Allergy 1996: 51: 66fHi75
`
`Primed in UK - all rights reserved
`
`Copvright © Munksgaard 1996
`
`
`ALLERGY
`ISSN 0105-4538
`
`Position paper
`The clinical safety of H1-receptor
`
`
`antagonists
`
`
`
`An EAACI position paper*
`
`Passalacqua G, Bousquet J, Bachert C, Church MK, Bindslev-Jensen C,
`
`
`
`
`G.Passalacqua, J. Bousquet,
`
`
`
`Nagy L, Szemere P, Davies RJ, Durham SR, Horak F, Kontou-Fili K,
`
`C.Bachert, M. K. Church,
`
`
`
`
`Malling H-J, van Cauwenberge P, Canonica GW. The clinical safety of H1-
`
`C.Bindslev-Jensen, L. Nagy,
`
`
`
`receptor antagonists. An EAACI position paper.
`
`P.Szemere, R. J. Davies,
`
`Allergy 1996: 51:
`
`
`666-675. © Munksgaard 1996.
`
`S. R. Durham, F. Horak,
`
`
`K.Kontou-Fili, H.-J. Malling, P. van
`
`Cauwanberge, G. W. Canonica
`
`Prof. G. W. Canonica
`y Service
`
`Allergy and Clinical Immunolog
`
`
`DIMI Department of Internal Medicine
`Genoa University
`
`Viale Benedetto XV, 6, 16132 Genova
`Italy
`
`
`
`Accepted for publication 25 April 1996
`
`
`
`Antihistamines, or H1-antagonists, despite their
`
`
`
`In this paper, we review the available data on
`
`
`
`
`
`
`pronounced unwanted effects, were the first effica­
`
`the safety of the newer antihistamines and their
`cious drugs to be used for the symptomatic
`relief
`
`
`
`
`risk/benefit ratios in order to provide helpful infor­
`
`
`
`
`of allergic diseases. In recent years, pharma­
`
`
`
`mation for both specialists and general practition­
`
`
`
`
`cologic research has produced a new generation of
`ers.
`
`
`antihistamines, the so-called newer or second­
`
`
`antihistamines, with high potency and
`generation
`The histaminergic system
`
`
`
`
`
`
`minimal sedative effects as compared to the older
`
`
`
`or classical antihistamines. Recently, the newer
`
`
`
`Histamine, originally identified by Henry Dale in
`
`antihistamines have become the focus of medical
`
`
`
`1910 (2), has been recognized since the 1920s as a
`
`
`
`major pathogenetic mediator of allergic disorders,
`
`
`
`
`scientific interest for two reasons. Firstly, many of
`
`
`such as hay fever, urticaria (3), and anaphylaxis.
`these drugs have been claimed to have additional
`
`
`
`The exact mechanism of action remained unknown
`
`
`
`antiallergic properties, and, secondly, there are
`
`
`several reports of possible cardiotoxic effects and
`
`
`until 1966 when the histamine was H1 receptor
`
`
`
`
`
`identified ( 4 ). This receptor is distributed widely
`
`
`
`carcinogenicity. In particular, the safety issue is of
`
`
`ce because of the widespread use
`
`central importan
`
`
`on many tissues in the body, including smooth­
`
`
`of antihistamines in current medical practice. Fur­
`
`
`
`
`
`muscle cells of the bronchial tree, the intestine, and
`
`the vasculature. The predominant features of H1 -
`
`
`
`thermore, since antihistamines are used to treat
`
`
`non-life-threatening disorders, their risk/benefit
`
`
`stimulation are bronchoconstriction, spas­
`receptor
`
`
`
`tic contraction of intestinal smooth muscle, and
`
`
`ratio must be carefully evaluated (1).
`
`
`
`vasodilation. Knowledge of the histaminergic sys­
`
`
`tem has recently been extended by the discovery
`
`(5), stimulation of which pro­
`of the H2 receptor
`Drugs: C. Bachert
`
`
`motes gastric acid secretion, and the H3 receptor
`*EAACI Subcommittee on Antiallergic
`
`C. Bindslev-Jensen
`
`
`(Germany), J. Bousquet (France), (Denmark),
`
`
`(6), which is associated primarily with the central
`
`G. W. Canonica M. K. Church (UK), R. J. Davies (UK),
`(Italy),
`
`
`
`nervous system and whose functions are not com­
`
`S. R. Durham (UK), F. Horak (Austria), K. Kontou-Fili
`(Greece),
`
`
`
`
`pletely clarified, although a selective antagonist
`L. Nagy (Hungary),
`
`G. Passalacqua (Italy),
`
`
`H.-J. Malling (Denmark),
`
`(thioperamide) is now available.
