1.CETIRIZINE HISTORY
(How was Cetirizine discovered?)

The US FDA approved Cetirizine in 1995 for the treatment of Allergy.

Cetirizine is the most widely prescribed antihistamine. It is currently used in more than 90 countries.

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

2.CETIRIZINE FACTS

Cetirizine works by blocking Histamine H1 receptors. Cetirizine does not prevent the actual release of Histamine from mast cells, but prevents it binding to its receptors. This in turn prevents the release of other allergy chemicals and increased blood supply to the area, and provides relief from the typical symptoms of hayfever.

3.ABOUT CETIRIZINE 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.CETIRIZINE EFFECTIVENESS
(When is Cetirizine best taken?)

Absorption:
Cetirizine was rapidly absorbed with a time to maximum concentration (Tmax) of approximately 1 hour following oral administration of tablets or syrup in adults. Comparable bioavailability was found between the tablet and syrup dosage forms. When healthy volunteers were administered multiple doses of Cetirizine (10 mg tablets once daily for 10 days), a mean peak plasma concentration (Cmax) of 311 ng/ml was observed. No accumulation was observed. Cetirizine pharmacokinetics were linear for oral doses ranging from 5 to 60 mg. Food had no effect on the extent of Cetirizine exposure (AUC) but Tmax was delayed by 1.7 hours and Cmax was decreased by 23% in the presence of food.

Distribution:
The mean plasma protein binding of Cetirizine is 93%, independent of concentration in the range of 25-1000 ng/ml, which includes the therapeutic plasma levels observed.

Metabolism:
A mass balance study in 6 healthy male volunteers indicated that 70% of the administered radioactivity was recovered in the urine and 10% in the feces. Approximately 50% of the radioactivity was identified in the urine as unchanged drug. Most of the rapid increase in peak plasma radioactivity was associated with parent drug, suggesting a low degree of first-pass metabolism. Cetirizine is metabolized to a limited extent by oxidative O-dealkylation to a metabolite with negligible antihistaminic activity. The enzyme or enzymes responsible for this metabolism have not been identified.

Elimination:
The mean elimination half-life in 146 healthy volunteers across multiple pharmacokinetic studies was 8.3 hours and the apparent total body clearance for Cetirizine was approximately 53 ml/min.

5.CETIRIZINE EFFECTS ON SPECIAL POPULATION
How do different people react to Cetirizine?

Pediatric Patients:

When pediatric patients aged 7 to 12 years received a single, 5-mg oral Cetirizine capsule, the mean Cmax was 275 ng/ml. Based on cross-study comparisons, the weight-normalized, apparent total body clearance was 33% greater and the elimination half-life was 33% shorter in this pediatric population than in adults. In pediatric patients aged 2 to 5 years who received 5 mg of Cetirizine, the mean Cmax was 660 ng/ml. Based on cross-study comparisons, the weight-normalized apparent total body clearance was 81 to 111% greater and the elimination half-life was 33 to 41% shorter in this pediatric population than in adults.

In pediatric patients aged 6 to 23 months who received a single dose of 0.25 mg/kg Cetirizine oral solution (mean dose 2.3 mg), the mean Cmax was 390 ng/mL. Based on cross-study comparisons, the weight-normalized, apparent total body clearance was 304% greater and the elimination half-life was 63% shorter in this pediatric population compared to adults. The average AUC(0-t) in children 6 months to <2 years of age receiving the maximum dose of Cetirizine solution (2.5 mg twice a day) is expected to be two-fold higher than that observed in adults receiving a dose of 10 mg Cetirizine tablets once a day.

Geriatric Patients:

Following a single, 10-mg oral dose, the elimination half-life was prolonged by 50% and the apparent total body clearance was 40% lower in 16 geriatric subjects with a mean age of 77 years compared to 14 adult subjects with a mean age of 53 years. The decrease in Cetirizine clearance in these elderly volunteers may be related to decreased renal function. A dosing adjustment may be necessary in patients 77 years of age and older.

Effect of Gender:

The effect of gender on Cetirizine pharmacokinetics has not been adequately studied. 

Effect of Race:

No race-related differences in the kinetics of Cetirizine have been observed.

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

Renal Impairment:

The kinetics of Cetirizine were studied following multiple, oral, 10-mg daily doses of Cetirizine for 7 days in 7 normal volunteers (creatinine clearance 89-128 ml/min), 8 patients with mild renal function impairment (creatinine clearance 42-77 ml/min) and 7 patients with moderate renal function impairment (creatinine clearance 11-31 ml/min). The pharmacokinetics of Cetirizine was similar in patients with mild impairment and normal volunteers. Moderately impaired patients had a 3-fold increase in half-life and a 70% decrease in clearance compared to normal volunteers.

