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European Review for Medical and Pharmacological Sciences 2011; 15: 601-636 Pharmacological inducing ototoxicity, vestibular symptoms and : a reasoned and updated guide

G. CIANFRONE1, D. PENTANGELO1, F. CIANFRONE2, F. MAZZEI1, R. TURCHETTA1, M.P. ORLANDO1, G. ALTISSIMI1

1Department of Otolaryngology, Audiology and Phoniatrics, “Umberto I” University , Sapienza University, Rome (); 2Institute of , School of , Catholic University of the Sacred , Rome (Italy)

Abstract. – The present work on -in- Introduction duced ototoxicity, tinnitus and repre- sents the update and revision of a previous 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 side effects causing ototoxicity or symptoms ototoxic effects or just a symptomatology like tin- such as tinnitus or 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- ologist (also in consideration of the possible which supervise pharmaceutical production. medico-legal implications) to focus the attention 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 their audiological and otoneurological side-ef- 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- er consultation. have a wider variety of drugs of the same family 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 and the fectiveness and safety; in any case the optimiza- features of the active ingredients are con- tion of the pharmacological/therapeutic ratio has cerned. 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 Key Words: was previously published in 2005, regarding unde- sired side effects of drugs of the otoaudiologic field, , Side-effects, Ototoxicity, Tinni- which has had a positive result and has drawn inter- tus, Vertigo. est from both general and specialized practitioners1.

Corresponding Author: Giancarlo Cianfrone, MD; e-mail: [email protected] 601 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 issue. 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 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 by taking proper precautions. vulnerability and/or a minimal asymptomatic Pharmaco-dynamic interactions take place 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. that disorders) or iatrogenic (oto-surgery). affect brain and respiratory functions. On the contrary, certain drugs could reduce the effective- Pharmacological Action ness of others because they compete for the same Influencing Factors receptors. Factors affecting the pharmacological action Pharmaco-kinetic interactions can take place are: the drug itself (dosage, chemical, physical or at the following levels: physical/chemical properties), the combination with other drugs or substances (interaction and Absorption: affecting of a drug other types of interference), pharmaceutical by altering the absorption coefficient or the to- preparation (which affects the bio-availability of tal quantity of the drug absorbed; 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 , 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 the drug and consequently its activity; sometimes a change from being curative to being : 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 ance of certain drugs. the pharmacological action2. We can understand that the problem of drug Interactions interactions during co-administration is impor- An additional consideration has to be given to tant and delicate. As an example, on “ 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

602 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 be- Italian Department of Health3, the combination comes more sensitive with age and many com- of an like with vanco- mon drugs like , benzodi- cymin, , , or am- azepine, anti-psychotics, Parkinson’s photericin might increase the risk for ototoxicity drugs have to be used with caution. In a similar and , but even the association of way other organs could be more reactive to cer- amikacin with non-ototoxic drugs like tain molecules i.e. non-steroidal anti-hyperten- , according to the source, might in- sive or anti-inflammatory drugs. The reasons crease the risk for ototoxicity. 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- amounts of drugs in their system. 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-, 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 of knowledge or just carelessness, and other age-re- Drug Accumulation 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 proper drug administration schedule. the equivalent quantity of the previous dose has been eliminated causing an increase in plasma Pharmaceutical Drugs: concentration leading to possible toxic phenome- Pre-marketing Studies 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 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 (AIFA) was recently established in Italy. Studies is suspended2. 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 pathologies. 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 period of time”.

603 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 reactions undetected before approval. 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 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. periments previously done. cephalalgia). The mechanism is unclear. ADRs of the B type are often of an allergic, immunologic or idiosyncratic nature and take Drug Safety Monitoring 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 lated to the pharmacologic treatment6. little or no relation to dosage, they don’t repre- Drug safety monitoring has four main objec- sent an extension of the pharmacological reaction tives7: and are difficult to identify for a number of rea- sons. They tend to affect certain organs: , • To detect new ADRs as soon as possible. hematopoietic system and . The time frame • To improve and distribute information regard- between the medication intake and the appear- ing known or suspected ADRs. 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 medical practices. () these reactions take place normally after five days from beginning of the treatment Most common ADRs are severe and related to (time in which cells become hyper-sensitive to new drugs released on the market8. 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 weeks. system (15-20%), and skin (10-11%). Patients often have predispositions that are not The most common drugs8,9 causing ADRs are always evident. Certain reactions have an im- the cardiovascular ones. munological base, others recognise a metabolic genetic error or an acquired deficiency to a cer- tain , causing an abnormal metabolic ADR Classification and Definition pathway or an accumulation of toxic . 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 and unpredicted10. 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 cation and on the most effective methods to iden- or thromboembolic complications in- tify them12. duced by pills. These events can be ADRs of the A type are the most common 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 lated pathology.

604 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- the pharmacological therapy. lated and non-life threatening. 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 leading to alterations either transitory or permanent of the ADR Costs 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- duce public health costs. 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 needed and the length- ening of hospitalisation periods, etc18,24,27,30,31. Incidence and Frequency of ADRs Evaluating the incidence and frequency of Ototoxicity 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 many ways is still unknown. 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 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- meter alterations as well15-29. tem or both32-34. ADRs are responsible for 3-7% of all hospital- Toxic damage is often shown by symptoms 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 gies20,21,23-29. 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 , genetic factors and geo- deafness32-33-34. graphic factors) and to the medication (type of A possible genetic predisposition is assumed drug, , 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 of compliance affect ADR incidence. translating research from animal models to hu- Pharmaceutical producers declare the frequen- mans41. As an example, guinea pigs and humans cy of 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 to >=10% (very common). 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- Corti (cochleotoxic).

605 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- metric deficit is detected. 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 free radicals. 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 , to complete deaf- even with subjective changes of sensitivity to the ness. can take place along with ei- drug, hearing is usually preserved if hematic lev- ther temporary or permanent tinnitus. Clinical- els remain within the suggested limits. ly cochlear damage appears sooner than Ototoxic drugs shouldn’t be prescribed for vestibular damage that could even be severe be- topical 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 (in most cases bilateral)47. eardrops containing or other ototoxic Early detection of toxicity enables the adjust- drugs in chronic otitis even in the presence of a ment of dosage, the of therapy and perforated eardrum42,43. 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 be monitored through audiometric exams Medical Sciences (CMIOS), in order to standard- throughout the therapy. According to the Amer- ise the terminology regarding medication safety, ican Speech-Language-Hearing Association 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- of the therapy. ments to refer to ADRs. The high frequency analysis would supply 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 ways reliable signs to pre-alert. therapy. Transient evoked (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- inner ear.

606 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 and mally to the amino- explaining the rea- transport alter ionic 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 such mutation51-53,58. 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 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 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- lated ototoxicity44. 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- is as ef- subject and that it is partially related to the genet- fective as a set of daily injections, thus a smaller ic differences of the subjects39. quantity of the medication to the same re- Identifying genetic variations and so predict- sults50. 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- cisplatin39. 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- actions). 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 vidual country contexts. amino-glycosides51-53. 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 ) located on the mi- and used abroad, which can induce otologic and tochondrial RNA12S has been discovered51. The otoneurologic side effects, such as: A1555G mutation is very common in , 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 glycoside ototoxicity51,54-57. possible onset of tinnitus;

607 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 mentable hearing damage; of side effects listed and numbered: 3. The vertigo generating action only, without any evident toxic action on the hearing appara- 1. Drugs with the explicit indication, by the phar- tus. 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 ble generation of tinnitus; 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 cines Agency (AIFA). (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 ety of Great Britain. 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 sity and type of adverse reaction. 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 ent ENT interests. contribution to professionals in this field. In order to provide an easier and better refer- ence, active principles in this book have been Work Plan and Hints for grouped and listed in different ways: Directory Consultation 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 ical lists for easy reference. indications and pharmaco-clinical actions.

608 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, risk for ADRs. we indicated the side effect frequency for each The following suggestions may be given: drug using a grading scale from a to e going from “very common” to “very rare”. 1. During anamnesis the pharmaco-therapeutic profile of the patient accurately mark, previ- Pharmaceutical company indications about ous, current and scheduled intakes of drugs side effect frequency are normally expressed as with potential risk of ADR, making note of the follows: 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%) risk. 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 cient 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. with missing data. We have to be reassuring with the patient and warn 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 disturbances could 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- ENT/Audiology specialists, whenever they bances will be strictly monitored and that will should encounter problems connected to poten- be softened by protecting treatments tially risky pharmacological treatments, cannot and/or small dosage adjustments. 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- quent and penetrating. 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 side effects. 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- elastic and individualistic way. 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 , 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-

609 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- or total depending on the case. 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- be given to the patient. 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 of frequency (very common-very rare) of side ef- fects, at least for those drugs for which data is available; 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 ENT/Audiology Specialist 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 country he/she operates in. 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 type of side effect. consideration of the possible medical-legal impli- In such instances, especially with drugs with cations. 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 cautious. 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 cluded in those used in some countries. 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- side effects). clinical action and with a reference to the relevant side effect, 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 motility disorders possible associated symptomatology of labyrinthi- • Antimuscarinic cal alteration vertigo and the possible generation of – Butylscopolamine ...... 3 tinnitus); – ...... 3 2. Drugs tinnitus-generating (there is no mention of – Sulphate ...... 3 ototoxicity); Antisecretory and protective drugs on gastric mucosa 3. Drugs vertigo-generating (there is no mention of • H2 blockers ototoxicity); – ...... 3

