Fexofenadine Drug Monograph
Fexofenadine Drug Monograph
An anti-histamine gaining popularity nowadays is Fexofenadine Hydrochloride. Its brand names include Allegra, Telfast and Fastofen. It has been categorized both under second- (1) and third-generation (2) anti-histamines, which acts as a Histamine-1 receptor antagonist, however being modified to not easily cross the blood-brain barrier. With this, Fexofenadine causes less drowsiness, as compared to first-generation histamine-receptor antagonists (3). It’s systematic name (IUPAC) is 2-[4-[1-hydroxy-4-[4-(hydroxy-diphenyl- methyl)-1-piperidyl]butyl]phenyl]-2- methyl-propanoic acid (4).
Figure 1 shows the chemical structure of the drug. Source: http://en. wikipedia. org/wiki/Fexofenadine It is a metabolite of Terfenadine, with a molecular weight of 538. 13. It is freely soluble in methanol and ethanol, slightly soluble in chloroform and water, and insoluble in hexane. Its empirical formula is C32H39NO4•HCl. This drug appears to be a white to off-white crystalline powder (5). The drug is known to be a racemate and exists as a zwitterion in aqueous media at physiological pH (6).
Fexofenadine was originally synthesized in 1993 by Massachusetts-based biotechnology company Sepracor, which then sold the development rights to Hoechst Marion Roussel (now part of Sanofi-Aventis), (7) and was later approved by the Food and Drug Administration (FDA) in 1996. The drug is available in 60 mg capsules, and 30 mg, 60 mg, 120 mg (Australia), and 180 mg tablets (9). Pictures for these available forms are presented in Figure 2. Fexofenadine is an antihistamine with selective peripheral H 1-receptor antagonist activity (10).
Among studies done with sensitized guinea pigs and rats, it is shown to inhibit antigen-induced bronchospasm and histamine release from peritoneal mast cells (5, 8). It competes with histamine for H1-receptor sites on effector cells in the gastrointestinal tract, blood vessels and respiratory tract. It is commonly indicated to treat to relieve symptoms that are associated with seasonal allergic rhinitis, such as sneezing; rhinorrhea; itchy eyes, nose, and throat; and red, watery eyes (5).
It is also indicated for the treatment of uncomplicated skin manifestations of chronic idiopathic urticaria, whereby it significantly reduces pruritus and number of wheals (11). In a study done by Ngamphaiboon, et. al. , (12) it showed that Fexofenadine 30 mg bid causes a significant improvement in all allergic symptoms even nasal blockage, which is not usually obtained with oral antihistamines. An explanation for this could be that Fexofenadine might also have an anti-inflammatory property besides its antihistaminic property.
The drug’s absorption is rapid following oral administration (5). The bioavailabilities of Fexofenadine capsule and tablet formulations are equivalent when administered in equal doses. Its pharmacokinetics is linear for oral doses up to 240 mg a day (120 mg twice a day). The volume of distribution is 5. 4 to 5. 8 liters/kilogram (13). Tissue distribution studies in rats using radiolabeled Fexofenadine show that it does not cross the blood-brain barrier. The drug’s protein binding is high (at 60 to 70%), predominantly to albumin and alpha 1-acid glycoprotein.
About 5% of the total dose is metabolized, while approximately 0. 5 to 1. 5% by cytochrome P450 3A4 isoenzyme metabolism and 3. 5% transformed to a methyl ester metabolite by intestinal microflora (5). Elimination occurs after 14. 4 hours in healthy subjects (5). Patients with altered physiologic systems eliminate the drug at various rates. This is shown in Table 1. Mean Elimination Half-Life (5) Patients with mild renal impairment Creatinine clearance of 41-80 mL per minute 59% longer compared to healthy subjects
Patients with severe renal impairment Creatinine clearance of 11-40 mL per minute 79% longer compared to healthy subjects Patients on dialysis 31% longer compared to healthy subjects Table 1: Various Mean Half-lives of Patients with Impaired Excretory Systems The onset of action is known to be 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 Fexofenadine.
