BACKGROUND AND OBJECTIVE: Vertigo derived from peripheral vestibular disorders is quite frequently encountered in daily clinical practice and can be a severely disabling symptom associated with substantial impairment of health-related quality of life for the affected patients. Betahistine, a structural analogue of histamine and presumably the most widely prescribed anti-vertigo drug worldwide, has previously been shown to be an effective and safe treatment for these patients. The objective of the present study was to evaluate whether the fixed combination of cinnarizine and dimenhydrinate (Arlevert®) is non-inferior and thus a potentially useful alternative to betahistine dihydrochloride in the treatment of patients suffering from peripheral vestibular vertigo. METHODS: In this prospective, multicenter, double-blind, randomized, non-inferiority clinical trial, outpatients from 8 ENT clinics in Austria, Bulgaria, the Czech Republic and Russia were randomly assigned to receive three times daily one tablet of either the fixed combination cinnarizine 20 mg/dimenhydrinate 40 mg or betahistine dihydrochloride 16 mg for 4 weeks. Primary endpoint was the reduction of the mean vertigo score (MVS), a validated 12-item composite score defined as the mean of 6 vertigo symptoms (dystasia and walking unsteadiness, staggering, rotary sensation, tendency to fall, lift sensation, blackout) and 6 trigger factors for vertigo (change of position, bowing, getting up, driving by car/train, head movements, eye movement), after 4 weeks of therapy, as judged by the patient on a 5-point visual analogue scale (VAS). The non-inferiority margin was set to 0.3. Secondary outcomes included the patient's and investigator's judgment of global efficacy, the patient's rating of impairment of daily activities, and safety/tolerability of the treatments. RESULTS: Three hundred and six patients (mean age 53.5 years, approximately 60% female) were enrolled and randomized to the fixed combination cinnarizine/dimenhydrinate (n = 152) or betahistine (n = 154) groups; 297 patients completed the study and 294 (146 and 148, respectively) were valid for the per-protocol analysis, which was used for the non-inferiority analysis. Treatment with cinnarizine/dimenhydrinate led to a stronger reduction of the MVS [least squares mean (LSM)] after 4-week therapy (primary endpoint) in comparison to betahistine (0.395 vs 0.488; difference: - 0.093, 95% CI - 0.180; - 0.007, p = 0.035); since the upper limit of the two-sided 95% confidence interval was not only below the non-inferiority margin of 0.3, but also entirely below 0, superiority of the fixed combination could be demonstrated. The combination preparation was also more effective after 1 week of therapy and received more favorable patient's ratings on overall efficacy and impairment of daily activities. Both treatments were very well tolerated. Only 12 patients (3.92%) reported 13 non-serious adverse events; 2 cinnarizine/dimenhydrinate-treated patients discontinued the study prematurely due to adverse events as compared to 5 betahistine-treated patients. CONCLUSION: The fixed combination of cinnarizine 20 mg and dimenhydrinate 40 mg was found to be not only non-inferior, but superior to betahistine 16 mg in the improvement of peripheral vestibular vertigo. Furthermore, taking into account a good and slightly favorable safety profile, the present study provides evidence that the fixed-combination preparation is a potent and even superior alternative to betahistine in the treatment of vertigo related to peripheral vestibular disorders. STUDY REGISTRATION: EudraCT No. 2011-004025-27.

Berlin Chemie AG Menarini Berlin Germany

ENT Clinic 3rd Medical Faculty Charles University of Prague Prague Czech Republic

ENT Clinic Medical University of Innsbruck and ENT Center for Vertigo Innsbruck Austria

ENT Clinic Medical University of Sofia St Ivan Rilski Hospital Sofia Bulgaria

ENT Clinic Regional Hospital Budweis Budweis Czech Republic

Federal State Institution St Petersburg Research Institute of Ear Throat Nose and Speech St Petersburg Russia

Hennig Arzneimittel Flörsheim am Main Germany

Moscow Research Practical Center of Otolaryngology n a L 1 Sverzhevsky Moscow Russia

North West State Medical University n a 1 I Mechnikov of Ministry of Health and Social Development St Petersburg Russia

Clin Drug Investig. 2020 Jan;40(1):99-100. doi: 10.1007/s40261-019-00871-9. PubMed

Clin Drug Investig. 2020 Jan;40(1):101-102. doi: 10.1007/s40261-019-00872-8. PubMed

Zobrazit více v PubMed

Brandt T, Dieterich M, Strupp M. Vertigo and dizziness—common complaints. 2. London: Springer; 2013.

