Public Assessment Report Scientific discussion Dimenhydrinat “Trimb” 20 mg lozenges (Dimenhydrinate) DK/H/2835/001/DC Date: 4 December 2018 This module reflects the scientific discussion for the approval of Dimenhydrinat ”Trimb”. The procedure was finalised on 20 September 2018. For information on changes after this date please refer to the module ‘Update’. I. INTRODUCTION Based on the review of the quality, safety and efficacy data, the Member States have granted a marketing authorisation for Dimenhydrinat ”Trimb” 20 mg lozenges, from Trimb Healthcare AB. The product is indicated for prevention of motion sickness in adults and children over 6 years of age. A comprehensive description of the indications and posology is given in the SmPC. Motion sickness is a well-known nausea and vomiting syndrome in otherwise healthy people. The physical signs of motion sickness occur in both humans and animals during travel by sea, automobile or airplane and in space. Furthermore, some other special situations, such as simulators, the cinema and video games, have been described as causing pseudomotion sickness. Children between 2 and 12 years old are most susceptible to motion sickness, and women are more frequently affected than men. Predisposing factors include pregnancy and migraines and possibly a side difference in the mass of otoconia in the vestibular organs. Therapy is directed towards decreasing conflicting sensory input, accelerating the process of adaptation and controlling nausea and vomiting. To control these vegetative symptoms, scopolamine and antihistamines are the most effective drugs. Motion sickness is caused by certain types of motion and is induced during passive locomotion in vehicles, generated by unfamiliar body accelerations, to which the person has not adapted, or by an intersensory conflict between vestibular and visual stimuli. Motion sickness indiscriminately affects air, sea, road and space travelers. All individuals (humans and animals) possessing an intact vestibular apparatus can get motion sickness given the right quality and quantity of provocative stimulation, although there are wide and consistent individual differences in the degree of susceptibility. The cardinal signs of motion sickness are nausea, vomiting, pallor and cold sweating. Histamine H1 receptors are involved in the development of motion sickness signs and symptoms, including emesis. Upon provocative motion stimuli, a neural mismatch signal activates the histaminergic neuron system in the hypothalamus, and the histaminergic descending impulse stimulates H1 receptors in the brainstem’s emetic center. The histaminergic input to the emetic center through H1 receptors is independent of dopamine D2 receptors in the chemoreceptor trigger zone in the area postrema and serotonin 5-HT3 receptors in the visceral afferent, which are also involved in the emetic reflex. Dimenhydrinate is used most commonly as an antiemetic because it is primarily a histamine type 1 (H1) antagonist, but it also possesses an antimuscarinic effect. The other component of dimenhydrinate, 8- chlorotheophylline, is a xanthine derivative. By blocking adenosine receptors, xanthine derivatives likely produce excitation and psychostimulation. The marketing authorisation has been granted pursuant to Article 10a (bibliographic application) of Directive 2001/83/EC. This type of application does not require submission of the results of preclinical tests or clinical trials if the Applicant can demonstrate that the active substance of the medicinal product has been in well-established medicinal use within the EU for at least 10 years, with recognised efficacy and an acceptable level of safety. Dimenhydrinate has been extensively used in humans for several decades and can be considered an active substance with well-established used for the intended indication. II. QUALITY ASPECTS II.1 Introduction PAR Scientific discussion 2/21 Dimenhydrinat ”Trimb” lozenges are presented as anise flavoured lozenges containing 20 mg of dimenhydrinate. The lozenge is clear to yellowish, round and with a diameter of 19±1 mm. The finished product is to be marketed in PVC-PVDC/Aluminium blisters in pack sizes of 24. The lozenges contain: Isomalt (E953); saccharin sodium (E954); masking (propylene glycol (E1520), triethyl citrate (E1505)); anise flavour (glyceryl triacetate (E1518) and mouth watering (arabic gum (E414), citric acid (E330) and sodium citrate (E331)). The RMS has been assured that acceptable standards of GMP (see Directive 2003/94/EC) are in place for this product type at all sites responsible for the manufacturing of the active substance as well as for the manufacturing and assembly of this product prior to granting its national authorisation. II.2 Drug Substance The manufacturer