Untitled
Eur opean
Rev iew for
Med ical and
Pharmacol ogical
Sci ences
Pharmacological drugs inducing ototoxicity, G. CIANFRONE1, D. PENTANGELO1, F. CIANFRONE2, F. MAZZEI1,R. TURCHETTA1, M.P. ORLANDO1, G. ALTISSIMI1
1Department of Otolaryngology, Audiology and Phoniatrics, “Umberto I” University Hospital,Sapienza University, Rome (Italy); 2Institute of Otorhinolaryngology, School of Medicine, Catholic University of the Sacred Heart,Rome (Italy)
Abstract. – The present work on drug-in-
Introduction duced ototoxicity, tinnitus and vertigo repre-
The panorama of the pharmacological origin
guide to adverse drug reactions for italian physi-
iatrogenic noxae able to induce either harmful
cians (2005). The panorama of drug-induced
ototoxic effects or just a symptomatology like tin-
such as tinnitus or dizziness and vertigo has en-
nitus or balance disturbances, without any harm-
larged in recent years, thanks to a better knowl-
ful consequence, has widened in the last few
edge and a more specific attention of pharma-
years. The reason for this is the progress of scien-
ceutical firms and drug-control institutions. In
tific knowledge, the increased awareness of the
daily clinical practice, there is a need for the
pharmaceutical companies and of the institutions,
family physician and the ENT specialist or audi-
which supervise pharmaceutical production.
ologist (also in consideration of the possible
Only through continuous updating and experi-
on the possible risk of otological side effects.
ence sharing it’s possible to offer patients the
This would allow a clinical risk-benefit evalua-
certainty of receiving the treatment that is appro-
tion, weighing the possible clinical advantage in
priate, safe and effective and based upon the
their field of competence against possible oto-
most credited clinical studies. This approach is
logical side-effects. The list of active ingredients
definitely challenging but necessary in order to
and drugs is subdivided in categories based on
attain positive effects towards the improvement
fects, that have been signaled by the drug com-
of patient’s conditions and quality of life.
panies and/or ministerial notes. Drugs have also
In every day medical practice physicians, oto-
been subcategorized with regards to the field in
laryngologists and audiologists, need to focus on
which they are applied, the therapeutic indica-
the risks of otologic side effects, also from a le-
tions and the clinical behaviour. They have also
gal point of view. It will then be beneficial to
been organized in alphabetical order, for an easi-
have a wider variety of drugs of the same family
er consultation.
The guide above, even if initially conceived
at hand, therefore, having a wider range of op-
for being used in Italy, also presents a more
tions meeting the main therapeutic line. Physi-
general and international interest, expecially as
cians have to daily balance the drug between ef-
for as the concepts of pharmacology and the
fectiveness and safety; in any case the optimiza-
features of the active ingredients are con-
tion of the pharmacological/therapeutic ratio has
to be strictly related to the compromise between
The guide is, therefore, useful as for as we
are concerned to any physician, regardless of
clinical advantages and undesired side effects.
the country he/she operates in.
Today’s work on ototoxic, tinnitus and vertigo
induced drugs is a revision and an update of what
was previously published in 2005, regarding unde-sired side effects of drugs of the otoaudiologic field,
Pharmacovigilance, Side-effects, Ototoxicity, Tinni-
which has had a positive result and has drawn inter-
est from both general and specialized practitioners1.
Corresponding Author: Giancarlo Cianfrone, MD; e-mail: [email protected]
G. Cianfrone, D. Pentangelo, F. Cianfrone, F. Mazzei, R. Turchetta, M.P. Orlando, G. Altissimi
In the specialised medical practice of otolaryn-
ly. The current, sometimes marginal, knowledge
gology and audiology there is the need to evalu-
of drug behaviours make interactions a delicate
ate the patient from a pharmaceutical point of
view to assess the potential risks of otologic side
The effects of a drug could be affected by the
effects. This will allow the evaluation of clinical
presence of either of another drug or of food gen-
advantages versus otologic adverse events. The
erating an interaction that could be dangerous
aim is to optimise the drug administration sched-
when causing an increase in toxicity or a de-
ule in order to obtain a therapeutic improvement
crease in effectiveness. Food creates rare and less
while sustaining the least number of side effects
important clinical interactions by effecting the
in the otovestibular apparatus. Sometimes symp-
speed and the degree of absorption of a drug.
tomatic or harmful effects do not show up imme-
Fortunately combinations of drugs to be avoided
diately after the first treatment but after a certain
are only a handful and many drugs with interac-
time, varying from subject to subject. This delay
tion issues can be administered simultaneously
could be explained by an increase in the organs
vulnerability and/or a minimal asymptomatic
event after the first treatment and will later be re-
when the effects of a drug are interfered with by
vealed by the next dosage. In other instances side
the presence of another drug on the action site.
effects could be induced by following non-patho-
They arise between drugs which share the same
genic non-iatrogenic noxae (trauma, noise, infec-
or opposite therapeutic effects and that act upon
tions, circulatory, metabolic or endocrynologic
the same physiologic system i.e. sedatives that
affect brain and respiratory functions. On thecontrary, certain drugs could reduce the effective-
ness of others because they compete for the same
Factors affecting the pharmacological action
Pharmaco-kinetic interactions can take place
are: the drug itself (dosage, chemical, physical or
physical/chemical properties), the combinationwith other drugs or substances (interaction and
Absorption: affecting bioavailability of a drug
other types of interference), pharmaceutical
by altering the absorption coefficient or the to-
preparation (which affects the bio-availability of
the active principle) or other factors relating to
Distribution: the circulation of a drug can be in
the patient using the drug and by the space/time
an inactive form, binded to proteins, or in an
context in which the drug is administered.
active form, not binded; administration of
It is well known how the season, the climate,
drugs competing for the same proteic linkage
the altitude, the temperature etc. may interfere
might cause an increase in the “free quota” of
with the pharmacological action determining
sometimes a change from being curative to being
Metabolism: interactions can take place between
toxic. Ultimately the patient is the factor that
drugs metabolized by the same enzymatic sys-
most affects the pharmacological action, it de-
tem, they can act as enzymatic inductors accel-
pends on the general physiological state of the
erating the metabolism of the other drug and
subject, on the pathological conditions involved,
so reducing its effectiveness, or as enzymatic
on his capability to metabolise and so eliminate
inhibitors slowing down the metabolism of the
the drug, on his sensitivity, which could be high
other drug creating accumulation and thus an
(up to the induction of hyper-sensitivity phenom-
increased risk for dosage related side effects;
ena both idiosyncratic or allergic) or low. At last
Elimination of the drug: interactions can cause
factors like gender, age, race, body weight and
an alteration of both active tubular separation
even social condition and psychological profile
and glomerular filtration during renal clear-
are also important in determining or influencing
We can understand that the problem of drug
interactions during co-administration is impor-
An additional consideration has to be given to
tant and delicate. As an example, on “Medicines
pharmaco-dynamic and pharmaco-kinetic ac-
for Children”, the paediatric therapeutic formula-
tions between different drugs used simultaneous-
ry issued by the Royal College of Paediatricians
Pharmacological drugs inducing ototoxicity, vestibular symptoms and tinnitus
and Child Health, which is also included in the
remain in their system for a longer period of time
“Children Drugs User Guide” published by the
creating accumulation. The nervous system be-
Italian Department of Health3, the combination
comes more sensitive with age and many com-
of an aminoglycoside like amikacin with vanco-
mon drugs like opioid analgesics, benzodi-
cymin, ciclosporin, cisplatin, furosemide or am-
azepine, anti-psychotics, Parkinson’s disease
photericin might increase the risk for ototoxicity
drugs have to be used with caution. In a similar
and nephrotoxicity, but even the association of
way other organs could be more reactive to cer-
tain molecules i.e. non-steroidal anti-hyperten-
cephalosporin, according to the source, might in-
sive or anti-inflammatory drugs. The reasons
above are why elderly patients are more sensitive
To this day it is not possible to anticipate the
to side affects and tend to accumulate massive
otologic effects of a single drug, of a combina-
tion of drugs, or of drugs combined with non-ia-
There is also a need to consider other factors
trogenic events such as exposition to noise. It
like self-medication, very common among the el-
looks like predisposition or genetic vulnerability
derly who often use drugs unnecessarily or don’t
might play an important role in such instances.
seek medical advice, either because of lack ofknowledge or just carelessness, and other age-re-
lated factors like loss of memory, eyesight and
Drug accumulation can take place when the
manual dexterity which can all interfere with a
drug is reintroduced too early, that being before
the equivalent quantity of the previous dose hasbeen eliminated causing an increase in plasma
concentration leading to possible toxic phenome-
na due to accumulation. Accumulation is thus in-
Before a new medication is released on the
versely proportional to the percentage of the
market and prescribed to people, it needs to be
dosage eliminated between administrations.
proved safe, active and effective and that the rela-
Drug accumulation can also take place be-
tion between the risk of side effects and thera-
cause of a reduced elimination of the drug (i.e.
peutic benefits is beneficial. The owner of the
patients with a kidney failure condition) or be-
medication, normally the pharmaceutical compa-
cause of a pathologic state which slows down the
ny, is responsible for collecting all of this infor-
hepatic and extra-hepatic metabolic processes.
mation. Developing a new medication normally
Co-administration of drugs can also cause accu-
takes a long period of time, sometimes a few
mulation as mentioned above because of either
years, in pre-clinical laboratory studies on ani-
pharmaco-dynamic or pharmaco-kinetic interfer-
mals and clinical studies on humans.
ences. Finally, we can observe accumulation
Agencies like the Food and Drugs Administra-
when using drugs with a slow elimination rate
tion (FDA) in the USA and the European Medi-
and/or a longer half-life, either because of the
cines Agency (EMEA) in the EU rule pharma-
slowness in reaching equilibrium or in the de-
ceutical research. The Italian Medicines Agency
crease of plasma concentration once the therapy
(AIFA) was recently established in Italy. Studies
on both animals and humans have to be submit-
In our otoaudiologic field we experience this
ted to these agencies in order to obtain approval
problem because of the age group our patients
for market release and for clinical use.