Peak serum concentration is achieved at 209 ng/mL after a single 60-mg dose as an oral solution; 142 ng/mL after a single 60-mg tablet; 494 ng/mL after a single 180-mg oral tablet; and 286 ng/mL after 10 doses of 60-mg as an oral solution every 12 hours, all performed among healthy volunteers (5). Time to peak effect is at 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 Fexofenadine.
The drug’s effect is evident at 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 Fexofenadine. Additionally, tolerance to the antihistamine effect of Fexofenadine was not demonstrated following 28 days of dosing. Renal clearance is at 3 to 4 L per hour, with approximately 11% of a radioactive Fexofenadine dose being excreted in the urine. Meanwhile, approximately 80% of a radioactive Fexofenadine dose is excreted in the feces.
However, it is unclear whether this represents unabsorbed drug or is the result of biliary excretion (14). Route Onset Peak Duration Oral Rapid 3 hours 14 hours The drug’s pharmacokinetics is summarized in Table 2, as shown. Table 2: Pharmacokinetics of Fexofenadine No carcinogenic potential was shown in 18- and 24-month studies done where mice and rats were given oral Terfenadine doses of 50 and 150 mg per kg of body weight (mg/kg) per day respectively (15). 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 dosage (5).
Also, Fexofenadine was not mutagenic in in vitro bacterial or animal studies, as well as in vivo animal studies (16). Taking fertility into consideration, dose-related reductions in implants and increases in postimplantation losses were seen in rats given oral doses of Terfenadine 150 mg/kg. These doses resulted in AUC values for Fexofenadine of three times the human therapeutic value based on the recommended dosage (5). Adequate and well-controlled studies in humans have not been done to try out effect on pregnancy.
However, 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. In rats given oral doses of Terfenadine 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, respectively. Additionally, it is not known whether Fexofenadine is distributed into breast milk (17).
Thus, the Food and Drug Administration (FDA) classifies this drug under Pregnancy Category C (18). Among the pediatric population, clinical trials with 438 children, ages 6 to 11 years were safely treated for seasonal allergic rhinitis with Fexofenadine 30 mg twice daily, for up to 2 weeks (19, 20). However, the safety and efficacy of Fexofenadine in children up to 6 years of age has not been established (21). 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 (22).
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. The following drug interactions and/or related problems have been emphasized on the basis of their potential clinical significance. Concurrent administration of Fexofenadine with Ketoconazole (20) and Erythromycin (23) has been found to increase plasma Fexofenadine concentrations; however, no differences in adverse effects or increased QT c intervals were seen Erythromycin.
Also, administration of Fexofenadine within 15 minutes of dosing with an aluminum and magnesium hydroxide-containing antacid has decreased the Fexofenadine area under the time-concentration curve by 41% and C max by 43%. There is a known interaction between this drug, when taken with apple juice, grapefruit juice, and orange juice. Studies have shown that these juices may decrease Fexofenadine effects (24). Concurrent use with alcohol also increases the chances of CNS depression (27, 28). The mechanism of these interactions has been evaluated in in vitro, in situ, and in vivo animal models.
These studies indicate that ketoconazole or erythromycin co-administration enhances fexofenadine gastrointestinal absorption. In vivo animal studies also suggest that in addition to increase absorption, ketoconazole decreases fexofenadine hydrochloride gastrointestinal secretion, while erythromycin may also decrease biliary excretion (23). This drug also may prevent, reduce, or mask positive result in diagnostic skin tests (29). Additionally, the medical considerations/contraindications included have been selected on the basis of their potential clinical significance, but not necessarily inclusive.
