16m Edition
`
`Kasper Braunwald
`
`Fauci
`
`WARRISON’S
`
`Jameson
`
`Hauser
`
`Longo
`
`MYLAN PHARMS. INC. EXHIBIT 1021 PAGE 1
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`MYLAN PHARMS. INC. EXHIBIT 1021 PAGE 1
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`fects, as with digoxin' theophylline, some antiarrhythmics' aminogly-
`cyclosporine. and anticonvulsants. The common situation of
`"".i¿er,
`ãirt-ord., elimination implies that average, maximum' and minimum
`concentrations a¡e related linearly to the dosing rate' Ac-
`"r"u¿v-rtrt"
`the maintenance dose may be adjusted on the basis of the
`"".¿inelv.
`,^tio Uãt*..n the desiled and measured concentrations ot steody starc;
`in,. .^rtnpl. if a doubling of the steady-state plasma concentration is
`cìesired. the dose should be doubled'
`For drugs that have zero-order kinetics (e.g., phenytoin and the-
`oohvlline), plasma concentrations change disproportionately more
`,trrn th. alteration in the dosing rate. In this situation, changes in dose
`shoulcl be small to minimize the degree of unpredictability, and plasma
`concentration monitoring should be used to ensure that dose modifi-
`cation achieves the desired level'
`DETERMINATI()N 0t MAINTENANCE D0SE An increase in dosage is usually
`best achieved by changing the drug dose but not the dosing interval,
`e.g., by giving 200 mg every 8 h instead of 100 mg every 8 h. However,
`rhis approach is acceptable only if the resulting maximum concentra-
`tion is not toxic and the trough value does not fall below the minirnurn
`effective concentration for an undesirable period of time' Altelna-
`tively, the steady state may be changed by altering the frequency of
`intermittent dosing but not the size of each dose. In this case, the
`magnitude of the fluctuations around the average steady-state level will
`change-the shorter the closing interval, the smaller the difference
`between peak and trough levels (Fig. 3-3).
`Fìuctuation within a dosing interval is cletermined by the relation-
`ship between the dosing interval and the drug's half-life. If the dosing
`interval is equal to the drug's half-life, fluctuation is about twofold,
`which is usually acceptable. With drugs that have a low therapeutic
`ratio, dosage changes should be conservative (<50a/o dose change) and
`not more frequent than every three to fou¡ half-lives. Other drugs, such
`as many antihypertensives, have little dose-related toxicity so the ther-
`apeutic ratio is large. Even if drug is eliminated rapidly, it can be given
`infrequently. Thus, 75 mg of captopril will result in reduced blood
`pressul'e fol up to l2 h, even though captopril elimination half-life is
`about 2 h; this is because the dose raises the concentration of drug in
`plasma many times higher than the threshold for its pharmacologic
`effect.
`
`ETITCTS ()I DISEASE ()N DRUG CONCENTRATI()N AND RESP()NSE
`RtNAL DlStASt Renal excretion ofparent drug and metabolites is gen-
`erally accomplished by glomerular filtration and by specific clrug trans-
`porters, only now being identified. If a drug or its metabolites are
`primarily excreted through the kidneys and increased dlug levels are
`associatecl with adverse effects, drug dosages must be reduced in pa-
`tients with renal dysfunction to auãid toxicity. The antiarrhythmics
`dofetilide ancl sotaiol undergo predominant renal excretion and carry
`a risk of QT prolongation and árrhythmias if doses are not recluced in
`renal disease. Thus, in end-stage renal disease, sotalol can be given as
`40 mg after dialysis {every seóond day), compared to the usual daily
`oose,80 to 120 mg every 12 h. The narcotic analgesic meperidine
`undergoes extensive hepatic rnetabolism, so that renal failure has little
`e\ct on its plasma concentration. However, its metabolite, noÍme-
`pendine. does unclergo renal exc¡etion, accumulates in renal failure,
`antl probably u..or,í. lor lhe signs of central nel'vous system exci-
`latron, such as irritability, twitching, and seizures, that appear when
`multiple_doses of meperidine are aãministered to patients with renal
`0tsease..Protein binding of some drugs (e.g., phenytòin) may be altered
`tn uretnia, .o mearuririg free clrug concentration may be desirable.
`non-end-stage reñal diseasl changes in renal árug clearance are
`^^ln
`Senerally proportiãnar to those in creatinine clearance, which may be
`<ìirectly ol esrimated frorn the serum creatinine (Chap. 259).
