1.CLARINEX HISTORY
(How was Clarinex discovered?)

Clarinex is a product of by Schering - Plough Pharmaceuticals.

The US FDA approved Clarinex in February 2002.

Schering-Plough has global business facilities in more than 50 countries across six continents.

Schering-Plough offers medicines in the following areas:

• Allergy & Respiratory
• Animal Health
• Anti-Infectives
• Arthritis & Immunology
• Cancer Therapies
• Cholesterol-Lowering/Cardiovascular
• Erectile Dysfunction
• Foot Care
• Hepatitis

Skin Disorders & Sun Care in adverse events for subgroups of patients as defined by gender, age, or race.  

Note: World-drugs.net sells generic version of Clarinex

2.CLARINEX FACTS

Clarinex is used in the treatment of –

Seasonal Allergic Rhinitis

Clarinex is indicated for the relief of the nasal and non-nasal symptoms of seasonal allergic rhinitis in patients 2 years of age and older.

Perennial Allergic Rhinitis

Clarinex is indicated for the relief of the nasal and non-nasal symptoms of perennial allergic rhinitis in patients 6 months of age and older.

Chronic Idiopathic Urticaria

Clarinex is indicated for the symptomatic relief of pruritus, reduction in the number of hives, and size of hives, in patients with chronic idiopathic urticaria 6 months of age and older.

 

3.ABOUT CLARINEX 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.CLARINEX EFFECTIVENESS
(When is Clarinex best taken?)

Absorption
Following oral administration of Clarinex 5 mg once daily for 10 days to normal healthy volunteers, the mean time to maximum plasma concentrations (Tmax) occurred at approximately 3 hours post dose and mean steady state peak plasma concentrations (Cmax) and area under the concentration-time curve (AUC) of 4 ng/mL and 56.9 ng.hr/mL were observed, respectively. Neither food nor grapefruit juice had an effect on the bioavailability (Cmax and AUC) of desloratadine.

Distribution
Clarinex and 3-hydroxydesloratadine are approximately 82% to 87% and 85% to 89%, bound to plasma proteins, respectively. Protein binding of Clarinex and 3-hydroxydesloratadine was unaltered in subjects with impaired renal function.

Metabolism
Clarinex is extensively metabolized to 3-hydroxydesloratadine, an active metabolite, which is subsequently glucuronidated. The enzyme(s) responsible for the formation of 3-hydroxy-desloratadine have not been identified. Data from clinical trials indicate that a subset of the general population has a decreased ability to form 3-hydroxydesloratadine, and are poor metabolizers of Clarinex. In pharmacokinetic studies (n= 3748), approximately 6% of subjects were poor metabolizers of Clarinex (defined as a subject with an AUC ratio of 3-hydroxydesloratadine to desloratadine less than 0.1, or a subject with a Clarinex half-life exceeding 50 hours). These pharmacokinetic studies included subjects between the ages of 2 and 70 years, including 977 subjects aged 2-5 years, 1575 subjects aged 6-11 years, and 1196 subjects aged 12-70 years. There was no difference in the prevalence of poor metabolizers across age groups. The frequency of poor metabolizers was higher in Blacks (17%, n=988) as compared to Caucasians (2%, n=1462) and Hispanics (2%, n=1063). The median exposure (AUC) to Clarinex in the poor metabolizers was approximately 6-fold greater than in the subjects who are not poor metabolizers. Subjects who are poor metabolizers of Clarinex cannot be prospectively identified and will be exposed to higher levels of desloratadine following dosing with the recommended dose of desloratadine. In multidose clinical safety studies, where metabolizer status was identified, a total of 94 poor metabolizers and 123 normal metabolizers were enrolled and treated with Clarinex for 15-35 days. In these studies, no overall differences in safety were observed between poor metabolizers and normal metabolizers. Although not seen in these studies, an increased risk of exposure-related adverse events in patients who are poor metabolizers cannot be ruled out.  

Elimination
The mean elimination half-life of Clarinex was 27 hours. Cmax and AUC values increased in a dose proportional manner following single oral doses between 5 and 20 mg. The degree of accumulation after 14 days of dosing was consistent with the half-life and dosing frequency. A human mass balance study documented a recovery of approximately 87% of the 14C-desloratadine dose, which was equally distributed in urine and feces as metabolic products. Analysis of plasma 3-hydroxydesloratadine showed similar Tmax and half-life values compared to desloratadine.

5.CLARINEX EFFECTS ON SPECIAL POPULATION
(How do different people react to Clarinex?)