`P. van Cauwenberge
`
`P. Szemere (Hungary),
`(Belgium).
`
`666
`
`AVENTIS EXHIBIT 2144
`Mylan v. Aventis, IPR2016-00712
`
`

`
`Antihistamines: general aspects
`
`Classification
`The pharmacologic class of antihistamines includes
`a
`large number of compounds with various
`pharmacokinetic-pharmacodynamic properties. A
`classification, although difficult to make, is there-
`fore required. Various criteria have been proposed,
`including chemical structure, rapidity of onset of
`action, pharmacodynamic properties, etc. In prac-
`tical terms, the most useful classification is that
`based on both H, selectivity and the absence of
`sedation. These criteria allow us to distinguish two
`main subclasses of H,-receptor antagonists: the
`first-generation or older antihistamines and the new
`or second-generation or nonsedating antihista-
`mines. Under this system, ketotifen and oxatomide
`differ from the remaining newer antihistamines in
`that they exert serotonergic and anticholinergic
`actions. Thus, these compounds should be more
`properly defined as “intermediate” antihistamines.
`Furthermore, the recent description of additional
`“antiallergic” properties for some of the new com-
`pounds has suggested a further possible subdivision
`of new antihistamines. A large number of data on
`this topic are available and need careful global
`revision. For this reason, the evaluation of the
`antiallergic effects of the new antihistamines will
`be the subject of a separate position statement.
`
`First-generation antihistamines
`The first H,-receptor antagonists became commer-
`cially available in the 1940s (7) and were widely
`prescribed subsequently. However, this group of
`compounds, which
`includes chlorpheniramine,
`diphenhydramine, hydroxyzine, promethazine,
`pyrilamine, and triprolidine, has many troublesome
`side-effects. The most problematic effect, sedation,
`severely limits their clinical use and may result in
`suspension of therapy. The sedative effect of older
`compounds is a consequence of their lipid solubil-
`ity, which allows penetration of the blood-brain
`barrier (8). Furthermore, the older molecules,
`because of their poor receptor selectivity (9), also
`exert some blockade of muscarinic cholinergic, a-
`adrenergic, and tryptaminergic receptors, a fact
`which may partially explain the additional adverse
`effects observed in clinical practice, such as consti-
`pation, difficult urination, xerostomia, cough, nau-
`sea, and vomiting. The effects on other receptors
`may also contribute to their observed sedative
`effects. Furthermore, the older antihistamines have
`a short half-life, necessitating multiple daily dosing
`to maintain satisfactory H, blockade. The older
`antihistamines are no longer in routine use for the
`
`Safety of Hpeceptor antagonists
`
`treatment of allergic disorders, at least in Europe.
`Only hydroxyzine, because of its marked anti-
`pruritic and mildly sedative effect, is still used to
`treat chronic urticaria and atopic dermatitis. How-
`ever, the older antihistamines (particularly chlor-
`pheniramine) retain some importance as sedative
`or antipsychotic drugs and are used intravenously,
`after epinephrine, in the emergency treatment of
`anaphylaxis. Finally, the capacity of the older anti-
`histamines to counter motion sickness, probably
`because of their central antimuscarinic actions, can
`also be advantageous.
`
`Second-generation antihistamines
`The commercially available newer antihistamines
`include acrivastine, astemizole, azelastine, ceti-
`rizine, ebastine, levocabastine, loratadine, keto-
`tifen, oxatomide, and
`terfenadine. For
`these
`molecules, a large number of clinical trials and
`experimental data are available in the literature. In
`addition, some other new molecules, including
`emedastine, epinastine, mizolastine, noberastine,
`and setastine, are currently undergoing clinical
`trials (10).
`The newer antihistamines have higher affinity for
`H, receptors than the older ones and almost neg-
`ligible affinity for other amine receptors. In addi-
`tion, these molecules are relatively large, have long
`side-chains, and are poorly soluble in lipid. There-
`fore, the blood-brain barrier penetration, the sed-
`ative effects, and the additive effects with alcohol
`are also reduced. Another possible reason for the
`limited sedative effects of the newer antihistamines
`is their selectivity for the peripheral, rather than
`the central, H, receptors, although the existence of
`differences between these receptors is still a matter
`of debate (11, 12).