Patients on hemodialysis (n=5) given a single, 10-mg dose of Cetirizine had a 3-fold increase in half-life and a 70% decrease in clearance compared to normal volunteers. Less than 10% of the administered dose was removed during the single dialysis session.

Dosing adjustment is necessary in patients with moderate or severe renal impairment and in patients on dialysis.

Hepatic Impairment: Sixteen patients with chronic liver diseases (hepatocellular, cholestatic, and biliary cirrhosis), given 10 or 20 mg of Cetirizine as a single, oral dose had a 50% increase in half-life along with a corresponding 40% decrease in clearance compared to 16 healthy subjects. 

7.OTHER/ALTERNATE USES OF CETIRIZINE
(What else does Cetirizine treat?)

Cetirizine can also be used to relieve the symptoms of a condition called chronic idiopathic urticaria. This is a chronic itchy rash, similar to nettle rash, but with no apparent cause. Blocking the actions of Histamine relieves the itching and reduces the rash associated with this condition.

8.ADVERSE/SIDE EFFECTS of CETIRIZINE
(What are the side effects of Cetirizine?)

Controlled and uncontrolled clinical trials conducted in the United States and Canada included more than 6000 patients aged 12 years and older, with more than 3900 receiving Cetirizine at doses of 5 to 20 mg per day. The duration of treatment ranged from 1 week to 6 months, with a mean exposure of 30 days.

Most adverse reactions reported during therapy with Cetirizine were mild or moderate. In placebo-controlled trials, the incidence of discontinuations due to adverse reactions in patients receiving Cetirizine 5 or 10 mg was not significantly different from placebo (2.9% vs. 2.4%, respectively).

The most common adverse reaction in patients aged 12 years and older that occurred more frequently on Cetirizine than placebo was somnolence. The incidence of somnolence associated with Cetirizine was dose related, 6% in placebo, 11% at 5 mg and 14% at 10 mg. Discontinuations due to somnolence for Cetirizine were uncommon (1.0% on Cetirizine vs. 0.6% on placebo). Fatigue and dry mouth also appeared to be treatment-related adverse reactions. There were no differences by age, race, gender or by body weight with regard to the incidence of adverse reactions.

The table below lists adverse experiences in patients aged 12 years and older which were reported for Cetirizine 5 and 10 mg in controlled clinical trials in the United States and that were more common with Cetirizine than placebo.

Adverse Experiences Reported in Patients Aged 12 Years and Older in Placebo-Controlled United States Cetirizine Trials (Maximum Dose of 10 mg) at Rates of 2% or Greater (Percent Incidence)
Adverse Experience	Cetirizine (N=2034)	Placebo (N=1612)
Somnolence	13.7	6.3
Fatigue	5.9	2.6
Dry Mouth	5.0	2.3
Pharyngitis	2.0	1.9
Dizziness	2.0	1.2

In addition, headache and nausea occurred in more than 2% of the patients, but were more common in placebo patients.

Pediatric studies were also conducted with Cetirizine. More than 1300 pediatric patients aged 6 to 11 years with more than 900 treated with Cetirizine at doses of 1.25 to 10 mg per day were included in controlled and uncontrolled clinical trials conducted in the United States. The duration of treatment ranged from 2 to 12 weeks. Placebo-controlled trials up to 4 weeks duration included 168 pediatric patients aged 2 to 5 years who received Cetirizine, the majority of whom received single daily doses of 5 mg. A placebo-controlled trial 18 months in duration included 399 patients aged 12 to 24 months treated with Cetirizine (0.25 mg/kg bid), and another placebo-controlled trial of 7 days duration included 42 patients aged 6 to 11 months who were treated with Cetirizine (0.25 mg/kg bid).

The majority of adverse reactions reported in pediatric patients aged 2 to 11 years with Cetirizine were mild or moderate. In placebo-controlled trials, the incidence of discontinuations due to adverse reactions in pediatric patients receiving up to 10 mg of Cetirizine was uncommon (0.4% on Cetirizine vs. 1.0% on placebo).

The table below lists adverse experiences which were reported for Cetirizine 5 and 10 mg in pediatric patients aged 6 to 11 years in placebo-controlled clinical trials in the United States and were more common with Cetirizine than placebo. Of these, abdominal pain was considered treatment-related and somnolence appeared to be dose-related, 1.3% in placebo, 1.9% at 5 mg and 4.2% at 10 mg. The adverse experiences reported in pediatric patients aged 2 to 5 years in placebo-controlled trials were qualitatively similar in nature and generally similar in frequency to those reported in trials with children aged 6 to 11 years.

