- 244 Downloads
Desloratadine (Clarinex®, Neoclarityn™ Aerius®, Azomyr®, Opulis, Allex), the principal metabolite of loratadine, is itself an orally active, nonsedating, peripheral histamine H1-receptor antagonist. It is indicated in the US and Europe for the treatment of seasonal allergic rhinitis (SAR), perennial allergic rhinitis (PAR) and chronic idiopathic urticaria (CIU). It has a rapid onset of effect, efficacy throughout a 24-hour dosage interval, and sustained efficacy in these allergic conditions, as demonstrated in placebo-controlled trials of up to 6 weeks’ duration in adult and adolescent patients. At present, there are no published direct comparisons of desloratadine and other H1-antihistamines; however, the principal, potential clinical advantages of desloratadine over late-generation H1-antihistamines are the drug’s decongestant activity, which has been corroborated in several studies of patients with allergic rhinitis, and its anti-inflammatory effects. Indeed, the decongestant activity of desloratadine did not differ from that of pseudoephedrine in a trial in patients with SAR, and in patients with SAR and coexisting asthma, desloratadine reduced asthma symptoms and β2-agonist use, and improved forced expiratory flow in 1 second. However, these issues warrant further study.
Desloratadine is generally well tolerated. The overall incidence of adverse events in adults, adolescents and children was not significantly different to that with placebo, and similar proportions of desloratadine or placebo recipients reported events such as pharyngitis, dry mouth, myalgia, somnolence, dysmenorrhoea or fatigue. Desloratadine does not cause sedation or prolong the corrected QT (QTc) interval, can be administered without regard to concurrent intake of food and grapefruit juice, and appears to have negligible potential for drug interactions mediated by several metabolic systems.
Conclusion: Although comparative studies with second-generation and other recently developed H1-antihistamines are needed to define the drug’s clinical profile more clearly, desloratadine can be expected to claim a prominent place in the management of allergic disorders in general, and in the amelioration of specific symptoms of allergy (e.g. nasal congestion) in patients with such disorders.
In vitro, desloratadine has marked selectivity for histamine H1 receptors, where it is approximately 50–200 times more potent than loratadine, fexofenadine or cetirizine. Desloratadine has no marked antimuscarinic activity at concentrations likely to be attained clinically.
A single dose of desloratadine 5mg had a rapid onset of action (≈28 minutes) in patients with seasonal allergic rhinitis (SAR). Nasal patency and nasal airflow are maintained to a greater extent with desloratadine than with placebo following allergen challenge in patients with SAR. Several studies also reveal that desloratadine 5–7.5 mg/day significantly reduces nasal congestion after a single dose, and for up to 4 weeks during multiple-dose therapy; however, no significant additional decongestant activity was reported for the 7.5mg over the 5mg dose. Significant desloratadine-induced improvements have been documented in total nasal symptoms and nasal discharge, sneezing, itchy nose, eyes, ears or palate, and tearing. Similar efficacy outcomes have been reported in patients with perennial allergic rhinitis (PAR).
Single-dose desloratadine 5mg suppressed histamine-induced wheal and flare to a lesser extent than fexofenadine 180mg and cetirizine 10mg in studies in healthy volunteers. However, the relevance of such findings to clinical efficacy in patients with chronic idiopathic urticaria (CIU) remains unclear.
Desloratadine does not significantly inhibit cardiac potassium channels in vitro. In healthy volunteers, multiple-dose administration of desloratadine at nine times the recommended dosage had no clinically relevant effect on ECG parameters. Furthermore, several studies in healthy volunteers and patients with SAR suggest that desloratadine is without significant CNS activity: a single dose of desloratadine 5 or 7.5mg, unlike diphenhydramine 50mg, had no sedative or performance-impairing activity compared with placebo. In healthy volunteers, desloratadine does not potentiate the effects of alcohol.
Desloratadine is rapidly absorbed after oral administration, and the pharmacokinetic profile is linear across the single-dose range of 5–20mg. The multiple- and single-dose pharmacokinetic profiles of desloratadine are generally similar. Steady-state plasma concentrations are reached by day 7 of treatment with desloratadine 5 mg/day. After administration of desloratadine 5 mg once daily for 10 days in healthy volunteers, a mean peak plasma concentration (Cmax) of 3.98 μg/L was achieved in a mean time 3.17 hours; mean area under the plasma concentration-time curve from time zero to 24 hours (AUC24h) was 56.9 μg · h/L. Food does not markedly alter the oral bioavailability of desloratadine. About 82–87% of a dose of desloratadine is bound to plasma proteins.