fall into and because of the often chronic audio-
In 1970 the British Committee on the Safety
vestibular conditions we treat. As a matter of fact
of Drugs (today called Committee on Safety of
we often treat older patients suffering from other
Medicines) stated in its annual report4 “it is
conditions and following other pharmacological
well known that a medication that is effective
treatments, especially the ones with chronic
involves a number of risks. Furthermore it is
not certain that all risks can be identified before
Elderly patients must use extreme caution us-
its release to the public, not all trials on ani-
ing drugs because they often have to use a num-
mals and humans will reveal all the possible
ber of different drugs, increasing the risk of inter-
side-effects of a medication. This data will only
actions and adverse reactions. They tend to have
be available after a medication has been admin-
a slower metabolism so food and drugs are elimi-
istered to a large number of patients over a long
nated at a slower rate; consequently drugs tend to
G. Cianfrone, D. Pentangelo, F. Cianfrone, F. Mazzei, R. Turchetta, M.P. Orlando, G. Altissimi
It has recently been determined5 that 51 per-
caused by an excessive pharmacological action
cent of the approved drugs show severe adverse
or by a secondary pharmacological action of the
medication or even by pharmaco-kinetic interfer-
Adverse Drug Reactions (ADRs) can thus be
ences. Even though their incidence and morbidity
identified either before or after the experimental
is high they seldom cause a threat to the patient’s
phases that lead to final market release. Pre-mar-
life. They can normally be detected before mar-
keting clinical trials seldom identify or determine
ket release and can be replicated in the laborato-
the frequency of severe adverse reactions. The
ry. Nevertheless, their identification can be more
information sheet of the medication states the in-
complex under certain conditions like: when only
formation available at the time of approval. The
a minority of the subjects show a reaction, or
result of this process is that once the medication
when there isn’t a direct relation with dosage, or
is released on the market both doctor and patient
when the reaction is common or not important,
are often unaware that they are continuing to test
or when it is difficult to obtain on animals, or
the drug even to a much greater level than the ex-
when they coincide with other causes (e.g.
ADRs of the B type are often of an allergic,
immunologic or idiosyncratic nature and take
place in a minority of patients (less than 1 per
Drug safety monitoring is the process of evalu-
1000) and they are normally unexpected and un-
ating the undesirable side effects potentially re-
predictable. They are generally severe and have
little or no relation to dosage, they don’t repre-
Drug safety monitoring has four main objec-
sent an extension of the pharmacological reaction
and are difficult to identify for a number of rea-sons. They tend to affect certain organs: liver,
• To detect new ADRs as soon as possible.
hematopoietic system and skin. The time frame
• To improve and distribute information regard-
between the medication intake and the appear-
ance of the symptoms and the low retrospective
• To evaluate the advantages of a medication
frequency of the symptoms lead to consider the
versus another or over other types of therapy.
medication responsible for the reaction. Except
• To provide information in order to improve
for conditions of immediate hypersensitivity
(anaphylaxis) these reactions take place normallyafter five days from beginning of the treatment
Most common ADRs are severe and related to
(time in which cells become hyper-sensitive to
the drug) and there is no upper limit even though
The main effects observed8,9 are related to the
most reactions take place within the first twelve
gastro enteric system (31-35%), central nervous
Patients often have predispositions that are not
The most common drugs8,9 causing ADRs are
always evident. Certain reactions have an im-
munological base, others recognise a metabolicgenetic error or an acquired deficiency to a cer-tain enzyme, causing an abnormal metabolic
pathway or an accumulation of toxic metabolites.
Adverse reactions to medication have different
Regarding type C ADRs we need to say that,
forms, are heterogeneous and often unexpected
especially when medication is used over many
years or for the rest of one’s life, they can induce
They can be classified, as per the Inman11 pro-
new medical conditions or change the incidence
posal, in three types A, B and C depending on
of the existing ones. Examples of this risk can be
their characteristics, on the difficulty of identifi-
identified with the possible incidence of breast
cation and on the most effective methods to iden-
cancer or thromboembolic complications in-
duced by birth control pills. These events can be
severe and fairly common and can significantly
ones and are defined by the World Health Organ-
affect public health. The late onset of a disease
isation (WHO) as side effects. They tend to be
makes it difficult to identify it as a pharmaco-re-
fairly common and dosage-related. They can be
Pharmacological drugs inducing ototoxicity, vestibular symptoms and tinnitus
ADRs regarding our field can definitely be at-
try to improve the utilisation of this grading scale
tributed to the first group, type A. They are in
as a main element in the general management of
fact undesired effects, common type, dosage re-
Because of this, the data we now hold will
Specifically, ototoxicity is regarded as an ad-
soon be updated and become more detailed.
verse reaction affecting the inner ear leading toalterations either transitory or permanent of the
auditory or vestibular functions. We believe that
Adverse reactions do not only affect people’s
research over the last decades on the suspected
health but have a great economic impact as well.
drugs action mechanisms still has a long way to
The research on ADR costs has only recently
go. It is then very important to gain a deeper
started, following the Institutions request to re-
knowledge of these action mechanisms in the fu-
ture in order to let the patient benefit from the
Works published in the last years have tried to
most effective means of prevention derived from
quantify costs and research had to be based on
therapy13. Complete or partial loss of the auditory
factors like the increase in incidence on medical
or vestibular functions can have a severe impact
exams, the number of hospitalisations, the num-
on quality of life and socioeconomic status14.
ber of additional therapies needed and the length-ening of hospitalisation periods, etc18,24,27,30,31.
Evaluating the incidence and frequency of
ADRs is not simple because the comparison be-
Let’s now make a few considerations on oto-
tween published studies is not always possible
toxicity without expecting them to be exhaustive
due to the differences in exposition to the specif-
on such a complex and articulated topic that in
ic drug of different populations or the differences
in the ADR detection methods. In fact, some
Ototoxicity is defined by the toxic capacity of
studies only account for adverse reactions while
certain drugs or toxins relative to the inner ear
others also account for overdose or because cer-
structures (particularly to the cochlea and the
tain studies consider only the manifested clinical
vestibular cells) or the acoustic nerve. Ototoxic
conditions and others consider laboratory para-
drugs can act on the cochlea, the vestibular sys-
ADRs are responsible for 3-7% of all hospital-
isation cases. The U.S. prospective studies
like tinnitus, vertigo, hyperacusis and deafness.
showed ADRs in 10-20% of all hospitalisations,
Hearing impairment, tinnitus and vertigo are the
in which 10-20% were severe. The incidence of
most important medical conditions of the inner
death caused by ADRs is unknown, they suggest-
ear due to a drug-induced damage. The onset of
ed rates between 0.5 and 0.9% but they included
these symptoms can be simultaneous or singular,
patients with complex and severe patholo-
they can develop rapidly or gradually and can be
reversible or not. The ototoxic action can lead, in
Incidence and severity of ADRs can be influ-
the most severe cases, to remarkable functional
enced by many factors related to the patient (age,
reductions of the hearing capability or complete
gender, present diseases, genetic factors and geo-
graphic factors) and to the medication (type of
A possible genetic predisposition is assumed
drug, route of administration, therapy duration,
to be facilitating the ototoxic action35-40. There is
dosage and bio-availability). Incidence and
a remarkable difference in ototoxic sensitivity
severity are probably higher in older people. It is
among different animal species. This information
unclear how prescription errors and patients lack
has to be carefully taken into consideration when
translating research from animal models to hu-
Pharmaceutical producers declare the frequen-
mans41. As an example, guinea pigs and humans
cy of side effect occurrences on certain medica-
share the same ototoxic dosage of cisplatin,
tions. Such information is reported through a
while guinea pigs showed much more tolerant to
grading system going from < 0,01% (very rare)
gentamicin than humans41. These drugs can be
dangerous for both the auditory and the vestibu-
Nowadays, drug safety surveillance institu-
lar parts and to a greater extent to the organ of
tions tend to persuade the pharmaceutical indus-
G. Cianfrone, D. Pentangelo, F. Cianfrone, F. Mazzei, R. Turchetta, M.P. Orlando, G. Altissimi
Because almost every ototoxic drug is elimi-
tion of levels of ototoxicity from the beginning of
nated through the kidneys the reaching of levels
the treatment, sometimes even before any audio-
of toxicity is facilitated by renal failure. Whenev-
er the renal function is altered ototoxic drug
The simultaneous exposition to noise is a
dosages, eliminated through the kidneys, have to
worsening factor due to the increased release of
be corrected so that hematic levels remain within
therapeutic limits. Serum levels of the drug (high
Cochlear dysfunction can span from a light
or minimal) should be checked in order to get the
increase of the hearing threshold, only de-
correct therapeutical levels. As a matter of fact
tectable through audiometry, to complete deaf-
even with subjective changes of sensitivity to the
ness. Hearing loss can take place along with ei-
drug, hearing is usually preserved if hematic lev-
ther temporary or permanent tinnitus. Clinical-
ly co c hlea r dama ge app ear s s oon er than
Ototoxic drugs shouldn’t be prescribed for
vestibular damage that could even be severe be-
topical medications in the event of an eardrum
fore the onset of vertigo. The actual extent of
perforation since the inner ear fluids, through the
vestibular damage is hard to assess, vestibular
secondary eardrum of the oval window, could ab-
damages can go undetected especially if the
sorb the drug. This practice is quite debated but it
damage development is slow and progressive
is fairly common to find a clinical usage of
eardrops containing antibiotics or other ototoxic
Early detection of toxicity enables the adjust-
drugs in chronic otitis even in the presence of a
ment of dosage, the suspension of therapy and
the change of medication. In many instances
Ototoxic antibiotics should not be used on
damage evolves over time: in a group of paedi-
pregnant women. Hearing impaired and elderly
atric patients, damage of 11% at the beginning of
people should not be given ototoxic medica-
treatment increased to 44% two years later49.
