Cetirizine dihydrochloride and Phenylpropanolamine Tablets ALERID D Tablets COMPOSITION Each tablet contains: Cetirizine dihydrochloride.....

5 mg Phenylpropanolamine 25 mg DOSAGE FORM Oral tablets DESCRIPTION Cetirizine is a highly potent long-acting peripheral H1-receptor antagonist which acts both on the early and late allergic response. Phenylpropanolamine is an orally active sympathomimetic amine and exerts a decongestant action on the nasal mucosa. PHARMACOLOGY Pharmacodynamics Cetirizine: Cetirizine, a human metabolite of hydroxyzine, is an antihistamine; its principal effects are mediated via selective inhibition of peripheral H1 receptors. The antihistaminic activity of cetirizine has been clearly documented in a variety of animal and human models. In vivo and ex vivo animal models have shown negligible anticholinergic and antiserotonergic activity. In clinical studies, however, dry mouth was more common with cetirizine than with placebo. In vitro receptor binding studies have shown no measurable affinity for other than H1 receptors. Autoradiographic studies with radiolabelled cetirizine in the rat have shown negligible penetration into the brain. Ex vivo experiments in the mouse have shown that systemically administered cetirizine does not significantly occupy cerebral H1 receptors. Phenylpropanolamine: The mechanism of action of phenylpropanolamine has not been conclusively determined. The drug may directly stimulate adrenergic receptors but probably indirectly stimulates both - and -adrenergic effects result from stimulation of cyclic adenosine 3, 5-monophosphate (AMP) production by activation of the enzyme adenyl activity. With prolonged use or too frequent administration, indirectly acting sympathomimetics may deplete norepinephrine in sympathetic nerve endings and tachyphylaxis may develop. Tachyphylaxis induced by one indirectly acting sympathomimetic may result in refractoriness to other drugs of the same class. Phenylpropanolamine presumably acts on -adrenergic receptors in the mucosa of the respiratory tract producing vasoconstriction which results in shrinkage of swollen mucus

membranes, reduction of tissue hyperemia, edema and nasal congestion, and an increase in nasal airway patency. Phenylpropanolamine increases heart rate, force of contraction, and cardiac output and excitability, possibly by indirectly stimulating -adrenergic receptors in the heart. In one study in normotensive patients, increases in blood pressure following 20-50 mg of IV phenylpropanolamine were comparable to those induced following IV administration of 25 mg of amphetamine sulfate or 5-20 mg of hydroxyamphetamine. IN animals, renal and pulmonary blood flow has been variably affected, and coronary blood flow has been increased by phenylpropanolamine. The drug reportedly decreases menstrual flow in some menorrhagic women. Phenylpropanolamine causes CNS stimulation and reportedly has an anorexigenic effect that is much weaker than that of amphetamine. Like ephedrine, phenylpropanolamine produces mydriasis; accommodation, light reflexes, and intraocular pressure are unchanged. Phenylpropanolamine reportedly produces closure of the bladder neck and contraction of the posterior urethra in males with stress incontinence. This action may be caused by stimulation of sympathetic fibers in the hypogastric nerve. Animal studies have failed to confirm any bronchodilator effect of phenylpropanolamine. Pharmacokinetics Cetirizine: Absorption: Cetirizine was rapidly absorbed with a time to maximum concentration (Tmax) of approximately 1 hour following oral administration of tablets, chewable tablets, or syrup in adults. Comparable bioavailability was found between the tablet and syrup dosage forms. Comparable bioavailability was also found between the cetirizine tablet and the cetirizine chewable tablet, taken with or without water. When healthy volunteers were administered multiple doses of cetirizine (10 mg tablets once daily for 10 days), a mean peak plasma concentration (Cmax) of 311ng/mL was observed. No accumulation was observed. Cetirizine pharmacokinetics were linear for oral doses ranging from 560 mg. Food had no effect on the extent of exposure (AUC) of the cetirizine tablet or chewable tablet, but Tmax was delayed by 1.7 hours and 2.8 hours, respectively, and Cmax was decreased by 23% and 37%, respectively, in the presence of food. Distribution: The mean plasma protein binding of cetirizine is 93%, independent of concentration in the range of 251,000 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 faeces. 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 the 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. Phenylpropanolamine: Absorption: Phenylpropanolamine is readily absorbed from the GI tract and there is no evidence of first-pass metabolism. Following oral administration, phenylpropanolamine is absorbed mainly from the intestines. In one study, peak plasma concentrations of 100ng/mL were reached in 1-2 hours and concentrations remained greater than 60ng/mL for 6 hours following oral administration of 50 mg of phenylpropanolamine hydrochloride to fasting adults. Following administration of 150 mg of an extended release preparation of the drug, peak plasma concentrations of 300ng/mL occurred after 3.5 hours and Phenylpropanolamine concentrations remained greater than 180ng/mL for 12 hours. After oral administration of a single 20- or 375-mg dose of Phenylpropanolamine as an oral solution in pediatric patients (6-12 years of age), mean peak serum as an oral solution in pediatric patients (6-12 years of age), mean peak serum concentrations of 185 or 285 ng/mL, respectively, were achieved after 2.1 or 2.7 hours, respectively, were achieved after 2.1 or 2.7 hours respectively. Nasal decongestion reportedly occurs within 15039 minutes after oral administration of 25 mg of phenylpropanolamine hydrochloride and appears to persist for 3 hours. Plasma concentrations of the drug required for a therapeutic effect are not known. Distribution: Following IV administration of phenylpropanolamine, the volume of distribution of the drug is reported to be 3.4 L/kg. Following oral administration of a single 20- or 37.5 mg dose of phenylpropanolamine as an oral solution in pediatric patients (6-12 years of age), mean apparent volumes of distribution as steady-state were 2.5 or 2.8 L/kg, respectively. Animal studies indicate that phenylpropanolamine is distributed into various tissues and fluids, including CSF and brain. Metabolism & Elimination: Phenylpropanolamine reportedly has a half-life of 3-6 hours. In one study in children (612 years of age) who received a single oral dose of 20 or 37.5 mg of Phenylpropanolamine hydrochloride as a solution, the terminal eliminiation half-life averaged 2.4 or 2.8 hours, respectively, when the urinary pH was 7.