`The effects of the binding of the new antihista-
`mines to the H, receptor are not readily reversible
`by simple washout of the antagonist. The half-lives
`of the new antihistamines are quite variable, ranging
`from 2 h for acrivastine to 9.5 days for demethyl-
`astemizole, the active metabolite of astemizole
`(13, 14). Furthermore, the pharmacodynamics of
`H, blockade is not directly predictable from a
`knowledge of the metabolic half-life of a drug. In
`fact, the tissue distribution, the generation of active
`metabolites, and the poor reversibility of receptor
`binding, prolong their clinical effects, e.g., inhibi-
`tion of the wheal and flare reaction in the skin,
`independently of their serum concentrations.
`For example, terfenadine (60-1 20 mg) rapidly
`suppresses the wheal and flare reaction (15), an
`effect which persists for at least 24 h (16). A single
`dose of astemizole is not completely effective in
`suppressing the wheal and flare reaction (17, 18),
`
`667
`
`

`
`Passalacqua et a].
`
`while a long period of treatment results in potent
`and long-lasting inhibition of the cutaneous reac-
`tion (14, 19). For this reason, astemizole is indi-
`cated for long-term treatments, but not for prompt
`relief of symptoms. The suppression of the wheal
`and flare response by a single dose of loratadine
`(10 mg) is demonstrable within 1 h (20) and lasts
`12-24 h (12,20,21). Administered as a single dose,
`cetirizine (10 mg) causes prompt suppression
`(within 1 h) of the wheal and flare response, lasting
`up to 24 h (22,23). The wheal and flare suppression
`after azelastine administration is dose dependent,
`peaking at about 4 h and lasting up to 1 week after
`a short course of treatment (24). With levocabas-
`tine, which has been developed for topical admin-
`istration only, peak plasma levels are attained 2 h
`after nasal administration, and steady state is
`reached in 7-10 days (25).
`Almost all these compounds are largely meta-
`bolized by the liver (12), some of them producing
`active metabolites. Examples include a carboxylic
`acid derivative
`from
`terfenadine, demethyl-
`astemizole from astemizole, carboethoxy-lorata-
`dine from loratadine, and demethyl-azelastine from
`azelastine. An exception to this is cetirizine, which
`is poorly metabolized and largely excreted unmodi-
`fied in the urine (26). Whereas loratadine is meta-
`bolized in the liver and excreted in feces, the
`metabolite of loratadine is excreted in the urine.
`This leads to an equivalent renal and hepatic
`clearance of this drug (27).
`
`Sedative effects of antihistamines
`The pharmacokinetic properties of the second-
`generation antihistamines, including poor lipid sol-
`ubility, selectivity for H, receptors, and negligible
`crossing of
`the blood-brain barrier, partially
`explain their reduced sedative effects (28). The
`term “sedation” describes a wide range of subjec-
`tive experiences and can mean drowsiness, increas-
`ing likelihood of falling asleep, loss of alertness,
`decreased concentration, and, in more medical
`terms, global reduction of psychomotor perform-
`ance. In this regard, the histaminergic system has
`
`been clearly demonstrated to affect alertness, vigi-
`lance, and slow-wave activity on the electro-
`encephalogram (EEG) during sleep (29).
`The problem of sedation is of great importance
`for the safety of workers and drivers (30) and for
`the school performance of children. Thus, the
`widespread use of these drugs requires rigorous
`scientific assessment and measurement of any unto-
`ward sedative effects. This can be done by both
`clinical and instrumental tests (31, 32), the most
`common of which are driving tests (both actual and
`simulated), psychomotor tests, the Stanford auto-
`evaluation scale for sleepiness, the EEG, and
`acoustic evoked potentials (Table 1). Driving tests,
`because of their simple execution and the possibii-
`ity of using driving simulators, are particularly
`suitable for the global evaluation of psychomotor
`performance (33); therefore, they have been widely
`used in the reported studies. Each of the several
`psychomotor tests investigates predominantly one
`particular aspect of performance such as coordina-
`tion, reaction time, memory, alertness, etc. A rigor-
`ous, double-blind study of the potential sedative
`effects of antihistamines should be conducted in
`healthy volunteers, possibly with comparison with
`a sedative antihistamine or evaluation of possible
`additive effects with alcohol. A remarkable
`number of well-conducted trials on healthy volun-
`teers have demonstrated reduced sedative effects
`of the newer antihistamines compared with first-
`generation drugs.
