Is
`
`My ANTIHISTAMINE
`
`SAFE?
`
`by Laurel Ashworth, PharmD
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`(FDA) has
`The Food and Drug Administration
`announced its intention to withdraw the approval of ter­
`fenadine (Seldane), terfenadine,with pseudoephedrine
`(Seldane D), and generic versiotls of terfenadine.' Before
`granting approval for the marketing of fexofenadine
`(Allegra), terfenadine's active metabolite, the FDA deter­
`mined terfenadine's benefits outweigh its risks, despite its
`known potential for serious cardiac effects.
`
`Although its therapeutic benefits are equivalent to those
`of terfenadine, fexofenadine appears to be free of the poten­
`tial for adverse cardiac effects. 2 Patients who take terfena­
`dine or h-ave taken it in the past have heard or read about
`the FDA's intent to withdraw terfenadine from/the market
`and are understandably concerned.
`
`To varying degrees, antihistamines possess sedative, anti­
`histaminic, anticholinergic, and/or antiemetic effects:'
`Diphenhydramine (Benadryl), for example, has pronounced
`sedative and moderate antihistaminic effects. Thus it is
`commonly used as a sleeping aid or as treatment for allergic
`and nonallergic pruritic symptoms. Brompheniramine
`(Dimetane) and chlorpheniramine (Chlor-Trimetin) have
`strong antihistaminic activity, minimal sedation, and can
`provide temporary relief of runny nose and sneezing as a
`result of the common cold. Proniethazine (Phenergan)
`has potent antiemetic properties. For all their benefits, con­
`ven\ional antihistamines have one overwhelming drawback:
`many patients cannot take them and function normally in
`the work-a-day world because antihistamines make them
`too sleepy.
`
`In 1985, terfenadine was introduced to the American mar­
`ket to relieve the symptoms of allergic rhinitis without
`causing drowsiness. Astemizole (Hismanal) followed in
`1988, loratadine (Claritin) in 1993, and fexofenadine in
`July 1996. The indications for these four products appear
`in Table 1. Despite the fact their cost is many-fold higher
`than older antihistamines, these new agents enjoy
`Widespread use. They are relatively long-acting and effec­
`tive, have minimal unpleasant (anticholinergic) effects,
`and cause little or no sedation: In the common vernacular,
`
`Table I
`Comparison of FDA-approved Indications
`for Nonsedating Antihistamines8
`
`,9.,1,'2
`
`INDICATION
`Seasonal allergic
`Idiopathic chronic
`rhinitis
`urticaria '
`X
`X
`X
`X­
`X
`
`X
`
`Astemizole
`Fexofenadine
`Loratadine
`Terfenadine
`
`JUNE 1997, VOL. 2 NO.3
`
`HOME CARE PROVIDER 117
`
`Petitioner Torrent Pharmaceuticals Limited - Exhibit 1018 - Page 1
`
`

`
`Table 2
`Dosing Guidelines for Nonsedating Antihistamines8
`
`,9,11,11
`
`WHEN PAT1ENTS ASK
`
`._-,_._"_._-,----_.~.__.,_._---­
`Parameter
`Normal dose:
`people 212 years
`
`Fexofenadine
`-_._,.-.-"-,_._---_._,._--_._~,_._ •. _.
`60 mg BID
`
`- - -­
`
`Loratadine
`-- ­ --­ --­
`- ­ - -­
`10 mg once daily
`
`-
`
`- -
`
`-
`
`Terfenadine
`60 mg BID
`
`Astemizole
`-,-,._---~--------,-_._--,--,_.__.
`10 mg once daily
`22 ho~rs after meals
`with no additional
`
`_____________________i2.2.cl.~_!_h2.u..r
`Dosage change
`Avoid drug
`_in..l1.e..E.a,1:i<:._cJy_.~.flJ..~~~~n___
`.
`Use only with caution
`Dosage change
`in renal dysfunction
`
`_
`
`_
`
`_ .__._._---------.-._-­
`60 mg once daily
`
`10 mg every other day
`._._---_.__._._- ~._-.-_---_.- -_. --_ .
`10 mg every other
`day if GFR < 30 mLlmin
`
`Contraindicated
`
`.-._-.---- -­ ---_.-. ._--.--­
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`they are known as the "nonsedating" antihistamines. During
`1996, 12,834,000 prescriptions were fil1ed for loratadine,
`ranking it number 16 in the top 200 m«st commonly
`dispensed drugs in America. s Seldane ranked number 86
`with 4,938,000 prescriptions filled in 1996 5
`
`TERFENADINE TROUBLES
`:Several years after terfenadine was marketed, case reports
`of serious cardiac arrhythmias (torsades de pointes) a~d
`deaths associated with terfenadine use began to appear in
`the medical literature 6,' In time, it became clear that car­
`diotoxicity was promoted by elevated terfenadine levels.
