![Structure of betahistine. Betahistine dihydrochloride [N-Methyl-2-(2-pyridyl) ethylamine dihydrochloride; molecular formula C8H12N2.2HCl; molecular mass 209.12g/mol] was the first betahistine salt to be developed and approved for clinical use-in Canada in 1968. It was subsequently registered in Europe in 1970 for the treatment of](https://www.researchgate.net/profile/Avijit-Hazra-2/publication/318644139/figure/fig1/AS:519112862715904@1500777559778/Structure-of-betahistine-Betahistine-dihydrochloride-N-Methyl-2-2-pyridyl-ethylamine_Q320.jpg)
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www.ijbcp.com International Journal of Basic & Clinical Pharmacology | August 2017 | Vol 6 | Issue 8 Page 1833
IJBCP International Journal of Basic & Clinical Pharmacology
Print ISSN: 2319-2003 | Online ISSN: 2279-0780
Review Article
Betahistine dihydrochloride or betahistine mesilate: two sides of the
same coin or two different coins
Avijit Hazra*, Niteeka Maroo
INTRODUCTION
An active pharmaceutical ingredient may be used not
only in different dosage forms but also in chemical
variants such as different salts, esters, states of hydration,
stereoisomers and so on. Selection of the salt or ester
form is generally made in early development during the
preformulation stage as it may impact on the
physicochemical properties of the product, in particular
crystal form, solubility, hygroscopicity, chemical stability
and dissolution rate. There may also be differences in
bioavailability with different salt or ester forms of a drug.
Clarification of these seemingly minor differences may,
on occasions, be helpful for physicians seeking to
optimize treatment and minimize risk and inconvenience
to the patient.
Betahistine is a histamine modulatory drug used for the
treatment of vertigo of Ménière’s disease and other
disorders of vestibular origin.1 Two salt formulations of
the drug are currently being marketed in India-
betahistine dihydrochloride and betahistine mesilate.
Prompted by queries from otorhinolaryngology
colleagues, regarding differences between the two, we
thought it worthwhile to conduct a comparative review of
these two salt forms. To the best of our knowledge, this is
ABSTRACT
The antivertigo drug betahistine exerts a histamine modulatory action in the
vestibular system and the brain. It is marketed both as the dihydrochloride and
the mesilate salt in India. We conducted a published literature based systematic
review to ascertain differences, in any, between the salt and ester forms of the
drug. Search of the Medline database was supplemented by searching through
references in full text papers and retrieving summary of product characteristic
literature. Although the weight of published evidence is greater for betahistine
dihydrochloride, in the absence of head-to-head studies comparing the efficacy
of the two formulations in Ménière's disease and other vertigo disorders of
vestibular origin, it is not possible to conclude that there are definite differences
in this regard. However, potentially relevant differences exist to suggest that the
two forms are not interchangeable for the treatment of vestibular dysfunction.
Molecular weight comparison indicates that the pill burden would be higher for
betahistine mesilate for delivering equivalent doses. There could be ethnically
influenced differences in pharmacokinetic behavior. There are concerns of
potential long-term DNA toxicity due to mesilate ester contaminants during
production of betahistine mesilate, which is not there for the hydrochloride
form. Detailed post-marketing surveillance data exists only for the
dihydrochloride salt. Otorhinolaryngologists and other physicians seeking to
optimize treatment with betahistine should be aware of these differences.
Keywords: Betahistine dihydrochloride, Betahistine mesilate, Ménière's
disease, Vertigo, Vestibular dysfunction
DOI: http://dx.doi.org/10.18203/2319-2003.ijbcp20173266
Department of Pharmacology,
Institute of Postgraduate
Medical Education and Research
(IPGME&R), 244B Acharya J.
C. Bose Road, Kolkata 700020,
West Bengal, India
Received: 09 May 2017
Accepted: 06 June 2017
*Correspondence to:
Dr. Avijit Hazra,
Email: blowfans@yahoo.co.in
Copyright: © the author(s),
publisher and licensee Medip
Academy. This is an open-
access article distributed under
the terms of the Creative
Commons Attribution Non-
Commercial License, which
permits unrestricted non-
commercial use, distribution,
and reproduction in any
medium, provided the original
work is properly cited.
Hazra A et al. Int J Basic Clin Pharmacol. 2017 Aug;6(8):1833-1840
International Journal of Basic & Clinical Pharmacology | August 2017 | Vol 6 | Issue 8 Page 1834
the first review looking at differences of potential clinical
significance between these two betahistine forms.
METHODS
We conducted a Medline search for peer-reviewed
publications covering the period till May 2016 using the
keywords ‘betahistine dihydrochloride’, ‘betahistine
mesilate’, ‘betahistine mesylate’, ‘betahistine’, ‘vertigo’
and ‘vestibular dysfunction’. Searches were refined with
the search limits 'animals', ‘humans’, ‘randomized
controlled trial’, ‘clinical trial’, ‘meta-analysis’ and
‘practice guideline’ in order to identify papers of
relevance to us. Full texts were retrieved through the
Science Direct gateway and by contacting colleagues
with full text access to concerned journals. Further
articles of relevance were found using the reference
citations in full text papers. Summary of product
characteristic (SPC) literature available online were
verified by contacting the manufacturer of betahistine in
India. Few Russian and Chinese language articles of
relevance were located. Information from English
language abstracts of these articles were used.