Risk-benefit should be considered when medical problems such as renal function impairment and hypersensitivity to Fexofenadine exist. Renal function impairment prevents the proper elimination of the drug. However, based upon increases in the bioavailability and half-life of Fexofenadine, once-daily administration is recommended initially in patients with impaired renal function (5). The drug’s adverse and side effects are shown in Table 3. Central Nervous System Fatigue, dizziness, drowsiness, headache, nausea Musculoskeletal System Back pain Gastro-intestinal System Nausea, dyspepsia Genitourinary System Dysmenorrhea
Other Viral infections such as colds and influenza Observed side-effects among pediatric population Cough, fever, otitis media, sinusitis (25) [It is not cardiotoxic and is safe for pediatric patients as young as 6 years of age (26)] Table 3: Fexofenadine’s Adverse Effects Reports of fexofenadine overdose are infrequent (30). Conversely, the following effects have been selected on the basis of their potential clinical significance but not necessarily inclusive: dizziness, drowsiness, and dry mouth. To decrease absorption during overdose, consider standard measures to remove any unabsorbed drug.
Hemodialysis, however, does not effectively remove Fexofenadine from the blood (with only up to 1. 7% removed). There is no known antidote to Fexofenadine (31). Treatment is generally symptomatic and supportive. Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric evaluation (32). Patient teaching for a client taking Fexofenadine includes proper dosing and storage. If used regularly, using as soon as possible may be the best way to treat symptoms. Using any remaining doses for that day should be used at regularly spaced intervals. Patients are not encouraged to double dose.
This drug should be stored at controlled room temperature, between 20 and 25 °C (68 and 77 °F), and should be protected from moisture (33). If the patient were to undergo diagnostic skin tests, he should be instructed to stop taking the drug as it prevents, reduces, and masks positive skin test response (34). Patients should be advised to take this drug with any liquid, other than fruit juices, as it decreases the effect of Fexofenadine. Also, they should be warned to avoid alcohol and hazardous activities that require alertness until nervous system effects of this drug are known (32, 33).
Patients should be made aware that drowsiness is a common side effect, and should be advised to take proper precaution. Moreover, the drug’s side effects should be explained to the patient so drug compliance is ensured (34, 35). Current drug investigation looks into the bioequivalence of this drug among different trade names. One of these investigations sponsored by Mylan Pharmaceuticals studies on Mylan’s fexofenadine 180 mg tablets to Aventis’ Allegra® 180 mg tablets following a single, oral 180 mg (1 x 180 mg) dose administered under fasting conditions (22). Reference List 1.
Dicpinigaitis PV, Gayle YE. Effect of the second-generation antihistamine, fexofenadine, on cough reflex sensitivity and pulmonary function. British Journal of Clinical Pharmacology. November 2003 56 (5): 501–4 2. Vena GA, Cassano N, Filieri M, Filotico R, D’Argento V, Coviello C. Fexofenadine in chronic idiopathic urticaria: a clinical and immunohistochemical evaluation. International Journal of Immunopathology and Pharmacology. 2002. 15 (3): 217–224 3. Handley DA, Magnetti A, Higgins AJ. Therapeutic advantages of third generation antihistamine. Expert Opin Invest Drug 1998. 7: 1045-54. 4.
Chemindustry. Fexofenadine [online] 2008 [cited 2009 February 5]; Available from: URL: http://www. chemindustry. com/chemicals/551136. html 5. Product Information: Allegra, fexofenadine. Hoechst Marion Roussel, Kansas City, MO, (PI revised 6/98) reviewed 1/2000 6. Food and Drug Administration. Food and Drug Administration Prescribing Report: ALLEGRA (fexofenadine hydrochloride) Capsules and Tablets [online] 2000 [cited 2009 February 5]; Available at http://www. fda. gov/Cder/foi/label/2000/20872lbl. pdf 7. Lednicer, Daniel. The Organic Chemistry of Drug Synthesis. New York: Wiley Interscience; 1999
University/College: University of California
Type of paper: Thesis/Dissertation Chapter
Date: 8 October 2016
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