610 Pharmacological drugs inducing ototoxicity, vestibular symptoms and tinnitus

– ...... 3 – ...... 3 – ...... 3 – ...... 3 – ...... 3 – + ...... 3 • Chelates and complexes – ...... 3 – ...... 3 – hydrochloride ...... 3 • analogues – hydrochloride ...... 3 – ...... 3 – maleate ...... 2,3 • pump inhibitors and – ...... 3 • Anti-hypertensive vasodilators – ...... 3 – ...... 3 – ...... 3 – (related with rapid . . . . . 3 – ...... 3 reduction of pressure) – sodium ...... 3 • Centrally-acting anti-hypertensive drugs Anti-diarrheal drugs – hydrochloride ...... 3 • Gastrointestinal motility inhibitors – Methyl dopa ...... 3 – hydrochloride ...... 3 – Moxonidina ...... 3 Chronic intestinal disorders • Alpha blockers • – ...... 3 – ...... 2,3 – ...... 3 • inhibitors • Drugs used for regulate - system – ...... 3 – Ace inhibitors ...... 3 Cardiovascular System Captopril + diuretics ...... 3 ...... 3 Positive Cilazapril + diuretics ...... 3 • maleate ...... 2,3 – ...... 3 Enalapril + diuretics ...... 2,3 – ...... 3 ...... 3 Diuretics Fosinopril + diuretics ...... 3 • and related diuretics ...... 3 – Chlorthalidone ...... 3 Lisinopril + diuretics ...... 3 – Hydrochlorotiazide ...... 3 hydrochloride ...... 2,3 – ...... 3 Moexipril + diuretics ...... 2,3 • Loop diuretics ...... 3 – Furosemide ...... 1 Perindopril + diuretics ...... 3 – Torsemide (usually in high and rapid ...... 1 ...... 3 parenteral administration and in Quinapril+diuretics ...... 3 renal failure) ...... 3 • Potassium-sparing and other diuretics Ramipril+diuretics ...... 3 – and ...... 2,3 ...... 3 Anti-arrhythmics Trandolapril + channel blockers . . . . 3 • Supraventricular and ventricular – Angiotensin II blockers – hydrochloride ...... 3 cilexetil ...... 3 – ...... 2,3 Candesartan + diuretics ...... 3 – hydrochloride ...... 3 ...... 3 • Ventricular arrhythmias ...... 2 – hydrochloride ...... 3 Irbesartan+diuretics ...... 2,3 Beta blockers potassium ...... 3 – ...... 3 Losartan potassium+ ...... 3 – ...... 3 medoxomil ...... 3 – Atenolol + diuretics ...... 3 Olmesartan medoxomil+diuretics ...... 3 – Atenolol + blockers ...... 3 ...... 3 – fumarate ...... 3 Telmisartan + diuretics ...... 3 – Bisoprolol fumarate + diuretics ...... 3 + diuretics ...... 2,3 – ...... 3 • , calcium channel blockers and – hydrochloride ...... 3 other drugs used for – hydrochloride ...... 3 – Nitrates – tartrate ...... 3 ...... 3 – Metoprolol + diuretics ...... 3 ...... 3

611 G. Cianfrone, D. Pentangelo, F. Cianfrone, F. Mazzei, R. Turchetta, M.P. Orlando, G. Altissimi

Isosorbide mononitrate ...... 3 • immunotherapy – Calcium channel blockers – ...... 3 ...... 2,3 hydrochloride ...... 3 ...... 3 Central Nervous System ...... 3 ...... 3 and drugs hydrochloride ...... 3 • hydrochloride ...... 2,3 – ...... 3 ...... 3 Nifedipine + atenolol ...... 3 ...... 3 ...... 3 ...... 3 hydrochloride ...... 3 ...... 3 • Peripheral vasodilators and related drugs ...... 3 – ...... 3 – , e Sympathomimetics Zaleplon ...... 3,4 • Cardiopulmonary resuscitation Zolpidem tartrate ...... 3,4 – ...... 3 Zopiclone ...... 3 Parenteral – – Fondaparinux ...... 3 Sodium oxybate ...... 3 Anti- agents • – bisulfate ...... 3 – Benzodiazepines ...... – Dipyridamole ...... 3 ...... 3 Anti-fibrinolytic and hemostatic drugs ...... 3 – Tranexamic (in rapid intravenous ...... 3 Diazepam ...... 3 ) ...... 3 Blood derivatives ...... 3 – Human factor VIII ...... 3 – – Human coagulation factor IX ...... 3 Buspirone hydrochloride ...... 3 Lipid – lowering medications – • Meprobamate ...... 3 – ...... 3 – ...... 3 • ...... 3 – ...... 3 Drugs used for and related disorders • • Atypical – ...... 2,3 – ...... 3 – sodium ...... 3 – ...... 3 – ...... 3 – dipotassium ...... 3 – ...... 3 – ...... 3 – Simvastatin + ...... 3 – ...... 3 • oil – ...... 3 – Omega-3 acid ethyl ...... 3 • antidepressants and related drugs – Tricyclic hydrochloride ...... 2,3 Drugs used in asthma and chronic obstructive Amitriptyline hydrochloride + . . 2,3 pulmonary disease hydrochloride ...... 2,3 • receptor (sympathomimetics) hydrochloride ...... 2,3 – Beta 2 selective agonists hydrochloride ...... 2,3 ...... 3 ...... 2,3 • Antimuscarinic bronchodilators /nortriptyline ...... 2,3 – Tiotropium ...... 3 ...... 2,3 Cromoglycate, related therapies and anti- – Related antidepressant • Anti-leukotrienes hydrochloride ...... 2,3 • ...... 3 hydrochloride ...... 2,3 and drugs used for alleric reactions • Selective reuptake inhibitors • antihistamines – ...... 2,3 – Chlorpheniramine maleate ...... 2 – ...... 3 – ...... 3 – ...... 3

612 Pharmacological drugs inducing ototoxicity, vestibular symptoms and tinnitus

– maleate ...... 3 – ...... 3 – ...... 3 – ...... 3 – ...... 3 – ...... 2,3 • Other antidepressants – ...... 3 – ...... 3 – ...... 3 – ...... 3 – ...... 3 – ...... 3 – ...... 3 – ...... 2,3 – ...... 3,4 Central nervous system and drugs used for – ...... 3 attention deficit disorders and hyperactivity – ...... 3 • ...... 3 – ...... 3 • Metilphenidate hydrochloride ...... 3 – ...... 3 • ...... 3 • Drugs used for Drugs used in and vertigo – ...... 3 • Serotonin antagonists (5-ht3 receptor antagonists) – Diazepam ...... 3 – mesylate ...... 3 – Phenytoin sodium ...... 3 – ...... 3 – Lorazepam ...... 3 – ...... 2,3 and related disorders drugs – ...... 3 • drugs used for parkinsonism • Neurokinin receptor antagonists – receptor agonists – ...... 2,3 ...... 3 • Levodopa + ...... 3 – Scopolamine hydrobromide ...... 3 Levodopa + ...... 3 Analgesics Levodopa + carbidopa + ...... 3 • Non opioid maleate ...... 3 – Acetylsalicylic acid ...... 1 ...... 3 – + phosphate ...... 3 ...... 3 • Opioid analgesics ...... 3 – ...... 2,3 – b inhibitors – ...... 3 Resagiline ...... 3 – hydrochloride ...... 3 hydrochloride ...... 3 – ...... 3 – Catechol o methyltransferase inhibitors – hydrochloride ...... 3 hydrochloride ...... 3 – ...... 3 Entacapone ...... 3 – hydrochloride ...... 3 – Antimuscarinic drugs used for parkinsonism – ...... 3 hydrochloride ...... 3 • Neuropathic (trigeminal neuralgia) hydrochloride ...... 3 – ...... 3 • Drugs used for essential , corea, and – Oxcarbazepine ...... 3 related disorders • Anti drugs – ...... 3 • Migraine acute treatment • Torsional and other involuntary – Acetylsalicylic acid ...... 1 movements – NSAIDs ...... 2,3 – a ...... 3 • 5-hydroxy agonists Drugs – ...... 2,3 • dependence – ...... 2,3 – Benzodiazepines ...... 3 – ...... 2,3 • Cigarette smoke – ...... 3 – ...... 2,3 – ...... 3 – drug facts ...... 2,3 – ...... 3 – Varenicicline ...... 2,3 • drugs • Opioid dependence – tartrate ...... 3 – Buprenorphine ...... 2,3 • Migraine prophylaxis – Methadone hydrochloride ...... 3 – ...... 3 – hydrochloride ...... 3 Antiepileptic drugs • Drugs used for • control – hydrochloride ...... 3 – Carbamazepine ...... 3 – ...... 2,3 – ...... 3 – hydrochloride ...... 3 – Clonazepam ...... 3 – ...... 3

613 G. Cianfrone, D. Pentangelo, F. Cianfrone, F. Mazzei, R. Turchetta, M.P. Orlando, G. Altissimi

Infectious Diseases – ...... 3,4 – ...... 3,4 Antibiotics – ...... 2,3,4 • – ...... 3,4 – Broad-spectrum penicillins • drugs Amoxycillin + clavulanate ...... 3 – ...... 1 • and other beta lactamase – ...... 3 – Cephalosporins and – ...... 3 ...... 3 – ...... 3 ...... 3 – ...... 3 Cephalexin ...... 3 – ...... 3,4 sodium ...... 3 – Terbinafinae ...... 3 ...... 3 – ...... 2,3,4 ...... 3 Antiviral drugs ...... 3 • Human immunodeficiency virus ...... 3 – Nucleoside analog reverse transcriptase inhibitors ...... 3 Abacavir ...... 3 ...... 3 Abacavir+lamivudine ...... 3 ...... 3 Abacavir+lamivudina+ ...... 3 ...... 3 ...... 3 • Other beta lactamase antibiotics Emtricitabine ...... 3 – ...... 3 Emtricitabine+tenofovir ...... 3 – ...... 3 Lamivudinae ...... 3 – + ...... 1 Stavudine ...... 3 • Tenofovir disoproxil ...... 3 – ...... 2 Zidovudine ...... 3 – ...... 1 Zidovudine + lamivudine ...... 3 – ...... 3 – Protease inhibitors • ...... 3 – Amikacin ...... 1 Fosamprenavir ...... 3 – Gentamycin ...... 1 ...... 3 – Netilmycin ...... 1 Lopinavir+ ...... 3 – ...... 1 Ritonavir ...... 3 • ...... 3 – ...... 1 Tipranavir ...... 3 – ...... 1 – Non-nucleoside reverse transcriptase inhibitors – ...... 1 ...... 3 – ...... 3 – Other antiretroviral drugs • Other antibiotics Enfuvirtide ...... 3 – ...... 3 • Herpes virus – ...... 2,3 – Herpes simplex and zoster – Quinupristin + dalfopristin ...... 3 Acyclovir ...... 3 – ...... 1 Famcyclovir ...... 3 – ...... 1 pranobex ...... 3 • antibiotics Valacyclovir ...... 3 – ...... 3 – Citomegalovirus • Sulfonamides and sodium ...... 3 – ...... 2,3 Gancyclovir ...... 1 – + trimethoprim ...... 2,3 Valgancyclovir ...... 3 Antituberculosis drugs • Viral – ...... 3 – Entecavir ...... 3 – ...... 3 •Flu – Rifampicin+isoniazid ...... 3 – Amantadine hydrochloride ...... 3 – Streptomycin ...... 1 – Oseltamivir ...... 3,4 • and ...... • Human respiratory syncytial virus – Metronidazole ...... 3 – Ribavirin ...... 2,3 – Tinidazole ...... 3 agents • Fluoroquinolones • Antimalarial – ...... 2,3,4 – ...... 2,4

