Indian J Otolaryngol Head Neck Surg

(November 2019) 71(Suppl 2):S1060–S1068; DOI 10.1007/s12070-017-1120-7

ORIGINAL ARTICLE

Cinnarizine: A Contemporary Review

Milind Vasant Kirtane1 • Anita Bhandari2 • Prashant Narang3 • Ravi Santani3

Received: 27 October 2016 / Accepted: 4 April 2017 / Published online: 25 April 2017
 Association of Otolaryngologists of India 2017

Abstract Cinnarizine, is approved for nausea, vomiting, Keywords Cinnarizine
Vertigo
Dimenhydrinate

motion sickness, inner ear disorders and is considered as Drug combinations
first-line pharmacotherapy for management of vertigo. It
acts by anti-vasoconstrictor activity, reducing blood
viscosity and reducing nystagmus in labyrinth. Lack of Introduction
adequate literature on clinical evidence of cinnarizine and
its combination (dimenhydrinate) in vertigo management Cinnarizine is a well-established anti-vertigo drug initially
prompted this review. A specific MEDLINE literature synthesized as an anti-histamine [1]. It is the mainstay
search strategy was designed combining Medical Subject therapy for vestibular disorders [2], approved for nausea,
Headings, free-text keywords (like cinnarizine and vertigo) vomiting, motion sickness, vertigo and tinnitus associated
using Boolean operators (1970–2016) for clinical studies, with Ménière’s disease and other middle ear disorders, as a
clinical reviews and meta-analyses of cinnarizine. Analyses nootropic drug (memory and cognitive function enhancer)
of studies validated cinnarizine’s efficacy in peripheral and and as adjunct therapy for peripheral arterial disease [3].
central vertigo versus placebo or other therapies, and was Betahistine, prochlorperazine and dimenhydrinate are also
well-tolerated by the patients recruited across different used to treat vertigo (Table 1). Cinnarizine and/ or its
studies. Cinnarizine and/ or its combinations are favorable combination is approved in India for the management of
in management of vestibular disorders wherein cinnarizine vertigo [4]. Limited publications of cinnarizine ?
acts predominantly peripherally on labyrinth and dimenhydrinate have been reported in last two decades.
dimenhydrinate acts centrally on vestibular nuclei and This contemporary review aims to evaluate the role of
associated centers in brainstem. Combination therapy of cinnarizine and/ or its combinations in vertigo.
cinnarizine and/ or its combinations demonstrated a better
safety profile than either of the mono-components, offering
a viable therapeutic option in vertigo management. Methods

A literature search was done on MEDLINE. The search

strategy included Medical Subject Headings and free-text
& Ravi Santani keywords (cinnarizine, dimenydrinate and vertigo) using
rsantani@its.jnj.com Boolean operators (‘OR’ and ‘AND’). English publications
1 of mainly clinical studies of cinnarizine and combination
Department of Otolaryngology, P.D. Hinduja National
Hospital and Medical Research Centre, Mumbai, therapy (cinnarizine ? dimenhydrinate), clinical reviews,
Maharashtra, India meta-analysis involving cinnarizine and guidelines for
2
Vertigo and Ear Clinic, Jaipur, Rajasthan, India management of vertigo in various conditions were
3 collected for the period from 1970 to 2016. Data in
Medical Affairs Department, Janssen India, Arena Space,
Behind Majas Depot, Off JVLR, Jogeshwari East, Mumbai, prescribing information leaflets, manufacturing as well as
Maharashtra 400060, India labelling data were also incorporated.

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Indian J Otolaryngol Head Neck Surg (November 2019) 71(Suppl 2):S1060–S1068 S1061

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

Mechanism of Action nausea and vomiting in a range of conditions including

transient ischemic attacks. Cinnarizine’s anti-vasoconstrictive
Cinnarizine, developed as an anti-histamine, subsequently and protective action against hyperviscosity of blood along
manifested a number of pharmacological effects, most with its peripheral anti-ischemic action may be helpful in
significantly: labyrinthine suppressant action and peripheral improving blood flow thus playing an important role in
anti-vasoconstrictive effects [5]. Cinnarizine inhibits smooth various therapeutic indications [7].
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) Anti-vasoconstrictor Action
receptors and dopamine D2 receptors [6]. Thus, the
mechanism of action of cinnarizine is multimodal (Fig. 1). Vasodilators can cause relaxation irrespective of whether
Insufficient cerebral blood circulation has been hypothesized the altered Ca2? dependent tone is caused by intrinsic
to cause ‘vertiginous symptoms’ like tinnitus, dizziness, (myogenic) or extrinsic (vasoconstrictor) activity.