HISTORICAL PERSPECTIVE AND
PHYSICOCHEMICAL DIFFERENCES
Betahistine [N-methyl-2-(pyridin-2-yl) ethylamine;
molecular formula C8H12N2; molecular mass 136.19
g/mol; ATC code N07CA01- belonging to class
antivertigo preparations] is a structural analogue of
histamine. It was first introduced for the symptomatic
treatment of vascular and vasomotor disorders such as
cluster headaches and vascular dementia.2 Subsequently it
was used in Ménière's disease and has been explored in
other vertigo disorders of central and peripheral origin
such as multiple sclerosis and motion sickness.3,4 The
structure of betahistine is depicted in Figure 1.
Figure 1: Structure of betahistine.
Betahistine dihydrochloride [N-Methyl-2-(2-pyridyl)
ethylamine dihydrochloride; molecular formula
C8H12N2.2HCl; molecular mass 209.12g/mol] was the
first betahistine salt to be developed and approved for
clinical use- in Canada in 1968. It was subsequently
registered in Europe in 1970 for the treatment of
Ménière's disease. It is currently registered in over 110
countries worldwide. Betahistine mesilate [N-methyl-2-
(pyridin-2-yl) ethylamine dimethanesulfonate; molecular
formula C8H12N2.2(CH4O3S); molecular mass
328.41g/mol) was first marketed in 1969 in Japan and is
now marketed in several countries worldwide. The
mesilate form of betahistine was introduced for treating
dizziness and the feeling of dizziness resulting from
Ménière's disease and vertigo.
Thus two formulations of betahistine are currently
available for prescription use. Firstly, there is betahistine
dihydrochloride (brand names of innovator company
Abbott include BETASERC®, SERC®, VERTIN®) which
is indicated (with slight variations depending on the
country) for the treatment of vertigo, tinnitus and hearing
loss associated with Ménière's syndrome and also vertigo
of other causes, with a maximum recommended dose of
16 mg thrice daily.5 Secondly, betahistine mesilate (brand
name of innovator company Eisai Pharmaceuticals being
MERISLON®) which is indicated for dizziness and
feeling of dizziness resulting from Ménière's disease,
Ménière's syndrome and vertigo, with a maximum
recommended dose of 12 mg three times a day.6
ACTIVITY OF BETAHISTINE
Betahistine’s mechanism of action is only partly known.
Various potential effects have been suggested based on
preclinical as well as clinical studies. Through its
histaminergic action, it may improve microcirculation of
the inner ear labyrinth and cochlea and reduce
endolymphatic pressure.1 The parent drug as well as two
metabolites, aminoethylpyridine and
hydroxyethylpyridine (but not the major metabolite
pyridylacetic acid), have been shown to increase cochlear
blood flow in guinea pig model.7 Betahistine is a partial
histamine H1 receptor agonist and a potent H3 receptor
antagonist.8,9 H3 receptors exhibit constitutive activity,
and recent data suggest that H3 receptor antagonists
actually act as inverse agonists. The therapeutic effects of
betahistine may result from enhancement of
histaminergic neuronal activity through inverse agonism
at presynaptic H3 autoreceptors.10 An H4 receptor has
been cloned recently and shown to be co-expressed with
H3 receptors in vestibular neurons in the Scarpa’s
ganglion.11,12 Its modulation may also influence
vestibular system function and betahistine may work
through combined H3 and H4 receptor effects.12 Besides
having a vascular action in the inner ear, betahistine also
exerts modulatory effects in the central nervous system
and may exert excitatory effects on neuronal activity in
cortical and subcortical structures.12 It interacts strongly
with the histaminergic system to increase histamine
synthesis and release in the tuberomammillary nuclei of
the posterior hypothalamus. These latter effects are
consistent with the concept of a neuromodulatory role
that histamine plays in the regulation of vestibular
function both centrally and peripherally.12
Hazra A et al. Int J Basic Clin Pharmacol. 2017 Aug;6(8):1833-1840
International Journal of Basic & Clinical Pharmacology | August 2017 | Vol 6 | Issue 8 Page 1835
Taken together, these properties underlie the currently
approved use of betahistine in Ménière's disease, a
vestibular disorder characterized by the triad of vertigo,
tinnitus and hearing loss, and in the symptomatic
treatment of vestibular vertigo.13 Clinical efficacy has
been demonstrated in multiple double-blind, randomized,
placebo or active controlled studies performed in diverse
patient groups.14-17
In recent years, histamine has emerged as a key
neurotransmitter in the regulation of feeding behavior and
betahistine has been proposed as a treatment for obesity.18
However, a recent randomized placebo-controlled trial of
betahistine dihydrochloride in obese women failed to
show change in either appetite or food intake.19
Interestingly this appetite reducing role of betahistine is
re-emerging lately with experimental and clinical
evidence of successful use of betahistine in ameliorating
weight gain associated with the widely used antipsychotic
drug olanzapine.20,21
MANUFACTURING ASPECTS
Mesilate salts are alternative to conventional
hydrochloride salts because they help to obtain crystalline
forms of amine containing drugs like betahistine, have
higher solubility and may offer higher bioavailability.22
Preclinical studies show that certain mesilate esters (e.g.