614 Pharmacological drugs inducing ototoxicity, vestibular symptoms and tinnitus

– ...... 1 – Terlipressin ...... 3 – Doxycycline ...... 2 metabolism regulators – ...... 2,3 • Calcitonin and parathyroid – hydrochloride + ...... 3 – Salmon calcitonin ...... 3 • Anti-parasitic drugs against amoeba and trichomonas – Parathyroid hormone ...... 3 – Metronidazole ...... 3 – ...... 3 – Tinidazole ...... 3 • Bisphosphonates and other bone metabolism • regulators – ...... 3 – Bisphosphonates • Anti-pneumocystosis drugs Pamidronate ...... 3 – Proguanil hydrochloride + atovaquone ...... 3 Risedronate ...... 2,3 – isethionate ...... 3 Zoledronate ...... 3 Antihelmintic drugs Other endocrine drugs • Anti-cestode parasites drugs • regulators – Teniacide – Antagonists and inhibitors ...... 3 ...... 3 ...... 3 Endocrine System – analogue ...... 3,4 Anti-diabetic agents ...... 3 • Oral blood--lowering drugs acetate ...... 3 – Sulfonylurea class ...... 3 ...... 3 – Other oral blood-glucose-lowering drugs Obstetric, Gynecology and Urology ...... 3 Pioglitazone + metformin ...... 3 Obstetric drugs • Prostaglandins and oxytocic drugs • – Dinoprostone ...... 3 – ...... 3 – maleate ...... 2,3 – ...... 3 – ...... 3 – ...... 3 • drugs – ...... 3 – Atosiban ...... 3 – ...... 3 Drugs used for vaginal – ...... 3 • Topical hormone replacement therapy Female – Topical ...... 3 • Estrogens and hormone replacement therapy Hormonal contaceptives – ...... 3 • Vaginal route – Estradiol + progestin ...... 3 – + ...... 3 – ...... 3 (post-coital) – Estrogens conjugated + progestin ...... 3 • Hormonal methods – Ethinylestradiol ...... 3 – ...... 3 – ...... 3 Progestin contraceptives • Progestinics • Progestin contraceptives (oral route) ...... 3 – ...... 3 Drugs used for genito-urinary disorders – acetate ...... 3 • Drugs used for – ...... 3 – Alpha blockers – Norethisterone + estradiol ...... 3 hydrochloride ...... 3 – ...... 3 Doxazosin ...... 3 Hypothalamic-hypophyseal hormones hydrochloride ...... 3 • Hypothalamic, adenohypophyseal hormones Terazosin ...... 3 and Drugs used for urinary disorders and incontinence – Antiestrogens • Clomiphene citrate ...... 3 – Duloxetine ...... 3 – Adenohypophyseal hormones – hydrochloride ...... 3 • receptor antagonists – Oxibutynin hydrochloride ...... 3 – Pegvisomant ...... 3 Drugs used in – Thyrotropin alfa ...... 3 • Alprostadil ...... 3 • Neurohypophyseal hormones and antagonists Phosphodiesterase type 5 inhibitors – Neurohypophyseal hormones • Sildenafil ...... 3

615 G. Cianfrone, D. Pentangelo, F. Cianfrone, F. Mazzei, R. Turchetta, M.P. Orlando, G. Altissimi

• ...... 3 injection ...... 3 • ...... 3 • Drugs used in megaloblastic – ...... 3 Tumors and Immunosuppresssion • Drugs used in hypoplastic and hemolytic and in anemia in kidney diseases Cytotoxic drugs – Iron-chelating agents • Vinca and Deferoxamine mesylate ...... 3,4 – Etoposide ...... 1 • Drugs used for treatment of essential – solphate ...... 1 thrombocytosis – solphate ...... 1 – ...... 3 – solphate ...... 1 Minerals – ...... 1 • Hypercalcaemia and hypercalciuric Other antineoplastic drugs – Cinacalcet ...... 3 • ...... 3 Vitamins • derivatives • Vitamins d – ...... 1 – Alfacalcidol ...... 3 – Cisplatin ...... 1 – ...... 3 – ...... 1 – Cholecalciferol ...... 3 • kinase inhibitors – Dihydrotachysterol ...... 3 – ...... 2,3 – Ergocalciferol ...... 3 – ...... 2,3 – ...... 3 – ...... 2 Metabolic disorders – ...... 3 • Drugs used in metabolic disorders • – Fabry disease – Trastuzumab ...... 3 Agalsidase alfa - beta ...... 2,3 • – Gaucher disease – Tretinoin ...... 3,4 Imiglucerase ...... 3 Drugs altering immune system response Miglustat ...... 3 • Drugs suppressing the immune system – ...... 3 Muscle Skeletal System – ...... 3 • Corticosteroids and other immunosuppressors Drugs used in rheumatological diseases and – ...... 3,4 • Non steroidal anti inflammatory drugs Other immunomodulator drugs – ...... 2,3 • – Mefenamic acid ...... 2,3 – Natalizumab ...... 3 – ...... 2,3 Sex hormones and hormone antagonists in tumors – Acetylsalicilic acid ...... 1 • Progestinics – ...... 2,3 – Medroxyprogesterone acetate ...... 3 – Dexibuprofene ...... 2,3 – acetate ...... 3 – Dexketoprofene ...... 2,3 – Norethisterone ...... 3 – potassium ...... 2,3 • Hormone antagonists – Diclofenac sodium ...... 2,3 – – Diclofenac + misoprostol ...... 2,3 ...... 3 – ...... 2,3 ...... 3 – ...... 2,3 ...... 3 – ...... 2,3 • cancer and releasing – Indomethacin ...... 2,3 hormone – ...... 2,3 – Buserelin ...... 3,4 – ...... 2,3 – ...... 3 – ...... 2,3 – Goserelin ...... 3 – ...... 2,3 – Leuprorelin acetate ...... 3 – ...... 2,3 – Triptorelin ...... 3 – ...... 2,3 – ...... 2,3 Blood and Nutrition • Drugs modifying the rheumatic diseases course – Antimalarial drugs Anemia and other hematic disorders Chloroquine ...... 1 • Iron deficiency anemia Hydroxichloroquine sulphate ...... 1 – Iron injection for anemia – Drugs modifying the immune response

616 Pharmacological drugs inducing ototoxicity, vestibular symptoms and tinnitus

Azathioprine ...... 3 Diagnostic and perioperative preparations, ...... 3 photodynamic treatment Metotrexate ...... 3 • Perioperative ocular drugs – Cytokines inhibitors – Aproclonidin ...... 3 ...... 3 – Diclofenac sodium ...... 2,3 Infliximab ...... 3 – Flurbiprofen sodium ...... 2,3 Sulfasalazine ...... 2,3 • Retrofoveal choroid neovascularization • Gout and hyperuricemia cytotoxic drugs induced – sodium ...... 1 – Gout long-term control Allopurinol ...... 3 Ear, Nose and Oropharynx Drugs used in neuromuscolar diseases • Skeletal muscle relaxants Anti-inflammatory steroids and associated – ...... 3 • Ciprofloxacin + hydrocortisone ...... 2,3,4 – sodium ...... 3 • + acetonide ...... 1 – Diazepam ...... 3 • sulphate + neomycin sulphate + – ...... 3 • hydrochloride ...... 1 • Limbs night cramps • Polimyxyn b sulphate + neomycin sulphate + Quinine ...... 2,4 • Lidocaine hydrochloride + hydrocortisone ...... 1 • Tobramycin ...... 1 Eye Medicaments • Tobramycin + dexamethasone ...... 1 Drugs used for oropharynx Antinfective eye preparations • Drugs used for oral ulceration and inflammation • Antibacterial – Flurbiprofen ...... 2,3 – Ciprofloxacin ...... 2,3,4 • Treatment of oral dryness – Gentamycin ...... 1 – Systemic treatment – Levofloxacin ...... 3,4 hydrochloride ...... 3 – Neomycin + antibiotics ...... 1 – Neomycin + ...... 1 Skin – Ofloxacin ...... 3 – Tobramycin ...... 1 Eczema and preparations Corticosteroids and other anti inflammatory preparations • Immune response regulators • Corticosteroids and associated antibacterials – Azathioprine ...... 3 – Dexamethasone + neomycin ...... 1 – Infliximab ...... 3 – Dexamethasone + netilmycin ...... 1 – Metotrexate ...... 3 – Dexamethasone + tobramycin ...... 1 and rosacea – + neomycin ...... 1 • Topical anti acne preparations – + gentamycin ...... 1 – Topical and anti acne preparations – Hydrocortisone + neomycin + cloramfenicol . . 1 Tretinoin ...... 3,4 – + neomycin ...... 1 • Anti acne preparations (oral route) • Other anti inflammatory preparations – Oral anti acne antibiotics – Lodoxamide ...... 3 Doxycycline ...... 2 – ...... 3 Erythromycin (reversible hearing loss at Mydriatic and cycloplegics high dosages) ...... 4 • Antimuscarinics Minocycline ...... 1 – Atropine solphate ...... 3 – Oral used for acne – hydrochloride ...... 3 ...... 4 – bromhydrate ...... 3 Protective substances against uv radiations – ...... 3 • Photodamage treatment – Diclofenac sodium ...... 2,3 • Beta blockers Anti infective skin preparations – Timolol maleate ...... 2,3 • Anti bacterial preparations • Sympathomimetics – Topical anti bacterial preparations (if – tartrate ...... 3 you have to treat a large area of skin – Brimonidine tartrate + timolol ...... 3 ototoxicity may be a risk associated with • Carbonic anhydrase inhibitors and systemic drugs aminoglycosides and polymyxin use) – ...... 3,4 Neomycin sulphate ...... 1 – ...... 3 Polymyxin ...... 1 – ...... 3 • Anti mycotic preparations – Dorzolamide + timolol ...... 3 – ...... 3