`Xt¡,1suLed
`rnls.estimate,
`couplecl with the knowledge of how much dr.ug is nor-
`urdrly excreted renally vs nonrenally, all,ows an estimate of the dose
`requiled. in pracrice, mosr decisions involving dosing ad-
`iilÏtrylt
`liì::.:lt in patients wiih renal faiture use published recommended
`ouJustments in dosage or closing interval baseà on the severity ofrenal
`
`m
`
`dysfunction indicated by creatinine clearance. Any such modification
`of dose is a first approximation and should be followed by plasma
`concentration data (if available) and clinical observation to further
`optimize therapy for the individual patient.
`UVER DISEASE In contrast to the predictable decline in renal clearance
`of drugs in renal insufficiency, the effects of hepatitis or cirrhosis on
`drug disposition range from impaired to increased drug clearance, in
`an unpredictable fashion. Standard tests of liver function are not usefui
`in adjusting doses. First-pass metabolism may decrease, and thus oral
`bioavailability increase, as a consequence of disrupted hepatocyte
`function, alterecl liver architecture, ancl portacaval shunts. The oral
`availability for high-first-pass drugs such as morphine, meperidine,
`midazolam, and nifedipine is almost doubled in patients with cirrhosis,
`compared to those with normal liver function. Therefole, the size of
`the oral dose of such dlugs should be reduced in this setting.
`HEART ffllURE AND 5H0CK Under conditions of decreased tissue per-
`fusion, the cardiac output is redistributed to presel've blood flow to the
`heart and brain at the expense ofother tissues (Chap. 216). As a result,
`drugs may be distributed into a smaller volume of distribution, higher
`dl'ug concentrations will be present in the plasma, and the tissues that
`are best perfused (the brain and heart) will be exposed to these higher
`concentrations. If either the brain or heart is sensitive to the drug, an
`alteration in response will occur. As well, decreased perfusion of the
`kidney and liver may impair drug clearance. Thus, in severe congestive
`heart failure, in hemorrhagic shock, and in cardiogenic shock, response
`to usual dlug doses may be excessive, and dosage reduction rnay be
`necessary. For exarnple, the clearance of lidocaine is reduced by about
`507o in heart failure, and therapeutic plasma levels are achieved at
`infusion rates only about half those usually required. The volume of
`distribution of lidocaine is also reduced, so loading regimens should
`be reduced.
`DRUG USE lN THE ELDERIY Aging results in changes in organ function,
`especially of the organs involved in drug disposition. Therefore, phar-
`macokinetics are often different in elderly inclividuals than in younger
`adults. In the elderly, muitiple pathologies and medications used to
`treat them result in more drug interactions and adverse effects.
`Even in the absence of kidney disease, t'enal clearance may be
`reduced by 35 to 50Vo in eiderly patients. Dosage adjustments are
`the¡efore necessary for drugs that are eliminated mainly by the kid-
`neys. Because muscle mass and therefore creatinine produclion are
`reduced in oider individuals, a normal serum creatinine concentt'ation
`can be present even though creatinine ciearance is impaired; dosages
`should be adjustecl on the basis of creatinine clearance, as discussed
`above. Aging also results in a decrease in the size of and blood flow
`to the liver and possibly in the activity of hepatic drug-metabolizing
`enzymes; accordingly, the hepatic clearance of some dlugs is impairecl
`in the elderly. As with liver disease, these changes ale not readily
`predicted.
`Elderly pâtients may display altered drug sensitivity, Examples in-
`clude increased analgesic effects of opioicls, increased sedation from
`benzodiazepines and other CNS depressants, and increased risk of
`bleeding while receiving anticoagulant therapy, even when clotting
`parameters a¡e well controlled. Exaggerated responses to cardiovas-
`cular drugs are also common because of the impaired responsiveness
`of normal homeostatic mechanisms. Conversely, the elderly display
`decreased sensitivity to B-adrenergic receptor blockers.
`Adverse drug reactions are especially common in the elderly,
`because of altered pharmacokinetics and pharmacodynamics, the fre-
`quent use of multidrug regimens, and concomitant ciisease. For ex-
`ample, use of long half-1if'e benzodiazepines is linked to the occul'rence
`of hip fractures in elderly patients, perhaps reflecting both a risk of
`falls from these drugs (due to increased sedation) and the increased
`incidence of osteoporosis in elderly patients. In population surveys of
`the noninstitutionalized elderly, as many as 107o had at least one ad-
`velse drug reaction in the previous year.