methyl methanesulfonate, ethyl methanesulfonate or
isopropyl methanesulfonate) are potentially toxic
substances by virtue of DNA alkylation; they can form
reactive, direct-acting intermediates that are potentially
genotoxic and carcinogenic.22 Concerns over the possible
formation of such esters during the preparation of
mesilate drug substances, by addition of methane sulfonic
acid (MSA) to the free base dissolved in an alcoholic
solvent, have led regulatory agencies to require that all
applicants detail their synthetic method employed. Where
necessary, the production method is to be validated to
ensure that alkyl mesilates are not detectable in the final
product.
Under optimal manufacturing conditions, mechanistic
considerations relating mainly to the low nucleophilicity
of the mesilate anion and experimental data indicate that
alkyl mesilates should not form, except from MSA
impurities, during mesilate synthesis.22 Nevertheless, in
2008, the European Medicines Evaluation Agency
(EMEA) issued a directive to all marketing authorization
holders for medicinal products containing mesilates (and
also [di]isetionates, tosilates or besilates) to assess the
risk of contamination with mesilate esters and related
compounds in pharmaceuticals.23 This directive on risk
analysis also required disclosure of procedures related to
the cleaning processes and the solvents used. It can be
assumed that under this guidance mesilates can be taken
without any risks. However, the status and findings of
such risk assessment exercise by marketing authorization
holders is currently unknown. No similar risks or
concerns have emerged for the dihydrochloride salt.
Comparison of the content of active substance and oral
pharmacokinetic profile
The molecular weight of betahistine dihydrochloride is
209g/mol, while that of betahistine mesilate is 328g/mol;
the molecular weight of betahistine is 136g/mol, the
dihydrochloride group is 73g/mol and the mesilate group
is 192g/mol. Therefore, each tablet of betahistine
dihydrochloride 16 mg contains betahistine 10.4mg,
equivalent to two tablets of betahistine mesilate 12mg,
each containing 4.9mg betahistine. It may be noted that
betahistine mesilate is currently not available in higher
strength tablets, which may be a potential disadvantage
with respect to the pill burden on the patient.
Table 1: Oral pharmacokinetic profiles of betahistine
dihydrochloride and betahistine mesilate.
Parameter
Betahistine
dihydrochloride24
Betahistine
mesilate25
Study subjects
Indian (n = 12)
Chinese
(n = 20)
Dose administered
(Single dose)
24mg oral in
fasting state
24mg oral
in fasting
state
Peak plasma
concentration
(Cmax)*
786.7ng/mL
339.4ng/mL
Time to peak
plasma
concentration
(Tmax)*
0.7 hour
1 hour
Area under plasma
concentration time
curve (AUC0–)*
3524ng.h/mL
1154
ng.h/mL
Elimination half-
life (t1/2)*
3.5 hours
Range: 2-
11.4 hours
Mean: 5.2
hours
* This is of the principal metabolite 2-pyridylacetic acid.
Betahistine itself undergoes almost complete first-pass
metabolism in man so that plasma concentration of the parent
drug is very low. The principal metabolite, 2-pyridylacetic acid,
is pharmacologically inactive and is primarily excreted by renal
route.
Following an open label trial in patients with Ménière's
disease, it has been suggested that a higher dose of
betahistine (as dihydrochloride) and longer-term
treatment would be more effective than low dose and
short-term treatment.15 The maximum dose recommended
for betahistine dihydrochloride according to product
literature is 48 mg per day (divided in 2-3 doses). Given
the possibility that higher doses of betahistine are more
effective, it may be worthwhile attempting to reach the
maximum recommended daily dose as optimal treatment
for an individual patient. Ménière's disease and other
forms of vestibular vertigo are usually chronic conditions
and therefore good patient compliance is needed to re-
establish the patient’s functioning and quality of life. A
Hazra A et al. Int J Basic Clin Pharmacol. 2017 Aug;6(8):1833-1840
International Journal of Basic & Clinical Pharmacology | August 2017 | Vol 6 | Issue 8 Page 1836
reduced pill burden through higher strength tablets should
contribute to improved compliance.
Table 1 summarizes the pharmacokinetic differences of
the two formulations. Given that both genetic and
environmental factors can influence drug metabolism, it
is possible that these pharmacokinetic differences in
Indian and Chinese subjects relate to ethnicity.24,25
Alternatively, differences may be attributable to the
different chemical forms used in these two studies.
Comparative studies in similar volunteer groups are
needed to answer this question convincingly.