Desloratadine is extensively metabolised to its principal active metabolite, 3-hydroxy desloratadine, which is subsequently deactivated by glucuronidation. The cytochrome P450 (CYP) isoenzyme that metabolises desloratadine has not been identified, but CYP3A4 and CYP2D6 are unlikely to be extensively involved. Although approximately 20% of African Americans and 6–7% of the general population are slow metabolisers of desloratadine, the clinical significance of this is unknown.
After administration of desloratadine 5mg for 10 days in healthy volunteers, the terminal phase half-life was 26.8 hours. About 40% of an administered dose is excreted in the urine and about 45% in the faeces as metabolites.
Pharmacokinetic equivalence was established in healthy children aged 2–5 or 6–11 years who received desloratadine 1.25 or 2.5mg as an oral syrup formulation and adults who received desloratadine 5mg as a tablet.
Age, sex and race appear to have no major effect on the pharmacokinetics of desloratadine. However, because of altered Cmax, AUC and apparent oral clearance, desloratadine dosage adjustments are advocated in the US in patients with hepatic or renal impairment of all severities.
Desloratadine does not interact significantly with individual inhibitors of CYP3A4 or CYP2D6, such as erythromycin, ketoconazole, cimetidine and fluoxetine, or with azithromycin. No changes in ECG parameters were evident when these compounds were administered concomitantly with desloratadine. In contrast, increases in fexofenadine AUC of 67–164% were reported when erythromycin, ketoconazole or azithromycin was administered with fexofenadine. Moreover, unlike desloratadine, fexofenadine has been shown to interact with food, antacids and grapefruit juice such that its absorption is markedly reduced.
Several randomised, double-blind, multicentre or single-centre studies demonstrated the superior efficacy of desloratadine relative to placebo in patients with SAR. In a dose-ranging study in >1000 patients, desloratadine 5–20 mg/day versus placebo significantly reduced day 2 and 2-week mean morning instantaneous scores for total symptoms (i.e. nasal itching, nasal stuffiness/congestion, rhinor-rhoea and sneezing) [p < 0.01]. Dosages of 7.5, 10 or 20 mg/day had no efficacy advantage over 5 mg/day, and the 2.5 mg/day regimen had no advantage over placebo. Desloratadine 5 mg/day significantly reduced mean morning/evening reflective scores for total, total nasal and total non-nasal symptoms versus placebo in two 2-week studies in a total of 672 evaluable patients during the spring or fall allergy season and in another 2-week study in 218 patients during three allergy seasons (all p < 0.05). Furthermore, desloratadine 5 mg/day significantly reduced mean morning/evening nasal congestion scores versus placebo in a 2-week study in 346 patients with SAR (p < 0.05). In another well-designed trial, which involved >1000 patients, the reduction in mean nasal congestion score over 2 weeks with desloratadine 5 mg/day did not differ from that with pseudoephedrine 240 mg/day, and desloratadine had significant, additive decongestant activity when given in combination with pseudoephedrine. Pooled data from a database of >1300 patients with SAR also ascribe to desloratadine the ability to significantly reduce nasal congestion/stuffiness versus placebo (p ≤ 0.02).
In two observational studies of a total of ≈54 000 patients with SAR, desloratadine reduced scores for total, nasal, ocular, asthma and dermal symptoms, and for sleep disturbance by approximately 55–75% versus baseline, and 85% of patients were less bothered by their most troublesome symptom after desloratadine treatment. Two other studies showed that desloratadine improved quality of life compared with placebo in domains of the Rhinoconjunctivitis Quality of Life Questionnaire and Short Form-36 in a total of >800 patients with SAR.
Two randomised, double-blind, placebo-controlled, multicentre studies have demonstrated the efficacy of desloratadine in reducing rhinitis symptoms in patients with SAR and coexisting asthma. These trials evaluated a total of 613 patients aged ≥15 years who were randomised to receive desloratadine 5 mg/day or placebo for 4 weeks. Besides producing significant improvements (p < 0.05 vs placebo) in overall, total asthma, total nasal and total non-nasal symptoms, and nasal congestion, desloratadine significantly reduced the use of rescue antiasthmatic medication with β2-agonists, and scores for the specific asthma symptoms of cough and wheezing. A subgroup analysis of 189 patients with baseline forced expiratory flow in 1 second (FEV1) ≤80% also revealed significant improvement in FEV1 during and at the end of desloratadine treatment (p ≤ 0.02). Moreover, in a postmarketing surveillance study in which approximately 40% of almost 50 000 patients with SAR reported at least one symptom of asthma at baseline, desloratadine significantly reduced mean asthma symptom-sum score by >70% ( p < 0.0001).