`the
`Dhorranintra et al. (34) demonstrated
`absence of sedation with astemizole using driving
`tests, while similar results were obtained by Hind-
`march & Bhatti (35) in comparing astemizole and
`chlorpheniramine with and without alcohol. Bate-
`man et al. (36) confirmed the lack of effect of
`astemizole on ethanol metabolism. In 85 subjects,
`Moser et al. (37) demonstrated that astemizole (30
`mg) did not impair responses in psychomotor and
`subjective assessment tests, while significant seda-
`tion was obtained with ketotifen (1 mg). Moreover,
`astemizole, 30 mg q.i.d. for 7 days, did not affect
`the oculovestibular reflex in 20 subjects evaluated
`in a double-blind study (38).
`
`Table 1 Tests evaluating sedation
`
`Driving tests
`
`Psychomotor
`
`Sublective
`
`Instrumental
`
`Actual driving or driving simulator weaving,
`steering, gate acceptance, brake reaction time
`
`Memory. mental arithmetic. auditory vigilance
`Glass-bead picking
`
`Stanford scale for sleepiness
`Visual analog scale
`
`Flying simulator
`
`668
`
`Critical tracking
`Card sorting
`Digit-symbol substitution
`
`Continuous EEG
`P300 latency
`Multiple latency
`Flicker fusion
`Vestibular-ocular reflex
`
`

`
`Terfenadine has been reported to have signifi-
`cant sedative effects only at 240 mg, while at a dose
`of 120 mg it did not affect driving or psychomotor
`performance (39). In a study in 20 volunteers (40),
`terfenadine (120mg for 3 days) did not affect
`psychomotor tests or reaction time. Similar results
`were obtained with different psychomotor tests
`after giving single doses of terfenadine of 60mg
`(41) and 120mg (42). Goetz et al. (43) demon-
`strated the absence of sedation with terfenadine,
`60 mg b.i.d., in a subchronic treatment study. The
`absence of sedation in healthy volunteers was also
`demonstrated for terfenadine by the evaluation of
`evoked acoustic potentials (44) and in a multiple
`sleep latency test (45). Finally, terfenadine, 120 mg
`q.d. for 7 days, did not affect EEG parameters (46).
`Loratadine, given in single doses of 10 and 20 mg
`(47) and in multiple doses (48), did not show any
`significant sedative effects when evaluated by driv-
`ing tests or psychomotor tests (49). Loratadine in
`a single 20-mg dose neither modified psychomotor
`performance nor caused a subjective sedation (50).
`Furthermore, loratadine impaired the visual-motor
`performances of healthy subjects (51) at a dose of
`40, but not 20 or 10, mg q.d., while a single 10-mg
`dose did not affect flying simulator performance in
`40 healthy subjects (52). Finally, a single 10-nig
`dose of loratadine did not affect driving perform-
`ance and the EEG recorded during driving (53).
`As for cetirizine, in two placebo-controlled
`studies, Gengo et al. demonstrated that 5, 10, and
`20 mg did not impair psychomotor and driving
`performance as compared to 25 mg hydroxyzine
`(54) or diphenhydramine 50mg (55). A study
`performed on 60 healthy volunteers (56) with
`psychomotor and driving tests showed the absence
`of sedative effect of cetirizine in doses of 5,10, and
`20 mg. In a study evaluating driving performances,
`memory, and sleep latency in 27 healthy volunteers,
`cetirizine 10 mg q.d. or terfenadine 120 mg q.d. for
`4 days did not affect the test results (57). Triprolidine
`was used as positive control. Moreover, no differ-
`ence was found between cetirizine and placebo with
`a visual analog scale either in a subchronic study
`(58) or with a single dose of 10 mg (59). The safety
`of a single 10-mg dose of cetirizine was confirmed
`in a further study investigating P300 latency (60).
`On the other hand, in a clinical study of cetirizine
`efficacy (61) in allergic rhinitis, a significant incidence
`of mild to moderate sedation was reported with 10-
`and 20-mg doses. Finally, in a study by Ramaekers
`et al. (53), a single 10-mg dose of cetirizine
`appeared to affect significantly actual driving per-
`formance, even though the authors themselves did
`not consider the effect to be of clinical relevance.
