Cetirizine diHCl, pseudoephedrine HCl.
One tablet contains 5 mg cetirizine dihydrochloride and 120 mg pseudoephedrine hydrochloride.
ATC Code: R01B A52.
Pharmacology: Pharmacodynamics: The pharmacodynamic activity of cetirizine-pseudoephedrine is directly related to an additive effect of the activity of each of its components. Cetirizine is a H1-receptor antagonist with additional anti-allergic properties: it inhibits the histamine-related early phase of the allergic reaction and also reduces the migration of certain inflammatory cells and the release of certain mediators associated with the late allergic response; it reduces the histamine or pollen-induced reactions in nasal provocation tests.
Pseudoephedrine is an orally active sympathomimetic agent with predominantly alphamimetic properties. Due to its vasoconstrictive activity, it has a decongestive effect on the nasal mucosa.
Pharmacokinetics: After oral administration, cetirizine is rapidly and almost completely absorbed. Maximal plasma concentrations are generally obtained within 1 hour under fasting conditions. Cetirizine does not undergo any appreciable first pass metabolism. After repeated oral administration, the daily urinary excretion of unchanged cetirizine is approximately 65% of the dose. The absorption and the elimination of cetirizine are independent of the dose. The plasma half-life of cetirizine is approximately 9 hours. This value is increased in patients with reduced renal function. Cetirizine is highly bound to plasma protein (93%). Its volume of distribution is small: approximately 0.5 l/kg.
Pseudoephedrine given as the sustained-release formulation cetirizine-pseudoephedrine provides maximum plasma levels 2 to 6 hours after multiple dosing. It is excreted mainly unchanged in the urine. The rate of urinary excretion is reduced in case of alkalinisation of urine, especially at pH-values above 5.5. After repeated oral administration (every 12 hours), at steady-state, the apparent elimination half-life is estimated to be approximately 9 hours. A high fat meal was not found to modify the bioavailability of both active ingredients, but it resulted however in a reduced and delayed peak plasma concentration of cetirizine. There was no evidence for a relevant pharmacokinetic interaction between cetirizine and pseudoephedrine. The dose should be reduced to half the usual recommended dose in patients with renal insufficiency.
Toxicology: Pre-clinic data: Animals studies (performed with cetirizine and pseudoephedrine combined at the ratio 5:120 w/w) have demonstrated a no-toxic effect level ≥30 mg/kg/day in the rat and 40 mg/kg/day in the Cynomoglus monkey (≥8 and 11 times the recommended dose in man). Systemic exposure at these doses was higher in monkey but lower in rat than that obtained in man.
A no-effect level of 40 mg/kg/day was established in reproduction toxicity studies in the rat (for combination of cetirizine and pseudoephedrine at the ratio 5:120 w/w). Due to the low level of systemic exposure obtained in this species, these results cannot be considered as demonstrating the safety of use in pregnant and breast-feeding women.
The combination cetirizine/pseudoephedrine is neither mutagenic nor clastogenic and therefore unlikely to present a carcinogenic risk for humans.
Zyrtec-D is indicated for the short-term treatment of symptoms associated with seasonal and perennial allergic rhinitis such as nasal congestion, sneezing, rhinorrhea, nasal and ocular pruritus, in adults and children aged 12 years and above.
It should be administered when both the antiallergenic properties of cetirizine dihydrochloride and the nasal decongestant activity of pseudoephedrine hydrochloride are desired.
Normal daily dosage: For adults and children from the age of 12 years, the normal dosage is 1 coated tablet taken twice daily (mornings and evenings), in sufficient liquid, and swallowed whole without chewing or crunching. Zyrtec-D may be taken during or between meals.
Treatment duration: Zyrtec-D may be taken only as long as do last the complaints linked to an obstructed nose and it should not be taken over a period exceeding 2 weeks. Once nasal obstruction has abated, treatment may be prolonged if necessary, by using cetirizine alone.
Patients suffering from renal and hepatic insufficiency: Patients suffering from renal or hepatic insufficiency should only take 1 tablet per day.
Zyrtec-D should not be taken by patients suffering from severe renal insufficiency.
Information on overdosing with respect to fixed combinations of cetirizine and pseudoephedrine is not available.
The information hereinafter is based on information from experience with cetirizine and pseudoephedrine used as mono preparations.
Symptoms: Cetirizine-component: The symptoms that were observed in cases of clear overdose affected the central nervous system or were related to a possible anticholinergic effect. Adverse effects that were observed after taking at least the five-fold quantity of the recommended daily dosage included the following: confusion, diarrhea, numbness, tiredness, headache, unwellness, mydriasis, pruritis, restlessness, sedation, somnolence, stupor, tachycardia, tremor, urinary retention.
