1.ALLEGRA HISTORY
(How was Allegra discovered?)

Allegra is a product of Sanofi-Aventis. 

Sanofi-Aventis was formed in 2004 when Sanofi-Synthelabo merged with Aventis.

The Sanofi-Aventis Group is the world's 3rd largest pharmaceutical company, ranking number 1 in Europe. Backed by a world-class R&D organization, Sanofi-Aventis is developing leading positions in seven major therapeutic areas:

• cardiovascular disease,
• thrombosis,
• oncology,
• diabetes,
• central nervous system,
• internal medicine, and
• vaccines.  

Note: World-drus.net sells brand as well as generic version of Allegra

2.ALLEGRA FACTS

Allegra is a non-sedating prescription used in the treatment of:

Seasonal Allergic Rhinitis

Allegra is indicated for the relief of symptoms associated with seasonal allergic rhinitis in adults and children 6 years of age and older. Symptoms treated effectively were sneezing, rhinorrhea, itchy nose/palate/throat, itchy/watery/red eyes.

 

Chronic Idiopathic Urticaria

Allegra is indicated for treatment of uncomplicated skin manifestations of chronic idiopathic urticaria in adults and children 6 years of age and older. Allegra significantly reduces pruritus and the number of wheels.

3.ABOUT ALLEGRA MEDICATION

Antihistamines

Pharmacology

In allergic reactions an allergen (a type of antigen) interacts with and cross-links surface IgE antibodies on mast cells and basophils. Once the mast cell-antibody-antigen complex is formed, a complex series of events occurs that eventually leads to cell-degranulation and the release of histamine (and other chemical mediators) from the mast cell or basophil. Once released, histamine can react with local or widespread tissues through histamine receptors.

 

Histamine, acting on H1-receptors, produces pruritis, vasodilatation, hypotension, flushing, headache, tachycardia, bronchoconstriction, increases vascular permeability, potentiates pain, and more.

While H1-antihistamines ameliorate these effects, it is only efficacious if administered prior to the allergen-challenge. In severe allergies, such as anaphylaxis or angioedema, these effects may be so severe as to be life threatening.

Clinical use of antihistamines

Indications

H1-antihistamines are clinically used in the treatment of histamine-mediated allergic conditions. Specifically, these indications may include:

• allergic rhinitis
• allergic conjunctivitis
• allergic dermatological conditions (contact dermatitis)
• urticaria
• pruritus (atopic dermatitis, insect bites)
• anaphylactic or anaphylactoid reactions - adjunct only
• nausea and vomiting (first-generation H1-antihistamines)
• sedation (first-generation H1-antihistamines)

Antihistamines can be administered topically (through the skin, nose, or eyes) or systemically, based on the nature of the allergic condition.

Adverse drug reactions

Adverse drug reactions are most commonly associated with the first-generation H1-antihistamines. This is due to their relative lack of selectivity for the H1-receptor.

The most common adverse effect is sedation - this "side effect" being utilised in many OTC sleeping-aid preparations. Other common adverse effects in first-generation H1-antihistamines include: dizziness, tinnitus, blurred vision, euphoria, uncoordination, anxiety, insomnia, tremor, nausea and vomiting, constipation, diarrhoea, dry mouth, and dry cough. Infrequent adverse effects include: urinary retention, palpitations, hypotension, headache, hallucination, and psychosis.

The newer second-generation H1-antihistamines are far more selective for peripheral histamine H1-receptors and, correspondingly, have a far improved tolerability profile compared to the first-generation agents. The most common adverse effects noted for second-generation agents include: drowsiness, fatigue, headache, nausea and dry mouth.

First-generation H1-receptor antagonists

These are the oldest antihistaminergic drugs and are relatively inexpensive and widely available. They are effective in the relief of allergic symptoms, but are typically moderately to highly potent muscarinic acetylcholine receptor-antagonists (anticholinergic) agents as well. These agents also commonly have action at a-adrenergic receptors and/or 5-HT receptors. This lack of receptor-selectivity is the basis of the poor tolerability-profile of some of these agents, especially compared with the second-generation H1-antihistamines. Patient response and occurrence of adverse drug reactions vary greatly between classes and between agents within classes.

The first H1-antihistamine discovered was piperoxan, by Forneau and Daniel Bovet (1933) in their efforts to develop a guinea pig animal-model for anaphylaxis. Bovet went on to win the 1957 Nobel Prize in Physiology or Medicine for his contribution. Following their discovery, the first-generation H1-antihistamines were developed in the following decades. They can be classified on the basis of chemical structure, and agents within these groups have similar properties.

