Side effects in children 6 months to 5 years old were similar to placebo. Side effects varied by age. The most commonly reported side effects were: vomiting, pyrexia, cough, otitis media and diarrhea.
Consumers used to have to make a decision when allergy symptoms struck. They could put up with the combined misery of sneezing, itchy eyes, and a runny nose, or they could struggle blearily against the head-drooping drowsiness brought on by taking an antihistamine. Now, however, consumers can banish allergy symptoms without having to schedule a siesta. They need only drop by their local supermarket to pick up a nonsedating antihistamine.
Their choices include Allegra, Zyrtec, and Clarinex, which are available by prescription, and Claritin, which is available over the counter. Although antihistamines can cut down on sneezing, eye itching, and nasal secretions, they’re not much good at clearing a stuffy nose. So these drugs are also offered with a decongestant ingredient such as pseudoephedrine hydrochloride.
Millions of consumers casually take these medications today, but nonsedating antihistamines had a bumpy start. The first of this class of drug to go on the market was Seldane (terfenadine), which was introduced in 1985 by Hoechst Marion Roussel. The company is now known as Sanofi-Aventis.
In the body, terfenadine is normally metabolized into fexofenadine–the active ingredient responsible for the antihistamine’s activity–by converting a methyl into a carboxylate group. But metabolism of terfenadine can be hindered by liver disease, grapefruit juice, and other medications such as the antibiotic erythromycin. When terfenadine builds up in the bloodstream as a result, it blocks cardiac potassium channels, leading to serious and sometimes fatal heart rhythm abnormalities.
The Food & Drug Administration initially judged that terfenadine’s benefits outweighed its risks because the drug doesn’t cause sleepiness–a significant safety advantage for people who used antihistamines. But the agency pushed Hoechst Marion Roussel to develop an antihistamine based on fexofenadine itself, which lacks terfenadine’s risks. After the safer alternative Allegra (fexofenadine hydrochloride) was approved in July 1996, FDA announced that it would withdraw its approval for terfenadine products. Hoechst Marion Roussel then pulled Seldane from the market.
Other nonsedating antihistamines approved by FDA include Hismanal, which was approved in 1988 but withdrawn from the market in 1999 because of cardiovascular and other safety problems; Claritin, approved in 1993; Zyrtec, approved in 1995; and Clarinex, approved in 2002.
THE NUMBER OF people who could benefit from these drugs is staggering. In the U.S. alone, more than 35 million people suffer from seasonal allergies, reports the American Academy of Allergy, Asthma & Immunology.
Their symptoms result from an excessive immune response to the proteins found in allergens such as pollen or mold. When a susceptible person inhales pollen, the immune system begins pumping out immunoglobulin E (IgE) antibodies that are specific for the pollen proteins. The antibodies then fasten onto the surface of mast cells–connective tissue cells that are abundant in the nose, eyes, lungs, and gastrointestinal tract.
When this unlucky person is again exposed to pollen grains, the IgE antibodies latch onto the new batch of allergens and also begin cross-linking. These interactions trigger a release of histamines and other chemical messengers from the mast cells attached to the antibodies.
The histamine molecules then bind to receptors on cells in blood vessels, the gastrointestinal tract, and the respiratory tract–collectively known as peripheral H1 receptors. In turn, this coupling leads blood vessels to dilate and leak fluid, smooth muscle to constrict, and mucus secretion to increase. Sneezing, a runny nose, and red, itchy, watery eyes are the inelegant result.
Antihistamines block the interaction between histamine molecules and their target cells by binding to the cell receptors themselves. But the interaction between antihistamines and H1 receptors can have two very different effects. Binding of antihistamines to peripheral H1 receptors reduces allergy symptoms. But H1 receptors also exist in the central nervous system, and antihistamines that bind to them cause sedation, cognitive impairment, and other effects. In fact, the sedative effect can be so strong that such products are sometimes used as sleeping aids.