`The concomitant use of terfenadine with certain macrolide
`antibiotics and imidazole antifungals delayed the bio­
`transfonnation of terfenadine to its active metabolite, allow­
`ing toxic levels of the parent drug to accumulate, The
`ingestion of large quantities of terfenadine in excess of the
`dosage prescribed and/or the presence of significant hep­
`atic impairment likewise contributed to terfenadine-asso­
`ciated cardiotoxkity.' The dosage guidelines recommended
`by the manufacturers appear in Table 2.
`
`Subsequent to these case reports, the FDA required the
`manufacturer to issue a "Dear Doctor Letter" in August
`1990. In July 1992, terfenadine manufacturers were required
`to add a "black-box warning" to their package insert: The
`new product labeling alerted users to a possible interaction
`. if terfenadine were taken simultaneously with erythromycin,
`tr~leandomycin, ketoconazole, or itraconazole. The warn­
`ing since has been expanded to include c1arithromycin, a
`newer imtibiotic of the erythromycin (macrolide) family.'
`Similar serious cardiovascular adverse events have occurred
`with the concomitant administration of a~temizole and
`ketoconazole tablets, itraconazole, erythromycin, or qui­
`nine. Today, the black-box warning in the astemizole
`package insert bears a striking resemblance to the terfena­
`dine insert,.'
`
`Although patient counseling and prominent warnings have
`reduced the incidence of terfenadine-induced cardiotoxicity
`
`secondary to drug-drug interactions, the FDA believes the
`incidence of these interactions is still unacceptably high
`and therefore is taking steps to remove terfenadine-contain­
`ing products from the market. The parent compounds,
`not the metabolites, for both terfenadine and astemizole
`are cardiotoxic,.',o Thus far, loratadine and fexofenadine
`have not bee!13ssociated with adverse cardiac events.",12
`
`,
`
`'
`To compr;ehend why one member of a closely related ther­
`apeutic dass (the nonsedating antihistamines) can provoke
`cardiotoxicity while another does not, users need to under­
`stand the enzymes that metabolize these drugs. The term
`cytochrome P450 refers to a group of enzymes located on
`the endoplasmic reticulum. Although present in all tissues,
`the highest concentrations are Found in the liver and smal1
`intestine, with much smaller quantities in the kidneys,
`lungs, and brain."14 The primary biologic functions of these
`enzymes appear to be twofold: metabolism of endogenous
`compounds and detoxification of exogenous compounds. IS
`
`Cyp CONCERNS
`In the literature, the abbreviation CYP is used to denote
`cytochrome P450, As of 1993, 12 families common to al1
`mammals have been identified. In humans, enzymes of
`the CYP1, CYP2, and CYP3 families are responsible for
`most drug metabolism and account for at least 70% of the
`total CYP content in human liver samples." The CYP iso­
`forms are very specific with regard to their substrates,
`inhibitors, or inducers. For example, isoform CYPtA2
`metabolizes theophylline; CYP2D6 is important in the bio­
`transfonmation of antidepressants and antipsychotics;
`CYP2C9 metabolizes phenytoin and the nonsteroidal anti­
`inflammatory drugs. 10
`
`Terfemidine undergoes oxidation by CYP3A4 to desalkyl
`and hydroxy metabolites. The hydroxy metabolite, in turn,
`is converted to a carboxylic acid derivative (fexofenadine),
`whose plasma concentration~ exceed those of the parent·'
`compound by;::: 1oO-fold. 16 In the absence of liver disease
`or drug interactions, terfenadine is barely detectable in
`
`118 HOME CARE PROVIDER
`
`JUNE 1997, VOL 2 NO.3
`
`Petitioner Torrent Pharmaceuticals Limited - Exhibit 1018 - Page 2
`
`

`
`WHEN PATIENTS ASK
`
`Table 3
`Pharmacokinetic Parameters of Nonsedating Antihistamines3
`,B,9,11,12
`
`Parameter
`Onset of activity
`
`Half-life
`
`Astemizole
`*
`20 to 60 hours
`
`Fexofenadine
`I hour
`~ 14 hours
`
`Loratadine
`I hour
`B hours-parent
`28 hours-metabolite
`
`Terfenadine
`2 to 4 hours
`16 to 23 hours
`
`Protein binding
`
`97%
`
`60 to 70%
`
`97 to 99%
`
`------)'--=-~*:*_----­
`97%
`
`* Without a loading dose, t ll2 may be up to I week, Biphasic elimination: 20 hours for distribution phase; 7 to II days for elimination phase
`** Hydroxylated metabolites, primarily desmethylastemizole
`*** Descarboethoxyloratadine is active and has a t ll2 of 17 to 24 hours
`**** The active metabolite is fexofenadine
`
`plasma except when concomitant
`medications inhibit its metabolism,17,1B
`Fexofenadine, rather than terfenadine,
`is responsible for the antihistaminic
`activity and apparently has no effect
`on the heart, On the other hand,
`terfenadine has no antihistaminic activ­
`ity but inhibits potassium slow chan­
`nels in cardiac tissue in a concentration­
`dependent fashion_ This inhibition
`can prolong the QTc interval of the
`electrocardiogram and increases the
`risk of potentially fatal arrhythmias.'9
`21 The situation is similar for astemi­
`zole in that substantial first-pass
`metabolism occurs and active metaqo­
`lites are formed, 10 Table 3 summari~es
`selected pharmacokinetic 'parameters
`of the nonsedating antihistamines.
