ALERID D Tablets (Cetirizine hydrochloride + Phenylephrine hydrochloride)

Table of Content

Composition

Each tablet contains:
Cetirizine hydrochloride .....5 mg
Phenylephrine hydrochloride ...10 mg

Dosage Form

Oral tablets

Pharmacology

Pharmacodynamics

Cetirizine
Cetirizine, a human metabolite of hydroxyzine, is a potent and selective antagonist of peripheral H1-receptors. In vitro receptor binding studies have shown no measurable affinity for other than H1-receptors.

In addition to its anti-H1 effect, cetirizine was shown to display anti-allergic activities: at a dose of 10 mg once or twice daily, it inhibits the late phase recruitment of eosinophils, in the skin and conjunctiva of atopic subjects submitted to allergen challenge.

Studies in healthy volunteers show that cetirizine, at doses of 5 and 10 mg strongly inhibits the wheal and flare reactions induced by very high concentrations of histamine into the skin, but the correlation with efficacy is not established.

In a 35-day study in children aged 5 to 12 years, no tolerance to the antihistaminic effect (suppression of wheal and flare) of cetirizine was found. When a treatment with cetirizine is stopped after repeated administration, the skin recovers its normal reactivity to histamine within 3 days.

In a six-week, placebo-controlled study of 186 patients with allergic rhinitis and concomitant mild to moderate asthma, cetirizine 10 mg once daily improved rhinitis symptoms and did not alter pulmonary function. This study supports the safety of administering cetirizine to allergic patients with mild to moderate asthma.

In a placebo-controlled study, cetirizine given at the high daily dose of 60 mg for seven days did not cause statistically significant prolongation of QT interval.

At the recommended dosage, cetirizine has demonstrated that it improves the quality of life of patients with perennial and seasonal allergic rhinitis.

Phenylephrine
Phenylephrine is a sympathomimetic agent with mainly direct effects on adrenergic receptors. It has predominantly alpha adrenergic activity and is without stimulating effects on the central nervous system. The sympathomimetic effect of phenylephrine produces vasoconstriction which in turn relieves nasal congestion.

Pharmacokinetics

Cetirizine
The steady-state peak plasma concentrations is approximately 300 ng/mL and is achieved within 1.0 ± 0.5 h. No accumulation is observed for cetirizine following daily doses of 10 mg for 10 days. The distribution of pharmacokinetic parameters such as peak plasma concentration (Cmax) and area under curve (AUC), is unimodal in human volunteers.

The extent of absorption of cetirizine is not reduced with food, although the rate of absorption is decreased. The extent of bioavailability is similar when cetirizine is given as solutions, capsules or tablets.

The apparent volume of distribution is 0.50 l/kg. Plasma protein binding of cetirizine is 93 ± 0.3 %. Cetirizine does not modify the protein binding of warfarin.

Cetirizine does not undergo extensive first pass metabolism. About two-third of the dose are excreted unchanged in urine. The terminal half-life is approximately 10 hours.

Cetirizine exhibits linear kinetics over the range of 5 to 60 mg.

Special populations

Elderly: Following a single 10 mg oral dose, half-life increased by about 50 % and clearance decreased by 40% in 16 elderly subjects compared to the normal subjects. The decrease in cetirizine clearance in these elderly volunteers appeared to be related to their decreased renal function.

Children, infants and toddlers: The half-life of cetirizine was about 6 hours in children of 6-12 years and 5 hours in children 2-6 years. In infants and toddlers aged 6 to 24 months, it is reduced to 3.1 hours

Renally impaired patients: The pharmacokinetics of the drug were similar in patients with mild impairment (creatinine clearance higher than 40 mL/min) and healthy volunteers. Patients with moderate renal impairment had a 3-fold increase in half-life and 70% decrease in clearance compared to healthy volunteers.

Patients on hemodialysis (creatinine clearance less than 7 mL/min) given a single oral 10 mg dose of cetirizine had a 3-fold increase in half-life and a 70% decrease in clearance compared to normals. Cetirizine was poorly cleared by haemodialysis. Dosing adjustment is necessary in patients with moderate or severe renal impairment.

Hepatically impaired patients: Patients with chronic liver diseases (hepatocellular, cholestatic, and biliary cirrhosis) given 10 or 20 mg of cetirizine as a single dose had a 50% increase in half-life along with a 40% decrease in clearance compared to healthy subjects.