`
`MYLAN PHARMS. INC. EXHIBIT 1021 PAGE 10
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`

`

`Poor
`metabolizers
`(PMs)
`
`+
`
`Extensive metabolizers (ËMs)
`
`30
`
`20
`
`0
`
`Ultrarapid
`metabolizers
`
`6oo
`
`.o-
`
`Ø ooEz
`
`0
`
`+ Greater activity
`Lesser act¡vity -+
`flGURt 3-6 CYP2D6 metaboljc activitu
`assessed in 290 subjects bU adminisrra-
`',1as
`tion 0f a test dose of a probe substrate and measurement of urinarg formation 0f the
`CYP2D6-generated metaboljte. The heavu arroü/ indicates a clear antim0de, separating
`poor metabolizer subjects (black), with two loss-0f-function CYPzD6 alleles. lndividuali
`with 0ne or two functional alleles are grouped together as extensjve metabolizers
`(biue). Also shown are ultrarapid metabolizers, with 2 to 11 functionaì copies 0f the
`gene (red) and t2 functional copies (green), dispìaging the greatest enzUme activitu.
`(Adapted bA permission t'rom M-L Dqhl et al: I Pharmacol Exp Ther 274:516, lgg|)-
`
`nosuppressive azathioprine. Homozygotes for alleles encoding the
`inactive TPMT (1 in 300 individuals) predictably exhibit severe and
`potentially fatal pancytopenia on standard doses of azathioprine or 6-
`mercaptopurine. On the other hand, homozygotes for fully functional
`alleles may display less anti-inflammatory or antileukemic effect with
`the drugs. These data illustrate the potential power of a genomic ap-
`proach to optimize therapy, especially in the setting of high-risk phar-
`macokinetics.
`N-acetylation is catalyzed by hepatic N-acetyl transferase (NAT),
`which actually represents the activity of two genes, NAT-1 and NAT-
`2. Both enzymes transfer an acetyl group from acetyl coenzyme A to
`the drug; NAT-1 activity is generally constant, while polymorphisms
`in NAT-2 result in individual differences in the rate at which drugs are
`acetylated and thus define "rapid acetylators" and "slow acetylators."
`Slow acetylators make up -50Vo of European- and African-derived
`populations but are less common among Asians.
`Slow acetylators have an increased incidence of the drug-induced
`lupus syndrome during procainamide and hydralazine therapy and of
`hepatitis with isoniazid. Induction of CYPs (e.g., by rifampin) also
`increases the risk of isoniazid-related hepatitis, likely reflecting gen-
`eration of reactive metabolites of acetylhydrazine, itself an isoniazid
`metabolite.
`Polymorphisms that reduce transcription of uridine diphosphate
`glucuronosyltransferase (UGTl A1) cause benign hyperbilirubinemia
`(Gilbert's disease; Chap.284). These have also been associated with
`diarrhea and increased bone marrow depression with the antineoplastic
`irinotecan, whose active metabolite is normally detoxified by this
`pathway.
`CYP Variants CYP3A4 is the mosr abundant hepatic and intestinal Cyp
`and is also the enzyme responsible for metabolism of the greatest
`number of drugs in therapeutic use. CYP3A4 activity is highly variable
`(up to an order of magnitude) among individuals, but the distribution
`is unimodal, suggesting that the variability does not arise from variants
`in the CYP3A4 gene. The mechanisms underlying this variability are
`not yet well understood. A closely related gene, encoding Cyp3A5
`(which shares substrates with CYP3A4), does display loss-of-function
`variants, especially in African-derived populations. Cyp3A refers to
`both enzymes.
`CYP2D6 accounts for very little total hepatic CYP by weight bur
`is second to CYP3A4 in the number of commonly used drugs that it
`metabolizes. CYP2D6 is polymorphically distributed, with aboutTVo
`of European- and African-derived populations (but very few Asians)
`displaying the PM phenotype (Fig. 3-6). Over 70 loss-of-funcrion var-
`iants in the CYP2D6 gene have been desøibed; the pM phenotype
`arises in individuals with two such alleles. In addition, individuals with
`multiple functional copies of the CYP2D6 gene (ultrarapid metabol-
`izers) have been identified, particularly among northern Africans.
