human continuously 

cultured conjunctival epithelial cell line (WK) and a fibroblast cell line 

(HEL). METHODS: By means of flow cytometry analysis, we evaluated ICAM-1 

and CD29 expression by WK and HEL epithelial cells in basal condition (at 

baseline) or after IFN gamma or TNF alpha stimulation in the presence or in 

the absence of terfenadine and fexofenadine. We also performed 

immunoenzymatic assays in order to evaluate soluble ICAM-1 released by WK 

cells and procollagen type I and III and IL6 released by HEL cells. 

RESULTS: Terfenadine and fexofenadine significantly reduced ICAM-1 basal 

expression on WK cells at the concentration of 1 microg/mL and 50 

microg/mL, respectively. In addition, both terfenadine and fexofenadine 

were able to decrease soluble ICAM-1 levels in IFN gamma-stimulated WK 

cells. On HEL fibroblasts, fexofenadine only was able to inhibit ICAM-1 

upregulation induced by IFN gamma. Concerning the release of fibroblast 

products, we observed a dose-dependent decrease of spontaneous IL6 release 

only in the presence of fexofenadine. CONCLUSION: This study shows that 

terfenadine and fexofenadine exert a biologic effect directly on epithelial 

cells and fibroblasts reducing ICAM-1 expression and partially reducing 

soluble ICAM-1 release. 

===================================================================== 

13.) Pharmacokinetics, pharmacodynamics, and tolerance of single- and 

multiple-dose fexofenadine hydrochloride in healthy male volunteers. 

===================================================================== 

Clin Pharmacol Ther 1998 Dec;64(6):612-21 

Russell T, Stoltz M, Weir S 

Department of Clinical Pharmacokinetics, Hoechst Marion Roussel Inc., 

Kansas City, MO 64137-1405, USA. 

BACKGROUND: Fexofenadine is a selective, nonsedating H1-receptor antagonist 

that relieves symptoms of allergic conditions. METHODS: Two randomized, 

double-blind, parallel-group, placebo-controlled dose-escalation studies 

were performed in healthy men to determine the maximum tolerated oral dose, 

pharmacokinetics, pharmacodynamics, and safety of fexofenadine 

hydrochloride. In the first study, 87 subjects (6 in the active drug group 

and 2 in the placebo group) received single oral doses of fexofenadine 

hydrochloride ranging from 10 to 800 mg or placebo. In the second study, 32 

subjects (3 in the active drug group and 1 in the placebo group) received 

multiple fexofenadine hydrochloride doses ranging from 20 to 690 mg or 

placebo twice daily for 28 1/2 days. Serial plasma and urine samples were 

collected. Fexofenadine concentrations were determined by HPLC and 

fluorescence. Wheal and flare response to intradermal histamine was used to 

evaluate antihistaminic activity. RESULTS: Fexofenadine hydrochloride was 

rapidly absorbed, reaching peak concentrations in 0.83 to 1.33 hours. 

Single-dose mean concentration ranged from 46 to 6383 ng/mL, and 

steady-state maximum plasma concentration ranged from 58 to 4677 ng/mL. 

Mean area under the plasma concentration-time curve was approximately 

proportional to dose. Oral clearance, renal clearance, and cumulative 

percent of drug excreted in urine were similar after single and multiple 

doses and were generally constant over the dose range studied. Inhibition 

of skin wheal and flare was shown for single doses of 40 mg and higher and 

for all multiple doses. No fexofenadine dose-related trends or apparent 

differences from placebo were found for any safety parameter. CONCLUSIONS: 

Fexofenadine hydrochloride was well tolerated at oral doses up to 11 times 

the recommended therapeutic dose. In addition, fexofenadine hydrochloride 

showed significant antihistaminic activity and dose-proportional 

pharmacokinetics over a wide dosing range. 

===================================================================== 

14.) Pharmacokinetic overview of oral second-generation H1 antihistamines. 

===================================================================== 

Int J Clin Pharmacol Ther 1998 May;36(5):292-300 

Gonzalez MA, Estes KS 

P'Kinetics Inc., Pembroke Pines, Florida 33027-2219, USA. 

Specific H1 antihistamines have become the standard of treatment for relief 

of symptoms associated with seasonal allergic rhinitis. First-generation 

antihistamines are small lipophilic molecules that are associated with 

numerous adverse events largely because of their propensity to cross the 

blood-brain barrier and their cholinergic activity. Second-generation 

antihistamines, being more lipophobic, offer the advantages of a lack of 

CNS and cholinergic effects such as sedation and dry mouth, which are 

commonly seen in first-generation antihistamines. Their longer duration of 

action also enables a more patient-friendly dosing regimen which increases 

patient compliance. This paper reviews the pharmacokinetic properties of 

these second-generation agents and is intended to provide comparisons that 

help explain differences in dosing profiles and drug interactions for 

members of this class of drugs. With the announced withdrawal of 

terfenadine from the U.S. market in early 1997, 4 second-generation 

antihistamines are currently widely available: astemizole, loratadine, 

cetirizine, and fexofenadine. Terfenadine and astemizole both produce 

significant cardiac QT interval prolongation that may progress to a rare 

but fatal cardiac ventricular tachycardia known as torsades de pointes. 

While only terfenadine has been withdrawn due to its adverse effects 

profile, significant warnings were recently issued for astemizole. The 

pharmacokinetic profiles of loratadine and cetirizine are reflective of the 

advantages of these agents as non-cardiotoxic antihistamines. With respect 

to the newest agent fexofenadine, the major metabolite of terfenadine, 

published reports are minimal, but its pharmacokinetics differs from that 

of terfenadine. 

===================================================================== 

15.) Fexofenadine. 

===================================================================== 

Drugs 1998 Feb;55(2):269-74; discussion 275-6 

Markham A, Wagstaff AJ 

Adis International Limited, Auckland, New Zealand. demail@adis.co.nz 

The nonsedating histamine H1 receptor antagonist fexofenadine is the active 

metabolite of terfenadine. It reduced the allergic response in animal 

models of allergy and did not prolong the QT interval (QTc) in dogs or 

rabbits at plasma concentrations many times higher than those seen after 

administration of therapeutic dosages. Similarly, relative to placebo, 

fexofenadine did not affect mean QTc in patients given dosages of up to 480 

mg/day for 2 weeks or in volunteers who received up to 800 mg/day for 6 

days or 240 mg/day for 12 months. In a double-blind clinical trial, oral 

fexofenadine 120 or 180mg once daily controlled symptoms in patients with 

seasonal allergic rhinitis as effectively as cetirizine. Other double-blind 

clinical trials showed that fexofenadine 40 to 240mg twice daily was 

significantly more effective than placebo. Fexofenadine 180 or 240mg once 

daily was significantly more effective than placebo in patients with 

chronic idiopathic urticaria. The drug was well tolerated in these clinical 

trials, with an adverse event profile similar to that seen with placebo. 

The most common adverse events were headache, throat irritation, viral 

infection, nausea, dysmenorrhoea, drowsiness, dyspepsia and fatigue. 

===================================================================== 

16.) Efficacy and safety of fexofenadine hydrochloride for treatment of 

seasonal allergic rhinitis. 