Dosing adjustment is only necessary in hepatically impaired patients if concomitant renal impairment is present.

Phenylephrine
Phenylephrine is readily absorbed after oral administration but is subject to extensive presystemic metabolism, much of which occurs in the enterocytes. As a consequence, systemic bioavailability is only about 40%. Following oral administration, peak plasma concentrations are achieved in 1-2 hours. The mean plasma half-life is in the range of 2-3 hours. Penetration into the brain appears to be minimal.

Following absorption, the drug is extensively metabolised in the liver. Both phenylephrine and its metabolites are excreted in the urine.

The volume of distribution is between 200 and 500 litres, but there are no data on the extent of plasma protein binding.

Indications

ALERID D Tablets are indicated for the relief of symptoms of allergic rhinitis and nasal congestion.

Dosage and Administration

Adults and children above (12 years of age)

One 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

General

Cetirizine
At therapeutic doses, no clinically significant interactions have been demonstrated with alcohol (for a blood alcohol level of 0.5 g/L). Nevertheless, precaution is recommended if alcohol is taken concomitantly.

Caution should be taken in patients with predisposition factors of urinary retention (e.g. spinal cord lesion, prostatic hyperplasia) as cetirizine may increase the risk of urinary retention.

Caution in epileptic patients and patients at risk of convulsions is recommended.

The use of the film-coated tablet formulation is not recommended in children aged less than 6 years since this formulation does not allow for appropriate dose adaptation.

Allergy skin tests are inhibited by antihistamines and a wash-out period (of 3 days) is required before performing them.

Phenylephrine
This medicine should be used with caution in patients with occlusive vascular disease including Raynaud's Phenomenon. Do not take for longer than 7 days, unless your doctor agrees. If symptoms do not go away talk to your doctor. Keep all medicines out of the reach of children.

Warning: Do not exceed the stated dose.

Drug Interactions

Cetirizine
Due to the pharmacokinetic, pharmacodynamic and tolerance profile of cetirizine, no interactions are expected with this antihistamine. Actually, neither pharmacodynamic nor significant pharmacokinetic interaction was reported in drug-drug interactions studies performed, notably with pseudoephedrine or theophylline (400 mg/day).

The extent of absorption of cetirizine is not reduced with food, although the rate of absorption is decreased.

Phenylephrine
Should not be given to patients being treated with monoamine oxidase inhibitors or within 14 days of stopping such treatment. May enhance the effects of anticholinergic drugs such as tricyclic antidepressants. May increase the possibility of arrhythmias in digitalised patients. May enhance the cardiovascular effects of other sympathomimetic amines (e.g. decongestants).

This medicine should not be taken together with vasodilators, Beta-blockers or enzyme inducers such as alcohol.

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 Tablets should be used in pregnancy only if clearly needed.

Lactation

Cetirizine has been reported to be excreted in human breast milk. ALERID D Tablets 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

Clinical studies have shown that cetirizine at the recommended dosage has minor undesirable effects on the CNS, including somnolence, fatigue, dizziness and headache. In some cases, paradoxical CNS stimulation has been reported.

Although cetirizine is a selective antagonist of peripheral H1-receptors and is relatively free of anticholinergic activity, isolated cases of micturition difficulty, eye accommodation disorders and dry mouth have been reported.

Instances of abnormal hepatic function with elevated hepatic enzymes accompanied by elevated bilirubin have been reported. Mostly this resolves upon discontinuation of the treatment with cetirizine dihydrochloride.

Clinical Trials

Double blind controlled clinical trials comparing cetirizine to placebo or other antihistamines at the recommended dosage (10 mg daily for cetirizine), of which quantified safety data are available, included more than 3200 subjects exposed to cetirizine.