Ethylenediamines

Ethylenediamines were the first group of clinically-effective H1-antihistamines developed.

• mepyramine (pyrilamine)
• antazoline
• Ethanolamines

Diphenhydramine was the prototypical agent in this group. Significant anticholinergic adverse effects, including sedation, are observed in this group but the incidence of gastrointestnal adverse effects is relatively low.

• diphenhydramine
• carbinoxamine
• doxylamine
• clemastine
• dimenhydrinate

Alkylamines

The isomerism is a significant factor in the activity of the agents in this group. E-triprolidine, for example, is 1000-fold more potent than Z-triprolidine. This difference relates to the positioning and fit of the molecules in the histamine H1-receptor binding site. Alkylamines are considered to have relatively fewer sedative and gastrointestinal adverse effects, but relatively greater incidence of paradoxical CNS stimulation.

• pheniramine
• chlorphenamine (chlorpheniramine)
• dexchlorphenamine
• brompheniramine
• triprolidine

Piperazines

These compounds are structurally-related to the ethylenediamines and the ethanolamines; and produce significant anticholinergic adverse effects. Compounds from this group are often used for motion sickness, vertigo, nausea and vomiting. The second-generation H1-antihistamine cetirizine also belongs to this chemical group.

• hydroxyzine
• meclizine

Tricyclics

These compounds differ from the phenothiazine antipsychotics in the ring-substitution and chain characteristics. (Nelson, 2002) They are also structurally related to the tricyclic antidepressants, explaining the antihistaminergic adverse effects of those two drug classes and also the poor tolerability profile of tricyclic H1-antihistamines. The second-generation H1-antihistamine loratadine was derived from compounds in this group.

• promethazine
• alimemazine (trimeprazine)
• cyproheptadine
• azatadine

Second-generation H1-receptor antagonists

These are newer drugs that are much more selective for peripheral H1 receptors in preference to the central nervous system histaminergic and cholinergic receptors. This selectivity significantly reduces the occurrence of adverse drug reactions compared with first-generation agents, while still providing effective relief of allergic conditions.

Systemic

• acrivastine
• astemizole
• cetirizine
• levocetirizine
• fexofenadine
• loratadine
• desloratadine
• mizolastine
• terfenadine (withdrawn from most markets due to risk of cardiac arrhythmias and replaced with fexofenadine)

Topical

• azelastine
• levocabastine
• olopatadine

Other agents

Inhibitors of histamine release

These agents appear to stabilise the mast cells to prevent degranulation and mediator release.

• cromoglicate (cromolyn)
• nedocromil

H2-receptor antagonists

Main article: H2-receptor antagonist

Clinically-relevant histamine H2-receptors are found principally in the parietal cells of the gastric mucosa. H2-receptor "antagonists" are also inverse agonists, rather than true antagonists; and are used to reduce the secretion of gastric acid. Examples include cimetidine, ranitidine, and famotidine.

H3- and H4-receptor antagonists

These are experimental agents and do not yet have defined clinical uses.

Other agents with antihistaminergic activity

Many drugs, used for other indications, possess unwanted antihistaminergic activity. These include tricyclic antidepressants, antipsychotics, etc. 

4.ALLEGRA EFFECTIVENESS
(When is Allegra best taken?)

Absorption

Allegra was rapidly absorbed following oral administration of a single Allegra dose of two 120 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 dose of Allegra capsule to healthy volunteers, the mean maximum plasma concentration was 131 ng/mL. Following single Allegra dose oral administrations of either the 120 or 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. Allegra 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 Allegra in adults. Co-adminstration of 180 mg Allegra tablet with a high fat meal decreased the AUC and cmax of fexofenadine by 21 and 20% respectively.

Distribution:

Allegra is 60% to 70% bound to plasma proteins, primarily albumin and a1-acid glycoprotein.

Metabolism:

Approximately 5% of the total dose of Allegra was eliminated by hepatic metabolism.

Elimination:

The mean elimination half-life of Allegra was 14.4 hours following administration of 60 mg twice daily in healthy volunteers.

Human mass balance studies documented a recovery of approximately 80% and 11% of the Allegra dose in the feces and urine, respectively. Because the absolute bioavailability of Allegra has not been established, it is unknown if the fecal component represents primarily unabsorbed drug or the result of biliary excretion.

5.ALLEGRA EFFECTS ON SPECIAL POPULATION
(How do different people react to Allegra?)

Nursing Mothers

It is not known if Allegra is excreted in human milk. There are no adequate and well-controlled studies in women during lactation. Because many drugs are excreted in human milk, caution should be exercised when Allegra is administered to a nursing woman.