Fig. 1 Mechanism of action of cinnarizine. RBC red blood cell

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Cinnarizine, on the other hand, has no direct vasodilatory pharmacologically relevant concentrations of cinnarizine
action and does not directly interfere with the potential of (0.05–3 lM) elicited depolarization and increased
smooth muscle cells to develop tone. Instead it selectively voltage-dependent activation of Ca2? currents, which
inhibits spasmogen-stimulated Ca2? influx and thus enhanced transmitter release.
differentiates increased Ca2? influxes in response to
vasoconstrictors as opposed to those caused by intrinsic
myogenic changes in membrane potential [8] and hence, is Clinical Evidence
described as an anti-vasoconstrictor.
Vertigo accounts for *5% of total prevalence and an
incidence of 1.4% in adults. This high presentation rate is
Action on Blood Viscosity probably due to the large number of underlying conditions
reported along with the symptom [15]. An Indian study
Increased blood viscosity is an important factor in reducing conducted in 2001 estimated the overall prevalence of
blood flow in patients with ischemic diseases and vertigo in rural adult community as 0.7% [16]. The
intermittent claudication [9]. Historical data have shown underlying cause might be either of the following reasons;
that cinnarizine decreases blood viscosity in patients with an involvement of labyrinth in the inner ear, or due to
ischemic diseases. Many studies have proposed that the dysfunction of the vestibular nerve, or the defect may
ability of cinnarizine to reduce blood viscosity is attributed involve vestibular nuclei, or other centers responsible for
to its effects on red blood cell(s) (RBCs), thereby the maintenance of balance. For vertigo patients in the
preserving the flexibility and deformability of RBCs. It has latter two categories, the anti-vasoconstrictor properties of
been postulated that this might be due to the ability of cinnarizine might be beneficial in restoring blood flow by
cinnarizine to block Ca2? entry in ischemic RBCs [7]. improving the microcirculation in the affected region [17].
Another hypothesis adds that flunarizine, a cinnarizine
derivative, protects against Ca2? dependent ionophore
A23187-induced crenation of human RBCs, a condition Peripheral Vertigo
associated with decreased membrane deformability [10].
This type of vertigo is due to problems originating in the
peripheral nervous system like benign paroxysmal
Action on Labyrinth positional vertigo, acute vestibular neuronitis, or Ménière’s
disease. Some of the common triggers of peripheral vertigo
The action of cinnarizine on peripheral vestibular include alcohol and also drugs like anti-depressants,
structures has been demonstrated in various clinical antihypertensives, salicylates, hypnotics and sedatives.
studies. During the early years of development (1976), Neurologic symptoms, hearing loss, severe nausea and
cinnarizine 25 mg at a thrice-daily (TID) dosage was noted vomiting may be concomitant conditions presenting along
to be significantly superior to placebo in reducing the with peripheral vertigo [18]. Efficacy of cinnarizine in
amplitude, duration and speed of the slow phase of various causes of peripheral vertigo has been established in
post-rotational nystagmus and the total number of beats different clinical studies (Table 2).
(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 Central Vertigo
peripheral labyrinthine disorders [12]. Mechanism of
action of cinnarizine in the labyrinth involves inhibition of Central vertigo may be caused by vascular insufficiency/
Ca2? ion translocation across cell membranes of the cerebral ischemia involving vestibular centers in brainstem,
vestibular sensory cells in the ampullae. Overstall et al. cerebellum and disorders of the thalamus leading to
[13] however, have suggested that cinnarizine normalizes dizziness and unsteadiness. Cinnarizine has proven to be
endolymph flow by preventing constriction of the stria effective in patients suffering from vertigo of central
vascularis. An additional mechanism of action of origin. It improves the microcirculation in the affected
cinnarizine in vestibular vertigo hypothesized that parts of brain like vestibular nuclei which results in
cinnarizine modulates transmitter release in vestibular hair improved central vestibular function. In one of the earliest
cells (patch-clamp model). Haasler et al. [14] demonstrated studies in 1972, cinnarizine was shown to benefit patients
that inhibition of pressure-dependent K? currents in with central vertigo due to impaired cerebral circulation,

