Cinnarizine: A Contemporary Review

Abstract

Cinnarizine, is approved for nausea, vomiting, motion sickness, inner ear disorders and is considered as first-line pharmacotherapy for management of vertigo. It acts by anti-vasoconstrictor activity, reducing blood viscosity and reducing nystagmus in labyrinth. Lack of adequate literature on clinical evidence of cinnarizine and its combination (dimenhydrinate) in vertigo management prompted this review. A specific MEDLINE literature search strategy was designed combining Medical Subject Headings, free-text keywords (like cinnarizine and vertigo) using Boolean operators (1970–2016) for clinical studies, clinical reviews and meta-analyses of cinnarizine. Analyses of studies validated cinnarizine’s efficacy in peripheral and central vertigo versus placebo or other therapies, and was well-tolerated by the patients recruited across different studies. Cinnarizine and/ or its combinations are favorable in management of vestibular disorders wherein cinnarizine acts predominantly peripherally on labyrinth and dimenhydrinate acts centrally on vestibular nuclei and associated centers in brainstem. Combination therapy of cinnarizine and/ or its combinations demonstrated a better safety profile than either of the mono-components, offering a viable therapeutic option in vertigo management.

Introduction

Cinnarizine is a well-established anti-vertigo drug initially synthesized as an anti-histamine [1]. It is the mainstay therapy for vestibular disorders [2], approved for nausea, vomiting, motion sickness, vertigo and tinnitus associated with Ménière’s disease and other middle ear disorders, as a nootropic drug (memory and cognitive function enhancer) and as adjunct therapy for peripheral arterial disease [3]. Betahistine, prochlorperazine and dimenhydrinate are also used to treat vertigo (Table 1). Cinnarizine and/ or its combination is approved in India for the management of vertigo [4]. Limited publications of cinnarizine + dimenhydrinate have been reported in last two decades. This contemporary review aims to evaluate the role of cinnarizine and/ or its combinations in vertigo.

Table 1.

Mechanism of action of most commonly used drugs in vertigo management

Drug	Mechanism of action
Betahistine [2]	Antagonist of H3R; partial, weak agonist of H1R and H2R
Cinnarizine [2]	L-type Ca2+ channel blocker, H1 anti-histaminic action (slight), potential antagonist of nicotinic AChR, pressure-sensitive potassium channel blocker
Dimenhydrinate [2]	Antagonist of H1R and AChR
Prochlorperazine [32]	Dopaminergic antagonist-acts at chemoreceptor trigger zone reducing neural impulses to vomiting center; cannot prevent vertigo/motion sickness but useful in treating accompanying nausea and vomiting

AChR acetyl choline receptor, H3R histamine H3 receptor, H1R histamine H1 receptor, H2R histamine H2 receptor

Methods

A literature search was done on MEDLINE. The search strategy included Medical Subject Headings and free-text keywords (cinnarizine, dimenydrinate and vertigo) using Boolean operators (‘OR’ and ‘AND’). English publications of mainly clinical studies of cinnarizine and combination therapy (cinnarizine + dimenhydrinate), clinical reviews, meta-analysis involving cinnarizine and guidelines for management of vertigo in various conditions were collected for the period from 1970 to 2016. Data in prescribing information leaflets, manufacturing as well as labelling data were also incorporated.

Mechanism of Action

Cinnarizine, developed as an anti-histamine, subsequently manifested a number of pharmacological effects, most significantly: labyrinthine suppressant action and peripheral anti-vasoconstrictive effects [5]. Cinnarizine inhibits smooth muscle cell contraction in the vasculature by blocking L-and T-type voltage-gated calcium channel. It is also known to bind to histamine H1 receptors, muscarinic (acetyl choline) receptors and dopamine D2 receptors [6]. Thus, the mechanism of action of cinnarizine is multimodal (Fig. 1). Insufficient cerebral blood circulation has been hypothesized to cause ‘vertiginous symptoms’ like tinnitus, dizziness, nausea and vomiting in a range of conditions including transient ischemic attacks. Cinnarizine’s anti-vasoconstrictive and protective action against hyperviscosity of blood along with its peripheral anti-ischemic action may be helpful in improving blood flow thus playing an important role in various therapeutic indications [7].

