Review: Clinical Trial Outcomes For reprint orders, please contact [email protected] 4 Review: Clinical Trial Outcomes Rupatadine for the treatment of allergic rhinitis and urticaria: a look at the clinical data Clin. Invest. The second-generation antihistamine rupatadine is a new long-acting and Erminia Ridolo*,1, Marcello non-sedating drug that exerts a potent dual-antagonist activity towards the histamine Montagni1, Filippo Fassio2, H1 receptor and the PAF receptor. Rupatadine is prescribed for the relief of symptoms Ilaria Massaro3, Oliviero 4 5 of seasonal and perennial allergic rhinitis and in the treatment of chronic urticaria. Rossi , Cristoforo Incorvaia & Giorgio Walter Canonica6 Clinical trials have shown that rupatadine, which shows a rapid onset of action and 1Department of Clinical & Experimental prolonged duration of activity, is effective and well tolerated. Safety data indicate Medicine, University of Parma, Parma, Italy that rupatadine does not affect the cardiovascular system, without relevant changes 2Department of Biomedicine, Immunology in the corrected QT interval, or significantly affect psychomotor activity at the doses & Cell Therapies Unit, AOU Careggi, used in clinical practice. Here, we review the efficacy and safety profile of rupatadine University of Florence, Italy 3 in patients with allergic rhinitis and urticaria. Centre for Research, Transfer & High Education DENOTHE, University of Florence, Florence, Italy Keywords: allergic rhinitis • chronic urticaria • histamine • platelet-activating factor 4Department of Biomedicine, • rupatadine Immunoallergology Unit, Azienda Ospedaliero-Universitaria Careggi, Florence, Italy The new antihistamine rupatadine is a potent, distinct clinical entities both respond to anti- 5Pulmonary Rehabilitation Unit, ICP orally active, non-sedating, long-acting antag- histamine treatment. This review focuses on Hospital, Milan, Italy onist of both histamine H1 receptors and PAF the clinical characteristics of rupatadine and 6Allergy & Respiratory Diseases Clinic, receptors. It is one of the newest second-gen- the evidence of its efficacy in the treatment of DIMI, University of Genoa, IRCCS AOU San Martino-IST, Genoa, Italy eration antihistamines and is currently pre- AR and urticaria. *Author for correspondence: scribed in the treatment of chronic urticaria Tel.: +39 0521702028 16 (CU) and seasonal or perennial allergic rhi- Pharmacokinetic properties of Fax: +39 0521 703920 17 nitis (AR) in patients older than 12 years of rupatadine [email protected] age [1–3] . Izquierdo et al. evaluated the pharmacoki- The role of histamine in allergic inflam- netic properties of orally administered rupa- 5 mation is unequivocal. However, other tadine in healthy volunteers of both genders, mediators are clearly involved in the aller- including elderly subjects [6]. Rupatadine is gic process and the roles of these mediators rapidly absorbed after oral administration are beginning to be better defined. Simi- (median T of 0.8 h with a single daily 2014 max lar to histamine, PAF is known to provoke dose, or 0.75–1 h with multiple doses). After increased vascular permeability and bron- absorption, the drug undergoes extensive choconstriction, and seems to be involved in hepatic metabolism by CYP3A4, which is bronchial hyper-reactivity, a common feature primarily responsible for rupatadine metabo- of asthma. Therefore, PAF is being increas- lism. The most important route of elimina- ingly recognized as an important mediator in tion for the drug is via the bile. the allergic response, as is demonstrated by Test subjects were administered rupatadine its role in anaphylaxis [4,5]. in addition to known CYP3A4 inhibitors, AR and urticaria are clinical conditions to investigate metabolic drug–drug inter- that represent one of the most ordinary rea- actions. Ketoconazole and erythromycin, sons for a patient to visit their general prac- which inhibit CYP3A4 activity, were found titioner or allergist. Importantly, these two to inhibit rupatadine metabolism, and when part of 10.4155/CLI.14.26 © 2014 Future Science Ltd Clin. Invest. (2014) 4(5), 453–461 ISSN 2041-6792 453 Review: Clinical Trial Outcomes Ridolo, Montagni, Fassio et al. concomitantly administered, increased the exposure Barbanoj et al. observed that 10 or 20 mg rupatadine to rupatadine by ten-times and two- to three-times, did not significantly affect the psychomotor activity of respectively. However, despite the consequent increase healthy volunteers [12] . At a higher dose of 40 or 80 mg, in plasma concentrations of the parent compound, no rupatadine caused mild deterioration or a more signifi- clinically relevant consequences such as ECG changes cant impairment of psychomotor activity, respectively. or