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Cetirizine dihydrochloride and Phenylpropanolamine Tablets

ALERID D Tablets

COMPOSITION

Each tablet contains:Cetirizine dihydrochloride.....5 mgPhenylpropanolamine 25 mg

DOSAGE FORMOral tablets

DESCRIPTIONCetirizine is a highly potent long-acting peripheral H1-receptor antagonist which actsboth on the early and late allergic response.

Phenylpropanolamine is an orally active sympathomimetic amine and exerts adecongestant action on the nasal mucosa.

PHARMACOLOGYPharmacodynamicsCetirizine:Cetirizine, a human metabolite of hydroxyzine, is an antihistamine; its principal effectsare mediated via selective inhibition of peripheral H1 receptors. The antihistaminicactivity of cetirizine has been clearly documented in a variety of animal and humanmodels. In vivo and ex vivo animal models have shown negligible anticholinergic andantiserotonergic activity. In clinical studies, however, dry mouth was more common withcetirizine than with placebo. In vitro receptor binding studies have shown no measurableaffinity for other than H1 receptors. Autoradiographic studies with radiolabelled cetirizinein the rat have shown negligible penetration into the brain. Ex vivo experiments in themouse have shown that systemically administered cetirizine does not significantlyoccupy cerebral H1 receptors.

Phenylpropanolamine:The mechanism of action of phenylpropanolamine has not been conclusivelydetermined. The drug may directly stimulate adrenergic receptors but probably

indirectly stimulates both - and -adrenergic effects result from stimulation of cyclicadenosine 3, 5-monophosphate (AMP) production by activation of the enzyme adenylactivity. With prolonged use or too frequent administration, indirectly actingsympathomimetics may deplete norepinephrine in sympathetic nerve endings andtachyphylaxis may develop. Tachyphylaxis induced by one indirectly actingsympathomimetic may result in refractoriness to other drugs of the same class.

Phenylpropanolamine presumably acts on -adrenergic receptors in the mucosa of therespiratory tract producing vasoconstriction which results in shrinkage of swollen mucus


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membranes, reduction of tissue hyperemia, edema and nasal congestion, and anincrease 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 IVphenylpropanolamine were comparable to those induced following IV administration of25 mg of amphetamine sulfate or 5-20 mg of hydroxyamphetamine. IN animals, renaland pulmonary blood flow has been variably affected, and coronary blood flow has beenincreased by phenylpropanolamine. The drug reportedly decreases menstrual flow insome menorrhagic women.

Phenylpropanolamine causes CNS stimulation and reportedly has an anorexigeniceffect that is much weaker than that of amphetamine.

Like ephedrine, phenylpropanolamine produces mydriasis; accommodation, light

reflexes, and intraocular pressure are unchanged. Phenylpropanolamine reportedlyproduces closure of the bladder neck and contraction of the posterior urethra in maleswith stress incontinence. This action may be caused by stimulation of sympatheticfibers in the hypogastric nerve.

Animal studies have failed to confirm any bronchodilator effect of phenylpropanolamine.

PharmacokineticsCetirizine:

Absorption:Cetirizine was rapidly absorbed with a time to maximum concentration (Tmax) of

approximately 1 hour following oral administration of tablets, chewable tablets, or syrupin adults. Comparable bioavailability was found between the tablet and syrup dosageforms. Comparable bioavailability was also found between the cetirizine tablet and thecetirizine chewable tablet, taken with or without water. When healthy volunteers wereadministered multiple doses of cetirizine (10 mg tablets once daily for 10 days), a meanpeak plasma concentration (Cmax) of 311ng/mL was observed. No accumulation wasobserved. 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 chewabletablet, but Tmax was delayed by 1.7 hours and 2.8 hours, respectively, and Cmax wasdecreased by 23% and 37%, respectively, in the presence of food.

Distribution:The mean plasma protein binding of cetirizine is 93%, independent of concentration inthe 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 theadministered radioactivity was recovered in the urine and 10% in the faeces.