617 G. Cianfrone, D. Pentangelo, F. Cianfrone, F. Mazzei, R. Turchetta, M.P. Orlando, G. Altissimi

Immunological Medicines and Vaccines Infectious Diseases Cholera vaccine ...... 3 Antibiotics Meningococcal vaccine • Other beta lactamase antibiotics Meningococcal group c polysaccharide – Imipenem + cilastatin • Conjugate vaccine ...... 3 • Tetracyclines • Meningococcal acwy vaccine ...... 3 – Minocycline • Aminoglycosides – Amikacin – Gentamycin General anesthesia – Netilmycin • Intravenous – Tobramycin – ...... 3 • Macrolides • Antimuscarinic drugs – Azithromycin – Atropine ...... 3 – Clarithromycin – Scopolamine hydrobromide ...... 3 – Erythromycin • Perioperative analgesic and sedative drugs • Other antibiotics – Anxiolytics and neuroleptics – Teicoplanin Diazepam ...... 3 – Vancomycin Lorazepam ...... 3 • Antituberculosis drugs ...... 3 – Streptomycin Temazepam ...... 3 • Antifungal drugs – analgesics – Amphotericin b ...... 3 Antiviral drugs Fentanyl ...... 3 • Herpes virus infection ...... 3 – Citomegalovirus • Drugs used in malignant Ganciclovir – Dantrolene sodium ...... 3 Antiprotozoal agents Local anesthesia • Antimalarial • Lidocaine – Chloroquine – Lidocaine hydrochloride ...... 3 Tumors and Immunosuppresssion Cytotoxic drugs • Vinca alkaloid and etoposide Sub-index A1 – Etoposide – Vinblastine solphate Ototoxic Drugs – Vincristine solphate – Vindesine solphate (Ototoxicity may include both the possible associ- – Vinorelbine ated symptomatology of labyrinthical alteration verti- Other antineoplastic drugs go and the possible generation of tinnitus). • Platinum derivatives – Carboplatin – Cisplatin Cardiovascular System – Oxaliplatin Diuretics • Loop diuretics Muscle Skeletal System – Furosemide – Torsemide (usually in high and rapid parenteral Drugs used for rheumatological diseases and gout administration and in renal failure) • Non steroidal anti inflammatory drugs – Acetylsalicilic acid • Drugs that modify the rheumatic diseases course Central Nervous System – Antimalarial drugs Analgesics Chloroquine • Non opioid analgesic Hydroxichloroquine sulphate – Acetylsalicylic acid • Anti migraine drugs Eye Medicaments – Migraine acute treatment Acetylsalicylic acid Antinfective eye preparations

618 Pharmacological drugs inducing ototoxicity, vestibular symptoms and tinnitus

• Antibacterial Cardiovascular System – Gentamycin Diuretics – Neomycin + antibiotics – Neomycin + corticosteroid • Potassium-sparing and other diuretics – Tobramycin – Amiloride and hydrochlorothiazide Corticosteroids and other anti inflammatory preparations Anti-arrhythmics • Corticosteroids and associated antibacterials • Supraventricular and ventricular arrhythmias – Dexamethasone + neomycin – Flecainide acetate Beta blockers – Dexamethasone + netilmycin – Dexamethasone + tobramycin • Timolol maleate Hypertension and heart failure – Fluocinolone acetonide + neomycin – Fluorometholone + gentamycin • Drugs used for regulate renin-angiotensin system – Hydrocortisone + neomycin + cloramfenicol – Ace inhibitors – Prednisolone + neomycin Enalapril maleate Diagnostic and perioperative preparations, Enalapril+diuretics photodynamic treatment Moexipril hydrochloride • Retrofoveal choroid neovascularization Moexipril+diuretics – Pegaptanib sodium – Angiotensin ii receptor blockers Irbesartan Irbesartan+diuretics Ear, Nose and Oropharynx Valsartan + diuretics Anti-inflammatory steroids and associated antimicrobial • Nitrates, calcium channel blockers and other drugs • Neomycin + fluocinolone acetonide used for angina • Polymyxin b sulphate + neomycin sulphate + – Calcium channel blockers lidocaine hydrochloride Amlodipine • Polimyxyn b sulphate + neomycin sulphate + Nicardipine hydrochloride Lipid – lowering medications lidocaine hydrochloride + hydrocortisone • Tobramycin • Statins • Tobramycin + dexamethasone – Atorvastatin Respiratory System Skin Acne and rosacea Antihistamines and drugs used for alleric reactions • Anti acne preparations (oral route) • Sedative antihistamines – Oral anti acne antibiotics – Chlorpheniramine maleate Erythromycin Minocycline Central Nervous System Anti infective skin preparations • Anti bacterial preparations Antidepressants – 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 Neomycin sulphate Amitriptyline hydrochloride + perphenazine Polymyxin Clomipramine hydrochloride Dosulepin hydrochloride Fluphenazine/ nortriptyline Imipramine hydrochloride Nortriptyline Sub-index A2 Trimipramine – Related antidepressant Drugs Tinnitus-Generating Mianserin hydrochloride Trazodone hydrochloride (There is no mention of ototoxicity). • Selective serotonin reuptake inhibitors – Citalopram Gastrointestinal System • Other antidepressants – Venlafaxine Chronic intestinal disorders Drugs used in nausea and vertigo • Aminosalicylates • Serotonin antagonists (5-ht3 receptor antagonists) – Sulfasalazine – Palonosetron

619 G. Cianfrone, D. Pentangelo, F. Cianfrone, F. Mazzei, R. Turchetta, M.P. Orlando, G. Altissimi

• Neurokinin receptor antagonists Obstetric, Gynecology and Urology – Aprepitant Obstetric drugs Analgesics • Prostaglandins and oxytocic drugs • Opioid analgesics – Ergometrine maleate – Buprenorphine • Anti migraine drugs Tumors and Immunosuppresssion – Migraine acute treatment NSAIDs Other antineoplastic drugs – 5-hydroxy tryptamine agonists • Protein kinase inhibitors Almotriptan – Dasatinib Eletriptan – Imatinib Frovatriptan – Sorafenib Antiepileptic drugs • Epilepsy control Blood and Nutrition – Gabapentin Metabolic disorders Drugs addiction • Drugs used in metabolic disorders • Cigarette smoke – Fabry disease – Bupropion Agalsidase alfa-beta – Nicotine drug facts – Varenicicline Muscle Skeletal System • Opioid dependence – Buprenorphine Drugs used in rheumatological diseases and gout Drugs used for dementia • Non steroidal anti inflammatory drugs • Galantamine – Aceclofenac – Celecoxib – Dexibuprofene Infectious Diseases – Dexketoprofene – Diclofenac potassium Antibiotics – Diclofenac sodium • – Diclofenac + misoprostol – Doxycycline – Etoricoxib • Other antibiotics – Flurbiprofen – Linezolid – Ibuprofen • Sulfonamides and trimethoprim – Indomethacin – Sulfadiazine – Ketoprofen – Sulfamethoxazole+trimethoprim – Mefenamic acid • Fluoroquinolones – Meloxicam – Ciprofloxacin – Nabumetone – Norfloxacin – Naproxen Antifungal drugs – Piroxicam • Voriconazole – Sulindac Antiviral drugs – Tenoxicam • Human respiratory syncytial virus – Tiaprofenic acid – Ribavirin • Drugs modifying the rheumatic diseases course Antiprotozoal agents – Cytokines inhibitors • Antimalarial Sulfasalazine – Doxycycline Drugs used in neuromuscolar diseases – Mefloquine • Skeletal muscle relaxants – Quinine – Limbs night cramps Quinine

Endocrine System Eye Medicaments Antinfective eye preparations Bone metabolism regulators • Antibacterial • Bisphosphonates and other bone metabolism regu- – Ciprofloxacin lators Glaucoma treatment – Bisphosphonates • Beta blockers Risedronate – Timolol maleate

620 Pharmacological drugs inducing ototoxicity, vestibular symptoms and tinnitus

Diagnostic and perioperative preparations, – Loperamide hydrochloride photodynamic treatment Chronic intestinal disorders • Perioperative ocular drugs • Aminosalicylates – Diclofenac sodium – Sulfasalazine – Flurbiprofen sodium • Cytokines inhibitors – Infliximab Ear, Nose and Oropharynx Cardiovascular System Anti-inflammatory steroids and associated antimicrobial • Ciprofloxacin + hydrocortisone Positive inotropes Drugs used for oropharynx • Cardiac glycoside • Drugs used for oral ulceration and inflammation – Digitoxin – Flurbiprofen – Digoxin Diuretics • Thiazide and related diuretics Skin – Chlorthalidone Acne and rosacea – Hydrochlorotiazide • Anti acne preparations (oral route) – Indapamide – Oral anti acne antibiotics • Potassium-sparing and other diuretics Doxycycline – Amiloride and hydrochlorothiazide Protective substances against uv radiations Anti-arrhythmics • Photodamage • Supraventricular and ventricular arrhythmias – Diclofenac sodium – Amiodarone hydrochloride – Flecainide acetate – Propafenone hydrochloride • Ventricular arrhythmias Sub-index A3 – Mexiletine hydrochloride Beta blockers Drugs vertigo-generating • Acebutolol • Atenolol (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 • Carvedilol intestinal motility disorders • Celiprololo hydrochloride • Antimuscarinic • Esmolol hydrochloride – Butylscopolamine bromide • Metoprolol tartrate – Propantheline bromide • Metoprolol + diuretics – Sulphate atropine • Nadolol Antisecretory and protective drugs on • Nebivolol gastric mucosa • Oxprenolol + diuretics • H2 blockers • Pindolol – Cimetidine • Propranolol hydrochloride – Famotidine • Sotalol hydrochloride – Nizatidine • Timolol maleate – Ranitidine Hypertension and heart failure • Chelates and complexes • Anti-hypertensive vasodilators – Sucralfate – Sildenafil • Prostaglandins analogues – Sodium nitroprusside (related with rapid – Misoprostol reduction of ) • Proton pump inhibitors • Centrally-acting anti-hypertensive drugs – Esomeprazole – Clonidine hydrochloride – Lansoprazole – Methyl dopa – Omeprazole – – Pantoprazole • Alpha blockers – Rabeprazole sodium – Doxazosin Anti-diarrheal drugs – Terazosin • Gastrointestinal motility inhibitors • Drugs used for regulate renin-angiotensin system