===================================================================== 

Ann Allergy Asthma Immunol 1997 Nov;79(5):443-8 

Bernstein DI, Schoenwetter WF, Nathan RA, Storms W, Ahlbrandt R, Mason J 

Division of Immunology, University of Cincinnati, College of Medicine, 

Ohio, USA. 

BACKGROUND: H1-receptor antagonists are effective for the treatment of 

seasonal allergic rhinitis. In rare circumstances, some second-generation 

H1-receptor antagonists have been associated with prolongation of the 

corrected QT interval (QTc), thus increasing the risk of ventricular 

arrhythmias. Fexofendine HCl, the carboxylic acid metabolite of 

terfenadine, is a new second-generation antihistamine that is nonsedating 

and does not cause electrocardiographic effects. OBJECTIVE: To investigate 

the clinical efficacy and safety of fexofenadine HCl in the treatment of 

ragweed seasonal allergic rhinitis and to characterize the dose-response 

relationship of fexofenadine HCl at dosages of 60, 120, and 240 mg bid. 

METHODS: A multicenter, 14-day, placebo-controlled, double-blind trial was 

conducted with patients suffering from moderate to severe ragweed seasonal 

allergic rhinitis who met symptom severity criteria after a 3-day placebo 

baseline period. Patients with minimal or very severe symptoms during the 

baseline period were excluded. Patients were randomized to receive 

fexofenadine HCl (60, 120, or 240 mg bid) or placebo at 12-hour dosing 

intervals (7:00 AM and 7:00 PM). The primary efficacy measure was 

patient-assessed 12-hour reflective total symptom score before the evening 

dose (trough). RESULTS: Five hundred seventy patients completed the trial. 

Fexofenadine HCl at each dosage provided significant improvement in total 

symptom score (P < or = .003) and in all individual nasal symptoms compared 

with placebo. The frequency of adverse events was similar among 

fexofenadine HCl and placebo groups, with no dose-related trends. No 

sedative effects or electrocardiographic abnormalities, including 

prolongations in QTc were detected. CONCLUSIONS: Fexofenadine HCl is both 

effective and safe for the treatment of ragweed seasonal allergic rhinitis. 

Because there was no additional efficacy at higher dosages, 60 mg bid 

appears to be the optimal therapeutic dosage for these patients. 

===================================================================== 

17.) Dose proportionality and comparison of single and multiple dose 

pharmacokinetics of fexofenadine (MDL 16455) and its enantiomers in healthy 

male volunteers. 

===================================================================== 

Author 

Robbins DK; Castles MA; Pack DJ; Bhargava VO; Weir SJ 

Address 

North America Pharmacokinetics Department, Hoechst Marion Roussel, Inc., 

Kansas City, MO 64134-0627, USA. doris.robbins-weilert@hmrag.com 

Source 

Biopharm Drug Dispos, 19(7):455-63 1998 Oct 

Abstract 

The pharmacokinetics and dose proportionality of fexofenadine, a new 

non-sedating antihistamine, and its enantiomers were characterized after 

single and multiple-dose administration of its hydrochloride salt. A total 

of 24 healthy male volunteers (31 +/- 8 years) received oral doses of 20, 

60, 120 and 240 mg fexofenadine HCl in a randomized, complete four-period 

cross-over design. Subjects received a single oral dose on day 1, and 

multiple oral doses every 12 h on day 3 through the morning on day 7. 

Treatments were separated by a 14-day washout period. Serial blood and 

urine samples were collected for up to 48 h following the first and last 

doses of fexofenadine HCl. Fexofenadine and its R(+) and S(-) enantiomers 

were analysed in plasma and urine by validated HPLC methods. Fexofenadine 

pharmacokinetics were linear across the 20-120 mg dose range, but a small 

disproportionate increase in area under the plasma concentration-time curve 

(AUC) (< 25%) was observed following the 240 mg dose. Single-dose 

pharmacokinetics of fexofenadine were predictive of steady-state 

pharmacokinetics. Urinary elimination of fexofenadine played a minor role 

(10%) in the disposition of this drug. A 63:37 steady-state ratio of R(+) 

and S(-) fexofenadine was observed in plasma. This ratio was essentially 

constant across time and dose. R(+) and S(-) fexofenadine were eliminated 

into urine in equal rates and quantities. All doses of fexofenadine HCl 

were well tolerated after single and multiple-dose administration. 

===================================================================== 

18.) Fexofenadine's effects, alone and with alcohol, on actual driving and 

psychomotor performance. 

===================================================================== 

Author 

Vermeeren A; O'Hanlon JF 

Address 

Institute for Human Psychopharmacology, Maastricht University, The 

Netherlands. 

Source 

J Allergy Clin Immunol, 101(3):306-11 1998 Mar 

Abstract 

BACKGROUND: Fexofenadine is the hydrochloride salt of terfenadine's active 

metabolite. OBJECTIVE: Fexofenadine's effects on performance were assessed 

in this study for the purpose of determining its safety of use by patients 

who engage in potentially dangerous activities, especially car driving. 

METHODS: Fexofenadine was administered in daily doses of 120 or 240 mg, 

each in single and divided units given over 5 days. Two milligrams of 

clemastine given twice daily and placebo were given in similar series. 

Twenty-four healthy volunteers (12 men, 12 women; age range, 21 to 45 

years) participated in a double-blind six-way crossover study. Psychomotor 

tests (critical tracking, choice reaction time, and sustained attention) 

and a standardized actual driving test were undertaken between 1.5 to 4 

hours after administration of the morning dose on days 1, 4, and 5 of each 

series. On day 5, subjects were challenged with a moderate alcohol dose 

before testing. RESULTS: Fexofenadine did not impair driving performance. 

On the contrary, driving performance was consistently better during twice 

daily treatment with 120 mg fexofenadine than during treatment with 

placebo, significantly so on day 4. Both of the 240 mg/day regimens 

significantly attenuated alcohol's adverse effect on driving on day 5. 

Effects in psychomotor tests were not significant, with the exception of 

the critical tracking test in which the first single doses of fexofenadine, 

120 and 240 mg, had significantly impairing effects. CONCLUSION: It was 

concluded that fexofenadine has no effect on performance after being taken 

in the recommended dosage of 60 mg twice daily. 

Language 

===================================================================== 

19.) Onset of action, efficacy, and safety of a single dose of fexofenadine 

hydrochloride for ragweed allergy using an environmental exposure unit. 

===================================================================== 

Author 

Day JH; Briscoe MP; Welsh A; Smith JN; Clark A; Ellis AK; Mason J 

Address 

Division of Allergy, Kingston General Hospital, Ontario, Canada. 

Source 

Ann Allergy Asthma Immunol, 79(6):533-40 1997 Dec 

Abstract 

BACKGROUND: Fexofenadine hydrochloride is the active acid metabolite of 

terfenadine. Fexofenadine's anti-allergic properties require confirmation 

in a clinical setting. OBJECTIVE: The purpose of this study was to 

characterize the time to onset of clinically important relief of symptoms 

of allergic rhinitis in subjects taking single doses of either 60 mg or 120 

mg fexofenadine HCl, or placebo, after exposure to ragweed pollen in a 

controlled environment. Other objectives were to assess the efficacy and 

safety of single doses of fexofenadine HCl. METHODS: One hundred forty-six 

ragweed-sensitive subjects were primed in the off-season with ragweed 

pollen in the environmental exposure unit. One hundred thirty-six subjects 

who adequately responded to priming entered a single-dose placebo phase. 