Approximately 50% of the radioactivity was identified in the urine as unchanged drug.


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Most of the rapid increase in peak plasma radioactivity was associated with the parentdrug, suggesting a low degree of first-pass metabolism. Cetirizine is metabolized, to alimited extent, by oxidative O-dealkylation to a metabolite with negligible antihistaminicactivity. The enzyme or enzymes responsible for this metabolism have not beenidentified.

Elimination:The mean elimination half-life in 146 healthy volunteers across multiple pharmacokineticstudies was 8.3 hours and the apparent total body clearance for cetirizine wasapproximately 53 mL/min.

Phenylpropanolamine:Absorption:Phenylpropanolamine is readily absorbed from the GI tract and there is no evidence offirst-pass metabolism. Following oral administration, phenylpropanolamine is absorbedmainly 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 hoursfollowing oral administration of 50 mg of phenylpropanolamine hydrochloride to fastingadults. Following administration of 150 mg of an extended release preparation of thedrug, peak plasma concentrations of 300ng/mL occurred after 3.5 hours andPhenylpropanolamine concentrations remained greater than 180ng/mL for 12 hours.

After oral administration of a single 20- or 375-mg dose of Phenylpropanolamine as anoral solution in pediatric patients (6-12 years of age), mean peak serum as an oralsolution in pediatric patients (6-12 years of age), mean peak serum concentrations of185 or 285 ng/mL, respectively, were achieved after 2.1 or 2.7 hours, respectively, wereachieved after 2.1 or 2.7 hours respectively.

Nasal decongestion reportedly occurs within 15039 minutes after oral administration of25 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 thedrug is reported to be 3.4 L/kg. Following oral administration of a single 20- or 37.5 mgdose of phenylpropanolamine as an oral solution in pediatric patients (6-12 years ofage), mean apparent volumes of distribution as steady-state were 2.5 or 2.8 L/kg,respectively. Animal studies indicate that phenylpropanolamine is distributed intovarious tissues and fluids, including CSF and brain.

Metabolism & Elimination:Phenylpropanolamine reportedly has a half-life of 3-6 hours. In one study in children (6-12 years of age) who received a single oral dose of 20 or 37.5 mg ofPhenylpropanolamine hydrochloride as a solution, the terminal eliminiation half-lifeaveraged 2.4 or 2.8 hours, respectively, when the urinary pH was 7.


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Like other Phenylpropanolamines, small amounts of the drug are slowly metabolized inthe liver to an active hydoxylated metabolite. About 80 -90% of a dose ofPhenylpropanolamine is excreted unchanged in the urine within 24 hours. In children,about 66% of a dose of phenylpropanolamine is excreted unchanged in the urine within24 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 sodiumbicarbonate, some of the drug is reabsorbed in the renal tubule and the rate of urinaryexcretion is slowed.

In healthy individuals, renal clearance is about 6.83-10.8 mL/minute per kg. Followingoral administration of a single 20 or 37.5 mg dose of phenylpropanolaminehydrochloride as a solution in pediatric patients (6-12 years of age), total bodyclearance averaged 13.6 or 13.3 mL/minute per kg, respectively. These clearance rateswere faster than values previously reported in adults under similar conditions.

INDICATIONSALERID DTablets are indicated for the relief of symptoms of allergic rhinitis.

DOSAGE AND ADMINISTRATIONAdults and children above (12 years of age):1 tablet twice daily.

The tablet should be swallowed whole and not crushed or chewed.

CONTRAINDICATIONSALERID DTablets are contraindicated in patients with hypersensitivity to cetirizine orits parent compound hydroxyzine.

It is also contraindicated in patients with severe hypertension or coronary arterydisease, patients receiving monoamine oxidase inhibitor (MAO) therapy and in patientswith hepatic dysfunction.

