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D01KPV
PharmaCompass
D01KPV
Also known as: 83799-24-0, Carboxyterfenadine, Terfenadine carboxylate, Terfenadine-cooh, Terfenadine acid metabolite, Allegra
Molecular Formula
C32H39NO4
Molecular Weight
501.667  g/mol
InChI Key
RWTNPBWLLIMQHL-UHFFFAOYSA-N
FDA UNII
E6582LOH6V

Fexofenadine hydrochloride (Allegra) is an antihistamine drug used in the treatment of hayfever and similar allergy symptoms. It was developed as a successor of and alternative to terfenadine. Fexofenadine, like other second and third-generation antihistamines, does not readily pass through the blood-brain barrier, and so causes less drowsiness than first-generation histamine-receptor antagonists.
1 2D Structure

2 Identification
2.1 Computed Descriptors
2.1.1 IUPAC Name
2-[4-[1-hydroxy-4-[4-[hydroxy(diphenyl)methyl]piperidin-1-yl]butyl]phenyl]-2-methylpropanoic acid
2.1.2 InChI
InChI=1S/C32H39NO4/c1-31(2,30(35)36)25-17-15-24(16-18-25)29(34)14-9-21-33-22-19-28(20-23-33)32(37,26-10-5-3-6-11-26)27-12-7-4-8-13-27/h3-8,10-13,15-18,28-29,34,37H,9,14,19-23H2,1-2H3,(H,35,36)
2.1.3 InChI Key
RWTNPBWLLIMQHL-UHFFFAOYSA-N
2.1.4 Canonical SMILES
CC(C)(C1=CC=C(C=C1)C(CCCN2CCC(CC2)C(C3=CC=CC=C3)(C4=CC=CC=C4)O)O)C(=O)O
2.2 Other Identifiers
2.2.1 UNII
E6582LOH6V
2.3 Synonyms
2.3.1 Depositor-Supplied Synonyms

1. 83799-24-0

2. Carboxyterfenadine

3. Terfenadine Carboxylate

4. Terfenadine-cooh

5. Terfenadine Acid Metabolite

6. Allegra

7. Fexofendine

8. Fexofenadine [inn:ban]

9. Mdl 16455

10. Telfast (tn)

11. Telfast

12. Fexofenadine (inn)

13. Hsdb 7486

14. Chembl914

15. 2-(4-(1-hydroxy-4-(4-(hydroxydiphenylmethyl)piperidin-1-yl)butyl)phenyl)-2-methylpropanoic Acid

16. Chebi:5050

17. 4-(1-hydroxy-4-(4-(hydroxydiphenylmethyl)-1-piperidinyl)butyl)-alpha,alpha-dimethylbenzeneacetic Acid

18. Rwtnpbwllimqhl-uhfffaoysa-n

19. Terfenidine Carboxylate, Mdl 16455

20. Ak-75768

21. Allegra (tn)

22. F 9427

23. Allegra-d 12 Hour

24. 2-(4-{1-hydroxy-4-[4-(hydroxydiphenylmethyl)piperidin-1-yl]butyl}phenyl)-2-methylpropanoic Acid

25. 2-[4-(1-hydroxy-4-{4-[hydroxy(diphenyl)methyl]piperidin-1-yl}butyl)phenyl]-2-methylpropanoic Acid

26. Q-201113

27. 139965-10-9

28. 2-[4-[1-hydroxy-4-[4-[hydroxy(diphenyl)methyl]-1-piperidyl]butyl]phenyl]-2-methyl-propanoic Acid

29. 2-[4-[1-hydroxy-4-[4-[hydroxy(diphenyl)methyl]piperidin-1-yl]butyl]phenyl]-2-methylpropanoic Acid