Like other Phenylpropanolamines, small amounts of the drug are slowly metabolized in the liver to an active hydoxylated metabolite. About 80 -90% of a dose of Phenylpropanolamine is excreted unchanged in the urine within 24 hours. In children, about 66% of a dose of phenylpropanolamine is excreted unchanged in the urine within 24 hours. The rate of urinary excretion of phenylpropanolamine is accelerated when urine is acidified to a pH of about 5 by prior administration of ammonium chloride. When the urine is alkalinized to a pH of about 8 by prior administration of sodium bicarbonate, some of the drug is reabsorbed in the renal tubule and the rate of urinary excretion is slowed. In healthy individuals, renal clearance is about 6.83-10.8 mL/minute per kg. Following oral administration of a single 20 or 37.5 mg dose of phenylpropanolamine hydrochloride as a solution in pediatric patients (6-12 years of age), total body clearance averaged 13.6 or 13.3 mL/minute per kg, respectively. These clearance rates were faster than values previously reported in adults under similar conditions. INDICATIONS ALERID D Tablets are indicated for the relief of symptoms of allergic rhinitis. DOSAGE AND ADMINISTRATION Adults and children above (12 years of age): 1 tablet twice daily. The tablet should be swallowed whole and not crushed or chewed. CONTRAINDICATIONS ALERID D Tablets are contraindicated in patients with hypersensitivity to cetirizine or its parent compound hydroxyzine. It is also contraindicated in patients with severe hypertension or coronary artery disease, patients receiving monoamine oxidase inhibitor (MAO) therapy and in patients with hepatic dysfunction. WARNINGS AND PRECAUTIONS Cetirizine: The occurrence of somnolence has been reported in some patients taking cetirizine; due caution should therefore be exercised when driving a car or operating potentially dangerous machinery. Concurrent use of cetirizine with alcohol or other CNS depressants should be avoided because additional reductions in alertness and additional impairment of CNS performance may occur. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine. Phenylpropanolamine: No data available