Pseudoephedrine-component: Possible symptoms and signs after an overdose of pseudoephedrine are hypertension, tachycardia, sinus arrhythmia, drowsiness, nausea, vomiting, mydriasis, agitation, tremor, hyperreflexia, hallucinations and generalized seizures.
Action to be taken in the case of overdose (measures for a combination of the two substances): Treatment of an overdose is purely symptomatic. There is no known specific antidote. Activated charcoal at a dose of 1 g/kg body weight may be given for primary decontamination after the ingestion of large quantities.
Tachycardia and hypertension may occur but often do not require any treatment. Administration of a benzodiazepine is recommended for agitated patients with hypertension/tachycardia. If progression of these effects is severe, the use of labetalol, phentolamine or nitroprusside may be considered. Benzodiazepines are also the drugs of first choice for agitation and seizures.
Haemodialysis is not effective for either substance.
In cases of known hypersensitivity to one of its ingredients, to ephedrine or any of the piperazine; in patients receiving dihydroergotamine (see Interactions); during treatment with MAOI and also for 2 weeks after their discontinuation (see Interactions); in case of severe hypertension or severe coronary artery disease; in cases of renal insufficiency, uncontrolled hyperthyroidism, severe arrhythmias, pheochromocytoma, narrow-angle glaucoma or urinary retention; in patients with a history of stroke; or in patients at high risk of developing haemorrhagic stroke; 3rd trimester of pregnancy (see Use in Pregnancy & Lactation).
Zyrtec-D is not recommended in children under 12 years of age.
Due to the presence of pseudoephedrine, care should be taken when administering Zyrtec-D in patients with diabetes mellitus, overactive thyroid gland, high blood pressure, tachycardia, cardiac arrhythmia, ischemic heart disease, liver or renal insufficiency, prostate hyperplasia as well as increased eye-pressure in the treatment of elderly patients.
Caution (see Interactions) is also required in patients taking: sympathomimetic drugs such as decongestants, appetite suppressants, psychostimulants such as amphetamines (combined effects on the cardiovascular system); tricyclic antidepressants, antihypertensive drugs (reduction of antihypertensive effects); alcohol or other CNS depressants (enhanced CNS depression and impaired performance), digitalis (risk of cardiac arrhythmia); as well as in conditions where anticholinergic activity is undesirable, such as prostatic hypertrophy or bladder outflow obstruction.
Caution should also be exercised in patients with factors which could increase the risk of haemorrhagic stroke, as concomitant use of vasoconstrictors such as bromocriptine, pergolide, lisuride, cabergoline, ergotamine, or any other decongestant drug used as nasal decongestant, either by oral route or by nasal route (phenylpropanolamine, phenylephrine, ephedrine), due to the risk of vasoconstriction and increased blood pressure.
Due to vasoconstrictor effect of pseudoephedrine, caution is recommended in patients who are at risk for hypercoagulability, as in inflammatory bowel disease.
Caution is required in hypertensive patients who are treated concomitantly with NSAIDs, because both pseudoephedrine and NSAIDs can increase blood pressure.
As for other centrally acting stimulants, abuse has been observed for pseudoephedrine.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Patients suffering from renal insufficiency: Zyrtec-D should not be administered in patients with intermediately pronounced or severe renal insufficiency, and only 1 tablet per day should be administered in patients suffering from a light renal insufficiency.
There have been rare cases of posterior reversible encephalopathy (PRES) / reversible cerebral vasoconstriction syndrome (RCVS) reported with sympathomimetic drugs, including pseudoephedrine. Symptoms reported included sudden onset of severe headache, nausea, vomiting, and visual disturbances. Most cases improved or resolved within a few days following appropriate treatment. Psuedoephedrine should be discontinued immediately and medical advice sought if signs/symptoms of PRES/RCVS develop.
Effects on ability to drive and handle machines: Cetirizine may lead to increased sleepiness. Therefore Zyrtec-D has an influence on the ability to drive or operate machinery.
No negative effect of pseudoephedrine on the vigilance has been reported nor is expected.
Pregnancy: There are no adequate data on the use of cetirizine-pseudoephedrine in pregnant women. The use of pseudoephedrine during the first trimester of pregnancy has been associated with an increased frequency of gastroschisis (a developmental defect in the abdominal wall with intestinal herniation).
Due to the vasoconstrictive properties of pseudoephedrine, it should not be used during the third trimester as it can induce a reduction in uteroplacental circulation. Data on a limited number of exposed pregnancies indicate no adverse effects of cetirizine on pregnancy or on the health of the fetus/newborn child. There is insufficient animal data with respect to pregnancy, embryonal/fetal development, parturition or post natal development (see Pharmacology: Toxicology: Preclinic data under Actions). Zyrtec-D should not be used during pregnancy and is contraindicated in the third trimester of pregnancy.