30. Benzeneacetic Acid, 4-(1-hydroxy-4-(4-(hydroxydiphenylmethyl)-1-piperidinyl)butyl)-alpha,alpha-dimethyl-

31. Mdl-16455

32. Ncgc00015453-05

33. 138452-21-8

34. Unii-e6582loh6v

35. Sr-01000075889

36. Fastofen (tn)

37. Tilfur (tn)

38. Spectrum_001914

39. Allegra-d 24 Hour

40. Ac1l1fqb

41. Spectrum2_001179

42. Spectrum3_001921

43. Spectrum4_000204

44. Spectrum5_001474

45. D01kpv

46. Schembl4900

47. Lopac0_000488

48. Bspbio_003521

49. Kbiogr_000807

50. Kbioss_002456

51. Spbio_001197

52. Gtpl4819

53. Stock6s-26154

54. Bdbm22874

55. Ctk8f0592

56. Kbio2_002449

57. Kbio2_005017

58. Kbio2_007585

59. Kbio3_002742

60. Molport-002-508-207

61. Hms3261b17

62. Hms3370c16

63. Tox21_500488

64. Bbl029080

65. Mfcd00871892

66. Stk624102

67. Akos005557315

68. Api0002698

69. Bcp9000683

70. Ccg-204579

71. Db00950

72. Lp00488

73. Mcule-4193800017

74. Va10906

75. Ncgc00015453-03

76. Ncgc00015453-04

77. Ncgc00015453-06

78. Ncgc00092389-02

79. Ncgc00092389-03

80. Ncgc00092389-04

81. Ncgc00261173-01

82. An-35997

83. Cc-28419

84. Ls-28827

85. Sbi-0050472.p002

86. Ax8130353

87. Kb-222040

88. Rt-012680

89. Bg01774111

90. Eu-0100488

91. Ft-0626423

92. St24047207

93. 5315-ep2281815a1

94. 5315-ep2289878a1

95. 5315-ep2295409a1

96. 5315-ep2301933a1

97. 5315-ep2305640a2

98. 5315-ep2308562a2

99. 5315-ep2311827a1

100. 5315-ep2314590a1

101. 5315-ep2371811a2

102. C06999

103. D07958

104. Ab00876239_06

105. Ab00876239_07

106. 439f408

107. 799f240

108. C-22951

109. L000869

110. Sr-01000075889-1

111. Brd-a73368467-003-02-8

112. 2,1,3-benzoxadiazole, 4-(4-methyl-1-piperazinyl)-7-nitro-, 3-oxide

113. (+)-4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-alpha,alpha-dimethylbenzeneacetic-acid

114. 159389-12-5

115. 2-(4-(1-hydroxy-4-(4-(hydroxydiphenylmethyl)-piperidin-1-yl)butyl)phenyl)-2-methylpropanoic Acid

116. 2-[4-(1-hydroxy-4-{4-[hydroxy(diphenyl)methyl]piperidino}butyl)phenyl]-2-methylpropanoic Acid

117. 2-[4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidyl]butyl]phenyl]-2-methyl-propanoic Acid

118. 4-[4-(4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-alpha, Alpha-dimethylbenzeneacetic Acid

119. 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl] -alpha,alpha-dimethylbenzeneacetic Acid

120. 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-alpha,alpha-dimethylbenzeneacetic Acid

121. 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-alpha,alpha-dimethylphenylacetic Acid

122. 4-[4[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-alpha,alpha-dimethylbenzeneacetic Acid

123. 76815-58-2

124. Racemic 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-alpha,alpha-dimethylbenzeneacetic Acid

2.4 Create Date
2005-03-25
3 Chemical and Physical Properties
Molecular Weight 501.667 g/mol
Molecular Formula C32H39NO4
Hydrogen Bond Donor Count3
Hydrogen Bond Acceptor Count5
Rotatable Bond Count10
Exact Mass501.288 g/mol
Monoisotopic Mass501.288 g/mol
Topological Polar Surface Area81 A^2
Heavy Atom Count37
Formal Charge0
Complexity678
Isotope Atom Count0
Defined Atom Stereocenter Count0
Undefined Atom Stereocenter Count1
Defined Bond Stereocenter Count0
Undefined Bond Stereocenter Count0
Covalently Bonded Unit Count1
4 Drug and Medication Information
4.1 Drug Information
1 of 1  
Drug NameALLEGRA
Active IngredientFEXOFENADINE HYDROCHLORIDE
CompanySANOFI AVENTIS US (Application Number: N021963)

4.2 Therapeutic Uses

Histamine H1 antagonists

National Library of Medicine's Medical Subject Headings online file (MeSH, 2006)


Antihistaminic

O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 718


Fexofenadine is indicated to relieve symptoms that are associated with seasonal allergic rhinitis, such as sneezing;rhinorrhea; itchy eyes, nose and throt; and red watery eyes. /Included in US product label/

Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2006., p. 1470


Fexofenadine is indicated for the treatment of uncomplicated skin manifestations of chronic idiopathic urticaria. It significantly reduces pruritus and the number of wheals. /Included in US product label/

Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2006., p. 1470


4.3 Drug Warning

In controlled clinical studies in patients 12 years of age and older with allergic rhinitis receiving oral fexofenadine hydrochloride dosages of 60 mg twice daily or placebo, drowsiness or fatigue occurred in 1.3% of patients, compared with 0.9% of those receiving placebo. In these studies in patients receiving fexofenadine hydrochloride dosages of 180 mg once daily (as conventional tablets) or placebo, headache was reported in 10.6 or 7.5% of patients, respectively. In controlled studies in children 6-11 years of age with seasonal allergic rhinitis receiving fexofenadine hydrochloride dosages of 30 mg twice daily or placebo, headache was reported in 7.2 or 6.6% of patients, respectively, while pain was reported in 2.4 or 0.4% of patients, respectively.

McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 33


Sleep disorder, insomnia, or paroniria has occurred in patients receiving fexofenadine hydrochloride.

McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 33


During controlled clinical studies, nausea and dyspepsia were reported in 1.6 and 1.3%, respectively, of patients receiving oral fexofenadine hydrochloride dosages of 60 mg twice daily versus 1.5 and 0.6%, respectively, of those receiving placebo.

McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 33


Clinical data from over 2000 patients indicate that fexofenadine hydrochloride lacks the cardiotoxic potential of its parent drug terfenadine. In 714 patients with seasonal allergic rhinitis, fexofenadine hydrochloride dosages of 60-240 mg twice daily were not associated with statistically significant mean increases in the QT interval corrected for rate (QTc) in controlled clinical studies. In addition, in 231 healthy individuals, fexofenadine hydrochloride dosages of 240 mg given once daily for 1 year also were not associated with statistically significant increases in the mean QTc. Even at dosages exceeding these (e.g., up to 400 mg twice daily for 6 days in 40 patients, up to 690 mg twice daily for about 1 month in 32 patients, up to 800 mg given in a single dose in 87 patients), statistically significant mean increases in the QTc or other ECG abnormalities have not been reported in healthy adults or patients with seasonal allergic rhinitis.

McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 33


Rash, urticaria, pruritus, and hypersensitivity reactions including angioedema, chest tightness, dyspnea, flushing, or anaphylaxis have been reported rarely in patients receiving fexofenadine hydrochloride.

McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 34


Viral infection (eg, cold, influenza) or dysmenorrhea was reported in 2.5 or 1.5% of patients 12 years of age and older receiving fexofenadine hydrochloride in dosages of 60 mg twice daily, respectively. In controlled clinical studies in adults and children 12 years of age and older receiving fexofenadine hydrochloride dosages of 180 mg once daily or placebo, upper respiratory tract infection was reported in 3.2 or 3.1% of patients, respectively, while back pain was reported in 2.8 or 1.4% of patients, respectively.

McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 34


In controlled studies in children 6-11 years of age with seasonal allergic rhinitis receiving fexofenadine hydrochloride 30 mg twice daily, upper respiratory tract infection, coughing, accidental injury, fever, and otitis media occurred in 4.3, 3.8, 2.9, 2.4, and 2.4% of children, respectively, while these adverse effects were reported in 1.7, 1.3, 1.3, 0.9, and 0%, respectively, in those receiving placebo.

McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 34


In controlled studies in adults and children 12 years and older with chronic idiopathic urticaria receiving fexofenadine hydrochloride dosages of 60 mg twice daily or placebo, both back pain and sinusitis were reported in 2.2 or 1.1% of patients, respectively.

McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 34


Fexofenadine is contraindicated in patients who are hypersensitive to the drug or any ingredient in its formulation.

McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 34


Safety and efficacy of fexofenadine hydrochloride have not been established in children younger than 6 years of age.

McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 34


It is not known if fexofenadine hydrochloride is distributed into breast milk ... Since there are no adequate and controlled studies to date on the use of fexofenadine during lactation in humans and because many drugs are excreted in human milk, the manufacturer states that fexofenadine alone or in fixed combination with pseudoephedrine hydrochloride should be used with caution in nursing women, and a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.

McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 34


FDA Pregnancy Risk Category: C /RISK CANNOT BE RULED OUT. Adequate, well controlled human studies are lacking, and animal studies have shown risk to the fetus or are lacking as well. There is a chance of fetal harm if the drug is given during pregnancy; but the potential benefits may outweigh the potential risk./

Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2006., p. 1471


In clinical trials, dysmenorrhea occurred in 1.5% of patients receivingoral fexofenadine 60 mg twice daily, compared to 0.3% in patients receiving placebo.