corrected QT (QTc) interval modifications were This impairment was of similar severity as that caused by noted, and the number of adverse events reported did 25 mg hydroxyzine. not increase [7]. In other studies with CYP3A4 inhibi- In another study, ethanol (0.8 g/kg of body weight) tors, the concomitant administration of azithromycin in addition to 10 mg of rupatadine did not impair cog- or fluoxetine did not produce clinically relevant modi- nitive or psychomotor performance to a greater extent fications in the mean pharmacokinetic parameters than did ethanol alone. Compared to ethanol alone, 20 of rupatadine and its active metabolites [8,9]. How- mg of rupatadine was found to exacerbate cognitive and ever, concomitant administration of rupatadine with psychomotor decline [13] . This effect was similar to that other known CYP3A4 inhibitors should be carefully observed upon co-administration of ethanol and a single considered. dose of cetirizine (10 mg) or hydroxyzine (25 mg). Simi- Systemic exposure to rupatadine after food intake larly, 10 mg of rupatadine was not found to potentiate increased by 23% compared with that under fast- lorazepam-induced mental impairment [14] . In a practical ing conditions, while Tmax was delayed by 1 h. These assessment of ‘mental alertness’ performed using a car- changes did not appear to have clinical consequences, driving test, the effects of 10 mg rupatadine were com- and thus, the compound can be administered with or pared with those of 50 mg hydroxyzine in 20 healthy without food. volunteers. No difference in mental alertness was found between volunteers taking rupatadine or the placebo. Tolerability and safety of rupatadine Meanwhile, the mental alertness of volunteers who took Picado [2], as well as Keam and Plosker [10] indepen- hydroxyzine was impaired to an extent comparable to dently reviewed the results from published Phase III that associated with a blood alcohol level of 0.9% [15] . clinical trials of rupatadine. They claimed that this ’Torsade de pointes’ is a potentially fatal type of ven- antihistamine at a dosage of 10 mg once daily was tricular arrhythmia and a prolonged QTc interval on an well tolerated. In addition, the percentage of adverse ECG is typically associated with drug-induced torsade effects observed at this dose did not differ signifi- de pointes. The initial belief that cardiotoxicity was an cantly from those associated with placebo. In clini- effect of all classes of non-sedating antihistamines proved cal trials involving patients receiving rupatadine at unfounded, since fexofenadine, the active metabolite of the dose of 10 mg once daily (n = 2025) or placebo terfenadine, and other second-generation antihistamines (n = 1315), somnolence, headache, and fatigue were did not produce this cardiotoxic effect [16] . the most common treatment-related adverse events The cardiac safety of rupatadine has been extensively reported (incidence: 9.5, 6.8, and 3.2% of patients, investigated. More than 6000 ECGs were analyzed from respectively, in the active group and 3.4, 5.6, and healthy volunteers and patients given rupatadine at daily 2.0% of patients, respectively, in the placebo group). doses ranging from 2.5 to 80 mg and under various con- Overall, the majority of adverse effects were of mild- ditions. No clinically relevant changes in QT/QTc inter- to-moderate severity. These data were confirmed by a vals were observed, despite co-administration of other clinical long-term safety study in which patients with CYP3A4 inhibitors [7]. perennial AR were exposed to the drug for 12 months A randomized, double-blind, placebo-controlled [11] . Furthermore, in patients treated with rupatadine clinical trial, involving 160 healthy volunteers, called 10 mg once daily, the incidence of adverse effects the ‘Thorough QT/QTc study’ was designed to deter- decreased with time [1] . mine whether rupatadine had a significant effect on QTc Because sedation is a common side effect of many interval prolongation. This trial did not demonstrate a first-generation antihistamines, compounds that do not statistically or a clinically significant effect on cardiac cause sedation are clearly more advantageous in clinical repolarization in patients given rupatadine at doses up practice. Sedation negatively affects patients’ quality of to 100 mg (ten-times the recommended daily dose) [17] . life, and the use of sedating drugs is complicated or even The US FDA has proposed classification of drugs avoided for patients engaged in tasks requiring mental on the basis of risks for a mother and her fetus. Drugs alertness. Although one typical characteristic of second- assigned to categories A and B are considered to be a generation H1-antihistamines is their lack of effects on low risk