Comparison of clinical efficacy
There are potentially relevant differences in the number
and quality of clinical studies on the efficacy of
betahistine dihydrochloride and mesilate for their
licensed indications. Around 34 published studies on use
of betahistine dihydrochloride in Ménière's disease were
identified, along with over 20 studies in treating recurrent
vertigo, in comparison to 10 studies with betahistine
mesilate. No head-to-head comparison studies were
located.
A meta-analysis of randomized, double-blind, parallel-
group or cross-over studies on the efficacy of betahistine
dihydrochloride and betahistine mesilate versus placebo
in vertiginous syndromes, such as paroxysmal positional
vertigo and vertigo secondary to arterial deficiency of the
vertebrobasilar area (i.e., symptoms not related to
Ménière's disease) has been conducted.26 Of 104
publications obtained through search of Medline,
EMBASE and CINAHL databases, 7 studies involving a
total of 367 patients were extracted and analyzed. This
meta-analysis also looked at the sub-groups identified by
the experimental design (parallel or crossover design),
range of dosages (32-48mg/day) and treatment duration
(3 weeks to 4 months). Results confirm the therapeutic
benefit of betahistine, both as dihydrochloride and
mesilate, versus placebo. Clinical improvement in the
pooled sample showed odds ratio of 3.52 (95%
confidence interval 2.40-5.18) in favor of betahistine,
while analysis of sub-groups suggests maximum efficacy
with doses of 32-36mg and treatment periods of 3-8
weeks.
A more recent meta-analysis of 12 double blind,
randomized, placebo controlled trials with betahistine in
Ménière's disease or vestibular vertigo reached a similar
conclusion.27 The author used a new effect parameter, the
odds of a favorable treatment outcome. For each study a
separate odds ratio was estimated. All but one of the
study-specific odds ratios were >1.0, implying a
favorable effect of betahistine on vertigo symptoms in
rest 11 studies. The pooled meta-analytical odds ratio was
2.58 (95% confidence interval 1.67-3.99). When analyzed
separately, for Ménière's disease, the meta-analytical
odds ratio was 3.37 (95% CI 2.14-5.29) and for vestibular
vertigo, the odds ratio was 2.23 (95% CI 1.20-4.14).
Betahistine dihydrochloride
The clinical efficacy of betahistine dihydrochloride in
Ménière's disease in particular and vertiginous disorders
in general has been documented through multiple
randomized, double blind, controlled studies.
Results from a non-blinded trial in which Ménière's
disease patients received either a low dose of betahistine
dihydrochloride (16 or 24mg thrice daily) or a higher
dose (48mg thrice daily) demonstrate the utility of the
higher dose.15 After 12 months of treatment the mean
(median) number of attacks dropped from 7.6 (4.5) to 4.4
(2.0) (p <0.001) in the low dosage group, and from 8.8
(5.5) to 1.0 (0.0) (p <0.001) in the high dosage group.
The number of attacks showed significantly greater
reduction in the high dosage group. The treatment was
well tolerated in both groups. Although the highest
approved dose of betahistine dihydrochloride is currently
48mg/day in 2-3 divided doses, results from this study,
with the caveat of its open-label design, suggest that a
higher dose may provide still greater therapeutic benefit.6
A recently conducted randomized, double-blind, placebo
controlled study investigated the extent to which
betahistine dihydrochloride 24 mg thrice daily improved
vestibular compensation in 16 Ménière's disease patients
undergoing curative unilateral vestibular neurotomy
(UVN).17 There was statistically significant improvement
with active treatment over placebo, with regards to static
posturography, motion analysis and perception of
verticality, at one week and at one month. These findings
were corroborated by subjective vertigo scale assessment-
patients on betahistine dihydrochloride became
effectively normal one month after UVN compared to 3
months with placebo. Improvement in torsional eye
movement was not significant.
Studies also document the benefits of betahistine
dihydrochloride in vestibular dysfunction not associated
with Ménière's disease. In a trial in benign paroxysmal
positional vertigo, addition of betahistine to liberatory
maneuvers and gradual otolith dispersal technique of
Brandt and Daroff produced faster recovery compared to
maneuvering alone.28 Small studies also document
beneficial effects in vertebrobasilar insufficiency, balance
disorders following head trauma and attenuation of
postoperative nausea, vomiting and dizziness after middle
ear surgery.29-31
Comparative studies between betahistine and other drugs
used in the management of vertigo of vestibular origin
are few in number but have shown the benefits of
betahistine. Albera et al, compared the effect of
betahistine dihydrochloride and flunarizine on dizziness
handicap in patients with recurrent vestibular vertigo,
through a double-blind, randomized, multicenter study,
and observed greater benefit with the former at 8 weeks.32
Bodla et al, compared the compared the efficacy and
tolerability of cinnarizine 25mg with betahistine
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International Journal of Basic & Clinical Pharmacology | August 2017 | Vol 6 | Issue 8 Page 1837
dihydrochloride 16mg in the treatment of otogenic
vertigo.33 Both drugs were given thrice daily for 4 weeks.