621 G. Cianfrone, D. Pentangelo, F. Cianfrone, F. Mazzei, R. Turchetta, M.P. Orlando, G. Altissimi

– Ace inhibitors Anti-platelet agents Captopril • Clopidogrel bisulfate Captopril + diuretics • Dipyridamole Cilazapril Anti-fibrinolytic and hemostatic drugs Cilazapril + diuretics • (in rapid intravenous injection) Enalapril maleate Blood derivatives Enalapril + diuretics • Human coagulation factor VIII Fosinopril • Human coagulation factor IX Fosinopril+diuretics Lipid – lowering medications Lisinopril • Fibrates Lisinopril + diuretics – Bezafibrate Moexipril hydrochloride – Fenofibrate Moexipril + diuretics – Gemfibrozil Perindopril • Statins Perindopril + diuretics – Atorvastatin Quinapril – Pravastatin sodium Quinapril + diuretics – Rosuvastatin Ramipril – Simvastatin Ramipril+diuretics – Simvastatin + ezetimibe Trandolapril • Fish oil Trandolapril + calcium channel blockers – Omega-3 acid ethyl esters – Angiotensin ii receptor blockers Candesartan cilexetil Candesartan + diuretics Respiratory System Eprosartan Irbesartan Drugs used in asthma and chronic obstructive Irbesartan + diuretics pulmonary disease Losartan potassium • agonists (sympathomimetics) Losartan potassium + diuretics – Beta 2 selective agonists Olmesartan medoxomil Salmeterol Olmesartan medoxomil + diuretics • Antimuscarinic bronchodilators Telmisartan – Tiotropium Telmisartan + diuretics Cromoglycate, related therapies and anti-leukotrienes Valsartan + diuretics • Anti-leukotrienes • Nitrates, calcium channel blockers and – Montelukast other drugs used for angina Antihistamines and drugs used for alleric reactions – Nitrates • Sedative antihistamines Nitroglycerin – Ketotifen Isosorbide dinitrate • Allergen immunotherapy Isosorbine mononitrate – Omalizumab • Calcium channel blockers Amlodipine Diltiazem hydrochloride Central Nervous System Felodipine Isradipine Hypnotic and anxiolytic drugs Lacidipine • Hypnotics Lercanidipine hydrochloride – Benzodiazepines Nicardipine hydrochloride Diazepam Nifedipine Flurazepam Nifedipine + atenolol Lormetazepam Nisoldipine Nitrazepam Verapamil hydrochloride Temazepam • Peripheral vasodilators and related drugs – Zaleplon, zolpidem e zopiclone – Pentoxifylline Zaleplon Sympathomimetics Zolpidem tartrate • Cardiopulmonary resuscitation Zopiclone – Adrenaline – Sodium oxybate Parenteral anticoagulants Sodium oxybate • Fondaparinux • Anxiolytics

622 Pharmacological drugs inducing ototoxicity, vestibular symptoms and tinnitus

– Benzodiazepines – Aprepitant Alprazolam • Scopolamine Chlordiazepoxide – Scopolamine hydrobromide Diazepam Analgesics Lorazepam • Non opioid analgesic Oxazepam – Paracetamol + codeine phosphate – Buspirone • Opioid analgesics Buspirone hydrochloride – Buprenorphine – Meprobamate – Fentanyl Meprobamate – Methadone hydrochloride Barbiturates – Morphine • Phenobarbital – Oxycodone hydrochloride Drugs used for psychosis and related disorders – Pentazocine • Atypical antipsychotics – Pethidine hydrochloride – Amisulpride – Tramadol – Aripiprazole (trigeminal neuralgia) – Clorazepate dipotassium – Carbamazepine – Olanzapine – Oxcarbazepine – Quetiapine Anti migraine drugs – Risperidone – Migraine acute treatment Antidepressants Nsaids • Tricyclic antidepressants and related drugs – 5-hydroxy tryptamine agonists – Tricyclic antidepressant Almotriptan Amitriptyline hydrochloride Eletriptan Amitriptyline hydrochloride + perphenazine Frovatriptan Clomipramine hydrochloride Rizatriptan Dosulepin hydrochloride Sumatriptan Fluphenazine/nortriptyline Zolmitriptan Imipramine hydrochloride – Ergot alkaloids drugs Nortriptyline Ergotamine tartrate Trimipramine – Migraine prophylaxis – Related antidepressant Pizotifen Mianserin hydrochloride Antiepileptic drugs Trazodone hydrochloride • Epilepsy control • Selective serotonin reuptake inhibitors – Carbamazepine – Citalopram – Clobazam – Escitalopram – Clonazepam – Fluoxetine – Ethosuximide – Fluvoxamine maleate – Gabapentin – Paroxetine – Lamotrigine – Sertraline – Levetiracetam • Other antidepressants – Oxcarbazepine – Duloxetine – Phenytoin – Mirtazapine – Pregabalin – Reboxetine – Primidone – Venlafaxina – Tiagabine Central nervous system stimulants and drugs used for – Topiramate attention deficit disorders and hyperactivity – Vigabatrin • Atomoxetine – Zonisamide • Metilphenidate hydrochloride • Drugs used for status epilepticus • Modafinil – Clonazepam Drugs used in nausea and vertigo – Diazepam • Serotonin antagonists (5-ht3 receptor – Phenytoin sodium antagonists) – Lorazepam – Dolasetron mesylate Parkinsonism and related disorders drugs – Ondansetrone • Dopaminergic drugs used for parkinsonism – Palonosetron – agonists – Tropisetron Cabergoline • Neurokinin receptor antagonists Levodopa + benserazide

623 G. Cianfrone, D. Pentangelo, F. Cianfrone, F. Mazzei, R. Turchetta, M.P. Orlando, G. Altissimi

Levodopa + carbidopa • Other beta lactamase antibiotics Levodopa + carbidopa + entacapone – Aztreonam Lisuride maleate – Ertapenem Pergolide • Tetracycline Pramipexole – Tigecicline Ropinirole • Macrolides – inhibitors – Telithromycin Resagiline • Other antibiotics Selegiline hydrochloride – Daptomycin – Catechol o methyltransferase inhibitors – Linezolid Amantadine hydrochloride – Quinupristin + dalfopristin Entacapone • Polymyxin antibiotics – Antimuscarinic drugs used for parkinsonism – Colistin Orphenadrine hydrochloride • Sulfonamides and trimethoprim Trihexyphenidyl hydrochloride – Sulfadiazine – Drugs used for essential tremor, corea, tic and – Sulfamethoxazole + trimethoprim related disorders • Antituberculosis drugs Riluzole – Isoniazid – Torsional dystonia and other involuntary – Rifampicin movements – Rifampicin + isoniazid Botulinum toxin A • Metronidazole and tinidazole Drugs addiction – Metronidazole • – Tinidazole – Benzodiazepines • Fluoroquinolones • Cigarette smoke – Ciprofloxacin – Bupropion – Levofloxacin – Nicotine drug facts – Moxifloxacin – Varenicicline – Norfloxacin • Opioid dependence – Ofloxacin – Buprenorphine • Antifungal drugs – Methadone hydrochloride – Fluconazole – Naltrexone hydrochloride – Flucytosine Drugs used for dementia – Griseofulvin • Donepezil hydrochloride – Itraconazole • Galantamine – Posaconazole • Memantine hydrochloride – Terbinafinae • Rivastigmine – Voriconazole Antiviral drugs • Human immunodeficiency virus Infectious Diseases – Nucleoside analog reverse transcriptase inhibitors Abacavir Antibiotics Abacavir + lamivudine • Penicillins Abacavir + lamivudina+zidovudine – Broad-spectrum penicillins Didanosine Amoxycillin + clavulanate Emtricitabine • Cephalosporins and other beta lactamase Emtricitabine + tenofovir – Cephalosporins and cephamycins Lamivudinae Cefaclor Stavudine Cefadroxil Tenofovir disoproxil Cefazolin sodium Zidovudine Cefixime Zidovudine + lamivudine Cefotaxime – Protease inhibitors Cefpodoxime Atazanavir Cefprozil Fosamprenavir Cefradine Indinavir Ceftazidime Lopinavir + ritonavir Ceftriaxone Ritonavir Cefuroxime Saquinavir Cephalexin Tipranavir

624 Pharmacological drugs inducing ototoxicity, vestibular symptoms and tinnitus

– Non-nucleoside reverse transcriptase inhibitors – Estradiol + progestin Efavirenz – Estriol – Other antiretroviral drugs – Estrogens conjugated + progestin Enfuvirtide – Ethinylestradiol • Herpes virus infection – Tibolone – Herpes simplex and zoster • Progestinics Acyclovir – Dydrogesterone Famcyclovir – Medroxyprogesterone acetate Inosine pranobex – Norethisterone Valacyclovir – Norethisterone + estradiol – Citomegalovirus – Progesterone Foscarnet sodium Hypothalamic-hypophyseal hormones Valgancyclovir • Hypothalamic, adenohypophyseal hormones • Viral hepatitis and antiestrogens – Entecavir – Antiestrogens •Flu Clomiphene citrate – Amantadine hydrochloride – Adenohypophyseal hormones – Oseltamivir • Growth antagonists • Human respiratory syncytial virus – Pegvisomant – Ribavirin – Thyrotropin alfa Antiprotozoal agents • Neurohypophyseal hormones and antagonists • Antimalarial – Neurohypophyseal hormones – Mefloquine Terlipressin – Proguanil hydrochloride + atovaquone Bone metabolism regulators • Anti-parasitic drugs against amoeba and • Calcitonin and parathyroid hormone trichomonas – Parathyroid hormone – Metronidazole – Salmon calcitonin – Tinidazole – Teriparatide • Leishmaniasis • Bisphosphonates and other bone metabolism regulators – Sodium stibogluconate – Bisphosphonates • Anti-pneumocystosis drugs Pamidronate – Pentamidine isethionate Risedronate – Proguanil hydrochloride + atovaquone Zoledronate Antihelmintic drugs Other endocrine drugs • Anti-cestode parasites drugs • Gonadotropins regulators – Teniacide – Antagonists and inhibitors Niclosamide Danazol Ganirelix – Gonadorelin analogue Endocrine System Buserelin Goserelin Anti-diabetic agents Leuprorelin acetate • Oral blood-glucose-lowering drugs Triptorelin – Sulfonylurea class Glipizide Obstetric, Gynecology and Urology – Other oral blood-glucose-lowering drugs Pioglitazone Obstetric drugs Pioglitazone + metformin • Prostaglandins and oxytocic drugs Corticosteroids – Dinoprostone • Glucocorticoid steroids – Ergometrine maleate – Betamethasone – Gemeprost – Deflazacort • Tocolytic drugs – Dexamethasone – Atosiban – Hydrocortisone Drugs used for vaginal atrophy – Methylprednisolone • Topical hormone replacement therapy – Triamcinolone – Topical estrogens Female sex hormones Hormonal contraceptives • Estrogens and hormone replacement therapy • Vaginal route – Estradiol – Etonogestrel + ethinylestradiol