`CYP2D6 represents the main metabolic pathway for a number of drugs
`
`æ
`
`ffi¡tfiTrã
`
`Accordingly, optimization of drug therapy in the elderly, particu-
`larly in frail patients, is often difficult, as these multiple factors ac-
`centuate interindividual variability in drug response, Initial doses
`should be less than the usual adult dosage and should be increased
`slowly. The number of medications, and doses per day, should be kept
`as low as Possible.
`
`GEI{ETIC DETERMINANTS OT THE RESP()NSE Tf) DRUGS
`PRINCIPIES 0t GEI{ETIC VARIATI0N AND HUMAN TRATTS (See also Chap.58)
`Variants in the human genome resulting in variation in level of ex-
`pression or function of molecules important for pharmacokinetics and
`pharmacodynamics are increasingly recognized. These may be muta-
`tions (very rare variants, often associated with disease) or polymor-
`phisms, variants that are much more common in a population. Variants
`may occur at a single nucleotide or involve insertion or deletion of
`one or more nucleotides. They may be in the exons (coding regions)
`or introns. Exonic polymorphisms may or may not alter the encoded
`protein, and variant proteins may or may not display altered function.
`Similarly, polymorphisms in intronic regions (including those that reg-
`ulate gene expression) may or may not alter protein level.
`As variation in the human genome is increasingly well docu-
`mented, associations are being described between polymorphisms and
`various traits (including response to drug therapy). Some ofthese rely
`on well-developed chains ofevidence, including in vitro studies dem-
`onstrating variant protein function, familial aggregation of variant al-
`lele with the trait, and association studies in large populations. In other
`cases, the associations are less compelling. Identifying "real" associ-
`ations is one challenge that must be overcome before genomics, and
`in particular the concept of genotyping to identify optimal drugs (or
`dosages) in individual patients prior to prescribing, can be considered
`for widespread clinical practice. Nevertheless, the appeal of this ap-
`proach is considerable.
`Rates of drug efficacy and adverse effects often vary among ethnic
`groups. Many explanations for such differences are plausible; genomic
`approaches have now established that functionally important variants
`determining differences in drug response often display differing dis-
`tributions among ethnic groups. This finding may have importance for
`drug use among ethnic groups, as well as in drug development.
`
`GENtTlcAttY DETTRMINED DRUG D|SP0S|T|ON AND VARIABLE EfttCTS The
`concept that genetically determined variations in drug metabolism
`might be associated with variant drug levels, and hence effect, was
`advanced at the end of the nineteenth century, and the first examples
`of familial clustering of unusual drug responses due to this mechanism
`were noted in the mid-twentieth century. Clinically important genetic
`variants have been described in multiple molecular pathways of drug
`disposition (Table 3-1). These variants are identifled either by directly
`establishing DNA sequence (genotyping) or by phenotyping: exposing
`a large group of otherwise healthy subjects to a specific probe substrate
`for the metabolizing enzyme under study and observing the distribu-
`tion of activity (Fig. 3-6). A distinct multimodal disrriburion argues
`for a predominant effect of variants in a single gene in the metabolism
`of that substrate. Individuals with two alleles (variants) encoding for
`nonfunctional protein make up one group, often termed poor meta-
`bolizers (PM phenotype); many variants can produce such a loss of
`function, complicating the use of genotyping in clinical practice. In-
`dividuals with one functional allele make up a second (intermediate
`metabolizers), and those with two functional alleles a third (extensive
`metabolizers, EMs). On the other hand, a unimodal distribution of
`activity argues against the presence of important single loss-of-func-
`tion alleles in the population under study.
`Tlansferase Variants Ofthe variants in genes encoding drug-metaboliz-
`ing enzymes that have been described to date, one, in the TpMT gene,
`has been adopted as routine clinical practice in some specialized cen-
`ters. TPMT bioinactivates the antileukemic drug 6-mercaptopurine.
`Further, 6-mercaptopurine is itself an active metabolite of the immu-
`
`MYLAN PHARMS. INC. EXHIBIT 1021 PAGE 11
`
`

`

`re
`
`m
`
`ilr¡FftilIlFlt''?ltlr
`receptor that controls intracellular calcium in skeletal muscle and other
`tissues may be asymptomatic until exposed to certain general anes-
`thetics, which trigger ihe syndrome of malignant hyperthemia' Certain
`unilu.Áytrt*l.s ãñd other drugs can produce marked QT prolongation
`ãnJ to.å¿"s de pointes (Cha;.214)' and in some patients this adverse
`."pr"r.nts unmasking àf previously subclinical congenital long
`"iï"",
`QT syndrome.