Betahistine treatment led to significantly greater
improvements in mean vertigo scores compared to
cinnarizine. This was evident as early as 1 week after
starting treatment, and at the end of 4 weeks, betahistine
decreased the intensity of vertigo symptoms about 2-fold
compared with cinnarizine. Both drugs were well
tolerated.
Monzani et al, reported their 10 year experience of
combination treatment with betahistine and the calcium
channel blocker nimodipine versus betahistine alone in
the long-term treatment of Ménière's disease.34 A total of
113 medical records were analyzed; 53 patients received
betahistine dihydrochloride (32mg daily) for six months,
and 60 patients were treated with the same regimen plus
nimodipine (40mg daily) as added therapy during the
same period. A moderate reduction of the impact of
vertigo on quality of life was obtained in patients on
betahistine, but a more pronounced effect was achieved
in patients treated by combination therapy. In the latter
group, better control of vertigo was seen with a greater
reduction of frequency of attacks. Both protocols resulted
in a significant improvement of static postural control,
although a larger effect on body sway in all tests was
obtained by the combination of drugs. Only the
combination achieved beneficial effect with regards to
tinnitus annoyance and hearing loss. The authors
concluded that nimodipine represents a potential valid
add-on therapy to betahistine for Ménière's disease.
Some dose comparison studies are also reported in
literature. Gananca et al, conducted an open label
comparison of betahistine at doses of 16 mg thrice daily
and 24mg twice daily, with 60 subjects in each group,
and found that efficacy and tolerability were similar in
the treatment of vertigo in Ménière's disease. The
treatment duration was 24 weeks.35
Betahistine mesilate
Pialoux et al, studied betahistine mesilate in patients with
Ménière's disease or isolated tinnitus for
efficacy/tolerance ratio.36 The study was conducted in
two stages - a conventional open trial, followed by a
comparative crossover trial. The drug was clearly
effective in relieving vertigo and associated symptoms
without tolerability problems.
In a study of oral multidrug treatment for subjective
tinnitus, patients were given betahistine mesilate, vitamin
B complex and diazepam in combination.37 After 5
weeks, 54% of patients felt treatment had been effective.
Thus betahistine mesilate, as part of a multidrug
treatment combination, may provide relief for some
patients with tinnitus. In another study with 60 adult
patients of subjective tinnitus, 30 were given betahistine
mesilate and flunarizine while another 30 received
Vitamin B6 and flunarizine.38 Tinnitus loudness matching
assessment after 1 week showed that the betahistine
group fared better - the responder proportion was 65.5%
compared with 39.3% among controls - a statistically
significant difference. There were no serious adverse
reactions. Vestibular paroxysmia is a rare episodic
peripheral vestibular disorder that can cause acute short
attacks of vertigo. It is generally treated by
carbamazepine. Yi et al, compared carbamazepine,
carbamazepine plus betahistine mesilate and
oxcarbazepine plus betahistine mesilate in treating
vestibular paroxysmia in a retrospective review.39 After
12 weeks' treatment, the carbamazepine plus betahistine
mesilate group had a greater reduction in the frequency of
vertigo, vertigo duration and vertigo score than the other
two groups. The oxcarbazepine plus betahistine group
also did better than betahistine alone group. The authors
concluded that betahistine provides useful augmentation
of the effect of either carbamazepine or oxcarbazepine in
the treatment of vestibular paroxysmia.
Despite the above examples, evidence of efficacy for the
mesilate formulation appears to be limited compared to
that available for the dihydrochloride salt. Only 6
publications over the last 10 years, on the effects of
betahistine mesilate in vertigo, were identified during
database searches and these are mostly Chinese language
papers. On balance therefore, at the moment the weight
of scientific evidence lies with betahistine
dihydrochloride rather than with betahistine mesilate.
COMPARISON OF SAFETY
In general, both forms of betahistine are safe.
Manufacturers’ product literature, heeding betahistine's
role in increasing histamine levels throughout the body,
warn of the possibility of hypersensitivity reactions. For
both formulations, pheochromocytoma, peptic ulceration
and bronchial asthma are listed as contraindications or
situations requiring special precaution.
There is extensive clinical experience with betahistine
dihydrochloride. Over 130 million patients in 82
countries are estimated to have used this drug since its
registration in 1968.40 Worldwide post-marketing
surveillance data of over 35 years reveal a satisfactory
safety profile.40 There are no concerns of treatment-
emergent carcinogenicity or genotoxicity among a total
of 554 suspected adverse drug reaction (ADR) reports,
spanning 994 individual signs and symptoms, reviewed
by the marketing authorization holder. The principal
findings are summarized in Table 2. In a more recent 3-
month multicentre, open-label post-marketing
surveillance study of betahistine (24mg twice daily or
16mg thrice daily) in patients with vertigo of peripheral
vestibular origin, Benecke et al, reported that patients
with recurrent peripheral vestibular vertigo experience
improvements in objective measures of health-related
quality of life with satisfactory tolerability at this dose
level.41 A total of 76 ADRs were recorded from 49
patients (2.4%), of which 75 were classified as mild or
Hazra A et al. Int J Basic Clin Pharmacol. 2017 Aug;6(8):1833-1840
International Journal of Basic & Clinical Pharmacology | August 2017 | Vol 6 | Issue 8 Page 1838
moderate and 54 were possibly related to betahistine.
