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Index

Parts Content Page No.


Product Profile 03
Pharmacology 02-07
- Mechanism of Action 03
- Pharmacokinetics 03-05
- Pharmacodynamics 05
Part IV
- Pregnancy Category 05
- Carcinogenic/Mutagenic Potential 06
- Adverse effect 06
- Interaction 06-07
- Clinical Trials 07-08
Reference 09-10
Product Profile

Name of the product:


Fexofenadine Hydrochloride

Chemical Name:
2-(4-{1-hydroxy-4-[4-(hydroxydiphenylmethyl)piperidin-1-yl]butyl}phenyl)-2-methylpropanoic acid

Structural Formula:

. HCl

Molecular Formula:
C32H39NO4HCl

Molecular Weight: 501.656

CAS Registry Number: 1 83799-24-0 (Fexofenadine)

DESCRIPTION

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.

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B. Pharmacology

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.

Pharmacokinetics

Fexofenadine hydrochloride is rapidly absorbed following oral administration. Tmax occurred approximately 1-
3 hours postdose. The mean Cmax was approximately 142ng/mL following the administration of a single 60mg
dose, approximately 289ng/mL following a single 120mg dose and approximately 494ng/mL following a single
180mg dose. In 7-12 year old allergic rhinitis patients, cross study comparisons indicated that fexofenadine area
under the curve following oral administration of a 60mg dose was 56% greater compared to healthy adult
subjects given the same dose. Additionally, fexofenadine clearance in paediatric patients has been determined to
be approximately 40% lower than in adults. In view of this a dose of 30mg twice daily in paediatric patients will
provide plasma fexofenadine concentration that are comparable to those associated with efficacy in adults.
Administration of a 15 mg dose of fexofenadine to paediatric subjects aged 6 to 23 months, and of a 30 mg dose
to paediatric subjects 2 to 11 years, produced exposures comparable to those seen with a dosage of 60 mg
administered to adults.
The absolute bioavailability following fexofenadine hydrochloride administration is calculated to be 33%.
Fexofenadine is 6075% bound to plasma proteins in healthy subjects. Fexofenadine undergoes negligible
metabolism. Absorption of fexofenadine is not significantly altered by food.
Following a single 60mg oral dose, 80% and 11.5% of total fexofenadine dose was excreted in the faeces and
urine respectively. Following multiple dosing, fexofenadine has a mean terminal elimination half-life of 11-16
hours. The major route of elimination is believed to be biliary excretion while up to 10% of the ingested dose is
excreted unchanged through the urine.
The single and multiple dose pharmacokinetics of fexofenadine are linear between 20mg and 120mg doses. A
dose of 240mg twice daily produced slightly greater than proportional increase (8.8%) in steady state area under
the curve.
The pharmacokinetics of fexofenadine in seasonal allergic rhinitis patients are similar to those in healthy
subjects. One study indicated that females may be exposed to higher plasma levels than males, however, there
was no indication of any difference in safety or efficacy. Elderly patients, patients with hepatic impairment and
patients with cardiac disease exposed to fexofenadine by administration of terfenadine showed no statistically

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significant differences in pharmacokinetic parameters for fexofenadine compared to healthy individuals.
Although peak plasma level and half-life were increased 68% and 15% respectively in elderly patients and 54%
and 19% respectively in patients with renal disease regardless of disease severity, these levels are within the
range of plasma levels shown to be well tolerated in adequate and well controlled safety and efficacy trials.

After oral application, about one-third of the drug is absorbed into the bloodstream. Maximum plasma
concentrations are reached after one to three hours. Fexofenadine is effective from one hour to 24 hours after
application, with maximum effectiveness after six hours. Only a small percentage is metabolized in the liver,
mainly to the methyl ester and to azacyclonol; both are pharmacologically irrelevant. Most of the substance is
eliminated unchanged via the feces (80%) and urine

Absorption:

Bioavailability
Rapidly absorbed from the GI tract following oral administration, with peak plasma concentrations achieved in
about 2.6 hours after administration as conventional capsules or in about 1.82 hours after administration as
extended-release tablets in fixed combination with pseudoephedrine hydrochloride. Conventional capsules and
tablets are bioequivalent when administered at equal doses. Bioavailability is generally (30-41) %

Onset
Antihistaminic effect occurs within 13 hours.

Duration
Antihistaminic effect persists for about 12 hours following oral administration of 20- or 40-mg doses.

Food
No substantial alterations in fexofenadine pharmacokinetics observed in adults when contents of the 60-mg
capsules were mixed with applesauce prior to administration. Administration with fruit juices (e.g., apple,
grapefruit, orange) may reduce fexofenadine bioavailability compared with administration with water.
Decreased rate and/or extent of absorption of fexofenadine observed when the fixed-combination preparations
were administered concomitantly with a high-fat meal. (See Administration under Dosage and Administration.)