Drug Interactions Cetirizine: No clinically significant drug interactions have been found with theophylline at a low dose, azithromycin, pseudoephedrine, ketoconazole, or erythromycin. There was a small decrease in the clearance of cetirizine caused by a 400-mg dose of theophylline; it is possible that larger theophylline doses could have a greater effect. Phenylpropanolamine: MAO inhibitors increase the effect of sympathomimetic amines, and may prolong and intensify the effects of antihistamines. Beta-adrenergic amines may reduce the antihypertensive effects of some drugs e.g. Methyldopa and Reserpine. Others ALERID D should be used with caution in patients with hypertension and ischaemic heart disease. Although investigations indicate that cetirizine does not intensify the effect of alcohol, it is advisable to avoid alcohol consumption. Pregnancy There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, ALERID-D should be used in pregnancy only if clearly needed. Lactation Cetirizine has been reported to be excreted in human breast milk. ALERID-D is not recommended for use by lactating mothers. Paediatric Use This combination cannot be used in children below the age of 12 years. UNDESIRABLE EFFECTS Cetirizine In objective tests of psychomotor function the incidence of sedation with cetirizine was similar to that of placebo. There have been occasional reports of mild and transient side effects such as drowsiness, fatigue, headache, dizziness, agitation, dry mouth and gastro-intestinal discomfort. If desired the dose might be taken as 5mg in the morning and 5 mg in the evening. Undesirable effects reported from post-marketing experience are listed in the following table per System Organ Class and per frequency. Blood and lymphatic disorders: Very rare: thrombocytopenia. Cardiac disorders: Rare: tachycardia. Eye disorders: Very rare: accommodation disorder, blurred vision.

Gastro-intestinal disorders: Uncommon: diarrhoea. General disorders and administration site conditions: Uncommon: asthenia, malaise; Rare: oedema. Immune system disorders: Rare: hypersensitivity; Very rare: anaphylactic shock Hepatobiliary disorders: Rare: abnormal hepatic function (increased transaminases, alkaline, phosphatase, -GT and bilirubin). Investigations: Rare: weight increase. Nervous system disorders: Uncommon: paraesthesia; Rare: convulsions, movement disorders; Very rare: dysgeusia, syncope. Psychiatric disorders: uncommon : agitation ; rare : aggression, confusion, depression, hallucination, insomnia. Renal and urinary disorders: Very rare: dysuria, enuresis, micturition difficulties. Skin and subcutaneous tissue disorders: Uncommon: pruritus, rash, Rare: urticaria, Very rare: angioneurotic oedema, erythema multiforme. Phenylpropanolamine The incidence of adverse effects is low in patients receiving therapeutic doses of phenylpropanolamine. The CNS stimulant effects of phenylpropanolamine may result in nervousness, restlessness, insomnia/ sleeplessness, dizziness and headache. Nausea and palpitations also may occur. Increases in blood pressure may occur and are usually proportionate to dosage. At least one manufacturer recommends that blood pressure be monitored regularly during phenylpropanolamine therapy. In some patients, severe reactions including headache, feelings of tightness in the chest, greatly elevated blood pressure, ventricular or atrial premature contractions, and paroxysms of ventricular and atrial tachycardia have occurred with usual therapeutic doses; these effects probably represent idiosyncratic reactions to the drug. Excessive doses of phenylpropanolamine may produce tachycardia, pupillary dilation, excitation, and arrhythmias; cases of heart attack, stroke, intracranial bleeding, parenchymal cerebral hemorrhage, seizures, and death possibly associated with phenylpropanolamine also have been reported. Patients receiving high doses of combination products containing phenylpropanolamine and an antihistamine (i.e., diphenylpraline, chlorpheniramine) have experienced acute psychotic (i.e., diphenylpraline, chlorpheniramine) have experienced acute psychotic reactions and excessive CNS stimulation. OVERDOSAGE Cetirizine Overdosage has been reported with cetirizine. In one case, an adult patient who took 150 mg of cetirizine was somnolent, but did not display any other clinical signs or

abnormal blood chemistry or haematology results. In an 18-month old paediatric patient who took an overdose of cetirizine (approximately 180 mg), restlessness and irritability were observed initially; this was followed by drowsiness. Should overdose occur, treatment should be symptomatic or supportive, taking into account any concomitantly ingested medications. There is no known specific antidote to cetirizine. Cetirizine is not effectively removed by dialysis, and dialysis will be ineffective unless a dialysable agent has been concomitantly ingested. Phenylpropanolamine There are several published case reports of deliberate overdoses, with elevations of blood pressure a predominant feature. Fatality occurred in patient whereby Tachycardia was the main clinical feature. There have been several reports of individual taking an over dose of phenylpropanolamine and suffering a cerebral hemorrhage. Other effects reported are intense renal vasoconstriction leading to acute tubular necrosis, PACKAGING INFORMATION ALERID D Tablets Blister pack of 10 tablets Last updated: June 2010