Geriatric
In older subjects following multiple-dose administration of Clarinex Tablets, the mean Cmax and AUC values for Clarinex were 20% greater than in younger subjects (< 65 years old). The oral total body clearance (CL/F) when normalized for body weight was similar between the two age groups. The mean plasma elimination half-life of Clarinex was 33.7 hr in subject's 65 years old. The pharmacokinetics for 3-hydroxydesloratadine appeared unchanged in older versus younger subjects. These age-related differences are unlikely to be clinically relevant and no dosage adjustment is recommended in elderly subjects.

Pediatric Subjects
In subjects 6 to 11 years old, a single dose of Clarinex 5 mL containing 2.5 mg of desloratadine, resulted in desloratadine plasma concentrations similar to those achieved in adults administered a single dose of Clarinex 5 mg Tablet.

Gender
Female subjects treated for 14 days with Clarinex Tablets had 10% and 3% higher desloratadine Cmax and AUC values, respectively, compared with male subjects. The 3-hydroxydesloratadine Cmax and AUC values were also increased by 45% and 48%, respectively, in females compared with males. However, these apparent differences are not likely to be clinically relevant and therefore no dosage adjustment is recommended.

Race
Following 14 days of treatment with Clarinex Tablets, the Cmax and AUC values for desloratadine were 18% and 32% higher, respectively, in Blacks compared with Caucasians. For 3-hydroxydesloratadine there was a corresponding 10% reduction in Cmax and AUC values in Blacks compared to Caucasians. These differences are not likely to be clinically relevant and therefore no dose adjustment is recommended.

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

Renally Impaired
Clarinex pharmacokinetics following a single dose of 7.5 mg was characterized in patients with mild (n=7; creatinine clearance 51-69 mL/min/1.73 m2), moderate (n=6; creatinine clearance 34-43 mL/min/1.73 m2), and severe (n=6; creatinine clearance 5-29 mL/min/1.73 m2) renal impairment or hemodialysis dependent (n=6) patients. In patients with mild and moderate renal impairment, median Cmax and AUC values increased by approximately 1.2- and 1.9-fold, respectively, relative to subjects with normal renal function. In patients with severe renal impairment or who was hemodialysis dependent, Cmax and AUC values increased by approximately 1.7- and 2.5- fold, respectively. Minimal changes in 3-hydroxydesloratadine concentrations were observed. Clarinex and 3-hydroxydesloratadine were poorly removed by hemodialysis. Plasma protein binding of desloratadine and 3-hydroxy-desloratadine was unaltered by renal impairment. Clarinex Dosage adjustment for patients with renal impairment is recommended.

Hepatically Impaired
Clarinex pharmacokinetics were characterized following a single oral dose in patients with mild (n=4), moderate (n=4), and severe (n=4) hepatic impairment as defined by the Child-Pugh classification of hepatic function and 8 subjects with normal hepatic function. Patients with hepatic impairment, regardless of severity, had approximately a 2.4-fold increase in AUC as compared with normal subjects. The apparent oral clearance of Clarinex in patients with mild, moderate, and severe hepatic impairment was 37%, 36%, and 28% of that in normal subjects, respectively. An increase in the mean elimination half-life of Clarinex in patients with hepatic impairment was observed. For 3-hydroxydesloratadine, the mean Cmax and AUC values for patients with hepatic impairment were not statistically significantly different from subjects with normal hepatic function. Clarinex Dosage adjustment for patients with hepatic impairment is recommended.

7.OTHER/ALTERNATE USES OF CLARINEX
(What else does Clarinex treat?)

Clarinex can also be used for the treatment of hives.

8.ADVERSE/SIDE EFFECTS of CLARINEX
(What are the side effects of Clarinex?)

Allergic Rhinitis
In multiple-dose placebo-controlled trials, 2,834 patients ages 12 years or older received Clarinex Tablets at doses of 2.5 mg to 20 mg daily, of whom 1,655 patients received the recommended daily dose of 5 mg. In patients receiving 5 mg daily, the rate of adverse events was similar between Clarinex and placebo-treated patients. The percent of patients who withdrew prematurely due to adverse events was 2.4% in the Clarinex group and 2.6% in the placebo group. There were no serious adverse events in these trials in patients receiving desloratadine. All adverse events that were reported by greater than or equal to 2% of patients who received the recommended daily dose of Clarinex Tablets (5.0 mg once-daily), and that were more common with Clarinex Tablets than placebo, are listed in Table 5.

Incidence of Adverse Events Reported by 2% or More of Adult and Adolescent Allergic Rhinitis Patients in Placebo-Controlled, Multiple-Dose Clinical Trials with the Tablet Formulation of Clarinex
Adverse Experience	Clarinex Tablets 5 mg (n=1,655)	Placebo (n=1,652)
Pharyngitis	4.1%	2.0%
Dry Mouth	3.0%	1.9%
Myalgia	2.1%	1.8%
Fatigue	2.1%	1.2%
Somnolence	2.1%	1.8%
Dysmenorrhea	2.1%	1.6%