of the active substance, dimenhydrinate, has obtained a Certificate of Suitability. The drug substance is controlled in line with the respective Ph.Eur monograph, as attested by the CEP covering the manufacturing process of the active substance. The control tests and specification for drug substance are adequately drawn up by the Applicant and in line with the CEP and additional requirements on solvents. The CEP does not cover stability studies as no re-test period is reported. The Applicant has provided container closure system and stability data and the proposed re-test period and storage conditions are considered acceptable. II.3 Medicinal Product The development of the product has been described. The choice of excipients is justified and their functions explained. The manufacturing process is described in sufficient details and the process and its associated in process controls are considered acceptable. The drug product is a lozenge and the product specification covers appropriate parameters for this dosage form. The shelf life and release specification for related substance are in general considered acceptable. A follow-up measure is needed since an impurity is formed above the ICH Q3B qualification threshold and should be identified and qualified. The Applicant has initiated these studies, and will submit when complete. Validations of the analytical methods have been presented, and the Applicant provided demonstration of the stability indicating capability of the methods. Batch analyses have been performed on 3 batches. The batch analysis results show that the finished products meet the specifications proposed. The conditions used in the stability studies are according to the ICH stability guideline. A shelf life of 24 months with no special storage condition is acceptable. The analytical methods are shown to be suitable for stability measurements and control. PAR Scientific discussion 3/21 III. NON-CLINICAL ASPECTS III.1 Pharmacology The pharmacological effects of dimenhydrinate and diphenhydramine were described in several older publications, whereas the publications of abuse potential were of a more recent date. An overview of pharmacological studies referred in this assessment report with calculated (whenever possible) human equivalent doses is found in the table below. Overview of active doses of dimenhydrinate and diphenhydramine in animal models of anti-emesis and abuse potential and their estimated human equivalent dose. Species Endpoint Active dose Human Compound Reference equivalent dose* Anaesthetised Diminished 1.5 mg/kg i.v. No Diphenhydramine Jaju and Cat excitability of the conversion Wang, vestibular factor 1971 complex. available Anaesthetised Diminished 2.5-5.0 mg/kg No Dimenhydrinate Jaju and Cat excitability of the i.v. conversion Wang, vestibular factor 1971 complex. available Dog Delay of onset, 50 mg/day 28 mg/kg Dimenhydrinate Gralla et reduction of p.o. al, 1979 number and (on average duration of emetic 11 episodes after mg/kg/day) irradiation of abdominal area Dog Delay of onset, 25 mg/day 14 mg/kg Diphenhydramine Gralla et reduction of p.o. al, 1979 number and (on average duration of emetic 11 episodes after mg/kg/day) irradiation of abdominal area Dog Reduced second 25 mg/day 14 mg/kg Diphenhydramine Gralla et stage of irradiation p.o. al, 1979 –induced emesis (on average 11 mg/kg/day) Rat CPP (abuse 60 mg/kg i.p. 9.6 mg/kg Dimenhydrinate Halpert et potential) al, 2003 Rat CPP (abuse 37.8 mg/kg 6 mg/kg Diphenhydramine Halpert et potential) i.p. al, 2003 Rat Locomotor 25 and 40 4 and 6.5 Dimenhydrinate Halpert et stimulation mg/kg i.p. mg/kg al, 2003 Rat Locomotor 27-37.8 4.4 – 6 Diphenhydramine Halpert et stimulation mg/kg i.p. mg/kg al, 2003 Mice CPP (abuse 30 mg/kg i.p. 2.4 mg/kg Dimenhydrinate Nguyen et potential) al, 2010 Mice CPP when co- 3 mg/kg i.p. 0.24 Dimenhydrinate Nguyen et administered with mg/kg al, 2010 low dose cocaine (7.5 mg/kg), which PAR Scientific discussion 4/21 in itself did not induce CPP *Human equivalent dose is calculated using conversion factors in Table 1 of FDA: Guidance for Industry. Estimating the Maximum Safe Starting Dose on initial Clinical Trials for Therapeutics in Adult Healthy Volunteeers, 2005. CPP: Conditioned Place Preference The anti-motion sickness effects of diphenhydramine and dimenhydrinate was investigated in an anesthetised cat model. The neuronal activity was enhanced by physical stimulation of the labyrinth via angular (turntable) or linear (swing) acceleration, or by electrical stimulation of one of the vestibular nerve branches with a bipolar electrode. Both diphenhydramine (1.5 mg/kg i.v.) and dimenhydrinate (2.5-5.0 mg/kg i.v.) suppressed the spontaneous as well as the enhanced vestibular neuronal firing. These findings