Walther LE. Current diagnostic procedures for diagnosing vertigo and dizziness. GMS Curr Top Otorhinolaryngol Head Neck Surg. 2017;16:2. PubMed PMC

Neuhauser HK, von Brevern M, Radtke A, Lezius F, Feldmann M, Ziese T, Lempert T. Epidemiology of vestibular vertigo: a neurotologic survey of the general population. Neurology. 2005;65(6):898–904. doi: 10.1212/01.wnl.0000175987.59991.3d. PubMed DOI

Neuhauser HK, Radtke A, von Brevern M, Lezius F, Feldmann M, Lempert T. Burden of dizziness and vertigo in the community. Arch Intern Med. 2008;168(19):2118–2124. doi: 10.1001/archinte.168.19.2118. PubMed DOI

Neuhauser HK, Lempert T. Vertigo: epidemiologic aspects. Semin Neurol. 2009;29:473–481. doi: 10.1055/s-0029-1241043. PubMed DOI

Strupp M, Brandt T. Diagnosis and treatment of vertigo and dizziness. Dtsch Arztebl Int. 2008;105(10):173–180. PubMed PMC

Strupp M, Brandt T. Peripheral vestibular disorders. Curr Opin Neurol. 2013;26:81–89. doi: 10.1097/WCO.0b013e32835c5fd4. PubMed DOI

Kruschinski Carsten, Kersting Markus, Breull Alf, Kochen Michael M., Koschack Janka, Hummers-Pradier Eva. Diagnosehäufigkeiten und Verordnungen bei Schwindel im Patientenkollektiv einer hausärztlichen Routinedatenbank. Zeitschrift für Evidenz, Fortbildung und Qualität im Gesundheitswesen. 2008;102(5):313–319. doi: 10.1016/j.zefq.2008.05.001. PubMed DOI

Maarsingh OR, Dros J, Schellevis FG, Van Weert HC, Bindels PJ, van der Horst HE. Dizziness reported by elderly patients in family practice: prevalence, incidence, and clinical characteristics. BMC Family Practice. 2010;11:2. doi: 10.1186/1471-2296-11-2. PubMed DOI PMC

Agus S, Benecke H, Thum C, Strupp M. Clinical and demographic features of vertigo: findings from the REVERT registry. Front Neurol. 2013;4(48):1–8. doi: 10.3389/fneur.2013.00048. PubMed DOI PMC

Lacour M. Betahistine treatment in managing vertigo and improving vestibular compensation: clarification. J Vestib Res. 2013;23:139–151. PubMed

Della Pepa C, Guidetti G, Eandi M. Betahistine in the treatment of vertiginous syndromes: a meta-analysis. Acta Otorhinolaryngol Ital. 2006;26:208–215. PubMed PMC

Nauta JJ. Meta-analysis of clinical studies with betahistine in Ménière’s disease and vestibular vertigo. Eur Arch Otorhinolaryngol. 2014;271(5):887–897. doi: 10.1007/s00405-013-2596-8. PubMed DOI

Murdin L, Hussain K, Schilder AGM. Betahistine for symptoms of vertigo. Cochrane Database Syst Rev 2016; 6: CD010696. 10.1002/14651858.cd010696.pub2. PubMed PMC

Godfraind T, Towse G, Van Nueten JM. Cinnarizine: a selective calcium entry blocker. Drugs Today. 1982;18:27–42.

Arab SF, Düwel P, Jüngling E, Westhofen M, Lückhoff A. Inhibition of voltage-gated calcium currents in type II vestibular hair cells by cinnarizine. Naunyn Schmiedebergs Arch Pharmacol. 2004;369:570–575. doi: 10.1007/s00210-004-0936-3. PubMed DOI

Jaju BP, Wang SC. Effects of diphenhydramine and dimenhydrinate on vestibular neuronal activity of cat: a search for the locus of their antimotion sickness action. J Pharmacol Exp Ther. 1971;176:718–724. PubMed

Dollery C. Therapeutic Drugs. Second edition. Churchill Livingstone; 1999. Vol. 1, Diphenhydramine D152–56.

Kessler L, Bognar-Steinberg I, Baumann W, Skurczynski W. Treatment of vestibular vertigo: comparison of a fixed combination of cinnarizine 20mg and dimenhydrinate 40mg with the 2.5-fold higher dosed active drugs in monotherapy. A prospective, randomized, reference-controlled, two-center, double-blind study. Arch Sensol Neurootol Sci Pract. 2012;7:1–13.

