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The Fexofenadine
and the QT interval. La Fexofenadina y el intervalo QT.
********************************** EDITORIAL ESPAÑOL: ===================== Hola amigos Dermagicos, LA FEXOFENADINA, es el metabolito activo de la terfenadinA aprobado para su mercadeo en 1.997 y recientemente introducido en Venezuela. Ha demostrado ser uno de los nuevos antihistamínicos "aparentemente" no asociado a trastornos cardiacos, principalmente arritmias, pero: The Lancet en JUNIO de 1.999 publica efectos de la fexofenadina en el intervalo QT (alargamiento). Leer referencia 0.) De la nueva generación de antihistamínicos el ASTEMIZOL, TERFENADINA Y EBASTINA están asociado a arritmias cardiacas. Recordemos que la TERFENADINA de quien DERIVA LA FEXOFENADINA fue RETIRADA DEL MERCADO MUNDIAL EL 27 DE FEBRERO DE 1998, por causar ARRITMIAS CARDIACAS GRAVES (TORSADES DE POINTS) y MUERTE. Y en 1999 el ASTEMIZOL también fue sacado del mercado mundial por producir los mismos efectos dañinos al corazón. Estas 28 referencias nos ILUSTRAN sobre la fexofenadina y otros Antihistamínicos y sus efectos. Al final una Monografía del producto Allegra. (FEXOFENADINA). Saludos a todos !!! Dr. José 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 proven to be one of the new antihistamines "apparently" not associated with cardiac disorders, primarily arrhythmias, but: The Lancet in June 1999 published the effects of FEXOFENADINE on the QT interval (lengthening). Read reference 0.) Of the new generation of antihistamines, ASTEMIZOLE, TERFENADINE and EBASTINE are associated with cardiac arrhythmias. Remember that TERFENADINE, from which FEXOFENADINE is derived, was withdrawn from the global market on February 27, 1998, for causing severe cardiac arrhythmias (torsades de pointes) and death. And in 1999, astemizole was also withdrawn from the global market for producing the same harmful effects on the heart. These 28 references enlighten us about fexofenadine and other antihistamines and their effects. Finally, a monograph on the AlLEGRA product. (FEXOFENADINE). Greetings to ALL, !! Dr. José Lapenta R.,,, ================================================================ DERMAGIC/EXPRESS(62) ================================================================ REFERENCIAS BIBLIOGRÁFICAS / BIBLIOGRAPHICAL REFERENCES ================================================================ 0.) QT lengthening and life-threatening arrhythmias associated with fexofenadine. 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);Introductory 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. ===================================================================== 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) ; Introductory Version ===================================================================== VA CLASSIFICATION (Primary/Secondary);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);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;Metabolite of terfenadine1. Molecular weight: 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 ;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 ;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);not necessarily inclusive (>> = major clinical significance). Risk-benefit should be considered when the following medical problems exist >> Renal function impairment ;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; 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);not necessarily inclusive: Those indicating need for medical attention only if they continue or are bothersome Incidence less frequent; (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;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); 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); 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; See Usual adult and adolescent dose1. Strength(s) usually available U.S.; 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;US), Rev 7/96. ==================================================================== DATA-MÉDICOS/DERMAGIC-EXPRESS No (62) 14/07/99 DR. JOSÉ LAPENTA R. ==================================================================== |
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Produced by Dr. José Lapenta R.
Dermatologist
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