625 G. Cianfrone, D. Pentangelo, F. Cianfrone, F. Mazzei, R. Turchetta, M.P. Orlando, G. Altissimi

Emergency contraception (post-coital) – Goserelin • Hormonal methods – Leuprorelin acetate – Levonorgestrel – Triptorelin 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 – Alpha blockers • Iron deficiency anemia Alfuzosin hydrochloride – Iron injection for anemia Doxazosin Iron sucrose injection Tamsulosin hydrochloride • Drugs used in megaloblastic anemia Terazosin – Hydroxocobalamin Drugs used for urinary disorders and incontinence • Drugs used in hypoplastic and hemolytic anemias • Urinary incontinence and in anemia in kidney diseases – Duloxetine – Iron-chelating agents – Flavoxate hydrochloride Deferoxamine mesylate – Oxibutynin hydrochloride • Drugs used for treatment of essential thrombocytosis Drugs used in erectile dysfunction – Anagrelide • Alprostadil Minerals Phosphodiesterase type 5 inhibitors • Hypercalcaemia and hypercalciuric • Sildenafil – Cinacalcet • Tadalafil Vitamins • Vardenafil • Vitamins d – Alfacalcidol Tumors and Immunosuppresssion – Calcitriol – Cholecalciferol Other antineoplastic drugs – Dihydrotachysterol • Cetuximab – Ergocalciferol • Protein kinase inhibitors – Paricalcitol – Dasatinib Metabolic disorders – Imatinib • Drugs used for metabolic disorders – Sunitinib – Fabry disease • Trastuzumab Agalsidase alfa - beta – Trastuzumab – Gaucher disease • Tretinoin Imiglucerasi – Tretinoin Miglustat Drugs altering immune system response • Drugs suppressing the immune system Muscle Skeletal System – Azathioprine – Mefenamic acid Drugs used in rheumatological diseases and gout • Corticosteroids and other immunosuppressors • Non steroidal anti inflammatory drugs – Tacrolimus – Aceclofenac Other immunomodulator drugs – Celecoxib • Natalizumab – Dexibuprofene – Natalizumab – Dexketoprofene Sex hormones and hormone antagonists in tumors – Diclofenac potassium • Progestinics – Diclofenac sodium – Medroxyprogesterone acetate – Diclofenac + misoprostol – – Etoricoxib – Norethisterone – Flurbiprofen • Hormone antagonists – Ibuprofen – Breast cancer – Indomethacin – Exemestane – Ketoprofen – Letrozole – Mefenamic acid – Toremifene – Meloxicam • and gonadotropin releasing – Nabumetone hormone agonist – Naproxen – Buserelin – Piroxicam – Flutamide – Sulindac

626 Pharmacological drugs inducing ototoxicity, vestibular symptoms and tinnitus

– Tenoxicam Drugs used for oropharynx – Tiaprofenic acid • Drugs used for oral ulceration and inflammation • Drugs modifying the immune response – Flurbiprofen – Azathioprine • Treatment of oral dryness – Leflunomide – Systemic treatment – Metotrexate Pilocarpine hydrochloride • Cytokines inhibitors – Adalimumab – Infliximab Skin – Sulfasalazine • Gout and hyperuricemia cytotoxic drugs induced Eczema and psoriasis preparations – Gout long-term control • Immune response regulators Allopurinol – Azathioprine Drugs used in neuromuscolar diseases – Infliximab • Skeletal muscle relaxants – Metotrexate – Baclofen Acne and rosacea – Dantrolene sodium • Topical anti acne preparations – Diazepam – Topical retinoids and anti acne preparations – Tizanidine Tretinoin Protective substances against uv radiations Eye Medicaments • Photodamage – Diclofenac sodium Antinfective eye preparations Anti infective skin preparations • Antibacterial • Anti mycotic preparations – Ciprofloxacin – Ketoconazole – Levofloxacin – Ofloxacin Corticosteroids and other anti inflammatory preparations Immunological Medicines and Vaccines • Other anti inflammatory preparations – Lodoxamide Cholera vaccine – Olopatadine Meningococcal vaccine Mydriatic and cycloplegics • Meningococcal group c polysaccharide conjugate • Antimuscarinics vaccine – Atropine solphate • Meningococcal acwy vaccine – Cyclopentolate hydrochloride – Homatropine bromhydrate – Tropicamide Anesthesia Glaucoma treatment • Beta blockers General anesthesia – Timolol maleate • Intravenous anesthetics • Sympathomimetics – Propofol – Brimonidine tartrate • Antimuscarinic drugs – Brimonidine tartrate + timolol – Atropine • Carbonic anhydrase inhibitors and systemic drugs – Scopolamine hydrobromide – Acetazolamide • Perioperative analgesic and sedative drugs – Brinzolamide – Anxiolytics and neuroleptics – Dorzolamide Diazepam – Dorzolamide + timolol Lorazepam Diagnostic and perioperative preparations, Midazolam photodynamic treatment Temazepam • Perioperative ocular drugs – Opioids analgesics – Aproclonidin Alfentanil – Diclofenac sodium Fentanyl – Flurbiprofen sodium Remifentanil • Drugs used in Ear, Nose and Oropharynx – Dantrolene sodium Local anesthesia Anti-inflammatory steroids and associated antimicrobial • Lidocaine • Ciprofloxacin + hydrocortisone – Lidocaine hydrochloride

627 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 – Tacrolimus “hearing disturbances” (drugs with aspecific otologic Sex hormones and hormone antagonists in tumors side effects), it is advisable to have a conservative ap- • Hormone antagonists proach to these drugs and to evaluate in each case the – Prostate cancer and gonadotropin releasing possible intensity and type of adverse reaction. hormone agonist Buserelin Central Nervous System Hypnotic and anxiolytic drugs Blood and Nutrition • Hypnotics – Zaleplon, zolpidem e zopiclone Anemia and other hematic disorders Zaleplon • Drugs used in hypoplastic and hemolytic anemias Zolpidem tartrate and in anemia in kidney diseases Antiepileptic drugs – Iron-chelating agents • Epilepsy control Deferoxamine mesylate – Pregabalin (hyperacusia) Muscle Skeletal System

Infectious Diseases Drugs used in neuromuscolar diseases • Skeletal muscle relaxants Antibiotics – Limbs night cramps • Fluoroquinolones Quinine – Ciprofloxacin – Levofloxacin – Moxifloxacin Eye Medicaments – Norfloxacin – Ofloxacin Antinfective eye preparations Antifungal drugs • Antibacterial – Posaconazole – Ciprofloxacin – Voriconazole – Levofloxacin Antiviral drugs Glaucoma treatment •Flu • Carbonic anhydrase inhibitors and systemic drugs – Oseltamivir – Acetazolamide Antiprotozoal agents • Antimalarial Ear, Nose and Oropharynx – Quinine Anti-inflammatory steroids and associated antimicrobial Endocrine System • Ciprofloxacin + hydrocortisone

Other endocrine drugs • Gonadotropins regulators Skin – Gonadorelin analogue Buserelin Acne and rosacea • Topical anti acne preparations Tumors and Immunosuppresssion – Topical retinoids and anti acne preparations Tretinoin Other antineoplastic drugs Anti acne preparations (oral route) • Tretinoin • Oral retinoid used for acne – Tretinoin • Isotretinoin

628 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 609).

Reference Reference numbers Drugs classes ADR numbers Drugs classes ADR

1 Abacavir + Lamivudine 3 52 Aztreonam 3 2 Abacavir 3 53 + Neomycin 1 3 Abacvir + Lamivudine + Zidovudine 3 54 Baclofen 3 4 Acebutolol 3b 55 + Hydrochlorothiazide ,3b 5 + Timolol Maleate 2,3 56 Benazepril Hydrochloride 2,3 6 Aceclofenac 2e,3e 57 Betamethasone + Bekanamicin + 1 7 Acetazolamide 3,4 8 Acetylsalicylic Acid 1 58 Betamethasone + Tetryzoline 3 9 Acetylsalicylic Acid + 1 59 Betamethasone 3 10 Acyclovir 3 60 Betamethasone + Clorfenamin 2,3 11 Adalimumab 3b 61 Bezafibrate 3 12 Adrenaline 3 62 Hydrochloride 3 13 Agalsidase Alfa - Beta 2,3 63 Bisoprolol Fumarate + Diuretics 3c 14 Alfacalcidol 3 64 Bisoprolol Fumarate 3b 15 Alfentanil 3 65 Botulinum Toxin A 3b 16 Alfuzosin Hydrochloride 3 66 Brimonidine Tartrate + Timolol 3c 17 Hydrochloride 3 67 Brimonidine Tartrate 3b 18 Allopurinol 3 68 Brinzolamide 3c 19 Almotriptan 2c,3b 69 3 20 Alpha 1 Antitrypsin 3 70 Mesylate 3 21 Alprazolam 3b 71 3 22 Alprostadil 3 72 3 23 Amantadine Hydrochloride 3 73 Hydrochloride 3e 24 Hydrochloride 3 74 + Adrenaline 3 25 Amifostine 3 75 Bupivacaine Hydrochloride 3 26 Amikacin 1 76 Buprenorphine 2d,3b 27 Amikacin Sulphate 1 77 Bupropion 2c,3b 28 Amiloride And Hydrochlorothiazide 2,3 78 Buserelin 3,4 29 Amiodarone Hydrochloride 3 79 Buspirone Hydrochloride 3b 30 Amisulpride 3 80 + Canrenoate Potassium 3e 31 Amitriptyline Chlordiazepoxide 2,3 81 Butylscopolamine Bromide 3 32 Amitriptyline Hydrochloride 2,3 82 Buxamine 3 33 Amitriptyline Hydrochloride + 2,3 83 Buxamine + Fenobarbital + Fenitoine 3 Perphenazine 84 Buxamine + Diazepam 3 34 Amlodipine 2,3 85 Cabergoline 3b 35 Amoxycillin + Clavulanate 3 86 3 36 Amphotericin B 1 87 Calcitriol 3 37 Anagrelide 3b 88 Calcium Carbonate + 3 38 3d Cholecalciferol (Vitamin D3) 39 Aprepitant 2,3 89 Calcium Channel Blockers 3 40 Aproclonidin 3c 90 Candesartan + Diuretics 3 41 Aripiprazole 3b 91 Candesartan Cilexetil 3 42 + Adrenaline 2,3 92 Captopril + Diuretics 3 43 Atazanavir 3c 93 Captopril 3 44 Atenolol + Diuretics 3 94 Carbamazepine 3a 45 Atenolol 3 95 Carboplatin 1 46 Atomoxetine 3 96 Carvedilol 3a 47 Atorvastatin 2,3 97 Cefaclor 3d 48 Atosiban 3b 98 Cefadroxil 3 49 Atropine Sulphate 3 99 Cefazolin Sodium 3 50 Azathioprine 3 100 2d,3d 51 Azithromycin 1,3d 101 Cefixime 3