Physicians Desk Reference 60th ed, Thomson PDR, Montvale, NJ 2006., p. 2859


To gain insight into possible mechanisms of and predisposing factors for torsades de pointes during terfenadine therapy, spontaneous reports in the US Food and Drug Administration's Spontaneous Reporting System database were examined. Based on the characteristics of the cases, in vitro cardiac electrophysiologic studies were conducted to test the hypothesis that terfenadine, and not its major metabolite, has actions similar to those of quinidine and is responsible for this form of cardiac toxicity. Spontaneous reports from the general medical community. As of April 1, 1992, 25 cases of torsades de pointes had been reported to the Food and Drug Administration's Spontaneous Reporting System. Predisposing factors in these cases indicated that the parent drug /(terfenadine)/, but not its metabolite /(fexofenadine)/, may have actions similar those of quinidine that are responsible for inducing arrhythmia. In vitro studies found that terfenadine is equipotent to quinidine as a blocker of the delayed rectifier potassium current in isolated feline myocytes. The metabolite, terfenadine carboxylate, did not inhibit this potassium current even at concentrations 30 times higher than the concentration of terfenadine producing a half-maximal effect. Since blockade of the potassium channel did not occur with the major metabolite of terfenadine, episodes of torsades de pointes are most likely the result of a quinidine-like action of the parent drug and of factors that impair the normally rapid metabolism of terfenadine. Dosage restriction and awareness of the clinical conditions and drug interactions capable of inhibiting the metabolism of terfenadine are essential for prevention of this serious reaction.

Woosley RL et al; JAMA 269 (12): 1532-6 (1993)


The effect of /fexofenadine/ 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, /the authors/ conclude that fexofenadine HCl has no significant effect on QTc, even at doses > 10-fold higher than that is efficacious for SAR.

Pratt CM et al; Am J Cardiol 83 (10): 1451-4 (1999)


4.4 Drug Indication

For management of Seasonal allergic rhinitis


FDA Label


5 Pharmacology and Biochemistry
5.1 Pharmacology

Fexofenadine is a second-generation, long lasting H1-receptor antagonist (antihistamine) which has a selective and peripheral H1-antagonist action. Histamine is a chemical that causes many of the signs that are part of allergic reactions, such as the swelling of tissues. Histamine is released from histamine-storing cells (mast cells) and attaches to other cells that have receptors for histamine. The attachment of the histamine to the receptors causes the cell to be "activated," releasing other chemicals which produce the effects that we associate with allergy. Fexofenadine blocks one type of receptor for histamine (the H1 receptor) and thus prevents activation of cells by histamine. Unlike most other antihistamines, Fexofenadine does not enter the brain from the blood and, therefore, does not cause drowsiness. Fexofenadine lacks the cardiotoxic potential of terfenadine, since it does not block the potassium channel involved in repolarization of cardiac cells.


Fexofenadine is a second generation, long-lasting selective histamine H1 receptor antagonist with antiinflammatory property. Fexofenadine is a highly selective and reversible competitor at peripheral H1 histamine receptors in the gastrointestinal (GI) tract, blood vessels, and bronchial smooth muscle. This agent interferes with mediators release from mast cells either by inhibiting calcium ion influx across mast cell/basophil plasma membrane or by inhibiting intracellular calcium ion release within the cells. In addition fexofenadine may also inhibit the late-phase allergic reaction by acting on leukotrienes or prostaglandins, or by producing an anti-platelet activating factor effect. Overall, this agent blocks the actions of endogenous histamine, thereby leads to temporary relief of the negative symptoms associated with histamine and achieve effects such as decreased vascular permeability, reduction of pruritus and localized smooth muscle relaxation.


5.2 MeSH Pharmacological Classification

Histamine H1 Antagonists, Non-Sedating

A class of non-sedating drugs that bind to but do not activate histamine receptors (DRUG INVERSE AGONISM), thereby blocking the actions of histamine or histamine agonists. These antihistamines represent a heterogenous group of compounds with differing chemical structures, adverse effects, distribution, and metabolism. Compared to the early (first generation) antihistamines, these non-sedating antihistamines have greater receptor specificity, lower penetration of BLOOD-BRAIN BARRIER, and are less likely to cause drowsiness or psychomotor impairment.