`Topical administration of levocabastine to the
`eye or nose did not cause significant sedation in
`
`Safety of H,-receptor antagonists
`
`either subchronic (62) or single-dose (63) studies.
`Similar results were found with topical azelastine
`(64). Oral acrivastine at single doses of 4, 8, and
`16 mg did not affect psychomotor tests (65) when
`compared with a positive control (triprolidine).
`Single doses of 10 and 50 mg of ebastine did not
`affect psychomotor performance, but the 50-mg
`dose caused a significant subjective sedation (66).
`Finally, ebastine, administered orally at 10, 20. or
`30 mg for 5 days, did not impair driving perform-
`ance in contrast to triprolidine 10 mg (67).
`
`Arrhythmogenic effect
`Recently, there have been several reports that
`therapy with some of the newer antihistamines may
`be associated with cardiotoxicity, particularly pro-
`longation of the Q-T interval and precipitation of
`the potentially life-threatening condition of torsade
`de pointes. While the histaminergic system may
`exert a small, but significant. effect on cardiac
`electric activity (68), it is unlikely that blockade of
`this by antihistamines is responsible for
`the
`reported cardiotoxicity, as the effect is unrelated to
`H,-receptor blocking activity. Rather, the effect
`appears to be related to the particular chemical
`structure of some drugs. To appreciate this, one
`must realize that the antihistamines have evolved
`from the same basic chemical structure as local
`anesthetics, antipsychotics, P-adrenoceptor block-
`ers, and some calcium-channel blockers. Several
`members of this group - for example, haloperidol
`have the capacity to reduce the
`and sotalol
`-
`magnitude of outward repolarizing K' currents,
`enhance inward depolarizing Na' or Ca2+ currents,
`or both, thereby triggering the development of
`early depolarizations that
`initiate the cardiac
`abnormalities. Thus, it is hardly surprising that
`some of the more complex antihistamine molecules
`also have the potential to exert such effects.
`In 1968, Lauria et al. (69) investigated the pos-
`sible effects of hydroxyzine on the cardio-vascular
`system of elderly subjects, following a previous
`experimental study showing a hypotensive effect
`(70), but found no significant effect. In 1975,
`Hollister (71) reported electrocardiographic alter-
`ations, particularly T-wave lowering and flattening
`together with prolongation of the Q-T interval
`(although without correction for rate), in patients
`treated with hydroxyzine. It is of note that this
`study was performed in elderly people receiving
`huge doses of the drug, 300mg daily for 9 days.
`Further reports (Table 2) on the cardiac adverse
`effects of antihistamines appeared sporadically (72-
`7.9, and the problem remained of limited interest in
`subsequent years, until new reports appeared on the
`arrhythmogenic effects of the newer antihistamines.
`
`669
`
`

`
`Passalacqua et al.
`
`Table 2 Reported cardiac adverse effects of older antihistamines
`
`Drug
`
`Hydroxyzine
`Hydroxyzine
`Pheniramine
`
`Hydroxyzine
`Cryproheptadine
`Pyrilamine
`
`Patient no.
`
`Event
`
`Note
`
`Author(s)
`
`Reference
`
`9
`27
`1
`
`1
`1
`1
`
`None (sedation)
`ECG abnormality
`Ventricular arrhythmia.
`torsade de pointes
`Tachycardia
`Torsade de pointes. death
`Cardiogenic shock
`
`50-57 mg
`300 mg
`Oral dose unknown,
`plasma 10 pg/ml
`25 mg
`32 mg
`> I 0 g
`
`Lauria et al
`Hollister
`Bobik & McLean
`
`Magera et al
`BOUJU et al
`Freedberg et al
`
`69
`71
`72
`
`73
`74
`75
`
`In 1986, Craft (76) reported a case of prolonged
`Q-T interval and torsade de pointes in a patient
`after an overdose of astemizole (200 mg). In 1988,
`two further reports (77, 78) of ventricular tachy-
`arrhythmia, one with a normal dose and another with
`a high dose of astemizole, appeared, and, in 1989,
`Bishop & Gaudry (79) described a prolonged Q-T
`interval after astemizole overdose. During the
`same period, several reports of ventricular arrhyth-
`mia appeared also for terfenadine. Davies et al.