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Table 2 Cinnarizine in peripheral vertigo

Peripheral Study design Sample size Cinnarizine Comparator Result
causes dosage

Labyrinthitis Double-blind 14 45–90 mg/day Prochlorperazine 70%–80% improvement in severity of

crossover [33] for 4 weeks nausea and vomiting. 50%–60%
improvement in tinnitus. Efficacy
similar to prochlorperazine
MD Double-blind 20 45–90 mg/day Prochlorperazine 70%–80% improvement in symptom
crossover [33] for 4 weeks severity with cinnarizine and
prochlorperazine
MD Double-blind, 37 2 9 75 mg for Betahistine 3 9 16 mg for Betahistine resulted in higher
randomized study 8 weeks 8 weeks reduction of symptoms compared
[26] with cinnarizine
MD (with Open-label, 52 MD 20 mg BID/OD Combined therapy: betahistine Cinnarizine, proactively prevented
and non-randomized (n = 29 48 mg/day ? cinnarizine vertigo spells especially in MD
without [34] were 20 mg BID (1 month) and patients with migrane
migraine) migraineurs) 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
Peripheral Double-blind, 221 adult 150 mg OD for Nimopidine 30 mg oral tablet Nimopidine and cinnarizine reduced
vertigo multinational pilot 12 weeks TID (one with breakfast, incidences of moderate vertigo
study [35] (with dinner) lunch and dinner) episodes by 78.8% and 65.8%
respectively and severe vertigo
incidences were decreased by
85.0% and 89.8%, respectively
Recurrent Randomized, 88 patients 2 9 15 mg TID Betahistine dihydrochloride Both drugs reported equal efficacy in
vertigo crossover study 2 9 12 mg TID reducing the duration and severity
[36] of symptoms at the end of
6 months
Seasickness Double-blind 335 15 mg TID for Placebo Vomiting prevented significantly by
placebo-controlled 5–7 days cinnarizine (75%, p \ 0.001) as
[37] whilst at compared with placebo (43%).
seasickness Drowsiness was reported by 8%
receiving cinnarizine and 5%
receiving placebo
Induced NR [38] 6 healthy 15 mg TID Betahistine 8 mg TID Nystagmus duration and average eye
vestibular volunteers speed were similar between
nystagmus 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

irrespective of whether the symptom was a primary Pharmacokinetic Data

manifestation or a complication of some other disease
process [19]. Later, an in-vivo model demonstrated that Pharmacokinetic data revealed that post-administration,
cinnarizine increases blood flow to the lateral vestibular plasma levels of cinnarizine peak in 1–3 h. Total 91.0% of
nucleus selectively in a non-dose dependent manner, cinnarizine is plasma-protein bound which is extensively
without affecting the reticulo-cortical, thalamo-cortical and metabolized, largely by CYP2D6. The elimination half-life
sensory trigeminal systems [20]. Table 3 shows important for cinnarizine varied from 4 to 24 h; 33.0% of the
clinical studies of cinnarizine in the management of vertigo metabolites were eliminated by urine and 66.0% in the
of central origin. feces [21]. Cinnarizine has a Cmax of 275 ± 36 ng/mL,