629 G. Cianfrone, D. Pentangelo, F. Cianfrone, F. Mazzei, R. Turchetta, M.P. Orlando, G. Altissimi

102 Disodium 3 161 Dexamethasone 3 103 Sodium 3d 162 Dexamethasone + Neomycin 1 104 Cefotaxime 3 163 Dexamethasone + 1 105 Cefpodoxime 3 164 Dexamethasone + Tobramycin 1 106 Cefprozil 3c 165 Dexibuprofene 2c,3b 107 Ceftazidime 3c 166 Dexketoprofene 2e,3c 108 Ceftibutene 2,3d 167 Diazepam 3 109 Sodium 3 168 Diclofenac + Misoprostol 2,3 110 Ceftriaxone 3d 169 Diclofenac Epolamine 2e,3e 111 Cefuroxime 3 170 Diclofenac Potassium 2e,3e 112 Celecoxib 2c,3c 171 Diclofenac Sodium 2e,3e 113 Celiprololo Hydrochloride 3 172 (Sodium) 2,3 114 Cephalexin 3 173 Didanosine 3 115 Cephradin 3 174 Digitoxin 3 116 Cetuximab 3a 175 Digoxin 3 117 Chlordiazepoxide 3 176 3e 118 Chloroquine 1 177 Dihydrocodeine + 3e 119 Chlorpheniramine Maleate 2b 178 Dihydrocodeine + Pentetrazol 3e 120 Chlorthalidone 3 179 Dihydroergokryptine Mesylate 3 121 Cholecalciferol 3 180 Mesylate 3 122 Chondroitin Sulphate 3 181 Hydrochloride 1 123 Cilazapril + Diuretics 3 182 Dihydrotachysterol 3 124 Cilazapril 3b 183 Diltiazem Hydrochloride 3 125 Cimetidine 3 184 Dinoprostone 3 126 3 185 3 127 Cinacalcet 3b 186 Diosmin + 3 128 1,2c,3b 187 Diphtheria, Vaccine Adsorbed 3d 129 Ciprofloxacin + Hydrocortisone 2b,3c, 188 Dipyridamole 3e 4d 189 Dolasetron Mesylate 3 130 Ciprofloxacin 2d,3c, 190 Donepezil Hydrochloride 3b 4d 191 Dorzolamide 3 131 Cisplatin 1a 192 Dorzolamide + Timolol 3c 132 Citalopram 2b,3b 193 Dosulepin Hydrochloride 2b,3b 133 Clarithromicin 1e,2d, 194 Doxazosin 3b 3e 195 Doxycycline 2 134 + 3 196 Duloxetine 3c Chlordiazepoxide 197 Dydrogesterone 3 135 Clobazam 3 198 Efavirenz 3c 136 Clomiphene Citrate 3c 199 Eletriptan 2c,3b 137 Clomipramine Hydrochloride 2b,3a 200 Emtricitabine + Tenofovir 3a 138 Clonazepam 3 201 Emtricitabine 3b 139 Clonidine Hydrochloride 3 202 Enalapril + Diuretics 2c,3c 140 Clopidogrel Bisulfate 3d 203 Enalapril Maleate 2c,3c 141 Clorazepate Dipotassium 3 204 Enfuvirtide 3b 142 3 205 Entacapone 3b 143 Cocarboxyilase + Pyridoxine + 3 206 Entecavir 3b Hydroxocobalamin 207 Eprosartan 3d 144 Codeine + 3 208 Ergocalciferol 3 145 Codeine Phosphate + Ivy 3e 209 Ergometrine Maleate 2,3 146 Colistin 3 210 Ergotamine Tartrate 3 147 Hydrochloride 2,3 211 Ertapenem 3 148 Cyclopentolate Hydrochloride 3 212 Erythromycin 1 149 + Ethinyl Estradiol 3d 213 Escitalopram 3b 150 Danazol 3e 214 Esmolol Hydrochloride 3 151 Dantrolene Sodium 3b 215 Esomeprazole 3c 152 Daptomycin 3c 216 3 153 Dasatinib 2c,3d 217 Estradiol + Progestin 3c 154 Deferoxamine Mesylate 3,4 218 Estradiol 3c 155 Defibrotide 3 219 Estriol 3 156 Deflazacort 3 220 Estrogens Conjugated + Progestin 3 157 3d 221 Ethacrynic Acid 1 158 Delapril + Indapamide 3d 222 Ethinylestradiol 3c 159 3 223 Ethosuximide 3 160 Hydrochloride 2b,3b 224 3

630 Pharmacological drugs inducing ototoxicity, vestibular symptoms and tinnitus

225 Etonogestrel + Ethinylestradiol 3c 282 Ibuprofen 2d,3d 226 Etoposide 1 283 Icodextrin + Sodium + 3b 227 Etoricoxib 2c,3c Sodium Lactate + Calcium Chloride 228 Exemestane 3b + Magnesium Chloride 229 3d 284 Idebenone 3 230 Famotidine 3b 285 Idroxine Hydrochloride 2,3 231 3c 286 Imatinib 2c,3c 232 Felodipine 3c 287 Imiglucerase 3c 233 Fenofibrate 3 288 Imipenem + Cilastatin 1 234 Fentanyl Citrate 3 289 Imipramine Hydrochloride 2,3 235 Flavoxate Hydrochloride + 3 290 Indapamide 3 291 Indinavir 3a 236 Flavoxate Hydrochloride 3d 292 Indomethacin 2,3 237 Flecainide Acetate 2b,3b 293 Indomethacin + + 2,3,4 238 Fluconazole 3b Proclorperazina 239 Flucytosine 3 294 Infliximab 3b 240 Fluocinolone Acetonide + Neomycin 1 295 Inosine Pranobex 3 241 Fluorometholone + Gentamycin 1 296 Irbesartan + Diuretics 2e,3e 242 Fluoxetine 3b 297 Irbesartan 2 243 Fluphenazine/Nortriptyline 2,3 298 Iron Sucrose Injection 3 244 Flurazepam 3 299 Isoniazid + Ethambutol + Pyridoxine 3 245 Flurbiprofen Sodium 2,3 300 Isoniazid 3 246 Flurbiprofen 2,3 301 Isosorbide Dinitrate 3 247 Flurithromycin Ethylsuccinate 3 302 3e 248 Flutamide 3d 303 Isotretinoin 4e 249 Fluvoxamine Maleate 3b 304 Hydrochloride 3 250 Fondaparinux 3d 305 Isradipine 3 251 Fosamprenavir 3b 306 Itraconazole 3c 252 Foscarnet Sodium 3 307 3 253 Fosinopril 3c 308 Ketoconazole 3 254 Fosinopril + Diuretics 3 309 Ketoprofen 2,3e 255 Frovatriptan 2c,3c 310 Tromethamine 3,4 256 Furosemide 1d,2d 311 Ketotifen 3 257 Gabapentin 2,3 312 Lacidipine 3 258 Galantamine 2,3b 313 Lamivudine 3 259 Gancyclovir 1,3b 314 Lamotrigine 3 260 Ganirelix 3 315 Lansoprazole 3 261 Gemeprost 3e 316 Leflunomide 3b 262 Gemfibrozil 3e 317 Lercanidipine Hydrochloride 3b 263 Gentamycin 1 318 Lertapenem 3c 264 Glipizide 3 319 Letrozole 3b 265 Goserelin 3 320 Leuprorelin Acetate 3 266 Griseofulvin 3d 321 Levetiracetam 3b 267 Haemophilus B (Meningococcal 3d 322 Hydrochloride 3b Protein Conjugate) Hepatitis B 323 Levodopa + Benserazide 3 Vaccine Recombinant 324 Levodopa + Carbidopa 3c 268 + 1 325 Levodopa + Carbidopa + Entacapone 3c 269 Hepatitis A Inactivated & 3d 326 3 Hepatitis B (Recombinant) Vaccine 327 Levofloxacin 3c,4e 270 Hepatitis B Vaccine (Rdna) 3d 328 Levonorgestrel 3b 271 Homatropine Bromhydrate 3 329 Levosimendan 3b 272 Human Coagulation Factor IX 3c 330 Lidocaine + Adrenaline 3 273 Human Coagulation Factor VIII 3 331 Lidocaine + Bromide 3 274 Human Cytomegalovirus 3 332 Lidocaine + Hydrocortisone 3 Immunoglobulin For Intravenous 333 Lidocaine + Nor Adrenaline 3 Administration 334 Lidocaine Hydrochloride 3 275 Hydrochlorotiazide 3 335 Hydrochloride 2e,3e 276 Hydrochlorotiazide + 3 336 Linezolid 2c,3c 277 Hydrocortisone 3 337 Lisinopril 3b 278 Hydrocortisone + Neomycin + 1 338 Lisinopril+ Diuretics 3b Cloramfenicol 339 Lisuride Maleate 3e 279 Hydroxichloroquine Sulphate 1 340 Lodoxamide 3 280 Hydroxocobalamin 3 341 Hydrochloride 1b,2b, 281 Hydroxyprogesterone Caproate 3 3b