`
`.- L,^ 2-l ì Codeine is biotransformed by CYP2D6 to the potent ac-
`l,tri;.tu¡il; morpìine' so its effects are blunted in PMs and ex-
`^ -ñêrAïedin ultraraprd metabolizers' With beta blockers metabolized
`??!åüî"ø rtncluding ophthalmic timolol and the antiaffhvthmic pro-
`:itf,,ioniñü subjecls d'isplav greater signs of beta blockade (includ-
`l'ij"'iîïãí*r¿ia and bronchospasm) than EMs' Further' in EM
`elimination bt"ot"t nonlinear at higher doses
`Ï'r#,;;**none
`-^ fnr exâÍtple, a trlpllng of the dose may lead to a tenfold increase
`Tñe oral hvpoglvcemic agent phenformin was
`::';;;;ä"tratio;.
`Ïtrïåj-no-"|ãr." it octationallyóaused profound lactic acidosis; this
`i;:i;';;";t as a result of high òoncentrations in CYP2D6 PMs' ul-
`iliråi,tä'*",iolizers may require verv high dosages of tricvclic an-
`iìi..,."rrunt, to achieve a thérapeutic effect' and with codeine may
`ffiilñ;;t;nt .upto,ia and nãusea due to verv rapid generation of
`morPhine'
`"'"
`fn" eV pt enotype for CYP2C19 is common (20o/o) among Asians'
`to SVo¡- inEuropean-derived-populations' The impact of
`""¿'r"r".i:
`î"**"rptto CYP2C I 9-med'iated metabolism has been demonstrated
`f ump inhibitor omeprazole, where ulcer cure rares with
`iïililil";
`..standard,, dosages were markedly lower in EM patients (29(To) than
`ij PM; (100o/r). Thus, understanding the importanre of this polymor-
`';irm"
`*""1¿ have been important in developing the drug, and know-
`i""", natient's CYP2C19 genotype should improve therapy'
`"'"i;;;.;
`.o-*on allJlic va-riants of CYP2C9 that encode proteins
`wit¡, icrss of catalytic function' These variant alleles are associated with
`u iáqulr"rn"nt foi lower maintenance dose of warfarin'Inrarer (12o/o)
`individuals homozygous for these variant alleles' maintenance war-
`.uv"ù-. difflcult to establish' and the risk of bleeding
`il;';;;;g",
`.åóri"^tiãnt upi.ut, increased' Similarly' patients with loss-of-func-
`ti- CVpZCS aiieles display increased rates of neurologic complica-
`iiãrr *ittt phenytoin and of hypoglycemia with glipizide'
`VARIABIilTY lN THt M0LICUIAR IARGETS WIIH WHICH DRUGS INTERACT As
`,nol.cula, approaches identify specific gene products as târgets of drug
`action, n.tyi,orphisms ttlat âttér the expression or function of these
`d,'rt¿ targeis-and thus modulate their actions in patients-are also
`beiig reJognized. For example, genome-wide searches in families with
`pr"níurrr.ïUheimer's disease have associated variants in the APOE
`iocus with the disease (Chap' 350). -ìhe E4 allele of the gene has been
`associated with a worse prognosis, a finding that has been attributed
`to reduced expression of cho-line acetyltransferase' Further' this poly-
`morphism is also linked to response to the acetylcholinesterase inhib-
`itor tacrine; a beneficial response appears to be more common ln
`patients with the prognosticaliy more bènign A POE2 ot APOE3 alleles
`iin which the target-molecule is expressed more abundantly)'
`Multiple polfmorphisms identifled in the Br-adrenergic receptor
`appear to be linked to speciflc phenotypes in asthma and congestive
`heãrt failure, diseases in it.,ictr þr-recepior function might be expected
`to determine prognosis. Polymorphisms in the p¡receptor gene have
`also been ar*.iãt.¿ *ith iesponr" to inhaled Br-receptor agonists'
`while those in the B,-adrenergic receptor gene have been associated
`with variabilitv in'heart rate slowing and blood pressure lowering'
`Similarly, ,.rotnr. to the 5lipoxygenase inhibitor zileuton in asthma
`has been lintå¿ to polymorphìsmi ihat determine the expression level
`of the 5-lipoxvn.nur.' g"n". Herceptin, which potentiates anthracyc-
`line-relateå .urãloto*i.i"ty, is ineffective in breast cancers that do not
`express the herceptin recãptor; thus, "genotyping" the tumor is a mech-
`anism to avoid pàtentially toxic therapy in patients who would derive
`no benefit.