Fig. 1.

Mechanism of action of cinnarizine. RBC red blood cell

Anti-vasoconstrictor Action

Vasodilators can cause relaxation irrespective of whether the altered Ca²⁺ dependent tone is caused by intrinsic (myogenic) or extrinsic (vasoconstrictor) activity. Cinnarizine, on the other hand, has no direct vasodilatory action and does not directly interfere with the potential of smooth muscle cells to develop tone. Instead it selectively inhibits spasmogen-stimulated Ca²⁺ influx and thus differentiates increased Ca²⁺ influxes in response to vasoconstrictors as opposed to those caused by intrinsic myogenic changes in membrane potential [8] and hence, is described as an anti-vasoconstrictor.

Action on Blood Viscosity

Increased blood viscosity is an important factor in reducing blood flow in patients with ischemic diseases and intermittent claudication [9]. Historical data have shown that cinnarizine decreases blood viscosity in patients with ischemic diseases. Many studies have proposed that the ability of cinnarizine to reduce blood viscosity is attributed to its effects on red blood cell(s) (RBCs), thereby preserving the flexibility and deformability of RBCs. It has been postulated that this might be due to the ability of cinnarizine to block Ca²⁺ entry in ischemic RBCs [7]. Another hypothesis adds that flunarizine, a cinnarizine derivative, protects against Ca²⁺ dependent ionophore A23187-induced crenation of human RBCs, a condition associated with decreased membrane deformability [10].

Action on Labyrinth

The action of cinnarizine on peripheral vestibular structures has been demonstrated in various clinical studies. During the early years of development (1976), cinnarizine 25 mg at a thrice-daily (TID) dosage was noted to be significantly superior to placebo in reducing the amplitude, duration and speed of the slow phase of post-rotational nystagmus and the total number of beats (p < 0.05) [11]. After 2 years, evidence confirmed that cinnarizine significantly reduced the velocity of the slow phase of caloric induced nystagmus in patients with peripheral labyrinthine disorders [12]. Mechanism of action of cinnarizine in the labyrinth involves inhibition of Ca²⁺ ion translocation across cell membranes of the vestibular sensory cells in the ampullae. Overstall et al. [13] however, have suggested that cinnarizine normalizes endolymph flow by preventing constriction of the stria vascularis. An additional mechanism of action of cinnarizine in vestibular vertigo hypothesized that cinnarizine modulates transmitter release in vestibular hair cells (patch-clamp model). Haasler et al. [14] demonstrated that inhibition of pressure-dependent K⁺ currents in pharmacologically relevant concentrations of cinnarizine (0.05–3 µM) elicited depolarization and increased voltage-dependent activation of Ca²⁺ currents, which enhanced transmitter release.

Clinical Evidence

Vertigo accounts for ~5% of total prevalence and an incidence of 1.4% in adults. This high presentation rate is probably due to the large number of underlying conditions reported along with the symptom [15]. An Indian study conducted in 2001 estimated the overall prevalence of vertigo in rural adult community as 0.7% [16]. The underlying cause might be either of the following reasons; an involvement of labyrinth in the inner ear, or due to dysfunction of the vestibular nerve, or the defect may involve vestibular nuclei, or other centers responsible for the maintenance of balance. For vertigo patients in the latter two categories, the anti-vasoconstrictor properties of cinnarizine might be beneficial in restoring blood flow by improving the microcirculation in the affected region [17].