`(80) and McConnel & Stanner (81) reported ven-
`tricular dysrhythmia after overdose of terfenadine,
`while Monahan et al. described an episode of
`torsade de pointes with a recommended therapeu-
`tic dose of terfenadine in association with keto-
`conazole and cefaclor (82). Tobin et al. (83)
`reported prolonged Q-T interval in a case of
`accidental poisoning with astemizole (100 mg), and
`Hoppu et al. (84) reported prolonged Q-T interval
`and torsade de pointes in six children who had
`consumed high doses of astemizole, about 12-fold
`higher than those recommended. Clark & Love
`(85) also reported a case of Mobitz-type 2 heart
`block with torsade de pointes after astemizole
`overdose (250 mg). In two further case reports, Q-
`T prolongation and
`torsade de pointes were
`described with astemizole, but one of the patients
`presented Romano-Ward syndrome, a congenital
`prolonged Q-T interval (86), and the other had a
`previous prolonged Q-T interval and mitral pro-
`lapse (87). In a patient with liver cirrhosis, the
`administration of 240 mg of terfenadine caused
`prolongation of the Q-T interval and ventricular
`ectopic beats (88). Saviuc et al. (89) reported a case
`of prolonged Q-T interval and torsade de pointes
`after astemizole poisoning (200 mg) together with
`hydroxyzine and ethanol consumption. Similar
`arrhythmogenic effects, namely, prolonged Q-T
`interval, ventricular bigeminism, and A-V block,
`were described in five children after relatively high
`doses of astemizole (90). Finally, Good et al. (91)
`recently reported a case of ventricular tachycardia
`with prolonged Q-T interval after loratadine in a
`patient suffering from ischemic coronary disease
`and coadministration of quinidine.
`
`670
`
`As summarized in Table 3, in almost all of the
`cases reported in the literature, an overdose of the
`drug was present; i.e., consumption exceeded that
`recommended by the manufacturer. However, in
`several cases, impaired liver function or the con-
`current use of drugs which interfered with the
`activity of the liver enzyme cytochrome P450 was
`associated with cardiotoxicity (92). As almost all of
`the newer antihistamines undergo hepatic mefa-
`bolism via the cytochrome P450 system, compro-
`mised liver function may result in accumulation of
`the parent drug, which, if it has quinidine-like
`effects, may result in unwanted cardiac effects. The
`impairment by erythromycin and ketoconazole of
`the metabolism of terfenadine with subsequent
`drug accumulation and adverse effects on cardiac
`depolarization has been confirmed by Honig (93)
`and Eller (94). Two cases of possible interaction
`between itraconazole and terfenadine, with subse-
`quent torsade de pointes (95) and ventricular fibril-
`lation (96), have also been reported. These findings
`have been confirmed by Zimmermann et al. (97)
`and Moore et al. (98). Furthermore, van Peer et al.
`(99) demonstrated that ketoconazole also inhibits
`loratadine metabolism. It is of note that the possi-
`ble interference by the macrolides on drug meta-
`bolism has been recognized since the work of
`Pessayre in 1983 (100). Using a guinea pig model
`to study the effects of antihistamines on cardiac
`rhythm, Hey et al. demonstrated that intravenous
`terfenadine, astemizole, and ebastine induced sig-
`nificant arrhythmogenic effects which were
`enhanced by ketoconazole, while cetirizine, care-
`bastine, and norastemizole appeared to be devoid
`of cardiac effects (101,102). Cetirizine and acrivas-
`tine are excreted with no metabolism and, together
`with loratadine which is about 40% excreted in the
`urine (26, 27), therefore appear to be the least
`likely to be arrhythmogenic.