Placebo-responders were disqualified from the study, leaving 99 subjects 

with adequate symptoms to be randomized and given a single dose of either 

fexofenadine HCl 120 mg (33), 60 mg (33) or placebo (33), after 60 minutes 

of allergen exposure. Exposure continued over five hours and subjects 

recorded symptoms every 20 minutes. This study was of a randomized, 

placebo-controlled, double-blind, parallel design. RESULTS: Median time to 

onset for relaxed criteria clinically important relief was 60 minutes for 

both fexofenadine treatment groups, and 100 minutes for placebo (P = .018). 

The proportion with relief was 82% at 60 mg, 85% at 120 mg, and 64% for 

placebo. Treated groups had reductions in symptom scores double that of 

placebo. CONCLUSIONS: Fexofenadine is safe and efficacious at single doses 

of 60 mg and 120 mg. Average time to onset was 60 minutes using controlled 

pollen exposure in an environmental exposure unit. 

===================================================================== 

20.) Effectiveness and safety of fexofenadine, a new nonsedating 

H1-receptor antagonist, in the treatment of fall allergies. 

===================================================================== 

Author 

Bronsky EA; Falliers CJ; Kaiser HB; Ahlbrandt R; Mason JM 

Address 

Intermountain Clinical Research, Salt Lake City, Utah 84102, USA. 

Source 

Allergy Asthma Proc, 19(3):135-41 1998 May-Jun 

Abstract 

Fexofenadine HCl is a new, nonsedating H1-receptor antagonist approved for 

treatment of seasonal allergic rhinitis (SAR). In a double-blind, 

randomized, placebo-controlled, multicenter trial, 588 patients with fall 

SAR rated the severity of their symptoms using a scoring system at a 

screening visit and during a 3-day placebo lead-in period. Patients who did 

not respond to placebo and met symptom severity criteria were randomized to 

receive placebo or fexofenadine HCl at 40, 60, or 120 mg bid at 7:00 a.m. 

and 7:00 p.m. for 14 days. Patients continued to rate the severity of their 

symptoms immediately before receiving each dose (at trough). A total of 545 

patients were included in an intent-to-treat analysis. The change from 

baseline in the primary efficacy variable (average daily 7:00 p.m. 

reflective symptom scores) was significantly greater in patients receiving 

all dosages of fexofenadine HCl than placebo (p < 0.01). All active dosages 

produced significant decreases (p < 0.05) in secondary end points: 7:00 

a.m. reflective symptom scoring; 7:00 a.m. and 7:00 p.m. scoring 1-hour 

before dose; and bedtime scoring 1-3 hours after the 7:00 p.m. dose. All 

dosages of fexofenadine HCl were well tolerated, and no effect on QTc was 

observed. In conclusion, fexofenadine HCl is safe and effective in the 

treatment of fall SAR, with 60 mg bid being the optimal therapeutic dosage. 

===================================================================== 

21.) Effect of fexofenadine on eosinophil-induced changes in epithelial 

permeability and cytokine release from nasal epithelial cells of patients 

with seasonal allergic rhinitis. 

===================================================================== 

Author 

Abdelaziz MM; Devalia JL; Khair OA; Bayram H; Prior AJ; Davies RJ 

Address 

Academic Department of Respiratory Medicine, St. Bartholomew's and the 

Royal London School of Medicine and Dentistry, The London Chest Hospital, 

United Kingdom. 

Source 

J Allergy Clin Immunol, 101(3):410-20 1998 Mar 

Abstract 

Recent studies have suggested that antihistamines, widely used in the 

treatment of symptoms of patients with allergic rhinitis, may also possess 

antiinflammatory properties. The mechanisms underlying this property, 

however, are not clearly understood. We have cultured epithelial cells from 

nasal biopsy specimens from patients with seasonal allergic rhinitis 

outside the pollen season and studied the effect of 0 to 10(-3) mol/L 

fexofenadine, the main active metabolite of terfenadine, on 

eosinophil-induced changes in electrical resistance (measure of 

permeability) and release of proinflammatory mediators from these cells. 

Additionally, we have studied the effect of this drug on eosinophil 

chemotaxis and adherence to endothelial cells induced by conditioned medium 

from these human nasal epithelial cell (HNEC) cultures. Incubation of HNEC 

in the presence of eosinophils treated with opsonized latex beads 

significantly decreased the electrical resistance of these cultures, an 

effect that was abrogated by treatment of the cultures with 10(-9) to 

10(-3) mol/L fexofenadine. Similarly, incubation of HNEC in the presence of 

eosinophils treated with latex beads also significantly increased the basal 

release of the chemokine "regulated upon activation, normal T cell 

expressed and secreted" (RANTES) (from 96.0 to 613.0 fg/microg cellular 

protein; p < 0.05), IL-8 (from 42.0 to 198.5 pg/microg cellular protein; p 

< 0.05), granulocyte-macrophage colony-stimulating factor (GM-CSF) (from 

0.54 to 3.4 pg/microg cellular protein; p < 0.05), and soluble 

intercellular adhesion molecule-1 (sICAM-1) (from 7.8 to 18.4 pg/microg 

cellular protein; p < 0.05) from HNEC. The eosinophil-induced release of 

IL-8, GM-CSF, and sICAM-1 from the HNEC was significantly attenuated by 

treatment with fexofenadine. Analysis of the effects of conditioned medium 

from HNEC demonstrated that this significantly increased both eosinophil 

chemotaxis and adherence to endothelial cells. Addition of 10(-6) to 10(-3) 

mol/L fexofenadine to the conditioned medium significantly attenuated 

eosinophil chemotaxis and adherence to endothelial cells. These results 

suggest that fexofenadine may reduce nasal inflammation by modulating the 

release of proinflammatory mediators and adhesion molecules from HNEC. 

===================================================================== 

22.) Peripheral H1-blockade effect of fexofenadine. 

===================================================================== 

Author 

Simons FE; Simons KJ 

Address 

Faculty of Medicine, University of Manitoba, Winnipeg, Canada. 

Source 

Ann Allergy Asthma Immunol, 79(6):530-2 1997 Dec 

Abstract 

BACKGROUND: Studies of the suppressive effect of H1-receptor antagonists on 

the histamine-induced wheal and flare are useful for assessing peripheral 

H1-blockade. OBJECTIVE: To compare the peripheral H1-blockade produced by 

fexofenadine, 60 mg twice daily or 120 mg once daily; loratadine, 10 mg 

once daily; and placebo during 24 hours. METHODS: In this randomized, 

double-blind, single-dose, crossover study in 20 subjects, the wheals and 

flares produced by epicutaneous tests with histamine phosphate 1 mg/mL were 

measured before and at intervals (20, 40, 60 minutes, hourly until 12 

hours, and 24 hours) after the ingestion of fexofenadine, 60 mg twice 

daily; fexofenadine, 120 mg once daily; loratadine, 10 mg once daily; or 

placebo. RESULTS: All active medications effectively suppressed the 

histamine-induced wheal and flare for 24 hours compared with placebo. 