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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 Double-blind [40] 117 25 mg BID/TID Vincamine Cinnarizine was superior to vincamine against
diseases dizziness and tinnitus
BID twice-daily, TID thrice-daily, NA not applicable

tmax 3.0 ± 0.5 h, AUC? 4437 ± 948 ng h/mL and Many randomized, double-blind clinical studies have
terminal half-life was 23.6 ± 3.2 h post 72 h of clearly demonstrated the efficacy and tolerability of the
administration [22]. fixed dose combination of cinnarizine ? dimenhydrinate in
comparison with standard monotherapies in various defined
pathological entities, including otogenic vertigo, vestibular
Dosage Recommendations neuropathy, vertigo in vertebrobasilar insufficiency and
Ménière’s disease (Table 4).
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 Renal and Hepatic Insufficiency
15 mg is available. Cinnarizine is recommended as 25 mg
TID or 75 mg once-daily dosing for maintenance therapy No specific studies have been reported on the use of
for symptoms of labyrinthine disorders, including vertigo, cinnarizine in patients with hepatic or renal dysfunction.
dizziness, tinnitus, nystagmus, nausea and vomiting. The However, it is recommended that cinnarizine be used with
maximum recommended dosage for cinnarizine is 225 mg care in patients with such conditions [25].
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 Pregnancy and Lactation
every 6 h during the journey [21].
No teratogenic effects with use of cinnarizine have been
reported in pre-clinical studies [21]. The safety of
Role of Cinnarizine in Combination cinnarizine in pregnant or lactating women has not been
with Dimenhydrinate in Vertigo established in clinical studies. Cinnarizine should be used
during pregnancy only if the therapeutic benefits justify the
The fixed dose combination of cinnarizine ? dimenhydrinate, potential risks for the fetus/infant as indicated by a
with its dual mechanism of action, allows the simultaneous physician. As there is no data available on secretion of
functional regulation of the peripheral and central cinnarizine in breast milk, nursing should be discouraged in
vestibular components [23]. Cinnarizine acts women using cinnarizine [21].
predominantly peripherally on the labyrinth, causing
increased cerebral and cochlear perfusion as well as
vestibular suppression through inhibition of Ca2? channels Safety Profile
in vestibular sensory cells; thus improving inner ear
circulation. Dimenhydrinate acts centrally on the vestibular Cinnarizine and its combinations have shown no safety
nuclei and associated centers in the brainstem; and concerns and are well-tolerated. An analysis of seven
additionally acts as an anti-histamine, anti-cholinergic, placebo-controlled, double-blind clinical studies of
anti-emetic and anti-vertiginous activity alleviating acute cinnarizine (30–225 mg/day) was conducted to evaluate
vertigo attacks. Due to these combined pharmacological safety in total 740 patients (cinnarizine: 372 patients and
properties of cinnarizine ? dimenhydrinate, the fixed dose placebo: 368 patients). Drowsiness/somnolence was
combination is favorable in the management of various encountered in some patients (\10%), especially at the
vestibular disorders [24] (Fig. 2). start of treatment. Therefore, caution should be exercised

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Fig. 2 Mechanism of action of fixed dose combination of cinnarizine and dimenhydrinate

when concomitant drugs having central nervous system out in primary and secondary care private practices,
depressant action are taken and activities like driving and combination of cinnarizine ? dimenhydrinate therapy was
operating machinery should be avoided [21]. Nausea and evaluated in the treatment of vertigo of various origins. In
weight gain were other adverse events reported during addition to reduction in mean vertigo score in the 1275
some of the clinical studies [21, 26]. patients, nausea, vomiting and tinnitus were also reduced
Incidences of extrapyramidal symptoms and drug-induced by 84%, 85% and 51%, respectively, and non-serious
Parkinsonism were very rare during the post-marketing adverse events were reported in 4.2% of the population
surveillance studies. The results on recurrent labyrinthine [29]. Overall, combination of cinnarizine ? dimenhydrinate
disturbances have demonstrated that cinnarizine administered demonstrated a better benefit-risk ratio than either individual
for the long-term control of labyrinthine disorders does not monotherapy [30].
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 Limitations
disease.
The combination of cinnarizine ? dimenhydrinate was Consensus rating of the article quality was not performed
evaluated for adverse events. An analysis of data from five because it was beyond the scope of the current review. The
randomized, double-blind clinical studies concluded that reliability of the article selection and classification was not
combination of cinnarizine ? dimenhydrinate was assessed because only one reviewer was involved in the
well-tolerated and with 90.3% of the patients reported the process albeit the potential source of bias is minimal since
tolerability as ‘very good’ or ‘good’. Most common side only basic descriptive information was extracted from each
effects reported were fatigue or somnolence, closely article. As the studies selected for this review spanned a
followed by dry mouth. Other adverse events reported were course of four decades, it is very likely that the endpoints,
headache, abdominal pain, nausea and tremors [27, 28]. In conduct of study and analysis variability could have been
a German, prospective, non-interventional study carried overlooked.