`Drugs may also interact with genetic pathways of disease' to elicit
`or exacerbate svmptoms of the underlying conditions. In the porphyr-
`ras' CYP inducårs äre thought to increase the activity of enzymes prox-
`tmal to the deficient
`exacerbating or triggering attacks (Chap'
`"nryrri",
`J37)' Deficiency of glucåse-6-phosphate dehydrogenase (G6PD)' most
`often in individíul, ãr ef.i.unìr M-editeranean descent, increases risk
`of hemolytic anemia in response to primaquine and a number of other
`orugs thai do not cause heåolysis in patients with adequate quantities
`ot this enzyme 1Chap. 93). Pátients ;ith mutations in the ryanodine
`
`P0|.YM0RPHISMSTHAIM0Dul"ATtTHEBl()toGlccoNTEnWlTHll{WHICHTHE
`uiuc-nna¡r lNTERAcfl0Ns 0ccUR The interaction of a drug with its
`.o1".uf* target is translated into a clinical action ìn a complex bio-
`i"gi" .ifi"" tlhat is itself often perturbed by disease' Thus' polymor-
`pt.,i.-, tttut determine variabiiity in this biology may profoundly
`influence drug response, although the genes involved are not them-
`,-J", at""tfi targets of drug aðtion. The common insertion/deletion
`iVDt p;iy-";pniJn in the ACE gene determines prognosis in many
`ìVpá l,f "heart^disease, including heart failure' In patients with heart
`iäiture treate¿ with B-adrenergicblockers, the best response to therapy
`ha, b."n associated with the DD genotype, the group with the worst
`ptãgt*i.. itt" mechanism underlying this outcome is uncertain' but
`å ¿i.., effect of beta blockers on ACE seems unlikely; rather the IID
`g*oiyp" likely affects the biology of heart failure to allow an im-
`itou"i*tp*se to beta blockers' Similarly' polymorphisms in genes
`'important ior lipid homeostasis (such as the ABCAI transporter and
`the cholesteroÌ ester transport protein) modulate response to HMG-
`CoA reductase inhibitors. ìn one large study' the combination of di-
`ur"tl. ur" combined with a variant in the adducin gene (encoding a
`protein important for renal tubular sodium absorption)
`"yiort.f"tuf
`decreased stroke or myocardial infarction risk' while neither factor
`alone has an effect. Common polymorphisms in ion channel genes that
`are not themselves the target oi QT-prolonging drugs may nevertheless
`influence the extent to wñich those drugs affect the electrocardiogram
`and produce arrhYthmias.
`
`PR0SPECTSt0RlNC0RP()RAT|NGGENtTlclNt0RMAIl0tllNToctlNlcAtPRAcIlcE
`These and many other examples of associations between speciflc geno-
`types and drug responses rãise the tantalizing prospect that patients
`iitt unO".go rãutinã genotyping for loci known to.modulate drug lev-
`els or respónse prior to receiving a prescription' The twin goals are to
`iOentity patients likely to exhibii adverse effects and those most likely
`,ã tàtói,¿ well. Obsiacles that must be overcome before this vision
`a reality include replication of even the most compelling
`;;;;"t
`urro.iutionr, deÅonstrations of cost-effectiveness' development of
`.".ãäv tt""fre genotyping technologies, and ethical issues involved
`i"-æ."rypi"g. iVnif.-tt.t"t" barriers seem daunting' the field is very
`rapidlv' Indeed' one major result of understanding
`;;;;;ä;;"lving
`ái irrË -r" of genJics in árug action has been improved screening of
`ã."g, ¿"titg îhe deuelopmJnt process to.reduce the likelihood of
`metabolism or unanticipated toxicity (such as torsades
`t igf;fy "^¡"frf.
`de pointes).
