Core Safety Profile. Pharmaceutical form(s)/strength: Prolonged release tablet 5 mg cetirizine / 120 mg pseudoephedrine. Date of FAR:

Transcription

1 Core Safety Profile Active substance: Cetirizine + Pseudoephedrine Pharmaceutical form(s)/strength: Prolonged release tablet 5 mg cetirizine / 120 mg pseudoephedrine P - RMS: BE/H/PSUR/0019/001 Date of FAR:

2 4.2 Posology and method of administration Posology Adults and children aged 12 years and older One tablet twice daily (morning and evening), with or without food. The duration of treatment should not exceed the period of symptoms, and should not exceed 2 to 3 weeks. When adequate relief from nasal symptoms is obtained, treatment with cetirizine should be continued, if appropriate. Method of administration The tablets should be swallowed with some liquid and should not be chewed or crushed. Special population Renal impairment In patients with moderate renal insufficiency, dosage should be reduced to one tablet per day. Hepatic impairment In patients with moderate hepatic insufficiency, dosage should be reduced to one tablet per day. 4.3 Contra-indications Cetirizine-pseudoephedrine is contra-indicated in patients with: known hypersensitivity to one of the ingredients, to ephedrine or any other piperazine severe hypertension or severe coronary artery disease severe renal insufficiency uncontrolled hyperthyroidism severe arrhythmias pheochromocytoma elevated intraocular pressure urinary retention a history of stroke high risk of developing haemorrhagic stroke Cetirizine-pseudoephedrine is contra-indicated in patients concomitantly treated with: dihydroergotamine MAOI and also for 2 weeks after their discontinuation Cetirizine-pseudoephedrine is not recommended in children under 12 years of age as it has not been studied in this age group. 4.4 Special warnings and precautions for use Due to the presence of pseudoephedrine, cetirizine-pseudoephedrine should be used with caution in patients with diabetes mellitus, hyperthyroidism, arterial hypertension, tachycardia, cardiac arrhythmia, ischemic heart disease, moderate renal or hepatic insufficiency, and in the elderly. Cetirizine-Pseudoephedrine 12/17 FAR BE/H/PSUR/0019/001 Caution is also required in patients taking: sympathomimetic drugs such as decongestants, appetite suppressants, psychostimulants such as amphetamines (combined effects on the cardiovascvular 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), 2/6

3 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, Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine. 4.5 Interactions with other medicinal products and other forms of interaction No interaction studies have been performed with the combination cetirizinepseudoephedrine. Pharmacokinetic interaction studies were conducted with cetirizine and cimetidine, ketoconazole, erythromycin, azithromycin, antipyrine and pseudoephedrine; no pharmacokinetic interactions were observed. In a multiple dose study of theophylline (400 mg once a day) and cetirizine, there was a small (16%) decrease in clearance of cetirizine, while the disposition of theophylline was not altered by concomitant cetirizine administration. Studies with cetirizine and cimetidine, glipizide, diazepam, and pseudoephedrine have revealed no evidence of adverse pharmacodynamic interactions. Studies with cetirizine and azithromycin, erythromycin, ketoconazole, theophylline, antipyrine and pseudoephedrine have revealed no evidence of adverse clinical interactions. In particular, concomitant administration of cetirizine with macrolides or ketoconazole has never resulted in clinically relevant ECG changes. 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. Concomitant use of symphatomimetic amines with monoamine oxidase (MAO) inhibitors can result in hypertensive crisis. Because of the long duration of action of MAO inhibitors, this interaction is still possible 15 days after stopping such a 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 Special warnings and precautions for use). 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 pomp inhibitors increase the rate of pseudoephedrine absorption; kaolin decreases it. Concurrent use with halogenated anaesthetic agents may provoke or worsen ventricular arrhythmia. 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. 3/6

4 4.6 Pregnancy and lactation 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. Cetirizinepseudoephedrine should not be used during pregnancy. Lactation Cetirizine and pseudoephedrine are excreted into human milk. Therefore, Cetirizinepseudoephedrine should not be used during lactation. 4.7 Effects on ability to drive and use machines Objective measurements of driving ability, sleep latency and assembly line performance, under cetirizine, have not demonstrated any clinically relevant effects at the recommended dose. It should nevertheless be noted that variations in these effects exist with different drugs in different individuals: in clinical trials, subjective feelings of somnolence have been reported. At doses higher than normally recommended, central nervous system effects may occur. No negative effect of pseudoephedrine has been reported nor is expected. However, patients are advised not to exceed the recommended dose if driving a car or operating potentially dangerous machinery. The patient should not drive if he feels drowsy or dizzy. 4.8 Undesirable effects Clinical studies In controlled clinical trials, adverse reactions reported in more than 1 % of the patients receiving the combination cetirizine/pseudoephedrine, 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 reactions (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. 4/6

5 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). Immune system disorders Rare: hypersensitivity Psychiatric disorders Common: nervousness, insomnia Uncommon: anxiety, agitation Rare: hallucinations Very rare: psychotic disorder Nervous system disorders Common: vertigo, dizziness, headache, somnolence Rare: convulsions, tremor Very rare: dysgeusia, cerebrovascular accident (stroke) Eye disorders Not known: accommodation disorder, blurred vision, mydriasis, eye pain, visual impairment, photophobia Cardiac disorders Common: tachycardia Rare: arrhythmia Vascular disorders Rare: pallor, hypertension Very rare: circulatory collapse Respiratory, thoracic and mediastinal disorders Not known: dyspnoea Gastrointestinal disorders Common: dry mouth, nausea Rare: vomiting Very rare: colitis ischaemic Hepatobiliary disorders Rare: hepatic function disorders (increase in transaminases, alkaline phosphatase, gamma- GT, bilirubin) Skin and subcutaneous tissues disorders Rare: dry skin, rash, sweating increased, urticaria Very rare: fixed drug eruption, angioneurotic oedema Renal and urinary disorders Rare: dysuria General disorders and administration site conditions Frequent: asthenia 5/6

6 4.9 Overdose Symptoms observed after an overdose of cetirizine are mainly associated with CNS effects or with effects that could suggest an anticholinergic effect. In large doses, sympathomimetics may induce a toxic psychosis with delusions and hallucinations. Some patients may develop cardiac arrhythmias, circulatory collapse, convulsions, coma, and respiratory failure, which can be lethal. Acute overdosage with cetirizine-pseudoephedrine may produce diarrhoea, dizziness, fatigue, headache, malaise, mydriasis, urinary retention, tachycardia, cardiac arrhythmia, arterial hypertension, signs of CNS depression (sedation, apnoea, unconsciousness, cyanosis and cardiovascular collapse) or stimulation (insomnia, hallucinations, tremor, seizures) which could be fatal. Treatment, preferably in a hospital setting, should be symptomatic and supportive, taking into account any concomitantly ingested medications. Should vomiting not occur spontaneously, it should be induced. Gastric lavage is recommended. There are no known antidotes. Sympathomimetic amines should not be used. Hypertension and tachycardia can be controlled with use of alpha-blockers and/or beta-blockers. Seizures can be treated with intravenous diazepam (or diazepam given rectally in the case of children). Cetirizine and pseudoephedrine are poorly eliminated by haemodialysis. 6/6