To date, two studies have been published of the efficacy of desloratadine in patients with perennial allergic rhinitis. In these large-scale trials, desloratadine had a rapid onset of effect, as indicated in one study by a significant reduction (vs placebo) in mean total symptom score (TSS) 12 hours after the first study dose. Desloratadine efficacy was also sustained, compared with placebo, as evident from improvements in mean 4-week morning/evening instantaneous TSS and reflective scores for total nasal and total non-nasal symptoms, and peak nasal inspiratory flow.
Desloratadine has shown efficacy in patients with CIU. In two randomised, double-blind trials, desloratadine 5 mg/day for 6 weeks significantly decreased (p < 0.001 vs placebo) the primary efficacy mean symptom score for pruritus. These effects were observed after the first dose and were maintained throughout the 6-week trials. Secondary analysis scores for pruritus and interference with sleep and daily activities, and number and size of hives were also reduced in comparison with placebo. In addition, desloratadine was effective throughout a 24-hour dosage interval. In an open-label trial, approximately 50% of patients had no symptoms of urticaria after desloratadine therapy (5 mg/day for 4 weeks). Similarly, in a postmarketing surveillance study in 9246 patients with CIU, desloratadine significantly reduced CIU symptoms and decreased the effect of CIU on sleep and daily activities versus baseline (p < 0.001).
Tolerability information is available from randomised, double-blind studies of desloratadine involving a total of 3124 adult or adolescent patients with allergic rhinitis (with or without coexisting asthma) or CIU in which desloratadine 1.25–20 mg/day was administered for 2–6 weeks. In placebo-controlled trials evaluating desloratadine 5 mg/day, the total incidence of treatment-related adverse events was similar in desloratadine-treated patients and placebo recipients (15–22% vs 14% of patients). Additional information from the manufacturer’s prescribing information reveals that in 3307 patients with allergic rhinitis who received the recommended desloratadine dosage of 5 mg/day (n = 1655) or placebo (1652) the most frequently reported adverse events that occurred more commonly with desloratadine than with placebo and were reported by ≥2% of desloratadine recipients were pharyngitis (4.1% vs 2.0%), dry mouth (3.0% vs 1.9%), myalgia (2.1% vs 1.8%), somnolence (2.1% vs 1.8%), dysmenorrhoea (2.1% vs 1.6%) and fatigue (2.1% vs 1.2%); however, these differences were not statistically significant. None of the adverse events was serious, most were mild or moderate in severity, and treatment withdrawal due to adverse events was required in only a few patients. Desloratadine had no clinically relevant effects on vital signs, physical examinations, laboratory tests (including tests of renal and hepatic function), or on ECG parameters (including QTc interval).
In a postmarketing surveillance study in which almost 80 000 patients with SAR were treated with desloratadine, 287 patients (overall incidence of 0.37% of patients) reported adverse events. The most common events considered possibly or probably related to treatment were fatigue, headache, nausea, dry mouth and diarrhoea (all ≤0.07%).
Desloratadine 1.25 or 2.5 mg/day was well tolerated in two randomised, double-blind, placebo-controlled trials in 111 and 120 children with allergic rhinitis or CIU aged <12 years. The incidence of headache (the most frequently reported adverse event) in children aged 2–5 or 6–11 years with desloratadine (1.8% and 1.7%) was lower than with placebo (5.4% and 6.7%), although differences were not statistically significant.
Dosage and Administration
In the US and Europe, desloratadine is approved for the treatment of allergic rhinitis (caused by perennial indoor or seasonal outdoor allergens) and CIU in adult and adolescent patients aged ≥12 years. Desloratadine is also approved in Europe for the treatment of perennial or seasonal allergic rhinitis and CIU in children aged 2–11 years. Desloratadine is administered orally as a standard or rapidly disintegrating tablet (adults and adolescents only) or as a syrup formulation. The recommended once-daily dosage in adult and adolescent patients is 5mg. The dosage of the oral syrup formulation in children aged 2–5 years is 1.25mg once daily and in those aged 6–11 years is 2.5mg once daily. Desloratadine can be administered without regard to the intake of food or grapefruit juice.