`On the other hand, several studies have demon-
`strated the safety of the antihistamines mentioned
`in healthy subjects in the absence of macrolide
`antibiotic or ketoconazole therapy. Warin (103)
`reported no ECG abnormalities in 12 subjects
`consuming 120-360 mg terfenadine, while Offenloch
`
`

`
`Safety of H,-receptor antagonists
`
`Table 3 Reported cardiac adverse effect of new antihistamines
`
`Drug
`
`Astemizole
`Astemizole
`Astemizole
`Astemizole
`Terfenadine
`Terfenadine
`Terfenadine
`Astemizole
`Astemizole
`Astemizole
`Terfenadine
`Terfenadine
`Terfenadine
`Terfenadine
`Astemizole
`Astemizole
`Terfenadine
`Astemizole
`Astemizole
`Loratadine
`
`Patient
`no
`
`~
`
`1
`1
`1
`1
`4
`1
`1
`1
`6
`1
`8
`1
`5
`1
`1
`1
`1
`1
`5
`1
`
`Event
`
`Note
`
`Author(s1
`
`Reference
`
`TDP
`TOP
`TOP
`prol. 0-T
`prol. Q-T
`TDP
`TDP, cardiac arrest
`pro1 0-T
`TDP, bradycardia
`prol. Q-T, TDP
`pro1 0-T, TDP
`TDP
`TDP, syncope
`TDP
`TOP. pro1 0-T
`TDP
`TDP. syncope
`TDP, pro1 0-T
`A-V block, bradycardia
`Tachycardia, pro1 0-T
`
`200 mg"
`20 mg
`10 mg
`250 mg"
`Plus ibuprophen
`Plus ketozonazole
`360 mgiday"
`100 mg"
`20-200 mg"
`250 mg"
`Plus erythromycin
`Plus ketoconazole
`Plus ketoconazole/josamicin
`120 mg plus itraconazole
`Congenital prol. 0-T
`Previous prol. Q-T
`Plus itraconazole
`200 mg"
`2-1 2 mg/kg
`Plus quinidine
`
`Craft
`Snook et al
`Simons et al
`Bishop & Gaudry
`Davies et al
`Moiiahan et al
`McConnel & Stanner
`Tobin et al
`Hoppu et al
`Clark & Love
`Honig et al
`Ztmmermann et al
`Moore et a1
`Pohjola-Sintonen et al
`Broadhurst & Nathan
`Sakemi & van Natta
`Crane & Smith
`Saviuc et al
`Wiley et al
`Good et a1
`
`76
`71
`78
`79
`80
`82
`81
`83
`84
`85
`93
`9:
`98
`95
`86
`87
`96
`89
`90
`91
`
`TDP=torsade de points, "pro1 =prolonged, *overdose
`
`& Kahner (104) demonstrated the safety of terfena-
`dine in a study involving 10 volunteers. In two
`recent studies conducted in healthy volunteers,
`loratadine (40 mg q.i.d.) (109, cetirizine (20-60 mg
`q.i.d.) (106), and acrivastine (107) have been shown
`not to affect the Q-Tc. Finally, to date, there are
`no case reports of adverse cardiac effects by
`acrivastine, azelastine, cetirizine, or ketotifen.
`Apart from the specific contraindications cited,
`the incidence of cardiotoxic adverse effects appears
`to be negligible in view of the widespread use of
`antihistamines (108). Furthermore, it should be re-
`emphasized that cardiotoxicity is almost invariably
`associated with high circulating levels of the parent
`form of a small number of antihistamines (often
`prodrugs) that are metabolized by the liver to
`agents with potent HI-blocking activity but which
`do not exert cardiac effects.
`
`Carcinogenicity
`A recent experimental study on mice by Brandes
`et al. (109) proposed a possible carcinogenic effect
`of some antihistamines. It is of note that the same
`authors previously reported similar results with
`the antidepressant drugs fluoxetine and amitriptyl-
`ine (110). Briefly, a population of mice with
`induced melanoma or fibrosarcoma were given
`intraperitoneal doses of astemizole, loratadine,
`hydroxyzine, doxylamine, or cetirizine in doses
`comparable to those given in clinical practice. After
`21 days, the wet weights of the tumors were
`
`assessed and compared to those of control groups.
`An increase of the tumor growth was greatest for
`astemizole and loratadine, followed by hydrox-
`yzine, while doxylamine and cetirizine were com-
`parable to placebo. However, the results obtained
`in rodents are not immediately transferable to man,
`because of both the different experimental condi-
`tions used and the differences in cellular metabolic
`systems (111). Finally, the results obtained by
`Brandes et al. were not reproduced in subsequent
`studies (112). These results, although interesting
`from a speculative viewpoint, are not consistent
`with clinical experience, as no report of carcino-
`genicity has been published during more than 50
`years of clinical trials and clinical use of anti-
`histamines. Furthermore, no link between anti-
`histamine treatment and carcinogenicity has ever
`been suspected. Indeed, surveying these results, the
`US Food and Drug Administration (FDA) con-
`cluded that the codbenefit ratio and the clinical
`use of antihistamines should not be modified (113).