WARNINGS AND PRECAUTIONSCetirizine:The occurrence of somnolence has been reported in some patients taking cetirizine;due caution should therefore be exercised when driving a car or operating potentiallydangerous machinery. Concurrent use of cetirizine with alcohol or other CNSdepressants should be avoided because additional reductions in alertness andadditional impairment of CNS performance may occur.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactasedeficiency or glucose-galactose malabsorption should not take this medicine.

Phenylpropanolamine:No data available


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Drug InteractionsCetirizine:No clinically significant drug interactions have been found with theophylline at a lowdose, azithromycin, pseudoephedrine, ketoconazole, or erythromycin. There was a

small decrease in the clearance of cetirizine caused by a 400-mg dose of theophylline; itis possible that larger theophylline doses could have a greater effect.

Phenylpropanolamine:MAO inhibitors increase the effect of sympathomimetic amines, and may prolong andintensify the effects of antihistamines. Beta-adrenergic amines may reduce theantihypertensive effects of some drugs e.g. Methyldopa and Reserpine.

OthersALERID D should be used with caution in patients with hypertension and ischaemicheart disease. Although investigations indicate that cetirizine does not intensify the

effect of alcohol, it is advisable to avoid alcohol consumption.

PregnancyThere 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.

LactationCetirizine has been reported to be excreted in human breast milk. ALERID-D is notrecommended for use by lactating mothers.

Paediatric UseThis combination cannot be used in children below the age of 12 years.

UNDESIRABLE EFFECTSCetirizineIn objective tests of psychomotor function the incidence of sedation with cetirizine wassimilar to that of placebo. There have been occasional reports of mild and transient sideeffects such as drowsiness, fatigue, headache, dizziness, agitation, dry mouth andgastro-intestinal discomfort. If desired the dose might be taken as 5mg in the morningand 5 mg in the evening.

Undesirable effects reported from post-marketing experience are listed in the followingtable 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.


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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, movementdisorders; 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.

PhenylpropanolamineThe incidence of adverse effects is low in patients receiving therapeutic doses ofphenylpropanolamine. The CNS stimulant effects of phenylpropanolamine may result innervousness, restlessness, insomnia/ sleeplessness, dizziness and headache. Nausea

and palpitations also may occur. Increases in blood pressure may occur and areusually proportionate to dosage. At least one manufacturer recommends that bloodpressure be monitored regularly during phenylpropanolamine therapy. In somepatients, severe reactions including headache, feelings of tightness in the chest, greatlyelevated blood pressure, ventricular or atrial premature contractions, and paroxysms ofventricular and atrial tachycardia have occurred with usual therapeutic doses; theseeffects probably represent idiosyncratic reactions to the drug. Excessive doses ofphenylpropanolamine may produce tachycardia, pupillary dilation, excitation, andarrhythmias; cases of heart attack, stroke, intracranial bleeding, parenchymal cerebralhemorrhage, seizures, and death possibly associated with phenylpropanolamine alsohave 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) haveexperienced acute psychotic reactions and excessive CNS stimulation.

OVERDOSAGECetirizineOverdosage has been reported with cetirizine. In one case, an adult patient who took150 mg of cetirizine was somnolent, but did not display any other clinical signs or


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abnormal blood chemistry or haematology results. In an 18-month old paediatric patientwho took an overdose of cetirizine(approximately 180 mg), restlessness and irritabilitywere 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 tocetirizine. Cetirizineis not effectively removed by dialysis, and dialysis will be ineffectiveunless a dialysable agent has been concomitantly ingested.

PhenylpropanolamineThere are several published case reports of deliberate overdoses, with elevations ofblood pressure a predominant feature. Fatality occurred in patient whereby Tachycardiawas the main clinical feature. There have been several reports of individual taking anover dose of phenylpropanolamine and suffering a cerebral hemorrhage. Other effectsreported are intense renal vasoconstriction leading to acute tubular necrosis,

PACKAGING INFORMATIONALERID D Tablets Blister pack of 10 tablets

Last updated: June 2010

alerid d tablets

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