Fexofenadine 60 mg twice daily and fexofenadine 120 mg once daily had a 

faster onset of action than loratadine in this experimental model. 

CONCLUSIONS: Peripheral H1-blockade studies are useful for investigation of 

the differences among H1-receptor antagonists. They complement large 

clinical trials in which efficacy is subjectively assessed using symptom 

scores, and which are more likely to demonstrate similarities among the 

different medications in this class, and among different doses of the same 

H1-receptor antagonist. 

===================================================================== 

23.) Is my antihistamine safe? 

===================================================================== 

Author 

Ashworth L 

Address 

Mercer University's Southern School of Pharmacy, Atlanta, GA 30341-4155, USA. 

Source 

Home Care Provid, 2(3):117-20 1997 Jun 

Abstract 

The Food and Drug Administration (FDA) has announced its intention to 

withdraw the approval of terfenadine (Seldane), terfenadine with 

pseudoephedrine (Seldane D), and generic versions of terfenadine. Before 

granting approval for the marketing of fexofenadine (Allegra), 

terfenadine's active metabolite, the FDA determined terfenadine's benefits 

outweight its risks, despite its, known potential for serious cardiac 

effects. 

===================================================================== 

24.) Drug interactions with the nonsedating antihistamines. 

===================================================================== 

Author 

Ament PW; Paterson A 

Address 

Latrobe Area Hospital, Pennsylvania, USA. 

Source 

Am Fam Physician, 56(1):223-31 1997 Jul 

Abstract 

The nonsedating antihistamines are frequently prescribed agents. 

Well-documented drug-drug interactions with two of these agents, 

terfenadine and astemizole, may result in serious adverse effects, 

including death, when they are prescribed along with macrolide antibiotics 

and/or the antifungal agents itraconazole or ketoconazole. Fexofenadine and 

loratadine appear to be the least likely nonsedating antihistamines to 

interact with other medications and to result in a life-threatening 

interaction. This article reviews the known drug-drug interactions 

involving nonsedating antihistamines and provides a basis from which the 

clinician can predict potential interactions. 

======================================================================= 

25.) Correspondence : QT lengthening and arrhythmias associated with fexofenadine 

The lancet, Volume 353 Issue 9169 

======================================================================= 

======================================================================= 

26.) FDA, DEPARTMENT OF HEALTH AND HUMAN SERVICES, FEXOFENADINE AND TERBINAFINE 

======================================================================= 

[Federal Register: January 14, 1997 (Volume 62, Number 9)] 

[Notices] 

[Page 1889-1892] 

From the Federal Register Online via GPO Access [wais.access.gpo.gov] 

Food and Drug Administration 

[Docket No. 96N-0512] 

Hoechst Marion Roussel, Inc., and Baker Norton Pharmaceuticals, 

Inc.; Terfenadine; Proposal To Withdraw Approval of Two New Drug 

Applications and One Abbreviated New Drug Application; Opportunity for 

a Hearing 

AGENCY: Food and Drug Administration, HHS. 

ACTION: Notice. 

SUMMARY: The Food and Drug Administration (FDA) is proposing to 

withdraw approval of two new drug applications (NDA's) and one 

abbreviated new drug application (ANDA) for drug products containing 

terfenadine. NDA 18-949 (Seldane) and NDA 19-664 (Seldane-D) are held 

by Hoechst Marion Roussel (HMR), Inc., P.O. Box 9627, Kansas City, MO 

64134-0627. ANDA 74-475 is held by Baker Norton Pharmaceuticals, Inc., 

4400 Biscayne Blvd., Miami, FL 33137. On July 25, 1996, FDA approved 

HMR's NDA 20-625 for fexofenadine> hydrochloride (Allegra). <Fexofenadine> 

is the active metabolite of terfenadine that is responsible for the 

desired beneficial properties of terfenadine. When patients take 

terfenadine, parent terfenadine is ordinarily present in their blood at 

very low concentrations, because the terfenadine molecule is 

metabolized to form <fexofenadine>. <Fexofenadine> is responsible for 

providing patients with essentially all the clinical benefits of taking 

terfenadine. If terfenadine's metabolism is inhibited, either by 

another drug or by intrinsic liver disease, the level of parent 

terfenadine can rise to levels that can cause serious side effects in 

people as a result of the effect of parent terfenadine on cardiac 

potassium channels. Inhibition of these channels causes delayed cardiac 

repolarization (prolonged electrocardiographic <QT> interval) and 

increases the risk of a characteristic kind of ventricular tachycardia 

called torsades de pointes and possibly the risk of other rhythm 

abnormalities. <Fexofenadine> hydrochloride, however, has not been shown 

to affect cardiac potassium channels and has been shown not to cause 

prolongation of the electrocardiographic <QT> interval, even at larger- 

than-recommended doses. Based on all data to date, <fexofenadine> 

hydrochloride appears to lack parent terfenadine's risk of serious 

cardiovascular adverse events. The basis for the proposed withdrawal of 

the applications is a finding that the availability of <fexofenadine> 

hydrochloride provides patients with an alternative that can provide 

essentially all the benefits of terfenadine, because it is identical in 

molecular structure to the metabolized (active) form of terfenadine, 

without the serious and potentially fatal risks associated with 

terfenadine when terfenadine's metabolism is inhibited either by 

another drug or by intrinsic liver disease. Because of the availability 

of <fexofenadine> hydrochloride, terfenadine is not shown to be safe for 

use under the conditions of use that formed the basis upon which the 

applications were approved. 

DATES: A hearing request is due on February 13, 1997; data and 

information in support of the hearing request are due on March 17, 

1997. 

ADDRESSES: A request for hearing, supporting data, and other comments 

are to be identified with docket no. 96N-0512 and submitted to the 

Dockets Management Branch (HFA-305), Food and Drug Administration, 

12420 Parklawn Dr., rm. 1-23, Rockville, MD 20857. 

FOR FURTHER INFORMATION CONTACT: 

For information on medical/scientific issues: John K. Jenkins, 

Center for Drug Evaluation and Research (HFD-570), Food and Drug 

Administration, 5600 Fishers Lane, Rockville, MD 20857, 301-827- 

[[Page 1890]] 

1050. 

For general information concerning this notice: David T. Read, 

Center for Drug Evaluation and Research (HFD-7), Food and Drug 

Administration, 7520 Standish Pl., Rockville, MD 20855, 301-594-2041. 

SUPPLEMENTARY INFORMATION: 

I. Background 

Terfenadine is an antihistamine, indicated for the relief of 

symptoms associated with seasonal allergic rhinitis such as sneezing, 

rhinorrhea, pruritus, and lacrimation. Terfenadine was the first 

antihistamine approved in the United States that was not associated 

with more somnolence than placebo in clinical trials. The absence of an 

increased risk of somnolence over placebo is an important safety 

advantage to many people who use antihistamines. NDA 18-949 for Seldane 

tablets (terfenadine 60 milligrams (mg)) was approved by FDA on May 8, 

1985. NDA 19-664 for Seldane-D tablets (terfenadine 60 mg and the 

decongestant pseudoephedrine hydrochloride 120 mg) was approved by FDA 

on August 19, 1991. 