The first generation of antihistamines, which includes compounds such as Benadryl and Chlor-Trimeton, bind to both types of H1 receptor and are termed nonselective. Thus patients who take these compounds have to put up with sleepiness if they want relief of allergy symptoms.
The second- and third-generation antihistamines, on the other hand, are nonsedating because they selectively bind to peripheral H1 receptors. They are considerably less likely to bind to the H1 receptors in the central nervous system because they are much less capable of crossing the blood-brain barrier.
ALLEGRA-D® (fexofenadine hydrochloride and pseudoephedrine hydrochloride) Extended-Release Tablets for oral administration contain 60 mg fexofenadine hydrochloride for immediate-release and 120 mg pseudoephedrine hydrochloride for extended-release. Tablets also contain as excipients: microcrystalline cellulose, pregelatinized starch, croscarmellose sodium, magnesium stearate, carnauba wax, stearic acid, silicon dioxide, hypromellose and polyethylene glycol.
Fexofenadine hydrochloride, one of the active ingredients of ALLEGRA-D, is a histamine H1-receptor antagonist with the chemical name (±)-4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-butyl]- , -dimethyl benzeneacetic acid hydrochloride.
The molecular weight is 538.13 and the empirical formula is C32H39NO4oHCl. Fexofenadine hydrochloride is a white to off-white crystalline powder. It is freely soluble in methanol and ethanol, slightly soluble in chloroform and water, and insoluble in hexane. Fexofenadine hydrochloride is a racemate and exists as a zwitterion in aqueous media at physiological pH.
Fexofenadine HCL is the generic name for Allegra. The generic name represents the medications nonproprietary or chemical name, whereas, the brand name is the name a pharmaceutical give to a medication for marketing purposes.
Antihistamines are known for their sedative effects. However, some studies suggested mild stimulant effects in the case of fexofenadine. The goals of this study are to examine whether fexofenadine possesses stimulating properties and to determine whether such stimulating effects are related to workload. Sixteen healthy volunteers received a single dose of 180 and 360 mg fexofenadine and placebo on separate test days. Drug effects were assessed using a divided attention task (DAT), continuous performance task (CPT) and motor choice reaction time test (MCRT). Sensitivity of the tasks was increased by manipulating the workload during task performance. Event Related brain Potentials (ERPs) were measured in the DAT and CPT to study the underlying neurophysiological processes. An interaction effect of Treatment and Workload was found on tracking performance in the DAT and on movement time in the MCRT. Performance on the DAT was less affected by increments in workload after fexofenadine as compared to placebo. P1 and P3 latency were affected by Treatment x Workload and Treatment respectively and indicated faster attentional and information processing latencies following fexofenadine treatment. Treatment did not influence performance in the CPT task or in the ERPs measured during this task. The MCRT demonstrated faster movement times following fexofenadine treatment. These results suggest that although the neurophysiological data indicate central nervous system (CNS) activation after fexofenadine treatment, the magnitude of the centrally activating effects is too small to produce relevant performance improvement at the behavioural level.
Allergies are easy to treat for many children, they simply take an allergy medication, such as Allegra (fexofenadine), Claritin (loratadine), Singulair (montelukast), or Zyrtec (cetirizine), and their allergy symptoms get under easy control.
Other children have more hard-to-control allergies though, and suffer either with their allergy symptoms or try many different allergy medicines without relief. It is much better to get help to learn treat your child’s allergies more effectively.
Human histamine skin wheal and flare studies following single and twice daily doses of 20 and 40 mg Fexofenadine hydrochloride demonstrated that the drug exhibits an antihistamine effect by 1 hour, achieves maximum effect at 2 to 3 hours, and an effect is still seen at 12 hours. There was no evidence of tolerance to these effects after 28 days of dosing. The clinical significance of these observations is unknown.