Detailed post-marketing safety data for betahistine
mesilate is not available in published form. Tolerability
issues that have been investigated are summarized in
Table 2.42,43
Table 2: Safety profiles of betahistine hydrochloride and betahistine mesilate.
Betahistine dihydrochloride
Betahistine mesilate
• From global postmarketing safety data, skin
reactions are the most frequently reported
complaints.40 They are usually self-limiting
maculopapular rash with pruritus or urticaria, and
reversible on drug withdrawal.
• One report of anaphylactoid reaction and one of
Stevens-Johnson syndrome, without fatal outcome.
• Gastrointestinal complaints mostly concern nausea
and vomiting or nonspecific mild abdominal pain.
• Hepatobiliary involvement includes rise in hepatic
enzyme levels, without death or liver failure.
• Nervous system related ADRs are heterogeneous and
do not suggest any specific profile.
• Asthma or bronchospasm has been reported 8 times.
• Four deaths are included in the postmarketing
surveillance data - the causal relationship to
betahistine dihydrochloride in two reports has been
assessed as unrelated, in one as unlikely and in the
other as not assessable.
• Detailed post-marketing safety data for betahistine
mesilate is not available in published form.
• Investigated for drowsiness and impact on the ability
to drive machines. Effect of repeated dosing (72mg
thrice daily) on low speed driving performance tests
was investigated in healthy volunteers - there was no
difference from placebo in any of the tests
performed.42
• Influence on vigilance investigated. Spontaneous
brain electrical activity on the
electroencephalogram, acoustic late evoked
potentials, and reaction time were measured before
and 90 and 180 minutes after drug intake. The drug
(12mg) did not impair capacity.43
• In the study of betahistine mesilate
pharmacokinetics in Chinese men, all 20 subjects
receiving 24mg of the drug completed the evaluation
without significant vital sign changes or other
treatment emergent adverse effects.25
Betahistine is devoid of mutagenic, carcinogenicity and teratogenic potential.
CONCLUSION
Review of the published evidence suggests that
potentially relevant differences exist between the two
available forms of betahistine, the dihydrochloride and
the mesilate. Therefore, it cannot be stated that the two
are readily interchangeable for the treatment of vestibular
dysfunction. Patient convenience and consequent
adherence to treatment is a vital aspect of drug therapy,
particularly in chronic diseases, and this is facilitated by
reduced pill burden. Chemical structure and molecular
weight comparison suggest that for delivery of equivalent
dose, a patient would need to take fewer tablets of
betahistine dihydrochloride than of betahistine mesilate,
taking currently available formulations and maximum
recommended doses into account. Although there are no
reports of clinical toxicity linked to betahistine mesilate,
concerns over the potential long-term DNA damage risk
of contaminated mesilates remain. There is no such
concern with the dihydrochloride salt. There are no
notable short-term safety concerns with either form. The
quantum of published clinical trials is greater for
betahistine dihydrochloride. This could be due to the
wider availability of this salt form. It could also be due to
greater visibility of the concerned manufacturer or greater
support for studies with the dihydrochloride salt. A dose
effect relationship has been clearly documented only for
the dihydrochloride form. However, in the absence of
head-to-head comparisons between the two, it is not
possible to conclude whether there is any difference in
efficacy. Nevertheless, recent trials seem to be have
conducted only with the dihydrochloride salt and
postmarketing surveillance activity is also greater for this
form, suggesting that clinical development of betahistine
dihydrochloride has progressed continuously, unlike that
of the mesilate form. Otorhinolaryngologists and other
physicians seeking to optimize treatment with betahistine
should be aware of these differences.
ACKNOWLEDGEMENTS
Authors would like to thank their colleagues in the
Department of Otorhinolaryngology, IPGME&R,
Kolkata, for helpful suggestions regarding the
manuscript. Abbott India Ltd. deserves our thanks for
responding to our request for supply of summary of
product characteristics literature and for help in retrieving
full texts of some articles.
Funding: No funding sources
Conflict of interest: None declared
Ethical approval: Not required
REFERENCES
1. Strupp M, Brandt T. Peripheral vestibular disorders.
Curr Opin Neurol. 2013;26:81-9.
Hazra A et al. Int J Basic Clin Pharmacol. 2017 Aug;6(8):1833-1840
International Journal of Basic & Clinical Pharmacology | August 2017 | Vol 6 | Issue 8 Page 1839
2. Mira E. Betahistine in the treatment of vertigo.
History and clinical implications of recent
pharmacological researches. Acta Otorhinolaryngol
Ital. 2001;21(3,66):1-7.
3. Popova NF, Chugunova MA, Kunel'skaia NL,
Shagaev AS, Boĭko AN, Gusev EI. Betahistine in the
treatment of vestibular and coordination disturbances
in multiple sclerosis [Article in Russian]. Zh Nevrol
Psikhiatr Im S S Korsakova. 2011;111:77-81.