`
`AN IMPROVED
`
`
`inhibit the metabolism of loratadine
`and its metabolite descarboethoxy­
`loratadine (DCl). Fortunately
`these interactions appear to be of
`little clinical significance because
`neither electrocardiographic
`abnormalities nor other adverse car­
`diac events have been observed as
`a result of elevated plasma concen­
`trations of DCL. 2 loratadine's
`apparent lack of cardiotoxic effects
`.may be attributable in part to the
`fact that it does not block the potas­
`sium channel involved in repolar­
`ization of cardiac cel1s, Prolonged
`QTc interval has not been detect­
`ed clinically with fexofenadine. 2
`
`•
`
`,
`
`Terfenadine, astemizole, and lorata­
`dine are metabolized by CYP3A4,22
`The imidazole antifungal agents keto­
`conazole and itraconazole are potent
`and relatively specific inhibitors of
`CYP3A activity, Of the two,however,
`only ketoconazole has been associated with terfena­
`dine-induced ventricular arrhythmias, 18,23 Although itra­
`conazole impairs terfenadine metabolism to a lesser
`degree than ketoconazole, available evidence suggests
`itraconazole should not be administered with terfenadine
`or astemizole because of its potential to inhibit CYP3A to
`the same degree as ketoconazole, At usual therapeutic
`doses, fluconazole does not detectably impair terfenadine
`c1'earance,B The new antifungal agent terbinafine does not
`appear toinhibit CYP to a clinically significant extent. 2
`
`Studies show that ketoconazole and erythromycin can
`
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`The macrolide antibiotics are also
`inhibitors of CYP3A. Azithromycin
`does not appear to inhibit terfena­
`dine metabolism to a significant
`extent, in contrast to erythromycin
`and clarithromycin. 2 Grapefruit
`juice, which contains flavonoids
`that can inhibit CYP3A4, alsb can
`increase plasma levels of unmetabolized terfenadine," An
`improved understanding of the way CYP enzymes metab­
`olize drugs has the potential to improve drug therapy
`by al10wing clinicians to better predict whic;h therapies
`are likely to interact adversely with one another and
`take steps to avoid such situations.
`
`LEARNING FROM MISFORTUNE
`Life teaches by negative as well as positive examples,
`Valuable lessons were learned from careful analysis of the
`unfortunate astemizole- and terfenadine-associated cases
`of torsades de pointes and the codependency that non-
`
`JUNE 1997, VOL 2 NO.3
`
`HOME CARE PROVIDER 119
`
`Petitioner Torrent Pharmaceuticals Limited - Exhibit 1018 - Page 3
`
`

`
`,I
`:t
`
`WHEN PATIENTS ASK
`
`cytochrome P450 31>.(41 in ~-deaIKylation and Chydroxylation
`Drug Metab Dispos 1992;21 :403-9
`17. Honig PK, Woosley Rl, Zamoni K, Conner D, Cantilena l
`Changes in the pharmacokinetics ond electrocardiographic
`pharmacodynamb of terfenadine with concomitant administrat'on
`of erythromycin. Clin Pharmacol Ther 1992;52:231-8.
`18. Honig PK, Wortham DC, Zamani K, Conner DP, Mullin JC,
`Cantilena lR. Terferadine-ketoconazole interaction: pharmacoki­
`netic and electrocardiographic consequences. JAMA
`1993;2691513-8.
`19. Woosley Rl, Chen Y, Freiman JP, G:llis RA Mechanism of the
`cardiotoxic actions of terfenadine. JAMA 1993 ;269: 1532-6.