tions if a non-toxic alternative is available. An
Ototoxicity is considered a pharmacological
evaluation of a pre-existing condition of hear-
adverse reaction affecting the inner ear, charac-
ing impairment should be done before prescrib-
terized by cochlear or vestibular dysfunction.
ing ototoxic antibiotics. Hearing ability has to
The Council for International Organisations of
Medical Sciences (CMIOS), in order to standard-
throughout the therapy. According to the Amer-
ise the terminology regarding medication safety,
has produced a list of definitions of ADRs and
(ASHA) a tonal audiometric exam should be
the relative proper procedures. The developments
carried out 24 hours after the beginning of the
of deafness, tinnitus or vertigo associated with
therapy and every two or three days for the rest
pharmacological treatment are minimum require-
While an ototoxic damage can be determined
even more precise and reliable results44-47.
by a routine anamnesis, ototoxic loss of hearing
The reason for this monitoring is to obtain a
can only be determined by comparison of audio-
physio-pathological description of the ototoxic
grams from before and after the treatment. To di-
agents derived damages, outlining the clinical as-
agnose a pharmacologically caused deafness it is
pects of the damages to the cochlea and to the
necessary to verify through audiometry an in-
vestibular receptors, keeping track of the changes
crease of the equal loudness contour by 15dB
over time48. High frequencies are generally more
over one or more frequencies. In any case it is
sensitive to the treatment and high-pitched tinni-
hard to mention pharmacological etiology with-
tus or vertigo can take place, but they are not al-
out having audiograms from before and after the
Transient evoked otoacoustic emission (TEOAE)
Legal debates over iatrogenic damage due to
and distortion product otoacoustic emission
ototoxicity are very rare and only attaining se-
(DPOAE) tests are today considered gold-standard
vere cases that led to communication disorders
exams in ototoxicity control, allowing assessment
(severe hearing loss over many frequencies)48.
of cochlea function at high frequencies in just a
Drugs ototoxicity is a very delicate issue be-
few minutes. Clinical studies confirm the strict re-
cause many pathologies are treated through the
lationship between otoemission and ototoxicity.
use of drugs that are potentially harmful to the
Otoemissions as a matter of fact allow the detec-
Pharmacological drugs inducing ototoxicity, vestibular symptoms and tinnitus
There is evidence about inner ear tissues be-
Bacteric ribosomal RNA is the amino-glyco-
ing immunologically, biochemically and func-
sides target and the mutated human form A1555G
tionally related to kidney tissues. It seems that
is very similar to the bacteric one, it binds abnor-
medications affecting sodium and potassium
mally to the amino-glycoside explaining the rea-
transport alter ionic homeostasis of the inner ear
son for deafness even at low dosages of the drug.
causing functional problems like hearing loss,
Some authors report that 17% of the subjects in-
tinnitus and vertigo44. Renal pharmacological
terested by amino-glycoside ototoxic effects have
adverse reactions have been studied in the effort
of finding predictive signs of possible ADRs re-
A recent study on the frequency of mitochondric
lated to the inner ear or to the labyrinth and
mutation over a selected Japanese population
about medication class’s influence upon ionic
specifically selected because had experienced post-
transportation. Resulting data showed that renal
streptomycin tinnitus has shown the possibility that
ADRs couldn’t be considered markers of phar-
a new and rare mutation, C1556T, could appear
macologically induced disturbances to the inner
along with the A1555G as a hearing loss risk factor,
ear or labyrinth. Nevertheless, the ability of
specifically as a tinnitus-generating factor. It must
these drugs to influence the ion transport system
be noted that according to the available literature
and the ion channels and so influencing the ear
the A1555G mutation doesn’t create any vulnera-
and kidney ionic homeostasis could be a pre-
bility of the vestibular apparatus even though the
dicting factor for a possible pharmaceutical re-
chromosomal mutation is present in all mitochon-
dria of every tissue. The C1494T is another 12S ri-
No dosage appears to be safe in amino-glyco-
bosomal RNA mutation that can cause even if to a
side therapies no matter what the administration
lesser degree amino-glycoside susceptibility59.
route is (parenteral, intratympanic, per os, in-
We have seen that the way cisplatin causes
trathecal). Certain studies show how a daily sin-
ototoxicity varies significantly from subject to
gle administration of amino-glycosides is as ef-
subject and that it is partially related to the genet-
fective as a set of daily injections, thus a smaller
quantity of the medication leads to the same re-
Identifying genetic variations and so predict-
ing the severity of ototoxic effects would be an
In any case monitoring the cochleo-vestibular
important step towards a better-addressed use of
function is always very important. Genetic pre-
disposition has been suspected for severe deaf-ness onsets just after a few amino-glycoside in-jections. As far as medication interactions are
Guide Presentation
concerned, specifically between amino-glyco-sides and other drugs, the issue has been covered
This work on ototoxic, tinnitus and vertigo-
in the preceding paragraph (see page 602, Inter-
generating medications is, an update and a revi-
sion of the previous guide published in 2005, re-
Individual susceptibility and organ vulnerabili-
garding collateral and undesired effects of med-
ty are debated issues because of their relevance
ications in the oto-audiologic field1. We have ad-
and criticality and often related to genetic char-
justed the Italian pharmacological context, re-
acteristics. Several studies today reveal how cer-
garding active principles, to the international An-
tain mitochondrial chromosome mutations can
glo-Saxon one, intentionally omitting in this re-
represent one of the genetic factors for hypersen-
view commercial products as they pertain to indi-
sitivity, vulnerability and predisposition towards
This guide should be a practical, comprehen-
A hereditary non-syndromic familiar form as-
sive list of drugs (actually of the active principles
sociated with the A1555G mutation (substitution
of the drugs) used in this country and yet known
of a guanine with an adenine) located on the mi-
and used abroad, which can induce otologic and
tochondrial RNA12S has been discovered51. The
A1555G mutation is very common in Spain,reaching 25%45. Due to the high incidence in this
1. Ototoxicity, as a neurosensorial hearing dam-
country, detection of the genetic mutation is car-
age also including the possible associated
ried out systematically in order to avoid amino-
labirintine vertigo symptomatology and/or the
G. Cianfrone, D. Pentangelo, F. Cianfrone, F. Mazzei, R. Turchetta, M.P. Orlando, G. Altissimi
2. The onset of tinnitus only, with no docu-
More specifically these are the various types
3. The vertigo generating action only, without
any evident toxic action on the hearing appara-
1. Drugs with the explicit indication, by the phar-
maceutical company and/or the Health Depart-ment, of “potentially otologically harmful”,
These side effects have a different weight from
generally indicated as ototoxicity (ototoxic
a practical point of view. In fact, while adverse re-
drugs); ototoxicity is meant as a neurosensori-
actions related to ototoxicity can justify higher
al hearing damage (going from light hearing
levels of alert based on the ADR scale according
impairment to deafness) and may include both
to Hartwig et al60, side effect-generating tinnitus
the possible associated symptomatology of
and vertigo hold a certainly lower level of gravity.
labyrinthical alteration vertigo and the possi-
Data contained in publication is a complex
elaboration of the information found on the
2. Drugs with the explicit indication, by the phar-
“Guida all’uso dei Farmaci” (2008), based on the
maceutical company and/or the Health Depart-
British National Formulary (BNF), by the Italian
ment, as potentially tinnitus-generating, gener-
Department of Health and by the Italian Medi-
ally called tinnitus, hissing ear, or acouphene
(drugs openly declared as tinnitus generating);
The Guide mentioned is a translation and an
a potential tinnitus risk is reported for these
adaptation to the Italian context of the British
drugs and there is no mention of ototoxicity;
National Formulary, a prestigious publication
3. Drugs with the explicit indication, by the phar-
created in Great Britain many years ago and
maceutical company and/or the Health Depart-
made possible thanks to a scientific collaboration
ment, as potentially vertigo-generating drugs,
agreement between AIFA, the British Medical
generally called vertigo or dizziness (drugs open-
Association and the Royal Pharmaceutical Soci-
ly declared as vertigo generating). Information of
potential vertigo associated with the drug is re-
The Drugs User’s Guide is an easy to access
ported while there is no mention of ototoxicity;
manual, where the most relevant information re-
4. Drugs with possible audiologic effects, indi-
garding the active principals of the drugs on our
cated as “hearing disturbances” (drugs with
market are gathered. It gives reference to the
aspecific otologic side effects), it is advisable
conditions for which they are suggested and
to have a conservative approach to these drugs
valuable indications for prescriptions to cate-
and to evaluate in each case the possible inten-
gories of patients particularly subject to the risk
of undesired reactions like elderly people, chil-dren and subjects with severe chronic conditions
Certain drugs can clearly be found in more
who require co-administration of more drugs.
than one sub-category as they can lead to differ-
For this reason we believe it to be a useful
contribution to professionals in this field.
In order to provide an easier and better refer-
ence, active principles in this book have been
In this work the list of the pharmacological ac-
Index A : general index, where we find the active
tive principles is divided into sub-categories based
principles sorted mainly in reference to the ap-
on the type of audiologic and otoneurologic side
paratus they act upon, to the generic indications
effects (hearing losses and disturbances, tinnitus,
and to the pharmaco-clinical action and with a
balance disorders and vertigo) reported by the
reference to the relevant side effect, using the
pharmaceutical companies and/or by the Health
grading scale 1 to 4 mentioned above. We liter-
Department directives (the type of side effect is in-
ally reproduced the “Guida all’uso dei Farmaci”
dicated in our lists with a number from 1 to 4).
(2008) layout to facilitate consultation.
Whenever possible we kept in consideration
Sub-indexes A1-A2-A3-A4: the pharmacological
the classification of drugs based on the apparatus
active principles have been divided into four
they attain to, the therapeutic indications and the
side affect categories while maintaining the
pharmaco-clinical actions and we made alphabet-
same order of index A, by apparatuses, clinical
indications and pharmaco-clinical actions.