4. Matsnev EI, Sigaleva EE. Efficacy of histaminergic
drugs in experimental motion sickness. J Vestib Res.
2007;17:313-21.
5. SERC®-16. Summary of Product Characteristics
uploaded to UK electronic Medicines Compendium
(eMC) [Document on the internet]. BGP Products
Limited, UK. 2015 April 14 [cited 2016 May 28].
Available at:
https://www.medicines.org.uk/emc/medicine/2086.
6. MERISLON® Summary of Product Characteristics
[Document on the internet]. Eisai Co., Japan. 2009
[cited 2016 May 28]. Available at:
http://www.eisai.jp/medical/products/di/EPI/MRS_T
_EPI.pdf.
7. Bertlich M, Ihler F, Sharaf K, Weiss BG, Strupp M,
Canis M. Betahistine metabolites,
aminoethylpyridine, and hydroxyethylpyridine
increase cochlear blood flow in guinea pigs in vivo.
Int J Audiol. 2014;53:753-9.
8. Tighilet B, Trottier S, Mourre C, Chotard C, Lacour
M. Betahistine dihydrochloride interaction with the
histaminergic system in the cat: neurochemical and
molecular mechanisms. Eur J Pharmacol.
2002;446:63-73.
9. Tighilet B, Trottier S, Lacour M. Dose- and duration-
dependent effects of betahistine dihydrochloride
treatment on histamine turnover in the cat. Eur J
Pharmacol. 2005;523:54-63.
10. Gbahou F, Davenas E, Morisset S, Arrang JM.
Effects of betahistine at histamine H3 receptors:
mixed inverse agonism/agonism in vitro and partial
inverse agonism in vivo. J Pharmacol Exp Ther.
2010;334:945-54.
11. Desmadryl G, Gaboyard-Niay S, Brugeaud A, Travo
C, Broussy A, Saleur A, et al. Histamine H4 receptor
antagonists as potent modulators of mammalian
vestibular primary neuron excitability. Br J
Pharmacol. 2012;167:905-16.
12. Lacour M. Betahistine treatment in managing vertigo
and improving vestibular compensation: clarification.
J Vestib Res. 2013;23:139-51.
13. Strupp M, Dieterich M, Brandt T. The treatment and
natural course of peripheral and central vertigo.
Dtsch Arztebl Int. 2013;110:505-15.
14. 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;32:387-
99.
15. Strupp M, Hupert D, Frenzel C, Wagner J, Hahn A,
Jahn K, et al. Long-term prophylactic treatment of
attacks of vertigo in Ménière’s disease - comparison
of a high with a low dosage of betahistine in an open
trial. Acta Otolaryngol. 2008;128:520-4.
16. Sokolova L, Hoerr R, Mishchenko T. Treatment of
vertigo: a randomized, double-blind trial comparing
efficacy and safety of Ginkgo biloba extract EGb 761
and betahistine. Int J Otolaryngol. 2014:682439.
17. Redon C, Lopez C, Bernard-Demanze L, Dumitrescu
M, Magnan J, Lacour M, et al. Betahistine treatment
improves the recovery of static symptoms in patients
with unilateral vestibular loss. J Clin Pharmacol.
2011;51:538-48.
18. Barak N. Betahistine: what's new on the agenda?
Expert Opin Investig Drugs. 2008;17:795-804.
19. Ali AH, Yanoff LB, Stern EA, Akomeah A,
Courville A, Kozlosky M, et al. Acute effects of
betahistine hydrochloride on food intake and appetite
in obese women: a randomized, placebo-controlled
trial. Am J Clin Nutr. 2010;92:1290-7.
20. Lian J, Huang XF, Pai N, Deng C. Betahistine
ameliorates olanzapine-induced weight gain through
modulation of histaminergic, NPY and AMPK
pathways. Psychoneuroendocrinology. 2014;48:77-
86.
21. Poyurovsky M, Fuchs C, Pashinian A, Levi A,
Weizman R, Weizman A. Reducing antipsychotic-
induced weight gain in schizophrenia: a double-blind
placebo-controlled study of reboxetine-betahistine
combination. Psychopharmacology (Berl).
2013;226:615-22.
22. Snodin DJ. Residues of genotoxic alkyl mesilates in
mesilate salt drug substances: real or imaginary
problems? Regul Toxicol Pharmacol. 2006;45:79-90.
23. European Medicines Agency Inspections document
EMEA/44714/2008. European Medicines Agency,
London. 2008 January 24 [cited 2012 Jan 20].
Available at:
http://www.ema.europa.eu/Inspections/docs/4471408
en.pdf.
24. Tomar MS, Patni A, Kumar S, Thudi NR, Dubey SK,
Khuroo AH, et al. Pharmacokinetics of 2-pyridyl
acetic acid, a major betahistine metabolite in healthy
Indian volunteers. Der Pharmacia Lettre. 2009;1:52-
9.
25. Chen XY, Zhong DF, Duan JL, Yan BX. LC-MS-MS
analysis of 2-pyridylacetic acid, a major metabolite
of betahistine: application to a pharmacokinetic study
in healthy volunteers. Xenobiotica. 2003;33:1261-71.