Peripheral Vertigo

This type of vertigo is due to problems originating in the peripheral nervous system like benign paroxysmal positional vertigo, acute vestibular neuronitis, or Ménière’s disease. Some of the common triggers of peripheral vertigo include alcohol and also drugs like anti-depressants, antihypertensives, salicylates, hypnotics and sedatives. Neurologic symptoms, hearing loss, severe nausea and vomiting may be concomitant conditions presenting along with peripheral vertigo [18]. Efficacy of cinnarizine in various causes of peripheral vertigo has been established in different clinical studies (Table 2).

Table 2.

Cinnarizine in peripheral vertigo

Peripheral causes	Study design	Sample size	Cinnarizine dosage	Comparator	Result
Labyrinthitis	Double-blind crossover [33]	14	45–90 mg/day for 4 weeks	Prochlorperazine	70%–80% improvement in severity of nausea and vomiting. 50%–60% improvement in tinnitus. Efficacy similar to prochlorperazine
MD	Double-blind crossover [33]	20	45–90 mg/day for 4 weeks	Prochlorperazine	70%–80% improvement in symptom severity with cinnarizine and prochlorperazine
MD	Double-blind, randomized study [26]	37	2 × 75 mg for 8 weeks	Betahistine 3 × 16 mg for 8 weeks	Betahistine resulted in higher reduction of symptoms compared with cinnarizine
MD (with and without migraine)	Open-label, non-randomized [34]	52 MD (n = 29 were migraineurs)	20 mg BID/OD	Combined therapy: betahistine 48 mg/day + cinnarizine 20 mg BID (1 month) and then betahistine 20 mg/day (for 2 weeks) and betahistine 20 mg every 2 days (for 2 more weeks) and then successively restarted Total duration: 6 months	Cinnarizine, proactively prevented vertigo spells especially in MD patients with migrane
Peripheral vertigo	Double-blind, multinational pilot study [35]	221 adult	150 mg OD for 12 weeks (with dinner)	Nimopidine 30 mg oral tablet TID (one with breakfast, lunch and dinner)	Nimopidine and cinnarizine reduced incidences of moderate vertigo episodes by 78.8% and 65.8% respectively and severe vertigo incidences were decreased by 85.0% and 89.8%, respectively
Recurrent vertigo	Randomized, crossover study [36]	88 patients	2 × 15 mg TID	Betahistine dihydrochloride 2 × 12 mg TID	Both drugs reported equal efficacy in reducing the duration and severity of symptoms at the end of 6 months
Seasickness	Double-blind placebo-controlled [37]	335	15 mg TID for 5–7 days whilst at seasickness	Placebo	Vomiting prevented significantly by cinnarizine (75%, p < 0.001) as compared with placebo (43%). Drowsiness was reported by 8% receiving cinnarizine and 5% receiving placebo
Induced vestibular nystagmus	NR [38]	6 healthy volunteers	15 mg TID	Betahistine 8 mg TID	Nystagmus duration and average eye speed were similar between pre-treatment rotation and betahistine therapy (p > 0.05). Sudden stoppage of cinnarizine therapy reported significant differences in nystagmus duration at initial acceleration as well as average eye speed (p < 0.05)

BID twice-daily, TID thrice-daily, MD Ménière’s disease, NR not reported, OD once-daily

Central Vertigo

Central vertigo may be caused by vascular insufficiency/cerebral ischemia involving vestibular centers in brainstem, cerebellum and disorders of the thalamus leading to dizziness and unsteadiness. Cinnarizine has proven to be effective in patients suffering from vertigo of central origin. It improves the microcirculation in the affected parts of brain like vestibular nuclei which results in improved central vestibular function. In one of the earliest studies in 1972, cinnarizine was shown to benefit patients with central vertigo due to impaired cerebral circulation, irrespective of whether the symptom was a primary manifestation or a complication of some other disease process [19]. Later, an in-vivo model demonstrated that cinnarizine increases blood flow to the lateral vestibular nucleus selectively in a non-dose dependent manner, without affecting the reticulo-cortical, thalamo-cortical and sensory trigeminal systems [20]. Table 3 shows important clinical studies of cinnarizine in the management of vertigo of central origin.

Table 3.