`
`INTERACTI()NS BETWEEI'I DRUGS
`Drug interactions can complicate therapy by adversely increasing or
`ã"..?uting the action of a dìug; interactions may. be based on changes
`in árug disposition or in druf response in the absence of changes in
`ãt"g fã".h. Interactions ntuit be consiclered in the dffirential díag'
`,,oíi, of any unustnl response occuning during drug therapy' P,re-
`scrluerå sháuld recogn tzà that patients often come to them with a
`drugs acquìred during previou.s medical experiences' often
`i"g".t
`"f
`*irft .tfripf" physicians who måy not be aware-of all the patient's
`medicationì. Á meticulous drug history should include examination of
`it" fu,ø*'t medications and,lf necessary' calls to the pharmacist to
`iã""',irv prescriptions. It should also address the use of agents not often
`volunteered during questioning, such as over-the-counter (OTC)
`O."gt, tt"^f,n food'supþlements, and topical agents such as eye drops'
`List"s of interactions are available from a number of electronic sources'
`ífl. pru"ti.ing physician cannot be expected to memorize these' How-
`
`L o l
`
`s
`re
`
`Þd
`
`pd
`of
`l*o
`þn-
`tuid
`
`lul.
`rnla
`þirh
`fstic
`ithis
`
`'P
`
`YP
`iatest
`iable
`ution
`dants
`fY are
`P3A5
`[ction
`lers to
`
`tht but
`thât it
`t¡¿t'7 70
`\sians)
`bn var-
`hotype
`¡ls with
`¡etabol-
`¡fricans.
`cf drugs
`
`MYLAN PHARMS. INC. EXHIBIT 1021 PAGE 12
`
`

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`ÍABIE 3-2 Drugs wíth a High Risk of Generating Phdrndcokinetic lnteruLtilns
`Dtug
`Mechanism
`
`Examples
`
`Antacids; bile acid sequestrânts
`
`Reduced absorption
`
`Proton pump inhibitors; H.-
`receptor blockers
`Rifampin; carbamazepine;
`barbiturates; phenytoin; St.
`John's wort; glutethimide
`Tricyclic antidepressants;
`fluoxetine; quinidine
`Cimetidine
`
`Ketoconazole, itraconazole;
`erythromycin, clarithromycin;
`calcium channel blockers;
`ritonavir
`
`Altered gastric pH
`
`lnduction of hepatic metabolism
`
`Inhibitors of CYP2D6
`
`lnhibitor of multiple
`CYPs
`Inhibitor of CYP3A
`
`Allopurinol
`
`Amiodarone
`
`Xanthine oxidase
`inhibitor
`Inhibitor of many CYPs
`and of P-glycoprotein
`Gemfibrazol (and other fibrates) CYP3A inhibition
`
`Quinidine; amiodaronei
`verapamil; cyclosporine;
`itraconazole; erythromycin
`Phenylbutazone, probenecid;
`salicylates
`
`P-glycoprotein inhibition
`
`Inhibition of renal tubula¡
`transport
`
`Antacids/tetracyclines; cholestryamine/
`digoxin
`Ketoconazole absorption decreased
`
`Decreased concentration and effects of:
`warfarin; quinidine; cyclosporine;
`losartan
`lncreased beta blockade; decreased
`codeine effect
`Increased concentration and effects of:
`warfarin; theophylline; phenytoin
`Increased concentration and toxicity of:
`some HMG-CoA reductase inhibitors;
`cyclosporine; cisapride, terfenadine
`(now withdrawn)
`Increased concentration and effects of:
`indinavir (with ritonavir);
`Decreased clea¡ance and dose
`requirement for:
`cyclosporine (with calcium channel
`blockers)
`Azathioprine and 6-mercaptopurine
`toxicity
`Decreased clearance (risk of toxicity)
`for:
`warfarin; digoxin; quinidine
`Rhabdomyolysis when co-prescribed
`with some HMG-CoA reductase
`inhibitors
`Risk of digoxin toxicity
`
`as warfarin and some antiaffhvth-
`mics. Individuals vary in the ex-
`tent to which drug metabolism
`can be induced, likely through
`genetic mechanisms.
`lnhibition of Cellular Uptake or
`Binding Tricyclic anridepres-
`sants, doxepin, and chlorproma-
`zine are potent inhibitors of
`norepinephrine uptake into adre-
`nergic neurons and prevent the
`uptake of the guanidinium anti-
`hypertensive agents (such as gua-
`nethidine and guanadrel), thereby
`abolishing their antihypertensive
`effects. Similarly, the antihyper-
`tensive effect of clonidine is par-
`tially antagonized by tricyclic
`antidepressants.