Special Populations
In patients with mild to severe renal impairment (Cl cr of 1180 mL/minute) and in those on hemodialysis (Cl cr
10 mL/minute), peak plasma fexofenadine concentrations were increased by 87111 and 82%, respectively,
compared with those in healthy adults. In geriatric patients 65 years of age, peak plasma fexofenadine
concentrations were 99% greater than in younger adults.

Distribution

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Extent
Distribution into human body tissues and fluid not fully elucidated; distributes into the small and large
intestines, stomach, pancreas, liver, and kidney in animals.Distributed more extensively into plasma than blood
or saliva. Does not appear to cross the blood-brain barrier. Not known whether fexofenadine crosses the placenta
or distributes into milk.

Plasma Protein Binding


6070% (mainly albumin and 1-acid glycoprotein).

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

Excretion: Feces (~80%) and urine (~11%) as unchanged drug

Pharmacodynamics
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.

Protein binding: (60-70) %

Half Life: 14.4 hours

Pregnancy Category:

Category B2.
Reproductive toxicity of fexofenadine in animals was assessed through terfenadine exposure. Data from
supporting pharmacokinetic studies, showing the extent of fexofenadine exposure, demonstrate that these
studies are relevant to the assessment of fexofenadine hydrochloride. No evidence of teratogenicity was
observed in animal reproduction studies (rat and rabbit) when terfenadine was given at oral doses of up to
300mg/kg/day throughout organogenesis which corresponds to levels of systemic fexofenadine exposure 4 and

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32fold higher, respectively, than those anticipated in clinical use. No effects on male or female fertility or
perinatal or postnatal development were observed in terfenadine animal studies at non-maternally toxic doses.
There are no studies in pregnant women exposed to fexofenadine hydrochloride alone or through the
administration of terfenadine. As with other medications, Fexophenadrine should be used during pregnancy only
if the potential benefit justifies the potential risk to the foetus. There are no studies of Fexophenadrine in
lactating women. Fexophenadrine is not recommended for nursing women and should only be used if in the
physicians judgement, the potential benefit outweighs the potential risk to the infant. There are no data on the
content of human milk after administering fexofenadine hydrochloride. However, when terfenadine was
administered to nursing mothers, fexofenadine was found to cross into human breast milk.
Exposure of rats to fexofenadine and terfenadine through the administration of terfenadine at doses of 150 and
300mg/kg/day throughout pregnancy and lactation (corresponding to systemic exposure at levels (AUC)
approximately 3 and 6fold higher than those anticipated in clinical use) caused decreased pup weight gain and
survival in offspring. The relative risks of these effects from terfenadine or fexofenadine are unknown. Effects
on pups exposed to fexofenadine only during lactation are not known.

Carcinogenic/Mutagenic Potential

The carcinogenic potential of fexofenadine was assessed using terfenadine studies with supporting
pharmacokinetics studies showing fexofenadine exposure (via plasma AUC values). No evidence of
carcinogenicity was observed in rats and mice given terfenadine.

Adverse Effects
Fexophenadrine is generally well tolerated. In placebo controlled clinical trials involving seasonal allergic
rhinitis and chronic idiopathic urticaria the most commonly reported adverse events were headache (>3%),
drowsiness, nausea, fatigue and dizziness (1-3%). The incidence of these events observed with fexofenadine
hydrochloride was similar to that observed with placebo and no apparent dose trends were revealed in adverse
events.

Events that have been reported during controlled clinical trials involving seasonal allergic rhinitis and chronic
idiopathic urticaria patients with incidences less than 1% and similar to placebo, and have been reported rarely
during post marketing surveillance, include: fatigue, insomnia, nervousness and sleep disorders or paroniria. In
rare cases, rash, urticaria, pruritis and hypersensitivity reactions such as angiooedema, dyspnoea, chest
tightness, flushing and systemic anaphylaxis have been reported. No notable dose effects on QTc were found.

Adverse events reported in placebo-controlled chronic idiopathic urticaria studies were similar to those reported
in placebo-controlled seasonal allergic rhinitis studies. In placebo controlled trials involving paediatric patients
(6-11 years of age), adverse events were similar to those observed in trials involving patients 12 years and older,
with incidences similar to placebo. In controlled clinical trials involving paediatric patients 6 months to 5 years
of age, there were no unexpected adverse events in patients treated with fexofenadine hydrochloride.

Interactions

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Since fexofenadine does not undergo hepatic biotransformation, it is unlikely to interact with drugs that rely
upon hepatic metabolism. Interaction studies with erythromycin and ketoconazole have shown that although the
plasma levels of fexofenadine are increased 23 fold, there were no changes to QT interval and there were no
changes to the incidence of any adverse events. The concentration of fexofenadine experienced by individuals
during the interaction studies are well within the range experienced in acute and chronic dose-tolerance studies.
Animal studies have shown that the increase in plasma levels of fexofenadine observed after co-administration
of erythromycin or ketoconazole, appears to be due to an increase in gastrointestinal absorption and either a
decrease in biliary excretion or gastrointestinal secretion, respectively. No interaction between fexofenadine and
omeprazole was observed. However, the administration of an antacid containing aluminium and magnesium
hydroxide gels 15 minutes prior to fexofenadine hydrochloride caused a reduction in bioavailability, most likely
due to binding in the gastrointestinal tract. It is advisable to leave 2 hours between administration or
fexofenadine hydrochloride and aluminium and magnesium hydroxide containing antacids.