Pytel J, Nagy G, Toth A, Spellenberg S, Schwarz M, Repassy G. Efficacy and tolerability of a fixed low-dose combination of cinnarizine and dimenhydrinate in the treatment of vertigo: a 4-week, randomized, double-blind, active- and placebo-controlled, parallel-group, outpatient study. Clin Ther. 2007;29(1):84–98. doi: 10.1016/j.clinthera.2007.01.010. PubMed DOI

Cirek Z, Schwarz M, Baumann W, Novotný M. Efficacy and tolerability of a fixed combination of cinnarizine and dimenhydrinate versus betahistine in the treatment of otogenic vertigo. A double-blind, randomized clinical study. Clin Drug Investig. 2005;25:377–389. doi: 10.2165/00044011-200525060-00003. PubMed DOI

Scholtz AW, Schwarz M, Baumann W, Kleinfeldt D, Scholtz HJ. Treatment of vertigo due to acute unilateral vestibular loss with a fixed combination of cinnarizine and dimenhydrinate: a double-blind, randomized, parallel-group clinical study. Clin Ther. 2004;26:866–877. doi: 10.1016/S0149-2918(04)90130-0. PubMed DOI

Otto V, Fischer B, Schwarz M, Baumann W, Preibisch-Effenberger R. Treatment of vertebrobasilar insufficiency-associated vertigo with a fixed combination of cinnarizine and dimenhydrinate. Int Tinnitus J. 2008;14:57–67. PubMed

Hahn A, Sejna I, Stefflova B, Schwarz M, Baumann W. A fixed combination of cinnarizine/dimenhydrinate for the treatment of patients with acute vertigo due to vestibular disorders. A randomized, reference-controlled, clinical study. Clin Drug Investig. 2008;28:89–99. doi: 10.2165/00044011-200828020-00003. PubMed DOI

Hahn A, Novotný M, Shotekov PM, Cirek Z, Bognar-Steinberg I, Baumann W. Comparison of cinnarizine/dimenhydrinate fixed combination with the respective monotherapies for vertigo of various origins. Clin Drug Investig. 2011;31(6):371–383. doi: 10.2165/11588920-000000000-00000. PubMed DOI

Scholtz AW, Steindl R, Burchardi N, Bognar-Steinberg I, Baumann W. Comparison of the therapeutic efficacy of a fixed low-dose combination of cinnarizine and dimenhydrinate with betahistine in vestibular neuritis. A randomized, double-blind, non-inferiority study. Clin Drug Investig. 2012;32(6):387–399. doi: 10.2165/11632410-000000000-00000. PubMed DOI

Novotný M, Kostrica R. Fixed combination of cinnarizine and dimenhydrinate versus betahistine dimesylate in the treatment of Menière’s disease: a randomized, double-blind, parallel-group clinical study. Int Tinnitus J. 2002;8:115–123. PubMed

Novotný M, Bognar-Steinberg I, Baumann W. Fixed combination of cinnarizine and dimenhydrinate versus betahistine dimesylate in the treatment of Menière’s disease: post hoc non-inferiority analysis of a prospective, randomized, double-blind study. Arch Sensol Neurootol-ASN. 2011:6 [online]. https://neurootology.org/archives/649. Accessed 13 May 2019.

Schremmer D, Bognar-Steinberg I, Baumann W, Pytel J. Efficacy and tolerability of a fixed combination of cinnarizine and dimenhydrinate in treatment of vertigo: analysis of data from five randomized, double-blind clinical studies. Clin Drug Invest. 1999;18(5):355–368. doi: 10.2165/00044011-199918050-00003. DOI

Jaeschke R, Singer J, Guyatt GH. Measurement of health status. Ascertaining the minimal clinically important difference. Control Clin Trials. 1989;10:407–415. doi: 10.1016/0197-2456(89)90005-6. PubMed DOI

Juniper EF, Guyatt GH, William A, Griffith LE. Determining a minimal important change in a disease-specific Quality of Life Questionnaire. J Clin Epidemiol. 1997;47:81–87. doi: 10.1016/0895-4356(94)90036-1. PubMed DOI

Osoba D, Rodrigues G, Myles J, Zee B, Pater J. Interpreting the significance of changes in health-related quality-of-life scores. J Clin Oncol. 1998;16:139–144. doi: 10.1200/JCO.1998.16.1.139. PubMed DOI

FDA Guidance for Industry. Non-inferiority clinical trials to establish effectiveness. 2016. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/non-inferiority-clinical-trials.15546fnl.pdf. Accessed 4 Sep 2019.

Oosterveld WJ. Betahistine dihydrochloride in the treatment of vertigo of peripheral vestibular origin: a double-blind placebo controlled study. J Laryngol Otol. 1984;98:37–41. doi: 10.1017/S0022215100146158. PubMed DOI

Mira E, Guidetti G, Ghilardi PL, Fattori B, Malannino N, Maiolino L, et al. Betahistine dihydrochloride in the treatment of peripheral vestibular vertigo. Eur Arch Otorhinolaryngol. 2003;260:73–77. PubMed