Pharmacological drugs inducing ototoxicity, vestibular symptoms and tinnitus
Index B: in this index the active principles are
predisposition to auditory pathologies or the co-
listed in alphabetical order, each with a numer-
existence of non-iatrogenic neuro-sensorial audi-
ical reference to the relevant type of side ef-
ologic pathologies are all elements which could
fect. Whenever possible according to data
interfere with iatrogenic factors increasing the
available to us, believing it to be very useful,
we indicated the side effect frequency for each
drug using a grading scale from
a to
e goingfrom “very common” to “very rare”.
1. During anamnesis the pharmaco-therapeutic
profile of the patient accurately mark, previ-
ous, current and scheduled intakes of drugs
side effect frequency are normally expressed as
with potential risk of ADR, making note of the
molecule, the commercial name, the posology,length of treatment and type of ADR and other
a Very common (≥ 10%)
possible additional and collateral factors of
b Common (≥ 1% e < 10%)
c Uncommon (≥ 0,1% e <1%)
2. When dealing with a life-saving treatment or a
d Rare ( ≥ 0,01% e < 0,1%)
treatment that cannot be stopped and/or is a re-
e Very rare (< 0,01%)
sult of a long series of therapeutic trials, it is
f Unknown, because available data is insuffi-
improper to operate or to advise the patient’s
doctor for any changes of the therapeutic pro-file, generating unnecessary fears in the pa-
It must be said that this grading is sometimes
tient. This is valid if we face an ototoxic drug
not published or known by the manufacturers so
treatment or, even more, if we deal only with
we haven’t assigned a grading letter to drugs
tinnitus and/or vertigo inducing drugs.
We have to be reassuring with the patient andwarn him (in line with the current prescrip-tions of the law and with the professional ad-
Final Considerations and
vises on using proper care about the patient’s
Behavioural Strategies for
consent, when the treatment involves the use
Practitioners
of ototoxic drugs) that possible disturbancescould be a normal consequence of the impor-
Based upon what was said so far, the suggest-
tant treatment the patient is undergoing. The
ed behaviour for General Practitioners or for
patient must also be informed that the distur-
bances will be strictly monitored and that will
should encounter problems connected to poten-
be softened by cell protecting treatments
tially risky pharmacological treatments, cannot
be as univocal, peremptory and directional.
This soft, minimizing yet directional approach
As we mentioned in the foreword, the practi-
could reveal very useful with patients showing
tioner must always have the objective of finding
tinnitus as a central symptom, whose psycho-
the right balance between effectiveness and safe-
logical involvement is well known to be fre-
ty keeping in mind that pharmacological pro-
gramming optimisation also means obtaining a
3. The doctor’s behaviour towards patients whose
reasonable compromise between clinical advan-
pathologies are less severe and where medica-
tages and risks related to adverse or undesired
tion can be modified on both posology and
type, is definitely different. In such cases, if
For this reason it is impossible to generalise
using ototoxic drugs, it is possible to act be-
the strategies a practitioner has to follow. Instead
fore irreversible alterations take place, by talk-
every patient needs to be studied transversally
ing to the patient’s doctor and trying to co-
and observed longitudinally in an absolutely
manage the case by small therapeutic adjust-
ments or more radical changes of the pharma-
In each case the coexistence of additional risk
cological profile. When dealing with non oto-
factors like old age, kidney conditions, dysmeta-
toxic tinnitus and or vertigo inducing drugs
bolic conditions, environmentally-related condi-
and in presence of a symptomatology, and the
tions of exposition to noise, genetic or familiar
relationship the drug intake and the sympto-
G. Cianfrone, D. Pentangelo, F. Cianfrone, F. Mazzei, R. Turchetta, M.P. Orlando, G. Altissimi
matology being unclear, it is possible with a
ed, identifying subjects with risk of genetic pre-
dechallenge/rechallenge strategy either partial
disposition and reducing self-medication in-
stances along with a proper policy on the pa-
Since harmful consequences for the auditory
tient’s drug use education will certainly help
system cannot be predictable when using non-
narrowing the number of ototoxicity cases.
ototoxic drugs, there is wider flexibility re-
The Specialist is ultimately responsible for di-
garding the medical and legal information to
agnosis, medical care, giving advise, preven-
tion and rehabilitation when dealing with the
4. While managing different strategies it is advis-
effects of medications on the inner ear.
able to keep in consideration the concept offrequency (very common-very rare) of side ef-fects, at least for those drugs for which data isavailable; such element, which we classified
Conclusions
with the “a, b, c, d, e” codes, might reveal use-ful and sometimes determinant when choosing
This work represents the update and the revi-
the strategic behaviour to be adopted by the
sion of the previous guide on the unwanted side
effects in the oto-audiological field. We believe it
5. With the current knowledge to this date, it is
has a larger international value and is to be con-
impossible to advise the patient’s doctor and
sidered useful to any physician regardless of the
the specialist on behavioural strategies when
dealing with drugs of category 4 (“hearing dis-
The risk of drug side-effects has become a
turbances”) because the data available is very
burning issue, therefore, in daily clinical practice,
limited on frequency and none on the specific
doctors need to focus in that direction also in
consideration of the possible medical-legal impli-
In such instances, especially with drugs with
ADR’s rated “common” or “very common”,
It will be useful and necessary to periodically
the only advise that could be given is to be
update the data of the guide on the basis of the
new acquisitions about drugs. Obviously, in the
We can finally say that a reasonable use of the
pharmacological scene of each country, there
drug, including the early identification of the
might be some drugs which are not included in
minimum effective dose, is certainly the best
the above mentioned list or, on the contrary,
way to reduce ototoxicity incidence.
some of the drugs listed here might not be in-
A better diffusion of the monitoring techniques
would be useful even though they are still quite
The general interest of this document survives,
unknown today and rarely requested. Although
as it may provide a pratical and useful guide for
ototoxic phenomena incidence is underestimat-
physicians in their daily professional activity.
Index A
General index, where we find the active principles
4. Drugs with possible audiologic effects, indicated as
sorted mainly in reference to the apparatus they act
“hearing disturbances” (drugs with aspecific otologic
upon, to the generic indications and to the pharmaco-
clinical action and with a reference to the relevant sideeffect, using the grading scale 1 to 4 mentioned above:
Gastrointestinal System Antispasmotic and other drugs used for intestinal
1. Ototoxic drugs (ototoxicity may include both the
possible associated symptomatology of labyrinthi-
cal alteration vertigo and the possible generation of
– Butylscopolamine bromide . . . . . . . . . . . . . . . . 3
– Propantheline bromide . . . . . . . . . . . . . . . . . . . 3
2. Drugs tinnitus-generating (there is no mention of
– Sulphate atropine . . . . . . . . . . . . . . . . . . . . . . . 3
Antisecretory and protective drugs on gastric mucosa
3. Drugs vertigo-generating (there is no mention of
– Cimetidine . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Pharmacological drugs inducing ototoxicity, vestibular symptoms and tinnitus
– Famotidine . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Nadolol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Nizatidine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Nebivolol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Ranitidine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Oxprenolol + diuretics . . . . . . . . . . . . . . . . . . . 3
– Pindolol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Sucralfate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Propranolol hydrochloride . . . . . . . . . . . . . . . . 3
– Sotalol hydrochloride . . . . . . . . . . . . . . . . . . . . 3
– Misoprostol . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Timolol maleate . . . . . . . . . . . . . . . . . . . . . . . 2,3
– Esomeprazole . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Lansoprazole . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Sildenafil . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Omeprazole . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Sodium nitroprusside (related with rapid . . . . . 3
– Pantoprazole . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Rabeprazole sodium . . . . . . . . . . . . . . . . . . . . . 3
• Centrally-acting anti-hypertensive drugs
– Clonidine hydrochloride . . . . . . . . . . . . . . . . . . 3
– Methyl dopa . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Loperamide hydrochloride . . . . . . . . . . . . . . . . 3
– Moxonidina . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Doxazosin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Sulfasalazine . . . . . . . . . . . . . . . . . . . . . . . . . 2,3
– Terazosin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
• Drugs used for regulate renin-angiotensin system
– Infliximab . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Captopril . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3Captopril + diuretics . . . . . . . . . . . . . . . . . . . . 3
Cardiovascular System
Cilazapril . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Cilazapril + diuretics . . . . . . . . . . . . . . . . . . . .3
Enalapril maleate . . . . . . . . . . . . . . . . . . . . . 2,3
– Digitoxin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Enalapril + diuretics . . . . . . . . . . . . . . . . . . . 2,3
– Digoxin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Fosinopril . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Fosinopril + diuretics . . . . . . . . . . . . . . . . . . . 3
Lisinopril . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Chlorthalidone . . . . . . . . . . . . . . . . . . . . . . . . . 3
Lisinopril + diuretics . . . . . . . . . . . . . . . . . . . 3
– Hydrochlorotiazide . . . . . . . . . . . . . . . . . . . . . . 3
Moexipril hydrochloride . . . . . . . . . . . . . . . 2,3
– Indapamide . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Moexipril + diuretics . . . . . . . . . . . . . . . . . . 2,3
Perindopril . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Furosemide . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Perindopril + diuretics . . . . . . . . . . . . . . . . . . 3
– Torsemide (usually in high and rapid . . . . . . . . 1
Quinapril . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Quinapril+diuretics . . . . . . . . . . . . . . . . . . . . . 3
Ramipril . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
• Potassium-sparing and other diuretics
Ramipril+diuretics . . . . . . . . . . . . . . . . . . . . . 3
– Amiloride and hydrochlorothiazide . . . . . . . . 2,3
Trandolapril . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Trandolapril + calcium channel blockers . . . . 3
• Supraventricular and ventricular arrhythmias
– Angiotensin II receptor blockers