Anti-Allergic Agents

Agents that are used to treat allergic reactions. Most of these drugs act by preventing the release of inflammatory mediators or inhibiting the actions of released mediators on their target cells. (From AMA Drug Evaluations Annual, 1994, p475)


5.3 ATC Code

R - Respiratory system
R06 - Antihistamines for systemic use
R06A - Antihistamines for systemic use
R06AX - Other antihistamines for systemic use
R06AX26 - Fexofenadine


5.4 Absorption, Distribution and Excretion

Absorption

33%


Fexofenadine hydrochloride is rapidly absorbed from the GI tract following oral administration. Following oral administration of two 60-mg fexofenadine hydrochloride capsules, peak plasma concentrations are achieved in about 2.6 hours. Following oral administration of a single 60-mg capsule or 60- or 180-mg conventional tablet in healthy individuals, mean peak plasma concentrations were 131, 142, and 494 ng/mL, respectively. In healthy men, peak plasma concentrations of 167 ng/mL were achieved within 1.42 hours following oral administration of 60-mg fexofenadine hydrochloride doses every 12 hours for 9 doses.

McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 35


Following oral administration of fexofenadine hydrochloride capsules in fasting children (mean age: 8-11.6 years) with a history of allergic rhinitis with or without mild asthma, peak plasma fexofenadine concentrations of about 178 or 286 ng/mL were attained in approximately 2.4 hours after a 30- or 60-mg dose, respectively.

McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 36


Following oral administration of a 60-mg dose of fexofenadine hydrochloride, the AUC was 56% greater in children 7-12 years of age with allergic rhinitis than in healthy adults. Plasma exposure in children receiving 30 mg of fexofenadine hydrochloride is similar to that of adults receiving 60 mg of the drug. Limited data indicate that peak plasma fexofenadine concentrations in adolescents (12-16 years of age) were similar to those in adults, while peak plasma concentrations in geriatric adults (65 years of age and older) were 99% greater than in healthy individuals younger than 65 years of age. AUC also was higher in geriatric adults (65-80 years of age) than in younger adults (19-45 years of age)...

McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 36


Peak plasma concentrations of fexofenadine were 87 and 111% higher in patients with mild (creatinine clearance of 41-80 mL/minute) to severe (creatinine clearance of 11-40 mL/minute) renal impairment, respectively, compared with those observed in healthy adults. In patients undergoing dialysis (creatinine clearance of 10 mL/minute or less), peak plasma concentrations of fexofenadine were 82% higher than in healthy adults.

McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 36


Volume of distribution is 5.4 to 5.8 litrs/kilogram

Thomson/Micromedex. Drug Information for the Health Care Professional. Volume 1, Greenwood Village, CO. 2006., p. 1470


Distribution of fexofenadine into human body tissues and fluids has not been fully elucidated. Following oral administration of fexofenadine hydrochloride in animals, the drug is distributed into the small and large intestines, stomach, pancreas, liver, and kidney. Fexofenadine distributes more extensively into plasma than into blood or saliva. The drug does not appear to cross the blood-brain barrier.

McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 36


It is not known if fexofenadine crosses the placenta or is distributed into breast milk.

McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 36


Fexofenadine is 60-70% bound to plasma proteins, principally albumin and alpha1-acid glycoprotein.

McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 36


Following oral administration of single 30- or 60-mg doses of fexofenadine hydrochloride as capsules in fasting children (mean age: 8-11.6 years), the apparent volume of distribution was about 5.4 or 5.8 L/kg, respectively.

McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 36


Limited data indicate that oral clearance of the drug is 33% lower in females than in males, although renal clearance of the drug appears to be similar in both genders. In addition, oral clearance in geriatric adults (65-80 years of age) was lower than in younger adults (19-45 years of age). Following oral administration of a 30- or 60-mg dose of fexofenadine hydrochloride capsules in fasting children (mean age: 8-11.6 years), clearance rates averaged about 14.4 or 18.4 mL/minute per kg, respectively.

McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 36


Fexofenadine is eliminated principally in feces; however, because the absolute bioavailability of fexofenadine hydrochloride has not been established, it remains to be established whether fecal component represents unabsorbed drug or it is the result of biliary excretion. The drug also is excreted in urine, and approximately 80 and 11-12% of the drug is excreted in feces and urine, respectively.

McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 36


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. 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. 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.

Russell T et al; Clin Pharmacol Ther 64 (6): 612-21 (1998)


5.5 Metabolism/Metabolites

Metabolism

Approximately 5% of the total dose is metabolized, by cytochrome P450 3A4 and by intestinal microflora.