In the placebo-controlled trials of pediatric patients 6 to 24 months of age, the incidences of adverse experiences, were similar in the Cetirizine and placebo treatment groups in each study. Somnolence occurred with essentially the same frequency in patients who received Cetirizine and patients who received placebo. In a study of 1-week duration in children 6-11 months of age, patients who received Cetirizine exhibited greater irritability/fussiness than patients on placebo. In a study of 18 months duration in patients 12 months and older, insomnia occurred more frequently in patients who received Cetirizine compared to patients who received placebo (9.0% v. 5.3%). In those patients who received 5 mg or more per day of Cetirizine as compared to patients who received placebo, fatigue (3.6% v. 1.3%) and malaise (3.6% v. 1.8%) occurred more frequently.

Adverse Experiences Reported in Pediatric Patients Aged 6 to 11 Years in Placebo-Controlled United States Cetirizine Trials (5 or 10 mg Dose) Which Occurred at a Frequency of ³ 2% in Either the 5-mg or the 10-mg Cetirizine Group, and More Frequently Than in the Placebo Group
		Cetirizine
Adverse Experiences	Placebo (N=309)	5 mg (N=161)	10 mg (N=215)
Headache	12.3%	11.0%	14.0%
Pharyngitis	2.9%	6.2%	2.8%
Abdominal Pain	1.9%	4.4%	5.6%
Coughing	3.9%	4.4%	2.8%
Somnolence	1.3%	1.9%	4.2%
Diarrhea	1.3%	3.1%	1.9%
Epistaxis	2.9%	3.7%	1.9%
Bronchospasm	1.9%	3.1%	1.9%
Nausea	1.9%	1.9%	2.8%
Vomiting	1.0%	2.5%	2.3%

 

The following events were observed infrequently (less than 2%), in either 3982 adults and children 12 years and older or in 659 pediatric patients aged 6 to 11 years who received Cetirizine in U.S. trials, including an open adult study of six months duration. A causal relationship of these infrequent events with Cetirizine administration has not been established.

Autonomic Nervous System : Anorexia, flushing, increased salivation, urinary retention.

Cardiovascular : Cardiac failure, hypertension, palpitation, tachycardia.

Central and Peripheral Nervous Systems : Abnormal coordination, ataxia, confusion, dysphonia, hyperesthesia, hyperkinesia, hypertonia, hypoesthesia, leg cramps, migraine, myelitis, paralysis, paresthesia, ptosis, syncope, tremor, twitching, vertigo, visual field defect.

Gastrointestinal: Abnormal hepatic function, aggravated tooth caries, constipation, dyspepsia, eructation, flatulence, gastritis, hemorrhoids, increased appetite, melena, rectal hemorrhage, stomatitis including ulcerative stomatitis, tongue discoloration, tongue edema.

Genitourinary: Cystitis, dysuria, hematuria, micturition frequency, polyuria, urinary incontinence, urinary tract infection.

Hearing and Vestibular: Deafness, earache, ototoxicity, tinnitus.

Metabolic/Nutritional: Dehydration, diabetes mellitus, thirst.

Musculoskeletal: Arthralgia, arthritis, arthrosis, muscle weakness, myalgia.

Psychiatric: Abnormal thinking, agitation, amnesia, anxiety, decreased libido, depersonalization, depression, emotional lability, euphoria, impaired concentration, insomnia, nervousness, paroniria, sleep disorder.

Respiratory System: Bronchitis, dyspnea, hyperventilation, increased sputum, pneumonia, respiratory disorder, rhinitis, sinusitis, upper respiratory tract infection.

Reproductive : Dysmenorrhea, female breast pain, intermenstrual bleeding, leukorrhea, menorrhagia, vaginitis.

Reticuloendothelial: Lymphadenopathy.

Skin: Acne, alopecia, angioedema, bullous eruption, dermatitis, dry skin, eczema, erythematous rash, furunculosis, hyperkeratosis, hypertrichosis, increased sweating, maculopapular rash, photosensitivity reaction, photosensitivity toxic reaction, pruritus, purpura, rash, seborrhea, skin disorder, skin nodule, urticaria.

Special Senses : Parosmia, taste loss, taste perversion.

Vision : Blindness, conjunctivitis, eye pain, glaucoma, loss of accommodation, ocular hemorrhage, xerophthalmia.

Body as a Whole : Accidental injury, asthenia, back pain, chest pain, enlarged abdomen, face edema, fever, generalized edema, hot flashes, increased weight, leg edema, malaise, nasal polyp, pain, pallor, periorbital edema, peripheral edema, rigors.

Occasional instances of transient, reversible hepatic transaminase elevations have occurred during Cetirizine therapy. Hepatitis with significant transaminase elevation and elevated bilirubin in association with the use of Cetirizine has been reported.

Post-Marketing Experience

In the post-marketing period, the following additional rare, but potentially severe adverse events have been reported: aggressive reaction, anaphylaxis, cholestasis, convulsions, glomerulonephritis, hallucinations, hemolytic anemia, hepatitis, orofacial dyskinesia, severe hypotension, stillbirth, suicidal ideation, suicide and thrombocytopenia.