Lactation: Cetirizine and pseudoephedrine are excreted into human milk. Therefore, Zyrtec-D should not be used during lactation.
Drug safety information from clinical tests:
In controlled clinical trials, adverse reactions reported in more than 1% of the patients receiving the combination cetirizine/psuedoephedrine, were not different from those reported for cetirizine or pseudoephedrine alone.
Post Marketing Experience:
Undesirable effects encountered with cetirizine are mainly related to CNS depressant or paradoxical CNS stimulation effects, to anticholinergic-like activity or hypersensitivity reaction (including anaphylactic shock), while the undesirable effects of pseudoephedrine are more likely related to CNS stimulation, and cardiovascular disorders. Isolated cases of stroke and ischemic colitis associated with pseudoephedrine use have been identified in literature.
The following undesirable effects have been reported. They are displayed according to MedDRA primary System Organ Classes and by estimated frequency. Frequencies are defined as follows: Very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10000, <1/1000); very rare (<1/10000), not known (cannot be estimated from the available data): See Table.
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No interaction studies have been performed with the combination cetirizine-pseudoephedrine.
Cetirizine-component: Simultaneous use with pseudoephedrine, cimetidine, ketoconazole, erythromycin or azithromycin does not influence the pharmacokinetic parameters of cetirizine. No pharmacokinetic interactions were observed. According to in vitro tests, cetirizine does not influence the protein-bonding effect of warfarin.
Simultaneous administration with azithromycin, erythromycin, ketoconazole, theophylline and pseudoephedrine showed no relevant changes in the clinical laboratory parameters, vital functions and ECG.
In a study with the simultaneous administration of theophylline (400 mg daily) and cetirizine (20 mg daily), a slight but statistically significant elevation of the 24-hour AUC of 19% was found for cetirizine as well as 11% for theophylline. Furthermore, the maximum plasma levels increased to 7.7% and 6.4% respectively for cetirizine and theophylline. Simultaneously, the clearance of cetirizine lessened by -16% as well as -10% in the case of theophylline while cetirizine was being taken by patients who had received prior treatment with theophylline. Prior treatment with cetirizine did not, however, significantly influence the pharmacokinetic parameters of theophylline.
After a single dose of 10 mg cetirizine, the effect of alcohol (0.8%) was not significantly potentiated; a statistically significant interaction with Diazepam 5 mg was proven for one of 16 psychometric tests.
Simultaneous administration of 10 mg cetirizine daily with glipicide led to a slight drop in the glucose parameters. This effect is not clinically relevant. Nonetheless, separate administration - glipicide in the morning and cetirizine in the evening - is recommended. The extent of to which cetirizine is absorbed is not reduced by simultaneous food intake although the absorption is decreased by 1 hour.
In a multiple dose study of ritonavir (600 mg twice daily) and cetirizine (10 mg daily), the extent of exposure to cetirizine was increased by about 40% while the disposition of ritonavir was slightly altered (-11%) further to concomitant cetirizine administration.
Allergy skin tests are inhibited by antihistamines and an appropriate wash-out period is required before performing them.
A high fat meal was not found to modify the bioavailability of both active ingredients, but it resulted however in a reduced and delayed peak plasma concentration of cetirizine.
Pseudoephedrine-component: Simultaneous treatment with pseudoephedrine and MAOI (Monoamine Oxidase Inhibitors) can result in hypertensive crisis. Because of the long duration of action of MAOI (Monoamine Oxidase Inhibitors), this interaction may be observable during a period of 15 days following MAOI treatment.
Sympathomimetic amines may reduce the antihypertensive effects of beta-adrenergic blockers and of drugs that interfere with sympathetic activity such as methyldopa, guanethidine and reserpine (see Precautions).
Administration of linezolid with pseudoephedrine may result in an increase in blood pressure in normotensive patients.
Increased ectopic pacemaker activity can occur when pseudoephedrine is used concomitantly with digitalis; use of cetirizine-pseudoephedrine is therefore to be avoided in digitalized patients.
Antacids and proton pump inhibitors increase the rate of pseudoephedrine absorption; kaolin decreases it.
Concurrent use with halogenated anaesthetic agents may provoke or worsen ventricular arrhythmia.
Impact of diagnostic methods: As the pertinence of skin allergy tests is reduced in the presence of antihistamines, it is recommended to observe an appropriate washing-out period prior to undertaking skin tests.
Zyrtec-D should be stored out of reach of children.
R06AE07 - cetirizine ; Belongs to the class of piperazine derivatives used as systemic antihistamines.
PR tab (white to off-white, round biconvex) x 10's.