– Amiodarone hydrochloride . . . . . . . . . . . . . . . 3
Candesartan cilexetil . . . . . . . . . . . . . . . . . . . . 3
– Flecainide acetate . . . . . . . . . . . . . . . . . . . . . . 2,3
Candesartan + diuretics . . . . . . . . . . . . . . . . . 3
– Propafenone hydrochloride . . . . . . . . . . . . . . . . 3
Eprosartan . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Irbesartan . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
– Mexiletine hydrochloride . . . . . . . . . . . . . . . . . 3
Irbesartan+diuretics . . . . . . . . . . . . . . . . . . . 2,3
Losartan potassium . . . . . . . . . . . . . . . . . . . . . 3
– Acebutolol . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Losartan potassium+diuretic . . . . . . . . . . . . . . 3
– Atenolol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Olmesartan medoxomil . . . . . . . . . . . . . . . . . . 3
– Atenolol + diuretics . . . . . . . . . . . . . . . . . . . . . 3
Olmesartan medoxomil+diuretics . . . . . . . . . . 3
– Atenolol + calcium channel blockers . . . . . . . . 3
Telmisartan . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Bisoprolol fumarate . . . . . . . . . . . . . . . . . . . . . 3
Telmisartan + diuretics . . . . . . . . . . . . . . . . . . 3
– Bisoprolol fumarate + diuretics . . . . . . . . . . . 3
Valsartan + diuretics . . . . . . . . . . . . . . . . . . 2,3
– Carvedilol . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
• Nitrates, calcium channel blockers and
– Celiprolol hydrochloride . . . . . . . . . . . . . . . . . 3
– Esmolol hydrochloride . . . . . . . . . . . . . . . . . . . 3
– Metoprolol tartrate . . . . . . . . . . . . . . . . . . . . . . 3
Nitroglycerin . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Metoprolol + diuretics . . . . . . . . . . . . . . . . . . . 3
Isosorbide dinitrate . . . . . . . . . . . . . . . . . . . . . 3
G. Cianfrone, D. Pentangelo, F. Cianfrone, F. Mazzei, R. Turchetta, M.P. Orlando, G. Altissimi
Isosorbide mononitrate . . . . . . . . . . . . . . . . . . 3
– Omalizumab . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Amlodipine . . . . . . . . . . . . . . . . . . . . . . . . . 2,3Diltiazem hydrochloride . . . . . . . . . . . . . . . . . 3Felodipine . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Central Nervous System
Isradipine . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3Lacidipine . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Lercanidipine hydrochloride . . . . . . . . . . . . . . 3
Nicardipine hydrochloride . . . . . . . . . . . . . . 2,3
Nifedipine . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Diazepam . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Nifedipine + atenolol . . . . . . . . . . . . . . . . . . . 3
Flurazepam . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Nisoldipine . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Lormetazepam . . . . . . . . . . . . . . . . . . . . . . . . 3
Verapamil hydrochloride . . . . . . . . . . . . . . . . 3
Nitrazepam . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
• Peripheral vasodilators and related drugs
Temazepam . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Pentoxifylline . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Zaleplon . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3,4
Zolpidem tartrate . . . . . . . . . . . . . . . . . . . . . 3,4
– Adrenaline . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Zopiclone . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Fondaparinux . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Sodium oxybate . . . . . . . . . . . . . . . . . . . . . . . 3
– Clopidogrel bisulfate . . . . . . . . . . . . . . . . . . . . 3
– Benzodiazepines . . . . . . . . . . . . . . . . . . . . . . . . .
– Dipyridamole . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Alprazolam . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Anti-fibrinolytic and hemostatic drugs
Chlordiazepoxide . . . . . . . . . . . . . . . . . . . . . . 3
– Tranexamic acid (in rapid intravenous . . . . . . . 3
Diazepam . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Lorazepam . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Oxazepam . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Human coagulation factor VIII . . . . . . . . . . . . . 3
– Human coagulation factor IX . . . . . . . . . . . . . . 3
Buspirone hydrochloride . . . . . . . . . . . . . . . . 3
Meprobamate . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Bezafibrate . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Fenofibrate . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
• Phenobarbital . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Gemfibrozil . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Drugs used for psychosis and related disorders
– Atorvastatin . . . . . . . . . . . . . . . . . . . . . . . . . . 2,3
– Amisulpride . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Pravastatin sodium . . . . . . . . . . . . . . . . . . . . . . 3
– Aripiprazole . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Rosuvastatin . . . . . . . . . . . . . . . . . . . . . . . . . . . .3
– Clorazepate dipotassium . . . . . . . . . . . . . . . . . . 3
– Simvastatin . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Olanzapine . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Simvastatin + ezetimibe . . . . . . . . . . . . . . . . . . 3
– Quetiapine . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Risperidone . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Omega-3 acid ethyl esters . . . . . . . . . . . . . . . . . 3
Antidepressants • Tricyclic antidepressants and related drugs
Respiratory System
Amitriptyline hydrochloride . . . . . . . . . . . . 2,3
Drugs used in asthma and chronic obstructive
Amitriptyline hydrochloride + perphenazine . . 2,3
Clomipramine hydrochloride . . . . . . . . . . . . 2,3
• Adrenergic receptor agonists (sympathomimetics)
Dosulepin hydrochloride . . . . . . . . . . . . . . . 2,3
Imipramine hydrochloride . . . . . . . . . . . . . . 2,3
Salmeterol . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Nortriptyline . . . . . . . . . . . . . . . . . . . . . . . . 2,3
Fluphenazine/nortriptyline . . . . . . . . . . . . . . 2,3
– Tiotropium . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Trimipramine . . . . . . . . . . . . . . . . . . . . . . . 2,3
Cromoglycate, related therapies and anti-leukotrienes
Mianserin hydrochloride . . . . . . . . . . . . . . . 2,3
• Montelukast . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Trazodone hydrochloride . . . . . . . . . . . . . . 2,3
Antihistamines and drugs used for alleric reactions
• Selective serotonin reuptake inhibitors
– Citalopram . . . . . . . . . . . . . . . . . . . . . . . . . . 2,3
– Chlorpheniramine maleate . . . . . . . . . . . . . . . . 2
– Escitalopram . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Ketotifen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Fluoxetine . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Pharmacological drugs inducing ototoxicity, vestibular symptoms and tinnitus
– Fluvoxamine maleate . . . . . . . . . . . . . . . . . . . . 3
– Ethosuximide . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Paroxetine . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Phenytoin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Sertraline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Gabapentin . . . . . . . . . . . . . . . . . . . . . . . . . . . 2,3
– Lamotrigine . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Duloxetine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Levetiracetam . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Mirtazapine . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Oxcarbazepine . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Reboxetine . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Primidone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Venlafaxine . . . . . . . . . . . . . . . . . . . . . . . . . . 2,3
– Pregabalin . . . . . . . . . . . . . . . . . . . . . . . . . . . 3,4
Central nervous system stimulants and drugs used for
– Tiagabine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
attention deficit disorders and hyperactivity
– Topiramate . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
• Atomoxetine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Vigabatrin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
• Metilphenidate hydrochloride . . . . . . . . . . . . . . . 3
– Zonisamide . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
• Modafinil . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Clonazepam . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
• Serotonin antagonists (5-ht3 receptor antagonists)
– Diazepam . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Dolasetron mesylate . . . . . . . . . . . . . . . . . . . . . 3
– Phenytoin sodium . . . . . . . . . . . . . . . . . . . . . 3
– Ondansetron . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Lorazepam . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Palonosetron . . . . . . . . . . . . . . . . . . . . . . . . . 2,3
Parkinsonism and related disorders drugs
– Tropisetron . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
• Dopaminergic drugs used for parkinsonism
– Aprepitant . . . . . . . . . . . . . . . . . . . . . . . . . . . 2,3
Cabergoline . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Levodopa + benserazide . . . . . . . . . . . . . . . . . 3
– Scopolamine hydrobromide . . . . . . . . . . . . . . . 3
Levodopa + carbidopa . . . . . . . . . . . . . . . . . . 3
Levodopa + carbidopa + entacapone . . . . . . . 3
Lisuride maleate . . . . . . . . . . . . . . . . . . . . . . . 3
– Acetylsalicylic acid . . . . . . . . . . . . . . . . . . . . . . 1
Pergolide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Paracetamol + codeine phosphate . . . . . . . . . . . 3
Pramipexole . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Ropinirole . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Buprenorphine . . . . . . . . . . . . . . . . . . . . . . . . 2,3
– Fentanyl . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Resagiline . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Methadone hydrochloride . . . . . . . . . . . . . . . . . 3
Selegiline hydrochloride . . . . . . . . . . . . . . . . . 3
– Morphine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Catechol o methyltransferase inhibitors
– Oxycodone hydrochloride . . . . . . . . . . . . . . . . 3
Amantadine hydrochloride . . . . . . . . . . . . . . 3
– Pentazocine . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Entacapone . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Pethidine hydrochloride . . . . . . . . . . . . . . . . . . 3
– Antimuscarinic drugs used for parkinsonism
– Tramadol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Orphenadrine hydrochloride . . . . . . . . . . . . . . 3
• Neuropathic pain (trigeminal neuralgia)
Trihexyphenidyl hydrochloride . . . . . . . . . . . 3
– Carbamazepine . . . . . . . . . . . . . . . . . . . . . . . . 3
• Drugs used for essential tremor, corea, tic and
– Oxcarbazepine . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Riluzole . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
• Torsional dystonia and other involuntary
– Acetylsalicylic acid . . . . . . . . . . . . . . . . . . . . . . 1
– NSAIDs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2,3
– Botulinum toxin a . . . . . . . . . . . . . . . . . . . . . . . 3
– Almotriptan . . . . . . . . . . . . . . . . . . . . . . . . . . 2,3
– Eletriptan . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2,3
– Benzodiazepines . . . . . . . . . . . . . . . . . . . . . . . . 3