`20. Monahan BP, Ferguson Cl, Kileavy ES, Lloyd BK, Troy J,
`Cantilena lR. Torsades de pO·lrtes occurring in association with
`terfenadine use. JAMA 1990;264:2788-90.
`21. Woosley Rl, Chen Y, Pinney SP. Terfenadine and cardiac death.
`j Allergy Clin Immunol 1993;91 :262.
`22. Ketter TA, Flockhart DA, Past RM. The emerging role of
`cytochrome P450 3A in psychopharmocology. J Clin
`Psychopharmacol 1995; 15:387-98.
`23. Von Moltke ll, Greenblatt DJ, Duan SX, HarmatzJS, Wright CE,
`Shaderpj Inhibition of terfenadine metabolism in vitro byazole
`antifungal agents and by selective serotonin reuplake inhibitor
`anti,J~pressants: relatior to pharmacokinetic interactions in vivo. J
`Clrn Psychophacmacol 1996: 16: 104-12.
`24. Haria M, Fitton A, Peters DH
`loratadine: a reappraisal of its
`" pharmacological properties ond therapeutiC uses in allergiC disor­
`ders. Drugs 1994;48:617-37.
`.25. Honig P, WOrtham D, lazarev A, Cantilena lR Grapefruit iuice
`alters the systemic bioavailability and cardiac repolarizalion of
`terfenadine in poor metabolizers ofterfenadine. JClin Pharmacol
`1996;36:345-51.
`
`sedating antihistamines and certain antibiotics/antifungals
`have for specific isoenzymes. From these cases and the
`research they generated came an appreciation of the mul­
`tifaceted, highly specific nature of the CYP family of
`enzymes. In recent years, we have become aware that a
`patient's ethnicity, gender, and inherent CYP idiosyncracies
`influence how he or she metabolizes drugs. Much work
`remains to be done, but at least the process has begun that
`will lead to a better understanding of why two similarly
`matched patients can respond in entirely different ways
`to a given dose of the same medication. We have so much
`yet to learn about the clinical nuances of cytochrome P450.
`
`REFERENCES
`1. Cruzan SM. FDA talk paper [cited 13 january 1997]. Available at
`http://w'ivw. fda. gov/bbs/topics/ANSWERS/ANS00780. hlml
`2. Fexofenadine. Med lett DrugTher 1996;38(9861:95-6
`! 3. Hebel SK, publisher. Focts and comparisons. St. louis (MOl: Facts
`·and Comparisons; 1993: p. 188
`4. Masheter He. Terfenadme: the first nonsedating antihistamine.
`Clin Rev Allergy Immunol 1993: 11 :5-34.
`5
`The top 200 drugs American Druggist 1997;214i2j:30-7.
`6. Mathews DR, McNutt B, Okerholm R, Flicker M, McBride G.
`Torsades de poinfes occurring in association with terfenadine use.
`JAMA 1991 ;266:2375-6.
`7. Crane jK, Shih H-T. Syncope ond cardiac arrhythmia due to an
`interaction between itraconazole and terfenadine. Am J Med
`1993;95:456.
`8. Product information. Seldane brand of lerfenadine. Hoechst
`Marion Roussel, Kansas City [MOl; 1995.
`9. Product information Hismanal brand of astemizole. Janssen
`Pharmaceutica, Titusville (t'-UI; 1993.
`10. Cupp MJ, Tracy TS. Role of the cytochrome P450 3A subfamily
`in drug interactions. US Pharmacist 1997;22:HS9-21.
`11. Product information. Claritin branq of lorotadine. Schering Corp.,
`Kenilworth INJ); September 1995.
`12 Product informotion. Allegra brand of fexofenadine Hoechst
`Marion Rbussel, Kansas City (MOl; August 1996.
`13. Slaughter RI, Edwards Dj. Recent advances: the cytochrome
`P450 enzymes. Ann Pharmocother 1995;29:619-24.
`14. Murray M, Reidy GF. SelectiVity in the inhibition of mammalian
`cytochromes P450 by chemical agents. Pharmocol Rev
`1990;42:85-101.
`15. Krishna D, Klotz U. Extrahepatic metabolism of drugs in humons.
`Clin Pharmacokinet 1994;26: 144-60.
`'
`': 16. Yun C, Okerholm RA, Guengerich FP. OXidation of the antihis­
`taminic drug terfenadine in the human liver microsomes: role of
`
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`120 HOME CARE PROVIDER
`
`JUNE 1997, VOL. 2 1\0. 3
`
`J.
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`Petitioner Torrent Pharmaceuticals Limited - Exhibit 1018 - Page 4