Other antihistamines now available in the United States that were 

not associated with more somnolence than placebo in clinical trials are 

astemizole (Hismanal) and loratadine (Claritin), approved on December 

29, 1988, and April 12, 1993, respectively. Most significant to this 

proceeding, on July 25, 1996, FDA approved HMR's NDA 20-625 for 

<fexofenadine> hydrochloride 60 mg capsules (Allegra). <Fexofenadine> is 

the metabolite of terfenadine responsible for its desired 

antihistaminic efficacy. <Fexofenadine> hydrochloride was also not 

associated with more somnolence than placebo in clinical trials. 

After the approval of terfenadine in 1985, there began to be 

reports of certain serious cardiac adverse events associated with 

terfenadine use in patients taking certain antimicrobials or with 

significant liver dysfunction. Very little parent terfenadine normally 

circulates in the plasma because orally administered terfenadine 

undergoes extensive first pass metabolism by a specific cytochrome P- 

450 isoenzyme (CYP3A4). This metabolic pathway may be impaired in 

patients with liver dysfunction (e.g., alcoholic cirrhosis) or who are 

taking drugs such as ketoconazole, itraconazole, or macrolide 

antimicrobials (e.g., clarithromycin, erythromycin, or troleandomycin). 

These drugs are all inhibitors of the cytochrome P-450 isoenzyme. 

Interference with the normal metabolism of terfenadine can lead to 

elevated plasma terfenadine levels. At these elevated levels, 

terfenadine can delay cardiac repolarization (prolong the 

electrocardiographic <QT> interval) because of its effects on cardiac 

potassium channels. The delayed cardiac repolarization increases the 

risk of serious ventricular tachyarrhythmias, most characteristically a 

kind of ventricular tachycardia called torsades de pointes. This 

arrhythmia can cause dizziness and syncope when it is short-lived, but 

it may persist and degenerate into unstable ventricular tachycardia or 

ventricular fibrillation. Ventricular fibrillation is fatal if not 

promptly reversed. These serious and possibly fatal events can occur at 

the recommended dose of terfenadine if it is taken along with other 

medications that interfere with its metabolism or if it is administered 

to someone with significant hepatic dysfunction. 

In an effort to inform the medical and patient communities about 

the serious and potentially fatal cardiac adverse effects associated 

with inappropriate use of terfenadine, the labeling for Seldane and 

Seldane-D have been revised many times. In 1992, terfenadine labeling 

was revised to include a prominent boxed warning cautioning against its 

use in certain settings, particularly with the drugs that inhibit its 

metabolism. In addition, ``Dear Health Care Professional'' letters 

warning health care practitioners of the serious risk of inappropriate 

use of terfenadine were issued by the sponsor in 1990, 1992, and 1996. 

Although the revised labeling and ``Dear Health Care Professional'' 

letters have significantly reduced the inappropriate prescribing of 

terfenadine together with the drugs that block its metabolism, such 

prescribing and dispensing has not been eliminated and almost certainly 

cannot be. Three recently published studies indicate that 

coprescription and codispensing of medications contraindicated with 

terfenadine continues to occur (Refs. 1, 2, and 3). The Cavuto study 

also demonstrates that the computerized drug-interaction screening 

programs used by many pharmacists, who are the last line of defense 

against prescribing errors, do not completely prevent prescribing and 

filling of prescriptions for potentially dangerous combinations of 

terfenadine and contraindicated drugs. 

Terfenadine is an antihistamine that is intended to be used when 

symptoms of seasonal allergic rhinitis occur. Patients often do not 

consume all of the pills they receive in a prescription of terfenadine 

for a single episode of seasonal allergic rhinitis, and may keep the 

remaining pills for later use when needed, as patients often do with 

over-the-counter antihistamines. Because of the nature of seasonal 

allergies, a long period of time (e.g., from early fall to spring) can 

elapse between the time the drug and any associated warning from a 

health care practitioner or pharmacist is received and the time 

terfenadine is used. Such intermittent dosing of terfenadine increases 

the probability that some patients may be taking one of the 

contraindicated medications, such as one of the frequently prescribed 

antimicrobials listed above, at the same time the patient self- 

diagnoses his or her seasonal allergy symptoms and takes the remaining 

terfenadine from the pill container in the medicine chest. 

This problem of concomitant use is further compounded by the 

growing list of medications known to inhibit the metabolism of 

terfenadine, many of which are taken for chronic medical conditions and 

may be prescribed by health care practitioners other than the 

practitioner who prescribed the terfenadine. Labeling changes and even 

perfect performance by prescribers and close attention by pharmacists, 

therefore, cannot completely eliminate the risks of serious cardiac 

adverse events associated with the inappropriate use of terfenadine. 

Very low to undetectable blood levels of parent terfenadine are 

found in patients taking the recommended dose of terfenadine. For this 

reason, parent terfenadine appears to have very little, if any, impact 

on the therapeutic efficacy that is associated with terfenadine use. 

The discovery of terfenadine's ability to delay cardiac 

repolarization and its associations with serious and sometimes fatal 

cardiac adverse events when used inappropriately led to evaluation of 

its principal active metabolite as a potentially safer alternative 

antihistamine. It was discovered that the metabolite that is 

responsible for the desired therapeutic effect of terfenadine, 

<fexofenadine>, does not affect cardiac potassium channels. The agency, 

therefore, encouraged HMR to initiate the development of a drug product 

with only the active metabolite <fexofenadine> as the active 

antihistamine. Even at doses considerably in excess of those 

recommended for use, <fexofenadine> hydrochloride has not been shown to 

prolong the <QT> interval. It therefore should not have, and has not been 

shown to have, the serious cardiovascular adverse events potentially 

associated with unmetabolized terfenadine. No new 

[[Page 1891]] 

adverse reaction, not already associated with terfenadine, would be 

expected because the many people who have taken terfenadine have been, 

in fact, exposed primarily to <fexofenadine> manufactured by their body. 

An NDA for <fexofenadine> hydrochloride was approved by FDA on July 

25, 1996. Nearly 5 months of marketing of this product in the United 

States have not resulted in any reports of serious cardiac arrhythmias. 