Pediatric Use

The recommended dose in patients 6 to 11 years of age is based on cross-study comparison of the pharmacokinetics of Allegra in adults and pediatric subjects and on the safety profile of Allegra in both adult and pediatric subjects at doses equal to or higher than the recommended doses.

Three clinical safety studies comparing 15 mg twice daily (n=85) and 30 mg twice daily (n=330) of an experimental formulation of Allegra to placebo (n=430) have been conducted in pediatric subjects aged 6 months to 5 years. In general, Allegra was well tolerated in these studies. No unexpected adverse events were seen given the known safety profile of Allegra and likely adverse reactions for this patient population.

The safety and effectiveness of Allegra in pediatric patients under 6 years of age have not been established.

Geriatric Use

Clinical studies of Allegra tablets and capsules did not include sufficient numbers of subjects aged 65 years and over to determine whether this population responds differently from younger subjects. Other reported clinical experience has not identified differences in responses between the geriatric and younger subjects. Allegra is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Effect of Gender

Across several trials, no clinically Allegra.

6.ALLEGRA EFFECTS ON MEDICAL CONDITIONS
(How does Allegra affect your existing condition/ailment?)

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 Allegra 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. 

Hepatically Impaired.

The pharmacokinetics of Allegra in subjects with hepatic disease did not differ substantially from that observed in healthy volunteers. 

7.OTHER/ALTERNATE USES OF ALLEGRA
(What else does Allegra treat?)

Allegra can also be used for the treatment of hives.

8.ADVERSE/SIDE EFFECTS of ALLEGRA
(What are the side effects of Allegra?)

In placebo-controlled seasonal allergic rhinitis clinical trials in subjects 12 years of age and older, which included 2461 subjects receiving Allegra capsules at doses of 20 mg to 240 mg twice daily, adverse events were similar in Allegra and placebo-treated subjects. All adverse events that were reported by greater than 1% of subjects who received the recommended daily dose of Allegra (60 mg capsules twice daily), and that were more common with Allegra than placebo.

In a placebo-controlled clinical study in the United States, which included 570 subjects aged 12 years and older receiving Allegra tablets at doses of 120 or 180 mg once daily, adverse events were similar in Allegra and placebo-treated subjects. Table below also lists adverse experiences that were reported by greater than 2% of subjects treated with Allegra tablets at doses of 180 mg once daily and that were more common with Allegra than placebo.

The incidence of adverse events, including drowsiness, was not dose-related and was similar across subgroups defined by age, gender, and race.

Adverse experiences in subjects aged 12 years and older reported in placebo-controlled seasonal allergic rhinitis clinical trials in the United States Twice-daily dosing with Allegra at rates of greater than 1%

Adverse experience	Allegra 60 mg Twice Daily (n=679)	Placebo Twice Daily (n=671)
Viral Infection (cold, flu)	2.5%	1.5%
Nausea	1.6%	1.5%
Dysmenorrhea	1.5%	0.3%
Drowsiness	1.3%	0.9%
Dyspepsia	1.3%	0.6%
Fatigue	1.3%	0.9%

Once-daily dosing with Allegra tablets at rates of greater than 2%

Adverse experience	Allegra 180 mg Once Daily (n=283)	Placebo (n=293)
Headache	10.6%	7.5%
Upper Respiratory Tract Infection	3.2%	3.1%
Back Pain	2.8%	1.4%

The frequency and magnitude of laboratory abnormalities were similar in Allegra and placebo-treated subjects.

The table below lists adverse experiences in subjects aged 6 to 11 years of age which were reported by greater than 2% of subjects treated with Allegra tablets at a dose of 30 mg twice daily in placebo-controlled seasonal allergic rhinitis studies in the United States and Canada that were more common with Allegra than placebo.

Adverse experiences reported in placebo-controlled seasonal allergic rhinitis studies in pediatric subjects aged 6 to 11 in the United States and Canada at rates of greater than 2%

Adverse experience	Allegra 30 mg Twice Daily (n=209)	Placebo (n=229)
Headache	7.2%	6.6%
Accidental Injury	2.9%	1.3%
Coughing	3.8%	1.3%
Fever	2.4%	0.9%
Pain	2.4%	0.4%
Otitis Media	2.4%	0.0%
Upper Respiratory Tract Infection	4.3%	1.7%

Three clinical safety studies in 845 children aged 6 months to 5 years comparing 15 mg twice daily (n=85) and 30 mg twice daily (n=330) of an experimental formulation of Allegra to placebo (n=430) have been conducted. In general, Allegra was well tolerated in these studies. No unexpected adverse events were seen given the known safety profile of Allegra and likely adverse reactions for this patient population.