Data-Medicos 
Dermagic/Express No. 65 
14 Julio 1.999. 14 July 1.999. 

~ La fexofenadina y el intervalo QT ~ 
~The Fexofenadine and the QT interval~ 

EDITORIAL ESPANOL 
================= 
Hola amigos Dermagicos, la FEXOFENADINA, metabolito activo de la terfenadina aprobado para su mercadeo en 1.997 y recientemente introducido en Venezuela ha demostrado ser uno de los nuevos antihistaminicos 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 generacion de antihistaminicos el ASTEMIZOL, TERBINAFINA Y EBASTINA estan asociado a arritmias cardiacas. Estas 28 referencias nos ILUSTRAN sobre la fexofenadina y otros Antihistaminicos y sus efectos. Al final una monografia del producto Allegra. 


Saludos a todos !!! 

Dr. Jose Lapenta R.,,, 

EDITORIAL ENGLISH 
================= 
Hello Dermagic friends, the FEXOFENADINA, active metabolite of the terfenadine approved for 
their marketing in 1.997 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 ASTEMIZOL, TERBINAFINE AND EBASTINE are associated to heart arrhythmias. These 28 references ILLUSTRATE us on the fexofenadina, the Antihistamines and their effects. At the end a monograph of the product Allegra. 

Greetings to ALL, !! 
Dr. Jose Lapenta R.,,, 
==================================================================== 
REFERENCIAS BIBLIOGRAFICAS / BIBLIOGRAPHICAL REFERENCES 
==================================================================== 
===================================================================== 
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 
===================================================================== 
===================================================================== 
1.) The efficacy and safety of fexofenadine HCl and pseudoephedrine, alone 
and in combination, in seasonal allergic rhinitis. 
===================================================================== 
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). 

===================================================================== 
2.) Cardiovascular safety of second-generation antihistamines. 
===================================================================== 
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. 

===================================================================== 
3.) Clinical pharmacology of new histamine H1 receptor antagonists. 
===================================================================== 
Clin Pharmacokinet 1999 May;36(5):329-52 

Simons FE, Simons KJ 
Faculty of Medicine, University of Manitoba, Winnipeg, Canada. 
[email protected] 

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. 

===================================================================== 
4.) QT lengthening and arrhythmias associated with fexofenadine. 
Lancet 1999 Jun 12;353(9169):2072-3 Giraud T 
Letter 
===================================================================== 
===================================================================== 
5.) Comparison of the effects of terfenadine with fexofenadine on nasal 
provocation tests with allergen. 
===================================================================== 
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. 

===================================================================== 
6.) Comparative tolerability of second generation antihistamines. 
===================================================================== 
Drug Saf 1999 May;20(5):385-401 

Horak F, Stubner UP 
ENT-Clinic, University of Vienna, Austria. [email protected] 

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. 

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

===================================================================== 
8.) Cardiovascular safety of fexofenadine HCl. 
===================================================================== 
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. 

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

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

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

===================================================================== 
12.) Terfenadine and fexofenadine reduce in vitro ICAM-1 expression on 
human continuous cell lines. 
===================================================================== 
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. [email protected] 

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. [email protected] 
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-MEDICOS/DERMAGIC-EXPRESS No (64) 07/07/99 DR. JOSE LAPENTA R. 
==================================================================== 

Produced by Dr. Jose Lapenta R. Dermatologist 
                 Maracay Estado Aragua Venezuela 1.999 
           Telf: 0416-6401045- 02432327287-02432328571