Clinical Trials
Histamine is the major mediator of allergic reactions. Newer H1 antihistaminics like levocetirizine,
fexofenadine, and desloratadine are used in the treatment of seasonal and perennial allergic rhinitis and urticaria.
The ability to block the cutaneous response to intradermal histamine is used to evaluate the potential of
antihistamines.
Aims:
To compare the potency, onset, and duration of action of the commonly used antihistamines-levocetirizine,
fexofenadine, and desloratadine
Methods:
Thirty volunteers were given three single doses of levocetirizine, fexofenadine and desloratadine at weekly
intervals. A pretest was performed by using the intradermal histamine prick test. After administration of the
drugs, the intradermal test was repeated at , 1, 2, 3, 6 and 24 h, and the sizes of the wheal were measured. The
mean values were taken and were compared by using Levene's t-test.
Results:
At 30 min, fexofenadine showed a statistically significant suppression of wheal size compared to levocetirizine
and desloratadine. Two and three hours after administration, levocetirizine and fexofenadine showed statistically
significant inhibition of wheal size while only levocetirizine had this effect after six hours when compared to
desloratadine. Desloratadine showed greater inhibition of wheal size at the end of 24 h when compared to
levocetirizine and fexofenadine but this was not statistically significant.
Conclusions:
Fexofenadine had the earliest onset of action while levocetirizine showed maximum inhibition of wheal
response after three and six hours.

Introduction

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Histamine is the major mediator of allergic reactions and acts mainly through the histamine receptors, H1 and
H2 found in cutaneous blood vessels and H3 in the brain. Antihistamines are drugs which block H1 receptors
and suppress the wheal and flare reaction caused by histamine. Levocetirizine, fexofenadine and desloratadine
are second generation antihistamines that are commonly used in the treatment of urticaria and perennial allergic
rhinitis. The potency of an antihistamine is assessed by its ability to block the wheal and flare reaction. We have
conducted a study to compare the onset and potency of levocetirizine, fexofenadine and desloratadine by using
the histamine wheal suppression test.

Methods
This study was done on 30 healthy volunteers (18-50 years of age) after obtaining their informed consent. The
volunteers were not taking any antihistamines, steroids or immunosuppressants for seven days prior to the study.
None of them had any history of atopy, drug hypersensitivity or use of alcohol. Pregnant and lactating women
were excluded. Volunteers were administered levocetirizine 5 mg, desloratadine 5 mg and fexofenadine 180 mg
at weekly intervals to prevent any carryover effect of the drugs. Levocetirizine was administered in the 1 st
week, desloratadine in the 2 nd week and fexofenadine in the 3rd week. A prick test was performed before the
administration of each drug and after , 1, 2, 3, 6, 24 hours following the administration of the drug. The test
was performed in a marked square area of 1 x 1 cm at different sites each time, on the flexor aspect of the
forearm. The size of the histamine-induced wheal was recorded each time. A drop of 0.1% w/v of histamine
solution was placed on the flexor aspect of the forearm. The skin was pricked through the histamine solution
with a lancet. The tip of lancet was kept parallel to the skin surface and the skin lifted by tenting by the lancet at
an angle of 45-60 o . After one minute, the test site was wiped with filter paper to remove the excess histamine
solution. The size of the wheal was calculated by measuring the maximum diameter of the wheal and the
orthogonal diameter with a transparent scale after ten minutes. The readings were analyzed statistically by
applying the Levene's T test for comparison of drugs. A P value of 0.05 was considered to be statistically
significant.

Result
The mean values of wheal sizes in response to intradermal histamine challenge for levocetirizine 5 mg,
desloratadine 5 mg and fexofenadine 180 mg after , 1, 2, 3, 6, 24 hours following drug administration are
shown in [Table 1].
Table 1 :Mean of wheal suppression in mm

Pretest hour 1 hour 2 hour 3 hour 6 hour 24 hour


Levocetrizine 5.069 4.724 3.758 2.517 1.517 1.965 2.965
Fexofenadine 5.233 4.300 3.600 2.233 1.500 2.133 3.166
Desloratidine 5.096 4.709 4.032 3.387 2.548 2.548 2.838

Half an hour after administration, fexofenadine showed a statistically significant suppression of wheal size
compared to levocetirizine ( P = 0.040) and desloratadine ( P = 0.036). However, after one hour, all the three
drugs showed a decrease in wheal size that was not statistically significant. After two and three hours,

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levocetirizine ( P = 0.000) and fexofenadine ( P = 0.000) showed a statistically significant inhibition of wheal
size when compared to desloratadine. Only levocetirizine showed a statistically significant inhibition of wheal
response after six hours ( P = 0.24), while all three drugs showed substantial (but not statistically significant)
reduction in wheal size ( P > 0.05).

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