Prior to the approval of <fexofenadine> hydrochloride, the agency 

considered terfenadine to be safe (i.e., its benefits outweighed its 

risks) despite terfenadine's known serious adverse effects when its 

metabolism was blocked and despite the availability of alternative 

antihistamines that, like terfenadine, were not associated with greater 

somnolence than placebo in clinical trials. This is because the agency 

recognizes that responses to drugs are not uniform among individuals 

and, for reasons that are often unclear and difficult to discover, some 

patients may respond better, with respect to therapeutic effectiveness 

or tolerance, to one drug than to another. Terfenadine certainly 

provided a unique therapeutic benefit when it was the only available 

antihistamine that was not associated with more somnolence than placebo 

in clinical trials, and it continued to provide a benefit and choice to 

patients even after the approval of astemizole and loratadine (e.g., 

some patients may have found that terfenadine provided some advantage 

over either of the other two products or may have been unable to 

tolerate the alternative medications for a variety of medical reasons, 

including drug allergy). So long as terfenadine represented a unique 

molecule, the agency concluded that terfenadine's risks, which had been 

greatly reduced by labeling changes and public awareness, were 

acceptable in light of its benefits. It is only now, when there is an 

alternative that is identical to the molecule that provides the 

therapeutic benefits of terfenadine, that terfenadine's benefits do not 

outweigh its risks. This is because essentially all of its benefits can 

be obtained with <fexofenadine> hydrochloride without the cardiovascular 

risk caused by <QT> prolongation. 

Currently, there is no combination of <fexofenadine> hydrochloride 

and pseudoephedrine approved for marketing in the United States. 

Although the absence of a <fexofenadine> hydrochloride/pseudoephedrine 

combination product may be inconvenient for patients currently taking 

Seldane-D, there are available over-the-counter extended-release 

pseudoephedrine 120 mg products that could be taken with <fexofenadine> 

hydrochloride to provide symptomatic relief comparable to that provided 

by Seldane-D for the treatment of seasonal allergic rhinitis. The minor 

inconvenience to patients of having to take separate <fexofenadine> 

hydrochloride and extended-release pseudoephedrine doses is more than 

offset by the cardiac safety advantage of <fexofenadine> hydrochloride 

over terfenadine. 

Accordingly, the Director of the Center for Drug Evaluation and 

Research concludes with respect to NDA 18-949 (terfenadine 60 mg) that: 

(1) Prior to the approval of <fexofenadine> hydrochloride, terfenadine 

provided a unique therapeutic alternative for which the risks 

associated with the use of terfenadine were acceptable; (2) terfenadine 

provides no therapeutic benefit to any patient population that is not 

also provided by <fexofenadine> hydrochloride, because <fexofenadine> 

hydrochloride is identical in molecular structure to terfenadine's 

therapeutically active metabolite; (3) current data demonstrate that 

<fexofenadine> hydrochloride lacks the serious cardiovascular risks 

associated with misuse of terfenadine, and approximately 5 months of 

marketing experience with <fexofenadine> hydrochloride in the United 

States has not resulted in any reports of serious cardiac arrythmias; 

(4) despite the many interventions undertaken by the agency and by HMR 

(three ``Dear Health Care Professional'' letters, multiple labeling 

changes, and extensive education campaigns), residual coprescribing, 

codispensing, and concomitant use of terfenadine with a growing list of 

medications that inhibit its metabolism continues and cannot be 

expected to be completely eliminated; and (5) terfenadine, therefore, 

is no longer shown to be safe for use under the conditions that formed 

the basis upon which the application was initially approved. The 

Director also finds that ANDA 74-475 refers to NDA 18-949 (Seldane, 60 

mg terfenadine oral tablets) as the listed drug. The Director further 

finds that the conclusions set out above for NDA 18-949 apply with 

respect to NDA 19-664 (terfenadine 60 mg and pseudoephedrine 120 mg), 

and that the inconvenience to patients of taking separate doses of 

<fexofenadine> hydrochloride and extended-release pseudoephedrine is more 

than offset by the cardiac safety advantage of <fexofenadine 

hydrochloride over terfenadine. The Director is proposing to withdraw 

approval of NDA 18-949 and NDA 19-664 in accordance with section 

505(e)(2) of the Federal Food, Drug, and Cosmetic Act (the act) (21 

U.S.C. 355(e)(2)). The Director is proposing to withdraw approval of 

ANDA 74-475 in accordance with section 505(j)(5) of the act. 

II. Notice of Opportunity for a Hearing 

The Director has evaluated the information discussed above and, on 

the grounds stated, is proposing to withdraw approval of NDA 18-949, 

NDA 19-664, and ANDA 74-475. Therefore, notice is given to HMR and 

Baker Norton Pharmaceuticals, Inc. that the Director proposes to issue 

an order under section 505(e)(2) of the act, withdrawing approval of 

NDA 18-949 and NDA 19-664, and all amendments and supplements thereto, 

and under section 505(j)(5) of the act, withdrawing approval of ANDA 

74-475, and all amendments and supplements thereto. The Director finds 

that new evidence of clinical experience, not contained in NDA 18-949 

and NDA 19-664 or not available to the Director until after the 

applications were approved, evaluated together with the evidence 

available to the Director when the applications were approved, shows 

that terfenadine is not shown to be safe for use under the conditions 

which formed the basis upon which the applications were approved. The 

Director also finds that ANDA 74-475 refers to the drug that is the 

subject of NDA 18-949. 

In accordance with section 505 of the act and part 314 (21 CFR part 

314), HMR and Baker Norton Pharmaceuticals, Inc. are hereby given an 

opportunity for a hearing to show why approval of the NDA's should not 

be withdrawn. 

An applicant who decides to seek a hearing shall file: (1) On or 

before February 13, 1997, a written notice of appearance and request 

for hearing, and (2) on or before March 17, 1997, the data, 

information, and analyses relied on to demonstrate that there is a 

genuine issue of material fact to justify a hearing, as specified in 

Sec. 314.200. Any other interested person may also submit comments on 

this notice. The procedures and requirements governing this notice of 

opportunity for a hearing, a notice of appearance and request for a 

hearing, information and analyses to justify a hearing, other comments, 

and a grant or denial of a hearing are contained in Secs. 314.151 and 

314.200, and in 21 CFR part 12. 

The failure of an applicant to file a timely written notice of 

appearance and request for hearing, as required by Sec. 314.200, 

constitutes an election by that person not to use the opportunity for a 

[[Page 1892]] 

hearing concerning the action proposed and a waiver of any contentions 

concerning the legal status of that person's drug products. Any new 

drug product marketed without an approved new drug application is 

subject to regulatory action at any time. 

III. References 

The following references have been placed on display in the Dockets 

Management Branch (address above) and may be seen by interested persons 

between 9 a.m. and 4 p.m., Monday through Friday. 

1. Thompson, D., and G. Oster, ``Use of Terfenadine and 

Contraindicated Drugs,'' Journal of the American Medical 

Association, 275(17):1339-1341, 1996. 

2. Cavuto, N. J., R. L. Woosley, and M. Sale, ``Pharmacies and 

Prevention of Potentially Fatal Drug Interactions'' (letter), 

Journal of the American Medical Association, 275(14):1086-1087, 

1996. 

3. Carlson, A. M., and L. S. Morris, ``Coprescription of 

Terfenadine and Erythromycin and Ketoconazole: An Assessment of 

Potential Harm,'' Journal of the American Pharmaceutical 

Association, NS36(4):263-269, 1996. 