26. Della Pepa C, Guidetti G, Eandi M. Betahistine in the
treatment of vertiginous syndromes: a meta-analysis.
Acta Otorhinolaryngol Ital. 2006;26:208-15.
27. Nauta JJ. Meta-analysis of clinical studies with
betahistine in Ménière's disease and vestibular
vertigo. Eur Arch Otorhinolaryngol. 2014;271:887-
97.
28. Cavaliere M, Mottola G, Iemma M. Benign
paroxysmal positional vertigo: a study of two
Hazra A et al. Int J Basic Clin Pharmacol. 2017 Aug;6(8):1833-1840
International Journal of Basic & Clinical Pharmacology | August 2017 | Vol 6 | Issue 8 Page 1840
manoeuvres with and without betahistine. Acta
Otorhinolaryngol Ital. 2005;25:107-12.
29. Kaźmierczak H, Pawlak-Osińska K, Kaźmierczak W.
Betahistine in vertebrobasilar insufficiency. Int
Tinnitus J. 2004;10:191-3.
30. Naguib MB, Madian YT. Betahistine dihydrochloride
with and without early vestibular rehabilitation for
the management of patients with balance disorders
following head trauma: a preliminary randomized
clinical trial. J Chiropr Med. 2014;13:14-20.
31. Mukhopadhyay S, Niyogi M, Ray R, Mukhopadhyay
BS, Dutta M, Mukherjee M. Betahistine as an add-
on: The magic bullet for postoperative nausea,
vomiting and dizziness after middle ear surgery? J
Anaesthesiol Clin Pharmacol. 2013;29:205-10.
32. Albera R, Ciuffolotti R, Di Cicco M, De Benedittis
G, Grazioli I, Melzi G, et al. Double-blind,
randomized, multicenter study comparing the effect
of betahistine and flunarizine on the dizziness
handicap in patients with recurrent vestibular vertigo.
Acta Otolaryngol. 2003;123:588-93.
33. Bodla R, Thota P, Sarabu A, Mohantha GP,
Shanmugam R. Comparison of efficacy and
tolerability of cinnarizine with betahistine in the
treatment of otogenic vertigo. Int J Pharmaceut Res.
2011;3:36-40.
34. Monzani D, Barillari MR, Ciufelli AM, Aggazzotti
CE, Neri V, Presutti L, et al. Effect of a fixed
combination of nimodipine and betahistine versus
betahistine as monotherapy in the long-term
treatment of Ménière's disease: a 10-year experience.
Acta Otorhinolaryngol Ital. 2012;32:393-403.
35. Gananca MM, Caovilla HH, Gananca FF.
Comparable efficacy and tolerability between twice
daily and three times daily betahistine for Ménière's
disease. Acta Oto-Laryngologica. 2009;129:487-92.
36. Pialoux P. Study of a programmed release
preparation of betahistine mesilate in the treatment of
Ménière's disease. Ann Otolaryngol Chir Cervicofac.
1981;98:483-6.
37. Ohsaki K, Ueno M, Zheng HX, Wang QC, Nishizaki
K, Nobuto Y, et al. Evaluation of tinnitus patients by
peroral multi-drug treatment. Auris Nasus Larynx.
1998;25:149-54.
38. Ma FR, Xin Y, Zhao YM, Lü JQ. Efficacy of
Betahistine Mesilate combined with Flunarizine
Hydrochloride for treating tinnitus. Chinese Journal
of Otorhinolaryngology Head and Neck Surgery.
2006 Apr;41(4):269-73.
39. Yi C, Wenping X, Hui X, Xin H, Xiue L, Jun Z, et al.
Efficacy and acceptability of oxcarbazepine vs.
carbamazepine with betahistine mesilate tablets in
treating vestibular paroxysmia: a retrospective
review. Postgrad Med. 2016;128:492-5.
40. Jeck-Thole S, Wagner W. Betahistine: a retrospective
synopsis of safety data. Drug Saf. 2006;29:1049-59.
41. Benecke H, P'rez-Garrigues H, bin Sidek D, Uloziene
I, Sondag E, Theeuwes A. Effects of betahistine on
patient-reported outcomes in routine practice in
patients with vestibular vertigo and appraisal of
tolerability: experience in the OSVaLD study. Int J
Tinnitus. 2010 Jun 1;16(1):14-24.
42. Betts T, Harris D, Gadd E. The effects of two anti-
vertigo drugs (betahistine and prochlorperazine) on
driving skills. Br J Clin Pharmacol. 1991;32:455-8.
43. Schneider D, Kiessling B, Wieczorek M, Bognar-
Steinberg I, Schneider L, Claussen CF. Influence of 3
antivertiginous medications on the vigilance of
healthy volunteers. Int J Clin Pharmacol Ther.
2003;41:171-81.
Cite this article as: Hazra A, Maroo N. Betahistine
dihydrochloride or betahistine mesilate: two sides of
the same coin or two different coins. Int J Basic Clin
Pharmacol 2017;6:1833-40.