- 3.Meltzer EO, Prenner BM, Nayak A. Efficacy and tolerability of once-daily 5mg desloratadine, an H1-receptor anatagonist, in patients with seasonal allergic rhinitis: assessment during the spring and fall allergy seasons. Desloratadine Study Group. Clin Drug Invest 2001; 21(1): 25–32CrossRefGoogle Scholar
- 5.Schering-Plough Corporation. Schering-Plough announces Clarinex (desloratadine) tablets approved for allergic rhinitis and chronic idiopathic urticaria. Media Rel Available from URL: http://www.schering-plough.com [Accessed 2002 Feb12]
- 6.Negro-Álvarez JM, Miralles-López JC. Chronic idiopathic urticaria treatment. Allergol Immunopathol (Madr) 2001 Jul 31; 29(4): 129–32Google Scholar
- 16.Kreutner W, Hey JA, Anthes J, et al. Preclinical pharmacology of desloratadine, a selective and nonsedating histamine H1 receptor antagonist. 1st communication: receptor selectivity, antihistaminic activity, and antiallergenic effects. Arzneimit-telForschung 2000 Apr; 50(4): 345–52Google Scholar
- 21.Kowalski ML, Lewandowska A, Wozniak J, et al. Desloratadine inhibits calcium ionophore induced LTC4 generation by nasal polyp tissue [abstract no. 13]. Ann Allergy Asthma Immunol 2002 Jan; 88: 79Google Scholar
- 26.Wu R, Anthes JC, Kreutner W, et al. Desloratadine exhibits inverse agonism and inhibits NEkB activity [abstract no. 859]. J Allergy Clin Immunol 2003; 111 (2 Pt 2): S280Google Scholar
- 32.Handley DA, McCullough JR, Fang Y, et al. Descarboethoxyloratadine, a metabolite of loratadine, is a superior antihistamine [abstract no. P164]. The American College of Allergy, Asthma & Immunology 1996 Annual Meeting; 1996 Nov 8–13; Boston, 65Google Scholar
- 33.Cunningham D, Molnar C, Ellis J, et al. The effects of desloratadine on heart rate and blood pressure in anesthetized rats: evidence for potent antimuscarinic activity in vivo [abstract]. Ann Allergy Asthma Immunol 2001 Jan; 86: 85Google Scholar
- 34.Horak F, Stübner UP, Zieglmayer R, et al. Onset and duration of action of desloratadine after controlled pollen challenges in patients with seasonal allergic rhinitis [abstract no. 1000]. Allergy 2000; 55 Suppl. 63: 279Google Scholar
- 38.Jalowayski AA, Meltzer EO, Harris AG. Desloratadine treatment improves nasal patency as measured objectively by high-resolution rhinomanometry in patients with seasonal allergic rhinitis [abstract no. 41 plus poster]. Presented at the American Academy of Allergy Asthma and Immunology 60th Anniversary Meeting; 2003 March 7–12; Denver (CO). J Allergy Clin Immunol 2003 Feb; 111 (2 Pt 2): S81CrossRefGoogle Scholar
- 39.Horak F, Stübner UP, Zieglmayer R, et al. Effect of desloratadine versus placebo on nasal airflow and subjective measures of nasal obstruction in subjects with grass pollen-induced allergic rhinitis in an allergen-exposure unit. J Allergy Clin Immunol 2002 Jun; 109(6): 956–61PubMedCrossRefGoogle Scholar
- 41.Stuebner UP, Horak F, Zieglmeyer R, et al. Desloratadine reduces nasal congestion and other signs and symptoms of allergic rhinitis (AR) induced by house dust mite (HDM) allergen exposure in the Vienna challenge chamber [abstract no. 42 plus poster]. Presented at the American Academy of Allergy Asthma and Immunology 60th Anniversary Meeting; 2003 March 7–12; Denver (CO). J Allergy Clin Immunol 2003 Feb; 111 (2 Pt 2): S81CrossRefGoogle Scholar
- 43.Frossard N, Purohit A, Kovacs S, et al. Fexofenadine is superior to loratadine and desloratadine in onset of action of histamine-induced wheal and flare inhibition [abstract no. P34]. Ann Allergy Asthma Immunol 2003; 90: 124Google Scholar
- 44.Frossard N, Purohit A, Melac M, et al. Comparative activity of cetirizine 10mg and desloratadine 5mg on histamine-induced skin wheal and flare responses during 24 hours [abstract no. P25]. Ann Allergy Asthma Immunol 2003 Jan; 90(1): 121Google Scholar