Cinnarizine in central vertigo

Central causes	Study design	Sample size	Cinnarizine dosage	Comparator	Result
Atherosclerosis	Open-label [39]	82	25 mg TID 4 weeks	NA	Significant improvement (p < 0.001) in dizziness, unsteady gait, tinnitus, concentration loss, memory loss, inactivity, listlessness, headache and troubled sleep
Cardiovascular diseases	Double-blind [40]	117	25 mg BID/TID	Vincamine	Cinnarizine was superior to vincamine against dizziness and tinnitus

BID twice-daily, TID thrice-daily, NA not applicable

Pharmacokinetic Data

Pharmacokinetic data revealed that post-administration, plasma levels of cinnarizine peak in 1–3 h. Total 91.0% of cinnarizine is plasma-protein bound which is extensively metabolized, largely by CYP2D6. The elimination half-life for cinnarizine varied from 4 to 24 h; 33.0% of the metabolites were eliminated by urine and 66.0% in the feces [21]. Cinnarizine has a C_max of 275 ± 36 ng/mL, t_max 3.0 ± 0.5 h, AUC_∞ 4437 ± 948 ng h/mL and terminal half-life was 23.6 ± 3.2 h post 72 h of administration [22].

Dosage Recommendations

Cinnarizine has been used in varying doses from 15 mg TID to 150 mg/day in different clinical studies for vertigo [Tables 2, 3]. In Europe, cinnarizine dosage as low as 15 mg is available. Cinnarizine is recommended as 25 mg TID or 75 mg once-daily dosing for maintenance therapy for symptoms of labyrinthine disorders, including vertigo, dizziness, tinnitus, nystagmus, nausea and vomiting. The maximum recommended dosage for cinnarizine is 225 mg daily [21]. For motion sickness, the dosage for adults and adolescents aged 13 years and above is 25 mg tablet: one tablets at least half an hour before travelling and one tablet every 6 h during the journey [21].

Role of Cinnarizine in Combination with Dimenhydrinate in Vertigo

The fixed dose combination of cinnarizine + dimenhydrinate, with its dual mechanism of action, allows the simultaneous functional regulation of the peripheral and central vestibular components [23]. Cinnarizine acts predominantly peripherally on the labyrinth, causing increased cerebral and cochlear perfusion as well as vestibular suppression through inhibition of Ca²⁺ channels in vestibular sensory cells; thus improving inner ear circulation. Dimenhydrinate acts centrally on the vestibular nuclei and associated centers in the brainstem; and additionally acts as an anti-histamine, anti-cholinergic, anti-emetic and anti-vertiginous activity alleviating acute vertigo attacks. Due to these combined pharmacological properties of cinnarizine + dimenhydrinate, the fixed dose combination is favorable in the management of various vestibular disorders [24] (Fig. 2).

Fig. 2.

Mechanism of action of fixed dose combination of cinnarizine and dimenhydrinate

Many randomized, double-blind clinical studies have clearly demonstrated the efficacy and tolerability of the fixed dose combination of cinnarizine + dimenhydrinate in comparison with standard monotherapies in various defined pathological entities, including otogenic vertigo, vestibular neuropathy, vertigo in vertebrobasilar insufficiency and Ménière’s disease (Table 4).

Table 4.