631 G. Cianfrone, D. Pentangelo, F. Cianfrone, F. Mazzei, R. Turchetta, M.P. Orlando, G. Altissimi

342 Loperamide Hydrochloride 3e 400 Naltrexone Hydrochloride 3b 343 Lopinavir + Ritonavir 3d 401 Naproxen 2b,3d 344 Lorazepam 3b 402 Natalizumab 3b 345 Lormetazepam 3 403 Nebivolol 3b 346 Losartan Potassium 3b 404 Neomycin + Antibiotics 1 347 Losartan Potassium + Diuretics 3b 405 Neomycin + Corticosteroid 1 348 Acetyl Salicylate 1b,2b, 406 Neomycin + Dexamethasone + 1 3b + Tetryzoline 349 Hydrochloride 3 407 Neomycin + Dexamethasone + 1 350 Measles, Mumps And Rubella 1e Virus Vaccine Live Attenuated 408 Neomycin + Fluocinolone Acetonide 1 351 Meclofenamate Sodium 2,3 409 Neomycin Sulphate 1 352 Medroxyprogesterone + Estrogens 3 410 Methylsulfate 3d Conjugated 411 Netilmicin 1e 353 Medroxyprogesterone Acetate 3 412 Nicardipine Hydrochloride 2,3e 354 Mefenamic Acid 2,3 413 3d 355 Mefloquine 2,3b 414 Niclosamide 3 356 Megestrol Acetate 3 415 Nicotine Drug Facts 2,3b 357 Meloxicam 2c,3c 416 Nifedipine 3d 358 Memantine Hydrochloride 3b 417 Nifedipine + Atenolol 3 359 Meningococcal Acwy Vaccine 3 418 3c,4e 360 Meningococcal Group C 3e 419 Nimesulide Beta – Dex 3e,4e Polysaccharide Conjugate Vaccine 420 Nisoldipine 3 361 + Adrenaline 2,3 421 Nitrazepam 3 362 Mepivacaine Hydrochloride 2,3 422 Nitroglycerin 3 363 Meprobamate 3 423 Nizatidine 3 364 Metformin + Glybenclamide 3 424 3 365 Metformin Hydrochloride 3b 425 Norethisterone + Estradiol 3 366 Methadone Hydrochloride 3b 426 3 367 Methyl Dopa + Hydrochlorotiazide 3e 427 Norethisterone 3 368 Methyl Dopa 3 428 Norfloxacin 2e,3b, 369 Maleate 2e,3e 4e 370 Methylpranolol + Pilocarpine 3 429 Nortriptyline 2,3 Hydrochloride 430 Octatropine Methyl Bromide and 3d 371 Methylprednisolone 3 Diazepam 372 Methylprednisolone + Lidocaine 3 431 Ofloxacin 3e,4e 373 Metilphenidate Hydrochloride 3 432 Olanzapine 3b 374 Hydrochloride 3 433 Olmesartan Medoxomil + Diuretics 3b 375 Metoprolol + Diuretics 3e 434 Olmesartan Medoxomil 3e 376 Metoprolol Tartrate 3b 435 Olopatadine 3c 377 Metotrexate 3 436 Omalizumab 3c 378 Metronidazole 3e 437 Omega-3 Acid Ethyl Esters 3 379 Mexiletine Hydrochloride 3d 438 Omeprazole 3c 380 Mianserin Hydrochloride 2,3 439 Ondansetrone 3d 381 Midazolam 3e 440 Oral Cholera Vaccine 3d 382 Hydrochloride 3 441 Orphenadrine Hydrochloride 3 383 Miglustat 3a 442 Oseltamivir 3b,4b 384 Minocycline 1,3d 443 Otilonio Bromide 3 385 Mirtazapine 3b 444 Otilonio Bromide + Diazepam 3e 386 Misoprostol 3 445 Oxaliplatin 1c 387 Modafinil 3c 446 2e,3e, 388 Moexipril + Diuretics 2d,3d 4e 389 Moexipril Hydrochloride 2e,3e 447 Oxazepam 3 390 Montelukast 3d 448 Oxcarbazepine 3b 391 Moroctocog Alfa 3 449 Oxibutynin Hydrochloride 3 392 Morphine Hydrochloride 3 450 Oxprenolol + Diuretics 3 393 Morphine Hydrochloride + 3 451 Oxycodone Hydrochloride 3c Atropine Sulphate 452 Palonosetron 2c,3b 394 Moxifloxacin 3b,4d 453 Pamidronate 3c 395 Moxonidine 3b 454 Pantoprazole 3d 396 Muromonab - Cd3 1 455 Paracetamol + 2,3 397 3b 456 Paracetamol + Codeine Phosphate 3 398 Nabumetone 2d,3d 457 Parathyroid Hormone 3b 399 Nadolol 3e 458 Paricalcitol 3c

632 Pharmacological drugs inducing ototoxicity, vestibular symptoms and tinnitus

459 Sulphate 1e 519 Resagiline 3b 460 Paroxetine 3b 520 + Chlorthalidone 3 461 Mesylate 3 521 Reserpine + + 3 462 Pegaptanib Sodium 1c,3c 463 Pegvisomant 3b 522 Ribavirin 2b,3b 464 Pentamidine Isethionate 3 523 Rifampicin 3 465 Pentazocine 3b 524 Rifampicin + Isoniazid 3 466 Pentoxifylline 3 525 Riluzole 3c 467 Pergolide 3a 526 Risedronate 2,3 468 Perindopril 3b 527 Risperidone 3c 469 Perindopril + Diuretics 3c 528 Ritonavir 3b 470 Pethidine Hydrochloride 3 529 Rivastigmine 3a 471 Phenobarbital 3 530 Rizatriptan 3b 472 Phenytoin 3 531 Ropinirole 3b 473 Phenytoin Sodium 3e 532 Maleate 3b 474 Pilocarpine Hydrochloride 3b 533 Rosuvastatin 3b 475 Pindolol 3b 534 Hydrochloride 3e 476 Pioglitazone + Metformin 3 535 3e 477 Pioglitazone 3b 536 Hydrochloride 3b 478 3 537 Salmeterol 3 479 3 538 Salmon Calcitonin 3c 480 3 539 Morphine 3d 481 Piroxicam 2d,3d 540 Saquinavir 3 482 Pizotifen 3 541 Scopolamine Hydrobromide 3d 483 Polimyxyn B Sulphate + Neomycin 1 542 Scopolamine Methylbromide/ 3 Sulphate + Lidocaine Hydrochloride Diazepam + Hydrocortisone 543 Selegiline Hydrochloride 3b 484 Polymyxin B Sulphate + Neomycin 1 544 Sertraline 3a Sulphate + Lidocaine Hydrochloride 545 Sildenafil 3b 485 Polymyxin 1 546 Simvastatin + Ezetimibe 3d 486 Posaconazole 3c,4d 547 Simvastatin 3d 487 Pramipexole 3b 548 Sodium Neridronate 3b 488 + 3d 549 Sodium Nitroprusside 3 489 Pravastatin Sodium 3d 550 Sodium Oxybate 3b 490 3 551 Sodium Stibogluconate 3 491 Prednisolone + Neomycin 1 552 Somatostatin 3 492 Pregabalin 3a,4d 553 Sorafenib 2b 493 3 554 Sotalol Hydrochloride 3b 494 Primidone 3e 555 Hydrochloride 3 495 Progesterone 3d 556 Stavudine 3b 496 Oral Contraceptive 3 557 Streptomycin 1 497 Proguanil Hydrochloride + Atovaquone 3 558 Sucralfate 3c 498 Propafenone Hydrochloride 3e 559 Sulfadiazine 2,3 499 Propantheline Bromide 3d 560 Sulfametoxazolo + Trimethoprim 2e,3e 500 Propofol 3 561 Sulfasalazine 2d,3d 501 Propranolol Hydrochloride 3 562 Sulindac 2b,3b 502 Propyphenazone + + Caffeine 3 563 Sumatriptan 3b 503 Propyphenazone + Codeine 3d 564 Sunitinib 3b 504 Pamoate 3 565 Tacrolimus 3b,4b 505 Pyrimethamine + Sulfamethoperazine 2,3 566 Tadalafil 3 506 Quetiapine 3a 567 Tamsulosin Hydrochloride 3b 507 Quinapril + Diuretics 3b 568 Teicoplanin 1e,2e, 508 Quinapril 3b 3e 509 Quinine 2,4 569 Telithromycin 3c 510 Quinupristin + Dalfopristin 3c 570 Telmisartan + Diuretics 3b 511 Rabbit Anti-Human Thymocyte 3 571 Telmisartan 3c Immunoglobulin 572 Temazepam 3 512 Rabeprazole Sodium 3b 573 Tenofovir Disoproxil 3a 513 Ramipril 3d 574 Tenoxicam 2,3c 514 Ramipril + Diuretics 3d 575 Terazosin 3b 515 Ranitidine 3d 576 3 516 Raubasine 3d 577 Teriparatide 3b 517 Reboxetine 3b 578 Terlipressin 3 518 Remifentanil 3 579 Tetanus Vaccine 3e

633 G. Cianfrone, D. Pentangelo, F. Cianfrone, F. Mazzei, R. Turchetta, M.P. Orlando, G. Altissimi

580 Thiamine + Pyridoxine + 3 611 Trihexyphenidyl Hydrochloride 3 Hydroxocobalamin 612 Dihydrochloride 3e 581 Thiopental Sodium 3 613 Trimipramine 2b,3b 582 Thyrotropin Alfa 3b 614 Triptorelin 3 583 Tiagabine 3a 615 Tropicamide 3 584 Tiaprofenic Acid 2,3 616 Tropisetron 3 585 Tibolone 3e 617 Hydrochloride 3e 586 Ticlopidine Hydrochloride 3 618 Valacyclovir 3c 587 Tigecicline 3b 619 Valgancyclovir 3b 588 Timolol + Pilocarpine Hydrochloride 2 620 Valsartan + Diuretics 2c,3d 589 Timolol Maleate 2,3 621 Vancomycin 1d 590 Tinidazole + 3 622 Vardenafil 3b 591 Tinidazole 3 623 Varenicicline 2,3 592 Tiotropium 3c 624 Varicella Virus Vaccine Live 3e 593 Tipranavir 3c 625 Venlafaxine 2b,3b 594 Tizanidine 3 626 Verapamil Hydrochloride 3b 595 Tobramycin 1 627 Vigabatrin 3 596 Tobramycin + Dexamethasone 1 628 -P-Hydroxybenzoate 3e 597 Topiramate 3b 629 Vinblastine Sulphate 1d 598 Toremifene 3d 630 Vincristine Sulphate 1 599 Torsemide 1e,2e 631 Vindesine Sulphate 1 600 Tramadol 3a 632 Vinorelbine 1 601 Trandolapril 3 633 Voriconazole 2d,3b, 602 Trandolapril + Calcium Channel 3b 4d Blockers 634 Sodium 3d 603 Tranexamic Acid 3 635 Zaleplon 3c,4c 604 + 3 636 Zidovudine 3 605 Trapidil 3e 637 Zidovudine + Lamivudine 3d 606 Trastuzumab 3b 638 Zoledronate 3c 607 Trazodone Hydrochloride 2e,3e 639 Zolmitriptan 3b 608 Tretinoin 3a,4a 640 Zolpidem Tartrate 3,4 609 Triamcinolone 3 641 Zonisamide 3a 610 3 642 Zopiclone 3

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