- 45.Banfield C, Cutler D, Shneyer L, et al. Desloratadine suppresses histamine- and allergen-induced cutaneous wheal and flare responses in allergic subjects during 6 months’ treatment [abstract no. 666 plus poster]. Presented at the American Academy of Allergy Asthma and Immunology 60th Anniversary Meeting; 2003 March 7–12; Denver (CO). J Allergy Clin Immunol 2003 Feb; 111 (2 Pt 2): S235CrossRefGoogle Scholar
- 48.Skoner DP, Gentile DA, Gungor A, et al. The effects of desloratadine (DL) on the allergic inflammatory response of the nasal mucosa associated with seasonal allergic rhinitis (SAR): a nasal mucosal biopsy study (NMBX) [abstract no. 51]. Journal Allergy Clin Immunol 2003; 111 (2 Pt 2): S83CrossRefGoogle Scholar
- 52.Kay G. No sedation or performance impairment with desloratadine, a novel antihistamine [abstract]. Ann Allergy Asthma Immunol 2001 Jan; 86: 84Google Scholar
- 53.Ridout F, Meadows R, Johnsen S, et al. Effects of desloratadine 5, 10 and 20 mg, and promethazine 25 mg on cognitive and psychomotor performance [abstract no. P35]. Ann Allergy Asthma Immunol 2003 Jan; 90(1): 124Google Scholar
- 55.Schering-Plough. Data on file. 2003 May 14Google Scholar
- 56.Satish U, Streufert S, Dewan M, et al. Improved productivity in patients with seasonal allergic rhinitis: impact of desloratadine [abstract no. P28]. Ann Allergy Asthma Immunol 2003 Jan; 90(1): 122Google Scholar
- 57.Hughes K, Craig T, Mende C, et al. The effect of desloratadine on sleep and daytime somnolence in subjects with allergic rhinitis [abstract]. Am J Respir Crit Care Med 2001 Apr; 163 Suppl. Pt 2: A192Google Scholar
- 59.The European Agency for the Evaluation of Medicinal Products. Scientific Discussion: Aerius [online]. Available from URL: http://www.eudra.org/humandocs/Humans/EPAR/aerius/aerius.htm [Accessed 2003 Apr 9]
- 63.Anonymous. Desloratadine (3543). 2003 Mosby’s Drug Consult Available from URL: http://www.mosbydrugs.com [Accessed 2003 Jan 15]
- 67.Banfield C, Gupta S, Affrime M, et al. Pharmacokinetic equivalence of pediatric dosages of desloratadine syrup in children and standard 5-mg desloratadine tablets in adults [abstract no. 278 plus poster]. Presented at the American Academy of Allergy Asthma and Immunology 58th Annual Meeting; 2002 March 1–6; New York. J Allergy Clin Immunol 2002 Jan; 109 Suppl.: S103CrossRefGoogle Scholar
- 68.Schering Corporation. Clarinex (desloratadine) tablets, reditabs tablets [online]. Available from URL: http://www.clarinex.com [Accessed 2003 Apr 29]
- 71.Favreau LV, Johnson WW, Chu A, et al. Desloratadine is not transported by human organic anion transport polypeptide-A [abstract no. P29]. Ann Allergy Asthma Immunol 2003 Jan; 90(1): 122Google Scholar
- 74.Banfield C, Gupta S, Kantesaria B, et al. No drug interaction between fluoxetine and desloratadine, a new nonsedating once-daily antihistamine [abstract]. J Allergy Clin Immunol 2001 Feb; 107 Suppl.: S161Google Scholar
- 75.Khalilieh K, Krishna G, Marino M, et al. Lack of an interaction with coadministration of desloratadine and cimetidine [abstract]. Ann Allergy Asthma Immunol 2002 Jan; 88: 110Google Scholar
- 78.Kerney DL. Real world treatment with desloratadine in SAR patients [abstract no. P32]. Ann Allergy Asthma Immunol 2003 Jan; 90(1): 123Google Scholar
- 81.Meltzer EO, Harris AG. Desloratadine 5mg once daily significantly improves individual and total symptoms compared with placebo in patients with seasonal allergic rhinitis [abstract no. 61 plus poster]. Presented at the American Academy of Allergy Asthma and Immunology 60th Anniversary Meeting; 2003 March 7–12; Denver (CO). J Allergy Clin Immunol 2003; 111 (2 Pt 2): S86CrossRefGoogle Scholar