Cinnarizine in combination with dimenhydrinate: clinical evidence

Causes of vertigo	Study design	Sample size	Comparator	Result
Ménière’s disease	Double-blind, randomized control [41]	82	Betahistinea 12 mg TID for 12 weeks	Both drugs led to a marked reduction of vertigo symptom score. Similar efficacy and safety were reported between the combination and betahistine
Otogenic vertigo	Prospective, double-blind, randomized, comparative, single-center study [42]	61	Betahistine 12 mg TID for 4 weeks	Fixed dose combination decreased the intensity of vertigo symptoms about twofold than betahistine (p = 0.001) at 4 weeks and this was more evident post 4 weeks of treatment (p = 0.009)
Vertebrobasilar insufficiency	Double-blind, randomized control [43]	37	Betahistinea 12 mg TID for 4 weeks or placebo	Fixed dose combination showed significantly greater reductions of vertigo symptom score as compared to patients receiving betahistine (p < 0.01)
Vertebrobasilar insufficiency	NR [44]	78	Cinnarizine and dimenhydrinate BID for 60 consecutive days	Dual action of the combination therapy revealed symptom reduction of tinnitus (38.7%) and dizziness (43.1%). Reduction was also observed in the tinnitus handicap inventory and dizziness handicap inventory score at final examination (p < 0.001)
Vestibular disorders	Double-blind, randomized control [24]	66	Betahistine 12 mg TID for 4 weeks	The cinnarizine + dimenhydrinate fixed dose combination therapy reported significantly greater improvements in mean vertigo scores than betahistine (p = 0.013)
Vestibular neuritis	Double-blind, randomized control [31]	62	Betahistine 12 mg each TID for 4 weeks	The fixed dose combination therapy reported significantly greater improvements in mean vertigo score than betahistine (p < 0.001). Activities of daily living also improved significantly with the combination than betahistine (p < 0.01)
Vertigo of peripheral or central, combined peripheral/central origin	Randomized, double-blind, active- and placebo-controlled, parallel-group, outpatient study [45]	246	Placebo, TID for 4 weeks	In those patients with mean vertigo score ≤0.5 after 4 weeks of treatment, the fixed dose combination was effective in 62.3% of patients than 29.5% in cinnarizine 50 mg, 30.5% in dimenhydrinate 100 mg and 24.1% in placebo group
Vertigo of various origins	Prospective, double-blind, randomized active-controlled, multicenter study [23]	182	Cinnarizine 20 mg or dimenhydrinate 40 mg, each TID for 4 weeks	Reduction in mean vertigo score post four weeks of treatment with the fixed dose combination was significantly greater than each of the monotherapy alone (p = 0.0001)
Acute unilateral vestibular loss	Prospective, single-center, randomized, double-blind, parallel-group [29]	50	Cinnarizine 20 mg or dimenhydrinate 40 mg, TID for 4 weeks	Fixed dose combination was significantly more effective than either of the monotherapy (cinnarizine, p < 0.001 and dimenhydrinate, p < 0.01)
Vertigo and tinnitus of peripheral or central origin	Double-blind, randomized control [46]	122	Cinnarizine 20 mg or dimenhydrinate 40 mg, TID for 4 weeks	Fixed dose combination was more effective than either of its constituent drugs used as monotherapy

^aBetahistine dimesylate was used as an active comparator of cinnarizine + dimenhydrinate clinical study. BID twice-daily, TID thrice-daily, NR not reported

Renal and Hepatic Insufficiency

No specific studies have been reported on the use of cinnarizine in patients with hepatic or renal dysfunction. However, it is recommended that cinnarizine be used with care in patients with such conditions [25].

Pregnancy and Lactation

No teratogenic effects with use of cinnarizine have been reported in pre-clinical studies [21]. The safety of cinnarizine in pregnant or lactating women has not been established in clinical studies. Cinnarizine should be used during pregnancy only if the therapeutic benefits justify the potential risks for the fetus/infant as indicated by a physician. As there is no data available on secretion of cinnarizine in breast milk, nursing should be discouraged in women using cinnarizine [21].

Safety Profile

Cinnarizine and its combinations have shown no safety concerns and are well-tolerated. An analysis of seven placebo-controlled, double-blind clinical studies of cinnarizine (30–225 mg/day) was conducted to evaluate safety in total 740 patients (cinnarizine: 372 patients and placebo: 368 patients). Drowsiness/somnolence was encountered in some patients (<10%), especially at the start of treatment. Therefore, caution should be exercised when concomitant drugs having central nervous system depressant action are taken and activities like driving and operating machinery should be avoided [21]. Nausea and weight gain were other adverse events reported during some of the clinical studies [21, 26].