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Table 4 Cinnarizine in combination with dimenhydrinate: clinical evidence

Causes of vertigo Study design Sample Comparator Result
size

Ménière’s disease Double-blind, randomized 82 Betahistinea 12 mg Both drugs led to a marked reduction of vertigo
control [41] TID for 12 weeks symptom score. Similar efficacy and safety
were reported between the combination and
betahistine
Otogenic vertigo Prospective, double-blind, 61 Betahistine 12 mg TID Fixed dose combination decreased the intensity
randomized, comparative, for 4 weeks of vertigo symptoms about twofold than
single-center study [42] betahistine (p = 0.001) at 4 weeks and this
was more evident post 4 weeks of treatment
(p = 0.009)
Vertebrobasilar Double-blind, randomized 37 Betahistinea 12 mg Fixed dose combination showed significantly
insufficiency control [43] TID for 4 weeks or greater reductions of vertigo symptom score as
placebo compared to patients receiving betahistine
(p \ 0.01)
Vertebrobasilar NR [44] 78 Cinnarizine and Dual action of the combination therapy revealed
insufficiency dimenhydrinate BID symptom reduction of tinnitus (38.7%) and
for 60 consecutive dizziness (43.1%). Reduction was also
days observed in the tinnitus handicap inventory
and dizziness handicap inventory score at final
examination (p \ 0.001)
Vestibular disorders Double-blind, randomized 66 Betahistine 12 mg TID The cinnarizine ? dimenhydrinate fixed dose
control [24] for 4 weeks combination therapy reported significantly
greater improvements in mean vertigo scores
than betahistine (p = 0.013)
Vestibular neuritis Double-blind, randomized 62 Betahistine 12 mg each The fixed dose combination therapy reported
control [31] TID for 4 weeks 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 Randomized, double-blind, 246 Placebo, TID for In those patients with mean vertigo score B0.5
or central, combined active- and 4 weeks after 4 weeks of treatment, the fixed dose
peripheral/central placebo-controlled, combination was effective in 62.3% of patients
origin parallel-group, outpatient than 29.5% in cinnarizine 50 mg, 30.5% in
study [45] dimenhydrinate 100 mg and 24.1% in placebo
group
Vertigo of various Prospective, double-blind, 182 Cinnarizine 20 mg or Reduction in mean vertigo score post four weeks
origins randomized active-controlled, dimenhydrinate of treatment with the fixed dose combination
multicenter study [23] 40 mg, each TID for was significantly greater than each of the
4 weeks monotherapy alone (p = 0.0001)
Acute unilateral Prospective, single-center, 50 Cinnarizine 20 mg or Fixed dose combination was significantly more
vestibular loss randomized, double-blind, dimenhydrinate effective than either of the monotherapy
parallel-group [29] 40 mg, TID for (cinnarizine, p \ 0.001 and dimenhydrinate,
4 weeks p \ 0.01)
Vertigo and tinnitus of Double-blind, randomized 122 Cinnarizine 20 mg or Fixed dose combination was more effective than
peripheral or central control [46] dimenhydrinate either of its constituent drugs used as
origin 40 mg, TID for monotherapy
4 weeks
a
Betahistine dimesylate was used as an active comparator of cinnarizine ? dimenhydrinate clinical study. BID twice-daily, TID thrice-daily, NR
not reported

Expert Opinion theories have been postulated on interaction of various

drugs with vestibular compensation though the supporting
Pharmacotherapy plays an important role in control of evidence is lacking, but duration of therapy is known to
vertiginous symptoms in patients with vestibular disorders. play an important role in timely management of vestibular
Therapy duration should be decided by the treating disorders. It has been demonstrated that the combination of
physician based on the etiology of symptoms. Multiple cinnarizine ? dimenhydrinate causes partial recovery of

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the caloric nystagmus at the affected site, resulting in References

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