- 84.Kim KT, Sussman GL, Hebert J, et al. Effect of once-daily desloratadine in patients with perennial allergic rhinitis (PAR): a double-blind, placebo-controlled study [abstract no. 25 plus poster]. Presented at the American Academy of Allergy Asthma and Immunology 60th Anniversary Meeting; 2003 March 7–12; Denver (CO). J Allergy Clin Immunol 2003; 111 (2 Pt 2): S76CrossRefGoogle Scholar
- 89.Schmier J, Leidy N, Prasad M. Health-related quality of life outcomes of desloratadine in patients with moderate-to-severe SAR [abstract]. Ann Allergy Asthma Immunol 2001 Jan; 86: 111Google Scholar
- 90.Corren J, Salmun LM. Quality of life in patients with seasonal allergic rhinitis is improved by desloratadine [abstract no. 676 plus poster]. Presented at the XIXth Congress of the European Academy of Allergology and Clinical Immunology; 2000 July 1–5; Lisbon. Allergy 2000; 55 Suppl. 63: 191Google Scholar
- 92.Nathan R. Desloratadine relieved nasal congestion in patients with seasonal allergic rhinitis and concurrent asthma [abstract]. Desloratadine Study Group. Ann Allergy Asthma Immunol 2001 Jan; 86: 84Google Scholar
- 93.Berger WE. Desloratadine reduces seasonal allergic rhinitis symptoms in patients with seasonal allergic rhinitis and asthma [abstract plus poster]. Desloratadine Study Group. J Allergy Clin Immunol 2001 Feb; 107 Suppl.: S162Google Scholar
- 94.Ratner PH. Desloratadine improved asthma symptoms and reduced bronchodilator use in 2 studies of patients with asthma and SAR [abstract]. Desloratadine Study Group. Ann Allergy Asthma Immunol 2001 Jan; 86: 109Google Scholar
- 95.Corren J. Desloratadine improved FEV1 in patients with asthma and allergic rhinitis with baseline FEV1 ≤80% [abstract]. Desloratadine Study Group. Am J Respir Crit Care Med 2001 Apr; 163 Suppl. Pt 2: A189Google Scholar
- 96.Bloom M, Herron J, Staudinger H. Desloratadine syrup is safe and well tolerated in chidlren with allergic rhinitis and chronic idiopathic urticaria [abstract]. Ann Allergy Asthma Immunol 2002 Jan; 88: 79Google Scholar
- 98.Schering Corporation. Data on file. 2003 Jul 11Google Scholar
- 99.The European Agency for the Evaluation of Medicinal Products. Summary of product characteristics: Neoclarityn [online]. Available from URL: http://www.eudra.org/humandocs/Humans/EPAR/neoclaratyn/neoclaratynM.htm [Accessed 2003 Apr 9]
- 100.Pharmacos. Pharmaceuticals: Community register of medicinal products for human use [online]. Available from URL: http://pharmacos.eudra.org/F2/register/alfregister.htm [Accessed 2003 Apr 9]
- 101.The European Agency for the Evaluation of Medicinal Products. Package leaflet: Allex [online]. Available from URL: http://www.eudra.org/humandocs/Humans/EPAR/allex/allex.htm [Accessed 2003 Apr 9]
- 102.The European Agency for the Evaluation of Medicinal Products. Package leaflet: Aerius [online]. Available from URL: http://www.eudra.org/humandocs/Humans/EPAR/aerius/aeriusM.htm [Accessed 2003 Apr 9]
- 103.The European Agency for the Evaluation of Medicinal Products. Package leaflet: Opulis [online]. Available from URL: http://www.eudra.org/humandocs/Humans/EPAR/Opulis/OpulisM.htm [Accessed 2003 Apr 9]
- 104.The European Agency for the Evaluation of Medicinal Products. Package leaflet: Neoclarityn [online]. Available from URL: http://www.eudra.org/humandocs/Humans/EPAR/neoclaratyn/neoclaratynM.htm [Accessed 2003 Apr 9]
- 105.The European Agency for the Evaluation of Medicinal Products. Committee for Proprietary Medicinal Products December 2002 plenary meeting monthly report [online]. Available from URL: http://www.emea.eu.int/pdfs/human/press/pr/624802en.pdf [Accessed 2003 Apr 29]
- 106.The European Agency for the Evaluation of Medicinal Products. Package leaflet: Azomyr [online]. Available from URL: http://www.eudra.org/humandocs/Humans/EPAR/azomyr/azomyrM.htm [Accessed 2003 Apr 9]