`
`Salicylates + increased risk of
`methotrexate toxicity
`
`PHARMACOKINETIC INTERACTIONS
`CAUSING INCREASED DRUG DETIVTRY
`T0 TARGET 5lTE5 r tnhibition of
`Drug Metabolism Inhibition of
`drug metabolism can lead to re-
`duced clearance, plolonged half-
`life, accumulation of drug during
`maintenance therapy, and thus
`adverse effects. In contrast to in-
`duction, new protein synthesis is
`not involved, and the effect de-
`velops as drug and any inhibitor
`metabolites accumulate (a func-
`tion of their elimination half-
`lives). Since shared substrates of a single enzyme can compete for
`access to the active site of the protein, many CYP substrates can also
`be considered inhibitors. However, some drugs are especially potent
`as inhibitors (and occasionally may not even be substrates); it is in the
`use of agents of the latter type that clinicians must be most alert to the
`potential for interactions.
`Cimetidine (but not other Hr-receptor blockers) is a potent inhibitor
`of the oxidative metabolism of many drugs, including warfarin, quin-
`idine, nifedipine, lidocaine, theophylline, and phenytoin. Severe ad-
`verse reactions can develop as a consequence.
`The antifungal agents ketoconazole and itraconazole are potent in-
`hibitors of enzymes in the CYP3A family. When fluconazole levels
`are elevated as a result of higher doses and/or renal insufficiency, this
`drug can also inhibit CYP3A. The macrolide antibiotics erythromycin
`and clarithromycin inhibit CYP3A4 to a clinically significant extent,
`but azithromycin does not. Some of the calcium channel blockers,
`including diltiazem, nicardipine, and verapamil can also inhibit
`CYP3A, as can some of the enzyme's substrates, such as cyclosporine.
`Examples of CYP3A substrates also include quinidine, lovastatin, sim-
`vastatin, atorvastatin, nifedipine, lidocaine, erythromycin, methylpred-
`nisolone, carbamazepine, midazolam, and triazolam.
`Phenytoin, an inducer of many systems including Cyp3A, inhibits
`CYP2C9. CYP2C9 metabolism of losartan to its active metabolite is
`inhibited by phenytoin, with potential loss of antihypertensive effect.
`Accumulation of the prokinetic drug cisapride and the antihista-
`mine terfenadine due to CYP3A inhibition led to QT prolongation and
`torsades de pointes. Measures to prevent co-prescription of these
`agents with CYP3A inhibitors were unsuccessful, and alternative safer
`agents were developed, so these drugs were eventually withdrawn.
`Cyclosporine can cause serious toxicity when its metabolism via
`CYP3A4 is inhibited by erythromycin, ketoconazole, diltiazem, ni-
`cardipine, or verapamil. The risk of myopathy with some HMG-CoA
`reductase inhibitors (lovastatin, simvastatin, atoryastatin) is thought to
`be increased by CYP3A4 inhibition. One agent in this class, cerivas-
`
`ever, certain drugs consistently run the risk of generating interactions,
`through mechanisms that are well understood; examples (not an ex-
`haustive listing) are presented below and in Table 3-2. When such
`drugs are started or stopped, prescribers must be especially alert to the
`possibility of interactions.
`
`PHARMAC()KINETIC
`
`INTIRASTI()NS CAUSING DIMINISHED DRUG DTI.IVTRY T()
`TARGTT slTt5 I lmpaired Gastrointestinal Absorption Aluminum ions,
`present in antacids, can form insoluble chelates with the tetracyclines,
`preventing their absorption. Kaolin-pectin suspensions bind digoxin,
`and when the substances are administered together, digoxin absotption
`is reduced by about one-half. Resins that sequester bile acids in the
`gut can bind other drugs, such as digoxin. Ketoconazole is a weak base
`that dissolves well only at acidic pH. Histamine Ftr, receptor antago-
`nists and proton pump inhibitors reduce gastric acidity and thus impair
`the dissolution and absorption of ketoconazole.
`lnduction of CYP or Transporter Activitu Expression of some genes re-
`sponsible for drug elimination, notably CYP3A and MDRI , can be
`markedly increased by "inducing" dr.ugs, such as rifampin, carba-
`mazepine, phenytoin, St. John's wort, and glutethimide and by smok-
`ing, exposure to chlorinated insecticides such as DDT (CyplA2), and
`chronic alcohol ingestion. One mechanism for this coordinate induc-
`tion of multiple pathways is increased expression of common tran-
`scription factors (e.g., hepatocyte nuclear factor 4a). Administrat