From this pooling, the following adverse reactions were reported for cetirizine 10 mg in the placebo-controlled trials at rates of 1.0% or greater:
Adverse reactions

(WHO-ART)

Cetirizine 10 mg

(n= 3260)

Placebo

(n = 3061)

Body as a whole - general disorders

Fatigue

Central and peripheral nervous system disorders

Dizziness

Headache

1.63%

1.10%

7.42%

0.95%

0.98%

8.07%

Gastro-intestinal system disorders

Abdominal pain

Dry mouth

Nausea

0.98%

2.09%

1.07%

1.08%

0.82%

1.14%

Psychiatric disorders

Somnolence

9.63%

5.00%

Respiratory system disorders

Pharyngitis

1.29%

1.34%

Although statistically more common than under placebo, somnolence was mild to moderate in the majority of cases. Objective tests as demonstrated by other studies have demonstrated that usual daily activities are unaffected at the recommended daily dose in healthy young volunteers.

Adverse reactions at rates of 1 % or greater in children aged from 6 months to 12 years, included in placebo-controlled clinical trials are:
Adverse Reactions

(WHO-ART)

Cetirizine

(n=1656)

Placebo

(n =1294)

Gastro-intestinal system disorders 

Diarrhoea

1.0%

0.6%

Psychiatric disorders

Somnolence

1.8%

1.4%

Respiratory system disorders

Rhinitis

1.4 %

1.1 %

Body as a whole - general disorders

Fatigue

1.0%

0.3%

Post-marketing Experience

In addition to the adverse reactions reported during clinical studies and listed above, the following undesirable effects have been reported in post-marketing experience.

Undesirable effects are described according to MedDRA System Organ Class and by estimated frequency based on post-marketing experience.

Frequencies are defined as follows: Very common (≥1/10); common (≥1/100 to to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data)

Blood and lymphatic disorders: 

Very rare: thrombocytopenia

Immune system disorders:

Rare: hypersensitivity

Very rare: anaphylactic shock

Metabolism and nutrition disorders:

Not known: increased appetite

Psychiatric disorders:

Uncommon: agitation

Rare: aggression, confusion, depression, hallucination, insomnia

Very rare: tics

Not known: suicidal ideation

Nervous system disorders:

Uncommon: paraesthesia

Rare: convulsions

Very rare: dysgeusia, syncope, tremor, dystonia, dyskinesia

Not known: amnesia, memory impairment

Eye disorders:

Very rare: accommodation disorder, blurred vision, oculogyration

Ear and labyrinth disorders:

Not known: vertigo

Cardiac disorders:

Rare: tachycardia

Gastro-intestinal disorders:

Uncommon: diarrhoea

Hepatobiliary disorders:

Rare: hepatic function abnormal (increased transaminases, alkaline phosphatase, γ-GT and bilirubin)

Skin and subcutaneous tissue disorders:

Uncommon: pruritus, rash

Rare: urticaria

Very rare: angioneurotic oedema, fixed drug eruption

Renal and urinary disorders:

Very rare: dysuria, enuresis

Not known: urinary retention

General disorders and administration site conditions:

Uncommon: asthenia, malaise

Rare: oedema

Investigations:

Rare: weight increased

Phenylephrine
Adverse effects may include tachycardia, cardiac arrhythmias, palpitations, hypertension, nausea, vomiting, headache and occasionally urinary retention in males.

Overdosage

Cetirizine
Symptoms
Symptoms observed after an overdose of cetirizine are mainly associated with CNS effects or with effects that could suggest an anticholinergic effect.

Adverse events reported after an intake of at least 5 times the recommended daily dose are: confusion, diarrhoea, dizziness, fatigue, headache, malaise, mydriasis, pruritus, restlessness, sedation, somnolence, stupor, tachycardia, tremor, and urinary retention.

Management
There is no known specific antidote to cetirizine.

Should overdose occur, symptomatic or supportive treatment is recommended. Gastric lavage should be considered following ingestion of a short occurrence.

Cetirizine is not effectively removed by dialysis.

Phenylephrine
Symptoms of overdosage include irritability, restlessness, palpitations, hypertension, difficulty in micturition, nausea, vomiting, thirst and convulsions. In severe overdosage gastric lavage and aspiration should be performed. Symptomatic and supportive measures should be undertaken, particularly with regard to cardiovascular and respiratory systems. Convulsions should be controlled with intravenous diazepam. Chlorpromazine may be used to control marked excitement and hallucinations. Severe hypertension may need to be treated with an alpha-adrenoreceptor blocking drug, such as phentolamine. A beta blocker may be required to control cardiac arrhythmias.

Packaging Information

ALERID D: Blister pack of 10 tablets