– Frovatriptan . . . . . . . . . . . . . . . . . . . . . . . . . . 2,3
– Rizatriptan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Bupropion . . . . . . . . . . . . . . . . . . . . . . . . . . . 2,3
– Sumatriptan . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Nicotine drug facts . . . . . . . . . . . . . . . . . . . . . 2,3
– Zolmitriptan . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Varenicicline . . . . . . . . . . . . . . . . . . . . . . . . . 2,3
– Ergotamine tartrate . . . . . . . . . . . . . . . . . . . . . . 3
– Buprenorphine . . . . . . . . . . . . . . . . . . . . . . . 2,3
– Methadone hydrochloride . . . . . . . . . . . . . . . . . 3
– Pizotifen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Naltrexone hydrochloride . . . . . . . . . . . . . . . . . 3
– Donepezil hydrochloride . . . . . . . . . . . . . . . . . 3
– Carbamazepine . . . . . . . . . . . . . . . . . . . . . . . . 3
– Galantamine . . . . . . . . . . . . . . . . . . . . . . . . . 2,3
– Clobazam . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Memantine hydrochloride . . . . . . . . . . . . . . . . 3
– Clonazepam . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Rivastigmine . . . . . . . . . . . . . . . . . . . . . . . . . . 3
G. Cianfrone, D. Pentangelo, F. Cianfrone, F. Mazzei, R. Turchetta, M.P. Orlando, G. Altissimi
Infectious Diseases
– Levofloxacin . . . . . . . . . . . . . . . . . . . . . . . . . 3,4– Moxifloxacin . . . . . . . . . . . . . . . . . . . . . . . . . 3,4
– Norfloxacin . . . . . . . . . . . . . . . . . . . . . . . . . 2,3,4
– Ofloxacin . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3,4
Amoxycillin + clavulanate . . . . . . . . . . . . . . . 3
– Amphotericin b . . . . . . . . . . . . . . . . . . . . . . . . . 1
• Cephalosporins and other beta lactamase
– Fluconazole . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Flucytosine . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Cefaclor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Griseofulvin . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Cefadroxil . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Itraconazole . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Cephalexin . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Posaconazole . . . . . . . . . . . . . . . . . . . . . . . . . 3,4
Cefazolin sodium . . . . . . . . . . . . . . . . . . . . . . 3
– Terbinafinae . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Cefixime . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Voriconazole . . . . . . . . . . . . . . . . . . . . . . . . 2,3,4
Cefotaxime . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Cefpodoxime . . . . . . . . . . . . . . . . . . . . . . . . . 3
Cefprozil . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Nucleoside analog reverse transcriptase inhibitors
Cefradine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Abacavir . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Ceftazidime . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Abacavir+lamivudine . . . . . . . . . . . . . . . . . . . 3
Ceftriaxone . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Abacavir+lamivudina+zidovudine . . . . . . . . . 3
Cefuroxime . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Didanosine . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Emtricitabine . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Aztreonam . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Emtricitabine+tenofovir . . . . . . . . . . . . . . . . . 3
– Ertapenem . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Lamivudinae . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Imipenem + cilastatin . . . . . . . . . . . . . . . . . . . . 1
Stavudine . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Tenofovir disoproxil . . . . . . . . . . . . . . . . . . . . 3
– Doxycycline . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
Zidovudine . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Minocycline . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Zidovudine + lamivudine . . . . . . . . . . . . . . . . 3
– Tigecycline . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Atazanavir . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Amikacin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Fosamprenavir . . . . . . . . . . . . . . . . . . . . . . . . 3
– Gentamycin . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Indinavir . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Netilmycin . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Lopinavir+ritonavir . . . . . . . . . . . . . . . . . . . . . 3
– Tobramycin . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Ritonavir . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Saquinavir . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Azithromycin . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Tipranavir . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Clarithromycin . . . . . . . . . . . . . . . . . . . . . . . . . 1
– Non-nucleoside reverse transcriptase inhibitors
– Erythromycin . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Efavirenz . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Telithromycin . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Enfuvirtide . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Daptomycin . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Linezolid . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2,3
– Quinupristin + dalfopristin . . . . . . . . . . . . . . . . 3
Acyclovir . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Teicoplanin . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Famcyclovir . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Vancomycin . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Inosine pranobex . . . . . . . . . . . . . . . . . . . . . . . 3
Valacyclovir . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Colistin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Foscarnet sodium . . . . . . . . . . . . . . . . . . . . . . 3
– Sulfadiazine . . . . . . . . . . . . . . . . . . . . . . . . . . 2,3
Gancyclovir . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
– Sulfamethoxazole + trimethoprim . . . . . . . . . 2,3
Valgancyclovir . . . . . . . . . . . . . . . . . . . . . . . . 3
– Isoniazid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Entecavir . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Rifampicin . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Rifampicin+isoniazid . . . . . . . . . . . . . . . . . . . . 3
– Amantadine hydrochloride . . . . . . . . . . . . . . . . 3
– Streptomycin . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
– Oseltamivir . . . . . . . . . . . . . . . . . . . . . . . . . . 3,4
• Metronidazole and tinidazole . . . . . . . . . . . . . . . . .
– Metronidazole . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Ribavirin . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2,3
– Tinidazole . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Ciprofloxacin . . . . . . . . . . . . . . . . . . . . . . . 2,3,4
– Quinine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2,4
Pharmacological drugs inducing ototoxicity, vestibular symptoms and tinnitus
– Chloroquine . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
– Terlipressin . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Doxycycline . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
– Mefloquine . . . . . . . . . . . . . . . . . . . . . . . . . . . 2,3
– Proguanil hydrochloride + atovaquone . . . . . . . 3
– Salmon calcitonin . . . . . . . . . . . . . . . . . . . . . . . 3
• Anti-parasitic drugs against amoeba and trichomonas
– Parathyroid hormone . . . . . . . . . . . . . . . . . . . . 3
– Metronidazole . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Teriparatide . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Tinidazole . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
• Bisphosphonates and other bone metabolism
– Sodium stibogluconate . . . . . . . . . . . . . . . . . . . 3
Pamidronate . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Proguanil hydrochloride + atovaquone . . . . . . . 3
Risedronate . . . . . . . . . . . . . . . . . . . . . . . . . 2,3
– Pentamidine isethionate . . . . . . . . . . . . . . . . . . 3
Zoledronate . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Niclosamide . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Danazol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3Ganirelix . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Endocrine System
Buserelin . . . . . . . . . . . . . . . . . . . . . . . . . . . 3,4
Goserelin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Leuprorelin acetate . . . . . . . . . . . . . . . . . . . . . 3
Triptorelin . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Glipizide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Other oral blood-glucose-lowering drugs
Obstetric, Gynecology and Urology
Pioglitazone . . . . . . . . . . . . . . . . . . . . . . . . . . 3Pioglitazone + metformin . . . . . . . . . . . . . . . . 3
– Dinoprostone . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Betamethasone . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Ergometrine maleate . . . . . . . . . . . . . . . . . . . 2,3
– Deflazacort . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Gemeprost . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Dexamethasone . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Hydrocortisone . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Atosiban . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Methylprednisolone . . . . . . . . . . . . . . . . . . . . . 3
– Triamcinolone . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Topical estrogens . . . . . . . . . . . . . . . . . . . . . . . 3
• Estrogens and hormone replacement therapy
– Estradiol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Estradiol + progestin . . . . . . . . . . . . . . . . . . . . . 3
– Etonogestrel + ethinylestradiol . . . . . . . . . . . . 3
– Estriol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Emergency contraception (post-coital)
– Estrogens conjugated + progestin . . . . . . . . . . . 3
– Ethinylestradiol . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Levonorgestrel . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Tibolone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
• Progestin contraceptives (oral route) . . . . . . . . . . 3
– Dydrogesterone . . . . . . . . . . . . . . . . . . . . . . . . 3
Drugs used for genito-urinary disorders
– Medroxyprogesterone acetate . . . . . . . . . . . . . . 3
– Norethisterone . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Norethisterone + estradiol . . . . . . . . . . . . . . . . 3
Alfuzosin hydrochloride . . . . . . . . . . . . . . . . . 3
– Progesterone . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Doxazosin . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Tamsulosin hydrochloride . . . . . . . . . . . . . . . . 3
• Hypothalamic, adenohypophyseal hormones
Terazosin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Drugs used for urinary disorders and incontinence
Clomiphene citrate . . . . . . . . . . . . . . . . . . . . . 3
– Duloxetine . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Flavoxate hydrochloride . . . . . . . . . . . . . . . . . . 3
– Oxibutynin hydrochloride . . . . . . . . . . . . . . . . 3
– Pegvisomant . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Drugs used in erectile dysfunction
– Thyrotropin alfa . . . . . . . . . . . . . . . . . . . . . . . . 3
• Alprostadil . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