A request for a hearing may not rest upon mere allegations or 

denials, but must present specific facts showing that there is a 

genuine and substantial issue of fact that requires a hearing. If it 

conclusively appears from the face of the data, information, and 

factual analyses in the request for a hearing that there is no genuine 

and substantial issue of fact that precludes the withdrawal of approval 

of the applications, or when a request for hearing is not made in the 

required format or with the required analyses, the Commissioner of Food 

and Drugs will enter summary judgment against the person who requests 

the hearing, making findings and conclusions, and denying a hearing. 

All submissions pursuant to this notice of opportunity for a 

hearing are to be filed in four copies. Except for data and information 

prohibited from public disclosure under 21 U.S.C. 331(j) or 18 U.S.C. 

1905, the submissions may be seen in the Dockets Management Branch 

(address above) between 9 a.m. and 4 p.m., Monday through Friday. 

This notice is issued under the Federal Food, Drug, and Cosmetic 

Act (sec. 505 (21 U.S.C. 355)) and under authority delegated to the 

Director of the Center for Drug Evaluation and Research (21 CFR 5.82). 

Dated: January 7, 1997. 

Janet Woodcock, 

Director, Center for Drug Evaluation and Research. 

[FR Doc. 97-714 Filed 1-10-97; 8:45 am] 

BILLING CODE 4160-01-F 

======================================================================= 

27.) Non-sedating antihistamines and cardiac arrhythmia 

======================================================================= 

Andrew C Rankin 

Non-sedating antihistamines are a widely used treatment for seasonal 

allergic rhinitis. Since the late 1980s there have been concerns about 

cardiotoxicity with reports of life-threatening cardiac arrhythmia, first 

with astemizole1 and later with terfenadine.2 Attention has focused on 

terfenadine, which had been the most widely used. Its safety is under 

review within the European Union and its withdrawal has been 

proposed by the US Food and Drug Administration. Initial concern 

that the cardiotoxicity was a class effect of non-sedating 

antihistamines has proved unfounded, since fexofenadine, the active 

metabolite that mediates the antihistamine actions of terfenadine, does 

not have its cardiac actions.3 

The arrhythmia reported in association with astemizole and 

terfenadine was a polymorphic ventricular tachycardia, termed 

"torsades de pointes" because of the changing electrical axis on the 

electrocardiogram. This potentially fatal arrhythmia is associated with 

prolongation of the QT interval on the surface electrocardiogram 

during sinus rhythm. Long-QT syndromes may be inherited or 

acquired. The acquired forms are most commonly due to drug 

actions or electrolyte disturbance. At the cellular level, the 

QT-interval prolongation is associated with an increase in the 

duration of the cardiac action potential, which in turn can be ascribed 

to alterations in ionic currents, in particular those carried by 

potassium ions.4 

Terfenadine is a pro-drug. Torsades de pointes has occurred when 

there has been increased plasma concentrations of the pro-drug, 

either due to overdose or reduced hepatic metabolism. The first 

reported case of torsades de pointes associated with terfenadine at 

normal dosage was of a young woman with sinusitis who also 

self-prescribed ketoconazole for vaginal candidosis.2 The imidazole 

antifungals ketoconazole and itraconazole inhibit the cytochrome 

P-450, which is responsible for hepatic oxidative metabolism of 

terfenadine, resulting in accumulation of the pro-drug. The macrolide 

antibiotics erythromycin and clarithromycin also inhibit this 

metabolism, as does grapefruit juice. Terfenadine, at the 

recommended dose of 120 mg daily, can lengthen the QT interval 

slightly,5 but concomitant oral ketoconazole produced marked 

QT-interval prolongation that correlated with the increased plasma 

concentrations of unmetabolished terfenadine.6 Thus, the drug 

interaction increased the risk of arrhythmia. 

The ionic mechanism underlying the QT interval prolongation has 

been elucidated by in-vitro studies. Terfenadine, but not its 

metabolite, blocked ventricular potassium channels, particularly the 

rapidly activating component of the delayed rectifier,3,7 including such 

potassium channels cloned from human heart.8 This 

potassium-channel blockade increased the duration of the action 

potential and the QT interval.7 Other antihistamines have been less 

extensively studied but astemizole also blocked potassium channels 

and prolonged the QT interval,7 whereas loratidine or cetirizine 

(which have been linked to cardiac and sudden deaths9) did not.1 

Despite evidence for a mechanism whereby this widely used 

treatment for hay fever may cause ventricular arrhythmia or sudden 

death, it has remained freely available because the observed risk with 

terfenadine use is very low. An observational cohort evaluation of 

over 500 000 Medicaid recipients showed no evidence of an 

excessive risk of life-threatening ventricular arrhythmia with 

terfenadine, and found the risk to be less than that observed with 

over-the-counter sedating antihistamines or with ibuprofen, selected 

for comparison because of absence of known cardiac arrhythmic 

toxicity.10 However, the increased risk of terfenadine with 

concomitant ketoconazole or erythromycin was confirmed. The 

concurrent use of terfenadine and contraindicated drugs has declined 

since the medical profession was altered to the problem in the early 

1990s, but continues to occur.11 Over-the-counter availability makes 

the regulation of concurrent drug use difficult to enforce. There is the 

additional concern about (the few) individuals with undiagnosed 

hereditary long-QT syndrome who are at risk from any factor that 

further prolongs the QT interval. 

The risk of cardiac arrhythmia with non-sedating antihistamines has 

now been clarified, and can be minimised with suitable precautions 

such as avoiding specific drug interactions. In the UK, concern that 

this could be achieved only with medical supervision has prompted a 

change to prescription-only use of terfenadine. All drug treatments 

have potential side-effects but risk of death from a self-prescribed 

treatment for hay fever was unacceptable. Despite the low absolute 

risk, it is prudent to recommend the use of alternative non-sedating 

antihistamines that do not have a proven proarrhythmic potential. 

===================================================================== 

28.) FEXOFENADINE (Systemic)&frac34;Introductory Version 

===================================================================== 

VA CLASSIFICATION (Primary/Secondary)&frac34;AH900 

Commonly used brand name(s): 

Allegra. 

Note: For a listing of dosage forms and brand names by country 

availability, see Dosage Forms section(s). 

Category 

Antihistaminic (H1-receptor). 

Indications 

Accepted 

Rhinitis, seasonal allergic (treatment)&frac34;Fexofenadine is indicated to 

relieve symptoms that are associated with seasonal allergic rhinitis, such 

as sneezing; rhinorrhea; itchy eyes, nose, and throat; and red, watery eyes1. 

Pharmacology/Pharmacokinetics 

Physicochemical characteristics: 

Chemical group&frac34;Metabolite of terfenadine1. 

Molecular weight&frac34; 

538.13 

Mechanism of action/Effect: 

Fexofenadine is an antihistamine with selective peripheral H1-receptor 

antagonist activity. It inhibits antigen-induced bronchospasm in sensitized 

guinea pigs and histamine release from peritoneal mast cells in rats.1 

Absorption: 

Rapid following oral administration1. 

Distribution: 

Tissue distribution studies in rats using radiolabeled fexofenadine show 

that it does not cross the blood-brain barrier1. 

Protein binding: 

60 to 70% bound primarily to albumin and alpha1-glycoprotein1. 