Incidences of extrapyramidal symptoms and drug-induced Parkinsonism were very rare during the post-marketing surveillance studies. The results on recurrent labyrinthine disturbances have demonstrated that cinnarizine administered for the long-term control of labyrinthine disorders does not have serious side effects [27]. However, patients with Parkinson’s disease should be prescribed cinnarizine only if the advantages outweigh the possible risk of aggravating the disease.

The combination of cinnarizine + dimenhydrinate was evaluated for adverse events. An analysis of data from five randomized, double-blind clinical studies concluded that combination of cinnarizine + dimenhydrinate was well-tolerated and with 90.3% of the patients reported the tolerability as ‘very good’ or ‘good’. Most common side effects reported were fatigue or somnolence, closely followed by dry mouth. Other adverse events reported were headache, abdominal pain, nausea and tremors [27, 28]. In a German, prospective, non-interventional study carried out in primary and secondary care private practices, combination of cinnarizine + dimenhydrinate therapy was evaluated in the treatment of vertigo of various origins. In addition to reduction in mean vertigo score in the 1275 patients, nausea, vomiting and tinnitus were also reduced by 84%, 85% and 51%, respectively, and non-serious adverse events were reported in 4.2% of the population [29]. Overall, combination of cinnarizine + dimenhydrinate demonstrated a better benefit-risk ratio than either individual monotherapy [30].

Limitations

Consensus rating of the article quality was not performed because it was beyond the scope of the current review. The reliability of the article selection and classification was not assessed because only one reviewer was involved in the process albeit the potential source of bias is minimal since only basic descriptive information was extracted from each article. As the studies selected for this review spanned a course of four decades, it is very likely that the endpoints, conduct of study and analysis variability could have been overlooked.

Expert Opinion

Pharmacotherapy plays an important role in control of vertiginous symptoms in patients with vestibular disorders. Therapy duration should be decided by the treating physician based on the etiology of symptoms. Multiple theories have been postulated on interaction of various drugs with vestibular compensation though the supporting evidence is lacking, but duration of therapy is known to play an important role in timely management of vestibular disorders. It has been demonstrated that the combination of cinnarizine + dimenhydrinate causes partial recovery of the caloric nystagmus at the affected site, resulting in gradual decrease in spontaneous nystagmus with minimal effect on vigilance which does not affect the vestibular invoked myogenic potential outcomes. This might suggest that the central compensation processes is not suppressed by the combination therapy [30, 31].

Conclusion

Cinnarizine has gained significant importance and has been established as a first-line pharmacotherapy in vertigo management basis clinical evidences generated over the last four decades. Recent literature has proven that the fixed dose combination of cinnarizine + dimenhydrinate is an effective therapeutic option in treating vertigo due to various causes. Treatment with cinnarizine + dimenhydrinate combination was efficacious and demonstrated good tolerability among the majority of patients. Thus, this combination therapy in vertigo of various origins seems viable and beneficial alternative in the treatment of vertigo. In conclusion, cinnarizine and its combinations can make an important contribution to healthcare by optimal treatment of patient presenting with vertigo, one of the most common presenting symptom across all specialties of medicine.

Key Messages

• Cinnarizine, established as a first-line pharmacotherapy in vertigo management is efficacious due to its peripheral and central action.

• A thorough literature survey emphasized clinical efficacy and safety of cinnarizine versus placebo and other comparators.

• Combination therapy of cinnarizine and dimenhydrinate is likely a viable and beneficial alternative in vertigo treatment.

Compliance with Ethical Standards

Conflict of interest

None.

Disclosure

Dr. Ravi Santani and Dr. Prashant Narang are employees and/or shareholders of Janssen, India. All authors contributed to the data interpretation and development of the review. All authors met ICMJE criteria and all those who fulfilled those criteria are listed as authors. All authors had access to the study data, provided direction and comments on the manuscript, made the final decision about where to publish these data and approved submission to the journal.