• Neurohypophyseal hormones and antagonists
Phosphodiesterase type 5 inhibitors
• Sildenafil . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
G. Cianfrone, D. Pentangelo, F. Cianfrone, F. Mazzei, R. Turchetta, M.P. Orlando, G. Altissimi
• Tadalafil . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Iron sucrose injection . . . . . . . . . . . . . . . . . . . 3
• Vardenafil . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Hydroxocobalamin . . . . . . . . . . . . . . . . . . . . . . 3
Tumors and Immunosuppresssion
• Drugs used in hypoplastic and hemolytic
Deferoxamine mesylate . . . . . . . . . . . . . . . . 3,4
– Etoposide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
• Drugs used for treatment of essential
– Vinblastine solphate . . . . . . . . . . . . . . . . . . . . . 1
– Vincristine solphate . . . . . . . . . . . . . . . . . . . . . 1
– Anagrelide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Vindesine solphate . . . . . . . . . . . . . . . . . . . . . . 1
– Vinorelbine . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
– Cinacalcet . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
• Cetuximab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Carboplatin . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
– Alfacalcidol . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Cisplatin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
– Calcitriol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Oxaliplatin . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
– Cholecalciferol . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Dihydrotachysterol . . . . . . . . . . . . . . . . . . . . . . 3
– Dasatinib . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2,3
– Ergocalciferol . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Imatinib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2,3
– Paricalcitol . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Sorafenib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
– Sunitinib . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Trastuzumab . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Agalsidase alfa - beta . . . . . . . . . . . . . . . . . . 2,3
– Tretinoin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3,4
Imiglucerase . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Drugs altering immune system response
Miglustat . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Mefenamic acid . . . . . . . . . . . . . . . . . . . . . . . . 3
Muscle Skeletal System
– Azathioprine . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
• Corticosteroids and other immunosuppressors
Drugs used in rheumatological diseases and gout
– Tacrolimus . . . . . . . . . . . . . . . . . . . . . . . . . . . 3,4
• Non steroidal anti inflammatory drugs
– Aceclofenac . . . . . . . . . . . . . . . . . . . . . . . . . . 2,3
– Mefenamic acid . . . . . . . . . . . . . . . . . . . . . . . 2,3
– Natalizumab . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Tiaprofenic acid . . . . . . . . . . . . . . . . . . . . . . . 2,3
Sex hormones and hormone antagonists in tumors
– Acetylsalicilic acid . . . . . . . . . . . . . . . . . . . . . . 1
– Celecoxib . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2,3
– Medroxyprogesterone acetate . . . . . . . . . . . . . . 3
– Dexibuprofene . . . . . . . . . . . . . . . . . . . . . . . 2,3
– Megestrol acetate . . . . . . . . . . . . . . . . . . . . . . . 3
– Dexketoprofene . . . . . . . . . . . . . . . . . . . . . . . 2,3
– Norethisterone . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Diclofenac potassium . . . . . . . . . . . . . . . . . . . 2,3
– Diclofenac sodium . . . . . . . . . . . . . . . . . . . . . 2,3
– Diclofenac + misoprostol . . . . . . . . . . . . . . . . 2,3
Exemestane . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Etoricoxib . . . . . . . . . . . . . . . . . . . . . . . . . . . 2,3
Letrozole . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Flurbiprofen . . . . . . . . . . . . . . . . . . . . . . . . . 2,3
Toremifene . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Ibuprofen . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2,3
• Prostate cancer and gonadotropin releasing
– Indomethacin . . . . . . . . . . . . . . . . . . . . . . . . 2,3
– Ketoprofen . . . . . . . . . . . . . . . . . . . . . . . . . . 2,3
– Buserelin . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3,4
– Meloxicam . . . . . . . . . . . . . . . . . . . . . . . . . . . 2,3
– Flutamide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Nabumetone . . . . . . . . . . . . . . . . . . . . . . . . . 2,3
– Goserelin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Naproxen . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2,3
– Leuprorelin acetate . . . . . . . . . . . . . . . . . . . . . . 3
– Piroxicam . . . . . . . . . . . . . . . . . . . . . . . . . . . 2,3
– Triptorelin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Sulindac . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2,3– Tenoxicam . . . . . . . . . . . . . . . . . . . . . . . . . . . 2,3
Blood and Nutrition
• Drugs modifying the rheumatic diseases course
Anemia and other hematic disorders
Chloroquine . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Hydroxichloroquine sulphate . . . . . . . . . . . . 1
Pharmacological drugs inducing ototoxicity, vestibular symptoms and tinnitus
Azathioprine . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Diagnostic and perioperative preparations,
Leflunomide . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Metotrexate . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Aproclonidin . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Adalimumab . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Diclofenac sodium . . . . . . . . . . . . . . . . . . . . . 2,3
Infliximab . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Flurbiprofen sodium . . . . . . . . . . . . . . . . . . . 2,3
Sulfasalazine . . . . . . . . . . . . . . . . . . . . . . . . 2,3
• Retrofoveal choroid neovascularization
• Gout and hyperuricemia cytotoxic drugs induced
– Pegaptanib sodium . . . . . . . . . . . . . . . . . . . . . . 1
Allopurinol . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Ear, Nose and Oropharynx Drugs used in neuromuscolar diseases • Skeletal muscle relaxants
Anti-inflammatory steroids and associated antimicrobial
– Baclofen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
• Ciprofloxacin + hydrocortisone . . . . . . . . . . . 2,3,4
– Dantrolene sodium . . . . . . . . . . . . . . . . . . . . . . 3
• Neomycin + fluocinolone acetonide . . . . . . . . . . . 1
– Diazepam . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
• Polymyxin b sulphate + neomycin sulphate +
– Tizanidine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
• Lidocaine hydrochloride . . . . . . . . . . . . . . . . . . . . 1
• Polimyxyn b sulphate + neomycin sulphate +
Quinine . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2,4
• Lidocaine hydrochloride + hydrocortisone . . . . . . 1• Tobramycin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Eye Medicaments
• Tobramycin + dexamethasone . . . . . . . . . . . . . . . 1
Drugs used for oropharynx
• Drugs used for oral ulceration and inflammation
– Flurbiprofen . . . . . . . . . . . . . . . . . . . . . . . . . . 2,3
– Ciprofloxacin . . . . . . . . . . . . . . . . . . . . . . . 2,3,4
– Gentamycin . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
– Levofloxacin . . . . . . . . . . . . . . . . . . . . . . . . . 3,4
Pilocarpine hydrochloride . . . . . . . . . . . . . . . . 3
– Neomycin + antibiotics . . . . . . . . . . . . . . . . . . . 1– Neomycin + corticosteroid . . . . . . . . . . . . . . . . 1
Skin
– Ofloxacin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3– Tobramycin . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Corticosteroids and other anti inflammatory preparations
• Corticosteroids and associated antibacterials
– Azathioprine . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Dexamethasone + neomycin . . . . . . . . . . . . . . . 1
– Infliximab . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Dexamethasone + netilmycin . . . . . . . . . . . . . . 1
– Metotrexate . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Dexamethasone + tobramycin . . . . . . . . . . . . . 1
– Fluocinolone acetonide + neomycin . . . . . . . . . 1
– Fluorometholone + gentamycin . . . . . . . . . . . . 1
– Topical retinoids and anti acne preparations
– Hydrocortisone + neomycin + cloramfenicol . . 1
Tretinoin . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3,4
– Prednisolone + neomycin . . . . . . . . . . . . . . . . 1
– Lodoxamide . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Doxycycline . . . . . . . . . . . . . . . . . . . . . . . . . . 2
– Olopatadine . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
high dosages) . . . . . . . . . . . . . . . . . . . . . . . . . 4
Minocycline . . . . . . . . . . . . . . . . . . . . . . . . . . 1
– Atropine solphate . . . . . . . . . . . . . . . . . . . . . . . 3
– Cyclopentolate hydrochloride . . . . . . . . . . . . . . 3
Isotretinoin . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
– Homatropine bromhydrate . . . . . . . . . . . . . . . . 3
Protective substances against uv radiations
– Tropicamide . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Diclofenac sodium . . . . . . . . . . . . . . . . . . . . . 2,3
– Timolol maleate . . . . . . . . . . . . . . . . . . . . . . . 2,3
– Topical anti bacterial preparations (if
– Brimonidine tartrate . . . . . . . . . . . . . . . . . . . . . 3
– Brimonidine tartrate + timolol . . . . . . . . . . . . . 3
ototoxicity may be a risk associated with
• Carbonic anhydrase inhibitors and systemic drugs
– Acetazolamide . . . . . . . . . . . . . . . . . . . . . . . . 3,4
Neomycin sulphate . . . . . . . . . . . . . . . . . . . . . 1
– Brinzolamide . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Polymyxin . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
– Dorzolamide . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Dorzolamide + timolol . . . . . . . . . . . . . . . . . . . 3
– Ketoconazole . . . . . . . . . . . . . . . . . . . . . . . . . . 3
G. Cianfrone, D. Pentangelo, F. Cianfrone, F. Mazzei, R. Turchetta, M.P. Orlando, G. Altissimi
Immunological Medicines and Vaccines Infectious Diseases Cholera vaccine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Meningococcal group c polysaccharide
• Conjugate vaccine . . . . . . . . . . . . . . . . . . . . . . . . . 3
• Meningococcal acwy vaccine . . . . . . . . . . . . . . . . 3
Anesthesia
– Propofol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Atropine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Scopolamine hydrobromide . . . . . . . . . . . . . . . 3
• Perioperative analgesic and sedative drugs
Diazepam . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Lorazepam . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Midazolam . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Temazepam . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Alfentanil . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Fentanyl . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Remifentanil . . . . . . . . . . . . . . . . . . . . . . . . . . 3
– Dantrolene sodium . . . . . . . . . . . . . . . . . . . . . . 3
– Lidocaine hydrochloride . . . . . . . . . . . . . . . . . . 3
Tumors and Immunosuppresssion Cytotoxic drugs • Vinca alkaloid and etoposide
Sub-index A1 Ototoxic Drugs
– Vincristine solphate – Vindesine solphate
(Ototoxicity may include both the possible associ-
ated symptomatology of labyrinthical alteration verti-
go and the possible generation of tinnitus).