`
`Conclusions
`With respect to efficacy and nonsedation, the
`newer antihistamines show a very favorable risk/
`benefit ratio. Their efficacy in the treatment of
`perennial and seasonal allergic rhinoconjunctivitis
`and of urticaria has been clearly demonstrated in
`the literature and is supported by long clinical
`experience (27, 114-116). Thus, these clinical con-
`ditions represent the ideal indications for the use
`
`67 1
`
`

`
`Passalacqua et al.
`
`~I
`
`of the newer antihistamines. The best-known and
`most troublesome side-effect, sedation, appears to
`be largely avoidable with the second-generation
`antihistamines, as reviewed by Hindmarch (117)
`and O’Hanlon & Ramaekers (lla), when pre-
`scribed at the recommended doses. Thus, long-term
`treatment is both safe and recommended.
`The possible, but extremely rare, cardiotoxic
`effects appear to be related, in most cases, to an
`overdose or reduced hepatic metabolism of certain
`drugs, with abnormal accumulation and consequent
`effect on cardiac repolarization. The arrhyth-
`mogenic effects can be avoided if simple but impor-
`tant rules are followed (119):
`Do not exceed the dose prescribed by the man-
`ufacturer: an increased plasma concentration
`does not necessarily improve the clinical efficacy,
`but does increase the risk of drug accumulation.
`Avoid the concurrent administration of drugs
`which are known to interfere with the hepatic
`metabolism of antihistamines; e.g., azolic anti-
`fungal drugs such as ketoconazole or macrolide
`antibiotics such as erythromycin.
`Particular care must be taken when administer-
`ing antihistamines to subjects with significant
`impairment of liver function or to subjects with
`significant risk of cardiac rhythm disturbance,
`particularly prolonged Q-T interval or A-V
`block.
`In patients at risk of cardiac rhythm disturbance,
`choose antihistamines which do not have quini-
`dine-like actions and which are not metabolized
`via the cytochrome P450 pathway.
`In conclusion, the newer antihistamines appear
`to be useful and relatively safe drugs, but require,
`like all drugs, careful case-by-case evaluation in
`order to recognize the possible contraindications.
`
`2.
`
`3.
`
`References
`1.
`Simons FER. A new classification of H,-receptor antag-
`onists. Allergy 1995;50 Suppl 24:7-11.
`Dale HH, Laidlaw PP. The physiological action of beta-
`imidazolylethilamine. J Ph ysiol 19 10;41:3 18-44.
`Lewis T. The blood vessels of the human skin and their
`response. London: Shaw & Sons, 1927.
`4.
`Ash ASF, Schild HO. Receptors mediating some actions
`of histamine. Br J Pharmacol 1966;27:427-39.
`Black W, Dunian WAM, Durant CJ, Ganellin CR, Parsons
`EM. Definition and antagonism of histamine H2 recep-
`tors. Nature 1972;236:385-90.
`Arrang JM, Garbarg M, Lancelot JC, Lecomte JM,
`Schwartz JC. Highly potent and selective ligands for
`histamine H, receptors. Nature 1987;327:117-23.
`Staub AM, Bovet D. Action de la thymoxyethil-diethyl-
`amine et des Ctheres phenoliques sur le choc anaphylac-
`tique du cobaye. CR SOC Biol 1937;125:818.
`Goldberg MJ, Spector R, Chiang CK. Transport of
`diphenhydramine in the central nervous system. J Phar-
`macol Exp Ther 1987;240:717-22.
`672
`
`5.
`
`6.
`
`7.
`
`8.
`
`10.
`
`11.
`
`12.
`
`13.
`
`14.
`
`15.
`
`16.
`
`9. Janssens MML, Howarth P. The antihistamines of the
`’nineties. Clin Rev Allergy 1993;11:111-53.
`Timmermann H. Factors involved in the incidence of
`central nervous system effects of HI blockers. In: Church
`MK, Rhioux JP, editors. Therapeutic index of antihista-
`mines. Lewiston, NY. Hogrefe & Huber, 199219-31.
`Ahn HS, Barnett A. Selective displacement of 3H
`mepyramine from peripheral vs central nervous system
`receptors by loratadine, a non-sedating antihistamine. Eur
`J Pharmacol 1986;127:153-5.
`Ruat M, Bouthenet ML, Schwartz JC, Ganellin CR.
`Histamine H, receptor in health: unique electrophoretic
`mobility and auto