About 5% of a single oral dose of fexofenadine is metabolized.

McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 36


Negligible amounts of fexofenadine (about 0.5-1.5% of a dose) are metabolized in the liver by the cytochrome P-450 microsomal enzyme system to an inactive metabolite, while about 3.5% of a fexofenadine dose is metabolized by a second metabolic pathway (unrelated to the cytochrome P-450 microsomal enzyme system) to the methyl ester derivative of fexofenadine. The methyl ester metabolite of fexofenadine is found only in feces, and it has been suggested that the intestinal flora probably are involved in this metabolism.

McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 36


5.6 Biological Half-Life

14.4 hours


Following oral administration of 60 mg of fexofenadine hydrochloride twice daily in healthy individuals, the mean elimination half-life of the drug at steady state reportedly is about 14.4-14.6 hours; mean elimination half-life reportedly was similar in geriatric adults (65 years of age or older) who received a single 80-mg oral dose of fexofenadine hydrochloride.

McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 36


... Elimination half-life was about 18 hours in fasting children (mean age: 8-11.6 years) who received single oral 30- or 60-mg doses of fexofenadine hydrochloride as capsules.

McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 36


In patients with mild (creatinine clearance of 41-80 mL/minute) to severe (creatinine clearance of 11-40 mL/minute) renal impairment, mean elimination half-lives were 59 and 72% longer than those observed in healthy individuals, respectively.

McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 36


In patients undergoing dialysis (creatinine clearance of 10 mL/minute or less), elimination half-life was 31% longer than in healthy individuals.

McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 36


5.7 Mechanism of Action

Like other H1-blockers, Fexofenadine competes with free histamine for binding at H1-receptors in the GI tract, large blood vessels, and bronchial smooth muscle. This blocks the action of endogenous histamine, which subsequently leads to temporary relief of the negative symptoms (eg. nasal congestion, watery eyes) brought on by histamine. Fexofenadine exhibits no anticholinergic, antidopaminergic, alpha1-adrenergic or beta-adrenergic-receptor blocking effects.


Fexofenadine is a specific, selective, histamine H1-receptor antagonist. ... Fexofenadine has been shown to inhibit histamine release from peritoneal mast cells in rats. Unlike terfenadine, fexofenadine does not block the potassium channel involved in repolarization of cardiac cells (i.e., blockade of the delayed rectifier potassium current IK). As a result, fexofenadine lacks the cardiotoxic potential of terfenadine. Fexofenadine also does not possess appreciable anticholinergic, antidopaminergic, or alpha- or beta-adrenergic blocking effects at usual antihistaminic doses in pharmacologic studies.

McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 35


It has been suggested that the increased safety profile of fexofenadine compared with the parent drug results from the lack of fexofenadine-induced cardiotoxicity in addition to only minimal metabolism of fexofenadine in the liver by the cytochrome P-450 microsomal enzyme system. Evidence from animal models using fexofenadine have suggested that the apparent lack of cardiotoxic effects of the drug may have resulted at least in part from lack of blockade of the potassium channel involved in repolarization of cardiac cells (ie, blockade of the delayed rectifier potassium current IK). Prolongations in the QTc interval were not reported in dogs receiving oral fexofenadine hydrochloride dosages of 10 mg/kg daily for 5 days or in rabbits receiving an IV fexofenadine hydrochloride dose of 10 mg/kg (resulting in plasma fexofenadine concentrations 28 or 63 times the therapeutic plasma concentrations in humans, respectively, based on a dosage of 60 mg of fexofenadine hydrochloride given twice daily). In addition, no effect was observed on calcium-channel current, delayed potassium-channel current, or action potential duration in guinea pig myocytes, sodium current in rat neonatal myocytes, or on the delayed rectifier potassium channel cloned from human heart at fexofenadine concentrations up to 1.0 X10-5 M (approximately equivalent to 32 times the therapeutic plasma concentrations in humans, based on a dosage of 60 mg of fexofenadine hydrochloride given twice daily).

McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 33


In vitro, terfenadine exhibits a similar affinity for histamine H1-receptors from brain and peripheral tissues; however, in vivo, unlike first generation antihistamines, terfenadine and fexofenadine do not readily cross the blood-brain barrier and therefore do not appear to interact appreciably with H1-receptors within the CNS at usual doses.

McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2006., p. 35


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