Cardiovascular System Muscle Skeletal System
– Furosemide– Torsemide (usually in high and rapid parenteral
Drugs used for rheumatological diseases and gout
• Non steroidal anti inflammatory drugs
• Drugs that modify the rheumatic diseases course
Central Nervous System Eye Medicaments Pharmacological drugs inducing ototoxicity, vestibular symptoms and tinnitus
Cardiovascular System
• Potassium-sparing and other diuretics
Corticosteroids and other anti inflammatory preparations
• Supraventricular and ventricular arrhythmias
• Corticosteroids and associated antibacterials
• Drugs used for regulate renin-angiotensin system
– Hydrocortisone + neomycin + cloramfenicol
Diagnostic and perioperative preparations,
• Retrofoveal choroid neovascularization
Ear, Nose and Oropharynx
• Nitrates, calcium channel blockers and other drugs
Anti-inflammatory steroids and associated antimicrobial
• Polymyxin b sulphate + neomycin sulphate +
• Polimyxyn b sulphate + neomycin sulphate +
Respiratory System Skin Antihistamines and drugs used for alleric reactions
Central Nervous System Anti infective skin preparations • Anti bacterial preparations
– Topical anti bacterial preparations (if you have to
• Tricyclic antidepressants and related drugs
treat a large area of skin ototoxicity may be a risk
associated with aminoglycosides and polymyxin use)
Amitriptyline hydrochloride + perphenazine
Clomipramine hydrochloride Dosulepin hydrochlorideFluphenazine/ nortriptylineImipramine hydrochlorideNortriptyline
Sub-index A2 Drugs Tinnitus-Generating
Mianserin hydrochloride Trazodone hydrochloride
(There is no mention of ototoxicity).
• Selective serotonin reuptake inhibitors
Gastrointestinal System
• Serotonin antagonists (5-ht3 receptor antagonists)
G. Cianfrone, D. Pentangelo, F. Cianfrone, F. Mazzei, R. Turchetta, M.P. Orlando, G. Altissimi
Obstetric, Gynecology and Urology Tumors and Immunosuppresssion Antiepileptic drugs • Epilepsy control
Blood and Nutrition
– Nicotine drug facts – Varenicicline
Muscle Skeletal System Drugs used in rheumatological diseases and gout
• Non steroidal anti inflammatory drugs
– Aceclofenac – Celecoxib– Dexibuprofene
Infectious Diseases
– Dexketoprofene – Diclofenac potassium
• Drugs modifying the rheumatic diseases course
Drugs used in neuromuscolar diseases
Endocrine System Eye Medicaments
• Bisphosphonates and other bone metabolism regu-
Pharmacological drugs inducing ototoxicity, vestibular symptoms and tinnitus
Diagnostic and perioperative preparations,
Ear, Nose and Oropharynx Cardiovascular System Anti-inflammatory steroids and associated antimicrobial • Ciprofloxacin + hydrocortisone
• Drugs used for oral ulceration and inflammation
Diuretics • Thiazide and related diuretics
Skin
• Potassium-sparing and other diuretics
Protective substances against uv radiations
• Supraventricular and ventricular arrhythmias
– Amiodarone hydrochloride – Flecainide acetate– Propafenone hydrochloride
Sub-index A3 Drugs vertigo-generating
(There is no mention of ototoxicity).
• Atenolol + calcium channel blockers• Atenolol + diuretics
Gastrointestinal System
• Bisoprolol fumarate • Bisoprolol fumarate + diuretics
Antispasmotic and other drugs used for
Antisecretory and protective drugs on
– Sodium nitroprusside (related with rapid
• Centrally-acting anti-hypertensive drugs
• Drugs used for regulate renin-angiotensin system
G. Cianfrone, D. Pentangelo, F. Cianfrone, F. Mazzei, R. Turchetta, M.P. Orlando, G. Altissimi
Anti-fibrinolytic and hemostatic drugs
• Tranexamic acid (in rapid intravenous injection)
Candesartan cilexetil Candesartan + diuretics
Respiratory System Drugs used in asthma and chronic obstructive
• Adrenergic receptor agonists (sympathomimetics)
Cromoglycate, related therapies and anti-leukotrienes
• Nitrates, calcium channel blockers and
Antihistamines and drugs used for alleric reactions
Central Nervous System
• Peripheral vasodilators and related drugs
Pharmacological drugs inducing ototoxicity, vestibular symptoms and tinnitus
Drugs used for psychosis and related disorders
Neuropathic pain (trigeminal neuralgia)
• Tricyclic antidepressants and related drugs
Amitriptyline hydrochloride + perphenazine
• Selective serotonin reuptake inhibitors
Central nervous system stimulants and drugs used for
attention deficit disorders and hyperactivity
• Serotonin antagonists (5-ht3 receptor
Parkinsonism and related disorders drugs
• Dopaminergic drugs used for parkinsonism
G. Cianfrone, D. Pentangelo, F. Cianfrone, F. Mazzei, R. Turchetta, M.P. Orlando, G. Altissimi
– Catechol o methyltransferase inhibitors
– Antimuscarinic drugs used for parkinsonism
– Drugs used for essential tremor, corea, tic and
– Torsional dystonia and other involuntary
Antiviral drugs • Human immunodeficiency virus
Infectious Diseases
– Nucleoside analog reverse transcriptase inhibitors
• Cephalosporins and other beta lactamase
Pharmacological drugs inducing ototoxicity, vestibular symptoms and tinnitus
– Non-nucleoside reverse transcriptase inhibitors
• Hypothalamic, adenohypophyseal hormones
• Neurohypophyseal hormones and antagonists
• Anti-parasitic drugs against amoeba and
• Bisphosphonates and other bone metabolism regulators
– Proguanil hydrochloride + atovaquone
Obstetric, Gynecology and Urology
– Other oral blood-glucose-lowering drugs
• Estrogens and hormone replacement therapy
G. Cianfrone, D. Pentangelo, F. Cianfrone, F. Mazzei, R. Turchetta, M.P. Orlando, G. Altissimi
Emergency contraception (post-coital)
Progestin contraceptives • Progestin contraceptives (oral route)
Blood and Nutrition Drugs used for genito-urinary disorders • Drugs used for urinary retention
Anemia and other hematic disorders
Drugs used for urinary disorders and incontinence
• Drugs used in hypoplastic and hemolytic anemias
• Drugs used for treatment of essential thrombocytosis
Drugs used in erectile dysfunction
Phosphodiesterase type 5 inhibitors
Tumors and Immunosuppresssion Drugs altering immune system response • Drugs suppressing the immune system
Muscle Skeletal System Drugs used in rheumatological diseases and gout
• Corticosteroids and other immunosuppressors
• Non steroidal anti inflammatory drugs
Sex hormones and hormone antagonists in tumors
• Prostate cancer and gonadotropin releasing
Pharmacological drugs inducing ototoxicity, vestibular symptoms and tinnitus
• Drugs used for oral ulceration and inflammation
• Gout and hyperuricemia cytotoxic drugs induced
Drugs used in neuromuscolar diseases
– Topical retinoids and anti acne preparations
Protective substances against uv radiations
Eye Medicaments Corticosteroids and other anti inflammatory preparation s
• Meningococcal group c polysaccharide conjugate
– Cyclopentolate hydrochloride– Homatropine bromhydrate– Tropicamide
Glaucoma treatment • Beta blockers
• Carbonic anhydrase inhibitors and systemic drugs
• Perioperative analgesic and sedative drugs
Diagnostic and perioperative preparations,
Anti-inflammatory steroids and associated antimicrobial
G. Cianfrone, D. Pentangelo, F. Cianfrone, F. Mazzei, R. Turchetta, M.P. Orlando, G. Altissimi
Sub-Index A4 Drugs altering immune system response • Corticosteroids and other immunosuppressors
Drugs with possible audiologic effects, indicated as
“hearing disturbances” (drugs with aspecific otologic
Sex hormones and hormone antagonists in tumors
side effects), it is advisable to have a conservative ap-
proach to these drugs and to evaluate in each case the
– Prostate cancer and gonadotropin releasing
possible intensity and type of adverse reaction.
Central Nervous System Blood and Nutrition Anemia and other hematic disorders
• Drugs used in hypoplastic and hemolytic anemias
Muscle Skeletal System Drugs used in neuromuscolar diseases
Infectious Diseases
– Ciprofloxacin– Levofloxacin– Moxifloxacin
Eye Medicaments
• Carbonic anhydrase inhibitors and systemic drugs
Antiprotozoal agents • Antimalarial
Ear, Nose and Oropharynx Anti-inflammatory steroids and associated antimicrobial
Endocrine System Other endocrine drugs • Gonadotropins regulators
Skin Acne and rosacea • Topical anti acne preparations
– Topical retinoids and anti acne preparations
Tumors and Immunosuppresssion Anti acne preparations (oral route)
Pharmacological drugs inducing ototoxicity, vestibular symptoms and tinnitus
Index B
In this index the active principles are listed in al-
very useful, we indicated the side effect frequency
phabetical order, each with a numerical reference to
for each drug using a grading scale from a to e go-
the relevant type of side effect. Whenever possible
ing from “very common” to “very rare” (see page
according to data available to us, believing it to be
Reference Reference numbers Drugs classes ADR numbers Drugs classes ADR G. Cianfrone, D. Pentangelo, F. Cianfrone, F. Mazzei, R. Turchetta, M.P. Orlando, G. Altissimi
Pharmacological drugs inducing ototoxicity, vestibular symptoms and tinnitus
G. Cianfrone, D. Pentangelo, F. Cianfrone, F. Mazzei, R. Turchetta, M.P. Orlando, G. Altissimi
Pharmacological drugs inducing ototoxicity, vestibular symptoms and tinnitus
G. Cianfrone, D. Pentangelo, F. Cianfrone, F. Mazzei, R. Turchetta, M.P. Orlando, G. Altissimi
––––––––––––––––––
Acknowledgements
5)
MOORE, TJ, PSATY BM, FURBERG, CD . Time to act on
drug safety. JAMA 1998; 279: 1571-1573.
This work has been supported by A.I.R.S. Onlus, the
6)
BEGAUD B, CHASLERIE A, HARAMBURU F . Organiza-
Italian Association for Research on Deafness. We wish
tion et rèsultat de la pharmacovigilance en
to thank the Italian Medicines Agency (AIFA) for their
France. Rev Epidèmiol Santè Publique 1994;
collaboration and bibliography support.
7)
EDWARDS IR . Who cares about pharmacovigilance?
Eur J Clin Pharmacol 1997; 53: 83-88.
8)
LUMLEY CE, WALKER SR, HALL GC, SRAUNTON N. GROB
PR . The under-reporting of adverse reactions
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