Histamine skin wheal and flare studies in 7 to 12 year old subjects showed that following a single dose of 30 or 60 mg, antihistamine effect was observed at 1 hour and reached a maximum by 3 hours. Greater than 49% inhibition of wheal area, and 74% inhibition of flare area were maintained for 8 hours following the 30 and 60 mg dose.
Pharmacokinetics in special populations (for renal, hepatic impairment, and age), obtained after a single dose of 80 mg Fexofenadine hydrochloride, were compared to those from healthy volunteers in a separate study of similar design.
Geriatric Subjects
In older subjects (≥65 years old), peak plasma levels of Fexofenadine were 99% greater than those observed in younger subjects (<65 years old). Mean Fexofenadine elimination half-lives were similar to those observed in younger subjects.
Pediatric Subjects
Cross study comparisons indicated that Fexofenadine area under the curve (AUC) following oral administration of a 60 mg dose of Fexofenadine hydrochloride to 7–12 year old pediatric subjects with allergic rhinitis was 56% greater compared to healthy adult volunteers given the same dose. Plasma exposure in pediatric subjects given 30 mg Fexofenadine hydrochloride is comparable to adults given 60 mg.
Renally Impaired
In subjects with mild to moderate (creatinine clearance 41–80 mL/min) and severe (creatinine clearance 11–40 mL/min) renal impairment, peak plasma levels of Fexofenadine were 87% and 111% greater, respectively, and mean elimination half-lives were 59% and 72% longer, respectively, than observed in healthy volunteers. Peak plasma levels in subjects on dialysis (creatinine clearance ≤10 mL/min) were 82% greater and half-life was 31% longer than observed in healthy volunteers. Based on increases in bioavailability and half-life, a dose of 60 mg once daily is recommended as the starting dose in patients with decreased renal function. (See DOSAGE AND ADMINISTRATION).
Hepatically Impaired
The pharmacokinetics of Fexofenadine in subjects with hepatic disease did not differ substantially from that observed in healthy volunteers.
Effect of Gender
Across several trials, no clinically significant gender-related differences were observed in the pharmacokinetics of Fexofenadine hydrochloride.
Fexofenadine hydrochloride was rapidly absorbed following oral administration of a single dose of two 60 mg capsules to healthy male volunteers with a mean time to maximum plasma concentration occurring at 2.6 hours post-dose. After administration of a single 60 mg capsule to healthy volunteers, the mean maximum plasma concentration was 131 ng/mL. Following single dose oral administrations of either the 60 and 180 mg tablet to healthy adult male volunteers, mean maximum plasma concentrations were 142 and 494 ng/mL, respectively. The tablet formulations are bioequivalent to the capsule when administered at equal doses. Fexofenadine hydrochloride pharmacokinetics are linear for oral doses up to a total daily dose of 240 mg (120 mg twice daily). The administration of the 60 mg capsule contents mixed with applesauce did not have a significant effect on the pharmacokinetics of Fexofenadine in adults.
Co-administration of 180 mg Fexofenadine hydrochloride tablet with a high fat meal decreased the AUC and Cmax of Fexofenadine by 21 and 20% respectively.
Fruit juices such as grapefruit, orange and apple may reduce the bioavailability and exposure of fexofenadine. This is based on the results from 3 clinical studies using histamine induced skin wheals and flares coupled with population pharmacokinetic analysis. The size of wheal and flare were significantly larger when fexofenadine hydrochloride was administered with either grapefruit or orange juices compared to water. Based on the literature reports, the same effects may be extrapolated to other fruit juices such as apple juice. The clinical significance of these observations is unknown. In addition, based on the population pharmacokinetics analysis of the combined data from grapefruit and orange juices studies with the data from a bioequivalence study, the bioavailability of fexofenadine was reduced by 36%. Therefore, to maximize the effects of fexofenadine, it is recommended that ALLEGRA tablets should be taken with water (see Pharmacokinetics and DOSAGE AND ADMINISTRATION).