Biotransformation: 

About 5% of the total dose is metabolized1; approximately 0.5 to 1.5% by 

hepatic metabolism and 3.5% by intestinal microflora. 

Half-life: 

Elimination: 14.4 hours in healthy subjects; in patients with mild renal 

impairment (creatinine clearance of 41 to 80 mL per minute) and severe 

renal impairment (creatinine clearance of 11 to 40 mL per minute), the mean 

elimination half-life was 59% and 72% longer, respectively, than in healthy 

subjects. In patients on dialysis, half-life was 31% longer than in healthy 

subjects1. 

Onset of action: 

Within 1 hour, as determined by a reduction in rhinitis symptoms following 

administration of a single 60-mg dose to patients exposed to ragweed pollen 

and by human histamine skin wheal and flare studies following 

administration of single and twice-daily doses of 20 and 40 mg of 

fexofenadine1. 

Time to peak effect: 

2 to 3 hours, as determined by human histamine skin wheal and flare studies 

following administration of single and twice-daily doses of 20 and 40 mg of 

fexofenadine1. 

Duration of action: 

Effect evident 12 hours after administration, as determined by clinical 

studies in patients with seasonal allergic rhinitis given a single 60-mg 

dose, and by human histamine skin wheal and flare studies in patients given 

single and twice-daily doses of 20 and 40 mg of fexofenadine1. 

Note: Tolerance to the antihistamine effect of fexofenadine was not 

demonstrated following 28 days of dosing1. 

Elimination: 

Approximately 80% and 11% of a radioactive fexofenadine dose is excreted in 

the feces and urine, respectively1. 

Precautions to Consider 

Carcinogenicity 

Fexofenadine showed no carcinogenic potential in 18- and 24-month studies 

in mice and rats given oral terfenadine doses of 50 and 150 mg per kg of 

body weight (mg/kg) per day, respectively. These doses resulted in area 

under the plasma concentration-time curve (AUC) values for fexofenadine of 

up to four times the human therapeutic value based on the recommended dosage1. 

Mutagenicity 

Fexofenadine was not mutagenic in in vitrobacterial or animal studies and 

in vivo animal studies1. 

Pregnancy/Reproduction 

Fertility&frac34;Dose-related reductions in implants and increases in 

postimplantation losses were seen in rats given oral doses of terfenadine &sup3; 

150 mg/kg. These doses resulted in AUC values for fexofenadine of up to 

three times the human therapeutic value based on the recommended dosage1. 

Pregnancy&frac34;Adequate and well-controlled studies in humans have not been done1. 

Fexofenadine was not teratogenic in studies in which rats or rabbits were 

given oral doses of terfenadine of up to 300 mg/kg per day. These doses 

resulted in AUC values for fexofenadine of up to 4 and 37 times the human 

therapeutic value based on the recommended dosage, respectively.1 

In rats given oral doses of terfenadine &sup3; 150 mg/kg, dose-related decreases 

in pup weight and survival were observed. These doses resulted in AUC 

values for fexofenadine of three or more times the human therapeutic value 

based on the recommended dosage, respectively1. 

FDA Pregnancy Category C1. 

Breast-feeding 

It is not known whether fexofenadine is distributed into breast milk1. 

Pediatrics 

In clinical trials, 205 children 12 to 16 years of age have been safely 

treated with fexofenadine for up to 2 weeks; adverse effects were similar 

to those occurring in patients older than 16 years. However, the safety and 

efficacy of fexofenadine in children up to 12 years of age has not been 

established.1 

Geriatrics 

In patients 65 years of age and older, peak plasma concentrations of 

fexofenadine were 99% greater than those in healthy subjects younger than 

65 years of age. Mean elimination half-lives were similar in the two 

groups. Adverse effects were similar to those occurring in patients up to 

60 years of age.1 

Drug interactions and/or related problems 

Note: In two studies involving 24 healthy subjects each, no differences in 

adverse events or QTc interval were seen when 120 mg of fexofenadine two 

times a day was administered concurrently with 500 mg of erythromycin every 

eight hours or 400 mg of ketoconazole once a day under steady-state 

conditions.1 

Medical considerations/Contraindications 

The medical considerations/contraindications included have been selected on 

the basis of their potential clinical significance (reasons given in 

parentheses where appropriate)&frac34;not necessarily inclusive (>> = major 

clinical significance). 

Risk-benefit should be considered when the following medical problems exist 

>> Renal function impairment&frac34;based upon increases in the half-life of 

fexofenadine, once-daily administration is recommended initially in 

patients with impaired renal function 

1 

Hypersensitivity to fexofenadine&frac34; 

Side/Adverse Effects 

The following side/adverse effects have been selected on the basis of their 

potential clinical significance (possible signs and symptoms in parentheses 

where appropriate)&frac34;not necessarily inclusive: 

Those indicating need for medical attention only if they continue or are 

bothersome 

Incidence less frequent&frac34;(&pound; 2.5% but more common with fexofenadine than with 

placebo)1Drowsiness1; dysmenorrhea1 (painful menstrual bleeding); 

dyspepsia1 (stomach upset); fatigue1 (unusual feeling of tiredness) 

Patient Consultation 

In providing consultation, consider emphasizing the following selected 

information (>> = major clinical significance): 

Before using this medication 

>> Conditions affecting use, especially: 

Hypersensitivity to fexofenadine 

Other medical problems, especially renal function impairment 

Proper use of this medication 

>> Proper dosingMissed doseIf used regularly&frac34;using as soon as possible; 

using any remaining doses for that day at regularly spaced intervals; not 

doubling doses 

>> Proper storage 

Side/adverse effects 

Signs of potential side effects, especially drowsiness, dysmenorrhea, 

dyspepsia, and fatigue 

Oral Dosage Forms 

Fexofenadine Hydrochloride Capsules 

Usual adult and adolescent dose 

Antihistaminic (H1-receptor)&frac34; 

Oral, 60 mg two times a day1. 

Note: For patients with decreased renal function, an initial dose of 60 mg 

once a day is recommended1. 

Usual adult and adolescent prescribing limits 

60 mg two times a day1. 

Usual pediatric dose 

Antihistaminic (H1-receptor)&frac34; 

Children up to 12 years of age: Safety and efficacy have not been determined1. 

Children 12 years of age and older: See Usual adult and adolescent dose1. 

Usual geriatric dose 

Antihistaminic (H1-receptor)&frac34; 

See Usual adult and adolescent dose1. 

Strength(s) usually available 

U.S.&frac34; 

60 mg (Rx)[Allegra]. 

Packaging and storage: 

Store at controlled room temperature, between 20 and 25 &deg;C (68 and 77 &deg;F). 

Protect from moisture.1 

References 

1Allegra package insert (Hoechst Marion Roussel&frac34;US), Rev 7/96. 

==================================================================== 

DATA-MÉDICOS/DERMAGIC-EXPRESS No (64) 07/07/99 DR. JOSE LAPENTA R. 

==================================================================== 

Produced by Dr. José Lapenta R. Dermatologist
Venezuela 1.998-2.024

Producido por Dr. José Lapenta R. Dermatólogo Venezuela 1.998-2.0024

Tlf: 0414-2976087 - 04127766810